Amides leaving group

The perhydrolysis reaction could theoretically continue to give four moles of peracid per mole of TAED but stops at this stoichiometry because of the substantial increase in the conjugate acid pify of the leaving group going from an amide (p-R = 17) to an amine (pif = 35) (94,95). Nonanoyloxybenzene sulfonate (NOBS) [101482-85-3] is used in detergent products in the United States and Japan. The NOBS perhydrolysis reaction is shown in equation 20 (96). 

In the case of esters, carboxylate anions, amides, and acid chlorides, the tetrahedral adduct may undergo elimination. The elimination forms a ketone, permitting a second addition step to occur. The rate at which breakdown of the tetrahedral adduct occurs is a function of the reactivity of the heteroatom substituent as a leaving group. The order of stability of the... 

The principal difference hes in the poorer ability of amide ions to act as leaving groups, compared to alkoxides. As a result, protonation at nitrogen is required for breakdown of the tetrahedral intermediate. Also, exchange between the carbonyl oxygen and water is extensive because reversal of the tetrahedral intermediate to reactants is faster than its decomposition to products. 

With 1-hydroxytryptophan derivatives, similar substituent effects are observed (99H2815). In order to realize better yields of 5-substituted tryptophans, car-boxy and amino groups are transformed to ester and/or amide groups, choosing the 1-methoxy moiety as a leaving group. As a result, ( )-Ab-acetyl-5-chlorotryptophan methyl ester (219, 52%) is obtained together with 220 (7%) from ( )-218 by the reaction with aqueous HCl (Scheme 32). ( )-5-Bromo-Ab-methoxycarbonyltryptophan methylamide (222, 50%) becomes readily available... 

Following formation of the amide intermediate, a second nucleophilic addition of hydroxide ion to the amide carbonyl group then yields a tetrahedral alkoxide ion, which expels amide ion, NHZ-, as leaving group and gives the car-boxylate ion, thereby driving the reaction toward products. Subsequent acidification in a separate step yields the carboxylic acid. We ll look at this process in more detail in Section 21.7. 

Closely related to the carboxylic acids and nitriles discussed in the previous chapter are the carboxylic acid derivatives, compounds in which an acyl group is bonded to an electronegative atom or substituent that can net as a leaving group in a substitution reaction. Many kinds of acid derivatives are known, but we ll be concerned primarily with four of the more common ones acid halides, acid anhydrides, esters, and amides. Esters and amides are common in both laboratory and biological chemistry, while acid halides and acid anhydrides are used only in the laboratory. Thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the structural similarity between acid anhydrides and acy) phosphates. 

Conversion of Amides into Carboxylic Acids Hydrolysis Amides undergo hydrolysis to yield carboxylic acids plus ammonia or an amine on heating in either aqueous acid or aqueous base. The conditions required for amide hydrolysis are more severe than those required for the hydrolysis of add chlorides or esters but the mechanisms are similar. Acidic hydrolysis reaction occurs by nucleophilic addition of water to the protonated amide, followed by transfer of a proton from oxygen to nitrogen to make the nitrogen a better leaving group and subsequent elimination. The steps are reversible, with the equilibrium shifted toward product by protonation of NH3 in the final step. 

Basic hydrolysis occurs by nucleophilic addition of OH- to the amide carbonyl group, followed by elimination of amide ion (-NH2) and subsequent deprotonation of the initially formed carboxylic acid by amide ion. The steps are reversible, with the equilibrium shifted toward product by the final deprotonation of the carboxylic acid. Basic hydrolysis is substantially more difficult than the analogous acid-catalyzed reaction because amide ion is a very poor leaving group, making the elimination step difficult. 

Amide reduction occurs by nucleophilic addition of hydride ion to the amicle carbonyl group, followed by expulsion of the oxygen atom as an alumi-nate anion leaving group to give an iminium ion intermediate. The intermediate iminium ion is then further reduced by JL1AIH4 to yield the amine. 

In these reactions (12-41-12-44), a carbonyl group is attacked by a hydroxide ion (or amide ion) giving an intermediate that undergoes cleavage to a carboxylic acid (or an amide). With respect to the leaving group, this is nucleophilic substitution at a carbonyl group and the mechanism is the tetrahedral one discussed in Chapter 10. 

AU these results indicate that silylated amides and, in particular, silylated lactams such as 388 will react with methyl or ethyl cyanoacetate or malonate and malodinitrile in the presence of HMDS 2 (to convert the leaving group MeaSiOH 4 into HMDSO 7) via the O-silylated forms such as 384b or 389 to give similar products such as 385 and HMDSO 7 (Scheme 4.54). 

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