Synthesis and self-association of an imine-containing m-phenylene ethynylene macrocycle

Article abstract of DOI:10.1021/jo010918o

The purpose of this study was to test the suitability of the imine bond as a structural unit within the backbone of phenylene ethynylene macrocycles and oligomers by determining the ability of m-phenylene ethynylene macrocycle 1 to form π-stacked aggregates in both solution and the solid state. Macrocycle 1, with two imine bonds, was synthesized in high yield from diamine 4 and dialdehyde 5. The imine-forming macrocyclization step was carried out under a variety of conditions, with the best yield obtained simply by refluxing the reactants in methanol. The self-association behavior of 1 in various solvents was probed by ¹H NMR. The association constants (K_E) in acetoned₆ and tetrahydrofuran-d₈ were determined by fitting the concentration-dependent chemical shifts with indefinite self-association models. The results showed that solvophobically driven intermolecular π-π stacking could be preserved in the imine-containing m-phenylene ethynylene macrocycles. Interestingly, in acetone macrocycle 1 exhibited a stronger tendency to form a dimer rather than higher aggregates. We postulate that this behavior may be due to electrostatic attraction between dipolar imine groups. The solid-state packing of 1 was studied by wide- and small-angle X-ray powder diffraction (WAXD and SAXD). Bragg reflections of 1 were consistent with a hexagonal packing motif similar to our previous studies on m-phenylene ethynylene macrocycles that formed columnar liquid crystal phases.

Full text of DOI:10.1021/jo010918o

3548
J . Org. Chem. 2002, 67, 3548-3554
Syn th esis a n d Self-Associa tion of a n Im in e-Con ta in in g
m -P h en ylen e Eth yn ylen e Ma cr ocycle
Dahui Zhao and J effrey S. Moore*
Department of Chemistry and Material Science & Engineering, University of Illinois,
Urbana, Illinois 61801
moore@scs.uiuc.edu
Received September 11, 2001
The purpose of this study was to test the suitability of the imine bond as a structural unit within
the backbone of phenylene ethynylene macrocycles and oligomers by determining the ability of
m-phenylene ethynylene macrocycle 1 to form π-stacked aggregates in both solution and the solid
state. Macrocycle 1, with two imine bonds, was synthesized in high yield from diamine 4 and
dialdehyde 5. The imine-forming macrocyclization step was carried out under a variety of conditions,
with the best yield obtained simply by refluxing the reactants in methanol. The self-association
behavior of 1 in various solvents was probed by 1H NMR. The association constants (KE) in acetone-
d6 and tetrahydrofuran-d8 were determined by fitting the concentration-dependent chemical shifts
with indefinite self-association models. The results showed that solvophobically driven intermo-
lecular π-π stacking could be preserved in the imine-containing m-phenylene ethynylene macro-
cycles. Interestingly, in acetone macrocycle 1 exhibited a stronger tendency to form a dimer rather
than higher aggregates. We postulate that this behavior may be due to electrostatic attraction
between dipolar imine groups. The solid-state packing of 1 was studied by wide- and small-angle
X-ray powder diffraction (WAXD and SAXD). Bragg reflections of 1 were consistent with a hexagonal
packing motif similar to our previous studies on m-phenylene ethynylene macrocycles that formed
columnar liquid crystal phases.
Sch em e 1
In tr od u ction
The self-organization behavior of a series of discrete
m-phenylene ethynylene oligomers in solution has been
extensively studied in our group.1 These oligomers col-
lapse into helical conformations in polar solvents and in
this conformation are capable of binding nonpolar guests
within the tubular cavity.1a,f,h It has been previously
shown that the folding propensity of the chain, as well
as the binding affinity of the helices, are dependent upon
the oligomer’s chemical structure, chain length, and the
solvent.1 As an extension of these studies, we have begun
to embark on a dynamic combinatorial2,3 approach to
synthesize oligo(m-phenylene ethynylene)s and thereby
identify functional, “masterpiece” sequences.4 It is con-
ceivable that the population of a copolymer library
comprised of oligomers with dynamically diversified chain
length and backbone structures could be biased by folding
in the presence of certain hydrophobic guests or simply
by the folding process itself. To examine this hypothesis,
we have chosen a set of m-phenylene ethynylene oligo-
mers with imine bonds in the backbone. The reversibly
formed imine bond was chosen as the ligation functional-
ity and is envisioned to allow for dynamic sequence
diversity (Scheme 1).5
The imine bond is more flexible than the ethynylene
unit due to its ability to undergo the facile syn-anti
isomerization (Scheme 2).6 The incorporation of the imine
bond into the oligomer backbone should diminish the
rigidity of the chain by introducing additional conforma-
tional freedom. This may result in the decreased stability
of the folded conformation for imine-containing oligomers
by compromising the π-π stacking propensity of the
backbone and/or increasing the number of conformational
(1) (a) Nelson, J . C.; Saven, J . G.; Moore, J . S.; Wolynes, P. G. Science
1997, 277, 1793. (b) Gin, M. S.; Yokozawa, T.; Prince, R. B.; Moore, J .
S. J . Am. Chem. Soc. 1999, 121, 2643. (c) Prince, R. B.; Saven, J . G.;
Wolynes, P. G.; Moore, J . S. J . Am. Chem. Soc. 1999, 121, 3114. (d)
Prince, R. B.; Brunsveld, L.; Meijer, E. W.; Moore, J . S. Angew. Chem.,
Int. Ed. 2000, 39, 228. (e) Gin, M. S.; Moore, J . S. Org. Lett. 2000, 2,
135. (f) Prince, R. B.; Barnes, S. A.; Moore, J . S. J . Am. Chem. Soc.
2000, 122, 2758. (g) Brunsveld, L.; Prince, R. B.; Meijer, E. W.; Moore,
J . S. Org. Lett. 2000, 2, 1525. (h) Tanatani, A.; Mio, M. J .; Moore, J . S.
J . Am. Chem. Soc. 2001, 123, 1792. (i) Brunsveld, L.; Meijer, E. W.;
Prince, R. B.; Moore, J . S. J . Am. Chem. Soc. 2001, 123, 7978.
(2) 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.
(3) For recent examples of dynamic combinatorial chemistry, see:
(a) Berl. V.; Huc, I.; Lehn, J .-M.; DeCian. A.; Fisher, J . Eur. J . Org.
Chem. 1999, 3089. (b) Baxter, P. N. W.; Khoury, R. G.; Lehn, J .-M.;
Baum, G.; Fenske, D. Chem. Eur. J . 2000, 6, 4140. (c) Otto, S.; Furlan,
R. L. E.; Sanders, J . K. M. J . Am. Chem. Soc. 2000, 122, 12063. (d)
Furlan, R. L. E.; Cousins, G. R. L.; Sanders, J . K. M. Chem. Commun.
2000, 1761. (e) Star, A.; Goldberg, I.; Fuchs, B. Angew. Chem., Int.
Ed. 2000, 39, 2685.
(4) Moore, J . S.; Zimmerman, N. W. Org. Lett. 2000, 2, 915.
(5) To´th, G.; Pinte´r, I.; Messmer, A. Tetrahedron Lett. 1974, 735.
(6) (a) Padwa, A. Chem. Rev. 1977, 77, 37. (b) Layer, R. W. Chem.
Rev. 1963, 63, 489.
10.1021/jo010918o CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/18/2001

Imine-Containing m-Phenylene Ethynylene Macrocycle
J . Org. Chem., Vol. 67, No. 11, 2002 3549
F igu r e 1. Schematic diagram depicting (a) the intermolecular association of macrocycles and (b) the helical conformation of
oligo(m-phenylene ethynylene)s.
Sch em e 2
states (i.e., the entropy) of the unfolded state. This article
will address the extent to which the incorporation of
imine bonds into the backbone may affect the π-π
stacking of phenylene ethynylene oligomers by examining
the intermolecular association of the analogous macro-
cycles.7
Previous studies have shown that the stability of the
folded helical conformation of m-phenylene ethynylene
oligomers correlates with the strength of the intermo-
lecular association of hexameric macrocycles having the
same backbone structure (Figure 1).7 This observation
is best explained by drawing an analogy between a
macrocycle and one turn within a helix of the linear
oligomer. Hence, macrocycle aggregates may be consid-
ered as a model system for the corresponding oligomers
in the folded conformation. The intermolecular stacking
tendency of macrocycles provides a measure of the
intramolecular folding propensity of oligomers having a
On the other hand, increasing attention has been drawn
to macrocycles containing the imine bond as the backbone
linkage, either due to their self-assembled cyclic structure
by virtue of imine condensation10 or to their unique
similar architecture. Therefore, by comparing the ag-
double helical motifs upon coordination of transition
gregation behavior of the imine-containing macrocycles
metals.11 In view of these interesting potential properties,
to macrocycles without imine bonds, we may expect to
the synthesis and characterization of 1 by itself is worth
pursuing.
elucidate the effect of incorporating imine bonds into the
m-phenylene ethynylene backbone. These results may be
(8) For reviews, see: (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.
extrapolated to predict the stability of helical conforma-
tions in imine-containing oligomers. To this end, macro-
cycle 1 was synthesized and its intermolecular aggrega-
tion behavior was investigated and compared with that
of macrocycles 2 and 3, both of which do not contain imine
bonds.
Additionally, there has been intense interest in shape-
persistent arylene ethynylene macrocycles with respect
to their well-defined supramolecular architecture in
solution, solid state, and liquid crystalline mesophase.8,9
(9) For recent examples: (a) Ho¨ger, S.; Enkelmann, V.; Bonrad, K.;
Tschierske, C. Angew. Chem., Int. Ed. 2000, 39, 2268. (b) Henze, O.;
Lentz, D.; Schlu¨ter, A. D. Chem. Eur. J . 2000, 6, 2362. (c) Tobe, Y.;
Nagano, A.; Kawabata, K.; Sonoda, M.; Naemura, K. Org. Lett. 2000,
2, 3265. (d) Nakamura, K.; Okubo, H.; Yamaguchi, M. Org. Lett. 2001,
3, 1097. (e) Ho¨ger, S.; Bonrad, K.; Mourran, A.; Beginn, U.; Mo¨ller, M.
J . Am Chem. Soc. 2001, 123, 5651.
(10) (a) Higuchi, M.; Kimoto, A.; Shiki, S.; Yamamoto, K. J . Org.
Chem. 2000, 65, 5680. (b) Gawron˜ski, J .; Kołbon, H.; Kwit, M.;
Katrusiak, A. J . Org. Chem. 2000, 65, 5768.
(11) Comba, P.; Fath, A.; Hambley. T. W.; Ku¨hner, A.; Richens. D.
T.; Viefort, A. Inorg. Chem. 1998, 37, 4389. (b) Fento, D. E.; Matthews,
R. W.; McPartlin, M.; Murphy, B. P.; Scowen, I. J .; Tasker, P. A. J .
Chem. Soc., Dalton Trans. 1996, 3421.
(7) Lahiri, S.; Thompson, J . L.; Moore, J . S. J . Am. Chem. Soc. 2000,
122, 11315.

3550 J . Org. Chem., Vol. 67, No. 11, 2002
Zhao and Moore
Sch em e 3a
a
Reagents and conditions: (a) trimethylsilylethynylene, Pd2(dba)3, CuI, PPh3, Et3N, 60 ˚C, 20 h; (b) TBAF, THF, rt; (c) Pd2(dba)3, CuI,
PPh3, Et3N, 70 ˚C, 36 h; (d) SnCl2‚2H2O, EtOH, refluxing, 0.5 h; (e) CH3(OCH2CH2)3OH, DEAD, PPh3, THF, rt. Tg ) (CH2CH2O)3CH3.
Ta ble 1. Con d ition s for Ma cr ocycliza tion Rea ction s
wherein the premixed 4 and 5 were heated at 90 °C in
vacuo for 12 h in the absence of any solvent, a mixture
of 1 and higher molecular weight oligomers was formed
(MW ranging from about 2600 to 13 000 as measured by
MALDI-TOF MS and GPC). The yield of macrocycle 1
under these solventless conditions was less than 60% on
solvent
temp
concn, mM
conversion,b %
CDCl3
room temp
room temp
refluxing
refluxing
90 °C
3
3
3
3
no reacn
<10
CDCl3/TFA-da
toluene
<10
methanol
>95c
<60d
1
neat reacn
the basis of H NMR integration.
a
b
Catalytic amount of TFA-d. Conversions of amine and alde-
hyde to imine were calculated on the basis of 1H NMR spectros-
copy. c The yield of 1 after purification by column chromatography
Macrocycle 1 exhibited good solubility in a variety of
solvents and good solution stability in the absence of
water. No aldehyde or amine protons were detected by
1H NMR when the spectrum of 1 was recorded in
chloroform, tetrahydrofuran (THF), acetonitrile, or di-
methyl sulfoxide (DMSO) solution for 3 days. Only a trace
amount of the imine was hydrolyzed into aldehyde and
amine after the sample was exposed to air for 3 months.
However, the imine bond was labile in the presence of
water; when 1 was kept in a DMSO-d6/D2O (1:1) solution
for 3 days, over 80% of the imine bonds were hydrolyzed
d
was 78%. High molecular weight products were also detected by
MALDI-TOF MS and GPC.
Resu lts
The synthesis of macrocycle 1 is outlined in Scheme 3.
The macrocyclization was accomplished through two
successive imine condensation reactions between trimeric
diamine 4 and dialdehyde 5.12 However, the macrocy-
clization of 4 and 5 was initially not successful under a
variety of conditions. When 4 and 5 were reacted under
many typical imine-forming conditions (e.g., in chloro-
form, chloroform with a catalytic amount of trifluoroacetic
acid, or refluxing toluene), the overall conversion of
aldehyde and amine to imine was below 10% based on
1
as shown by the H NMR spectrum.
The aggregation behavior of macrocycle 1 was inves-
1
tigated by H NMR spectroscopy. The spectra of 1 were
recorded at room temperature in a series of solvents
(Figure 2). Eleven distinct resonances were observed in
aromatic region of spectra recorded in CDCl3 and THF-
d8 at room temperature. At constant concentration with
increasing solvent polarity, pronounced upfield shifting
and resonance broadening were observed for the aromatic
protons and the imine proton (-CHdN-, δ ) 8.69 ppm
in CDCl3). The magnitude of upfielding shifting and
resonance broadening correlated with increasing polarity
of the solvent.
1
the H NMR spectra of the resulting mixtures (Table 1).
In contrast, a high yield of macrocycle 1 was obtained
by refluxing stoichiometric amounts of 4 and 5 in
methanol for 20 h. A 1H NMR spectrum of the crude
product showed that conversion to macrocycle 1 had
proceeded to over 95% completion, with no observable
side products. Under these conditions no oligomeric
products of a molecular weight higher than that of
macrocycle 1 were detected by MALDI-TOF MS, even
when the stoichiometry of 4 and 5 was not strictly
controlled. In contrast, under neat reaction conditions
Besides solvent polarity, the chemical shifts of the
aromatic protons and the imine proton were also sensitive
to the concentration of the macrocycle. In a given solvent,
as the concentration of 1 increased, similar upfield
shifting and resonance broadening was observed. The
chemical shifts of the aromatic protons and the imine
proton were measured at room temperature as a function
of concentrations in acetone-d6 (Figure 3) and THF-d8
(Figure 4).13 The data were first analyzed using a
(12) Reversible imine formation and exchange reactions have been
described with other systems: (a) Cantrill, S. J .; Rowan, S. J .; Stoddart,
J . F. Org. Lett. 1999, 1, 1363. (b) Rowan, S. J .; Stoddart, J . F. Org.
Lett. 1999, 1, 1913. (c) Ro, S.; Rowan, S. J .; Pease, A. R.; Cram, D. J .;
Stoddart, J . F. Org. Lett. 2000, 2, 2411.

Imine-Containing m-Phenylene Ethynylene Macrocycle
J . Org. Chem., Vol. 67, No. 11, 2002 3551
F igu r e 2. Aromatic region of 1H NMR spectra (500 MHz) of 1, at room temperature and a concentration of 3 mM, in a series of
solvents: (a) CDCl3, (b) THF-d8, (c) acetone-d6, (d) CD3CN, and (e) DMSO-d6.
F igu r e 4. Plot of chemical shift vs log [concentration/(mg/
F igu r e 3. Plot of chemical shift vs log [concentration/(mg/
mL)] in THF-d8 (b, imine H of 1; 2, aromatic H of 1; 9,
mL)] in acetone-d6 at room temperature (b, imine H of 1; 2,
aromatic H of 2 as previously reported).7 The curves represent
aromatic H of 1; 9, aromatic H of 2). The curves represent
the best fit of the experimental data to the isodesmic model of
the best fit of the experimental data to the isodesmic model of
indefinite association.
indefinite association.
macrocycle to an aggregate (or another single macrocycle)
nonlinear least-squares regression analysis in Math-
is identical (equal K model). Using the same method as
ematica 3.0 and then fitted to an equation derived from
previously described,7 the association constants (KE) of
the isodesmic model of indefinite association.14,15 In this
1 in these two solvents at room temperature were
model it is assumed that the free energy, and thus the
determined (Table 2). It is apparent from Figure 3 that
association constant KE, for successive addition of each
the chemical shift data obtained with acetone-d6 did not
fit the equal K model very well, so a modification to the
(13) For previously studied macrocycle 2, over the concentration
model was applied in which the association constant for
dimerization (K2) was allowed to differ from the associa-
tion constants for forming higher aggregates (KE′). The
1H NMR data were simulated and fitted by nonlinear
least-squares regression analysis using the computer
program Dynafit.16 Using the refined model, a better fit
range available for 1H NMR experiments, the largest chemical shift
change was observed in acetone-d6 with a modest change in THF-d8.
Therefore, acetone-d6 and THF-d8 were chosen as the solvents to
quantitatively compare the association constants of 1 to those of 2 and
investigate the effect of the imine bond on π-π stacking.
(14) Martin, R. B. Chem. Rev. 1996, 96, 3043.
(15) P ) Pmonomer - ∆(1 + (1 - (4KEct + 1)1/2)/(2KEct)) (P is the
observed chemical shift, Pmonomer is the chemical shift of monomer, KE
is the association constant, ct is the molar concentration of the
macrocycle, and ∆ is the chemical shift difference between monomer
and dimer).
(16) The program Dynafit: Kuzmicˇ, P. Anal. Biochem. 1996, 237,
260.

3552 J . Org. Chem., Vol. 67, No. 11, 2002
Zhao and Moore
Ta ble 2. Associa tion Con sta n ts (KE) of Ma cr ocycles
1 a n d 2
KE (M-1
)
1
solvent
imine Ha
aromatic Hb
2c
acetone-d6
THF-d8
3600 ( 1300
220 ( 40
4800 ( 1800
290 ( 50
13 000
350
a
Calculated KE of 1 on the basis of the chemical shift of imine
b
H. Calculated KE of 1 on the basis of the chemical shift of
aromatic H. c Previously reported KE of 2.7
F igu r e 6. UV-vis spectra of 1 in chloroform (s) and aceto-
nitrile (- - -) at a concentration of 2.0 × 10-5 M. The inset
shows the UV-vis spectra of 5 in the same solvents with two
absorbance bands at ca. 290 and 300 nm, corresponding to the
cisoid and transoid states of the oligo(m-phenylene ethynylene)
unit, respectively.
F igu r e 5. Plot of chemical shift vs log [concentration/mM] in
acetone-d6 (b, imine H of 1). The solid curve (s) represents
the best fit of the experimental data to the modified isodesmic
model of indefinite association (K2 ) 12 700 ( 1100 M-1
,
KE′ ) 2570 ( 440 M-1) and the dashed curve (- - -) represents
the best fit to the isodesmic model (KE ) 3600 ( 1300 M-1).
F igu r e 7. WAXD profile of macrocycle 1 at room temperature.
Ta ble 3. X-r a y P ow d er Diffr a ction Da ta of 1
was obtained (Figure 5). The best fits of K2 and KE′ based
on the chemical shifts of imine proton in acetone-d6
solution were 12 700 and 2570 M-1, respectively.
In addition to the concentration study on macrocycle
d-spacing (Å)
obs
calcda
corresponding to
3.6
4.4
12.4
14.3
24.5
aromatic stacking
1
side chain interdigitation
hexagonal lattice (200)
hexagonal lattice (110)
hexagonal lattice (100)
1, a variable temperature (VT) H NMR study was also
12.3
14.1
24.5
conducted in CD2Cl2. The purpose of this study was to
examine the possibility of a dynamic process such as the
conformational isomerism shown along with the chemical
structure of 1. Upfield shifting and broadening of the
aromatic and imine proton resonances was observed as
the temperature was lowered from +20 to -50 °C. Thus
we are not able to conclude if conformational isomerism
is slowing down at low temperature.
UV-vis absorbance spectra of macrocycle 1 were
recorded in chloroform and acetonitrile at a concentration
of 2.0 × 10-5 M. Only one dominant absorbance band
with a λmax at ca. 290 nm was observed for 1 independent
of the solvent utilized, while two distinct λmax were
observed for the open chain trimeric precursor 5 (Figure
6). This is consistent with the all-cisoid state of the cyclic
phenylene ethynylene backbone of 1.1a
Macrocycle 1 is an off-white, waxy solid at room
temperature. Although no discernible phase transition
was identified by differential scanning calorimetry (DSC)
between -100 and +200 ˚C, 1 showed strong birefrin-
gence under plane polarized light. The birefringence
persisted upon heating from 25 to 270 °C, where 1 began
to decompose. In addition, the solid-state packing of 1
was probed by X-ray powder diffraction. The X-ray
a
Based on hexagonal lattice with a lattice parameter a )
28.3 Å.
samples were prepared using a solvent-evaporation
method previously described.17 Wide- and small-angle
X-ray diffraction (WAXD and SAXD) profiles of 1 were
collected at room temperature (Figure 7). The d-spacing
data derived from WAXD Bragg reflections are listed in
Table 3. The SAXD profile gave one peak corresponding
to a d-spacing value of 25.0 Å, in agreement with the
lowest angle reflection observed by WAXD.
Discu ssion
Although the cyclic structure of 1 precludes the syn
conformation of the imine bond, a concerted rotation
around the relatively flexible phenylene-imine-phen-
ylene linkage would allow the macrocycle to experience
a double inversion, that is, to isomerize between two
equivalent conformers assuming that a nearly planar
(17) Mio, M. J .; Prince, R. B.; Moore, J . S.; Kuebel, C.; Martin, D.
C. J . Am. Chem. Soc. 2000, 122, 6134.

Imine-Containing m-Phenylene Ethynylene Macrocycle
J . Org. Chem., Vol. 67, No. 11, 2002 3553
conformation is the most stable state. Many of the
conformational states occurring during this inversion
process would not be planar, possibly compromising the
stacking ability of the macrocycle. This would result in
the observed decreased self-association constant of 1
relative to 2. Macrocycles experiencing nonplanar con-
formations would be expected to have a diminished
results of 1 in THF and macrocycle 2 in both acetone and
THF are well-described by the isodesmic model, a good
fit using this model could not be obtained for macrocycle
1 in acetone (Figure 3). This suggested that a different
type of self-association was being exhibited by 1 in
acetone, and thus a different model would be needed.
Previous reports have suggested that a modification
to the isodesmic model, in which the association constant
of dimerization (K2) is allowed to vary from the subse-
quent higher order association constants (i.e., all subse-
quent KE′s, which are assumed to be equal), may provide
a viable alternative when the isodesmic model fails.14 In
this new model, a K2 larger than KE′ represents a tight
dimerization followed by weaker isodesmic association
to form higher aggregates. On the other hand, a smaller
K2 indicates a disfavored dimerization followed by stron-
ger isodesmic association (essentially cooperative ag-
gregation). Our efforts to fit the chemical shift data of 1
in acetone-d6 solution to this alternative model using the
program Dynafit16 gave better agreement of the data to
the new model over the entire range of concentration that
was studied (Figure 5). Interestingly, the best fit K2
(12 700 M-1) was approximately 5 times larger than KE′
(2570 M-1). Although there have been reports of systems
1
stacking propensity.14 The H NMR spectra were care-
fully examined to investigate these potential conforma-
tional dynamics. Since only 11 distinct aromatic reso-
nances, including that of the imine proton, were observed
for macrocycle 1 at room temperature, it is suggested that
this crankshaft-like rotation was occurring rapidly in
solution on the NMR time scale. To investigate the time
scale of this interconversion, variable temperature 1H
NMR experiments were conducted in CD2Cl2. At low
temperatures, it was thought that the macrococyle might
become locked in a planar conformation, resulting in
some of the aromatic resonances splitting due to the
differentiated chemical environments of the protons.
Unfortunately, aggregation was observed as the temper-
ature was decreased, as evidenced by the upfield shifting
and line broadening of the resonances. It was thus not
possible to verify the existence of the isolated planar
macrocyclic conformation.
14
which exhibit a K2 larger than KE′ none of these sys-
Upfield shifting in 1H NMR spectra has been well-
documented as a signature of aromatic stacking interac-
tions.14,18 Previously in our laboratory it was demon-
strated that macrocycles 2 and 3, both of which have been
proven by vapor pressure osmometry to form intermo-
lecular aggregates in solution, experienced significant
upfield shifting of their aromatic protons in polar sol-
vents.7,19 This indicated that the π-π stacking interaction
between phenylene ethynylene units is sensitive to
tems have demonstrated such a significant magnitude
of difference between K2 and KE′ when both K2 and KE′
have substantial absolute values.
For neutral molecules without a significant steric
hindrance, like our macrocycle, a K2 smaller than KE′ is
usually expected and predominantly observed.14 This may
be attributed to the extra entropy expense involved in
dimerization. On the other hand, when K2 is found to be
larger than KE, steric hindrance related to further
association to the dimeric form or electrostatic repulsion
in charged molecules have been postulated as possible
reasons why a smaller KE′ is observed.14 However, neither
of these explanations satisfied our system here. A new
rational explanation was needed to account for the
peculiar, nonintuitive self-association behavior of mac-
rocycle 1. As previously demonstrated in our laboratory,
macrocycle 2 with a backbone exclusively composed of
phenylene ethynylene units followed the self-association
behavior predicted by the isodesmic model. The only
structural difference between macrocycles 1 and 2 is that
a pair of ethynylene units in 2 have been replaced by
polar imine bonds in 1. Along with this structural change,
a dipole moment is introduced into the originally apolar
framework.21 A pair of macrocycles with dipole moments
within their skeleton may prefer to orient in a certain
direction relative to each other when dimerizing, most
likely stacking in an antiparallel orientation with regard
to the -CHdN- units (Figure 8). If this hypothesis is
valid, the symmetry of the dimer would diminish or even
eliminate the charge separation, leading to the observed
weakness of the higher order association following the
tight dimerization.20,22
1
solvent polarity. H NMR spectra of macrocycle 1 dis-
played a similar solvent dependent upfield shifting and
resonance broadening, indicating that the macrocycle was
aggregating in solution and that the extent of self-
association was dependent upon the solvent polarity.20
The chemical shifts of 1 in a given solvent were also
sensitive to the macrocycle concentration, consistent with
increased intermolecular aggregation at higher concen-
tration.
The association constants obtained from the nonlinear
least-squares regression analysis in Mathematica were
fairly large (Table 2). Although the association constants
of 1 were smaller compared to those of macrocycle 2 in
the same solvent,7 the significant absolute values of KE
indicated that aggregation was occurring. Thus, the most
important conclusion is that imine bond does not severely
1
disrupt π-stacking. Surprisingly, although the H NMR
(18) (a) Pople, J . A. J . Chem. Phys. 1956, 24, 1111. (b) J ohnson, C.
E., J r.; Bovey, F. A. J . Chem. Phys. 1958, 29, 1012. (c) Giessner-Prettre,
C.; Pullman, B. Biopolymers 1976, 15, 2277. (d) Abraham, R. J .; Fell,
S. C. M.; Smith, K. M. Org. Magn. Reson. 1977, 9, 367. (e) Hamuro,
Y.; Geib, St. J .; Hamilton, A. D. J . Am. Chem. Soc. 1997, 119, 10587.
(19) Shetty, A. S.; Zhang, J .; Moore, J . S. J . Am. Chem. Soc. 1996,
118, 1019.
(20) Imine units brought into close vicinity of one another in dimeric
form may facilitate the imine metathesis/exchange reaction as shown
in Scheme 1. However, according to ref 5, we do not expect the reaction
to take place at an observed rate under the conditions of the NMR
experiments. Moreover, when macrocycle 1, at a concentration of 5
mM in CD3CN where 1 is proven to form aggregates, was treated with
catalytic amount of acid, the conditions under which the imine
metathesis/exchange reaction has been both reported5 and proven by
our independent study to proceed properly at room temperature, no
higher molecular weight product was observed by MALDI-TOF mass
spectroscopy. The high stability of 1 may result from the optimal planar
conformation of the hexameric macrocycle for aggregation.
Our previous studies on macrocycle 3, which has a disc-
shaped backbone and alkyl side chains, exhibited an
(21) Bulgarevitch, S. B.; Adamova, S. I.; Polunin, A. A.; Kogan, V.
A.; Osipov, O. A. Zh. Obshch. Khim. 1977, 47, 1144.
(22) Results from crystallographic data search on aromatic imines
from the Cambridge Structural Database (CSD) supported out hy-
pothesis by showing that in the solid state aromatic imines exhibit a
preference to be aligned with phenyl rings intermolecularly stacked
face-to-face and imine units oriented antiparallel with respect to one
another.

3554 J . Org. Chem., Vol. 67, No. 11, 2002
Zhao and Moore
F igu r e 8. Representative stacking orientation of macrocycle 1 in a dimer (left, antiparallel orientation; right, parallel orientation).
ordered columnar mesophase with a slightly offset hex-
ynylene macrocycle was proposed to be responsible for
the uncommon self-association, and the enhanced strength
of dimerization could be derived from an electrostatic
(dipole-dipole) interaction between the two monomeric
components. In the solid state, WAXD and SAXD mani-
fested columnar structures of face-to-face stacked mac-
rocycle 1 packed in a hexagonal lattice, indicating that
in the solid state a nearly planar disc-like shape was
conserved in 1.
The self-association behavior exhibited by 1 in both
solution and the solid state suggests that the imine bond
is compatible with the m-phenylene ethynylene system
and does not significantly interfere with π-π stacking
interactions. Therefore, this functionality is anticipated
to serve as a suitable reversible ligating group enabling
exchange or metathesis reactions among m-phenylene
ethynylene oligomers of various lengths and backbone
structures in order to realize the function-driven synthe-
sis of “masterpiece” sequences. These studies are under
investigation in our laboratory and will be reported in
due course. The interesting self-association behavior of
the macrocycle has also lead us to envision controllable
adjustment of the association strength and folding stabil-
ity of phenylene ethynylene oligomers by manipulating
the orientation of the imine units in the backbone
through sequence design.
agonal packing.23,24 As macrocycles 1 and 3 have similar
1
backbone structures, and H NMR studies have shown
that the imine bond did not preclude the intermolecular
association of the macrocycle in solution, ordered colum-
nar architectures were also considered to be possible for
macrocycle 1 in the solid state. The strong birefringence
shown by 1 when examined under the polarized optical
microscope supported the existence of mesophase order.
More conclusive evidence for an ordered solid-state
structure came from the X-ray powder diffraction studies.
In the WAXD profile of 1, a reflection with a d-spacing
corresponding to the stacking of the macrocycle (3.6 Å)
confirmed that the macrocycles were face-to-face in the
solid state and suggested that the aromatic interaction
was still effective after incorporating the imine bond into
the backbone. Although there is evidence suggesting that
1 undergoes conformational isomerization (crankshaft-
like motion) in solution due to the flexibility of the imine
linkage, the presence of the 3.6 Å d-spacing of the ring-
to-ring distance within a stack, suggests that 1 is forced
to take up a nearly planar conformation when packed in
the solid state. Presumably this is the case for solution
aggregates too. The reflections in the WAXD profile, with
d-spacing values of 24, 14, 12, and 3.6 Å (Table 3), were
also in good agreement with the reflections observed for
3.23,24 The ratio of the first three of these d-spacing values
(1:1/x3:1/2) index to a hexagonal lattice. These observa-
tions indicate that 1 exhibits a hexagonally packed
columnar structure at room temperature.
Ack n ow led gm en t. Fiancial support for this re-
search was provided by the National Science Foundation
(Grant No. CHE 00-91931). This work was also partially
supported by the Petroleum Research Fund (Grant No.
33013-AC7), administered by the American Chemical
Society, and U.S. Department of Energy, Division of
Material Science (Grant No. DEFG02-91-ER45439). D.Z.
thanks the University of Illinois for fellowship as-
sistance, Dr. Matthew J . Mio for conducting X-ray
diffraction experiments, Shreyasi Lahiri for providing
macrocycle 2, and Ned W. Zimmerman for reading the
manuscript. We thank Naveen Nathan for the design
of the cover art.
Con clu sion s
m-Phenylene ethynylene macrocycle 1 with two imine
bonds in its backbone has been synthesized and charac-
terized. The intermolecular π-π stacking and association
ability of macrocycle 1 in solution were probed by 1H
NMR, and it was shown that 1 formed aggregates in
solution and exhibited a favored dimer formation process
followed by weakened strength in the subsequent as-
sociation steps to form higher aggregates. The dipole
moment present in this imine-containing phenylene eth-
Su p p or tin g In for m a tion Ava ila ble: Text describing the
syntheses and NMR and MS data of 4-12 and 1 and the
method used to fit 1H NMR data to the nonequal K model.
This material is available via the Internet at http://pubs.acs.org.
(23) Zhang, J .; Moore, J . S. J . Am. Chem. Soc. 1994, 116, 2655.
(24) Mindyuk, O. Y.; Stetzer, M. R.; Heiney, P. A.; Nelson, J . C.;
Moore, J . S. Adv. Mater. 1998, 10, 1363.
J O010918O