Mechanism and origin of stereoselectivity and regioselectivity in cobalt-catalyzed C–H functionalization of arylphosphinamide†

Chuanchuan Luo‡ , Saibo Cao‡, Hao-Ran Yang* and Yang Wang*
Department of Material and Chemical Engineering, Zhengzhou University of Light Industry, 136 Science Avenue, Zhengzhou, Henan province, 450001 P. R. China. E-mail: yanghr@zzuli.edu.cn; wangyang@zzuli.edu.cn

First published on 19th June 2025

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Introduction

The distinct reactivity of cobalt complexes, particularly for high-valence Co(III) catalysts, renders Co-based systems highly attractive for C–C/C–heteroatom bond formation.^1–7 The growing appeal of these systems stems from earth abundance, cost efficiency, and multipurpose catalytic behavior. Two complementary strategies have emerged for Co(III)-catalyzed asymmetric C–H activation. The first approach consists of employing an achiral Cp*Co(III) catalyst in combination with an external chiral carboxylic acid (CCA) ligand to achieve enantiocontrol (Scheme 1A).^8–15 The second strategy is pioneered by Cramer and consists of utilizing chiral Cp^xCo(III) complexes bearing customized cyclopentadienyl (Cp^x) ligands (Scheme 1B).^16–18 These methodologies have been demonstrated to be remarkably successful, but both fundamentally depend on the use of pseudotetrahedral CpCo(III) catalytic systems, which have inherent limitations. The synthetic challenges associated with Cp^xCo(III) catalysts, including multistep preparation protocols and limited structural flexibility, have strongly constrained progress in this field. Daugulis and coworkers introduced in situ generated Co(III)-catalyzed C–H functionalization as a more sustainable alternative (Scheme 1C).¹⁹ This innovative approach consists of in situ oxidation of commercially available Co(II) salts to form active Co(III) species, bypassing the need for preformed catalysts while offering superior atom economy and cost efficiency.^20–26 However, the development of an asymmetric variant of this practical methodology remains an outstanding challenge in the field.

Chiral phosphorus compounds constitute a privileged class of molecules that have found widespread application as chiral ligands and organocatalysts in asymmetric synthesis.^27–30 Consequently, considerable effort has been expended toward developing efficient asymmetric synthetic methods. Recent advances in transition-metal-catalyzed enantioselective C–H functionalization have resulted in a powerful strategy for constructing chiral frameworks, including P-stereogenic phosphorus compounds.^31–34 However, existing methodologies predominantly utilize noble metal catalysts, such as Pd, Rh, and Ir systems.^35–42 The development of catalytic systems in which earth-abundant 3d transition metals are employed to access these valuable chiral compounds remains largely unexplored to date.

Shi and coworkers recently reported the first successful example of Co-catalyzed enantioselective C–H activation involving arylphosphonamides (Scheme 2).⁴³ Octahedral Co(III) complexes are demonstrated as crucial catalysts for achieving stereocontrol of this transformation. A catalytic paradigm has thus been established for constructing chiral phosphorus compounds through earth-abundant transition-metal catalysis.

As illustrated in Scheme 2, selective C–H activation at the phenyl group adjacent to phosphorus enables the formation of P-stereogenic centers with exceptional enantioselectivity (98% ee). Despite the considerable progress made by Shi and coworkers in elucidating the mechanism of this transformation, several critical issues remain to be unresolved: (1) identification of the most energetically favorable reaction pathway remains challenging; (2) the molecular basis for achieving such high stereoselectivity requires further clarification; (3) although [2,1]-insertion of terminal alkynes consistently yields single regioisomeric products, the fundamental origins of this regiocontrol need to be systematically investigated. Building upon our group's extensive expertise in computational mechanistic studies of both organometallic^44–47 and organocatalytic^48–54 processes, we conduct a comprehensive density functional theory (DFT) investigation into this Co-catalyzed C–H functionalization system. The DFT calculation has been extensively utilized for the mechanistic investigation of reactions catalyzed by transition-metals^55–64 and organocatalysts.^65–72 The aim of this study is to determine the energetically preferred reaction pathway and thereby uncover the structural and electronic determinants governing stereoselectivity and regioselectivity.

Experimental

Computational details

All quantum chemical calculations are performed using the Gaussian 09 software package.⁷³ Geometry optimizations were conducted using the M06-L functional^74,75 at 298 K and 1 atm. The 6-31G(d,p) basis set^76,77 is used for the C, H, O, N and P atoms, whereas the SDD basis set^78,79 is used for the Co atom. Solvation effects are incorporated into the optimization procedures using the integral equation formalism polarizable continuum model (IEF-PCM)^80,81 with 2-methyl-2-propanol (^tBuOH) as the solvent. Vibrational frequency analyses are systematically performed at an identical theoretical level to characterize the stationary points in the system: (1) all intermediates were confirmed by the absence of imaginary frequencies and (2) transition states were verified by possessing exactly one imaginary frequency corresponding to the motion of the reaction coordinate. To improve the accuracy of the computed energy, single-point calculations are executed using M06-L with Grimme's D3 dispersion correction combined with the Def2-TZVP basis set^82,83 for all atomic centers. An interaction region indicator (IRI) analysis is conducted using the Multiwfn software package,⁸⁴ and subsequent visualization was performed using the Visual Molecular Dynamics (VMD) molecular graphics system.⁸⁵

To test the accuracy of the results obtained at the M06-L/6-31G(d,p) (sdd for Co atom)//IEF-PCM(^tBuOH) level, the structures of the stereoselectivity-determining step are re-optimized using B3LYP,⁸⁶ B3PW91,⁸⁷ Cam-B3LYP,⁸⁸ M06-2X,⁸⁹ ωB97X-D⁹⁰ methods. The computational results are summarized in Table S1 of the ESI.† Compared with the results calculated using the M06-L method, the computational outcomes obtained at the different methods have tiny differences and same trends, thus, we think the conclusions based on the results calculated using the M06-L functional are reliable.

Results and discussion

Reaction mechanism

Initial calculations show that the ligand exchange of Saloxs and Co(OAc)₂ is exothermic and a feasible process (ΔG = −10.2 kcal mol⁻¹, Fig. S1 of the ESI†), which is then oxidized by Mn(OAc)₂ to yield the Co^III–Saloxs species. Thus, the Co^III–Saloxs species should be the catalytically active species and is selected as the starting material in our theoretical study (Scheme 3).

The catalytic process proceeds through four key steps. The cycle commences with ligand exchange, followed by N–H deprotonation to form the N,N-bidentate cobalt intermediate Int-I. This intermediate undergoes concerted metalation–deprotonation (CMD)^91,92 to cleave the aromatic C(sp²)–H bond via a six-membered transition state, yielding the cyclometalated intermediate Int-II. This intermediate reacts with the alkyne to induce alkyne insertion,^93,94 which can occur through two distinct pathways. The major pathway proceeds through [2,1]-insertion of the terminal alkyne into the Co–C bond to form Int-III, whereas the alternative [1,2]-insertion pathway generates the regioisomeric intermediate Int-III′. Finally, Int-III undergoes reductive elimination followed by reoxidation to release the P-stereogenic product while regenerating the active Co^III–Saloxs species. The reaction mechanism and origins of stereoselectivity and regioselectivity will be discussed in detail in the following sections.

Formation of a five-membered metallacycle

Our computational investigation begins with Co^III–Saloxs as the catalytically active species (Fig. 1). The reaction is initiated by the substrate 1a and Co^III–Saloxs to form the intermediate 4 via an endothermic process (14.7 kcal mol⁻¹).

As illustrated in Fig. 2, coordination of the N–H bond to the cobalt center induces considerable bond elongation (1.07 Å vs. 1.01 Å in the free substrate), demonstrating catalytic weakening of the N–H bond through Co–N coordination. This activation enables a concerted hydrogen abstraction process to occur, where the acetate ligand (AcO⁻) facilitates N–H cleavage via a six-membered cyclic transition state (5-ts). This process has an energy barrier of 15.7 kcal mol⁻¹. Subsequent elimination of acetic acid generates the five-membered cobaltacycle intermediate 6, for which the Gibbs free energy is 1.7 kcal mol⁻¹ lower than that of the reactant. In addition, we have also recalculated the energies of N–H deprotonation process at 50 °C to verify the effects of temperature. The computational results show that the Gibbs free energies obtained at 25 °C have a tiny difference from the values obtained at 50 °C. Thus, we think the temperature used in the calculations have the same tendency and little influence on the results.

Stereoselective C–H bond activation

Subsequently, the five-membered cobaltacycle intermediate 6 undergoes stereoselective C–H bond activation at either of the prochiral phenyl groups (shown in cyan/orange in Fig. 3), where the absolute configuration is established around the phosphorus atom. As depicted in Fig. 3, the cleavage of the orange-colored phenyl C–H bond forms an R-configured P-stereocenter through the transition state 7-ts-r, whereas the activation of the cyan-colored phenyl C–H bond generates an S-configured P-stereocenter via the transition state 7-ts-s.

The energy barriers to these two stereoselective pathways associated with transition states 7-ts-s and 7-ts-r are 17.0 and 21.1 kcal mol⁻¹ (Fig. 1), respectively. Thus, the S-configured C–H activation pathway is energetically more favorable than the R-configured C–H activation pathway. The C–H bond is elongated from 1.09/1.08 Å (Fig. 2) in intermediate 6 to 1.31/1.32 Å (Fig. 3) in transition state 7-ts-r/7-ts-s, showing that the C–H bond is broken during the C–H bond activation process.

In the experiment, there is a large excess of NaOPiv in the reaction; the OAc ligands at the metal will be substituted to some degree or other by pivolate. Thus, we have then considered the pivolate-ligated cobalt species promoted C–H functionalization of arylphosphinamide. Three pathways are calculated and compared and the detailed results are provided in Fig. S2 of the ESI.† The computational results show that the energy barriers of N–H deprotonation process are 16.3, 19.5, and 16.6 kcal mol⁻¹, respectively. The energy barriers of pivolate-participated C–H activation process is 22.4 and 18.2 kcal mol⁻¹ associated with R- and S-configured pathways, respectively. These computational results show that the energy barriers involved in pivolate-ligated cobalt species promoted C–H functionalization are disfavored than those in acetate-ligated cobalt species.

Alkyne insertion and reductive elimination

Subsequently, the metallacycle species undergoes the [2,1]-insertion with the terminal alkyne 2a to afford the seven-membered ring intermediates 10-r and 10-s via the transition states 9-ts-r and 9-ts-s, respectively. The energy barriers to the [2,1]-insertion process associated with the transition states 9-ts-r and 9-ts-s are 26.9 and 23.6 kcal mol⁻¹ (Fig. 2), respectively.

Alternatively, the metallacycle species can undergo the [1,2]-insertion with the terminal alkyne 2a to give a regioselective isomer. Only S-configured [1,2]-insertion is considered. As depicted in Scheme 4, the energy barrier to the [1,2]-insertion pathway via the transition state 9′-ts-s is 28.1 kcal mol⁻¹, which is 4.5 kcal mol⁻¹ higher than that to the S-configured [2,1]-insertion pathway. This energy difference aligns with the experimental observations that only a single regioisomer is obtained.

Next, the reductive elimination of the seven-membered ring intermediate yields the final product and Co(I) species via the transition state 11-ts. The computational results presented in Fig. 1 show that the reductive elimination process can overcome the energy barriers of 16.6 and 17.9 kcal mol⁻¹ associated with 11-ts-s and 11-ts-r, respectively.

The energy barriers to the individual steps for the R-configured pathway are 15.7, 21.1, 26.9, and 17.9 kcal mol⁻¹ and 15.7, 17.0, 23.6, and 16.6 kcal mol⁻¹ for the S-configured pathway. Thus, the S-configured pathway is more energetically favorable than the R-configured pathway and the alternative [1,2]-insertion requires 4.5 kcal mol⁻¹ more energy than [2,1]-insertion. These computational results are in good agreement with the experimental observations.

Origins of selectivities

On the basis of the analyses presented above, the energy barriers to the formation of the P-stereogenic center during the C–H bond activation process for the R- and S-configured isomers are 21.1 and 17.0 kcal mol⁻¹, respectively. The highest energy barrier is associated with the alkyne insertion process, which should therefore be the rate-determining step. Consequently, we identify the sequential C–H activation and alkyne insertion processes as the stereoselectivity-determining step. Other than [2,1]-alkyne insertion, [1,2]-insertion can also occur during the reaction; thus, the alkyne insertion process also determines the regioselectivity, with [2,1]-alkyne insertion proceeding preferentially.

Origin of stereoselectivity

The calculated energy barrier to the entire S-configured pathway is calculated to be 3.3 kcal mol⁻¹ lower than that to the entire R-configured pathway (Fig. 1). This energy difference corresponds to an enantiomeric excess (ee) of 99.3%, which aligns well with the experimentally observed 98% ee. To obtain an in-depth understanding of the origin of stereoselectivity, an IRI analysis is performed to visualize the noncovalent interactions in the stereoselective transition states.

During the C–H activation process, the C–H⋯N and C–H⋯π noncovalent interactions between the ligand and substrate 1a occur in both 7-ts-r and 7-ts-s. These two types of noncovalent interactions contribute equally to the corresponding transition state. The LP⋯π noncovalent interaction only exists in 7-ts-r, whereas three C–H⋯O noncovalent interactions occur only in 7-ts-s. In conclusion, there are more noncovalent interactions in the transition state 7-ts-s than in 7-ts-r, which is why the S-configured C–H activation process occurs preferentially.

The computational results presented above show that the alkyne insertion process also determines the stereoselectivity; thus, an IRI analysis is also performed on 9-ts. As shown in Fig. 4, the π⋯π and C–H⋯O noncovalent interactions exist in both 9-ts-r and 9-ts-s. For the π⋯π noncovalent interaction, the distances between the phenyl group of the alkyne 2a and the quinoline moiety are 3.04 and 2.98 Å in 9-ts-r and 9-ts-s, respectively, which contribute equally to the corresponding transition state. There is one C–H⋯O noncovalent interaction in 9-ts-r and the distance between the two interacting moieties is 2.52 Å. In 9-ts-s, the distance of the C–H⋯O noncovalent interaction between the two interacting moieties is larger than that in 9-ts-r. Thus, the C–H⋯O noncovalent interactions are stronger in the R-configured transition state than in the S-configured transition state, but this advantage is offset by the unique C–H⋯π and LP⋯π noncovalent interactions in the S-configured transition state 9-ts-s. Therefore, the predominant non-covalent interactions in the S-configured transition state govern the high-level stereoselectivity.

Origin of regioselectivity

Regioselective alkyne insertion occurs between the intermediates 8 and 2a, where the [1,2]-insertion and [2,1]-insertion modes lead to the formation of the seven-membered cobaltacycles 10′-s and 10-s, respectively. The energy barriers to these two insertion modes are 28.1 and 23.6 kcal mol⁻¹ associated with transition states 9′-ts-s and 9-ts-s, respectively. These results indicate that the [2,1]-insertion mode is more favorable than the [1,2]-insertion mode, which is in accordance with the experimental observations. The regioselectivity of this process is verified by the FMO analysis. As shown in Fig. 5, the FMOs of the regioselective transition states can be divided into two interacting moieties, i.e., 8-s-part and 2a-part. In the [2,1]-insertion mode, the HOMO of 2a directly interacts with the LUMO of 8-s directly to realize the alkyne insertion and the energy gap between the two interacting moieties is 2.23 eV. However, in the [1,2]-insertion mode, the HOMO of 2a interacts with the LUMO+2 of 8-s and the corresponding energy gap (3.69 eV) is higher than that for the [2,1]-insertion mode. This result indicates that a higher energy gap between the two interacting moieties results in a higher energy barrier to [1,2]-insertion, such that [2,1]-insertion occurs preferentially.

Conclusions

In this study, DFT is used to systematically investigate the mechanism and origins of the selectivities (i.e., the stereoselectivity and regioselectivity) of the Co-catalyzed C–H functionalization of arylphosphinamide. The computational results show that the most energetically favorable pathway has four elementary steps: N–H deprotonation, stereoselective C–H bond activation, stereoselective and regioselective alkyne insertion, and reductive elimination. The C–H bond activation and alkyne insertion steps are identified to be the stereoselectivity-determining process, which lead to the formation of the S-configurational isomer forming as the major product. An IRI analysis shows that the predominant non-covalent interactions found in the S-configured transition state considerably lower the relative Gibbs free energy, inducing stereoselectivity. The alkyne insertion process determines the regioselectivity, where the [2,1]-insertion mode is more energetically favorable than the [1,2]-insertion mode. An FMO analysis shows that the regioselectivity is determined by the energy gap between the two interacting moieties in the possible transition states.

Data availability

The data supporting this article have been included as part of the ESI.†

Author contributions

Luo C. C. and Cao S. B.: data curation, formal analysis, and investigation; Yang H.-R.: conceptualization, supervision, review & editing; Wang Y.: conceptualization, supervision, funding acquisition, writing – original draft, review & editing.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the National Natural Science Foundation of China (21903072), the Key R&D and Promotion Projects (Science and Technology Key Projects) of Henan Province (no. 242102310470), and the Key Projects of Colleges and Universities in Henan Province (no. 24B150045). We also thank Edanz (http://www.liwenbianji.cn) for editing a draft of this manuscript.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d5cy00519a

‡ Luo C. C. and Cao S. B. contributed equally.

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