Acetyl chlorides

Acetyl chloride [75-36-5], C H OCl, mol wt 78.50, is a colodess, corrosive, irritating liquid that fumes in air. It has a stifling odor and reacts very rapidly with water, readily hydrolyzing to acetic acid and hydrochloric acid. As little as 0.5 parts per million activate the flow of tears, and often provoke a burning sensation in the eyes, nose, and throat. Acetyl chloride is toxic. Its high reactivity with hydroxyl, sulfhydryl, and amine groups leads to modifications that block the action of many important enzymes needed by living tissue. 

The common physical properties of acetyl chloride are given in Table 1. The vapor pressure has been measured (2,7), but the experimental difficulties are considerable. An equation has been worked out to represent the heat capacity (8), and the thermodynamic ideal gas properties have been conveniently organized (9). 

The important chemical properties of acetyl chloride, CH3COCl, were described in the 1850s (10). Acetyl chloride was prepared by distilling a mixture of anhydrous sodium acetate [127-09-3], C2H302Na, and phosphorous oxychloride [10025-87-3], POCl3, and used it to interact with acetic acid yielding acetic anhydride. Acetyl chloride s violent reaction with water has been used to model liquid-phase reactions. 

A fixed-bed reactor for this hydrolysis that uses feed-forward control has been described (11) the reaction, which is first order in both reactants, has also been studied kinetically (12—14). Hydrogen peroxide interacts with acetyl chloride to yield both peroxyacetic acid [79-21-0], C2H403, and acetyl peroxide [110-22-5], C4H604 (15). The latter is a very dangerous explosive. 

Reactions of acetyl chloride that are formally analogous to hydrolysis occur with alcohols, mercaptans, and amines primary or secondary compounds form corresponding acetates or amides tertiary alcohols generally yield the tertiary alkyl chlorides. Acetyl chloride can split the ether linkages of many ordinary ethers and acetals. It equilibrates with fatty acids to provide measureable amounts of the mixed acetic—alkylcarboxylic anhydride or acyl chloride, either of which may be employed in esterifications. For example, lauric acid [143-07-7], and acetyl chloride undeigo the reactions 

Some hydrogen chloride is evolved and small quantities of volatile phosphorus compounds are formed, due to such reactions as the following  

CH3COOH + PCI3 — CH3COOPCI2 + HCl 3CH3COOH + PCI3 — P(0C0CH3)3 + 3HC1 

These may be largely removed by redistilling from a small quantity of glacial acetic acid. 

Commercial preparations of acetyl chloride are best freed from volatile phos. phorus compounds and dissolved hydrogen chloride by redistillation from 5-10 per cent, of the volume of pure dimethylaniline. 

Very pure acid chlorides may be obtained by reaction between the anhydrous sodium salt of the acid and phosphorus oxychloride, for example  

Thionyl chloride. This reagent (b.p. 76°) is generally used in excess of the theoretical quantity it cannot be employed for acetyl chloride (b.p. 52°) because of the difficulty of separation by fractional distillation. Excellent results are obtained, however, with butyric acid and acids of higher molecular weight, for example  

The reason for using an excess of, say, 1 mol of thionyl chloride is to avoid anhydride formation  

Acetyl cliloiide reacts with aromatic hydrocarbons and olefins in suitably inert solvents, such as carbon disulfide or petroleum ether, to furnish ketones (16). These reactions are catalyzed by anhydrous aluminum cliloiide and by other inorganic chlorides (17). The order of catalytic activity increases in the order 

Acetyl cliloiide is manufactured commercially in Europe and the Far East. Some acetyl cliloiide is produced in the United States for captive applications such as acetylation of pharmaceuticals. 

Preparation of Acetyl Chloride (SECTION 274).—Connect a 200-cc. dry distilling flask with a separatory funnel and a condenser for use as a receiver, attach to the latter, by means of a 

Acetyl chloride boils at 51°. The experiment should yield about 40 grams. 

Properties of Acetyl Chloride (SECTION 275).—(a) Acetyl chloride and water.—Cautiously add about 0.5 cc. of acetyl chloride to 2 cc. of ice-water. Observe if two layers form, and then 

Acetyl chlotide is reduced by vatious organometaUic compounds, eg, LiAlH (18). / fZ-Butyl alcohol lessens the activity of LiAlH to form lithium tti-/-butoxyalumium hydtide [17476-04-9] C22H2gA102Li, which can convert acetyl chlotide to acetaldehyde [75-07-0] (19). Triphenyl tin hydtide also reduces acetyl chlotide (20). Acetyl chlotide in the presence of Pt(II) or Rh(I) complexes, can cleave tetrahydrofuran [109-99-9] C HgO, to form chlorobutyl acetate [13398-04-4] in about 72% yield (21). Although catalytic hydrogenation of acetyl chlotide in the Rosenmund reaction is not very satisfactory, it is catalyticaHy possible to reduce acetic anhydride to ethylidene diacetate [542-10-9] in the presence of acetyl chlotide over palladium complexes (22). Rhodium trichloride, methyl iodide, and ttiphenylphosphine combine into a complex that is active in reducing acetyl chlotide (23). 

Fit up the apparatus shown in Fig. 54. It consists of a distilling flask (250 C.C.), which is attached to a condenser. A small 

ilt miu (liloiidc tube. I lic (Ustniiuj vessel is jH ovidod. itli. 1 link, iluiPii h, 1 t.ij) funnel is inserted. The flrisk 

Coloiiiless liquid uitli a pilligeill smell it fumes II Mint.u I uith moist. ui ii. [i. sp. gr. rio at. to.  

To about i (.e. of ethyl. dcohol m a test tube, add i (.e. of. leetyl tliloiide drop liy drop, cooling under the tap. I licn 

Add two drops of acetyl chloride to a drop of aniline. A vigorous action occurs, and a solid separates. This is acetanilide, and may be obtained in larger crystals by dissolving in boiling water and cooling slowly. 

HIGHLY FLAMMABLE, CAUSES BURNS Physical Properties 

Colorless, fuming, volatile liquid with a pungent odor bp, 52°C.  

Flash point, 4°C ignition temperature, 390°C. Extinguish fire with dry chemical or carbon dioxide.2 

Violently decomposed by alcohol and rapidly decomposed by water with formation of hydrochloric acid and acetic acid. Miscible with benzene, chloroform, ether, glacial acetic acid, and petroleum ether. 3 

Dimethyl Sulfoxide. Dimethyl sulfoxide decomposes violently on contact with acetyl chloride.4 

Meth-Cohn, O. Suschitzky, H. In Advances in Heterocyclic Chemistry Katritzky, A. R. Boulton, J., Eds. Academic Press New York, 1972 Vol. 14, p 213. 

Purification HCl-free material can be prepared either by distillation from dimethylaniline or by standard degassing procedures.  

Handling, Storage, and Precautions acetyl chloride should be handled only in a well-ventilated fume hood since it is volatile and toxic via inhalation. It should be stored in a sealed container under an inert atmosphere. Spills should he cleaned up by covering with aq sodium bicarbonate.  

Analysis of Reagent Purity a GC assay for potency has been described to check qualitatively for the presence of HCl, a common impurity, add a few drops of a solution of crystal violet in chloroform a green or yellow color indicates that HCl is 

Friedel-Crafts Acetylation. Arenes undergo acetylation to afford aryl methyl ketones on treatment with acetyl chloride (AcCl) together with a Lewis acid, usually aluminum chlorides. This reaction, known as the Friedel-Crafts acetylation, is valuable as a preparative method because a single positional isomer is produced from arenes that possess multiple unsubstituted electron-rich positions in many instances. 

Apart from differences in the handling of these materials, their reactivity and applications are basically the same as that of their unlabeled counterparts. However, whereas synthetic organic chemists rarely consider synthesizing compounds that are so routinely available commercially, it is often important for isotope chemists to do so, whether for reasons of economy, timely availability, stability or simple expediency. Therefore, a selection of characteristic examples will be presented in the following sections. 

With appropriate reaction partners and conditions, [ C] acetyl chloride may be caused to react in situ inunediately after it is generated (e.g. sodium [ C]acetate, oxalyl chloride, dichloromethane 0°C, 3h or sodium [ C]acetate, phosphorus oxychloride, dichlor-omethane 0°C, 20 min 40 °C, 2h ). 

The less frequently used [ CJacetyl bromide is accessible similarly upon treatment of [ CJacetic acid with benzoyl bromide or phosphorus tribromide.  

While the preceding malonic ester synthesis enables elongation of the labeled acetyl carbon chain by two carbon atoms, extension by one carbon is achieved when [ C]acetyl chloride is treated with diazomethane followed by quenching of the resulting diazoketone with gaseous HCl. The product in this example, l-chloro[2- C]propan-2-one (3), may 

One of the most common uses of [ C]acetyl chloride is its Lewis acid- (AICI3, SnCLi) catalyzed Friedel-Crafts reaction with aromatic or heteroaromatic substrates to produce labeled aryl/heteroaryl methyl ketones. As these intermediates are subject to several types of transformations, they have been used as key intermediates for the synthesis of a wide variety of a,)8-functionalized aryl/heteroaryl alkyl target compounds. For example, aryl/ heteroaryl methyl ketones can be (a) halogenated in the methyl group to provide substrates for reaction with carbon or nitrogen nucleophiles, (b) deprotonated so as to react with appropriate electrophilic partners, (c) subjected to stereoselective carbonyl group reduction to alcohols, or (d) reduced to aryl/heteroaryl alkyls. Such transformations can be conducted sequentially in many combinations. 

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Acetylation will proceed particularly smoothly with acetyl chloride if pyridine is present to absorb the hydrogen chloride as fast as it is formed. 

Required Salicylic acid, 10 g. pyridine, 7 ml. acetyl chloride. 

Dissolve 10 g. of salicylic acid (o-hydroxybenzoic acid) in 7 ml. of dry pyridine contained in a too ml. conical flask. Then without delay (since this solution if allowed to stand tends to become a semi-solid mass) run in 7 5 ml. (8 3 g.) of acetyl chloride, adding about i ml. of the chloride at a time, and shaking the mixture continuously during the addition. The heat of the reaction causes the temperature of the mixture to rise rapidly ... 

Required Anhydrous sodium acetate, 21 g. acetyl chloride, IS ml. 

Add a few drops of the distillate to an aqueous silver nitrate solution containing some dilute nitric acid and warm gently no silver chloride should be precipitated, indicating the complete absence of unchanged acetyl chloride. 

TTie true ketones, in which the >CO group is in the side chain, the most common examples being acetophenone or methyl phenyl ketone, C HjCOCH, and benzophenone or diphenyl ketone, C HjCOC(Hj. These ketones are usually prepared by a modification of the Friedel-Crafts reaction, an aromatic hydrocarbon being treated with an acyl chloride (either aliphatic or aromatic) in the presence of aluminium chloride. Thus benzene reacts with acetyl chloride... 

Required Aluminium chloride, 30 g. benzene, 75 ml. acetyl chloride, 20 ml. 

Required Aluminium chloride, 3 g. benzene, 7 5 mi. acetyl chloride, 2 ml. 

Acyl halides, both aliphatic and aromatic, react with the sodium derivative, but the product depends largely on the solvent used. Thus acetyl chloride reacts with the sodium derivative (E) suspended in ether to give mainly the C-derivative (t) and in pyridine solution to give chiefly the O-derivative (2). These isomeric compounds can be readily distinguished, because the C-derivative (1) can still by enolisation act as a weak acid and is therefore... 

The p-methylacetophenone is readily prepared by the Friedel-Crafts reaction cf. p. 254), toluene being treated with acetyl chloride in the presence of alumfnium chloride. The toluene is employed in considerable excess so that it... 

METHYLACETOPHENONE. Required Toluene, 250 ml. acetyl chloride, 35 ml. aluminium chloride, 40 g. 

Acetyl chloride, benzoyl chloride (and substituted derivatives). 

Physical properties. Colourless liquids when pure, benzoyl chloride, CjHjCOCl, is frequently pale yellow. Acetyl chloride, CH3COCI, has a pungent odour, fumes in moist air and is immediately hydrolysed by cold water. Benzoyl chloride also has a pungent odour, is lachry matory, and is hydrolysed only slowly by cold water, in which it is insoluble. 

N.B. In all these reactions acetyl chloride reacts with much greater vigour than the other compounds, and accordingly tests with this substance must be carried out toith extreme care. 

Action of silver nitrate. Acidify 2 ml. of aqueous AgNOj solution with dil. HNO3 and add the acid chloride drop by drop with shaking. Acetyl chloride and benzoyl chloride give a precipitate of AgCl. Filter, wash with water, and then with methylated spirit to remove any benzoic acid the AgCl remains. 

Anilides, (a) To 1 ml. of aniline in a small conical flask add very slowly and carefully about i ml. of acetyl chloride. A vigorous reaction occurs and a solid mass is formed. Add just sufficient water (about 15 ml.) to dissolve the solid completely on boiling. On cooling, crystals of acetanilide separate out filter and determine the m.p. 

Pungent odour. Formic acid, acetic acid, acetyl chloride, acetic anhydride, benzoyl chloride, benzyl chloride, pyridine. Benzoquinone (when warmed with water). 

Method 1. Use the apparatus depicted iu Fig. Ill, 56, 1, but omit the thermometer also attach a cotton wool (or calcium chloride) tube to the side arm of the filter fiask receiver in order to prevent the entrance of moisture into the apparatus. Mount the reaction fiask in a water bath e.g., a large beaker or other convenient vessel). It is important that all the apparatus be perfectly dry, since both phosphorus trichloride and acetyl chloride are decomposed by water. The set-up should be assembled in the fume eupboard. 

Treat the distillate with 2 drops of glacial acetic acid (to destroy the phosphorus esters present) and redistil using the same apparatus as before except that the separatory funnel is replaced by a thermometer. Collect the liquid which passes over at 50-56°. Transfer the acetyl chloride to a weighed glass-stoppered bottle (since cork and rubber stoppers are attacked) and determine the weight. The yield is 22 g. 

Carry out the following simple experiments with acetyl chloride (compare Section 111,86). 

Acetyl chloride Sodium acetate Acetic anhydride... 

An equivalent result may be obtained by treating excess of sodium acetate with phosphorus oxychloride acetyl chloride is an intermediate product and the final result is ... 

By dehydration with acetyl chloride, acetic anhydride or with phosphotus oxychloride, for example ... 

Method A. In a 500 ml. round-bottomed flask, fitted with a reflux condenser attached to a gas trap (Fig. II, 13, 8), place 59 g. of succinic acid and 117-5 g. (107-5 ml.) of redistilled acetyl chloride. Reflux the mixture gently upon a water bath until all the acid dissolves (1-2 hours). Allow the solution to cool undisturbed and finally cool in ice. Collect the succinic anhydride, which separates in beautiful crystals, on a Buchner or sintered glass funnel, wash it with two 40 ml. portions of anhydrous ether, and dry in a vacuum desiccator. The yield of succinic anhydride, m.p. 118-119°, is 47 g. 

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