Acetylation using acetyl chloride

Anthralin [1143-38-0] is acetylated using acetyl chloride in toluene and a pyridine catalyst to furnish 1,8-dihydroxy-lO-acetylanthrone [3022-61-5], an intermediate in the preparation of medications used in treating skin disorders, such as warts, psoriasis, and acne (38). Sugar esters can be similarly prepared from acetyl chloride under anhydrous conditions (39). 

A number of electrophilic substitution reactions have been shown to take place in the cyclopentadiene ring of these cyclopentadienylidene derivatives, for example, bromination [187,190-192], acetylation using acetyl chloride and tin(lV) chloride [190-193], nitration using tetranitromethane [193] and diazocoupling [191,193]. Reaction takes place preferentially at the site next to the exocyclic bonding but may also take place at alternative sites, e.g.[190,191]... 

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... 

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. 

Transfer the reaction product to a 500 ml. Claisen flask and distil over a wire gauze or from an air bath. Some acetyl chloride and acetic acid passes over first, the temperature then rises, and the fraction, b.p. 150-200°, is collected separately run out the water from the condenser when the temperature reaches 150°. The fraction, b.p. 150-200°, solidifies on cooling. Drain off any hquid from the crystals as rapidly as possible, and redistil the solid using an air condenser. CoUect the fraction b.p. 182-192° this sets to a sohd mass on cooling and melts at 63°. The yield of monochloroacetic acid is 150-175 g. 

Acetyl chloride (111,86, J scale use 25 ml. distilling flask PCI3 may be added all at once and mixture then heated for 15 minutes at 40-50°). 

Alkoxythiazoles are prepared by heterocyclization (274, 462). The Williamson method using catalytic amounts of KI and cupric oxide is also possible (278. 288, 306). 5-Acetoxy-4-alkenylthiazoles are obtained by treatment of 242 with acetyl chloride and triethylamine or with acetic anhydride and pyridine (450). Similarly, the reaction of diphenylketene with 242 affords 5-acyloxy-4-alkenylthiazoles (243) (Scheme 120) (450). The readiness of these o-acetylations suggests that 4-alkylidene thiazoline-5-one might be in equilibrium with 4-alkenyl-5-hydroxythiazoles (450). 

The important chemical properties of acetyl chloride, CH COCl, were described ia the 1850s (10). Acetyl chloride was prepared by distilling a mixture of anhydrous sodium acetate [127-09-3J, C2H202Na, and phosphorous oxychloride [10025-87-3] POCl, and used it to interact with acetic acid yielding acetic anhydride. Acetyl chloride s violent reaction with water has been used to model Hquid-phase reactions. 

A fixed-bed reactor for this hydrolysis that uses feed-forward control has been described (11) the reaction, which is first order ia both reactants, has also been studied kiaeticaHy (12—14). Hydrogen peroxide interacts with acetyl chloride to yield both peroxyacetic acid [79-21-0] and acetyl peroxide... 

Although acetyl chloride is a convenient reagent for deterrnination of hydroxyl groups, spectroscopic methods have largely replaced this appHcation in organic chemical analysis. Acetyl chloride does form derivatives of phenols, uncompHcated by the presence of strong acid catalysts, however, and it finds some use in acetylating primary and secondary amines. 

Acetyl chloride can be used as a substitute for acetic anhydride in many reactions. Whereas the anhydride requites a mineral acid catalyst for acetylation, acetyl chloride does not. Acetyl chloride is utilized in a wide range of reactions wherein its comparatively high price is offset by convenience. Should its nominal cost be lowered, acetyl chloride would be a powerhil competitor for acetic anhydride in large scale manufacturing. 

Chloroacetyl chloride is manufactured by reaction of chloroacetic acid with chlorinating agents such as phosphoms oxychloride, phosphoms trichloride, sulfuryl chloride, or phosgene (42—44). Various catalysts have been used to promote the reaction. Chloroacetyl chloride is also produced by chlorination of acetyl chloride (45—47), the oxidation of 1,1-dichloroethene (48,49), and the addition of chlorine to ketene (50,51). Dichloroacetyl and trichloroacetyl chloride are produced by oxidation of trichloroethylene or tetrachloroethylene, respectively. 

The synthesis of 2,4-dihydroxyacetophenone [89-84-9] (21) by acylation reactions of resorcinol has been extensively studied. The reaction is performed using acetic anhydride (104), acetyl chloride (105), or acetic acid (106). The esterification of resorcinol by acetic anhydride followed by the isomerization of the diacetate intermediate has also been described in the presence of zinc chloride (107). Alkylation of resorcinol can be carried out using ethers (108), olefins (109), or alcohols (110). The catalysts which are generally used include sulfuric acid, phosphoric and polyphosphoric acids, acidic resins, or aluminum and iron derivatives. 2-Chlororesorcinol [6201-65-1] (22) is obtained by a sulfonation—chloration—desulfonation technique (111). 1,2,4-Trihydroxybenzene [533-73-3] (23) is obtained by hydroxylation of resorcinol using hydrogen peroxide (112) or peracids (113). 

Uses. The lowest member of this class, ketene itself, is a powerful acetylating agent, reacting with compounds containing a labile hydrogen atom to give acetyl derivatives. This reaction is used only when the standard acetylation methods with acetic anhydride or acetyl chloride [75-36-5] do not work weU. Most of the ketene produced worldwide is used in the production of acetic anhydride. Acetic anhydride is prepared from the reaction of ketene and acetic acid. 

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. 

Acylation. Reaction conditions employed to acylate an aminophenol (using acetic anhydride in alkaU or pyridine, acetyl chloride and pyridine in toluene, or ketene in ethanol) usually lead to involvement of the amino function. If an excess of reagent is used, however, especially with 2-aminophenol, 0,A/-diacylated products are formed. Aminophenol carboxylates (0-acylated aminophenols) normally are prepared by the reduction of the corresponding nitrophenyl carboxylates, which is of particular importance with the 4-aminophenol derivatives. A migration of the acyl group from the O to the N position is known to occur for some 2- and 4-aminophenol acylated products. Whereas ethyl 4-aminophenyl carbonate is relatively stable in dilute acid, the 2-derivative has been shown to rearrange slowly to give ethyl 2-hydroxyphenyl carbamate [35580-89-3] (26). 

Acid hahdes, eg, ben2oyl chloride, acetyl chloride, and ben2oyl bromide, have been used to prepare Si—Cl and Si—Br compounds from organosilanes. Acetyl chloride proceeds to higher yield when cataly2ed by aluminum chloride. 

Trityl Ethers. Treatment of sucrose with four molar equivalents of chlorotriphenylmethyl chloride (trityl chloride) in pyridine gives, after acetylation and chromatography, 6,1, 6 -tri-O-tritylsucrose [35674-14-7] and 6,6 -di-O-tritylsucrose [35674-15-8] in 50 and 30% yield, respectively (16). Conventional acetylation of 6,1, 6 -tri-O-tritylsucrose, followed by detritylation and concomitant C-4 to C-6 acetyl migration using aqueous acetic acid, yields a pentaacetate, which on chlorination using thionyl chloride in pyridine and deacetylation produces 4,l, 6 -trichloro-4,l, 6 -trideoxygalactosucrose [56038-13-2] (sucralose), alow calorie sweetener (17). 

Manufacture of 2-acetylthiophenes involves direct reaction of thiophene or alkylthiophene with acetic anhydride or acetyl chloride. Preferred systems use acetic anhydride and have involved iodine or orthophosphoric acid as catalysts. The former catalyst leads to simpler workup, but has the disadvantage of leading to a higher level of 3-isomer in the product. Processes claiming very low levels of 3-isomer operate with catalysts that are proprietary, though levels of less than 0.5% are not easily attained. 

More useful than the preceding methods is cleavage of alkoxides by acetyl chloride or bromide. One, two, three, or four alkoxyls can be replaced by chloride or bromide. Benzoyl chloride gives poor yields, however. The tri- and tetrachlorides, which are stronger Lewis acids than mono- and dichlorides, coordinate with the alkyl acetate formed and yield distillable complexes (46,55,56). 

Friedel-Crafts Acylation. The Friedel-Crafts acylation procedure is the most important method for preparing aromatic ketones and thein derivatives. Acetyl chloride (acetic anhydride) reacts with benzene ia the presence of aluminum chloride or acid catalysts to produce acetophenone [98-86-2], CgHgO (1-phenylethanone). Benzene can also be condensed with dicarboxyHc acid anhydrides to yield benzoyl derivatives of carboxyHc acids. These benzoyl derivatives are often used for constmcting polycycHc molecules (Haworth reaction). For example, benzene reacts with succinic anhydride ia the presence of aluminum chloride to produce P-benzoylpropionic acid [2051-95-8] which is converted iato a-tetralone [529-34-0] (30). 

Hydrolysis. 1,1,1-Trichloroethane heated with water at 75—160°C under pressure and in the presence of sulfuric acid or a metal chloride catalyst decomposes to acetyl chloride, acetic acid, or acetic anhydride (54). However, hydrolysis under normal use conditions proceeds slowly. The hydrolysis is 100—1000 times faster with trichloroethane dissolved in the water phase than vice versa. Refluxing 1,1,1-trichloroethane with ferric and gallium chloride... 

The second most important nucleophilic substitution in pyridazine A-oxides is the replacement of a nitro group. Nitro groups at the 3-, 4-, 5- and 6-position are easily substituted thermally with a chlorine or bromine atom, using acetyl chloride or hydrobromic acid respectively. Phosphorus oxychloride and benzoyl chloride are used less frequently for this purpose. Nitro groups in nitropyridazine A-oxides are easily replaced by alkoxide. The... 

Acylation of pyridazinethiones with acetyl chloride or benzoyl chloride gives the corresponding S-acylated products. 6-Mercaptopyridazine-3(2//)-thione gives either mono- or di-S-acylated products. A bispyridazinyl derivative is formed when phosgene or thiophos-gene is used as acylating agent. 

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