Preparation of Acyl Chlorides

Because they are readily available from a number of synthetic reactions, carboxylic acids are the most common starting materials for the preparation of the other members of this family. Conversion of a carboxylic acid to an acyl chloride provides access to any of the other derivatives because the acyl chloride is at the top of the reactivity scale. Bui how can the acyl chloride be prepared from the acid when the acid is lower on the reactivity scale This can be accomplished by using an even more reactive compound to drive the equilibrium in the desired direction. The reagent that is employed in the vast majority of cases is thionyl chloride, SOCl2. Phosphorus trichloride, PC13, and phosphorus pentachloride, PC15, are also used occasionally. Examples are provided in the following equations  

Q Thionyl chloride reacts like an acyl chloride. In this step, its sulfur-oxygen double bond plays the role of the carbonyl group of an acyl chloride. The nucleophile, the oxygen of the carboxylic acid, attacks the sulfur and displaces the pi electrons onto the oxygen. 

This compound is a mixed anhydride of the carboxylic acid and sulfurous acid and is more reactive than the acyl chloride. 

Mechanism of the reaction of a carboxylic acid with thionyl chloride. 

The major use for acyl chlorides is as starting materials for the preparation of the other carboxylic acid derivatives. Acyl fluorides, bromides, and iodides could potentially be employed to prepare the other derivatives also. However, because they offer no advantages over the acyl chlorides, they are seldom used. 

---

This preparation illustrates the use of phosphorus pentachloride for the preparation of acyl chlorides in this case no difficulty is experienced in separating the 3,5-dinitrobenzoyl chloride from the phosphorus oxychloride formed simultaneously (c/. p. 240), because the former is readily isolated as a crystalline... 

The acylation of hydrogen chloride by imidazolides is especially of interest for the preparation of acyl chlorides that cannot be prepared, or can only be prepared with difficulty, due to their instability. A distinguished example is the preparation of formyl chloride by this route ... 

The reagents and methods employed for coupling in solid-phase synthesis are the same as for synthesis in solution, but a few are excluded because they are unsuitable. The mixed-anhydride method (see Section 2.6) and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (see Section 2.15) are not used because there is no way to eliminate aminolysis at the wrong carbonyl of the anhydride. Acyl azides (see Section 2.13) are too laborious to make and too slow to react. The preparation of acyl chlorides (see Section 2.14) is too complicated for their routine use this may be rectified, however, by the availability of triphosgene (see Section 7.13). That leaves the following choices, bearing in mind that a two to three times molar excess of protected amino acid is always employed. 

Difficult N-acylations, such as those of A-alkylanilines or a-alkylamino acid derivatives, are most conveniently performed with acyl halides in non-nucleophilic solvents (e.g. DCM, DCP) in the presence of pyridine or DIPEA [13]. Acyl halides can be prepared on insoluble supports under conditions similar to those used in solution. Typical reagents for the preparation of acyl chlorides include oxalyl chloride [19-21], thionyl chloride [22,23], and triphosgene [13]. Anhydrous solvents must be used for all wash-... 

RCOH + S0C12 RCC1 Preparation of acyl chlorides. Acyl chlorides are commonly... 

Cyanuric chloride has been used for the preparation of acyl chlorides, amides, and peptides. Conversion of cyanuric chloride into 2-chloro-4,6-dimethoxy-l,3,5-triazine (CDMT, 6) leads to a reagent that upon reaction with carboxylic acids produces the highly reactive 2-acyloxy-4,6-dimethoxy-l,3,5-triazines.P l The resulting active ester is a powerful acylating agent for alcohols and amines. The activation is performed in presence of a base, preferentially NMM, which leads to intermediate formation of 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM, 7)P l (Scheme 5). This addition product is readily prepared from the commercially available CDMT (6) and NMM in THF and can be stored as solid compound in the cold.P P l It offers the advantage that it can be used in a one-... 

Thionyl chloride (39) in the presence of a few drops of DMF (catalyst) is a valuable reagent for the conversion of sulfonic acids (31) into the sulfonyl chlorides (32) (Scheme 32). This resembles the well-known reaction of thionyl chloride with carboxylic acids for the preparation of acyl chlorides, and has the advantage that both the by-products are gaseous. 

Preparation of Acyl Chlorides.—Acetyl chloride and its homologues may be prepared by the action of phosphorus pentachloride on the fatty acids or their salts —... 

A new resin-supported chlorinating reagent 289, based on CC, has been developed and used in the facile preparation of acyl chlorides (Scheme 54). Compared to the conventional synthesis of acyl chlorides using thionyl or oxalyl chloride, the solid-phase methodology is odorless, and the handling process is very convenient since purification can be affected by simple filtration <2002TL8909>. 

Another interesting strategy to achieve a waste-minimized Mizoroki-Heck reaction was recently reported by Miura et al. (Scheme 7.13) [31]. Using aroyl chlorides 57, the Mizoroki-Heck reaction proceeded well under base-free conditions, liberating only hydrochloric acid and carbon monoxide as byproducts (57 59). However, due to the particularly waste-intensive preparation of acyl chlorides, it remains questionable whether this procedure would be suitable for large-scale alkene arylation. 

Chlorination of alcohols by Thionyl Chloride the preparation of acyl chlorides from lactones and anhydrides, and the bromi-nation and iodination of aromatic rings by Benzyltrimethylammo-nium Tribromide and Benzyltrimethylammonium Dichloroio-date, respectively, are all effectively catalyzed by the presence of ZnCl2. In addition, ZnCl2 acts as a source of chloride for the halogenation of primary, secondary, and allylic alcohols using Triphenylphosphine-DiethylAzodicarboxylate. ... 

The acylstannanes 874 and 875 are prepared by the reaction of acyl chlorides with (MciSnl - The symmetrical 1,2-diketones 877 can be prepared by the reaction of an excess of benzoyl chloride with (EtjSn) . Half of the benzoyl chloride is converted into the benzoyltin reagent 876, which is then coupled with the remaining benzoyl chloride under a CO atmosphere to afford the a-diketone 877[748], Triethyl phosphite is used as a ligand. 

This chapter concerns the preparation and reactions of acyl chlorides acid anhydrides thioesters esters amides and nitriles These com pounds are generally classified as carboxylic acid derivatives and their nomenclature is based on that of carboxylic acids... 

Diazoketones that are readily prepared from acyl chlorides and diazomethane [92] also undergo a variety of fluorination reactions... 

What combination of acyl chloride or acid anhydride and arene would you choose to prepare each of the following compounds by Friedel-Crafts acylation ... 

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... 

Ketones can also be prepared from acyl chlorides by reaction at low temperature using an excess of acyl chloride. Tetrahydrofuran is the preferred solvent.91 The reaction conditions must be carefully controlled to prevent formation of tertiary alcohol by addition of a Grignard reagent to the ketone as it is formed. 

All monomers, surfactants, buffers, and chain transfer agents were used as provided. Water was deionized. Purchased organic peroxides were all reagent grade. Organic peroxides were prepared from the reaction products of acyl chlorides and sodium peroxide. Activity was determined by iodometric titration. 

Treatment of acyl chlorides with dialkylcadmium, prepared by the... 

Catalytic hydrogenation is hardly ever used for this purpose since the reaction by-product - hydrogen chloride - poses some inconveniences in the experimental procedures. Most transformations of acyl chlorides to alcohols are effected by hydrides or complex hydrides. Addition of acyl chlorides to ethereal solutions of lithium aluminum hydride under gentle refluxing produced alcohols from aliphatic, aromatic and unsaturated acyl chlorides in 72-99% yields [5i]. The reaction is suitable even for the preparation of halogenated alcohols. Dichloroacetyl chloride was converted to dichloro-... 

Nowadays, the most economical way of preparing hydroxamic acid derivatives is the reaction of hydroxylamine with acid chlorides or esters . Unfortunately, the preparation of acid chlorides is often tedious. In addition, it is very difficult to avoid further acylation during the reaction with hydroxylamine. 

Acylation of ester enolates can also be carried out with more reactive acylating agents such as acid anhydrides and acyl chlorides. These reactions must be done in inert solvents to avoid solvolysis of the acylating agent. The preparation of diethyl benzoylmalonate (entry 1 in Scheme 2.14) is an example employing an acid anhydride. Entries 2-5 illustrate the use of acyl chlorides. Acylations with these more reactive compounds can be complicated by competing O-acylation. /V-Mcthoxy-iV-methylamidcs are also useful for acylation of ester enolates. 

The alkynyl ketones 840 can be prepared by the reaction of acyl chlorides with terminal alkynes. Cul in the presence of Et3N is the cocatalyst[719]. (1-Alkynyl)tributylstannanes are also used for the alkynyl ketone synthesis[720]. The a, 9-alkynic dithio and thiono esters 842 can be prepared by the reaction of the corresponding acid chloride 841 with terminal alkynes[721,722],... 

Benzoyl chlorides, like other acyl chlorides, react readily with alcohols to form the corresponding esters (259). The reaction requires 19 h to be completed, and it has been studied in the analysis of carbohydrates, aminosugars, and glycosides (260). Because the preparation of acyl derivatives of monosaccharides is difficult, phenyldimethylsilyl chloride has been also investigated as an alternative label (261). After dissolving the analytes in dimethylformamide and addition of... 

---