Identification of dimethyl sulfide in dimethyl sulfoxide and implications for metal-thiolate disulfide exchange reactions

Article abstract of DOI:10.1039/c5ra04985g

The concentration of dimethyl sulfide (DMS) in seven different samples of research grade dimethyl sulfoxide (DMSO), including one deuterated sample, was measured by GC-MS. The average concentration of DMS is 0.48 ± 0.14 mM (range: 0.44-0.55 mM) and ca. 0.

Full text of DOI:10.1039/c5ra04985g

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Identification of dimethyl sulfide in dimethyl
sulfoxide and implications for metal-thiolate
Cite this: RSC Adv., 2015, 5, 40603
disulfide exchange reactions†
Received 21st March 2015
Accepted 27th April 2015
a
a
a
a
Gamage S. P. Garusinghe, S. Max Bessey, Chelsea Boyd, Mostapha Aghamoosa,
ab
a
a
Brian G. Frederick, Mitchell R. M. Bruce* and Alice E. Bruce*
DOI: 10.1039/c5ra04985g
www.rsc.org/advances
The concentration of dimethyl sulfide (DMS) in seven different samples in high dielectric solvents, such as water or DMSO, than in low
17
of research grade dimethyl sulfoxide (DMSO), including one deuter- dielectric solvents such as THF or CH Cl . Since the metal
2
2
ated sample, was measured by GC-MS. The average concentration of thiolate complexes and disuldes employed in our kinetic
DMS is 0.48 ꢀ 0.14 mM (range: 0.44–0.55 mM) and ca. 0.35 mM in studies are not water-soluble, DMSO was selected as a solvent
1
DMSO-d
6
. The presence of DMS in DMSO is potentially problematic with a high dielectric constant (3 ¼ 46.45) for these studies.
for compounds that are susceptible to reaction with DMS and are During the course of kinetic investigations, we observed that
present at mM–mM concentrations. Standard methods of purification addition of bis(4-nitrophenyl)disulde to DMSO, in the absence
of DMSO were unsuccessful in removing all traces of DMS.
of any metal thiolate, formed a pale red solution with an
absorbance near 500 nm. Bis(4-nitrophenyl)disulde is isolated
as a pale yellow solid aer recrystallization from boiling n-
butanol. When the disulde is dissolved in solvents such as
Dimethyl sulfoxide (DMSO) is an aprotic, polar solvent that is
widely used in chemistry and biology. It dissolves hydrophobic
CH
i.e. there is no absorbance at 500 nm). We suspected that the
species responsible for the color in solutions of DMSO was 4-
nitrophenylthiolate because addition of base (NEt ) to a DMSO
2 2 3
Cl , CH CN, acetone, or THF, the solution does not turn red
1–4
and hydrophilic solutes, is used as a cryoprotectant for bio-
(
5
6
logical samples, and is a component in drug delivery.
Researchers have taken advantage of the miscibility of DMSO
with water, organic solvents, and ionic liquids (IL) to solubilize
polymers and enhance reaction chemistry. For example, recent
reports describe the benecial effects of a DMSO : IL co-solvent
3
solution of 4-nitrophenylthiol produced a similar red solution
18
with lmax ¼ 502 nm. Over the course of time, we observed that
when bis(4-nitrophenyl)disulde is dissolved in a variety of
DMSO solvents obtained from different commercial suppliers, a
similar red color was produced. Thus, we hypothesized that an
impurity in DMSO reacts with the disulde to form 4-nitro-
phenylthiolate. DMSO is an odorless solvent, however a faint
odor of sulde can oen be detected even in samples of high
purity DMSO (anhydrous, >99.9%, etc.). Since the
manufacturing process typically involves oxidation of dimethyl
sulde (DMS), we considered the possibility that our DMSO
solvents contained trace amounts of DMS.
7
as a green solvent for hydrolysis of cellulose; and a
DMSO : water co-solvent to promote thiol–disulde dynamic
8
combinatorial chemistry. DMSO can also participate in
reactions. Some examples include: playing an essential role as
9
,10
a ligand for transition metal catalysts,
an oxidant for the
1
1,12
oxidation of thiols or alcohols, and a participant in the
oxidation of gold phosphine complexes.
1
3
We have employed DMSO as a solvent in our kinetic studies
of the inuence of solvent dielectric on metal thiolate–disulde
14–16
exchange reactions.
Our interest lies in comparing metal-
We report UV-vis and GC-MS experiments that conrm the
presence of DMS in DMSO samples and provide estimates for
the concentration of DMS in seven different samples of high
purity DMSO, including a deuterated sample. Further we have
found that commonly used methods for purifying DMSO do
not, in our hands, completely remove DMS. Our ndings are
signicant for chemists and biologists who use DMSO as a
solvent, in particular for dilute solutions (millimolar or less) in
mediated thiolate–disulde exchange to metal-free thiol–
disulde exchange, the latter of which proceeds at a slower rate
a
Department of Chemistry, University of Maine, Aubert Hall, Orono, Maine 04469,
USA. E-mail: mbruce@maine.edu; abruce@maine.edu
b
Laboratory for Surface Science and Technology, University of Maine, Barrows Hall,
Orono, Maine 04469, USA
†
Electronic supplementary information (ESI) available: Purication and analysis which the solutes may be sensitive to reaction with suldes.
of bis(4-nitrophenyl)disulde; experimental details for GC-MS experiments and
UV-vis experiments. Fig. 1A shows the visible spectrum of a
red solution prepared by dissolving bis(4-nitrophenyl)disulde
procedures and tabulated results for Gaussian calculations. See DOI:
1
0.1039/c5ra04985g
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ꢂ
+
RSH % RS + H
(3)
GC-MS experiments. Quantitative analysis using GC-MS was
carried out to determine the amount of DMS in seven different
samples of DMSO. A standard bracket method was developed,
using calibration standards of DMS in dioxane with pentane as
internal standard, as described in ESI.† Samples were
purchased from ve different chemical suppliers and included
a variety of research grades: ACS reagent, anhydrous, HPLC,
high purity ($99.99%), and one deuterated solvent, DMSO-d
chemical purity $ 99.5%). All the sample bottles were newly
6
(
opened just prior to testing. According to our results, the
average DMS concentration in the nondeuterated DMSO
Fig. 1 UV-vis spectra of 4-nitrophenylthiolate generated by dissolving samples is 0.48 ꢀ 0.14 mM and the deuterated sample of DMSO
bis(4-nitrophenyl)disulfide in DMSO. (A) 20 mM bis(4-nitrophenyl)
contains ca. 0.35 mM.
disulfide prepared in the dark, (B) after exposure of solution A to room
This concentration of DMS is especially signicant when the
light, (C) after addition of neat DMS to solution B, (D) after exposure of
concentration of solutes, which are sensitive toward reaction with
DMS, are millimolar or less. For example, in our H NMR kinetic
solution C to room light.
1
exchange studies on metal thiolate complexes and bis(4-
nitrophenyl)disulde at concentrations in the 1–4 mM range, the
in DMSO (20 mM). The peak at 502 nm, which is assigned as 4-
18
presence of DMS represented 12–48% of the reactant concentra-
tions and signicantly complicated kinetic analysis. Further,
attempts to employ UV-vis spectroscopy to monitor reaction rates
nitrophenylthiolate, photobleaches in room light and disap-
pears over the course of several minutes (Fig. 1B). Addition of an
aliquot of neat DMS (z50 mL in 2 mL) to the photobleached
solution regenerates the peak at 502 nm (Fig. 1C). Exposure of
this solution to room light again bleaches the color (Fig. 1D).
These ndings are consistent with the hypothesis that DMS
reduces bis(4-nitrophenyl)disulde to 4-nitrophenylthiolate,
which is responsible for the red solution.
15
at concentrations in the 25–50 mM range, have proven unreliable
because the amount of DMS present in DMSO represents a 10 to
20-fold excess of the reactant disulde of interest.
Purication trials. Attempts to remove DMS from DMSO by
using standard purication procedures were unsuccessful in
22,23
our hands.
These attempts included storing samples of
The photobleaching demonstrated in Fig. 1 suggests that the
reaction producing 4-nitrophenylthiolate is reversed by expo-
sure to room light. This result is consistent with a literature
report of the photo-oxidative coupling of 4-nitrophenylthiol to
˚
DMSO over CaH
2
, alumina, anhydrous MgSO
4
, or 4 A molecular
sieves for two weeks, either in a N -lled dry box or exposed to
2
air; passing DMSO down columns of alumina (acidic and basic)
ꢁ
19
or silica; and distillation of DMSO (at 80 C) under reduced
bis(4-nitrophenyl)disulde in THF/water solvent mixtures.
pressure. The various methods for purifying DMSO were qual-
itatively evaluated by adding several milligrams of recrystallized
bis(4-nitrophenyl)disulde to an aliquot of DMSO (details
regarding purication of disulde are provide in ESI†). In each
The yield for disulde is highest using a wavelength of light at
which the thiolate strongly absorbs (lmax ¼ 455 nm in THF/
water) and the reaction requires the presence of thiol and
thiolate.
of the attempts described above, a pink color appeared (lmax
02 nm), which was interpreted as failure to remove all traces of
DMS from DMSO.
¼
DMSO is a useful solvent for the oxidation of thiols (RSH) to
disuldes (eqn (1)). The reaction is typically carried out at
5
ꢁ
elevated temperatures (80–100 C), with aliphatic thiols
Since the reaction of DMS and disulde to form DMSO and
thiolate is a redox reaction, we reasoned that electrochemical
oxidation might also remove DMS from DMSO. Oxidation of
DMS to DMSO is reported to occur in the potential range of 0.8–
requiring a higher temperature than aromatic thiols. The
reaction mechanism is proposed to proceed via nucleophilic
attack of thiolate on protonated DMSO to yield disulde, DMS
11
and water. Use of chromatographic neutral alumina as a
catalyst for DMSO-promoted oxidation of thiols has also been
1
.1 V, while oxidation of DMSO to DMSO
2
occurs at more
24–26
20
positive potentials (ca. 1.6–1.7 V).
Bulk electrolysis was
reported.
carried out at 0.7–0.9 V in a two-compartment electrochemical
cell on 15 mL of DMSO solution containing 0.1 M Bu NPF as
2RSH + (CH
3
)
2
SO % RSSR + (CH
3
)
2 2
S + H O
(1)
4
6
the electrolyte (Pt working and auxiliary electrodes; Ag wire
The reverse of the reaction shown in eqn (1) suggests that in reference). Electrolysis was judged to be complete (aer about 2
the presence of water, DMS may be capable of reducing bis(4- hours) when addition of bis(4-nitrophenyl)disulde to the
27
nitrophenyl)disulde to 4-nitrophenylthiol. Further, since 4- electrolyzed solution did not produce a pink color. Thus it
2
1
nitrophenylthiol is mildly acidic (pK
a
¼ 5.5 in DMSO solution ) appears that DMS can be removed by electrolysis; however, this
we expect the thiolate to be stabilized in DMSO. This sequence process is not ideal as a purication method since it requires
is summarized by eqn (2) and (3) (where R ¼ 4-nitrophenyl).
RSSR + (CH ) S + H O % 2RSH + (CH ) SO (2)
long times to purify small volumes, and it also necessitates
adding electrolyte, which is counterproductive to producing a
higher purity sample of DMSO.
3
2
2
3 2
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2
(CH ) SO % (CH ) S + (CH ) SO
(4) 13 G. S. P. Garusinghe, S. M. Bessey, M. Aghamoosa,
M. McKinnon, A. E. Bruce and M. R. M. Bruce, Inorganics,
2015, 3, 40–54.
3
2
3 2
3 2
2
Disproportionation. The presence of DMS in a variety of
samples of DMSO led us to consider the possibility that 14 A. Chandrasoma, A. E. Bruce and M. R. M. Bruce, Solvent
disproportionation of DMSO might be contributing to the
Dielectric Effect on Metal Assisted Thiolate-Disulde
Exchange: No Free Thiolate, American Chemical Society,
2010, p. INOR-494.
source of DMS (eqn (4)). Disproportionation of DMSO is cata-
28
lyzed by UV light, and occurs at elevated temperatures for
ꢁ
29
extended periods of time (>150 C for 24 h). Using National 15 M. Aghamoosa, G. S. Garusinghe, A. E. Bruce and
Bureau of Standards thermodynamic parameters, Wood esti-
M. R. M. Bruce, Effect of Solvent on the Rate of Gold(I)-
Assisted Thiolate-Disulde Exchange, American Chemical
Society, 2010, p. INOR-414.
ꢁ
mated that the disproportionation of DMSO is favorable (DG ¼
ꢂ1 30
ꢂ98 kJ mol ). Ab initio calculations using B3LYP/6-31G*
31
theory and basis set in Gaussian 09, also indicate a similar 16 G. S. Garusinghe, A. E. Bruce and M. R. M. Bruce, Solvent
ꢁ
ꢂ1

nding, i.e. DG ¼ ꢂ57 kJ mol in the gas phase (3 ¼ 0) and
Effects on Metal-Assisted Thiolate-Disulde Exchange (M ¼
ꢁ
ꢂ1
DG ¼ ꢂ58 kJ mol in DMSO (3 ¼ 46.83). While calculations
Zn, Au), American Chemical Society, 2010, p. INOR-171.
indicate that disproportionation of DMSO is thermodynami- 17 G. S. Garusinghe, M. R. M. Bruce and A. E. Bruce, Comparing
cally favorable, the relatively low concentration of DMS in a
variety of samples of DMSO suggests that it is not kinetically
Metal Assisted Thiolate Disulde Exchange Reactions (M ¼ Au,
Zn), American Chemical Society, 2010, p. INOR-676.
favorable. The presence of DMS may be a consequence of the 18 S. M. Bessey, M. Aghamoosa, G. S. P. Garusinghe,
DMSO manufacturing process. However a longer-term study to
monitor the shelf life of DMSO may be needed to shed light on
the issue of disproportionation.
A. Chandrasoma, A. E. Bruce and M. R. M. Bruce, Inorg.
Chim. Acta, 2010, 363, 279–282.
19 H. J. Kim, J. H. Yoon and S. Yoon, J. Phys. Chem. A, 2010, 114,
12010–12015.
2
2
2
2
0 M. Hirano, S. Yakabe, H. Monobe and T. Morimoto, J. Chem.
Res., Synop., 1998, 472–473.
1 F. G. Bordwell and D. L. Hughes, J. Org. Chem., 1982, 47,
Conclusions
The GC-MS analysis shows that samples of research grade
DMSO from a variety of commercial suppliers contain trace
amounts of DMS. UV-vis studies in solutions of bis(4-
nitrophenyl)disulde are consistent with the presence of DMS
in DMSO samples. The average concentration of DMS (0.48 ꢀ
3224–3232.
2 W. L. F. Armarego and D. D. Perrin, Purication of Laboratory
Chemicals, Fourth Edition, Pergamon, 1997.
3 A. J. Gordon and R. A. Ford, A Chemist's Companion. A
Handbook of Practical Data, Techniques, and References,
Wiley-Interscience, 1972.
0.14 mM) found in DMSO is potentially problematic for reac-
tants that are susceptible to reaction with DMS and are present
at mM-mM concentrations. Standard methods of purication of
DMSO were unsuccessful, in our hands, in removing all traces
of DMS.
24 I. Radoi and G. Mara, Bul. Stiint. Teh. Inst. Politeh. Traian
Vuia Timisoara, Ser. Chim., 1984, 29, 59–64.
2
2
5 G. Mara, M. Nemes and I. Radoi, Rev. Chim., 1987, 38, 408–411.
6 A. V. Bukhtiarov, A. V. Lebedev, A. P. Tomilov and
O. V. Kuz'min, Zh. Obshch. Khim., 1988, 58, 2718–2724.
7 Addition of bis(4-nitrophenyl)disulde to a DMSO solution
2
Notes and references
6
containing 0.1 M TBAPF , prior to electrolysis, generates
1
2
3
C. Reichardt, Solvents and Solvent Effects in Organic
Chemistry, Wiley-VCH, 2008.
D. Martin, A. Weise and H. J. Niclas, Angew. Chem., Int. Ed. 28 G. R. Harvey and R. F. Lang, Geophys. Res. Lett., 1986, 13, 49–51.
Engl., 1967, 6, 318–334.
T. Clark, J. S. Murray, P. Lane and P. Politzer, J. Mol. Model.,
the pink color, i.e. excess electrolyte does not suppress
formation of thiolate.
29 Gaylord Chemical, Technical Bulletin Reaction Solvent Dimethyl
Sulfoxide (105B DMSO), http://www.gaylordchemical.com/
uploads/images/pdfs/literature/105B.pdf, accessed 3/10/2015.
30 P. M. Wood, FEBS Lett., 1981, 124, 11–14.
2008, 14, 689–697.
4
5
Y. Marcus, The Properties of Solvents, Wiley, 1998.
Y. C. Song and D. E. Pegg, Tissue and Cell Processing; an 31 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
Essential Guide, Wiley-Blackwell, 2012.
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda,
J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao,
H. Nakai, T. Vreven, J. A. Montgomery Jr, J. E. Peralta,
F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,
K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand,
K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar,
J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene,
J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo,
6
7
A. McKim and G. Kvakovsky, Spec. Chem. Mag., 2009, 29, 50–52.
J. Iglesias, J. A. Melero, M. Paniagua, M. Teresa Andreola and
E. Barragan, Biomass Bioenergy, 2014, 62, 158–165.
J. Atcher and I. Alfonso, RSC Adv., 2013, 3, 25605–25608.
T. Diao, P. White, I. Guzei and S. S. Stahl, Inorg. Chem., 2012,
8
9
5
1, 11898–11909.
0 W. Zierkiewicz and T. Privalov, Organometallics, 2005, 24,
019–6028.
1
6
1
1
1 W. W. Epstein and F. W. Sweat, Chem. Rev., 1967, 67, 247–260.
2 W. Ge, X. Zhu and Y. Wei, RSC Adv., 2013, 3, 10817–10822.
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R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin,
K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas,
J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox,
Gaussian 09, Revision D.01, 2009.
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