Development of L-Proline-Based Chiral Ionic Liquids for Asymmetric Michael Reaction

Round 1

Reviewer 1 Report

This paper by Branco and coworkers describes the synthesis, characterization and use as organocatalysts of a series of proline derived chiral ionic liquids. The tested reaction is an asymmetric Michael addition and the best results are comparable with those obtained with L-proline, used as reference organocatalyst.

Although a lot of work has been carried out in this paper, there are some criticisms, listed below.

For this reason, I suggest major revisions prior to publication.

1) References are not well used. In particular, at page 1, refs 18 and 19 should describe the use of proline as organocatalyst, and they are not on this subject.

At page 6, refs 22 and 23 should descrobe the use of proline derivatives in Michael addition, and they are not.

Also ref 24 seems not appropriate.

Moreover, at least one of the synthesized CIL is known in the literature, but the citation is not reported (S H Duan et al 2018 IOP Conf. Ser.: Mater. Sci. Eng. 292 012040 )

2) page 1, line 39 “....proline is a bifunctional amino acid....”. All amino acids are bifunctional molecules.

3) page 5, lines 135-137: I do not understand the meaning

4) page 6, lines 163-165: add a reference for the use of trifluoroacetic acid in this reaction

5) Table 2, ee (%): put in not the fact that (I suppose) the ee is referred to the syn isomer

6) Tables 2, 3 and 4: I think conversions are not sufficient to compare the various entries.

7) Table 2 (and possibly the others), entries 1 and 2: I do not understand why a higher amount of catalyst leads to doubled reaction times

8) Table 4: why in many cases is the dr not reported?

9) main criticism: the authors claim recycling, but only in one case the reaction product is isolated and the catalyst NOT recycled. There is no demonstration that the catalyst is still active and not converted into simple proline

10) main criticism: there is thus no advantage in synthesizing such a CIL instead of using proline

Author Response

Reviewer 1 (R1) considered that “This paper by Branco and coworkers describes the synthesis, characterization and use as organocatalysts of a series of proline derived chiral ionic liquids. The tested reaction is an asymmetric Michael addition and the best results are comparable with those obtained with L-proline, used as reference organocatalyst. Although a lot of work has been carried out in this paper, there are some criticisms, listed below. For this reason, I suggest major revisions prior to publication.”

Authors: Thank you for your comments about the manuscript. It is important to emphasize that the asymmetric Michael addition reaction can be performed using L-proline dissolved in ILs or new Chiral ionic liquids (CILs) based on L-proline dissolved in ILs. One of the advantage to use CILs is related to the recycling tests using supercritical CO₂. It is more efficient to perform the recycling with CILs dissolved in ILs.

R1: References are not well used. In particular, at page 1, refs 18 and 19 should describe the use of proline as organocatalyst, and they are not on this subject.

Authors: The references were changed as suggested by reviewer.

The refs 18 and 19 are now the following:

[18]Obregón-Zúñiga A., Milán M., Juaristi E., Improving the Catalytic Performance of (S)-Proline as Organocatalyst in Asymmetric Aldol Reactions in the Presence of Solvate Ionic Liquids: Involvement of a Supramolecular Aggregate. Org. Lett. 2017, 19, 5, 1108–1111.

[19] a) Huang, L., Li, Y., Lin, Q., Lou, B, Chen, Y., Enantioselective permeations of amino acids through L-proline-modified gold nanochannel membrane: an experimental and theoretical study. Amino Acids, 2018, 50, 1549-1556, b) List B., Lerner R. A., Proline-Catalyzed Direct Asymmetric Aldol Reactions J. Am. Chem. Soc. 2000, 122, 10, 2395–2396.

We decided to keep the reference 19a) and changed the reference 18 for a more recent article using (S)-proline in ILs.

R1: At page 6, refs 22 and 23 should describe the use of proline derivatives in Michael addition, and they are not. Also ref 24 seems not appropriate

Authors: The refs 22 and 23 were changed according the suggestion.

The new references are:

[22] Wagner M., Contie Y., Ferroud C., Revial G., Enantioselective Aldol Reactions and Michael Additions Using Proline Derivatives as Organocatalysts, Int. J. Org. Chem., 2014, 4, 55-67.

[23] Yang, M., Zhang, Y., Zhao, J., Yang, Q., Ma, Y., Cao, X., A Recyclable Organocatalyst for Asymmetric Michael Addition. Catal Lett., 2016, 146, 587–595 shows the use of proline derivatives in Michael Reaction.

The reference 24 is a work using cysteine derived organocatalyst applied in enantioselective Michael reaction by comparison with conventional L-proline. In our opinion, this reference is appropriate in the context of the manuscript.

R1: Moreover, at least one of the synthesized CIL is known in the literature, but the citation is not reported (S H Duan et al 2018 IOP Conf. Ser.: Mater. Sci. Eng. 292 012040 )

Authors: The reference indicated by Reviewer was included as ref 27

[27] Duan S. H., Kai T., Chowdhury F. A., Taniguchi I., Kazama S., Effect of addition of Proline, ionic liquid [Choline][Pro] on CO2 separation properties of poly(amidoamine) dendrimer / poly(ethylene glycol) hybrid membranes. Materials Science and Engineering 2018, 292, 012040

R1: page 1, line 39 “....proline is a bifunctional amino acid....”. All amino acids are bifunctional molecules.

Authors: We agree with the reviewer comment but the idea to include this sentence is justified by the possibility to play with amino group as organic cation (by simple protonation) or carboxylic acid as anion (by deprotonation). In our opinion, this sentence is important in order to emphasize the bifunctionality of the aminoacid in the context of our work.

R1: page 5, lines 135-137: I do not understand the meaning.

Authors: We would like to clarify the following sentence: “Commercial L-proline, 1, as a crystalline neutral solid with higher melting temperature (Tm=228 °C, decomposes), can be transformed in amorphous salts by simple change in the counter-ion.”

Using the strategy to transform the commercial L-proline (neutral or zwitterionic form) into a cation or anion in combination with suitable counter-ions allowed us to avoid the original crystallization of L-proline obtaining amorphous salts. In general, this prepared salts showed higher thermal stability as well as higher solubility in a variety of organic solvents or water.

R1: page 6, lines 163-165: add a reference for the use of trifluoroacetic acid in this reaction

Authors: The reference 25 was added to the text.

R1: Table 2, ee (%): put in not the fact that (I suppose) the ee is referred to the syn isomer

Authors: This information was added as footnote of the table 2.

R1: Tables 2, 3 and 4: I think conversions are not sufficient to compare the various entries.

Authors: The efficiency of the catalytic reaction is compared for all entries by conversion using 1H-NMR spectra to determine the values.  This is a usual methodology for a comparative study about the catalytic performance.  

R1: Table 2 (and possibly the others), entries 1 and 2: I do not understand why a higher amount of catalyst leads to doubled reaction times.

Authors: This information was corrected after the confirmation of each result in the table.

R1: Table 4: why in many cases is the dr not reported?

Authors: We decided to include the dr (syn:anti) values for all entries were the HPLC analysis were repeated at least 3 times. In some cases was not possible to repeat and we decided to not include the value.

R1: main criticism: the authors claim recycling, but only in one case the reaction product is isolated and the catalyst NOT recycled. There is no demonstration that the catalyst is still active and not converted into simple proline

Authors: It is important to note that the catalytic reaction media was recycled in the cases using scCO2 at least three times without any significant decrease in the catalytic performance (similar yields and ee´s were observed). This part was completed with success and an additional sentence was added in the manuscript.

R1: main criticism: there is thus no advantage in synthesizing such a CIL instead of using proline

Authors: According with this work is possible to observe some advantages using CIL based proline instead proline. In particular the isolation/purification of the product using scCO2 is easier as well as it is possible to recycle the reaction media at least three times.

Reviewer 2 Report

Authors described the preparation of L-proline based ionic liquids and thir application in Michael additions. The experimental part is very detailed as well as the experiments' design. Some comments have to be addressed on the manuscript:

- I miss some more references, especially those for ionic liquids. Please also divided reference 1 in two separate references.

- When results are expressed with one decimal number, the error is also required to have one decimal number, so modify this at line 104.

- (R)- and (S)- must be in italic letters.

- I miss the measurement of the ILs viscosities. Authors determine some parameters for these solvents, but the viscosity gives valuable information.

- It is impossible to measure 100% conversion, so >99% would be preferable.

- Table 2: Indicate how conversion is determined.

- Can the authors considere the ILs to be catalytic when working at 30% or 60% mol? We are at a stoichiometric level, so I do not see the point of calling these systems a catalyst.

- Have the authors performed any experiment in order to establish a mechanism for the IL catalysis? Do they think it will be the same reaction pathway when proline is the anion than when is used as the cation of the IL?

- Compounds are initially numbered in the text, and suddenly, at Table 4, letters are used. Please unify this, use letters or numbers for all the compounds in the manuscript.

- Figure 4. HPLC is not very clear, there is an important shoulder that makes very difficult to ensure the enantiomeric excess that authors calculate. This HPLC needs to be improved.

- The section focused on the scCO2 extraction seems very interesing, by this reason the auhtors should develop it a bit more. Are they able to recover the ILs? Can these ILS be reused in other "catalytic" processes?

Author Response

Reviewer 2 (R2) considers that “Authors described the preparation of L-proline based ionic liquids and their application in Michael additions. The experimental part is very detailed as well as the experiments' design. Some comments have to be addressed on the manuscript:

R2: I miss some more references, especially those for ionic liquids. Please also divided reference 1 in two separate references. When results are expressed with one decimal number, the error is also required to have one decimal number, so modify this at line 104.

Authors: Thank for your comments. The references were correct as suggested by reviewer.

R2: (R)- and (S)- must be in italic letters.

Authors: This was changed as suggested by reviewer.

R2: I miss the measurement of the ILs viscosities. Authors determine some parameters for these solvents, but the viscosity gives valuable information.

Authors: The IL viscosity determination is in progress but in the context of this manuscript we decided not include. The work is mainly focused in the catalytic studies using CILs based on L-proline.

R2: It is impossible to measure 100% conversion, so >99% would be preferable.

Authors: The correction was done.

R2: Table 2: Indicate how conversion is determined.

Authors: The conversion values were determined by 1H-NMR comparing the starting material peaks and product peaks. It is relatively easy to compare by NMR the peaks of both substrate and product in the aromatic region in order to calculate the conversion.

R1: Can the authors considere the ILs to be catalytic when working at 30% or 60% mol? We are at a stoichiometric level, so I do not see the point of calling these systems a catalyst.

Authors: The amount of the catalyst is 30% or 60% mol as mentioned in the literature for asymmetric Michael reaction. It is a possible discussion to consider or not catalytic but is commonly accept in all articles about this topic like that.

R2: Have the authors performed any experiment in order to establish a mechanism for the IL catalysis? Do they think it will be the same reaction pathway when proline is the anion than when is used as the cation of the IL?

Authors: We are considering the same reaction pathway when proline is the anion or cation. We didn´t any experiment in order to check the mechanism but the available information in the literature and our results indicated a similar process.

R2: Compounds are initially numbered in the text, and suddenly, at Table 4, letters are used. Please unify this, use letters or numbers for all the compounds in the manuscript.

Authors: The numbers refer to the proline derivatives, and the letters to the Michael product. 

R2: Figure 4. HPLC is not very clear, there is an important shoulder that makes very difficult to ensure the enantiomeric excess that authors calculate. This HPLC needs to be improved.

Authors: We checked all chromatograms and the HPLC conditions but unfortunately, it is not possible to improve the separation. After many HPLC analyses, we decided to keep this figure 4.

R2: The section focused on the scCO2 extraction seems very interesing, by this reason the auhtors should develop it a bit more. Are they able to recover the ILs? Can these ILS be reused in other "catalytic" processes?

Authors: The scCO2 extraction of the chiral product seems to be very efficient in order to recycle the catalytic reaction media. We already added the information that the CIL can be recycled at least three times without any significant decrease in the catalytic performance (yields and ee´s). We are very interested to explore more this type of extraction in future works.

Round 2

Reviewer 1 Report

The revised version of the paper is suitable for publication

Reviewer 2 Report

Authors have addressed all the comments made by me, so the manuscript can be published in its actual form.