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. 2025 Nov 20;147(48):44372–44383. doi: 10.1021/jacs.5c14937

Kinetics and Mechanism of Enantioselective Cu-Catalyzed Alcohol Silylation

Pedro H Helou de Oliveira †,‡, Jan Seliger †, Shoutong Rao §, Guy C Lloyd-Jones ‡,*, Guoqiang Wang §,*, Martin Oestreich †,*
PMCID: PMC12679643  PMID: 41264555

Abstract

The enantioselective Cu-catalyzed dehydrogenative Si–O coupling of secondary benzylic alcohols with (nBu)3SiH was investigated using a combination of in situ 1H/19F NMR spectroscopic reaction monitoring, isotopic labeling, kinetic modeling, and computational studies. Macrokinetic behavior is governed by substrate-inhibited L*CuOR·ROH resting states: rates rise with conversion when [(nBu)3SiH] > [ROH] and fall when [(nBu)3SiH] < [ROH]. Alcohols bearing electron-withdrawing substituents are stronger inhibitors and show overall lower macrokinetic reactivity, but react faster than alcohols with electron-donating substituents in intermolecular competitions, indicating that inhibition is more substituent-sensitive than the product-committing step. Divergence between intrinsic enantioselectivity and observed macrokinetic rates of enantiomers in isolation results from enantiomer-dependent inhibition, and a product-committing σ-bond-metathesis step is consistent with measured Eyring activation parameters and a Si–H/Si–D KIE ≤ 1.3. Eyring and Hammett analyses, as well as DFT calculations, support an H-bonding inhibition mode for the L*CuOR·ROH resting state. Stoichiometric styrene as an additive suppresses H2 generation and mitigates catalyst deactivation, increasing process safety and efficiency. Dynamic kinetic resolution, enabled by addition of a ruthenium racemization cocatalyst, results in reaction rates comparable to those of the faster enantiomer while improving overall efficiency.

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Introduction

Copper hydride-catalyzed transformations play an important role in modern synthetic organic chemistry. In 1984, Brunner and Miehling reported on an asymmetric hydrosilylation of acetophenone using diphenylsilane, catalytic CuOtBu, and chiral phosphine ligands such as (−)-diop. , Pioneering contributions by Stryker and co-workers in 1988, established hexameric [(Ph3P)­CuH]6 as a stoichiometric reagent for the conjugate reduction of α,β-unsaturated carbonyl compounds. A decade later, Lipshutz and co-workers identified hydrosilanes as mild terminal reducing agents for the in situ regeneration of the reactive copper hydride species from a postulated copper enolate intermediate. , Based on these discoveries, a substantial body of work has since been developed, including asymmetric reactions which utilize modular precatalyst systems generated from copper salts and chiral phosphine ligands. Early research efforts in this area focused on enantioselective hydrosilylation of ketones and conjugate reduction of α,β-unsaturated carbonyl compounds (Scheme A and B). , The latter set the stage for both enantio- and diastereoselective reductive coupling reactions of activated alkenes and carbon electrophiles as well as (formal) hydrofunctionalizations of activated and unactivated alkenes (Scheme C). −

1. Classes of Asymmetric Copper Hydride-Catalyzed Transformations and Selected Key Mechanistic Features.

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Our laboratory has a long-standing interest in the application of Cu–H catalysis in the kinetic resolution (KR) of alcohols by stereoselective dehydrogenative Si–O coupling with hydrosilanes (Scheme D). In 2017, we disclosed that a precatalyst system consisting of commercially available CuCl, NaOtBu, and (R,R)-Ph-BPE, effects the enantioselective silylation of secondary racemic benzylic and allylic alcohols using (nBu)3SiH. We have also developed a protocol for nonenzymatic dynamic kinetic resolution (DKR) of secondary benzylic alcohols, in which the Cu–H-catalyzed process proceeds in tandem with a rapid in situ racemization of the alcohol effected by a bifunctional ruthenium pincer complex.

A generic mechanism for these transformations, based on literature precedent, − ,− individual experimental findings, and quantum-chemical calculations on a truncated system, is shown in Scheme . Accordingly, both enantiomers of the alcohol 1 are deprotonated by the chiral copper hydride complex L*CuH, liberating dihydrogen and giving rise to diastereomeric copper-alkoxide complexes L*CuOR S and L*CuOR R . These undergo rapid exchange with both enantiomers of the bulk alcohol 1, resulting in a nondegenerate dynamic equilibrium system of the form [L*CuOR S + (R)-1 ⇋ L*CuOR R + (S)-1]. The diastereomeric copper alkoxides undergo transmetalation with the hydrosilane to liberate silyl ethers (S)-2 and (R)-2 and regenerate the copper hydride L*CuH. The transmetalation is postulated to involve σ-bond metathesis, with retention of configuration at carbon and silicon, in what is hypothesized to be the enantiodetermining step. d, m The latter conclusion is supported by the influence of hydrosilane substituents on the enantioselectivity. While the existing evidence supports the overarching features of the process (Scheme ), a detailed understanding of the mechanism has not been achieved. In this context, we have pursued experimental and computational approaches to elucidate the elementary steps that effect turnover, the catalyst speciation and resting state, and the enantiodetermining transition state. We report herein a holistic kinetic and mechanistic analysis of the KR and DKR dehydrogenative Si–O coupling (Scheme D).

Results and Discussion

1. Initial Kinetic Investigations

We began by studying the reaction of (S)-1-(4-fluorophenyl)­ethanol, (S)-1a, and tri-n-butylhydrosilane, (nBu)3SiH, in C6D6 (Figure ). Reactions were monitored by in situ 1H and 19F­{1H} NMR spectroscopy, with 4-fluoroanisole as dual internal standard. To ensure homogeneous conditions and consistent catalyst concentrations across experiments, reactions were initiated with solutions of preformed L*CuOtBu (L* = (R,R)-Ph-BPE, see Supporting Information Section 2.6). Styrene was employed as a sacrificial alkene, i.e., to undergo hydrocupration by L*CuH, forming L*CuCH­(Me)­Ph and thus suppress the formation of H2, without affecting initial reaction rates (see Supporting Information Section 3.1). Control experiments revealed that neither a change of solvent from toluene to C6D6 nor the introduction of styrene had a significant influence on the enantioselectivity.

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Selected spectra (2.3–2.6 ppm and 3.6–5.2 ppm) and temporal concentration profile from in situ 1H NMR reaction monitoring data of the L*CuOtBu-catalyzed dehydrogenative coupling of (S)-1-(4-fluorophenyl)­ethanol ((S)-1a, 200 mM, δH = 4.40 ppm prior to initiation), and (nBu)3SiH (200 mM, δH = 4.00 ppm) in the presence of styrene (274 mM, δH = 5.07 ppm) in C6D6 at 298 K. The products silyl ether ((S)-2a, δH = 4.72 ppm) and ethylbenzene (δH = 2.45 ppm) are shown, see Supporting Information Section 3.1 for details.

Material balances were consistent throughout reactions, and no significant intermediates or side products were detected during reaction monitoring, other than small quantities of H2, which were generated when [(S)-1a]0 > [styrene]0 (see Supporting Information Figure S8, Entry 9). Thus, equimolar alcohol, hydrosilane, and styrene are consumed, and converted to equimolar silyl ether (S)-2a and ethylbenzene (Figure ). During the reaction monitoring, the 1H NMR signals of (S)-1a progressively shift downfield, as [(S)-1a] t decreases (Figure ) and the 19F­{1H} NMR signal shifts upfield. Both effects are evident in the spectra immediately after initiation of the reaction with L*CuOtBu (0.005 M, 2.5 mol %) and are indicative of rapid exchange of (S)-1a with one or more copper species, resulting in time-averaged, concentration-weighted chemical shifts. In contrast, the 1H and 19F­{1H} NMR signals of the other reactants and products were invariant throughout (see Supporting Information Section 3.1).

Systematic variations in [(nBu)3SiH]0 resulted in directly proportional changes in reaction rates. Conversely, variations in [(S)-1a]0 resulted in inversely proportional changes in the reaction rate, indicative that the alcohol substrate is an inhibitor. The styrene concentration has no significant affect on the reaction rate if it is present in excess, consistent with rapid styrene hydrocupration by a copper hydride species (see Supporting Information Section 3.1). Reaction rates scaled linearly with [Cu]0, as did product ee with ligand ee (no nonlinear effect, see Supporting Information Section 5.1 for details). A single, fixed-nuclearity Cu catalyst is the simplest explanation for the concurrence of both observations, although mixed aggregation states of Cu which coincidentally yield first-order kinetics and a linear ee response cannot be excluded.

The above features result in the temporal concentration profile for the evolving silyl ether, (S)-2a, being dependent on the initial mole ratio of (S)-1a/(nBu)3SiH (Figure ). When the ratio is close to unity (i.e., [(S)-1a]0/[(nBu)3SiH]0 ≈ 1) approximately pseudozero-order evolutions are observed (Figure and Figure , III) until [(S)-1a] t and [(nBu)3SiH] t are substantially depleted and begin to approach the catalyst concentration, [Cu] t , which is identical to its initial value, [Cu]0, if no deactivation process is present (see for discussion). In contrast, there is significant curvature in the product evolution profile when either (nBu)3SiH or (S)-1a is in excess over the other. Thus, when [(S)-1a]0/[(nBu)3SiH]0 > 1, the rate progressively decreases (Figure , IV–VI). Conversely, when [(S)-1a]0/[(nBu)3SiH]0 < 1, the rate progressively increases (Figure , I and II). Overall, the kinetics for the reaction of (S)-1a are consistent with the steady-state rate approximation shown in eq (see Figure for reaction scheme), where k rxn is an empirical turnover coefficient, and K i is an empirical inhibition constant. The turnover rate, v s , approaches a pseudozero-order rate constant, k obs, when [(S)-1a] t /[(nBu)3SiH] t ≈ 1, as shown in eq (see Supporting Information Section 8.1 for details).

νS≈krxn[(nBu)3SiH]t[Cu]t1+Ki[(S)‐1a]t 1
νS≈kobs[(nBu)3SiH]t[(S)‐1a]t; whenKi[(S)‐1a]t≫1 2

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Temporal concentration profiles of (S)-2a generation under varied initial conditions: [Cu]0 = 0.005 M (I–VI). [styrene]0 = 0.27 M (I–VI). [(S)-1a]0 = 0.2 M (I–III) [(S)-1a]0 = 0.32 M (IV), 0.41 M (V), 0.65 M (VI), [(nBu)3SiH]0 = 0.4 M (I), 0.27 M (II), 0.2 M (III–VI).

2. Mismatched, Racemic, and Pseudoracemic Alcohol 1a

The slower-reacting enantiomer (R)-1a undergoes dehydrogenative coupling with kinetics analogous to those of (S)-1a (eq ), and v 0,S /v 0,R = 4.3 under pseudozero-order conditions (Figure ). In contrast to the reactions of the isolated S- and R-enantiomers, racemic 1a undergoes dehydrogenative coupling with a nonlinear temporal concentration profile under conditions where the reactant ratio is unity, i.e., [1a]0/[(nBu)3SiH]0 ≈ 1 (Figure , I). Analysis of the 1H NMR signals of the methine protons of (S)-1a and (R)-1a revealed a significant differential in their progressive downfield shifts (Δδ S > Δδ R ). Furthermore, an analogous upfield shift of the respective 19F­{1H} NMR signals was observed (see Supporting Information Section 3.4). Evidence that the observed shift dynamics of (S)-1a result from interactions between L*CuOR S and (S)-1a was obtained from a mixture of L*, mesityl copper (MesCu), and (S)-1a assembled in situ and subjected to NMR spectroscopic analysis (see Supporting Information Section 5.3 for details). These effects are consistent with a significant difference in the inhibition association constants, with the overall faster reacting enantiomer (S)-1a rapidly and reversibly binding more strongly to L*CuOR than (R)-1a.

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Dehydrogenative coupling of rac-1a (200 mM), (nBu)3SiH (200 mM), styrene (274–327 mM, see Supporting Information for details of individual reactions), and L*CuOtBu (5 mM) in C6D6 at 298 K (KR, I, SI Section 3.4), and a reaction under identical conditions with the addition of a racemization catalyst, Ru­(CNN)­(dppb)­OtBu (prepared in situ from Ru­(CNN)­(dppb)­Cl , and NaOtBu, 5 mM, DKR, II, SI Section 3.5). A comparison of the (nBu)3SiH consumption of I, II, and dehydrogenative couplings of enantiopure (R)-1a (SI Figure S9, Entry 18), and enantiopure (S)-1a (Figure ) is shown (III). A blue line is added to the reaction of rac-1a for comparison with the reaction of (R)-1a as a visual aid.

Subsequently, the behavior of the system under DKR conditions, facilitated by Ru­(CNN)­(dppb)­OtBu , cocatalysis, was investigated. Separate time-averaged 19F­{1H} NMR signals of identical intensities were detected for (S)-1a and (R)-1a throughout the reaction, indicative that alcohol 1a is dynamically racemic throughout the dehydrogenative coupling. Identical conclusions are drawn by analysis of the pseudoquintet corresponding to the methine signals of (S)-1a and (R)-1a during 1H NMR reaction monitoring. Racemization is thus rapid in comparison to the concurrent dehydrogenative coupling process, as is ideal for a DKR process (k rac ≥ 400·k obs, see Supporting Information Section 8.3 for discussion). Moreover, the racemization restores the pseudozero-order kinetic regime (Figure , II) at a reaction rate that is similar to that of the dehydrogenative coupling of (S)-1a (Figure , III). The nonlinear kinetic regime in the absence of Ru cocatalysis (Figure , I) is thus the result of a progressive change in (S)-1a/(R)-1a ratio, as is expected in a KR process, whereas the (S)-1a/(R)-1a ratio is constant under DKR conditions.

As the reactive species L*CuOR S and L*CuOR R rapidly equilibrate, formation of (S)-2a is irreversible, and L*CuOR complexes are in low concentrations relative to (nBu)3SiH, the relative rate of the substrate-committing elementary reactions, k S/k R, can be estimated by competition experiments. The pseudoenantiomeric pairs, (S)-1a-C D /(R)-1a (Figure , I) and (S)-1a/(R)-1a-C D (Figure , II), facilitate the direct 1H NMR spectroscopic resolution and quantification of the stereochemical ratios in the substrates and products. The changes in pseudoenantiomeric substrate ratio, R A, with fractional conversion, F L, were fitted to first-order competition models to give (k S·KIE H/D(S))/k R = 7.2 and k S/(k R·KIE H/D(R)) = 7.6 (Figure ). If the small inverse secondary kinetic isotope effect (KIE), k H/k D ≈ 0.97, is enantiomer-independent, then the kinetic resolution factor, k S/k R, is 7.4 (see Supporting Information Section 4.5). The rate-differential between (S)-1a and (R)-1a in competition is thus greater than that in independent reactions, v 0,S /v 0,R = 4.3. This is consistent with an inhibition constant for (S)-1a, K i,S , which is greater than K i,R by a factor of 7.4/4.3 = 1.7, despite (S)-1a undergoing faster overall transformation to (S)-2a than (R)-1a to (R)-2a.

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Determination of the relative reactivity of 1a enantiomers via intermolecular competitions between (S)-1a-C D /(R)-1a (I), and (S)-1a/(R)-1a-C D (II), see Supporting Information Section 4.2 for detailed discussion of the data fitting to a Bigeleisen–Wolfsberg equation.

3. Activation Parameters and Primary Si–H and O–H Kinetic Isotope Effects

The temperature dependence of the rates of the Cu-catalyzed reaction between (S)-1a and (nBu)3SiH in the 288–308 K temperature range was determined under pseudozero-order conditions. Eyring analysis of the empirical rate coefficient, k obs = v 0/[Cu]0, gave approximate activation parameters (Figure , I, see Supporting Information Section 3.6). The enthalpy of activation (ΔH‡ = 14 kcal·mol–1), entropy of activation (ΔS‡ = −23 cal·K–1·mol–1), and free energy of activation (ΔG‡ = 21 kcal·mol–1 at 298 K) are consistent with a highly ordered transition state with loss of translational degrees of freedom, as would be expected for σ-bond metathesis (Figure ) in an apolar aprotic solvent. ,

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Summary of temperature and isotope effects: Eyring activation parameters (I), H/D isotope effect of hydroxy group measured via intermolecular competition (II), and H/D isotope effects of hydrosilane measured via intermolecular competition and independent kinetic measurements (III). k H/k D values reported with a single asterisk (*) represent intermolecular competition, those reported with double asterisks (**) represent independent kinetic measurements. Concentrations in (II) and (III) are given for intermolecular competition experiments. The independent H/D KIE value for (S)-1a-O D is represented as ∼1 at the same rate as (S)-1a at initial reaction stages, see Supporting Information Section 4.6 for details.

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Schematic potential energy surface of dehydrogenative couplings of p-substituted (S)-1 derivatives. Proposed resting and transition states consistent with the obtained experimental data are shown.

To further probe the process, the primary KIE for the Cu-catalyzed reaction of (S)-1a with (nBu)3SiD versus (nBu)3SiH was determined by intermolecular competition (k H/k D = 1.3) and from independent reactions (k H/k D = 1.2). The small normal primary KIE values are again consistent with a σ-bond metathesis process and agree with theoretical calculations (Figure ). Deuterium incorporation in the ethylbenzene coproduct occurred exclusively at the terminus, forming PhCH2CH2D, consistent with prior reports on the reactions of Cu–D complexes with styrene (Figure , III).

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A: Computed catalytic cycle for reactions of (S)-1a and (R)-1a with (nBu)3SiH, styrene in the presence of a L*Cu catalyst system. Values under species are relative free energies in kcal·mol–1 referenced to L*CuOR S . See Supporting Information Section 7.1 for details. Kinetic simulations employing the standard state computational free energies are depicted for mole fraction of catalyst species [L*CuOR S ·(S)-1a], L*CuOR S , [L*CuOR S ·(S)-1a·(S)-1a], and L*Cu-(R)-CH­(Me)­Ph during a reaction as (S)-1a is consumed (B, Initial conditions: [Cu]0 = 0.005 M, [styrene]0 = 0.274 M, [(S)-1a]0 = 0.200 M, [(nBu)3SiH]0 = 0.200 M, data simulated from experimental kinetic parameters is shown for comparison as dashed lines (Figure , see Supporting Information Section 8.1 for details), and for the variation of [(nBu)3SiH]0 and [(S)-1a]0, with [(S)-1a]0/[(nBu)3SiH]0 = 0.2–5 (C, Initial conditions: [Cu]0 = 0.005 M, [styrene]0 = 1.0 M, [(S)-1a]0 = 0.200–1.0 M, [(nBu)3SiH]0 = 0.200–1.0 M).

Reaction of the O-deuteriatedalcohol (S)-1a-O D under the standard reaction conditions shown in Figure proceeded with the same initial rates as a reaction of (S)-1a (v 0,OH/v 0,OD = 1), but departed from the pseudozero-order kinetic regime at an earlier stage than that of (S)-1a (see Supporting Information Section 4.6). This results from a large primary KIE attending the reaction of (S)-1a-O H/D with L*CuCH­(Me)­Ph, with the change in kinetic regime which arises from the partial accumulation of the latter as the alcohol is depleted. The primary KIE for the deprotonation step was determined as k H/k D = 8.0 through intramolecular competition (Figure , II), in agreement with theoretical calculations (Figure ).

4. Alkoxide and Alcohol Substituent Effects

Further details on the elementary reaction of L*CuOR S with (nBu)3SiH were obtained from linear free energy relationships (LFERs), determined using p-substituted copper alkoxides generated via equilibration with the corresponding alcohols, (S)-1a (X = F), (S)-1b (X = H), (S)-1c (X = Me), (S)-1d (X = OMe), and (S)-1e (X = CF3). Copper alkoxides bearing an electron-withdrawing aromatic substituent react preferentially in intermolecular competition experiments (Figure , I). However, the difference in reactivity is small, with ρ = +0.6 using standard Hammett substituent parameters.

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Substituent effects of p- substituted derivatives of (S)-1. Hammett correlation of intermolecular competition experiments between pairs of (S)-1 derivatives (I), and independent reactions of alcohols (S)-1 (II, p-substituent X: a = F, b = H, c = Me, d = OMe, e = CF3). Experimental data (circles) and a linear extrapolation from the initial slope of the reaction (∼10% conversion) are shown in (II) for the independent reactions.

In contrast to the competition experiments, independent reactions of the alcohols (S)-1 undergo faster turnover when they have electron donating aromatic substituents (Figure , II, see Supporting Information Section 4.4 for detailed discussion). The faster reacting systems (X = H, Me, OMe) depart at an earlier stage from the pseudozero-order kinetic regime. Conversely, the reaction of (S)-1e (X = CF3) undergoes acceleration as (S)-1e is consumed. The data indicate that, under conditions where [(S)-1]0/[(nBu)3SiH]0 ≈ 1, the concentration range enabling pseudozero-order kinetics is alcohol-dependent. These features likely result from competing interactions, as while alcohols with electron-withdrawing group (EWG) substituents form L*CuOR complexes which are more reactive toward (nBu)3SiH, they also inhibit turnover by more strongly favoring the formation of off-cycle resting state complexes L*CuOR·ROH. A resting state in which ROH acts as an H-bond donor to a Cu-alkoxide oxygen acceptor (Figure ) is consistent with the observed electronic effects and kinetic behavior. The free energy difference for inhibition, ΔG Inhib , increases when X = EWG, while the relative barrier for turnover, ΔG ‡ TS , decreases. The opposite effects are induced when X = EDG. Thus, in intermolecular competition where all preceding equilibria are rapid, the relative rates are determined by Δ­(ΔG ‡ TS ) (Figure , I), whereas relative reaction rates for the substrates in isolation (Figure , II) are governed by Δ­(ΔG Inhib + ΔG ‡ TS ). This model rationalizes the alcohol-dependent concentration windows within which pseudozero-order kinetic regimes persist, consistent with differences in ΔG Inhib across alcohols. The acceleration (X = CF3, F), and deceleration (X = OMe, Me, H) observed with alcohol conversion reflect that ΔG Inhib is more sensitive to substituent X than ΔG ‡ TS , in agreement with Hammett and Swain-Lupton analyses (see Supporting Information Section 4.4 for detailed discussion).

5. Kinetic Model

A minimal kinetic model that accounts for all of the experimental features of the Cu-catalyzed reaction of (S)-1a and (nBu)3SiH in the presence of styrene was constructed using a local parameter solution from simultaneous least-squares fits across multiple data sets (Figure ). The model assumes that the precatalyst, L*CuOtBu, is rapidly and irreversibly converted to L*CuOR S (k act, see Supporting Information Section 8.3 for discussion), consistent with generated tBuOH being at low concentrations and likely a poor inhibitor and substrate (see Section 4). Additionally, the model assumes no off-cycle higher-order aggregates of (S)-1a in order to avoid a model prone to overfitting. Equilibration of L*CuOR S with the off-cycle hydrogen-bonded adduct [L*CuOR S ·(S)-1a] (K i) and of its higher homologue [L*CuOR S ·(S)-1a·(S)-1a] (K’i) accounts for the inhibition by (S)-1a, with the latter included to better account for increasing inhibition at high (S)-1a concentrations. The on-cycle copper alkoxide L*CuOR S reacts with (nBu)3SiH via Si–H/Cu–O σ-bond metathesis to generate (S)-2a and L*CuH (k 1). There are two pathways for L*CuOR S regeneration from L*CuH: hydrocupration of styrene (k 2) followed by deprotonation of (S)-1a by L*CuCH­(Me)­Ph (k 3), or direct deprotonation of (S)-1a by L*CuH (k 4). Furthermore, a pathway for L*CuH deactivation through dimerization was included (k dim, see Supporting Information Section 3.3 for discussion).

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Kinetic model for reactions of (S)-1a (Top) and comparison of simulation (lines) with experimental data (open circles, 1H NMR spectroscopy, [(S)-2a] t , initial conditions: [Cu]0 = 0.005 M (I–VI). [styrene]0 = 0.27 M (I–VI). [(S)-1a]0 = 0.2 M (I–III), 0.32 M (IV), 0.41 M (V), 0.65 M (VI), [(nBu)3SiH]0 = 0.4 M (I), 0.27 M (II), 0.2 M (III–VI) (Bottom). For fitted kinetic parameters see Supporting Information Section 8.1.

The model satisfactorily correlates with experimental data across a broad range of conditions, including the acceleration of reactions when [(S)-1a]0/[(nBu)3SiH]0 < 1, and deceleration when [(S)-1a]0/[(nBu)3SiH]0 > 1 (Figure ). Although k 1 is at least an order of magnitude larger than the other major on-cycle rate coefficients, k 2, k 3, k 4, and k dim, under most conditions the dominant resting state is off-cycle because K i/k 1 ≈ 4 × 102 s. The latter accounts for the earlier departure from the pseudozero-order kinetic regime with (S)-1a-O D versus (S)-1a, and changes in catalyst speciation detected by 1H and 31P­{1H} NMR spectroscopy when [(S)-1a] t approaches [Cu]0. Furthermore, the model is fully applicable to (R)-1a based on the obtained (R)-1a data (see Supporting Information Section 8.1 for discussion).

6. Computational Investigations

DFT calculations were employed to elucidate the observed experimental trends and verify the feasibility of proposed intermediates (see Figure , A for full catalytic cycle and Supporting Information Section 7.1 for computational details). The calculations indicate that all of the H-bonded adducts, [L*CuOR·1a], are more stable than the parent monomeric copper alkoxides, and are therefore the major resting state under the reaction conditions. Coordination of the alcohol oxygen atom to the Cu center was found to be ≥ 3 kcal·mol–1 less favorable than the proposed H-bonding inhibition mode (see Supporting Information Section 7.2). The homologated inhibition adduct of (S)-1a, [L*CuOR S ·(S)-1a·(S)-1a], employed in the kinetic model to account for stronger inhibition at high (S)-1a concentrations (Figure ) was predicted to be –0.6 kcal·mol–1 more favorable than [L*CuOR S ·(S)-1a]. While this indicates that higher-order inhibition effects through this mode are feasible, these will only be evident when (S)-1a is present at high concentrations. Dissociation of inhibited species to the reactive copper-alkoxide L*CuOR is followed by σ-bond metathesis with (nBu)3SiH via TS-I (ΔG ‡ S = 16.8 kcal·mol–1, ΔG ‡ R = 17.7 kcal·mol–1), forming silyl ether 2a and L*CuH. , The L*CuH coproduct reacts with styrene via TS-II to form (R)-isophenethyl copper, L*Cu-(R)–CH­(Me)­Ph (ΔG ‡ = 8.4 kcal·mol–1), which subsequently deprotonates 1a in TS-III (ΔG ‡ S = 17.6 kcal·mol–1, ΔG ‡ R = 19.6 kcal·mol–1), regenerating L*CuOR and irreversibly generating PhEt.

The reactions of both 1a enantiomers have large magnitude, negative free energies of turnover (ΔG Cycle ) (S)-1a = –41.9 kcal·mol–1, ΔG Cycle (R)-1a = –39.3 kcal·mol–1 relative to the L*CuORS reference state), in agreement with an overall irreversible reaction. Alternatively, L*CuH may react directly with either enantiomer of 1a via TS-IV to form L*CuOR and H2 (ΔG ‡ S = 9.2 kcal·mol–1, ΔG ‡ R = 11.5 kcal·mol–1), and free energies of turnover calculated for this pathway are still indicative of an overall irreversible reaction (ΔG Cycle S-1a = –16.0kcal·mol–1, ΔG Cycle R-1a = –13.4 kcal·mol–1relative to the L*CuORS reference state).

Eyring activation parameters calculated for TS-I (from L*CuOR S ·(S)-1a as the ground state, ΔH‡ = 16 kcal·mol–1, ΔS‡ = –12 cal·K–1·mol–1) as well as KIEs calculated for TS-I and TS-III (Figure , A) are in good agreement with the experimentally determined values (Figure and Figure ). Translation of the computed standard state free energies for species in Figure into rate and equilibrium constants for the kinetic model in Figure results in holistic qualitative agreement with experimental observations. These include the predicted speciation of L*CuX (Figure , B), and the extent and direction of curvature in the evolution of temporal concentrations (Figure , C). Overall, the agreement with the experimental kinetic model indicates that the manifested computational errors are mostly systematic in nature.

Conclusion

The kinetics and mechanism of the copper-catalyzed dehydrogenative silylation of (S)-1-(4-fluorophenyl)­ethanol, (S)-1a, with tri-n-butylhydrosilane, (nBu)3SiH (Figure ), using styrene to undergo hydrocupration and avoid H2 generation, have been investigated using 1H and 19F­{1H} NMR spectroscopy reaction monitoring, isotopic labeling, and computation. Initial experimental evidence showed styrene insertion into a copper hydride intermediate to be rapid and [styrene]0 not to affect the reaction kinetics when used in excess. Increasing values of [(nBu)3SiH]0 and [Cu]0 showed a positive correlation with reaction rate. Conversely, the alcohol substrate was found to be an inhibitor, with the observed reaction rate correlating negatively with [(S)-1a]0. Consequently, the substrate ratio [(S)-1a]0/[(nBu)3SiH]0 governs the observed macrokinetic regime, with values close to unity resulting in pseudozero-order temporal concentration profiles (Figure ).

A similar kinetic regime was observed with the slower reacting enantiomer (R)-1a (see Supporting Information Figure S9, Entry 16), but not with racemic 1a (Figure , I), which elicited biphasic kinetics that tended toward linear after full consumption of (S)-1a (see Supporting Information Section 3.4). This was interpreted as evidence that the speciation of the catalyst resting state is enantiomer dependent in the reactions of 1a. Addition of a racemization catalyst, Ru­(CNN)­(dppb)­OtBu, resulted in a temporal concentration profile of rac-1a that was virtually identical to that of (S)-1a (Figure , II and III). This is consistent with the hypothesis that constant enantiomeric ratio results in constant speciation of the catalyst resting state, and that the catalyst resting state in the DKR experiment is identical or of comparable energy to that of reactions involving only (S)-1a (see Supporting Information Section 3.5).

The relative rate of the substrate-committing elementary reactions of the two enantiomers of the alcohol was determined as k S/k R = 7.4 using pseudoracemic mixtures of isotopically labeled 1a enantiomers (Figure , I and II) and correcting for the kinetic isotope effect resulting from deuteriation at the benzylic carbon. The relative rate was also estimated directly by 19F­{1H} NMR reaction monitoring of the reaction of rac-1a (see Supporting Information Sections 3.4 and 4.5). It was also observed that an increased ligand loading did not affect the overall kinetics or enantioselectivity of the process (see Supporting Information Section 4.5). The k S/k R value significantly differed from the macrokinetic value obtained from independent reactions of enantiopure (R)-1a and (S)-1a (v 0,S /v 0,R = 4.3). Unlike macrokinetic rates v 0, values of k S/k R do not depend on the catalyst resting state, but only on relative product-committing transition state energies. This difference provides compelling evidence that the catalyst resting state speciation is a function of the evolving enantiomeric composition of 1a. The effects of changes in temperature and isotopic substitution at reactive sites were investigated over a temperature range of 288–308 K (Figure , I), yielding the enthalpy (ΔH‡ = 14 kcal·mol–1) and entropy of activation (ΔS‡ = −23 cal·K–1·mol–1). Additionally, H/D KIEs were observed for (S)-1a/(S)-1a-O D (k H/k D = 8.0, Figure , II), and (nBu)3SiH/(nBu)3SiD (k H/k D = 1.3, Figure , III) in intermolecular competition experiments. The activation parameters and Si–H/D KIE are consistent with a highly ordered transition state with loss of translational degrees of freedom, while the O–H/D KIE value is consistent with a strong change in vibrational properties in the transition state relative to the ground state, such as in a deprotonation step.

The reaction kinetics for (S)-1 derivatives bearing other substituents than fluorine ((S)-1b–e) in their aromatic ring were subsequently investigated. For intermolecular competitions the electron-richer alcohols react slower (Figure , I). Conversely, in their independent reactions the electron-richer (S)-1 alcohols generally react faster (Figure , II). This shows that different factors govern catalyst inhibition and substrate-committing reactivity. Modes of inhibition and reactivity that are holistically consistent with experimental observations include inhibition of the catalytically active species L*CuOR S via H-bonding, and a substrate-committing step involving Si–H/Cu–O σ-bond metathesis (Figure ).

A minimal kinetic model accounting for all experimental observations was developed and shown to correlate well with the experimental data (Figure ). The reaction of 1a was also investigated with theoretical calculations in broad agreement with experimental observations, reproducing measured H/D KIEs, the relative energies of elementary steps, and the overall enantioselectivity. Moreover, when the experimental kinetic model was applied using the energies obtained from theoretical calculations, the computed catalytic cycle is in good agreement with the predicted catalyst speciation (Figure ).

These mechanistic investigations have resulted in a holistic representation of the general reactivity in systems containing secondary benzylic alcohols, (nBu)3SiH, styrene, and L*CuOtBu in benzene, and the general features identified are expected to be applicable across various secondary alcohols with comparable electronics and across hydrosilanes of comparable hydricity. While substrate inhibition by derivatives of 1 undergoing kinetic resolution limits the turnover rates, this can be attenuated by slow addition of 1 to stoichiometric quantities of (nBu)3SiH in the presence of a racemization cocatalyst, e.g., Ru­(CNN)­(dppb)­OtBu. Furthermore, it was found that the absence of styrene from the reaction mixture resulted in eventual stalling and potential catalyst deactivation (see Supporting Information Section 3.3) while generating stoichiometric, potentially hazardous quantities of H2. Overall, it is shown that a combination of a racemization catalyst (such as Ru­(CNN)­(dppb)­OtBu) and styrene, or other substrates able to efficiently undergo hydrocupration at comparable rates, are unlikely to compromise the process kinetics of benzylic secondary alcohols while improving overall efficiency and safety.

Supplementary Material

ja5c14937_si_001.pdf (7.3MB, pdf)
ja5c14937_si_002.xyz (322.7KB, xyz)

Acknowledgments

We thank Dr. Sebastian Kemper (TU Berlin) for his expert advice on NMR measurements, and Dr. Andrés García-Domínguez (University of Edinburgh) for fruitful discussions. We also thank Lisa A. Böser (TU Berlin) for her help with the organization of the collected data at the beginning of the manuscript writing. This research was supported by the Deutsche Forschungsgemeinschaft (Oe 249/14-1) and the Fonds der Chemischen Industrie (predoctoral fellowship to J.S., 2018–2020). M.O. is indebted to the Einstein Foundation Berlin for an endowed professorship. G.W. thanks the National Natural Science Foundation of China for financial support (Grant No. 22273035). G.C.L-J. thanks the EPSRC Programme Grant “Boron: Beyond the Reagent” (EP/W007517). P.H.H.O. thanks the University of Edinburgh for the Edinburgh Global Research Scholarship. We thank the High-Performance Computing Center (HPCC) of Nanjing University and the University of Edinburgh Compute and Data Facility (ECDF) for computing resources.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.5c14937.

  • Experimental details, reaction profiles, and characterization data, as well as computational details (PDF)

  • Computational geometries (XYZ)

The authors declare no competing financial interest.

References

  1. For selected reviews on the use of copper hydride in synthesis, see:; a Pirnot M. T., Wang Y., Buchwald S. L.. Copper Hydride Catalyzed Hydroamination of Alkenes and Alkynes. Angew. Chem. Int. Ed. 2016;55:48–57. doi: 10.1002/anie.201507594. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Dherbassy Q., Manna S., Talbot F. J. T., Prasitwatcharakorn W., Perry G. J. P., Procter D. J.. Copper-catalyzed functionalization of enynes. Chem. Sci. 2020;11:11380–11393. doi: 10.1039/D0SC04012F. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Garduño J. A., García J. J.. Homogeneous Copper Catalysts for Hydrogenation and Hydrofunctionalization of Carbonyl Compounds, CO2, CC Bonds, and Alkynes. ChemCatChem. 2025;17:e202401693. doi: 10.1002/cctc.202401693. [DOI] [Google Scholar]
  2. The nature of the active catalyst was not discussed, and the procedure did not initially attract any attention; see:; Brunner H., Miehling W.. J. Organomet. Chem. 1984;275:C17–C21. doi: 10.1016/0022-328X(84)85066-4. [DOI] [Google Scholar]
  3. For an overview on copper(I)-alkoxide chemistry, see:; a Tsuda T., Hashimoto T., Saegusa T.. Cuprous tert-Butoxide. A New and Useful Metalation Reagent. J. Am. Chem. Soc. 1972;94:658–659. doi: 10.1021/ja00757a069. [DOI] [Google Scholar]; b Whitesides G. M., Sadowski J. S., Lilburn J.. Copper­(I) alkoxides. Synthesis, reactions, and thermal decompositions. J. Am. Chem. Soc. 1974;96:2829–2835. doi: 10.1021/ja00816a027. [DOI] [Google Scholar]; c Danopoulos A. A., Simler T., Braunstein P.. N-Heterocyclic Carbene Complexes of Copper, Nickel, and Cobalt. Chem. Rev. 2019;119:3730–3961. doi: 10.1021/acs.chemrev.8b00505. [DOI] [PubMed] [Google Scholar]; d Lazreg F., Nahra F., Cazin C. S. J.. Copper–NHC Complexes in Catalysis. Coord. Chem. Rev. 2015;293–294:48–79. doi: 10.1016/j.ccr.2014.12.019. [DOI] [Google Scholar]
  4. a Mahoney W. S., Brestensky D. M., Stryker J. M.. Selective Hydride-Mediated Conjugate Reduction of α,β-Unsaturated Carbonyl Compounds Using [(Ph3P)­CuH]6 . J. Am. Chem. Soc. 1988;110:291–293. doi: 10.1021/ja00209a048. [DOI] [Google Scholar]; b Mahoney W. S., Stryker J. M.. Hydride-Mediated Homogeneous Catalysis. Catalytic Reduction of α,β-Unsaturated Ketones Using [(Ph3P)­CuH]6 and H2 . J. Am. Chem. Soc. 1989;111:8818–8823. doi: 10.1021/ja00206a008. [DOI] [Google Scholar]
  5. Lipshutz B. H., Keith J., Papa P., Vivian R.. A convenient, efficient method for conjugate reductions using catalytic quantities of Cu­(I) Tetrahedron Lett. 1998;39:4627–4630. doi: 10.1016/S0040-4039(98)00855-7. [DOI] [Google Scholar]
  6. For representative reviews on copper hydride catalysis, see:; a Jordan A. J., Lalic G., Sadighi J. P.. Coinage Metal Hydrides: Synthesis, Characterization, and Reactivity. Chem. Rev. 2016;116:8318–8372. doi: 10.1021/acs.chemrev.6b00366. [DOI] [PubMed] [Google Scholar]; b Deutsch C., Krause N., Lipshutz B. H.. CuH-Catalyzed Reactions. Chem. Rev. 2008;108:2916–2927. doi: 10.1021/cr0684321. [DOI] [PubMed] [Google Scholar]; c Rendler S., Oestreich M.. Polishing a Diamond in the Rough: “Cu–H” Catalysis with Silanes. Angew. Chem., Int. Ed. 2007;46:498–504. doi: 10.1002/anie.200602668. [DOI] [PubMed] [Google Scholar]
  7. For selected examples, see:; a Lipshutz B. H., Noson K., Chrisman W.. Ligand-Accelerated, Copper-Catalyzed Asymmetric Hydrosilylations of Aryl Ketones. J. Am. Chem. Soc. 2001;123:12917–12918. doi: 10.1021/ja011529e. [DOI] [PubMed] [Google Scholar]; b Lipshutz B. H., Lower A., Noson K.. Copper­(I) Hydride-Catalyzed Asymmetric Hydrosilylation of Heteroaromatic Ketones. Org. Lett. 2002;4:4045–4048. doi: 10.1021/ol026755n. [DOI] [PubMed] [Google Scholar]; c Lipshutz B. H., Noson K., Chrisman W., Lower A.. Asymmetric Hydrosilylation of Aryl Ketones Catalyzed by Copper Hydride Complexed by Nonracemic Biphenyl Bis-phosphine Ligands. J. Am. Chem. Soc. 2003;125:8779–8789. doi: 10.1021/ja021391f. [DOI] [PubMed] [Google Scholar]
  8. For selected examples, see:; a Appella D. H., Moritani Y., Shintani R., Ferreira E. M., Buchwald S. L.. Asymmetric Conjugate Reduction of α,β-Unsaturated Esters Using a Chiral Phosphine–Copper Catalyst. J. Am. Chem. Soc. 1999;121:9473–9474. doi: 10.1021/ja992366l. [DOI] [Google Scholar]; b Moritani Y., Appella D. H., Jurkauskas V., Buchwald S. L.. Synthesis of β-Alkyl Cyclopentanones in High Enantiomeric Excess via Copper-Catalyzed Asymmetric Conjugate Reduction. J. Am. Chem. Soc. 2000;122:6797–6798. doi: 10.1021/ja0009525. [DOI] [Google Scholar]; c Hughes G., Kimura M., Buchwald S. L.. Catalytic Enantioselective Conjugate Reduction of Lactones and Lactams. J. Am. Chem. Soc. 2003;125:11253–11258. doi: 10.1021/ja0351692. [DOI] [PubMed] [Google Scholar]; d Lipshutz B. H., Servesko J. M.. CuH-Catalyzed Asymmetric Conjugate Reductions of Acyclic Enones. Angew. Chem., Int. Ed. 2003;42:4789–4792. doi: 10.1002/anie.200352313. [DOI] [PubMed] [Google Scholar]; e Czekelius C., Carreira E. M.. Catalytic Enantioselective Conjugate Reduction of β,β-Disubstituted Nitroalkenes. Angew. Chem., Int. Ed. 2003;42:4793–4795. doi: 10.1002/anie.200352175. [DOI] [PubMed] [Google Scholar]; f Lipshutz B. H., Servesko J. M., Petersen T. B., Papa P. P., Lover A. A.. Asymmetric 1,4-Reductions of Hindered β-Substituted Cycloalkenones Using Catalytic SEGPHOS–Ligated CuH. Org. Lett. 2004;6:1273–1275. doi: 10.1021/ol0400185. [DOI] [PubMed] [Google Scholar]; g Lipshutz B. H., Servesko J. M., Taft B. R.. Asymmetric 1,4-Hydrosilylations of α,β-Unsaturated Esters. J. Am. Chem. Soc. 2004;126:8352–8353. doi: 10.1021/ja049135l. [DOI] [PubMed] [Google Scholar]; h Czekelius C., Carreira E. M.. Convenient Catalytic, Enantioselective Conjugate Reduction of Nitroalkenes Using CuF2 . Org. Lett. 2004;6:4575–4577. doi: 10.1021/ol048035h. [DOI] [PubMed] [Google Scholar]
  9. For selected examples, see: additions to aldehydes and ketones:; a Deschamp J., Chuzel O., Hannedouche J., Riant O.. Highly Diastereo- and Enantioselective Copper-Catalyzed Domino Reduction/Aldol Reaction of Ketones with Methyl Acrylate. Angew. Chem., Int. Ed. 2006;45:1292–1297. doi: 10.1002/anie.200503791. [DOI] [PubMed] [Google Scholar]; b Chuzel O., Deschamp J., Chausteur C., Riant O.. Copper­(I)-Catalyzed Enantio- and Diastereoselective Tandem Reductive Aldol Reaction. Org. Lett. 2006;8:5943–5946. doi: 10.1021/ol062398v. [DOI] [PubMed] [Google Scholar]; c Saxena A., Choi B., Lam H. W.. Enantioselective Copper-Catalyzed Reductive Coupling of Alkenylazaarenes with Ketones. J. Am. Chem. Soc. 2012;134:8428–8431. doi: 10.1021/ja3036916. [DOI] [PubMed] [Google Scholar]; d Yang Y., Perry I. B., Lu G., Liu P., Buchwald S. L.. Copper-catalyzed asymmetric addition of olefin-derived nucleophiles to ketones. Science. 2016;353:144–150. doi: 10.1126/science.aaf7720. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Li C., Liu R. Y., Jesikiewicz L. T., Yang Y., Liu P., Buchwald S. L.. CuH-Catalyzed Enantioselective Ketone Allylation with 1,3-Dienes: Scope, Mechanism, and Applications. J. Am. Chem. Soc. 2019;141:5062–5070. doi: 10.1021/jacs.9b01784. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Li C., Shin K., Liu R. Y., Buchwald S. L.. Engaging Aldehydes in CuH-Catalyzed Reductive Coupling Reactions: Stereoselective Allylation with Unactivated 1,3-Diene Pronucleophiles. Angew. Chem., Int. Ed. 2019;58:17074–17080. doi: 10.1002/anie.201911008. [DOI] [PMC free article] [PubMed] [Google Scholar]; Additions to imines:; g Du Y., Xu L.-W., Shimizu Y., Oisaki K., Kanai M., Shibasaki M.. Asymmetric Reductive Mannich Reaction to Ketimines Catalyzed by a Cu­(I) Complex. J. Am. Chem. Soc. 2008;130:16146–16147. doi: 10.1021/ja8069727. [DOI] [PubMed] [Google Scholar]; h Yang Y., Perry I. B., Buchwald S. L.. Copper-Catalyzed Enantioselective Addition of Styrene-Derived Nucleophiles to Imines Enabled by Ligand-Controlled Chemoselective Hydrocupration. J. Am. Chem. Soc. 2016;138:9787–9790. doi: 10.1021/jacs.6b06299. [DOI] [PMC free article] [PubMed] [Google Scholar]; Nucleophilic substitutions on alkyl bromides, allyl phosphates and chlorides, and carboxylic anhydrides:; i Wang Y.-M., Bruno N. C., Placeres Á. L., Zhu S., Buchwald S. L.. Enantioselective Synthesis of Carbo- and Heterocycles through a CuH-Catalyzed Hydroalkylation Approach. J. Am. Chem. Soc. 2015;137:10524–10527. doi: 10.1021/jacs.5b07061. [DOI] [PMC free article] [PubMed] [Google Scholar]; j Han J. T., Jang W. J., Kim N., Yun J.. Asymmetric Synthesis of Borylalkanes via Copper-Catalyzed Enantioselective Hydroallylation. J. Am. Chem. Soc. 2016;138:15146–15149. doi: 10.1021/jacs.6b11229. [DOI] [PubMed] [Google Scholar]; k Kojima Y., Miura M., Hirano K.. Copper-Catalyzed Regio- and Enantioselective Hydroallylation of 1-Trifluoromethylalkenes: Effect of Crown Ether. ACS Catal. 2021;11:11663–11670. doi: 10.1021/acscatal.1c02947. [DOI] [Google Scholar]; l Bandar J. S., Ascic E., Buchwald S. L.. Enantioselective CuH-Catalyzed Reductive Coupling of Aryl Alkenes and Activated Carboxylic Acids. J. Am. Chem. Soc. 2016;138:5821–5824. doi: 10.1021/jacs.6b03086. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. For selected examples, see: formal hydroamination:; a Miki Y., Hirano K., Satoh T., Miura M.. Copper-Catalyzed Intermolecular Regioselective Hydroamination of Styrenes with Polymethylhydrosiloxane and Hydroxylamines. Angew. Chem., Int. Ed. 2013;52:10830–10834. doi: 10.1002/anie.201304365. [DOI] [PubMed] [Google Scholar]; b Zhu S., Niljianskul N., Buchwald S. L.. Enantio- and Regioselective CuH-Catalyzed Hydroamination of Alkenes. J. Am. Chem. Soc. 2013;135:15746–15749. doi: 10.1021/ja4092819. [DOI] [PMC free article] [PubMed] [Google Scholar]; Hydroboration:; c Noh D., Chea H., Ju J., Yun J.. Highly Regio- and Enantioselective Copper-Catalyzed Hydroboration of Styrenes. Angew. Chem., Int. Ed. 2009;48:6062–6064. doi: 10.1002/anie.200902015. [DOI] [PubMed] [Google Scholar]; d Xi Y., Hartwig J. F.. Diverse Asymmetric Hydrofunctionalization of Aliphatic Internal Alkenes through Catalytic Regioselective Hydroboration. J. Am. Chem. Soc. 2016;138:6703–6706. doi: 10.1021/jacs.6b02478. [DOI] [PubMed] [Google Scholar]; Hydrosilylation:; e Gribble M. W. Jr., Pirnot M. T., Bandar J. S., Liu R. Y., Buchwald S. L.. Asymmetric Copper Hydride-Catalyzed Markovnikov Hydrosilylation of Vinylarenes and Vinyl Heterocycles. J. Am. Chem. Soc. 2017;139:2192–2195. doi: 10.1021/jacs.6b13029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. For recent reviews, see:; a Hirano K., Miura M.. Hydroamination, Aminoboration, and Carboamination with Electrophilic Amination Reagents: Umpolung-Enabled Regio- and Stereoselective Synthesis of N-Containing Molecules from Alkenes and Alkynes. J. Am. Chem. Soc. 2022;144:648–661. doi: 10.1021/jacs.1c12663. [DOI] [PubMed] [Google Scholar]; b Wang H., Buchwald S. L.. Copper Catalyzed, Enantioselective Hydrofunctionalization of Alkenes. Org. React. 2019;100:121–205. doi: 10.1002/0471264180.or100.03. [DOI] [Google Scholar]
  12. For selected mechanistic studies of copper hydride-catalyzed ketone hydrosilylations, see:; a Díez-González S., Stevens E. D., Scott N. M., Petersen J. L., Nolan S. P.. Synthesis and Characterization of [Cu­(NHC)2]­X Complexes: Catalytic and Mechanistic Studies of Hydrosilylation Reactions. Chem.Eur. J. 2008;14:158–168. doi: 10.1002/chem.200701013. [DOI] [PubMed] [Google Scholar]; b Gathy T., Peeters D., Leyssens T.. Mechanism of ketone hydrosilylation by Cu­(I) catalysts: A theoretical study. J. Organomet. Chem. 2009;694:3943–3950. doi: 10.1016/j.jorganchem.2009.08.017. [DOI] [Google Scholar]; c Issenhuth J.-T., Notter F.-P., Dagorne S., Dedieu A., Bellemin-Laponnaz S.. Mechanistic Studies on the Copper-Catalyzed Hydrosilylation of Ketones. Eur. J. Inorg. Chem. 2010:529–541. doi: 10.1002/ejic.200900961. [DOI] [Google Scholar]; d Vergote T., Nahra F., Merschaert A., Riant O., Peeters D., Leyssens T.. Mechanistic Insight into the (NHC)­copper­(I)-Catalyzed Hydrosilylation of Ketones. Organometallics. 2014;33:1953–1963. doi: 10.1021/om401097q. [DOI] [Google Scholar]; e Trose M., Nahra F., Poater A., Cordes D. B., Slawin A. M. Z., Cavallo L., Cazin C. S. J.. Investigating the Structure and Reactivity of Azolyl-Based Copper­(I)–NHC Complexes: The Role of the Anionic Ligand. ACS Catal. 2017;7:8176–8183. doi: 10.1021/acscatal.7b02737. [DOI] [Google Scholar]; f Tran B. L., Neisen B. D., Speelman A. L., Gunasekara T., Wiedner E. S., Bullock R. M.. Mechanistic Studies on the Insertion of Carbonyl Substrates into Cu-H: Different Rate-Limiting Steps as a Function of Electrophilicity. Angew. Chem., Int. Ed. 2020;59:8645–8653. doi: 10.1002/anie.201916406. [DOI] [PubMed] [Google Scholar]; g Xu G., Leloux S., Zhang P., Meijide Suárez J., Zhang Y., Derat E., Ménand M., Bistri-Aslanoff O., Roland S., Leyssens T., Riant O., Sollogoub M.. Capturing the Monomeric (L)­CuH in NHC-Capped Cyclodextrin: Cavity-Controlled Chemoselective Hydrosilylation of α,β-Unsaturated Ketones. Angew. Chem., Int. Ed. 2020;59:7591–7597. doi: 10.1002/anie.202001733. [DOI] [PubMed] [Google Scholar]; h Speelman A. L., Tran B. L., Erickson J. D., Vasiliu M., Dixon D. A., Bullock R. M.. Accelerating the insertion reactions of (NHC)­Cu–H via remote ligand functionalization. Chem. Sci. 2021;12:11495–11505. doi: 10.1039/D1SC01911B. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. For selected mechanistic studies of copper hydride-catalyzed, enantioselective (formal) alkene hydrofunctionalizations and reductive couplings with carbon electrophiles, see: formal hydroamination:; a Bandar J. S., Pirnot M. T., Buchwald S. L.. Mechanistic Studies Lead to Dramatically Improved Reaction Conditions for the Cu-Catalyzed Asymmetric Hydroamination of Olefins. J. Am. Chem. Soc. 2015;137:14812–14818. doi: 10.1021/jacs.5b10219. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Tobisch S.. CuH-Catalysed Hydroamination of Styrene with Hydroxylamine Esters: A Coupled Cluster Scrutiny of Mechanistic Pathways. Chem.Eur. J. 2016;22:8290–8300. doi: 10.1002/chem.201600230. [DOI] [PubMed] [Google Scholar]; c Lu G., Liu R. Y., Yang Y., Fang C., Lambrecht D. S., Buchwald S. L., Liu P.. Ligand–Substrate Dispersion Facilitates the Copper-Catalyzed Hydroamination of Unactivated Olefins. J. Am. Chem. Soc. 2017;139:16548–16555. doi: 10.1021/jacs.7b07373. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Thomas A. A., Speck K., Kevlishvili I., Lu Z., Liu P., Buchwald S. L.. Mechanistically Guided Design of Ligands That Significantly Improve the Efficiency of CuH-Catalyzed Hydroamination Reactions. J. Am. Chem. Soc. 2018;140:13976–13984. doi: 10.1021/jacs.8b09565. [DOI] [PMC free article] [PubMed] [Google Scholar]; Hydroboration:; e Van Hoveln R., Hudson B. M., Wedler H. B., Bates D. M., Le Gros G., Tantillo D. J., Schomaker J. M.. Mechanistic Studies of Copper­(I)-Catalyzed 1,3-Halogen Migration. J. Am. Chem. Soc. 2015;137:5346–5354. doi: 10.1021/ja511236d. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Xi Y., Hartwig J. F.. Mechanistic Studies of Copper-Catalyzed Asymmetric Hydroboration of Alkenes. J. Am. Chem. Soc. 2017;139:12758–12772. doi: 10.1021/jacs.7b07124. [DOI] [PMC free article] [PubMed] [Google Scholar]; Additions of alkene-derived nucleophiles to pyridines:; g Gribble M. W. Jr., Liu R. Y., Buchwald S. L.. Evidence for Simultaneous Dearomatization of Two Aromatic Rings under Mild Conditions in Cu­(I)-Catalyzed Direct Asymmetric Dearomatization of Pyridine. J. Am. Chem. Soc. 2020;142:11252–11269. doi: 10.1021/jacs.0c04486. [DOI] [PMC free article] [PubMed] [Google Scholar]; For a related study on the influence of reversible copper hydride elimination from monoborylated alkyl copper intermediates on the enantioselectivity, see:; h Lee J., Radomkit S., Torker S., del Pozo J., Hoveyda A. H.. Mechanism-based enhancement of scope and enantioselectivity for reactions involving a copper-substituted stereogenic carbon centre. Nat. Chem. 2018;10:99–108. doi: 10.1038/nchem.2861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. a Rendler S., Auer G., Oestreich M.. Kinetic Resolution of Chiral Secondary Alcohols by Dehydrogenative Coupling with Recyclable Silicon-Stereogenic Silanes. Angew. Chem., Int. Ed. 2005;44:7620–7624. doi: 10.1002/anie.200502631. [DOI] [PubMed] [Google Scholar]; b Klare H. F. T., Oestreich M.. Chiral Recognition with Silicon-Stereogenic Silanes: Remarkable Selectivity Factors in the Kinetic Resolution of Donor-Functionalized Alcohols. Angew. Chem., Int. Ed. 2007;46:9335–9338. doi: 10.1002/anie.200703847. [DOI] [PubMed] [Google Scholar]; c Karatas B., Rendler S., Fröhlich R., Oestreich M.. Kinetic resolution of donor-functionalised tertiary alcohols by Cu–H-catalysed stereoselective silylation using a strained silicon-stereogenic silane. Org. Biomol. Chem. 2008;6:1435–1440. doi: 10.1039/b802186d. [DOI] [PubMed] [Google Scholar]; d Rendler S., Plefka O., Karatas B., Auer G., Fröhlich R., Mück-Lichtenfeld C., Grimme S., Oestreich M.. Stereoselective Alcohol Silylation by Dehydrogenative Si–O Coupling: Scope, Limitations, and Mechanism of the Cu–H-Catalyzed Non-Enzymatic Kinetic Resolution with Silicon-Stereogenic Silanes. Chem.Eur. J. 2008;14:11512–11528. doi: 10.1002/chem.200801377. [DOI] [PubMed] [Google Scholar]; e Steves A., Oestreich M.. Facile preparation of CF3-substituted carbinols with an azine donor and subsequent kinetic resolution through stereoselective Si–O coupling. Org. Biomol. Chem. 2009;7:4464–4469. doi: 10.1039/b911534j. [DOI] [PubMed] [Google Scholar]; f Weickgenannt A., Mewald M., Muesmann T. W. T., Oestreich M.. Catalytic Asymmetric Si–O Coupling of Simple Achiral Silanes and Chiral Donor-Functionalized Alcohols. Angew. Chem., Int. Ed. 2010;49:2223–2226. doi: 10.1002/anie.200905561. [DOI] [PubMed] [Google Scholar]; g Dong X., Weickgenannt A., Oestreich M.. Broad-spectrum kinetic resolution of alcohols enabled by Cu–H-catalysed dehydrogenative coupling with hydrosilanes. Nat. Commun. 2017;8:15547. doi: 10.1038/ncomms15547. [DOI] [PMC free article] [PubMed] [Google Scholar]; h Dong X., Kita Y., Oestreich M.. Kinetic Resolution of α-Hydroxy-Substituted Oxime Ethers by Enantioselective Cu–H-Catalyzed Si–O Coupling. Angew. Chem., Int. Ed. 2018;57:10728–10731. doi: 10.1002/anie.201802947. [DOI] [PubMed] [Google Scholar]; i Seliger J., Dong X., Oestreich M.. Kinetic Resolution of Tertiary Propargylic Alcohols by Enantioselective Cu–H-Catalyzed Si–O Coupling. Angew. Chem., Int. Ed. 2019;58:1970–1974. doi: 10.1002/anie.201813229. [DOI] [PubMed] [Google Scholar]; j Seliger J., Oestreich M.. Dynamic Kinetic Resolution of Alcohols by Enantioselective Silylation Enabled by Two Orthogonal Transition-Metal Catalysts. Angew. Chem. Int. Ed. 2021;60:247–251. doi: 10.1002/anie.202010484. [DOI] [PMC free article] [PubMed] [Google Scholar]; k Papadopulu Z., Oestreich M.. Kinetic Resolution of Neopentylic Secondary Alcohols by Cu–H-Catalyzed Enantioselective Silylation with Hydrosilanes. Org. Lett. 2021;23:438–441. doi: 10.1021/acs.orglett.0c03943. [DOI] [PubMed] [Google Scholar]; l Papadopulu Z., Kazeroonian N., Irran E., Oestreich M.. One out of Four: Kinetic Resolution of Stereoisomeric Mixtures of Secondary Alcohols with a Quaternary Carbon Atom in the β-Position by Cu–H-Catalyzed Enantioselective Silylation. ACS Org. Inorg. Au. 2022;2:164–168. doi: 10.1021/acsorginorgau.1c00050. [DOI] [PMC free article] [PubMed] [Google Scholar]; For a recent review, see:; m Seliger J., Oestreich M.. Making the Silylation of Alcohols Chiral: Asymmetric Protection of Hydroxy Groups. Chem.Eur. J. 2019;25:9358–9365. doi: 10.1002/chem.201900792. [DOI] [PubMed] [Google Scholar]
  15. Lorenz C., Schubert U.. An Efficient Catalyst for the Conversion of Hydrosilanes to Alkoxysilanes. Chem. Ber. 1995;128:1267–1269. doi: 10.1002/cber.19951281220. [DOI] [Google Scholar]
  16. Liu R. Y., Buchwald S. L.. CuH-Catalyzed Olefin Functionalization: From Hydroamination to Carbonyl Addition. Acc. Chem. Res. 2020;53:1229–1243. doi: 10.1021/acs.accounts.0c00164. and references cited therein. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. a Semba K., Fujihara T., Xu T., Terao J., Tsuji Y.. Copper-Catalyzed Highly Selective Semihydrogenation of Non-Polar Carbon-Carbon Multiple Bonds using a Silane and an Alcohol. Adv. Synth. Catal. 2012;354:1542–1550. doi: 10.1002/adsc.201200200. [DOI] [Google Scholar]; b Whittaker A. M., Lalic G.. Monophasic Catalytic System for the Selective Semireduction of Alkynes. Org. Lett. 2013;15:1112–1115. doi: 10.1021/ol4001679. [DOI] [PubMed] [Google Scholar]
  18. Ben-Tal Y., Boaler P. J., Dale H. J. A., Dooley R. E., Fohn N. A., Gao Y., García-Domínguez A., Grant K. M., Hall A. M. R., Hayes H. L. D., Kucharski M. M., Wei R., Lloyd-Jones G. C.. Mechanistic Analysis by NMR Spectroscopy: A Users Guide. Prog. Nucl. Magn. Reson. Spectrosc. 2022;129:28–106. doi: 10.1016/j.pnmrs.2022.01.001. [DOI] [PubMed] [Google Scholar]
  19. In a reaction performed in the absence of styrene in a closed system, stoichiometric formation of H2 (δH = 4.48 ppm) was observed. The reaction showed an initially linear temporal concentration profile, comparable to that of reactions in the presence of styrene, followed by a decrease in rate and eventual stalling of the reaction (see ).
  20. a Geiger Y., Achard T., Maisse-François A., Bellemin-Laponnaz S.. Absence of Non-Linear Effects Despite Evidence for Catalyst Aggregation. Eur. J. Org. Chem. 2021:2916–2922. doi: 10.1002/ejoc.202100183. [DOI] [Google Scholar]; b Kalow J. A., Doyle A. G.. Mechanistic Investigations of Cooperative Catalysis in the Enantioselective Fluorination of Epoxides. J. Am. Chem. Soc. 2011;133:16001–16012. doi: 10.1021/ja207256s. [DOI] [PubMed] [Google Scholar]; c Balsells J., Davis T. J., Carroll P., Walsh P. J.. Insight into the Mechanism of the Asymmetric Addition of Alkyl Groups to Aldehydes Catalyzed by Titanium–BINOLate Species. J. Am. Chem. Soc. 2002;124:10336–10348. doi: 10.1021/ja0171658. [DOI] [PubMed] [Google Scholar]
  21. For examples involving similar substrate inhibition regimes under catalytic conditions, see:; a Johnston C. P., West T. H., Dooley R. E., Reid M., Jones A. B., King E. J., Leach A. G., Lloyd-Jones G. C.. Anion-Initiated Trifluoromethylation by TMSCF3: Deconvolution of the Siliconate–Carbanion Dichotomy by Stopped-Flow NMR/IR. J. Am. Chem. Soc. 2018;140:11112–11124. doi: 10.1021/jacs.8b06777. [DOI] [PMC free article] [PubMed] [Google Scholar]; b García-Domínguez A., Helou de Oliveira P. H., Thomas G. T., Sugranyes A. R., Lloyd-Jones G. C.. Mechanism of Anion-Catalyzed C–H Silylation Using TMSCF3: Kinetically-Controlled CF3-Anionoid Partitioning As a Key Parameter. ACS Catal. 2021;11:3017–3025. doi: 10.1021/acscatal.1c00033. [DOI] [Google Scholar]; c García-Domínguez A., West T. H., Primozic J. J., Grant K. M., Johnston C. P., Cumming G. G., Leach A. G., Lloyd-Jones G. C.. Difluorocarbene Generation from TMSCF3: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions. J. Am. Chem. Soc. 2020;142:14649–14663. doi: 10.1021/jacs.0c06751. [DOI] [PubMed] [Google Scholar]; d Minshull H. B., Lloyd-Jones G. C.. TMSCF3-Mediated Conversion of Salicylates into α,α-Difluoro-3-coumaranones: Chain Kinetics, Anion-Speciation, and Mechanism. J. Org. Chem. 2023;88:17450–17460. doi: 10.1021/acs.joc.3c02219. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Jannsen N., Reiß F., Drexler H.-J., Konieczny K., Beweries T., Heller D.. The Mechanism of Rh­(I)-Catalyzed Coupling of Benzotriazoles and Allenes Revisited: Substrate Inhibition, Proton Shuttling, and the Role of Cationic vs Neutral Species. J. Am. Chem. Soc. 2024;146:12185–12196. doi: 10.1021/jacs.4c02679. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Lancaster H. G., Goodall J. C., Douglas S. P., Ashfield L. J., Duckett S. B., Perutz R. N., Weller A. S.. Platinum­(II) Phenylpyridyl Schiff Base Complexes as Latent, Photoactivated, Alkene Hydrosilylation Catalysts. ACS Catal. 2024;14:7492–7505. doi: 10.1021/acscatal.4c01353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Baratta W., Chelucci G., Gladiali S., Siega K., Toniutti M., Zanette M., Zangrando E., Rigo P.. Ruthenium­(II) Terdentate CNN Complexes: Superlative Catalysts for the Hydrogen-Transfer Reduction of Ketones by Reversible Insertion of a Carbonyl Group into the Ru–H Bond. Angew. Chem., Int. Ed. 2005;44:6214–6219. doi: 10.1002/anie.200502118. [DOI] [PubMed] [Google Scholar]
  23. The computed value (KIE H/D(S) = KIE H/D(R) = 0.95) is enantiomer independent and is of similar magnitude to the value obtained experimentally for (S)-1a (KIE H/D(S) = 0.97).
  24. Waterman R.. σ-Bond Metathesis: A 30-Year Retrospective. Organometallics. 2013;32:7249–7263. doi: 10.1021/om400760k. [DOI] [Google Scholar]
  25. Sadow A. D., Tilley T. D.. Synthesis and Characterization of Scandium Silyl Complexes of the Type Cp*2ScSiHRR‘. σ-Bond Metathesis Reactions and Catalytic Dehydrogenative Silation of Hydrocarbons. J. Am. Chem. Soc. 2005;127:643–656. doi: 10.1021/ja040141r. [DOI] [PubMed] [Google Scholar]
  26. Hansch C., Leo A., Taft R. W.. Chem. Rev. 1991;91:165–195. doi: 10.1021/cr00002a004. Values for σ para were obtained from: [DOI] [Google Scholar]
  27. All kinetic modeling was carried out using standard numerical techniques. For examples and applications, see ref . For details, see .
  28. While the experimental formation of 1a oligomers and higher-order associated structures in solution cannot be excluded, a model which accounts for discrete oligomers would result either in a too large number of elementary reactions or in inactive reservoirs of (S)-1a if no further elementary reactions are added, which would be inconsistent with the higher inhibition observed with increasing (S)-1a concentrations; see for detailed discussion.
  29. For an extensive study on L*CuH dimerization for L = NHC, see:; Ryan D. E., Fuller J. T., Patrick E. A., Erickson J. D., Speelman A. L., Carroll T. G., Schenter G. K., Ginovska B., Raugei S., Bullock R. M., Tran B. L.. Mechanistic Insights into Molecular Copper Hydride Catalysis: The Kinetic Stability of CuH Monomers toward Aggregation Is a Critical Parameter for Catalyst Performance. J. Am. Chem. Soc. 2025;147:14280–14298. doi: 10.1021/jacs.4c17955. [DOI] [PubMed] [Google Scholar]
  30. a Frisch, M. J. ; Trucks, G. W. ; Schlegel, H. B. ; Scuseria, G. E. ; Robb, M. A. ; Cheeseman, J. R. ; Scalmani, G. ; Barone, V. ; Petersson, G. A. ; Nakatsuji, H. ; Li, X. ; Caricato, M. ; Marenich, A. V. ; Bloino, J. ; Janesko, B. G. ; Gomperts, R. ; Mennucci, B. ; Hratchian, H. P. ; Ortiz, J. V. ; Izmaylov, A. F. ; Sonnenberg, J. L. ; D., Williams-Young , Ding, F. ; Lipparini, F. ; Egidi, F. ; Goings, J. ; Peng, B. ; Petrone, A. ; Henderson, T. ; Ranasinghe, D. ; Zakrzewski, V. G. ; Gao, J. ; Rega, N. ; Zheng, G. ; Liang, W. ; Hada, M. ; Ehara, M. ; Toyota, K. ; Fukuda, R. ; Hasegawa, J. ; Ishida, M. ; Nakajima, T. ; Honda, Y. ; Kitao, O. ; Nakai, H. ; Vreven, T. ; Throssell, K. ; Montgomery, J. A., Jr. , Peralta, J. E. ; Ogliaro, F. ; Bearpark, M. J. ; Heyd, J. J. ; Brothers, E. N. ; Kudin, K. N. ; Staroverov, V. N. ; Keith, T. A. ; Kobayashi, R. ; Normand, J. ; Raghavachari, K. ; Rendell, A. P. ; Burant, J. C. ; Iyengar, S. S. ; Tomasi, J. ; Cossi, M. ; Millam, J. M. ; Klene, M. ; Adamo, C. ; Cammi, R. ; Ochterski, J. W. ; Martin, R. L. ; Morokuma, K. ; Farkas, O. ; Foresman, J. B. ; Fox, D. J. . Gaussian 16, Revision C.01; Gaussian, Inc.: Wallingford, CT, 2016. [Google Scholar]; b Stephens P. J., Devlin F. J., Chabalowski C. F., Frisch M. J.. Ab Initio Calculation of Vibrational Absorption and Circular Dichroism Spectra Using Density Functional Force Fields. J. Phys. Chem. 1994;98:11623–11627. doi: 10.1021/j100096a001. [DOI] [Google Scholar]; c Grimme S., Ehrlich S., Goerigk L.. Effect of the Damping Function in Dispersion Corrected Density Functional Theory. J. Comput. Chem. 2011;32:1456–1465. doi: 10.1002/jcc.21759. [DOI] [PubMed] [Google Scholar]; d Hehre W. J., Ditchfield R., Pople J. A.. Self-Consistent Molecular Orbital Methods. XII. Further Extensions of Gaussian-Type Basis Sets for Use in Molecular Orbital Studies of Organic Molecules. J. Chem. Phys. 1972;56:2257–2261. doi: 10.1063/1.1677527. [DOI] [Google Scholar]; e Francl M. M., Pietro W. J., Hehre W. J., Binkley J. S., Gordon M. S., DeFrees D. J., Pople J. A.. Self-Consistent Molecular Orbital Methods. XXIII. A Polarization-Type Basis Set for Second-Row Elements. J. Chem. Phys. 1982;77:3654–3665. doi: 10.1063/1.444267. [DOI] [Google Scholar]; f Rassolov V. A., Pople J. A., Ratner M. A., Windus T. L.. 6–31G* Basis Set for Atoms K through Zn. J. Chem. Phys. 1998;109:1223–1229. doi: 10.1063/1.476673. [DOI] [Google Scholar]; g Andrae D., Häußermann U., Dolg M., Stoll H., Preuß H.. Energy-Adjusted Ab Initio Pseudopotentials for the Second Row Elements. Theor. Chem. Acc. 1990;77:123–141. doi: 10.1007/BF01114537. [DOI] [Google Scholar]; h Luchini G., Alegre-Requena J. V., Funes-Ardoiz I., Paton R. S.. GoodVibes: Automated Thermochemistry for Heterogeneous Computational Chemistry Data. F1000Research. 2020;9:291. doi: 10.12688/f1000research.22758.1. [DOI] [Google Scholar]; i Neese F., Wennmohs F., Becker U., Riplinger C.. The ORCA Quantum Chemistry Program Package. Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2022;12:e1606. doi: 10.1002/wcms.1606. [DOI] [Google Scholar]; j Mardirossian N., Head-Gordon M.. ωB97X-V: A 10-Parameter, Range-Separated Hybrid, Generalized Gradient Approximation Density Functional with Nonlocal Correlation, Designed by a Survival-of-the-Fittest Strategy. Phys. Chem. Chem. Phys. 2014;16:9904–9924. doi: 10.1039/c3cp54374a. [DOI] [PubMed] [Google Scholar]; k Marenich A. V., Cramer C. J., Truhlar D. G.. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B. 2009;113:6378–6396. doi: 10.1021/jp810292n. [DOI] [PubMed] [Google Scholar]; l Weigend F., Ahlrichs R.. Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn: Design and Assessment of Accuracy. Phys. Chem. Chem. Phys. 2005;7:3297–3305. doi: 10.1039/b508541a. [DOI] [PubMed] [Google Scholar]; m Anderson, T. L. ; Kwan, E. E. . PyQuiver. 2020; available from: www.github.com/ekwan/PyQuiver.; n Helmich-Paris B., De Souza B., Neese F., Izsák R.. An Improved Chain of Spheres for Exchange Algorithm. J. Chem. Phys. 2021;155:104109. doi: 10.1063/5.0058766. [DOI] [PubMed] [Google Scholar]; o Neese F.. An Improvement of the Resolution of the Identity Approximation for the Formation of the Coulomb Matrix. J. Comput. Chem. 2003;24:1740–1747. doi: 10.1002/jcc.10318. [DOI] [PubMed] [Google Scholar]
  31. When both enantiomers of 1a are present, enantioselectivity is determined by the absolute energy difference of TS-I for the respective enantiomers of 1a, as both transition states must be treated relative to the same global ground state. Under these conditions, ΔΔG ‡ S/R = −3.5 kcal·mol–1, which is equivalent to k S/k R ≈ 400, overestimating the experimentally obtained value of ΔΔG ‡ S/R = −1.2 kcal·mol–1 by 2.3 kcal·mol–1, a prediction still within the expected error of the ωB97X-V functional; see; Goerigk L., Hansen A., Bauer C., Ehrlich S., Najibi A., Grimme S.. A look at the density functional theory zoo with the advanced GMTKN55 database for general main group thermochemistry, kinetics and noncovalent interactions. Phys. Chem. Chem. Phys. 2017;19:32184–32215. doi: 10.1039/C7CP04913G. for details. [DOI] [PubMed] [Google Scholar]
  32. Dale H. J. A., Leach A. G., Lloyd-Jones G. C.. Heavy-Atom Kinetic Isotope Effects: Primary Interest or Zero Point? J. Am. Chem. Soc. 2021;143:21079–21099. doi: 10.1021/jacs.1c07351. Despite the larger barrier difference than that measured experimentally (see ref for details), the good agreement between computed and measured kinetic isotope effects indicates that the modeled transition state is likely a good representation of the system’s reactivity. Kinetic isotope effects are more robust diagnostic tools of given transition states as a model than their predicted free energies, as they tend to suffer less from common systematic error sources within DFT calculations, such as implicit solvation models, intrinsic functional errors, and basis set incompleteness. For a detailed discussion, see: [DOI] [PubMed] [Google Scholar]
  33. One of the reviewers noted differences in selected bond lengths between the two diastereomeric transition states TS-I-(R) (Cu–O = 2.05 Å, O–Si = 1.90 Å, Si–H = 1.62 Å, H–Cu = 1.75 Å, Cu–P = 2.28 Å and 2.30 Å) and TS-I-(S) (Cu–O = 2.14 Å, O–Si = 1.85 Å, Si–H = 1.70 Å, H–Cu = 1.66 Å, Cu–P = 2.25 Å and 2.30 Å). While these features may be consistent with poorer fit of (R)-1a within the (R,R)-BPE ligand environment, we concur with the reviewer’s caution that this and related observations on transition state metrics may be too speculative at this stage to be conclusively diagnostic.

Associated Data

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Data Citations

  1. m Anderson, T. L. ; Kwan, E. E. . PyQuiver. 2020; available from: www.github.com/ekwan/PyQuiver.

Supplementary Materials

ja5c14937_si_001.pdf (7.3MB, pdf)
ja5c14937_si_002.xyz (322.7KB, xyz)

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