Sodium Hypochlorite Pentahydrate as a Chlorinating Reagent: Application to the Tandem Conversion of β,γ-Unsaturated Carboxylic Acids to α,β-Unsaturated Lactones

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 

Title: Sodium Hypochlorite Pentahydrate as a Useful Chlorinating Reagent. Application to the Tandem Conversion of β,γ-Unsaturated Carboxylic Acids to α,β-Unsaturated Lactones

 

Recommendation: Major revisions needed as noted.

The manuscript, titled "Sodium Hypochlorite Pentahydrate as a Useful Chlorinating Reagent. Application to the Tandem Conversion of β,γ-Unsaturated Carboxylic Acids to α,β-Unsaturated Lactones," explores the use of sodium hypochlorite pentahydrate (NaClO·5H2O) as a green chlorinating reagent in organic synthesis. As a reviewer, I have evaluated the manuscript there are some questions and suggestions for consideration, and the authors should try to address more clearly.

1.      Why you use sodium hypochlorite pentahydrate (NaClO·5H2O) as a chlorinating reagent for the tandem conversion of β,γ-unsaturated carboxylic acids to α,β-unsaturated lactones?

2.      Please explain more about the significance of this workstudy in the context of green chemistry and sustainable synthesis?

3.      The paper discusses the optimization of reaction conditions, such as varying the equivalents of NaClO·5H2O, reaction temperature, and reaction time. How did you determine these optimal conditions, and were there any unexpected challenges encountered during this process?

4.      Please explain the mechanisms behind the observed transformations, particularly the formation of α,β-unsaturated lactones from β,γ-unsaturated carboxylic acids, and the electrophilic chlorination of activated aromatic compounds?

5.      The scope of substrates explored in the study covers both aromatic and aliphatic β,γ-unsaturated carboxylic acids. There are differences in the reactivity or selectivity observed between these two types of substrates?

6.      In the electrophilic chlorination of 1,3,5-trimethoxybenzene, a good yield of the chlorinated product was obtained. How does this reaction compare to existing methods for achieving similar transformations, and what advantages does the use of NaClO·5H2O offer in this context?

7.      Please add about the future direction if this work in the manuscript. Especially the mitigation of by product in future works, if any.

8.      The paper mentions the formation of side products in some reactions. How do you plan to address or mitigate the formation of these byproducts in future studies?

 

 

Comments on the Quality of English Language

its ok.

Author Response

The manuscript, titled "Sodium Hypochlorite Pentahydrate as a Useful Chlorinating Reagent. Application to the Tandem Conversion of β,γ-Unsaturated Carboxylic Acids to α,β-Unsaturated Lactones," explores the use of sodium hypochlorite pentahydrate (NaClO·5H2O) as a green chlorinating reagent in organic synthesis. As a reviewer, I have evaluated the manuscript there are some questions and suggestions for consideration, and the authors should try to address more clearly.

[Response] Thank you for your time to evaluate the paper and valuable suggestions.

1. Why you use sodium hypochlorite pentahydrate (NaClO·5H2O) as a chlorinating reagent for the tandem conversion of β,γ-unsaturated carboxylic acids to α,β-unsaturated lactones?

[Response] We discovered this reaction accidentally in our lab while seeking effective oxidants in some other reactions. Therefore, there is no clear answer to this question.

2. Please explain more about the significance of this workstudy in the context of green chemistry and sustainable synthesis?

[Response] Thanks for this suggestion. The green and sustainable aspect is an important feature of our paper. We stress this point more clearly in the revised manuscript (lines 180-181 and 190-198).

3. The paper discusses the optimization of reaction conditions, such as varying the equivalents of NaClO·5H2O, reaction temperature, and reaction time. How did you determine these optimal conditions, and were there any unexpected challenges encountered during this process?

[Response] Optimization of the reaction conditions was discussed with the data shown in Tables 1 and 2. The difficulty in this process was that the yield of the desired product was not high. We tried to suppress the side reactions, but it was not completely successful because the reaction was necessarily carried out under heterogeneous conditions only.

4. Please explain the mechanisms behind the observed transformations, particularly the formation of α,β-unsaturated lactones from β,γ-unsaturated carboxylic acids, and the electrophilic chlorination of activated aromatic compounds?

[Response] The mechanism of the formation of α,β-unsaturated lactones from β,γ-unsaturated carboxylic acids was shown in Scheme 3, in which NaClO is first converted to HOCl as an active chlorinating agent. Similarly, HOCl should be an active chlorinating agent in the reaction of activated aromatic compounds. In addition to a slightly modified version of Scheme 3, we explained the mechanisms more clearly in the text (lines 180-181 and 190-198.

5. The scope of substrates explored in the study covers both aromatic and aliphatic β,γ-unsaturated carboxylic acids. There are differences in the reactivity or selectivity observed between these two types of substrates?

[Response] According to our experience, it seems that the reaction of aromatic β,γ-unsaturated carboxylic acids gives better results in the yields than that of aliphatic compounds. This would be because the aliphatic substrate reaction is sluggish. We explained this point more clearly in the revised manuscript (lines 141-148).

6. In the electrophilic chlorination of 1,3,5-trimethoxybenzene, a good yield of the chlorinated product was obtained. How does this reaction compare to existing methods for achieving similar transformations, and what advantages does the use of NaClO·5H2O offer in this context?

[Response] Usually, the conversion from 13 to 14 requires a chlorinating reagent, such as N-chlorosuccinimide, and a catalyst. The reaction yields exceed 90 % (for example, RSC Advances (2022), 12(12), 7115-7119; Dalton Transactions (2016), 45(37), 14603-14608). Compared to these excellent yields, the reaction using NaClO.5H2O is not so good, but still, the simple procedure and formation of no harmful byproduct can be stressed. With the addition of another example, we discussed this point in the revised manuscript (lines 190-198).

7. Please add about the future direction if this work in the manuscript. Especially the mitigation of by product in future works, if any.

[Response] A lot of work should be done in the future, such as suppression of the side reactions to expand the substrate scope. But this is obvious without saying. So, we eliminated the last sentence in the revised manuscript.

8. The paper mentions the formation of side products in some reactions. How do you plan to address or mitigate the formation of these byproducts in future studies?

[Response] The side products, such as epoxide 4 and chloride 5, are also useful compounds for further transformation. Therefore, it must be desirable to selectively synthesize unsaturated lactone 3, epoxide 4, and chlorides 5 by changing the reaction conditions. We are planning to work on this line. However, we do not have any useful data on this point. 

Reviewer 2 Report

Comments and Suggestions for Authors

The authors did an interesting study in tandem conversion of β,γ- unsaturated carboxylic acids to β,γ- unsaturated lactones using NaClO.5H2O with various reaction conditions. The manuscript was well prepared. However, I would like to ask for additional information before accepting it for publication:

1- The first testing condition mentions that when NaClO.5H2O equiv is 5 at rt, the reaction created 20% 4a (Table 1, entry 8). However, even though the 3 eq (entry 4) at 0^oC showed that a side product was formed, it is necessary to show the information of the same condition when the catalyst and reagent concentration were changed. More information on 5 eq needs to be mentioned.

2- Table 3 shows the different compounds formed via reaction using CH₃CN. However, at entry 1, the starting temperature was room temperature, which caused the forming of a side product. What would happen if the reaction temperature was 0^oC? The same question also goes to entry 4 of Table 3. Please add this information to your study. 

Author Response

The authors did an interesting study in tandem conversion of β,γ- unsaturated carboxylic acids to β,γ- unsaturated lactones using NaClO.5H2O with various reaction conditions. The manuscript was well prepared. However, I would like to ask for additional information before accepting it for publication:

[Response] Thank you for your time to evaluate the paper and valuable suggestions.

1- The first testing condition mentions that when NaClO.5H2O equiv is 5 at rt, the reaction created 20% 4a (Table 1, entry 8). However, even though the 3 eq (entry 4) at 0^oC showed that a side product was formed, it is necessary to show the information of the same condition when the catalyst and reagent concentration were changed. More information on 5 eq needs to be mentioned.

[Response] Thanks for this comment. According to the suggestion, we added the data in Table 1, entry 5. When 5 eq NaClO.5H2O was employed at O °C, the yields of lactone 3a and epoxide 4a were both decreased.

2- Table 3 shows the different compounds formed via reaction using CH₃CN. However, at entry 1, the starting temperature was room temperature, which caused the forming of a side product. What would happen if the reaction temperature was 0^oC? The same question also goes to entry 4 of Table 3. Please add this information to your study. 

[Response] Thanks for this comment. Indeed, the reaction conditions shown in Table 3 were optimized to increase the yield of 3. Under different conditions, the yields became significantly low. This point is now clearly written in the text (lines 141-148).

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have demonstrated the use of NaClO.5H₂O as a chlorinating reagent in organic synthesis and the transformation of unsaturated carboxylic acid to unsaturated lactones. Synthetic protocols to achieve such a transformation are impactful, thus the work is suitable for publication in Processes MDPI upon addressing the comments below:

•       This synthetic protocol is still underdeveloped and would have benefitted from more optimization work to get higher yields. The model substrate 2a has a yield of 62%, and the rest of the substrate scope shown in Table 3 is at 21%, 23%, 56%, 0%, 16% and 8%. In contrast, some of the previously reported synthetic protocols are high performing (e.g. the yields for the method by Yueng and co-workers are >95%, even though they used high equivalents of the N-halosuccimide).
•       Can the authors comment on the scalability of the synthetic protocol. The paper would benefit from demonstrating that the synthesis can be scaled up to at least 1.0 g scale with the model substrate (E)-4-phenylbut-3-enoic acid.
•       Can the authors re-evaluate the claim on novelty considering that chlorination of 1,3,5-trimethoxybenzene and analogues using HOCl has been reported by Roberts and Sivey in 2012 (dx.doi.org/10.1021/es203094z).

Author Response

The authors have demonstrated the use of NaClO.5H₂O as a chlorinating reagent in organic synthesis and the transformation of unsaturated carboxylic acid to unsaturated lactones. Synthetic protocols to achieve such a transformation are impactful, thus the work is suitable for publication in Processes MDPI upon addressing the comments below:

[Response] Thank you for your positive comments. We addressed all the comments as shown below.

• This synthetic protocol is still underdeveloped and would have benefitted from more optimization work to get higher yields. The model substrate 2ahas a yield of 62%, and the rest of the substrate scope shown in Table 3 is at 21%, 23%, 56%, 0%, 16% and 8%. In contrast, some of the previously reported synthetic protocols are high performing (e.g. the yields for the method by Yueng and co-workers are >95%, even though they used high equivalents of the N-halosuccimide).

[Response] Yeung and coworkers reported excellent conversion yields as well as asymmetric yields in the transformation from β,γ-unsaturated carboxylic acids to α,β-unsaturated lactones [ref. 59] using NBS. However, NBS is a halogenating agent with poor atom economy as already mentioned in the text (lines 60-61). Therefore, the reaction using NaClO.5H2O would have an advantage, especially if the conversion yields can be improved. Of course, we are currently working on this line and would like to report the results in future.

• Can the authors comment on the scalability of the synthetic protocol. The paper would benefit from demonstrating that the synthesis can be scaled up to at least 1.0 g scale with the model substrate (E)-4-phenylbut-3-enoic acid.

[Response] We reported the results in ca. 100 mg scale reactions for the case of substrate 2b (Table 3, entry 1). However, due to some technical problems, we could not carry out the reaction in a gram scale. Scaling-up is an important process, so we will try this in the future work.

• Can the authors re-evaluate the claim on novelty considering that chlorination of 1,3,5-trimethoxybenzene and analogues using HOCl has been reported by Roberts and Sivey in 2012 (dx.doi.org/10.1021/es203094z).

[Response] Thank you for reminding us this interesting work by Sivey and Roberts. We cite this paper as ref. 70 now.

Reviewer 4 Report

Comments and Suggestions for Authors

Review of the manuscript.

General remarks.

The idea of the research is interesting and I believe that much more could be done to present a valuable manuscript. In my opinion, the overall quality of the presented manuscript is low or average. First of all I find the title of the manuscript highly misleading, especially with regard to the expression “useful chlorinating reagent”. Seeing this title, I would expect that the authors present a method for the synthesis of some chlorinated products, but the main body of the manuscript are a few, not very successful cyclization reactions. However, most importantly I was not convinced by the authors that the presented methodology and reagent is “useful” as stated in the title of the manuscript. The authors presented only five examples of cyclization reactions which proceeded in very low or moderate yields at best (after optimization). What is more, the process results in the side products (also those not identified by the authors) and it seems to be difficult to control and predict its outcome. After reading the manuscript it seems to me that either the process is not generally useful and the authors resigned from its further development, or these are just some preliminary results of possibly interesting study. Moreover, in my opinion the linguistic correction of the manuscript is necessary. The good side of the manuscript is that it is well documented and I believe that the presented results are trustworty. Overall, I am of the opinion that the manuscript can be accepted only after major revision and with additional experiments to demonstrate the utility of the method – otherwise it should be rejected. In its current form (apart from the necessary linguistic correction) it may be published as a communication in other, lower impact journal (for example Synthetic Communications). 

Other comments

·         The reaction mechanism scheme should be more detailed.

·         Line 71 – “apparently not soluble…” –  so is it soluble, poorly soluble or not soluble? This statement is imprecise.

·         Line 182 – “wide usability of 1 as a chlorinating reagent” – you have only a few poor examples, I wouldn’t call it “wide usability”.

·         Chlorination of 13 is interesting but this is a completely different story wich could be further explored as a separate study.

Comments on the Quality of English Language

Selected comments on English language:

Line 20. “The conversion would be initiated by electrophilic attack 20 of HOCl to the C=C bond of 2 to generate a chloronium ion intermediate, which would be…” – rephrase without “would”

Line 31. “…NaClO must have the potential…” – NaClO have the potential – without “must”

Line 32. “…it would produce…” – it produces – without “would”

Line 39 and 51. “transformation processes” – transformations or processes

Line 44. “variation” – variations

Line 71. “NaClO·5H2O (1) is apparently not soluble…” – this statement is too imprecise

Line 72. “rigorously” – vigorously?

Line 72. “progression” – progress ?

Line 73. “After certain periods of time,…” – rephrase please

Line 75. “separated through the column” – what kind of column? Doric? Corinthian?

Line 84. “any characterizable products were not obtained” – rephrase please

Line 93. “epoxide oxygen placed in the opposite” – oxygen is placed

Line 95. “Other products, probably decomposed compounds…” – rephrase please

Line 103 and 105. “Indeed, 1 apparently dissolved in MeOH, DMF, and EtOH, while in acetone it seemed…” “did not dissolve apparently.” – these statements are too imprecise

Line 106. “…reaction underwent even….” – the reaction took place ?

Line 113. “Formation of 5 would be due to the insolubility in aqueous solutions” – insolubility of what? rephrase please

Line 133, 145, 191 etc. “transformation reactions” – transformations or reactions.

Line 195. “show the usefulness…” – show the potential usefulness (maybe)

Line 200. “NaClO·5H2O (1) was found to be a useful…” – these are very strong words taking in account the scarce and poor results presented in the manuscript – maybe “was found to be a potentially useful…” would be more honest.

Author Response

General remarks.

The idea of the research is interesting and I believe that much more could be done to present a valuable manuscript.

[Response] Thanks for your interest. Since the reaction was carried out under heterogeneous conditions, the control of the side reactions was not easy. Usually, the formation of significant amounts of unknown byproducts was observed.

In my opinion, the overall quality of the presented manuscript is low or average. First of all I find the title of the manuscript highly misleading, especially with regard to the expression “useful chlorinating reagent”. Seeing this title, I would expect that the authors present a method for the synthesis of some chlorinated products, but the main body of the manuscript are a few, not very successful cyclization reactions. However, most importantly I was not convinced by the authors that the presented methodology and reagent is “useful” as stated in the title of the manuscript. The authors presented only five examples of cyclization reactions which proceeded in very low or moderate yields at best (after optimization).

[Response] Thanks for this comment. We agree that the title is misleading, so we delete “Useful” from the title.

What is more, the process results in the side products (also those not identified by the authors) and it seems to be difficult to control and predict its outcome. After reading the manuscript it seems to me that either the process is not generally useful and the authors resigned from its further development, or these are just some preliminary results of possibly interesting study.

[Response] Indeed, it was challenging to determine the structure of all side products. Nonetheless, it has not been completely successful so far. In the meantime, we are seriously concerned with the possibility that other groups will report the same reactions before our paper. The reaction we describe here is simple and easy to carry on. Therefore, we decided to report it at this stage although the impact of the data is not yet at the maximum. Nevertheless, we still believe that our paper should have a positive influence on the organic synthesis community since this is a completely new application of NaClO in organic processes.

Moreover, in my opinion the linguistic correction of the manuscript is necessary.

[Response] Thanks for the corrections of English. We corrected them accordingly. See below too.

The good side of the manuscript is that it is well documented and I believe that the presented results are trustworty. Overall, I am of the opinion that the manuscript can be accepted only after major revision and with additional experiments to demonstrate the utility of the method – otherwise it should be rejected. In its current form (apart from the necessary linguistic correction) it may be published as a communication in other, lower impact journal (for example Synthetic Communications). 

[Response] We added data in Table 1, entry 5, and the chlorination of 16 in Scheme 5. Also, we largely revised the manuscript so that the points raised by the referees could become clearer to increase the impact. According to these revisions, we believe that the paper is now suitable for Processes.

Other comments

 

The reaction mechanism scheme should be more detailed.

[Response] Scheme 3 was modified slightly. In addition, the paragraph of the reaction mechanism was rewritten with more detailed explanations (line 180-181).

Line 71 – “apparently not soluble…” –  so is it soluble, poorly soluble or not soluble? This statement is imprecise.

[Response] We deleted “apparently” from the text.

Line 182 – “wide usability of 1 as a chlorinating reagent” – you have only a few poor examples, I wouldn’t call it “wide usability”.

[Response] We deleted “wide” from the text (line 183).

Chlorination of 13 is interesting but this is a completely different story wich could be further explored as a separate study.

[Response] Thanks for this comment. Of course, this will be explored in our laboratory. Indeed, we added the reaction of 16 as Scheme 5 in the revised manuscript. Since chlorination of 13 and 16 is essentially the same as the chlorination of β,γ-unsaturated carboxylic acids (2) in that HOCl works as a source of Cl+, we keep the reaction of 13 in this paper.

 

Comments on the Quality of English Language

Selected comments on English language:

Line 20. “The conversion would be initiated by electrophilic attack 20 of HOCl to the C=C bond of 2 to generate a chloronium ion intermediate, which would be…” – rephrase without “would”

[Response] Done.

Line 31. “…NaClO must have the potential…” – NaClO have the potential – without “must”

[Response] Done.

Line 32. “…it would produce…” – it produces – without “would”

[Response] Done.

Line 39 and 51. “transformation processes” – transformations or processes

[Response] Done.

Line 44. “variation” – variations

[Response] Done.

Line 71. “NaClO·5H2O (1) is apparently not soluble…” – this statement is too imprecise

[Response] Done.

Line 72. “rigorously” – vigorously?

[Response] Done.

Line 72. “progression” – progress ?

[Response] Done.

Line 73. “After certain periods of time,…” – rephrase please

[Response] Done.

Line 75. “separated through the column” – what kind of column? Doric? Corinthian?

[Response] Done.

Line 84. “any characterizable products were not obtained” – rephrase please

[Response] Done.

Line 93. “epoxide oxygen placed in the opposite” – oxygen is placed

[Response] Done.

Line 95. “Other products, probably decomposed compounds…” – rephrase please

[Response] Done.

Line 103 and 105. “Indeed, 1 apparently dissolved in MeOH, DMF, and EtOH, while in acetone it seemed…” “did not dissolve apparently.” – these statements are too imprecise

[Response] Done.

Line 106. “…reaction underwent even….” – the reaction took place ?

[Response] Done.

Line 113. “Formation of 5 would be due to the insolubility in aqueous solutions” – insolubility of what? rephrase please

[Response] Done.

Line 133, 145, 191 etc. “transformation reactions” – transformations or reactions.

[Response] Done.

Line 195. “show the usefulness…” – show the potential usefulness (maybe)

[Response] Done.

Line 200. “NaClO·5H2O (1) was found to be a useful…” – these are very strong words taking in account the scarce and poor results presented in the manuscript – maybe “was found to be a potentially useful…” would be more honest.

[Response] Done.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

It's okay in the revised form.

Reviewer 2 Report

Comments and Suggestions for Authors

The author addressed all questions asked in this revision. All information is well described. I recommend acceptance for publication of this version of the manuscript. 

Reviewer 4 Report

Comments and Suggestions for Authors

The manuscript was improved according to the reviewers comments. The title and the overall expression of the manuscript is no longer as misleading as it was. I am still of the opinion that more examples would be necessary to prepare a higher impact article, however I understand that these are the preliminary results of an interesting area of research and the authors may be worried about not being the first to report it. Therefore, the urgency of the manuscript may justify its publication. I also think that the manuscript's English language should be checked and possibly corrected by a proofreader, however at this point it can the task of the editor. The manuscript can be accepted and published after proofreading.

Comments on the Quality of English Language

The manuscript's English language may be checked and possibly corrected by a proofreader