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 ¹ H 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.