CREST-A program for the exploration of low-energy molecular chemical space.

Conformer-rotamer sampling tool (CREST) is an open-source program for the efficient and automated exploration of molecular chemical space. Originally developed in Pracht et al. [Phys. Chem. Chem. Phys. 22, 7169 (2020)] as an automated driver for calculations at the extended tight-binding level (xTB), it offers a variety of molecular- and metadynamics simulations, geometry optimization, and molecular structure analysis capabilities. Implemented algorithms include automated procedures for conformational sampling, explicit solvation studies, the calculation of absolute molecular entropy, and the identification of molecular protonation and deprotonation sites. Calculations are set up to run concurrently, providing efficient single-node parallelization. CREST is designed to require minimal user input and comes with an implementation of the GFNn-xTB Hamiltonians and the GFN-FF force-field. Furthermore, interfaces to any quantum chemistry and force-field software can easily be created. In this article, we present recent developments in the CREST code and show a selection of applications for the most important features of the program. An important novelty is the refactored calculation backend, which provides significant speed-up for sampling of small or medium-sized drug molecules and allows for more sophisticated setups, for example, quantum mechanics/molecular mechanics and minimum energy crossing point calculations.

Hydrocarbon Macrocycle Conformer Ensembles and 13 C-NMR Spectra.

NMR as a routine analytical method provides important three-dimensional structure information of compounds in solution. Here we apply the recently released CRENSO computational workflow for the automated generation of conformer ensembles to the quantum mechanical calculation of 13 C-NMR spectra of a series of flexible cycloalkanes up to C20 H40 . We evaluate the computed chemical shifts in comparison with corresponding experimental data in chloroform. It is shown that accurate and properly averaged theoretical NMR data can be obtained in about a day of computation time on a standard workstation computer. The excellent agreement between theory and experiment enables one to deduce preferred conformations of large, non-rigid macrocycles under ambient conditions from our automated procedure.

Computer-aided simulation of infrared spectra of ethanol conformations in gas, liquid and in CCl4 solution.

The recently developed efficient protocol combining implicit and explicit, accurate quantum-mechanical modeling of the condensed state (Katsyuba et al., J. Chem. Phys. 155, 024507 [2021]) is used to describe the IR spectra of liquid ethanol and its solutions in CCl4 . The relative abundance of the anti and gauche conformers of ethanol is shown to increase from ~40:60 in the gas phase to ~55:45 in the liquid phase. In spite of a moderate impact of media effects on the conformational composition of the liquid, the solvent strongly influences vibrational frequencies, IR intensities, and normal modes of each conformer, producing qualitatively different spectra compared to the gas phase and CCl4 solution. Further, these solvent effects affecting IR frequencies and intensities depend not only on the conformation of the solvated molecule but also on the solvating species. Nevertheless, vibrational frequencies of anti and gauche conformers of liquid ethanol and its several isotopomers practically coincide with each other. Convenient liquid-state conformational markers in the fingerprint region of IR spectra are revealed for the hydroxyl-deuterated species: CH3 CH2 OD, CH3 CHDOD, CH3 CD2 OD, and CD3 CD2 OD.

Automated Quantum Chemistry-Based Calculation of Optical Rotation for Large Flexible Molecules.

The calculation of optical rotation (OR, [α]D) for nonrigid molecules was limited to small systems due to the challenging problem of generating reliable conformer ensembles, calculating accurate Boltzmann populations and the extreme sensitivity of the OR to the molecules' three-dimensional structure. Herein, we describe and release the crenso workflow for the automated computation of conformer ensembles in solution and corresponding [α]D values for flexible molecules. A comprehensive set of 28 organic drug molecules (28-144 atoms) with experimentally determined values is used in our assessment. In all cases, the correct OR sign is obtained with an overall mean relative deviation of 72% (mean absolute deviation of 82 °[dm(g/cm3)]-1 for experimental values in the range -160 to 287 °[dm(g/cm3)]-1). We show that routine [α]D computations for very flexible, biologically active molecules are both feasible and reproducible in about a day of computation time on a standard workstation computer. Furthermore, we observed that the effect of energetically higher-lying structures in the ensemble on the OR is often averaged out and that in 23 out of 28 cases, the correct OR sign is obtained by just considering only the lowest free energy conformer. In four example cases, we show that the approach can also describe the OR of pairs of flexible diastereomers properly. In summary, even very sensitive, multifactorial physicochemical properties appear reliably predictable with minimal user input from efficiently automated quantum chemical methods.

Efficient Quantum Chemical Calculation of Structure Ensembles and Free Energies for Nonrigid Molecules.

The application of quantum chemical, automatic multilevel modeling workflows for the determination of thermodynamic (e.g., conformation equilibria, partition coefficients, pKa 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 r2SCAN-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.

Oxidation Under Reductive Conditions: From Benzylic Ethers to Acetals with Perfect Atom-Economy by Titanocene(III) Catalysis.

Described here is a titanocene-catalyzed reaction for the synthesis of acetals and hemiaminals from benzylic ethers and benzylic amines, respectively, with pendant epoxides. The reaction proceeds by catalysis in single-electron steps. The oxidative addition comprises an epoxide opening. An H-atom transfer, to generate a benzylic radical, serves as a radical translocation step, and an organometallic oxygen rebound as a reductive elimination. The reaction mechanism was studied by high-level dispersion corrected hybrid functional DFT with implicit solvation. The low-energy conformational space was searched by the efficient CREST program. The stereoselectivity was deduced from the lowest lying benzylic radical structures and their conformations are controlled by hyperconjugative interactions and steric interactions between the titanocene catalyst and the aryl groups of the substrate. An interesting mechanistic aspect is that the oxidation of the benzylic center occurs under reducing conditions.

Benchmark Study of Electrochemical Redox Potentials Calculated with Semiempirical and DFT Methods.

The calculation of redox potentials by semiempirical quantum mechanical (SQM) approaches is evaluated with a focus on the recently developed GFNn-xTB methods. The assessment is based on a data set comprising 313 experimental redox potentials of small to medium-sized organic and organometallic molecules in various solvents. This compilation is termed as ROP313 (reduction and oxidation potentials 313) and divided for analysis purposes into the organic subset OROP and the organometallic subset OMROP. Corresponding data for a few common density functional theory (DFT) functionals employing extended AO basis sets and small basis-set DFT composite schemes are computed for comparison. Continuum solvation models are used to calculate the important solvation free energy contribution. The results for ROP313 show that the GFNn-xTB methods provide a robust, efficient, and generally applicable workflow for the routine calculation of redox potentials. The GFNn-xTB methods outperform the PMx competitor for the OROP subset (mean absolute deviation from the experiment, MADGFN2-xTB = 0.30 V, MADGFN1-xTB = 0.31 V, PM6-D3H4 = 0.61 V, PM7 = 0.60 V), almost reaching low-cost DFT quality (MADB97-3c = 0.25 V) at drastically reduced computational cost (2-3 orders of magnitude). All SQM methods perform considerably worse for the OMROP subset. Here, the GFN2-xTB still yields semiquantitative results slightly better and more robustly than with the PMx methods (MADGFN2-xTB = 0.74 V, PM6-D3H4 = 0.78 V, PM7 = 0.82 V). The proposed workflow enables large-scale quantum chemical computations of organic and, to a lesser extent, organometallic molecule redox potentials on common laptop computers in seconds to minutes of computation time enabling, e.g., screening of extended compound libraries.

The first microsolvation step for furans: New experiments and benchmarking strategies.

The site-specific first microsolvation step of furan and some of its derivatives with methanol is explored to benchmark the ability of quantum-chemical methods to describe the structure, energetics, and vibrational spectrum at low temperature. Infrared and microwave spectra in supersonic jet expansions are used to quantify the docking preference and some relevant quantum states of the model complexes. Microwave spectroscopy strictly rules out in-plane docking of methanol as opposed to the top coordination of the aromatic ring. Contrasting comparison strategies, which emphasize either the experimental or the theoretical input, are explored. Within the harmonic approximation, only a few composite computational approaches are able to achieve a satisfactory performance. Deuteration experiments suggest that the harmonic treatment itself is largely justified for the zero-point energy, likely and by design due to the systematic cancellation of important anharmonic contributions between the docking variants. Therefore, discrepancies between experiment and theory for the isomer abundance are tentatively assigned to electronic structure deficiencies, but uncertainties remain on the nuclear dynamics side. Attempts to include anharmonic contributions indicate that for systems of this size, a uniform treatment of anharmonicity with systematically improved performance is not yet in sight.

Automated exploration of the low-energy chemical space with fast quantum chemical methods.

We propose and discuss an efficient scheme for the in silico sampling for parts of the molecular chemical space by semiempirical tight-binding methods combined with a meta-dynamics driven search algorithm. The focus of this work is set on the generation of proper thermodynamic ensembles at a quantum chemical level for conformers, but similar procedures for protonation states, tautomerism and non-covalent complex geometries are also discussed. The conformational ensembles consisting of all significantly populated minimum energy structures normally form the basis of further, mostly DFT computational work, such as the calculation of spectra or macroscopic properties. By using basic quantum chemical methods, electronic effects or possible bond breaking/formation are accounted for and a very reasonable initial energetic ranking of the candidate structures is obtained. Due to the huge computational speedup gained by the fast low-cost quantum chemical methods, overall short computation times even for systems with hundreds of atoms (typically drug-sized molecules) are achieved. Furthermore, specialized applications, such as sampling with implicit solvation models or constrained conformational sampling for transition-states, metal-, surface-, or noncovalently bound complexes are discussed, opening many possible applications in modern computational chemistry and drug discovery. The procedures have been implemented in a freely available computer code called CREST, that makes use of the fast and reliable GFNn-xTB methods.

Influencing the Self-Sorting Behavior of [2.2]Paracyclophane-Based Ligands by Introducing Isostructural Binding Motifs.

Two isostructural ligands with either nitrile (Lnit ) or isonitrile (Liso ) moieties directly connected to a [2.2]paracyclophane backbone with pseudo-meta substitution pattern have been synthesized. The ligand itself (Lnit ) or its precursors (Liso ) were resolved by HPLC on a chiral stationary phase and the absolute configuration of the isolated enantiomers was assigned by XRD analysis and/or by comparison of quantum-chemical simulated and experimental electronic circular dichroism (ECD) spectra. Surprisingly, the resulting metallosupramolecular aggregates formed in solution upon coordination of [(dppp)Pd(OTf)2 ] differ in their composition: whereas Lnit forms dinuclear complexes, Liso exclusively forms trinuclear ones. Furthermore, they also differ in their chiral self-sorting behavior as (rac)-Liso undergoes exclusive social self-sorting leading to a heterochiral assembly, whereas (rac)-Liso shows a twofold preference for the formation of homochiral complexes in a narcissistic self-sorting manner as proven by ESI mass spectrometry and NMR spectroscopy. Interestingly, upon crystallization, these discrete aggregates undergo structural transformation to coordination polymers, as evidenced by single-crystal X-ray diffraction.

The Chiral Trimer and a Metastable Chiral Dimer of Achiral Hexafluoroisopropanol: A Multi-Messenger Study.

1,1,1,3,3,3-hexafluoro-propan-2-ol aggregates preferentially into an achiral dimer of achiral monomers, but the trimer is found to prefer three metastable chiral monomer units arranged into a strained OH⋅⋅⋅O hydrogen-bonded ring, which is reinforced by secondary CH⋅⋅⋅FC interactions. This is shown by a combination of infrared, microwave, and Raman spectroscopy in supersonic jet expansions and supported by high-level quantum chemical calculations. It involves an activation of the monomers by >15 kJ mol-1 , clearly driven by the much stronger hydrogen-bond interaction available to the gauche and even more to the cis monomer units.

Raising the Bar in Aromatic Donor-Acceptor Interactions with Cyclic Trinuclear Gold(I) Complexes as Strong π-Donors.

Aromatic donor-acceptor interactions are of high importance in supramolecular chemistry, materials science and biology. Compared to other noncovalent interactions, such as hydrogen bonding, the binding is often weak. Here we show that strong donor-acceptor interactions between planar aromatics with binding free energies down to -10.1 kcal mol-1 and association constants of up to 2.34 × 107 L mol-1 for 1:1 complexes can be realized using cyclic trinuclear complexes of gold(I) with pyridinate, imidazolate, or carbeniate ligands. Data were obtained through NMR and UV/vis absorption spectroscopic studies and supported by quantum chemical calculations for a variety of acceptors. By using a specifically designed bridged naphthalene diimide-based acceptor with only one binding site, we furthermore show that a 1:2 (donor:acceptor) binding model is best suited to quantify the donor and acceptor/complex equilibrium. Scanning electron microscopy on selected donor-acceptor pairs shows crystalline supramolecular assemblies. We anticipate this study to be relevant for the future design of supramolecular systems and chemical sensors and the determination of binding energies between planar donors and acceptors.

Synthesis of 1,3-Amino Alcohols by Hydroxy-Directed Aziridination and Aziridine Hydrosilylation.

We describe an approach to N-tosyl 1,3-amino alcohols that consists of a diastereoselective aziridination reaction of acyclic allylic alcohols and an unprecedented regioselective hydrosilylation of α-hydroxy aziridines. The products contain up to three contiguous stereocenters. Computational studies outline key aspects of the aziridination mechanism, which is different and more intricate than anticipated.

Donor-acceptor interactions between cyclic trinuclear pyridinate gold(i)-complexes and electron-poor guests: nature and energetics of guest-binding and templating on graphite.

Donor-acceptor-type interactions between π-electron systems are of high relevance in the design of chemical sensors. Due to their electron-rich nature, cyclic trinuclear complexes (CTCs) of gold(i) are ideal receptor sites for electron-deficient aromatic analytes. Scanning tunneling microscopy provided insight into the structures of two-dimensional crystals of pyridinate gold CTCs that form on a graphite template at the solid/liquid interface. One polymorph thereof - in turn - templated the on-top co-adsorption of π-acidic pyrazolate CTCs as electron-poor guests up to a certain threshold. From NMR titration experiments, we quantified free energies of -6.1 to -7.5 kcal mol-1 for the binding between pyridinate gold(i) CTCs and π-acidic pyrazolate CTCs. Quantum chemical calculations revealed that these interactions are largely dominated by London dispersion. These results give a more detailed insight into a rational design of sensitive CNT- or graphene-based sensors for π-acidic analytes, such as electron-deficient aromatics.

The furan microsolvation blind challenge for quantum chemical methods: First steps.

Herein we present the results of a blind challenge to quantum chemical methods in the calculation of dimerization preferences in the low temperature gas phase. The target of study was the first step of the microsolvation of furan, 2-methylfuran and 2,5-dimethylfuran with methanol. The dimers were investigated through IR spectroscopy of a supersonic jet expansion. From the measured bands, it was possible to identify a persistent hydrogen bonding OH-O motif in the predominant species. From the presence of another band, which can be attributed to an OH-π interaction, we were able to assert that the energy gap between the two types of dimers should be less than or close to 1 kJ/mol across the series. These values served as a first evaluation ruler for the 12 entries featured in the challenge. A tentative stricter evaluation of the challenge results is also carried out, combining theoretical and experimental results in order to define a smaller error bar. The process was carried out in a double-blind fashion, with both theory and experimental groups unaware of the results on the other side, with the exception of the 2,5-dimethylfuran system which was featured in an earlier publication.

SN 2 Reactions at Tertiary Carbon Centers in Epoxides.

Described herein is a novel concept for SN 2 reactions at tertiary carbon centers in epoxides without activation of the leaving group. Quantum chemical calculations show why SN 2 reactions at tertiary carbon centers are proceeding in these systems. The reaction allows flexible synthesis of 1,3-diol building blocks for natural product synthesis with excellent control of the relative and absolute configurations.