Imides alkaline hydrolysis

Amides (except urea and thiourea), imides and nitriles, after the above alkaline hydrolysis, give derivatives similarly to those from the alkaline solution obtained from ammonium salts (p. 360). (A) If the original compound is aromatic, acidification of the cold solution deposits the crystalline acid. (B) The cold solution, when carefully neutralised (p. 332) and treated with benzylthiuronium chloride, deposits the thiuromum salt. 

If the amide is an N-(mono- or di)-substituted amide, or the imide an N-substituted imide, the above alkaline hydrolysis will give a solution... 

Alkaline hydrolysis of the adducts 6 and 7, which is fairly mild in the case of the imide adducts, liberates 3-hydroxycarboxylic acids 8 or ent-8 and simultaneously regenerates the chiral auxiliary reagent. Furthermore, both enantiomers of the 3-hydroxycarboxylic acid are available in almost optically pure form depending on which reagent is chosen as the starting material. 

Simple amides are satisfactory protective groups only if the rest of the molecule can resist the vigorous acidic or alkaline hydrolysis necessary for their removal. For this reason, only amides that can be removed under mild conditions have been found useful as amino-protecting groups. Phthalimides are used to protect primary amino groups. The phthalimides can be cleaved by treatment with hydrazine. This reaction proceeds by initial nucleophilic addition at an imide carbonyl, followed by an intramolecular acyl transfer. 

For the preparation of anthranilic acid the starting material is phthalimide, the cyclic imide ring of which is opened by alkaline hydrolysis in the first step of the reaction to give the sodium salt of phthalimidic acid (the half amide of phthalic acid). The intermediate undergoes the Hofmann reaction in the manner outlined on p. 783 yielding o-aminobenzoic acid (anthranilic acid). 

Among these, in particular, the acetate [17] and the silyloxyl [31] derivatives are often used as the protecting groups for the hydroxyl (alcohol) function. For example, polymers of 2-acetoxyethyl vinyl ether are readily transformed into a polyalcohol, poly(2-hydroxyethyl vinyl ether), by alkaline hydrolysis [17]. Due to the polar pendant functions, the polymers are of course hydrophilic and often water-soluble, and serve as hydrophilic segments in so-called amphiphilic polymers, as will be discussed later (Sections III.D and VI.B.5). Other important protecting groups include the malonate [23] and the imides [29,30], which lead to polymeric carboxylic acids and amines, respectively (Scheme 1). 

A few 6- and 8-cyanopurines have been prepared and undergo characteristic nitrile addition reactions rather readily. Thus, alkaline hydrolysis produces carboxamides, then carboxylic acids, alcoholysis leads to imidates, ammonolysis to amidines, hydrazinolysis to amidhydrazines, hydroxylamine to amidoximes, and hydrogen sulfide to thioamides. Acid hydrolysis tends to give the decarboxylated acid derivative. Reduction either by sodium-ethanol or, preferably, by catalytic hydrogenation affords aminoalkylpurines and addition of Grignard reagents produces, in the first place, acylpurines. As with aldehydes, most of the compounds examined have been relatively non-polar derivatives. Table 28 lists some reactions and relevant literature. 

After tri-n-butylamine is removed from the mixture, we may use the salt s acidity to isolate it in solution. The succinimide will remain in the organic layer and the primary amine may be produced from it by reacting the imide with hydrazine. Similarly, we may regenerate the secondary amine from the amide by alkaline hydrolysis. 

Imides are rather more resistant to alkaline hydrolysis than are amides. 

In the first case, reaction with amines leads to amides amido acids formed when amines react with cyclic anhydrides can be recyclized to cyclic imides (p. 344). When mixed acyclic or asymmetrical cyclic anhydrides react, a mixture of products can be formed, although the stronger acid usually gives an ester (or amide) (56). Reaction of alcohols with anhydrides very often takes place even in the cold certain anhydrides, however, are resistent to heat and can be crystallized from ethanol (57) they can be cleaved by heating with sodium ethoxide in ethanol or benzene. If the acids formed by hydrolysis are solid and suitable for identification, this procedure can be considered as the simplest for identification purposes. When anhydrides of liquid acids are to be identified, the reaction with aromatic amines is generally employed mixed anhydrides are best identified by chromatography of acids formed on alkaline hydrolysis. 

Pseudo-first-order rate constants (kobs) for alkaline hydrolysis of 4-nitrophthal-imide (6), in the absence of micelles, obeyed Equation 3.27 with kon = 46.3 x 10- semonotonic decrease with the increase in [CTABrlj at a constant value of [NaOH] and [6]. These results could be explained in terms of both PP and PIE models with almost equal precision (i.e., with similar residual errors and least-squares values). Although the value of k /kw is nearly 25 Af, the value of k o is apparently so low that the increase in [HOm ] due to ion-exchange Br/HO has apparently no effect on the rate of alkaline hydrolysis of 6 in the micellar pseudophase. Thus, the use of PIE model in this and related reaction systems seems to be meaningless. 

But the values of k bs for hydrolysis amides, under highly alkaline medium, follow Equation 7.54, whereas Equation 7.55 has been found to explain ko s vs. [HO] profiles for alkaline hydrolysis of imide and ester groups of substrates containing an acidic group of pK < 15. 

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

The amidine bond is quite stable at acid pH however, it is susceptible to hydrolysis and cleavage at alkaline pH. Derivatized proteins may be assayed by amino acid analysis after acid hydrolysis without loss of imidate modifications. 

Imidoester crosslinkers are highly water-soluble, but undergo continuous degradation due to hydrolysis. The half-life of the imidate functionality is typically less than 30 minutes, especially in the alkaline conditions of the reaction medium (Hunter and Ludwig, 1962 Browne and Kent, 1975). Concentrated stock solutions may be prepared before addition of a small amount to a conjugation reaction, but they should be dissolved rapidly and used immediately. 

The three forms are interconvertible and were found in greatest yields when 12 N HCl at 100°C was employed. Short periods of hydrolysis at 100°C with 5.7 A HCl gave lower yields of the a,/3- and /8-forms. Longer periods of hydrolysis at 37°C with 5.7 A HCl did not produce detectable amounts of either the a,/ - or d-form. The latter method seems to be preferred for partial hydrolysis if the interconversions of aspartyl residues are to be avoided. Hydrolysis of the a,/3-imide at alkaline pH values leads predominantly to the /8-form (Swallow and Abraham, 1958 Bernhard, 1958). Naughton el al. (1960) noted that this type of reaction occurred with the peptide aspartyltyrosine on partial hydrolysis of A-chain of insulin (Sanger... 

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