Optical Activity in Saturated Cyclic Amines: Untangling the Roles of Nitrogen-Inversion and Ring-Puckering Dynamics.

Area of Science:

• Physical Chemistry
• Computational Chemistry
• Spectroscopy

Background:

• Understanding the relationship between molecular structure and optical activity is crucial in stereochemistry.
• Cyclic amines exhibit complex conformational dynamics, including nitrogen inversion and ring puckering, which can influence their chiroptical properties.
• Previous studies have explored the optical activity of chiral molecules, but the interplay of conformational flexibility and solvent effects in saturated cyclic amines requires further elucidation.

Purpose of the Study:

• To investigate the dispersive optical activity of (R)-2-methylpyrrolidine (R-2MPY) and (S)-2-methylpiperidine (S-2MPI) under isolated and solvated conditions.
• To elucidate the roles of large-amplitude molecular motions, such as nitrogen-center inversion and ring-puckering, in determining optical activity.
• To compare experimental results with quantum-chemical predictions to validate theoretical models for predicting chiroptical properties.

Main Methods:

• Experimental measurement of optical rotatory dispersion (ORD) profiles for R-2MPY and S-2MPI in various solvents.
• Quantum-chemical calculations using density-functional theory (DFT) and coupled-cluster (CC) methods to determine molecular geometries and predict chiroptical signatures.
• Conformational analysis to identify low-lying energy structures and simulation of ensemble-averaged optical response using an independent-conformer ansatz and a polarizable continuum model (PCM) for solvation.

Main Results:

• Experimental ORD profiles for R-2MPY and S-2MPI were nearly mirror images and showed similar dependencies on solvent polarity.
• Quantum-chemical calculations identified four low-lying conformers for each molecule, differing in the orientation of substituents.
• Theoretical models incorporating coupled-cluster (CCSD) rotatory powers and free-energy calculations (CBS-APNO) accurately reproduced the intrinsic behavior of isolated molecules, but agreement decreased in solution, with solvent polarity stabilizing structures with larger dipole moments.

Conclusions:

• The study successfully correlated the dispersive optical activity of R-2MPY and S-2MPI with their conformational landscapes and dynamics.
• Prior claims of significant chiroptical contributions from twisted heterocyclic frameworks were refuted.
• Distinct ring-puckering mechanisms in R-2MPY (hindered pseudorotation) and S-2MPI (semi-inversion) were implicated in their observed chiroptical behaviors and solvent-dependent responses.