Cl Intermolecular Interactions Research Articles

Comparative structural analysis of anhydrous and monohydrated polymorphs of diclofenac diethylammonium: Implications for stability, dissolution, and bioavailability

Diclofenac diethylammonium belongs to the class of non-steroidal anti-inflammatory drugs, and it is widely used to relieve pain and reduce systemic inflammation. This drug exists in polymorphic forms, which can directly affect the ability to process the drug, as well as drug product dissolution, stability, and bioavailability. Considering the worldwide regulatory guidance for polymorphs in drug substances, a detailed structural analysis of two polymorphs exhibiting the anhydrous and monohydrated structures of diclofenac diethylammonium is presented here, using the supramolecular arrangement and its relationship with structural-physicochemical properties. The polymorph’s structures show conformational differences in the carboxylic group caused by coordinated water molecules presented in the monohydrated polymorphic structure. Both polymorphs have the supramolecular arrangement stabilized by NH···O and CH···Cl intermolecular interactions, but the monohydrated molecule presents a strong OH···O intermolecular interaction due to the presence of a water molecule. Hirshfeld surface analysis showed CH···π and π···π contacts in the anhydrous and monohydrated polymorphs, respectively. Theoretical results, including solvent effect with explicit and implicit approaches for water, indicated the kinetic stability of the diclofenac diethylammonium drug and showed susceptible electrophilic attacks occurring in the region close to the carbonyl oxygen atom.

Molecular modeling and solubility of olopatadine hydrochloride polymorphs

Olopatadine hydrochloride is a selective H1 receptor antagonist used in ophthalmic solutions to treat the signs and symptoms of allergic conjunctivitis. This compound presents a phenomenon known as polymorphism, which can cause changes on physicochemical characteristics. Considering the worldwide regulatory requirements for drug registration and the complexity of the pharmacotechnical development of ophthalmic preparations, both supramolecular arrangements (carried out by the Hirshfeld surface) and theoretical calculations (through the quantum theory of atoms in molecules) led to understand the physicochemical properties of polymorphs I and II and possible differences in solubility. The supramolecular arrangement for both polymorphs consists of the chloride anion participating in strong NH ⋯ Cl and OH ⋯ Cl intermolecular interactions as well as two weak CH ⋯ Cl intermolecular interactions, which generate an ionic tetramer. The shape index HS shows the hydrophobic space, which is around the ionic tetramer formed by CH ⋯ π intermolecular interaction for form I as well as π ⋯ π stacking for form II. The supramolecular crystal arrangement provides an essential aspect of its solubility in drug polymorphs.

Liquid structures of chloroethenes from molecular simulations and electronic structure calculations

The structures of six liquid chloroethenes viz., chloroethene, 1,1-Dichloroethene, cis- and trans-1,2-Dichloroethene, trichloro- and tetrachloroethene, are explored using the all-atom molecular dynamics simulations, molecular simulations with the 3D-reference interaction site model and the Kovalenko-Hirata closure relation (3D-RISM-KH), and dispersion corrected density functional theory. The liquid structures have different local orientations stabilized by possible π-stacking, π⋅⋅⋅Cl, and H⋅⋅⋅Cl intermolecular interactions. The RISM computations and MD simulations are in good agreement with each other, and provided important structural details. The electronic structure calculations support the presence of dimeric structures in the liquid form as well as the findings from the molecular simulations.

Ferromagnetic Coupling and Single-Ion Magnet Phenomenon in Mononuclear Ruthenium(III) Complexes Based on Guanine Nucleobase

Two mononuclear RuIII complexes of formula trans-[RuCl4(Hgua)(dmso)]·2H2O (1) and trans-[RuCl4(Hgua)(gua)]·3H2O (2) [Hgua = protonated guanine (gua), dmso = dimethyl sulfoxide] have been synthesized and characterized magnetostructurally. 1 and 2 crystallize in the monoclinic system with space groups P21/n and Pc, respectively. Each RuIII ion in 1 and 2 is bonded to four chloride ions and one (1) or two (2) nitrogen atoms from guanine molecules and one sulfur atom (1) of a dmso solvent molecule, generating axially compressed octahedral geometries in both cases. In their crystal packing, the RuIII complexes are connected through an extended network of N-H⋯Cl hydrogen bonds and π⋯Cl intermolecular interactions, forming novel supramolecular structures of this paramagnetic 4d ion. Variable-temperature dc magnetic susceptibility data were obtained from polycrystalline samples of 1 and 2 and their plots show a different magnetic behavior. While 1 is a ferromagnetic compound at low temperature, 2 exhibits a behavior of magnetically isolated mononuclear RuIII complexes with S = 1/2. The study on ac magnetic susceptibility data reveal slow relaxation of the magnetization, when external dc fields are applied, only for 2. These results highlight the presence of field-induced single-ion magnet (SIM) behavior for this mononuclear guanine-based RuIII complex.

A combined experimental and theoretical study on the synthesis, spectroscopic characterization of Magnesium(II) porphyrin complex with DMAP axial ligand and antifungal activity

We report in the present paper the synthesis, the spectroscopic, structural, and electrochemical properties of a new magnesium(II) coordination compound namely the bis(4-dimethylaminopyridine)[meso-tetra(p-tolyl)porphyrinato)]magnesium(II) dichloromethane disolvate complex with the formula [Mg(TTP)(DMAP)2]•2CH2Cl2 (I). This species crystallizes in the triclinic crystal system with the centrosymmetric space group P-1. The crystal lattice of (I) is stabilized by C__H…Cg (Cg is the centroid of a phenyl ring) and C__H…Cl intermolecular interactions. Further insights on these weak intermolecular contacts are provided by the Hirshfeld surface analysis. This new Mg(II) porphyrin species was characterized by 1H NMR, IR, fluorescence, UV/Vis spectroscopy and ESI-HRMS mass spectrometry. A cyclic voltammetry investigation of this new metalloporphyrin was also reported. Furthermore, the bioactivity of the H2TTP free base porphyrin, the [Mg(TTP)] starting material and [Mg(TTP)(DMAP)2]•2CH2Cl2 (I) was evaluated in vitro, by examining their inhibitory effect against three strains of Candida viz. C. albicans, C. glabrata and C. tropicalis with MIC values in the range 2.5 to 10 μg.mL−1. The screening of the susceptibility of M. canis and T. rubrum clinical strains on the three porphyrinic derivatives is also reported.

Manifestation of Intermolecular Interactions in the IR Spectra of 2- and 4-Methylmethcathinones Hydrochlorides: DFT Study and Hirshfeld Surfaces Analysis

This paper reports a Hirshfeld surfaces analysis of crystalline 2- and 4-methylmethcathinone (2-MMC and 4-MMC) hydrochlorides to analyze NH∙Cl and CH∙∙∙Cl intermolecular interactions and approve the formation of the NН2+–Cl– salt fragment in both 2-MMC∙HCl and 4-MMC∙HCl crystals. Two isomeric dimers were separated from the corresponding crystal packing to model IR spectra of the crystalline 2-MMC∙HCl and 4-MMC∙HCl species within the framework of density functional theory (DFT) and B3LYP/6-31G(d,p) approach. All observed IR bands were assigned and interpreted in the experimental spectra of the 2-MMC∙HCl and 4-MMC∙HCl standard crystal samples representing an important aspect of the forensic problem solvation. A detailed analysis of the nature of IR spectra for both isomers has shown that intermolecular interactions between the NН2+ and Cl– ionic moieties occur in two crystalline samples. The presence of the ionized form of the 2- and 4-MMC∙HCl compounds with the NН2+Cl– fragment is a key condition for the correct reproduction of the IR spectra when calculating the corresponding dimer structures as a model of a crystalline sample.

Study on the synthesis, physicochemical, electrochemical properties, molecular structure and antifungal activities of the 4-pyrrolidinopyridine Mg(II) meso-tetratolylporphyrin complex

A novel magnesium(II) metalloporphyrin namely the bis(4-pyrrolidinopyridine)[meso-tetra(p-tolyl)porphyrinato)]magnesium(II) dichloromethane desolate complex with the formula [Mg(TTP)(4-pypo)2]·CH2Cl2 (I) has been synthetized and fully characterized by UV–Vis, fluorescence, IR, 1H NMR spectroscopy and mass spectrometry. The X-ray molecular structure shows that I presents two molecules (1 and 2) [Mg1(TTP)(4-pypo)2] and [Mg2(TTP)(4-pypo)2] in the asymmetric unit while the Hirshfeld surface analysis on this hexacoordinated Mg(II) porphyrin species indicates that the crystal lattice is mainly sustained by C__H…C, C__H…Cg (Cg is the centroid of a phenyl ring) and C__H…Cl intermolecular interactions. The cyclic voltammetry data of I is also reported. The bioactivity of the H2TTP, the [Mg(TTP)] starting material and [Mg(TTP)(4-pypo)2]·CH2Cl2 (I) was evaluated in vitro, by examining their inhibitory effect against three strains of Candida viz. C. albicans, C. glabrata and C. tropicalis with MIC values in the range 2.5 to 10 µg.mL−1. The screening of the susceptibility of M. canis and T. rubrum clinical strains on the three porphyrinic derivatives is also reported.

P–Nitrobenzyl-substituted N–heterocyclic carbene in Silver(I) and Gold(I) complexes and their antibacterial activities

The synthesis of the silver(I) N–heterocyclic carbene [Ag(NBMIM)Cl]2 (2) from the reaction of imidazolium salt {NBMIM}Cl (1a) (NBMIM = 1–methyl–3–(4–nitrobenzyl)–1H–imidazol–3–ium) and silver(I) oxide was achieved. Compound {NBMIM}PF6 (1b) was also obtained by a counteranion exchange reaction. Compound 2 was used as a transmetalation agent to form Au(I) monocarbene complex (3a) and biscarbene complex (3b), by using [AuCl(SMe2)]. All compounds were characterized in solution by infrared spectroscopy and by 1H and 13C{1H} NMR. The molecular structures of compounds {NBMIM}PF6 (1b), [Ag(NBMIM)Cl]2 (2), and [Au(NBMIM)Cl] (3a) were also determined by single crystal X–ray diffraction studies. The molecular structure of silver complex 2 showed a 1D–staircase structure with Ag⋯Ag and Ag⋯Cl intermolecular interactions. Compounds 2 and 3a were also characterized by elemental analysis, powder X–ray diffraction (PXRD), Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC) measurement. In preliminary in vitro antibacterial assays, compounds 2 and 3a were tested against four bacterial strains: two Gram positive (S. aureus and B. subtilis) and two Gram negative species (P. aeruginosa and E. coli) by Kirby–Bauer’s disk diffusion method. Compound 2 exhibited moderate antibacterial activity against both types of bacteria. Both silver(I) and gold(I) N–heterocyclic carbenes showed from good to high antibacterial activity against S. aureus and P. aeruginosa and moderate activity against B. subtilis and E. coli strains.

Influence of chlorine and methyl substituents and their position on the antimicrobial activities and crystal structures of 4-methyl-1,6-diphenylpyrimidine-2(1H)-selenone derivatives.

Derivatives of 4-methyl-1,6-diphenylpyrimidine-2(1H)-selenone show very strong antimicrobial activity. In order to extend the current knowledge about the features responsible for the biological activity, crystal structure analyses are presented for 4-methyl-1-(2-methylphenyl)-6-phenylpyrimidine-2(1H)-selenone (1), 4-methyl-1-(3-methylphenyl)-6-phenylpyrimidine-2(1H)-selenone (2), 4-methyl-1-(4-methylphenyl)-6-phenylpyrimidine-2(1H)-selenone (3) (all C18H16N2Se) and 1-(4-chlorophenyl)-4-methyl-6-phenylpyrimidine-2(1H)-selenone (4) (C17H13ClN2Se). Furthermore, the antibacterial and antifungal activities of these compounds were evaluated. All the presented derivatives crystallize in the space group P21/c with one molecule in the asymmetric unit. The molecular geometries differ slightly in the mutual orientation of the rings. The packing of molecules in the crystals is dominated by C-H...N and C-H...Se intermolecular interactions. Additionally, in the crystal structure of 4, C-H...Cl intermolecular interactions are observed. The introduction of a methyl or chlorine substituent improves the biological activity, while its position significantly affects biological activity only in case of the chlorine substituent.

Trans-Di-aqua-bis-(N,N,N'-tri-methyl-ethylenedi-amine)-nickel(II) dichloride.

In the title salt, [Ni(C5H12N2)2(H2O)2]Cl2, the asymmetric unit is comprised of half of the complex cation and a chloride ion with the NiII atom of the cation situated about a twofold rotation axis. The six-coordinate NiII atom of the cation is connected to four N atoms from two methyl-substituted ethyelenedi-amine ligands and two water mol-ecules in a slightly distorted octa-hedral environment. The five-membered chelate ring is in a slight envelope conformation. The crystal packing features O-H⋯Cl and N-H⋯Cl inter-molecular inter-actions with the Cl- ion forming weak bifurcated hydrogen bonds with nearby water mol-ecules and N-H inter-actions, leading to a three-dimensional supra-molecular network structure.

Structural characterization and physicochemical features of new coordination polymer homopiperazine-1,4-diium tetrachlorocadmate(II)

The present paper reports the synthesis of a new organic-inorganic hybrid compound, homopiperazine-1,4-diium tetrachlorocadmate(II) (C5H14N2)CdCl4, by slow evaporation method at room temperature. The single crystal X–ray diffraction proves that it crystallizes in the P21/n monoclinic space group with the following cell parameters: a = 5.910(5) Å, b = 16.476(3) Å, c = 12.605(3) Å, β = 97.26(4)°, V = 1217.7(11) Å3, Z = 4. Its atomic arrangement can be described as an alternation of organic and inorganic layers along the b-axis. The crystal packing was governed by the N-H⋯Cl intermolecular interactions between the (C5H14N2)2+ cations and the one dimensional polymeric {[CdCl3(μ3-Cl)3]2-}n anions. The powder X-ray diffraction confirms the phase purity. The three-dimensional Hirshfeld surface (3D-HS) analysis and the two-dimensional fingerprint plots (2D-FP) reveal that the structure is dominated by H⋯Cl/Cl⋯H and H⋯H contacts. The functional groups present in the crystal were studied by FTIR spectroscopy. Furthermore, the optical and PL properties of the compound were investigated in the solid state at room temperature and correlated to the HOMO-LUMO gap.

Structural investigation, Hirshfeld surface analysis, characterization and computational studies of a novel chlorobismuthate(III) complex

Abstract A novel bismuthates(III) complex, (C6H14N)4[BiCl6]Cl·2H2O, was synthesized and characterized by X-ray diffraction and FT-IR spectroscopy. Its structure consists of protonated cyclohexylamine cations, discrete [BiCl6]3− anions, chlorine anions and water molecules. The chlorobismuthate(III) anions alternate with the water molecules O1 as to form hydrogen-bonded helical chain running along the crystallographic b-axis with a period of 17.622 A. These components are connected into a three-dimensional network via hydrogen bonds. In addition, the ground state geometry, vibrational wavenumbers and Natural bond orbital (NBO) analysis were studied by means of density functional theory (DFT/B3LYP) with LanL2DZ basis set. Theoretical results are within the range of the experimental data. The NBO analysis reveals the influence of the N–H…O, N–H…Cl and O H…Cl intermolecular interactions on crystal packing. Moreover, the electrochemical behavior of this complex was investigated in DMSO by cyclic voltammetry (CV).

Synthesis, Structure and Properties of a Novel Tetranuclear Copper Cluster-Based Polymer with Di-Schiff-Base

A novel tetranuclear cluster-based polymer {[Cu4(L)2(NO3)2(DMF)2]·(CH2Cl2)2}n (1, H3L = (1Z,2E,N′E)-N′,2-bis(2-hydroxybenzylidene)hydrazinecarbohydrazonic acid) was synthesized through diffusion method. The structure of 1 was characterized by elemental analysis, IR, and single crystal X-ray diffraction. 1 is tetranuclear copper cluster which further constructed 1-D chain through double Cu–O bonds. Luminescent and magnetic properties of 1 have been studied. Hirshfeld surfaces analysis revealed that complex 1 was supported mainly by H···H, O···H and H···Cl intermolecular interactions.

Synthesis and characterization of an iron(III) complex of an ethylenediamine derivative of an aminophenol ligand in relevance to catechol dioxygenase active site

An ethylene diamine derivative of a bis(phenol)diamine ligand (H2L) was synthesized via the Mannich reaction and subsequent ring cleavage of the produced imidazoline ring (H2LIm), and then it was characterized by 1H NMR and IR spectroscopies and CHN analysis. The iron(III) complex (FeLCl) of this ligand was synthesized and characterized by IR, UV–Vis, X-ray and magnetic susceptibility studies. X-ray analysis reveals that in FeLCl the iron(III) center has a distorted square pyramidal coordination sphere and is surrounded by a chlorine atom, two amine nitrogen and two phenolate oxygen atoms of the ligand. Variable-temperature magnetic susceptibility measurements indicate that FeLCl is a paramagnetic high spin iron(III) complex. It shows weak antiferromagnetic interactions through NH⋯Cl intermolecular interactions. The ligand-centered electrochemical oxidation of this complex, due to the oxidation of phenolate group to phenoxyl radicals, as well as the electrochemical metal-centered reduction of the ferric ion to the ferrous ion were investigated. In addition, the efficient cleavage by oxygenation of 3,5-di-tert-butyl-catechol with FeLCl in the presence of dioxygen was observed.

Crystal structure of tetrakis-(acetyl-acetonato)di-chloridodi-μ3-methano-lato-tetra-μ2-methano-lato-tetra-iron(III).

The title complex, [Fe4(C5H7O2)4(CH3O)6Cl2] or [Fe4(acac)4(μ2-OMe)4(μ3-OMe)2Cl2] (acac = acetyl-acetonate), crystallizes in the ortho-rhom-bic Pbca space group with one half of the mol-ecule per asymmetric unit, the other half being completed by inversion symmetry. The core structure consists of a face-sharing double pseudo-cubane entity with two opposite corners missing. Weak C-H⋯Cl inter-molecular inter-actions result in a two-dimensional layered structure parallel to the ac plane.

Crystal structure of a mixed-ligand dinuclear Ba-Zn complex with 2-meth-oxy-ethanol having tri-phenyl-acetate and chloride bridges.

The dinuclear barium-zinc complex, μ-chlorido-1:2κ(2) Cl:Cl-chlorido-2κCl-bis-(2-meth-oxy-ethanol-1κO)bis-(2-meth-oxy-ethanol-1κ(2) O,O')bis-(μ-tri-phenyl-acetato-1:2κ(2) O:O')bariumzinc, [BaZn(C20H15O2)2Cl2(C3H8O2)4], has been synthesized by the reaction of barium tri-phenyl-acetate, anhydrous zinc chloride and 2-meth-oxy-ethanol in the presence of toluene. The barium and zinc metal cations in the dinuclear complex are linked via one chloride anion and carboxyl-ate O atoms of the tri-phenyl-acetate ligands, giving a Ba⋯Zn separation of 3.9335 (11) Å. The irregular nine-coordinate BaO8Cl coordination centres comprise eight O-atom donors, six of them from 2-meth-oxy-ethanol ligands (four from two bidentate O,O'-chelate inter-actions and two from monodentate inter-actions), two from bridging tri-phenyl-acetate ligands and one from a bridging Cl donor. The distorted tetra-hedral coordination sphere of zinc comprises two O-atom donors from the tri-phenyl-acetate ligands and two Cl donors (one bridging and one terminal). In the crystal, O-H⋯Cl, O-H⋯O and C-H⋯Cl inter-molecular inter-actions form a layered structure, lying parallel to (001).

Synthesis, Spectroscopic Characterization and X-ray Structure Analysis of 6-(2,5-Dichlorothiophen-3-yl)-3,4-dihydro-4-(4-methoxyphenyl)pyrimidine-2(1H)-thione

The title compound was prepared by the condensation of (E)-1-(2,5-dichlorothiophen-3-yl)-3-(4-methoxy)prop-2-en-1-one and thiourea in the presence of KOH. In the title compound, C34H28Cl16N4O2S4, the asymmetric unit consists of two independent molecules and four independent chloroform molecules. The heterocyclic pyrimidine-2(1H)-thione rings adopt a flattened boat conformation. The methoxyphenyl rings are perpendicular to the pyrimidine-2(1H)-thione rings with dihedral angles of 81.20 and 79.85° in both independent molecules. The dichlorothiophene rings are twisted compared to the pyrimidine-2(1H)-thione rings with dihedral angles of 40.59 and 39.36° in the independent molecules. The methoxyphenyl group has an axial orientation. Intermolecular C–H···S, C–H···O, C–H··· π vertex-to-face intermolecular interactions between chloroform C–H groups and the center of the phenyl rings and extensive Cl···Cl intermolecular interactions are found in the crystal structure. All interactions consolidate a three dimensional network. The molecular structure was further analyzed using spectroscopic methods. Mass ESI-HMRS measurements were performed. The HRESIMS analysis revealed the molecular formula, C15H12Cl2N2OS2, with [M+H]+ and [M+H+2]+ and [M+H+4]+ isotopic clusters characteristic for a dichlorinated compound. The compound was also thoroughly characterized by 1H, 13C, NMR spectra and 2D NMR spectra (COSY, HSQC and HMBC). Synthesis, characterization, molecular, crystal structure and crystal supramolecularity of the three dimensional network structure of 6-(2,5-dichlorothiophen-3-yl)-3,4-dihydro-4-(4-methoxyphenyl)pyrimidine-2(1H)-thione are reported.

1-[Bis(4-fluoro-phen-yl)meth-yl]-4-[(2Z)-3-phenyl-prop-2-en-1-yl]piperazine-1,4-diium dichloride hemihydrate.

The asymmetric unit of the title monohydrated salt, 2C26H28F2N2 2+·4Cl−.H2O, consists of a 1-[bis­(4-fluoro­phen­yl)meth­yl]-4-[(2Z)-3-phenyl­prop-2-en-1-yl]piperazine-1,4-diium cation with a diprotonated piperizine ring in close proximity to two chloride anions and a single water mol­ecule that lies on a twofold rotation axis. In the cation, the piperazine ring adopts a slightly distorted chair conformation. The dihedral angles between the phenyl ring and the 4-fluoro­phenyl rings are 89.3 (9) and 35.0 (5)°. The two fluoro­phenyl rings are inclined at 65.0 (5)° to one another. In the crystal, N—H⋯Cl hydrogen bonds and weak C—H⋯Cl inter­molecular inter­actions link the mol­ecules into chains along [010]. In addition, weak C—H⋯O inter­actions between the piperizine and prop-2-en-1-yl groups with the water mol­ecule, along with weak C—H⋯Cl inter­actions between the prop-2en-1-yl and methyl groups with the chloride ions, weak C—H⋯F inter­actions between the two fluoro­phenyl groups and weak O—H⋯Cl inter­actions between the water mol­ecule and chloride ions form a three-dimensional supra­molecular network.

N‐Heterocyclic Carbene Complexes of Copper(I) Thiocyanate: Synthesis and Structural Characterization

AbstractThe synthesis and characterization of three N‐heterocyclic carbene (NHC) complexes of copper(I) thiocyanate [Cu(IMes)(NCS)]2 (1), [Cu(IXy)(NCS)]2 (2), and [Cu(IPr)(NCS)] (3) [IMes = 1,3‐bis(2,4,6‐trimethylphenyl)imidazol‐2‐ylidene, IXy = 1,3‐bis(2,6‐dimethylphenyl)imidazol‐2‐ylidene, IPr = 1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene] are described. Single crystal diffraction and IR spectroscopy shows that reaction of one equivalent of sodium thiocyanate with [Cu(NHC)Cl] results in the formation of solid‐state centrosymmetric dimers for 1 and 2 with bridging thiocyanate ligands bound through both N and S. In contrast, the equivalent reaction with IPr gives a monomeric species with N bound thiocyanate. In the solution state, all the structures of complexes 1–3 would appear to be monomeric, as evidenced by both solution state FT‐IR and 13C NMR spectroscopic studies. In addition the precursor to complex 2 [Cu(IXy)Cl] (4) was structurally characterized by X‐ray diffraction revealing a one‐dimensional chain structure that propagates through C–H···Cl intermolecular interactions with both methyl and aromatic hydrogen atoms.

Thermodynamic Study of Chlorobenzonitrile Isomers: A Survey on the Polymorphism, Pseudosymmetry, and the Chloro···Cyano Interaction

The relationships among structural and thermodynamic properties of 2-, 3-, and 4-chlorobenzonitrile were investigated, in the present work, using several experimental techniques (Knudsen effusion, differential scanning calorimetry, and combustion calorimetry) and computational studies. The CN···Cl intermolecular interactions are weaker in 2-chlorobenzonitrile, reflecting a lower enthalpy of sublimation. The two polymorphic forms of 4-chlorobenzonitrile were observed by differential scanning calorimetry and interpreted in terms of the strength of CN···Cl intermolecular interactions. The entropic differentiation due to the pseudosymmetry observed in the crystalline packing of 2-chlorobenzonitrile was evaluated. Using adequate working reactions and the respective standard molar enthalpies of formation, in the gaseous phase, the halogen-cyano intramolecular interaction was also evaluated. The theoretically estimated gas-phase enthalpies of formation were calculated using high-level ab initio molecular orbital calculations at the G3MP2B3 and MP2/cc-pVTZ levels of theory. The computed values support very well the experimental results obtained in this work.