Crystal Packing Research Articles

Application of computational techniques on non-covalent interactions, H-bond nature of monomeric and dimeric form of crystal structures, and topological insights of glycine glutaric acid

This study utilizes DFT to investigate and optimize the structure of Glycine Glutaric acid (GGA) crystal in both monomer and dimer forms, assessing its electronic and optical properties. Relaxed PES scanning identified potential conformers within the COOH and NH2 functional groups. FT-IR spectrum confirmed these groups and simulated spectra were correlated with the experimental data. The stable monomer was selected for detailed analysis of electronic charge transfer using MEP, FMOs, and UV–visible absorbance spectra. Non-covalent interactions, primarily O–H⋯O and N–H⋯O hydrogen bonds, were explored using optimized structures. Solvent effects, analyzed via the IEFPCM method, revealed heightened reactivity in the aqueous phase. Topological studies (AIM, LOL, ELF, and RDG) and Hirshfeld surface analysis were applied to understand inter and intramolecular contacts, with crystal packing dominated by O⋯H/H⋯O interactions contributing to 63.4 % efficiency. As per DFT prediction, the GGA exhibits strong NLO potential due to significantly higher polarizability and hyperpolarizability (⟨β⟩= 1.3618 × 10−30 e.s.u.) indicating promising nonlinear optical properties.

Driving Forces in the Formation of Paracetamol Cocrystals and Solvate with Naphthalene, Quinoline and Acridine.

Paracetamol is an important analgesic and antipyretic drug showing poor tabletability. Among the various approaches used to improve this property, understanding the forces that govern the crystal packing is revealed to be crucial. We prepared three stable compounds: (par)2∙(nap) (1), (par)∙(quin) (2), and (par)∙(acr) (3) (nap-naphthalene, quin-quinoline, acr-acridine) being cocrystals or solvate. The structural studies showed that all the reported compounds are composed of alternately arranged layers of paracetamol and coformer. Several supramolecular motifs in the paracetamol layer were identified: R44(22) in (1); R64(20) and R22(8) in (2); and R22(8), R42(12), and R44(26) rings in (3). The stability of the crystal network was studied by interactions analysis performed by Hirshfeld surface and fingerprint approaches and the energy between the closest units in the crystal network was calculated. It showed that the strongest interactions were found between blocks connected by N-H⋯O=C and O-H⋯O/N hydrogen bonds due to an important coulombic factor. The dispersive energy becomes important for tail-to-tail (and head-to-tail) arranged paracetamol units, and it prevails in the case of stacking interactions between coformer molecules. The importance of dispersive forces increases with the size of the aromatic system of the coformer. XAS studies confirmed the successful preparation of compounds and provided some details about electron structure.

Scope and design of diversified supramolecular synthons of 5-hydroxyisophthalic acid: Crystallographic and theoretical investigations

The designed creation of cocrystals between 5-hydroxyisophthalic acid and diverse N-donor bases has been investigated by supramolecular synthon formations. The structures of four binary cocrystals are determined using single crystal X-ray diffraction technique. The resemblances and distinctions in supramolecular synthon structures have been analyzed and discussed. The interaction pattern changes with alteration in the structure and basicity of the N atoms of the respective bases. The acid···pyridine hetero-synthon, a supramolecular synthon between unlike functional groups, plays a major role in forming all the cocrystals. Apart from acid···pyridine synthon, hydroxyl···pyridine hetero-synthons are observed in HPA:DPE-I and HPA:DPE-I cocrystal. Whereas, acid···hydroxyl heterosynthons are found in HPA:AZO and HPA:TMP cocrystals. As hetero-synthons are energetically preferred regarding homosynthons, the latter is not observed in the structures. It is noticed that apart from strong O–H···N hydrogen bonds, comparatively weak C–H···O hydrogen bonds are also crucial in crystal packing and stability. DFT calculations along with Hirshfeld analysis have been performed to estimate the energetic characteristics of different interactions and crystal packing of the aforementioned cocrystals. Further, energetic characteristics of the synthons involving distinct non-covalent interactions, such as O–H···N, C–H···O and C–H⋯π interactions, are explored by intricate combination of computational methods i.e. QTAIM analysis and the non-covalent interaction (NCI) plot index.

Phenylenethynylene derivatives of [2.2]paracyclophane: A relationship between crystal structure and fluorescent properties in a solid state

Isomeric di- and tetrasubstituted derivatives of [2.2]paracyclophane containing 1,4-bis(phenylethynyl)benzene as a main component were synthesized. It was found that when shifting from 1,4-bis(phenylethynyl)benzene, 1, to pseudo-para-disubstituted 4,16-di-{phenylethynyl(1,4-phenylene)ethynyl}[2.2]paracyclophane, 2, and then to tetrasubstituted 4,7,12,15-tetra-phenylethynyl[2.2]paracyclophane, 3, the difference between fluorescence maxima in solid state and in solution decreases. Analysis of crystal structure using Hirschfeld method revealed that observed phenomenon correlates well with proportion of C-C contacts in crystal packing of compounds. It has been found, that for [2.2]paracyclophane derivatives 2 and 3, the main contribution to this effect is due to π–π contacts of the proximal paracyclophane groups of neighboring molecules, rather than to stacking interactions discovered for 1. The different polymorphic forms of compound 1 that are present both in film and in solid state are discussed.

Polymorph Screening of Core-Chlorinated Naphthalene Diimides with Different Fluoroalkyl Side-Chain Lengths.

In this work, naphthalenediimide (NDI) derivatives are widely studied for their semiconducting properties and the influence of the side-chain length on the crystal packing is reported, along with the thermal properties of three core-chlorinated NDIs with different fluoroalkyl side-chain lengths (CF3-NDI, C3F7-NDI and C4F9-NDI). The introduction of fluorinated substituents at the imide nitrogen and addition of strong electron-withdrawing groups at the NDI core are used to improve the NDI derivatives air stability. The new compound, CF3-NDI, was deeply analyzed and compared to the well-known C3F7-NDI and C4F9-NDI, leading to the discovery and solution of two different crystal phases, form α and solvate form, and a solid solution of CF3-NDI and CF3-NDI-OH, formed by the decomposition in DMSO.

Crystal structure, Hirshfeld surface analysis, DFT optimized mol-ecular structure and the mol-ecular docking studies of 1-[2-(cyano-sulfan-yl)acet-yl]-3-methyl-2,6-bis-(4-methyl-phen-yl)piperidin-4-one.

The two mol-ecules in the asymmetric unit of the title compound, C23H24N2O2S, have a structural overlap with an r.m.s. deviation of 0.82 Å. The piperidine rings adopt a distorted boat conformation. Intra- and inter-molecular C-H⋯O hydrogen bonds are responsible for the cohesion of the crystal packing. The inter-molecular inter-actions were qu-anti-fied and analysed using Hirshfeld surface analysis. The mol-ecular structure optimized by density functional theory (DFT) at the B3LYP/6-311++G(d,p)level is compared with the experimentally determined mol-ecular structure in the solid state.

Synthesis, crystal structure, and Hirshfeld surface analysis of 1,3-di-hydro-2H-benzimidazol-2-iminium 3-carb-oxy-4-hy-droxy-benzene-sulfonate.

The asymmetric unit of the title salt, C7H8N3 +·C7H5O6S-, comprises two 1,3-di-hydro-2H-benzimidazol-2-iminium cations and two 2-hy-droxy-5-sulfobenzoate anions (Z' = 2). In the crystal, the mol-ecules inter-act through N-H⋯O, O-H⋯O hydrogen bonds and C-O⋯π contacts. The hydrogen-bonding inter-actions lead to the formation of layers parallel to (01). Hirshfeld surface analysis revealed that H⋯H contacts contribute to most of the crystal packing with 38.9%, followed by H⋯O contacts with 36.2%.

Copper(II) complexes of hindered diazines: methylquinoxalines

Five new copper(II) complexes of substituted quinoxaline ligands have been prepared and characterized via single crystal X-ray diffraction, including [Cu(5-Mequinox)2(NO3)2] (2), [Cu(5-Mequinox)(NO3)(H2O)(μ-1,3-NO3)]n (3), the chloride salt (5-MequinoxH)2[Cu3Cl8] (4), the complex [Cu(6-Mequinox)2(NO3)2] (5) and [(2-carboxylato-3-methylquinox)(2-hydroxymethyl-3-methylquinox)nitratocopper(II)]. CH3CN (6) [quinox = quinoxaline; 5-Mequinox = 5-methylquinoxaline; 6-Mequinox = 6-methylquinoxaline]. None of the complexes produced diazine bridged chain structures (as seen in [(quinox)Cu(NO3)2]n (1)), although 3 forms chains via a bridging nitrate ion. Crystal packing is controlled primarily through hydrogen bonding and π-stacking of nitrate ions. The temperature dependent magnetic susceptibility data of the parent compound [(quinox)Cu(NO3)2]n are also reported and discussed.

Crystal structures and properties of derivatives of the alkaloid matrine: salts and hydrate forms.

We report the crystal structures of three matrine derivatives, namely, the salts (1R,2R,9S,17S)-6-oxo-7,13-diazatetracyclo[7.7.1.02,7.013,17]heptadecan-13-ium (2E)-3-(3,4-dihydroxyphenyl)prop-2-enoate (matrine caffeinate) sesquihydrate, C15H25N2O+·C9H7O4-·1.5H2O (Matrine-CA), and the 2-hydroxybenzoate (salicylate) monohydrate, C15H25N2O+·C7H5O3-·H2O (Matrine-SA), as well as the 1.75-hydrate form, (1R,2R,9S,17S)-7,13-diazatetracyclo[7.7.1.02,7.013,17]heptadecan-6-one 1.75-hydrate, C15H24N2O·1.75H2O (Matrine-H). Each derivative exhibited a consistent molecular conformation for the matrine core, which is notably distinct from that of the anhydrous form. Notably, both salts crystallized in the orthorhombic space group P212121, with an asymmetric unit featuring one cation and one anion. Within the two salt structures, intermolecular proton transfer between matrine and the acid is observed, culminating in the formation of a matrine cation protonated at the tertiary amine N site. The Matrine-CA crystal packing is manifested as a three-dimensional (3D) network arising from one-dimensional (1D) supramolecular helical chains, stabilized by N-H...O and O-H...O hydrogen bonds. In the case of Matrine-SA, the matrine cation is interconnected via hydrogen bonds with salicylate anions and water molecules, also forming a 1D helical motif. The structure of the hydrate form, Matrine-H, is reported again with the disordered solvent molecules accurately located. To further elucidate the structural attributes, Hirshfeld surface analysis and fingerprint plots are employed, offering a nuanced perspective on the intermolecular contacts and interactions within these crystalline forms.

The influence of the axial group on the crystal structures of boron subphthalocyanines.

The crystal structures of 16 boron subphthalocyanines (BsubPcs) with structurally diverse axial groups were analyzed and compared to elucidate the impact of the axial group on the intermolecular π-π interactions, axial-group interactions, axial bond length and BsubPc bowl depth. π-π interactions between the isoindole units of adjacent BsubPc molecules most often involve concave-concave packing, whereas axial-group interactions with adjacent BsubPc molecules tend to favour the convex side of the BsubPc bowl. Furthermore, axial groups that contain O and/or F atoms tend to have significant hydrogen-bonding interactions, while axial groups containing arene site(s) can participate in π-π interactions with the BsubPc bowl, both of which can strongly influence the crystal packing. Bulky axial groups did tend to disrupt the π-π interactions and/or axial-group interactions, preventing some of the close packing that is seen in BsubPcs with less bulky axial groups. The atomic radius of the heteroatom bonded to boron directly influences the axial bond length, whereas the axial group has minimal impact on the BsubPc bowl depth. Finally, the crystal growth method did not generally appear to have a significant impact on the solid-state arrangement, with the exception of water occasionally being incorporated into crystal structures when hygroscopic solvents were used. These insights can help with the design and fine-tuning of the solid-state structures of BsubPcs as they continue to be developed as functional materials in organic electronics.

Micro‐Ring Morphology of Ag7NCs and Light‐Induced Reversible Interconversion of FCC Ag14NCs via Cu2+ ions‐Mediated Particle‐Assisted Reversible Interconversion

AbstractDespite the remarkable progress made on intercluster conversion in atomically precise metal nanoclusters (MNCs) and their self‐organization to develop microscopic molecular architecture with well‐defined size and shape, achieving light‐induced reversible structural transformation and the development of micro‐ring self‐assembly in MNCs have, so far, remained elusive. The present investigation touches on these two long‐standing quests by showcasing a new route, light‐induced Particle‐Assisted Reversible Interconversion (PARI) for the reversible transformation from Face Centered Cubic (FCC) Ag14NCs to Ag7NCs. Our studies reveal that the lack of plasmonic silver nanoparticles (AgNPs) in the system results in the formation of Ag7NCs with metallic kernels having centrosymmetric crystal packing. The molecular self‐organization of Ag7NCs through various non‐covalent interactions such as C−H⋅⋅⋅O, C−H⋅⋅⋅H−C, and C−H⋅⋅⋅π leads to the formation of micro‐ring morphology, a unique molecular architecture in MNCs. The in situ generated AgNPs due to the acceleration of the reaction kinetics by Cu2+ ions facilitate the growth of Ag14NCs with FCC metallic kernel. These two structural units of AgNCs show light‐induced reversible structural transformation which is also associated with the reversible tuning of their spectroscopic and morphological signatures. This PARI‐guided interconversion strategy put forward a most appropriate example of a structure–property relationship in MNCs.

A comparative theoretical study on the structural, spectral, microtopology exploration (ELF, RDG, IRI, TDM), NBO and nonlinear optical properties of Red170 from different solvents and substituents

The effect of solvents and substituents on the C.I. Pigment PR170, the best known member of the naphthol red family, is investigated. Both PR170 and its alkoxy derivatives were analyzed using FTIR, 1H NMR and UV–Vis spectroscopy. The study included the evaluation of the average local ionization energy (ALIE), MEP, HOMO-LUMO analysis. The nature of intra- and intermolecular contacts in the crystal structure was also investigated using crystal packing and Hirshfeld surface analysis. Covalent and non-covalent interactions in PR170 were comprehensively described by IRI, RDG and ELF. In addition, Natural Bonding Orbital (NBO) and Fukui function calculations were performed. An analysis of the UV–Vis electronic transitions for different solvents was carried out, providing insight into the charge transfer processes within both PR170 and its derivatives. In particular, the research indicated a CT-type excitation at the S2 level during the hole-electron transfer analysis. The NLO results showed that PR170 is a promising candidate for nonlinear optical materials.

Micro-Ring Morphology of Ag7NCs and Light-Induced Reversible Interconversion of FCC Ag14NCs via Cu2+ ions-Mediated Particle-Assisted Reversible Interconversion.

Despite the remarkable progress made on intercluster conversion in atomically precise metal nanoclusters (MNCs) and their self-organization to develop microscopic molecular architecture with well-defined size and shape, achieving light-induced reversible structural transformation and the development of micro-ring self-assembly in MNCs have, so far, remained elusive. The present investigation touches on these two long-standing quests by showcasing a new route, light-induced Particle-Assisted Reversible Interconversion (PARI) for the reversible transformation from Face Centered Cubic (FCC) Ag14NCs to Ag7NCs. Our studies reveal that the lack of plasmonic silver nanoparticles (AgNPs) in the system results in the formation of Ag7NCs with metallic kernels having centrosymmetric crystal packing. The molecular self-organization of Ag7NCs through various non-covalent interactions such as C-H⋅⋅⋅O, C-H⋅⋅⋅H-C, and C-H⋅⋅⋅π leads to the formation of micro-ring morphology, a unique molecular architecture in MNCs. The in situ generated AgNPs due to the acceleration of the reaction kinetics by Cu2+ ions facilitate the growth of Ag14NCs with FCC metallic kernel. These two structural units of AgNCs show light-induced reversible structural transformation which is also associated with the reversible tuning of their spectroscopic and morphological signatures. This PARI-guided interconversion strategy put forward a most appropriate example of a structure-property relationship in MNCs.

Comparison of two crystal polymorphs of NowGFP reveals a new conformational state trapped by crystal packing.

Crystal polymorphism serves as a strategy to study the conformational flexibility of proteins. However, the relationship between protein crystal packing and protein conformation often remains elusive. In this study, two distinct crystal forms of a green fluorescent protein variant, NowGFP, are compared: a previously identified monoclinic form (space group C2) and a newly discovered orthorhombic form (space group P212121). Comparative analysis reveals that both crystal forms exhibit nearly identical linear assemblies of NowGFP molecules interconnected through similar crystal contacts. However, a notable difference lies in the stacking of these assemblies: parallel in the monoclinic form and perpendicular in the orthorhombic form. This distinct mode of stacking leads to different crystal contacts and induces structural alteration in one of the two molecules within the asymmetric unit of the orthorhombic crystal form. This new conformational state captured by orthorhombic crystal packing exhibits two unique features: a conformational shift of the β-barrel scaffold and a restriction of pH-dependent shifts of the key residue Lys61, which is crucial for the pH-dependent spectral shift of this protein. These findings demonstrate a clear connection between crystal packing and alternative conformational states of proteins, providing insights into how structural variations influence the function of fluorescent proteins.

Surface-mutagenesis strategies to enable structural biology crystallization platforms.

A key prerequisite for the successful application of protein crystallography in drug discovery is to establish a robust crystallization system for a new drug-target protein fast enough to deliver crystal structures when the first inhibitors have been identified in the hit-finding campaign or, at the latest, in the subsequent hit-to-lead process. The first crucial step towards generating well folded proteins with a high likelihood of crystallizing is the identification of suitable truncation variants of the target protein. In some cases an optimal length variant alone is not sufficient to support crystallization and additional surface mutations need to be introduced to obtain suitable crystals. In this contribution, four case studies are presented in which rationally designed surface modifications were key to establishing crystallization conditions for the target proteins (the protein kinases Aurora-C, IRAK4 and BUB1, and the KRAS-SOS1 complex). The design process which led to well diffracting crystals is described and the crystal packing is analysed to understand retrospectively how the specific surface mutations promoted successful crystallization. The presented design approaches are routinely used in our team to support the establishment of robust crystallization systems which enable structure-guided inhibitor optimization for hit-to-lead and lead-optimization projects in pharmaceutical research.

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.

Unravelling the importance of hydrogen bonds and dihydrogen interactions in the supramolecular assembly of a caryolan-1-ol derivative: an experimental and theoretical investigation

We report here the synthesis of a caryolan-1-ol derivative, namely [(1R, 2S, 5R, 8S)-1-hydroxy-4,4,8-trimethyltricyclo[6.3.1.02,5]dodecan-6-one] (3), characterized by structural single-crystal X-ray diffraction, FTIR and 1H and 13C NMR spectroscopies. The crystal structure reveals weak noncovalent interactions along with O-H···O hydrogen bonding interactions that forms 1D network architectures. Hirshfeld surfaces and their two-dimensional fingerprint plots allow us to visualize the intermolecular contacts and their relative contributions to the total Hirshfeld surface for the compound. A comparative analysis against related compounds was carried out. The interaction energies for the molecular pair involving O-H···O hydrogen bonds indicated a dominant contribution to packing stabilization coming from the Coulombic components. Energy framework calculations afforded to analyse and visualize the topology of the intermolecular interactions responsible for the crystal packing, showing that dispersion energy prevail over the electrostatic one in the structure of 3. Theoretical calculations have been performed to analyse the unconventional noncovalent interactions observed in the solid-state structure of 3 using the quantum theory of atoms in molecules (QTAIM), noncovalent interactions plot (NCIplot) and natural bond orbital (NBO) computational tools.

Crystal structures, NCI-RDG, Hirshfeld surface and energy framework analysis of tetra aryl substitute bispidine and oxaquinuclidine core containing derivatives: A potential COVID-19 drug candidate

Two of the title compounds are crystallized in P21/c and monoclinic face groups. Each crystal unit cell has four molecules. There are two piperidine rings: one in the chair conformation and another one in the boat conformation. The piperidine nitrogen in the boat conformation is joined to the oxygen-containing chair conformation piperidine ring to produce the oxaquinuclidine ring (-N-CH2O-). Furthermore, because of the steric barrier between rings, all aryl groups are oriented in an equatorial position. The crystal network is maintained through several interactions, including C—H⋯O/N/Cl/π. The crystal void and interaction energy studies gave additional evidence of the strength of the crystal packing and intermolecular linkage. Crystal 3b has less cavity than crystal 3c, indicating that it is densely packed. The dispersion energy contribution dominates the stability, according to the analysis of the electrostatic, dispersion, and total energy frameworks. Reduced density gradient (RDG), electron localization function (ELF), and localized orbital locator (LOL) analysis were used to determine the molecular interaction, electron pair density, and maximally localized orbitals overlapping sites, respectively. This approach reveals that oxaquinuclidine ring steric hindrance and the electron densities throughout the molecules. Density function theory (DFT) provides more evidence for the ring's orientation and the molecules' reactivity. A molecular docking investigation of four essential COVID-19 proteins was carried out using these theoretical ideas. This investigation demonstrates that each protein's reactivity varies; certain proteins have more interaction with high electron density molecules (electron-donating substituent), while others have more interaction with low electron density molecules (electron-withdrawing substituent). The ADMET and drug-likeness investigations reveal that methoxy group substituted molecules perfectly correlate with the required pharmacological characteristics. The cytotoxicity of the five compounds was assessed using the HEK293T cell.

Crystal structure, Hirshfeld surface analysis, DFT and the mol-ecular docking studies of 3-(2-chloro-acet-yl)-2,4,6,8-tetra-phenyl-3,7-di-azabicyclo-[3.3.1]nonan-9-one.

In the title compound, C33H29ClN2O2, the two piperidine rings of the di-aza-bicyclo moiety adopt distorted-chair conformations. Inter-molecular C-H⋯π inter-actions are mainly responsible for the crystal packing. The inter-molecular inter-actions were qu-anti-fied and analysed using Hirshfeld surface analysis, revealing that H⋯H inter-actions contribute most to the crystal packing (52.3%). The mol-ecular structure was further optimized by density functional theory (DFT) at the B3LYP/6-31 G(d,p) level and is compared with the experimentally determined mol-ecular structure in the solid state.

Crystal structure and Hirshfeld surface analysis of 1-[6-bromo-2-(3-bromo-phen-yl)-1,2,3,4-tetra-hydro-quinolin-4-yl]pyrrolidin-2-one.

This study presents the synthesis, characterization and Hirshfeld surface analysis of 1-[6-bromo-2-(3-bromo-phen-yl)-1,2,3,4-tetra-hydro-quinolin-4-yl]pyrrolidin-2-one, C19H18Br2N2O. In the title compound, the pyrrolidine ring adopts a distorted envelope configuration. In the crystal, mol-ecules are linked by inter-molecular N-H⋯O, C-H⋯O and C-H⋯Br hydrogen bonds, forming a three-dimensional network. In addition, pairs of mol-ecules along the c axis are connected by C-H⋯π inter-actions. According to a Hirshfeld surface study, H⋯H (36.9%), Br⋯H/H⋯Br (28.2%) and C⋯H/H⋯C (24.3%) inter-actions are the most significant contributors to the crystal packing.