Cl···Cl Interactions in Molecular Crystals: Insights from the Theoretical Charge Density Analysis

The structure, IR harmonic frequencies and intensities of normal vibrations of 20 molecular crystals with the X–Cl···Cl–X contacts of different types, where X = C, Cl, and F and the Cl···Cl distance varying from ∼3.0 to ∼4.0 Å, are computed using the solid-state DFT method. The obtained crystalline wave functions have been further used to define and describe quantitatively the Cl···Cl interactions via the electron-density features at the Cl···Cl bond critical points. We found that the electron-density at the bond critical point is almost independent of the particular type of the contact or hybridization of the ipso carbon atom. The energy of Cl···Cl interactions, <i>E</i>_int, is evaluated from the linking <i>E</i>_int and local electronic kinetic energy density at the Cl···Cl bond critical points. <i>E</i>_int varies from 2 to 12 kJ/mol. The applicability of the geometrical criterion for the detection of the Cl···Cl interactions in crystals with two or more intermolecular Cl···Cl contacts for the unique chlorine atom is not straightforward. The detection of these interactions in such crystals may be done by the quantum-topological analysis of the periodic electron density

Inhibiting Low-Frequency Vibrations Explains Exceptionally High Electron Mobility in 2,5-Difluoro-7,7,8,8-tetracyanoquinodimethane (F₂‑TCNQ) Single Crystals

Organic electronics requires materials with high charge mobility. Despite decades of intensive research, charge transport in high-mobility organic semiconductors has not been well understood. In this Letter, we address the physical mechanism underlying the exceptionally high band-like electron mobility in F₂-TCNQ (2,5-difluoro-7,7,8,8-tetracyanoquinodimethane) single crystals among a crystal family of similar compounds F_<i>n</i>-TCNQ (<i>n</i> = 0, 2, 4) using a combined experimental and theoretical approach. While electron transfer integrals and reorganization energies did not show outstanding features for F₂-TCNQ, Raman spectroscopy and solid-state DFT indicated that the frequency of the lowest vibrational mode is nearly twice higher in the F₂-TCNQ crystal than in TCNQ and F₄-TCNQ. This phenomenon is explained by the specific packing motif of F₂-TCNQ with only one molecule per primitive cell so that electron–phonon interaction decreases and the electron mobility increases. We anticipate that our findings will encourage investigators for the search and design of organic semiconductors with one molecule per primitive cell and/or the poor low-frequency vibrational spectrum

Hydration of the Carboxylate Group in Anti-Inflammatory Drugs: ATR-IR and Computational Studies of Aqueous Solution of Sodium Diclofenac

Diclofenac (active ingredient of Voltaren) has a significant, multifaceted role in medicine, pharmacy, and biochemistry. Its physical properties and impact on biomolecular structures still attract essential scientific interest. However, its interaction with water has not been described yet at the molecular level. In the present study, we shed light on the interaction between the steric hindrance (the intramolecular N–H···O bond, etc.) carboxylate group (−CO₂^–) with water. Aqueous solution of sodium declofenac is investigated using attenuated total reflection-infrared (ATR-IR) and computational approaches, i.e., classical molecular dynamics (MD) simulations and density functional theory (DFT). Our coupled classical MD simulations, DFT calculations, and ATR-IR spectroscopy results indicated that the −CO₂^– group of the diclofenac anion undergoes strong specific interactions with the water molecules. The combined experimental and theoretical techniques provide significant insights into the spectroscopic manifestation of these interactions and the structure of the hydration shell of the −CO₂^– group. Moreover, the developed methodology for the theoretical analysis of the ATR-IR spectrum could serve as a template for the future IR/Raman studies of the strong interaction between the steric hindrance −CO₂^– group of bioactive molecules with the water molecules in dilute aqueous solutions

Peroxosolvates: Formation Criteria, H₂O₂ Hydrogen Bonding, and Isomorphism with the Corresponding Hydrates

The Cambridge Structural Database has been used to investigate the detailed environment of H₂O₂ molecules and hydrogen-bond patterns within “true” peroxosolvates in which the H₂O₂ molecules do not interact directly with the metal atoms. A study of 65 crystal structures and over 260 hydrogen bonds reveals that H₂O₂ always forms two H-bonds as proton donors and up to four H-bonds as a proton acceptor, but the latter can be absent altogether. The necessary features of peroxosolvate coformers are clarified. (1) Coformers should not participate in redox reactions with H₂O₂ and should not catalyze its decomposition. (2) Coformers should be Brønsted bases or exhibit amphoteric properties. The efficiency of the proposed criteria for peroxosolvate formation is illustrated by the synthesis and characterization of several new crystals. Conditions preventing the H₂O₂/H₂O isomorphous substitution are essential for peroxosolvate stability: (1) Every H₂O₂ in the peroxosolvate has to participate in five or six hydrogen bonds. (2) The distance between the two proton acceptors forming H-bonds with the H₂O₂ molecule should be longer than the distance defined by the nature of the acceptor atoms

Influence of Secondary Interactions on the Structure, Sublimation Thermodynamics, and Solubility of Salicylate:4-Hydroxybenzamide Cocrystals. Combined Experimental and Theoretical Study

Cocrystal screening of 4-hydroxy­benzamide with a number of salicylates (salicylic acid, SA; 4-amino­salicylic acid, PASA; acetyl­salicylic acid, ASA; and salicyl­salicylic acid, SSA) was conducted to confirm the formation of two cocrystals, [SA+4-OHBZA] (1:1) and [PASA+4-OHBZA] (1:1). Their structures were determined using single-crystal X-ray diffraction, and the hydrogen-bond network topology was studied. Thermodynamic characteristics of salicylic acid cocrystal sublimation were obtained experimentally. It was proved that PASA cocrystallization with 4-OHBZA makes the drug more stable and prevents the irreversible process of decarboxylation of PASA resulting in formation of toxic 3-amino­phenol. The pattern of non-covalent interactions in the cocrystals is described quantitatively using solid-state density functional theory followed by Bader analysis of the periodic electron density. It has been found that the total energy of secondary interactions between synthon atoms and the side hydroxyl group of the acid molecule in [SA+4-OHBZA] (1:1) and [PASA+4-OHBZA] (1:1) cocrystals is comparable to the energy of the primary acid–amide hetero­synthon. The theoretical value of the sublimation enthalpy of [SA+4-OHBZA], 231 kJ/mol, agrees fairly well with the experimental one, 272 kJ/mol. The dissolution experiments with [SA+4-OHBZA] have proved that the relatively large cocrystal stability in relation to the stability of its components has a negative effect on the dissolution rate and equilibrium solubility. The [PASA+4-OHBZA] (1:1) cocrystal showed an enhancement of apparent solubility compared to that of the corresponding pure active pharmaceutical ingredient, while their intrinsic dissolution rates are comparable

Noncovalent Interactions in Crystalline Picolinic Acid N‑Oxide: Insights from Experimental and Theoretical Charge Density Analysis

This study provides a detailed description of noncovalent interactions of different types and strengths in the title crystal using a combined experimental and theoretical study of the charge density distribution. The nature of the noncovalent interactions is visualized using information theory and through the superposition of the gradient fields in the electron density and electrostatic potential. The energy of the intramolecular O–H···O bond, intermolecular C–H···O bonds, and π-stacking interactions, <i>E</i>_int, are evaluated from empirical correlations between <i>E</i>_int and geometrical and electron-density bond critical point parameters. The complete set of noncovalent interactions including the strong intramolecular O–H···O (<i>E</i>_int > 90 kJ/mol) and weak C–H···O (<i>E</i>_int < 10 kJ/mol) hydrogen bonds, and π-stacking interactions (<i>E</i>_int < 4 kJ/mol) is quantitatively described. The results from the experimental charge density analysis are compared with periodic quantum calculations using density functional theory with the Grimme dispersion correction. It was found that the Grimme dispersion correction did not provide a good simultaneous description of both weak and strong noncovalent interactions in the studied crystal. It is shown that the obtained energies of noncovalent interactions lead to a reasonable value of the lattice energy. The latter is treated as the total intermolecular interaction energy

Noncovalent Interactions in Crystalline Picolinic Acid N‑Oxide: Insights from Experimental and Theoretical Charge Density Analysis

This study provides a detailed description of noncovalent interactions of different types and strengths in the title crystal using a combined experimental and theoretical study of the charge density distribution. The nature of the noncovalent interactions is visualized using information theory and through the superposition of the gradient fields in the electron density and electrostatic potential. The energy of the intramolecular O–H···O bond, intermolecular C–H···O bonds, and π-stacking interactions, <i>E</i>_int, are evaluated from empirical correlations between <i>E</i>_int and geometrical and electron-density bond critical point parameters. The complete set of noncovalent interactions including the strong intramolecular O–H···O (<i>E</i>_int > 90 kJ/mol) and weak C–H···O (<i>E</i>_int < 10 kJ/mol) hydrogen bonds, and π-stacking interactions (<i>E</i>_int < 4 kJ/mol) is quantitatively described. The results from the experimental charge density analysis are compared with periodic quantum calculations using density functional theory with the Grimme dispersion correction. It was found that the Grimme dispersion correction did not provide a good simultaneous description of both weak and strong noncovalent interactions in the studied crystal. It is shown that the obtained energies of noncovalent interactions lead to a reasonable value of the lattice energy. The latter is treated as the total intermolecular interaction energy

Weak Interactions Cause Packing Polymorphism in Pharmaceutical Two-Component Crystals. The Case Study of the Salicylamide Cocrystal

Two polymorphs of the salicylamide cocrystal with oxalic acid have been obtained and described. Form I of the cocrystal was prepared by three alternative methods in various solvents, while formation of form II was achieved only by a special crystallization procedure. Single-crystal X-ray analysis has revealed that polymorphs consist of conformationally identical salicylamide and oxalic acid molecules, which are assembled into supramolecular units connected via a network of very similar hydrogen bonds. The packing arrangements of the cocrystal polymorphs, however, were found to be different, suggesting a rare example of packing polymorphism. The stability relationship between the polymorphs has been rationalized by using a number of experimental methods, including thermochemical analysis, solubility, and solution calorimetry measurements. Similarities and differences in intermolecular contacts across two polymorphs have been visualized using the Hirshfeld surface analysis. The Bader analysis of the theoretical electron density has enabled us to quantify the pattern of noncovalent interactions in the considered cocrystals. Applicability of different theoretical schemes for evaluation of the lattice energy of the two-component organic crystals has been discussed

Evaluation of the Lattice Energy of the Two-Component Molecular Crystals Using Solid-State Density Functional Theory

The lattice energy <i>E</i>_latt of the two-component crystals (three co-crystals, a salt, and a hydrate) is evaluated using two schemes. The first one is based on the total energy of the crystal and its components computed using the solid-state density functional theory method with the plane-wave basis set. The second approach explores intermolecular energies estimated using the bond critical point parameters obtained from the Bader analysis of crystalline electron density or the pairwise potentials. The <i>E</i>_latt values of two-component crystals are found to be lower or equal to the sum of the absolute sublimation enthalpies of the pure components. The computed energies of the supramolecular synthons vary from ∼80 to ∼30 kJ/mol and decrease in the following order: acid–amide > acid–pyridine > hydroxyl–acid > amide–amide > hydroxyl–pyridine. The contributions from different types of noncovalent interactions to the <i>E</i>_latt value are analyzed. We found that at least 50% of the lattice energy comes from the heterosynthon and a few relatively strong H-bonds between the heterodimer and the adjacent molecules

Salicylamide Cocrystals: Screening, Crystal Structure, Sublimation Thermodynamics, Dissolution, and Solid-State DFT Calculations

A new cocrystal of 2-hydroxybenzamide (A) with 4-acetamidobenzoic acid (B) has been obtained by the DSC screening method. Thermophysical analysis of the aggregate [A:B] has been conducted and a fusion diagram has been plotted. Cocrystal formation from melts was studied by using thermomicroscopy. A cocrystal single-crystal was grown and its crystal structure was determined. The pattern of noncovalent interactions has been quantified using the solid-state DFT computations coupled with the Bader analysis of the periodic electron density. The sublimation processes of A-B cocrystal have been studied and its thermodynamic functions have been calculated. The classical method of substance transfer by inert gas-carrier was chosen to investigate sublimation processes experimentally. The lattice energy is found to be 143 ± 4 kJ/mol. It is lower than the sum of the corresponding values of the cocrystal pure components. The theoretical value of the lattice energy, 156 kJ/mol, is in reasonable agreement with the experimental one. A ternary phase diagram of solubility (A-B–ethanol) has been plotted and the areas with solutions for growing thermodynamically stable cocrystals have been determined