Amide hydrolysis involving

Base catalyzed nitrile hydrolysis involves nucleophilic addition of hydroxide ion to the polar C N bond to give an imine anion in a process similar to nucleophilic addition to a polar C=0 bond to give an alkoxide anion. Protonation then gives a hydroxy imine, which tautomerizes (Section 8.4) to an amide in a step similar to the tautomerization of an enol to a ketone. The mechanism is shown in Figure 20.4. 

In semi-cristalline polymers, rate-enhancement under stress has been frequently observed, e.g. in UV-photooxidation of Kapron, natural silk [80], polycaprolactam and polyethylene terephthalate [81]. Quantitative interpretation is, however, difficult in these systems although the overall rate is determined by the level of applied stress, other stress-dependent factors like the rate of oxygen diffusion or change in polymer morphology could occur concurrently and supersede the elementary molecular steps [82, 83], Similar experiments in the fluid state showed unequivocally that flow-induced stresses can accelerate several types of reactions, the best studied being the hydrolysis of DNA [84] and of polyacrylamide [85]. In these examples, hydrolysis involves breaking of the ester O —PO and the amide N —CO bonds. The tensile stress stretches the chain, and therefore, facilitates the... 

These reactions involve a diazonium ion (see 12-47) and are much faster than ordinary hydrolysis for benzamide the nitrous acid reaction took place 2.5 x lo times faster than ordinary hydrolysis. Another procedure for difficult cases involves treatment with aqueous sodium peroxide. In still another method, the amide is treated with water and f-BuOK at room temperature. " The strong base removes the proton from 107, thus preventing the reaction marked k j. A kinetic study has been done on the alkaline hydrolyses of A-trifluoroacetyl aniline derivatives. Amide hydrolysis can also be catalyzed by nucleophiles (see p. 427). 

Amide hydrolysis at alkaline pH involves a tetrahedral anionic intermediate, which was mimicked by the transition state analogue [49], an /V-aryl arylphosphonamidate, appropriately related to substrate anilide [50] (Fig. 18) (Appendix entry 2.8). 

Before discussmg the mechanism of cleavage of carboxylic acid esters and amides by hydrolases, some chemical principles are worth recalling. The chemical hydrolysis of carboxylic acid derivatives can be catalyzed by acid or base, and, in both cases, the mechanisms involve addition-elimination via a tetrahedral intermediate. A general scheme of ester and amide hydrolysis is presented in Fig. 3. / the chemical mechanisms of ester hydrolysis will be... 

Like with primary amides (see Sect. 4.2.1), bacterial amidases can be useful for the transformation of secondary amides in drug synthesis. Bacterial amidases have been extensively studied in the presence of penicillins and other [i-lactam antibiotics, for which two hydrolysis reactions are possible. One of these is carried out by enzymes known as penicillinases or /3-lactamases that open the /3-lactam ring this aspect will be discussed in Chapt. 5. The second type of hydrolysis involves cleavage of the side-chain amide bond (4.47 to 4.48) and is carried out by an enzyme called penicillinacylase (penicillin amidohydrolase, EC 3.5.1.11). Both types of hydrolysis inactivate the antibiotic [29-31],... 

A simple example in this class with which to begin is A,A-diethyl-m-to-luamide 0V,/V-dicthyl-3-mcthylbenzamidc, DEET, 4.82), an extensively used topical insect repellant. The hydrolysis product 3-methylbenzoic acid was detected in the urine of rats dosed intraperitoneally or topically with DEET. However, amide hydrolysis represented only a minor pathway, the major metabolites resulting from methyl oxidation and A-dealkylation [52], Treatment of rats with /V,/V-dicthylbcnzamidc (4.83), a contaminant in DEET, produced the same urinary metabolites as its secondary analogue, A-ethylbenzamide (see Sect. 4.3.1.2). This observation can be explained by invoking a metabolic pathway that involves initial oxidative mono-A-deethylation followed by enzymatic hydrolysis of the secondary amide to form ethylamine and benzoic acid [47], Since diethylamide was not detected in these experiments, it appears that A,A-diethylbenzamide cannot be hydrolyzed by amidases, perhaps due to the increased steric bulk of the tertiary amido group. 

Fig. 5.20. Modes of coordination of transition metal ions with /3-lactam antibiotics. Complex A In penicillins, the metal ion coordinates with the carboxylate group and the /3-lactam N-atom. This complex stabilizes the tetrahedral intermediate and facilitates the attack of HO-ions from the bulk solution. Complex B In benzylpenicillin Cu11 binds to the deprotonated N-atom of the amide side chain. The hydrolysis involves an intramolecular attack by a Cu-coordinated HO- species on the carbonyl group. Complex C In cephalosporins, coordination of the metal ion is by the carbonyl O-atom and the carboxylate group. Because the transition state is less stabilized than in A, the acceleration factor of metal ions for the hydrolysis of cephalosporins is lower than for penicillins. Complex D /3-Lactams with a basic side chain bind the metal ion to the carbonyl and the amino group in their side chain. This binding mode does not stabilize the tetrahedral transition complex and, therefore, does not affect the rate of... 

In ester hydrolysis, rate-limiting formation of the tetrahedral intermediate usually apphes (Sec. 6.3.1) since the alkoxide group is easily expelled. In contrast, amide hydrolysis at neutral pH involves rate-limiting breakdown of the tetrtihedral intermediate, because RNH is a poor leaving group. The catalytic effect of metal ions on amide hydrolysis has been ascribed to accelerated breakdown of the tetrahedral intermediate. 

As we have indicated in Section 23-12, amide hydrolysis can be an important route to amines. Hydrolysis under acidic conditions requires strong acids such as sulfuric or hydrochloric, and temperatures of about 100° for several hours. The mechanism involves protonation of the amide on oxygen followed by attack of water on the carbonyl carbon. The tetrahedral intermediate formed dissociates ultimately to the carboxylic acid and the ammonium salt ... 

Many xenobiotic compounds, such as pesticides, are esters, amides, or organophosphate esters, and hydrolysis is a very important aspect of their metabolic fates. Hydrolysis involves the addition of H20 to a molecule accompanied by cleavage of the molecule into two species. The two most common types of compounds that undergo hydrolysis are esters... 

Characterization of HIV-1 protease as a member of the aspartic acid protease family provided the rationale for most of the efforts to design inhibitors (Kohl et al, 1988 Krausslich et al., 1988 Navia et al., 1989 Pearl and Taylor, 1987). Previous efforts to develop therapeutically useful inhibitors of the mechanistically related enzyme renin had demonstrated that potent inhibitors could be prepared by replacing the scissile amide bond of a substrate analogue with a nonhydrolyzable isostere to mimic the tetrahedral intermediate or transition state involved in amide hydrolysis (Greenlee, 1990). Although several dipeptide isosteres have been used to successfully generate highly potent HIV-1 protease inhibitors, a relatively small number have resulted in compounds that reached clinical development. 

The mechanism of the btiaic hydrolysis involves nucleophilic addition uf hydrnucleophilic addition to a polar carbonyl OO bund. Next, the initially formed Itydrojiy iminc isomerizes to an amide in a etep similar to tht isomorixa-tion of an enol to a kctoiw (Section 8.5 J. FVrther hydrolyaie of the amide, as discussed in the previous section, then yields the carboxylic acid i Figure 21.121. 

Basic conditions for the hydrolysis of pseudoephedrine amides typically involve heating the substrate with tetra-n-butylammo-nium hydroxide in a mixture of ferf-butyl alcohol and water... 

In a stereocontrolled route to thromboxane B2, Corey and coworkers used the Eschenmoser rearrangement for the preparation of lactone (91 Scheme 14). The product of the 3,3-sigmatropic shift, amide (90), is directly iodolactonized, thus avoiding often troublesome amide hydrolysis conditions. Another application involving a carbohydrate derivative was demonstrated by Fraser-Reid and coworkers (Scheme 15). Reductive elimination of benzylidene (92), followed by in situ alkylation, Wittig reaction, DIBAL-H reduction and rearrangement, led to amide (94), which was transformed into the corresponding pyranoside diquinane by double radical cyclization. 

Hydrolysis of amides is typical of the reactions of carboxylic acid derivatives. It involves nucleophilic substitution, in which the —NH2 group is replaced by —OH. Under acidic conditions hydrolysis involves attack by water on the pro-tonated amide ... 

Under alkaline conditions hydrolysis involves attack by the strongly nucleophilic hydroxide ion on the amide itself ... 

Acid-catalyzed nitrile hydrolysis is similar to amide hydrolysis and occurs by initial protonation of the nitrogen atom, followed by nucleophilic addition of water. Write all the steps involved in the acidic hydrolysis of a nitrile to yield a carboxylic acid, using curved arrows to represent electron flow in each step. 

In chickens, the mechanism did not involve amide hydrolysis (which occurred in the metabolism of this acetanilide) with subsequent N-... 

Yano, H., Hirayama, F., Arima, H., Uekama, K. Hydrolysis behavior of prednisolone 21-hemisuccinate/ 3-cyclodextrin amide conjugate involvement of intramolecular catalysis of amide group in drug release. Chem. Pharm. Bull. 2000, 48, 1125-1128. 

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