C O M M U N I C A T I O N S
Table 1. Estimated Yield of 6a-c by HPLC
conditions
estimated yield (%)a
equiv 2bb
Acknowledgment. This material is based upon work supported
by the National Science Foundation under Grant No. 0106608 and
the U.S. Department of Energy, Division of Materials Sciences,
under Award No. DEFG02-91ER45439, through the Frederick Seitz
Materials Research Laboratory at the University of Illinois at
Urbana-Champaign. We thank Dr. Thomas. S. Hughes for discus-
sions on the molecular modeling of the oligomer bound with rodlike
ligand.
solv
6a
6b
6c
total 6
CHCl3
calcdc
CH3CN
CH3CN
0
-
0
6 ( 1
8
19 ( 1
10 ( 1
8 ( 1
5 ( 1
8
16 ( 1
9 ( 1
19
-
72
85
16
37 ( 2
66 ( 3
2
a Quantitative analysis using peak areas. Error estimates are based on
experimental reproducibility of duplicate runs. b Equivalents to total amount
of starting 3 and 4. c Assumes all metathesis equilibria have equilibrium
constants of unity, as expected for CHCl3 data (see text).
1
Supporting Information Available: Synthesis of 3, 4, and 6, H
NMR, MALDI-MS, and HPLC charts for the products of the metathesis
reaction, and nonlinear least-squares fitting curve for binding study,
and the molecular modeling of the oligomer bound with rodlike ligand
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) For reviews, see: (a) Ganesan, A. Angew. Chem., Int. Ed. Engl. 1998,
37, 2828. (b) Klekota, B.; Miller, B. L. Trends Biotechnol. 1999, 17, 205.
(c) Lehn, J.-M. Chem. Eur. J. 1999, 5, 2455. (d) Cousins, G. R. L.;
Poulsen, S.-A.; Sanders, J. K. M. Curr. Opin. Chem. Biol. 2000, 4, 270.
(e) Lehn, J.-M.; Eliseev, A. V. Science 2001, 291, 2331. (f) Rowan, S. J.;
Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Angew.
Chem., Int. Ed. 2002, 41, 898.
(2) (a) Diederich, F.; Stang, P. J. Templated Organic Synthesis; Wiley-
VCH: Weinheim, 2000. (b) Summerer, D.; Marx, A. Angew. Chem., Int.
Ed. 2002, 41, 89.
Figure 2. HPLC traces after the metathesis reactions (a) in CHCl3, (b) in
CH3CN and (c) in CH3CN in the presence of 2b.
shifting is driven by the stabilizing energy of folding (∆Gfold),11b,f,14
thus disfavoring those oligomers that are not folded (3, 4a). In fact,
∆Gfold for independently synthesized 6a and 6c were determined
to be 5.5 and 7.5 kcal‚mol-1, respectively, as measured by solvent
denaturation experiments.11b,f This is comparable to ∆Gfold of 1 (n
) 18, ca. 7.0 kcal‚mol-1) despite the presence of two imine bonds
that presumably could distort the helical conformation. The observed
ratio of 6a:6b:6c (ca. 1:2:1) can be rationalized on the basis of a
statistical product distribution. Oligomers 6a and 6c were formed
from 4a, 5a and 4b, 5b, respectively, while 6b was formed either
from 4a and 5b, or from 4b and 5a. The free energy change in
forming each of the high-molecular weight products 6a-c is
expected to be similar.15
(3) (a) Otto, S.; Furlan, R. L. E.; Sanders J. K. M. J. Am. Chem. Soc. 2000,
122, 12063. (b) Cousins, G. R. L.; Furlan, R. L. E.; Ng, Y.; Redman, J.
E.; Sanders J. K. M. Angew. Chem., Int. Ed. 2001, 40, 423.
(4) (a) Huc, I.; Lehn, J.-M. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 2106. (b)
Polyakov, V. A.; Nelen, M. I.; Nazarpack-Kandlousy, N.; Ryabov, A.
D.; Eliseev, A. V. J. Phys. Org. Chem. 1999, 12, 357. (c) Ramstrom, O.;
Lehn, J.-M. ChemBioChem 2000, 1, 41. (d) Goral, V.; Nelen, M. I.;
Eliseev, A. V.; Lehn, J.-M. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 1347.
(e) Moore, J. S.; Zimmerman, N. W. Org. Lett. 2000, 2, 915.
(5) Karan, C.; Miller, B. L. J. Am. Chem. Soc. 2001, 123, 7455.
(6) Hiraoka, S.; Fujita, M. J. Am. Chem. Soc. 1999, 121, 10239.
(7) Crego Calama, M.; Timmerman, P.; Reinhoudt, D. N. Angew. Chem.,
Int. Ed. 2000, 39, 755.
(8) Hof, F.; Nuckolls, C.; Rebek, J., Jr. J. Am. Chem. Soc. 2000, 122, 4251.
(9) Nicolau, K. C.; Hughes, R.; Cho, S. Y.; Winssinger, N.; Smethurst, C.;
Labischinski, H.; Endermann, R. Angew. Chem., Int. Ed. 2000, 39, 3823.
(10) For a recent review, see Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T.
S.; Moore, J. S. Chem. ReV. 2001, 101, 3893.
(11) (a) Nelson, J. C.; Saven, J. G.; Moore, J. S.; Wolynes, P. G. Science 1997,
277, 1793. (b) Prince, R. B.; Saven, J. G.; Wolynes, P. G.; Moore, J. S.
J. Am. Chem. Soc. 1999, 121, 3114. (c) Prince, R. B.; Barnes, S. A.; Moore,
J. S. J. Am. Chem. Soc. 2000, 122, 2758. (d) Tanatani, A.; Mio, M. J.;
Moore, J. S. J. Am. Chem. Soc. 2001, 123, 1792. (e) Tanatani, A.; Hughes,
T. S.; Moore, J. S. Angew. Chem., Int. Ed. 2002, 41, 325. (f) Oh, K.;
Jeong K.-S.; Moore, J. S. Nature 2001, 414, 889.
Most importantly, the product distribution of the metathesis
reaction in acetonitrile in the presence of 2b shifts to favor 6b, the
high-molecular weight oligomer of intermediate length (Figure 2).
As shown in Table 1, when 2 equiv of 2b are present, the total
amount of oligomers 6 increases even though the yields of 6a and
6c decrease. This is because there is substantial increase in the
amount of 6b. The selective formation of 6b was predicted since
this chain length has the highest affinity for 2b among the products
6a-c. To estimate the effect of adding the rodlike ligand 2b to the
metathesis reaction, the binding affinities16 of 6 with 2b were
determined by circular dichroism (CD) measurements.17 The binding
constant for 6 was comparable to that for 1, and the affinity reached
its maximum for the 20-mer 6 (n ) n′ ) 7), similar to the case of
1.11e The maximum binding constant of 6 (n ) n′ ) 7) to 2b in
acetonitrile was 7.0 × 103 M-1, corresponding to a binding energy
of 5.2 kcal‚mol-1. On the basis of an equilibrium model and
estimations of binding affinity for 6a-6c,18 we conclude that the
enhancement of 6b in the metathesis reaction in the presence of
2b was driven by ligand bindingsa form of dynamic templation.
In summary, we have shown that the imine metathesis equilibra-
tion of helical oligomers can be shifted by ligand binding to enhance
the formation of the oligomer with the highest affinity to this ligand.
Dynamic templation using a size-selective ligand was demonstrated
by selective synthesis of unsymmetrical oligomer 6b. Since rodlike
ligands of different length can be synthesized, the method may be
extended to the size-selective synthesis of longer oligomers and
polymers.
(12) Mixed solvents (NEt3/i-PrOH/CHCl3, 0.02/3.8/96.2) were used as an eluent
with a UV detector operating at 290 nm.
(13) To´th, G.; Pinte´r, I., Messmer, A. Tetrahedron Lett. 1974, 15, 735.
(14) Pace, C. N.; Shirley, B. A.; Thomson, J. A. In Protein Structure:
A
Practical Approach; Creighton, T. E., Ed.; IRL Press: New York, 1989;
pp 311-330.
(15) Previously, we showed that the folding driving force becomes significant
beyond the 6-mer and increases proportionally as the number of repeat
units.11b,f Thus, the number of repeat units that contribute toward ∆Gfold
,
(i.e., number of repeat unit: 6) is 4 for 5a, 6 for 4b, 10 for 5b, 10 for 6a,
16 for 6b, and 22 for 6c, and the differences between the sum of the
folded units on the right and left sides in each equilibrium is 6, respectively,
suggesting that the distribution of products 6a-c is not strongly biased
by folding.
(16) The program Dynafit was used for nonlinear least-squares fitting; Kuzmic,
P. Anal. Biochem. 1996, 237, 260.
(17) Although 6b (which is not easily synthesized by conventional methods)
was produced as the main product under these metathesis conditions,
the purification of the products was not facile, and hence the binding
constants for 20-mer 6 (n ) n′ ) 7) and 24-mer 6 (n ) n′ ) 9) were
measured instead. Since the metathesis was conducted in acetonitrile,
the binding affinities in acetonitrile were important for the estimation.
However, the induced CD signals for 6a and 6c in acetonitrile were too
small relative to the CD signal caused by excess amount of 2b. Thus,
the measurements were conducted in 40% aqueous acetonitrile (0.1%
triethylamine was added to prevent the hydrolysis of imine bonds) from
which the binding constant for the series of 6 in acetonitrile could be
estimated.
(18) See Supporting Information.
JA025698Q
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J. AM. CHEM. SOC. VOL. 124, NO. 21, 2002 5935