Intrinsic Chiroptical Response: Can We Predict the Right Answer for the Right Reasons?

The “intrinsic handedness” that distinguishes the mirror-image forms (enantiomers) of a chiral molecule gives rise to a variety of intriguing phenomena, perhaps none of which has had as profound and sustained an impact on the physical sciences as the characteristic interactions that take place with polarized light. Although the signatures of this optical activity have been recognized for over two centuries, their fruitful application for the determination of absolute stereochemical configuration has been revolutionized by the advent of computational paradigms capable of predicting such properties from first principles. Efforts to probe the dispersive circular birefringence (CB) of isolated chiral molecules at nonresonant wavelengths will be presented, with emphasis directed towards the marked influence that intramolecular dynamics and intermolecular forces can exert on intrinsic electronic response. Requisite isolated-molecule measurements have been made possible by ongoing development of cavity ring-down polarimetry (CRDP), an ultrasensitive chiroptical probe that has permitted the first quantitative studies of optical rotatory dispersion (ORD or wavelength-resolved CB) to be conducted in rarefied gaseous media. Quantum-chemical analyses have been enlisted to unravel the provenance of experimental findings and to elucidate the synergism among electronic and nuclear degrees of freedom that ultimately governs observed behavior. By alleviating the pronounced effects incurred from environmental perturbations (e.g., solvation), vapor-phase ORD benchmarks will be shown to afford a critical assessment of burgeoning optical-activity calculations, as well as an incisive means to expose the strengths and shortcomings inherent to various computational protocols.