Preparation and reactivity of metal-containing monomers

The stability constants of some bi- and trivalent metal complexes with methyl-, trifluoromethyl-, and phenyl-substituted 6-heptene-1,3-diones have been determined by pH-metric titration at 20 °C and an ionic strength = 0.1. It is proposed that vinyl groups of ligands are involved in complexation.For Part 44 seeIzv. Akad. Nauk, Ser. Khim., 1995, 1827 [Russ. Chem. Bull., 1995,44, 1758 (Engl. Transl.)].Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2404–2408, December, 1995.This work was partially financially supported by the International Science Foundation (Grant No. NJB000).     

The geometry of intermolecular interactions in some crystalline fluorine-containing organic compounds

The propensity of C-F groups to form C-F H-C interactions with C-H groups on other molecules has been analyzed. Crystal structures of molecules containing only carbon, hydrogen, and fluorine, but no oxygen, nitrogen, or other hydrogen-bond-forming elements, were chosen for an initial study in which the intermolecular interactions in crystal-structure determinations of polycyclic aromatic hydrocarbons and their analogous fluoro derivatives were analyzed. It is found that C-F H-C interactions occur, but they are weak, as judged by the intermolecular distances and the angles involved. In a study of crystal structures of molecules containing other elements in addition to carbon, hydrogen, and fluorine, it was found that when an oxygen atom is in a neighboring position on an interacting molecule, a C-O group is more likely than a C-F group to form a linear interaction to the hydrogen atom of a C-H group. Thus, in spite of the high electronegativity of the fluorine atom, a C-F group competes unfavorably with a C-O^–, C-OH, or C=O group to form a hydrogen bond to an O-H, N-H, or C-H group. It is found, however, particularly for polycyclic aromatic hydrocarbons with substituted CF₃ groups that, in the absence of other functional groups that can form stronger interactions, C-F H-C interactions may serve to align molecules and give a different crystal packing from that in the pure hydrocarbon (where fluorine is replaced by hydrogen). Thus, C-F H-X (X = C, N, O) interactions are very weak, much weaker than C=O H-X interactions, but they cannot be ignored in predictions of modes of molecular packing in complexes and in crystals.     

Group separation of alkyl-substituted aromatic hydrocarbons by high-performance liquid chromatography using perfluorocarbon modified silica gel

Summary The behaviour of perfluorocarbon modified silica gel has been investigated in HPLC for the group separation of alkyl-substituted aromatic hydrocarbons. Using dry alkanes as eluents, the influence of the substituted alkyl groups on the retention of mono- and polycyclic aromatics is very small. Therefore, aromatic hydrocarbons can be separated in order of their increasing -electron energy characterized by a linear correlation between ink and the resonance energy. The method is useful for the group separation of crude oil distillates into groups according to aromatic ring types.Presented at the 14th International Symposium on Chromatography London, September, 1982.     

Transport method for determining the association constants of complexes formed between aromatic hydrocarbons andα- andβ-cyclodextrin in water

The association constants of 1 : 1 complexes formed in water between six aromatic hydrocarbons (o-,m-, andp-xylene, naphthalene, anthracene, and pyrene) and- and-cyclodextrin were determined by the transport method. The values are in good agreement with those determined by other methods.     

Separation of drug enantiomers by capillary electrophoresis: α-cyclodextrin as chiral solvating agent

Summary Enantiomer separation by capillary zone electrophoresis was studied for a set of 59 chiral drugs. With -cyclodextrin as chiral solvating agent, six enantiomeric pairs could be resolved. Baseline separation was achieved for clidinium bromide, oxomemazine and tetryzoline, whereas ketamine, orphenadrine, tropicamide and others require further optimization. Aliphatic and monocyclic compounds prevail among compounds recognized by -cyclodextrin. Statistical analysis reveals that a medium degree of migration retardation offers the best chance for successful separation.Part II. For Part I see reference [18].     

Metal complexes of chiral pentaazacrowns as conformational templates for beta-turn recognition

Examples of reverse turns as recognition motifs in biological systems can be found in high-resolution crystal structures of antibody-peptide complexes. Development of peptidomimetics is often based on replacing the amide backbone of peptides by sugar rings, steroids, benzodiazepines, or other hetero- and carbocycles. In this approach, the chemical scaffold of the peptide backbone can be replaced while retaining activity as long as the pharmacophoric groups of the peptide side chains stay in relatively the same place; in other words, similar functional groups must overlap in space for interaction with critical receptor sites. This study evaluates the potential of metal complexes of chiral pentaazacrowns (PAC) derived by reduction of cyclic pentapeptides as -turn mimetics. Due to the limited flexibility of the pendant chiral side groups in these metal complexes, one can potentially elicit information about the receptor-bound conformation from their binding affinities. 11 PAC crystal structures with different substitution patterns complexed with 3 different metals (Mn, Fe, Cd) as a prototypical database of potential side-chain orientations. Complexation with different metals induces subtle differences in the conformations of a particular azacrown scaffold. The lack of parameterization of transition metals for force field calculations precludes a thorough theoretical study. Thus, this study utilizes a simple geometrical comparison between the experimental data for crystalline PAC complexes and the side-chain orientations seen in classic -turns. The FOUNDATION program was used to overlap the C-C vectors of the corresponding ideal -turn side-chains to all possible leaving groups of the PAC complexes. When comparing the relative orientations of the chiral side chains, a strong overlap of the bonds (between about 0.1 Å to about 0.5 Å RMS for 3 residues and up to about 1 Å RMS for 4 residues) was observed for many of the molecules. Such metal complexes may lack complete peptidomimetic activity due to the lack of spatial overlap of all four side-chain residues, however, if only three peptide side chains are needed for receptor recognition and/or binding, the metal complexes should show biological activity.     

Analysis of steroids XXXIX. Estimation of the impurity profile of 5α-androst-2-ene-17-one

Summary The impurity profile of 5-androst-2-ene-17-one was investigated by using two different capillary gas chromatographic (GC) and a reverse phase high performance liquid chromatographic systems (HPLC). The impurities were identified by retention matching with authentic standards, diode-array UV spectroscopy, on-line gas chromatography-mass spectrometry (GC-MS), off-line HPLC-MS and NMR spectroscopy. The following impurities were identified and quantitated: ring A saturated, isomeric (1-ene, 3-ene, 4-ene, 5-ene) analogues, 3 and 3-hydroxy as well as 3-phenyl derivatives.For Part XXXVIII, see Reference [1]. This paper is Part III in a series of papers Estimation of Impurity Profiles of Drugs and Related Materials. For Part II, see Reference [2].     

Complex formation between polyethylene oxide-containing nonionic surfactants and α- and β-cyclodextrins

The inclusion complexes based on polyethylene oxide (PEO)-containing nonionic surfactants and ()-cyclodextrins (CD) were synthesized. Their composition and crystal structure were studied. The inclusion complexes of the surfactants with -CD form a crystal structure similar to that of the -CD—PEO complex. The inclusion complexes of the nonionic surfactants with -CD form a structure similar to that of the -CD—PEO complex. The structural models of the crystalline complexes were proposed. The micelle-forming abilities of the surfactants in dilute solutions in the presence of CD were studied. The CD binding to a surfactant molecule in aqueous solutions begins from the PEO fragment. Possible reasons for the formation of inclusion complexes between noncomplementary surfactant and -CD molecules were discussed. The thermal stability was studied, and the possibility of thermal dissociation of the pseudo-complementary -CD—surfactant complexes was shown.     

Thermolytic transformations of polyfluoroorganic compounds

Copyrolysis of 4-chlorotetrafluorobenzotrichloride with chlorodifluoromethane (as the source of difluorocarbene) gave 4-chlorodifluoromethyl--chlorohexafluorostyrene, 1,4-dichlorotetrafluorobenzene, and 4-(chlorodifluoromethyl)chlorotetrafluorobenzene along with 4-chloro--chlorohexafluorostyrene. Possible routes for the formation of these products have been offered.For Part 30, see Ref. 1.Translated fromIzevstiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2199–2202, December, 1994.     

Wasserphotolyse mit Hilfe von funktionellen Tris-(2,2′-bipyridin)ruthenium(II)-Komplexen

19 Tris(2,2-bipyridyl)ruthenium(II) complexes with functional groups were synthesized and investigated as sensitizers in photochemical hydrogen production by visible light with the four component system Ru(bipy) ₃ ²⁺ , methylviologen, ethylenediamintetraacetic acid and colloidal platinum ruthenium-bipyridine complexes with electron accepting groups, e.g. halogen or carboxylate were found to be most effective in hydrogen generation.

Herrn Prof. Dr. mult.Viktor Gutmann zum 65. Geburtstag gewidmet.     

Diffusion Evidence for a Stepwise Association Between Alkyl p-Hydroxybenzoates and β-Cyclodextrin Forming 1 : 2 Complex

The incorporation of a homologous series of alkyl p-hydroxybenzoates into -cyclodextrin was studied by diffusion measurements. In some cases, all the anionic species and the larger neutral solute, butyl p-hydroxybenzoate, the occurrence of two species with different diffusion coefficients was observed, as CD concentration increased. Based on their derived hydrodynamic radii, these species were ascribed to 1 : 1 and 1 : 2 (solute:CD) complexes. The interaction of the neutral, mono and bianionic species of p-hydroxybenzoic acid with -CD was also investigated, but, in this case, only 1 : 1 complexes were observed. The strength of solute-CD interaction was estimated from the observed decrease in diffusion coefficients at higher CD concentrations and no significant effect was verified within the homologous series that could be ascribed to hydrophobic effects. A smaller extent of interaction was estimated for the anionic species, possibly due to the contribution from electrostatic repulsion with ionised CD hydroxyl groups. These results prove the potential of diffusion measurements as an invaluable tool in assessing complex stoichiometry and in providing insights in the incorporation process.     

In vitro Release Study of Tretinoin from Tretinoin/Cyclodextrin Derivative Complexes

The effects of -cyclodextrin, hydroxypropyl -cyclodextrin and dimethyl -cyclodextrin complexes on the in vitro release of tretinoin gels were investigated. The experiments were carried out in a Franz cell using a silicone membrane as a barrier for the diffusion of the vehicle. Two types of vehicle were compared: a hydroalcoholic gel in which both tretinoin and the inclusion complexes are soluble, and an aqueous gel in which only the complexes are soluble but tretinoin is dispersed. As expected, the release rate of free tretinoin in the hydroalcoholic gel is much faster than in the aqueous gel. However, with the aqueous gel, the cyclodextrin complexation enhances the diffusion rate of the active drug through the membrane, especially with the hydroxypropyl cyclodextrin inclusion compound. The release of tretinoin is related not only to the stability constant of the inclusion, but also to the binding properties of the inclusion compounds to the vehicle.     

Complex Formation Between Alkane-α,ω-Diols and Cyclodextrins Studied by Partial Molar Volume and Compressibility Measurements

The binding of a series of alkane-,-diols, HO(CH₂)_nOH, n = 4 to 7, to - and -cyclodextrin (CD) has been studied by measurements of partial molar volumes (PMVs) and isentropic partial molar compressibilities (PMCs) at 25°C. From the PMV and PMC data, changes in the partial molar quantities upon going from a free state in aqueous solution to a complexed state were evaluated for the diols. Negative changes in PMV and PMC were observed for complex formation with -CD, while positive values were obtained for the -CD complexes. Equilibrium constants for the different complexes, assuming the formation of 1:1 complexes, were evaluated from the PMV and/or PMC data, and were found to increase with increasing chain length of the included diol for both - and -CD complexes. The equilibrium constant for complex formation is generally higher for the -CD than for the -CD complexes.     

Synthesis, Properties, and Crystal and Molecular Structures of New Ni(II) Complexes with Sterically Hindered Methoxy-β-iminoketones

This paper describes a procedure for the synthesis of two new volatile complexes, C₂₂H₄₀N₂NiO₄ and C₂₀H₃₆N₂NiO₄, based on sterically hindered methoxy--iminoketones. The compounds were investigated by IR spectroscopy and DTA. Full crystal-chemical analysis has been carried out. The structures are molecular. The complexes have close geometrical characteristics; the distances are Ni–O 1.826 and Ni–N 1.842 ; the O–Ni–N chelate angle is 93.2°. The complexes have an intramolecular hydrogen bond N–H...O, estimated at 2.54 (2.08) . In both structures, the packing of complexes is similar to that in nickel(II) dipivalylmethanate.     

On the Distribution of π-Electrons into Rings of Conjugated Hydrocarbons Containing a Linear Polyacene Fragment

Summary. A method for assessing the -electron contents (EC) of rings of benzenoid hydrocarbons, based on the examination of their Kekulé structures, was recently put forward by Balaban and Randi. We now show that all hexagons belonging to a linear polyacene fragment of a conjugated hydrocarbon (not necessarily benzenoid) have mutually equal EC-values.     

Additive nodal increments for approximate calculation of the total π-electron energy of benzenoid hydrocarbons

An approximate method that allows efficient calculation of the total -electron energy (E ) of benzenoid hydrocarbons is presented. It is based on an additive scheme taking into account the characteristic features of variously annelated benzene rings expressed in terms of the numbers corresponding to the different nodes of the dual graph of the hydrocarbon molecule. The parameters of the model are fitted by a test calculation on 1030 hydrocarbons. The mean square error obtained in E is 0.07%. The method provides a connection between the names of hydrocarbons and their stabilities.     

Enhancement of Oral Bioavailability of Rofecoxib Using β-Cyclodextrin

The purpose of the present work was to investigate the effect ofcomplexation of rofecoxib with -cyclodextrin on its dissolutioncharacteristics and bioavailability. Inclusion complexes of rofecoxibwith -cyclodextrin were made by freeze-drying technique. Phasesolubility studies were conducted as suggested by Higuchi and Connors.The samples were characterized by performing dissolution studies, X-rayDiffraction studies and Differential Scanning Calorimetry. The complexeswere compressed into tablets and compared in-vitro with various marketedformulations. A single dose study on healthy human volunteers was performedin comparison with a marketed formulation of rofecoxib (without-cyclodextrin) to investigate the relative bioavailability.Phase solubility studies confirmed the formation of a 1 : 1complex in solution of rofecoxib with -cyclodextrin. Tablets ofsolid inclusion complexes of rofecoxib with -cyclodextrin preparedby freeze drying technique showed enhanced dissolution rate in distilledwater in comparison with all the marketed formulations analyzed. This isattributed to the increased solubility and wettability along with decreasedcrystallinity caused by complex formation, which is confirmed, by XRD and DSCstudies. The bioequivalence studies performed showed statistically significantenhancement in bioavailability as compared to the marketed formulation.Apparently, tablets containing complexes of rofecoxib with -cyclodextrinshows faster onset of action due to improved solubility, enhanced dissolutionand faster absorption of the molecule. The results of this investigation withrofecoxib in -cyclodextrin lend ample credence to its better oralbioavailability on complexation.     

Preferential inclusion of food colours via formation of their inclusion complexes withβ-cyclodextrin (β-CD)

The encapsulation of commercially utilized food colours with-cyclodextrin is reported. Thus, inclusion complexes of Sunset Yellow, Amaranth, Ponceau 4R, Carmoisine, Fast Red E, Tartrazine and Erythrosine with-CD were prepared. The formation of inclusion complexes was established by, among other methods, UV, reflectance and X-ray diffraction techniques. The host-to-guest ratio was determined by a UV spectral method. The effect of inclusion with-CD on binary mixtures such as Raspberry Red, Tomato Red and Orange Red was also studied.     

Some peculiarities of π—π interactions between tetraphenylporphine metal complexes and aromatic solvents

The — complexes of metal tetraphenylporphinates with benzene, toluene, and xylenes were characterized by means of thermogravimetry. The ability of metalloporphyrins to form — complexes with certain -donor molecules depends largely on the -acceptor capacity of the macroheterocycle, and on the peculiarities of the metal—porphyrin coordinative linkage. Stoichiometry, energy parameters, and thermal stability of the - complexes of metalloporphyrins with various aromatic ligands are determined to a great extent by the molecular structure of solvents.Translated fromIzyestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp.850–853, May, 1993.