Alkyl methylphosphonic acids

Purdon JG, Pagotto JG, Miller RK. 1989. Preparation, stability, and quantitative analysis by gas chromatography and gas chromatography-electron impact mass spectrometry of tert-butyldimethylsilyl derivatives of some alkylphosphonic and alkyl methylphosphonic acids. J Chromatogr 475 261-272. 

S.-A.A. Fredriksson, L.-G. Hammarstrom, L. Henriksson and H.-A.A. Lakso, Trace determination of alkyl methylphosphonic acids in environmental and biological samples using gas chromatography/negative-ion chemical ionization mass spectrometry and tandem mass spectrometry, J. Mass Spectrom., 30, 1133-1143 (1995). 

The phosphonic acids are strong acids (pKA 2) and under typical LC conditions exist mostly in the deprotonated form. They are therefore well suited to both negative and positive ionization. Kosti-ainen et al. (24) reported negative-ion ESI (ionspray) spectra for alkyl methylphosphonic acids (alkyl MPAs), 0-ethyl methylphosphonothioic acid, and... 

M. Katagi, M. Tatsuno, M. Nishikawa and H. Tsuchihashi, On-line solid-phase extraction liquid chromatography-continuous flow frit fast atom bombardment mass spectrometric and tandem mass spectrometric determination of hydrolysis products of nerve agents alkyl methylphosphonic acids by p-bromophenacyl derivatization, J. Chromatogr., A, 833, 169-179 (1999). 

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... 

Rodin, I.A., Shpak, A.V., Shpigim, O.A., Rybalchenko, I.V., Savelieva, E.I. (2007). Highly sensitive determination of alkyl methylphosphonic acids - degradation products of chemical warfare nerve agents by HPLC-MS in rats plasma. European Conference on Analytical Chemistry Euroanalysis XIV , Antwerpen, Belgium, September 9-14, 684 pp. 

Alkyl, Cycloalkyl, Arylalkyl and Related Acids. An improved synthesis of alkyl methylphosphonic acids (159) has been reported. It involves partial trans-esterification of trimethyl phosphite, followed by an Arbuzov reaction of the... 

Other methods involving LC with MS-MS (Noort et al., 1998) and indirect photometric detection (Katagi et al., 1997) have also been reported. Various methods on the assay of alkyl methylphosphonic acids in biological fluids are presented in Table 19.1. 

FIGURE 19.2 Hydrolysis pathway of sarin (GB), soman (GD), and cyclosarin (GIO hydrolysis pathway of nerve agents proceeds through the alkyl methylphosphonic acids, isopropyl methylphosphonic acid (IMPA), pinacolyl methylphosphonic acid (PMPA), and cyclohexyl methylphosphonic acid (CMPA) to methylphos-ponic acid (MPA). Analysis of the alkyl methylphosphonic acids allows identification of the parent agent, while assay of MPA is nonspecific. 

The alkyl methylphosphonic acids provide a convenient marker for determining exposure to nerve agents. Numerous modifications for the assay of these compounds have been developed for blood or urine, and several have been applied to actual human exposure cases. Important factors in considering this test are extent of exposure and time following the event. One of the most severely poisoned victims of the Matsumoto sarin attack demonstrated measurable IMPA in the urine on the seventh day. To put the severity of this case in perspective, AChE values were in the range of 5%-8% of normal (Nakajima et al., 1998). However, in most cases, hydrolysis products should not be considered to be present for more than 24-48 h following exposure. The methods used to verify human exposure to nerve agents based on assay of hydrolysis products are presented in Table 19.2. 

Bossle PC, Martin JJ, Sarver EW et al. (1983). High-performance liquid chromatography analysis of alkyl methylphosphonic acids by derivatization. J Chromatogr, 267, 209-212. 

There are numerous methods for the analysis of alkyl methylphosphonic acids in urine and blood, mostly using GC-MS and GC-MS-MS. These have been recently reviewed (Black and Muir, 2003 Black and Noort, 2005) and only a representative selection is summarized here. Isolation from urine is usually achieved by hydrophobic SPE (Cis, Cs or polymeric) at low pH, or by anion-exchange SPE. Phosphonic acids require derivatization for GC-MS analysis, and at least four different derivatives have been applied to biomedical samples. Silylation (trimethylsilyl or rm-butyldimethylsilyl) are commonly used for environmental analysis and were used in the analyses of samples from casualties of the Mat-sumoto and Tokyo terrorist attacks (e.g. Minami et al, 1997 Nakajima et al, 1998). In these cases, the first samples were collected within hours of the exposure and the detection limits... 

Miki A, Katagi M, Tsuchihashi H et al. (1999). Determination of alkyl methylphosphonic acids, the main metabohtes of organophosphorus nerve agents, in biofluids by gas chromatography-mass spectrometry by liquid-liquid-solid-phase-transfer-catalyzed pentafluorobenzylation. J Anal Toxicol, 23, 86-93. 

The alkyl methylphosphonic acids are polar and involatile and must be derivatized before analysis by gas chromatography. The simplest derivatization involves conversion into the methyl esters using diazomethane , or trimethylphenylammonium hydroxide in the hot injection port. However, the GC properties of the methyl esters, particularly dimethyl methylphosphonate, are not ideal and may give rise to poor peak shapes at low concentrations. Alternative derivatives are the trimethylsilyl or err-butyldimethylsi-jyji 14,133 latter are more stable than the trimethylsilyl esters and provide good... 

Mawhinney, D.B., et al. (2007) Enhancing the response of alkyl methylphosphonic acids in negative electrospray ionization liquid chromatography tandem mass spectrometry by post-column addition of organic solvents. Journal of the American Society for Mass Spectrometry, 18,1821-1826. 

Kanamori-Kataoka, M., Seto, Y. (2008) Laboratory identification of the nerve gas hydrolysis prodncts alkyl methylphosphonic acids and methylphosphonic acid, by gas chromatography-mass spectrometry after tert-butyldimethylsUylation./oMmoZ of Health Science (Tokyo, /apan), 54(5), 513-523. 

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