Development of Efficient and Selective Processes for the Synthesis of Commercially Important Chlorinated Phenols

Keith Smith,Gamal A El-Hiti

doi:10.3390/org2030012

Abstract

para-Selective processes for the chlorination of phenols using sulphuryl chloride in the presence of various sulphur-containing catalysts have been successfully developed. Several chlorinated phenols, especially those derived by para-chlorination of phenol, ortho-cresol, meta-cresol, and meta-xylenol, are of significant commercial importance, but chlorination reactions of such phenols are not always as regioselective as would be desirable. We, therefore, undertook the challenge of developing suitable catalysts that might promote greater regioselectivity under conditions that might still be applicable for the commercial manufacture of products on a large scale. In this review, we chart our progress in this endeavour from early studies involving inorganic solids as potential catalysts, through the use of simple dialkyl sulphides, which were effective but unsuitable for commercial application, and through a variety of other types of sulphur compounds, to the eventual identification of particular poly(alkylene sulphide)s as very useful catalysts. When used in conjunction with a Lewis acid such as aluminium or ferric chloride as an activator, and with sulphuryl chloride as the reagent, quantitative yields of chlorophenols can be obtained with very high regioselectivity in the presence of tiny amounts of the polymeric sulphides, usually in solvent-free conditions (unless the phenol starting material is solid at temperatures even above about 50 °C). Notably, poly(alkylene sulphide)s containing longer spacer groups are particularly para-selective in the chlorination of m-cresol and m-xylenol, while, ones with shorter spacers are particularly para-selective in the chlorination of phenol, 2-chlorophenol, and o-cresol. Such chlorination processes result in some of the highest para/ortho ratios reported for the chlorination of phenols.

Highlights

Phenols are used as intermediates in the production of a variety of valuable industrial products such as pharmaceuticals [1], explosives [2], picric acid [3], azo dyes [4], antioxidants [5], plastics [6], and disinfectants [7]
Since the use of solids in substitution reactions of aromatic compounds had in some cases led to significant enhancement in para-selectivity, we hoped that the halogenation of phenols could be controlled in similar ways
Use of the cyclic dialkyl sulphides tetrahydrothiopyran and some methyl-substituted tetrahydrothiopyrans (6–9; Figure 3) produced similar results to dibutyl sulphide in reactions with phenol and m-cresol, and we showed that smaller quantities of both the dialkyl sulphide (0.28 mmol for 50 mmol of 1) and aluminium chloride (25–50 mg for 50 mmol of 1) could be used to gain similar levels of selectivity [63]

Summary

Introduction

Phenols are used as intermediates in the production of a variety of valuable industrial products such as pharmaceuticals (e.g., aspirin) [1], explosives [2], picric acid [3], azo dyes [4], antioxidants [5], plastics [6], and disinfectants [7]. We are concerned with commercially important chlorophenols, especially those derived by para-chlorination of those phenols that can be obtained in bulk from the distillation of crude petroleum or coal tar, notably phenol, o-cresol, m-cresol, and m-xylenol. Such chlorination reactions generally produce mixtures of ortho- and para-substituted phenols [8]. Commercial Importance of Chlorinated Phenols Chlorinated phenols and in particular 4-chloro isomers are useful intermediates in organic syntheses or as end products themselves They are produced on an industrial scale and used in the production of antiseptics, herbicides, pesticides, and dyes [9].

Research Group Background in Selective Aromatic Substitution Reactions

Early Studies of Halogenation of Phenols

Results with Simple Dialkyl Sulphides and Some Cyclic Analogues