Esterification of p-aminobenzoic acid

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... 

Ethyl p-aminobenzoate (esterification of p-aminobenzoic acid). Place 80ml of absolute ethanol in a 250-ml two-necked flask equipped with a double surface reflux condenser and a gas inlet tube. Pass dry hydrogen chloride (Section 4.2.38, p. 438) through the alcohol until saturated - the increase in weight is about 20 g - remove the gas inlet tube, introduce 12 g (0.088 mol) of p-aminobenzoic acid and heat the mixture under reflux for 2 hours. Upon cooling, the reaction mixture sets to a solid mass of the hydrochloride of ethyl p-aminobenzoate. It is better, however, to pour the hot solution into c. 300 ml of water (no hydrochloride separates) and add solid sodium carbonate carefully to the clear solution until it is neutral to litmus. Filter off the precipitated ester at the pump and dry in the air. The yield of ethyl p-aminobenzoate, m.p. 91 °C, is 10 g (69%). Recrystallisation from rectified (or methylated) spirit does not affect the m.p. 

In the procedure described in this section, you will perform the Fischer esterification of p-aminobenzoic acid (16) with ethanol to give ethyl p-aminobenzoate (17), more commonly known as benzocaine, according to Equation 20.4. Benzocaine is a useful topical anesthetic, and the discovery of its anesthetic properties represents an interesting example of "rational drug design" as described in the Historical Highlight at the end of this chapter. 

Consider the equilibrium for the esterification of p-aminobenzoic acid (16) to give ethyl p-aminobenzoate (17) shown in Equation 20.4. 

Ethyl -aminobenzoate has been prepared by the esterification of p-aminobcnzoic acid1 and by the reduction of ethyl /i-nitrobenzoate with ammonium sulfide.2 Although commer-dally the reagent used is usually iron and water in presence of a little acid, in the laboratory the catalytic reduction as described in the procedure is by far the most convenient. 

Endomethylene tetrahydrophthalic anhydride and the methyl derivate are also claimed for imide formation with aminoethanol [209]. The reaction of the endomethylene tetrahydrophthalic anhydride with hexahydro-p-aminobenzoic acid followed by a esterification with ethylene glycol and terephthalic acid yields an unsaturated imidoester curable by Michael addition with polyamines [210]. 

Case-II. A similar situation wherein reduction of the nitro function precedes esterification. In this specific case the initial reaction involving the oxidation ofp-nitrotoluene gives rise to the formation of p-nitrobenzoic acid which on further reduction with tin and HCl yields p-aminobenzoic acid (PABA) and PABA being soluble in both acid and base is rather difficult to isolate. Moreover, PABA may be isolated only under precisely neutral conditions and that too after removal of the metal ions which eventually form complexes with it. 

The experiments described in this chapter illustrate some of the representative reactions of carboxylic acids and their derivatives. For example, you will perform a Fischer esterification, one of the classic reactions in organic chemistry that was discovered by the Nobel laureate Emil Fischer (see the Historical Highlight at the end of Chapter 23 for an account of the life of this famous chemist), to prepare the anesthetic agent benzocaine from p-aminobenzoic acid (Sec. 20.2). In another experiment, you will synthesize the mosquito repellent N,N-diethyl-7n-toluamide (DEET) by a two-step process that involves the conversion of a carboxylic acid into an acid chloride and subsequent reaction with an amine to produce the desired amide (Sec. 20.3). 

Bacteria use p-aminobenzoic acid only for conversion to 7,8-dihydrofolic acid (Woods, 1962 Griffin and Brown, 1964). Thus, E, coli condenses p-aminobenzoic acid (and, alternatively, p-aminobenzoylglutamic acid) with 2-amino-4-oxo-6-hydroxymethyl-7,8-dihydropteridine (9.12) (as the 6-pyrophosphate) to give dihydropteroic acid (and alternatively, dihydrofolic acid) (Jaenicke and Chan, i960). The sulphonamides competitively inhibit the isolated enzyme dihydrofolate synthetase which catalyses these steps (G. Brown, 1962). From Lactobacillus plantarum two enzymes responsible for this synthesis have been isolated in a pure state (Shiota, Baugh, Jackson and Dillard, 1969). The first of these catalyses the esterification of 2-amino-4-oxo-6-hydroxymethyl-7,8-dihydropteridine (9.12) to its pyrophosphoryl derivative. The second is Brown s dihydrofolate synthetase. This second enzyme has also been isolated from several strains of... 

The mode of action of sulfonamides was greatly clarified by Woods in 1940. It had been shown that tissue extracts, pus, bacteria, and particularly yeast extract contained a heat-stable substance of low molecular weight which would inhibit the action of sulfonamides on bacteria (Stamp, 1939). Woods, recalling that enzymes are inhibited by substances which chemically and sterically resemble their substrates (see Section 9.3.1), adopted this hypothesis that the inhibitory substance in yeast is the substrate of an enzyme widely distributed in nature, and that it resembles sulfanilamide chemically. He found activity was concentrated in an alkali-soluble fraction of yeast, and that it ran parallel to a colour test for an aromatic amino-group. Activity was lost on esterification or acetylation, recovered on hydrolysis, and lost again on treatment with nitrous acid (Woods, 1940). Thus he made it clear that the active substance was an aromatic amino-acid. Because -aminobenzoic acid (/ AB) 2,12, p. 31) is the aromatic amino acid that most resembles sulfanilamide 2.13) he tried it as an inhibitor of bacteriostasis, and found that one molecule could prevent 5000 to 25 000 molecules of sulfanilamide from functioning. 

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