Self-organization of spheroidal molecular assemblies in polar solvents

Article abstract of DOI:10.1021/ol9910924

(formula presented) We report a number of 1:1 noncovalent complexes composed of a symmetrical trisphosphonate and various symmetrical trisammonium or trisamidinium compounds. The spheroidal complexes show high thermodynamic stability, with association con

Full text of DOI:10.1021/ol9910924

ORGANIC
LETTERS
2000
Vol. 2, No. 1
29-32
Self-Organization of Spheroidal
Molecular Assemblies in Polar Solvents
,†
,‡
Thomas Grawe,† Thomas Schrader,* Marion Gurrath,* Arno Kraft,*,†,§ and
Frank Osterod†
Institut fu¨r Organische Chemie und Makromolekulare Chemie and Institut fu¨r
Pharmazeutische Chemie, Heinrich-Heine-UniVersita¨t Du¨sseldorf,
UniVersita¨tsstrasse 1, D-40255 Du¨sseldorf, Germany
thomas.schrader@uni-duesseldorf.de
Received September 27, 1999
ABSTRACT
We report a number of 1:1 noncovalent complexes composed of a symmetrical trisphosphonate and various symmetrical trisammonium or
trisamidinium compounds. The spheroidal complexes show high thermodynamic stability, with association constants Ka reaching 106 M-1 in
methanol and in some cases even exceeding 103 M-1 in water. The observed Ka values correlate well with the different degree of preorganization
of the complexation partners.
Self-organization of complementary moieties into new
functional structures represents a fundamental process that
is used extensively by Nature. Among others, the DNA
double helix is formed spontaneously by the template-
directed dimerization of complementary nucleic acid strands.1
Chemists have recently designed various types of molecular
capsules which self-assemble from smaller components by
virtue of multiple noncovalent interactions.2 However, most
of these model systems rely on weak directed hydrogen
bonds and are hence restricted to nonpolar solvents (for the
few exceptions, see ref 3). We now report on a simple and
versatile access to capsule-like complexes, which display a
pronounced complex stability even in water. These non-
covalent complexes are composed of highly charged comple-
mentary building blocks based on ammonium (or amidinium)
and phosphonate ions.4
Molecular mechanics simulations reproducibly revealed
a favorable symmetrical complex between trisphosphonate
† Institut fu¨r Organische Chemie und Makromolekulare Chemie.
‡ Institut fu¨r Pharmazeutische Chemie.
(3) Exceptions include the following. Molecular capsules in water using
the hydrophobic effect: (a) Zhao, S.; Luong, J. H. T. J. Chem. Soc., Chem.
Commun. 1995, 663-664. (b) Harada, A.; Takahashi, S. J. Chem. Soc.,
Chem. Commun. 1988, 1352-1353. (c) Boulas, P.; Kuntner, W.; Jones,
M. T.; Kardish, K. M. J. Phys. Chem. 1994, 98, 1282-1287. (d) Venema,
F.; Rowan, A. E.; Nolte, R. J. M. J. Am. Chem. Soc. 1996, 118, 257-258.
Metal chelates: (e) Lehn, J. M. Angew. Chem., Int. Ed. Engl. 1990, 29,
1347-1360. (f) Lee, J.; Schwabacher, A. W. J. Am. Chem. Soc. 1994, 116,
8382-8383. (g) Klu¨fers, P.; Schuhmacher, J. Angew. Chem., Int. Ed. Engl.
1994, 33, 1863-1865. (h) Saalfrank, R. W.; Burak, R.; Reihs, S.; Lo¨w, N.;
Hampel, F.; Stachel, H.-D.; Lentmaier, J.; Peters, K.; Peters, E.-M.; von
Schnering, H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34, 993-995. (i)
Takeda, N.; Umemoto, K.; Yamaguchi, K.; Fujita, M. Nature 1999, 398,
794-796. (j) Olenyuk, B.; Whiteford, J. A.; Fechtenko¨tter, A.; Stang, P. J.
Nature 1999, 398, 796-798.
§ Present address: Department of Chemistry, Heriot-Watt University,
Edinburgh EH14 4AS, U.K.
(1) (a) Po¨rschke, D.; Eigen, M. J. Mol. Biol. 1971, 62, 361-381. (b)
Craig, M. E.; Crothers, D. M.; Doty, P. J. Mol. Biol. 1971, 62, 383-401.
(2) For an excellent review, see: (a) Conn, M. M.; Rebek, J. Chem.
ReV. 1997, 97, 1647-1668. Some very recent work on self-organized
molecular capsules based on hydrogen bonds: (b) Heinz, T.; Rebek, J.
Nature 1998, 394, 764-767. (c) Martin, T.; Obst, U.; Rebek, J. Science
1998, 281, 1842-1845. (d) Mammen, M.; Simanek, E. E.; Whitesides, G.
M. J. Am. Chem. Soc. 1996, 118, 12614-12623. (e) Kikuchi, Y.; Tanaka,
Y.; Sutarto, S.; Kobayashi, K.; Toi, H.; Aoyama, Y. J. Am. Chem. Soc.
1991, 114, 10302-10306. (f) Vreekamp, R. H.; Verboom, W.; Reinhoudt,
D. N. J. Org. Chem. 1996, 61, 4282-4288. (g) Mogck, O.; Bo¨hmer, V.;
Vogt, W. Tetrahedron 1996, 52, 8489-8496. (h) Sessler, J. L.; Wang, R.
J. Am. Chem. Soc. 1996, 118, 9808-9809. (i) Prins, L. J.; Huskens, J.; de
Jong, F.; Timmermann, P.; Reinhoudt, D. N. Nature 1999, 398, 498-502.
(4) A relatively vague self-organization of a molecular capsule based
on flexible ammonium carboxylate ion pairs has been described: Lee, S.
B.; Hong, J.-I. Tetrahedron Lett. 1996, 37, 8501-8504.
10.1021/ol9910924 CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/18/1999

1 and trisammonium ion 2 that exhibits a cyclic arrangement
of alternating positive and negative charges interconnected
by a regular network of linear hydrogen bonds.6 These
structures were calculated to be far more stable than the
respective simple ion pairs.7 The idea of generating a compact
spheroidal assembly with an alternating order of molecular
arms coming from the top and bottom unit seemed to be
very encouraging (Figure 1).
Figure 1. Force-field-optimized structure of the complex from
trisphosphonate 1 and its complementary analogous trisammonium
salt 2. Left: side view of a CPK model. Right: calculated Connolly
surface5 (dotted line represents the solvent accessible area around
the complex).
Trisphosphonate 1 was prepared in two steps by a
Michaelis-Arbuzov reaction from 1,3,5-tris(bromomethyl)-
benzene, followed by hydrolysis of the trisphosphonate
hexamethyl ester with aqueous tetrabutylammonium hydrox-
ide. Complexes composed of 1 and symmetrical trisammo-
nium and trisamidinium compounds gave rise to sharp signals
Figure 2. Symmetrical trisammonium and trisamidinium cations
and hexazacrown 8 used for the NMR titrations with trisphospho-
nate 1. All structures are depicted in the C3V-symmetrical conforma-
tion necessary for complexation.
1
in H, 13C, and 31P NMR spectra (Figure 2). Upfield shifts
1
for H NMR signals were indicative of complexation. Job
plots supported a perfect 1:1 stoichiometry.8 Evaluation of
NMR titration curves with nonlinear regression methods
revealed a large thermodynamic stability, with association
constants Ka reaching 106 M-1 in methanol (Figure 3, Table
1).9
charges described in Figure 1. Such a combination of weak
multipoint interactions is reminiscent of many natural,
selective, and strong recognition processes.14
Molecular mechanics simulations of the complex between
1 and 2 soaked in a solvent shell of explicit water molecules
This was an interesting result considering our initial
experiments with R,ω-diammonium ions and xylylene bis-
phosphonates, which also formed 1:1 complexes in solution.
However, their association constants were several orders of
magnitude lower than those of their C3V-symmetrical coun-
terparts investigated in this paper.13 Even with shorter
hydrogen bond lengths and two additional charges in the
trisphosphonate complexes, the drastic increase in binding
energy can be best explained by a network of alternating
(5) (a) Connolly, M. L. Science 1983, 221, 709-713. (b) Connolly, M.
L. J. Appl. Crystallogr. 1983, 16, 548.
(6) Molecular Modelling Program: CERIUS2 by Molecular Simulations
Inc. Force field: Dreiding 2.21.
(7) For flat structures, which form simple ion pairs, see: Schneider, H.-
J.; Schiestel, T.; Zimmermann, P. J. Am. Chem. Soc. 1992, 114, 7698-
7703.
(8) (a) Job, P. Ann. Chim. 1928, 9, 113-203. (b) Blanda, M. T.; Horner,
J. H.; Newcomb, M. J. Org. Chem. 1989, 54, 4626-4636.
(9) (a) Schneider, H. J.; Kramer, R.; Simova, S.; Schneider, U. J. Am.
Chem. Soc. 1988, 110, 6442-6448. (b) Wilcox, C. S. In Frontiers in
Supramolecular Chemistry and Photochemistry; Schneider, H.-J., Du¨rr, H.,
Eds; VCH: Weinheim, 1991; pp 123-143. (c) Macomber, R. S. J. Chem.
Educ. 1992, 69, 375-378.
(10) Kraft, A.; Fro¨hlich, R. Chem. Commun. 1998, 1085-1086.
(11) Bowen, T.; Planalp, R. P.; Brechbiel, M. W. Bioorg. Med. Chem.
Lett. 1996, 6, 807-810.
Figure 3. Typical NMR titration curve showing the change in the
1
chemical shift ∆δ ) δobserved - δ0 for two H NMR signals of
trisamidine 7 (c ) 0.1 mM) on addition of trisphosphonate 1 in
CD3OD.
30
Org. Lett., Vol. 2, No. 1, 2000

in complexes of 1 with 6, 2, and 4, which contain three, six,
and nine freely rotating bonds, respectively. Thus, the Ka
values in Table 1, spanning several orders of magnitude,
convincingly reflect the different degree of preorganization
of the complexation partners. The smallest value for tris-
imidazoline 3 probably originates from the fact that the
trication prefers an almost planar conformation but has to
be strongly twisted for complexation.18 Trisamidine 7, on
the other hand, is already ideally preoriented prior to
complexation as a result of the congestion of three bulky
N,N′-diethyl-substituted amidinium groups at the 1,3,5-
positions of the benzene ring.12 This preorganization of 7
(similar to 6) explains the remarkably high association
constants with 1 in organic solvents, where hydrogen bonds
considerably contribute to the overall binding strength. It
would be interesting to check if the transition from three
methyl groups in 5 to the corresponding triethyl-substituted
triamine leads to increased binding due to preorganization
as Anslyn demonstrated with his citrate receptor.19
In contrast to most molecular capsules known to date,
several of our trisammonium trisphosphonates form strong
complexes even in water, with Ka values varying between
103 and 104 M-1 (Table 1). In water, however, the dominating
electrostatic interaction of the hard ammonium cation is
superior to that of the delocalized amidinium cation. There-
fore, here the distribution of association constants becomes
much more uniform.
Table 1. Association Constants Ka [M-1] for 1:1 Complexes
between Symmetrical Trications and 1 Determined by NMR
Titrations in Methanol and Water at 20 °C
tricationa
Ka [M-1] in CD3OD Ka [M-1] in D2Oc
trisimidazoline 310
tren 4
mesitylenetriamine 5
mesitylenetriamine 2
cyclohexanetriamine 611
trisamidine 712a
3.0 × 103 ( 16%b
4.8 × 104 ( 48%
8.0 × 104 ( 34%
1.4 × 105 ( 11%
9.9 × 105 ( 32%
1.1 × 106 ( 8%
2.6 × 103 ( 13%
4.0 × 103 ( 6%
1.1 × 103 ( 15%
1.0 × 103 ( 9%
a Ammonium and amidinium chlorides except for 6 which was used as
a bromide. b Errors are standard deviations. c pD = 7.0.
(layer thickness: 5 Å) employing a more sophisticated energy
minimization approach (quasi Newton-Raphson algorithm15a)
also indicated a high stability for the 1:1 complex even in a
highly competitive solvent environment. The calculations
starting from different hydrogen bond patterns converged
toward the proposed hydrogen bond network that is char-
acterized by a staggered orientation of the substituents and
regularly bridging hydrogen bonds.15b
It is well known that a self-organization process is
governed by a delicate balance between enthalpic gain and
entropic cost. Both starting materials are flexible molecules
with various rotatable bonds that need to be conformationally
fixed in the final complex. In this respect, the required
entropy loss for the self-organization process lies between
Rebek’s tennisball (composed of rigid halfs) and White-
sides’s rosette (composed of highly flexible components).16
Because in our example the three binding sites are all
covalently linked to an aromatic core, only torsional degrees
of freedom contribute to the free binding energy (Figure 4).
Preliminary experiments in the direction of defined higher
aggregates were already very promising. Thus, a Job plot
proved unambiguously that, even in water, a 2:1 complex
was formed between two half-spheres of 1 and a belt of
hexaza-18-crown-6 8 (Figure 5). This shows that our
Figure 4. Schematic presentation of the self-organization process
involved in the formation of a 1:1 complex from a mixture of 1
and a trisammonium or trisamidinium ion (2-7).
Figure 5. Schematic presentation of the self-organization process
involved in the formation of a neutral 2:1 complex from a mixture
of 1 and hexaza-18-crown-6 (8).
The varying number of flexible bonds within the trisammo-
nium ions should therefore reflect their total difference in
torsional entropy.17 This correlation has indeed been found
approach for the design of molecular capsules, by using a
combination of preorientation and an array of alternating
charges, can be effectively transferred to systems with more
(12) (a) Kraft, A. J. Chem. Soc., Perkin Trans. 1 1999, 705-714. Two
crystal structures of bulky N,N′-disubstituted aromatic amidines confirm
the strong twist of the amidine moieties: (b) Tinant, B.; Dupont-Fenfau,
J.; Declercq, J.-P.; Podlaha, J.; Exner, O. Collect. Czech Chem. Commun.
1989, 54, 3245-3251. (c) Boere´, R. T.; Klassen, V.; Wolmersha¨user, G. J.
Chem. Soc., Dalton Trans. 1998, 4147-4154.
(15) (a) Mackay, D. H.; Cross, A. J.; Hagler, A. T. In Prediction of
Protein Structure and the Principles of Protein Conformation; Fasman, G.
D., Ed.; Plenum Press: New York, 1989; pp 317-358. (b) INSIGHT II,
version 98.0, 1999, MSI, San Diego, CA.
(16) (a) Wyler, R.; de Mendoza, J.; Rebek, J. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1699-1700. (b) Branda, N.; Wyler, R.; Rebek, J. Science
1994, 263, 1267-1268. (c) Seto, C. T.; Whitesides, G. M. J. Am. Chem.
Soc. 1993, 115, 905-916. (d) Seto, C. T.; Whitesides, G. M. J. Am. Chem.
Soc. 1993, 115, 1330-1340.
(13) Ka values typically range from 101 to 102 M-1 in methanol: Grawe,
T.; Schrader, T. Unpublished results.
(14) Mammen, M.; Choi, S.-K.; Whitesides, G. M. Angew. Chem., Int.
Ed. 1998, 37, 2754-2794.
Org. Lett., Vol. 2, No. 1, 2000
31

than two components. At present we are devising larger,
highly preorganized capsules with the aim of testing their
abilities to accommodate guests in polar media. The transport
of drugs, sensors, markers, or reagents by such artificial
container molecules would, especially in physiological
solution, open the door for a wide range of possible
applications.2
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft for financial support. M.G. thanks the Land
Nordrhein-Westfalen for a Lise-Meitner-Habilitationsstipen-
dium.
Supporting Information Available: Experimental pro-
cedures and full characterization for compounds 1, 2, and 5,
entropy estimations, NMR titration curves, Job plots, and
force-field calculations of complex geometries for selected
complexes. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) For an application of Whitesides’s entropy model to our complexes,
see the Supporting Information. (a) Mammen, M.; Shakhnovich, E. I.;
Whitesides, G. M. J. Org. Chem. 1998, 63, 3168-3175. (b) Mammen, M.;
Shakhnovich, E. I.; Whitesides, G. M. J. Org. Chem. 1998, 63, 3821-
3830.
(18) NMR chemical shift data indicate a preference for a planar
conformation of 3 prior to complexation as supported by two crystal
structures: (a) ref 10. (b) Kraft. A.; Osterod, F.; Fro¨hlich, R. J. Org. Chem.
1999, 64, 6425-6433.
(19) Metzger, A.; Lynch, V. M.; Anslyn, E. V. Angew. Chem., Int. Ed.
Engl. 1997, 36, 862-865.
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