Acetanilide, chlorination

N-chlorination of amides, although it can be observed (Mauger and Soper, 1946), is very much slower than amine chlorination and is not likely to occur under normal water treatment conditions. N-Methylacetamide reacts more than a million times slower than ammonia (Morris, 1967). The unreactivity of the N-H bond in amides is further illustrated by the fact that acetanilide chlorinates at the ring 4-position rather than the amide nitrogen (Houben and Weyl, 1962). 

Acetanilide, p-chloro-acetanilide, 2,5-dichloro-acetanilide Apply sample solution and treat with chlorine vapor in the trough chamber for 20 s, then heat to 60°Cfor 5 min in a ventilated drying cupboard. Various chlorination patterns are produced. [44]... 

The presence of acetanilide in these residues may be confirmed by boilin the residue for two to three minutes with HCl, and when cool, adding a few drops of 0 5 per cent, of chlorinated lime solution, in such a manner that the liquids do not mix. A fine blue colour results if acetanilide be present. 

Acetanilide has been used medicinally as a pain-killing zene, which is chlorinated as a first step. Reaction of remedy. chlorobenzene with base gives phenol ... 

Addition of up to a tenfold molar excess of hydrogen chloride did not appreciably alter the reaction rate. Orton and Bradfield227 obtained the same kinetic form for the chlorination of formanilide, acetanilide, benzanilide, and benzene-sulphonanilide in 99 % aqueous acetic acid at 20 °C reaction rates were higher than previously obtained with the less aqueous medium, and this medium effect has been subsequently found to be general. 

De la Mare and Hassan254 obtained second-order rate coefficients (in parenthesis) for the following 4-methylacetanilide (1.53), 2-methylacetanilide (0.193), 2,6-dimethylacetanilide (0.0118), acetanilide (0.93), 4-acetamidodiphenyl (0.248) and 1,4-diacetamidobenzene (0.231) the results for the acetanilides demonstrated the effect of steric hindrance to coplanarity thereby inhibiting resonance of the nitrogen lone pair with the aromatic ring. The rate coefficients for chlorination of 3-chloroacetanilide (0.215), 4-chloroacetanilide (0.010) 3-nitroacetanilide (6.7 x 10 5) and phenyl benzoate (3.2 x 10-6) have also been measured258,261. 

Chlorinated anilines are produced by the hydrolysis of a range of acetanilide, urea, and carbamate herbicides, and are therefore widely distributed in agricultural soils. Mechanisms for their loss... 

A limited number of pure substances are available from NIST, primarily clini-cally-relevant compounds such as cholesterol, urea, uric acid, creatinine, glucose, cortisol, tripalmitin, and bilirubin (NIST SRM website). These compounds are certified for purity (greater than 99 %) and are used as primary calibrants in definitive methods for these clinical analytes (see below). Several additional pure substances are available for specific applications such as microchemistry, i.e. elemental composition (acetanilide, anisic acid, cystine nicotinic acid, o-bromobenzoic acid, p-fluoro-benzoic acid, m-chlorobenzoic acid), polarimetric standards (sucrose and dextrose), acidimetric standard (benzoic acid and boric acid). Only three pure substance NIST RMs are available for environmental contaminants, namely the chlorinated pesticides, lindane, 4,4 -DDT, and 4,4 -DDE. 

Scheme 11.2 shows some representative halogenation reactions. Entries 1 and 2 involve Lewis acid-catalyzed chlorination. Entry 3 is an acid-catalyzed chlorination using NCS as the reagent. Entry 4 shows a high-yield chlorination of acetanilide by i-butyl hypochlorite. This seems to be an especially facile reaction, since anisole is not chlorinated under these conditions, and may involve the A-chloroamide as an intermediate. Entry 5 describes a large-scale chlorination done with NCS. The product was used for the synthesis of sulamserod, a drug candidate. 

TMBA-ICI4 (1.3 g, 3.1 mmol) is added to the acetanilide (3.1 mmol) in AcOH (30 ml) and the mixture is stirred for 24 h at room temperature. The precipitated TMBA-ICI2 is collected and the filtrate is evaporated under vacuum. The residue is washed with NaHSO, (5%, 10 ml), NaHCO, (5%, 15 ml) and extracted with CH.CI, (3 x 20 ml). The organic extracts are filtered through A120, and evaporated to yield the chlorinated acetanilide. 

The electrochemical cyclization reaction is less successful with the N-(3-phenylallyl)acetanilide 60 which has two potential bond cleavage sites from the radical-anion [173]. Carbon-nitrogen bond cleavage with loss of a 3-phenylallyl radical, leaving an amide nitrogen anion, is favoured over carbon-chlorine bond cleavage. 

It of interest to note that the isobutyl group may also be replaced by a heterocyclic ring. The route to this compound, pirprofen (51-6), starts with the direct methylation of unesterihed 4-nitrophenylacetic acid (51-1). The observed selectivity for monoalkylation in this case may reside in the structure of the dianion, whose most stable form is presumably that depicted in (51-2). Catalytic reduction of the product (51-3) gives the corresponding aniline this is then converted to its acetanilide (51-4) with acetic anhydride. Treatment with chlorine followed by hydrolysis gives the chloroaniline (51-5). Double alkylation of this last intermediate with 1,4-dichloro-but-2-ene (depicted as the cis isomer for aesthetic reasons) forms the dihydropyrrole ring. There is thus obtained the NSAID pirprofen (51-6) [52]. 

Acylation of the amino substituent decreases the rate of bromination by 1010 (Robertson et al., 1953). Acetanilide is, accordingly, somewhat more readily studied. The partial rate factors for bromination, chlorination, and mercuration are presented in Table 4. 

Hassan (1958) have determined the relative rates of chlorination in the two positions of para-substituted acetanilides (33) for the assignment of TOfh, m HAc and mf (42). A similar approach was employed with para-... 

Aniline, 4,4 -azodi-, 40,18 Aniline, reaction with hexachloroace-tone to form a,reaction with maleic anhydride, 41,94 o-Anisaldehyde, 44, 4 Anisoin, reduction to deoxyanisoin by tin and hydrochloric add, 40, 16 Anthracene, chlorination by cupric chloride, 43,15... 

Bhattacharjee369, who has brominated acetanilide suspended in aqueous solution of potassium bromide and hydrogen peroxide in presence of vanadium pent oxide catalyst. Chloroperoxidase has been mimicked using supported manganese phorphyrin catalyst in the oxychlorination of dimedone370 and by clay-supported iron(III) chloride in the oxy-chlorination of toluene and anisole371. The kinetics and mechanism of the haloper-oxidases have been studied extensively372,373. 

Microsolvent effects in the cyclodextrin cavity have also been observed in hypochlorite chlorination of acetophenone1029. Higher para selectivity has been observed in the bromination of acetanilide and benzanilide in presence of cyclodextrins or amylose1030 and in the anodic chlorination of anisole with cyclodextrin-modified electrode1031. 

The direct chlorination or bromination of aniline takes place more easily than that of benzene, the result being the symmetrical tri-chlor or tri-brom aniline, viz., i-amino 2-4-6-tri-chlor benzene, C6H2CI3-(NH2) and I-amino 2-4-6-tri-brom benzene, CeH2Br3(NH2). The mono-halogen anilines are prepared by reducing mono-chlor nitro benzenes, or by halogenating acetanilide and then hydrolyzing. 

Elemental analysis of duplicate samples of econazole nitrate was performed using a Perkin-Elmer 2400 CBN analyser. Approximately 3-mg quantities of material were combusted and measured against an acetanilide standard. The chlorine determination was based on oxygen flask combustion followed by titration against mercuric perchlorate which had been standardized against sodium chloride and chlorobenzoic acid. The oxygen content of the samples was calculated by difference. 

Scheme 15 Pd(II)-catalyzed copper-promoted ortho-chlorination of acetanilide...

Chlorination of the acetanilide by chlorine then occurs rapidly. In the transition state there is a reduction of polarity due to the partial cancellation of positive and negative charges, and consequently a decreased interaction with the solvent. Hence both reactants and... 

---