Shape-persistent and shape-adaptable macrocycles based on restricted rotation: Studies building toward 'macromolecular playdough'

Article abstract of DOI:10.1055/s-2002-32539

A rigid 48-membered macrocycle 1 was synthesized and studied that comprises two atropisomeric N,N′-diarylnaphthalenediimide building blocks that adopt stable syn and anti conformations due to restricted rotation about two C_aryl-N_imide bonds. The resulting macrocycle maintains three distinct conformations: anti/anti; syn/anti and syn/syn conformers that are stable and separable at room temperatures, and each with distinct shapes and sizes as measured by GPC. At elevated temperatures, macrocycle 1 was conformationally flexible and showed interconversion of the respective isomers. Conformational preferences established at higher temperatures were preserved on cooling to room temperature as the restricted rotation was reestablished and the macrocycle becomes conformationally rigid.

Full text of DOI:10.1055/s-2002-32539

PAPER
1239
Shape-Persistent and Shape-Adaptable Macrocycles Based on Restricted
Rotation: Studies Building Toward ‘Macromolecular Playdough’
Shape-Persistent
a
o
nd
S
hape-A
d
n
aptable Mac
g
rocycles
B
ase
d
on
S
Restricte
d
Rot
.
ation Chong, Ken D. Shimizu*
Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC 29208, USA
E-mail: shimizu@mail.chem.sc.edu
Received 15 April 2002
control of shape has been extended to synthetic molecules
termed ‘foldamers’.6,7
Abstract: A rigid 48-membered macrocycle 1 was synthesized and
studied that comprises two atropisomeric N,N -diarylnaphthalene-
diimide building blocks that adopt stable syn and anti conforma-
tions due to restricted rotation about two Caryl–Nimide bonds. The
resulting macrocycle maintains three distinct conformations: anti/
anti, syn/anti and syn/syn conformers that are stable and separable
at room temperatures, and each with distinct shapes and sizes as
measured by GPC. At elevated temperatures, macrocycle 1 was
conformationally flexible and showed interconversion of the re-
spective isomers. Conformational preferences established at higher
temperatures were preserved on cooling to room temperature as the
restricted rotation was reestablished and the macrocycle becomes
conformationally rigid.
A disadvantage of foldamers is that their shapes are highly
environmentally dependent. Removal of the foldamers
from the promoting environment into another often leads
to conformational changes (unfolding). Our goal has been
to design and study molecules and polymers that combine
the advantages of conformationally flexible and shape-
persistent systems to better control conformation on the
molecular level.8–11 At higher temperatures, the molecules
are conformationally flexible and thus, can be shaped and
molded into specific conformations. On cooling to ambi-
ent temperature, the new conformations can then be
‘saved’ as the molecules becomes rigid and shape-persis-
tent. The entire process is reversible and the molecule can
be shaped and reshaped like ‘molecular playdough’, pro-
viding access to a variety of shapes and therefore of prop-
erties from a single molecular system. This combination
of conformational flexibility and stability was achieved in
our systems via restricted rotation about two Caryl–Nimide
bonds within a rigid N,N-diarylnaphthalene diimide
framework (Figure 1). The rotational barrier is sufficient-
ly high (> 25 kcal/mol), resulting in stable syn and anti
conformations at room temperature that can be thought of
as ‘folded’ and ‘unfolded’ forms of the molecule, respec-
tively. These isomeric forms have been shown to display
very different dipole, solubility, shape, and recognition
properties.8–11 These systems are complementary to the
azobenzene based polymers and macrocycles12,13 that
contain building blocks that can adopt similar convergent
cis and divergent trans conformations that can be
switched via UV irradiation.14–16
Key words: restricted rotation, atropisomerism, foldamers, macro-
cycles, cyclizations, conformation
While covalent synthesis still plays a central role in the
development of new organic materials, it does not cede
complete control over molecular properties. For example,
the synthesis of a molecule with a specific connectivity
can still yield a mixture of conformations and therefore a
mixture of properties. Conformational control offers an
alternative route toward controlling molecular properties.
To describe this process of rationally shaping or molding
a molecule into a specific conformation, we introduce the
term: ‘conformational synthesis.’
The most common method to achieve a ‘conformational
synthesis’ is to synthesize a molecule with a rigid frame-
work. In this manner, traditional covalent synthesis can be
used to directly control molecular shape. Examples of rig-
id molecular systems include rigid-rod polymers,1 molec-
ular clefts,2 and shape-persistent macrocycles3 that all
possess unique shape based properties. Nature, on the oth-
er hand, takes a very different route toward controlling
molecular shape, utilizing flexible macromolecules such
as DNA, proteins, and oligosaccharides that fold up into
the desirable conformations. This strategy has a number
of advantages. First, a greater diversity of properties is
possible from a single molecule or macromolecule. This
leads to the possibility of conformational combinatorial li-
braries.4,5 Second, conformational changes in flexible sys-
tems provide a mechanism to dynamically control the
properties on the molecular level. Recently, this dynamic
Figure 1
Conformational control over these atropisomeric systems
has been demonstrated by exploiting the differences in di-
pole and recognition properties between the two isomers.
For example, heating a bipyridine version of this platform
in the presence of an appropriate guest (a metal ion) fa-
Synthesis 2002, No. 9, 01 07 2002. Article Identifier:
1437-210X,E;2002,0,09,1239,1244,ftx,en;C11902SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

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Y. S. Chong, K. D. Shimizu
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vored the formation of the folded syn-isomer that is more The synthesis of macrocycle 1 (Scheme 1) began with the
proficient in chelating to the metal ion.10 A unique feature construction of aniline 7. First, 4-cyanophenol 3 was alky-
of these systems is that they can maintain or ‘remember’ lated with 1-bromo-octadecane to enhance the solubility
their new conformations even upon removal of the tem- of the eventual macrocycle. This was followed by nitra-
plating guest due to the stability of the isomers.
tion and reduction to yield amine 6. Hydrolysis of nitrile
6 yielded amino acid 7. Condensation of amino acid 7
with the 1,4,5,8-naphthalene dianhydride furnished a mix-
ture diimides syn- and anti-8 that were esterified with pro-
pargyl alcohol via the acid chloride. At this point, the syn
and anti conformers of 2 could be differentiated by their
polarity differences and were separated by flash chroma-
tography.
Up until now, our systems have been restricted to only
two shapes: syn and anti. We report here the extension of
our shape adaptable molecules based on restricted rotation
to systems with more than two shapes. This was accom-
plished by connecting two or more of the atropisomeric
N,N -diaryl naphthalenediimide building blocks together,
potentially yielding 2n conformations. For example, con-
nection of two diimide units yields a molecule with three
unique conformations: syn/syn-, syn/anti-, and anti/anti-1
(Figure 2).17 The shape and size differences in the three
isomeric forms of 1 are further accentuated by its macro-
cyclic structure and rigid bis(alkyne) linkages.
Figure 2 Representation of the three stable conformers of macro-
cycle 1.
The specific molecular constituents of macrocycle 1 are
shown in Figure 3. Macrocycle 1 is comprised of two
N,N -diarylnaphthalenediimide units connected together
by bis(alkyne) linkers. Sanders et al. has reported a large
atropisomeric porphyrin based macrocycle that displays
similar atropisomerism.18 The barrier of rotation, howev-
er, in Sander’s system was less than 25 kcal/mol, and the
individual isomers were unstable at room temperature. By
comparison, the atropisomeric macrocycles 1 based on the
N,N -diaryl-1,4,5,8-naphthalenediimide core have rota-
tional barriers > 25 kcal/mole and therefore are able to
hold their individual shapes and maintain shape-persis-
tence at room temperature.
Scheme 1 (a) CH3(CH2)17Br, K2CO3 [R = (CH2)17CH3]; (b) HNO3;
(c) Pd–C, cyclohexene, reflux; (d) NaOH, EtOH, reflux; (e) dry DMF,
reflux; (f) Oxalyl chloride, CH2Cl2, cat. DMF, reflux; (g) TEA, pro-
pargyl alcohol, CH2Cl2.
The rotational barriers about the Caryl–Nimide bonds in di-
imide 2 were measured kinetically by following the rates
of isomerization of the pure syn and anti isomers in chlo-
roform at 64 °C. From the observed half-life of both iso-
mers (11 h at 64 °C), a rotational barrier of 27.2 kcal/mol
was calculated, which corresponds to a half-life of 93 days
at 23 °C.19 This relatively high barrier of rotation is inte-
gral to the design of this system to form room temperature
stable conformational isomers.
Conformational assignments of stable isomers of macro-
cyclic precursors 2 were initially made on the basis of
their polarity differences as measured by TLC. This meth-
od has been successful in assigning other atropisomeric
systems including tetraaryl porphyrins20 and also other
N,N -diaryl diimide systems.21 Thus, the convergent syn-2
was assigned as the more polar isomer (lower Rf), as it
was expected to have a larger dipole moment due to its
convergent symmetry. Corroboration for this TLC-based
assignment was provided by observation that the higher Rf
(anti-2) was preferred under equilibration conditions in an
apolar solvent such as toluene (63:47, anti-2/syn-2) pre-
sumably due to its smaller dipole moment.9 In contrast,
heating in a more polar solvent such as DMSO does not
allow expression of the different dipole moments of the
isomers (50:50, anti-2/syn-2).
Figure 3 The three stable conformers of macrocycle 1.
Synthesis 2002, No. 9, 1239–1244 ISSN 0039-7881 © Thieme Stuttgart · New York

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Shape-Persistent and Shape-Adaptable Macrocycles Based on Restricted Rotation
1241
Macrocyclization of dialkyne 2 (Scheme 2) was carried
out under high dilution (0.002 M) using a large excess of
CuCl and Cu(OAc)2. The isomers of 2 were sufficiently
stable to allow macrocyclization with a minimal degree of
isomerization. When the macrocyclization was carried out
using the convergent syn-2, the syn/syn-macrocycle 1 was
formed in 40% yield. A small amount of syn/anti-1 (5%)
was also isolated presumably from isomerization of the
macrocyclic precursor 2 from syn to anti over the long
course of the reaction (1 week). Macrocyclization of the
divergent anti-2 under identical conditions yielded a dif-
ferent atropisomeric macrocycle (anti/anti-1) in much
lower yield (15%) along with 7% of syn/anti-1. The lower
yield of the macrocyclization of anti-2 is most likely due
to the ring strain of the anti/anti isomer (vide infra), which
requires bridging from one side of the naphthalene diim-
ide surface to the other. Thus, the observed lower yield of
the anti-2 versus syn-2 yields further corroboration for the
correct assignment of the macrocyclic precursors.
Figure 4 Two-dimensional TLC of a mixture of atropisomers of
macrocycle 2. The TLC was first run in the vertical direction, heated
for 5 min at 250 °C and then run in the horizontal direction.
terconversion, and therefore, this method was particularly
useful in identifying related atropisomers in a crude reac-
tion mixture.
The relative thermodynamic stability of the three isomeric
macrocycles was determined by equilibrating the macro-
cycles at 110 °C in toluene, cooling to room temperature
and measuring the isomeric ratio by 1H NMR in CDCl3. A
52:37:11 (syn/syn to syn/anti to anti/anti) equilibrium ra-
tio was observed. The greater stability of the syn contain-
ing structures in apolar solvents was opposite to the trend
observed for acyclic diimide 2, in which the anti-isomer
was favored. A possible explanation for the greater stabil-
ity of the syn containing isomers of macrocycle 1 is the
conformational constraints generated by its macrocyclic
structure that generates ring strain in the anti containing
structures. Molecular modeling (MM2) was able to repli-
cate the stability trend of the three isomers. The effect ap-
pears to be similar to that observed for alkenes in cyclic
and acyclic systems. In acyclic systems, trans-alkenes are
more stable; whereas, in small cyclic systems cis-alkenes
are more stable. An observation that was consistent with
the premise that the stabilities of the isomers of macrocy-
cle 1 were governed more by ring strain than differences
in dipole moments was that the isomeric ratio in 1, unlike
in the macrocyclic precursors 2, was relatively solvent in-
dependent.
Scheme 2 (a) CuCl, Cu(OAc)2, pyridine, DMF, 1 week; (b) tolue-
ne, reflux, 4 h.
Further characterization of the three stable isomers was
made by NMR, MS, and GPC studies. All three com-
pounds had the same molecular weight, 2258 au, howev-
er, they could be easily differentiated by the symmetries
The atropisomeric relationship between the three macro-
cyclic compounds was established by demonstrating that
the compounds all interconverted on heating. A particu-
larly illustrative study, in this respect, was two-dimen-
sional TLC (Figure 4). The isomers were first separated
on a square TLC plate into the three conformers. The iso-
mers were well separated, with the syn/syn being the most
polar (lowest Rf) followed by the syn/anti and finally the
least polar anti/anti (highest Rf).14,22 The plate was then
heated to re-isomerize the conformers and then allowed to
run in the perpendicular direction. This gave a total of
nine spots, including six new ‘cross peaks’. A control
two-dimensional TLC conducted without heating, for
comparison, yielded only the spots on the diagonal. The
appearance of spots off of the diagonal is indicative of in-
1
of their respective H NMR spectra (Figure 5). The syn/
syn and anti/anti have identical atropisomeric units, and
therefore has higher symmetry than the syn/anti isomer
that has two sets of aromatic peaks.
Finally, the atropisomers of macrocycle 1 were character-
ized by GPC. Despite the identical molecular weights of
all three macrocycles, GPC analysis was able to differen-
tiate the isomers with respect to their hydrodynamic vol-
umes (Figure 6). Based on their elution order, the syn/syn-
1 was the largest and the anti/anti-1 the smallest. The rel-
ative differences in the GPC estimated molecular weights
were about 15% between the syn/anti-1 and either the
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Y. S. Chong, K. D. Shimizu
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Figure 5 1H NMRs of the atropisomers of macrocycle 1 in CDCl3.
Figure 7 CPK renditions of the MM2 minimized structures of the
atropisomers of macrocycle 1 syn/syn (top), anti/anti (bottom left)
and syn/anti (bottom right). The octadecyl chains have been omitted
for viewing clarity.
1H NMR and 13C NMR spectra were performed on a Varian: Mer-
cury 300 MHz NMR spectrometer, Varian: Mercury 400 MHz
NMR spectrometer, and a Varian: Inova 500 MHz NMR spectrom-
eter. Peak intensities were determined using the standard deconvo-
lution routine in the Varian VNMR 6.1B software. Visual
inspection of the difference mode spectra (simulation/data) was
used to test fit. Infared spectra were performed on a Perkin Elmer
1600 series FT-IR spectrometer using NaCl plates. Mass spectra
were performed on a Finnigan 4521C system using a GC probe for
volatile samples and a solid probe for nonvolatile samples. High
resolution mass spectroscopy (HRMS) was performed on a VG
705Q spectrometer. Matrix-assisted laser desorption–ionization
(MALDI) FTMS spectra were performed on a Bruker FTMS mass
spectrometer. Elemental analysis was performed by Atlantic Micro-
lab, Inc. Gel permeation chromatography was performed on a Wa-
ters Styragel HR-4E (7.8 300 mm) column using HPLC grade
CHCl3, at a rate of 1 mL/min, with the detector set at 254 nm. Poly-
styrene standards were obtained from Polymer Standards as well as
the PSS Winpc 6 data acquisition and analysis software. All re-
agents were purchased from either Aldrich or Acros and used as re-
ceived.
Figure 6 Overlay of GPC traces of syn/syn-1 (blue), anti/syn-1
(purple), anti/anti-1 (red).
anti/anti-1 or syn/syn-1.23 This verifies both the shape-
persistent properties of the macrocyclic atropisomers and
their apparent differences in shape.
The elution order was consistent with the sizes predicted
by molecular modeling (Figure 7). Overall, the introduc-
tion of each anti-diimide unit introduces a twist into the
macrocycle that reduces its size. The syn/syn-isomer was
clearly the largest with a square inner cavity having a 15
Å separation between naphthalene surfaces. Compounds
anti/syn-1 and anti/anti-1 are very similar in cavity size.
The differences between these isomers are due to orienta-
tion of the four long octadecyl groups (not shown) that
project outward from the macrocyclic framework.
4-Octadecyloxybenzonitrile (4)
The mixture of 4-cyanophenol (10.3 g, 86.7 mmol), 1-bromo-octa-
decane (35 g, 104 mmol), K2CO3 (67 g, 485 mmol) in acetone (500
mL) was heated to reflux for 2 days while stirring vigorously. After
cooling, white solid was removed by filtration, and washed with ac-
etone. The combined filtrate was concentrated and dissolved in
EtOAc. The solution was washed with H2O (2 200 mL) and brine
(1 200 mL). The organic layer was dried (MgSO4). The removal
of solvent in vacuo gave 4.
In conclusion, connecting atropisomeric units together is
a viable method to generate larger structures capable of
more than just two conformations. In this case, the dimer-
ization of two N,N -diarylnaphthalenediimide units gener-
ated a large shape-persistent macrocycle that forms three
stable conformational isomers. Under elevated tempera-
tures, isomerization occurs and the three conformational
isomers interconvert. In this manner, these macrocycles
are shape-adaptable when heated and shape-persistent
when cooled. The three isomers were shown to have
unique polarities, symmetries, NMR chemical shifts, as
well as hydrodynamic volumes, which also assisted in
their conformational assignments.
Yield: 31.7 g (98%); white solid.
FTIR (KBr): 3074, 3048, 2912, 2849, 2558, 2218, 1895, 1607,
1574, 1509, 1473, 1418, 1400, 1373, 1302, 1259, 1172, 1115, 1054,
1035, 1009, 987, 834, 812, 756, 728, 718, 652 cm–1.
1H NMR (300 MHz, CDCl3): = 7.53 (d, J = 8.6 Hz, 2 H), 6.90 (d,
J = 8.5 Hz, 2 H), 3.96 (t, J = 6.4 Hz, 2 H), 1.82–1.23 (m, 32 H), 0.85
(t, J = 6.6 Hz, 3 H).
13C NMR (75 MHz, CDCl3): = 162.5, 133.9, 119.3, 115.2, 103.7,
68.4, 33.93, 32.87, 31.95, 29.73, 29.70, 29.60, 29.56, 29.47, 29.39,
29.35, 29.0, 28.80, 28.21, 25.95, 22.71, 14.13.
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Shape-Persistent and Shape-Adaptable Macrocycles Based on Restricted Rotation
1243
3-Nitro-4-octadecyloxybenzonitrile (5)
chromatography on silica gel (5% MeOH–CH2Cl2) to yield both
To 4 (32.13 g, 86.46 mmol) was added dropwise fuming nitric acid
(35 mL) at 0 °C. The slurry mixture was then stirred at r.t. overnight.
The mixture was poured into ice water. The resulting light yellow
precipitate was filtered and washed with H2O. The precipitate was
dissolved in EtOAc, and washed with sat. aq NaHCO3 and H2O. The
organic layer was dried (MgSO4), and evaporated in vacuo to give
5.
syn-8 and anti-8 isomers.
Yield: 337 mg (55%); light brown solid.
FTIR (KBr): 3441, 2919, 2849, 2036, 1718, 1633, 1512, 1447,
1342, 1281, 1253, 1091 cm–1.
1H NMR (400 MHz, DMSO-d6): = 8.74 (s, 4 H), 8.73 (s, 4 H),
8.05–7.97 (m, 8 H), 7.29 (d, J = 8.8 Hz, 2 H), 7.12 (d, J = 8.4 Hz, 2
H), 4.04 (br s, 4 H), 4.01 (br s, 4 H), 1.45–0.79 (m, 140 H).
Yield: 33.3 g (93%); light yellow solid.
13C NMR (100 MHz, CDCl3): = 162.23, 157.71, 132.69, 131.76,
131.00, 127.11, 126.72, 122.95, 112.01, 68.70, 42.26, 31.66, 29.44,
29.39, 29.22, 29.17, 29.09, 28.80, 28.44, 25.39, 13.79.
FTIR (KBr): 3120, 3070, 2954, 2915, 2852, 2236, 1624, 1560,
1539, 1489, 1474, 1350, 1302, 1278, 1170, 964, 930, 906, 835, 764,
716, 674 cm–1.
1H NMR (300 MHz, CDCl3): = 8.11 (d, J = 2.1 Hz, 1 H), 7.77 (dd,
J = 2.1, 8.8 Hz, 1 H), 7.14 (d, J = 8.8 Hz, 1 H), 4.15 (t, J = 6.4 Hz,
2 H), 1.86–1.23 (m, 32 H), 0.86 (t, J = 6.9 Hz, 3 H).
MS (FAB) calcd for C64H86N2O10: 1042.6. Found: 1042.6.
syn/anti-2
To a stirring solution of 8 (600 mg, 0.58 mmol) in CH2Cl2 (20 mL)
was added oxalyl chloride (1 mL, 11.50 mmol) and a few drops of
DMF. It was allowed to reflux for 4 h. The reaction mixture was
then concentrated down in vacuo to yield a yellow solid. It was then
taken up in CH2Cl2 (5 mL) before slow addition of Et3N (2.4 mL,
17.25 mmol) and propargyl amine (1 mL, 2.30 mmol) and allowed
to stir for 2 h. Additional CH2Cl2 (50 mL) was added and washed
with brine (3 50 mL), dried (MgSO4), filtered, and concentrated
down in vacuo to yield a light yellow solid. The crude product was
purified by column chromatography on silica gel (pure CH2Cl2) to
yield two isomers: the higher Rf anti-1 (187.9 mg, 29%) and the
lower Rf syn-2 (142.2 mg, 22%).
13C NMR (100 MHz, CDCl3): = 155.5, 139.7, 137.4, 129.6, 116.9,
115.1, 103.8, 70.6, 32.1, 29.87, 29.83, 29.71, 29.63, 29.54, 29.34,
28.82, 25.89, 22.87, 14.3.
HRMS (EI) calcd for C15H40N2O3: 416.3039. Found: 416.3043.
3-Amino-4-octadecyloxybenzonitrile(6)
To a solution of 5 (0.62 g, 1.48 mmol) in EtOH (80 mL) was added
cyclohexene (6 mL, 59 mmol) and 10% Pd/C (0.054 g, 0.51 mmol).
The mixture was heated to refluxed overnight while stirring vigor-
ously. After cooling, the reaction mixture was filtered and washed
with EtOAc. The filtrate was collected and concentrated to give 6.
Yield: 0.57 g (99%); light yellow solid.
syn-2
FTIR (KBr): 3490, 3382, 2920, 2845, 2216, 1718, 1618, 1590,
1542, 1513, 1458, 1438, 1396, 1342, 1298, 1239, 1143, 1080, 1020,
953, 852, 807, 792, 754, 726, 670, 620 cm–1.
1H NMR (300 MHz, CDCl3): = 7.01 (dd, J = 2.0, 8.3 Hz, 1 H),
6.89 (d, J = 2.0 Hz, 1 H), 6.75 (d, J = 8.3 Hz, 1 H), 4.00 (t, J = 5.5
Hz, 2 H), 1.83–1.24 (m, 32 H), 0.87 (t, J = 6.9 Hz, 3 H).
FTIR (KBr): 3444, 2922, 2844, 1717, 1678, 1611, 1578, 1506,
1450, 1339, 1278, 1244, 1233, 1194, 1117, 983, 767 cm–1.
1H NMR (300 MHz, CDCl3): = 8.83 (s, 4 H), 8.21 (dd, J = 2.2, 8.8
Hz, 2 H), 8.04 (d, J = 2.2 Hz, 2 H), 7.13 (d, J = 8.8 Hz, 2H), 4.88 (d,
J = 2.5 Hz, 4H), 4.06 (t, J = 6.6 Hz, 4 H), 2.49 (t, J = 2.5 Hz, 2 H),
1.73–1.09 (m, 64 H), 0.86 (t, 6.7 Hz, 6 H).
13C NMR (100 MHz, CDCl3): = 149.8, 136.9, 123.5, 119.8, 116.7,
110.9, 103.8, 68.7, 32.1, 29.9, 29.8, 29.7, 29.5, 29.2, 26.2, 22.9,
14.3.
13C NMR (75 MHz, CDCl3): = 164.87, 162.52, 158.74, 133.26,
132.14, 131.51, 127.63, 127.22, 123.77, 122.40, 112.67, 77.97,
75.26, 69.25, 52.62, 32.14, 29.92, 29.71, 29.65, 29.58, 29.27, 28.88,
25.85, 22.90, 14.33.
HRMS (FAB) calcd for C25H42N2O: 386.3297. Found: 386.3299.
MS (FAB) calcd for C70H90N2O10: 1118.7. Found: 1118.7.
3-Amino-4-Octadecyloxybenzoic Acid (7)
Anal calcd for C70H90N2O10: C, 75.10; H, 8.10; N, 2.50. Found: C,
75.56; H, 8.25; N, 2.30.
To a stirring solution of 6 (7.61 g, 19.69 mmol) in ethylene glycol
(50 mL) was added NaOH (3.94g, 98.44 mmol) and the mixture was
allowed to reflux for 30 h. The reaction mixture was then precipitat-
ed out of aq HCl (1 N; 300 mL), filtered, and dried in vacuo to give
7. The product was used without further purification.
anti-2
FTIR (KBr): 3444, 2922, 2844, 1717, 1678, 1611, 1578, 1506,
1450, 1339, 1278, 1244, 1233, 1194, 1117, 983, 767 cm–1.
Yield: 7.75 g (97%); light brown solid.
1H NMR (300 MHz, CDCl3): = 8.84 (s, 4 H), 8.22 (dd, J = 2.2, 8.8
Hz, 2H), 8.03 (d, J = 2.2 Hz, 2 H), 7.13 (d, J = 8.8 Hz, 2 H), 4.89 (d,
J = 2.5 Hz, 4 H), 4.06 (t, J = 6.3 Hz, 4 H), 2.49 (t, J = 2.5 Hz, 2 H),
1.69–1.05 (m, 64 H), 0.86 (t, 6.6 Hz, 6 H).
13C NMR (75 MHz, CDCl3): = 164.88, 162.53, 158.71, 133.28,
132.12, 131.53, 127.66, 127.20, 123.82, 122.41, 112.70, 77.98,
75.20, 69.26, 52.61, 32.13, 29.89, 29.69, 29.61, 29.57, 29.23, 28.88,
25.89, 22.89, 14.32.
FTIR (KBr): 3359, 2912, 2845, 2352, 1656, 1516, 1460, 1219,
1080, 1040, 884 cm–1.
1H NMR (300 MHz, DMSO-d6): = 7.23 (d, J = 2.2 Hz, 1 H), 7.16
(dd, J = 2.2, 8.4 Hz, 1 H), 6.80 (d, J = 8.2 Hz, 1 H), 4.85 (br s, 1 H),
3.97 (t, J = 6.5 Hz, 2 H), 1.74–1.14 (m, 32 H), 0.83 (t, J = 6.5 Hz, 3
H).
13C NMR (75 MHz, DMSO-d6):
= 168.31, 149.87, 138.10,
123.62, 119.28, 115.00, 111.02, 68.46, 31.99, 29.72, 29.51, 29.39,
26.18, 22.78, 14.60.
MS (FAB) calcd for C70H90N2O10: 1118.7. Found: 1118.7.
syn/syn-, syn/anti-, and anti/anti-1
HRMS (EI) calcd for C25H43NO3: 405.3243. Found: 405.3236.
To a stirring solution of syn-2 (75 mg, 0.07 mmol) in pyridine (10
mL) and DMF (25 mL) was added CuCl (199 mg, 2.01 mmol) and
Cu(OAc)2 (670 mg, 3.35 mmol) and the mixture was allowed to stir
at r.t. for 7 d. It was then precipitated out of aq HCl (1 N, 200 mL),
filtered, and dried in vacuo to give a brown solid. The crude product
was purified by column chromatography on silica gel (2% MeOH,/
syn/anti-Diimide Diacid 8
To a stirring solution of 7 (500 mg, 1.23 mmol) in DMF (10 mL)
was added 1,4,5,8-tetracarboxylic dianhydride (157.4 mg, 0.59
mmol) and the mixture was allowed to reflux for 18 h. The reaction
mixture was then precipitated out of aq HCl (1 N, 150 mL), filtered,
and dried in vacuo. The crude products were purified by column
Synthesis 2002, No. 9, 1239–1244 ISSN 0039-7881 © Thieme Stuttgart · New York

1244
Y. S. Chong, K. D. Shimizu
PAPER
CH2Cl2) to yield syn/syn-1 (30.0 mg, 40%) and syn/anti-1 (3.7 mg,
5%) as a light yellow solid.
Acknowledgment
This work was supported by research grants from the National Sci-
ence Foundation (DMR 9807470), Petroleum Research Fund
(33328-G7), and the Research Corporation, Research Innovation
Award (#RI0081).
anti/anti-1
FTIR (KBr): 2924, 2849, 1720, 1677, 1613, 1581, 1512, 1448,
1346, 1277, 1250, 1192, 1117, 983, 764, 636 cm–1
1H NMR (300 MHz, CDCl3): = 8.83 (s, 8 H), 8.16 (dd, J = 2.2, 8.8
Hz, 4 H), 7.98 (d, J = 1.9 Hz, 4 H), 7.07 (d, J = 8.8 Hz, 4 H), 4.94
(s, 8 H), 4.01 (t, J = 6.4 Hz, 8 H), 1.60–0.81 (m, 140 H).
13C NMR (125 MHz, CDCl3): = 164.42, 162.24, 158.54, 133.16,
131.97, 131.27, 127.44, 127.02, 123.49, 121.96, 112.42, 73.68,
70.49, 69.01, 52.52, 31.91, 29.68, 29.49, 29.45, 29.35, 29.06, 28.66,
25.63, 22.68, 14.11.
References
(1) Bunz, U. H. F. Chem. Rev. 2000, 100, 1605.
(2) Rebek, J. Jr. Angew. Chem., Int. Ed. Engl. 1990, 29, 245.
(3) Hoger, S. J. Polym. Sci. Pol. Chem. 1999, 37, 2685.
(4) Lehn, J. M. Chem.–Eur. J. 1999, 5, 2455.
(5) Lehn, J. M.; Eliseev, A. V. Science 2001, 291, 2331.
(6) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
(7) Nelson, J. C.; Saven, J. G.; Moore, J. S.; Wolynes, P. G.
Science 1997, 277, 1793.
HRMS (MALDI-FTMS; M + Na+) calcd for C140H176N4O20:
2257.90. Found: 2258.02.
syn/anti-1
(8) Degenhardt, C. F.; Shortell, D. B.; Adams, R. D.; Shimizu,
K. D. J. Chem. Soc., Chem. Commun. 2000, 929.
(9) Choi, D.-S.; Chong, Y. S.; Whitehead, D.; Shimizu, K. D.
Org. Lett. 2001, 3, 3757.
(10) Chong, Y. S.; Smith, M. D.; Shimizu, K. D. J. Am. Chem.
Soc. 2001, 123, 7463.
FTIR (KBr): 2924, 2849, 1720, 1677, 1613, 1581, 1512, 1448,
1346, 1277, 1250, 1192, 1117, 983, 764, 636 cm–1.
1H NMR (300 MHz, CDCl3): = 8.81 (s, 4 H), 8.76 (s, 4 H), 8.17
(dd, J = 2.1, 8.6 Hz, 2 H), 8.15 (dd, J = 2.2, 8.5 Hz, 2 H), 8.01 (d,
J = 2.2 Hz, 2 H), 7.95 (d, J = 2.2 Hz, 2 H), 7.09 (d, J = 8.8 Hz, 2 H),
7.07 (d, J = 9.1 Hz, 2 H), 4.92 (s, 4 H), 4.89 (s, 4 H), 4.04–3.98 (m,
8 H), 1.54–0.82 (m, 140 H).
13C NMR (125 MHz, CDCl3): = 164.62, 164.34, 162.30, 158.61,
158.43, 133.06, 132.01, 131.34, 131.23, 127.47, 127.04, 126.92,
123.65, 123.32, 121.88, 112.48, 112.36, 73.66, 70.63, 70.38, 69.07,
68.99, 52.77, 52.55, 31.91, 29.68, 29.52, 29.46, 29.41, 29.35, 29.02,
28.63, 25.65, 25.57, 22.68, 14.11.
(11) Degenhardt, C. F.; Smith, M. D.; Shimizu, K. D. Org. Lett.
2002, 4, 723.
(12) Bauer, M.; Vogtle, F. Chem. Ber. 1992, 125, 1675.
(13) Losensky, H. W.; Spelthann, H.; Ehlen, A.; Vogtle, F.;
Bargon, J. Angew. Chem., Int. Ed. Engl. 1988, 27, 1189.
(14) Junge, D. M.; McGrath, D. V. J. Am. Chem. Soc. 1999, 121,
4912.
(15) Beattie, M. S.; Jackson, C.; Jaycox, G. D. Polymer 1998, 39,
2597.
(16) Ikeda, T. Macromolecules 1998, 31, 1104.
(17) In this system, there are fewer than 2n conformations due to
the symmetry of the molecules.
HRMS (MALDI-FTMS; M + Na+) calcd for C140H176N4O20:
2257.90. Found: 2258.02.
syn/syn-1
(18) Bampos, N.; Marvaud, V.; Sanders, J. K. M. Chem.–Eur. J.
1998, 4, 335.
FTIR (KBr): 2924, 2849, 1720, 1677, 1613, 1581, 1512, 1448,
1346, 1277, 1250, 1192, 1117, 983, 764, 636 cm–1
(19) Calculated from the Arrhenius equation assuming an ideal
1H NMR (300 MHz, CDCl3): = 8.81 (s, 8 H), 8.19 (dd, J = 2.2, 8.8
Hz, 4 H), 7.98 (d, J = 2.2 Hz, 4 H), 7.11 (d, J = 8.8 Hz, 4 H), 4.92
(s, 8 H), 4.04 (t, J = 6.6 Hz, 8 H), 1.60–0.82 (m, 140 H).
13C NMR (125 MHz, CDCl3): = 164.48, 162.26, 158.60, 133.25,
131.82, 131.30, 127.39, 126.96, 123.39, 121.91, 112.53, 73.82,
70.51, 69.03, 52.60, 31.91, 29.69, 29.46, 29.41, 29.35, 29.03, 28.61,
25.59, 22.67, 14.11.
value of A = 2.08 1010s–1deg–1.
(20) Sanders, G. M.; Van Dijk, M.; Machiels, B. M.; van
Veldhuizen, A. J. Org. Chem. 1991, 56; 1301.
(21) Shimizu, K. D.; Dewey, T. M.; Rebek, J. J. Am. Chem. Soc.
1994, 116, 5145.
(22) Li, S.; McGrath, D. V. J. Am. Chem. Soc. 2000, 122, 6795.
(23) Molecular weight estimates were made based on polystyrene
standard. GPC conditions were Waters Styragel HR 4E in
CHCl3 at 1 mL min–1.
HRMS (MALDI-FTMS; M + Na+) calcd for C140H176N4O20:
2257.90. Found: 2258.02.
Synthesis 2002, No. 9, 1239–1244 ISSN 0039-7881 © Thieme Stuttgart · New York