Mechanistic investigations on Pinnick oxidation: a density functional theory study

A computational study on Pinnick oxidation of aldehydes into carboxylic acids using density functional theory (DFT) calculations has been evaluated with the (SMD)-M06-2X/aug-pVDZ level of theory, leading to an important understanding of the reaction mechanism that agrees with the experimental observations and explaining the substantial role of acid in driving the reaction. The DFT results elucidated that the first reaction step (FRS) proceeds in a manner where chlorous acid reacts with the aldehyde group through a distorted six-membered ring transition state to give a hydroxyallyl chlorite intermediate that undergoes a pericyclic fragmentation to release the carboxylic acid as a second reaction step (SRS). 1H NMR experiments and simulations showed that hydrogen bonding between carbonyl and t-butanol is unlikely to occur. Additionally, it was found that the FRS is a rate-determining and thermoneutral step, whereas SRS is highly exergonic with a low energetic barrier due to the Cl(III) → Cl(II) reduction. Frontier molecular orbital analysis, intrinsic reaction coordinate, molecular dynamics and distortion/interaction analysis further supported the proposed mechanism.


General Comments
I am missing a Scheme/Figure in the article that summarized the actual experimental conditions that transfer the corresponding aldehydes to carboxylic acids (including solvent, temperature, additives, reaction time, yield, …). The calculated barrier should then be compared to these conditions. In Figure 4, the hydrogen-bonded adduct 7t-BuOH shows a cis-orientation. I would have assumed that the alcohol binds from the side of the hydrogen atom (and not the alkyl chain). Have the authors checked this isomeric structure and what is the relative energy. The discussion of Figure 5 (NMR shifts) is not really clear. Obviously, there is a significant shift upon mixing acrolein and tBuOH. What do the authors mean with the statement "if this slight shift … is true"? Do they question their own findings here? Why do the authors study the FMOs in that much detail? If this is considered to be an ene-type reaction, the authors should compare their findings to literature-known examples. Similarly, the discussion of the IRC is not really clear (or necessary). Obviously, the shape prompted the authors to perform MD simulations. However, these simulations are not really described in the computational section. How many different starting geometries have been selected (e.g., how many different trajectories have been analyzed?). I get the impression that only one trajectory was used. If this is true, the results are statistically irrelevant and should not be discussed. I am surprised to find that the MD simulations did not include implicit tBuOH molecules. This would give a better answer whether the alcohol plays an important role here or not. Have the authors included other mechanistic scenarios into their investigations? From the top of my head, I am wondering if an alcohol could act as a proton shuttle through a 7-or 8-membered transition state? Finally, the authors analyze differently substituted cinnamaldehyde derivatives. Please check the numbering carefully as the number 7 appears frequently with and without letters. Given the accuracy of the chosen method (see above), I am wondering in general how reliable the energetic differences are. How well do they correlate e.g., with Hammett constants? Certainly, it is not necessary to show all structures and transition states on one page. Select 1-2 examples and show and discuss them. Similarly, I am wondering whether the distortion/interaction analysis is meaningful and helpful. The activation energy changed by less than 1 kcal/mol which is clearly within the error margin of the BSSE at the given level.

Minor Comments
The whole manuscript needs a careful editing. I am not a native speaker myself but there are many spelling mistakes, incomplete sentences and otherwise unusual wordings. Personally, I do not like the wording "first reaction step FRS" as it is a meaningless expression. It might be better to refer to the rate-limiting step which gives additional mechanistic insight. Why do the authors use numbers in Fig. 1 but not refer to them in the text. This would help to better understand the written statement. On page 2, right column, the authors write that the proton transfer between dihydrogenphosphate and chlorite is thermodynamically feasible but give a positive reaction free energy. This does not fit. In the context of the distortion/interaction analysis, the authors should also mention the closely related activation-strain model by Bickelhaupt. In the Supporting information, please check the numbers for the individual structures (e.g., Structure 8 should be TS8, I guess). Furthermore, please additionally quote the imaginary Review form: Reviewer 2 Is the manuscript scientifically sound in its present form? No

Do you have any ethical concerns with this paper? No
Have you any concerns about statistical analyses in this paper? No

Recommendation?
Major revision is needed (please make suggestions in comments)

Comments to the Author(s)
The paper of Hussein and co-workers presents a computational study on the mechanism of the Pinnick oxidation of aldehydes into carboxylic acids. The paper is focused on the analysis of the Proton Transfer (PT) and nucleophilic attack (NA) to the carbonyl group of the aldehyde; followed by a second process involving a pericyclic fragmentation. The stepwise and concerted mechanisms were assessed for the PT+NA process; although the work reported only the results for the concerted path, since the TS for the PT of the stepwise mechanism was not found. The authors performed MD and distortion/interaction-activation strain analyses to get further insights on the mechanisms. The topic of this study is interesting, since Pinnick oxidation is a relevant reaction and this work can provide useful information regarding the reaction mechanism. On this basis, this manuscript can be suitable for publication in Royal Society Open Science. However, some important issues should be addressed: 1. In Figure 2, the depicted stepwise mechanism is incomplete. The TS for the nucleophilic attack to the carbonyl group (after the PT step) should be included in the figure. 2. Even if the TS for the PT step of the stepwise mechanism was not found, the authors should comment about the search for the NA step of the stepwise mechanism. This is important, since the stepwise mechanism cannot be ruled out just because the TS for the PT was not located. Are there available experimental data for the kinetics of this reaction?
3. The MD performed with Gaussian09 correspond to the Born-Oppenheimer Molecular Dynamics (BOMD)? In this regard, the MD of a single trajectory does not provide any meaningful insight in terms of the timescale associated to the mechanism. The MD with quasiclassical (QCT) trajectories should be used instead in order to properly sample the normal modes on the TS before the propagation of the BOMD trajectories (see for example: Angew. Chem. Int. Ed. (2014) 53, 8664; and JACS (2015) 137, 4749). This normal mode sampling together with the propagation of a few trajectories should be enough to get the correct information regarding the timescale of the involved processes in the reaction mechanism.
4. Distortion-interaction analyses of these types of reactions focusing solely on the TS are not always informative. More insight would likely be obtained by performing distortion-interaction analyses along the reaction coordinate.

Recommendation?
Accept with minor revision (please list in comments)

Comments to the Author(s)
The article represents a well designed research work. High-level of DFT calculations on Pinnick oxidation of aldehyde into carboxylic acid were carried out. The theoretical results were validated by the experimental observations. Overall, the present study gives new insight of the reaction mechanism of Pinnick oxidation which might have broad readership. I have only one minor comment for the authors. They should check the whole manuscript for typo errors. There are multiple typo errors throughout the manuscript. One example is the symbol errors especially at page 2, 3 and 5.

19-Nov-2019
Dear Dr Hussein: Title: A Dynamically Concerted Transition State in the Oxidation of Aldehydes to Carboxylic Acid by Chlorous Acid Manuscript ID: RSOS-191568 Thank you for your submission to Royal Society Open Science. The chemistry content of Royal Society Open Science is published in collaboration with the Royal Society of Chemistry.
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Once again, thank you for submitting your manuscript to Royal Society Open Science and I look forward to receiving your revision. If you have any questions at all, please do not hesitate to get in touch. ********************************************** RSC Associate Editor: Comments to the Author: (There are no comments.) RSC Subject Editor: Comments to the Author: (There are no comments.) ********************************************** Reviewers' Comments to Author: Reviewer: 1 Comments to the Author(s) In their manuscript "A Dynamically Concerted Transition State in the Oxidation of Aldehydes to Carboxylic Acid by Chlorous Acid", Hussein and colleagues computationally analyze the Pinnick oxidation of acrolein derivatives. Despite the exuberant abstract, the paper does not descrive a "meticulously high-level density functional theory" analysis. There are so many problems (see below) with this manuscript and I am sorry to say that I currently recommend rejecting the article. Computational Method: M06-2X with a double-zeta basis set (aug-cc-pVDZ, not aug-PVDZ as written in the abstract) is NOT a highly accurate and high-level method. I do not want to argue about the problems that M06-2X has compared to other functionals, but a double-zeta basis set typically is associated with a large BSSE. Given the size of the molecules, I would expect a M06-2X/quadruple-zeta basis set to be a "standard" method to calculate electronic in 2019. For a high-level method, I do expect double-hybrid functionals or DLPNO-CCSD(T) calculations with at least triple-zeta basis sets as the minimum. Furthermore, the authors argue that they employ the SMD solvation model for tBuOH at 298.15 K. As tBuOH has a melting point of 26 °C, the mixture will be a highly viscous solution at best. Therefore, a continuum model will not adequately describe the experimental conditions very well. In fact, as far as I know, tBuOH is usually mixed with other solvents like THF or water.
How does this affect the calculations? What is the role of 2-methyl-2-butene that is used as a scavenger in these reactions (in terms of energetic contributions)? The authors state on page 2 "IRC calculation in the presence of tBuOH was performed". When inspecting Figure 7, no tBuOH molecule is shown. Do the authors refer to a single explicit tBuOH molecule or the SMD solvation model? This makes a huge difference! Next, the authors do not comment on the conformational flexibility of their structures. How did the authors analyze the conformational preference for all structures except HOClO? For that compound, the authors study the conformational preference in the ground state and assume that the same preference is found for all other structures (if I understand the text correctly "we then explored the mechanism of the reaction based on a cis HOClO"). This might be correct but is not verified here and the Curtin-Hammett principle dictates that this does not have to be the case (i.e., there might be lower energy transition states which adopt a trans HOClO geometry). This needs to be clarified. In general, I am not sure why this section (HOClO conformation) needs to be discussed at all in the paper. The conformational preference for HOClO is known and can be found in typical textbooks for inorganic chemistry.

General Comments
I am missing a Scheme/Figure in the article that summarized the actual experimental conditions that transfer the corresponding aldehydes to carboxylic acids (including solvent, temperature, additives, reaction time, yield, …). The calculated barrier should then be compared to these conditions. In Figure 4, the hydrogen-bonded adduct 7t-BuOH shows a cis-orientation. I would have assumed that the alcohol binds from the side of the hydrogen atom (and not the alkyl chain). Have the authors checked this isomeric structure and what is the relative energy. The discussion of Figure 5 (NMR shifts) is not really clear. Obviously, there is a significant shift upon mixing acrolein and tBuOH. What do the authors mean with the statement "if this slight shift … is true"? Do they question their own findings here? Why do the authors study the FMOs in that much detail? If this is considered to be an ene-type reaction, the authors should compare their findings to literature-known examples. Similarly, the discussion of the IRC is not really clear (or necessary). Obviously, the shape prompted the authors to perform MD simulations. However, these simulations are not really described in the computational section. How many different starting geometries have been selected (e.g., how many different trajectories have been analyzed?). I get the impression that only one trajectory was used. If this is true, the results are statistically irrelevant and should not be discussed. I am surprised to find that the MD simulations did not include implicit tBuOH molecules. This would give a better answer whether the alcohol plays an important role here or not. Have the authors included other mechanistic scenarios into their investigations? From the top of my head, I am wondering if an alcohol could act as a proton shuttle through a 7-or 8-membered transition state? Finally, the authors analyze differently substituted cinnamaldehyde derivatives. Please check the numbering carefully as the number 7 appears frequently with and without letters. Given the accuracy of the chosen method (see above), I am wondering in general how reliable the energetic differences are. How well do they correlate e.g., with Hammett constants? Certainly, it is not necessary to show all structures and transition states on one page. Select 1-2 examples and show and discuss them. Similarly, I am wondering whether the distortion/interaction analysis is meaningful and helpful. The activation energy changed by less than 1 kcal/mol which is clearly within the error margin of the BSSE at the given level.

Minor Comments
The whole manuscript needs a careful editing. I am not a native speaker myself but there are many spelling mistakes, incomplete sentences and otherwise unusual wordings. Personally, I do not like the wording "first reaction step FRS" as it is a meaningless expression. It might be better to refer to the rate-limiting step which gives additional mechanistic insight. Why do the authors use numbers in Fig. 1 but not refer to them in the text. This would help to better understand the written statement.
On page 2, right column, the authors write that the proton transfer between dihydrogenphosphate and chlorite is thermodynamically feasible but give a positive reaction free energy. This does not fit. In the context of the distortion/interaction analysis, the authors should also mention the closely related activation-strain model by Bickelhaupt. In the Supporting information, please check the numbers for the individual structures (e.g., Structure 8 should be TS8, I guess). Furthermore, please additionally quote the imaginary Reviewer: 2 Comments to the Author(s) The paper of Hussein and co-workers presents a computational study on the mechanism of the Pinnick oxidation of aldehydes into carboxylic acids. The paper is focused on the analysis of the Proton Transfer (PT) and nucleophilic attack (NA) to the carbonyl group of the aldehyde; followed by a second process involving a pericyclic fragmentation. The stepwise and concerted mechanisms were assessed for the PT+NA process; although the work reported only the results for the concerted path, since the TS for the PT of the stepwise mechanism was not found. The authors performed MD and distortion/interaction-activation strain analyses to get further insights on the mechanisms. The topic of this study is interesting, since Pinnick oxidation is a relevant reaction and this work can provide useful information regarding the reaction mechanism. On this basis, this manuscript can be suitable for publication in Royal Society Open Science. However, some important issues should be addressed: 1. In Figure 2, the depicted stepwise mechanism is incomplete. The TS for the nucleophilic attack to the carbonyl group (after the PT step) should be included in the figure.
2. Even if the TS for the PT step of the stepwise mechanism was not found, the authors should comment about the search for the NA step of the stepwise mechanism. This is important, since the stepwise mechanism cannot be ruled out just because the TS for the PT was not located. Are there available experimental data for the kinetics of this reaction? 3. The MD performed with Gaussian09 correspond to the Born-Oppenheimer Molecular Dynamics (BOMD)? In this regard, the MD of a single trajectory does not provide any meaningful insight in terms of the timescale associated to the mechanism. The MD with quasiclassical (QCT) trajectories should be used instead in order to properly sample the normal modes on the TS before the propagation of the BOMD trajectories (see for example: Angew. Chem. Int. Ed. (2014) 53, 8664;and JACS (2015) 137, 4749). This normal mode sampling together with the propagation of a few trajectories should be enough to get the correct information regarding the timescale of the involved processes in the reaction mechanism.
4. Distortion-interaction analyses of these types of reactions focusing solely on the TS are not always informative. More insight would likely be obtained by performing distortion-interaction analyses along the reaction coordinate.

Reviewer: 3
Comments to the Author(s) The article represents a well designed research work. High-level of DFT calculations on Pinnick oxidation of aldehyde into carboxylic acid were carried out. The theoretical results were validated by the experimental observations. Overall, the present study gives new insight of the reaction mechanism of Pinnick oxidation which might have broad readership. I have only one minor comment for the authors. They should check the whole manuscript for typo errors. There are multiple typo errors throughout the manuscript. One example is the symbol errors especially at page 2, 3 and 5.
Author's Response to Decision Letter for (RSOS-191568.R0) See Appendix A.

Do you have any ethical concerns with this paper? No
Have you any concerns about statistical analyses in this paper? No

Recommendation?
Accept as is We are grateful to the Reviewers and the Editorial Staff for their time and effort to review our manuscript. Please find below our responses to the comments received from the Reviewers and the Royal Society Open Science office, which we believe that we have addressed. Any changes have been highlighted in the manuscript. We have changed the title of the manuscript from "A Dynamically Concerted Transition State in the Oxidation of Aldehydes to Carboxylic Acid by Chlorous Acid" to "Mechanistic Investigations on Pinnick Oxidation: A DFT Study" to be more objective.