Letter to the Editor pubs.acs.org/journal/ascecg
Cite This: ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
Response to “Comment on ‘In Situ Derivatization of (RS)‑Mexiletine and Enantioseparation Using Micellar Liquid Chromatography: A Green Approach’” Shiv Alwera* Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee 247667, India
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ACS Sustainable Chem. Eng. 2018, 6 (9), 11653−11661. DOI: 10.1021/acssuschemeng.8b01869 ACS Sustainable Chem. Eng. 2019, 7 (3). DOI: 10.1021/acssuschemeng.8b06684 n the Comment to my article, Lentini et al. wrote, “In principle, the proposed method might be useful to prepare both mexiletine enantiomers and to evaluate their enantiomeric purity (ep)”, but the current method is not for the preparation or synthesis of enantiopure enantiomers of the mexiletine. This method is a chromatography separation method for the separation of racemic mexiletine into its enantiomers. (1) The elution order was confirmed with the help of the experimental results, and it was also supported by the theoretical observation/calculations (I tried to give the possible mechanism of separation) by developing the lowest energy structures of both of the diastereomers of the mexiletine. So for that purpose, I prepared 8−10 possible conformers for both diastereomers, and then, I optimized all of the structures using Gaussian 09 Rev. A.02 software and the hybrid density function B3LYP with 6-31G*. After optimization, I selected the lowest energy structures among them and then again optimized these structures (four to five times) using the same commands (for checking the reproducibility of these structures). When the results of the theoretical observations were found similar to the results obtained by the experimental method, then these figures were added in my article where I tried to predict the possible mechanism of separation. Some literature reports as examples follow: The chromatographic developer always tries to predict the reason or mechanism of the separation of a diastereomeric derivative during the chromatographic process, and because of that, there are many publications available that predict different reasons for separation. Among them, some are prediction elution order by DFT calculation and some are hypothetical prediction (without DFT), e.g., (A) after optimizing structures by DFT calculations: cis−trans conformation of diastereomers by Nagar and Bhushan (http://dx.doi.org/10.1039/c3ay41893f) and Bhushan and Vashistha (http://dx.doi.org/10.1016/j.chroma. 2014.12.033) and effect of hydrogen bonding in separation by Vashistha and Bhushan (http://dx.doi.org/10.1016/j.tetasy. 2015.01.017) and (B) without DFT optimization (imaginary hypothesis) by Malik and Bhushan (http://dx.doi.org/10. 1039/c7nj02898a) and cis−trans structure of diastereomers by Singh (https://doi.org/10.1002/bmc.4415). In the current case, the structures of the diastereomers were optimized, and the obtained results were compared with experimental results. Only after were these results reported in my original article.
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However, Lentini et al. have some doubt, and according to them, they optimized diastereomers structure using the same method as reported in their previous publication (http://dx. doi.org/10.1016/j.bpj.2012.11.3830). I read that publication and found that they used SPARTAN PRO software for their calculations, but in my case, I used Gaussian 09 Rev. A.02 software. That is why I asked my colleague about this who works in the field of theoretical chemistry, and according to him, using two different commands/methods in same software can give different results. So the results of two different softwares cannot be compared. The comments of Lentini et al. did gave me the opportunity to check/test my optimized structure with different methods; so I again optimized these structures (reported in my original article) the same as they did (using Gaussian software). This time, I checked their stability in solvents, but still (observation studies repeated two times) the results of the theoretical observation were found to be the same as I reported in my original article. (The optimized structures of the diastereomers of mexiletine are given in the table below). After optimizing the lowest energy structures, the terminal C−C distance (axial length) values found are as follows: LM-1 = 17.12 ± 0.24 Å; LM-2 = 14.98 ± 0.08 Å (results are similar as reported in my original article; please see the figures). (2) The mexiletine obtained at the end of the experiment was an oily liquid, and it is characterized as the same (reported in the Characterization section of my original article). Mexiletine is marketed as the salt of HCl (I also purchased it as solid mexiletine hydrochloride). At the end of the experiment, it converted into hydrochloric salt (slightly offwhite), and its melting point was recorded (reported in the Characterization section of my original article) and compared with the starting material. It was found as the same (further confirmation of purity). (3) The enantiopurity and optical purity are two different terms and definitely may have different result values. But in this case, there is no need to present the data in terms of enantiopurity because the researchers working in the field of organic synthesis or asymmetric synthesis use chiral HPLC for determining their sample’s enantiopurity (Sasikumar et al., http://dx.doi.org/10.1016/j.tetasy.2009.11.014, and Loughhead et al., http://dx.doi.org/10.1021/jo982287c; The ee or ep of the compound was determined by chiral HPLC analysis), Received: February 14, 2019
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DOI: 10.1021/acssuschemeng.9b00896 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
ACS Sustainable Chemistry & Engineering
Letter to the Editor
and in the current work, the diastereomeric derivatives were separated and recovered by using HPLC. Similarly, the native enantiomers were obtained by HPLC, so it is obvious that the enantiopurity is 100% for the current method. Because of that,
I was interested in reporting the optical purity as compared to “ep”. Generally, it is important to report these results in terms of enantiopurity for the researchers working in the field of organic synthesis or synthetic medicinal chemistry. B
DOI: 10.1021/acssuschemeng.9b00896 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
ACS Sustainable Chemistry & Engineering
Letter to the Editor
In the present work, when using levofloxacin as a chiral selector, it shows very slight overlapping, not more than 1%− 2%. During the collection of the sample, we refused to collect in that region, and still, we got 92%−93% yield (recovered enantiomers again checked for their purity by repeating the
same derivatization method at the micromole level followed by the HPLC separation method). Also, the beauty of this molecule, levofloxacin, is that when using that molecule as chiral selector it reduces the elution time (very low, suitable for green development) with very good separation. Because of the C
DOI: 10.1021/acssuschemeng.9b00896 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
ACS Sustainable Chemistry & Engineering
Letter to the Editor
doubts of Lentini et al. that it is not good for an assay, I want to state that this method is now popular in the field of indirect enantioseparation, and researchers are adopting the same method for analysis of different racemic compounds. (It is the best confirmation of my developed method for its reproducibility.) Researchers are not only using HPLC but also trying or testing with other separation techniques like thin layer chromatography (very good separation reported: Singh, http:dx.doi.org/10.1002/bmc.4415; Vashistha et al., http:dx. doi.org/10.1007/s10337-017-3367-2; Lal et al. J. Chem. Pharm. Res. 2015, 7 (7), 791−798; Lal and Kaur, http://dx.doi.org/ 10.14233/ajchem.2017.20831; Chung et al., http://dx.doi.org/ 10.1093/chromsci/bmv010. The current method is not only applicable to HPLC but also can be used for different techniques like thin layer chromatography, LC-MS, and other techniques. In my original paper, the obtained yield was good, so the method can be used on the preparative scale as well as analytical scale. Also, the extensive development of similar methods using the same/current method gives further confirmation/proof that the method can be used for the assay of different racemic compounds.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Shiv Alwera: 0000-0002-5897-2166
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DOI: 10.1021/acssuschemeng.9b00896 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
