Influence of intramolecular hydrogen bonding on the conformational equilibrium of cis‐3‐N,N‐dimethylaminocyclohexanol compared with trans‐3‐N,N‐dimethylaminocyclohexanol and cis‐ and trans‐3‐N,N‐dimethylamino‐1‐methoxycyclohexane

Abstract 1H NMR data show that concentration increase shifts the conformational equilibrium of cis‐3‐N,N‐dimethylaminocyclohexanol (1) (cis‐3‐DACH) from the 1aa conformer, stabilized by an intramolecular hydrogen bond (IAHB), to the 1ee conformer [43% (0.01 M) to 70% (0.40 m), in CCl4], which can form intermolecular hydrogen bonds (IEHB). The percentage of 1ee conformer also increases with the solvent basicity from 36% in C6D12 to 89% in DMSO. The conformational equilibrium of the trans isomer (trans‐3‐DACH) is also dependent on concentration, since 1ae increases from 77% (0.05 M) to 84% (0.40 M) in CCl4 but not with the solvent polarity. The occurrence of an IAHB in cis‐3‐DACH was confirmed by the study of a model compound, cis‐3‐N,N‐dimethylamino‐1‐methoxycyclohexane (2) (cis‐3‐DAMCH), lacking an OH group and presenting a single conformer 2ee (∼95%). The corresponding trans isomer (trans‐3‐DAMCH) behaves similarly to trans‐3‐DACH, since the 2ae conformer occurs as ∼83%, in the studied solvents. The PCMODEL program gave very good coupling constant values for the qualitative analysis of energy changes in the study of concentration and solvent effects, since the energy values obtained for cis and trans isomers of 3‐DACH were in good agreement with the theoretically calculated [B3LYP/6–311+g(d,p) level] values. The averaged calculated energy of the IAHB, for conformer 1aa of cis‐3‐DACH, with optimization of the reference structure and at several levels of theory, is 5.74 kcal mol−1 (1 kcal = 4.184 kJ).