Polymer-supported cationic templates for molecular recognition of anionic hosts in water

Article abstract of DOI:10.1039/b802982b

Translocating solution-phase molecular recognition of oppositely charged hosts and guests to the solid phase represents a major challenge; we report a successful immobilisation strategy which allows selective host-guest interactions in water unencumbered by unwanted ion exchange-type interactions. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802982b

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COMMUNICATION
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Polymer-supported cationic templates for molecular recognition of
anionic hosts in waterw
a
a
b
b
Pol Besenius, Peter A. G. Cormack,* R. Frederick Ludlow, Sijbren Otto*
a
and David C. Sherrington*
Received (in Cambridge, UK) 21st February 2008, Accepted 11th April 2008
First published as an Advance Article on the web 29th April 2008
DOI: 10.1039/b802982b
Translocating solution-phase molecular recognition of oppo-
sitely charged hosts and guests to the solid phase represents a
major challenge; we report a successful immobilisation strategy
which allows selective host–guest interactions in water unencum-
bered by unwanted ion exchange-type interactions.
organic solvents, we demonstrated the importance of careful
design of the resin for achieving highly selective and efficient
2
0
molecular recognition. We now report an extension of this
work to what is probably the most intricate system of all:
molecular recognition of a charged guest covalently linked to a
polymer support by solution-based host molecules of various
degrees of opposite charge in aqueous media, where supra-
An increasing number of applications of supramolecular
1
chemistry rely on immobilisation of one of the partners
27
molecular chemistry represents an exceptional challenge.
2
–7
engaged in molecular recognition, e.g. in sensing devices
The goal of the present work was to design polymeric supports
that are highly compatible with such conditions, while avoid-
ing non-selective ion-exchange type interactions.
8
,9
and in molecularly imprinted polymers (MIPs). Another
area in which translocation of solution-phase molecular re-
cognition to the solid phase is desirable is dynamic combina-
torial chemistry. This technique relies on selective molecular
recognition inducing a shift in the composition of complex
equilibrium mixtures towards the host with the highest affinity
As a test system we selected one of our disulfide-based
2
8–34
DCLs made from anionic dithiol building blocks 1 and
2 (Fig. 1). In the presence of cationic guest 3 in solution,
unambiguous amplification of receptors (1)(2)
, and to a lesser
2
1
0–12
for a particular guest (or vice versa).
1
Immobilisation of the
21,22
extent (1)
reported amplification of (1)(2)
3
amplification of (1) has not been observed before. A success-
3
, is observed (Fig. 2). While we have previously
3–20
29,30,32
guest
(template) or indeed the building blocks
simpli-
2
with other guests,
the
fies analysis of the reactions and can also aid in the subsequent
isolation of products.
ful resin would allow selective binding of these two receptors
to an immobilised analogue of guest 3 without simultaneously
binding some of the higher, more charged oligomers that
would occur if an ion-exchange-type mechanism was
taking place.
It is now clear that molecular recognition of a species is not
always unaffected by immobilisation, particularly when both
host and guest are charged. For example, Anslyn et al. have
2
3
reported the use of commercially available Tentagel resin
2
bound receptors immobilised on micro-machined silicon.
4,25
Polyacrylamide-type resins were expected to be highly com-
patible with molecular recognition in water. The general
strategy adopted was to functionalise adamantylamine with
a spacer, followed by coupling of the latter to a polymerisable
acrylamide type vinyl monomer (Fig. 3). A control experiment
using 4a as a template in the DCL made from 1 and 2 gave
essentially the same results as that shown in Fig. 2 for the
parent template 3, demonstrating that the introduction of the
The authors acknowledge that differential ion-exchange chro-
matography is taking place, in addition to the desired selective
3
molecular recognition events. Our own early attempts at
immobilising a cationic guest on an Argogel resin revealed
binding that was completely dominated by unwanted ion
exchange behaviour in which the most highly charged species
2
6
are the most retained. Undoubtedly, therefore, the influence
of the polymer backbone on host–guest chemistry under
heterogeneous conditions is not negligible, an aspect which
we believe has not been given sufficient consideration. In our
recent parallel investigations of the use of polymer-supported
templates in dynamic combinatorial libraries (DCLs) in
a
WestCHEM, Department of Pure and Applied Chemistry, University
of Strathclyde, 295 Cathedral Street, Glasgow, UK G1 1XL.
E-mail: Peter.Cormack@strath.ac.uk; D.Sherrington@strath.ac.uk;
Fax: þ44 (0)141 548 4246; Tel: þ44 (0)141 548 2799
b
Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: so230@cam.ac.uk;
Fax: þ44 (0)1223 336017; Tel: þ44 (0)1223 336343
w Electronic supplementary information (ESI) available: Additional
DCL results and control experiments; experimental procedures for
DCL production and their analysis by LC–MS; experimental and
analytical details for precursor, monomer and polymer syntheses. See
DOI: 10.1039/b802982b
Fig. 1 Exposing a DCL composed of anionic building blocks 1 and
rac-2 to cationic guest 3 leads to the amplification of receptors (1)(2)
and (1)
2
3
.
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Fig. 2 HPLC analyses of a DCL made from building blocks 1 and
rac-2 (2 mM in total) (a) in absence of template, and (b) after 72 h
exposure to template 3 (2 mM).
Fig. 4 HPLC analyses of a DCL made from building blocks 1 and
rac-2 (2 mM in total) (a) in absence of template, and (b) after 72 h
ꢁ1
exposure to AM GT 4b (4 mg ml ), (c) borate buffer wash of AM GT
b, and (d) elution with ethanol.
4
3 2
tion of (1) and (1) (2). Indeed this trace looks very similar to
that obtained in control reactions using resins AM GT and
DMAM GT containing no template (cf. Fig. S2 and S3, ESIw).
With the latter, of course, no templating effect is possible and
the small changes seen in the library distribution may be due
simply to minor differential partitioning of library members
between the aqueous supernatant phase and the swollen
polymer resin phase. Even more disappointingly, the HPLC
traces of the buffer wash and the solution from the ethanol
elution (Fig. 4c and d) indicate that none of the library
members are strongly retained on AM GT 4b, confirming an
absence of any significant involvement of the immobilised
template. Perhaps understandably, therefore, we were not
optimistic with regard to the likely behaviour of resin-bound
template DMAM GT 4b. However, we were delighted to find
that the results using this resin were quite different. Compar-
ison of the HPLC traces in Fig. 5 with those in Fig. 2 confirms
that the compounds which are selectively amplified by solution
phase template 3 are also amplified by resin DMAM GT 4b,
and furthermore they are selectively retained by the resin and
eventually emerge in the ethanol wash. It is clear, therefore, that
the DMAM-based gel-type polymer support is fully
3
5
Fig. 3 Synthesis of polymerisable template 4b: (a) MsCl, Ag
2
O,
35
CH
2
5
Cl
2
, rt, 48 h, 48%; (b) NaN
c) (i) Ph P, dry THF, N , rt, 12 h; (ii) H
trifluoroacetamide, Et N, MeOH, rt, 12 h, 90%; (e) MsCl, Et
CH Cl , rt, 12 h, 96%; (f) N-(1-adamantyl)-N-methylamine, NaI,
CO
3
, dry DMF, N
2
, 120 1C, 2 h, 95%;
3
36
(
3
2
2
O, rt, 10 h, 88%; (d) ethyl
3
7
3
3
N,
38
2
2
36
K
2
3
, CH
3
CN, reflux, 36 h, 82%; (g) 6 M NaOH, rt, 12 h, 97%;
CO , CH Cl , rt, 12 h, 99%.
36
(h) acryloyl chloride, DMAP, K
2
3
2
2
ethylene oxide spacer did not affect the host–guest interactions
(cf. Fig. S1, ESIw).
The design and choice of polymer morphology (lightly
crosslinked swellable gel-type versus more heavily crosslinked
macroporous resins) and template loading was based on our
previous work on polymer-supported templates in organic
2
0
solvents. These studies revealed that the more open gel-type
resins with a relatively low guest loading gave the best results
in templating combinatorial libraries of macrocyclic hydra-
zones. While it was unclear whether these observations would
translate to a wholly non-related system (different solvent,
different guest, different set of hosts and different polymer
matrix), they appeared to provide a good starting point. Thus,
monomer 4b (20 wt%) was polymerised in an inverse-suspen-
sion polymerisation procedure to yield spherical gel-type (GT)
resins AM GT 4b and DMAM GT 4b using acrylamide (AM)
or dimethylacrylamide (DMAM) (76 wt%), respectively, as
diluting/structural comonomer, and methylene bisacrylamide
(
MBA; 4 wt%) as crosslinker in B6.5 fold excess of water
cf. Fig. S4 and S5, ESIw).
(
The first polymer-supported template examined was AM
GT 4b. This was added to an equimolar mixture of building
blocks 1 and 2 (2 mM in total) in 50 mM borate buffer (pH 8)
to give an overall template concentration of 2 mM. After
equilibration, the beads are filtered off, washed with borate
buffer to remove any weakly bound species and eluted with
ethanol to liberate the more strongly retained host molecules.
Rather disappointingly, the HPLC trace of the filtered super-
natant solution (Fig. 4b) showed little evidence for amplifica-
Fig. 5 HPLC analyses of a DCL made from building blocks 1 and
rac-2 (2 mM in total) (a) in absence of template, and (b) after 72 h
ꢁ1
exposure to DMAM GT 4b (4 mg ml ), (c) borate buffer wash of
DMAM GT 4b, and (d) elution with ethanol.
2
810 | Chem. Commun., 2008, 2809–2811
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compatible with the library conditions, giving rise to efficient
host–guest interactions that parallel those in solution. When
the HPLC traces from the filtrate, wash and elution are
summed up, essentially the same library composition is ob-
tained as under templating conditions in solution. Of particu-
lar significance is the fact that the same template to building
block ratio (1 : 1) was used when working with the resin as
compared to the solution-based libraries, and bearing in mind
the highly water swollen state of the resin (cf. Fig. S5, ESIw),
this suggests that most immobilised template in DMAM GT 4b
is accessible to the hosts. The only difference between the AM
and DMAM resins is the two methyl groups on the acrylamide
monomer. We therefore tentatively ascribe the strikingly
different templating behaviour to the strong hydrogen bond-
ing donor capability of the acrylamide polymer segments. We
speculate that extensive hydrogen bonding between amide
hydrogens and carbonyl groups within the AM GT 4b resin
may inhibit local access to the immobilised template or that
the DMAM GT resin may provide a more favourable hydro-
phobic micro-environment around the template. Competitive
interaction of the AM primary amide groups with reactants or
products seems less likely since, as indicated above, control
experiments involving unfunctionalised AM GT and DMAM
GT show that neither of these resin matrices has any signifi-
cant influence on the product distribution (cf. Fig. S2 and S3,
ESIw).
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ꢁ
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