Acid halides acylation

Reactions of acid halides (acyl halides). Acyl halides are very reactive and easily converted to esters, anhydrides, amides, N-substituted amides, and carboxylic acids. In the following reactions, X represents any halide. 

Phosphoramidites (89), derived from enamines, react with carboxylic acids in an irreversible manner because of the low basicity of the eliminated enamine. The anhydrides (90) may also conveniently be obtained from enol phosphites. Reactions of (89) with phenol were also studied and the kinetics found to be characteristic for bimolecular processes . In contrast to other carboxylic acid halides, acyl fluorides give tervalent phosphorus fluorides with tervalent esters (Scheme 7). ... 

Acyl compounds (Section 17.1) A compound containing the group (R—C = 0) —, usually derived from a carboxylic acid, such as an ester, acid halide (acyl halide), amide, or carboxylic acid anhydride. 

The functional group of an acid halide (acyl halide) is an acyl group (RCO —) bonded to a halogen atom (Section 13.7). The most common acid halides are acid chlorides ... 

Most of the known acylations have been described for 2-aminothiazoles, the activity of the acylating agent being in the order, acid halides > anhydrides > esters > acids — amides. 

The treatment of enamines with acid halides which possess no a hydrogens results in the simple acylation of the enamine (7,12,62-67). If the acid halide possesses an a hydrogen, however, ketenes are produced in situ through base-catalyzed elimination of hydrogen chloride from the acid halide. The base catalyst for this reaction may be the enamine itself or some other base introduced into the reaction mixture such as triethylamine. However, if the ketene is produced in situ instead of externally, there still remains the possibility of a side reaction between the acid halide and the enamine other than the production of ketene (67,84). 

Methylation of 1-hydroxyindoles can be achieved readily by the reaction with diazomethane, Mel, orMc2S04 in the presence of an appropriate base, as described in previous reviews (79MI1, 90AHC105, 91YGK205, 99H1157). Alkylation and acylation also work well with alkyl halides, acyl halides, acid anhydrides, and acids in the presence of acid activators such as DCC and so on. 

Closely related to the carboxylic acids and nitriles discussed in the previous chapter are the carboxylic acid derivatives, compounds in which an acyl group is bonded to an electronegative atom or substituent that can net as a leaving group in a substitution reaction. Many kinds of acid derivatives are known, but we ll be concerned primarily with four of the more common ones acid halides, acid anhydrides, esters, and amides. Esters and amides are common in both laboratory and biological chemistry, while acid halides and acid anhydrides are used only in the laboratory. Thioesters and acyl phosphates are encountered primarily in biological chemistry. Note the structural similarity between acid anhydrides and acy) phosphates. 

Acid halides are named by identifying first the acyl group and then the halide. The acyl group name is derived from the carboxylic acid name by replacing the -ic acid ending with -yl or the -carboxylic acid ending with -carbonyl, as described previously in Section 20.1 and shown in Table 20.1 on page 753. For example ... 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Conversion of Acid Halides into Acids Hydrolysis Acid chlorides react with water to yield carboxylic acids. This hydrolysis reaction is a typical nucleophilic acyl substitution process and is initiated by attack of water on the acid chloride carbonyl group. The tetrahedral intermediate undergoes elimination of Cl and loss of H+ fo give the product carboxylic acid plus HC1. 

Conversion of Acid Halides into Anhydrides Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion gives an acid anhydride. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way. 

Carboxylic acids can be transformed into a variety of carboxylic acid derivatives in which the carboxyl -OH group has been replaced by another substituent. Acid halides, acid anhydrides, esters, and amides arc the most common such derivatives in the laboratory thioesters and acyl phosphates are common in biological molecules. 

Acid halide (Section 21.1) A functional group with an acyl group bonded to a halogen atom, RCOX. 

R2NC1, 91, 92 phenyl acetate, Fries rearrangement of, 475 phenyacetyl halides, acylation by, 173 2-phenylbenzoic acid, cycliacylation, 185 phenyl ethers, alkylation of, 149 —, bromination of, 130 —, hydrogen exchange with, 260 —, rearrangement of, 476 phenyl ethyl mercury, mercuridemercuration of, 359, 360... 

Acylation of Carboxylic Acids With Acyl Halides... 

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... 

Aldehydes have been prepared from carboxylic acids or acyl halides by first converting them to certain types of amides that are easily reducible. The following are some examples ... 

Diaryl sulfones can be formed by treatment of aromatic compounds with aryl sulfonyl chlorides and a Friedel-Crafts catalyst. This reaction is analogous to Friedel-Crafts acylation with carboxylic acid halides (11-14). In a better procedure, the aromatic compound is treated with an aryl sulfonic acid and P2O5 in polypho-sphoric acid. Still another method uses an arylsulfonic trifluoromethanesulfonic anhydride (ArS020S02CF3) (generated in situ from ArS02Br and CF3S03Ag) without a catalyst. ... 

Similar additions have been successfully carried out with carboxylic acids, anhydrides, acyl halides, carboxylic esters, nitriles, and other types of compounds. These reactions are not successful when the alkene contains electron-withdrawing groups such as halo or carbonyl groups. A free-radical initiator is required, usually peroxides or UV light. The mechanism is illustrated for aldehydes but is similar for the other compounds ... 

Rearrangement of hydroxamic acids and acyl halides (Lossen)... 

Catalytic amounts of I fCl4-AgC104 and Hf(OTf)4 are used for activation of acid halides and acid anhydrides for Friedel -Crafts acylation (Scheme 42) 178 the reactions of both reactive and unreactive aromatic substrates proceed smoothly in the presence of Hf(OTf)4. Furthermore, the Fries rearrangement179,180 and direct C-acylation of phenolic compounds181,182 take place using Hf(OTf)4. Formation of esters and Mannich-type reactions and allylation of imines have been also reported.152... 

In a similar approach (Equation 53), the use of a resin-bound nitrile allowed access to the corresponding resin-bound amidoximes 274, which could be converted into 1,2,4-oxadiazoles 275 via acylation with either an appropriate acid halide/ anhydride in the presence of a base or a carboxylic acid in the presence of a coupling reagent followed by cyclization, where the latter step was performed by heating in pyridine or diglyme and could be accelerated by the use of a microwave oven. Cleavage from the resin was easily achieved by the use of TFA in dichloromethane <2000BML1431>. 

---