Nature of the chain propagation in the photostimulated reaction of 1-bromonaphthalene with sulfur-centered nucleophiles

The reactivity of -SC(NH)NH2 (1), MeCOS- (2), and PhCOS- (3) toward 1-naphthyl radicals was studied in DMSO. The photostimulated reaction of anions 1, 2, and 3 with 1-bromonaphthalene (4) after quenching with MeI renders 1-(methylthio)naphthalene (6) as a main product together with bis(1-naphthyl) sulfide (7) and naphthalene (5). The thioacetate ion (2) and thiobenzoate ion (3) were unreactive toward 4 as electron-donor under photostimulation; however, in the presence of potassium tert-butoxide anion (entrainment conditions), they gave the mentioned products 5, 6, and 7, after the addition of MeI. Quenching of the triplet state of 4 was assigned as the photoinduced initiation step, with a rate constant value of (4.6+/-0.5)x10(8) M-1 s-1 for tert-butoxide anion and a rough estimated value of (8+/-7)x10(7) M-1 s-1 for anion 1. By using hydrogen abstraction from DMSO as the competitive reaction, the absolute rate constants for the addition of anions 1, 2, and 3 to 1-naphthyl radicals have been determined to be 1.0x10(9), 1.2x10(9), and 3.5x10(9) M-1 s-1, respectively. This reactivity order is in agreement with the stability of the resulting radical anions (ArNu)*- (10-12)*-. The inhibition experiments of the photoinduced substitution reaction in the presence of radical scavengers and the global quantum yield higher than the unity are evidence of a radical chain mechanism for these substitution reactions by anions 1 and 2. Anion 3 adds to the 1-naphthyl radical, but is neither able to initiate nor to keep the propagation cycle. Evaluation of the electron-transfer driving forces for the reaction between (ArNu)*- and 4 together with the absence of a chain reaction for the anion 3 indicate that the propagation in the proposed mechanism is given by an acid-base reaction between the radical .C(O)Me or .C(NH)NH2 (13) and a base.     

Reactions of 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulfonate) dianion, ABTS2-, with *OH, (SCN)2*-, and glycine or valine peroxyl radicals

ABTS2-, 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulfonate) dianion, was used as a reference to compare the reactivity of peroxyl radicals of two amino acids, glycine and valine, in aqueous solutions at natural pH. Peroxyl radicals were produced by pulse radiolysis and the product of their reaction with ABTS2- the ABTS*- radical was observed spectrophotometrically. Experimental kinetic traces were fitted using chemical simulation. The rate constants of reactions of glycine and valine peroxyl radicals with ABTS2- were (6.0+/-0.2)x10(6) and (1.3+/-0.1)x10(5) M-1.s-1, respectively. Moreover, it was found that only 60% of glycine radicals formed upon its reaction with *OH radicals reacted with molecular oxygen to yield peroxyl radicals. Comparison of experimental data with simulations of chemical reactions in irradiated ABTS and ABTS/NaSCN solutions showed that ABTS*- forms in the reaction with *OH with a yield of 43% and rate constant of (5.4+/-0.2)x10(9) M-1.s-1 and in the reaction with (SCN)2*- with a yield of 57% and rate constant of (8.0+/-0.2)x10(8) M-1.s-1.     

The role of geometry on regioselectivity and rate of fluorination of fluorene and diphenylmethane with Selectfluor F-TEDA-BF4

Diphenylmethane and fluorene were used as target molecules in an investigation of the effect of the geometry of aromatic molecules on the regioselectivity and rate of fluorination with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor F-TEDA-BF4). In acetonitrile at 80 degrees C ring fluorination of diphenylmethane was accompanied by oxidation of the saturated carbon atom, while in trifluoroacetic acid only ring fluorination with an ortho-para regioselectivity of 1.8:1 was observed. Fluorene was converted in acetonitrile as well as in trifluoroacetic acid into 2- and 4-fluoro substituted products in the relative ratio of 2:1 and 1.2:1, respectively. The reactions in acetonitrile obey a simple rate equation: v = d[F-TEDA]/dt = k2 x [F-TEDA] x [Substrate] and the second order rate constants for the reactions in acetonitrile at 65 degrees C were determined; values of 0.6 x 10(-4) M-1 s-1 for diphenylmethane and 35.5 x 10(-4) M-1 s-1 for fluorene were obtained. The reaction rates for the various functionalisations of fluorene relative to those for diphenylmethane were found to be considerably influenced by the type of functionalisation. Relative rate factors (k(rel) = k2(fluorene)/k2(diphenylmethane)) with values between 59 for fluorination and 712 for chlorination were determined, while the corresponding data for the biphenyl/diphenylmethane pair were only slightly dependent on the type of functionalisation. A reaction pathway involving electron transfer, thus forming cation radical intermediates, was proposed as the main process in the case of fluorination of fluorene with F-TEDA-BF4.     

Thermodynamics and kinetics of the nickel(II)-salicylhydroxamic acid system. Phenol rotation induced by metal ion binding

The kinetics and the equilibria of Ni(II) binding to p-hydroxybenzohydroxamic acid (PHBHA) and salicylhydroxamic acid (SHA) have been investigated in an aqueous solution at 25 degrees C and I=0.2 M by the stopped-flow method. Two reaction paths involving metal binding to the neutral acid and to its anion have been observed. Concerning PHBHA, the rate constants of the forward and reverse steps are k1=(1.9+/-0.1)x10(3) M-1 s-1 and k-1=(1.1+/-0.1)x10(2) s-1 for the step involving the undissociated PHBHA and k2=(3.2+/-0.2)x10(4) M-1 s-1 and k-2=1.2+/-0.2 s-1 for the step involving the anion. Concerning SHA, the analogous rate constants are k1=(2.6+/-0.1)x10(3) M-1 s-1, k-1=(1.3+/-0.1)x10(3) s-1, k2=(5.4+/-0.2)x10(3) M-1 s-1, and k-2=6.3+/-0.5 s-1. These values indicate that metal binding to the anions of the two acids concurs with the Eigen-Wilkins mechanism and that the phenol oxygen is not involved in the chelation. Moreover, a slow effect was observed in the SHA-Ni(II) system, which has been put down to rotation of the benzene ring around the C-C bond. Quantum mechanical calculations at the B3LYP/lanL2DZ level reveal that the phenol group in the most stable form of the Ni(II) chelate is in trans position relative to the carbonyl oxygen, contrary to the free SHA structure, where the phenol and carbonyl oxygen atoms both have cis configuration. These results bear out the idea that the complex formation is coupled with phenol rotation around the C-C bond.     

General method for determination of the activation,deactivation, and initiation rate constants in transition metal-catalyzed atom transfer radical processes

A general method for the determination of the activation (ka), deactivation (kd), and initiation (ki) rate constants in atom transfer radical processes is reported. The method involves the monomer trapping techniques and the analytical solution of the persistent radical effect. For tert-butyl 2-bromopropionate, using ATRP catalyst [CuI(dNbpy)2][Br] and methyl methacrylate in CH3CN at 22 degrees C, the values of ka, kd, and ki were determined to be (9.4 +/- 0.6) x 10-3 M-1 s-1, (8.5 +/- 1.2) x 106 M-1 s-1 and (5.5 +/- 0.9) x 104 M-1 s-1, respectively. The determined initiation rate constant was in good agreement with the literature value (6.0 x 104 M-1 s-1), confirming the validity of the proposed approach. For methyl 2-bromopropionate, under the same conditions, ka, kd, and ki values were found to be (26 +/- 5.9) x 10-3 M-1 s-1, (29 +/- 7.3) x 106 M-1 s-1, and (5.7 +/- 1.6) x 104 M-1 s-1, respectively.     

Reactions of radicals with hydrolyzed Bi(III) ions: a pulse radiolysis study

Radiolytic reduction of BiOClO4 in aqueous solutions leads to the formation of bismuth clusters and larger nanoparticles. The mechanisms of redox reactions of the polycationic Bi(III) species that exist in the solution were investigated with pulse radiolysis. The kinetic and spectral properties of the transients formed by the reaction of these species with the primary radicals from water radiolysis are reported. The single-electron reduction product, Bi9(OH)224+, absorbs at lambdamax = 273 nm, while the OH adduct, Bi9(OH)235+, has a broad absorption spectrum with a maximum at 280 nm and a shoulder at 420 nm. Several rate constants were measured: k (e-aq + Bi9(OH)225+) = 1.2 x 1010 M-1 s-1 and k (OH + Bi9(OH)225+) = 1.5 x 109 M-1 s-1. The reduced species, Bi9(OH)224+ further reacts with (CH3)2COH radicals, but not with CH2C(CH3)2OH radicals from t-butanol, to produce a doubly reduced polynuclear species. A few reactions of the reduction of the Bi salt in the presence of poly(acrylic acid) are also described. In the presence of the polymer, a metal-polymer complex is formed prior to the irradiation, and the reduction reactions are significantly slowed down.     

Isofagomine lactams,synthesis and enzyme inhibition

The synthesis of isofagomine lactams (2-oxoisofagomines) corresponding to the biologically important hexoses is presented. The D-glucose/D-mannose analogue (3S,4R,5R)-3,4-dihydroxy-5-hydroxymethylpiperidin-2-one (9) was synthesised in 9 steps from D-arabinose, the D-galactose analogue (3S,4S,5R)-3,4-dihydroxy-5-hydroxymethylpiperidin-2-one (10) was synthesised in 11 steps from D-arabinose and the L-fucose analogue (3R,4R,5R)-3,4-dihydroxy-5-methylpiperidin-2-one (11) was synthesised in 12 steps from L-arabinose. The three lactams 9-11 were found to be glycosidase inhibitors with micro- to nanomolar inhibition constants. The lactam 10 showed slow onset inhibition of beta-galactosidase from A. Oryzae. The rate constants for this process were determined to be k(on) = 2.55 x 10(4) M-1 s-1 and k(off) = 1.7 x 10(-3) s-1. The activation energies and standard thermodynamic functions were also determined.     

Kinetics and mechanism of acid-catalyzed oxidation of bromide ions by the aqueous chromyl(IV) ion

The reaction between the aqueous chromyl ion, CraqO2+, and Br- is acid-catalyzed and generates Br2. Kinetic studies that utilized a superoxochromium ion, CraqOO2+, as a kinetic probe yielded a mixed third-order rate law, -d[CraqO2+]/dt=k[CraqO2+][Br-][H+], where k=608+/-11 M-2 s-1. Experimental data strongly favor a one-electron mechanism, but the reaction is much faster than predicted on the basis of the reduction potential for the Br*/Br- couple. The reduction of CraqO2+ by transition-metal complexes, on the other hand, exhibits "normal" behavior, that is, k=(1.37x10(3)+1.94x10(3) [H+]) M-1 s-1 for Os(1,10-tris-phenanthroline)(3)2+ and <10 M-1 s-1 for Ru(2,2'-bipyridine)3(2+) at 0.1 M H+. The reduction of CraqOO2+ by Br2*- takes place with a rate constant k=(1.23+/-0.20)x10(9) M-1 s-1, as determined by laser-flash photolysis.     

Absolute rate constants for the quenching of reactive excited states by melanin and related 5,6-dihydroxyindole metabolites: implications for their antioxidant activity

The triplet-excited state of benzophenone and the singlet-excited state of 2,3-diazabicyclo[2.2.2]oct-2-ene (Fluorazophore-P) have been employed as kinetic probes to obtain information on the antioxidant activity of the skin and eye pigment melanin and its biogenetic precursors 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA). The excited states were generated by the laser-flash photolysis technique and their reaction kinetics was examined by time-resolved transient absorption or fluorescence spectroscopy, respectively. The reaction between triplet benzophenone and DHI produced with unit efficiency the corresponding 6O-centered semiquinone radical, which was characterized by its characteristic transient absorption. The quenching rate constants for DHI (3.1-8.4 x 10(9) M-1 s-1) and DHICA (3.3-5.5 x 10(9) M-1 s-1) were near the diffusion-controlled limit, indicating excellent antioxidant properties. Kinetic solvent effects were observed. The reactivity of synthetic melanin, assessed through the quenching rate constant of Fluorazophore-P and normalized to the number of monomer units, was more than one order of magnitude lower (2.7 x 10(8) M-1 s-1) than that of its precursors. The trend of the quenching rate constants, i.e. DHI > DHICA approximately alpha-tocopherol > melanin, along with the preferential solubility of DHICA in aqueous environments, serves to account for several experimental results from biochemical studies on the inhibition of lipid peroxidation by these natural antioxidants.     

Repair reactions of pyrimidine-derived radicals by aliphatic thiols

Pyrimidinyl radicals of various structures (Pyr*) were generated in aqueous and alcohol-containing solutions by means of pulse radiolysis to determine the rate constants of their repair reactions by different thiols (RSH = cysteamine, 2-mercaptoethanol, cysteine, and penicillamine): Pyr* + RSH --> PyrH + RS*. C5-OH and C6-OH adduct radicals of the pyrimidines react with thiols with k9 = (1.2-10.0) x 10(6) dm3 mol(-1) s(-1). Similar repair rate constants were found for uracil- and thymine-derived N1-centered radicals, k31 = (1.5-6.1) x 10(6) dm3 mol(-1) s(-1). However, pyrimidine radical anions protonated at their C6 position and C6-uracilyl radicals, with carbonyl groups at their C5 position, react with thiols faster, with k24 = (0.5-7.6) x 10(7) dm3 mol(-1) s(-1) and k14 = (1.4-4.8) x 10(7) dm3 mol(-1) s(-1), respectively. Quantum chemical calculations, at the B3LYP/6-31G(d,p) and self-consistent reaction field polarizable continuum model level point to the combined effects of the energy gap between interacting molecular orbitals, charge distribution within different pyrimidine-derived radicals, and the coefficients of the atomic orbitals as the possible reasons for the differences in the rate constants of repair.     

Rate and driving force for protonation of aryl radical anions in ethanol

Aryl radical anions created in liquid alcohols decay on the microsecond time scale by transfer of protons from the solvent. This paper reports a 4.5 decade range of rate constants for proton transfer from a single weak acid, ethanol, to a series of unsubstituted aryl radical anions, Ar-*. The rate constants correlate with free energy change, DeltaG(o), despite wide variations in the two factors that contribute to DeltaG(o): (a) the reduction potentials of the aryls and (b) the Ar-H* bond strengths in the product radicals. For aryl radical anions containing CH2OH substituents, such as 2,2'-biphenyldimethanol*- which is protonated with a rate constant of 3x10(9) s(-1), the faster rates do not fit well in the free energy correlation, suggesting a change in mechanism.     

Type I and type II photosensitization by the antibacterial drug nalidixic acid. A laser flash photolysis study.

The 355 nm laser flash photolysis of nalidixic acid at pH 9.2 leads to the formation of the nalidixate anion triplet state (absorption lambda max = 620 nm; 5700 less than or equal to epsilon T less than or equal to 9000 M-1cm-1; 0.6 less than or equal to phi T less than or equal to 1). The first order triplet state decay (kT = 7.7 x 10(3) s-1) is accompanied by a diffusion controlled triplet-triplet annihilation. Oxygen efficiently quenches the triplet state (k = 3.2 x 10(9) M-1s-1). The nalidixate radical dianion (absorption lambda max = 650 nm; epsilon = 3000 M-1cm-1) is produced by the diffusion controlled reductive quenching of the triplet state by tryptophan and tyrosine. The superoxide anion (O2-.) is produced by diffusion controlled reaction of the radical dianion with oxygen. The O2-. is characterized by its reactions with ferricytochrome c and superoxide dismutase. The physiological form of nalidixic acid is thus a good Type I and Type II photosensitizer.     

SINGLET AND TRIPLET REACTIVITY IN THE PHOTOREDUCTION OF OXONINE(3,7-DIAMINOPHENOXAZIN-5-IUM CHLORIDE) BY IRON (II)

The oxazine dye, oxonine (3,7-diaminophenoxazin-5-ium chloride), 1, is photoreduced by Fe (II) sulfate in dilute sulfuric acid. The reaction mechanism is analogous to that for the photo-reduction of thiazine dyes by Fe (II), the most important difference being that reduction of oxonine occurs predominantly from its excited singlet state, S1, rather than from the triplet state, T1. The latter is formed with an intersystem crossing (isc) quantum yield of ca 1.7 x 10(-3). The quenching of S1 by Fe (II) has a rate constant kSQ = 2.2 +/- 0.1 x 10(9) M-1 s-1 and affords the one electron reduced product, semioxonine (R), with a limiting quantum yield, phi SR, of 0.26 +/- 0.02. In contrast, quenching of T1, generated by bromide ion quenching of S1 or by diacetyl sensitization, occurs with KTQ approximately 1.2 x 10(6) M-1 s-1, extrapolated to zero ionic strength, and affords R with a limiting probability, phi TR = 1.1 +/- 0.2. Three possible reasons for the lower quantum yield of the more exothermic S1 reduction are discussed. These are energy transfer from S1 to Fe (II), different rates of escape of R from the encounter complex as a consequence of the different states of protonation of R as initially formed from S1 and T1, and spin allowed back electron transfer in an exciplex formed between S1 and Fe (II). Evidence is also presented for a very low probability (ca 1%) induced isc from the encounter of S1 with paramagnetic Fe (II). Rate parameters for other processes important to the overall reduction mechanism such as disproportionation of R to leucooxonine L and oxonine, k(R)DIS = 1.7 +/- 0.2 x 10(9) M-1 s-1, oxidation of R by Fe (III), k(R)OX = 1.5 +/- 0.1 x 10(5) M-1 s-1, and oxidation of L by Fe (III), kLOX = 1.1 +/- 0.1 x 10(3) M-1 s-1, have also been measured. These results are contrasted with those for the closely related thionine/Fe(II) photoredox reaction, the most well understood system for photogalvanic energy conversion.     

Electron transfer between guanosine radical and amino acids in aqueous solution. 1. Reduction of guanosine radical by tyrosine

As a model of chemical DNA repair, the reductive electron transfer from the aromatic amino acid tyrosine to the radical of the purine base guanosine monophosphate (GMP) was studied by time-resolved chemically induced dynamic nuclear polarization (CIDNP). The guanosyl radicals were photochemically generated in the quenching reaction of the triplet excited dye 2,2'-dipyridyl. Depending on the pH of the aqueous solution, four different guanosyl radicals were observed. The identification of the radicals was possible because of the high sensitivity of CIDNP to distinguish them through their ability or disability of participating in the degenerate electron hopping reaction with the diamagnetic molecules of guanosine monophosphate in the ground state. The CIDNP kinetics in this three-component system containing the dye, GMP, and N-acetyl tyrosine is strongly dependent on the efficiency of the electron-transfer reaction from tyrosine to the nucleotide radical. Quantitative analysis of the CIDNP kinetics obtained at different concentrations of the amino acid, together with the comparison with the CIDNP kinetics of the two-component systems (dipyridyl/tyrosine and dipyridyl/GMP) allowed for the determination of the rate constant ke of the reductive electron-transfer reaction for five pairs of reactants, with different protonation states depending on the pH: GH++*/TyrOH (pH 1.3), G+*/TyrOH (pH 2.9), G(-H)*/TyrOH (pH 7.5), G(-H)*/TyrO- (pH 11.3), and G(-2H)-*/TyrO- (pH 13.3). The rate constant ke varies from (7.1 +/- 3.0) x 10(8) M-1 s-1 (pH 1.3, 2.9) to less than 6 x 10(6) M-1 s-1 (pH 13.3).     

Kinetics and mechanism of peroxyl radical reactions with nitroxides

Cyclic nitroxides (>NO*) are stable radicals of diverse size, charge, lipophilicility, and cell permeability, which provide protection against oxidative stress via various mechanisms including SOD-mimic activity, oxidation of reduced transition metals and detoxification of oxygen- and nitrogen-centered radicals. However, there is no agreement regarding the reaction of nitroxides with peroxyl radicals, and many controversies in the literature exist. The question of whether nitroxides can protect by scavenging peroxyl radicals is important because peroxyl radicals are formed in biological systems. To further elucidate the mechanism(s) underlying the antioxidative effects of nitroxides, we studied by pulse radiolysis the reaction kinetics of piperidine, pyrrolidine, and oxazolidine nitroxides with several alkyl peroxyl radicals. It is demonstrated that nitroxides mainly reduce alkyl peroxyl radicals forming the respective oxoammonium cations (>N+=O). The most efficient scavenger of peroxyl radicals is 2,2,6,6-tetramethylpiperidine-N-oxyl (TPO), which has the lowest oxidation potential among the nitroxides tested in the present study. The rate constants of peroxyl reduction are in the order CH2(OH)OO*>CH3OO*>t-BuOO*, which correlate with the oxidation potential of these peroxyl radicals. The rate constants for TPO vary between 2.8x10(7) and 1.0x10(8) M-1 s-1 and for 3-carbamoylproxyl (3-CP) between 8.1x10(5) and 9.0x10(6) M-1 s-1. The efficacy of protection of nitroxides against inactivation of glucose oxidase caused by peroxyl radicals was studied. The results demonstrate a clear correlation between the kinetic features of the nitroxides and their ability to inhibit biological damage inflicted by peroxyl radicals.     

Tuning copper-dioxygen reactivity and exogenous substrate oxidations via alterations in ligand electronics

Copper(I)-dioxygen adducts are important in biological and industrial processes. For the first time we explore the relationship between ligand electronics, CuI-O2 adduct formation and exogenous substrate reactivity. The copper(I) complexes [CuI(R-MePY2)]+ (1R, where R = Cl, H, MeO, Me2N) were prepared; where R-MePY2 are 4-pyridyl substituted bis[2-(2-pyridyl)ethyl]methylamine chelates. Both the redox potential of 1R (ranging from E1/2 = -270 mV for 1Cl to -440 mV for 1MeN vs FeCp2/FeCp2+) and nuCO of the CO adducts of 1R (ranging from 2093 cm-1 for 1Cl-CO to 2075 cm-1 for 1Me2N-CO) display modest but expected systematic shifts. Dioxygen readily reacts with 1H, 1MeO, and 1Me2N, forming the side-on peroxo-CuII2 complexes [{CuII(R-MePY2)}2(O2)]2+ (2R, also containing some bis-mu-oxo-CuIII2 isomer), but there is no reaction with 1Cl. Stopped-flow studies in dichloromethane show that the formation of 2Me2N from dioxygen and 1Me2N proceeds with a k = 8.2(6) x 104 M-2 s-1 (183 K, DeltaH = -20.3(6) kJ mol-1, DeltaS = -219(3) J mol-1 K-1). Solutions of 2R readily oxidize exogenous substrates (9,10-dihydroanthracene --> anthracene, tetrahydrofuran (THF) --> 2-hydroxytetrahydrofuran (THF-OH), N,N-dimethylaniline --> N-methylaniline and formaldehyde, benzyl alcohol --> benzaldehyde, benzhydrol --> benzophenone, and methanol --> formaldehyde), forming the bis-mu-hydroxo-CuII2 complexes [{CuII(R-MePY2)(OH)}2]2+ (3R). Product yields increase as the R-group is made more electron-donating, and in some cases are quantitative with 2Me2N. Pseudo-first-order rate constants for THF and methanol oxidation reactions demonstrate a remarkable R-group dependence, again favoring the strongest ligand donor (i.e., R = Me2N). For THF oxidation to THF-OH a nearly 1500-fold increase in reaction rate is observed (kobs = 2(1) x 10-5 s-1 for 2H to 3(1) x 10-2 s-1 for 2Me2N), while methanol oxidation to formaldehyde exhibits an approximately 2000-fold increase (kobs = 5(1) x 10-5 s-1 for 2H to 1(1) x 10-1 s-1 for 2Me2N).     

On the mechanism of reaction of radicals with tirapazamine

Ketyl radicals produced by photolysis of ketones or di-tert-butyl peroxide (DTBP) in alcohol solvents react rapidly with tirapazamine (TPZ). The acetone ketyl radical (ACOH) reacts with TPZ with an absolute second-order rate constant of (9.7 +/- 0.4) x 108 M-1 s-1. The reaction kinetics can be followed by monitoring the bleaching of TPZ absorption at 475 nm or the formation of a reaction product which absorbs at 320 and 410 nm. The ACOD radical reacts with TPZ in 2-propanol-OD with an absolute rate constant of (6.7 +/- 0.5) x 108 M-1 s-1, corresponding to a kinetic isotope effect (KIE) of 1.4. Deuteration of the radical on carbon (ACOH-d6) retards the reaction of the radical with TPZ even further (absolute rate constant = (4.8 +/- 0.04) x 108 M-1 s-1). This result corresponds to a KIE of 2.0. Radicals derived from dioxane and diisopropyl ether by flash photolysis of DTBP in ethereal solvent react with TPZ more slowly than do ketyl radicals. It is concluded that ketyl radicals react, in part, with TPZ in organic solvents by transfer of a hydrogen atom from the OH and CH3 groups of the ketyl radical to the oxygen atom at the N4 position of TPZ to form acetone or acetone enol and a radical derivative of TPZ (TPZH). The latter species absorbs at 320 and 405 nm, has a lifetime of hundreds of microseconds in alcohol solvents, and decays by disproportionation to form TPZ and a reduced heterocycle. The reduced heterocycle eventually forms a desoxytirapazamine by a polar mechanism. The results are supported by density functional theory calculations. It is proposed that dioxanyl radical will also react, in part, with TPZ by transfer of a hydrogen atom from the carbon adjacent to the radical center to the oxygen atom at the N4 position of TPZ. This produces the enol ether and the previously mentioned TPZH radical. It is further posited that ether radicals react a bit more slowly than ketyl radicals because they lack the second mode of hydrogen transfer (from the OH group) that is present in the ACOH radical. Our data are permissive of the possibility that ether radicals add to TPZ at a rate that is competitive with beta-hydrogen atom transfer.     

Slowing of cisplatin aquation in the presence of DNA but not in the presence of phosphate: improved understanding of sequence selectivity and the roles of monoaquated and diaquated species in the binding of cisplatin to DNA

1H-15N HSQC NMR spectroscopy is used to study the aquation reactions of cisplatin in 9 mM NaClO4 and 9 mM phosphate (pH 6) solutions at 298 K. For the first time in a single reaction and, therefore, under a single set of reaction conditions, the amounts of all species formed are followed and the rates of aquation, diaquation, and related anation processes are determined in both media. Binding of phosphate to aquated Pt species is observed, but the initial rate of aquation is not affected by the presence of 9 mM phosphate. The reaction between cisplatin and the 14-base-pair self-complementary oligonucleotide 5'-d(AATTGGTACCAATT)-3', having a GpG intrastrand binding site, is investigated. Various kinetic models for this reaction are evaluated and the most appropriate found to be that with a reversible aquation step and a single binding site for the self-complementary duplex. The rate constant for aquation is (1.62 +/- 0.02) x 10(-5) s-1, with the anation rate constant fixed at 4.6 x 10(-3) M-1 s-1, the value obtained from the aquation studies. The rate constants for monofunctional binding of cis-[PtCl(15NH3)2-(OH2)]+ to the sequence were 0.48 +/- 0.19 and 0.16 +/- 0.06 M-1 s-1 for the 3'- and 5'-guanine bases, respectively. Closure rate constants for the monofunctional adducts are (2.55 +/- 0.07) x 10(-5) and (0.171 +/- 0.011) x 10(-5) s-1, for the 3'- and 5'-guanines, respectively. The presence of DNA slows the aquation of cisplatin by 30-40% compared to that observed in 9 mM NaClO4 or 9 mM phosphate, and there is some evidence that the degree of slowing is sequence dependent. The possibility that cis-[Pt(OH)(NH3)2(OH2)]+ contributes to the binding of cisplatin to DNA is investigated, and it is found that about 1% followed this route, the majority of the binding occurring via the monoaquated species cis-[PtCl(NH3)2(OH2)]+. Comparison of the rates of disappearance of cisplatin in reactions at single defined GpG, ApG, GpA, GpTpG and 1,2-interstrand GG binding sites shows that the adduct profile is determined at the level of monofunctional adduct formation.     

The unusual reaction of semiquinone radicals with molecular oxygen

Hydroquinones (benzene-1,4-diols) are naturally occurring chain-breaking antioxidants, whose reactions with peroxyl radicals yield 1,4-semiquinone radicals. Unlike the 1,2-semiquinone radicals derived from catechols (benzene-1,2-diols), the 1,4-semiquinone radicals do not always trap another peroxyl radical, and instead the stoichiometric factor of hydroquinones varies widely between 0 and 2 as a function of ring-substitution and reaction conditions. This variable antioxidant behavior has been attributed to the competing reaction of the 1,4-semiquinone radical with molecular oxygen. Herein we report the results of experiments and theoretical calculations focused on understanding this key reaction. Our experiments, which include detailed kinetic and mechanistic investigations by laser flash photolysis and inhibited autoxidation studies, and our theoretical calculations, which include detailed studies of the reactions of both 1,4-semiquinones and 1,2-semiquinones with O2, provide many important insights. They show that the reaction of O2 with 2,5-di-tert-butyl-1,4-semiquinone radical (used as model compound) has a rate constant of 2.4 +/- 0.9 x 10(5) M-1 s-1 in acetonitrile and as high as 2.0 +/- 0.9 x 10(6) M-1 s-1 in chlorobenzene, i.e., similar to that previously reported in water at pH approximately 7. These results, considered alongside our theoretical calculations, suggest that the reaction occurs by an unusual hydrogen atom abstraction mechanism, taking place in a two-step process consisting first of addition of O2 to the semiquinone radical and second an intramolecular H-atom transfer concerted with elimination of hydroperoxyl to yield the quinone. This reaction appears to be much more facile for 1,4-semiquinones than for their 1,2-isomers.     

Kinetic studies of a fast, reversible alkene radical cation cyclization reaction

The radical cation formed by mesylate heterolysis from the 1,1-dimethyl-7,7-diphenyl-2-mesyloxy-6-heptenyl radical was studied in several solvents. Computational results suggest that the initially formed acyclic radical cation is a resonance hybrid with partial positive charge in both double bonds of 1,1-diphenyl-7-methyl-1,6-octadiene (10). Thiophenol trapping was used as the competing reaction for kinetic determinations. The acyclic radical cation rapidly equilibrates with a cyclic distonic radical cation, and thiophenol trapping gives acyclic product 10 and cyclic products, mainly trans-1-(diphenylmethyl)-2-(1-methylethenyl)cyclopentane (11). The rate constants for cyclization at ambient temperature were k = (0.5-2) x 10(10)(s-1), and those for ring opening were k = (1.5-9) x 10(10)(s-1). Laser flash photolysis studies in several solvents show relatively slow processes (k = (2.5-260) x 10(5)(s-1) that involve rate-limiting trapping reactions for the equilibrating radical cations. In mixtures of fluoroalcohols RfCH2OH in trifluoromethylbenzene, variable-temperature studies display small, and in one case a negative, activation energies, requiring equilibration reactions prior to the rate-limiting processes. Fast equilibration of acyclic and cyclic radical cations implies that product ratios can be controlled by the populations of the acyclic and cyclic species and relative rate constants for trapping each.