Conformational control by 'zipping-up' an anion-binding unimolecular capsule

Article abstract of DOI:10.1039/b800339d

A flexible capsule has been designed in which the anion-binding preorganisation is enhanced by a urea 'zipper'. The Royal Society of Chemistry.

Full text of DOI:10.1039/b800339d

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Conformational control by ‘zipping-up’ an anion-binding unimolecular
capsulew
David R. Turner,a Martin J. Patersonb and Jonathan W. Steed*a
Received (in Austin, TX, USA) 9th January 2008, Accepted 5th February 2008
First published as an Advance Article on the web 21st February 2008
DOI: 10.1039/b800339d
A flexible capsule has been designed in which the anion-binding
preorganisation is enhanced by a urea ‘zipper’.
are further from the pyridinium moiety.10 We therefore de-
signed the extended compound 1 with two well-separated
binding compartments, one comprising a trimeric 3-aminopyr-
idinium pocket and the other involving the three remote urea
groups. This tripodal 3-aminopyridinium pocket binds
strongly to chloride as a result of charge assisted NHÁ Á ÁClÀ
and CHÁ Á ÁClÀ hydrogen bonding, a binding mode that brings
about a conformational change from the preferreÀd ‘2-up,
1-down’ conformer that predominates in the PF6 salt.14
The likely limiting conformational behaviour for the extended
host 1 is shown in Scheme 1. We rationalized that in non-polar
solvents the tendency of urea derivatives to self-associate20–23
would favour the 3-up conformer by ‘zipping’ up the upper
portion of the compound, thus preorganising the molecule for
ClÀ anion binding. In more polar media, urea self-association
is less significant22 and hence rearrangement to ‘out’ confor-
mers and ‘down’ conformers would be more likely, resulting in
less preorganisation.
The so-called ‘pinwheel’ trialkylbenzene-derived anion hosts
have proved to be highly versatile tripodal receptors of
enduring interest over the past decade.1–8 The trialkylbenzene
core provides some degree of preorganisation into a conical
conformation with all three binding or sensing ‘arms’ co-
aligned. However, in most cases the compounds remain highly
flexible. This flexibility can be a very useful property since the
system’s conformational response to induced-fit anion binding
can be applied in controlling sensor response by control of
reporter group mutual proximity.4,9–16 A few more rigid
pinwheel-based cryptands have also been reported,17,18 as well
as other interesting rigid amide-based anion cryptands.19 In
seeking to control the conformational characteristics of these
tripodal anion receptors, it is desirable to engineer compounds
that are more preorganised than the very flexible tripods but
still retain their ability to change conformation. One solution
to this problem is to design compounds that are conforma-
tionally preorganised by supramolecular interactions that are
remote from the binding site. We now report a pinwheel-based
compound designed to reversibly close-up into a unimolecular
capsule by remote hydrogen bonding, preorganising it for
anion binding.
Compounds 1a and 1b were prepared and fully character-
ized (see ESI for experimental detailsw). Compound 1a proved
insoluble in all solvents other than DMSO, however 1b was
soluble in a wide range of solvents and was metathesised to
give the hexafluorophosphate salt. The chloride-binding abil-
ity of 1bÁ(PF6)3 was examined by 1H NMR titration of the host
with NBu4Cl in three solvents: acetone (in which ureaÁ Á Áurea
interactions are significant), acetonitrile and DMSO (where
solvent competition will reduce the degree of ureaÁ Á Áurea
hydrogen bonding). In both acetone and acetonitrile, addition
of less than one equivalent of chloride led to significant
broadening of some parts of the spectrum consistent with
slow exchange of free and bound chloride. Importantly,
We have previously shown that conformationally flexible 3-
aminopyridinium based tripodal hosts bind strongly to
ClÀ.14–16 Exchanging the secondary amine for the stronger
hydrogen bond donor urea analogues results in significant
changes to the compounds’ conformational characteristics but
it is clear that anion binding occurs via the charged pyridinium
and lower urea NH group in the same way as the aminopyr-
idinium hosts, rather than at the ‘upper’ urea NH groups that
a Department of Chemistry, Durham University, South Road, Durham,
UK DH1 3LE. E-mail: jon.steed@durham.ac.uk
b Department of Chemistry, Heriot-Watt University, Edinburgh, UK
EH14 4AS
w Electronic supplementary information (ESI) available: Experimental
details for the synthesis of the new receptor, NMR titration data, and
computational discussion. See DOI: 10.1039/b800339d
Scheme 1 The functional arms in the three-up conformer of 1 (centre)
may rotate to (a) face away from the cavity to give an ‘out’ conforma-
tion or (b) move to the opposing side of the receptor to give a ‘2-up,
1-down’ conformer.
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however, the characteristic urea NH resonances at 5.97 and
7.92 ppm are neither broadened nor significantly shifted on
initial exposure to ClÀ. In contrast, the pyridinium CH
resonance at 8.08 ppm broadens immediately and shifts sig-
nificantly (Dd = 0.80 ppm at one equivalent ClÀ) suggesting
that ClÀ binding occurs as expected at the pyridinium/amine
site, not the urea groups. Similarly the secondary amine NH
resonance shifts from 6.38 ppm to 8.27 ppm (Dd = 1.89 ppm)
upon addition of one equivalent of chloride, although it is
broadened into the baseline until 0.7 equivalents of anion has
been added. In analogous 3-aminopyridinium compounds
lacking the urea functionality we have observed slow exchange
of free and bound chloride below room temperature.14 The
presence of the urea groups appears to slow the equilibrium
still further, consistent with an increased rigidity of the host.
After addition of 1 equivalent of the anion the spectrum
becomes sharper with little further change in the chemical
shift of the pyridinium CH resonance, however both of the
urea NH resonances immediately begin to change chemical
shift significantly and continue to do so up to 1.6 equivalents
at which point precipitation occurs in both solvents (Fig. 1).
We postulate that following intra-cavity binding of the first
equivalent of anion, anion binding at the free urea residue
causes aggregation and ultimately leads to precipitation. With
the limited data available, a good fit was obtained for a 1 : 2
host : anion model with K11 = 104 MÀ1 and K12 = 102 MÀ1
.
This value of K11 is comparable to those observed for unsub-
stituted 3-aminopyridinium hosts.14 The sharpening of the
pyridinium CH resonance upon addition of one equivalent
of anion suggests that the anion has a role in ‘locking in’ the
3-up conformation, working synergically with the intramole-
cular urea hydrogen bonding. Similar results are observed on
titration with BrÀ although the broadening is less significant
and the magnitude of chemical shift change is smaller.
Titration of 1b in DMSO does not result in precipitation.
Binding is depressed with the maximum Dd being ca. 0.5 ppm
even after addition of five equivalents of chloride. The titration
plot is a shallow curve, indicative of weak binding. The
essentially linear dependence on anion concentration up to 5
equivalents contrasts to related compounds binding chloride
in DMSO10 and suggests that multiple anions are binding,
with both aminopyridinium and urea binding sites on different
arms acting independently. While the urea carbonyl is a
relatively poor hydrogen bond acceptor, chloride is a strong
enough acceptor to compete with the polar solvent.24
At room temperature, in acetone solution, the 1H NMR
spectrum of 1bÁ(PF6)3 exhibits time-averaged C3v symmetry in
both the presence and absence of chloride. We examined the
temperature dependence of the spectrum from 290 K to 180 K
in the presence of 0.8 equivalents of ClÀ. The two resonances
assigned to the urea NH protons shift markedly with tem-
perature, consistent with increasing residence time in a more
enthalpically favoured conformation involving changes in
these hydrogen bonding groups as temperature decreases
(Fig. 2).
One alternative possibility to the formation of single mole-
cule capsules of the type shown in Scheme 1 is dimerisation via
the urea groups to form a capsule with six-urea groups in a
hydrogen bonded belt.20,22 We sought evidence from ESI-MS
and NMR dilution to rule out this possibility. The ESI-MS
spectra of the pure salts 1bÁ(X)3 (X = Br or PF6) both show
high intensity peaks corresponding to [1b À X]+, [1b À 2X]2+
and [1b À 3X]3+ but no evidence for the formation of dimers.
Addition of one equivalent of tetrabutylammonium fluoride,
chloride, bromide or iodide to solutions of 1bÁ(PF6)3 and
examination of the ESI-MS spectra gave peaks corresponding
Fig. 1 (a) NMR titration of 1bÁ(PF6)3 with NBu4+ClÀ in acetone-d6,
Fig. 2 VT 1H NMR spectra of 1bÁ(PF6)3 with 0.8 equivalents of
NBu4+ClÀ in acetone-d6. Urea NH resonances are marked by arrows.
(b) plots of the pyridinium CH and urea NH resonances.
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Fig. 3 DFT model of 1bÁClÀ showing the urea tape ‘zipper’ motif.
to the expected m/z for [1b + X À 2PF6]+ and [1b + X À
3PF6]2+ (X = Cl, Br, I) except in the case of FÀ which gives
only [1b + F À 2PF6]+. No peaks assignable to dimeric
capsules were observed. These experiments show that the hosts
bind well to halides but remain as monomers. In confirmation,
the 1H NMR spectra of 1bÁ(PF6)3 both alone and in the
presence of one equivalent of ClÀ proved invariant with
concentration in acetone-d6.
We carried out a DFT optimization for 1bÁClÀ, using
B3LYP and a mixed basis within the Gaussian 03 program.25
The basis consisted of 6-311++G* on chloride, 6-31+G* on
oxygen and nitrogen, 4-31G on carbon and hydrogen. The
hydrogen atoms involved in possible hydrogen-bonding re-
gions were further augmented with a diffuse set of s and p
functions.10 The DFT model of the 3-up conformer of 1bÁCl is
shown in Fig. 3. The model reproduces the expected trigonal
prismatic hydrogen bonded arrangement around the ClÀ ion
comprising three NHÁ Á ÁClÀ and three pyridinium CHÁ Á ÁClÀ
interactions, consistent with previous crystallographic and
NMR spectroscopic results in related compounds, and shows
that this anion binding mode is compatible with the proposed
urea tape ‘zipper’ motif.
In conclusion we have shown that in relatively non-polar
solvents, intramolecular hydrogen bonding between remote
functional groups can increase the preorganisation of an
anion-binding unimolecular capsule. This work suggests new
strategies for conformational control and increasing preorga-
nisation in flexible anion hosts.
We thank the EPSRC for a studentship (D.R.T) and for
provision of computing facilities.
Notes and references
1 A. Metzger, V. M. Lynch and E. V. Anslyn, Angew. Chem., Int. Ed.
Engl., 1997, 36, 862.
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