Advanced Quantum Mechanical Simulations of Circular Dichroism Spectra

In quantum chemistry, scientists aim to solve the time-independent Schrödinger equation by employing a variety of approximation techniques whose accuracy are typically inversely proportional to their computational cost. This problem is amplified when it comes to chiral molecules, whose stereochemical assignments and associated chiroptical properties can be incredibly sensitive to small changes in their three-dimensional structure, requiring highly accurate theoretical methods. On the other hand, due to the polynomial scaling with system size, it is sometimes impractical to apply such methods to chemical compounds of broad scientific interest, especially when a multitude of low-energy conformations have to be accounted for as well. As a result, the assignment of absolute configurations to chiral compounds remains a tedious task. However, the characterization of these compounds is something that many different scientists are significantly invested in. The ultimate goal, then, is twofold: to gain useful insight by utilizing the electronic structure methods at your disposal while simultaneously developing new approximation techniques that can be used to push the boundaries on what is currently capable in computational chemistry. Therefore, we start by applying widely accepted density functional theory methods to predict optical rotations and electronic circular dichroism for naturally occurring antiplasmodial and anticancer drug candidates. We find that by comparing the computational results directly with those obtained through experimental measurement, we can provide reliable absolute config- uraitonal assignments to a variety of chiral compounds with numerous stereogenic centers. We also present the first ever prediction of vibrational circular dichroism with second-order Møller-Plesset perturbation theory. This extension opens the door to systematically improvable correlated wave function methods that can be employed when density functional theory fails or when higher accuracy results are required.