Fully Automated Quantum-Chemistry-Based Computation of Spin–Spin-Coupled Nuclear Magnetic Resonance Spectra

We present a composite procedure for the quantum-chemical computation of spin–spin-coupled 1H NMR spectra for general, flexible molecules in solution that is based on four main steps, namely conformer/rotamer ensemble (CRE) generation by the fast tight-binding method GFN-xTB and a newly developed search algorithm, computation of the relative free energies and NMR parameters, and solving the spin Hamiltonian. In this way the NMR-specific nuclear permutation problem is solved, and the correct spin symmetries are obtained. Energies, shielding constants, and spin–spin couplings are computed at state-of-the-art DFT levels with continuum solvation. A few (in)organic and transition-metal complexes are presented, and very good, unprecedented agreement between the theoretical and experimental spectra was achieved. The approach is routinely applicable to systems with up to 100–150 atoms and may open new avenues for the detailed (conformational) structure elucidation of, for example, natural products or drug molecules.