Synthesis,experimental and in silico studies of N‐fluorenylmethoxycarbonyl‐O‐tert‐butyl‐N‐methyltyrosine,coupled with CSD data: a survey of interactions in the crystal structures of Fmoc–amino acids

Recently, fluorenylmethoxycarbonyl (Fmoc) amino acids (e.g. Fmoc–tyrosine or Fmoc–phenylalanine) have attracted growing interest in biomedical research and industry, with special emphasis directed towards the design and development of novel effective hydrogelators, biomaterials or therapeutics. With this in mind, a systematic knowledge of the structural and supramolecular features in recognition of those properties is essential. This work is the first comprehensive summary of noncovalent interactions combined with a library of supramolecular synthon patterns in all crystal structures of amino acids with the Fmoc moiety reported so far. Moreover, a new Fmoc‐protected amino acid, namely, 2‐{[(9H‐fluoren‐9‐ylmethoxy)carbonyl](methyl)amino}‐3‐{4‐[(2‐hydroxypropan‐2‐yl)oxy]phenyl}propanoic acid or N‐fluorenylmethoxycarbonyl‐O‐tert‐butyl‐N‐methyltyrosine, Fmoc‐N‐Me‐Tyr(t‐Bu)‐OH, C₂₉H₃₁NO₅, was successfully synthesized and the structure of its unsolvated form was determined by single‐crystal X‐ray diffraction. The structural, conformational and energy landscape was investigated in detail by combined experimental and in silico approaches, and further compared to N‐Fmoc‐phenylalanine [Draper et al. (2015). CrystEngComm, 42 , 8047–8057]. Geometries were optimized by the density functional theory (DFT) method either in vacuo or in solutio. The polarizable conductor calculation model was exploited for the evaluation of the hydration effect. Hirshfeld surface analysis revealed that H…H, C…H/H…C and O…H/H…O interactions constitute the major contributions to the total Hirshfeld surface area in all the investigated systems. The molecular electrostatic potentials mapped over the surfaces identified the electrostatic complementarities in the crystal packing. The prediction of weak hydrogen‐bonded patterns via Full Interaction Maps was computed. Supramolecular motifs formed via C—H…O, C—H…π, (fluorenyl)C—H…Cl(I), C—Br…π(fluorenyl) and C—I…π(fluorenyl) interactions are observed. Basic synthons, in combination with the Long‐Range Synthon Aufbau Modules, further supported by energy‐framework calculations, are discussed. Furthermore, the relevance of Fmoc‐based supramolecular hydrogen‐bonding patterns in biocomplexes are emphasized, for the first time.     

Synthesis,crystal structure and studies on the interaction with albumin of a new silver(I) complex based on 2‐(4‐nitrobenzenesulfonamido)benzoic acid

In the present work, the two‐dimensional (2D) polymer poly[[μ₄‐2‐(4‐nitrobenzenesulfonamido)benzoato‐κ⁴O¹:O¹:O^1′:N⁶]silver(I)] (AgL), [Ag(C₁₃H₉N₂O₆S)]_n, was obtained from 2‐(4‐nitrobenzenesulfonamido)benzoic acid (HL), C₁₃H₁₀N₂O₆S. FT–IR, ¹H and ¹³C{¹H} NMR spectroscopic analyses were used to characterize both compounds. The crystal structures of HL and AgL were determined by single‐crystal X‐ray diffraction. In the structure of HL, O—H…O hydrogen bonds between neighbouring molecules result in the formation of dimers, while the silver(I) complex shows polymerization associated with the O atoms of three distinct deprotonated ligands (L^?). Thus, the structure of the Ag complex can be considered as a coordination polymer consisting of a one‐dimensional linear chain, constructed by carboxylate bridging groups, running parallel to the b axis. Neighbouring polymeric chains are further bridged by Ag—C monohapto contacts, resulting in a 2D framework. Fingerprint analysis of the Hirshfeld surfaces show that O…H/H…O hydrogen bonds are responsible for the most significant contacts in the crystal packing of HL and AgL, followed by the H…H and O…C/C…O interactions. The Ag…Ag, Ag…O/O…Ag and Ag…C/C…Ag interactions in the Hirshfeld surface represent 12.1% of the total interactions in the crystal packing. Studies of the interactions of the compounds with human serum albumin (HSA) indicated that both HL and AgL interact with HSA.     

The role of different nonspecific interactions and halogen contacts in the crystal structure organization of 5‐chloroisatoic anhydride

The crystal structure of 6‐chloro‐2,4‐dihydro‐1H‐3,1‐benzoxazine‐2,4‐dione (5‐chloroisatoic anhydride), C₈H₄ClNO₃, has been determined and analysed in terms of connectivity and packing patterns. The compound crystallizes in the noncentrosymmetric space group Pna2₁ with one molecule in the asymmetric unit. The role of different weak interactions is discussed with respect to three‐dimensional network organization. Molecules are extended into one‐dimensional helical arrangements, making use of N—H…O hydrogen bonds and π–π interactions. The helices are further organized into monolayers via weak C—H…O and lone pair–π interactions, and the monolayers are packed into a noncentrosymmetric three‐dimensional architecture by C—Cl…π interactions and C—H…Cl and Cl…Cl contacts. A Hirshfeld surface (HS) analysis was carried out and two‐dimensional (2D) fingerprint plots were generated to visualize the intermolecular interactions and to provide quantitative data for their relative contributions. In addition, tests of the antimicrobial activity and in vitro cytotoxity effects against fitoblast L929 were performed and are discussed.     

Different supramolecular architectures mediated by different weak interactions in the crystals of three N‐aryl‐2,5‐dimethoxybenzenesulfonamides

The synthesis and evaluation of the pharmacological activities of molecules containing the sulfonamide moiety have attracted interest as these compounds are important pharmacophores. The crystal structures of three closely related N‐aryl‐2,5‐dimethoxybenzenesulfonamides, namely N‐(2,3‐dichlorophenyl)‐2,5‐dimethoxybenzenesulfonamide, C₁₄H₁₃Cl₂NO₄S, (I), N‐(2,4‐dichlorophenyl)‐2,5‐dimethoxybenzenesulfonamide, C₁₄H₁₃Cl₂NO₄S, (II), and N‐(2,4‐dimethylphenyl)‐2,5‐dimethoxybenzenesulfonamide, C₁₆H₁₉NO₄S, (III), are described. The asymmetric unit of (I) consists of two symmetry‐independent molecules, while those of (II) and (III) contain one molecule each. The molecular conformations are stabilized by different intramolecular interactions, viz. C—H…O interactions in (I), N—H…Cl and C—H…O interactions in (II), and C—H…O interactions in (III). The crystals of the three compounds display different supramolecular architectures built by various weak intermolecular interactions of the types C—H…O, C—H…Cl, C—H…π(aryl), π(aryl)–π(aryl) and Cl…Cl. A detailed Hirshfeld surface analysis of these compounds has also been conducted in order to understand the relationship between the crystal structures. The d _norm and shape‐index surfaces of (I)–(III) support the presence of various intermolecular interactions in the three structures. Analysis of the fingerprint plots reveals that the greatest contribution to the Hirshfeld surfaces is from H…H contacts, followed by H…O/O…H contacts. In addition, comparisons are made with the structures of some related compounds. Putative N—H…O hydrogen bonds are observed in 29 of the 30 reported structures, wherein the N—H…O hydrogen bonds form either C (4) chain motifs or R ₂²(8) rings. Further comparison reveals that the characteristics of the N—H…O hydrogen‐bond motifs, the presence of other interactions and the resultant supramolecular architecture is largely decided by the position of the substituents on the benzenesulfonyl ring, with the nature and position of the substituents on the aniline ring exerting little effect. On the other hand, the crystal structures of (I)–(III) display several weak interactions other than the common N—H…O hydrogen bonds, resulting in supramolecular architectures varying from one‐ to three‐dimensional depending on the nature and position of the substituents on the aniline ring.     

2,4‐Dimethyl‐1,3‐thiazole‐5‐carboxylic acid: an X‐ray structural study at 100 K and Hirshfeld surface analysis

The crystal structure of the title thiazolecarboxylic acid derivative, C₆H₇NO₂S, (I), has been determined from single‐crystal X‐ray analysis at 100 K. In the crystal packing, an interplay of O—H...N and C—H...O hydrogen bonds connects the molecules to form C(6)R₂²(8) polymeric chains, which are further linked via weak C—H...O hydrogen bonds into a two‐dimensional supramolecular framework. The relative contributions of different interactions to the Hirshfeld surface in (I) and a few related thiazolecarboxylic acid derivatives indicate that the H...H, N...H and O...H contacts can account for about 50–70% of the total Hirshfeld surface area in this class of compound.     

Synthesis,characterization, X-ray diffraction studies and biological evaluation of tert-butyl 4-(2-ethoxy-2-oxoethyl)-piperazine-1-carboxylate and tert-butyl 4-(2-hydrazino-2-oxoethyl)piperazine-1-carboxylate

Two derivatives of N-Boc piperazine, an ester derivative, i.e., tert-butyl 4-(2-ethoxy-2-oxoethyl)-piperazine-1-carboxylate (1), and, a hydrazide derivative tert-butyl 4-(2-hydrazino-2-oxoethyl)piperazine-1-carboxylate (2) were synthesized and were characterized by FT-IR, ¹H & ¹³C NMR and LCMS spectroscopic studies. The structures of both 1 and 2 were further confirmed by single crystal X-ray diffraction analysis. The molecule of 1 is linear in shape with the ethyl acetate moiety adopting fully extended conformation, while the molecule of 2 is L-shaped with the molecule being twisted at the C10 atom. The crystal structure of 1 adopts a two-dimensional zig-zag architecture featuring C–H…O intermolecular interactions, while that of 2 features strong N–H…O hydrogen bonds and intermolecular interactions of the type N–H…N and C–H…N, resulting in a two-dimensional structure. Furthermore, a detailed analysis of the intermolecular interactions and crystal packing of 1 and 2 via Hirshfeld surface analysis and fingerprint plots was performed. The antibacterial and antifungal activities of both the compounds have been studied against several microorganisms, and were found to be moderately active.     

The solid‐state structure of the β‐blocker metoprolol: a combined experimental and in silico investigation

Metoprolol {systematic name: (RS)‐1‐isopropylamino‐3‐[4‐(2‐methoxyethyl)phenoxy]propan‐2‐ol}, C₁₅H₂₅NO₃, is a cardioselective β₁‐adrenergic blocking agent that shares part of its molecular skeleton with a large number of other β‐blockers. Results from its solid‐state characterization by single‐crystal and variable‐temperature powder X‐ray diffraction and differential scanning calorimetry are presented. Its molecular and crystal arrangements have been further investigated by molecular modelling, by a Cambridge Structural Database (CSD) survey and by Hirshfeld surface analysis. In the crystal, the side arm bearing the isopropyl group, which is common to other β‐blockers, adopts an all‐trans conformation, which is the most stable arrangement from modelling data. The crystal packing of metoprolol is dominated by an O—H…N/N…H—O pair of hydrogen bonds (as also confirmed by a Hirshfeld surface analysis), which gives rise to chains containing alternating R and S metoprolol molecules extending along the b axis, supplemented by a weaker O…H—N/N—H…O pair of interactions. In addition, within the same stack of molecules, a C—H…O contact, partially oriented along the b and c axes, links homochiral molecules. Amongst the solid‐state structures of molecules structurally related to metoprolol deposited in the CSD, the β‐blocker drug betaxolol shows the closest analogy in terms of three‐dimensional arrangement and interactions. Notwithstanding their close similarity, the crystal lattices of the two drugs respond differently on increasing temperature: metoprolol expands anisotropically, while for betaxolol, an isotropic thermal expansion is observed.     

Crystal structures,packing features,Hirshfeld surface analyses and DFT calculations of hydrogen‐bond energy of two homologous 8a‐aryl‐2,3,4,7,8,8a‐hexahydropyrrolo[1,2‐a]pyrimidin‐6(1H)‐ones

The crystal structures and packing features of two homologous Meyer's bicyclic lactams with fused pyrrolidone and medium‐sized perhydropyrimidine rings, namely, 8a‐phenyl‐2,3,4,7,8,8a‐hexahydropyrrolo[1,2‐a]pyrimidin‐6(1H)‐one, C₁₃H₁₆N₂O ( 1 ), and 8a‐(4‐methylphenyl)‐2,3,4,7,8,8a‐hexahydropyrrolo[1,2‐a]pyrimidin‐6(1H)‐one, C₁₄H₁₈N₂O ( 2 ), were elucidated, and Hirshfeld surface plots were calculated and drawn for visualization and a deeper analysis of the intermolecular noncovalent interactions. Molecules of 1 and 2 are weakly linked by intermolecular C=O…H—N hydrogen bonds into chains, which are in turn weakly linked by other C=O…H—C_ar interactions. The steric volume of the substituent significantly affects the crystal packing pattern.     

Synthesis,crystal structure and study of the crystal packing in the complex bis(4‐aminopyridine‐κN1)dichloridocobalt(II)

Despite the large number of reported crystalline structures of coordination complexes bearing pyridines as ligands, the relevance of π–π interactions among these hereroaromatic systems in the stabilization of their supramolecular structures and properties is not very well documented in the recent literature. The title compound, [CoCl₂(C₅H₆N₂)₂], was obtained as bright‐blue crystals suitable for single‐crystal X‐ray diffraction analysis from the reaction of 4‐aminopyridine with cobalt(II) chloride in ethanol. The new complex was fully characterized by a variety of spectroscopic techniques and single‐crystal X‐ray diffraction. The crystal structure showed a tetrahedral complex stabilized mainly by bidimensional motifs constructed by π–π interactions with large horizontal displacements between the 4‐aminopyridine units, and N—H…Cl hydrogen bonds. Other short contacts, such as C—H…Cl interactions, complete the three‐dimensional arrangement. The supramolecular investigation was extended by statistical studies using the Cambridge Structural Database and a Hirshfeld surface analysis.     

Supramolecular architectures in two 1:1 cocrystals of 5‐fluorouracil with 5‐bromothiophene‐2‐carboxylic acid and thiophene‐2‐carboxylic acid

In solid‐state engineering, cocrystallization is a strategy actively pursued for pharmaceuticals. Two 1:1 cocrystals of 5‐fluorouracil (5FU; systematic name: 5‐fluoro‐1,3‐dihydropyrimidine‐2,4‐dione), namely 5‐fluorouracil–5‐bromothiophene‐2‐carboxylic acid (1/1), C₅H₃BrO₂S·C₄H₃FN₂O₂, (I), and 5‐fluorouracil–thiophene‐2‐carboxylic acid (1/1), C₄H₃FN₂O₂·C₅H₄O₂S, (II), have been synthesized and characterized by single‐crystal X‐ray diffraction studies. In both cocrystals, carboxylic acid molecules are linked through an acid–acid R ₂²(8) homosynthon (O—H…O) to form a carboxylic acid dimer and 5FU molecules are connected through two types of base pairs [homosynthon, R ₂²(8) motif] via a pair of N—H…O hydrogen bonds. The crystal structures are further stabilized by C—H…O interactions in (II) and C—Br…O interactions in (I). In both crystal structures, π–π stacking and C—F…π interactions are also observed.     

Water‐mediated intermolecular interactions in 1,2‐O‐cyclohexylidene‐myo‐inositol: a quantitative analysis

The syntheses of new myo‐inositol derivatives have received much attention due to their important biological activities. 1,2‐O‐Cyclohexylidene‐myo‐inositol is an important intermediate formed during the syntheses of certain myo‐inositol derivatives. We report herein the crystal structure of 1,2‐O‐cyclohexylidene‐myo‐inositol dihydrate, C₁₂H₂₀O₆·2H₂O, which is an intermediate formed during the syntheses of myo‐inositol phosphate derivatives, to demonstrate the participation of water molecules and hydroxy groups in the formation of several intermolecular O—H…O interactions, and to determine a low‐energy conformation. The title myo‐inositol derivative crystallizes with two water molecules in the asymmetric unit in the space group C 2/c , with Z = 8. The water molecules facilitate the formation of an extensive O—H…O hydrogen‐bonding network that assists in the formation of a dense crystal packing. Furthermore, geometrical optimization and frequency analysis was carried out using density functional theory (DFT) calculations with B3LYP hybrid functionals and 6‐31G(d), 6‐31G(d,p) and 6‐311G(d,p) basis sets. The theoretical and experimental structures were found to be very similar, with only slight deviations. The intermolecular interactions were quantitatively analysed using Hirshfeld surface analysis and 2D (two‐dimensional) fingerplot plots, and the total lattice energy was calculated.     

How the oxazole fragment influences the conformation of the tetraoxazocane ring in a cyclohexanespiro‐3′‐(1,2,4,5,7‐tetraoxazocane): single‐crystal X‐ray and theoretical study

Single crystals of (2S,5R)‐2‐isopropyl‐5‐methyl‐7‐(5‐methylisoxazol‐3‐yl)cyclohexanespiro‐3′‐(1,2,4,5,7‐tetraoxazocane), C₁₆H₂₆N₂O₅, have been studied via X‐ray diffraction. The tetraoxazocane ring adopts a boat–chair conformation in the crystalline state, which is due to intramolecular interactions. Conformational analysis of the tetraoxazocane fragment performed at the B3LYP/6‐31G(d,2p) level of theory showed that there are three minima on the potential energy surface, one of which corresponds to the conformation realized in the solid state, but not to a global minimum. Analysis of the geometry and the topological parameters of the electron density at the (3,?1) bond critical points (BCPs), and the charge transfer in the tetraoxazocane ring indicated that there are stereoelectronic effects in the O—C—O and N—C—O fragments. There is a two‐cross hyperconjugation in the N—C—O fragment between the lone electron pair of the N atom (lpN) and the antibonding orbital of a C—O bond (σ*_C—O) and vice versa between lpO and σ*_C—N. The oxazole substituent has a considerable effect on the geometry and the topological parameters of the electron density at the (3,?1) BCPs of the tetraoxazocane ring. The crystal structure is stabilized via intermolecular C—H…N and C—H…O hydrogen bonds, which is unambiguously confirmed with PIXEL calculations, a quantum theory of atoms in molecules (QTAIM) topological analysis of the electron density at the (3,?1) BCPs and a Hirshfeld analysis of the electrostatic potential. The molecules form zigzag chains in the crystal due to intermolecular C—H…N interactions being electrostatic in origin. The molecules are further stacked due to C—H…O hydrogen bonds. The dispersion component in the total stabilization energy of the crystal lattice is 68.09%.     

Exploring a solvated dimer of Gefitinib: a quantitative analysis

Gefitinib or Iressa is an orally administered anilinoquinazoline used in cancer chemotherapy for the treatment of lung and breast cancer. It is reported to exist in two polymorphic forms, a stable form I and a metastable form II. Both of the forms belong to the triclinic P space group. In this work, we report the crystallization of Gefitinib to form a methanol solvate [systematic name: N‐(3‐chloro‐4‐fluorophenyl)‐7‐methoxy‐6‐[3‐(morpholin‐4‐yl)propoxy]quinazolin‐4‐amine methanol hemisolvate, C₂₂H₂₄ClFN₄O₃·0.5CH₃OH] that was theoretically and experimentally investigated. The unit cell is composed of two independent Gefitinib molecules (A and B) that form a stable molecular complex with methanol in the crystal lattice. To understand the crystal lattice stabilization, a combination of techniques, namely X‐ray diffraction, IR spectroscopy, thermogravimetric/differential scanning calorimetry (TG‐DSC), Hirshfeld surface analysis and CLP‐PIXEL methods were used. The analysis of the crystal structure of this dimer revealed a three‐dimensional isostructurality with the already reported form II. The A and B molecules are connected via trifurcated C—H…O and N—H…O hydrogen bonding. In addition, the presence of the methanol molecule stabilizes the crystal structure via C—H…O, N—H…O and C—H…Cl interactions between the two monomers. The IR analysis of the dimer has shown characteristic fingerprint values when compared to the commercial form. The TG‐DSC analysis of the solvated dimer is in good agreement with the patent reporting cocrystals of Gefitinib. Finally, theoretical calculations by the CLP‐PIXEL method and Hirshfeld surface and two‐dimensional (2D) fingerprint plot analysis were carried out in order to quantify the different intermolecular interactions and their energies in the crystal packing.     

Synthesis,structural characterization,EPR spectroscopy and Hirshfeld surface analysis of a novel Cu2+‐doped 3,14‐diethyl‐2,13‐diaza‐6,17‐diazoniatricyclo[16.4.0.07,12]docosane bis(perchlorate)

Cyclam derivatives and their metal complexes have been found to exhibit an anti‐HIV effect and stimulate the activity of stem cells from bone marrow. The strength of their binding to the CXCR4 receptor correlates with anti‐HIV and stem‐cell activities. Knowledge of the conformation and crystal packing of various macrocyclic metal complexes has become important in developing new effective anti‐HIV drugs. The synthesis and preparation of single crystals of a new Cu²⁺‐doped macrocyclic compound, (3,14‐diethyl‐2,6,13,17‐tetraazatricyclo[16.4.0.0^7,12]docosane)copper(II) bis(perchlorate)–3,14‐diethyl‐2,13‐diaza‐6,17‐diazoniatricyclo[16.4.0.0^7,12]docosane bis(perchlorate) (0.69/0.31), {[Cu(C₂₂H₄₄N₄)](ClO₄)₂}_0.69·(C₂₂H₄₆N₄²⁺·2ClO₄^?)_0.31, is reported. Characterization by X‐ray diffraction analysis shows that the asymmetric unit contains half of a centrosymmetric molecule. The macrocyclic ligand in the compound adopts the most stable trans‐III conformation. The Cu—N distances of 2.015 (3) and 2.047 (3) Å are normal, but the long axial Cu—O bond of 2.795 (3) Å may be due to a combination of the Jahn–Teller effect and the strong in‐plane ligand field. The crystal structure is stabilized by hydrogen bonding between secondary N—H groups, the N atoms of the macrocycle and the O atoms of the perchlorate anions. Hirshfeld surface analysis with 2D (two‐dimensional) fingerprint plots indicates that the main contributions to the crystal packing are from H…H (58.0%) and H…O/O…H (41.9%) interactions. Electron paramagnetic resonance (EPR) properties are also described.     

Invariom‐model refinement and Hirshfeld surface analysis of well‐ordered solvent‐free dibenzo‐21‐crown‐7

Crown ethers and their supramolecular derivatives are well‐known chelators and scavengers for a variety of cations, most notably heavier alkali and alkaline‐earth ions. Although they are widely used in synthetic chemistry, available crystal structures of uncoordinated and solvent‐free crown ethers regularly suffer from disorder. In this study, we present the X‐ray crystal structure analysis of well‐ordered solvent‐free crystals of dibenzo‐21‐crown‐7 (systematic name: dibenzo[b ,k ]‐1,4,7,10,13,16,19‐heptaoxacycloheneicosa‐2,11‐diene, C₂₂H₂₈O₇). Because of the quality of the crystal and diffraction data, we have chosen invarioms, in addition to standard independent spherical atoms, for modelling and briefly discuss the different refinement results. The electrostatic potential, which is directly deducible from the invariom model, and the Hirshfeld surface are analysed and complemented with interaction‐energy computations to characterize intermolecular contacts. The boat‐like molecules stack along the a axis and are arranged as dimers of chains, which assemble as rows to form a three‐dimensional structure. Dispersive C—H…H—C and C—H…π interactions dominate, but nonclassical hydrogen bonds are present and reflect the overall rather weak electrostatic influence. A fingerprint plot of the Hirshfeld surface summarizes and visualizes the intermolecular interactions. The insight gained into the crystal structure of dibenzo‐21‐crown‐7 not only demonstrates the power of invariom refinement, Hirshfeld surface analysis and interaction‐energy computation, but also hints at favourable conditions for crystallizing solvent‐free crown ethers.     

Structural and computational analysis of intermolecular interactions in a new 2‐thiouracil polymorph

The crystallization and characterization of a new polymorph of 2‐thiouracil by single‐crystal X‐ray diffraction, Hirshfeld surface analysis and periodic density functional theory (DFT) calculations are described. The previously published polymorph (A ) crystallizes in the triclinic space group P , while that described herein (B ) crystallizes in the monoclinic space group P 2₁/c . Periodic DFT calculations showed that the energies of polymorphs A and B , compared to the gas‐phase geometry, were −108.8 and −29.4 kJ mol⁻¹, respectively. The two polymorphs have different intermolecular contacts that were analyzed and are discussed in detail. Significant differences in the molecular structure were found only in the bond lengths and angles involving heteroatoms that are involved in hydrogen bonds. Decomposition of the Hirshfeld fingerprint plots revealed that O…H and S…H contacts cover over 50% of the noncovalent contacts in both of the polymorphs; however, they are quite different in strength. Hydrogen bonds of the N—H…O and N—H…S types were found in polymorph A , whereas in polymorph B , only those of the N—H…O type are present, resulting in a different packing in the unit cell. QTAIM (quantum theory of atoms in molecules) computational analysis showed that the interaction energies for these weak‐to‐medium strength hydrogen bonds with a noncovalent or mixed interaction character were estimated to fall within the ranges 5.4–10.2 and 4.9–9.2 kJ mol⁻¹ for polymorphs A and B , respectively. Also, the NCI (noncovalent interaction) plots revealed weak stacking interactions. The interaction energies for these interactions were in the ranges 3.5–4.1 and 3.1–5.5 kJ mol⁻¹ for polymorphs A and B , respectively, as shown by QTAIM analysis.     

Design,synthesis, in silico analysis with PPAR‐γ receptor and study of non‐covalent interactions in unsymmetrical heterocyclic/phenyl fleximer

This work deals with the design, synthesis, in silico analysis, crystallization, and the interpretation 2‐cyano‐3‐{4‐[2‐(phthalimid‐nyl)‐propoxy]‐phenyl}‐acrylic acid ethyl ester (7). Analog 7 is designed based on rosiglitazone. The quantitative analysis of Compound 7 has been performed through single‐crystal X‐Ray Diffraction (XRD) and Hirshfeld surface analysis. Fleximer 7 has studied the role of flexibility in non‐covalent interactions and binding affinity with PPAR‐γ receptors. Both phthalimide ring and phenyl rings are linked with propylene linker. 2‐cyano‐3‐{4‐[2‐(phthalimid‐nyl)‐propoxy]‐phenyl}‐acrylic acid ethyl ester has Z = 8 in the crystal packing and stabilized by intermolecular non‐covalent interactions like C? H…O, C? H…N, C? H…л, and л…л, and so forth.     

Exploring concomitant/conformational dimorphism in a difluoro‐substituted phosphoramidate derivative

The concomitant occurrence of dimorphs of diphenyl (3,4‐difluorophenyl)phosphoramidate, C₁₈H₁₄F₂NO₃P, was observed via a solution‐mediated crystallization process with variation in the symmetry‐free molecules (Z′). The existence of two forms, i.e. Form I (block, Z′ = 1) and Form II (needle, Z′ = 2), was characterized by single‐crystal X‐ray diffraction, differential scanning calorimetry and powder X‐ray diffraction. Furthermore, a quantitative analysis of the energetics of the different intermolecular interactions was carried out via the energy decomposition method (PIXEL), which corroborates with inputs from the energy framework and looks at the topology of the various intermolecular interactions present in both forms. The unequivocally distinguished contribution of strong N—H…O hydrogen bonds along with other interactions, such as C—H…O, C—H…F, π–π and C—H…π, mapped on the Hirshfeld surface is depicted by two‐dimensional fingerprint plots. Apart from the major electrostatic contribution from N—H…O hydrogen bonds, the crystal structures are stabilized by contributions from the dispersion energy. The closely related melting points and opposite trends in the calculated lattice energies are interesting to investigate with respect to the thermodynamic stability of the observed dimorphs. The significant variation in the torsion angles in both forms helps in classifying them in the category of conformational polymorphs.