Can Multivalency Be Expressed Kinetically? The Answer Is Yes

Article abstract of DOI:10.1021/ja0395285

Inspired by the concept of multivalency and in pursuit of ever more intricate artificial molecular machines, we investigated the strict self-assembly of a triply threaded two-component superbundle, starting from a tritopic receptor in which three benzo[24

Full text of DOI:10.1021/ja0395285

Published on Web 02/10/2004
Can Multivalency Be Expressed Kinetically? The Answer Is Yes
Jovica D. Badjic´, Stuart J. Cantrill, and J. Fraser Stoddart*
California NanoSystems Institute and Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, 405 Hilgard AVenue, Los Angeles, California 90095-1569
Received November 10, 2003; E-mail: stoddart@chem.ucla.edu
The preparation of supermolecules by way of strict self-assembly
has attracted considerable interest, particularly in the bottom-up
construction1 of molecular machines and devices. Paraquat deriva-
tives have been used2 in the preparation of interpenetrating
complexes (pseudorotaxanes) and the derived mechanically inter-
locked compounds, catenanes, and rotaxanes. Multivalent interac-
tions,3 incorporating both statistical and chelate contributions, are
very important in nature and have been explored in the noncovalent
synthesis4 of various elaborate supermolecules by us5 and others.6
Inspired by the multivalency concept,3 we report here the strict self-
assembly of a triply threaded two-component superbundle 3in-[1⊃2]-
[PF6]6, which can be used7 in building (Figure 1) photo- and redox-
active molecular devices. It transpires that a trifurcated trisbipyri-
dinium salt [1][PF6]6 and a tritopic triscrown ether 2 form the
thermodynamically stable 3in-[1⊃2][PF6]6 by way of a metastable
Figure 1. Schematic representation of the stepwise self-assembly of the
doubly threaded complex 2in-[1⊃2][PF6]6 obtained fleetingly from
two-component triply threaded supramolecular bundle 3in-[1⊃2][PF6]6 by
a singly threaded intermediate species 1in-[1⊃2][PF6]6.
way of a doubly threaded 2in-[1⊃2][PF6]6 intermediate, starting from the
The trifurcated trisbipyridinium salt [1][PF6]6 was synthesized
(Supporting Information) in four steps from 1,3,5-tris(p-formyl-
phenyl)benzene,8 while the synthesis of the tritopic crown ether 2
has been described9 previously. On the basis of molecular modeling
and our previous studies on and knowledge of related systems,10
3in-[1⊃2][PF6]6 should be stabilized by (i) π-π stacking inter-
actions11 between the triphenylene core of the tritopic crown ether
2 and the benzenoid core of [1][PF6]6, (ii) π-π stacking inter-
actions11 between the catechol rings in 2 and the bipyridinium units
in [1][PF6]6, and (iii) [C-H‚‚‚O] interactions12 between the R-bi-
pyridinium protons in [1][PF6]6 and some of the oxygen atoms in
the polyether loops of 2.
trifurcated trisbipyridinium salt [1][PF6]6 and the triscrown ether 2.
When equimolar amounts (5 mM) of [1][PF6]6 and 2 were mixed
in CD3COCD3, the 1H NMR spectrum (253 K), recorded im-
mediately (Figure 2b) after mixing, displayed a complex array of
well-defined resonances. The absence of any resonances corre-
sponding to either free [1][PF6]6 (Figure 2a) or 2 (Figure 2d) is
suggestive of a strong interaction between the two components.
Closer inspection of the 1H NMR spectrum (Figure 2b) of the
mixture reveals that all of the signals can be divided rather easily
into two sets with approximately 2:1 ratios in their intensities,
suggesting the formation of either a doubly or singly threaded
supermolecule with averaged Cs symmetry. The significant down-
field shift of the doublet observed at δ 10.0, corresponding to four
R-bipyridinium protons in [1][PF6]6 is presumably a result of the
formation of [CR-H‚‚‚O] interactions12 with the crown ether oxygen
atoms in 2 and in accordance with the threading of two bipyridinium
arms through two crown ethers as represented by 2in-[1⊃2][PF6]6
in Figure 1. With the aid of 1H-1H COSY and TROESY 2D NMR
spectroscopic experiments (Supporting Information), it was possible
to assign most of the resonances in Figure 2b to a 1:1 complex
with averaged Cs symmetry, i.e., a doubly threaded superbundle,
which is kinetically stable13 on the NMR timescale. Furthermore,
the upfield shifts of the aromatic core proton signals, Ha in [1]-
Figure 2. Partial 1H NMR spectra (500 MHz, CD3COCD3, 5.0 mM each,
253 K) of (a) [1][PF6]6, (b) an equimolar mixture of [1][PF6]6 and 2
immediately after the mixing, (c) an equimolar mixture of [1][PF6]6 and 2
235 h after the mixing, and (d) triscrown ether 2.
[PF6]6 and Hm in 2, suggest that the two central aromatic cores
reside in this 1:1 complex within π-π stacking distance of each
other, thus stabilizing the superbundle. The singlet for the methyl
protons (Me) in the 1H NMR spectrum of [1][PF6]6 separates (Figure
2b) into two broad singlets with relative intensities of 2:1 which
correspond, respectively, to two complexed and one uncomplexed
arms of 2in-[1⊃2][PF6]6.
1
Interestingly, the H NMR spectrum of the equimolar mixture
of [1][PF6]6 and 2 changed very gradually with time, until after
235 h, the initial set of resonances with relative intensity ratios of
2:1 were replaced (Figure 2c) with a new set of resonances. On
1
the basis of H-1H COSY and TROESY 2D NMR spectroscopic
evidence (Supporting Information), we have assigned the new set
9
2288
J. AM. CHEM. SOC. 2004, 126, 2288-2289
10.1021/ja0395285 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Kinetic and Thermodynamic Parameters for the
Conversion of 2in- [1⊃2][PF6]6 to 3in-[1⊃2][PF6]6
References
k1a
k2a
K
∆G qThinSpaceb
∆G q b
∆G
b
1
2
(1) (a) Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart, J. F. Angew. Chem.,
Int. Ed. 2000, 39, 3343-3391. (b) Leigh, D. A.; Wong, J. K. Y.; Dehez,
F.; Zerbetto, F. Nature 2003, 424, 174-179. (c) Balzani, V.; Credi, A.;
Venturi, M. Molecular DeVices and Machines: A Journey into the Nano
World; Wiley-VCH: Weinheim, Germany, 2003.
4.7 ( 0.1 1.4 ( 0.1 3.4 ( 0.1 20.9 ( 0.3 21.5 ( 0.3 -0.60 ( 0.01
a
b
In s-1 × 106. In kcal mol-1
.
(2) (a) Wisner, J. A.; Loeb, S. J. Angew. Chem., Int. Ed. 1998, 37, 2838-
2840. (b) Huang, F.; Gibson, H. W.; Bryant, W. S.; Negvekar, D. S.;
Fronczek, F. R. J. Am. Chem. Soc. 2003, 125, 9367-9371. (c) Davidson,
G. J. E.; Loeb, S. J. Angew. Chem., Int. Ed. 2003, 42, 74-77.
(3) (a) Mammen, M.; Choi, S.-K.; Whitesides, G. M. Angew. Chem., Int. Ed.
1998, 37, 2754-2794. (b) Gestwicki, J. E.; Cairo, C. W.; Strong, L. E.;
Oetjen, K. A.; Kiessling, L. L. J. Am. Chem. Soc. 2002, 124, 14922-
14933. (c) Kitov, P. I.; Bundle, D. R. J. Am. Chem. Soc. 2003, 125,
16271-16284. (d) Ercolani, G. J. Am. Chem. Soc. 2003, 125, 16097-
16103.
of resonances to a single 1:1 complex with averaged C3V symmetry,
i.e., 3in-[1⊃2][PF6]6. The resonances of the central aromatic core
protons, namely Ha in [1][PF6]6 and Hm in 2, showed significant
upfield shifts, compared to the corresponding resonances of the
free components (Figure 2a,d), indicating intimate π-π stacking9,11
of the central aromatic cores. The previously enantiotopic OCH2
protons in 2 (Figure 2a) become diastereotopic in 3in-[1⊃2][PF6]6
(Figure 2c) when all three bipyridinium units became threaded
through the crown ether moieties. Furthermore, the resonances for
the six equiValent R-bipyridinium He protons in 3in-[1⊃2][PF6]6
(Figure 2c) are dramatically shifted, as compared to the signals
for these same protons in [1][PF6]6 (Figure 2a) as a result of
[CR-H‚‚‚O] interactions.12 The single resonance for the Me protons
in 3in-[1⊃2][PF6]6 (Figure 2c) also confirms the binding of all three
bipyridinium units.
(4) (a) Whitesides, G. M.; Mathias, J. P.; Seto, C. T. Science 1991, 254, 1312-
1319. (b) Wintner, E. A.; Conn, M. M.; Rebek, J., Jr. Acc. Chem. Res.
1994, 27, 198-203. (c) Crego-Calama, M.; Reinhoudt, D. N. Science 2002,
295, 2403-2407.
(5) Fulton, D. A.; Cantrill, S. J.; Stoddart, J. F. J. Org. Chem. 2002, 67, 7968-
7981 and references therein.
(6) (a) Rao, J.; Lahiri, J.; Isaacs, L.; Weis, R. M.; Whitesides, G. M. Science
1998, 280, 708-711. (b) Kitov, P. I.; Sadawska, J. M.; Mulvey, J. P.;
Armstrong, G. D.; Ling, H.; Pannu, N. S.; Read, R. J.; Bundle, D. R.
Nature 2000, 403, 669-672. (c) Gibson, H. W.; Yamaguchi, N.; Hamilton,
L.; Jones, J. W. J. Am. Chem. Soc. 2002, 124, 4653-4665.
(7) Ashton, P. R.; Ballardini, R.; Balzani, V.; Credi, A.; Dress, K. R.; Ishow,
E.; Kleverlaan, C. J.; Kocian, O.; Preece, J. A.; Spencer, N.; Stoddart, J.
F.; Venturi, M.; Wenger, S. Chem. Eur. J. 2000, 6, 3558-3574.
(8) 1,3,5-Tris(p-formylphenyl)benzene was reduced initially with NaBH4 to
1,3,5-tris(p-hydroxybenzyl)benzene, followed by chlorination with N-
chlorosuccinimide to yield 1,3,5-tris(p-chlorobenzyl)benzene. Further
reaction with 4,4′-bipyridine, followed by anion exchange, produced [6]-
[PF6]3, which was then reacted with p-methylbenzyl bromide to yield [1]-
[PF6]6 after anion exchange. For further details, see Supporting Informa-
tion.
(9) (a) Fyfe, M. C. T.; Lowe, J. N.; Stoddart, J. F.; Williams, D. J. Org. Lett.
2000, 9, 1221-1224. (b) Balzani, V.; Clemente-Leon, M.; Credi, A.;
Lowe, J. N.; Badjic´, J. D.; Stoddart, J. F.; Williams, D. J. Chem. Eur. J.
2003, 9, 5348-5360.
(10) (a) Ashton, P. R.; Langford, S. J.; Spencer, N.; Stoddart, J. F.; White, A.
J. P.; Williams, D. J. Chem. Commun. 1996, 1387-1388. (b) Ashton, P.
R.; Glink, P. T.; Mart´ınez-D´ıaz, M. V.; Stoddart, J. F.; White, A. J. P.;
Williams, D. J. Angew. Chem., Int. Ed. Engl. 1996, 35, 1930-1933.
(11) (a) Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc. 1990, 112, 5525-
5534. (b) Adams, H.; Hunter, C. A.; Lawson, K. R.; Perkins, J.; Spey, S.
E.; Urch, C. J.; Sanderson, J. M. Chem. Eur. J. 2001, 7, 4863-4877.
(12) (a) Desiraju, G. R. Acc. Chem. Res. 1991, 24, 290-296. (b) Raymo, F.
M.; Bartberger, M. D.; Houk, K. N.; Stoddart, J. F. J. Am. Chem. Soc.
2001, 123, 9264-9267. (c) Steiner, T. Angew. Chem., Int. Ed. 2002, 41,
48-76.
(13) At temperatures below 253 K, an equimolar mixture (8.5 mM) of 4,4′-
dibenzylbipyridinium bis(hexafluorophosphate) and DB24C8 in CD3-
COCD3 reveals peaks in the 1H NMR spectra for the 1:1 complex as well
as for the free species, i.e., complexation-decomplexation is slow on the
NMR timescale. Thus, it is not surprising that 2in-[1⊃2][PF6]6 is
kinetically stable at 253 K.
(14) The experimental data points were fitted to a model for the reversible
first-order reaction by nonlinear square fitting using SigmaPlot 8.0
software. For further details, see: Espenson, J. H. Chemical Kinetics and
Reaction Mechanisms; McGraw-Hill: New York, 1995; Chapter 3.
(15) For some further examples of strict self-assembly, see: (a) Zimmerman,
S. C. Science 1997, 276, 543-544. (b) Conn, M. M.; Rebek, J., Jr. Chem.
ReV. 1997, 97, 1647-1668. (c) Fujita, M. Acc. Chem. Res. 1999, 32,
53-61. (d) Lehn, J.-M. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4763-
4768. (e) Felix, O.; Crego-Calama, M.; Luyten, I.; Timmerman, P.;
Reinhoudt, D. N. Eur. J. Org. Chem. 2003, 8, 1463-1474.
(16) By comparison (ref 9), a trifurcated trisammonium salt, wherein the three
bipyridinium units in [1][PF6]6 are replaced by three CH2NH2+CH2 units,
forms a triply threaded superbundle with 2 instantaneously. No intermedi-
ates are observed on the laboratory timescale. We suspect that the
difference in the rates of formation of the two superbundles can be traced
back to the relative rigidity of [1]6+ compared with its trisammonium-
based analogue.
1
The change in the H NMR spectrum of an equimolar mixture
of [1][PF6]6 and 2, each 5.5 mM, at 253 K with time (235 h) was
monitored (Supporting Information) by 1H NMR spectroscopy. The
concentration of the initially formed 2in-[1⊃2][PF6]6 decreases,
while the concentration of 3in-[1⊃2][PF6]6 increases. When the
concentration of the initially formed 2in-[1⊃2][PF6]6 was plotted
versus time and the data points were fitted (Supporting Information)
to the model for a reversible first-order rate reaction, good
agreement was found.14 This finding supports the evidence for the
presence of two species, i.e., 2in-[1⊃2][PF6]6 and 3in-[1⊃2][PF6]6,
in admixture and slowly equilibrating. The calculated rate constants
for the forward (k1) and backward (k2) reactions and the corre-
q
sponding free energies (∆G1q and ∆G2 ) are presented in Table 1.
The high energy barrier (20.9 kcal mol-1) for the formation of 3in-
[1⊃2][PF6]6 suggests that the initial rapid formation of 2in-[1⊃2]-
[PF6]6 is followed by a much slower binding step, during which
time the third and uncomplexed bipyridinium arm is appropriately
positioned such that the final threading process can take place. The
singly threaded complex 1in-[1⊃2][PF6]6 is most certainly being
formed along the way. Presumably, however, the relatively short
lifetime of this 1:1 complex does not allow us to detect it by
conventional NMR spectroscopy.
In conclusion, we have discovered that the strict self-assembly4,15
of a two-component triply threaded superbundle 3in-[1⊃2][PF6]6
from its components in solution is very much a two-step process,16
with the first one being kinetically and the second one thermo-
dynamically controlled. This observation begs the important ques-
tion: are there instances17 in nature where multivalency is expressed
as a kinetically controlled process, prior to an equilibrium state
being reached and, if so, what are the biological consequences, if
any?
(17) Indeed, there are instances in nature, e.g., a recent study carried out on
the high-avidity, reversible low-affinity multivalent interactions of the
lectin XL35 with the jelly coat proteins surrounding oocytes in Xenopus
laeVis shows that they require a very long time to reach equilibrium, so
long in fact that the partners do not attain true equilibrium on the timescale
of the biological event, namely polyspermy, yet are such that their
metastable mode of interaction is probably more than enough to guarantee
an insurmountable physical block to polyspermy. See: Arranz-Plaza, E.;
Tracy, A. S.; Siriwardena, A.; Pierce, J. M.; Boons, G.-J. J. Am. Chem.
Soc. 2002, 124, 13035-13046.
Acknowledgment. We thank Alshakim Nelson and Scott
Vignon for useful discussions. This research was supported by an
NSF grant (CHE 0317170) and also in part by two equipment grants
(CHE 9974928 and CHE 0092036), also from the NSF.
Supporting Information Available: Experimental details for the
synthesis of [1][PF6]6, 1H-1H COSY, TROESY 2D NMR spectra of
2in-[1⊃2][PF6]6 and 3in-[1⊃2][PF6], and rate constant measurements
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
JA0395285
9
J. AM. CHEM. SOC. VOL. 126, NO. 8, 2004 2289