Chloride Acyl halides

Reaction of thiols or thiolates with acyl halides, chlorides in particular, represents the standard method for preparing thiol carboxylic esters (c/. ref. 33 and the literature cited therein). Since thiols ate strong nucleophiles, the acylation even takes place in the absence of base. However, to obtain excellent yields under mild conditions, tertiary amines are added or metal (Si, Sn, T1 Cu ) derivatives of the thiols are used. The following examples demonstrate the scope of the method. 

The hydride is an excellent reagent for drying bydrocaibons, ethers (inclwling dioxane and tetrahydroftirane), amines (including pyridine), esters, the butanols (but not methanol or ethanol, which form alkoxides). Since the hydride is an effective condensation catalyst, it should not be used to dry aldriiydes, reactive ketones, acids, or acyl halides. Chlorides and bromides should be dried over calcium hydride only at moderate temperatures. 

A variety of preactivated acyl derivatives has been developed for peptide bond formation. These include acyl halides [chlorides [66], fluorides [67,68]], acyl azides [69,70], active esters [e.g., pentafluorophenyl (OPfp) [71], o-nitrophenyl (ONp) [72], 3,4-dihydro-4-oxo-l,2,3-benzotriazin-3-yl (ODhbt) [73]], mixed anhydrides [3], and symmetrical anydrides [74,75]. 

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 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. 

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],... 

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... 

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... 

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... 

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). 

With Acyl Halides, Hydrogen Halides, and Metallic Halides. Ethylene oxide reacts with acetyl chloride at slightly elevated temperatures in the presence of hydrogen chloride to give the acetate of ethylene chlorohydrin (70). Hydrogen haUdes react to form the corresponding halohydrins (71). Aqueous solutions of ethylene oxide and a metallic haUde can result in the precipitation of the metal hydroxide (72,73). The haUdes of aluminum, chromium, iron, thorium, and zinc in dilute solution react with ethylene oxide to form sols or gels of the metal oxide hydrates and ethylene halohydrin (74). 

Pyrrole and alkylpyrroles can be acylated by heating with acid anhydrides at temperatures above 100 °C. Pyrrole itself gives a mixture of 2-acetyl- and 2,5-diacetyl-pyrrole on heating with acetic anhydride at 150-200 °C. iV-Acylpyrroles are obtained by reaction of the alkali-metal salts of pyrrole with an acyl halide. AC-Acetylimidazole efficiently acetylates pyrrole on nitrogen (65CI(L)1426). Pyrrole-2-carbaldehyde is acetylated on nitrogen in 80% yield by reaction with acetic anhydride in methylene chloride and in the presence of triethylamine and 4-dimethylaminopyridine (80CB2036). 

Triazoles are acylated with acyl halides, usually initially at the 1-position, but the acyl group may migrate to the 2-position on heating or on treatment with base. Thus acetylation with acetyl chloride often gives 1-acetyl derivatives, which rearrange to the 2-isomers above 120 °C (74AHCil6)33). 

There are alternatives to the addition-elimination mechanism for nucleophilic substitution of acyl chlorides. Certain acyl chlorides are known to react with alcohols by a dissociative mechanism in which acylium ions are intermediates. This mechanism is observed with aroyl halides having electron-releasing substituents. Other acyl halides show reactivity indicative of mixed or borderline mechanisms. The existence of the SnI-like dissociative mechanism reflects the relative stability of acylium ions. 

The formation of acyl halide-Lewis acid complexes have been observed by several methods. For example, both 1 1 and 1 2 complexes of acetyl chloride, with AICI3 can be observed by NMR spectroscopy. The existence of acylium ions has been demonstrated by X-ray diffraction studies on crystalline salts. For example, crystal structure determinations have been reported for /i-methylphenylacylium and acetylium ions as SbFg salts. There is also a good deal of evidence from NMR measurements which demonstrates that acylium ions can exist in nonnucleophilic solvents. " The positive charge on acylium ions is delocalized onto the oxygen atom. This delocalization is demonstrated in particular by the short O—C bond lengths in acylium ions, which imply a major contribution from the structure having a triple bond ... 

Acylation of various oxygen functions by use of common and commercially available fluonnated carboxylic acid denvatives such as trifluoroacetic anhydride or the corresponding acyl halides have already been discussed sufficiently in the first edition [10] Therefore only exceptional observations will be described in this section In the past 15 years, many denvatizations of various nonfluonnated oxygen compounds by fluoroacylation were made for analytical purposes. Thus Mosher s acid chlorides for example became ready-to-use reagents for the determination of the enantiomeric purity of alcohols and amines by NMR or gas-liquid chromatographic (GLC) techniques [//] (equation 1)... 

Codeposition of silver vapor with perfluoroalkyl iodides at -196 °C provides an alternative route to nonsolvated primary perfluoroalkylsilvers [272] Phosphine complexes of trifluaromethylsilver are formed from the reaction of trimethyl-phosphme, silver acetate, and bis(trifluoromethyl)cadmium glyme [755] The per-fluoroalkylsilver compounds react with halogens [270], carbon dioxide [274], allyl halides [270, 274], mineral acids and water [275], and nitrosyl chloride [276] to give the expected products Oxidation with dioxygen gives ketones [270] or acyl halides [270] Sulfur reacts via insertion of sulfur into the carbon-silver bond [270] (equation 188)... 

In the first step, 2-chloro-4-aminobenzoyl chloride hydrochloride is prepared by refluxing a mixture of 25 cc of purified thionyl chloride and 10 g of 2-chloro-4-aminobenzoic acid until all of the solid has gone into solution. To the cooled solution is added 150 cc of dry ethyl ether. A brisk stream of dry hydrogen chloride is passed into the solution until the precipitation of 2-chloro-4-aminobenzoyl chloride hydrochloride is complete. The acyl halide is removed by filtration and dried in a vacuum desiccator. 

Brown and Jensen395 suggested that the rate equation (194) for the reaction of benzene with excess benzoyl chloride could be interpreted according to the mechanisms given by the reactions (201) and (202), (203) and (204) and (205) and (206) which refer to nucleophilic attack of the aromatic upon the polarised acyl halide-catalyst complex, upon the free acylium ion, and upon an ion pair derived from the acyl halide-catalyst complex, viz. 

Virtually any alkyl or acyl halide capable of undergoing bimolecular nucleophilic replacement may enter into the Arbusov reaction. The usual reactivity sentence is acyl > primary alkyl > secondary alkyl with a sequence of halides iodide > bromide > chloride. There is some excellent literature on the Arbusov reaction which has been summarized in several reviews [6,22, 74, 78-82],... 

Dialkyl phosphites react with acyl halides such as lauroyl chloride to yield surface-active acid esters of acylphosphonic acid [84-87] see Eq. (40). 

Acyl halides can also be converted to carboxylic acids by using ethers instead of alcohols, in MeCN in the presence of certain catalysts such as cobalt(II) chloride. ... 

The scope of this reaction is similar to that of 10-21. Though anhydrides are somewhat less reactive than acyl halides, they are often used to prepare carboxylic esters. Acids, Lewis acids, and bases are often used as catalysts—most often, pyridine. Catalysis by pyridine is of the nucleophilic type (see 10-9). 4-(A,A-Dimethylamino)pyridine is a better catalyst than pyridine and can be used in cases where pyridine fails. " Nonbasic catalysts are cobalt(II) chloride " and TaCls—Si02. " Formic anhydride is not a stable compound but esters of formic acid can be prepared by treating alcohols " or phenols " with acetic-formic anhydride. Cyclic anhydrides give monoesterified dicarboxylic acids, for example,... 

Imides can be prepared by the attack of amides or their salts on acyl halides, anhydrides, and carboxylic acids or esters. The best synthetic method for the preparation of acyclic imides is the reaction between an amide and an anhydride at 100°C catalyzed by H2S04. When acyl chlorides are treated with amides in a2 l molar ratio at low temperatures in the presence of pyridine, the products are N,N-diacylamides, (RCO)3N. ... 

Tertiary alkyl azides can be prepared by stirring tertiary alkyl chlorides with NaN3 and ZnCl2 in 82 ° or by treating tertiary alcohols with NaN3 and CF3-COOH or with HN3 andTiCl4 or BF3. Acyl azides, which can be used in the Curtius reaction (18-14), can be similarly prepared from acyl halides, anhydrides, " esters, or other acyl derivatives. ° Acyl azides can also be prepared... 

These reactions are most important for the preparation of acyl fluorides. " Acyl chlorides and anhydrides can be converted to acyl fluorides by treatment with polyhydrogen fluoride-pyridine solution" or with liquid HF at — 10°C. Formyl fluoride, which is a stable compound, was prepared by the latter procedure from the mixed anhydride of formic and acetic acids. Acyl fluorides can also be obtained by reaction of acyl chlorides with KF in acetic acid or with DAST. Carboxylic esters and anhydrides can be converted to acyl halides other than fluorides by the inorganic acid halides mentioned in 10-77, as well as with PhsPXa (X = Cl or but this is seldom done. Halide exchange can be carried out in a... 

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