Catalytic Epoxidation of 3-Carene and Limonene with Aqueous Hydrogen Peroxide, and Selective Synthesis of α-Pinene Epoxide from Turpentine

Round 1

Reviewer 1 Report

The manuscript presents an improved and effective catalytic system for epoxidation of monoterpenes from available and low-cost starting reagents, with easy separation and reusage of products and hence suitable for implementation in industrial scale.

The manuscript is somewhat short, generally well written and within the scope of the journal. The experimental procedures are convincing and well described. Discussion on a possible mechanism of reaction and interpretation of catalysis is not attempted.

An Supplementary with the NMR, GC, mass spectra and other experimental data regarding products identification would be appropriate.

I do recommend the manuscript for publication after minor revision.

Minor points - check and align with the journal format (spaces, double spaces, reference format - ref. 27, 33, etc.).

Author Response

We express our gratitude to the reviewer for careful reading and important comments.

1.”Discussion on a possible mechanism of reaction and interpretation of catalysis is not attempted.”  Response 1. Since we did not carry out special studies on the mechanisms of the ongoing processes, and the reagents used are quite widely known for the described type of processes, we did not find it possible to speculate about this. Nevertheless, we provide a link to our previous review and article (refs. 7 and 34), where issues of "activation" of aqueous hydrogen peroxide are discussed.

2. «An Supplementary with the NMR, GC, mass spectra and other experimental data regarding products identification would be appropriate.» Response 2. We are grateful to the reviewer for this valuable comment and are adding the scanned data to the “supplementary materials” section.
3. «Minor points - check and align with the journal format (spaces, double spaces, reference format - ref. 27, 33, etc.).» Response 3. We are grateful to the reviewer for pointing out this negligence. We will definitely fix this.

Author Response File: Author Response.pdf

Reviewer 2 Report

The manuscript entitled “Catalytic Epoxidation of 3-Carene and Lemonene with Aqueous Hydrogen Peroxide, and Selective Synthesis of A-Pinene Epoxide from Turpentine” describes the epoxidation of technical α-pinene 1, 3-Carene 2, and limonene 3 (i.e. the most easily accessible natural monoterpenes according to the introduction section) with aqueous hydrogen peroxide in the presence of manganese sulfate, salicylic acid, sodium bicarbonate, and acetonitrile. I do not recommend publication in Catalysts and I have based my recommendation on the following points:

1. Epoxidation of α-pinene was previously achieved using 30% hydrogen peroxide solution (10 equivalent) in the presence of manganese sulfate, sodium bicarbonate, and DMF as a solvent affording the desired product in a yield of 54% which is higher than the yield obtained using the method described in the current manuscript (Please, refer to Ref 14). So, in my opinion, the current work can be considered as incremental addition to previously reported research.
2. Did the authors try to optimise the reaction conditions aiming to get higher selectivity/yield for α-pinene?!! Why not?
3. Why was 33% hydrogen peroxide solution used for epoxidation of 3-Carene 2 and Limonene 3 while 36% hydrogen peroxide solution was used for α-pinene 1?!!
4. Lines 105-107: It is more appropriate for the authors not to anticipate/claim experimental outcomes unless they have conducted, optimised, and reported their results/ findings.
5. ¹³C-NMR and Mass Spectrometric data are missing for all compounds reported in the Materials and Methods section.
6. Lines 20-23: Introduction section: References to support claims are missing.

Author Response

We express our gratitude to the referee for careful reading and important comments .
.

1. "Epoxidation of α-pinene was previously achieved using 30% hydrogen peroxide solution (10 equivalent) in the presence of manganese sulfate, sodium bicarbonate, and DMF as a solvent affording the desired product in a yield of 54% which is higher than the yield obtained using the method described in the current manuscript (Please, refer to Ref 14). So, in my opinion, the current work can be considered as incremental addition to previously reported research." Response 1. In this particular example, we emphasize that in this work we are not epoxidizing pure α-pinene, but turpentine. In the referenced article, 14 pure α-pinene was used for epoxidation. This reagent is much more expensive than turpentine, by about two orders of magnitude. Thus, the method proposed in this work allows, in contrast to the above-mentioned article, to produce "chemical separation of turpentine" with the release of pure α-pinene epoxide with a cost that is about 50 times lower than that obtained from pure α-pinene. We would also like to point out that the oxidized residue from turpentine after the isolation of α--pinene epoxide is also a valuable product both for the isolation of individual substances and as a technical product in itself
2. "Did the authors try to optimise the reaction conditions aiming to get higher selectivity/yield for α-pinene?!! Why not?" Response 2. Yes, we have done extensive research to optimize the reaction conditions. We searched for the optimal range of conditions for the epoxidation of difficult to epoxidized terpene - beta-pinene, and described it in our article (ref. 34). In this work, we also investigated various conditions for epoxidation, but they all turned out to be less adequate than those described in the article. Particularly important is the composition and order of addition of the reagents at a specific temperature. As it turns out, the transfer of any of the activators - manganese sulfate, salicylic acid from a mixture with terpene to a mixture with hydrogen peroxide leads to a drop in the yield and an increase in the proportion of resins in the mixture. A decrease in the reaction temperature leads either to a dramatic increase in the induction period before the onset of epoxidation, or to a complete absence of reaction. An increase in the reaction temperature by several degrees leads to a strong increase in the proportion of products with the opening of the epoxy cycle and the formation of resins. The fact that the conditions we describe turned out to be optimal for various monoterpenes allowed us to successfully epoxidize them in a mixture, namely, to epoxidize turpentine.
3. "Why was 33% hydrogen peroxide solution used for epoxidation of 3-Carene 2 and Limonene 3 while 36% hydrogen peroxide solution was used for α-pinene 1?!!" Response 3. This work was carried out over a long period of time, using different batches of hydrogen peroxide. Before introducing hydrogen peroxide into the reaction, we checked its concentration and, for each case, we simply accurately describe the conditions that were applied. Thus, we unwittingly established the fact that it is the applied excess of hydrogen peroxide that is important, and small changes in its concentration have little effect on the product yield. It is possible that maintaining exactly the same reaction conditions for laboratory work does not cause any difficulties, but we considered this article as an incentive for the application of the described method in industry. In an industrial setting, the acceptability of different concentrations of aqueous hydrogen peroxide can be an additional advantage.
4. "Lines 105-107: It is more appropriate for the authors not to anticipate/claim experimental outcomes unless they have conducted, optimised, and reported their results/ findings." Response 4. We just wanted to mention the most acceptable methods for obtaining these compounds in their pure form. These are the ways we deal with them now in our ongoing work. But we do not insist on this phrase, which could help a reader who is not too experienced in this field. If the editors consider it unnecessary, we agree to exclude it. 
5. ^"13C-NMR and Mass Spectrometric data are missing for all compounds reported in the Materials and Methods section. " Response 5. This work is devoted to the preparation of known compounds from known reagents. None of the described substances are new, therefore we did not consider it relevant to present the spectral data again, which are already described in the literature (for example, refs. 35-38). However, we have provided the proton NMR data that are the most characteristic for the compounds in this work, and have now added various spectra to the “supplementary materials” section.
6. "Lines 20-23: Introduction section: References to support claims are missing." Response 6. We believe the first two sentences are introductory. They are nevertheless supported by the references that follow in the same paragraph, but especially reference number 7 in the next paragraph of the introduction, which is our extensive overview on this topic.

Author Response File: Author Response.pdf

Reviewer 3 Report

It is a good synthetic work offering a convenient method for preparation of three interesting epoxides. Just a few minor suggestion to improve the presentation. 1) yields of products should be given in the Schemes. 2) discussion of the stereochemical composition of limonene product is good; what about the first two examples? 3) the issue of the SDE (Self-Disproportionation of Diastereomers) should be discussed; it is clear that with these mixtures, it is not easy to perform the SDE-test, but ratio of diastereomers (by NMR) before and after distillation can be reported. Again, the authors should discuss the SDE to show they are aware of the phenomenon via achiral chromatography, distillation and sublimation; these compounds are volatile enough to effect the enantiomeric ratio by evaporation (sublimation). 

Author Response

We express our gratitude to the reviewer for careful reading and important comments .

1. «yields of products should be given in the Schemes.» Response 1. We are grateful to the reviewer for a valuable comment and will correct the reaction schemes.
2. discussion of the stereochemical composition of limonene product is good; what about the first two examples? Response 2. We are grateful to the reviewer for a valuable comment and will add appropriate explanations to the text of the article. Our epoxidation system has a typical selectivity for epoxidation with peracids, so the usual selectivity is observed for α-pinene and 3-carene, namely 2,3-epoxy-cis-pinan (14575-92-9) and trans-3,4 -epoxy-caran. Their spectral characteristics fully coincide with the literature.
3. the issue of the SDE (Self-Disproportionation of Diastereomers) should be discussed; it is clear that with these mixtures, it is not easy to perform the SDE-test, but ratio of diastereomers (by NMR) before and after distillation can be reported. Again, the authors should discuss the SDE to show they are aware of the phenomenon via achiral chromatography, distillation and sublimation; these compounds are volatile enough to effect the enantiomeric ratio by evaporation (sublimation). " Response 3. We are grateful to the reviewer for a valuable comment and will add appropriate explanations to the text of the article. In supplementary materials, we present the NMR data of the study of the composition of mixtures of limonene diepoxides from different syntheses. We did not observe any significant differences in the composition of the mixtures. At the same time, enrichment in some isomers could be observed during distillation. We did not observe isomerization of isomers of limonene diepoxides into each other when they were kept with a catalytic system or during distillation. Regarding the volatility of these substances, limonene diepoxide appears the least volatile compared to 3-carene and α-pinene epoxides. An effort was made to eliminate distillation losses. Thus, we avoided significant heating during distillation, used cryogenic traps, checked distilled solvents for the absence of products, and checked the convergence of the material balance.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

I have gone through the responses provided by the authors and I am still convinced that the work provided is incremental does not deserve to be published in Catalysts as it will be of no interest to the readers. I also recommend nominating a third reviewer for this manuscript just to keep it fair for the authors.

Author Response

We express our gratitude to the reviewer for careful reading and important comments. We regret that we could not find words to justify the importance of this study, which could influence the opinion of the reviewer.