Allophanates- Potentially Useful Reversible Highly Crystalline Solid Derivatives of Alcohols

kilomentor | 28 January, 2012 15:44

In scale-up during chemical process development, Kilomentor has proposed that it is not just minimizing the number of synthetic steps that leads most often to the most cost efficient process, but more often the simplicity and ruggedness of the steps. This is because it is the time and other resources that get invested in the separation and purification functions rather than the reaction per se that contributes most to the overall cost. It is quite possible that preparing a solid derivative and then converting it back to the original functionality may have cost advantages and purity advantages.

Alcohols that are liquids at ambient temperature in particular may be better isolated as a solid derivative rather than as selected fractions from a fractional distillation. Similarly even if an alcohol is a solid, if it is low melting and present in a product mixture, a better yield of pure product may be available by making a derivative and then converting it back to free alcohol. No alcohol derivative introduces more polarity in terms of hydrogen bond donors and acceptors for the same small increase in molecular weight than the allophanate derivative.

The allophanate derivative ( C-O-CO-NH -CO-NH2) is formed by condensation of the alcohol function with two equivalents of isocyanic acid, O=C=NH (or which can also be represented as its tautomer cyanic acid).

The formation of the allophanate can be expected to increase the water solubility relative to the parent alcohol compound and decrease its solubility in organic solvents. Residual cyanuric acid formed during the preparation of allophanates is somewhat soluble in cold water but particularly in hot water. It is insoluble in cold methanol, ether, acetone, benzene and chloroform. Because of its acidity it: Ka₁ 6.31X 10^-8 pKa₁ 7.20; Ka₂ 7.94 X 10^-12pKa₂ 11.14; it is quite soluble in alkaline media.

Except for those arising from lower alcohols, allophanate are well melting, highly crystalline compounds suitable for isolation . The compounds are easily recrystallized and the parent alcohol can be regenerated by warming the allophanate with methanoic alkali.

Depolymerization of cyanuric acid can be done at 360-400 C in a slow stream of carbon dioxide. The gas can be absorbed directly into the neat alcohol or the reagent can be absorbed in an organic solvent such as ether to create a 30-35% by weight solution.

Consider the hypothetical reduction of 4-methyl-3-penten-2-one, (mesityloxide), bp 129 C, by hydrogenation. There are three possible products that are alcohols: 4-methyl-2-pentanol, bp 132 C, (ketone and double bond reduced); 4-methyl-4-penten-2-ol, bp 131.7 C, (only ketone reduced): and 4-methyl-3-penten-2-ol, bp 132 C, (ketone reduced and double bond isomerized). It is likely that reaction conditions can be found that lead to substantially one desired substance but such an enriched mixture still could not be separated based on boiling points. A solution that could be considered is the formation of the allophanate derivatives and recrystallization to achieve the predominant compound pure followed by hydrolysis back to the parent alcohol.

The Prins reaction is expected to produce a 1,3-diol from formaldehyde and an olefin. This is not necessarily a clean reaction. In fact the infrequency of its application suggests that it may lead to multiple products. Formation of the bis-allophanates as a method to obtain a pure crystalline product seems to me to be interesting.

The literature suggests that allophanates are derivatives that can be expected to crystallize from even quite difficult mixtures. For example the method was useful in the isolation and purification of various vitamins from natural sources. Fieser & Fieser in Organic Chemistry, the Third Edition, Reinhold Publishing Company, 1956. “The isolation of two pure factors from wheat-germ oil concentrates in 1936 was simplified by the discovery of crystalline derivatives, allophanates, resulting from esterification of the factors with cyanic acid….. on hydrolysis of the derivatives, the two pure active factors were obtained as highly active pale yellow oils named alpha and beta tocopherol.”

Similarly the derivative was used by Windaus and coworkers in isolating Vitamin D₃ from an irradiation mixture. This is reported in Fieser & Fieser’s, Reagents for Organic Chemistry Vol. 1 pg. 171:

“Treatment of the crude, oily mixture with isocyanic acid afforded directly a solid product easily purified by recrystallization from acetone and converted into pure vitamin by hydrolysis.” Vitamin D₃ has mp 82-84 C while the allophanate had mp 173-174 C, so one can see the inherent advantage. The co-products of the hydrolysis are conveniently totally water soluble!