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Apr 4, 2016 - Alkynoates into Allenoates: Enantioselectivity and Reversibility. A. DFT Study. Hongyan Xiao,. †,‡. Yusuke Kobayashi,. §. Yoshiji T...
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Proton Transfer Mechanism of Organocatalyzed Isomerization of Alkynoates into Allenoates: Enantioselectivity and Reversibility. A DFT Study Hongyan Xiao,†,‡ Yusuke Kobayashi,§ Yoshiji Takemoto,§ and Keiji Morokuma*,‡ †

Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, People’s Republic of China ‡ Fukui Institute for Fundamental Chemistry, Kyoto University, 34-4 Takano Nishihiraki-cho, Kyoto 606-8103, Japan § Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Kyoto 606-8501, Japan S Supporting Information *

ABSTRACT: The mechanisms of organocatalyzed isomerization of α-unsubstituted (system I) and α-substituted (system II) alkynoates into allenoates mediated by benzothiadiazine catalyst were systematically investigated using the density functional theory (DFT) method. Four reaction paths in both systems were explored in detail, all involving two proton-transfer steps and some including a conformational change step in the intermediate. In all of these paths, the first proton transfer involves the proton (H7) of the substrate transferred to the amine nitrogen (N13) of the catalyst, giving the intermediate, and the other involves the same proton (H7) in the intermediate transferred back from the catalyst to the carbon atom (C6) of the substrate, forming the final product complex. The most favorable reaction path in system I, the anti-cis path, is very similar to the best path in system II, the anti-R path. The ratedetermining (first proton transfer) barrier height for the anti-cis path of system I is substantially smaller (by about 15 kJ/mol) than that for the anti-R path of system II, indicating that system I is more reactive than system II. The reverse barrier from the product complex back to the reactant complex in system I is only 20.4 kJ/mol higher than the forward barrier. On the other hand, the reverse barrier is 29.4 kJ/mol higher than the forward barrier in system II. Thus, making this isomerization in system I is more reversible at room temperature, while the isomerization in system II is irreversible. The origins of differences in reactivity, reversibility, and selectivity are revealed in terms of hydrogen-bond structures, charge distributions, and energy decomposition analysis of some key structures. KEYWORDS: organocatalyzed isomerization, proton transfer, enantioselectivity, reversibility, alkynoates, allenoates, density functional theory, artificial force induced reaction

1. INTRODUCTION

ization of 3-alkynoates to allenoates using density functional theory (DFT) methods.11 Takemoto et al. studied organocatalyzed isomerization of αunsubstituted5 and α-substituted6 alkynoates into disubstituted and trisubstituted allenoates, respectively, using a bifunctional hydrogen-bond donor catalyst, benzothiadiazine. Hereafter, we denote these two isomerization reactions as systems I and II, respectively (see Scheme 1). In these experimental studies it was found that systems I and II both have high enantioselectivity and good yield and generate products in the S absolute configuration. The isomerization reaction is reversible in system I. In system II, the reaction is irreversible, although the isomerization from (R)-alkynoate to (S)-allenoate is fast. Takemoto et al. explained that the α-substituent on alkynoate was responsible for the suppression of the reverse

Allenes form an important class of unsaturated hydrocarbons with two π orbitals perpendicular to each other. Allenes exist in many natural products, with rich characteristics of structures and intriguing biological activities.1 The synthesis, properties, and applications of allenes have been reviewed extensively.1,2 In recent years, with the development of new synthetic methods, the organocatalytic enantioselective synthesis of chiral allenes has gained considerable attention.3−9 The kinetic resolution of racemic and chiral allenes has also been an attractive method for building chiral blocks in synthetic organic chemistry. Enantioselective isomerization of alkynoates is one of the most atom-economical ways to allenoates.3,5,6,10 In 2000, Shioiri et al. for the first time described catalytic synthesis of allenes via isomerization of alkynes under phase-transfercatalyzed conditions.10 Tan and Huang reported enantioselective isomerization of 3-alkynoates to allenoates using a chiral guanidine catalyst.3 Hu et al. investigated the mechanism and stereochemistry of guanidine-catalyzed enantioselective isomer© XXXX American Chemical Society

Received: January 6, 2016 Revised: March 31, 2016

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ACS Catalysis Scheme 1. Isomerization of Alkynoates to Allenoates

Scheme 2. Energy Decomposition Analysis between the Intermediate (IM1) and Transition State (TS2)

coordinate (IRC) calculations. To evaluate the basis set effect, the potential energy surfaces (PESs) of all paths were also calculated by the B3LYP-GD3+PCM/6-311++G** method at the B3LYP-GD3+PCM/6-31G* optimized structures. The trends in energy were similar at the two levels, suggesting that the present B3LYP-GD3+PCM/6-31G* results were reasonable (see Figures S4 and S5 in the Supporting Information). Hereafter, unless otherwise stated, all energy data used in the following discussion were total electronic energies at the B3LYP-GD3+PCM/6-31G* level. We also evaluated the free energy surfaces (FESs) including the entropy contribution at the B3LYP-GD3+PCM/6-31G* level, as shown in Figures S6 and S7 in the Supporting Information. The trends in FESs of all reactions are similar to those of the PESs. All electronic structure calculations were performed with the Gaussian 09 software package.30 To gain insight into the different energy contributions between substrate and catalyst in detail, the energy decomposition analysis (EDA) at the B3LYP-GD3+PCM/631G* level for transition state TS2 with respect to intermediate IM1 was carried out. As shown in Scheme 2, each optimized structure (AB) was divided into a pair of ions (A and B), where the representative labels A and B are the substrate and catalyst parts, respectively. The energy difference ΔE⧧ between the optimized transition state TS2 (ABTS2) and intermediate IM1 (ABIM1) can be divided into three energy terms. One is the deformation (DEF) energy, defined as the energy difference between the isolated A and B in the optimized transition state structure of TS2 (denoted as ATS2 and BTS2) and those in the optimized intermediate structure of IM1 (denoted as AIM1 and BIM1). The other two terms are the interaction (INT) energies, INTTS2 of the optimized TS2 relative to the pair of ions ATS2 and BTS2 and INTIM1 of the optimized IM1 relative to the pair of ions AIM1 and BIM1. As shown in Scheme 2, ΔE⧧ = DEF + INTTS2 − INTIM1.

reaction. However, the detailed reaction mechanism remains unclear. The asymmetric organocatalytic reaction using small organic molecules as catalysts is a hot topic both experimentally and theoretically.12−16 In the present study, we employed the density functional theory method to study theoretically the mechanism of organocatalyzed isomerization of alkynoates into allenoates mediated by the benzothiadiazine catalyst. The favorable fast reaction path has been found to involve two proton-transfer steps, with the first one being the ratedetermining step. The hydrogen-bond structure, Mulliken charge population, and energy decomposition analysis of some key structures and processes in both systems I and II were discussed in detail, and the difference between systems I and II was also analyzed. The present computational study will be useful for understanding the asymmetric organocatalytic reaction mechanism and will provide a systematic theoretical analysis method.

2. COMPUTATIONAL METHODS Density functional theory17,18 was used to study all of the electronic structures and all of the related reaction pathways. A self-consistent reaction field (SCRF) method based on the polarizable continuum model (PCM)19−21 was used to simulate the solvent effect for THF. The Becke three-parameter exchange functional22 with the nonlocal correlation of Lee− Yang−Parr23 (B3LYP), supplemented with the D3 version of Grimme’s dispersion correction (GD3)24 in combination with the 6-31G*25,26 basis set was adopted. The recently developed artificial force induced reaction (AFIR) method27 in the GRRM14 code in the global reaction route mapping (GRRM) strategy28,29 was employed to find approximate structures of local minima (substrates, catalyst, products, complexes (COMs) between substrate and catalyst) and intermediates (INTs), as well as transition states (TSs). For details of AFIR calculations, see the Supporting Information. All of the approximate structures were then reoptimized to the true structures without artificial force at the B3LYPGD3+PCM/6-31G* level. Transition states and connected minima were validated by means of normal-mode analysis and intrinsic reaction

3. RESULTS AND DISCUSSION 3.1. Mechanism of α-Unsubstituted Alkynoate Isomerization into Disubstituted Allenoate (System I). 3.1.1. Initial Substrate−Catalyst Complex. In reference to the previous study,11 we searched and determined four kinds of 2989

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Figure 1. B3LYP-GD3+PCM/6-31G* optimized structures of substrate, catalyst, and substrate−catalyst complexes in system I. Relative energies (kJ/mol) of the complexes are given in brackets.

Figure 2. anti-cis path in system I with the relative energies (kJ/mol) at the B3LYP-GD3+PCM/6-31G* level given in brackets. The optimized structures are shown in Figure S1 in the Supporting Information.

substrate−catalyst complexes, i.e. anti-cis-, anti-trans-, syn-cis-, and syn-trans-COM. As shown in Figure 1, cis and trans stand for two different conformations of substrate, where the carbonyl oxygen of the substrate can be in a cis or trans position relative to the alkyne. anti and syn stand for the relative position of the tBu group of the substrate with respect to the NMe2 group of the chiral catalyst. In these four complexes, the carbonyl oxygen of the substrate coordinates to the −NH group of the catalyst forming one hydrogen bond O1−H11 with about 1.9−2.0 Å. The relative energies of anti-cis-COM,

anti-trans-COM, syn-cis-COM, and syn-trans-COM are 0.0, 22.5, 15.2, and 31.3 kJ/mol at the B3LYP-GD3+PCM/6-31G* level, respectively. The dispersion energy corrections at this level are 0.0, 27.1, 11.3, and 23.1 kJ/mol, respectively, indicating that anti-cis-COM is stabilized preferentially over the other complexes by dispersion. When the structure of anticis-COM was checked carefully, it was found that the phenyl group of the substrate and the benzene ring of the catalyst face each other nearly in parallel due to the dispersion interaction. 2990

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Figure 3. anti-trans path in system I with the relative energies (kJ/mol) at the B3LYP-GD3+PCM/6-31G* level given in brackets. The optimized structures are shown in Figure S1 in the Supporting Information.

substrate via the transition state anti-cis-TS2, forming the final S configuration product as well as releasing the catalyst. 3.1.2.2. anti-trans Path: trans-Substrate + Catalyst → anti-trans-COM → anti-trans-TS1 → anti-trans-IM1→ antitrans-TS*→ anti-trans-IM2 → anti-trans-TS2 → anti-transIM3 → Product (R) + Catalyst. Similar to the anti-cis path, the anti-trans path also includes one conformation adjustment step between two proton-transfer steps but gives the final R configuration product. The first step is the transfer of the proton (H7) (see Figure 3 and Figure S1 in the Supporting Information) on the sp3 carbon (C4) of the substrate to the NMe2 nitrogen atom (N13) of the catalyst via the transition state anti-trans-TS1, giving the ion-pair intermediate anti-transIM1. The second step is the redirection of the proton H7 in the NMe2 group to the carbon atom (C6) of the substrate via the transition state anti-trans-TS*, where the H7−C6 distance changes from 3.488 Å in anti-trans-IM1 to 3.095 Å in anti-transTS* and 2.258 Å in anti-trans-IM2. The third step is the proton (H7) migration from the catalyst to the carbon atom (C6) of the substrate via the transition state anti-trans-TS2, forming the final R configuration product as well as releasing the catalyst. 3.1.2.3. syn-cis Path. This involves only two proton-transfer steps and generates the R configuration product. No conformational change is required. 3.1.2.4. syn-trans Path. This is similar to the anti-trans path and includes two proton-transfer steps and one conformation

3.1.2. Four Reaction Pathways. There are four reaction pathways from initial four substrate−catalyst complexes, respectively. The relevant reaction paths including the optimized structures are shown in Figures 2 and 3 and Figure S1 in the Supporting Information, and the potential energy profiles of the entire reaction are plotted in Figure 4. 3.1.2.1. anti-cis Path: cis-Substrate + Catalyst → anti-cisCOM → anti-cis-TS1 → anti-cis-IM1 → anti-cis-TS* → anticis-IM2 → anti-cis-TS2 → anti-cis-IM3 → Product (S) + Catalyst. This path takes place via two proton-transfer steps and one conformation adjustment step. The first step is the transfer of the proton (H7) (see Figure 2 and Figure S1 in the Supporting Information) on the sp3 carbon (C4) of the substrate to the NMe2 nitrogen atom (N13) of the catalyst via the transition state anti-cis-TS1, giving the ion-pair intermediate anti-cis-IM1. The second step is the redirection of the proton H7 in the NMe2 group to the carbon atom (C6) of substrate via the transition state anti-cis-TS*, where the H7−C6 distance changes from 3.771 Å in anti-cis-IM1 to 2.912 Å in anti-cis-TS* and 2.139 Å in anti-cis-IM2. This is driven by the change in the intermolecular torsion angle of H8−C4−C18−C17 from 100.3° in anti-cis-IM1 to 128.8° in anti-cis-TS* and 141.1° in anti-cis-IM2, which results in the corresponding decrease in distance of H16−N14 from 4.178 to 3.504 and 2.548 Å and makes anti-cis-IM2 stable. The third step is the back proton (H7) transfer from the catalyst to the carbon atom (C6) of 2991

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Figure 4. Potential energy surfaces in system I calculated at the B3LYP-GD3+PCM/6-31G* level. Relative energies (kJ/mol) are given in brackets.

Figure 5. Structures (Å), relative energies (kJ/mol), and hydrogen-bond numbers of IM1 and TS2 in system I calculated at the B3LYP-GD3+PCM/ 6-31G* level.

adjustment step but generates the S configuration product. These two paths including the optimized structures are shown in Figure S1 in the Supporting Information. 3.1.3. Potential Energy Profiles of Four Reaction Pathways. The profiles of potential energy for the four reaction pathways discussed above are shown in Figure 4, where the energy of the optimized anti-cis-COM was taken as the energy reference point. The anti-cis path has the lowest barriers and is

the most favorable path. For the anti-cis path, the energy of the second proton-transfer step (TS2, 44.7 kJ/mol) is 10.6 kJ/mol lower than that of the first proton-transfer step (TS1, 55.3 kJ/ mol). In this path, the rate-determining step is the first proton transfer and generates the S configuration product. The less favorable syn-cis path includes two proton-transfer steps, but the barrier at the second proton-transfer step (IM1 → TS2, 32.5 kJ/mol) is higher than the reverse energy barrier 2992

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Table 1. Mulliken Charge Populations (e) in the anti-cis Path in System I at the B3LYP-GD3+PCM/6-31G* Level substrate (including H7) C(O)OtBu sp3 > sp2 C4 H7 sp C5 sp > sp2 C6 phenyl catalyst N10H heterocycle C6H10 NMe2

COM

TS1

IM1

TS*

IM2

TS2

IM3

0.019 0.053 −0.355 0.272 −0.068 0.092 0.025 −0.019 −0.295 −0.031 0.418 −0.112

−0.204 −0.088 −0.506 0.346 0.006 0.053 −0.016 0.204 −0.298 −0.025 0.521 0.007

-0.306 −0.268 −0.446 0.401 0.004 0.031 −0.030 0.306 −0.303 −0.031 0.557 0.083

−0.322 −0.240 −0.447 0.418 −0.013 −0.010 −0.029 0.322 −0.301 −0.033 0.560 0.096

−0.301 −0.235 −0.376 0.414 0.190 −0.283 −0.010 0.301 −0.291 −0.046 0.563 0.075

−0.198 −0.118 −0.323 0.353 0.311 −0.459 0.039 0.198 −0.284 −0.043 0.528 −0.003

0.032 0.005 −0.245 0.264 0.285 −0.391 0.114 −0.032 −0.289 −0.046 0.419 −0.116

Table 2. EDA (in kJ/mol) for IM1 to TS2 of Four Reaction Paths in System I at the B3LYP-GD3+PCM/6-31G* Levela complex anti-cis anti-trans syn-cis syn-trans a

DEF A 9.1 27.9 23.0 26.1

(0.0) (18.8) (13.9) (17.0)

DEF B 47.7 74.4 47.0 59.8

(0.0) (26.7) (−0.7) (12.1)

DEF (A+B) 56.8 102.3 70.0 85.9

(0.0) (45.5) (13.2) (29.1)

INTTS2 −315.1 −295.7 −271.8 −274.5

(0.0) (19.4) (43.3) (40.6)

INTIM1 −258.1 −219.5 −234.3 −212.7

(0.0) (38.6) (23.8) (45.4)

ΔE⧧ −0.2 26.1 32.5 24.2

(0.0) (26.3) (32.7) (24.4)

The relative values are given in parentheses, where every term for anti-cis is taken as 0.

of the first proton-transfer step (IM1 → TS1, 15.1 kJ/mol). Thus, the first step is reversible31,32 in the syn-cis path. Since anti-cis-COM and anti-trans-COM easily transform to each other via a low barrier (32.5 kJ/mol, as shown in Figure S1 in the Supporting Information), the reaction along the anti-cis path with the lower energy barrier should be dominant. Both anti-trans and syn-trans paths are higher in energy than the two cis paths and are not likely to be important. 3.1.4. Analysis of Four Pathways. From the PESs in Figure 4, one can see that the stability of COM, IM1 (and TS1), and TS2 play an important role in determining the potential energy profile and selectivity. Therefore, we will further study their structures, Mulliken charge populations, and energy decomposition analysis to find the origin of preference of the anti-cis path in the isomerization of α-unsubstituted alkynoate into disubstituted allenoate. 3.1.4.1. Number of Hydrogen Bonds (HBs). For IM1s, the carbonyl oxygen of substrate forms two hydrogen bonds with two −HN groups of the catalyst in the range of 1.7−2.0 Å, except for syn-cis-IM1, which has only one hydrogen bond. For the two trans paths, after the conformation adjustment step, the number of hydrogen bonds decreases and the TS2 energies increase. For the syn-cis path, there is only one hydrogen bond in both IM1 and TS2, and the strength of the hydrogen bond decreases as its distance increases from 1.689 Å in IM1 to 1.830 Å in TS2. For the energetically most favorable anti-cis path, the hydrogen bond network (also including a loose bond, 2.3−2.8 Å, made from the phenyl hydrogen atom of the substrate and the oxygen atom of the catalyst), as seen in Figure S1 in the Supporting Information and Figure 5, is always maintained, which is qualitatively consistent with the lowest energy of this path. Therefore, the anti-cis path to give S-allenoate is most favored in terms of hydrogen bond network. 3.1.4.2. Mulliken (MK) Population Analysis. To check the nature of the hydrogen transfer mechanism, the MK charges of the substrate (excluding the transferred H atom), the transferred H atom (H7), and the catalyst for four reaction paths from COM to IM3 were calculated. The relevant MK

charges for the anti-cis path are given in Table 1. The MK charge information on the other three paths is given in Tables S1−S3 in the Supporting Information. As shown in Table 1, the H7 atom in the CH bond bears a partial positive charge in COM. The H7 charge increases rapidly from COM via TS1 to IM1, indicating that this is a proton transfer reaction. The H7 charge changes little in the conformation adjustment step, while it decreases rapidly from TS2 to IM3, indicating the completion of the second proton transfer step. All of the MK population analysis results showed that isomerization of α-unsubstituted alkynoate to disubstituted allenoate involves a proton transfer and a back proton transfer. Although the small basis set 6-31G* was used to calculate the MK population, overall the trends in charges should usually be correct. 3.1.4.3. Energy Decomposition Analysis. In order to analyze the detailed energy contributions, the EDA energy values (see Scheme 2) for the difference from IM1 to TS2 were calculated and are shown in Table 2. The total difference ΔE⧧ for the anticis path is the smallest among these four paths and indicates that this path takes place most easily from IM1 to TS2. On comparison of the syn-cis path with the most favorable anti-cis path, the deciding term is INTTS2 − INTIM1, which indicates that the interaction between the substrate and catalyst at TS2 (relative to IM1) is more favorable in anti-cis than in syn-cis. In fact, the interaction itself is stronger in anti-cis than in syn-cis at TS2 as well as at IM1. As discussed above, the overlap of the substrate phenyl group and the catalyst benzo group is larger in anti-cis, where two are in a face-to-face arrangement that would favor both the orbital interaction and the dispersion interaction. On comparison between the trans configurations (anti-trans and syn-trans) with the cis configurations (anti-cis and syn-cis), the DEF (A+B) energy, in particular DEF B, disfavors the trans configurations, as much as 16−46 kJ/mol. This is consistent with a larger conformation change, especially at the catalyst part, required from IM1 to TS2 to reach the TS*. On the whole, the larger negative INT and smaller positive DEF values together make the anti-cis path from IM1 to TS2 the most preferable. 2993

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Figure 6. B3LYP-GD3+PCM/6-31G* optimized structures (Å) of substrate, catalyst, and substrate−catalyst complexes in system II. The relative energies (kJ/mol) of complexes are given in brackets.

Figure 7. Potential energy surfaces in system II calculated at the B3LYP-GD3+PCM/6-31G* level. Relative energies (kJ/mol) are given in brackets.

In summary, among these four paths, the anti-cis path to give the S product is the energetically most favorable path. The reaction from the substrate−catalyst complex COM consists of the first H7 proton transfer from the substrate to the amine of the catalyst to form the intermediate IM1, the conformational change of IM1 to give IM2, and the transfer of the same H7 proton from the protonated catalyst back to the different carbon of the substrate to give the product−catalyst complex IM3. The first proton-transfer step is the rate-determining step for the overall reaction for this path. The forward reaction path from anti-cis-COM (cis-alkynoate isomerization into Sallenoate) has a 55.3 kJ/mol barrier, while the backward reaction path from the anti-cis-IM3 (S-allenoate isomerization into cis-alkynoate) has a 75.7 kJ/mol barrier. The energy

difference is rather small and indicates that the isomerization of α-unsubstituted alkynoate into disubstituted allenoate mediated by benzothiadiazine catalyst is reversible. This reversibility agrees with the experimental observation5 and distinguishes the isomerization of α-unsubstituted alkynoate from that of αsubstituted alkynoate. 3.2. Mechanism of α-Substituted Alkynoate Isomerization into Trisubstituted Allenoate (System II). 3.2.1. Initial Substrate−Catalyst Complex and Four Reaction Pathways. In system II, the substrate has R and S configurations (Figure 6) due to a methyl substituted on the α carbon atom (C4) of the alkynoate. Similar to the case for system I, system II includes four initial substrate−catalyst complexes (Figure 6) and four relevant reaction pathways 2994

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ACS Catalysis

in anti-R than in syn-S at TS2 as well as at IM1. On comparison between the anti-S and syn-R configurations with the anti-R and syn-S configurations, the DEF (A+B) energy disfavors the anti-S and syn-R configurations, about 28−34 kJ/mol. On the whole, the larger negative INT and smaller positive DEF values together make the anti-R path from IM1 to TS2 the most preferable. In summary, among these four paths, the anti-R path is the most favored in this chiral system. The computed results indicate that the α-substituted alkynoate isomerization into trisubstituted allenoate mediated by the benzothiadiazine catalyst consists of proton transfer and proton back-transfer steps, as in the case of α-unsubstituted alkynoate. Furthermore, as shown in Figure 7, as the first proton-transfer step possesses the highest energy barrier, it is the rate-determining step for the overall reaction in the anti-R path. The forward path from anti-R-COM has a barrier of 70.7 kJ/ mol at anti-R-TS1, while the backward path from anti-R-IM3 has a 100.1 kJ/mol barrier also at anti-R-TS1. The energy difference, 29.4 kJ/mol, corresponds to the energy difference between the product complex anti-R-IM3 and the reactant complex anti-R-COM. This difference is large and indicates that the α-substituted alkynoate isomerization into trisubstituted allenoate mediated by benzothiadiazine catalyst might be irreversible, which agrees with the experimental observation.6 This is in contrast with the same isomerization reaction of the α-unsubstituted alkynoate to disubstituted allenoate, system I, in which the barriers for the forward and backward reactions are 55.3 and 75.7 kJ/mol, with a difference of 20.4 kJ/mol between anti-cis-IM3 and anti-cis-COM. The PESs with a larger basis set (6-311++G**) and FESs at the present basis set (6-31G*) are similar to the PESs with the present basis set (6-31G*). Therefore, we confirm that system II is irreversible and system I is reversible. A comparison of Figures 4 and 7 indicates that the overall anti products in system II are more stabilized (−29.4 kJ/mol relative to the corresponding reactant) than those in system I (−20.4 kJ/mol) by 9.0 kJ/mol. In system II, in comparison to system I, the electron-donating methyl group at carbon 4 obviously strengthens the hydrogen bonds with amine protons of the catalysts in the product complexes. On the other hand, as discussed before, the barrier at TS1 in system II (70.7 kJ/mol) is about 15 kJ/mol higher than that in system I (55.3 kJ/mol); system II is less reactive, or has a slower rate, than system I. This is, as already discussed, due to a higher steric repulsion at TS1 in system II than in system I caused by the methyl group. The reversibility of a reaction is defined by the ratio of reverse and forward reactions, which is determined by the difference between the reverse and forward barriers. This difference, which is equivalent to the absolute value of exothermicity of the reaction, is 20.4 kJ/mol for system I and 29.4 kJ/mol for system II. The 9.0 kJ/mol difference suggests that the reversibility of system II is only 2.7% of that of system I at the room temperature. This is in qualitative agreement with the experimental result that the reverse reaction is not observed in system II.

including the optimized structures (Figure S2 in the Supporting Information). The relative energies of anti-R-COM, anti-SCOM, syn-S-COM, and syn-R-COM are 0.0, 28.1, 15.5, and 34.6 kJ/mol at the B3LYP-GD3+PCM/6-31G* level, respectively, where the dispersion interaction energies (0.0, 30.0, 16.3, and 30.3 kJ/mol, respectively) are essential. The differences between different complexes are slightly larger in system II than in system I, because of the existence of a 4-methyl group in system II. The potential energy profiles of the entire reaction are plotted in Figure 7. These paths are closely related to those in system I and will be discussed only briefly. 3.2.1.1. anti-R Path: R-Substrate + Catalyst → anti-R-COM → anti-R-TS1 → anti-R-IM1 → anti-R-TS2 → anti-R-IM3 → Product (S) + Catalyst. This path is higher in energy (70.7 kJ/ mol at TS1 vs 55.3 kJ/mol at TS1 in system I) than the anti-cis path in system I, apparently due to more steric repulsion caused by the newly introduced C4 methyl group. An apparent difference between the two paths is that TS* and IM2, which exist for system I (Figure 4), do not exist for system II (Figure 7); the IM2 seems to have been destabilized and became higher than TS* and disappeared. Thus, this path for system II consists of two proton-transfer steps producing the final S configuration product, without a conformational minimum at IM2. 3.2.1.2. anti-S Path: S-Substrate + Catalyst → anti-S-COM → anti-S-TS1 → anti-S-IM1 → anti-S-TS* → anti-S-IM2 → anti-S-TS2 → anti-S-IM3 → Product (R) + Catalyst. This path (see Figure S2 in the Supporting Information) is very similar to the anti-trans path in system I, involving two proton-transfer steps (H7 from C4 to N13 and back to C6) with the conformational minimum (IM2), forming the final R configuration product. The syn-S path, like syn-cis path in system I, only involves two proton-transfer steps, finally giving the R product. The syn-R path, similar to the syn-trans path in system I, involves two proton-transfer steps and one conformation adjustment step, finally giving the S product. 3.2.2. Analysis of Four Reaction Pathways. As shown in Figure 7, the energy of the optimized anti-R-COM was taken as the energy reference point. Among the four paths, the anti-R path is the most favorable with a 70.7 kJ/mol barrier. The other three paths have higher barriers. Considering the similarities with system I, the four pathways in system II were analyzed only briefly as follows. In terms of number of hydrogen bonds, the situation for system II (Figure S3 in the Supporting Information) is very similar to that for system I. For the most favorable anti-R path, the hydrogen bond network (also including a loose interaction between the substrate benzene CH and a catalyst oxygen atom) is maintained, consistent with its stability. The Mulliken population analysis (Tables S4−S7 in the Supporting Information) also shows a trend very similar to that in system I. Isomerization of α-alkynoate also involves a proton transfer and a back proton transfer. For energy decomposition analysis, results from IM1s to TS2s in system II are shown in Table S8 in the Supporting Information. A trend similar to that found for system I can be seen, although the differences among the four paths were reduced. On comparison of the most favorable antiR path with the syn-S pathway, the deciding term is INTTS2 − INTIM1, which indicates that the interaction between the substrate and catalyst at TS2 (relative to IM1) is more favorable in anti-R than in syn-S. In fact, the interaction itself is stronger

4. CONCLUSIONS In this study we used the B3LYP-GD3+PCM/6-31G* method to investigate the mechanisms of organocatalyzed isomerization of alkynoate to allenoate. On comparison of the PESs of both systems I and II, it was found that each of the four pairs of paths, anti-cis and anti-R paths, anti-trans and anti-S paths, syn2995

DOI: 10.1021/acscatal.6b00038 ACS Catal. 2016, 6, 2988−2996

Research Article

ACS Catalysis cis and syn-S paths, and syn-trans and syn-R paths, has the same trend in energy and the same product configuration. However, due to the methyl substituted in system II, the energy barriers in the first proton transfer are ∼9.5−15.9 kJ/mol higher than the corresponding energy barriers in system I; the relative energies of product−catalyst complexes are ∼4.1−10.3 kJ/mol lower than those in system I. As discussed above, anti-cis and anti-R paths are dominant paths in systems I and II, respectively, and the first proton-transfer step of these two paths possesses the highest energy barrier and is the ratedetermining step for the overall reaction. The experimental studies5,6 reported that the isomerization of α-unsubstituted alkynoates into allenoates (system I) is reversible, while the isomerization of α-substituted alkynoates into allenoates (system II) is irreversible. The present computational results indicate two reasons responsible for the suppression of the reverse reaction of α-substituted alkynoate isomerization. One is that α-substituted (methyl-substituted) alkynoate increases the energy barrier of the rate-determining step, and the other is that an α-substituted alkynoate generates more stable complexes between products and catalyst. Therefore, the theoretical calculations clearly explain the experimental observations. Furthermore, the α-substitution in system II increases the energy barrier of the rate-determining step and makes the final product more stable, thus making the entire process irreversible, while the isomerization of α-unsubstituted alkynoate in system I is reversible. The origin of selectivity has been discussed in terms of the hydrogen-bond structure, Mulliken charge population, and EDA analysis. On the whole, our computational results supported the experimental findings, and we proposed the isomerization mechanism of alkynoate to allenoate mediated by benzothiadiazine.

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Science (RCCS) at the Institute for Molecular Science are also acknowledged.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscatal.6b00038. AFIR calculation method, reaction paths, hydrogen-bond numbers of system II, PESs with high level basis set, FESs, Mulliken charge population and EDA, and Cartesian coordinates of the optimized structures in all reaction paths (PDF)

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*E-mail for K.M.: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to Prof. Satoshi Maeda for the use of the developmental version of the GRRM program. This work was partially supported by grants from Japan Society for the Promotion of Science (Grants-in-Aid for Scientific Research Nos. 24245005, 26105733, and 15H02158) at Kyoto University, and by a grant (H.X.) from the National Natural Science Foundation of China (Grant Nos. 21473227 and 21003143). The computer resources at the Institute for Information Management and Communication (IIMC) of Kyoto University and at the Research Center of Computer 2996

DOI: 10.1021/acscatal.6b00038 ACS Catal. 2016, 6, 2988−2996