Covalent reinforcement of hydrogen-bonded discs into stably folded helical structures

Article abstract of DOI:10.1021/ol201526g

The presence of covalent tethers significantly enhanced the stability of structures consisting of helically arranged benzenetricarboxamide units that otherwise undergo very weak hydrogen-bonding interaction. The resultant molecular structures were probed

Full text of DOI:10.1021/ol201526g

ORGANIC
LETTERS
2011
Vol. 13, No. 15
4008–4011
Covalent Reinforcement of
Hydrogen-Bonded Discs into Stably
Folded Helical Structures
Zhongzhu Chen,†,‡,^ Nathaniel D. Urban,§,^ Yi Gao, Wenrui Zhang,†,‡ Jingen Deng,†
Jin Zhu,*,† Xiao Cheng Zeng,*, and Bing Gong*,§
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu,
610041, China, Graduate University of Chinese Academy of Sciences, Beijing 100049,
China, Department of Chemistry, University at Buffalo, State University of New York,
Buffalo, New York 14260, United States, and Department of Chemistry, University of
Nebraska;Lincoln, Lincoln, Nebraska 68588, United States
bgong@acsu.buffalo.edu; jinzhu@cioc.ac.cn; xczeng@phase2.unl.edu
Received June 7, 2011
ABSTRACT
The presence of covalent tethers significantly enhanced the stability of structures consisting of helically arranged benzenetricarboxamide units
that otherwise undergo very weak hydrogen-bonding interaction. The resultant molecular structures were probed by computational study, which
predicted folded conformations consisting of helically arranged discs. Experimental studies confirmed the H-bonding interaction between the
disk units, the monomeric nature of the corresponding molecules in solution, and the helical conformations of such molecules.
Various columnar assemblies have resulted from the
stacking of disk-like and cyclic molecules.1 Reported ex-
amples include stacks of aromatic molecules,2 hydrogen-
bonded columns formed by 1,3,5-benzenetricarboxa-
mides,3 and tubular assemblies formed from stacked cyclic
peptides4 and oligosaccharides.5 Columnar assemblies
have attracted wide interest because they represent unique
motifs for creating nanoscaled structures. Unfortunately,
the self-assembly of disk-like or cyclic molecules is difficult
to control. The resultant stacks usually have ill-defined
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† Chengdu Institute of Organic Chemistry.
‡ Graduate University of Chinese Academy of Sciences.
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§ University at Buffalo, State University of New York.
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University of Nebraska;Lincoln.
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T.; Hanabusa, K. Macromolecules 2005, 38, 8983. (c) Wilson, A. J.;
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Chem. Soc. 2008, 130, 606. (e) Greef, T. F. A.; de ; Nieuwenhuizen,
M. M. L.; Stals, P. J. M.; Fitie, C. F. C.; Palmans, A. R. A.; Sijbesma,
R. P.; Meijer, E. W. Chem. Commun. 2008, 36, 4306. (f) Stals, P. J. M.;
Everts, J. C.; Bruijn, R. de; Filot, I. A. W.; Smulders, M. M. J.; Martin-
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^ These authors contributed equally to this work.
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r
10.1021/ol201526g
Published on Web 07/08/2011
2011 American Chemical Society

lengths, with few systems providing well-aligned columns.
Strategies for controlling both the length of a stack and the
alignment of the constituent discs or rings not only provide
new insights into the organization of the corresponding
assemblies but also enhance the ability to construct new
structures and to manipulate various materials properties
associated with the generated structures.6 A particularly
effective strategy for curbing the growth of a self-assembling
stack is to introduce oligomeric tethers7 that define the
number of stacking units, which, in many cases, may lead
to new foldamers.8 Polymeric tethers9 have also been
adopted to enhance the alignment and stability of colum-
nar structures consisting of stacked discs. Herein we
describe the creation of folded helical structures consisting
of multiply H-bonded aromatic rings that are covalently
grafted to tethers derived from oligoamines.
1a or 1b, serves as a control. These structures are designed
based on these considerations: (1) analogous 1,3,5-benze-
netricarboxamides were reported to self-assemble into
H-bonded columns of undefined lengths in the solid state
and to undergo H-bond-mediated assembly in organic
solvents (e.g., hydrocarbon) of very low polarity;3 (2)
chiral side chains based on the n-octyl ester of alanine
allow the chirality of covalently tethered stacks to be
probed; (3) the synthesis of the oligoamine tethers consist-
ing of the ꢀNH(CH2)3ꢀ units and other analogous tethers
is known,10 which allows the total length, and thus the
number of NH groups, of an oligoamine tether to be
controlled and adjusted. In addition to defining the num-
ber of “discs”, the presence of the covalent tethers serves to
greatly enhance the otherwise weak intermolecular
H-bonds between the discs into much more favorable
intramolecular ones, leading to discrete stacks with sig-
nificantly enhanced stabilities.
Compounds 1a and 1b, consisting of 1,3,5-benzenetria-
mide (“disc”) units attached to oligoamine tethers, were
designed. Compound 2, corresponding to a single disc of
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Figure 1. Side (left) and top (right) views of the structures of (a)
1a0 and (b) 1b0 optimized using the density functional theory
(DFT) within generalized-gradient approximation in the form
of a BLYP functional.11 For clarity, hydrogen atoms other than
those of the amide groups are not shown. Hydrogen bonds are
shown as green dashed lines.
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To probe the conformations of covalently tethered discs,
the structures of1a0 and 1b0, whichcorrespond to1aand 1b
with R1 and R2 being replaced by methyl groups, were
computationally optimized. As shown in Figure 1a, the
two parallel discs of 1a0 associate with each other via three
(8) For representative reviews on foldamers, see: (a) Gellman, S. H.
Acc. Chem. Res. 1998, 31, 173. (b) Kirshenbaum, K.; Zuckermann,
R. N.; Dill, K. A. Curr. Opin. Struct. Biol. 1999, 9, 530. (c) Gong, B.
Chem.;Eur. J. 2001, 7, 4336. (d) Hill, D. J.; Mio, M. J.; Prince, R. B.;
Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893. (e) Cheng, R. P.;
Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219. (f)
Cubberley, M. S.; Iverson, B. L. Curr. Opin. Chem. Biol. 2001, 5, 650.
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Goodman, C. M.; Choi, S.; Shandler, S.; DeGrado, W. F. Nat. Chem.
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Z. T.; Hou, J. L.; Li, C. Acc. Chem. Res. 2008, 41, 1343. (n) Horne, W. S.;
Gellman, S. H. Acc. Chem. Res. 2008, 41, 1399. (o) Saraogi, I.; Hamilton,
A. D. Chem. Soc. Rev. 2009, 38, 1726.
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Am. Chem. Soc. 2003, 125, 15935. (b) Wilson, A. J.; Masuda, M.;
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(c) Fitie, C. F. C.; Tomatsu, I.; Byelov, D.; Jeu, W. H.; Sijbesma, R. P.
Chem. Mater. 2007, 20, 2394. (d) Kastler, M.; Pisula, W.; Davies, R. J.;
Gorelik, T.; Kolb, U.; Mullen, K. Small 2007, 3, 1438. (e) Fitie, C. F. C.;
Mendes, E.; Hempenius, M. A.; Sijbesma, R. P. Macromolecules 2011,
44, 575.
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A.; Drandarov, K.; Chesnov, S.; Guggisberg, A.; Popaj, K.; Sergeyev, S.;
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Org. Lett., Vol. 13, No. 15, 2011
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intramolecular H-bonds among their amide side chains,
˚
and 1b (1 mM, 9.61ꢀ10.18 ppm for protons a, 7.67ꢀ8.03
ppm for protons c) showed significant downfield shifts in
comparison to those of 2 (4 mM, 7.90 ppm for proton a,
7.16 ppm for protons c), suggesting that the amide groups
of 1a and 1b were mostly involved in a highly favorable
intramolecular H-bonding interaction. The intramolecu-
larly H-bonded conformations of 1a and 1b were further
supported by comparing the concentration-dependent 1H
NMR spectra of 1a and 1b with those of 2 recorded in
CDCl3 at room temperature.11 The spectra of 2 showed
that, from 0.1 to 32 mM, the signal of amide proton a
underwent a significant shift from 7.33 to 8.63 ppm, while
proton c moved from 6.85 to 7.52 ppm. The observed large
shifts of the amide signals of 2 with concentration are
consistent withthe weakH-bonding between the molecules
with an interdisc distance of ∼3.6 A. The simultaneous
˚
satisfaction of the side-chain H-bonding distance (∼4.9 A
between the amide groups) and the interplanar stacking
distance leads to an overall helical conformation. Similar
to 1a0, the conformation of 1b0 is defined by a helically
˚
arranged stack, with an average distance of ∼5 A between
two H-bonded side chain amide groups and interplanar
˚
distances of ∼3.6 to 3.8 A between adjacent discs
(Figure 1b). The optimized conformation of a model
compound reveals that the ꢀ(CH2)3ꢀ spacer adopted for
˚
1a and 1b provides a length (∼5 A between adjacent N
˚
atoms) matching the distance (∼4.9 A) between H-bonded
side-chain amide groups. In contrast, the conformations of
another model compound indicate that a ꢀ(CH2)2ꢀ
spacer is too short to accommodate two H-bonded amide
groups.11
1
of 2. In contrast, the amide H signals of 1a showed no
detectable shift from 0.1 to 32 mM, being at 9.83 ppm
(protons a) and 7.69 ppm (protons c). Similarly, the amide
1H signals of 1b did not exhibit any detectable shift from
0.1 to 32 mM, with the chemical shifts of protons a
remaining in the range of 9.61 to 10.20 ppm and those of
proton c appearing between 7.61 and 8.07 ppm. These
results confirmed the intramolecular nature of the
H-bonding interactions associated with 1a and 1b, which
in turn is consistent with the optimized conformations
shown in Figure 1.
As shown in Scheme 1, treating oligoamines 3a and 3b11
with bromoacetyl bromide led to 4a and 4b. The modified
disc 511 was then coupled with 4a or 4b via thioether
linkages. The reaction between bromoacetyl and thiol
groups,12 which is well-known for its high efficiency, was
chosen to ensure the attachment of the discs to all the
reactive sites of the covalent tether. Indeed, compounds 1a
and 1b were obtained in satisfactory yields (52% for 1a,
56% for 1b) after extensive purification using column
chromatography followed by preparative TLC.11 Com-
pound 2 was prepared based on simple acylation.11
1
While data from H NMR studies demonstrate that 2
engages in intermolecular H-bonding, and point to the
presence of intramolecular H-bonding among the amide
side chains of 1a or 1b, the possibility that 1a and 1b may
associate via intermolecular H-bonding could not be ruled
out. The molecules of 1a or 1b could, albeit unlikely,
associate via intermolecular H-bonding into dimers or
higher oligomers with such high stabilities that lead to
the downfield shifts and concentration-independence ob-
served for their amide proton signals. To further examine
the presence or absence of intermolecular aggregates,
vapor pressure osmometry (VPO) studies were performed
on 1a and 1b in CHCl3 at room temperature.11 Using
polystyrene as molecular weight standards, VPO measure-
mentsonsolutionsof1afrom 5 to40mMconsistently gave
aggregation numbers that were close to one. VPO analysis
on 1b (5 mM to 40 mM) in CHCl3 revealed similar
aggregation numbers around one. The VPO results con-
firmed that, on average, the molecules of 1a or 1b existed
mostly as monomers in solution. Thus, the significant
downfield chemical shifts observed for the amide protons
of 1a or 1b in comparison to those of 2 must be mainly
contributed by intramolecular H-bonding that results in
folded conformations.
Scheme 1. Synthesis of Compounds 1a and 1b
The folded conformations of both 1a and 1b were then
probed by using CD spectroscopy in CHCl3. Consistent
with the helical conformations predicted by ab initio
computation (see Figure 1), strong CD signals with max-
ima at 304 nm and minima at 327 nm were observed in the
CD spectra of 1a (Figure 2a). As shown in Figure 2b, the
CD spectra of 1b and those of 1a are very similar, with
maxima at 308 nm and minima at 328 nm. The observed
CD signals for both 1a and 1b suggested that these two
The H-bonding interactions between the discs of 1a and
1
1b were probed by using H NMR.11 At comparable
concentrations in CDCl3, the amide protons of 1a (2
mM, 9.83 ppm for protons a, 7.70 ppm for protons c)
(11) Please see Supporting Information for details.
(12) Englebretsen, D. R.; Garnham, B.; Alewood, P. F. J. Org. Chem.
2002, 67, 5883.
4010
Org. Lett., Vol. 13, No. 15, 2011

(CHCl3/CH3OH = 60/40, v/v) also revealed strong CD
signals with linear concentration and temperature-depen-
dence. In contrast, no meaningful CD signals could be
recorded for 2 from 20 to 200 μM in CHCl3, suggesting
that, within this concentration range, compound 2 could
not undergo any meaningful aggregation or assembly.
These observations corroborate the above conclusion
made based on 1H NMR and VPO studies; i.e., the chiral
structures of 1a and 1b are of a molecular, instead of
supramolecular, nature, which also demonstrates the cri-
tical role played by covalent tethers in reinforcing the
association between the discs and in maintaining the chiral
conformations of these two compounds.
In summary, attaching disk-like benzenetricarboxamide
units to covalent tethers has led to molecular structures
adopting well-defined helical conformations that are
further stabilized by favorable intramolecular H-bonding.
The conformations of 1a and 1b predicted by ab initio
1
computation were supported by results from H NMR,
which revealed the dramatically enhanced H-bonding
interactions between the dics; VPO, which confirmed the
overall monomeric nature of the molecules in solution; and
CD, which pointed to chiral confomrations that can be
best rationalized with those predicted by ab initio calcula-
tion. This study serves to demonstrate the effectiveness of
covalent tethers in guiding and stabilizing otherwise
weakly associating structural units into folded molecular
structures of defined conformations.
Figure 2. Concentration-dependent CD spectra of (a) 1a and (b)
1b recorded in CHCl3 at room temperature.
compounds adopt similar chiral conformations with a
handedness that is biased owing to the transfer of chirality
from the UV-silent side chains to the stacked aromatic
rings. From 20 to 200 μM, the CD spectra recorded for
both 1a and 1b share the same shape (Figure 2), with the
increase in the intensities of CD signals being linear across
this concentration range.11 Besides, from ꢀ10 to 50 ꢀC, the
CD spectra of 1a and 1b revealed little change in shape and
a linear change of signal intensity with temperature. CD
spectra of 1b recorded in a solvent of enhanced polarity
Acknowledgment. This work was supported by the
Natural Science Foundation of China (NSFC Grants
21072187, 20772123, and 20428202) and the U.S. National
Science Foundation (CBET-1036171 and CBET-
1066947).
Supporting Information Available. 1H NMR spectra,
CD, and analytical data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 15, 2011
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