Effect of terminal group sterics and dendron packing on chirality transfer from the central core of a dendrimer

Article abstract of DOI:10.1021/ol016409q

(formula presented) The conformational properties of intramolecularly hydrogen-bonded dendrimers constructed from (S)-1,1′-bi-2-naphthol as a chiral central core are described. Circular dichroism studies revealed that chirality transfer to the periphery o

Full text of DOI:10.1021/ol016409q

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3129-3132
Effect of Terminal Group Sterics and
Dendron Packing on Chirality Transfer
from the Central Core of a Dendrimer
Preete Gandhi, Baohua Huang, Judith C. Gallucci, and Jon R. Parquette*
Department of Chemistry, The Ohio State UniVersity, Columbus, Ohio 43210
parquett@chemistry.ohio-state.edu
Received July 9, 2001
ABSTRACT
The conformational properties of intramolecularly hydrogen-bonded dendrimers constructed from (S)-1,1′-bi-2-naphthol as a chiral central
core are described. Circular dichroism studies revealed that chirality transfer to the periphery occurs only when sterically demanding terminal
esters are employed and when packing interactions are present.
The potentially globular morphology of dendrimers suggests
that these structurally well-defined, three-dimensional macro-
molecules may be excellent synthetic mimics of proteins.1
Therefore, there has been tremendous interest in character-
izing and controlling the conformational equilibria of den-
drimer systems.2 An understanding of the structural factors
that control the conformational behavior of dendrimers would
facilitate the design of functional systems that capitalize on
their supramolecular organization for function in potential
applications. However, recent evidence indicates that the
structures of most dendrimers are quite flexible wherein
terminal groups “backfold” toward the interior of the
structure.3 Consistent with this highly dynamic conforma-
tional equilibria, the majority of chiral dendrimers that have
been reported exhibit optical rotations or circular dichroisms
that vary linearly with the number of repeating chiral
chromophores, suggesting a lack of stable secondary struc-
tural order.4 However, some peptide-based dendrimers have
been reported to exhibit SEC behavior that suggested the
presence of folded conformations.5
(3) (a) Mourey, T. H.; Turner, S. R.; Rubinstein, M.; Frechet, J. M. J.;
Hawker, C. J.; Wooley, K. L. Macromolecules 1992, 25, 2401. (b) Wooley,
K. L.; Klug, C. A.; Tasaki, K.; Schaefer, J. J. Am. Chem. Soc. 1997, 119,
53. (c) De Backer, S.; Prinzie, Y.; Verheijen, W.; Smet, M.; Desmedt, K.;
Dehaen, W.; De Schryver, F. C. J. Phys. Chem. A 1998, 102, 5451. (d)
Gorman, C. B.; Hager, M. W.; Parkhurst, B. L.; Smith, J. C. Macromolecules
1998, 31, 815. (e) Topp, A.; Bauer, B. J.; Tomalia, D. A.; Amis, E. J.
Macromolecules 1999, 32, 7232. (f) Kao, H.-M.; Stefanescu, A. D.; Wooley,
K. L.; Schaefer, J. Macromolecules 2000, 33, 6214.
(1) Newkome, G. R.; Moorefield, C. N.; Vogtle, F. Dendritic Mol-
ecules: Concepts, Syntheses, PerspectiVes; VCH: Weinheim, New York,
(4) For some reviews of chiral dendrimers, see: (a) Seebach, D.; Rheiner,
P. B.; Greiveldinger, G.; Butz, T.; Sellner, H. Top. Curr. Chem. 1998, 197,
125. (b) Peerlings, H. W. I.; Meijer, E. W. Chem. Eur. J. 1997, 3, 1563.
(c) Thomas, C. W.; Tor, Y. Chirality 1998, 10, 53.
1996.
(2) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. ReV. 1999,
99, 1665.
10.1021/ol016409q CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/08/2001

The ability to transmit smaller amounts of chiral informa-
tion over increasingly greater length scales will be critical
in developing highly responsive macromolecular materials
that function through their supramolecular conformations.
We have recently reported that chiral, helical secondary
structure can be induced in dendrimers rigidified through
intramolecular hydrogen-bonding interactions.6 Chiral, non-
racemic subunits incorporated at the periphery bias the helical
secondary structure toward an M-type chirality as a result
of intramolecular packing interactions that produce cooper-
ativity in the conformational equilibria of the peripheral
subunits.7 However, controlling the helical bias at the
periphery of a dendrimer using a chiral subunit placed at
the central core requires transmission of chiral information
over a longer distance to more achiral groups than placement
at the periphery requires (Figure 1). Therefore, biasing the
of (C12H25O2C)2[G1]-Cl (2)6c in the presence of KH in DMF
at 70 °C (Scheme 1).9 Second generation dendrimer (5) was
Scheme 1. Synthesis of Dendrimers with
(S)-1,1′-bi-2-naphthol Central Core and Dodecyl Ester Termini
Figure 1. Placement of chiral, nonracemic subunit at central core
or termini to bias dendron conformation.
conformation of a dendrimer with a single, chiral central core
is significantly more difficult than with several chiral
peripheral groups. Accordingly, dendrimers constructed from
chiral, nonracemic central cores have not exhibited chirally
biased conformational equilibria in the branch segments or
at the periphery.8 In this communication, we show that both
intramolecular packing interactions and increased steric
demands of the termini are required to bias the helical
conformation of a dendrimer elaborated from (S)-1,1′-bi-2-
naphthol as a central core.
prepared in a similar fashion using (C12H25O2C)4[G2]-Cl (3).
Although the overall conversion to bis-arylated dendrimer
was relatively low, displacement of the chloride was carried
out at e80 °C to avoid racemization of (S)-1,1′-bi-2-naphthol
(1).10
Circular dichroic spectra (molar ellipticity) for (S)-1,1′-
bi-2-naphthol (1) and the first (4) and second (5) generation
dendrimers are shown in Figure 2. The peak at approximately
Dendrimer construction proceeded by base-mediated O-
arylation of dendrons having a chloro function at the focal
point. Accordingly, the first generation dendrimer (4) was
prepared by treating (S)-1,1′-bi-2-naphthol (1) with 2 equiv
(5) (a) Kim, Y.; Zeng, F.; Zimmerman, S. C. Chem. Eur. J. 1999, 5,
2133. (b) Brouwer, A. J.; Mulders, S. J. E.; Liskamp, R. M. J. Eur. J. Org.
Chem. 2001, 10, 1903.
(6) (a) Recker, J.; Tomcik, D. J.; Parquette, J. R. J. Am. Chem. Soc.
2000, 122, 10298. (b) Huang, B.; Parquette, J. R. J. Am. Chem. Soc. 2001,
123, 2689. (c) Huang, B.; Parquette, J. R. Org. Lett. 2000, 2, 239.
(7) For examples of cooperativity in helical polymers, see: (a) Green,
M. M.; Peterson, N. C.; Sato, T.; Teramoto, A.; Cook, R.; Lifson, S. Science
1995, 268, 1860. (b) Langeveld-Voss, B. M. W.; Waterval, R. J. M.; Janssen,
R. A. J.; Meijer, E. W. Macromolecules 1999, 32, 227. (c) Palmans, A. R.
A.; Vekemans, J. A. J. M.; Havinga, E. E.; Meijer, E. W. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2648.
Figure 2. CD spectra of (1) and first (4) and second (5) generation
dendrimers with dodecyl termini.
(8) (a) Seebach, D.; Lapierre, J. M.; Skobridis, K.; Greiveldinger, G.
Angew. Chem., Int. Ed. Eng. 1994, 33, 440. (b) Seebach, D.; Lapierre, J.
M.; Greiveldinger, G.; Skobridis, K. HelV. Chim. Acta 1994, 77, 1673. (c)
Chaumette, J.-L.; Laufersweiler, M. J.; Parquette, J. R. J. Org. Chem. 1998,
63, 9399. (d) Rohde, J. M.; Parquette, J. R. Tetrahedron Lett. 1998, 39,
9161. (e) Peerlings, H. W. I.; Meijer, E. W. Eur. J. Org. Chem. 1998, 573,
3. (f) Chen, Y.-M.; Chen, C.-F.; Xi, F. Chirality 1998, 10, 661. (g) Dubber,
M.; Lindhorst, T. K. Chem. Commun. 1998, 1265. (h) Hu, Q.-S.; Pugh, V.;
Sabat, M.; Pu, L. J. Org. Chem. 1999, 64, 7528. (i) Lellek, V.; Stibor, I. J.
Mater. Chem. 2000, 10, 1061. (j) Rosini, C.; Superchi, S.; Peerlings, H.
W. I.; Meijer, E. W. Eur. J. Org. Chem. 2000, 61. (k) Gong, L.-Z.; Hu,
Q.-S.; Pu, L. J. Org. Chem. 2001, 66, 2358.
240 nm is the long wavelength portion of an exciton couplet
centered at 220 nm (1B transition) due to excitonic coupling
of a transition polarized along the long axis of each
binaphthyl ring consistent with the S axial-type stereochem-
istry of the 1,1′-binaphthyl central core.11 The intensity of
this couplet has been shown to decrease as the dihedral angle
between these electric transition moments expands.8j,11
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Org. Lett., Vol. 3, No. 20, 2001

Consequently, the decrease in intensity of the couplet going
from 1 to 5 is due to an increasing steric effect imparted by
the dendrons on the binaphthyl core that increases this
dihedral angle. The terminal anthranilate chromophores
exhibit a π f π* transition in the UV spectrum at 316 nm
that is polarized along the axis containing C3 and C6 of the
anthranilate ring (see TDDFT electronic structure calcula-
tions, Supporting Information).12 The lack of any Cotton
effects (CE) in the region of 316 nm indicates that the
binaphthyl core was not creating a chirally biased helical
conformation at the periphery in 4 or 5.
the tert-butyl esters induced a more rigidly helical conforma-
tion in the dendrons (Figure 3). A clear, orthorhombic crystal
We reasoned that increasing the steric demands of the
terminal esters would induce a more rigidly helical confor-
mation relating the terminal anthranilate groups. This
structural modification should enhance the helical conforma-
tion in a manner that would more effectively express the
chirality of the central core. An X-ray structure of second
generation dendron, (CH3O2C)4[G2]-Cl, displaying methyl
anthranilate groups at the periphery supported this hypothesis.6c
In the solid state, this dendron displayed a “flattened”
nonhelical orientation of adjacent methyl anthranilate ter-
minal groups that was, in part, due to the insufficient steric
requirements of the methyl ester groups.
Figure 3. X-ray structures of (t-C4H9O2C)2[G1]-NH2 (6c) and (t-
C4H9O2C)4[G2]-Br (7-Br). Each dendron of the interdigitated dimer
in the asymmetric unit for 7-Br is designated by dark and light
shading.
with a Pnn2 space group was obtained for first generation
dendron 6c by crystallization from CH2Cl2.14 In contrast to
the flattened conformation of (CH3O2C)4[G2]-Cl in the solid
state,6c 6c displayed a helical conformation relating the two
tert-butyl anthranilate terminal groups.
Therefore, to increase the degree of helicity, tert-butyl
esters were incorporated at the periphery following a
synthetic sequence analogous to that reported for the dodecyl
ester terminated dendrons (Scheme 2).6c To increase the focal
Second generation dendron 7-Br similarly crystallized
from CH2Cl2, affording a clear, monoclinic crystal with a
C2/c space group.15 Similar to (CH3O2C)4[G2]-Cl, X-ray
diffraction showed that the asymmetric unit was a dimer
composed of two virtually identical, interdigitated mono-
dendrons with four associated molecules of CH2Cl2. The
dimeric structure is stabilized by face-to-face π stacking
interactions that sandwich the focal A ring of one dendron
between the adjacent terminal D rings of the other dendron.
The stacked arrangements display closest edge-to-edge
distances that vary from 3.33 to 3.68 Å. Whereas the
analogous dendron with methyl ester termini could assume
a conformation that permitted all seven rings to pair in
stacked arrangements, the tert-butyl esters create a more
helical arrangement of the anthranilate rings that sterically
precludes distortion of the T-shaped conformation to permit
further stacking interactions.
Scheme 2. Synthesis of tert-butyl Ester Terminated Dendronsa
a Key: (a) tert-butyl anthranilate, pyr-CH2Cl2, DMAP; (b) NaN3,
DMF, 50 °C; (c) H2/Pd-C EtOAc/MeOH; (d) 4-halopyridine-2,6-
dicarbonyl halide (X ) Cl, Br), pyr-CH2Cl2.
Dendrimer synthesis proceeded by O-arylation of (S)-1,1′-
bi-2-naphthol (1) with 6a-Cl in the presence of Cs2CO3 at
80 °C; however, only mono-8 was obtained in 63% yield as
a result of the low reactivity of the focal chloride (Scheme
3). In contrast, employing the more reactive 6a-Br under
the same conditions afforded bis-8 in 56% yield. Unfortu-
point electrophilicity, dendron monobromides were prepared
in addition to the corresponding chlorides by employing
4-bromopyridine-2,6-dicarbonyl bromide13 in each genera-
tional growth step.
X-ray crystal structures of first (6c) and second (7-Br)
generation dendrons provided preliminary confirmation that
(12) The direction of the electric transition moment was calculated for
methyl 2-acetamidobenzoate using TDDFT theory and the B3LYP functional
(see Supporting Information).
(13) Prepared in 66% yield by treating chelidamic acid with PBr5 and
purified by distillation (see Supporting Information).
(9) Exposure of (S)-1,1′-bi-2-naphthol (1) to these reaction conditions
did not cause significant racemization.
(10) Kyba, E. B.; Koga, K.; Sousa, L. R.; Siegel, M. G.; Cram, D. J. J.
Am. Chem. Soc. 1973, 95, 2692.
(11) Bari, L. D.; Pescitelli, G.; Salvadori, P. J. Am. Chem. Soc. 1999,
121, 7998 and references therein.
(14) General crystallographic information: T ) 203 K; Pnn2, a )
22.4784 Å (5), b ) 11.5942 Å (2), c ) 12.1470 Å (3); â ) 90.135° (1); V
) 10714.3 (3) Å3; Z ) 8; 18847 unique data; Rw ) 0.063; GOF ) 1.060.
(15) General crystallographic information: T ) 150 K; C2/c, a ) 20.3270
Å (1), b ) 30.0453 Å (2), c ) 25.0005 Å (2); â ) 94.3803 (3); V ) 15224
(2) Å3; Z ) 8; 13431 unique data; Rw ) 0.0775; GOF ) 1.033.
Org. Lett., Vol. 3, No. 20, 2001
3131

wavelength portion of a positive excitonic couplet centered
at 316 nm arising from a π f π* transition at 316 nm
polarized along the anthranilate axis containing C3 and C6.
The longer wavelength branch of the couplet is more intense
than the shorter wavelength branch as a result of mixing of
the couplet transition with other transitions, suggesting a
highly congested environment.17 On the basis of the direction
of the electric transition moment associated with this
transition and the positive chirality of the couplet, the
absolute sense of helical chirality between each pair of
anthranilate chromophores can be assigned as P-type helicity
(see Supporting Information) (Figure 1). The intensity of the
couplet was relatively insensitive to solvent choice with the
exception of trifluoroethanol and acetonitrile, in which the
couplet intensity was significantly reduced.18 The helical bias
was present up to 110 °C in bis(2-butoxyethyl)ether, indicat-
ing that this conformational preference was quite thermally
stable.
Scheme 3. Synthesis of tert-Butyl Ester Terminated
Dendrimers
It is noteworthy that although the mono-8 failed to express
the chirality of the central core at the periphery of the
molecule, bis-8 expressed a stable P-type helical preference
identical to that of (S)-1,1′-bi-2-naphthol, which can also be
considered as a P-type helix.19 In dendrons constructed with
chiral terminal groups, we have previously observed that the
helical bias became more stable with increasing dendrimer
generation.6 This observation could be explained by the
presence of intraterminal group packing interactions that
induce correlated conformational equilibria of the peripheral
subunits, causing small energetic differences between con-
formational states to be magnified.7 The difference in
conformational behavior of mono-8 and bis-8 is consistent
with this interpretation, since intradendron packing-type
interactions would be present in bis-8 but not in mono-8.
Consequently, we can conclude that the increased steric
requirements of the terminal groups in conjunction with
dendron packing interactions are crucial for effective transfer
of core chirality to the helical conformation of the dendrimer.
Current efforts are directed at biasing the secondary structure
of larger dendrimers using chiral central cores with a
longterm goal of controlling conformational equilibria on
increasingly greater length scales.
nately, we have been unable to prepare the second generation
dendrimer using 7-Cl or 7-Br, presumably for steric rea-
sons.16
Circular dichroism studies were carried out to determine
whether this modification of the terminal groups would
sufficiently rigidify the helical conformation to permit the
chiral core to bias the helical equilibrium (Figure 4). The
Acknowledgment. This work was supported by the
National Science Foundation CAREER program (CHE 98-
75458).
Supporting Information Available: Experimental pro-
cedures and analytical data for 2-8, output for the TDDFT-
B3LYP calculations, ORTEP diagrams in stereo of 6c and
7-Br, and tables of X-ray structural data. This material is
available free of charge via the Internet at http://pubs.acs.org.
Figure 4. CD spectra mono-8 (top-left) and bis-8 (top-right) as a
function of solvent at 25 °C and temperature dependence of bis-8
in bis(2-butoxyethyl)ether (bottom).
OL016409Q
(16) The source of the lower apparent reactivity of the tert-butyl ester
dendrons relative to the dodecyl analogues is unknown.
(17) For a discussion, see: Gottarelli, G.; Mason, S. F.; Torre, G. J.
Chem. Soc. B 1970, 1349.
(18) Although the denaturing effect of these solvents cannot be fully
rationalized, a solvent-induced disruption of the hydrogen-bonding interac-
tions present in the dendrons is likely to be responsible.
(19) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; p 1120.
lack of any significant Cotton effects in the region of 316
nm of mono-8 indicated that the peripheral helicity was
unbiased by the core. The CD spectra were also not affected
by changes in solvent or temperature. However, the spectra
of bis-8 displayed an intense CE at 327 nm in several
different solvents at 25 °C. This CE corresponds to the long
3132
Org. Lett., Vol. 3, No. 20, 2001