Sulfur mustard, hydrolysis

Higuchi, K., Kajiki, A., Nakamura, M., Harada, S., Pula, P.J., Scott, A.L., Dannenberg, A.M., Jr. (1988). Proteases released in organ culture by acute dermal inflammatory lesions produced in vivo in rabbit skin by sulfur mustard hydrolysis of synthetic peptide substrates for trypsin-like and chymotrypsin-like enzymes. Inflammation 12 311-34. 

Sulfur mustard hydrolysis is surface-controlled , with products formed at the... 

Harris, B. L., F. Shanty, and W. J. Wiseman. 1984. Chemicals in War. In Kirk-Othmer Encyclopedia of Chemical Technology, 3rd ed. pp. 395-397. New York Wiley Interscience. Karvaly, G., A. Gachalyi, and J. Furesz. 2005. Quantitative analysis of the sulfur mustard hydrolysis product thiodiglycol in in vivo microdialysates using gas chromatography... 

Figure 4.7 Micro-LC-S-FPD chromatograms obtained after the addition of various percentages of w-propanol to a TDG sample. Final TDG concentration, 10pgmL [32], Reprinted from Determination of the sulfur mustard hydrolysis product thiodiglycol by microcolumn liquid chromatography coupled on-line with sulfur flame photometric detection using large-volume injections and peak compression, Edwin W.J. Flooijschuur, Charles E. Kientz, Udo A. Th. Brinkman Journal of Chromatography A 849(2) 433-44, 1999, with permission from Elsevier...

Solid. More susceptible to hydrolysis than Sulfur mustard (C03-A001). 

This material is a precursor for Sulfur mustard (C03-A001) and is also commonly found as an impurity and degradation product formed during its hydrolysis. 

The above evidence should not be interpreted as meaning that hydrolytic dehalogenation can never be demonstrated unambiguously. Indeed, the next subsection will document reactions of multiple dehalogenation that are only consistent with a hydrolytic mechanism. But before doing so, we examine here the hydrolysis of medicinal nitrogen mustards and of their sulfur analogue, the infamous sulfur mustard. 

In dilute solution, the primary hydrolysis product of sulfur mustard is thiodiglycol (TDG) (Figure 12). In the environment, TDG may be oxidized to its thiodiglycol sulfoxide (TDGO), and more rarely to the sulfone, though the latter may be an important... 

Hooijschuur et al. (54) also reported the analysis of the hydrolysis products of sulfur mustard homologues (11), using micro-LC/ESI/MS (triple quadrupole) and micro-LC/FPD in sulfur mode. To improve sensitivity, large-volume injection was used with peak compression by adding suitable coeluting alcohols. LC employed a 0.28-mm ID packed C18 column, eluted isocratically with water-methanol (80 20 v/v)-0.2% formic acid, flow rate 6 xl/min. Spectra were dominated by MH+, [MH — H20]+,... 

E.W.J. Hooijschuur, Ch.E. Kientz, A.G. Hulst and U.A.Th. Brinkman, Determination of hydrolysis products of sulfur mustards by reversed-phase microcolumn liquid chromatography coupled online with sulfur flame photometric detection and electrospray ionization mass spectrometry using large-volume injections and peak compression, Anal Chem., 72, 1199-1206 (2000). 

R.M. Black and R.W, Read, Biological fate of sulfur mustard, l,l-thiobis(2-chloroethane) identification of 3-lyase metabolites and hydrolysis products in human urine, Xenobiotica, 25, 167-173 (1995). 

Figure 4. Metabolites of sulfur mustard identified by mass spectrometry, derived from hydrolysis and oxidation (s)...

Figure 5. Urinary excretion profiles of metabolites derived from hydrolysis and the (5-lyase pathway in the rat following cutaneous application of sulfur mustard (dose = 2 p,mol/animal, data points mean of 4 animals dotted fine = hydrolysis products, solid fine = (5-lyase metabolites). (Reproduced from the Journal of Analytical Toxicology by permission of Preston Publications A Division of Preston Industries, Inc.)...

Figure 7. Scheme for the combined analysis of urine for sulfur mustard metabolites derived from hydrolysis and the... 

The metabolism of nerve agents is much simpler than that of sulfur mustard. The major pathway for elimination is via enzyme-mediated hydrolysis by esterases, plus some chemical hydrolysis, as shown in Figure 10. In the case of the methylphosphonofluoridates and V agents, the major product is an alkyl methylphosphonic acid (alkyl MPA) (16). A small fraction of the nerve agent binds... 

The water solubility of sulfur mustard has been reported as 0.092 g per 100 g water at 22°C (DA, 1974), and 5 X 10 M at room temperature (MacNaughton and Brewer, 1994). In dilute aqueous solutions sulfur mustard hydrolyzes almost completely to thiodiglycol and hydrochloric acid (Papirmeister et al., 1991). For dissolved HD, the hydrolysis half-life ranges from about 4 to 15 min for temperatures of 20-25°C however, bulk HD may persist in water for up to several years (Small, 1984). Small (1984) reported that it would take 15 days for the mass of a 1 cm droplet of HD in quiescent water to decrease by one half. 

Sulfur mustard can be very persistent in soil (Rosenblatt et al., 1995). Persistence depends on the soil type, pH, moisture content, and whether the agent is at the soil surface or buried. Small (1984) reported that when HD was applied to the soil surface, volatilization would be the main route of HD loss (half-life about 30 min), but if the soil was wet, hydrolysis would be the main loss pathway. When sprayed onto soil, a vesicant action was still apparent after about 2 weeks when the agent leaked into the soil, however, a vesicant action was still present after 3 years (DA, 1974). Rosenblatt et al. (1995) state that the persistence of sulfur mustard in soil is due to the formation of oligomeric degradation products that coat the surface of the mustard agent and that are resistant to hydrolysis. 

CWAs have been widely eondemned since they were first used on a massive scale during World War I. However, they are still stockpiled and used in many countries as they are cheap and relatively easy to produee, and can cause mass casualties. Although the blood agent CK is extremely volatile and undergoes rapid hydrolysis, the degradation of three types of vesicant CWAs, the sulfur mustards, nitrogen mustards, and Lewisite, results in persistent products. For... 

Vycudilik (1985) had already used gas chromatography-mass spectrometry (GC-MS) to eonfirm the presence of sulfur mustard in urine samples. Sodium ehloride was added to the sample to facilitate extraction and slow down the hydrolysis in the aqueous sample, and the analyte was then extraeted with diethylether. The solvent was evaporated and the residue dissolved in methylene chloride. After purifieation - by shaking the sample solution for 1 h with silieagel - the solvent was again evaporated. The residue was again dissolved in methylene chloride and used for chromatography. 

Initial efforts by Noort et al. (1996,1997) to detect protein adducts of sulfur mustard focused on the 4-(2-hydrox-yethylthioethyl)-L-aspartate, 5-(2-hydroxyethylthioethyl)L-glutamate, the cysteine and the N-terminal valine adduct and two histidine adducts, Nl- and N3-(2-hydroxyethylth-ioethyl)-L-histidine, respectively. Acidic hydrolysis and pronase digestion were used to release these adducts from... 

In the case of sulfur-mustard, the situation is somewhat more complex. It is marginally soluble in water tending to form droplets, and hydrolysis occurs at the droplet surface. This property has made measuring the hydrolysis rate constant difficult, and half-lives anywhere from 2 to 30 hours are reported. Chemically, the hydrolysis of HD involves the sequential replacement of the chlorine atoms by hydroxyl groups through cyclic sulfonium ion intermediates to form thiodiglycol (TDG), Reaction (2). If a median... 

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