Anilides hydrolysis

D. Petkov, E. Christova, and I. Stoineva (1978), Catalysis and leaving group binding in anilide hydrolysis by chymotrypsin. Biochim. Biophys. Acta 527, 131-141. 

Reflux Distillation Unit. The apparatus shown in Fig. 38 is a specially designed distillation-unit that can be used for boiling liquids under reflux, followed by distillation. The unit consists of a vertical water-condenser A, the top of which is fused to the side-arm condenser B. The flask C is attached by a cork to A. This apparatus is particularly suitable for the hydrolysis of esters (p. 99) and anilides (p. 109), on a small scale. For example an ester is heated under reflux with sodium hydroxide solution while water is passed through the vertical condenser water is then run out of the vertical condenser and passed through the inclined condenser. The rate of heating is increased and any volatile product will then distil over. 

Hydrolysis of Acetanilide. Anilides in general, such as acetanilide and benzanilide (p. 245), may be hydrolysed by caustic alkalis or by acids. Alkaline hydrolysis, however, is usually very slow, and therefore... 

Hydrolysis to p-Nitroaniline. For this purpose use 70 sulphuric acid, the usual reagent employed for the hydrolysis of anilides (p. 108). Add 5 g. of the recrystallised />-nitro-acetanilide to 30 ml. of 70%sulphuric acid, and boil the mixture gently under a reflux water-condenser for 20 minutes. Then pour the clear hot solution into about 150 ml. of cold water, and finally add an excess of sodium hydroxide solution until precipitation of the yellow p-nitroaniline is complete. Coo the mixture in ice-water if necessary, and then filter at the pump, wash well... 

Isocyanide reaction. Heat together gently 0 2 g. of the anilide, 3 ml. of ethanolic NaOH solution and i ml. of chloroform hydrolysis of the anilide occurs, and the odour of the isocyanide can be detected after about i minute s heating. [This test clearly differentiates an anilide of type R CONHC Hj from one of type R CO N(CH3)CeH5.]... 

Anilides and a-Naphthalides. The Grignard reagents prepared from alkyl halides react with phenyl isocyanate (CgHjN=C=0) or with a-uaphthy l isocyanate (C,oH, N=C=0) to yield addition products that are converted by hydrolysis into anihdes and a-naphthalides respectively RX + Mg —> RMgX... 

Benzoyl compounds are readily hydrolysed by heating with about 70 per cent, sulphuric acid (alkaline hydrolysis is very slow for anilides) ... 

Similar sulfenylation reactions of the 2-subsdtuted cyclic enamines of -keto carboxylic acid anilides are also possible, The trifluoromethanesulfenyl substitution takes place according to ring size Sulfenylation occurs at positions 2 and 5 with five-membered rings, at posibon 6 with six-membered tings, and at position 7 with seven-membered rings [5J (equation 4) (Table 1). Acid hydrolysis of the enamines proceeds readily to form the corresponding keto compounds. 

Toliiic anilide, on hydrolysis, forms toluic acid and aniline, whereas beii2oic toluide yields benzoic acid and toluidine. It follows therefoie that, in the original compound, the first contains the hydroxyl neaier the phenyl group and the second nearer the tolyl group. 

Enamines of cyclic ketones do not form cycloaddition products, but give the mono- or dicarboxanilides (110,111). Thus the enamine (113) on reaction with 1 equivalent of phenyl isocyanate gave 160. Treatment of 113 with 2 equivalents, or 160 with 1 equivalent, of phenyl isocyanate gave the 2,6-disubstituted product (161). Mild acid hydrolysis of 160 and 161 produced the corresponding cyclohexanone(2-mono- and 2,5-di)carbox-anilides (110). 

Trimethylacetic acid may be made by the hydrolysis of tert-butyl cyanide with weak hydrochloric acid at ioo0.1 It is also obtained by oxidation of trimethylpyroracemic acid with silver oxide or potassium dichromate and sulfuric acid,2 by oxidation of tertf-butylethylene with permanganate solution,3 or by oxidation of dimethyl 2,2-propanol with chromic acid.4 Schroeter reports the formation of trimethylacetic acid by rearrangement of the oxime of trimethylacetophenone to give the anilide of trimethylacetic acid, which can be hydrolyzed to give the acid.5... 

A(yl halides may be identified by —hydrolysis to the corresponding acids (the latter may be further characterised as in Section IV,175) conversion into amides (Section IV,191), anilides or p-toluidides (Section IV,100) and conversion into solid esters (Section IV,183). 

The oxidative formation of p-benzoquinones from anilides such as 7-108 was used for the synthesis of the core scaffold of the natural products elisabethin A (7-106) and pseudopterosin A aglycone (7-107) (Scheme 7.30). Exposure of anilide 7-108 to DMP [53] led to the formation of the o-imidoquinone 7-109, which underwent an intramolecular Diels-Alder reaction to give 7-110 in 28% yield after hydration. In a competitive pathway, the p-quinone 7-111 is also formed from 7-108, which on heating in toluene again underwent an intramolecular Diels-Alder reaction to give cycloadduct 7-112 in 25% overall yield. Hydrolysis of 7-112 furnished the carbocyclic skeleton 7-113 of elisabethin A (7-106). 

The nitrogen atoms of the twisted amides discussed on pages 107-108 are to a greater or lesser extent pyramidal, and incipient lone pairs electron density is thus available for reactions with electrophiles. The classic example is the cage lactam [57] first prepared by Pracejus (1959), which has an amide nitrogen with near normal amine basicity. Brown and coworkers have measured rates of alkaline hydrolysis of a series of anilides [58] and [59] with related structures and find that the rate increases with increasing divergence... 

At this point, we can integrate much of what has been discussed above in a single case study. Antibody NPN43C9 was reported in 1988 as the first example of catalysis of hydrolysis of an amide bond, in fact of an active anilide. Its structure and mode of action have been well studied (Janda et al., 1988b), which makes it an appropriate example for this purpose. 

Amide hydrolysis at alkaline pH involves a tetrahedral anionic intermediate, which was mimicked by the transition state analogue [49], an /V-aryl arylphosphonamidate, appropriately related to substrate anilide [50] (Fig. 18) (Appendix entry 2.8). 

Fig. 18 Antibody NPN43C9, raised against the phosphonamidate hapten [49], was capable of accelerating the hydrolysis of the anilide [50].

While ester, carbonate, carbamate and anilide hydrolyses have been catalysed effectively by antibodies, the difficult tasks of hydrolysis of an aliphatic amide or a urea remain largely unsolved. Much of this problem hinges on the fact that breakdown of a TF is the rate-determining step, as established by much... 

This subsection is devoted to the metabolic reactivity of the amide bond in anilides, i.e., compounds whose amino moiety is attached to an aromatic ring. Based on the nature of the acyl moiety, a number of classes of anilides exist, three of which are of particular interest here, namely arylacetamides, acylani-lides, and aminoacylanilides. The first group contains several analgesic-antipyretic drugs, the second A4-acyl derivatives of sulfonamides, and the third a number of local anesthetics. Particular attention will be paid to structure-metabolism relationships in the hydrolysis of these compounds. Cases where hydrolysis leads to toxification will be summarized in the last part of the chapter. 

Hydrolysis of the amide bond generally leads to inactivation of the substrate and accelerates excretion of the products. In the case of aminoacyl-anilides, however, such hydrolysis may represent a pathway of toxification, since it liberates aromatic amines, which are potentially hematotoxic, nephrotoxic, hepatotoxic, and/or carcinogenic. 

Having discussed amides that carry an aromatic group on either the nitrogen or the carboxy side of the amide bond (i.e., anilides or benzamides, respectively), we continue our presentation with compounds in which the amide bond links two aromatic systems. The simplest structure in this class is A-phenylbenzamide (4.154). The influence of the nature and position of substitution on the rate of hydrolysis of a series of A-phenylbenzamides was investigated in mouse and sheep liver homogenates, with the goal of elucidating the metabolism of the anthelminthic niclosamide (4.158) [102],... 

Dissolved metals and metal-containing surfaces play an important role in the transformation of organic contaminants in the subsurface environment. Metal ions can catalyze hydrolysis in a way similar to acid catalysis. Organic hydrolyzable compounds susceptible to metal ion catalysis include carboxylic acids, esters, amides, anilides, and phosphate-containing esters. Metal ions and protons... 

The naphthalene-catalyzed (3-12%) lithiation of deprotonated chloro phenols and anilides 236 performed with n-butylUthium in THF at 0 or —78 °C, respectively, gave the corresponding functionalized aryllithium intermediates 237 which, by reaction with electrophiles and final hydrolysis, yielded the corresponding polyfunctionalized molecules 238 (Scheme 79) . 

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