The metal chelating properties of flavonoids suggest that they may play a role in metal-overload diseases and in all oxidative stress conditions involving a transition metal ion. A detailed study has been made of the ability of flavonoids to chelate iron (including Fe3+) and copper ions and its dependence of structure and pH. The acid medium may be important in some pathological conditions. In addition, the ability of flavonoids to reduce iron and copper ions and their activity-structure relationships were also investigated. To fulfill these objectives, flavones (apigenin, luteolin, kaempferol, quercetin, myricetin and rutin), isoflavones (daidzein and genistein), flavanones (taxifolin, naringenin and naringin) and a flavanol (catechin) were investigated. All flavonoids studied show higher reducing capacity for copper ions than for iron ions. The flavonoids with better Fe3+ reducing activity are those with a 2,3-double bond and possessing both the catechol group in the B-ring and the 3-hydroxyl group. The copper reducing activity seems to depend largely on the number of hydroxyl groups. The chelation studies were carried out by means of ultraviolet spectroscopy and electrospray ionisation mass spectrometry. Only flavones and the flavanol catechin interact with metal ions. At pH 7.4 and pH 5.5 all flavones studied appear to chelate Cu2+ at the same site, probably between the 5-hydroxyl and the 4-oxo groups. Myricetin and quercetin, however, at pH 7.4, appear to chelate Cu2+ additionally at the ortho-catechol group, the chelating site for catechin with Cu2+ at pH 7.4. Chelation studies of Fe3+ to flavonoids were investigated only at pH 5.5. Only myricetin and quercetin interact strongly with Fe3+, complexation probably occurring again between the 5-hydroxyl and the 4-oxo groups. Their behaviour can be explained by their ability to reduce Fe3+ at pH 5.5, suggesting that flavonoids reduce Fe3+ to Fe2+ before association.

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Most complexes of azides and transition metals involve the N 3Ϫ azide anion as a ligand other than an organic azide. Complexes of organic azides with metals are involved in biological applications and in the deposition of nitrenes on metal surfaces, producing nitride layers for semi-conductors preparation; this makes the study of these interactions an important issue. This work describes a study of the complexation of nickel and cobalt by 3-azidopropionitrile by means of electrospray ionization mass spectrometry (ESI-MS). Complexes were obtained from solutions of NiCl 2 and CoCl 2 in methanol/water. In the case of nickel, other NiX 2 salts were investigated (where X ϭ Br or NO 3 ) and other solvents were also studied (notably ethanol/water). All complexes detected were single positively charged, with various stoichiometries, some resulted from the fragmentation of the ligand, the loss of N 2 , and HCN being quite common. The most abundant cations observed were [Ni(II)AzAzX] ϩ , where X ϭ Cl, Br, NO 3 . Some of the complexes showed solvation with methanol/ethanol/water. Metal reduction was observed in complexes where a radical was lost, resulting from the homolytic cleavage of a metalOnitrogen bond. Collision induced dissociation (CID) experiments followed by tandem mass spectrometry (MS-MS) analysis were not absolutely conclusive about the coordination site. However, terminal ions observed from the fragmentation routes were explained by a proposed gas-phase mechanism. Density functional theory calculations were carried out and provided structures for some complexes, pointing to the possibility of 3-azidopropionitrile acting as a mono-or a bidentate ligand. (J Am Soc Mass Spectrom 2007, 18, 453-465)

The relevance of metal interactions with azides has led us to the study of the complexation of some transition metals, nickel and cobalt, by azidoacetone by means of electrospray ionization mass spectrometry (ESI-MS). Complexes were obtained from solutions of NiCl(2) and CoCl(2) , in methanol/water. Nickel was electrosprayed with other counter ion, bromide (Br), as well as other solvent (ethanol/water). For nickel and cobalt, the complexes detected were single positively charged, with various stoichiometries, some resulted from the fragmentation of the ligand, the loss of N(2) being quite common. The most abundant species were [Ni(II)Az(2)X](+) where X = Cl, Br and Az = azidoacetone. Some of the complexes showed solvation with the solvent components. Metal reduction was observed in complexes where a radical was lost, resulting from the homolytic cleavage of a metal coordination bond. Collision-induced dissociation (CID) experiments followed by tandem mass spectrometry (MS-MS) analysis were not absolutely conclusive about the coordination site. However, terminal ions of the fragmentation routes were explained by a gas-phase mechanism proposed where a C-C bond was activated and the metal inserted subsequently. Density functional theory calculations provided structures for some complexes. In [Ni(II)Az(2)X](+) species, one azidoacetone ligand is monodentate and the dominant binding location is the alkylated nitrogen and not the carbonyl group. The other azidoacetone ligand is bidentate showing coordination through alkylated nitrogen and the carbonyl group. These are also the preferential binding sites for the most stable isomer of [Ni(II)AzX](+) species.

The relative gas-phase acidities were determined for eight flavonoids, applying the kinetic method, by means of electrospray-ion trap mass spectrometry. The experimental acidity order, myricetin > luteolin > quercetin > (+/-)-taxifolin > kaempferol > apigenin > (+)-catechin > (+/-)-naringenin shows good agreement with the order obtained by theoretical calculations at the B3LYP/6-311 + G(2d,2p)//HF/6-31G(d) level. Moreover, these calculations provide the gas-phase acidities of the different OH groups for each flavonoid. The calculated acidity values (Delta(ac)H), corresponding to the most favorable deprotonation, cover a narrow range, 314.8-330.1 kcal/mol, but the experimental method is sensitive enough to differentiate the acidity of the various flavonoids. For all the flavones and the flavanol, catechin, the 4'-hydroxyl group is the most favored deprotonation site whereas for the flavanones studied, taxifolin and naringenin, the most acidic site is the 7-hydroxyl group. On the other hand, the 5-hydroxyl, in flavones and naringenin, and the 3-hydroxyl, in taxifolin and catechin, are always the less acidic positions. The acidity pattern observed for this family of compounds mainly depends on the following structural features: The ortho-catechol group, the 2,3 double bond and the 4-keto group.

The present work describes a study of the complexation of calcium and magnesium by 3-azidopropionitrile by means of electrospray ionization mass spectrometry (ESI-MS). Complexes were obtained from solutions of calcium and magnesium salts of the type CaX2 and MgX2 (where X = Cl or NO3) in water and methanol/water. The complexes detected were mainly double positively charged, with various stoichiometries not depending on the solvent, since water and 3-azidopropionitrile were always the main ligands. Solvation with methanol was not observed unlike in a previous study of complexation of nickel and cobalt by 3-azidopropionitrile. The complex ions [M(II)Az4(H2O)](2+), [M(II)Az5](2+) (where M = Ca and Mg) are the most abundant for both metals, and both counter ions. Tandem mass spectrometric (MS/MS) analysis showed that, under collision-induced dissociation (CID) conditions, the most important processes occurring were loss of neutral ligands and the replacement of 3-azidopropionitrile by water. A complex species containing reduced alkaline earth metal was due to radical loss, resulting from homolytic cleavage in the azide ligand. Some terminal ions, in the fragmentation sequences, point to the nitrile group as the coordination site in the 3-azidopropionitrile. Density functional theory (DFT) calculations confirmed this coordination site and proved that 3-azidopropionitrile behaves as a monodentate ligand in the systems under study. Moreover, the theoretical study proved that the presence of water ligand introduces stability through a hydrogen bond established between the water molecule and one nitrogen atom of the azido group. In addition, the strong dipole moment of 3-azidopropionitrile (4.76 D), which is mainly related to presence of the nitrile group, favors the stabilization of the metal-ligand complexes through charge-dipole interactions and the coordination of the metal to the nitrile group.

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