Computational Analysis of the Asymmetric Hydrogenation of γ-Ketoacids: Weak Interactions and Kinetics

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In the manuscript, Golovanov and Pospelov have reported a computational study on the mechanism of asymmetric hydrogenation of γ-ketoacids catalyzed by the Ni(S,S)-QuinoxP* system, which was conducted via DFT calculations combined with NCI (noncovalent interaction) analysis and sobEDAw energy decomposition analysis. The main stages of the reaction mechanism were clarified, including the formation of the NiH(S,S-QuinoxP*)⁺ catalytic species, hydride transfer, and hydrogen "metathesis" step, with the hydride transfer from Ni to the carbonyl carbon of the substrate identified as both the rate-limiting and stereochemistry-determining step. Unlike conventional experimental studies on Ni-catalyzed γ-ketoacid hydrogenation that lack detailed mechanistic explanations, this work visualized and quantified the weak interactions contributing to stereoselectivity, such as the π-alkyl interactions in TS1-R and the alkyl chain-tert-butyl interactions in TS3-R, and the DFT-calculated 96% enantiomeric excess (ee) of the product showed good agreement with experimental data. Overall, after addressing the aforementioned comments, this manuscript might be suitable for publication in Molecules after major revision.

1. The other DFT methods should be used to test the reliability of the selected DFT method.
2. The energy of S-configurational transition state is higher than that of the R-configurational TS in the first step, is this correct? The Ni-H species has been assumed as the initial catalyst, is this proper? Why the addition of H2 could significantly improve the energies?
3. The quality of the figures should be significantly improved for publication.
4. Conformation searches should be performed for the stereoselectivity-determining step.
5. The abstract fails to specify the specific chemical process corresponding to the "rate-limiting step", which is the step of hydrogen transfer from Ni to the carbonyl carbon of the substrate.
6. In the research background section, only the catalysis of transition metals replacing noble metals is mentioned in a general manner, without clarifying the research focus of the asymmetric hydrogenation of γ-ketoacids or introducing γ-ketoacids themselves.
7. Scheme 1 fails to clearly indicate core structures, such as the coordination of Ni in the catalytic species.
8. No arrow is labeled when ketoacid is added in Scheme 1.
9. For transition states and the structures before and after them, solid lines and dashed lines should be correctly used to indicate bond formation and cleavage.
10. There is no labeling of R/S configurations in the entire catalytic cycle; additionally, the difference in Ni-H₂ bond distance between 3-R and 3-S needs to be highlighted, and the bond length can be directly labeled between Ni and H₂ for easier understanding.
11. It is recommended to label the type of each step in the catalytic cycle and correspond these labels to the step numbers described in the main text.
12. The structures of TS1 and TS2 are missing from the mechanism diagram.
13. The mechanism diagram is crudely drawn: the H₂ in structure 4 is placed at the bottom, and the arrows of the cycle are overall asymmetric.
14. Scheme 2 lacks coordinate axes—it does not clearly label the vertical axis for Gibbs free energy and the corresponding energy unit, and the horizontal axis for reaction progress does not correspond to specific steps.
15. The energy difference between enantiomers should be labeled for key steps to correlate with the conclusion of 96% ee.
16. For Scheme 2, solid lines and dashed lines should also be correctly used to indicate bond formation and cleavage for transition states and the structures before and after them.
17. The description of NCI analysis is insufficient; for instance, the π-alkyl interaction region in TS1-R and the strong interaction sites in TS3-R need to be described in the text in correspondence with the visualized results in the figures to facilitate readers' understanding.
18. The kinetic analysis is inadequate—it only mentions that hydrogen metathesis kinetically favors the formation of R-type products without supplementing kinetic parameters such as the ratio of rate constants for the R/S pathways; a simple derivation or citation of rate data is required to support the conclusion.

Author Response

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Reviewer 2 Report

Comments and Suggestions for Authors

The work carried out by the authors is interesting and well executed. However, it presents two very important specific problems with regard to the mechanism they propose, which should be verified before the article can be published in Molecules. The authors propose an ad hoc mechanism for an expected result, but do not take into account the alternatives.

The first of these concerns is the source of hydrogen in the formation of complex 1. The dissociation energy of the hydrogen molecule and that of an OH bond in trifluoroethanol are very similar, and so, the solvent could be very likely to be the source of this hydrogen. Furthermore, the ligand also has a COOH group which also has a similar dissociation energy than the previous examples, especially if we take into account the strong hydrogen bonds that could be established with the solvent. Therefore, there are several competitive mechanisms. I think that authors should include explicit solvent to better improve their study.

Secondly, the authors directly propose that the complex is formed with the carbonyl group of interest and that hydrogen transfer takes place on it, but they do not consider that it could take place on the other part of the ligand that also has a carbonyl group, either in the form of COOH or COO-.

A minor point: the text between lines 54 and 56 should be revised because it does not make sense. Also, please control the use of the word 'particle' instead of 'structure'.

Author Response

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Reviewer 3 Report

Comments and Suggestions for Authors

Authors carried out DFT calculations to investigate a reaction mechanism for the asymmetric hydrogenation of gamma-keto acids, however, there are some issues that needs to be addressed before publication. 

1. Authors carried out DFT calculations using Gaussian 16; however, it is not clear to me whether the geometry is optimized in vacuum space, followed by single point calculations using SMD model, or the geometry was optimized using SMD  model. Please clarify.
2. A detailed reaction pathway was proposed over the Ni complex, is there any other competing pathway that could lead to different products (selectivity related issues)? Please clarify. 
3. On page two, authors discussed the potential formation of mono- and dihydride and their dimer structures. I think the authors should also investigate the stability of the considered Ni complex, such as the possibility of the formation of the dihydride and their dimer forms and their impact on the reaction energetics and kinetics. I think this is important to discuss in this paper.
4. Authors constructed the reaction free energy diagram, scheme 2, however, it is not clear in terms of the spin states. I'm wondering for the Ni complex, is there any possible spin crossing, which could lead to even lower kinetic barrier and reaction energetics? This should be investigated and discussed in the manuscript. 
5.  I think it would also be interesting to add the frontier orbitals, electrostatic potential mapping, or charge distribution for the Ni complex with/without reaction intermediates and transition state, to visualize how the electronic structures change at various reaction steps, and elaborate on the catalytic properties regarding this type of catalysts and future design principles. 

Author Response

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Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I recommend the publication of the revised manuscript.

Author Response

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Reviewer 2 Report

Comments and Suggestions for Authors

Authors have successfully explained some issues concerning the first version and now is more clarified. Some other questions about the manuscript:

Scheme 2. Put the delta of delta of G (2.4) upper in the scheme because in this position is not possible to adscribe to TS1.

I think that the complete structure of the key-stereochemical step should be presented in a separate figure in the manuscript.

Explain the different terms of the Eyring Polanyi equation in the manuscript.

Conclusions are somewhat scarce. There are no findings explained. No mention, i.e., is made to the preferred calculated stereochemistry and some energy data.

Author Response

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Reviewer 3 Report

Comments and Suggestions for Authors

The authors have thoroughly addressed all points raised, significantly improving the manuscript

Comments on the Quality of English Language

English reads better than before. 

Author Response

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