A Brønsted Acidic Deep Eutectic Solvent for N-Boc Deprotection

Round 1

Reviewer 1 Report

Authors developed convenient approach to Boc-deprotection, which is very relevant for polysubstituted substrates. The method is based on cholinechloride-containing deep euthectic solvents, with ChCl is available from biomass treatment or can be easily synthesized. Mild conditions and short reaction time were achieved when pTSA was applied as Bronsted acid. The influence of acidity and viscosity of the medium on the yield of deprotection process was studied. Wide scope of Boc-protected amines was considered. No degradation of methyl ester or Fmoc groups was observed, that represent valuable findings. The described method is really promising for application not only in dipeptides synthesis, but also for different regioselective procedures in drug design.

The manuscript can be accepted after minor revision. Some comments:

Lines 241-247 Visualization of this description in the scheme would be beneficial

Line 122 – space between “yields” and “and”

Experimental part – bottom indexes should be applied for CH2, NH2, CH2Ph et al (lines 317, 318, 363, 411 etc), chemical shift values 1.80 (line 353), 1.24 (line 358)

Ref 28 - extra (2019)

Ref 47-51 year in bold

Author Response

Response to Reviewer 1 comments:

we thank the reviewer for the interest in our manuscript and for the appreciations. We have made all the suggested corrections as reported in the pdf-file attached.

Lines 241-247 Visualization of this description in the scheme would be beneficial

Thank you for the suggestion. We have added a scheme with our proposed mechanism for this reaction.

Line 122 – space between “yields” and “and”

We corrected this.

Experimental part – bottom indexes should be applied for CH2, NH2, CH2Ph et al (lines 317, 318, 363, 411 etc), chemical shift values 1.80 (line 353), 1.24 (line 358)

We made these corrections.

Ref 28 - extra (2019)

We made this correction.

Ref 47-51 year in bold

We made this correction.

Reviewer 2 Report

This paper does describe an interesting and relevant piece of work. However:

I don't feel that there is sufficient critical comparison to current established methods, either in terms of a direct comparative experiment added to your tables of data, or in terms of the "green-ness" of the methods. In order to be suitable for publication making the claims this paper does about the relative sustainability of this method, it will be necessary to add in a detailed comparison of the sustainability of your DES method to at least one or two of the conventional methods you discuss. This should include appropriate use of green-chemistry metrics (including purification, where appropriate - though your discussion should touch on how this also applies to SPPS) and a critical discussion of the hazards, and origins (petrochemical vs biomass) of the materials used and waste produced. You may wish to bring on board a collaborator with more experience of Green Chemistry if this is outside the authors' expertise.

I would also ask that you consider adding control experiments for each component of your DES mixture(s) separately to confirm the activity, or lack thereof, of each component.

The content of Table 1 should be improved such that multiple variables (DES mixture, temperature, time) are not changed between experiments, muddying the effect that each change has - a more systematic approach is needed.

Some minor points:

- Consider improving the format of chemical structures - atoms are very small and hard to read. 

- Referring to a generic chemist as "himself" is not very inclusive, please use gender neutral language or rephrase.

Author Response

We thank the reviewer for the careful reading of the manuscript and the constructive remarks. We have taken the comments on board to improve and clarify the manuscript.

I don't feel that there is sufficient critical comparison to current established methods, either in terms of a direct comparative experiment added to your tables of data, or in terms of the "green-ness" of the methods. In order to be suitable for publication making the claims this paper does about the relative sustainability of this method, it will be necessary to add in a detailed comparison of the sustainability of your DES method to at least one or two of the conventional methods you discuss. This should include appropriate use of green-chemistry metrics (including purification, where appropriate - though your discussion should touch on how this also applies to SPPS) and a critical discussion of the hazards, and origins (petrochemical vs biomass) of the materials used and waste produced.

We have added further detail, and a better structure, to explain how our method can furnish an improvement over conventional methodologies for Boc deprotection in terms of sustainability. In this regard, we calculated the values of PMI and E-factor, that are two key mass-based metrices useful for the evaluation of the greenness of a synthetic process. Furthermore, we have made a comparison to established methods reported in the manuscript. The following paragraphs were added:

“To understand the efficiency of our protocol with respect to conventional methods already reported in the literature for the deprotection of the Boc group, we calculated the process mass intensity (PMI) and complete environmental factor (E-factor). These two metrics are key mass-based metrices useful for the evaluation of the greenness of a synthetic process. [48-50]: The E-Factor takes into account waste byproducts, solvent losses and anything else that can be regarded as a waste; PMI instead, take into account the mass of all the material used in a synthetic process relative to the amount of final product. Table 5 shows the two metrics calculated for our procedure and compares them with those of other reported methodologies.

The PMI and E-factor for our procedure were calculated as 68 and 67, respectively, whereas those of other procedures were found to be higher (see supporting information for calculation). Nevertheless, the ideal E factor is 0 and higher E factors are relatively less amenable. However, it matters what kind of wastes are produced because in our protocol, choline chloride and p-toluensulfonic acid may be of little concern compared to toxic organic volatile solvents and corrosive acids. Therefore, this data indicates the feasibility, greenness and sustainability of our process.”

In addition we inserted a Table (Table 5 ) that better explains the results obtained by this comparison.
We added also references 48, 49 and 50 regarding the calculation of green metrics.
In the supplementary information file, we added the calculation carried out for the different methodologies.

I would also ask that you consider adding control experiments for each component of your DES mixture(s) separately to confirm the activity, or lack thereof, of each component.

Both ChCl and pTSA are solids components at room temperature, therefore it resulted complicated to perform the experiment using the single component of DES mixture. However, we repeated the reaction using pTSA and only after the addition of an organic solvent (DCM) the reaction afforded the deprotected amine.

The content of Table 1 should be improved such that multiple variables (DES mixture, temperature, time) are not changed between experiments, muddying the effect that each change has - a more systematic approach is needed.

For a better comprehension of the Table 1 we have added the following comment in the text “For a systematic study of the action of the investigated systems, all reactions were conducted at room temperature, except in the case of the DES prepared using citric acid which required a temperature of 50°C due to its high viscosity that limits the application as a reaction medium. The times shown in the table refer to the respective points of maximum conversion of the substrate, as verified by GC/MS.” In addition, we have used the notes in the table to clarify the changes in the different experiments.

Consider improving the format of chemical structures - atoms are very small and hard to read.

The format of chemical structures has been improved. We hope that now they are easy to be read.

Referring to a generic chemist as "himself" is not very inclusive, please use gender neutral language or rephrase.

the chemist to orient himself towards a "green" synthetic design has been changed in “Chemists to orient themselves”

Reviewer 3 Report

The authors demonstrated that selective deprotection of the N-Boc group from aliphatic and aromatic amines and its derivatives using reactive deep-eutectic solvent (choline chloride:pTSA) catalyst under room temperature conditions. This approach is simple and eco-friendly. The work is interesting although with few ambiguous claims. It is recommended for publication in “Catalysts” after minor revision. Specific comments are as follows:

1.     Novelty of this work is missing. Add a table showing a comparison of the present study with previously published works.

2.     Authors should state the complete form of each abbreviation at its first appearance.

3.     We found several typos/grammatical mistakes (lines: 62, 86, 155, 164, 270, 275, 278 and 290, and so on). Please correct the errors the throughout the manuscript to enhance the quality of the manuscript.

4.     FeCl₃ is good catalyst compared to pTSA. Why ChCl:FeCl₃ catalyst showing lower catalytic activity compare to ChCl:pTSA (Table 1).

5.     Provide the references (lines: 116, 182, and 240, etc.)

6.     Check that all references are relevant to the contents of the manuscript.

7.     Some related literature could be cited to enrich the introduction part, for example: Advanced Synthesis & Catalysis 2010, 352, 2507-2514; Journal of Molecular Catalysis A: Chemical 2012, 352, 70-74; Journal of Catalysts 2014, 2014, 515428 (1-6).

8.     Remove section 3.3. in the manuscript, because it is available in the supporting information (Section 3).

9.     Last table caption and explanations are missing and please correct the labels :”Riff” and “Mp” and “Te”.

Author Response

We thank the reviewer for the constructive suggestions. We incorporate them in the new version as explained below, and hope to raise the final scoring

Novelty of this work is missing. Add a table showing a comparison of the present study with previously published works.

We have added further detail, and a better structure, to explain how our method can furnish an improvement over conventional methodologies for Boc deprotection in terms of sustainability. In this regard, we calculated the values of PMI and E-factor, that are two key mass-based metrices useful for the evaluation of the greenness of a synthetic process. Furthermore, we have made a comparison to established methods reported in the manuscript. The following paragraphs were added:”

“To understand the efficiency of our protocol with respect to conventional methods already reported in the literature for the deprotection of the Boc group, we calculated the process mass intensity (PMI) and complete environmental factor (E-factor). These two metrics are key mass-based metrices useful for the evaluation of the greenness of a synthetic process. [48-50]: The E-Factor takes into account waste byproducts, solvent losses and anything else that can be regarded as a waste; PMI instead, take into account the mass of all the material used in a synthetic process relative to the amount of final product. Table 5 shows the two metrics calculated for our procedure and compares them with those of other reported methodologies.

The PMI and E-factor for our procedure were calculated as 68 and 67, respectively, whereas those of other procedures were found to be higher (see supporting information for calculation). Nevertheless, the ideal E factor is 0 and higher E factors are relatively less amenable. However, it matters what kind of wastes are produced because in our protocol, choline chloride and p-toluensulfonic acid may be of little concern compared to toxic organic volatile solvents and corrosive acids. Therefore, this data indicates the feasibility, greenness and sustainability of our process.”

In addition we inserted a Table (Table 5 ) that better explains the results obtained by this comparison.

In the supplementary information file, we added the calculation carried out for the different methodologies.

Authors should state the complete form of each abbreviation at its first appearance.

We reported the complete form for each abbreviation as its first appearance

We found several typos/grammatical mistakes (lines: 62, 86, 155, 164, 270, 275, 278 and 290, and so on). Please correct the errors the throughout the manuscript to enhance the quality of the manuscript.

We have corrected the typos/grammatical mistakes through the manuscript

FeCl3 is good catalyst compared to pTSA. Why ChCl:FeCl3 catalyst showing lower catalytic activity compare to ChCl:pTSA (Table 1).

It is true that FeCl3 is a good Lewis acids catalysts nevertheless the use of this DES in the Boc deprotection caused a loss of the free amine in water making its recovery complicated respect to the ChCl:pTSA DES. We added the following sentence in the text:
“However, as previously reported, the employment of FeCl3 makes the work-up procedure more complicated as a large amount of the deprotected compound went into the water with iron during work-up.”

Provide the references (lines: 116, 182, and 240, etc.)

We had forgotten to add these references. We provided the requested references

Check that all references are relevant to the contents of the manuscript.

We checked all the references of the manuscript

Some related literature could be cited to enrich the introduction part, for example: Advanced Synthesis & Catalysis 2010, 352, 2507-2514; Journal of Molecular Catalysis A: Chemical 2012, 352, 70-74; Journal of Catalysts 2014, 2014, 515428 (1-6).

The introduction section was enriched by addition of the suggested literature regarding the use of pTSA as a catalysts. (Ref 34)

Remove section 3.3. in the manuscript, because it is available in the supporting information (Section 3).

We have removed section 3.3 because it is already reported in the supporting information

Last table caption and explanations are missing and please correct the labels :”Riff” and “Mp” and “Te”.

We added table caption for the last table, and we corrected the labels as suggested.

Round 2

Reviewer 1 Report

Authors inproved the manuscript very well according to comments, the article can be accepted.

Reviewer 2 Report

This paper is significantly improved since the initial review. I feel that with minor proof-reading to improve English this will be ready for publication.

Reviewer 3 Report

Accept in present form