Amide in base

Hydrolysis of amides in base requires similarly vigorous conditions. Hot solutions of hydroxide are sufficiently powerful nucleophiles to attack an amide carbonyl group, though even when the tetrahedral intermediate has formed, NH2 tp aH 35) has only a slight chance of leaving when OH (p aH 15) is an alternative. Nonetheless, at high temperatures, amides are slowly hydrolysed by concentrated base. 

Upon warming with 10-20 per cent, sodium or potassium hydroxide solution, no ammonia is evolved (distinction from primary amides). The base, however, is usually liberated upon fusion with soda lime (see experimental details in Section IV,175) and at the same time the acyl group yields a hydrocarbon. Thus benz-p-toluidide affords p-tolu-idine and benzene. 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

In base the tetrahedral intermediate is formed m a manner analogous to that pro posed for ester saponification Steps 1 and 2 m Figure 20 8 show the formation of the tetrahedral intermediate m the basic hydrolysis of amides In step 3 the basic ammo group of the tetrahedral intermediate abstracts a proton from water and m step 4 the derived ammonium ion dissociates Conversion of the carboxylic acid to its corresponding carboxylate anion m step 5 completes the process and renders the overall reaction irreversible... 

Section 20 17 Like ester hydrolysis amide hydrolysis can be achieved m either aque ous acid or aqueous base The process is irreversible m both media In base the carboxylic acid is converted to the carboxylate anion m acid the amine is protonated to an ammonium ion... 

The amide group is readily hydrolyzed to acrylic acid, and this reaction is kinetically faster in base than in acid solutions (5,32,33). However, hydrolysis of N-alkyl derivatives proceeds at slower rates. The presence of an electron-with-drawing group on nitrogen not only facilitates hydrolysis but also affects the polymerization behavior of these derivatives (34,35). With concentrated sulfuric acid, acrylamide forms acrylamide sulfate salt, the intermediate of the former sulfuric acid process for producing acrylamide commercially. Further reaction of the salt with alcohols produces acrylate esters (5). In strongly alkaline anhydrous solutions a potassium salt can be formed by reaction with potassium / /-butoxide in tert-huty alcohol at room temperature (36). 

A AlI lation. 1-Substitution is favored when the indole ring is deprotonated and the reaction medium promotes the nucleophilicity of the resulting indole anion. Conditions which typically result in A/-alkylation are generation of the sodium salt by sodium amide in Hquid ammonia, use of sodium hydride or a similar strong base in /V, /V- dim ethyl form am i de or dimethyl sulfoxide, or the use of phase-transfer conditions. 

Amides in general are stable to elevated processing temperatures, ak oxidation, and dilute acids and bases. StabiUty is reduced in amides containing unsaturated alkyl chains unsaturation offers reactive sites for many reactions. 

The unexpected biological activities of tetracyclines, such as 5a-epi-6-epitetracychne [19543-88-5] C22H24N20g, and 7-chloro-5a,lla-dehydro-6-epitetracycline [22688-60-4] C22H22ClN20g, make predicting stmcture-activity relationships difficult (64). Aside from the C-2 amide Mannich-base derivatives, variation at other centers in the molecule, ie, C-4, 4a, 5a, 12a, decreases the biological activity. 

The acid-base reactions that occur after the amide bond is broken make the overall hydrolysis ineversible in both cases. The amine product is protonated in acid the carboxylic acid is deprotonated in base. 

The addition of phenylisocyanate to aldehyde-derived enamines resulted in the formation of aminobutyrolactams (438,439). As aminal derivatives these produets can be hydrolyzed to the linear aldehyde amides and thus furnish a route to derivatives of the synthetically valuable malonaldehyde-acid system. With this class of reactions, a second acylation on nitrogen becomes possible and the six-membered cyclization products have been reported (440). Closely related to the reactions of enamines with isocyanates is the condensation of cyclohexanone with urea in base (441). 

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. 

Phenylcyclopropane has been prepared by the base catalyzed decomposition of 5-phenylpyrazoline (33 %),2 by the reaction of 1,3-dibromo-l phenylpropane with magnesium (68%),3 and by the reaction of 3-phenylpropyltrimethylammomum iodide with sodium amide in liquid ammonia (80%)4 However, the method frequently used at present is the reaction of styrene with the methylene iodide-zinc reagent (32%)5... 

Although some examples of C-substitutions of silylated Schiff bases and iminium salts, in particular the formation of / -lactams, have already been mentioned in Sections 5.1.3 and 5.1.5 (cf. also C-substitutions of lactones and amides in Section 4.8) in this section several additional and typical C-substitutions of 0,0- and 0,N-acetals and of iminium salts derived from carbonyl groups are discussed. 

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