The adsorption and decomposition of dimethyl methylphosphonate (DMMP) have been examined on four different metal oxide surfaces:  aluminum oxide, magnesium oxide, lanthanum oxide, and iron oxide. Aluminum, magnesium, and lanthanum oxides are observed to behave in much the same way, with initial binding of the PO species to the surface at an acid site, followed by stepwise elimination of the methoxy groups, beginning at temperatures as low as 50 °C, which combine with surface hydrogens to yield methanol that evolves from the surface. The final product observed for these oxides is a surface-bound methylphosphonate, with the P−CH3 bond intact, which is resistant to further oxidation even in the presence of 70 Torr of oxygen at 300−400 °C. Adsorption on iron oxide yields a different sequence of events, with the initial adsorption occurring again with the PO moiety binding to an acid site, although there is some indication of the formation of a second type of surface complex. The primary interaction on iron oxide appears to be much stronger than with the other oxides, and probably involves the unidentate coordination of the DMMP to a Lewis acid site on the surface. Nonselective elimination of both the methoxy and the phosphorus-bound methyl groups begins only after heating above 200 °C, but occurs with total elimination of the methyl and methoxy groups observed after heating above 300 °C in vacuum. The ease with which iron oxide cleaves the P−CH3 bond is attributed to the availability of multiple oxidation states to the iron atom. Participation of the Fe(III)/Fe(II) redox couple in the reaction provides a low-energy path for oxidative cleavage of the P−CH3 bond. The other oxide surfaces cannot provide a similar path, and on these surfaces the P−CH3 bond is resistant to cleavage. The use of infrared diffuse reflectance techniques, observing, in particular, the methyl stretch region of the infrared spectrum, has allowed the almost complete characterization of the decomposition processes which occur after DMMP adsorbs on aluminum oxide, magnesium oxide, lanthanum oxide, and iron oxide.

Rare adverse reactions to drugs that are of unknown etiology, or idiosyncratic reactions, can produce severe medical complications or even death in patients. Current hypotheses suggest that metabolic activation of a drug to a reactive intermediate is a necessary, yet insufficient, step in the generation of an idiosyncratic reaction. We review evidence for this hypothesis with drugs that are associated with hepatotoxicity, one of the most common types of idiosyncratic reactions in humans. We identified 21 drugs that have either been withdrawn from the U.S. market due to hepatotoxicity or have a black box warning for hepatotoxicity. Evidence for the formation of reactive metabolites was found for 5 out of 6 drugs that were withdrawn, and 8 out of 15 drugs that have black box warnings. For the other drugs, either evidence was not available or suitable studies have not been carried out. We also review evidence for reactive intermediate formation from a number of additional drugs that have been associated with idiosyncratic hepatotoxicity but do not have black box warnings. Finally, we consider the potential role that high dosages may play in these adverse reactions.

The adsorption and decomposition reactions of dimethyl methylphosphonate (DMMP) on a commercial γ-Al 2 O 3 , a γ-Al 2 O 3 -supported iron oxide, and a sol-gel-prepared alumina have been examined at temperatures from 25 to 400 °C. The capacities of these solids for the decomposition of DMMP have been measured, and the identities and amounts of the decomposition products determined over the entire temperature range. The alumina surfaces yield higher total amounts of decomposition products than the supported iron oxide material, with the sol-gel alumina showing very high activity. When corrected for surface area, however, the supported iron oxide material shows an activity equal to that of the γ-Al 2 O 3 support. The sol-gel alumina shows a higher activity at all temperatures up to saturation of the surface, presumably because of the presence of transitional phases that yield more reactive surface sites. At 25 °C, the commercial γ-Al 2 O 3 shows a total decomposition capacity of 117 µmol/g, the alumina-supported iron oxide material a capacity of 93 µmol/g, and the sol-gel alumina a capacity of 208 µmol/g. At 100 °C, these capacities increase by about a factor of 3, and at 200 °C and above, all of the materials show some capacity for sustained decomposition of DMMP.

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The adsorption of dimethyl methylphosphonate (DMMP) on alumina-supported iron oxide has been examined. DMMP reacts on adsorption at room temperature, apparently through cleavage of the phosphorus−carbon bond. This bond is observed to be extremely resistant to cleavage when DMMP is adsorbed on oxides such as alumina, magnesia, and lanthana. The phosphorus−methoxy bonds, which are the most readily cleaved on the other oxides, appear at least initially to remain intact on the alumina-supported iron oxide. The hypothesis proposed to account for the unusual activity of the iron oxide surface is an oxidation pathway involving the Fe(II)/Fe(III) redox couple.