Aromatic oligoamide macrocycles with a backbone of reduced constraint

Article abstract of DOI:10.1021/ol4021207

Oligoamide macrocycles with a backbone partially constrained by hydrogen bonds have been prepared. These macrocycles, carrying multiple H-bonding side chains, underwent strong aggregation in solution and form long fibers in the solid state. In contrast to the strong and specific complexation of the guanidinium ion by analogous macrocycles with fully H-bond-constrained backbones, these macrocycles failed to recognize the same cation, indicating that reducing backbone constraint has led to a drastic change in their cavity.

Full text of DOI:10.1021/ol4021207

ORGANIC
LETTERS
2013
Vol. 15, No. 18
4762–4765
Aromatic Oligoamide Macrocycles
with a Backbone of Reduced Constraint
Mark Kline,† Xiaoxi Wei,† and Bing Gong*,†,‡
Department of Chemistry, The State University of New York at Buffalo, Buffalo,
New York 14260, United States, and College of Chemistry, Beijing Normal University,
Beijing 100875, China
bgong@buffalo.edu
Received July 26, 2013
ABSTRACT
Oligoamide macrocycles with a backbone partially constrained by hydrogen bonds have been prepared. These macrocycles, carrying multiple
H-bonding side chains, underwent strong aggregation in solution and form long fibers in the solid state. In contrast to the strong and specific
complexation of the guanidinium ion by analogous macrocycles with fully H-bond-constrained backbones, these macrocycles failed to recognize
the same cation, indicating that reducing backbone constraint has led to a drastic change in their cavity.
Rigid macrocycles1 with a variety of backbones2ꢀ9 have
attracted much attention. These macrocycles offer advan-
tages including shapes unaffected by synthetic modi-
fications, nondeformable lumens, and the presentation
of functional groups at defined locations. Major progress
has been made in recent years in the synthesis of rigid
macrocycles.3ꢀ9 For example, we reported the efficient
preparation of macrocycles 1,5 their larger analogs,10 and
those with different backbones7 based on either one-pot5,10
or segment condensation.10,11 The formation of 1 and other
macrocycles sharing similar backbones is characterized by
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† The State University of New York at Buffalo.
‡ Beijing Normal University.
€
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10.1021/ol4021207
Published on Web 09/09/2013
2013 American Chemical Society

very high efficiency that is attributed to the fully rigidified
backbones of the corresponding oligomeric precursors.10
These macrocycles exhibited novel properties.12 For exam-
ple, macrocycles 1, with their noncollapsible cavity having
numerous hydrogen bond acceptors, showed very high
selectivity toward the guanidinium ion.13 Macrocycles 1
formed transmembrane single ion channels with high con-
ductance, presumably due to their columnar stacking.14 The
strong columnar aggregation of 1 was confirmed by our
recent structural studies.15
dispersed in a wide concentration range in CDCl3, suggest-
ing that these molecules, with secondary amide side chains
being attached to their peripheries, abolished the otherwise
strong aggregation observed for 1.
Besides their efficient formation, macrocycles1 and their
larger analogs offer multiple sites, including side chains
and peripheral aromatic hydrogens, that are amenable
to various structural modifications. In an attempt to better
control the assembly of these cyclic compounds, we de-
signed and prepared macrocycles 2 in which a secondary
amide group was placed in between the two alkoxy groups
of each of the three diaminobenzene residues.16 The intro-
duced secondary amide groups, being sandwiched in be-
tween the alkoxy side chains and thus perpendicular to the
plane of the benzene rings to which they are attached,
should engage in intermolecular H-bonding interactions
that force 2 to stack into H-bonded columns. In contrast to
such an expectation, the 1H NMR signals of 2 remain well
Despite their drastically different propensity for aggre-
gation, macrocycles 1 and 2 have very similar backbones
that are rigidified by intramolecular three-center H-bonds and
the same, nondeformable inner cavity. Indeed, with a cavity
that is rich in amide O-atoms, macrocycles 2, like 1, also
complex the guanidinium ion with very high selectivity,16
suggesting that additional amide side chains did not alter
the property of the inner cavities of these macrocycles.
The unexpected lack of aggregation for 2 indicates that
even a modest structural variation could result in a drastic
change in properties, which prompted us to explore addi-
tional modifications on these macrocycles. For example,
removing some of the alkoxy side chains from 1 (or 2)
would reduce the number of intramolecular H-bonds,
leading to oligoamide backbones with increased rotational
freedom and also allowing the attachment of various side
chains onto the benzene residues. This may lead to macro-
cycles with novel behavior.
Based on these considerations, we designed macrocycles
3, which can be regarded as being derived from 1 by
removing the alkoxy groups, i.e., the corresponding intra-
molecular H-bonds, away from the diaminobenzene residues
while attaching additional amide side chains. Macrocycles 3
may also be regarded as being derived from 2 by removing
the alkoxy groups away from the diaminobenzene residues
of the latter. The backbone amide H-atoms of 3 should
still be involved in intramolecular H-bonds with the remain-
ing alkoxy oxygens, while the side chain amide groups of 3
should be able to engage in intermolecular H-bonding.17
The preparation of 3 was first attempted by treating the
corresponding monomeric diacid chloride and diamines
based on the similar one-pot procedures we reported for
preparing 1.5 In contrast to the efficient formation of 1, the
attempted one-pot reaction failed to yield 3 in any mean-
ingful yields. This result indicates that, without the kind of
H-bond-constrained conformations18 that are characteristic
(5) Yuan, L. H.; Feng, W.; Yamato, K.; Sanford, A. R.; Xu, D. G.;
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aromatic polyamides that share the same backbone with 3: Cao, J. X.;
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Org. Lett., Vol. 15, No. 18, 2013
4763

of the oligomeric precursors of 1, the uncyclized oligoamide
precursors of 3 are too flexible to promote efficient macro-
cyclization.
diamine 6 with monomeric diacid 7, was adopted for
preparing 3d (Scheme 2). It was found that the coupling
of 6 (1 mM) and 7 (1 mM) was most effective when
performed in DMF with HATU at 60 °C for 72 h, which
led to 3d in a total yield of 70% after purification.
Scheme 1. Synthesis of Macrocycles 3
Scheme 2. Synthesis of Macrocycle 3d
The cyclic nature of 3aꢀd was confirmed with multiple
techniques. The molecular ion ([M þ Naþ]) peaks of 3aꢀd
from MALDI-FTICR have isotope distributions that
match those based on computer simulation of the cyclic
structures [see the Supporting Information (SI)]. Consis-
The synthesis of 3 was then explored by coupling
trimeric diacids 4 and diamines 5 (Scheme 1), a strategy
we reported before.11 Thus, under high-dilution condi-
tions, a solution of 4a (68.6 μmol), EDC (205.8 μmol), and
HOBt (205.8 μmol) in CHCl3 (10 mL) and that of 5a in
CHCl3 (10 mL) were simultaneously added at a constant
and identical rate (10 mL/h) to 117 mL of CHCl3 under
stirring. The reaction mixture was stirred for 6 h at rt
and heated under reflux for 72 h. After being concentrated
to half of the original volume, the reaction mixture was
heated under reflux for an additional 48 h, washed with
HCl (1 M), K2CO3 (1 M), and brine, and then dried
over anhydrous Na2SO4. Removing solvent left a residue
that was purified with column chromatography (silica
gel followed by basic alumina), giving 3a as a yellow solid
(68 mg, 49%).
Surprisingly, macrocycle 3b, which only differs from 3a
in its amide side chains, could be prepared from 4b and 5b
without the need for adopting high-dilution conditions.
Thus, to a solution of diacid 4b (0.218 mmol), diamine 5b
(0.218 mmol), and diisopropylethylamine (0.894 mmol) in
CH2Cl2 (20 mL), HATU (0.447 mmol) in CH2Cl2 (5 mL)
was added in one portion under stirring. The reaction
mixture became clear after 45 min, which was warmed
up to 45 °C, stirred for 48 h, washed with 0.1 M HCl, 5%
NaHCO3, and brine, and dried over anhydrous Na2SO4.
Removing CH2Cl2 left a residue that was purified with
column chromatography, leading to 3b in 67% yield as an
off-white solid. The same conditions were adopted for the
preparation of 3c from 4c (∼10 mM) and 5c (∼10 mM) in
CH2Cl2. Macrocycle 3c was obtained as a pale yellow solid
in a yield of 46% after purification.
1
tent with the cyclic backbones, each of the H NMR
spectra of 3aꢀd (Figures S1, S3, S5, and S7 in the SI)
recordedin a polar solvent (DMSO-d6/CDCl3 or DMF-d7)
reveals a total of six well dispersed signals in the aromatic
and amide region. The 13C NMR spectrum of each macro-
cycle contains signals of aromatic and amide carbons
expected of the cyclic structure (Figures S2, S4, S6, and
S8; see the SI).
Macrocycle 3a is readily soluble in both nonpolar and
polar solvents including CHCl3, CH2Cl2, THF, DMSO,
and DMF, followed by 3b and 3c with reduced solubilities
in these solvents, and with 3d being modestly soluble
in CHCl3 and only going into DMSO and DMF upon
heating. Thus, by adjusting side chains, it should be
possible to systematically tune the solubility of the corre-
sponding macrocycle.
In contrast to well dispersed signals observed in polar
1
solvents, the H NMR spectra of 3aꢀd in CDCl3 do not
reveal any signals in the amide and aromatic region
and only contains peaks corresponding to its side chains
(see the SI). These results point to the significantly de-
creased molecular motion for 3 in CDCl3 due to aggrega-
tion involving the oligoamide backbones. Thus, unlike
the nonaggregational 2, macrocycles 3 behaved similarly
to 1 by undergoing strong aggregation. That such aggrega-
tion is interrupted in polar solvents suggests the involve-
ment of forces such as H-bonding and/or dipoleꢀdipole
interactions.
We recently demonstrated that shape-persistent macro-
cycles bearing multiple H-bonding side chains underwent
highly directional self-assembly to form nanotubular
structures.19 It is expected that such a H-bond-enforced
aligning strategy is a generally good one. The multiple
amide side chains of 3 should thus allow better alignment
of these macrocycles.
Attempts to prepare 3d were hampered by the limited
solubilities of trimeric diacid 4d and diamine 5d. An
alternative strategy, involving the coupling of pentameric
(18) Yuan, L. H.; Zeng, H. Q.; Yamato, K.; Sanford, A. R.; Feng, W.;
Atreya, H.; Sukumaran, D. K.; Szyperski, T.; Gong, B. J. Am. Chem.
Soc. 2004, 126, 16528.
4764
Org. Lett., Vol. 15, No. 18, 2013

Surprisingly, examining samples of 3a or 3d mixed with
guanidinium chloride or guanidinium tetraphenylborate
under a variety of conditions (i.e., ratios of 1:1, 1:5, 1:10,
and 1:1000, in different solvents, and standing for 3 or 16h)
using MALDI-FTICR failed to detect any interaction
between 3 and the guanidinium ion. Given the rigidity of
benzene rings and backbone amide groups, it is unlikely
that the backbones and cavities of 3 would collapse.
Instead, this observation suggests that the cavity of these
macrocycles is different from that of 1 or 2. Replacing the
three-center H-bonds of 1 or 2 with the two-center
H-bonds of 3 may have resulted in some (or all) of the
backbone amide groups to twist away from being nearly
coplanar with the benzene residues. The resultant cavity
can no longer bind the guanidinium ion due to the absence
of well-positioned, inward pointing amide O-atoms.
In summary, we have prepared a new series of aro-
matic oligoamide macrocycles with a backbone of reduced
H-bond constraints, which allows the introduction of
additional secondary amide side chains. The synthesis
of macrocycles 3, whose precursors do not have fully
rigidified, crescent conformations, could only be achieved
by coupling their oligomeric precursors. With amide side
chains capable of multiple intermolecular H-bonding,
macrocycles 3 exhibited strong aggregation. The direc-
tional assembly of 3 was indicated by SEM, which revealed
very long fibers consisting of closely packed filaments.
Unlike the nearly exclusive binding of the guanidinium ion
observed for 1 and 2, macrocycles 3 failed to show any
binding of this ion. This surprising result is explained by
the backbone of 3, which is only partially constrained and
thus encloses a cavity that does not have well-positioned
amide oxygens necessary for effective binding. These find-
ings indicate the structural-functional richness of aromatic
oligoamide macrocycles. Further studies on these macro-
cycles should reveal additional novelties.
Figure 1. (a) The SEM image of a sample of 3d reveals a fibrous
bundle. (b) Enlarged (zoomed-in) SEM image of the same
sample showing the edge of the fibrous bundle.
The involvement of the side chain amide groups of 3 in
intermolecular H-bonding was probed with IR spectro-
scopy (see the SI). Incomparison tothatof a trimersharing
part of the backbone and the same side chain, the IR
spectrum of 3d (1 mM) in CHCl3 indicates that the side
chain amide carbonyls give a stretching band with a pro-
minent shoulder from 1647 and 1641 cmꢀ1 that noticeably
shifts (22 cmꢀ1) to a lower frequency. In CHCl3 containing
17% CH3CN, this shoulder weakened noticeably (see the
SI). These results are consistentwith the involvement of the
side chain amide groups of 3d in an intermolecular
H-bonding interaction. The high directionality of multiple
H-bonding, along with backbone stacking interaction,
may very likely lead to well aligned stacks consisting of
these macrocycles.
That 3d indeed engaged in directional aggregation
was revealed by scanning electron microscopy (SEM). As
shown in Figure 1, the SEM image of a solid sample of 3d
reveals long, largely straight fibers with lengths over tens of
micrometers. The fibers consist of closely packed filaments
with diameters around 0.4 μm. The SEM image provides
clear evidence indicating the highly anisotropic nature of
the self-assembly of this macrocycle.
Acknowledgment. ThisworkwassupportedbytheNSF
(CHE-1306326 and CHE-0091977), the NIH (S10RR029517
from the National Center for Research Resources), and the
NSFC (91227109).
As we reported, the internal cavity of 1 or 2 contains six
well positioned, inward-pointing amide oxygen atoms and
binds the guanidinium ion strongly and specifically.13,16
Supporting Information Available. Synthesis, com-
pound characterizations, and additional spectroscopic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Zhou, X. B.; Liu, G. D.; Yamato, K.; Shen, Y.; Cheng, R. X.;
Wei, X. X.; Bai, W. L.; Gao, Y.; Li, H.; Liu, Y.; Liu, F. T.; Czajkowsky,
D. M.; Wang, J. F.; Dabney, M. J.; Cai, Z. H.; Hu, J.; Bright, F. V.; He,
L.; Zeng, X. C.; Shao, Z. F.; Gong, B. Nat. Commun. 2012, 3, 949. DOI:
10.1038/ncomms1949.
The authors declare no competing financial interest.
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