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cantly lower than the microbial toxicity of parabens, it is sufficient to impose a limit on the titer and yield of p-hydroxybenzoic acid synthesized by a microbe directly from glucose. Shikimic acid, in contrast to p-hydroxybenzoic acid, is not toxic to microbes.

Despite the promise of synthesizing p-hydroxybenzoic acid by chemical dehydration of microbially synthesized shikimic acid, there are a number of significant hurdles that have to be surmounted. The yield of p-hydroxybenzoic acid obtained from shikimic acid using CF₃SO₃H as the dehydration catalyst was 75%. In all of the acid-catalyzed dehydrations of shikimic acid, by-products were formed that proved to be difficult to remove without significant loss of product p-hydroxybenzoic acid. Dehydration of shikimic acid required the use of acetic acid as the reaction solvent to avoid the high concentrations of mineral acid (8-12 M) that would be required to catalyze dehydration of shikimic acid in aqueous solution. Acid-catalyzed dehydrations also had to be carried out with purified shikimic acid. Attempts to convert shikimic acid in clarified fermentor broth failed to produce significant yields of p-hydroxybenzoic acid, thus necessitating that shikimic acid be isolated from the fermentor broth prior to its acidcatalyzed dehydration. Additional product loss was encountered during purification of p-hydroxybenzoic acid from acid-catalyzed dehydration of shikimic acid. Combining the yield for microbe-catalyzed conversion of glucose into shikimic acid (14%), the percent recovery of shikimic acid from fermentor broth (86%), and the yield for acid-catalyzed dehydration of shikimic acid after product purification (50%), the overall yield for converting glucose into p-hydroxybenzoic acid is 6%. For comparison, the typical range of yields our group has achieved for direct microbe-catalyzed conversion of glucose into p-hydroxybenzoic acid is 4-13%.

In any multistep synthesis of a chemical product, even relatively small incremental losses in yield in individual reactions, isolations, or purifications have a cumulatively large impact on lowering overall yield. The loss of shikimic acid during isolation from fermentation broth, the crude yield for acidcatalyzed dehydration of shikimic acid, and the loss of p-hydroxybenzoic acid during product purification reduce the overall yield of p-hydroxybenzoic acid synthesized from glucose. Indeed, the overall yield for synthesis of p-hydroxybenzoic acid via acid-catalyzed dehydration of shikimic acid is reduced to the point where this route does not have an advantage in yield relative to direct, microbe-catalyzed conversion of glucose into p-hydroxybenzoic acid. However, significant improvements in the yield of microbe-catalyzed synthesis of shikimic acid can likely be achieved. Homogeneous or heterogeneous, shape-selective acid catalysts that are compatible with use in water at elevated temperatures also need to be elaborated. The availability of such catalysts could improve the yield for conversion of shikimic acid into p-hydroxybenzoic acid, reduce the generation of difficult-to-purify by-products, and avoid the need to use CH₃CO₂H as the reaction solvent.

Hydroquinone is a pseudocommodity chemical ($5/kg) produced globally at volumes of 4.5-5.0 × 10⁷ kg per year. ¹⁶ The major use of hydroquinone is as a photographic developer. Hydroquinone is also employed as a precursor to antioxidants used in rubber and food applications as well as an intermediate in dye manufacture. Oxidation of aniline is the oldest process ( Figure 12.4, top) for hydroquinone production and accounts for a relatively modest percentage of global hydroquinone synthesis (approximately 4 × 10⁶ kg/per year). ¹⁶ Aniline is initially oxidized by manganese dioxide (MnO₂) in aqueous sulfuric acid (H₂SO₄). Benzoquinone is then reduced by Fe⁰ or hydrogenated to afford product hydroquinone. This manufacturing technique generates large quantities of manganese sulfate (MnSO₄), ammonium sulfate ((NH₄)₂SO₄), and iron oxide salts. ^{16, 17}

Hydroperoxidative synthesis ^{16, 17} ( Figure 12.4, middle) accounts for approximately 2.5 × 10⁷ kg of hydroquinone production per year. p-Diisopropylbenzene is synthesized by zeolite-catalyzed Friedel-Crafts reaction of benzene or cumene with propylene or isopropanol. Air oxidation of p-diisopropylbenzene proceeds at 90-100°C in an aqueous NaOH solution containing organic bases along with cobalt