Metal directed assembly of ditopic containers and their complexes with alkylammonium salts

Article abstract of DOI:10.1039/b509189f

A new self-folding cavitand has been assembled through metal coordination to give a thermodynamically stable ditopic receptor of nanosize dimensions which has been used in the reversible binding of di-alkylammonium and n-alkylammonium salts. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b509189f

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COMMUNICATION
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Metal directed assembly of ditopic containers and their complexes with
alkylammonium salts{
Edoardo Menozzi and Julius Rebek, Jr.*
Received (in Columbia, MO, USA) 30th June 2005, Accepted 6th September 2005
First published as an Advance Article on the web 11th October 2005
DOI: 10.1039/b509189f
The binding of di-alkylammonium salt, decamethonium di-
A new self-folding cavitand has been assembled through
metal coordination to give a thermodynamically stable ditopic
receptor of nanosize dimensions which has been used in the
reversible binding of di-alkylammonium and n-alkylammo-
nium salts.
triflate 4, known to be a nicotinic antagonist at the neuromuscular
1
junction,8 was analyzed by H NMR and ESI-MS to study the
cooperative effect of the two concave surfaces relative to the
binding of a standard n-alkylammonium salt.
The monofunctionalized phenylpyridyl hexaamide cavitand 1
was prepared by reacting hexaamide diol cavitand5f with 4-49-
(a,a9-dibromotolyl)pyridine6 in DMF; this reaction is completely
stereoselective due to the size of the phenylpyridyl group which can
not be easily accommodated inside the resorcinarene cavity. A
crystal structure of cavitand 1 was obtained from CH2Cl2/EtOH
(Fig. 1), which shows that the amide groups at the upper rim of the
cavitand form a seam of six hydrogen bonds which maintain the
cavitand in a vase conformation. In the solid state this cavitand is
able to include a phthalimide molecule which fills the space of the
cavity and shows p–p interactions with the aromatic walls. A water
molecule is also present in the cavity and it forms a hydrogen
bond with a carbonyl group at the upper rim of the cavitand.
The orientation of the phenylpyridyl moiety is ‘‘outward’’, in the
correct geometry for the self-assembly of a ditopic receptor.
Large nanoscale molecular containers obtained through cova-
lent bonds generally exist as C-shaped and S-shaped diastero-
isomers.9 They are generally separated through chromatographic
techniques and characterized using 2D NMR spectrometry. In
contrast, metal connected ditopic cavitand complexes can be
obtained in quantitative yield following the typical cage self-
assembly protocol.10 The ditopic structure 2 was obtained by
mixing cavitand 1 with [Pt(dppp)(CF3SO3)2] (2 : 1 molar ratio) at
room temperature in acetone. The exclusive formation of the
desired cis ditopic complex was dictated by the presence of the
bidentate dppp ligand. The self-assembly of 2 was monitored by 1H
NMR (Fig. 2). Addition of [Pt(dppp)(CF3SO3)2] (0.5 equivalents)
to a solution of cavitand 1 in acetone-d6 (4 : 1 ratio) gave as the
Molecule-within-molecule complexes can be formed irreversibly,
as in carcerands,1 or reversibly, as in self-assembled capsules.2 In
between, hemicarcerands with larger portals offer a possibility for
the guest to move in and out more or less freely.3 These supra-
molecular structures can be formed through covalent bonds4,5 or
through metal–ligand interactions.6 The advantages of using
transition metals in the self-assembly involve the greater direction-
ality offered by metal–ligand coordinative bonds relative to weak
electrostatic and p–p stacking interactions or even hydrogen bonds
and the higher kinetic stability of the coordinative bonds. Both
depend on selection of the appropriate metal precursors and
ligands.7 We report here a new type of cavitand 1 which combines
the advantages of a deep vase-like cavity obtained through a
network of hydrogen bonds and the presence of a phenylpyridyl
group able to coordinate to a square-planar metal complex like
[Pt(dppp)(CF3SO3)2].
A thermodynamically stable molecular
dimer 2 of nanosize dimensions is formed (Scheme 1).
Scheme 1 i) Self-assembly of 2 by mixing 1 and [Pt(dppp)(CF3SO3)2]; ii)
Inclusion of alkylammonium salts 3, 4 in molecular dimer 2.
The Skaggs Institute for Chemical Biology and Department of
Chemistry, The Scripps Research Institute, MB-26, 10550 North Torrey
Pines Road, La Jolla, California 92037. E-mail: jrebek@scripps.edu;
Fax: 858 784 2876; Tel: 858 784 2255
{ Electronic supplementary information (ESI) available: synthetic details,
X-ray crystallographic data, molecular modeling and 1H NMR of
inclusion complexes. See http://dx.doi.org/10.1039/b509189f
Fig. 1 X-ray crystal of cavitand 1 crystallized from CH2Cl2/EtOH.
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Table 1 Data of alkylammonium salts included in cavitand 1 and
dimer 2
DGu/
Guest Host Ka (253 K) Kcal mol21 ESI-MS X: CF3SO3
a
2
3
4
1
1
20 M21
15 M21
21.5
21.4
[3@1-X]+ 5 1491
[4@1-X]+ 5 1821
[4@1-2X]2+ 5 836
3
4
a
2
2
2100 M22
95 M21
23.8
22.3
[(2*3@2)-2X]2+ 5 1997
[(2*3@2)-3X]3+ 5 1281
[4@2-2X]2+ 5 1996
[4@2-3X]3+ 5 1281
Hosts 1 or 2 at 2 mM were mixed with guests 3 or 4 at y30 mM
concentration in acetone-d6. The relative binding affinities were
determined by direct integration of the corresponding N(CH3)3
peaks of the encapsulated and free guests.
simultaneously coordinated in the cavities: ESI-MS shows
prominent peaks in the gas phase consistent with 1 : 1 inclusion
complex 4@2 (Table 1).
Fig. 2 Self-assembly of molecular dimer 2 in acetone-d6: (a) Free
cavitand 1; (b) Cavitand 1 + [Pt(dppp)(CF3SO3)2] 4 : 1; (c) Cavitand
1 + [Pt(dppp)(CF3SO3)2] 2 : 1.
1H NMR studies of complex 4@2 show inclusion signals
already at 300 K; at 273 K two different N(CH3)3 peaks can be
clearly seen. This slight difference in the chemical shifts may be due
to the different arrangement of hydrogen bonds at the upper rim
of the cavitands; they can be either clockwise or anti-clockwise
(Fig. 3).
only species present in solution the free cavitand and the ditopic
complex. No evidence of partially complexed products could be
detected. After the addition of another 0.5 equivalents of the metal
complex (2 : 1 cavitand/metal complex final ratio), only the ditopic
receptor 2 was present in solution. The first coordination of
cavitand 1 on the Pt center facilitates the entrance of the second
cavitand molecule, driving the reaction to the thermodynamically
favored final product which is obtained in quantitative yield.
Further evidence of the formation of 2 was obtained by ESI-MS,
which recorded prominent peaks at [(MH)+ 2 CF3SO3]2+ 5 1793
and [M 2 2CF3SO3]2+ 5 1718.
As already mentioned inclusion of n-alkylammonium molecules
3 in molecular dimer 2 (2*3@2) yields a complex with lower kinetic
stability: to follow the complexation by NMR the experiment
has to be performed at 253 K where the two cavities of 2 are
simultaneously occupied by two trimethylammonium ‘‘knobs’’ and
no evidence of inclusion of a single guest molecule 3 could be
Large nanoscale host molecules rarely show kinetically stable
complexes,9,11 since the large holes in their structures permit fast
entry and exit of solvents and most guests. The corresponding
NMR chemical shift changes describe an average of the guest’s
many environments. Alkylammonium salts 3 and 4 have been used
in host–guest complexation experiments with cavitand 1. These
guests form kinetically stable 1 : 1 inclusion complexes on the
NMR timescale in acetone-d6 at low temperatures (273 K, 253 K;
see ESI{). The electron-rich aromatic surfaces of the host provide
cation–p attractions with the partially positive hydrogens on the
surface of the guests. ESI-MS clearly shows that in both cases only
one guest molecule is contained in the gas phase in cavitand 1
(prominent peak at [3@1-CF3SO3]+; [4@1-CF3SO3]+, Table 1).
The affinity of 3 and 4 for this kind of cavity is relatively low;
the presence of the phenylpyridyl group interrupts the network of
hydrogen bonds and changes the shape of the cavity to something
more elliptical than spherical (see structure of cavitand 1, Fig. 1).
As a result the guests move rapidly in and out from the cavity at
room temperature.
In order to reduce the guest exchange rate and form inclusion
complexes with a higher kinetic stability we decided to test the
binding performance of molecular dimer 2. In this case the
preorganization of the two cavities obtained by metal-directed self-
assembly reduces the exchange rate in the case of di-alkylammo-
nium 4 compared to n-alkylammonium 3. In the self-assembled
Fig. 3 Downfield and upfield regions of the 1H NMR (600 MHz,
acetone-d6): (a) Molecular dimer 2, 300 K; (b) 4@2, 300 K; (c) 4@2, 273 K;
(d) 4@2, 253 K. At [2] 5 2 mM; [4] 5 35 mM.
dimer
2 the two trimethylammonium ‘‘knobs’’ of 4 are
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R1 5 0.1956, wR2 5 0.3467, Extinction coefficient: 0.0074(6), Largest diff.
peak and hole: 0.980 and 20.612 e A23. CCDC 278172 & 278173. See
http://dx.doi.org/10.1039/b509189f for crystallographic data in CIF or
other electronic format.
detected (see ESI{). Further evidence of the formation of 2 : 1
inclusion complex (2*3@2) was obtained by ESI-MS (Table 1).
The thermodynamic data relative to inclusion complexes 4@2
and (2*3@2) show a different trend (Table 1). The DGu of the
former is lower because the longer guest 4 has to modify its
conformation to adapt to the shape of 2. The two shorter guests 3
are included in the cavities independently each other and they do
not have to modify their conformations (see ESI{).
˚
1 (a) J. A. Bryant, M. T. Blanda, M. Vincenti and D. J. Cram, J. Am.
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and J. M. Cram, Container Molecules and their Guests, Royal society of
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116, 111; (d) D. J. Cram, R. Jaeger and K. Deshayes, J. Am. Chem.
Soc., 1993, 115, 10111.
In order to investigate if the intramolecular process that takes
place between guest 4 and dimer 2 shows a cooperative effect over
the intermolecular one that occurs between guest 3 and dimer 2,
the effective molarity (EM) was evaluated, which is defined as the
12
ratio Kintra/Kinter
.
When the concentration of binding sites is
lower than the EM, the intramolecular binding is favored over
the intermolecular one, whereas the opposite occurs when the
concentration of binding sites is greater than the EM. Therefore,
an intramolecular process could display positive or negative
cooperativity depending on the concentration. In our case the
binding constant for the inclusion complex (2*3@2) can be
obtained from the independent contribution of two intermolecular
interactions and can be written as Ka(2*3@2) 5 Kinter.2 In the other
case Ka(4@2) is obtained from an intermolecular process and an
intramolecular one, it can be written as Ka(4@2)5 2KintraKinter
4 For selected examples of ditopic receptors see: (a) K. Araki, K. Hisaichi,
T. Kanai and S. Shinkai, Chem. Lett., 1995, 569; (b) J. Wang and
C. D. Gutsche, J. Am. Chem. Soc., 1998, 120, 12226; (c) T. Haino,
M. Yanase and F. Fukazawa, Angew. Chem. Int. Ed., 1998, 37, 997; (d)
A. Arduini, A. Pochini and A. Secchi, Eur. J. Org. Chem., 2000, 2325;
(e) J. Wang, S. G. Bodige, W. H. Watson and C. D. Gutsche, J. Org.
Chem., 2000, 65, 8260.
(see ESI{). From these data we calculate that EM
5
Ka(4@2)/2Ka(2*3@2) 5 2.2 mM. Thus if [2] ¡ 1.1 mM the inclusion
of 4 takes place with a positive cooperative effect gained from the
preorganization of the self-assembled structure.
5 (a) D. J. Cram, L. M. Tunstad and C. B. Knobler, J. Org. Chem., 1992,
57, 528; (b) I. Higler, P. Timmerman, W. Verboom and D. N. Reinhoudt,
J. Org. Chem., 1996, 61, 5920; (c) I. Higler, W. Verboom, F. C. J. M. van
Veggel, F. de Jong and D. N. Reinhoudt, Liebigs Ann./Recl., 1997, 1577;
(d) R. G. Chapman and J. C. Sherman, J. Am. Chem. Soc., 1998, 120,
9818; (e) F. C. Tucci, A. R. Renslo, D. M. Rudkevich and J. Rebek, Jr.,
Angew. Chem. Int. Ed., 2000, 39, 1076; (f) U. Lucking, F. C. Tucci,
D. M. Rudkevich and J. Rebek, Jr., J. Am. Chem. Soc., 2000, 122, 8880;
(g) S. D. Starnes, D. M. Rudkevich and J. Rebek, Jr., J. Am. Chem.
Soc., 2001, 123, 4659; (h) J. L. Irwin and M. S. Sherburn, Org. Lett.,
2001, 3, 225; (i) E. S. Barrett, J. L. Irwin, P. Turner and M. S. Sherburn,
Org. Lett., 2002, 4, 1455; (j) A. Lu¨tzen, O. Hass and T. Bruhn,
Tetrahedron Lett., 2002, 43, 1807; (k) L. M. Tunstad, J. E. Nunez,
S.-W. Kang and C. E. Godinez, 219th ACS National Meeting San
Francisco, CA, Abstr., p. 111.
In conclusion, the self-assembled container reported here
represents a new species of molecular host, distinct from the
covalently sealed carcerands and the reversibly formed hydrogen-
bonded capsules. It is formed by metal-directed self-assembly in
quantitative yield, has nanoscale dimensions and is able to
reversibly bind di-alkylammonium salt 4. The formation of the
inclusion complex 4@2 is slow on the NMR time scale and takes
place with cooperative effect if performed at host concentration
lower than 1.1 mM. The application of this host as a sensor for
chemical analysis or as a reaction chamber is underway.{
6 E. Menozzi, M. Busi, R. Ramingo, M. Campagnolo, S. Geremia and
E. Dalcanale, Chem. Eur. J., 2005, 11, 3136.
7 S. Leininger, B. Olenyuk and P. J. Stang, Chem. Rev., 2000, 100, 853.
8 http://www.neurosci.phrm.utoledo.edu/MBC3320/acetylcholine.htm.
9 U. Lu¨cking, F. C. Tucci, D. M. Rudkevich and J. Rebek, Jr., J. Am.
Chem. Soc., 2000, 122, 8880.
The authors are grateful to the Skaggs Institute and the
National Institutes of Health for financial support. We also thank
Prof. G. Ercolani (University of Rome Tor Vergata) for advice
and Raj K. Chadha, PhD for the crystal data of cavitand 1.
10 (a) L. Pirondini, F. Bertolini, B. Cantadori, F. Ugozzoli, C. Massera and
E. Dalcanale, Proc. Natl. Acad. Sci. USA, 2002, 99, 4911; (b) R. Pinalli,
V. Cristini, V. Sottili, S. Geremia, M. Campagnolo, A. Caneschi and
E. Dalcanale, J. Am. Chem. Soc., 2004, 126, 6516.
Notes and references
{ Crystal data of 1: C93H94N8O18, M 5 1611.76, Temperature: 183(2) K,
Wavelength: 0.71073 A, Monoclinic, space group: P21/n (No. 14, C2h5),
11 (a) For other approaches toward nanosize host molecules, see:
P. Timmerman, K. G. A. Nierop, E. A. Brinks, W. Verboom,
F. C. J. M. van Veggel, W.-P. van Hoorn and D. N. Reinhoudt, Chem.
Eur. J., 1995, 1, 132; (b) I. Higler, P. Timmerman, W. Verboom and
D. N. Reinhoudt, J. Org. Chem., 1996, 61, 5920; (c) I. Higler,
W. Verboom, F. C. J. M. van Veggel, F. de Jong and D. N. Reinhoudt,
Liebigs Ann./Recl., 1997, 1577; (d) N. Chopra and J. C. Sherman,
Angew. Chem., Int. Ed., 1999, 38, 1955; (e) A. Lu¨tzen, A. Renslo,
C. A. Schalley, B. M. O’Leary and J. Rebek, Jr., J. Am. Chem. Soc.,
1999, 121, 7455.
˚
˚
˚
˚
a 5 11.284(2) A, b 5 26.028(5) A, c 5 28.804(6) A, a 5 90u, b 5 92.98(3)u,
c 5 90u, Volume: 8448(3) A , Z: 4, Density: 1.267 Mg m23, Absorption
3
˚
coefficient: 0.089 mm21, F(000): 3408, Crystal size: 0.32 6 0.15 6 0.04 mm,
h range for data collection: 1.06 to 22.50u, Limiting indices 212 ¡ h ¡ 12,
226 ¡ k ¡ 28, 231 ¡ l ¡ 31, Reflections collected: 49055, Independent
reflections: 11037 (Rint 5 0.1450), Completeness to h 5 25.00u: 99.9%,
Absorption correction: Empirical, Max. and min. transmission: 0.9965 and
0.9722, Refinement method: Full-matrix least-squares on F2, Data/
restraints/parameters: 11037/5/1050, Goodness-of-fit on F2: 1.131, Final R
indices I . 2s (I): R1 5 0.1293, wR2 5 0.3080, R indices (all data):
12 G. Ercolani, J. Am. Chem. Soc., 2003, 125, 16097.
5532 | Chem. Commun., 2005, 5530–5532
This journal is ß The Royal Society of Chemistry 2005