Oxidative Addition of (Hetero)aryl (Pseudo)halides at Palladium(0): Origin and Significance of Divergent Mechanisms Matthew J. Kania, Albert Reyes, Sharon R. Neufeldt This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in Journal of the American Chemical Society, copyright © American Chemical Society after peer review. To access the final edited and published work see https:// doi.org/10.1021/jacs.4c04496 Made available through Montana State University’s ScholarWorks Oxidative Addition of (Hetero)aryl (Pseudo)halides at Palladium(0): Origin and Significance of Divergent Mechanisms Matthew J. Kania, Albert Reyes, and Sharon R. Neufeldt* Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, United States Supporting Information Placeholder ABSTRACT: Two limiting mechanisms are possible for oxidative addition of (hetero)aryl (pseudo)halides at Pd(0): a 3-centered concerted and a nucleophilic displacement mechanism. Until now, there has been little understanding about when each mechanism is relevant. Prior investigations to distinguish between these pathways were limited to a few specific combinations of substrate and ligand. Here, we computationally evaluated over 180 transition structures for oxidative addition in order to determine mechanistic trends based on substrate, ligand(s), and coordination number. Natural abundance 13C kinetic isotope effects provide experimental results consistent with computational predictions. Key findings include that (1) differences in HOMO symmetries dictate that, alt- hough 12e– PdL is strongly biased toward a 3-centered concerted mechanism, 14e– PdL2 often prefers a nucleophilic displacement mechanism; (2) ligand electronics and sterics, including ligand bite angle, influence the preferred mechanism of reaction at PdL2; (3) phenyl triflate always reacts through a displacement mechanism regardless of catalyst structure due to the stability of a triflate anion and the inability of oxygen to effectively donate electron density to Pd; and (4) the high reactivity of C—X bonds adjacent to nitrogen in pyridine substrates relates to stereoelectronic stabilization of a nucleophilic displacement transition state. This work has implica- tions for controlling rate and selectivity in catalytic couplings, and we demonstrate application of the mechanistic insight toward chemodivergent cross-couplings of bromochloroheteroarenes. INTRODUCTION Pd-catalyzed cross-coupling reactions of (hetero)aryl (pseudo)halides are a mainstay of organic synthesis. The cata- lytic cycles for these transformations begin with oxidative ad- dition at Pd(0).1 Because this step is often rate- and/or selectiv- ity-determining, understanding its mechanism is valuable for improving cross-coupling methodology. Oxidative addition of aryl halides is traditionally envisioned as proceeding through a 3-centered concerted transition state.2 However, a second limit- ing mechanism is also possible: the more polar “nucleophilic displacement” (“SN”3 or “SNAr-like”4) mechanism (e.g., Scheme 1A).5 During the nucleophilic displacement pathway, palladium does not interact significantly with the leaving group. Instead, the (pseudo)halide dissociates as an anion. At present there is minimal understanding of when each of these two mechanisms is relevant.3,4 A recent study from our group demonstrated that the mechanism of oxidative addition can have ramifications for controlling site selectivity in cross-cou- pling of dichloroheteroarenes (Scheme 1B).6 Thus, it is now clear that a better understanding of the factors controlling mech- anism may facilitate rational design of selective cross-cou- plings. Scheme 1. Concerted and Nucleophilic Displacement Mech- anisms for Oxidative Addition at Pd(0). Prior reports implicate different mechanisms for a few spe- cific combinations of substrate and ligands based on computational3,4,6a,7–11 or experimental studies.4,12–14 Maseras used density functional theory (DFT) calculations to evaluate the oxidative addition of PhBr at 12e– PdL and 14e– PdL2 with a limited number of ligands (L = PH3, PF3, PMe3, and PPh3, Scheme 1A).3 This work provided evidence that, during reac- tion with PhBr, PdL likely favors a concerted mechanism while the preferred mechanism for PdL2 is ligand- and solvent-de- pendent.15 Experimental Eyring parameters and Hammett val- ues tentatively support a concerted mechanism for Ar—Br,4 Ar—I,12,13 and 2-pyridyl—I4 cleavage at Pd(PPh3)n, but indicate a nucleophilic displacement mechanism for the reaction of Ph— Cl at Pd(dippp)14 and 2-pyridyl—X (X = Cl, Br) at Pd(PPh3)n.4 Concurrently with the present work, computations by Paci and Leitch showed that substituents on 2-chloropyridines and re- lated compounds influence the preferred mechanism for oxida- tive addition at Pd(PCy3)2 due to frontier molecular orbital sym- metry changes.16 Because prior studies comparing concerted to displacement mechanisms are limited to very few experimentally relevant lig- ands, we sought to computationally compare these mechanisms for a wide range of substrates and ligands. Natural abundance 13C kinetic isotope effects (KIE) were also used to distinguish between mechanisms in two catalytic systems, and these exper- iments corroborate DFT calculations. Through molecular mod- eling, we find general trends that describe the mechanistic bi- ases of PdL vs. PdL2 as well as mechanistic preferences of dif- ferent substrate classes. In a practical sense, these results em- phasize that engineering complementarity between the innate biases of the catalyst and of the substrate can enable manipu- lation of site selectivity in cross-coupling reactions. We demon- strate this phenomenon in the context of cross-couplings of bro- mochloroheteroarenes. COMPUTATIONAL METHODS Calculations were performed with Gaussian 16.17 Geometry optimizations of stationary points were carried out in implicit solvent using the CPCM continuum solvation model18 for tetra- hydrofuran with the MN15L19 functional, the LANL2DZ20 ba- sis set and pseudopotential for Pd and I, and a combination of 6-31+G(d) and 6-31G(d) for the other atoms (see page S20). Frequency analyses were carried out at the same level to evalu- ate the zero-point vibrational energy and verify the nature of the stationary points according to the appropriate number of nega- tive eigenvalues of the Hessian matrix. The final reported ener- gies were obtained from single point energy calculations on the optimized geometries using CPCM(THF), the MN15L func- tional, the SDD basis set and pseudopotential for Pd, and 6- 311++G(2d,p) for all other atoms.21,22 Gaussian 16 defaults were used for temperature and pressure (298.15 K and 1 atm). Gibbs free energy values are reported after applying Cramer and Truhlar’s quasi-harmonic correction to entropy23 with a fre- quency cutoff of 100 cm-1. Additional computational details are available in the Supporting Information. RESULTS AND DISCUSSION Computational Modeling of Diverse Oxidative Addition Transition Structures. Both concerted and nucleophilic dis- placement transition structures were constructed for 75 combi- nations of PdLn and substrate (Figure 1A). Where relevant, mul- tiple possible ligand and substrate conformations were consid- ered (examples in Figure 1B), and the lowest energy confor- mation of each type of transition structure is represented in Figure 1C. The lowest energy conformations for each mecha- nism type were typically those highlighted in Figure 1B (see pages S24-S29 for details on exceptions). In particular, (1) for monoligated concerted mechanisms, the ligand is usually ap- proximately trans to the leaving group; (2) for monoligated dis- placement mechanisms, the ligand is always approximately trans to the ortho ring atom;3 (3) for bisligated concerted mech- anisms, Pd is usually pseudo-tetrahedral rather than square pla- nar;24 and (4) for bisligated displacement mechanisms, Pd is usually pseudo-square planar.25 For most transition structures involving PhOTf, the sulfonyl oxygens point away from Pd. In some cases, only one mechanism type could be located. For ex- ample, some 3-centered input structures consistently optimized to nucleophilic displacement structures, and vice versa. In total, 184 unique transition structures were obtained, of which 142 represent the minimum energy geometry for a given mecha- nism. We first wanted to ensure that our characterization of each output structure as “concerted” or “displacement” was reliable. Thus, three geometric parameters were analyzed for each tran- sition structure: the Pd---Cipso distance, the Pd---Yortho distance, and an adjusted value of the Pd---X distance (Figure 1C). To account for the varying atomic radii of X, the Pd---X value was normalized by measuring the difference between the Pd---X distance in the transition structure compared to a simple com- puted oxidative addition adduct (PMe3)2PdII(Ph)X (X = F, Cl, Br, I, OH; see page S24). The Pd--- Yortho value is defined as the distance between Pd and the nearest ortho ring atom (either car- bon or nitrogen). These three geometric parameters for the min- imum energy transition structures of each type (concerted and displacement) are plotted in Figure 1C (an animated version of this plot is available as Supplemental Information for better 3D visualization). In the plot, the optimized structures loosely cluster into two groups representing the two limiting mechanisms. The 3-cen- tered concerted mechanisms (circles) are characterized by shorter Pd---X distances and longer Pd---Cipso and Pd---Yortho distances. Conversely, the displacement mechanisms (squares) display much longer Pd---X distances, consistent with very lit- tle interaction between Pd and the leaving group. The Pd---Cipso bonds in the displacement mechanisms are essentially com- pletely formed, with distances similar to the Pd—C bond of (PMe3)2PdII(Ph)X (2.01 Å). Furthermore, Pd tends to lean to- ward one of the ortho atoms in the displacement mechanism as shown by the shorter Pd--- Yortho values. For PhOTf, 5-centered transition structures are also possible for oxidative addition at monoligated PdL, involving interaction between Pd and an S=O oxygen instead of the ipso oxygen.10 Analysis of the three key geometric parameters revealed that the 5-centered transition structures all fall within the nucleophilic displacement cluster, not the concerted cluster. With the exception of L = IPr, the 5- centered structures are higher energy than an alternative confor- mation in which triflate is rotated away from Pd, so most of the 5-centered structures are not represented in Figure 1C (see Fig- ure S8 for a version of the plot that includes these higher-energy structures). Figure 1. (A) Combinations of substrates and ligands that were computationally evaluated. (B) Mechanisms, ligation states, and confor- mations that were evaluated. The highlighted conformations represent those that were typically lowest energy for each mechanism type (for exceptions, see pages S24-S29). (C) Geometric parameters of the lowest-energy conformations calculated for each mechanism type. Energetic Trends with PdL. We next compared the free en- ergies of the concerted and displacement mechanisms for each combination of PdLn with substrate (Figure 2). The direction of the columns in this graph indicates which mechanism is fa- vored. In cases where only one mechanism could be located, that mechanism is assumed to be favored, although the ∆∆G‡ value cannot be quantified (columns marked with an asterisk). When Pd is mono-ligated,26 a 3-centered concerted mechanism is predicted to be favored over a displacement mechanism for all combinations of ligands with phenyl halides (Figure 2A). In several cases, only a concerted mechanism could be located. Phenyl triflate is different from the phenyl halides though: for this substrate, a displacement mechanism is favored over a con- certed mechanism with all ligands. Compared to PhCl and the other chloropyridines, 2-chloropyridine shows a weaker prefer- ence for a concerted mechanism with most ligands. Together, these results indicate that monoligated Pd tends to react through a 3-centered concerted mechanism. However, aryl triflates (and, to some extent, 2-chloropyridine) are innately biased toward a displacement mechanism, and this predisposition overrides pal- ladium’s preference. Energetic Trends with PdL2. With bisligated PdL2, a dis- placement mechanism is favored for all substrates when L = PMe3 or L = bidentate ligands with natural bite angles smaller than ~99° (dppm, dppe, dppbz, dcype, Figure 2B).27.28 The trend with bidentate ligands is consistent with the previously com- puted mechanism for oxidative addition of ArBr at Pd(dppf).29 In several cases, only a displacement mechanism could be lo- cated. However, this trend changes with monodentate ligands PPh3 and PCy3, which are bulkier than PMe3, or with the wide bite angle ligand XantPhos (natural bite angle ≈ 110°).27,30 For these ligands, a displacement mechanism is only favored for PhOTf and 2-chloropyridine, while a concerted mechanism is favored for phenyl halides. These results suggest that PdL2 is innately predisposed to react through a displacement mecha- nism, although a large L—Pd—L bite angle can mitigate this bias. A triflate leaving group or an α-nitrogen predisposes the substrate for a displacement mechanism: this mechanism is fa- vored for PhOTf and 2-chloropyridine, even with Xantphos and all of the monodentate ligands. Figure 2. Difference in free energies of activation for displacement versus concerted transition structures for (A) monoligated Pd and (B) bisligated Pd. Overview of 13C KIE Studies. DFT calculations give pre- dictions that can be sensitive to method choice.31 Thus, we next sought to check our calculations against experimental results. Our calculations predict the relative free energies of two types of transition structures (3-centered concerted vs. displacement) for each combination of ligand, substrate, and coordination number. Relative free energies of activation (∆∆G‡ values) are often measured experimentally by comparing product ratios. However, product ratio measurements are not applicable to dis- tinguishing mechanisms of oxidative addition for these sub- strates, since both transition structures would ultimately lead to the same products in catalytic reactions (and likely also in stoi- chiometric reactions).32 Thus, we turned to natural abundance 13C KIE quantitative NMR studies using the method developed by Singleton.33,34 We anticipated that the two mechanisms could be distinguished by 13C KIE values at the ipso position of the substrate due to differences in the vibrational modes involving that carbon during the corresponding transition structures. We selected two Pd-catalyzed Suzuki cross-coupling systems to study: (1) reaction of the aryl chloride 1 using the bulky monodentate ligand PtBu3 and (2) reaction of aryl triflate 2 us- ing PPh3 (Scheme 2). Both reactions were conducted in THF. The tert-butyl group on the substrates serves as an internal iso- tope standard, with the KIE at the methyl carbons assumed to be 1.000. Each cross-coupling reaction was run on a 16.0 mmol scale to ~80-92% conversion. The unreacted substrate was re- covered and its carbon isotope distribution was compared to the isotope distribution in a standard sample (a sample of substrate from the same source that had not been subjected to the cross- coupling conditions). The changes in integrations at each posi- tion relative to the 1° carbons of tert-butyl were used to calcu- late 13C KIE values (see pages S4–S14 for details). These ex- perimental KIE values were then compared to the values pre- dicted by DFT.35 The experimental KIE values reflect the iso- topic sensitivity of the first substrate-committing step, which is expected to be C—X cleavage in all cases. Formation of a π- complex between Pd and substrate precedes C—X cleavage in these systems, but calculations at the level of theory used herein suggest that this step is reversible and has a much lower barrier than C—X cleavage, so it should not contribute significantly to the observed KIE values (see pages S35-S36).36 All DFT KIE values represent the average of several dispersion-containing DFT methods (see pages S37-S44). Experimental KIE values are reported as an average representing 6 FIDs for each of 2 separate trials (the KIE from each trial is reported separately). For each KIE value, the number in parentheses represents the error in the final digit based on a 95% confidence interval (see pages S4–S14). Scheme 2. 13C Kinetic Isotope Effect Studies Indicate (A) a Concerted Mechanism for Oxidative Addition of a Chloroa- rene at Pd(PtBu3) and (B) a Displacement Mechanism for Oxidative Addition of an Aryl Triflate at Pd(PPh3)2. 13C KIE Studies on an ArCl/PtBu3 System. Our DFT cal- culations indicate that monoligated Pd(PtBu3) strongly prefers to react with aryl chlorides through a 3-centered concerted mechanism over a nucleophilic displacement mechanism [∆∆G‡ = 12.5 kcal/mol for 1 (Scheme 2) and ∆∆G‡ = 11.8 kcal/mol for PhCl, Figure 2A]. Reaction at Pd(PtBu3)2 is not possible with such a bulky ligand.37,38 There is evidence that ox- idative addition may be possible at bisligated Pd(PtBu3)(solv) in coordinating solvents like MeCN or DMF, but not in THF.22 Accordingly, just two mechanisms were considered with this ligand (Scheme 2): a 3-centered concerted mechanism and a nu- cleophilic displacement mechanism at monoligated Pd(PtBu3). The computed KIE at Cipso is larger for the concerted mecha- nism [1.043(1)] than the displacement mechanism [1.027(2)], which is consistent with prior observations comparing con- certed versus step-wise mechanisms for SN2 and SNAr reac- tions.39 The computed 2° KIE values at Cortho are much smaller than at Cipso, but slightly larger for the displacement mecha- nism—in which Pd interacts with the ortho atom—compared to the concerted mechanism. For the Suzuki coupling of 1 cata- lyzed by Pd/PtBu3, we obtained experimental KIE values at Cipso of 1.037(4) and 1.039(4), which are similar to the computed KIE for the 3-centered concerted mechanism, and significantly larger than the computed KIE for the displacement mechanism. The experimental KIE value at Cortho is not useful for distin- guishing mechanisms as it is within error of both computed val- ues. Overall, the experimental KIE values at Cipso support the computational prediction that a 3-centered concerted mecha- nism at monoligated Pd(PtBu3) is favored for oxidative addition of aryl chlorides. 13C KIE Studies on an ArOTf/PPh3 System. Our calcula- tions indicate that the lowest energy pathway for oxidative ad- dition of aryl triflates is a nucleophilic displacement mechanism involving PdL2 when L = PPh3 (Scheme 2). Prior literature sug- gests that PPh3 may promote reaction at either PdL or PdL2.4,38,40 For example, Hirschi and Vetticatt proposed that aryl bromides react at monoligated Pd(PPh3) under Suzuki-Miyaura catalytic conditions using Pd(PPh3)4.40 The computed transition structure for this oxidative addition is best described as a 3-centered con- certed mechanism. On the other hand, Maes and Jutand demon- strated that 2-chloropyridines react with bisligated Pd(PPh3)2 through a displacement (SNAr-like) mechanism.4 Thus, four mechanisms were computationally considered for oxidative ad- dition of aryl triflates at Pd/PPh3: (1) 3-centered at Pd(PPh3) [computed KIE of 1.063(1) at Cipso]; (2) displacement at Pd(PPh3) [computed KIE of 1.053(1)]; (3) 3-centered at Pd(PPh3)2 [computed KIE of 1.065(1)]; and (4) displacement at Pd(PPh3)2 [computed KIE of 1.046(3)]. For the Suzuki coupling of 2 catalyzed by Pd/PPh3, we obtained experimental KIE val- ues at Cipso of 1.045(4) and 1.047(3), which most closely match the computed KIE for displacement at Pd(PPh3)2. As such, the experimental KIE is consistent with the computational predic- tion that a nucleophilic displacement mechanism at bisligated Pd(PPh3)2 is favored for oxidative addition of aryl triflates. This outcome is also consistent with other literature evidence sug- gesting that aryl triflates react preferentially at PdL2.37a,37c,38,41 Furthermore, in combination with Hirschi and Vetticatt’s re- port, this result demonstrates that the mechanism of oxidative addition at Pd/PPh3—both its geometry as well as palladium’s coordination number—may change when comparing aryl bro- mides to triflates. Finally, the near agreement between the com- putationally predicted and experimentally implicated mecha- nisms for both the ArCl/PtBu3 (vide supra) and the ArOTf/PPh3 systems suggests that meaningful conclusions can be drawn from the DFT data. Figure 3. (A) The HOMO symmetry of PdL predisposes it to donate into a single ring atom, while the HOMO symmetry of PdL2 is best suited to donate into two ring atoms. (B) The LUMOs of PdL and PdL2 both have σ-symmetry. (C) Distortion-interaction analysis of oxida- tive addition of PhCl at PdL2. All energies are measured relative to the preceding PhCl-PdL2 π-complex. (D) The lower energy LUMO of Pd(PPh3)2 compared to Pd(PMe3)2 facilitates stronger interaction during a concerted mechanism via donation from chloride non-bonding electrons. (E) Bisligated displacement transition structures experience more distortion energy for both the catalyst and substrate fragments because of more crowding between fragments and a more product-like Ph—Cl distance. Calculated NBO charges on chloride are shown. On 3D images, hydrogens are hidden for clarity. Why Do PdL and PdL2 Have Different Mechanistic Pref- erences? For reactions with phenyl halides, PdL always reacts through a 3-centered mechanism, whereas PdL2 often prefers a displacement mechanism. These differences can be understood on the basis of frontier molecular orbitals.6a,11,42 Mono- and bisligated Pd use filled orbitals of different symmetry to donate electron density into an aryl (pseudo)halide π* orbital (Figure 3A). The HOMO of PdL resembles an L—Pd σ/dz 2 hybrid, and it interacts with the substrate in a primarily σ fashion (Figure 3A, left). Thus, PdL can effectively donate electron density to only a single atom of the substrate (Cipso). In contrast, when PdL2 is bent into a geometry appropriate for interacting with the substrate, the HOMO is dxy-like and presents π-symmetry with two equally sized lobes of opposite phases. Therefore, the HOMO of PdL2 can achieve good orbital overlap with the sub- strate’s π* orbital by interacting with a second atom that has an antibonding relationship to Cipso (Figure 3A, right).43 For all of the substrates we investigated, even in the ground state there is a larger π* orbital coefficient at an ortho ring atom compared to the (pseudo)halide leaving group (e.g., 13% at Cortho vs. 9% at Cl for undistorted PhCl; see Figure 4B), which is consistent with PdL2 preferring to interact with Cortho. The LUMOs of both PdL and PdL2 have σ-symmetry (Figure 3B), so the shape of these unoccupied orbitals is less relevant to determining the pre- ferred mechanism. How Do Ancillary Ligand Sterics and Bite Angle Affect Mechanism for PdL2? As observed by Maseras,3 our calcula- tions suggest that 14e– PdL2 may react through either a con- certed or displacement mechanism, depending on its ligands. To better understand the effect of ligands on the mechanistic pref- erence of PdL2, we conducted a distortion-interaction analysis on several of the transition structures involving PhCl (Figure 3C).44 For this analysis, each transition structure was separated into two distorted fragments, PdL2 and PhCl. Distortion ener- gies for each fragment [∆Edist(PdL2) and ∆Edist(PhCl)] were calcu- lated by comparing the distorted fragments to the corresponding fragments derived from the preceding π-complex. The interac- tion energy between the fragments (∆Eint) is calculated as the difference between the energy of the transition state (∆E‡) and the sum of the distortion energies (∆Edist). Total distortion ener- gies are positive (unfavorable), while interaction energies are typically negative (favorable). In general, both the catalyst and the PhCl fragments experi- ence much more distortion in displacement transition structures compared to concerted ones. The geometry of the transition structures is consistent with this trend: in a displacement mech- anism, the catalyst fragment has more overlap with the plane of the arene (leading to crowding between the phosphine ligands) and the C—Cl distance is more product-like compared to a con- certed mechanism (Figure 3E). Thus, for a sufficiently bulky ligand like PCy3, the preference for a concerted mechanism is distortion-controlled: there is a particularly large amount of dis- tortion experienced by both Pd(PCy3)2 and PhCl in a displace- ment mechanism, while the catalyst fragment actually experi- ences a slight relief of distortion in the concerted mechanism (compared to the preceding π-complex).45,46 On the other hand, displacement transition structures benefit from much larger in- teraction energies. The large interaction energy during displace- ment mechanisms is consistent with stronger overlap between the catalyst’s HOMO and chlorobenzene’s π* orbital (vide su- pra). Therefore, when sterics are not a significant factor (for PMe3 and the small bite angle diphosphines dppe and dppbz),47 the preference for a displacement mechanism is primarily inter- action-controlled. A comparison between PPh3 and PMe3/PCy3 suggests that ligand electronics also play a role in the favored mechanism. PPh3 is not a particularly bulky ligand, but Pd(PPh3)2 still pre- fers a concerted mechanism for reaction with PhCl. Both the distortion and the interaction energies in a displacement mech- anism with Pd(PPh3)2 are small compared to mechanisms in- volving Pd(PMe3)2 and Pd(PCy3)2. However, the interaction en- ergy during a concerted mechanism with Pd(PPh3)2 is relatively large (Figure 3C), which may be attributed to Cl  σ*Pd bond- ing (Figure 3D). Donation from halide to Pd is expected to be stronger when Pd has a lower energy LUMO (is more electron- deficient), as in the case of Pd supported by triarylphosphines. Similarly, the displacement mechanism involving Pd(PPh3)2 does not benefit from as much interaction energy as a mecha- nism involving trialkylphosphines because the HOMO of Pd(PPh3)2 is lower-energy (see page S45) and it cannot donate as strongly into the PhCl π* orbital. Why are Aryl Triflates Biased Toward a Displacement Mechanism? Our calculations indicate that PhOTf uniformly prefers to react through a nucleophilic displacement mecha- nism, even with monoligated PdL (see Figure 2 and Scheme 2B). This prediction is consistent with experimental studies demonstrating that (a) oxidative addition of triflates leads to cat- ionic complexes,48 (b) oxidative addition of triflates at PdL2 is faster in more polar media,49 and (c) aryl triflates are extremely unreactive toward monoligated PdL22,37,49,50 (PdL is biased to- ward a concerted mechanism). This extremely strong prefer- ence of triflates to react through a displacement mechanism can be understood in part based on triflate’s stability as an anion. Displacement transition structures are much more polar than concerted structures, with a high degree of negative charge buildup on the leaving group (examples in Figure 3E).4,7,8,14 Tri- flate is better able to accommodate this charge compared to any of the halides,11 as evidenced by the acidity of its conjugate acid [pKa of TfOH in DCE = –11.3, compared to HBr (–4.4) and HCl (0.2)].51 Conversely, the high energy of concerted transition structures involving triflate can be understood based on frontier molecular orbital interactions. During oxidative ad- dition, orbital mixing between the catalyst and substrate frag- ment occurs in both directions (to a first approximation, HOMOPd  π*substrate as well as π/nsubstrate  LUMOPd). Analysis of the PhX molecular orbitals indicates that interaction between Pd and triflate in a concerted mechanism is disfavored because triflate bears a particularly small coefficient in both the HOMO and π* orbitals (Figure 4). For example, only 7% of the HOMO of PhOTf resides on the C—O oxygen atom, compared to a much larger contribution from the halides of PhCl or PhBr (25% and 30%, respectively, Figure 4A). The relatively small coeffi- cient on oxygen is consistent with the more intuitive concepts of hard and soft, where oxygen is a harder, more electronegative atom with lower-energy valence electrons. Thus, in a 3-centered concerted mechanism, Pd receives relatively little stabilization of its building positive charge when interacting with oxygen compared to one of the halides. The ortho carbon of PhOTf has a larger HOMO coefficient (15%) than oxygen, so orbital mix- ing with palladium’s LUMO is more effective during a dis- placement mechanism. For orbital mixing in the other direction (HOMOPd  π*substrate), PhOTf is again biased against a con- certed mechanism because the oxygen of the C—O bond has a very small π* coefficient compared to the halides in the analo- gous PhX substrates (3%, 9%, and 10% on O, Cl, and Br, re- spectively, Figure 4B). Figure 4. (A) Percent contributions of halide (or oxygen), Cipso, and Cortho to the highest occupied molecular orbital of PhX substrates. (B) Percent contribution of the same atoms to the lowest energy unoccupied molecular orbitals that do not contain a node passing through C—X (LUMO+1 for PhCl and PhBr, and LUMO for PhOTf). Figure 5. (A) Bond strengths do not trend with (B) the energies of concerted mechanisms for oxidative addition at Pd(PCy3)2, but they do trend with (C) the energies of displacement mechanisms at Pd(PCy3)2. (D) A concerted mechanism for reaction of 2-chloropyridine does not benefit from stereoelectronic C—Cl weakening in the same way as (E) a displacement mechanism. Free energies of activation in (B) and (C) are measured relative to separated reactions chloropyridine + Pd(PCy3)2. Why Does an Adjacent Nitrogen Atom Bias the Mecha- nism Toward Displacement? Nitrogen atoms in 6-membered heteroarenes have long been considered to have an activating effect on adjacent C—X bonds. For example, 2,x-di- halopyridines (x = 3, 4, or 5) usually undergo cross-coupling selectively at the C2—halide.52 Houk and Merlic noted that a trend in bond strengths could explain this preference: the C—X bond α to nitrogen is weaker than a more distal C—X bond (Figure 5A).53 Nevertheless, monoligated PdL and some Pd clusters have recently been shown to react at the more distal, stronger C4—X bond of 2,4-dihalopyridines,6,54,55 suggesting that an adjacent nitrogen primarily activates C—X bonds to- ward reaction with 14e– PdL2 (not 12e– PdL). Our calculations show that PdL2 strongly prefers to react with 2-chloropyridine through a displacement mechanism, even when supported by ligands that promote a concerted reaction for aryl halides (PPh3, PCy3, Xantphos, see Figure 2B).11 We hypothesized that the conventionally high reactivity of C—X bonds adjacent to nitro- gen is intimately tied to their preference for a displacement mechanism. Supporting this hypothesis, we found that concerted activa- tion barriers for oxidative addition of 2-, 3-, and 4-chloro- pyridine at Pd(PCy3)2 are nearly identical and do not trend with bond dissociation energies (Figure 5B). That is, even though C2—Cl is a weaker bond in the ground state, it is not necessarily easier to break through a concerted mechanism. This result in- dicates that, at least with Pd(PCy3)2, the lower C2—Cl bond dissociation energy is primarily advantageous during a dis- placement mechanism. A C2—Cl bond is remarkably easy to break through a displacement mechanism (Figure 5C). Analysis of transition state geometries suggests that stereoelectronic fac- tors play a role in favoring a displacement mechanism for C2— Cl. In the ground state of 2-chloropyridine, the C—Cl bond is weakened because of the neighboring lone pair.53b,56 Nitrogen’s lone pair resides in an orbital that is parallel to C2—Cl, and thus destabilizes this bond through hyperconjugation.56,57 During ox- idative addition through either mechanism, the C—Cl bond is distorted out of the plane of the pyridine ring. In a concerted mechanism, distortion of the C—Cl bond means that it is no longer parallel to the non-bonding orbital on nitrogen, so some of nitrogen’s bond-weakening effect is lost (Figure 5D). Conversely, in a displacement mechanism in which nitrogen forms a partial bond to Pd, the nitrogen atom adopts a pseudo- tetrahedral electronic geometry (Figure 5E).58 Thus, the orbital containing nitrogen’s lone pair remains largely parallel to the C—Cl bond even as it distorts out-of-plane, and the lone pair continues to facilitate C—Cl cleavage through hyperconjuga- tion. In addition to this stereoelectronic effect, we also consid- ered whether a proximal nitrogen enables more favorable charge distribution than a distal nitrogen during displacement transition states. However, NBO charge calculations suggest that charge distributions do not play a significant role in the rel- ative energies of TS6-TS8 (see pages S45-S46). Practical Implications: Dihaloheteroarene Site Selectiv- ity. This work highlights that the preferred mechanism for oxi- dative addition is influenced by both ligand and substrate. Thus, engineering complementarity between catalyst and sub- strate should enable control of site selectivity through control of the oxidative addition mechanism. To test this hypothesis, we evaluated three 2-chloropyridine derivatives that also contain a bromide distal to nitrogen. Aryl bromides are usually consid- ered to be more reactive than chlorides in cross-coupling reac- tions due to the relative weakness of a C—Br bond. However, in these substrates, a displacement mechanism for oxidative ad- dition of the C—Cl bond would be especially stabilized by an interaction between Pd and the ortho nitrogen. Accordingly, the use of bidentate ligands that promote a nucleophilic displace- ment mechanism would complement the substrate bias for re- action at the C2—Cl bond through a displacement mechanism. Conversely, the use of ligands that favor a concerted mecha- nism would mitigate the stabilizing influence of the ortho nitro- gen, and preferential reaction at the weaker C—Br bond is ex- pected. Consistent with this hypothesis, substrates 9-11 preferentially undergo catalytic amination at bromide when using bulky monodentate ligands PtBu3 or SIPr (Scheme 3). These ligands should promote reaction at PdL,38,50c which generally prefers a concerted mechanism. On the other hand, bidentate ligands with moderate bite angles59 promote reaction at the chloride next to nitrogen.60 In these cases, reaction at PdL2 through a displace- ment mechanism is expected. In contrast, more reaction at the distal bromide is observed with the wide bite-angle ligand Xantphos. Notably, the chemoselectivity trends with 9 are con- sistent with observations reported by Ji61 and by Tan and Sig- man62 for catalytic amination. Scheme 3. Ligands that Promote a Displacement Mecha- nism Favor Reaction at C—Cl Adjacent to N, While Lig- ands that Promote a Concerted Mechanism Favor Reaction at a Distal C—Br.a aMonodentate ligands were loaded at 12 mol %, bidentate lig- ands at 6 mol %. GC-FID yields calibrated against undecane as an internal standard, average of 2 trials. CONCLUSION The broad computational study presented herein illustrates clear trends in the preferred mechanism for oxidative addition at Pd0 based on substrate, ligand(s), and palladium’s coordina- tion number. 13C KIE studies on a system involving a 3-centered concerted mechanism and one involving a nucleophilic dis- placement mechanism provide experimental support for the DFT calculations. The predicted mechanistic biases suggests a strategy for chemodivergent cross-coupling of bromo-2-chloro- pyridine derivatives, and this work demonstrates the realization of that strategy through rational ligand variation. Because oxidative addition is often the rate- or selectivity- determining step of cross-couplings, the ability to predict its mechanism can facilitate finding the right match between sub- strate and catalyst to achieve faster reactions or higher site-se- lectivity. The key findings in this work can be summarized through a set of suggested guidelines for predicting the likely mechanism of oxidative addition of aryl electrophiles at Pd(0): (a) With aryl halides, a 3-centered concerted mechanism is likely when using traditional monodentate phosphines (includ- ing PPh3). Depending on the size of the monodentate ancillary ligand and the identity of the halide, oxidative addition may take place at PdL, which uniformly prefers a concerted mechanism. Alternatively, oxidative addition may take place at PdL2, which is also likely to favor a concerted mechanism unless L is very small (e.g., PMe3), due in part to steric crowding in the displace- ment mechanism. (b) On the other hand, aryl halides are more likely to react through a displacement mechanism when employing bidentate phosphines with conventional bite angles (< ~105°) due in part to the strong interaction energy between catalyst and substrate fragments in a displacement mechanism and minimization of unfavorable distortion energy. (c) Aryl triflates essentially always react through a displace- ment mechanism. This preference can be attributed to the sta- bility of anionic triflate and the weak coordinating ability of tri- flate oxygens to Pd. (d) For halides adjacent to pyridine nitrogens, the displace- ment mechanism is particularly favored in part because of a ste- reoelectronic effect by which a nitrogen lone pair weakens the C—X bond during a displacement mechanism. These guidelines can serve as a starting point63 for rationally engineering cross-coupling outcomes when oxidative addition is the selectivity-determining or turnover-limiting step. AUTHOR INFORMATION Corresponding Author * Email: sharon.neufeldt@montana.edu. ORCID Matthew J. Kania: 0000-0003-4445-9780; Albert Reyes: 0000- 0001-8944-6444; Sharon R. Neufeldt: 0000-0001-7995-3995. Notes The authors declare no competing financial interest. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Experimental and computational details, NMR spectra, and calcu- lated energies (PDF) Cartesian coordinates of minimum-energy calculated struc-tures (XYZ) Animated version of Figure 1C (MP4) NMR spectra for KIE studies (ZIP) ACKNOWLEDGMENT This work was supported by NSF (CHE-1848090 and CHE- 2400070). The computational studies used Expanse at the San Di- ego Supercomputer Center and Bridges-2 at the Pittsburgh Super- computing Center through allocations CHE-170089 and CHE- 230031 from the Advanced Cyberinfrastructure Coordination Eco- system: Services & Support (ACCESS) program, which is sup- ported by NSF grants #2138259, #2138286, #2138307, #2137603, and #2138296. Computational efforts were also performed on the Tempest High Performance Computing System, operated and sup- ported by University Information Technology Research Cyber- infrastructure at Montana State University. Support for MSU’s NMR Center was provided by the NSF (Grants NSF-MRI:CHE- 2018388 and NSF-MRI:DBI-1532078), MSU, and the Murdock Charitable Trust Foundation (2015066:MNL). Funding for the mass spectrometry facility was provided in part by NIH NIGMS (P20GM103474 and S10OD28650), the Murdock Charitable Trust Foundation, and MSU. 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