Oxyhalogen-Sulfur Chemistry: Kinetics and Mechanism of Oxidation of

Subscriber access provided by Purdue University Libraries

Article

Oxyhalogen-Sulfur Chemistry: Kinetics and Mechanism of Oxidation of 1,3-Dimethylthiourea by Acidic Bromate Olufunke Olagunju, and Reuben Hazvienzani Simoyi J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b07587 • Publication Date (Web): 09 Aug 2017 Downloaded from http://pubs.acs.org on August 10, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

The Journal of Physical Chemistry A is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Physical Chemistry

July 31, 2017

Prof. Reuben H. Simoyi, Department of Chemistry, Portland State University, Portland, OR 97207-0751, USA. ____________________________________________________________

Oxyhalogen-Sulfur Chemistry: Kinetics and Mechanism of Oxidation of 1,3Dimethylthiourea by Acidic Bromate

by

Olufunke Olagunju and Reuben H. Simoyi* Department of Chemistry, Portland State University, Portland, OR 97207-0751, USA. School of Chemistry and Physics, University of KwaZulu-Natal, Westville Campus, Durban 4014. South Africa.

Corresponding author email address: [email protected] . Phone: 503-725-3895 The authors declare no competing financial interest.

ACS Paragon Plus Environment

-1-


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 42

ABSTRACT The mechanism of oxidation of the well-known radical scavenger, dimethylthiourea, DMTU, by acidic bromate was studied. The stoichiometry of the reaction is 4:3: 4BrO3+3CS(NHMe)2 +3H2O → 3SO42- + 3CO(NHMe)2 + 6H+ + 4Br-. In excess acidic bromate, the reaction stoichiometry is 8:5: 8BrO3- + 5CS(NHMe)2 + H2O → 5SO42- + 5CO(NHMe)2 + 4Br2 + 2H+. In excess bromate, the reaction displays well-defined clock reaction characteristics in which, initially, there is a quiescent period before formation of bromine. The direct reaction of aqueous bromine with DMTU, with a bimolecular rate constant of k = (1.95±0.15)x105 M-1 s-1, is much faster than reactions that form bromine such that formation of bromine indicates complete consumption of DMTU. ESI spectrometry showed evidence for an oxidation pathway that passes through the sulfenic, sulfinic and sulfonic acids before formation of sulfate. In contrast to the oxidation of tetramethylthiourea, these oxo-acid intermediates are not as abundant, nor as stable. The final product of oxidation was dimethylurea, the desulfurized DMTU. EPR spectroscopy implicates more than one set of radical species. The absence of the dimeric DMTU species, even in excess reductant indicates negligible formation of thiyl radicals. This also precludes substantial formation of the sulfenic acid intermediate which would form the dimer from a condensation-type reaction with unreacted DMTU. A 20-step reaction mechanism network was modeled which gave a reasonable fit with experimental data.


-2-

Page 3 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Introduction About 20 years ago, our lab launched into the study of oxyhalogen-sulfur kinetics and mechanistic studies.1 The rationale for mounting such studies was to unravel the seemingly omnipresent exotic dynamics derived from the oxidation of thioureido compounds with oxyhalogens.

The thioureido group, especially thiourea, is also one of

the most biologically active moieties. Several therapeutic drugs are derived from the thiourea group.2-4 The simplest member of the thiocarbamide family is thiourea. Thiourea derivatives form a vast group of highly reactive and physiologically important compounds. Substituted thioureas have varying physiological effects that range from therapeutic to toxic. Animal studies on the chronic toxicity of thiourea have shown that when it is administered in drinking water, thiourea induces thyroid adenomas and carcinomas in rats.5 No-one yet knows the origin of tumorigenicity in this series of chemicals, but there is speculation that this could be attributed to thiourea’s strong antithyroid activity which leads to a disruption of the pituitary-thyroid hormonal regulatory system.6 Toxic reactive oxygen species (ROS’s) such as superoxide radicals, hydroxyl radicals and hydrogen peroxide have been implicated in oxidative damage of cellular macromolecules. N, N’- dimethylthiourea, DMTU, has been shown to be one of the most effective scavengers for ROS’s with an exceptionally high affinity for the hydroxyl radical and hypochlorous and hypobromous acid.7,8 Evidence of DMTU’s deactivating abilities was first reported by Curtis et al who detected formation of dimethylthiourea dioxide after administration of DMTU to H2O2-producing mixtures of phorbol 12myristate 13-acetate and human neutrophils.9 The physiological effects of DMTU,


-3-


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 42

however, have been confusing: although, in most situations, it is effective in decreasing oxidant-mediated injury, it has sometimes inexplicably failed to reduce injury in some biological systems where oxygen metabolites were ostensibly causing damage. In some instances, increasing DMTU dosage did not afford protection, and was, in fact, associated with more injury.10,11 In rats, DMTU causes accumulation of intravenously-injected radioisotope-labeled albumin in lung tissue, which suggests damage to lung vasculature, but, surprisingly did not alter other parameters that are often used as indicators of severe edematous lung injury.11 For example, DMTU administration did not induce increases in blood hematocrit levels, increase in lung weights, or development pleural effusions; although it significantly decreased blood glutathione levels.10 The nucleophilic nature of the sulfur center in the physiological environment dictates that most of the metabolic activations of organosulfur compounds are oxidative. Since the general path to metabolic activation of DMTU is oxidative (specifically through S-Oxygenation), a thorough knowledge of its oxidation mechanism as well as its oxidation metabolites should be essential in any attempts at rationalizing DMTU’s physiological effects. Previously, we studied the oxidation mechanisms of substituted thioureas, and no generic oxidation pathways were obtained.12-15 Physiological effects of substituted thioureas span a wide range, also suggesting their oxidative bioactivation mechanisms are also different.16-19 We report, in this manuscript, on the oxidation of DMTU by acidic bromate and bromine. We used bromate as an oxidant because it is a precursor to HOBr, hypobromous acid. HOBr is a very relevant oxidant in the physiological environment: Stimulated granulocytes produce oxidizing agents (e.g. H2O2) and secrete granular proteins into the extracellular medium which contributes to their


-4-

Page 5 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


antimicrobial, cytotoxic and cytolytic activities20. Each group of cells contains a specific peroxidase which catalyzes the reactions of hydrogen peroxide with halogens. The enzyme myeloperoxidase which is abundant in neutrophils catalyzes the oxidation of Clions by H2O2 to yield HOCl:21 H2O2 + Cl-/Br- + Myeloperoxidase/H+ → HOCl/HOBr + H2O (R1) HOCl and HOBr are capable of destroying a variety of microoganisms and mammalian cell targets.22 They are also believed to be involved in the inflammatory response.22

Experimental Section

All stock solutions were prepared fresh each day before use using doubly-distilled and deionized water (Barnstead Sybron Corporation water purification unit). The following analytical grade chemicals were used: N,N’-dimethylthiourea, DMTU (Sigma-Aldrich), sodium bromate, sodium bromide, potassium iodide, soluble starch, sodium thiosulfate, perchloric acid, 72%, hydrochloric acid (Fisher) and sodium perchlorate (Acros). Aqueous bromine solutions were prepared by dilution of liquid bromine in water and standardized through an iodometric titration. This titration allowed us to determine the absorptivity of aqueous bromine as 142 M-1 cm-1 at 390 nm. This absorptivity coefficient was then used to standardize daily preparations of stock bromine concentrations. These stock solutions were kept capped and were stored in dark Winchester bottles. Methods The slower oxidations of DMTU by bromate in low acid concentrations were followed on a conventional Perkin-Elmer Lambda 2S UV-Vis spectrophotometer. Oxidations in higher acid concentrations were faster and had to be followed by the use of a Hi-Tech


-5-


Scientific Double-Mixing SF61-DX2 stopped-flow spectrophotometer. All reaction solutions were thermostated at 25.0 ± 0.5 0C and run in a medium of 1.0 M ionic strength (NaClO4). Stoichiometric determinations of the oxidation of DMTU by bromate were performed by mixing fixed concentrations of DMTU with varying concentrations of acidic bromate. These solutions were left to incubate overnight after which the product solutions were scanned spectrophotometrically for aqueous bromine. The total oxidizing power left at the end of the reaction was determined by another iodometric titration after adding excess potassium iodide. The stoichiometry of the Br2 – DMTU reaction was also determined spectrophotometrically, and by titration (in excess bromine conditions only).

7

6

5

S2O32- (mL)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 42

4

3

2

1

0 0

2

4

6

[BrO3-]

8

10

12

14

3

X 10 M


-6-

Page 7 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 1 Stoichiometric determination using iodometric titration of product solutions. DMTU concentrations were fixed at 3.0x10-3 M. Intercept on the x-axis shows that 4 moles of bromate are needed to oxidize 3 moles of DMTU before formation of bromine.

Results Stoichiometry. Oxidation of DMTU in excess bromate produced bromine as a final product. Bromine production was from the reaction of the reduction product, bromide, with the excess bromate left after a complete oxidation of DMTU. An accurate stoichiometry could then be obtained by determining the total residual oxidizing power of the product solution (BrO3- + Br2) after a complete consumption of DMTU. This stoichiometry will deliver the appropriate oxidant to reductant ratio, but will not deliver the nature and type of oxidation products. Addition of excess iodide into the reaction solutions incubated overnight gave iodine which could be titrated against thiosulfate. A plot could then be made of the thiosulfate titer versus the initial bromate concentrations (see Figure 1). The extrapolated bromate axis intercept of this plot represents the amount of bromate needed to completely oxidize DMTU with no bromate left to oxidize iodide for the iodometric titration. The advantage of this titrimetric method arises from the use of several data points for an overall evaluation of the stoichiometry, and also (that) one does not have to work close to the stoichiometric ratio which would deliver smaller and less accurate titers. In Figure 1, for a fixed 0.003 M DMTU concentration, the bromate concentration needed to just completely consume this concentration of DMTU is 0.00388 M. This would suggest a stoichiometry of 4:3:

4BrO3- + 3CS(NHMe)2 + 3H2O → 3SO42- + 3CO(NHMe)2 + 6H+ + 4Br- (R2)


-7-


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 42

A 4:3 ratio had also been derived for the bromate-thiourea reaction.23 Most strong to mild oxidants oxidize thiocarbamides to sulfate and their urea analogues.1,12,13,24 Quantitative determination of sulfate was performed gravimetrically through BaSO4 precipitation. Barium sulfate yields, taken from several experiments, showed that, on the average, 98.8% of the sulfur in DMTU was converted to sulfate. In excess bromate conditions, bromine is produced in the reaction mixture by the well-known BrO3- - Brreaction in acidic medium: BrO3- + 5Br- + 6H+ → 3Br2(aq) + 3H2O

(R3)

For a fixed amount of DMTU, successive experiments with increasing BrO3concentrations past stoichiometry R2 showed a concomitant linear increase in bromine product concentrations at t∞. This continues until a concentration is attained in which further increases in [BrO3-]0 no longer deliver an increase in bromine formation. This is the second limiting stoichiometry in which all bromide ions produced in stoichiometry R2 are consumed by the excess bromate. This stoichiometry was determined spectrophotometrically by observing final absorbance of bromine (λ = 390 nm), and noting the saturation point in initial bromate concentrations. This stoichiometry could also be deduced as a linear combination of reactions R2 and R3 that eliminates bromide. Thus adding 5R2 + 4R3 gives the experimentally observed stoichiometry of 8 to 5:

8BrO3- + 5CS(NHMe)2 + H2O → 5SO42- + 5CO(NHMe)2 + 4Br2 + 2H+


(R4)

-8-

Page 9 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The stoichiometry of the direct oxidation of DMTU by bromine was determined both titrimetrically and spectrophotometrically. The titrimetric technique involved mixing variable concentrations of known bromine solutions with fixed DMTU solution concentrations while maintaining bromine in excess (any residual yellow color left after mixing the two regents indicated excess bromine). The final reaction solution was titrated iodometrically to determine the amount of excess bromine. The bromine absorption peak at 390 nm was isolated (see Figure 2), and thus quantitative bromine concentration determinations could be made spectrophotometrically at this wavelength. The bromine – DMTU reaction, using these two methods, gave a stoichiometry of 4:1 with quantitative conversion of the sulfur to sulfate:

4Br2 + CS(NHMe)2 + 5H2O → SO42- + CO(NHMe)2 + 8Br- + 10H+


(R4)

-9-


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 42

0.400

0.35

390 nm: Bromine peak 0.30

0.25

A

0.20

0.15

0.10

0.05

0.000 200.0

250

300

350

400

450 nm

500

550

600

650

700.0

Figure 2 Rapid scans showing formation of bromine at 390 nm. The 232 nm peak, expected for DMTU, was not observed as an active peak. Spectral scans were taken on the conventional UV-Vis spectrophotometer every 30 seconds. [DMTU] = 2.5 x 10-3 M, [BrO3- ] = 3.0 x 10-2 M, [HClO4] = 2.5 x 10-1 M.

Reaction Kinetics DMTU and oxidation product dimethylurea, DMU; have no significant absorptivity in the visible range (λ ≥ 330 nm). They do absorb strongly in the UV region, however. Aqueous bromine is the only species that absorbs in the visible range at 390 nm. The reaction could thus be monitored at the bromine peak of 390 nm. DMTU and its oxidation intermediates appear to all absorb in the same UV region such that as the reaction progressed, no measurable absorbance changes could be observed in the


- 10 -

Page 11 of 42

wavelength region of 260 nm and below (see Figure 2). Figure 2 shows rapid scans of a typical reaction solution in excess bromate. There is initially a quiescent period in which there are no changes in the reaction’s progress indicators (cell potential, pH changes and absorbance readings at 390 nm). After this quiescent period (we dub this an ‘induction period’), bromine formation is observed that rises to a peak that is determined by stoichiometry R4 in which the maximum bromine absorbance observed corresponds to 80 % of the initial concentration of DMTU. Until stoichiometry R4 is attained, the final amount of bromine obtained is determined by initial DMTU concentrations.

0.4

0.3

Absorbance 390 nm

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


d c 0.2 b

a

0.1

0.0 0

100

200

300

400

Time (s)

Figure 3a As acid concentrations increase there is a decrease in induction period and concurrent increase in the formation of bromine. This shows an inverse relationship between induction period and concentration of acid. [DMTU]0 = 2.5 x 10-3 M, [BrO3- ]0 = 3.0 x 10-2 M, [HClO4]0 = a) 2.0 x 10-1 M, b) 2.25 x 10-1 M, c) 2.5 x 10-1 M, d) 2.75 x 10-1 M.


- 11 -


Figure 3a shows the absorbance – time traces obtained for this reaction at varying initial acid concentrations. The induction period is shortened by higher acid concentrations, and the rate of production of bromine at the end of the induction period is also strongly catalyzed by acid. Acid, however, does not affect the final concentration of bromine obtained, it is purely a catalyst which influences the rate of reaction but is not a stoichiometric reagent by itself. Within a wide range of acid concentrations, there is an inverse squared dependence of the induction period on acid concentrations (see Figure 3b). This effect saturates at very high acid concentrations and tails off at pH higher than 3. The formation of bromine is an indicator of an important stage of the reaction where . 5

-1

4

-2

1/T ind. x 10 s

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 42

3

2

1

0 0

2

4

6

8

[H+]2 x 102 M2

Figure 3b Inverse of induction time plot for acid variation in Figure 3a. This shows a linear plot. Fixed: [DMTU] = 2.5 x 10-3M, [BrO3-] = 3.0 x 10-2M, I NaClO4 = 1M.

[HClO4] = a) 2.00 x 10-1M, b) 2.25 x 10-1M, c) 2.50 x 10-1M, d) 2.75 x 10-1M.


- 12 -

Page 13 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


reactions that form bromine are more effective than those that consume bromine. Since attainment of this section of the reaction has an inverse acid dependence, this indicates that the major precursor reaction that leads to the formation of bromine must have a square dependence on acid. Bromate concentrations also decrease the induction period and the rate of bromine formation after the induction period.. Bromate has an inverse dependence on the induction period (Figure 4). This inverse dependence persists over nearly all ranges of bromate concentrations, although this dependence is abruptly discontinuous as soon as initial bromate concentrations dip below those required for stoichiometry R3. Only excess bromate concentrations form bromine and hence can generate a measurable induction period. The [BrO3-]0-axis intercept in Figure 4 is important in corroborating stoichiometry R2. The intercept concentration represents the point where the induction period approaches infinity (hence no formation of bromine).


- 13 -


3.0

2.5

2.0

-2

-1

1/Tind x 10 (s )

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 42

1.5

1.0

0.5

0.0 0

1

2

3

4

5

6

[BrO3- ]o x 102 (M)

Figure 4 Inverse of induction time against bromate concentrations which also confirms the stoichiometry of the oxidation of DMTU by bromate to be 3 moles of DMTU to 4 moles of bromate. Intercept on the x-axis is 8.0 x 10-3 M bromate, while [DMTU]0 = 6.0 x 10-3 M.

Any slight increase in bromate from this concentration will give rise to a measurable induction period (very long, though, and hence a small value of 1/Tind). So, for a fixed initial concentration of DMTU (which, in this case is 0.006 M), the amount of bromate needed to just satiate stoichiometry R3 with no formation of bromine detected was deduced in Figure 4 as 0.008 M (the intercept value). This is exactly the stoichiometry deduced in R4.


- 14 -

Page 15 of 42

0.4 e 0.3

Absorbance 390 nm

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


d

c

0.2

b 0.1

a

0.0 0

200

400

600

800

1000

Time (s)

Figure 5 Increasing concentrations of DMTU in excess bromate shows little change in induction period but there is an increase in final bromine absorbance. Increasing the concentrations of DMTU increases the rate of formations of bromine. This is expected from stoichiometry R3 where reductant, DMTU, is limiting. [BrO3-] = 3.0 x 10-2 M, [HClO4] = 2.25 x 10-1 M, [DMTU] = a) 7.0 x 10-4 M, b) 1.2 x 10-3 M, c) 1.7 x 10-3 M, d) 2.3 x 10-3 M, e) 3.0 x 10-3 M.

The effects of DMTU concentrations on the induction period are more complex than those of acid and bromate which are monotonic with a simple functional dependence. In high excess of bromate with oxidant-to-reductant ratio, [BrO3-]0/[DMTU]0 greater than 10, the induction period is relatively insensitive to changes in DMTU concentrations (see Figure 5) even though higher DMTU concentrations in this range will deliver higher


- 15 -


bromine formation rates with a first order dependence in DMTU. As the DMTU concentrations are further increased, however, the induction period also increases. This increase will continue until ratio falls below 4 and no bromine formation is formed. If the bromine is formed solely from reaction R3, then the increase in its rate of formation with DMTU implies that there is a positive order relationship between rate of formation of bromide and DMTU. Figure 6a shows the catalytic effect of bromide ions, even though they also constitute the major product in the reduction of bromate. Very small amounts of added bromide ions to the reaction mixture dramatically reduce the induction period,

0.25 e d 0.20 c

Absorbance 390 nm

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 42

b 0.15

a

0.10

0.05

0.00 0

200

400

600

800

1000

Time (s)

Figure 6a The effect of added bromide to DMTU- bromate oxidation shows decrease in induction period and increase in final bromine concentration.


- 16 -

Page 17 of 42

[DMTU]0 = 1.25 x 10-3 M, [HClO4]0 = 2.5 x 10-1 M, [BrO3- ]0 = 1.5 x 10-2 M, [Br - ] = a) 0, b) 2.5 x 10-4 M, c) 5.0 x 10-4 M, c) 7.5 x 10-4 M, d) 1.0 x 10-3 M.

rate of formation of bromine, and total amount of bromine formed at the end of the reaction. As amounts of added bromide ions are increased past the initial DMTU concentrations, the catalytic effect saturates. The increase in bromine concentrations formed at the end of the reaction also saturates and will be limited by the initial concentrations of excess bromate in the reaction mixture. Figure 6b shows that this effect on bromide on the stoichiometry is simply additive, since the amount of bromine formed

0.26

Maximum amount of bromine at 390 nm.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.24

0.22

0.20

0.18

0.16

0.14

0.12 0

2

4

6 -

8

10

12

4

[Br ]o x 10 (M)

Figure 6b The plot of maximum absorbance of bromine against bromide concentrations shows linear dependence. Plot also shows maximum absorbance of bromine that is possible at the initial conditions in Figure 6a to be 0.14.

has a linear relationship with bromide with an intercept that represents the bromine concentrations that would have been formed in the absence of added bromide.


- 17 -


The direct reaction of bromine and DMTU is much faster that the BrO3- - DMTU reaction with a half-life of only 5 – 10 seconds, while induction periods measured of the reaction are in the orders of 50 seconds and above, depending on the acid concentrations (see Figure 7a). Figure 7a shows a series of experimental runs which span from excess DMTU to excess bromine. Those run in excess bromine had residual bromine concentrations at the end of the reaction. A plot of residual concentrations [Br2]∞ (ordinate axis) vs the initial bromine concentrations, [Br2]0 (abscissa), was linear, with the intercept on the [Br2]0 axis corresponding to the stoichiometry of the Br2 – DMTU reaction (plot not shown). In this case, for a fixed amount of [DMTU]0 of 0.001 M, amount of [Br2]0 needed to just consume the [DMTU]0 with no excess bromine

1.6 1.4

Absorbance (390 nm)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 42

1.2 1.0

e

0.8 d 0.6 c

0.4

b

0.2

a 0.0 0

50

100

150

200

250

Time(s)

Figure 7a


- 18 -

Page 19 of 42

Progressive increase in bromine concentrations while keeping [DMTU]0 constant. [DMTU]0 = 1.0 x 10-3 M, [Br2] = a) 2.7 x 10-3 M, b) 4.1 x 10-3 M, c) 5.5 x 10-3 M, d) 8.2 x 10-3 M, e) 9.6 x 10-3 M.

left was 0.0040 M; which corresponds to the formerly-derived 4:1 stoichiometric ratio. Reactions run in pseudo-first order conditions, with [DMTU]0/[Br2]0 ratio > 10 were so fast that they exceeded the limits of our Hi-Tech Scientific stopped-flow spectrophotometer which has an approximate mixing time of 1 ms. Figure 7b shows that the reaction is first order in bromine with an intercept kinetically indistinguishable from zero. No acid was added to these reaction solutions, although ionic strength was maintained at 1.0 M. Addition of acid shows a very slight retardation which was only evident at very high acid concentrations of 1.0 M and higher. A separate DMTU dependence set of kinetics runs also showed a first order dependence in DMTU. The bimolecular rate constant was derived as k = (1.95±0.15) x 105 M-1 s-1.

2.0

Initial rate (M s-1) x 10-2

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1.5

1.0

0.5

0.0 0

2

4

6

8

10

12

[Br2]0 x 103 M


- 19 -


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 42

Figure 7b Plot of initial rate for the variation of bromine (data in Figure 7a). Plot shows a direct relationship between initial rate and bromine concentration. [DMTU]0 = 1.0 x 10-3 M [Br2]0 = (b) 4.1 x 10-1 M; (c) 5.5 x 10-3 M; (d) 7.3 x 10-3 M; (e) 9.6 x 10-3 M Lower concentrations with lower absorbances, were less accurate, and thus trace (a) was not included in this plot.

MECHANISM The kinetics data obtained for these reactions allow us to make the following simple deductions: (a) The sharp end to the induction period and the lack of transient bromine production in excess DMTU conditions suggests that the reaction of bromine with DMTU is much faster than the reactions that form bromine (e.g. reaction R3). This would suggest that the end of the induction period indicates the total consumption of DMTU and its oxidation intermediates. (b) The reaction’s first order dependence on bromate and bromide, coupled with the second order dependence on acid would implicate the well-known precursor composite reaction to all bromate oxidations in acidic medium:25

BrO3- + Br- + 2H+ ⇄ HBrO2 + HOBr

(R6)

In most of the experimental runs performed for this experiments, there was no added bromide to the reaction solutions. Most bromate solutions contain at least 5x10-6 M Brwhich is in equilibrium with bromate. One school of thought is that this residual bromide concentration is sufficient to initiate the reaction. Simple calculations, using the known


- 20 -

Page 21 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


rate constants (forward and reverse) for reaction R6 have shown that this initial concentration of bromide is insufficient to initiate the reaction at the experimentallyobserved rates. Calculated induction periods with these bromide concentrations were 4 to 5x longer than those experimentally-observed. It would appear, then, that the reaction system should generate bromide ions in another pathway by a direct reaction of DMTU and acidic bromate. We postulate the following sequence of reactions as a plausible source of bromide ions:

H+ + BrO3- ⇄ HBrO3 HBrO3 + (NHMe)2C=S → HBrO2 + (MeN=)(NHMe)C-SOH

(R7) (R8)

HBrO2 + (MeN=)(NHMe)C-SOH → HOBr + (MeN=)(NHMe)C-SO2H

(R9)

HOBr + (MeN=)(NHMe)C-SO2H → H+ + Br- + (MeN=)(NHMe)C-SO3H

(R10)

Reductants in steps R8 to R10 can be any 2-electron reductant, but since we could not detect high quantities of the oxo-acid intermediates, it is reasonable to expect that they will be much more rapidly oxidized that the substrate DMTU itself. Thus the slowest step in this sequence is reaction R8. Further oxidations by oxybromine species HBrO2 and HOBr are always faster than those by bromic acid. The bromate ion, itself, is known to be inert, and hence most exotic reaction dynamics observed with bromate oxidations involve the initial generation and accumulation of the reactive species, HBrO2, HOBr and Br2. 2528

Addition of reactions R7 to R10 shows production of Br- which can then be used to

establish rate-determining step R6. Combining reaction R6 to the R7 – R10 sequence shows, stoichiometrically, that two bromide ions ends up giving 3 bromide ions in a form


- 21 -


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 42

of autocatalysis. Accumulation of bromide ions, however, switches the rate-determining step for the reaction from R8 to R6. Since the reaction is strongly second order in acid, reaction sequence R7 to R10 is only relevant in the early stages of the reaction while bromide ions accumulate.

Oxidation sequence of DMTU. Formation of sulfate and dimethylurea involves an 8-electron transfer from the sulfur center. Sulfur chemistry is well-known for its stabilization of various oxidation states from -2 to +6. The oxidation sequence can be experimentally determined by adding specific oxidation equivalents of a strong oxidant and observe the stable oxidation states obtained. For DMTU, we progressively added equivalents of aqueous bromine up to the 4 equivalents required for full oxidation of DMTU to dimethylurea and sulfate. Figure 8 shows the Electrospray ionization (ESI) spectrum that resulted in the addition of one equivalent of aqueous bromine. Stoichiometrically, this is equivalent to a 2-electron transfer that should result in the formation of a sulfenic acid or S-oxide, (MeN=)(NHMe)C-SOH. Figure 8 spectrum was taken after sufficient incubation for the reaction to go to completion. The spectrum shows the expected dominant peak of the substrate, DMTU at m/z = 105.05 since it was in stoichiometric excess. There is a peak for the full oxidation product, dimethylurea at m/z = 89.07. There is a very small peak for the sulfenic acid at m/z = 121.958 as well as a slightly larger peak for the sulfinic acid at 137.038. The sulfonic acid has the largest oxo-acid intermediate peak at 151.054. Increasing the ratio of bromine decreased the peak for the substrate while increasing the peak for the product, as expected. None of the peaks for the sulfenic and sulfinic acids,


- 22 -

Page 23 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


however, increased to appreciable amounts as oxidant concentrations were increased. The conclusion is that these oxo-acids are extremely unstable and will quickly either oxidize further or decompose upon formation. A similar study of the oxidation pathway for tetramethylthiourea (TMTU) had shown extensive speciation, with substantial formation of the formerly elusive sulfenic acid.29 DMTU is unable to as efficiently stabilize the intermediate sulfenic and sulfinic oxo-acids. Bisulfite peak can be observed at 81.5206.


- 23 -


T: FTMS + c ESI Full ms [50.00-350.00] 89.07102 100 95 105.04836

90 85 80 75

79.02127

70 65 R e la tiv e A b u n d a n c e

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 42

60 55 50 45 40 35 30 25

81.52058

20

103.08678

15 10 90.52589 101.00342 84.08079 93.50399

5

151.05396 107.04405

121.95822 127.04435 137.03828

159.12434

0 80

90

100

110

120

130

140 m/z

175.10194

150

160

168.86066 170

189.40607 183.56073 180

Figure 8: ESI spectrum of a 1:1 mixture of DMTU:Br2. The dominant peak is for DMTU (m/z = 105.048 in the positive mode) since it is in excess. Other peaks are for the product and bromide. The sulfonic acid is very abundant at 151.054

Possible radical species involvement. Possible radical species involvement were examined in this manuscript. DMTU is a well-known radical scavenger, and it is plausible that its pathway to oxidation might involve a radical pathway.7,30,31 Radicals were trapped by 5,5-dimethyl-1-pyrroline-N-oxide, DMPO, on an X-Band EPR spectrometer. DMPO trap was added to various mixtures of DMTU and acidic bromate and EPR spectra were obtained. The signal strength was mediated by DMTU


- 24 -

192.30214 190

200

Page 25 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


concentrations, but its genesis should involve the standard bromine dioxide radicals as the dominant species, and not thiyl-type radicals. ESI data showed no trace of dimeric DMTU even in excess reductant. This would suggest negligible amounts of thiyl-type radicals. None of the standard DMPO adduct radical spectra such as those with hydroxyl radical and superoxide radical are evident in the EPR spectrum shown in Figure 9. The spectrum appears to result from more than one radical species. There is a distinct imbedded 1:2:2:1 pattern with hyperfine coupling constants which we could not attribute to any known radical species in literature. The Belousov-Zhabotinskii reaction mechanism in highly acidic media has established the existence of the bromine dioxide radical as the backbone in the generation of autocatalysis which is the essential nonlinearity for oscillatory behavior:32-34 BrO3- + HBrO2 + H+ → 2BrO2· + H2O

R15

Oxidation by bromine dioxide radical is via a one-electron transfer: BrO2• + H+ + Red → HBrO2 + Red+

R16

Combining R15 and 2R16 shows that HBrO2 is produced autocatalytically via quadratic autocatalysis in which one mole of bromous acid, HBrO2 results in 2 moles of bromous acid, resulting in an ever-increasing reaction rate. The BrO2· radical can react with the enol form of DMTU to produce a sulfur-based radical:

BrO2· + Me(H)N((Me)N=)C-SH → HBrO2 + Me(H)N((Me)N=)C-S·


(R17)

- 25 -


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 42

The radical electron can delocalize over the N-C-N framework of the thioureido group, and thus unavailable to form the dimeric DMTU. A similar radical, chlorine dioxide, also produces the signature 1:2:2:1 pattern with DMPO.35 There are two potential problems associated with detecting chlorine dioxide and bromine dioxide – mediated radicals. The first involves possible oxidation of the trap by bromine dioxide.35 The second involves the generation of a second trapping agent, different from DMPO, that is generated by the oxidation of DMPO.36 Another source of radicals is from the cleavage of the C – S bond of the dimethylthiourea dioxide, which, in acidic medium, exists mainly in its zwitterionic form (dimethylaminoiminomethanesulfinic acid, DMAIMSA) the sulfinic acid, (MeN=)(NHMe)C-SO2H. Generally, in sulfinic acids of thioureas and substituted thoiureas the C – S bonds are inordinately long, making it easy to cleave to yield a highly reducing sulfur leaving group that can initiate a cascade of other radicals, especially in aerobic environments. We previously synthesized sulfinic acids of methylthiourea37 and dimethylthiourea.38 We noted that the C-S bond for the DMAIMSA, at 0.188 nm; was the longest, and thus most easily cleaved, rendering it the least stable of these series of oxo-acids. In alkaline environments, the decomposition of the sulfinic acid could be represented by Scheme A. Sulfoxylate anion, HSO2-, is known to react rapidly with molecular oxygen to produce the radical anion SO2-• and superoxide:39 SO22- + O2 → SO2-• + O2-•


R18

- 26 -

Page 27 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 9: Effect of varying DMTU concentrations on the formation of free radicals using the DMPO trap. The spectrum appears to contain a mixture of at least 2 sets of radicals. Trap DMPO concentration fixed a 0.10 M. Also [BrO3-]0 = 0.05 M; [H+]0 = 0.20 M. Varying [DMTU]0. Radical peaks increase (a) to (e): (a) no DMTU, (b) 1.25 mM, (c) 2.5 mM, (c) 5.0 mM, (d) 10.0 mM, and (e) 20.0 mM.

O

+ C

O-

O H

C

S

OH

- H+

+

HSO2- 2e-

H

C

O

SO2 (aq)

Scheme A. SO2-• also rapidly reacts with oxygen:


- 27 -


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

SO2-• + O2

→ SO2(aq) + O2-•

Page 28 of 42

R19

The characteristic DMPO – O2·- spectrum, however, was not observed in Figure 9. The crystal structure of DMAIMSA, however, showed it to be strictly zwitterionic (see Figure 10); with equivalent N-C and S-O bonds. Its analogue, formamidine sulfinic acid (aminoiminomethanesulfinic acid, AIMSA), is used as an efficient reducing and bleaching agent in textile industry due for its rapid decomposition and subsequent formation of radicals.40 This article, by Lewis et al40, also confirmed that AIMSA exists strictly in the zwitterionic form. Thus the zwitterionic form of DMAIMSA can homolytically cleave the C-S bond to yield sulfur dioxide – type radicals which will further yield a cascade of radicals of an indeterminate nature. The arrangement for the molecular structure of DMAIMSA provides the opportunity for a three-center fourelectron Α-interaction of filled N pΑ and the vacant C pΑ orbitals at the formally cationic carbon center. This helps to account for the very short C-N bonds observed for C(1) – N(1) (1.33 Å) and C(1) – N(2) (1.30 Å); while the C – N bonds further away from this center are close to the theoretically accepted value of 1.47 Å (both N(1) – C(2) and N(2) – C(3) are 1.46 Å long). The orientation of the methyl groups with respect to the sulfinic acid group lies in between both pointing away from this group and both pointing towards the oxygen atoms. The very long C-S bond is perplexing. Covalent radii predict 1.79 Å, but the observed value is 1.88 Å.41 This can be compared with the values observed for the unsubstituted thiourea dioxide, (NH2)2CSO2 with 1.867 Å,42 thiourea trioxide (NH2)2CSO3 with 1.815 Å and the sulfonic acid analogue of DMAIMSA, (MeHN)2CSO3, with a bond length of 1.820 Å.43 Recent experimental results from this laboratory have shown that thiourea dioxides are much more reactive than their trioxides.44 The longer


- 28 -

Page 29 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


C-S bond lengths in the dioxides clearly suggests that this reactivity is based on the cleavage of the C-S bond to yield a highly-reducing species.45 The two S-O bonds are nearly equivalent at 1.479 Å and 1.476 Å. They are shorter than the unique S-O bonds in unsubstituted thiourea dioxide (1.496 Å) and much longer than those in thiourea trioxide (1.431 to 1.446 Å). The density of DMAIMSA, at 1.496 g cm-3 is much lower than that recorded for thiourea trioxide of 1.948 g cm-3.43 This shows the absence of the extensive H-bonding in DMAIMSA that exists in thiourea trioxide.43 All this structural information confirms the instability of DMAIMSA. This is also corroborated by the fact that the DMAIMSA peak in Figure 8 is weak.


- 29 -


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 42

Figure 10: The zwitterionic crystal structure of DMAIMSA. Both C-S bonds and C-N bonds are equivalent; suggesting a delocalized positive charge on the N-C-N framework.

Overall Reaction Mechanism. The overall reaction scheme involves three reactions occurring simultaneously; R2, R3 and R5. Two are relatively slow (R2 and R3), and one is fast (R5). R2 and R3 are strongly catalyzed by acid, while R5 is relatively unaffected by acid except in very highly acidic conditions which were not utilized in this study. There were no stable intermediates observed between DMTU and the product, dimethylurea, such that the rate-


- 30 -

Page 31 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


determining step was the initial oxidation of DMTU to the putative sulfenic acid. Further oxidation of the sulfenic acid is very rapid. This is evidenced by the fact that, even in conditions of excess reductant, all sulfenic acid molecules formed are more relatively oxidized to urea and sulfate before another DMTU molecule is oxidized to sulfenic acid. The overall reaction scheme is shown in Table 1. Simulations were performed using the program Kintecus, developed by James Ianni.46 The simulations, shown in Figure 11, were very simple, since they effectively involved only one adjustable parameter, kM1.


- 31 -


0.4 Time [Sim (b Plot)] vs Absor [Sim (b Plot)] Time [Expt (b Plot)] vs Absor [Expt (b Plot)] Time[Sim (d Plot)] vs Abs[Sim (d Plot)] Time[Expt (d Plot)] vs Abs[Expt(d Plot)]

0.3

Absorbance (390 nm)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 32 of 42

0.2

0.1

0.0 0

100

200

300

400

Time (s)

Figure 11. Computer simulation for the initial conditions of the reaction shown in Figure 3. Traces (b) and (d) were simulated. [DMTU]0 = 2.5 x 10-3 M; [BrO3-]0 = 0.003 M. [H+]0 = (a) 0.225 M; (b) = 0.275 M.

The rest of the kinetics parameters were derived from the standard well-known oxybromine chemistry.25,27,28 The forward rate constant used for reaction M1 determined the induction period, time taken before formation of bromine. Oxidations of the sulfenic,


- 32 -

Page 33 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


sulfinic and sulfonic acids were deliberately rendered fast and not rate-determining. Pathway M7 to M9, involving formation of thiyl radicals and the dimeric species was not important in this mechanism, and this set of reactions plus M19 and M20 could be removed from the mechanism without any loss in accuracy of the model. kM12 was determined from this study. Subsequent oxidations of the oxo-acids were deliberately made faster than this value. ESI spectrum Figure 8 shows that there is a need for disproportionation reaction M16 and M17 since the sulfenic and sulfinic acids were not observed even with excess reductant. This suggests that the sulfenic acid is extremely labile and will rapidly disproportionate, stepwise, to sulfate and thiol in the absence of further oxidant. Figure 11 shows a reasonably good fit to the experimental data. Conclusion. The mechanism of this oxidation is in contrast to that derived for the comparable oxidation of tetramethylthiourea, TTTU in which all the intermediate oxo-acids were observed in substantial quantities before formation of sulfate and the urea analogue.13 The lack of hydrogen atoms on the nitrogen atoms in TTTU means that intermediate oxoacids cannot exist in neutral form, but only as zwitterions. These zwitterions are stable in acidic medium.29 In basic medium, however, the positively-disposed carbon center is vulnerable to nucleophilic attack and thus will decompose readily to yield the sulfur-based radical species that are known to be genotoxic.39 Thus TTTU is a wellknown teratogen and fetotoxin in the physiological environment (pH 7.4)47 while DMTU is an efficient radical scavenger due to its ease of oxidation.30 This proves that closelyrelated thioureas can impart vastly different physiological effects.16


- 33 -


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 34 of 42

Acknowledgements. This work was supported by a National Science Foundation grant number CHE-1056366 and a partial Research Professor grant from the University of KwaZulu-Natal. Dr. K. Chipiso ran the ESI-MS spectrum shown in Figure 8.


- 34 -

Page 35 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TABLE 1: Mechanism used for simulating the S-oxidation of DMTU. RSH is the enol form of DMTU

Reaction

Reaction

kf; kr

M1

BrO3- + RSH + H+→ HBrO2 + RSOH

8.0x10-1; 0

M2

HBrO2 + RSH →HOBr + RSOH

1.0x108; 0

M3

HOBr + RSH → Br- + H+ + RSOH

1.0x1010; 0

M4

BrO3- + 2H+ + Br- ⇄ HBrO2 + HOBr

2.1; 1.0x10-4

M5

HBrO2 + Br- + H+ ⇄ 2HOBr

2.0x106; 2.0x10-5

M6

HOBr + Br- + H+ ⇄ Br2 + H2O

8.9x109; 1.1x102

M7

BrO3- + HBrO2 + H+ →2BrO2· + H2O

1.1x10-4; approx. 0

M8

BrO2· + RSH → RS· + HBrO2

5.0; 0

M9

2RS· → RSSR

100

M10

HOBr + RSOH →RSO2H + Br- + H+

1.0x109

M11

HOBr + RSO2H → RSO3H + Br- + H+

1.0x109

M12

Br2(aq) + RSH + H2O → RSOH + 2Br-

1.95x105

+2H+ M13

Br2(aq) + RSOH + H2O → RSO2H + 2Br-

1.0x109

+2H+ M14

Br2(aq) + RSO2H + H2O → RSO3H + 2Br-

2.5x1010

+2H+ M15

Br2(aq) + RSO3H + 2H2O → SO42- + RC=O

1.5x106

+ 2Br- + 4H+


- 35 -


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 36 of 42

M16

RSO2H + RSO2H ⇄ RSOH + RSO3H

1.0x103; 1.0x101

M17

RSOH + RSO3H + H2O→ RSH + RC=O +

1.0x102

SO42- + 2H+ M18

RSOH + RSH → RSSR + H2O

1.0x10-4

M19

RSSR + HOBr + H2O → 2RSOH + Br- + H+

1.0x103

M20

RSSR + Br2 + 2H2O → 2RSOH + 2Br- +

1.0x104

2H+

Legend. RSOH: sulfenic acid; RSO2H: sulfinic acid; RSO3H: sulfonic acid


- 36 -

Page 37 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


References (1) Chinake, C. R.; Simoyi, R. H. New Experimental-Data on the Chlorite-Thiourea Reaction. J. Phys. Chem. 1993, 97, 11569-11570. (2) D'Cruz, O. J.; Venkatachalam, T. K.; Uckun, F. M. Novel Thiourea Compounds As Dual-Function Microbicides. Biol. Reprod. 2000, 63, 196-205. (3) Egan, T. J.; Koch, K. R.; Swan, P. L.; Clarkson, C.; Van Schalkwyk, D. A.; Smith, P. J. In Vitro Antimalarial Activity of a Series of Cationic 2,2'-Bipyridyland 1,10-Phenanthrolineplatinum(II) Benzoylthiourea Complexes J. Med. Chem. 2004, 47, 2926-2934. (4) Mujtaba, Q.; Burrow, G. N. Treatment of Hyperthyroidism in Pregnancy With Propylthiouracil and Methimazole. Obstet. Gynecol. 1975, 46, 282-286. (5) Ryu, B. J.; Hwang, M. K.; Park, M.; Lee, K.; Kim, S. H. Thiourea Compound AW00178 Sensitizes Human H1299 Lung Carcinoma Cells to TRAIL-Mediated Apoptosis. Bioorg. Med. Chem. Lett. 2012, 22, 3862-3865. (6) Opitz, R.; Trubiroha, A.; Lorenz, C.; Lutz, I.; Hartmann, S.; Blank, T.; Braunbeck, T.; Kloas, W. Expression of Sodium-Iodide Symporter MRNA in the Thyroid Gland of Xenopus Laevis Tadpoles: Developmental Expression, Effects of Antithyroidal Compounds, and Regulation by TSH. J. Endocrinol. 2006, 190, 157-170. (7) Axelsson, J.; Rippe, A.; Sverrisson, K.; Rippe, B. Scavengers of Reactive Oxygen Species, Paracalcitol, RhoA, and Rac-1 Inhibitors and Tacrolimus Inhibit Angiotensin II-Induced Actions on Glomerular Permeability. Am. J. Physiol Renal Physiol 2013, 305, F237-F243. (8) Chang, H. L.; Tseng, Y. L.; Ho, K. L.; Shie, S. C.; Wu, P. S.; Hsu, Y. T.; Lee, T. M. Reactive Oxygen Species Modulate the Differential Expression of Methionine Sulfoxide Reductase Genes in Chlamydomonas Reinhardtii Under High Light Illumination. Physiol Plant 2014, 150, 550-564. (9) Curtis, W. E.; Muldrow, M. E.; Parker, N. B.; Barkley, R.; Linas, S. L.; Repine, J. E. N,N'-Dimethylthiourea Dioxide Formation From N,N'-Dimethylthiourea Reflects Hydrogen Peroxide Concentrations in Simple Biological Systems. Proc. Natl. Acad. Sci. U. S A 1988, 85, 3422-3425. (10) Beehler, C. J.; Simchuk, M. L.; McCord, J. M.; Repine, J. E. Effects of Dimethylthiourea in Hyperoxic Injury. J. Lab Clin. Med. 1992, 119, 508-513. (11) Beehler, C. J.; Simchuk, M. L.; Toth, K. M.; Drake, S. K.; Parker, N. B.; White, C. W.; Berger, E. M.; Sanderson, R. J.; Repine, J. E. Blood Sulfhydryl Level


- 37 -


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 38 of 42

Increases During Hyperoxia: a Marker of Oxidant Lung Injury. J. Appl. Physiol (1985. ) 1989, 67, 1070-1075. (12) Chigwada, T. R.; Chikwana, E.; Ruwona, T.; Olagunju, O.; Simoyi, R. H. SOxygenation of Thiocarbamides. 3. Nonlinear Kinetics in the Oxidation of Trimethylthiourea by Acidic Bromate. J. Phys. Chem. A 2007, 111, 11552-11561. (13) Chigwada, T.; Mbiya, W.; Chipiso, K.; Simoyi, R. H. S-Oxygenation of Thiocarbamides V: Oxidation of Tetramethylthiourea by Chlorite in Slightly Acidic Media. J. Phys. Chem. A 2014, 118, 5903-5914. (14) Chigwada, T. R.; Chikwana, E.; Simoyi, R. H. S-Oxygenation of Thiocarbamides I: Oxidation of Phenylthiourea by Chlorite in Acidic Media. J. Phys. Chem. A 2005, 109, 1081-1093. (15) Chigwada, T. R.; Simoyi, R. H. S-Oxygenation of Thiocarbamides II: Oxidation of Trimethylthiourea by Chlorite and Chlorine Dioxide. J. Phys. Chem. A 2005, 109, 1094-1104. (16) Scott, A. M.; Powell, G. M.; Upshall, D. G.; Curtis, C. G. Pulmonary Toxicity of Thioureas in the Rat. Environ. Health Perspect. 1990, 85, 43-50. (17) Lee, P. W.; Arnau, T.; Neal, R. A. Metabolism of Alpha-Naphthylthiourea by Rat Liver and Rat Lung Microsomes. Toxicol. Appl. Pharmacol. 1980, 53, 164-173. (18) Lee, P. W.; Neal, R. A. Metabolism of Methimazole by Rat Liver Cytochrome P450-Containing Monoxygenases. Drug Metab Dispos. 1978, 6, 591-600. (19) Boyd, M. R.; Neal, R. A. Studies on the Mechanism of Toxicity and of Development of Tolerance to the Pulmonary Toxin, Alpha-Naphthylthiourea (ANTU). Drug Metab Dispos. 1976, 4, 314-322. (20) Thomas, E. L.; Grisham, M. B.; Jefferson, M. M. Myeloperoxidase-Dependent Effect of Amines on Functions of Isolated Neutrophils. J. Clin. Invest 1983, 72, 441-454. (21) Thomas, E. L.; Bozeman, P. M.; Jefferson, M. M.; King, C. C. Oxidation of Bromide by the Human Leukocyte Enzymes Myeloperoxidase and Eosinophil Peroxidase. Formation of Bromamines. J. Biol. Chem. 1995, 270, 2906-2913. (22) Jesaitis, A. J.; Dratz, E. A. The Molecular Basis of Oxidative Damage by Leukocytes; CRC Press: Boca Raton, 1992. (23) Simoyi, R. H. New bromate oscillator: The bromate-thiourea reaction in a CSTR. J. Phys. Chem. 1986, 90, 2802-2804..


- 38 -

Page 39 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(24) Chinake, C. R.; Simoyi, R. H. New Experimental-Data on the Chlorite-Thiourea Reaction. J. Phys. Chem. 1993, 97, 11569-11570. (25) Noyes, R. M. Chemical Oscillations and Instabilities. 39. A Generalized Mechanism for Bromate-Driven Oscillators by Bromide. J. Am. Chem. Soc. 1980, 102, 4644-4649. (26) Adigun, R. A.; Mhike, M.; Mbiya, W.; Jonnalagadda, S. B.; Simoyi, R. H. Oxyhalogen-Sulfur Chemistry: Kinetics and Mechanism of Oxidation of Chemoprotectant, Sodium 2-Mercaptoethanesulfonate, MESNA, by Acidic Bromate and Aqueous Bromine. J. Phys. Chem. A 2014, 118, 2196-2208. (27) Noyes, R. M.; Field, R. J.; Thompson, R. C. Mechanism of Reaction of Bromine(V) With Weak One-Electron Reducing Agents. J. Am. Chem. Soc. 1971, 93, 7315-7316. (28) Sortes, C. E.; Faria, R. B. Revisiting the kinetics and mechanism of bromatebromide reaction. J. Braz. Chem. Soc. 2001 12, 775-779.. (29) Chigwada, T.; Mbiya, W.; Chipiso, K.; Simoyi, R. H. S-Oxygenation of Thiocarbamides V: Oxidation of Tetramethylthiourea by Chlorite in Slightly Acidic Media. J. Phys. Chem. A 2014, 118, 5903-5914. (30) Linas, S. L.; Shanley, P. F.; White, C. W.; Parker, N. P.; Repine, J. E. O2 Metabolite-Mediated Injury in Perfused Kidneys Is Reflected by Consumption of DMTU and Glutathione. Am. J. Physiol 1987, 253, F692-F701. (31) Bishop, M. J.; Chi, E. Y.; Su, M.; Cheney, F. W. Dimethylthiourea Does Not Ameliorate Reperfusion Lung Injury in Dogs or Rabbits. J. Appl. Physiol 1988, 65, 2051-2056. (32) Mrakavova, M.; Melichercik, M.; Olexova, A.; Treindl, L. The Autocatalytic Reduction of Ferriin by Malonic Acid With Regard to the Ferroin-Catalyzed Belousov-Zhabotinsky Reaction. Coll. Czechoslovak Chem. Commun. 2003, 68, 23-34. (33) Sirimungkala, A.; Forsterling, H. D.; Dlask, V.; Field, R. J. Bromination Reactions Important in the Mechanism of the Belousov-Zhabotinsky System. J. Phys. Chem. A 1999, 103, 1038-1043. (34) Szalai, I.; Oslonovitch, J.; Forsterling, H. D. Oscillations in the Bromomalonic Acid/Bromate System Catalyzed by [Ru(Phen)(3)](2+). J. Phys. Chem. A 2000, 104, 1495-1498. (35) Ozawa, T.; Miura, Y.; Ueda, J. Oxidation of Spin-Traps by Chlorine Dioxide (ClO2) Radical in Aqueous Solutions: First ESR Evidence of Formation of New Nitroxide Radicals. Free Radic. Biol. Med. 1996, 20, 837-841.


- 39 -


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 40 of 42

(36) Bernofsky, C.; Bandara, B. M.; Hinojosa, O. Electron Spin Resonance Studies of the Reaction of Hypochlorite With 5,5-Dimethyl-1-Pyrroline-N-Oxide. Free Radic. Biol. Med. 1990, 8, 231-239. (37) Aslabban, M.; Adigun, R. A.; DeBenedetti, W. J.; Mbiya, W.; Mhike, M.; Morakinyo, M. K.; Otoikhian, A. A.; Ruwona, T.; Simoyi, R. H. Detailed Mechanistic Studies into the Reactivities of Thiourea and Substituted Thiourea Oxo-Acids Part I: Decompositions and Hydrolyses of Dioxides in Basic Media. J. Phys. Chem. A 2014. (38) Ojo, J. F.; Petersen, J. L.; Otoikhian, A.; Simoyi, R. H. Organosulfur Oxoacids. Part 1. Synthesis, Structure, and Reactivity of Dimethylaminoiminomethanesulfinic Acid (DMAIMSA). Can. J. Chem. 2006, 84, 825-830. (39) Makarov, S. V.; Mundoma, C.; Svarovsky, S. A.; Shi, X.; Gannett, P. M.; Simoyi, R. H. Reactive Oxygen Species in the Aerobic Decomposition of Sodium Hydroxymethanesulfinate. Arch. Biochem. Biophys. 1999, 367, 289-296. (40) Lewis, D.; Mama, J.; Hawkes, J. An Investigation into the Structure and Chemical Properties of Formamidine Sulfinic Acid. Appl. Spectrosc. 2014, 68, 1327-1332. (41) Huheey, J.; Keiter, E. A.; Keiter, R. L. Inorganic Chemistry of Structure and Reactivity; Harper Collins College Publishing: New York, 1993; pp 114. (42) Song, J. S.; Kim, E. H.; Kang, S. K.; Yun, S. S.; Suh, I.-H.; Choi, S. S.; Lee, S. XRay Crystal Structure for Thiourea Dioxide. Bull. Korean Chem. Soc. 1996, 17, 201-205. (43) Makarov, S. V.; Mundoma, C.; Penn, J. H.; Petersen, J. L.; Svarovsky, S. A.; Simoyi, R. H. Structure and Stability of Aminoiminomethanesulfonic Acid. Inorg. Chim. Acta 1999, 286, 149-154. (44) Makarov, S. V.; Mundoma, C.; Penn, J. H.; Svarovsky, S. A.; Simoyi, R. H. New and Surprising Experimental Results From the Oxidation of Sulfinic and Sulfonic Acids. J. Phys. Chem. A 1998, 102, 6786-6792. (45) Svarovsky, S. A.; Simoyi, R. H.; Makarov, S. V. Reactive Oxygen Species in Aerobic Decomposition of Thiourea Dioxides. Journal of the Chemical SocietyDalton Transactions 2000, 511-514. (46) Ianni, J. C. Kintecus Version 3. 1995. (47) Teramoto, S.; Kaneda, M.; Aoyama, H.; Shirasu, Y. Correlation Between the Molecular Structure of N-Alkylureas and N-Alkylthioureas and Their Teratogenic Properties. Teratology 1981, 23, 335-342.


- 40 -

Page 41 of 42

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TOC Graphic


- 41 -


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

TOC Graphic

ACS Paragon Plus Environment Printed by BoltPDF (c) NCH Software. Free for non-commercial use only.

Page 42 of 42

Oxyhalogen-Sulfur Chemistry: Kinetics and Mechanism of Oxidation of

Recommend Documents