Development of alternative technology for the production of meta-substituted phenolic compounds

English: Both m-cresol and resorcinol are important industrial starting materials in the production of many phenolic products. In a process similar to the one for the production of phenol, cresols are produced by reaction of toluene with propylene to give mixtures of o-, m- and p-isopropyltoluene. The corresponding cresols are subsequently obtained together with acetone via the hydroperoxides by air oxidation. Due to their close boiling points, m- and p-cresol are not separable by distillation and has to be obtained from these mixtures by elaborate adduct crystallisation, derivatization or chromatographic procedures, which results in pure synthetic m-cresol to be a very expensive commodity. Since it is known that mcresol can be produced selectively from o- or p-toluic acid, which is readily available from the corresponding xylene, by application of Keading’s Dow Phenol process, it was decided to investigate this methodology as an alternative for the synthesis of pure mcresol. In order to be in a position to optimise this process, it was decided to investigate the mechanism of the reaction through the use of X-ray diffractometry, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), infrared spectrometry (IR) and MALDI-TOF mass spectrometry. The starting point in the copper catalysed process for transforming o-toluic acid into mcresol, has been established by X-ray diffractometry to be the formation of tetrakis(μ2-2-methylbenzoato)bis(2-methylbenzoic acid)copper(II), with the typical paddlewheel structure of Cu(II) carboxylates, when o-toluic acid was reacted with basic copper(II)carbonate and magnesium oxide in refluxing toluene. Apart from the expected four o-toluic acid entities forming the paddlewheel structure, the crystal structure also indicated another toluic acid molecule to be attached to each copper atom through the carbonyl of the carboxylic acid moiety. Extension of the X-ray crystallographic investigation to the copper salts of p-toluic acid, m-toluic acid, p-ethylbenzoic acid, and 2,6-dimethylbenzoic acid indicted all of these compounds, except the copper (II) salt of p-toluic acid, to have structures similar to that of tetrakis(μ2-2-methylbenzoato)bis(2- methylbenzoic acid)copper(II). While the structure of tetrakis(μ2-4-methylbenzoato) bis(4-methylbenzoic acid)copper(II) basically also showed the paddlewheel configuration, the extra two toluic acid molecules attached to the copper atoms in the all of the other cases were absent in the structure of this compound. In this instance, interactions between an oxygen atom of one molecule and the copper of an adjacent molecule leading to an infinite “polymer” type chain along the a-axis of the crystal, was observed. Evidence gathered from DSC, TGA, and MALDI-TOF MS investigations of the transformation of tetrakis(μ2-2-methylbenzoato)bis(2-methylbenzoic acid)copper(II) into the product, suggested that this copper benzoate rearranges and cleaves into o-toluic acid and copper(I) 2-methyl-6-{[(2-methylphenyl)-carbonyl]oxy}benzoate at 164 °C. Decarboxylation of the latter at 249.5 °C gave o-toluic acid and 3-methylphenyl 2- methylbenzoate, which is hydrolysed into o-toluic acid and the desired product, m-cresol. In contrast to the copper salt of o-toluic acid, which showed clear temperature differences for the different steps in the reaction process, the salt of p-toluic acid displayed one continuous decomposition between 160 and 260 oC, thus rendering the identification of reaction intermediates at specific temperatures more or less impossible. In a process similar to that of cresols, resorcinol is commercially produced by selective formation of m-diisopropylbenzene followed by oxidative cleavage of the dihydroperoxide which is obtained through aerial oxidation of the diisopropylbenzene. While this process is used globally, it is hampered by large recycle streams arising from poor o/p selectivity during the alkylation of benzene as well as the limitation of low conversion (20%) in the oxidation step due to the explosivity of the hydroperoxide intermediate. Since it has been demonstrated that the Diels-Alder reaction could be applied to the synthesis of p-cresol from isoprene and vinyl acetate, application of this methodology to the synthesis of resorcinol, was subsequently investigated. Danishefsky’s diene (trans-1-methoxy-3-trimethylsilyloxy-1,3-butadiene), with the appropriate functional groups already trapped in the required enolic form, was selected as model substrate for the preliminary experiments with model dienophiles, methyl vinyl ketone and butyl acrylate and the novel cis- and trans-products, 4-acetyl-3- methoxycyclohexanone and butyl 2-methoxy-4-oxocyclo-hexanecarboxylate, obtained, albeit in low yields (7.49 and 6.59 % and 7.53 and 9.66 % respectively). When the reaction was extended to the more relevant methyl propiolate as dienophile, no direct Diels-Alder products could, however, be isolated and only methyl 4-hydroxybenzoate and methyl 4-{[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]oxy}benzoate were isolated from the reaction mixture in 5.51 and 5.74 % yields respectively. The formation of the phydroxybenzoate is explicable in terms of methanol elimination from the primary Diels- Alder product, while it is clear that the second product originates from conjugate addition of the formed hydroxybenzoate to methyl propiolate. While seemingly negative, the last Diels-Alder reaction, however, showed that the envisaged methodology could in principle be used for the preparation of resorcinol, but that care would have to be taken in order to avoid unwanted methanol release. If Chan’s diene [1,3-bis-(trimethylsilyloxy)-1- methoxy-1,3-butadiene] or an equivalent to it, could be used in a Diels-Alder reaction with an acrylate, the tendency towards methanol elimination might, however, be advantageous as it might lead to the mono-silylated resorcinol derivative in a single step. The viability of this Diels-Alder strategy towards the synthesis of resorcinol will form part of a future investigation. While negative from the point view of methodology for the synthesis of resorcinol, the Diels-Alder reaction between methyl propiolate and Danishefsky’s diene represents a new catalytic process for the preparation of methyl 4-hydroxybenzoate. This compound is widely used as a preservative in food, cosmetics and pharmaceuticals, while its free acid form (p-hydroxybenzoic acid), which is produced by Kolbe-Schmidt carboxylation of potassium phenolate with carbon dioxide, finds application in the liquid crystal industry.