Synthesis of a series of monomeric styrene sulfobetaine precursors

Article abstract of DOI:10.1016/j.tetlet.2010.12.100

Procedures for the synthesis of five sulfobetaine monomers as styrene derivatives are given. The five molecules form a homologous row differing in the distance between the inner quaternary amine and the outer sulfonic acid from one methylene group to five methylene groups. Syntheses are achieved by a sequence of nucleophilic substitutions starting from commercially available precursors.

Full text of DOI:10.1016/j.tetlet.2010.12.100

Tetrahedron Letters 52 (2011) 1101–1104
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Tetrahedron Letters
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Synthesis of a series of monomeric styrene sulfobetaine precursors
⇑
Lukas Sonnenschein, Andreas Seubert
Department of Chemistry, University of Marburg, Hans-Meerwein Str., D-35037 Marburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Procedures for the synthesis of five sulfobetaine monomers as styrene derivatives are given. The five mol-
ecules form a homologous row differing in the distance between the inner quaternary amine and the
outer sulfonic acid from one methylene group to five methylene groups. Syntheses are achieved by a
sequence of nucleophilic substitutions starting from commercially available precursors.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 3 November 2010
Revised 17 December 2010
Accepted 22 December 2010
Available online 7 January 2011
Keywords:
Sulfobetaine
Monomeric precursor
Styrene derivative
Zwitterionic molecules of the sulfobetaine type are frequently
utilized in different fields of chemistry. They are applied as zwitter-
ionic surfactants1 or as surface modificators.2 They can also be at-
tached to silica or polymeric backbones and serve as stationary
phases in zwitterionic hydrophilic interaction chromatography
(ZIC-HILIC)3,4 or for solid phase extraction.5,6
functional groups, a tertiary amine carrying a sulfonic acid was
prepared first. This amine can then be used for the substitution
of chloride from 4-vinylbenzylic chloride (Schemes 1 and 2).
For these applications sulfobetaines containing polymerizable
functional groups are essential. Methacrylate derivatives are of
interest as the polymers obtained there from7 can be used on
membranes to prevent fouling8 or they can be attached to titanium
alloys to reduce thrombogenicity.9
-
N+
SO3
n = 1-5
A parameter which is not often considered, despite a profound
effect on the chemical and physical properties of the molecules,
is the distance between the ammonium and the sulfonate group.
Weers et al. investigated a few zwitterionic tensides with spacers
varying the distance between the charged groups.10 They found
that the distance between the charges has an enormous influence
on the critical micellar concentration and on the hydrophilicity of
the molecules.
n = 1 =
n = 2 =
n = 3 =
1
2
3
4
5
n = 4 =
n = 5 =
Figure 1. Structure of the synthesized sulfobetaine monomers.
To investigate these effects on zwitterionic ion chromatography
(ZIC) separations, we have prepared a row of homologous mono-
meric zwitterionic precursors as styrene derivatives. The struc-
tures of these molecules are given in Figure 1. By applying a
grafting reaction, these precursors can be attached to a polymeric
backbone and used for ZIC and ZIC-HILIC separations.4
Syntheses of monomeric zwitterionic precursors were achieved
by subsequent nucleophilic substitutions involving two or three
reaction steps for all five molecules. For the sulfobetaines 1 and
2 having one and two methylene groups between the charged
O
O
H2O
N
S
HO
S
N
H
ONa
ONa
(97%)
O
O
6
45°C
EtOH
(100%)
Cl
N+
SO3
-
1
⇑
Corresponding author. Tel.: +49 6421 28 25661; fax: +49 6421 28 22124.
E-mail address: seubert@staff.uni-marburg.de (A. Seubert).
Scheme 1. Synthesis of 4-vinylbenzyl-dimethylammonio methanesulfonate 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.100

1102
L. Sonnenschein, A. Seubert / Tetrahedron Letters 52 (2011) 1101–1104
O
O
S
NaO
H2O
Cl
S
N
N
4h Reflux
(84%)
HO
ONa
O
HCl
7
HCl
50°C
EtOH
(80%)
Cl
-
SO3
N+
2
Scheme 2. Synthesis of 4-vinylbenzyl-dimethylammonio ethanesulfonate 2.
N,N-Dimethylamino methanesulfonate 6 was prepared accord-
ing to a procedure published by King and Skonieczny11 starting
from sodium hydroxymethanesulfonate and an aqueous solution
of N,N-dimethylamine. The reaction is carried out at room temper-
ature yielding 97% of the desired product. The product is slowly
added to a cooled solution of 4-vinylbenzyl chloride in ethanol
under nitrogen atmosphere and heated to 45 °C for 24 h leading
to 4-vinylbenzyl-dimethylammonio methanesulfonate 1 in quanti-
tative yields.12
Preparation of the molecule with two methylene groups be-
tween the amine and the sulfonic acid proceeds via a different path
beginning with the tertiary amine 2-chloro-N,N-dimetylethyl-
amine hydrochloride. According to a procedure by Palmi et al.13
the tertiary amine is sulfonated using sodium metabisulfite giving
N,N-dimethyltaurine hydrochloride 7 in 84% yield. The yield can be
increased from the reported 58–84% by preparing the sodium salt
instead of the free sulfonic acid. The lower yield in literature pro-
cedure is likely to be due to the loss of product during work-up.
The excess sodium metabisulfite is removed using a strongly acidic
cation exchange resin in the H+-form. 4-Vinylbenzyl-dimethylam-
monio ethanesulfonate 2 is prepared by slowly adding the sulfo-
nate to a cooled solution of 4-vinylbenzyl chloride in ethanol
under nitrogen atmosphere and heating the mixture to 50 °C for
18 h.14 Due to the reduced reactivity of hydrochlorides, ammo-
nium hydroxide has to be added to the mixture to increase reaction
rates. The final reaction gives 80% yield.
The molecules 3–5 are synthesized in a slightly different way
by nucleophilic reaction of 1,3-propanesultone, 1,4-butanesultone,
and 5-bromopentane-1-sulfonate with 4-vinylbenzyl-N,N-dimeth-
ylamine 8 (Schemes 3 and 4). For these molecules better yields and
more efficient synthesis routes are obtained when the amination of
4-vinylbenzyl-chloride was carried out as the first reaction step.
The amination is achieved by slowly adding an aqueous solution
of N,N-dimethylamine to 4-vinylbenzyl chloride in ethanol under
nitrogen atmosphere. Possibly due to the formation of the less
reactive N,N-dimethylamine hydrochloride the product 8 can
only be obtained in 62% yield. Even increasing the amount of
N,N-dimethylamine added to a constant amount of 4-vinylbenzyl
H2O/EtOH
45°C, 18 h
N
H
Cl
N
(62%)
8
50°C
Acetonitrile
(84%)
O
O
or
-
N+
SO3
S
S
O
O
O
O
n = 1
n = 2
3
4
Scheme 3. Synthesis of 4-vinylbenzyl-dimethylammonio propanesulfonate 3 and 4-vinylbenzyl-dimethylammonio butanesulfonate 4.
EtOH
Reflux
18 h
O
S
O
NaO
Br
Br
S
Br
(65%)
NaO
ONa
O
9
EtOH/H2O
45°C, 18 h
(81%)
N
-
N+
SO3
5
Scheme 4. Synthesis of 4-vinylbenzyl-dimethylammonio pentanesulfonate 5.

L. Sonnenschein, A. Seubert / Tetrahedron Letters 52 (2011) 1101–1104
1103
6. Tsukamoto, T.; Yamamoto, A.; Kamichatani, W.; Inoue, Y. Chromatographia
2009, 70, 1525–1530.
7. Yuan, J.; Chen, L.; Jiang, X.; Shen, J.; Lin, S. Colloids Surf., B 2004, 39, 87–94.
8. Sakuragi, M.; Tsuzuki, S.; Obuse, S.; Wada, A.; Matoba, K.; Kubo, I.; Ito, Y. Mat.
Sci. Eng., C 2010, 30, 316–322.
9. Ye, S.-H.; Johnson, C. A., Jr.; Woolley, J. R.; Murata, H.; Gamble, L. J.; Ishihara, K.;
Wagner, W. R. Colloids Surf., B 2010, 79, 357–364.
10. Weers, J. G.; Rathman, J. F.; Axe, F. U.; Crichlow, C. A.; Foland, L. D.; Scheuing, D.
R.; Wiersema, R. J.; Zielske, A. G. Langmuir 1991, 7, 854–867.
11. King, J. F.; Skonieczny, S. Phosphorus and Sulfur 1985, 25, 11–20.
chloride does not improve yields. Fortunately N,N-dimethylamine
hydrochloride precipitates from 4-vinylbenzyl-N,N-dimethylamine
8 when the solvent is removed and can be easily be filtrated from
the product. Analogous formations of N,N-dimethylamine hydro-
chloride can be observed during the reaction of 5-bromopentane-
1-sulfonate with N,N-dimethylamine. Therefore the preparation
of 4-vinylbenzyl-N,N-dimethylamine 8 is carried out as the first
step, because both educts are commercially available and reason-
ably priced.
The final synthetic steps leading to 3 and 4 follow the polymer
analogous reaction described by Jiang and Irgum15 (Scheme 3).
Compound 3 has already been prepared and used for polymerization
by McCormick and Shen before.16,17 The sultone rings are opened in
a nucleophilic substitution by 4-vinylbenzyl-N,N-dimethylamine 8
forming both charged groups. Yields for both of these reactions are
84%.18
The molecule having five methylene groups between the amine
and the sulfonic acid is prepared by the reaction of 5-bromopen-
tane-1-sulfonate 9 with 4-vinylbenzyl-N,N-dimethylamine 8. 5-
Bromopentane-1-sulfonate 9 is generated in a separate reaction
step (Scheme 4) according to a procedure by Fujii and Cook.19 An
excess of 1,5-dibromopentane in ethanol/water (100:30) is heated
to reflux and a solution of sodium sulfite in water is slowly added
to the stirred solution. The unwanted reaction of both halides of
one molecule with sodium sulfite is thus effectively prevented.
The reaction yields 65%. The sulfonate is then added to a solution
of 4-vinylbenzyl-N,N-dimethylamine 8 in ethanol/water under
nitrogen atmosphere and heated to 45 °C for 18 h giving 5 with
81% yield.20
12. Synthesis of 4-vinylbenzyl-dimethylammonio methanesulfonate 1: Under
a
nitrogen atmosphere 2.82 ml of 4-vinylbenzyl chloride (0.020 mol, 1.0 equiv)
are dissolved in 20 ml of ethanol and cooled to 273 K. 3.22 g of N,N-
dimethylamino methanesulfonate 6 (0.020 mol, 1.0 equiv) in 50 ml ethanol/
water (1:1) are slowly added over a period of 15 min. The reaction mixture is
heated to 45 °C for 24 h, then the solvent is removed. The product is washed
with acetonitrile to give 6.26 g (0.020 mol, 100%) of 1 as a colorless powder. 1
H
NMR (300 MHz, D2O): 7.57 (m, 4H, CHaromat); 6.81 (dd, 1H, 3J = 11.0 and
17.7 Hz, CHolefin); 5.93 (d, 1H, 3J = 17.7 Hz, CHtrans); 5.40 (d, 1H, 3J = 11.0 Hz,
CHcis); 4.73 (s, 2H, CH2,benzyl); 4.41 (s, 2H, CH2); 3.26 (s, 6H, 2 Â CH3). 13C NMR
(75 MHz, D2O): 140.0 (Cq); 135.7 (CHolefin); 133.5 (2 Â CHaromat); 126.8
(2 Â CHaromat); 125.9 (Cq); 116.4 (CH2,olefin); 72.5 (CH2); 69.2 (CH2,benzyl); 51.0
(2 Â CH3). Anal. Calcd for C12H17ClNNaO3S: C, 45.9; H, 5.5; N, 4.5. Found: C,
44.8; H, 5.7; N, 4.0.
13. Palmi, M.; Youmbi, G. T.; Fusi, F.; Sgaragli, G. P.; Dixon, H. B. F.; Frosini, M.;
Tipton, K. F. Biochem. Pharmacol. 1999, 58, 1123–1131.
14. Synthesis of 4-vinylbenzyl-dimethylammonio ethanesulfonate 2: Under
a
nitrogen atmosphere 10.69 ml of 4-vinylbenzyl chloride (0.076 mol,
1.1 equiv) are dissolved in 30 ml of ethanol and cooled to 273 K. 12.0 g of
N,N-dimethyltaurine hydrochloride 7 (0.069 mol, 1.0 equiv) in 180 ml ethanol/
water (2:1) are slowly added over a period of 15 min, then 4.00 ml of concd
ammonium hydroxide are added. The reaction mixture is heated to 323 K for
18 h, then the solvent is removed. The product is washed with acetonitrile to
give 18.30 g (0.055 mol, 80%) of 2 as a colorless powder. 1H NMR (300 MHz,
D2O): 7.47 (m, 4H, CHaromat); 6.68 (dd, 1H, 3J = 11.0 and 17.7 Hz, CHolefin); 5.81
(d, 1H, 3J = 17.7 Hz, CHtrans); 5.28 (d, 1H, 3J = 11.0 Hz, CHcis); 4.48 (s, 2H,
CH2,benzyl); 3.60 (m, 2H, SCH2); 3.38 (m, 2H, NCH2); 3.01 (s, 6H, 2 Â CH3). 13C
NMR (75 MHz, D2O): 140.0 (Cq); 135.8 (CHolefin); 133.5 (2 Â CHaromat); 127.0
(2 Â CHaromat); 126.2 (Cq); 116.5 (CH2,olefin); 67.9 (CH2,benzyl); 59.9 (SCH2); 50.0
(2 Â CH3); 44.4 (NCH2). Anal. Calcd for C13H19ClNNaO3S: C, 47.6; H, 5.8; N, 4.3.
Found: C, 45.9; H, 6.3; N, 4.4%.
To ensure the composition of the prepared products, the coun-
ter ions of the sulfobetaine monomers 1–5 are determined using
anion exchange chromatography and the CHN-values from com-
bustion elemental analysis. While the molecules 1, 2, and 5 are
present with sodium and chloride (1 and 2) or sodium and bromide
(5) as counter ions for the charged functional groups, the mole-
cules 3 and 4 do not show any counter ions. This observation can
easily be explained by looking at the synthesis routes. Sulfobeta-
ines 1, 2, and 5 are prepared using nucleophilic substitutions of ha-
lides by tertiary amines. The used sulfonic acids were present as
sodium salts. In contrast, the sulfobetaines 3 and 4 are synthesized
from sultones. The quaternary amine and the sulfonic acid are pre-
pared in one step by a ring opening nucleophilic substitution thus
excluding the presence of further anions or cations in solution.
In conclusion simple synthetic routes for the preparation of a
homologous row of sulfobetaine monomers as styrene derivatives
could be found. All synthesized molecules have been successfully
used for polymerization reactions. They were attached to highly
porous highly crosslinked PS/DVB core materials with particle
15. Jiang, W.; Irgum, K. Anal. Chem. 2001, 73, 1993–2003.
16. (a) McCormic, C. L.; Lowe, A. B. Acc. Chem. Res. 2004, 37, 312–325; (b) Donovan,
M. S.; Sumerlin, B. S.; Lowe, A. B.; McCormic, C. L. Macromolecules 2002, 35,
8663–8666.
17. (a) Liu, P.-S.; Chen, Q.; Liu, X.; Yuan, B.; Wu, S.-S.; Shen, J.; Lin, S.-C.
Biomacromolecules 2009, 10, 2809–2816; (b) Liu, P.-S.; Chen, Q.; Wu, S.-S.;
Shen, J.; Lin, S.-C. J. Membr. Sci. 2010, 350, 387–394.
18. General procedure for the synthesis of 4-vinylbenzyl-dimethylammonio
propanesulfonate
3 and 4-vinylbenzyl-dimethylammonio butanesulfonate 4:
Under a nitrogen atmosphere 3.22 g of 4-vinylbenzyl-N,N-dimethylamine 8
(0.020 mol, 1.0 equiv) are dissolved in 100 ml of acetonitrile and 1 equiv of the
sultone (1,3-propanesultone or 1,4-butanesultone) is added. The reaction
mixture is heated to 323 K for 48 h, then the solvent is removed. The products
are washed with acetonitrile to give 5.40 g of 3 (0.017 mol, 84%) or 5.1 g of 4
(0.017 mol, 85%) as colorless powders.
Data for 4-vinylbenzyl-dimethylammonio propanesulfonate 3: 1H NMR (300 MHz,
D2O): 7.55 (m, 4H, CHaromat); 6.82 (dd, 1H, 3J = 11.0 and 17.7 Hz, CHolefin); 5.93
(d, 1H, 3J = 17.7 Hz, CHtrans); 5.40 (d, 1H, 3J = 11.0 Hz, CHcis); 4.48 (s, 2H,
CH2,benzyl); 3.43 (m, 2H, NCH2); 3.03 (s, 6H, 2 Â CH3); 2.96 (t, 2H, 3J = 7.4 Hz,
SCH2); 2.30 (m, 2H, –CH2–). 13C NMR (75 MHz, D2O): 139.8 (Cq); 135.7
(CHolefin); 133.2 (2 Â CHaromat); 126.5 (2 Â CHaromat); 126.3 (Cq); 116.3
(CH2,olefin); 67.8 (CH2,benzyl); 62.3 (NCH2); 49.5 (2 Â CH3); 47.3 (SCH2); 18.3
(CH2). Anal. Calcd for C14H21NO3S: C, 59.3; H, 7.5; N, 4.9%. Found: C, 58.5; H,
7.4; N, 4.8%.
sizes of 4.6
stationary phases with exchange capacities in the range 50–
l
m by a grafting reaction.21,4 Thereby zwitterionic
Data for 4-vinylbenzyl-dimethylammonio butanesulfonate 4: 1H NMR (300 MHz,
D2O): 7.54 (m, 4H, CHaromat); 6.81 (dd, 1H, 3J = 11.0 and 17.7 Hz, CHolefin); 5.92
(d, 1H, 3J = 17.7 Hz, CHtrans); 5.39 (d, 1H, 3J = 11.0 Hz, CHcis); 4.44 (s, 2H,
CH2,benzyl); 3.29 (m, 2H, NCH2); 3.00 (s, 6H, 2 Â CH3); 2.96 (t, 2H, 3J = 7.6 Hz,
SCH2); 2.02 (m, 2H, –CH2–); 1.78 (m, 2H, –CH2–). 13C NMR (75 MHz, D2O):
139.8 (Cq); 135.7 (CHolefin); 133.2 (2 Â CHaromat); 126.7 (2 Â CHaromat); 126.5
(Cq); 116.3 (CH2,olefin); 67.6 (CH2,benzyl); 63.4 (NCH2); 50.0 (2 Â CH3); 49.6
(SCH2); 21.1 (CH2); 21.0 (CH2). Anal. Calcd for C15H23NO3S: C, 60.6; H, 7.8; N,
4.7. Found: C, 58.5; H, 7.9; N, 4.3.
250 lmol/g PS/DVB were prepared and used in zwitterionic ion
chromatography.4,22
Acknowledgment
This work was supported by Metrohm AG, Herisau, Switzerland.
19. Fujii, A.; Cook, E. S. J. Med. Chem. 1975, 18, 502–505.
20. Synthesis of 4-vinylbenzyl-dimethylammonio pentanesulfonate 5: Under
a
References and notes
nitrogen atmosphere 6.0 g of 5-bromopentane-1-sulfonate (0.024 mol,
9
1 equiv) are dissolved in 60 ml of ethanol/water (1:1) and cooled to 273 K.
3.87 g of 4-vinylbenzyl-N,N-dimethylamine 8 (0.024 mol, 1.0 equiv) are added
in one portion. The reaction mixture is heated to 318 K for 18 h, then the
solvent is removed. The product is washed with acetonitrile to give 7.19 g
(0.019 mol, 81%) of 5 as a colorless powder. 1H NMR (300 MHz, D2O): 7.76
(m, 4H, CHaromat); 6.95 (dd, 1H, 3J = 11.0 and 17.7 Hz, CHolefin); 6.09 (d, 1H,
3J = 17.7 Hz, CHtrans); 5.56 (d, 1H, 3J = 11.0 Hz, CHcis); 4.72 (s, 2H, CH2,benzyl);
3.53 (m, 2H, NCH2); 3.26 (s, 6H, 2 Â CH3); 3.03 (m, 2H, SCH2); 2.14 (m, 2H,
NCH2CH2); 1.97 (m, 2H, SCH2CH2); 1.70 (m, 2H, CH2). 13C NMR (75 MHz,
1. Seibt, H.; Ohme, R.; Ballschuh, D. Tenside, Surfactants, Detergents 1991, 28, 337–
347.
2. Aldred, N.; Li, G.; Gao, Y.; Clare, A. S.; Jiang, S. Biofouling 2010, 26, 673–683.
3. Nesterenko, E. P.; Nesterenko, P. N.; Paull, B. Anal. Chim. Acta 2009, 652, 3–21.
4. Sonnenschein, L.; Seubert, A., J. Chromatogr., A, doi:10.1016/j.chroma.2010.
12.101.
5. Tsukamoto, T.; Yasuma, M.; Yamamoto, A.; Hirayama, K.; Kihou, T.; Kodama, S.;
Inoue, Y. J. Sep. Sci. 2009, 32, 3591–3595.

1104
L. Sonnenschein, A. Seubert / Tetrahedron Letters 52 (2011) 1101–1104
21. Raskop, M.; Seubert, A.; Grimm, A. (Metrohm AG, Switzerland) European
D2O): 139.8 (Cq); 135.7 (CHolefin); 133.2 (2 Â CHaromat); 126.7 (2 Â CHaromat);
126.5 (Cq); 116.3 (CH2,olefin); 67.6 (CH2,benzyl); 63.4 (NCH2); 50.0 (2 Â CH3);
Patent 1842592A1, 2007.
49.6 (SCH2); 21.1 (CH2); 21.0 (CH2). Anal. Calcd for C16H25BrNNaO3S: C, 46.4;
H, 6.1; N, 3.4. Found: C, 47.6; H, 5.8; N, 3.1.
22. Sonnenschein, L.; Seubert, A. J. Chromatogr. Sci., submitted for publication.