Ligand additivity relationships enable efficient exploration of transition metal chemical space.

To accelerate the exploration of chemical space, it is necessary to identify the compounds that will provide the most additional information or value. A large-scale analysis of mononuclear octahedral transition metal complexes deposited in an experimental database confirms an under-representation of lower-symmetry complexes. From a set of around 1000 previously studied Fe(II) complexes, we show that the theoretical space of synthetically accessible complexes formed from the relatively small number of unique ligands is significantly (∼816k) larger. For the properties of these complexes, we validate the concept of ligand additivity by inferring heteroleptic properties from a stoichiometric combination of homoleptic complexes. An improved interpolation scheme that incorporates information about cis and trans isomer effects predicts the adiabatic spin-splitting energy to around 2 kcal/mol and the HOMO level to less than 0.2 eV. We demonstrate a multi-stage strategy to discover leads from the 816k Fe(II) complexes within a targeted property region. We carry out a coarse interpolation from homoleptic complexes that we refine over a subspace of ligands based on the likelihood of generating complexes with targeted properties. We validate our approach on nine new binary and ternary complexes predicted to be in a targeted zone of discovery, suggesting opportunities for efficient transition metal complex discovery.

Quantum Chemical Roots of Machine-Learning Molecular Similarity Descriptors.

In this work, we explore the quantum chemical foundations of descriptors for molecular similarity. Such descriptors are key for traversing chemical compound space with machine learning. Our focus is on the Coulomb matrix and on the smooth overlap of atomic positions (SOAP). We adopt a basic framework that allows us to connect both descriptors to electronic structure theory. This framework enables us to then define two new descriptors that are more closely related to electronic structure theory, which we call Coulomb lists and smooth overlap of electron densities (SOED). By investigating their usefulness as molecular similarity descriptors, we gain new insights into how and why Coulomb matrix and SOAP work. Moreover, Coulomb lists avoid the somewhat mysterious diagonalization step of the Coulomb matrix and might provide a direct means to extract subsystem information that can be compared across Born-Oppenheimer surfaces of varying dimension. For the electron density, we derive the necessary formalism to create the SOED measure in close analogy to SOAP. Because this formalism is more involved than that of SOAP, we review the essential theory as well as introduce a set of approximations that eventually allow us to work with SOED in terms of the same implementation available for the evaluation of SOAP. We focus our analysis on elementary reaction steps, where transition state structures are more similar to either reactant or product structures than the latter two are with respect to one another. The prediction of electronic energies of transition state structures can, however, be more difficult than that of stable intermediates due to multi-configurational effects. The question arises to what extent molecular similarity descriptors rooted in electronic structure theory can resolve these intricate effects.

Gaussian Process-Based Refinement of Dispersion Corrections.

We employ Gaussian process (GP) regression to adjust for systematic errors in D3-type dispersion corrections. We refer to the associated, statistically improved model as D3-GP. It is trained on differences between interaction energies obtained from PBE-D3(BJ)/ma-def2-QZVPP and DLPNO-CCSD(T)/CBS calculations. We generated a data set containing interaction energies for 1248 molecular dimers, which resemble the dispersion-dominated systems contained in the S66 data set. Our systems represent not only equilibrium structures but also dimers with various relative orientations and conformations at both shorter and longer distances. A reparametrization of the D3(BJ) model based on 66 of these dimers suggests that two of its three empirical parameters, a1 and s8, are zero, whereas a2 = 5.6841 bohr. For the remaining 1182 dimers, we find that this new set of parameters is superior to all previously published D3(BJ) parameter sets. To train our D3-GP model, we engineered two different vectorial representations of (supra-)molecular systems, both derived from the matrix of atom-pairwise D3(BJ) interaction terms: (a) a distance-resolved interaction energy histogram, histD3(BJ), and (b) eigenvalues of the interaction matrix ordered according to their decreasing absolute value, eigD3(BJ). Hence, the GP learns a mapping from D3(BJ) information only, which renders D3-GP-type dispersion corrections comparable to those obtained with the original D3 approach. They improve systematically if the underlying training set is selected carefully. Here, we harness the prediction variance obtained from GP regression to select optimal training sets in an automated fashion. The larger the variance, the more information the corresponding data point may add to the training set. For a given set of molecular systems, variance-based sampling can approximately determine the smallest subset being subjected to reference calculations such that all dispersion corrections for the remaining systems fall below a predefined accuracy threshold. To render the entire D3-GP workflow as efficient as possible, we present an improvement over our variance-based, sequential active-learning scheme [ J. Chem. Theory Comput. 2018 , 14 , 5238 ]. Our refined learning algorithm selects multiple (instead of single) systems that can be subjected to reference calculations simultaneously. We refer to the underlying selection strategy as batchwise variance-based sampling (BVS). BVS-guided active learning is an essential component of our D3-GP workflow, which is implemented in a black-box fashion. Once provided with reference data for new molecular systems, the underlying GP model automatically learns to adapt to these and similar systems. This approach leads overall to a self-improving model (D3-GP) that predicts system-focused and GP-refined D3-type dispersion corrections for any given system of reference data.