Acid hydrolysis of amides

Hydrolysis of Acid Amides.—The amides are exactly analogous acyl compounds, CH3—CO— NH2, and they are quite easily hydrolyzed as follows ... 

After acid hydrolysis, best carried out with hydrochloric acid in a sealed tube, the alcohol and the amine set free (see the hydrolysis of acid amides on p. 272) are identified, if possible, after their separation. 

Acid amides have weakly amphoteric properties, and thus give salts such as CjHsCONHj.HCl with strong acids, and salts of the type C HsCONHNa with strong bases. These compounds have to be prepared at low temperatures to avoid hydrolysis, and are difficult to isolate. The mercury derivatives can, however, usually be readily prepared, because mercuric oxide is too feebly basic to cause hydrolysis of the amide, and the heavy mercuric derivatives crystallise well. 

Hydrolysis of primary amides cataly2ed by acids or bases is very slow. Even more difficult is the hydrolysis of substituted amides. The dehydration of amides which produces nitriles is of great commercial value (8). Amides can also be reduced to primary and secondary amines using copper chromite catalyst (9) or metallic hydrides (10). The generally unreactive nature of amides makes them attractive for many appHcations where harsh conditions exist, such as high temperature, pressure, and physical shear. 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

Conversion of the nitrile to the amide has been achieved by both chemical and biological means. Several patents have described the use of modified Raney nickel catalysts ia this appHcation (25,26). Also, alkaH metal perborates have demonstrated their utiHty (27). Typically, the hydrolysis is conducted ia the presence of sodium hydroxide (28—31). Owiag to the fact that the rate of hydrolysis of the nitrile to the amide is fast as compared to the hydrolysis of the amide to the acid, good yields of the amide are obtained. Other catalysts such as magnesium oxide (32), ammonia (28,29,33), and manganese dioxide (34) have also been employed. 

This compound undergoes hydrolysis of the amide group intramolecularly catalyzed by the neighboring carboxylic acid group. The rate equation, in the pH range 1—... 

Hydrolysis of the amide 720 gave the acid 721. Boiling 721 in acetic acid for a prolonged period gave the dihydrofuro[3,4-6]quinoline 722 whose possible mechanism of formation is shown in Scheme 125 (85JCS(P1)1897). 

Acidic hydrolysis of the amide group at pH 4.5 is a very slow reaction. Strong acidic conditions leads to a progressive insolubilization of the reaction product because of formation of cyclic imide structures ... 

O Further hydrolysis of the amide gives the anion of a carboxylic acid by a mechanism we ll discuss in Section 21.7. 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

A very simple and elegant alternative to the use of ion-exchange columns or extraction to separate the mixture of D-amino add amide and the L-amino add has been elaborated. Addition of one equivalent of benzaldehyde (with respect to die D-amino add amide) to the enzymic hydrolysate results in the formation of a Schiff base with die D-amino add amide, which is insoluble in water and, therefore, can be easily separated. Add hydrolysis (H2SQ4, HX, HNO3, etc.) results in the formation of die D-amino add (without racemizadon). Alternatively the D-amino add amide can be hydrolysed by cell-preparations of Rhodococcus erythropolis. This biocatalyst lacks stereoselectivity. This option is very useful for amino adds which are highly soluble in die neutralised reaction mixture obtained after acid hydrolysis of the amide. 

The depolymerization of nylon-6,6 and nylon-4,6 involves hydrolysis of the amide linkages, which are vulnerable to both acid- and base-catalyzed hydrolysis. In a DuPont patent,9 waste nylon-6,6 was depolymerized at a temperature... 

The main application of the enzymatic hydrolysis of the amide bond is the en-antioselective synthesis of amino acids [4,97]. Acylases (EC 3.5.1.n) catalyze the hydrolysis of the N-acyl groups of a broad range of amino acid derivatives. They accept several acyl groups (acetyl, chloroacetyl, formyl, and carbamoyl) but they require a free a-carboxyl group. In general, acylases are selective for i-amino acids, but d-selective acylase have been reported. The kinetic resolution of amino acids by acylase-catalyzed hydrolysis is a well-established process [4]. The in situ racemization of the substrate in the presence of a racemase converts the process into a DKR. Alternatively, the remaining enantiomer of the N-acyl amino acid can be isolated and racemized via the formation of an oxazolone, as shown in Figure 6.34. 

Further evidence for this mechanism is that a small but detectable amount of 0 exchange (see p. 425) has been found in the acid-catalyzed hydrolysis of benz-amide. (The exchange has also been detected for the base-catalyzed... 

The hydrolysis of phosphinous amides leading to their constituents, amine and phosphinous acid, is an easy process that is usually followed by the selfcondensation of the acid to yield the diphosphane monoxides 21 [117, 118] (Scheme 21). 

Nature has developed exquisite catalysts for a variety of reactions, for example, the hydrolysis of an amide bond. In the absence of a catalyst, amide bonds are extremely stable, making them ideal bonds to link amino acids in order to create... 

One of the reactions that occurs under acidic conditions involves the hydrolysis of the amide linkages in penicillin. The structure of penicillin (Fig. 13.7.1) indicates... 

Similarly, hydrolysis of tertiary amides of carboxylic acids is usually slow under conventional conditions. Hydrolysis of a morpholide occurred in only 48% yield with 2M HC1 at reflux after 4h, yet proceeded in 70% yield after only 10 min at 200 °C in the MBR (Scheme 2.2) [26]. The convenience of operation and the rapid throughput enabled preparation of multiple batches of the corresponding acid in a few hours. 

Mesitoic acid has been prepared by carbonation of mesityl-magnesium bromide 2-4 by hydrolysis of its amide prepared by condensation of mesitylene with carbamyl chloride under the influence of aluminum chloride 6 by oxidation of isodurene with dilute nitric acid 6-7 by distillation of 2,4,6-trimethylmandelic acid (low yield) 8 by dry distillation of 2,4,6-trimethyIphenyl-glyoxylic acid 9 by oxidation of the latter with potassium permanganate 10 and by treating 2,4,6-trimethylphenylglyoxylic acid with concentrated sulfuric acid in the cold11 or with heating.12... 

Fig. 4.2. The effect of chain length (li) on the degree of hydrolysis [%] of primary amides by rat liver preparations (5 h at pH 7.4). Black bars amides of normal saturated fatty acids hatched bar isohexanamide unshaded bars amides of m-phenyl-substituted saturated fatty...

The hydrolysis of the amide bond in chloramphenicol (4.26), which liberates dichloroacetic acid (4.27) and the primary amine (4.28), has been shown in bacteria, rodents, and humans [13-15]. In the microsomal fraction of guinea pig liver, moreover, the enzyme responsible for hydrolysis has been identified as one of the B-type carboxylesterase isoenzymes [16]. 

Butylpicolinic acid (fusaric acid, 4.68) is a major metabolite of 5-bu-tylpicolinamide (SCH 10985, 4.67) in the plasma of rats, dogs, and humans. The biological activity of this compound (an inhibitor of dopamine-/3-hy-droxylase) is mainly due to its metabolite fusaric acid, indicating that, in this example, the hydrolysis of the amide group is bioactivating [41]. 

Other examples of secondary benzamides include the therapeutic class of orthopramides, which are, again, markedly resistant to hydrolysis. Thus, hydrolysis of the amide bond is a minor metabolic pathway in humans for the antiemetic drug metoclopramide (4.76) [49]. Clebopride (4.77), an anti-dopaminergic agent, was found to be hydrolyzed to a limited extent in rabbit liver homogenates and in dogs to 4-amino-5-chloro-2-methoxybenzoic acid (4.78) and to the amine 4.79 [48] [50], Attempts to detect in vivo formation of this metabolite in rats, rabbits, or humans were not successful [50],... 

Tertiary benzamides whose N-atom is part of a cyclic system can also be hydrolyzed metabolically as shown in the following examples. The hydrolysis of the amide group in 6-[4-(3,4-dimethoxybenzoyl)piperazin-l-yl]-3,4-di-hydro-1 //-quinolin-2-one (OPC-8212, 4.85), an inotropic agent, occurred in rats, mice, dogs, monkeys, and humans [54], After oral administration to rats, both products of hydrolysis, namely 3,4-dimethoxybenzoic acid (veratric acid, 4.86) and piperazine-l//-quinolin-2-one (4.87) were detected in the plasma, urine, and feces. 

The intrinsic inertness of the peptide bond is demonstrated by a study of the chemical hydrolysis of N-benzoyl-Gly-Phe (hippurylphenylalanine, 6.37) [67], a reference substrate for carboxypeptidase A (EC 3.4.17.1). In pH 9 borate buffer at 25°, the first-order rate constant for hydrolysis of the peptide bond ( chem) was 1-3 x 10-10 s-1, corresponding to a tm value of 168 y. This is a very slow reaction indeed, confirming the intrinsic stability of the peptide bond. Because the analytical method used was based on monitoring the released phenylalanine, no information is available on the competitive hydrolysis of the amide bond to liberate benzoic acid. 

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