Isotope effects, dynamics, and the mechanism of solvolysis of aryldiazonium cations in water

The mechanism of the heterolytic solvolysis of p-tolyldiazonium cation in water was studied by a combination of kinetic isotope effects, theoretical calculations, and dynamics trajectories. Significant (13)C kinetic isotope effects were observed at the ipso (k(12)C/k(13)C = 1.024), ortho (1.017), and meta (1.013) carbons, indicative of substantial weakening of the C(2)-C(3) and C(5)-C(6) bonds at the transition state. This is qualitatively consistent with a transition state forming an aryl cation, but on a quantitative basis, simple S(N)1 heterolysis does not account best for the isotope effects. Theoretical S(N)2Ar transition structures for concerted displacement of N(2) by a single water molecule lead to poor predictions of the experimental isotope effects. The best predictions of the (13)C isotope effects arose from transition structures for the heterolytic process solvated by clusters of water molecules. These structures, formally saddle points for concerted displacements on the potential energy surface, may be described as transition structures for solvent reorganization around the aryl cation. Quasiclassical dynamics trajectories starting from these transition structures afforded products very slowly, compared to a similar S(N)2 displacement, and the trajectories often afforded long-lived aryl cation intermediates. Critical prior evidence for aryl cation intermediates is reconsidered with the aid of DFT calculations. Overall, the nucleophilic displacement process for aryldiazonium ions in water is at the boundary between S(N)2Ar and S(N)1 mechanisms, and an accurate view of the reaction mechanism requires consideration of dynamic effects.     

S-oxidation of thiazolidinedione with hydrogen peroxide, peroxynitrous acid, and C4a-hydroperoxyflavin: a theoretical study

Quantum chemical analysis was carried out to model metabolism of glitazone class of drugs through oxygen transfer process to the sulfur atom of thiazolidinedione ring with different oxidants such as H(2)O(2), HOONO, and C4a-hydroperoxyflavin. Complete optimization (geometric and energy parameters) of all the required structures and transition states on the reaction path was carried out using MP2(full)/6-31+G(d,p). Charge and second-order delocalization analyses of important structures were carried out using the NBO method. The effect of solvent on the oxygen transfer to sulfur of thiazolidinedione was studied by including one, two, or three explicit water molecules. These calculations revealed that explicit solvent (water) effectively contributed in the sulfoxidation of thiazolidinedione and led to remarkable reduction in the energy barrier by ～10 kcal/mol as compared to the gas phase. These results were found to be consistent with previously reported S-oxidation of dimethyl sulfide. When explicit water molecules were included, solvent molecules stabilize the charge separation at the transition state via specific interactions, and oxidation occurs via stretching of the O-O bond of oxidants and gradual formation of S-O bond. This study is helpful in understanding the metabolite generation due to the S-oxidation process in the glitazone series of antidiabetic drugs under physiological conditions.     

Mechanism of the oxidation of organic sulphides by permanganate ion

The kinetics of the oxidation of number of aryl methyl, alkyl phenyl, dialkyl and diphenyl sulphides by permanganate ion to yield the sulphoxides, have been studied. The reaction is first order with respect to the sulphide and permanganate and is independent of hydrogen ion concentration. The reaction exhibited negative polar reaction constants and a small degree of steric hindrance. The lack of solvent isotope effect and the observed solvent effect ( m = 0.39 for McSPh) are explained by an electrophilic attack of permanganate-oxygen on the sulphide yielding a polar transition state. A moderate anchimeric assistance was observed in the oxidation ofo-C00Me ando-C00H substituted methyl phenyl sulphide. A mechanism involving a one-step electrophilic oxygen transfer from permanganate ion to the sulphide and a polar product-like transition state, has been proposed.     

Bicarbonate surfoxidants: micellar oxidations of aryl sulfides with bicarbonate-activated hydrogen peroxide

The mechanism and kinetics of bicarbonate-catalyzed oxidations of sulfides by H(2)O(2) at the aqueous /cationic micellar interface have been investigated. The general term surfoxidant is introduced to describe the combination of an ionic surfactant with a reactive counterion that is itself an oxidant or activates an oxidant from the bulk solution to form an oxidant counterion. It is shown that the new catalytic cationic surfoxidant CTAHCO(3) (cetyltrimethylammonium bicarbonate) significantly enhances the overall oxidation rates as compared to the addition of bicarbonate salts to CTACl and CTABr, for which the halide counterions must undergo equilibrium displacement by the oxidant anion (peroxymonocarbonate, HCO(4)(-)). General equations based on the classic pseudophase model have been derived to account for the preequilibrium reaction in the aqueous and micellar phases, and the resulting model can be used to describe any micellar reaction with associated preequilibria. Rate constants and relevant equilibrium constants for HCO(4)(-) oxidations of aryl sulfides at micellar surfaces have been estimated for CTAHCO(3), CTACl, and CTABr. The second-order rate constants in the Stern layer (k(2)(m)) for sulfide oxidations by HCO(4)(-) are estimated to be approximately 50-fold (PhSEtOH) and approximately 180-fold (PhSEt) greater than the background rate constant k(m)(0) for oxidation by H(2)O(2) at the micellar surface. The estimated values of k(2)(m) are lower than the corresponding values in water by a factor of 20-70 depending on the substrate, but the high local concentration of the bicarbonate activator in the surfoxidant and the local accumulation of substrate as a result of strong binding to the micelle lead to a net increase in the observed reaction rates. Comparisons of CTAHCO(3)-activated peroxide to other highly reactive oxidants such as peroxymonosulfate (HSO(5)(-)) in aqueous surfactant media suggest a wide variety of potential applications for this green oxidant.     

An investigation by means of correlation analysis into the mechanisms of oxidation of aryl methyl sulfides and sulfoxides by dimethyldioxirane in various solvents

Relative rate constants have been measured for the oxidation of aryl methyl sulfides and sulfoxides by dimethyldioxirane in acetone, in mixtures of acetone with aprotic co-solvents of both higher and lower relative permittivity, and in aqueous acetone mixtures. Correlation analyses of the effects of substituents in the different solvents show that, with one exception, reactions take place via a single step mechanism in which the formation of the new SO bond and the elimination of acetone occur concertedly. The exception was oxidation of the sulfides in aqueous acetone containing the highest proportion of water of those studied (20% v/v). Here, the behaviour of the reaction is consistent with a two-step mechanism in which the oxidant reversibly attacks the sulfide to form an open-chain sulfonium betaine that subsequently fragments to sulfoxide and acetone. There is no evidence for the participation of an intermediate dioxathietane as has been found in the case of sulfide oxidations by (trifluoromethyl)methyldioxirane in CH(2)Cl(2) and similar aprotic solvents. It is not justified to generalise a mechanism involving a betaine, with or without a derived dioxathietane, to the reactions of dimethyldioxirane in acetone.     

Transition state differences in hydrolysis reactions of alkyl versus aryl phosphate monoester monoanions

Although aryl phosphates have been the subject of numerous experimental studies, far less data bearing on the mechanism and transition states for alkyl phosphate reactions have been presented. Except for esters with very good leaving groups such as 2,4-dinitrophenol, the monoanion of phosphate esters is more reactive than the dianion. Several mechanisms have been proposed for the hydrolysis of the monoanion species. (18)O kinetic isotope effects in the nonbridging oxygen atoms and in the P-O(R) ester bond, and solvent deuterium isotope effects, have been measured for the hydrolysis of m-nitrobenzyl phosphate. The results rule out a proposed mechanism in which the phosphoryl group deprotonates water and then undergoes attack by hydroxide. The results are most consistent with a preequilibrium proton transfer from the phosphoryl group to the ester oxygen atom, followed by rate-limiting P-O bond fission, as originally proposed by Kirby and co-workers in 1967. The transition state for m-nitrobenzyl phosphate (leaving group pK(a) 14.9) exhibits much less P-O bond fission than the reaction of the more labile p-nitrophenyl phosphate (leaving group pK(a) = 7.14). This seemingly anti-Hammond behavior results from weakening of the P-O(R) ester bond resulting from protonation, an effect which calculations have shown is much more pronounced for aryl phosphates than for alkyl ones.     

On the mechanisms of oxidation of organic sulfides by H2O2 in aqueous solutions

The mechanism of oxidation of organic sulfides in aqueous solutions by hydrogen peroxide was investigated via ab initio calculations. Specifically, two reactions, hydrogen transfer of hydrogen peroxide to form water oxide and the oxidation of dimethyl sulfide (DMS) by hydrogen peroxide to form dimethyl sulfoxide, were studied as models of these processes in general. Solvent effects are included both via including explicitly water molecules and via the polarizable continuum model. The former was found to have a much more significant effect than the latter. When explicit water molecules are included, a mechanism different from those proposed in the literature was found. Specific interactions including hydrogen bonding with 2-3 water molecules can provide enough stabilization for the charge separation of the activation complex. The energy barrier of the oxidation of DMS by hydrogen peroxide was estimated to be 12.7 kcal/mol, within the experimental range of the oxidation of analogous compounds (10-20 kcal/mol). The major reaction coordinates of the reaction are the breaking of the O-O bond of H2O2 and the formation of the S-O bond, the transfer of hydrogen to the distal oxygen of hydrogen peroxide occurring after the system has passed the transition state. Reaction barriers of the hydrogen transfer of H2O2 are an average of 10 kcal/mol or higher than the reaction barriers of the oxidation of DMS. Therefore, a two-step oxidation mechanism in which, first, the transfer of a hydrogen atom occurs to form water oxide and, second, the transfer of oxygen to the substrate occurs is unlikely to be correct. Our proposed oxidation mechanism does not suggest a pH dependence of oxidation rate within a moderate range around neutral pH (i.e., under conditions in which hydronium and hydroxide ions do not participate directly in the reaction), and it agrees with experimental observations over moderate pH values. Also, without including a protonated solvent molecule, it has activation energies that correspond to measured activation energies.     

The biological buffer bicarbonate/CO2 potentiates H2O2-mediated inactivation of protein tyrosine phosphatases

Hydrogen peroxide is a cell signaling agent that inactivates protein tyrosine phosphatases (PTPs) via oxidation of their catalytic cysteine residue. PTPs are inactivated rapidly during H(2)O(2)-mediated cellular signal transduction processes, but, paradoxically, hydrogen peroxide is a rather sluggish PTP inactivator in vitro. Here we present evidence that the biological buffer bicarbonate/CO(2) potentiates the ability of H(2)O(2) to inactivate PTPs. The results of biochemical experiments and high-resolution crystallographic analysis are consistent with a mechanism involving oxidation of the catalytic cysteine residue by peroxymonocarbonate generated via the reaction of H(2)O(2) with HCO(3)(-)/CO(2).     

Mechanistic studies of Ce(IV)-mediated oxidation of beta-dicarbonyls: solvent-dependent behavior of radical cation intermediates

The Ce(IV)-initiated oxidation of synthetically relevant beta-diketones and beta-keto silyl enol ethers was explored in three solvents: acetonitrile, methylene chloride, and methanol. The studies presented herein show that the rate of reaction between Ce(IV) and the substrates is dependent upon the polarity of the solvent. Thermochemical studies and analysis are interpreted to be consistent with transition state stabilization by solvent being primarily responsible for the rate of substrate oxidation. Kinetic investigation of radical cations obtained from oxidations of beta-diketones reveals that a more ordered transition state for the radical cation decay is achieved through the direct involvement of methanol in the deprotonation of the intermediate. In the case of radical cations derived from beta-keto silyl enol ethers, experimental data support a mechanism involving unimolecular decay of the intermediate. Remarkably, radical cations derived from beta-diketones and beta-keto silyl enol ethers are surprisingly stable in methylene chloride.     

Regioselective synthesis of 1,4‐disubstituted triazoles using bis[(L)prolinato‐N,O]Zn complex as an efficient catalyst in water as a sole solvent

A concise, convenient and mild route for one‐pot regioselective synthesis of N‐aryl‐ and N‐alkyltriazoles in water as a sole solvent is reported. The methodology involves a three‐component reaction comprising aryl/alkyl‐alkyne, sodium azide and aryl/alkyl/allyl halide catalyzed by zinc(II) L ‐prolinate. Prominent features of our protocol are incorporation of transition metal catalyst other than copper, water as the reaction medium, recyclability of catalyst and avoidance of hazardous aryl azide as a reactant. Copyright © 2011 John Wiley & Sons, Ltd.     

Copper-catalyzed asymmetric oxidation of sulfides

Copper-catalyzed asymmetric sulfoxidation of aryl benzyl and aryl alkyl sulfides, using aqueous hydrogen peroxide as the oxidant, has been investigated. A relationship between the steric effects of the sulfide substituents and the enantioselectivity of the oxidation has been observed, with up to 93% ee for 2-naphthylmethyl phenyl sulfoxide, in modest yield in this instance (up to 30%). The influence of variation of solvent and ligand structure was examined, and the optimized conditions were then used to oxidize a number of aryl alkyl and aryl benzyl sulfides, producing sulfoxides in excellent yields in most cases (up to 92%), and good enantiopurities in certain cases (up to 84% ee).     

Mechanistic study of protein phosphatase-1 (PP1), a catalytically promiscuous enzyme

The reaction catalyzed by the protein phosphatase-1 (PP1) has been examined by linear free energy relationships and kinetic isotope effects. With the substrate 4-nitrophenyl phosphate (4NPP), the reaction exhibits a bell-shaped pH-rate profile for kcat/KM indicative of catalysis by both acidic and basic residues, with kinetic pKa values of 6.0 and 7.2. The enzymatic hydrolysis of a series of aryl monoester substrates yields a Br?nsted beta(lg) of -0.32, considerably less negative than that of the uncatalyzed hydrolysis of monoester dianions (-1.23). Kinetic isotope effects in the leaving group with the substrate 4NPP are (18)(V/K) bridge = 1.0170 and (15)(V/K) = 1.0010, which, compared against other enzymatic KIEs with and without general acid catalysis, are consistent with a loose transition state with partial neutralization of the leaving group. PP1 also efficiently catalyzes the hydrolysis of 4-nitrophenyl methylphosphonate (4NPMP). The enzymatic hydrolysis of a series of aryl methylphosphonate substrates yields a Br?nsted beta(lg) of -0.30, smaller than the alkaline hydrolysis (-0.69) and similar to the beta(lg) measured for monoester substrates, indicative of similar transition states. The KIEs and the beta(lg) data point to a transition state for the alkaline hydrolysis of 4NPMP that is similar to that of diesters with the same leaving group. For the enzymatic reaction of 4NPMP, the KIEs are indicative of a transition state that is somewhat looser than the alkaline hydrolysis reaction and similar to the PP1-catalyzed monoester reaction. The data cumulatively point to enzymatic transition states for aryl phosphate monoester and aryl methylphosphonate hydrolysis reactions that are much more similar to one another than the nonenzymatic hydrolysis reactions of the two substrates.     

Mechanism of (Salen)manganese(III)‐Catalyzed Oxidation of Aryl Phenyl Sulfides with Sodium Hypochlorite

The oxidation of 4‐substituted phenyl phenyl sulfides was carried out with several oxo(salen)manganese(V) complexes in MeCN/H₂O 9 : 1. The kinetic data show that the reaction is first‐order each in the oxidant and sulfide. Electron‐attracting substituents in the sulfides and electron‐releasing substituents in salen of the oxo(salen)manganese(V) complexes reduce the rate of oxidation. A Hammett analysis of the rate constants for the oxidation of 4‐substituted phenyl phenyl sulfides gives a negative ρ value (ρ=?2.16) indicating an electron‐deficient transition state. The log k₂ values observed in the oxidation of each 4‐substituted phenyl phenyl sulfide by substituted oxo(salen)manganese(V) complexes also correlate with Hammett σ constants, giving a positive ρ value. The substituent‐, acid‐, and solvent‐effect studies indicate direct O‐atom transfer from the oxidant to the substrate in the rate‐determining step.     

Synthesis of dendritic oligo(aryl sulfone)s as supports for synthesis

A short, divergent route to G₁ oligo(aryl sulfone)s and a G₂ oligo(aryl sulfone) dendrimer using nucleophilic aromatic substitution reactions is described. A range of tetrasubstituted pentasulfones are proposed for applications as homogeneous supports for synthesis. Key to achieving selectivity in the syntheses is the activation of leaving groups by sulfide to sulfone oxidation. Preparation of the G₂ oligo(aryl sulfone) is low-yielding due to competition from SET processes that are interesting from a mechanistic point of view. The utility of the supports is exemplified with a four step synthesis of a dipeptide and by ‘react and release’ synthesis of amides.     

Mechanism of the sulfurisation of phosphines and phosphites using 3-amino-1,2,4-dithiazole-5-thione (xanthane hydride)

Contrary to a previous report, the sulfurisation of phosphorus(III) derivatives by 3-amino-1,2,4-dithiazole-5-thione (xanthane hydride) does not yield carbon disulfide and cyanamide as the additional reaction products. The reaction of xanthane hydride with triphenyl phosphine or trimethyl phosphite yields triphenyl phosphine sulfide or trimethyl thiophosphate, respectively, and thiocarbamoyl isothiocyanate which has been trapped with nucleophiles. The reaction pathway involves initial nucleophilic attack of the phosphorus at sulfur next to the thiocarbonyl group of xanthane hydride followed by decomposition of the phosphonium intermediate formed to products. The Hammett rho-values for the sulfurisation of substituted triphenyl phosphines and triphenyl phosphites in acetonitrile are approximately -1.0. The entropies of activation are very negative (-114+/-15 J mol-1 K-1) with little dependence on solvent which is consistent with a bimolecular association step leading to the transition state. The negative values of DeltaS(not equal) and rho values indicate that the rate limiting step of the sulfurisation reaction is formation of the phosphonium ion intermediate which has an early transition state with little covalent bond formation. The site of nucleophilic attack has been also confirmed using computational calculations.     

Titanium–salan‐catalyzed asymmetric sulfoxidations with H2O2: design of more versatile catalysts

Titanium–salan complexes with 3,3’‐diphenyl substituents in the salicylidene rings of the salan ligand are efficient sulfoxidation catalysts, capable of catalyzing the asymmetric oxidation of bulky aryl benzyl sulfides with H₂O₂ with good to high enantioselectivities. In this paper, substituent effects on titanium‐salan‐catalyzed enantioselective oxidation of sulfides to sulfoxides have been systematically investigated. Titanium–salan catalysts with halogen substituents at the 5,5’‐positions (3,3’‐H₂dihydrogen substituted) have been found to catalyze the oxidation of both bulky aryl benzyl sulfides and small alkyl phenyl sulfides with good to high enantioselectivities. Kinetic data witness a direct attack of the sulfide to the electrophilic active oxygen species; a consistent reaction mechanism is proposed. Copyright © 2013 John Wiley & Sons, Ltd.     

Asymmetric oxidation of sulfides catalyzed by chiral (salen)Mn(III) complexes with a pyrrolidine backbone

Catalytic properties of a series of chiral (pyrrolidine salen)Mn(III) complexes for asymmetric oxidation of aryl methyl sulfides were evaluated. Moderate activity, good chemical selectivity and low enantioselectivity were attained with iodosylbenzene as a terminal oxidant. Enantioselectivity of sulfide oxidation was affected slightly by polar solvent and the sulfoxidation carried out in THF for thioanisole and in CH₃CO₂Et for electron‐deficient sulfides gave better enatioselctivities. The addition of the donor ligand PPNO (4‐phenylpyridine N‐oxide) or MNO (trimethylamine N‐oxide) only has a minor positive effect on the enantioselectivity. Also explored was the steric effect of the N_aza‐substituent in the backbone of (pyrrolidine salen)Mn(III) complexes on the enantioselectivity of sulfide oxidation. The sulfides' access pathway is discussed based on the catalytic results. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of poly(aryl ether) dendrimers using an aryl carbonate and mixtures of metal carbonates and metal hydroxides

Four generations of poly(aryl ether) dendrimers containing aryl sulfide or aryl sulfone groups, and aryl fluoride terminal functionality, have been synthesized using the divergent initiator core method and bis(4-fluorophenyl) sulfone as the core precursor. The strategy is based on the divergent approach and an activation/condensation sequence that involves oxidation of the aryl sulfide group and the displacement of the activated halide moiety by a phenolate ion. The phenolate is easily generated in situ from an aryl carbonate. No reaction intermediates were detected when the condensation reaction was carried out utilizing a very active metal carbonate, such as cesium carbonate, in conjunction with magnesium hydroxide or calcium carbonate which removes some of the fluoride ions formed. The samples were characterized by HPLC, MALDI-TOF-MS, NMR, and SEC. Imperfections in some of the molecules of the dendrimers, formed by reaction of the core precusors with an impurity present in the phenol, were also identified by MALDI-TOF-MS. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35 : 1781–1798, 1997     

Kinetic studies on the oxidation of aryl methyl sulfides and sulfoxides by dimethyldioxirane; absolute rate constants and activation parameters for 4-nitrophenyl methyl sulfide and sulfoxide

The oxidations of methyl 4-nitrophenyl sulfide and sulfoxide by dimethyldioxirane, in acetone and mixtures of acetone with water, methanol, acetonitrile and hexane, have been followed by UV-Vis spectroscopy to monitor the decay of the substrates. The data show that, under all the conditions studied, both oxidations obey second-order kinetics. Grunwald-Winstein and Kamlet-Taft analyses of the influence of solvents on the second-order rate constants have been used to obtain mechanistic information on the two reactions. Activation parameters for the two oxidations in acetone and aqueous acetone have been calculated from rate constants for reactions in the temperature range 283-313 K and compared with those from sulfide and sulfoxide oxidations with other oxidants. For sulfoxide oxidations in acetone and 1-20% v/v water in acetone, the results support a concerted nucleophilic displacement by sulfur of oxygen from dimethyldioxirane with the rate being dependent on the solvent's polarity. Sulfide oxidations in acetone and 1-5% v/v water in acetone also proceed by a concerted mechanism. However, in the most polar solvent system studied, 20% v/v water in acetone, the mechanism changes in favour of a two-step reaction involving a betaine intermediate. Importantly, the sulfide oxidation shows a different solvent dependence to that of the sulfoxide, with the rate of oxidation being determined by the hydrogen bond donor capacity and electron-pair donicity of the solvent.     

On the role of the conserved aspartate in the hydrolysis of the phosphocysteine intermediate of the low molecular weight tyrosine phosphatase

The usual rate-determining step in the catalytic mechanism of the low molecular weight tyrosine phosphatases involves the hydrolysis of a phosphocysteine intermediate. To explain this hydrolysis, general base-catalyzed attack of water by the anion of a conserved aspartic acid has sometimes been invoked. However, experimental measurements of solvent deuterium kinetic isotope effects for this enzyme do not reveal a rate-limiting proton transfer accompanying dephosphorylation. Moreover, base activation of water is difficult to reconcile with the known gas-phase proton affinities and solution phase pK(a)'s of aspartic acid and water. Alternatively, hydrolysis could proceed by a direct nucleophilic attack by a water molecule. To understand the hydrolysis mechanism, we have used high-level density functional methods of quantum chemistry combined with continuum electrostatics models of the protein and the solvent. Our calculations do not support a catalytic activation of water by the aspartate. Instead, they indicate that the water oxygen directly attacks the phosphorus, with the aspartate residue acting as a H-bond acceptor. In the transition state, the water protons are still bound to the oxygen. Beyond the transition state, the barrier to proton transfer to the base is greatly diminished; the aspartate can abstract a proton only after the transition state, a result consistent with experimental solvent isotope effects for this enzyme and with established precedents for phosphomonoester hydrolysis.