4-Nitroacetanilide, hydrolysis

Treating aniline with acetic anhydride, or refluxing together aniline with glacial acetic acid, yields acetanilide (21). Nitration with mixed acids affords p-nitroacetanilide hydrolysis of the acetyl group gives p-nitroaniiine (15b). 

Prepared by heating p-nitrochlorobenzene with concentrated aqueous ammonia in an autoclave at 170°C. It is also prepared by alkaline hydrolysis of p-nitroacetanilide or by nitrating and hydrolysing benzylideneaniline. 

The basic hydrolysis of p-nitroacetanilide is retarded by a-CD, whereas that of trifluoroacetanilide and its m-nitro derivative is modestly enhanced... 

Protection of the amino group by acetylation, as in acetanilide, therefore usually permits monosubstitution reactions with appropriate electrophilic reagents to proceed smoothly. Thus with bromine, p-bromoacetanilide is the main product the small quantity of the ortho isomer simultaneously formed can be easily eliminated by recrystallisation (Expt 6.67) hydrolysis of p-bromoacetanilide gives p-bromoaniline. Nitration leads similarly to p-nitroacetanilide which can be hydrolysed to p-nitroaniline (Expt 6.68). 

Hydrolysis of p-nitroacetanilide. Boil a mixture of 15 g (0.083) of p-nitroacetanilide and 75 ml of 70 per cent w/w sulphuric acid (3) under a reflux condenser for 20-30 minutes or until a test sample remains clear upon dilution with 2-3 times its volume of water. The p-nitroaniline is now present in the liquid as the sulphate. Pour the clear hot solution into 500 ml of cold water and precipitate the p-nitroaniline by adding excess of 10 per cent sodium hydroxide solution or of concentrated ammonia solution. When cold (cool the mixture in ice-water, if necessary), filter the yellow crystalline precipitate at the pump, wash it well with water and drain thoroughly. Recrystallise it from a mixture of equal volumes of rectified (or industrial) spirit and water or from hot water. Filter, wash and dry. The yield of p-nitroaniline, m.p. 148 °C, is 11 g (96%). 

An example of the first type is represented by the hydrolysis of acyl derivatives of />-nitrophenol or />-nitroaniline (77). Because 7>-nitrophenyl acetate or -nitroacetanilide are reduced in alkaline media with consumption of four electrons, whereas the reduction of -nitrophenol and p- nitroaniline involves six electrons, the increase in the limiting current can be used to study the rate of hydrolysis. 

Khmer [2] found that acetanilide when nitrated also yields o- nitroacetanilide, from which o- nitroaniline may be obtained by hydrolysis. The nitration of acetanilide... 

Nitroacetanilides, obtained by alkaline hydrolysis of l-arylamino-l-methylthio-2-nitroethenes, are readily cyclised to isatin-3-oximes by the use of concentrated sulfuric acid or trifluoromethanesulfonic acid at room temperature the latter giving somewhat higher yields. Although this methodology is related to the Sandmeyer methodology, it has no obvious benefit over the latter (Scheme 7). 

Dinitro-4, 4 -diamino-azobenzene, H2N.(02N).C(5H3.N N.C6H3(N02).NH2 red plates or orn ndls (from phenol + ethanol), rap 340-41° was obtd by hydrolysis with H2SO4 of 4, 4 -diacetamido-3, -dinitro-azobenzene, itself obtd by coupling of 2-nitro-4-nitrosoacetanilide 4-amino-2-nitroacetanilide in acetic acid (Ref 2)... 

Amide hydrolysis is a key step in the widespread strategy of protection/deprotection of amino groups for synthetic purposes, usually carried out in homogeneous phase with mineral acids. It is shown here that under mild conditions (batch reactor, liquid phase, 75°C) large pore zeolites (HY, HBeta, HMOR) can catalyse the hydrolysis of various aromatic amides. The best results are obtained over HY zeolite samples with Si/Al ratios of 16 and 30 e.g. complete and selective hydrolysis of 2-nitroacetanilide after 2-4 hours reaction for a zeolite/substrate ratio of 0.5 g/mmol. For similar values of the Si/Al ratio HBeta and rather all HMOR samples are much less active than HY samples, which is probably related to diffusion limitations. 

In this study protonated large pore zeolites of different structures (HY, HBeta and HMordenite) and framework Si-to-Al ratios were used in liquid phase in a batch reactor. The zeolites were calcined at 500°C and the hydrolysis was conducted at 75°C. The procedure was optimised in terms of solvent, activation, type and amount of catalyst for the hydrolysis of nitroacetanilides, currently carried out with 10 % sulphuric acid [14], and then extended to other substituted amides. The reaction, followed by GC with nitrobenzene as internal standard, was clean and no by-products or degradation were detected. 

The influence of the solvent was studied for the hydrolysis of 2-, 3- and 4-nitroacetanilide using an HY zeolite (Si/Al=30) as catalyst. From Table 1 it can be seen that the reaction rate was higher when a mixture of methanol-water (1 1) was used as solvent than with methanol or with water separately. The slower hydrolysis rate in water, when compared to methanol or to methanol-water, can be explained by the lower solubility of the aromatic amides. The hydrolysis in the presence of methanol could be due to the small amounts of water present in the commercial synthesis grade methanol used. While this is enough to accomplished the reaction, methanolysis cannot be ruled out. 

Hydrolysis of nitroacetanilides with HY zeolite (Si/Al=30) (2 g/mmol) in different solvents... 

It can be emphasized that be the hydrolysis of 2-nitroacetanilide is slower with HY zeolite (100 %, 5.5 h) than with a 10 % H2SO4 solution (100 %, 45 min.) [14]. However the work-up with solid acid catalyst was much easier and after washing and calcination, the used HY catalyst exhibite little loss in activity when compared to the fresh catalyst, hence can be reused (Table 1). 

Figure 1. Conversion-time plots for the hydrolysis of 2-nitroacetanilide in MeOH H20 (1 1) with activated (o) and non activated (A) HY zeolite (Si/Al=30) (2 g/mmol).

Figure 2. Hydrolysis of 2-nitroacetanilide with different amounts of HY zeolite (SVA1=30) in a 2 h run.

Figure 3 compares the conversion-time plots for the hydrolysis of 2-nitroacetanilide over zeolites with different pore structures (HY, HBeta and HMOR) and different framework Si/Al ratios. 

For acetylcholinesterase, it is thought that the protonated imidazole of His acts as a general-acid to assist departure of aniline during hydrolysis of anilide substrates. Based on analysis of the isotope effect in light and heavy water, it was estimated that departure of o-nitroaniline during hydrolysis of o-nitroacetanilide is accompanied by a modest solvent isotope near 1.5, supporting the general-acid role of ImH+-His ° [19]. 

The hydrolysis rate of poly (ortho esters) can be further manipulated by a combination of hydrophilicity and the use of diols that contain a pendant carboxylic acid, such as 9,10-dihydroxystearic acid [36]. Figure 16 shows the release of a marker compound p-nitroacetanilide from a hydrophobic matrix prepared from a 60/40 mole ratio of frans-cyclohexanedimethanol and 1,6-hexanediol containing varying amounts of 9,10-dihydroxystearic acid. While there is a noticeable effect, it is relatively minor. However, when the hydrophilicity of the matrix is increased by using a 60/10/30 mole ratio of trans-cyclohexanedimethanol, 1,6-hexanediol and triethylene glycol, the effect of 9,10-dihydroxystearic acid is greatly magnified, as shown in Fig. 17. 

Nitrodiphenylamine 542 3-Nitroacetanilide (12 g) and bromobenzene (21 g) are dissolved in nitrobenzene and treated with potassium carbonate (5 g). The mixture is heated at 180° for 10 h with addition of small amounts of potassium iodide and copper powder, then gradually at up to 210° during a further 8 h. Steam-distillation leaves behind a brown oil that becomes viscous on cooling. After separation of the aqueous layer the oil is dissolved in ethanol, filtered, and, for hydrolysis, boiled for 3 h with concentrated hydrochloric acid (20-25 ml). Then adding water precipitates 3-nitrodiphenylamine as a brown oil that rapidly crystallizes (11.3 g, 80%). Recrystallization from ethanol gives brick-red crystals, m.p. 112°. 

Nitration of acetanilide gives />-nitroacetanilide in excellent yield with only a trace of the ortho isomer. Acidic hydrolysis of />-nitroacetanilide (Section 18.8F) removes the acetyl group and gives y>-nitroaniline, also in good yield. 

Table 11.2 Inhibition of the micellar catalysis of the hydrolysis of 4-nitroacetanilide...

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