Alcohols in esterification

Mineral acid speeds up both processes by protonating carbonyl oxygen and thus rendering carbonyl carbon more susceptible to nucleophilic attack (Sec. 20.4). In hydrolysis, the nucleophile is a water molecule and the leaving group is an alcohol in esterification, the roles are exactly reversed. 

Fig. 3.11 Taft relationship of alkyl substituents in alcohols in esterification of acetic (A), propanoic ( ), and pentanoic ( ) acids.

It is used as a catalyst in esterification, dehydration, polymerization and alkylation reactions. Converted by e.g., ihionyl chloride, to melhanesulphonyl chloride (mesyl chloride) which is useful for characterizing alcohols, amines, etc. as melhanesulphonyl (mesyl) derivatives. 

The mechanism of esterification of an alcohol in the presence of a mineral acid is now considered to involve the following steps. 

Ethyl p-aminobenzoate (esterification of p-aminobenzoic acid). Place 80 ml. of absolute ethyl alcohol in a 250 ml. conical flask equipped with a two-holed cork and wash-bottle tubes. Pass dry hydrogen chloride (Section 11,48,2) through the alcohol until saturated—the increase in weight is about 20 g.—and transfer the solution to a 250 ml. round-bottomed flask. Introduce 12 g. of p-aminobenzoic acid, fit a double surface condenser to the flask, and reflux the mixture for 2 hours. Upon... 

Usually no difficulties are encountered in the esterification of thiazole acids. Direct esterification with alcohol and add in the presence of an acid catalyst (7, 61, 62), or prior conversion to the add chloride (6, 63, 64) followed by reaction with an alcohol in basic conditions give good yields. 

Esters. Most acryhc acid is used in the form of its methyl, ethyl, and butyl esters. Specialty monomeric esters with a hydroxyl, amino, or other functional group are used to provide adhesion, latent cross-linking capabihty, or different solubihty characteristics. The principal routes to esters are direct esterification with alcohols in the presence of a strong acid catalyst such as sulfuric acid, a soluble sulfonic acid, or sulfonic acid resins addition to alkylene oxides to give hydroxyalkyl acryhc esters and addition to the double bond of olefins in the presence of strong acid catalyst (19,20) to give ethyl or secondary alkyl acrylates. 

Acidic Cation-Exchange Resins. Brmnsted acid catalytic activity is responsible for the successful use of acidic cation-exchange resins, which are also soHd acids. Cation-exchange catalysts are used in esterification, acetal synthesis, ester alcoholysis, acetal alcoholysis, alcohol dehydration, ester hydrolysis, and sucrose inversion. The soHd acid type permits simplified procedures when high boiling and viscous compounds are involved because the catalyst can be separated from the products by simple filtration. Unsaturated acids and alcohols that can polymerise in the presence of proton acids can thus be esterified directiy and without polymerisation. 

Esterification is frequendy carried out by direct reaction of the carboxyhc acid with an alcohol in the presence of a small amount of mineral acid, usually concentrated sulfuric or hydrochloric acid. The esters of commercial importance in both 0- and -hydroxyben2oic acid are the methyl esters. Direct esterification has the advantage of being a single-step synthesis, but being an equihbrium it is easily reversed. The reaction to the ester is driven by either of... 

Succinic acid diesters are also obtained by one-step hydrogenation (over Pd on charcoal) and esterification of maleic anhydride dissolved in alcohols (40) carbonylation of acrylates in the presence of alcohols and Co complex catalysts (41—43) carbonylation of ethylene in alcohol in the presence of Pd or Pd—Cu catalysts (44—50) hydroformylation of acetylene with Mo and W complexes in the presence of butanol (51) and a biochemical process from dextrose/com steep Hquor, using Jinaerobiumspirillum succiniciproducens as a bacterium (52). 

The butyl alcohols undergo esterification with organic acids in the usual manner in the presence of trace amounts of mineral acid catalysts. Esterification is fastest with /-butyl alcohol and slowest with the primary alcohols although /-butyl alcohol undergoes substantial dehydration in the presence of the typical acid esterification catalysts. 

Other Esters. The esterification of acetic acid with various alcohols in the vapor phase has been studied using several catalysts precipitated on pumice (67). 

It is thus apparent that at the commencement of vegetation of the peppermint the oil is rich in menthol, hut only a small amount is present in the esterified condition. Menthone only exists in small quantity. As the green parts of the plant develope, the proportion of esterified menthol increases, as has heen found to be the case with other alcohols. This esterification, however, only takes place in the leaves, and when the essential oil extends towards the flowering tops, it becomes poorer in esters. 

Esters are usually prepared from carboxylic acids by the methods already discussed. Thus, carboxylic acids are converted directly into esters by SK2 reaction of a carboxyfate ion with a primary alkyl halide or by Fischer esterification of a carboxylic acid with an alcohol in the presence of a mineral acid catalyst. In addition, acid chlorides are converted into esters by treatment with an alcohol in the presence of base (Section 21.4). 

With a secure route to pentacyclic amine 2, the completion of the total synthesis of 1 requires only a few functional group manipulations. When a solution of 2 in ethanol is exposed to Pd-C in an atmosphere of hydrogen, the isopropenyl double bond is saturated. When a small quantity of HCI is added to this mixture, the hydro-genolysis of the benzyl ether is accelerated dramatically, giving alcohol 15 in a yield of 96%. Oxidation of the primary alcohol in 15 with an excess of Jones reagent, followed by Fischer esterification, gives ( )-methyl homosecodaphniphyllate [( )-1] in an overall yield of 85 % from 2. 

From the results of Malek et al.49,561 m 205,206,211) it may be concluded that the various metal derivatives used in esterifications exhibit many common catalytic characteristics. Thus, these authors190 established relationships concerning the free energies of esterification of thirteen ortho-, meta- and para-substituted benzoic adds by 1,2-ethanediol. They obtained Hammett parameters which do not differ greatly from those found for the add-catalyzed esterifications of the same adds with various alcohols. They concluded... 

The direct biocatalytic esterification of a chiral acid with a simple achiral alcohol in organic media is a reversible process and, in order to bias the equilibrium to the... 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

The following experimental results are presented on the use of solid acid catalysts in esterification of dodecanoic acid with 2-ethylhexanol and methanol. In the next figures, conversion is defined as X [%] = 100-(1 - [Acid]fi ai / [Acid]Muai), and the amount of catalyst used is normahzed cat [%] - 100-A/cat / (A/acid + Milcohol)-Several alcohols were used to show the range of apphcability. The selectivity was assessed by testing the formation of side products in a suspension of catalyst in alcohol. Under the reaction conditions, no products were detected by GC analysis. 

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... 

This disadvantage can be ruled out by spacers between the allylic and the acrylic group [15], but the selectivity in favor of the allylic group is not improved. An acetylenic triple bond instead helps to clarify the situation. 2-Propynoxyethyl acrylate, available in 90 % yield from ethoxylated propargylic alcohol by esterification, is hydrosilylated very smoothly only at the triple bond, leaving the acrylic side virtually untouched (Eq. 5). 

The effect of the mode of heating was also studied in heterogeneously catalyzed esterification of acetic acid by isopentyl alcohol in the presence of Amberlyst-15 cation exchange resin catalyst [38], Scheme 10.2. 

In a lipase-catalyzed reaction, the acyl group of the ester is transferred to the hydroxyl group of the serine residue to form the acylated enzyme. The acyl group is then transferred to an external nucleophile with the return of the enzyme to its preacylated state to restart the catalytic cycle. A variety of nucleophiles can participate in this process. For example, reaction in the presence of water results in hydrolysis, reaction in alcohol results in esterification or transesterification, and reaction in amine results in amination. Kirchner et al.3 reported that it was possible to use hydrolytic enzymes under conditions of limited moisture to catalyze the formation of esters, and this is now becoming very popular for the resolution of alcohols.4... 

Catalytic sol-gel lipase immobilizates were rapidly commercialized (by Fluka) after their invention in 1995 because of their remarkably stable activity in esterification reactions (and also in the kinetic resolution of chiral alcohols and amines) along with unique stability (residual activity of 70% even after 20 reaction cycles is common). The original procedure for the encapsulation produced by the fluoride-catalysed hydrolysis of mixtures of RSi(OCH3)3 and Si(OCH3)4 has been improved... 

Aldono-1,5-lactones and free aldonic acids react with alcohols in the presence of hydrogen chloride to give the corresponding alkyl aldonates (84). The reaction is slower with 1,4-lactones. Because esterification takes place very slowly in the absence of an acidic catalyst, aldonic acids and their lactones may be recrystallized from boiling alcohols without appreciable esterification (85). However, in some instances, alkyl esters are formed under these conditions. For example, essentially pure ethyl L-mannonate was isolated (6.4% yield) from the mother liquors of crystallization L-man-nono-1,4-lactone, obtained by Kiliani synthesis from L-arabinose (86). Similarly, repeated recrystallization from ethanol of crude 2,3,4,6-tetra-O-acetyl-D-glucono- 1,5-lactone afforded the corresponding ethyl gluconate derivative (87). 

G. P. Carlson, In vitro Esterification of Fatty Acids by Various Alcohols in Rats and Rabbits , Toxicol. Lett. 1994, 70, 57-61. 

At first sight, it appears that it should be feasible to prepare such esters regioselectively using a similar biocatalytic approach to that employed for the 6- and 7-amino acylation of 6-APA and 7-ADCA shown above. Unfortunately, owing to the poor nucleophilicity of alcohols, biocatalytic esterification in aqueous media is far more challenging than amida-tion. Therefore, it was not until the pioneering work of Klibanov and co-workers, who first demonstrated the use of enzymes in neat organic solvents, that this option became viable (see Section 1.4). 

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