Chiral Ionic Liquids Based on l-Cysteine Derivatives for Asymmetric Aldol Reaction
Round 1
Reviewer 1 Report
The authors report the synthesis of new bioinspired chiral ionic liquids (CILs) based on amino acids. The obtained ILs were applied as chiral catalysts for asymmetric aldol reactions. Overall, the presented results are interesting for readership. After reading of the manuscript my view is that this paper present useful data and I recommend it for publication in this journal after major revisions addressing the following issues:
1) Original papers from MacMillan (K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 17, 4243–4244) and List (B. List, R. A. Lerner, C. F. Barbas, J. Am. Chem. Soc. 2000, 122, 10, 2395–2396) should be cited.
2) The structure of proline in Figure 1 is wrong. Should be drawn carboxylic acid group and not an aldehyde group!
3) The numbering of the entries in Table 1 after entry 10 is wrong.
4) It is no make sense to mention structure of the catalysts in footnote under Tables 1 and 2 (the numbering in Table is enough).
5) The authors mentioned that the cysteine-based organocatalyst can be recovered and reused. Moreover, the transfer from normal cysteine to IL based catalysts is a main goal of the preparing recyclable catalysts. So, this reviewer would like to see the results with recycled catalyst.
6) Page 5, lines 132 and 139, probably should be Tables 1 and 2?
7) The authors mentioned that relative and absolute configurations of the products and enantiomeric excess values were determined by comparison with the known 1H NMR. They should describe it in detail how? For example, they used shift reagents or prepared the diastereomeric products using chiral agents (for ee determination)? For instance, to determine the absolute configuration of obtained chiral products the authors could measure an optical rotation. I'm doubt that the simple 1H NMR can help to determine relative and absolute configurations of the products, especially an enantiomeric excess.
8) In experimental section, instead of Et2O should be Et2O, instead of ml should be mL (page 5, line 141). Same for µL.
9) In conclusion, in the sentence “…several room temperature ILs based on L-cysteine units…” (page 6, line 205) I don’t understand what does mean room temperature?
10) The retention times (for chiral HPLC analysis) for the products should be provided in experimental section.
Author Response
General comment:
As suggested by the reviewers, the introduction of the manuscript was re-written to present a more detailed description of the subject and include all the relevant references.
Reviewer 1 (R1) considered that “The authors report the synthesis of new bioinspired chiral ionic liquids (CILs) based on amino acids. The obtained ILs were applied as chiral catalysts for asymmetric aldol reactions. Overall, the presented results are interesting for readership”.
Authors: Thank you for your comments about the results of the manuscript.
R1: After reading of the manuscript my view is that this paper present useful data and I recommend it for publication in this journal after major revisions addressing the following issues:
1) Original papers from MacMillan (K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 17, 4243–4244) and List (B. List, R. A. Lerner, C. F. Barbas, J. Am. Chem. Soc. 2000, 122, 10, 2395–2396) should be cited.
Authors: We agree with reviewer. We failed to include these two important works into our manuscript. It is corrected in the manuscript.
R1: 2) The structure of proline in Figure 1 is wrong. Should be drawn carboxylic acid group and not an aldehyde group!
Authors: The structure of proline was already corrected in the figure 1.
R1: 3) The numbering of the entries in Table 1 after entry 10 is wrong.
Authors: It is corrected.
R1: 4) It is no make sense to mention structure of the catalysts in footnote under Tables 1 and 2 (the numbering in Table is enough).
Authors: It is corrected.
R1: 5) The authors mentioned that the cysteine-based organocatalyst can be recovered and reused. Moreover, the transfer from normal cysteine to IL based catalysts is a main goal of the preparing recyclable catalysts. So, this reviewer would like to see the results with recycled catalyst.
Authors: It is corrected. Two cycles were performed in order to proof the recycling process.
R1: 6) Page 5, lines 132 and 139, probably should be Tables 1 and 2?
Authors: It is corrected.
R1: 7) The authors mentioned that relative and absolute configurations of the products and enantiomeric excess values were determined by comparison with the known 1H-NMR. They should describe it in detail how? For example, they used shift reagents or prepared the diastereomeric products using chiral agents (for ee determination)? For instance, to determine the absolute configuration of obtained chiral products the authors could measure an optical rotation. I'm doubt that the simple 1H NMR can help to determine relative and absolute configurations of the products, especially an enantiomeric excess.
Authors: For the determination of absolute configurations of the products and enantiomeric excess values were determined by comparison with the known 1H-NMR using Mosher salt as shift reagent. The determination of enantiomeric excess using NMR studies was followed according previous articles in the literature (Rothchild, R. Determining Enantiomeric Excess by Direct NMR Methods and by Indirect Methods. Chem. Educator 1, 1–9 (1996). https://doi.org/10.1007/s00897960036a)
R1: 8) In experimental section, instead of Et2O should be Et2O, instead of ml should be mL (page 5, line 141). Same for µL.
Authors: It is corrected.
R1: 9) In conclusion, in the sentence “…several room temperature ILs based on L-cysteine units…” (page 6, line 205) I don’t understand what does mean room temperature?
Authors: Ionic liquids are molten salts that melt below 100ºC, and room temperature ionic liquids (RTILs) are liquids at room temperature. This is a well-established and commonly used term (Chem. Rev. 1999, 99, 2071−2083). However, for the purpose of clarity, the appropriate definition was added in the body of the introduction (page 2, lines 47-48).
R1: 10) The retention times (for chiral HPLC analysis) for the products should be provided in experimental section.
Authors: The enantiomeric excesses were determined by NMR studies and only for one example chiral HPLC analysis were used in order to validate the NMR experiences. This information was added in the experimental section of the manuscript.
Reviewer 2 Report
The paper by L. C. Branco et al. describes the use of several S-methyl-cysteine Ionic Liquids as catalyst of choice for the direct, asymmetric aldol reaction in water or DMSO as solvents.
Regrettably, the paper is presented inaccurately: Figure and Schemes are confused, hard to read and strewn with errors of every type, starting from the wrong stereochemistry of the cysteines, the focus of the work!!. Also, the text is greatly lacking in both its use of style and language. Despite few NMR data given at the end of the paper, the supplementary material embedding NMR spectra, chiral HPLC chromatograms, and so on…. is completely missing. In this context, the Authors stated that: “The preparation and characterization of the different chiral Room Temperature ILs (RTILs) was already described by our group..” but no references have been given and all the structure characterization data of the IL are completely missing.
On these bases, this reviewer retains that this manuscript, as it stands, doesn’t possess the requisites for publication in a journal of such high scientific repute, as Catalysts.
Author Response
Reviewer 2 mentioned that “The paper by L. C. Branco et al. describes the use of several S-methyl-cysteine Ionic Liquids as catalyst of choice for the direct, asymmetric aldol reaction in water or DMSO as solvents.
Regrettably, the paper is presented inaccurately: Figure and Schemes are confused, hard to read and strewn with errors of every type, starting from the wrong stereochemistry of the cysteines, the focus of the work!!. Also, the text is greatly lacking in both its use of style and language. Despite few NMR data given at the end of the paper, the supplementary material embedding NMR spectra, chiral HPLC chromatograms, and so on…. is completely missing. In this context, the Authors stated that: “The preparation and characterization of the different chiral Room Temperature ILs (RTILs) was already described by our group..” but no references have been given and all the structure characterization data of the IL are completely missing.
On these bases, this reviewer retains that this manuscript, as it stands, doesn’t possess the requisites for publication in a journal of such high scientific repute, as Catalysts.
Authors: Thank you for the comments. Many of the comments were considered and corrected in the manuscript.
The development of new chiral catalysts based on cysteine derivatives as proline alternative is an important research topic. In this manuscript, we showed different RTILs based on cysteine derivatives and characterized them by spectroscopic techniques. Then, some of the Chiral RTILs were used as chiral catalyst for asymmetric aldol reaction in aqueous (water) or organic (DMSO) media. All chiral products were isolated and analysed by NMR for enantiomeric excesses determination as other publications in the literature. In our opinion, this manuscript possess the scientific requisites for publication in Catalysts journal.
Reviewer 3 Report
This paper describes the application of some chiral ionic liquids derived from L-cysteine as catalysts for some prototypical intermolecular aldol reactions (acetone, cyclohexanone plus 2- or 4-nitrobenzaldehydes). In general the results are worse than or at most very similar to those obtained with L-proline! Therefore, their use is hard to justify.
On the other hand, one obvious advantage of ionic liquid catalysts (recyclability) has been completely overlooked by the authors.
Moreover, there are several important flaws that must be corrected.
Entries 1 and 2 in Table 1, and the phrase "The preliminary investigation confirmed that L-proline is an effective organocatalyst for asymmetric aldol reactions" are unnecessary.
Structure of L-proline in Figure 1 does not show stereochemistry.
Structure of the ketone in Scheme for Table 1 (CH3–CO–R2) is not compatible with the legend R2 = acetone or cyclohexanone. Similar thing with R1 in the aldehydes.
In Materials and Methods, there are several mistakes.
The authors say: "the preparation and characterization of the different chiral Room Temperature (sic) ILs was already described by our group". But the references are not given.
Aldol compounds should be numbered.
First one (acetone + 2-nitrobenzaldehyde): Entry missing in Table 1 (no 89% yield appears). Ee is missing. HPLC data for major/ minor enantiomers is missing. Absolute configuration is missing in the text.
Similar thing for the second compound (acetone + 4-nitrobenzaldehyde). Ee? HPLC or NMR data for each enantiomer?
Third and fourth compunds (cyclohexanone + nitrobenzaldehydes). It is probably the anti isomer, but the structure lacks this information. Dr of the crude aldol mixture should be given. Which is the absolute configuration? HPLC or NMR data for each enantiomer is missing. Protons in 2 are described as triplets with only one coupling constant, which does not match with previous data on the same compounds. References are missing. Are the remaining three compounds new? If yes, HRMS should be provided. If not, references should be provided.
A Supporting Information with HPLC traces and with NMR spectra for all compounds must be provided.
In summary, major revision is necessary.
Author Response
Reviewer 3 (R3) considered that “This paper describes the application of some chiral ionic liquids derived from L-cysteine as catalysts for some prototypical intermolecular aldol reactions (acetone, cyclohexanone plus 2- or 4-nitrobenzaldehydes). In general the results are worse than or at most very similar to those obtained with L-proline! Therefore, their use is hard to justify.
On the other hand, one obvious advantage of ionic liquid catalysts (recyclability) has been completely overlooked by the authors.
Authors: Thank you for your comments. The asymmetric aldol reaction between cyclohexanone with 2- or 4-nitrobenzaldehyde using chiral ILs based on cysteine derivative showed better yields and enantiomeric excesses comparing to L-proline. The recycling process was also added to the manuscript.
R3: Entries 1 and 2 in Table 1, and the phrase "The preliminary investigation confirmed that L-proline is an effective organocatalyst for asymmetric aldol reactions" are unnecessary. Structure of L-proline in Figure 1 does not show stereochemistry.Structure of the ketone in Scheme for Table 1 (CH3–CO–R2) is not compatible with the legend R2 = acetone or cyclohexanone. Similar thing with R1 in the aldehydes.
Authors: The different corrections were made in the manuscript.
R3: In Materials and Methods, there are several mistakes.The authors say: "the preparation and characterization of the different chiral Room Temperature (sic) ILs was already described by our group". But the references are not given.
Authors: The synthetic methods were optimized in our laboratory and a reference was included.
R3: Aldol compounds should be numbered.
Authors: The compounds were already numbered as suggested.
R3: First one (acetone + 2-nitrobenzaldehyde): Entry missing in Table 1 (no 89% yield appears). Ee is missing. HPLC data for major/ minor enantiomers is missing. Absolute configuration is missing in the text.
Similar thing for the second compound (acetone + 4-nitrobenzaldehyde). Ee? HPLC or NMR data for each enantiomer?
Authors: NMR studies were used for the determination of enantiomeric excesses as described in different articles in the literature (example: Rothchild, R. Determining Enantiomeric Excess by Direct NMR Methods and by Indirect Methods. Chem. Educator 1, 1–9 (1996). https://doi.org/10.1007/s00897960036a).
Chiral HPLC was only used in one aldol product in order to validate the ee determination by NMR.
R3: Third and fourth compunds (cyclohexanone + nitrobenzaldehydes). It is probably the anti isomer, but the structure lacks this information. Dr of the crude aldol mixture should be given.
Authors: The dr of the crude aldol mixtures was added in the tables.
R3: Which is the absolute configuration? HPLC or NMR data for each enantiomer is missing. Protons in 2 are described as triplets with only one coupling constant, which does not match with previous data on the same compounds. References are missing. Are the remaining three compounds new? If yes, HRMS should be provided. If not, references should be provided.
Authors: The previous data about the synthesis and characterization of these chiral ILs will be published elsewhere. In order to complete all requested information, the Supplementary information with the synthesis and NMR description of all chiral ILs based cysteine derivatives as well as NMR data of the chiral aldol products was was included.
Round 2
Reviewer 1 Report
The authors have revised the manuscript taking into consideration the comments of all reviewers. The article is publishable in Catalysts after minor correction:
Although the authors have performed two cycles in order to proof the recycling process, I still would like to see the result of ee of the product with recycled catalyst, and not just the yield! Moreover, the results should be mentioned in a main text and conclusion part, and not just in materials and methods part. This is one of the important results of the paper!
Author Response
Reviewer 1 (R1) consider that “The authors have revised the manuscript taking into consideration the comments of all reviewers. The article is publishable in Catalysts after minor correction”.
R1: Although the authors have performed two cycles in order to proof the recycling process, I still would like to see the result of ee of the product with recycled catalyst, and not just the yield! Moreover, the results should be mentioned in a main text and conclusion part, and not just in materials and methods part. This is one of the important results of the paper!
Authors: The details about the recycling was added to the manuscript including the ee of the product with recycled catalyst. For recycling, we selected the reaction between acetone and 2-nitrobenzaldehyde (product 1) as mentioned in table 1. After 2 cycles the yield (70%) and ee (53%) was kept.
We are convinced that for all examples from tables 1 and 2 will be possible to recycled the CIL catalyst at least two or three times without any decrease in the yield and enantiomeric excess.
Reviewer 2 Report
I've read the revised version of the paper and still, I consider this work of very low quality with an important experimental part regarding the ee% determination completely missing. For these reasons I have to reject again this paper for publication in Catalysts.Author Response
Reviewer 2 (R2) considered that “I've read the revised version of the paper and still, I consider this work of very low quality with an important experimental part regarding the ee% determination completely missing. For these reasons I have to reject again this paper for publication in Catalysts.”
Authors: The discovery of alternative chiral organocatalysts to L-proline is an important research topic as the recent chemistry nobel prize attributed to organocatalysis highly recognized.
In this work, new chiral ionic liquids based on L-cysteine derivative were prepared and characterized. Some of these novel CILs can be used as chiral organocatalysts for asymmetric aldol reaction between acetone or cyclohexanone and substituted nitrobenzaldehyde in good yields and moderate to high enantiomeric excesses.
Contrarily to reviewer comments, some results are even better than L-proline and the ESI included NMR spectra with all prepared CIL and the chiral aldol products. Additionally, we included two 1H-NMR spectra as examples about the determination of enantiomeric excess using mosher acid salt methodology according to literature. It is important to note that many publications in catalysis journals don´t include HPLC or NMR spectra of the ee determination and only included the results in experimental section.
Reviewer 3 Report
The authors have addressed most of the issues. However, there are still some concerns.
Figure of the major aldol adducts of cyclohexanone in Table 1 is wrong, the anti aldol is the main product but the structure corresponds to the syn aldol.
In Tables 1 and 2, %ee of cyclohexanone adducts corresponds to the anti aldol, I assume (not specified)
Procedure for catalyst recovery: The aromatic aldehyde used is not specified. The drop in yield is substantial (82% drops to 77%). The %ee of the reaction with the recovered catalyst is not given. These data are insufficient to assess the reusability of the ionic liquid catalyst.
Experimental: For compounds 3, 4 and 6 the (R,R) configuration is given. Note that the anti isomer is (S)-2-(R)-hydroxy. With proline, the absolute configuration of the major enantiomer of the syn-isomer is (S,S).
Literature references for known compounds are not given.
The authors say that "In order to complete all requested information, the Supplementary information with the synthesis and NMR description of all chiral ILs based cysteine derivatives as well as NMR data of the chiral aldol products was was(sic) included".
I have not been able to find this Supporting Information.
The article is not ready for publication.
Author Response
Reviewer 3 (R3) considered that “The authors have addressed most of the issues. However, there are still some concerns.”
R3: Figure of the major aldol adducts of cyclohexanone in Table 1 is wrong, the anti-aldol is the main product but the structure corresponds to the syn aldol.
Authors: Thank you for your comment. The figure was corrected as suggested.
R3: In Tables 1 and 2, %ee of cyclohexanone adducts corresponds to the anti aldol, I assume (not specified)
Authors: The details are included in the footnote of the tables 1 and 2 ([d] Anti:syn diastereomers were determined from 400.13Hz 1H NMR spectroscopy). The anti aldol is the main product.
R3: Procedure for catalyst recovery: The aromatic aldehyde used is not specified. The drop in yield is substantial (82% drops to 77%). The %ee of the reaction with the recovered catalyst is not given. These data are insufficient to assess the reusability of the ionic liquid catalyst.
Authors: The details about the recycling was added to the manuscript including the ee of the product with recycled catalyst. For recycling, we selected the reaction between acetone and 2-nitrobenzaldehyde (product 1) as mentioned in table 1. After 2 cycles the yield (70%) and ee (53%) was kept without any significant change.
We are convinced that for all examples from tables 1 and 2 will be possible to recycled the CIL catalyst at least two or three times without any decrease in the yield and enantiomeric excess.
R3: Experimental: For compounds 3, 4 and 6 the (R,R) configuration is given. Note that the anti isomer is (S)-2-(R)-hydroxy. With proline, the absolute configuration of the major enantiomer of the syn-isomer is (S,S).
Authors: Thank you for your comments. The additional information was included as suggested.
R3: Literature references for known compounds are not given.
Authors: Thank you for your comment. The literature references were included in the manuscript.
R3: The authors say that "In order to complete all requested information, the Supplementary information with the synthesis and NMR description of all chiral ILs based cysteine derivatives as well as NMR data of the chiral aldol products was was(sic) included".
I have not been able to find this Supporting Information.
Authors: The revised ESI was included. We decided to include two 1H-NMR spectra as examples about the determination of enantiomeric excess using mosher acid salt methodology according to literature.In the ESI are presented all NMR spectra of the prepared chiral ionic liquids as well as chiral aldol products. Additionally, figures 31 and 32 showed the determination of enantiomeric excesses by 1H-NMR using Mosher acid according literature. All ee´s were determined using similar method and for example, two spectra are presented. Figure 31 illustrates the example of reaction between acetone with 2-hydroxy-5-nitrobenzaldehyde using CIL [S-MeCysNH3][NTf2] as catalyst; Table 2, entry 8 and Figure 32 illustrates the example of reaction between acetone with 3-hydroxy-4-nitrobenzaldehyde using L-proline as catalyst; Table 2, entry 5.
