S-Oxygenation of Thiocarbamides V: Oxidation of Tetramethylthiourea by Chlorite in Slightly Acidic Media

Abstract

The reaction between tetramethylthiourea (TTTU) and slightly acidic chlorite has been studied. The reaction is much faster than comparable oxidations of the parent thiourea compound as well as other substituted thioureas. The stoichiometry of the reaction in excess oxidant showed a complete desulfurization of the thiocarbamide to yield the corresponding urea and sulfate: 2ClO2(-) + (Me2N)2C ═ S + H2O → (Me2N)2C ═ O + SO4(2-) + 2Cl(-) + 2H(+). The reaction mechanism is unique in that the most stable metabolite before formation of the corresponding urea is the S-oxide. This is one of the rare occasions in which a low-molecular-weight S-oxide has been stabilized without the aid of large steric groups. ESI-MS data show almost quantitative formation of the S-oxide and negligible formation of the sulfinic and sulfonic acids. TTTU, in contrast to other substituted thioureas, can only stabilize intermediate oxoacids, before formation of sulfate, in the form of zwitterions. With a stoichiometric excess of TTTU over oxidant, the TTTU dimer is the predominant product. Chlorine dioxide, which is formed from the reaction of excess chlorite and HOCl, is a very important reactant in the overall mechanism. It reacts rapidly with TTTU to reform ClO2(-). Oxidation of TTTU by chlorite has a complex dependence on acid as a result of chlorous acid dissociation and protonation of the thiol group on TTTU in high-acid conditions, which renders the thiol center a less effective nucleophile.

Oxyhalogen–Sulfur Chemistry: Kinetics and Mechanism of Oxidation of 1,3-Dimethylthiourea by Acidic Bromate

“…23 Most strong to mild oxidants oxidize thiocarbamides to sulfate and their urea analogues. 1,12,13,24 Quantitative determination of sulfate was performed gravimetrically through BaSO 4 precipitation. Barium sulfate yields, taken from several experiments, showed that, on the average, 98.8% of the sulfur in DMTU was converted to sulfate.…”

Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG

“…In this case only one metabolite was found, corresponding to 3-phenyl- N -[(4-piperidin-1-ylphenyl)carbamoyl]propanamide ( Figure S2 ). This derivative likely arises from sequential EthA reactions on the sulfur atom of the carbamothioyl moiety ( Chigwada et al., 2014 ). However, this last metabolite showed no effect on PyrG activity.…”

Reactivity of Small Oxoacids of Sulfur

“…If at least one substituent R is a hydrogen atom, thioureas form relatively stable dioxides and trioxides. Tetraalkylthioureas, for example, tetramethylthiourea form in aqueous solutions relatively stable monoxides in the course of oxidation by bromine, bromate [50], chlorite [51], and hydrogen peroxide [52]; while formation of tetramethylthiourea dioxide and trioxide has not been observed at all. Indeed, higher oxides were earlier shown to be unavailable by means of oxidation of tetramethylthiourea by peroxides and alternative pathways of synthesis should be employed [53,54].…”