Nickel-Based Catalysts for the Selective Monoarylation of Dichloropyridines: Ligand Effects and Mechanistic Insights Geraldo Duran-Camacho, Douglas C. Bland, Fangzheng Li, Sharon R. Neufeldt, and Melanie S. Sanford This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in ACS Catalysis, copyright © American Chemical Society after peer review. To access the final edited and published work see https://doi.org/10.1021/ acscatal.4c00648 Made available through Montana State University’s ScholarWorks Nickel-Based Catalysts for the Selective Monoarylation of Dichloro- pyridines: Ligand Effects and Mechanistic Insights Geraldo Duran-Camacho,† Douglas C. Bland,‡ Fangzheng Li,‡ Sharon R. Neufeldt*,§ Melanie S. San- ford*† †Department of Chemistry, University of Michigan, 930 North Avenue, Ann Arbor, Michigan, 48104, United States ‡Product & Process Technology R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana, 46268, United States §Department of Chemistry and Biochemistry, Montana State University, Bozeman, Montana, 59717, United States Keywords: cross-coupling, nickel catalysis, dichloropyridines, site-selectivity, monoarylation ABSTRACT: This report describes a detailed study of Ni phosphine catalysts for the Suzuki-Miyaura coupling of dichloropyridines with halogen-containing (hetero)aryl boronic acids. With most phosphine ligands these transformations afford mixtures of mono- and diarylated cross-coupling products as well as competing oligomerization of the boronic acid. However, a ligand screen revealed that PPh2Me and PPh3 afford high yield and selectivity for monoarylation over diarylation as well as minimal competing oligomerization of the boronic acid. Several key observations were made regarding the selectivity of these reactions, including: (1) phosphine ligands that afford high selectivity for monoarylation fall within a narrow range of Tolman cone angles (between 136º and 157º); (2) more electron-rich trialkylphosphines afford predominantly diarylated products, while less-electron rich di- and triarylphosphines favor monoarylation; (3) diarylation proceeds via intramolecular oxidative addition; and (4) the solvent (MeCN) plays a crucial role in achieving high monoarylation selectivity. Experimental and DFT studies suggest that all these data can be explained based on the reactivity of a key intermediate: a Ni0-π complex of the monoarylated product. With larger, more electron-rich trialkylphosphine ligands, this π complex undergoes intramolecular oxidative addition faster than ligand substitution by the MeCN solvent, leading to selective diarylation. In contrast, with relatively small di- and triarylphosphine ligands, associative ligand substitution by MeCN is competitive with oxidative addition, resulting in selective formation of monoarylated products. The generality of this method is demonstrated with a variety of dichloropyridines and chloro-substituted aryl boronic acids. Furthermore, the optimal ligand (PPh2Me) and solvent (MeCN) are leveraged to achieve the Ni-catalyzed monoarylation of a broader set of dichloroarene substrates. Introduction Dihalo(hetero)arenes, particularly dihalopyridines, have at- tracted considerable attention as electrophiles in transition metal-catalyzed cross-coupling reactions.1 The selective mono- arylation of these substrates affords monohalobiaryls, a com- mon motif in bioactive molecules (Figure 1).2,3 Furthermore, the presence of a second electrophilic site on the product can be leveraged to access multiple functionalized (hetero)arenes, which also appear in drugs and agrochemicals (Figure 1).4 Figure 1. Bioactive molecules accessible from cross-coupling reactions of 2,x-dihalopyridines (x = 3, 4, or 5) Palladium-catalyzed cross-coupling reactions of 2,x-di- halopyridines (x = 3, 4, or 5) with aryl nucleophiles have been well-studied, and most Pd catalysts exhibit high selectivity for monoarylated product A (Scheme 1a).5,6 In contrast, analogous reactions with nickel catalysts typically afford mixtures of A and the diarylated product B (Scheme 1a).7 The Ni-catalyzed reactions are further complicated when the aryl nucleophile contains a halide substituent, as this often leads to competing oligomerization/polymerization processes.8 Our overall objec- tive was to identify a Ni catalyst system that promotes the se- lective C2-arylation of dichloropyridines with halide-substi- tuted arylboronic acids. Scheme 1. Arylation of dichloropyridines: (a) Precedented re- activity with Pd and Ni; (b) Selective monoarylation with Ni Herein, we report that selectivity in these transformations is highly sensitive to two factors: (1) the structure of the phos- phine ligand and (2) the reaction solvent. The combination of diphenylmethylphosphine (PPh2Me) as ligand and acetonitrile (MeCN) as solvent proved optimal for achieving selective mon- oarylation of a variety of dichloropyridines and chloro-substi- tuted aryl boronic acids (Scheme 1b). A combination of exper- imental and computational mechanistic studies provide insight into the origin of selectivity in this system. Finally, we demon- strate the generality of these findings (specifically the optimal ligand and solvent choice) for achieving selective monoaryla- tion to other dichloroarene substrates. Results and Discussion Our initial studies examined the Suzuki-Miyaura coupling of methyl-2,5-dichloropicolinate (1a) with (2-fluorophenyl)bo- ronic acid to benchmark reactivity and selectivity. Ni(cod)2 and PCy3 were selected as the pre-catalyst and ligand, respectively, as this combination has been widely used for Ni-catalyzed Su- zuki-Miyaura couplings, including those involving chloro- pyridine substrates.9 The reaction was examined in THF and MeCN, two solvents that are commonly used in related cross- coupling reactions.6a,6f,6g,9b-e,10 As shown in Scheme 2a, the re- actions afford mixtures of monoarylated 2a, diarylated 3a, and homocoupled boronic acid (Ar-Ar). In both solvents,9c dia- rylated 3a was the major product and was formed in comparable yield (28% versus 38%) and selectivity (3a : 2a = 3.1 : 1 versus 3.8 : 1). Overall, slightly higher reactivity was observed in MeCN (TON = 17 versus 13 in THF). As such, this was used as the solvent moving forward. We next evaluated the Ni/PCy3 catalyst in an analogous re- action with (4-chloro-2-fluoropheny)boronic acid, which con- tains a potentially reactive aryl chloride substituent. This re- sulted in a 2 : 1 mixture of diarylated 3j and the corresponding monoarylation product 2j in low yields (14% and 7%, respec- tively), with no homocoupling observed. Further analysis re- vealed that the boronic acid was completely consumed, and an insoluble solid was generated. These observations implicate the oligomerization of (4-chloro-2-fluorophenyl)boronic acid to form C.8 Scheme 2. Product selectivity in Ni-catalyzed arylation of 1a with (a) simple aryl boronic acid and (b) chloro-containing aryl boronic acida,b aConditions: 1a (1.0 equiv, 0.1 mmol), ArB(OH)2 (1.1 equiv), Ni(cod)2 (5 mol%), PCy3 (20 mol%), K2CO3 (3.0 equiv), solvent (c = 0.2 M), 60 ºC, 20 h. bYields determined by 19F NMR spectros- copy with trifluorotoluene as internal standard. Having established the baseline reactivity of the Ni(cod)2/PCy3 catalyst, we sought to identify phosphine ligands that afford high selectivity and yield for the monoarylation product, while limiting the polymerization of chloro-containing aryl boronic acids. We hypothesized that the challenges of polymerization were related to that of the mono- versus diaryla- tion selectivity (vide infra), and thus first focused on addressing the latter issue. A series of phosphine ligands with varied elec- tronic (mono-, di- and trialkyl substituents) and steric (wide range of Tolman cone angles) properties were evaluated. These ligands were first tested in the Ni-catalyzed coupling of 1a with 2.2 equiv of (2-fluorophenyl)boronic acid to afford 2a and/or 3a. Table 1 shows the phosphines that afforded >4 : 1 selectiv- ity for either 2a or 3a. Data for all of the ligands examined are available in Table S1. Table 1. Survey of monodentate phosphine ligands for the Ni- catalyzed arylation of 1aa,b entry ligand 2a (%) 3a (%) 2a : 3a 1 PnBu3 2 23 1 : 12 2 PEt3 4 35 1 : 8.7 3 PtBu2Me 4 64 1 : 16 4 PiPr3 17 72 1 : 4.2 5 PPh3 62 8 7.7 : 1 0 6 PPh2Me 83 14 5.9 : 1 . 7 PPh2Et 55 5 11 : 1 . 8 PPh2 iPr 39 3 13 : 1 . 9 PPh2Cy 33 2 17 : 1 . aReactions performed on 0.1 mmol scale (c = 0.2 M). bYields de- termined by 19F NMR spectroscopy with trifluorotoluene as inter- nal standard. This phosphine screen uncovered several ligands (most nota- bly PPh2Me, entry 6) that afford high yield and >5 : 1 selectivity for monoarylation, even when using 2.2 equiv of the boronic acid. Further optimization revealed that the use of 10 mol % of PPh2Me in combination with the commercially available, air- stable NiII precatalyst (PPh2Me)2Ni(o-tolyl)Cl11 resulted in 12 : 1 selectivity and 92% yield of 2a (Scheme 3). Finally, when the loading of boronic acid was reduced to 1.1 equiv, 2a and 3a were formed in 88% and 5%, respectively.12 Scheme 3. Air-stable NiII precatalyst for the arylation of 1a The observed ligand effects appear to originate from a com- bination of steric and electronic factors. To better understand these, we compared the experimental selectivities and yields to various descriptors of phosphine ligands.13 Steric effects in this transformation are most clearly visualized by plotting the com- bined yields of 2a (blue) and 3a (grey) as a function of the Tol- man cone angle (Figure 2a).14,15 This plot shows that phos- phines that afford high selectivity for monoarylation are gener- ally clustered within a relatively narrow range of cone angles (~136º to 157º). At slightly higher or lower cone angles (±10º or more), the diarylated product predominates. Moreover, the overall yield of 2a + 3a decreases sharply with very large phos- phines such as PtBu3 and P(o-tolyl)3 (cone angle ≥ 170º). The latter effect is even better visualized by plotting the overall yield versus the minimum percent buried volume (min %Vbur) of the phosphine, which shows a clear break at %Vbur ~ 32% (Figure 2b). This value represents the cut-off between mono- and bis- ligation in Ni0-phosphine oxidative addition transition states,13a suggesting that the mono-ligated Ni0 species are inactive for this cross-coupling. To visualize electronic effects, we plotted the combined yields of 2a and 3a versus various electronic parameters (Tol- man electronic parameter, TEP; semiempirical electronic pa- rameter, SEP; pKb; phosphine substitution; Figure S4). In most of these cases, the parameters are only available for a subset of the ligands, making it difficult to draw definitive conclusions. Clustering the phosphines based on their substitution pattern [trialkyl, (dialkyl)aryl, (diaryl)alkyl, and triaryl] revealed the clearest trend (Figure 2c). The more electron rich and stronger sigma-donor trialkylphosphines generally afford good to excel- lent selectivity for the diarylated product 3a. In contrast, less electron rich and better π-accepting di- and triarylphosphines afford monoarylated 2a as the major product. The highest over- all yield of and selectivity for 2a is observed with PPh2Me and PPh3, ligands that have cone angles in the optimal range (136º and 145º, respectively) along with di- or triaryl substitution. Figure 2. Analysis of arylation of 1a using steric parameters (a) Tolman cone angle (θ ) and (b) minimum percent buried volume (%Vbur). (c) Product distribution as a function of phosphine substi- tution pattern (Ar = aryl). Reaction conditions from Table 1. Show- ing monoarylated product (blue), and diarylated product (gray). To further rationalize the observed ligand effects on selec- tivity we considered the pathways to products 2a and 3a in more detail (Scheme 4). The formation of 2a is expected to proceed via a standard Suzuki coupling mechanism, involving initial ox- idative addition at the more activated C(2)–Cl bond of 1a, transmetalation of the boronic acid to form intermediate I, C–C bond-forming reductive elimination to generate π-complex 2a- Ni0,16 and dissociation of 2a to release the product. In contrast, 3a could be formed via two distinct pathways starting from 𝜋𝜋- complex 2a-Ni0. In the first (Scheme 4a, Path A), the organic intermediate 2a could dissociate from Ni0 and subsequently re- engage with the catalyst to undergo C(5)–Cl oxidative addition. Alternatively, oxidative addition into the C(5)–Cl bond could occur in an intramolecular fashion at π-complex 2a-Ni0, without the release of free 2a (Scheme 4a, Path B).9c To distinguish these possibilities, we conducted a competi- tion study using equimolar quantities of dichloropyridine 1a, aryl(chloro)pyridine 2a’, and (2-fluorophenyl)boronic acid (Scheme 4b). This experiment was performed using PtBu2Me, which afforded the highest selectivity for the diarylated product in Table 1. All of the possible intermediates/products (2a, 2a’, 3a and 3a’) have distinct 19F NMR signals, enabling quantitative analysis of the product mixture by 19F NMR spec- troscopy. As summarized in Scheme 4b, the major product after 20 h was 3a, derived from selective diarylation of 1a. Only traces of the monoarylated product 2a were detected. Further- more, <5% of 2a’ underwent C(5)-arylation to produce 3a’. When the reaction was analyzed at shorter time points (1 h or 3 h, respectively), the yield of 3a was lower, but only traces of 2a were observed (see Supporting Information for complete de- tails). Collectively, these data suggest that free 2a is not an in- termediate en route to 3a. Instead, diarylation of 1a appears to involve two sequential Suzuki-Miyaura cross-coupling reac- tions without dissociation of the Ni0–π intermediate, 2a-Ni0 Scheme 4. Determining diarylation mechanism: (a) Proposed pathways; (b) Competition experiment; (c) Proposed mechanism aReactions performed on 0.1 mmol scale (c = 0.2 M). bYields determined by 19F NMR using trifluorotoluene as internal standard. This proposed pathway is analogous to the mechanism of living catalyst-transfer polymerization (CTP) reactions, where the intramolecular oxidative addition of a Ni0–π intermediate enables a chain-growth pathway.8 Indeed, the oligomerization of (4-chloro-2-fluoropheny)boronic acid observed in Scheme 2b with PCy3 as the ligand likely occurs via this pathway. In CTP polymerization, the steric and electronic properties of lig- ands have been shown to play a pivotal role in productive reac- tivity by controlling the rate of ligand displacement at the π– complex.8b,c We hypothesize that the ligand effects in our sys- tem are similarly related to the relative reactivity of 2a-Ni0 to- wards ligand substitution (for example, with the coordinating solvent acetonitrile) versus intramolecular oxidative addition (Scheme 5). In terms of steric effects, relatively small cone an- gle ligands are expected to facilitate associative substitution of solvent at 2a-Ni0 to release mono-arylated product 2a. Increas- ing the cone angle of the phosphine (and hence steric crowding at the Ni0 center) is expected to slow associative substitution relative to intramolecular oxidative addition, thus favoring dia- rylation product 3a. The phosphine substitution effects can also be rationalized based on the reactivity of 2a-Ni0. All other things being equal, more electron rich, sigma-donating trial- kylphosphines are expected to increase the relative rate of oxidative addition17 compared to their di- or triaryl counter- parts, thus pushing selectivity towards diarylation. Scheme 5. Proposed ligand exchange/solvent coordination as selectivity step for monoarylation of 1a To experimentally probe the proposed role of acetonitrile in displacing the monoarylated product from 2a-Ni0, we evaluated the impact of solvent on product distribution with PPh2Me and PPh3 (Table 2).18 Under our standard conditions, both ligands afford high selectivity for the monoarylated product 2a, with ratios of 18 : 1 for PPh2Me and >20 : 1 for PPh3 (Table 2, entries 1 and 4). Changing the solvent from MeCN19 to THF led to a decrease in selectivity with PPh2Me, shifting the ratio to 10 : 1 (Table 2, entry 2), but still favoring monoarylation. More dra- matically, a reversal of selectivity was observed with PPh3 in THF, leading to diarylated product 3a in 43% yield and 1 : 8.6 selectivity (Table 2, entry 5). We next titrated various equivalents of MeCN into the THF reaction mixtures, with the hypothesis that this would serve to displace the monoarylated product from 2a-Ni0 and thus shift selectivity back towards 2a. Indeed, the addition of just 0.5 equiv of MeCN restored high (17 : 1) selectivity with PPh2Me (Table 2, entry 3). With PPh3, the selectivity responded in a dose-dependent manner, with increasing formation of 2a as more MeCN was added (Table 2, entries 6-8). Finally, to rule out effects related to solvent polarity changes, we examined the impact of highly polar yet weakly coordinating sulfolane as an additive.20 The reaction with PPh3 afforded 3a as the major product, with comparable yield and selectivity as in THF alone. This result indicates that the role of MeCN is not simply to in- crease the polarity of the reaction mixture. Instead, it implicates MeCN serving as a coordinating ligand to displace the mono- arylated product from 2a-Ni0. Table 2. Solvent effect on product selectivitya,b en- try PR3 solvent additive (equiv) 2a (%) 3a (%) 2a : 3a 1 PPh2Me MeCN --- 88 5 18 : 1 2 THF --- 90 9 10 : 1 3 THF MeCN (0.5) 85 5 17 : 1 4 PPh3 MeCN --- 53 1 53 : 1 5 THF --- 5 43 1 : 8.6 6 THF MeCN (0.5) 51 21 2.4 : 1 7 THF MeCN (1) 76 24 3.2 : 1 8 THF MeCN (2) 80 11 7.2 : 1 9 THF sulfolane (1) 4 46 1 : 11 aReactions performed on 0.1 mmol scale (c = 0.2 M). bYields de- termined by 19F NMR using trifluorotoluene as internal standard. [Ni] = (PR3)2Ni(o-tolyl)Cl. Density functional theory (DFT) calculations were con- ducted to probe the reactivity of the Ni0 π-complex,21 using PPh3 as a representative ligand that favors monoarylation (Fig- ure 3) and PiPr3 as a representative ligand that favors diaryla- tion (Figure 4). These symmetrical phosphines were selected to simplify the calculations by minimizing the number of accessi- ble ligand conformers. The pi-bound substrate for the calcula- tions was 2r, which contains a phenyl group at the 2-position. Thermodynamic quantities were calculated at 60 ºC, applying corrections for concentrations consistent with the conditions in Table 1 (see SI for details).22,23 In the PPh3 system, intramolec- ular oxidative addition (3-TS-PPh3) and associative displace- ment of Ni0 by MeCN (2-TS-PPh3) are energetically compara- ble (∆G‡ = 17.5 and 16.7 kcal/mol) at the level of theory used. The difference in these activation barriers is 0.8 kcal/mol favor- ing diarylation, whereas the experimental selectivity with PPh3 corresponds to ∆∆G‡ ~1.4 kcal/mol favoring monoarylation. Overall, the computed ∆∆G‡ differs from experiment by 2.2 kcal/mol, an error value within range of what is typical for DFT. Most importantly, the calculations implicate a ligand displace- ment pathway that is energetically competitive with oxidative addition. An alternative pathway for release of 2r involving direct dissociation to generate 2r and 14e– Ni(PPh3)2 is much less likely due to the high free energy of the coordinatively un- saturated nickel(0) fragment (26.1 kcal/mol). Thus, overall the calculations are consistent with the involvement of MeCN in displacing Ni0 from the monoarylated product, rather than direct dissociation of 2r from Ni(PPh3)2. The DFT calculations with PiPr3 as the ligand show very dif- ferent results (Figure 4). Here, the barrier for oxidative addition at 2r-Ni0-PiPr3 is significantly lower than that with PPh3 (∆G‡ = 10.3 versus 16.7 kcal/mol, respectively), while the lowest en- ergy pathway for ligand displacement has a significantly higher ∆G‡ of 19.5 kcal/mol (compared to 17.5 kcal/mol for PPh3). Furthermore, the calculations indicate that this ligand displace- ment takes place by a different mechanism than for the PPh3 analogue, involving (i) initial dissociation of one PiPr3 ligand, (ii) coordination of MeCN to form (PiPr3)(MeCN)Ni0-2r, and (iii) reaction of this new π-complex with PiPr3 to release 2r. In contrast, a transition structure involving associative substitution at the (PiPr3)2Ni0–π intermediate (analogous to 2-TS in Figure 3) could not be located. Unlike Ni(PPh3)2, direct dissociation of Ni(PiPr3)2 may be feasible based on the calculated thermody- namics of this step, but we were unable to find a transition state for this pathway. Overall, these results suggest that a combina- tion of faster oxidative addition and slower release of 2r from Ni0 result in a preference for diarylation product 3r with PiPr3. Figure 3. Computed reaction free energy diagram for pathways leading to mono- and diarylation of 1a using PPh3. Figure 4. Computed reaction free energy diagram for pathways leading to mono- and diarylation of 1a using PiPr3. We next evaluated the scope of this transformation with re- spect to the dichloropyridine (Table 3) and aryl boronic acid (Table 4) components. Using PPh2Me as the ligand, a variety of 2,3- and 2,5-dichloropyridines underwent selective monoary- lation at the 2-position, affording products 2a-h with high se- lectivity. Notably, 2,4-dichloropyridine was an exception, re- sulting in an intractable mixture of mono- and diarylated prod- ucts (see Supporting Information for details about low perform- ing substrates). Boronic acids bearing chloride substituents at the meta and para positions also reacted in high yields, with no detectable oligomerization or over-arylation.24 Again, the combination of PPh2Me as a ligand with MeCN as a solvent is believed to ac- celerate displacement of the initial Ni0–π intermediate, thus lim- iting CTP-like polymerization of the boronic acids. For in- stance, monoarylated product 2j was obtained in 75% yield with our Ni/PPh2Me catalyst system (Table 4), while the Ni/PCy3 initial results afforded just 7%, largely due to competing oli- gomerization of the boronic acid (Scheme 2b). Other chloride- substituted (hetero)aryl boronic acids were also compatible (2i- 2q), albeit affording slightly lower yields. Overall, a range of functionalities were well-tolerated, including ester, nitrile, amino, methoxy and fluoride. Table 3. Selective Ni-catalyzed monoarylation of dichloro- pyridine derivatives with (2-fluorophenyl)boronic acida aReactions performed on a 0.3 mmol scale (c = 0.2 M). Combined 19F NMR yields of mono- (2) and diarylated (3) products reported with the respective ratio (2:3). bIsolation of 1.0 mmol scale reac- tion. c1.5 equiv of ArB(OH)2 were used. Isolated yield of monoary- lated product (2) in parenthesis. [Ni] = (PPh2Me)2Ni(o-tolyl)Cl. Table 4. Selective Ni-catalyzed monoarylation of 1a with vari- ous chloro-containing (aryl)boronic acidsa aIsolated yields of reactions performed on a 0.3 mmol scale (c = 0.2 M). b1.5 equiv of ArB(OH)2 were used. cFrom N-Boc indole. [Ni] = (PPh2Me)2Ni(o-tolyl)Cl. The investigations above all focus on one specific class of electrophiles: 2,x-dichloropyridines. Thus, a key outstanding question is whether the pyridine moiety is crucial for obtaining high monoarylation selectivity (since the nitrogen of the sub- strate could potentially play a key role in displacing the π-com- plex). To address this question, we undertook a final set of stud- ies to evaluate the generality of the observed ligand and solvent effects with other dichloroarenes.25 We first examined the cross-coupling of (2-fluorophenyl)boronic acid with 1,3-dichlo- robenzene (1s) using Ni(cod)2 as the catalyst (Table 5). With PPh2Me as ligand and MeCN as solvent, the monoarylated product 2s was obtained in 4 : 1 selectivity (Table 5, entry 1). Changing the solvent to THF under otherwise identical condi- tions afforded an erosion of selectivity to 2 : 1 (entry 2). Fur- thermore, moving to PCy3 as a ligand and THF as the solvent led to 1 : 8 selectivity for the diarylated product (entry 4). This selectivity increased to 1 : 13 when the stoichiometry of the bo- ronic acid was increased from 1.1 to 2.2 equiv (compare entries 4 and 6). Overall, the results with this substrate show nearly identical ligand and solvent effects to those with 2,x-dichloro- pyridines, indicating the generality of these results. Table 5. Exploring product selectivity in Ni-catalyzed arylation of 1,3-dichlorobenzenea,b en- try PR3 solvent ArB(OH)2 (equiv) 2s (%) 3s (%) 2s : 3s 1 PPh2Me MeCN 1.1 63 16 4 : 1 2 THF 1.1 50 24 2 : 1 3 PCy3 MeCN 1.1 6 36 1 : 6 4 THF 1.1 6 48 1 : 8 5 MeCN 2.2 9 63 1 : 7 6 THF 2.2 7 90 1 : 13 aReactions performed on 0.1 mmol scale (c = 0.2 M). bYields de- termined by 19F NMR using trifluorotoluene as internal standard. Finally, we scaled up the coupling of 1s and its regioisomers [1,2-dichlorobezene (1t) and 1,4-dichlorobenzene (1u)] under the optimal monoarylation conditions. As summarized in Table 6, the monoarylated products 2s-u were formed with good to excellent levels of selectivity and were isolated in 56%, 80%, and 39% yield, respectively. Table 6. Ni-catalyzed monoarylation of dichlorobenzene deriv- atives with (2-fluorophenyl)boronic acida aReactions performed on a 0.3 mmol scale (c = 0.2 M). Combined 19F NMR yields of mono- (2) and diarylated (3) products reported with the respective ratio (2:3). Isolated yield of monoarylated prod- uct (2) in parenthesis. [Ni] = (PPh2Me)2Ni(o-tolyl)Cl. In summary, a Ni phosphine catalyst has been identified for the selective Suzuki-Miyaura coupling of dichloropyridine de- rivatives with halogen-containing (hetero)aryl boronic acids. A ligand screen showed that PPh2Me is the optimal ligand for achieving high selectivity and yield for monoarylation with a wide range of dichloropyridine and boronic acid substrates. Several key observations were made regarding the selectivity of these reactions, including: (1) more electron-rich trial- kylphosphines afford diarylation as the major product, while less-electron rich di- and triarylphosphines favor monoaryla- tion; (2) the di- and triarylphosphines lie in a narrow range of Tolman cone angles (between 136º and 157º); (3) diarylation proceeds via intramolecular oxidative addition; and (4) the sol- vent (MeCN) plays a crucial role in achieving high monoaryla- tion selectivity. Experimental and DFT studies suggest that these effects arise from the reactivity of a key intermediate: the Ni0-π complex of the mono-arylated product. With larger, more electron-rich trialkylphosphines, this π-complex undergoes in- tramolecular oxidative addition faster than ligand substitution by solvent, leading to selective diarylation. In contrast, with rel- atively small di- and triarylphosphine ligands, associative lig- and substitution by MeCN is competitive with oxidative addi- tion, resulting in selective formation of the monoarylated prod- uct. Finally, we demonstrated that these ligand and solvent ef- fects can be applied to other dihaloarenes, affording selective monoarylation of dichlorobenzene derivatives. Overall, these studies demonstrate how the interplay of substrate, phosphine ligand, and solvent can impact selectivity in the Ni-catalyzed Suzuki-Miyaura couplings of polyfunctional substrates. Mov- ing forward, we anticipate that these results will inform the de- velopment and optimization of other Ni-catalyzed C–C cou- pling reactions to form both small molecules and oligomers/pol- ymers. AUTHOR INFORMATION Corresponding Author * Melanie S. Sanford – Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States; Email: mssanfor@umich.edu * Sharon R. Neufeldt – Department of Chemistry and Biochem- istry, Montana State University, Bozeman, Montana 59717, United States; Email: sharon.neufeldt@montana.edu Author Contributions The manuscript was written through contributions of all authors. / All authors have given approval to the final version of the manu- script. Funding Sources Any funds used to support the research of the manuscript should be placed here (per journal style). ORCID Melanie S. Sanford: 0000-0001-9342-9436 Sharon R. Neufeldt: 0000-0001-7995-3995 Notes The authors declare no competing financial interest. ASSOCIATED CONTENT Supporting Information Experimental and computational details, characterization data, NMR spectra, FAIR data (including the primary NMR FID files), and Cartesian coordinates of minimum-energy calculated struc- tures. ACKNOWLEDGMENT Corteva Agriscience is acknowledged for supporting the experi- mental work described herein. The DFT studies and analysis were supported by the NIH (R35GM137971 to S. R. N.). Calculations were performed on Expanse at SDSC and on Bridges2 at PSC through allocation CHE-230038 from the Advanced Cyberinfra- structure Coordination Ecosystem: Services & Support (ACCESS) program, which is supported by NSF grants #2138259, #2138286, #2138307, #2137603, and #2138296. The authors thank Dr. María T. Morales-Colón (currently at Merck & Co., Inc., Rahway, NJ, USA) for helpful insights and discussions. ABBREVIATIONS SMCC, Suzuki-Miyaura cross coupling; TON, turn over number; OA, oxidative addition; TM, transmetallation; RE, reductive elim- ination; MeCN, acetonitrile; CTP, catalyst-transfer polymerization. REFERENCES 1. (a) Scott, N. W. J.; Ford, M. J.; Jeddi, N.;Eyles, A.; Simon, L.; Whitwood, A. C.; Tanner, T.; Willans, C. E.; Fairlamb, I. J. S. A . A Dichotomy in Cross-Coupling Site Selectivity in a Dihalogen- ated Heteroarene: Influence of Mononuclear Pd, Pd Clusters, and Pd Nanoparticles – the Case for Exploiting Pd Catalyst Specia- tion. J. Am. Chem. 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Russ. J. Inorg. Chem. 2012, 57, 386-389. (b) Bresciani, G.; Biancalana, L.; Pampaloni, G.; Zac- chini, S.; Ciancaleoni, G.; Marchetti, F. A Comprehensive Anal- ysis of the Metal-Nitrile Organo-Diiron System. Molecules 2021, 26, 7088-7011. 20. Elias, E. K.; Rehbein, S. M.; Neufeldt, S. R. Solvent Coordination to Palladium can Invert the Selectivity of Oxidative Addition. Chem. Sci. 2022, 13, 1618-1628. 21. Ring-walking from C2 to C5 was not considered for our calcula- tions and could also play a role in selectivity. Allen and co-work- ers reported barriers ranging from 3.6 to 10.6 kcal/mol for Ni(dppp) [dppp = 1,3-bis(diphenylphosphino)propane] ring- walking along the edges of 2-bromopyridine. These are less than or approximately equal to our calculated values of ∆G‡ for oxida- tive addition and ligand substitution. Bilbrey, J. A.; Bootsma, A. N.; Barlett, M. A.; Locklin, J.; Wheeler, S. E.; Allen, W. D. Ring- Walking of Zerovalent Nickel on Aryl Halides. J. Chem. Theory Comput. 2017, 13, 1706-1711. 22. Calculations were performed at the CPCM(MeCN)-MN15L/6- 311++G(2d,p)/SDD(Ni)// CPCM(MeCN)-MN15L/6- 31G(d)/LANL2DZ(Ni) level of theory. 23. All thermodynamic quantities were computed with the GoodVibes code (333 K) applying corrections for concentration, ([Ni] = 0.01 M, [2r] = 0.2 M, and [MeCN] = 19.1 M): Luchini, G.; Alegre- Requena, J. V.; Funes-Ardoiz, I.; Paton, R. S. GoodVibes: Automated Thermochemistry for Heterogeneous Computational Chemistry Data. F1000Research 2020, 9, 291. 24. ortho-chloro(phenyl)boronic acids were avoided to prevent prod- uct inhibition by a (2-pyridyl) directed oxidative addition at the o–Cl bond. 25. An extensive literature search uncovered a single example of Ni- catalyzed selective monoarylation of a dihaloarene. In this reac- tion, Ni(PPh3)4 was used as a catalyst for the Suzuki-Miyaura cou- pling of 1,2-dibromobezene with (p-tolyl)boronic acid in THF to afford a 2.5 : 1 mixture of the mono : diarylated products. The authors then optimized for diarylation and found, similar to our work, that switching to Ni(cod)2/ PCy3 led to selective diarylation. See ref. 9c for details. Copy Cover Page.pdf Blank Page Blank Page