Carbamates, acid/base hydrolysis

Acid/base stress testing is performed to force the degradation of a drug substance to its primary degradation products by exposure to acidic and basic conditions over time. Functional groups likely to introduce acid/base hydrolysis are amides (lactams), esters (lactones), carbamates, imides, imines, alcohols (epimerization for chiral centers), and aryl amines. 

Carboxyhc acid ester, carbamate, organophosphate, and urea hydrolysis are important acid/base-catalyzed reactions. Typically, pesticides that are susceptible to chemical hydrolysis are also susceptible to biological hydrolysis the products of chemical vs biological hydrolysis are generally identical (see eqs. 8, 11, 13, and 14). Consequentiy, the two types of reactions can only be distinguished based on sterile controls or kinetic studies. As a general rule, carboxyhc acid esters, carbamates, and organophosphates are more susceptible to alkaline hydrolysis (24), whereas sulfonylureas are more susceptible to acid hydrolysis (25). 

Many carbamates have been used as protective groups. They are arranged in this chapter in order of increasing complexity of stmcture. The most useful compounds do not necessarily have the simplest stmctures, but are /-butyl (BOC), readily cleaved by acidic hydrolysis benzyl (Cbz or Z), cleaved by catalytic hy-drogenolysis 2,4-dichlorobenzyl, stable to the acid-catalyzed hydrolysis of benzyl and /-butyl carbamates 2-(biphenylyl)isopropyl, cleaved more easily than /-butyl carbamate by dilute acetic acid 9-fluorenylmethyl, cleaved by /3-elimination with base isonicotinyl, cleaved by reduction with zinc in acetic acid 1-adamantyl, readily cleaved by trifluoroacetic acid and ally], readily cleaved by Pd-catalyzed isomerisation. 

When a carbonyl group is bonded to a substituent group that can potentially depart as a Lewis base, addition of a nucleophile to the carbonyl carbon leads to elimination and the regeneration of a carbon-oxygen double bond. Esters undergo hydrolysis with alkali hydroxides to form alkali metal salts of carboxylic acids and alcohols. Amides undergo hydrolysis with mineral acids to form carboxylic acids and amine salts. Carbamates undergo alkaline hydrolysis to form amines, carbon dioxide, and alcohols. 

Fig. 11.11. Mechanism postulated for hydrolysis of organic isocyanates involving electrophilic addition of H20 with general base catalysis. The product of hydration is a carbamic acid that spontaneously decomposes to the primary amine with loss of C02 [117].

Initially, water can cause the hydrolysis of the anhydride or the isocyanate, Scheme 28 (reaction 1 and 2), although the isocyanate hydrolysis has been reported to occur much more rapidly [99]. The hydrolyzed isocyanate (car-bamic acid) may then react further with another isocyanate to yield a urea derivative, see Scheme 28 (reaction 3). Either hydrolysis product, carbamic acid or diacid, can then react with isocyanate to form a mixed carbamic carboxylic anhydride, see Scheme 28 (reactions 4 and 5, respectively). The mixed anhydride is believed to represent the major reaction intermediate in addition to the seven-mem bered cyclic intermediate, which upon heating lose C02 to form the desired imide. The formation of the urea derivative, Scheme 28 (reaction 3), does not constitute a molecular weight limiting side-reaction, since it too has been reported to react with anhydride to form imide [100], These reactions, as a whole, would explain the reported reactivity of isocyanates with diesters of tetracarboxylic acids and with mixtures of anhydride as well as tetracarboxylic acid and tetracarboxylic acid diesters [101, 102]. In these cases, tertiary amines are also utilized to catalyze the reaction. Based on these reports, the overall reaction schematic of diisocyanates with tetracarboxylic acid derivatives can thus be illustrated in an idealized fashion as shown in Scheme 29. 

A common method for the preparation of primary amines involves the hydrolysis of isocyanates or isothiocyanates.4 The latter react more slowly and more vigorous conditions are required. The reaction is catalyzed by acids or bases. In this case simple addition of water to the carbon-nitrogen double bond would give an N-substituted carbamic acid (3). Such compounds are unstable and break down to carbon dioxide (or COS in the case of isothiocyanates) and the amine ... 

Most of the older methods of fluorimetric analysis of pesticides involved hydrolysis to form fluorescent anions. Co-ral (coumaphos) [147] was hydrolyzed in alkali to the hydroxybenzopyran, which was subsequently determined by means of its fluorescence. Guthion (azinphosmethyl) was hydrolyzed to anthranilic acid for fluorimetric analysis [148,149]. A method was developed [150] for Maretin (N-hydroxynaphthalimide diethyl phosphate) in fat and meat which involved hydrolysis in 0.5 M methanolic sodium hydroxide followed by determination of the fluorescence of the liberated naphthalimide moiety. Carbaryl (1-naphthyl N-methylcarbamate) and its metabolites have been determined by a number of workers using base hydrolysis and the fluorescence of the resulting naphtholate anion [151-153]. Nanogram quantities of the naphtholate anion could be detected. Zectran (4-dimethylamino-3,5-xylyl N-methylcarbamate) has been determined by the fluorescence of its hydrolysis product [154]. The fluorescence behaviour of other carbamate insecticides in neutral and basic media has been reported [155]. Gibberellin spray used on cherries has been determined fluorimetrically after treatment with strong acid [156]. Benomyl (methyl N-[l-(butylcarbamoyl)-2-benzimidazolyl]carbamate) has been analyzed by fluorimetry after hydrolysis to 2-aminobenzimidazole [157]. 

Oxidation-reduction (redox) reactions, along with hydrolysis and acid-base reactions, account for the vast majority of chemical reactions that occur in aquatic environmental systems. Factors that affect redox kinetics include environmental redox conditions, ionic strength, pH-value, temperature, speciation, and sorption (Tratnyek and Macalady, 2000). Sediment and particulate matter in water bodies may influence greatly the efficacy of abiotic transformations by altering the truly dissolved (i.e., non-sorbed) fraction of the compounds — the only fraction available for reactions (Weber and Wolfe, 1987). Among the possible abiotic transformation pathways, hydrolysis has received the most attention, though only some compound classes are potentially hydrolyzable (e.g., alkyl halides, amides, amines, carbamates, esters, epoxides, and nitriles [Harris, 1990 Peijnenburg, 1991]). Current efforts to incorporate reaction kinetics and pathways for reductive transformations into environmental exposure models are due to the fact that many of them result in reaction products that may be of more concern than the parent compounds (Tratnyek et al., 2003). 

Much of the a-deprotonation chemistry of the amides is mirrored by hindered thioamides, imides, ureas, carbamates and phosphonamides,28 and the important asymmetric versions of these reactions are discussed in chapters 5 and 6. Difficulties removing the heavily substituted groups required for protection of the carbonyl group in these compounds have been overcome in such cases as the urea 75, which is resistant to strong base, but which undergoes acid-catalysed hydrolysis and retro-Michael reaction to reveal the simpler derivative 76.54... 

So, also the selectivity based on the CO consumed was very high (100%). However, when the aniline was carbonylated in the presence of methanol at T>100 °C, relevant amounts of CO2, increasing upon increase of temperature, were obtained. The CO2 formation only under these conditions suggests that it is not formed by direct oxidation of CO, but likely by hydrolysis of DPU (reaetion 3) followed by decomposition of resulting carbamic acid (CO(NHPh)(OH)) in CO2 and aniline. 

The determination of the carbamoyl group in starch carbamates is based on cleavage of the carboxyamido group from the carbamate in alkaline hydrolysis. For this determination, the ammonia liberated is steam-distilled into boric acid followed by titration with 0.05 M aqueous sulfuric acid.2665 Additional information on starch carbamates can be found in the article by Roberts.2666... 

From the hydrolysis of a polyether-based PU a diamine (or a polyamine) such as toluene diamine or diphenylmethane diamine, a polyol and carbon dioxide are formed. The resulting diamines are the precursors used for the synthesis of isocyanates [11,12,16,18]. The resulting polyol is the polyether polyol used for the initial synthesis of PU. Carbon dioxide results from the decomposition of the very unstable carbamic acid formed by the hydrolysis (20.2) ... 

Confirmation of the position assigned to the ether oxygen of strychnine (and hence in strychninolic acid) is found in the results of the Beckmann rearrangement of 12-isonitrosostrychnine (12-oximinostrychnine) (C21H21O3N3) (XVIII). Thionyl chloride (also tosyl chloride) causes a rearrangement of 12-isonitrosostrychnine to an isomeric carbamic acid (XIX) and a substituted urea (XX) (20). Hydrolysis of XIX by barium hydroxide affords an aldehydic base (XXI), barium cyanide and barium carbonate, while alkaline hydrolysis of XX yields norstrychninic acid (XXII). This may be interpreted by partial formulas as follows ... 

Carbachol (see structure above), the carbamate analogue of acetylcholine, shows no selectivity for muscarinic or nicotinic receptors. Because it is a carbamate ester, carbachol is more resistant toward acid-, base-, or enzyme (AChE)-catalyzed hydrolysis than acetylcholine. It also is reported to exhibit weak anticholinesterase activity. Both of these actions work to prolong the duration of action of carbachol. Because of erratic absorption and its actions at nicotinic receptors, use of carbachol has been limited to the treatment of glaucoma and for the induction of miosis in ocular surgery. Carbachol is available as an intraocular solution and an ophthalmic solution. 

They are susceptible to acid, neutral, and base hydrolysis, though in most cases, base hydrolysis will dominate at environmentally significant conditions. Hydrolysis data tabulated by Mabey and Mill (1978) for the carbamates indicate that hydrolysis half-lives at pH 7 at 25°C range from seconds to hundreds of thousands of years (Table 2.6). 

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