Acid chloride alcoholysis

Conversion of Acid Halides into Esters Alcoholysis Acid chlorides react with alcohols to yield esters in a process analogous to their reaction with water to yield acids. In fact, this reaction is probably the most common method for preparing esters in the laboratory. As with hydrolysis, alcoholysis reactions are usually carried out in the presence of pyridine or NaOH to react with the HC1 formed. 

The acid chlorides are generally more reactive than the corresponding acid anhydrides. In fact, the alcoholysis of acid chlorides is probably the best laboratory method for preparing esters. Frequentiy, basic materials are added during the course of the reaction to neutralize by-product hydrochloric acid. When the basic material is aqueous caustic, the procedure is referred to as the Schotten-Baumann procedure (73). Esterification of tertiary alcohols by acid chlorides is described in Reference 74. Esters of tertiary alcohols can also be formed through an intermediate /-butyl thioate group (75) ... 

Alcoholysis of the acid chloride of a dicarboxylic acid with a polyhydroxy alcohol ... 

Acid chloride, alcohols from, 804 alcoholysis of, 802-803 amides from, 803-804 amines from, 933-935 amjnolysis of, 803-804 carboxylic acids from, 802 electrostatic potential map of, 791... 

Benzothiepins synthesized by a double Knoevenagel condensation (see Section 2.1.1.2.) contain free carboxylic acid groups if the reaction product is isolated under acidic conditions. Rcesterification can be performed by two methods via formation of the acid chloride and subsequent alcoholysis, or by reaction with diazomethane, e.g. the conversion of 3-benzo-thiepin-2,4-diearboxylic acid (5, R = C02H) with thionyl chloride and methanol gives the dimethyl ester 5 (R = C02Me) in 47% yield, while the diazomethane pathway provides 60% of the dimethyl ester.65 Use of excess diazomethane leads to cycloadducts (see Section 2.2.4.). 

The compounds referred to as azolides are heterocyclic amides in which the amide nitrogen is part of an azole ring, such as imidazole, pyrazole, triazole, tetrazole, benzimidazole, benzotriazole, and their substituted derivatives. In contrast to normal amides, most of which show particularly low reactivities in such nucleophilic reactions as hydrolysis, alcoholysis, aminolysis, etc., the azolides are characterized by high reactivities in reactions with nucleophiles within the carbonyl group placing these compounds at about the same reactivity level as the corresponding acid chlorides or anhydrides. 11... 

Ethyl 3-oxoalkanoates when not commercially available can be prepared by the acylation of tert-butyl ethyl malonate with an appropriate acid chloride by way of the magnesium enolate derivative. Hydrolysis and decarboxylation in acid solution yields the desired 3-oxo esters [59]. 3-Keto esters can also be prepared in excellent yields either from 2-alkanone by condensation with ethyl chloroformate by means of lithium diisopropylamide (LDA) [60] or from ethyl hydrogen malonate and alkanoyl chloride usingbutyllithium [61]. Alternatively P-keto esters have also been prepared by the alcoholysis of 5-acylated Mel-drum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione). The latter are prepared in almost quantitative yield by the condensation of Meldrum s acid either with an appropriate fatty acid in the presence of DCCI and DMAP [62] or with an acid chloride in the presence of pyridine [62] (Scheme 7). 

The reaction of phosphonic acid chloride (254) with (S)-proline ethyl ester afforded a mixture of diasteromeric amides (255) in high diastereoselectivity. The diastereomers (255) can easily be purified by chromatography. The chiral, practically optical pure organophosphorus compound (256) was obtained from purified (255) by acid alcoholysis. 

Esters are less reactive than acid chlorides and acid anhydrides. They are converted to carboxylic acid hy acid or base hydrolysis, and to another ester by acid or base alcoholysis (transesterification). The 1°, 2° or 3° amides are obtained from esters by treatment with ammonia or 1° or 2° amines, respectively. 

Investigations into the mechanism of hydrolysis and alcoholysis of acyl halides have been largely concerned with acyl chlorides and in particular with benzoyl chloride and the related aromatic acid chlorides. This was a result of the relatively slow rate of hydrolysis of benzoyl chloride compared with acetyl chloride (although their alcoholysis rates are easily measurable) and it is only comparatively recently90 that stop-flow techniques have been used to measure the faster rate of hydrolysis. However, in spite of this limitation, considerable progress has been made towards elucidation of the mechanism or mechanisms of hydrolysis and alcoholysis of these halides. 

The detailed mechanism, or mechanisms, of the solvolysis of acid chlorides is still a matter of dispute. There are at least four possible mechanisms, (a)-(d) below, all of which have been proposed either to act separately or in various combinations, and there is a unified mechanism, that of Minato93 which will be discussed later. The bimolecular mechanisms (a) and (b) differ in that (a) includes a tetrahedral intermediate whereas (b) does not. The former is commonly accepted as the most likely for the bimolecular mechanism and the arguments against (b) have been stated in the introduction. There is, however, good evidence for (A), at least in the case of the hydrolysis of chloracetyl chloride94. The acylium ion mechanism (c) and the hydrated carbonium ion mechanism (d) are both unimolecular mechanisms. Whereas the acylium ion XXVII has never been directly observed in hydrolysis or alcoholysis reactions, it is favoured as an intermediate by many workers, although it is kinetically indistinguishable from XXVIII. 

Early measurements established79 80,113 that electron-withdrawing substituents increased the rate of hydrolysis, alcoholysis or aminolysis114 of the acid chloride RCOC1, and that in the aliphatic series the rate decreased with... 

The apparent order in wateris found to be 2 for solvent 1-5% water/acetone11, 1.4 for 1-4% ethanol/carbon tetrachloride144 and 2.0 for 1-40% ethanol/ ether144. This, however, may be a result of specific solvation. As pointed out by Kivinen92, Minato partly based his mechanism on different rates of solvolysis of acid chlorides in diethyl ether/ethanol and carbon tetrachloride/ethanol mixtures. This cannot be used as a criterion for detailed mechanism since, for example, Salomaa150 has found that the apparent order with respect to ethanol of the rate of alcoholysis of methyl chloromethyl ether (an SN1 reaction) in... 

Methylindoline and 1,3-dimethylindoline are phosphorylated by phosphorus trichloride at 100-120°C (3 h). Here 5-dichlorophosphinylindoline 36a,b is obtained from approximately half the indoline, while the other half is converted into the corresponding hydrochloride (indoline is regenerated from it by treatment with alkali) [34, 35]. With phosphorus trichloride 1,2,3,3-tetramethylindoline forms dichlorophosphine 36c with a quantitative yield [36]. The acid chlorides 36 undergo hydrolysis (37), amidation (38), and alcoholysis (39). Phosphonites 38 and 39 are converted into thiophosphonates and phosphonates 40, 41 and enter into the Arbuzov reaction (42) [160] ... 

Fig. 13.65. Acylation of various malonic diester or malonic half-ester enolates with carboxylic acid chlorides. Spontaneous decarboxylation of the acylation products to furnish /3-ketoesters (see variants 1 and 2) and transformation of the acylation products into /3-ketoesters by way of alcoholysis/decarboxylation (see variant 3).

Derivatives of the 2-phenyl-1,3,4-oxadiazole-5-carboxylic acids give the usual reactions of acids on careful treatment.103 Thus the alcoholysis of the 5-acid chlorides with methanol or ethanol leads to the corresponding ester. Alkaline hydrolysis at 30° produces the carboxylic acid which on warming is decarboxylated to 2-phenyl-1,3,4-oxadiazole. Even a slight increase in the severity of the reaction conditions produces ring cleavage.103 The alkaline hydrolysis of 2-phenyl-5-(p-cyanophenyl)-1,3,4-oxadiazole with addition of H202 leads to 2-phenyl-5-(p-carboxamidophenyl)-1,3,4-oxadiazole.23... 

Addition tube, 20, 21 Alanine, /3-(3,4-dihydroxyphenyl)-N-METHYL-, 22, 89, 91 Alcoholic hydrochloric acid, 22, 77, 83 standardization, 22, 80 Alcoholysis, 20, 67 Aldehyde synthesis, 20, 14 from acid chlorides by Rosenmund reaction, 21, 84, 87, 88, 110 Alkylation of thiourea, 22, 59 Alkylchlororesorcinols, 20, 59 Alkylene bromide, 20, 24 S-Alkylthiuronium halides, 22, 60 dl-ALLOTHREONINE, 20, 10 ... 

---