Rapid Evaluation of the Mechanism of Buchwald–Hartwig Amination and Aldol Reactions Using Intramolecular ¹³C Kinetic Isotope Effects

Abstract

A practical approach is introduced for the rapid determination of ¹³C kinetic isotope effects that utilizes a “designed” reactant with two identical reaction sites. The mechanism of the Buchwald–Hartwig amination of tert-butylbromobenzene with primary and secondary amines is investigated under synthetically relevant catalytic conditions using traditional intermolecular ¹³C NMR methodology at natural abundance. Switching to 1,4-dibromobenzene, a symmetric bromoarene as the designed reactant, the same experimental ¹³C KIEs are determined using an intramolecular KIE approach. This rapid methodology for KIE determination requires substantially less material and time compared to traditional approaches. Details of the Buchwald–Hartwig amination mechanism are investigated under varying synthetic conditions, namely a variety of halides and bases. The enantioselectivity-determining step of the l-proline catalyzed aldol reaction is also evaluated using this approach. We expect this mechanistic methodology to gain traction among synthetic chemists as a practical technique to rapidly obtain high-resolution information regarding the transition structure of synthetically relevant reactions under catalytic conditions.

Graphical Abstract

INTRODUCTION

Many organic reactions involve bonding changes at a carbon atom. Determination of ¹³C kinetic isotope effects (KIEs) is a powerful tool that provides intimate details about the nature of bonding changes that occur at a carbon atom during the transition state (TS) of the rate-determining step (RDS) of a reaction. A landmark report by Singleton in 1995 introduced the use of quantitative ¹³C NMR methodology for the high-precision determination of ¹³C KIEs at natural abundance.¹ An important addition to this methodology was the use of density functional theory (DFT) calculations for the quantitative interpretation of experimental ¹³C KIEs, using conventional transition-state theory with a one-dimensional tunneling correction to predict KIEs.² Consequently, a correlation between the transition-state geometry and experimental KIEs has been well established.³ This combined experimental and theoretical approach has led to the resolution of several highly debated reaction mechanisms in organic chemistry.⁴

There are two complementary approaches for the determination of intermolecular ¹³C KIEs at natural abundance—starting material or product analysis. Taking the Buchwald–Hartwig amination of aryl halides as an example,⁵ Scheme 1 illustrates the design of the experiment for these two approaches. In both approaches, the “KIE sample” is the minor component in the reaction mixture, which can make its isolation challenging. As a result, to obtain a sufficient sample for ¹³C KIE determination (1–2 mmol), these experiments are typically performed on a 10–20 mmol scale (Scheme 1 approaches #1 and #2). Consequently, the use of this powerful mechanistic probe has been limited to easily scalable reactions requiring relatively inexpensive reagents. Additionally, altering reaction conditions (solvent, ligand, catalyst, etc.) can change the RDS and/or mechanism, and measurement of ¹³C KIEs on large-scale reactions for each set of conditions can be prohibitive.

Scheme 1.

Intermolecular Approaches for ¹³C KIE Determination at Natural Abundance (Singleton Method)

A third approach for the determination of ¹³C KIEs at natural abundance finds application in reactions that utilize a symmetric molecule as a reactant. When a symmetric molecule, with two identical reaction sites (distinguishable only by the isotope at each site), is desymmetrized during the course of a reaction, then the ratio of the two isotopomeric products formed reflects the intramolecular KIE for the first step that irreversibly desymmetrizes the molecule in the reaction. At natural abundance, this ratio of isotopomers is obtained by the relative integration of peaks of the two relevant carbon atoms in the ¹³C spectrum of the product (Ca and Ca^‡, Scheme 2).

Scheme 2.

Utilizing Symmetric Molecules for Determination of ¹³C KIE at Natural Abundance

Singleton introduced the use of intramolecular ¹³C KIEs at natural abundance with an elegant study of the mechanism of the Baeyer–Villiger oxidation of cyclohexanone to ε-caprolactone (Scheme 2).⁶ In this example, the symmetry-breaking step probed by intramolecular KIEs occurred after the rate-limiting formation of the initial tetrahedral intermediate. In the other examples shown in Scheme 2, Singleton exploited intramolecular ¹³C KIE measurements to evaluate phenomenon such as tunneling and energy labeling in organic reactions.^7,8 In reactions where the rate-limiting step coincides with the symmetry-breaking step, intramolecular ¹³C KIEs provide the exact same information as intermolecular KIE experiments.⁹ In these cases, performing an intramolecular KIE experiment has several advantages over an intermolecular KIE experiment that include: (1) analysis of a single sample for KIE determination, (2) insensitivity to fractional conversion since KIE is obtained as an intramolecular measurement, (3) KIE can be determined even when reactants are used in excess, and (4) requires significantly smaller-scale reactions since product from a high-conversion reaction can be used for analysis.

One key disadvantage is that this approach is limited to reactions utilizing symmetric reactants. We sought to exploit this by developing a simple but powerful strategy that extends the benefits of intramolecular KIE determination to reactions that do not typically use a symmetric substrate, using a purposely designed symmetric reactant with two identical reaction sites (Scheme 2). The only caveat is that only one position may undergo reaction (i.e., no double addition product), so the “standard” carbon used to determine the KIE is not compromised. In this study, we benchmark this strategy against the traditional intermolecular product KIE methodology to study the mechanism of the Buchwald–Hartwig amination. We then apply this strategy to rapidly obtain valuable mechanistic information for this reaction under different reaction conditions.

RESULTS AND DISCUSSION

We chose the Buchwald–Hartwig amination to benchmark this intramolecular ¹³C KIE method since the mechanism of this reaction is well known, providing a reliable mechanistic platform for the interpretation of experimental KIEs. Additionally, this reaction can be performed using a variety of different aryl halide reactants, solvents, ligands, and bases. This allows us to utilize the novel intramolecular KIE method as a rapid probe of potential changes in the reaction mechanism/RDS with varying reaction parameters.

A series of mechanistic studies in the early 2000s by Buchwald, Hartwig, and Blackmond established the currently accepted catalytic cycle for the Buchwald–Hartwig amination (Figure 1).¹⁰ According to this catalytic cycle, oxidative addition (OA) of 1 occurs to the κ2-Pd⁰-BINAP complex (Pd⁰L) in the RDS. A Pd^II OA complex (4) presumably binds the amine (2) followed by deprotonation of the amine proton by the alkoxide to form a new Pd^II complex (5). Reductive elimination (RE) from 5 yields amination product 3 and regenerates the Pd⁰L catalyst. Based on this catalytic cycle, the KIE at the carbon atom attached to the halide (KIE_C–X) reports on the TS of the OA step (RDS).

Figure 1.

Catalytic cycle for the Buchwald–Hartwig amination reaction.

Traditional ¹³C Intermolecular Product KIE Study.

We chose the prototypical Buchwald–Hartwig amination of 4-tert-butylbromobenzene (1a) with two different amines, n-hexylamine (2a) and N-methylpiperazine (2b) for the determination of intermolecular ¹³C KIEs by analysis of the product. Following the protocol shown in Scheme 1, Traditional Approach # 2, duplicate reactions were conducted on a 15 mmol scale for both amines (2a and 2b) and taken to low conversion. Products 3aa/3ab were isolated (as the minor component) from each reaction mixture, and intermolecular ¹³C KIEs were determined in a standard way, by comparative ¹³C NMR analysis with samples of 3aa/3ab isolated from a 100% conversion reaction (no isotopic fractionation).¹ Resulting KIE_C–Br for 1a, from two independent measurements for each amine, is ~2.5% for both amines (Figure 2). Each of these four KIE measurements required 18 mmol of 1a (15 mmol for the KIE sample (20% conversion) +3 mmol for the Standard sample (100% conversion)) and about 9 h of NMR spectrometer time.

Figure 2.

Experimental ¹³C KIEs using the traditional intermolecular product KIE approach. Also shown is the transition structure for the widely accepted rate-determining oxidative addition of 1a, along with predicted KIE_C–Br.

For the quantitative interpretation of experimental KIEs, the TS of the OA step of the Buchwald–Hartwig amination was investigated using four different DFT methods—(a) a B3LYP-GD3(BJ)^11,12 functional and a Def2-TZVP basis set and ECP for Pd and I, and a Def2-SVP basis set for all other atoms, (b) an M06–2X¹³ functional with a LANL2DZ basis set and ECP for Pd and I, and a 6–311G** basis set for all other atoms, (c) a B3LYP functional with a SDDAll basis set and ECP for Pd and I, and a 6–311G** basis set for all other atoms, and (d) an M06-L¹⁴ functional with a Def2-TZVP basis set and an SDD ECP for Pd and I, and a Def2-SVP basis set for all other atoms—with a polarizable continuum model (PCM)¹⁵ solvent model for toluene on all methods as implemented in Gaussian 09.¹⁶ A comparative analysis shows that KIE predictions and geometries are similar across all methods (see the Supporting Information). The geometries and predicted KIEs in the manuscript are from the DFT method (a). From the scaled vibrational frequencies of the transition structures, predicted ¹³C KIEs were obtained using the program ISOEFF98.^17,18 An infinite parabola tunneling correction was applied to all predicted KIEs.¹⁹

Predicted ¹³C KIE for the TS for OA of 1a to the κ2-Pd⁰-BINAP complex (TS-OA-1a, Figure 2) is 1.025, which is in excellent agreement with experimental measurements. Therefore, our experimental and theoretical ¹³C KIE study supports the currently accepted mechanism of the Buchwald–Hartwig amination reaction, where OA of aryl halide to a κ2-Pd⁰-BINAP complex is the first irreversible step (and likely RDS) in the catalytic cycle.

Proof-of-Principle ¹³C KIE Study Using Symmetric Bromoarene.

Having determined the KIE_C–Br for 1a via the traditional product KIE approach, we next sought to determine KIE_C–Br for the “designed” reactant 1,4-dibromobenzene (1a_sym). Equimolar reactions of 1a_sym and amine (2a or 2b) were each carried out on a 3 mmol scale under standard Buchwald–Hartwig amination conditions and quenched at 50–70% conversion of 1a_sym (to minimize the likelihood of double amination). Reaction mixtures were analyzed by ¹H NMR and gas chromatography mass spectrometry (GC–MS) to verify that only mono-aminated products 3aa_desym/3ab_desym were formed. These mono-aminated products were isolated (~1–1.2 mmol) from the respective reaction mixtures via column chromatography and KIE_C–Br determined from the relative integrations of C_a versus Ca^‡ in the quantitative ¹³C NMR spectrum using well-established protocols for obtaining accurate relative integrations for two peaks within a single spectrum.²⁰ The resulting ¹³C KIEs for 1a_sym, from two independent measurements for each amine, is shown in Figure 3. Each of these four KIE measurements required 3 mmol of 1a_sym and about 4 h of NMR spectrometer time. This corresponds to a >80% decrease in material required and a >50% decrease in spectrometer time to obtain the same mechanistic information as the traditional intermolecular methodology (vide supra).

Figure 3.

Experimental intramolecular ¹³C KIEs obtained using the symmetric bromoarene. Also shown is the transition structure for the widely accepted model for oxidative addition of 1a_sym, along with the predicted KIE_C–Br.

For the quantitative interpretation of the KIEs for the reaction of 1a_sym, we located the TS for OA of 1a_sym to the κ2-Pd⁰-BINAP complex (TS-OA-1a_sym, Figure 3). The predicted ¹³C KIE for this TS is in excellent agreement with the experimental KIE. These results demonstrate that the intramolecular KIE approach using the symmetric bromoarene arrives at the same mechanistic conclusion as the traditional intermolecular product KIE approach, providing an important benchmark validating the use of this simple and efficient approach for the rapid determination of experimental ¹³C KIEs.

Effect of Varying Halide on the Mechanism of Buchwald–Hartwig Amination.

We decided to investigate the title reaction of aryl chlorides and aryl iodides using designed reactants 1,4-dichlorobenzene (1b_sym) and 1,4-diiodobenzene (1c_sym) (shown in Figure 4). For direct comparison to the KIEs obtained with 1a_sym (Figure 3), reactions of 1b_sym/1c_sym with 2a were run on a 3 mmol scale and taken to 50–70% conversion with respect to the aryl halide. The resulting mono-amination products 3ba_desym/3ca_desym were isolated (1–1.2 mmol) from the reaction mixture, and KIE_C–Cl and KIE_C–I were determined as described previously. Following this, TSs for OA to the κ2-Pd⁰-BINAP complex for 1b_sym (TS-OA-1b_sym) and 1c_sym (TS-OA-1c_sym) were located to quantitatively evaluate the experimental KIE_C–Cl and KIE_C–I.

Figure 4.

Utilization of symmetric aryl halides to probe the effects of aryl halide on the mechanism of the Buchwald–Hartwig amination.

Upon changing from aryl bromide (KIE_C–Br ~ 1.023) to aryl chloride (KIE_C–Cl ~ 1.032), there is an increase in the magnitude of the experimental isotope effect. Gratifyingly, this increase is accurately predicted by DFT calculations; the predicted KIE_C–X for the TS-OA-1a_sym and TS-OA-1b_sym are 1.023 and 1.033, respectively (Figure 4). The magnitude of the ¹³C KIE prediction parallels the trend in C–X bond-length (r_C–Br = 2.16 Å versus r_C–Cl = 2.05 Å) at the respective TSs. These results indicate that the Buchwald–Hartwig amination of aryl chloride also proceeds via a mechanism involving OA of aryl chloride to a κ2-Pd⁰-BINAP complex in the first irreversible step (and likely RDS) in the catalytic cycle.

The experimental KIE_C–I, determined from two independent experiments using 1c_sym as a designed reactant, yielded values that are very close to unity (Figure 4). This result is in variance with the previously discussed values for KIE_C–Cl and KIE_C–Br, both of which are consistent with OA being the first irreversible step for the aryl bromides/aryl chlorides. The predicted KIE_C–I for transition structure TS-OA-1c_sym is 1.012, which is higher than the experimental KIE_C–I of unity. Interpretation of this result is that the carbon atom attached to iodine is not involved in the first irreversible step in the catalytic cycle for 1c_sym; this rules out OA and RE (predicted RE KIE_C–I of 1.028, structure in the Supporting Information) as the first irreversible step. Two possibilities emerge as an explanation for the observed KIE_C–I—(a) binding of 1c_sym to a Pd⁰ complex is irreversible or (b) either amine binding or deprotonation of bound amine to form the pre-RE complex 5 (Figure 1) is the first irreversible step in the catalytic cycle. Further experiments are required to confirm the exact mechanism of the Buchwald–Hartwig amination of aryl iodides. However, the key takeaway is that vital information regarding changes in TS geometry and/or mechanism upon changing reactants is obtained from a single reaction performed under standard catalytic conditions.

Effect of Base on Oxidative Addition TS.

In 2001, elegant kinetic studies by Hartwig revealed two pathways for OA, in the Buchwald–Hartwig amination reaction of aryl chlorides and secondary amines catalyzed by Pd[P(t-Bu)₃]₂, that varied depending on the nature of the base used for the reaction (Figure 5).²¹ When NaOC(Me)₃ was used as the base, the reaction was found to be first order in aryl chloride, zero order in amine, and positive order in base. This led to the proposal of a base-dependent pathway in which tert-butoxide displaces one of the ligands on the catalyst to form an anionic [P(t-Bu)₃Pd⁰ (OC(Me)₃)]⁻ complex Pd⁰L₁(OR)⁻, which adds aryl chloride in the turnover limiting step. When the bulkier NaOC(Et)₃ was used, the reaction was zero order in base suggesting that OA of aryl halide occurred to a neutral Pd⁰P(t-Bu)₃ complex (Pd⁰L₁) in the turnover limiting step.

Figure 5.

Utilization of symmetric aryl chloride to probe the effects of base on the oxidative addition transition structure.

We sought to probe this base-dependent mechanism of OA using intramolecular ¹³C KIEs with 1b_sym. Accordingly, separate reactions of 1b_sym and 2b were conducted using in situ formed Pd[P(t-Bu)₃]₂ as the catalyst and either NaOC(Me)₃ or NaOC(Et)₃ as the base. Intriguingly, the experimental KIE_C–Cl determined by intramolecular KIE analysis of 3bb_desym was drastically different depending on the base used (Figure 5). Duplicate measurements in the presence of NaOC(Me)₃ as a base yielded a KIE_C–Cl value of ~1.026. On the other hand, corresponding measurements in the presence of NaOC(Et)₃ as a base resulted in KIE_C–Cl values of ~1.041. To interpret the origin of this difference, we modeled the TS for OA to 1b_sym using neutral PdL₁ (TS-OA_L1-1b _sym) or anionic PdL₁(OR)⁻ with Na⁺ as the counterion (TS-OA_L1+Base-1b_sym). The resulting transition structures (Figure 5) are fundamentally different—while TS-OA_L1–1b_sym corresponds to a classic OA-type TS, the anionic TS-OA_L1+Base-1b_sym resembles an S_NAr- type TS. The S_NAr- type TS has a shorter forming Pd–C bond (r_Pd–C = 1.97 Å) and consequently gives a lower prediction of KIE_C–Cl (1.021) compared to the OA-type TS, which has a longer forming Pd–C bond (r_Pd–C = 2.19 Å) and a larger predicted KIE_C–Cl (1.039). Gratifyingly, both predictions are in good agreement²² with our experimental KIE_C–Cl values and validate Hartwig’s mechanistic proposal that the less bulky base proceeds via the base-mediated anionic Pd⁰ pathway and the bulky base proceeds via OA to a neutral Pd⁰L₁ complex. These results indicate that ¹³C KIEs are a sensitive probe of the ligand environment at a metal center during the KIE-determining step of a reaction, a finding that makes ¹³C KIEs a valuable addition to the tools available to probe transition metal-catalyzed reactions under synthetically relevant conditions.

Scope and Limitations.

Finally, to illustrate the utility of this methodology in other areas of catalysis, we studied the l-proline catalyzed aldol reaction²³ of acetone (6) and aromatic aldehydes using terephthaldehyde (7) as a designed reactant (Figure 6). The aldol product 8, isolated from a carefully monitored reaction taken to ~50% conversion of 7, was used for the determination of intramolecular ¹³C KIEs. The resulting ¹³C KIEs for 7, from two independent measurements, is shown in Figure 6. Gratifyingly, the ~1.045 KIE observed on the aldehyde carbon atom is in excellent agreement with the predicted KIEs for the widely accepted Houk-List transition state for C–C bond formation (TS-CC-7, Figure 6).²⁴ This result establishes C–C bond formation as the enantioselectivity-determining step of the reaction.

Figure 6.

Utilization of a symmetric aromatic aldehyde to probe the mechanism of the l-proline catalyzed aldol reaction.

The examples presented in this manuscript illustrate the advantages of using reactants with two identical reaction sites for the rapid determination of ¹³C KIEs at natural abundance. As mentioned earlier, an important caveat for the success of this approach is the careful exclusion of “double reaction.” Formation of even minor amounts of the product resulting from reaction at both sites will affect the ¹³C isotopic composition at the standard carbon (Scheme 2) and hence compromise the intramolecular KIE measurement. This limitation of intramolecular KIE determination can often be overcome using an excess of the symmetric reactant and/or terminating the reaction at low conversions. However, in reactions where the desymmetrized product is significantly more reactive than the symmetric starting materials, it might be difficult to avoid trace amounts of difunctionalization.

This novel approach has the potential to expand the scope of reactions amenable to KIE analysis. Intermolecular KIE approaches are not applicable to reactions where a non-symmetric reactant is used in large excess since high reaction conversion (80 or 100% required for starting material or product analysis, respectively) cannot be achieved. In these cases, the use of a designed symmetric reactant as a surrogate for the native reactant will allow for the determination of relevant KIEs by isolation of the desymmetrized product. Additionally, reactions where two processes run in competition to deliver two different products (such as S_N2 versus E2 products in reactions of alkyl halides with a base) represent another class of reactions that cannot typically be studied using intermolecular KIE approaches. The use of a designed symmetric reactant and isolation of the mono-functionalized products from each reaction channel will allow for the determination of KIEs for both processes from a single reaction. This novel strategy is also expected to find application in studying dimerization reactions and reactions where the mechanism evolves as a function of time, two classes of reactions that are typically not suited for intermolecular KIE approaches. Finally, it is worthwhile to note that this approach can also be utilized to determine deuterium KIEs without explicit labeling, via ²H NMR at natural abundance, by the design of appropriate reactants with homotopic or enantiotopic hydrogen atoms. A detailed discussion of the full potential of this novel approach is included on page S20 of the Supporting Information.

CONCLUSIONS

In conclusion, we have benchmarked a novel method for the rapid determination of ¹³C KIEs at natural abundance. This method relies on the use of “designed” symmetric reactants and utilizes only a fraction of the material used for traditional ¹³C KIE experiments. Challenging problems in transition metal catalysis can be addressed using this method without arduous kinetic studies or synthesis of putative reaction intermediates, as evidenced by the rapid evaluation of the mechanism of the Buchwald–Hartwig amination under a variety of different reaction conditions. Additionally, the application of this approach to study an organocatalytic aldol reaction has been demonstrated. The potential application to other challenging mechanistic studies is also discussed. This approach will be particularly useful in reaction optimization to rapidly probe the effect of changing reaction parameters (solvent, ligand, catalyst, concentration, etc.) on the reaction mechanism. We expect this methodology to gain traction in the mechanistic study of organic reactions both in industry and academia.