Synthesis and structure of intramolecularly hydrogen bonded dendrons

Article abstract of DOI:10.1021/ol990250o

(matrix presented)A convenient synthesis of monodendrons whose conformation is restricted through the intervention of intramolecular hydrogen bonding and repulsive electrostatic interactions is described. X-ray crystal structure analysis of the second gen

Full text of DOI:10.1021/ol990250o

ORGANIC
LETTERS
2000
Vol. 2, No. 3
239-242
Synthesis and Structure of
Intramolecularly Hydrogen Bonded
Dendrons
Baohua Huang and Jon R. Parquette*
Department of Chemistry, The Ohio State UniVersity, Columbus, Ohio 43210
parquett@chemistry.ohio-state.edu
Received August 24, 1999 (Revised Manuscript Received November 23, 1999)
ABSTRACT
A convenient synthesis of monodendrons whose conformation is restricted through the intervention of intramolecular hydrogen bonding and
repulsive electrostatic interactions is described. X-ray crystal structure analysis of the second generation dendron shows the presence of a
propeller-type secondary structure and indicates that the dendrons have assembled into a symmetrically interdigitated dimer in the solid
1
state. H NMR and IR spectral data are in agreement with the presence of intramolecular hydrogen bonding between the amides and the
pyridine N throughout the dendron structure in solution.
Many recent studies suggest that, in the absence of attractive
or repulsive secondary interactions between otherwise flex-
ible dendritic subunits, many dendrimers are conformation-
ally flexible, especially at lower generations.1,2 The devel-
opment of strategies to restrict this conformational flexibility
remains as an important goal, because future applications
of these materials will rely on an ability to control their
properties through their three-dimensional organization. Inter-
and intramolecular self-assembly and self-organization are
driven by the cooperative interplay of multiple molecular
recognition processes such as hydrogen-bonding, van der
Waals, electrostatic, and hydrophobic interactions.3 Although
the development of secondary and tertiary structure relies
on the simultaneous action of all these recognition mecha-
nisms, several laboratories have demonstrated that a single
mechanism can be used to dominate the secondary structure
of monodendrons and their supramolecular assemblies.4 For
example, Percec described a series of monodendrons that
maintain a flat-tapered, half-disk, conical or hemispherical
shape depending on their substitution patterns and generation
(3) (a) Buckingham, A. D. In Principles of Molecular Recognition;
Buckingham, A. D., Legon, A. C., Roberts, S. M., Eds.; Chapman and
Hall: New York, 1993; p 1. (b) Molecular Design and Bioorganic Catalysis;
Wilcox, C. S., Hamilton, A. D., Eds.; North Atlantic Treaty Organization,
Scientific Affairs Division; Kluwer Academic Publishers: Dordrecht,
Boston, 1996. (c) Vo¨gtle, F.; Alfter, F. Supramolecular Chemistry: An
Introduction; Wiley: Chichester, New York, 1991. (d) Delaage, M.
Molecular Recognition Mechanisms; VCH: New York, Paris, 1991. (e)
Lawrence, D. S.; Jiang, T.; Levett, M. Chem. ReV. 1995, 95, 2229. (f)
Lindsey, J. S. New J. Chem. 1991, 15, 153.
(4) (a) Percec, V. J. Macromol. Sci., Pure Appl. Chem. 1996, A33, 1479.
(b) Percec, V.; Johansson, G.; Schlueter, D.; Ronda, J. C.; Ungar, G. I.
Macromol. Symp. 1996, 101, 43. (c) Zeng, F.; Zimmerman, S. C. Chem.
ReV. 1997, 97, 1681. (d) Narayanan, V. V.; Newkome, G. R. Top. Curr.
Chem. 1998, 197, 19. (e) Fischer, M.; Vo¨gtle, F. Angew. Chem., Int. Ed.
1999, 38, 885. (f) Emrick, T.; Fre´chet, J. M. J. Curr. Opin. Colloid Interface
Sci. 1999, 4, 15.
(1) For a recent review of studies relevant to the conformational behavior
of dendrimers, see: Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem.
ReV. 1999, 99, 1665.
(2) Phenylacetylene dendrimers maintain a “shape-persistent” structure
in the absence of secondary interactions: (a) Moore, J. S. Acc. Chem. Res.
1997; 30; 402. (b) Pesak, D. J.; Moore, J. S. Angew. Chem., Int. Ed. Engl.
1997, 36, 1636. (c) Kawaguchi, T.; Walker, K. L.; Wilkins, C. L.; Moore,
J. S. J. Am. Chem. Soc. 1995, 117, 2159. (d) Xu, Z.; Kahr, M.; Walker, K.
L.; Wilkins, C. L.; Moore, J. S. J. Am. Chem. Soc. 1994, 116, 4537.
10.1021/ol990250o CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/05/2000

number. By attaching various functional groups to the focal
point or periphery of these monodendrons, it was shown that
different supramolecular interactions such as van der Waals,
hydrogen bonds, hydrophobic and fluorophobic effects, and
ion complexation by crown ethers could dominate the
formation of supramolecular assemblies of these monoden-
drons in the liquid crystalline state.5 Zimmerman demon-
strated the supramolecular construction of a nanometer-sized
dendrimer by self-organization of functionalized monoden-
drons through intermolecular hydrogen-bonding interactions.6
Intramolecular hydrogen-bonding interactions between ter-
minal amides are thought to be responsible for the rigidity
of the outer shell of amidated poly(propylene imine) den-
drimers.7 However, there are few examples wherein den-
drimer conformation at each generational shell is restricted
through intramolecular hydrogen bonding. Intramolecular
hydrogen-bonding interactions have been exploited to im-
prove the rigidity of an extended-core discotic liquid crystal.8
The goal of this paper is to describe the synthesis and
structural characterization of monodendrons whose confor-
mation is restricted through the intervention of intramolecular
hydrogen-bonding and electrostatic interactions present in
the AB2 building block.
Pyridine-2,6-dicarboxamide derivatives exist in a confor-
mation that places the amide NH groups in close proximity
to the pyridine N due to intramolecular hydrogen bonding
and repulsive electrostatic interactions between the amide
oxygens.9 This conformational preference has been exploited
to control the three-dimensional folding of molecular recep-
tors10 and catenanes.11 Moreover, Hamilton and co-workers
demonstrated that linking two anthranilamides through a
pyridine-2,6-dicarboxylic acid moiety produces a helical
conformation in the resultant molecule that is stabilized by
several intramolecular hydrogen bonds.12 The ability of these
pyridine-2,6-dicarboxamide derivatives to coordinate to
metals such as copper has also been utilized to create a rigid
metallohelical complex that, in one case, experienced
spontaneous resolution in the crystal lattice.13 On this basis,
we constructed dendritic wedges using 4-aminopyridine-2,6-
dicarboxamide as the branching AB2 unit to preorganize the
interior of the dendrons through intramolecular hydrogen-
bonding interactions.
4-Chloropyridine-2,6-dicarbonyl chloride (2) was chosen
as the branching monomer wherein convergent generational
growth is accomplished using amide bond-forming reactions
with the acid chlorides and focal point activation occurs by
NaN3 displacement of the 4-chloro group followed by
hydrogenation. Initially, methyl esters were incorporated as
terminal groups; however, beginning at the second genera-
tion, solubility was poor in all common organic solvents
(THF, DMF, DMSO, EtOAc), except for chlorinated solvents
such as CHCl3 and CH2Cl2, which afforded only moderate
solubility. Therefore, dodecyl ester groups were placed on
the periphery to improve the solubility of the dendrons.
Monomer 2 was prepared by treating chelidamic acid (1)
with neat POCl3 at 100 °C (Scheme 1).14 The synthesis was
initiated by exposing dodecyl anthranilate, prepared by
transesterifcation of methyl anthranilate with dodecyl alcohol,
to 2 in pyridine, which afforded the first-generation dendron
[(C12H25O2C)2-[G1]-Cl] (3a). Displacement of the 4-chloro
group with NaN3 in DMF at 50 °C installed an azido group
at the focal point, giving dendron [(C12H25O2C)2-[G1]-N3]
(3b). Hydrogenation over Pd-C in THF at 50 psi gave the
amino dendron [(C12H25O2C)2-[G1]-NH2] (3c) in quantitative
yield, which was subsequently elaborated to the second-
generation dendron [(C12H25O2C)4-[G2]-Cl] (4a) by reaction
with 2 in pyridine. The solubility of 4a was significantly
enhanced in many solvents relative to the methyl ester
analogue; however, in polar solvents such as DMSO and
DMF, solubility was limited. Therefore, conversion of 4a
to the corresponding azide by displacement with NaN3 was
performed in THF-DMF (1:3) at 50 °C to maintain
homogeneous conditions. Subsequent hydrogenation over
Pd-C and reaction with 2 afforded the third-generation
dendron [(C12H25O2C)8-[G3]-Cl] (5a). Repetition of the NaN3
displacement-hydrogenation activation sequence afforded
(5) (a) Percec, V.; Johansson, G.; Ungar, G.; Zhou, J. J. Am. Chem. Soc.
1996, 118, 9855. (b) Balagurusamy, V. S. K.; Ungar, G.; Percec, V.;
Johansson, G. J. Am. Chem. Soc. 1997, 119, 1539. (c) Hudson, S. D.; Jung,
H. T.; Percec, V.; Cho, W. D.; Johansson, G.; Ungar, G.; Balagurusamy,
V. S. K. Science 1997, 278, 449. (d) Percec, V.; Cho, W. D.; Mosier, P.
E.; Ungar, G.; Yeardley, D. J. P. J. Am. Chem. Soc. 1998, 120, 11061. (e)
Percec, V.; Ahn, C. H.; Ungar, G.; Yeardley, D. J. P.; Moller, M.; Sheiko,
S. S. Nature 1998, 391, 161. (f) Percec, V.; Ahn, C.-H.; Bera, T. K.; Ungar,
G.; Yeardley, D. J. P. Chem. Eur. J. 1999, 5, 1070.
(6) (a) Zimmerman, S. C.; Zeng, F.; Reichert, D. E. C.; Kolotuchin, S.
V. Science 1996, 271, 1095. (b) Thiyagarajan, P.; Zeng, F.; Ku, C. Y.;
Zimmerman, S. C. J. Mater. Chem. 1997, 7, 1221. (c) Suarez, M.; Lehn,
J.-M.; Zimmerman, S. C.; Skoulios, A.; Heinrich, B. J. Am. Chem. Soc.
1998, 120, 9526.
(7) (a) Stevelmans, S.; van Hest, J. C. M.; Jansen, J. F. G. A.; van Boxtel,
D. A. F. J.; de Brabander-van den Berg, E. M. M.; Meijer, E. W. J. Am.
Chem. Soc. 1996, 118, 7398. (b) Put, E. J. H.; Clays, K.; Persoons, A.;
Biemans, H. A. M.; Luijkx, C. P. M.; Meijer, E. W. Chem. Phys. Lett.
1996, 260, 136. (c) Bosman, A. W.; Janssen, R. A. J.; Meijer, E. W.
Macromolecules 1997, 30, 3606. (d) Bosman, A. W.; Bruining, M. J.;
Kooijman, H.; Spek, A. L.; Janssen, R. A. J.; Meijer, E. W. J. Am. Chem.
Soc. 1998, 120, 8547.
(8) (a) Palmans, A. R. A.; Vekemans, J. A. J. M.; Meijer, E. W. Recl.
TraV. Chim. Pays-Bas 1995, 114, 277. (b) Palmans, A. R. A.; Vekemans,
J. A. J. M.; Fischer, H.; Hikmet, R. A.; Meijer, E. W. Chem. Eur. J. 1997,
3, 300. (c) Palmans, A. R. A.; Vekemans, J. A. J. M.; Havinga, E. E.; Meijer,
E. W. Angew. Chem., Int. Ed. Engl. 1997, 36, 2648. (d) Palmans, A. R. A.;
Vekemans, J. A. J. M.; Hikmet, R. A.; Fischer, H.; Meijer, E. W. AdV.
Mater. 1998, 10, 873. (e) Langeveld-Voss, B. M. W.; Waterval, R. J. M.;
Janssen, R. A. J.; Meijer, E. W. Macromolecules 1999, 32, 227.
(9) For X-ray crystal structures, see: (a) Newkome, G. R.; Fronczek, F.
R.; Kohli, D. K. Acta Crystallogr. 1981, B37, 2114. (b) Alcock, N. W.;
Moore, P.; Reader, J. C.; Roe, S. M. J. Chem. Soc., Dalton Trans. 1988,
2959. (c) Malone, J. F.; Murray, C. M.; Dolan, G. M.; Docherty, R.; Lavery,
A. J. Chem. Mater. 1997, 9, 2983.
(10) (a) Hunter, C. A.; Purvis, D. H. Angew. Chem., Int. Ed. Engl. 1992,
6, 792. (b) Crisp, G. T.; Jiang, Y.-L. Tetrahedron 1999, 55, 549.
(11) Leigh, D. A.; Murphy, A.; Smart, J. P.; Deleuze, M. S.; Zerbetto,
F. J. Am. Chem. Soc. 1998, 120, 6458.
(12) (a) Hamuro, Y.; Geib, S. J.; Hamilton, A. D. J. Am. Chem. Soc.
1997, 119, 10587. (b) Hamuro. Y.; Geib, S. J.; Hamilton, A. D. J. Am.
Chem. Soc. 1996, 118, 7529.
(13) (a) Kawamoto, T.; Hammes, B. S.; Haggerty, B.; Yap, G. P. A.;
Rheingold, A. L.; Borovik, A. S. J. Am. Chem. Soc. 1996, 118, 285. (b)
Yu, Q.; Baroni, T. E.; Liable-Sands, L.; Rheingold, A. L.; Borovic, A. S.
Tetrahedron Lett. 1998, 39, 6831.
(14) Bhattacharya, S.; Snehalatha, K.; George, S. K. J. Org. Chem. 1998,
63, 27.
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Org. Lett., Vol. 2, No. 3, 2000

Scheme 1a
a Key: (a) POCl3; (b) dodecyl anthranilate, pyridine, DMAP; (c) NaN3, THF/DMF; (d) H2/Pd-C, THF/CH3OH; (e) 2, pyridine, DMAP.
the third-generation dendritic amine 5c. Characterization with
regard to molecular weight, structure, and dispersity was
accomplished by FAB (3a-c) or MALDI-TOF (4a-c, 5a-
c; see Supporting Information) MS, NMR, and SEC analysis,
respectively. Molecular weights determined by MS were
consistent with the expected structures, and SEC indicated
the monodispersity of all the dendrons.
A clear, monoclinic crystal with a P21/c space group was
obtained for the second-generation dendron 4a (R ) Me)
by crystallization from CH2Cl2.15 X-ray diffraction showed
that the asymmetric unit was a dimer composed of two
virtually identical, interdigitated monodendrons with two
associated molecules of CH2Cl2 (Figure 1).16 The dimeric
with the corresponding B and C rings of the second dendron;
however, the focal A ring of one dendron is sandwiched
between the adjacent terminal D rings of the other dendron,
resulting in a structure containing approximate D2 symmetry.
Both monodendrons display all six of the expected bifurcated
hydrogen bonds between the amide NH’s and the pyridine
N, having pyN- - -H bond distances ranging from 2.13 to
2.23 Å. Additionally, two of the four terminal ester carbonyl
oxygens participate in additional hydrogen bonds with the
outer shell amide NH’s. This network of hydrogen bonds
serves to restrict the branches of each monodendron to a
cisoid conformation, and due to pairwise steric interactions
between adjacent aryl subunits, the dendron assumes an
overall propeller shape (Figure 2). The unit cell contains both
Figure 1. CPK depiction of the asymmetric unit of the X-ray
structure of 4a (R ) Me).
structure displays extensive face-to-face π-stacking interac-
tions; all seven rings in 4a are paired in stacked arrangements
having closest edge-to-edge distances varying from 3.47 to
3.83 Å. Rings B and C of the first dendron are π-stacked
Figure 2. ORTEP diagram in stereo of an isolated monodendron
drawn at the 50% probability level.
Org. Lett., Vol. 2, No. 3, 2000
241

right- and left-handed propeller conformations. This confor-
mational preference contrasts with the Fre´chet-type polyaryl
ether dendrons, which adopt a planar disklike conformation
in the solid state.17 Since crystallization is a kinetically
controlled process, this X-ray structure does not necessarily
represent the energy minimum of the system.
dendritic wedge and the termini.5 The broadening observed
in the proton NMR spectrum of 5a may be due to aggregation
occurring that segregates the polar dendritic interior from
the nonpolar terminal aliphatic chains. Aggregates that
sequester the polar interior from the solvent would be
stabilized in relatively nonpolar solvents such as toluene that
interact well with the nonpolar termini but poorly with the
interior.22 Polar solvents such as DMSO that interact favor-
ably with the interior could be expected to dissociate the
aggregate and simplify the spectra, which is observed. Meijer
has observed a similar solvent dependence in the aggregation
of an intramolecularly H-bonded discotic molecule containing
aliphatic terminal groups;8b this behavior was also evident
in stilbenoid and phenylacetylene dendrimers reported by
Meier23 and Moore,2b respectively. The propensity of the
dendrons to aggregate increases with molecular weight. For
example, while 3c (mol wt 757) and 4c (mol wt 1659) do
not exhibit a tendency to aggregate in CDCl3, reaction of
trimesic acid trichloride with the first-generation dendron 3c
affords a dendrimer (mol wt 2427) that aggregates in
CDCl3.24 The exact nature of this aggregation is currently
under investigation.
In conclusion, we have described a convenient strategy
to prepare monodendrons based on an AB2 subunit with a
conformational preference that is directed by intramolecular
hydrogen bonding and repulsive electrostatic interactions.
These hydrogen-bonded dendritic networks offer a new
scaffold for designing intramolecularly ordered macromol-
ecules. We are currently constructing these dendrons with
chiral, nonracemic terminal groups so that circular dichroism
can be used to gain information concerning the conformation
of these materials in solution.
1H NMR and IR spectral data are in good agreement with
the presence of intramolecular hydrogen-bonding between
the amides and the pyridine N throughout the dendron
structure in solution (see the Supporting Information). The
proton NMR spectra display a unique downfield resonance
for each set of the amide N-H’s corresponding to a given
generational shell. For example, the amide N-H groups
exhibit a single, sharp low-field resonance at 12.75 ppm for
the first-generation dendron 3a, two slightly broadened
resonances (12.23 and 11.16 ppm) for the second-generation
species 4a, and three slightly broadened resonances (12.46,
11.51, and 11.22 ppm) for the third-generation dendron 5a.
It is noteworthy that even in DMSO/CDCl3 (1:3) at 50 °C
the N-H resonances in 5a do not experience significant
upfield shifts relative to 3a-c and 4a-c in CDCl3, suggest-
ing that the intramolecular H bonds are quite robust. The
infrared spectra in CDCl3 (10 mM)18 of 3a-c, 4a-c, and
5a-c exhibited broad N-H stretching bands at 3234-3374
cm-1 characteristic of hydrogen-bonded N-H groups, but
no peaks were observed in the free N-H stretching region
(3400-3500 cm-1).19,20
1
The 13C and H NMR spectra of 3a-c and 4a-c were
well-resolved in CDCl3 at ambient temperature; however,
the proton NMR spectrum of 5a in CDCl3 (10 mM) was
extremely broadened and structureless even at 50 °C. Dilution
to 1 mM in CDCl3 did not improve the spectrum. Despite
the excellent solubility of 5a in toluene, recording the
spectrum in toluene-d8 further increased the complexity of
the spectrum, which did not improve upon heating to 90 °C.
Interestingly, the spectral resolution improved dramatically
in a mixture of DMSO-d6 and CDCl3 (1:3, 10 mM)21 at 50
°C (see the Supporting Information). Similar behavior was
observed for 5b,c.
Acknowledgment. We thank Dr. Judith Gallucci for the
X-ray structure determination of 4a (R ) Me). This work
was supported by The Ohio State University and the National
Science Foundation CAREER program (Grant No. CHE 98-
75458). Acknowledgment is also made to the donors of the
Petroleum Research Fund, administered by the American
Chemical Society, for partial support of this work.
Percec et al. have reported that polyaryl ether dendrimers
with perhydrogenated or perfluorinated alkyl termini ag-
gregate in such a way that segregation occurs between the
Supporting Information Available: Experimental pro-
cedures and analytical data for 2a-c, 3a-c, 4a-c, and 5a-
1
c, H NMR spectra of 5a in CDCl3 and DMSO-d6/CDCl3
(15) Compound 4a (R ) C12H25) was obtained as a waxy solid for which
high-quality crystals could not be obtained. However, the methyl ester
derivative was a crystalline solid rather than a wax.
(16) General crystallographic information: T ) 173(1) K; P21/c, a )
13.5199(2) Å, b ) 29.2090(4) Å, c ) 27.1316(4) Å; â ) 90.135(1)°; V )
10 714.3(3) Å3; Z ) 8; 18 847 unique data; Rw ) 0.063; GOF ) 1.060.
(17) For an X-ray structure of a second-generation poly(aryl ether)
dendron, see: Karakaya, B.; Claussen, W.; Gessler, K.; Saenger, W.;
Schlu¨ter, A.-D. J. Am. Chem. Soc. 1997, 119, 3296.
(1:3) at elevated temperatures, ORTEP diagrams in stereo
of the asymmetric unit, unit cell, and isolated dendrons of
4a, and tables of X-ray structural data for 4a. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL990250O
(18) Decreasing the concentration of 5a in CDCl3 from 10 to 1 mM
produced no change in the IR spectrum, supporting the presence of
intramolecular hydrogen bonds.
(22) For an example of a heterocyclic dendrimer that aggregates in
solution see: (a) Kraft, A. Osterod, F. J. Chem. Soc., Perkin Trans. 1 1998,
1019. (b) Osterod, F. Kraft, A. Chem. Commun. 1997, 1435. (c) Kraft, A.
Liebigs Ann./Recl. 1997, 1463. (d) Kraft, A. Chem. Commun. 1996, 2103.
(d) Kraft, A. Chem. Commun. 1996, 77.
(23) Meier, H.; Lehmann, M. Angew. Chem., Int. Ed. 1998, 37, 643.
(24) Similar broadening was observed in the 1H NMR spectrum in CDCl3;
however, in 1:1 CDCl3/DMSO-d6 the spectrum was well-resolved. Tomcik,
D.; Parquette, J. R. Unpublished results.
(19) (a) Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1993, 115, 4228.
(b) Gellman, S. H.; Dado, G. P.; Liang, G.-L.; Adams, B. R. J. Am. Chem.
Soc. 1991, 113, 1164.
(20) Amino dendron 2c exhibited an N-H stretch at 3479 cm-1 due to
the free NH2 function.
(21) This solvent mixture was necessary due to the poor solubility of 5a
in pure DMSO.
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