Another Way to Separate Phenolics by Crystallizing of Co-crystals?

When Kilomentor comes upon some very specific information that might have general utility for separations of a function group class, he saves it in his personal files, until an appropriate process chemistry situation arises.  The trick is (i) to have saved the information and (ii) to read these notes over sufficiently so that when the possible application comes up, some internal mental alert will sound to remind himself that he has some information that might be useful. Then, it is easy enough to retrieve it, examine it in more depth and see whether it really could be part of a rugged, time-saving, and even perhaps an elegant solution.

In this blog, I would like to examine the content of the patent US5081263 which on its face teaches an improved means to purify meta or para-substituted hydroxylphenyl or hydroxylnaphthyl carboxylic acids.

The inventive trick is that the authors have discovered that aryl carboxylic acids bearing a phenolic group, not in an ortho position to the carboxyl group, can be advantageously crystallized from p-dioxane because co-crystals are formed using this particular solvent.

The inventors explain that “the particular feature of the said adducts is that hydrogen bridge bonds exist between the hydroxyl groups of the aromatic compounds and the oxygen atoms of the dioxane, so that the adducts are 2:1 adducts…..and the carboxyl groups of two hydroxycarboxylic acid molecules are, in turn, dimerized, so that relatively long chain-like arrangements can form.”

In other words, (and this is my interpretation), the carboxylic acid functionality has a strong preference in this medium to exist as acid dimers leaving the phenol hydroxyls un-associated, and in p-dioxane they strongly prefer making two hydrogen bonds between the two phenols and the two ether oxygens of a single dioxane molecule.  This leads to high molecular weight co-crystals.

The patent provides information to suggest that the molecules that might do this can have other non-interfering functional groups and they propose fluorine, chlorine, bromine or a nitro group as potentially not interfering. Interestingly, this nitro can be ortho to the phenol and the dioxane co-crystal will still form. A specific example is a crystallization of 4-hydroxy-3-nitrobenzoic acid.  Other teachings in the patent indicate that the crystallization of the cocrystals can be from mixtures of dioxane and water or dioxane and ethanol, so it would seem that hydroxyalkyl is also a  non-interfering. 

Useful as all this might be for separating hydroxylaryl carboxylic acids, it would seem that the usefulness might be broader and more significant. Carboxylic acids are not typically difficult to purify. In many other articles, KiloMentor has argued that in fact carboxylic acids are preferred intermediates in synthetic process design precisely because if a mixture is produced during synthesis, they can be separated by simple acid-base extraction from all non-acids and a mixture of acids can be separated by pH-controlled extraction, or extractive crystallization or by reversible formation of a myriad of salt derivatives.

The gift the patent may be providing is the possibility that phenolic, diphenolic, or even polyphenolic compounds may form co-crystals with p-dioxane, and simple phenols may form simple 2:1 adducts with dioxane. Now the separation of diphenols, phenols, and non-phenols is a more challenging goal than the separation of a group of carboxylic acids. Yes, phenols are weakly acidic and some of the strategies for separating acidic compounds, in general, do work but it is not as rugged a methodology and interfering reactivity from the more alkaline conditions (such as oxidation) can raise several ugly problems. 

High molecular weight phenols, called pseudophenols because their alkali salts are not extracted into water, may be extracted from hydrocarbon solvents with Claisen's alkali. 

Phenols also can form O-sulfate water-soluble salts that are easily extracted and crystallized.

At the same time it is quite true that this idea may not work out in any particular situation, but the key pedagogical point is that if you have collected the concept and have sufficient familiarity to recall it in the appropriate situation, you get one more simple isolation possibility to evaluate. Choosing from more potential and distinctly different approaches increase your chances for simple, rugged, elegant solutions.