Noncovalent Interaction Energies Research Articles

Electrostatically embedded symmetry-adapted perturbation theory.

Symmetry-adapted perturbation theory (SAPT) is an abinitio approach that directly computes noncovalent interaction energies in terms of electrostatics, exchange repulsion, induction/polarization, and London dispersion components. Due to its high computational scaling, routine applications of even the lowest order of SAPT are typically limited to a few hundred atoms. To address this limitation, we report here the addition of electrostatic embedding to the SAPT (EE-SAPT) and ISAPT (EE-ISAPT) methods. We illustrate the embedding scheme using water trimer as a prototype example. Then, we show that EE-SAPT/EE-ISAPT can be applied for efficiently and accurately computing noncovalent interactions in large systems, including solvated dimers and protein-ligand systems. In the latter application, particular care must be taken to properly handle the quantum mechanics/molecular mechanics boundary when it cuts covalent bonds. We investigate various schemes for handling charges near this boundary and demonstrate which are most effective in the context of charge-embedded SAPT.

Range Separation of the Interaction Potential in Intermolecular and Intramolecular Symmetry-Adapted Perturbation Theory.

Symmetry-adapted perturbation theory (SAPT) is a popular and versatile tool to compute and decompose noncovalent interaction energies between molecules. The intramolecular SAPT (ISAPT) variant provides a similar energy decomposition between two nonbonded fragments of the same molecule, covalently connected by a third fragment. In this work, we explore an alternative approach where the noncovalent interaction is singled out by a range separation of the Coulomb potential. We investigate two common splittings of the 1/r potential into long-range and short-range parts based on the Gaussian and error functions, and approximate either the entire intermolecular/interfragment interaction or only its attractive terms by the long-range contribution. These range separation schemes are tested for a number of intermolecular and intramolecular complexes. We find that the energy corrections from range-separated SAPT or ISAPT are in reasonable agreement with complete SAPT/ISAPT data. This result should be contrasted with the inability of the long-range multipole expansion to describe crucial short-range charge penetration and exchange effects; it shows that the long-range interaction potential does not just recover the asymptotic interaction energy but also provides a useful account of short-range terms. The best consistency is attained for the error-function separation applied to all interaction terms, both attractive and repulsive. This study is the first step toward a fragmentation-free decomposition of intramolecular nonbonded energy.

Metal Complexes of Cobalt Chloride with Vinyl‐, Allyl‐ and Styrylbenzimidazole Ligands: Synthesis, Structure, and Properties

AbstractThree N‐substituted benzimidazole cobalt(II) complexes have been synthesized and fully characterized by elemental analysis, FT‐IR spectroscopy, and X‐ray crystallography. The crystal packing formation features were studied by AIM analysis, and the energy and nature of both weak noncovalent interactions in the crystal and metal–ligand coordination bonds were assessed. These N‐coordinated cobalt(II) complexes were screened for antimicrobial activities against Gram‐negative (Escherichia coli, Bacillus subtilis) and Gram‐positive (Enterococcus durans) bacteria. Minimal inhibitory concentrations (MIC = 6.2 mg/mL) were found for complex cobalt chloride with allylbenzimidazole ligands against E. durans and E. coli. Its antimicrobial activity is several times higher compared to the reference gentamicin. Molecular docking made it possible to consider the nature of binding of cobalt metal complexes with vinyl‐, allyl‐ and styrylbenzimidazole ligands to biological targets and estimate their energy. The binding energy meanings depend on protein and ligand type, and reaches 8 kcal/mol.

An Energetic and Topological Approach to Understanding the Interplay of Noncovalent Interactions in a Series of Crystalline Spiropyrrolizine Compounds.

Synthesis of quinoline-containing spiropyrrolizine was achieved via a 1,3-dipolar cycloaddition reaction of azomethine ylide (generated in situ from ninhydrin and l-proline) and (E)-2-styrylquinoline. The synthesized compounds were characterized by 1H NMR, 13C NMR, HRMS, and single-crystal XRD analysis. The XRD data revealed that the solid-state structures of the compounds belong to the monoclinic system of the space group P21/c and are stabilized through various weak noncovalent interactions such as C-H···O, C-H···π, and π···π interactions. The noncovalent interactions are characterized and quantified through Hirshfeld surface analysis. Moreover, the interaction energies of the intermolecular noncovalent interactions are calculated through PIXEL calculation. The PIXEL calculation provides precise interaction energy with an energy decomposition scheme. Energy Framework calculations have also been performed to delve deeper into understanding the intermolecular interactions. The intermolecular interactions are further characterized using Bader's theory of "atoms in molecules" (QTAIM) and the "noncovalent" (NCI) interaction plot index. The nature and strength of noncovalent interactions are analyzed from the topological parameters at (3, -1) bond critical points (BCPs).

Theoretical insights into enantioselective [2 + 1] cyclopropanation reactions of diazo compounds with electron-deficient olefins.

The cyclopropane skeleton plays a significant role in bioactive molecules due to its distinctive structural properties. This has sparked keen interest and in-depth exploration in the field of stereoselective synthesis of cyclopropane derivatives. In the present study, the mechanism and the origin of stereoselectivity of diastereodivergent synthesis of cyclopropane derivatives via the catalyst-free [2 + 1]-cyclopropanation reactions of 3-diazo-N-methylindole (R1) with two types of electron-deficient olefins (R2 and R3) in both aqueous and toluene media have been studied using the DFT calculations. The findings indicate that these [2 + 1] cycloaddition reactions proceed in two stages, where the first step is not only the rate-determining step but also critically dictates the stereoselectivity of the product. The calculated diastereomeric ratios are in agreement with the experimental results. Furthermore, by utilizing non-covalent interaction (NCI) analysis and energy decomposition analysis based on molecular force fields (EDA-FF), we elucidated that the electrostatic interactions between reactant fragments in the transition state TS1s for the first step are the predominant factors determining the stereoselectivity, as opposed to the experimentally hypothesized steric hindrance and π-π stacking interactions. The geometrical structures of all minima and transition states on the potential energy surface (PES) in solvents water and toluene were fully optimized using the DFT method at the M06-2X(D3)/SMD/6-31 + G(d,p) level of theory. Single-point energy calculations were carried out based on the optimized geometries in the solution at the M06-2X(D3)/6-311 + G(d,p) level. All the DFT calculations were performed using the Gaussian 09 software. The optimized molecular structures were visualized using CYLview software. NCI analysis was performed using the Multiwfn and VMD softwares. The Multiwfn program was also used for CDFT and EDA-FF analyses.

Quantum Mechanics Characterization of Non-Covalent Interaction in Nucleotide Fragments.

Accurate calculation of non-covalent interaction energies in nucleotides is crucial for understanding the driving forces governing nucleic acid structure and function, as well as developing advanced molecular mechanics forcefields or machine learning potentials tailored to nucleic acids. Here, we dissect the nucleotides' structure into three main constituents: nucleobases (A, G, C, T, and U), sugar moieties (ribose and deoxyribose), and phosphate group. The interactions among these fragments and between fragments and water were analyzed. Different quantum mechanical methods were compared for their accuracy in capturing the interaction energy. The non-covalent interaction energy was decomposed into electrostatics, exchange-repulsion, dispersion, and induction using two ab initio methods: Symmetry-Adapted Perturbation Theory (SAPT) and Absolutely Localized Molecular Orbitals (ALMO). These calculations provide a benchmark for different QM methods, in addition to providing a valuable understanding of the roles of various intermolecular forces in hydrogen bonding and aromatic stacking. With SAPT, a higher theory level and/or larger basis set did not necessarily give more accuracy. It is hard to know which combination would be best for a given system. In contrast, ALMO EDA2 did not show dependence on theory level or basis set; additionally, it is faster.

Origins of the unphysical noncovalent interaction energy curves obtained with the 2011 and 2012 Minnesota density functionals.

With the noncovalent interaction energy curves of the methane dimer [(CH4)2], we have clarified two different origins of the unphysical noncovalent interaction energy curves obtained with the Minnesota density functionals of M11-L, MN12-L, and MN12-SX. For the M11-L functional, the unphysical inflection point on the (CH4)2 interaction energy curve originates from the inclusion of the long-range exchange. As to the MN12-L and MN12-SX functionals, the lack of smoothness restraints results in unphysical inflection points on the corresponding (CH4)2 interaction energy curves. As a result, exchange functionals are as important as dispersion corrections for density functionals to map noncovalent interaction energy surfaces reasonably. Moreover, very highly parameterized functionals with smoothness restraints are suggested for investigating noncovalent interaction energy surfaces.

Investigating Hydrogen Bonding in Quinoxaline-Based Thermally Activated Delayed Fluorescent Materials.

In recent years, hydrogen bonding (H bonding) as an intramolecular locking strategy has been proposed to enhance photoluminescence, color purity, and photostability in thermally activated delayed fluorescence (TADF) materials. Rigidification as a design strategy is particularly relevant when using electron-deficient N-heterocycles as electron acceptors, because these materials often suffer from poor performance as orange to near-infrared emitters as a result of the energy gap law. To critically evaluate the presence of H bonding in such materials, two TADF-active donor-acceptor dyads, ACR-DQ and ACR-PQ, were synthesized. Despite their potential sites for intramolecular H bonding and emissions spanning yellow to deep red, computational analyses (including frequency, natural bond orbital, non-covalent interaction, and potential energy surface assessments) and crystal structure examinations collectively suggest the absence of H bonding in these materials. Our results indicate that invoking intramolecular H bonding should be done with caution in the design of rigidified TADF materials.

Ab initio dispersion potentials based on physics-based functional forms with machine learning.

In this study, we introduce SAPT10K, a comprehensive dataset comprising 9982 noncovalent interaction energies and their binding energy components (electrostatics, exchange, induction, and dispersion) for diverse intermolecular complexes of 944 unique dimers. These complexes cover significant portions of the intermolecular potential energy surface and were computed using higher-order symmetry-adapted perturbation theory, SAPT2+(3)(CCD), with a large aug-cc-pVTZ basis set. The dispersion energy values in SAPT10K serve as crucial inputs for refining the abinitio dispersion potentials based on Grimme's D3 and many-body dispersion (MBD) models. Additionally, Δ machine learning (ML) models based on newly developed intermolecular features, which are derived from intermolecular histograms of distances for element/substructure pairs to simultaneously account for local environments as well as long-range correlations, are also developed to address deficiencies of the D3/MBD models, including the inflexibility of their functional forms, the absence of MBD contributions in D3, and the standard Hirshfeld partitioning scheme used in MBD. The developed dispersion models can be applied to complexes involving a wide range of elements and charged monomers, surpassing other popular ML models, which are limited to systems with only neutral monomers and specific elements. The efficient D3-ML model, with Cartesian coordinates as the sole input, demonstrates promising results on a testing set comprising 6714 dimers, outperforming another popular ML model, component-based machine-learned intermolecular force field (CLIFF), by 1.5 times. These refined D3/MBD-ML models have the capability to replace the time-consuming dispersion components in symmetry-adapted perturbation theory-based calculations and can promptly illustrate the dispersion contribution in noncovalent complexes for supramolecular assembly and chemical reactions.

How do spin-scaled double hybrids designed for excitation energies perform for noncovalent excited-state interactions? An investigation on aromatic excimer models.

Time-dependent double hybrids with spin-component or spin-opposite scaling to their second-order perturbative correlation correction have demonstrated competitive robustness in the computation of electronic excitation energies. Some of the most robust are those recently published by our group (M. Casanova-Páez, L. Goerigk, J. Chem. Theory Comput. 2021, 20, 5165). So far, the implementation of these functionals has not allowed correctly calculating their ground-state total energies. Herein, we define their correct spin-scaled ground-state energy expressions which enables us to test our methods on the noncovalent excited-state interaction energies of four aromatic excimers. A range of 22 double hybrids with and without spin scaling are compared to the reasonably accurate wavefunction reference from our previous work (A. C. Hancock, L. Goerigk, RSC Adv. 2023, 13, 35964). The impact of spin scaling is highly dependent on the underlying functional expression, however, the smallest overall errors belong to spin-scaled functionals with range separation: SCS- and SOS- PBEPP86, and SCS-RSX-QIDH. We additionally determine parameters for DFT-D3(BJ)/D4 ground-state dispersion corrections of these functionals, which reduce errors in most cases. We highlight the necessity of dispersion corrections for even the most robust TD-DFT methods but also point out that ground-state based corrections are insufficient to completely capture dispersion effects for excited-state interaction energies.

The formation of nickelalactone in CO2/C2H4 coupling reaction: A benchmark, dispersion correction, and energy decomposition analysis

The oxidative coupling of CO2 and ethylene for synthesizing acrylic acid and its derivatives is considered one of the “dream reactions” in catalysis. The formation of acrylic acid by CO2/C2H4 coupling is hardly possible due to the endothermic nature of the reaction. This work reports a comprehensive study of the nickelalactone formation from CO2/C2H4 coupling over Ni-catalysts. We have evaluated the accuracy of the DLPNO-CCSD(T) method in determining the barrier heights and the reaction energetics for the nickelalactone formation. Extrapolation to the complete basis set limit was performed using two-point extrapolation methods. It was found that the DLPNO-CCSD(T) method, in combination with the complete basis set cc-pVTZ/cc-pVQZ extrapolation, gives the error within 1.0 kcal/mol. To gain a molecular understanding of the formation of acrylic acid by CO2/C2H4 coupling, the distortion-interaction model was used as an energy decomposition method to analyze the inner- and outer-sphere reaction transition states, considering two competing pathways. It was found that i) the inner-sphere reaction is superior to the outer-sphere reaction owing to the lower distortion energy and stronger interactions, ii) three prominent pairs of orbital interactions exist between the Ni-C2H4 complex and the CO2 molecule, and iii) the dispersion correction is crucial to obtaining reliable non-covalent interaction energies.

In Silico Investigations on the Synergistic Binding Mechanism of Functional Compounds with Beta-Lactoglobulin.

Piceatannol (PIC) and epigallocatechin gallate (EGCG) are polyphenolic compounds with applications in the treatment of various diseases such as cancer, but their stability is poor. β-lactoglobulin (β-LG) is a natural carrier that provides a protective effect to small molecule compounds and thus improves their stability. To elucidate the mechanism of action of EGCG, PIC, and palmitate (PLM) in binding to β-LG individually and jointly, this study applied molecular docking and molecular dynamics simulations combined with in-depth analyses including noncovalent interaction (NCI) and binding free energy to investigate the binding characteristics between β-LG and compounds of PIC, EGCG, and PLM. Simulations on the binary complexes of β-LG + PIC, β-LG + EGCG, and β-LG + PLM and ternary complexes of (β-LG + PLM) + PIC, (β-LG + PLM) + EGCG, β-LG + PIC) + EGCG, and (β-LG + EGCG) + PIC were performed for comparison and characterizing the interactions between binding compounds. The results demonstrated that the co-bound PIC and EGCG showed non-beneficial effects on each other. However, the centrally located PLM was revealed to be able to adjust the binding conformation of PIC, which led to the increase in binding affinity with β-LG, thus showing a synergistic effect on the co-bound PIC. The current study of β-LG co-encapsulated PLM and PIC provides a theoretical basis and research suggestions for improving the stability of polyphenols.

Generalized perturbative singles corrections to the random phase approximation method: Impact on noncovalent interaction energies of closed- and open-shell dimers.

The post-Kohn-Sham (KS) random phase approximation (RPA) method may provide a poor description of interaction energies of weakly bonded molecules due to inherent density errors in approximate KS functionals. To overcome these errors, we develop a generalized formalism to incorporate perturbative singles (pS) corrections to the RPA method using orbital rotations as a perturbation parameter. The pS schemes differ in the choice of orbital-rotation gradient and Hessian. We propose a pS scheme termed RPA singles (RPAS)[Hartree-Fock (HF)] that uses the RPA orbital-rotation gradient and time-dependent HF Hessian. This correction reduces the errors in noncovalent interaction energies of closed- and open-shell dimers. For the open-shell dimers, the RPAS(HF) method leads to a consistent error reduction by 50% or more compared to the RPA method for the cases of hydrogen-bonding, metal-solvent, carbene-solvent, and dispersion interactions. We also find that the pS corrections are more important in error reduction compared to higher-order exchange corrections to the RPA method. Overall, for open shells, the RPAS(HF)-corrected RPA method provides chemical accuracy for noncovalent interactions and is more reliable than other perturbative schemes and dispersion-corrected density functional approximations, highlighting its importance as a reliable beyond-RPA correction.

Development of a machine learning finite-range nonlocal density functional.

Kohn-Sham density functional theory has been the most popular method in electronic structure calculations. To fulfill the increasing accuracy requirements, new approximate functionals are needed to address key issues in existing approximations. It is well known that nonlocal components are crucial. Current nonlocal functionals mostly require orbital dependence such as in Hartree-Fock exchange and many-body perturbation correlation energy, which, however, leads to higher computational costs. Deviating from this pathway, we describe functional nonlocality in a new approach. By partitioning the total density to atom-centered local densities, a many-body expansion is proposed. This many-body expansion can be truncated at one-body contributions, if a base functional is used and an energy correction is approximated. The contribution from each atom-centered local density is a single finite-range nonlocal functional that is universal for all atoms. We then use machine learning to develop this universal atom-centered functional. Parameters in this functional are determined by fitting to data that are produced by high-level theories. Extensive tests on several different test sets, which include reaction energies, reaction barrier heights, and non-covalent interaction energies, show that the new functional, with only the density as the basic variable, can produce results comparable to the best-performing double-hybrid functionals, (for example, for the thermochemistry test set selected from the GMTKN55 database, BLYP based machine learning functional gives a weighted total mean absolute deviations of 3.33kcal/mol, while DSD-BLYP-D3(BJ) gives 3.28kcal/mol) with a lower computational cost. This opens a new pathway to nonlocal functional development and applications.

M11pz: A Nonlocal Meta Functional with Zero Hartree-Fock Exchange and with Broad Accuracy for Chemical Energies and Structures.

The accuracy of Kohn-Sham density functional theory depends strongly on the approximation to the exchange-correlation functional. In this work, we present a new exchange-correlation functional called M11pz (M11 plus rung-3.5 terms with zero Hartree-Fock exchange) that is built on the M11plus functional with the goal of using its rung-3.5 terms without a Hartree-Fock exchange term, especially to improve the accuracy for strongly correlated systems. The M11pz functional is optimized with the same local and rung-3.5 ingredients that are used in M11plus but without any percentage of Hartree-Fock exchange. The performance of M11pz is compared with eight local functionals, and M11pz is found to be in top three when the errors or ranks are averaged over eight grouped and partially overlapping databases: AME418/22, atomic and molecular energies; MGBE172, main-group bond energies; TMBE40, transition-metal bond energies; SR309, single-reference systems; MR54, multireference systems; BH192, barrier heights; NC579, noncovalent interaction energies; and MS20, molecular structures. For calculations of band gaps of solids, M11pz is the second best of the nine tested functionals that have zero Hartree-Fock exchange.

Plane Waves Versus Correlation-Consistent Basis Sets: A Comparison of MP2 Non-Covalent Interaction Energies in the Complete Basis Set Limit.

Second-order Møller-Plesset perturbation theory (MP2) is the most expedient wave function-based method for considering electron correlation in quantum chemical calculations and, as such, provides a cost-effective framework to assess the effects of basis sets on correlation energies, for which the complete basis set (CBS) limit can commonly only be obtained via extrapolation techniques. Software packages providing MP2 energies are commonly based on atom-centered bases with innate issues related to possible basis set superposition errors (BSSE), especially in the case of weakly bonded systems. Here, we present noncovalent interaction energies in the CBS limit, free of BSSE, for 20 dimer systems of the S22 data set obtained via a highly parallelized MP2 implementation in the plane-wave pseudopotential molecular dynamics package CPMD. The specificities related to plane waves for accurate and efficient calculations of gas-phase energies are discussed, and results are compared to the localized (aug-)cc-pV[D,T,Q,5]Z correlation-consistent bases as well as their extrapolated CBS estimates. We find that the BSSE-corrected aug-cc-pV5Z basis can provide MP2 energies highly consistent with the CBS plane wave values with a minimum mean absolute deviation of ∼0.05 kcal/mol without the application of any extrapolation scheme. In addition, we tested the performance of 13 different extrapolation schemes and found that the X-3 expression applied to the (aug-)cc-pVXZ bases provides the smallest deviations against CBS plane wave values if the extrapolation sequence is composed of points D and T, while performs slightly better for TQ and Q5 extrapolations. Also, we propose as a reliable alternative to extrapolate total energies from the DTQ, TQ5, or DTQ5 data points. In spite of the general good agreement between the values obtained from the two types of basis sets, it is noticed that differences between plane waves and (aug-)cc-pVXZ basis sets, extrapolated or not, tend to increase with the number of electrons, thus raising the question of whether these discrepancies could indeed limit the attainable accuracy for localized bases in the limit of large systems.

Can G4-like composite Ab Initio methods accurately predict vibrational harmonic frequencies?

Minimally empirical G4-like composite wavefunction theories [E. Semidalas and J. M. L. Martin, J. Chem. Theory Comput. 16, 4238–4255 and 7507–7524 (2020)] trained against the large and chemically diverse GMTKN55 benchmark suite have demonstrated both accuracy and cost-effectiveness in predicting thermochemistry, barrier heights, and noncovalent interaction energies. Here, we assess the spectroscopic accuracy of top-performing methods: G4-n, cc-G4-n, and G4-n-F12, and validate them against explicitly correlated coupled-cluster CCSD(T*)(F12*) harmonic vibrational frequencies and experimental data from the HFREQ2014 dataset, of small first- and second-row polyatomics. G4-T is three times more accurate than plain CCSD(T)/def2-TZVP, while G4-T ano is two times superior to CCSD(T)/ano-pVTZ. Combining CCSD(T)/ano-pVTZ with MP2-F12 in a parameter-free composite scheme results to a root-mean-square deviation of 5 cm − 1 relative to experiment, comparable to CCSD(T) at the complete basis set limit. Application to the harmonic frequencies of benzene reveals a significant advantage of composites with ANO basis sets – MP2/ano-pVmZ and [CCSD(T)-MP2]/ano-pVTZ (m = Q or 5) – over similar protocols based on CCSD(T)/def2-TZVP. Overall, G4-type composite energy schemes, particularly when combined with ANO basis sets in CCSD(T), are accurate and comparatively inexpensive tools for computational vibrational spectroscopy.

Role of non-covalent interactions in 2,5-di-Me-pyrazine-di-N-oxide - tertiary butyl alcohol - single-walled and multi-walled carbon nanotubes electrocatalytic systems

Oxidation of tert-butyl alcohol (tert-BuOH, Me3COH), a compound with a high C-H bond breaking energy in the absence of precious metals or their oxides as catalysts and using metal-free electrodes, is an inexpensive process and is of interest for practical applications in electrocatalysis and sensors. In this work, electrocatalytic systems 2,5-di-Me-pyrazine-di-N-oxide (Pyr1) - tert-BuOH – single - walled (SWCNT) and multi-walled (MWCNT) carbon nanotube paper electrodes in 0.1 M Bu4NClO4 solution in acetonitrile (MeCN) were studied by the methods of cyclic voltammetry, quantum chemical modeling and electron paramagnetic resonance (EPR) electrolysis. Calculaition of energies of non-covalent interactions between the components of the electrocatalytic system in complexes Me3COH*Me3COH, Me3COH*MeCN, Pyr1*Me3COH and the adsorption energy of Me3COH and complexes of Pyr1*Bu4NClO4, Pyr1*Me3COH, Pyr1*MeCN and Me3COH *Bu4NClO4 on CNTs surface using a cluster model describing the surface of conducting carbon nanotubes (10, 10) was performed. The study made it possible to reveal the regularities characteristic of aromatic-di-N-oxide – CNT electrocatalytic systems and to propose a mechanism of tert-BuOH oxidation in the presence of electrochemically generated radical cation Pyr1. The data will be useful at using CNT electrodes in electrocatalytic processes, as well as aromatic di-N-oxide-CNT catalytic systems in electrocatalysis and sensors.

Quantitative investigations of intermolecular interactions in 2-amino-3-nitropyridine polymorphs: Inputs from quantum mechanical calculations

Two polymorphic forms (Form–I and Form–II) of 2-amino-3-nitropyridine are structurally characterized by single crystal X-ray diffraction analysis and compared with another polymorphic form (Form–III, retrieved from CSD) with a detailed analysis of the Hirshfeld surfaces and fingerprint plots facilitating a comparison of intermolecular interactions. X-ray crystallography exposes that the polymorphs generate completely different network structures through hydrogen bonding interactions. Polymorphic Form–I exhibit a layer assembly through the cooperative face-to-face π⋯π and lone pair⋯π interactions, whereas Form–II, and Form–III displays hydrogen bonds only. A detailed investigation of Hirshfeld surface analysis reveals much more detailed scrutiny of intermolecular interactions experienced by the polymorphic forms of 2-amino-3-nitropyridine. The quantitative analysis of the interaction energies involving various noncovalent interactions was computed and compared to get a deeper insight into the role of such interactions in stabilizing the polymorphs. The interaction energies of non-covalent interactions are calculated through theoretical DFT calculations as well as the PIXEL method. The PIXEL method provides us precise interaction energy calculation with an energy decomposition scheme. Higher electrostatic interaction shows higher interaction energy while the lower interaction energy corresponds to the higher dispersive interaction. The lattice energies of the polymorphs are also obtained via the PIXEL method. The nature and strength of these interactions have been studied using Bader's quantum theory of atoms in molecules. The topological analysis unequivocally establishes the presence of (3, −1) bond critical point, suggesting that the intermolecular interactions are closed-shell interactions. The NCI (Non-covalent Interaction) plots are further employed to identify and characterize the non-covalent interactions of the polymorphs.

A Combination of Virtual and Experimental Screening Tools for the Prediction of Nitrofurantoin Multicomponent Crystals with Pyridine Derivatives

Thirty-four binary systems of nitrofurantoin with pyridine derivatives were analyzed by combining virtual (molecular complementarity prediction and hydrogen bond propensity calculations) and experimental (liquid-assisted grinding) screening methods. A new modification of the hydrogen bond propensity calculation method (the integrated hydrogen bond propensity calculation method) with significantly improved virtual screening efficiency was proposed. Novel cocrystals of nitrofurantoin with 3-aminopyridine and 2-(1H-Imidazol-2-yl)pyridine were discovered. The crystal structures of the new cocrystals were determined from single-crystal X-ray diffraction data, and the hydrogen bond patterns were studied in conjunction with the Molecular Electrostatic Potential maps of the components. The nitrofurantoin cocrystal with 3-aminopyridine was found to exist in two polymorphic modifications. The origins of the different stability of the polymorphic forms were rationalized both in terms of total lattice enthalpy and free energy derived from periodic DFT-D3 calculations and in terms of the non-covalent interaction energy distribution in crystal.