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A solvent-assisted grinding method has been used to prepare co-crystals in substituted dihydropyrimidines (DHPM) that constitutes pharmacologically active compounds. These were characterized using FT-IR, PXRD, and single-crystal X-ray diffraction. In order to explore the possibility of formation of halogen (XB) and hydrogen bonding (HB) synthons in the solid state, co-crystallization attempts of differently substituted DHPM molecules, containing nitro, hydoxy, and chloro substituents, with different co-formers, such as 1,4-diiodo tetrafluorobenzene (1,4 DITFB) and 3-nitrobenzoic acid (3 NBA) were performed. The XB co-crystals (C2aXB, C2bXB, and C2cXB) prefer the formation of C-I⋅⋅⋅O/C-I⋅⋅⋅S XB synthon, whereas the HB co-crystal (C2dHB) is stabilized by N-H⋅⋅⋅O H-bond formation. Hirshfeld surface analysis revealed that the percentage contribution of intermolecular interactions for XB co-crystals prefer equal contribution of XB synthon along with HB synthon. Furthermore, the interaction energy was analyzed using energy frameworks, which suggests that their stability, a combination of electrostatics and dispersion, is enhanced through XB/HB in comparison to the parent DHPMs.

Extensive research in the field of noncovalent interactions has shown that hydrogen bonds are responsible for the association of molecules leading to the formation of different crystal structures. ...

In the current study, two novel Knoevenagel condensation products of substituted napthofuran-2-carbaldehydes were designed, synthesized and characterized. In order to study the intermolecular interactions of title compounds, single crystals were grown by slow evaporation solution growth technique at room temperature and crystal structure has been determined by single crystal X-ray diffraction technique. Both the molecules crystallize in the monoclinic centrosymmetric space group P21/c with one molecule in the asymmetric unit. In compound [4] the molecules are connected via bifurcated C-H···O=C and C-H···N=C H-bonds and van der Waals interactions forming a layered structure, whereas in compound [5a] the molecular conformation is stabilized via intramolecular C-H···O H-bond and molecule interacts with other molecule generated via 21-screw via bifurcated C-H···O=C along with C-H···N=C H-bonds, which are interacting with nitro- of other molecule generated via same symmetry operation, forming bifurcated C-H···O-N H-bonds, which helps in formation of molecular sheet-like structure.Further, in order to understand the various types and nature of intermolecular interactions in the supramolecular structure Hirshfeld surface analysis and fingerprint plot analysis was carried out.

The field of intra- and intermolecular interactions has received a major boost in the past one decade. Significant advances in both instrumentation (for experimental purposes) and computational resources (development of theoretical models) have provided strong impetus to this area of research. The understanding of the nature, energetics and the topological characteristics of these interactions are the driving forces which govern intermolecular recognition. This is strongly dependent on the state of aggregation of the substance. The environment (solid, liquid and gas) plays an extremely crucial and subtle role in deciphering the mechanism via which molecules interact with each other. In the past two decades, there has been rigorous development in the understanding of strong hydrogen bonds. The focus has now shifted towards the quantitative assessment of weak intermolecular interactions, of the type C–H···X (X = F in particular), X···X, X(lp)···π along with σ–hole-directed intermolecular interactions involving tetrels, chalcogens, pnictogens, halogens and the aerogens. In addition, there is increasing evidence for the assessment of the relevance of π–hole-based interactions in tetrels, chalcogens, and pnictogens as well. The current perspective highlights the importance of the above-mentioned interactions and their associated electronic features. This has strong implications in the area of materials and related applied sciences with relevance towards the technological applications of these interactions in terms of understanding structure–property correlation in the mechanical, optical and electrical properties of matter.

In this study, a series of electron-rich helical hosts, viz. Pyr-HAC, Anth-HAC and Ben-HAC, containing pyrene, anthracene and benzene residues, respectively, at their periphery, were screened for their interaction with different planar electron-deficient organic guests (PEDOGs). A strong and highly selective charge-transfer interactions (CTI) was observed between the host Pyr-HAC and the guest 1,2,4,5-tetracyano-benzene (TCNB), leading to a yellow-to-bright-red color change in both the solubilized and the solid state. The interaction between Pyr-HAC and TCNB also induced profound structural and morphological changes. Pyr-HAC self-assembled into belt-like morphology created by homochiral stacking of the host molecules, but in the Pyr-HAC⊃TCNB complex, square bipyramids containing intertwined heterochiral C2 -double helices of Pyr-HAC were observed. Other PEDOGs did not induce any of the above changes in Pyr-HAC. Detailed UV/Vis absorption and fluorescence spectroscopy, NMR, and X-ray diffraction studies confirmed this selectivity, which arises due to CTI assisted by complementary, directional intermolecular hydrogen bonding (DIHB) between Pyr-HAC and TCNB. This allowed for the exclusive extraction of TCNB from a solution enriched in other PEDOGs. Thus, this study provides a ground work for designing responsive helical hosts towards CTI-driven selective "catch-and-release" of guests.

Four new binary luminescent co-crystals and a co-crystal stoichiomorph comprising aromatic compounds and 1,4-diiodotetrafluorobenzene were successfully synthesized by the solvent drop grinding method. Structural features of these co-crystals indicate that the relative interplay of σ- and π-hole directed intermolecular interactions were observed to be responsible for modulating luminescence properties of those materials. Investigation of photoluminescence properties reveals that there is a substantial change in emission color from the starting aromatic materials to co-crystals. The I⋯N and σ-hole⋯π halogen bonds along with π-hole⋯π interactions have been instrumental towards altering the emissive properties of the luminescent materials.

We report a rare incidence of crystal dimorphism in the case of molecule N1,N2-bis(3-(trifluoromethyl)phenyl)oxalamide which exhibits a variable fractional number of symmetry free molecules (Z′) in the structures. The extensive solution mediated and melt crystallization results in form I (Z′ = 1/2, half molecule) and form II (Z′ = 1/2 + 1/2, two half molecules) polymorphic forms, respectively, and exclusively. A quantitative structural description with the energetics of intermolecular interactions for both polymorphs has been demonstrated thoroughly. The existence of two different molecular conformations and better energetic stabilization of the interaction topology rationalizes the high Z′ structure selection by the molecule in the case of form II.

Five new binary co-crystals have been prepared through molecular self-assembly of π-electron-rich molecules, such as phenanthrene, benzo[c]cinnoline, and phenazine, in the presence of π-electron-de...

A total of 23 benzamides are obtained through a simple reaction between chloro-/bromo-/iodoaniline and trifluoromethylbenzoyl chloride and characterized using single-crystal X-ray diffraction. Crystal structures of three series of benzamides based on N-chlorophenyl–trifluoromethyl–benzamide (nine compounds), N-bromophenyl–trifluoromethyl–benzamide (six compounds), and N-iodophenyl–trifluoromethyl–benzamide (eight compounds) are prepared to analyse the halogen-mediated noncovalent interactions. The influences of Cl/Br/I and trifluoromethyl substituents on the respective interactions are examined in the presence of a strong N—H...O hydrogen bond. This exercise has resulted in the documentation of frequently occurring supramolecular synthons involving halogen atoms in the crystal packing of benzamide molecules in the solid state. In the present study, a detailed quantitative evaluation has been performed on the nature, energetics, electrostatic contributions, and topological properties of short and directional intermolecular interactions derived from the electron density on halogenated benzamides in the solid state. Besides these, the occurrence of three-, two- and one-dimensional isostructurality in halogen (Cl or Br or I) substituted benzamide analogues is also investigated. A `region of co-existence' involving halogen-based intermolecular interactions in the vicinity of the sum of the van der Waals radii has been identified. Thus, the nature of the halogen (effective size), type of interaction and the packing characteristics via presence of additional interactions establish the subtle, yet important, role of cooperativity in intermolecular interactions in crystal packing.

The role of different intermolecular interactions in the crystal structures of halogen-substituted indoles which are fused with six-membered or seven-membered cyclic rings is investigated here. Several crystal structures show isostructural characteristics due to the presence of similar supramolecular motifs. In the absence of any strong hydrogen bonds, the molecular packing of reported structures is primarily stabilized by the presence of non-classical N—H...π and C—H...π interactions in addition to C—H...X (X = F/Cl/Br) interactions. The nature and energetics of primary and secondary dimeric motifs are partitioned into the electrostatics, polarization, dispersion and exchange–repulsion components using the PIXEL method. Short and directional N—H...π interactions are further explored by a topological analysis of the electron density based on quantum theory of atoms in molecules.

Experimental in situ cryo-crystallization studies performed on aniline derivatives depicts that the molecular packing of these compounds is through the utilization of Csp3/sp2 F⋯F Csp3/sp2, N H⋯F Csp3/sp2, and C H⋯F Csp3/sp2 interactions in the presence of strong N H⋯N hydrogen bonds. This exercise has resulted in the identification of frequently occurring supramolecular synthons involving highly electronegative, less polarizable fluorine atoms in the packing of molecules of F and CF3 substituted anilines which are liquids at ambient temperature and pressure in the solid state. These studies demonstrate the nature, energetics and topological properties derived from the electron density in compounds based on F and CF3 substituted anilines (8 anilines) in the solid state. The energetics obtained from PIXELC associated with inclusive intermolecular interactions with significantly high electrostatic contribution is mentionable. The topological analysis brings out the bonding character of these interactions in the crystal packing. It is indeed noteworthy that in situ cryo-crystallization in 2-fluoro-6-(trifluoromethyl)aniline forms unique C(sp2) Fδ+⋯Fδ− C(sp2) contacts stabilized via electrostatics between the two molecules in the asymmetric unit in addition to N H⋯N H-bonds. This feature is also observed in a related isomeric compound, namely 2-fluoro-3-(trifluoromethyl)aniline and establishes the importance of weak fluorine-centered halogen interactions in nucleation and crystal growth.

We report the experimental observation and detailed quantum chemical analysis of the rare bifurcated type Se···π and Te···π “double” chalcogen bonded synthons observed through the in situ cryocrystallization of two room temperature organochalcogen liquids, namely, diphenylselenide and diphenyl telluride. The attractive intermolecular interactions between the heavier chalcogens and π-clouds are primarily stabilized by the dispersion forces, which is in contrast to many known model examples in the literature. Electrostatic and orbital delocalization effects also play a secondary but important role in the overall stabilization, besides providing directionality to these interactions.

A series of differently substituted host molecules have been employed to systematically investigate the nature and strength of the stacking interactions with hexafluorobenzene in the solid state. The hexafluorobenzene guest binds to the crystal lattice of the parent compound, the N-ethynylphenyl benzamide host and its nine other halogenated (-F/-CF3/-Cl/-Br at ortho/meta/para positions individually) analogues via stacking of aromatic rings. The geometrical and energetic features of intermolecular interactions in host–guest molecules have been investigated, and the results elucidate the dominancy of dispersion in the stabilization of the aryl-hexafluorobenzene stacking, while the electrostatic component also plays an important role. The plots of the molecular electrostatic potential provide a fundamental basis of the electrostatic complementarity that exists in between the host and the guest. The topological characterization reveals unambiguous evidence for the direct participation of the substituents in c...

The nature and characteristics of the intermolecular OC⋯OC π-hole tetrel bond in the solid state have been explored and the driving force for tetrel bond formation is the electrostatically driven π-hole interaction between the most electropositive carbon atom of the carbonyl group and the most electronegative oxygen atom in the crystal. NBO calculations establish the n → π* orbital interaction present and CSD analysis quantitatively establishes the Burgi–Dunitz angle to be ∼97.7° driven via tetrel bond formation.

In this report, the occurrence of three-, two-, and one-dimensional (3D, 2D, and 1D) isostructurality in phenyl benzoate (D00) and their fluorinated analogues was investigated in terms of their molecular assembly in solid state structures. A one-dimensional C–H···O═C chain is observed as a robust motif (∼ −21 kJ/mol) in the formation of the supramolecular architectures in these isostructural compounds. The isomorphous crystal structures exhibit 3D isostructurality or vice versa. The crystal packing shows that weak intermolecular C–H···F, C–H···O, C–H···π interactions, and π···π stacking are the main contributors providing stability toward the crystal lattice. The nature and energetics of all the geometrically or energetically equivalent building blocks associated with similar or different intermolecular interactions delineate the role of different molecular pairs in the crystal structures. The fingerprint plots of the isostructural set of crystal structures help to understand the similarities and the diff...

Strong hydrogen bonds play a significant role in crystal packing. In particular, the involvement of interactions involving fluorine in controlling the crystal packing requires appropriate attention, especially in the presence of other strong hydrogen bonds. In the present study, a detailed quantitative assessment has been performed of the nature, energetics and topological properties derived from the electron density in model compounds based on fluorinated benzamides (a total of 46 fluorine-substituted benzamides containing multiple fluorine atoms) in the solid state. The primary motivation in the design of such molecules is to enhance the acidity of the interacting H atoms in the presence of an increasing number of F atoms on the molecular scaffold, resulting in increased propensity towards the formation of intermolecular interactions involving organic fluorine. This exercise has resulted in the identification of new and frequently occurring supramolecular synthons involving F atoms in the packing of molecules in the solid state. The energetics associated with short and directional intermolecular Csp 2—H...F—Csp 2 interactions with significantly high electrostatic contributions is noteworthy, and the topological analysis reveals the bonding character of these ubiquitous interactions in crystal packing in addition to the presence of Csp 2—F...F—Csp 2 contacts.

In the present study, we have synthesized and structurally characterized two biologically active derivatives of 1,2,4 triazoles, namely 3-(4-fluoro-3-phenoxyphenyl)-1-(piperidin-1-ylmethyl)-1H-1,2,4-triazole-5(4H)-thione (TR) and 1-((3-(4-fluoro-3-phenoxyphenyl)-5-(methylthio)-1H-1,2,4-triazol-1-yl)methyl)piperidine (TR1) via single crystal X-ray diffraction. Both the structures show the presence of various intermolecular interactions in the crystalline solid such as C H…F, C H…S, C H…N, C H…O, C H … π, and π … π intermolecular interactions. The role of these interactions in molecular packing was analyzed, and the nature of these interactions was evaluated through computational procedures using PIXEL. Hirshfeld analysis further reveals that the contribution of H…F interactions was more prominent towards packing as compared to H…N/O intermolecular interactions.

Solvent drop grinding experiments on riluzole, an organofluorine drug, with different carboxylic acids (mono and di) and pyridine derivatives, resulted in the formation of 10 different co-crystals, one polymorph of a co-crystal, and a salt. The crystal packing is primarily stabilized via strong N–H···O, O–H···N, O–H···O, and N–H···N hydrogen bonds, in addition to secondary interactions of the type C–H···F/O and S···F intermolecular contacts. The melting point of the new crystalline phases was observed to be present in the range of 90–140 °C which is closely related to the melting point (118 °C) of the original API. It was observed that the co-crystals depicted enhanced the solubility and dissolution rate in comparison to that of the free drug.

Amongst the halogens, the involvement of bromine atoms in various types of intermolecular interactions is comparatively the least studied. In this manuscript, we report the formation of C Br⋯π interactions, with the π-rings being the cyclopentadienyl (Cp) rings of a ferrocene molecule in a newly synthesized compound (E)-1,3-dibromo-5-(2-(ferrocenyl)vinyl)benzene. We have also performed a detailed quantitative analysis on C Br⋯π interactions observed in the synthesized molecule and in several related molecules found in the Cambridge Structure Database (CSD) showing the presence of these interactions. A topological analysis based upon QTAIM theory and electrostatic potential ESP mapped on the Hirshfeld surface of these molecules confirm that these interactions are better described as “halogen bonds” wherein the electropositive region (σ-hole) on the Br-atom interacts with the electronegative region over the Cp-ring of the ferrocene. Further, the electronegative region on the bromine atom (perpendicular to the C Br bond) was observed to be involved in the formation of highly directional C H⋯Br interactions with the ∠C Br⋯H close to 90°. Thus the bromine atom is acting as both a “halogen bond donor” and “hydrogen bond acceptor” in the crystal packing with the two interactions being mutually orthogonal.

The present study focuses on a series of novel hydrazones of 2- [3-cyano-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carbohydrazide (5a-l) for their larvicidal activity against Anopheles arabiensis. The synthesis of the title compounds was achieved by the conventional reflux method, and structures of the novel compounds were ascertained by FT-IR, NMR (1H &13C), LC-MS, and elemental analysis. Compound (5l) was studied by single crystal X-ray diffraction for intra and intermolecular interactions. Title compounds (E)-2-(3-cyano-4-isobutoxyphenyl)-N'-(4-fluoro-3-phenoxybenzylidene)-4-methylthiazole-5-carbohydrazide (5a) and (E)-N'-(4-Chlorobenzylidene)-2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carbohydrazide (5g) emerged as promising larvicidal agents against Anopheles arabiensis.

The disparity in the electronic nature of organic (C–X) and inorganic (M–X) halogens in a supramolecular context has been demonstrated herein. Metal complexes [Zn(hyd-X)Cl2]·nDMF of three o-halophenyl substituted hydrazide based ligands hyd-X (hyd = hydrazide, X = F, Cl and Br) have been synthesized and characterized by single crystal XRD. The C–X halogen atom in these complexes is involved in either intramolecular X⋯O interaction (when X = Cl/Br) or intramolecular N–H⋯X (when X = F) hydrogen bonding. Supramolecular networks propagated via intermolecular C–X⋯N halogen bonds and N–H⋯X(M) hydrogen bonds are observed in crystal structures of the complexes. Intramolecular X⋯O interaction and intramolecular N–H⋯F hydrogen bonds exert decisive roles in locking the molecular conformation of these compounds. DFT, AIM and NBO studies have been employed to acquire quantitative accounts of the halogen mediated non-covalent interactions.

In the current study, we report the existence of 3D isostructurality behaviour in pairs of isomeric molecules existing as E–Z isomers. The polymorphic forms E1 and E2 of (E)-2-fluoro-N′-(3-phenyl) benzimidamide are individually isostructural with (E)-2-fluoro-N′-phenylbenzimidamide and (E)-2-fluoro-N′-(2-fluorophenyl) benzimidamide, respectively. Furthermore, a similar compound, (Z)-3-fluoro-N′-(4-fluorophenyl) benzimidamide, is isostructural with (Z)-4-fluoro-N′-(4-fluorophenyl) benzimidamide. The structural feature has been analyzed in terms of the nature and energetics of the equivalent supramolecular building blocks associated with the presence of various intermolecular interactions in the crystal packing. The crystal packing similarities have been investigated quantitatively via XPac analysis and the energy vector model. It is noteworthy to observe the presence of a rarely observed N–H⋯F interaction which plays an important role in the crystal packing of [(Z)-3-fluoro-N′-(4-fluorophenyl) benzimidamide]/[(Z)-4-fluoro-N′-(4-fluorophenyl) benzimidamide]. The NCI isosurface signifies the “attractive” nature of the N–H⋯F and N–H⋯π interactions and the different types of C–H⋯F dimeric motifs. An analysis of the two-dimensional fingerprint plots also provides a quantitative understanding of the occurrence of isostructurality in these compounds.

In this study, we have performed a detailed analysis of the nature and strength of different intermolecular interactions present in the crystal structures of four biologically active derivatives of 1,3,4-oxadiazol-2(3H)-thiones. The study was primarily focused on obtaining detailed physical insights into the differential nature of the σ-hole and π-hole interactions that exist in the solid state in this class of compounds. It is found that the directionality of an interaction plays a very important role in categorizing these interactions as being σ-hole and π-hole in origin. The presence of a σ-hole (on the S, Cl and Br atoms) and π-holes (in the oxadiazole and benzyl rings) is clearly evident from the molecular electrostatic potential maps. The presence of these ubiquitous interactions was further confirmed via QTAIM analysis by the presence of (3, −1) bond critical points (bcps) between the interacting atoms with acceptable topological parameters (ρbcp; ∇2ρbcp). Furthermore, Hirshfeld 2D fingerprint plots helped in quantitatively determining the role of different interactions in the crystal packing of the four reported structures.

In this study, we have investigated the nature and characteristics of different intermolecular interactions present in a series of seven N-(substituted phenyl)-2-naphthamides. The seven structures comprise 2-naphthyl ring systems linked by amide bridges to N-bound phenyl 1, or substituted benzene rings 3–7, or in the case of 2, a cyclohexane ring. A common feature of the crystal packing for all but the o-nitro derivative 7 is the presence of a strong intermolecular N–H⋯O interaction. In the case of 7, the possibility of such an interaction is obviated by the formation of an intramolecular N–H⋯O hydrogen bond. An additional feature of the crystal packing for 1–6 is the significant roles that C–H⋯π contacts play in generating three-dimensional networks. In contrast for 7, the intramolecular N–H⋯O hydrogen bond precludes the formation of molecular chains but the planar nature of this molecule allows significant π⋯π stacking interactions to stabilize the packing.

In this study, we have investigated the supramolecular pattern in two dicarboxylic acids, namely isopropylmalonic acid (1) and n-butylmalonic acid (2), via the presence of different hydrogen bonding patterns and aliphatic chains associated with the respective acids. The crystal structure is formed via the presence of strong O H⋯O and C H⋯O H-bonds, in the solid-state. The nature and energetics of the different supramolecular architectures in these two molecules have been further analyzed quantitatively via the PIXEL method. Hirshfeld surface analysis and fingerprint plots help to evaluate the contribution of different types of intermolecular contacts in the crystal packing. MESP calculations have been done to delineate the negative and positive areas of the electrostatic potential in different regions of the molecule in the crystal environment.

The role of intermolecular interactions, in particular those involving organic fluorine, in molecular crystals are of importance. In the current study, six derivatives of benzoyl ferrocene containing fluoro/trifluoromethyl functional groups are synthesized. Their structures have been determined using single crystal X-ray diffraction. The hydrogen bonds in the crystal lattice involving fluorine and oxygen atoms as acceptors are of significance. A quantitative assessment of the contribution of various intermolecular interactions via Hirshfeld surface analysis has been performed and the nature of the contributing interactions, as a cooperative interplay of electrostatics and dispersion interactions has been established via inputs from energy frameworks. It is observed that there exists a relationship between the acidity of the participating hydrogens and the nature and associated energetics of the intermolecular interactions of the type C H…O and C H…F which contribute towards the overall packing of molecules in the solid state.

Theoretical charge density studies are performed on the photoluminescent co-crystal of phenanthrene (PHNT) and tetrafluoro-1,4-benzoquinone (TFBQ) using the multipole modelling of theoretical structure factors. The topological analysis of the electron density is performed for all intramolecular covalent bonds and various important intermolecular interactions in the solid state. In addition to the presence of C–H⋯F interactions, the presence of aromatic stacking interactions has been confirmed via bond paths, topological properties and electrostatic potential isosurfaces of the electron density. The stacking interactions between the electron deficient and electron rich aromatic rings are demonstrated using the net atomic charges and electrostatic potential isosurfaces, which is responsible for the observed photoluminescent properties of the co-crystal. The molecular orbitals involved in the electronic transitions during UV–vis spectroscopic measurements have been identified and the electron density difference maps (EDDMs) arising from these transitions to different excited states have been plotted on isosurfaces which is in agreement with the Charge-Transfer (CT) nature of this co-crystal.

In this study, the nature and characteristics of the intramolecular and intermolecular interactions in crystal structures of the fluoro-substituted 7,7,8,8-tetracyanoquinodimethane (TCNQ) family of molecules, i.e. F x -TCNQ (x = 0, 2, 4), are explored. The molecular geometry of the reported crystal structures is directly dependent on the degree of fluorination in the molecule, which consequently also results in the presence of an intramolecular N[triple-bond]C...F—C π-hole tetrel bond. Apart from this, the energy framework analysis performed along the respective transport planes provides new insights into the energetic distribution in this class of molecules.

The nanomechanical responses of two crystalline phases of a dihydropyrimidine analogue (1) were similar irrespective of the presence (or absence) of the guest solvent. In contrast, the mechanical responses of two differently solvated forms of the second related (2) crystals were significantly different. These contrasting behaviors are rationalized in terms of intermolecular interactions and energy distributions. We acknowledge IISER Bhopal for research facilities andinfra-structure.Wethank Miss. Annie Cleetus for helping us in re-crystallization of solvatomorphs. MSRNKacknowledges SERB,DST (India) for an Early Career Researcher Award (File No:ECR/2016/000827).

The concomitant occurrence of dimorphs of diphenyl (3,4-difluorophenyl)phosphoramidate, C18H14F2NO3P, was observedviaa 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 outviathe 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 ofconformational polymorphs.

In this study, we have analyzed the role of different intermolecular interactions in the polymorphic modifications of 3-chloro-N-(2-fluorophenyl)benzamide (I) and 2-iodo-N-(4- bromophenyl)benzamide (II). The crystals were obtained via slow evaporation method with the alteration of solvents for crystallization. The already reported form [Cryst. Growth Des. (2011) 11:1578] crystallizes in P2 $$_{1}$$ /c with Z $$^\prime $$ =2 [Form IA], while the new form crystallizes in Pna2 $$_{1}$$ with Z $$^\prime $$ =1 [Form IB]. The latter compound crystallizes in P2 $$_{1}$$ /n with Z $$^\prime $$ =1 [Form IIA] and in Pbca with Z $$^\prime $$ =1 [Form IIB]. Weak Cl $$\cdot \cdot \cdot $$ Cl and C-H $$\cdot \cdot \cdot $$ F interactions in the former (IA, IB) and weak I $$\cdot \cdot \cdot $$ I and C-H $$\cdot \cdot \cdot \uppi $$ interactions in the latter (IIA, IIB) play a vital role in the formation of different polymorphic modifications leading to the observation of conformational and packing polymorphs, respectively. PIXEL calculations show that most of the interactions present in the crystal structures are dispersive in nature. 2D Fingerprint plots revealed that the relative contribution of different intermolecular interactions in different polymorphic forms was different. SYNOPSIS We have analyzed the role of different intermolecular interactions and evaluated their contributions in the polymorphic modifications of 3-chloro-N-(2-fluorophenyl)benzamide (I) and 2-iodo-N-(4- bromophenyl)benzamide (II).

The synthesized compound (Z)-4-fluoro-N′-(3-fluorophenyl)benzimidamide exhibits solvatomorphism in the solid state. The anhydrous and the hydrate forms were obtained at room temperature from slow evaporation of cyclohexane and hexane solvents, respectively. Both forms crystallize in the triclinic P with two symmetry-independent molecules in the asymmetric unit. The crystal packing of the anhydrous form is stabilized via a strong N–H⋯N chain, whereas the hydrate form is stabilized via a strong (N–H⋯N)–(N–H⋯O)–(O–H⋯N) chain. The water molecule plays an important role in the crystal packing by the formation of “extremely short” N–H⋯O and O–H⋯N hydrogen bonds, which are further supported by weak O–H⋯F–C and C–H⋯O interactions. The basic structural building motifs were structurally and energetically equivalent in both forms. PIXEL and QTAIM approaches provide quantitative insights into the nature and energetics of strong as well as weak intermolecular interactions. The NCI descriptor shows the “attractive” nature of the rarely observed O–H⋯F interaction. The thermal stabilities of the solvatomorphs were characterized via differential scanning calorimetry, hot stage microscopy, and thermogravimetric analysis. Hirshfeld surface analysis and 2D fingerprint plots of the individual molecules present in both forms differentiate the trends in crystal packing as well as the contribution from the different intermolecular interactions.

The crystal structure landscape of an unsubstituted benzanilide was generated and a number of hypothetical structures were accessed with experimentally obtained crystal structures of mono-, di-, tetra- and penta-fluorobenzanilides. Thus, chemical modification allows us to access the “high energy” forms of the parent compound, thereby delineating the significant role of weak intermolecular interactions.

The characteristics of the C(sp,sp2,sp3)–H⋯F–C(sp,sp2,sp3) intermolecular interactions present in molecular crystals on the basis of the hybridization of the carbon atom in the interaction have been analyzed. The Cambridge Structure Database has been extensively searched for the existence of such interactions as a function of the different combinations of hybridization possible for C–H⋯F–C interactions. The parameters in the search involve restriction with the following limits: 2.1 A < H⋯F distance < 3.0 A and 110° < C–H⋯F angle < 180°. PIXEL calculations performed on selected molecular pairs showed that C–H⋯F interactions are mainly of a dispersive nature. In molecules involving the presence of a C–H donor atom wherein the carbon exists in sp hybridization, preferential electrostatic contribution was observed. A full topological analysis using the QTAIM approach confirms the presence of a BCP in all the extracted molecular pairs in the crystal geometry, thereby confirming the presence of the C–H⋯F interaction regardless of the hybridization of the participating atoms. Both the electron density (ρ) and the Laplacian (∇2ρ) evaluated at the BCP showed exponential dependence on the bond path length for all the existing interactions.

We have investigated the role of N–H⋯π interaction in the formation of Z/E configurational isomers (including dimorphism of the E isomer) of 2-fluoro-N′-(3-fluorophenyl)benzimidamide. The decrease in crystallization temperature by ~20 °C results in the formation of a new isomer (Z isomer). Single crystal X-ray diffraction, thermal characterization (differential scanning calorimetry, hot stage microscopy), FTIR spectroscopy and theoretical calculations have been used to validate the existence of the different conformers in the solid state. The single point energy difference between the E and Z isomer is 21.8 kJ mol−1 and the energy barrier for isomerization is 103.7 kJ mol−1, obtained from theoretical calculations. The difference in thermal energy is similar to the results obtained from theoretical studies, signifying the role of temperature in polymorphism as well as in Z/E isomerization. A comprehensive analysis of the crystal packing and energetic features has been performed based on the molecular conformation and supramolecular packing involving strong N–H⋯N hydrogen bonds, weak C–H⋯N, C–H⋯F, N–H⋯π, and C–H⋯π intermolecular interactions, and π–π stacking to evaluate the role of intermolecular interactions in the solid state. Lattice energies have been calculated using the PIXEL method. Hirshfeld surface fingerprint plots also provide a platform for the evaluation of the contribution of different atom⋯atom contacts to the packing.

The knowledge about the prevalence of weak interactions in terms of the nature and energetics associated with their formation is of significance in organic solids. In the present study, we have systematically explored the existence of different types of intermolecular interactions in ten out of the fifteen newly synthesized trifluoromethyl derivatives of isomeric N-methyl-N-phenylbenzamides. Detailed analyses of all the crystalline solids were performed with quantitative inputs from interaction energy calculations using the PIXEL method. These studies revealed that in the absence of a strong hydrogen bond, the crystal packing is mainly stabilized by a cooperative interplay of weak C–H⋯OC, C–H⋯π, and C(sp2)/(sp3)–H⋯F–C(sp3) hydrogen bonds along with other related interactions, namely, π⋯π and C(sp3)–F⋯F–C(sp3). It is of interest to observe the presence of short and directional weak C–H⋯OC hydrogen bonds in the packing, having a substantial electrostatic (coulombic + polarization) contribution towards the total stabilization energy. The C(sp3)–F group was recognized in the formation of different molecular motifs in the crystal packing as utilizing different intermolecular interactions. The contribution from electrostatics among the different weak hydrogen bonds was observed in the decreasing order: C–H⋯OC > C–H⋯F–C(sp3) > C–H⋯π. Furthermore, there was an increase in the electrostatic component with a concomitant decrease in the dispersion component for the shorter and directional hydrogen bonds.

The cooperative roles of various structural motifs associated with the presence of different intermolecular interactions in the formation of molecular crystals are investigated in a series of trifluoromethylated phenylhydrazones. Out of the six compounds analysed, two exhibit three-dimensional structural similarities with geometrically equivalent building blocks, while a third exists as two polymorphic forms crystallized from ethanol solutions at low temperature (277 K) and room temperature (298 K), respectively. The compounds were characterized via single-crystal and powder X-ray diffraction techniques and differential scanning calorimetry. In the absence of any strong hydrogen bonding, the supramolecular constructs are primarily stabilized via molecular pairs with a high dispersion-energy contribution, due to the presence of molecular stacking along the molecular backbone along with C—H...π interactions in the solid state, in preference to an electrostatic contribution. The interaction energies for the most stabilizing molecular building blocks are in the range −29 to −43 kJ mol−1. In addition, weak N—H...F, C—H...F and N—H...C interactions and F...F, F...C, F...N and C...N contacts act as secondary motifs, providing additional stability to the crystal packing. The overall molecular arrangements are carefully analysed in terms of their nature and energetics, and the roles of different molecular pairs towards the crystal structure are delineated. A topological study using the quantum theory of atoms in molecules was used to characterize all the atomic interactions in the solid state. It established the presence of (3, −1) bond critical points and the closed-shell nature of all the interactions.

A comprehensive analysis of the crystal packing and the energetic features of a series of four biologically active molecules belonging to the family of substituted 4-(benzylideneamino)-3-(4-fluoro-3-phenoxyphenyl)-1H-1,2,4-triazole-5-(4H)-thione derivatives have been performed based on the molecular conformation and the supramolecular packing. This involves the formation of a short centrosymmetric R22(8) N–H···S supramolecular synthon in the solid state, including the presence of C–H···S, C–H···O, C–H···N, C–H···F, C–H···Cl, C–F···F–C, C–Cl···Cl–C, and C–H···π intermolecular interactions along with π–π stacking to evaluate the role of noncovalent interactions in the crystal. The presence of such synthons has a substantial contribution toward the interaction energy (−18 to −20 kcal/mol) as obtained from the PIXEL calculation, wherein the Coulombic and polarization contribution are more significant than the dispersion contribution. The geometrical characteristics of such synthons favor short distance, and t...

Two nitro substituted ethyl (2E)-2-cyano-3-phenylprop-2-enoate with molecular formula C12H10N2O4 have been synthesized and characterized by single-crystal X-ray diffraction. These two structures assemble via weak C–H···O=C/O (nitro group), C–H···N, and π–π intermolecular interactions which contribute towards the stability of the crystal packing. The lattice energies have been calculated using the PIXEL approach. Furthermore, high level DFT + Disp calculations for comparison with the pairing energies obtained from PIXEL method have been performed. An analysis of Hirshfeld surfaces and fingerprint plots facilitates a comparison of intermolecular interactions, which are the key elements in building different supramolecular architectures. The manuscript highlights the evaluation of molecular conformation and crystal packing in two nitro derivatives of ethyl (2E)-2-cyano-3-phenylprop-2-enoate. 1. Molecular conformation in the solid state and compared with that in the gas phase. 2. Vibrational frequency calculations using TURBOMOLE. 3. Lattice Energy calculations using PIXEL. 4. Hirshfeld surface analysis to investigate intermolecular calculations.

In the present study, we have prepared and structurally characterized a derivative of 1,2,4 triazoles, namely 3-(4-fluoro-3-phenoxyphenyl)-1-((4-methylpiperazin-1-yl)methyl)-1H-1,2,4-triazole-5-thiol (T-1) via single crystal X-ray diffraction. The crystal structure was observed to be stabilized by the presence of various intermolecular interactions in the crystalline solid such as O-H ⋯S, C-H ⋯F, C-H ⋯S, C-H ⋯N, C-H ⋯O, C-H ⋯π, lp⋯π and π⋯π intermolecular interactions. The interaction energy of these interactions was evaluated through PIXEL method with decomposition of the total energy into the coulombic, polarization, dispersion and repulsion contribution. The study of the nature of H-bonds with sulfur reveals that stabilization due to contribution from polarization plays a significant role. It is noteworthy that the presence of the solvent molecules in the crystal structure were observed to provide stabilization to an otherwise destabilized molecular pair (comprising of two molecules of 1,2,4 triazoles in the asymmetric unit).

The determination of the crystal and molecular structure of organic compounds has contributed immensely towards the area of crystal engineering. This contributes towards the understanding of the molecular geometry and the different intermolecular interactions which control crystal packing. An approach which quantifies the energetics associated with the formation of different “molecular pairs” is of importance to recognize the hierarchy of intermolecular interactions present in the crystal. We intend to explore different computational tools which contribute towards the field of crystal engineering. In this regard, the crystal structure of 7-hydroxy-4-methyl-2H-chromen-2-one and its hydrate were re-determined and their crystal packing were analyzed in terms of the interaction energy of different intermolecular interactions, calculated by PIXEL method, contributing towards the stabilization of the crystal packing. The system is so chosen such that it allows the analysis of weak interactions like C–H···O, C–H···π, π···π, lp···π etc. in the presence of strong O–H···O hydrogen bonds and also allows for a systematic exploration of the effect of solvent (water in the present case) on the crystal packing. The calculation of the lattice energy reveals that the anhydrous form is 7 kcal/mol more stable than the corresponding hydrate. The major stabilization towards the crystal packing were observed to come from strong O–H···O=C hydrogen bonds (9 kcal/mol) in case of the anhydrous form while in case of its hydrate, water acts as both an acceptor and a donor of the hydrogen bonds, the interaction energy ranging from 5 to 9 kcal/mol. The weak C–H···O hydrogen bond were found to be the second highest contributor (I.E = 3.5–5.5 kcal/mol) towards the stabilization of the packing in both the crystal structures. The main differences in the crystal packing were observed in the presence of weaker interactions in their crystal packing. The weak C–H···π, O(lp)···C=O interactions were observed in the crystal packing of the anhydrous form while the π···π, O(lp)···π interactions stabilize the crystal packing in case of its hydrate. This phenomenon were further well supported by the analysis of the Hirshfeld surfaces mapped with different properties, 2D-fingerprint plots, electrostatic potential mapped on the Hirshfeld surface and electron density isosurface (calculated by ab initio calculation at DFT-D3/B97-D) at both solid state and optimized geometry.

The X-ray crystallographic structures of two biologically active molecules, namely (±)-ethyl-3-benzyl-1-methyl-2-oxoindoline-3-carboxylate (I) and (±)-3-methyl-but-2-en-1-yl-1,3-dimethyl-2-oxoindoline-3-carboxylate (II) have been investigated based on the molecular conformation and supramolecular packing of the molecules in the solid state. These two structures assemble via C–H···O=C and C–H···π intermolecular interactions which contribute towards the stability of the crystal packing. In order to gain quantitative insights into the nature of non-covalent interaction between different molecules the interaction energy of the molecular pairs obtained after analysis of the crystal structures for both the molecules has been performed by using the PIXEL approach along with high level DFT+Disp calculations. Hirshfeld surface analysis and the associated fingerprint plots provide rapid quantitative insight into the intermolecular interactions in molecular solids. This article provides support to the fact that every molecule can be explored in detail for an understanding of its solid state structure via experimental and computational tools in crystal engineering. This manuscript outlines the significance (nature and energetic) of weak intermolecular interactions in ethyl-3-benzyl-1-methyl-2-oxoindoline-3-carboxylate and 3-methyl-but-2-en-1-yl-1,3-dimethyl-2-oxoindoline-3-carboxylate in the solid state (using PIXEL) and comparison with that in the gas phase (using TURBOMOLE) and their partitioning into coulombic, polarization, dispersive and repulsive components. Furthermore, Hirshfeld surface analysis has also been used to probe such intermolecular interactions.

In the present study, we have synthesized and characterized two biologically active 1,2,4-triazole derivatives, a fluoro derivative, namely (E)-3-(4-fluoro-3-phenoxyphenyl)-4-((4-fluorobenzylidene)amino)-1-(morpholinomethyl)-1H-1,2,4-triazole-5(4H)-thione (TRZ-1), and a chloro derivative, namely (E)-4-((4-chlorobenzylidene)amino)-3-(4-fluoro-3-phenoxyphenyl)-1-(morpholinomethyl)-1H-1,2,4-triazole-5(4H)-thione (TRZ-2), via single crystal and powder X-ray diffraction. The chloro derivative crystallizes in an anhydrous form (TRZ-2A) and a solvated one (TRZ-2B) due to the presence of a toluene molecule in the crystal. This solvatomorphic behavior has been studied in detail using different thermal techniques, namely DSC and TGA, combined with hot stage microscopy (HSM). All of the three crystal structures show the presence of different intermolecular interactions of the type C–H⋯O, C–H⋯SC, C–H⋯π, C–H⋯X (X = –F, –Cl), π⋯π and lp⋯π interactions. The fingerprints for all these interactions were evaluated using Hirshfeld surfaces. The nature and energetics associated with these interactions were characterized using PIXEL and supported by ab initio quantum mechanical calculations using TURBOMOLE. In addition, the calculations performed on the evaluation of the electrostatic potential provide deeper insights into the nature of lp⋯π interactions.

The discovery of three polymorphs of N-(3,5-difluorophenyl)-2,4-difluorobenzamide, of which two exist as concomitant polymorphs, highlights the significance of short, linear C-H⋅⋅⋅F intermolecular interactions in the solid state. The formation of these polymorphs can be regulated by monitoring the scan rate in differential scanning calorimetry. The phases have been characterized structurally and the investigation of the mechanical properties depicts that Form 1 is stiffer and harder than Form 2 by 50 % and 33 %, respectively.

Weak intermolecular interactions observed in crystalline materials are often influenced or forced by stronger interactions such as classical hydrogen bonds. Room temperature liquids offer a scenario where such strong interactions are absent so that the role and nature of the weak interactions can be studied more reliably. In this context, we have analyzed the common organic reagent benzoyl chloride (BC) and a series of its fluorinated derivatives using in situ cryocrystallography. The intermolecular interaction energies have been estimated and their topologies explored using energy framework analysis in a series of ten benzoyl chloride analogues, which reveal that the π⋯π stacking interactions serve as the primary building blocks in these crystal structures. The crystal packing is also stabilized by a variety of interaction motifs involving weak C–H⋯O/F/Cl hydrogen bonds and F⋯F, F⋯Cl, and Cl⋯Cl interactions. It is found that fluorination alters the electrostatic nature of the benzoyl chlorides, with subsequent changes in the formation of different weak interaction motifs. The effects of fluorination on these weak intermolecular interactions have been systematically analyzed further via detailed inputs from a topological analysis of the electron density and Hirshfeld surface analysis.

In the current study, the crystal structure of 1-(3-nitrophenyl)-2,2,2-trifluoroethanone (A1) and (E)-4-((4-fluorophenyl) diazenyl)phenol (A2) has been analyzed for the characterization of the presence of a `unique' and `rare' intermolecular C(sp3/sp2)—F...O contact, which has been observed to play a significant role in the crystal packing. Theoretical charge-density calculations have been performed to study the nature and strength associated with the existence of this intermolecular F...O contact, wherein the F atom is attached to ansp3-hybridized C atom in the case of A1 and to ansp2hybridized carbon in the case of A2. The crystal packing of the former contains two `electronically different' Csp3—F...O contacts which are present across and in between the layers of molecules. In the latter case, it is characterized by the presence of a very `short' (2.708 Å) and `highly directional' (168° at ∠C4—F1...O1 and 174° at ∠C10—O1...F1) Csp2—F...O contact. According to the Cambridge Structural Database (CSD) study, it is a rare example in molecular crystals. Topological features of F...O contacts in the solid state were compared with the gas-phase models. The two-dimensional and three-dimensional static deformation density obtained from theoretical multipole modeling confirm the presence of a charge depleted region on the F atoms. Minimization of the electrostatic repulsion between like charges are observed through subtle arrangements in the electronic environment in two of the short intermolecular F...O contacts. These contacts were investigated using inputs from pair energy decomposition analysis, Bader's quantum theory of atoms in molecules (QTAIM), Hirshfeld surface analysis, delocalization index, reduced density gradient (RDG) plot, electrostatic potential surface and distributed atomic polarizability. The intermolecular energy decomposition (PIXEL) and RDG–NCI (non-covalent interaction) analysis of the F...O contacts establish the interaction to be dispersive in nature. The mutual polarization of an O atom by fluorine andviceversaprovides real physical insights into the role of atomic polarizability in interacting atoms in molecules in crystals.

The study of the influence of aromatic C–F group in directing crystal packing is an important area of current research. The role of the aromatic C–F group in the formation of weak intermolecular interactions in the absence of strong hydrogen bond donors and acceptors has been analyzed in a series of 15 newly synthesized fluorine substituted (mono- and di-) isomeric N-benzylideneanilines. It was observed that five compounds (out of a total number of 15) were liquids at room temperature, while others have low melting points (

The covalent chemistry of the main group element fluorine is well understood. In contrast, its noncovalent chemistry, which forms the pillar of the paradigm of supramolecular chemistry, is still in its infancy. The latter involves a complete understanding of the different interactions (both intermolecular and intramolecular) involving donor and acceptor atoms. This perspective highlights the recent developments in the understanding of noncovalent interactions in relation to organic fluorine (partially fluorinated compounds) and the versatility and importance of such interactions to the scientific community.

The determination of the crystal and molecular structures of a large number of compounds containing the C(sp2)-F bond has been investigated in detail in halogenated benzanilides and also in liquids, namely the fluorinated amines. It has been observed that when the fluorine atom is present in the ortho or meta position with respect to the amide functionality in benzanilides or the amino group in fluorinated amines which are liquids at room temperature, the fluorine atom exhibits positional disorder. This is associated with changes in patterns of intermolecular interactions which affect crystal packing. Furthermore, the presence of a fluorine atom on the benzanilide framework, in the presence of a heavier halogen (chloro, bromo and iodo), meta or ortho to the amide group does not eliminate the disorder associated with these molecules. In this article, we highlight the salient features present in halogenated compounds exhibiting disorder in the position of organic fluorine with concomitant changes in crystal packing. This feature is also compared with related compounds exhibiting similarity in electronic features, namely positional disorder.

The supramolecular structures of eight aryl protected ethyl-6-methyl-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates have been analyzed to determine the role of different functional groups on the molecular geometry, conformational characteristics and the packing of these molecules in the crystal lattice. Out of these the parafluoro substituted compound on the aryl ring exhibits conformational polymorphism, due to the different conformation of the ester moiety. This behaviour has been characterized using both powder and single-crystal X-ray diffraction, optical microscopy and differential scanning calorimetry performed on both these polymorphs. The compounds pack via the cooperative interplay of strong N–H⋯OC intermolecular dimers and chains forming a sheet like structure. In addition, weak C–H⋯OC and C–H⋯π interactions impart additional stability to the crystal packing.