Amide acid-catalyzed hydrolysis

As an example, experimental kinetic data on the hydrolysis of amides under basic conditions as well as under acid catalysis were correlated with quantitative data on charge distribution and the resonance effect [13]. Thus, the values on the free energy of activation, AG , for the acid catalyzed hydrolysis of amides could be modeled quite well by Eq. (5)... 

Whereas acid catalyzed hydrolysis of peptides cleaves amide bonds indiscriminately and eventually breaks all of them enzymatic hydrolysis is much more selective and is the method used to convert a peptide into smaller fragments... 

Caibamates ate formed from an amine with a wide variety of reagents, of which the chloroformate is the most common amides are formed from the acid chloride. -Alkyl caibamates are cleaved by acid-catalyzed hydrolysis A/-alkylamides are cleaved by acidic or basic hydrolysis at teflux. conditions that cleave peptide bonds. 

The mechanism for acid-catalyzed hydrolysis of amides involves attack by water on the protonated amide. An inqjortant feature of the chemistry of amides is that the most basic site in an amide is the carbonyl oxygen. Very little of the N-protonated form is present. The major factor that contributes to the stability of the O-protonated form is the... 

Reaction 12, the acid-catalyzed hydrolysis of substituted benzamides, has p = — 0.22, so the reaction is modestly facilitated by electron-donating groups. This suggests that protonation of the amide is kinetically important ... 

Amides undergo acid-catalyzed hydrolysis, the rate constant typically passing through a maximum at 2-6 M acid. Develop a hypothesis to account for the maximum. 

Further evidence for this mechanism is that a small but detectable amount of 0 exchange (see p. 425) has been found in the acid-catalyzed hydrolysis of benz-amide. (The exchange has also been detected for the base-catalyzed... 

Enzyme-catalyzed transfer of KDO from CMP-KDO (127) into a lipid-A acceptor has been studied by Heath and coworkers,1 using a cell-free system from Escherichia coli O 111 J-5. LPS from the organism did not function as an acceptor, and only weak acceptor-activity was displayed147-148 by lipid A preparations obtained by mild, acid-catalyzed hydrolysis of LPS. Base-catalyzed, hydrolytic removal of the ester-linked, but not the amide-linked, fatty acid residues from lipid A resulted in an acceptor of maximal activity1 (see Scheme 38 compare Scheme 39). 

FIGURE 3.8 Deprotection of carboxyl groups by acid-catalyzed hydrolysis (A) of amides and (B) of esters. Protonation generates a relatively stable carbenium ion that usually requires heat to fragment it. 

Fig. 3.1. General scheme for chemical hydrolysis of carboxylic acid esters and amides. Pathway a Proton (general acid) catalyzed hydrolysis. Pathway b HO (general base) catalyzed...

In proton-catalyzed hydrolysis (specific acid catalyzed hydrolysis), protonation of the carbonyl O-atom leads to polarization of the carbonyl group, facilitating addition of the nucleophile, i. e., a H20 molecule (Fig. 3.1, Pathway a). The acid-catalyzed hydrolysis of esters is reversible because the neutral alcohol or phenol released is nucleophilic, whereas hydrolysis of amides is irreversible because the amine released is protonated in the acidic medium and, hence, has considerably reduced nucleophilicity. 

The last group of aliphatic amides to be discussed are the tertiary amides, which, by definition, carry two alkyl substituents on the N-atom. Investigations of their chemical stability have disclosed a surprising difference between tertiary and secondary amides, since the rate of acid-catalyzed hydrolysis of N,N-dimethyl amides is higher than that of A-methyl amides. If steric fac-... 

The degradation of support-bound a-amino acid amides has been used to prepare retro-inverso peptide mimetics ([226], second equation in Figure 10.6). These compounds are of interest because of their potentially improved metabolic stabilities, selectivities, and biological activities compared with peptides [226], Although retro-inverso peptides are aminals susceptible to acid-catalyzed hydrolysis, N,N -diacylated aminals can be sufficiently stable to withstand the conditions of Boc-group removal [227] or of acidolytic cleavage of peptides from Wang resin [226]. 

The amide bonds in peptides and proteins can be hydrolyzed in strong acid or base Treatment of a peptide or protein under either of these conditions yields a mixture of the constituent amino acids. Neither acid- nor base-catalyzed hydrolysis of a protein leads to ideal results because both tend to destroy some constituent ammo acids. Acid-catalyzed hydrolysis destroys tryptophan and cysteine, causes some loss of serine and threonine, and converts asparagine and glutamine to aspartic acid and glutamic acid, respectively. Base-catalyzed hydrolysis leads to destruction of serine, threonine, cysteine, and cystine and also results in racemization of the free amino acids. Because acid-catalyzed hydrolysis is less destructive, it is often the method of choice. The hydrolysis procedure consists of dissolving the protein sample in aqueous acid, usually 6 M HC1, and heating the solution in a sealed, evacuated vial at 100°C for 12 to 24 hours. 

Acid-catalyzed hydrolysis of the two amide bonds produces L-alanine and regenerates the L-proline so that it can be used again. 

The critical feature of the Edman degradation is that it allows the N-terminal amino acid to be removed without cleaving any of the other peptide bonds. Let s see how this occurs. The mechanism of the reaction is shown in Figure 26.3. First the nucleophilic nitrogen of the N-terminal amino acid attacks the electrophilic carbon of phenyl isothiocyanate. When anhydrous HF is added in the next step, the sulfur of the thiourea acts as an intramolecular nucleophile and attacks the carbonyl carbon of the closest peptide bond. II is the intramolecular nature of this step and the formation of a five-membered ring that result in the selective cleavage of only the N-terminal amino acid. The mechanism for this part of the reaction is very similar to that for acid-catalyzed hydrolysis of an amide (see Section 19.5). However, because no water is present, only the sulfur is available to act as a nucleophile. The sulfur is ideally positioned for intramolecular attack at the carbonyl carbon of the N-terminal amino acid, so only this amide bond is broken. 

Under acidic conditions, the mechanism of amide hydrolysis resembles the acid-catalyzed hydrolysis of an ester. Protonation of the carbonyl group activates it toward nucleophilic attack by water to give a tetrahedral intermediate. Protonation of the amino group enables it to leave as the amine. A fast exothermic proton transfer gives the acid and die protonated amine. 

Draw the important resonance contributors for both resonance-stabilized cations (in brackets) in the mechanism for acid-catalyzed hydrolysis of an amide. 

Asymmetric alkylation of amides. The enolates of amides (2) obtained by acylation of ( + )- or ( —)-l are alkylated consistently with >95% de. The stereoselectivity is independent of the base, solvent, or temperature. The products are converted without racemization into the corresponding acids by dcmethylation (BCl,) followed by acid-catalyzed hydrolysis. 

Nitriles can be hydrolyzed to give either amides or carboxylic acids.The amide is formed initially, but since amides are also hydrolyzed with acid or basic treatment, the carboxylic acid is readily formed. When the acid is desired, the reagent of choice is aq. NaOH containing 6-12% H2O2, though acid-catalyzed hydrolysis is also frequently carried out. A dry hydrolysis of nitriles has been reported.The hydrolysis of nitriles to carboxylic acids is one of the best methods for the preparation of these compounds. Nearly all nitriles give the reaction, with either acidic or basic catalysts. Hydrolysis of cyanohydrins, RCH(OH)CN, is usually carried out under acidic conditions, because basic solutions cause competing... 

The dramatic increases in reaction rates that occur in enzyme-catalyzed reactions can be seen for representative systems in the data given in Table 2.2.4 The hydrolysis of the representative amide benzamide by acid or base yields second-order rate constants that are over six orders of magnitude lower than that measured for ben-zoyl-L-tyrosinamide in the presence of the enzyme a-chymotrypsin. An even more dramatic rate enhancement is observed for the hydrolysis of urea The acid-catalyzed hydrolysis is nearly 13 orders of magnitude slower than hydrolysis with the enzyme urease. The disprotionation of hydrogen peroxide into water and molecular oxygen is enhanced by a factor of 1 million in the presence of catalase. 

Pagni and Kabalka reported acid-catalyzed hydrolysis of nitrile selectively into amide on the surface of unactivated AI2O3. The AI2O3 surface is polar and contains a layer of OH groups, which could serve as the source of water in this reaction (Scheme 5.30). 

The chemistry behind amino acid analysis is nothing more than acid-catalyzed hydrolysis of amide (peptide) bonds. The peptide is hydrolyzed by heating in 6 M hydrochloric acid for about 24 h to give a solution that contains all the amino acids. This mixture is then separated by ion-exchange chromatography, which separates the amino acids mainly according to their acid-base properties. As the amino acids leave the chromatography column, they are mixed with ninhydrin and the intensity of the ninhydrin... 

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