Non-aggregational aromatic oligoamide macrocycles

Article abstract of DOI:10.1039/c2cc16912f

Attaching peripheral amide groups to the backbone of cyclic aromatic oligoamides 1 leads to new macrocycles 2 that show drastically changed behavior including modest yields of formation and no tendency to aggregate while maintaining a rigid backbone and a

Full text of DOI:10.1039/c2cc16912f

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COMMUNICATION
Non-aggregational aromatic oligoamide macrocyclesw
Xiangxiang Wu,ae Guoxing Liang,a Gang Ji,c Hoong-Kun Fun,d Lan He*b and Bing Gong*af
Received 8th November 2011, Accepted 19th December 2011
DOI: 10.1039/c2cc16912f
Attaching peripheral amide groups to the backbone of cyclic
aromatic oligoamides 1 leads to new macrocycles 2 that show
drastically changed behavior including modest yields of formation
and no tendency to aggregate while maintaining a rigid backbone
and a defined, guest-binding internal cavity.
Macrocyclic molecules have long attracted wide attention.1
Rigid macrocycles,2 such as those with arylene ethynylene,3
aromatic amide,4,5 aromatic hydrazide,6 Schiff base,7 and other8
Macrocycles 2 were designed to probe the possibility of tuning
backbones, offer advantages including shape-persistency unaffected
by synthetic modifications, lumens of defined sizes, and the ability
to present functional groups at defined locations.2 Many rigid
macrocycles are now available based on efficient synthetic methods
reported in recent years.3–7 We have described the highly efficient
formation of macrocycles 1,4 their larger analogs,9 and those with
different backbones,6 based on either one-pot4,9 or segment
condensation.9,10 The observed high efficiencies are attributed
to the folding of uncyclized oligomeric precursors.9 These
macrocycles have exhibited novel properties. For example,
the non-collapsible cavity of 1 is selective for the guanidinium
ion.12 Highly conducting transmembrane single ion channels
are formed as a result of the columnar stacking of 1.13 Besides,
macrocycles 1 were recently found to undergo unusually
strong and directional columnar aggregation.14 Macrocycles
1 and their larger analogs, with their side chains and peripheral
aromatic hydrogens, provide multiple sites for structural
variation. Herein we report the design, synthesis, and study
of macrocycles 2, which can be regarded as being derived by
replacing three exterior aromatic hydrogen atoms of 1 with
secondary amide groups.
the aggregation propensity of the cyclic oligoamide backbones via
structural modification.5 It was conceived that by incorporating
H-bonding groups onto the periphery of 1, the resultant macro-
cycles 2 would exhibit changed aggregation behavior due to the
H-bonding capability, steric hindrance and backbone electronic
property endowed by the amide side chains. The R1 side chain was
chosen to impart chiral elements into the macrocycles to monitor
the formation of chiral assemblies. The resultant macrocycles could
associate via H-bonding interaction, and may thus exist as well
dispersed molecular species in polar media. Molecularly dispersed 2
should avoid the complications caused by the strong stacking of 1
and facilitate structural characterization and monitoring of inter-
molecular interaction. If the backbone-rigidifying three-center
H-bonds of 1 also persist in 2, the peripheral amide groups should
not affect the persistent shapes of the macrocyclic backbone and the
internal cavity.
Our study9 suggests that folding of uncyclized oligomer
precursors into crescent shapes is responsible for the efficient
formation of 1, with yields from 85% to over 90%,4 based on
one-pot4,9 or segment condensation.10 If the uncyclized precursors
of 2 also fold, similar folding-assisted cyclization could lead to 2 in
high yields. To probe the effect of the incorporated amide groups
on the conformations of the uncyclized precursors of 2, oligo-
amides 3 and 4 were designed and preparedw based on what we
described before.10,11 Single crystals of 3 from methanol/pyridine
(1/1, v/v) and those of 4 from CHCl3/toluene (1/2, v/v) were then
obtained by slow evaporation of solvents at room temperature.z
a College of Chemistry and College of Resources Science and
Technology, Beijing Normal University, Beijing 100875, China
b National Institutes for Food and Drug Control, Beijing 100050,
China. E-mail: helan1961@hotmail.com
c Institute of Biophysics, Chinese Academy of Sciences,
Beijing 100101, China
d X-Ray Crystallography Unit, School of Physics,
Universiti Sains Malaysia, 11800 USM, Penang, Malaysia
e Henan University of Traditional Chinese Medicine,
Zhengzhou 450008, China
f Department of Chemistry, University at Buffalo, State University of
New York, Buffalo, NY 14260, USA. E-mail: bgong@buffalo.edu;
Fax: +1 716 645 6963; Tel: +1 716 645 4307
w Electronic supplementary information (ESI) available: Synthetic
procedures; analytical data; additional NMR and mass spectra;
method for determining association constants. CCDC 852892 (3)
and 852893 (4). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc16912f
c
2228 Chem. Commun., 2012, 48, 2228–2230
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The solid-state structures of 3 and 4 show that the peripheral
amide groups do not interfere with the backbone three-center
H-bonds (Fig. 1). Both 3 and 4 have crescent shapes that are
enforced by these three-center H-bonds. The peripheral amide
group of 3 has a dihedral angle of B551 with the benzene ring it
attaches to, and those of 4 are nearly perpendicular to the benzene
rings to which they connect. Consequently, these amide groups do
not participate in intramolecular H-bonding interaction with the
adjacent O atoms. Such an observation demonstrates that
modifying backbone-rigidified crescent oligoamides15 at the
peripheral positions does not disturb the folded conformations.
Therefore, it was reasoned that these peripheral amide side
chains, which do not change the rigidity of the oligoamide
backbone, should not change the overall persistent shape of 2.
The folding of 3 and 4 indicates that the precursors of 2
must also fold into similar shapes, which suggests that 2, like 1,
could form in high yields. Surprisingly, repeated attempts to
prepare 2 by treating the corresponding diacid chlorides with
diamines led to a mixture containing cyclic and noncyclic
oligomers of 4 to 12 residuesw, which is in sharp contrast to
the ‘‘cleanness’’ observed in the formation of 1.4 By coupling
trimers 5 and 6 under dilution, macrocycles 2 were obtained in
moderate crude yields (Scheme 1). Purification using column
chromatography led to 2a and 2b as yellow or white solids
in yields of 15% and 17%.w Thus, in comparison to the high
yields of 1, introducing amide side chains drastically lowers the
yields of 2. The modest yields of 2 have raised very interesting
mechanistic questions about the formation of 1. Additional
factors besides folding of precursors, such as intermolecular
stacking, may also contribute to the unusually high yields of 1.
In both 3 and 4, the side-chain amide protons are H-bonded
to the ester carbonyl oxygens of another molecule, while the
oxygen atoms of these peripheral amide groups do not engage
in any H-bonding. Thus, the peripheral amide groups of 2, being in
the same local environment as those of 3 and 4, should not be
‘‘consumed’’ by intramolecular H-bonding and may be predisposed
for intermolecular H-bonding, leading to H-bonded aggregates.
1
However, in contrast to the severely broadened H NMR
signals of 1 due to strong aggregation,4,14 no obvious line-
broadening was revealed by the 1H NMR spectra of 2a in
CDCl3, CD3OD or DMSO-d6w, suggesting that 2a underwent
insignificant aggregation in these solvents. Examination of
the presence of intermolecular H-bonding by following
concentration-dependent shifts of protons 2 of 2a was hampered
by the limited solubility (r1 mM in CDCl3) of this compound.
Macrocycle 2b, with its greatly enhanced solubility, also gave
sharp 1H NMR signals. The 1H NMR spectra of 2b recorded in
CDCl3 from 10 mM to 0.3 mM indicated no meaningful shifts of
the aromatic and amide proton resonancesw, which suggests that,
like 2a, macrocycle 2b does not undergo noticeable aggregation.
The lack of concentration-dependent shift of protons 2 of 2b
points to insignificant intermolecular H-bonding interaction in
CDCl3. These results demonstrate that, compared to the strongly
aggregating 1, macrocycles 2 have a very low propensity for
aggregation in solution.
Our study revealed that the internal cavity of 1 had a very
high affinity toward the guanidinium (Gua) ion.11 As shown in
Fig. 2a, the presence of one equivalent of GuaCl leads to
significant changes in both the chemical shifts and line-width
1
of the H NMR signals of 2b. The strong binding of the Gua
1
ion to 1b was indicated by the noticeably different H spectra
of 2b with or without added GuaCl in CD3OD (Fig. 2b). That
the Gua ion indeed binds into the cavity of 2b is shown by the
ROESY spectrum of 2b (2 mM) and GuaCl (2 mM) in CDCl3,
which reveals a strong ROE contact between the proton signal
of the Gua ion and that of proton c of 2b.w
Attempts to determine the association constant (Ka)
between 1 and the Gua ion were hampered by the strong
aggregation of 1.12,14 The well-resolved 1H NMR spectra of 2b
should allow the Ka values to be determined based on concen-
tration-dependent shifts of 1H NMR signals. However, in
CDCl3, the association constant between 2b and the Gua ion
could not be determined because diluting the solution from
1
10 mM to 0.2 mM led to no detectable shift of H signals.w
Ka values of (1.2 ꢀ 0.1) ꢁ 106 Mꢂ1 and (2.2 ꢀ 0.2) ꢁ 106 Mꢂ1
between 2b and the Gua ion in pure CDCl3 were obtained by
extrapolating Ka’s obtained from CDCl3 with 5%, 10%, 15%,
and 20% DMSO-d6 or CD3OD.w16 Thus, like 1, macrocycle 2b
strongly complexes the Gua ion, which demonstrates that the
peripheral amide side chains do not change the recognition
ability and likely, the shape of the internal cavity.
Fig. 1 The solid-state structures of (a) compound 3 and (b) compound 4.
The backbone amide groups are involved in intramolecular three-center
H-bonds (dashed green lines). Hydrogen atoms, except those of amide
groups, are omitted for clarity.
In summary, attaching amide groups onto the backbone of
1 leads to macrocycles 2 that exhibit very different properties.
The observed behavior of 2 can be explained by the obstruction of
intermolecular stacking due to the presence of the peripheral amide
side chains. The low yields of 2 have raised new mechanistic
questions that warrant further systematic studies. The deter-
mination of the association constant of the guanidinium ion
and 1, which was impeded by the strong aggregation of 1, has
now been accomplished with 2b. The observed strong binding
of the guanidinium ion to 2b demonstrates that, in spite of the
dramatic change of properties caused by the amide side chains,
Scheme 1
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2228–2230 2229

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(upper) and 2b (1 mM, bottom) in CD3OD, recorded at room temperature.
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a variety of large cations and other polar molecular species.
This work was supported by the Cultivation Fund of the
Key Scientific and Technical Innovation Project, Ministry of
Education of China Grant 706009 (to BG), the NSFC Grant
21072021 and the Special Fund for Agro-scientific Research in
the Public Interest Grant 201103027 (to LH), the US National
Science Foundation grants CBET-1036171 and CBET-
1066947 (to BG), National Science and Technology Major
Projects for Major New Drugs Innovation and Development
2011ZX09307-002-01 (to LH) and the Research University
Grant of USM 1001/PFIZIK/811160 (to HKF).
Notes and references
%
z Crystal data for 3: C51H71N3O15, M = 966.11, triclinic, space group P1,
a = 13.8349(5), b = 14.3436(5), c = 15.2208(4) A, a = 75.917(2), b =
86.728(2), g = 66.006(2)1, U = 2673.52(15) A3, Z = 2, m(Mo-Ka) =
0.088 mmꢂ1, 17 070 reflections measured (9373 unique, Rint = 0.0313).
R1[I 4 2s(I)] = 0.0819. The final wR(F2) was 0.3087 (all data).
CCDC 852892. Crystal data for 4: C82H112N6O24ꢃ0.5C7H8, M =
15 L. H. Yuan, H. Q. Zeng, K. Yamato, A. R. Sanford, W. Feng,
H. Atreya, D. K. Sukumaran, T. Szyperski and B. Gong, J. Am.
Chem. Soc., 2004, 126, 16528–16537.
16 Receptors with binding constants (most measured in methanol)
ranging from a few hundreds to 105 Mꢂ1 range were reported for
guanidinium ions: A. V. Eliseev and M. I. Nelen, J. Am. Chem. Soc.,
1997, 119, 1147–1148; T. W. Bell, A. B. Khasanov and M. G. B.
Drew, J. Am. Chem. Soc., 2002, 124, 14092–14103.
1611.89, monoclinic, space group C2/c,
a
=
31.4547(10),
b
=
25.7172(7), c = 26.8169(9) A, a = 90.00, b = 120.999(2), g = 90.001,
U = 18594.6(10) A3, Z = 8, m(Cu-Ka) = 0.693 mmꢂ1, 124 790 reflections
measured (13 676 unique, Rint = 0.0428). R1[I 4 2s(I)] = 0.1536. The
final wR(F2) was 0.4703 (all data). CCDC 852893.
c
2230 Chem. Commun., 2012, 48, 2228–2230
This journal is The Royal Society of Chemistry 2012