The Thermodynamically Stable Form of Solid Barbituric Acid: The Enol Tautomer

Abstract

Stabilizing the unstable: In textbooks barbituric acid is always drawn in its keto tautomeric form, which is indeed preferred in solution and in most polymorphic phases. However, phase IV, obtained by grinding, consists of molecules in the enol form, as shown by neutron powder diffraction. This phase is found to be the most stable one at room temperature; the “unstable” enol tautomer is stabilized by a higher number of hydrogen bonds.

Determination of crystal structures and tautomeric states of 2-ammoniobenzenesulfonates by laboratory X-ray powder diffraction

“…Such a strong kinetic hindrance was observed, e.g. for the thermodynamically stable phase of barbituric acid, which is formed only by grinding and has never be found in (re)crystallisation experiments; even phase transition in suspension works only, if seed crystals of the thermodynamically stable phase are present [50]. In order to investigate, if 3 could crystallise in the same structure as 1, and if 4 could adopt the same structures as 1, 2 or 3, additional grinding and slurry experiments were performed on 3 and 4 by heterogenous seeding with 5% of crystals of the corresponding derivatives.…”

Single‐Crystal X‐ray Diffraction Structure of the Stable Enol Tautomer Polymorph of Barbituric Acid at 224 and 95 K

“…[9] Crystal growth from ethanol solution using as imilar procedure resulted in crystals with the same density as those from methanol. This is 3-4-fold below saturation at 60 8 8C.…”

“…[4][5][6][7] Ball-mill grinding experiments showed that atautomeric form can be prepared in this fashion. [9] Slurry experiments in methanol, ethanol, and butanol showed that this alternative tautomeric polymorph is the thermodynamically stable form. [2].Itwas,however,inferred from X-ray and neutron powder diffraction data that this tautomeric form is the enol structure (2;F igure 1).…”

“…[8] Ther esulting material was investigated by solid-state NMR and vibrational spectroscopy.A no bvious feature of the Raman spectrum of the new polymorphic form was the relative absence of the characteristic C = Os tretch vibrations.O nt his basis,i tw as concluded that the most likely possibility was the tri-hydroxy aromatic tautomer [8] as noted in Ref. [9] In that work cooling and evaporation methods of crystal growth and several solvents,i nitial temperatures,i nitial concentrations,and cooling rates were employed. [9] Slurry experiments in methanol, ethanol, and butanol showed that this alternative tautomeric polymorph is the thermodynamically stable form.…”

“…[2].Itwas,however,inferred from X-ray and neutron powder diffraction data that this tautomeric form is the enol structure (2;F igure 1). [9] Thed ensity of the tri-keto tautomer at room temperature [4] is 1.589 gcm À3 .T his distinct density difference permits easy detection of candidate tautomers using density gradient analysis. [9] In that work cooling and evaporation methods of crystal growth and several solvents,i nitial temperatures,i nitial concentrations,and cooling rates were employed.…”