Halides acyl

Acyl halides are among the most reactive of carboxylic acid derivatives. Acyl chlorides are more common and less expensive than bromides or iodides. They can be prepared from acids by reaction with thionyl chloride. 

An acyl halide is a carboxylic acid derivative in which the —OH group is replaced by a halogen atom. 

The mechanism is similar to that for the formation of chlorides from alcohols and thionyl chloride. The hydroxyl group is converted to a good leaving group by thionyl chloride, followed by a nucleophilic acyl substitution in which chloride is the nucleophile (compare with Sec. 7.10). Phosphorus pentachloride and other reagents can also be used to prepare acyl chlorides from carboxylic acids. 

Acyl halides react rapidly with most nucleophiles. For example, they are rapidly hydrolyzed by water. 

For this reason, acyl halides have irritating odors. Benzoyl chloride (eq. 10.35), for 

Acyl halides are invaluable acylating reagents and their preparation is therefore of great importance. The conversion of an aliphatic carboxylic acid into the corresponding acyl chloride is usually achieved by heating the acid with thionyl chloride. 

This reagent is particularly convenient as the by-products of the reaction do not contaminate the product, and excess thionyl chloride is usually separable by fractional distillation. If the boiling point of the acyl chloride is too near to that of thionyl chloride the excess of the latter can be destroyed by the addition of pure formic acid. 

Phosphorus trichloride and phosphorus pentachloride are also suitable reagents for acid chloride formation, but their use is largely restricted to aromatic carboxylic acids. (Section 6.14.1, p. 1073). 

Experiment 5.138 BUTYRYL CHLORIDE (Butanoyl chloride) Me-(CH)2)2-C02H + SOCl2 ------- Me-(CH2)2-COCl + S02 + HC1 

Fit a 100-ml two-necked flask with a dropping funnel and a reflux condenser connected at the top to a gas absorption trap (Fig. 2.61). Place 36g (21.5ml, 0.3 mol) of redistilled thionyl chloride in the flask and 22 g (23 ml, 0.25 mol) of butyric acid in the separatory funnel. Heat the flask gently on a water bath, and add the butyric acid during the course of 30-40 minutes (1). When all the acid has been introduced, heat on a water bath for 30 minutes. Rearrange the apparatus and distil collect the crude acid chloride boiling between 70 and 110 °C. Finally, redistil from a flask provided with a short fractionating column and collect the butyryl chloride at 100-101 °C. The yield is 23 g (86%). 

The addition of various modifiers, such as quinoline-sulfitr, thiourea, 52 or, especially, tetramethylthiourea 53 to the reaction mixture, is sometimes necessary in order to inhibit the further hydrogenation of the aldehyde. This is particularly true for the formation of aryl aldehydes that are hydrogenated over palladium under mild conditions. 54.155 barium sulfate support is, itself, a moderate inhibitor and is generally sufficient for regulating the preparation of unsubstituted aliphatic aldehydes. However, if another support, such as charcoal, is used for the palladium, one of the standard inhibitors must be added to moderate the reaction. When these added inhibitors are present, the 

High yields of aromatic aldehydes have been obtained by the hydrogenolysis of the acid chlorides over Pd/C at room temperature and atmospheric pressure in ethyl acetate containing some ethyl di-iso-propylamine (Eqn. 20.65). 56 

Thionyl chloride reacts with carboxylic acids in the way as shown in the scheme below. In the first step the reaction yields HCl and the intermediate benzoyl chlorosulfonate  

Benzoyl chlorosulfonate immediately rearranges into the acyl chloride (benzoyl chloride in our example) and SO2. This reaction is an interesting example of internal nucleophilic substitution. The internal nucleophile is the chlorine atom (it is electron-rich) which attacks the carbonyl carbon. The final products are benzoyl chloride and SO2. 

The nomenclature of acyl halides is simple. Their names are deduced from the name of the constituent acid with the suffix -yl or -oyl and the name of the halide. 

Methanoyl chloride (Formyl chloride) Ethanoyl bromide (Acetyl bromide) Propanoyl chloride 

Like thionyl chloride, acyl halides are sensitive to moisture and quickly hydrolyze into the corresponding carboxylic acid and HCl. This is an example of the nucleophilic substitution at the unsaturated carbon with H2O as the nucleophile. 

Kinetic studies of the alcoholysis of /3,/3-dimethylacryloyl chloride (49) with 14 alcohols in benzene at a reactant ratio of 1 1 have shown that the reaction probably proceeds via a charge-transfer complex. Reaction rates at high pressures (200, 500 and 1000 bar) of the reaction between a series of quinolines and benzoyl chloride in MeCN have been determined, together with those with 4-methyl- and 4-nitro-benzoyl chloride. Rate constants increased with increasing pressure, and it was concluded that those reactions proceed via an associative 5 n2 mechanism.  

For the methanolyses in MeCN at 25.0 °C of benzoyl chloride and 11 para- or mete-substituted derivatives (50), the kinetics of methyl ester (51) formation have 

The specific rates of solvolysis of methyl chloroformate, MeOCOCl, are very well correlated by the extended Grunwald-Winstein equation over a wide range of solvents the pathway is believed to be predominantly addition-elimination, except that a positive deviation for solvolysis in 90% l,l,l,3,3,3-hexafiuoropropan-2-ol suggests an 80% contribution from an ionization mechanism.  

Kinetic studies on the reactions of X-phenyl chloroformates (52) with Y-pyridines in MeCN showed that the electron-rich formate moiety (O—C=0) overlaps with the pyridine tt-system, allowing rate-limiting formation of a tetrahedral intermediate. A similar conclusion was made following kinetic studies of the reactions of secondary alicyclic amines with phenyl (52 X = H) and 4-nitrophenyl chloroformate (52 X = 4-NO2) in aqueous solution, but the results for the aminolysis (anilines) of the same substrates in MeCN were considered to be more consistent with a concerted process.  

Kinetic studies at 15 and 25 °C of the solvolysis of a series of substituted phenyl chloroformates (52 X = OMe, Me, H, Cl, NO2) in MeOH, MeOD, H2O, D2O and 50% D20-Me0D have shown that the reaction proceeds via an associative 5n2 and/or a general-base-catalysed addition-elimination (SaN) mechanism.  

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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 conversion of an aliphatic carboxylic acid into the a-bromo- (or a-chloro ) acid by treatment with bromine (or chlorine) in the presence of a catal3rtic amount of phosphorus tribromide (or trichloride) or of red phosphorus is known as the Hell-Volhard-Zelinsky reaction. The procedure probably involves the intermediate formation of the acyl halide, since it is known that halogens react more rapidly with acyl haUdes than with the acids themselves ... 

The mechanism of acylation with acyl halides is usually regarded as involving the acyl cation (acyl carbonium or acylium ion) ... 

The liquid phosphorus oxychloride, b.p. 107°, is a by-product and is removed by fractional distillation under normal pressure. Unless the b.p. of the acid chloride differs very considerably (say, <] 100°) from that of the phosphorus oxychloride, the acyl halide is liable to contain traces of the latter. In such circumstances it is preferable to use thionyl chloride for the preparation of the acid chloride. 

By the reaction between a solution of an acyl halide in a dry organic solvent, such as toluene, with a cold solution of sodium peroxide, for example ... 

My early work with acyl fluorides also involved formyl fluoride, ITCOF, the only stable acyl halide of formic acid, which was first made in 1933 by Nyesmeyanov, who did not, however, pursue its chemistry. 1 developed its use as a formylating agent and also explored formyla-tion reactions with CO and HF, catalyzed by BF3. 

Aromatic acyl halides and sulfonyl halides undergo oxidative addition, followed by facile elimination of CO and SO2 to form arylpalladium complexes. Benzenediazonium salts are the most reactive source of arylpalladium complexes. 

Acyl halides react with organometallic reagents without catalysts, but sometimes the Pd-catalyzed reactions give higher yields and selectivity than the Lincatalyzed reactions. Acyl halides react with Pd(0) to form the acylpalladium complexes 846, which undergo facile transmetallation. 

The Pd-catalyzed hydrogenoiysis of acyl chlorides with hydrogen to give aldehydes is called the Rosenmund reduction. Rosenmund reduction catalyzed by supported Pd is explained by the formation of an acylpalladium complex and its hydrogenolysis[744]. Aldehydes can be obtained using other hydrides. For example, the Pd-catalyzed reaction of acyl halides with tin hydride gives aldehydes[745]. This is the tin Form of Rosenmund reduction. Aldehydes are i ormed by the reaction of the thio esters 873 with hydrosilanes[746,747]. 

The reaction of benzoyl chloride with (Me3Si)2 affords benzoyltrimethylsi-lane (878)[626,749,750]. Hexamethyldigermane behaves similarly. The siloxy-cyclopropane 879 forms the Pd homoenolate of a ketone and reacts with an acyl halide to form,880. The 1,4-diketone 881 is obtained by reductive elimination of 880 without undergoing elimination of /7-hydrogen[751]. 

Acyl halides are intermediates of the carbonylations of alkenes and organic-halides. Decarbonylation of acyl halides as a reversible process of the carbo-nylation is possible with Pd catalyst. The decarbonylation of aliphatic acid chlorides proceeds with Pd(0) catalyst, such as Pd on carbon or PdC, at around 200 °C[109,753]. The product is a mixture of isomeric internal alkenes. For example, when decanoyl chloride is heated with PdCF at 200 C in a distillation flask, rapid evolution of CO and HCl stops after I h, during which time a mixture of nonene isomers was distilled off in a high yield. The decarbonylation of phenylpropionyl chloride (883) affords styrene (53%). In addition, l,5-diphenyl-l-penten-3-one (884) is obtained as a byproduct (10%). formed by the insertion of styrene into the acyl chloride. Formation of the latter supports the formation of acylpalladium species as an intermediate of the decarbonylation. Decarbonylation of the benzoyl chloride 885 can be carried out in good yields at 360 with Pd on carbon as a catalyst, yielding the aryl chloride 886[754]. 

The reduction of acyl halides with hydrogen to form aldehydes using Pd catalyst is well known as the Rosenmund reduction[756]. Some acyl chlorides give decarbonyiation products rather than aldehydes under Rosenmund conditions. The diene 890 was obtained by decarbonyiation in an attempted Rosenmund reduction of acetyloleanolic acid chloride (889)[757], Rosenmund reduction of sterically hindered acyl chlorides such as diphenyl- and tnpheny-lacetyl chloride (891) gives the decarbonylated products 892[758],... 

The acylpalladium complex formed from acyl halides undergoes intramolecular alkene insertion. 2,5-Hexadienoyl chloride (894) is converted into phenol in its attempted Rosenmund reduction[759]. The reaction is explained by the oxidative addition, intramolecular alkene insertion to generate 895, and / -elimination. Chloroformate will be a useful compound for the preparation of a, /3-unsaturated esters if its oxidative addition and alkene insertion are possible. An intramolecular version is known, namely homoallylic chloroformates are converted into a-methylene-7-butyrolactones in moderate yields[760]. As another example, the homoallylic chloroformamide 896 is converted into the q-methylene- -butyrolactams 897 and 898[761]. An intermolecular version of alkene insertion into acyl chlorides is known only with bridgehead acid chlorides. Adamantanecarbonyl chloride (899) reacts with acrylonitrile to give the unsaturated ketone 900[762],... 

One type of o-aminobenzyl anion synthon is a mixed Cu/Zn reagent which can be prepared from o-toluidines by / i.s-trimethylsilylation on nitrogen, benzylic bromination and reaction with Zn and CuCN[l]. Reaction of these reagents with acyl halides gives 2-substituted indoles. 

The simplest procedures for 2-acylation involve reaction of an jV-protected 2-lithioindole with an acyl halide, anhydride or ester. Such reactions typically give good yields of 2-acylindoles. Table 10.3 presents some examples. Aryl... 

Friedel-Crafts acylation An analogous reaction occurs when acyl halides react with benzene in the presence of alumi num chloride The products are acylben zenes... 

Another version of the Friedel-Crafts reaction uses acyl halides instead of alkyl halides and yields aryl ketones... 

The organic halide that reacts with the arene must be an alkyl halide (Section 12 6) or an acyl halide (Section 12 7)... 

Vinylic halides and aryl halides do not form carbocations under conditions of the Friedel-Crafts reaction and so cannot be used in place of an alkyl halide or an acyl halide... 

Rearrangement is especially prevalent with primary alkyl halides of the type RCH2CH2X and R2CHCH2X Aluminum chloride induces ionization with rearrangement to give a more stable carbocation Benzylic halides and acyl halides do not rearrange... 

Acyl halides are named by placing the name of the appropriate halide after that of the acyl group... 

Although acyl fluorides bromides and iodides are all known classes of organic com pounds they are encountered far less frequently than are acyl chlorides Acyl chlorides will be the only acyl halides discussed m this chapter... 

After acyl halides acid anhydrides are the most reactive carboxylic acid derivatives Three of them acetic anhydride phthahc anhydride and maleic anhydride are mdus trial chemicals and are encountered far more often than others Phthahc anhydride and maleic anhydride have their anhydride function incorporated into a nng and are referred to as cyclic anhydrides... 

Acyl Halides. Acyl halides, in which the hydroxyl portion of a carboxyl group is replaced by a halogen, are named by placing the name of the corresponding halide after that of the acyl radical. When another group is present that has priority for citation as principal group or when the acyl halide is attached to a side chain, the prefix haloformyl- is used as, for example, in fiuoro-formyl-. 

Appaiendy a molai equivalent of catalyst (AlCl ) combines with the acyl halide, giving a 1 1 addition compound, which then acts as the active acylating agent. Reaction with aromatics gives the AlCl complex of the product ketone hberating HX ... 

Cyclo acylations leadUy take place in intermoleculai acylations involving bifunctional acylating agents. Both functional groups may be acyl (as in the case of a,CO-diacyl halides) or one may be an alkylating group (as in unsaturated acyl halides or certain haloacyl halides) (18). 

Using a,P-unsaturated acyl halides, alkenes are acylated to give a,P,a, P -unsaturated ketones, which undergo spontaneous intramolecular Na2arov cyclizations to cyclopentenones, important precursors of natural products (173). 

Carboxylic acid hydiazides are prepared from aqueous hydrazine and tfie carboxylic acid, ester, amide, anhydride, or halide. The reaction usually goes poody with the free acid. Esters are generally satisfactory. Acyl halides are particularly reactive, even at room temperature, and form the diacyl derivatives (22), which easily undergo thermal dehydration to 1,3,4-oxadiazoles (23). Diesters give dihydtazides (24) and polyesters such as polyacrylates yield a polyhydrazide (25). The chemistry of carboxyhc hydrazides has been reviewed (83,84). 

Addition to Carbonyl Compounds. Unlike Grignard and alkykitliium compounds, trialkylboranes are inert to carbonyl compounds. The air-catalyzed addition to formaldehyde is exceptional (373). Alkylborates are more reactive and can transfer alkyl groups to acyl halides. The reaction provides a highly chemoselective method for the synthesis of ketones (374). 

Reaction with Acyl Halides. Acyl halides react at loom tempeiatuie with mono- and dialkanolamines to give amides (10,11). 

Mixed aiihydiosulfides can be leaddy obtained by adding an acetone solution of the xanthate to an acetone solution of the acyl halide at —35 C (53) ... 

Acyl halides may also be added to ethylene ia the presence of aluminum chloride to form halogenated ketones. At low temperatures, ethylene reacts with halogens to yield dihaloethanes. At high temperatures, trichloroethylene and perchloroethylene are formed. The most profitable route for chloroethylene is via ethylene dichloride (see Chlorocarbonsandchlorohydrocarbons). 

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