Nitrogen mustards, 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. 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

In Approach (B), aniline is converted into the corresponding nitrogen mustard, which is formylated to the benzaldehyde nitrogen mustard V. The alanine moiety is constructed via the Erlenmeyer reaction with hippuric acid, reduction, and hydrolysis [23,34—38]. 

The hydrolysis of melphalan (and of most aromatic nitrogen mustards) represents the most important degradation mechanism and has been extensively studied. The first reports showed a 22% hydrolysis under the standard conditions designed by Ross for the assessment of aromatic nitrogen mustard reactivity (30 min reflux in acetone—water 1 1, v/v) [10,84]. Rate constants for the disappearance of melphalan in various media are listed in Table VI. 

The hydrolysis products (23-25) of the three nitrogen mustards listed in Schedule 1 of the CWC were included in the general LC/APCI/MS screening procedures of Black and Read, 14 26 . These procedures, and those of other laboratories, have successfully identified Af-methyldiethanolamine (23) and N-clhyldiclhanolaminc (24) in OPCW proficiency tests. More specific methods based on LC/ESI/MS have been reported for the trace analysis of ethanolamines in environmental residues (66) and biomedical samples (67). 

A number of modifications/improvements to methods for the analysis of metabolites of sulfur and nitrogen mustards, and hydrolysis products of nerve agents, have been reported in a special issue of the Journal of Analytical Toxicology, 28 (5) (2004) pp. 305-392. 

S.W. Lemire, D.L. Ashley and A.M. Calafat, Quantitative determination of the hydrolysis products of nitrogen mustards in human urine by liquid chromatography-electrospray ionization tandem mass spectrometry, J. Anal. Toxicol., 27, 1-6 (2003). 

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... 

Figure 6. Nitrogen mustards and their hydrolysis products...

Intrastrand cross-linking of the nitrogen mustard mechloethamine (216) has been observed and the products released after acid hydrolysis have been characterised and foimd to have the structure (217). ... 

Cyclophosphamide was synthesized by Arnold and coworkers - in the hope that it would be inert until activated by an enzyme present in the body, especially in the tumour. The activation mechanism is believed to require an initial oxidative dealkylation, followed by a spontaneous or phosphoramidase-catalysed hydrolysis to the parent nitrogen mustard. 

It is well-established that the reactivity of aromatic nitrogen mustards in hydrolysis reactions correlates positively with the degree of electron release to the nitrogen (7). The rate constants for alkaline hydrolysis of a series of aniline mustards correlate well with a, as shown by Equation 1 (equation 23 of ref. 8). 

Little information on the hydrolysis of nitrogen mustards was located. Nitrogen mustards are stable during storage, and, in the presence of water, form dimers (Forsman et al. 1979 Franke 1982). Hydrolysis of HN3 is slower than that of the sulfur mustards, but the hydrolysis of HNl and HN2 is probably more rapid. The mechanism of hydrolysis is similar, with formation of a cyclic intermediate. Solubilities range from 0.16 g/L for HN3 to 12 g/L for HN2... 

Nitrogen mustards, in general, react slower than the sulphur mustards. The hydrolysis of nitrogen mustards was extensively studied recently. " The products of hydrolysis are non-toxic. The solubility in water for HN-3 is 0.16 g. The time frame for a total decomposition in fresh water is approximately 3 weeks. For the tertiary amine, HN-1, the solubility in water is much higher. 

Write a mechanism for the hydrolysis of the nitrogen mustard bis(2-chloroethyl) methylamine. 

Figure 4.9 Degradation products of Nitrogen Mustard N-methyldiethanolamine (MDEA), N-ethyldiethanolamine (EDEA) and triethanolamine (TEA) [31]. Reprinted from Executive Summary of Chemical Warfare Agents and their Hydrolysis Products from the US EPA Standardized Analytical Methods and GC-MS Analytical Method for the Analysis of Chemical Warfare Agent Degradation Products listed in the EPA Standardized Analytical Methods US EPA, Theodore A. Haigh...

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