Beyond the Simple Copper(II) Coordination Chemistry with Quinaldinate and Secondary Amines.

Copper(II) acetate has reacted in methanol with quinaldinic acid (quinoline-2-carboxylic acid) to form [Cu(quin)2(CH3OH)]∙CH3OH (1) (quin- = an anionic form of the acid) with quinaldinates bound in a bidentate chelating manner. In the air, complex 1 gives off methanol and binds water. The conversion was monitored by IR spectroscopy. The aqua complex has shown a facile substitution chemistry with alicyclic secondary amines, pyrrolidine (pyro), and morpholine (morph). trans-[Cu(quin)2(pyro)2] (2) and trans-[Cu(quin)2(morph)2] (4) were obtained in good yields. The morpholine system has produced a by-product, trans-[Cu(en)2(H2O)2](morphCOO)2 (5) (morphCOO- = morphylcarbamate), a result of the copper(II) quinaldinate reaction with ethylenediamine (en), an inherent impurity in morpholine, and the amine reaction with carbon dioxide. (pyroH)[Cu(quin)2Cl] (3) forms on the recrystallization of [Cu(quin)2(pyro)2] from dichloromethane, confirming a reaction between amine and the solvent. Similarly, a homologous amine, piperidine (pipe), and dichloromethane produced (pipeH)[Cu(quin)2Cl] (11). The piperidine system has afforded both mono- and bis-amine complexes, [Cu(quin)2(pipe)] (6) and trans-[Cu(quin)2(pipe)2] (7). The latter also exists in solvated forms, [Cu(quin)2(pipe)2]∙CH3CN (8) and [Cu(quin)2(pipe)2]∙CH3CH2CN (9). Interestingly, only the piperidine system has experienced a reduction of copper(II). The involvement of amine in the reduction was undoubtedly confirmed by identification of a polycyclic piperidine compound 10, 6,13-di(piperidin-1-yl)dodecahydro-2H,6H-7,14-methanodipyrido[1,2-a:1',2'-e][1,5]diazocine.

Nanomechanical properties of selected single pharmaceutical crystals as a predictor of their bulk behaviour.

PURPOSE: The main goal of this research was to assess the mechanical properties of APIs' polymorphic forms at the single-crystal level (piroxicam, famotidine, nifedipine, olanzapine) in order to predict their bulk deformational attributes, which are critical for some pharmaceutical technology processes. METHODS: The mechanical properties of oriented single crystals were determined using instrumented nanoindentation (continuous stiffness measurement). All polymorphic forms investigated were previously identified using a combination of calorimetric and spectroscopic techniques. RESULTS: Mechanical properties such as Young's modulus and indentation hardness were consistent with the molecular packing of the polymorphic forms investigated with respect to crystal orientation. For mechanically interlocked structures, characteristic of most polymorphic forms, response of single crystals to indentation was isotropic. The material's bulk elastic properties can be successfully predicted by measuring Young's modulus of single crystals because a good linear correlation with a bulk parameter such as the tablets' elastic relaxation index was determined. CONCLUSIONS: The results confirm the idea that the intrinsic mechanical properties of pharmaceutical crystals (Young's modulus) largely control and anticipate their deformational behavior during tablet compression. Young's modulus and indentation hardness represent a very valuable and effective tool in preformulation studies for describing materials' mechanical attributes, which are important for technological processes in which materials are exposed to deformation.

Two new mononuclear manganese(III) salen complexes.

Two new Mn(III)-salen complexes with 4-aminopyridine (4-apy) have been prepared and structurally characterized. [Mn(ac)(4-apy)(sal)], 1,exhibits mononuclear molecular structure with an octahedral environment around the Mn center. Salen ligand occupies all four basal positions, while the axial sites are occupied by endocyclic nitrogen atom of the 4-apy ligand and acetato oxygen atom. [Mn(4-apy)2(sal)]PF6, 2, is an ionic compound in which the coordination cations, [Mn(4-apy)2(sal)]+, exhibit octahedral geometry. Both axial sites are occupied by endocyclic nitrogen atoms of the 4-aminopyridine ligands. Cations are connected into zig-zag chains via H-bonds. The positive charge is compensated by PF6- anions located between the chains.

Bromidobis[2-(pyridin-2-yl)methanol-κ(2)N,O]copper(II) bromide monohydrate.

The title compound, [CuBr(C6H7NO)2]Br·H2O, is an ionic mononuclear complex in which the [CuBr(C6H7NO)2](+) cation possesses distorted square-pyramidal geometry. The Cu(II) centre is coordinated by two neutral 2-(pyridin-2-yl)methanol (2-pyMeOH) ligands and a terminal bromide ligand. The 2-pyMeOH ligands are coordinated in a bidentate chelating manner through the pyridine N and hydroxy O atoms, forming a five-membered chelate ring with the Cu(II) centre. The planes of the pyridine rings are twisted by 58.71 (14)° with respect to each other. The charge is balanced by a noncoordinating bromide anion which, together with a solvent water molecule, links the components through hydrogen bonds into infinite chains propagating along the a axis. The mononuclear cations appear to associate in pairs through weak interactions between the metal atom of one cation and the halogen atom of an adjacent cation.

Fluconazole-malonic acid (1/1).

Co-crystallizaton of the anti-fungal drug fluconazole [2-(2,4-difluoro-phen-yl)-1,3-bis-(1H-1,2,4-triazol-1-yl)propan-2-ol] with malonic acid in acetonitrile solution resulted in the formation of the title 1:1 co-crystal, C13H12F2N6O·C3H4O4. The geometry around the central fluconazole atom is distorted tetrahedral. The dihedral angles between the triazole rings and the fluorinated phenyl ring are 30.64 (7) and 61.91 (5)°. In the crystal, the basic packing motif may be envisioned as a cyclic aggregate formed of two fluconazole mol-ecules linked by two malonic acid mol-ecules through O-H⋯N and O-H⋯O hydrogen bonds. Such aggregates are further connected into (001) layers by further O-H⋯N hydrogen bonds. The structure also features weak non-classical C-H⋯O and C-H⋯N inter-actions.

Treatment of Symptomatic Focal Hepatic Hemangioma with Propranolol in Neonates: Is It Efficient?

Hepatic hemangiomas (HH) - classified into congenital hepatic hemangiomas (CHH) or infantile hepatic hemangiomas (IHH) - are benign vascular tumors that are mainly asymptomatic, but may cause clinical problems that require treatment. While focal, multifocal, and diffuse IHH are responsive to propranolol treatment, CHH is mainly focal and thought to be resistant to treatment with propranolol. The clinical and imaging distinctions between CHH and IHH in cases of focal lesions can be challenging, while histopathological distinction is mostly lacking in the clinical setting. We report 4 neonatal symptomatic cases of focal HH treated with propranolol, with partial or complete resolution of the tumor, and the positive hemodynamic effect of propranolol in one case. We believe that although clear differentiation cannot be achieved between CHH and IHH without histopathological examination in cases of focal HH in neonates, propranolol treatment should be attempted in symptomatic cases since its benefits outweigh the possible small risk of side effects of propranolol.

A new polymorphic form of bis(acetato-κO)bis[2-(pyridin-2-yl)ethanol-κ2N,O]nickel(II).

A new polymorph of a mononuclear nickel(II) acetate complex with 2-(pyridin-2-yl)ethanol ligands, [Ni(CH(3)COO)(2)(C(7)H(9)NO)(2)], has been prepared and structurally characterized. Its molecular structure resembles the structures of two previously reported polymorphs in that the Ni(II) atom is located on an inversion centre and is coordinated by pairs of acetate and 2-(pyridin-2-yl)ethanol ligands. The acetate anions are coordinated in a monodentate manner, while the 2-(pyridin-2-yl)ethanol ligands are coordinated in a bidentate chelating mode involving the endocyclic N atom and the hydroxy O atom of the ligand side chain. A strong bifurcated intramolecular hydrogen-bond interaction was observed involving the hydroxy O atom as donor and both acetate O atoms as acceptors. No classical intermolecular hydrogen-bond contacts were observed. However, the crystal packing is effected through π-π and C-H...π interactions, giving rise to a different packing arrangement. A brief comparison of the three polymorphic forms is presented.

Two concomitant polymorphs of monomeric nickel acetate with 2-pyridineethanol.

A new mononuclear nickel(II) acetate with 2-pyridineethanol, Ni(ac)2(2-PyEtOH)2 has been prepared. The reaction product is a mixture of two polymorphic forms that crystallize concomitantly: triclinic (PI) and monoclinic (P21/c). Their structures have been determined at 150 K. The molecular structure of the mononuclear complex shows similar geometry in both polymorphic structures but they differ notably in the arrangement of mononuclear entities in space. The crystal densities are significantly different, nevertheless they behave as concomitant polymorphs.

Bis(acetato-κO)bis-[2-(pyridin-2-yl)ethanol-κ(2)N,O]copper(II).

The title compound, [Cu(CH(3)COO)(2)(C(7)H(9)NO)(2)], is a monomeric complex with an octa-hedral geometry. The Cu(II) atom is located on an inversion center and is coordinated by acetate and 2-(pyridin-2-yl)ethanol ligands. The acetate group is coordinated in a monodentate manner, while the 2-(pyridin-2-yl)ethanol is coordinated as a bidentate ligand involving the endocyclic N atom and the hy-droxy O atom of the ligand side chain. An intra-molecular hydrogen bond is observed between the hy-droxy O atom and the non-coordinated acetate O atom. No classical inter-molecular hydrogen-bond contacts were observed. However, the crystal packing is effected by C-H⋯O inter-actions, which link the mononuclear entities into layers parallel to the bc plane.

A 1:1 cocrystal of fluconazole with salicylic acid.

The interaction of the antifungal pharmaceutical agent fluconazole with salicylic acid in acetonitrile solution yields the 1:1 cocrystal 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol-2-hydroxybenzoic acid (1/1), C(13)H(12)F(2)N(6)O·C(7)H(6)O(3). The asymmetric unit consists of one molecule of fluconazole and one molecule of salicylic acid, both in their neutral forms. Both crystal agents form head-to-tail hydrogen-bonded dimers, which are further connected into hydrogen-bonded extended zigzag tapes propagating along the ac diagonal.

Intermolecular C-H...pi interactions in 1,5-diphenyl-3-(2-pyridyl)-2-pyrazoline.

The title compound, C(20)H(17)N(3), is a derivative of 1,3,5-triaryl-2-pyrazoline and can act as an N,N'-bidentate ligand. This molecule features strong fluorescence that can be explained by an extended pyridyl-C=N-N-phenyl system. The three-dimensional structure is formed by means of an extended network of weak C-H...pi hydrogen bonds supported by pi-pi interactions.

Three Concomitant Crystal Forms of Monomeric Cobalt Chloride with 3-Pyridinemethanol.

Three new crystal forms of a mononuclear cobalt(II) chloride with 3-pyridinemethanol (3PM), CoCl2(3PM)4, have been prepared: triclinic (P1̄) and monoclinic (P21/c) polymorphs and its dihydrate which crystallises in the triclinic P1̄ space group. The three crystal forms differ by the orientation of 3PM ligands in the mononuclear entities and consequently in their packing arrangements. All three forms crystallise concomitantly. Their crystal structures have been determined at 150K.

A new copper(II) basic sulfate: poly[3-aminopyridinium mu3-hydroxido-di-mu3-sulfato-bis[aquacopper(II)]].

The crystal structure of the title basic copper(II) sulfate, {(C(5)H(7)N(2))[Cu2(OH)(SO4)2(H2O)2]}n, shows an unprecedented structural arrangement of two distinct copper centres. CuO6 and CuO5 polyhedra are linked through bridging hydroxide and sulfate anions to form negatively charged infinite chains propagated along the a axis. The negative charge is balanced by 3-aminopyridinium cations that are held in the structure by extensive hydrogen bonding to the inorganic chains. Additionally, the cationic arrangement features pi-pi stacking.

Structures of artificial sweeteners--cyclamic acid and sodium cyclamate with other cyclamates.

In the course of a study on artificial sweeteners, new crystal structures of cyclamic acid, sodium cyclamate, potassium cyclamate, ammonium cyclamate, rubidium cyclamate and tetra-n-propylammonium cyclamate have been determined. Cyclamic acid exists in its zwitterionic form in the crystalline state. The zwitterions are connected through hydrogen bonds of the N-H...O type to form two-dimensional sheets. The sodium, potassium, ammonium and rubidium cyclamates are isostructural, with the cyclamate moieties linked through hydrogen bonds into linear chains. Taking into account the connectivity through cations, two-dimensional layers with a hydrophobic surface are constructed. In tetra(n-propyl)ammonium cyclamate the large, non-coordinating cation apparently prevents the formation of chains and thereby facilitates the centrosymmetric head-to-head discrete dimeric arrangement of the cyclamate moieties.

A dimeric cobalt(II)-suberate complex with 3-aminopyridine.

The title complex, mu-octane-1,8-dioato-bis[bis(3-aminopyridine)chloro(methanol)cobalt(II)], [Co2(C8H12O4)Cl2(C5H6N2)4(CH4O)2], is located on a crystallographic centre of inversion. The coordination around each of the Co centres is distorted octahedral, involving two N, three O and one Cl atom. Discrete dimers are connected in a three-dimensional arrangement through N-H...O, N-H...Cl and O-H...O hydrogen-bond interactions.

The solution structures and dynamics and the solid-state structures of substituted cyclopentadienyltitanium(IV) trifluorides.

Organotitanium fluorides (C5Me4R)TiF3 (R = H, Me, Et) sublimate with formation of crystalline dimers. From solution, we obtained crystals of dimers and tetramers. The tetramer [{(C5Me5)TiF3}4] irreversibly dissociates in the solid state to dimers (DeltaH = 8.33 kcal mol(-1)). The variable-temperature (1)H and (19)F NMR spectroscopy measurements of the toluene-d(8) solution of [{(C5Me5)TiF3}2] revealed at 202 K one monomeric, two dimeric (with C2h and Cs symmetry), two tetrameric (with D2 and C2v symmetry), and two trimeric (both C2 symmetry) molecules. With the increase in temperature and dilution of the solution, the composition of the solution shifts to the smaller molecules. The thermodynamic and activation parameters for the reversible dissociation of dimers to monomers in the solution are DeltaH = 9.2 kcal mol(-1), DeltaS = 24.2 cal mol(-1) K(-1), DeltaH(double dagger) = 12.2 kcal mol(-1), DeltaS(double dagger) = 9.7 cal mol(-1) K(-1). The dissociation path with a weakly double-bridged transition-state dimer was proposed. The thermodynamic parameters for the reversible dissociation of the C2v tetramer to the dimers in solution are DeltaH = 7.9 kcal mol(-1) and DeltaS = 26.8 cal mol(-1) K(-1). From both tetramers, the D2 molecule is 0.34(5) kcal mol(-1) lower in enthalpy and 6.5(5) cal mol(-1) K(-1) lower in entropy than the C2v molecule. The structures of both trimers were proposed. The low-temperature 19F NMR spectra of the CDCl3 solution of [{(C5Me5)TiF3}2] are consistent with equilibria of a monomer, two dimers (with C2h and Cs symmetry), and a trimer. The vapor pressure osmometric molecular mass determination of CDCl3 solution of [{(C5Me5)TiF3}2] at 302 K is consistent with the equilibrium of the dimer and the monomer.

4-aminopyridinium hydrogen maleate.

The title compound, C(5)H(7)N(2)(+)...C(4)H(3)O(4)(-), crystallizes in space group P2(1) with one ion pair in the asymmetric unit. The hydrogen maleate anion possesses nearly planar geometry and displays an extremely short intramolecular O--H...O hydrogen bond, with an O...O distance of 2.4198 (19) A. Classical N-H...O hydrogen bonds, together with short C--H...O contacts, generate an extensive hydrogen-bonding network.

Specific potassium binding stabilizes pI258 arsenate reductase from Staphylococcus aureus.

Arsenate reductase (ArsC) from Staphylococcus aureus plasmid pI258 catalyzes the reduction of arsenate to arsenite and plays a role in bacterial heavy metal resistance. The high resolution x-ray structure of ArsC reveals the atomic details of the K+ binding site situated next to the catalytic P-loop structural motif of this redox enzyme. A full thermodynamic study of the binding characteristics of a series of monovalent cations (Li+, Na+, K+, Rb+, and Cs+) and their influence on the thermal stability of ArsC was performed with isothermal titration calorimetry, circular dichroism spectroscopy, and differential scanning calorimetry. Potassium has the largest affinity with a Ka of 3.8 x 10(3) m(-1), and the effectiveness of stabilization of ArsC by monovalent cations follows the binding affinity order: K+ > Rb+ > Cs+ > Na+ > Li+. A mutagenesis study on the K+ binding side chains showed that Asn-13 and Asp-65 are essential for potassium binding, but the impact on the stability of ArsC was the most extreme when mutating Ser-36. Additionally, the thermal stabilization by K+ is significantly reduced in the case of the ArsC E21A mutant, showing the importance of a Glu-21-coordinated water molecule in its contact with K+. Although potassium is not essential for catalysis, in its presence the kcat/KM increases with a factor of 5. Altogether, the interaction of K+ with specific residues in ArsC is an enthalpydriven process that stabilizes ArsC and increases the specific activity of this redox enzyme.

2-aminothiazole and 2-aminothiazolinone derivatives.

The reaction of different substituted alpha-cyanooxiranes with thiourea resulted in the formation of the 2-aminothiazolinone derivative 2-amino-5-(2,5-dimethoxyphenyl)-1,3-thiazol-4(5H)-one, C(11)H(12)N(2)O(3)S, (I), and the 2-aminothiazole derivative ethyl 2-amino-5-(2,5-dimethoxyphenyl)-1,3-thiazole-4-carboxylate, C(14)H(16)N(2)O(4)S, (II). The geometries of the two crystallographically independent molecules in (II) are nearly identical but mirror related. The crystal structures of both compounds contain two types of intermolecular hydrogen bonds.