Water-soluble aminoxyls (nitroxides): 2-Methyl-2-[(N-(4-tert-butylphenyl)oxyl]propanesulfonate and (1-oxyl-2,5,5-trimethylpyrrolidin-2-yl)methanesulfonate

Article abstract of DOI:10.1039/b110766f

Two charged aminoxyls, ammonium (1-oxyl-2,5,5-trimethylpyrrolidin-2-yl)methanesulfonate and ammonium 2-methyl-2-[(N-(4-tert-butylphenyl)oxyl]propanesulfonate, obtained by methods easily adaptable to the preparation of various other aminoxyls are totally s

Full text of DOI:10.1039/b110766f

Water-soluble aminoxyls (nitroxides):
2-methyl-2-[(N-(4-tert-butylphenyl)oxyl]propanesulfonate and
(1-oxyl-2,5,5-trimethylpyrrolidin-2-yl)methanesulfonate
Lucien Marx and André Rassat
Ecole Normale Supérieure and CNRS, 24 Rue Lhomond, F75231 Paris Cedex 05, France.
E-mail: andre.rassat@ens.fr; Fax: +33 (0)144323325; Tel: +33 (0)144323265
Received (in Cambridge, UK) 9th January 2002, Accepted 11th February 2002
First published as an Advance Article on the web 22nd February 2002
Two charged aminoxyls, ammonium (1-oxyl-2,5,5-tri-
methylpyrrolidin-2-yl)methanesulfonate and ammonium
2-methyl-2-[(N-(4-tert-butylphenyl)oxyl]propanesulfonate,
obtained by methods easily adaptable to the preparation of
various other aminoxyls are totally soluble in water but are
partially associated in other solvents.
boiling methanolic ammonia to 2b (85%). 2b was found to be
soluble in water at a concentration greater than 400 mM.
If these highly water-soluble nitroxides happen to possess a
sufficiently low toxicity, they could also find some use as
contrast agents or probes for in vivo magnetic resonance
(NMR,18 ESR19 or PEDRI20) imaging.
Solutions (1024 M) of 1b and 2b in water display the typical
EPR spectra, the centre of each line being situated on the base-
line. At the same concentration in ethanol, the spectrum is
different: the centres of the two outer lines are above and below
the base-line respectively, and the upper extremity of the three
lines show an apparent decrease towards high field. As shown
by spectral simulation, this apparent imbalance in the derivative
spectrum is due to a broad absorption-line superimposed onto
the three-line spectrum. This broad line can be attributed to the
presence of a supplementary species with a large volume and/or
strong spin–spin dipolar interactions,21 i.e. a dimer or a larger
aggregate, in equilibrium with the monomeric anions. On the
spectrum of 2b at the same concentration in CH2Cl2, the broad
line is more apparent, indicating a higher concentration of these
condensed species. Thus, at 1024 M, these organic salts are not
totally dissociated in solvents less polar than water, even if their
solutions are totally limpid. They do not dissolve in a solvent of
lower polarity such as Et2O.
The usual piperidine and pyrrolidine aminoxyls are in general
sufficiently soluble in water for some uses, such as spin-
labeling1 or dynamic nuclear polarization in biological fluids.2
They are not soluble enough in water in nitroxide-mediated
controlled free-radical polymerization (NMCRP)3 of hydro-
philic monomers,4 where co-solvents have been used.5
Their solubility in water may be increased by introduction of
charged substituents.6 In particular, if these groups are close to
the aminoxyl function, they may also induce inductive and
steric effects different from those of the usual nitroxides. Since
the effectiveness of one of the most successful mediators7 for
NMCRP has been attributed to these effects,8 it could be
interesting to test the behavior of such molecules in NMCRP in
water. Carboxylate9 and ammonium10 aminoxyls of this type
have been reported but, to our knowledge, no sulfonate salts.
We have prepared the sulfonate derivatives 1a† , 1b†
(Scheme 1) and 2a†, 2b† (Scheme 2) in which the sulfur atom
is separated from the aminoxyl nitrogen by three and four bonds
respectively.
Following a general procedure for the preparation of
sulfonate esters,11 1a was prepared by addition of 2,5,5-trime-
thyl-1-pyrroline N-oxide (3)12 to a solution of a-lithio methane-
sulfonate; formation of the expected hydroxylamine was not
observed, probably because of its direct oxidation during work
up. 1a was isolated in 7% yield after chromatography (Scheme
1). Although the yield is quite low, this reaction provides a rapid
and easy access to 1a. Boiling methanolic ammonia13 converted
1a to the sulfonate salt 1b in 46% yield. 1b dissolves readily in
cold water and in methanol.
In principle, various sulfonated nitroxides can be obtained
from other nitrones or other primary amines by the two schemes
used here; in addition, the intermediate secondary amines
For the preparation of 2a and 2b, a Strecker14 reaction with
4-tert-butylaniline 4 and acetone gave (90%) the a-aminonitrile
5, converted15 by concentrated sulfuric acid, at room tem-
perature to the amide 6 (89%), and then at 105 °C in methanol
with TsOH to the methyl ester 7 (68%). Following Weinreb et
al.,16 7 gave 8 (68%), reduced by LiAlH4 in THF to the
aldehyde 9 (82%). The unsaturated sulfonate ester 10 (75%),
obtained by the method of Ghosez et al.17 was then reduced by
NaBH4 to the saturated sulfonate ester 11† (61%) in ethanol, at
room temperature. Oxidation with m-CPBA in CH2Cl2 (Scheme
2) gave the new aminoxyl 2a (90%) which was converted in
Scheme 2 Reagents and conditions: i, AcOH, KCN, Me2CO, 20 °C, 2 h,
90%; ii, H2SO4, 20 °C, 48 h, 89%; iii, TsOH, MeOH, sealed tube, 105 °C,
36 h, 68%; iv, Me3Al, MeN(H)OMe.HCl, benzene, 69 °C, 14 h, 68%; v,
LiAlH4, THF, 278 °C, 4 h, 83%; vi, (EtO)2P(O)CH(Li)SO3Et, THF, from
278 °C to 20 °C, 18 h, 75%; vii, NaBH4, EtOH, 20 °C, 2 h, 62%; viii, m-
CPBA, CH2Cl2, 20 °C, 3 h, 90%; ix, NH3, MeOH, reflux, 85%.
Scheme 1 Reagents and conditions: i, LiCH2SO3Et, THF, 250 °C, 2 h, 7%;
ii, NH3, MeOH, reflux, 46%.
632
CHEM. COMMUN., 2002, 632–633
This journal is © The Royal Society of Chemistry 2002

4 J. Qiu, B. Charleux and K. Matyjaszewski, Prog. Polym. Sci., 2001, 26,
2083.
corresponding to 5–10 may easily yield other aminoxyls of
different polarity.
We thank the French Ministry of Education (ENS), the
French Ministry of Defense and CNRS for financial support.
5 (a) B. Keoshkerian, M. K. Georges and D. Boils-Boissier, Macromole-
cules, 1995, 28, 6381; (b) L. I. Gabaston, S. A. Furlong, R. A. Jackson
and S. P. Armes, Polymer, 1999, 40, 4505; (c) M. Bouix, J. Gouzi, B.
Charleux, J. P. Vairon and P. Guinot, Macromol. Rapid Commun., 1998,
19, 209.
6 For instance, see: (a) I. V. Koptyug, S. H. Bossmann and J. Nicholas, J.
Am. Chem. Soc., 1996, 118, 1435; (b) J. Sunamoto, K. Akiyoshi, T.
Kihara and M. Endo, Bull. Chem. Soc. Jpn., 1992, 65, 1041; (c) J. R.
Mehlhorn and L. Packer, Can. J. Chem., 1982, 60, 1452; (d) L. T. L.
Wong, R. Schwenk and J. C. Hsia, Can. J. Chem., 1974, 52, 3381; (e)
S. E. Bottle, D. G. Gillies, D. L. Hughes, A. S. Micallef, A. I. Smirnov
and L. H. Sutcliffe, J. Chem. Soc., Perkin Trans. 2, 2000, 1285; (f) L.
Marx, R. Chiarelli, T. Guiberteau and A. Rassat, J. Chem. Soc., Perkin
Trans. 1, 2000, 1181; and references therein.
Notes and references
†
Selected data for 1a, 1b, 2a, 2b and 11: 1a: yellow oil; EIMS: m/z (%)
250 ([M]+, 41); Anal. Calc. for C10H20NSO4: C, 48.00; H, 8.25; N, 5.60.
Found: C, 47.85; H, 8.00; N, 5.23%. EPR: cyclohexane, aN = 13.69 G;
EtOH, aN = 14.5 G.
1b: yellow solid; mp 190°C; MS (FAB): m/z (%) 221 ([M-(NH4+)]2,
100); Anal. Calc. for C8H19N2SO4: C, 40.16; H, 7.95; N, 11.71. Found: C,
40.09; H, 8.06; N, 11.65%; EPR, H2O, aN = 16.12 G; EtOH, aN = 15
G.
7 For instance, see: S. Grimaldi, J. P. Finet, F. Le Moigne, A. Zeghdaoui,
P. Tordo, D. Benoit, M. Fontanille and Y. Gnanou, Macromolecules,
2000, 33, 1141.
2a: red oil; MS (CI, NH3): m/z (%) 344 ([M + 2H]+, 5.4) 328 (100); Anal.
Calc. for C17H28NSO4: C, 59.64; H, 8.18; N, 4.09. Found: C, 59.67; H, 8.35;
N, 3.89%; EPR: toluene, aN = 12.45 G, aHortho = 1.82 G, aHmeta = 0.80 G;
EtOH, aN = 13.37 G, aHortho = 1.77 G, aHmeta = 0.89 G.
2b: red solid; mp 168 °C; MS (FAB): m/z (%) 314 ([M-(NH4+)]2, 100),
298 (74); EPR, H2O, aN = 14.51 G, (unresolved aH); EtOH, aN = 13.35 G,
aHortho = 0.96 G, aHmeta = 0.53 G.
11: white solid; mp 63 °C; dH(250 MHz, CDCl3) 7.12 (d, J = 8.64Hz,
2H), 6.595 (d, J = 8.64 Hz, 2H), 3.411 (q, J = 7.03 Hz, 2H), 3.142 (d, 2H),
2.130 (m, 2H), 1.264 (t, J = 7.03 Hz, 3H), 1.232 (s, 6H), 1.200 (s, 9H);
dC(50 MHz, CDCl3) 143.03, 141.94, 125.84, 117.04, 65.98, 52.73, 46.13,
34.14, 33.76, 31.31, 28.45, 14.92; EIMS: m/z (%) = 327 ([M]+, 16.53), 312
(13.38), 190 (100); Anal. Calc. for C17H29NSO3: C, 62.38; H, 8.86; N, 4.28.
Found: C, 62.20; H, 9.04; N, 4.31%.
8 P. Tordo, private communication.
9 (a) J. F. W. Keana and S. Pou, J. Org. Chem., 1989, 54, 2417; (b) J. F.
W. Keana, G. S. Heo and G. T. Gaughan, J. Org. Chem., 1985, 50, 2346;
(c) K. Hideg and L. Lex, J. Chem. Soc., Perkin Trans. 1, 1987, 1117.
10 (a) M. A. Schwartz, J. W. Parce and H. M. Mc Connell, J. Am. Chem.
Soc., 1979, 101, 3592; (b) D. A. Reid, S. E. Bottle and A. S. Micallef,
Chem. Commun., 1998, 1907.
11 W. E. Truce and D. J. Vrencur, J. Org. Chem., 1970, 35, 1226.
12 R. Bonnett, R. F. C. Brown, V. M. Clark, L. O. Sutherland and A. Todd,
J. Chem. Soc., 1959, 2094.
13 B. Musicki and T. S. Widlanski, J. Org. Chem., 1990, 55, 4231.
14 A. J. Kiessling and C. K. Mc Clure, Synth. Commun., 1997, 923.
15 D. F. Taber and M. Rahimizadeh, J. Org. Chem., 1992, 57, 4037.
16 S. Nahm and S. Weinreb, Tetrahedron Lett., 1981, 22, 3815.
17 J. C. Carretero, M. Demillequand and L. Ghosez, Tetrahedron, 1987,
43, 5125.
18 V. Dedieu, P. Fau, P. Otal, J. P. Renou, V. Emerit, F. Joffre and D.
Vincensini, Magnetic Resonance Imaging, 2000, 18, 1221.
19 K. Saito, S. Kazama, H. Tanizawa, T. Ito, M. Tada, T. Ogata and H.
Yoshioka, Biosci., Biotechnol., Biochem., 2001, 65, 787.
20 P. Puwanich, D. J. Lurie and M. A. Foster, Physics in Medicine and
Biology, 1999, 44, 2867.
1 For instance, (a) Biological Magnetic Resonance, Vol 14: Spin
Labelling, ed. L. Berliner, Plenum Press, New York, 1998; (b) N.
Kocherginsky and H. M. Swartz, Nitroxide Spin Labels, Reactions in
Biology and Chemistry, CRC Press, Boca Raton, 1995.
2 D. Grucker, T. Guiberteau, B. Eclancher, J. Chambron, R. Chiarelli, A.
Rassat, G. Subra and B. Gallez, J. Magn. Reson., 1995, 106, 101.
3 (a) M. K. Georges, R. P. N. Veregin, P. M. Kazmaier and G. K. Hamer,
Macromolecules, 1993, 26, 2987; (b) C. J. Hawker, J. Am. Chem. Soc.,
1994, 116, 11185; (c) K. Matyjaszewski, Controlled/Living Radical
Polymerization: Progress in ATRP, NMP, and RAFT,ACS Symp.
Series, 2000, vol. 768.
21 L. Marx and A. Rassat, Angew. Chem., Int. Ed., 2000, 39, 4494 ; and
references therein.
CHEM. COMMUN., 2002, 632–633
633