The Amide Bond

FIGURE 9-5 Schematic diagram of the amide bond showing the jr-bonding system. 

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Amides are the least reactive caiboxyhc acid deiivative and the only nucleophilic acyl substitution reaction they undeigo is hydrolysis Amides are fanly stable m water but the amide bond is cleaved on heating m the presence of strong acids 01 bases Nomi nally this cleavage produces an amine and a caiboxyhc acid... 

The acid-base reactions that occur after the amide bond is broken make the overall hydrolysis irreversible m both cases The amine product is protonated m acid the car boxylic acid is deprotonated m base... 

The leader of DuPont s effort was Wallace H Carothers who reasoned that he could reproduce the properties of silk by constructing a polymer chain held together as is silk by amide bonds The neces sary amide bonds were formed by heating a dicar boxylic acid with a diamine Hexanedioic acid adipic acid) and 1 6 hexanediamme hexamethylenedi-amine) react to give a salt that when heated gives a polyamide called nylon 66 The amide bonds form by a condensation reaction and nylon 66 is an example of a condensation polymer... 

A key biochemical reaction of ammo acids is their conversion to peptides polypeptides and proteins In all these substances ammo acids are linked together by amide bonds The amide bond between the ammo group of one ammo acid and the carboxyl of another IS called a peptide bond Alanylglycme is a representative dipeptide... 

Acid hydrolysis cleaves the amide bonds of the 2 4 dimtrophenyl labeled peptide giving the 2 4 dimtrophenyl labeled N terminal ammo acid and a mixture of unlabeled ammo acids... 

A major advance was devised by Pehr Edman (University of Lund Sweden) that has become the standard method for N terminal residue analysis The Edman degrada tion IS based on the chemistry shown m Figure 27 12 A peptide reacts with phenyl iso thiocyanate to give a phenylthwcarbamoyl (PTC) denvative as shown m the first step This PTC derivative is then treated with an acid m an anhydrous medium (Edman used mtromethane saturated with hydrogen chloride) to cleave the amide bond between the N terminal ammo acid and the remainder of the peptide No other peptide bonds are cleaved m this step as amide bond hydrolysis requires water When the PTC derivative IS treated with acid m an anhydrous medium the sulfur atom of the C=S unit acts as... 

An alternative approach to peptide sequencing uses a dry method in which the whole sequence is obtained from a mass spectrum, thereby obviating the need for multiple reactions. Mass spec-trometrically, a chain of amino acids breaks down predominantly through cleavage of the amide bonds, similar to the result of chemical hydrolysis. From the mass spectrum, identification of the molecular ion, which gives the total molecular mass, followed by examination of the spectrum for characteristic fragment ions representing successive amino acid residues allows the sequence to be read off in the most favorable cases. 

Deamidation of soy and other seed meal proteins by hydrolysis of the amide bond, and minimization of the hydrolysis of peptide bonds, improves functional properties of these products. For example, treatment of soy protein with dilute (0.05 A/) HCl, with or without a cation-exchange resin (Dowex 50) as a catalyst (133), with anions such as bicarbonate, phosphate, or chloride at pH 8.0 (134), or with peptide glutaminase at pH 7.0 (135), improved solubiHty, whipabiHty, water binding, and emulsifying properties. 

The mechanism for photodegradation at short wavelengths is generaUy beUeved to be initiated by the photolytic cleavage of the amide bond (eq. 17), which has the lowest bond strength in aUphatic polyamides (220 kj/mol (53 kcal/mol))... 

The ability of lipases to synthesize the amide bond has been shown (26). Mucor miehei lipase (NOVO tipozyme) has been used in the reaction of laurylamine and oleic acid at 60°C. Water was shown to inhibit the synthesis of this Ai-lauryloleamide (27). 

A nitrogen atom at X results in a variable downfield shift of the a carbons, depending in its extent on what else is attached to the nitrogen. In piperidine (45 X = NH) the a carbon signal is shifted by about 20 p.p.m., to ca. S 47.7, while in A-methylpiperidine (45 X = Me) it appears at S 56.7. Quaternization at nitrogen produces further effects similar to replacement of NH by A-alkyl, but simple protonation has only a small effect. A-Acylpiperidines show two distinct a carbon atoms, because of restricted rotation about the amide bond. The chemical shift separation is about 6 p.p.m., and the mean shift is close to that of the unsubstituted amine (45 X=NH). The nitroso compound (45 X = N—NO) is similar, but the shift separation of the two a carbons is somewhat greater (ca. 12 p.p.m.). The (3 and y carbon atoms of piperidines. A- acylpiperidines and piperidinium salts are all upfield of the cyclohexane resonance, by 0-7 p.p.m. 

The a-ionization of 7-methylpteridines can also be utilized in aldol-type condensation reactions. 7-Methyl-pterin and -lumazine and 2,4-diaminopteridine condense readily in aqueous base with aromatic aldehydes to afford 7-alkylidenepteridines (77JOC2951). A Claisen condensation requires the protection of the acidic hydrogens of the amide bonds. 

The stereochemistry of pyrazolidines has briefly been discussed in Section 4.04.1.4.3. The pyrazolidine ring in (429) in the crystal state is not planar and the configuration about the amide bond is E as represented. 

Polymerization of /3-lactams, involving cleavage of the amide bond, can be induced by treatment with strongly basic catalysts or by acylating agents (75S547 p. 581). 

It should be noted that when a BOC-protected amide is subjected to MeONa treatment the amide bond is cleaved in preference to the BOC group (85-96% yield) because of the difference in steric factors. The BOC group can be removed by the methods used to remove it from simple amines. 

Two of the three single bonds involved in each unit are flexible, and their detailed conformation dictates overall polypeptide structures and (ultimately) function. The amide bond is generally assumed to be rigid. Why (See also Chapter 10, Problem 1.)... 

Application of the Knorr pyrazole synthesis has also been demonstrated on solid support. ° To prepare trisubstituted pyrazoles, the diketone was linked to the solid support to make 57 using a linker with an amide bond. Alkylation of the diketone followed by condensation of the hydrazine with the resulting diketone gave the desired pyrazoles as mixtures of isomers. Subsequent cleavage of the amide bond linker then provided the pyrazole amides 59. ... 

The amide bond that links different amino acids together in peptides is no different from any other amide bond (Section 24.3). Amide nitrogens are non-basic because their unshared electron pair is delocalized by interaction with the carbonyl group. This overlap of the nitrogen p orbital with the p orbitals of the carbonyl group imparts a certain amount of double-bond character to the... 

C—N bond and restricts rotation around it. The amide bond is therefore planar, and the N—H is oriented 180° to the C=0. 

Problem 26.9 Draw the structure of M-P-V-G, and indicate the amide bonds. 

Proteins can be cleaved specifically at the amide bond on the carboxyl side of methionine residues by reaction with cyanogen bromide. BrC=N. 

As can be seen in Figure 6.12, penicillin G contains two amide functionalities, of which the (Madam linkage is extremely susceptible to basic and nucleophilic attack. Therefore, deavage of the phenylacetyl side chain could not be performed using classical base hydrolysis. The problem of selectivity was resolved by taking advantage of the fad that the amide bond to be hydrolysed is secondary rather than tertiary. 

Coordinating properties of the amide bond. Stability and structure of metal ion complexes of peptides and related ligands. H. Sigel and R. B. Martin, Chem. Rev., 1982, 82, 385-426 (409). 

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