Generation-independent dimerization behavior of quadruple hydrogen-bond-containing oligoether dendrons

Article abstract of DOI:10.1021/ol0603716

A new series of self-assembling G1-G3 dendronized dimers bearing oligoether dendrons and a dimeric 2-ureido-4-pyrimidinone (UPy) quadruple hydrogen-bonding core were prepared and characterized. It was found that the nonpolar microenvironment created by th

Full text of DOI:10.1021/ol0603716

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1811-1814
Generation-Independent Dimerization
Behavior of Quadruple
Hydrogen-Bond-Containing Oligoether
Dendrons
Chun-Ho Wong,† Hak-Fun Chow,*,† Sin-Kam Hui,‡ and Kong-Hung Sze‡
Department of Chemistry and The Center of NoVel Functional Molecules, The Chinese
UniVersity of Hong Kong, Shatin, New Territories, Hong Kong SAR, and Department
of Chemistry, The UniVersity of Hong Kong, Pokfulam Road, Hong Kong SAR
hfchow@cuhk.edu.hk
Received February 13, 2006
ABSTRACT
A new series of self-assembling G1−G3 dendronized dimers bearing oligoether dendrons and a dimeric 2-ureido-4-pyrimidinone (UPy) quadruple
hydrogen-bonding core were prepared and characterized. It was found that the nonpolar microenvironment created by the dendrons preserved
the UPy unit in its DDAA tautomeric form. As a result, the stabilities of the dimers were exceptionally strong for all three generations (Kdim*
-
1
> 2
×
107
M
in CDCl3 at 25 °C). Furthermore, the steric size of the dendrons did not exhibit a significant effect on their dimerization behavior.
Dendronized polymers belong to an important class of
macromolecules that possess many applications due to their
unique structural features. These applications have been
successfully applied to areas such as catalysis,1 light harvest-
ing,2 gene transfection,3 optoelectronics,4 and nanotechnol-
ogy.5 Most often, dendronized polymers were prepared by
the covalent assemblies of the dendritic monomers.6 How-
ever, such strategies were known to suffer from low degrees
of polymerization (DP) and slow reaction rates because of
steric congestions and kinetic problems associated with the
polymerization process. Previously, we showed that poly-
functional amino acid-based dendrimers and dendrons formed
nondiscrete nanoscopic-sized aggregates or dendritic gels via
intermolecular hydrogen-bond interactions.7 On the other
hand, the preparation of discrete, cyclic dendritic supra-
molecular self-assemblies using dendritic monomers bearing
preorganized multiple hydrogen-bonding units has been
reported by Zimmerman.8 We are therefore interested in
† The Chinese University of Hong Kong.
‡ The University of Hong Kong.
(1) (a) Suijkerbuijk, B. M. J. M.; Shu, L.; Klein Gebbink, R. J. M.;
Schlu¨ter, A. D.; van Koten, G. Organometallics 2003, 22, 4175. (b) Deng,
G.-J.; Yi, B.; Huang, Y.-Y.; Tang, W.-J.; He, Y.-M.; Fan, Q.-H. AdV. Synth.
Catal. 2004, 346, 1440.
(2) Sato, T.; Jiang, D.-L.; Aida, T. J. Am. Chem. Soc. 1999, 121, 10658.
(3) Go¨ssl, I.; Shu, L.; Schlu¨ter, A. D.; Rabe, J. P. J. Am. Chem. Soc.
2002, 124, 6860.
(5) (a) Stocker, W.; Schu¨rmann, B. L.; Rabe, J. P.; Fo¨ster, S.; Lindner,
P.; Neubert, I.; Schlu¨ter, A. D. AdV. Mater. 1998, 10, 793. (b) Barner, J.;
Mallwitz, F.; Shu, L.; Schlu¨ter, A.-D.; Rabe, J. P. Angew. Chem., Int. Ed.
2003, 42, 1932.
(6) Zhang, A.; Shu, L.; Bo, Z.; Schlu¨ter, A. D. Macromol. Chem. Phys.
2003, 204, 328.
(4) Setayesh, S.; Grimsdale, A. C.; Weil, T.; Enkelmann, V.; Mu¨llen,
K.; Meghdadi, F.; List, E. J. W.; Leising, G. J. Am. Chem. Soc. 2001, 123,
946.
(7) (a) Mong, T. K.-K.; Niu, A.; Chow, H.-F.; Wu, C.; Li, L.; Chen, R.
Chem.-Eur. J. 2003, 7, 686. (b) Chow, H.-F.; Zhang, J. Chem.-Eur. J.
2005, 11, 5817. (c) Chow, H.-F.; Zhang, J. Tetrahedron 2005, 61, 11279.
10.1021/ol0603716 CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/06/2006

Figure 1. Structures of self-assembling dendronized dimers 12-32.
using a self-assembling approach to synthesize high DP
dendronized polymers using dendritic monomers bearing two
nonpreorganized, self-complementary hydrogen-bonding units.
This approach should also furnish dendronized polymers with
tunable properties as the binding strength among the dendritic
monomers is subjected to solvent and microenvironment
effects.9 However, the successfulness of this approach relies
on the assumption that the binding constant between the
subunits is not drastically reduced by the increasing size of
the dendritic sectors; otherwise, oligomers instead of den-
dronized polymers will be formed as the major products.
However, a recent report by Kaifer10 on the dimerization
behavior of a series of monofunctionalized dendrons bearing
the 2-ureido-4-pyrimidinone11 (UPy) quadruple hydrogen-
bonding unit indicated a substantial decrease of the dimer-
ization constant for the G3 dimer.12 It was rationalized that
this resulted from both the steric effect and the polar
microenvironment exerted by the highly polar oligoamide
dendrons. Their study, therefore, cast serious doubts on the
feasibility of forming high DP self-assembling dendronized
polymers using the hydrogen-bonding approach, especially
for dendronized polymers constructed from higher generation
monomeric units. However, we envisaged that one may
restore the stability of the dimeric states by changing the
microenvironment around the hydrogen-bonding units. Hence,
we prepared a series of monofunctional, UPy-containing
dendrons bearing nonpolar oligoether dendritic sectors 12-
32 (Figure 1) and studied their dimerization behavior. In
contrast to Kaifer’s findings, all of our dimers, irrespective
of the generation, possess high dimerization constants (Kdim*
> 2 × 107 M-1 in CDCl3 at 25 °C). Our studies show that
the microenvironment of the dendrons is of paramount
importance in dictating the strength of binding, and the
binding strength is almost unperturbed by steric effects.
For the synthetic work, dendritic benzylamines 4-6 were
prepared from their corresponding dendritic alcohols 7-9
via Mitsunobu-type Gabriel synthesis (for the G1 and G2
series) or LiAlH4 reduction of dendritic azide (for the G3
series).13 Dendritic alcohols 7-9 were prepared from methyl
3,5-dihydroxybenzoate using a convergent approach. The
resulting dendritic amines 4-6 were then coupled to imid-
azolide 10 to afford the corresponding dendronized dimers
12-32 in high yields (Scheme 1).14 The purities and structural
Scheme 1. Synthesis of Self-Assembling Dendronized Dimers
(8) (a) Zimmerman, S. C.; Zeng, F.; Reichert, D. E. C.; Kolotuchin, S.
V. Science 1996, 271, 1095. (b) Corbin, P. S.; Lawless, L. J.; Li, Z.; Ma,
Y.; Witmer, M. J.; Zimmerman, S. C. Proc. Natl. Acad. Sci. U.S.A. 2002,
99, 5099.
(9) (a) Schmuck, C.; Wienand, W. Angew. Chem., Int. Ed. 2001, 40,
4363. (b) Ciferri, A. Macromol. Rapid Commun. 2002, 23, 511.
(10) Sun, H.; Kaifer, A. E. Org. Lett. 2005, 7, 3845.
(11) (a) Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.;
Ky Hirschberg, J. H. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W.
Science 1997, 278, 1601. (b) Beijer, F. H.; Sijbesma, R. P.; Kooijman, H.;
Spek, A. L.; Meijer, E. W. J. Am. Chem. Soc. 1998, 120, 6761.
(12) Recently, another series of a dendronized dimeric system has also
been reported. However, no dimerization constants were given. See: Hahn,
U.; Gonza´lez, J. J.; Huerta, E.; Segura, M.; Eckert, J.-F.; Cardinali, F.; de
Mendoza, J.; Nierengarten, J.-F. Chem.-Eur. J. 2005, 11, 6666.
identities of all dendritic compounds were fully characterized
by 1H and 13C NMR, HRMS, GPC, and/or elemental analysis.
(13) See Supporting Information for details.
1812
Org. Lett., Vol. 8, No. 9, 2006

The dimerization properties were studied by 1H NMR, 1H
NOESY/ROESY, vapor pressure osmometry (VPO), HRMS-
ESI, and FT-IR. It was known that 4[1H]-pyrimidinone was
a stronger dimerizing tautomer (via DDAA array) than
pyrimidin-4-ol (via DADA array) because of attractive
The absolute values of the dimerization constant (Kdim*)
of the dendronized dimers in CDCl3 could not be determined
1
through H NMR dilution studies because of the extremely
large dimerization constants. However, no new peaks or
shifting of existing peaks (∆δ < 0.01 ppm) was observed
for 12-32 even at low concentrations (Figure 3).13 Assuming
1
secondary interactions.11b Indeed, the H NMR spectra of
the dimers 12-32 in CDCl3 showed a set of characteristic
NH signals (δ 13.0, 12.0, and 10.8 ppm) that were assigned
to the 4[1H]-pyrimidinone tautomers (Figure 2).11b In contrast
1
Figure 3. Stacked H NMR spectra (600 MHz) of the hydrogen-
bonding region of diluted samples (1.0 mM-10 µM) of G3 dimer
32 in CDCl3 at 25 °C.
more than 95% dimer formation at the lowest concentration
studied (10 µM), we estimated that the lower limit of Kdim*
was around 2 × 107 M-1 for all dendronized dimers 12-32
(condition 1 in Table 2).13 Furthermore, the 1H NMR
Table 2. Dimerization Constants of Dendronized Dimers
12-32 and Nondendronized Dimer 152
Figure 2. Partial 1H NMR spectra (300 MHz) of 12-32 in CDCl3.
to Kaifer’s dimers, the signals of the possible weaker DADA
pyrimidin-4-ol tautomers were not observed in our dimers,
indicating that the microenvironment in our system was
significantly different from those of Kaifer’s.10,15 This
preservation of the UPy unit in its DDAA tautomeric form
was highly important, as it guaranteed a much stronger
binding (107 vs 105 M-1) between the quadruple hydrogen-
bonding units.11b The sole presence of the 4[1H]-pyrimidi-
none tautomers was further supported by 1H NOESY/
ROESY correlation analysis.13 The observed tautomeric
behavior was identical to that reported in the literature.11b
Additionally, the presence of dimers was confirmed by VPO
measurements and by the presence of [2M + H]+ peaks for
dimers 12-32 in HRMS-ESI studies (Table 1).
Kdim* (M-1
)
conditions
R ) Bu
G1 G2
G3
(1) CDCl3 at 25 °C
6 × 107 a >2 × 107 >2 × 107 >2 × 107
(2) 10% v/v DMSO-d6 2 × 102 1 × 102
2 × 102
3 × 104
2 × 102
1 × 104
in CDCl3 at 25 °C
(3) CDCl3 at 50 °C
3 × 104 1 × 104
a
See ref 18.
Table 1. Measured Molecular Weights of Dendronized Dimers
12-32 by VPO and HRMS-ESI
spectrum of a 1:1 mixture of 12 and 32 in CDCl3 revealed
the formation of a heterodimer 1‚3 together with the
VPOa
HRMS-ESI [2M + H]+
dimers theoretical measured
theoretical
measured
(14) Keizer, H. M.; Sijbesma, R. P.; Meijer, E. W. Eur. J. Org. Chem.
2004, 2553.
(15) A comparative study on the steric and microenvironmental properties
of the Fre´chet-type oligoether dendrons and Newkome-type oligoamide
dendrons had been reported. See: Ong, W.; Grindstaff, J.; Sobransingh,
D.; Toba, R.; Quintela, J. M.; Peinador, C.; Kaifer, A. E. J. Am. Chem.
Soc. 2005, 127, 3353.
12
22
32
805
1518
2944
760 ((50)
1530 ((80)
2980 ((140)
805.4607
1517.8582
2942.6532
805.4606
1517.8585
2942.6473
a Solvent: CHCl3. Temperature: 30.0 °C.
Org. Lett., Vol. 8, No. 9, 2006
1813

homodimers 12 and 32 in a molar ratio of 2:1:1.13 Hence,
steric effect did not play a significant role in determining
the dimerization constants in these oligoether-based dimers.
Comparative studies on the relative stabilities of dimers
12-32 were conducted in 10% v/v DMSO-d6 in CDCl3
solution at 25 °C and in pure CDCl3 at 50 °C (conditions 2
and 3 in Table 2). Under these conditions, the dimeric 4[1H]-
pyrimidinone tautomers were found to be in equilibrium with
the corresponding monomeric 6[1H]-pyrimidinone tautomers
(i.e., 1′-3′). In addition, a nondendronized analogue 15′ (i.e.,
R ) Bu)11b was also included as a comparison. The values
of Kdim* under these conditions were calculated from the
ratios of integrations of the relevant 1H NMR signals.16 The
results indicated that dendronized dimers 12-32 and the
nondendronized analogue 152 possessed the same dimeriza-
tion stabilities under identical conditions. In the presence of
10% v/v DMSO-d6 in CDCl3, the values of Kdim* were in
the order of 102 M-1 and were consistent with the literature
values.11b As expected, the dimerization constants dropped
to 104 M-1 at 50 °C in CDCl3. We concluded here that (1)
the relatively nonpolar microenvironment of the oligoether
dendrons17 did not disfavor the dimeric state and (2) the
dimerization was not hindered by the largest G3 dendron.
Despite these findings, the branching pattern (nonaromatic
AB3 vs aromatic AB2) and the branch length (4-atom vs
2-atom spacing) are different between Kaifer’s and our
dendrimers. Hence, it was difficult to compare directly the
steric environment between these two series of compounds.
Nonetheless, a significantly different microenvironment was
established between these two classes of dendrons, and this
factor led to the lowering of dimerization constants in
Kaifer’s oligoamide dendrons.
and 1523 cm-1).19 Furthermore, the absence of absorptions
at 2500 cm-1 (O-H‚‚‚OdC) and 3200-3260 cm-1 (intra-
molecular N-H‚‚‚N) indicated that the pyrimidin-4-ol tau-
tomer virtually did not exist in the solid state.11b,20
In summary, we disclosed a new series of UPy-containing
oligoether dendrons which dimerize strongly even in the
presence of a large G3 dendron (Kdim* > 2 × 107 M-1 in
CDCl3 at 25 °C). These dimers used DDAA as the binding
mode via the 4[1H]-pyrimidinone tautomers in CDCl3 and
in the solid state. Under certain monomer-favoring condi-
tions, the dimerization constants of the various dendronized
dimers were found to be nearly the same as that of the
nondendronized dimer 152. These findings illustrated that
the stabilities of dendronized dimers 12-32 were not
weakened by the steric effect imposed by the dendrons. It
therefore appeared that the nonpolar microenvironment
created by the oligoether dendrons played a much more
important role in preserving the dimeric state. In contrast,
the highly polar microenvironment imposed by Kaifer’s
oligoamide dendrons resulted in the destabilization of their
dimeric structures.10 Hence, a nonpolar dendritic environment
is needed to ensure a high dimerization constant for the
quadruple hydrogen-bonding unit. Work is now being carried
out on the synthesis of these self-assembling dendronized
polymers.
Acknowledgment. This paper is dedicated to Dr. T.-L.
Chan. This research is supported by a Strategic Investments
Scheme administrated by The Chinese University of Hong
Kong. K.-H. Sze acknowledges the financial support from
the University Grants Committee of Hong Kong (RGC HKU
7350/04M) and the University of Hong Kong (UGC). We
thank K.-H. Low for obtaining FT-IR spectra. H.-F. Chow
is a receipent of the Croucher Senior Research Fellowship,
Hong Kong (2006-07).
In the solid state, all dimers were shown to exist in the
4[1H]-pyrimidinone tautomeric form. The solid-state FT-IR
spectra of dimers 12-32 showed the characteristic peak
pattern for the presence of this tautomer (1695, 1658, 1589,
Supporting Information Available: Details of synthetic
1
procedures and H and 13C NMR spectra of all dendritic
(16) The values of Kdim* were determined from the ratios of integrations
of the UPy-CH3, CdCH, or CH2N signals. It was noted that the volume
factor was not taken into account in the equation that appeared in ref 11b.
See Supporting Information for details.
(17) It was suggested that the microenvironment of the oligoether
dendrons was very polar (comparable to the polarity of DMF). Our
compounds, however, existed mainly in dimeric form in many organic
solvents (e.g., CDCl3, CD2Cl2, THF-d8, acetone-d6, and toluene-d8). This
indicated that oligoether dendrons are not so polar as suggested. See:
Hawker, C. J.; Wooley, K. L.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1993,
115, 4375.
compounds and 152; 1H NOESY/ROESY and FT-IR spectra
of 12-32; GPC measurements. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0603716
(19) Sa´nchez, L.; Rispens, M. T.; Hummelen, J. C. Angew. Chem., Int.
Ed. 2002, 41, 838.
(18) So¨ntjens, S. H. M.; Sijbesma, R. P.; van Genderen, M. H. P.; Meijer,
E. W. J. Am. Chem. Soc. 2000, 122, 7487.
(20) Armstrong, G.; Alonso, B.; Massiot, D.; Buggy, M. Magn. Reson.
Chem. 2005, 43, 405.
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Org. Lett., Vol. 8, No. 9, 2006