Synthesis, Electrochemical and Spectroscopic Characterization of Selected Quinolinecarbaldehydes and Their Schiff Base Derivatives

Round 1

Reviewer 1 Report

The authors report the use of the classical Reimer-Tiemann, Vilsmeier-Haack and Duff formylation methodologies to synthesize quinolinecarbaldehydes with carbonyl group located at C5 and/or in C7 positions. A comparative analysis in terms of experimental (including NMR, electrochemical measurements, X-ray,…) and computational studies is presented to explain the selectivity of these transformations.

The manuscript could be accepted after minor revisions as followings.

• The manuscript should be revised by a native English-speaker.
• The title of the manuscript should be changed for avoiding the word ‘and’ three times.
• On page 1, in abstract, it should be written ‘A new approach’ instead of ‘A new approaches’ and ‘formylation transfomations’ instead of ‘formylation trasfomations’.
• On page 2, line 46, ‘Aldehydes’ instead of ‘Adehydes’.
• On page 2, the reaction conditions for the Reimer-Tiemann, Vilsmeier-Haack, and Duff formylation reactions should be clearly written in the manuscript (temperature, solvent, time,..). The same for the synthesis of Schiff bases on scheme 5.
• On page 2, scheme 1, two different reaction products are labelled as ‘2’. This is quite confusing. It could be changed to ‘2’ and ‘2’’, for example to differentiate them properly.
• On page 3, scheme 3, the number 3 in ‘CH3’ should be written in subscript.
• On page 5, line 145, authors write about the molecules 3. However, it is not indicated where the structures of these molecules are. Much later, they are on page 8. They should indicate in which scheme they are between parentheses.
• On page 5, line 154, parentheses ‘(…)’ should be used instead of ‘[(…]’.

Author Response

please see the attachment

Author Response File: Author Response.docx

Reviewer 2 Report

I found the manuscript hard to read through and understand in places, with sentence structures alternating between an eloquent and brunt delivery. I recommend you organise the manuscript to deliver key messages more succinctly, probably with a reduction of word count, particularly over pages 3 to 5. I am happy with the characterization but some other corrections are given below:

(1) It would be helpful to show generic schemes for the 3 named reactions in the introduction, as this does not occur until Scheme 3.

(2) It is unusual that Scheme 1 contains a large table. Ordinarily a combined scheme and table would captioned as a Table.

(3) Can you explain why the three different formylation methods were not performed for each substrate in Scheme 1? Some comments are made later on, after the characterization (e.g. limitation of acidic conditions for Duff reaction) which I would expect to see earlier in the manuscript. I do not understand the a/a' and i/i' entries, are they from the same reaction but the yields of each regioisomer after separation? If so, because C7 formylation is minimal I would remove those entries, keeping discussion of regioselectivity to the main text. When there is more than one reaction for a substrate, the yields from different protocols could be listed in separate columns in the table within Scheme 1. The resulting table, wider and shorter, would also fill the space below the scheme better.

(4) Can you rewrite lines 102-103: "Absence of methyl group in C2 (R) position could have influence for increase yield of products. R substituent can undergo further side reaction"? Do you mean the methyl at C2 prevents potential formylation at this position so you get a better yield of product with the intended substitution pattern, or the reactivity at C5 or C7 is changed by the electronic properties of a C2 substituent? Can you make reference to relevant compounds from the table in Scheme 1 here to illustrate the comparison between reactants with and without the C2 methyl group?

(5) Regarding Figure 1 and the associated text, please explain the notation in the caption (e.g. atomic charges (units) of selected atoms (key to to color coding)...). In the text, clearly define what the values mean, e.g. the difference in the delta values (blue numbers in Figure 1) between C5 and C7.

(6) Line 376: Please change "Next chloroform (8.3 ml; 103.5 mmol) was subsequently gently dropped within an hour" to "Chloroform (8.3 ml; 103.5 mmol) was then added dropwise to the reaction mixture over the course of 1 hour" (or equivalent).

Author Response

Response to Reviewer-2

In according to letter from 13^rd of April 2020 concerning decision of submission of our manuscript I would like to thank you very much Dear Reviewers for so many very important remarks and advices. I hope that present version did not contain any of mentioned problems.

(1) It would be helpful to show generic schemes for the 3 named reactions in the introduction, as this does not occur until Scheme 3.

This part was corrected. The Scheme 3, now Scheme 1 is in the beginning of Results and discussion. Now Scheme 1 shows not only generic knowledge, but also help to understand our message, we hope.

(2) It is unusual that Scheme 1 contains a large table. Ordinarily a combined scheme and table would captioned as a Table.

This part was corrected. Thank you so much for your help. We appreciate it.

(3) Can you explain why the three different formylation methods were not performed for each substrate in Scheme 1?

Dear Reviewer, this is an Excellent question, and we thank you so much. We tried to check reactivity of three different formylation methods, and we described the most important results in the manuscript showing e.g. some limitation, like using amino substituents for Duff reaction. The preliminary results for light promotion Reimer-Tiemann type reaction possible needs more serious literature checking, and for this moment results are not satisfy. For Vilsmeier-Haack reaction every reagents possess hydroxyl or possibly all nucleophilic substituents like e.g. NH₂ can react with POCl₃ and Vilsmeier’s reagent. We added the appropriate information to the text and adequate reference.

Some comments are made later on, after the characterization (e.g. limitation of acidic conditions for Duff reaction) which I would expect to see earlier in the manuscript. I do not understand the a/a' and i/i' entries, are they from the same reaction but the yields of each regioisomer after separation?

Yes, there are from the same reaction.

If so, because C7 formylation is minimal I would remove those entries, keeping discussion of regioselectivity to the main text. When there is more than one reaction for a substrate, the yields from different protocols could be listed in separate columns in the table within Scheme 1. The resulting table, wider and shorter, would also fill the space below the scheme better.

This part was corrected. We remove those entries from the table. Thank you so much for your help. We appreciate it. Now looks better, more transparent, we hope.

(4) Can you rewrite lines 102-103: "Absence of methyl group in C2 (R) position could have influence for increase yield of products. R substituent can undergo further side reaction"? Do you mean the methyl at C2 prevents potential formylation at this position so you get a better yield of product with the intended substitution pattern, or the reactivity at C5 or C7 is changed by the electronic properties of a C2 substituent? Can you make reference to relevant compounds from the table in Scheme 1 here to illustrate the comparison between reactants with and without the C2 methyl group?

Can the presence of methyl group at C2 position have influence for the yield? Until now, we have only one example. The sentence “Absence of methyl group in C2 (R) position could have influence for increase yield of products. R substituent can undergo further side reaction” can suggest that we should have higher yield, but we isolated lower yield. Our theoretical calculation and presented ideas suggest that absence of methyl group in C2 (R) position should increase yield of products. My Ph.D. students few times check reactivity of both mentioned reactants and proved that in our condition our message is rather correct. He has huge problem with isolation of double formylated compound with hydrogen at C2 (R) position (without methyl group). He always identified all 3 possible formylated compounds. We should find better isolation procedure. For isolation yield could have influence: a) the solubility of product b) isolation procedure (filtration, chromatography etc.) c) influence of solubility of products for reactivity of reagents during experiment. The reaction leading to double formylation could be hindered by the low solubility of monoformylated reagent. We deleted this text, and we will try to find additional explanation, and/or to find better isolation procedure.

(5) Regarding Figure 1 and the associated text, please explain the notation in the caption (e.g. atomic charges (units) of selected atoms (key to to color coding)...). In the text, clearly define what the values mean, e.g. the difference in the delta values (blue numbers in Figure 1) between C5 and C7.

This part was corrected. We fully agree that the explanation in text of manuscript was not clear. We greatly thank the reviewer. The paragraph was modified.

(6) Line 376: Please change "Next chloroform (8.3 ml; 103.5 mmol) was subsequently gently dropped within an hour" to "Chloroform (8.3 ml; 103.5 mmol) was then added dropwise to the reaction mixture over the course of 1 hour" (or equivalent).

This part was corrected. Thank you so much for your help. We appreciate it.

Some improvements about the writing have been done. We have revised the whole manuscript carefully and tried to avoid any grammar or syntax error. In addition, we have asked several colleagues who are skilled authors of English language papers to check the English. We believe that the language is now acceptable for the review process. Thank you so much for your help. We appreciate it.

Yours sincerely, Jacek Nycz (on behalf of all co-authors)