Molecularly imprinted polymers with halogen bonding-based molecular recognition sites

Article abstract of DOI:10.1016/j.tetlet.2005.10.098

Molecular recognition materials bearing halogen bonding-based binding sites were synthesized by a non-covalent imprinting technique using a 2,3,5,6-tetrafluoro-4-iodostyrene (TFIS) as the functional monomer. The binding sites were generated by co-polymeri

Full text of DOI:10.1016/j.tetlet.2005.10.098

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 9025–9027
Molecularly imprinted polymers with halogen
bonding-based molecular recognition sites
a
b
a
Toshifumi Takeuchi,a,b, Yuji Minato, Masayoshi Takase and Hideyuki Shinmori
*
aGraduate School of Science and Technology, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
bPRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Saitama 332-0012, Japan
Received 24 September 2005; revised 18 October 2005; accepted 20 October 2005
Abstract—Molecular recognition materials bearing halogen bonding-based binding sites were synthesized by a non-covalent
imprinting technique using a 2,3,5,6-tetrafluoro-4-iodostyrene (TFIS) as the functional monomer. The binding sites were generated
by co-polymerizing TFIS, styrene and divinylbenzene in the presence of the template molecule (4-dimethylaminopyridine—DMAP).
The imprinted polymer preferentially adsorbed aminopyridine derivatives, suggesting that halogen bonding may play a role in the
selective recognition of analytes by the synthesized synthetic receptor.
Ó 2005 Elsevier Ltd. All rights reserved.
Halogen atoms can act as electron acceptors and inter-
act with chemical species that have an ability to act as
electron donors.1 This non-covalent interaction can be
strong enough to modulate the aggregation of organic
molecules in solid,2 liquid,3 liquid crystal4 and gas
phases,5 and the term Ôhalogen bondingÕ has been sug-
gested in order to emphasize the similarity with hydro-
gen bonding, which is frequently the key non-covalent
interaction in chemistry, biology, and materials science.6
It is well known that halogen molecules or alkyl and aryl
halides tend to form complexes with atoms containing
lone pairs.1,6 Interactions occurring between various
amino (or pyridine) derivatives and iodoperfluoro com-
pounds give rise to crystalline complexes, which have
been confirmed by X-ray analyses.7 So far halogen
bonding has not well-tried for use in solution, but it
seems to attract wide interest as a non-covalent interac-
tion. Recent articles6,7 have shown that halogen bonding
is a strong, specific and directional interaction which
gives well-defined supramolecular systems.
cross-linker(s) in the presence of a template molecule
to be recognized. The resulting polymers have selective
binding sites complementary to the template. In non-
covalent imprinting,9 functional monomers are chosen
to complement to template moleculeÕs functional
groups. After the polymerization with cross-linker(s),
templates are removed by washing with solvents that
should weaken the interaction. The advantage of using
non-covalent interaction is the ease of pre-organization
of complexes between a functional monomer(s) and a
template. Previously, we have reported the selective syn-
thetic polymer receptors prepared by molecular imprint-
ing, in which the hydrogen bonds were mainly utilized in
the binding sites.10 On the other hand, Whitcombe
et al.11 have demonstrated that the covalently imprinted
polymers showed significantly uptake of 2,3,7,8-tetra-
chlorodibenzodioxin (TCDD). TCDD bound to the
polymer possibly by halogen bonding with aromatic
chlorine atoms and p–p interactions in the binding sites,
however, they did not clearly show the contribution of
halogen bonding.
Molecular imprinting has been known as a preparation
technique to yield selective molecular recognition mate-
rials.8 Molecularly imprinted polymers are synthesized
by copolymerization of a functional monomer(s) and a
In this letter, we attempt to construct a molecular recog-
nition material by molecular imprinting using halogen
bonding for DMAP (template molecule) and its relative
compounds, in which halogen bonding could be a main
interaction in the binding sites. Figure 1 shows an illus-
tration of halogen-bonded molecular recognition site
generation in this work. The used functional monomer,
2,3,5,6-tetrafluoro-4-iodostyrene (TFIS), was synthesized
Keywords: Halogen bonding; Molecularly imprinted polymer; Mole-
cular recognition.
*
Corresponding author. Tel./fax: +81 78 803 6158; e-mail: takeuchi@
scitec.kobe-u.ac.jp
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.098

9026
T. Takeuchi et al. / Tetrahedron Letters 46 (2005) 9025–9027
N
F
F
F
F
F
F
F
F
F
F
F
F
N
I
N
I
N
Crosslinking
agents
I
TFIS
Washing
F
F
F
F
F
F
Binding site by
halogen bonding
I
I
F
F
Figure 1. Possible structure of molecularly imprinted polymer using DMAP as template.
from 4-amino-2,3,5,6-tetrafluorobenzoic acid according
to Scheme 1. The functional monomer is substituted
by four fluorine atoms at 2, 3, 5and 6 positions, in order
to enhance the electron acceptability on the iodine atom,
and is expected to interact with two nitrogen atoms of
N,N-dimethylamino and pyridyl in a DMAP. The route
relies on the stepwise Sandmeyer reaction for the iodin-
ation followed by the reduction of carboxyl group using
diisobutylaluminiumhydride (DIBAL) and Wittig reac-
tion of 2,3,5,6-tetrafluoro-4-iodobenzaldehyde. TFIS
was purified by silica gel column chromatography (elu-
ent: n-hexane) in total 14% yield. DMAP-imprinted
polymer was prepared as follows:6–8 TFIS (0.3 mmol)
and DMAP (0.1 mmol) was dissolved in CHCl3
(2.0 ml), and styrene (0.4 mmol) and divinylbenzene
(4.5mmol) were added as crosslinking agents, then
2,2Õ-azobis(2,4-dimethyl valeronitrile) (0.08 mmol) was
added as an initiator of the radical polymerization.
The polymerization mixture was purged with nitrogen
gas, sealed, then heated at 60 °C for 12 h. The resulting
polymer was ground and sieved to yield the polymer
particles (size: less than 32 lm). The particles were
washed with methanol, and 87% of the template was
removed from the polymer by the treatment.
The binding characteristics and imprint effect of the
polymers were evaluated after the incubation in aceto-
nitrile solutions of DMAP and structurally related com-
pounds (250 lM) shown in Figure 2. The polymer
(10 mg) was added to acetonitrile (1.0 ml) containing
DMAP or related compounds. After the suspensions
were rotated for 24 h at 20 °C, the polymer particles
were removed by filtration with a syringe fitted with a
disposable 5 lm filter cartridge. The filtrate solutions
were analyzed by an Agilent GC–MS system (model
6890N GC/5973MSD, column: HP-5ms).
In order to evaluate the selectivity of the DMAP-
imprinted polymer, the binding of various analytes were
examined (Fig. 2). The imprinted polymer weakly
adsorbed N,N-dimethylaniline 2, 4-picoline 3, aniline
5, and pyridine 6, which possess an amino (N,N-dimethyl-
amino) or a pyridyl group, compared with the binding
of DMAP 1 that has two bondable sites in its structure.
The selectivity developed is most likely due to two-point
molecular recognition. Thus, the two halogen bonding
between the lone pair on the nitrogen atom and the
iodine atom is formed in the binding site. The interac-
tion is halogen bonding, rather than hydrogen bonding,
because neither hydrogen donor nor acceptor exists in
the polymer matrix. Better binding ability for 2-substi-
tuted pyridine and quinoline derivatives, such as 2-
aminopyridine 7 and 8-aminoquinoline 11, were shown
on the binding of the imprinted polymer, as contrast
with 2-picoline 8, 1-naphthylamine 9 and quinoline 10.
However, the binding abilities of 7 and 11 were inferior
to that of DMAP. This means that the molecular recog-
nition is affected by the steric hindrance for the
imprinted cavity.
COOH
COOH
F
F
F
F
F
F
F
F
1) NaNO2/HCl
2) NaI
NH2
I
DIBAL
CHO
F
F
F
F
H2C PPh3
TFIS
Among the analytes used in this work, 4-aminopyridine
4 showed the strongest binding to the imprinted poly-
mer. This value was ca. 1.7 times as large as that of
DMAP. It could be explained that 4-aminopyridine
I
Scheme 1. Synthesis of functional monomer TFIS.

T. Takeuchi et al. / Tetrahedron Letters 46 (2005) 9025–9027
9027
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
as the main interaction driving the intermolecular recog-
nition process with suitable analytes in solution. Further
details of characterization on binding sites of imprinted
polymer should be addressed to improve the effective-
ness of molecular recognition and it will be reported
elsewhere.
References and notes
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1
2
3
4
5
6
7
8
9
10 11
Compounds
NH2
N
N
N
N
N
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1
2
3
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NH2
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N
N
NH2
N
5
6
7
8
NH2
NH2
N
N
9
10
11
Figure 2. Binding abilities of the imprinted polymer for DMAP and
related compounds: 1, DMAP; 2, N,N-dimethylaniline; 3, 4-picoline; 4,
4-aminopyridine; 5, aniline; 6, pyridine; 7, 2-aminopyridine; 8,
2-picoline; 9, 1-naphthylamine; 10, quinoline; 11, 8-aminoquinoline.
was better fitted in the imprinted cavity for the two point
halogen bonding between nitrogen and iodine atom
because of a less bulkiness basic group at 4-position.
Consequently, the selectivity for the imprinted polymer
was affected by the orientation of the functional groups
as well as the size of analytes.
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In conclusion, we have newly developed the halogen
bonding-based bidentate imprinted polymer, which can
selectively bind pyridine derivatives attached with a 4-
basic group. This is the first example for use of halogen
bonding in the field of molecularly imprinted polymers
11. Lubke, M.; Whitcombe, M. J.; Vulfson, E. N. J. Am.
¨
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