Computational Mechanistic Study of Stereoselective Suzuki Coupling

Article pubs.acs.org/Organometallics

Computational Mechanistic Study of Stereoselective Suzuki Coupling of an α-Cyano-Activated Secondary Alkyl Bimal Pudasaini and Benjamin G. Janesko* Department of Chemistry, Texas Christian University, Fort Worth, Texas, United States S Supporting Information *

ABSTRACT: Palladium-catalyzed cross-couplings of secondary alkyls are promising tools for the stereoselective formation of carbon−carbon bonds. We report a computational mechanistic study of the stereoselective Suzuki coupling between (S)-2chloropropanenitrile and phenylboronic acid, following a recent experimental report on related α-cyanohydrin triflates (J. Am. Chem. Soc. 2010, 132, 2524). Added Lewis base helps accelerate SN2 oxidative addition, leading to the experimentally observed inversion of configuration. Undesired β-hydride elimination side reactions are reduced by the activating cyano group’s inductive effects, by cyano-PdII coordination, and by excess boronic acid. The catalyst ligand’s trans influence and steric bulk also affect the rate of β-hydride elimination, suggesting design rules for alkyl cross-coupling ligands.

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phine (PMe3) unless noted otherwise. On the basis of the discussion above, we assumed that the catalytically relevant PdII intermediates are coordinatively unsaturated. Trimethylphosphine thus served as a computationally tractable model for more realistic, bulky phosphine ligands. Similarly, chloride served as a computationally tractable model for the bulky triflate pseudohalide used experimentally. We used the Gaussian 09 suite of programs31 to perform density functional theory (DFT) calculations with the M06 hybrid meta-GGA exchange-correlation functional.32 Geometries, free energy corrections, and solvent corrections were evaluated with the LANL08 basis set33,34 and relativistic effective core potential for Pd and the 6-31+G(d,p) basis for other atoms.35−38 Total energies were evaluated with a larger 6-311+G(2d,2p) basis set on non-Pd atoms. Solvent corrections used the polarizable continuum model (PCM), the tetrahydrofuran dielectric constant,39,40 and gas-phase geometries unless noted otherwise. The semilocal DFT energy and potential were numerically integrated using integration grids with 99 radial and 590 angular points per atom. All stationary points were verified with frequency calculations. All transition states had one negative eigenvalue (imaginary frequency) in their nuclear Hessian. Intrinsic reaction coordinate41,42 (IRC) calculations verified that all transition states lead to the correct reactants and products. Counterpoise corrections43 were applied to all complexation and dissociation energies. Barriers to formation and dissociation of noncovalent complexes were assumed to be negligible.1,44 Turnover frequencies (TOF) were calculated from an Arrhenius treatment of the reaction barrier (eq 1) following the energetic span approximation.45,46

INTRODUCTION Palladium-catalyzed cross-coupling reactions (Figure 1) are widely used to form carbon−carbon bonds between aryl and alkenyl (pseudo)halides and organometallics.1−4 Chiral secondary alkyl halides are attractive intermediates in the syntheses of biomolecules, pharmaceuticals, and natural products. However, extending Pd-catalyzed cross-couplings to unactivated secondary alkyls remains challenging, due to slow oxidative addition to sterically hindered Csp3−X bonds (Figure 1) and alkyl ligands’ susceptibility to β-hydride elimination (Figure 2).5−15 β-Hydride elimination preferentially occurs when the β hydrogen interacts agostically with a coordinatively unsaturated PdII intermediate.16−19 (Coordinatively saturated PdII−alkyl complexes may, in contrast, be stable enough to isolate and characterize.)20−22 Unfortunately, coordinatively unsaturated intermediates appear important for the activity of crosscoupling. Sterically demanding phosphine ligands shift the equilibrium of coordinatively saturated vs unsaturated PdII toward unsaturation23−25 and increase oxidative addition26−28 and reductive elimination rates,29 suggesting that the relevant intermediates are tricoordinated monophosphino−PdII complexes.30 Falck and He recently reported stereospecific cross-coupling between arylboronic acids and the activatived secondary alkyl α-cyanohydrin triflate.10 Here we model the catalytic cycle of Figure 1 for the reaction in ref 10. We focus on rationalizing the experimentally observed stereoselectivity to inversion of configuration and the selectivity to coupling vs β-hydride elimination products.

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TOF =

k bT −ΔG⧧ / RT e h

(1) 47

Conformational analyses were performed as follows. For each complex, an initial guess was made on the basis of the crystal structure homology. This geometry was optimized and then subjected to manual

COMPUTATIONAL METHODS Received: May 24, 2012 Published: June 13, 2012

We chose (S)-2-chloropropane nitrile and phenylboronic acid as model coupling reactants and modeled the ligand as trimethylphos© 2012 American Chemical Society

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Figure 1. Presumed catalytic cycle of Suzuki−Miyaura cross coupling. vibrational frequencies, and distances are reported in kcal mol−1, cm−1, and Å, respectively. Pictures of calculated geometries display atoms as white (H), gray (C), red (O), blue (N), pink (B), light blue (F), green (Cl), orange (P), and teal (Pd). Peripheral hydrogen atoms are removed in the figures for clarity. Energy level diagrams depict association and dissociation energies as dotted lines.

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RESULTS AND DISCUSSION Oxidative Addition and Stereochemistry. The Suzuki couplings in ref 10 had high selectivity to stereochemical inversion. The product stereochemistry is largely determined by the initial oxidative addition of Pd0 to the chiral alkyl

Figure 2. Presumed mechanism of β-hydride elimination.18 scans over the dihedrals of all rotatable bonds using increments of ∼30°. Each new geometry was optimized, and the lowest energy structure was assumed to be the global minimum. Gibbs free energies,

Figure 3. Calculated geometries and Gibbs free energy surfaces (kcal mol−1) for oxidative addition of PMe3−Pd0 to (S)-2-chloropropanenitrile. Energies from geometry optimizations in the solvent are shown in parentheses. 4611

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Table 1. Calculated Gibbs Free Energies (ΔG in kcal mol−1) and Dipole Moments (in D) for the Oxidative Addition Intermediates in Figure 3a reactant complex 1-Cl 1-CNa 1-CNb 1-N

transition state

ΔGcomplex

dipole

−0.9 −4.7 −6.3 −8.2

3.17 3.61 6.09 2.48

TS12-Cl-I TS12-CNa-I TS12-CNb-SN2

ΔGcomplex⧧

dipole

TOF

15.7 18.9 16.5

6.06 1.59 11.09

9.4 × 10−5 2.6 × 10−4 2.6 × 10−1

a Transition state free energies ΔGcomplex⧧ are relative to the corresponding reactant complexes. Turnover frequencies (TOF, s−1) are calculated from reaction barriers relative to the initial reactant complex 1-N.

Figure 4. Free energy surfaces for oxidative addition in the presence of chloride. Details are as in Figure 3.

electrophile (Figure 1). Proposed oxidative addition mechanisms include nucleophilic substitution (SN2) of halogen by Pd, giving inversion of stereochemistry,48−50 Pd insertion into the carbon−halogen bond, giving retention of stereochemistry,11,51,52 and radical pathways proceeding through PdI.53,54 Path selectivity and product stereoselectivity depend on factors such as solvent choice, reactant and ligand sterics, and the Pd0 catalyst’s coordination state, nucleophilicity, and ability to form PdI.27,28,48,52,53,55−63 Here we consider SN2 and direct insertion pathways for oxidative addition of monoligated Pd0 PMe 3 to (S)-2chloropropanenitrile. (Radical pathways and diligated Pd0 may be treated in future work.) Figure 3 shows the calculated geometries and free energy surfaces, and Table 1 tabulates free energies and dipole moments of relevant stationary points. The most stable initial reactant complex, 1-N, has the reactant nitrile acting as a σ-donor to Pd0. The reactant complexes 1-CNa and 1-CNb show η2 NC interactions64 with Pd0. 1-CNb undergoes SN2 oxidative addition to form the cationic product 2-CN(+) via the transition state TS12-CNb-SN2, producing the experimentally observed inversion of configuration. If the reactant complexes can easily isomerize, then the barriers to SN2 and insertion are 18.3 and 22.4 kcal mol−1 relative to the stable 1-N reactant. This is consistent with the experimental observation of selectivity to SN2.10

The SN2 transition state, TS12-CNb-SN2, has a large dipole moment (11.09 D) consistent with charge separation leading to a cationic Pd product. Similar charge separation is expected for SN2 by neutral diligated Pd0. de Jong and Bickelhaupt suggested that charge separation approaching the SN2 product complex [Ln-Pd-alkyl]+-Cl− continuously increases the complex free energy.65 Maseras and co-workers found that such chargeseparated complexes were stabilized by Pd−O interactions in SN2 addition of Pd(PMe3) and Pd(PMe3)2 to α-bromo sulfoxide.56 While TS12-CNb-SN2 has stabilizing Pd−CN interactions (Figure 3), the barriers are significantly larger than are seen in the case of α-bromo sulfoxide.56 We explored solvent stabilization of the transition state dipole moment by reoptimizing the geometries in implicit solvent. This allowed IRC calculations to converge to the ion-paired SN2 product THF-2-IP which had a large 27.8 D dipole moment. However, it did not lower the SN2 barrier. The optimum reaction conditions reported in ref 10 included 4 equiv each of KF and H2O. Given this, and given the large dipole moment of the SN2 transition state, we explored whether Lewis base coordination to Pd0 could further stabilize the SN2 pathway. Amatore and co-workers have extensively studied such effects in SN2 oxidative addition of Pd0 to alkyl halides,62,66 proposing anionic tricoordinated Pd0 and pentacoordinated PdII oxidative addition intermediates. Subsequent experi4612

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Figure 5. Calculated geometries of oxidative addition products with β-agostic interactions. Bond distances are given in Å and Cβ−Hβ vibrational frequencies in cm−1.

Figure 6. Free energy surface for β-hydride elimination from oxidative addition products. Details are as in Figure 3.

ments62,63,67 and calculations68−71 have considered the role of halide ions in oxidative addition of Pd0 to aryl halides or pseudohalides. The aforementioned study of de Jong and Bickelhaupt found that anion coordination significantly accelerated SN2 addition of Pd0 to Csp3−Cl relative to direct insertion.65 Studies of solvent effects in oxidative addition suggest that other Lewis bases may show similar effects.72 Here, we consider the relatively simple case of chloride anion coordinating to Pd0PMe3 and suggest that qualitatively similar effects may occur for Pd0(PMe3)2 and for other Lewis bases. As in previous computational studies of anion effects in crosscoupling,65,70 we did not explicitly treat a positively charged counterion. Test calculations support this approximation, showing that the reaction K − Cl + Pd(PMe3) → K+ + [Cl − Pd(PMe3)]− has a small predicted ΔG of −0.2 kcal mol−1 for geometries optimized in continuum solvent. Figure 4 reports calculated geometries and free energies for oxidative addition73 in the presence of Cl−. The most facile oxidative addition proceeds from 1-CNb+Cl through transition state TS12-CNb+Cl-SN2, yielding the SN2 oxidative addition product 2-trans-CN+Cl. The barrier ΔGcomplex⧧ relative to the most stable species (2-chloropropanenitrile + [Cl-PdPMe3]−) is only 13.0 kcal mol−1, a significant drop in reaction barrier

from the neutral pathway. Thus, coordination of Lewis bases to Pd0 is predicted to further improve the observed selectivity to SN2. β-Hydride Elimination from Oxidative Addition Products. Cl− dissocation from 2-trans-CN+Cl (Figure 4) yields the coordinatively unsaturated oxidative addition product 2trans-CN. The facile Suzuki coupling in ref 10 means that this intermediate must undergo transmetalation (Figure 1) faster than β-hydride elimination. 2-trans-CN can isomerize to the βagostic complexes 2-cis-beta and 2-trans-beta (Figure 5), both of which may undergo β-hydride elimination.18,74 (Cis and trans denote the arrangement of Csp3 and Cl ligands from the original Csp3−Cl bond.) Here we investigate how the activating α-cyano group, and the cis−trans equilibrium, affect β-hydride elimination. Figure 6 shows the calculated free energy surface for β-hydride elimination. (This surface omits isomerization free energy barriers, due to the complexity of isomerization by ligand association/dissociation. Related works suggest that these barriers are rather low.1,44) We first consider the effect of the activating α-cyano group. Figure 5 also shows the species 2H-cis-beta and 2H-trans-beta obtained from oxidative addition to a putative unactivated alkyl electrophile. Spectroscopic,75 X-ray, and neutron diffraction 4613

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The undesirable β-hydride elimination is strongly affected by the identity of the ligand trans to the β-agostic interaction site. Table 2 shows that the less thermodynamically stable complex 2-cis-beta, in which the weakly trans-influencing chloride is trans to the β-agostic bond, has substantial Hβ donation and a short Pd−Hβ bond, a large Pd−Hβ bond order, and a long Cβ− Hβ bond. Corresponding trans effects on kinetics are seen in the observation that 2-cis-beta and 2H-cis-beta undergo facile β-hydride elimination. Similar effects on β-hydride transfer in NiII complexes were discussed in ref 90. We conclude that βhydride elimination is slowed both by the inductive effects of the α-cyano group and by the PMe3 ligand’s trans influence and trans effect on Pd−Hβ interactions. Transmetalation vs β-Hydride Elimination from Oxidative Addition Products. The facile Suzuki coupling reported in ref 10 implies that the oxidative addition products must undergo transmetalation much faster than β-hydride elimination. Several transmetalation pathways have been proposed, all requiring added Lewis base.1,3,91 We explored two pathways, with the model Lewis base F− initially binding either to arylboronic acid91 or to the oxidative addition product 2-trans-beta.92 (While other transmetalation pathways likely exist, these suffice for our focus on selectivity vs β-hydride elimination.) Figure 7 shows that these transmetalation pathways give free energy barriers ΔGtot⧧ of 10.9 and 1.3 kcal mol−1 relative to free 2-trans-beta, PhB(OH)2, and F−. Both barriers are significantly lower than the 14.5 kcal mol−1 ΔGtot⧧ barrier to β-hydride elimination (Figure 6). However, the transmetalation pathways include tetracoordinated “thermodynamic sinks” 4-F and 4B-OB. Transmetalation barriers ΔGcomplex⧧ from these thermodynamic sinks are a relatively high 17.4 and 24.1 kcal mol−1. This is consistent with a mechanism where the large experimental excess of transmetalation reagents (2 equiv of arylborane, 4 equiv of KF)10 drives the equilibrium between free and bound oxidative addition product (e.g., 2-trans-beta + PhB(OH)2F− ⇌ 4AOB) to the right. This presumably accelerates transmetalation (which is first order in borane concentration in a related system93) and slows β-hydride elimination. Reductive vs β-Hydride Elimination from Transmetalation Products. Dissociation of boron reagent from 5-trans-OB (Figure 7) yields the coordinatively unsaturated transmetalation product 5-trans-beta (Figure 8), analogous to the 2-trans-beta oxidative addition product in Figure 5. Like their counterparts in Figure 5, 5-trans-beta and 5-cis-beta both may undergo β-hydride elimination.18,74 Cis and trans here denote the arrangement of the Csp3 and Csp2 groups entering the final Csp3−Csp2 bond (Figure 1). Only cis transmetalation products directly undergo reductive elimination.94,95 Here we investigate how cis−trans isomerization affects the relative rates of β-hydride elimination (Figure 9) and reductive elimination (Figure 10). In contrast to the increased stability of trans complexes in Figure 5, 5-cis-beta is 3.2 kcal mol−1 more thermodynamically stable than 5-trans-beta. This is again consistent with ligand trans influences. Csp3 prefers to be trans to the more weakly trans-influencing ligand: chloride in 2-trans-beta and PMe3 in 5-cis-beta. As for the oxidative addition products, similar effects are seen for η2 complexes. 5-cis-CN is 4.3 kcal mol−1 more stable than 5-trans-CN (Figure 9). Analyses of geometry and bond order (Table 3) confirm that the more stable 5-cis-beta complex has shorter and stronger Pd−Cα bonds than 5-cis-CN.

studies76 show that agostic interactions may be identified by an elongation of the participating C−H bond, a red shift of the C− H bond stretching frequency, and a decrease in Pd−H separation.17,19 By all of these criteria, the α-cyano group weakens the β-agostic interactions in 2-cis-beta vs 2H-cis-beta and in 2-trans-beta vs 2H-trans-beta. This correlates with an increase in β-hydride elimination barriers. β-hydride elimination from 2-cis-beta via TS23-cis-beta has a ΔG⧧ value of 14.5 kcal mol−1 relative to 2-trans-beta (Figure 6). The corresponding βhydride elimination from 2H-cis-beta has a ΔG⧧ value of only 10.7 kcal mol−1 relative to 2H-trans-beta. While 2H-trans-beta can directly undergo β-hydride elimination with the barrier ΔG⧧ = 14.6 kcal mol−1, we were unable to find a direct βhydride elimination product from 2-trans-beta. (Geometry optimizations of products with β-hydrogen on Pd converged back to the 2-trans-beta reactant geometry. Similar results were obtained with the B3LYP77,78 and PBEh79−81 density functionals.) This is consistent with previous findings that electronwithdrawing groups adjacent to the β-carbon can reduce βhydride elimination.74,82 We next consider cis−trans isomerization. Both the unactivated and α-cyano-activated complexes in Figure 5 are more stable in the trans conformation: 2-trans-beta is 10.0 kcal mol−1 more stable than 2-cis-beta, and 2H-trans-beta is 8.6 kcal mol−1 more stable than 2H-cis-beta. Similar effects occur for η2 complexes, with 2-trans-CN 7.2 kcal mol−1 more stable than 2-cis-CN (Figure 6). Similar effects also occur for transition states: β-hydride elimination from 2H-trans-beta has a higher overall barrier than from 2H-cis-beta, and no direct β-hydride elimination pathway was found from 2-transbeta. (These effects are confirmed by ab initio wave function calculations reported in the Supporting Information.) This stabilization of trans oxidative addition products is consistent with the ligands’ mutual “trans influence”,83−86 the extent to which a ligand X on metal M decreases the strength of an M−Y bond in the trans position.87 (The related “trans effect” shows how X affects the kinetics of M−Y dissociation.) The relative trans influences of the ligands in Figure 5 are Cl− < PMe3 < Csp2 ≈ Csp3.87 The most stable complexes in Figure 5 all have the strongly trans-influencing alkyl trans to the weakly trans-influencing chloride. Test calculations on Me− (PMe3PdII)−X (X = F, Cl, Br; Supporting Information) confirm this trend, showing that the thermodynamic preference for having Me and X trans increases with increasing electronegativity and decreasing trans influence of X. Analyses of geometry and Wiburg bond order88 (Table 2) confirm that the more stable 2-trans-beta complex has shorter and stronger Pd−Cα and Pd−P bonds, and weaker and longer Pd−Cl bonds, than 2-cis-beta. (Note that bond length descriptors do not always correlate with trans influence.89) Table 2. Bond Lengths (Å) and Wiberg Bond Indices for Oxidative Addition Product Conformations 2-cis-beta and 2trans-beta 2-cis-beta

2-trans-beta

bond

length

bond index

length

bond index

Pd−Cl Pd−P Pd−Cα Pd−Hβ Cβ−Hβ

2.340 2.371 2.083 1.851 1.184

0.642 0.548 0.517 0.148 0.750

2.373 2.249 2.062 2.066 1.138

0.581 0.669 0.530 0.073 0.830 4614

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Figure 7. Free energy surfaces for transmetalation of oxidative addition products. Details are as in Figure 3.

with the experimentally observed selectivity to reductive elimination. (Note that the excess Lewis base used experimentally10 can coordinate to the PdII intermediate and slow reductive elimination.74,94,95) A noteworthy result in Figure 9 involves the activating αcyano group. We previously studied74 reductive and β-hydride elimination from γ-substituted secondary alkyls.96 σ donation from the activating γ-amide to PdII gave a deep thermodynamic sink, which was “blocked” by dialkylbiaryl phosphine ligands. In contrast, the weaker η2 α-cyano interaction in 5-cis-CN does not preclude facile reductive elimination. This is consistent with the fact that ref 10, unlike ref 96, did not require a dialkylbiaryl97 or hemilabile98 phosphine ligand. Ligand Design Rules: Trans Influence vs Steric Bulk. The above results suggest “design rules” for ligands L (Figure 1) in alkyl cross-coupling catalysts. The optimal ligand trans influence will be (a) much larger than that of halides or pseudohalides to favor trans oxidative addition products such as 2-trans-beta, and (b) much smaller than that of Csp2 or Csp3 to favor cis transmetalation products such as 5-cis-beta. Optimal ligands apparently also require sufficient steric bulk to stabilize coordinatively unsaturated PdII intermediates.26−29 However, such steric bulk invariably favors cis complexes with the ligand adjacent to a vacant coordination site. Table 4 quantifies this interplay between trans influence and steric bulk using the figures of merit ΔGOA and ΔGTM, both ideally large and positive. ΔGOA is the free energy difference between undesired cis and desired trans oxidative addition products: e.g., 2-cis-beta vs 2-trans-beta. ΔGTM is the difference between undesired trans and desired cis transmetalation products: e.g., 5-trans-beta vs 5-cis-beta. “DMAPP(tBu)2” denotes the (p-(dimethylamino)phenyl)di-tert-butylphosphine ligand used experimentally.10

Figure 8. Calculated geometries of transmetalation products with βagostic interactions. Details are as in Figure 5.

The undesirable β-hydride elimination from transmetalation products is again strongly affected by the identity of the ligand trans to the β-agostic interaction site. Table 3 shows that 5trans-beta has a shorter and stronger Pd−Hβ bond than 5-cisbeta, just as Table 2 shows that 2-cis-beta has a shorter and stronger Pd−Hβ bond than 2-trans-beta. β-Hydride elimination from 5-trans-beta via TS56-trans-beta has a 16.1 kcal mol−1 barrier relative to 5-cis-CN, lower than the corresponding 17.2 kcal mol−1 from 5-cis-beta (Figure 9). (The former reaction gives the protodeboration product 6-BEP-trans.) Figures 9 and 10 show that the ligand effects on selectivity to reductive vs β-hydride elimination are similar to those discussed for transmetalation. The initial transmetalation product 5trans-beta cannot directly undergo reductive elimination but undergoes β-hydride elimination with a 10.7 kcal mol−1 barrier. Isomerizations to 5-cis-Ph and 5-cis-CN allow reductive elimination with barriers of 9.6 and 14.3 kcal mol−1, respectively (Figure 10), and increased β-hydride elimination barriers (Figure 9). Overall free energy barriers ΔGcomplex⧧ relative to the most stable complex 5-cis-CN are lower for reductive elimination than for β-hydride elimination, consistent 4615

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Figure 9. Free energy surfaces for β-hydride elimination from transmetalation products. The dotted line separates cis and trans conformers; other details are as in Figure 3.

Figure 10. Free energy surfaces for reductive elimination from transmetalation products. Details are as in Figure 3.

mol−1 but decreases the barrier to β-hydride elimination from the oxidative addition product by 7.1 kcal mol−1. The experimental DMAP-P(tBu)2 ligand10 provides a reasonable trade-off, with modestly large values for both ΔGOA and ΔGTM. DMAP-P(tBu)2 also increases the barrier to β-hydride elimination from the oxidative addition product by 3.2 kcal mol−1 over P(tBu)3. This helps rationalize the success of DMAP-P(tBu)2 in ref 10.

Table 4 shows that the small model PMe3 ligand gives a large ΔGOA value but only a small ΔGTM value, suggesting that it is suboptimal for selectivity to reductive elimination. The steric bulk of P(tBu)3 increases ΔGTM at the expense of destabilizing the desirable trans oxidative addition product and decreasing ΔGOA. Kinetics calculations support these effects. Replacing PMe3 with P(tBu)3 increases the barrier to β-hydride elimination from the transmetalation product by 7.0 kcal 4616

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ACKNOWLEDGMENTS This work was supported by startup funds from Texas Christian University. We thank Jean-Luc Montchamp for useful discussions.

Table 3. Bond Lengths (Å) and Wiberg Bond Indices for Transmetalation Product Conformations 5-cis-beta and 5trans-betaa 5-cis-beta

a

5-trans-beta

bond

length

bond index

length

bond index

Pd−Csp2 Pd−P Pd−Cα Pd−Hβ Cβ−Hβ

2.025 2.367 2.092 2.061 1.142

0.642 0.544 0.445 0.076 0.837

2.071 2.252 2.139 1.976 1.156

0.559 0.656 0.406 0.091 0.805

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Table 4. Relative Gibbs Free Energies ΔGOA and ΔGTM (kcal mol−1) of Undesirable Isomers of the Oxidative Addition and Transmetalation Products for Various Catalyst Ligands La

a

ΔGOA

ΔGTM

PMe3 PtBu3 DMAP-P(tBu)2

10.0 1.6 5.1

3.2 14.5 13.7

Details are given in the text.

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CONCLUSION This study presents mechanistic insights into stereoselective cross-coupling of an α-cyano activated secondary alkyl electrophile. The experimentally observed stereoselectivity is suggested to be aided by Lewis base acceleration of SN2 oxidative addition. Undesired β-hydride elimination from the oxidative addition product is slowed by the inductive effects of the activating α-cyano group, the phosphine ligand’s trans influence, and coordination of the experimental excess of transmetalating reagents to the oxidative addition product. βHydride elimination from the reductive elimination product is also predicted to depend on the ligand’s trans influence. The labile α-cyano group, unlike previously studied γ-amides, avoids a thermodynamic sink that slows reductive elimination.74,96 (We speculate that the experimentally used triflate (OTf) pseudohalide may further slow β-hydride elimination from oxidative addition products by having one of the pendant oxygen atoms interact with coordinatively unsaturated PdII.) This exploration of the interplay of ligands’ steric effects and trans influence offers insight into the success of the ligand used experimentally, as well as “design rules” that may aid in developing new alkyl cross-coupling catalysts.

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AUTHOR INFORMATION

REFERENCES

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Cα denotes the sp3 carbon bound to Pd.

L

Article

S Supporting Information *

Text, tables, and figures giving calculated geometries and energies for all complexes, turnover frequencies of reaction paths, an example of conformational analysis, tests of trans influence, and benchmarks of M06 geometries99,100 and βhydride elimination barriers. This material is available free of charge via the Internet at http://pubs.acs.org. Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. 4617

dx.doi.org/10.1021/om300455g | Organometallics 2012, 31, 4610−4618

Organometallics

Article

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