Oxidation of Suprofen and Clopidogrel to their Sulfoxides and effect of substituents on results

Author: Sergi Betkhoshvili
Keywords: Sulfoxides, High-Performance Liquid Chromatography, Nucleophilicity, Thiophene ring
Annotation:

Thiophene S-oxides are important intermediates for synthesis of variety of organic compounds. One of the most reliable ways to produce bicyclic S-oxides is by Diels Alder reactions where thiophene S-oxides act as dienes. The purpose of this study has been to synthesize Thiophene sulfoxides from Suprofen and Clopidogrel as both contain thiophene group. The comparison between rates of these reactions can give us insight into sulfur nucleophilicity in thiophene group regarding substituent effects. To avoid possible further oxidation of sulfoxide to sulfone, relatively mild oxidizing agent 77% mCPBA was used with 1:1 molar equivalence. Generally, oxidation with mCPBA takes place with mechanism of nucleophilic attack (here, by sulfur) on electrophilic oxygen of peroxyacid. The reaction was conducted in chloroform as a solvent. The reaction rate was quite slow at 0ºC (Ice bath), since even after 3 hours from the mixing the reagents no significant change was observed with thin-layer chromatography (1 n-hexane : 1 EtOAc, and 9 CH2Cl2 : 1 CH3OH (by volume)) (then reaction mixture was left on room temperature for the next laboratory session and thin-layer chromatography (4 n-Hexane : 1 EtOAc) showed the change had happened), while in case of clopidogrel oxidation observable change had happened within two and half hours. After oxidation of Suprofen, HPLC analysis of mixture showed unexpected and vague results, while it’s possible to explain the composition of mixture after oxidation of Clopidogrel. In both cases Infrared Spectra suggests sulfoxide group, however, it is not obvious whether these signals genuinely correspond to sulfoxide groups or not. Initial expectation has been that both of the reactions would go slow due to thiophene aromaticity, however clopidogrel oxidation went faster. The conclusion of the study is that it is highly probable that this difference is caused by the different substituents on those compounds and their effect on reactivity, however, in order to figure out the exact relation we need to use same molar concentrations and conditions in both experiments in further studies.