Synthesis of phosphine derivatives of [Fe2(CO)6(µ-sdt)] (sdt = SCH2SCH2S) and investigation of their proton reduction capabilities.

The reactions of [Fe2(CO)6(µ-sdt)] (1) (sdt = SCH2SCH2S) with phosphine ligands have been investigated. Treatment of 1 with dppm (bis(diphenylphosphino)methane) or dcpm (bis(dicyclohexylphosphino)methane) affords the diphosphine-bridged products [Fe2(CO)4(µ-sdt)(µ-dppm)] (2) and [Fe2(CO)4(µ-sdt)(µ-dcpm)] (3), respectively. The complex [Fe2(CO)4(µ-sdt)(κ2-dppv)] (4) with a chelating diphosphine was obtained by reacting 1 with dppv (cis-1,2-bis(diphenylphosphino)ethene). Reaction of 1 with dppe (1,2-bis(diphenylphosphino)ethane) produces [{Fe2(CO)4(µ-sdt)}2(µ-κ1-dppe)] (5) in which the diphosphine forms an intermolecular bridge between two diiron cluster fragments. Three products were obtained when dppf (1,1'-bis(diphenylphosphino)ferrocene) was introduced to complex 1; they were [Fe2(CO)5(µ-sdt)(κ1-dppfO)] (6), the previously known [{Fe2(CO)5(µ-sdt)}2(µ-κ1-κ1-dppf)] (7), and [Fe2(CO)4(µ-sdt)(µ-dppf)] (8), with complex 8 being produced in highest yield. Single crystal X-ray diffraction analysis was performed on compounds 2, 3 and 8. All structures reveal the adoption of an anti-arrangement of the dithiolate bridges, while the diphosphines occupy dibasal positions. Infra-red spectroscopy indicates that the mono-substituted complexes 5, 6, and 7 are inert to protonation by HBF4.Et2O, but complexes 2, 3, 4 and [Fe2(CO)5(µ-sdt)(κ1-PPh3)] (9) show shifts of their ν(C-O) resonances that indicate that protons bind to the metal cores of the clusters. Addition of the one-electron oxidant [Cp2Fe]PF6 does not lead to any discernable shift in the IR resonances. The redox chemistry of the complexes was investigated by cyclic voltammetry, and the abilities of complexes to catalyze electrochemical proton reduction were examined.

Applying the Crystalline Sponge Method to Agrochemicals: Obtaining X-ray Structures of the Fungicide Metalaxyl-M and Herbicide S-Metolachlor.

The crystalline sponge method is a technique that provides the ability to elucidate the absolute structure of noncrystalline or hard to crystallize compounds through single-crystal X-ray diffraction by removing the need to obtain crystals of the target compound. In this study the crystalline sponges {[(ZnX2)3(2,4,6-tris(4-pyridyl)-1,3,5-trazine)2].x(solvent)} n (X = I, Br) were used to obtain X-ray structures of the agrochemical active ingredients metalaxyl-M and S-metolachlor. The effect of the temperature used during guest uptake and the influence of changing the host framework ZnX2 nodes on guest encapsulation were investigated. Additionally, three compounds containing chemical fragments similar to those of metalaxyl-M and S-metolachlor (phenylacetaldehyde, N-ethyl-o-toluidine, and methyl phenylacetate) were also encapsulated. This allowed for the effect of guest size on the position that guests occupy within the host frameworks to be examined. The disorder experienced by the guest compounds was documented, and an analysis of the intermolecular host-guest interactions (CH···π and π ···π) used for guest ordering within the host frameworks was also undertaken in this study.

Two new monofunctional platinum(II) dithiocarbamate complexes: phenanthriplatin-type axial protection, equatorial-axial conformational isomerism, and anticancer and DNA binding studies.

The syntheses of two platinum(ii) dithiocarbamate complexes (1 and 2) that show quinoplatin- and phenanthriplatin-type axial protection of the Pt-plane are described. The Pt-plane of complex 2 is axially more protected than that of complex 1. Furthermore, both complexes adopt two different stereochemical conformations in the solid state (based on single-crystal X-ray structures) owing to the structurally flexible piperazine backbone; i.e., C-e,e-Anti (1) and C-e,a-Syn (2), where "C" stands for the chair configuration, "e" and "a" stand for the equatorial and axial positions and "Anti" (opposite side) and "Syn" (same side) represent the relative orientations in space of the terminal substituents on the piperazine ring. In complex 2, the C-e,a-Syn conformation may provide additional steric hindrance to the Pt-plane. Despite the lower lipophilicity of 2 as compared to that of 1, the in vitro anticancer action against selected cancer cell lines is better for the former revealing the superior role of the axial protection over lipophilicity in modulating anticancer activity. The activity against the cancer promoting protein NF-κB signifies that the mode of cancer cell death may be the result of hindering the activity of NF-κB in the initiation of apoptosis. The apoptotic mode of cell death has been established earlier in a study using Annexin V-FITC. Finally, DNA binding studies revealed that the complex-DNA adduct formation is spontaneous and the mode of interaction is non-intercalative (electrostatic/covalent).

Reactions of triosmium and triruthenium clusters with 2-ethynylpyridine: new modes for alkyne C-C bond coupling and C-H bond activation.

The reaction of the trimetallic clusters [H2Os3(CO)10] and [Ru3(CO)10L2] (L = CO, MeCN) with 2-ethynylpyridine has been investigated. Treatment of [H2Os3(CO)10] with excess 2-ethynylpyridine affords [HOs3(CO)10(µ-C5H4NCH=CH)] (1), [HOs3(CO)9(µ3-C5H4NC[double bond, length as m-dash]CH2)] (2), [HOs3(CO)9(µ3-C5H4NC[double bond, length as m-dash]CCO2)] (3), and [HOs3(CO)10(µ-CH[double bond, length as m-dash]CHC5H4N)] (4) formed through either the direct addition of the Os-H bond across the C[triple bond, length as m-dash]C bond or acetylenic C-H bond activation of the 2-ethynylpyridine substrate. In contrast, the dominant pathway for the reaction between [Ru3(CO)12] and 2-ethynylpyridine is C-C bond coupling of the alkyne moiety to furnish the triruthenium clusters [Ru3(CO)7(µ-CO){µ3-C5H4NC[double bond, length as m-dash]CHC(C5H4N)[double bond, length as m-dash]CH}] (5) and [Ru3(CO)7(µ-CO){µ3-C5H4NCCHC(C5H4N)CHCHC(C5H4N)}] (6). Cluster 5 contains a metalated 2-pyridyl-substituted diene while 6 exhibits a metalated 2-pyridyl-substituted triene moiety. The functionalized pyridyl ligands in 5 and 6 derive via the formal C-C bond coupling of two and three 2-ethynylpyridine molecules, respectively, and 5 and 6 provide evidence for facile alkyne insertion at ruthenium clusters. The solid-state structures of 1-3, 5, and 6 have been determined by single-crystal X-ray diffraction analyses, and the bonding in the product clusters has been investigated by DFT. In the case of 1, the computational results reveal a rare thermodynamic preference for a terminal hydride ligand as opposed to a hydride-bridged Os-Os bond (3c,2e Os-Os-H bond).

Experimental and computational preference for phosphine regioselectivity and stereoselective tripodal rotation in HOs3(CO)8(PPh3)2(µ-1,2-N,C-η1,κ1-C7H4NS).

The site preference for ligand substitution in the benzothiazolate-bridged cluster HOs3(CO)10(µ-1,2-N,C-η1,κ1-C7H4NS) (1) has been investigated using PPh3. 1 reacts with PPh3 in the presence of Me3NO to afford the mono- and bisphosphine substituted clusters HOs3(CO)9(PPh3)(µ-1,2-N,C-η1,κ1-C7H4NS) (2) and HOs3(CO)8(PPh3)2(µ-1,2-N,C-η1,κ1-C7H4NS) (3), respectively. 2 exists as a pair of non-interconverting isomers where the PPh3 ligand is situated at one of the equatorial sites syn to the edge-bridging hydride that shares a common Os-Os bond with the metalated heterocycle. The solid-state structure of the major isomer establishes the PPh3 regiochemistry at the N-substituted osmium center. DFT calculations confirm the thermodynamic preference for this particular isomer relative to the minor isomer whose phosphine ligand is located at the adjacent C-metalated osmium center. 2 also reacts with PPh3 to give 3. The locus of the second substitution occurs at one of the two equatorial sites at the Os(CO)4 moiety in 2 and gives rise to a pair of fluxional stereoisomers where the new phosphine ligand is scrambled between the two equatorial sites at the Os(CO)3P moiety. The molecular structure of the major isomer has been determined by X-ray diffraction analysis and found to represent the lowest energy structure of the different stereoisomers computed for HOs3(CO)8(PPh3)2(µ-1,2-N,C-η1,κ1-C7H4NS). The fluxional behavior displayed by 3 has been examined by VT NMR spectroscopy, and DFT calculations provide evidence for stereoselective tripodal rotation at the Os(CO)3P moiety that serves to equilibrate the second phosphine between the two available equatorial sites.

Alkyne activation and polyhedral reorganization in benzothiazolate-capped osmium clusters on reaction with diethyl acetylenedicarboxylate (DEAD) and ethyl propiolate.

The reactivity of the face-capped benzothiazolate clusters HOs3(CO)9[µ3-C7H3(R)NS] (1a, R = H; 1b, R = 2-CH3) with alkynes has been investigated. 1a reacts with DEAD at 67 °C to furnish the isomeric alkenyl clusters Os3(CO)9(µ-C7H4NS)(µ3-EtO2CCCHCO2Et) (2a and 3a). X-ray crystallographic analyses of 2a and 3a have confirmed the stereoisomeric relationship of these products and the regiospecific polyhedral expansion that follows the formal transfer of the hydride to the coordinated alkyne ligand in HOs3(CO)9(µ-C7H4NS)(η2-DEAD). The significant structural differences between the two isomers, as revealed by the solid-state structures, derives from the regiospecific cleavage of one of the three Os-Os bonds in the intermediate alkenyl cluster Os3(CO)9(µ-C7H4NS)(η1-EtO2CCCHCO2Et), which follows hydride transfer to the coordinated alkyne ligand in the pi compound HOs3(CO)9(µ-C7H4NS)(η2-DEAD). Control experiments confirm the reversibility of the reaction leading to the formation of 2a and 3a. Whereas heating either isomer in refluxing THF or benzene affords a binary mixture containing 2a and 3a, thermolysis in refluxing toluene leads to the activation of the alkenyl ligand and formation of the new cluster Os3(CO)9(µ-C7H4NS)(µ3-EtO2CCCH2) (4). 4 was independently synthesized from 1a and ethyl propiolate at room temperature. The computed mechanisms that account for the formation of 2a and 3a are presented, along with the mechanism for the reaction of 1a with ethyl propiolate to give 4.

Crystal structure of [butane-2,3-dione bis-(4-methyl-thio-semicarbazonato)-κ(4) S,N (1),N (1'),S'](pyridine-κN)zinc(II).

In the structure of the title complex, [Zn(C8H14N6S2)(C5H5N)], the Zn(II) ion has a pseudo-square-pyramidal coordination environment and is displaced by 0.490 Šfrom the plane of best fit defined by the bis-(thio-semicarbazonate) N2S2 donor atoms. Chains sustained by intermolecular N-H⋯N and N-H⋯S hydrogen-bonding interactions extend parallel to [10-1].

Erythroivorensin: A novel anti-inflammatory diterpene from the root-bark of Erythrophleum ivorense (A Chev.).

The stem- and root-bark of Erythrophleum ivorense (A Chev., family, Fabaceae) are routinely employed in the West African traditional medicine to treat inflammation and a variety of other disease conditions. Although the chemistry and pharmacology of cassaine-type diterpene alkaloids isolated from the stem-bark of the plant are fairly established, the root-bark has not yet been investigated. In the present study, the crude aqueous-alcohol extract of the root-bark was demonstrated to display a time- and dose (30-300 mg/kg p.o.)-dependent anti-inflammatory effect in chicks. Comprehensive chromatographic analysis coupled with spectroscopic and X-ray study further allowed the assignment of one of the major anti-inflammatory constituents as a novel cassaine-type diterpene, erythroivorensin. The other major constituents were known anti-inflammatory compounds: a triterpene, betulinic acid and a flavonoid, eriodictyol. The dose (10-100mg/kg p.o.)-dependent anti-inflammatory effects of the three compounds were either comparable or more significant than the positive control, diclofenac.

One-step protecting-group-free synthesis of azepinomycin in water.

We report an efficient, atom economical general acid-base catalyzed one-step multi-gram synthesis of azepinomycin from commercially available compounds in water. We propose that the described pH-dependent Amadori rearrangement, which couples an amino-imidazole and simple sugar, is of importance as a potential step toward predisposed purine nucleotide synthesis at the origins of life.

Stereoselective synthesis of 1,2-diamine containing indolines by a conjugate addition nitro-Mannich reaction.

A conjugate addition nitro-Mannich reaction followed by nitro reduction and intramolecular N-arylation gives diastereomerically pure substituted 1,2-diamine containing indolines. Placing the N-arylation cyclisation handle on the imine precursor derived from an ortho-bromine substituted aromatic aldehyde gave the corresponding ß-nitroamines in 55-72% yields as single diastereoisomers. Nitro reduction was effected with modified quantities of Zn/HCl and a subsequent Pd(0) catalysed Buchwald Hartwig cyclisation gave indoline products in 40-70% yields as single diastereoisomers.

Antiinflammatory properties of the stem-bark of Anopyxis klaineana and its major constituent, methyl angolensate.

Anopyxis klaineana (Pierre) Engl. (Rhizophoraceae) is one of the reputed West African folkloric medicines that has never been investigated for its pharmacological effects or phytochemical constituents. In the present study, the antiinflammatory properties of the stem-bark extracts were evaluated using the carrageenan-induced paw oedema model in chicks. The petroleum ether, ethyl acetate and methanol extracts all showed a time and dose-dependent antiinflammatory effect over the 5-h observation period. Phytochemical analysis of the most active extract (methanol extract) yielded the principal constituent that was identified as methyl angolensate through extensive spectroscopic and X-ray analysis studies. Although slightly less potent (ED50 , 4.05 ± 0.0034 mg/kg, orally) than the positive control, diclofenac (ED50 , 2.49 ± 0.023, intraperitoneally n = 5), this first ever compound isolated from A. klaineana showed promising antiinflammatory activity that may account to some of the reported medicinal uses of the plant.

The triflic acid-mediated cyclization reactions of N-cinnamoyl-1-naphthylamines.

N-cinnamoyl-1-naphthylamines undergo a cyclization reaction with triflic acid to form 4-phenyl-3,4-dihydro-1H-naphth[1,8-bc]azepin-2-ones and 4-phenyl-3,4-dihydro-1H-benzo[h]quinolin-2-ones. However, the N-benzyl analogues also undergo a unique cascade reaction to form novel heptacyclic structures via a 1,2-addition followed by a 4-addition to the naphthalene. With an electron-rich N-benzyl substituent, the heptacycle is the sole product.

Absorbing a Little Water: The Structural, Thermodynamic, and Kinetic Relationship between Pyrogallol and Its Tetarto-Hydrate.

The anhydrate and the stoichiometric tetarto-hydrate of pyrogallol (0.25 mol water per mol pyrogallol) are both storage stable at ambient conditions, provided that they are phase pure, with the system being at equilibrium at aw (water activity) = 0.15 at 25 °C. Structures have been derived from single crystal and powder X-ray diffraction data for the anhydrate and hydrate, respectively. It is notable that the tetarto-hydrate forms a tetragonal structure with water in channels, a framework that although stabilized by water, is found as a higher energy structure on a computationally generated crystal energy landscape, which has the anhydrate crystal structure as the most stable form. Thus, a combination of slurry experiments, X-ray diffraction, spectroscopy, moisture (de)sorption, and thermo-analytical methods with the computationally generated crystal energy landscape and lattice energy calculations provides a consistent picture of the finely balanced hydration behavior of pyrogallol. In addition, two monotropically related dimethyl sulfoxide monosolvates were found in the accompanying solid form screen.

Complex Polymorphic System of Gallic Acid-Five Monohydrates, Three Anhydrates, and over 20 Solvates.

We report the structure of the fifth monohydrate of gallic acid and two additional anhydrate polymorphs and evidence of at least 22 other solvates formed, many containing water and another solvent. This unprecedented number of monohydrate polymorphs and diversity of solid forms is consistent with the anhydrate and monohydrate crystal energy landscapes, showing both a wide range of packing motifs and also some structures differing only in proton positions. By aiding the solution of structures from powder X-ray diffraction data and guiding the screening, the computational studies help explain the complex polymorphism of gallic acid. This is industrially relevant, as the three anhydrates are stable at ambient conditions but hydration/dehydration behavior is very dependent on relative humidity and phase purity.

Reductive nitro-Mannich route for the synthesis of 1,2-diamine containing indolines and tetrahydroquinolines.

A one-pot, 1,4-hydride addition nitro-Mannich reaction between a set of nitroalkenes 3 and a wide range of N-p-methoxyphenyl-protected aldimines, derived from alkyl, aryl and heteroaryl aldehydes, followed by Zn/HCl reduction leads to stereochemically defined 1,2-diamines. These underwent palladium-catalyzed cyclization and depending upon the presence or not of the trifluoroacetamide protecting group gave either tetrahydroquinolines 18 or indolines 14 in high overall yield and diastereoselectivity (19 examples each). In each case, the more nucleophilic pendant amine cyclizes to give a benzofused saturated heterocyclic 5- or 6-membered ring, with an additional vicinal amino stereocenter in each.

The complexity of hydration of phloroglucinol: a comprehensive structural and thermodynamic characterization.

Hydrate formation is of great importance as the inclusion of water molecules affects many solid state properties and hence determines the required chemical processing, handling, and storage. Phloroglucinol is industrially important, and the observed differences in the morphology and diffuse scattering effects with growth conditions have been scientifically controversial. We have studied the anhydrate and dihydrate of phloroglucinol and their transformations by a unique combination of complementary experimental and computational techniques, namely, moisture sorption analysis, hot-stage microscopy, differential scanning calorimetry, thermogravimetry, isothermal calorimetry, single crystal and powder X-ray diffractometry, and crystal energy landscape calculations. The enthalpically stable dihydrate phase is unstable below 16% relative humidity (25 °C) and above 50 °C (ambient humidity), and the kinetics of hydration/dehydration are relatively rapid with a small hysteresis. A consistent atomistic picture of the thermodynamics of the hydrate/anhydrate transition was derived, consistent with the disordered single X-ray crystal structure and crystal energy landscape showing closely related low energy hydrate structures. These structures provide models for proton disorder and show stacking faults as intergrowth of different layers are possible. This indicates that the consequent variability in crystal surface features and diffuse scattering with growth conditions is not a practical concern.

Computational prediction of salt and cocrystal structures--does a proton position matter?

The lattice energy landscape is calculated for three pyridinium carboxylate salts and the corresponding pyridine·carboxylic acid cocrystals. Experimentally, one system crystallizes as a salt, another as a cocrystal and the acidic proton in the third is disordered across the N(arom)...O hydrogen bond vector. A novel structure of a 1:1 4-cyanopyridine·4-fluorobenzoic acid cocrystal (I) was characterized to provide the cocrystal as a system with an isolated carboxylic acid-pyridine heterosynthon. By contrast, the 4-dimethylaminopyridinium maleate salt (GUKVUE) shows the effects of an internal hydrogen bond, and the proton-disordered pyridine·isophthalic acid crystal (IYUPEX) shows the effects of competing intermolecular hydrogen bonds. All three crystal structures were found low in energy on the lattice energy landscape for the correct proton connectivity. For all three systems, comparing the salt and cocrystal energy landscapes shows the importance of the proton position for the relative stabilities of structures, despite the expected similarities between the ionized and neutral forms of the carboxylic acid-pyridine heterosynthon. The systems with additional hydrogen bonds have some hydrogen bonding motifs that are only favourable for the salt or for the cocrystal. This illustrates the sensitivity of the range of thermodynamically plausible crystal structures to whether the molecules are assumed to be ionized or neutral.

Solid-State Forms of ß-Resorcylic Acid: How Exhaustive Should a Polymorph Screen Be?

An extensive experimental screen, coupled with a computational study, revealed seven new solid-state forms of ß-resorcylic acid. The known, stable polymorph II° shows a reversible phase transformation to the new, kinetically stable, probably disordered high temperature form I. The study provides a consistent picture of the solid-state of ß-resorcylic acid.

A computationally inspired investigation of the solid forms of (R)-1-phenylethylammonium-(S)-2-phenylbutyrate.

Following the computation of a lattice energy landscape which predicted that there should be more stable, denser forms of (R)-1-phenylethylammonium-(S)-2-phenylbutyrate, crystallizations from a range of solvents were performed to search for other polymorphs and investigate the possibility that the known P4(1) structure could be a hydrate. Extensive crystallization experiments from a wide range of solvents gave fine needles or microcrystalline samples. A redetermination of the P4(1) structure by powder X-ray diffraction located all protons, and in conjunction with other experimental and computational evidence showed that the structure was anhydrous. Evidence for two additional forms was found as mixtures with form I. These include an orthorhombic form, possibly a Z' = 3 polymorph, and another as yet unidentified form obtained as a minor component from dichloromethane solution. However, both these forms appear to be metastable with respect to form I (P4(1)), which is therefore probably the most thermodynamically stable form that can be crystallized from solution under ambient conditions. This determination of the solid state behavior of the less readily crystallized member of the diastereomeric salt system (R)-1-phenylethylammonium-(R/S)-2-phenylbutyrate provides a challenge to the theoretical modeling to explain its ideal resolution behavior.

A facile synthesis of dibenzopyrroloazepinones as tetracyclic allocolchicinoids--an unusual 1,2-phenyl shift.

A facile synthesis of dibenzopyrroloazepinones via an electrophilic cyclisation of a biphenyl-acyliminium ion is described; an unusual 1,2-phenyl shift occurs when the C-1' carbon is the more nucleophilic than the C-2' carbon.