Synthesis, characterization, and self-assembled nanofibers of carbohydrate-functionalized mono- and di(2,2′:6′,2″- terpyridinyl)arenes

Article abstract of DOI:10.1039/b914743h

Self-assembly of novel linear and branched carbohydrate-functionalized mono- and di(2,2′:6′,2″-terpyridinyl)arenes afforded access to a series of twisted self-organized nanofibers. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b914743h

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Synthesis, characterization, and self-assembled nanofibers of
carbohydrate-functionalized mono- and di(2,20:60,200-terpyridinyl)arenesw
Yi-Tsu Chan,a Charles N. Moorefieldb and George R. Newkome*a
Received (in Austin, TX, USA) 21st July 2009, Accepted 8th September 2009
First published as an Advance Article on the web 20th October 2009
DOI: 10.1039/b914743h
Self-assembly of novel linear and branched carbohydrate-
functionalized mono- and di(2,20:60,200-terpyridinyl)arenes afforded
access to a series of twisted self-organized nanofibers.
Supramolecular-based assemblies, constructed via intermolecular
non-covalent interactions, such as van der Waals forces,
hydrogen bonding, ionic and coordinative interactions,1,2 have
been a major contributor to functional nanostructures.3
Achiral bolaamphiphiles,4,5 possessing a dumbbell shape and
without internal structural perturbation, self-assembled into a
linear ordered stacking pattern; whereas with internal
disorder, helical motifs were realized.6 Recently, gels7–9
formed from small molecules have been investigated for their
nanoscale chirality.10–12 The appearance of a disaccharide,
specifically furanosylfuranose or pyranosylpyranose (cellobiose),
on terpyridine has been reported as a new class of oligo-
pyridine ligands.13 Some sugar-substituted oligopyridines have
Scheme 2 Reagents and conditions: (a) CH2Cl2, 30 1C; (b) Et3N,
MeOH, 30 1C.
been used to form metal complexes of copper,14–16 zinc,16
iron,17,18 ruthenium,17 rhenium,19 and technetium.19 Herein,
10 and 12, respectively. Their structures were established
(1H NMR) by the presence of peaks at 3.14 ppm (CH2NHCO),
4.72 ppm (10) and 4.55 ppm (12) (CH2NHCO) possessing the
desired 2 : 1 ratio as well as five new peaks (13C NMR) at
156.3, 169.8, 170.1, 170.9, and 171.4 ppm, corresponding to
the urea and four ester carbonyl moieties, respectively. The
ESI-MS spectra further support these structures by peaks at
m/z 875.9 [M + Na]+ (calcd m/z = 876.4) for 10 and m/z
1107.7 [M + Na]+ (calcd m/z = 1107.5) for 12.
we report the construction of linear and branched carbohydrate-
functionalized mono-4- and di-3,5-(2,20:60,200-terpyridin-40-
yl)arenes as well as their self-assembly into twisted nanofibers,
which have utilitarian potential in cell adhesion,20 gene delivery,21
and tissue engineering.22,23
Synthesis (Scheme 1) of the sugar-modified monomers
began with the alkylation of 4-terpyridinylphenol24 (1) and
3,5-di(terpyridinyl)phenol25 (2) with either N-(10-bromodecyl)-
phthalimide (3) or N-(6-bromohexyl)phthalimide (4) linkers to
give imides 5a–6b, followed by deprotection with hydrazine to
afford the free amines 7a–8b. Specifically, 7a and 8a
(Scheme 2) were subsequently treated with 2,3,4,6-tetra-O-
acetyl-b-D-glucopyranosyl isocyanate26 (9) to give (76–77%)
The acetylated precursors were deprotected by using triethyl-
amine in MeOH to give (B85%) the desired monomers 11 and
13. Characterization of their structures was supported (1H and
13C NMR) by the disappearance of peaks assigned to the
acetyl group and ESI-MS spectra of peaks at m/z 708.3
[M + Na]+ (calcd m/z = 708.4) for 11 and m/z 939.6
[M + Na]+ (calcd m/z = 939.4) for 13.
The branched, sugar-functionalized, mono- and di(terpyridinyl)-
arenes were obtained using the ubiquitous acrylate–diamine
protocol for 1 - 2 N-branching.27 Thus, Michael addition
(Scheme 3) of the terminal amines 7b and 8b to methyl acrylate
in MeOH and a mixed solvent of THF and MeOH,
respectively, afforded (99%) the corresponding methyl diesters
14 and 15. Their structures were confirmed by the appearance
of peaks (13C NMR) for the ester carbonyl groups at
173.2 ppm and the molecular ion peaks at m/z 597.3
[M + H]+ (calcd m/z = 597.3) for 14 and m/z 828.4
[M + H]+ (calcd m/z = 828.4) for 15 in ESI-MS spectra.
Treatment of 14 and 15 with excess ethylenediamine in MeOH
gave the diamines 16 and 17, respectively, whose structures
were supported by the disappearance (1H NMR) of methyl
Scheme 1 Reagents and conditions: (a) 3 or 4, K2CO3, DMF, 80 1C;
(b) N2H4, EtOH, reflux.
a Departments of Polymer Science and Chemistry,
The University of Akron, Akron, OH 44325-4717, USA.
E-mail: newkome@uakron.edu; Web: www.dendrimers.com;
Fax: +1 330 972 2413; Tel: +1 330 972 6458
b Maurice Morton Institute for Polymer Science,
The University of Akron, Akron, OH 44325, USA
w Electronic supplementary information (ESI) available: Detailed
experimental procedures with analytical data. See DOI: 10.1039/b914743h
ꢀc
This journal is The Royal Society of Chemistry 2009
6928 | Chem. Commun., 2009, 6928–6930

View Article Online
from 60 to 20 1C, precipitates, partial gels, and steady gels
were obtained, respectively; at higher concentrations, 11
remained a precipitate and 19 remained completely soluble.
Herein we focused on the nanofiber precipitates. In comparison
with compounds 11, 13, and 21, 19 is highly soluble in both
H2O and MeOH at 20 1C due to its enhanced hydrophilic
composition. However, a cloudy solution was formed by
cooling the solution of 19 (1 mg mlꢁ1) in a less polar solvent,
isopropyl alcohol, from 80 to 20 1C. TEM images of 19
(Fig. S1, ESIw) show spherical aggregates with diameters of
200–300 nm, suggesting that self-assembled morphologies are
dependent on both solvent environment and the volume ratio
of the hydrophilic and hydrophobic units.28
After cooling to 20 1C, the solutions of 11, 13, and 21 were
allowed to set undisturbed for two days in sealed vials. Fig. 2
shows TEM images obtained from casting a dilute suspension
(diluted ten times with the original solvent system) of the fibers
onto a 200-mesh carbon-coated Cu grid. Low-magnification
images (Fig. 2A, C, and E) show hyperbranched and inter-
twined networks of fibrous assemblies with lengths of several
micrometres. These features are very similar to the supra-
molecular structures that had been found in gels formed from
Scheme 3 Reagents and conditions: (a) methyl acrylate, MeOH–THF,
30 1C; (b) ethylenediamine, MeOH, 30 1C; (c) 9, CH2Cl2, reflux, 3 h;
(d) Et3N, MeOH, 30 1C.
peaks and the appearance of triplets for the amide at 7.50 ppm
(16) and 7.62 ppm (17). Reactions of 16 and 17 with 2.2 eq.
isocyanate 9 in CH2Cl2 at 40 1C generated the branched
acetylated monoterpyridine 18 (65%) and bisterpyridine 20
1
(43%), which were characterized by H, 13C, and 2D COSY
NMR spectra, as well as confirmed by the ESI-MS peaks
at m/z 1399.4 [M + H]+ (calcd m/z = 1399.6) and m/z 1630.8
[M + H]+ (calcd m/z = 1630.7), respectively. Further
deprotection of 18 and 20 afforded the desired branched
carbohydrate-functionalized monoterpyridine 19 (88%) and
bisterpyridine 21 (84%), which were supported by [1H NMR,
(CD3)2SO] the peaks at 7.94 ppm (t) for CH2CONH, 6.51 ppm
(d) for CONH–Glu, and 6.04 ppm (t) for CH2NHCO and also
by (13C NMR) peaks at 171.5 and 157.2 ppm, corresponding
to the amide and urea carbonyl moieties, respectively. The
MALDI-TOF mass spectra also confirmed the structures by
peaks at m/z 1063.5 [M + H]+ (calcd m/z = 1063.5) for 19
and m/z 1316.6 [M + Na]+ (calcd m/z = 1316.6) for 21.
The self-assembled fibers of 11, 13, and 21 were prepared by
cooling a clear solution (1 mg mLꢁ1) in a suitable ratio (Fig. 1)
of water and MeOH from 60 to 20 1C. The fibers could be
redissolved upon warming, while upon cooling, they reformed,
thereby, showing this process is completely reversible. Notably,
when solutions of 13 and 21 were prepared with increasing
concentrations (1 to 3 mg mlꢁ1; Table S1, ESIw) and cooled
Fig. 2 TEM images of self-assembled 11 (A) in low magnification and
(B) in high magnification. TEM images of self-assembled 13 (C) in low
magnification, and (D) showing repeating twists (inset). TEM images
of self-assembled 21 showing (E) three-dimensional networks and (F)
merging points at arrows.
Fig. 1 A solution of 13 in MeOH (1 mg mLꢁ1) (A) at 60 1C and (B) at
20 1C.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6928–6930 | 6929

View Article Online
of Fig. 3B), which presumably provides an electrostatic-based
driving force component for aggregation. Bis(terpyridine)
electrostatic attraction is estimated to decrease the total energy
by B30 kcal molꢁ1 per stacked pair in the aggregate.
In summary,
a series of carbohydrate-functionalized
mono- and di(terpyridinyl)arenes has been synthesized by urea
glucosidation of the terpyridinyl alkyl amines as well as
characterized. By simply cooling homogeneous solutions of 11,
13, and 21 to 20 1C, self-assembled nanofibers formed; addition
of KCl and Fe(II) destroyed the ordered arrays affording a
colorless solution and new tpy–Fe(II)–tpy complex, respectively.
The authors gratefully thank the National Science Foundation
(DMR-0812337, DMR-0705015) and the Ohio Board of
Regents for financial support.
Notes and references
1 J.-M. Lehn, Supramolecular Chemistry: Concepts and Perspectives,
WILEY-VCH, Weinheim, 1995.
2 J.-M. Lehn, Chem. Soc. Rev., 2007, 36, 151.
3 J. L. Atwood and J. W. Steed, Organic Nanostructures,
WILEY-VCH, Weinheim, 2008.
4 G. R. Newkome, G. R. Baker, M. J. Saunders, P. S. Russo,
V. K. Gupta, Z. Yao, J. E. Miller and K. Bouillion, J. Chem.
Soc., Chem. Commun., 1986, 752.
5 G. R. Newkome, G. R. Baker, S. Arai, M. J. Saunders,
P. S. Russo, K. J. Theriot, C. N. Moorefield, L. E. Rogers,
J. E. Miller, T. R. Lieux, M. E. Murray, B. Phillips and
L. Pascal, J. Am. Chem. Soc., 1990, 112, 8458.
6 G. R. Newkome, C. N. Moorefield, G. R. Baker, R. K. Behera,
G. H. Escamilla and M. J. Saunders, Angew. Chem., Int. Ed. Engl.,
1992, 31, 917.
Fig. 3 (A) Space-filling representation of the minimized-energy
structures of carbohydrate-functionalized terpyridines 11, 13, and 21
and (B) a proposed model of self-assembled nanofibers of 13 and a
view of the bis(terpyridine) molecular surface with mapped electron
rich (red) and poor (blue) regions.
low molecular-mass organic gelators.7 In the cases of 11 and
13, the supramolecular structures have regularly repeating
twists (Fig. 2B and D) and diameters ranging from 4 to 100 nm
(most fibers with 15–20 nm diameter). The self-assembled 21
(Fig. 2E) has an observed average diameter ca. 150 nm due
presumably to the packing requirements of a greater molecular
volume. Arrows in Fig. 2F show some merging points from
which the small and primary fibers associate into large fibers.
Molecular modeling (ESIw) of the sugar-functionalized
monoterpyridine 11 and bisterpyridines 13 and 21 revealed that
the three monomers have a similar length (ca. 3 nm; Fig. 3A).
The models of 11 and 13 show that the length contributed by
the terpyridine portion is estimated to be 1 nm and the length of
the aliphatic part to be ca. 2 nm. In the model of 21, the lengths
of linker and branch are about 0.8 nm and 1.5 nm, respectively.
A proposed model for the fibers (Fig. 3B; shown unsolvated)
shows the hydrophobic terpyridines stacked on the interior of
the aggregate surrounded, or wrapped, by the hydrocarbon
linkers and hydrophilic carbohydrates, which are oriented
towards the exterior; this presumably reduces interfacial energy
in a polar environment. Additionally, H-bonding interactions
between the urea groups also facilitate the stacking. This feature
is operative in the nanofibers reported by Meijer et al.,11 as well
as Jung and co-workers.29 The 4 nm diameter of the modeled
structure is consistent with observed TEM diameters of the
primary fibers. Distances measured for a 3601 twist in the fibers
ranged from 100 to 150 nm. This corresponds to a twist angle
between monomers from 1.0 to 1.41, respectively, with a 4 A
distance between terpyridines. Further support for the proposed
structure is given by considering the bis(terpyridine) molecular
surface with the calculated regions of electron density color
coded in red (electron rich) and blue (electron poor) (lower left
7 R. G. Weiss and P. Terech, Molecular Gels-Materials with
Self-Assembled Fibrillar Networks, Springer, Dordrecht, 2006.
8 A. R. Hirst, B. Escuder, J. F. Miravet and D. K. Smith,
Angew. Chem., Int. Ed., 2008, 47, 8002.
9 P. Dastidar, Chem. Soc. Rev., 2008, 37, 2699.
10 A. l. Brizard, R. Oda and I. Huc, Low Molecular Mass Gelator:
Chirality Effects in Self-assembled Fibrillar Networks, Springer,
Berlin/Heidelberg, 2005, p. 167.
11 C. C. Lee, C. Grenier, E. W. Meijer and A. P. H. J. Schenning,
Chem. Soc. Rev., 2009, 38, 671.
12 D. K. Smith, Chem. Soc. Rev., 2009, 38, 684.
13 E. C. Constable, C. E. Housecroft and A. Mahmood, Carbohydr.
Res., 2006, 343, 2567.
14 R. Roy and J. M. Kim, Tetrahedron, 2003, 59, 3881.
15 S. Sakamoto, T. Tamura, T. Furukawa, Y. Komatsu, E. Ohtsuka,
M. Kitamura and H. Inoue, Nucleic Acids Res., 2003, 31, 1416.
16 S. Orlandi, R. Annunziata, M. Benaglia, F. Cozzi and L. Manzoni,
Tetrahedron, 2005, 61, 10048.
17 E. C. Constable and S. Mundwiler, Polyhedron, 1999, 18, 2433.
18 E. C. Constable, R. Frantz, C. E. Housecroft, J. Lacour and
A. Mahmood, Inorg. Chem., 2004, 43, 4817.
19 M. Gottschaldt, D. Koth, D. Muller, I. Klette, S. Rau, H. Gorls,
B. Schafer, R. P. Baum and S. Yano, Chem.–Eur. J., 2007, 13, 10273.
20 B.-S. Kim, D.-J. Hong, J. Ba and M. Lee, J. Am. Chem. Soc., 2005,
127, 16333.
21 Y. Aoyama, T. Kanamori, T. Nakai, T. Sasaki, S. Horiuchi,
S. Sando and T. Niidome, J. Am. Chem. Soc., 2003, 125, 3455.
22 J. D. Hartgerink, E. Beniash and S. I. Stupp, Science, 2001, 294, 1684.
23 Y. b. Lim, K. S. Moon and M. Lee, Chem. Soc. Rev., 2009, 38, 925.
24 K. Hanabusa, T. Hirata, D. Inoue, M. Kimura and H. Shirai,
Colloids Surf., A, 2000, 169, 307.
25 P. Wang, C. N. Moorefield and G. R. Newkome, Org. Lett., 2004,
6, 1197.
26 Y. Ichikawa, Y. Matsukawa, T. Nishiyama and M. Isobe, Eur. J.
Org. Chem., 2004, 586.
27 G. R. Newkome and C. D. Shreiner, Polymer, 2008, 49, 1.
28 J. H. Ryu, D. J. Hong and M. Lee, Chem. Commun., 2008, 1043.
29 E. J. Cho, N. H. Kim, J. K. Kang and J. H. Jung, Chem. Mater.,
2009, 21, 3.
ꢀc
This journal is The Royal Society of Chemistry 2009
6930 | Chem. Commun., 2009, 6928–6930