Nonaggregational shape-persistent cyclo[6]aramide and its macrocyclic effect toward binding secondary ammonium salts in moderately polar media

Article abstract of DOI:10.1021/ol401930u

Simply by introducing steric side chains, the shape-persistent cyclo[6]aramides were found to exhibit nonaggregational behavior and strong association (3 × 10⁴ M^-1) ability in acetone for binding secondary ammonium salt. The complexa

Full text of DOI:10.1021/ol401930u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Nonaggregational Shape-Persistent
Cyclo[6]aramide and Its Macrocyclic
Effect toward Binding Secondary
Ammonium Salts in Moderately
Polar Media
Jinchuan Hu, Long Chen, Yi Ren, Pengchi Deng, Xiaowei Li, Youjia Wang, Yiming Jia,
Jian Luo, Xinshi Yang, Wen Feng,* and Lihua Yuan*
Key Laboratory for Radiation Physics and Technology of Ministry of Education,
Institute of Nuclear Science and Technology, College of Chemistry,
Key State Laboratory of Biotherapy, Sichuan University, Chengdu 610064, China
lhyuan@scu.edu.cn; wfeng9510@scu.edu.cn
Received July 9, 2013
ABSTRACT
Simply by introducing steric side chains, the shape-persistent cyclo[6]aramides were found to exhibit nonaggregational behavior and strong
association (3 ꢀ 104 Mꢁ1) ability in acetone for binding secondary ammonium salt. The complexation can be switched in an on-and-off fashion
using AgPF6 and TBACl, contrasting sharply with their corresponding acyclic pentamer and demonstrating the macrocyclic effect.
With a noncollapsible framework and cavity that are
distinguishable from less conformationally rigid cyclic
molecules such as crown ethers and calixarenes, shape-
persistent macrocycles of different size, shape, and topol-
ogy have aroused great interest in the past years.1 Among
them, macrocyclic aromatic oligoamides with full amide
linkage2,3 have seen a fast increase concomitant with the
development of hydrogen bonding-directed reactions.
Shape-persistent aromatic oligoamide macrocycles devel-
oped by Gong and co-workers3 represent an interesting
class of cyclic compounds that structurally differ from
most of the other oligoamide cycles2,4 in the interior where
(1) For selected reviews, see: (a) Moore, J. S. Acc. Chem. Res. 1997,
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Zeng, H. Q. Angew. Chem., Int. Ed. 2011, 50, 10612.
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Zhang, W.; Moore, J. S. Angew. Chem., Int. Ed. 2006, 45, 4416. (g)
MacLachlan, M. J. Pure Appl. Chem. 2006, 78, 873. (h) Gong, B. Acc.
Chem. Res. 2008, 41, 1376. (i) Zhao, X.; Li, Z. T. Chem. Commun. 2010,
46, 1601. (j) Yamato, K.; Kline, M.; Gong, B. Chem. Commun. 2012, 48,
12142. (k) Fu, H. L.; Liu, Y.; Zeng, H. Q. Chem. Commun. 2013, 49,
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ar400030e. (m) Ong, W. Q.; Zeng, H. Q. J. Incl. Phenom. Macrocycl.
Chem. 2013, 76, 1.
r
10.1021/ol401930u
XXXX American Chemical Society

amide carbonyl atoms are predisposed introvertively.
These macrocyclic oligoamides with six residues and their
derivatives serve as highly selective receptors for accom-
modatingtheguanidinium ion5 and conductingtransmem-
brane pores in ion-channel study.6
We recently revealed the unusually high efficient kinetic
macrocyclization that is rare for macrocycle formation
involving a large number of reacting units.3b Furthermore,
these macrocycles carrying linear alkyl side chains exhibit a
strong preference for directional self-assembly in both
polar and nonpolar solvents.3e With the hydrophilic inter-
nal pores or channel, these macrocycles are also expected
to interact with metal ions or hydrogen bond donors.
This has been demonstrated by our finding that cyclo-
[6]aramides, as we named it for brevity, function as an
excellent extractant in the separation of lanthanide and
thorium elements.7
Despite much progress made in using secondary ammo-
nium salts for the preparation of hostꢁguest complexes
with many 3D macrocycles including crown ethers,8
cucurbiturils,9 calixarenes,10 and pillararenes,11 as well as
pore-containingaromaticoligoamides,12 thecomplexation
between shape-persistent 2D macrocycles and secondary
ammonium salts is rare.13 To construct supramolecular
architecture such as rotaxane, the binding affinity between
host and secondary ammonium salts is among one of the
most important parameters for evaluating the complexing
ability of macrocyclic hosts. The earliest report using
benzo-24-crown-8 only afforded a binding constant of
135ꢁ261 Mꢁ1 in acetone.14 Recently, use of a smaller
crown analog, benzo-21-crown-7, led to the increased
value of 527ꢁ1062 Mꢁ1 in the same solvent.8b In chloro-
form, the calix[6]arene10 derivative and pillar[5]arene11a
only provided the association affinity corresponding
to binding constants of 3.5 ꢀ 104 and 1.09 ꢀ 103 Mꢁ1
,
respectively. Further enhancement of the binding ability in
solvents, particularly in polar surroundings, is still highly
demanding. In addition, severe aggregation often leads to
issues concerning low solubility and difficulty in structural
characterization. This impedes greatly applications of
aromatic oligoamide macrocyles with six residues, where
nonaggregational ability is important for hostꢁguest
chemistry.5b
Herein we report on nonaggregational, soluble macro-
cycle 1a which is realized simply by replacing linear alkyl
groups with branched side chains and its binding toward
various secondary ammonium hexafluorophosphates
2aꢁe in moderately polar solvent, acetone (Figure 1).
The binding process is switchable in an on-and-off manner
by adding a silver ion and chloride anion. Besides tunable
complexation, a macrocyclic effect was observed by com-
paring its corresponding open-chain anologes, i.e., penta-
mer 3a and 3b. We are not aware of the examples of
binding secondary ammonium salts with aromatic oligoa-
mide macrocycles with full amide linkage. A high binding
constant has been achieved in this study, which is surpass-
ing the known values recorded to date.
(3) (a) Yuan, L. H.; Feng, W.; Yamato, K.; Sanford, A. R.; Xu,
D. G.; Guo, H.; Gong, B. J. Am. Chem. Soc. 2004, 126, 11120. (b) Feng,
W.; Yamato, K.; Yang, L. Q.; Ferguson, J. S.; Zhong, L. J.; Zou, S. L.;
Yuan, L. H.; Zeng, X. C.; Gong, B. J. Am. Chem. Soc. 2009, 131, 2629.
(c) Yang, L. Q.; Zhong, L. J.; Yamato, K.; Zhang, X. H.; Feng, W.;
Deng, P. C.; Yuan, L. H.; Zeng, X. C.; Gong, B. New J. Chem. 2009, 33,
729. (d) Zou, S. L.; He, Y. Z.; Yang, Y. A.; Zhao, Y.; Yuan, L. H.; Feng,
W.; Yamato, K.; Gong, B. Synlett. 2009, 9, 1437. (e) Yang, Y. A.; Feng,
W.; Hu, J. C.; Zou, S. L.; Gao, R. Z.; Yamato, K.; Kline, M.; Cai, Z. H.;
Gao, Y.; Wang, Y. B.; Li, L. B.; Yang, Y. L.; Yuan, L. H.; Zeng, X. C.;
Gong, B. J. Am. Chem. Soc. 2011, 133, 18590. (f) Wang, Y. B.; Li, Y. B.;
Luo, Y.; Xu, M.; Zhang, X. M.; Guo, Y. Y.; Wei, G. H.; Yuan, L. H.;
Gong, B.; Yang, Y. L.; Wang, C. ChemPhysChem 2012, 13, 3598.
(4) (a) Li, F.; Gan, Q.; Xue, L.; Wang, Z. M.; Jiang, H. Tetrahedron
Instead of modifying the backbone via introducing
substituents,5b it was reasoned that introducing steric
hindrance around the macrocyclic periphery should lead
to altered association ability and thus decreased aggrega-
tion. Such a possibility was first explored by macrocycle 1a
that contains hindered groups.15 Much greater solubility
was found for 1a (>100 mM) compared to 1b (25 mM) in
chloroform. Surprisingly, sharp signals for 1a were ob-
served in the 1H NMR spectra in CDCl3 or CD3COCD3.15
Previous results for cyclo[6]aramides, e.g., 1b, bearing
linear alkyl side chains revealed the severely broadened
1H NMR signals due to strong aggregation.3e In addition,
€
Lett. 2009, 50, 2367. (b) Dzyuba, E. V.; Kaufmann, L.; Low, N. L.;
Meyer, A. K.; Winkler, H. D. F.; Rissanen, K.; Schalley, C. A. Org. Lett.
2011, 13, 4838.
(5) (a) Sanford, A. R.; Yuan, L. H.; Feng, W.; Yamato, K.; Flowers,
R. A.; Gong, B. Chem. Commun. 2005, 41, 4720. (b) Wu, X. X.; Liang,
G. X.; Ji, G.; Fun, H. K.; He, L.; Gong, B. Chem. Commun. 2012, 48,
2228.
(6) Helsel, A. J.; Brown, A. L.; Yamato, K.; Feng, W.; Yuan, L. H.;
Clements, A. J.; Harding, S. V.; Szabo, G.; Shao, Z. F.; Gong, B. J. Am.
Chem. Soc. 2008, 130, 15784.
(7) Zhong, L. J.; Chen, L.; Feng, W.; Zou, S. L.; Yang, Y. Y.; Liu, N.;
Yuan, L. H. J. Incl. Phenom. Macrocycl. Chem. 2012, 63, 4079.
(8) (a) Zong, Q. S.; Zhang, C.; Chen, C. F. Org. Lett. 2006, 8, 1859. (b)
Zhang, C. J.; Li, S. J.; Zhang, J. Q.; Zhu, K. L.; Li, N.; Huang, F. H. Org.
Lett. 2007, 9, 5553. (c) Zhang, Z. J.; Zhang, H. Y.; Wang, H.; Liu, Y.
Angew. Chem., Int. Ed. 2011, 50, 10834. (d) Hsueh, S. Y.; Ko, J. L.; Lai,
C. C.; Liu, Y. H.; Peng, S. M.; Chiu, S. H. Angew. Chem., Int. Ed. 2011,
50, 6643.
1
the concentration-dependent H NMR experiments dis-
closed no shifts of all protons of 1a from 10 to 0.3 mM,15
indicating that no aggregation occurred. Macrocycle 1c,
with shorter branched side chains, gave signals that are not
so sharp compared to those of 1a.15 In stark constrast, 1d
bearing linear n-octyl groups was actually insoluble in the
same solvent.3a The nonaggregational behavior of 1a was
further confirmed by UVꢁvis spectra and dynamic light
scattering (DLS) techniques.15 As expected, no blue or red
shift was found in the concentration-dependent UVꢁvis
(9) (a) Lee, J. W.; Kim, K.; Kim, K. Chem. Commun. 2001, 37, 1042.
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(b) Marquez, C.; Hudgins, R. R.; Nau, W. M. J. Am. Chem. Soc. 2004,
126, 5806. (c) Kim, S. K.; Park, K. M.; Singha, K.; Kim, J.; Ahn, Y.;
Kim, K.; Kim, W. J. Chem. Commun. 2010, 46, 692.
(10) Gaeta, C.; Troisi, F.; Neri, P. Org. Lett. 2010, 12, 2092.
(11) (a) Han, C. Y.; Yu, G. C.; Zheng, B.; Huang, F. H. Org. Lett.
2012, 14, 1712. (b) Li, C. J.; Shu, X. Y.; Li, J.; Fan, J. Z.; Chen, Z. X.;
Weng, L. H.; Jia, X. S. Org. Lett. 2012, 14, 4126.
(12) (a) Li, C.; Ren, S, F.; Hou, J. L.; Yi, H. P.; Zhu, S. Z.; Jiang,
X. K.; Li, Z. T. Angew. Chem., Int. Ed. 2005, 44, 5725. (b) Gan, Q.;
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Ferrand, Y.; Bao, C. Y.; Kauffmann, B.; Grelard, A.; Jiang, H.; Huc, I.
(14) Ashton, P. R.; Chrystal, E. J. T.; Glink, P.; Menzer, T. S.;
Schiavo, C.; Spencer, N.; Stoddart, J. F.; Tasker, P. A.; White, A. J. P.;
Williams, D. J. Chem.;Eur. J. 1996, 2, 709.
Science 2011, 331, 1172.
(13) Xu, X. N.; Wang, L.; Wang, G. T.; Lin, J. B.; Li, G. Y.; Jiang,
X. K.; Li, Z. T. Chem.;Eur. J. 2009, 15, 5763.
(15) See the Supporting Information for details.
B
Org. Lett., Vol. XX, No. XX, XXXX

spectra in CHCl3. The results from DLS experiments
showed that the average size of 1a was 2.1 nm (1.0 mM)
and 1.3 nm (5.0 mM) in CHCl3. These data were close to
the calculated value of the backbone size (ca. 1.5 nm) of
macrocycle 1a.3f These results demonstrate that, compared
to the strongly aggregating 1b and 1d, macrocycles 1a
and 1c have a very low propensity for aggregation in
solution.
time scale. More direct evidence for the complexation
came from a high resolution electrospray ionization mass
spectra (HRESI-MS) study.15 A highly intense fragment
ion of [MꢁPF6]þ was found at m/z 2480.7222 for 1a 2a,
3
indicating the presence of the hostꢁguest species in 1:1
stoichiometry.
The formation of the complex 1a 2a was further
3
evidenced by 2D ROESY (10 mM in acetone-d6).15 ROE
correlations were observed between the methylene proton
H1 of 2a and protons Ha and Hb of 1a, suggesting that the
positively charged moiety ꢁNH2þꢁ resides in the cavity of
1a. The optimized geometry of complex 1a 2a which was
3
obtained using the density functional theory (DFT) calcu-
lation indicated that cyclo[6]aramide 1a was pierced by
2a.15 In other words, this implies the threading of an alkyl
group through the cavity of the macrocycle to form a
pseudorotaxane.
Then, a series of secondary ammonium salts 2bꢁe were
examined for their interactions with 1a. A 1:1 stoichiome-
try was obtained for all salts by a molar ratio method using
a 1H NMR technique.15 The HRESI-MSconfirmed the 1:1
complexation of 1a 2b and 1a 2c. A common fragment
3
3
ion of [MꢁPF6]þ was found at m/z 2500.9089 for 1a 2b
3
and at 2534.8940 for 1a 2c.15
1
The H NMR titration experiment of 1a with 2a from
3
0 to 1.8 equiv revealed a substantial downfield change
for methylene protons 2a-H1 (Δδ = 0.15 ppm) and 2a-H2
(Δδ = 0.13 ppm),15 indicating that ammonium hydrogens
are involved in intermolecular H-bonding. By fitting the
concentration-dependent change of the chemical shifts of
proton 2a-H2 to a 1:1 binding motif,15 an association
constant of 2.54 ꢀ 104 Mꢁ1 (ΔG = ꢁ25.1 kJ/mol) was
obtained (Table 1). Replacing one of two butyl groups of
2a led to 2b, which offered a Ka value of 3.38 ꢀ 104 Mꢁ1
(ΔG = ꢁ25.8 kJ/mol), indicative of only a marginal
change upon threading. However, 2c with two larger
benzyl groups via substituting two butyl groups of 2a
provided a Ka of 7.50 ꢀ 103 Mꢁ1 (ΔG = ꢁ22.1 kJ/mol),
a ca. 3-fold decrease with respect to 2a in association
affinity. It indicates that secondary dialkylammonium salt
2a or 2b fits the cavity of 1a better than 2c. These Ka values
are higher in moderately polar solvent, indicating that the
macrocycle 1a is able to bind strongly secondary dialky-
lammonium salts in acetone. To the best of our knowledge,
the Ka values (>104 Mꢁ1) represent the highest binding
constants reported to date for shape-persistent macrocyles
and secondary ammonium salts.
Figure 1. Chemical structures and proton designations of cyclo-
[6]aramides 1aꢁd and secondary ammonium salts 2aꢁe.
The first encouraging evidence for the interaction of
1a with an equimolar dibutylammonium salt 2a was from
1H NMR spectra in acetone-d6 (Figure 2).
The chemically driven uncomplexing and recomplexing
processes were further investigated (Figure 3). When
1 equiv of AgPF6 was added to the solution of 1a and 2c
(1:1 in molar ratio) in acetone-d6, the interior aromatic
protons Ha and Hb showed a significant upfield shift (0.41
ppm and 0.25 ppm) along with a concomitant downfield
shift of amide Hc (0.16 ppm) and exterior protons He/Hf,
indicating the strong interaction of the silver ion and 1a
Figure 2. 1H NMR spectra (600 MHz, acetone-d6, 298 K) of (a)
1.0 mM cyclo[6]aramide 1a, (b) 1.0 mM cyclo[6]aramide 1a and
2a, and (c) 1.0 mM 2a.
All signals of protons Ha, HbꢁHf from amide and
aromatic regions in 1a shifted downfield except for Ha,
and the signals of protons H1 and H2 in 2a also followed
the same trend by a downfield shift of 0.15 and 0.12 ppm,
respectively. Only one set of signals were found for an
equimolar solution of 1a and 2a, showing fast-exchange
complexation between 1a and 2a on the 1H NMR
to form a stable complex 1a Agþ. This suggests disrup-
3
tion of the complexation of 1a 2c due to the more compe-
tive complexing ability of the silver ion with respect
3
to ꢁNH2þꢁ species. At the same time, the signals of
Org. Lett., Vol. XX, No. XX, XXXX
C

methylene protons of 2c remained almost unchanged
compared to those of free salt, strongly indicating
dethreading of 2c from the cavity of 1a. Upon addition
of 1 equiv of tetrabutylammonium chloride (TBACl), the
spectral pattern obtained was almost identical to the one
from the solution of 1a and 2c. This suggests the reforma-
tion of threaded structures. The reversible change upon the
addition of Agþ and Clꢁ demonstrates the possibility for
manipulating the complexation behavior of 1a and 2c by
external chemical stimulus. As expected, the complexing
process of 1a and 2a could also be manipulated using this
method.15 In addition, the cesium ion driven uncomplex-
ing process was similar to that observed with presence of
the silver ion.15
compounds have the same number of introverted amide
oxygens as 1a. 1H NMR spectra of a solution of 3a or 3b
and 2a exhibited actually the presence of each component
that corresponds to its free species.15 This clearly shows a
lack of interaction with secondary dialkylammonium salt
with the acyclic analogs, reflecting the essential role the
cycle played in facilitating the binding process.
Table 1. Stoichiometries and Association Constants of
Complexes in Acetone-d6 at 298 K
complex
molar ratioa
Ka (Mꢁ1 b
)
ΔG (kJ/mol)c
Figure 4. Chemical structures of pentamers 3a (fully hydrogen
bonded) and 3b (partially hydrogen bonded).
1a 2a
1:1
1:1
1:1
1:1
1:1
(2.54 ( 1.18) ꢀ 104
(3.38 ( 1.64) ꢀ 104
(7.50 ( 1.44) ꢀ 103
(8.03 ( 1.67) ꢀ 103
(4.60 ( 0.62) ꢀ 102
ꢁ25.1
ꢁ25.8
ꢁ22.1
ꢁ22.3
ꢁ15.2
3
1a 2b
3
1a 2c
3
1a 2d
In conclusion, we have demonstrated that the presence
of steric side groups dramatically decreased the strong
aggregation that typically accompanies macrocycles per-
ipherally tethered with linear alkyl groups. The cyclo-
[6]aramide 1a has shown capability in binding secondary
ammonium salts in acetone with varying association
affinity depending strongly on the molecular structure of
the secondary ammonium salts. The binding constants
(>104 Mꢁ1) achieved for 1a with 2b represents the largest
value reported to date in moderately polar solvent for
shape-persistent macrocycles. The complexation can be
switched in an on-and-off fashion using AgPF6 and
TBACl. The macrocyclic effect has been shown to play a
determined role in manipulating the association process.
These cyclo[6]aramides containing hindered side chains
are expected to hold potential as candidates of novel
wheels for constructing mechanically interlocked architec-
tures, such as molecular switches, molecular muscles, and
other supramolecular machines.
3
1a 2e
3
a The 1:1 stoichiometry of each complex was established by the molar
ratio method. b The association constant Ka values were obtained by
proton NMR titration. c The Gibbs free energies (ΔG) of complexation
were calculated from the Ka values, using the equation ΔG = ꢁRT ln Ka.
Acknowledgment. We are grateful to the National
Natural Science Foundation of China (21172158), NSAF-
(11076018), the National Fund of China for Fostering
Talents in Basic Science (J1210004), and the Open Project
of State Key Laboratory of Supramolecular Structure and
Materials (SKLSSM201320) for funding this work,
Analytical & Testing Center of Sichuan University for
NMR analysis, and Analytical & Testing Center of College
of Chemistry for HRESI-MS.
Figure 3. Partial 1H NMR spectra (400 MHz, acetone-d6, 298 K)
of (a) 2.0 mM 1a, (b) 2.0 mM 1a and 2c, (c) 2.0 mM 1a and
2c þ 2.0 mM AgPF6, (d) 2.0 mM 1a and 2c þ 2.0 mM AgPF6 þ
2.0 mM TBACl, and (e) 2.0 mM 2c.
Interestingly, a remarkable macrocyclic effect was ob-
served when pentamer 3a with a backbone rigidified by full
three-center H-bonds or 3b containing partial intramole-
cular H-bonds in a more flexible conformation was empo-
lyed as a host for complexing 2a (Figure 4). Both
Supporting Information Available. Experimental pro-
cedures, analytical data. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX