Kinetics and Mechanistic Studies of the Hydrolysis of Diisocyanate-Derived Bis-thiocarbamates of Cysteine Methyl Ester

• Published in: Chemical research in toxicology 2006-03, Vol.19 (3), p.341-350
• Main Authors: Chipinda, Itai, Stetson, Sarah J, Depree, Gary J, Simoyi, Reuben H, Siegel, Paul D
• Format: Article
• Language: English
• Subjects: Algorithms; Chromatography, High Pressure Liquid; Cysteine - analogs & derivatives; Cysteine - chemistry; Half-Life; Hydrogen-Ion Concentration; Hydrolysis; Indicators and Reagents; Isocyanates - chemistry; Kinetics; Methylamines - chemical synthesis; Models, Chemical; Temperature; Thiocarbamates - chemistry
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx050311t

Diisocyanates (dNCOs) are the most commonly reported cause of chemically induced occupational asthma, but the ultimate antigenic form is unknown. Reactions of the three most common monomeric dNCOs, hexamethylene dNCO (HDI), methylene diphenylisocyanate (MDI), and toluene dNCO (TDI), with cysteine methyl ester (CME) gave the corresponding bis-dithiocarbamates (HDI−CME, TDI−CME, and MDI−CME). The dissociation kinetics of these bis-thiocarbamates, in aqueous conditions, was followed spectrophotometrically under varying pH and temperature conditions. Reaction of the adducts with methylamine or human serum albumin (HSA) produced diurea, monourea, and diamine products, and this was consistent with the base-catalyzed elimination reaction (E1cB) pathway being the dominant, but not exclusive, dissociation mechanism. The hydrolysis of the adducts was first-order with respect to OH- concentration and overall second-order (HDI−CME, k = 3.36 × 102 M-1 min-1; TDI−CME, k = 2.49 × 104 M-1 min-1; and MDI−CME, k = 5.78 × 104 M-1 min-1 at pH 7.4) with deviation from second-order when the dNCO had an aromatic functional group. Arrhenius plots gave activation energies (HDI−CME, E a = 70.6 kJ/mol; TDI−CME, E a = 46.1 kJ/mol; and MDI−CME, E a = 44.5 kJ/mol) that were consistent with the following order of stability:  HDI−CME > TDI−CME > MDI−CME. Therefore, the stability of different dNCO-derived thiocarbamates in aqueous environments can vary greatly. Thiocarbamate dissociation rates and type of products formed may potentially influence antigenicity and subsequent hypersensitivity/toxic reactions following dNCO exposures.