Para-Hydroxybenzoate

TE Haag, DF Loncrini. Esters of para-hydroxybenzoic acid. In JJ Kabara, ed. Cosmetic and Drug Preservation. New York Marcel Dekker, 1984, pp 63-77. 

The great potential of QM/MM calculations has attracted much attention in the past decade and the number of studies published in recent years is now so large that it is not possible to cover them all here. Among recent QM/MM applications at different levels are para-hydroxybenzoate hydrolase [56, 74], citrate synthase [4-6, 52], uracil-DNA glycosylase [88], neuraminidase [89, 90], aldose reductase [91], human thrombin [92], glutathione S-transferases [57], and HIV protease [93]. 

Phenols are generally named as derivatives of the simplest member of the family, phenol, e.g. < -chlorophenol. Sometimes trivial or special names are also used, e.g. m-cresol. Occasionally, phenols are named as hydroxy-compounds, e.g. para-hydroxybenzoic acid. Numbering is often used to denote the position(s) of the substituent(s) on a phenol skeleton, e.g. 2,4-dinitrophenol. 

Liquid dosage forms which are disperse systems (colloidal, i.e., microspheres, nanoparticles, and micelles suspensions and emulsions) often contain preservatives which are methyl, ethyl, propyl, and butyl esters of para-hydroxybenzoic acid in various combinations. A typical example is the antacid suspensions which have high pH values which make the esters of the preservatives susceptible to hydrolysis. One way to circumvent this problem is to use several preservatives in combination with the hope that some quantities of the preservatives will remain to prevent the suspension from microbial attack. A report showing the assay of the four esters and the parent acid (one of the decomposition products) in drug products in which all the preservatives were used has been given [13]. 

Let s compare the ionization of ortho- and para-hydroxybenzoic acids ... 

Chemical properties appropriate to a compound found at a branch point of metabolism are displayed by chorismic acid. Simply warming the compound in acidic aqueous solution yields a mixture of prephen-ate and para-hydroxybenzoate (corresponding to reactions h and l of Fig. 25-1). Note that the latter reaction is a simple elimination of the enolate anion of pyruvate. As indicated in Fig. 25-1, these reactions correspond to only two of several metabolic reactions of the chorismate ion. In E. coli the formation of phe-nylpyruvate (steps h and i, Fig. 25-1) is catalyzed by a single protein molecule with two distinctly different enzymatic activities chorismate mutase and prephenate dehydratase.34-36 However, in some organisms the enzymes are separate.37 Both of the reactions catalyzed by these enzymes also occur spontaneously upon warming chorismic acid in acidic solution. The chorismate mutase reaction, which is unique in its mechanism,373 is discussed in Box 9-E. Stereochemical studies indicate that the formation of phenylpyruvate in Fig. 25-1, step z, occurs via a... 

These compounds include the methyl, ethyl, propyl, and butyl esters of para-hydroxybenzoic acid. In the United Slates and a number of other countries, the methyl and propyl esters are preferred, while European food processors favor the ethyl and butyl esters. The parabens were first described in 1924 as having antimicrobial activity and initially were used in cosmetic and pharmaceutical products. 

A paired-ion, reversed-phase high-performance liquid chromatographic method was developed for the simultaneous determination of sweeteners (dulcin, saccharin-Na, and acesulfame-K), preservatives (sodium dehydroacetate, SA, salicyclic acid, BA, succinic acid, methyl-para-hydroxybenzoic acid, ethyl-para-hydroxybenzoic acid, n-propyl-para-hydroxybenzoic acid, n-butyl-para-hydroxybenzoic acid, and isobutyl-para-hydroxybenzoic acid), and antioxidants (3-tertiary-butyl-4-hydroxyanisole and tertiary-butyl-hydroquinone). A mobile phase of acetonitrile-50 ml aqueous tr-hydroxyisobutyric acid solution (pH 4.5) (2.2 3.4 or 2.4 3.6, v/v) containing 2.5 mM hexadecyltrimethylammonium bromide and a Clg column with a flow rate of 1.0 ml/min and detection at 233 nm were used. This method was found to be very reproducible detection limits ranged from 0.15 to 3.00 p,g. The retention factor (k) of each additive could be affected by the concentrations of hexadecyltrimethylammonium bromide and a-hydroxyisobu-tyric acid and the pH and ratio of mobile phase. The presence of additives in dried roast beef and sugared fruit was determined. The method is suitable for routine analysis of additives in food samples (81). 

A validated method (No. 63) for the analysis of benzoic acid, sorbic and para-hydroxybenzoic acids in fruit juices has been published in the IFU handbook (Anon, 1995e). In this method the resolution takes place on a C8 reverse-phase column. With this solvent system (methanolic/ammonium acetate, pH 4.55) sorbic and benzoic acids elute quite quickly and the less polar para-hydroxybenzoate esters elute much later. The method does stipulate that caution has to be taken by orange juice due to possible interferences by natural materials in the juice that elute close to benzoic acid. As sorbic and benzoic acids elute quite early in the chromatogram using this method, it would... 

Modelling can pinpoint functional groups and analyse catalytic interactions. In several enzymes, catalytic interactions have been identified via calculation. For example, in the flavin-dependent monooxygenases, para-hydroxybenzoate hydroxylase and phenol hydroxylase, a conserved proline residue was found from QM/MM modelling, which specifically stabilizes the transition state for aromatic hydroxy-lation.12,13... 

The first fibers from a thermotropic liquid crystalline melt whose properties were reported were spun from a copolyester of para-hydroxybenzoic acid (PHB) and PET by workers at Tennessee Eastman Co. The preparation of the copolymer proceeds in two stages. First, / ara-acetoxybenzoic acid is reacted with PET in an acidolysis step to give a copolyester prepolymer, which in the second step is condensed further to a higher degree of polymerization suitable for fiber formation. 

This group of chemicals, which are found naturally in many fruits, are used as preservatives, a function that they also perform within fruit. Benzoic acid itself may be used, or more commonly sodium benzoate (a salt) or ethyl or methyl para-hydroxybenzoate, also known as parabens. They have sometimes associated with adverse effects. Anaphylaxis-like reactions have been reported as well as urticaria. About 4 per cent of people who suffer from asthma may experience breathlessness and wheezing when exposed to benzoates. Parabens are often used as preservatives cosmetics. 

Moran GR, Entsch B, Palfey BA, Ballou DP. Electrostatic effects on substrate activation in para-hydroxybenzoate hydroxylase studies of the mutant Lysine 297 Methionine. Biochemistry 1997 36 7548-7556. 

Viscosity. The best summary of the effect of inner H bonds on viscosity is that of Friend and Hargreaves (722). They show in conclusive fashion that the viscosity of orbonded compounds—another reflection of the tendency toward normalcy resulting from internal satisfaction of H bonding capacity. Figure 1-2 shows the structure of ortho- and para-hydroxybenzoic acid. 

A recent study of para-hydroxybenzoate hydroxylase (PHBH) by Bidder et al. [49,50] provides an interesting example of the validation of QM/MM calculations on the enzyme mechanism by comparison with experimental data. The correlation found between calculated activation barriers and the logarithm of experimental rate constants for a series of alternative substrates also provides support for the proposed mechanism hydroxylation of hydroxylation. These studies are a good example of QM/MM reaction pathway calculations for an enzyme, including technical aspects of system set-up and practical considerations, and so will be outlined here in some detail. 

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