Organosulfur oxoacids. Part 2. A novel dimethylthiourea metabolite - Synthesis and characterization of the surprisingly stable and inert dimethylaminoiminomethane sulfonic acid

Article abstract of DOI:10.1139/V10-125

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.

Full text of DOI:10.1139/V10-125

1247
Organosulfur oxoacids. Part 2. A novel
dimethylthiourea metabolite — Synthesis and
characterization of the surprisingly stable and
inert dimethylaminoiminomethane sulfonic acid
Jeffrey L. Petersen, Adenike A. Otoikhian, Moshood K. Morakinyo, and
Reuben H. Simoyi
Abstract: 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 ortho-
rhombic 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.
Key words: thiourea, metabolites, bioactivation.
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Resume : On a effectue la synthese d’un nouveau metabolite du thiocarbamide de la dimethylthiouree (DMTU), un pro-
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duit biologiquement actif. On s’attend a ce que l’activation metabolique du DMTU dans un environnement physiologique
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devrait etre dominee par une S-oxygenation qui conduit a la formation successive d’acides sulfenique, sulfinique et sulfo-
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nique avant de donner un sulfate et de la dimethyluree. Seuls les acides sulfinique et sulfonique sont suffisamment stables
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pour etre isoles. Dans ce travail, on rapporte la premiere synthese, l’isolation et la caracterisation de l’acide sulfonique,
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l’acide dimethylaminoiminomethanesulfonique (ADMAIMSO). Il cristallise dans le systeme orthorhombique, groupe
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d’espace Pbca et dans sa forme cristalline solide il existe sous la forme de zwitterion. La charge negative est delocalisee
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sur les oxygenes de l’acide sulfonique et la charge positive est concentree sur le squelette planaire N–C–N plutot que stric-
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tement sur le centre carbone cationique d’hybridation sp . Par opposition a son analogue l’acide sulfinique, le AD-
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MAIMSO est extremement inerte dans des environnements acides et il peut maintenir son titre pour plusieurs semaines a
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des pH de 6 ou moins. Il est toutefois assez reactif dans des conditions de pH physiologique et il peut etre oxyde en dime-
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thyluree et en sulfate par des oxydants doux, tel une solution aqueuse d’iode.
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Mots-cles : thiouree, metabolites, bioactivation.
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[Traduit par la Redaction]
handling a large numbers of xenobiotics.5 Our bodies, how-
ever, do not have a consistent answer to sulfur-based xeno-
biotics. Nearly all relevant sulfur chemistry in the human
body is of organic origin. The range of physiological effects
associated with organic sulfur chemistry spans from thera-
peutic to toxic.6 There is no other group of compounds that
displays such a wide range of biological activity. While the
action and effects of organosulfur compounds on human
health is well-documented, the mechanisms by which these
effects are expressed are not known. Drug design and the
Introduction
N,N’-Dimethylthiourea (DMTU) is a well-known sulfur-
based radical scavenger.1–4 It is a small, highly diffusible
molecule that efficiently scavenges toxic oxygen metabolites
and reduces oxidative injury in many biologic systems.
There have been very few studies undertaken on the fate
and nature of the metabolites formed after such antioxidants
have mediated oxidative injury.
Our bodies have evolved several very efficient methods of
Received 28 May 2010. Accepted 26 July 2010. Published on the NRC Research Press Web site at canjchem.nrc.ca on 25 November
2010.
J.L. Petersen. C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506-6045, USA.
A.A. Otoikhian, M.K. Morakinyo, and R.H. Simoyi.1 Department of Chemistry, Portland State University, Portland, OR 97207-0751,
USA.
1Corresponding author (e-mail: rsimoyi@pdx.edu).
Can. J. Chem. 88: 1247–1255 (2010)
doi:10.1139/V10-125
Published by NRC Research Press

1248
Can. J. Chem. Vol. 88, 2010
Table 1. Crystal data and structure refinement for DMAIMSOA.
ability to predict physiological effects is dependent upon our
ability to understand the mechanism of metabolic activation
of the relevant drug.
Empirical formula
Formula weight
Temperature (K)
C3H8N2O3SꢀH2O
170.19
295(2)
Sulfur compounds, such as DMTU, undergo a variety of
metabolic reactions in the physiological environment such
as oxidations, reductions, hydrolysis, and conjugations.7 Sul-
fur, in most organic configurations, however, is nucleophilic,
and nucleophilic atoms are usually susceptible to metabolic
oxidations.8 Thus, the oxidation of sulfur-containing com-
pounds represents a very important aspect of sulfur metabo-
lism. Oxidations of sulfur compounds appear to be involved
in many cellular functions, including the reductive degrada-
tion of polypeptide hormones and proteins, regulation of
protein synthesis, maintenance of intracellular redox poten-
tial, and protection of the cell from oxidative damage.9 The
aerobic physiological environment encourages S-oxygenation
as the major metabolic activation pathway for most organo-
sulfur compounds where the sulfur center is successively
oxygenated, sometimes all the way to the sulfate, culminating
in the cleavage of the attendant C–S bond.10,11
The molecular basis for S-oxygenation is not well-
understood, although S-oxygenation of xenobiotics by mi-
crosomes supplemented with NADPH and oxygen has been
known for years. In general, metabolism of chemically sta-
ble compounds depends on enzyme catalysis, and both the
microsomal cytochrome P-450 system and the flavin-containing
monooxygenases have been implicated in S-oxygenations
catalyzed by microsomes.8,12,13
˚
Wavelength (A)
0.71073
Crystal system
Space group
Orthorhombic
Pbca
Unit cell dimensions
˚
a (A)
12.533(1)
9.624(1)
12.918(1)
˚
c (A)
˚
c (A)
a (8)
b (8)
g (8)
90
90
90
1558.1(2)
3
˚
Volume (A )
Z
8
Density (calculated; g/cm3)
Absorption coefficient (cm–1)
F(000)
1.451
3.81
720
0.20 ꢁ 0.40 ꢁ 0.44
Crystal size (mm3)
q range for data collection (8) 3.10–25.00
Limiting indices
0 £ h £ 14
0 £ k £ 11
–15 £ l £ 0
Reflections collected
Independent reflections
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2s(I)]
R indices (all data)
1356
1356
Full-matrix least-squares on F2
1356/0/102
DMTU, although in most situations is effective in de-
creasing oxidant-mediated injury, has, however, inexplicably
failed, on occasions, to reduce injury in some biological sys-
tems where oxygen metabolites were ostensibly causing
damage.14,15 It has also been experimentally shown that in-
creasing the DMTU dose in rats did not increase protection
and may, in fact, be associated with more injury. DMTU
should exercise its physiological effects after metabolic acti-
vation and it is generally accepted that these physiological
effects are derived from its metabolites.
1.022
R1 = 0.0462, wR2 = 0.1032
R1 = 0.0838, wR2 = 0.1205
Largest diff. peak and hole (e 0.241 and –0.307
–3
˚
A )
Table 2. Atomic coordinates (ꢁ104) and equivalent isotropic
2
displacement parameters (A ꢁ 103) for SO3C(NHMe)2ꢀH2O.
˚
U(eq) is defined as one third of the trace of the orthogonalized
Uij tensor.
In a previous publication from this laboratory,16 we syn-
thesized the first stable metabolite of DMTU, dimethylami-
noiminomethanesulfinic acid (DMAIMSA). This metabolite
was surprisingly very reactive and its aerobic decomposition
in slightly basic to basic environments produced dithionite
and a cascade of reactive oxygen species that were geno-
toxic, and could explain some of the inadvertent toxicity as-
sociated with DMTU. The general progress of the oxidation
of a sulfur center initially proceeds through the sulfenic acid
(unstable except in sterically hindered sulfenic acids),17–19
then to the sulfinic acid (e.g., DMAIMSA), and then the sul-
fonic acid before cleavage of the C–S bond to form sulfate
and an organic residue.20 The existence of DMAIMSA had
always been conjectured, but no one had managed to pre-
pare and characterize this metabolite until the work of Otoi-
khian and co-workers.16,21,22
Since the sulfonic acid (dimethylaminoiminomethanesul-
fonic acid, DMAIMSOA) is expected to be the next metabo-
lite after formation of DMAIMSA, we undertook to
synthesize and characterize this metabolite, and hopefully,
from its reactivity, be able to rationalize some of the ob-
served conflicting physiological effects of DMTU. We re-
port in this manuscript on this oxidation metabolite of
x
y
z
U(eq)
37(1)
60(1)
50(1)
58(1)
66(1)
39(1)
41(1)
32(1)
49(1)
57(1)
S
3569(1)
3597(2)
3329(2)
4444(2)
4487(3)
2636(2)
1469(2)
2427(3)
1825(3)
1158(3)
278(1)
–1207(3)
811(3)
985(3)
2529(4)
1527(3)
372(3)
783(3)
2042(4)
–468(4)
6551(1)
6619(2)
5538(2)
7046(2)
4164(3)
8142(2)
7079(2)
7335(3)
8854(3)
6185(3)
O(1)
O(2)
O(3)
O(4)
N(1)
N(2)
C(1)
C(2)
C(3)
DMTU. Despite its similarity to DMAIMSA, DMAIMSOA
proved to be very different from DMAIMSA in terms of
structure and reactivity.
Experimental
Materials
DMTU, hydrogen peroxide, and acetonitrile (Sigma-Aldrich)
were purchased and used without any further purification.
Published by NRC Research Press

Petersen et al.
1249
Some batches of DMTU were damp and oily and could not
form DMAIMSOA upon applying the synthetic procedure
outlined below. Instead, the product formed slowly turned
yellow upon exposure to the atmosphere and at ambient
temperatures. The consistency of the DMTU batches was
extremely important for the generation of high and consis-
tent yields of DMAIMSOA. Aqueous iodine solutions were
prepared by dissolving iodine crystals (Sigma-Aldrich) in
distilled water followed by filtration and storage in the
dark. Standard solutions of sodium hydroxide were pur-
chased from Fisher Scientific.
Description of the X-ray structural analysis of
C3H8N2O3SꢀH2O
A colorless crystal of C3H8N2O3SꢀH2O was wedged in a
glass capillary and then optically aligned on the four-circle
of a Siemens P4 automated X-ray diffractometer. The reflec-
tions that were used for the unit cell determination were lo-
cated and indexed by the automatic peak search routine
provided by XSCANS.23 C3H8N2O3SꢀH2O crystallizes in the
15
2h
centrosymmetric space group Pbca (D , No. 61). The final
lattice parameters and orientation matrix were calculated
from a nonlinear least-squares fit of the orientation angles
of at least 35 reflections at 22 8C. The lattice parameters
and other pertinent crystallographic information are sum-
marized in Table 1 for C3H8N2O3SꢀH2O.
Synthesis of DMAIMSOA
N,N’-Dimethylaminoiminomethanesulfonic acid (DMAIMSOA)
was prepared according to a modified form of a synthetic
procedure given in the literature for the synthesis of dime-
thylaminoiminomethanesulfinic acid (DMAIMSA).16 N,N’-
Dimethylthiourea (DMTU; 10.42 g, 0.10 mol) were dis-
solved in 80 mL of a 50% acetonitrile–water solution, which
was chilled in an acetone–CO2 ice bath at –50 8C. To this
ice-cold solution, 3 equiv (0.30 mol) of hydrogen peroxide,
which was measured as a 30.61 mL aliquot of a 30% con-
centrated solution, were added dropwise with the rate of ad-
dition maintained such that the temperature of the reaction
mixture did not exceed –30 8C. The 3:1 ratio of hydrogen
peroxide to DMTU had to be strictly maintained to avoid
the production of mixtures of oxoacids. The frozen mixture
was allowed to sit until it melted and it was then stirred at
room temperature for 2 h. The resulting long, colorless, nee-
dle-like crystals were filtered and washed twice with a 50%
acetonitrile–water solution and deionized water and then
dried in a desiccator. Typical yields before recrystallization
were approximately 90%. Further recrystallization and puri-
fication was performed using the same strength of acetoni-
trile solution. Most of the product was lost during the
washing and recrystallization of DMAIMSOA, thus giving a
lower overall yield since it is highly soluble in water.
Intensity data were measured with graphite-monochromated
˚
Mo Ka radiation (l = 0.710 73 A) and variable u scans.
Background counts were measured at the beginning and at
the end of each scan with the crystal and counter kept sta-
tionary. The intensities of three standard reflections were
measured after every 100 reflections and did not show any
evidence of crystal decay. The raw data were corrected for
Lorentz-polarization effects.
Initial coordinates for the nonhydrogen atoms were deter-
mined by a combination of direct methods and difference
Fourier calculations with the use of SHELXTL 6.1.24 The
crystallographic asymmetric unit contains a molecule of
water that is located in a general position and is hydrogen
bonded to the O(2) atom. The hydrogen atoms of the water
molecule were located and their positions and isotropic tem-
perature parameters were refined. Idealized positions for the
remaining hydrogen atoms were included as fixed contribu-
tions using a riding model with isotropic temperature factors
set at 1.2 times that of the adjacent nonhydrogen atom. The
positions of the methyl hydrogen atoms were optimized by a
rigid rotating group refinement with idealized angles. Full-
matrix least-squares refinement, based upon the minimiza-
tion of Swi |Fo – Fc | with weighting wi–1 = [s2(Fo ) +
2
2 2
2
(0.0528P)2 + 0.880P] where P = (max(Fo , 0) + 2Fc )/3,
converged to give the final discrepancy indices25 provided
in Table 1. A correction for secondary extinction was applied.
The maximum and minimum residual electron density peaks in
2
2
Methods
UV–vis spectra were taken on a PerkinElmer Lambda 2S
spectrophotometer equipped with a thermostatable compart-
–3
˚
ment. Most experiments were performed at 25
0.5 8C.
the final difference Fourier map were 0.241 and –0.307 e A ,
respectively (Table 2). The linear absorption coefficient,
atomic scattering factors, and anomalous dispersion correc-
tions were calculated from values found in the International
Tables of X-ray Crystallography.26
Distilled and deionized water were utilized to prepare all
standard solutions used in these experiments. The reaction
between DMAIMSOA and HOCl was monitored by follow-
ing the absorbance of DMAIMSOA at 215 nm where an ab-
sorptivity coefficient of 9025 (mol/L)–1 cm–1 had been
deduced. The reaction between DMAIMSOA and iodine (as
well as iodate) was followed by the use of the iodine–
triiodide isosbestic point, which had been experimentally de-
termined as 465 nm in this work and other previous studies
from our laboratory using the same spectrophotometer.21
Only freshly prepared iodine solutions were utilized. A Hi-
Tech Scientific SF-DX2 stopped-flow spectrophotometer
was used to follow the kinetics of DMAIMSOA oxidations
and hydrolysis. KinetAsyst 2.1 software (High-Tech Scien-
tific) was used for data acquisition and analysis. Tempera-
ture control was maintained with a NesLab RTE-101
thermostat bath. Some reaction solutions were degassed
with argon and tightly capped to reduce the effects of dis-
solved oxygen.
Results and discussion
Description of the molecular structure of DMAIMSOA
(SO3C(NHMe)2)
The molecular structure of DMAIMSOA was determined
by X-ray crystallography. The perspective view is shown in
Fig. 1. Like its sulfinic acid analogue,16 it exists in its zwit-
terionic form in solid crystal form. The positive charge is
delocalized over the N(2)–C(1)–N(1) framework with the
sp2 hybridization at the central carbon atom. Bond angles
around this carbon atom add up to 3608. The C(1)–N bond
˚
distances of 1.291(4) and 1.306(4) A are significantly
˚
shorter than a C–N bond distance of 1.47 A, indicating con-
siderable double bond character in both of them. The whole
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Can. J. Chem. Vol. 88, 2010
Fig. 1. Perspective view of the molecular structure of DMAIMSOA
with the atom labeling scheme. Thermal ellipsoids are scaled to en-
close 30% probability.
Fig. 2. Comparison traces of iodine oxidation of DMAIMSA and
DMAIMSOA showing the relative inertness of DMAIMSOA to
oxidation. Iodine solutions with DMAIMSOA held their titer for
hours with no measurable consumption of iodine observed. [I2]o =
5.24 ꢁ 10–4 mol/L, (a) [DMAIMSA]o = 2.0 ꢁ 10–4 mol/L, and (b)
[DMAIMSOA]o = 2.0 ꢁ 10–4 mol/L.
formally cationic carbon center, imparting partial double
bond character to both bonds, and hence their deviation
from the expected value for a single bond. The negative
charge is delocalized on the three oxygen atoms on the sul-
fonic acid group. The S–O bonds are also nearly equivalent,
˚
ranging between 1.433(3) and 1.440(3) A. These are shorter
than a normal S–O bond owing to the delocalization of the
negative charge over the three oxygen atoms. These three S–
˚
O bonds are approximately 0.04 A shorter than the two S–O
˚
bonds in DMAIMSA, which are at approximately 1.48 A.
The three oxygens form a nearly symmetric triangular base
around the sulfur center except for the oxygen atom in close
proximity to the methyl group, which is slightly displaced
from this pyramidal shape by about 28 (Table 3).
˚
Table 3. Interatomic distances (A)
and bond angles (8) for DMAIMSOA.
˚
˚
The C–S bond, at 1.820(3) A, is 0.03 A longer than a typ-
˚
˚
ical C–S bond of 1.79 A, but is noticeably shorter than the
Interatomic distances (A)
˚
˚
C–S bonds of 1.880 A in DMAIMSA and 1.867 A in unsub-
stituted aminoiminomethanesulfinic acid (AIMSA, thiourea
dioxide). Both sulfinic acids are highly reactive with easy
cleavage of the C–S bond to release highly reducing sulfur-
based leaving groups.27 DMAIMSOA is not densely packed,
and has a density of 1.451 g cm–3, which is comparable to
that exhibited by DMAIMSA of 1.496 g cm–3. Although
DMAIMSOA shows hydrogen bonding through O(2) to the
single water of crystallization in the unit cell, it is incapable
of supporting strong and extensive hydrogen bonding, which
would have been expected to increase its density as was ob-
served with aminoiminomethanesulfonic acid (AIMSOA,
thiourea trioxide) with a density of 1.948 g cm–3.28
S—O(1)
S—O(2)
S—O(3)
S—C(1)
1.433(3)
1.437(3)
1.440(3)
1.820(3)
1.291(4)
1.458(4)
1.306(4)
1.463(5)
N(1)—C(1)
N(1)—C(2)
N(2)—C(1)
N(2)—C(3)
Bond angles (8)
O(1)–S–O(2)
O(1)–S–O(3)
O(2)–S–O(3)
O(1)–S–C(1)
O(2)–S–C(1)
O(3)–S–C(1)
N(1)–C(1)–N(2)
N(1)–C(1)–S
C(1)–N(2)–C(3)
C(1)–N(1)–C(2)
N(2)–C(1)–S
114.7(2)
115.2(2)
113.3(2)
104.6(2)
104.2(1)
103.1(2)
123.9(3)
115.9(2)
127.7(3)
123.8(3)
120.1(3)
Reactivity of DMAIMSOA
DMAIMSA is known to be highly reactive, and its aero-
bic decomposition in mildly acidic and basic environments
quickly and rapidly produces dithionite.16 Its oxidation to di-
methylurea and sulfate is facile. Figure 2 shows a simple ex-
periment carried out to evaluate the rates of oxidation of
DMAIMSA and DMAIMSOA in slightly acidic media (pH
5.0) by the weak biological oxidant iodine. While
DMAIMSA is oxidized at a reasonable rate with bimolecu-
lar kinetics with a rate constant of 20.5 (mol/L)–1 s–1,
three-bond network, after the s-bond framework, then com-
prises four electrons, both derived from the nitrogen p-
orbitals, which interact with the vacant pp-orbitals of the
Published by NRC Research Press

Petersen et al.
1251
Fig. 3. (a) UV spectral of incubated DMAIMSOA in water at a
slightly acidic pH of 6 showing its inertness. The spectra scan was
taken at 24 h intervals for 7 days. There is very little change in the
absorbance of DMAIMSOA. [DMAIMSOA] = 1.0 ꢁ 10–4 mol/L.
(b) UV spectra scan of the same DMAIMSOA solution as in
Fig. 3a at a physiological pH of 7.4 phosphate buffer. At this
slightly basic pH there is a noticeable decomposition of DMAIM-
SOA. (c) The effect of pH on the rate of decomposition of
DMAIMSOA in 0.05 mol/L phosphate buffer. Substantial decom-
position starts at pH conditions greater than 7. [DMAIMSOA] =
1.0 ꢁ 10–4 mol/L; pH (a) 6.2 (unbuffered), (b) 6.2, (c) 6.6, (d) 7.0,
(e) 7.4, and (f) 8.2.
DMAIMSOA remains inert to oxidation at this pH. This was
a noticeable difference in the reactivities of these aminosul-
fur oxoacids. This discrepancy in their reactivities has
brought about a new school of thought that suggests,
strongly, that in acidic media, the sulfonic oxoacid is un-
likely to be an intermediate in the oxidation of the thiouredo
group to sulfate and an organic residue.29
Figure 3 also displays the inertness of DMAIMSOA. In
Fig. 3a, DMAIMSOA solutions are dissolved in water at a
slightly acidic pH of 6 and allowed to sit, capped, and in
the dark for a week. Other aminosulfur oxoacids show ex-
tensive decomposition in aqueous solutions.16 Figure 3a
shows that, even after 7 days, there is very little change in
the absorbance of DMAIMSOA monitored at 215 nm. Fig-
ure 3b, on the other hand, shows the same DMAIMSOA sol-
ution, this time in a pH 7.4 buffer, which is slightly basic
and is the physiological pH. At these conditions, there is no-
ticeable decomposition of DMAIMSOA. The slight change
in pH from Figs. 3a to 3b can impart a remarkable change
in reactivity. Figure 3c shows, much more vividly, the rates
of decomposition of DMAIMSOA at various pH conditions.
In all traces, the pH was maintained by phosphate-type buf-
fer solutions. The phosphate anions in this buffer mixture
are not innocent, and are known to increase the rate of de-
composition of aminosulfur oxoacids owing to their nucleo-
philic nature. Figure 3c shows that substantial
decomposition commences at pH conditions greater than 7.
While there is no decomposition observed around pH 6 (Fig.
3c, trace a), at pH 8.2 (Fig. 3c, trace f), however, complete
decomposition of DMAIMSOA is attained within 3 min.
Reactions with iodine and acidic iodate
It is not possible to spectrophotometrically observe I2–
DMAIMSOA reactions at high pH conditions because most
of the aqueous iodine is converted into hypoiodous acid,
which has no absorption in the visible range in neutral and
acidic environments. Iodine, however, exists mostly in the
aqueous molecular form and its consumption can be fol-
lowed at 460 nm (see Fig. 4a). Figure 4a shows an initially
reasonably fast rate of iodine consumption, which quickly
slows down and shuts itself down about 300 s into the reac-
tion. Figure 4a has an expanded scale, and shows that very
little aqueous iodine is actually consumed. These I2–
DMAIMSOA solutions can be left overnight and the absorb-
ance values reread after 24 h. After 24 h, the ratio of iodine
consumed is shown in Fig. 4b. The linearity shows that the
only reaction occurring is the consumption of iodine by
DMAIMSOA. The expected stoichiometry for the oxidation
of DMAIMSOA by iodine is 1:1
½1ꢂ
ðMeHNÞðMeN¼ÞCSO3H þ I2ðaqÞ þ 2H2O !
ðMeHNÞ2C¼O þ SO42ꢃ þ 2Iꢃ þ 4Hþ
The percent consumption of iodine should allow for the
calculation of the fraction of DMAIMSOA that is ‘‘oxi-
dizable’’ because these fractions in Fig. 4b remain basically
invariant on further incubation of the reaction solutions.
This percentage iodine consumption is calculated on the ba-
sis of the stoichiometry in eq. [1] in which a 1:1 mol ratio of
DMAIMSOA–I2 is considered to be 100%. Using the plot in
Fig. 4b and reaction stoichiometry in eq. [1], a simple calcu-
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1252
Can. J. Chem. Vol. 88, 2010
Fig. 4. (a) Absorbance traces showing the consumption of aqueous iodine by DMAIMSOA in unbuffered solutions. Despite the initial rea-
sonably fast rate of consumption, very little aqueous iodine is consumed. [I2(aq)] = 3.82 ꢁ 10–4 mol/L, [DMAIMSOA] = (a) 0.0, (b) 0.001,
(c) 0.005, (d) 0.010, and (e) 0.015 mol/L. (b) A linear plot showing the percent consumption of iodine in Fig. 4a after 24 h of I2–DMAIM-
SOA incubation. (c) Multiple spectral scan measurements of the reaction of DMAIMSOA and acidic iodate taken every 2 min showing the
formation of iodine at 460 nm. A very small amount of iodine is formed indicating that at these conditions only a negligible fraction of
DMAIMSOA is oxidizable. [DMAIMSOA] = 0.025 mol/L, [IO3 ] = 0.025 mol/L, and [H+] = 0.05 mol/L. (d) Comparison traces of the
–
percent formation of iodine in the reactions of freshly prepared (closed circles) and 3-day-old (open triangles) DMAIMSOA solutions with
acidic iodate. [DMAIMSOA] = 0.025 mol/L, [IO3 ] = 0.025 mol/L, and [H+] = 0.05 mol/L.
–
lation shows that 0.77% of DMAIMSOA is oxidized after
24 h of reaction time. This shows that, at these conditions,
only a very small fraction of DMAIMSOA is oxidized or
oxidizable. In the acidic environment, iodate can also be
used to evaluate the response of DMAIMSOA to oxidation.
By using excess iodate concentrations, the amount of iodine
produced can be utilized to calculate the amount of
DMAIMSOA oxidized (see Fig. 4c). Initially, iodate oxi-
dizes DMAIMSOA to produce iodide (reaction stoichiome-
try in eq. [2]), which is subsequently oxidized by the excess
iodate to give iodine (reaction in eq. [3]) as the final reduc-
tion product of iodate.
give the overall stoichiometry that gives iodine as the final
product:
½4ꢂ
2IO3ꢃ þ 5ðMeHNÞðMeN¼ÞCSO3H þ 4H2O !
I2 þ 5ðMeHNÞ2C¼O þ 5SO42ꢃ þ 8Hþ
One can thus correlate the amount of iodine formed to the
amount of DMAIMSOA consumed through the 5:1 ratio.
Figure 4c shows that very little iodine is formed, also con-
firming that very little DMAIMSOA is oxidized under these
–
conditions. IO3 is inert in basic environments, and thus this
type of correlation can only be effected in this acidic envi-
ronment. Previous work in our laboratory27,31 and by
others32 had always conjectured that such aminosulfur oxoa-
cids initially undergo an irreversible, entropy-driven hydrol-
½2ꢂ
IO3ꢃ þ 3ðMeHNÞðMeN¼ÞCSO3H þ 3H2O !
Iꢃ þ 3ðMeHNÞ2C¼O þ 3SO42ꢃ þ 6Hþ
ysis to give
a
reducing sulfur species, which in
Followed by the Dushman reaction:30
DMAIMSOA’s case is bisulfite:
½3ꢂ
IO3ꢃ þ 5Iꢃ þ 6Hþ ! 3I2 þ 3H2O
½5ꢂ
ðMeHNÞðMeN¼ÞCSO3H þ H2O !
ðMeHNÞ2C¼O þ HSO3ꢃ þ Hþ
The addition of 5(eq. [2]) and eq. [3] eliminates iodide to
Published by NRC Research Press

Petersen et al.
1253
Fig. 5. (a) UV spectral scans of the HOCl–DMAIMSOA reaction after 48 h of reaction time at pH 7.4 in 0.05 mol/L phosphate buffer.
[DMAIMSOA] = 2.0 ꢁ 10–4 mol/L, [HOCl] = (a) 0 (not buffered), (b) 0 (buffered), (c) 5.00 ꢁ 10–5, (d) 7.50 ꢁ 10–5, (e) 1.00 ꢁ 10–4, (f)
1.25 ꢁ 10–4, (g) 1.50 ꢁ 10–4, (h) 1.75 ꢁ 10–4, (i) 2.00 ꢁ 10–4, (j) 3.00 ꢁ 10–4, (k) 4.00 ꢁ 10–4, (l) 5.00 ꢁ 10–4, (m) 6.00 ꢁ 10–4, (n) 7.00 ꢁ
10–4, (o) 8.00 ꢁ 10–4, (p) 9.00 ꢁ 10–4, and (q) 1.00 ꢁ 10–3 mol/L. (b) Absorbance traces at 292 nm showing variation of DMAIMSOA with
HOCl at a pH of 7.4 in 0.05 mol/L phosphate buffer. [HOCl] = 2.0 ꢁ 10–3 mol/L, [DMAIMSOA] = (a) 2.0 ꢁ 10–4, (b) 4.0 ꢁ 10–4, (c) 6.0 ꢁ
10–4, (d) 8.0 ꢁ 10–4, (e) 1.0 ꢁ 10–3, (f) 1.2 ꢁ 10–3, and (g) 1.4 ꢁ 10–3 mol/L. (c) Absorbance traces at 215 nm showing the effect of pH on
the HOCl–DMAIMSOA reaction in 0.05 mol/L phosphate buffer for a freshly prepared DMAIMSOA. [HOCl] = 3.0 ꢁ 10–3 mol/L and
[DMAMSOA] = 5.0 ꢁ 10–5 mol/L. (d) Absorbace traces of the same reaction in Fig. 5c but with a 7-day-old incubated DMAIMSOA.
The oxidations observed in Figs. 4a–4c are effectively the
oxidation of bisulfite released in the reaction in eq. [5]. The
extent of the reaction in eq. [5] (a sort of pseudoequilibrium
constant since eq. [5] is assumed to be irreversible) is
strongly dependent on pH, and any value derived for this re-
action has to be associated with a specific pH value. Further
studies are needed to evaluate the general base catalysis that
can be evoked by the anions that make up the various buf-
fers that might be used to maintain the pH. It is anticipated
that the type and concentrations of the buffers themselves
would influence the observed extent of the reaction in eq.
[5]. The reaction in eq. [5] is an extremely slow process,
which proceeds at a faster rate in basic conditions. Figure
4d shows that the reaction in eq. [5] is a prerequisite for the
observed oxidations in Figs. 4a and 4c. Some DMAIMSOA
reaction solutions were used immediately after preparation
(Fig. 4d, dark circles), while other solutions were incubated
tions (Fig. 4d, open triangles). It is evident that after 30 min
more of the DMAIMSOA is observed to have been oxidized
with the incubated solutions (1.23%) over those that were
not incubated (1.03%).
Reactions in basic environments
For these experiments, hypochlorous acid was used as the
–
oxidant. OCl has an absorption peak at 292 nm, and does
not interfere with the DMAIMSOA peak at 215 nm as HOI
does. Thus, the reaction between HOCl and DMAIMSOA
can be followed at both 215 and 292 nm. Figure 5a shows
a series of spectral scans of the HOCl–DMAIMSOA reac-
tion after 48 h of reaction time at pH 7.4 in a phosphate buf-
fer. Activity is observed at both wavelengths, showing a
very viable and facile reaction. The stoichiometry of this re-
action was derived to be 1:1 using barium sulfate precipita-
tion.
–
for 3 days before being used in the DMAIMSOA–IO3 reac-
Published by NRC Research Press

1254
Can. J. Chem. Vol. 88, 2010
½6ꢂ
ðMeHNÞðMeN¼ÞCSO3H þ HOCl þ H2O !
uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax +44 1223 336033; or deposit@ccdc.cam.ac.uk).
ðMeHNÞ2C¼O þ SO42ꢃ þ Clꢃ þ 3Hþ
Absorbance traces in Fig. 5b were monitored at 292 nm,
and show that the reaction essentially goes to completion
and is over within 20 s. Any rate constant derived from
these data is only relevant for this pH condition and for this
buffer strength and concentration. The final observed rate of
reaction is derived from a complex interaction of the buffer
anions with DMAIMSOA and their effect in facilitating the
reaction in eq. [5]. The positively charged carbon center is
susceptible to nucleophilic attack with the result that the C–
S bond is weakened, facilitating its cleavage. Figures 5c and
5d show that the incubation of solutions is not an important
factor for reactions run in basic environments. Freshly pre-
pared solutions gave nearly the same reaction times as those
incubated for a week. Examination of the initial absorbance
readings for the incubated solutions, however, show that the
initial DMAIMSOA absorbances are depressed from the val-
ues recorded for unincubated solutions. The data, taken at
215 nm in Figs. 5c and 5d, are more difficult to explain if
indeed the reaction in eq. [5] is irreversible. Thus, in basic
environments, some equilibrium is attained, although some
irreversible entropically favored decomposition also still
Acknowledgements
This work was supported by Research Grant No. CHE
0614924 from the National Science Foundation.
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