A Combined Experimental and Computational Study of Halogen and Hydrogen Bonding in Molecular Salts of 5-Bromocytosine.

Although natural or artificial modified pyrimidine nucleobases represent important molecules with valuable properties as constituents of DNA and RNA, no systematic analyses of the structural aspects of bromo derivatives of cytosine have appeared so far in the literature. In view of the biochemical and pharmaceutical relevance of these compounds, six different crystals containing proton-transfer derivatives of 5-bromocytosine are prepared and analyzed in the solid-state by single crystal X-ray diffraction. All six compounds are organic salts, with proton transfer occurring to the Nimino atom of the pyridine ring. Experimental results are then complemented with Hirshfeld surface analysis to quantitively evaluate the contribution of different intermolecular interactions in the crystal packing. Furthermore, theoretical calculations, based on different arrangements of molecules extracted from the crystal structure determinations, are carried out to analyze the formation mechanism of halogen bonds (XBs) in these compounds and provide insights into the nature and strength of the observed interactions. The results show that the supramolecular architectures of the six molecular salts involve extensive classical intermolecular hydrogen bonds. However, in all but one proton-transfer adducts, weak to moderate XBs are revealed by C-Br…O short contacts between the bromine atom in the fifth position, which acts as XB donor (electron acceptor). Moreover, the lone pair electrons of the oxygen atom of adjacent pyrimidine nucleobases and/or counterions or water molecules, which acts as XB acceptor (electron donor).

Short X···N Halogen Bonds With Hexamethylenetetraamine as the Acceptor.

Hexamethylenetetramine (HMTA) and N-haloimides form two types of short (imide)X···N and X-X···N (X = Br, I) halogen bonds. Nucleophilic substitution or ligand-exchange reaction on the peripheral X of X-X···N with the chloride of N-chlorosuccinimide lead to Cl-X···N halogen-bonded complexes. The 1:1 complexation of HMTA and ICl manifests the shortest I···N halogen bond [2.272(5) Å] yet reported for an HMTA acceptor. Two halogen-bonded organic frameworks are prepared using 1:4 molar ratio of HMTA and N-bromosuccinimide, each with a distinct channel shape, one possessing oval and the other square grid. The variations in channel shapes are due to tridentate and tetradentate (imide)Br···N coordination modes of HMTA. Density Functional Theory (DFT) studies are performed to gain insights into (imide)X···N interaction strengths (ΔEint). The calculated ΔEint values for (imide)Br···N (-11.2 to -12.5 kcal/mol) are smaller than the values for (imide)I···N (-8.4 to -29.0 kcal/mol). The DFT additivity analysis of (imide)Br···N motifs demonstrates Br···N interaction strength gradually decreasing from 1:1 to 1:3 HMTA:N-bromosuccinimide complexes. Exceptionally similar charge density values ρ(r) for N-I covalent bond and I···N non-covalent bond of a (saccharin)N-I···N motif signify the covalent character for I···N halogen bonding.

Experimental results and computational insight into sequential reactions of ß-(2-aminophenyl)-α,ß-ynones with aryl isocyanates/benzoyl isothiocyanate.

The investigation on tandem addition/cyclization reactions of ß-(2-aminophenyl)-α,ß-ynones with aryl isocyanates/benzoyl isothiocyanate is reported. Experimental results show the suitable conditions to selectively direct the reaction outcome towards the product of 6-exo-dig N-, O-, or S-annulation of the in situ generated alkynyl urea/thiourea intermediate. The reaction of a variety of ß-(2-aminophenyl)-α,ß-ynones with aryl isocyanates/benzoyl isothiocyanate led to the selective formation of quinazoline or benzoxazine/benzothiazine derivatives, respectively. Density functional theory calculations provide a plausible rationale for the reaction outcome.

Crystal structure and Hirshfeld surface analysis of a third polymorph of 2,6-di-meth-oxy-benzoic acid.

A third crystalline form of the title compound, C9H10O4, crystallizing in the centrosymmetric monoclinic space group P21/c, has been identified during screening for co-crystals. The asymmetric unit comprises a non-planar independent mol-ecule with a synplanar conformation of the OH group. The sterically bulky o-meth-oxy substituents force the carb-oxy group to be twisted away from the plane of the benzene ring by 74.10 (6)°. The carb-oxy group exhibits the acidic H atom disordered over two sites between two O atoms. A similar situation has been found for the second tetra-gonal polymorph reported [Portalone (2011 ▸). Acta Cryst. E67, o3394-o3395], in which mol-ecules with the OH group in a synplanar conformation form dimeric units via strong O-H⋯O hydrogen bonds. In contrast, in the first ortho-rhom-bic form reported [Swaminathan et al. (1976 ▸). Acta Cryst. B32, 1897-1900; Bryan & White (1982 ▸). Acta Cryst. B38, 1014-1016; Portalone (2009 ▸). Acta Cryst. E65, o327-o328], the mol-ecular components do not form conventional dimeric units, as an anti-planar conformation adopted by the OH group favors the association of mol-ecules in chains stabilized by linear O-H⋯O hydrogen bonds.

Synthesis of potential HIV integrase inhibitors inspired by natural polyphenol structures.

Drawing inspiration from the structural features of some natural polyphenols, the synthesis of two different model compounds as potential inhibitors of HIV integrase (IN) has been described. The former was characterised by a diketo acid (DKA) bioisostere, such as a ß-hydroxycarbonyl moiety, between two fragments containing aromatic groups, while in the latter an epoxide linked two polyoxygenated aromatic residues. The moieties present in the structures are thought to function by chelating divalent metal ions on the enzyme catalytic site. Overall, 10 compounds were prepared and some of that submitted to molecular modelling studies (to investigate their interactions with the active site of IN), to metal titration studies (to detect their chelating capability) and to biological assays.

(Chalcogen)semicarbazones and their cobalt complexes differentiate HL-60 myeloid leukaemia cells and are cytotoxic towards tumor cell lines.

Cobalt complexes with semi- and thiosemicarbazones of 8-quinolinecarboxaldehyde have been synthesized and characterized by X-ray diffraction analysis. These novel complexes and a previously synthesized cobalt complex with a selenium-based selenosemicarbazone ligand showed myeloid differentiation activity on all trans retinoic acid resistant HL-60 acute myeloid leukaemia cells. They also showed varying levels of cytotoxicity on five human tumor cell lines: cervix carcinoma cells (HeLa), lung adenocarcinoma cells (A549), colorectal adenocarcinoma cells (LS-174), breast carcinoma cells (MDA-MB-361), and chronic myeloid leukaemia (K562) as well as one normal human cell line: fetal lung fibroblast cells (MRC-5). Leukaemia differentiation was most strongly induced by a metal-free oxygen ligand and the selenium ligand, whilst the latter and the cobalt(ii) complex with an oxygen ligand showed the strongest dose-dependent cytotoxic activity. In four out of five investigated tumor cell lines, it was of the same order of magnitude as cisplatin. These best compounds, however, had lower toxicity on non-transformed MRC-5 cells than cisplatin.

Supramolecular association in proton-transfer adducts containing benzamidinium cations. III. Three molecular salts of 3-methoxy-, 4-methoxy- and 3,4,5-trimethoxybenzoates with benzamidine.

Three molecular salts, benzamidinium 3-methoxybenzoate, C7H9N2(+)·C8H7O3(-), (I), benzamidinium 4-methoxybenzoate, C7H9N2(+)·C8H7O3(-), (II), and benzamidinium 3,4,5-trimethoxybenzoate monohydrate, C7H9N2(+)·C10H11O5(-)·H2O, (III), were formed from the proton-transfer reactions of 3-methoxy, 4-methoxy- and 3,4,5-trimethoxybenzoic acids with benzamidine (benzenecarboximidamide, benzam). Monoclinic salts (I) and (II) have a 1:1 ratio of cation to anion. In monoclinic salt (III), two cation-anion pairs and two water molecules constitute the asymmetric unit. In all three molecular salts, the amidinium fragments and the carboxylate groups are completely delocalized, and the delocalization favours the aggregation of the molecular components into nonplanar dimers with an R(2)(2)(8) graph-set motif by N(+)-H···O(-) (±) charge-assisted hydrogen bonding (CAHB). Of the three molecular salts, (I) and (II) show similar conformations of the anionic components and exhibit bidimensional isostructurality, which consists of alternating R(2)(2)(8) and R(6)(4)(16) rings resulting in a corrugated sheet propagated parallel to the crystallographic ab plane. In molecular salt (III), the R(2)(2)(8) synthon is retained but the supramolecular structure is different, due to the presence of three bulky methoxy substituents and a water molecule. The structures reported here further demonstrate the robustness of R(2)(2)(8) hydrogen-bonded synthons having the benzamidinium cation as a building block, whereas N(+)-H···O(-) hydrogen bonds external to the salt bridge contribute to the overall structure organization.

Benzamidinium 2-meth-oxy-benzoate.

The title mol-ecular salt, C7H9N2 (+.)C8H7O3 (-), was synthesized by reaction between benzamidine (benzene-carboximidamide) and 2-meth-oxy-benzoic acid. In the cation, the amidinium group has two similar C-N bonds [1.3070 (17) and 1.3145 (16) Å] and is almost coplanar with the benzene ring, making a dihedral angle of 5.34 (12)°. In the anion, the meth-oxy substituent forces the carboxyl-ate group to be twisted by 69.45 (6)° with respect to the plane of the aromatic fragment. In the crystal, the components are connected by two N(+)-H⋯O(-) (±)CAHB (charge-assisted hydrogen bonds), forming centrosymmetric ionic dimers with graph-set motif R 2 (2)(8). These ionic dimers are then joined in ribbons running along the b-axis direction by another R 4 (2)(8) motif involving the remaining N(+)-H⋯O(-) hydrogen bonds. Remarkably, at variance with the well known carb-oxy-lic dimer R 2 (2)(8) motif, the carboxyl-ate-amidinium pair is not planar, the dihedral angle between the planes defined by the CN2 (+) and CO2 (-) atoms being 18.57 (12)°.

Cytosinium orotate dihydrate.

The title compound, C4H6N3O(+)·C5H3N2O4(-)·2H2O or Cyt(+)·Or(-)·2H2O, was synthesized by a reaction between cytosine (4-amino-2-hy-droxy-pyrimidine, Cyt) and orotic acid (2,4-dihy-droxy-6-carb-oxy-pyrimidine, Or) in aqueous solution. The two ions are joined by two N(+)-H⋯O(-) (±)-(CAHB) hydrogen bonds, forming a dimer with graph-set motif R2(2)(8). In the crystal, the ion pairs of the asymmetric unit are joined by four N-H⋯O inter-actions to adjacent dimers, forming hydrogen-bonded rings with R2(2)(8) graph-set motif in a two-dimensional network. The formation of the three-dimensional array is facilitated by water mol-ecules, which act as bridges between structural sub-units linked in R3(2)(8) and R3(2)(7) hydrogen-bonded rings. The orotate anion is essentially planar, as the dihedral angle between the planes defined by the carboxylate group and the uracil fragment is 4.0 (4)°.

4-Meth-oxy-benzamidinium bromide.

The title salt, C8H11N2O(+)·Br(-), was synthesized by the reaction between 4-meth-oxy-benzamidine (4-amidino-anisole) and hydro-bromic acid. In the cation, the amidinium group has two similar C-N bonds [1.304 (2) and 1.316 (2) Å], and its plane forms a dihedral angle of 31.08 (5)° with the benzene ring. The ions are associated in the crystal into a three-dimension hydrogen-bonded supra-molecular network featuring N-H(+)⋯Br(-) inter-actions.

Supramolecular association in proton-transfer adducts containing benzamidinium cations. II. Concomitant polymorphs of the molecular salt of 2,6-dimethoxybenzoic acid with benzamidine.

Two concomitant polymorphs of the molecular salt formed by 2,6-dimethoxybenzoic acid, C(9)H(10)O(4) (Dmb), with benzamidine, C(7)H(8)N(2) (benzenecarboximidamide, Benzam) from water solution have been identified. Benzamidinidium 2,6-dimethoxybenzoate, C(7)H(9)N(2)(+)·C(9)H(9)O(4)(-) (BenzamH(+)·Dmb(-)), was obtained through protonation at the imino N atom of Benzam as a result of proton transfer from the acidic hydroxy group of Dmb. In the monoclinic polymorph, (I) (space group P2(1)/n), the asymmetric unit consists of two Dmb(-) anions and two monoprotonated BenzamH(+) cations. In the orthorhombic polymorph, (II) (space group P2(1)2(1)2(1)), one Dmb(-) anion and one BenzamH(+) cation constitute the asymmetric unit. In both polymorphic salts, the amidinium fragments and carboxylate groups are completely delocalized. This delocalization favours the aggregation of the molecular components of these acid-base complexes into nonplanar dimers with an R(2)(2)(8) graph-set motif via N(+)-H···O(-) charge-assisted hydrogen bonding. Both the monoclinic and orthorhombic forms exhibit one-dimensional isostructurality, as the crystal structures feature identical hydrogen-bonding motifs consisting of dimers and catemers.

Potassium caffeate/caffeic acid co-crystal: the rat race between the catecholic and carboxylic moieties in an atypical co-crystal.

The vast literature concerning caffeic acid and its derivatives lacks any reference to the solid state structures of its inorganic salts as these crystals are quite difficult grow. Most of the already published works deal with computational studies of these compounds as well as investigations of their behaviour in solution. Having obtained good quality potassium caffeate/caffeic acid co-crystals, we solved their structure and used a robust approach, already applied to caffeic acid alone, to compare the X-ray structure with the one inferred by Molecular Dynamics (MD), focusing our attention on the structure-property relationships. The reliability of this method is confirmed by the overall agreement extended up to the anisotropic displacement parameters calculated, on one hand, by means of MD and the ones gathered, on the other hand, by X-ray measurements. Moreover, the lack of experimental evidence of an enthalpically favored polymorph, arising from the MD calculations, were explained on the basis of the Shannon's entropy.

4-Meth-oxy-benzamidinium 2,6-dimeth-oxy-benzoate.

The title compound, C(8)H(11)N(2)O(+)·C(9)H(9)O(4) (-), was synthesized by the reaction of 4-meth-oxy-benzamidine (4-amidino-anisole) and 2,6-dimeth-oxy-benzoic acid. The structure consists of non-planar pairs of hydrogen-bonded 4-meth-oxy-benzamidinium cations and 2,6-dimeth-oxy-benzoate anions. In the cation, the amidinium group is tilted by 27.94 (10)° with respect to the benzene ring. In the anion, the sterically bulky ortho-meth-oxy substituents force the carb-oxy-ate group to be twisted away from the plane of the benzene ring by 73.24 (6)°. The ions are further associated in the crystal into chains along the b-axis direction by inter-molecular N-H⋯O hydrogen bonds.

4-Meth-oxy-benzamidinium nitrate.

The title salt, C8H11N2O(+)·NO3(-), was synthesized by a reaction between 4-meth-oxy-benzamidine (4-amidino-anisole) and nitric acid. The asymmetric unit comprises a non-planar 4-meth-oxy-benzamidinium cation and a nitrate anion. In the cation, the amidinium group has two similar C-N bond lengths [1.302 (3) and 1.313 (3) Å] and its plane forms a dihedral angle of 32.66 (5)° with the mean plane of the benzene ring. The nitrate-amidinium ion pair is not planar, as the dihedral angle between the planes defined by the CN2(+) and NO3(-) units is 19.28 (6)°. The ionic components are associated in the crystal via N-H⋯O hydrogen bonds, resulting in a three-dimensional network.

4-Meth-oxy-benzamidinium hydrogen oxalate monohydrate.

The title hydrated salt, C8H11N2O(+)·C2HO4(-)·H2O, was synthesized by a reaction of 4-meth-oxy-benzamidine (4-amidino-anisole) and oxalic acid in water solution. In the cation, the amidinium group forms a dihedral angle of 15.60 (6)° with the mean plane of the benzene ring. In the crystal, each amidinium unit is bound to three acetate anions and one water mol-ecule by six distinct N-H⋯O hydrogen bonds. The ion pairs of the asymmetric unit are joined by two N-H⋯O hydrogen bonds into ionic dimers in which the carbonyl O atom of the semi-oxalate anion acts as a bifurcated acceptor, thus generating an R(1)2(6) motif. These subunits are then joined through the remaining N-H⋯O hydrogen bonds to adjacent semi-oxalate anions into linear tetra-meric chains running approximately along the b axis. The structure is stabilized by N-H⋯O and O-H⋯O inter-molecular hydrogen bonds. The water mol-ecule plays an important role in the cohesion and the stability of the crystal structure being involved in three hydrogen bonds connecting two semi-oxalate anions as donor and a benzamidinium cation as acceptor.

4-Meth-oxy-benzamidinium chloride monohydrate.

In the cation of the title compound, C(8)H(11)N(2)O(+)·Cl(-)·H(2)O, the C-N bonds of the amidinium group are identical within experiemental error [1.305 (2) and 1.304 (2) Å], and its plane forms a dihedral angle of 25.83 (8)° with the phenyl ring. The ionic components are associated in the crystal into polymeric hydrogen-bonded supra-molecular tapes stabilized by N-H(+)⋯Cl(-) and N-H(+)⋯Ow inter-molecular hydrogen bonds, and by Ow-H⋯Cl(-) inter-actions.

4-Meth-oxy-benzamidinium hydrogen sulfate.

The title salt, C(8)H(11)N(2)O(+)·HSO(4) (-), has been synthesized by the reaction between 4-meth-oxy-benzamidine and sulfuric acid. The asymmetric unit comprises a nonplanar 4-meth-oxy-benzamidinium cation and one hydrogen sulfate anion. In the cation, the amidinium group has two identical C-N bonds [1.306 (2) and 1.308 (2) Å], and its plane forms a dihedral angle of 6.49 (8)° with the mean plane of the benzene ring. The ionic components are associated in the crystal via N-H(+)⋯O(-), resulting in chains running approximately along the b-axis direction whicg are interconnected by O-H⋯O(-) hydrogen bonds.

4-Meth-oxy-benzamidinium acetate.

The title compound, C8H11N2O(+)·CH3CO2(-), was synthesized by a reaction between 4-meth-oxy-benzamidine (4-amidino-anisole) and acetic acid. In the cation, the amidinium group forms a dihedral angle of 11.65 (17)° with the mean plane of the benzene ring. The ionic components are associated in the crystal via N-H(+)⋯O(-) hydrogen bonds, resulting in a one-dimensional structure consisting of dimers and catemers and orientated approximately along the c axis.

A new polymorph of 2,6-dimeth-oxy-benzoic acid.

A new crystalline form of 2,6-dimeth-oxy-benzoic acid, C(9)H(10)O(4), crystallizing in a tetra-gonal unit cell has been identified during screening for co-crystals. The asymmetric unit comprises a non-planar independent mol-ecule with a synplanar conformation of the carb-oxy group. The sterically bulky o-meth-oxy substituents force the carb-oxy group to be twisted away from the plane of the benzene ring by 65.72 (15)°. The carb-oxy group is disordered over two sites about the C-C bond [as indicated by the almost equal C-O distances of 1.254 (3) and 1.250 (3) Å], the occupancies of the disordered carboxym H atoms being 0.53 (5) and 0.47 (5). In the known ortho-rhom-bic form reported by Swaminathan et al. [Acta Cryst. (1976), B32, 1897-1900], due to the anti-planar conformation adopted by the OH group, the mol-ecular components are associated in the crystal in chains stabilized by linear O-H⋯O hydrogen bonds. However, in the new tetra-gonal polymorph, mol-ecules form dimeric units via pairs of O-H⋯O hydrogen bonds between the carb-oxy groups.

Solid-phase molecular recognition of cytosine based on proton-transfer reaction. Part II. supramolecular architecture in the cocrystals of cytosine and its 5-Fluoroderivative with 5-Nitrouracil.

BACKGROUND: Cytosine is a biologically important compound owing to its natural occurrence as a component of nucleic acids. Cytosine plays a crucial role in DNA/RNA base pairing, through several hydrogen-bonding patterns, and controls the essential features of life as it is involved in genetic codon of 17 amino acids. The molecular recognition among cytosines, and the molecular heterosynthons of molecular salts fabricated through proton-transfer reactions, might be used to investigate the theoretical sites of cytosine-specific DNA-binding proteins and the design for molecular imprint. RESULTS: Reaction of cytosine (Cyt) and 5-fluorocytosine (5Fcyt) with 5-nitrouracil (Nit) in aqueous solution yielded two new products, which have been characterized by single-crystal X-ray diffraction. The products include a dihydrated molecular salt (CytNit) having both ionic and neutral hydrogen-bonded species, and a dihydrated cocrystal of neutral species (5FcytNit). In CytNit a protonated and an unprotonated cytosine form a triply hydrogen-bonded aggregate in a self-recognition ion-pair complex, and this dimer is then hydrogen bonded to one neutral and one anionic 5-nitrouracil molecule. In 5FcytNit the two neutral nucleobase derivatives are hydrogen bonded in pairs. In both structures conventional N-H...O, O-H...O, N-H+...N and N-H...N- intermolecular interactions are most significant in the structural assembly. CONCLUSION: The supramolecular structure of the molecular adducts formed by cytosine and 5-fluorocytosine with 5-nitrouracil, CytNit and 5FcytNit, respectively, have been investigated in detail. CytNit and 5FcytNit exhibit widely differing hydrogen-bonding patterns, though both possess layered structures. The crystal structures of CytNit (Dpka = -0.7, molecular salt) and 5FcytNit (Dpka = -2.0, cocrystal) confirm that, at the present level of knowledge about the nature of proton-transfer process, there is not a strict correlation between the Dpka values and the proton transfer, in that the acid/base pka strength is not a definite guide to predict the location of H atoms in the solid state. Eventually, the absence in 5FcytNit of hydrogen bonds involving fluorine is in agreement with findings that covalently bound fluorine hardly ever acts as acceptor for available Brønsted acidic sites in the presence of competing heteroatom acceptors.