Conformational preferences of trans-1,2- and cis-1,3- cyclohexanedicarboxylic acids in water and dimethyl sulfoxide as a function of the ionization state as determined from NMR spectroscopy and density functional theory quantum mechanical calculations

The populations of diaxial (aa) and diequatorial (ee) conformers of trans-1,2- and cis-1,3-cyclohexanedicarboxylic acids (CDCAs; 1 and 2, respectively) and their salts were determined in water and dimethyl sulfoxide (DMSO) solutions from vicinal proton-proton NMR J couplings (³J _HH). Optimized geometries and free energies for these compounds were obtained at the M06-2X/cc-pVTZ(-f)++ level. Although carboxylic acid groups in cyclohexane rings are generally believed to be far more stable (∼2 kcal/mol) in equatorial than axial positions, this investigation demonstrated that an aa conformation (normally assumed to be completely insignificant for these compounds) can be favored depending on the medium and ionization state: strong ee preferences (>90%) were observed in water and DMSO for both diacids and their salts, except for the dianion of 1 in DMSO, which was found to be substantially aa (∼57%). The possibility of intramolecular hydrogen bonding (H-bonding) was also investigated; the ratios of the ionization constants (K₁/K₂) indicated an absence of intramolecular H-bonding because K₁/K₂ ≪ 10⁴ (a standard criterion for non-H-bonding in dicarboxylic acids) for both 1 and 2 in water and also for 2 in DMSO. For 1, K₁/K₂ increased drastically in DMSO (K₁/K₂ = 4 × 10⁶), where ³J_HH and the ratio K₁/K_E = 10, K_E being the acidity constant of the monomethyl ester of 1, indicated the formation of an intramolecular H-bond for the monoanion in this solvent. An explanation for the observation of compact dianions in solution in terms of the generalized Born equation is also provided.