Esterification of tertiary alcohols

Normal Fischer esterification of tertiary alcohols is unsatisfactory because the acid catalyst required causes dehydration or rearrangement of the tertiary substrate. Moreover, reactions with acid chlorides or anhydrides are also of limited value for similar reasons. However, treatment of acetic anhydride with calcium carbide (or calcium hydride) followed by addition of the dry tertiary alcohol gives the desired acetate in good yield. 

A 500-mI, three-necked, round-bottom flask is fitted with a condenser, a thermometer, and a mechanical stirrer all openings are protected by drying tubes. In the flask is placed a mixture of 61.2 g (0.61 mole) of acetic anhydride and 27 g (about 0.4 mole) of finely pulverized calcium carbide, and the mixture is refluxed for 2 hours. After cooling to 70°, 29.6 g (0.4 mole) of dry r-butyl alcohol is added and the mixture is refluxed for 4 days with continuous stirring. The mixture is cooled and the thick slurry is decomposed by careful addition to ice, followed by steam distillation. The ester layer is separated. 

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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) ... 

Esterification of tertiary alcohols poses several problems and expensive catalysts, like dimethylamino pyridine, are recommended. While esterification/transesterification/hydrolysis involving primary and secondary alcohols has been reported both with chemocatalysts and biocatalysts, terf-alcohol based esters have not found success. Recent work of Yeo et al. (1998) reports successful results for /er/-butyl octonoate using a new strain of lipase. This is a significant finding as the production of esters based on fert-alcohols (and reciprocally with hindered acids) may well be possible with biocatalysts, avoiding expensive catalysts and allowing easier separation. 

The rate of esterification depends on the structures of the acid and the alcohol in question primary alcohols are esterified faster than secondary or tertiary ones, and the same series primary > secondary > tertiary holds for the carboxylic acids. Difficulties arise in esterification of tertiary alcohols with the usual acid catalysts in that olefins are readily formed under their influence. Also, in the aromatic series steric effects can reduce the rate of esterification, e.g., arf/ia-substituted carboxylic acids react with difficulty. 

When a solution of a carboxylic acid and an alcohol in pyridine is treated with tosyl chloride, an ester is formed rapidly in excellent yield. This procedure is useful especially in the esterification of tertiary alcohols. The combination of a carboxylic acid and tosyl chloride serves as a convenient method of in situ preparation of symmetrical acid anhydrides for further formation of esters and amides (eq 19). The novelty of this protocol is that the acid can be recycled through the anhydride stage in the presence of the alcohol, thereby resulting in complete conversion to the ester (eq 20). Reactivity is determined hy the strength of the acid strong acids facilitate the esterifications. ... 

Several polymeric analogues of 4-(iV,N-dimethylamino)pyridine (DMAP) have been used as catalysts for esterification of tertiary alcohols, hydrolyses of active esters and other substitutions... 

This reaction has wide application for the preparation of esters. The difficulties encountered in method 285 because of a reversible reaction are avoided. Esters of tertiary alcohols and phenols are best prepared in this way. The formation of tertiary halides from tertiary alcohols is prevented by carrying out the reaction in the presence of powdered magnesium or dimethylaniline which react with the hydrogen chloride as it is formed. The esterification of phenols is effected in the same manner. Magnesium or pyridine is added to combine with the hydrogen halide. Pyridine has replaced aqueous alkali formerly used for this purpose... 

Alkylative esterification of carboxylic acids with alkyl halides are effected by action with TMG (1) [65]. An ester is given by the TMG (1) mediated reaction of y-hydroxy-a,p-unsaturated carboxylic acid with methyl iodide without lactone formation after isomerization [65a]. Barton s base effectively works in the alkylation of sterically hindered carboxylic acid [3]. Ethanolysis of the acetate of tertiary alcohol occurred easily in 86% yield in the presence of BTMG (2) [66] (Scheme 4.24). 

Acyloxy-4,6-dimethoxy-[l,3,5]-triazines 301, obtained by reaction between carboxylic acids and CDMT 137, have been used as acylating agents for the synthesis of esters from primary, secondary, and tertiary alcohols (Scheme 59). Because of the mild acylation conditions, the method could be applied to esterification of labile alcohols with aromatic and aliphatic acids in good yields <1999S593>. 

The projected free radical cyclization proceeded as planned to give 172. Ozonolysis of the vinyl group, oxidation of the resulting aldehyde to an acid, and alkylation with diazomethane provided projected intermediate 162. Reduction of the lactone provided 173. Treatment of 173 with 6-methoxytryptamine and pivalic acid then provided a nearly equal mixture of lactams 174 (isoreserpine stereochemistry at Cg) and 175 (reserpine stereochemistry at C3). The correct C3 stereoisomer was moved forward to 176 (protection of the tertiary alcohol followed by reduction of the lactam). The silyl ethers were removed, the secondary ether was re-protected, and reaction with samarium iodide accomplished reduction of the a-hydroxy ester to provide 177. Removal of the TBS group and esterification of the alcohol completed the synthesis of reserpine. 

In the forward direction, tetrahydrothiapyrone 146 served as the precursor of both 143 and 144. Metallation of 143 (an allylic sulfide) using -butyllithium, followed by a reaction of the derived carbanion with 144, gave 147 after dehydration of the intermediate tertiary alcohol. Metallation of 147 followed by alkylation of the resulting anion with bromide 145, provided 148. Hydrolysis of the THP ether followed by reduction of the allylic C-S bonds with lithium in diethylamine, gave fe-sulfide 149. This reaction would have been expected to proceed via allyic radical and/or anion intermediates and thus, loss of olefin regiochemistry might have been anticipated, but the reaction seems to have proceeded without a major problem. Esterification of the alcohol (and most likely the thiols) and reduction of the homoallyic C-S bonds with Raney-Ni, gave 150. The synthesis of CJH (1) was completed in the usual manner. 

Kinetics of esterification between organic acids and alcohols have been extensively studied. There are two different opinions about the ways in which performs its catalytic effect. One of the opinions is that the organic acid is activated initially, (Royals (1954)) i.e. the organic acid molecule gets a hydrogen ion from the catalyst before it is esterified with a molecule of primary or secondary alcohol. In the case of tertiary alcohol, such as t-butyl alcohol, the hydroxyl group of the alcohol, rather than that of the acid is eliminated. The other opinion was introduced by Goldschmidt... 

Why are the esters of tertiary alcohols prepared by reaction with acid chlorides rather than by the Fischer esterification method ... 

Olefins add anhydrous acetic acid to give esters, usually of secondary or tertiary alcohols propjiene [115-07-1] yields isopropyl acetate [108-21-4], isobutjiene [115-11-7] gives tert-huty acetate [540-88-5]. Minute amounts of water inhibit the reaction. Unsaturated esters can be prepared by a combined oxidative esterification over a platinum group metal catalyst. Eor example, ethylene-air-acetic acid passed over a palladium—Hthium acetate catalyst yields vinyl acetate. 

Formic acid forms esters with primary, secondary, and tertiary alcohols. The high acidity of formic acid makes use of the usual mineral acid catalysts unnecessary in simple esterifications (17). Formic acid reacts with most amines to form formylamino compounds. With certain diamines imida2ole formation occurs, a reaction that has synthetic utiHty (18) ... 

AC2O, AcCl, Pyr, DMAP, 24-80°, 1-40 h, 72-95% yield. The use of DMAP increases the rate of acylation by a factor of 10. These conditions will acylate most alcohols, including tertiary alcohols. The use of DMAP (4-N,N-dimethylaminopyridine) as a catalyst to improve the rate of esterification is quite general and works for other esters as well. 

Esterification. The esterification of rosin provides important commercial products for the adhesive industry. Rosin esters are formed by the reaction of rosins with alcohols at elevated temperatures. Because the carboxyl group of the resin acids is hindered by attachment to a tertiary carbon, esterification with an alcohol can only be accomplished at elevated temperatures. This hindrance is in turn responsible for the high resistance of the resin acid ester linkage to cleavage by water, acid and alkali. 

Linalol is a tertiary alcohol of the formula Cj HjgO, which, with its acetic ester (and traces of other esters) forms the basis of the perfume,of bergamot and lavender oils. By dehydration linalol is converted into terpenes of which the principal are limonene and dipentene, and by esterification into its acetic ester. The examination of the essential oil at different periods of the development of the bergamot fruit has led Charabot and Laloue to the following conclusions. As the fruit matures the essential oil undergoes the following modifications —... 

Substitution as a preceding reaction. In addition to the well known determination of primary and secondary alcohols via esterification with acetic anhydride in pyridine at about 98° C, esterification is possible at room temperature in ethyl acetate with perchloric acid117 or 2,4-dinitrobenzenesulphonic acid118 as a catalyst. However, as tertiary alcohols preferably split off their hydroxy group, they can be adequately determined by OH-substitution with HBr in glacial acetic acid according to... 

As has been mentioned, preparation of esters of the C-17 hydroxyl group of selected progestins affords compounds with prolonged action. Similar chemical treatment of a corticoid would almost certainly lead to an ester of the sterically more accessible primary alcohol at C-21. In an interesting method for achieving esterification of the more hindered and less reactive tertiary 17-hydroxyl, prednisolone... 

The next step is not immediately obvious. The generation of an ethyl ester from a lactone can be accommodated by transesterification (we might alternatively consider esterification of the free hydroxyacid). The incorporation of chlorine where we effectively had the alcohol part of the lactone leads us to nucleophilic substitution. That it can be SnI is a consequence of the tertiary site. Cyclopropane ring formation from an Sn2 reaction in which an enolate anion displaces a halide should be deducible from the structural relationships and basic conditions. 

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