Optical signatures of molecular dissymmetry: combining theory with experiments to address stereochemical puzzles

Abstract

Modern chemistry emerged from the quest to describe the three-dimensional structure of molecules: van't Hoff's tetravalent carbon placed symmetry and dissymmetry at the heart of chemistry. In this Account, we explore how modern theory, synthesis, and spectroscopy can be used in concert to elucidate the symmetry and dissymmetry of molecules and their assemblies. Chiroptical spectroscopy, including optical rotatory dispersion (ORD), electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and Raman optical activity (ROA), measures the response of dissymmetric structures to electromagnetic radiation. This response can in turn reveal the arrangement of atoms in space, but deciphering the molecular information encoded in chiroptical spectra requires an effective theoretical approach. Although important correlations between ECD and molecular stereochemistry have existed for some time, a battery of accurate new theoretical methods that link a much wider range of chiroptical spectroscopies to structure have emerged over the past decade. The promise of this field is considerable: theory and spectroscopy can assist in assigning the relative and absolute configurations of complex products, revealing the structure of noncovalent aggregates, defining metrics for molecular diversity based on polarization response, and designing chirally imprinted nanomaterials. The physical organic chemistry of chirality is fascinating in its own right: defining atomic and group contributions to optical rotation (OR) is now possible. Although the common expectation is that chiroptical response is determined solely by a chiral solute's electronic structure in a given environment, chiral imprinting effects on the surrounding medium and molecular assembly can, in fact, dominate the chiroptical signatures. The theoretical interpretation of chiroptical markers is challenging because the optical properties are subtle, resulting from the strong electric dipole and the weaker electric quadrupole and magnetic dipole perturbations by the electromagnetic field. Moreover, OR arises from a combination of nearly canceling contributions to the electronic response. Indeed, the challenge posed by the chiroptical properties delayed the advent of even qualitatively accurate descriptions for some chiroptical signatures until the past decade when, for example, prediction of the observed sign of experimental OR became accessible to theory. The computation of chiroptical signatures, in close coordination with synthesis and spectroscopy, provides a powerful framework to diagnose and interpret the dissymmetry of chemical structures and molecular assemblies. Chiroptical theory now produces new schemes to elucidate structure, to describe the specific molecular sources of chiroptical signatures, and to assist in our understanding of how dissymmetry is templated and propagated in the condensed phase.

Figure 1

The absolute configuration of bistramide C was determined using NMR NOEs, J-couplings with TD-DFT calculations of molar optical rotations and circular dichroism (CD). From a total of 1024 stereoisomers that are theoretically possible for this structure, a pool of 16 and then 3 stereoisomers were identified as potential structures using the NMR and α_D data. Finally, out of the 3 possible stereoisomers, the absolute configuration of (+)-(6R,9S,11S,15R,16S,22R,23S, 27S,31S,34S)-bistramide C was deduced from its CD spectrum.

Figure 2

Measured (green) and computed Raman optical activity spectra derived from the extended left-handed PPII (blue) and the compact right-handed α_R (red) helical conformations of an alanine dipeptide model in aqueous solution. The fact that the simulated spectra account for the key experimental spectral features indicates that the dipeptide model assumes these conformations in aqueous solution.

Figure 3

Boltzmann-weighted atomic contribution maps (BWAMs) of the optical rotation (OR) of calyculin A (A) and B (B) fragments. The atoms are colored according to their contributions to the OR, which highlights the large effects arising from the CN group and the two adjacent carbon atoms. The difference BWAM (C) of the calyculin A and B fragments also clearly visualizes the dominance of the CN group in optical activity.

Figure 4

The concentration-dependent specific rotation, [α]_D, of (R)-pantolactone in carbon tetrachloride (CCl₄) at 26 °C. The computed [α]_D= χ_I[α_I] + χ_II[α_II] (red line) values are based on the theoretically obtained thermally averaged specific rotation of the monomer ([α_I]) and dimer ([α_II]) species (top structures). The mole fractions χ_I and χ_II of the monomer and dimer species were determined with the experimental K_eq = 8.9 ± 0.6 M^-1 at 26 °C.

Figure 5

Measured (dashed line) and computed (solid line) ORD of (S)-methyloxirane in water (●) and benzene (■). The hydrogen bonded methyloxirane-water adduct (top structure) dominates the ORD in aqueous solution. In contrast, the chiral benzene cluster (bottom structure) dominates the ORD in benzene.,

Figure 6

Distribution of optical rotation of (S)-methyloxirane-water adduct at 589 nm, [α]_D, as a function of water molecule position defined by the angle τ. The inserts show structures with water molecules on the same or opposite face of the oxirane ring from the methyl group, defined as the syn-or anti-configurations, respectively. The anti-configuration dominates the positive [α]_D of (S)-methyloxirane in water.

Figure 7

Schematic representations (A) of a chiral adsorbate (R-methylthiirane; green) and a gold cluster (yellow). Induced chiral-image charge densities using particle-in-a-box model illustrate (B) that the negatively charged sulfur groups (yellow) of the adsorbate dissymmetrically perturb the electron density in the box, leaving positive image charges in the central region (blue), and negative charges (red) on the edge of the box.

Figure 8

ORD (A) and depolarized right-angle ICP RayOA curves (B) of (+)-(5S, 11S)- Tröger’s base calculated using HF (▲) and DFT with B3LYP (■), BHLYP (●), BLYP (▼) functionals. Calculations used the 6-31G* basis set with the B3LYP/6-311G** optimized geometry. The predicted ORD curves show significant variation depending on the choice of the QM method. In contrast, the RayOA curves are uniformly negative in sign and possess nearly identical curvatures.

Figure 9

Chirality descriptors for an olfactophore model of structure-odor correlations. β_G² and β_A² are RayOA invariants derived from the dynamic molecular tensor properties G′ and A. The musky odorants (red) have negative β_G² and β_A². In contrast, the odorless compounds have positive β_G² and β_A². Thus, dynamic molecular tensor properties may be used as descriptor of structure-odor correlations.