Novel monodisperse PEG-grafted polystyrene resins: synthesis and application in gel-phase 13C NMR spectroscopy

Article abstract of DOI:10.1016/j.tetlet.2008.09.128

A series of novel polystyrene-oligo(oxyethylene) graft copolymers containing monodisperse PEG units (n = 2-12) have been synthesized and examined concerning their applicability for gel-phase ¹³C NMR spectroscopy. A strong correlation between the graft length and the line widths in the gel-phase spectra was observed. By grafting a PEG chain with only eight units, it was possible to obtain results similar to TentaGel resin. Additionally, TOF-SIMS images were recorded in order to evaluate the homogeneity of the resin.

Full text of DOI:10.1016/j.tetlet.2008.09.128

Tetrahedron Letters 49 (2008) 7103–7105
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel monodisperse PEG-grafted polystyrene resins: synthesis and
1
3
application in gel-phase C NMR spectroscopy
a
a,*
a
b
b
Christian Braunshier , Christian Hametner , Johannes Fröhlich , Johannes Schnöller , Herbert Hutter
a
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, A-1060 Vienna, Austria
Institute of Chemical Technologies and Analytics, Vienna University of Technology, Getreidemarkt 9/164, A-1060 Vienna, Austria
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel polystyrene-oligo(oxyethylene) graft copolymers containing monodisperse PEG units
Received 4 October 2007
Revised 17 September 2008
Accepted 22 September 2008
Available online 26 September 2008
13
(n = 2–12) have been synthesized and examined concerning their applicability for gel-phase C NMR
spectroscopy. A strong correlation between the graft length and the line widths in the gel-phase spectra
was observed. By grafting a PEG chain with only eight units, it was possible to obtain results similar to
TentaGel resin. Additionally, TOF-SIMS images were recorded in order to evaluate the homogeneity of
the resin.
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Solid-phase organic synthesis
NMR spectroscopy
PS-PEG graft copolymers
TOF-SIMS
Solid-phase organic synthesis (SPOS) has historically been the
most important method for synthesis of polypeptides and oligonu-
cleotides. The extension of SPOS to the broader area of small, drug-
like organic molecules has more recently become important for
combinatorial chemistry. Due to the establishment of high-
throughput-screening (HTS) processes over the last years, there
has been immense work devoted to developing suitable resins.
The most commonly used solid supports are cross-linked poly-
styrene (PS) and poly(styrene-oxyethylene) graft copolymers
gel-phase spectra. In this letter, we report a systematic investiga-
tion of the effect of PEG group length on the quality of gel-phase
C NMR spectra, using the line width of an attached sensor mole-
1
3
cule as the major criterion.
As shown in Scheme 1, the initial step in the resin synthesis was
the monoprotection of glycols 1a–f (n = 2, 4, 6, 8, 10, 12) by conver-
3
sion with tert-butyldimethylsilyl chloride (TBSCl) (glycols 1a,b,c
(n = 2, 4, 6) are commercially available; the higher homologues
have been synthesized according to a procedure by Keegstra and
4
5
(
PS-PEG).
The last mentioned supports, first reported by Bayer and Rapp,1
display good swelling in a variety of solvents from medium to high
co-workers ). In the second step, these protected glycols (2a–f)
were attached to polymer-bounded phenol by applying a Mitsun-
6
3
obu reaction (DEAD, PPh ) as key step in this reaction scheme.
1
3
polarity. In addition, they provide good quality gel-phase C NMR
spectra, which are useful for non-destructive on-resin analysis.
For deprotection, the resins 3a–f were swollen in THF and were
treated with a 1.0 M solution of TBAF in THF to give the novel
monodisperse PEG-grafted resins 4a–f in quantitative yield. Each
reaction step on solid phase was monitored using IR and gel-phase
2
The copolymers are produced by grafting ethylene oxide to the
PS backbone creating long flexible polydisperse chains (the com-
mercial resins TentaGel and ArgoGel bear about 60–70 PEG units)
that provide a ‘solution-like’ environment for attached moieties.
The main drawback of such resins is the low degree of substitution
1
3
C NMR spectroscopy.
We have selected a number of small molecules with easily
assignable NMR spectra as sensor molecules in a recent study of
gel-phase C NMR spectroscopy covering commercial resins.7 Of
these, 4-(dimethylamino)-butyric acid hydrochloride was chosen
for the present work as its high polarity makes it a very demanding
sensor for gel-phase NMR, which is usually carried out in solvents
of low to medium polarity due to the swelling abilities of the resin
backbone. The acid was attached to the resins’ hydroxyl groups
13
(
about 0.2–0.3 mmol/g) compared to classical PS resin (e.g., Merri-
field, 1–1.5 mmol/g) and a huge signal in the gel-phase spectra
resulting from the 60–70 oxyethylene units. In our strategy, we
substituted this long PEG chain against shorter monodisperse
oligo(oxyethylene) tethers (n = 2–12 units) with the objective
of increasing the loading and minimizing the PEG signal in the
8
using a carbodiimide-based coupling method.
1
3
A gel-phase C NMR spectrum was recorded for each of the
*
Corresponding author. Tel.: +43 1 58801 15412; fax: +43 1 58801 15499.
E-mail address: christian.hametner@tuwien.ac.at (C. Hametner).
loaded resins 5a–f. Figure 1 shows spectra of 5d and commercially
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.128

7
104
C. Braunshier et al. / Tetrahedron Letters 49 (2008) 7103–7105
OR
ii
OR
iv
O
H
O
n
O
n
PS
O
n
PS
N
.HCl
O
1
a-f R=H
3a-f R=TBS
4a-f R=H
i
a-f: n=2,4,6,8,10,12
iii
5a-f
Sensor molecule
2
a-f R=TBS
Scheme 1. Reagents and conditions: (i) TBSCl (0.5–1 equiv), imidazole or pyridine, DCM, 24 h; (ii) polymer-bounded phenol, DEAD (5 equiv), Ph
3
P (5 equiv), DCM/THF = 1/1,
2
4 h; (iii) TBAF (5 equiv), THF, 1 h; (iv) 4-(dimethylamino)-butyric acid hydrochloride (5 equiv), DIC (5 equiv), HOBt (5 equiv), DMAP (1 equiv), DCM/DMF = 9/1, 24–48 h.
(
(
a)
b)
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
Figure 1. Gel-phase 13C NMR spectra of resin 5d (b) compared to TentaGel loaded with the same sensor molecule (a).
available TentaGel resin loaded with the same sensor molecule
recorded under identical conditions. The increase of signal inten-
sity and the decrease of the PEG peak height in the spectrum of
Table 1
Swelling volume (mL/g)b of selected resins at 25 °C in different solvents
Entry
Resin
loadingc
MeOH
DMF
THF
DCM
5
d are clearly visible. In order to characterize each spectrum by a
Merrifielda
1
2
3
4
5
1.5
1.1
0.9
0.7
0.3
0.7
1.5
2.1
2.1
2.7
4.3
6.8
6.7
6.0
4.1
7.5
8.5
7.1
7.3
4.2
7.3
7.8
8.0
8.6
5.7
single value, an average half-height line width of all non-quater-
nary carbon peaks of the immobilized sensor molecule was deter-
mined. In Figure 2, the results of the line width analysis are shown:
due to the improving solvation and mobility of the attached moi-
ety, the line width decreases with increasing number of ethylene
glycol units. Already eight units (resin 5d, avg. line width
4b (n = 4)
4d (n = 8)
4f (n = 12)
a
TentaGel
a
Obtained from Advanced ChemTech.
Based on the weight difference between dry and swollen beads, recalculating
the data to express it as mL/g.
b
1
0.1 Hz) are sufficient to obtain high-quality spectra, although
c
In mmol/g, for resins 4b,d,f determined gravimetrically.
the higher homologues get a little closer to TentaGel resin
(
n ꢀ 68, avg. line width 9.5 Hz).
Table 1 shows the loadings (which of course show a small de-
In order to test the ability of our resins to perform as support,
we carried out a known reaction sequence leading to 3,5-di-
benzylhydantoin using one of our resins (4d, n = 8) as well as
commercially available Tentagel support. This four-step sequence
was selected because it involves a variety of reactions and reagents
in different solvents. Although in both cases an overall yield of
approximately 50% was obtained, this is equivalent to an amount
of 90 mg of the final product when starting from 1 g of 4d, but only
crease with increasing PEG length) and swelling ability of the novel
PEG resins in different solvents. Except for methanol (where swell-
ing is known to be generally poor), the new resins provide good
swelling from four glycol units and above.
9
1
1
1
1
1
8.0
6.0
4.0
2.0
0.0
2
5 mg when using 1 g of Tentagel. Thus, a substantially lower
amount of our resin is needed to obtain an intended quantity of
a target compound.
In conclusion, we have shown that polystyrene resins grafted
with short, monodisperse PEG units can easily be synthesized from
polymer-bounded phenol and offer advantageous properties for
gel-phase NMR spectroscopy. In combination of loading and spec-
tral quality resin 4d with eight ethylene glycol units showed best
results. The advantage of the higher loading of our resins has been
shown in a four-step reaction sequence.
1
0
TOF-SIMS measurements: Additionally, secondary ion mass
spectrometry was performed on some selected examples of the
resins loaded with the sensor molecule 4-(dimethylamino)-butyric
acid hydrochloride (5b,d,f; see Fig. 3 as well as Supplementary
data).
8.0
0
2
4
6
8
10
12
14
Ethylene glycol units
Figure 2. Effect of PEG group length on the average half-height line width of the
sensor molecule.

C. Braunshier et al. / Tetrahedron Letters 49 (2008) 7103–7105
7105
2.
Reviews: (a) Dal Cin, M.; Davalli, S.; Marchioro, C.; Passarini, M.; Perini, O.;
Provera, S.; Zaramella, A. Farmaco 2002, 57, 497–510; (b) Vaino, A. R.; Janda, K.
D. J. Comb. Chem. 2000, 2, 579–596; (c) Yan, B. Acc. Chem. Res. 1998, 31, 621–
6
30.
Ishizone, T.; Han, S.; Okuyama, S.; Nakahama, S. Macromolecules 2003, 36, 42–
9.
Keegstra, E.; Zwikker, J.; Roest, M.; Jenneskens, L. J. Org. Chem. 1992, 57, 6678–
680.
Characterization data for compound 2d: H NMR (CDCl
3.
4.
5.
4
6
1
3
): d 3.75–3.44 (m, 32H),
.76 (br s, 1H), 0.83 (s, 9H), 0.00 (s, 6H). 13C NMR (CDCl
): d 72.6 (t), 72.5 (t),
0.7 (t), 70.5 (t, 10C), 70.3 (t), 62.6 (t), 61.7 (t), 25.9 (q, 3C), 18.3 (s), ꢁ5.3 (q, 2C).
Si: C, 54.52, H, 9.98. Found: C, 54.48, H,
2
7
3
Anal. Calcd for
.72.
22 48 9
C H O
9
6.
Experimental procedure for Mitsunobu reaction on solid phase: Diethyl
azodicarboxylate (5 equiv) was added dropwise to a mixture of 1.0 equiv of
polymer-bounded phenol (100–200 mesh, 1% divinylbenzene, Aldrich,
1
.7 mmol/g) in dry DCM/THF = 1/1 (50 mL/g resin) under argon. Then, the
Figure 3. TOF-SIMS images of immobilized sensor molecule on TentaGel (left) and
resin 5d (right).11
monoprotected glycol 2 (5 equiv), dissolved in dry THF, was added and finally
triphenylphosphine was added slowly. The reaction mixture was stirred
overnight, filtered, and the solid residue was washed three times with DCM/
THF = 1/1, DCM, isopropanol, DCM and finally with methanol. The resulting
resin 3 was dried to constant weight in vacuo.
The figures display the elemental distribution of 35Cl within the
samples. Thus, the attached molecules on individual beads of the
resin can be depicted directly via their chlorine atoms, and the cor-
responding intensity gives an indication of the amount of loading.
Further investigations to utilize the TOF-SIMS technique to study
SPOS resins will be undertaken.
7. Braunshier, C.; Hametner, C. QSAR Comb. Sci. 2007, 26, 908–918.
8.
General procedure for preparation of resin 5: Resin 4 was suspended in dry DCM/
DMF = 9/1 (15 mL/g resin), and then 4-(dimethylamino)-butyric acid
hydrochloride (5.0 equiv) and 1-hydroxybenzotriazole (5.0 equiv) were added
in a minimum amount of dry DMF. 4-(N,N-dimethylamino)-pyridine (1.0 equiv)
0
in dry DMF and N,N -diisopropylcarbodiimide (5.0 equiv.) were added to the
mixture and were stirred under argon at room temperature for 2 days. The
resulting suspension was filtered and the solid residue was washed three times
with DMF, then with DCM, and finally with methanol. The resin was dried to
constant weight in vacuo.
Supplementary data
9
.
Kita, R.; Svec, F.; Fréchet, M. J. J. Comb. Chem. 2001, 3, 564–571.
Some representative IR spectra and more examples of gel-phase
C NMR spectra of prepared resins, as well as TOF-SIMS images of
further resins. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2008.09.128.
10. TOF-SIMS measurements were carried out on a TOF-SIMS 5 instrument (ION-
1
3
þ
TOF GmbH, Münster, Germany), equipped with a Bi
cluster ion source at
n
þ
2
5 keV energy. Images were recorded using Bi
ion clusters for enhanced
3
secondary ion yield, with a primary ion dose density of 1.0E ions/cm2 to
12
13
13
operate under static SIMS conditions.
1
1. The field of view is always 128 ꢂ 128 pixels, independent from the
The color scale depends on ‘mc value’ (maximum counts per pixel), not on the
tc value’ (total counts).
lm scale.
References and notes
‘
1
1
2. Nagy, G.; Walker, A. V. Int. J. Mass Spectrosc. 2006, 262, 144–153.
3. Verdier, S.; Metson, J. B.; Dunlop, H. M. J. Mass Spectrosc. 2007, 42, 11–19.
1
.
Bayer, E.; Hemmasi, B.; Albert, K.; Rapp, W.; Dengler, M. Peptides, Structure and
Function. Hruby, V. J., Rich, D. H., Eds; Proceedings of the 8th American Peptide
Symposium; Pierce Chemical Company: Rockford, IL, 1983; pp 87–90.