Structural chemistry of aldols

Structural investigation of organic compounds gives not only fundamental knowledge in chemistry but also guideline for design of functional materials and its synthetic strategies. The structure of aldols was systematically investigated. Intrinsic conformational preference was elucidated by DFT calculation of the simplest aldol, 3-hydroxypropanal. The "eclipsed" conformation with intramolecular hydrogen bond is the most stable. Cyclohexanone-derived aldols, which can fix at "eclipsed" conformation, were selected as standard compounds for systematic analysis of solution-phase behavior and crystal structure. The combination of molecular-weight measurement, NMR and IR studies in solution elucidated the detailed geometry of these typical aldols. The equilibrium distribution between conformers is controlled by the intramolecular and intermolecular hydrogen bond, gauche interactions between the vicinal substituents, and sometimes CH/pi attraction. Since the conformational preference is not always fitted with the assumption in the empirical method for determining the relative configuration (Stiles-House method), this method must be used with the greatest care. The preferred structure in solution often differs greatly from the crystalline-state geometry. Generally the racemic C(3)-unsubstituted cyclohexanone-based aldols crystallize as a monomer or a heterochiral dimer with the stable "eclipsed" conformation. The enantiomerically pure aldols, however, tend to form intermolecular hydrogen bonds generating a helical chain. Introduction of a C(3) substituent completely destroys the stable conformation yielding an unusual C(2)-C(3) trans-diaxial conformation. This enables the formation of a hydrogen-bonded polymer along screw axis or glide plane.