Reactions of Acid Chlorides

Acid chlorides form amides when reacted with amines or ammonia. 

Acid chlorides react with alcohols to form esters. 

Acid chlorides readily react with nucleophiles to form nucleophilic substitution products, 

The reaction of acid chiorides with water is rapid. Exposure of an acid chioride to moist air on a humid day ieads to some hydroiysis, giving the acid chioride a very acrid odor, due to the HCi formed as a by-product. 

Acid chlorides react with oxygen nucleophiles to form anhydrides, carboxylic acids, and esters. 

Acid chlorides also react with ammonia and 1° and 2° amines to form 1°, 2°, and 3° amides, respectively. Two equivalents of NH3 or amine are used. One equivalent acts as a nucleophile to replace Cl and form the substitution product, while the second equivalent reacts as a base with the HCl by-product to form an ammonium salt. 

As an example, reaction of an acid chloride with diethylamine forms the 3° amide N,A -diethyl-m-toluamide, popularly known as DEET. DEET, the active ingredient in the most widely used insect repellents, is effective against mosquitoes, fleas, and ticks. 

In general, we will examine nucleophilic acyl substitution with four different nucleophiles, as shown in the following equations. 

These reactions are used to make anhydrides, carboxylic acids, esters, and amides, but not acid chlorides, from other acyl compounds. Acid chlorides are the most reactive acyl compounds (they have the best leaving group), so they are not easily formed as a product of nucleophilic substitution reactions. They can only be prepared from carboxylic acids using special reagents, as discussed in Section 22.10A. 

---

As with polyesters, the amidation reaction of acid chlorides may be carried out in solution because of the enhanced reactivity of acid chlorides compared with carboxylic acids. A technique known as interfacial polymerization has been employed for the formation of polyamides and other step-growth polymers, including polyesters, polyurethanes, and polycarbonates. In this method the polymerization is carried out at the interface between two immiscible solutions, one of which contains one of the dissolved reactants, while the second monomer is dissolved in the other. Figure 5.7 shows a polyamide film forming at the interface between an aqueous solution of a diamine layered on a solution of a diacid chloride in an organic solvent. In this form interfacial polymerization is part of the standard repertoire of chemical demonstrations. It is sometimes called the nylon rope trick because of the filament of nylon produced by withdrawing the collapsed film. 

Petoxycatboxyhc acids also have been prepared by the reaction of acid chlorides, anhydrides, or boric-catboxyhc anhydrides with hydrogen or sodium peroxide. These reactions ate carried out at low temperature and with excess peroxide to avoid the formation of diacyl peroxides (44,168,181,184). 

Unsyimnetiical diacyl peroxides (20, = alkyl 01 aiyl) are prepared by the reaction of acid chlorides or anhydrides with peroxycarboxyhc... 

The submitters have shown that these reactions proceed by dehydro-chlorination of the acid chloride to the ketene, which is then trapped by reaction with the phosphorane. The resulting betaine decomposes to the allenic ester via an oxaphosphetane. In contrast, the reaction of acid chlorides with 2 equivalents of phosphoranes involves initial acylation of the phosphorane followed by proton elimination from the phosphonium salt. ... 

Conversion of Acid Halides into Amides Aminolysis Acid chlorides react rapidly with ammonia and amines to give amides. As with the acid chloride plus alcohol method for preparing esters, this reaction of acid chlorides with amines is the most commonly used laboratory method for preparing amides. Both monosubstituted and disubstituted amines can be used, but not trisubstituted amines (R3N). 

Reaction of Acid Chlorides with Organometallic Reagents Grignard reagents react with acid chlorides to yield tertiary alcohols in which two of the substituents are the same. 

Carbon-phosphorus double bonds are also formed in addition reactions of tris(trimethylsilyl)phosphine 1692 (which can be readily prepared from white phosphorus, sodium, and TCS 14 [13a,b,c]) to give oxazohum fluorides 1691 which then give the azaphospholes 1694, via 1693 [3, 14]. On addition of 1692 to 1695, the diazaphosphole 1696 [3, 15] is prepared, whereas l,3-azaphospholo[l,2a]pyridines 1698 [16] are formed from 1692 and 1697, and 1,3-thiaphospholes 1700 are formed from the dithiohum fluorides 1699 [17]. l,3-Benzodiphospholyl anions 1703 are generated by reaction of acid chlorides with the dihthium salts 1701, via 1702 [18] (Scheme 11.3). 

Tetrazolium salts have found use as phase transfer catalysts in the oxidation of benzaldehyde640 and toluene193 and the displacement reaction of acid chlorides with sodium azide.639... 

Reduction is also observed in the reaction of acid chlorides with Grignard reagents Whitmore, F.C., Whitaker, J.S., Mosher, W.A., Brevick, O.N., Wheeler,... 

Rasmussen et al. (.15) on reactions of acid chloride groups on the surface of a polyethylene sheet with nucleophiles in aqueous solution, but because of the small number of reacting groups, highly sensitive spectroscopic techniques had to be used to follow the process. 

Reaction of acid chlorides or activated esters 657 with subunits containing piperidazine ring 656 is used for the synthesis of softball monomers intermediates 658 (Section 12.10.15.5), which are formed as mixtures of the corresponding isomers (Scheme 108) <1997JA77, 1998CEJ1449, 1998JA3650, 2001JA5213>. 

Rizpolozhenskii, N.I., Akamasin, V.D., and Eliseenkova, R.M., Reaction of acid chlorides of trivalent phosphorus acids with allyl mercaptan and allyl alcohol, Bull. Acad. Sci. U.S.S.R., 77, 1973. 

Catalysed reaction of acid chlorides and anhydrides with alcohols and phenols (Table 3.11)... 

The phase-transfer catalysed reaction of alkyl halides with potassium carbonate in dimethylacetamide, or a potassium carbonate/potassium hydrogen carbonate mixture in toluene, provides an excellent route to dialkyl carbonates without recourse to the use of phosgene [55, 56], An analogous reaction of acid chlorides with sodium hydrogen carbonate in benzene, or acetonitrile, produces anhydrides (3.3.29.B, >80%), although there is a tendency in acetonitrile for aliphatic acid chlorides to hydrolyse yielding the acids [57]. 

Acid chlorides, RCOCl, undergo ready attack by weaker nucleophiles, e.g. H2O, ROH. The question then arises whether, with the better potential leaving group Cl , the reactions of acid chlorides could proceed either via a single step 8 2 type pathway (cf. p. 78) involving a T.S., in which attack by and loss of Q are essentially synchronous or via an 8 1 type pathway (cf. p. 79) in which the slow step is RCOCl RCO Cl , followed by fast attack by Y on the acyl cation, RCO . In fact, most reactions of acid chlorides probably proceed via the now familiar tetrahedral intermediate pathway, though there may be some exceptions. 

Acid anhydride formed by the reaction of acid chloride with carboxylic acid inthe presence of pyridine. 

Many of the polymers that are produced by the usual high-temperature reactions could be produced at lower temperatures by using the faster Schotten Baumann reactions of acid chlorides. Thus polyesters and polyamides could he produced by replacing the diacid or di-eser reactant by the corresponding diacyl chloride... 

The uncatalyzed reaction of acid chlorides with organozincs is sluggish and inefficient. It is often complicated by side-reactions and usually leads to low yields of the... 

Acyl cyanides can be prepared by reaction of acid chlorides with cyanotrimethyl-silane at 60-70°1 or with copper cyanide.2. ... 

Isocyanates (5, 719).1 The reaction of acid chlorides with azidotrimethylsilane is catalyzed by trace amounts of powdered KN3 and 18-crown-6. For instance the ncid chloride I only undergoes reaction with the silane under catalysis. 

Chemical React ions. Forster (Ref 8) described the interaction of benzhydroximic chloride with NaNs to give wh ndls (mp 124°) of l-hydroxy-5-phenyltetrazole which de-compd spontly. The reaction of acid chlorides with NaN, was described by Schrocter (Ref 9) Waltmann (Ref 83) and Kiss Vinkler (Ref 124). While Schroeter found that coml NaNs reacted smoothly and rapidly with acid chlorides to form isocyanates (Also see Refs... 

Regioselective [3 + 2] annulation has been reported for the preparation of a wide variety of furans. Reaction of acid chlorides with trialkylsilyl-substituted allenes under the influence of A1C13 (CH2C12, — 20°C) yields the desired compounds (Scheme 52). The intramolecular variant of this method has also been described (89JA4407). 

Fluorinated diaeyl peroxides have acquired an important role in organo-fluorine chemistry and have become the subject of intensive research.202-204 Bis(per)fluoroaIkanoyI or -aroyl peroxides are generally synthesized in excellent to moderate yields in the same manner as for nonfluorinated peroxides, that is by reaction of acid chlorides or anhydrides with sodium peroxide or hydrogen peroxide.205-206 Similarly, perfluoroalkanoyl chlorides and fluorides, many of which are accessible by industrial processes, react with hydrogen peroxide in the presence of hydroxide to give the diacyl peroxides l.206-207... 

The procedure may be adapted for the preparation of other acyl isocyanates (i.e., dichloroacetyl, trichloroacetyl, phenyl-acetyl, diphenylacetyl, benzoyl, etc) and is generally more convenient than the reaction of acid chlorides with silver cyan-ate3 4 Acyl isocyanates react with amines, alcohols, and mer-captans to yield acyl ureas, carbamates, and thiocarbamates. 

---