A folded, secondary structure in step-growth oligomers from covalently linked, crowded aromatics

Article abstract of DOI:10.1021/ja034001d

This study delineates general methods to create a new class of folded oligomers by covalently attaching overcrowded aromatics to each other. Crucial to observing the secondary structure in these oligomers was the employment of C-shaped linkers. These link

Full text of DOI:10.1021/ja034001d

Published on Web 03/28/2003
A Folded, Secondary Structure in Step-Growth Oligomers
from Covalently Linked, Crowded Aromatics
Wei Zhang, Dana Horoszewski, John Decatur, and Colin Nuckolls*
Contribution from the Department of Chemistry, Columbia UniVersity,
New York, New York 10027
Received January 1, 2003; E-mail: cn37@columbia.edu
Abstract: This study delineates general methods to create a new class of folded oligomers by covalently
attaching overcrowded aromatics to each other. Crucial to observing the secondary structure in these
oligomers was the employment of C-shaped linkers. These linkers preorganize the strands to form
intramolecular hydrogen bonds. In solution, one- and two-dimensional 1H NMR data show well-defined
columnar conformations. The side chains in these oligomers are critical for the secondary structure to
emerge in solution. Using tris(dodecyloxy)phenethyl side chains in combination with tert-butyl side chains
in the terminal subunit provides a soluble trimer and prevents intermolecular association above millimolar
concentrations. This new folding motif, formed through a synergy between hydrogen bonds and π-stacking,
is so robust that even dimers have secondary structure in solution.
Introduction
In recent years, there has been intense interest in the design,
synthesis, and study of abiotic oligomers of defined length that
fold into well-defined secondary structures known as foldamers.1
Crowded aromatics such as 1 (Figure 1a) were recently shown2
to be a general method to create discotic-like liquid crystals3
held together by hydrogen bonds.4 Detailed below are the
synthetic methods to covalently attach these mesogens to each
other (Figure 1b) and data showing that only when certain linkers
are employed do the oligomers fold into well-defined columnar
conformations in solution. This new folded motif, formed
through a synergy between hydrogen bonds1 and π-stacking,5
Figure 1. (a) Previously reported mesogen.2 (b) Schematic representing a
covalently linked trimer of 1.
is so robust that even dimers have secondary structures in
solution.
(1) For foldamers, see: (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F.
Chem. ReV. 2001, 101, 3219-3232. (b) Hill, D. J.; Mio, M. J.; Prince, R.
B.; Hughes, T. S.; Moore, J. S. Chem. ReV. 2001, 101, 3893-4011. (c)
Seebach, D.; Beck, A. K.; Rueping, M.; Schreiber, J. V.; Sellner, H. Chimia
2001, 55, 98-103.
(2) (a) Bushey, M. L.; Hwang, A.; Stephens, P. W.; Nuckolls, C. J. Am. Chem.
Soc. 2001, 123, 8157-8158. (b) Bushey, M. L.; Hwang, A.; Stephens, P.
W.; Nuckolls, C. Angew. Chem., Int. Ed. 2002, 41, 2828-2831. (c) Nguyen,
T.-Q.; Bushey, M. L.; Brus, L. E.; Nuckolls, C. J. Am. Chem. Soc. 2002,
124, 15051-15054.
(3) For leading references on discotic liquid crystals, see: (a) Guillon, D. Struct.
Bonding 1999, 95, 41-82. (b) Chandrasekhar, S.; Prasad, S.; Krishna, A.
Contemp. Phys. 1999, 40, 237-245. (c) Chandrasekhar, Ranganath, G. S.
Rep. Prog. Phys. 1990, 53, 57-84. (d) Boden, N.; Bushby, R. J.; Clements,
J.; Movaghar, B. J. Mater. Chem. 1999, 9, 2081-2086.
Results and Discussion
Synthesis. To screen for the efficacious linkers and side
chains, a synthetic method is required that differentiates the
amide side chains of 1. The synthesis of the monoacid, diamides
6-8 is shown in Scheme 1.6 The hexasubstituted aromatic core
is prepared by a Lewis acid-induced double chloromethylation
of methyl 2,4,6-tris(dodecyloxy)benzoate.7 Conversion to di-
acetate 48 followed by saponification and oxidation9 produces
the diacid, monoester 5. The acid functions are coupled with
(4) Hydrogen bonds used to stabilize π-stacks: (a) Matsunaga, Y.; Miyajima,
N.; Nakayasu, Y.; Sakai, S.; Yonenaga, M. Bull. Chem. Soc. Jpn. 1988,
61, 207-210. (b) Brunsveld, L.; Zhang, H.; Glasbeek, M.; Vekemans, J.
A. J. M.; Meijer, E. W. J. Am. Chem. Soc. 2000, 122, 6175-6182 and
references therein. (c) Yasuda, Y.; Iishi, E.; Inada, H.; Shirota, Y. Chem.
Lett. 1996, 7, 575-576. (d) Lightfoot, M. P.; Mair, F. S.; Pritchard, R. G.;
Warren, J. E. J. Chem. Soc., Chem. Commun. 1999, 19, 1945-1946. (e)
Ranganathan, D.; Kurur, S.; Gilardi, R.; Karle, I. L. Biopolymers 2000,
54, 289-295. (f) Paleos, C. M.; Tsiourvas, D. Angew. Chem., Int. Ed. Engl.
1995, 34, 1696-1711 and references therein. (g) Brienne, M. J.; Gabard,
J.; Lehn, J. M.; Stibor, I. J. Chem. Soc., Chem. Commun. 1989, 24, 1868-
70. (h) Goldmann, D.; Dietel, R.; Janietz, D.; Schmidt, C.; Wendorff, J. H.
Liq. Cryst. 1998, 24, 407-411. (i) Ungar, G.; Abramic, D.; Percec, V.;
Heck, J. A. Liq. Cryst. 1996, 21, 73-86. (j) Percec, V.; Ahn, C.-H.; Bera,
T. K.; Ungar, G.; Yeardley, D. J. P. Chem.- Eur. J. 1999, 5, 1070-1083.
(k) Malthete, J.; Levelut, A. M.; Liebert, L. AdV. Mater. 1992, 4, 37-41.
(l) Pucci, D.; Veber, M.; Malthete, J. Liq. Cryst. 1996, 21, 153-155.
(5) Foldamers that utilize π-stacking: (a) see ref 1b. (b) Lokey, R. S.; Iverson,
B. L. Nature 1995, 375, 303-305. (c) Tanatani, A.; Yamaguchi, K.;
Azumaya, I.; Fukutomi, R.; Shudo, K.; Kagechika, H. J. Am. Chem. Soc.
1998, 120, 6433-6442.
(6) Spectra and experimental procedures are contained in the Supporting
Information.
(7) By the method of: Schirch, P. F. T.; Boekelheide, V. J. Am. Chem. Soc.
1981, 103, 6873-6878.
(8) Similar to: (a) Wallenfels, K.; Witzler, F.; Friedrich, K. Tetrahedron 1967,
23, 1845-1855. (b) Anthony, J. E.; Khan, S. I.; Rubin, Y. Tetrahedron
Lett. 1997, 38, 3499-3502.
(9) A two-step oxidation sequence was used first to yield the bis(aldehyde)
((a) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
7, 639-666) and then the bis(carboxylic acid) ((b) Lindgren, B. O.; Nilsson,
T. Acta Chem. Scand. 1973, 27, 888).
9
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10.1021/ja034001d CCC: $25.00 © 2003 American Chemical Society

Folded, Secondary Structure in Step-Growth Oligomers
A R T I C L E S
Scheme 1 a
Scheme 2 a
a Reagents and conditions: (a) ClCH2OMe, ZnCl2; (b) AcONa, AcOH,
∆; (c) (i) KOH, rt; (ii) TPAP, NMO, 4-Å molecular sieves; (iii) NaClO2,
NaH2PO4, t-BuOH/2-methyl-2-butene; (d) (i) SOCl2; (ii) R1NH2, Et3N; (iii)
KOH, ∆.
a Reagents and conditions: (a) (i) KOH (1 equiv), rt; (ii) TPAP, NMO,
4-Å molecular sieves; (iii) NaClO2, NaH2PO4, t-BuOH/2-methyl-2-butene;
(b) R1NH2, EDC, HOAt, DMAP; (c) (i) KOH, ∆; (ii) BocNH-X-NH2, EDC,
HOAt, DMAP; (iii) TPAP, NMO, 4-Å molecular sieves; (iv) NaClO2,
NaH2PO4, t-BuOH/2-methyl-2-butene; (d) 8-NH-X-NH2, EDC, HOAt,
DMAP; (e) (i) HCl in Et2O; (ii) 6, EDC, HOAt, DMAP.
The synthesis shown in Scheme 2 allows each of the amide
side chains to be individually addressed so that higher oligomers
can be constructed.6 The monoalcohol results from hydrolysis
of one of the acetate functions of 4. This compound is then
elaborated through a sequence similar to that used in Scheme 1
to produce the key bifunctional intermediate 18. Through a
coupling/deprotection strategy similar to what was used for
heterodimer 12, the trimer 20 can be synthesized. This route is
universal and should allow for the synthesis of higher step-
growth oligomers.
Determination of Secondary Structure. An energy-mini-
mized molecular model11 of a trimer that adopts a columnar
motif due to the three hydrogen bonds between each subunit is
shown in Figure 3. The linker used in this model is the 1,8-
naphthalenediol-derived linker I. Models using linker II show
a similar structure. Linker IV, derived from 2,6-naphthalenediol,
serves as a control experiment, being too rigid and linear to
allow intramolecular hydrogen bonds to form. An important
feature of the models is that they display a folded motif if the
linkers are linear alkyl (longer than 10 carbons) like III or
curved and more rigid like I and II. The studies below test the
importance of a C-shaped, preorganized linker.
Figure 2. (a) Homo- and heterodimers synthesized with linker I. (b)
Homodimers with linkers II-IV.
Shown in Table 1 is a comparison of the amide 1H resonances
for the homodimers 9-11 and 13-15 and monomer 1. Of the
solvents tested (including acetone, benzene, chloroform, dichlo-
romethane, DMF, and dimethyl sulfoxide), only THF-d8 was
able to dissolve each of the compounds listed in Table 1. For
linker I or II with phenethyl side chains, the amide resonances
occur around 8 ppm. However, the resonances for dimers with
amines, and the ester is saponified to yield the monoacids 6-8
in 31-36% yield from 2.
The monoacid, diamides 6-8 are coupled10 with the primary
diamines of linkers I-IV (shown in Figure 2) to yield
homodimers 9-11 and 13-15. A monoprotected version of
linker I allowed the heterodimer 12 to be synthesized from
coupling two different subunits, 8 and 6.6
(11) Molecular modeling was performed using MacroModel v.7.0 and the
Amber* forcefield: Mohamadi, F.; Richards, N. G. J.; Guida, W. C.;
Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still,
W. C. J. Comput. Chem. 1990, 11, 440-467.
(10) By the method of: Xu, Y.; Miller, M. J. J. Org. Chem. 1998, 63, 4314-
4322.
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A R T I C L E S
Zhang et al.
Figure 3. Top and side views of an energy-minimized11 computer model
for a trimer that is tethered with a substituted naphthalene linker. The
oligomer folds itself into a columnar conformation in solution (side chains
omitted to clarify the view).
Table 1. Amide 1H NMR Resonances for 1 and Homodimers
9-11 and 13-15a
linker
nonlinker
linker
side chain
N−H/ppm
N−H/ppm
monomer
dimer
1
phenethyl
7.18
9
10
11
13
14
15
I
I
I
II
III
IV
phenethyl
t-Bu
TDP
phenethyl
phenethyl
phenethyl
8.21
7.63
8.07
8.08
7.19
7.32
8.03
6.67
7.81
7.97
7.30
7.20
a For 9-11 and 13-15, 1 mM, THF-d8, 333 K. For 1, 2 mM, THF-d8,
333 K.
linkers III and IV and for the monomer 1 occur ∼1 ppm upfield.
The large downfield shifts of amide resonances are diagnostic
of hydrogen bond formation. Therefore, the C-shaped linkers
with subunits derived from 7 are able to form intramolecular
hydrogen bonds while the energetic cost is too great to
reorganize the linear alkyl linker III.
Figure 4. NOE couplings and 1H NMR spectra (1 mM in CD2Cl2, 303 K)
for (a) 12 and (b) 20.
are almost insoluble in these solvents due to an extended
intermolecular hydrogen bond network being formed.
Also demonstrated by the data in Table 1, the choice of side
chain is critical for a folded conformation to be observed in
solution. Oligomers initially synthesized employed the phenethyl
side chains because they had proven effective in yielding regular
columnar assemblies from 1.2 The bulkiness of the side chains
for dimer 10 is too great, and its amide resonances are shifted
upfield relative to 9 and 12 (shown for 12 in Figure 4a).
The tris(dodecyloxy)phenethyl (TDP) side chain was used
to impart greater solubility to the oligomers,12 and its amide
resonances are downfield shifted similar to those from the
subunit with phenethyl side chains. As an example of the
solubilizing power of the TDP side chain, a trimer was initially
synthesized with phenethyl side chains and proved to be soluble
only below millimolar quantities in dichloromethane. In contrast,
trimer 20 with the TDP side chains is soluble beyond 20 mM
in dichloromethane.
For the heterodimer 12 derived from two different subunits
one with TDP and one with tert-butyl amide subunits, there
are distinct sets of amide resonances, two upfield (∼6-7 ppm)
and two downfield (∼7.6-8 ppm) shown in Figure 4a. The
downfield amide resonances are derived from the TDP side-
chain amides and one of the linker amides, and the far upfield-
shifted resonances are from the tert-butyl amides and the
remaining proton on the linker amide. This implies that the tert-
butyl amides are able to act as the hydrogen bond acceptor
through their carbonyls and the TDP amides act as the hydrogen
bond donor and that each of the linker amides acts independently
as a donor and as an acceptor. Dilution experiments on 12 reveal
that its amide resonances are constant (within 0.015 ppm)
between 3 and 0.2 mM.
Shown in Figure 4a is the result of a two-dimensional
ROESY-NMR experiment for heterodimer 12 in CD2Cl2.13
There are three NOE couplings between the TDP side chains
(both the aromatic singlet and the two methylenes) and the tert-
butyl side chains. In molecular models of an extended confor-
mation, these protons are >10 Å from each other, much too far
Another strong indication that there are intramolecular
hydrogen bonds in dimers with C-shaped linkers is their
solubility profile. 9 and 11-13 are freely soluble in chloroform
and dichloromethane while dimers with linear linkers (14, 15)
(12) These side chains have proven useful in solubilizing other discotics; see
refs 4i,j.
(13) By the procedure of: Bothner-By, A. A.; Stephens, R. L.; Lee, J.; Warren,
C. D.; Jeanloz, R. W. J. Am. Chem. Soc. 1984, 106, 811-813.
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Folded, Secondary Structure in Step-Growth Oligomers
A R T I C L E S
to display through space couplings, but are held ∼2.3-2.7 Å
apart by the intramolecular hydrogen bonds in the folded
conformation.
studies are derivatizing each subunit differently to see whether
columns with programmed functionality can yield tertiary and
quaternary structure in solution.
1
In the H NMR spectrum (Figure 4b) for trimer 20, nine
Experimental Section
amide protons reside in three sets of peaks. The set of overlapped
resonances at 8.5-8.7 ppm is assigned to the six hydrogen-
bonded amide protons in the top and middle subunits (the green
circles in Figure 4b). Similar to dimer 12, the resonances for
the tert-butyl amides are far upfield-shifted, indicating that they
are exposed to solvent. The 1H NMR spectrum is simple,
implying that one conformation dominates the signal. The
position of the amide resonances, ∼0.6 ppm further downfield
compared to similar protons in heterodimer 12, indicates that
the intramolecular amide hydrogen bonds are stronger in the
heterotrimer than in the heterodimer. The origin of the strength-
ened hydrogen bonds is likely due to a cooperative mechanism
where two of the subunits coming together preorganizes the
system for hydrogen bonding to the third subunit.
Synthesis. Synthetic details and characterization for 2-20, diamine
linkers I-IV, and the monoprotected linker from I are contained in
the Supporting Information.
1H NMR Experiments from Table 1. Solutions of homodimer
studies were 1 mM in THF-d8 for desired solubility. All spectra taken
at 333 K were referenced relative to the isotopic impurity peak in THF-
d8 at 3.62 ppm. A small peak present in those spectra around 10.6 ppm
originated from the solvent as evidenced by a control 1H NMR spectrum
1
of blank THF-d8. One-dimensional H NMR spectra of heterodimer
12 and trimer 20 were taken in CD2Cl2 at 1 mM and 303 K and were
referenced relative to the isotopic impurity peak in CD2Cl2 at 5.36 ppm.
COSY and ROESY Experiments. Two-dimensional 1H NMR
spectra were obtained on a Bruker DRX-500 spectrometer using
standard Bruker pulse sequences, and the data were processed with
Bruker XWin-NMR version 3.1 software. One-millimolar samples of
dimer 12 and trimer 20 in CD2Cl2 were degassed by freeze-pump-
thaw cycles17 and placed in sealed NMR tubes. Proton signals were
assigned from COSY18 and ROESY13 spectra. ROESY spectra were
recorded with a mixing time of 250 ms and 54-62 scans. The COSY
and ROESY spectra are given in the Supporting Information for 12
and 20.
Over a dozen unambiguous through-space NOE couplings,
indicated in Figure 4b, were obtained for trimer 20 that confirm
a folded columnar structure.6 Dilution experiments for 20 show
1
that its H NMR resonances are constant (within 0.015 ppm)
from 0.2 mM to higher than 8 mM, meaning the trimer is less
apt to form intermolecular aggregates than the dimer.
Conclusion
This study delineates a general method to synthesize a new
class of folded oligomers from crowded aromatics. Although,
meta-disposed aromatic amides have been shown previously by
Hunter to form intermolecular “zipperlike” complexes,14 it
appears unprecedented for them to fold in solution into columnar
structures such as those from 12 and 20. There are two critical
ingredients to produce a stable columnar secondary structure
from these oligomers: one, the linkers need to hold the subunits
in proximity with each other, and two, the side chains need to
be relatively unhindered.
Even though oligomers15 and polymers16 of discotics have
been previously synthesized, the affinity between the subunits
is low, and folding does not occur in short polymer strands from
substituted triphenylenes.15 The affinity between the subunits
in the oligomers created for this study is high, and even when
they are only two subunits long, a well-defined solution
conformation results. Unlike most foldamers,1,5 each subunit
of these oligomers is highly substituted and functional. Ongoing
Acknowledgment. We acknowledge financial support from
the Chemical Sciences, Geosciences and Biosciences Division,
Office of Basic Energy Sciences, U.S. D.O.E. (DE-FG02-
01ER15264) and U.S. National Science Foundation, Nanoscale
Exploratory Research Grant (DMR-01-02467). This work is
supported in part by the Nanoscale Science and Engineering
Initiative of the National Science Foundation under NSF Award
Number CHE-0117752. C.N. thanks the Beckman Young
Investigator Program (2002) and the Dupont Young Investigator
Program (2002). We thank Dr. Y. Itagaki (Columbia University)
for assistance with the mass spectrometry.
Supporting Information Available: Preparation of 2-20;
COSY and ROESY NMR spectra for 12 and 20 (PDF). This
material is available free of charge via the Internet at http://
pubs.acs.org. See any current masthead page for ordering
information and Web access instructions.
(14) Bisson, A. P.; Carver, F. J.; Eggleston, D. S.; Haltiwanger, R. C.; Hunter,
C. A.; Livingstone, D. L.; McCabe, J. F.; Rotger, C.; Rowan, A. E. J. Am.
Chem. Soc. 2000, 122, 8856-8868.
(15) For a dimer from a traditional discotic, see: Tsukruk, V. V.; Bengs, H.;
Ringsdorf, H. Langmuir 1996, 12, 754-757.
JA034001D
(16) For examples of discotic polymers, polymerized through their side chains,
see: (a) Wang, T.; Yan, D.; Zhou, E.; Karthaus, O.; Ringsdorf, H. Polymer
1998, 39, 4509-4513. (b) Weck, M.; Dunn, A. R.; Matsumoto, K.; Coates,
G. W.; Lobkovsky, E. B.; Grubbs, R. H. Angew. Chem., Int. Ed. 1999, 38,
2741-2745.
(17) By the method of: Claridge, T. D. W. High-Resolution NMR Techniques
in Organic Chemistry; Pergamon: Amsterdam, 1999.
(18) By the procedure of: Rance, M.; Sorenson, O. W.; Bodenhausen, G.;
Wagner, G.; Ernst, R. R.; Wu¨thrich, K. Biochem. Biophys. Res. Commun.
1983, 117, 479-485.
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