NI-CATALYZED CROSS-COUPLING REACTIONS OF PHENOL-DERIVED ELECTROPHILES by John Emmet Alam Russell A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry MONTANA STATE UNIVERSITY Bozeman, Montana July 2022 ©COPYRIGHT by John Emmet Alam Russell 2022 All Rights Reserved i DEDICATION To all my family and friends who have encouraged and supported me throughout the pursuit of this doctorate. ii ACKNOWLEDGEMENTS Firstly, my immense gratitude goes to my advisor, Dr. Sharon Neufeldt, for all her patience and support over the course of my graduate studies. I greatly benefited from her mentorship and guidance throughout my time at MSU. I learned a tremendous amount from her availability to answer questions and her willingness to give input and difficult assignments. I appreciated the balanced approach Sharon took towards mentorship, giving ample freedom to explore and find solutions but also not leaving me on my own, especially early on. I’ve enjoyed the variety of cross- coupling projects I’ve worked on throughout my time here, even though not all were successful. Sharon, knowing my desire to teach, encouraged me to take opportunities that would help me achieve that end. Thanks go to my graduate committee members Dr. Mary Cloninger, Dr. Thomas Livinghouse, and Dr. Michael Mock for their continued efforts and support. I also want to acknowledge the technical expertise and patience of Dr. Brian Tripet of the MSU Department of Chemistry and Biochemistry NMR Facility and the boundless patience of Doreen Brown. I want to thank the many Neufeldt group members who I’ve had the pleasure of working with; those I’ve worked most closely with include Emily Elias, Steven Rehbein, Emily Entz, and Leidy Hooker. The active and friendly group culture has been a joy to be part of and has made my time as a graduate student exciting and full of laughs. I am grateful for the financial support from Montana State University, and the National Science Foundation. iii TABLE OF CONTENTS 1. INTRODUCTION ....................................................................................................................... 1 References ................................................................................................................................... 8 2. NICKEL-CATALYZED STILLE CROSS-COUPLING OF C—O ELECTROPHILES ................................................................................................... 12 Contribution of Authors and Co-Authors .................................................................................. 12 Manuscript Information Page .................................................................................................... 12 Abstract ...................................................................................................................................... 13 Associated Content .................................................................................................................... 17 Author Information .................................................................................................................... 17 Acknowledgements ................................................................................................................... 17 References ................................................................................................................................. 17 3. SMALL PHOSPHINE LIGANDS ENABLE SELECTIVE OXIDATIVE ADDITION OF Ar—O OVER Ar—Cl BONDS AT NICKEL (0) .......................................... 20 Contribution of Authors and Co-Authors .................................................................................. 20 Manuscript Information Page .................................................................................................... 20 Abstract ...................................................................................................................................... 21 Introduction ............................................................................................................................... 21 Results and Discussion .............................................................................................................. 22 DFT Calculations with PMe3 ............................................................................................. 22 DFT Calculations with PCy3 and PPh3 .............................................................................. 22 Stoichiometric Oxidative Addition Studies ....................................................................... 22 Catalytic Studies on Chemoselective Cross-Coupling ...................................................... 24 Computational Analysis of Selectivity Origin .................................................................. 24 Conclusion ................................................................................................................................. 27 Associated Content .................................................................................................................... 28 Author Information .................................................................................................................... 28 Acknowledgements ................................................................................................................... 28 References ................................................................................................................................. 28 iv TABLE OF CONTENTS – CONTINUED 4. NICKEL CATALYZED CROSS-COUPLINGS OF ARYL METHYL ETHERS .................. 31 Introduction ............................................................................................................................... 31 I. Introduction to Cross-Coupling Reactions and Phenol-Derived Electrophiles .............. 31 II. An Overview of Nickel Catalysis of Cross-Coupling Reactions of Aryl Methyl Ethers ....................................................................................... 32 III. Computational Studies of Cross-Coupling Reactions with Phenol-Derived Electrophiles ............................................................................................ 34 IV. Expanding the Scope of the Nickel Catalyzed Cross-Coupling of Aryl Methyl Ethers ............................................................................................................ 36 V. Mechanistic Studies on Oxidative Addition into C—O Bonds .................................... 37 VI. Background for Ligand Development ......................................................................... 39 VII. Project Goals and Hypotheses ................................................................................... 42 Results and Discussion .............................................................................................................. 43 Conclusion ................................................................................................................................. 51 Experimental Section ................................................................................................................. 54 General Materials and Methods ......................................................................................... 54 General Procedure for Suzuki-Miyaura Cross-Coupling of Aryl Methyl Ethers .............. 55 General Procedure for Kumada Cross-Coupling of Aryl Methyl Ethers .......................... 58 Synthesis of (2-(Dicyclohexylphosphino)phenyl)methanol PO 2 .................................... 62 References ................................................................................................................................. 64 5. CONCLUSION ......................................................................................................................... 68 References ................................................................................................................................. 77 REFERENCES CITED ................................................................................................................. 78 APPENDICES ............................................................................................................................... 87 APPENDIX A: Chapter Two Supplemental ..................................................................... 88 APPENDIX B: Chapter Three Supplemental .................................................................. 192 v LIST OF TABLES Table Page 2.1 Optimization of the Ni-Catalyzed Stille Coupling ...................................................... 14 2.2 Inhibition of Catalysis by Chloride Sources ................................................................ 15 2.3 Effect of Fluoride Source on Cross Coupling ............................................................. 16 3.1 Ligand Effect on Selectivity of Oxidative Addition .................................................... 23 3.2 Selectivity of Ni/PR3 for Reaction of Various Phenol Deriviatives in Competition with 1-Chloronaphthalene ...................................................................... 23 3.3 Optimization of a Chemoselectivie Suzuki-Miyaura Cross-Coupling of 4-Chlorophenyl Tosylate ......................................................................................... 24 3.4 Suzuki-Miyaura Cross-Coupling of Chlorophenol Derivatives through Selective Cleavage of C—O bonds ............................................................................. 25 3.5 Distortion-Interaction Analsis of Relevant PMe3- and PCy3-Containing Transition Structures ................................................................................................... 27 4.1 Optimization and exploration of Ni-catalyzed Suzuki-Miyaura cross- coupling of Ar-OMe with hydroxyphosphine and NHC-OH ligands ......................... 46 4.2 Optimization and exploration of Ni-catalyzed Kumada cross-coupling of Ar-OMe with hydroxyphosphine and NHC-OH ligands ........................................ 47 4.3 Comparing the reactivity of hydroxyphosphine ligands to commercial phosphine ligands ........................................................................................................ 49 4.4 Extra optimizations results for NHC-OH under Suzuki conditions with various additives .......................................................................................................... 56 4.5 Extra optimization results for the Suzuki conditions using NHC 1 as the nickel source and testing various additives ........................................................... 56 4.6 Vials displaying the use of PMe3 nickel precatalysts that were effective for obtaining chemoselective cross-coupling of aryl-OTs over aryl-Cl ...................... 57 4.7 Extra optimization results for the hydroxyphosphine ligands under the Suzuki conditions with various additives .................................................................... 57 vi LIST OF TABLES CONTINUED Table Page 4.8 Additional optimization results using NHC 1 and NHC-OH ...................................... 59 4.9 Additional optimization results with the hydroxyphosphine ligands .......................... 60 4.10 Additional reactions exploring the performance of various ligands .......................... 61 vii LIST OF FIGURES Figure Page 1.1 (A) One relevant example showing the intolerance of aryl halides in cross coupling of phenolic electrophiles and (B) two pharmacologically relevant compounds where selectivity could be useful ................................................. 3 2.1 (a) Computational analysis of mechanistic possibilities for transmetalation. (b) Stoichiometric oxidative addition gives 43 which does not react with KF. (c) Complex 43 reacts with LiCl ................................................................................. 16 3.1 Free energy profile for oxidative addition of the C—O and C—Cl bonds of 1 at Ni(PMe3)2 ............................................................................................................. 22 3.2 Calculated free energies of activation (in kcal mol-1 for oxidative addition with PMe3, PPh3, and PCy3, measured from the preceeding π complex ..................... 22 3.3 31P{1H} NMR studies on oxidative addition at Ni/PCy3 ............................................. 23 3.4 31P{1H} NMR studies on oxidative addition at Ni/PMe3 ............................................ 23 3.5 Chemodivergent oxidative addition with selectivity controlled by the metal’s ligation state .................................................................................................... 25 3.6 (A) Calculated NBO charges and HOMO energies for optimized Ni(PR3)2 structure, (B) NBO charges at carbon in chlorophenyl tosylate .................................. 26 3.7 Oxidative addition transition structures using Ni(PMe3)2 and Ni(PCy3)2 ................... 26 3.8 (A) Definition of distortion and interaction energy. (B) Selectivity is determined by the difference in distortion energy (ΔΔEdist) and interaction energy (ΔΔEint) when comparing oxidative addition at tosylate vs chloride .............. 27 4.1 Relative reactivity of phenols and phenol derivatives in cross-coupling reactions ....................................................................................................................... 32 4.2 General energy diagrams for the insertion of nickel into aryl halide bonds (A) and aryl methyl ether (B) ...................................................................................... 38 4.3 Examples of ligands effective for Pd-catalyzed Suzuki-Miyaura cross- coupling with more reactive electrophiles that are ineffective for the Ni- catalyzed coupling of aryl ethers ................................................................................. 40 viii LIST OF FIGURES CONTINUED Figure Page 4.4 A general hydroxyphosphine ligand and likely modes of push-pull type C(sp2)—X bond oxidative addition ............................................................................. 40 4.5 Examples of bidentate ligands with the potential of an anionic pendant arm ............. 53 ix LIST OF SCHEMES Scheme Page 1.1 Percec’s Ni-catalyzed Stille coupling with aryl mesylates resulting in homocoupling ............................................................................................................ 3 1.2 Previous investigations into palladium catalyzed chemoselective Suzuki-Miyaura cross-coupling reactions ..................................................................... 4 1.3 Examples of Ni-catalyzed cross-coupling with aryl methyl ethers ............................... 5 1.4 General reaction schemes for each project .................................................................... 6 2.1 Ni-Catalyzed Stille Coupling of Phenol-Derived Electrophiles .................................. 13 2.2 Scope of (a) Aryl Sulfamates, (b) other Phenol Derivatives, and (c) Organostannanes ............................................................................................. 14 3.1 Ni- and Pd-Catalyzed Suzuki-Miyaura Couplings of Non-Triflate Chlorophenol Derivatives ............................................................................................ 21 3.2 Chemoselective Oxidative Addition with PMe3 .......................................................... 24 4.1 (a) Wenkert’s pioneering conditions for the cross-coupling of aryl ethers. (b) An example of Dankwardts’s reaction improvements ........................................... 33 4.2 (a) The pioneering work by Tobisu and Chatani of the Ni-catalyzed Suzuki-Miyaura cross-coupling of aryl ethers. (b) Further improvements to the cross-coupling of aryl ethers with organoboron nucleophiles ............................... 36 4.3 Select examples of Ni-catalyzed Kumada cross-coupling of aryl carbamates with a hydroxyphosphine ligand ................................................................................. 41 4.4 Select examples of Ni-catalyzed Kumada cross-coupling of aryl chlorides Hydroxy-NHC/Ni complex (NHC 1) .......................................................................... 42 4.5 General reaction schemes for Suzuki and Kumada cross-coupling reactions (top) and the ligand or complex targets (bottom) ........................................................ 43 4.6 Reactions of an Ar-OMe under Stille and Negishi conditions using PO 2 ................. 50 5.1 Proposed chemoselective Ni-catalyzed Stille coupling ............................................... 69 x LIST OF SCHEMES CONTINUED Scheme Page 5.2 (A) Percec’s conditions leading to homocoupling of the aryl mesylate and (B) a proposed combination of conditions to further study why no homocoupling was observed in our work .................................................................... 70 5.3 Comproportionation of Ni(II) and Ni(0) to form Ni(I) as suggested in previous literature ........................................................................................................ 72 5.4 Showing the application of authentic monoarylated products to form the diarylated product ........................................................................................................ 73 5.5 (A) examples of PCy3 working with nickel to efficiently couple Ar-OMe under Kumada and Suzuki conditions. Possible hydroxyphosphine ligand (B) and NHC (C) targets .............................................................................................. 75 5.6 Preliminary results without any added ligand ............................................................. 75 xi ABSTRACT Herein we present in three parts our work on a variety of Ni-catalyzed cross-coupling reactions using phenol-derived electrophiles. The first part details an efficient Ni-catalyzed Stille cross-coupling of C—O electrophiles through a combination of computational and experimental methods. These allowed for the investigation of the mechanism and showed the formation of a novel 8-centered transition state involving KF. Chloride inhibits the reaction through forming a low-energy Ni(II)-chloride species during oxidative addition that has a high activation barrier towards transmetalation. This methodology was shown effective for a wide variety of C—O electrophiles and organostannanes including several difficult bond constructions. The second part explores the development of a chemoselective Ni-catalyzed Suzuki cross-coupling that is selective for C—O bonds in the presence of C—Cl bonds. This selectivity is unusual since organohalides typically undergo oxidative addition with Ni(0) and Pd(0) at similar or faster rates to phenol- derived electrophiles. We were able to pair computational and experimental investigations to develop a reliable strategy and understand the likely origin of this unique selectivity. Stoichiometric experiments showed that small phosphines, like PMe3 and PPhMe2, are unique in their ability to facilitate the selective reaction at C—O bonds in the presence of C—Cl bonds. Computational investigations show the electronic and steric properties of these small ligands are crucial for a close interaction between nickel and a sulfonyl oxygen during oxidative addition, the step where selectivity is determined. The third part looked at the use of aryl methyl ethers as an electrophile under Ni-catalyzed Suzuki-Miyaura and Kumada cross-coupling conditions. Three ligands bearing chelating arms were synthesized, two known and one new, to explore the respective scopes and how these ligands compare to more commonly used ligands such as PCy3 or ICy. We saw no success under Suzuki-Miyaura conditions but found the hydroxyphosphine ligands facilitated the Ni-catalyzed Kumada cross-coupling of Ar-OMe, which had not been reported. Further investigations proved the hydroxyphosphines had no apparent benefit over commercial ligand as far as yield, scope, or mild reaction conditions. 1 CHAPTER ONE INTRODUCTION Organic chemistry is a field with many synthetic tools. Arguably one of the most utilized tools is that of late transition metal catalyzed cross-coupling reactions. Transition metal catalyzed cross-coupling reactions are valuable tools to form new C—C bonds more efficiently, simplifying the synthesis of complex molecules. The importance of transition metal catalyzed cross-coupling reactions was recognized when the 2010 Nobel Prize in Chemistry was awarded to Richard Heck, Ei-ichi Negishi, and Akira Suzuki.1 Palladium has long been the catalyst of choice for the lion’s share of cross-coupling reactions including the cross-coupling reactions discussed in this document, the Stille, Suzuki-Miyaura, and Kumada cross-coupling reactions. While Pd is an effective catalyst in a variety of cross-coupling reactions, it struggles to oxidatively add into less reactive electrophiles effectively and is largely limited to reactions of aryl halides and aryl triflates. Both palladium and nickel are group ten metals and because of this they behave similarly in many of the same elementary reactions. Nickel lies directly above palladium in the periodic table, which gives nickel reactivity that cannot be obtained with palladium. Nickel is more earth-abundant than palladium (eighth most abundant transition metal versus one of the five rarest metals),2 and is more cost effective. Perhaps the most attractive reason to study nickel as a catalyst is due to its ability to catalyze cross-coupling reactions with less reactive electrophiles including various phenol- derived electrophiles.3 Phenol-derived electrophiles display greater synthetic application as directing groups4 than aryl halides. This greater synthetic utility combined with the increased availability and lowered cost of phenols make them a desirable electrophile.5 2 Palladium and nickel are similar in many ways but there are a few key differences to identify. Due to the position of nickel on the periodic table it is a slightly harder element that has a smaller atomic radius than palladium. Nickel is also less electronegative than palladium making it undergo oxidative addition more readily. This easier oxidative addition allows nickel to react with cross-coupling electrophiles that are considerably less reactive with palladium as the catalyst. These differences give nickel the ability to oxidatively add into less reactive bonds that would either be unreactive with palladium or require more forceful reaction conditions. Nickel can oxidatively add into C—O bonds that typically are less reactive towards oxidative addition.3 The application of nickel catalysts gives an opportunity for the cross-coupling of C—O bonds under more mild conditions. This has allowed recent developments in the nickel catalysis of phenol derivatives as useful electrophiles in Suzuki-Miyaura,6 Negishi,7 and Kumada reactions8 among various other cross-coupling reactions.5 The Stille coupling is a common cross-coupling reaction that works well with aryl halide electrophiles. However, a Ni-catalyzed Stille coupling using non-triflate phenolic derivatives had not been developed prior to our work. This cross-coupling uses an organostannane and an aryl halide or pseudohalide to form a new C—C bond. A common application of the Stille coupling is in the synthesis of natural products.9 The reaction conditions tolerate a wide variety of functional groups on the electrophile and nucleophile making this cross-coupling reaction one of the more versatile cross-coupling methods. The palladium catalyzed Stille coupling works quite well with aryl halides and aryl triflates8 but the coupling of less-reactive phenolic derivatives is more limited in scope.10 An initial attempt at developing a Ni-catalyzed Stille cross-coupling of phenolic electrophiles was attempted by Percec, but homocoupling was the major project obtained (Scheme 1).7a This result, attributed to sluggish transmetalation, delayed further exploration into the Ni- 3 catalyzed Stille cross-coupling of phenolic derivatives until our group revisited this reaction in recent years.11 cat. NiCl2(PPh3)2 MeO MeO C MeO C CO Me 2C OMs + Ph SnBu3 2 Ph + 2 2 Zn, Et4NI, THF, 67 ºC (24%) (64%) predominantly homocoupling Scheme 1. Percec’s Ni-catalyzed Stille coupling with aryl mesylates resulting in homocoupling. The use of nickel as a catalyst has many advantages but there are still several challenges. One challenge of nickel catalysis is controlling chemo- and site-selectivity in the presence of multiple (pseudo)halides with similar reactivity. Previous to the work in this document, the nickel catalyzed chemoselective coupling of non-triflate phenol derivatives had not been published. For many years, published work showed the presence of aryl halides prohibited reaction at C—O bonds due to the greater reactivity of aryl halides (Figure 1). Cl A B Cl O HO OSO B(OH) 2NMe2 2 NiCl2(PCy ) Cl N 3 2 + K3PO4, toluene complex O O O mixture including N MW, 180 °C polymers O O Cl Cl Cl N CH CH H 3 3 Lumefantrine Felodipine Figure 1. (A) One relevant example showing the intolerance of aryl halides in cross coupling of phenolic electrophiles12 and (B) two pharmacologically relevant compounds where selectivity during cross coupling could result in a more efficient synthesis.13 The lack of a viable path to obtain selectivity with a nickel catalyst becomes an issue when the target molecule contains aryl halides (Figure 1). The use of different phosphines in several studies have resulted in orthogonal selectivity between aryl halides and aryl triflates in palladium- catalyzed Suzuki-Miyaura coupling.14,15,16,17,18 These studies suggest that a large factor in 4 determining whether the coupling takes place at a C—Cl bond or a C—OTf bond is the bulkiness of the phosphine, which impacts the coordination number of Pd during oxidative addition (Scheme 2). Fu 2000 and Schoenebeck/Houk 2010 via: via: ‡ ‡ Cy3P PCy3 cat. Pd cat. Pd PtBu PCy Pt 3 Bu Pd Cl o-tol 3 Cl OTf 3 o-tol OTf Pd o-tolB(OH)2 o-tolB(OH)2 Ar OTf 87% KF, THF, r.t. KF, THF, r.t. 95% Cl Ar Scheme 2. Previous investigations into palladium catalyzed chemoselective Suzuki-Miyaura cross-coupling reactions.16 The transition states shown were determined through DFT calculations.20 Additional experimental19 and computational20,21 studies on the Pd-catalyzed cross-coupling of aryl triflates in the presence of aryl chlorides also suggest the ligation state of palladium during oxidative addition influences the selectivity of the reaction.19,20,21 When a less hindered ligand such as PCy3 is used a PdL2 species is favored, this bisligated species is more electron-rich and prefers to react at the C—OTf bond due to more effective interactions with the C—OTf bond that is much more polarized when compared with the C—Cl bond. With a less sterically hindered ligand such as P(tBu)3, palladium prefers to be monoligated (PdL) resulting in palladium being less electron- rich and reacting preferentially at the C—Cl bond because of the smaller distortion energy of these bonds.20 The origins of selectivity in Pd-catalyzed Suzuki-Miyaura couplings between C—Cl and C—OTf bonds is well studied, but the role ligands play on controlling the selectivity between different electrophiles in Ni-catalyzed cross-couplings is much less studied. We undertook the first mechanistic study of a ligand-controlled Ni-catalyzed Suzuki-Miyaura cross-coupling. Phenols are widely available and can be readily transformed into effective electrophiles. Bulkier phenol-derived electrophiles, such as sulfamates, tosylates, and mesylates often work quite well with a nickel catalyst in various cross-coupling reactions but current methods to synthesize 5 these electrophiles often result in one equivalent of halogen waste being generated. Many aryl methyl ethers can be readily generated through breaking lignin down into small fragments and are commercially available, bypassing this synthetic step. While aryl methyl ethers have an advantage over many other phenol-derived electrophiles by not resulting in loss of a halogen equivalent, they are also significantly less reactive. Because of this, aryl methyl ethers can be carried through multiple synthetic steps and can even serve as protecting groups22 in multi-step synthetic reactions. The use of aryl methyl ethers in Ni-catalyzed cross-coupling reactions has been documented under Kumada coupling conditions and under more forceful Suzuki-Miyaura coupling conditions (Scheme 3).5h,6f,8a,8d,23 A - Dankwardt 2004 B - Tobisu, Chatani 2014 Ni(cod)2 (10 mol%) OMe NiCl2(PCy3)2 (5 mol%) Ph OMe ICy (20 mol%) p-tol PCy3 (10 mol%) O NaOtBu (25 mol%) + Ph MgBr + p-tol B (EtO)2CH2, Et2O, 35 ºC, 15h O CsF (2.0 equiv) Me Me Ph toluene, 120 °C, 12h Ph 93% 76% Scheme 3. Examples of Ni-catalyzed cross-coupling with aryl methyl ethers – (A) Kumada conditions improved by Dankwardt8d and (B) Suzuki conditions developed by Tobisu and Chatani.23f The work in this dissertation is divided into three areas of methodology development: the Ni-catalyzed Stille cross-coupling of aryl sulfamates, the Ni-catalyzed chemoselective Suzuki- Miyaura cross-coupling of aryl tosylates over aryl chlorides, and the Ni-catalyzed cross-coupling of aryl methyl ethers. While these three projects involve different electrophiles and types of cross- couplings, they are all catalyzed by nickel, the electrophiles are all phenolic in nature, and they are all cross-coupling reactions. The overall goal of this research was to explore Ni-catalyzed cross- coupling methods to establish efficient and reliable methods to create new bonds from phenol- derived electrophiles. The first project (Scheme 4A) was explored through a combination of 6 catalytic, stoichiometric, and computational studies that established the methodology and explained why previous attempts at developing a Ni-catalyzed Stille cross-coupling with phenolic electrophiles had been unsuccessful. The success of the second project (Scheme 4B) was achieved through extensive mechanistic studies, both computational and experimental, to understand the origins of selectivity in a Ni-catalyzed Suzuki-Miyaura coupling and the effect ligands play on the selectivity of the oxidative addition step. The third project (Scheme 4C) was explored through synthesizing and using various ligands that had not been reported for the Ni-catalyzed Suzuki- Miyaura or Kumada couplings of aryl methyl ethers and screening reaction variables to obtain the best product yield. Overall, these projects increase the knowledge of Ni-catalyzed cross-couplings and have the potential for making synthetic chemistry more efficient through eliminating steps to obtain the target or using more readily available A - Chapter 2 electrophiles. OSO R 2 2 cat. Ni(cod) R 2 ligand + 2 Chapter 2 details the development of the R SnBu3 KF, dioxane R1 80 ºC, 18 h R1 first efficient, Ni-catalyzed Stille coupling of R = NMe2, p-tol, Me B - Chapter 3 phenol-derived electrophiles. Through the OTs OTs cat. Ni(0) cat. Ni(0) PMe or Ar 3 most PR3 PPhMe2 course of this project, we established a broad ArB(OR1)2 ArB(OR1)2 Ar scope and examined the transmetalation step of Cl Cl Easily obtained Our work this system. These investigations showed the C - Chapter 4 OMe cat. Ni(0) Ph importance of KF and the inhibitory effect of a PR3 or NHC + Ph Nuc solvent, temp, time R R chloride source in this reaction. Chapter 3 Nuc = organoboron or organomagnesium Scheme 4. General reaction schemes for discusses the investigation and development of a each project. Ni-catalyzed chemoselective Suzuki-Miyaura cross-coupling using small phosphine ligands. This reaction was highly selective for reaction at 7 the C—OTs bond when small tri- or dimethyl phosphines were used. DFT computations suggest this unique selectivity does not arise from the typical origin of metal ligation state. Chapter 4 delves into the development of Ni-catalyzed cross-couplings of Ar-OMe through the use of ligands bearing anionic arms. These are arms that bear a group that can be deprotonated under basic conditions resulting in them becoming anionic. Three ligands bearing anionic arms were synthesized, and two of these were used successfully in the Kumada coupling of Ar-OMe. 8 References 1. The Nobel Prize in Chemistry 2010. https://www.nobelprize.org/prizes/chemistry/2010/summary/ (Accessed March 10, 2022). 2. Haxel, G. B.; Hedrick, J. B.; Orris, G. J. Rare Earth Elements—Critical Resources for High Technology. https://pubs.usgs.gov/fs/2002/fs087-02/ (Accessed March 10, 2022). 3. Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Recent advances in homogeneous nickel catalysis. Nature 2014, 509, 299–309. 4. Macklin, T. K.; Snieckus, V. Directed Ortho Metalation Methodology. The N,N-Dialkyl Aryl O-Sulfamate as a New Directed Metalation Group and Cross-Coupling Partner for Grignard Reagents. Org. Lett. 2005, 7, 2519–2522. 5. For selected reviews on C—O electrophiles, see: (a) Yu, D. G.; Li, B. J.; Shi, Z. J. Exploration of New C—O Electrophiles in Cross-Coupling Reactions. Acc. Chem. Res. 2010, 43, 1486– 1495; (b) Li, B. J.; Yu, D. G.; Sun, C. L.; Shi, Z. J. Activation of "Inert" Alkenyl/Aryl C—O Bond and Its Application in Cross-Coupling Reactions. Chem. Eur. J. 2011, 17, 1728–1759; (c) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A. M.; Garg, N. K.; Percec, V. Nickel-Catalyzed Cross-Couplings Involving Carbon-Oxygen Bonds. Chem. Rev. 2011, 111, 1346–1416; (d) Mesganaw, T.; Garg, N. K. Ni- and Fe-Catalyzed Cross-Coupling Reactions of Phenol Derivatives. Org. Proc. Res. Dev. 2013, 17, 29–39; (e) Yamaguchi, J.; Muto, K.; Itami, K. Recent Progress in Nickel-Catalyzed Biaryl Coupling. Eur. J. Org. Chem. 2013, 2013, 19–30; (f) Tobisu, M.; Chatani, N. Catalytic Transformations Involving the Activation of sp2 Carbon-Oxygen Bonds. Top. Organomet. Chem. 2013, 44, 35–53; (g) Cornella, J.; Zarate, C.; Martin, R. Metal-catalyzed activation of ethers via C—O bond cleavage: a new strategy for molecular diversity. Chem. Soc. Rev. 2014, 43, 8081–8097; (h) Tobisu, M.; Chatani, N. Cross-Couplings Using Aryl Ethers via C—O Bond Activation Enabled by Nickel Catalysts. Acc. Chem. Res. 2015, 48, 1717–1726; (i) Tobisu, M.; Chatani, N. Nickel-Catalyzed Cross-Coupling Reactions of Unreactive Phenolic Electrophiles via C— O Bond Activation. Top. Curr. Chem. 2016, 374, 41. 6. Selected seminal examples: (a) Percec, V.; Bae, J. Y.; Hill, D. H. Aryl Mesylates in Metal- Catalyzed Homocoupling and Cross-Coupling Reactions. 2. Suzuki-Type Nickel-Catalyzed Cross-Coupling of Aryl Arenesulfonates and Aryl Mesylates with Arylboronic Acids. J. Org. Chem. 1995, 60, 1060–1065; (b) Zim, D.; Lando, V. R.; Dupont, J.; Monteiro, A. L. NiCl2(PCy3)2: A simple and efficient catalyst precursor for the Suzuki cross-coupling of aryl tosylates and arylboronic acids. Org. Lett. 2001, 3, 3049–3051; (c) Tang, Z. Y.; Hu, Q. S. Room-temperature Ni(0)-catalyzed cross-coupling reactions of aryl arenesulfonates with arylboronic acids. J. Am. Chem. Soc. 2004, 126, 3058–3059; (d) Guan, B. T.; Wang, Y.; Li, B. J.; Yu, D. G.; Shi, Z. J. Biaryl Construction via Ni-Catalyzed C—O Activation of Phenolic Carboxylates. J. Am. Chem. Soc. 2008, 130, 14468–14470; (e) Quasdorf, K. W.; Tian, X.; Garg, N. K. Cross-Coupling Reactions of Aryl Pivalates with Boronic Acids. J. Am. Chem. Soc. 2008, 130, 14422–14423; (f) Tobisu, M.; Shimasaki, T.; Chatani, N. Nickel-catalyzed 9 cross-coupling of aryl methyl ethers with aryl boronic esters. Angew. Chem. Int. Ed. 2008, 47, 4866–4869. 7. Selected examples: (a) Percec, V.; Bae, J. Y.; Hill, D. H. Aryl Mesylates in Metal-Catalyzed Homo-Coupling and Cross-Coupling Reactions. 4. Scope and Limitations of Aryl Mesylates in Nickel-Catalyzed Cross-Coupling Reactions. J. Org. Chem. 1995, 60, 6895–6903; (b) Li, B. J.; Li, Y. Z.; Lu, X. Y.; Liu, J.; Guan, B. T.; Shi, Z. J. Cross-Coupling of Aryl/Alkenyl Pivalates with Organozinc Reagents through Nickel-Catalyzed C—O Bond Activation under Mild Reaction Conditions. Angew. Chem. Int. Ed. 2008, 47, 10124–10127; (c) Wang, C.; Ozaki, T.; Takita, R.; Uchiyama, M. Aryl Ether as a Negishi Coupling Partner: An Approach for Constructing C—C Bonds under Mild Conditions. Chem. Eur. J. 2012, 18, 3482–3485; (d) Tao, J. L.; Wang, Z. X. Pincer-Nickel-Catalyzed Cross-Coupling of Aryl Sulfamates with Arylzinc Chlorides. Eur. J. Org. Chem. 2015, 2015, 6534–6540. 8. Selected examples: (a) Wenkert, E; Michelotti, E. L.; Swindell, C. S. Nickel-induced conversion of carbon-oxygen into carbon-carbon bonds. One-step transformations of enol ethers into olefins and aryl ethers into biaryls. J. Am. Chem. Soc. 1979, 101, 2246–2247; (b) Hayashi, T.; Katsuro, Y.; Okamoto, Y.; Kumada, M. Nickel-Catalyzed Cross-Coupling of Aryl Phosphates with Grignard and Organo-Aluminum Reagents - Synthesis of Alkylbenzenes, Alkenylbenzenes and Arylbenzenes from Phenols. Tetrahedron Lett. 1981, 22, 4449–4452; (c) Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus, V. Ni(0)-Catalyzed Cross Coupling of Aryl O-Carbamates and Aryl Triflates with Grignard Reagents - Directed Orthometallation-Aligned Synthetic Methods for Polysubstituted Aromatics Via a 1,2-Dipole Equivalent. J. Org. Chem. 1992, 57, 4066–4068; (d) Dankwardt, J. W. Nickel-catalyzed cross- coupling of aryl Grignard reagents with aromatic alkyl ethers: An efficient synthesis of unsymmetrical biaryls. Angew. Chem. Int. Ed. 2004, 43, 2428–2432; (e) Yu, D. G.; Li, B. J.; Zheng, S. F.; Guan, B. T.; Wang, B. Q.; Shi, Z. J. Direct Application of Phenolic Salts to Nickel-Catalyzed Cross-Coupling Reactions with Aryl Grignard Reagents. Angew. Chem. Int. Ed. 2010, 49, 4566–4570. 9. For examples see: (a) Kurti, L.; Czako, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier: Burlington, 2005; (b) Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A. Enantioselective Total Synthesis of Quadrigemine C and Psycholeine. J. Am. Chem. Soc. 2002, 124, 9008–9009; (c) Masse, C. E.; Yang, M.; Solomon, J.; Panek, J. S. Total Synthesis of (+)-Mycotrienol and (+)-Mycotrienin I:  Application of Asymmetric Crotylsilane Bond Constructions. J. Am. Chem. Soc. 1998, 120, 4123–4134; (d) Martin, S. F.; Humphrey, J. M.; Ali, A.; Hillier, M. C. Enantioselective Total Syntheses of Ircinal A and Related Manzamine Alkaloids. J. Am. Chem. Soc. 1999, 121, 866–867; (e) Kende, A. S.; Kawamura, K.; DeVita, R. J. Enantioselective total synthesis of neooxazolomycin. J. Am. Chem. Soc. 1990, 112, 4070–4072; (f) Kende, A. S., Koch, K.; Dorey, G.; Kaldor, I.; Liu, K. Enantioselective total synthesis of lankacidin C. J. Am. Chem. Soc. 1993, 115, 9842–9843; (g) Hong, C. Y, Kishi, Y. Total synthesis of onnamide A. J. Am. Chem. Soc. 1991, 113, 9693–9694; (h) Tanimoto, N.; Gerritz, S. W.; Sawabe, A.; Noda, T.; Filla, S. A.; Masamune, S. The Synthesis of Naturally Occurring (—)-Calyculin A. Angew. Chem. Int. Ed. 2003, 33, 673–675; (i) Evans, D. A.; Black, W. C. Total synthesis of (+)-A83543A [(+)-lepicidin A]. J. Am. Chem. Soc. 1993, 115, 4497–4513; (j) Tang, W.; Prusov, E. V. Total Synthesis of Ripostatin A. Org. Lett. 2012, 10 14, 4690–4693; (k) Coleman, R. S.; Walczak, M. C.; Campbell, E. L. Total Synthesis of Lucilactaene, A Cell Cycle Inhibitor Active in p53-Inactive Cells. J. Am. Chem. Soc. 2005, 127, 16036–16039. 10. Buchwald, S. L.; Naber, J. R.; Fors, B. P.; Wu, X. X.; Gunn, J. T. Stille Cross-Coupling Reactions of Aryl Mesylates and Tosylates Using a Biarylphosphine Based Catalyst System. Heterocycles 2010, 80, 1215. 11. Russell, J. E. A.; Entz, E. D.; Joyce, I. M.; Neufeldt, S. R. Nickel-Catalyzed Stille Cross Coupling of C–O Electrophiles. ACS Catal. 2019, 9, 3304–3310. 12. Baghbanzadeh, M.; Pilger, C.; Kappe, C. O. Rapid Nickel-Catalyzed Suzuki-Miyaura Cross- Couplings of Aryl Carbamates and Sulfamates Utilizing Microwave Heating. J. Org. Chem. 2011, 76, 1507–1510. 13. Lumefantrine and felodipine are FDA-approved drugs that contain C—C bonds that could be formed through our chemoselective Ni-catalyzed Suzuki cross-coupling method. 14. Kamikawa, T.; Hayashi, T. Control of Reactive Site in Palladium-Catalyzed Grignard Cross- Coupling of Arenes Containing both Bromide and Triflate. Tetrahedron Lett. 1997, 38, 7087– 7090. 15. Espino, G.; Kurbangalieva, A.; Brown, J. M. Aryl bromide/triflate selectivities reveal mechanistic divergence in palladium-catalysed couplings; the Suzuki-Miyaura anomaly. Chem. Commun. 2007, 1742–1744. 16. Littke, A. F.; Dai, C.; Fu, G. Versatile Catalysts for the Suzuki Cross-Coupling of Arylboronic Acids with Aryl and Vinyl Halides and Triflates under Mild Conditions. J. Am. Chem. Soc. 2000, 122, 4020–4028. 17. Kalvet, I.; Magnin, G.; Schoenebeck, F. Rapid Room-Temperature, Chemoselective Csp2— Csp2 Coupling of Poly(pseudo)halogenated Arenes Enabled by Palladium(I) Catalysis in Air. Angew. Chem. Int. Ed. 2017, 56, 1581–1585. 18. Reeves, E. K.; Humke, J. N.; Neufeldt, S. R. N-Heterocyclic Carbene Ligand-Controlled Chemodivergent Suzuki-Miyaura Cross Coupling. J. Org. Chem. 2019, 84, 11799–11812. 19. Niemeyer, Z. L.; Milo, A.; Hickey, D. P.; Sigman, M. S. Parameterization of phosphine ligands reveals mechanistic pathways and predicts reaction outcomes. Nature Chem. 2016, 8, 610– 617. 20. Schoenebeck, F.; Houk, K. N. Ligand-Controlled Regioselectivity in Palladium-Catalyzed Cross-Coupling Reactions. J. Am. Chem. Soc. 2010, 132, 2496–2497. 21. Lyngvi, E.; Sanhueza, I. A.; Schoenebeck, F. Dispersion Makes the Difference: Bisligated Transition States Found for the Oxidative Addition of Pd(PtBu3)2 to Ar-OSO2R and 11 Dispersion-Controlled Chemoselectivity in reactions with Pd[P(iPr)(tBu2)]2. Organometallics 2015, 34, 805–812. 22. SynArchive.com Protecting groups. https://synarchive.com/protecting-group (Accessed March 10, 2022). 23. For examples see: (a) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli, M. Transformation of carbon-oxygen into carbon-carbon bonds mediated by low-valent nickel species. J. Org. Chem. 1984, 49, 4894–4899; (b) Miyaura, N. Metal-Catalyzed Reactions of Organoboronic Acids and Esters. Bull. Chem. Soc. Jpn. 2008, 81, 1535–1553; (c) Shimasaki, T.; Konno, Y.; Tobisu, M.; Chatani, N. Nickel-Catalyzed Cross-Coupling Reaction of Alkenyl Methyl Ethers with Aryl Boronic Esters. Org. Lett. 2009, 11, 4890–4892; (d) Xie, L.-G.; Wang, Z.-X. Cross‐Coupling of Aryl/Alkenyl Ethers with Aryl Grignard Reagents through Nickel‐ Catalyzed C—O Activation. Chem. Eur. J. 2011, 17, 4972–4975; (e) Iglesias, M. J.; Prieto, A.; Nicasio, M. C. Kumada–Tamao–Corriu Coupling of Heteroaromatic Chlorides and Aryl Ethers Catalyzed by (IPr)Ni(allyl)Cl. Org. Lett. 2012, 14, 4318–4321; (f) Tobisu, M.; Yasutome, A.; Kinuta, H.; Nakamura, K.; Chatani, N. 1,3-Dicyclohexylimidazol-2-ylidene as a Superior Ligand for the Nickel-Catalyzed Cross-Couplings of Aryl and Benzyl Methyl Ethers with Organoboron Reagents. Org. Lett. 2014, 16, 5572–5575. 12 CHAPTER TWO NICKEL-CATALYZED STILLE CROSS-COUPLING OF C—O ELECTROPHILES Contribution of Authors and Co-Authors Manuscript in Chapter Two. Author: John E. A. Russell Contributions: Prepared compounds of interest. Synthesized reagents and prepared compounds of interest. Conducted mechanistic studies. Helped revise the manuscript and SI. Co-Author: Emily D. Entz Contributions: Helped continue optimization of reaction conditions and synthesize reagents. Prepared compounds of interest. Helped revise the manuscript and SI. Co-Author: Ian M. Joyce Contributions: Worked on early optimization and helped synthesize reagents. Co-Author: Sharon R. Neufeldt Contributions: Conceptualization, data curation, formal analysis, funding acquisition, computational experiments, project administration, supervision, visualization, writing – original draft; writing – review and editing. Manuscript Information John E. A. Russell, Emily E. Entz, Ian M. Joyce, Sharon R. Neufeldt ACS Catalysis Status of Manuscript: ____ Prepared for submission to a peer-reviewed journal ____ Officially submitted to a peer-reviewed journal ____ Accepted by a peer-reviewed journal _X___ Published in a peer-reviewed journal American Chemical Society Submitted February 19, 2019 Published online March 4, 2019 Published in issue 4 April 5, 2019 DOI: 10.1021/acscatal.9b0074 13 14 15 16 17 18 19 20 CHAPTER THREE SMALL PHOSPHINE LIGANDS ENABLE SELECTIVE OXIDATIVE ADDITION OF Ar—O OVER Ar—Cl BONDS AT NICKEL (0) Contribution of Authors and Co-Authors Manuscript in Chapter Three Co-First Author: John E. A. Russell Contributions: Conducted stoichiometric oxidative addition studies to explore the selectivity with various ligands. Synthesized compounds and catalysts of interest. Wrote the SI and helped revise figures and manuscript. Co-First Author: Emily D. Entz Contributions: Conducted catalytic studies. Synthesized compounds of interest. Wrote the SI and helped revise figures and manuscript. Co-Author: Leidy V. Hooker Contributions: Greatly helped with early investigations, optimizations, and rational. Co-Author: Sharon R. Neufeldt Contributions: Conceptualization, data curation, formal analysis, funding acquisition, computational experiments, project administration, supervision, visualization, writing – original draft; writing – review and editing. Manuscript Information Emily E. Entz, John E. A. Russell, Leidy V. Hooker, Sharon R. Neufeldt Journal of the American Chemical Society Status of Manuscript: ____ Prepared for submission to a peer-reviewed journal ____ Officially submitted to a peer-reviewed journal ____ Accepted by a peer-reviewed journal _X___ Published in a peer-reviewed journal American Chemical Society Submitted June 29, 2020 Published online August 17, 2020 Published in issue 36 September 9, 2020 DOI: 10.1021/jacs.0c06995 21 22 23 24 25 26 27 28 29 30 31 CHAPTER FOUR NICKEL CATALYZED CROSS-COUPLINGS OF ARYL METHYL ETHERS Introduction I. Introduction to Cross-Coupling Reactions and Phenol-Derived Electrophiles. Cross-coupling occurs between an electrophile and a nucleophile resulting in a new C—C or C—heteroatom bond through the action of a transition metal catalyst. The transition metal catalyzed cross-coupling reaction is a common and valuable strategy to form new bonds, simplifying the synthesis of complex molecules. Transition metal catalyzed cross-coupling reactions take many different appearances in the form of different nucleophiles, two varieties are the focus of this report. Aryl halides are historically the preferred electrophilic coupling partner but as more research has occurred, phenol-derived electrophiles have gained prominence. Phenol- derived electrophiles display several advantages as the electrophilic cross-coupling partner when compared to aryl halides. Among these advantages are the low cost and wide availability of phenols, the precursor to phenol-derived electrophiles. The variety of available phenol-derived electrophiles spans a spectrum of reactivity with a phenol being the least reactive and triflate being the most reactive (Figure 1).1 Many of these phenol-derived electrophiles can be carried through multiple synthetic steps, or they can direct other synthetic steps. Aryl ethers, especially aryl methyl ethers (Ar-OMe), are among the least reactive phenol-derived electrophiles (Figure 1). However, one advantage aryl methyl ethers have over the more reactive phenol-derived electrophiles is the greater atom economy of the leaving group. Furthermore, unlike many other phenol-derived electrophiles, many Ar-OMe reagents are commercially available. 32 Increasing reactivity O O O Ar Ar S O R O Me Ester Mesylate O O O O O Ar OH Ar R O Ar Ar S Ar S Phenol O OR O p-tol Ether O CF3 Carbonate Tosylate Triflate O O O Ar = any aryl group Ar Ar S R = usually Me or Et O NR2 O NR2 Carbamate Sulfamate Figure 1. Relative reactivity of phenols and phenol derivatives in cross-coupling reactions. II. An Overview of Nickel Catalysis of Cross-Coupling Reactions of Aryl Methyl Ethers. Nickel has a long history as a catalyst in cross-coupling reactions. However, when it was discovered that palladium could also catalyze cross-coupling reactions, development and understanding of nickel catalysis slowed down until recently.2 The resurgence of nickel has been driven partially due to nickel being seen as a cheaper, more earth-abundant alternative to palladium. Nickel is also able to catalyze cross-coupling reactions using electrophiles that are largely unreactive under palladium catalysis.1,3 This ability of nickel to react with more inert phenolic electrophiles has led to nickel being studied for new cross-coupling applications. Wenkert, in 1979, developed the first Ni-catalyzed Kumada-Tamao-Corriu-type cross- coupling of aryl ethers with Grignard reagents (Scheme 1a).4 However, this reaction did not garner significant interest until many years later, partially due to the development of aryl triflates as competent phenol-derived electrophiles for similar couplings. Due to low-valent nickel possessing unique reactivity in the activation of typically unreactive C(ar)—O bonds, the Kumada coupling of aryl methyl ethers has reemerged as a focus of active research over the past 20 years. The first major advancement since Wenkert’s initial work was achieved by Dankwardt in the early 21st century (Scheme 1b). Dankwardt improved on Wenkert’s conditions, which used PPh3 as a ligand for the nickel catalyst, by exploring alkylphosphine ligands such as PCy3 and PiPr3. This 33 significantly improved the yields and scope of the reaction.5 The original conditions developed by Wenkert resulted in a scope largely limited to fused aromatic rings,4 whereas Dankwardt expanded this scope to include a wider variety of aryl methyl ethers.5 In the years following Dankwardt’s work, other trialkylphosphines6 were studied in addition to N-heterocyclic carbene (NHC) ligands bearing bulky aryl groups such as 2,6-diisopropylphenyl.7 These studies have shown the ligands that result in the best yields and the broadest scope typically have the three following traits: significant steric bulk, monodenticity, and strong s-donating ability. A - Wenkert 1979 B - Dankwardt 2004 OMe Ph OMe NiCl (PCy ) (5 mol%) Ph 2 3 2 NiCl (PPh ) (10 mol%) PCy (10 mol%) + Ph MgBr 2 3 2 + Ph MgBr 3 benzene, reflux, 24h (EtO)2CH2, Et2O, 35 ºC, 15h 77% Me Me 93% Scheme 1. (a) Wenkert’s pioneering conditions for the cross-coupling of aryl ethers. (b) An example of reaction improvements reported by Dankwardt. In 2008, Tobisu and Chatani explored the Ni-catalyzed cross-coupling of aryl ethers with organoboron reagents.8 Consistent with the ligand trends observed with the Kumada coupling of aryl methyl ethers, they found the Ni(cod)2/PCy3 catalytic system was suitable for this application (Scheme 2a).9 Although they were able to develop a Ni-catalyzed Suzuki-Miyaura cross-coupling of Ar-OMe that showed exceptional functional group tolerance, anisole derivatives remined inert under their best conditions. Further developments on the Ni-catalyzed Suzuki-Miyaura cross- coupling of aryl ethers with organoboron reagents showed that NHC ligands substituted with bulky alkyl groups (e.g. cyclohexyl groups, aka ICy) (Scheme 2b) tend to work better than phosphine ligands mostly due to their better s-donating ability.10 Unlike the improved conditions for the Kumada coupling of aryl methyl ethers, the Suzuki conditions are mostly restricted to naphthalene derivatives or higher π-extended aromatic substrates, which has hindered further reaction 34 development. 11 The limitations in the electrophile scope under Suzuki conditions are often attributed to a high energy barrier during oxidative addition. III. Computational Studies of Cross-Coupling Reactions with Phenol-Derived Electrophiles. There have been many different computational investigations regarding the oxidative addition of nickel into C—O bonds. 12 These different investigations each add a little more information about the oxidative addition step: the magnitude of the energy barrier and how this barrier is affected by reaction conditions. In general, the disparity in reactivity between methoxynaphthalene derivatives and simpler aromatic ethers such as anisole or anisole derivatives have resulted in the best Suzuki-Miyaura coupling of Ar-OMe being limited to extended π-electron systems and aryl groups with electron withdrawing groups. Naphthalene derivatives have extended π-electron systems which allow for the dearomatization of one arene ring while retaining aromaticity in the other during π-complexation which is prior to the rate determining step (oxidative addition).12b Oxidative addition for the cross-coupling of Ar-OMe typically occurs through a 3-centered transition state from the preceding π-complex. Overall, this has the effect of lowering the energy barrier for the rate determining step, making it easier to obtain the oxidative addition product when compared to simpler aromatic systems. This difference is observed experimentally with the different yields between using methoxynaphthalene derivatives and anisole derivatives.4,5,9,10,11 An early computational investigation into the Ni-catalyzed Suzuki-Miyaura coupling of aryl carbamates and sulfamates found that for both phenol-derived electrophiles the oxidative addition step was the rate determining step (RDS).12a Cornella, Gómez-Bengoa, and Martin reported an experimental and theoretical study that entailed exploring the oxidative addition step into the Car—OMe bond.12b They were able to show the Ni-catalyzed cleavage of C—OMe bonds 35 can proceed through different pathways depending on what nickel source is used. Their initial computations were also able to show that oxidative addition was the RDS and was preceded by a π-complexation event, previous to which nickel was bisligated. However, they also explored the cleavage of C—OMe bonds in the presence of silanes and showed that in this case the catalytically active species was a Ni(I)-silane and the RDS was migratory insertion into the naphthalene backbone oxidative addition was not a mechanistic step. Additional studies conducted by other groups investigating the Ni-catalyzed cleavage of C—OMe bonds showed in many cases that oxidative addition is the RDS preceded by a π-complexation step.12d,f,g,h,k,l However two investigations under Kumada conditions that after the π-complex is formed, transmetalation occurs prior to oxidative addition or at least a non-typical mechanism is at play.12c,e Wang and Uchiyama showed the order of transmetaltion and oxidative addition were also swapped in the presence of organolithium and organozinc reagents.12i While many of the computational investigations support a monoligated nickel species as the catalyst in the lowest energy pathways, when dispersion is accounted for in the calculations, the lowest energy transition states often involve a bisligated nickel species.12j,13 Further studies following the Martin report investigated the role of various additives in aiding the oxidative addition step. These show through computational studies that the presence of a Lewis acid can interact with the etheric oxygen weakening the C—O bond, this in turn has the effect of making the oxidative addition of nickel into the inert C—OMe bond less energy demanding;12c,h,i,k,l the role of the Lewis acid can be fulfilled by the organometallic nucleophile. Grignard reagents are exceptional at stabilizing the transition state and helping the etheric oxygen act as a leaving group, but organoaluminum reagents are also able to play a cooperative role with nickel to facilitate the oxidative addition into the C—OMe bond. The combined data obtained from 36 these theoretical investigations indicate that the RDS is oxidative addition of nickel into the C— OMe bond preceded by a π-complexation event. The activation barrier can be decreased under Kumada conditions through the application of Lewis acids, this has the effect of stabilizing the oxidative addition transition state but this has not been found to be the case under Suzuki conditions. While much is known about the Ni-catalyzed cleavage of C—OMe bonds through the oxidative addition step, with only a handful of the studies being conducted on cross-coupling reactions, this information has thus far not been translated into expanding the scope beyond the current limitations. IV. Expanding the Scope of the Nickel Catalyzed Cross-Coupling of Aryl Methyl Ethers. The initial development of the Ni-catalyzed cross-coupling of aryl methyl ethers reported by Wenkert was largely limited to methoxynaphthalene derivatives, and other Ar-OMe attempted resulted in very low yields.4 Pursuant improvements on the Wenkert conditions conducted by several groups expanded the viable scope through exploring various ligands and further optimizing reaction conditions.5,7,14 The result of these studies and improvements expanded the viable scope of the reaction to include electron-neutral anisole derivatives and sterically demanding aryl methyl ethers as the electrophilic coupling partner. Thus, current methods for coupling Grignard reagents with aryl methyl ethers have very few scope limitations. A - Tobisu, Chatani 2008 B - Tobisu, Chatani 2014 Ni(cod)2 (10 mol%) OMe Ni(cod) (5 mol%) Ph OMe p-tol 2 ICy (20 mol%) PCy (20 mol%) NaOt + 3 + Bu (25 mol%) O B O O O CsF (2.25 equiv) B CsF (2.0 equiv) Ph toluene, 120 °C, 12h 74% p-tol Ph toluene, 120 °C, 12h Ph 76% Scheme 2. (a) The pioneering work by Tobisu and Chatani of the Ni-catalyzed Suzuki-Miyuara cross-coupling of aryl ethers. (b) Further improvements to the cross-coupling of aryl ethers with organoboron nucleophiles. 37 Tobisu and Chatani first developed the Ni-catalyzed cross-coupling of aryl methyl ethers with organoboron reagents in 2008, but the scope was limited almost exclusively to methoxynaphthalene derivatives and PCy3 used as the ligand (Scheme 2A).9a This very limited scope was expanded to include anisole derivatives that had electron withdrawing substituents with ICy10 as the ligand (Scheme 2B). However, the scope of the reaction was still limited, likely due to the different reactivity between methoxynaphthalene derivatives and many anisole derivatives. V. Mechanistic Studies on Oxidative Addition into C—O Bonds. The lack of a viable strategy resulting in the efficient cross-coupling of less reactive aryl methyl ethers has led to further exploration into the Suzuki-Miyaura cross-coupling of aryl ethers stalling out until more can be understood about the nature of this problem and why it appears prevalent in Ni-catalyzed cross-coupling of low-reactivity electrophiles. 15 Previous work by Nakamura provides one explanation for why the same difference in reactivity observed between methoxynaphthalene and anisole is less pronounced when using the corresponding aryl-chlorides and -bromides. Their work suggests that ligand exchange (π-complexation) is the first irreversible step and oxidative addition follows immediately, so the ability of the substrate to form a π-arene metal complex could change how the reaction progressed (Figure 2A).16 These investigations have little relevance for the coupling of Ar-OMe because of the greater reactivity of aryl halides. Studies exploring the Ni-catalyzed cleavage of less reactive C—O bonds show the π-complexation event is associated with only a small energy increase followed by a rate determining step (Figure 2B). 12 The difference in reactivity between π-extended systems and simpler aromatic systems is most often observed with aryl ethers,3,4,7,9 aryl fluorides,15a aryl amides,15f aryl esters,15d,e,g,h and phenols.15b,c 38 A P B L Ni P Ni P P X OMe Ni P L Ni X P NiL Ni P 2 NiL OMe = Br and Cl Ni P X OMe X Figure 2. General energy diagrams for the insertion of nickel into aryl halide bonds16a (A) and aryl methyl ether (B) bonds.12b A closer look at the literature suggests the extent of this disparate reactivity is at least partially dependent on the nature of the ligand. Recall that under the original Wenkert conditions with PPh3 as the ligand, the reaction scope was limited to naphthyl ethers. However, later development by Dankwardt widened the scope to include phenyl ethers when different ligands bearing alkyl groups were used (e.g. PCy3, PCy2Ph, PiPr3, and IPr).5,6,7 Occasionally when Grignard reagents or other really reactive nucleophiles are employed in a cross-coupling reaction, it is possible to have transmetalation occur prior oxidative addition while the Suzuki cross-coupling follows the traditional order with oxidative addition occurring before transmetalion. This switching of the steps could help explain the observed dependance on the identity of the nucleophile, Grignard reagents appear to allow for a wider Ar-OMe scope than when organoboron reagents are used. The first report of a Ni-catalyzed Kumada cross-coupling of aryl methyl ethers displayed a significant difference in reactivity between naphthyl and phenyl ethers, but Dankwardt’s work along with others seem to have remedied this problem.5,6,7 This survey of literature suggests the low reactivity of certain electrophiles arises from the high activation barrier of oxidative addition. This high activation barrier can be overcome by the application of a sufficiently reactive nucleophile like a increasing energy increasing energy 39 Grignard reagent or using a more advantageous ligand such as PCy3, IPr, or ICy to expand the reaction scope beyond methoxynaphthalene derivatives and other electrophiles with extended π- systems. VI. Background for Ligand Development. The previous literature investigating the oxidative addition of nickel into C—OMe bond yields helpful information regarding how this process occurs and what decreases the activation barrier. The information gleaned from previous experimental and computational studies on the coupling of Ar-OMe and the corresponding oxidative addition step provide a solid base of precedent for this work. Finding a way to overcome this widespread disparity in reactivity among the less-reactive electrophiles would significantly facilitate the further development of Ni- catalyzed aromatic transformations. One possible way to overcome this challenge is to generate a more electron-rich active nickel species through exploring new ligands and tuning their electronic nature. Another way would be to develop ligands with pendant arms that could act as a directing group to guide nickel into the C—OMe bond or this pendant arm could chelate to a Lewis acid and draw electron density away from the C—OMe bond lowering the energy barrier. It is widely accepted that the nature of the ligand plays a large role in Pd-catalyzed cross-coupling reactions and tremendous work has been put into studying ligand design.17 Unfortunately, this work is not readily applicable to nickel catalysis, especially with aryl ether electrophiles.9 In fact, several ligands capable of promoting Pd-catalyzed Suzuki-Miyaura cross-coupling are largely ineffective in the Ni-catalyzed Suzuki-Miyaura cross-coupling of aryl ethers (Figure 3).9 However, a study looking at various NHC ligands revealed that ICy allowed for a larger scope of electrophiles including aryl methyl ethers that do not contain a fused ring structure. Unfortunately, electron-rich anisole derivatives still proved challenging.10 One potential solution would be to further tune and 40 develop ligands to effectively generate an anionic nickel species or a Ni-ate species that would facilitate the oxidative addition into C(ar)—O bonds with a lower activation barrier. iPr P P P PCy2 i iPr iPr Pr N N N N Cl iPr Cl iPr i 93% 0% 0% Pr 0% 0% 0% Figure 3. Examples of ligands effective for Pd-catalyzed Suzuki-Miyaura cross-coupling of aryl methyl ethers with more reactive electrophiles that are ineffective for the Ni-catalyzed version, the only exception is PCy3.9a Same reaction conditions as Scheme 2a. Published results show that NHC ligands tend to work better than phosphine ligands for the cross-coupling of Ar-OMe under Suzuki conditions. Hydroxyphosphine ligands also show promise for facilitating the cross-coupling of low-reactivity electrophiles through the generation of an anionic nickel species. Hydroxyphosphine ligands (Figure 4A) have found a niche in Kumada-Tamao-Corriu (Kumada) reactions18 but display characteristics that could be helpful in overcoming the high oxidative addition energy barrier under Suzuki conditions. PR R Li R 2 L1 Me PPh Cu 2 2 O OH Cu R L M1 Ni R M2 Mg R Li Br X H MeO A B C D Figure 4. A general hydroxyphosphine ligand and likely modes of push-pull type C(sp2)—X bond oxidative addition. These ligands allow for a bimetallic, push-pull design that promotes cross-coupling. In the context of this project, a bimetallic push-pull system occurs when magnesium coordinates to and pulls electron density away from the leaving group, allowing nickel to approach and undergo oxidative addition more readily. The precedent for this push-pull mechanism originates from a mechanistic 41 study of the oxidative addition of lithium diorganocuprate(I) into an alkenyl bromide: both theory and experiments suggest that d10 Cu(I) and cationic Li(I) cooperate to activate the C—Br bond in the transition state (TS) B (Figure 4).18 A similar scenario, C, is expected for Ni(0) with a hydroxyphosphine ligand that is able to simultaneously coordinate to a group-10 metal (M1) and a Lewis acidic metal (M2); this coordination to a group-10 metal did not happen with the diorganocuperate (Figure 4B). OCONEt2 Ni(acac)2 (3 mol%) Ph PPh PO 1 (3 mol%) 2 + Ph MgBr Et2O, 25 °C, time OH R 1.5 equiv R PO 1 OCONEt2 OCONEt2 OCONEt2 OCONEt2 OCONEt2 Me Me Me NMe2 Me 1h 1h 1h 12h 1.5h 95% 94% 96% 9% 95% Scheme 3. Select examples of Ni-catalyzed Kumada cross-coupling of aryl carbamates with a hydroxyphosphine ligand. This bimetallic mechanism (Figure 4D) involving nickel and magnesium was supported by computations. The lowest energy transition state has magnesium coordinated to both the substrate and ligand oxygens (Figure 4D). The hydroxyphosphine ligands are less sterically demanding than PCy3 yet they promote the Ni-catalyzed cross-coupling of Grignard reagents with aryl carbamates and other low-reactivity electrophiles (Scheme 3).18 Computations regarding the application of hydroxyphosphine ligands to cross-coupling reactions indicate that the pendant group is helping to direct nickel to activate the C—OMe bond through chelation with a Lewis acid.18 Hydroxyphosphine ligands also have the ability to generate anionic nickel once the hydroxy arm is deprotonated. While these ligands appear to increase the reactivity of certain electrophiles when compared to more standard ligands under the same conditions, hydroxyphosphine ligands had not 42 been explored with aryl ethers or under Suzuki-Miyaura (SM) cross-coupling conditions. Following the development of hydroxyphosphine and the literature showing the effectiveness of NHC ligands, an NHC ligand bearing a hydroxy pendant arm was developed by the Anantharaman group.19 They were able to turn their NHC-OH ligands into a bis-NHC-O/Ni complex and display the catalytic reactivity with aryl chlorides (Scheme 4). Due to the hydroxy arm, NHC-OH and the corresponding NHC-O/Ni complex could make nickel anionic or could chelate Lewis acids to facilitate oxidative addition. Cl NHC 1 (1 mol%) Ph N N N PhMgBr (1.5 equiv) Ni O THF, 30 °C, 4h O R R N N N NHC 1 Cl Cl Cl Cl Cl N Me OMe CF3 88% 81% 91% 32% 61% Scheme 4. Select examples of Ni-catalyzed Kumada cross-coupling of aryl chlorides with the hydroxy-NHC/Ni complex (NHC 1). VII. Project Goals and Hypotheses. The previous studies on the Ni-catalyzed Suzuki and Kumada couplings supplied excellent indications regarding which ligands tend to work well (e.g. PCy3 and ICy). However, none of these ligands adequately overcome the energy barrier of oxidative addition, which limits the scope of the electrophile that can be used in the Ni-catalyzed cross-coupling reaction. Ligands bearing anionic arms pose a potential solution to lower this energy barrier and expand the scope through two different pathways. These ligands could facilitate the generation of an anionic nickel species or could participate in the push-pull system described above and thereby weaken the C(ar)—O 43 bond. Our hypothesis was two-fold: An anionic ligand can be used (1) to generate an anionic nickel species or (2) to synthesize a ligand bearing a pendant arm with the potential to coordinate to a Lewis acid and direct nickel into the C—OMe bond. Ligand targets were informed by previous attempts in the Ni-catalyzed cross-coupling of Ar-OMe and the literature reports of ligands bearing hydroxyl arms being used in Ni-catalyzed cross-coupling reactions.18,19 Results and Discussion There are some examples in the literature of ligand bearing anionic arms participating in cross-coupling reactions.18,19 The ligands reported by Nakamura and Anantharaman provide an excellent starting point for our investigations into the cross-coupling of Ar-OMe under Suzuki conditions with the goal of expanding the scope. Initially, we synthesized the hydroxyphosphine ligand developed by Nakamura (PO 1 in Scheme 5) before exploring novel hydroxyphosphine ligands.18 Relying on previous studies in the literature of cross-coupling Ar-OMe,9,10 we identified a novel ligand (PO 2 in Scheme 5) that has increased steric bulk relative to PO 1 and should therefore favor the oxidative addition of nickel into the C—OMe bond. Suzuki-Miyaura conditions - Ni(cod)2 (10 mol%) Kumada conditions - Ni(cod)2 (10 mol%) ligand (10 mol%) ligand (10 mol%) OMe or Ph OMe or Ph NHC 1 (10 mol%) NHC 1 (10 mol%) + O O + B Ph MgBr solvent, temp, time solvent, temp, time R Ph R R R Ligand targets - PPh OH N N N 2 PCy2 N N OH OH Ni O N Cl O PO 1 PO 2 NHC-OH N N N NHC 1 Scheme 5. General reaction schemes for Suzuki and Kumada cross-coupling reactions (top) and the ligand or complex targets (bottom). 44 Previous literature exploring Kumada cross-coupling with documented hydroxyphosphine ligands did not report any attempts at using aryl ethers as the electrophile. However, due to the reactivity they observed with aryl carbamates in addition to the computational studies supporting a bimetallic push-pull system, we hypothesized that hydroxyphosphine ligands could facilitate the cross- coupling of Ar-OMe under Kumada and Suzuki conditions. Thus, the hydroxyphosphine ligands provided a starting point for ligand tuning to optimize the product formation (Scheme 5). Because of the apparent success NHCs have at promoting the cross-coupling of Ar-OMe under Suzuki conditions, a third ligand target that is an NHC bearing a hydroxymethyl-substituted pyridine ring was also proposed (Scheme 5). The presence of the hydroxymethyl substituent allows the NHC ligand to participate in the push-pull system of the hydroxyphosphine ligands. Moreover, the hydroxy arm could be deprotonated and make nickel anionic. The hydroxy-NHC (NHC-OH, Scheme 5) we chose to study was the one reported by Anantharaman in their efficient catalysis of the Kumada cross-coupling of aryl chlorides.19 There is no precedent for this particular ligand promoting the oxidative addition of nickel into C(ar)—O bonds, but it could make nickel more anionic due to the oxygen arms similarly to the hydroxyphosphine ligands. After synthesizing the desired ligands, they were used under the best literature conditions for the Ni-catalyzed Suzuki- Miyaura cross-coupling of Ar-OMe.20 We started our investigation by following the best literature conditions but substituting PO 1 as the ligand (Table 1 entry 1). When initially there was no yield observed with the hydroxyphosphine ligand, the reaction conditions were varied21 to try to obtain the desired product (Table 1), and the other targeted ligands PO 2 and the bis-NHC-O/Ni complex were also tested. Prior literature reports suggested the Lewis acidity of magnesium could play a role in the overall reactivity of ligands bearing an anionic arm.18b Other literature provides computational evidence for the presence of Lewis acids facilitating the oxidative addition of nickel 45 into C—OMe bonds and cooperating in the process.12c,h,i,j,k Because of this, we explored the addition of various Lewis acids (Table 1 entries 2-5) and other additives (Table 1 entries 6-8) in an effort to generate a similar push-pull type system for oxidative addition to that suggested in literature.18 However, our experimental results showed the addition of Lewis acids under Suzuki conditions did not lead to the cross-coupling product (Table 1 entries 2-5 and 9-12).22 The results from the various Lewis acids screens suggest these ligands were not able to sufficiently stabilize the transition state leading to oxidative addition; the activation barrier for the RDS was not significantly lowered by these ligands under the conditions shown in Table 1. Often when NHC ligands are reported in the literature of Ar-OMe cross-couplings, they are stirred with a base (NaOtBu in this case) to generate the free carbene before adding to the reaction. Due to this, in some of our investigations with NHC-OH, we stirred our ligand with Ni(cod)2 and NaOtBu prior to adding the remainder of the reactants (Table 1 entry 11), but we saw no yield in our system. PO 1 was treated to the same prestir with Ni(cod)2 and NaOtBu to deprotonate the hydroxyl group. However, no product was observed in that case either, suggesting either deprotonation did not occur or the donating effect of the anionic group was not sufficient (Table 1 entry 12). Wang and Uchiyama provide computational support for PhMgBr donating a Ph group to Ni0 forming a reactive Ni-ate species.12e Because of the precedent, we attempted stirring the nickel, ligand, and a sub-stoichiometric amount PhMgBr for 15 minutes (Table 1 entries 13 and 14) to investigate the possible formation of a reactive Ni-ate species before adding the remainder of the reagents. This attempt also did not result in formation of product. Under the conditions shown in Table 1 entries 13 and 14, the most likely reason for lack of product formation is that a sub-stoichiometric amount PhMgBr was not able to adequately promote the desired push- pull mechanism 46 Table one shows the results of a variety of additives and bases, but none of the conditions shown resulted in the desired product with any of the ligands. Additional variations on these reaction conditions are provided in the experimental section but also do not afford product. With these negative results, and keeping in mind that these ligands and complexes with the exception of NHC-OH were reported for Kumada reactions, we next turned to exploring the cross-coupling of Ar-OMe with the more reactive Grignard nucleophile PhMgBr, as shown in Table 2. Table 1. Optimization and exploration of Ni-catalyzed Suzuki-Miyaura cross-coupling of Ar- OMe with hydroxyphosphine and hydroxy-NHC ligands. Ni(cod)2 (10 mol%) ligand (10 mol%) OMe or Ph O O NHC 1 (10 mol%) + B + Ph base, additive 1 toluene, 120 °C, 24h 2 3 Entry Additive (equiv) Base (equiv) Ligand Ni source 1 (%) 2 (%) 3 (%) 1 None CsF (3.0) PO 1 Ni(cod)2 >99 NR 48 2 MgBr2 (2.0) K3PO4 (3.0) PO 1 Ni(cod)2 >99 NR 52 3 LiBr (2.0) K3PO4 (3.0) PO 1 Ni(cod)2 >99 NR 49 4 ZnBr2 (2.0) K3PO4 (3.0) PO 1 Ni(cod)2 >99 NR 46 5 AlCl3 (2.0) K3PO4 (3.0) PO 1 Ni(cod)2 >99 NR 44 6 KF (2.0) K3PO4 (3.0) PO 1 Ni(cod)2 >99 NR 51 7 NaOtBu (2.0) K3PO4 (3.0) PO 1 Ni(cod)2 >99 NR 47 8 CsF (2.0) K3PO4 (3.0) PO 1 Ni(cod)2 >99 NR 48 9 MgBr2 (2.0) NaOH (5.0) PO 1 Ni(cod)2 >99 NR 43 10 MgBr2 (2.0) K3PO4 (3.0) NHC-OH Ni(cod)2 >99 NR 50 11 MgBr a 2 (2.0) K3PO4 (3.0) NHC-OH Ni(cod)2 >99 NR 48 12 ZnBr a 2 (2.0) K3PO4 (5.0) PO 1 Ni(cod)2 >99 NR 46 13 H2O (5.0) K3PO4 (5.0) NA NHC 1b >99 NR 54 14 None K3PO4 (5.0) NA NHC 1b >99 NR 50 15 None K3PO4 (5.0) PO 2 Ni(cod)2 >99 NR 2 16 H2O (1.0) K3PO4 (5.0) PO 2 Ni(cod)2 >99 NR 25 17 H2O (5.0) CsF (5.0) PO 2 Ni(cod)2 >99 NR 39 aLigand and Ni(cod)2 were stirred in toluene with NaOtBu (30 mol%) for 2 hours before adding to the reaction vial. bNHC 1 was stirred with PhMgBr (30 mol%) for 20 minutes before adding to the reaction vial. Since PO 1, PO 2, and NHC 1 had been used under Kumada conditions in the literature to couple other electrophiles but not aryl methyl ethers. We initially started the investigation with the more reactive nucleophile largely using the best literature conditions except substituting Ni(cod)2 47 for Ni(acac)2 (Scheme 3 and multiple entries in Table 2). Gratifyingly, the desired product was formed in calibrated GC yields up to 89% under Kumada conditions. Since all ligands and complexes shown in table 2 (PO 1, PO 2, NHC-OH, and NHC 1) allowed for the formation new C—C bonds from Ar-OMe, the next task was to determine if these ligands would allow for better reactivity than that seen with more conventional ligands (Table 2). Our experimental results show that the NHC-OH ligand (Table 2 entries 1 and 2) and the bis-NHC-O/Ni complex (Table 2 entries 3-6) both work but not as well as the hydroxyphosphine ligands (See SI for more data with the NHC ligands). Gratifyingly, both versions of the hydroxyphosphine ligand (PO 1 and PO 2) facilitated moderate to high yield in the coupling of 1-methoxynaphthalene with phenylmagnesium bromide. Entry 7 in Table 2 shows a 58% calibrated yield that increases to 71% when the temperature is raised to 60 °C (Table 2 entry 8), but the yield deteriorates as the temperature is increased further (Table 2 entry 9). Table 2. Optimization and exploration of Ni-catalyzed Kumada cross-coupling of Ar-OMe with hydroxyphosphine and hydroxy-NHC ligands. Ni(cod)2 (10 mol%) ligand (10 mol%) OMe or Ph NHC 1 (10 mol%) + Ph MgBr + toluene, temp, 24h 1 1.5 equiv 2 3 Entry Solvent Ligand Ni source Temp 1 (%) 2 (%) 3 (%) 1 THF NHC-OH Ni(cod)2 30 °C 93 <5 27 2 toluene NHC-OH Ni(cod)2 30 °C 72 41 82 3 THF NA NHC 1 30 °C 87 13 23 4 toluene NA NHC 1 30 °C 42 49 32 5 CPME NA NHC 1 30 °C 87 13 28 6 dioxane NA NHC 1 30 °C 99 2 20 7 toluene PO 1 Ni(cod)2 30 °C 35 58 48 8 toluene PO 1 Ni(cod)2 60 °C 27 71 47 9 toluene PO 1 Ni(cod)2 80 °C 26 65 48 10 THF PO 1 Ni(cod)2 60 °C 71 28 47 11 dioxane PO 1 Ni(cod)2 60 °C 66 33 39 12 CPME PO 1 Ni(cod)2 60 °C 74 25 38 13 toluene PO 2 Ni(cod)2 60 °C <2 89 8 48 When compared to a selection of other solvents, toluene resulted in the best product yield (Table 2 entries 10-12). PO 2 results in high yields when used under the optimized conditions for PO 1 (Table 2 entry 13), likely due to the increased electron donating ability of the cyclohexyl groups. Optimization of this reaction with hydroxyphosphine ligands resulted in the reaction giving moderate to high yields at a temperature of 60 °C. Both hydroxyphosphine ligands resulted in moderate to high yields of the cross-coupled product under Kumada conditions. To determine if the observed reactivity was due to the anionic pendant arm or not, the reaction results were compared to commercial PPh3 and PCy3 ligands (Table 3). PO 1 and PO 2 both resulted in better yields than PPh3 (Table 3 entries 2-4) suggesting the hydroxyphosphine ligands do facilitate Ni-catalyzed cross-coupling of Ar-OMe better than the original Wenkert conditions. Unfortunately, PO 1 and PO 2 both performed worse than the inexpensive, commercially available PCy3 at 24 hours and the optimized temperature (Table 3 entries 1, 2 and 4). This suggests the potential benefit of the anionic arm is not greater than the benefit derived from the alkyl groups. We further explored the reactivity of PO 2 and PCy3 by comparing the yield at lower temperatures (Table 3 entries 5 and 6), shorter reaction times (Table 3 entries 7 and 8), and with less reactive substrates (Table 3 entries 9-12) but in all cases, commercial PCy3 performed at least as well as the novel ligand suggesting that under these conditions, the presence of a hydroxyl arm is no better than three alkyl groups. Based on the previous literature, bulkier ligands like PCy3 tend to result in a better yield of the cross-coupling product.9,10 To explore if turning one alkyl ring into an aryl ring for PO 2 is responsible for the decreased performance, we compared PO 2 to a series of commercial ligands (PPh2Cy, PPhCy2, and PCy3). As shown in Table 3, the observed yield does not appear to heavily depend on the number of alkyl groups on the phosphine (entries 13-17). Nearly quantitative GC 49 yields are obtained for the series of commercial ligands (>99%) whereas PO 2 only resulted in a yield of 69% but when the ligand loading of PO 2 was increased to 20 mol%, a >99% GC yield was obtained. Table 3. Comparing the reactivity of hydroxyphosphine ligands to commercial, monodentate phosphine ligands. OMe Ni(cod)2 (10 mol%) Ph ligand (mol%) + Ph MgBr + toluene, 60 °C, 1 1.5 equiv time 2 3 Entry Ligand (mol%) Temp Time 1 (%) 2 (%) 3 (%) 1 PCy3 (20) 60 °C 24h <1 >99 24 2 PO 2 (10) 60 °C 24h <1 >99 27 3 PPh3 (20) 60 °C 24h 37 61 38 4 PO 1 (10) 60 °C 24h 19 74 45 5 PCy3 (20) 25 °C 24h <1 >99 22 6 PO 2 (10) 25 °C 24h 5 92 22 7 PCy3 (20) 60 °C 1h <1 99 29 8 PO 2 (10) 60 °C 1h 6 85 26 9a PCy3 (20) 60 °C 24h 15 84 30 10b PCy3 (20) 60 °C 24h 61 27 20 11a PO 2 (10) 60 °C 24h 84 15 25 12b PO 2 (10) 60 °C 24h 98 2 24 13 PCy3 (20) 60 °C 3h <1 >99 25 14 PPhCy2 (20) 60 °C 3h <1 >99 18 15 PPh2Cy (20) 60 °C 3h 2 >99 24 16 PO 2 (20) 60 °C 3h 2 >99 19 17 PO 2 (10) 60 °C 3h 4 69 39 aAnisole was used as the aryl ether. b2,6-dimethylanisole was used as the aryl ether. The ligand loading results of PO 2 suggest the benefits of a second phosphine attached to nickel outweigh the influence of possible Lewis acid chelation arising from the pendant arm. Additionally, the ligand comparison results show that just one alkyl group present on the phosphine is enough to facilitate a high yield under our conditions (Table 3) and PO 2 performs comparably at the same loading. As seen in these results, when PO 2 and similar commercial ligands are compared at the same ligand loading, similar yields are obtained. However, these results are not consistent with what would be expected if PO 2 binds to nickel in a bidentate fashion similar to what is shown in 50 Figure 4. These results indicate that a Ni:phosphine ratio of 1:2 is more advantages than the presence of a pendant arm. Additional studies including comparing PCy3 with PO 2 at the same ligand loading at room temperature and also with a variety of less reactive Ar-OMe are needed to fully understand these results. Following up on these results of our novel PO 2 being outperformed by commercial ligands, we explored the coupling of Ar-OMe under other coupling conditions. To our knowledge, there have not been any reports for the Ni-catalyzed Stille or Negishi cross-coupling of Ar-OMe, and an advancement in this area would be notable. We set up the corresponding reactions with PO 2 (Scheme 6) under conditions that have been successful with other phenolic electrophiles to test the reactivity with Ar-OMe. Our hypothesis was that since these nucleophiles are typically seen as more reactive than organoboron reagents, they would potentially allow for the cross-coupling of Ar-OMe. Unfortunately, there was no reaction observed and primarily starting material was observed in the GC chromatograph (Scheme 6). At this point in the development of hydroxyphosphine ligands, they appear to primarily be effective under Kumada conditions. This suggests two possibilities: (1) the presence of an organomagnesium reagent causes transmetalation to occur before oxidative addition or (2) organomagnesium can participate in the expected bimetallic mechanism while other nucleophiles cannot effectively fulfill this role. Importantly, this role in the bimetallic mechanism apparently cannot be filled by the addition of a Lewis acid, either. Stille conditions - Negishi conditions - Ph SnBu OMe 3 Ni(cod) (10 mol%) Ph OMe Ph ZnCl 2 Ni(cod)2 (10 mol%) Ph PO 2 (10mol%) PO 2 (10mol%) KF (3 equiv) dioxane, 80 °C, 24h >99% dioxane, 80 °C, 24h NR >99% NR Scheme 6. Reactions of an Ar-OMe under either Stille or Negishi conditions using PO 2. 51 As far as our investigations went, ligands bearing coordinating hydroxyl arms are not capable of facilitating the Ni-catalyzed cross-coupling of Ar-OMe under Suzuki-Miyaura conditions. This is displayed by the results in Table 1. When these ligands were applied to Ni- catalyzed Kumada conditions, they were found to be capable of facilitating the cross-coupling of Ar-OMe (Table 2). These ligands were effective at facilitating the Ni-catalyzed cross-coupling Ar- OMe under Kumada conditions in better yields than PPh3 but unfortunately were less effective than PCy3 (Table 3). After comparing PO 2 to the commercial phosphine ligands PPh2Cy, PPhCy2, and PCy3, we concluded that the hydroxymethyl substituent does not play a significant role in the performance of PO 2. Possible reasons for the observed lack of reactivity under Suzuki-Miyaura conditions include the deprotonated hydroxyl group was not able to coordinate to nickel or the coordination of an anionic group did not make the active nickel species sufficiently more nucleophilic to overcome the energy barrier but additional studies are needed to better understand the results described herein. Conclusion The purpose of this project was to develop an efficient Ni-catalyzed Suzuki-Miyaura cross- coupling of Ar-OMe that overcame the significant energy barrier leading to oxidative addition to widen the scope of this coupling reaction beyond the current limitations. There were two hypotheses going into this project: (1) generating an anionic nickel species through the application of a hydroxyphosphine ligand or some other anionic bidentate ligand would facilitate oxidative addition of nickel into the C—OMe bond, and (2) ligands bearing pendant arms could chelate to a Lewis acid, directing nickel to the C—OMe bond and facilitating oxidative addition. Our aim was to develop an effective Ni-catalyzed cross-coupling reaction of aryl methyl ethers through 52 developing ligands that would address the two points of our hypothesis and reduce the barrier of oxidative addition into the C—OMe bond. We were successful at synthesizing the targeted ligands bearing hydroxy pendant arms. When these ligands were tested under Suzuki-Miyaura conditions however, they were not able to facilitate the formation of the cross-coupled product. Why these ligands were not able to promote the cross-coupled product under Suzuki-Miyaura conditions remains unclear, but it is possible the coordination of the hydroxy group to nickel was disfavored, and added Lewis acids were not able to fill the chelating role. Under Kumada conditions, all the synthesized ligands and complexes led to the formation of the desired product, likely due to the more reactive nature of the organomagnesium reagents. Additionally, previously published computational results using hydroxyphosphine ligands under Kumada conditions suggest that the Grignard reagent chelates to both the hydroxymethyl substituent and the methyl ether, thereby facilitating oxidative addition. Unfortunately, PCy3 and other commercial ligands resulted in better yields than the hydroxyphosphine ligands. Our investigations also suggested that a Ni:P ratio of 1:2 is more advantageous than the presence of the hydroxy arm and the benefit it could provide as seen by the results of the ligand comparisons. Further exploration into this project should mainly be directed towards ligand development. Following up on the work with hydroxyphosphine ligands in this report, future investigations could include the synthesis of trialkyl-hydroxyphosphine ligands to have a better comparison to PCy3. Additional studies would explore why PCy3 and PCy2Ph result in better reaction yields than PO 2, since the yields do not appear to be strictly due to the substituents on phosphorous. Another type of ligand that could yield promising results would be a hydroxydiphosphine-type ligand (Figure 5). A ligand of this type could allow for two electron donating phosphorus atoms to be bound to the nickel atom leaving the pendant arm available for coordination to a Lewis acid. Ligands bearing 53 a semi-labile pendant arm in addition to atoms other than phosphorus able to bind to nickel (maybe an NHC) would be of interest as well (Figure 5). N N N N N N R N N R Cl OH PR2 PR2 OH OH Cl 2Cl HO PR2 N Cy Figure 5. Examples of bidentate ligands with the potential of an anionic pendant arm. Pursuing ligand of this type would allow for nickel to remain bound to two electron donating atoms throughout the catalytic cycle as suggested in the computations12j while facilitating the coordination of a Lewis acid to draw electron density away from the Car—OMe bond. A better understanding of the commercial ligands compared to PO 2 could be to look at their yields with less reactive Ar-OMe such as simple anisole derivatives or at lower temperatures. Other areas of investigation could include looking into the use of stronger bases and a pre-stir of the ligand and catalyst with various Lewis acids to form the hydroxyphosphine/Ni complex and set up the push- pull mechanism.18 It would be intriguing to synthesize hydroxyphosphine/Ni complexes and use them as the catalyst in further exploration in the cross-coupling of Ar-OMe. This would ensure the hydroxy arm is deprotonated and favored to follow the push-pull system described in the literature. This work, while not able to achieve our initial aim, provides a consistent synthesis of hydroxyphosphine ligands. The comparison of a novel hydroxyphosphine ligand to a series of commercial ligands under Kumada conditions is also presented. These hydroxyphosphine ligands could make nickel anionic once deprotonated, or they could act as a directing group by chelating through a Lewis acid. Both outcomes could make oxidative addition more attainable to a wider variety of Ar-OMe electrophiles. Experimentally, however, the hydroxyphosphine ligands are 54 ineffective under Suzuki-Miyaura conditions described herein at promoting the cross-coupling of Ar-OMe. Experimental Section General Materials and Methods. NMR spectra was recorded on a Bruker Ascend Avance NEO 400 MHz (400.132 MHz for 1H, 100.623 MHz for 13C, or 161.967 MHz for 31P) spectrometer. 1H and 13C NMR chemical shifts are reported in parts per million (ppm) relative to TMS, with the residual solvent used as an internal reference [1H: CHCl3 (7.26 ppm); 13C CDCl3 (77.16 ppm)].23 31P chemical shifts are reported in ppm relative to phosphoric acid. Multiplicities are reported as follows: doublet of doublets (dd), triplet of doublets (td), quartet (q), multiplet or multiple overlapping signals (m). GC data were collected using a Shimadzu GC-2010 Plus with a flame ionization detector equipped with a SH-Rxi-5ms capillary column (15 m x 0.25 mm ID x 0.25 μm df). Phenylboronic acid, LiCl, LiBr, ZnBr2, NaI, NH4F, CsF, Cs2CO3, NaF, 1-methylimidazole, 2- chloro-3-pyridinol, p-toluenesulfonic acid monohydrate, ethylene glycol, CPME, 2- bromobenzaldehyde, Mg turnings, 2-bromotoluene, PCy3, 4-methylanisole, and 2,6- dimethylanisole were obtained from Oakwood Chemical and used as received. Lithium aluminum hydride, neopentyl glycol, Ni(cod)2, potassium phosphate, aluminum chloride, calcium chloride, potassium fluoride, sodium tert-butoxide, sodium bromide, potassium tert-butoxide, 1- chloronaphthalene, NiCl2 • 6H2O, and 1,2-dibromoethane were obtained from Acros Organics as used as received. DCM, MgSO4, EtOAc, hexanes, Et2O, NaOH, NaCl, MgBr2, NH4Cl, KCl, MeCN, EtOH, and Na2SO4 were obtained from Fisher Chemical and used as received. Potassium diphenylphosphide, KBr, MgCl2, ZnCl2, Mg(ClO4)2, AlEt3, and AlMe3 were obtained from Sigma- 55 Aldrich and used as received. Chlorodicyclohexylphosphine, 2’-fluoroacetophenone, 1- methoxynaphthalene, PPh2Cy, anisole, NaBf4, and Li2CO3 were obtained from TCI America and used as received. Tributylphenylstannane, PPh3, NaCN, NaOEt, K2CO3, and MgO were obtained from Alfa Aesar and used as received. PPhCy2 was obtained from Strem Chemicals and used as received. CDCl3 was obtained from Cambridge Isotope Laboratories and used as received. 1,4- dioxane and phenylmagnesium bromide (1.6M in CPME, 4) were obtained from Acros in ACROSeal bottles (extra dry) and used as received. n-butyl lithium (2.5M in hexanes) and t-butyl lithium (1.7M in pentane) were obtained from Sigma-Aldrich in Sure/Seal bottles and used as received. THF and toluene were obtained from Fisher Chemical and degassed and dried with a JC Meyer solvent system prior to use. PO 1,18b NHC-OH,19 NHC 1,19 5,5-dimethyl-2-phenyl-1,3,2- dioxaborinane (5),24 (PPh3)2NiCl2,25 chlorophenylzinc,26 2-(2-bromophenyl)-1,3-dioxolane,27 and 1-[2-(diphenylphosphino)phenyl]ethenone, 28 dicyclohexyl[2-(1,3-dioxolan-2- yl)phenyl]phosphine29 and 2-(dicyclohexylphosphino)-benzaldehyde (6)29 were synthesized by literature procedures. General Procedure for Suzuki-Miyaura Cross-Coupling of Aryl Methyl Ethers. In a nitrogen atmosphere glovebox, the base (3.0 equiv or 5.0 equiv), 1 (14.5 μL, 0.1 mmol, 1.0 equiv), 5 (28.5 mg, 0.15 mmol, 1.5 equiv), and any indicated additives were combined in a one-dram vial equipped with a stir bar. In a second vial was prepared a stock solution of Ni(cod)2 and the appropriate ligand in toluene (0.033 mM with respect to nickel) or NHC 1 in toluene (0.033 mM with respect to nickel). 300 μL of the nickel stock solution was added to the reaction vial (0.01 mmol of nickel, 10 mol%). The vial was sealed with a cap with a PTFE-lined septum and removed from the glovebox. The reactions were stirred at 120 °C for 24 h unless otherwise indicated. Undecane (10.5 μL, 0.5 equiv) was then added as an internal GC standard and the vial was diluted to the top with 56 Et2O and mixed well. As aliquot of the reaction mixture was filtered through celite and analyzed by GC. Table 4. Extra optimization results for NHC-OH under the Suzuki conditions with various additives. OMe Ni(cod)2 (10 mol%) Ph O O ligand (10 mol%) + B + Ph base, additive 1 toluene, 120 °C, 24h 2 3 Entry Additive (equiv) Base (equiv) Ligand 1 (%) 2 (%) 3 (%) 1 Mg(ClO4)2 (2.0) K3PO4 (3.0) NHC-OH >99 NR NR 2 MgO (2.0) K3PO4 (3.0) NHC-OH >99 NR NR 3 MgBr2 (2.0) K3PO4 (3.0) NHC-OH >99 NR NR 4 MgCl2 (2.0) K3PO4 (3.0) NHC-OH >99 NR NR 5 Mg(ClO4)2 (2.0) NaOtBu (3.0) NHC-OH >99 NR NR 6 MgO (2.0) NaOtBu (3.0) NHC-OH >99 NR NR 7 MgBr2 (2.0) NaOtBu (3.0) NHC-OH >99 NR NR 8 MgCl2 (2.0) NaOtBu (3.0) NHC-OH >99 NR NR 9 ZnBr2 (2.0) NaOtBu (3.0) NHC-OH >99 NR NR 10 AlCl3 (2.0) NaOtBu (3.0) NHC-OH >99 NR NR 11 Mg(ClO4)2 (2.0) K a 3PO4 (3.0) NHC-OH >99 NR NR 12 MgO (2.0) K3PO4 (3.0) NHC-OHa >99 NR NR 13 MgBr2 (2.0) K3PO4 (3.0) NHC-OHa >99 NR NR 14 MgCl2 (2.0) K3PO a 4 (3.0) NHC-OH >99 NR NR 15 None K3PO4 (5.0) NHC-OHab >99 NR NR aLigand and Ni(cod)2 were stirred in toluene with NaOtBu (30 mol%) for 2 hours before adding to the reaction vial. bBoronic ester was stirred with nBuLi (1.0 equiv) for 5 minutes before placing in the freezer. Table 5. Extra optimization results of the Suzuki conditions using NHC 1 as the nickel source and testing various additives. OMe Ph O O NHC 1 (10 mol%) + B + Ph base, additive 1 toluene, 120 °C, 24h 2 3 Entry Additive (equiv) Base (equiv) Ni source 1 (%) 2 (%) 3 (%) 1 Mg(ClO4)2 (2.0) K3PO4 (3.0) NHC 1 >99 NR NR 2 MgO (2.0) K3PO4 (3.0) NHC 1 >99 NR NR 3 MgBr2 (2.0) K3PO4 (3.0) NHC 1 >99 NR NR 4 MgCl2 (2.0) K3PO4 (3.0) NHC 1 >99 NR NR 5 None K3PO4 (3.0) NHC 1 >99 NR NR ~Table 5 continued on the next page~ 57 ~Table 5 continued from the previous page~ 6 H2O (5.0) K3PO4 (5.0) NHC 1a >99 NR 54 7 None K3PO4 (5.0) NHC 1a >99 NR 50 8 None K3PO4 (5.0) NHC 1 >99 NR 62 9 AlMe3 (2.0) K3PO4 (5.0) NHC 1 >99 NR 52 10 AlEt3 (2.0) K3PO4 (5.0) NHC 1 >99 NR 74 aNHC 1 was stirred with PhMgBr (30 mol%) for 20 minutes before adding to the reaction vial. Table 6. Vials displaying the use of PMe3 nickel precatalysts that were effective for obtaining chemoselective cross-coupling of aryl-OTs over aryl-Cl. OMe Ph O O (PMe3)2Ni(X)(o-tolyl) (10 mol%) + B + Ph CsF (4.0 equiv) 1 toluene, 120 °C, 24h 2 3 Entry X 1 (%) 2 (%) 3 (%) 1 OTs >99 NR 48 2 Cl >99 NR 53 Table 7. Extra optimization results for NHC-OH under the Suzuki conditions with various additives. OMe Ni(cod)2 (10 mol%) Ph O O ligand (10 mol%) + B + Ph base, additive 1 toluene, 120 °C, 24h 2 3 Entry Additive (equiv) Base (equiv) Ligand 1 (%) 2 (%) 3 (%) 1 MgO (2.0) K3PO4 (3.0) PO 1 >99 NR NR 2 MgCl2 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 3 MgBr2 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 4 LiCl (2.0) K3PO4 (3.0) PO 1 >99 NR NR 5 LiBr (2.0) K3PO4 (3.0) PO 1 >99 NR NR 6 ZnCl2 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 7 ZnBr2 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 8 AlCl3 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 9 NaCl (2.0) K3PO4 (3.0) PO 1 >99 NR NR 10 KBr (2.0) K3PO4 (3.0) PO 1 >99 NR NR 11 CaCl2 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 12 KF (2.0) K3PO4 (3.0) PO 1 >99 NR NR 13 NaOtBu (2.0) K3PO4 (3.0) PO 1 >99 NR NR 14 K3PO4 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 15 K2CO3 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 16 NaOEt (2.0) K3PO4 (3.0) PO 1 >99 NR NR ~Table 7 continued on the next page~ 58 ~Table 7 continued from the previous page~ 17 NaI (2.0) K3PO4 (3.0) PO 1 >99 NR NR 18 NaBF4 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 19 NH4F (2.0) K3PO4 (3.0) PO 1 >99 NR NR 20 NaBr (2.0) K3PO4 (3.0) PO 1 >99 NR NR 21 NH4Cl (2.0) K3PO4 (3.0) PO 1 >99 NR NR 22 KCl (2.0) K3PO4 (3.0) PO 1 >99 NR NR 23 NaCN (2.0) K3PO4 (3.0) PO 1 >99 NR NR 24 CsF (2.0) K3PO4 (3.0) PO 1 >99 NR NR 25 KOtBu (2.0) K3PO4 (3.0) PO 1 >99 NR NR 26 Cs2CO3 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 27 NaF (2.0) K3PO4 (3.0) PO 1 >99 NR NR 28 Mg(ClO4)2 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 29 Li2CO3 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 30 AlEt3 (2.0) K3PO4 (3.0) PO 1 >99 NR NR 31 [(CH3)2CHO]3B (2.0) K3PO4 (3.0) PO 1 >99 NR NR 32 None K3PO4 (3.0) PO 1a >99 NR NR 33 MgBr2 (2.0) K3PO4 (3.0) PO 1a >99 NR NR 34 None K3PO4 (5.0) PO 1 >99 NR NR 35 MgBr2 (2.0) K3PO4 (5.0) PO 1 >99 NR NR 36 MgO (2.0) K3PO4 (5.0) PO 1 >99 NR NR 37 None NaOH (5.0) PO 1 >99 NR NR 38 MgBr2 (2.0) NaOH (5.0) PO 1 >99 NR NR 39 MgO (2.0) NaOH (5.0) PO 1 >99 NR NR 40 MgO (2.0) K3PO4 (5.0) PO 1a >99 NR NR 41 MgCl2 (2.0) K3PO4 (5.0) PO 1a >99 NR NR 42 ZnBr2 (2.0) K3PO4 (5.0) PO 1a >99 NR NR 43 None K3PO4 (5.0) PO 1ab >99 NR NR 44 None K3PO4 (5.0) PO 1 >99 NR 80 45 AlMe3 (2.0) K3PO4 (5.0) PO 1 >99 NR 78 46 AlEt3 (2.0) K3PO4 (5.0) PO 1 >99 NR 81 47 None K3PO4 (5.0) PO 2 >99 NR 2 48 H2O (1.0) K3PO4 (5.0) PO 2 >99 NR 25 49 H2O (1.0) NaOtBu (5.0) PO 2 >99 NR 30 50 H O (1.0) KOt 2 Bu (5.0) PO 2 >99 NR 18 51 H2O (1.0) CsF (5.0) PO 2 >99 NR 23 52 H2O (1.0) KF (5.0) PO 2 >99 NR 24 53c H2O (1.0) CsF (5.0) PO 2 >99 NR 19 54 H2O (5.0) CsF (5.0) PO 2 >99 NR 39 aLigand and Ni(cod)2 were stirred in toluene with NaOtBu (30 mol%) for 2 hours before adding to the reaction vial. bBoronic ester was stirred with nBuLi (1.0 equiv) for 5 minutes before placing in the freezer. cAlso had MgBr2 (2.0 equiv) in the reaction. General Procedure for Kumada Cross-Coupling of Aryl Methyl Ethers. In a nitrogen atmosphere glovebox, 1 (14.5 μL, 0.1 mmol, 1.0 equiv), 4 (93.8 μL, 0.15 mmol, 1.5 equiv), and any indicated 59 additives were combined in a one-dram vial equipped with a stir bar. In a second vial was prepared a stock solution of Ni(cod)2 and the appropriate ligand in toluene (0.033 mM with respect to nickel) or NHC 1 in toluene (0.033 mM with respect to nickel). 300 μL of the nickel stock solution was added to the reaction vial (0.01 mmol of nickel, 10 mol%). The vial was sealed with a cap with a PTFE-lined septum and removed from the glovebox. The reactions were stirred at 60 °C for 24 h unless otherwise indicated. Undecane (10.5 μL, 0.5 equiv) was then added as an internal GC standard and the vial was diluted to the top with Et2O and mixed well. As aliquot of the reaction mixture was filtered through celite and analyzed by GC. Table 8. Additional optimization results using NHC 1 or NHC-OH. Ni(cod)2 (10 mol%) ligand (10 mol%) OMe or Ph NHC 1 (10 mol%) + Ph MgBr + solvent, temp, time 1 2 3 Entry Solvent Ligand Ni source (mol%) Temp Time 1 (%) 2 (%) 3 (%) 1 THF NHC-OH Ni(cod)2 (10) 30 °C 24h 93 <5 27 2 THF NA NHC 1 (10) 30 °C 24h 33 67 34 3 toluene NHC-OH Ni(cod)2 (10) 30 °C 24h 72 41 82 4 toluene NA NHC 1 (10) 30 °C 24h 13 85 69 5 toluene NA NHC 1 (10) 30 °C 24h 64 35 43 6 toluene NA NHC 1 (10) 25 °C 24h 76 23 44 7a toluene NA NHC 1 (10) 30 °C 24h 73 19 30 8 toluene NA NHC 1 (10) 30 °C 24h 66 25 44 9b toluene NA NHC 1 (10) 30 °C 24h 40 40 56 10 toluene NA NHC 1 (10) 30 °C 2h 91 8 34 11 toluene NA NHC 1 (10) 30 °C 4h 75 14 34 12 toluene NA NHC 1 (10) 30 °C 8h 76 24 36 13 toluene NA NHC 1 (10) 30 °C 12h 61 39 42 14 toluene NA NHC 1 (10) 30 °C 24h 62 36 39 15 toluene NA NHC 1 (10) 30 °C 48h 44 50 40 16 toluene NA NHC 1 (2.5) 30 °C 24h 39 27 50 17 toluene NA NHC 1 (5.0) 30 °C 24h 37 27 48 18 toluene NA NHC 1 (10.0) 30 °C 24h 42 49 32 19 toluene NA NHC 1 (15.0) 30 °C 24h 47 43 30 20 toluene NA NHC 1 (20.0) 30 °C 24h 52 39 29 21 THF NA NHC 1 (10) 30 °C 24h 87 13 23 ~Table 8 continued on the next page~ 60 ~Table 8 continued from the previous page~ 22 toluene NA NHC 1 (10) 30 °C 24h 39 48 32 23 CPME NA NHC 1 (10) 30 °C 24h 87 13 28 24 dioxane NA NHC 1 (10) 30 °C 24h 99 2 20 25 DCM NA NHC 1 (10) 30 °C 24h >99 <1 41 26 toluene NA NHC 1 (10) 30 °C 24h 55 23 42 27 toluene NA NHC 1 (10) 60 °C 24h 41 24 41 28 toluene NA NHC 1 (10) 80 °C 24h 39 25 41 29 toluene NA NHC 1 (10) 100 °C 24h 37 26 39 30 toluene NA NHC 1 (10) 30 °C 24h 54 23 40 31 toluene NA NHC 1 (10) 30 °C 72h 53 22 40 32 toluene NA NHC 1 (10) 30 °C 24h 69 17 42 33 toluene NA NHC 1 (10) 30 °C 24h 45 26 53 34c toluene NA NHC 1 (10) 30 °C 24h 93 6 26 35d toluene NA NHC 1 (10) 30 °C 24h >99 <1 15 a1.0 equiv of PhMgBr was used. b2.0 equiv of PhMgBr was used. cAlMe3 (2.0 equiv) was added. dAlEt3 (2.0 equiv) was added. Table 9. Additional optimization results with the hydroxyphosphine ligands. OMe Ni(cod)2 (10 mol%) Ph ligand (mol%) + Ph MgBr + solvent, temp, time 1 2 3 Entry Solvent Ligand (mol%) Temp Time 1 (%) 2 (%) 3 (%) 1 toluene PO 1 (10) 30 °C 24h 35 58 48 2a toluene PO 1 (10) 30 °C 24h 96 13 20 3b toluene PO 1 (10) 30 °C 24h >99 <1 13 4 toluene PO 1 (10) 25 °C 24h 49 51 42 5 toluene PO 1 (10) 60 °C 24h 27 71 47 6 toluene PO 1 (10) 80 °C 24h 26 65 48 7 toluene PO 1 (10) 100 °C 24h 36 57 47 8 toluene PO 1 (10) 30 °C 24h 34 58 40 9 toluene PO 1 (10) 60 °C 24h 29 69 40 10 toluene PO 1 (12) 60 °C 24h 26 69 38 11 toluene PO 1 (15) 60 °C 24h 27 71 35 12 toluene PO 1 (20) 60 °C 24h 27 72 34 13 toluene PO 1 (10) 60 °C 24h 22 66 52 14 THF PO 1 (10) 60 °C 24h 71 28 47 15 dioxane PO 1 (12) 60 °C 24h 66 33 39 16 CPME PO 1 (15) 60 °C 24h 74 25 38 17 Et2O PO 1 (20) 60 °C 24h 44 60 42 18 toluene PO 1 (10) 60 °C 24h 25 68 50 19 toluene PO 1 (10) 40 °C 24h 26 63 49 ~Table 9 continued on the next page~ 61 ~Table 9 continued from the previous page~ 20 toluene PO 1 (10) 50 °C 24h 29 65 49 21 toluene PO 1 (10) 70 °C 24h 23 67 50 22 toluene PO 1 (10) 60 °C 2h 32 68 48 23 toluene PO 1 (10) 60 °C 6h 26 72 51 24 toluene PO 1 (10) 60 °C 10h 26 70 47 25 toluene PO 1 (10) 60 °C 24h 24 75 49 26 toluene PO 1 (10) 60 °C 48h 24 72 47 27 toluene PO 2 (10) 60 °C 24h <2 89 8 28c toluene PO 1 (10) 60 °C 24h 90 9 13 aAlMe3 (2.0 equiv) was added. bAlEt3 (2.0 equiv) was added. c o-tolylphenyl MgBr (1.5 equiv) was used. Table 10. Additional reactions exploring the performance of various ligands. OMe Ni(cod)2 (10 mol%) Ph ligand (mol%) + Ph MgBr + toluene, temp, time 1 2 3 Entry Ligand (mol%) Temp Time 1 (%) 2 (%) 3 (%) 1 PCy3 (20) 60 °C 2h <1 >99 25 2 PCy3 (20) 60 °C 6h <1 90 22 3 PCy3 (20) 60 °C 8h <1 >99 25 4 PCy3 (20) 60 °C 24h <1 >99 24 5 PO 2 (10) 60 °C 2h <1 85 26 6 PO 2 (10) 60 °C 6h <1 90 26 7 PO 2 (10) 60 °C 8h <1 94 26 8 PO 2 (10) 60 °C 24h <1 >99 27 9 PPh3 (20) 60 °C 24h 37 61 38 10 PO 1 (10) 60 °C 24h 19 74 45 11 PCy3 (20) 25 °C 24h <1 >99 22 12 PO 2 (10) 25 °C 24h 5 92 22 13 PCy3 (20) 60 °C 30min <1 96 4 14 PCy3 (20) 60 °C 1h <1 99 29 15 PCy3 (20) 60 °C 1.5h <1 98 30 16 PCy3 (20) 60 °C 2h <1 98 27 17 PCy3 (20) 60 °C 2.5h <1 97 27 18 PCy3 (20) 60 °C 3h <1 95 27 19 PO 2 (10) 60 °C 30min 13 94 30 20 PO 2 (10) 60 °C 1h 6 85 26 21 PO 2 (10) 60 °C 1.5h 5 86 27 22 PO 2 (10) 60 °C 2h <1 82 26 23 PO 2 (10) 60 °C 2.5h <1 81 25 24 PO 2 (10) 60 °C 3h <1 84 25 25 PCy3 (20) 60 °C 24h <1 >99 23 ~Table 10 continued on the next page~ 62 ~Table 10 continued from the previous page~ 26 PCy3 (10) 60 °C 24h <1 95 29 27 PPhCy2 (20) 60 °C 24h <1 >99 17 28 PPhCy2 (10) 60 °C 24h <1 >99 20 29 PCy3 (20) 60 °C 24h <1 >99 27 30 PPhCy2 (20) 60 °C 24h <1 >99 17 31 PPh2Cy (20) 60 °C 24h <1 >99 23 32 PCy3 (20) 60 °C 3h <1 >99 25 33 PCy3 (10) 60 °C 3h <1 96 30 34 PPhCy2 (20) 60 °C 3h <1 >99 18 35 PPhCy2 (10) 60 °C 3h <1 97 23 36 PPh2Cy (20) 60 °C 3h 2 >99 24 37 PPh2Cy (10) 60 °C 3h <1 >99 25 38 PO 2 (20) 60 °C 3h 2 >99 19 39 PO 2 (10) 60 °C 3h 4 69 39 Synthesis of (2-(Dicyclohexylphosphino)phenyl)methanol PO 2. Synthesized by a modified literature procedure.18b In a nitrogen atmosphere glovebox, LiAlH4 (28.1 mg, 0.74 mmol, 1.5 equiv) and THF (5mL) were added to an oven-dried 25 mL round bottom flask and 6 was dissolved in 3 mL of THF in a 20 mL vial and sealed with a rubber septum. The round bottom flask was removed from the glovebox and cooled to 0 °C while stirring under nitrogen. While stirring at 0 °C, 6 was added dropwise over 10 minutes with nitrogen pressure. Then the reaction mixture was stirred for 30 minutes at 0 °C before diluting with another 5 mL of THF, treating successively with degassed H2O (0.1 mL), degassed 15% aq. NaOH (0.1 mL), and degassed H2O (0.3 mL). The RBF containing the reaction mixture was brought back into the glovebox and filtered through a short silica plug under vacuum and washed with Et2O (5 mL) and DCM (1.5 mL). After this, the filtrate was transferred to a 20 mL vial, capped loosely, placed in a vacuum chamber which was sealed, the chamber was removed from the glovebox, and all volatiles were removed under hi-vac. Once all volatiles were removed, the product was purified by KugelRohr. This was achieved by bringing the vacuum chamber with the crude product inside back into the glovebox, the crude product was transferred into a 50 mL RBF, sealed with a rubber septum, removed from the glovebox, and 63 attached to the KugelRohr after flushing the system with nitrogen. Once the distillation was complete, the RBF containing the product was removed, quickly sealed with a rubber septum, and transferred into the glovebox. Once inside the glovebox, the product was dissolved in DCM (3 mL) and filtered through a short silica plug under vacuum to remove any phosphine oxides. The filtrate was transferred to a 20 mL vial, capped loosely, placed in a vacuum chamber which was sealed, removed from the glovebox, and placed under hi-vac to remove all volatiles. PO 2 was obtained as a viscous opaque oil was obtained after all volatiles were removed to result in a 80% yield of 121.7 mg. 1H NMR (400 MHz, CDCl3, δ): 7.51-7.45 (m, 1H), 7.37-7.26 (multiple signals, 3H), 4.86 (dd, J = 7.3, 1.4 Hz, 2H), 3.05 (q, J = 7.3 Hz, 1H), 2.01-1.88 (multiple signals, 3H), 1.65 (td, J = 46.5, 12.1 Hz, 8H), 1.38-0.97 (multiple signals, 11H); 13C{1H} NMR (100 MHz, CDCl3, δ): 147.1 (d, JCP = 24.0 Hz), 132.4 (d, JCP = 17.9 Hz), 132.3 (d, JCP = 3.3 Hz), 128.3, 127.8 (d, JCP = 7.4 Hz), 126.3, 64.2 (d, JCP = 18.3 Hz), 32.9 (d, JCP = 10.1 Hz), 29.7 (d, JCP = 16.2 Hz), 28.2 (d, JCP = 7.6 Hz), 26.3 (d, JCP = 12.5 Hz), 26.1 (d, JCP = 8.0 Hz), 24.8; 31P{1H} NMR (162 MHz, CDCl3, δ): -15.3. 64 References 1. Tasker, S., Standley, E. & Jamison, T. Recent advances in homogeneous nickel catalysis. 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Chem. Soc. 2016, 138, 6711−6714; (g) Wititsuwannakul, T.; Tantirungrotechai, Y.; Surawatanawong, P. Density Functional Study of Nickel N‑Heterocyclic Carbene Catalyzed C−O Bond Hydrogenolysis of Methyl Phenyl Ether: The Concerted β‑H Transfer Mechanism. ACS Catal. 2016, 6, 1477−1486; (h) Xu, L.; Chung, L. W.; Wu, Y.- D. Mechanism of Ni-NHC Catalyzed Hydrogenolysis of Aryl Ethers: Roles of the Excess Base. ACS Catal. 2016, 6, 483−493; (i) Kojima, K.; Yang, Z.-K.; Wang, C.; Uchiyama, M. Ethereal C–O Bond Cleavage Mediated by Ni(0)-Ate Complex: A DFT Study. Chem. Pharm. Bull. 2017, 65, 862–868; (j) Schwarzer, M. C.; Konno, R.; Hojo, T.; Ohtsuki, A.; Nakamura, K.; Yasutome, A.; Takahashi, H.; Shimasaki, T.; Tobisu, M.; Chatani, N.; Mori, S. Combined Theoretical and Experimental Studies of Nickel-Catalyzed Cross-Coupling of Methoxyarenes with Arylboronic Esters via C–O Bond Cleavage. J. Am. Chem. Soc. 2017, 139, 10347–10358; (k) Uthayopas, C.; Surawatanawong, P. Aryl C–O oxidative addition of phenol derivatives to nickel supported by an N-heterocyclic carbene via a Ni0 five-centered complex. Dalton Trans. 2019, 48, 7817–7827; (l) Liu, C.-Y.; Wititsuwannakul, T.; Hsieh, C.-H.; Tsai, C.-Y.; Wang, T.-H.; Ambre, R.; Chen, W.-C.; Surawatanawong, P.; Ong, T.-G. Nickel-mediated cross-coupling via C–O activation assisted by organoaluminum. J. Chin. Chem. Soc. 2020, 67, 376–382. 13. For a complete discussion on the differences in calculated energies when dispersion is and is not included: Hooker, L. V.; Neufeldt, S. R. Ligation state of nickel during C—O bond activation with monodentate phosphines. Tetrahedron, 2018, 74, 6717–6725. 14. (a) Tobisu, M.; Yasutome, A.; Kinuta, H.; Nakamura, K.; Chatani, N. Org. Lett. 2014, 16, 5572−5575; (b) Zhang, J.; Xu, J.; Xu, Y.; Sun, H.; Shen, Q.; Zhang, Y. Organometallics, 2015, 34, 5792–5800. 66 15. For examples see: (a) Tobisu, M.; Xu, T.; Shimasaki, T.; Chatani, N. Nickel-Catalyzed Suzuki–Miyaura Reaction of Aryl Fluorides. J. Am. Chem. Soc. 2011, 133, 19505–19511; (b) Yu, D.-G.; Li, B.-J.; Zheng, S.-F.; Guan, B.-T.; Wang, B.-Q.; Shi, Z.-J. Direct Application of Phenolic Salts to Nickel-Catalyzed Cross-Coupling Reactions with Aryl Grignard Reagents. Angew. Chem. Int. Ed. 2010, 49, 4566–4570; (c) Yu, D.-G.; Shi, Z.-J. NHC-Cu-Catalyzed Enantioselective Hydroboration of Acyclic and Exocyclic 1,1- Disubstituted Aryl Alkenes. Angew. Chem. Int. Ed. 2011, 50, 7097–7100; (d) Muto, K.; Yamaguchi, J.; Itami, K. Nickel-Catalyzed C–H/C–O Coupling of Azoles with Phenol Derivatives. J. Am. Chem. Soc. 2012, 134, 169–172; (e) Ehle, A. R.; Zhou, Q.; Watson, M. P. Nickel(0)-Catalyzed Heck Cross-Coupling via Activation of Aryl C–OPiv Bonds. Org. Lett. 2012, 14, 1202–1205; (f) Tobisu, M.; Nakamura, K.; Chatani, N. Nickel-Catalyzed Reductive and Borylative Cleavage of Aromatic Carbon–Nitrogen Bonds in N-Aryl Amides and Carbamates. J. Am. Chem. Soc. 2014, 136, 5587–5590; (g) Correa, A.; León, T.; Martin, R. Ni-Catalyzed Carboxylation of C(sp2)– and C(sp3)–O Bonds with CO2. J. Am. Chem. Soc. 2014, 136, 1062–1069; (h) Koch, E.; Takise, R.; Studer, A.; Yamaguchi, J.; Itami, K. Ni-Catalyzed α-arylation of esters and amides with phenol derivatives. Chem. Commun. 2015, 51, 855–857. 16. For selected examples, see: (a) Yoshikai, N.; Matsuda, H.; Nakamura, E. Ligand Exchange as the First Irreversible Step in the Nickel-Catalyzed Cross-Coupling Reaction of Grignard Reagents. J. Am. Chem. Soc. 2008, 130, 15258–15259; (b) Bryan, Z. J.; McNeil, A. J. Evidence for a preferential intramolecular oxidative addition in Ni-catalyzed cross- coupling reactions and their impact on chain-growth polymerizations. Chem. Sci. 2013, 4, 1620–1624; (c) Sontag, S. K.; Bilbrey, J. A.; Huddleston, N. E.; Sheppard, G. R.; Allen, W. D.; Locklin, J. π-Complexation in Nickel-Catalyzed Cross-Coupling Reactions. J. Org. Chem. 2014, 79, 1836–1841. 17. For an example, see Martin, R.; Buchwald, S. L. Palladium-Catalyzed Suzuki−Miyaura Cross-Coupling Reactions Employing Dialkylbiaryl Phosphine Ligands. Acc. Chem. Res. 2008, 41, 1461–1473. 18. (a) Yoshikai, N.; Mashima, H.; Nakamura, E. Nickel-Catalyzed Cross-Coupling Reaction of Aryl Fluorides and Chlorides with Grignard Reagents under Nickel/Magnesium Bimetallic Cooperation. J. Am. Chem. Soc. 2005, 127, 17978–17979; (b) Yoshikai, N.; Matsuda, H.; Nakamura, E. Hydroxyphosphine Ligand for Nickel-Catalyzed Cross- Coupling through Nickel/Magnesium Bimetallic Cooperation. J. Am. Chem. Soc. 2009, 131, 9590–9599. 19. Bhat, I. A.; Avinash, I.; Anantharaman, G. Nickel(II)- and Palladium(II)-NHC Complexes from Hydroxypyridine Functionalized C,O Chelate Type Ligands: Synthesis, Structure, and Catalytic Activity toward Kumada–Tamao–Corriu Reaction. Organometallics, 2019, 38, 1699–1708. 20. The best literature conditions:10 Ar-OMe (1.0 equiv), organoboron (1.5 equiv), Ni(cod)2 (3 mol%), ligand (3 mol%), CsF (2.0 equiv) in toluene (300 uL) at 120 °C for 24h. 67 21. All optimization with the hydroxyphosphine ligands were conducted with the triaryl- hydroxyphosphine ligand due to the easier synthesis and more stable nature of the ligand. 22. It is worth noting that Tobisu and Chatani think the coordination of an ether oxygen to a Lewis acid, MgI2 is unlikely based on their experimental observations.12f 23. Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. Organometallics 2010, 29, 2176–2179. 24. Entz, E. D.; Russell, J. E. A.; Hooker, L. V.; Neufeldt, S. R. Small Phosphine Ligands Enable Selective Oxidative Addition of Ar−O over Ar−Cl Bonds at Nickel(0). J. Am. Chem. Soc. 2020, 142, 15454−15463. 25. Standley, E. A.; Smith, S. J.; Müller, P.; Jamison, T. F. A Broadly Applicable Strategy for Entry into Homogeneous Nickel(0) Catalysts from Air-Stable Nickel(II) Complexes. Organometallics 2014, 33, 2012–2018. 26. Chen, Y.; Tang, M.; Wu, Y.; Su, X.; Li, X.; Xu, S.; Zhuo, S.; Ma, J.; Yuan, D.; Wang, C.; Hu, W. A One-Dimensional π–d Conjugated Coordination Polymer for Sodium Storage with Catalytic Activity in Negishi Coupling. Angew. Chem. Int. Ed. 2019, 58, 14731– 14739. 27. He, B.; Zheng, L.-S.; Phansavath, P.; Ratovelomanana-Vidal, V. RhIII-Catalyzed Asymmetric Transfer Hydrogenation of α-Methoxy β-Ketoesters through DKR in Water: Toward a Greener Procedure. ChemSusChem, 2019, 12, 3032–3036. 28. Coote, S. J.; Dawson, G. J.; Frost, C. G.; Williams, J. M. J. The Preparation of Functionalised Aryl Phosphines from Aryl Fluorides by Nucleophilic Aromatic Substitution with Potassium Diphenylphosphide. Synlett 1993, 7, 509–510. 68 CHAPTER FIVE CONCLUSION This body of research shows that nickel is an effective catalyst to obtain new C—C bonds in multiple cross-coupling systems using C—O electrophiles that are largely inaccessible electrophiles under palladium catalysis. Chapter 2 explored the development of a Ni-catalyzed Stille cross-coupling of phenol-derived electrophiles through catalytic and stoichiometric experimental studies, supported by computational studies. We were able to provide strong experimental evidence for nickel being able to catalyze the cross-coupling of aryl sulfamates under Stille coupling conditions. Additionally, we were able to show this methodology supports coupling organostannanes with aryl tosylates and aryl mesylates. Our Ni-catalyzed system shows promise for constructing difficult bonds from aryl sulfamates and organostannanes, specifically aryl- heteroaryl, aryl-alkenyl, and aryl-alkynyl bonds that were largely inaccessible from other cross- coupling methods employing non-triflate phenol derivatives. This work overcame the limitations of homocoupling, thus enabling Stille cross-coupling at a variety of phenolic derived sites. In addition, computational studies provided insight into why this system was successful in comparison to previous studies. Through computational studies, we were able to study the transmetalation step of the catalytic cycle to learn how our system worked and possible reasons why previous attempts were unsuccessful. The DFT studies showed that when a chloride source is present in the reaction, a Ni(II)-chloride species is generated resulting in an energy barrier of ΔG‡ = 24.3 kcal/mol to reach the required transition state. However, when no chloride is present, the most favored pathway is through an eight-centered transition state involving KF and the organostannane resulting in an 69 energy barrier of ΔG‡ = 15.0 kcal/mol. This data suggests transmetalation is significantly slower when a Ni(II)-chloride species is involved due to the increased energy barrier of the transition state. Experimental results using Ni(II)-Cl and Ni(II)-sulfamate oxidative addition complexes as catalysts allowed us to explore this inhibitory effect further. Experimental results confirmed that chloride could replace sulfamate and result in a more stable nickel complex that would prevent transmetalation. The importance of KF was also confirmed experimentally supporting the eight-centered transition state found by DFT. When the fluoride counterion was changed, the product yield was greatly reduced or completely inhibited. These experimental results combined with computational results provide a possible explanation of why Percec’s attempt at developing a Ni-catalyzed Stille cross-coupling of aryl mesylates was unsuccessful, resulting primarily in homocoupling.1 Our work showed the avoidance of chloride sources, the inclusion of KF, and the application of mono-, di-, or trialkylphosphine ligands resulted in a wide variety of aryl sulfamates and organostannanes undergoing cross-coupling in excellent yields. The computations suggested the presence of chloride in the reaction leads to a stable Ni(II) oxidative addition complex which inhibits transmetalation. Our computational studies suggest KF is crucial in transmetalation because of the formation of an eight-centered transition state. Experimental results confirmed the importance of KF for this reaction through exploring various fluoride counterions and the absence of KF. We successfully developed a system that OTf cat. Ni(0) OTf cat. Ni(0) R phosphine A phosphine B tolerated a wide variety of substrates and R SnBu3 R SnBu3 explored the mechanism. Through the course of R Cl Cl Scheme 1. Proposed chemoselective Ni- the project a couple of areas of further exploration catalyzed Still coupling. 70 arose that were out of the project scope at the time. It would be intriguing to further investigate the observed inhibitory effect of chloride and if it extends to other halides or to triflate. The inhibitory effect of chloride comes from forming a stable Ni(II)-chloride complex during oxidative addition making the activation barrier for transmetalation prohibitive. This could provide further insight into the inhibitory effect, especially if more reactive halides or triflate doesn’t hinder product formation. Assuming that triflate does not inhibit the transmetalation step, it would be interesting to see if a triflate could outcompete chloride for binding with nickel, preventing the Ni(II)-chloride species from forming. From the experimental results in chapter 2, we know that once the Ni(II)- chloride species is formed it cannot be displaced by sulfamate. However, since chloride and triflate are more similar in their reactivities, it is conceivable that triflate might be able to displace chloride, allowing the catalytic cycle to proceed. If the inhibitory effect could be overcome, it is conceivable that a triflate-selective Ni-catalyzed Stille cross-coupling could be developed, adding to the toolbox of Ni-catalyzed chemoselectivity (Scheme 1). A - Percec’s conditions cat. NiCl2(PPh3)2 MeO C OMs + Ph SnBu MeO2C Ph + MeO2C CO2Me 2 3 Zn, Et4NI, THF, 67 ºC (24%) (64%) B - Combined conditions OMs cat. Ni(cod) Ph cat. Ni(cod) OSO NMe 2 2 2 2 PPhEt2 PPhEt2 + Ph SnBu Ph SnBu 3 + Zn, Et4NI Zn, Et4NI 3 THF, 67 ºC THF, 67 ºC CO2Me CO2Me CO2Me Scheme 2. (A) Percec’s conditions leading to homocoupling of the aryl mesylate and (B) a proposed combination of conditions to further study why no homocoupling was observed in our work. Another possible topic for further study would be revisiting Percec’s1 results and switching the NiCl2(PPh3)2 catalyst to our Ni(cod)2/PPhEt2 catalyst but otherwise keeping their conditions the 71 same (Scheme 2). This could provide further experimental insight into why they obtained homocoupling as the major product and allow for further understanding the importance of the fluoride ion in facilitating Ni-catalyzed Stille cross-coupling. Chapter 3 explored chemoselectivity of chloroaryl tosylates in Ni-catalyzed Suzuki- Miyaura cross-coupling. This investigation showed that coupling at the tosylate site was favored over chloride due to a combination of ligand sterics and electronics unique to small phosphine ligands. Through a combination of DFT calculations and experiments, stoichiometric and catalytic, we identified a variety of ligands that resulted in excellent selectivity of C—OTs bonds in the presence of C—Cl bonds. Our studies focused on the oxidative addition step of the catalytic cycle since chemoselectivity is usually determined during this step due to oxidative addition being the rate determining step. To our knowledge, this work demonstrates the first experimentally evaluated use of PMe3 in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions. We were surprised by the initial DFT calculations that showed that PMe3 resulted in selective reaction at the C—OTs bond in the presence of C—Cl bonds. DFT studies predicted a preference for reaction at tosylate in the following order, PMe3 > PCy3 > PPh3. This order was substantiated by stoichiometric oxidative addition studies that evaluated a selection of phosphine ligands with a variety of electronic and steric properties. Triaryl phosphines promote exclusive reaction at C—Cl bonds while tri- and dimethyl phosphines are the only types of phosphines that promote selective reaction at tosylate in this system. Further DFT calculations suggest that unlike other literature examples of chemoselective cross-couplings, our system does not appear to rely on the ligation state of nickel. Instead, selectivity in our Ni-catalyzed system likely is controlled through a combination of electronic and steric factors that are typical of small phosphine ligands. 72 After exploring the origin of selectivity through computations and experiments, we demonstrated this tosylate-selective Suzuki-Miyaura reaction catalyzed by Ni/PMe3 tolerated a variety of boronic ester coupling partners and aryl tosylates. This scope maintained excellent selectivity for reaction at the C—OTs bond. We successfully developed a reliable pathway to a Ni-catalyzed Suzuki-Miyaura cross-coupling of aryl tosylates in the presence of aryl chlorides with high selectivity but there are a few areas that could be improved or explored further. Throughout the development of our chemoselective Ni-catalyzed Suzki-Miyaura cross- coupling, there were reproducibility issues that would be fixed by synthesizing a fresh batch of the desired precatalyst. Further investigation into the precatalyst decomposition pathway would be advantageous to better understand nickel precatalysts. Literature precedent suggests the catalytically active Ni(0) species and an unactivated Ni(II) precatalyst could undergo comproportionation resulting in a low-reactivity Ni(I) species (Scheme 3).2 The proposed investigation would likely entail EPR studies comparing freshly synthesized precatalyst to an older batch and explore various aryl substituents and the effect they have on catalyst decomposition. R’ activation R’ R P +base R3P 0 comproportionation X 3 Ni R P I II + R” 3 + NiI Ni X Ni (HO) B PR3 R’ R3P PR3 PR3 2 R’ PR catalytically R 3 3P active NiII metastable, stable, X PR less catalytically active catalytically poor R” 3 oxidative addition catalysis Scheme 3. Comproportionation of Ni(II) and Ni(0) to form Ni(I) as suggested in previous literature. Another unanswered question from this work stems from the observation of one of the chloroaryl tosylates resulting in diarylation as the major product, the o-chlorophenyl tosylate. Understanding why this occurs could help increase the knowledge of our chemoselective system 73 and the catalytic cycle. We hypothesize that after finishing the reductive elimination step of the catalytic cycle, nickel is still closely associated with the substrate due to π-complexation and therefore prefers to undergo oxidative addition with the C—Cl bond instead of dissociating completely to react with a new C—OTs bond. Previous experimental and computational studies suggest that after reductive elimination, the π-complexation can persist and nickel will walk to the next reactive site instead of dissociating and forming a new π-complex.3 One potential reason diarylation was only observed with the o-chlorophenyl tosylate is likely due to the proximity of the second reactive site meaning nickel would not have to walk very far to undergo oxidative addition. This is supported by previous studies that also suggest that continuing π-complexation of nickel to the substrate after reductive elimination is not thermodynamically favorable for cross- coupling reactions of polyhaloarenes.3a To confirm if this is the case, time trials of this reaction would need to be performed to determine if one product is indeed forming faster than the other and then watching how the product ratios track. Another way to investigate the hypothesis of the π-complexation favoring nickel oxidatively adding into the C—Cl bond after cross-coupling with C—OTs, would be to perform an intermolecular competition reaction of both monoarylated products (Scheme 4); a reaction occurring primarily at the C—OTs bond would indicate a π- complex between the catalyst and substrate leads to diarylation. Understanding this diarylation process in our chemoselective method would help understand the catalytic cycle and how it changes with different substitution patterns of the substrate. OTs Ph O (PMe3)2Ni(OTs)(1-naphthyl) (5 mol%) Ph + + Ph B Ph Cl O K3PO4 (6 equiv), H2O (50 mol%) 1,4-dioxane, 80 °C Ph Scheme 4. Showing the application of authentic monoarylated products to from the diarylated product to determine if π-complexation is responsible for the observed diarylation.4 74 Chapter 4 detailed the exploration of Ni-catalyzed cross-coupling reactions using aryl methyl ethers as the electrophile. We started our investigation by synthesizing ligands bearing anionic arms, hydroxyphosphine and NHC ligands, that would add electron density to nickel allowing it to add into the electron-dense C—OMe bond more effectively. Initially, our goal was to use these ligands to facilitate the coupling of Ar-OMe under relatively mild Suzuki-Miyaura conditions. Unfortunately none of the ligands we synthesized were able to promote any cross- coupling of Ar-OMe with organoboron reagents. Our secondary goal was to show the first use of hydroxyphosphine ligands or hydroxy-NHC ligands in the Ni-catalyzed Kumada cross-coupling of Ar-OMe. While the bis-NHC-O/Ni complex facilitated low yields of the cross-coupled product, the two hydroxyphosphine ligands promoted the formation of the desired product in moderate to high yields. However, while determining if the observed yield was due to the anionic arm on the hydroxyphosphine ligand, we found commercial PCy3 was at least as good as the best performing hydroxyphosphine ligand. Even though the application of hydroxyphosphine ligands proved to be no better at promoting the Ni-catalyzed Kumada cross-coupling of Ar-OMe than PCy3, we were able to establish that hydroxyphosphine ligands were capable at promoting the formation of the cross-coupled product from Ar-OMe. Additionally, we established a reliable pathway to synthesize a novel dialkylaryl-hydroxyphosphine ligand in moderate yields. Our initial goal was not met but that leaves the door open for various future avenues of research into this field of study. The focus of this project was the synthesis and application of different ligands of the phosphine and NHC varieties bearing an anionic arm to obtain better reactivity of aryl methyl ethers. These arms would ideally be able to increase the electron density around nickel. While we were successful at synthesizing a few different ligands, they were not able to promote cross- coupling under Suzuki and or Kumada conditions in comparison to PCy3. Literature shows that 75 PCy3 works well under Kumada conditions5 and exhibits some reactivity under Suzuki conditions6 (Scheme 5A). Therefore, it would be intriguing to develop a synthesis of trialkyl- hydroxyphosphine ligands that bear significant steric bulk and show excellent s-donating ability (Scheme 5B). The further exploration and development of NHC ligands bearing various anionic arms could also lead to a solution to the low reactivity of aryl methyl ethers (Scheme 5C). A - Dankwardt 2004 (left) and Tobisu, Chatani 2008 (right) OMe NiCl (PCy ) (5 mol%) Ph Ph Ni(cod) (5 mol%) OMe 2 3 2 2 PCy3 (10 mol%) PCy3 (10 mol%) + Ph MgBr O O + (EtO)2CH2, Et2O, 35 ºC, 15h CsF (2.25 equiv) B Me Me toluene, 120 °C, 12h Ph 93% 84% B - Possible hydroxyphosphine ligand targets C - Possible NHC targets PCy2 R PCy2 PtBu2 N Cy N N N Cy N N Cy OH OH OH N R Cl Cl Cl R R R OH OH R OH Scheme 5. (A) Examples of PCy3 working with nickel to efficiently couple Ar-OMe under Kumada and Suzuki conditions. Possible hydroxyphosphine ligand (B) and NHC targets (C). A final area of further investigation arises from the results with either very little added ligand or no ligand at all (Scheme 6). These reactions resulted in a low yield suggesting that there could be the potential to develop a Ni-catalyzed Kumada cross-coupling of Ar-OMe in the absence of any added ligand which has not been reported in the literature. To rule out other reaction pathways, a reaction was run under the same conditions but without any nickel and no product was observed. Unfortunately, the yield without any added ligand is poor (<40%), but with further investigation and optimization, this yield could OMe Ph MgBr Ph Ni(cod)2 (10 mol%) + Ph likely be improved. Currently there are other toluene, 60 °C, 24h Ph 37% 64% projects in the Neufeldt lab investigating ligand- Scheme 6. Preliminary ligand-free results. free catalysis, these projects could inform how a 76 Ni-catalyzed Kumada coupling of Ar-OMe could be developed and improved. Developing a ligand-free Ni-catalyzed Kumada cross-coupling of Ar-OMe would contribute to the small body of work already established7 by using a less-reactive electrophile. The research described herein focused on studying Ni-catalyzed cross-coupling reactions of phenolic electrophiles. All three of these projects explored different cross-coupling reactions, each with a different phenol-derived electrophile displaying a range of reactivity. Through these investigations we often paired experimental work with computational studies to help explain what was observed. The first two projects relied heavily on computational work to explain some of our observations and the final project was explored through experimental work. This body of work established the first efficient Ni-catalyzed Stille cross-coupling of phenolic electrophiles, the first highly selective Ni-catalyzed Suzuki cross-coupling of aryl tosylates in the presence of aryl chlorides, and the investigation of the Ni-catalyzed cross-coupling of Ar-OMe. All three projects leave some questions and avenues for further development. 77 References 1. Percec, V.; Bae, J. Y.; Hill, D. H. Aryl Mesylates in Metal-Catalyzed Homo-Coupling and Cross-Coupling Reactions. 4. 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Joyce, and Sharon R. Neufeldt* Department of Chemistry and Biochemistry, Montana State University Bozeman, MT 59717, USA Correspondence: sharon.neufeldt@montana.edu S 1 90 Table of Contents I. Experimental Details S3 A. General Materials and Methods S3 B. Synthesis of Starting Materials S4 i. Synthesis of Aryl Sulfamate Precursors to 4, 7, 9, and 11 S4 ii. Synthesis of Aryl Tosylates S6 iii. Synthesis of Aryl Tributylstannane Precursors to 18, 20, 21, 23, and 24 S7 C. Reaction Optimization and Additive Screening (Expanded Tables 1, 2, and 3) S9 D. Cross-Coupling Reactions S10 E. Mechanistic Experiments S18 i. Procedures for Equations 1 and 2 S18 ii. Synthesis, Isolation, and Characterization of Oxidative Addition Complexes 43 and 44 S19 iii. NMR Studies on the Reaction of 43 with KF and LiCl (Figure 1b and c) S21 iv. Evaluating the Catalytic Competence of 42 and PMe3 S24 v. Procedures for Equations 3 and 4 S25 II. Computational Details S26 A. General Methods S26 B. Graphical Guide to Numbered Compounds S27 C. Table of Energies, Entropies, and Lowest Frequencies of Minimum Energy Structures S28 III. X-Ray Crystallographic Details for Compounds 43 and 44 S29 IV. Cartesian Coordinates of Minimum Energy Calculated Structures S38 S 2 91 I. Experimental Details A. General Materials and Methods NMR spectra were recorded at 298 K on a Bruker DRX 500 MHz (500.233 MHz for 1H, 125.795 MHz for 13C, 202.487 MHZ for 31P, 470.639 MHz for 19F) or a Bruker DPX 300 MHz (282.425 MHz for 19F) spectrometer. 1H and 13C NMR chemical shifts are reported in parts per million (ppm) relative to TMS, with the residual solvent peak used as an internal reference [1H: CHCl3 (7.26 ppm) or C6D5H (7.16 ppm); 13C: CDCl3 (77.16 ppm) or C6D6 (128.06 ppm)].1 31P chemical shifts are reported in ppm relative to phosphoric acid, with Ph3PO used as an internal reference (25.55 ppm in C6D6). Multiplicities are reported as follows: singlet (s), doublet (d), doublet of doublets (dd), doublet of doublets of doublets (ddd), triplet (t), quartet (q), quintet (quint), multiplet or multiple overlapping signals (m), and broad resonance (br). GC data were collected using a Shimadzu GC-2010 Plus with a flame ionization detector equipped with a SH-Rxi-5ms capillary column (15 m x 0.25 mm ID x 0.25 µm df). HRMS data were collected on an Agilent 6538 UHD- QTOF or a Bruker MicroTOF. Melting points were measured using a Thomas-Hoover “Uni-Melt” capillary melting point apparatus. PCy3, PBu3, Mg turnings, Bu3SnCl, LiCl, Ph3PO, 1-naphthol, 4-fluorophenol, 4-hydroxybenzonitrile, methyl 4-hydroxybenzoate, 4-acetamidophenol, 4-methoxyphenol, 1-bromo-4-ethylbenzene, 2-bromo-m- xylene, 1-bromo-4-fluorobenzene, 3-bromoanisole, 1-bromonaphthalene, 2-tributylstannylthiazole, 2- tributylstannylpyridine, tributyl(vinyl)stannane, 1-ethoxytributylstannane, allyltributylstannane, and 2,6- di-tert-butyl-4-methylphenol (BHT) were obtained from Oakwood Chemical and used as received unless otherwise noted. PPhEt2 and PPh2Cy were obtained from TCI America and used as received. PPhMe2, NaH (60% dispersion in oil), N,N-dimethylsulfamoyl chloride, TsCl, dibromoethane, KF, undecane, 2-naphthol, 4-ethylphenol, and 4-chlorotoluene (36) were obtained from Acros and used as received. 1,4-Dioxane, dimethoxyethane (DME), and pyridine were obtained from Acros in ACROSeal bottles (extra dry) and used as received. PPh2Me, PPh3, Et3N, sesamol, 2-(tributylstannyl)furan, 1-methyl-2-(tributylstannyl)pyrrole, 2- (tributylstannyl)thiophene, 2-(tributylstannyl)oxazole, and 12-crown-4 were obtained from Alfa Aesar and used as received. Et2O, hexanes, EtOAc, MgSO4, HCl, NaHCO3, NaCl, and NaOH were obtained from Fisher Chemical and used as received unless otherwise noted. Benzene was obtained from Beantown Chemical or Riedel-de Haën and used as received. PhSnBu3 and tributyl(phenylethynyl)tin were obtained from Sigma- Aldrich and used as received. PPhCy2 was obtained from Strem and used as received. THF was obtained from Fisher Chemical and degassed and dried with a JC Meyer solvent system prior to use. Ni(cod)2 was obtained from Alfa Aesar or Acros and used as received. Aryl sulfamate 1 and the aryl sulfamate precursors to compounds 10, 12, and 13 were prepared according to a literature procedure.2 Aryl sulfamates 37 and 42 were prepared according to a literature procedure.3 Aryl mesylate 174, the aryl tributylstannane 1 Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. Organometallics 2010, 29, 2176. 2 Quasdorf, K. W.; Riener, M.; Petrova, K. V.; Garg, N. K. J. Am. Chem. Soc. 2009, 131, 17748. 3 Hooker, L. V.; Neufeldt, S. R. Tetrahedron 2018, 74, 6717. 4 Mori, A.; Mizusaki, T.; Ikawa, T.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Chem. Eur. J. 2007, 13, 1432. S 3 92 precursors to 19 and 225, and aryl sulfamate 356 were prepared according to literature procedures. CDCl3 and C6D6 were obtained from Cambridge Isotope Laboratories and used as received. Flash column chromatography was performed on SiliCycle silica gel 60 (40-63 µm particle size) and thin layer chromatography was performed on SiliCycle TLC plates pre-coated with extra hard silica gel 60 F254. B. Synthesis of Starting Materials i. Synthesis of Aryl Sulfamate Precursors to 4, 5, 6, 7, 8, 9, and 11 General Procedure. Aryl sulfamates were prepared according to a modified literature procedure:2 NaH (1.2 equiv, 60% dispersion in oil) was cooled to 0 ºC in a pear-shaped flask. A solution of the substituted phenol (1 equiv) in DME was added dropwise by cannula to the NaH. The resulting homogeneous solution was warmed to rt for 10 min and then cooled to 0 ºC. A solution of N,N-dimethylsulfamoyl chloride (1.0–1.25 equiv) in DME was added dropwise by cannula to the reaction vessel. The reaction was warmed to rt, stirred overnight, and then quenched with several drops of H2O. DME was removed by rotary evaporation, and the solid residue was then dissolved in Et2O (50 mL) and H2O (15 mL) and transferred to a separatory funnel. The layers were separated, and the organic layer was washed with 1 M KOH (15 mL), then H2O (15 mL). The combined aqueous layers were then extracted with Et2O (3 x 20 mL), washed with brine (15 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by recrystallization. Me Naphthalen-2-yl dimethylsulfamate (S1, precursor to 4): Aryl sulfamate S1 O O S N Me was prepared according to the general procedure using NaH (431 mg, 10.78 mmol, O 1.20 equiv), 2-naphthol (1.29 g, 8.97 mmol, 1.00 equiv), N,N-dimethylsulfamoyl S1 chloride (1.2 mL, 11.2 mmol, 1.25 equiv), and DME (30 mL). The crude solid was recrystallized from hexanes yielding S1 as a light tan powder (1.29 g, 57% yield). Spectral data are consistent with those previously reported.7 Me 4-Fluorophenyl dimethylsulfamate (S2, precursor to 5): Aryl sulfamate S2 O O S N Me was prepared according to the general procedure using NaH (440 mg, 11.00 mmol, F O 1.23 equiv), 4-fluorophenol (1.34 g, 8.97 mmol, 1.00 equiv), N,N-dimethylsulfamoyl S2 chloride (1.0 mL, 9.33 mmol, 1.04 equiv), and DME (30 mL). The crude solid was recrystallized from a 4:1 solution of hexanes and ethyl acetate yielding S2 as a white powder (453 mg, 23% yield); 19F NMR (282 MHz, CDCl3, d): –115.2. Spectral data are consistent with those previously reported.6 5 Gligorich, K. M.; Cummings, S. A.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129, 14193. 6 Molander, G. A.; Shin, I. Org. Lett. 2013, 15, 2534. 7 Leowanawat, P.; Zhang, N.; Percec, V. J. Org. Chem. 2012, 77, 1018. S4 93 Me 4-Cyanophenyl dimethylsulfamate (S3, precursor to 6): Aryl sulfamate S3 O O S N Me was prepared according to the general procedure using NaH (431 mg, 10.78 mmol, NC O 1.20 equiv), 4-hydroxybenzonitrile (1.08 g, 9.06 mmol, 1.00 equiv), N,N- S3 dimethylsulfamoyl chloride (1.0 mL, 9.33 mmol, 1.03 equiv), and DME (30 mL). The crude solid was recrystallized from a 4:1 solution of hexanes and EtOAc yielding S3 as a pale pink solid (1.36 g, 67% yield). Spectral data are consistent with those previously reported.8 Me Methyl 4-((N,N-dimethylsulfamoyl)oxy)benzoate (S4, precursor to 7): O O S N Me Aryl sulfamate S4 was prepared according to the general procedure using NaH MeO O (435 mg, 10.87 mmol, 1.20 equiv), methyl 4-hydroxybenzoate (1.34 g, 8.97 mmol, O S4 1.00 equiv), N,N-dimethylsulfamoyl chloride (1.0 mL, 9.33 mmol, 1.04 equiv), and DME (30 mL). The crude solid was recrystallized from a 1:1 solution of hexanes and EtOAc yielding S4 as a white crystalline solid (1.23 g, 53% yield). Spectral data are consistent with those previously reported.8 Me 4-Acetamidophenyl dimethylsulfamate (S5, precursor to 9): Aryl O O O S N Me sulfamate S5 was prepared according to the general procedure using NaH (432 Me N O mg, 10.76 mmol, 1.20 equiv), 4-acetamidophenol (1.36 g, 9.00 mmol, 1.00 H S5 equiv), N,N-dimethylsulfamoyl chloride (1.2 mL, 11.2 mmol, 1.24 equiv), and DME (30 mL). The crude solid was recrystallized from a 1:1 solution of hexanes and EtOAc yielding S5 as a pale pink powder (218.4 g, 9.4% yield); m.p. 102–105 ºC [uncorrected, measured against benzoic acid (111–114 ºC)]; 1H NMR (500 MHz, CDCl3, d): 7.52 (d, J = 8.9 Hz, 2H), 7.45–7.30 (br s, 1H), 7.22 (d, J = 8.9 Hz, 2H), 2.97 (s, 6H), 2.17 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3, d): 168.4, 146.3, 136.6, 122.5, 121.0, 38.9, 24.7; HRMS (ESI/Q-TOF) m/z: [M + H]+ Calcd for C10H15N2O4S 259.0742; Found 259.0722. O Me Benzo[d][1,3]dioxol-5-yl dimethylsulfamate (S6, precursor to 11): Aryl O O S N Me sulfamate S6 was prepared according to the general procedure using NaH (438 mg, O O 10.95 mmol, 1.22 equiv), sesamol (1.24 g, 8.97 mmol, 1.00 equiv), N,N- S6 dimethylsulfamoyl chloride (1.0 mL, 9.33 mmol, 1.04 equiv), and DME (30 mL). The crude solid was recrystallized from a 1:1 solution of hexanes and isopropanol yielding S6 as a white powder (1.67 g, 76% yield). Spectral data are consistent with those previously reported.9 8 Leowanawat, P.; Zhang, N.; Resmerita, A.-M.; Rosen, B. M.; Percec, V. J. Org. Chem. 2011, 76, 9946. 9 Yue, H.; Guo, L.; Liu, X.; Rueping, M. Org. Lett. 2017, 19, 1788. S 5 94 ii. Synthesis of Aryl Tosylates 14, 15, and 16 General Procedure. Aryl tosylates were prepared according to a modified literature procedure:10 Substituted phenol (1 equiv) and TsCl (1.8 equiv) were added to a 100 mL round bottom flask with pyridine and stirred under nitrogen at 45 ºC overnight. The reaction mixture was allowed to cool to room temperature before adding H2O (5 mL) to the reaction mixture and stirring at room temperature for 2.5 h. The reaction mixture was then diluted with 25 mL benzene and 10 mL H2O and transferred to a separatory funnel. The aqueous and organic layers were separated, and the organic layer was extracted with 10% aqueous HCl (2 x 25 mL), saturated aqueous NaHCO3 (1 x 25 mL) and brine (1 x 25 mL). The organic layer was dried over MgSO4, filtered, concentrated, and purified by recrystallization. Me Naphthalen-1-yl 4-methylbenzenesulfonate (14): Aryl tosylate 14 was prepared according to the general procedure using 1-naphthol (1.00 g, 3.47 mmol, 1.00 equiv), TsCl O (2.38 g, 6.24 mmol, 1.8 equiv), and pyridine (10.0 mL). The crude solid was recrystallized O S O from hexanes yielding 14 as a pale pink solid (1.51 g, 73% yield). Spectral data are consistent with those previously reported.11 14 Me 4-Methoxyphenyl 4-methylbenzenesulfonate (15): Aryl tosylate 15 O O was prepared according to the general procedure using 4-methoxyphenol (862 S O mg, 3.47 mmol, 1.00 equiv), TsCl (2.38 g, 6.24 mmol, 1.80 equiv), and pyridine MeO 15 (10.0 mL). The crude solid was recrystallized from hexanes yielding 15 as a white solid (1.39 g, 72% yield). Spectral data are consistent with those previously reported.11 Me 4-Cyanophenyl 4-methylbenzenesulfonate (16): Aryl tosylate 16 was O O prepared according to the general procedure using 4-hydroxybenzoate (827 mg, S O 3.47 mmol, 1.00 equiv), TsCl (2.38 g, 6.24 mmol, 1.80 equiv), and pyridine (10.0 NC 16 mL). The crude solid was recrystallized from hexanes yielding 16 as a white solid (1.29 g, 68% yield). Spectral data are consistent with those previously reported.11 10 Nervig, C. S.; Waller, P. J.; Kalyani, D. Org. Lett. 2012, 14, 4838. 11 Kuroda, J.-i.; Inamoto, K.; Hiroya, K.; Doi, T. Eur. J. Org. Chem. 2009, 2251. S6 95 iii. Synthesis of Aryl Tributylstannane Precursors to 18, 20, 21, 23, and 24 General Procedure: Aryl tributylstannanes were prepared according to a modified literature procedure:5 To an oven-dried 100 mL Schlenck flask equipped with a stirbar and a condenser under a N2 atmosphere, was added THF and magnesium turnings (1.60 equiv). The magnesium turnings were pre-activated by crushing with a mortar and pestle in a N2- filled glovebox. To the stirred mixture was added 1,2-dibromoethane (~30 drops) followed by the aryl bromide (1.00 equiv), added dropwise over ~5 minutes. The mixture slowly turned dark brown and the stirred mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and was transferred by cannula into a dried 100 mL Schlenk flask equipped with a stirbar and condenser under a N2 atmosphere. To the stirred mixture was added Bu3SnCl (1.20 equiv) dropwise over ~5 minutes. The stirred mixture was heated to reflux for 4 h and then cooled to room temperature. Aqueous 1.0 M NaOH (~3 x the volume of THF) was added and the mixture was stirred for ~1 h and then transferred to a separatory funnel. The aqueous layer was extracted with Et2O [3 x (3 x the volume of THF)], and the organic extracts were combined, washed with brine, dried over MgSO4, and filtered. The solvent was removed by rotary evaporation, and the crude residue was purified by flash column chromatography on silica gel. Tributyl(4-ethylphenyl)stannane (S7, precursor to 18): Aryl stannane S7 was Bu Sn prepared according to the general procedure using 1-bromo-4-ethylbenzene (2.8 mL, 3 S7 20.0 mmol, 1.0 equiv), Mg turnings (790 mg, 32.0 mmol, 1.6 equiv), and Bu3SnCl (6.7 mL, 24.0 mmol, 1.2 equiv). The crude residue was purified by flash column chromatography on silica gel (Rf =0.3 in 100% hexanes) to yield S7 as a colorless oil (4.64 g, 59% yield); 1H NMR (500 MHz, CDCl3, d): 7.40 (d, J = 7.9 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 2.65 (q, J = 7.6 Hz, 2H), 1.59–1.53 (m, 6H), 1.38–1.31 (m, 6H), 1.26 (t, J = 7.6 Hz, 3H), 1.07–1.03 (m, 6H), 0.90 (t, J = 7.3 Hz, 9H); 13C{1H} NMR (126 MHz, CDCl3, d): 144.1, 138.4, 136.7, 127.8, 29.3, 29.0, 27.6, 15.6, 13.8, 9.7; HRMS (ESI/Q-TOF) m/z: [M – Bu–]+ Calcd for C16H27Sn 339.1129; Found 339.1108. Me Tributyl(2,6-dimethylphenyl)stannane (S8, precursor to 20): Aryl stannane S8 was Bu Sn prepared according to the general procedure using 2-bromo-m-xylene (2.7 mL, 20.0 mmol, 3 Me 1.0 equiv), Mg turnings (778 mg, 32.0 mmol, 1.6 equiv), and Bu3SnCl (6.5 mL, 24.0 mmol, S8 1.2 equiv). The crude residue was purified by flash column chromatography on silica gel (Rf = 0.89 in 100% hexanes) to yield S8 as a colorless oil (4.66 g, 59% yield); 1H NMR (500 MHz, CDCl3, d): 7.14–7.08 (m, 1H), 7.02–6.95 (m, 2H), 2.42 (s, 6H), 1.56–1.50 (m, 6H), 1.39–1.32 (m, 6H), 1.14–1.04 (m, 6H), 0.91 (t, J = 7.3 Hz, 9H); 13C{1H} NMR (126 MHz, CDCl3, d): 145.3, 142.5, 128.3, 126.7, 29.3, 27.6, 25.9, 13.8, 12.8. Spectral data are consistent with those previously reported.12 12 Dughera, S. Synthesis 2006, 7, 1117. S 7 96 F Tributyl(4-fluorophenyl)stannane (S9, precursor to 21): Aryl stannane S9 was prepared according to the general procedure using 1-bromo-4-fluorobenzene (2.2 mL, Bu3Sn 20.0 mmol, 1.0 equiv), Mg turnings (778 mg, 32.0 mmol, 1.6 equiv), and Bu3SnCl (6.50 S9 mL, 24.0 mmol, 1.2 equiv). The crude residue was purified by flash column chromatography on silica gel (Rf =0.8 in 100% hexanes) to yield S9 as a colorless oil (6.65 g, 86% yield). Spectral data are consistent with those previously reported.13 Tributyl(3-methoxyphenyl)stannane (S10, precursor to 23): Aryl stannane Bu3Sn OMe S10 was prepared according to the general procedure using 3-bromoanisole (2.5 mL, S10 20.0 mmol, 1.0 equiv), Mg turnings (778 mg, 32.0 mmol, 1.6 equiv), and Bu3SnCl (6.5 mL, 24.0 mmol, 1.2 equiv). A portion of the crude residue (53% by mass) was purified by flash column chromatography on silica gel (Rf =0.47 in 100% hexanes) to yield S10 as a colorless oil (1.56 g, 37% yield based on the portion of the crude material purified by column chromatography). Spectral data are consistent with those previously reported.14 Tributyl(naphthalen-1-yl)stannane (S11, precursor to 24): Aryl stannane S11 was prepared according to the general procedure using 1-bromonaphthalene (2.8 mL, 20.0 Bu3Sn mmol, 1.0 equiv), Mg turnings (778 mg, 32.0 mmol, 1.6 equiv), and Bu3SnCl (6.5 mL, 24.0 S11 mmol, 1.2 equiv). The crude residue was purified by flash column chromatography on silica gel (Rf =0.67 in 100% hexanes) to yield S11 as a colorless oil (4.67 g, 56% yield). Spectral data are consistent with those previously reported.15 13 Ren, Y.; Dienes, Y.; Hettel, S.; Parvez, M.; Hoge, B.; Baumgartner, T. Organometallics 2009, 28, 734. 14 Lakshmi, B. V.; Wefelscheid, U. K.; Kazmaier, U. Synlett 2011, 345. 15 Gu, Y.; Martín, R. Angew. Chem. Int. Ed. 2017, 56, 3187. S8 97 C. Reaction Optimization and Additive Screening (Expanded Tables 1, 2, and 3) General Procedure. In a nitrogen atmosphere glovebox, the fluoride salt (KF, LiF, NaF, or CsF, 0.15 mmol, 3.0 equiv, if applicable), 1 (12.6 mg, 0.05 mmol, 1.0 equiv), PhSnBu3 (18.4 mg, 0.05 mmol, 1.0 equiv), and any indicated additives were combined in a one-dram vial equipped with a stir bar. In a second vial was prepared a stock solution of Ni(cod)2 and phosphine (0.01 M in Ni(cod)2, 0.02 M in phosphine). The Ni/phosphine stock solution [250 µL (0.0025 mmol, 5 mol% of Ni(cod) and 0.005 mmol, 10 mol% of phosphine)] was added to the reaction vial. The vial was sealed with a PTFE-lined cap, removed from the glovebox, and stirred at the indicated temperature for 18 h. The reaction vial was cooled to room temperature, and undecane was added as a GC standard. The reaction mixture was diluted with Et2O and shaken vigorously. An aliquot was removed, filtered through celite, and analyzed by GC. Table S1 corresponds to Tables 1, 2, and 3 in the manuscript, with additional entries not included in the manuscript. OSO NMe SnBu3 2 2 (1 equiv) Ni(cod)2 + ligand 1 solvent, base 18 h 2 3 (not detected) Table S1. Reaction optimization and additive screening. en- mol % of Ligand Temp 2 try Ni(cod)2 (mol %) (ºC) Solvent Base Additive(s) (% yield)a 1 5 PCy3 (10) 60 dioxane KF (3 equiv) -- 27b 2 5 PCy3 (10) 80 dioxane KF (3 equiv) -- 60b 3 5 PCy3 (10) 80 dioxane KF (3 equiv) LiCl (3 equiv) n.d. 4 5 PBu3 (10) 80 dioxane KF (3 equiv) -- 88b 5 5 PPhEt2 (10) 80 dioxane KF (3 equiv) -- ≥99b 6 5 PPhEt2 (10) 80 toluene KF (3 equiv) -- 49 7 none PPhEt2 (10) 80 dioxane KF (3 equiv) -- n.d. 8 5 none 80 dioxane KF (3 equiv) -- n.d. 9 5 PPhEt2 (10) 80 dioxane KF (3 equiv) CuI (5 mol %) n.d. 10 5 PPhEt2 (10) 80 dioxane KF (2 equiv) -- ≥99 11 5 PPhEt2 (10) 80 dioxane KF (1 equiv) -- 43 12 5 PPhMe2 (10) 80 dioxane KF (3 equiv) -- 96b 13 5 PPh2Me (10) 80 dioxane KF (3 equiv) -- ≥99b 14 5 PPh3 (10) 80 dioxane KF (3 equiv) -- 52b 15 5 PPhEt2 (10) 80 dioxane -- -- n.d. 16 5 PPhEt2 (10) 80 dioxane KF (3 equiv) LiCl (10 mol%) 13b 17 5 PPhEt2 (10) 80 dioxane KF (3 equiv) 12-crown-4 (2o ≥99b mol%) 18 5 PPhEt2 (10) 80 dioxane KF (3 equiv) LiCl (10 mol%), 12- 13b crown-4 (2o mol%) 19 5 PPhEt2 (10) 80 dioxane KF (3 equiv) NBu4Cl (10 mol%) 10b 20 5 PPhEt2 (10) 80 dioxane KF (3 equiv) KCl (10 mol%) 42b 21 5 PPhEt2 (10) 80 dioxane KF (3 equiv) ZnCl2 (10 mol%) n.d. 22 5 PPhEt2 (10) 80 dioxane K3PO4 -- 6 (3 equiv) 23 5 PPhEt2 (10) 80 dioxane LiF (3 equiv) -- n.d. 24 5 PPhEt2 (10) 80 dioxane NaF (3 equiv) -- n.d. 25 5 PPhEt2 (10) 80 dioxane CsF (3 equiv) -- 54b aGC yield calibrated against undecane as an internal standard. Estimated error ± ~5%. n.d. = not detected. bAverage of two trials. S9 98 D. Cross-Coupling Reactions General Procedure. In a nitrogen atmosphere glovebox, KF (87.2 mg, 1.50 mmol, 3.00 equiv), C—O substrate (0.50 mmol, 1.00 equiv), and organostannane (0.50 mmol, 1.00 equiv) were combined in a one- dram vial equipped with a stir bar. In a second vial was prepared a stock solution of Ni(cod)2 and phosphine in 1,4-dioxane. An aliquot of the Ni/phosphine stock solution was added to the reaction vial. The vial was sealed with a PTFE-lined cap, removed from the glovebox, and stirred at 80 ºC for 18 h. The crude reaction mixture was concentrated onto silica gel by rotary evaporation, and the crude material was purified by flash column chromatography on silica gel that had been pre-treated with 1% Et3N. For products that may be prone to oxidation or polymerization (25–29, 31–34), BHT was added prior to initial concentration on silica gel, and again after purification by column chromatography prior to concentrating column fractions (for these products, percent yields are calculated after subtracting out the mass of BHT) . 1-Phenylnaphthalene (2): (from aryl sulfamate 1) Compound 2 was prepared according to the general procedure using tributylphenylstannane (183.6 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 1.00 mL of a solution of Ni(cod)2 (0.025 mmol, 5 mol%) and PPhMe2 (0.05 mmol, 10 mol%) in 1,4-dioxane. 2 Purification by flash column chromatography (99% hexanes, 1% Et3N) afforded product 2 as a white solid (75.6 mg, 74% yield, Rf = 0.42 in 100% hexanes). Spectral data are consistent with those previously reported.16 (from aryl tosylate 14) Compound 2 was prepared according to the general procedure using tributylphenylstannane (183.6 mg , 0.50 mmol, 1.00 equiv), 14 (149.2 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhEt2 (0.05 mmol, 10 mol %) in 1,4-dioxane. Purification by flash column chromatography (99% hexanes, 1% Et3N) afforded product 2 as a white solid (88.5 mg, 87% yield). (from aryl mesylate 17) Compound 2 was prepared according to the general procedure using tributylphenylstannane (163.2 µL, 0.50 mmol, 1.00 equiv), 17 (111.1 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.05 mmol, 10 mol %) and PBu3 (0.10 mmol, 20 mol %) in 1,4-dioxane. Purification by flash column chromatography (99% hexanes, 1% Et3N) afforded product 2 as a white solid (94.5 mg, 93% yield). 2-Phenylnaphthalene (4): Compound 4 was prepared according to the general procedure using tributylphenylstannane (183.6 mg, 0.50 mmol, 1.00 equiv), 4 naphthalen-2-yl dimethylsulfamate (S1, 125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhEt2 (0.05 mmol, 10 mol %) in 1,4-dioxane. Purification by flash column chromatography (99% hexanes, 1% Et3N) 16 Zhang, Z.; Wang, Z. J. Org. Chem. 2006, 71, 7485. S1 0 99 afforded product 4 as a white solid (83.7 mg, 82% yield, Rf = 0.48 in 100% hexanes). Spectral data are consistent with those previously reported.17 4-Fluoro-1,1'-biphenyl (5): Compound 5 was prepared according to the general procedure using tributylphenylstannane (163.2 µL, 0.50 mmol, 1.00 equiv), 4- F 5 fluorophenyl dimethylsulfamate (S2, 109.6 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 1.00 mL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhEt2 (0.05 mmol, 10 mol %) in 1,4-dioxane. Purification by flash column chromatography (99% hexanes, 1% Et3N) afforded product 5 as a white powder (74.7 mg, 87% yield, Rf = 0.66 in 100% hexanes). Spectral data are consistent with those previously reported.18 [1,1'-Biphenyl]-4-carbonitrile (6): (from aryl sulfamate S3) Compound 6 was prepared according to the general procedure using tributylphenylstannane (163.2 µL, NC 6 0.50 mmol, 1.00 equiv), 4-cyanophenyl dimethylsulfamate (S3, 113.1 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv) and 1.00 mL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhEt2 (0.05 mmol, 10 mol %) in 1,4-dioxane. Purification by flash column chromatography (89% hexanes, 10% EtOAc, 1% Et3N) afforded product 6 as a white crystalline solid (73.6 mg, 82% yield, Rf = 0.51 in 90% hexanes, 10% EtOAc). Spectral data are consistent with those previously reported.19 (from aryl tosylate 16) Compound 6 was prepared according to the general procedure using tributylphenylstannane (183.6 mg, 0.50 mmol, 1.00 equiv), 16 (136.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhMe2 (0.05 mmol, 10 mol %) in 1,4-dioxane. Purification by flash column chromatography (99% hexanes, 1% Et3N) afforded product 6 as a white crystalline solid (66.3 mg, 74% yield). Methyl [1,1'-biphenyl]-4-carboxylate (7): Compound 7 was prepared according to the general procedure using tributylphenylstannane (163.2 µL, 0.50 Me O 7 mmol, 1.00 equiv), methyl 4-((N,N-dimethylsulfamoyl)oxy)benzoate (S4, 129.6 O mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 1.00 mL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhMe2 (0.05 mmol, 10 mol %) in 1,4-dioxane. Purification by flash column chromatography (98% hexanes, 1% EtOAc, 1% Et3N) afforded product 7 as a white solid (62.5 mg, 59% yield, Rf = 0.15 in 99% hexanes, 1% EtOAc). Spectral data are consistent with those previously reported.20 17 Cho, C.-H.; Yun, H.-S.; Park, K. J. Org. Chem. 2003, 68, 3017. 18 Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661. 19 Grossman, O.; Gelman, D. Org. Lett. 2006, 8, 1189. 20 Ackermann, L.; Gschrei, C. J.; Althammer, A.; Riederer, M. Chem. Commun. 2006, 1419. S1 1 100 4-Ethyl-1,1'-biphenyl (8): Compound 8 was prepared according to the general procedure using tributylphenylstannane (163.2 µL, 0.50 mmol, 1.00 equiv), 4- 8 ethylphenyl dimethylsulfamate (114.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhEt2 (0.05 mmol, 10 mol %) in 1,4-dioxane. Purification by flash column chromatography (99% hexanes, 1% Et3N) afforded product 8 as a yellow solid (68.0 mg, 75% yield, Rf = 0.69 in 100% hexanes). Spectral data are consistent with those previously reported.21 N-([1,1'-biphenyl]-4-yl)acetamide (9): Compound 9 was prepared according O to the general procedure using tributylphenylstannane (163.2 µL, 0.50 mmol, 1.00 Me N equiv), 4-acetamidophenyl dimethylsulfamate (S5, 129.2 mg, 0.50 mmol, 1.00 H 9 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.05 mmol, 10 mol %) and PBu3 (0.10 mmol, 20 mol %) in 1,4-dioxane. Purification by flash column chromatography (40% hexanes, 59% EtOAc, 1% Et3N) afforded product 9 as a white powder (70.0 mg, 66% yield, Rf = 0.50 in 40% hexanes, 60% EtOAc). 1H NMR (500 MHz, CDCl3, d): 7.59–7.55 (m, 6H), 7.44–7.41 (m, 2H), 7.34–7.31 (m, 1H), 2.21 (s, 3H). The NH signal apparently overlaps with the residual solvent signal based on broadening of the base of the CHCl3 signal at 7.26. Spectral data are consistent with those previously reported.22 4-Methoxy-1,1'-biphenyl (10): (from aryl sulfamate) Compound 10 was prepared according to the general procedure using tributylphenylstannane (163.2 µL, 0.50 Me O 10 mmol, 1.00 equiv), 4-methoxyphenyl dimethylsulfamate (115.6 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 1.00 mL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PBu3 (10.1 mg, 0.05 mmol, 10 mol %) in 1,4-dioxane. Purification by flash column chromatography (79% hexanes, 20% benzene, 1% Et3N) afforded product 10 as a white powder (72.9 mg, 85% yield, Rf = 0.42 in 80% hexanes, 20% benzene). Spectral data are consistent with those previously reported.22 (from aryl tosylate 15) Compound 10 was prepared according to the general procedure using tributylphenylstannane (183.6 mg, 0.50 mmol, 1.00 equiv), 15 (139.4 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.05 mmol, 10 mol %) and PBu3 (0.10 mmol, 20 mol %) in 1,4-dioxane. Purification by flash column chromatography (99% hexanes, 1% Et3N) afforded product 10 as a white powder (70.1 mg, 76% yield). 21 Tsubouchi, A.; Muramatsu, D.; Takeda, T. Angew. Chem. Int. Ed. 2013 52, 12719. 22 Zhou, W.-J.; Wang, K.-H.; Wang, J.-X. Adv. Synth. Catal. 2009, 351, 1378. S1 2 101 5-Phenylbenzo[d][1,3]dioxole (11): Compound 11 was prepared according to the O general procedure using tributylphenylstannane (163.2 µL, 0.50 mmol, 1.00 equiv), O benzo[d][1,3]dioxol-5-yl dimethylsulfamate (S6, 122.6 mg, 0.50 mmol, 1.00 equiv), KF 11 (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.05 mmol, 10 mol %) and PBu3 (0.10 mmol, 20 mol %) in 1,4-dioxane. Purification by flash column chromatography (99% hexanes, 1% Et3N) afforded product 11 as a brown oil (89.5 mg, 89% yield, Rf = 0.50 in 100% hexanes). Spectral data are consistent with those previously reported.23 Me 2-Methyl-1,1'-biphenyl (12): Compound 12 was prepared according to the general procedure using tributylphenylstannane (163.2 µL, 0.50 mmol, 1.00 equiv), 2-methylphenyl 12 dimethylsulfamate (107.6 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhEt2 (0.05 mmol, 10 mol %) in 1,4- dioxane. Purification by flash column chromatography (99% hexanes, 1% Et3N) afforded product 12 as a colorless oil (66.3 mg, 79% yield, Rf = 0.57 in 100% hexanes). Spectral data are consistent with those previously reported.24 Me 2,6-Dimethyl-1,1'-biphenyl (13): Compound 13 was prepared according to the general procedure using tributylphenylstannane (163.2 µL, 0.50 mmol, 1.00 equiv), 2,6- Me dimethylphenyl dimethylsulfamate (114.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 13 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.05 mmol, 10 mol %) and PPhEt2 (0.10 mmol, 20 mol %) in 1,4-dioxane. Purification by flash column chromatography (99% hexanes, 1% Et3N) afforded product 13 as a colorless oil (66.8 mg, 73% yield, Rf = 0.74 in 100% hexanes). Spectral data are consistent with those previously reported.25 1-(4-ethylphenyl)naphthalene (18): Compound 18 was prepared according to the general procedure using tributyl(4-ethylphenyl)stannane (S7, 197.6 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 1.50 mL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhEt2 (0.05 mmol, 10 mol %) in 1,4- dioxane. Purification by flash column chromatography (79% hexanes, 20% EtOAc, 1% Et3N) 18 afforded product 18 as a light yellow oil (108.2 mg, 93% yield, Rf = 0.51 in 80% hexanes, 20% EtOAc). Spectral data are consistent with those previously reported.26 23 Scheuermann, G. M.; Rumi, L.; Steurer, P.; Bannwarth, W.; Mülhaupt, R. J. Am. Chem. Soc. 2009, 131, 8262. 24 Zim, D.; Lando, V. R.; Dupont, J.; Monteiro, A. L. Org. Lett. 2001, 3, 3049. 25 Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9950. 26 Sabounchei, S. J.; Panahimehr, M.; Ahmadi, M.; Nasri, Z.; Khavasi, H. R. J. Organomet. Chem. 2013, 723, 207. S1 3 102 1-(o-Tolyl)naphthalene (19): Compound 19 was prepared according to the general Me procedure using tributyl(2-methylphenyl)stannane (190.6 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 1.00 mL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPh2Me (0.05 mmol, 10 mol %) in 1,4-dioxane. 19 Purification by flash column chromatography (99% hexanes, 1% Et3N) afforded product 19 as a white solid (99.5 mg, 91% yield, Rf = 0.55 in 100% hexanes). Spectral data are consistent with those previously reported.27 1-(2,6-Dimethylphenyl)naphthalene (20): Compound 20 was prepared according to Me Me the general procedure using tributyl(2,6-dimethylphenyl)stannane (S8, 197.6 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 1.00 mL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPh2Me (0.05 20 mmol, 10 mol %) in 1,4-dioxane. Purification by flash column chromatography (79% hexanes, 20% benzene, 1% Et3N) afforded product 20 as a white solid (112.8 mg, 97% yield, Rf = 0.53 in 80% hexanes, 20% benzene). Spectral data are consistent with those previously reported.28 F 1-(4-Fluorophenyl)naphthalene (21): Compound 21 was prepared according to the general procedure using tributyl(4-fluorophenyl)stannane (S9, 192.6 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhEt2 (0.05 mmol, 10 mol %) in 1,4- dioxane. Purification by flash column chromatography (99% hexanes, 1% Et3N) afforded 21 product 21 as a pale yellow solid (85.9 mg, 77% yield, Rf = 0.54 in 100% hexanes). Spectral data are consistent with those previously reported.29 CF3 1-(4-(Trifluoromethyl)phenyl)naphthalene (22): Compound 22 was prepared according to the general procedure using tributyl(4-(trifluoromethyl)phenyl)stannane (217.6 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 1.00 mL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhMe2 (0.05 mmol, 10 mol %) in 1,4-dioxane. Purification by flash column chromatography (99% hexanes, 22 1% Et3N) afforded product 22 as a white powder (109.5 mg, 80% yield, Rf = 0.53 in 100% hexanes). Spectral data are consistent with those previously reported.30 27 Wolf, C.; Xu, H. J. Org. Chem. 2008, 73, 162. 28 Lipshutz, B. H.; Siegmann, K.; Garcia, E.; Kayser, F. J. Am. Chem. Soc. 1993, 115, 9276. 29 Quasdorf, K. W.; Antoft-Finch, A.; Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Ramgren, S. D.; Houk, K. N.; Snieckus, V.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 6352. 30 Shi, S.; Meng, G.; Szostak, M. Angew. Chem. Int. Ed. 2016, 55, 6959. S1 4 103 Me O 1-(3-Methoxyphenyl)naphthalene (23): Compound 23 was prepared according to the general procedure using tributyl(3-methoxyphenyl)stannane (S10, 198.6 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 1.50 mL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPh2Me (0.05 mmol, 10 mol %) 23 in 1,4-dioxane. Purification by flash column chromatography (89% hexanes, 10% benzene, 1% Et3N) afforded product 23 as a colorless oil (70.3 mg, 64% yield, Rf = 0.34 in 90% hexanes, 10% benzene). Spectral data are consistent with those previously reported.31 Methyl 4-(naphthalen-1-yl)benzoate (24): Compound 24 was prepared according to the general procedure using tributyl(naphthalen-1-yl)stannane (S11, 208.6 mg, 0.50 mmol, 1.00 equiv), 1 (129.6 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 24 670 µL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhEt2 (0.05 mmol, 10 mol %) O O in 1,4-dioxane. Purification by flash column chromatography (79% hexanes, 20% EtOAc, 1% Me Et3N) afforded product 24 as a white solid (98.1 mg, 75% yield, Rf = 0.66 in 80% hexanes, 20% EtOAc). Spectral data are consistent with those previously reported.7 2-(Naphthalen-1-yl)furan (25): Compound 25 was prepared according to the general O procedure using 2-(tributylstannyl)furan (178.6 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 25 (0.025 mmol, 5 mol %) and PPhEt2 (0.05 mmol, 10 mol %) in 1,4-dioxane. BHT was added prior to concentration onto silica gel to inhibit product decomposition. Purification by flash column chromatography (99% hexanes, 1% Et3N) followed by addition of BHT (~0.4 mol%) afforded product 25 as a yellow oil (80.1 mg, 82% yield, Rf = 0.57 in 100% hexanes). Spectral data are consistent with those previously reported.32 1-Methyl-2-(naphthalen-1-yl)-1H-pyrrole (26): Compound 26 was prepared according Me N to the general procedure using 1-methyl-2-(tributylstannyl)pyrrole (185.1 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.05 mmol, 10 mol %) and PPhEt2 (0.10 mmol, 20 mol %) in 1,4- 26 dioxane. BHT was added prior to concentration onto silica gel to inhibit product decomposition. Purification by flash column chromatography (99% hexanes, 1% Et3N) followed by addition of BHT (~0.3 mol%) afforded product 26 as a colorless oil (78.8 mg, 76% yield, Rf = 0.44 in 100% hexanes). Spectral data are consistent with those previously reported.33 31 Cella, R.; Cunha, R. L. O. R.; Reis, A. E. S.; Pimenta, D. C.; Klitzke, C. F.; Stefani, H. A. J. Org. Chem. 2006, 71, 244. 32 Denmark, S. E.; Baird, J. D. Org. Lett. 2006, 8, 793. 33 Liu, Y.-X.; Xue, D.; Wang, J.-D.; Zhao, C.-J.; Zou, Q.-Z.; Wang, C.; Xiao, J. Synlett 2013, 24, 507. S1 5 104 2-(Naphthalen-1-yl)thiophene (27): Compound 27 was prepared according to the general S procedure using 2-(tributylstannyl)thiophene (186.6 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 1.00 mL of a stock solution 27 of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhEt2 (0.05 mmol, 10 mol %) in 1,4-dioxane. BHT was added prior to concentration onto silica gel to inhibit product decomposition. Purification by flash column chromatography (99% hexanes, 1% Et3N) followed by addition of BHT (~0.8 mol%) afforded product 27 as a light yellow oil (100.8 mg, 95% yield, Rf = 0.56 in 99% hexanes). Spectral data are consistent with those previously reported.32 2-(Naphthalen-1-yl)oxazole (28): Compound 28 was prepared according to the general O N procedure using 2-tributylstannyloxazole (179.1 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 1.00 mL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhMe2 (0.05 mmol, 10 mol %) in 1,4-dioxane (1.00 mL). BHT 28 was added prior to concentration onto silica gel to inhibit product decomposition. Purification by flash column chromatography (94% hexanes, 5% EtOAc, 1% Et3N) followed by addition of BHT (~0.3 mol%) afforded product 28 as a light yellow oil (83.8 mg, 86% yield, Rf = 0.37 in 95% hexanes, 5% EtOAc). Spectral data are consistent with those previously reported.34 2-(Naphthalen-1-yl)thiazole (29): Compound 29 was prepared according to the general S N procedure using 2-tributylstannylthiazole (187.1 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.05 mmol, 10 mol %) and PPhMe2 (0.10 mmol, 20 mol %) in 1,4-dioxane. BHT was 29 added prior to concentration onto silica gel to inhibit product decomposition. Purification by flash column chromatography (94% hexanes, 5% EtOAc, 1% Et3N) followed by addition of BHT (~0.8 mol%) afforded product 29 as a light yellow oil (86.1 mg, 81% yield, Rf = 0.33 in 95% hexanes, 5% EtOAc). Spectral data are consistent with those previously reported.34 2-(Naphthalen-1-yl)pyridine (30): Compound 30 was prepared according to the general N procedure using 2-tributylstannylpyridine (184.1 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.05 mmol, 10 mol %) and PPhMe2 (0.10 mmol, 20 mol %) in 1,4-dioxane. 30 Purification by flash column chromatography (89% hexanes, 10% EtOAc, 1% Et3N) afforded product 30 as a pale red oil (70.4 mg, 69% yield, Rf = 0.31 in 90% hexanes, 10% EtOAc); 1H NMR (500 MHz, C6D6, d): 8.66 (ddd, J = 4.8. 1.7, 0.9 Hz, 1H), 8.39–8.37 (m, 1H), 7.69–7.68 (m, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.59 (dd, J = 7.1, 1.2 Hz, 1H), 7.31–7.26 (m, 3H), 7.20 (ddd, J = 7.8, 1.1, 1.1 Hz, 1H), 7.14 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H), 6.72 (ddd, J = 7.5, 4.8, 1.3 Hz, 1H); 13C{1H} NMR (126 MHz, C6D6, d): 159.9, 149.9, 34 Zhu, F.; Tao, J.-L.; Wang, Z.-X. Org. Lett. 2015, 17, 4926. S1 6 105 139.4, 135.9, 134.6, 131.9, 129.1, 128.6, 128.0, 126.54, 126.53, 126.1, 125.5, 125.0, 121.8. Spectral data are consistent with those previously reported.35 1-Vinylnaphthalene (31): Compound 31 was prepared according to the general procedure using tributyl(vinyl)stannane (158.6 mg, 0.50 mmol, 1.00 equiv), 1 (125.8 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.05 mmol, 31 10 mol %) and PPhMe2 (0.10 mmol, 20 mol %) in 1,4-dioxane. BHT was added prior to concentration onto silica gel to inhibit product decomposition. Purification by flash column chromatography (99% hexanes, 1% Et3N) followed by addition of BHT (~2.6 mol%) afforded product 31 as a colorless oil (46.6 mg, 58% yield, Rf = 0.68 in 100% hexanes). Spectral data are consistent with those previously reported.36 O 1-(1-Ethoxyvinyl)naphthalene (32): Compound 32 was prepared according to the general procedure using 1-ethoxytributyl(vinyl)tin (180.6 mg, 0.50 mmol, 1.00 equiv), 1 (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 1.00 mL of a solution of 32 Ni(cod)2 (0.05 mmol, 10 mol %) and PPhEt2 (0.10 mmol, 20 mol %) in 1,4-dioxane. BHT was added prior to concentration onto silica gel to inhibit product decomposition. Purification by flash column chromatography (99% hexanes, 1% Et3N) followed by addition of BHT (~0.2 mol%) afforded product 32 as a light yellow oil (85.1 mg, 86% yield, Rf = 0.47 in 100% hexanes). 1H NMR (500 MHz, CDCl3, d): 8.18–8.16 (m, 1H), 7.85–7.82 (m, 2H), 7.54 (dd, J = 7.1, 1.3 Hz, 1H), 7.52–7.46 (m, 2H), 7.44 (dd, J = 8.2, 7.1 Hz, 1H), 4.51 (d, J = 2.0 Hz, 1H), 4.40 (d, J = 2.0 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3, d): 161.4, 136.1, 133.8, 131.4, 129.0, 128.2, 126.8, 126.2, 126.0, 125.9, 125.3, 87.1, 63.7, 14.7; HRMS (ESI/Q-TOF) m/z: [M + H]+ Calcd for C14H15O 199.1117; Found 199.1092. 2-Allylnaphthalene (33): Compound 33 was prepared according to the general 33 procedure using allyltributylstannane (165.6 mg, 0.50 mmol, 1.00 equiv), naphthalen- 2-yl dimethylsulfamate (S1, 125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, S12 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.025 mmol, 5 mol %) and PPhMe2 33 : S12 ~ 9 : 1 (0.50 mmol, 5 mol %) in 1,4-dioxane. BHT was added prior to concentration onto silica gel to inhibit product decomposition. Purification by flash column chromatography (99% hexanes, 1% Et3N) followed by addition of BHT (~0.5 mol%) afforded a clear oil comprising a ~9:1 mixture of 33 : S12 (64.4 mg, 76% yield, Rf = 0.60 in 100% hexanes). Spectral data are consistent with those previously reported.37,38 35 Núñez, A.; Sánchez, A.; Burgos, C.; Alvarez-Builla, J. Tetrahedron 2004, 60, 6217. 36 Bajracharya, G. B.; Pahadi, N. K.; Gridnev, I. D.; Yamamoto, Y. J. Org. Chem. 2006, 71, 6204. 37 Seomoon, D.; Lee, P. H. J. Org. Chem. 2008, 73, 1165. 38 Dong, D.-J.; Li, Y.; Wang, J.-Q.; Tian, S.-K. Chem. Commun. 2011, 47, 2158. S1 7 106 1-(Phenylethynyl)naphthalene (34): Compound 34 was prepared according to the general procedure using tributyl(phenylethynyl)stannane (175 µL, 0.50 mmol, 1.00 equiv), 1 dimethylsulfamate (125.7 mg, 0.50 mmol, 1.00 equiv), KF (87.2 mg, 1.50 mmol, 3.00 equiv), and 670 µL of a solution of Ni(cod)2 (0.05 mmol, 10 mol %) and PPhMe2 (0.10 mmol, 20 mol %) in 1,4-dioxane. BHT was added prior to concentration onto silica gel to inhibit product 34 decomposition. Purification by flash column chromatography (99% hexanes, 1% Et3N) followed by addition of BHT (~1.0 mol%) afforded product 34 as a light yellow oil (74.1 mg, 64% yield, Rf = 0.42 in 100% hexanes. 1H NMR (500 MHz, CDCl3, d): 8.46 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.63–7.59 (m, 1H), 7.57–7.54 (m, 1H), 7.47 (dd, J = 7.8, 7.8 Hz, 1H), 7.43–7.36 (m, 3H); 13C{1H} NMR (126 MHz, CDCl3, d): 133.44, 133.38, 131.8, 130.5, 128.9, 128.6, 128.53, 128.46, 126.9, 126.6, 126.4, 125.4, 123.6, 121.1, 94.5, 87.7. Spectral data are consistent with those previously reported.39 E. Mechanistic Experiments i. Procedures for Equations 1 and 2 OSO NMe PhSnBu3 (1 equiv) 2 2 Ni(cod)2 (5 mol %) PPhEt2 (10 mol %) Cl no reaction (1) 35 KF (3 equiv) 1,4-dioxane, 80 ºC, 18 h Procedure for Equation 1. In a nitrogen atmosphere glovebox, KF (8.7 mg, 0.15 mmol, 3.00 equiv), 35 (10.4 mg, 0.05 mmol, 1.00 equiv), and PhSnBu3 (18.4 mg, 0.05 mmol, 1.00 equiv) were combined in a one-dram vial equipped with a stir bar. In a second vial was prepared a stock solution of Ni(cod)2 and PPhEt2 (0.01 M in Ni(cod)2, 0.02 M in PPhEt2) in 1,4-dioxane. The Ni/phosphine stock solution [250 µL (0.0025 mmol, 5 mol% of Ni(cod) and 0.005 mmol, 10 mol% of PPhEt2) was added to the first vial. The reaction vial was sealed with a PTFE-lined cap, removed from the glovebox, and stirred at 80 ºC for 18 h. The reaction vial was cooled to room temperature, and undecane was added as a GC standard. The reaction mixture was diluted with Et2O and shaken vigorously. An aliquot was removed, filtered through celite, and analyzed by GC. 39 Thakur, K. G.; Sekar, G. Synthesis 2009, 2785. S1 8 107 Cl OSO2NMe2 PhSnBu3 (1 equiv) Ph Ph Ni(cod)2 (5 mol %) + PPhEt2 (10 mol %) + (2) 36 37 KF (3 equiv) Me Et 1,4-dioxane, 80 ºC, 18 h Me Et (≤5%) (≤5%) Procedure for Equation 2. In a nitrogen atmosphere glovebox, KF (8.7 mg, 0.15 mmol, 3.00 equiv), 36 (5.9 µL mg, 0.05 mmol, 1.00 equiv), ), 37 (11.5 mg, 0.05 mmol, 1.00 equiv), and PhSnBu3 (16.3 µL, 0.05 mmol, 1.00 equiv) were combined in a one-dram vial equipped with a stir bar. In a second vial was prepared a stock solution of Ni(cod)2 and PPhEt2 (0.01 M in Ni(cod)2, 0.02 M in PPhEt2) in 1,4-dioxane. The Ni/phosphine stock solution [250 µL (0.0025 mmol, 5 mol% of Ni(cod) and 0.005 mmol, 10 mol% of PPhEt2) was added to the first vial. The vial was sealed with a PTFE-lined cap, removed from the glovebox, and stirred at 80 ºC for 18 h. The reaction vial was cooled to room temperature, and undecane was added as a GC standard. The reaction mixture was diluted with Et2O and shaken vigorously. An aliquot was removed, filtered through celite, and analyzed by GC. About 5% or less of each of the possible cross-coupled products were detected, and otherwise only unreacted starting materials were observed. ii. Synthesis, Isolation, and Characterization of Oxidative Addition Complexes 43 and 44 OSO2NMe2 Ni(cod)2 (1 equiv) Et2PhP OSO2NMe2 Me PPhEt2 (2 equiv) Ni PPhEt2 1,4-dioxane Me 42 r.t., overnight F F 43 Complex 43. In a nitrogen atmosphere glovebox, Ni(cod)2 (137.5 mg 0.50 mmol, 1.00 equiv), PPhEt2 (138.2 mg 1.00 mmol, 2.00 equiv), 42 (116.6 mg, 0.50 mmol, 1.00 equiv), and 1,4-dioxane (2.50 mL) were combined in a one dram vial equipped with a magnetic stir bar, sealed with a PTFE-lined cap, and allowed to stir at room temperature overnight. The crude reaction mixture was concentrated under vacuum to provide a dark orange residue. In the glovebox, the crude residue was washed with degassed hexanes (6 x 4 mL). The remaining residue was dried under vacuum to yield product 43 as a yellow powder (180 mg, 67%). X-ray quality crystals were grown from THF/pentane at –25 ºC. 1H NMR (500 MHz, C6D6, d): 7.29–7.26 (m, 4H), 7.02–7.00 (m, 6H), 6.46 (td, 4JHP = 8.7 Hz, 4JHF = 2.7 Hz, 1H), 6.34–6.28 (m, 2H), 2.70 (s, 6H), 2.63 (s, 3H), 2.15–2.08 (m, 2H), 1.79–1.74 (m, 4H), 1.55–1.49 (m, 2H), 0.98 (app quint, J = 8.0 Hz, 6H), 0.81 (app quint, J = 7.6 Hz, 6H); 13C{1H} NMR (126 MHz, C6D6, d): 163.1 (dt, 1JCF = 239.0 Hz, 5JCP = 2.7 Hz), 146.0 (dt, 3JCF = 5.4 Hz, 3JCP = 3.0 Hz), 137.0 (dt, 3JCF = 5.7 Hz, 3JCP = 4.0 Hz), 134.2 (td, 2JCP = 35.4 Hz, 4JCF = 1.8 Hz), 132.7 (t, JCP = 4.4 Hz), 132.5 (t, JCP = 18.5 Hz), 130.2, 115.4 (dt, 2JCF = 18.9 Hz, 4JCP = 3.0 Hz), 111.6 (dt, 2JCF = 19.1 Hz, 4JCP = 2.8 Hz), 40.7, 26.4, 14.3 (t, 1JCP = 11.8 Hz), 13.6 (t, 1JCP = 11.6 Hz), 8.7, 8.2 (two aromatic 13C signals are coincidentally overlapping); 31P{1H} NMR (203 MHz, C6D6, d): 8.9; 19F NMR (C6D6, d): –124.6. Structure was verified by X-ray diffraction (see p. S29). S1 9 108 OSO NMe Ni(cod)2 (1 equiv) 2 2 OSO NMe PPhEt (2 equiv) Et2PhP 2 2 Et2PhP F Me 2 KF (1 equiv) Ni Ni PPhEt2 PPhEt2 1,4-dioxane Me Me 42 r.t., overnight F F 43 F sole product not observed Complex 43: Synthesis in the Presence of KF. In an unsuccessful attempt to isolate a nickel-fluoride species, substrate 42 was reacted with Ni(cod)2 and PPhEt2 in the presence of KF. In a nitrogen atmosphere glovebox, Ni(cod)2 (137.5 mg 0.50 mmol, 1.00 equiv), PPhEt2 (138.2 mg 1.00 mmol, 2.00 equiv), 42 (116.6 mg, 0.50 mmol, 1.00 equiv), KF (29.0 mg, 0.50 mmol, 1.00 equiv), and 1,4-dioxane (2.50 mL) were combined in a one dram vial equipped with a magnetic stir bar, sealed with a PTFE-lined cap, and allowed to stir at room temperature overnight. The crude reaction mixture was concentrated under vacuum to provide a dark orange residue. In the glovebox, the crude residue was washed with degassed hexanes (6 x 4 mL). The remaining residue was dried under vacuum to yield product 43 as a yellow powder (155.6 mg, 50%). Spectra were consistent with compound 43 as described above. Cl Ni(cod) (1 equiv) Et2PhP Cl Me 2 PPhEt (2 equiv) Ni 2 PPhEt2 1,4-dioxane Me r.t., overnight 45 F F 44 Complex 44. In a nitrogen atmosphere glovebox, Ni(cod)2 (137.5 mg 0.50 mmol, 1.00 equiv), PPhEt2 (138.2 mg 1.00 mmol, 2.00 equiv), 45 (60.9 µL, 0.50 mmol, 1.00 equiv), and 1,4-dioxane (2.50 mL) were combined in a one dram vial equipped with a magnetic stir bar, sealed with a PTFE-lined cap, and allowed to stir at room temperature overnight. The crude reaction mixture was filtered through celite and the celite was washed with 1,4-dioxane (2 mL). The filtrate was concentrated under vacuum to provide an air-stable burnt orange residue. Dry MeOH (3 mL) was added to the residue and the mixture was sonicated for 15 minutes, resulting in formation of a yellow precipitate. The precipitate was collected by filtration and washed with cold hexanes (3 x 2 mL). The collected precipitate was dried under vacuum to yield product 44 as a yellow powder (103.2 mg, 39%). X-ray quality crystals were grown from THF/pentane at 20 ºC. 1H NMR (500 MHz, C6D6, d): 7.43 (app s, 4H), 7.05 (app s, 6H), 6.79–6.76 (m, 1H), 6.63–6.57 (m, 2H), 2.62 (s, 3H), 2.11– 2.08 (m, 2H), 1.66–1.62 (m, 2H), 1.38–1.34 (m, 2H), 1.30–1.25 (m, 2H), 0.92 (app quint, J = 7.9 Hz, 6H), 0.72 (app quint, J = 7.4 Hz, 6H); 13C{1H} NMR (126 MHz, C6D6, d): 161.9 (dt, 1JCF = 238.6 Hz, 5JCP = 2.8 Hz), 144.3 (dt, 3JCF = 4.9 Hz, 3JCP = 2.6 Hz), 143.0 (td, 2JCP = 34.3 Hz, 4JCF = 2.0 Hz), 136.3 (dt, 3JCF = 5.1 Hz, 3JCP = 4.9 Hz), 132.3 (t, JCP = 17.6 Hz), 131.8 (t, JCP = 4.2 Hz), 129.1, 114.5 (dt, 2JCF = 18.5 Hz, 4JCP = 2.8 Hz), 111.0 (dt, 2JCF = 18.6 Hz, 4JCP = 2.3 Hz), 26.1 (d, 4JCF = 1.6 Hz), 14.1 (t, 1JCP = 13.0 Hz), 13.8 (t, 1JCP = 13.0 Hz), 8.0, 7.5 (two aromatic 13C signals are coincidentally overlapping); 31P{1H} NMR (203 MHz, C6D6, d): 11.9; 19F NMR (C6D6, d): –124.8; Anal. Calcd for C27H36ClFNiP2: C, 60.54; H, 6.77. Found: C, 60.25; H, 6.95. Structure was verified by X-ray diffraction (see p. S29). S2 0 109 iii. NMR Studies on the Reaction of 43 with KF and LiCl OSO2NMe2 Ni(cod) (1 equiv) Et2PhP OSO2NMe2 Me 2 PPhEt2 (2 equiv) Ni PPhEt2 1,4-dioxane Me 80 ºC, 1 h F 42 F 43 Demonstration that 43 is formed from 42 after 1 h at 80 ºC in dioxane. In a nitrogen atmosphere glovebox, Ni(cod)2 (5.5 mg 0.02 mmol, 1.00 equiv), PPhEt2 (6.6 mg 0.04 mmol 2.00 equiv), 42 (4.7 mg, 0.02 mmol, 1.00 equiv), and 1,4-dioxane (700 µL) were combined in a one dram vial equipped with a magnetic stir bar and sealed with a PTFE-lined cap. The vial was removed from the glovebox and stirred at 80 ºC for one hour, then transferred back into the glovebox, opened, and placed inside a drying chamber. The drying chamber was sealed, removed from the glovebox, and connected to a vacuum pump. The crude reaction mixture was concentrated under vacuum to provide a yellow-orange residue. The vacuum chamber was sealed (while under vacuum) and brought back into the glovebox. In the glovebox, the crude residue was taken up in C6D6 (1.0 mL) and filtered through celite. The filtrate was added to an NMR tube equipped with an external Ph3PO standard (as a solution in C6D6 contained within a capillary tube). The spectral data (Figure S1B on p. S22) are consistent with those of the previously isolated sulfamate compound 43 (Figure S1A). OSO2NMe2 Ni(cod) (1 equiv) Et2PhP OSO2NMe2 KF Me 2 PPhEt2 (2 equiv) Ni (1 equiv) no PPhEt2 significant 1,4-dioxane Me 1,4-dioxane reaction 42 80 ºC, 1 h 43 80 ºC, 1 h F F Reaction of 43 with KF. In a nitrogen atmosphere glovebox, Ni(cod)2 (5.5 mg 0.02 mmol, 1.00 equiv), PPhEt2 (6.6 mg 0.04 mmol, 2.00 equiv), 42 (4.7 mg, 0.02 mmol, 1.00 equiv), and 1,4-dioxane (700 µL) were combined in a one dram vial equipped with a magnetic stir bar and sealed with a PTFE-lined cap. The vial was removed from the glovebox and stirred at 80 ºC for one hour, then transferred back into the glovebox and KF (1.2 mg, 0.02 mmol, 1.00 equiv) was added. The vial was again sealed, removed from the glovebox, and stirred at 80 ºC for another hour, then transferred back into the glovebox, opened, and placed inside a drying chamber. The drying chamber was sealed, removed from the glovebox, and connected to a vacuum pump. The crude reaction mixture was concentrated under vacuum to provide a yellow-orange residue. The vacuum chamber was sealed (while under vacuum) and brought back into the glovebox. In the glovebox, the crude residue was taken up in C6D6 (1.0 mL) and filtered through celite. The filtrate was added to an NMR tube equipped with an external Ph3PO standard (as a solution in C6D6 contained within a capillary tube). The spectral data (Figure S1C on p. S22) are consistent with those of the previously isolated sulfamate compound 43 (Figure S1A), indicating that no significant reaction with KF takes place under these conditions. S2 1 110 OSO2NMe2 Ni(cod) (1 equiv) Et2PhP OSO2NMe2 LiCl Et2PhP Cl Me 2 PPhEt2 (2 equiv) Ni (1 equiv) Ni PPhEt2 PPhEt2 1,4-dioxane Me 1,4-dioxane Me 42 80 ºC, 1 h 80 ºC, 1 h F F 43 F 44 Reaction of 43 with LiCl. In a nitrogen atmosphere glovebox, Ni(cod)2 (5.5 mg 0.02 mmol, 1.00 equiv), PPhEt2 (6.6 mg 0.04 mmol, 2.00 equiv), 42 (4.7 mg, 0.02 mmol, 1.00 equiv), and 1,4-dioxane (700 µL) were combined in a one dram vial equipped with a magnetic stir bar and sealed with a PTFE-lined cap. The vial was removed from the glovebox and stirred at 80 ºC for one hour, then transferred back into the glovebox and LiCl (0.8 mg, 0.02 mmol, 1.00 equiv) was added. The vial was again sealed, removed from the glovebox, and stirred at 80 ºC for another hour, then transferred back into the glovebox, opened, and placed inside a drying chamber. The drying chamber was sealed, removed from the glovebox, and connected to a vacuum pump. The crude reaction mixture was concentrated under vacuum to provide a yellow-orange residue. The vacuum chamber was sealed (while under vacuum) and brought back into the glovebox. In the glovebox, the crude residue was taken up in C6D6 (1.0 mL) and filtered through celite. The filtrate was added to an NMR tube equipped with an external Ph3PO standard (as a solution in C6D6 contained within a capillary tube). The spectral data (Figure S1D on p. S22) are consistent with those of the previously isolated nickel(II) chloride compound 44 (Figure S1E), indicating that 43 reacts with LiCl to form 44 by anion exchange. S2 2 111 Figure S1. Comparison of 31P NMR spectra of oxidative addition complexes. No other signals are detected outside of the window shown. Free phosphine (PPhEt2) appears at about –15.8 (a trace amount of free phosphine can be seen in (A), but is not detected in the other spectra). Ph3PO was added as an internal (A) or external chemical shift standard (B, C, D, E); the molar equivalents of Ph3PO was not standardized across spectra. S2 3 112 iv. Evaluating the Catalytic Competence of 42 and PMe3 Substrate 42 and phosphine ligand PMe3 were employed as model compounds for the stoichiometric and computational studies, respectively. To confirm the relevance of these models to catalytic conditions, 42 and PMe3 were evaluated under catalytic cross-coupling conditions. OSO NMe PhSnBu3 (1 equiv) 2 2 Ni(cod)2 (5 mol%) Ph Me ligand (10 mol%) Me KF (3 equiv) 1,4-dioxane, 80 ºC, 18 h F 42 F 46 General Procedure. In a nitrogen atmosphere glovebox, KF (8.7 mg, 0.15 mmol, 3.0 equiv), 42 (11.7 mg, 0.05 mmol, 1.0 equiv), and PhSnBu3 (18.4 mg, 0.05 mmol, 1.0 equiv) were combined in a one-dram vial equipped with a stir bar. In a second vial was prepared a stock solution of Ni(cod)2 and phosphine in 1,4- dioxane (0.01 M in Ni(cod)2, 0.02 M in phosphine). The Ni/phosphine stock solution [250 µL (0.0025 mmol, 5 mol% of Ni(cod) and 0.005 mmol, 10 mol% of phosphine)] was added to the reaction vial. The vial was sealed with a PTFE-lined cap, removed from the glovebox, and stirred at 80 ºC for 18 h. The reaction vial was cooled to room temperature, and undecane was added as a GC standard. The reaction mixture was diluted with Et2O and shaken vigorously. An aliquot was removed, filtered through celite, and analyzed by GC. Table S2. Results of using 42 and PMe3 under catalytic cross coupling conditions. 46 entry Ligand (% yield)a 1 PPhEt2 ≥99 2 PMe3 25 aGC yield calibrated against undecane as an internal standard. Average of two trials. Discussion. Using a typical ligand for the Ni-catalyzed Stille coupling (PPhEt2), substrate 42 gives quantitative conversion to cross-coupled product 46. This result demonstrates that 42 is a competent substrate for catalysis. About 25% yield of 46 is obtained with PMe3, demonstrating that this small phosphine is a competent ligand for nickel under catalytic cross coupling conditions, albeit less effective than ligands such as PPhEt2. S2 4 113 v. Procedures for Equations 3 and 4 Et2PhP Cl Ph Ni PhSnBu3 (1 equiv) Me PPhEt2 (3) Me 1,4-dioxane, 80 ºC, 18 h F 44 F 46 without KF: n.d. KF (3 equiv): ≤5% Et2PhP OSO2NMe2 Ph Ni PhSnBu3 (1 equiv) Me PPhEt2 (4) Me 1,4-dioxane, 80 ºC, 18 h F 43 F 46 without KF: n.d. KF (3 equiv): 42% General Procedure. In a nitrogen atmosphere glovebox, KF (2.2 mg, 0.0375 mmol, 3.0 equiv), 43 (7.8 mg, 0.0125 mmol, 1.0 equiv) or 44 (6.7 mg, 0.0125 mmol, 1.0 equiv), PhSnBu3 (4.6 mg, 0.0125 mmol, 1.0 equiv), and 1,4-dioxane (250 µL) were combined in a one-dram vial equipped with a stir bar. The reaction vial was sealed with a PTFE-lined cap, removed from the glovebox, and stirred at 80 ºC for 18 h. The reaction vial was cooled to room temperature, and undecane was added as a GC standard. The reaction mixture was diluted with Et2O and shaken vigorously. An aliquot was removed, filtered through celite, and analyzed by GC. Yields are GC yields calibrated against undecane as an internal standard (n.d. = not detected). Discussion. When complex 44 is heated with PhSnBu3 and KF in 1,4-dioxane, only trace yield of the cross- coupled product 46 is observed (eq 3). This result in consistent with the hypothesis that the Ni-catalyzed Stille coupling is inhibited by chloride sources due to formation of a Ni(II)–chloride intermediate (such as 44) that is slow to undergo transmetalation with organostannanes. In contrast, Ni(II)-sulfamate complex 43 provides ~42% yield of 46 under the same conditions using KF (eq 4). Notably, no cross coupling product is observed with either complex in the absence of KF, which supports the hypothesis that KF is necessary for the transmetallation step. S2 5 114 II. Computational Details A. General Methods Calculations were performed with Gaussian 09 (see reference in the next section). An ultrafine integration grid and the keyword 5d were used for all calculations. Geometry optimizations of stationary points were carried out in the gas phase with the M06L40 functional with the LANL2DZ41 pseudopotential for Ni and Sn, the 6-31+G(d) basis set for O, F, K, and Cl, and the 6-31G(d) basis set for all other atoms. Frequency analyses were carried out at the same level to evaluate the zero-point vibrational energy and thermal corrections at 298 K. The nature of the stationary points was determined in each case according to the appropriate number of negative eigenvalues of the Hessian matrix. Forward and reverse intrinsic reaction coordinate (IRC) calculations were carried out on representative optimized transition structures to ensure that the TSs indeed connect the appropriate reactants and products.42–44 Notably, the potential energy surface is quite flat near the transition states for transmetallation, so most IRC calculations terminated early. Multiple conformations were considered for all structures when applicable, as well as configurational isomers of the complexes. In all cases, the trans complexes (with Ph trans to X, where X ≠ PMe3) are significantly lower energy than the cis complexes (with Ph trans to PMe3). The lowest energy conformations/configurations are reported. Single point energy calculations were performed on the gas- phase optimized geometries using the M06L functional with the SDD45,46 pseudopotential for Ni and Sn and the 6-311++G(2d,p) basis set for all other atoms. Bulk solvent effects in 1,4-dioxane were considered implicitly in the single point energy calculations through the CPCM continuum solvation model.47 Images of optimized structures were generated with CYLview.48 40 Zhao, Y.; Truhlar, D. G. J. Chem. Phys. 2006, 125, 194101–194118. 41 Hay, P.J.; Wadt, W.R. J. Chem. Phys. 1985, 82, 299–310. 42 Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154–2161. 43 Gonzalez, C.; Schlegel, H.B. J. Phys. Chem. 1990, 94, 5523–5527. 44 Fukui, K. Acc. Chem. Res. 1981, 14, 363–368. 45 Dolg, M.; Wedig, U.; Stoll, H.; Preuss, H. J. Chem. Phys. 1987, 86, 866–872. 46 Andrae, D.; Haussermann, U.; Dolg, M.; Stoll, H. Preuss, H. Theor. Chim. Acta 1990, 77, 123–141. 47 Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem. 2003, 24, 669–681. 48 CYLview, 1.0b; Legault CY, Université de Sherbrooke, 2009 (http://www.cylview.org) S2 6 115 B. Graphical Guide to Numbered Compounds PMe3 LiOSO2NMe2 KOSO2NMe2 KF LiCl PhSnMe3 PMe3 O PMe3 Ph Ni O S O PMe3 PMe3 PMe3 Ph Ni OSO NMe Me NMe2 2 2 K Ph Ni OSO2NMe2 Ph Ni Cl Ph Ni F Sn F SnMe PMe PMe PMe 3 3 3 3 Me Me 38 39C 39D 40A 40B ‡ O ‡ PMe Me3P3 Me2N ‡ PMe3 PMe S 3 Ph Ni O O O PMe Ph Ni Cl Ph Ni F S NMe Ph Ni O 3 Me 2 Me K Ph Ni Cl Sn O F SnMe Sn 3 SnMe3 Me Me Me Me SnMe3 40C 40D TSA TSB TSC ‡ PMe3 PMe O 3 PMe S 3 Ph O PMe Ni PMe O S NMe Ph Ni O O 3 3 Ph Ni F 2 NMe2 K Ph Ni Cl Ph Ni F O Me SnMe3 SnMe3 SnMe3 Sn Me Sn F Me Me Me Me TSD 41A 41B 41C 41D S2 7 116 C. Energies, Entropies, and Lowest Frequencies of Minimum Energy Structures Table S3. Energies, Entropies, and Lowest Frequencies of Minimum Energy Structuresa Structure Eelec Eelec + ZPE H (Hartree) S Gb Lowest # of (Hartree) (Hartree) (cal (Hartree) freq. imag mol–1 (cm–1) freq. K–1) PhSnMe3 -354.796223 -354.597565 -354.582613 122.1 -354.640650 22.2 0 PMe3 -461.118031 -461.004584 -460.996950 77.7 -461.033891 177.2 0 LiOSO2NMe2 -766.120786 -766.021721 -766.012132 89.6 -766.054721 75.3 0 KOSO2NMe2 -1358.503420 -1358.406352 -1358.395691 98.6 -1358.442554 53.3 0 KF -699.858880 -699.857943 -699.854340 54.3 -699.880123 411.2 0 LiCl -467.849208 -467.847802 -467.844347 50.9 -467.868529 617.1 0 38 -2083.499890 -2083.080254 -2083.048892 194.6 -2083.141350 12.3 0 39C -1785.239697 -1784.917462 -1784.892992 163.8 -1784.970798 24.2 0 39D -1424.866893 -1424.544609 -1424.520067 165.0 -1424.598476 31.1 0 40A -1977.147957 -1976.643118 -1976.604833 227.1 -1976.712725 21.9 0 40B -2677.039145 -2676.532788 -2676.491084 241.9 -2676.606008 24.5 0 40C -1678.887033 -1678.479988 -1678.448427 198.6 -1678.542783 14.0 0 40D -1318.524969 -1318.117733 -1318.086484 196.0 -1318.179588 16.8 0 TSA -1977.141716 -1976.636676 -1976.599395 219.7 -1976.703790 -42.3 1 TSB -2677.038604 -2676.532389 -2676.491478 237.5 -2676.604323 -32.0 1 TSC -1678.884716 -1678.477900 -1678.447086 193.1 -1678.538844 -33.1 1 TSD -1318.519477 -1318.112177 -1318.081675 191.8 -1318.172789 -16.6 1 41A -1977.144387 -1976.638726 -1976.600822 223.7 -1976.707097 30.3 0 41B -2677.054323 -2676.547636 -2676.505941 243.1 -2676.621426 28.5 0 41C -1678.887227 -1678.479824 -1678.448344 196.4 -1678.541649 29.7 0 41D -1318.520299 -1318.112890 -1318.081565 198.6 -1318.175909 24.3 0 aEnergy values calculated at the CPCM(1,4-dioxane)-M06L/6-311++G(2d,p)/SDD(Ni,Sn)//M06L/6- 31+G(d)(O,F,K,Cl)/6-31G(d)(C,H,N,P,S)/LANL2DZ(Ni,Sn) level, referred to as (CPCM)/M06L/BS2//M06L/BS1. 1 Hartree = 627.51 kcal mol-1. Thermal corrections at 298.15 K. bSolvent-corrected free energy given by G[(CPCM)/M06L/BS2] = Eelec[(CPCM)/M06L/BS2] + Gcorr[M06L/BS1], where Gcorr is the thermal correction to Gibbs free energy obtained in the gas phase. S2 8 117 III. X-Ray Crystallographic Details for Compounds 43 and 44 CCDC Deposition Numbers: 1881432 (43) and 1898148 (44) X-ray diffraction data for 43 and 44 were collected at 100 K on a Bruker D8 Venture using MoΚα-radiation (λ=0.71073 Å). Data have been corrected for absorption using SADABS49 area detector absorption correction program. Using Olex2,50 the structure was solved with the SHELXT51 structure solution program using Direct Methods and refined with the SHELXL52 refinement package using least squares minimization. All non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms of the investigated complex were located from difference Fourier maps but finally their positions were placed in geometrically calculated positions and refined using a riding model. Isotropic thermal parameters of the placed hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). Calculations and refinement of structures were carried out using APEX3,53 SHELXTL,54 and Olex2 software. Table S4. Crystal data and structure refinement for 43. Identification code MSU_SN10(1-JR-172) Empirical formula C29H42FNNiO3P2S Formula weight 624.34 Temperature/K 100 Crystal system monoclinic Space group P21/m a/Å 8.6752(3) b/Å 12.5702(4) c/Å 14.4059(5) α/° 90 β/° 101.7950(10) γ/° 90 Volume/Å3 1537.78(9) Z 2 ρcalcg/cm3 1.348 µ/mm-1 0.839 F(000) 660.0 Crystal size/mm3 0.21 × 0.16 × 0.03 Radiation MoKα (λ = 0.71073) 2Θ range for data collection/° 5.778 to 55.106 Index ranges -11 ≤ h ≤ 11, -16 ≤ k ≤ 15, -18 ≤ l ≤ 18 Reflections collected 42439 Independent reflections 3706 [Rint = 0.0268, Rsigma = 0.0127] Data/restraints/parameters 3706/0/194 Goodness-of-fit on F2 1.070 Final R indexes [I>=2σ (I)] R1 = 0.0238, wR2 = 0.0593 Final R indexes [all data] R1 = 0.0275, wR2 = 0.0613 Largest diff. peak/hole / e Å-3 0.43/-0.28 49 Sheldrick, G. M. (1996). SADABS: Area Detector Absorption Correction; University of Göttingen, Germany. 50 Dolomanov, O.V.; Bourhis, L.J.; Gildea, R.J.; Howard, J.A.K.; Puschmann, H., J. Appl. Cryst. 2009, 42, 339-341. 51 Sheldrick, G. M. Acta Cryst. 2015, A71, 3-8. 52 Sheldrick, G. M. Acta Cryst. 2015, C71, 3-8. 53 Bruker (2016). APEX3. Bruker AXS Inc., Madison, Wisconsin, USA. 54 Sheldrick, G.M. Acta Cryst. 2008, A64, 112-122. S2 9 118 Table S5. Crystal data and structure refinement for 44. Identification code MSU_SN11(2-JR-16) Empirical formula C27H36ClFNiP2 Formula weight 535.66 Temperature/K 100 Crystal system monoclinic Space group P21/n a/Å 11.8371(9) b/Å 14.1571(10) c/Å 16.2044(12) α/° 90 β/° 99.776(3) γ/° 90 Volume/Å3 2676.1(3) Z 4 ρcalcg/cm3 1.330 µ/mm-1 0.964 F(000) 1128.0 Crystal size/mm3 0.26 × 0.14 × 0.08 Radiation MoKα (λ = 0.71073) 2Θ range for data collection/° 5.858 to 61.18 Index ranges -16 ≤ h ≤ 16, -20 ≤ k ≤ 20, -23 ≤ l ≤ 23 Reflections collected 72735 Independent reflections 8200 [Rint = 0.0440, Rsigma = 0.0284] Data/restraints/parameters 8200/0/294 Goodness-of-fit on F2 1.040 Final R indexes [I>=2σ (I)] R1 = 0.0304, wR2 = 0.0658 Final R indexes [all data] R1 = 0.0460, wR2 = 0.0708 Largest diff. peak/hole / e Å-3 0.48/-0.30 Table S6. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 43. Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor. Atom x y z U(eq) Ni1 6992.0(2) 7500 7336.5(2) 10.43(7) S1 8820.3(5) 7500 9436.8(3) 13.78(9) P1 6986.7(3) 5748.2(2) 7187.4(2) 11.41(8) F1 881.0(15) 7500 4413.0(9) 35.6(3) O1 8811.7(14) 7500 8393.3(8) 14.0(2) O2 8173.9(11) 6529.0(7) 9732.5(6) 20.9(2) N1 10703.1(18) 7500 9963.8(10) 17.0(3) C1 5120(2) 7500 6380.0(12) 13.2(3) C2 3670(2) 7500 6678.4(13) 16.5(3) C3 2255(2) 7500 6007.8(15) 22.1(4) C4 2282(2) 7500 5056.8(14) 22.5(4) C5 3663(2) 7500 4727.0(13) 19.4(4) C6 5072(2) 7500 5397.6(12) 14.7(3) C7 3585(2) 7500 7712.6(14) 22.9(4) C8 5319.6(14) 5063.3(10) 7503.7(9) 15.0(2) C9 4110.7(17) 4607.3(13) 6840.4(10) 26.6(3) C10 2889.7(19) 4070.0(16) 7133.6(12) 37.6(4) C11 2877.7(17) 3979.0(14) 8089.2(11) 31.3(3) ~Table S6 continued on the next page~ S30 119 ~Table S6 continued from the previous page~ C12 4059.0(17) 4442.0(12) 8752.4(10) 26.1(3) C13 5266.9(16) 4988.4(11) 8465.5(9) 21.7(3) C14 8666.4(14) 5061.9(10) 7920.6(9) 15.5(2) C15 8664.6(16) 3855.2(10) 7782.0(9) 20.4(3) C16 7023.9(15) 5282.5(10) 5989.9(8) 15.5(2) C17 8511.5(16) 5642.0(13) 5662.8(10) 25.3(3) C18 11554.6(17) 8469.2(11) 9796.6(10) 23.3(3) Table S7. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 44. Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor. Atom x y z U(eq) Ni1 2644.3(2) 2435.2(2) 4065.6(2) 11.13(5) Cl1 2812.7(3) 1133.5(2) 3323.6(2) 16.25(7) P1 1226.7(3) 1805.4(2) 4598.5(2) 12.33(7) P2 4357.0(3) 2947.3(2) 3950.4(2) 12.16(7) F1 1658.8(8) 5916.1(6) 5992.0(6) 26.4(2) C1 2423.9(11) 3562.7(9) 4659.6(8) 12.7(2) C2 1661.6(11) 4261.9(9) 4272.8(8) 13.7(2) C3 1420.7(11) 5055.9(10) 4726.2(9) 16.2(3) C4 1922.1(12) 5141.8(10) 5555.2(9) 16.7(3) C5 2674.4(11) 4483.0(10) 5960.4(9) 16.6(3) C6 2927.2(11) 3699.0(9) 5501.4(8) 14.6(3) C7 1054.2(12) 4164.5(11) 3378.5(9) 19.7(3) C8 1977.6(11) 1069.9(9) 5441.1(8) 13.9(2) C9 2397.2(12) 182.2(10) 5264.3(9) 18.1(3) C10 3052.0(13) -344.9(11) 5890.4(10) 22.5(3) C11 3315.8(13) 8.3(11) 6699.5(10) 24.1(3) C12 2918.3(13) 889.9(12) 6882.8(9) 24.3(3) C13 2247.0(13) 1416.9(11) 6257.7(9) 20.0(3) C14 247.5(12) 1003.4(10) 3940.1(9) 18.8(3) C15 -486.5(14) 1527.8(13) 3216.7(10) 29.4(4) C16 269.5(12) 2549.0(10) 5096.8(9) 17.3(3) C17 -628.9(13) 2032.8(11) 5503.6(11) 26.5(3) C18 5273.2(11) 2661.8(10) 4940.7(8) 14.9(3) C19 5197.1(13) 1757.9(11) 5272.6(9) 21.8(3) C20 5869.5(14) 1509.1(13) 6033.0(10) 30.2(4) C21 6606.5(14) 2168.4(14) 6471.4(10) 31.6(4) C22 6683.6(13) 3064.7(13) 6157.7(9) 27.0(3) C23 6029.2(12) 3313.8(11) 5391.0(9) 20.3(3) C24 5070.3(12) 2357.8(10) 3169.3(9) 17.7(3) C25 6301.3(13) 2675.0(11) 3162.4(10) 23.8(3) C26 4605.0(12) 4199.6(10) 3784.8(9) 18.4(3) C27 4091.3(15) 4529.8(12) 2904.3(11) 30.8(4) Table S8. Anisotropic Displacement Parameters (Å2×103) for 43. The Anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+2hka*b*U12+…]. Atom U11 U22 U33 U23 U13 U12 Ni1 13.26(11) 8.88(11) 8.81(10) 0 1.46(8) 0 ~Table S8 continued on the next page~ S31 120 ~Table S8 continued from the previous page~ S1 17.2(2) 14.4(2) 9.69(18) 0 2.59(15) 0 P1 14.07(15) 9.17(15) 10.92(14) 0.02(10) 2.41(11) -0.43(11) F1 22.7(6) 40.5(8) 35.6(7) 0 -13.1(5) 0 O1 16.4(6) 15.0(6) 9.5(5) 0 0.1(4) 0 O2 26.4(5) 20.0(5) 17.3(4) 2.1(4) 6.8(4) -4.7(4) N1 18.8(7) 18.0(8) 12.2(7) 0 -1.6(6) 0 C1 16.0(8) 8.6(7) 14.3(8) 0 1.8(6) 0 C2 19.2(9) 10.8(8) 19.6(8) 0 4.3(7) 0 C3 16.1(9) 17.5(9) 32.2(10) 0 3.5(8) 0 C4 19.6(9) 15.9(9) 26.2(10) 0 -9.0(7) 0 C5 28.4(10) 11.1(8) 15.4(8) 0 -3.2(7) 0 C6 19.5(8) 9.8(8) 14.2(8) 0 2.2(7) 0 C7 24.1(10) 24.8(10) 22.1(9) 0 10.4(8) 0 C8 16.0(6) 11.5(6) 17.9(6) 2.4(4) 4.6(5) 0.2(4) C9 24.8(7) 34.5(8) 19.4(6) 2.6(6) 1.7(5) -10.5(6) C10 26.7(8) 53.0(11) 30.4(8) 3.7(7) -0.3(6) -20.8(7) C11 23.1(7) 36.8(9) 35.3(8) 9.9(7) 9.2(6) -8.7(6) C12 27.2(7) 31.1(8) 22.3(7) 6.0(6) 10.6(6) -2.5(6) C13 23.2(7) 23.8(7) 18.8(6) -0.8(5) 5.7(5) -4.6(5) C14 16.7(6) 13.3(6) 15.4(5) 1.5(4) 0.8(4) 1.7(5) C15 23.7(7) 13.0(6) 23.6(6) 1.3(5) 2.9(5) 3.6(5) C16 19.9(6) 13.9(6) 12.6(5) -2.4(4) 3.3(4) 1.0(5) C17 22.7(7) 36.3(8) 18.7(6) 0.1(6) 7.9(5) 2.4(6) C18 22.7(7) 23.9(7) 21.4(6) -2.7(5) 0.3(5) -5.9(5) Table S9. Anisotropic Displacement Parameters (Å2×103) for 44. The Anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+2hka*b*U12+…]. Atom U11 U22 U33 U23 U13 U12 Ni1 11.25(8) 11.00(8) 11.05(8) -0.68(6) 1.68(6) 0.48(6) Cl1 17.87(15) 14.78(15) 16.68(15) -5.35(12) 4.58(12) -2.14(11) P1 11.66(15) 11.96(15) 13.46(16) -0.96(12) 2.38(12) -0.02(12) P2 12.27(15) 11.48(15) 12.68(15) 1.77(12) 2.04(12) 0.97(12) F1 30.6(5) 23.1(4) 24.5(5) -11.9(4) 1.3(4) 7.8(4) C1 11.7(5) 12.5(6) 14.5(6) -0.5(5) 3.8(5) -0.6(5) C2 13.5(6) 14.3(6) 13.4(6) 0.3(5) 2.4(5) -0.1(5) C3 15.0(6) 15.0(6) 18.2(7) 0.0(5) 2.1(5) 2.6(5) C4 17.6(6) 14.4(6) 18.8(7) -6.3(5) 4.8(5) 0.1(5) C5 15.5(6) 20.3(7) 13.8(6) -3.1(5) 1.3(5) -2.8(5) C6 11.7(6) 15.7(6) 16.0(6) 1.1(5) 1.1(5) 0.6(5) C7 21.7(7) 22.1(7) 14.5(6) -1.0(5) 0.5(5) 5.7(5) C8 13.1(6) 14.9(6) 14.4(6) 1.9(5) 4.1(5) 0.0(5) C9 21.5(7) 15.9(6) 17.2(6) -0.6(5) 4.4(5) 0.7(5) C10 26.3(7) 17.1(7) 24.7(7) 3.1(6) 6.1(6) 6.3(6) C11 24.5(7) 27.5(8) 20.3(7) 7.9(6) 3.8(6) 7.6(6) C12 27.3(8) 29.8(8) 15.5(7) 0.8(6) 3.2(6) 6.6(6) C13 23.5(7) 20.3(7) 16.6(7) -1.5(6) 4.2(5) 5.6(6) C14 15.1(6) 20.4(7) 20.4(7) -5.5(6) 2.2(5) -4.4(5) C15 21.6(7) 36.2(9) 26.8(8) -6.0(7) -6.3(6) 0.1(7) C16 15.4(6) 15.1(6) 22.2(7) -0.8(5) 5.7(5) 2.4(5) C17 22.5(7) 23.9(8) 37.1(9) -2.4(7) 16.4(7) -0.6(6) C18 11.7(6) 19.1(6) 14.4(6) 1.4(5) 3.4(5) 3.4(5) ~Table S9 continued on the next page~ S32 121 ~Table S9 continued from the previous page~ C19 19.3(7) 24.0(7) 21.7(7) 6.8(6) 2.6(5) 0.7(6) C20 25.6(8) 37.4(9) 27.4(8) 17.6(7) 4.0(6) 4.1(7) C21 20.0(7) 57.4(12) 16.9(7) 11.9(7) 1.5(6) 4.5(7) C22 19.9(7) 44.6(10) 15.9(7) -4.2(7) 1.3(6) -0.9(7) C23 17.9(7) 24.5(7) 18.5(7) -2.0(6) 3.4(5) 0.6(5) C24 18.4(6) 19.7(7) 16.1(6) 0.2(5) 6.4(5) 2.0(5) C25 21.7(7) 25.2(8) 27.6(8) 2.9(6) 12.7(6) 0.2(6) C26 16.9(6) 13.1(6) 25.6(7) 4.0(5) 4.5(5) -0.9(5) C27 29.8(8) 24.0(8) 36.4(9) 15.9(7) -0.3(7) 0.8(6) Table S10. Bond Lengths for 43. Atom Atom Length/Å Atom Atom Length/Å Ni1 P11 2.2124(3) C1 C6 1.407(2) Ni1 P1 2.2124(3) C2 C3 1.399(3) Ni1 O1 1.9563(12) C2 C7 1.507(2) Ni1 C1 1.9027(17) C3 C4 1.375(3) S1 O1 1.5018(12) C4 C5 1.376(3) S1 O21 1.4434(9) C5 C6 1.394(2) S1 O2 1.4434(9) C8 C9 1.3899(18) S1 N1 1.6545(16) C8 C13 1.3987(17) P1 C8 1.8193(13) C9 C10 1.393(2) P1 C14 1.8314(12) C10 C11 1.384(2) P1 C16 1.8283(12) C11 C12 1.379(2) F1 C4 1.370(2) C12 C13 1.3848(19) N1 C181 1.4700(16) C14 C15 1.5298(18) N1 C18 1.4699(16) C16 C17 1.5298(18) C1 C2 1.411(2) 1+X,3/2-Y,+Z Table S11. Bond Lengths for 44. Atom Atom Length/Å Atom Atom Length/Å Ni1 Cl1 2.2277(4) C5 C6 1.3965(19) Ni1 P1 2.2020(4) C8 C9 1.3988(19) Ni1 P2 2.1907(4) C8 C13 1.3966(19) Ni1 C1 1.9047(13) C9 C10 1.386(2) P1 C8 1.8239(14) C10 C11 1.388(2) P1 C14 1.8306(14) C11 C12 1.384(2) P1 C16 1.8316(14) C12 C13 1.393(2) P2 C18 1.8230(14) C14 C15 1.528(2) P2 C24 1.8370(14) C16 C17 1.529(2) P2 C26 1.8243(14) C18 C19 1.397(2) F1 C4 1.3692(15) C18 C23 1.401(2) C1 C2 1.4124(18) C19 C20 1.394(2) C1 C6 1.4061(18) C20 C21 1.388(3) C2 C3 1.3985(19) C21 C22 1.376(3) C2 C7 1.5107(18) C22 C23 1.393(2) C3 C4 1.3787(19) C24 C25 1.527(2) C4 C5 1.3768(19) C26 C27 1.526(2) S33 122 Table S12. Bond Angles for 43. Atom Atom Atom Angle/˚ Ato m Atom Atom Angle/˚ P1 Ni1 P11 168.902(18) C2 C1 Ni1 117.49(13) O1 Ni1 P11 93.491(10) C6 C1 Ni1 125.04(13) O1 Ni1 P1 93.491(10) C6 C1 C2 117.47(16) C1 Ni1 P11 86.856(10) C1 C2 C7 121.90(16) C1 Ni1 P1 86.856(10) C3 C2 C1 120.09(17) C1 Ni1 O1 175.53(6) C3 C2 C7 118.01(17) O1 S1 N1 105.17(7) C4 C3 C2 119.78(18) O2 S1 O1 111.88(4) F1 C4 C3 118.74(18) O21 S1 O1 111.88(4) F1 C4 C5 118.74(18) O2 S1 O21 115.48(8) C3 C4 C5 122.52(17) O2 S1 N1 105.74(5) C4 C5 C6 117.54(17) O21 S1 N1 105.74(5) C5 C6 C1 122.59(17) C8 P1 Ni1 115.64(4) C9 C8 P1 123.34(10) C8 P1 C14 102.25(6) C9 C8 C13 118.71(12) C8 P1 C16 104.66(6) C13 C8 P1 117.94(10) C14 P1 Ni1 115.29(4) C8 C9 C10 120.35(13) C16 P1 Ni1 114.22(4) C11 C10 C9 120.18(14) C16 P1 C14 103.17(6) C12 C11 C10 119.92(14) S1 O1 Ni1 128.10(8) C11 C12 C13 120.21(13) C181 N1 S1 114.01(8) C12 C13 C8 120.59(13) C18 N1 S1 114.01(8) C15 C14 P1 114.35(9) C18 N1 C181 111.96(15) C17 C16 P1 112.01(9) 1+X,3/2-Y,+Z Table S13. Bond Angles for 44. Atom Atom Atom Angle/˚ Atom Atom Atom Angle/˚ P1 Ni1 Cl1 91.190(14) F1 C4 C3 118.43(12) P2 Ni1 Cl1 93.375(14) F1 C4 C5 118.78(12) P2 Ni1 P1 160.959(15) C5 C4 C3 122.79(13) C1 Ni1 Cl1 176.86(4) C4 C5 C6 117.65(12) C1 Ni1 P1 87.83(4) C5 C6 C1 122.14(12) C1 Ni1 P2 88.50(4) C9 C8 P1 120.30(10) C8 P1 Ni1 102.58(4) C13 C8 P1 120.81(10) C8 P1 C14 105.19(7) C13 C8 C9 118.57(12) C8 P1 C16 104.92(6) C10 C9 C8 120.52(13) C14 P1 Ni1 118.15(5) C9 C10 C11 120.37(14) C14 P1 C16 103.62(7) C12 C11 C10 119.83(14) C16 P1 Ni1 120.65(5) C11 C12 C13 119.97(14) C18 P2 Ni1 105.81(4) C12 C13 C8 120.72(13) C18 P2 C24 103.38(6) C15 C14 P1 111.53(11) C18 P2 C26 104.98(7) C17 C16 P1 116.29(10) C24 P2 Ni1 116.66(5) C19 C18 P2 118.32(11) C26 P2 Ni1 120.57(5) C19 C18 C23 118.70(13) C26 P2 C24 103.64(7) C23 C18 P2 122.97(11) C2 C1 Ni1 119.67(10) C20 C19 C18 120.48(15) C6 C1 Ni1 122.24(10) C21 C20 C19 119.84(16) C6 C1 C2 117.90(12) C22 C21 C20 120.43(14) C1 C2 C7 121.73(12) C21 C22 C23 120.08(15) C3 C2 C1 120.14(12) C22 C23 C18 120.45(15) C3 C2 C7 118.10(12) C25 C24 P2 114.98(10) C4 C3 C2 119.36(12) C27 C26 P2 112.75(11) S34 123 Table S14. Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for 43. Atom x y z U(eq) H3 1277 7500 6209 27 H5 3657 7500 4067 23 H6 6037 7500 5183 18 H7A 3291 8211 7895 34 H7B 4615 7306 8095 34 H7C 2794 6983 7820 34 H9 4117 4662 6184 32 H10 2063 3765 6676 45 H11 2057 3598 8288 38 H12 4044 4386 9408 31 H13 6067 5315 8926 26 H14A 9649 5356 7775 19 H14B 8674 5215 8596 19 H15A 8960 3690 7177 31 H15B 7609 3575 7779 31 H15C 9423 3528 8302 31 H16A 6969 4496 5976 19 H16B 6087 5559 5544 19 H17A 8487 5376 5021 38 H17B 9441 5360 6096 38 H17C 8559 6421 5662 38 H18A 11655 8493 9132 35 H18B 12605 8466 10208 35 H18C 10971 9096 9939 35 Table S15. Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for 44. Atom x y z U(eq) H3 916 5532 4465 19 H5 3010 4559 6532 20 H6 3456 3243 5767 18 H7A 1327 4655 3034 30 H7B 226 4235 3358 30 H7C 1215 3541 3164 30 H9 2232 -61 4711 22 H10 3322 -951 5765 27 H11 3768 -354 7126 29 H12 3103 1136 7435 29 H13 1969 2019 6388 24 H14A 697 507 3713 23 H14B -258 692 4286 23 H15A 11 1814 2860 44 H15B -928 2023 3440 44 H15C -1013 1082 2885 44 H16A 745 2937 5531 21 H16B -134 2987 4669 21 H17A -1179 1719 5070 40 H17B -1033 2488 5804 40 H17C -250 1560 5898 40 H19 4683 1309 4978 26 H20 5823 890 6251 36 ~Table S15 continued on the next page~ S35 124 ~Table S15 continued from the previous page~ H21 7061 2000 6991 38 H22 7184 3514 6464 32 H23 6096 3930 5172 24 H24A 5071 1669 3273 21 H24B 4614 2471 2607 21 H25A 6646 2271 2782 36 H25B 6746 2625 3729 36 H25C 6302 3332 2972 36 H26A 4267 4573 4198 22 H26B 5441 4321 3883 22 H27A 3271 4380 2791 46 H27B 4477 4208 2495 46 H27C 4196 5214 2862 46 Table S16. Atomic Occupancy for 43. Atom Occupancy Atom Occupancy Atom Occupancy H7A 0.5 H7B 0.5 H7C 0.5 S36 125 Figure S2. X-ray crystal structure of 43. All thermal ellipsoids drawn at the 50% probability level. Figure S3. X-ray crystal structure of 44. All thermal ellipsoids drawn at the 50% probability level. S3 7 126 IV. Cartesian Coordinates of Minimum Energy Calculated Structures PhSnMe3 O 0.384480 1.235111 -0.775158 Charge: 0 Multiplicity: 1 N -1.800280 0.000026 -0.352666 C -3.182838 1.192883 -0.000016 C -2.425088 -1.211323 0.165183 C -1.788903 1.197802 0.000012 H -3.468931 -1.221950 -0.168610 C -1.054321 0.003699 0.000026 H -1.915129 -2.085084 -0.246528 C -1.773715 -1.200778 0.000017 H -2.405069 -1.262801 1.267300 C -3.166572 -1.215356 -0.000006 C -2.424993 1.211439 0.165143 C -3.874192 -0.015519 -0.000034 H -1.914963 2.085147 -0.246595 H -3.731030 2.134377 -0.000027 H -3.468834 1.222139 -0.168654 H -1.268328 2.157651 0.000048 H -2.404972 1.262951 1.267258 H -1.241820 -2.155408 0.000052 H -3.702129 -2.164073 -0.000003 H -4.963150 -0.023002 -0.000067 KF Sn 1.096325 0.007373 -0.000001 Charge: 0 Multiplicity: 1 C 1.793844 -1.028327 -1.745947 K 0.000000 0.000000 0.721969 H 2.883300 -1.139755 -1.735924 F 0.000000 0.000000 -1.524157 H 1.356727 -2.031447 -1.802792 H 1.517883 -0.494356 -2.660961 C 1.747964 2.049938 0.000399 LiCl H 1.382117 2.581501 0.885648 Charge: 0 Multiplicity: 1 H 2.840633 2.119787 -0.000021 Cl 0.000000 0.000000 0.308238 H 1.381445 2.582081 -0.884226 Li 0.000000 0.000000 -1.746685 C 1.793797 -1.029013 1.745550 H 2.883340 -1.139610 1.736029 H 1.516939 -0.495871 2.660780 38 H 1.357414 -2.032507 1.801518 Charge: 0 Multiplicity: 1 Ni 0.384013 -0.002097 0.383291 C 2.222614 0.083189 -0.040756 PMe3 C 2.620005 0.060012 -1.385967 Charge: 0 Multiplicity: 1 C 3.223253 0.134088 0.940544 P -0.000047 0.000042 -0.614852 C 3.971049 0.076404 -1.737733 C 0.999757 1.270620 0.282371 H 1.863242 0.029452 -2.173464 H 2.055695 1.185644 0.002824 C 4.573573 0.152990 0.590583 H 0.668415 2.276987 0.003434 H 2.947871 0.155239 1.997166 H 0.922159 1.171362 1.373796 C 4.953170 0.120567 -0.750413 C -1.600369 0.230384 0.282373 H 4.255879 0.054848 -2.789708 H -2.055298 1.187006 0.002610 H 5.334068 0.190463 1.370831 H -2.305886 -0.560211 0.003873 H 6.006998 0.132165 -1.023473 H -1.475460 0.213229 1.373780 P 0.541446 -2.235256 0.295086 C 0.600658 -1.501044 0.282324 P 0.343038 2.235786 0.361945 H -0.000105 -2.373392 0.002217 C 1.636036 3.097474 1.328170 H 1.638211 -1.716527 0.004096 H 2.626737 2.812922 0.959269 H 0.552699 -1.384485 1.373737 H 1.523403 4.185587 1.250285 H 1.575590 2.815153 2.384672 C -1.198070 2.992996 0.979003 LiOSO2NMe2 H -1.385039 2.668250 2.007166 Charge: 0 Multiplicity: 1 H -1.132943 4.087771 0.951264 O -0.898493 0.118483 1.347220 H -2.038534 2.658090 0.364619 S -0.560741 -0.272640 -0.081614 C 0.556030 2.945905 -1.303104 O -1.343027 0.703011 -0.922543 H 1.530377 2.646395 -1.703843 O -0.705252 -1.684755 -0.386275 H -0.229916 2.555726 -1.955689 N 1.059232 0.103924 -0.387445 H 0.502449 4.041105 -1.277119 C 1.391424 1.497480 -0.134318 C 0.444343 -2.870729 -1.411990 H 2.404505 1.678631 -0.508857 H 0.512080 -3.965502 -1.430566 H 0.705172 2.143377 -0.688316 H -0.506713 -2.557143 -1.854145 H 1.366011 1.756216 0.939103 H 1.269343 -2.455688 -2.001187 C 1.984954 -0.821070 0.260020 C -0.775403 -3.137768 1.179137 H 1.694466 -1.846831 0.027156 H -1.739682 -2.861897 0.742274 H 2.984497 -0.635937 -0.147519 H -0.630975 -4.222222 1.099438 H 2.019855 -0.690597 1.354932 H -0.779520 -2.853139 2.236217 Li -2.100455 1.359175 0.660002 C 2.077658 -3.007955 0.917622 H 2.934697 -2.651425 0.336964 H 2.248624 -2.736922 1.964728 KOSO2NMe2 H 2.021036 -4.100499 0.840814 Charge: 0 Multiplicity: 1 O -1.568675 -0.093059 0.808049 O 0.205969 -0.000002 1.336318 S -2.385626 -0.115617 -0.476350 K 2.706989 0.000024 0.129665 O -1.972312 0.929341 -1.425440 S -0.121943 -0.000037 -0.123103 O -2.490347 -1.478788 -1.030602 O 0.384380 -1.235254 -0.775092 N -3.909973 0.384279 0.111040 S3 8 127 C -4.862982 0.563784 -0.980918 H -3.802800 -1.540341 1.666474 H -5.765810 1.026501 -0.567052 H -2.179938 -2.274447 1.838344 H -4.436481 1.233479 -1.731191 C -2.867623 -2.026816 -1.147539 H -5.144094 -0.388063 -1.463136 H -2.278834 -2.937399 -1.000769 C -4.424502 -0.527887 1.127648 H -3.928703 -2.228583 -0.955596 H -3.684933 -0.641016 1.924171 H -2.750660 -1.709592 -2.188632 H -5.332846 -0.085105 1.551377 C -3.248777 0.710555 -0.311299 H -4.674664 -1.522180 0.719005 H -2.961635 1.508547 0.382173 H -3.085909 1.090733 -1.325204 H -4.313866 0.483706 -0.182078 39C C 3.248888 0.709983 -0.311396 Charge: 0 Multiplicity: 1 H 4.313934 0.482979 -0.182095 Ni -0.000326 0.565200 -0.093088 H 3.086128 1.090044 -1.325362 C 0.000753 -1.329553 -0.054691 H 2.961843 1.508118 0.381951 C 0.001191 -2.109778 -1.218817 C 2.867326 -2.027452 -1.147257 C 0.001156 -1.994915 1.180643 H 2.750494 -1.710342 -2.188399 C 0.001993 -3.503531 -1.152399 H 3.928357 -2.229389 -0.955215 H 0.000898 -1.625364 -2.197782 H 2.278356 -2.937905 -1.000412 C 0.001968 -3.389266 1.250149 C 2.722930 -1.349592 1.621351 H 0.000836 -1.417965 2.109227 H 2.463634 -0.610026 2.386479 C 0.002377 -4.149775 0.082360 H 2.179506 -2.274542 1.838635 H 0.002318 -4.089133 -2.072210 H 3.802473 -1.540682 1.666730 H 0.002271 -3.883379 2.222143 F -0.000235 -2.528475 0.003675 H 0.003003 -5.237284 0.134249 P -2.218763 0.565143 -0.041069 P 2.218105 0.567605 -0.041073 40A C 2.798985 1.149340 1.589574 Charge: 0 Multiplicity: 1 H 2.466520 0.456702 2.370310 C -0.627831 0.268035 2.854923 H 3.892471 1.228210 1.629657 C -1.942113 0.585895 3.194248 H 2.352191 2.129128 1.787016 C -0.377699 -0.672288 1.840466 C 3.021694 1.719631 -1.207115 H -2.148330 1.300195 3.990039 H 2.577699 2.711414 -1.078287 C -2.990957 -0.016421 2.505018 H 4.104219 1.770428 -1.037218 H 0.638991 -1.025458 1.694413 H 2.840587 1.397317 -2.237484 C -1.429504 -1.255549 1.101357 C 3.145077 -0.988042 -0.285750 C -2.736222 -0.906027 1.459570 H 2.814796 -1.737302 0.441526 H -4.020063 0.230836 2.764503 H 2.939303 -1.392691 -1.282155 H 0.211206 0.693119 3.405994 H 4.225121 -0.830302 -0.180066 Ni 0.168661 1.132945 0.469819 C -3.144036 -0.991513 -0.285777 H -3.582798 -1.323508 0.911285 H -4.224251 -0.834958 -0.180080 C -1.563414 1.720385 0.014891 H -2.937832 -1.395909 -1.282195 C -2.262280 1.195051 -1.079069 H -2.812930 -1.740431 0.441476 C -2.205398 2.671522 0.818092 C -3.023618 1.716319 -1.207077 C -3.583526 1.568986 -1.330521 H -2.842176 1.394223 -2.237456 H -1.785393 0.463628 -1.734028 H -4.106195 1.765939 -1.037164 C -3.524440 3.048730 0.566499 H -2.580692 2.708581 -1.078234 H -1.676275 3.118938 1.661254 C -2.800274 1.146197 1.589595 C -4.219431 2.495604 -0.507059 H -2.467022 0.453918 2.370313 H -4.116236 1.131016 -2.174811 H -2.354578 2.126482 1.787047 H -4.009441 3.781721 1.211397 H -3.893848 1.223839 1.629692 H -5.247860 2.792266 -0.706436 Cl -0.001606 2.844178 0.066593 P 0.835188 2.669766 -0.926645 C 0.858356 2.116594 -2.662417 H -0.150226 1.820221 -2.970113 39D H 1.205092 2.927853 -3.314652 Charge: 0 Multiplicity: 1 H 1.530431 1.257967 -2.755590 Ni -0.000060 -0.645324 -0.087505 C -0.094549 4.241337 -1.019344 C 0.000109 1.246318 -0.059079 H 0.429254 4.941626 -1.681431 C 0.000234 2.020791 -1.228858 H -1.103503 4.066309 -1.403747 C 0.000121 1.929264 1.168060 H -0.187317 4.695896 -0.028023 C 0.000366 3.415007 -1.177253 C 2.541342 3.234547 -0.615815 H 0.000231 1.528409 -2.204224 H 3.223995 2.396095 -0.776593 C 0.000255 3.324049 1.225353 H 2.796051 4.055817 -1.297022 H 0.000022 1.362535 2.103391 H 2.642493 3.579311 0.417855 C 0.000381 4.073990 0.050877 O 2.045009 0.660463 0.987320 H 0.000462 3.991702 -2.102951 S 2.739868 -0.381556 0.120857 H 0.000262 3.827546 2.192805 O 2.092673 -1.699990 0.173063 H 0.000487 5.162139 0.092301 Sn -1.032956 -2.565679 -0.581182 P 2.198576 -0.755785 -0.024384 C -0.024865 -1.458987 -2.119093 P -2.198715 -0.755421 -0.024450 H 0.875333 -1.983904 -2.453104 C -2.723228 -1.349393 1.621174 H -0.673151 -1.268279 -2.983053 H -2.463867 -0.609974 2.386422 H 0.312434 -0.496472 -1.712204 S3 9 128 C -3.000203 -3.082008 -1.286946 C 1.408804 -4.173438 -0.264410 H -2.953439 -3.729280 -2.169577 H 0.642592 -4.530049 -0.962817 H -3.586259 -3.607534 -0.524454 H 2.366194 -4.608761 -0.568034 H -3.558115 -2.180876 -1.571220 H 1.150754 -4.550243 0.731650 C 0.046152 -4.300442 0.044867 F 3.412194 -2.005081 -1.341471 H -0.518041 -4.880454 0.782493 K 3.990275 0.351752 -0.969546 H 0.262432 -4.954181 -0.806920 N 1.138338 2.356345 2.127452 H 0.998168 -3.995530 0.488772 C 1.969936 3.228605 2.954082 O 3.002887 0.142801 -1.235104 H 1.836098 4.297697 2.716731 N 4.208426 -0.567370 0.962463 H 1.682871 3.064477 3.998229 C 5.005941 -1.660338 0.414438 H 3.019885 2.960510 2.829052 H 5.850932 -1.830067 1.090618 C -0.280232 2.662875 2.283380 H 4.400749 -2.568313 0.374379 H -0.566197 2.444244 3.318404 H 5.399373 -1.439872 -0.592809 H -0.512472 3.716509 2.056328 C 4.965811 0.675400 1.035435 H -0.875004 2.014435 1.622829 H 5.824930 0.509297 1.694642 H 5.338985 1.007882 0.050521 H 4.340619 1.458866 1.471002 40C Charge: 0 Multiplicity: 1 C -0.246735 3.378471 0.566133 40B C -0.686615 3.150384 1.874392 Charge: 0 Multiplicity: 1 C 0.558515 2.446069 -0.065636 C -1.396989 -0.730456 3.003282 H -1.331134 3.877817 2.366056 C -2.345291 -1.741461 2.968472 C -0.297854 1.999096 2.540453 C -0.407769 -0.666862 2.009398 H 0.878062 2.643283 -1.090763 H -3.109145 -1.804542 3.742954 C 0.973201 1.253543 0.574959 C -2.316327 -2.686673 1.935959 C 0.530984 1.062015 1.905464 H 0.390531 0.071201 2.114014 H -0.620845 1.821867 3.565721 C -0.365585 -1.578309 0.927516 H -0.551975 4.281864 0.039655 C -1.364413 -2.583107 0.935242 Ni -0.574590 -0.505716 0.421393 H -3.057260 -3.485866 1.912550 H 0.884739 0.202717 2.472975 H -1.407756 0.000232 3.813449 Sn 2.525741 0.095711 -0.446503 Ni -0.870789 0.321592 -0.197891 C 1.672397 -1.267218 -1.875838 H -1.387991 -3.312999 0.120891 H 1.760544 -2.296736 -1.515165 C -2.685437 -0.178676 -0.237661 H 0.602374 -1.053570 -2.003165 C -3.182318 -1.173053 -1.088462 H 2.157768 -1.180196 -2.855101 C -3.566796 0.447125 0.648796 C 3.953990 -0.736625 0.906042 C -4.522564 -1.547890 -1.037495 H 4.959251 -0.341095 0.724160 H -2.512282 -1.676325 -1.788334 H 3.669386 -0.511155 1.938620 C -4.912115 0.070926 0.700866 H 3.972886 -1.826018 0.808418 H -3.205564 1.226189 1.323842 C 3.480974 1.635773 -1.622851 C -5.393433 -0.925977 -0.142040 H 3.738105 2.510586 -1.014824 H -4.888818 -2.333516 -1.698341 H 4.407111 1.262550 -2.075583 H -5.582740 0.564169 1.404518 H 2.836661 1.978202 -2.441467 H -6.441851 -1.217183 -0.104758 C -1.910779 0.632322 -0.270836 P -1.485474 1.818775 -1.701532 C -1.901811 1.047422 -1.608093 C -0.169679 2.364783 -2.846208 C -2.923640 1.109128 0.568527 H 0.183018 1.506470 -3.427817 C -2.853242 1.949382 -2.082658 H -0.565240 3.119916 -3.536828 H -1.129142 0.681314 -2.289001 H 0.660470 2.796575 -2.283477 C -3.878168 2.012362 0.094814 C -2.802665 1.368845 -2.887976 H -2.965192 0.787771 1.611224 H -2.909404 2.164964 -3.635058 C -3.845040 2.435675 -1.231395 H -2.553071 0.434470 -3.401560 H -2.820266 2.274121 -3.122803 H -3.757191 1.225012 -2.374054 H -4.653175 2.382016 0.766687 C -2.134449 3.367025 -0.984386 H -4.591921 3.135326 -1.603140 H -1.345815 3.856202 -0.405488 P -1.887180 -2.159304 -0.108940 H -2.477485 4.047599 -1.773499 C -2.525523 -2.937494 1.412675 H -2.980164 3.133648 -0.327887 H -3.136227 -2.218322 1.968518 O 1.062404 1.076164 -0.081369 H -3.138017 -3.817975 1.182080 S 1.591799 2.380962 0.479955 H -1.677370 -3.229774 2.039024 O 0.981811 3.558236 -0.157762 C -3.394545 -1.900387 -1.107130 O 3.067490 2.346790 0.486823 H -3.927945 -2.849232 -1.242159 Sn 1.561206 -2.039991 -0.287118 H -4.056460 -1.175720 -0.623405 C 2.768978 -1.277414 1.354487 H -3.130412 -1.495731 -2.089222 H 3.820755 -1.564232 1.228473 C -1.071597 -3.528756 -0.997722 H 2.693267 -0.193261 1.509597 H -0.189484 -3.846759 -0.435316 H 2.408516 -1.740558 2.281016 H -1.763573 -4.371291 -1.119710 C 0.843494 -1.211996 -2.161296 H -0.746854 -3.192251 -1.987637 H 1.250666 -1.804035 -2.989402 Cl 0.874424 -2.065676 1.335163 H -0.255723 -1.224326 -2.216415 H 1.162797 -0.171339 -2.298586 S4 0 129 40D C -3.974217 0.819126 -1.457191 Charge: 0 Multiplicity: 1 H -1.963437 0.339248 -2.051899 C 0.496558 3.356115 -0.146483 C -4.243833 1.730449 0.755004 C 0.929248 3.283605 -1.475209 H -2.448990 1.963461 1.914874 C -0.385732 2.408884 0.347025 C -4.802429 1.314730 -0.454062 H 1.627848 4.025691 -1.859545 H -4.399659 0.490561 -2.405444 C 0.472911 2.264714 -2.297472 H -4.884358 2.120695 1.546025 H -0.711504 2.483830 1.386748 H -5.877255 1.382216 -0.613323 C -0.870158 1.347701 -0.452661 P 0.047744 2.837121 -0.577278 C -0.412088 1.301243 -1.793210 C 0.230209 2.726754 -2.387367 H 0.799004 2.210809 -3.335843 H -0.652144 2.250076 -2.827242 H 0.863198 4.152404 0.500155 H 0.345288 3.728949 -2.818751 Ni 0.468323 -0.458179 -0.470675 H 1.115866 2.126788 -2.620443 H -0.801092 0.530470 -2.458859 C -1.256078 4.100928 -0.372355 Sn -2.479771 0.062239 0.317720 H -0.928528 5.047393 -0.819289 C -1.731335 -1.360733 1.754032 H -2.182669 3.774995 -0.853614 H -1.553869 -2.330914 1.277705 H -1.469961 4.265815 0.688327 H -0.774912 -1.000866 2.158977 C 1.557558 3.719190 -0.058167 H -2.415300 -1.496600 2.600071 H 2.429426 3.140421 -0.375078 C -3.924637 -0.571554 -1.121347 H 1.586960 4.714725 -0.518066 H -4.938524 -0.247739 -0.863583 H 1.583791 3.821596 1.030665 H -3.668606 -0.162004 -2.104481 O 1.726594 0.921055 0.907590 H -3.906868 -1.661510 -1.213464 S 2.662251 0.195907 -0.042052 C -3.476905 1.519017 1.595973 O 2.290727 -1.218931 -0.217227 H -3.717385 2.442966 1.056342 Sn -0.285692 -2.287099 -0.829020 H -4.417172 1.114882 1.991549 C 0.290583 -0.981723 -2.432536 H -2.858422 1.794801 2.459580 H 1.271989 -1.276990 -2.816661 C 2.011275 0.369887 0.230079 H -0.442106 -1.002411 -3.248547 C 2.107228 0.622241 1.605396 H 0.394937 0.050889 -2.080544 C 3.035654 0.840341 -0.600302 C -2.213820 -3.074223 -1.405067 C 3.166556 1.363561 2.128716 H -2.130265 -3.644233 -2.338311 H 1.327204 0.261205 2.280625 H -2.631354 -3.744634 -0.644858 C 4.098438 1.580973 -0.079759 H -2.942274 -2.271906 -1.578200 H 2.999041 0.644108 -1.673536 C 1.053718 -3.920601 -0.499149 C 4.164800 1.848636 1.285462 H 0.540423 -4.886646 -0.550981 H 3.209945 1.565170 3.199103 H 1.854486 -3.905342 -1.245330 H 4.878667 1.949353 -0.746219 H 1.524254 -3.823749 0.484087 H 4.993966 2.425365 1.692264 O 2.873638 0.963335 -1.284908 P 1.484334 -2.338006 -0.185535 N 4.096641 0.160603 0.874279 C 0.518108 -3.737188 -0.839656 C 5.126962 -0.644975 0.224074 H 0.335726 -3.589866 -1.907542 H 5.958475 -0.756540 0.928330 H 1.040807 -4.688209 -0.679451 H 4.725265 -1.634510 -0.004184 H -0.460392 -3.762526 -0.353039 H 5.508910 -0.183570 -0.702535 C 3.124020 -2.542292 -0.963046 C 4.576428 1.499719 1.195580 H 3.510176 -3.555307 -0.797422 H 5.423920 1.398095 1.882178 H 3.056086 -2.363681 -2.040956 H 4.911255 2.059487 0.304795 H 3.824752 -1.814549 -0.542444 H 3.785428 2.059591 1.700962 C 1.803566 -2.805800 1.549779 H 0.861405 -2.827481 2.107658 H 2.274709 -3.794507 1.608353 TSB H 2.461987 -2.065129 2.015019 Charge: 0 Multiplicity: 1 F -1.110558 -1.332124 -1.116196 C -1.291968 -0.866939 3.149956 C -2.263640 -1.859004 3.097070 C -0.406885 -0.704856 2.078082 TSA H -2.948569 -1.999274 3.932987 Charge: 0 Multiplicity: 1 C -2.355606 -2.686184 1.972900 C -0.273311 -0.825490 3.446114 H 0.399530 0.025213 2.169794 C -1.625063 -0.847629 3.763946 C -0.500616 -1.479071 0.899301 C 0.144877 -1.109403 2.141401 C -1.508720 -2.473978 0.896539 H -1.951818 -0.641851 4.782681 H -3.109909 -3.471919 1.936052 C -2.564259 -1.146383 2.773645 H -1.208515 -0.231924 4.033086 H 1.209790 -1.150620 1.931399 Ni -0.827991 0.344408 -0.248373 C -0.779086 -1.369893 1.108216 H -1.635506 -3.096827 0.006978 C -2.146329 -1.388414 1.474266 C -2.659238 -0.095332 -0.279471 H -3.626224 -1.169517 3.015509 C -3.221917 -1.002126 -1.185050 H 0.469277 -0.610332 4.212999 C -3.485464 0.486178 0.687325 Ni -0.204068 0.894826 0.375340 C -4.574166 -1.329522 -1.117179 H -2.903226 -1.577602 0.711489 H -2.595565 -1.475679 -1.944136 C -2.027740 1.130333 -0.037406 C -4.841845 0.157650 0.755926 C -2.593458 0.737159 -1.254460 H -3.070811 1.189603 1.412945 C -2.867925 1.648023 0.956991 C -5.390428 -0.749643 -0.145831 S4 1 130 H -4.992259 -2.045865 -1.824528 H -3.542607 -0.709849 -2.820171 H -5.468972 0.615519 1.521066 H -1.986059 -1.539419 -2.742734 H -6.447565 -1.004773 -0.093737 C 1.602781 -0.860184 -0.413555 P -1.402063 1.972266 -1.638116 C 1.601328 -1.079534 -1.795248 C -0.094111 2.513033 -2.796010 C 2.397755 -1.681901 0.394068 H 0.192083 1.671907 -3.436740 C 2.355877 -2.112929 -2.354314 H -0.465038 3.327364 -3.430805 H 0.995452 -0.450235 -2.452280 H 0.776424 2.864860 -2.238373 C 3.153485 -2.712951 -0.163867 C -2.773980 1.653806 -2.806128 H 2.408674 -1.537221 1.476758 H -2.867850 2.497122 -3.501358 C 3.134982 -2.932140 -1.540622 H -2.584018 0.741620 -3.381503 H 2.334248 -2.276268 -3.431929 H -3.718032 1.520631 -2.270187 H 3.757904 -3.350754 0.481403 C -1.957652 3.515276 -0.832361 H 3.726452 -3.735507 -1.976601 H -1.129920 3.946452 -0.262140 P 2.206119 1.821969 0.222976 H -2.299510 4.243597 -1.578208 C 2.850699 2.213942 1.884858 H -2.789068 3.288979 -0.155001 H 3.222189 1.301832 2.363761 O 1.140640 1.025645 -0.074662 H 3.667071 2.945100 1.835030 S 1.721688 2.289817 0.527182 H 2.033228 2.614452 2.492193 O 1.183710 3.510399 -0.092952 C 3.704712 1.346356 -0.706135 O 3.194175 2.182368 0.560853 H 4.455703 2.144077 -0.656175 Sn 1.420098 -2.064524 -0.371632 H 4.128730 0.421121 -0.304055 C 2.649144 -1.451726 1.311891 H 3.451089 1.159355 -1.754656 H 3.680744 -1.800528 1.175731 C 1.816572 3.457114 -0.488805 H 2.639246 -0.372402 1.509136 H 0.972843 3.892791 0.053431 H 2.251177 -1.931377 2.213875 H 2.686648 4.122124 -0.424179 C 0.765298 -1.162482 -2.230895 H 1.532033 3.349915 -1.540471 H 1.184464 -1.740229 -3.063296 Cl -0.661316 2.171018 1.428258 H -0.331328 -1.152909 -2.315595 H 1.108724 -0.124788 -2.325566 C 1.086016 -4.176005 -0.387326 TSD H 0.269185 -4.449983 -1.064956 Charge: 0 Multiplicity: 1 H 1.993254 -4.682905 -0.731950 C -1.896994 3.433495 -0.086635 H 0.830491 -4.550539 0.610003 C -2.610890 3.423663 -1.285658 F 3.269629 -2.126774 -1.394860 C -1.054824 2.373542 0.232724 K 4.000011 0.184937 -0.955276 H -3.267001 4.255541 -1.538828 N 1.236826 2.250342 2.165045 C -2.479838 2.345071 -2.155540 C 2.083097 3.076637 3.023142 H -0.486234 2.409711 1.162481 H 1.990069 4.154120 2.804912 C -0.916998 1.260609 -0.617430 H 1.771601 2.902643 4.058711 C -1.649672 1.274593 -1.821233 H 3.125378 2.774820 2.911135 H -3.033298 2.330414 -3.094406 C -0.172837 2.604378 2.301832 H -1.990567 4.278375 0.595346 H -0.491890 2.358049 3.320964 Ni 0.466662 -0.117948 -0.576661 H -0.359375 3.674013 2.109820 H -1.584798 0.421199 -2.495326 H -0.775620 2.004047 1.604211 Sn -1.742749 -0.967833 0.687036 C -1.163021 -2.968073 1.226991 H -1.434725 -3.675266 0.436793 TSC H -0.075985 -3.023156 1.367225 Charge: 0 Multiplicity: 1 H -1.629342 -3.288266 2.166189 C -0.658375 -3.479937 1.007812 C -3.715061 -0.774299 -0.089725 C -0.678265 -3.316759 2.395443 H -4.438970 -1.362452 0.485724 C -0.824026 -2.379826 0.181912 H -4.024494 0.276221 -0.063158 H -0.532841 -4.177684 3.046844 H -3.739708 -1.112621 -1.129965 C -0.892647 -2.057183 2.942004 C -1.578328 0.172975 2.524658 H -0.764488 -2.522733 -0.897045 H -2.266244 1.024814 2.495149 C -1.033985 -1.081687 0.702634 H -1.835746 -0.467120 3.377951 C -1.087427 -0.954728 2.106350 H -0.566703 0.562474 2.677556 H -0.921614 -1.927067 4.022882 F -0.874863 -1.413015 -1.234435 H -0.493787 -4.465674 0.575308 C 1.680729 1.068010 0.227609 Ni 0.512541 0.450365 0.402919 C 2.032277 0.946426 1.578003 H -1.283187 0.020671 2.547552 C 2.270284 2.094487 -0.521641 Sn -2.127843 0.306611 -0.707066 C 2.943380 1.827423 2.165212 C -1.101184 1.763631 -1.925302 H 1.597596 0.149748 2.186144 H -1.090478 2.728880 -1.409763 C 3.188635 2.967426 0.061333 H -0.061776 1.472490 -2.120631 H 1.996315 2.229704 -1.569034 H -1.610749 1.866634 -2.891823 C 3.526526 2.839876 1.407803 C -3.767305 1.132990 0.382640 H 3.197612 1.717871 3.219610 H -4.729298 0.834801 -0.048330 H 3.632700 3.762022 -0.538406 H -3.732605 0.798685 1.424125 H 4.237079 3.527392 1.863582 H -3.697802 2.224671 0.386592 P 2.127051 -1.631762 -0.779690 C -2.814942 -1.158826 -2.133504 C 3.531164 -1.042466 -1.792492 H -3.293573 -2.015471 -1.646688 H 3.960013 -0.149467 -1.324692 S4 2 131 H 4.310324 -1.807979 -1.890324 H 5.425209 0.566589 -1.176134 H 3.184535 -0.762879 -2.792857 C 4.548271 1.242676 1.286469 C 1.631449 -3.188745 -1.595984 H 5.451160 0.940991 1.828499 H 2.483855 -3.864573 -1.735486 H 4.781552 2.142154 0.690123 H 0.865921 -3.688466 -0.994385 H 3.768454 1.480230 2.014237 H 1.180470 -2.966389 -2.567597 C 2.978949 -2.208083 0.732705 H 3.427393 -1.352020 1.247417 41B H 2.266521 -2.679891 1.417987 Charge: 0 Multiplicity: 1 H 3.765807 -2.932768 0.491106 C 0.829175 -1.478680 3.464010 C 1.400862 -2.703473 3.117624 C 0.097621 -0.745302 2.530544 41A H 1.976451 -3.272797 3.845970 Charge: 0 Multiplicity: 1 C 1.207289 -3.193434 1.829818 C 0.784596 -2.821269 2.740293 H -0.287905 0.228809 2.830722 C -0.435228 -3.192007 3.303254 C -0.122664 -1.208233 1.220099 C 0.821817 -1.980302 1.633642 C 0.443326 -2.462980 0.909811 H -0.460709 -3.850832 4.170352 H 1.628733 -4.157099 1.539540 C -1.621764 -2.733229 2.737301 H 0.966930 -1.083956 4.471617 H 1.785263 -1.725644 1.202941 Ni -1.128623 -0.141508 -0.031618 C -0.363046 -1.464616 1.059282 H 0.230810 -2.927255 -0.057984 C -1.581173 -1.894542 1.627594 C -2.410372 -1.511661 0.079299 H -2.581732 -3.034153 3.154875 C -2.382196 -2.665525 -0.715837 H 1.716509 -3.194256 3.162682 C -3.515052 -1.337981 0.927608 Ni -0.242787 0.580687 0.496739 C -3.423151 -3.593137 -0.690069 H -2.521000 -1.565757 1.188803 H -1.541247 -2.842198 -1.391901 C -2.104572 0.864461 0.217768 C -4.559679 -2.262522 0.956632 C -2.672087 1.157821 -1.029695 H -3.567131 -0.464809 1.582524 C -2.945752 0.898545 1.341257 C -4.521362 -3.393916 0.144033 C -4.033990 1.440067 -1.157435 H -3.376830 -4.475640 -1.329013 H -2.052505 1.153316 -1.926901 H -5.406416 -2.099338 1.624082 C -4.304753 1.183403 1.217181 H -5.335238 -4.116917 0.166225 H -2.536331 0.690443 2.330924 P -2.428847 0.868124 -1.630029 C -4.856111 1.455087 -0.034309 C -1.627348 1.941452 -2.885610 H -4.450038 1.648544 -2.142891 H -0.878413 1.361962 -3.438714 H -4.936213 1.194725 2.105518 H -2.362494 2.326768 -3.603486 H -5.917146 1.678383 -0.131219 H -1.141792 2.785101 -2.387308 P -0.119522 2.816310 0.304891 C -3.336431 -0.294668 -2.719257 C -0.003308 3.435261 -1.407580 H -3.880633 0.248607 -3.501924 H -0.883018 3.126987 -1.981823 H -2.638770 -0.994677 -3.192962 H 0.053560 4.530868 -1.411958 H -4.045728 -0.886591 -2.132269 H 0.897233 3.023424 -1.874060 C -3.800643 1.918773 -1.022542 C -1.493926 3.805354 0.995732 H -3.386094 2.795909 -0.516776 H -1.260443 4.874446 0.923211 H -4.450834 2.247896 -1.842902 H -2.421463 3.601674 0.452128 H -4.401814 1.344727 -0.307511 H -1.659076 3.550201 2.047425 O 0.245264 1.495589 -0.007323 C 1.343311 3.556577 1.106743 S -0.026661 2.888005 0.523980 H 2.240629 3.229829 0.574931 O -1.108061 3.571508 -0.203685 H 1.275886 4.651067 1.078442 O 1.251854 3.631328 0.605160 H 1.415905 3.224903 2.146843 Sn 2.615916 -1.125378 -0.643227 O 1.728564 0.631093 0.914019 C 2.979412 -0.010035 1.131748 S 2.620872 0.401913 -0.289767 H 3.989457 0.416313 1.071623 O 2.298772 -0.857980 -0.982743 H 2.235045 0.776052 1.294700 Sn -0.482607 -1.644506 -1.264277 H 2.935406 -0.669412 2.003934 C 0.009083 -0.154850 -2.736050 C 1.040857 -0.897958 -2.065540 H 0.909782 -0.480897 -3.264901 H 1.458484 -1.084532 -3.063412 H -0.813594 -0.019039 -3.448133 H 0.205861 -1.583872 -1.886290 H 0.245886 0.809984 -2.274241 H 0.632487 0.118835 -2.034829 C -2.549115 -2.217949 -1.479358 C 3.607530 -3.002573 -0.753429 H -2.814199 -2.269929 -2.542835 H 2.913729 -3.798497 -1.043186 H -2.710901 -3.211036 -1.043788 H 4.409486 -2.956624 -1.497885 H -3.240624 -1.515802 -1.002759 H 4.045303 -3.271841 0.212836 C 0.651409 -3.443266 -1.480282 F 3.789398 0.086704 -1.705818 H 0.287955 -4.197052 -0.772373 K 2.771282 2.358798 -1.108682 H 0.552594 -3.850403 -2.493316 N -0.510624 2.660238 2.144265 H 1.708752 -3.252008 -1.281847 C -0.355120 3.873385 2.944264 O 2.705045 1.599696 -1.147732 H -1.040875 4.680333 2.634012 N 4.121008 0.115436 0.465122 H -0.575312 3.611081 3.984753 C 5.142029 -0.264345 -0.507997 H 0.674006 4.229249 2.877813 H 6.029902 -0.587085 0.046453 C -1.876344 2.147391 2.217491 H 4.779765 -1.101851 -1.108234 H -2.066697 1.821527 3.246490 S4 3 132 H -2.626896 2.902361 1.929701 H -0.800079 1.299433 -2.527917 H -1.977466 1.271584 1.555324 Sn -2.409913 -0.626724 0.455299 C -3.494365 -2.461434 0.320250 H -4.329733 -2.495992 1.028000 41C H -3.905055 -2.590810 -0.686477 Charge: 0 Multiplicity: 1 H -2.845049 -3.318169 0.528979 C -2.176837 2.943991 -1.203484 C -3.596766 1.062011 -0.017934 C -2.726113 2.532109 -2.417776 H -4.561961 1.015188 0.498442 C -1.470609 2.041214 -0.419388 H -3.081410 1.986665 0.260644 H -3.274326 3.240317 -3.037803 H -3.782586 1.095522 -1.095827 C -2.581441 1.209641 -2.825980 C -1.184910 -0.565362 2.197284 H -1.038405 2.388859 0.518179 H -0.825082 0.454081 2.367509 C -1.286415 0.697866 -0.816485 H -1.724495 -0.909277 3.087991 C -1.885526 0.301050 -2.030591 H -0.308902 -1.209796 2.053142 H -3.016497 0.877537 -3.767674 F -1.182132 -0.962919 -1.033149 H -2.294213 3.974430 -0.870929 C 2.214568 0.691593 0.147312 Ni 0.521118 -0.302579 -0.512128 C 2.456909 0.813312 1.523257 H -1.795788 -0.733528 -2.354516 C 3.238150 1.064111 -0.735542 Sn -1.607459 -0.746941 1.043767 C 3.687477 1.263394 2.001760 C -0.199355 -2.028414 2.065481 H 1.677338 0.539968 2.238992 H 0.756353 -1.518848 2.237934 C 4.470007 1.514108 -0.258044 H -0.604377 -2.327327 3.041087 H 3.072541 1.010084 -1.812992 H -0.012852 -2.918560 1.457199 C 4.702710 1.611076 1.112553 C -3.305338 -1.830200 0.341423 H 3.853724 1.342108 3.076663 H -4.067279 -1.143364 -0.041552 H 5.250954 1.798537 -0.963946 H -2.999030 -2.500088 -0.467468 H 5.663549 1.963361 1.484458 H -3.751159 -2.430989 1.141842 P 1.654900 -2.102589 -0.541464 C -2.174433 0.760298 2.470352 C 2.725594 -2.337749 -2.010428 H -3.003122 1.371400 2.097415 H 3.483753 -1.546762 -2.025207 H -2.487689 0.292951 3.411640 H 3.231108 -3.311399 -1.997180 H -1.335641 1.429657 2.693648 H 2.134489 -2.257623 -2.928374 Cl -0.160164 -2.333266 -1.399595 C 0.593487 -3.599626 -0.584765 C 1.270785 1.263081 0.249492 H 1.179851 -4.518340 -0.709663 C 1.712317 2.281653 -0.604829 H 0.027586 -3.675536 0.351249 C 1.388007 1.455709 1.630027 H -0.129754 -3.520993 -1.402622 C 2.246814 3.462964 -0.091501 C 2.823347 -2.499147 0.811012 H 1.614274 2.166436 -1.686196 H 3.615766 -1.743550 0.837642 C 1.913066 2.643360 2.145850 H 2.310495 -2.468160 1.778785 H 1.065701 0.676244 2.324737 H 3.272530 -3.491118 0.679078 C 2.347253 3.649366 1.286982 H 2.578434 4.246624 -0.772814 H 1.985639 2.777405 3.225214 H 2.760968 4.573204 1.687577 P 2.583040 -1.149482 -0.501631 C 3.148850 -1.276619 -2.232566 H 3.175090 -0.281496 -2.689311 H 4.149607 -1.721156 -2.296487 H 2.436858 -1.893289 -2.789902 C 2.786076 -2.845579 0.142289 H 3.805910 -3.205072 -0.042199 H 2.595734 -2.863392 1.220126 H 2.063842 -3.505583 -0.345571 C 3.952299 -0.264356 0.322651 H 3.760990 -0.199746 1.398939 H 4.902214 -0.787796 0.160309 H 4.031214 0.759384 -0.056324 41D Charge: 0 Multiplicity: 1 C -0.922136 3.785343 0.432496 C -1.544036 4.110103 -0.772747 C -0.235100 2.578217 0.562866 H -2.068461 5.058491 -0.883275 C -1.482068 3.211878 -1.835936 H 0.284967 2.368891 1.500803 C -0.176718 1.642604 -0.481836 C -0.814037 1.995622 -1.686451 H -1.960799 3.457420 -2.784820 H -0.957366 4.485247 1.268118 Ni 0.634312 -0.091304 -0.461339 S4 4 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 APPENDIX B CHAPTER THREE SUPPLEMENTAL 193 Supporting Information for Small Phosphine Ligands Enable Selective Oxidative Addition of Ar—O over Ar—Cl Bonds at Nickel(0) Emily D. Entz, John E. A. Russell, Leidy V. Hooker, and Sharon R. Neufeldt* Department of Chemistry and Biochemistry, Montana State University Bozeman, MT 59717, USA Correspondence: sharon.neufeldt@montana.edu S 1 194 Table of Contents I. Experimental Details A. General Materials and Methods S3 B. Stoichiometric Oxidative Addition Studies 1. Intermolecular Competition Studies S4 2. Intramolecular Competition: Synthesis, Isolation, and Characterization of 14 S32 3. Irreversibility of Oxidative Addition S35 C. Synthesis of Reagents 1. Aryl Grignard Reagents for use in Ni(II) Precatalyst Synthesis S38 2. Nickel(II) Precatalysts S39 3. Aryl Tosylates S47 4. Aryl Sulfamate 29 S49 5. Boronic Esters S49 D. Catalytic Reaction Optimization and Screening of Other Conditions S51 E. Cross-Coupling Reactions S57 F. X-Ray Crystallographic Details for Compound 14 S63 II. Computational Details A. General Comments S69 B. Graphical Guide to Numbered Compounds Including Relevant Geometry Parameters S70 C. Free Energy Diagrams S73 D. Table of Energies, Entropies, and Lowest Frequencies of Minimum Energy Structures S76 E. Evaluation of other DFT Methods S77 F. Distortion-Interaction Analyses S78 III. References S81 IV. Spectral Data S83 S 2 195 I. Experimental Details A. General Materials and Methods NMR spectra were recorded at 298 K on a Bruker Ascend Avance III HD 500 MHz (500.233 MHz for 1H, 125.795 MHz for 13C, or 202.487 MHZ for 31P), a Bruker DPX Avance I 300 MHz (121.511 MHz for 31P or 282.425 MHz for 19F), or a Bruker Avance III 600 MHz (600.130 MHz for 1H or 150.903 MHz for 13C) spectrometer. 1H and 13C NMR chemical shifts are reported in parts per million (ppm) relative to TMS, with the residual solvent peak used as an internal reference [1H: CHCl3 (7.26 ppm), CD3(CO)CHD2 (2.05 ppm) or C6D5H (7.16 ppm); 13C: CDCl3 (77.16 ppm) or C6D6 (128.06 ppm)].1 31P NMR chemical shifts are reported in ppm relative to phosphoric acid, with Ph3PO used as an internal reference (24.95 ppm in C6D6). Multiplicities are reported as follows: singlet (s), doublet (d), doublet of doublets (dd), triplet (t), quartet (q), quintet (quint), multiplet (m), and broad resonance (br). GC data were collected using a Shimadzu GC- 2010 Plus with a flame ionization detector equipped with a SH-Rxi-5ms capillary column (15 m x 0.25 mm ID x 0.25 µm df). HRMS data were collected on a Bruker Impact II (Q-TOF), a Waters GCT Premier HR- TOF, a Bruker MicroTOF, or a Bruker MicroTOF II. Phenylboronic acid, 4-tolylboronic acid, 4-methoxybenzeneboronic acid, 4- (trifluoromethyl)benzeneboronic acid, 4-chlorobenzeneboronic acid, 4-methoxycarbonylbenzeneboronic acid, 3,4-(methylenedioxy)benzeneboronic acid, 1-naphthol, 3-chlorophenol, 2-chloro-5- hydroxybenzotrifluoride, 1-bromonaphthalene, Mg turnings, 1-chloro-2-ethylbenzene, PCy3, Ph3PO, P(4- methoxyphenyl)3, 1-naphthol, o-cresol, trifluoromethanesulfonic anhydride, and diethylcarbamyl chloride were obtained from Oakwood Chemical and used as received. 4-Chlorophenol, 2,2-dimethyl-1,3- propanediol, potassium phosphate, 1,2-dibromoethane, NiCl2 ● 6H2O, o-tolylmagnesium chloride, Ni(cod)2, 1-chloronaphthalene (85% purity, remainder 2-chloronaphthalene), p-toluenesulfonyl chloride, N,N-dimethylsulfamoyl chloride, methanesulfonyl chloride, and trimethylacetyl chloride were obtained from Acros Organics and used as received. PPh3, PPhMe2, triethylamine, PPh2Me, P(n-Bu)3, and P(4- fluorophenyl)3 were obtained from Alfa Aesar and used as received. PMe3, dcypf, and P(i-Bu)3 were obtained from Strem Chemicals and used as received. 2-Chloro-m-xylene, PPhEt2, 2-chloronaphthalene, and 4-chloro-1-naphthol were obtained from TCI America and used as received. C6D6, d6-acetone, d8- toluene, and CDCl3 were obtained from Cambridge Isotope Laboratories and used as received. 1,4-Dioxane was obtained from Acros in an ACROseal bottle (extra dry) and used as received. 2-Chlorophenol, methylene chloride, Et2O, hexanes, EtOAc, MgSO4, HCl, NaHCO3, NaCl, pyridine, and NaOH were obtained from Fisher Chemical and used as received. THF and MeOH were obtained from Fisher Chemical and degassed and dried with a JC Meyer solvent system prior to use. 4-Chlorophenyl triflate (30),2 1-naphthyl triflate (S39),3 1-naphthyl mesylate (S42),4 1-naphthyl pivalate (S48),5 1-naphthyl dimethylsulfamate (S44),6 and 1-naphthyl diethylcarbamate (S46)6 were prepared according to literature procedures. (PMe3)2NiCl2, (PPhMe2)2NiCl2, and (PnBu3)2NiCl2 were prepared according to a literature procedure.7 Trans-bis(triphenylphosphine)(2-methylphenyl)nickel(II) chloride, trans-bis(tricyclohexylphosphine)(2- methylphenyl)nickel(II) chloride, and trans-bis(methyldiphenylphosphine)(2-methylphenyl)nickel(II) S 3 196 chloride were made according to a literature procedure.8 Authentic samples of oxidative addition adducts 9 and 10 were made according to a literature procedure.9 An authentic sample of Ni(PMe3)4 was made according to a literature procedure.10 Flash column chromatography was performed on SiliCycle silica gel 60 (40-63 µm particle size) and thin layer chromatography was performed on SiliCycle TLC plates pre- coated with extra hard silica gel 60 F254. B. Stoichiometric Oxidative Addition Studies. 1. Intermolecular Competition Studies General Procedure. In a nitrogen-atmosphere glovebox, a stock solution containing Ni(cod)2 and phosphine in a 1:2 ratio was prepared in 1,4-dioxane in a one-dram vial equipped with a magnetic stir bar (0.02 M with respect to Ni(cod)2). The solution was stirred until all solids were dissolved (typically about 10 min). To a second one-dram vial equipped with a stir bar was added 1-naphthyl chloride (85% purity; the balance is 2-naphthyl chloride, 2.7 µL, 0.02 mmol, 1.0 equiv) and/or phenolic electrophile (0.02 mmol, 1.0 equiv) and 1 mL of the Ni/phosphine stock solution (0.02 mmol, 1.0 equiv of Ni and 0.04 mmol, 2.0 equiv of PR3). The vial was then sealed with a PTFE-lined cap and stirred at room temperature for 2 h. 500 µL of the reaction mixture was then transferred to an NMR tube, along with a capillary tube insert containing a solution of PPh3O in C6D6 (0.1 M), and the sample was analyzed by 31P NMR. To obtain the spectrum of nickel(0)/phosphine in the absence of substrate, an aliquot (500 µL) of the Ni(cod)2/phosphine stock solution (after stirring for 2 hours) was transferred to an NMR tube, along with a capillary tube insert containing a solution of PPh3O in C6D6 (0.1 M), and the sample was analyzed by 31P NMR. When appropriate, the location of a 31P NMR signal for Ni(II)(2-naphthyl)(Cl) resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was confirmed by the separate reaction of a Ni(cod)2/phosphine solution with authentic 2-chloronaphthalene. S4 197 Competition Between 1-Chloronaphthalene and 1-Naphthyl Triflate with PCy3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl triflate (5.5 mg), and a Ni(cod)2/PCy3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at 46.0 ppm is assigned to a Ni(0)/PCy3 adduct (Figure S1, spectrum A). The signal at 9.9 ppm corresponds to free PCy3. The signals at 11.9 and 10.5 ppm are assigned to oxidative addition adducts 9 and S41, respectively (spectra B-D). Product S40 resulting from oxidative addition of 2- chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at 12.9 ppm in spectrum B. In the competition experiment (spectrum D), only a very small amount of S40 was detected, and it was integrated together with 9 to obtain a ratio of oxidative addition of C—Cl to C—O of 1 : 2.3. Figure S1. 31P NMR studies on oxidative addition at Ni/PCy3 using 1-chloronaphthalene and 1-naphthyl triflate. S 5 198 Competition Between 1-Chloronaphthalene and 1-Naphthyl Tosylate with PCy3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/PCy3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at 46.0 ppm is assigned to a Ni(0)/PCy3 adduct (Figure S2, spectrum A). The signal at 9.9 ppm corresponds to free PCy3. The signals at 11.9 and 10.9 ppm are assigned to oxidative addition adducts 9 and 10, respectively (spectra B-D). Product S40 resulting from oxidative addition of 2- chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at 12.9 ppm in spectrum B. In the competition experiment (spectrum D), only a very small amount of S40 was detected, and it was integrated together with 9 to obtain a ratio of oxidative addition of C—Cl to C—O of 1.5 : 1. Figure S2. 31P NMR studies on oxidative addition at Ni/PCy3 using 1-chloronaphthalene and 1-naphthyl tosylate. S6 199 Competition Between 1-Chloronaphthalene and 1-Naphthyl Mesylate with PCy3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl mesylate (4.5 mg), and a Ni(cod)2/PCy3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at 46.0 ppm is assigned to a Ni(0)/PCy3 adduct (Figure S3, spectrum A). The signal at 9.9 ppm corresponds to free PCy3. The signals at 11.9 and 10.1 ppm are assigned to oxidative addition adducts 9 and S43, respectively (spectra B-D). Product S40 resulting from oxidative addition of 2- chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at 12.9 ppm in spectrum B. In the competition experiment (spectrum D), only a very small amount of S40 was detected, and it was integrated together with 9 to obtain a ratio of oxidative addition of C—Cl to C—O of about 2.7 : 1 (some error is likely introduced into this ratio because the signal for S43 partially overlaps with that of free PCy3, making it difficult to accurately integrate the signal for S43). A Ni(cod)2 + 2 PCy3 PCy3 PPh3O (Reference) Ni(0)/PCy3 adduct B Ni(cod)2 + 2 PCy3 + 7 9 S40 C Ni(cod)2 + 2 PCy3 + S42 S43 D Ni(cod)2 + 2 PCy3 + 7 + S42 9 S40 S43 Figure S3. 31P NMR studies on oxidative addition at Ni/PCy3 using 1-chloronaphthalene and 1-naphthyl mesylate. S 7 200 Competition Between 1-Chloronaphthalene and 1-Naphthyl Dimethylsulfamate with PCy3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl dimethylsulfamate (5.0 mg), and a Ni(cod)2/PCy3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signal at 46.0 ppm is assigned to a Ni(0)/PCy3 adduct (Figure S4, spectrum A). The signal at 9.9 ppm corresponds to free PCy3. The signals at 11.9 and 33.4 ppm are assigned to oxidative addition adducts 9 and S45, respectively (spectra B-D). The structural assignment of S45 was made by analogy to a previously reported closely related complex resulting from oxidative addition of an aryl sulfamate at Ni(cod)2/PCy3.11 Product S40 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at 12.9 ppm in spectrum B. In the competition experiment (spectrum D), a small amount of S40 was detected, and it was integrated together with 9 to obtain a ratio of oxidative addition of C—Cl to C—O of 1.7 : 1. Figure S4. 31P NMR studies on oxidative addition at Ni/PCy3 using 1-chloronaphthalene and 1-naphthyl dimethylsulfamate. S8 201 Cl OCONEt2 Ni(cod)2 (1 equiv) PCy3 PCy3 (2 equiv) PCy3 O Ni 1-naphth + Cl Ni R + 1,4-dioxane O PHCy3 Et2N 7 S46 r.t., 2 h 9, 1-naphth S40, 2-naphth S47 >99 : 1 Competition Between 1-Chloronaphthalene and 1-Naphthyl Diethylcarbamate with PCy3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl diethylcarbamate (4.9 mg), and a Ni(cod)2/PCy3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signal at 46.0 ppm is assigned to a Ni(0)/PCy3 adduct (Figure S5, spectrum A). The signal at 9.9 ppm corresponds to free PCy3. The signal at 11.9 is assigned to oxidative addition adduct 9 (spectrum B). Product S40 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at 12.9 ppm in spectrum B. A new signal at 21.9 ppm was observed in the non-competition experiment with S46 (spectrum C) that is tentatively assigned to S47. However, this signal was not detected in the competition experiment (spectrum D); instead, only products 9 and S40 were observed, leading to an estimated ratio of oxidative addition of C—Cl to C—O of >99 : 1. Figure S5. 31P NMR studies on oxidative addition at Ni/PCy3 using 1-chloronaphthalene and 1-naphthyl diethylcarbamate. S9 202 Cl OPiv Ni(cod)2 (1 equiv) PCy3 PCy3 (2 equiv) PCy3 O Ni 1-naphth + Cl Ni R + 1,4-dioxane O PCy3 tBu 7 S48 r.t., 2 h 9, 1-naphth S40, 2-naphth S49 >99 : 1 Competition Between 1-Chloronaphthalene and 1-Naphthyl Pivalate with PCy3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl pivalate (4.6 mg), and a Ni(cod)2/PCy3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at 46.0 ppm is assigned to a Ni(0)/PCy3 adduct (Figure S6, spectrum A). The signal at 9.9 ppm corresponds to free PCy3. The signal at 11.9 is assigned to oxidative addition adduct 9 (spectrum B). Product S40 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1- chloronaphthalene) was detected at 12.9 ppm in spectrum B. A new signal at 22.2 ppm was observed in the non-competition experiment with S48 (spectrum C) that is tentatively assigned to S49. However, this signal was not detected in the competition experiment (spectrum D); instead, only products 9 and S40 were observed, leading to an estimated ratio of oxidative addition of C—Cl to C—O of >99 : 1. Figure S6. 31P NMR studies on oxidative addition at Ni/PCy3 using 1-chloronaphthalene and 1-naphthyl pivalate. S1 0 203 Competition Between 1-Chloronaphthalene and 1-Naphthyl Triflate with PMe3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl triflate (5.5 mg), and a Ni(cod)2/PMe3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at -20.8 ppm corresponds to Ni(PMe3)4 (Figure S7, spectrum A). The signal at -8.4 ppm is assigned to another unidentified Ni(0)/PMe3 adduct. No free PMe3 is detected at -61.9 ppm (outside the window shown in Figure S7) in any of the spectra. The signals at -12.8 and -16.2 ppm are assigned to oxidative addition adducts 11 and S51, respectively (spectra B-D). A small amount of product S50 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at -14.2 ppm in spectrum B. In the competition experiment (spectrum D), none of S50 could be detected. The ratio of oxidative addition of C—Cl to C—O in spectrum D is 1 : 88.6. Figure S7. 31P NMR studies on oxidative addition at Ni/PMe3 using 1-chloronaphthalene and 1-naphthyl triflate. S1 1 204 Competition Between 1-Chloronaphthalene and 1-Naphthyl Tosylate with PMe3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/PMe3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at -20.8 ppm corresponds to Ni(PMe3)4 (Figure S8, spectrum A). The signal at -8.4 ppm is assigned to another unidentified Ni(0)/PMe3 adduct. No free PMe3 is detected at -61.9 ppm (outside the window shown in Figure S8) in any of the spectra. The signals at -12.8 and -15.6 ppm are assigned to oxidative addition adducts 11 and 12, respectively (spectra B-D). A small amount of product S50 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at -14.2 ppm in spectrum B. In the competition experiment (spectrum D), none of S50 could be detected. The ratio of oxidative addition of C—Cl to C—O in spectrum D is 1 : 6.3. Figure S8. 31P NMR studies on oxidative addition at Ni/PMe3 using 1-chloronaphthalene and 1-naphthyl tosylate. S1 2 205 Competition Between 1-Chloronaphthalene and 1-Naphthyl Mesylate with PMe3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl mesylate (4.5 mg), and a Ni(cod)2/PMe3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at -20.8 ppm corresponds to Ni(PMe3)4 (Figure S9, spectrum A). The signal at -8.4 ppm is assigned to another unidentified Ni(0)/PMe3 adduct. No free PMe3 is detected at -61.9 ppm (outside the window shown in Figure S9) in any of the spectra. The signals at -12.8 and -15.4 ppm are assigned to oxidative addition adducts 11 and S52, respectively (spectra B-D). A small amount of product S50 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at -14.2 ppm in spectrum B. In the competition experiment (spectrum D), none of S50 could be detected. The ratio of oxidative addition of C—Cl to C—O in spectrum D is 1 : 10. Figure S9. 31P NMR studies on oxidative addition at Ni/PMe3 using 1-chloronaphthalene and 1-naphthyl mesylate. S1 3 206 Competition Between 1-Chloronaphthalene and 1-Naphthyl Dimethylsulfamate with PMe3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl dimethylsulfamate (5.0 mg), and a Ni(cod)2/PMe3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signal at -20.8 ppm corresponds to Ni(PMe3)4 (Figure S10, spectrum A). The signal at -8.4 ppm is assigned to another unidentified Ni(0)/PMe3 adduct. No free PMe3 is detected at -61.9 ppm (outside the window shown in Figure S10) in any of the spectra. The signals at -12.8 and -15.8 ppm are assigned to oxidative addition adducts 11 and S53, respectively (spectra B-D). A small amount of product S50 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1- chloronaphthalene) was detected at -14.2 ppm in spectrum B. In the competition experiment (spectrum D), none of S50 could be detected. The ratio of oxidative addition of C—Cl to C—O in spectrum D is 1 : 4.6. Figure S10. 31P NMR studies on oxidative addition at Ni/PMe3 using 1-chloronaphthalene and 1-naphthyl dimethylsulfamate. S1 4 207 Competition Between 1-Chloronaphthalene and 1-Naphthyl Diethylcarbamate with PMe3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl diethylcarbamate (4.9 mg), and a Ni(cod)2/PMe3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signal at -20.8 ppm corresponds to Ni(PMe3)4 (Figure S11, spectrum A). The signal at -8.4 ppm is assigned to another unidentified Ni(0)/PMe3 adduct. No free PMe3 is detected at -61.9 ppm (outside the window shown in Figure S11) in any of the spectra. The signal at -12.8 ppm is assigned to oxidative addition adduct 11 (spectra B and D). A small amount of product S50 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at -14.2 ppm in spectra B and D. No evidence for oxidative addition cleaving the C—OCONEt2 bond was detected in either spectrum C or D. In the competition experiment (spectrum D), only products 11 and S50 were observed, leading to an estimated ratio of oxidative addition of C—Cl to C—O of >99 : 1. Figure S11. 31P NMR studies on oxidative addition at Ni/PMe3 using 1-chloronaphthalene and 1-naphthyl dimethylcarbamate. S1 5 208 Competition Between 1-Chloronaphthalene and 1-Naphthyl Pivalate with PMe3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl pivalate (4.6 mg), and a Ni(cod)2/PMe3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at -20.8 ppm corresponds to Ni(PMe3)4 (Figure S12, spectrum A). The signal at -8.4 ppm is assigned to another unidentified Ni(0)/PMe3 adduct. No free PMe3 is detected at -61.9 ppm (outside the window shown in Figure S12) in any of the spectra. The signal at -12.8 ppm is assigned to oxidative addition adduct 11 (spectra B and D). A small amount of product S50 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at -14.2 ppm in spectra B and D. No evidence for oxidative addition cleaving the C—OPiv bond to make S55 was detected in either spectrum C or D. In the competition experiment (spectrum D), only products 11 and S50 were observed, leading to an estimated ratio of oxidative addition of C—Cl to C—O of >99 : 1. Figure S12. 31P NMR studies on oxidative addition at Ni/PMe3 using 1-chloronaphthalene and 1-naphthyl pivalate. S1 6 209 Cl OTf Ni(cod)2 (1 equiv) PPh3 (2 equiv) PPh3 PPh3 + Cl Ni R + TfO Ni 1-naphth 1,4-dioxane PPh3 PPh3 7 S39 r.t., 2 h S56, 1-naphth S57, 2-naphth S58 1 : 2.1 Competition Between 1-Chloronaphthalene and 1-Naphthyl Triflate with PPh3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl triflate (5.5 mg), and a Ni(cod)2/PPh3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at 39.8 ppm is assigned to a Ni(0)/PPh3 adduct (Figure S13, spectrum A). No free PPh3 is detected at -5.4 ppm (outside the window shown in Figure S13) in any of the spectra. The signals at 22.1 and 18.0 ppm are assigned to oxidative addition adducts S56 and S58, respectively (spectra B-D). The signal for product S57, resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1- chloronaphthalene), overlaps with that of S56. The ratio of oxidative addition of C—Cl to C—O in spectrum D is 1 : 2.1. Figure S13. 31P NMR studies on oxidative addition at Ni/PPh3 using 1-chloronaphthalene and 1-naphthyl triflate. S1 7 210 Competition Between 1-Chloronaphthalene and 1-Naphthyl Tosylate with PPh3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/PPh3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at 39.8 ppm is assigned to a Ni(0)/PPh3 adduct (Figure S14, spectrum A). No free PPh3 is detected at -5.4 ppm (outside the window shown in Figure S14) in any of the spectra. The signals at 22.1 and 17.7 ppm are assigned to oxidative addition adducts S56 and S59, respectively (spectra B-D), although very little reaction appears to have occurred in spectrum C. The signal for product S57, resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene), overlaps with that of S56. In the competition experiment (spectrum D), only product S56 (with overlapping S57) was observed, leading to an estimated ratio of oxidative addition of C—Cl to C—O of >99 : 1. Figure S14. 31P NMR studies on oxidative addition at Ni/PPh3 using 1-chloronaphthalene and 1-naphthyl tosylate. S1 8 211 Competition Between 1-Chloronaphthalene and 1-Naphthyl Mesylate with PPh3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl mesylate (4.5 mg), and a Ni(cod)2/PPh3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at 39.8 ppm is assigned to a Ni(0)/PPh3 adduct (Figure S15, spectrum A). No free PPh3 is detected at -5.4 ppm (outside the window shown in Figure S15) in any of the spectra. The signal at 22.1 ppm is assigned to oxidative addition adduct S56 (spectra B and D). The signal for product S57, resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene), overlaps with that of S56. No evidence for oxidative addition cleaving the C—OMs bond to make S60 was detected in either spectrum C or D. In the competition experiment (spectrum D), only product S56 (with overlapping S57) was observed, leading to an estimated ratio of oxidative addition of C—Cl to C—O of >99 : 1. Figure S15. 31P NMR studies on oxidative addition at Ni/PPh3 using 1-chloronaphthalene and 1-naphthyl mesylate. S1 9 212 Cl OSO2NMe2 Ni(cod)2 (1 equiv) PPh3 PPh3 (2 equiv) PCy3 O Ni 1-naphth + Cl Ni R + O 1,4-dioxane S N Me PCy3 7 S44 r.t., 2 h Me S56 O , 1-naphth S57, 2-naphth S61 >99 : 1 Competition Between 1-Chloronaphthalene and 1-Naphthyl Dimethylsulfamate with PPh3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl dimethylsulfamate (5.0 mg), and a Ni(cod)2/PPh3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signal at 39.8 ppm is assigned to a Ni(0)/PPh3 adduct (Figure S16, spectrum A). No free PPh3 is detected at -5.4 ppm (outside the window shown in Figure S16) in any of the spectra. The signals at 22.1 and 30.4 ppm are assigned to oxidative addition adducts S56 and S61, respectively (spectra B-D). However, the speciation of the C—O oxidative addition adduct (i.e., the structure of S61) is uncertain based on the splitting pattern of its 31P signal. The signal for product S57, resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene), overlaps with that of S56. The ratio of oxidative addition of C—Cl to C—O in spectrum D is >99 : 1. Figure S16. 31P NMR studies on oxidative addition at Ni/PPh3 using 1-chloronaphthalene and 1-naphthyl dimethylsulfamate. S2 0 213 Competition Between 1-Chloronaphthalene and 1-Naphthyl Diethylcarbamate with PPh3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl diethylcarbamate (4.9 mg), and a Ni(cod)2/PPh3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signal at 39.8 ppm is assigned to a Ni(0)/PPh3 adduct (Figure S17, spectrum A). No free PPh3 is detected at -5.4 ppm (outside the window shown in Figure S17) in any of the spectra. The signal at 22.1 ppm is assigned to oxidative addition adduct S56 (spectra B and D). The signal for product S57, resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1- chloronaphthalene), overlaps with that of S56. No evidence for oxidative addition cleaving the C—OCONEt2 bond to make S62 (nor its mono-PPh3 analogue with carbamate bound in a k2-fashion) was detected in either spectrum C or D. In the competition experiment (spectrum D), only product S56 (with overlapping S57) was observed, leading to an estimated ratio of oxidative addition of C—Cl to C—O of >99 : 1. Figure S17. 31P NMR studies on oxidative addition at Ni/PPh3 using 1-chloronaphthalene and 1-naphthyl diethylcarbamate. S2 1 214 Competition Between 1-Chloronaphthalene and 1-Naphthyl Pivalate with PPh3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl pivalate (4.6 mg), and a Ni(cod)2/PPh3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at 39.8 ppm is assigned to a Ni(0)/PPh3 adduct (Figure S18, spectrum A). No free PPh3 is detected at -5.4 ppm (outside the window shown in Figure S18) in any of the spectra. The signal at 22.1 ppm is assigned to oxidative addition adduct S56 (spectra B and D). The signal for product S57, resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene), overlaps with that of S56. No evidence for oxidative addition cleaving the C—OPiv bond to make S63 (nor its mono-PPh3 analogue with carbamate bound in a k2-fashion) was detected in either spectrum C or D. In the competition experiment (spectrum D), only product S56 (with overlapping S57) was observed, leading to an estimated ratio of oxidative addition of C—Cl to C—O of >99 : 1. Figure S18. 31P NMR studies on oxidative addition at Ni/PPh3 using 1-chloronaphthalene and 1-naphthyl pivalate. S2 2 215 Cl OTs Ni(cod)2 (1 equiv) P(4-OMeC6H4)3 (2 equiv) P(4-OMeC6H4)3 P(4-OMeC6H4)3 + Cl Ni R + TsO Ni 1-naphth 1,4-dioxane P(4-OMeC6H4)3 P(4-OMeC6H4)3 7 8 r.t., 2 h S64, 1-naphth S65, 2-naphth S66 >99 : 1 Competition Between 1-Chloronaphthalene and 1-Naphthyl Tosylate with P(4-MeOC6H4)3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/P(4-MeOC6H4)3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signal at 36.2 ppm is assigned to a Ni(0)/P(4-MeOC6H4)3 adduct (Figure S19, spectrum A). No free P(4-MeOPh)3 is detected at -10.3 ppm (outside the window shown in Figure S19) in any of the spectra. The signals at 18.6 and 14.4 ppm are assigned to oxidative addition adducts S64 and S66, respectively (spectra B-D). The signal for product S65, resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene), overlaps with that of S64. In the competition experiment (spectrum D), only products S64 (with overlapping S65) were observed, leading to an estimated ratio of oxidative addition of C—Cl to C—O of >99 : 1. Figure S19. 31P NMR studies on oxidative addition at Ni/P(4-MeOC6H4)3 using 1-chloronaphthalene and 1-naphthyl tosylate. S2 3 216 Cl OTs Ni(cod)2 (1 equiv) P(4-FC H ) (2 equiv) P(4-FC6H4)3 P(4-FC6H 6 4 3 4)3 + Cl Ni R + TsO Ni 1-naphth 1,4-dioxane P(4-FC6H4)3 P(4-FC6H4)3 7 8 r.t., 2 h S67, 1-naphth S68, 2-naphth S69 >99 : 1 Competition Between 1-Chloronaphthalene and 1-Naphthyl Tosylate with P(4-FC6H4)3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/P(4-FC6H4)3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signal at 37.5 ppm is assigned to a Ni(0)/P(4-FC6H4)3 adduct (Figure S20, spectrum A). No free P(4-FC6H4)3 is detected at -8.8 ppm (outside the window shown in Figure S20) in any of the spectra. The signals at 20.0 and 15.7 ppm are assigned to oxidative addition adducts S67 and S69, respectively (spectra B-D). Product S68 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at 19.8 ppm in spectrum B. In the competition experiment (spectrum D), only products S67 and S68 were observed, leading to an estimated ratio of oxidative addition of C—Cl to C—O of >99 : 1. Figure S20. 31P NMR studies on oxidative addition at Ni/P(4-FC6H4)3 using 1-chloronaphthalene and 1-naphthyl tosylate. S2 4 217 Competition Between 1-Chloronaphthalene and 1-Naphthyl Tosylate with PPhMe2. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/PPhMe2 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signals at 4.1 and -8.9 ppm are assigned to Ni(0)/PPhMe2 adducts (Figure S21, spectrum A). No free PPhMe2 is detected at -45.7 ppm (outside the window shown in Figure S21) in any of the spectra. The signals at -5.3 and -6.7 ppm are assigned to oxidative addition adducts S70 and S72, respectively (spectra B-D). A small amount of product S71 resulting from oxidative addition of 2- chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at -5.3 ppm in spectrum B. None of S71 was detected in the competition experiment (spectrum D). The ratio of oxidative addition of C—Cl to C—O in spectrum D is 1 : 5.7. Figure S21. 31P NMR studies on oxidative addition at Ni/PPhMe2 using 1-chloronaphthalene and 1-naphthyl tosylate. S2 5 218 Competition Between 1-Chloronaphthalene and 1-Naphthyl Tosylate with PPhEt2. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/PPhEt2 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signal at 23.6 ppm is assigned to a Ni(0)/PPhEt2 adduct (Figure S22, spectrum A). No free PPhEt2 is detected at -16.2 ppm (outside the window shown in Figure S22) in any of the spectra. The signals at 12.4 and 10.4 ppm are assigned to oxidative addition adducts S73 and S75, respectively (spectra B-D). A small amount of product S74 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at 12.0 ppm in spectrum B. In the competition experiment (spectrum D), a small amount of S74 was detected, and it was integrated together with S73 to obtain a ratio of oxidative addition of C—Cl to C—O of 2.2 : 1. Figure S22. 31P NMR studies on oxidative addition at Ni/PPhEt2 using 1-chloronaphthalene and 1-naphthyl tosylate. S2 6 219 Competition Between 1-Chloronaphthalene and 1-Naphthyl Tosylate with PPh2Me. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/PPh2Me stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signal at 21.0 ppm is assigned to a Ni(0)/PPh2Me adduct (Figure S23, spectrum A). No free PPh2Me is detected at -26.8 ppm (outside the window shown in Figure S23) in any of the spectra. The signals at 8.9 and 5.3 ppm are assigned to oxidative addition adducts S76 and S78, respectively (spectra B-D). A small amount of product S77 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at 8.0 ppm in spectrum B. In the competition experiment (spectrum D), a small amount of S77 was detected, and it was integrated together with S76 to obtain a ratio of oxidative addition of C—Cl to C—O of 1 : 1. Figure S23. 31P NMR studies on oxidative addition at Ni/PPh2Me using 1-chloronaphthalene and 1-naphthyl tosylate. S2 7 220 Competition Between 1-Chloronaphthalene and 1-Naphthyl Tosylate with P(n-Bu)3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/P(n-Bu)3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signal at 11.8 ppm is assigned to a Ni(0)/P(n-Bu)3 adduct (Figure S24, spectrum A). No free P(n-Bu)3 is detected at -32.0 ppm (outside the window shown in Figure S24) in any of the spectra. The signals at 4.4 and 1.5 ppm are assigned to oxidative addition adducts S79 and S81, respectively (spectra B-D). A small amount of product S80 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at 3.9 ppm in spectrum B. In the competition experiment (spectrum D), a small amount of S80 was detected, and it was integrated together with S79 to obtain a ratio of oxidative addition of C—Cl to C—O of 1.1 : 1. Figure S24. 31P NMR studies on oxidative addition at Ni/P(n-Bu)3 using 1-chloronaphthalene and 1-naphthyl tosylate. S2 8 221 Competition Between 1-Chloronaphthalene and 1-Naphthyl Tosylate with P(i-Bu)3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/P(i-Bu)3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). The signal at 9.1 ppm is assigned to a Ni(0)/P(i-Bu)3 adduct (Figure S25, spectrum A). The signal at -44.7 ppm corresponds to free P(i-Bu)3. The signals at 4.8 and 0.8 ppm are assigned to oxidative addition adducts S82 and S84, respectively (spectra B-D). A small amount of product S83 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1-chloronaphthalene) was detected at 3.0 ppm in spectrum B. In the competition experiment (spectrum D), a small amount of S83 was detected, and it was integrated together with S82 to obtain a ratio of oxidative addition of C—Cl to C— O of 2.9 : 1. Figure S25. 31P NMR studies on oxidative addition at Ni/P(i-Bu)3 using 1-chloronaphthalene and 1-naphthyl tosylate. S2 9 222 Cl OTs Ni(cod)2 (1 equiv) Fe Fe dcypf (1 equiv) + Cy2P PHCy2 + Cy2P PCy2 1,4-dioxane Ni Ni Cl R TsO 1-naphth 7 8 r.t., 2 h S85, 1-naphth S86, 2-naphth S87 >99 : 1 Competition Between 1-Chloronaphthalene and 1-Naphthyl Tosylate with dcypf. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg). A Ni(cod)2/dcypf stock solution was prepared with a 1:1 molar ratio of Ni(cod)2 to dcypf (corresponding to a 1:2 ratio of Ni to P atoms). Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). No Ni(0)/dcypf adduct could be detected in the acquisition window from +190 to -110.0 ppm (Figure S26, spectrum A). No free dcypf is detected at -9.3 ppm in any of the spectra. The signals at -4.8 and -8.1 ppm are assigned to oxidative addition adducts S85 and S87, respectively (spectra B-D). A trace amount of product S86 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1- chloronaphthalene) was detected at -8.7 ppm in spectrum B. In the competition experiment (spectrum D), only product S85 was observed, leading to an estimated ratio of oxidative addition of C—Cl to C—O of >99 : 1. Figure S26. 31P NMR studies on oxidative addition at Ni/dcypf using 1-chloronaphthalene and 1-naphthyl tosylate. S3 0 223 Competition Between 1-Chloronaphthalene and 1-Naphthyl Tosylate with PEt3. The studies were carried out according to the general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/PEt3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). The signal at 18.5 ppm is assigned to a Ni(0)/PEt3 adduct (Figure S27, spectrum A). No free PEt3 is detected at -19.5 ppm (outside the window shown in Figure S27) in any of the spectra. The signals at 11.5 and 8.6 ppm are assigned to oxidative addition adducts S88 and S90, respectively (spectra B-D). A small amount of product S89 resulting from oxidative addition of 2-chloronaphthalene (contaminant in 1- chloronaphthalene) was detected at 11.6 ppm in spectrum B. In the competition experiment (spectrum D), a small amount of S89 was detected, and it was integrated together with S88 to obtain a ratio of oxidative addition of C—Cl to C—O of 1.8 : 1. Figure S27. 31P NMR studies on oxidative addition at Ni/PEt3 using 1-chloronaphthalene and 1-naphthyl tosylate. S3 1 224 2. Intramolecular Competition: Synthesis, Isolation, and Characterization of 14. OTs Ni(cod)2 (1 equiv) Me3P Me3P PMe3 (2 equiv) Ni OTs Ni Cl PMe + PMe 1,4-dioxane 3 3 Cl TsO 13 Cl r.t., overnight 14 S91 89.6 : 1 Synthesis, Isolation, and Characterization. In a nitrogen-atmosphere glovebox, Ni(cod)2 (275.1 mg, 1.0 mmol, 1.0 equiv), PMe3 (152.2 mg, 2.0 mmol, 2.0 equiv), and 1,4-dioxane (5 mL) were combined in a 20 mL glass vial equipped with a magnetic stir bar. The mixture was stirred for 10 minutes, substrate 13 (332.8 mg, 1.0 mmol, 1.0 equiv) was added, the vial was sealed with a Teflon-lined cap, and the reaction mixture was stirred overnight at room temperature. The vial cap was then loosened and the vial was transferred into a glass vacuum chamber. The chamber was sealed, removed from the glovebox, and connected to a Schlenk line. The reaction mixture was concentrated under high vacuum to yield a yellow solid. While under vacuum, the vacuum chamber was sealed, transferred back into the glovebox, and then opened. Hexanes (5 mL) was added to the reaction vial, and the vial was sealed and removed from the glovebox. The hexanes mixture was sonicated for 15 minutes to provide a uniform suspension. The vial was again transferred into the glovebox and the yellow precipitate was collected on a fritted glass filter, washed with hexanes (6 x 1 mL), and transferred to a 1 dram vial. The loosely-capped vial was placed inside a glass vacuum chamber, and the chamber was sealed, removed from the glovebox, and connected to a Schlenk line. Volatiles were removed under high vacuum to yield 14 (476.9 mg, 80% yield) as a fine yellow powder isolated as an adduct with dioxane (Ni:dioxane = 1 : 0.5). 1H NMR (500 MHz, C6D6, d): 9.75 (d, J = 8.1 Hz, 1H), 8.28 (d, J = 8.1 Hz, 1H), 8.07 (d, J = 7.8 Hz, 2H), 7.38 (dd, J = 7.4, 7.4 Hz, 1H), 7.30 (dd, J = 7.4, 7.4 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.8 Hz, 2H), 3.35 (s, 4H, ½ molecule of 1,4-dioxane), 1.96 (s, 3H), 0.68 (t, J = 3.8 Hz, 18H); 13C{1H} NMR (151 MHz, C6D6, d): 150.3 (t, JCP = 37.4 Hz), 142.9, 140.6, 140.2, 133.5, 132.5 (t, JCP = 4.9), 130.4 (br), 129.0, 127.2 (br), 126.9, 126.7, 125.5, 125.3, 124.8 (br), 67.2 (1,4- dioxane), 21.1, 12.4 (t, JCP = 13.7 Hz); 31P{1H} NMR (203 MHz, C6D6, d): -17.4. HRMS (ESI/Q-TOF) m/z: [M - OTs - 1,4-dioxane]+ Calcd for C16H24ClNiP2 371.0390; Found 371.0378. X-ray quality crystals were grown from toluene/pentane at -25 °C. Structure was verified by X-ray diffraction (see p. S59 for details). The X-ray structure does not indicate dioxane in the crystal lattice, suggesting that it was displaced during the recrystallization procedure. Some toluene was detected in the crystal lattice by XRD. To further evaluate the presence of solvents in the crystals, a larger portion of 14 (synthesized in a separate experiment) was purified by recrystallization from toluene/pentane. After rinsing the crystals with pentane, crushing with a glass stir rod, and thoroughly drying the crystals under high vacuum, a 1H NMR spectrum of 14 dissolved in C6D6 indicated that most of the 1,4-dioxane was removed through this recrystallization process (14 : dioxane = 1 : 0.04). A significant amount of toluene was detected by 1H NMR (14 : toluene = 1 : 0.8), consistent with observation of this solvent in the crystal lattice by XRD. S3 2 225 31P NMR Analysis of Crude Reaction Mixture. A crude NMR was obtained after setting up an identical reaction as described above. The reaction was stopped after 2 hours, and an aliquot of the crude reaction mixture was transferred to an NMR tube, along with a capillary tube insert containing a solution of PPh3O in C6D6 (0.1 M). The sample was analyzed by 31P{1H} NMR. Figure S28 compares the crude reaction mixture (spectrum D) to the NMR spectrum for a Ni(cod)2/PMe3 mixture (spectrum A) and to similar oxidative addition adducts for reaction of a naphthyl chloride and tosylate. In spectrum A, the signal at -20.8 corresponds to (PMe3)4Ni, and the signal at -8.4 ppm is assigned to another unidentified Ni(0)/PMe3 adduct. Reaction of the Ni(cod)2/PMe3 mixture with 1-chloronaphthalene 7 results in a signal at -12.8 ppm and a much smaller signal at -14.2 ppm (spectrum B). The former is assigned to the oxidative addition adduct 11, while the latter is assigned to the adduct S50 resulting from oxidative addition of 2- chloronaphthalene (a contaminant in commercial 1-chloronaphthalene). In the intramolecular competition using 13, a very small signal is observed at -13.0 ppm, which is assigned to minor product S91 on the basis of its similar chemical shift to 11 (spectrum D). Reaction of the Ni(cod)2/PMe3 mixture with 1-naphthyl tosylate 8 results in a signal at -15.4 ppm assigned to oxidative addition adduct 12 (spectrum C). In the intramolecular competition using 13, the major product signal is observed at -15.7 ppm, which is assigned to product 14 on the basis of its similar chemical shift to 12 (spectrum D). The identity of 14 was further confirmed after isolation and characterization, as described above. In spectrum D, the ratio of 14 to putative S91 is 89.6 : 1. Although this reaction was only run for 2 hours (compared to overnight for isolation), it appears that the reaction was essentially complete at 2 hours based on the absence of any detectable Ni(0)/PMe3 adducts. S3 3 226 Figure S28. 31P NMR studies on oxidative addition at Ni/PMe3 using (B) 1-chloronaphthalene, (C) 1-naphthyl tosylate, and (D) 4-chloro-1-naphthyl tosylate. S3 4 227 3. Irreversibility of Oxidative Addition. The following studies were performed to gather insight into the reversibility (or lack thereof) of oxidative addition of either Ar—Cl or Ar—OTs under the stoichiometric reaction conditions. As described below, the results show no evidence for reversibility. This conclusion is in agreement with DFT studies (see section II), where the calculated barrier for reductive elimination at (PR3)2NiII(X)Ar (X = Cl or OTs) to give (PR3)2Ni0 + ArX (~30-40 kcal/mol) is much larger than the barrier for oxidative addition (~9-16 kcal/mol). Because oxidative addition is reversible, the distribution of oxidative addition products in the stoichiometric studies reflect the relative rates of oxidative addition (assuming no further decomposition of products). Irreversibility Studies using PCy3. The studies were carried out according to a modified general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/PCy3 stock solution. Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4-dioxane). Reaction of Ni(cod)2/PCy3 with 7 provides the chloride oxidative addition adducts 9 and S40 (resulting from oxidative addition of 2- chloronaphthalene, a contaminant in 1-chloronaphthalene) after 4 or 2 hours (Figure S29, A-B). When, after 2 hours, an equivalent of 8 is added and the reaction is allowed to stir for an additional 2 hours, no change is detected in the NMR spectrum (Figure S29C). A Cl Ni(cod) PCy 2 (1 equiv) OPPh3 PCy 3 PCy3 (2 equiv) 3 (reference) Cl Ni Cl Ni 1,4-dioxane PCy3 PCy3 7 r.t., 4 h S40 9 Ni(0)/PCy3 adduct PCy3 B Cl Ni(cod)2 (1 equiv) PCy3 (2 equiv) 1,4-dioxane 9 7 r.t., 2 h S40 C then OTs PCy3 TsO Ni PCy Cl 3 Ni(cod)2 (1 equiv) PCy3 (2 equiv) 8 10 9 not detected 1,4-dioxane r.t., 2 h r.t., 2 h S40 7 Figure S29. 31P NMR studies on oxidative addition at Ni/PCy3 using (A) 1-chloronaphthalene for 4 hours, (B) 1- chloronaphthalene for 2 hours, (C) 1-chloronaphthalene for 2 hours followed by 1-naphthyl tosylate for 2 hours. S3 5 228 Irreversibility Studies using PMe3. Studies were carried out according to a modified general procedure using 1-chloronaphthalene, 1-naphthyl tosylate (5.0 mg), and a Ni(cod)2/PMe3 stock solution containing a 1:1.9 ratio of Ni:PMe3. (Note: the amount of PPh3O reference was not standardized across the reactions shown in Figures S30-S31.) Reactions were analyzed by 31P{1H} NMR (203 or 122 MHz, 1,4- dioxane). Reaction of Ni(cod)2/PMe3 with a mixture of 7 and 8 for 2 h provides primarily product 12 as well as a small amount of 11 (Figure S30A). Reaction of Ni(cod)2/PMe3 with 7 alone provides the chloride oxidative addition adducts 11 and S50 (resulting from oxidative addition of 2-chloronaphthalene, a contaminant in 1-chloronaphthalene) after 1 hour (Figure S30B). A large amount of unreacted Ni(0)/PMe3 adducts remains at this time. If an equivalent of 8 is then added and the reaction is stirred for 1 hour, the unreacted Ni(0)/PMe3 adducts disappear and a new signal appears for 12; however, there is no apparent change in the signal for 11 (Figure S30C). A Cl OTs Ni(cod)2 (1 equiv) PMe3 PMe3 (1.9 equiv) TsO Ni + 1,4-dioxane PMe3 8 r.t., 2 h PMe 7 3 12 Cl Ni PMe3 OPPh3 11 (reference) B Cl Ni(cod)2 (1 equiv) Ni(PMe3)4 PMe3 (1.9 equiv) 1,4-dioxane 11 7 r.t., 1 h Ni0/PMe3 adduct S50 C then OTs 12 Cl Ni(cod)2 (1 equiv) PMe3 (1.9 equiv) 8 1,4-dioxane r.t., 1 h 11 7 r.t., 1 h S50 Figure S30. 31P NMR studies on oxidative addition at Ni/PMe3 using (A) 1-chloronaphthalene and 1-naphthyl tosylate for 2 hours, (B) 1-chloronaphthalene for 1 hour, and (C) 1-chloronaphthalene for 1 hour followed by 1-naphthyl tosylate for 1 hour. S3 6 229 Reaction of Ni(cod)2/PMe3 with 8 alone provides the tosylate oxidative addition adducts 12 after 1 hour (Figure S31B). When an equivalent of 7 is then added and the reaction is stirred for 1 hour further, a trace amount of the chloride adduct 12 appears; this signal is nearly indetectable and likely results from reaction of a trace amount of Ni(0) that remained before addition of 7 (Figure S31C). A Cl OTs PMe Ni(cod)2 (1 equiv) 3 PMe (1.9 equiv) TsO Ni 3 + PMe3 1,4-dioxane PMe 7 8 r.t., 2 h 3 12 Cl Ni PMe3 OPPh3 (reference) 11 B 12 OTs Ni(cod)2 (1 equiv) PMe3 (1.9 equiv) 1,4-dioxane 8 r.t., 1 h C then Cl 12 OTs Ni(cod)2 (1 equiv) PMe3 (1.9 equiv) 7 1,4-dioxane r.t., 1 h 8 r.t., 1 h 11 Figure S31. 31P NMR studies on oxidative addition at Ni/PMe3 using (A) 1-chloronaphthalene and 1-naphthyl tosylate for 2 hours, (B) 1-naphthyl tosylate for 1 hour, and (C) 1-naphthyl tosylate for 1 hour followed by 1-chloronaphthalene for 1 hour. S3 7 230 C. Synthesis of Reagents 1. Aryl Grignard Reagents for use in Ni(II) Precatalyst Synthesis 2,6-Dimethylphenylmagnesium chloride (S92). Grignard S92 was prepared according to a modified literature procedure.12 To an oven-dried 25 mL Schlenk flask equipped with a stir bar, under nitrogen, was added magnesium turnings that had been activated by crushing with a mortar and pestle (155.6 mg, 6.4 mmol, 1.6 equiv). The flask containing the Mg was heated at 100 °C while flushing with nitrogen for 1 hour before cooling to room temperature. Once cool, dry degassed THF (8 mL) was added and the mixture was stirred while adding degassed 1,2-dibromoethane (~10 drops). 2,6-Dimethylphenyl chloride was then added dropwise over ~2 minutes (530.0 uL, 4.0 mmol, 1.0 equiv). The mixture darkened slightly and was stirred while heating to reflux for 36 hours. The resulting Grignard reagent S92 as a solution in THF was used without purification for the synthesis of the corresponding Ni complex. Cl Mg, THF MgCl + Br Br Et Reflux, 48 h Et S93 2-Ethylphenylmagnesium chloride (S93). Grignard S93 was prepared according to a modified literature procedure.12 To an oven-dried 25 mL Schlenk flask equipped with a stir bar, under nitrogen, was added magnesium turnings (233.4 mg, 9.6 mmol, 1.6 equiv) that had been activated by crushing with a mortar and pestle. This flask was heated at 100 °C while flushing with nitrogen for 1 hour before cooling to room temperature. Once cool, dry degassed THF (12 mL) was added and the mixture was stirred while adding degassed 1,2-dibromoethane (~15 drops). 2-Ethylphenyl chloride (811.2 uL, 6.0 mmol, 1.0 equiv) was then added dropwise over ~2 minutes. The mixture darkened slightly and was stirred while heating to reflux for 48 hours. The resulting Grignard reagent S93 as a solution in THF was used without purification for the synthesis of the corresponding Ni complex. S3 8 231 1-Naphthylmagnesium bromide (S94). Grignard S94 was prepared according to a modified literature procedure.12 To an oven-dried 25 mL Schlenk flask equipped with a stir bar, under nitrogen, was added magnesium turnings (155.6 mg, 6.4 mmol, 1.6 equiv) that had been activated by crushing with a mortar and pestle. This flask was heated at 100 °C while flushing with nitrogen for 1 hour before cooling to room temperature. Once cool, dry degassed THF (8 mL) was added and the mixture was stirred while adding degassed 1,2-dibromoethane (~10 drops). 1-Naphthyl bromide (559.6 uL, 4.0 mmol, 1.0 equiv) was then added dropwise over ~2 minutes. The mixture darkened slightly and was stirred while heating to reflux for 48 hours. The resulting Grignard reagent S94 as a solution in THF was used without purification for the synthesis of the corresponding Ni complex. 2. Nickel(II) Precatalysts Trans-bis(trimethylphosphine)(2-methylphenyl)nickel(II) tosylate (19). In a nitrogen- atmosphere glovebox, Ni(cod)2 (275.1 mg, 1.0 mmol, 1.0 equiv), PMe3 (152.2 mg, 2.0 mmol, 2.0 equiv), and dioxane (5 mL) were combined in a 20 mL glass vial equipped with a magnetic stir bar. The mixture was stirred for 10 minutes, S95 (262.3 mg, 1.0 mmol, 1.0 equiv) was added, the vial was sealed with a Teflon- lined cap, and the reaction mixture was stirred overnight at room temperature. The vial cap was loosened, and the vial was transferred into a glass vacuum chamber. The chamber was sealed, removed from the glovebox, and connected to a Schlenk line. The reaction mixture was concentrated under high vacuum to yield a yellow solid. The vacuum chamber was sealed under vacuum, transferred back into the glovebox, and opened. Hexanes (5 mL) was added to the reaction vial, and the vial was sealed and removed from the glovebox. The hexanes mixture was sonicated for 15 minutes to provide a uniform suspension. The vial was again transferred into the glovebox and the yellow precipitate was collected on a fritted glass filter, washed with hexanes (6 x 1 mL), and transferred to a 1 dram vial. The loosely-capped vial was placed inside a glass vacuum chamber, and the chamber was sealed, removed from the glovebox, and connected to a Schlenk line. Volatiles were removed under high vacuum to yield 19 (387.2 mg, 82% yield) as a fine yellow powder. 1H NMR (500 MHz, C6D5CD3, d): 7.92 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 6.9 Hz, 2H), 6.88 (d, J = 7.6 Hz, 1H) 6.77–6.67 (multiple overlapping signals, 3H), 2.92 (s, 3H), 2.01 (s, 3H), 0.84 (t, J = 3.5 Hz, 18H); 13C{1H} S3 9 232 NMR (151 MHz, C6D6, d): 147.6 (t, JCP = 35.8 Hz), 143.3 (br), 142.2 (t, JCP = 3.6 Hz), 139.9, 135.2 (t, JCP = 4.5 Hz), 129.0, 127.6 (t, JCP = 7.1 Hz), 126.8, 124.2 (t, JCP = 6.6 Hz), 122.5 (t, JCP = 4.9 Hz), 26.4, 21.1, 12.4 (t, JCP = 13.6 Hz); 31P{1H} NMR (203 MHz, C6D6, δ): -17.5; HRMS (ESI/Q-TOF) m/z: [M - OTs]+ Calcd for C13H25NiP2 301.0779; Found 301.0757. Me3P Cl MgCl Ni PMe3 2 PMe3 Me Me NiCl2•6H2O (PMe3)2NiCl2 20 20 Trans-bis(trimethylphosphine)(2-methylphenyl)nickel(II) chloride (20). Complex 20 was prepared by analogy to a literature procedure.13 In a nitrogen-atmosphere glovebox, (PMe3)2NiCl27 (563.5 mg, 2.0 mmol, 1.0 equiv) and THF (34 mL) were combined in an oven-dried 100 mL Schlenk flask equipped with a stir bar. The flask was sealed with a septum and removed from the glovebox. After all solids were completely dissolved, the flask was cooled in an ice bath for ~5 minutes. o-Tolyl magnesium chloride (1.4 mL of a ~1.4 M solution in THF, 2.0 mmol, 1.0 equiv) was added dropwise via cannula while stirring vigorously, resulting in a color change from dark red to brownish-yellow. The reaction was stirred at 0 °C under nitrogen for 1 hour before warming to room temperature. After this time, anhydrous MeOH (2 mL) was added under nitrogen to quench any remaining Grignard. The solvent was then removed under reduced pressure on a Schlenk line, and the flask was back-filled with nitrogen. A minimal amount of anhydrous degassed MeOH (5 mL) was added to the flask, which was then sonicated to obtain a uniform suspension (~10 minutes) before cooling to -25 °C in the glovebox freezer overnight. The precipitate was collected on a fritted glass filter by vacuum filtration in the glovebox, washed with degassed hexane (2 x 2 mL), and dried under high vacuum to yield 20 as a yellow powder (627.9 mg, 93% yield). 1H NMR (600 MHz, C6D6, d): 7.33 (d, J = 7.2 Hz, 1H), 6.89–6.86 (multiple signals, 2H), 6.83 (m, 1H), 2.73 (s, 3H), 0.81 (t, J = 3.8 Hz, 18H); 13C{1H} NMR (151 MHz, C6D6, d): 156.2 (t, JCP = 34.9 Hz), 142.4 (t, JCP = 3.7 Hz), 135.0 (t, JCP = 4.5 Hz), 127.6 (t, JCP = 3.3 Hz), 124.3 (t, JCP = 3.0 Hz), 122.1 (t, JCP = 2.5 Hz), 26.5, 13.0 (t, JCP = 13.9 Hz); 31P{1H} NMR (122 MHz, C6D6, δ): -14.3; HRMS (ESI/Q-TOF) m/z: [M - Cl]+ Calcd for C13H25NiP2 301.0779; Found 301.0760. S4 0 233 Me Me3P Me Cl MgCl Ni PMe3 2 PMe Me Me 3 S92 NiCl2•6H2O (PMe3)2NiCl2 21 21 Trans-bis(trimethylphosphine)(2,6-dimethylphenyl)nickel(II) chloride (21). Complex 21 was prepared by analogy to a literature procedure.13 In a nitrogen-atmosphere glovebox, (PMe3)2NiCl27 (563.5 mg, 2.0 mmol, 1.0 equiv) and THF (34 mL) were combined in an oven-dried 100 mL Schlenk flask equipped with a stir bar. The flask was sealed with a septum and removed from the glovebox. After all solids were completely dissolved, the flask was cooled in an ice bath for ~5 minutes. S92 (4 mL of a ~0.5 M solution in THF, 2.0 mmol, 1.0 equiv) was added dropwise via cannula while stirring vigorously, resulting in a color change from dark red to brownish-yellow. The reaction was stirred at 0 °C under nitrogen for 45 min before warming to room temperature. After this time, anhydrous MeOH (2 mL) was added under nitrogen to quench any remaining Grignard. The solvent was then removed under reduced pressure on a Schlenk line, and the flask was back-filled with nitrogen. A minimal amount of anhydrous degassed MeOH (8 mL) was added to the flask, which was then sonicated to obtain a uniform suspension (~15 minutes) before cooling to -25 °C in the glovebox freezer overnight. The precipitate was collected on a fritted glass filter by vacuum filtration, washed with hexane (2 x 2 mL), and dried under high vacuum to yield 21 as a yellow powder (274.1 mg, 39% yield). 1H NMR (500 MHz, C6D6, d): 6.85 (m, 1H), 6.78–6.75 (multiple signals, 2H), 2.79 (s, 6H), 0.81 (t, J = 3.6 Hz, 18H); 13C{1H} NMR (151 MHz, C6D6, d): 156.2 (t, JCP = 34.2 Hz), 141.3 (t, JCP = 7.4 Hz), 124.9 (t, JCP = 3.2 Hz), 122.9 (br), 26.1, 13.8 (t, JCP = 13.8 Hz); 31P{1H} NMR (203 MHz, C6D6, δ): - 14.2; HRMS (ESI/Q-TOF) m/z: [M - Cl]+ Calcd for C14H28NiP2 315.0936; Found 315.0923. A minor impurity detected in the NMR spectra is believed to correspond to the nickel bromide analogue of 21 (Br source = dibromoethane from synthesis of the Grignard). Evidence for this assignment was obtained by synthesizing complex 21 from the magnesium bromide Grignard (prepared from xylyl bromide instead of chloride). The impurity in the original spectra was detected as the major product in the NMR spectra of the nickel complex prepared by this route. Me MgCl 2PhP Cl Ni PPhMe 2 PPhMe2 Me 2 NiCl2•6H2O (PPhMe2)2NiCl2 22•THF Me 22 Trans-bis(dimethylphenylphosphine)(2-methylphenyl)nickel(II) chloride (22). Complex 22 was prepared by analogy to a literature procedure.13 In a nitrogen-atmosphere glovebox, (PPhMe2)2NiCl27 (811.8 mg, 2.0 mmol, 1.0 equiv) and THF (34 mL) were combined in an oven-dried 100 mL Schlenk flask equipped with a stir bar. The flask was sealed with a septum and removed from the glovebox. After all solids were completely dissolved, the flask was cooled in an ice bath for ~5 minutes. o-Tolyl magnesium chloride S4 1 234 (1.4 mL of a ~1.4 M solution in THF, 2.0 mmol, 1.0 equiv) was added dropwise via cannula while stirring vigorously, resulting in a color change from dark red to dark yellow. The reaction was stirred at 0 °C under nitrogen for 1 hour before warming to room temperature. After this time, anhydrous MeOH (2 mL) was added under nitrogen to quench any remaining Grignard. The solvent was then removed under reduced pressure on a Schlenk line, and the flask was back-filled with nitrogen. A minimal amount of anhydrous degassed MeOH (5 mL) was added to the flask, which was then sonicated to obtain a uniform suspension (~10 minutes) before cooling to -25 °C in the glovebox freezer overnight. The precipitate was collected on a fritted glass filter by vacuum filtration, washed with hexane (2 x 2 mL), and dried under high vacuum to yield the mono-THF adduct of 22 as a yellow powder (579.2 mg, 54% yield). 1H NMR (600 MHz, C6D6, d): 7.63–7.60 (multiple signals, 4H), 7.08–7.05 (multiple signals, 6H), 6.91 (d, J = 7.5 Hz, 1H), 6.79–6.75 (multiple signals, 2H), 6.71 (ddd, J = 7.9, 7.9, 2.3 Hz, 1H), 3.59 (br, 4H, THF), 2.61 (s, 3H), 1.44–1.40 (m, 4H, THF), 1.21 (t, J = 3.7 Hz, 6H), 0.84 (t, J = 3.6 Hz, 6H); 13C{1H} NMR (151 MHz, C6D6, d): 153.6 (t, JCP = 34.7 Hz), 143.2 (t, JCP = 3.6 Hz), 136.0 (t, JCP = 4.5 Hz), 135.7 (t, JCP = 18.9 Hz), 131.5 (t, JCP = 5.2 Hz), 129.3, 128.3, 127.6 (t, JCP = 3.2 Hz), 124.0 (t, JCP = 2.0 Hz), 122.4 (t, JCP = 5.0 Hz), 67.9 (THF), 26.2, 25.8 (THF), 12.9 (t, JCP = 14.2 Hz), 11.3 (t, JCP = 15.3 Hz); 31P{1H} NMR (203 MHz, C6D6, δ): -7.4; HRMS (ESI/Q-TOF) m/z: [M - Cl - THF]+ Calcd for C23H29NiP2 425.1092; Found 425.1071. MgCl Me3P Cl Ni PMe3 2 PMe Et 3 S93 Et NiCl2•6H2O (PMe3)2NiCl2 S96 S96 Trans-bis(trimethylphosphine)(2-ethylphenyl)nickel(II) chloride (S96). Complex S96 was prepared by analogy to a literature procedure.8 In a nitrogen-atmosphere glovebox, (PMe3)2NiCl27 (563.5 mg, 2.0 mmol, 1.0 equiv) and THF (34 mL) were combined in an oven-dried 100 mL Schlenk flask equipped with a stir bar. The flask was sealed with a septum and removed from the glovebox. After all solids were completely dissolved, the flask was cooled in an ice bath for ~5 minutes. S93 (8 mL of a ~0.5 M solution in THF, 4 mmol, 1.0 equiv) was added dropwise via cannula while stirring vigorously, resulting in a color change from dark red to brownish-yellow. The reaction was stirred at 0 °C under nitrogen for 1 hour before warming to room temperature. After this time, anhydrous MeOH (2 mL) was added under nitrogen to quench any remaining Grignard. The solvent was then removed under reduced pressure on a Schlenk line, and the flask was back-filled with nitrogen. A minimal amount of anhydrous degassed MeOH (5 mL) was added to the flask, which was then sonicated to obtain a uniform suspension (~15 minutes) before cooling to -25 °C in the glovebox freezer overnight. The precipitate was collected on a fritted glass filter by vacuum filtration, washed with hexane (2 x 2 mL), and dried under high vacuum to yield S96 as a yellow powder (389.8 mg, 55% yield). 1H NMR (500 MHz, C6D6, d): 7.35–7.29 (m, 1H), 6.93–6.88 (multiple signals, 3H), 3.29 (q, J = 7.5 Hz, 2H), 1.35 (t, J = 7.5 Hz, 3H), 0.82 (t, J = 3.5 Hz, 18H), 13C{1H} NMR (151 MHz, C6D6, d): 155.8 (t, JCP = 34.5 Hz), 147.9 (br), 134.8 (br), 125.4 (br), 124.6 (br), 122.3 (br), 33.3, 14.8, 13.0 (t, JCP = 13.8 S4 2 235 Hz); 31P{1H} NMR (203 MHz, C6D6, δ): -14.3; HRMS (ESI/Q-TOF) m/z: [M - Cl]+ Calcd for C14H27NiP2 315.0936; Found 315.0916. A minor impurity detected in the NMR spectra is believed to correspond to the nickel bromide analogue of S96 (Br source = dibromoethane from synthesis of the Grignard). Evidence for this assignment was obtained by synthesizing complex S96 from the magnesium bromide Grignard (prepared from 2-bromo-1-ethylbenzene). The impurity in the original spectra was detected as the major product in the NMR spectra of the nickel complex prepared by this route. MgBr Me3P Cl Ni PMe3 2 PMe3 NiCl2•6H2O (PMe ) NiCl S94 3 2 2 11 11 Trans-bis(trimethylphosphine)(1-naphthyl)nickel(II) chloride (11). Complex 11 was prepared by analogy to a literature procedure.8 In a nitrogen-atmosphere glovebox, P(Me3)2NiCl27 (140.9 mg, 0.5 mmol, 1.0 equiv) and THF (8.5 mL) were combined in an oven-dried 25 mL Schlenk flask equipped with a stir bar. The flask was sealed with a septum and removed from the glovebox. After all solids were completely dissolved, the flask was cooled in an ice bath for ~5 minutes. S94 (1 mL of a ~0.5 M solution in THF, 0.5 mmol, 1.0 equiv) was added dropwise via cannula while stirring vigorously, resulting in a color change from dark red to brownish-yellow. The reaction was stirred at 0 °C under nitrogen for 1 hour before warming to room temperature. After this time, anhydrous MeOH (1 mL) was added under nitrogen to quench any remaining Grignard. The solvent was then removed under reduced pressure on a Schlenk line, and the flask was back-filled with nitrogen. A minimal amount of anhydrous degassed MeOH (3 mL) was added to the flask, which was then sonicated to obtain a uniform suspension (~10 minutes) before cooling to -25 °C in the glovebox freezer overnight. The precipitate was collected on a fritted glass filter by vacuum filtration, washed with hexane (2 x 2 mL), and dried under high vacuum to yield 11 as a yellow powder (177 mg, 95% yield). 1H NMR (600 MHz, C6D6, d): 9.25 (d, J, = 8.1 Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 7.0 Hz, 1H), 7.37 (dd, J = 7.5, 7.0 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.29 (dd, J = 7.5, 7.0 Hz, 1H), 7.12 (dd, J = 8.1, 8.0\ Hz, 1H), 0.74 (t, J = 3.8 Hz, 18H); 13C{1H} NMR (126 MHz, C6D6, d): 141.0 (br), 134.1 (br), 132.3, 132.1 (t, JCP = 5.3 Hz), 129.0, 126.1, 125.4, 125.1 (t, JCP = 3.2 Hz), 124.3, 121.9 (t, JCP = 5.3), 13.8 (t, JCP = 14.4 Hz); 31P{1H} NMR (122 MHz, C6D6, δ): -14.0; HRMS (ESI/Q-TOF) m/z: [M – Cl]+ Calcd for C16H25NiP2 337.0779; Found 337.0761. Et2PhP Cl MgCl Ni PPhEt2 2 PPhEt2 Me Me NiCl2•6H2O (PPhEt2)2NiCl2 S98 S98 S97 S4 3 236 Bis(diethylphenylphosphine)nickel(II) chloride (S97). The (PPhEt2)2NiCl2 intermediate was prepared by analogy to a literature procedure.7 NiCl2 ● 6H2O (475.4 mg, 2.0 mmol, 1.0 equiv) and EtOH (8 mL) were combined in an oven-dried 25 mL round bottom flask equipped with a stir bar. The flask was sealed with a rubber septum and the reaction mixture was sparged with nitrogen for ~15 minutes while cooling in an ice bath. A solution of PPhEt2 (767 µL, 4.4 mmol, 2.2 equiv) in THF (4.4 mL) was added dropwise through the septum via cannula under N2, during which time the mixture became cloudy and a dark red precipitate was formed. A reflux condenser was attached and the reaction was heated to reflux (~80 °C) while stirring for 1 hour. The reaction was allowed to cool to room temperature and then cooled further to -20 °C for 30 minutes Under air, the precipitate was collected on a fritted glass filter via vacuum filtration and washed with cold EtOH (2 x 5 mL). The red solid was dissolved in diethyl ether (10 mL), filtered a second time through a fritted glass filter via vacuum filtration to remove any remaining NiCl2 ● 6H2O, and dried under reduced pressure. The resulting red crystals were transferred to a 20 mL vial and dried under high vacuum to yield S97 as dark red crystals (812.1 mg, 88% yield). 1H NMR (600 MHz, C6D6, d): 7.73 (br, 4H), 7.14 (br, 4H), 7.02 (br, 2H), 2.33 (br, 4H), 2.17 (br, 4H), 1.07 (br, 12H); 13C{1H} NMR (126 MHz, C6D5CD3, d): 133.5, 133.4, 130.3, 128.6, 15.6 (br), 9.1 (the phosphorus signal is not detected, likely due to line broadening); HRMS (ESI/Q-TOF) m/z: [M - Cl]+ Calcd for C20H30ClNiP2 425.0859; Found 425.0832. Trans-bis(diethylphenylphosphine)(2-methylphenyl)nickel(II) chloride (S98). Complex S98 was prepared by analogy to a literature procedure.13 In a nitrogen-atmosphere glovebox, (PPhEt2)2NiCl2•THF (462.0 mg, 1.0 mmol, 1.0 equiv) and THF (3.2 mL) were combined in an oven-dried 25 mL Schlenk flask equipped with a stir bar. The flask was sealed with a septum and removed from the glovebox. After all solids were completely dissolved, the flask was cooled in an ice bath for ~5 minutes. o- Tolyl magnesium chloride (700 µL of a ~1.4 M solution in THF, 1.0 mmol, 1.0 equiv) was added dropwise via cannula while stirring vigorously, resulting in a color change from a dark red to a brownish-yellow. The reaction was stirred at 0 °C under nitrogen for 45 minutes before warming to room temperature. After this time anhydrous MeOH (1 mL) was added under nitrogen to quench any remaining Grignard. The solvent was then removed under reduced pressure on a Schlenk line, and the flask was back-filled with nitrogen. A minimal amount of anhydrous degassed MeOH (2.6 mL) was added to the flask which was sonicated to obtain an even suspension (~10 minutes) before cooling to -25 °C in the glovebox freezer overnight. The precipitate was collected on a fritted glass filter by vacuum filtration, washed with hexane (2 x 2 mL), and dried under high vacuum to yield S98 as a yellow powder (425.7 mg, 88% yield). 1H NMR (600 MHz, C6D6, d): 7.53 (br, 4H), 7.06 (multiple signals, 7H), 6.83 (br, 2H), 6.78 (br, 1H), 2.78 (s, 3H), 2.16 (br, 2H), 1.66 (q, J = 7.0 Hz, 2H), 1.40 (br, 2H), 1.28 (br, 2H), 0.94 (multiple signals, 6H), 0.73 (multiple signals, 6H); 13C{1H} NMR (151 MHz, C6D6, d): 151.7 (t, JCP = 33.6 Hz), 143.3 (t, JCP = 2.5 Hz), 136.8 (t, JCP = 3.9 Hz), 132.5 (t, JCP = 17.4 Hz), 132.0 (t, JCP = 4.3 Hz), 129.0, 128.3, 127.5 (t, JCP = 4.8 Hz), 123.9 (br), 122.5 (br), 26.6, 14.1 (t, JCP = 12.8 Hz), 13.9 (t, JCP = 13.1 Hz), 8.0, 7.5; 31P{1H} NMR (203 MHz, C6D6, δ): 13.4; HRMS (ESI/Q-TOF) m/z: [M - Cl]+ Calcd for C27H37NiP2 481.1718; Found 481.1701. S4 4 237 (n-Bu)3P Cl MgCl Ni P(n-Bu)3 2 P(n-Bu)3 Me NiCl2•6H2O (P(n-Bu)3)2NiCl Me 2 S99 S99 Trans-bis(tri-n-butylphosphine)(2-methylphenyl)nickel(II) chloride (S99). Complex S99 was prepared by analogy to a literature procedure.13 In a nitrogen-atmosphere glovebox, (P(n-Bu)3)2NiCl27 (422 mg, 0.79 mmol, 1.0 equiv) and THF (8.5 mL) were combined in an oven-dried 25 mL Schlenk flask equipped with a stir bar. The flask was sealed with a septum and removed from the glovebox. After all solids were completely dissolved, the flask was cooled in an ice bath for ~5 minutes. o-Tolyl magnesium chloride (600 µL of a ~1.4 M solution in THF, 0.79 mmol, 1.0 equiv) was added dropwise via cannula while stirring vigorously, resulting in a color change from dark red to yellowish-brown. The reaction was stirred at 0 °C under nitrogen for 1 hour before warming to room temperature. After this time, anhydrous MeOH (1 mL) was added under nitrogen to quench any remaining Grignard. The solvent was then removed under reduced pressure on a Schlenk line, and the flask was back-filled with nitrogen. A minimal amount of anhydrous degassed MeOH (3.4 mL) was added to the flask, which was then sonicated to obtain two separate liquid layers (~10 minutes) before cooling to -25 °C in the glovebox freezer overnight. The top layer (MeOH) was removed with a Pasteur pipette and discarded. The remaining liquid residue was mixed with a small portion of cold hexane, and allowed to separate into two liquid layers. The top layer (hexane) was removed and discarded, and the remaining liquid residue was transferred to a 20 mL vial and dried under high vacuum to yield S99 as a yellow-brown, sticky syrup (431 mg, 92% yield). 1H NMR (600 MHz, C6D6, d): 7.55 (d, J = 7.1 Hz, 1H), 6.90–6.87 (multiple signals, 2H), 6.84–6.82 (m, 1H), 3.02 (s, 3H), 1.59 (br, 12H), 1.50–1.42 (m, 12H), 1.30 (app sextet, J = 7.2 Hz, 12H), 0.89 (t, J = 7.2 Hz, 18H); 13C{1H} NMR (126 MHz, CDCl3, d): 154.2 (t, JCP = 33.2 Hz), 142.7 (t, JCP = 2.7 Hz), 136.8 (t, JCP = 3.6 Hz), 127.3 (br), 123.9 (br), 122.0 (br), 27.4, 26.8, 25.0 (t, JCP = 6.1 Hz), 22.6 (t, JCP = 11.9 Hz), 13.9; 31P{1H} NMR (203 MHz, C6D6, δ): 5.6; HRMS (ESI/Q-TOF) m/z: [M - Cl]+ Calcd for C31H61NiP2 553.3596; Found 553.3593. Trans-bis(trimethylphosphine)(1-naphthyl)nickel(II) tosylate (12). In a glovebox, Ni(cod)2 (275.1 mg, 1.0 mmol, 1.0 equiv), PMe3 (152.2 mg, 2.0 mmol, 2.0 equiv), and dioxane (5 mL) were combined in a 20 mL glass vial equipped with a magnetic stir bar. The mixture was stirred for 10 minutes, 8 (298.4 mg, 1.0 mmol, 1.0 equiv) was added, the vial was sealed with a Teflon-lined cap, and the reaction mixture was stirred overnight at room temperature. The vial cap was loosened, and the vial was transferred into a S4 5 238 glass vacuum chamber. The chamber was sealed, removed from the glovebox, and connected to a Schlenk line. The reaction mixture was concentrated under high vacuum to yield a yellow solid. The vacuum chamber was sealed under vacuum, transferred back into the glovebox, and opened. Hexanes (5 mL) was added to the reaction vial, and the vial was sealed and removed from the glovebox. The hexanes mixture was sonicated for 15 minutes to provide a uniform suspension. The vial was again transferred into the glovebox and the yellow precipitate was collected on a fritted glass filter, washed with hexanes (6 x 1 mL), and transferred to a 1 dram vial. The loosely-capped vial was placed inside a glass vacuum chamber, and the chamber was sealed, removed from the glovebox, and connected to a Schlenk line. Volatiles were removed under high vacuum to yield 12 (484.7 mg, 95% yield) as a fine yellow powder. 1H NMR (600 MHz, C6D6, d): 9.67 (d, J = 8.2 Hz, 1H), 8.09 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.2 Hz, 1H), 7.42 (dd, J = 8.2, 7.5 Hz, 1H), 7.33 (d, J = 7.0 Hz, 1H), 7.27 (dd, J = 8.2, 7.0 Hz, 1H), 7.24 ( d, J = 8.0 Hz, 1H), 7.01 (dd, J = 8.0, 7.5 Hz, 1H), 6.91 (d, J = 8.0 Hz, 2H), 1.97 (s, 3H), 0.73 (t, J = 3.8 Hz, 18H); 13C{1H} NMR (151 MHz, C6D6, d): 150.7 (t, JCP = 36.8 Hz), 143.1, 140.1, 139.9 (t, JCP = 2.6 Hz), 133.6 (t, JCP = 3.0 Hz), 133.1, 132.8 (t, JCP = 5.2 Hz), 129.0, 128.8, 126.7, 125.6, 124.7, 124.6 (t, JCP = 3.4 Hz), 122.3 (t, JCP = 2.6 Hz), 21.1, 12.5 (t, JCP = 13.7 Hz); 31P{1H} NMR (203 MHz, C6D6, δ): -17.1; HRMS (ESI/Q-TOF) m/z: [M - OTs]+ Calcd for C16H25NiP2 337.0779; Found 337.0761. S4 6 239 3. Aryl Tosylates General Procedure. Aryl tosylates were prepared according to a modified literature procedure.14 Substituted phenol (1 equiv) and TsCl (1.8 equiv) were combined in a 100 mL round bottom flask with pyridine and stirred under nitrogen at 45 ºC overnight. The reaction mixture was allowed to cool to room temperature, H2O (5 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with 25 mL benzene and 10 mL H2O and transferred to a separatory funnel. The aqueous and organic layers were separated, and the organic layer was extracted with 10% aqueous HCl (2 x 25 mL), saturated aqueous NaHCO3 (1 x 25 mL), and brine (1 x 25 mL). The organic layer was dried over MgSO4, filtered, concentrated, and purified by recrystallization. 4-Chlorophenyl 4-methylbenzenesulfonate (1). Aryl tosylate 1 was prepared O S according to the general procedure using 4-chlorophenol (2.00 g, 15.6 mmol, 1.00 equiv), O O TsCl (5.05 g, 26.5 mmol, 1.7 equiv), and pyridine (20.0 mL). The crude solid was recrystallized from hexanes providing 1 as a white crystalline solid (4.26 g, 97% yield). Cl Spectral data are consistent with those previously reported.15 1 Naphthalen-1-yl 4-methylbenzenesulfonate (8). Aryl tosylate 8 was prepared O S according to the general procedure using 1-naphthol (2.25 g, 15.6 mmol, 1.00 equiv), TsCl O O (5.05 g, 26.5 mmol, 1.7 equiv), and pyridine (20.0 mL). The crude solid was recrystallized from hexanes providing 8 as a pale tan solid (3.68 g, 79% yield). Spectral data are 8 consistent with those previously reported.15 4-Chloronaphthalen-1-yl 4-methylbenzenesulfonate (13). Aryl tosylate 13 was O S prepared according to the general procedure using 4-chloronaphthol (2.79 g, 15.6 mmol, O O 1.00 equiv), TsCl (5.05 g, 26.5 mmol, 1.7 equiv), and pyridine (20.0 mL). The crude solid was recrystallized from 95:5 pentane: EtOAc providing 13 as a pale tan solid (4.03 g, 78% Cl yield). Spectral data are consistent with those previously reported.16 13 4-Chloro-3-(trifluoromethyl)phenyl 4-methylbenzenesulfonate (33). Aryl O S tosylate 33 was prepared according to the general procedure using 4-chloro-3- O O trifluoromethylphenol (1.00 g, 5.0 mmol, 1.00 equiv), TsCl (1.62 g, 8.5 mmol, 1.7 equiv), and pyridine (7.0 mL). The crude solid was recrystallized from 95:5 pentane:EtOAc CF3 Cl providing 33 as a white crystalline solid (1.12 g, 64% yield). 1H NMR (600 MHz, C6D6, d): 33 7.47 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 2.8 Hz, 1H), 6.71 (dd, J = 8.7, 2.8 Hz, 1H), 6.63 (d, J = 8.7 1H), 6.55 (d, J = 8.2 Hz, 2H), 1.74 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3, d): 147.9, 146.4, 132.9, 131.8, 130.8 (q, JCF =2.0 Hz), 130.2, 129.7 (q, JCF = 32.2 Hz), 128.7, 127.1, 122.2 (q, JCF = 5.5), 122.0 (q, JCF S4 7 240 = 274.2 Hz), 21.9; 19F NMR (282 MHz, C6D6, d): -62.9. HRMS (ESI/Q-TOF) m/z: [M + Na]+ Calcd for C17H10ClF3O3SNa 372.9883; Found 372.9868. 2-Chlorophenyl 4-methylbenzenesulfonate (31). Aryl tosylate 31 was prepared O S according to the general procedure using 2-chlorophenol (2.00 g, 15.6 mmol, 1.00 equiv), O O Cl TsCl (5.05 g, 26.5 mmol, 1.7 equiv), and pyridine (20.0 mL). The crude solid was recrystallized from hexanes providing 31 as a white solid (2.42 g, 55% yield). Spectral data 31 are consistent with those previously reported.17 3-Chlorophenyl 4-methylbenzenesulfonate (35). Aryl tosylate 35 was prepared O S according to the general procedure using 3-chlorophenol (2.00 g, 15.6 mmol, 1.00 equiv), O O TsCl (5.05 g, 26.5 mmol, 1.7 equiv), and pyridine (20.0 mL). The crude solid was recrystallized from hexanes providing 35 as a pale pink solid (3.65 g, 83% yield). Spectral Cl 35 data are consistent with those previously reported.15 o-Tolyl 4-methylbenzenesulfonate (S95). Aryl tosylate S95 was prepared according O S to the general procedure using 2-methylphenol (2.00 g, 18.4 mmol, 1.0 equiv), TsCl (6.2 g, O O 32.0 mmol, 1.7 equiv), and pyridine (20 mL). The crude solid was recrystallized from 2:1 hexanes:EtOAc providing S95 as a white crystalline solid (2.73 g, 57% yield). Spectral data S95 are consistent with those previously reported.18 S4 8 241 4. Aryl Sulfamate 29 Me 4-Chlorophenyl dimethylsulfamate (29). Aryl sulfamate 29 was prepared according to O S N Me a modified literature procedure.19 NaH (440 mg of a 60% dispersion in oil, 11.00 mmol, 1.23 O O equiv) was cooled to 0 ºC in a pear-shaped flask. A solution of 4-chlorophenol (1.15 g, 8.97 mmol, 1.00 equiv) in DME was added dropwise by cannula to the NaH. The resulting Cl homogeneous solution was warmed to rt for 10 min and then cooled to 0 ºC. A solution of 29 N,N-dimethylsulfamoyl chloride (1.55 g, 10.76 mmol, 1.20 equiv) in DME was added dropwise by cannula to the reaction vessel (total volume of DME = 30 mL). The reaction was warmed to rt, stirred overnight, and then quenched with several drops of H2O. DME was removed by rotary evaporation, and the solid residue was then dissolved in Et2O (50 mL) and H2O (15 mL) and transferred to a separatory funnel. The layers were separated, and the organic layer was washed with 1 M KOH (15 mL), then H2O (15 mL). The combined aqueous layers were then extracted with Et2O (3 x 20 mL), washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (95% hexanes, 5% EtOAc, Rf = 0.52 in 95% hexanes/5%EtOAc) to afford product 29 as a white crystalline solid (1.75, 83% yield). Spectral data are consistent with those previously reported.20 5. Boronic Esters General Procedure. Aryl boronic esters were prepared according to a modified literature procedure.21 Aryl boronic acid (1 equiv), neopentyl glycol (1.2 equiv), MgSO4 (0.83 equiv) and THF were added to a 250 mL round bottom flask and refluxed at 70 ºC for 1 hour. The reaction mixture was allowed to cool to room temperature, then stirred at room temperature for 18 hours. The MgSO4 was removed by filtration and the reaction mixture was concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel or by taking up the residue in a nonpolar solvent and filtering through a silica plug or by recrystallization. Phenylboronic acid neopentylglycol ester (S100). Boronic ester S100 was prepared according to the general procedure using phenylboronic acid (1.22 g, 10 mmol, 1.0 equiv), O B O neopentyl glycol (1.25 g, 12 mmol, 1.2 equiv), MgSO4 (1.00 g, 8.3 mmol, 0.83 equiv), and THF (50 mL). The crude solid was recrystallized from 95:5 hexanes:EtOAc to provide S100 as a white solid S100 (1.50 g, 79% yield). Spectral data are consistent with those previously reported.22 4-Methylphenylboronic acid neopentyl glycol ester (S101). Boronic ester S101 was prepared according to the general procedure using 4-methylphenylboronic acid (1.36 g, 10 mmol, O B O 1.0 equiv), neopentyl glycol (1.25 g, 12 mmol, 1.2 equiv), MgSO4 (1.00 g, 8.3 mmol, 0.83 equiv), and THF (50 mL). The crude solid was purified by flash column chromatography on silica gel (Rf = 0.32 in 95% hexanes/5% EtOAc) to provide S101 as a white solid (1.93 g, 95% yield). Spectral data Me S101 are consistent with those previously reported.23 S4 9 242 4-Methoxyphenylboronic acid neopentyl glycol ester (16). Boronic ester 16 was prepared according to the general procedure using 4-methoxyphenylboronic acid (2.28 g, 15 mmol, 1.0 O B O equiv), neopentyl glycol (1.87 g, 18 mmol, 1.2 equiv), MgSO4 (1.50 g, 12.5 mmol, 0.83 equiv), and THF (75 mL). The crude solid was purified by flash column chromatography on silica gel (Rf = 0.44 in 95% hexanes/5% EtOAc) to provide 16 as a white solid (3.09 g, 94% yield). Spectral data are OMe 16 consistent with those previously reported.22 Benzo[d][1,3]dioxol-5-ylboronic acid neopentyl glycol ester (S102). Boronic ester S102 was prepared according to the general procedure using benzo[d][1,3]dioxol-5- O B O ylboronic acid (497.8 mg, 3 mmol, 1.0 equiv), neopentyl glycol (374.9 mg, 3.6 mmol, 1.2 equiv), MgSO4 (299.7 mg, 2.50 mmol, 0.83 equiv), and THF (15 mL). The crude solid was purified by flash O column chromatography on silica gel (Rf = 0.25 in 100% hexanes) to provide S102 as a white solid O S102 (501.0 mg, 72% yield). Spectral data are consistent with those previously reported.22 [4-(Methoxycarbonyl)phenyl]boronic acid neopentyl glycol ester (S103). Boronic ester S103 was prepared according to the general procedure using [4- O B O (methoxycarbonyl)phenyl]boronic acid (3.60 g, 20 mmol, 1.0 equiv), neopentyl glycol (2.50 g, 24 mmol, 1.2 equiv), MgSO4 (2.00 g, 16.6 mmol, 0.83 equiv), and THF (100 mL). The crude solid was recrystallized from 95:5 hexanes:EtOAc to provide S103 as a white solid (4.37 g, 88% yield). CO2Me S103 Spectral data are consistent with those previously reported.24 4-Trifluoromethylphenylboronic acid neopentyl glycol ester (S104). Boronic ester S104 was prepared according to the general procedure using 4-trifluoromethylphenylboronic acid O B O (949.6 mg, 5 mmol, 1.0 equiv), neopentyl glycol (624.9 mg, 6 mmol, 1.2 equiv), MgSO4 (752.3 mg, 6.25 mmol, 0.83 equiv), and THF (25 mL). The crude solid was recrystallized from 95:5 pentane:EtOAc to provide S104 as a white crystalline solid (1.12 g, 87% yield). Spectral data are CF3 S104 consistent with those previously reported.22 4-Chlorophenylboronic acid neopentyl glycol ester (S105). Boronic ester S105 was prepared according to the general procedure using 4-chlorophenylboronic acid (2.27 g, 15.0 mmol, O B O 1.0 equiv), neopentyl glycol (1.87 g, 18.0 mmol, 1.2 equiv), MgSO4 (1.5 g, 12.5 mmol, 0.83 equiv), and THF (25 mL). The crude solid was purified by flash column chromatography on silica gel (Rf = 0.37 in 95% hexanes/5% EtOAc) to provide S105 as a white solid (2.17 g, 64% yield). Spectral data Cl S105 are consistent with those previously reported.25 S5 0 243 D. Catalytic Reaction Optimization and Screening of Other Conditions General Procedure. Chloroaryl tosylate (0.1 mmol, 1.0 equiv) and boronic ester (1.5 equiv) were combined in a 1-dram vial equipped with a stir bar. The vial was transferred into a nitrogen-atmosphere glovebox where K3PO4 (0.3 mmol, 3.00 equiv) was added. A solution of Ni(II) precatalyst or Ni(cod)2 and phosphine ligand in 1,4-dioxane was prepared (14.3 mM with respect to nickel). 350 µL of the nickel stock solution was added to the reaction vial (0.005 mmol of nickel, 5 mol %). The vial was sealed with a cap equipped with a PTFE-lined septum and removed from the glovebox. Within 60 s, a degassed solution of water in 1,4- dioxane (50 µL of a 1.0 M solution, 0.5 equiv of H2O) was added through the septum cap, and the puncture hole in the septum was immediately sealed with electrical tape. The reactions were stirred at 80 °C for 24 h unless otherwise indicated. Undecane (10.5 µL, 0.5 equiv) was then added as an internal GC standard and the vial was diluted to the top with toluene and mixed well. An aliquot of the reaction mixture was filtered through celite and analyzed by GC. Table S1. Screen of ligands with Ni(cod)2. a OTs Ni(cod) (5 mol %) OTs PMP PMP O O 2 B ligand (9 mol %) + + K3PO4 (3 equiv) 1 1,4-dioxane 17 18 DA Cl 16 80 ºC, 24 h PMP Cl PMP OMe (1.5 equiv) entry ligand 1b 17 (%)b 18 (%)b DA (%)c selectivityd 1 PMe3 12 6 62 8 1 : 10 2 PPhMe2 3 6 69 12 1 : 11 3 PPhEt2 12 14 40 11 1 : 3 4 PPhCy2 54 11 5 9 2 : 1 5 PPh2Me 5 32 17 10 2 : 1 6 PCy3 49 4 4 6 1 : 1 7 PPh3 58 18 1 3 18 : 1 8 dmpe 36 1 15 9 1 : 15 9 dcypf 61 1 2 6 1 : 2 aPMP = p-methoxyphenyl. dmpe = 1,2-bis(dimethylphosphino)ethane. dcypf =1,2- bis(dicyclohexylphosphino)ferrocene. bCalibrated GC yield. cDA = diarylation; approximate yield assumes that the GC response factor of DA is identical to that of 17, which has the same number of C—H bonds. dRatio of 17:18. S5 1 244 Table S2. Screen of PMe3 loading with Ni(cod)2. a OTs O O Ni(cod)2 (5 mol %) OTs PMP PMP B PMe + 3 + K3PO4 (3 equiv) 1 1,4-dioxane 17 18 DA Cl 16 80 ºC, 24 h PMP Cl PMP OMe (1.5 equiv) entry PMe3 (mol %) 1b 17 (%)b 18 (%)b DA (%)c selectivityd 1 5 85 1 10 3 1 : 10 2 6 27 7 39 6 1 : 6 3 7 11 4 54 5 1 : 14 4 8 11 6 54 6 1 : 9 5 9 12 6 62 8 1 : 10 6 10 9 4 59 5 1 : 15 7 11 31 3 50 7 1 : 17 8 12 3 4 55 11 1 : 14 9 15 14 10 38 6 1 : 4 aPMP = p-methoxyphenyl. Average of two runs. bCalibrated GC yield. cDA = diarylation; approximate yield assumes that the GC response factor of DA is identical to that of 17, which has the same number of C—H bonds. dRatio of 17:18. Table S3. Screen of H2O loading with Ni(II) precatalyst 19.a Me3P OTs Ni PMe3 OTs OTs PMP PMP O B O Me (19, 5 mol %) + + K3PO4 (3 equiv) 1 H2O, 1,4-dioxane 17 18 DA Cl 16 80 ºC, 24 h PMP Cl PMP OMe (1.5 equiv) entry H2O (mol %) 1b 17 (%)b 18 (%)b DA (%)c selectivityd 1 0 37 3 60 4 1 : 20 2 10 32 3 67 6 1 : 23 3 20 36 3 66 4 1 : 22 4 30 22 3 75 6 1 : 25 5 40 11 3 82 9 1 : 27 6 50 5 2 88 8 1 : 44 7 100 1 2 89 12 1 : 45 aPMP = p-methoxyphenyl. Average of two runs. bCalibrated GC yield. cDA = diarylation; approximate yield assumes that the GC response factor of DA is identical to that of 17, which has the same number of C—H bonds. dRatio of 17:18. S5 2 245 Table S4. Screen of Ni(II) precatalysts.a OTs O O Ni(II) precatalyst OTs PMP PMP B (5 mol %) + + K3PO4 (3 equiv) 1 H2O (50 mol %) 17 18 DA Cl 16 1,4-dioxane PMP Cl PMP OMe 80 ºC, 24 h (1.5 equiv) Precatalysts: Me3P OTs Me P Me P Ni 3 OTs 3 Cl Me2PhP Cl Me3P Cl Ni Ni Ni Ni PMe3 PMe3 PMe3 PPhMe2 PMe3 12 19 20 22 Et S96 Et2PhP Cl (n-Bu)3P Cl Cy3P Cl Ph3P Cl Ni Ni Ni Ni PPhEt2 P(n-Bu)3 PCy3 PPh3 S98 S99 entry precatalyst 1b 17 (%)b 18 (%)b DA (%)c selectivityd 1 12 6 1 90 9 1 : 90 2 19 5 2 88 8 1 : 44 3 20 1 2 83 9 1 : 42 4e 22 9 5 73 7 1 : 15 5f S96 6 3 88 6 1 : 29 6f S98 8 9 49 8 1 : 5 7f S99 23 9 50 7 1 : 5 8 (o-tol)Ni(PCy3)2Cl 43 6 8 7 1 : 1 9 (o-tol)Ni(PPh3)2Cl 59 14 12 6 1 : 1 aPMP = p-methoxyphenyl. Average of 2 runs. bCalibrated GC yield. cDA = diarylation; approximate yield assumes that the GC response factor of DA is identical to that of 17, which has the same number of C—H bonds. dRatio of 17:18. eWith 4 mol % of of the mono-THF adduct of precatalyst 22. f1.2 equiv of 16, 6 equiv of K3PO4, and 18 hours. S5 3 246 Table S5. Base screen with precatalyst 19.a Me3P OTs Ni PMe3 OTs OTs PMP PMP O O Me B (19, 5 mol %) + + base (3 equiv) 1 H O (50 mol%) 17 18 DA Cl 2 16 1,4-dioxane PMP Cl PMP OMe 80 ºC, 24 h (1.5 equiv) entry base 17 (%)b 18 (%)b DA (%)c selectivityd 1 K2CO3 2 70 5 1 : 35 2 KF 3 51 5 1 : 17 3 Na2CO3 2 39 3 1 : 20 4 CsF 1 17 2 1 : 17 5 KOtBu 1 17 2 1 : 17 6 N(i-Pr)2Et 1 4 0 1 : 4 aPMP = p-methoxyphenyl. bCalibrated GC yield. cDA = diarylation; approximate yield assumes that the GC response factor of DA is identical to that of 17, which has the same number of C—H bonds. dRatio of 17:18. Table S6. Base equivalents screen with precatalyst 19.a Me3P OTs Ni PMe3 OTs Me OTs PMP PMP O B O (19, 5 mol %) + + K3PO4 1 H2O (50 mol%) 17 18 DA Cl 16 1,4-dioxane PMP Cl PMP OMe 80 ºC, 24 h (1.5 equiv) entry K3PO4 (equiv) 1b 17 (%)b 18 (%)b DA (%)c selectivityd 1 3 5 2 88 8 1 : 44 2 4 0 1 80 8 1 : 80 3 5 0 1 78 8 1 : 78 4 6 0 1 70 7 1 : 70 5 7 0 1 73 10 1 : 73 aPMP = p-methoxyphenyl. Average of two runs. bCalibrated GC yield. cDA = diarylation; approximate yield assumes that the GC response factor of DA is identical to that of 17, which has the same number of C—H bonds. dRatio of 17:18. S5 4 247 Table S7. Screen of precatalyst loading with 20.a Me3P Cl Ni PMe3 OTs O O Me OTs PMP PMP B (20) + + K3PO4 (5 equiv) 1 KOH (20 mol%) 17 18 DA Cl 16 1,4-dioxane PMP Cl PMP OMe 80 ºC, 24 h (1.2 equiv) entry 20 (mol %) 1b 17 (%)b 18 (%)b DA (%)c selectivityd 1 1 48 2 45 4 1 : 23 2 2 38 2 52 4 1 : 23 3 3 23 2 67 4 1 : 34 4 4 16 2 78 3 1 : 39 5 5 10 3 83 4 1 : 28 6 6 16 2 77 3 1 : 39 7 7 24 2 71 4 1 : 36 8 8 20 2 74 4 1 : 37 9 9 11 3 68 5 1 : 23 10 10 19 2 74 5 1 : 37 aPMP = p-methoxyphenyl. Reaction concentration in 1,4-dioxane = 0.33 M instead of 0.25 M. bCalibrated GC yield. cDA = diarylation; approximate yield assumes that the GC response factor of DA is identical to that of 17, which has the same number of C—H bonds. dRatio of 17:18. Table S8. Screen of boronic ester equivalents with precatalyst 20.a Me3P Cl Ni PMe3 OTs OTs PMP PMP O B O Me (20, 5 mol %) + + K3PO4 (5 equiv) 1 KOH (20 mol %) 17 18 DA Cl 16 1,4-dioxane PMP Cl PMP OMe 80 ºC, 24 h entry 16 (equiv) 1b 17 (%)b 18 (%)b DA (%)c selectivityd 1 1 32 2 65 3 1 : 33 2 1.1 23 3 74 3 1 : 25 3 1.2 18 2 78 3 1 : 39 4 1.3 22 2 75 3 1 : 38 5 1.4 21 2 75 4 1 : 38 6 1.5 22 2 74 3 1 : 37 aPMP = p-methoxyphenyl. Average of two runs. Reaction concentration in 1,4-dioxane = 0.33 M instead of 0.25 M. bCalibrated GC yield. cDA = diarylation; approximate yield assumes that the GC response factor of DA is identical to that of 17, which has the same number of C—H bonds. dRatio of 17:18. S5 5 248 Table S9. Screen of KOH equivalents with precatalyst 20.a Me3P Cl Ni PMe3 OTs Me OTs PMP PMP O B O (20, 5 mol %) + + K3PO4 (5 equiv) 1 KOH 17 18 DA Cl 16 1,4-dioxane PMP Cl PMP OMe 80 ºC, 24 h (1.2 equiv) entry KOH (mol %) 1b 17 (%)b 18 (%)b DA (%)c selectivityd 1 5 33 2 61 3 1 : 31 2 10 30 2 66 4 1 : 33 3 15 22 2 68 4 1 : 34 4 20 15 2 80 3 1 : 40 5 50 27 2 55 4 1 : 28 6 100 14 3 73 6 1 : 24 7 200 9 1 39 4 1 : 39 8 300 0 2 26 2 1 : 13 aPMP = p-methoxyphenyl. Reaction concentration in 1,4-dioxane = 0.33 M instead of 0.25 M. bCalibrated GC yield. cDA = diarylation; approximate yield assumes that the GC response factor of DA is identical to that of 17, which has the same number of C—H bonds. dRatio of 17:18. Table S10. Screen of reaction concentration with precatalyst 20.a Me3P Cl Ni PMe3 OTs Me OTs PMP PMP O B O (20, 5 mol %) + + K3PO4 (5 equiv) 1 KOH (20 mol%) 17 18 DA Cl 16 1,4-dioxane PMP Cl PMP OMe 80 ºC, 24 h (1.2 equiv) entry conc. (M) 1b 17 (%)b 18 (%)b DA (%)c selectivityd 1 0.25 11 3 89 4 1 : 30 2 0.33 14 2 83 5 1 : 42 3 0.40 19 2 72 4 1 : 36 4 0.50 16 2 34 0 1 : 17 aPMP = p-methoxyphenyl. bCalibrated GC yield. cDA = diarylation; approximate yield assumes that the GC response factor of DA is identical to that of 17, which has the same number of C—H bonds. dRatio of 17:18. S5 6 249 Table S11. Solvent screen with precatalyst 20.a Me3P Cl Ni PMe3 OTs Me OTs PMP PMP O B O (20, 5 mol %) + + K3PO4 (5 equiv) 1 KOH (20 mol%) 17 18 DA Cl 16 solvent PMP Cl PMP OMe 80 ºC, 24 h (1.2 equiv) entry solvent 1b 17 (%)b 18 (%)b DA (%)c selectivityd 1 THF 46 2 52 2 1 : 26 2 2-methyl THF 16 3 71 5 1 : 24 3 toluene 23 2 68 4 1 : 34 4 xylenes 56 3 32 6 1 : 11 aPMP = p-methoxyphenyl. Average of two runs. bCalibrated GC yield. cDA = diarylation; approximate yield assumes that the GC response factor of DA is identical to that of 17, which has the same number of C—H bonds. dRatio of 17:18. E. Cross-Coupling Reactions General Procedure. Chloroaryl tosylate, sulfamate, or triflate (0.5 mmol, 1.0 equiv) and boronic ester (1.2- 1.5 equiv) were combined in a 1-dram vial. The vial was transferred into a nitrogen-atmosphere glovebox where K3PO4 (3.0 mmol, 6.00 equiv) was added. Note: while the original optimization reactions used 3 equiv of K3PO4, we found that slightly higher yields were obtained in these larger scale reactions when using 6 equiv of K3PO4. A solution of Ni(II) precatalyst in 1,4-dioxane was prepared (17.6 mM with respect to nickel). 1.42 mL of the nickel stock solution was added to the reaction vial (0.025 mmol of nickel, 5 mol %). The vial was sealed with a cap equipped with a PTFE-lined septum and removed from the glovebox. Within 60 s, a degassed solution of water in 1,4-dioxane (100 µL of a 2.5 M solution, 0.5 equiv of H2O) was added through the septum cap, and the puncture hole in the septum was sealed with tape. The reactions were stirred at 80 °C for 30 h unless otherwise indicated. The reaction mixture was diluted with toluene and filtered through celite. The reaction mixture was concentrated under vacuum and the major product was purified by flash column chromatography. 4-Chloro-1-phenylnaphthalene (23). Compound 23 was prepared according to the general procedure using phenylboronic acid neopentylglycol ester (S100, 142.5 mg, 0.75 mmol, 1.5 equiv), 4-chloronaphthyl tosylate (13, 166.4 mg, 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 M solution in 1,4-dioxane, 0.5 equiv of H2O), and 23 Cl (PMe3)2Ni(OTs)(o-tol) (19, 1.42 mL of a 17.6 mM solution in 1,4-dioxane, 0.025 mmol, 5 mol %). The reaction was stirred at 80 °C for 30 h. Purification by flash column chromatography (Rf = 0.73 in 99% hexanes, 1% CH2Cl2) followed by recrystallization from 100% pentane afforded product 23 as a white solid (86.0 mg, 72% yield). 1H NMR (500 MHz, CDCl3, d): 8.37 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.64-7.61 (multiple signals, 2H), 7.52-7.44 (multiple signals, 6H), 7.34 (d, J = 7.6 Hz, 1H); 13C{1H} NMR S5 7 250 (126 MHz, CDCl3, d): 140.2, 139.8, 133.0, 131.5, 131.1, 130.2, 128.5, 127.7, 127.0, 126.9, 126.8, 125.9, 124.9 (two signals are coincidentally overlapping); HRMS (ESI/Q-TOF) m/z: [M]+ Calcd for C16H11Cl 238.0549; Found 238.0552. Me 4-Chloro-1-(4-methylphenyl)naphthalene (24). Compound 24 was prepared according to the general procedure using 4-methylphenylboronic acid neopentyl glycol ester (S101, 153.1 mg, 0.75 mmol, 1.5 equiv), 4-chloronaphthyl tosylate (13, 166.4 mg, 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 M solution in 1,4- dioxane, 0.5 equiv of H2O), and (PMe3)2Ni(OTs)(o-tol) (19, 1.42 mL of a 17.6 mM solution in 24 Cl 1,4-dioxane, 0.025 mmol, 5 mol %). The reaction was stirred at 80 °C for 30 h. Purification by flash column chromatography (Rf = 0.36 in 98% hexanes, 2% CH2Cl2) afforded product 24 as a white solid (77.3 mg, 61% yield). 1H NMR (500 MHz, CDCl3, d): 8.35 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.62- 7.60 (multiple signals, 2H), 7.48 (app t, J = 7.5 Hz, 1H), 7.36-7.30 (multiple signals, 5H), 2.45 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3, d): 139.9, 137.5, 137.2, 133.0, 131.3, 131.1, 130.1, 129.2, 127.0, 126.9, 126.8, 125.9, 124.9, 21.4 (two signals are coincidentally overlapping); HRMS (TOF MS EI+) m/z: [M]+ Calcd for C17H13Cl 252.0706; Found 252.0716. OMe 4-Chloro-1-(4-methoxyphenyl)naphthalene (25). Compound 25 was prepared according to the general procedure using 4-methoxyphenylboronic acid neopentyl glycol ester (16, 165.1 mg, 0.75 mmol, 1.5 equiv), 4-chloronaphthyl tosylate (13, 166.4 mg, 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 M solution in 1,4- dioxane, 0.5 equiv of H2O), and (PMe3)2Ni(OTs)(o-tol) (19, 1.42 mL of a 17.6 mM solution in 25 Cl 1,4-dioxane, 0.025 mmol, 5 mol %). The reaction was stirred at 80 °C for 24 h. Purification by flash column chromatography (Rf = 0.36 in 98% hexanes, 2% CH2Cl2) followed by recrystallization from 9:1 pentane:EtOAc afforded product 25 as a white solid (105.21 mg, 78% yield). 1H NMR (500 MHz, CDCl3, d): 8.35 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.62-7.57 (multiple signals, 2H), 7.50-7.48 (m, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 8.5 Hz, 2H), 3.90 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3, d): 159.3, 139.5, 133.2, 132.5, 131.3, 131.2, 131.1, 127.0, 126.9, 126.85, 126.8, 125.9, 124.9, 114.0, 55.6; HRMS (ESI/Q-TOF) m/z: [M + H]+ Calcd for C17H14ClO 269.0728; Found 269.0730. O 4-Chloro-1-(1,3-Benzodioxole)naphthalene (26). Compound 26 was prepared O according to the general procedure using benzo[d][1,3]dioxol-5-ylboronic acid neopentyl glycol ester (S102, 175.6 mg, 0.75 mmol, 1.5 equiv), 4-chloronaphthyl tosylate (13, 166.4 mg, 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 M solution in 1,4-dioxane, 0.5 equiv of H2O), and (PMe3)2Ni(OTs)(o-tol) (19, 1.42 mL of a 17.6 26 Cl mM solution in 1,4-dioxane, 0.025 mmol, 5 mol %). The reaction was stirred at 80 °C for 30 h. Purification by flash column chromatography (Rf = 0.50 in 98% hexanes, 2% CH2Cl2) followed by S5 8 251 washing with cold pentane afforded product 26 as a white solid (106.0 mg, 75% yield). 1H NMR (500 MHz, CDCl3, d): 8.35 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.62-7.60 (multiple signals, 2H), 7.50 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.94-6.93 (multiple signals, 3H), 6.05 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3, d): 147.8, 147.3, 139.4, 134.0, 133.1, 131.4, 131.1, 127.0, 126.9, 126.88, 126.7, 125.8, 124.9, 123.7, 110.8, 108.5, 101.4; HRMS (ESI/Q-TOF) m/z: [M]+ Calcd for C17H11ClO2 282.0442; Found 282.0448. CO2Me 4-Chloro-1-(4-(methoxycarbonyl)phenyl)naphthalene (27). Compound 27 was prepared according to the general procedure using [4-(methoxycarbonyl)phenyl]boronic acid neopentyl glycol ester (S103, 193.5 mg, 0.75 mmol, 1.5 equiv), 4-chloronaphthyl tosylate (13, 166.4 mg, 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 M solution in 1,4-dioxane, 0.5 equiv of H2O), and (PMe3)2Ni(OTs)(o- 27 Cl tol) (19, 1.42 mL of a 17.6 mM solution in 1,4-dioxane, 0.025 mmol, 5 mol %). The reaction was stirred at 80 °C for 20 h. Purification by flash column chromatography (Rf = 0.31 in 90% hexanes, 10% CH2Cl2) afforded product 27 as a white solid (92.0 mg, 62% yield). 1H NMR (500 MHz, CDCl3, d): 8.38 (d, J = 8.5 Hz, 1H), 8.2 (d, J = 8.1 Hz, 2H), 7.83 (d, J = 8.5 Hz, 1H), 7.63 (app t, J = 7.6 Hz, 2H), 7.55-7.49 (multiple signals, 3H), 7.34 (d, J = 7.6 Hz, 1H), 3.98 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3, d): 167.0, 144.9, 138.7, 132.6, 132.3, 131.1, 130.3, 129.8, 129.5, 127.3 127.2, 126.9, 126.4, 125.8, 125.0, 52.4; HRMS (ESI/Q-TOF) m/z: [M + H]+ Calcd for C18H14ClO2 297.0677; Found 297.0669 CF3 4-Chloro-1-(4-trifluoromethylphenyl)naphthalene (28). Compound 28 was prepared according to the general procedure using 4-trifluoromethylphenyl boronic acid neopentyl glycol ester (S104, 193.5 mg, 0.75 mmol, 1.5 equiv), 4-chloronaphthyl tosylate (13, 166.4 mg, 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 M solution in 1,4-dioxane, 0.5 equiv of H2O), and (PMe3)2Ni(OTs)(o-tol) (19, 1.42 mL of a 28 Cl 17.6 mM solution in 1,4-dioxane, 0.025 mmol, 5 mol %). The reaction was stirred at 80 °C for 30 h. Purification by flash column chromatography (Rf = 0.57 in 99% hexanes, 1% CH2Cl2) followed by recrystallization from 100% pentane afforded product 28 as a white solid (98.0 mg, 64% yield). 1H NMR (500 MHz, CDCl3, d): 8.38 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.67-7.63 (multiple signals, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.52 (app t, J = 8.2 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3, d): 143.8, 138.2, 132.6, 132.4, 131.1, 130.6, 130.0 (q, JCF = 32.6), 127.3, 127.0, 126.2, 126.0 (q, JCF = 209.2 Hz), 125.8, 125.5 (q, JCF = 4.0 Hz) , 125.0, 123.5; 19F (300 MHz, C6D6, d): -61.9. HRMS (TOF MS EI+) m/z: [M]+ Calcd for C17H10ClF3 306.0423; Found 306.0411. S5 9 252 OMe 4-Chloro-4'-methoxybiphenyl (18). From aryl tosylate 1. Compound 18 was prepared according to the general procedure using 4-methoxyphenyl boronic acid neopentyl glycol ester (16, 165.1 mg, 0.75 mmol, 1.5 equiv), 4-chlorophenyl tosylate (1, 141.4 mg, 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 M solution in 1,4-dioxane, 0.5 equiv of H2O), and (PMe3)2Ni(OTs)(1-naphthyl) (12, 1.42 mL of a 17.6 mM solution in 1,4-dioxane, 0.025 Cl mmol, 5 mol %). The reaction was stirred at 80 °C for 30 h. Purification by flash column 18 chromatography (Rf = 0.46 in 98% hexanes, 2% CH2Cl2) followed by recrystallization from 95:5 pentane:EtOAc afforded product 18 as a white solid (79.0 mg, 72% yield). Spectral data are consistent with those previously reported.26 From aryl sulfamate 29. Compound 18 was prepared according to the general procedure using 4- methoxyphenyl boronic acid neopentyl glycol ester (16, 132.1 mg, 0.60 mmol, 1.2 equiv), 4-chlorophenyl diethylsulfamate (29, 117.8 mg, 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 M solution in 1,4-dioxane, 0.5 equiv of H2O), and (PMe3)2Ni(OTs)(1-naphthyl) (12, 1.42 mL of a 17.6 mM solution in 1,4-dioxane, 0.025 mmol, 5 mol %). The reaction was stirred at 80 °C for 30 h. Purification by flash column chromatography (Rf = 0.46 in 98% hexanes, 2% CH2Cl2) followed by recrystallization from 95:5 pentane:EtOAc afforded product 18 as a white solid (42.5 mg, 39% yield). Spectral data are consistent with those previously reported.26 From aryl triflate 30. Compound 18 was prepared according to the general procedure using 4- methoxyphenyl boronic acid neopentyl glycol ester (16, 165.1 mg, 0.75 mmol, 1.5 equiv), 4-chlorophenyl triflate (30, 130.3 mg, 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 M solution in 1,4-dioxane, 0.5 equiv of H2O), and (PMe3)2Ni(OTs)(1-naphthyl) (12, 1.42 mL of a 17.6 mM solution in 1,4-dioxane, 0.025 mmol, 5 mol %). The reaction was stirred at 80 °C for 30 h. Purification by flash column chromatography (Rf = 0.46 in 98% hexanes, 2% CH2Cl2) followed by recrystallization from 95:5 pentane:EtOAc afforded product 18 as a white solid (52.3 mg, 48% yield). Spectral data are consistent with those previously reported.26 OMe 4,4''-Dimethoxy-1,1':2',1''-terphenyl (32). Compound 32 was prepared according to the general procedure using 4-methoxyphenylboronic acid neopentyl glycol ester (16, 165.1 mg, 0.75 mmol, 1.5 equiv), 2-chlorophenyl tosylate (31, 141.4 mg, OMe 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 32 M solution in 1,4-dioxane, 0.5 equiv of H2O), and (PMe3)2Ni(OTs)(1-naphthyl) (12, 1.42 mL of a 17.6 mM solution in 1,4-dioxane, 0.025 mmol, 5 mol %). The reaction was stirred at 80 °C for 30 h. Purification by flash column chromatography (Rf = 0.29 in 98% hexanes, 2% CH2Cl2) afforded product 32 as a white solid (50.5 mg, 35% yield). Spectral data are consistent with those previously reported.27 S6 0 253 OMe 4-Chloro-3-trifluoromethyl-4'-methoxybiphenyl (34). Compound 34 was prepared according to the general procedure using 4-methoxyphenylboronic acid neopentyl glycol ester (16, 132.1 mg, 0.60 mmol, 1.2 equiv), 4-chloro-3-trifluoromethylphenyl tosylate (33, 175.4 mg, 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 M CF3 solution in 1,4-dioxane, 0.5 equiv of H2O), and (PMe3)2Ni(OTs)(1-naphthyl) (12, 1.42 mL of a Cl 17.6 mM solution in 1,4-dioxane, 0.025 mmol, 5 mol %). The reaction was stirred at 80 °C for 34 30 h. Purification by flash column chromatography (Rf = 0.43 in 98% hexanes, 2% CH2Cl2) followed by washing with cold pentane afforded product 34 as a white solid (50.1 mg, 35% yield). Spectral data are consistent with those previously reported.2 OMe 3-Chloro-4'-methoxybiphenyl (36). Compound 36 was prepared according to the general procedure using 4-methoxyphenylboronic acid neopentyl glycol ester (16, 165.1 mg, 0.75 mmol, 1.5 equiv), 3-chlorophenyl tosylate (35, 141.4 mg, 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 M solution in 1,4-dioxane, 0.5 equiv of H2O), and Cl (PMe3)2Ni(Cl)(o-tol) (20, 1.42 mL of a 17.6 mM solution in 1,4-dioxane, 0.025 mmol, 5 mol %). 36 The reaction was stirred at 80 °C for 36 h. Purification by flash column chromatography (Rf = 0.36 in 98% hexanes, 2% CH2Cl2) afforded product 36 as a white solid (73.0 mg, 67% yield). Spectral data are consistent with those previously reported.26 Cl 1-(4-Chlorophenyl)naphthalene (S106). Compound S106 was prepared according to the general procedure using 4-chlorophenylboronic acid neopentyl glycol ester (S105, 168.4 mg, 0.75 mmol, 1.5 equiv), naphthyl tosylate (8, 149.2 mg, 0.50 mmol, 1.00 equiv), K3PO4 (636.8 mg, 3.0 mmol, 6.00 equiv), H2O (100 µL of a 2.5 M solution in 1,4-dioxane, 0.5 equiv of H2O), and (PMe3)2Ni(OTs)(o-tol) (19, 1.42 mL of a 17.6 mM solution in 1,4-dioxane, 0.025 S106 mmol, 5 mol %). The reaction was stirred at 80 °C for 24 h. Purification by flash column chromatography (Rf = 0.37 in 98% hexanes, 2% CH2Cl2) followed by recrystallization from 100% pentane afforded product S106 as a colorless crystalline solid (84.0 mg, 71% yield). Spectral data are consistent with those previously reported.28 Cross Coupling Results Using Bromophenyl Tosylate A modified version of the general procedure was followed using 4-methoxyphenylboronic acid neopentyl glycol ester (16, 33.0 mg, 0.15 mmol, 1.5 equiv), 4-bromophenyl tosylate (32.7 mg, 0.50 mmol, 1.00 equiv), K3PO4 (63.7 mg, 0.3 mmol, 3.00 equiv), H2O (50 µL of a 1.0 M solution in 1,4-dioxane, 0.5 equiv of H2O), and (PMe3)2Ni(OTs)(o-tol) (19, 350 µL of a 14.3 mM solution in 1,4-dioxane, 0.005 mmol, 5 mol %). The reaction was stirred at 80 °C for 24 h and analyzed by GC. The yield of 17 is a GC yield calibrated against S6 1 254 undecane as an internal standard. The results show that reaction at bromide is strongly favored over tosylate. Me3P OTs Ni PMe3 OTs Me OTs PMP PMP O B O (19, 5 mol %) + + K3PO4 (3 equiv) H Br 2O (50 mol%) 17 18 16 1,4-dioxane PMP Br PMP OMe 80 ºC, 24 h 68% ~5% ~7% (1.5 equiv) Attempted Cross Coupling with Heteroaromatic Coupling Partners Efforts to cross-couple using a heteroarylboronic ester or a chloropyridyl tosylate substrate were unsuccessful. In the former case, primarily starting material was left after 24 h. In the latter case, much of the starting material was consumed to provide a complex mixture of products according to GC analysis, suggestive of substrate decomposition. Me3P OTs OTs Ni PMe3 + O B O Me (19, 5 mol %) Cl trace products 13 N N K3PO4 (3 equiv) (84% remaining H2O (50 mol%) after 24 h) 1,4-dioxane 80 ºC, 24 h Me3P OTs Ni PMe3 Cl O B O Me (19, 5 mol %) complex mixture + K3PO4 (3 equiv) N OTs H2O (50 mol%) 16 (38% remaining OMe 1,4-dioxane after 24 h) 80 ºC, 24 h S6 2 255 F. X-Ray Crystallographic Details for Compound 14 X-ray diffraction data for 14 were collected at 100 K on a Bruker D8 Venture using MoΚα-radiation (λ=0.71073 Å). Data have been corrected for absorption using SADABS29 area detector absorption correction program. Using Olex2,30 the structure was solved with the SHELXT31 structure solution program using Direct Methods and refined with the SHELXL32 refinement package using least squares minimization. All non-hydrogen atoms were refined with anisotropic thermal parameters. Hydrogen atoms of the investigated complex were located from difference Fourier maps but finally their positions were placed in geometrically calculated positions and refined using a riding model. Isotropic thermal parameters of the placed hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). Calculations and refinement of structures were carried out using APEX3,33 SHELXTL,34 and Olex2 software. Table S12. Crystal data and structure refinement for 14. Identification code MSU_SN12 (2-JR-80) Empirical formula C26.5H35ClNiO3P2S Formula weight 589.70 Temperature/K 100 Crystal system monoclinic Space group P21/c a/Å 10.9661(6) b/Å 20.2493(11) c/Å 12.9096(7) α/° 90 β/° 102.242(2) γ/° 90 Volume/Å3 2801.5(3) Z 4 ρcalcg/cm3 1.398 µ/mm-1 1.003 F(000) 1236.0 Crystal size/mm3 0.41 × 0.28 × 0.23 Radiation MoKα (λ = 0.71073) 2Θ range for data collection/° 5.158 to 58.452 Index ranges -12 ≤ h ≤ 15, -27 ≤ k ≤ 27, -17 ≤ l ≤ 17 Reflections collected 54495 Independent reflections 7571 [Rint = 0.0330, Rsigma = 0.0209] Data/restraints/parameters 7571/45/327 Goodness-of-fit on F2 1.039 Final R indexes [I>=2σ (I)] R1 = 0.0534, wR2 = 0.1298 Final R indexes [all data] R1 = 0.0709, wR2 = 0.1453 Largest diff. peak/hole / e Å-3 2.11/-1.27 S63 256 Table S13. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 14. Ueq is defined as 1/3 of the trace of the orthogonalised UIJ tensor. Atom x Y z U(eq) Ni1 3507.8(3) 3903.3(2) 4832.1(3) 27.31(11) Cl1 -2117.4(9) 3475.3(7) 2185.5(8) 67.4(3) S1 5403.9(7) 3483.2(3) 6669.7(6) 32.62(17) P1 3975.4(7) 3147.2(3) 3737.6(7) 31.86(18) P2 2898.8(8) 4732.2(3) 5717.1(6) 31.53(18) O1 5213(2) 3912.6(9) 5705.2(16) 29.6(4) O2 5391(2) 2788.4(10) 6406.5(19) 43.9(6) O3 4571(2) 3669.2(11) 7352.8(18) 40.1(5) C1 1852(3) 3829.3(13) 4066(2) 31.8(6) C2 1369(3) 4162.5(16) 3138(3) 41.4(7) C3 143(4) 4052.0(19) 2566(3) 49.7(9) C4 -611(3) 3605.1(19) 2920(3) 45.7(8) C5 -198(3) 3248.0(15) 3868(3) 35.0(6) C6 -958(3) 2775.8(17) 4273(3) 43.0(8) C7 -522(3) 2448.2(16) 5181(3) 42.1(8) C8 696(3) 2559.7(14) 5759(3) 36.9(7) C9 1453(3) 3004.9(13) 5397(2) 31.9(6) C10 1045(3) 3367.0(13) 4446(2) 30.8(6) C11 6934(3) 3678.6(14) 7350(2) 31.2(6) C12 7126(3) 4103.9(19) 8207(3) 51.2(9) C13 8326(4) 4246(2) 8751(3) 53.7(10) C14 9353(3) 3967.1(15) 8460(3) 36.6(6) C15 9157(3) 3550.1(15) 7588(2) 36.9(7) C16 7969(3) 3402.9(15) 7042(2) 36.3(7) C17 10651(3) 4102.0(19) 9083(3) 46.3(8) C18 3155(3) 2367.5(15) 3709(4) 51.1(10) C19 3668(3) 3390.0(18) 2349(3) 45.4(8) C20 5607(3) 2909.7(15) 3979(3) 37.0(7) C21 1995(4) 5373.7(14) 4918(3) 43.8(8) C22 1931(3) 4510.7(14) 6648(3) 38.9(7) C23 4162(3) 5202.0(14) 6514(3) 41.8(8) C24 5274(13) 4428(5) 10039(9) 62(2) C25 6146(13) 4912(5) 10441(9) 74(4) C26 5845(13) 5575(5) 10270(10) 80(3) C27 4671(12) 5755(5) 9699(10) 62(2) C28 3798(12) 5272(6) 9297(10) 73(3) C29 4100(12) 4608(5) 9468(10) 80(3) C30 5535(12) 3717(5) 10161(9) 91(4) Table S14. Anisotropic Displacement Parameters (Å2×103) for 14. The Anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+2hka*b*U12+…]. Atom U11 U22 U33 U23 U13 U12 Ni1 35.4(2) 16.13(16) 37.6(2) -6.08(12) 23.89(16) -5.06(12) Cl1 41.5(5) 105.8(9) 53.2(5) -18.6(6) 5.9(4) 25.1(5) S1 45.9(4) 22.8(3) 35.5(4) 0.0(3) 22.9(3) -9.6(3) ~Table S14 continued on the next page~ S64 257 ~Table continued from the previous page~ P1 30.5(4) 23.3(3) 47.9(4) -15.7(3) 22.3(3) -7.5(3) P2 47.4(4) 15.4(3) 41.5(4) -4.6(3) 31.1(3) -4.7(3) O1 40.4(11) 21.8(9) 32.4(10) -2.1(7) 21.0(9) -7.8(8) O2 66.9(16) 21.5(10) 47.5(13) 1.1(9) 21.8(12) -12.6(10) O3 46.0(12) 41.4(12) 40.9(12) 2.9(10) 26.8(10) -9.8(10) C1 40.1(15) 21.7(12) 40.3(15) -4.7(10) 23.7(13) 1.6(10) C2 53.0(19) 33.8(15) 45.3(18) 3.9(13) 27.9(15) 11.3(14) C3 61(2) 52(2) 38.7(17) -0.5(15) 16.5(16) 29.5(18) C4 38.2(17) 56(2) 47.2(18) -11.9(16) 18.1(14) 14.2(15) C5 32.0(14) 36.0(15) 40.9(16) -13.5(12) 16.5(12) 5.3(11) C6 25.2(14) 47.4(18) 62(2) -25.9(16) 21.7(14) -4.4(12) C7 43.2(17) 33.8(15) 59(2) -14.0(14) 31.9(16) -10.4(13) C8 43.3(16) 26.1(13) 48.6(17) -7.1(12) 26.1(14) -4.7(12) C9 35.4(14) 22.2(12) 43.7(16) -5.5(11) 20.6(13) -2.5(10) C10 30.8(13) 24.4(12) 42.2(15) -9.6(11) 18.9(12) 1.0(10) C11 43.8(16) 24.2(12) 31.7(13) 2.8(10) 21.8(12) -3.1(11) C12 47.2(19) 53(2) 63(2) -29.5(18) 34.0(18) -10.9(16) C13 53(2) 52(2) 64(2) -30.3(18) 29.0(18) -14.1(17) C14 45.6(17) 31.6(14) 36.1(15) 5.4(12) 16.6(13) -1.0(12) C15 45.9(17) 36.5(15) 31.1(14) 7.3(12) 14.4(13) 15.4(13) C16 52.7(18) 30.8(14) 27.8(13) 1.3(11) 13.9(13) 10.8(13) C17 50(2) 44.7(18) 46.4(19) 2.6(15) 15.3(16) -0.9(15) C18 48.4(19) 25.8(14) 92(3) -24.5(16) 45(2) -13.4(13) C19 43.3(18) 50.2(19) 46.2(18) -21.0(15) 17.1(15) -1.2(15) C20 30.8(14) 33.8(14) 50.9(18) -15.3(13) 18.9(13) -2.5(11) C21 63(2) 22.4(13) 56(2) -0.2(13) 35.1(17) 6.3(13) C22 54.8(19) 24.4(13) 49.7(18) -4.5(12) 38.7(16) -3.8(12) C23 61(2) 23.4(13) 50.0(18) -14.1(12) 32.7(16) -12.9(13) C24 66(3) 65(5) 50(6) 5(4) 4(4) 5(4) C25 92(7) 60(6) 55(6) -19(5) -17(6) -2(5) C26 58(3) 74(6) 99(7) -31(5) -1(4) 0(4) C27 66(3) 65(5) 50(6) 5(4) 4(4) 5(4) C28 40(4) 83(7) 93(10) -19(6) 11(5) 6(4) C29 58(3) 74(6) 99(7) -31(5) -1(4) 0(4) C30 119(9) 43(4) 87(7) 5(5) -31(7) -26(5) Table S15. Bond Lengths for 14. Atom Atom Length/Å Atom Atom Length/Å Ni1 P1 2.2159(7) C5 C6 1.438(5) Ni1 P2 2.2118(7) C5 C10 1.429(4) Ni1 O1 1.968(2) C6 C7 1.343(5) Ni1 C1 1.881(3) C7 C8 1.404(5) Cl1 C4 1.741(4) C8 C9 1.373(4) S1 O1 1.497(2) C9 C10 1.419(4) S1 O2 1.447(2) C11 C12 1.382(4) S1 O3 1.448(2) C11 C16 1.396(4) S1 C11 1.766(3) C12 C13 1.383(5) P1 C18 1.814(3) C13 C14 1.381(5) ~Table S15 continued on the next page~ S65 258 ~Table S15 continued from the previous page~ P1 C19 1.820(4) C14 C15 1.386(4) P1 C20 1.814(3) C14 C17 1.505(5) P2 C21 1.817(4) C15 C16 1.377(5) P2 C22 1.820(3) C24 C25 1.3900 P2 C23 1.811(3) C24 C29 1.3900 C1 C2 1.379(5) C24 C30 1.471(13) C1 C10 1.443(4) C25 C26 1.3900 C2 C3 1.408(5) C26 C27 1.3900 C3 C4 1.368(6) C27 C28 1.3900 C4 C5 1.411(5) C28 C29 1.3900 Table S16. Bond Angles for 14. Atom Atom Atom Angle/˚ Atom Atom Atom Angle/˚ P2 Ni1 P1 171.76(4) C3 C4 C5 121.6(3) O1 Ni1 P1 92.96(6) C5 C4 Cl1 119.2(3) O1 Ni1 P2 92.93(6) C4 C5 C6 123.5(3) C1 Ni1 P1 86.44(8) C4 C5 C10 117.5(3) C1 Ni1 P2 88.18(8) C10 C5 C6 119.0(3) C1 Ni1 O1 174.98(10) C7 C6 C5 121.3(3) O1 S1 C11 103.56(12) C6 C7 C8 120.4(3) O2 S1 O1 112.15(13) C9 C8 C7 120.1(3) O2 S1 O3 114.84(14) C8 C9 C10 122.1(3) O2 S1 C11 107.20(15) C5 C10 C1 121.2(3) O3 S1 O1 111.14(13) C9 C10 C1 121.7(3) O3 S1 C11 107.11(14) C9 C10 C5 117.1(3) C18 P1 Ni1 115.69(11) C12 C11 S1 120.4(2) C18 P1 C19 103.17(19) C12 C11 C16 118.8(3) C18 P1 C20 103.85(16) C16 C11 S1 120.8(2) C19 P1 Ni1 114.95(11) C11 C12 C13 120.2(3) C20 P1 Ni1 115.24(10) C14 C13 C12 121.3(3) C20 P1 C19 102.18(16) C13 C14 C15 118.3(3) C21 P2 Ni1 115.94(11) C13 C14 C17 121.0(3) C21 P2 C22 103.12(16) C15 C14 C17 120.7(3) C22 P2 Ni1 115.87(10) C16 C15 C14 120.9(3) C23 P2 Ni1 114.45(11) C15 C16 C11 120.4(3) C23 P2 C21 101.92(16) C25 C24 C29 120.0 C23 P2 C22 103.71(16) C25 C24 C30 123.2(7) S1 O1 Ni1 114.79(11) C29 C24 C30 116.8(7) C2 C1 Ni1 124.6(2) C26 C25 C24 120.0 C2 C1 C10 117.5(3) C25 C26 C27 120.0 C10 C1 Ni1 117.8(2) C28 C27 C26 120.0 C1 C2 C3 121.7(3) C27 C28 C29 120.0 C4 C3 C2 120.5(3) C28 C29 C24 120.0 C3 C4 Cl1 119.3(3) S66 259 Table S17. Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for 14. Atom x y z U(eq) H2 1876.9 4474.85 2877.97 50 H3 -163.36 4289.65 1929.25 60 H6 -1784.65 2693.93 3890.92 52 H7 -1042.51 2138.93 5433.14 50 H8 997.11 2326.77 6400.81 44 H9 2276.63 3072.84 5796.76 38 H12 6433.08 4299.28 8423.64 61 H13 8445.53 4540.52 9336.03 64 H15 9853.35 3363.23 7364.9 44 H16 7851.82 3112 6452.07 44 H17A 11161.85 3703.38 9098.71 69 H17B 10615.65 4228.31 9808.52 69 H17C 11022.47 4462.17 8746.84 69 H18A 3458.8 2059.81 3235.07 77 H18B 2258.53 2440.44 3451.87 77 H18C 3304.85 2181.02 4425.64 77 H19A 3937.97 3037.1 1929.39 68 H19B 4128.29 3795.69 2273.37 68 H19C 2771.99 3467.92 2097.77 68 H20A 5839.61 2691.42 4670.72 56 H20B 6123.54 3304.02 3974.96 56 H20C 5737.86 2605.21 3423.04 56 H21A 2480.53 5559.76 4432.17 66 H21B 1798.65 5723.1 5382.03 66 H21C 1218.5 5184.39 4508.93 66 H22A 1167.73 4294.55 6266.5 58 H22B 1712.22 4910.38 6996.5 58 H22C 2392.49 4208.02 7183.22 58 H23A 4671.95 4911 7040.59 63 H23B 3817.49 5559.12 6877.31 63 H23C 4680.59 5390.24 6056.45 63 H25 6948.68 4788.87 10831.37 89 H26 6441.04 5905.87 10544.6 96 H27 4464.68 6208.95 9582.15 74 H28 2995.95 5395.02 8906.48 87 H29 3503.57 4278.01 9193.25 96 H30A 6433.58 3641.03 10247.64 136 H30B 5087.65 3482.53 9529.26 136 H30C 5257.26 3552.17 10786.58 136 S67 260 Table S18. Atomic Occupancy for 14. Atom Occupancy Atom Occupancy Atom Occupancy C24 0.5 C25 0.5 H25 0.5 C26 0.5 H26 0.5 C27 0.5 H27 0.5 C28 0.5 H28 0.5 C29 0.5 H29 0.5 C30 0.5 H30A 0.5 H30B 0.5 H30C 0.5 S68 261 Figure S32. X-ray crystal structure of 14. All thermal ellipsoids drawn at the 50% probability level. S6 8 262 II. Computational Details A. General Comments Calculations were performed with Gaussian 16.35 An ultrafine integration grid and the keyword 5d were used for all calculations. Unless otherwise specified in Section E, geometry optimizations of stationary points were carried out in the gas phase with the MN15L36 functional with BS1 (BS1 = the LANL2DZ37 pseudopotential for Ni, the 6-31+G(d) basis set for O and Cl, and the 6-31G(d) basis set for all other atoms). Frequency analyses were carried out at the same level to evaluate the zero-point vibrational energy and thermal corrections at 298.15 K. Gibbs free energy values are reported after applying Cramer and Truhlar’s anharmonic correction to frequencies that are less than 100 cm-1.38 The nature of the stationary points was determined in each case according to the appropriate number of negative eigenvalues of the Hessian matrix. Forward and reverse intrinsic reaction coordinate (IRC) calculations were carried out on the optimized transition structures to ensure that the TSs indeed connect the appropriate reactants and products.39 Multiple conformations were considered for all structures, and the lowest energy conformations are reported. A major conformational consideration is the orientation of the tosylate group (in particular, rotation around the C—OTs and CO—S bonds). Multiple conformations of this group were evaluated for each stationary point. It is also worth noting that the lowest-energy π-complexes are not necessarily directly connected to the oxidative addition transition structures on the potential energy surfaces (i.e., in some cases the IRC calculations lead to different higher-energy π complexes than the lowest-energy structures reported). This factor is unimportant to the overall energetics, assuming that the barrier to interconverting π-complexes is low (e.g., by nickel ring-walking or by tosylate rotation). An initial input geometry for PCy3 was obtained from the crystal structure of Ni(PCy3)(C2H4)2.40 Unless otherwise specified in Section E, single point energy calculations were performed on the gas-phase optimized geometries using the MN15L functional with BS2 (BS2 = the SDD41 pseudopotential for Ni and the 6-311++G(2d,p) basis set for all other atoms). Bulk solvent effects in 1,4-dioxane were considered implicitly in the single point energy calculations through the CPCM continuum solvation model.42 Images of optimized structures were generated with CYLview.43 S6 9 263 B. Graphical Guide to Numbered Compounds Including Relevant Geometry Parameters Substrate and Catalysts: Ni C O 128.7º P H S Cl 1 Ni(PMe3)2 155.3º 136.1º Ni(PCy3)2 Ni(PPh3)2 Substrate-Ni(0) π Complexes: 112.4º 112.6º 115.1º 2 S107 S108 (PMe3) (PCy3) (PPh3) S7 0 2.04 2.05 2.03 1.99 2.02 1.96 264 5-Centered Tosylate Oxidative Addition Transition Structures: 106.5º 116.2º 110.6º 2 2.1 1 .33 2.1 3 2 2 . . 0 2 5 8 2.52 4a-TS 37a-TS S109a-TS (PMe3) (PCy3) (PPh3) Dissociation Tosylate Oxidative Addition Transition Structures: 107.4º 115.4º 14 111.3º 2. 1 .13 2 2.3 2 .07 2.0 2.60 3 4b-TS 37b-TS S109b-TS (PMe3) (PCy3) (PPh3) Chloride Oxidative Addition Transition Structures: 111.7º 121.5º 115.0º 2.08 2.09 2.09 3-TS 38-TS S110-TS (PMe3) (PCy3) (PPh3) S7 1 2.45 1.82 1.83 2.1 2 0.49 1.82 1.86 2.36 1.8 14 .83 2 1.9 2.0 9 3.31 1.9 1 1.9 7 5 2.0 2.81 8 1.8 265 Post-Oxidative Addition cis-Ni(II) Complexes: 1.91 1.90 1.90 6 S111 S112 (PMe3) (PCy3) (PPh3) 1.92 1.90 1.92 5 S113 S114 (PMe3) (PCy3) (PPh3) Post-Oxidative Addition trans-Ni(II) Complexes: 1.88 2.03 1.86 1.97 1.87 2.02 S115 S116 S117 (PMe3) (PCy3) (PPh3) S7 2 1.96 2.26 1.97 2.31 1.97 2.27 266 2.27 1.88 2.27 1.89 2.27 1.90 S118 S119 S120 (PMe3) (PCy3) (PPh3) C. Free Energy Diagrams ∆G (kcal mol-1) PMe ‡ 3 ‡ Me P Me3P 3 Ni PMe3 +21.3 Ni OTs Cl Cl 3-TS O 4b-TS Cl OTs +16.1 O 1 S + +15.9 p-tol O Me3P Ni PHMe3 ‡ +13.1 Me3P PMe3 Ni O O Cl S O p-tol 4a-TS 0.0 2 Me3P PMe3 Ni Cl OTs PMe3 Me3P Ni OTs Cl 5 -18.4 PMe3 Cl Ni PMe3 -19.9 PMe3 6 OTs Cl Ni OTs -26.8 PMe3 S118 PMe3 -28.1 Cl Ni OTs S115 PMe3 Figure S33. Free energy diagram for oxidative addition at Ni(PMe3)2. S7 3 267 ∆G (kcal mol-1) PCy3 ‡ ‡ Cy P Cy3P PCy 3 3 Ni Ni O +13.9 OTs Cl Cl S O 38-TS O +10.2 p-tol Cl OTs 37a-TS ‡ 1 +9.8 +9.0 Cy3P + PCy3 Cy3P Ni PCy3 Ni Cl O 37b-TS 0.0 O S107 p-tol S O Cy3P PCy3 Ni Cl OTs PCy3 Cy3P Ni OTs Cl S113 PCy3 -17.1 Cl Ni OTs PCy3 -20.3 PCy3 S119 Cl Ni PCy -19.5 3 S111 OTs PCy3 -25.8 Cl Ni OTs S116 PCy3 Figure S34. Free energy diagram for oxidative addition at Ni(PCy3)2. S7 4 268 ‡ ∆G Ph P (kcal mol-1 3 ) PPh3 Ni Cl O S109b-TS O +22.2 p-tol S +20.2 O Ph3P PPh ‡ 3 Cl OTs Ni PPh3 ‡ +14.6 O O 1 Ph P Cl S + 3 Ni O p-tol Ph3P Ni PPh3 OTs +12.6 S109a-TS Cl S110-TS 0.0 S108 Ph3P PPh3 Ni PPh3 Cl OTs Ph3P Ni OTs Cl S114 -13.3 PPh3 Cl Ni OTs PPh3 -13.9 -16.0 PPh Cl Ni PPh S117 3 3 S112 OTs -18.8 PPh3 Cl Ni OTs PPh3 S120 Figure S35. Free energy diagram for oxidative addition at Ni(PPh3)2. S7 5 269 D. Table of Energies, Entropies, and Lowest Frequencies of Minimum Energy Structures Table S19. Energies, Entropies, and Lowest Frequencies of Minimum Energy Structuresa Structure Eelec Eelec + ZPE H (Hartree) S (cal Gb Gcorrectedc Lowest # of (Hartree) (Hartree) mol–1 (Hartree) (Hartree) freq. imag K–1) (cm–1) freq. 1 -1585.576471 -1585.362155 -1585.345004 134.8 -1585.409060 -1585.404237 14.1 0 Ni(PMe3)2 -1091.987595 -1091.758554 -1091.741331 127.7 -1091.801997 -1091.799893 33.0 0 Ni(PCy3)2 -2263.383871 -2262.412095 -2262.370156 237.0 -2262.482747 -2262.476721 18.6 0 Ni(PPh3)2 -2241.844806 -2241.294515 -2241.258731 220.7 -2241.363608 -2241.354081 19.1 0 2 -2677.623691 -2677.179426 -2677.144871 211.5 -2677.245346 -2677.238070 19.9 0 S107 -3849.013512 -3847.824263 -3847.765651 309.1 -3847.912499 -3847.903053 21.4 0 S108 -3827.482432 -3826.716526 -3826.663978 291.8 -3826.802617 -3826.790462 19.7 0 4a-TS -2677.600439 -2677.158602 -2677.123940 215.3 -2677.226213 -2677.217213 -154.5 1 37a-TS -3848.996278 -3847.808990 -3847.750445 309.1 -3847.897307 -3847.887452 -210.3 1 S109a-TS -3827.457161 -3826.692745 -3826.639886 296.7 -3826.780834 -3826.767163 -93.8 1 4b-TS -2677.596845 -2677.154215 -2677.119959 208.3 -2677.218944 -2677.212684 -179.1 1 37b-TS -3848.995622 -3847.809596 -3847.750277 318.8 -3847.901743 -3847.888691 -132.7 1 S109b-TS -3827.444945 -3826.680874 -3826.628041 294.8 -3826.768123 -3826.755151 -190.3 1 3-TS -2677.596066 -2677.153759 -2677.119019 215.8 -2677.221575 -2677.212475 -217.3 1 38-TS -3848.995262 -3847.808036 -3847.749289 310.9 -3847.896993 -3847.886834 -196.4 1 S110-TS -3827.460239 -3826.695856 -3826.642878 299.4 -3826.785117 -3826.770371 -203.7 1 6 -2677.657199 -2677.211581 -2677.177399 207.4 -2677.275921 -2677.269719 20.8 0 S111 -3849.044511 -3847.854905 -3847.795816 312.4 -3847.944255 -3847.934050 22.2 0 S112 -3827.504121 -3826.738169 -3826.685321 293.3 -3826.824664 -3826.812649 16.0 0 5 -2677.655934 -2677.209397 -2677.175029 213.0 -2677.276253 -2677.267375 14.4 0 S113 -3849.041451 -3847.851538 -3847.792524 313.0 -3847.941238 -3847.930350 18.3 0 S114 -3827.504724 -3826.737538 -3826.685084 288.5 -3826.822147 -3826.811724 18.0 0 S115 -2677.668825 -2677.223827 -2677.189032 213.4 -2677.290440 -2677.282845 18.3 0 S116 -3849.054150 -3847.865016 -3847.805686 314.7 -3847.955220 -3847.944214 14.1 0 S117 -3827.506564 -3826.741161 -3826.688088 295.0 -3826.828234 -3826.815908 16.9 0 S118 -2677.667477 -2677.222169 -2677.187262 219.7 -2677.291663 -2677.280769 7.2 0 S119 -3849.047741 -3847.857116 -3847.798018 319.8 -3847.949963 -3847.935370 11.2 0 S120 -3827.512977 -3826.746109 -3826.693118 297.6 -3826.834516 -3826.820467 14.5 0 aEnergy values calculated at the CPCM(1,4-dioxane)-MN15L/BS2//MN15L/BS1 level, where BS2 = 6- 311++G(2d,p)/SDD(Ni) and BS1 = 6-31+G(d)(O,Cl)/6-31G(d)(C,H,S,P)/LANL2DZ(Ni). 1 Hartree = 627.51 kcal mol-1. Thermal corrections at 298.15 K. bSolvent-corrected free energy given by G[(CPCM)/MN15L/BS2] = Eelec[(CPCM)/MN15L/BS2] + Gcorr[MN15L/BS1], where Gcorr is the thermal correction to Gibbs free energy obtained in the gas phase. cSolvent-corrected free energy given by G[(CPCM)/MN15L/BS2] = Eelec[(CPCM)/MN15L/BS2] + Gcorr*[MN15L/BS1], where Gcorr* is the thermal correction to Gibbs free energy obtained in the gas phase after applying Cramer and Truhlar’s anharmonic correction.38 S7 6 270 E. Evaluation of Other DFT Methods Figure S36 illustrates the difference between energy barriers for reaction at tosylate vs. chloride (∆∆G‡OTs-Cl) using a variety of DFT methods. A negative value of ∆∆G‡ means that reaction at tosylate is calculated to be more facile than reaction at chloride. Values were calculated based on lowest-energy transition structures for reaction at each site. The x-axis is labeled with the DFT method, where the second term represents the functional used for gas-phase optimization with BS1 and the first term is the functional used to obtain a single-point energy in implicit 1,4-dioxane (CPCM) with BS2. For example, the left-most entry, MN15L//MN15L represents the method used to obtain the numbers reported in the manuscript. The black and red arrows near the top of the graph illustrate the calculated trend in ∆∆G‡ going from PMe3 to PCy3 to PPh3. All the black arrows correspond to methods that predict the following trend for preference of reaction at tosylate: PMe3 > PCy3 > PPh3. The red arrows represent exceptions to the trend. Most methods follow this trend. Also, the majority of methods predict that PMe3 should favor reaction at tosylate (negative ∆∆G‡), and most methods predict that PPh3 should favor reaction at chloride (positive ∆∆G‡). ∆∆G‡ OTs–Cl PMe 10 3 PCy3 PPh3 8 6 4 2 0 -2 -4 Figure S36. Comparison of preference for oxidative addition at tosylate vs. chloride with various DFT methods. S7 7 MN15L // MN15L MN15 // MN15L M06 // MN15L wB97XD // MN15L M06L // M06L M06 // M06L M06-2X // M06L wB97XD // M06L B3LYP // M06L B3LYP-D3 // M06L B3LYP // B3LYP wB97XD // B3LYP reaction at OTs favored reaction at Cl favored 271 F. Distortion-Interaction Analysis Table S20 is an expanded version of Table 5 in the manuscript, and includes a distortion-interaction analysis of the transition structures using PPh3. Table S20. Expanded Table 5: Distortion-Interaction Analysis of Transition Structures. ∆E TS dist ‡ ‡ cat. subst. total ∆∆Edist ∆Eint ∆∆Eint ∆E ∆∆E 4a-TS 5.2 57.4 62.6 -48.0 14.6 45.0 -47.7 -2.7 4b-TS 2.9 53.5 56.4 -39.6 16.8 38.8 -39.3 -0.5 3-TS 1.3 16.3 17.6 -0.3 17.3 37a-TS 1.3 47.4 48.7 -37.9 10.8 37b-TS 2.6 52.8 55.4 41.9 -44.2 -42.6 11.2 -0.7 48.6 -48.9 -0.3 38-TS -3.9 10.7 6.8 4.7 11.5 S109a-TS 1.9 68.5 70.4 -54.5 15.9 S109b-TS 6.9 50.5 57.4 60.6 -33.9 -58.6 23.5 2.0 47.6 -38.0 9.6 S110-TS -4.3 14.1 9.8 4.1 13.9 Table S21 illustrates an alternate approach to distortion-interaction analysis that normalizes for differences in the earliness/lateness of transition structures. Transition structures involving C—O cleavage were analyzed at a C---O distance of 2.06±0.01 Å, and those involving C—Cl cleavage were analyzed at a C---Cl distance of 2.085±0.005 Å. For transition structures whose geometries fall outside of these ranges, analysis was instead performed at an appropriate point along each intrinsic reaction coordinate near to the transition state. As in Table S20, activation energies were measured from the preceding minimum-energy pi complex. Table S21. Distortion-Interaction Analysis Based on Structures Normalized for Earliness/Lateness. ∆E TS dist ∆∆E ∆Eint ∆∆E ∆E‡cat. subst. total dist int ∆∆E‡ 4a-TS 5.2 57.4 62.6 -48.0 14.6 45.0 -47.7 -2.7 4b-TS 2.9 53.5 56.4 -39.6 16.8 38.8 -39.3 -0.5 3-TS 1.3 16.3 17.6 -0.3 17.3 37a-TS* 1.3 52.7 54.0 -44.0 10.0 2.6 52.8 55.4 47.2 -48.7 -1.5 37b-TS -44.2 11.2 48.6 -48.9 -0.3 38-TS -3.9 10.7 6.8 4.7 11.5 S109a-TS* 1.7 61.0 62.7 -46.2 16.5 S109b-TS* 7.0 53.0 60.0 53.0 -36.9 -50.4 23.1 2.6 50.3 -41.1 9.2 S110-TS -4.3 14.1 9.8 4.1 13.9 *A nearby point on the IRC was analyzed instead of the actual transition structure. S7 8 PPh3 PCy3 PMe3 PPh3 PCy3 PMe3 272 The distortion-interaction analysis using PMe3 and PCy3 was also conducted using other functionals. We selected a few functionals (MN15, M06L, wB97XD, and B3LYP) for further analysis because these functionals provide a range of predictions (including incorrect predictions) about the Cl vs. OTs selectivity. Each of these functionals was used to calculate energy values [using BS2 in dioxane(CPCM)] of the structures or fragments of structures that had been optimized at the MN15L/BS1 level of theory. The results are summarized in Tables S22-S25. Statements from the manuscript have been extracted and reproduced below. The first set of statements holds true with all of the additional functionals, indicating that the distortion-interaction analysis conclusions are independent of DFT methods. The second set of statements do not hold true with all the functionals; these are the statements that relate to overall Cl vs. OTs predictions and represent failures of these functionals as illustrated previously in Figure S36. Statements from the manuscript that are functional-independent: • With both PCy3 and PMe3, reaction at tosylate involves greater distortion energy than reaction at chloride. • In fact, the catalyst distortion energy is actually slightly negative (favorable) during insertion of Ni(PCy3)2 into C—Cl (38-TS). • If reaction at tosylate is desired, the dissociation mechanism with Ni(PCy3)2 (37b-TS) has a larger distortion disadvantage than either 5-centered mechanism 37a-TS or 4a-TS. • However, this bending also leads to a large interaction energy advantage for [37b-TS] the dissociation mechanism (∆∆Eint). • The 5-centered mechanism with PCy3 (37a-TS) has a much smaller distortion disadvantage than either 37b-TS or 4a-TS. • However, 37a-TS also has less of an interaction energy advantage than the corresponding transition structure using PMe3. Statements from the manuscript that are functional-dependent: Note: these statements are valid using functionals that predict selectivity consistent with experiment, and are incorrect for functionals that are inconsistent with experiment. • The effects of ∆∆Edist and ∆∆Eint nearly cancel each other out for 37b-TS, and this dissociation mechanism for reaction at tosylate using PCy3 is only slightly lower-energy than reaction at chloride. • As a result, the effects of ∆∆Edist and ∆∆Eint again nearly cancel out and 37a-TS has a similar energy barrier as that for reaction at chloride (38-TS). • …a value of ∆∆Eint for 4a-TS that outweighs the influence of distortion energy (∆∆Edist) and makes reaction at tosylate more facile than reaction at chloride. S7 9 273 Table S22. Distortion-Interaction Analysis of Transition Structures using MN15. TS cat ∆E dist sub ∆E dist total ∆E dist ∆∆E dist ∆Eint ∆∆Eint ∆E‡ ∆∆E‡ 4a-TS 4.6 60.7 65.3 47.2 -44.8 -44.4 20.5 2.8 4b-TS 2.5 59.3 61.8 4 3.7 -39.1 -38.7 22.7 5.1 3-TS 0 .9 17.2 1 8.1 - 0.5 17.7 37a-TS 1.2 51.5 52.7 42.6 -34.0 -37.9 18.7 4.6 37b-TS 1.6 59.3 60.9 5 0.8 -41.4 - 45.3 19.5 5.4 38-TS -3.3 13.5 10.2 3.9 14.1 Table S23. Distortion-Interaction Analysis of Transition Structures using M06. TS cat ∆E dist sub ∆E dist total ∆E dist ∆∆E dist ∆Eint ∆∆Eint ∆E‡ ∆∆E‡ 4a-TS 5.1 58.8 63.9 47.2 -46.3 -46.2 17.5 1.0 4b-TS 3.1 58.1 61.3 44.6 -40.7 - 40.5 20.5 4.0 3 -TS 1.2 1 5.4 1 6.7 - 0.2 16.5 37a-TS 2.2 50.5 52.6 43.3 -34.6 -40.8 18.1 2.6 37b-TS 2.4 58.0 60.4 5 1.1 -44.9 - 51.1 15.5 0.0 38-TS -3.9 13.2 9.3 6.2 15.5 Table S24. Distortion-Interaction Analysis of Transition Structures using wB97XD. TS cat ∆E dist sub ∆E dist total ∆E dist ∆∆E dist ∆Eint ∆∆Eint ∆E‡ ∆∆E‡ 4a-TS 5.2 61.3 66.5 48.5 -50.7 -51.4 15.9 -2.9 4b-TS 3.4 60.3 63.6 4 5.6 -46.5 -47.2 17.1 -1.6 3-TS 1 .6 1 6.4 1 8.1 0 .7 18.8 37a-TS 1.4 51.8 53.2 43.6 -39.1 -45.2 14.0 -1.6 37b-TS 2.0 60.1 62.2 52.6 -50.7 -56.8 11.4 -4.2 38-TS -4.3 13.9 9.6 6.1 15.6 Table S25. Distortion-Interaction Analysis of Transition Structures using B3LYP. TS cat ∆E dist sub ∆E dist total ∆E dist ∆∆E dist ∆Eint ∆∆Eint ∆E‡ ∆∆E‡ 4a-TS 6.1 52.5 58.6 42.4 -50.5 -45.1 8.1 -2.7 4b-TS 4.4 59.2 63.6 47.4 -48.6 -43.1 15.1 4.3 3 -TS 1 .9 1 4.3 1 6.2 - 5.4 10.8 37a-TS 1.7 49.5 51.2 37.7 -37.6 -34.7 13.6 3.0 37b-TS 2.6 61.8 64.4 50.9 -56.7 - 53.8 7.7 -2.9 38-TS -5.1 18.6 13.5 -2.9 10.6 S8 0 274 III. References 1. Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. Organometallics, 2010, 29, 2176. 2. Reeves, E. K., Humke, J. N., Neufeldt, S. R. J. Org. Chem. 2019, 84, 11799. 3. 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