Facile syntheses of alkoxysilanated phosphorylcholines as surface modifiers: CuAAC and thiol-ene "click" reactions

Article abstract of DOI:10.1039/c4ra15716h

Eight alkoxysilanated phosphorylcholine (PC) compounds were synthesized from CuAAC (copper-catalyzed azide/alkyne cycloaddition) and thiol-ene "click" reactions. This methodology will provide simple and efficient routes for the synthesis of alkoxysilanated PC modifiers. To demonstrate modification ability of these products, they were implanted onto silica beads, and the loading rates were quantified.

Full text of DOI:10.1039/c4ra15716h

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Facile syntheses of alkoxysilanated
phosphorylcholines as surface modifiers: CuAAC
and thiol-ene “click” reactions†
Cite this: RSC Adv., 2015, 5, 14273
Received 3rd December 2014
Accepted 22nd January 2015
*
Lei Liu, Sung Jin Park, Ji-hyun Park and Myong Euy Lee
DOI: 10.1039/c4ra15716h
www.rsc.org/advances
Eight alkoxysilanated phosphorylcholine (PC) compounds were (MPC) and 3-trimethoxysilylpropylmethacrylate (MPS) were used
synthesized from CuAAC (copper-catalyzed azide/alkyne cycloaddi- to promote adhesion on contact lenses.6 Trimethoxysilyl groups
tion) and thiol-ene “click” reactions. This methodology will provide ended poly(MPC) was synthesized to coat a Mg–Al–Zn alloy.7
simple and efficient routes for the synthesis of alkoxysilanated PC Besides macromolecules, the other PC-containing compounds
modifiers. To demonstrate modification ability of these products, they were studied to modify not only large devices but also nano-sized
were implanted onto silica beads, and the loading rates were particles. Chloro-silanated PC was rst prepared to construct a
quantified.
bio-membrane on hydroxylated glasses.8 However, with tedious
processes requiring more than 5 steps, low total yields were
obtained that restricted further applications. Although Yousuke,
et al. obtained imine- and amide-bridged alkoxysilanated PCs,
complicated synthetic routes and purication processes were not
practical due to the moisture-sensitivity of alkoxysilyl groups.9 A
Pt/C-catalyzed hydrosilylation reaction of MPC with trimethox-
ysilane was carried out in methanol to synthesize methoxysila-
nated MPC for surface modication of medical alloys.7 However,
in our work, similar hydrosilylation reactions of MPC with tri-
alkoxysilanes did not yield the expected products because tri-
alkoxysilane reacted with alkyl alcohols to emit hydrogen gas in
the presence of Pt/C or a Karstedt catalyst. Thus, it appears that Pt-
catalyzed hydrosilylation is not suitable for the synthesis of
alkoxysilanated PC. Therefore, the development of a simple and
efficient method that combines alkoxysilyl groups with the PC
moiety is urgently needed.
As is well known, the CuAAC reactions to give 1,2,3-triazoles
show remarkably broad scope and exquisite selectivity.10 As the
most explored “click” reaction to date, CuAAC reaction has
quickly found applications in polymer, biological and applied
materials chemistry.11 Precedents for this approach include
several syntheses of functional alkoxysilanes,12 gra-
functionalization of polysiloxanes,13 and preparation of poly-
ferrocenylsilane block copolymers.14 Especially, our group
recently reported the syntheses and application of meth-
allylsilanated PCs as surface modiers via a CuAAC reaction.15
These attributes led us to propose that the CuAAC reaction
would be appropriate for the synthesis of alkoxysilanated PC.
Besides CuAAC reaction, we found that the thiol-ene “click”
reaction was widely used to synthesize dendrimers, function-
alized bio-molecules, biomacromolecules, and new polymeric
Phosphorylcholine (PC) has an ideal structure as described by
the “uid-mosaic model,” a model of the bio-membrane struc-
ture proposed by Singer and Nicolson.1 Phospholipids con-
taining PC as a head group are major components of all
eukaryotic cell membranes and make up at least 10% of all
bacterial membranes.2 Accordingly, PC derivatives show high
affinity for living organs and tissues and have been widely used
in the construction of bio-membranes and as excellent anti-
fouling surface modiers in various medical applications such
as blood-contact devices,3 bio-mimic membranes,4 and surface
treatments5 to inhibit cell adhesion or decrease undesirable
protein interactions.
One of the common methods for PC-related surface modi-
cation is to implant alkoxy- or halo-silyl functionalized PC
compounds onto hydroxylated surfaces like medical devices,6
metal alloys,7 and glasses.8 Formation of strong Si–O bonds
without the need of a catalyst makes this method particularly
useful for bridging functional groups and substrates. Efforts have
been made to synthesize PC-containing macromolecules with
methoxysilyl groups for modication of medical devices. For
instance, copolymers of 2-methacryloyloxyethylphosphorylcholine
Department of Chemistry & Medical Chemistry, College of Science and Technology,
Research & Education Center for Advanced Silicon Materials, Yonsei University,
Wonju, Gangwondo, 220-710, Republic of Korea. E-mail: melgg@yonsei.ac.kr; Fax:
+82-33-760-2182; Tel: +82-33-760-2237
† Electronic supplementary information (ESI) available: (1) Syntheses and
characterization of synthesized compounds. (2) XPS spectra of 2c-silica and
2g-silica. (3) NMR spectra of representive compounds. See DOI:
10.1039/c4ra15716h
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Scheme 2 Generic routes to synthesize 2e–h.
Table 2 Sulfur-bridged alkoxysilanated PCs (2e–h)
Scheme 1 Generic routes to synthesize 2a–d.
materials for applications ranging from lithography to porous
microparticles.11,16 In organo-silicon chemistry, this reaction
has proven to be an efficient method to synthesize functional-
ized silanes,17 silicon elastomeric materials18 and oxide-free
silicon surfaces.19 Thus, it was envisioned that thiol-ene
“click” reactions would be suitable for the synthesis of alkoxy-
silanated PCs.
Entry Silanes (1e–h)
Products (2e–h)
5
6
(EtO)3Si(CH2)3SH
(MeO)3Si(CH2)3SH
Herein, we report the syntheses of alkoxysilanated PCs via
CuAAC and thiol-ene “click” reactions. As shown in Scheme 1,
the CuAAC reaction could be used to synthesize triazole-bridged
alkoxysilanated PCs (2a–d). First, 3-azidopropylalkoxysilanes
(1a–d, Table 1) were synthesized from 3-chloropropylalkoxy-
silanes using reported methods,20 and propargylphosphoryl-
choline (PPC) was synthesized as reported in our previous
work.15 Equimolar amounts of 3-azidopropylalkoxysilane and
PPC (1 mmol) were mixed in the presence of CuI/DIPEA (2
mmol/4 mmol). Then, these reactants were dissolved in ethanol
under argon. Reactionsꢀcould be run in ethanol (5 mL) and
proceed smoothly at 60 C for 12 h. Table 1 shows that azides
(1a–d) smoothly coupled with PPC to produce alkoxysilanated
PCs (2a–d) as light yellow powders in yields of 90–92%.
Testing the method of thiol-ene “click” reaction began with
the preparation of allylphosphorylcholine (APC) as reported in
our previous work.21 Next, sulfur-bridged alkoxysilanated PCs
(2e–h) were synthesized via the benzophenone initiated thiol-
ene “click” reaction under a 300 nm UV lamp (Scheme 2). A
slight excess of 3-mercaptopropyl alkoxysilane (1e–h, 1.10
mmol) and APC (1 mmol) were dissolved in 2 mL of EtOH in the
7
(MeO)2MeSi(CH2)3SH
8
(MeO)Me2Si(CH2)3SH 1ha
a
1e–g are commercially available, 1h was synthesized from 1f according
to the reported method.22
Scheme 3 Representative silica surface modifications using 2c, 2g.
Table 1 Triazole-bridged alkoxysilanated PCs (2a–d)
presence of 2 mol% benzophenone. The reactions proceeded
for 15 min under argon at room temperature. Table 2 shows that
mercapto-silanes selectively participated in the thiol-ene reac-
tions to result in pure a-addition products (2e–h) as light yellow
powders in quantitative yields.
Entry
Silanes (1a–d)
Products (2a–d)
1
(MeO)3Si(CH2)3N3
To verify that all of the alkoxysilanated PCs were useful as
surface modiers, they were implanted onto silica beads as
shown in Scheme 3. The alkoxysilanated PC (1 mmol) and silica
beads (400 mg) were dispersed in 20 mL of an IPA/toluene (10
mL/10 mL) mixture. Aer heating at 90 ꢀC under N2 for 24 h, the
modied silica was ltered, washed with ethanol and toluene,
and dried in a vacuum oven for 24 h. The loading rates were
quantied as shown in Table 3.
2
3
(EtO)3Si(CH2)3N3
(EtO)2MeSi(CH2)3N3
Then, the resulting modied silica was characterized by
elemental analysis. As shown in Table 3, the loading rates of
alkoxysilanated PCs determined by nitrogen elemental analysis
varied from 0.31–0.63 mmol gꢁ1 demonstrated according to
4
(EtO)Me2Si(CH2)3N3
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Table 3 Loading rates of alkoxysilanated PCs (2a–h) onto silica beads
Products
2a
2b
2c
2d
2e
2fa
2g
0.42
2h
Loading rate (mmol gꢁ1
)
0.44
0.38
0.31
0.34
0.55
0.63
0.43
a
The loading rate for 2a–h was based on the N value of modied silica determined by elemental analysis. For example: calculation of the loading
rate of 2f modied silica 2f-silica (C (%) 9.0929, N (%) 0.8921) ¼ (0.8921 ꢂ 10ꢁ2 g of N/1 g of compound PC-modied silica 2f-silica) ꢂ (103 mmol of
N/14 g of N) ꢂ (1 mmol of 2f/1 mmol of N) ¼ 0.63 mmol 2f/1 g of compound PC-modied 2f-silica.
Table 4 Surface elemental compositions of modified silica determined by XPS
Surface elemental compositions (%)
Binding energy (eV)
Modied silica
O
Si
C
N
P
S
C1s
N1s
P2p
S2s, S2p
2c-silica
54.11
30.21
12.37
2.62
0.59
286.7 (C–H)
286.2 (C–N)
285.5 (C–O)
289.1 (C–S)
286.7 (C–H)
286.2 (C–N)
285.5 (C–O)
399.9 (C–N])
400.9 ((C)–N)
134.4
402.7 (+N(CH3)3)
403.1 (+N(CH3)3)
2g-silica
50.79
27.78
17.65
1.32
1.15
1.32
134.5
228.1 (S2s), 163.8 (S2p)
reported method.15 Methoxy-silanated modiers were more synthesized via CuAAC and thiol-ene “click” reactions. These
active than ethoxy-silanated modiers, and trimethoxysilanated reactions proceeded smoothly in high yields, and a preliminary
PCs (2a, 2f) gave the highest loading rates. Furthermore, study showed that the reactions could be easily scaled-up. The
loading rates were also affected by the steric effects of the PC synthesized alkoxysilanated PCs were demonstrated to be active
tail-moiety. Compared with “sulfur-bridged PC” tail-group of surface modiers by immobilization on silica beads. This
2e–h, “triazole-bridged PC” tail-group of 2a–d gave a greater methodology is suitable for the development of PC-containing
steric effect. Thus, loading rates of 2e–h were higher than these silicon materials applicable to blood-contact conditions and
of 2a–d.
To further evaluate the modied silica, the surface elemental
bio-mimic systems.
compositions of two representative modied silica beads were
determined by XPS as depicted in Table 4. The XPS C1s core-
level spectrum of the 2c-silica is comprised of three peak
components. With binding energies (BEs) at about 286.7, 286.2
and 285.5 eV, they are attributed to the C–H, C–N, C–O species,
respectively. The N1s core-level spectrum is splitting into three
peaks. The peaks at the BEs of about 399.9 and 400.9 eV are
attributed to imine nitrogen (C–N]) and amine nitrogen (C–N)
of triazole rings, respectively. The peak at the BE of about 402.7
eV is associated with the positively charged nitrogen (+N(CH3)3).
The P2p core-level spectrum is at about 134.4 eV. For 2g-silica,
the XPS C1s core-level spectrum is comprised of four peak
components. With BEs at about 289.1, 286.7, 286.2 and 285.5
eV, they are attributed to the C–S, C–H, C–N, C–O species,
respectively. The N1s core-level spectrum is single peak with BE
at about 403.1 eV (+N(CH3)3). The peak of P2p core-level spec-
trum is also at about 134.5 eV. The S2s and S2p core-levels are
observed at the BEs of about 228.1, and 163.8 eV, respectively.
These results indicate that the PC was successfully implanted
on silica beads.
Acknowledgements
This research was supported nancially by the Research and
Education Center for Advanced Silicon Materials (RECASM) and
the KCC Corporation. The authors also thank KCI for providing
chemicals.
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