Separation of o-/p-Hydroxyacetophenones by Selective Solubilization and Sorption on Weak Base Ion-Exchange Resins Vilas G. Gaikar* and Hyacinth M. Anasthas Department of Chemical Technology, University of Mumbai, Matunga, Mumbai 400 019, India A two-stage process has been developed for the separation of o-/p-hydroxyacetophenones (o-/p- HAP), both of which are intermediates for the pharmaceutical industry. The first step is the selective solubilization in a hydrocarbon solvent; o-HAP dissolves well in heptane and toluene, but p-HAP does not. The intermolecular hydrogen bonding among p-HAP molecules makes it almost insoluble in heptane and has solubility in toluene as low as 0.03 mol/kg of solvent. The first step gives a hydrocarbon solution of o-HAP with a very small amount of dissolved p-HAP, while pure p-HAP precipitates as a solid in high yield (∼90%). The traces of p-HAP from the organic solution can be removed in the second step using its selective sorption in weakly basic resins, giving a solution with o-HAP. The sorption of p-HAP on the resins by acid-base interactions between the resin’s amino group and p-HAP’s acidic hydroxy group is aided by the unfavorable solvation of p-HAP in the organic phase. Introduction Acylation of a phenol followed by Fries rearrangement gives a mixture of o- and p-hydroxyacetophenones (HAPs) (C 8 H 7 O 2 ). The composition of the product varies depending upon conditions of the reaction and catalyst. 1 Being intermediates in the pharmaceutical industry, pure HAPs have significant industrial importance. Their separation is conventionally carried out by crystalliza- tion or fractional distillation under reduced pressure or by steam distillation, as o-HAP is steam volatile. An improved and more efficient method for the resolution of these isomers will definitely be useful at the indus- trial level. Apart from the differences in their physical charac- teristics, the difference in the acidic strengths of HAPs can be exploited for their separation. As compared to o-HAP (pK a ) 10.22), p-HAP (pK a ) 8.05) is a stronger acid by 2 orders of magnitude and would react prefer- entially with a base of appropriate strength. For in- stance, in the process of dissociation extraction, which exploits the differences in dissociation constants (or pK a values) and distribution coefficients, a neutralizing agent is used in stoichiometric deficiency to react preferentially with the stronger component of a mix- ture. 2 Several such reactive techniques have been reviewed by Gaikar and Sharma. 2 Although highly selective, these methods suffer from the disadvantages of a net consumption of chemicals and the problem of disposal of waste streams generated during the recovery step. Jagirdar 3,4 had exploited the difference in solubilities of nitro-substituted compounds in organic solvents, such as toluene, to separate o-/p-nitrophenols and o-/p- nitroanilines. The ortho isomer in both cases is more organic soluble than its para counterpart. The complete separation of o/p isomers was not, however, possible by selective solubilization alone, and multistage reactive extraction using aqueous NaOH or aqueous HCl, as the case may be, had to be used after the first step to remove a few percent of p isomer dissolved in the organic solvent. Equilibrium separations using neutralizing agents cannot give complete removal of the p isomer, and the removal of its traces from the organic solutions becomes increasingly difficult as its concentration drops to lower values. Adsorptive techniques have a potential for separation of these close boiling point compounds, particularly when the component to be removed is present in trace quantities. Separation of alkylphenols and removal of acidic impurities from organic solvents by adsorption on commercial weakly basic ion-exchange resins have been reported recently with excellent capacity and selectivity. 5,6 A combination of selective solubilization with reactive adsorption on functionalized polymers may provide an attractive alternative for the separation of o-/p-HAPs. For the separation of phenols, a basic resin can function as the mass separating agent. The neutral- izing reaction between the acidic phenol and amino group on the polymeric resin should provide the separa- tion principle. Ion-exchange resins are commercially available in different forms, and the flexibility of tailor- ing them for specific needs by manipulating the func- tional group is advantageous for their application as separating agents. The regeneration of the weakly basic resins by a polar solvent, such as methanol or acetone, is a feasible option obviating the waste disposal problem commonly associated with the reactive techniques. If the primary adsorption is conducted from an inert hydro- carbon solvent, then the adsorbed solute can be easily washed off from the resin by a polar solvent. The net consumption of energy will then be decided by the efficiency of recovery methods for these solvents. The selective solubilization is explored in this work as the first step for the separation of HAPs because of the intra- and intermolecular hydrogen bonding in o-/ p-HAPs, respectively. It is also expected to modify the sorption characteristics of HAPs in the second step of the separation. The expected interaction is between the lone pair of electrons on nitrogen of the amino group of the resin and the acidic hydrogen of phenol. In the case of o-HAP, because of intramolecular H bonding, the * To whom correspondence may be addressed. Phone: 91- 22-4145616. Fax: 91-22-4145614. E-mail: vgg@udct.ernet.in. 1335 Ind. Eng. Chem. Res. 2002, 41, 1335-1343 10.1021/ie010471+ CCC: $22.00 © 2002 American Chemical Society Published on Web 02/02/2002