Folding Dendrons: The Development of Solvent-, Temperature-, and Generation-Dependent Chiral Conformational Order in Intramolecularly Hydrogen-Bonded Dendrons

Article abstract of DOI:10.1021/ja001225c

The synthesis of intramolecularly hydrogen-bonded dendrons with stereogenic terminal groups derived from (1S,2S)-(+)-thiomicamine up to the third generation is described. Circular dichroism (CD) studies reveal that the equilibria interconverting two diast

Full text of DOI:10.1021/ja001225c

10298
J. Am. Chem. Soc. 2000, 122, 10298-10307
Folding Dendrons: The Development of Solvent-, Temperature-, and
Generation-Dependent Chiral Conformational Order in
Intramolecularly Hydrogen-Bonded Dendrons
Janosch Recker, Dennis J. Tomcik, and Jon R. Parquette*
Contribution from the Department of Chemistry, The Ohio State UniVersity, Columbus, Ohio 43210
ReceiVed April 7, 2000
Abstract: The synthesis of intramolecularly hydrogen-bonded dendrons with stereogenic terminal groups derived
from (1S,2S)-(+)-thiomicamine up to the third generation is described. Circular dichroism (CD) studies reveal
that the equilibria interconverting two diastereomeric helical conformations (M and P helices) relating a pair
of anthranilamide termini depends on solvent, temperature, and dendrimer generation. A conformational
preference for M-type helicity along the periphery of the dendrons increased with increasing dendrimer generation
and in poor solvents as observed by CD. Equilibration of these diastereomeric helical conformations is rapid
at the first generation in all solvents and at all temperatures investigated; however, at the second generation
the equilibrium begins to bias a single diastereomeric helical conformation along the periphery that becomes
maximal at low temperatures and in poor solvents. At the third generation, the helical bias is intrinsically
higher so that the conformational preference of the termini becomes much less sensitive to solvent and
temperature, and the unfolding process becomes more difficult. We propose that nonbonded repulsive interactions
that increase with generation and in poor solvents couple the motions and conformational preferences of each
pair of terminal groups through their correlated rotations and contribute to the stability of the M helical
conformation of the terminal groups. This represents the first example of well-defined asymmetric secondary
structure occurring in a dendrimer system.
Introduction
of the nature of the conformational equilibrium present in these
dendrimers has not been forthcoming. In this work, we report
Nature consistently relies on large macromolecules such as
proteins to perform the many important chemical functions
required for life. A minimization of free energy that is
determined by the cooperative action of many noncovalent
interactions drives a folding process in these large molecules
to produce a specific 3-dimensional structure that is crucial for
function.1 The design of unnatural molecules that fold into
predictable and well-defined conformations can provide insight
into some of the interactions that control the folding of peptides
into stable tertiary structures.2 In particular, the conformation
of chiral dendrimers has been of great interest because their
highly branched structure creates a globular morphology that
potentially mimics globular proteins.3 The development of
higher levels of self-organization in a chiral dendrimer would
be expressed as asymmetric conformational order and should
be observable using chiroptical methods.4 Although numerous
chiroptical studies of chiral dendrimers have been reported, these
studies were unable to unambiguously ascertain the presence
of a secondary structural fold and most suggested a lack of
conformational order.4,6-16 More importantly, an understanding
(5) For a discussion of the relationship of optical activity to conformation
in linear polymers, see: (a) Farina, M. Top. Stereochem. 1987, 171. (b)
Pino, P.; Salvadori, P.; Chiellini, E.; Luisi, P. L. Pure Appl. Chem. 1968,
16(2-3), 469.
(6) (a) McElhanon, J. R.; McGrath, D. V. J. Org. Chem. 2000, 65(11),
3525. (b) McElhanon, J. R.; McGrath, D. V. J. Am. Chem. Soc. 1998, 120,
1647. (c) Junge, D. M.; McGrath, D. V. Tetrahedron Lett. 1998, 39, 1701.
(d) McGrath, D. V.; Wu, M.-J.; Chaudhry, U. Tetrahedron Lett. 1996, 37,
6077. (e) McElhanon, J. R.; Wu, M.-J.; Escobar, M.; McGrath, D. V.
Macromolecules 1996, 29, 8979. (f) Chang, H.-T.; Chen, C.-T.; Kondo,
T.; Siuzdak, G.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35,
182. (g) Balasubramanian, R.; Rao, P.; Maitra, U. Chem. Commun. 1999,
(23), 2353.
(7) (a) Kress, J.; Rosner, A.; Hirsch, A. Chem.-Eur. J. 2000, 6, 247.
(b) Chow, H.-F.; Mak, C. C. J. Chem. Soc., Perkin Trans. 1 1997, 91. (c)
Chow, H.-F.; Mak, C. C. Pure Appl. Chem. 1997, 69, 483. (d) Mak, C. C.;
Chow, H.-F. Chem. Commun. 1996, 1185. (e) Chow, H.-F.; Mak, C. C.
Tetrahedron Lett. 1996, 37, 5935.
(8) (a) Lartigue, M.-L.; Caminade, A.-M.; Majoral, J. P. Tetrahedron:
Asymmetry 1997, 8, 2697. (b) Issberner, J.; Boehme, M.; Grimme, S.;
Nieger, M.; Paulus, W.; Vo¨gtle, F. Tetrahedron: Asymmetry 1996, 7, 2223.
(c) Issberner, J.; Bohme, M.; Grimme, S.; Nieger, M.; Paulus, W.; Vogtle,
F. Tetrahedron Asymmetry 1996, 7, 7. (d) Newkome, G. R.; Lin, X.; Weis,
C. D. Tetrahedron: Asymmetry 1991, 2, 957.
(9) (a) Jansen, J. F. G. A.; Peerlings, H. W. I.; de Brabander-Van den
Berg, E. M. M.; Meijer, E. W. Angew. Chem., Int. Ed. Engl. 1995, 34,
1206. (b) Jansen, J.; de Brabander-Van den Berg, E. M. M.; Meijer, E. W.
Recl. TraV. Chim. Pays-Bas. 1995, 114, 225.
(10) (a) Murer, P. K.; Lapierre, J. M.; Greiveldinger, G.; Seebach, D.
HelV. Chim. Acta 1997, 80, 1648. (b) Murer, P.; Seebach, D. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2116.
(1) Creighton, T. E. Proteins: Structures and Molecular Properties, 2nd
ed.; W. H. Freeman: New York, 1993.
(2) (a) Barron, A. E.; Zuckermann, R. N. Curr. Opin. Chem. Biol. 1999,
3(6), 681. (b) Kirshenbaum, K.; Zuckermann, R. N.; Dill, K. A. Curr. Opin.
Struct. Biol. 1999, 9(4), 530. (c) Smith, M. D.; Fleet, G. W. J. J. Pept. Sci.
1999, 5(10), 425.
(3) (a) Fischer, M.; Vo¨gtle, F. Angew. Chem., Int. Ed. 1999; 38, 885.
(b) Smith, D. K.; Diederich, F. Chem.-Eur. J. 1998, 4(8), 1353.
(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.
(11) Murer, P.; Seebach, D. HelV. Chim. Acta 1998, 81, 603.
(12) (a) Seebach, D.; Lapierre, J. M.; Skobridis, K.; Greiveldinger, G.
Angew. Chem., Int. Ed. Engl. 1994, 33, 440. (b) Seebach, D.; Lapierre, J.
M.; Greiveldinger, G.; Skobridis, K. HelV. Chim. Acta 1994, 77, 1673. (c).
(13) Hu, Q.-S.; Pugh, V.; Sabat, M.; Pu, L. J. Org. Chem. 1999, 64,
4(20), 7528.
10.1021/ja001225c CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/04/2000

Conformational Order in H-Bonded Dendrons
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10299
the first example of a dendron that develops chiral secondary
structural order and describe how intramolecular hydrogen-
bonding, noncovalent packing interactions, solvophobic com-
pression, and dendrimer generation contribute to the stability
of a particular helical conformation.
consequence of the conformational flexibility of the branches.16
These seminal studies are consistent with recent evidence
suggesting that, in the absence of attractive or repulsive
secondary interactions between otherwise flexible dendritic
subunits, most dendrimers are conformationally quite flexible
especially at lower generations.17 Consequently, conformation-
ally flexible dendrimers do not adopt the well-defined supramo-
lecular structure necessary to induce higher levels of structural
self-organization.
Chiroptical studies of chiral dendrimers commonly infer
conformational information by comparing the chiroptical prop-
erties of several generations of dendrimers to that of the
repeating chiral subunit6-16 or of a suitable model compound.6a-c
Any deviation of the dendrimer optical activity, normalized for
the number of repeating chiral chromophores, and the optical
activity of the chiral subunit are interpreted as a shift in the
position of conformational equilibrium.5 The majority of chiral
dendrimers that have been described exhibit optical rotations
or circular dichroisms that vary linearly with the number of
repeating chiral chromophores, indicating that stable secondary
structural order was not developing. For example, several reports
demonstrated that dendrimers with fully chiral branches based
on chiral polyaryl ether6 or tartaric acid7 subunits exhibited
specific rotations linearly proportionate to the number of chiral
chromophores. Dendrimers with stereogenic substituents at the
surface also appear to exhibit chiroptical data that vary
proportionately to the number of stereogenic termini.8 In contrast
to these observations, Meijer observed that poly(propylene-
amine) dendrimers displaying amino acids on the periphery
undergo a decrease in specific rotation with dendrimer genera-
tion.9 However, this behavior could be attributed to the presence
of a densely packed periphery that significantly reduced the
conformational freedom of the chiral terminal groups creating
a number of frozen conformations with pseudo-enantiomeric
relationships. Seebach has also observed anomalous variations
in chiroptical data with dendrimer generation in fully chiral
dendrimers,10 and recently, in a related dendrimer system, a
variation in the sign and shape of the CD spectra with dendrimer
generation was observed in acetonitrile but not in a good solvent
such as dichloromethane.11 However, the nature of the confor-
mational equilibrium and the origin of the solvent effect could
not be determined. Chiroptical studies of dendrimers constructed
from a chiral central core also suggest that conformational
asymmetry is unlikely to be present. For example, Seebach has
shown that polyaryl ether dendrimers with a stereogenic core
and achiral branches exhibit molar rotations that remain
approximately constant with generation, indicating that chiral
conformations were not contributing to the observed rotations.12
Similarly, phenylacetylene dendrimers with a chiral 1,1′-bi-2-
naphthol central core exhibited CD spectra that were invariant
with generation, indicating the achiral dendrons were not
adopting chiral conformations.13 We and others have observed
variations in molar rotation with generation in dendrimers
containing chiral central cores that could be attributed to a
generation-dependent perturbation in the conformational equi-
librium of the central core rather than chiral conformational
order.14,15 Meijer reported that polyaryl ether dendrimers that
were chiral based on the linkage of three constitutionally
different dendritic wedges displayed no optical activity as a
The intramolecular self-organization necessary to induce a
molecule to fold into a specific conformation is driven by the
cooperative interplay of multiple molecular recognition pro-
cesses such as hydrogen-bonding, van der Waals, electrostatic,
and solvophobic interactions.18 Noncovalent interactions have
been exploited to promote intermolecular dendrimer self-
assembly; however, the effect of intramolecular interactions such
as hydrogen-bonding on dendrimer conformation has received
little attention.19 For example, Percec has prepared a series of
monodendrons that assemble into liquid crystalline mesophases
as a consequence of multiple, weak, intermolecular interac-
tions.20 Similarly, Zimmerman exploited intermolecular hydrogen-
bonding interactions to drive dendrimer self-assembly.21 Al-
though noncovalent interactions, especially hydrogen-bonding
interactions,22 have been used to direct the intramolecular folding
of linear oligomers, termed “foldamers,” into helical conforma-
tions,23 attractive forces such as hydrogen-bonding have not been
exploited as a method to create secondary structural order in
chiral dendrimers. Recently, we described a series of achiral
dendrons whose conformational properties were restricted
through the intervention of intramolecular hydrogen-bonding
and electrostatic interactions present in the AB2 building block.24
(17) For are 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.
(18) (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; J. Wiley: Chichester; New York, 1991. (d) Delaage, M.
Molecular Recognition Mechanisms; VCH Publishers:New York, NY,
Lavoisier-Tec & Doc:Paris, France, 1991. (e) Lawrence, D. S.; Jiang, T.;
Levett, M. Chem. ReV. 1995, 95, 2229. (f) Lindsey, J. S. New J. Chem.
1991, 15, 153.
(19) Noncovalent interactions at the periphery of dendrimers have been
reported to reduce backfolding. For a discussion, see ref 17.
(20) (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.
(21) (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.
(22) For a review of hydrogen bonding in natural and synthetic peptides,
see: Karle, I. L. J. Mol. Struct., 1999, 474; 103.
(14) (a) Chaumette, J.-L.; Laufersweiler, M. J.; Parquette, J. R. J. Org.
Chem. 1998, 63, 9399. (b) Rohde, J. M.; Parquette, J. R. Tetrahedron Lett.
1998, 39, 9161.
(23) For an excellent review, see: (a) Gellman, S. H. Acc. Chem. Res.
1998, 31, 173. Hydrogen-bond driven foldamers, see: (b) Applequist, J.;
Bode, K. A.; Appella, D. H.; Christianson, L. A.; Gellman, S. H. J. Am.
Chem. Soc. 1998, 120, 4891. Solvophobically driven foldamers: (c) Gin,
M. S.; Moore, J. S. Org. Lett. 2000, 2, 135. (d) Gin, M. S.; Yokozawa, T.;
Prince, R. B.; Moore, J. S. J. Am. Chem. Soc. 1999, 121, 2643. (e) Prince,
R. B.; Okada, T.; Moore, J. S. Angew. Chem., Int. Ed. 1999, 38, 233. (f)
Nelson, J. C.; Saven, J. G.; Moore, J. S. Wolynes, P. G. Science 1997, 277,
1793.
(15) (a) Lellek, V.; Stibor, I. J. Mater. Chem. 2000, 10(5), 1061. (b)
Rosini, C.; Superchi, S.; Peerlings, H. W. I.; Meijer, E. W. Eur. J. Org.
Chem. 2000, (1), 61. (c) Peerlings, H. W. I.; Meijer, E. W. Eur. J. Org.
Chem. 1998, 573, 3. (d) Chen, Y.-M.; Chen, C.-F.; Xi, F. Chirality 1998,
10, 661. (e) Chen, Y.-M.; Chen, C.-F.; Xi, F. Chirality 1998, 10(7), 661.
(16) (a) Peerlings, H. W. I.; Trimbach, D. C.; Meijer, E. W. Chem.
Commun. 1998, 497. (b) Peerlings, H. W. I.; Struijk, M. P.; Meijer, E. W.
Chirality 1998, 10, 46.
(24) Huang, B.; Parquette, J. R. Org. Lett. 2000, 2, 239.

10300 J. Am. Chem. Soc., Vol. 122, No. 42, 2000
Recker et al.
Each pair of termini, considered as “blades,” should twist in
the same sense to minimize steric repulsions, thereby coupling
the motions and conformations of each pair of termini. If such
sympathetic motion were operative, the helical preference of
each anthranilamide pair would be amplified by the presence
of adjacent pairs through pairwise nonbonded interactions.
Therefore, the equilibria interconverting the two diastereomeric
helical conformations of each pair of terminal anthranilamides
should increasingly favor a single helical conformation with
increasing generation. This hypothesis is supported by reports
demonstrating that intermolecular aggregation and template-
directed intramolecular aggregation of R-helical peptide blocks
enhances the stability of the R-helical conformation relative to
that of the monomeric peptide block.29 In these systems,
secondary structure is stabilized through inter- or intramolecular
hydrophobic packing interactions that correlate the conforma-
tions of each peptide block. These packing interactions should
occur likewise in the monodendrons, provided that the terminal
anthranilamide groups are held in close proximity by the
hydrogen-bonding interactions. An X-ray structure of a second
generation dendron displaying methyl anthranilate groups at the
periphery supports this supposition; however, the presence of
sterically unencumbered methyl ester termini generated insuf-
ficient nonbonded interactions to induce a helical disposition
of the terminal groups.24 Therefore, a relatively large aminodiol
((1S,2S)-(+)-thiomicamine) was used as the chiral terminal
substituent for this series of dendrons.
Figure 1. Perturbation of helical conformational equilibrium through
nonbonded interactions in an intramolecularly hydrogen-bonded den-
dron.
In the present work, we demonstrate that hydrogen-bonding
interactions direct the folding ability of chiral monodendrons;
however, the development of a stable, helical secondary structure
at the periphery of a monodendron requires concomitant
hydrophobic packing interactions that increase with dendrimer
generation and decreasing solvent quality.
Results and Discussion
Dendron Synthesis and Characterization. Accordingly,
4-chloropyridine-2,6-dicarbonyl chloride, 1, was chosen as the
branching monomer wherein convergent generational growth
was accomplished using amide bond-forming reactions with the
acid chlorides and focal point activation occurred by NaN3
displacement of the 4-chloro group followed by hydrogenation.
The AB2 unit, 1, was prepared by treating chelidamic acid with
PCl5 at 100 °C and was purified by sublimation. Synthesis of
the dendrons proceeded in a convergent fashion wherein
thiomicamine 2 was selectively N-acylated with 2-nitrobenzoyl
chloride then peracetylated with acetic anhydride (Scheme 1).
Hydrogenation over Pd-C followed by reaction with 1 afforded
the first generation dendron, 5a, displaying a chloro group at
the focal point. Focal activation was achieved through displace-
ment of the chloro group with NaN3 in DMF at 50 °C followed
by hydrogenation over Pd-C. Growth to the second generation
occurred by amidation of 1 in pyridine and repetition of the
NaN3 displacement-hydrogenation activation sequence fol-
lowed by condensation with 1 afforded the third generation
dendron 7. Characterization with regard to molecular weight,
structure, and dispersity was accomplished by EI, FAB or
MALDI-TOF MS, and NMR. The proton NMR spectra of the
second and third generation dendrons (6, 7) were broad and
structureless in CDCl3 but well-resolved in DMSO-d6. We
observed this behavior previously in a third generation dendron
containing dodecyl ester termini and attribute it to aggregation
that occurs in nonpolar solvents but not in polar solvents.24
Optical Rotation Studies. Optical rotation studies were
carried out to provide preliminary information concerning the
presence or absence of chiral substructures. However, changes
in aggregation state can give rise to large variations in optical
rotatory power.30 Therefore, optical rotations were recorded in
Design Considerations. Monodendrons up to the third
generation were constructed using 4-aminopyridine-2,6-dicar-
boxamide as the branching AB2 unit to preorganize the interior
of the dendrons through intramolecular hydrogen bonding
interactions, and chiral, nonracemic anthranilamide groups were
employed as termini. Pyridine-2,6-dicarboxamide derivatives
exist in a conformation 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 (Figure 1).25 These hydrogen-bonding interac-
tions, in conjunction with the preference of the terminal amides
to exist in an s-trans conformation, constrain the system such
that the terminal anthranilamide substituents are positioned
above and below the plane of the molecule resulting in a local
helical structure. Hamilton exploited this preference to enforce
a turn in a series of oligoanthranilamides to create a helical
“foldamer.”26 However, Borovik observed that, although chiral
anthranilamides linked through a pyridine-2,6-dicarboxamide
produced a helical conformation in the resultant molecule, the
sense of helical chirality was not influenced by the chiral
terminal substituent in the solid state or in solution.27
We hypothesized that, provided the monodendrons were
conformationally constrained by intramolecular hydrogen-
bonding interactions as shown in Figure 1, pairwise nonbonded
interactions between adjacent termini at higher generations
would facilitate the transmission of a single helical conformation
across the surface of the dendrimer through a correlated
propeller-like rotation of the peripheral anthranilamide groups.28
(25) 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.
(26) (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.
(27) Yu, Q.; Baroni, T. E.; Liable-Sands, L.; Rheingold, A. L.; Borovik,
A. S. Tetrahedron Lett. 1998, 39, 6831.
(28) For a discussion of the correlated rotation in molecular propellers,
see: Mislow, K. Acc. Chem. Res. 1976, 26, 6.
(29) (a) Mutter, M.; Vuilleumier, S. Angew. Chem., Int. Ed. Engl. 1989,
5, 535. (b) Sasaki, T.; Kaiser, E. T. J. Am. Chem. Soc. 1989, 111, 380. (c)
Ghadiri, M. R.; Soares, C.; Choi, C. J. Am. Chem. Soc. 1992, 114, 825. (d)
Dawson, P. E.; Kent, S. B. H. J. Am. Chem. Soc. 1993, 115, 7263. (e)
Higashi, N.; Koga, T.; Niwa, N.; Niwa, M. Chem. Commun. 2000, 361.
(30) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; p 1076.

Conformational Order in H-Bonded Dendrons
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10301
Scheme 1a
Key: (a) 2-NO2C6H4COCl, pyr., DMAP. (b) Ac2O, pyr., DMAP. (c) H2, Pd-C. (d) 1, CH2Cl2-pyr. (e) NaN3, DMF, 50 °C. (f) H2, Pd-C.
and absolute magnitude of the rotations were not linearly
dependent on dendrimer generation. For example, changes in
the sign of rotation were observed going from the zeroth (8) to
first (5a) and from the second (6a) to third generations (7). The
nonlinearity of rotation magnitude and sign suggested that chiral
secondary structure was developing in the dendrons; therefore,
further chiroptical studies were performed to gain specific
information concerning the conformational equilibria present
in the dendrons.
Circular Dichroism Studies. Circular dichroism (CD) was
investigated to determine the influence of chiral terminal groups
on the conformational equilibrium that interconverts the two
diastereomeric helical conformations relating each pair of
anthranilamide termini on the dendrons (Figure 1). To provide
a control compound incapable of developing helical secondary
structure, 4 was acylated with pyridine-2-carboxylic acid
affording G0-control 8. All spectra were carried out at the same
concentration for a given generation and were normalized with
respect to concentration and the number of chiral terminal groups
Figure 2. Molar ORD spectra (normalized for the number of chiral
termini) for 5a (1.00‚10-2 M), 6a (4.73‚10-3 M), 7 (2.29‚10-3 M), and
8 (1.92‚10-2 M) in DMSO at 23 °C.
so that differences in the CD spectra would reveal perturbations
1
DMSO at 23 °C because H NMR analysis indicated that the
dendrons were monomeric in this solvent. Optical rotatory
dispersion (ORD) spectra, normalized for concentration and the
number of chiral termini, are presented in Figure 2. The sign
of conformational equilibria. The CD spectrum of the G0
control, 8, and the first generation dendron 5a in CH2Cl2 at 25
°C revealed two Cotton Effects (CE) in the range of 240-400
nm (Figure 3). Both compounds displayed a positive CE at 260

10302 J. Am. Chem. Soc., Vol. 122, No. 42, 2000
Recker et al.
amido-N-methylbenzamide to model the terminal 2-acylamino-
benzamides responsible for the transition at 316 nm using the
three-parameter Lee-Yang-Parr (B3LYP) functional.34 The
structure was constrained in the calculation to a planar,
intramolecularly hydrogen-bonded conformer similar to the
conformation of this subunit in the dendrons.35 The lowest-
energy transition corresponded to a πfπ* transition at 302 nm
in reasonable agreement with the experimental value of this
electronic absorption (Table 1).36 The electric transition moment
associated with this transition runs along the axis containing
C3 and C6 of the anthranilamide ring. Therefore, the absolute
sense of helical chirality between each pair of anthranilamide
chromophores can be assigned to be M as shown in Figure 5
using the exciton chirality method pneumonic.
The conformational origin of the exciton couplet is supported
by the extreme solvent and temperature sensitivity of this
couplet. For example, the intensity of the exciton couplet
increases significantly in acetonitrile and dramatically in hexane/
CH2Cl2 (2:1) (Figure 6).37 Although CH2Cl2 is a good solvent
for 5-8, all of the dendrons are sparingly soluble in acetonitrile
and insoluble in hexane, which requires CH2Cl2 as a cosolvent
to dissolve the dendrons. Since the intensity of the couplet
increases with decreasing solvent quality, a solvophobic com-
pression of 6a must be occurring that increases nonbonded
packing interactions at the periphery and reduces conformational
freedom. This interpretation is consistent with several theoreti-
cal38 and experimental39 studies, indicating that dendrimers
collapse in poor solvents and expand in good solvents. Solvo-
phobic compression perturbs the conformational equilibrium of
the terminal anthranilamides so that a single helical conformation
becomes increasingly favored with decreasing solvent quality.40
Further, the addition of 1% ethanol to the CH2Cl2 solution of
Figure 3. UV (normalized to 1.6 µM) and CD spectra of 5-8 in CH2-
Cl2 at 25 °C. Concentrations for CD: 8, 1.9‚10-5 M; 5a, 8.0‚10-6 M;
6a, 3.7‚10-6 M; 7, 1.6‚10-6 M.
(33) The TDDFT-B3LYP calculations were run as implemented in:
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K.
N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J.
V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon, M.;
Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.7; Gaussian, Inc.:
Pittsburgh, PA, 1998.
(34) (a) Bauernschmitt, R.; Ahlrichs, R. Chem. Phys. Lett. 1996, 256,
454. (b) Stratmann, R. E.; Scuseria, G. E.; Frisch, M. J. J. Chem. Phys.
1998, 109, 8218. (c) Foresman, J. B.; Head-Gordon, M.; Pople, J. A.; Frisch,
M. J. J. Phys. Chem. 1992, 96, 135. Recently, the circular dichroism of
helicenes has been investigated using TDDFT methods, see: (d) Furche,
F.; Ahlrichs, R.; Wachsmann, C.; Weber, E.; Sobanski, A.; Vo¨gtle, F.;
Grimme, S. J. Am. Chem. Soc. 2000, 122, 1717.
(35) The conformation shown in Figure 1 provides a specific orientation
of the 2-acylaminobenzamide chromophore with respect the C2 axis of the
molecule. It is based upon X-ray crystal structures of closely related
structures (see refs 24-27).
(36) The transitions in Table 1 were assigned as σfπ* or πfπ* on the
basis of the symmetry of the ground and excited-state molecular orbitals
that contribute to the transition. (See Supporting Information).
(37) That the shorter branch of the couplet is stronger than the longer-
wavelength branch is likely due to mixing of the couplet transition with
other transitions. The degree of mixing could be expected to increase as
the chromophores become more congested at higher generations. For a
discussion, see: Gottarelli, G.; Mason, S. F.; Torre, G. J. Chem. Soc. B
1970, 1349.
nm (Band A) and a negative CE at 310 nm for 8 and 316 nm
for 5a (Band B). Although the shorter wavelength UV transitions
at 260 nm are due to overlapping transitions of several
chromophores, the longer wavelength transition (Band B) can
be attributed to a πfπ* transition of the 2-acylaminobenzamide
chromophore at the periphery of the dendron (see TDDFT-
B3LYP calculations, vide infra). All of the CEs were of
comparable intensity and lacked any apparent intrachromophore
excitonic coupling. However, the shape of Band B CEs were
slightly different. As will become apparent at higher generations,
the shape of the CE for this transition in 5a is due to a weak
excitonic coupling between the two anthranilamide chro-
mophores not present in 8. The spectra of 8 and 5a were
insensitive to solvent and temperature (Figure 4).31 Therefore,
we conclude that the chiral, nonracemic terminal groups in 5a
have little or no influence on the position of the conformational
equilibrium interconverting the two helical antipodes.
Comparison of the CD spectra of first and second generation
dendrons, 5a and 6a, revealed significant differences in the
transitions associated with Band B in CH2Cl2 at 25 °C. Although
G1 dendron 5a exhibited a negative CE centered at 316 nm
corresponding to the λmax of this transition, the second generation
dendron 6a showed an excitonically coupled transition with a
positive CE at 300 nm, a negative CE at 327 nm, and a zero-
crossing at 316 nm, corresponding to negative chirality as
defined by Nakanishi and Harada (Figure 3).32 Time-dependent
density-functional (TDDFT) methods33 were applied to 2-acet-
(38) (a) Murat, M.; Grest, G. S. Macromolecules 1996, 29, 9(4), 1278.
(b) Scherrenberg, R.; Coussens, B.; van Vliet, P.; Edouard, G.; Brackman,
J.; de Brabander, E.; Mortensen, K. Macromolecules 1998, 31, 1(2), 456.
(c) Welch, P.; Muthukumar, M. Macromolecules 1998, 31, 1(17), 5892.
(39) De Backer, S.; Prinzie, Y.; Verheijen, W.; Smet, M.; Desmedt, K.;
Dehaen, W.; De Schryver, F. C. J. Phys. Chem. A 1998, 102(28), 5451.
(40) For an example of a solvophobically driven folding event in
phenylacetylene oligomers see refs 23 c-f.
(31) In acetonitrile, G0 (8) exhibited a slightly higher intensity CE at
310 nm. The origin of this effect is not known.
(32) Harada, N.; Nakanishi, K. O. Circular Dichroic Spectroscopy:
Exciton Coupling in Organic Stereochemistry; University Science Books:
Mill Valley, CA, 1983.

Conformational Order in H-Bonded Dendrons
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10303
Figure 4. CD of G0, 8, and G1 dendron, 5a, as function of (a) solvent at 25 °C, (b) temp in CH3CN. [5a] ) 8.0‚10-6 M, [8] ) 1.9‚10-5 M.
Table 1. Electric Transition Moments of
2-Acetamido-N-methylbenzamide
Figure 5. Assignment of absolute helicity of terminal anthranilamides.
the intramolecular hydrogen-bonding interactions that partially
stabilize the helical conformation. Heating the sample in aceto-
nitrile to 60 °C completely destroys the exciton couplet and is
consistent with a thermal unfolding process occurring; however,
cooling to -20 °C dramatically increases amplitude of the
couplet at 316 nm and the CE at 260 nm. Interestingly, the shape
and amplitude of the transition between 200 and 240 nm at -20
°C changes relative to the CD observed at 35 and 60 °C, sug-
gesting that the chiral terminal groups are perturbing the
conformation of the internal regions of the dendron at this
temperature. However, due to the presence of overlapping transi-
tions in this region of the absorption spectrum, this effect cannot
be fully rationalized. In hexane/CH2Cl2 (2:1), the temperature
sensitivity is much less pronounced in accord with the increased
helical conformational bias in this solvent system. On the basis
of these observations, we can conclude that the increased
nonbonded repulsions present at the second generation contribute
significantly to the stabilization of the secondary structure that
develops across the periphery of the dendron. However, the
expression of maximal conformational order requires a concur-
rent solvophobic compression in conjuction with low temper-
atures to enhance intramolecular packing interactions.
At the third generation (7), the intensity of the couplet was
invariant with solvent and displayed an intensity similar to that
observed for 6a in hexane, indicating that the helical bias was
driven predominantly by the nonbonded repulsions and packing
interactions associated with the increased number of terminal
groups present at the third generation dendron (Figure 7).
transition
electric dipole moments
wavelength oscillator
typeb
(nm)
strength
x
y
z
1
2
3
4
5
6
7
8
9
πfπ*
σfπ*
σfπ*
πfπ*
σfπ*
πfπ*
πfπ*
σfπ*
πfπ*
302.2
272.3
263.2
246.1
238.1
232.8
211.6
211.2
208.0
201.0
0.1280
0.0003
0.0000
0.2171
0.0002
0.6880 -0.8944
0.0000
0.0533
0.0000
0.0000
0.0378
0.0000
0.0000
0.0000
0.0000
0.0000
0.0075
1.2192 -0.5217
0.0000 0.0000
0.1047 -0.5623 -0.6975
0.3312 -1.2985 -0.7882
0.0000
0.0413
0.1217
0.0000
0.0316 -0.5309
0.8546 0.2742
0.0000 -0.0106
0.0000
0.0000
10 πfπ*
a Calculated using TDDFT-B3LYP implemented in Gaussian 98.
b Assigned by inspection of the symmetry of the molecular orbitals
associated with the transition (see Supporting Information).
6a destroys the excitonic interaction resulting in a simple CE
centered at 316 similar to that observed at the first generation;
however, it has little effect on the CD spectrum in CH3CN or
hexane/CH2Cl2 (2:1). Presumably, this is due to disruption of

10304 J. Am. Chem. Soc., Vol. 122, No. 42, 2000
Recker et al.
Figure 6. CD of G2 dendron, 6a, as function of (a) solvent at 25 °C,
Figure 7. CD of G3 dendron, 7, as function of (a) solvent at 25 °C,
(b) temp in CH3CN, (c) temp in hexane/CH2Cl2 (2:1); [6a] ) 3.7‚10-6
(b) temp in CH3CN, (c) temp in hexane/CH2Cl2 (2:1); [7] ) 1.6‚10-6
M.
M.
and 7 as a function of concentration in CH2Cl2, CH3CN and
hexane/CH2Cl2 (2:1) (Figure 8).42 In the region between 230
and 400, only small changes were observed for 6a and 7 over
a 10-fold concentration range; however a few points are
noteworthy. In CH2Cl2 and CH3CN, the excitonic couplet
However, the temperature sensitivity of the couplet was higher
in CH3CN than in hexane/CH2Cl2 (2:1) as observed for 6a.
Whereas 6a was entirely unfolded in CH3CN at 60 °C, 7
maintained the excitonic couplet, albeit with decreased intensity
under these conditions. Further, the addition of 1% ethanol to
CH2Cl2 solution of 7 slightly reduced the intensity of the couplet
but did not change the shape of the couplet. These observations
indicate that conformational order is intrinsically more stable
at the third generation than at either the first or second
generations.
(41) For examples in which CD is enhanced by aggregation, see: (a)
Palmans, A. R. A.; Vekemans, J. A. J. M.; Havinga, E. E.; Meijer, E. W.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2648. (b) Nuckolls, C.; Katz, T. J.;
Verbiest, T.; Van Elshocht, S.; Kuball, H. G.; Kiesewalter, S.; Lovinger,
A. J.; Persoons, A. J. Am. Chem. Soc. 1998, 120, 8656. (c) Nuckolls, C.;
Katz, T. J.; Castellanos, L. J. Am. Chem. Soc. 1996, 118, 3767. (d) Huang,
D. W.; Matile, S.; Berova, N.; Nakanishi, K. Heterocycles 1996, 42, 723.
(e) Joda´l, I.; Kova´cs, Ott, J.; Snatzke, G. Chem. Ber. 1989, 122, 1207.
(42) The poor solubility of 7 in hexane/CH2Cl2 (21) did not permit a
sufficient concentration range to be accessible; therefore, concentration-
dependent CD spectra could not be recorded in this solvent.
Effect of Aggregation. The tendency of the second and third
generation dendrons to aggregate suggest that aggregation may
play a role in the conformational equilibria and CD spectra of
these dendrons.41 Therefore, the spectra were recorded for 6a

Conformational Order in H-Bonded Dendrons
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10305
Figure 8. CD of G2-C1 (6a) G3-C1 (7) as function of concentration at 25 °C.
centered at 316 nm increased slightly with increasing concentra-
tion; however, in hexane/CH2Cl2 (2:1) for G2-Cl, and for G3-
Cl in all solvents, the intensity of the couplet remained relatively
constant. The small increase in intensity of couplet for G2-Cl
may be associated with intermolecular packing interactions that
increase with greater aggregation. Intermolecular aggregation/
packing has been observed to enhance the stability of secondary
structure in proteins29 and may be operative to a small extent
in the dendrons under conditions in which the secondary
structure is less stable as for G2-Cl in CH2Cl2 and CH3CN. In
contrast, the CE at 260 nm increases with decreasing concentra-
tion for G2-Cl and the region below 230 nm (only observable
in CH3CN) varies significantly with concentration. Since several
transitions contribute to the CD spectra at 260 nm and below
235 nm, it is not possible to determine the origin of this
concentration dependence. However, we can conclude that the
effect of aggregation on the excitonic interaction at 316 nm is
small and that this couplet arises from intramolecular excitonic
coupling and not from intermolecular excitonic interactions due
to aggregation.
Conclusions
Intramolecular hydrogen bonding and electrostatic interactions
in the pyridine-2,6-dicarboxamide subunit dominate the folding
ability of these monodendrons; however, self-organization does
not occur in the absence of nonbonded packing interactions that
develop at the second and third generations. We hypothesize
that these nonbonded interactions couple the motions and
conformational preferences of each pair of terminal groups
through their correlated rotations. The increased intramolecular
packing of the terminal groups that occurs at higher generations
of these intramolecularly hydrogen-bonded dendrons likely
contributes significantly to the stabilization of the helical
conformation at the periphery. Consequently, the helical con-
formational preference increases with increasing dendrimer
generation and in poor solvents that enhance these nonbonded

10306 J. Am. Chem. Soc., Vol. 122, No. 42, 2000
Recker et al.
3H), 2.50 (s, 3H), 4.03 (dd, J ) 5.0, 11.5 Hz, 1H), 4.19 (dd, J ) 4.5,
11.5 Hz, 1H), 4.84 (m, 1H), 5.60 (bs, 2H), 6.06 (d, J ) 7.5 Hz, 1H),
6.42 (d, J ) 9.0 Hz, 1H), 6.73 (t, J ) 7.0 Hz, 1H), 6.74 (d, J ) 7.5
Hz, 1H), 7.28 (d, J ) 8.5 Hz, 2H), 7.30-7.32 (m, 2H), 7.35 (d, J )
8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) 15.9, 21.2, 21.5, 52.6, 63.7,
74.4, 115.8, 117.1, 117.8, 127.0, 127.5, 127.9, 133.1, 133.6, 140.0,
149.3, 169.4, 171.0, 171.1 ppm; HRMS for C21H24N2O5S (EI) (M+):
Calcd 416.1406; obsd 416.1406. Anal. Calcd for C21H24N2O5S: C,
60.56; H, 5.81; N, 6.73. Found: C, 60.53; H, 5.81; N, 6.68.
interactions. Equilibration of diastereomeric helical conforma-
tions is rapid at the first generation in all solvents and at all
temperatures investigated; however, at the second generation
the equilibrium begins to bias a single diastereomeric helical
conformation along the periphery that becomes maximal at low
temperature and in poor solvents. At the third generation, the
helical bias is intrinsically higher so that the conformational
preference of the termini becomes much less sensitive to solvent
and temperature, and the unfolding process becomes more
difficult. Since the maximal intensity of the couplet and other
CEs at low temperatures is similar in the second and third
generation monodendrons, the source of conformational order
can be attributed primarily to a shift in the conformational
equilibria interconverting two helical orientations of a pair of
anthranilamides.
4-Chloro-pyridine-2,6-dicarbonyl Chloride (1).24 Chelidamic acid
monohydrate (1.81 g, 9 mmol) was treated with phosphorus pentachlo-
ride (5.62 g, 27 mmol) in toluene (20 mL) and then heated at reflux
for 24 h. The toluene was removed by distillation at reduced pressure,
and 1 was obtained by sublimation at 110 °C at 0.1 mmHg as a white
1
solid (1.37 g, 63%). H NMR (250 MHz, CDCl3) δ 8.31 (s, 2Η).
4-Chloro-2,6-bis[(2-(1S,2S)-1-(4-methylthiophenyl)-1,3-propanediyl-
bisacetate) Carbamoylphenyl)carbamoyl]pyridine (5a). [G0]-NH2
(4) (10.47 g, 25.14 mmol) and DMAP (0.154 g, 1.26 mmol) was
dissolved in a mixture of CH2Cl2 (80 mL) and pyridine (20 mL).
4-chloro-pyridine-2,6-dicarbonyl chloride (1) (3.00 g, 12.58 mmol) in
13 mL CH2Cl2 was then added dropwise via syringe to this mixture
over 60 min. After stirring at room temperature for 16 h, the mixture
was taken up in CH2Cl2 (300 mL). The CH2Cl2 solution was washed
with 10% aqueous sulfuric acid (300 mL) and saturated sodium
bicarbonate solution (100 mL) and then dried over MgSO4 and
concentrated in vacuo. Purification by flash chromatography (SiO2) with
8:1 dichloromethane/ethyl acetate afforded [G1]-Cl (5a) (8.37 g 8.38
mmol, 67%) as a light yellow solid: mp 115 °C, dec (CH2Cl2/EtOAc).
1H NMR (400 MHz, CDCl3) δ 1.91 (s, 6H), 1.95 (s, 6H), 2.33 (s, 6H),
3.63 (dd, J ) 4.0, 11.6 Hz, 2H), 3.93 (dd, J ) 5.0, 7.4 Hz, 2H), 4.44
(m, 2H), 5.81 (d, J ) 6.8 Hz, 2H), 6.67 (d, J ) 9.2 Hz, 2H), 7.03 (d,
J ) 8.5 Hz, 4H) 7.04 (d, J ) 8.5 Hz, 4H), 7.14 (t, J ) 6.6 Hz, 2H),
7.44 (d, J ) 7.6 Hz, 2H), 7.45 (t, J ) 6.6 Hz, 2H), 8.25 (d, J ) 7.6
Hz, 2H), 8.30 (s, 2H), 12.00 (s, 2H); 13C NMR (100 MHz, CDCl3)
15.8, 21.1, 21.4, 52.8, 63.2, 74.2, 123.8, 125.3,125.8, 126.7, 127.7,
128.1, 132.7, 133.3, 137.3, 139.9, 148.6, 150.4, 161.5, 168.6, 170.8,
170.9 ppm; MS for C49H46ClN5O12S2 (FAB) (M+): Calcd 998.5; obsd
998.1. Anal. Calcd for C49H48ClN5O12S2: C, 58.94; H, 4.85; N, 7.01.
Found: C, 58.92; H, 4.81; N, 6.94.
4-Amino-2,6-bis((2-(1S,2S)-1-(4-methylthiophenyl)-1,3-propanediyl-
bisacetate) Carbamoylphenyl)carbamoyl)pyridine (5c). [G1]-Cl (5a)
(2.67 g, 2.67 mmol) and sodium azide (1.74 g, 26.7 mmol) were
dissolved in 20 mL of DMF, and the solution was stirred at 45 °C for
48 h. The solvent was removed in vacuo, and the crude was taken up
in CH2Cl2 (40 mL), washed with water (2 × 30 mL), dried over MgSO4,
and concentrated in vacuo. The crude azide (2.49 g, 2.49 mmol) was
dissolved in 50 mL of THF-methanol (1:1), and the solution was
degassed by sparging with argon for 10 min. Pd-C (10%, 0.249 g)
was added, and the mixture was hydrogenated at 1 atm H2 pressure for
48 h at room temperature. The catalyst was then removed by filtration
through a pad of Celite with THF. The solvent was removed in vacuo,
and the resultant solid was passed through a short plug of silica gel
using THF affording [G1]-NH2 (5c) as a white waxy solid (2.35 g,
2.40 mmol, 89%): mp 125 °C, dec (THF).1H NMR (400 MHz, CDCl3)
δ 1.84 (s, 6H), 1.94 (s, 6H), 2.36 (s, 6H), 3.60 (dd, J ) 4.5, 11.0 Hz,
1H), 3.96 (dd, J ) 4.8, 11.0 Hz, 2H), 4.52 (m, 2H), 5.81 (d, J ) 7.0
Hz, 2H), 6.68 (d, J ) 9.0 Hz, 2H), 7.01 (d, J ) 8.3 Hz, 4H) 7.05 (d,
J ) 8.3 Hz, 4H), 7.12 (t, J ) 7.6 Hz, 2H), 7.40 (t, J ) 7.6 Hz, 2H),
7.47 (d, J ) 6.4 Hz, 2H), 7.48 (s, 2H), 8.18 (d, J ) 8.2 Hz, 2H), 12.03
(s, 2H); 13C NMR (100 MHz, CDCl3) 14.8, 20.6, 20.9, 51.7, 62.67,
74.0, 108.9, 122.8, 124.5, 126.0, 126.5, 127.7, 129.2, 131.9, 134.1,
136.9, 138.6, 149.1, 158.0, 162.5, 168.3, 169.8, 170.4 ppm; MS for
C49H50N6O12S2 (FAB) (M+): Calcd 979.1; obsd 979.4. Anal. Calcd
for C49H50N6O12S2: C, 60.11; H, 5.15; N, 8.58. Found: C, 59.90; H,
5.13; N, 8.61.
Experimental Section
General. Melting points were determined in open capillaries and
1
are uncorrected. H NMR spectra were recorded at 250, 400, or 500
MHz and 13C NMR spectra at 100 or 125 MHz. EI or FAB mass spectra
were recorded at The Ohio State University Chemical Instrument
Center. MALDI-TOF spectrometry was performed using 2,5-dihy-
droxybenzoic acid as the matrix in tetrahydrofuran (THF). Circular
dichroism (CD) measurements were carried out on an Aviv 202 CD
spectrometer, using optical grade solvents and quartz glass cuvettes
with a 10 mm path length. Optical rotations were performed on a Perkin-
Elmer 241 MC polarimeter at a concentration of 10 mg/mL (c ) 1).
All reactions were performed under an argon or nitrogen atmosphere.
Dimethylformamide (DMF) was dried by distillation from barium oxide
or magnesium sulfate, THF was distilled from sodium/benzophenone
ketyl, and dichloromethane was distilled from calcium hydride.
Chromatographic separations were performed on silica gel 60 (230-
400 mesh, 60 Å) using the indicated solvents.
(1S,2S)-2-(2-Nitrobenzamido)-1-(4-methylthiophenyl)-1,3-pro-
panediylbisacetate (3). To a stirred solution of (1S,2S)-(+)-thio-
micamine, 2, (10.24 g, 48.0 mmol) and 4-(dimethylamino)pyridine
(DMAP) (1.17 g, 9.6 mmol) in 400 mL of pyridine, 2-nitrobenzoyl
chloride (9.05 g, 48.8 mmol) was added dropwise via syringe over 3
h at 0 °C. After the addition was complete, acetic anhydride (19.6 g,
192 mmol) was added, and the solution was then stirred at 60 °C for
3 h. Pyridine was removed by distillation under reduced pressure and
the resultant residue was dispersed in CH2Cl2 (400 mL). The CH2Cl2
solution was washed with 10% aqueous sulfuric acid (200 mL) and
saturated aqueous sodium bicarbonate (100 mL) and then dried over
MgSO4 and concentrated in vacuo. Purification by flash chromatography
(SiO2) using a gradient going from 20:1 to 8:1 dichloromethane/ethyl
acetate afforded [G0]-NO2 (3) (10.61 g, 0.024 mmol, 50%) as a light
yellow solid: mp 116-117 °C (CH2Cl2/EtOAc). 1H NMR (400 MHz,
CDCl3) δ 2.02 (s, 3H), 2.07 (s, 3H), 2.42 (s, 3H), 3.88 (dd, J ) 5.2,
11.7 Hz, 1H), 4.17 (dd, J ) 4.1, 11.7 Hz, 1H), 4.76 (m, 1H), 5.90 (d,
J ) 7.9 Hz, 1H), 6.17 (d, J ) 9 Hz, 1H), 7.19 (d, J ) 8.0 Hz, 2H),
7.25 (d, J ) 8.0 Hz, 2H), 7.29 (d, J ) 6 Hz, 1H), 7.51 (t, 1H), 7.60 (t,
1H), 7.98 (d, J ) 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) 15.9,
21.1, 21.5, 53.4, 63.4, 74.3, 125.0, 127.0, 127.9, 128.9, 131.1, 132.9,
133.3, 134.2, 140.3, 146.9, 166.7, 171.1, 171.2 ppm; HRMS for
C21H22N2O7S (EI) (M+): Calcd 446.1148; obsd 446.1144. Anal. Calcd
for C21H22N2O7S: C, 56.49; H, 4.97; N, 6.27. Found: C, 56.25; H,
4.99; N, 6.16.
(1S,2S)-2-(2-Aminobenzamido)-1-(4-methylthiophenyl)-1,3-pro-
panediylbisacetate (4). [G0]-NO2 (3) (15.92 g, 36 mmol) was dissolved
in 100 mL of ethyl acetate-methanol (1:1), and the solution was
degassed by sparging with argon for 10 min. 10% Pd-C (1.59 g) was
then added, and the mixture was hydrogenated at 1 atm H2 pressure
for 48 h at room temperature. The catalyst was then removed by
filtration through a pad of Celite with ethyl acetate (400 mL). The ethyl
acetate was removed in vacuo, and the resultant solid was passed
through a short plug of silica gel using ethyl acetate affording [G0]-
NH2 (4) as a white waxy solid (14.34 g, 34 mmol, 97%): mp 146-
148 °C (EtOAc). 1H NMR (400 MHz, CDCl3) δ 2.11 (s, 3H), 2.12 (s,
[G2]-Cl (6a). [G1]-NH2 (5c) (200 mg, 0.204 mmol), DMAP (5 mg,
0.041 mmol), and triethylamine (0.030 mL, 0.216 mmol) were dissolved
in CH2Cl2 (0.5 mL). 4-Chloro-pyridine-2,6-dicarbonyl chloride (1) (24
mg, 0.102 mmol) in 0.25 mL CH2Cl2 was then added dropwise via
syringe to this mixture over 20 min. After stirring at room temperature
for 16 h, the mixture was taken up in CH2Cl2 (2 mL). The CH2Cl2

Conformational Order in H-Bonded Dendrons
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10307
solution was washed with 10% aqueous sulfuric acid (1 mL) and
saturated aqueous sodium bicarbonate (1 mL) and then dried over
MgSO4 and concentrated in vacuo. Purification by flash chromatography
(SiO2) with 50:1 dichloromethane/methanol afforded [G2]-Cl (6a) (145
mg, 0.068 mmol, 67%) as a light yellow solid: mp 165 °C, dec (CH2-
Cl2/MeOH). 1H NMR (400 MHz, DMSO-d6) δ 1.85 (s, 12H), 1.93 (s,
12H), 2.40 (s, 12H), 3.62 (dd, J ) 4.5, 11.0 Hz, 4H), 3.98 (dd, J )
4.5, 11.0 Hz, 4H), 4.48 (m, 4H), 5.67 (d, J ) 8.0 Hz, 4H), 7.04 (d, J
) 8.0 Hz, 8H), 7.11 (d, J ) 8.0 Hz, 8H), 7.35 (t, J ) 7.5, 4H), 7.62
(t, J ) 7.6, 4H), 7.71 (d, J ) 8.0 Hz, 4H), 8.29 (d, J ) 8.0 Hz, 4H),
8.53 (s, 2H), 8.67 (d, J ) 8.5 Hz, 4H), 9.03 (s, 4H), 11.77 (s, 2H),
12.17 (s, 4H); 13C NMR (100 MHz, DMSO-d6) 14.8, 20.6, 21.0, 51.8,
62.6, 74.0, 115.2, 124.8, 125.9, 126.2, 127.7, 129.2, 132.1, 134.1, 136.8,
138.6, 149.1, 150.0, 161.6, 162.4, 168.1, 169.8, 170.3 ppm; MS for
C105H100ClN13O26S4 (FAB) (M+): Calcd 2123.7; obsd 2123.8. Anal.
Calcd for C105H100ClN13O26S4: C, 59.38; H, 4.75; N, 8.57. Found: C,
59.29; H, 4.87; N, 8.41.
[G2]-N3 (6b). [G2]-Cl (6a) (717 mg, 0.338 mmol) and sodium azide
(220 mg, 3.376 mmol) were dissolved in 3 mL of DMF, and the solution
was stirred at 45 °C for 3 d. The solvent was removed in vacuo, and
the crude was taken up in CH2Cl2 (10 mL), washed with water (2 × 5
mL), and then dried over MgSO4 and concentrated in vacuo. Purification
by flash chromatography (SiO2) with 50:1 dichloromethane/methanol
afforded [G2]-N3 (0.419 g, 0.197 mmol, 58%) as a light yellow solid.
1H NMR (500 MHz, DMSO-d6) δ 1.85 (s, 12H), 1.93 (s, 12H), 2.40
(s, 12H), 3.62 (dd, J ) 4.5, 11.0 Hz, 4H), 3.99 (dd, J ) 4.5, 11.0 Hz,
4H), 4.49 (m, 4H), 5.68 (d, J ) 8.0 Hz, 4H), 7.04 (d, J ) 8.0 Hz, 8H),
7.11 (d, J ) 8.0 Hz, 8H), 7.25 (t, J ) 8.0, 4H), 7.61 (t, J ) 8.0, 4H),
7.72(d, J ) 8.0 Hz, 2H), 8.08 (s, 2H), 8.30 (d, J ) 8.0 Hz, 4H), 8.66
(d, J ) 8.5 Hz, 4H), 9.03 (s, 4H), 11.74 (s, 2H), 12.17 (s, 4H); 13C
NMR (125 MHz, DMSO-d6) 14.8, 20.7, 21.0, 51.8, 62.6, 74.0, 115.2,
123.1, 124.8, 125.9, 126.2, 127.7, 129.3, 132.1, 134.1, 136.9, 138.6,
149.1, 150.0, 152.9, 161.7, 162.7, 162.8, 168.2, 169.8, 170.3 ppm; MS
for C105H100N16O26S4 (MALDI-TOF) (MH): Calcd 2128.3; obsd 2125.1.
[G2]-NH2(6c). [G2]-N3 (6b) (130 mg, 0.061 mmol) was dissolved
in 5 mL of THF/methanol (1:1), and the solution was degassed by
sparging with argon for 10 min. Pd-C (10%, 13 mg) was added, and
the mixture was hydrogenated at 1 atm H2 pressure for 48 h at room
temperature. The catalyst was then removed by filtration through a pad
of Celite with THF. The solvent was removed in vacuo and the residue
purified by flash chromatography (SiO2) going from 2 to 3% dichlo-
romethane/methanol affording [G1]-NH2 (6c) as a white waxy solid
(92 mg, 0.044 mmol, 72%): mp 150 °C, dec (CH2Cl2/MeOH). 1H NMR
(400 MHz, CDCl3) δ 1.87 (s, 12H), 1.95 (s, 12H), 2.43 (s, 12H), 3.65
(dd, J ) 4.5, 11.0 Hz, 4H), 4.00 (dd, J ) 4.5, 11.0 Hz, 4H), 4.50 (m,
4H), 5.70 (d, J ) 7.0 Hz, 4H), 7.06 (d, J ) 7.6 Hz, 8H), 7.14 (d, J )
8.0 Hz, 8H), 7.37 (t, J ) 7.6, 4H), 7.63 (t, J ) 7.6, 4H), 7.66 (s, 2H),
7.73 (d, J ) 7.8 Hz, 4H), 8.31 (d, J ) 8.0 Hz, 4H), 8.79 (d, J ) 8.6
Hz, 4H), 9.05 (s, 4H), 11.62 (s, 2H), 12.18 (s, 4H); 13C NMR (125
MHz, CDCl3) 15.3, 21.2, 23.2, 52.3, 63.1, 74.5, 110.7, 115.7, 123.6,
124.8, 125.3, 126.4, 128.2, 129.8, 132.6, 134.6, 137.3, 139.1, 149.4,
149.9, 150.4, 157.7, 162.3, 164.7, 168.7, 170.8.3, 170.8 ppm; MS for
molecular sieves (4 Å) (20 mg) were added, and the solution was stirred
for 10 min. 4-Chloro-pyridine-2,6-dicarbonyl chloride (1) (6 mg, 0.025
mmol) in 0.1 mL CH2Cl2 was then added dropwise via syringe to this
mixture over 5 min. After stirring at room temperature for 16 h, the
mixture was taken up in CH2Cl2 (2 mL). The CH2Cl2 solution was
washed with 10% aqueous sulfuric acid (1 mL) and saturated aqueous
sodium bicarbonate (1 mL) and then dried over MgSO4 and concen-
trated in vacuo. Purification by flash chromatography (SiO2) with 50:1
dichloromethane/methanol afforded [G3]-Cl (7) (60 mg, 0.0137 mmol,
1
54%) as a light yellow solid: mp 195 °C, dec (CH2Cl2/MeOH). H
NMR (400 MHz, CDCl3) δ 1.84 (s, 24H), 1.93 (s, 24H), 2.39 (s, 24H),
3.68(m, 8H), 3.99 (m, 8H), 7.49 (m, 8H), 5.69 (d, J ) 6.7 Hz, 8H),
7.04 (d, J ) 8.0 Hz, 16H), 7.12 (d, J ) 8.0 Hz, 16H), 7.58 (t, J ) 7.2
Hz, 8H), 7.70 (d, J ) 7.2 Hz, 8H), 8.29 (d, J ) 8.0 Hz, 8H), 8.52 (d,
J ) 8.0 Hz, 8H), 8.57 (s, 2H), 9.08 (s, 8H), 9.16 (s, 4H) 11.78 (m,
6H), 12.15 (s, 8H); 13C NMR (100 MHz, CDCl3) 16.6, 22.2, 22.5, 53.6,
64.3, 75.7, 117.0, 118.8, 124.8, 126.3, 127.8, 128.0, 129.3, 130.8, 133.6,
135.9, 138.6, 140.2, 150.9, 151.5, 151.7, 163.5, 165.0, 169.8, 171.3,
171.8 ppm; MS for C217H204ClN29O54S8 (MALDI) (M + Na): Calcd
4397.1; obsd 4395.3. Anal. Calcd for C217H204ClN29O54S8: C, 59.59;
H, 4.70; N, 9.29. Found: C, 59.61; H, 4.82; N, 9.03.
[G0]-Control (8). [G0]-NH2 (4) (300 mg, 0.72 mmol), picolinic acid
(133 mg, 1.08 mmol), DMAP (9 mg, 0.07 mmol), and 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (207 mg, 1.08
mmol) were dissolved in 4 mL of DMF. After the mixture stirred at
50 °C for 12 h, the DMF was removed in vacuo, and the crude mixture
was taken up in CH2Cl2 (10 mL), washed with water (2 × 10 mL),
dried over MgSO4, and concentrated in vacuo. Purification by flash
chromatography (SiO2) with 5:1 dichloromethane/ethyl acetate afforded
[G0]-control (8) (235 mg, 0.45 mmol, 63%) as a white waxy solid:
mp 193-194 °C (CH2Cl2/EtOAc). 1H NMR (400 MHz, CDCl3) δ 1.97
(s, 3H), 1.98 (s, 3H), 2.36 (s, 3H), 3.92 (dd, J ) 5.0, 11.5 Hz, 1H),
4.12 (dd, J ) 4.5, 11.5 Hz, 1H), 4.85 (m, 1H), 5.98 (d, J ) 7.5 Hz,
1H), 6.44 (d, J ) 9.0 Hz, 1H), 7.10 (t, J ) 7.5 Hz, 1H), 7.14 (d, J )
8.4 Hz, 2H), 7.18 (obscured t, 1H), 7.23 (d, J ) 8.4 Hz, 2H), 7.39 (d,
7.3 Hz, 2H), 7.49 (t, J ) 8.0 Hz, 1H), 7.81 (t, J ) 7.8 Hz, 1H), 8.21
(d, J ) 7.0 Hz, 1H), 8.68 (bs, 1H), 8.76 (d, J ) 8.3 Hz, 1H), 12.5 (s,
2H); 13C NMR (100 MHz, CDCl3) 15.8, 21.0, 21.4, 52.9, 63.6, 74.3,
122.2, 122.3, 123.0, 126.7, 126.9, 127.0, 127.8, 133.1, 133.2, 137.7,
139.2, 140.2, 149.0, 168.6, 170.9, 171.0 ppm; HRMS for C27H27N3O6S
(EI) (M+): Calcd 521.1621; obsd 521.1628. Anal. Calcd for
C27H27N3O6S: C, 62.17; H, 5.22; N, 8.06. Found: C, 62.41; H, 5.17;
N, 8.04.
Acknowledgment. The authors thank Chris Hadad for help
with the TDDFT-B3LYP calculations. Support for J.R during
the course of this work from the Fullbright Commission and
the University of Bonn is gratefully acknowledged. This work
was supported by the National Science Foundation CAREER
program (CHE 98-75458).
Supporting Information Available: Gaussian output for the
TDDFT-B3LYP calculations and molecular orbital plots for the
transitions described in Table 1 (PDF).This material is available
free of charge via the Internet at http://pubs.acs.org.
C105H102N14O26S4 (FAB) (MH): Calcd 2103; obsd 2103. Anal. Calcd
for C105H102N14O26S4: C, 59.93; H, 4.89; N, 9.32. Found: C, 59.74;
H, 5.01; N, 9.10.
[G3]-Cl (7). [G2]-NH2 (7) (106 mg, 0.050 mmol) was dissolved in
a mixture of CH2Cl2 (0.5 mL) and pyridine (0.050 mL). Dry powdered
JA001225C