Amines acetic anhydride

One disadvantage of using acetic anhydride is that with primary amines, traces of the diacctyl compound, RN(COCH3)2, niay be formed the chances of this secondary acetylation are, however, usually remote, and recrystallisation from an aqueous solvent will generally hydrolyse the diacetyl derivative rapidly back to the mono-acetyl compound. 

Some amines, e.g., aniline, can on the other hand be readily acetylated by dissolving them in cold dil. acetic acid and adding acetic anhydride the method is not however general. 

Although the acetylation of alcohols and amines by acetic anhydride is almost invariably carried out under anhydrous conditions owing to the ready hydrolysis of the anhydride, it has been shown by Chattaway (1931) that phenols, when dissolved in aqueous sodium hydroxide solution and shaken with acetic anhydride, undergo rapid and almost quantitative acetylation if ice is present to keep the temperature low throughout the reaction. The success of this method is due primarily to the acidic nature of the phenols, which enables them to form soluble sodium derivatives, capable of reacting with the acetic... 

Acetylation. Place 1 ml. of the substance (or, if solid, i g. of the powdered amine) in a small flask fitted with a reflux condenser (or in a test-tube fitted with a cold-finger, as in Fig. 35, p. 62), add 5 ml. of an acetic anhydride-acetic acid mixture (equal volumes) and reflux... 

Acetyl derivatives of aromatic amines may be prepared either witli acetic anhydride or acetic acid or with a mixture of both reagents. Primary amines react readily upon warming with acetic anhydride to yield, in the first instance, the mono-acetyl derivative, for example ... 

In general, however, the diacetyl derivatives are unstable in the presence of water, undergoing hydrolysis to the mono-acetyl compound, so that when they (or a mixture of mono- and di-acetyl derivatives) are crystallised from an aqueous solvent, e.g., dilute alcohol, only the mono-acetyl derivative is obtained. A further disadvantage of the use of acetic anhydride in the absence of a solvent is that all the impm-ities in the amine are generally present in the reaction product. Heavily substituted amines, t.g., 2 4 6-tribromoaniline, react extremely slowly with acetic anhydride, but in the presence of a few drops of concentrated sulphuric acid as catalyst acetylation occurs rapidly, for example ... 

The disadvantages attending the use of acetic anhydride alone are absent when the acetylation is conducted in aqueous solution according to the following procedure. The amine is dissolved in water containing one equivalent of hydrochloric acid, slightly more than one equivalent of acetic anhydride is added to the solution, followed by enough sodium acetate to neutralise the hydrochloric acid, and the mixture is shaken. The free amine which is liberated is at once acetylated. It must be pointed out that the hydrolysis of acetic anhydride at room temperature is extremely slow and that the free amine reacts much more readily with the anhydride than does the water this forms the experimental basis for the above excellent method of acetylation. 

Acetyl derivatives. Primary and secondary amines are best acetylated with acetic anhydride ... 

Certain ortho substituted derivatives of aromatic amines are difficult to acetylate under the above conditions owing to steric hindrance. The process is facilitated by the addition of a few drops of concentrated sulphuric acid (compare Section IV,47), which acts as a catalyst, and the use of a large excess of acetic anhydride. 

Excellent results may be obtained by conducting the acetylation in aqueous solution (cf. Section IV,45). Dissolve 0-5 g. of the amine in 2N hydrochloric acid, and add a little crushed ice. Introduce a solution of 5 g. of hydrated sodium acetate in 25 ml. of water, followed by 5 ml. of acetic anhydride. Shake the mixture in the cold until the smell of acetic anhydride disappears. Collect the solid acetyl derivative, and recrystallise it from water or dilute alcohol. 

Acetates. The acetates of monohydric phenols are usually liquids, but those of di and tri-hydric phenols and also of many substituted phenols are frequently crystaUine sohds. They may be prepared with acetic anhydride as detailed under Amines, Section IV,100,7. 

The quinaldine is separated from any unreacted aniline and from the alkyl-anilines by treatment with acetic anhydride, basified with sodium carbonate and steam distilled. Only the primary and secondary amines are acetylated the acetylated amines are now much less volatile so that separation from the steam-volatile quinaldine (a tertiary amine) is facile. 

Phenols, unlike amines, cannot be acetylated satisfactorily in aqueous solution acetylation proceeds readily with acetic anhydride in the presence of a little concentrated sulphuric acid as catalyst. Salicylic acid (o-hydroxy-benzoic acid) upon acetylation yields acetylsalicylic acid or aspirin ... 

Acetylation of the amine may also be effected by boiling with 20 ml. of glacial acetic acid and 14 ml. of acetic anhydride for 15-20 minutes, followed by decomposition of the excess of anhydride with water and, after boiling for 5 minutes, poirring with stirring into about 75 ml. of water the product is appreciably coloured. 

Anhydrides may often be hydrolysed in the cold with dilute alkali they also react with primary amines (compare Section 111,94). All anliydrides boil above 130° thus acetic anhydride has b.p. 140°. 

It will be observed that the reaction involves two equivalents of the amine and produces, in addition to the substituted amide, an equivalent quantity of the amine hydrochloride. Acetic anhydride, on the other hand, converts the amine quantitatively into the acyl derivative, for example ... 

For this reason, acetic anhydride is generally preferred for the preparation of acetyl derivatives, but acetyl chloride, in view of its greater reactivity, is a better diagnostic reagent for primary and secondary amines. 

Unusual cyclocarbonylation of allylic acetates proceeds in the presence of acetic anhydride and an amine to afford acetates of phenol derivatives. The cinnamyl acetate derivative 408 undergoes carbonylation and Friedel-Crafts-type cyclization to form the a-naphthyl acetate 410 under severe condi-tions[263,264]. The reaction proceeds at 140-170 under 50-70 atm of CO in the presence of acetic anhydride and Et N. Addition of acetic anhydride is essential for the cyclization. The key step seems to be the Friedel-Crafts-type cyclization of an acylpalladium complex as shown by 409. When MeOH is added instead of acetic anhydride, /3,7-unsaturated esters such as 388 are... 

Reaction with ammonia and amines (Section 20 14) Acid an hydrides react with ammonia and amines to form amides Two molar equivalents of amine are required In the example shown only one acyl group of acetic anhydride becomes incor porated into the amide the other becomes the acyl group of the amine salt of acetic acid... 

Acetic anhydride is a useful solvent in certain nitrations, acetylation of amines and organosulfur compounds for mbber processing, and in pesticides. Though acetic acid is unexceptional as a fungicide, small percentages of anhydride in acetic acid, or in cold water solutions are powerful fungicides and bactericides. There are no reports of this appHcation in commerce. It is possible that anhydride may replace formaldehyde for certain mycocidal apphcations. 

Acylation. Aliphatic amine oxides react with acylating agents such as acetic anhydride and acetyl chloride to form either A[,A/-diaLkylamides and aldehyde (34), the Polonovski reaction, or an ester, depending upon the polarity of the solvent used (35,36). Along with a polar mechanism (37), a metal-complex-induced mechanism involving a free-radical intermediate has been proposed. 

Isomer separation beyond physical fractional crystallization has been accompHshed by derivatization using methyl formate to make /V-formyl derivatives and acetic anhydride to prepare the corresponding acetamides (1). Alkaline hydrolysis regenerates the analytically pure amine configurational isomers. 

The N-oxide function has proved useful for the activation of the pyridine ring, directed toward both nucleophilic and electrophilic attack (see Amine oxides). However, pyridine N-oxides have not been used widely ia iadustrial practice, because reactions involving them almost iavariably produce at least some isomeric by-products, a dding to the cost of purification of the desired isomer. Frequently, attack takes place first at the O-substituent, with subsequent rearrangement iato the ring. For example, 3-picoline N-oxide [1003-73-2] (40) reacts with acetic anhydride to give a mixture of pyridone products ia equal amounts, 5-methyl-2-pyridone [1003-68-5] and 3-methyl-2-pyridone [1003-56-1] (11). 

Nitrile Intermediates. Most quaternary ammonium compounds are produced from fatty nitriles (qv), which are ia turn made from a natural fat or oil-derived fatty acid and ammonia (qv) (Fig. 2) (see Fats AND FATTY oils) (225). The nitriles are then reduced to the amines. A variety of reduciag agents maybe used (226). Catalytic hydrogenation over a metal catalyst is the method most often used on a commercial scale (227). Formation of secondary and tertiary amine side-products can be hindered by the addition of acetic anhydride (228) or excess ammonia (229). In some cases secondary amines are the desired products. 

Other Rea.ctlons, The anhydride of neopentanoic acid, neopentanoyl anhydride [1538-75-6] can be made by the reaction of neopentanoic acid with acetic anhydride (25). The reaction of neopentanoic acid with acetone using various catalysts, such as titanium dioxide (26) or 2irconium oxide (27), gives 3,3-dimethyl-2-butanone [75-97-8] commonly referred to as pinacolone. Other routes to pinacolone include the reaction of pivaloyl chloride [3282-30-2] with Grignard reagents (28) and the condensation of neopentanoic acid with acetic acid using a rare-earth oxide catalyst (29). Amides of neopentanoic acid can be prepared direcdy from the acid, from the acid chloride, or from esters, using primary or secondary amines. 

Catalytic hydrogenation of the nitrile function of cyanohydrins can give amines. As in the case of ordinary nitriles, catalytic reduction of cyanohydrins can yield a mixture of primary, secondary, and tertiary amines. Addition of acid or acetic anhydride to the reaction medium minimizes formation of secondary or tertiary amines through formation of the amine salt or acetamide derivative of the primary amine. 

A Methylanthrapyridone and Its Derivatives. 6-Bromo-3-methylanthrapyridone [81-85-6] (75) is an important iatermediate for manufacturiag dyes soluble ia organic solvents. These solvent dyes are prepared by replacing the bromine atom with various kiads of aromatic amines. 6-Bromo-3-methylanthrapyridone is prepared from 1-methyl amino-4-bromoanthra quin one (43) by acetylation with acetic anhydride followed by ring closure ia alkaU. The startiag material of this route is anthraquiaoae-l-sulfonic acid (16). 

However, this method is appHed only when esterification cannot be effected by the usual acid—alcohol reaction because of the higher cost of the anhydrides. The production of cellulose acetate (see Fibers, cellulose esters), phenyl acetate (used in acetaminophen production), and aspirin (acetylsahcyhc acid) (see Salicylic acid) are examples of the large-scale use of acetic anhydride. The speed of acylation is greatiy increased by the use of catalysts (68) such as sulfuric acid, perchloric acid, trifluoroacetic acid, phosphoms pentoxide, 2inc chloride, ferric chloride, sodium acetate, and tertiary amines, eg, 4-dimethylaminopyridine. 

The simplest method for acetamide preparation involves reaction of the amine with acetic anhydride or acetyl chloride with or without added base. Some other methods are listed below. 

Purification as their N-acetyl derivatives is satisfactory for primary, and to a limited extent secondary, amines. The base is refluxed with slightly more than one equivalent of acetic anhydride for half to one hour, cooled and poured into ice-cold water. The insoluble derivative is filtered off, dried, and recrystallised from water, ethanol, aqueous ethanol or benzene (CAUTION toxic ). The derivative can be hydrolysed to the parent amine by refluxing with 70% sulfuric acid for a half to one hour. The solution is cooled, poured onto ice, and made alkaline. The amine is steam distilled or extracted as above. Alkaline hydrolysis is very slow. 

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