Synthesis and association behavior of butadiyne-bridged [44](2,6)pyridinophane and [46](2,6)pyridinophane derivatives

Article abstract of DOI:10.1021/ol006318d

(matrix presented) Butadiyne-bridged [4₄](2,6)pyridinophane and [4₆](2,6)pyridinophane derivatives were synthesized, and their heteroassociations with the corresponding metacyclophanes and complexations with organic cations were investigated.

Full text of DOI:10.1021/ol006318d

ORGANIC
LETTERS
2000
Vol. 2, No. 21
3265-3268
Synthesis and Association Behavior of
Butadiyne-Bridged [44](2,6)Pyridinophane
and [46](2,6)Pyridinophane Derivatives
Yoshito Tobe,* Atsushi Nagano, Kazuya Kawabata, Motohiro Sonoda, and
Koichiro Naemura
Department of Chemistry, Faculty of Engineering Science, Osaka UniVersity,
Toyonaka, Osaka 560-8531, Japan
tobe@chem.es.osaka-u.ac.jp
Received July 10, 2000
ABSTRACT
Butadiyne-bridged [44](2,6)pyridinophane and [46](2,6)pyridinophane derivatives were synthesized, and their heteroassociations with the
corresponding metacyclophanes and complexations with organic cations were investigated.
Shape-persistent macrocyclic metacyclophanes with aromatic
rings connected by triple bonds have been the subject of
intensive study in view of their ability to self-associate and
to bind large organic substrates.1-4 We reported the synthesis
of butadiyne-bridged [44]metacyclophane 14a and [46]meta-
cyclophane 24b and their self-association behavior in solution.
Moreover, we found that [46]metacyclophane 3 having endo-
annular cyano groups associated in solution with 2 to form
heteroaggregates and that 3 bound organic cations to form
2:1 (host:guest) complexes.4b As an extension of this work,
we report here the synthesis and the association and
complexation behaviors of butadiyne-bridged [44](2,6)-
pyridinophane derivative 4 and its [46] congener 5. Since
the [44]metacyclophane with cyano groups as the nitrogen
binding units, which corresponds to 4, was not obtained
because of the repulsive interaction between the cyano
groups,4b compound 3 represents the smallest member of the
series of [4n]metacyclophanes having endo-annular binding
functionalities. Pyridinophane 5 should possess a larger
cavity than that of cyanocyclophane 3 while keeping the
planarity of the macrocyclic ring.5 It turned out that pyridi-
nophanes 4 and 5 exhibit association and binding behaviors
similar to those of cyanomacrocycle 3.
(1) For reviews: (a) Moore, J. S. Acc. Chem. Res. 1997, 30, 402. (b)
Haley, M. M.; Pak, J. J.; Brand S. C. Top. Curr. Chem. 1999, 201, 81.
(2) (a) Shetty, A. S.; Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1996,
118, 1019. (b) Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1994, 116, 2655.
(c) Vevkataraman, D.; Lee, S.; Zhang, J.; Moore, J. S. Nature 1994, 371,
591. (d) Zhang, J.; Moore, J. S. J. Am. Chem. Soc. 1996, 118, 1019. (e)
Shetty, A. S.; Fischer, P. R.; Stork, K. F.; Bohn, P. W.; Moore, J. S. J. Am.
Chem. Soc. 1996, 118, 9409.
(3) (a) Ho¨ger, S.; Enkelmann, V. Angew. Chem., Int. Ed. Engl. 1995,
34, 2713. (b) Morrison, D. L.; Ho¨ger, S. Chem. Commun. 1996, 2313. (c)
Ho¨ger, S.; Meckenstock, A.-D.; Mu¨ller, S. Chem. Eur. J. 1998, 4, 2423.
(d) Ho¨ger, S.; Meckenstock, A.-D. Chem. Eur. J. 1999, 5, 1686.
(4) (a) Tobe, Y.; Utsumi, N.; Kawabata, K.; Naemura, K. Tetrahedron
Lett. 1996, 37, 9325. (b) Tobe, Y.; Utsumi, N.; Nagano, A.; Naemura, K.
Angew. Chem., Int. Ed. 1998, 37, 1285.
The syntheses of 4 and 5 are outlined in Scheme 1. n-Octyl
ester 6, which was prepared by condensation of dichloro-
citrazinic acid6 with 1-octanol, was converted to the bis-
(5) The diagonal N-N distances of 3 and 5 estimated from their AM1-
optimized structures are 11 and 15 Å, respectively. The corresponding
distance of 4 is 10 Å.
(6) Aoki, K. Yakugaku Zasshi 1953, 73, 969.
10.1021/ol006318d CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/27/2000

Scheme 1a
a (i) Trimethylsilylacetylene, Pd2(dba)3‚CHCl3, CuI, Ph3P, Et3N, 70 °C, 94%; (ii) K2CO3, H2O, THF, rt, 36%, fully deprotected compound
isolated in 37%; (iii) CuCl, TMEDA, O2, acetone, rt, 90%; (iv) K2CO3, H2O, THF, rt ,10 45% 11 38%; (v) NBS, AgNO3, acetone, rt, 80%;
(vi) CuCl, TMEDA, O2, acetone, rt, 89%; (vii) K2CO3, H2O, THF, rt, 80%; (viii) Cu(OAc)2, pyridine, benzene, rt, 50%; (ix) Pd2(dba)3‚CHCl3,
CuI, (furyl)3P, pentamethylpiperidine, benzene, rt, 38%; (x) Bu4NF, AcOH, H2O, THF, rt, 80%; (xi) Cu(OAc)2, pyridine, benzene, rt, 29%.
R is n-octyl group.
(trimethylsilyl)ethynyl derivative 7 by Sonogashira coupling.7
Removal of the TMS group gave singly deprotected com-
pound 8 (36%) together with doubly deprotected compound
(37%) and unreacted 7 (19%) which were cleanly separated
3266
Org. Lett., Vol. 2, No. 21, 2000

by silica gel chromatography. Oxidative coupling8 of 8
afforded dimer 9 which was treated with potassium carbonate
to give partially deprotected 10 (45%), thoroughly depro-
tected 11 (38%), and recovered 9 (12%). Oxidative coupling8
of 10 afforded linear tetramer 13, and removal of the TMS
group gave 14. Intramolecular oxidative coupling of 14 under
high dilution conditions by Eglinton’s method9 yielded cyclic
tetramer 4 in 50% yield. Palladium-catalyzed heterocou-
pling10 of dibromide 12, prepared by bromination of 11 with
NBS, with 2 equiv of 10 gave linear hexamer 15. Depro-
tection of 13 gave unstable hexamer 16 which was subjected
to intramolecular coupling to furnish cyclic hexamer 5 in
29% yield.
having the same macrocyclic ring size as shown in Figure
2. The chemical shift change of 4 shown in Figure 2 was
Pyridinophanes 4 and 5 did not show concentration
1
dependence in the H NMR spectra in CDCl3 (10-2-10-4
M), indicating that these did not tend to self-associate. This
is probably due to the electrostatic repulsion between the
nitrogen atoms,4b as indicated by the electrostatic potential
plot (Figure 1) based on the AM1 method for the respective
Figure 2. 1H NMR titration of 4 and 5 with metacyclophanes 1
and 2 in CDCl3 at 30 °C following the chemical shift change of
the aromatic protons of 4 and 5: 2, 4 and 2; 4, 4 and 1 with a
theoretical curve obtained by nonlinear least-squares analysis; b,
5 and 1; O, 5 and 2.
analyzed by assuming the formation of homodimer of 1 with
a known dimerization constant of K1 (26 M-1 at 30 °C)4
and of heterodimer 1‚4 with an association constant of K2.
The nonlinear least-squares approximation yielded K2 of 72
M-1. In the case of heteroassociation between hexamers 2
and 5, however, similar treatment of the experimental data
did not give a good fit. This means that the tetramers 1 and
4 form a dimer 1‚4 mainly whereas the hexamers 2 and 5
aggregate to form dimer 2‚5 and higher aggregates.12
A
similar tendency to form higher aggregates was observed in
the hetetoaggregation between hexamer 2 and its cyano
derivative 3.4b By contrast, the chemical shifts of the aromatic
protons of 4 and 5 did not change upon addition of 2 and 1,
respectively, having different macrocyclic ring size as shown
in Figure 2. We assume that the driving force for the
heteroaggregate formation is dipole-dipole interaction be-
tween the pyridine rings of 4 and 5 and the benzene rings of
1 and 2.13 Since the dipoles of the individual aromatic ring
are arranged along the periphery of the planar macrocycle,
the macrocycles have no or, if any, little dipole moment.
Accordingly, the overall interaction between pyridinophanes
4 and 5 and cyclophanes 1 and 2 is similar to the
quadrupole-quadrupole interaction between the aromatic
rings substituted by electron-donating and -accepting groups.14
Such interaction should be sensitive to the shape of the
interacting molecules because the mutual overlap of the rings
Figure 1. Electrostatic potentials between -19 (red) to 20 (blue)
kcal/mol on the van der Waals molecular surface of the model
compounds 17 and 18 according to the AM1 calculations.
model compounds 17 and 18 for the tetramers 1 and 4.11 On
the other hand, the aromatic protons of 4 and 5 moved upfield
on addition of the corresponding metacyclophanes 1 and 2
(7) For a review, see: Sonogashira, K. ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp 521-
549.
(8) Hay, A. S. J. Org. Chem. 1962, 27, 3320.
(9) (a) Eglinton, G.; Galbraith, A. R. Proc. R. Chem. Soc. 1957, 350.
(b) Behr, O. M.; Eglinton, G.; Galbraith, A. R.; Raphael, R. A. J. Chem.
Soc. 1960, 3614.
(10) Cai, C.; Vasella, A. HelV. Chim. Acta 1995, 78, 2053.
(11) The AM1 calculations were performed using the SPARTAN ver.
5.0 program package; Wavefunction, Inc., Irvine, CA.
(12) An attemped nonlinear least-squares analysis of the data assuming
the formation of a heterodimer (with K2) and a heterotrimer (with K3) did
not give a unique solution.
(13) The calculated (AM1) dipole moment of methyl 2,6-diethynyl-
pyridine-4-carboxylate (1.26 D) is pointing from C(4) to the nitrogen atom,
whereas that of methyl 3,5-diethynylbenzoate (0.85 D) is pointing to the
opposite direction, i.e., to the ester group.
Org. Lett., Vol. 2, No. 21, 2000
3267

is essential to the interaction. The stronger tendency of 2
and 5 to form heteroaggregates than that of 1 and 4 is
ascribed to the larger number of the sites of the attractive
interaction.
the latter. It should be pointed out that all of the macrocycles
4, 5, and 3 form not only 1:1 but also 2:1 complexes, though
the structures of those complexes are not known.
In summary, we synthesized butadiyne-bridged pyridino-
phanes 4 and 5 which form heteroaggregates in solution with
the corresponding metacyclophanes 1 and 2 having the same
macrocyclic ring size and are capable of binding tropylium
cation to form 1:1 and 2:1 complexes. Further work on the
construction of supramolecular assemblies using these mo-
lecular units is in progress.
To examine the binding ability of pyridinophanes 4 and 5
toward large organic cations, we selected the tropylium ion
as a guest, even though it seems likely that the cation is
slightly larger than the cavity of 4 but is too small to fit the
cavity of 5. The chemical shift change of the aromatic protons
of 4 and 5 on titration with tropylium tetrafluoroborate in
CDCl3/CD3CN (17:3) at 30 °C was analyzed by assuming
the formation of a 1:1 complex (with K11) and a 2:1 complex
(with K21). The nonlinear least-squares regression analysis
gave K11 and K21 to be 3 × 103 and 3 × 104 M-1 for 4 and
1 × 102 and 4 × 102 M-1 for 5, respectively. The larger
binding constants of 4 than those of 5 are ascribed to the
size of the cavity of the former which fits better than that of
Acknowledgment. This work was supported by Grants-
in-Aid from the Ministry of Education, Science, Sports and
Culture of Japan and Nagase Science Foundation, to which
the authors are grateful.
Supporting Information Available: Experimental pro-
cedure and characterization of compounds 4 and 5. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) (a) Williams, J. H. Acc. Chem. Res. 1993, 26, 593. (b) Cozzi, F.;
Ponzini, F.; Annunziata, R.; Cinquini, M.; Siegel, J. S. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1019. (c) Coates, G. W.; Dunn, A. R.; Henling, L. M.;
Ziller, J. W.; Lobkovsky, E. B.; Grubbs, R. H. J. Am. Chem. Soc. 1998,
120, 3641. (d) Ponzini, F.; Zagha, R.; Hardcastle, K.; Siegel, J. S. Angew.
Chem., Int. Ed. 2000, 39, 2323.
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