Unveiling the Unexpected Reactivity of Electrophilic Diazoalkanes in [3+2] Cycloaddition Reactions within Molecular Electron Density Theory

Round 1

Reviewer 1 Report

            The contribution “Unveiling the Unexpected Reactivity of Electrophilic Diazoalkanes in [3+2] Cycloaddition Reactions within Molecular Electron Density Theory” by Luis R. Domingo, Mar Ríos-Gutiérrez and Nivedita Acharjee describes the in-depth theoretical studies on the title transformation. It is interesting paper, which provides new information on the mechanism of the [3+2] cycloaddition with use of diazoalkanes and NBDs which leads to interesting derivatives of practical use.

The importance of the paper was nicely explained in the introduction which showed how extensive this research area is. This was well supported by a great number of well-placed and up-to-date references.

The study approach seems well thought over (as shown in the computational methods) and seems like the level of theory was quite sophisticated. I cannot say anything of a critical nature here (I especially liked the ELF topological analysis of DAAs). For instance evaluated values of nucleophilicity and electrophilicity obtained using CDFT model seems very rational. Also the analysis of the reaction paths looks logic.

Concluding, the analysis of the mechanism of 32CA was performed at many levels and the final conclusion that there is a correlation between the populations of NNC core and the activation energy is valuable. Also the presented mechanism is useful for those that work with this and similar transformations, hence, I fully support the publication of these data in Chemistry and see no need to do any changes.

Author Response

We thank the nice comments given by Reviewer 1 accepting the manuscript.

Reviewer 2 Report

The present paper by Domingo, Ríos-Gutiérrez and Acharjee studies the [3+2] cycloaddition reaction between the norbornadiene and four diazoalkane molecules with different substituent functional groups. As the authors explicitly state throughout the manuscript, the predictions made by using the common chemical sense and the results obtained using the Conceptual DFT technique do not explain the experimental observations. Exploiting the Molecular Electron Density Theory (MEDT) developed by one of the authors of the current paper (LRD), they are able to obtain results in agreement with the experimental slowing-down of the studied reactions and to give an explanation of this behavior.

Overall the paper has a very good quality and it is suitable for publication in Chemistry. I believe the strong point of this paper is the large number of complementary tools the authors used. Moreover, the paper is on average well written and easy to read.

I only have few comments/remarks:

1) In section 3.2, page 5, line 164, the authors state that they used the “B3LYP/6-31G(d) computational level since it was used to define the electrophilicity and nucleophilicity scales [43,68,69].” The reason behind this is fully reasonable, however these results are the only ones in the paper that have been obtained with a different DFT functional and basis set. It would be nice to verify if the same trends shown in Table 2 are maintained. I anyway expect that this is the case.

2) In tables, I suggest to explicitly specify the units of measurement in the captions (for example, in Table 3 the units of measurement for ΔE, ΔH, ΔS and ΔG are missing).

3) The number of acronyms is very high and sometimes I had to look back in the paper for their meaning. Maybe, it will be useful to re-define the acronyms (maybe the less used, no need for 32CA o NBD and DAA) when they first occur in the sections.

4) There are some typos in the text. Few of them:

- Page 1: please remove the highlights in the keywords

- Page 7, line 204: “path” → “paths”

- Page 17, line 430: “disusbtituted” → “disubstituted”

- Page 17, line 431: “present” → “presents”

Author Response

We thank the nice comments and the suggestion given by Reviewer 2. All of them were made.

1) In section 3.2, page 5, line 164, the authors state that they used the “B3LYP/6-31G(d) computational level since it was used to define the electrophilicity and nucleophilicity scales [43,68,69].” The reason behind this is fully reasonable, however these results are the only ones in the paper that have been obtained with a different DFT functional and basis set. It would be nice to verify if the same trends shown in Table 2 are maintained. I anyway expect that this is the case.

R- In agreement with the referee’s comment, the MPWB1K/6-311G(d,p) reactivity indices have been computed and given is Table S3 in the Supplementary Material. As can be observed, the trends are mostly maintained.

2) In tables, I suggest to explicitly specify the units of measurement in the captions (for example, in Table 3 the units of measurement for ΔE, ΔH, ΔS and ΔG are missing).

R- In agreement with the referee’s suggestion, the units have been included in all tables.

3) The number of acronyms is very high and sometimes I had to look back in the paper for their meaning. Maybe, it will be useful to re-define the acronyms (maybe the less used, no need for 32CA o NBD and DAA) when they first occur in the sections.

R- All acronyms are defined in the text. The acronyms 32CA, TAC, MEDT, GEDT, CDFT, BET, ELF, QTAIM, NCI, FEDF, and NEDF are usual in MEDT studies.

Only the acronyms NBD (norbornadiene) and DAA (diazoalkane) are specific of this study.

In agreement with referee’s suggestion, acronyms LEDT, SCRF, NPA have been removed in this revised version.

4) There are some typos in the text. Few of them:

- Page 1: please remove the highlights in the keywords

R- The highlights in the keywords have been removed

- Page 7, line 204: “path” → “paths”

R- The suggested change has been done.

- Page 17, line 430: “disusbtituted” → “disubstituted”

R- The suggested change has been done.

- Page 17, line 431: “present” → “presents”

R- The suggested change has been done.