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42776-AC6
The Nonresonant Chiro-Optical Response of Isolated and Solvated Molecules
Molecular chirality plays pivotal roles in diverse fields of chemical, physical, and biological importance. The two molecules of opposite handedness comprising an enantiomeric pair exhibit wavelength-resolved optical activities (or interactions with circularly-polarized light) of equal magnitude yet opposite sign, thus affording a facile means for their relative discrimination. Nevertheless, the a priori correlation of a measured chiro-optical response with a specific enantiomer still presents formidable challenges, especially given the complexities accompanying strong environmental perturbations. Burgeoning theoretical methods promise to resolve these difficulties by computationally predicting requisite structure-property relationships; however, their ability to assist in the assignment of absolute stereochemical configuration remains a subject of study. The synergistic program of experimental and theoretical research conducted under the auspices of this PRF grant addresses such issues by probing the nonresonant optical activity (or circular birefringence) of model organic compounds under tandem solvated and isolated (solvent-free) conditions, where the latter vapor-phase work has exploited ultrasensitive Cavity Ring-Down Polarimetry (CRDP). Complementary quantum chemical calculations, performed at the highest levels of density-functional and coupled-cluster theory, have been employed to critically access and quantitatively interpret laboratory findings. A summary of the results that have emerged from these endeavors is as follows:
1. Solvation can influence nonresonant optical activity in pronounced and counterintuitive ways, with solvent-induced perturbations capable of modifying the magnitude and the sign of chiro-optical response evoked from rigid molecules.
2. Solvents of high dielectric constant (e.g., acetonitrile) consistently provide better mimics of isolated-molecule optical activity than their less-polar counterparts (e.g., cyclohexane), a finding that would appear to contradict conventional wisdom regarding the nature of solute-solvent interactions. Canonical models of implicit solvation (e.g., Onsager Reaction Field Theory) are incapable of rationalizing chiro-optical results obtained for nominally-rigid species.
3. Conformational flexibility (extrinsic non-rigidity) can modify optical activity grossly, with the pronounced temperature dependence exhibited by specific rotation parameters reflecting changes in the relative population of structural isomers that often possess antagonistic chiro-optical properties. Consequently, the differential stabilization of individual conformers upon solvation (owing, in part, to their unique distributions of charge density) strongly affects the overall response evoked from an ensemble of non-rigid chiral molecules.
4. Vibrational motion (intrinsic non-rigidity) can influence the chiro-optical response evoked from solvated and isolated species significantly. In some cases, vibrational averaging over zero-point displacement of the molecular framework is essential for the reliable prediction of optical activity from quantum chemical calculations.
5. Direct sum-over-states calculations of specific rotation have shown that contributions arising from an unphysically-large number of excited states must be included for convergence to be achieved with optical activity predictions deduced from linear response theory. This result highlights critical inadequacies of conventional quantum chemical basis sets, which describe core-electronic features well, but afford less attention to properties that are dominated by the peripheral distribution of electron density (viz., optical activity).
6. Molecules that attain chirality by virtue of stereogenic axes (e.g., allenes) have been found to exhibit surprisingly large and systematic differences between their isolated and solvated nonresonant chiro-optical properties, despite the fact that solution-phase specific rotation parameters depend only slightly on solvent medium. Significant discrepancies have been uncovered between density-functional and coupled-cluster predictions of optical activity for such species.
7. For non-rigid, polar molecules dissolved in media that do not support specific solute-solvent interactions, density-functional calculations of conformer-specific optical activity combined with polarizable continuum models of solvation (to gauge conformer populations) provide a viable approach for predicting nonresonant chiro-optical response. However, the results emerging from such thermal-averaging procedures depend critically upon the quality of attendant free-energy analyses (relative DG values for conformers must be obtained with <10% accuracy), as well as on the polarity differences among conformers (large changes are best suited for continuum dielectric models).
Molecules targeted by ongoing PRF efforts have been selected to embody diverse physical/chemical characteristics and unique structural/bonding motifs that reflect upon the issues mentioned above. This research program depends heavily on the active participation of graduate/undergraduate students and postdoctoral fellows, who often serve as the primary nexus for the synergistic exchange of ideas and information. Students are trained in a collegial atmosphere that encourages individual excellence, yet still fosters the cooperative spirit essential for fruitful execution of substantial efforts. All personnel share in the implementation and interpretation of chiro-optical studies, thereby gaining valuable experience in endeavors that span the entire realm of chemistry (from organic synthesis to chemical physics) and impact upon frontier disciplines of science. Consequently, a significant development of human resources, as embodied in the training of our future generation of scientists, engineers, and educators, is being accomplished in addition to completion of stated research goals.
