A new class of intramolecularly hydrogen-bonded dendrons based on a 2-methoxyisophthalamide repeat unit

Article abstract of DOI:10.1021/jo061351k

(Chemical Equation Presented). The synthesis and conformational properties of folded dendrons based on a 2-methoxyisophthalamide (2-OMe-IPA) repeat unit are described. The hydrodynamic properties of dendrons preorganized via the syn-syn conformational pre

Full text of DOI:10.1021/jo061351k

A New Class of Intramolecularly Hydrogen-Bonded Dendrons Based
on a 2-Methoxyisophthalamide Repeat Unit
Christopher J. Gabriel, Matthew P. DeMatteo, Noel M. Paul, Tomohisa Takaya,
Terry L. Gustafson, Christopher M. Hadad,* and Jon R. Parquette*
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue, Columbus, Ohio 43210
hadad.1@osu.edu; parquett@chemistry.ohio-state.edu
ReceiVed June 29, 2006
The synthesis and conformational properties of folded dendrons based on a 2-methoxyisophthalamide
(2-OMe-IPA) repeat unit are described. The hydrodynamic properties of dendrons preorganized via the
syn-syn conformational preference of 2-methoxyisophthalamide are compared with 2,6-pyridinedicar-
boxamide (2,6-pydic) analogues. The effect of subtle differences in the nature of the conformational
equilibria that exist within the 2-OMe-IPA and 2,6-pydic repeat units on the global structural properties
of the corresponding dendrons was explored computationally, by 1H-DOSY NMR spectroscopy and
time-resolved fluorescence anisotropy (TRFA) measurements. Whereas the syn-syn preference of the
2-OMe-IPA branched repeat unit is stabilized entirely by intramolecular hydrogen-bonding interactions,
this preference in the 2,6-pydic system is a consequence of both intramolecular hydrogen-bonding and
dipole minimization effects. However, nonspecific solvophobic compression is more important in
determining hydrodynamic properties than solvent-dependent shifts in the conformational equilibria of
the repeat unit for both dendron series.
Introduction
conformational equilibria to the global structure of a dendrimeric
macromolecule is a crucial factor in the design of well-defined,
three-dimensionally organized structures. Previous theoretical2
and experimental3 studies demonstrated that variations in
macromolecular architecture have an impact on the physical and
chemical properties of dendrimers in solution. For example,
studies comparing dendrimers with their linear isomers revealed
significant differences in hydrodynamic properties.4 However,
there are few studies directly evaluating the effect of localized
shifts in the conformational equilibria of a structural subunit
on the consequent global properties in solution. A recent study
The allosteric conformational interconversions responsible for
the modulation of function in proteins are highly dynamic
processes involving multiple, correlated conformational equi-
libria that transmit local conformational perturbations to the
global structure. Many of the applications and unique properties
envisaged for dendrimers rely on an ability to control the three-
dimensional organization of their structures over long length
scales.1 Accordingly, the nature of the conformational interplay
that communicates localized variations in the structure or
(1) (a) Boas, U.; Heegaard, P. M. H. Chem. Soc. ReV. 2004, 33, 43. (b)
Frechet, J. M. J. J. Polym. Sci., Part A: Polym. Chem. 2003, 41, 3713. (c)
Balzani, V.; Ceroni, P.; Maestri, M.; Vicinelli, V. Curr. Opin. Chem. Biol.
2003, 7, 657. (d) Yokoyama, S.; Otomo, A.; Nakahama, T.; Okuno, Y.;
Mashiko, S. Top. Curr. Chem. 2003, 228, 205. (e) Patri, A. K.; Majoros, I.
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10.1021/jo061351k CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/25/2006
J. Org. Chem. 2006, 71, 9035-9044
9035

Gabriel et al.
probing the effect of the local trans f cis photoisomerization
of azobenzene dendron/core linkages on the corresponding
hydrodynamic volumes observed comparatively small volume
changes in dendrimers,5 presumably due to the high segmental
mobility that exists within dendrimers constructed with flexible
bond connections.3c,6
We have recently developed a dendrimeric system that adopts
a compact, helical conformation due to the syn-syn conforma-
tional preference of the pyridine-2,6-dicarboxamide (2,6-pydic)
repeat unit.7 The preorganized structure of the 2,6-pydic repeat
unit appears to play a critical role in mediating the transfer of
local perturbations to the dendrimer structure. For example, a
2,6-pydic dendrimer system exhibited large variations in
hydrodynamic volumes upon relatively minor modifications of
the dendron/core linkage.8a Although it is possible to envisage
several potential, preorganized repeat units displaying a quali-
tatively similar conformational preference to that of the 2,6-
pydic system, the ultimate effect of small variations in confor-
mational equilibria of a dendritic subunit on the global properties
of a dendrimer are not well understood. For example, 2-meth-
oxyisophthalamide (2-OMe-IPA) represents a potential repeat
unit that exhibits a syn-syn conformational preference analogous
to the 2,6-pydic system and, therefore, might also serve as a
preorganizing subunit for dendrimeric structures. However, the
2-OMe-IPA and 2,6-pydic systems differ in both the nature and
the source of this conformational preference. Therefore, the goal
of this work focuses on understanding how apparently minor
differences in the conformational equilibria exhibited by these
two potentially similar repeat units are manifested at the global
hydrodynamic level.
Results and Discussion
Conformational Preference of 2-Methoxy-N,N′-diphenyl-
isophthalamide. Preorganization of the 2-OMe-IPA and 2,6-
pydic dendrons capitalizes on the preference of these repeat units
to exist predominantly in the syn-syn conformation. The structure
of 2-methoxy-N,N′-diphenylisophthalamide, 1, was optimized
by density functional theory (DFT) at the B3LYP/6-31G* level
of theory,8 and six unique conformations were located. These
conformations corresponded to three anti-anti conformers
differing in the relative orientation of the amide functions, one
syn-syn conformer tilting the amide groups toward opposite
faces, and two syn-anti conformers (see the Supporting Informa-
tion). Single-point energy calculations were performed in the
gas phase and using the PCM solvation model9 with CHCl3 and
DMSO as the solvents at the B3LYP/6-311+G** level of
theory. The syn-syn conformation is preferred over the syn-anti
conformation by 2.3 kcal/mol in the gas phase (Table 1).
However, the preference for the syn-syn conformation decreases
significantly as the polarity of the solvent increases. The syn-
syn conformation of 2-OMe-IPA 1 is lowest in energy because
this conformation permits intramolecular hydrogen-bonding
interactions to occur between the amide NHs and the methoxy
oxygen.10 Accordingly, the solvent dependence of the syn-syn
conformational preference is likely due to a disruption of the
favorability of the intramolecular hydrogen-bonding interactions
which stabilize this conformation. 2-Methoxy-N,N′-diphenyl-
isophthalate, 2, was similarly optimized and resulted in six
unique conformations which were virtually identical to those
located for 1. The absence of intramolecular hydrogen-bonding
interactions affords a preference for the anti-anti configuration
by 0.6 kcal/mol over the syn-anti conformation and by 1.5
kcal/mol over the syn-syn conformation. As the polarity of the
solvent increases, the preference for the anti-anti conformation
increases to the exclusion of all other conformations.
(3) (a) Peerlings, H. W. I.; Trimbach, D. C.; Meijer, E. W. Chem.
Commun. 1998, 497. (b) Stancik, C. M.; Pople, J. A.; Trollss, M.; Lindner,
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J. A.; Viernes, N. O. L.; Moore, J. S.; Sendijarevic, I.; McHugh, A. J.
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Z.; Gorman, C. B. Tetrahedron 2003, 59, 3853.
The charge distribution in the molecules was then determined
by natural population analysis11 at the B3LYP/6-311+G** level
of theory to ascertain the presence of hydrogen-bonding
interactions (Figure 1). By examining the distribution of charge
in these molecules, it is possible to examine the hydrogen-
bonding or dipole-dipole interactions stabilizing any given
conformation (see the Supporting Information for charge
(4) (a) Stiriba, S.-E.; Kautz, H.; Frey, H. J. Am. Chem. Soc. 2002, 124,
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Chem. 2003, 3666.
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Liao, L.-X.; Junge, D. M.; McGrath, D. V. Macromolecules 2002, 35, 319.
(d) Liao, L.-X.; Stellacci, F.; McGrath, D. V. J. Am. Chem. Soc. 2004,
126, 2181. (e) Grebel-Koehler, D.; Liu, D.; De Feyter, S.; Enkelmann, V.;
Weil, T.; Engels, C.; Samyn, C.; Muellen, K.; De Schryver, F. C.
Macromolecules 2003, 36, 578. (f) Kumar, G. S.; Neckers, D. C. Chem.
ReV. 1989, 89, 1915.
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Macromolecules 2004, 37, 6236. (b) Adhiya, A.; Wesdemiotis, C. Int. J.
Mass Spectrom. 2002, 214, 75-88. (c) Cameron, C. S.; Gorman, C. B.
AdV. Funct. Mater. 2002, 12, 17-20.
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M. A. Gustafson, T. L.; Parquette, J. R. J. Am. Chem. Soc. 2003, 125, 14518.
(c) Huang, B.; Parquette, J. R. J. Am. Chem. Soc. 2001, 123, 2689. (d)
Recker, J.; Tomcik, D. J.; Parquette, J. R. J. Am. Chem. Soc. 2000, 122,
10298. (e) Huang, B.; Parquette, J. R. Org. Lett. 2000, 3, 239.
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Lee, C.; Yang, W.; Par, R. G. Phys. ReV. B 1988, 37, 785. (d) Hehre, W.
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Chen, X.-Z.; Li, Z.-T. J. Org. Chem. 2004, 69, 6221. (c) Gong, B.; Zeng,
H.; Zhu, J.; Yuan, L.; Han, Y.; Cheng, S.; Furukawa, M.; Parra, R. D.;
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Smith, R. D.; Zheng, C.; Szyperski, T.; Zeng, X. C. Proc. Natl. Acad. Sci.
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1988, 88, 899.
9036 J. Org. Chem., Vol. 71, No. 24, 2006

Conformational Properties of Folded Dendrons
TABLE 1. Relative Energies and Dipole Moments of 1 and 2 at
kcal/mol. Likewise, 3 demonstrates a 10 kcal/mol preference
for syn-syn over anti-anti, whereas 4 has only a 2 kcal/mol
preference. As the polarity of the solvent increases, the
preference for the syn-syn conformation in both cases decreases
significantly. The preference for the syn-syn over the anti-anti
conformation in 3 remains virtually unchanged by solvent.
However, the preference for syn-syn over syn-anti conformations
decreases significantly from 6.3 kcal/mol in the gas phase to
3.9 kcal/mol in DMSO. Compound 4 exhibits a similar trend,
but the preference for syn-syn over syn-anti remains virtually
unchanged, whereas the preference in DMSO shifts from syn-
syn to anti-anti. It is also worthy of note that in more polar
solvents, the preference for any one conformation becomes very
small (less than 1 kcal/mol) in compound 4 in contrast to 3.
Although the preference for the syn-syn conformation is less
favored in the 2-methoxyisophthalamide unit (2-OMe-IPA) in
comparison with the pyridine-2,6-dicarboxamide (2,6-pydic)
system, the relative energetics are qualitatively similar. However,
intramolecular hydrogen bonding appears to play a more
important role in determining the conformational preference of
2-methoxyisophthalamides, as compared with the pyridine-2,6-
dicarboxamides. Accordingly, in contrast to 1 and 2, the decrease
in relative energy of the conformers in 3 and 4 generally
correlates with a decrease in the corresponding calculated dipole
moments. Therefore, intramolecular hydrogen bonding plays a
more important role than dipole moment minimization in
determining the conformational preference of 2-methoxyisoph-
thalamides, as compared with the pyridine-2,6-dicarboxamides.
Accordingly, polar aprotic solvents that interfere with intramo-
lecular hydrogen-bonding interaction would be more likely to
shift the conformational preference of 2-OMe-IPA dendrons than
for the 2,6-pydic congeners.
Synthesis of 2-OMe-IPA and 2,6-Pydic Dendrons. 2-Meth-
oxy-5-nitroisophthaloyl dichloride,12 7, prepared from 2,6-
dimethylanisole as shown in Scheme 1, was selected to serve
as the branched repeat unit for the 2-OMe-IPA dendron
synthesis. Condensation of tetraethylene glycol monomethyl
ether with isatoic anhydride in dioxane at 75 °C provided the
terminal anthranilate building block (9) in 88% yield. Tetra-
ethylene glycol was incorporated at the termini because of the
known ability of poly(ethylene glycol) moieties to impart
solubility in a variety of solvents.13
The dendrons were constructed via a convergent synthetic
protocol, whereby generational growth was achieved using
amide bond formation reactions of diacid chloride 7 and focal
activation was achieved by SnCl2 reduction of the nitro group
(Scheme 2). Accordingly, amide bond formation between 7 and
9 provided O2N-[G1] 10 in 82% yield. SnCl2 reduction of 10
followed by reaction with 7 afforded O2N-[G2] 11, which was
elaborated to O2N-[G3] 12 following the same protocol.
Characterization with regard to molecular weight, structure, and
dispersity was accomplished by electrospray ionization or
MALDI-TOF MS, NMR, and SEC analysis (Supporting Infor-
mation), respectively.
the B3LYP/6-311+G**//B3LYP/6-31G* Level of Theorya,b
X ) NH (1)
1 syn-syn
1 syn-anti
1 anti-anti
∆Grel (298 K) (gas phase)
∆Erel (PCM, CHCl3)
∆Erel (PCM, DMSO)
µ (gas phase)
0.0
0.0
0.0
3.3
4.3
4.7
2.3
1.3
0.9
3.3
4.1
4.4
4.6
3.1
1.6
5.5
7.1
8.0
µ (CHCl3)
µ (DMSO)
X ) O (2)
2 syn-syn
2 syn-anti
2 anti-anti
∆Grel (298 K) (gas phase)
∆Erel (PCM, CHCl3)
∆Erel (PCM, DMSO)
µ (gas phase)
1.5
2.3
2.7
2.4
2.8
2.9
0.6
1.3
1.6
1.3
1.6
1.8
0.0
0.0
0.0
3.1
3.8
4.2
µ (CHCl3)
µ (DMSO)
a Energy given in kcal/mol. b Dipole moment (µ) in Debye.
distribution diagrams). Upon examining the atomic charges of
1, it is apparent that there are hydrogen-bonding interactions
between the amide hydrogens and the methoxy oxygen in the
syn-syn and syn-anti conformations. This would appear to
explain the preference for the syn-syn conformation in the
various solvents and the fact that the syn-anti conformation is
the next most favorable conformation. Structure 2, on the other
hand, does not have the capability for hydrogen bonding, and
as such, the charge distribution is similar for all conformations.
Analysis of the calculated dipole moments shows that the
preferred energy minimum does not strictly correlate with
changes in dipole moment. The syn-syn and syn-anti conforma-
tions of 1 appear to have very similar dipole moments, but this
trend does not correlate with the energetic preference for the
syn-syn conformation, contrasting with N,N′-diphenylpyridine-
2,6-dicarboxamide, 3 (vide infra). The diester 2 displays a
preference for the anti-anti conformation which has the largest
dipole moment. This preference in the gas phase is likely a
consequence of steric interactions between the methoxy function
and the ester groups encountered in the syn-syn conformation.
The increased energetic preference for the anti-anti conformation
as the polarity of the solvent increases can be attributed to the
higher dipole moment.
Conformational Preference of N,N′-Diphenylpyridine-2,6-
dicarboxamide. Optimization of N,N′-diphenylpyridine-2,6-
dicarboxamide, 3, at the B3LYP/6-31G* level of theory revealed
four unique conformations. These conformations corresponded
to two different anti-anti conformers with the carboxamide
groups tilted slightly toward the same face of the pyridine ring
and to opposite faces, one planar syn-syn conformer and one
syn-anti conformer. The ester variant 4 afforded five unique
conformations corresponding to two anti-anti conformers, two
syn-syn conformations, and one syn-anti orientation.
Solid-State Structure of 2-OMe-IPA G1 Dendron. A clear,
colorless crystal (monoclinic, space group P1) of chiral dendron
H2N-[G1] 13 was obtained by slow evaporation from a mixture
of CHCl3 and hexane. X-ray diffraction showed that the
asymmetric unit was composed of two molecules of opposite
In contrast to 1 and 2, which display preferences for the syn-
syn and anti-anti conformations, respectively, both 3 and 4 prefer
the syn-syn conformation in the gas phase (Table 2). However,
3 prefers the syn-syn orientation over syn-anti by 6.3 kcal/mol,
whereas 4, which lacks the potential for stabilizing hydrogen-
bonding interactions, prefers the syn-syn orientation by 1.0
(12) Chapoteau, E.; Chowdhary, M. S.; Czech, B. P.; Kumar, A.; Zazulak,
W. J. Org. Chem. 1992, 57, 2804.
(13) Stone, M. T.; Moore, J. S. Org. Lett. 2004, 6, 469.
J. Org. Chem, Vol. 71, No. 24, 2006 9037

Gabriel et al.
FIGURE 1. Natural population analysis of repeat units 1 and 3 at the B3LYP/6-311+G**//B3LYP/6-31G* level of theory. All charges are in units
of electrons.
SCHEME 1. Synthesis of Dendron Building Blocksa
TABLE 2. Relative Energies and Dipole Moments of 3 and 4 at
the B3LYP/6-311+G**//B3LYP/6-31G* Level of Theorya,b
X ) NH (3)
3 syn-syn
3 syn-anti
3 anti-anti
∆Grel (298 K) (gas phase)
∆Erel (PCM, CHCl3)
∆Erel (PCM, DMSO)
µ (gas phase)
0.0
0.0
0.0
1.2
1.6
1.8
6.3
4.8
3.9
5.0
6.2
6.8
10.1
12.6
10.1
6.8
8.6
9.5
µ (CHCl3)
µ (DMSO)
X ) O (4)
4 syn-syn
4 syn-anti
4 anti-anti
a Key: (a) KMnO4, H2O, 64%; (b) HNO3-H2SO4, H2O, O °C, 88%;
(c) (COCl)2, CH2Cl2, DMF (cat.), quant; (d) tetraethyleneglycol monomethyl
ether, DMAP, dioxane, 75 °C, 88%.
∆Grel (298 K) (gas phase)
∆Erel (PCM, CHCl3)
∆Erel (PCM, DMSO)
µ (gas phase)
µ (CHCl3)
µ (DMSO)
0.0
0.0
0.7
0.1
0.1
0.2
1.0
1.0
1.5
3.1
3.8
4.2
2.1
0.4
0.0
5.3
6.6
7.3
dendrons, occurred for all 2-OMe-IPA dendrons. The infrared
spectra in CDCl3 of 10-12 exhibited broad N-H stretching
bands at 3256-3367 cm-1 characteristic of hydrogen-bonded
N-H groups and similar to the 2,6-pydic systems.7e
a Energy given in kcal/mol. b Dipole moment (µ) in Debye.
The conformational preferences of the 2,6-pydic and 2-OMe-
1
helical sense that exhibited the predicted syn-syn conformation
relating the carboxamides (Figure 2). Three-center hydrogen-
bonding interactions of the carboxamide N-Hs with the
2-methoxy oxygen (dN-H‚‚‚O-Me 2.345 and 2.016 Å) and the
ester carbonyl oxygens (dN-H‚‚‚O) 2.099 and 2.104 Å) stabilize
the syn-syn conformation. The differences in the hydrogen-bond
distances are a consequence of the lack of 2-fold symmetry in
the approximately helical conformation relating the terminal
anthranilates, which is reflected in the deviation of one of the
two carboxamide carbonyls from coplanarity with the isoph-
thalamide ring by 39.30°.
IPA dendrons were investigated in CDCl3 by 2D NOESY H
NMR spectroscopy. 2-OMe-IPA dendrons 10 and 11 revealed
NOE cross-peaks between the amide NH protons and both the
methoxyl and aromatic protons. These close contacts are
consistent with the occurrence of both the syn-syn and syn-anti
forms in the conformational ensemble, as predicted computa-
tionally (Figure 3). However, no cross-peaks indicating close
contacts between the amide NHs and the pyridyl ring protons
were observed for 2,6-pydic dendrons 14 or 15, consistent with
a greater syn-syn conformational preference.
Comparison of Hydrodynamic Properties. The DFT studies
suggest that the syn-syn conformation is stabilized primarily via
hydrogen-bonding interactions in the 2-OMe-IPA system,
whereas both dipole minimization and hydrogen bonding play
a role in the 2,6-pydic system (vide supra). This difference
affords the 2,6-pydic system a capacity to remain in a compact
Solution-State Structure. 1H NMR and IR spectral data were
in good agreement with the presence of intramolecular hydrogen
bonding throughout the dendron structure in solution for both
systems (Table 3). Large downfield shifts of the amide N-Hs,
similar to those observed for the pyridine-2,6-dicarboxamide
9038 J. Org. Chem., Vol. 71, No. 24, 2006

Conformational Properties of Folded Dendrons
SCHEME 2. Dendron Synthesisa
FIGURE 3. NOESY enhancements (500 MHz, CDCl3, 27 °C) of O2N-
[G1] (10) and O2N-[G2] (11).
2-OMe-IPA system might be expressed as an increase in
hydrodynamic volume in polar solvents.
Accordingly, the effect of solvent on the hydrodynamic
volumes of the 2-OMe-IPA dendrons (10-12) was compared
with analogous 2,6-pydic dendrons (14-16) displaying identical
tetraethyleneglycol terminal esters. Dendrons 14-16 were
constructed from anthranilate 7 and 4-chloropyridine-2,6-
dicarbonyl chloride following an analogous generational growth
protocol we previously reported for related pentaethyleneglycol
terminated 2,6-pydic systems.14 Comparison of the hydrody-
namic volume (Vhyd) of 2-OMe-IPA dendron 10, measured by
DOSY-NMR spectroscopy,15 relative to the calculated van der
Waals volume16 (Vvdw), indicated that the Vhyd of the dendron
was similarly compact in CDCl3 and CD3OD, but significantly
expanded in DMSO-d6 (Figure 4 and Supporting Information).
This structural expansion may have occurred, in part, due to
disruption of the intramolecular hydrogen-bonding interactions
by DMSO-d6. In contrast, the structure of 2,6-pydic dendron
14 was compact in all three solvents, slightly decreasing in Vhyd
going from CDCl3 f CD3OD f DMSO-d6. The differential
sensitivity of the Vhyd of 10 and 14 aligns with the DFT-predicted
local conformational behavior of the 2-OMe-IPA and 2,6-pydic
repeat units, respectively.
a Key: (a) DMAP (cat.) CH2Cl2-pyr; (b) SnCl2‚2H2O, EtOAc-MeOH,
reflux; (c) 3, DMAP (cat.) CH2Cl2-pyr.
Determination of the hydrodynamic properties of dendrons
11-12 and 15-16 by DOSY-NMR spectroscopy was compli-
cated by aggregation that occurred at the millimolar concentra-
tions required for the NMR measurement. The presence of
aggregated states in CD3OD, CDCl3, and DMSO-d6 at milli-
molar concentrations was evident in highly broadened 1H NMR
spectra and the particularly large Vhyd/Vvdw ratios measured by
DOSY-NMR (see the Supporting Information). Accordingly,
to circumvent aggregation, the molecular dimensions of den-
drons 11-12 and 15-16 were measured at submicromolar
concentrations by time-resolved fluorescence anisotropy (TRFA)
measurements17,18 using the time-correlated single-photon count-
ing method (TCSPC).19 The samples were then diluted in this
concentration range until the measured dimensions remained
constant to ensure the presence of a monomolecular species in
FIGURE 2. X-ray crystal structure of H2N-[G1] dendron (13)
indicating a syn-syn conformational preference in the solid state.
Hydrogens have been omitted on the left structure for clarity.
TABLE 3. 1H NMR Resonances of Amide N-Hs (ppm)a
CDCl3
NHb
DMSO-d6
dendron
NHa
NHc
9.78
NHa
NHb
NHc
O2N-[G1] (10)
O2N-[G2] (11)
O2N-[G3] (12)
Cl-[G1] (14)
Cl-[G2] (15)
Cl-[G3] (16)
11.95
11.82
11.83
12.65
11.49
11.53
11.53
12.44
12.45
12.43
9.69
9.78
11.01
10.84
10.97
11.45
(15) Young, J. K.; Baker, G. R.; Newkome, G. R.; Morris, K. F.; Johnson,
C. S. J. Macromolecules 1994, 27, 3464.
(16) Calculated using Edward’s increments: Edward, J. T. J. Chem. Educ.
1970, 47, 261.
(17) Fleming, G. R. Chemical Applications of Ultrafast Spectroscopy;
Oxford University Press: New York, 1986.
11.63
11.67
a Ha ) third shell (terminal); Hb ) second shell; Hc ) first shell (focal).
folded state in aqueous media.14 In contrast, the conformational
properties of 2-OMe-IPA could be expected to exhibit more
sensitivity to polar solvents such as MeOH or DMSO that
potentially disrupt hydrogen-bonding interactions. We reasoned
that the greater solvent sensitivity of syn-syn preference in the
(18) For examples of time-resolved fluorescence depolarization studies
on dendrimers, see: (a) De Backer, S.; Prinzie, Y.; Verheijen, W.; Smet,
M.; Desmedt, K.; Dehaen, W.; De Schryver, F. C. J. Phys. Chem A 1998,
102, 5451. (b) Hofkens, J.; Latterini, L.; De Belder, G.; Gensch, T.; Maus,
M.; Vosch, T.; Karni, Y.; Schweitzer, G.; De Schryver, F. C.; Hermann,
A.; Mullen, K. Chem Phys. Lett. 1999, 304, 1. Matos, M. S.; Hofkens, J.;
Verheijen, W.; De Schryver, F. C.; Hecht, S.; Pollak, K. W.; Frechet, J. M.
J.; Foreir, B.; Dehaen, W. Macromolecules 2000, 33, 2967.
(19) Buterbaugh, J. S.; Toscano, J. P.; Weaver, W. L.; Gord, J. R.; Hadad,
C. M.; Gustafson, T. L.; Platz, M. S. J. Am. Chem. Soc. 1997, 119, 3580.
(14) Hofacker, A. L.; Parquette, J. R. Angew. Chem., Int. Ed. 2005, 44,
1053.
J. Org. Chem, Vol. 71, No. 24, 2006 9039

Gabriel et al.
FIGURE 5. Calculated volume (cm3/mol) and percent contribution
of syn-syn (ss), syn-anti (sa), and anti-anti (aa) conformations as a
function of dielectric field in conformations with ∼12 kcal/mol of the
global minimum for 2-OMe-IPA repeat unit in 11.
Monte Carlo Conformational Analysis of 2-OMe-IPA and
2,6-Pydic Second-Generation Dendrons. To evaluate the
potential of localized conformational changes to perturb the
hydrodynamic volumes (Vhyd) of the 2-OMe-IPA and 2,6-pydic
systems relative to solvent quality, Monte Carlo conformational
analysis of model second-generation dendrons 11 and 15 was
performed using the AMBER* force field.23 These simulations
only estimate the dielectric effect of the solvent and do not
include any explicit solvent-solute interactions; therefore, they
provide some guidance on the relative magnitude of the effect
of intimate interactions between the dendron and the solvent
when compared to experiment. The NO2 group in 11 was
replaced by an H, and similarly, the Cl group in 15 was replaced
by an H. The Monte Carlo multiple minimum search protocol24
generated 100 000 starting conformers, which were subsequently
optimized with the AMBER* force field for the gas phase and
also in the presence of CHCl3 and DMSO dielectric fields.
Unique conformers within ∼12 kcal/mol of the global minimum
were further analyzed at the HF/6-31G* level of theory to
calculate their volumes using the Gaussian suite of programs.8
The Boltzmann contribution, calculated from the AMBER*
relative energies of each conformer, was then applied to the
calculated volumes, and these Boltzmann-weighted volumes
were summed to provide a conformationally averaged overall
volume of the structure. The molar volumes were then correlated
with geometrical trends of the corresponding shifts in the
equilibria interconverting the syn-syn, syn-anti, and anti-anti
conformations of the repeat unit that contribute to the confor-
mational ensemble.
FIGURE 4. Packing efficiency (Vhyd/Vvdw) as a function of generation
and solvent for 2,6-pydic and 2-OMe-IPA dendrons. Hydrodynamic
volumes measured by 1H-DOSY NMR (10-3 M) for 10 and 14 and by
TRFA (10-5-10-7 M) for 11, 12, 15, and 16.
solution.20 The fluorescence anisotropy decays showed a biex-
ponential profile consisting of a fast and a slow depolarization
component (see the Supporting Information). The fast decay
component likely represented an intramolecular energy-transfer
depolarization process,21 consistent with the presence of a
delocalized excited state, whereas the slow component cor-
responded to the global rotation of the molecule. The hydro-
dynamic volumes (Vhyd) were then calculated using the values
of the rotational correlation times (Θ2) via the Debye-Stokes-
Einstein relation (DSE) as reported previously.7b
The hydrodynamic volumes of second- and third-generation
2,6-pydic and the 2-OMe-IPA dendrons displayed similar
solvent dependencies that were different from first-generation
2-OMe-IPA dendron 10. Generally, with the exception of 10,
all dendrons exhibited a maximal Vhyd in CDCl3 that progres-
sively collapsed in the order CDCl3 > CD3OD > DMSO-d6.
This trend suggests that at higher generations, nonspecific
solvophobic compression is more important in determining
hydrodynamic properties than solvent-dependent shifts in the
conformational equilibria of the repeat unit. The observed Vhyd
compression correlates with apparent solvent quality, as evi-
denced by the qualitative observation that the dendrons tend to
be more soluble in CDCl3 than either CD3OD or DMSO-d6.
The similarity of the trends for both dendrons reflects the
dominance of the tetraethyleneglycol termini in determining
solubility characteristics. These solvent trends are congruent with
the tendency of other dendrimer systems to collapse in poor
solvents and expand in good solvents.22
As shown in Figure 5, the calculated volumes of 11 increased
slightly (∼4%) going from the gas phase f CHCl3 f DMSO,
in contrast with the experimental observation that the Vhyd (Table
4) was significantly larger in CHCl3 than in DMSO. The
(22) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. ReV. 1999,
99, 1665.
(23) The Monte Carlo Multiple Minimum search protocol was used to
generate 100 000 conformers of 11 and 15. These conformers were then
optimized under the AMBER* force field for gas phase, CHCl3, and DMSO
dielectric fields. Structures within ∼12 kcal/mol of the global minimum
after optimization were tabulated.
(24) As implemented in Macromodel 8.1, see: Mohamadi, F.; Richards,
N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.;
Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440.
(20) For use of the TRFA technique in 2,6-pydic dendrimers, see ref
7b.
(21) See ref 7b and: Tande, B. M.; Wagner, N. J.; Mackay, M. E.;
Hawker, C. J.; Jeong, M. Macromolecules 2001, 34, 8580.
9040 J. Org. Chem., Vol. 71, No. 24, 2006

Conformational Properties of Folded Dendrons
the dielectric effect alone. Furthermore, we should also note
that the calculated change in volume is small (on the order of
<5%), whereas the experimental change from CHCl3 to DMSO
is about a factor of 3.
In contrast to the gas-phase structure of the 2-OMe-IPA
dendron, the conformational ensemble that comprises the global
structure of the 2,6-pydic dendron 15 was composed of repeat
units existing exclusively in the syn-syn conformation (Figure
6). Similar to 2-OMe-IPA 11, the conformational equilibria shift
increasingly toward the syn-anti conformation as the polarity
increases going from CHCl3 (66ss/34sa/0aa) to DMSO (33ss/
64sa/2aa), but to a lesser extent. Moreover, the anti-anti
conformation contributes much less to the equilibrium, even in
DMSO, in which only 2% of the repeat units exist in the anti-
anti form.
This local conformational change in the repeat unit is
accompanied by an increase in the calculated volume similar
to 2-OMe-IPA 11, compared with the gas phase. However, both
computational and experimental data indicate that the volume
of 2,6-pydic 15 decreases slightly upon changing solvents from
CHCl3 to DMSO, contrasting with the calculated behavior of
2-OMe-IPA 11. Comparison of the calculated structures of 11
and 15 reveals that whereas the percentage of the anti-anti form
in 11 increases to 20% in DMSO, its contribution to the structure
of 15 is negligible. A closer inspection of the computational
structures that contribute to the ensemble below ∼12 kcal/mol
for 11 and 15 indicated that the focal shell repeat unit always
adopts the syn-syn conformation, which causes nearly every
peripheral position to exist in the syn-anti form. This arrange-
ment appears to pack more efficiently than when both syn-anti
and syn-syn forms coexist at the periphery of the dendrons in
CHCl3 (Figure 7). Because the conformational equilibria of 2,6-
pydic repeat units exhibits little solvent dependence, the
hydrodymic volumes are dominated by solvophobic interactions
at all three generations. In contrast, the conformation of the
2-OMe-IPA repeat unit is highly dependent on solvent. This
FIGURE 6. Calculated volume (cm3/mol) and percent contribution
of syn-syn (ss), syn-anti (sa), and anti-anti (aa) conformations as a
function of dielectric field in conformations within ∼12 kcal/mol of
the global minimum for 2,6-pydic repeat unit in 15.
expansion in calculated volume occurred in conjunction with a
shift in equilibria of the branched repeat unit from predominantly
syn-syn in the gas phase (75ss/25sa/0aa) to predominately syn-
anti in the presence of applied dielectric fields for CHCl3 (33ss/
63sa/2aa) and DMSO (33ss/46sa/20aa). These observations
suggest that the 2-OMe-IPA system would expand slightly in
solvents with high dielectric constants that can disrupt the
intramolecular hydrogen bonding that stabilizes the syn-syn
conformation in favor of the syn-anti and anti-anti forms.
However, these computational results are not consistent with
the experimental observations by TRFA methods. Since the
experimental situation includes both the dielectric effect of the
solvent as well as consideration of the intimate interactions
between the dendron and the hydrogen-bonding solvent, these
intimate interactions must be dramatically more important than
FIGURE 7. Comparison of packing of 2,6-pydic dendron 15 in CHCl3 (A) and DMSO (B) for representative conformers (top: side-on view,
bottom: end-on view). Hydrogens of the end chains have been hidden for clarity.
J. Org. Chem, Vol. 71, No. 24, 2006 9041

Gabriel et al.
Hz, 2H), 8.88 (s, 2H), 8.92 (d, J ) 8.0 Hz, 2H), 11.95 (s, 2H); 13
C
affords a differential effect of solvent on the first generation
dendron 10 compared with higher generations where solvent
compression dominates the Vhyd. Accordingly, we can conclude
that nonspecific solvophobic compression controls the hydro-
dynamic properties of both series of dendrons more strongly
than solvent-dependent shifts in the conformational equilibria
of the repeat units.
NMR (125 MHz, CDCl3) δ 59.0, 63.7, 64.6, 68.9, 70.5, 70.6, 70.6,
70.7, 71.9, 71.9, 116.4, 121.3, 123.6, 128.7, 130.2, 131.2, 134.6,
140.6, 143.0, 160.5, 162.5, 167.7; IR (neat) 3257, 3090, 2877, 1735,
1678, 1606, 1518, 1449, 1349, 1302, 1008; HR-QTOF-ESI-MS m/z
calcd for C41H53N3O17Na (M + Na)+ 882.3267, found 882.3305.
NH2-[G1] (4.34 g, 5.05 mmol, 100 mol %) and SnCl2‚2H2O
(11.39 g, 50.47 mmol, 1000 mol %) were dissolved in ethyl acetate
(50 mL) and methanol (5 mL) and heated at reflux for 3 h. Ethyl
acetate (50 mL) and saturated aqueous NaHCO3 (100 mL) were
added to the cooled solution resulting in the formation of a white
precipitate. The precipitate was removed by filtration through a
pad of Celite, and the filtrate was poured into a separatory funnel
and extracted with ethyl acetate (3 × 100 mL). The combined
organic layers were dried (MgSO4), and the solvent was removed
under reduced pressure (40 mmHg) affording a yellow oil.
Purification by flash chromatography (SiO2) with 5% methanol/
ethyl acetate gave the product as a clear oil (3.87 g, 92%): 1H
NMR (400 MHz, CDCl3) δ 3.33 (s, 6H), 3.48 (m, 4H), 3.62 (m,
20H), 3.78 (t, J ) 4.8 Hz, 4H), 3.88 (s, 3H), 4.00 (s, 2H), 4.45 (t,
J ) 4.4 Hz, 4H), 7.12 (td, J ) 8.0, 0.8 Hz, 2H), 7.33 (s, 2H), 7.57
(td, J ) 8.8, 1.6 Hz, 2H), 8.07 (dd, J ) 8.0, 1.6 Hz, 2H), 8.81 (dd,
J ) 8.4, 1.2 Hz) 11.72 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
59.9, 64.1, 64.3, 68.9, 70.4, 70.5, 70.5, 70.6, 71.8, 116.7, 119.5,
121.6, 123.0, 130.2, 131.1, 134.2, 140.8, 143.3, 148.1, 164.5, 167.2;
IR (neat) 3446, 3357, 3261, 2874, 1926, 1679, 1502, 1519, 1446,
1269, 1113; HR-QTOF-ESI-MS m/z calcd for C41H55N3O15Na (M
+ Na)+ 852.3531, found 852.3455.
In conclusion, dendrons based on 2-methoxyisophthalamides
adopt a compact conformation similar to related dendrons based
on pyridine-2,6-dicarboxamide. Whereas pyridine-2,6-dicar-
boxamides and 2-methoxyisophthalamides exhibit qualitatively
similar syn-syn preferences, a comparison of the conformational
equilibria exhibited by both systems reveals subtle differences:
(1) 2-OMe-IPA exhibits a lower syn-syn preference than 2,6-
pydic and a flatter energetic profile. (2) The syn-syn preference
of the 2-OMe-IPA branched repeat unit is stabilized entirely
by intramolecular hydrogen-bonding interactions. In contrast,
the syn-syn preference of 2,6-pydic is a consequence of
intramolecular hydrogen-bonding and dipole minimization ef-
fects. (3) Polar solvents decrease the syn-syn preference of the
first generation 2-OMe-IPA dendron more appreciably as
compared with the corresponding 2,6-pydic dendron. These
differences in local conformational equilibria are dominated by
solvophobic solvent interactions at the global structural level
and therefore exhibit compact volumes with similar solvent
dependencies.
NO2-[G2] (11). Following the procedure for preparation of NO2-
[G1] (10), NH2-[G1] (2.90 g, 3.49 mmol, 200 mol %), DMAP (43
mg, 0.35 mmol, 20 mol %), and 2-methoxy-5-nitroisophthaloyl
dichloride (0.490 g, 1.75 mmol, 100 mol %) were reacted in CH2-
Cl2 (10 mL) and pyridine (1 mL) to afford NO2-[G2] (11) as a
light yellow oil (2.72 g, 85%) after purification by flash chroma-
tography (SiO2) (100:20:4 CHCl3/acetone/ethanol): 1H NMR (250
MHz, CDCl3) δ 3.33 (d, 12H), 3.49-3.67 (m, 48H), 3.81 (t, J )
5.0 Hz, 8H), 4.04 (s, 6H), 4.22 (s, 3H), 4.48 (t, J ) 4.5 Hz, 8H),
7.61 (td, J ) 7.3, 0.75 Hz, 4H), 7.56 (t, J ) 7.0 Hz, 4H), 8.10 (dd,
J ) 8.0, 1.5 Hz, 4H), 8.44 (s, 4H), 8.82 (d, J ) 8.25 Hz, 4H), 8.86
(s, 2H), 9.69 (s, 2H), 11.81 (s, 4H); 13C NMR (125 MHz, CDCl3)
δ 58.9, 58.9, 64.1, 64.1, 64.5, 68.9, 70.4, 70.4, 70.5, 70.5, 70.5,
70.6, 71.8, 71.9, 116.6, 121.4, 123.2, 125.4, 128.7, 129.2, 130.1,
131.1, 134.1, 134.3, 140.6, 143.1, 152.7, 160.1, 161.6, 163.8, 167.4;
IR (neat) 3509, 3262, 3087, 2875, 2359, 2245, 1681, 1604, 1519,
1447 cm-1; MS (MALDI-TOF) for C91H113N7O35 calcd 1886.73,
obsd 1886.85.
NH2-[G2]. Following the procedure for preparation of NH2-[G1],
NO2-[G2] (11) (2.03 g, 1.09 mmol, 100 mol %) was reduced with
SnCl2‚2H2O (2.46 g, 10.91 mmol, 1000 mol %) in ethyl acetate (9
mL) and methanol (1 mL) at reflux for 3 h. Purification by flash
chromatography (SiO2) (100:20:4 CHCl3/acetone/ethanol) afforded
the amine as a clear oil (1.03 g, 94%): 1H NMR (400 MHz, CDCl3)
δ 3.35 (s, 12H), 3.53 (m, 8H), 3.60-3.69 (m, 40H), 3.83 (t, J )
4.4 Hz, 8H), 4.01 (s, 3H), 4.31 (s, 6H), 4.47 (t, J ) 4.0 Hz, 8H),
7.16 (t, J ) 7.2 Hz, 4H), 7.16 (buried s, 2H), 7.59 (t, J ) 7.6 Hz),
8.11 (dd, J ) 8.0 Hz, 1.2 Hz, 4H), 8.41 (s, 4H), 8.84 (d, J ) 8.4
Hz, 4H), 9.65 (s, 2H), 11.84 (s, 4H); 13C NMR (62.5 MHz, CDCl3)
δ 58.9, 64.1, 64.3, 64.4, 68.9, 70.4, 70.5, 70.5, 70.6, 71,8, 116.5,
120.1, 121.4, 123.0, 125.1, 126.1, 130.3, 131.0, 134.3, 134.6, 140.9,
144.4, 147.0, 152.3, 163.1, 164.0, 167.4; IR (neat), 3451, 3259,
2888, 1959, 1504, 966 cm-1; MS (MALDI-TOF) for C91H115N7O3
calcd 1856.75, obsd 1857.03.
Experimental Section
(2-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}ethyl)-2-aminoben-
zoate (9). Methyl tetra(ethyleneglycol) (10.00 g, 48.06 mmol),
isatoic anhydride (8.23 g, 50.47 mmol, 105 mol %), and N,N-
(dimethylamino)pyridine (1.17 g, 9.62 mmol, 20 mol %) were added
to a dry 250 mL round-bottomed flask fitted with a stir bar. Dioxane
(100 mL) was added to dissolve the reagents, and then activated 4
Å molecular sieves were added and the flask was heated to 75 °C.
After 48 h, the sieves were filtered, and the solvent was evaporated
in vacuo (40 mmHg) affording a brown oil. Purification by flash
chromatography (SiO2) with 1:1 CH2Cl2/diethyl ether gave the
product as a light yellow oil (15.70 g, 88%): 1H NMR (250 MHz,-
CDCl3) δ 3.36 (s, 3H), 3.53 (m, 2H) 3.60-3.68 (m, 10H), 3.80 (t,
J ) 4.0 Hz, 2H), 4.41 (t, J ) 4.0 Hz, 2H), 5.70 (br s, 2H), 6.61
(dd, 1H), 6.63 (ddd, 1H), 7.24 (ddd, J ) 1.4, 7.0, 8.3 Hz, 1H),
7.87 (dd, J ) 1.6, 8.0 Hz, 1H); 13C NMR (250 MHz CDCl3) δ
59.1, 63.6, 69.4, 70.6, 70.8, 70.9, 72.1, 110.9, 116.3, 116.8, 131.6,
134.3, 150.6, 168.1; IR (solution cell, CDCl3) 3505, 3884, 3055,
2889, 1690, 1617, 1590, 1293, 1248, 1162, 1098 br cm-1; HRMS
(ESI) m/z [Na]+ 350.1557 (calcd for C16H25NO6Na+ 350.1574).
NO2-[G1] (10). (2-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}-
ethyl)-2-aminobenzoate 9 (5.27 g, 14.19 mmol, 200 mol %) and
DMAP (173 mg, 1.42 mmol, 20 mol %) were dried under vacuum
over P2O5 for 8 h. The vacuum was replaced with nitrogen, the
reactants were dissolved in a mixture of CH2Cl2 (15 mL) and
pyridine (4 mL), and activated 4 Å sieves were added. 2-Methoxy-
5-nitroisophthaloyl dichloride, 712 (1.98 g, 7.10 mmol, 100 mol
%), was dissolved in CH2Cl2 (5 mL) and was added dropwise via
syringe over 2 h to the stirring yellow solution of amine 9 and
DMAP, and the solution was stirred for 4 h at room temperature.
The sieves were filtered, and the solvent was removed under
reduced pressure (40 mmHg) to give an orange oil. Purification by
flash chromatography (SiO2) with 1.5% methanol/ethyl acetate
afforded a clear oil (4.98 g, 82%): 1H NMR (500 MHz, CDCl3) δ
3.26 (s, 6H), 3.41 (m, 4H), 3.55 (m, 20 H), 3.80 (t, J ) 5.0 Hz,
4H), 4.21 (s, 3H), 4.47 (t, J ) 4.5 Hz, 4H), 7.21 (td, J ) 8.0 Hz,
0.5 Hz, 2H), 7.64 (td, J ) 8.8, 1.6 Hz, 2H), 8.13 (dd, J ) 8.0, 1.5
NO2-[G3] (12). Following the procedure for preparation of NO2-
[G1] (10), NH2-[G2] (0.675 g, 0.362 g mmol, 200 mol %), DMAP
(4.4 mg, 0.036 mmol, 20 mol %), and 2-methoxy-5-nitroisophtha-
loyl dichloride (0.490 g, 1.75 mmol, 100 mol %) were reacted in
CH2Cl2 (1 mL) and pyridine (0.1 mL) to afford NO2-[G3] (12) as
a light yellow oil (0.514 g, 73%) after purification by flash
chromatography (SiO2) (100:40:8 CHCl3/acetone/ethanol): 1H
9042 J. Org. Chem., Vol. 71, No. 24, 2006

Conformational Properties of Folded Dendrons
NMR (500 MHz, CDCl3) δ 3.35 (s, 24H), 3.46 (m, 16H), 3.52-
3.63 (m, 80H), 3.75 (br s, 12H), 3.98 (s, 12H), 4.04 (s, 6H), 4.24
(s, 3H), 4.27 (br s, 16H), 7.07 (t, J ) 7.5 Hz, 8H), 7.51 (t, J ) 7.0
Hz, 8H), 8.03 (d, J ) 7.5 Hz, 8H), 8.40 (br s, 12H), 8.63 (s, 2H),
8.74 (d, J ) 8.0 Hz, 8H), 9.78 (s, 4H), 9.94 (s, 2H), 11.82 (s, 8H);
13C NMR (125 MHz, CDCl3) δ 58.2, 58.9, 64.1, 64.3, 64.5, 68.9,
70.4, 70.5, 70.5, 70.6, 71.8, 116.5, 121.4, 123.1, 125.1, 128.9, 129.9,
131.0, 134.3, 134.7, 140.7, 152.0, 152.3, 162.8, 163.9, 167.4; IR
(thin film) 3303, 2876, 1676, 1586, 1519, 1467, 1300, 1256, 1108
cm-1; MS (MALDI-TOF) for C191H233N15O71 calcd 3897.95, obsd
3897.30.
1606, 1517, 1453, 1348, 1305; MS (ESI) for C30H31N3O11Na+ calcd
632.1850, obsd 632.1839.
D. H2N-[G1] (13). [G1] NO2 (90 mg, 0.143 mmol) was dissolved
in ethyl acetate (30 mL) and methanol (10 mL). Pd/C (10%, 0.014
g, 0.2 mmol) was added to the solution, and the mixture was
hydrogenated at 1 atm of H2 pressure for 48 h. The catalyst was
remove by filtration though a pad of Celite and rinsed with ethyl
acetate (30 mL). The solvent was removed under reduced pressure
(40 mmHg) to give a clear yellow oil. Purification by flash column
chromatography (SiO2) using 1:1 hexanes/ethyl acetate gave the
product (0.060 g, 88%) as a white solid: mp 71-73 °C; 1H NMR
(400 MHz, CDCl3) δ1.34 (d, J ) 6.48 Hz, 6H), 3.35 (s, 6H), 3.49
(dd, J ) 4.04, 10.6 Hz, 2H), 3.56, (dd, J ) 10.6, 6.3 Hz, 2H), 3.92
(s, 3H), 5.34 (m, 2H), 7.14 (ddd, J ) 8.16, 6.96, 1.08 Hz, 2H),
7.37 (s, 2H), 7.58 (ddd, J ) 8.68, 7.48, 1.6 Hz, 2H), 8.07 (dd, J )
7.96, 1.56 Hz, 2H), 8.82 (dd, J ) 8.28, 0.44 Hz, 2H), 11.79 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 14.5, 59.5, 64.5, 70.7, 75.3,
117.6, 120.1, 122.0, 123.3, 130.7, 131.3, 134.4, 141.2, 143.2, 148.8,
165.0, 167.2; IR (CDCl3) 3511, 3254, 3187, 2863, 2455, 2375,
1661, 1624, 1520, 1426; MS (ESI) for C31H35N3O9Na+ calcd
616.2265, obsd 616.2278
Cl-[G1] (14). A solution of 4-chloropyridine-2,6-dicarbonyl
dichloride (1.57 g, 6.57 mmol) in CH2Cl2 (4.5 mL) was added to
a solution of (2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethyl)-2-
aminobenzoate (9) (4.30 g, 13.13 mmol) and 4 Å molecular sieves
(2 g) in pyridine (8.7 mL) and CH2Cl2 (17.5 mL) over 1 h at room
temperature. After 16 h at room temperature, the solvents were
evaporated in vacuo, and the resultant residue was suspended in
CH2Cl2 and purified by flash chromatography (SiO2) with 10%
Et2O/CH2Cl2 to 50% Et2O/CH2Cl2 to 10% MeOH/CH2Cl2 to afford
the product as a clear yellow oil (5.31 g, 99%): Rf (EtOAc) 0.13;
Rf (5% MeOH/EtOAc) 0.34; Rf (10% MeOH EtOAc) 0.42; 1H NMR
(400 MHz, CDCl3) δ 3.34 (s, 6H), 3.49-3.52 (m, 8H), 3.54-3.62
(m, 20H), 4.18 (dd, J ) 4.8 Hz, 4H), 7.20 (ddd, J ) 1.0, 8.2, 8.2
Hz, 2H), 7.63 (ddd, J ) 1.6, 8.6, 8.6 Hz, 2H), 8.10 (dd, J ) 1.5,
8.0 Hz, 2H), 8.41 (s, 2H, pyr), 8.72 (dd, J ) 0.6, 8.3 Hz, 2H),
12.63 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 59.2, 64.4, 69.0,
70.6, 70.7, 72.1, 117.9. 121.8, 123.9, 125.7, 131.4, 134.6, 140.1,
148.4, 150.9, 161.2, 167.2; IR (CHCl3) 3356, 3254, 3089, 2883,
1685, 1606, 1582, 1534, 1454, 1308, 1261, 1086 cm-1; HRMS
(ESI) m/z [M + Na]+ 842.2891 (calcd 842.2874 for C39H50ClN3O14-
Na+).
Synthesis of (R)-O2N-[G1] (13). A. ((1R)-2-Methoxy-1-meth-
ylethyl)-2-nitrobenzoate. 2-Nitrobenzoyl chloride (3.24 g, 17.5
mmol, 100 mol %) was dissolved in CH2Cl2 (10 mL) and pyridine
(3 mL) in a 50 mL round-bottomed flask. (R)-1-Methoxy-2-propanol
(1.58 g, 1.71 mL, 17.5 mmol, 100 mol %) was added dropwise via
syringe, and the resulting clear orange solution was stirred at room
temperature for 12 h. The solvent was evaporated to give a crude
orange oil which was purified by flash chromatography (SiO2) with
2:1 hexanes/ethyl acetate to give a clear oil (3.77 g, 90%): 1H NMR
(400 MHz, CDCl3) δ 1.38 (d, J ) 6.5 Hz, 3H), 3.40 (s, 3H), 3.50
(dd, J ) 10.6, 4.1 Hz, 1H), 3.55 (dd, J ) 10.6, 6.0 Hz, 1H), 5.34
(dqd, J ) 6.5, 6.5, Hz, 1H), 7.62 (td, J ) 7.8, 1.6 Hz, 1H), 7.68
(td, J ) 7.5, 1.3 Hz, 1H), 7.75 (dd, J ) 7.5, 1.6 Hz, 1H), 7.93 (dd,
J ) 7.9, 1.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 16.4, 59.5,
72.1, 74.9, 124.2, 128.3, 130.2, 132.0, 133.3, 148.4, 165.3; IR
(CDCl3) 2990, 2934, 1731, 1537, 1352, 1294, 1257, 1111 cm-1
MS (ESI) for C11H13NO5Na+ calcd 262.0685, obsd 262.0684.
;
B. ((1R)-2-Methoxy-1-methylethyl)-2-aminobenzoate. ((1R)-
2-Methoxy-1-methylethyl)-2-nitrobenzoate (2.50 g, 10.45 mmol,
100 mol %) was dissolved in ethyl acetate (40 mL), methanol (20
mL), and Pd-C (0.250 g, 10 mol %). The solution was flushed
with N2 (g), and an H2 (g) balloon was attached, flushing the
solution with H2 three times. The solution was stirred for 24 h at
room temperature, and then it was filtered through Celite to remove
the Pd-C. The solvent was removed under reduced pressure (40
mmHg) to give a pink oil. Purification by flash column chroma-
tography (SiO2) 5:1 hexanes/ethyl acetate gave the product as a
1
white solid (1.99 g, 91%): mp 60-63 °C; H NMR (400 MHz,
CDCl3) δ 1.26 (d, J ) 6.4 Hz, 3H), 3.31 (s, 3H), 3.41 (dd, J ) 4.2,
10.5 Hz, 1H), 3.49, (dd, J ) 6.1, 10.5 Hz, 1H), 5.20 (dqd, J ) 4.2,
6.1, 6.5 Hz, 1H), 5.62 (bs, 2H), 6.54 (m, 2H), 7.16 (td, J ) 1.0,
7.3 Hz, 1H), 7.79 (dd, J ) 1.0, 7.7 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 17.2, 59.6, 69.6, 75.6, 111.6, 116.6, 117.1, 131.7, 134.4,
150.9, 167.9; IR (solution cell, CHCl3) 3504, 3381, 2934, 1686,
1615, 1589, 1560, 1487, 1292, 1247, 1160; MS (ESI) for C11H15-
NO3Na+ calcd 232.0944, obsd 232.0940
NH2-[G1]. A suspension of Cl-[G1] (14) (5.31 g, 6.47 mmol)
and sodium azide (8.42 g, 129.44 mol) in DMF (13 mL) was heated
to 75 °C for 4.5 h. The solvent was evaporated in vacuo, suspended
in EtOAc, and filtered through a pad of Celite. The filtrate was
evaporated affording N3-[G1] as an orange oil that was used without
further purification (5.33 g, quantitative); Rf (5% MeOH/EtOAc)
1
C. [G1] NO2. ((1R)-2-Methoxy-1-methylethyl)-2-aminobenzoate
(0.200 g, 0.96 mmol, 200 mol %) and DMAP (0.021 g, 0.17 mmol,
35 mol %) were dried under vacuum over P2O5 for 8 h. The vacuum
was replaced with nitrogen, the reactants were dissolved in a mixture
of CH2Cl2 (2 mL) and pyridine (1 mL), and activated 4 Å sieves
were added. 2-Methoxy-5-nitroisophthaloyl dichloride (0.133 g, 0.48
mmol, 100 mol %) was dissolved in CH2Cl2 (1 mL) and added
dropwise via syringe over 2 h to the stirring yellow solution of
amine and DMAP, and the solution was stirred for an additional 4
h at room temperature. The sieves were removed by filtration, and
the solvent was evaporated under reduced pressure to give an orange
oil. Purification by flash chromatography (SiO2) with a gradient of
3:1 to 1:1 hexanes /ethyl acetate gave the product as a clear oil
(0.175 g, 58%): 1H NMR (400 MHz, CDCl3) δ 1.28 (d, J ) 6.44
Hz, 6H), 3.37 (s, 6H), 3.50 (dd, J ) 10.6, 3.92 Hz), 3.58 (dd, J )
10.7, 6.4 Hz, 2H), 4.20 (s, 3H), 5.34 (m, 2H), 7.21 (ddd, J ) 8.27,
7.10, 1.11 Hz, 2H), 7.65 (ddd, J ) 8.70, 7.52, 1.61 Hz, 2H), 8.12
(dd, J ) 8.0, 1.56 Hz, 2H), 8.85 (obscured d, 2H), 8.88 (s, 2H),
11.99 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 16.7, 59.6, 64.0,
71.0, 75.3, 117.2, 121.7, 124.0, 129.0, 130.6, 131.5, 134.9, 141.0,
143.4, 160.9, 193.0, 167.6; IR (CH2Cl2) 3261, 2988, 2886, 1681,
0.34; H NMR (400 MHz, CDCl3) δ 3.35 (s, 6H), 3.52 (m, 8H),
3.60 (m, 20H), 4.20 (dd, J ) 4.8 Hz, 4H), 7.20 (dt, J ) 1.0, 7.6
Hz, 2H), 7.65 (dt, J ) 1.5, 7.8 Hz, 2H), 8.07 (s, 2H, pyr), 8.11
(dd, J ) 1.5, 8.0 Hz, 2H), 8.74 (dd, J ) 1.0, 8.3 Hz, 2H), 12.66 (s,
2H); IR (thin film) 3355, 3245, 2876, 1686 cm-1; HRMS (ESI)
m/z [M + Na]+ 849.3277 (calcd 849.3277 for C39H50N6O14Na+).
A degassed suspension of the crude N3-[G1] (5.35 g, 6.47 mmol)
and 10% Pd on carbon (0.53 g) in EtOAc (32 mL) was pressurized
to 50 psi using a Parr hydrogenator, and the mixture was shaken
for 13 h. The solution was filtered over Celite, and the solids were
rinsed with EtOAc (300 mL). The resultant filtrate was evaporated
giving a light yellow solid that was purified using flash chroma-
tography (SiO2) with 5% MeOH/EtOAc affording the amine as a
white gummy solid (4.69 g, 91%): mp 47-49 °C (CH2Cl2); Rf
(5% MeOH/EtOAc) 0.27; Rf (10% MeOH/EtOAc) 0.47; Rf (5%
MeOH/CH2Cl2) 0.33; 1H NMR (400 MHz, CDCl3) δ 3.32 (s, 6H),
3.42 (br m, 12H), 3.58 (br m, 16H), 4.18 (br dd, J ) 4.3, 4.9 Hz,
4H), 5.26 (br s, 2H), 7.18 (ddd, J ) 1.1, 7.3, 8.0 Hz, 2H), 7.62
(obs ddd, J ) 1.4, 7.4, 8.5 Hz, 2H), 7.58 (obs s, 2H), 8.04 (dd, J
) 1.5, 8.0 Hz, 2H), 8.64 (dd, J ) 0.9, 8.4 Hz, 2H), 12.46 (s, 2H);
13C NMR (100 MHz, CDCl3) δ 59.0, 64.4, 68.9, 70.5, 70.6, 72.0,
J. Org. Chem, Vol. 71, No. 24, 2006 9043

Gabriel et al.
110.1, 118.2, 121.8, 123.4, 131.4, 134.2, 140.2, 150.0, 156.6, 163.0,
167.2; IR (CHCl3) 3518, 3420, 3350, 3248,1683 cm-1; HRMS (ESI)
m/z [M + Na]+ 823.3372 (calcd 823.3372 for C39H52N4O14Na).
Cl-[G2] (15). Following the procedure for preparation of Cl-
[G1] (14), 4-chloropyridine-2,6-dicarbonyl dichloride (0.23 g, 0.95
mmol), NH2-[G1] (1.37 g, 1.71 mmol), DMAP (58 mg, 0.38 mmol),
and pyridine (0.30 g, 0.31 mL, 3.80 mmol) were reacted in THF
(2 mL) at room temperature for 72 h affording Cl-[G2] 15 following
purification by flash chromatography (SiO2) with 10% MeOH/
EtOAc to 5% MeOH/CH2Cl2) as an off-white solid (0.73 g, 48%):
mp 79-84 °C (CH2Cl2); Rf (10% MeOH/EtOAc) 0.06; Rf (5%
(t, J ) 4.5 Hz, 8H), 7.09 (s, 2H), 7.33 (t, J ) 8.0 Hz, 4H), 7.63 (s,
2H), 7.76 (td, J ) 8.25 Hz, 1.0 Hz, 4H), 8.06 (dd, J ) 8.0 Hz, 1.0
Hz, 4H), 8.66 (d, J ) 8.0 Hz, 4H), 9.09 (s, 4H), 11.62 (s, 2H),
12.52 (s, 4H); 13C NMR (125 MHz, DMSO-d6) δ 58.4, 64.6, 68.3,
70.0, 70.1, 70.1, 70.1, 70.2, 71.7, 110.7, 115.5, 118.3, 121.7, 124.4,
131.5, 134.9, 139.6, 148.9, 149.6, 150.1, 157.7, 162.0, 164.3, 167.0;
IR (CDCl3) 3526, 3439, 3310, 3241, 1687m cm-1; MS (MALDI-
TOF) for C85H106N10O30Na+ calcd 1769.71, obsd 1769.71.
Cl-[G3] (16). Following the procedure for preparation of Cl-
[G1] (14), 4-chloropyridine-2,6-dicarbonyl dichloride (0.093 g,
0.0039 mmol, 100 mol %), NH2-[G2] (0.136 g, 0.078 g mmol, 200
mol %), and DMAP (0.0010 g, 0.0078 mmol, 20 mol %) were
reacted at room temperature in a mixture of CH2Cl2 (0.5 mL) and
pyridine (0.1 mL) in the presence of 4 Å molecular sieves (0.2 g).
Purification by flash chromatography (SiO2) with 10:1 CH2Cl2
/methanol gave the product as a clear oil (0.101 g, 70%): 1H NMR
(500 MHz, CDCl3, 60 °C) δ 3.22 (s, 24H), 3.40 (t, J ) 4.5 Hz,
16H), 3.44-3.51 (m, 80H), 3.61 (t, J ) 5.0 Hz, 16H), 4.16 (t, J )
4.5 Hz, 16H), 7.25 (t, J ) 8.0 Hz, 8H), 7.65 (t, J ) 8.0 Hz, 8H),
8.03 (d, J ) 7.0 Hz, 8H), 8.22 (s, 2H), 8.59 (d, J ) 8.0 Hz, 8H),
9.03 (s, 8H), 9.14 (s, 4H), 11.45 (s, 2H), 11.60 (s, 4H), 12.33 (s,
8H); 13C NMR (125 MHz, CDCl3, 60 °C) δ 58.4, 64.5, 68.5, 70.1,
70.2, 70.3, 70.3, 71.8, 115.8, 116.9, 118.6, 121.9, 124.1, 131.3,
134.5, 139.8, 148.7, 149.3, 149.8, 150.2, 161.9, 163.2, 166.9; IR
1
MeOH/CH2Cl2) 0.38; H NMR (400 MHz, DMSO-d6) δ 3.18 (s,
12), 3.36 (m, 16H), 3.44 (obs m, 32H), 3.60 (br s, 8H), 4.15 (br s,
8H), 7.25 (dd, J ) 7.2 Hz, 4H), 7.67 (dd, J ) 7.0 Hz, 4H), 8.01
(d, J ) 7.6 Hz, 4H), 8.21 (s, 2H), 8.57 (d, J ) 8.0 Hz, 4H), 8.90
(s, 4H), 11.50 (s, 2H), 12.39 (s, 4H); 13C NMR (100 MHz, DMSO-
d6) δ 58.0, 64.1, 67.9, 69.6, 69.6, 69.7, 69.8, 71.2, 114.9, 117.6,
121.0, 123.8, 126.0, 130.9, 134.3, 139.2, 146.8, 148.6, 149.2, 149.5,
161.2, 161.4, 166.4; IR (thin film) 3510, 3314, 3248, 1710, 1692,
1680 cm-1; HRMS (ES) m/z [Na]+ 1788.6434 (calcd 1788.6470
for C85H104ClN9O30Na).
NH2-[G2]. A. N3-[G2]. Cl-[G2] 15 (0.200 g, 0.113 mmol, 100
mol %) and NaN3 (0.074 g, 1.13 mmol, 1000 mol %) were stirred
in dry DMF (5 mL) at 70 °C for 10 h. The DMF was evaporated
under reduced pressure (1 mmHg) to give a crude orange solid.
Purification by flash chromatography (SiO2) with 100:40:8 chlo-
roform/acetone/ethanol gave N3-[G2] as a clear oil (0.190 g,
95%): 1H NMR (500 MHz, DMSO-d6) δ 3.18 (s, 12H), 3.38-
3.46 (m, 48H), 3.59 (t, J ) 5.25 Hz, 8H), 4.16 (t, J ) 3.75 Hz,
8H), 7.34 (t, J ) 8.0 Hz, 4H), 7.78 (t, J ) 8.25 Hz, 4H), 8.07 (d,
J ) 8.0 Hz, 4H), 8.31 (s, 2H), 8.67 (d, J ) 8.25 Hz, 4H), 9.08 (s,
4H), 11.74 (s, 2H), 12.53 (s, 4H)1MS (MALDI-TOF) for
C85H104N12O30Na+ calcd 1796.80, obsd 1796.59.
(CHCl3) 3329, 3250, 1683 cm-1; MS (MALDI-TOF) for C177H212
ClN21O62Na+ calcd 3684.13, obsd 3684.45.
-
Acknowledgment. This work was supported by the National
Science Foundation (CHE-0239871 and CHE-00526864). Gen-
erous allocations of computer time at the Ohio Supercomputer
Center are gratefully acknowledged. M.P.D. also acknowledges
a Procter and Gamble fellowship.
Supporting Information Available: General synthetic methods,
B. NH2-[G2]. N3-[G2] (0.20 g, 0.113 mmol, 100 mol %) was
dissolved in ethyl acetate (10 mL) and methanol (5 mL) in a
hydrogenation jar. The solution was purged with N2 for 15 min,
and Pd-C (0.0010 g, 10 mol %) was added. The solution was
placed under H2 (50 psi) on a Parr hydrogenator for 12 h. The
Pd-C was removed by filtration, and the solvent was evaporated
under reduced pressure (40 mmHg) to give a crude yellow oil.
Purification by flash chromatography (SiO2) with 100:40:8 chlo-
roform/acetone/ethanol gave the product as a clear oil (0.190 g,
97%): 1H NMR (500 MHz, DMSO) δ 3.18 (s, 12H), 3.39 (t, J )
2.8 Hz, 8H), 3.42-3.45 (m, 40H), 3.58 (t, J ) 3.6 Hz, 8H), 4.16
setup details for TCSPC and fluorescence studies, SEC character-
ization of the dendrons, and DOSY H NMR data for dendrons
1
11, 12, 15, and 16. Summary of calculated energies, dipole
moments, and natural population analyses of all stationary points
located for 2-OMe-IPA and 2,6-pydic. Summary of energies,
dihedral angles, and molecular volumes of conformers within ∼12
kcal/mol of the global minimum for 11 and 15. Crystal structure
data for dendron 13 and a complete ref 8a. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO061351K
9044 J. Org. Chem., Vol. 71, No. 24, 2006