Theoretical Study of the Addition of CuâCarbenes to Acetylenes to

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Theoretical Study of the Addition of Cu– carbenes to Acetylenes to Form Chiral Allenes Kangbao Zhong, Chunhui Shan, Lei Zhu, Song Liu, Tao Zhang, Fenru Liu, Boming Shen, Yu Lan, and Ruopeng Bai J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13055 • Publication Date (Web): 19 Mar 2019 Downloaded from http://pubs.acs.org on March 19, 2019

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Journal of the American Chemical Society

Theoretical Study of the Addition of Cu–carbenes to Acetylenes to Form Chiral Allenes Kangbao Zhong, †# Chunhui Shan, †# Lei Zhu, † Song Liu, † Tao Zhang, † Fenru Liu, † Boming Shen, † Yu Lan,* †‡ Ruopeng Bai* † †

School of Chemistry and Chemical Engineering, Chongqing Key Laboratory of Theoretical and Computational Chemistry, Chongqing University, Chongqing 400030, China ‡

College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China

KEYWORDS: acetylene, Cu–carbene, DFT calculations, direct nucleophilic addition. ABSTRACT: Terminal alkynes have become one of the most versatile building blocks for C–C bond construction in the past few decades, and they are usually considered to convert to acetylides before further transformations. In this study, a novel direct nucleophilic addition mode for Cu(I)-catalyzed crosscoupling of terminal alkynes and N-tosylhydrazones to synthesize chiral allenes is proposed, and it was investigated by density functional theory with the M11-L density functional. Three different reaction pathways were considered and investigated. The computational results show that the proposed reaction pathway, which includes direct electrophilic attack of protonated acetylene, deprotonation of the vinyl cation, and catalyst regeneration, is the most favorable pathway. Another possible deprotonation–carbenation–insertion pathway is shown to be unfavorable. The direct electrophilic addition step is the rate- and enantioselectivity-determining step in the catalytic cycle. Noncovalent interaction analysis shows that the steric effect between the methyl group of the carbene moiety and the naphthalyl group of the bisoxazoline ligand is important to control the enantioselectivity. In addition, calculation of a series of chiral bisoxazoline ligands shows that a bulky group on the oxazoline ring is favorable for high enantioselectivity, which agrees with experimental observations. Moreover, copper acetylides are stable and their generation is a favorable pathway in the absence of chiral bisoxazoline ligands.

INTRODUCTION The carbon–carbon triple bond is one of the most basic functional groups, and it widely exists in pharmaceuticals, agrochemicals, and functional materials.1 Among these compounds, terminal alkynes have attracted significant attention because of their unique structural features and reactivities,2-7 and they have been widely investigated in the fields of organic synthesis, natural product chemistry, and materials science.1 The reaction modes of terminal alkynes are summarized in Figure 1. Because of the acidity of the terminal hydrogen atom of terminal alkynes, the C–H bond can be deprotonated to generate the corresponding acetylide, which usually acts as a nucleophile to react with possible electrophiles (type a). 810 The π bonds of alkynes are electron-rich, so electrophilic addition of electrophiles can occur to give the corresponding C–C double bonds (type b).11,12 The C–C triple bond can act as a ligand and coordinate to transition metal centers with moderate π-backbonding, which weakens the C≡C bond and enables subsequent nucleophilic attack to generate vinyl metal intermediates (type c). Moreover, coordination to a transition metal also increases the acidity of the terminal hydrogen atom of the terminal alkyne group, so subsequent deprotonation can also occur to give a metal–acetylide species (type d).13-26 In the past few decades, a series of new synthetic methodologies have enhanced alkyne chemistry and made alkynes one of the most versatile building blocks.27-35 Among these methodologies, transition-metal-catalyzed coupling reactions, such as Glaser–Hay reactions,36,37 Sonogashira reactions,38,39 Glaser–Eglinton reactions,40,41 Cadiot–Chodkiewicz reactions,42 and Castro–Stephens reactions,43,44 have received extensive attention as simple and convenient methods to construct internal C–C triple and double bonds.

Terminal alkynes usually undergo a deprotonation process to generate active acetylides before further conversion, such as transmetalation or nucleophilic addition.45-53 C–C bond formation without C–H bond cleavage of the terminal alkyne has been shown to be an unfavorable pathway. However, further mechanistic validation is required, especially under complex reaction conditions. For instance, in a previous study, we showed that direct nucleophilic addition of phenylacetylene to an imine occurs in the presence of a Ni catalyst, and deprotonation to generate nickel acetylide is unfavorable.23 These results show an

Figure 1. Activation modes of terminal alkynes.

alternative mode for terminal alkyne conversion could be possible in transition metal catalysis. Recently, Wang and co-workers reported a straightforward method to synthesize substituted allenes by Cu(I)-catalyzed cross-coupling of terminal alkynes and N-tosylhydrazones (Scheme 1a).54 Subsequently, they developed a Cu(I)-catalyzed cross-coupling reaction between carbenoids and aryl acetylenes (Scheme 1b).55 The excellent functional group compatibility, high yield, and good enantioselectivity make this reaction an efficient method for enantioselective synthesis of trisubstituted allenes.

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COMPUTATIONAL METHODS All of the density functional theory (DFT) calculations were performed with the Gaussian 09 series of programs.76 The B3-LYP functional77,78 with the standard 6-31G(d) basis set (SDD basis set for Cu) was used for the geometry optimizations in the gas phase. Harmonic vibrational frequency calculations were performed for all of the stationary points to determine whether they are local minima or transition structures and to derive the thermochemical corrections for the enthalpies and free energies. The M11-L functional79-82 proposed by Truhlar et al. with the 6-311+G(d,p) basis set (SDD basis set for Cu) was used to calculate the single-point energies in chloroform solvent to provide more accurate energy information.83-86 The solvent effect was considered by single-point calculations based on the gas-phase stationary points with the SMD87,88 continuum solvation model. The Gibbs free energies of the stationary points calculated using the M11-L functional are used to discuss the energies. The noncovalent interactions (NCI)89,90, lowest unoccupied molecular orbitals (LUMO), and electrostatic potentials Scheme 2. Possible Reaction Pathways for the Cu(I)-Catalyzed Cross-Coupling Reaction Between the Carbenoid and Acetylene. Figure 2. Possible mechanism for Cu(I)-catalyzed cross-coupling between a diazo group and a terminal alkyne.

In copper catalysis, the copper species generally plays two roles: terminal acetylene activation to generate a copper acetylide complex56-65 and carbenoid activation to give a metal–carbene species66-75 (Figure 2). Wang et al reported that the copper acetylide intermediate can react with a carbenoid to give a copper–carbene acetylide complex. They also speculated that the enantioselectivity is controlled by the intramolecular carbene insertion step. However, in our previous theoretical studies, we found that copper-assisted deprotonation of acetylene is a balanced process, but carbenation of copper is irreversible. Therefore, we infer that carbenation would occur before alkynylation. Indeed, when a copper–carbene species forms, the steric effect of a bulky ligand is unfavorable for further alkynylation. Electrophilic attack of the carbene moiety to acetylene also needs to be considered. Consequently, we became interested in this copper-catalyzed enantioselective trisubstituted allene synthesis reaction. In particular, we wanted to clarify the detailed alkyne conversion mode, that is, whether the copper acetylide is the key intermediate or the terminal alkyne directly adds to the copper–carbene moiety.

Scheme 1. Cu(I)-Catalyzed Cross-Coupling Reaction Between a Diazo group and a Terminal Alkyne.

(ESP) were calculated at the B3LYP/6-31G(d) (SDD for Cu) level.

RESULTS AND DISCUSSION Considering the rule of copper species, we propose three putative pathways for Cu-catalyzed cross-coupling of terminal alkynes and N-tosylhydrazones in Scheme 2. All of the pathways start with ligand-coordinated Cu(I) cationic species I. In the pathway proposed by Wang et al. (path A), after amine-assisted deprotonation of phenylacetylene, copper acetylide intermediate III is generated. Carbenation then occurs to give copper– carbene acetylide species V. An alternative pathway to generate species V involves carbenation of catalyst I followed by deprotonation of phenylacetylene (path B). Migratory insertion of the acetylide group into the carbene moiety then gives propargyl copper intermediate VI. Finally, chiral allene VII is generated by protonation of VI. We propose another path-


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Journal of the American Chemical Society way (path C) where once copper–carbene species VIII is generated, because of the electrophilicity of the carbene moiety, electrophilic addition of the terminal alkyne into the carbene π bond occurs to give vinyl cation

Figure 3. Cu(I)-catalyzed cross-coupling reaction between 1-(p-chlorophenyl)-1-diazoethane and phenylacetylene.

IX, which can be deprotonated by the amine to directly generate the common propargyl copper intermediate VI. With the above proposal in hand, theoretical calculations were performed to reveal the mechanism of the Cu(I)-catalyzed cross-coupling reaction between the carbenoid and acetylene. We initially focused on Wang’s proposed pathway (path A). As in their experimental work, we chose coupling of 1-(p-chlorophenyl)-1-diazoethane and phenylacetylene as the model reaction, in which the bisoxazoline ligand is selected as the chiral ligand. The amine-coordinated cationic copper(I) complex was chosen as the starting point for the free energy profiles (Figure 4). Coordination of phenylacetylene to the copper center generates intermediate 2, which is exergonic by 7.2 kcal/mol. Deprotonation of phenylacetylene in intermediate 2 by triethylamine then generates copper(I) acetylide 5 via transition state

Figure 4. Free energy profile of path A for the Cu(I)-catalyzed cross-coupling reaction between 1-(p-chlorophenyl)-1-diazoethane and phenylacetylene. The energies are in kcal/mol and represent the relative free energies calculated with the DFT/M11-L method in chloroform. The bond distances are in angstroms. Noncovalent interactions analysis of 7-ts (blue, attraction; green, weak interaction; red: steric effect).

4-ts, which is endergonic by 14.6 kcal/mol. The energy barrier for this step is 16.7 kcal/mol. Subsequent carbenation with coordination of carbenoid 6 occurs via transition state 7-ts by dissociation of nitrogen gas with an energy barrier of 26.2 kcal/mol to give copper–carbene acetylide complex 8. In the generated copper–carbene 8, the Cu–acetylide and Cu–carbene bond lengths are 1.93 and 1.88 Å, respectively. Next, migration insertion of the acetylide moiety into the Cu–carbene bond via three-membered ring transition state 9-ts releases 39.8 kcal/mol free energy, and propargyl copper complex 10 is generated. The C-Cu single bond length in 10 is 2.01 Å.

The energy barrier for the migration insertion step is 3.8 kcal/mol, indicating fast conversion of 8. Finally, protonation of 10 releases the final product 12 via transition state 11-ts, which is exergonic by 23.6 kcal/mol, and active catalyst copper species 1 is regenerated. The activation free energy for path A is 40.8 kcal/mol, indicating that it is an unfavorable pathway. The calculated rate-limiting step of path A is denitrogenation to generate copper–carbene acetylide complex 8. NCI analysis was performed to investigate the reactivity of this step. The calculated NCI map of transition state 7-ts is shown in Figure 4. It reveals that the interaction between the



benzyl group of the bisoxazoline ligand and the phenyl group of the reacting diazo compound (highlighted by the red circle) leads to significant steric repulsion, which is the reason for the high activation energy. The calculated high energy barrier of carbenation after alkynylation suggests that if the reaction order is changed, the extra steric repulsion will be released. Therefore, another pathway (path B) was also considered. The free energy profile of path B is shown in Figure 5. Ligand exchange with diazo 6 generates complex 13, which is endergonic by 7.6 kcal/mol. Subsequent denitrogenation of intermediate 13 occurs via transition state 14-ts by cleavage of the C–N bond with an energy barrier of only 5.2 kcal/mol to give copper–carbene intermediate 15, which releases 15.0 kcal/mol free energy. Phenylacetylene coordinated to intermediate 15 is deprotonated by the amine via transition state 16-ts with generation of the corresponding copper–carbene acetylide 8, which is endergonic by 29.3 kcal/mol. The energy barrier of deprotonation is 35.1 kcal/mol. Subsequent carbene insertion into the copper–acetylide bond and protonation are the same as path A, and they are not the rate-determining step. The total activation energy of path B is 35.1 kcal/mol. Because of the high energy barrier of the alkynylation step in path B, an alternative pathway is taken into account (path C), in which the terminal

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alkyne is directly attacked by the copper–carbene species (Figure 5). The energy barrier of direct intermolecular electrophilic addition of copper– carbene to phenylacetylene via transition state 17-ts is only 26.9 kcal/mol, which is 8.2 kcal/mol lower than that of the previously mentioned deprotonation step. In transition state 17-ts, the carbene carbon atom acts as electrophile to attack the C–C triple bond of phenylacetylene Vinyl cation species 18 is generated, in which the C–Cu bond length is 2.10 Å, and the length of the newly generated C–C single bond is 1.42 Å. The distances of Cu-C2 and Cu-C3 is 2.28 and 3.24 Å, and the bond angle of Cu-C1-C2 is 78.1o, which is indicates that there is no strong bonding between C-C double bond and copper center. To further validate our propose, we calculated the molecular orbitals of 18. The computational result shows that there is a strong orbital overlap between Cu and C1, and no obvious bonding was found between Cu and C2/C3 in occupied orbitals. Therefore, there is no coordination between copper and C-C double bond in 18. Direct nucleophilic addition is endergonic by only 7.1 kcal/mol. Vinyl cation 18 is deprotonated by the amine via transition state 19-ts, generating propargyl copper complex 10.

Figure 5. Free energy profiles of paths B and C. The energy values are in kcal/mol and represent the relative free energies calculated by the DFT/M11-L method in chloroform. The bond distances are in angstroms.


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Figure 6. Optimized structures of transition states 16-ts, 17-ts, 17′-ts, and 19-ts, intermediates 18 and 18′, and the molecular orbitals of intermediate 18. The bond lengths are in angstroms. AC2–C3–C4 is the C2–C3–C4 bond angle and ACu–C1–C2 is the Cu–C1–C2 bond angle.

The deprotonation step is exergonic by 17.6 kcal/mol and the energy barrier for this step is only 11.3 kcal/mol. Finally, similar to paths A and B, allene product 12 is released by protonation of 10 and active catalytic species 1 is regenerated by coordination of amine. The rate-determining step in path C is nucleophilic addition of acetylene and the overall activation energy is 26.9 kcal/mol, which agrees with experimental observation. To further investigate the possibility of the nucleophilic addition step with the carbene species, the electrostatic potential (ESP) surface was calculated and molecular orbital (MO) analysis was performed for copper– carbene species 15 with the M11-L density functional. The ESP surface shows that the positive charge in the carbene moiety is mainly located on the carbene carbon atom (Figure 7a). Moreover, the LUMO of 15 mainly consists of the p orbital of the carbene carbon atom (Figure 7b), which clearly reveal typical Fischer-type metal–carbene character. These results indicate that the carbene carbon atom is electron deficient and can be easily attacked by weak nucleophiles, such as terminal alkynes.

this step. The (R)-enantiomer 12 is generated by Si-face attack of the carbene via transition state 17-ts. Generation of the corresponding (S)-enantiomer 12′ is accomplished by the corresponding Re-face attack. The energy barrier of (S)-enantiomer generation via 17′-ts is 28.7 kcal/mol, which is 1.8 kcal/mol higher than that of 17-ts, indicating that generation of 12′ is unfavorable. Therefore, (R)-12 is considered to be the main product. The calculated enantiomeric excess (ee) is 91%, which is in good agreement with the experimental value (88% ee).

Figure 8. NCI analysis of 17-ts and 17′-ts (blue, attraction; green, weak interaction; red: steric effect).

Figure 7. (a) Electrostatic potential map of carbenoid copper intermediate 15. (b) LUMO energy of carbenoid copper intermediate 15 and the ratio of C1.

In the theoretical calculations, we found that nucleophilic addition is the rate-determining step and the enantioselectivity is also controlled in

To investigate the origin of the enantioselectivity, NCI analysis of the nucleophilic addition transition states 17-ts and 17′-ts was performed (Figure 8). There is a clear steric effect between the methyl group of the carbene moiety and the naphthalyl group of the bisoxazoline ligand in transition state 17′-ts, which reveals repulsion in this case. Furthermore, there is weak π-stacking between the phenyl group of the reacting acetylene and the naphthalyl group of transition state 17-ts. Therefore, the enantioselectivity is mainly controlled by the steric effect of the electrophilic addition transition state, which means that chiral bisoxazoline with large substituent groups is important for the enantioselectivity. From the above results, the substituent effect of the chiral bisoxazoline ligand is important for the enantioselectivity of copper-catalyzed crosscoupling of diazo compounds and terminal

Table 1. Theoretically Predicated and Experimentally Observed Enantioselectivities for a Series of Chiral Bisoxazoline Ligands.



R1

R2

ΔΔG‡ (kcal/mol)

1

Bn

2-Nap

1.8

96 : 4

94 : 6

2

Bn

Ph

0.7

77 : 23

87 :13

3

Me

Ph

0.1

55 : 45

67 : 33

Entry

er Calc.

Exp.

alkynes. Therefore, further theoretical calculations were performed to investigate how the chiral ligand affects the enantioselectivity of the allene. When the R group of bisoxazoline is changed from the 2-naphthalyl group to the phenyl group, the energy gap between Re-face and Si-face attack decreases to 0.7 kcal/mol, which is 1.1 kcal/mol lower than that with the naphthalyl group (Table 1). The corresponding calculated enantiomeric ratio (er) is 77:23, indicating an obvious enantioselectivity decrease. When the R group is changed from the benzyl to methyl (Table 1, entry 3), the energy gap between Re-face and Si-face attack decreases to only 0.1 kcal/mol, indicating poor enantioselectivity. In fact, the calculated er based on the energy profile is 55:45, which reasonably well agrees with the experimental result (67:33). These computational results are in agreement with our previous suggestion that the enantioselectivity is mainly controlled by the steric effect of the electrophilic addition transition state. Based on the calculated free energy profiles of the possible reaction pathways and the prediction of the origin of enantioselectivity, we can conclude that the catalytic cycle of copper-catalyzed cross-coupling of diazo compounds and terminal alkynes includes carbenation of the copper(I) catalyst, electrophilic attack of the terminal alkyne by the carbene moiety, and proton transfer. Both the rate- and enantioselectivity-determining steps are considered to be the electrophilic attack step. The theoretical calculations predict that a bulky ligand is unfavorable for alkynylation after carbenation of copper. Moreover, the Fischer-type cationic copper–carbene complex shows significant electrophilicity, so subsequent electrophilic attack of the terminal alkyne can easily occur. Following this idea, we propose that if a small ligand or ligand-free catalytic system is applied with a cuprate, an alternative pathway would occur. Therefore, we also investigated the mechanism of another copper-catalyzed cross-coupling of acetylene and N-tosylhydrazones pathway for achiral synthesis of allenes proposed by Wang et al. Differing from the above model reaction, a bidentate ligand-free copper-catalysis system, in which LiOtBu was used as base and ligand, and gives racemic allenes, was also reported experimentally. To further validate the effects of LiOtBu, the free energy profiles of paths A–C for Cu(I)-catalyzed cross-coupling between N-tosylhydrazones and phenylacetylene are also systematically taken into account (for details, see Supporting Information (SI)). The computational result shows that the deprotonation with LiOtBu is drastic exothermic, and the generated copper(I) acetylene intermediate is thermodynamic stable, which is different from the above results. Therefore, the deprotonation–carbenation–insertion pathway is the most favorable under strongly basic conditions.

CONCLUSIONS A novel electrophilic addition–deprotonation pathway for cationic Cu(I)-catalyzed cross-coupling of terminal alkynes and N-tosylhydrazones to synthesize chiral allenes has been investigated by DFT with the M11-L density functional. This novel pathway consists of four main steps:

(1) carbenation of the chiral bisoxazoline-coordinated copper species to generate a copper–carbene intermediate, (2) direct electrophilic addition of the carbene carbon moiety to the terminal alkyne to generate a vinyl cation species, (3) deprotonation of the vinyl cation to form a propargyl copper intermediate, and (4) and protonation to release the chiral substituted allene with regeneration of the copper catalyst. Differing from a previously reported mechanism, copper acetylide is not present in this new pathway. The calculated total activation energy is 26.9 kcal/mol. The direct electrophilic addition step is the rate-determining step in the catalytic cycle. DFT calculations reveal that the carbenation/migration insertion pathway proposed by Wang et al. is unfavorable because the overall activation energy is 40.8 kcal/mol. In addition, the enantioselectivity-determining step is predicted to be electrophilic attack of copper–carbene to the terminal alkyne. NCI analysis shows that the steric effect between the methyl group of the carbene moiety and the naphthalyl group of the bisoxazoline ligand is important to control the enantioselectivity. A series of chiral bisoxazoline ligands were considered. We found that a bulky group on the oxazoline is favorable for high enantioselectivity, which agrees with experimental observations. The theoretical calculations predict that a bulky ligand is unfavorable for alkynylation after carbenation of copper. Moreover, the Fischer-type cationic copper–carbene complex shows significant electrophilicity, so the subsequent electrophilic attack of acetylene can easily occur. Following this idea, we propose that if a small ligand or ligand-free catalytic system is applied with a cuprate, an alternative pathway will occur. A contrast study of the ligand-free cuprate-catalyzed cross-coupling reaction of carbenoids and terminal alkynes was also performed. The computational results show that the regular pathway involving alkynylation, carbenation, carbene insertion, and protonation is favorable in this case. We believe that this study will aid in the understanding of copper-catalyzed cross-coupling of carbenoids and terminal alkynes, and it will provide a practical theoretical guide for further experimental investigations.

ASSOCIATED CONTENT Supporting Information This material is available free of charge via the Internet at http://pubs.acs.org. Computational details, Cartesian coordinates and energies of all reported structures.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] *E-mail: [email protected] ORCID Yu Lan: 0000-0002-2328-0020 Ruopeng Bai: 0000-0002-1097-8526

Author Contributions #

These authors contributed equally.

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT This project was supported by the National Science Foundation of China (Grants 21822303 and 21772020), Fundamental Research Funds for the Central Universities (Chongqing University) (No. 2018CDXZ0002; 2018CDPTCG0001/4; 2018CDYJSY0055) and Chongqing Science and Technology Committee. We are also grateful for support by Chongqing Postdoctoral Science Special Foundation (XmT2018085) and graduate research and innovation foundation of Chongqing, China (Grant No. CYB18043).


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