Process Improvement for the Continuous Synthesis of N-Benzylhydroxylamine Hydrochloride

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this paper the authors have developed an optimised synthesis of N-benzylhydroxylamine using flow methods. Overall it is well written and makes appropriate reference to previous work in the area. Each parameter has been optimised carefully to come up with the final method. I recommend it can be accepted subject to the following (minor) modifications:

1. N-benzylhydroxylamine should be all one word with no space in the middle. Please correct this in the captions to Figures 1 and 2.
2. How have the % purity values in Table 2 been determined? This should be clearly stated in the experimental details section.
3. In the reference list, standard abbreviations for journals should be used: Bioorg. Med. Chem. Lett, J. Am. Chem. Soc, Org. Lett, Eur. J. Org. Chem. etc.
4. In the reference list for Patents the names of the inventors should be added at the start, just like authors for the journal publications.

Author Response

Response to Reviewer 1’s comments:

Comments and Suggestions for Authors

In this paper the authors have developed an optimised synthesis of N-benzylhydroxylamine using flow methods. Overall it is well written and makes appropriate reference to previous work in the area. Each parameter has been optimised carefully to come up with the final method. I recommend it can be accepted subject to the following (minor) modifications:

-- We really appreciate the reviewer’s positive comments on our work. We herein have carefully revised the manuscript according to the reviewer’s suggestions.

1. N-benzylhydroxylamine should be all one word with no space in the middle. Please correct this in the captions to Figures 1 and 2.

-- Thanks for the reviewer’s kind reminder. The captions to Figures 1 and 2 have been corrected in the revised main text.

2. How have the % purity values in Table 2 been determined? This should be clearly stated in the experimental details section.

-- Per the suggestion, the purity mentioned herein refers to the percentage of the area of the substance measured by the area normalization method in the liquid chromatography. The method of calculating of purity has been stated in the experimental section.

3. In the reference list, standard abbreviations for journals should be used: Bioorg. Med. Chem. Lett, J. Am. Chem. Soc, Org. Lett, Eur. J. Org. Chem. etc.

-- Thanks for the reviewer’s kind reminder. Standard abbreviations of Journal names have been used in the revised main text.

4. In the reference list for Patents the names of the inventors should be added at the start, just like authors for the journal publications.

-- Thanks for the reviewer’s kind reminder. The names of the inventors of the patents have been added in the revised main text.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Introduction:

Line 22 - The authors should include more specific examples of how and where N-benzylhydroxylamine is used. Which medications or specific processes rely on this intermediate? This could help connect the importance of the compound with its real-world applications.

Line 23 - The authors should expand a bit more on the advantages of constructing isoxazoline frameworks. How are these compounds used in pharmacology or other fields?

Line 27 - The authors should include more details about the role of Ticagrelor. For example, what is the significance of this molecule in the therapy for acute coronary syndrome, and how does the availability of N-benzylhydroxylamine impact the production of this drug?

Line 35 - I don’t understand. Are the authors suggesting that this process is a possibility or that it is the traditionally used method? It may be helpful to clarify whether this is indeed the traditional process or if there are other more common methods.

Line 38 - What are the costs involved, and why is sodium cyanoborohydride necessary in this specific case?

Line 39 - Have these reactions actually been used in the industry, or are they mostly proposed in academic studies?

Line 42 - The authors should elaborate a bit more on the challenges of hydroxylamine decomposition at high temperatures, mentioned later on. How exactly does the decomposition affect the process efficiency?

Line 49 - Why is the 65% yield in Lebel’s continuous method still not ideal for large-scale industrial applications? What could be done to improve this yield without increasing safety risks or costs?

 

Materials and Methods

Line 73 - The comma after "benzyl chloride" is unnecessary.

Line 83 - It would be important to mention whether the addition of the solids (hydroxylamine and sodium hydroxide) should be done slowly or under constant stirring. This may be relevant for the formation of possible precipitates or exothermic reactions.

Line 85 - It might be interesting to include more details about the stirring duration. What is the required time to ensure complete dissolution of the reagents?

Line 87 - Why are 60°C and 8 bar optimal conditions for this particular reaction? What factors were considered when choosing the temperature of 60°C and the pressure of 8 bar? Is there any data showing that these conditions are ideal for maximizing yield and minimizing decomposition risks?

Line 89 - What is the purpose of the preheating step, and how does it affect the reaction efficiency?

Line 92 - How was the residence time of 7.38 minutes optimized to achieve the best yield and minimize by-products?

Line 98 - The authors should explore a bit more about the dibenzyl impurities. How do these impurities affect the purity of the final product, and is there any method to reduce their formation?

Line 107 - The authors should mention the amount of activated carbon used or how this amount was determined for the efficient removal of colorants.

Line 108 - Is the cooling temperature between 0°C and -5°C the most efficient for crystallization? Have tests been conducted to investigate the effect of a wider temperature range?

Line 109 - Was it a vacuum filtration or a simple filtration? Does this choice affect the final yield?

Line 129 - What can be done to improve the recovery rate of hydroxylamine, which is 47%? Have other extraction or concentration techniques been tested?

 

In some parts of the text, the values are written XºC, while in others they are written as X ºC, with an extra space between the number and the degree symbol. To maintain uniformity, I suggest adopting a single format, preferably X ºC (with a space between the number and the degree symbol).

 

Results

Line 132 - The authors should explain why hydroxylamine hydrochloride was specifically selected over aqueous hydroxylamine solution, apart from the fact that the latter is classified as hazardous. Were there any particular benefits regarding stability, availability, or cost that made the hydrochloride the preferred choice?

Line 149 - Why did the yield of N-benzylhydroxylamine hydrochloride decrease significantly with lower amounts, and what was the cause of the increased byproducts like dibenzyl-substituted impurities?

Line 157 - The authors mention that increasing the temperature to 80°C did not improve the yield. It would be helpful to explain why this was the case. Were there any risks associated with increasing the temperature further, or did the reaction mechanism not benefit from higher temperatures?

Line 170 - The authors should clarify why increasing reactant concentrations to 0.3 mol/L and 0.5 mol/L didn’t change the crystallization yield significantly. Was the reaction fully optimized with these concentrations, or could further adjustments to other parameters improve the yield?

Line 173 - The authors mention a blockage at 1.0 mol/L concentration. Could they explain why this blockage occurred at higher concentrations? Was it due to viscosity, increased solid formation, or another reason? Also, was there a consideration of the maximum concentration that could be used before encountering such issues?

Table 2 – The table mentions "139 g" and "73 g + Recovered water phase," but the explanation of what exactly this implies is not completely clear. It would be helpful to detail whether the "Recovered water phase" refers to the amount of recovered solution, which would help contextualize the data presented.

- How might an increase in the number of recycling cycles affect the quality of the final product and the need for adjustments in reaction conditions?

- Can the recycling of hydroxylamine hydrochloride be applied to other synthesis reactions involving similar compounds? Are there any limitations or considerations to be made?

- What would be the next steps to improve the recovery rate of 47% for hydroxylamine hydrochloride? Have any attempts been made to optimize the extraction process?

 

Discussion

Line 209/210 - What were the specific ideal conditions (exact amount of reagents, exact temperature, reaction time)? Could you explain how these conditions were determined and whether varying the experimental conditions would substantially influence the final yield?

Could the authors provide more details on the impact of reducing the use of hydroxylamine hydrochloride in terms of cost and environmental feasibility? What is the percentage reduction compared to traditional methods?

Line 212 - Could the authors provide more data on how safety was ensured during the process? What kind of monitoring was implemented to prevent the thermal decomposition of hydroxylamine hydrochloride? Is the temperature of 60°C a safe condition for all amounts of hydroxylamine hydrochloride used in the process?

 

Conclusion:

Although the discussion provides important insights into the results, I would recommend adding a dedicated Conclusions section at the end of the paper. A conclusions section can help summarize the key findings, their implications, and suggest directions for future research. This would not only improve the structure of the paper but also make it easier for readers to understand the results.

 

References

The authors report 19 references, the majority of which are from older articles and patents (some from 2006, 2012), with only 2 references from the last 5 years, and present 7 patents. If possible, include more recent references to show that the work follows the latest trends in research.
When the authors report the patents, the year is not in bold.

Author Response

Response to Reviewer 2’s comments:

Comments and Suggestions for Authors

Introduction:

Line 22 - The authors should include more specific examples of how and where N-benzylhydroxylamine is used. Which medications or specific processes rely on this intermediate? This could help connect the importance of the compound with its real-world applications.

-- Per the reviewer’s suggestion, N-benzylhydroxylamine can undergo Michael addition and cyclization with unsaturated esters (alkenoates) to generate azoldone, which then proceeds hydrogenation to give β-amino acids. The content of N-benzylhydroxylamine have been added in the revised introduction.

Line 23 - The authors should expand a bit more on the advantages of constructing isoxazoline frameworks. How are these compounds used in pharmacology or other fields?

Thanks for the reviewer’s helpful suggestions. The following comment has been included in the revised main text: “Isoxazolidines are vital structures in the field of drug discovery, resembling a diverse array of natural building blocks and demonstrating a wide range of promising biological activities.”

Line 27 - The authors should include more details about the role of Ticagrelor. For example, what is the significance of this molecule in the therapy for acute coronary syndrome, and how does the availability of N-benzylhydroxylamine impact the production of this drug?

-- Per the reviewer’s suggestion, the following statements have been included in the main text: “Ticagrelor, a novel antiplatelet agent, has demonstrated superior efficacy over clopidogrel in reducing the occurrence of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome. The current synthesis method of ticagrelor, utilizing N-benzylhydroxylamine, is one of the most economically efficient approach.”

Line 35 - I don’t understand. Are the authors suggesting that this process is a possibility or that it is the traditionally used method? It may be helpful to clarify whether this is indeed the traditional process or if there are other more common methods.

-- The synthesis of N-benzylhydroxylamine hydrochloride using benzaldehyde and hydroxylamine hydrochloride is a straightforward and convenient method in the laboratory, as it minimizes by-product formation, offers stable yields, and operates under mild conditions. However, this route is not suitable for large-scale industrial production. In response to the reviewer’s comment, we have revised "traditionally" to "in the laboratory" in the updated introduction for clarity.

Line 38 - What are the costs involved, and why is sodium cyanoborohydride necessary in this specific case?

-- Per the reviewer’s comments, the price of sodium cyanoborohydride is about 300 $/kg, which is used as reducing reagent to convert benzaldehyde oxime to N-benzylhydroxylamine. While sodium borohydride could also serve as a reducing agent in this process, sodium cyanoborohydride is preferred due to its milder and more efficient reduction properties.

Line 39 - Have these reactions actually been used in the industry, or are they mostly proposed in academic studies?

-- Thanks for the reviewer’s comments. Route 3 in Figure 2 was found to be used in industry. This comment has also been included in the main text.

Line 42 - The authors should elaborate a bit more on the challenges of hydroxylamine decomposition at high temperatures, mentioned later on. How exactly does the decomposition affect the process efficiency?

-- Thanks for the reviewer’s suggestion.  The challenges of hydroxylamine decomposition at high temperatures were mentioned in Mannan’s work (Cisneros, L. O,; Rogers, W. J.; Mannan, M. S. Adiabatic calorimetric decomposition studies of 50 wt.% hydroxylamine/water. J Hazard Mater. 2001, 82, 13–24.) They mentioned that "Prior to the accident that destroyed the Concept Sciences plant, the final step in their routine production of HA from hydroxylamine sulfate was vacuum distillation at 50 ℃". However, the explosion risk of hydroxylamine aqueous solution under heating was not measured exactly.

Line 49 - Why is the 65% yield in Lebel’s continuous method still not ideal for large-scale industrial applications? What could be done to improve this yield without increasing safety risks or costs?

-- Lebel’s continuous method shows promise for large-scale industrial applications. However, the use of excess hydroxylamine (150 equivalents) increases production costs, and the unreacted hydroxylamine poses a safety risk under the reaction conditions (100°C). To improve the yield, optimizing the stoichiometry of hydroxylamine while maintaining reaction efficiency could reduce both costs and safety concerns. These comments have been included in the main text.

Materials and Methods

Line 73 - The comma after "benzyl chloride" is unnecessary.

-- Thanks for the reviewer’s kind reminder. The comma after "benzyl chloride" has been deleted in the revised main text.

Line 83 - It would be important to mention whether the addition of the solids (hydroxylamine and sodium hydroxide) should be done slowly or under constant stirring. This may be relevant for the formation of possible precipitates or exothermic reactions.

-- Since the neutralization of sodium hydroxide with hydroxylamine hydrochloride is an exothermic reaction, the addition of the solids should be carried out slowly, with constant stirring, and the mixture should be cooled in an ice bath to minimize safety risks. This approach also helps prevent the formation of clumps from the resulting sodium chloride solids. We have incorporated this information into the revised main text for clarity.

Line 85 - It might be interesting to include more details about the stirring duration. What is the required time to ensure complete dissolution of the reagents?

-- “Stir the mixture at 10-20 °C for 30 minutes and filter out the sodium chloride.” Per the reviewer’s suggestion, the stirring duration has been added in the revised main text.

Line 87 - Why are 60°C and 8 bar optimal conditions for this particular reaction? What factors were considered when choosing the temperature of 60°C and the pressure of 8 bar? Is there any data showing that these conditions are ideal for maximizing yield and minimizing decomposition risks?

-- The “reaction setup” was corrected as “The optimal reaction setup”. The reason to choose 60°C and 8 bar could be found in Part 3, as these reaction condition parameters were screened systematically.

Line 89 - What is the purpose of the preheating step, and how does it affect the reaction efficiency?

-- Per the reviewer’s comment, the preheating of benzyl chloride is necessary to better control the reaction temperature.

Line 92 - How was the residence time of 7.38 minutes optimized to achieve the best yield and minimize by-products?

-- The residence time of 7.38 minutes was calculated based on 10 modules, each with a liquid storage capacity of 8.2 mL, and a flow rate of 5 mL/min for both materials. According to the parameter screening experiment in Section 3, a flow rate of 5.0 mL/min yields the highest yield while minimizing by-products.

Line 98 - The authors should explore a bit more about the dibenzyl impurities. How do these impurities affect the purity of the final product, and is there any method to reduce their formation?

-- The dibenzyl impurity is the primary by-product in this substitution reaction and significantly impacts the yield and purity of the final product. To minimize the formation of dibenzyl impurities, one straightforward approach is to use a large excess of hydroxylamine, as demonstrated by Lebel. However, to reduce costs, we use  4 equivalents of hydroxylamine, employed a microchannel reactor to enhance the mixing, and optimized the reaction temperature and flow rate. As a result, the content of dibenzyl impurities was reduced to 17%, which can be effectively removed through a single recrystallization step.

Line 107 - The authors should mention the amount of activated carbon used or how this amount was determined for the efficient removal of colorants.

-- We used 5% w/w activated carbon for the removal of colorants, which was found to be efficient. The amount of activated carbon has been added in the revised main text.

Line 108 - Is the cooling temperature between 0°C and -5°C the most efficient for crystallization? Have tests been conducted to investigate the effect of a wider temperature range?

-- Per the reviewer’s comment, the temperature between 0°C and -5°C was found to be efficient for crystallization, while the effect of this parameter was not investigated systematically.

Line 109 - Was it a vacuum filtration or a simple filtration? Does this choice affect the final yield?

-- Vacuum filtration was used in our work. This information has been added in the revised main text.

Line 129 - What can be done to improve the recovery rate of hydroxylamine, which is 47%? Have other extraction or concentration techniques been tested?

-- The recovery of hydroxylamine hydrochloride was achieved by exploiting the solubility differences between hydroxylamine hydrochloride and sodium chloride in methanol. Since methanol is also the reaction solvent, the methanol solution containing the recycled hydroxylamine hydrochloride can be directly reused in the subsequent reaction cycle. No additional extraction or concentration techniques have been tested at this stage.

In some parts of the text, the values are written XºC, while in others they are written as X ºC, with an extra space between the number and the degree symbol. To maintain uniformity, I suggest adopting a single format, preferably X ºC (with a space between the number and the degree symbol).

-- Thanks for the reviewer’s kind reminder. The mentioned typos have been corrected in the revised main text.

Results

Line 132 - The authors should explain why hydroxylamine hydrochloride was specifically selected over aqueous hydroxylamine solution, apart from the fact that the latter is classified as hazardous. Were there any particular benefits regarding stability, availability, or cost that made the hydrochloride the preferred choice?

-- Hydroxylamine hydrochloride was specifically selected over aqueous hydroxylamine solution not only because the latter is classified as hazardous, but also due to its superior safety profile and practical advantages. Aqueous hydroxylamine is highly toxic, corrosive, and can irritate the respiratory system, skin, and eyes. Additionally, the volatilization of hydroxylamine from an aqueous solution poses significant occupational health risks, and its thermal stability is poor, as mentioned previously. In contrast, hydroxylamine hydrochloride is safer to handle. Furthermore, industrial-grade aqueous hydroxylamine is rarely available, with most supplies being in the form of hydroxylamine salts, which makes the hydrochloride a more accessible and stable choice

Line 149 - Why did the yield of N-benzylhydroxylamine hydrochloride decrease significantly with lower amounts, and what was the cause of the increased byproducts like dibenzyl-substituted impurities?

-- The decrease in yield of N-benzylhydroxylamine hydrochloride at lower hydroxylamine equivalents can be attributed to the continued reaction of N-benzylhydroxylamine with benzyl chloride, which leads to the formation of dibenzyl-substituted byproducts. Increasing the amount of hydroxylamine helps to suppress this side reaction. As observed in the parameter screening experiment, 4 equivalents of hydroxylamine provide an optimal dosage. Additionally, enhancing the mixing efficiency and reaction temperature facilitates the rapid reaction of benzyl chloride with hydroxylamine, thereby reducing the formation of dibenzyl-substituted byproducts.

Line 157 - The authors mention that increasing the temperature to 80°C did not improve the yield. It would be helpful to explain why this was the case. Were there any risks associated with increasing the temperature further, or did the reaction mechanism not benefit from higher temperatures?

-- Based on the experimental data, it was observed the reaction of benzyl chloride with hydroxylamine at 60°C was efficient to afford the highest yield. Increasing the temperature to 80°C did not enhance the yield, as it did not prevent the formation of dibenzyl-substituted byproducts. Furthermore, higher temperatures increased the risk of thermal decomposition of hydroxylamine. Therefore, 60°C was selected as the optimal reaction temperature.

Line 170 - The authors should clarify why increasing reactant concentrations to 0.3 mol/L and 0.5 mol/L didn’t change the crystallization yield significantly. Was the reaction fully optimized with these concentrations, or could further adjustments to other parameters improve the yield?

-- The outcome of chemical reactions is largely determined by the collision efficiency between reactant molecules. The microchannel reactor significantly enhances collision efficiency, improving it by a factor of 100 compared to conventional laboratory stirring, as noted in the introduction regarding the Corning microchannel reactor. Therefore, increasing the reactant concentration from 0.3 mol/L to 0.5 mol/L did not result in a significant change in yield, as the mixing efficiency remained similar, leaving little impact on the reaction. Further adjustments to other parameters, such as temperature or flow rate, may be needed to improve the yield.

Line 173 - The authors mention a blockage at 1.0 mol/L concentration. Could they explain why this blockage occurred at higher concentrations? Was it due to viscosity, increased solid formation, or another reason? Also, was there a consideration of the maximum concentration that could be used before encountering such issues?

-- The blockage at a concentration of 1.0 mol/L occurred because N-benzylhydroxylamine hydrochloride has low solubility in methanol. At this concentration, the generated N-benzylhydroxylamine hydrochloride could not fully dissolve in methanol, leading to the precipitation of solids. In continuous flow reactors, it is crucial to prevent line blockages, as they can result in high internal pressure, posing safety risks. For this reason, we did not explore concentrations higher than 0.5 mol/L to ensure the safety of the experiment.

Table 2 – The table mentions "139 g" and "73 g + Recovered water phase," but the explanation of what exactly this implies is not completely clear. It would be helpful to detail whether the "Recovered water phase" refers to the amount of recovered solution, which would help contextualize the data presented.

-- In the previous experiment cycle, 66 g of hydroxylamine hydrochloride was obtained by post-treating the aqueous phase after extracting N-benzylhydroxylamine hydrochloride. Therefore, it can be inferred that the recovered aqueous phase contains at least 66 g of hydroxylamine hydrochloride. While it would be more accurate to process the recovered water phase into solid hydroxylamine hydrochloride for precise feeding into the next reaction, this approach is less convenient. As a practical solution, we directly added 79 g of hydroxylamine hydrochloride to the recovered water phase, allowing for some excess input without significantly impacting the overall accuracy. Fortunately, the experimental results validated this approach.

- How might an increase in the number of recycling cycles affect the quality of the final product and the need for adjustments in reaction conditions?

-- Side products, such as dibenzyl-substituted byproducts, are extracted by ethyl acetate during post-treatment. Consequently, only water-soluble hydroxylamine hydrochloride and sodium chloride remain in the water phase. Based on our observations, recycling the process from 1 to 3 cycles did not significantly degrade the quality of the product, indicating that further cycles can be performed without negatively impacting the final outcome.

- Can the recycling of hydroxylamine hydrochloride be applied to other synthesis reactions involving similar compounds? Are there any limitations or considerations to be made?

-- We believe that the recycling of hydroxylamine hydrochloride could be applied to other similar reactions, as the solubility differences between the products and hydroxylamine can be exploited for separation.

- What would be the next steps to improve the recovery rate of 47% for hydroxylamine hydrochloride? Have any attempts been made to optimize the extraction process?

-- In Section 2.2.3, the aqueous solution of hydroxylamine hydrochloride is directly reused in the next reaction without further extraction or treatment. In Section 2.2.4, hydroxylamine hydrochloride is extracted using methanol to quantify the amount remaining in the aqueous phase. To improve the recovery rate, potential approaches could include performing multiple extractions with smaller volumes, extending the extraction time, and enhancing stirring efficiency. These adjustments may help optimize the recovery process.

Discussion

Line 209/210 - What were the specific ideal conditions (exact amount of reagents, exact temperature, reaction time)? Could you explain how these conditions were determined and whether varying the experimental conditions would substantially influence the final yield?

-- At the end of Section 3.1, "Condition Optimization of the Continuous-Flow Reaction," we summarized the ideal reaction conditions after process optimization, and thus we did not repeat the detailed description here. Based on the parameter screening experiment, it was observed that temperature, hydroxylamine dosage, and flow rate are the key factors that significantly influence the yield. Varying these conditions could have a substantial impact on the final yield, as they directly affect the reaction efficiency and byproduct formation.

Could the authors provide more details on the impact of reducing the use of hydroxylamine hydrochloride in terms of cost and environmental feasibility? What is the percentage reduction compared to traditional methods?

-- As mentioned above, when using conventional experimental equipment, it is necessary to use excessive hydroxylamine and high temperature (100℃) to improve the conversion rate and selectivity of the reaction. Heating a large amount of hydroxylamine has a high safety risk, and if the hydroxylamine is not recycled, the environmental pressure of treating hydroxylamine wastewater is great. Compared to Lebel's work, we reduced at least 97% hydroxylamine usage.

Line 212 - Could the authors provide more data on how safety was ensured during the process? What kind of monitoring was implemented to prevent the thermal decomposition of hydroxylamine hydrochloride? Is the temperature of 60°C a safe condition for all amounts of hydroxylamine hydrochloride used in the process?

-- Compared to conventional batch reactors, the microchannel reactor offers advantages such as rapid heat exchange and a small liquid hold-up volume. In this system, if hydroxylamine hydrochloride decomposition were to occur, the reaction volume in a single module is only 8.2 mL, limiting the energy released. Any generated heat would be quickly dissipated by the circulating thermal oil. This is why highly exothermic reactions—such as nitration and peroxidation—are particularly well-suited for microchannel reactors.

 

Conclusion:

Although the discussion provides important insights into the results, I would recommend adding a dedicated Conclusions section at the end of the paper. A conclusions section can help summarize the key findings, their implications, and suggest directions for future research. This would not only improve the structure of the paper but also make it easier for readers to understand the results.

-- We appreciate your suggestion regarding the addition of a dedicated Conclusions section. Upon review, we agree that the original Section 4 ("Discussion") would be more accurately labeled as "Conclusion" to better reflect its content. In the revised manuscript, we have adjusted this section accordingly and expanded it to include future research directions, as recommended. These modifications aim to improve the paper’s structure and enhance clarity for readers.

References

The authors report 19 references, the majority of which are from older articles and patents (some from 2006, 2012), with only 2 references from the last 5 years, and present 7 patents. If possible, include more recent references to show that the work follows the latest trends in research.
When the authors report the patents, the year is not in bold.

-- Thanks for the reviewer’s helpful suggestions. No more recent literatures were found within the last 5 years.  All the years of patents has been bolded in the revised main text.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I have reviewed the revised manuscript and overall, the changes have been well implemented. Thank you for your careful attention to the previous comments.

During this final check, I noticed a few minor issues that should be corrected:

 

Lines 23, 36, and 171, and in references (1, 11, 12, 13, 14): the letter "N" should be in italics when referring to chemical names (e.g., N-benzylhydroxylamine).

Line 64: there is a missing space between "100" and "ºC".

Line 74: please change "N-Benzylhydroxylamine" to "N-benzylhydroxylamine" to reflect the correct formatting.

In the scheme of Table 1: add a space between "2.0" and "mol/L".

In Table 1, the first column is correctly labeled as "Entry". However, throughout the text the manuscript refers to "Experiment X", which is inconsistent. Please replace "Experiment" with "entry" to match the table.

Review the title of Table 1 – it should refer to "N-Benzylhydroxylamine Hydrochloride" with the correct formatting of "N".

Also, please double-check formatting in the references section — there are some inconsistencies (e.g., the use of italics, punctuation, and spacing).

 

Once these small corrections are made, I believe the manuscript will be ready for acceptance.

Author Response

Comments and Suggestions for Authors

I have reviewed the revised manuscript and overall, the changes have been well implemented. Thank you for your careful attention to the previous comments.

During this final check, I noticed a few minor issues that should be corrected:

-- Thanks for the reviewer’s positive feedback on our revised manuscript.

Lines 23, 36, and 171, and in references (1, 11, 12, 13, 14): the letter "N" should be in italics when referring to chemical names (e.g., N-benzylhydroxylamine).

-- We have checked the full text to ensure that the letter "N" in all chemical names has been modified to italicized "N".

Line 64: there is a missing space between "100" and "ºC".

-- The missing space has been corrected in the revised main text.

Line 74: please change "N-Benzylhydroxylamine" to "N-benzylhydroxylamine" to reflect the correct formatting.

-- "N-Benzylhydroxylamine" has been corrected into "N-benzylhydroxylamine" in the revised main text.

In the scheme of Table 1: add a space between "2.0" and "mol/L".

-- The space between "2.0" and "mol/L" in the scheme of Table 1 has been added in the revised main text.

In Table 1, the first column is correctly labeled as "Entry". However, throughout the text the manuscript refers to "Experiment X", which is inconsistent. Please replace "Experiment" with "entry" to match the table.

-- The mentioned mistakes have been corrected.

Review the title of Table 1 – it should refer to "N-Benzylhydroxylamine Hydrochloride" with the correct formatting of "N".

--Thanks for the reviewer’s kind reminder. The mentioned mistake has been corrected.

Also, please double-check formatting in the references section — there are some inconsistencies (e.g., the use of italics, punctuation, and spacing).

-- We have carefully examined the references section and ensured that all punctuation and formats have been corrected.

Once these small corrections are made, I believe the manuscript will be ready for acceptance.

-- We appreciate the editor and the reviewers for bringing these issues to our attention. We have checked all the mentioned issues and necessary modifications have been made.