One-pot synthesis and AFM imaging of a triangular aramide macrocycle

Article abstract of DOI:10.1021/ja506646s

Macrocyclizations in exceptionally good yields were observed during the self-condensation of Nbenzylated phenyl p-aminobenzoates in the presence of LiHMDS to yield three-membered cyclic aramides that adopt a triangular shape. An ortho-alkyloxy side chain on the N-benzyl protecting group is necessary for the macrocyclization to occur. Linear polymers are formed exclusively in the absence of this Li-chelating group. A model that explains the lack of formation of other cyclic congeners and the demand for an N-(o-alkoxybenzyl) protecting group is provided on the basis of DFT calculations. High-resolution AFM imaging of the prepared molecular triangles on a calcite(10.4) surface shows individual molecules arranged in groups of four due to strong surface templating effects and hydrogen bonding between the molecular triangles.

Full text of DOI:10.1021/ja506646s

Communication
pubs.acs.org/JACS
One-Pot Synthesis and AFM Imaging of a Triangular Aramide
Macrocycle
†,∥
Christof Storz,† Michael Badoux,† Christopher M. Hauke,‡,§ Tomas Solomek, Angelika Kuhnle,‡
̌
́
̌
̈
Thomas Bally,† and Andreas F. M. Kilbinger*,†
†Department of Chemistry, University of Fribourg, Chemin du Musee
́
9, CH-1700 Fribourg, Switzerland
‡Institut fur Physikalische Chemie, Johannes Gutenberg Universitat Mainz, Duesbergweg 10-14, D-55099 Mainz, Germany
̈
̈
§Graduate School of Excellence Materials Science in Mainz, Staudinger Weg 9, D-55128 Mainz, Germany
∥RECETOX and Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic
S
* Supporting Information
Formation of cyclic aramides. During our work16,17 on
ABSTRACT: Macrocyclizations in exceptionally good
yields were observed during the self-condensation of N-
benzylated phenyl p-aminobenzoates in the presence of
LiHMDS to yield three-membered cyclic aramides that
adopt a triangular shape. An ortho-alkyloxy side chain on
the N-benzyl protecting group is necessary for the
macrocyclization to occur. Linear polymers are formed
exclusively in the absence of this Li-chelating group. A
model that explains the lack of formation of other cyclic
congeners and the demand for an N-(o-alkoxybenzyl)
protecting group is provided on the basis of DFT
calculations. High-resolution AFM imaging of the prepared
molecular triangles on a calcite(10.4) surface shows
individual molecules arranged in groups of four due to
strong surface templating effects and hydrogen bonding
between the molecular triangles.
polycondensation of phenyl p-aminobenzoates 1 substituted
with the acid labile N-2,4-dimethoxybenzyl and the more bulky
N-2,4-bis((2-ethylhexyl)oxy)benzyl group we observed, besides
the anticipated formation of linear polymers, an unexpected
formation of cyclic tri(p-benzamide)s 2. As shown in Scheme 1,
Scheme 1. Conformation-Directed Macrocyclization (n.o. =
not observed)
hape-persistent macrocycles1−4 are of special interest due
Sto their rigid backbone, which often leads to self-
aggregation into columnar stacks, and that can be eventually
used for transport and separation processes5,6 or as rigid
scaffolds with well-defined cavities for catalytic or biomimetic
applications.7,8
The preparation of macrocycles presents a major challenge
and has thus been studied intensively. A typical approach to a
macrocycle is an intramolecular end to end macrocyclization of
a linear α,ω-difunctionalized precursor which is synthesized in a
stepwise manner. Such a synthesis is often obstructed by
formation of undesired side products, low reaction yields, and
the need for high-dilution conditions.9,10 Therefore, highly
efficient preparations of macrocycles have become the subject
of considerable importance. Several strategies have been
reported to improve the efficiency of macrocyclizations such
as cyclooligomerization,4 intermolecular coupling between two
or more oligomeric fragments,4 or templated cyclizations11,12
and strategies based on dynamic covalent chemistry.13−15
Among the various methods to build a macrocycle, the one-pot
approach is of particular interest. However, most of the one-
step cyclizations described so far lead to rather low yields due
to the entropically disfavored nature of the cyclization and the
ensuing extensive separation and purification steps.
self-condensation of a 0.06 M solution of monomers 1 with 1.5
equiv of LiHMDS (1 M solution in THF) afforded the
corresponding cyclic trimers 2 and a linear polymer. The
formation of 2 was confirmed by high-resolution MALDI FT-
ICR mass spectrometry (Figure SI16,17) and NMR spectros-
copy (Figure SI7,8). The isolated yield of 2 (33% and 48% for
2a and 2b, respectively) was higher when the more bulky N-
protecting group was used. At increasing monomer concen-
trations, the formation of 2a diminished until a linear polymer
was the only product, whereas the yield of 2b was hardly
affected. The higher steric bulk of the 2-ethylhexyl group
presumably hinders the nucleophilic attack of 1 on the open-
ring form of the trimer and, therefore, prevents the polymer
chain growth even at a relatively high concentration of
monomer 1.
Received: July 2, 2014
Published: September 1, 2014
© 2014 American Chemical Society
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Communication
The formation of 2 was rather surprising because it has been
previously shown that the macrocyclization of methyl N-(2,4-
dimethoxybenzyl)-4-aminobenzoate in the presence of
LiHMDS to form 2 was unsuccessful, most probably because
preferred in tetramer 4 and presumably in longer congeners,39
while the four lowest-energy conformations of 3 or 3−
represent potential energy minima that directly lead to the
corresponding macrocycles (Tables SI3−SI6; Figures SI22 and
SI23). Thus, the probability of longer oligomers to unfold the
“helix” to adopt conformations that lead to macrocyclization is
very low compared to that of trimers, for which the
macrocyclization occurs also at relatively high monomer
concentration in spite of the penalizing strain energy.
of the deactivation of the methyl ester by the aminyl anion.18
A
more reactive ester group (phenyl ester) is apparently needed
for the self-condensation of the monomer to occur.19 In
addition, self-condensation of extended methyl aminobenzoates
(based on trans-stilbene and diphenylacetylene) that cannot be
deactivated by the aminyl anion has already been reported.20
When the monomer 1c, which bears only a p-alkoxy
substituted N-benzyl protecting group, was exposed to the
same reaction conditions described above (Scheme 1), only a
linear polymer resulted at both concentrations, as evidenced by
gel permeation chromatography (Table SI1).
Our calculations show that the Li+ ion is indeed strongly
coordinated to the deprotonated nitrogen atom in 1 (Table
SI7), and it will thus serve as an additional templating element
like the H-bonds in 3, and it will also affect the transition states
to macrocyclization.
The role of the N-(o-alkoxybenzyl) protecting group. These
transition states were located first for 3− in the absence of Li+.
We found four transition states that lead to tetrahedral
intermediates (see 6 in Scheme 2), from which the ester
alkoxy group departure provides the final macrocycle.
There are several examples of conformation-20−29 and H-
bonding-30−37 directed macrocyclizations based on amide bond
formation. In previous investigations of cyclic para-linked
oligoaramides the group of Azumaya et al. described the
synthesis of N-methylated cyclic trimers,22,26 similar to those
that we observe in our current work, with dehydration agents.
Yokozawa et al. showed the formation of N-alkylated cyclic
hexamers from dimers in the presence of a strong base under
high-dilution conditions.28
Scheme 2. A Model Macrocyclization Reaction
The preferential formation of trimers. The formation of the
three-membered macrocyclic aramides, which can easily be
shown to have more strain energy than their larger congener 4
(Figure 1, Table SI2), can be explained by biased
These transition states differ in relative orientation of the N-
Me and the ester methoxy groups. Coordination of a Li+
stabilizes the open-ring forms and increases the reaction barrier
considerably (from 5 to 11 to >16 kcal mol−1) for all but one of
the four transition states, which remained nearly unaffected
(entry 1 in Table 1, details in SI). This was then modified to
Table 1. Energies of the Macrocyclization Transition States
a
entry
compound
ΔE (0 K, kcal mol−1
)
1
2
3
4
3−···Li+
5a
10.0
12.4
11.6
9.0
5b
5c
a
Figure 1. Structures of the models used in the conformational search
(top) and the corresponding lowest-energy conformers of 3 and 4
(bottom). Other conformers can be found in the SI.
M06-2X/6-311+G(2d,p)/PCM energies on M06-2X/6-31G(d)/
PCM optimized geometries with nonscaled ZPVE corrections
included; details in SI.
conformations that the open-ring forms of 2 adopt in the
bear a substituted N-benzyl protecting group (5a−c in Scheme
2). The barriers found with the reoptimized transition states are
summarized in Table 1, and the structure of the lowest-energy
transition state is depicted in Figure 2. The presence of an o-
alkoxy group has further lowered the energy of the transition
state to macrocyclization, while it has increased for all other
derivatives considered. The structure of the transition state in
Figure 2 suggests that an N-(o-alkoxybenzyl) protecting group
with additional steric bulk may additionally help to prevent the
chain growth process by blocking the incoming nucleophilic
monomer in agreement with our experimental observation (see
Scheme 1).
solution. We performed calculations to support this notion
previously reported by groups of Yokozawa39 and Wilson.29
A
library of conformers of model open-ring trimer 3, tetramer 4
(Figure 1), and their conjugate bases was generated by a
conformational search algorithm followed by a subsequent
optimization using M06-2X density functional (details in SI).
The final computed energies were used to calculate the
Boltzmann distribution of the conformers in a THF solution.
The preferred cis conformation of N-substituted aromatic
amides38 confines 3 or 4 to preferentially adopt all-cis
conformations. A helical conformation is, therefore, strongly
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Communication
Figure 2. Macrocyclization transition state for 5c with a Li+ counterion
(gray dot) coordinated in between the amino nitrogen and the ester
carbonyl oxygen atoms; side-view (left) and bottom-view (right).
Figure 3. (a,b) NC-AFM topography images of the self-assembled
structures of 7 after the deposition on calcite(10.4). Note that the
calcite step edge, marked by the dashed line in (a), does not serve as
nucleation center. (b) Magnification of the structures shown in (a).
Already at this scale, the highly ordered inner structure is visible.
Deprotection of N-(o-alkoxybenzyl) protecting groups. An
acid-promoted deprotection of the two cyclic trimers 2a,b in
trifluoroacetic acid in the presence of triisopropylsilane and
heating at 65 °C for 18 h (Scheme 3) resulted in the cyclic
Scheme 3. Deprotection of Cyclic Trimers 2
tri(p-benzamide) 7 that has previously been reported by the
group of Wilson in a 10 step synthesis with an overall yield of
8%.24 With our improved one-step macrocyclization approach,
7 is now accessible in three straightforward steps with an overall
yield of 43%.
The AFM study of 7 on a calcite surface. The crystal structure
of 7 features three cis-amides positioned within the same plane
separated by 120° angles that are connected via H-bonding in
exclusively two dimensions.24 Such a structural feature could
lead to highly ordered H-bonded two-dimensional networks. A
sample of 7 was therefore sublimed onto a calcite(10.4) surface
and investigated by noncontact atomic force microscopy (NC-
AFM) in ultrahigh vacuum. Due to its comparatively high
surface energy, calcite has been proven to be a viable candidate
for molecular self-assembly on an insulating surface.40 Indeed,
NC-AFM measurements reveal the formation of islands that
form stable wetting layers with a highly ordered inner structure
(Figure 3).
Figure 4a shows a typical high-resolution image of the self-
assembled structure. The apparent height of the islands of 0.4−
0.5 nm and the spot size are in good agreement with the
molecular dimensions of 7. We hence assign each spot in the
image to a single molecule. The spots are arranged in units of
four, as indicated by the gray and black circles. These units
form molecular rows running from the upper left to the lower
right corner in the image. A possible model of the molecular
orientation is given in Figure 4b, largely matching the
molecule’s crystal structure.24 The rows’ repeat distance of
(2.0 0.1) nm along the substrate [01.0] direction is enlarged
Figure 4. (a) High-resolution NC-AFM topography image of a self-
assembled wetting layer of cyclic tri(p-benzamide) 7 on the
calcite(10.4) surface. The main crystal directions are given by the
arrows. (b) Possible model for the molecular orientation.
by ∼13% with respect to the crystal structure but exactly
matches four times the calcite repeat distance of 0.5 nm along
this direction. The deviation from the crystal structure is thus
most likely caused by the substrate’s strong templating effect,
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Journal of the American Chemical Society
Communication
(19) Yokozawa, T.; Sugi, R.; Asai, T.; Yokoyama, A. Chem. Lett. 2004,
33, 272.
causing the self-assembled structures to adapt to the surface
structure and orientation. This templating effect has been
observed for a considerable amount of organic molecules on
the calcite(10.4) surface.41
(20) Yokoyama, A.; Maruyama, T.; Tagami, K.; Masu, H.; Katagiri,
K.; Azumaya, I.; Yokozawa, T. Org. Lett. 2008, 10, 3207.
(21) Blankenstein, J.; Zhu, J. P. Eur. J. Org. Chem. 2005, 1949.
(22) Azumaya, I.; Okamoto, T.; Imabeppu, F.; Takayanagi, H.
Heterocycles 2003, 60, 1419.
(23) Katagiri, K.; Tohaya, T.; Masu, H.; Tominaga, M.; Azumaya, I. .
J. Org. Chem. 2009, 74, 2804.
(24) Campbell, F.; Kilner, C. A.; Wilson, A. J. Tetrahedron Lett. 2010,
51, 1361.
(25) Ohishi, T.; Suzuki, T.; Niiyama, T.; Mikami, K.; Yokoyama, A.;
Katagiri, K.; Azumaya, I.; Yokozawa, T. Tetrahedron Lett. 2011, 52,
7067.
In conclusion, we have demonstrated that cyclic tri(p-
benzamide)s 2 can be obtained via one-step macrocyclization in
exceptionally high yields using chelating N-protecting groups in
combination with LiHMDS. Furthermore, a model for the
macrocyclization is proposed and supported by DFT
calculations. The macrocycle 2 can be easily deprotected to
yield 7 that represents a shape-persistent “molecular triangle”.
High-resolution AFM revealed its highly ordered two-dimen-
sional orientation on calcite surfaces. Such ordered arrays of
macrocycles might prove useful for the encapsulation of guest
molecules or suitably sized cations with well-defined spatial
separation.
(26) Katagiri, K.; Ikeda, T.; Muranaka, A.; Uchiyama, M.; Tominaga,
M.; Azumaya, I. Tetrahedron: Asymmetry 2009, 20, 2646.
(27) Azumaya, I.; Kagechika, H.; Yamaguchi, K.; Shudo, K.
Tetrahedron Lett. 1996, 37, 5003.
(28) Yokoyama, A.; Shimizu, Y.; Yokozawa, T. Chem. Lett. 2005, 34,
1128.
ASSOCIATED CONTENT
■
(29) Campbell, F.; Plante, J.; Carruthers, C.; Hardie, M. J.; Prior, T.
J.; Wilson, A. J. Chem. Commun. 2007, 2240.
(30) Carver, F. J.; Hunter, C. A.; Shannon, R. J. J. Chem. Soc. Chem.
Comm. 1994, 1277.
(31) Xing, L. Y.; Ziener, U.; Sutherland, T. C.; Cuccia, L. A. Chem.
Commun. 2005, 5751.
(32) Du, Z. Y.; Ren, C. L.; Ye, R. J.; Shen, J.; Maurizot, V.; Lu, Y. J.;
Wang, J.; Zeng, H. Q. Chem. Commun. 2011, 47, 12488.
(33) Qin, B.; Ong, W. Q.; Ye, R. J.; Du, Z. Y.; Chen, X. Y.; Yan, Y.;
Zhang, K.; Su, H. B.; Zeng, H. Q. Chem. Commun. 2011, 47, 5419.
(34) Jiang, H.; Leger, J. M.; Guionneau, P.; Huc, I. Org. Lett. 2004, 6,
2985.
S
* Supporting Information
Experimental procedures and NMR, GPC, ESI-MS, MALDI
FT-ICR MS, and AFM data. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
andreas.kilbinger@unifr.ch
Notes
The authors declare no competing financial interest.
(35) Yuan, L. H.; Feng, W.; Yamato, K.; Sanford, A. R.; Xu, D. G.;
Guo, H.; Gong, B. J. Am. Chem. Soc. 2004, 126, 11120.
(36) Ferguson, J. S.; Yamato, K.; Liu, R.; He, L.; Zeng, X. C.; Gong,
B. Angew. Chem., Int. Ed. 2009, 48, 3150.
(37) 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.
(38) Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.;
Shudo, K. Tetrahedron Lett. 1989, 30, 6177.
(39) Tanatani, A.; Yokoyama, A.; Azumaya, I.; Takakura, Y.; Mitsui,
C.; Shiro, M.; Uchiyama, M.; Muranaka, A.; Kobayashi, N.; Yokozawa,
T. J. Am. Chem. Soc. 2005, 127, 8553.
ACKNOWLEDGMENTS
■
The authors thank the Deutsche Forschungsgemeinschaft
(DFG) and the Swiss National Science Foundation (SNF)
for funding. T.S. acknowledges the support from the Czech
Ministry of Education (LO1214).
REFERENCES
■
(1) Grave, C.; Schluter, A. D. Eur. J. Org. Chem. 2002, 3075.
(2) Zhao, D. H.; Moore, J. S. Chem. Commun. 2003, 807.
(3) MacLachlan, M. J. Pure. Appl. Chem. 2006, 78, 873.
(4) Zhang, W.; Moore, J. S. Angew. Chem., Int. Ed. 2006, 45, 4416.
(5) Pasini, D.; Ricci, M. Curr. Org. Synth. 2007, 4, 59.
(6) Bong, D. T.; Clark, T. D.; Granja, J. R.; Ghadiri, M. R. Angew.
Chem., Int. Ed. 2001, 40, 988.
(40) Rahe, P.; Lindner, R.; Kittelmann, M.; Nimmrich, M.; Kuhnle,
̈
A. Phys. Chem. Chem. Phys. 2012, 14, 6544.
(41) Rahe, P.; Kittelmann, M.; Neff, J. L.; Nimmrich, M.; Reichling,
M.; Maas, P.; Kuhnle, A. Adv. Mater. 2013, 25, 3948.
̈
(7) Rebek, J. Science 1987, 235, 1478.
(8) Martell, A. E.; Perutka, J.; Kong, D. Coord. Chem. Rev. 2001, 216,
55.
(9) Knops, P.; Sendhoff, N.; Mekelburger, H. B.; Vogtle, F. Top. Curr.
Chem. 1992, 161, 3.
(10) Rossa, L.; Vogtle, F. Top. Curr. Chem. 1983, 113, 1.
(11) Mccallien, D. W. J.; Sanders, J. K. M. J. Am. Chem. Soc. 1995,
117, 6611.
(12) Anderson, H. L.; Sanders, J. K. M. Angew. Chem., Int. Ed. 1990,
29, 1400.
(13) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.;
Stoddart, J. F. Angew. Chem., Int. Ed. 2002, 41, 898.
(14) Furlan, R. L. E.; Otto, S.; Sanders, J. K. M. Proc. Natl. Acad. Sci.
U.S.A. 2002, 99, 4801.
(15) Otto, S.; Furlan, R. L. E.; Sanders, J. K. M. J. Am. Chem. Soc.
2000, 122, 12063.
(16) Storz, C.; Schulze, M.; Kilbinger, A. F. M. Macromol. Rapid
Commun. 2011, 32, 238.
(17) Schulze, M.; Michen, B.; Fink, A.; Kilbinger, A. F. M.
Macromolecules 2013, 46, 5520.
(18) Campbell, F.; Wilson, A. J. Tetrahedron Lett. 2009, 50, 2236.
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