Mechanism of amides

FIGURE 20 6 Mechanism of amide formation in the reac tion of a secondary amine with an ethyl ester... 

FIGURE 27 13 The mechanism of amide bond formation by W W dicyclohexylcarbodiimide promoted condensation of a carboxylic acid and an amine... 

FIGURE 20.7 The mechanism of amide hydrolysis in acid solution. Steps 1 through 3 show the formation of the tetrahedral intermediate. Dissociation of the tetrahedral intermediate is shown in steps 4 through 6. 

FIGURE 20.8 The mechanism of amide hydrolysis in basic solution. 

The mechanism of amide formation is a source of insight into the properties of carboxylic acids and amines. Initially, we might expect an amine to act as a base and simply accept a proton from the carboxylic acid. Indeed, that does happen, and a quaternary ammonium salt is formed when the reagents are mixed in the absence of a solvent. For example,... 

There is much evidence for this mechanism, similar to that discussed for ester hydrolysis. A MO study on the mechanism of amide hydrolysis is available. In certain cases, kinetic studies have shown that the reaction is second order in OH , indicating that 107 can lose a proton to give 108. Depending on the nature... 

Nakajima, N., and Ikada, Y. (1995) Mechanism of amid formation by carbodiimides for bioconjugation in aqueous media. Bioconjugate Chem. 6, 123-130. 

The arrangement of the enzyme-substrate complex suggests a plausible reaction mechanism analogous to nonenzymatic mechanisms of amide hydrolysis (Section 24-4). The carboxyl group of Glu 270 can add to the amide carbonyl... 

Another approach to test a template mechanism is to use appropriate control compounds that can be expected to fail to yield the rotaxanes or catenanes, if the tentative mechanism is indeed operative. In order to gain further support for the template mechanism of amide rotaxane formation (Scheme 10), it is desirable to have additional evidence for the... 

SCHEME 14 AXLE CENTERPIECES 30 AND 31 THAT WERE USED AS CONTROL COMPOUNDS FOR A MORE DETAILED INVESTIGATION OF THE MECHANISM OF AMIDE ROTAXANE FORMATION. 

C. O. da Silva, B. Mennucci and T. Vreven, Combining microsolvation and polarizable continuum studies New insights in the rotation mechanism of amides in water, J. Phys. Chem. A, 107 (2003) 6630-6637. 

Mechanism of amide formation using dicyclohexylcarbodiimide. Test yourself on the concepts in this figure at OrganicChemistryNow. 

Amino Adds, Peptides, and Proteins 26.7 Laboratory Synthesis of Peptides Active Figure 26.4 Mechanism of Amide Formation Using Dicydohexylcarbodiimide (page 1151) Coached Tutorial Problem Reactions Used in Synthesis of Peptides (page 1151)... 

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. 

The mechanism of amide hydrolysis in acid is exactly the same as the mechanism of ester hydrolysis in acid (Section 22.11 A) except that the leaving group is different. 

The mechanism of amide hydrolysis in base has the usual two steps of the general mechanism for nucleophilic acyl substitution—addition of the nucleophUe followed by loss of a leaving group— plus an additional proton transfer. The initially formed carboxylic acid reacts further under basic conditions to form the resonance-stabilized carboxylate anion, and this drives the reaction to completion. Mechanism 22.10 is written for a 1° amide. 

Nakajima N, Ikada Y. Mechanism of amide formation by car-bodiimide for bioconjugation in aqueous media. Bioconj. Chem. 1995 6 123-130. 

Zinc enzymes catalyze the hydrolysis of amide bonds using a variety of active site structural motifs.77 An extensively studied enzyme of this class is carboxypeptidase A, which contains a mononuclear zinc center (Fig. 13) within the enzyme active site and catalyzes the hydrolysis of a C-terminal amino acid.78,79 The mechanism of amide cleavage in carboxypeptidase A has been studied extensively.77,78 In one proposed mechanistic pathway for this enzyme (Scheme 13), termed the zinc hydroxide mechanism , the zinc center activates a water molecule for deprotonation and also assists in polarization of the substrate carbonyl moiety, thus making it more susceptible to nucleophilic attack. The zinc center also provides transition state stabilization through charge neutralization. 

Figure 8 Mechanism of amide bond formation in native chemical ligation.

The first four steps of the mechanism for hydrolysis of nitriles in basic solution are given in Mechanism 19.8. These steps convert the nitrile to an amide, which then proceeds to the hydrolysis products according to the mechanism of amide hydrolysis in Mechanism 19.7 (page 846). 

The mechanism of amide-hydrogen exchange in proteins is well nnderstood. The exchange could be catalyzed by H+ and OH ions both. The rate constant for hydrogen exchange (fcex) is the snm of the rates for the acid- ( h) and base-catalyzed ( oh) reactions... 

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