Abstracts of our representative articles.
Risikat O. Ajibola and Reuben H. Simoyi.
S-Oxygenation of Thiocarbamides IV: Kinetics of Oxidation of Tetramethylthiourea by Aqueous Bromine and Acidic Bromate
Journal of Physical Chemistry A, 115, 2735-2744, 2011
The kinetics and mechanism of oxidation of tetramethylthiourea (TTTU) by bromine and acidic bromate has been studied in aqueous media. The kinetics of reaction of bromate with TTTU was characterized by an induction period followed by formation of bromine. The reaction stoichiometry was determined to be 4BrO3− + 3(R)2C═S + 3H2O → 4Br− + 3(R)2C═O + 3SO42− + 6H+. For the reaction of TTTU with bromine, a 4:1 stoichiometric ratio of bromine to TTTU was obtained with 4Br2 + (R)2C═S + 5H2O → 8Br− + SO42− + (R)2C═O + 10H+. The oxidation pathway went through the formation of tetramethythiourea sulfenic acid as evidenced by the electrospray ionization mass spectrum of the dynamic reaction solution. This S-oxide was then oxidized to produce tetramethylurea and sulfate as final products of reaction. There was no evidence for the formation of the sulfinic and sulfonic acids in the oxidation pathway. This implicates the sulfoxylate anion as a precursor to formation of sulfate. In aerobic conditions, this anion can unleash a series of genotoxic reactive oxygen species which can explain TTTU's observed toxicity. A bimolecular rate constant of 5.33 + 0.32 M−1 s−1 for the direct reaction of TTTU with bromine was obtained.
Itai Chipinda; Risikat O. Ajibola; Moshood M. Morakinyo; Tinashe B. Ruwona; Reuben H. Simoyi and Paul D. Siegel.
Rapid and Simple Kinetics Screening Assay for Electrophilic Dermal Sensitizers Using Nitrobenzenethiol
Chemical Research in Toxicology, 23
The need for alternatives to animal-based skin sensitization testing has spurred research on the use of in vitro, in silico, and in chemico methods. Glutathione and other select peptides have been used to determine the reactivity of electrophilic allergens to nucleophiles, but these methods are inadequate to accurately measure rapid kinetics observed with many chemical sensitizers. A kinetic spectrophotometric assay involving the reactivity of electrophilic sensitizers to nitrobenzenethiol was evaluated. Stopped-flow techniques and conventional UV spectrophotometric measurements enabled the determination of reaction rates with half-lives ranging from 0.4 ms (benzoquinone) to 46.2 s (ethyl acrylate). Rate constants were measured for seven extreme, five strong, seven moderate, and four weak/nonsensitizers. Seventeen out of the 23 tested chemicals were pseudo-first order, and three were second order. In three out of the 23 chemicals, deviations from first and second order were apparent where the chemicals exhibited complex kinetics whose rates are mixed order. The reaction rates of the electrophiles correlated positively with their EC3 values within the same mechanistic domain. Nonsensitizers such as benzaldehyde, sodium lauryl sulfate, and benzocaine did not react with nitrobenzenethiol. Cyclic anhydrides, select diones, and aromatic aldehydes proved to be false negatives in this assay. The findings from this simple and rapid absorbance model show that for the same mechanistic domain, skin sensitization is driven mainly by electrophilic reactivity. This simple, rapid, and inexpensive absorbance-based method has great potential for use as a preliminary screening tool for skin allergens.
Jeffrey L. Petersen, Adenike A. Otoikhian, Moshood K. Morakinyo, and Reuben H. Simoyi.
Organosulfur oxoacids. Part 2. A novel dimethylthiourea metabolite — Synthesis and characterization of the surprisingly stable and inert dimethylaminoiminomethane sulfonic acid
Chemical Research in Toxicology,
A new metabolite of the biologically active thiocarbamide dimethylthiourea (DMTU) has been synthesized and characterized. DMTU’s metabolic activation in the physiological environment is expected to be dominated by S-oxygenation, which produces, successively, the sulfenic, sulfinic, and sulfonic acids before forming sulfate and dimethylurea. Only the sulfinic and sulfonic acids are stable enough to be isolated. This manuscript reports on the first synthesis, isolation, and characterization of the sulfonic acid: dimethylaminoiminomethanesulfonic acid (DMAIMSOA). It crystallizes in the orthorhombic Pbca space group and exists as a zwitterion in its solid crystal form. The negative charge is delocalized over the sulfonic acid oxygens and the positive charge is concentrated over the planar N–C–N framework rather than strictly on the sp2-hybridized cationic carbon center. As opposed to its sulfinic acid analogue, DMAIMSOA is extremely inert in acidic environments and can maintain its titer for weeks at pH 6 and below. It is, however, reasonably reactive at physiological pH conditions and can be oxidized to dimethylurea and sulfate by mild oxidants such as aqueous iodine.
Moshood K. Morakinyo; Robert M. Strongin and Reuben H. Simoyi.
Modulation of Homocysteine Toxicity by S-Nitrosothiol Formation: A Mechanistic Approach
Journal of Physical Chemistry B, 114 (30),
The metabolic conversion of homocysteine (HCYSH) to homocysteine thiolactone (HTL) has been reported as the major cause of HCYSH pathogenesis. It was hypothesized that inhibition of the thiol group of HCYSH by S-nitrosation will prevent its metabolic conversion to HTL. The kinetics, reaction dynamics, and mechanism of reaction of HCYSH and nitrous acid to produce S-nitrosohomocysteine (HCYSNO) was studied in mildly to highly acidic pHs. Transnitrosation of this non-protein-forming amino acid by S-nitrosoglutathione (GSNO) was also studied at physiological pH 7.4 in phosphate buffer. In both cases, HCYSNO formed quantitatively. Copper ions were found to play dual roles, catalyzing the rate of formation of HCYSNO as well as its rate of decomposition. In the presence of a transition-metal ions chelator, HCYSNO was very stable with a half-life of 198 h at pH 7.4. Nitrosation by nitrous acid occurred via the formation of more powerful nitrosating agents, nitrosonium cation (NO+) and dinitrogen trioxide (N2O3). In highly acidic environments, NO+ was found to be the most effective nitrosating agent with a first-order dependence on nitrous acid. N2O3 was the most relevant nitrosating agent in a mildly acidic environment with a second-order dependence on nitrous acid. The bimolecular rate constants for the direct reactions of HCYSH and nitrous acid, N2O3, and NO+ were 9.0 x 10(-2), 9.50 x 10(3), and 6.57 x 10(10) M-1 s(-1), respectively. These rate constant values agreed with the electrophilic order of these nitrosating agents: HNO2 < N2O3 < NO+. Transnitrosation of HCYSH by GSNO produced HCYSNO and other products including glutathione (reduced and oxidized) and homocysteine-glutathione mixed disulfide. A computer modeling involving eight reactions gave a good fit to the observed formation kinetics of HCYSNO. This study has shown that it is possible to modulate homocysteine toxicity by preventing its conversion to a more toxic HTL by S-nitrosation.
Ruwona, T. B.; Johnson, V. J.; Schmechel, D.; Simoyi, R. H.; Beezhold, D. and Siegel, P. D.
Monoclonal Antibodies Against Toluene Diisocyanate Haptenated Proteins from Vapor-Exposed Mice
Hybridoma, 29 (3), 221-229
Toluene diisocyanate (TDI) is an industrially important polymer cross-linker used in the production of polyurethane. Workplace exposure to TDI and other diisocyanates is reported to be a leading cause of low molecular weight-induced occupational asthma (OA). Currently we have a limited understanding of the pathogenesis of OA. Monoclonal antibodies (MAbs) that recognize TDI bound proteins would be valuable tools/reagents, both in exposure monitoring and in TDI-induced asthma research. We sought to develop toluene diisocyanate (TDI)-specific MAbs for potential use in the development of standardized immunoassays for exposure and biomarker assessments. Mice were exposed 4 h/day for 12 consecutive weekdays to 50 ppb, 2,4; 2,6 TDI vapor (80/20 mixture). Splenocytes were isolated 24 h after the last exposure for hybridoma production. Hybridomas were screened in a solid-phase indirect enzyme-linked immunosorbent assay (ELISA) against a 2,4 TDI-human serum albumin (2,4 TDI-HSA) protein conjugate. Three hybridomas producing 2,4 TDI-HSA reactive IgM MAbs were obtained. The properties of these MAbs (isotype and reactivity to various protein-isocyanate conjugate epitopes) were characterized using ELISA, dot blot, and Western blot analyses. Western blot analyses demonstrated that some TDI conjugates form inter-and intra-molecular links, resulting in multimers and a change in the electrophoretic mobility of the conjugate. These antibodies may be useful tools for the isolation of endogenous diisocyanate-modified proteins after natural or experimental exposures and for characterization of the toxicity of specific dNCOs
Chikwana, E.; Davis, B.; Morakinyo, M. K. and
Simoyi, R. H.
Oxyhalogen-sulfur chemistry - Kinetics and mechanism of oxidation of methionine by aqueous iodine and acidified iodate
Canadian Journal of Chemistry-Revue Canadienne
de Chimie , 87 (6), 689-697
The oxidation of methionine (Met) by acidic iodate and aqueous iodine was studied. Though the reaction is a simple two-electron oxidation to give methionine sulfoxide (Met-S=O), the dynamics of the reaction are, however, very complex, characterized by clock reaction characteristics and transient formation of iodine. In excess methionine conditions, the stoichiometry of the reaction was deduced to be IO3- + 3Met -> I- + 3Met-S=O. In excess iodate, the iodide product reacts with iodate to give a final product of molecular iodine and a 2:5 stoichiometry: 2IO(3)(-) + 5Met + 2H(+) -> I-2 + 5Met-S=O + H2O. The direct reaction of iodine and methionine is slow and mildly autoinhibitory, which explains the transient formation of iodine, even in conditions of excess methionine in which iodine is not a final product. The whole reaction scheme could be simulated by a simple network of 11 reactions.
Itai Chipinda, Justin M. Hettick, Paul D. Siegel and Reuben Simoyi
Zinc diethyldithiocarbamate allergenicity: potential haptenation mechanisms
Contact Dermatitis, 5
Background: Zinc diethyldithiocarbamate (ZDEC) and its disulfide, tetraethylthiuram disulfide (TETD), are rubber accelerators and contact allergens that cross-react in some individuals. Objective: This study explored potential protein haptenation mechanisms of ZDEC and its oxidation products. Methods: ZDEC oxidation/reduction products and sites of protein binding were assessed using high-performance liquid chromatography and mass spectrometry. The murine local lymph node assay (LLNA) was employed to probe haptenation mechanisms of ZDEC by examining its allergenicity along with its oxidation products and through elimination of oxidation and chelation mechanisms by substituting cobalt for zinc [cobalt (II) dithiocarbamate, CoDEC]. Results: Oxidation of ZDEC by hypochlorous acid (bleach, HOCl), iodine, or hydrogen peroxide resulted in production of TETD, tetraethylthiocarbamoyl disulfide, and tetraethyldicarbamoyl disulfide (TEDCD). Albumin thiols reduced TETD with subsequent mixed disulfide formation/haptenation. ZDEC directly chelated the copper ion on the active site of the superoxide dismutase, whereas CoDEC did not bind to Cu proteins or form mixed disulfides with free thiols. ZDEC, sodium diethyldithiocarbamate, TEDCD, and TETD were all positive in the LLNA except CoDEC, which was non-allergenic. Conclusion: The thiol is the critical functional group in ZDEC's allergenicity, and haptenation is predominantly through chelation of metalloproteins and formation of mixed disulfides.
Itai Chipinda, Xing-Dong Zhang, Paul D. Siegel and Reuben Simoyi
Mercaptobenzothiazole allergenicity - role of the thiol group
Cutaneous and Ocular Toxicology,
The rubber accelerator, 2-mercaptobenzothiazole (MBT), is known to cause allergic contact dermatitis (ACD), but the mechanism is unknown. The role of the thiol group in MBT's allergenicity was investigated in the present study. Guinea pigs were sensitized to MBT using a modified guinea pig maximization test (GPMT) and reactivity was assessed toward 2-mercaptobenzothiazole disulfide (MBTS), 2-hydroxybenzothiazole (HBT; thiol-substituted), 2-(methylthio)benzothiazole (MTBT; thiol-blocked), and benzothiazole (BT; thiol-lacking). MBT and MBTS, but not BT, HBT, or MTBT, elicited ACD in MBT-sensitized animals, demonstrating that the thiol group is critical to MBT's allergenicity. In addition, both MBT and MBTS were shown to inhibit both glutathione reductase and thioredoxin reductase, and thus contribute to the stability of MBT-protein mixed disulfides. It is concluded that the probable haptenation mechanism of MBT is through initial oxidation to MBTS with subsequent reduction to form mixed disulfides with proteins
Oxyhalogen-sulfur chemistry - Kinetics and mechanism of the bromate oxidation of cysteamine
Canadian Journal of Chemistry-Revue Canadienne De Chimie, 86(5), 416-425, 2008
The kinetics and mechanism of the oxidation of the biologically important molecule, cysteamine, by acidic bromate and molecular bromine have been studied. In excess acidic bromate conditions, cysteamine is oxidized to N-brominated derivatives, and in excess cysteamine the oxidation product is taurine according to the following stoichiometry: BrO3- + H2NCH2CH2SH → H2NCH2CH2SO3H + Br-. There is quantitative formation of taurine before N-bromination commences. Excess aqueous bromine oxidizes cysteamine to give dibromotaurine: 5Br2 + H2NCH2CH2SH + 3H2O → Br2NCH2CH2SO3H + 8Br- + 8H+, while excess cysteamine conditions gave monobromotaurine. The oxidation of cysteamine by aqueous bromine is effectively diffusion-controlled all the way to the formation of monobromotaurine. Further formation of dibromotaurine is dependent on acid concentrations, with highly acidic conditions inhibiting further reaction towards formation of dibromotaurine. The formation of the N-brominated derivatives of taurine is reversible, with taurine regenerated in the presence of a reducing agent such as iodide. This feature makes it possible for taurine to moderate hypobromous acid toxicity in the physiological environment.
Itai Chipinda, Justin M. Hettick, Paul D. Siegel and Reuben Simoyi
Oxidation of 2-Mercaptobenzothiazole in Latex Gloves and Its Possible Haptenation Pathway
Chem. Res. Toxicol.,
The rubber accelerator, 2-mercaptobenzothiazole (MBT), has been reported to cause allergic contact dermatitis from gloves and other rubber products, but its chemical fate when exposed to occupational oxidants and the mechanism of its pathogenesis are not known. It was hypothesized that the thiol group is critical to MBT’s (its oxidation products or metabolites) covalent binding and/or haptenation to nucleophilic protein residues. Oxidative transformation of MBT to the disulfide 2,2′-dithiobis(benzothiazole) (MBTS) was observed within the glove matrix when hypochlorous acid, iodine, and hydrogen peroxide were used as oxidants. Cysteine reduced MBTS to MBT with subsequent formation of the mixed disulfide 2-amino-3-(benzothiazol-2-yl disulfanyl)propionic acid which was identified and characterized. Spectrophotometry and mass spectrometry experiments demonstrated the simultaneous reduction of MBTS and disulfide formation with Cys34 on bovine serum albumin, suggesting a potential route of protein haptenation through covalent bonding between protein cysteinyl residues and the MBT/MBTS thiol moiety. Metabolism of MBT using isoniazid and dexamethasone-induced rat liver microsomes, to give a protein reactive epoxide intermediate and provide an alternative protein haptenation mechanism, was not observed. The data suggest that the critical functional group on MBT is the thiol, and haptenation is via the formation of mixed disulfides between the thiol group on MBT and a protein sulfhydryl group.
Tabitha R. Chigwada,
S-Oxygenation of Thiocarbamides. 3. Nonlinear Kinetics in the Oxidation of Trimethylthiourea by Acidic Bromate
J. Phys. Chem. A,
The oxidation of trimethylthiourea (TMTU) by acidic bromate has been studied. The reaction mimics the dynamics observed in the oxidation of unsubstituted thiourea by bromate with an induction period before formation of bromine. The stoichiometry of the reaction was determined to be 4:3, thus 4BrO3- + 3R1R2C=S+ 3H2O → 4Br- + 3R1R2C=O + 3SO42- + 6H+. This substituted thiourea is oxidized at a much faster rate than the unsubstituted thiourea. The oxidation mechanism of TMTU involves initial oxidations through sulfenic and sulfinic acids. At the sulfinic acid stage, the major oxidation pathway is through the cleavage of the C-S bond to form a reducing sulfur leaving group, which is easily oxidized to sulfate. The minor pathway through the sulfonic acid produces a very stable intermediate that is oxidized only very slowly to urea and sulfate. The direct reaction of aqueous bromine with TMTU was faster than reactions that form bromine, with a bimolecular rate constant of (1.50 ± 0.04) × 102 M-1 s-1. This rapid reaction ensured that no oligooscillatory bromine formation was observed. The oxidation of TMTU was modeled by a simple reaction scheme containing 20 reactions.
Itai Chipinda and Reuben Simoyi
Formation and Stability of a Nitric Oxide Donor: S-Nitroso-N-acetylpenicillamine
J. Phys. Chem. B, 110 (10), 5052 -5061, 2006
The formation, reaction dynamics, and detailed kinetics and mechanism of the reaction between nitrous acid and N-acetylpenicillamine (NAP) to produce S-nitroso-N-acetylpenicillamine (SNAP) was studied in acidic medium. The nitrous acid was prepared in situ by the rapid reaction between sodium nitrite and hydrochloric acid. The reaction is first order in nitrite and NAP. It is also first order in acid in pH conditions at or slightly higher than the pKa of nitrous acid. In lower pH conditions, the catalytic effect of acid quickly saturates. Higher acid concentrations also induce a faster decomposition rate of the SNAP, thus precluding the quantitative formation of SNAP from HNO2 and NAP. Both HPLC and quadrupole time-of-flight mass spectrometry techniques proved that SNAP was the sole product produced. No nitrosation occurred on the secondary amine center in NAP, and only the thiol group reacted to form the nitrosothiol. Cu(I) ions were found to be effective SNAP-decomposition catalysts. Cu(II) ions had no effect on the stability of SNAP. Ambient oxygen in reaction solutions was found to have no effect on initial rates of formation of SNAP, products obtained, and stability of SNAP. The formation of SNAP occurs through two distinct pathways. One involves the direct reaction of NAP and HNO2 to form SNAP and eliminate water, and the second pathway involved the initial formation of the nitrosyl cation, NO+, which then nitrosates the thiol. The bimolecular rate constant for the reaction of NAP and HNO2 was derived as 2.69 M-1 s-1, while that of direct nitrosation by the nitrosyl cation was 3.00 × 104 M-1 s-1. A simple reaction network made up of four reactions was found to be sufficient in simulating the formation kinetics and acid-induced decomposition of SNAP.
Olufunke Olagunju, Paul D. Siegel, Rotimi Olojo, and Reuben H. Simoyi
Oxyhalogen-Sulfur Chemistry: Kinetics and Mechanism of Oxidation of N-Acetylthiourea by Chlorite and Chlorine Dioxide
J. Phys. Chem. A, 110 (7), 2396 -2410, 2006
The oxidation reactions of N-acetylthiourea (ACTU) by chlorite and chlorine dioxide were studied in slightly acidic media. The ACTU-ClO2- reaction has a complex dependence on acid with acid catalysis in pH > 2 followed by acid retardation in higher acid conditions. In excess chlorite conditions the reaction is characterized by a very short induction period followed by a sudden and rapid formation of chlorine dioxide and sulfate. In some ratios of oxidant to reductant mixtures, oligo-oscillatory formation of chlorine dioxide is observed. The stoichiometry of the reaction is 2:1, with a complete desulfurization of the ACTU thiocarbamide to produce the corresponding urea product: 2ClO2- + CH3CONH(NH2)C=S + H2O CH3CONH(NH2)C=O + SO42- + 2Cl- + 2H+ (A). The reaction of chlorine dioxide and ACTU is extremely rapid and autocatalytic. The stoichiometry of this reaction is 8ClO2(aq) + 5CH3CONH(NH2)C=S + 9H2O 5CH3CONH(NH2)C=O + 5SO42- + 8Cl- + 18H+ (B). The ACTU-ClO2- reaction shows a much stronger HOCl autocatalysis than that which has been observed with other oxychlorine-thiocarbamide reactions. The reaction of chlorine dioxide with ACTU involves the initial formation of an adduct which hydrolyses to eliminate an unstable oxychlorine intermediate HClO2- which then combines with another ClO2 molecule to produce and accumulate ClO2-. The oxidation of ACTU involves the successive oxidation of the sulfur center through the sulfenic and sulfinic acids. Oxidation of the sulfinic acid by chlorine dioxide proceeds directly to sulfate bypassing the sulfonic acid. Sulfonic acids are inert to further oxidation and are only oxidized to sulfate via an initial hydrolysis reaction to yield bisulfite, which is then rapidly oxidized. Chlorine dioxide production after the induction period is due to the reaction of the intermediate HOCl species with ClO2-. Oligo-oscillatory behavior arises from the fact that reactions that form ClO2 are comparable in magnitude to those that consume ClO2, and hence the assertion of each set of reactions is based on availability of reagents that fuel them. A computer simulation study involving 30 elementary and composite reactions gave a good fit to the induction period observed in the formation of chlorine dioxide and in the autocatalytic consumption of ACTU in its oxidation by ClO2.
Adenike Otoikhian and Reuben H. Simoyi
Oxidation of a Dimethylthiourea Metabolite by Iodine and Acidified Iodate: N,N'-Dimethylaminoiminomethanesulfinic Acid
Chem. Res. Toxicol., 18 (7), 1167 -1177, 2005
The two major metabolites after S-oxygenation of dimethylthiourea (dimethylaminoiminomethane sulfinic acid, DMAIMSA, and dimethylaminoiminomethane sulfonic acid, DMAIMSOA) were synthesized and tested for their reactivities in the presence of mild oxidants, aqueous iodine and acidic iodate. The stoichiometry of the iodate-DMAIMSA reaction is 2IO3- + 3NHCH3(=NCH3)CSO2H + 3H2O 3SO42- + 2I- + 3CO(NHCH3)2 + 6H+ (A). The reaction commences with immediate formation of aqueous iodine, which is produced from the reaction between the iodide product of stoichiometry (A) and reactant iodate. The instant accumulation of aqueous iodine is due to the very slow reaction of iodine with both DMAIMSA and DMAIMSOA. In excess iodate over that required for stoichiometry (A), the stoichiometry of the reaction is 4IO3- + 5NHCH3(=NCH3)CSO2H + 3H2O 5SO42- + 2I2 + 5CO(NHCH3)2 + 6H+ (B). Even though excess DMAIMSA solutions do not afford iodine, the initial rapid formation of iodine is still observed, which reaches a peak and then decays to conform to stoichiometry (A). The maximum transient iodine concentrations obtained are directly proportional to the acid concentrations because acid catalyzes formation of iodine and retards reactions that consume iodine. The zwitterionic forms of DMAIMSA and DMAIMSOA are very stable in acid, and DMAIMSOA, especially, is very inert and unreactive in low pH environments. The predominant pathway for the oxidation of DMAIMSOA is through an initial hydrolysis reaction to yield bisulfite and dimethylurea, while the oxidation of DMAIMSA proceeds through DMAIMSOA as well as through an early heterolytic cleavage of the C-S bond to produce a highly reducing sulfoxylate species, SO22-, which is later rapidly oxidized to sulfate. In aerobic conditions, the sulfoxylate species reacts with molecular oxygen to produce superoxide anion radical, which in turn will form hydrogen peroxide and hydroxyl radicals which will bring with them inadvertent genotoxicity.
Tabitha R. Chigwada, Edward Chikwana, and Reuben H. Simoyi
S-Oxygenation of Thiocarbamides I: Oxidation of Phenylthiourea by Chlorite in Acidic Media
J. Phys. Chem. A, 109 (6), 1081 -1093, 2005
The oxidation of 1-phenyl-2-thiourea (PTU) by chlorite was studied in aqueous acidic media. The reaction is extremely complex with reaction dynamics strongly influenced by the pH of reaction medium. In excess chlorite concentrations the reaction stoichiometry involves the complete desulfurization of PTU to yield a urea residue and sulfate: 2ClO2- + PhN(H)CSNH2 + H2O SO42- + PhN(H)CONH2 + 2Cl- + 2H+. In excess PTU, mixtures of sulfinic and sulfonic acids are formed. The reaction was followed spectrophotometrically by observing the formation of chlorine dioxide which is formed from the reaction of the reactive intermediate HOCl and chlorite: 2ClO2- + HOCl + H+ 2ClO2(aq) + Cl- + H2O. The complexity of the ClO2- - PTU reaction arises from the fact that the reaction of ClO2 with PTU is slow enough to allow the accumulation of ClO2 in the presence of PTU. Hence the formation of ClO2 was observed to be oligooscillatory with transient formation of ClO2 even in conditions of excess oxidant. The reaction showed complex acid dependence with acid catalysis in pH conditions higher than pKa of HClO2 and acid retardation in pH conditions of less than 2.0. The rate of oxidation of PTU was given by -d[PTU]/dt = k1[ClO2-][PTU] + k2[HClO2][PTU] with the rate law: -d[PTU]/dt = [Cl(III)]T[PTU]0/Ka1 + [H + ] [k1Ka1 + k2[H + ]]; where [Cl(III)]T is the sum of chlorite and chlorous acid and Ka1 is the acid dissociation constant for chlorous acid. The following bimolecular rate constants were evaluated; k1 = 31.5±2.3 M-1 s-1 and k2 = 114±7 M-1 s-1. The direct reaction of ClO2 with PTU was autocatalytic in low acid concentrations with a stoichiometric ratio of 8:5; 8ClO2 + 5PhN(H)CSNH2 + 9H2O 5SO42- + 5PhN(H)CONH2 + 8Cl- + 18H+. The proposed mechanism implicates HOCl as a major intermediate whose autocatalytic production determined the observed global dynamics of the reaction. A comprehensive 29-reaction scheme is evoked to describe the complex reaction dynamics.
Rotimi Olojo and Reuben H. Simoyi
Oxyhalogen-Sulfur Chemistry: Kinetics and Mechanism of the Oxidation of Thionicotinamide by Peracetic Acid
J. Phys. Chem. A, 108 (6), 1018 -1023, 2004
The kinetics and mechanism of oxidation of an important xenobiotic, thionicotinamide (TNA), using peracetic acid in slightly acidic media were studied by spectrophotometric techniques. The reaction is characterized by a very rapid initial oxidation of the sulfur atom of the thioamide group to the S-oxide, followed by a much slower decomposition of the S-oxide to form additional oxidation products, mainly the thionicotinamide sulfinic acid. In excess thionicotinamide, the stoichiometry of the reaction was determined to be CH3CO3H + (C5H5N)C(=S)NH2 (C5H5N)C(=NH)SOH + CH3COOH, whereas in excess peracetic acid the stoichiometry was 2:1, 2CH3CO3H + (C5H5N)C(=S)NH2 + H2O (C5H5N)C(=NH)SO2H + 2CH3COOH + 2H+. The sulfoxide is quite stable, but there was no experimental evidence for the existence of any stable sulfone-sulfonic acid intermediates. Results show that the sulfur atom in thionicotinamide is the reactive center, undergoing a stepwise addition of oxygen to form successively the sulfenic acid and the sulfinic acid. There appeared to be no further oxidation past the sulfinic acid and no formation of sulfate was observed. A bimolecular rate constant of (1.1 ± 0.3) × 103 M-1 s-1 was evaluated for initial rapid formation of the S-oxide, and an upper limit rate constant of 0.10 ± 0.02 M-1 s-1 was evaluated for the slower decomposition of the S-oxide.
Edward Chikwana and Reuben H. Simoyi
Oxyhalogen-Sulfur Chemistry: Kinetics and Mechanism of Oxidation of Amidinothiourea by Acidified Iodate
J. Phys. Chem. A, 108 (6), 1024 -1032, 2004
The oxidation of guanylthiourea, GTU, by mildly acidic iodate and molecular iodine has been studied. Its reaction with iodate shows an oligooscillatory formation and consumption of iodine in batch conditions. The major oxidation product is a ring-cyclized product of guanylthiourea, 3,5-diamino-1,2,4-thiadiazole (GTU-C), in which the thioureado moiety is oxidized to the unstable sulfenic acid that instantly attacks the distal amino group, eliminating water and forming the five-membered thiadiazole group. In excess GTU conditions, the stoichiometry of the reaction was 1:3 without any further oxidation past a 2-electron transfer, IO3- + 3H2NC(=NH)NH(C=S)NH2 I- + 3GTU-C + 3H2O, whereas in excess iodate conditions the stoichiometry is 2IO3- + 5H2NC(=NH)NH(C=S)NH2 + 2H+ 5GTU-C + I2(aq) + 6H2O. In high acid environments the reaction shows two peaks in iodine concentrations in batch conditions, and at lower acid concentrations one observes an induction period followed by a monotonic formation of iodine according to the Dushman reaction. The overall reaction is heavily catalyzed by iodide. The direct reaction of iodine and GTU is fast, with a bimolecular rate constant of (1.10 ± 0.20) × 104 M-1 s-1. This reaction is autoinhibitory with the product, iodide, inhibiting the reaction by forming the relatively inert I3- species. Acid also inhibits the oxidation of GTU by iodine by protonating the thiol group, thereby reducing its nucleophilicity. A simple mechanistic scheme comprising 9 elementary and composite reactions was found to be adequate in explaining the full reaction scheme
Nicholas Madhiri, Rotimi Olojo and Reuben H. Simoyi
Oxyhalogen–sulfur chemistry: kinetics and mechanism of oxidation of formamidine disulfide by acidic bromate
Physical Chemistry Chemical Physics, 2003, 5, 4149 - 4156
The kinetics and mechanism of the oxidation of formamidine disulfide, FDS, a dimer and major metabolite of thiourea, by bromate have been studied in acidic media. In excess bromate conditions the reaction displays an induction period before formation of bromine. The stoichiometry of the reaction is: 7BrO3–+3[(H2N(HN)CS–]2+9H2O6NH2CONH2+6SO42–+7Br–+12H+(A). In excess oxidant conditions, however, the bromide formed in reaction A reacts with bromate to give bromine and a final stoichiometry of: 14BrO3–+5[(H2N(HN)CS–]2+8H2O10NH2CONH2+10SO42–+7Br2+6H+(B). The direct reaction of bromine and FDS was also studied and its stoichiometry is: 7Br2+[(H2N(HN)CS–]2+10H2O2NH2CONH2+2SO42–+14Br–+18H+(C). The overall rate of reaction A, as measured by the rate of consumption of FDS, is second order in acid concentrations, indicating the dominance of oxyhalogen kinetics which control the formation of the reactive species HBrO2 and HOBr. The reaction proceeds through an initial cleavage of the S–S bond to give the unstable sulfenic acids which are then rapidly oxidized through the sulfinic and sulfonic acids to give sulfate. The formation of bromine coincides with formation of sulfate because the cleavage of the C–S bond to give sulfate occurs at the sulfonic acid stage only. The mechanism derived is the same as that derived for the bromate–thiourea reaction, suggesting that FDS is an intermediate in the oxidation of thiourea to its oxo-acids as well as to sulfate.
James Darkwa, Rotimi Olojo, Olufunke Olagunju, Adenike Otoikhian, and Reuben Simoyi
Oxyhalogen-Sulfur Chemistry: Oxidation of N-Acetylcysteine by Chlorite and Acidic Bromate
J. Phys. Chem. A, 107 (46), 9834 -9845, 2003
The kinetics and mechanism of the oxidation of an important organosulfur antioxidant, N-acetylcysteine, by chlorite and acidified bromate have been studied. In both cases, the final product is N-acetylcysteinesulfonic acid without cleavage of the C-S bond to form sulfate. There was also no evidence for the formation of N-chloramine nor N-bromamine as has been observed with other aminothiols such as taurine. N-Acetylcysteine was oxidized via a stepwise S-oxygenation process in which consecutively a sulfenic and a sulfinic acid were formed before formation of the cysteic acid product. The stoichiometry of the chlorite-N-acetylcysteine was experimentally deduced to be 3ClO2- + 2(CH3CO)HNCH(CO2H)CH2SH 3Cl- + 2(CH3CO)HNCH(CO2H)CH2SO3H. The reaction is characterized by an immediate and rapid production of chlorine dioxide without a measurable induction period. This is because the oxidation of N-acetylcysteine by chlorine dioxide is slow enough to allow for the chlorine dioxide to instantly accumulate without the induction period that characterizes most chlorite oxidations of organosulfur compounds. The global reaction dynamics for this reaction can be described fully by a truncated mechanism that utilizes only 8 reactions. The stoichiometry of the bromate-N-acetylcysteine reaction at stoichiometric ratios was deduced to be BrO3- + (CH3CO)HNCH(CO2H)CH2SH Br- + (CH3CO)HNCH(CO2H)CH2SO3H, while in excess bromate it was deduced to be 6BrO3- + 5(CH3CO)HNCH(CO2H)CH2SH + 6H+ 3Br2 + 5(CH3CO)HNCH(CO2H)CH2SO3H + 3H2O. This reaction proceeded with a prolonged induction period which gave way to a sudden formation of bromine. The rate of reaction between aqueous bromine and N-acetylcysteine is diffusion-limited which indicated that the end of the induction period coincided with a complete oxidation of N-acetylcysteine. The reaction was successfully modeled by the use of a reaction network made up of 12 elementary reactions. Despite their different physiological effects, both cysteine and N-acetylcysteine are oxidized by oxyhalogens via the same S-oxygenation pathway and gave the same oxidation metabolites and final product.
Bice S. Martincigh and Reuben Simoyi
Pattern Formation Fueled by Dissipation of Chemical Energy: Conclusive Evidence for the Formation of a Convective Torus
J. Phys. Chem. A, 106 (3), 482 -489, 2002
An exothermic, autocatalytic chemical reaction can produce a lateral instability which can result in a rapidly moving wave of chemical reactivity. The propagating wave is strongly influenced by thermocapillary effects. At high Marangoni numbers the traveling wave has shown irregular patterning and spatiotemporal irregularity that is aligned in the direction of wave propagation. At lower Marangoni numbers effective coupling occurs between thermocapilary and thermogravitational Rayleigh-Benard type effects. This coupling has produced powerful thermal plumes just behind the leading wave front as well as a series of concentric patterning that represent "transient" Turing patterns. Observations of these effects had led to the conjecture that the wave forms a series of convective tori as it propagates. In this paper recent experimental data are produced that clearly show the dynamic formation of convective tori at the wave front.
Serge A. Svarovsky and Reuben H. Simoyi
A Possible Mechanism for Thiourea-Based Toxicities: Kinetics and Mechanism of Decomposition of Thiourea Dioxides in Alkaline Solutions
J. Phys. Chem. B, 105 (50), 12634 -12643, 2001
The decomposition kinetics of a series of thiourea dioxides has been studied in alkaline media. In aerobic conditions the decomposition is characterized by an induction period, which is followed by the formation of dithionite, S2O42-. The rates of consumption of the thiourea dioxide and the formation of dithionite follow zero-order kinetics. No dithionite is formed in anaerobic conditions, although the thiourea dioxides can still rapidly decompose in the absence of oxygen to give sulfite and a urea as the decomposition products. No dithionite is formed until all the dioxygen in solution has been consumed, and hence the induction time is determined by the initial oxygen concentration in solution. A comprehensive mechanism that can adequately explain the decomposition is proposed in which the initial step is the cleavage of the C-S bond to give a urea residue and the sulfoxylate ion, SO22-. The sulfoxylate ion is next rapidly oxidized by oxygen to give the anion radical, SO2-, which is the precursor to the formation of dithionite via a rapid equilibrium. In aerobic environments the sufoxylate ion can produce the highly tissue-damaging series of reactive oxygen species superoxide, peroxide, and hydroxyl radical. These species could be responsible for the inherent toxicities associated with thioureas.
Sergei Makarov, Claudius Mundoma, John H. Penn, Serge A. Svarovsky, and Reuben H. Simoyi
New and Surprising Experimental Results from the Oxidation of Sulfinic and Sulfonic Acids
J. Phys. Chem. A, 102 (34), 6786 -6792, 1998
(H2N)2C=S, aminoiminomethanesulfinic acid, H2N(HN=)CSO2H
(AIMSA), and aminoiminomethanesulfonic acid, H2N(HN=)CSO3H
(AIMSOA) are all oxidized by mild oxidizing agents to a sulfate and an
organic residue. AIMSA and AIMSOA are the postulated intermediates in the
oxidation pathway of thiourea to sulfate. The oxidation of AIMSOA is
accompanied by a cleavage of the C-S bond to form sulfate. Surprisingly,
freshly prepared solutions of AIMSOA are oxidized by the common oxidants (oxyhalogens
and halogens) at rates that are much slower than oxidation rates of AIMSA by
the same oxidants. These results seem to suggest that AIMSOA may be
structurally different from AIMSA and that the decomposition of AIMSOA to
HSO3- is the prerequisite to its oxidation. The
oxidation pathway of AIMSA to SO42- also proceeds
through the formation of HSO3- and not predominantly
Cordelia Chinake, Oluwarotimi Olojo and Reuben H. Simoyi
Oxidation of Formaldehyde by Chlorite in Basic and Slightly Acidic Media
J. Phys. Chem. A, 102 (3), 606 -611, 1998
The reaction of chlorite and formaldehyde was studied in basic and slightly acidic media. Though the expected product was CO2, the oxidation of HCHO, however, gave nearly quantitative formation of ClO2, the oxidation product of ClO2-. In excess HCHO the stoichiometry of the reaction was deduced as 3ClO2- + HCHO + 2H+ HCOOH + 2ClO2(aq) + Cl- + 2H2O; but in high excess of ClO2- the stoichiometry was 6ClO2- + HCHO + 4H+ CO2(g) + 4ClO2(aq) + 3H2O + 2Cl-. The reaction is autocatalytic in HOCl. The first step of the reaction produces HOCl, which catalyzes the formation of ClO2 and further oxidation of HCOOH to CO2. ClO2 was found to be relatively unreactive toward HCHO and HCOOH, and hence it accumulated rapidly.
Cordelia R. Chinake and Reuben H. Simoyi
Experimental studies of spatial patterns produced by diffusion-convection - reaction systems
J. Chem. Soc., Faraday Trans., 1997, 93(7), 1345
The reactions between chlorite ions and a series of sulfur
compounds are bistable and autocatalytic in hypochlorous acid. Unstirred solution mixtures
of chlorite ions and thiourea, for example, can generate a travelling wave of chemical
reactivity at the surface fram a point of initial perturbation These reactions are highly
exothermic and exhibit a sharp temperature jump at the wave front (dT = 3 - 5 ºC). In
stoichiometric excess of chlorite ions and in unstirred solutions the travelling wave is
followed by spatial patterns in the bulk of the solution. The spatial patterns, which show
areas of varying acid concentrations, can be sustained for up to 15 min. Formation of the
travelling wave is due to thermocapillary effects. The transition to patterns is fuelled
by the coupling of buoyancy forces with thermocapillary convection.
Cordelia R. Chinake and Reuben H. Simoyi
Oxyhalogen - Sulfur Chemistry: Oxidation of Taurine by Chlorite in Acidic Medium
J. Phys. Chem., B 1997, 101, 1207
The reaction between chlorite and the aminosulfonic acid,
taurine, has been studied in neutral to acidic pH.
James Darkwa, Claudius Mundoma and Reuben H. Simoyi
Oxyhalogen-sulfur chemistry: Non-linear oxidation of 2-aminoethanethiolsulfuric acid (AETSA) by bromate in acidic medium
J. Chem. Soc., Faraday Trans., 1996, 92(22), 4407
The reaction between bromate and 2-aminoethanethiolsulfuric acid, H2NCH2CH2SSO3H (AETSA), has been studied in high acid environments. The stoichiometry in excess AETSA is BrO3- + H2NCH2CH2SSO3H + H2O à H2NCH2CH2SSO3H + SO42- + 2H+ + Br-. In excess BrO3 the stoichiometry is: 7BrO3- + H2NCH2CH2SSO3H à 5Br(H)NCH2CH2SO3H + 5SO42- + Br2 + 3H+ + H2O. The reaction displays clock reaction characteristics in which there is initial quiescence followed by a sudden and rapid formation of Br2(aq). The oxidation proceeds by successive addition of oxygen on the inner sulfur atom followed by cleavage of the S S bond to form taurine and SO42- . The Br2(aq) and the HOBr in solution oxidize the taurine to form a mixture of monobromotaurine and dibromotaurine. Computer simulations of a proposed 13-step reaction scheme produced a reasonable fit to the experimental data.
Cordelia R. Chinake and Reuben H. Simoyi
Kinetics and Mechanisms of the complex bromate-iodine reaction
Journal of Physical Chemistry, 1996, 100
The mechanism of the reaction between bromate and iodine in acidic medium (HClO4), in a closed system, has been investigated by both experimental and computer simulation techniques. The stoichiometry of the reaction is 2BrO3- + I2 ® 2IO3- + Br2. The reaction is preceded by an induction period whose length is inversely proportional to the concentration of bromate and the square of the acid concentration. The induction period increases upon the addition of iodide and bromide ions; with the effect of bromide ions being less marked. These ions consume HOI and HOBr molecules which are precursors to the oxidation of iodine. At the end of the induction period iodine is suddenly depleted while simultaneously a transient interhalogen iodine bromide, IBr, is formed and consumed rapidly. As soon as the IBr concentration reaches its maximum value, i.e., [IBr]max = 2[I2]o, it is rapidly consumed at an exponential rate given by -d[IBr]/dt = k1[IBr]. When all the IBr has been depleted molecular bromine is formed at the rate d[Br2]/dt = k2[H+][BrO3-][I2]. Values of k1 and k2 were evaluated as 0.47 ± 0.10 s-1 and 0.26 ± 0.02 M-2 s-1 respectively. A 17-step mechanism which encompasses the mechanisms of the bromate-iodine and bromate-iodide reactions gives good agreement between experimental data and computer simulation. An extensive set of experimental data is presented that supports a molecular mechanism over a radical-dominated one.
Bice S. Martincigh, Marcus J. B. Hauser, and Reuben H. Simoyi
Formation of thermal plumes in an autocatalytic exothermic chemical reaction
Physical Review E, v52(6), 1995
The reaction of chlorite and thiourea is bistable and displays a lateral instability that generates a traveling wave of sulfate, acid, and chlorine dioxide. The wave was visualized by the addition of barium chloride, which gave a white precipitate of barium sulfate. The wave propagates with three distinct regions of varying precipitation intensities. One of the regions is made up of a complete convective roll that forms powerful thermal plumes which rise to the surface of the reactant solution. The plumes originate from a coupling of Marangoni convection with multicornponent convection.
Cordelia R. Chinake and Reuben H. Simoyi
Fingering Patterns and Other Interesting Dynamics in the Chemical Waves Generated by the Chlorite-Thiourea Reaction
J. Chem. Soc. Faraday Trans, 1995, 91(11), 1635
The reaction between chlorite and thiourea is excitable and autocatalytic in HOCl. It produces a chemical wave of ClO2 when ClO2- is in stoichiometric excess over thiourea. The chemical wave has been studied in glass tubes of varying diameters. The dynamics of the wave front propagation have been studied as a function of convection, which is known to induce density gradients. The C102-thiourea reaction is highly exothermic, and the chemical wave has a positive isothermal density change. In vertical tubes the effect of the exothermicity of the reaction opposes the effect of the isothermal density change, giving an asymmetric and unstable wave front in descending waves. Multicomponent convection and fingering patterns have been observed in descending waves. Ascending waves propagate without structure and are generally slower than descending waves. In starch solutions fingering patterns are observed which propagate downward at greater than 10 times the normal front velocity. These fingers turn into rapidly-rising plumes after they reach the bottom of the tube. Formation of rising plumes is due to the hot interior of the finger which is lighter than the unreacted solution, but when the reacted solution propagates upward into the cold unreacted region, the cooling effect makes the solution heavier, giving a symmetric "mushroom-shaped" plume.
Bice S. Martincigh and Reuben H. Simoyi
Convective instabilities induced by an exothermic autocatalytic chemical reaction
Physical Review E, 1995, v52(2), 1606
A bistable or excitable exothermic chemical reaction can produce a traveling front of chemical reactivity upon being triggered. The dynamics of the wave propagatian are greatly influenced by the amount of heat generated at the wave front, which in turn is a function of (nonlinear) reaction kinetics, enthalpy change, and extent of reaction. The chemical reaction investigated here has shown complex propagative patterns, including accelerating big waves, convective rolls, double-diffusive convection, and spatiotemporal patterns. A model devised to explain the patterns involves a laterally heated fluid layer in which the basic flow loses stability in the form of hydrothermal waves. Wave motion is preceded by a global circulation between the hot and cold regions, with the velocity being praportional to the lateral temperature gradient. In this highly exothermic reaction the spatiotemporal patterns can be explained by a stability analysis of the Bernard-Marangoni convectian with lateral heating.
Marcus J.B. Hauser, Reuben H. Simoyi
Inhomogeneous precipitation patterns in a chemical wave. Effect of thermocapillary convection
Chemical Physics Letters 227, (1994), 593
Bice S. Martincigh, Cordelia R. Chinake & Reuben H. Simoyi
Self-organization with traveling waves: A case for a convective torus
A traveling wave of BaSO4 in the chlorite-thiourea reaction has shown concentric precipitation patterns upon being triggered by the autocatalyst, HOCl. The precipitation patterns show circular rings of alternate null and full precipitation regions. This self-organization appears to be the result of the formation of a convective torus.
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