Impact of dielectric constant of solvent on the formation of transition metal-ammine complexes.

The DFT-level computational investigations into Gibbs free energies (ΔG) demonstrate that as the dielectric constant of the solvent increases, the stabilities of [M(NH3 )n ]2+/3+ (n = 4, 6; M = selected 3d transition metals) complexes decrease. However, there is no observed correlation between the stability of the complex and the solvent donor number. Analysis of the charge transfer and Wiberg bond indices indicates a dative-bond character in all the complexes. The solvent effect assessed through solvation energy is determined by the change in the solvent accessible surface area (SASA) and the change in the charge distribution that occurs during complex formation. It has been observed that the SASA and charge transfer are different in the different coordination numbers, resulting in a variation in the solvent effect on complex stability in different solvents. This ultimately leads to a change between the relative stability of complexes with different coordination numbers while increasing the solvent polarity for a few complexes. Moreover, the findings indicate a direct relationship between ΔΔG (∆Gsolvent -∆Ggas ) and ΔEsolv , which enables the computation of ΔG for the compounds in a particular solvent using only ΔGgas and ΔEsolv . This approach is less computationally expensive.

Many-body Effects on Electronic Transport in Molecular Junctions: A Quantum Perspective.

This concept delves into quantum particle transport at the nanoscale, with a particular focus on how electrons move through molecular circuits. The thriving field of single molecular electronics benefits from the unique electrical and other properties of nanostructures. It concentrates on single molecular junctions that serve as bridges between electrodes. In this context, the electronic correlation-induced many-body effect gives rise to resonant states. These states, along with conductance, depend on electron spin. Thus, the field acts as a bridge between quantum and macroscopic worlds, unveiling unique behaviors of electrons. Additionally, external factors, such as magnetic fields and voltages, offer means to control the electron correlation in these junctions.

Similarities and Differences of Hydridic and Protonic Hydrogen Bonding.

Ab initio calculations were employed to investigate the interactions between selected electron-donating groups, characterized by M-H bonds (where M represents a transition metal and H denotes a hydridic hydrogen), and electron-accepting groups featuring both σ- and π-holes. The study utilized the ωB97X-D3BJ/def2-TZVPPD level of theory. Hydridic hydrogen complexes were found in all complexes with σ- and π-holes. A comparative analysis was conducted on the properties hydridic H-bond complexes, presented here and those studied previously, alongside an extended set of protonic H-bonds complexes. While the stabilization energies changes in M-H bond lengths, vibrational frequencies, intensities of the spectral bands, and charge transfer for these complexes are comparable, the nature of hydridic and protonic H-bonds fundamentally differ. In protonic H-bond complexes, the main stabilization forces arise from electrostatic contributions, while in hydridic H-bond complexes, dispersion energy, is the primary stabilization factor due to the excess of electrons and thus larger polarizability at hydridic H. The finding represents an important characteristic that distinguishes hydridic H-bonding from protonic H-bonds.

The Stability of Hydrogen-Bonded Ion-Pair Complex Unexpectedly Increases with Increasing Solvent Polarity.

The generally observed decrease of the electrostatic energy in the complex with increasing solvent polarity has led to the assumption that the stability of the complexes with ion-pair hydrogen bonds decreases with increasing solvent polarity. Besides, the smaller solvent-accessible surface area (SASA) of the complex in comparison with the isolated subsystems results in a smaller solvation energy of the latter, leading to a destabilization of the complex in the solvent compared to the gas phase. In our study, which combines Nuclear Magnetic Resonance, Infrared Spectroscopy experiments, quantum chemical calculations, and molecular dynamics (MD) simulations, we question the general validity of this statement. We demonstrate that the binding free energy of the ion-pair hydrogen-bonded complex between 2-fluoropropionic acid and n-butylamine (CH3CHFCOO-…NH3But+) increases with increased solvent polarity. This phenomenon is rationalized by a substantial charge transfer between the subsystems that constitute the ion-pair hydrogen-bonded complex. This unexpected finding introduces a new perspective to our understanding of solvation dynamics, emphasizing the interplay between solvent polarity and molecular stability within hydrogen-bonded systems.

Hydrogen Bonding with Hydridic Hydrogen-Experimental Low-Temperature IR and Computational Study: Is a Revised Definition of Hydrogen Bonding Appropriate?

Spectroscopic characteristics of Me3Si-H···Y complexes (Y = ICF3, BrCN, and HCN) containing a hydridic hydrogen were determined experimentally by low-temperature IR experiments based on the direct spectral measurement of supersonically expanded intermediates on a cold substrate or by the technique of argon-matrix isolation as well as computationally at harmonic and one-dimensional anharmonic levels. The computations were based on DFT-D, MP2, MP2-F12, and CCSD(T)-F12 levels using various extended AO basis sets. The formation of all complexes related to the redshift of the Si-H stretching frequency upon complex formation was accompanied by an increase in its intensity. Similar results were obtained for another 10 electron acceptors of different types, positive σ-, π-, and p-holes and cations. The formation of HBe-H···Y complexes, studied only computationally and again containing a hydridic hydrogen, was characterized by the blueshift of the Be-H stretching frequency upon complexation accompanied by an increase in its intensity. The spectral shifts and stabilization energies obtained for all presently studied hydridic H-bonded complexes were comparable to those in protonic H-bonded complexes, which has prompted us to propose a modification of the existing IUPAC definition of H-bonding that covers, besides the classical protonic form, the non-classical hydridic and dihydrogen forms.

The unusual stability of H-bonded complexes in solvent caused by greater solvation energy of complex compared to those of isolated fragments.

Here, the effect of solvent on the stability of non-covalent complexes, was studied. These complexes were from previously published S22, S66, and X40 datasets, which include hydrogen-, halogen- and dispersion-bonded complexes. It was shown that the charge transfer in the complex determines whether the complex is stabilized or destabilized in solvent.

Strong Be-N Interaction Induced Complementary Chemical Tuning to Design a Dual-gated Single Molecule Junction.

The interaction between pyridines and the π-hole of BeH2 leads to the formation of strong beryllium-bonded complexes. Theoretical investigations demonstrate that the Be-N bonding interaction can effectively regulate the electronic current through a molecular junction. The electronic conductance exhibits distinct switching behavior depending on the substituent groups at the para position of pyridine, highlighting the role of Be-N interaction as a potent chemical gate in the proposed device. The complexes exhibit short intermolecular distances ranging from 1.724 to 1.752 Å, emphasizing their strong binding. Detailed analysis of electronic rearrangements and geometric perturbations upon complex formation provides insights into the underlying reasons for the formation of such strong Be-N bonds, with bond strengths varying from -116.25 to -92.96 kJ/mol. Moreover, the influence of chemical substituents on the local electronic transmission of the beryllium-bonded complex offers valuable insights for the implementation of a secondary chemical gate in single-molecule devices. This study paves the way for the development of chemically gateable, functional single-molecule transistors, advancing the design and fabrication of multifunctional single-molecule devices in the nanoscale regime.

The Impact of the Solvent Dielectric Constant on A←NH3 Dative Bond Depends on the Nature of the Lewis Electron-Pair Systems.

The present work aims to determine to what extent the value of the dielectric constant of the solvent can influence the dative bond in Lewis electron pair bonding systems. For this purpose, two different systems, namely H3 B←NH3 and {Zn←(NH3 )}2+ , were studied in selected solvents with significantly different dielectric constants. Based on the results from state-of-the-art computational methods using DFT, constrained DFT, energy decomposition analyses, solvent accessible surface area, and charge transfer calculations, we found that the stability of the neutral H3 B←NH3 system increases with increasing solvent polarity. In contrast, the opposite trend is observed for the positively charged {Zn←(NH3 )}2+ . The observed changes are attributed to different charge redistributions in neutral and charged complexes, which are reflected by a different response to the solvent and are quantified by changes in solvation energies.

Trends in the stability of covalent dative bonds with variable solvent polarity depend on the charge transfer in the Lewis electron-pair system.

In general, the stability of neutral complexes with dative bonds increases as the polarity of the solvent increases. This is based on the fact that the dipole moment of the complex increases as the charge transferred from the donor to the acceptor increases. As a result, the solvation energy of the complex becomes greater than that of subsystems, causing an increase in the stabilization energy with increasing solvent polarity. Our research confirms this assumption, but only when the charge transfer is sufficiently large. If it is below a certain threshold, the increase in the complex's dipole moment is insufficient to result in a higher solvation energy than subsystems. Thus, the magnitude of the charge transfer in the Lewis electron-pair system determines the stability trends of dative bonds with varying solvent polarity. We used molecular dynamics (MD) simulations based on an explicit solvent model, which is considered more reliable, to verify the results obtained with a continuous solvent model.

Unexpected Strengthening of the H-Bond Complexes in a Polar Solvent Due to a More Efficient Solvation of the Complex Compared to Isolated Monomers.

It is generally assumed that hydrogen-bonded complexes are less stable in solvents than in the gas phase and that their stability decreases with increasing solvent polarity. This assumption is based on the size of the area available to the solvent, which is always smaller in the complex compared to the subsystems, thereby reducing the solvation energy. This reduction prevails over the amplification of the electrostatic hydrogen bond by the polar solvent. In this work, we show, using experimental IR spectroscopy and DFT calculations, that there are hydrogen-bonded complexes whose stability becomes greater with increasing solvent polarity. The explanation for this surprising stabilization is based on the analysis of the charge redistribution in the complex leading to increase of its dipole moment and solvation energy. Constrained DFT calculations have shown a dominant role of charge transfer over polarization effects for dipole moment and solvation energy.

Addition Reaction between Piperidine and C60 to Form 1,4-Disubstituted C60 Proceeds through van der Waals and Dative Bond Complexes: Theoretical and Experimental Study.

A combined computational and experimental study reveals the character of the C60 complexes with piperidine formed under different reaction conditions. The IR and NMR experiments detect the dative bond complex, which according to NMR, is stable in the oxygen-free environment and transforms to the adduct complex in the presence of O2. Computational studies on the character of reaction channels rationalize the experimental observations. They show that the piperidine dimer rather than a single piperidine molecule is required for the complex formation. The calculations reveal significant differences in the dative bond and adduct complexes' character, suggesting a considerable versatility in their electronic properties modulated by the environment. This capability offers new application potential in several fields, such as in energy storage devices.

Structure-directed formation of the dative/covalent bonds in complexes with C70piperidine.

The combined experimental-computational study has been performed to investigate the complexes formed between C70 carbon allotrope and piperidine. The results of FT-IR, H-NMR, and C-NMR measurements, together with the calculations based on the DFT approach and molecular dynamics simulations, prove the existence of dative/covalent bonding in C70piperidine complexes. The dative bond forms not only at the region of five- and six-membered rings, observed previously with C60, but also at the region formed of six-membered rings. The structure, i.e., nonplanarity, explains the observed dative bond formation. New findings on the character of interaction of secondary amines with C70 bring new aspects for the rational design of modified fullerenes and their applications in electrocatalysis, spintronics, and energy storage.

Cyclo[n]carbons Form Strong N → C Dative/Covalent Bonds with Piperidine.

The newly synthesized C18 ring is demonstrated as the smallest all-carbon acceptor that exhibits strong electron acceptance. This study provides a quantum-chemical investigation of the electron-acceptance behavior of monocyclic carbon rings with a particular emphasis on C18 through the formation of a dative bond with piperidine. The results show that Cn rings form strong dative bonds with piperidine, whereas the respective van der Waals (vdW) complexes are higher in energy. The main driving force is the release of angle strain of cyclo[n]carbons caused by the change in hybridization from sp to sp2 associated with the formation of the dative bond. On the contrary, other sp allotropes, diynes, favorably form vdW complexes. Molecular dynamics (MD) simulations support the stability of the dative bond throughout a simulation of 20 ps. This opens up the possibility of stabilizing highly reactive C18 through dative/covalent functionalization.

Multipodal insulin mimetics built on adamantane or proline scaffolds.

Multi-orthogonal molecular scaffolds can be applied as core structures of bioactive compounds. Here, we prepared four tri-orthogonal scaffolds based on adamantane or proline skeletons. The scaffolds were used for the solid-phase synthesis of model insulin mimetics bearing two different peptides on the scaffolds. We found that adamantane-derived compounds bind to the insulin receptor more effectively (Kd value of 0.5 µM) than proline-derived compounds (Kd values of 15-38 µM) bearing the same peptides. Molecular dynamics simulations suggest that spacers between peptides and central scaffolds can provide greater flexibility that can contribute to increased binding affinity. Molecular modeling showed possible binding modes of mimetics to the insulin receptor. Our data show that the structure of the central scaffold and flexibility of attached peptides in this type of compound are important and that different scaffolds should be considered when designing peptide hormone mimetics.

The Existence of a N→C Dative Bond in the C60 -Piperidine Complex.

The complexes formed between carbon allotropes (C20 , C60 fullerenes, graphene, and single-wall carbon nanotubes) and piperidine have been investigated by means of computational quantum chemical and experimental IR and NMR techniques. Alongside hydrogen bonds, the C⋅⋅⋅N tetrel bond, and lone-pair⋅⋅⋅π interactions, the unexpected N→C dative/covalent bond has been detected solely in complexes of fullerenes with piperidine. Non-planarity and five-member rings of carbon allotropes represent the key structural prerequisites for the unique formation of a dative N→C bond. The results of thermodynamics calculations, molecular dynamics simulations, and NMR and FTIR spectroscopy explain the specific interactions between C60 and piperidine. The differences in behavior of individual carbon allotropes in terms of dative bonding formation brings a new insight into their controllable organic functionalization.

Mutations at hypothetical binding site 2 in insulin and insulin-like growth factors 1 and 2 result in receptor- and hormone-specific responses.

Information on how insulin and insulin-like growth factors 1 and 2 (IGF-1 and -2) activate insulin receptors (IR-A and -B) and the IGF-1 receptor (IGF-1R) is crucial for understanding the difference in the biological activities of these peptide hormones. Cryo-EM studies have revealed that insulin uses its binding sites 1 and 2 to interact with IR-A and have identified several critical residues in binding site 2. However, mutagenesis studies suggest that Ile-A10, Ser-A12, Leu-A13, and Glu-A17 also belong to insulin's site 2. Here, to resolve this discrepancy, we mutated these insulin residues and the equivalent residues in IGFs. Our findings revealed that equivalent mutations in the hormones can result in differential biological effects and that these effects can be receptor-specific. We noted that the insulin positions A10 and A17 are important for its binding to IR-A and IR-B and IGF-1R and that A13 is important only for IR-A and IR-B binding. The IGF-1/IGF-2 positions 51/50 and 54/53 did not appear to play critical roles in receptor binding, but mutations at IGF-1 position 58 and IGF-2 position 57 affected the binding. We propose that IGF-1 Glu-58 interacts with IGF-1R Arg-704 and belongs to IGF-1 site 1, a finding supported by the NMR structure of the less active Asp-58-IGF-1 variant. Computational analyses indicated that the aforementioned mutations can affect internal insulin dynamics and inhibit adoption of a receptor-bound conformation, important for binding to receptor site 1. We provide a molecular model and alternative hypotheses for how the mutated insulin residues affect activity.

Optimization of norbornyl-based carbocyclic nucleoside analogs as cyclin-dependent kinase 2 inhibitors.

We report on the discovery of norbornyl moiety as a novel structural motif for cyclin-dependent kinase 2 (CDK2) inhibitors which was identified by screening a carbocyclic nucleoside analogue library. Three micromolar hits were expanded by the use of medicinal chemistry methods into a series of 16 novel compounds. They had prevailingly micromolar activities against CDK2 and the best compound of the series attained IC50 of 190 nM. The binding modes were explored in molecular details by modeling and docking. Quantum mechanics-based scoring was used to rationalize the affinities. In conclusion, the discovered 9-hydroxymethylnorbornyl moiety was shown by joint experimental-theoretical efforts to be able to serve as a novel substituent for CDK2 inhibitors. This finding opens door to the exploration of chemical space towards more effective derivatives targeting this important class of protein kinases.

Benchmark Data Sets of Boron Cluster Dihydrogen Bonding for the Validation of Approximate Computational Methods.

The success of approximate computational methods, such as molecular mechanics, or dispersion-corrected density functional theory, in the description of non-covalent interactions relies on accurate parameterizations. Benchmark data sets are thus required. This area is well developed for organic molecules and biomolecules but practically non-existent for boron clusters, which have been gaining in importance in modern drug as well as material design. To fill this gap, we have introduced two data sets featuring the most common non-covalent interaction of boron clusters, the dihydrogen bond, and calculated reference interaction energies at the "golden standard" CCSD(T)/CBS level. The boron clusters studied interact with formamide, methanol, water and methane at various distances and in two geometrical arrangements. The performance of the tested approximate methods is variable and recommendations for further use are given.

Ground state of the Fe(ii)-porphyrin model system corresponds to quintet: a DFT and DMRG-based tailored CC study.

Fe(ii)-porphyrins play an important role in many reactions relevant to material science and biological processes, due to their closely lying spin states. Although the prevalent opinion is that these systems posses the triplet ground state, the recent experiment on Fe(ii)-phthalocyanine under conditions matching those of an isolated molecule points toward the quintet ground state. We present a thorough DFT and DMRG-based tailored CC study of Fe(ii)-porphyrin model, in which we address all previously discussed correlation effects. We examine the importance of geometrical parameters, the Fe-N distances in particular, and conclude that the system possesses the quintet ground state.

Impressive Enrichment of Semiempirical Quantum Mechanics-Based Scoring Function: HSP90 Protein with 4541 Inhibitors and Decoys.

This paper describes the excellent performance of a newly developed scoring function (SF), based on the semiempirical QM (SQM) PM6-D3H4X method combined with the conductor-like screening implicit solvent model (COSMO). The SQM/COSMO, Amber/GB and nine widely used SFs have been evaluated in terms of ranking power on the HSP90 protein with 72 biologically active compounds and 4469 structurally similar decoys. Among conventional SFs, the highest early and overall enrichment measured by EF1 and AUC% obtained using single-scoring-function ranking has been found for Glide SP and Gold-ASP SFs, respectively (7, 75 % and 3, 76 %). The performance of other standard SFs has not been satisfactory, mostly even decreasing below random values. The SQM/COSMO SF, where P-L structures were optimised at the advanced Amber level, has resulted in a dramatic enrichment increase (47, 98 %), almost reaching the best possible receiver operator characteristic (ROC) curve. The best SQM frame thus inserts about seven times more active compounds into the selected dataset than the best standard SF.