We propose and discuss an efficient scheme for the in silico sampling for parts of the molecular low-energy chemical space by semiempirical tight-binding methods combined with a meta-dynamics driven search algorithm.

This review covers a family of atomistic, mostly quantum chemistry (QC) based semiempirical methods for the fast and reasonably accurate description of large molecules in gas and condensed phase. The theory is derived from a density functional (DFT) perturbation expansion of the electron density in fluctuation terms to various orders similar to the original density functional tight binding model. The term “eXtended” in their name (xTB) emphasizes the parameter availability for almost the entire periodic table of elements (Z ≤ 86) and improvements of the underlying theory regarding, for example, the atomic orbital basis set, the level of multipole approximation and the treatment of the important electrostatic and dispersion interactions. A common feature of most members is their consistent parameterization on accurate gas phase theoretical reference data for geometries, vibrational frequencies and noncovalent interactions, which are the primary properties of interest in typical applications to systems composed of up to a few thousand atoms. Further specialized versions were developed for the description of electronic spectra and corresponding response properties. Besides a provided common theoretical background with some important implementation details in the efficient and free xtb program, various benchmarks for structural and thermochemical properties including (transition‐)metal systems are discussed. The review is completed by recent extensions of the model to the force‐field (FF) level as well as its application to solids under periodic boundary conditions. The general applicability together with the excellent cost‐accuracy ratio and the high robustness make the xTB family of methods very attractive for various fields of computer‐aided chemical research. This article is categorized under: Electronic Structure Theory > Ab Initio Electronic Structure Methods Electronic Structure Theory > Semiempirical Electronic Structure Methods Software > Quantum Chemistry

The application of quantum chemical, automatic multilevel modeling workflows for the determination of thermodynamic (e.g., conformation equilibria, partition coefficients, pK a values) and spectroscopic properties of relatively large, nonrigid molecules in solution is described. Key points are the computation of rather complete structure (conformer) ensembles with extremely fast but still reasonable GFN2-xTB or GFN-FF semiempirical methods in the CREST searching approach and subsequent refinement at a recently developed, accurate r 2 SCAN-3c DFT composite level. Solvation effects are included in all steps by accurate continuum solvation models (ALPB, (D)COSMO-RS). Consistent inclusion of thermostatistical contributions in the framework of the modified rigid-rotor-harmonic-oscillator approximation (mRRHO) based on xTB/FF computed PES is also recommended.

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.