Deep cavitand receptors with pH-independent water solubility

Article abstract of DOI:10.1039/c0cc03388j

Pendant oligoethyleneglycol groups confer water solubility to a cavitand over a wide pH range. The kinetic stability of the host-guest complexes reveals an effective stabilization through hydrogen bonding even in the highly competitive aqueous environment.

Full text of DOI:10.1039/c0cc03388j

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Deep cavitand receptors with pH-independent water solubilityw
Agustı Lledo and Julius Rebek Jr.*
´
´
Received 20th August 2010, Accepted 22nd September 2010
DOI: 10.1039/c0cc03388j
Pendant oligoethyleneglycol groups confer water solubility to a
cavitand over a wide pH range. The kinetic stability of the
host–guest complexes reveals an effective stabilization through
hydrogen bonding even in the highly competitive aqueous
environment.
introduced by Diederich et al.6 that impart good solubility in
a wide pH range. Although aqueous solutions can disrupt the
intramolecular hydrogen bond seam that typically stabilizes
such receptors, we show here that 1 is a receptor for small
guests in water. The snug fit between complementary host and
guest shapes enhances the binding event and restores the
stabilization of its vase conformation.
Self-assembled systems held together with hydrogen bonds
and other weak forces are ubiquitous in Nature and in the
supramolecular literature.1 In the latter, most assemblies
operate in organic solvents rather than water, since disruption
of hydrogen bonds occurs in protic solvents.2 In aqueous
media, these systems operate largely on the basis of hydro-
phobic effects and lack the enthalpic stabilization often seen in
host–guest complexes.3 A common strategy to obtain water-
compatible receptors based on previously tested organic soluble
platforms consists of attaching ionizable functional groups,
carboxylates or ammoniums on their peripheries (Fig. 1).4
This is inappropriate for work spanning a wide range of pH
values and can also prevent binding of charged guests. Water
solubility can also be achieved with metal coordination
capsules at the cost of reducing the distinct fluxional or
dynamic behavior of deep cavitands.5
Following previous reports,4 the benzyl-protected tetra-
mesylate 2 was obtained in three steps from resorcinol and
4,5-dihydrofuran (Scheme 1).7 This compound was subjected
to reaction with tetraethyleneglycol monomethyl ether (TEG)
as its sodium salt, then debenzylated to yield the TEGylated
resorcinarene 4 which was only sparingly soluble in water.
Raising the cavitand walls was accomplished by the standard
condensation with 4,5-difluoro-1,2-dinitrobenzene; the nitro
groups were then reduced and acetylated to yield the octa-
acetamide cavitand 1. The compound was characterized by
NMR in acetone-d6 solution and by high resolution mass
spectrometry (see ESIw).
Cavitand 1 is soluble in water at the mM concentrations
typically used in the NMR studies, under neutral, acidic
(pD 1) or basic (pD 12) conditions. When no suitable guest
is present, the non-binding, C2v symmetric kite conformation
is favored. Its NMR spectrum in D2O features broad and
poorly resolved signals suggesting ill-defined aggregates of 1
with a characteristic resonance at 4.12 ppm for the methine
resonances of the kite form (Fig. 2a). It is likely that these
include dimeric ‘‘velcrand’’ structures.8 In the gas phase, 1
exists mainly as its velcrand dimer in doubly or triply charged
Here we disclose a deep cavitand receptor (1) derived from a
resorcinarene core that bears pendant oligoethyleneglycols
Fig. 1 Some earlier water-soluble deep cavitands bearing pendant
ionic functionalities and the new TEGylated platform 1.
The Skaggs Institute for Chemical Biology and Department of
Chemistry, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, USA. E-mail: jrebek@scripps.edu
w Electronic supplementary information (ESI) available: Synthetic
procedures and characterization data for compounds 1 and 3–5,
ESI-MS and DOSY data for dimer 1Á1 and complex 6aC1. See
DOI: 10.1039/c0cc03388j
Scheme 1 Synthesis of the TEGylated cavitand 1.
c
8630 Chem. Commun., 2010, 46, 8630–8632
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Fig. 2 Evolution of the NMR spectrum of 1 in D2O (1.75 mM)
before (a) and after the addition of 3.4 eq. (b), 5.6 eq. (c) and 40 eq.
(d) of 6a. Empty and filled circles indicate the resonances of the kite
and vase forms, respectively.
states (ESI MS, see ESIw for details). NMR diffusion experi-
ments suggest that the dimer is also the prevalent structure in
aqueous solution in the absence of guests (see below).
On addition of an appropriate guest (2-adamantaneamine
hydrochloride, 6a) to a D2O solution of the cavitand, extensive
changes in the spectrum are observed: both the aromatic
and the peripheral ‘‘feet’’ resonances appear as sharp and
well-resolved signals (Fig. 2b–d), and the methine resonance is
shifted downfield (d 5.81 ppm) in the region expected for the
vase conformation having (time-averaged) C4v symmetry. The
guest resonances appear in the far upfield region, shifted there
by the large anisotropy imparted by the 8 aromatic panels
of the receptor. Diffusion Ordered Spectroscopy (DOSY)9 reveals
a single diffusion coefficient (D = 8.9 Â 10À7 cm2 sÀ1) for all the
resonances in the spectrum of the complex. When guests are
absent, the broad resonances of the kite form lie also in a single
trace of the diffusion dimension (D = 7.1 Â 10À7 cm2 sÀ1). The
20% reduction in diffusion coefficient when compared to mono-
meric 6aC1 is in good agreement with a dimeric species. This
guest-induced shape switching behaviour is rarely encountered in
water although it has been well-documented with other stimuli.10
A variety of alkylammonium ions are bound in the
10À1–102 MÀ1 Ka range (Table 1) as ascertained by integration
of the NMR spectra (Fig. 3).11 Molecular models suggest that
binding should be favored by hydrogen bond interactions of
the ammonium group with the amide carbonyls on the
rim. This possibility is supported by the different behavior
of 1-adamantylmethylamine 6b and 1-adamantaneamine 6c:
removal of the methylene spacer largely eliminates binding.
Complex 6aC1 can also be characterized in the gas phase,
which emphasizes the intrinsic strength of the complexation
event. In solution, the formation of the complete amide
hydrogen bonded seam does not suffice to extract hydro-
phobic species (alkanes) or amphiphilic molecules such as
Fig. 3 Upfield regions of the NMR spectra for a variety of complexes
with 1 featuring the resonances for bound guests.
ammonium salts with long linear aliphatic chains. Exceptionally,
sodium dodecylsulfate was bound and some cyclic ketones
(cyclopentanone, cyclohexanone) were also taken up by the
cavitand.12
A van’t Hoff plot for the association constant of 6aC1 taken
at different temperatures reveals that the overall complex forma-
tion is enthalpically disfavored (DH = +17 Æ 2 kcal molÀ1
;
DS = +63 Æ 5 eu, Fig. 4). The binding of triethylammonium
Table 1 Binding data for cavitand 1a
Guest
6a
6b
7
8
À1
Kab/M
14
0.4
57
0.4
Fig. 4 Top: plot of ln Ka vs. 1/T for complexes 6aC1 (left, [1] =
1.71 mM, T = 295–320 K). Bottom: hydrogen bond balance in the
formation of complex 6aC1.
a
b
In D2O (pD 7, [1] 1.6–1.8 mM) at 300 K. Max. estimated error:
10%.
c
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chloride (10), where attractive cation–p interactions are avail-
e.g. benzimidazole17 or introverted functions.18 While the
binding of organic ammonium cations is overall enthalpically
disfavored, an effective stabilization of the vase form through
hydrogen bonding is evidenced by the kinetic stability of the
host–guest complexes. Implementation of the water-stabilized
scaffold is underway and results will be reported in due course.
We are grateful to the Skaggs Institute and NIH
(GM 27953) for financial support. A.L. thanks MICINN
(Ministry of Science and Innovation, Spain) for a postdoctoral
fellowship. We thank Dr Yoram Cohen for generous and
valuable advice concerning DOSY experiments.
able, is also entropically favored (DH = +20 Æ 1 kcal molÀ1
;
DS = +55 Æ 4 eu). The inner surface of the cavitand is devoid
of any solvent either in the velcrand dimer or the (occupied) vase
form. We attribute then this high entropic benefit to the
desolvation of the bulky alkylammonium cation. The high
enthalpy values can hardly be justified on the grounds of a
hydrogen bond inventory, which must be almost the same for
complex and components. The carbonyl groups available sites
for hydrogen bonding are shown in Fig. 4, bottom. Although
the folding process involves a net gain in intramolecular
hydrogen bonds, this is at the expense of breaking other
intermolecular ones to water molecules surrounding the
acetamide groups. Likewise, hydrogen bonding from water to
Notes and references
1 Selected reviews on the topic: M. Yoshizawa, J. K. Klosterman and
M. Fujita, Angew. Chem., Int. Ed., 2009, 48, 3418; G. Armstrong
and M. Buggy, J. Mater. Sci., 2005, 40, 547; J. d. Mendoza,
Chem.–Eur. J., 1998, 4, 1373; M. M. Conn and J. Rebek, Chem.
Rev., 1997, 97, 1647.
+
the NH3 group on the free guest can be supplanted by
hydrogen bonding to the carbonyls on the cavitand’s rim. Even
the energetically less significant p–p interactions found in the
velcrand dimer can be compensated by attractive CH–p inter-
actions in the host–guest complex. We postulate that the
enthalpic penalty on the binding event comes from a greater
ion pair separation of the guest in complex. This may arise from
repulsion between the electron rich rim of the cavitand and the
nearby chloride counteranion.13
2 T. Amaya and J. Rebek, J. Am. Chem. Soc., 2004, 126,
14149.
3 M. D. Giles, S. Liu, R. L. Emanuel, B. C. Gibb and S. M. Grayson,
J. Am. Chem. Soc., 2008, 130, 14430; S. M. Biros, R. G. Bergman
and K. N. Raymond, J. Am. Chem. Soc., 2007, 129, 12094;
C. L. D. Gibb and B. C. Gibb, J. Am. Chem. Soc., 2004, 126,
11408. See, however: D. B. Smithrud, T. B. Wyman and
F. Diederich, J. Am. Chem. Soc., 1991, 113, 5420.
In contrast with this unfavourable thermodynamic balance,
a survey of the guest exchange kinetics for complex 6aC1
reveals an effective stabilization by the amide hydrogen
bond seam. The 2D NOESY14 spectrum in D2O features off-
diagonal cross peaks arising from chemical exchange between
the resonances of free and bound guest and EXSY15 experi-
ments give a barrier of 17.6 kcal molÀ1 for the dissociative
process. This is in good agreement with values observed in
organic solvents that do not compete for hydrogen bonds
(Fig. 5).16 Using the methine resonances of the folded and
unfolded states of the cavitand in the calculation gives a value
of 17.8 kcal molÀ1 for the vase to kite transition.
4 S. M. Biros and J. Rebek, Chem. Soc. Rev., 2007, 36, 93; C. H. Haas,
S. M. Biros and J. Rebek, Chem. Commun., 2005, 6044; T. Haino,
D. M. Rudkevich, A. Shivanyuk, K. Rissanen and J. Rebek, Jr.,
Chem.–Eur. J., 2000, 6, 3797; T. Haino, D. M. Rudkevich and
J. Rebek, J. Am. Chem. Soc., 1999, 121, 11253.
5 M. Fujita, M. Tominaga, A. Hori and B. Therrien, Acc. Chem.
Res., 2005, 38, 369; S. Leininger, B. Olenyuk and P. J. Stang,
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6 L. Sebo, F. Diederich and V. Gramlich, Helv. Chim. Acta, 2000, 83,
93; O. Middel, W. Verboom and D. N. Reinhoudt, Eur. J. Org.
Chem., 2002, 2587.
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1996, 61, 1505.
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Chem. Soc., 1992, 114, 7748.
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44, 520; T. Brand, E. J. Cabrita and S. Berger, Prog. Nucl. Magn.
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and Y. R. Shen, J. Am. Chem. Soc., 2006, 128, 12610; M. Frei,
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In summary, we have introduced a new water-soluble
platform for deep cavitand receptors and showed the binding
behavior of its octaacetamide derivative. Cavitand 1 displays
water solubility in virtually the whole range of pH and should
be tolerant of other groups attached to the upper rim,
11 The assumption that
1 behaves as a dimeric species was
made based on diffusion data. Ka thus refers to the equilibrium
12 + 26a 2 26aC1.
12 As one referee pointed out, this implies that the CH–p interactions
in the enthalpic benefit of binding might be comparable in
magnitude to the hydrogen bonding interactions.
13 Positioning of counteranions at the open end of cavitand receptors
is well precedented: M. Kvasnica and B. W. Purse, New J. Chem.,
2010, 34, 1097; A. Shivanyuk, J. C. Friese and J. Rebek,
Tetrahedron, 2003, 59, 7067; J. L. Atwood and A. Szumna,
J. Am. Chem. Soc., 2002, 124, 10646.
14 The experiment was performed with a relatively short mixing time
(tmix = 125 ms) to minimize the evolution of nOe cross peaks.
15 C. L. Perrin and T. J. Dwyer, Chem. Rev., 1990, 90, 935.
16 R. J. Hooley, S. R. Shenoy and J. Rebek, Org. Lett., 2008, 10,
5397; F. C. Tucci, D. M. Rudkevich and J. Rebek, J. Org. Chem.,
1999, 64, 4555; D. M. Rudkevich, G. Hilmersson and J. Rebek,
J. Am. Chem. Soc., 1998, 120, 12216.
17 S. M. Biros, E. C. Ullrich, F. Hof, L. Trembleau and J. Rebek,
J. Am. Chem. Soc., 2004, 126, 2870; A. Shivanyuk and J. Rebek,
J. Am. Chem. Soc., 2003, 125, 3432; A. R. Far, A. Shivanyuk and
J. Rebek, J. Am. Chem. Soc., 2002, 124, 2854.
Fig. 5 2D NOESY spectrum of complex 6aC1 ([1] = 1.71 mM,
T = 310 K, mixing time 125 ms). The expansion is centred on the
upfield shifted resonances of the bound guest in the F2 dimension.
18 R. J. Hooley and J. Rebek, Chem. Biol., 2009, 16, 255.
c
8632 Chem. Commun., 2010, 46, 8630–8632
This journal is The Royal Society of Chemistry 2010