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The ibuprofen alkaline-earth compounds Ibuprofen-Mg and Ibuprofen-Ca were investigated by using combined solid state and solution studies. The molecular and crystal structures of the calcium (Ca_Ibu_Hy, a 1D-coordination polymer based on ibuprofen) and magnesium (Mg_Ibu_Hy_RT and Mg_Ibu_Hy_LT) ibuprofen dihydrate salts have been analyzed in depth by using X-ray diffraction (both single crystal and powder) and in-silico tools. Differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), variable temperature X-ray diffraction experiments were carried out to study the stability of the solid forms under different temperature conditions. The Mg_Ibu_Hy_LT → Mg_Ibu_Hy_RT transition, which occurs between 250 and 300 K, is fully reversible and consists of a mild rearrangement of the crystal structure. Upon raising the temperature, dehydration of the Mg_Ibu_Hy_RT phase occurs, which leads to a completely amorphous phase at T > 340 K. As a consequence, the RT phase of the MgII compound is stable in a quite narrow temperature range. The calcium salt, in turn, gives a partially crystalline anhydrous phase with rising temperature. The coordination behavior of ibuprofen towards MgII, CaII and SrII in a water–ethanol mixture has been studied by means of potentiometric titrations. Based on the almost identical formation constants for CaII- and MgII-Ibuprofen complexes and on the well-known great affinity of MgII-for water molecules, we speculated the formation of solvent-shared ion pairs in the latter case, where the MgII-carboxylate interaction is of the outer-sphere type.

A new organic-inorganic hybrid compound of formula: (H2L) (HgBr4)·2H2O [L = 3,3′-diaminobiphenylsulfone] has been obtained by slow evaporation. Its crystal structure determined by X–ray single crystal analysis reveals that this compound crystallizes in the monoclinic system with P21/c space group. The crystal packing is dominated by strong interactions between (H2L)2+ cations and the crystallization water molecules as provided as also evidenced by the Hirshfeld Surface analysis (HS), which highlight that the H⋯O/O⋯H contacts are by far the most important ones. The crystal packing was further investigated by using infrared and Raman spectroscopy, as well as computational techniques which allow to calculate the vibrational frequencies of the species. In addition, TGA, DTA and DSC analyses were carried out to study the thermal behavior. The UV–visible behavior was also investigated to determine the optical properties.

The discovery of cisplatin (cis-Pt(NH3)2Cl2) as an antineoplastic agent has focussed attention on the rational design of metal complexes that can be potentially used in cancer chemotherapy. Today, the pharmaceutical industry invests more than $1 billion each year in the development of new metal-based drugs to improve biological activities, in terms of cellular selectivity, therapeutic efficiency and minimization of side effects. Chemotherapies based on transition metals play a key role in cancer treatment, and among them platinum and palladium are the most fruitful. This article reviews the main recent advances in the design and synthesis of platinum- and palladium-based drugs, their structural features and biological studies of them. The rationale for the choice of the ligand, related to leaving groups, the geometry of the complex and the oxidation state of the metal ion, is discussed. An overview of the main biological techniques and approaches for testing the interaction of these molecules with the biological environment, mainly DNA, to validate the effect is also provided.

Flufenamic acid is a nonsteroidal anti-inflammatory drug characterized by a low solubility and a variable oral bioavailability. Flufenamic acid is present in the commercial products in two polymorphic enantiotropic forms (Form I and III). Bioinequivalence was observed for commercial solid dosage forms due to the different dissolution rate of batches. Aim of this work is the full characterization of the solid state properties of flufenamic acid in order to evidence reasons of its variable dissolution properties. Two different batches of pure drug obtained by different suppliers were fully characterized. In order to evaluate the effect of the technological processes used for tablet production, the powders were submitted to grinding, kneading, and compression. Thermal analysis and X-ray diffraction studies proved that the drug was provided by both suppliers as Form I, Form III is obtained by recrystallization from ethanol or ethanol/water of both batches and no changes were observed after the different mechanical treatments. No difference was observed between the two forms in terms of equilibrium solubility values. Dissolution rate studies evidenced a difference between the two batches due to their different particle size, which disappeared after sieving. Interestingly, a significant difference in terms of intrinsic dissolution rate and surface wettability of the two compacted powders was observed, even after sieving, probably related to a different behavior of the two powder samples under compaction. These results should be taken into account, during a tablet formulation, in order to obtain a reproducible dissolution performance of the drug, regardless of its original supplier.

The reduction with Vitride® of the cis and trans isomers of octahydro-2a,4a,6a,8a-tetraazacyclopenten[fg]acenaphthylene 1,2-diones (5 and 6) and octahydro-2a,4a,6a,8a-tetraazacyclopenten[fg]acenaphthylene 3,4-diones (7 and 8) led to the cis 9 and the so far unknown trans 10 isomers of decahydro-2a,4a,6a,8a-tetraazacyclopent[fg]acenaphthylene. The stereochemistry of 9 and 10 was determined by comparison of the NMR coupling constants of the proton signals of the ethinic bridge. The results were confirmed by the solid state structure of the trans isomer (10) determined by single crystal X-ray diffraction. Given that the trans bis-aminal species 2 and 4 can undergo rearrangement, i.e. stereoisomerization into the corresponding cis ones (1 and 3, respectively), the conformational behaviour of species 1–4 was investigated by means of both molecular mechanics (MM) and quantum chemical (QC) approaches. The theoretical study was completed by including diamides 5–8 and the final products 9 and 10.

The equilibrium and rearrangement phenomena encountered in two steps for the synthesis of 1,4,7,10-tetraazacyclododecane from triethylenetetramine, glyoxal and diethyl oxalate were studied and elucidated after the development of two micellar electrokinetic chromatographic (MEKC) methods. The latter were able to separate: (i) the four bis-aminals (2–5) obtained from the condensation of triethylenetetramine with glyoxal; (ii) the four diones (6–9) derived from the reaction of the bis-aminals with diethyl oxalate, whose solid state structures were determined by single crystal X-ray diffraction. The three not yet reported diones (6, 7 and 9) were synthesised by taking advantage of both the reaction conditions and the use of a particular catalyst (MeONa). A plausible reaction mechanism, as well as a discussion of the solid state structures, is presented.

The aim of the paper was to estimate the degrees of freedom, i.e. the flexibility, of four compounds (1‐4) belonging to the tertiary aromatic o-substituted oxo(thio) amide family in the perspective to exploit them as scaffolds for generating chemical libraries. A combined experimental and theoretical structural study was undertaken. Solid state X-ray structures of all the molecules are presented. Thermochemical data for 3 and 4, i.e. DHfus, DSfus and Tfus, were discussed on the basis of the solid state results. A survey of the 3D solid state key features retrieved in the Cambridge Crystallographic Database for molecular fragments featuring CaO(S) grouping directly bound to a phenyl ring is presented. Results from a molecular modelling approach (both force field and ab-initio based) applied to ad-hoc simplified molecules were discussed both from a geometrical and energetic point of view. q 2005 Elsevier B.V. All rights reserved.

The coordination properties of the ligand 2-[bis-(aminoethyl)-aminomethyl]-phenol (L) toward Cd(II) and Pb(II) are reported. The studies were carried out using potentiometric measurements (298.1 K, I=0.15 mol dm−3), UV–Vis absorption and 1H, 13C, 113Cd NMR spectra both in aqueous and non-aqueous solution. By potentiometric measurements performed in aqueous solution, L was found to form only mononuclear species with both the ions investigated; [MH−1L]+ is the main species formed. A dinuclear species with stoichiometry [M2(H−1L)2](ClO4)2 was almost quantitatively isolated in solid state from an aqueous solution in the pH range in which the [MH−1L]+ mononuclear species are present. This behavior is ascribed mainly to the low solubility of the dinuclear complex formed. L does not fulfill the coordination requirement of the ion in the mononuclear species and to saturate it, each metal ion binds the phenolate oxygen of another mononuclear species. The dinuclear species were characterized in organic solution by NMR and ESI mass spectroscopy. The results are confirmed by the crystal structure of [Cd2(H−1L)2](ClO4)2, which displays the two Cd(II) ions close to each other and bridged by two phenolic oxygens each belonging to a H−1L− species.

Three different 3,5-trans disubstituted piperidine derivatives, namely 1 (3R,5R)-1-benzyl-piperidine-3,5-diol, 2 (3R,5R)-1-benzyl-1-oxy-piperidine-3,5-diol and 3 (3R,5R)-1-benzyl-3,5-difluoro-piperidine 1-oxide were studied by using both experimental and theoretical methods. Solid state X-ray structures of all the molecules are presented. Structural differences and analogies in the piperidine rings are discussed in terms of intramolecular H-bond and non-bonded repulsions. In addition, the H-bonding pattern in each crystal packing is discussed in view of the hydroxy groups orientation. The geometrical parameters from ab initio calculations performed on simplified models of the studied molecules, in the gas phase, were also discussed. Finally, in all cases, attention was paid to the energetics of the experimentally isolated conformational isomer and to that obtained as the results of the ring and/or nitrogen inversion.

Gd(III) complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid bearing two and four hydroxymethyl moieties on the cyclen ring were prepared to be studied as low toxicity MRI contrast agents. The key intermediates in the syntheses of the two ligands are the corresponding bis and tetrasubstituted cyclen derivatives. Bis(hydroxymetyl)cyclen was obtained according the so-called ‘crab-like’ cyclization procedure. Photoelectron transfer-induced tetramerization of (R)-2-(benzyloxymethyl)-N-(benzyl)aziridine stereoselectively led to homochiral tetra(hydroxymethyl)cyclen. The X-ray crystal structure of the latter compound unambiguously proved the alike stereochemical configuration of the four stereogenic carbon atoms in the cyclen ring. Carboxymethylation of the cyclen derivatives followed by complexation with either GdCl3 or Gd(OAc)3 afforded the target complexes.

An investigation into the structure of the N-t-butyloxycarbonyl-N′-cyclohexyl-5,5-dimethyl-hydantoin (1) is presented. The structural characterisation was carried out by means of X-ray diffraction analysis: most part of the atoms lie on a crystallographic mirror plane and a lot of intra-molecular C–H⋯O interactions is present. Attention was paid to the side arms conformation and to the intra-molecular C–H⋯O contacts, which were examined by means of a comparison with appropriate solid state structures retrieved from the Cambridge Structural and ab initio calculations.

Five different squalene derivatives, ( 1 ) (18 Z )-29-methylidene-2,3-oxido hexanor- squalene; ( 2 ) (18 E )-29-methylidene-2,3-oxido hexanor squalene; ( 3 ) 18- heptanor -2,3-oxido-squalene 3; ( 4 ) (18 Z )-29-hydroxy-2,3-oxidosqualene; and ( 5 ) (18 E )-29-hydroxy-2,3-oxido-squalene, were studied with both theoretical and experimental methods. Chloroform solutions of these compounds were studied with different mono-, bidimensional and relaxation NMR methods. Analysis of the NMR spectroscopic data of these molecules in solution indicates that their central portion is relatively rigid, while their terminal portions are rather mobile. Further, NMR data of compounds 1 and 2 show that the cis conformation of the butadiene-like terminal group is the most stable conformation. Molecular mechanics and dynamic calculations in vacuum indicate that the mobility of the long squalene-like chain in compounds 1 – 3 is almost equivalent in all isoprenic moieties and that the higher mobility of the tails seems to be due to a cooperative increase of mobility in going from the center to the end of the chain. Theoretical results show that in compounds 4 and especially 5 there is a strong evidence of folded structures in vacuum, while in chloroform small percentages of folded structures become evident even for compounds 1 – 3 .

Dichlorocarbene, which is generated by reaction of CHCl3 with MeONa, is likely to chlorinate DMF to produce the Vilsmeier-Haack-Amold salt that, in the presence of excess MeONa, gives DMF dimethylacetal (2). This latter reacts with primary amides to yield the corresponding N,N-dimethyl-N′-acylformamidines. Solid state structure of N-[(dimethylamino)methylene]phenoxyacetamide (4) obtained by X-ray crystallography is also reported.

Crown ether complex formed by the dibenzo-18-crown-6 (DB18C6) macrocycle with ammonium and potassium hexafluorophosphate have been prepared and their crystal structures have been determined by single crystal X-ray analyses. The ammonium compound consists of a 2:1 mixture of NH4 (DB18C6)PF6 and free DB18C6 ligand (compound 1). Crystals are monoclinic, space group P21/c with a=12.638(2), b=13.118(4), c=20.927(9) A , β=106.21(2)°, V=3331(2) A 3 and Z=4 (R=0.0457) . The ammonium cation interacts with the six oxygen atoms of the crown ether and with two fluorine atoms of a PF6− anion. The potassium derivative (compound 2) consists of K(DB18C6)PF6 units. Crystals are monoclinic, space group P2/c, with a=15.744(8), b=7.945(3), c=37.59(2) A , β=94.27(4)° , V=4689(4) A 3 and Z=8 (R=0.0786) . The potassium atoms of the three independent complexes are linked to the six oxygen atoms of the DB18C6 ligand and to fluorine atoms of two PF6− anions. Molecular mechanics calculations were performed on the uncomplexed DB18C6 molecule by using the MM2 force field.

Thermal reaction of (E)-3,4,5,6,7-penta-O-acetyl-1,2-dideoxy-1-C-nitro-D-galacto-(1a) and-D-manno-hept-1-enitol(1b) with 2-methyl-3,4-diaryl-5-phenylcyclopentadienones (2a–c) afforded diastereoselectively 1-methyl-2,3-diaryl-4-phenyl-(5S,6R)-5-exo-(D-galacto-(3a–c) and -(5R,6S)-5-ero-(D-manno-penta-O-acetylpentitol-1-yl)-6-endo-nitrobicyclo[2.2.1]hept-2-en-7-ones (6a–c) and variable amounts of the 1-phenyl-4-methyl regioisomers 4a–c and 7a, depending upon the p-substituent in the aryl moiety. 1-C-Arylalditols 5, 8–9 are also obtained in refluxing xylene.

The title compound 4 reacted as a dienophile with open-chain and cyclic carbodienes as well as the 1-azadiene 16, to yield different polynuclear isoxazole systems. On the contrary, it gave rise preferentially to a Michael-type reaction with the dimethyluracil derivative 19 affording the cine-substitution product 23, whose structure was determined by an X-ray analysis. Some mechanistic features and synthetic opportunities are emphasized.

The title compounds afforded under relatively mild conditions the polycyclic systems 3a, 4, and 5 through alternative concomitant cycloadditions; the reactivity of the dicyanopyridazine system was critically influenced by the presence of methyl groups at the 3 and 6 positions. The skeleton of 3a and the stereochemistry of 5 were established by X-ray experiments.

A dinuclear Ni(II)–Zn(II) complex of 2-bis-(aminoethyl)-aminomethylphenol ( L ) was prepared by mixing the homo-dinuclear complexes of Ni(II) and Zn(II). The mixed hetero-dinuclear complex was characterized by X-ray analysis. Crystal data for the compound [NiZn(H -1 L ) 2 (H 2 O) 2 ][ClO 4 ] 2 revealed that it is monoclinic; space group P2 1 /n with a =20.137(2) A, b =9.480(1) A, c =15.934(1) A, β=100.45(1)°, V =2991.3(5) A 3 , Z =4, R =0.094.

A. Introduction 51 B. Macrocycles and macrobicycles able to incorporate several metal ions 52 C. Bis(macrocycles) 71 D. Bridged macrocyclic metal complexes 73 Acknowledgements 83 References 83

The nitroderivatives 1a–c were found to react with the title ynamine 2 under mild conditions to give the corresponding fused isoxazoles 3a–c, as proved by an X-ray diffraction of 3a; a plausible mechanistic pattern for these conversions is presented. Treatment of the nitroderivatives 1a–c with the ynamine 2 afforded the new bicyclic isoxazoles 3a–c as proved by an X-ray analysis of 3a.