Formation of DMSO and DMF radicals with minute amounts of base

Article abstract of DOI:10.1016/j.tet.2009.06.109

So far overlooked DMSO and DMF form long-lived radicals in the presence of small amounts of bases, DMF radicals being less stable than DMSO radicals. In solvent mixtures, the presence of DMSO prolonged the lifetime of DMF radicals. The occurrence of radic

Full text of DOI:10.1016/j.tet.2009.06.109

Tetrahedron 65 (2009) 7616–7619
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Formation of DMSO and DMF radicals with minute amounts of base
,
a
Christer L. Øpstad a, Thor-Bernt Melø b, Hans-Richard Sliwka a , Vassilia Partali
*
a Institutt for Kjemi, Norges Teknisk Naturvitenskapelige Universitet, 7491 Trondheim, Norway
b Institutt for Fysikk, Norges Teknisk Naturvitenskapelige Universitet, 7491 Trondheim, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2009
Received in revised form 5 June 2009
Accepted 25 June 2009
Available online 2 July 2009
So far overlooked DMSO and DMF form long-lived radicals in the presence of small amounts of bases,
DMF radicals being less stable than DMSO radicals. In solvent mixtures, the presence of DMSO prolonged
the lifetime of DMF radicals. The occurrence of radicals may explain previously reported unexpected
outcomes of reactions performed in these solvents. The commonly accepted inertness of these solvents
towards minor quantities of alkali seems not to be warranted.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
DMSO radicals
DMF radicals
Radical reactions
Solvent inertness
1. Introduction
of the solvents in the presence of alkali. Consequently, the fact sheet
of a DMSO manufacturer pledges the excellence of DMSO under
It has been noticed that dimethylsulfoxide (DMSO) can be oxi-
dized, sometimes with devastating consequences,1 and dime-
thylformamide (DMF), a simple amide, can easily be hydrolyzed.2
Explosions have been explained by exothermic polymerization of
formaldehyde, formed at the boiling point of DMSO.3 However, the
inertness of these solvents is neither guaranteed under much more
temperate conditions in the presence of trace amounts of base. Is
there really any doubt about the inertness of alkaline DMSO and
DMF? The pKa’s of 1200 compounds have been determined in
DMSO, solutions of potassium tert-butoxide in DMSO are frequently
used in base-catalyzed reactions, the potassium salt of DMSO
(dimsyl) acts as superbase in many chemical reactions, the Swern
and Kornblum oxidations rely on DMSO with an organic base, the
Shonogashira coupling is performed in DMSO with Cs2CO3, double
bonds have been displaced with KOH in DMSO (e.g., eugenol to
basic conditions.17
On the other hand, explosions have been reported during the
preparation of the methylsulfinyl carbanion (dimsyl anion, DMSOꢀ,
1b, Scheme 1).18–20 Other peculiar observations have been articu-
lated: DMSO played an ambiguous role in creating radicals during
the alkaline degradation of carbohydrates.21 Unexpected radicals
emerged in the Reissert reaction when performed in DMF with
NaH,22 although it was explicitly stated that no radicals are
obtained in alkaline DMF.20 DMSO and DMF radicals have other-
wise been generated by rather harsh conditions (photolysis, pulse
radiolysis, sonication) and detected at low temperatures.22–29
O
S
O
S
O
S
OH
H
- H2O
- e
H3C
CH2
H3C
C
H3C
CH2
isoeugenol, lutein to zeaxanthin, a- to b-pinene), and KOH in DMSO
H2
is an efficient base for asymmetric cyclization.4–11 The Suzuki
coupling is accomplished in DMF with Cs2CO3, Claisen rearrange-
ments are best carried out in DMF with MeLi, a one-pot Michael
addition was observed in DMF with NaOH, aminoacids racemise in
DMF with K2CO3 and sugar fatty acid esters are synthesized by
transesterification involving DMSO or DMF with KOH, K2CO3 or
other alkaline catalysts (Hass–Snell reaction).12–16 These fragmen-
tarily selected reactions seem beyond doubt to confirm the stability
1c
1a
1b
OH
H
O
H
CH2
CH3
O
H
CH2
O
H
CH2
CH3
- e
N
N
N
- H2O
CH3
2b
2a
2c
Scheme 1. Postulated initiation reaction to radicals of DMSO and DMF with base.
We have found that DMSO and DMF form long-lived radicals at
room temperature simply by adding a few drops of potassium
* Corresponding author. Tel.: þ47 73 59 5600; fax: þ47 73 59 6255.
E-mail address: hrs@nvg.ntnu.no (H.-R. Sliwka).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.109

C.L. Øpstad / Tetrahedron 65 (2009) 7616–7619
7617
methylate (MeOK) solution (25% in MeOH) to the solvents, e.g.,
10 L base solution to 10 mL solvent. Besides MeOK, other bases
a radical cluster (radical adducts with solvent molecules) in which
the radical position is rapidly delocalized (Fig. 3).
m
such as BuLi and EtOK react with the solvents, low soluble KOH
required longer reaction time. Pyridine and amines do not react.
Although we lack the opportunity at the moment to describe the
reactions and products in detail we think it advisable to present
here the spectra and chemical data verifying radical formation in
neat DMSO and DMF and in solvent mixtures after addition of small
quantities of base.
2. Results
Radicals of DMSO were formed instantaneously, reaching
a maximum between 2 and 4 min after base addition (Fig. 1). These
primary radicals had disappeared after 25 min being replaced by
secondary radicals, detectable after 6 min reaction time. The
magnitude of these new DMSO radicals increased slowly until
a steady state was reached after about 2 h. The secondary DMSO
radicals were stable at room temperature for at least 1 week. The
initially formed DMSO radicals showed a hyperfine splitting pat-
tern pointing to a localized radical character at one of the carbon
atoms.25 The splitting further indicates a coupling to two geminal
H-atoms. In contrast, the secondary radicals have lost the fine
splitting. The obtained EMR spectra, hyperfine splitting constants
and g-values were not in resemblance with previously reported
data on short-living DMSO-radicals.26,30
Figure 3. Delocalization within radical clusters of radical–solvent molecules.
The NMR spectra, recorded 10 min after addition of base to
DMSO, showed signals of many new diamagnetic species. Assess-
ment of the spectra and comparison with data in the literature
verified the predominant formation of reduction products such as
methane, methanethiol, and dimethylsulfide besides other non-
identified compounds in smaller amounts. Earlier works listed
oxidation products of DMSO, formed catalytically by residual iron
impurities.20,31–33 However, iron should not interfere in the re-
action, since DMSO-d6 can obviously be considered iron-free with
regard to NMR and EMR purity requirements.
The appearance of previously detected Oꢁ2ꢀ in alkaline DMSO
could not be confirmed in our experiments since we were neither
able toobserve an absorption similar tothe published UV spectra nor
could we see the characteristic EMR spectra of Oꢁ2ꢀ after attempted
spin trapping with PNB (a
-phenyl-N-tert-butylnitrone).34
Base addition to DMF generated a different radical transient
(Fig. 1). The signal intensity reached a maximum after 2–4 min, and
then faded away gradually until disappearance after 10–15 min. In
the EMR spectra of the DMF-d7 radical low intense, complex signals
without fine structure were observed. Interestingly, the presence of
1% DMSO in DMF increased the lifetime of the DMF radicals along
with amplified signal intensity in the EMR spectra (Fig. 4). More
DMSO had an adverse effect until a concentration of 50% DMSO in
DMF was reached, causing again signal enhancement (Fig. 5). The
signals from DMF dominated the EMR spectra up to 90% DMSO,
demonstrating an efficient radical transfer from DMSO to DMF
molecules. The lifetime of DMF radicals (10–15 min) was prolonged
Figure 1. Radical formation in DMSO and DMF after adding MeOK. Top lines: DMSO
2 min (d), 4 h (d); bottom line: DMF 2 min.
When radicals were generated from DMSO-d6 the EMR
spectra showed immediately the singlet of a free radical (Fig. 2).
Three minutes after base addition this singlet was split into a dou-
blet indicating possible DMSO-dimers, allowing the radical center
to shift between two different positions. The doublet coalesced
then again into a singlet similar to that observed in non-deuterated
DMSO. The long-lived final radical species may therefore constitute
120000
100000
80000
60000
40000
20000
0
334.00
334.50
335.00
Magnetic field [mT]
335.50
336.00
Figure 2. Radical formation in DMSO-d6 after adding MeOK: 2 min (——), 9 min (d),
75 min (– – –).
Figure 4. EMR spectra of DMF without DMSO (d), with 1% DMSO (- - -).

7618
C.L. Øpstad / Tetrahedron 65 (2009) 7616–7619
O
O
O O
O O
+ 2 DMSO
- 2 DMSO
4
2
+ 2 H
3
O
O
OH
Figure 5. Modulation of EMR-signal intensity from the DMF radical in the presence of
increasing amounts of DMSO.
OH
in the presence of DMSO to 3–4 h. In addition, the hyperfine
splitting of the DMF radicals was greatly improved with DMSO. The
now well resolved EMR signals represent three radical species, the
first one reaching maximum population at 2 min, the second rad-
ical attained its maximum after 6 min (the first radical had then
completely disappeared), the maximum of the third radical
appeared after 45 min with a subsequent slow decay during 4 h
(Figs. 6 and 7). The EMR signals of the third radical could only be
observed by ‘amplification’ with DMSO and was not seen in the
neat spectrum of DMF.
3
5
Scheme 2.
due to the formation of a stabilized paramagnetic radical anion
dimer (4).35,36 DMSO radicals could not be observed by EMR, in-
dicating an immediate electron transfer. Addition of CF3COOH
resulted again in NMR-detectable diamagnetic species, which were
identified as phenanthrenquinone (3) and phenanthrene-9,10-diol
(5) (Scheme 2). Diol 5 was, however, too sensitive to oxidation in air
and could not be isolated. Anthraquinone in basic DMSO reacted in
the same manner.
120000
100000
80000
60000
40000
20000
0
3. Discussion
By analogy to a previously proposed reaction mechanism, DMSO
radical formation is assumed to occur through an initial fast proton
abstraction from DMSO 1a by the base37 forming anion 1b
(DMSOꢀ), which loose a single electron resulting in radical 1c
(DMSOꢁ) (Scheme 1).25 A similar reaction sequence is expected for
DMF (2a/2b/2c). Radicals 1c and 2c have been identified after
pulse radiolysis and photolysis of DMSO and DMF.28,38–40
332
333
334
335
Magnetic field [mT]
336
337
338
The propagation of radicals has been based on the reaction of
DMSOꢀ (1b) with oxygen.20,31,34,37,41,42 In our experiments the
presence or absence of oxygen seems to be of no importance. Dis-
pelling oxygen by passing nitrogen through DMSO during 2 h be-
fore adding the base did not change the outcome of the reaction.
Different authors, irradiating DMSO and DMF with light or
ionizing rays, obtain many different radicals and products
(Scheme 3).38–40,43–45 The described reaction of the solvents with
alkali is obviously even more complex considering the results
obtained in solvent mixtures and, therefore, the exact de-
termination of the reaction sequences (initiation and propagation),
of radical species and products have so far escaped investigation.
Nonetheless, whatever the reaction mechanisms, the formation of
stable radicals, formed from pure solvents and bases under com-
mon laboratory conditions, was unequivocally detected by electron
magnetic resonance (EMR) spectroscopy, by NMR spectroscopy of
products, and chemically by electron-transfer reactions.
Figure 6. EMR spectra of three different DMF radical species in the presence of 1%
DMSO, after 2 min (d), 6 min (- - -), 30 min (d).
It is important to emphasize that some of the reported gaseous
products of the solvent radical reactions are potential dangerous,
e.g., H2, CH4, C2H6. They may not only develop from the solvents by
high energetic radiation, where risks are expected and appropri-
ately prevented, but could possibly also arise by common manip-
ulations, adding small amount of bases, where no risk is realized.
An additional hazardous factor would be the probable dissolution
of H2 or other gasses in the solvents.46,47 Taking into account that
only a fraction of the solvent molecules react over a relative long
time period the formation of gasses may remain unnoticed.
Figure 7. Formation and decay of three different DMF radical species in the presence
of 1% DMSO. Radical a d, radical b - - -, radical c – – –.
When the solvent radicals are generated in the presence of
conjugated dicarbonyl compounds, consecutive electron transfer
results in reduction to dienolates (Scheme 2). The yellow solution of
phenanthrenquinone (3) in DMSO showed the characteristic sig-
nals in the NMR spectra. A small amount of MeOK was then added
resulting in a pink solution with complete absence of NMR signals

C.L. Øpstad / Tetrahedron 65 (2009) 7616–7619
7619
a glass NMR tube with 5 mm outer diameter. 13C NMR spectra were
recorded with the inverse gated pulse sequence.
O
S
1c
H3C
CH2
Acknowledgements
O
CH3
S
S
S
S
CH3
S
OH
S
S
S
We are thankful to E. Mørkved (NTNU) for turning our attention
to the explosive nature of alkaline DMSO.
OH
OH
O
O
O
S
O
S
O
H2
CH4
C2H6
OH
OH
S
S
References and notes
O
O
1. Epstein, W. W.; Sweat, F. W. Chem. Rev. 1967, 67, 247–260.
2. Buncel, E.; Symons, E. A. J. Chem. Soc., Chem. Commun. 1970, 164–165.
3. Allan, G. G.; Moks, E.; Nelson, E. N. Chem. Ind. 1967, 1706–1707.
4. Reich, H. J. http://www.chem.wisc.edu/areas/reich/pkatable.
5. Bach, R. D.; Knight, J. W. Tetrahedron Lett. 1979, 3815–3818.
6. Tidwell, T. T. Synthesis 1990, 857–870.
O
H
CH2
CH3
N
2c
7. Yi, C. Y.; Hua, R. M. J. Org. Chem. 2006, 71, 2535–2537.
8. Jain, S. M.; Anand, S. M.; Gupta, D. K.; Sama, J. K.; Lal, S.; Dutt, P. IN192967, 2004.
9. Bernhard, K.; Giger, A. US5,780,693, 1998.
H
N
H
N
N
N
N
N
CH3
N
10. Webb, R.L. US3,264,362, 1966.
11. Kawabata, T.; Moriyama, K.; Kawakami, S.; Tsubaki, K. J. Am. Chem. Soc. 2008,
130, 4153–4157.
O
O
O
O
OH
O
N2 H2 CO
12. Perissutti, E.; Frecentese, F.; Lavecchia, A.; Fiorino, F.; Severino, B.; De Angelis,
F.; Santagada, V.; Caliendo, G. Tetrahedron 2007, 63, 12779–12785.
13. McIntosh, C. E.; Martinez, I.; Ovaska, T. V. Synlett 2004, 2579–2581.
14. Liang, Y. J.; Dong, D. W.; Lu, Y. M.; Wang, Y.; Pan, W.; Chai, Y. Y.; Liu, Q. Synthesis
2006, 3301–3304.
Scheme 3. Reported decay of DMSO radicals (1c) and DMF radicals (2c) obtained after
pulse radiolysis.
15. Yokoyama, Y.; Hikawa, H.; Murakami, Y. J. Chem. Soc., PerkinTrans.12001,1431–1434.
16. Hass, H. B.; Summit, N. J.; Snell, F. D. US2,893,990, 1959.
17. DMSO Product information Bulletin #123B; Gaylord Chemical Company: Slidell,
LA, USA, 2007.
18. French, F. A. Chem. Eng. News 1966, 11, 48.
19. Olson, G. A. Chem. Eng. News 1966, 13, 7.
20. Hyland, K.; Auclair, C. Biochem. Biophys. Res. Commun. 1981, 102, 531–537.
21. Calle, P.; Sanchez, A.; Sieiro, C. J. Chem. Soc., Perkin Trans. 2 1990, 1181–1185.
22. Melnikov, M. Y.; Belevskii, V. N.; Belopushkin, S. I.; Melnikova, O. L. Russ. Chem.
Bull. 1997, 46, 1245–1247.
23. Misik, V.; Kirschenbaum, L. J.; Riesz, P. J. Phys. Chem. 1995, 99, 5970–5976.
24. Stein, G.; Stiassny, G. Nature 1955, 176, 734–735.
25. Symons, M. C. R. J. Chem. Soc., Perkin Trans. 2 1976, 908–915.
26. Fo¨ldes-Papp, Z.; Gerber, G.; Stosser, R.; Schneider, G. J. Prakt. Chem.1991, 333, 293–301.
27. Shishlov, N. M.; Vasilev, Y. V.; Konovalov, V. V.; Korobeynikova, V. N. Radiat.
Phys. Chem. 1997, 49, 451–457.
4. Conclusion
The demonstrated facile generation of long-lived radicals from
DMF and DMSO is in variance with the generally accepted in-
ertness of these solvents towards a small amount of base. The
presence of radicals may perturb reactions performed in these
solvents. Elucidating the progression of the reactions as well as
identification of the radicals and secondary products call for future
investigations. The presented radical formation in DMSO and DMF
at slightly basic conditions invites the solvent producers to update
their fact sheets.
28. Hayon, E.; Hayashi, N.; Ibata, T.; Lichtin, N. N.; Matsumoto, A. J. Phys. Chem. 1971,
75, 2267–2272.
29. Kondo, T.; Kirschenbaum, L. J.; Kim, H.; Riesz, P. J. Phys. Chem. 1993, 97, 522–527.
30. Woodward, J. R.; Lin, T. S.; Sakaguchi, Y.; Hayashi, H. J. Phys. Chem. A 2000,104,557–561.
31. Haseloff, R. F.; Ebert, B.; Damerau, W. Anal. Chim. Acta 1989, 218, 179–184.
32. Rosenthal, I.; Mossoba, M. M.; Riesz, P. Can. J. Chem. 1982, 60, 1486–1492.
33. Qiao, X. L.; Chen, S. M.; Tan, L.; Zheng, H.; Ding, Y. D.; Ping, Z. H. Magn. Reson.
Chem. 2001, 39, 207–211.
34. Choi, M. F.; Hawkins, P. Spectrochim. Acta, Part A 1995, 51, 579–585.
35. Calderazzo, F.; Forte, C.; Marchetti, F.; Pampaloni, G.; Pieretti, L. Helv. Chim. Acta
2004, 87, 781–789.
36. Taguchi, K.; Fujii, S.; Yamano, S.; Cho, A. K.; Kamisuki, S.; Nakai, Y.; Sugawara, F.;
Froines, J. R.; Kumagai, Y. Free Radical Biol. Med. 2007, 43, 789–799.
37. Corey, E. J.; Chaykovs, M. J. Am. Chem. Soc. 1965, 87, 1345–1353.
38. Cooper, T. K.; Walker, D. C. Can. J. Chem. 1971, 49, 2248–2253.
39. Koulkes-Pujo, A.M.; Barat, F.; Mialocq, J.C.; Sutton, J. J. Photochem. 1973/74, 2,
439–450.
40. Pukhalskaya, G. V.; Kotov, A. G.; Pshezhetskii, S. Y. Khimiya Vysokikh Energii
1969, 3, 340–345.
41. Stolze, K.; Mason, R. P. Biochem. Biophys. Res. Commun. 1987, 143, 941–946.
42. Hashimoto, M.; Nakai, Y.; Kohno, M.; Tajima, K.; Kanaori, K.; Endo, N.; Makino,
K. Chem. Lett. 1997, 71–72.
43. Kroh, J.; Burzynska, E. Radiochem. Radioanal. Lett. 1976, 27, 101–108.
44. Kroh, J.; Burzynska, E. Nukleonika 1977, 22, 453–458.
45. Kroh, J.; Burzynska, E. Nukleonika 1977, 22, 443–451.
46. Brunner, E. J. Chem. Eng. Data 1985, 30, 269–273.
5. Experimental Section
Dimethylformamide (>99.8%) and dimethylsulfoxide (100%)
were purchased from VWR International, Fontenay sous Bois,
France, DMF-d7 (NMR grade 99.5% D), DMSO-d6 (NMR grade 99.9%
D) were from Sigma–Aldrich, St. Louis, USA and potassium meth-
oxide (25 wt % in MeOH) from Fluka, Switzerland.
EMR spectra were recorded on a JES-FR30 Free Radical Monitor
from JEOL, Tokyo, Japan. The microwave frequency was 9.1–9.5 GHz
with modulation width 0.05, sweep time 2 min, time constant 0.1 s,
and amplifier gain 500. The samples were prepared by adding the
appropriate solvent or mixture of solvents into the EMR quartz flat
cell (200 mL, 0.4 mm thickness) and then adding the base in a con-
centration of 0.1%. The lag time from mixing the components until
start of the analysis was 1–2 min. The reaction proceeded just as
well with analytical grade DMSO from open bottles or with dry
DMSO from sealed ampoules.
NMR spectra were recorded on a Bruker Avance DPX 300
spectrometer with a QNP probe. The samples were measured in
47. Dymond, J. H. J. Phys. Chem. 1967, 71, 1829–1831.