Hyperconjugative and Electrostatic Interactions as Anomeric Triggers in Archetypical 1,4-Dioxane Derivatives.

The anomeric effect accounts for the greater thermodynamic stability of axially arranged six-membered heterocycles holding an electronegative substituent at the C1 position. Within a frame of no general consensus, two different theories are typically claimed to justify this effect mostly based on either hyperconjugative or electrostatic factors. Here we report a theoretical-experimental study of the role of both as anomeric triggers in two archetypical 1,4-dioxane derivatives, using a suitable combination of spectroscopic (IR and vibrational circular dichroism) and computational techniques for the analysis of the solvation environment effect in their anomeric choices. VCD and IR spectroscopies are used as conformer-discriminating tools: a detailed analysis of the evolution of the spectral profiles allows assessing the theoretically predicted changes in the experimental α/ß ratios when changing the polar solvent, which are fully explained on the basis of an extensive NBO energy partition scheme that provides a detailed view of the role of hyperconjugative and electrostatic interactions as anomeric regulators. Our results suggest that the anomeric equilibrium cannot be described by a single stereoelectronic effect but by the combined contribution of hyperconjugation and electrostatic repulsions, so that the ß-anomeric choice in polar solvents is markedly driven by the strong attenuation of electrostatic repulsive interactions that occurs in solution.

Vibrational circular dichroism and theoretical study of the conformational equilibrium in (-)-S-nicotine.

We report an extensive study of the molecular and electronic structure of (-)-S-nicotine, to deduce the phenomenon that controls its conformational equilibrium and to solve its solution-state conformer population. Density functional theory, ab initio, and molecular mechanics calculations were used together with vibrational circular dichroism (VCD) and Fourier transform infrared spectroscopies. Calculations and experiments in solution show that the structure and the conformational energy profile of (-)-S-nicotine are not strongly dependent on the medium, thus suggesting that the conformational equilibrium is dominated by hyperconjugative interactions rather than repulsive electronic effects. The analysis of the first recorded VCD spectra of (-)-S-nicotine confirmed the presence of two main conformers at room temperature. Our results provide further evidence of the hypersensitivity of vibrational optical activity spectroscopies to the three-dimensional structure of chiral samples and prove their suitability for the elucidation of solution-state conformer distribution.

Effect of substituents and hydrogen bonding on barrier heights in dehydration reactions of carbon and silicon geminal diols.

Activation barrier heights for the dehydration reaction of geminal carbinols and silanediols R'R″X(OH)(2) (X = C, Si) were estimated at the B3LYP and MP2 levels of theory employing Dunning's correlation-consistent triple-zeta basis sets. It was shown that the barrier height for carbon derivatives steadily decreases upon substitution by R groups, usually termed as electron-donating, such as alkyl and amino groups. Substitution by electron-withdrawing groups leads, however, only to small changes in barrier heights compared to that of methanediol. A similar tendency was also found for silicon derivatives, but high activation barriers of this reaction remain even for amino group substituted silanediols. Introduction of additional water molecules into the reactive space of carbinol dehydration drastically reduces barrier heights and brings the transition state energy for methanediol close to the experimental value. The difference between dehydration barrier heights for both methanediol and carbinols with electron-rich substituents becomes well-defined for dimeric species. The higher acidity of the hydroxyl group protons in molecules containing halogens and C==O groups brings about a noticeable growth in the dehydration barrier heights of these compounds. This difference in barrier heights for oligomeric species may be the reason for the stability of carbinols with electron-rich substituents.

Study of the chelating properties of Ge(OH)2 functionality as metal binding group for Zn2+ cation in simplified protease-like environments: a DFT analysis.

The development of protease's inhibitors is an active field of research in the pharmaceutical industry. As concerns the design of new inhibitors, the theoretical study of the binding patterns and energies of known metal binding groups (MBGs) toward Zn(2+) using quantum-chemical calculations may offer a better understanding of their interaction models and may be useful for the improvement and design of novel ZBGs. Here the properties of gem-Ge(OH)(2)-based compounds as ZBG were assessed theoretically using DFT calculations. [Zn(Imdz)(2) R - OH(2)](2+) complexes (Imdz =imidazole rings; R = imidazole ring, acetic acid molecule or acetate anion) were used to partially reproduce the coordination sphere in metalloproteases (ACE, amgiotensin converting enzyme, and TLN, thermolysine) being inhibited by related compounds (i.e., silanediols). The MBG- Zn(2+) interaction was analyzed through the energy of the reaction: [Zn(Imdz)(2) R - OH(2)](2+) + L → [Zn(Imdz)(2) R - L](2+) + H(2)O using DFT (M06L/cc-pVDZ) in gas-phase and in solution (IEF-PCM). Although the functional used (M06L) has proven its efficiency to study systems containing transition metal governed by non-covalent interactions, dispersion effects were implemented by the correction of the computed energies using the DFT-D3 program. Accounting for dispersion effects produced a systematic increase of c.a. 13 kJ mol(-1) on the energies, whereas the effect of solvent goes in the opposite direction (i.e., BE under the IEF-PCM model are on average 125 kJ mol(-1) lower). The Ge(OH)(2) - Zn(2+) interaction seems to be similar (or even stronger) than the Si(OH)(2) -Zn(2+). Their better performance as ZBG is explained by the combined NBO-AIM analysis. The results of this work may encourage the preparation, isolation, and experimental assay of the chelating properties of these compounds, which may propose a new family of protease's inhibitors.