Zinc(II) complexes with intramolecular amide oxygen coordination as models of metalloamidases

Polydentate ligands (6-R1-2-pyridylmethyl)-R2(R1= NHCOtBu, R2= bis(2-pyridylmethyl)amine L1, bis(2-(methylthio)ethyl)amine L2 and N(CH2CH2)2S L3) form mononuclear zinc(II) complexes with intramolecular amide oxygen coordination and a range of coordination environments. Thus, the reaction of Zn(ClO4)2.6H2O with L1-3 in acetonitrile affords [(L)Zn](ClO4)2(L=L1, 1; L2, 2) and [(L3)Zn(H2O)(NCCH3)](ClO4)2 3. The simultaneous amide/water binding in resembles the motif that has been proposed to be involved in the double substrate/nucleophile Lewis acidic activation and positioning mechanism of amide bond hydrolysis in metallopeptidases. X-ray diffraction, 1H and 13C NMR and IR data suggests that the strength of amide oxygen coordination follows the trend 1>2 >3. L1-3 and undergo cleavage of the tert-butylamide upon addition of Me4NOH.5H2O (1 equiv.) in methanol at 50(1)degrees C. The rate of amide cleavage follows the order 1> 2> 3, L1-3. The extent by which the amide cleavage reaction is accelerated in 1-3 relative to the free ligands, L1-3, is correlated with the strength of amide oxygen binding and Lewis acidity of the zinc(II) centre in deduced from the X-ray, NMR and IR studies.     

Organometallic ruthenium(II) diamine anticancer complexes: arene-nucleobase stacking and stereospecific hydrogen-bonding in guanine adducts

Organometallic ruthenium(II) arene anticancer complexes of the type [(eta(6)-arene)Ru(II)(en)Cl][PF(6)] (en = ethylenediamine) specifically target guanine bases of DNA oligomers and form monofunctional adducts (Morris, R., et al. J. Med. Chem. 2001). We have determined the structures of monofunctional adducts of the "piano-stool" complexes [(eta(6)-Bip)Ru(II)(en)Cl][PF(6)] (1, Bip = biphenyl), [(eta(6)-THA)Ru(II)(en)Cl][PF(6)] (2, THA = 5,8,9,10-tetrahydroanthracene), and [(eta(6)-DHA)Ru(II)(en)Cl][PF(6)] (3, DHA = 9,10-dihydroanthracene) with guanine derivatives, in the solid state by X-ray crystallography, and in solution using 2D [(1)H,(1)H] NOESY and [(1)H,(15)N] HSQC NMR methods. Strong pi-pi arene-nucleobase stacking is present in the crystal structures of [(eta(6)-C(14)H(14))Ru(en)(9EtG-N7)][PF(6)](2).(MeOH) (6) and [(eta(6)-C(14)H(12))Ru(en)(9EtG-N7)][PF(6)](2).2(MeOH) (7) (9EtG = 9-ethylguanine). The anthracene outer ring (C) stacks over the purine base at distances of 3.45 A for 6 and 3.31 A for 7, with dihedral angles of 3.3 degrees and 3.1 degrees, respectively. In the crystal structure of [(eta(6)-biphenyl)Ru(en)(9EtG-N7)][PF(6)](2).(MeOH) (4), there is intermolecular stacking between the pendant phenyl ring and the purine six-membered ring at a distance of 4.0 A (dihedral angle 4.5 degrees). This stacking stabilizes a cyclic tetramer structure in the unit cell. The guanosine (Guo) adduct [(eta(6)-biphenyl)Ru(en)(Guo-N7)][PF(6)](2).3.75(H(2)O) (5) exhibits intramolecular stacking of the pendant phenyl ring with the purine five-membered ring (3.8 A, 23.8 degrees) and intermolecular stacking of the purine six-membered ring with an adjacent pendant phenyl ring (4.2 A, 23.0 degrees). These occur alternately giving a columnar-type structure. A syn orientation of arene and purine is present in the crystal structures 5, 6, and 7, while the orientation is anti for 4. However, in solution, a syn orientation predominates for all the biphenyl adducts 4, 5, and the guanosine 5'-monophosphate (5'-GMP) adduct 8 [(eta(6)-biphenyl)Ru(II)(en)(5'-GMP-N7)], as revealed by NMR NOE studies. The predominance of the syn orientation both in the solid state and in solution can be attributed to hydrophobic interactions between the arene and purine rings. There are significant reorientations and conformational changes of the arene ligands in [(eta(6)-arene)Ru(II)(en)(G-N7)] complexes in the solid state, with respect to those of the parent chloro-complexes [(eta(6)-arene)Ru(II)(en)Cl](+). The arene ligands have flexibility through rotation around the arene-Ru pi-bonds, propeller twisting for Bip, and hinge-bending for THA and DHA. Thus propeller twisting of Bip decreases by ca. 10 degrees so as to maximize intra- or intermolecular stacking with the purine ring, and stacking of THA and DHA with the purine is optimized when their tricyclic ring systems are bent by ca. 30 degrees, which involves increased bending of THA and a flattening of DHA. This flexibility makes simultaneous arene-base stacking and N7-covalent binding compatible. Strong stereospecific intramolecular H-bonding between an en NH proton oriented away from the arene (en NH(d)) and the C6 carbonyl of G (G O6) is present in the crystal structures of 4, 5, 6, and 7 (average N...O distance 2.8 A, N-H...O angle 163 degrees ). NMR studies of the 5'-GMP adduct 8 provided evidence that en NH(d) protons are involved in strong H-bonding with the 5'-phosphate and O6 of 5'-GMP. The strong H-bonding from G O6 to en NH(d) protons partly accounts for the high preference for binding of [(eta(6)-arene)Ru(II)en](2+) to G versus A (adenine). These studies suggest that simultaneous covalent coordination, intercalation, and stereospecific H-bonding can be incorporated into Ru(II) arene complexes to optimize their DNA recognition behavior, and as potential drug design features.     

Use of chelating ligands to tune the reactive site of half-sandwich ruthenium(II)-arene anticancer complexes

We show that the chelating ligand XY in Ru(II) anticancer complexes of the type [Ru(eta6-arene)(XY)Cl]n+ has a major influence on the rate and extent of aquation, the pKa of the aqua adduct, and the rate and selectivity of binding to nucleobases. Replacement of neutral ethylenediamine (en) by anionic acetylacetonate (acac) as the chelating ligand increases the rate and extent of hydrolysis, the pKa of the aqua complex (from 8.25 to 9.41 for arene=p-cymene), and changes the nucleobase specificity. For the complexes containing the hydrogen-bond donor en, there is exclusive binding to N7 of guanine in competitive nucleobase reactions, and in the absence of guanine, binding to cytosine or thymine but not to adenine. In contrast, when XY is the hydrogen-bond acceptor acac, the overall affinity for adenosine (N7 and N1 binding) is comparable to that for guanosine, but there is little binding to cytidine or thymidine.     

The first structural characterisation of a group 2 metal alkylperoxide complex: comments on the cleavage of dioxygen by magnesium alkyl complexes

A new high-yield synthesis of [(PhCH(2))(2)Mg(thf)(2)] and [[(PhCH(2))CH(3)Mg(thf)](2)] via benzylpotassium has allowed a simple entry into benzylmagnesium coordination chemistry. The syntheses and X-ray crystal structures of both [(eta(2)-Me(2)NCH(2)CH(2)NMe(2))Mg(CH(2)Ph)(2)] and [eta(2)-HC[C(CH(3))NAr'](2)Mg(CH(2)Ph)(thf)] (Ar'=2,6-diisopropylphenyl) are reported. The latter beta-diketiminate complex reacts with dioxygen to provide a 1:2 mixture of dimeric benzylperoxo and benzyloxo complexes. The benzylperoxo complex [[eta(2)-HC[C(CH(3))NAr'](2)Mg(mu-eta(2):eta(1)-OOCH(2)Ph)](2)] is the first example of a structurally characterised Group 2 metal-alkylperoxo complex and contains the benzylperoxo ligands in an unusual mu-eta(2):eta(1)-coordination mode, linking the two five-coordinate magnesium centres. The O[bond]O separation in the benzylperoxo ligands is 1.44(2) A. Reaction of the benzylperoxo/benzyloxo complex mixture with further [eta(2)-HC[C(CH(3))NAr'](2)Mg(CH(2)Ph)(thf)] results in complete conversion of the benzylperoxo species into the benzyloxo complex. This reaction, therefore, establishes the cleavage of dioxygen by this system as a two-step process that involves initial oxygen insertion into the Mg[bond]CH(2)Ph bond followed by O[bond]O/Mg[bond]C sigma-bond metathesis of the resulting benzylperoxo ligand with a second Mg[bond]CH(2)Ph bond. The formation of a 1:2 mixture of the benzylperoxo and benzyloxo species indicates that the rate of the insertion is faster than that of the metathesis, and this is shown to be consistent with a radical mechanism for the insertion process.     

Mercurimetric determination of chloride with diphenylcarbazide disodium disulfonate as an indicator

A procedure is given for the use of diphenylcarbazide disodium disulfonate as an indicator in the direct titration of chloride with mercuric nitrate. By adding ferric nitrate to form the carbazone and an inert green substance to serve as a color screen, a sharp and reversible endpoint changing from green to grey to purple is obtained. Studies were made on the indicator reaction and other factors, such as mercuric chloride concentration, pH, volume, temperature and the effect of various added salts. The pH must be adjusted to 1.8 to 2.0 for best results. A series of ten determinations on a sample gave a standard deviation of ±0.16 part per thousand.     

Oxo-tricyano complexes of molybdenum(IV) and tungsten(IV) with bidentate Schiff bases

Summary The reaction of [M(CN)₄O(OH₂)]^2– (M = Mo or W) with 2-acetylpyridine and methyl-or butyl-amine in a water-MeOH mixture gave [M(CN)₃O(L-L)]^- (L-L= Schiff base ligand), isolated as [AsPh₄]⁺ salts. The complexes have been characterized by elemental analysis, and electronic, i.r. and¹H-n.m.r. spectroscopy. The Schiff base ligands complex in a bidentate manner through the two nitrogen atoms giving mixed-ligand compounds similarly to 2,2-bipyridyl or 1,10-phenanthroline.On leave from the Faculty of Chemistry, Jagiellonian University, Kraków.