The Q-Tube-Assisted Green Sustainable Synthesis of Fused Azines: New Synthetic Opportunities via Innovative Green Technology

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The current manuscript deals with the sustainable synthesis of fused azines in Q-tube. The advantages of the new reactor compared to regular heat with reflux is clear, but as the reaction in MW showed comparable yields, it is worth to show deeper comparison between the two, and especially with respect to economical aspects, which were one of the main claims in favor of the new system during the introduction section.

Author Response

Reviewer 1 comments:

The current manuscript deals with the sustainable synthesis of fused azines in a Q-tube. The advantages of the new reactor compared to regular heat with reflux are clear, but as the reaction in MW showed comparable yields, it is worth showing a deeper comparison between the two, especially with respect to economic aspects, which were one of the main claims in favor of the new system during the introduction section.

Response:

We would like to thank the reviewer for his significant comment. It is well known that one of the important issues in accepting the research work is the novelty. Herewith, we are using the Q-tube as a novel reactor for the current reaction. In order to display the efficiency of the new reactor we did a comparison with the thermal and microwave assisted reaction. The results obtained showed the success of the Q-tube as a tool for the synthesis of the required products which is very close to the MW-assisted reaction. The advantage of the Q-tube over the MW could be summerised as: 1. Economic aspect, where the price of the Q-tube as a tool is almost 5% of the MW reactor, 2. Saving energy as the pressure used reduces the time of the reaction.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

1.     General comments. Very well written. Advantages to green chemistry approaches and aspects of this work are discussed satisfactorily.

 

2.     Editorial comments.

a.      Page 6, lines 134-7. Run on sentence. As reads, “The obtained products 3b and 3c are in complete agreement with the spectroscopic data for example the IR spectrum…” Recommend splitting into two sentences: “The obtained products 3b and 3c are in complete agreement with the spectroscopic data. For example, the IR spectrum…”

 

3.     Content comments.

a.      Supplemental Material. Compound characterization may be insufficient. If the synthesized molecules have been previously reported, a reference should be cited along with the melting point. If they are new compounds (a cursory search using Google Scholar gave no hits), then 13C NMR and either elemental analysis or high resolution MS should be reported for the new compounds.

b.     The green aspects of this work are important. First, the recyclability graph depicting regeneration of the catalyst for 7 cycles is excellent. It would also be useful for the authors to quantify certain other green parameters (atom economy, process mass intensity, energy expenditure, etc) for the Q-tube reactions versus conventional and microwave process mentioned in the paper.

c.      References cited in this communication are a good mix of historical and current research on the topic and provide the reader with proper context.

d.     The results of the optimization study the authors describe as well as the use of 2D H-H NOESY to elucidate product regiochemistry are explained very clearly and provide the reader with an understanding of how the reaction conditions were optimized and how the new compound structures were verified.

Author Response

Reviewer 2 comments:

1. General comments. Very well written. The advantages to green chemistry approaches and aspects of this work are discussed satisfactorily.
2. Editorial comments.: Page 6, lines 134-7. Run on sentence. As reads, “The obtained products 3b and 3c are in complete agreement with the spectroscopic data for example the IR spectrum…” Recommend splitting into two sentences: “The obtained products 3b and 3c are in complete agreement with the spectroscopic data. For example, the IR spectrum…”

Response:

Thank you very much for your esteemed comments and we make the required changes. 

3. Content comments.
4. Supplemental Material. Compound characterization may be insufficient. If the synthesized molecules have been previously reported, a reference should be cited along with the melting point. If they are new compounds (a cursory search using Google Scholar gave no hits), then 13C NMR and either elemental analysis or high-resolution MS should be reported for the new compounds.

Response:

Thank you very much for your essential comments we added the characterization for the synthesized compound including the elemental analysis in the supporting information.

1. The green aspects of this work are important. First, the recyclability graph depicting regeneration of the catalyst for 7 cycles is excellent. It would also be useful for the authors to quantify certain other green parameters (atom economy, process mass intensity, energy expenditure, etc) for the Q-tube reactions versus conventional and microwave process mentioned in the paper.

Response:

Thank you very much for the essential comments we added about the green metrics for our reaction in the supporting information file.

 

1. References cited in this communication are a good mix of historical and current research on the topic and provide the reader with proper context.

Response:

Thank you very much for your esteemed comment

1. The results of the optimization study the authors describe as well as the use of 2D H-H NOESY to elucidate product regiochemistry are explained very clearly and provide the reader with an understanding of how the reaction conditions were optimized and how the new compound structures were verified.

Response:

Thank you very much for your esteemed comment

 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript presents the synthesis of new fused azines using pressure and temperature in a catalytic reaction following the principles of green chemistry.

The authors use commercial equipment, the Q-Tube, as the reactor for the synthesis, they study the best catalyst for the test reaction and compare those results with conventional heating and microwave heating.

Although high-pressure chemistry is well established, and solvothermal reactors are quite affordable in a wide range of volumes, the system used in this manuscript has the advantage of being easy to manipulate and seems to have lower cooling time than conventional solvothermal reactors. However, the introduction looks more like a sales pitch than a scientific paper.

The question of whether the Q-tube is greener than the microwave reactor depends on different factors as the authors indicate.

This system has advantages, such as the price of the equipment, and the easiness of use, but the energetic preference is not clear. In this case, both systems use 100ºC and the autogenic pressure, and the results with the same temperature on a closed system are identical for both systems, or even slightly better for the microwave system (Table 1), so the important point is the energetic cost of achieving that 100ºC. Does the use of the Q-Tube save energy?

The chemical part of the manuscript is interesting and demonstrates that the procedure depicted is efficient, economical, and high-yielding.

The experimental part is correct, but the structural determination of the compounds synthesized in this work is incomplete. Only IR and 1H-NMR spectral data are provided. 13C-NMR and HRMS should be included unless the compounds are well-known, which does not seem to be the case.

Other aspects of the manuscript should be corrected before acceptance:

In Table 1, all the reaction conditions (temperature, scale of the reaction) should be indicated, as tables should be self-explanatory.

Some references are questionable. For the statement that the reaction rate doubles every 10º, the authors reference the IUPAC. Compendium of Chemical Terminology, which does only the definitions and does not explain that statement.

References 31 to 33 do not seem to refer to “the known behavior of α,β-unsaturated carbonyls towards amino pyrazole”.

 

The explanation of the catalytic activity of the catalyst used (lines 157-162 and Scheme 4) is confusing. Maybe a scheme with arrows indicating the different steps could be more useful. 

Comments on the Quality of English Language

There are small mistakes in the text.

i.e. line 67: On the other hand, a plethora of organic reactions, layered double hydroxides...  it should be FOR a plethora...

in line 148: The formed product 7 was found oxidized form. It should be found IN oxidized...

 

lines 159-162: This paragraph is quite confusing

Author Response

Reviewer 3 comments:

This manuscript presents the synthesis of new fused azines using pressure and temperature in a catalytic reaction following the principles of green chemistry. The authors use commercial equipment, the Q-Tube, as the reactor for the synthesis, they study the best catalyst for the test reaction and compare those results with conventional heating and microwave heating. Although high-pressure chemistry is well established, and solvothermal reactors are quite affordable in a wide range of volumes, the system used in this manuscript has the advantage of being easy to manipulate and seems to have lower cooling time than conventional solvothermal reactors. However, the introduction looks more like a sales pitch than a scientific paper. The question of whether the Q-tube is greener than the microwave reactor depends on different factors as the authors indicate. This system has advantages, such as the price of the equipment, and the easiness of use, but the energetic preference is not clear. In this case, both systems use 100ºC and the autogenic pressure, and the results with the same temperature on a closed system are identical for both systems, or even slightly better for the microwave system (Table 1), so the important point is the energetic cost of achieving that 100ºC. Does the use of the Q-Tube save energy?

Response:

Thank you very much for your esteemed comment, but as we talk about the new instrument Q-Tube we declare its advantages that get from experiments, therefore you feel this a sale pitch. It is well known that one of the important issues in accepting the research work is the novelty. Herewith, we are using the Q-tube as a novel reactor for the current reaction. In order to display the efficiency of the new reactor we did a comparison with the thermal and microwave assisted reaction. The results obtained showed the success of the Q-tube as a tool for the synthesis of the required products which is very close to the MW-assisted reaction. The advantage of the Q-tube over the MW could be summarised as: 1. Economic aspect, where the price of the Q-tube as a tool is almost 5% of the MW reactor, 2. Saving energy as the pressure used reduces the time of the reaction.

The chemical part of the manuscript is interesting and demonstrates that the procedure depicted is efficient, economical, and high-yielding.

The experimental part is correct, but the structural determination of the compounds synthesized in this work is incomplete. Only IR and 1H-NMR spectral data are provided. 13C-NMR and HRMS should be included unless the compounds are well-known, which does not seem to be the case.

Response:

Thank you very much for your essential comments we added the characterization for the synthesized compound including the elemental analysis in the supporting information.

Other aspects of the manuscript should be corrected before acceptance:

In Table 1, all the reaction conditions (temperature, scale of the reaction) should be indicated, as tables should be self-explanatory.

Response:

Thank you very much for your essential comments, we added the required data

 

Some references are questionable. For the statement that the reaction rate doubles every 10º, the authors reference the IUPAC. Compendium of Chemical Terminology, which does only the definitions and does not explain that statement.

Response:

Thank you very much for your essential comments, we replaced the reference.

References 31 to 33 do not seem to refer to “the known behavior of α,β-unsaturated carbonyls towards amino pyrazole”.

 Response:

Thank you very much for your essential comments, we replaced the unrelated references.

The explanation of the catalytic activity of the catalyst used (lines 157-162 and Scheme 4) is confusing. Maybe a scheme with arrows indicating the different steps could be more useful. 

 Response:

Thank you very much for your essential comments, we rewrote these lines.

Comments on the Quality of English Language

There are small mistakes in the text.

i.e. line 67: On the other hand, a plethora of organic reactions, layered double hydroxides...  it should be FOR a plethora...

in line 148: The formed product 7 was found oxidized form. It should be found IN oxidized...

lines 159-162: This paragraph is quite confusing

 Response:

Thank you very much for your essential comments, all the mentioned mistakes have been corrected

 

 

 

 

 

 

Author Response File: Author Response.pdf