Hierarchical growth of chiral self-assembled structures in protic media

Article abstract of DOI:10.1021/ja0005237

The location of nine chiral penta(ethylene oxide) side chains at the periphery of a C₃-symmetrical hydrogen-bonded extended core gives rise to a thermotropic discotic liquid crystalline material that shows lyotropic phases in polar, protic media. The molecular stacks self-assemble in a reversible and hierarchical fashion, and specific and subtle solvent-molecule interactions together with the created hydrophobic microenvironment account for an unprecedented stabilization of a preferred handedness of the helical stacks by cooperative intermolecular interactions. The presence of either chirality or achirality at the supramolecular level in the stacks can be tuned by temperature and solvent as judged from circular dichroism spectroscopy. A hierarchical growth of the self-assembly is revealed using a variety of spectroscopic techniques and differential scanning calorimetry.

Full text of DOI:10.1021/ja0005237

J. Am. Chem. Soc. 2000, 122, 6175-6182
6175
Hierarchical Growth of Chiral Self-Assembled Structures in Protic
Media†
L. Brunsveld,‡ H. Zhang,§ M. Glasbeek,§ J. A. J. M. Vekemans,‡ and E. W. Meijer*,‡
Contribution from the Laboratory of Macromolecular and Organic Chemistry, Dutch Polymer Institute,
EindhoVen UniVersity of Technology, P.O. Box 513, 5600 MB EindhoVen, The Netherlands, and the
Laboratory for Physical Chemistry, UniVersity of Amsterdam, Nieuwe Achtergracht 129,
1018 WS Amsterdam, The Netherlands
ReceiVed February 11, 2000
Abstract: The location of nine chiral penta(ethylene oxide) side chains at the periphery of a C3-symmetrical
hydrogen-bonded extended core gives rise to a thermotropic discotic liquid crystalline material that shows
lyotropic phases in polar, protic media. The molecular stacks self-assemble in a reversible and hierarchical
fashion, and specific and subtle solvent-molecule interactions together with the created hydrophobic
microenvironment account for an unprecedented stabilization of a preferred handedness of the helical stacks
by cooperative intermolecular interactions. The presence of either chirality or achirality at the supramolecular
level in the stacks can be tuned by temperature and solvent as judged from circular dichroism spectroscopy.
A hierarchical growth of the self-assembly is revealed using a variety of spectroscopic techniques and differential
scanning calorimetry.
Introduction
stability of the more directional bonding patterns, such as
hydrogen bonding, in protic media. For natural proteins7 and
(synthetic) foldamers,8 it is known that the stabilization of their
supramolecular structure (i.e., their native fold) in polar solvents
involves a variety of forces. Hydrophobicity has generally been
considered to be the main driving force for the collapse of the
random coil, whereas the well-defined 3-D structure is accounted
for by interactions such as hydrogen bonding. This specific
hydrogen bonding only arises in the created hydrophobic domain
of the protein, whereas in the random coil water is interfering.
Therefore, synthetic compounds large enough to create hydro-
phobic microdomains, capable of shielding the more sensitive
polar interactions from the protic solvent, should allow the
expression of all secondary interactions in a cooperative way
and the study of their individual contributions to the formation
of chiral superstructures. With this type of synthetic structures,
it should be feasible to bridge the gap between manmade
“simple” architectures and biomacromolecules and to create new
functional systems. Moreover, their properties will serve to aid
in the understanding of the distinct differences between super-
structure formation in apolar and polar media.
Remarkable control of chirality in supramolecular architec-
tures is demonstrated using cooperative hydrogen bonding,1
often in combination with π-π stacking.2,3 It has been shown
frequently that chirality present in the solubilizing side chain
of a (macro)molecule can be brought to expression at the next
hierarchical level of organization by inducing a preference for
one of two “supramolecular” conformations.3-5 Most of these
studies to transfer chiral information through molecular assembly
are carried out in aprotic organic media, due to the difficulty of
using the ensemble of secondary interactions in protic media.
As a result, the level of control in well-defined architectures of
synthetic chiral structures in protic media by a cooperative action
is very limited.6 This limitation is primarily due to the lack of
directionality of hydrophobic interactions and/or the lack of
* To whom correspondence should be addressed.
† This material is based upon work supported by the NRC Catalysis.
‡ Eindhoven University of Technology.
§ University of Amsterdam.
(1) (a) Rivera, J. M.; Martin, T.; Rebek, J., Jr. Science 1998, 279, 1021.
(b) Simanek, E. E.; Qiao, S.; Choi, I. S.; Whitesides, G. M. J. Org. Chem.
1997, 62, 2619.
(2) (a) Prins, L. J.; Huskens, J.; de Jong, F.; Timmerman, P.; Reinhoudt,
D. N. Nature 1999, 398, 498. (b) Russell, K. C.; Lehn, J.-M.; Kyritsakas,
N.; DeCian, A.; Fischer, J. New J. Chem. 1998, 123.
For assemblies in protic solvents, such as chromonics in
water, detailed information concerning the conformational
uniqueness of the self-assembled state is scarce.9 Recently it
was shown that R,ω-disubstituted sexithiophenes possess one
unique chiral self-assembly in protic media that dissociates
without an intermediate disordered state of aggregation,10 similar
(3) Palmans, A. R. A.; Vekemans, J. A. J. M.; Havinga, E. E.; Meijer,
E. W. Angew. Chem., Int. Ed. Engl. 1997, 36, 2648.
(4) (a) Yashima, E.; Maeda, K.; Okamoto, Y. Nature 1999, 399, 449.
(b) Langeveld-Voss, B. M. W.; Waterval, R. J. M.; Janssen, R. A. J.; Meijer,
E. W. Macromolecules 1999, 32, 227. (c) Mayer, S.; Maxein, G.; Zentel,
R. Macromolecules 1998, 31, 8522. (d) Gu, H.; Nakamura, Y.; Sato, T.;
Teramoto, A.; Green, M. M.; Jha, S. K.; Andreola, C.; Reidy, M. P.
Macromolecules 1998, 31, 6362. (e) Schlitzer, D. S.; Novak, B. M. J. Am.
Chem. Soc. 1998, 120, 2196. (f) Yashima, E.; Matsushima, T.; Okamoto,
Y. J. Am. Chem. Soc. 1997, 119, 6345. (g) Gulik-Krzywicki, T.; Fouquey,
C.; Lehn, J.-M. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 163. (h) Green M.
M.; Peterson, N. C.; Sato, T.; Teramoto, A.; Cook, R.; Lifson, S. Science
1995, 268, 1860. (i) Moore, J. S.; Gorman, C. B.; Grubbs, R. H. J. Am.
Chem. Soc. 1991, 113, 1704.
(6) Bonazzi, S.; DeMorais, M. M.; Gottarelli, G.; Mariani, P.; Spada,
G. P. Angew. Chem., Int. Ed. Engl. 1993, 32, 248.
(7) (a) Creighton, T. E. Proteins, structures and molecular properties;
W.H. Freeman and Company: New York, 1984. (b) Prediction of protein
structure and the principles of protein conformation; Fasman, G. D., Ed.;
Plenum Press: New York, 1990.
(8) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
(9) For a recent review on chromonics, see: Lydon, J. Curr. Opin. Colloid
Interface Sci. 1998, 3, 458.
(5) Prince, R. B.; Brunsveld, L.; Meijer, E. W.; Moore, J. S. Angew.
Chem., Int. Ed. 2000, 39, 228.
(10) Kilbinger, A. F. M.; Schenning, A. P. H. J.; Goldoni, F.; Feast, W.
J.; Meijer, E. W. J. Am. Chem. Soc. 2000, 122, 1820.
10.1021/ja0005237 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

6176 J. Am. Chem. Soc., Vol. 122, No. 26, 2000
BrunsVeld et al.
Figure 1. Chiral C3-symmetrical discotics 1 (apolar) and 2 (polar).
Figure 2. MALDI-TOF mass spectrum of 2, showing its sodium adduct
at m/z ) 3428.1 (theoretical m/z ) 3428.7).
to the behavior of chromonics.9 Moore et al., however, showed
recently that in the folding process of a series of oligo(m-
phenylene ethynylene)s, first a disordered state is formed before
a unique helical conformation is obtained.5 The hierarchical
folding is due to a stepwise occurrence of the diverse interac-
tions; first a hydrophobic collapse of the backbone takes place
followed by a structuring process in which the backbone
becomes highly ordered together with the side chains.
Scheme 1. Synthesis of Chiral
(2S)-2-Methyl-3,6,9,12,15-pentaoxahexadecanol 16
We have previously shown that hydrogen bonding in the C3-
symmetrical disk-shaped molecule 1 (Figure 1) favors planarity
and helps to create chiral columnar aggregates in dilute alkane
solutions in a highly cooperative fashion.3 The homochiral side
chains give preference to one helicity in the stacks of these
columns for which a cooperativity length of 280 Å (80
molecules) has been determined using a “sergeant-and-soldiers”
experiment.11 The expression of supramolecular chirality is due
to positional locking of the molecules that accompanies the self-
assembly; such a process is generally observed for supra-
molecular architectures in apolar media. Here, we demonstrate
that chiral columnar aggregates can be formed in polar, protic
media when chiral penta(ethylene oxide) side chains are present
at the periphery of the hydrogen-bonded extended core. In
addition, we show a remarkable and pronounced stepwise
growth of the self-assembly in protic solvents. This is in sharp
contrast to the self-assembly in apolar solvents. Thus, C3-
symmetrical disk 2 is designed to ensure solubility in polar
solvents in order to elucidate the individual contributions of
the secondary interactions (Figure 1). By locating the stereo-
chemical information in the side chain as close as possible to
the core of the disk, the most favorable cooperative interactions
of the side chains were guaranteed.
reaction of 4 with trimesic chloride (3) gives target compound
2 in an overall yield of 65% from 7 (Scheme 2). Extensive
molecular characterization of all molecules is in full agreement
with the structures assigned. The characteristic hydrogen-bonded
protons in 2 are observed at δ ) 15.5 and δ ) 14.4 ppm in
CDCl3, indicative of the strong hydrogen bonding within the
bipyridine unit. As an illustration, the mass spectrum of 2 is
depicted in Figure 2.
The thermotropic behavior of 2 was studied using differential
scanning calorimetry (DSC) and optical microscopy. The
thermotropic mesophase of 2 extends over a broad temperature
window; the Tg of 2 was found at -74 °C and the Tcl at 270
°C. Typical flowerlike patterns, indicative of a columnar
mesophase, are observed under the polarization microscope after
slow cooling from the melt.14
Results and Discussion
Synthesis and Characterization. The synthesis of chiral
(2S)-2-methyl-3,6,9,12,15-pentaoxahexadecanol is based on
standard synthetic transformations,12 and the chiral center was
derived from ethyl L-lactate (Scheme 1). All products were
The aggregation of 2 was studied in various solvents, and
we show here the results obtained with a variety of techniques
for n-butanol in detail (although the results may be generalized
1
characterized by H and 13C NMR spectroscopy and GC-MS;
all compounds had a purity >98%. The synthesis of 2 is based
on the consecutive acylation of the two amino groups of 2,2′-
bipyridine-3,3′-diamine (5).13 Equimolar reaction of 5 with
mesogenic molecule 7 at 0 °C affords monoacylated bipyridine
4 with a remarkable selectivity of 98%. Subsequent 3-fold
(14) Preliminary X-ray diffraction studies on a series of compounds such
as 1 and 2 substituted with different ethylene glycol side chains have
elucidated the columnar hexagonal ordered (Colho) mesophase of these
compounds in the liquid crystalline state. Apart from the reflections typical
for a Colho mesophase (100; 110; 200; 210; 001), sharp quadruplet splitted
reflections are found in shear aligned samples, suggesting a slight distortion
of, or higher order within, the Colho mesophase, probably due to a regular,
helical packing of the molecules within the stacks. For an example, see:
Brunsveld, L.; Vekemans, J. A. J. M.; Janssen, H. M.; Meijer, E. W. Mol.
Cryst. Liq. Cryst. 1999, 331, 449 and ref 13.
(11) Green, M. M.; Reidy, M. P.; Johnson, R. D.; Darling, G.; O’leary,
D. J.; Wilson, G. J. Am. Chem. Soc. 1989, 111, 6452.
(12) Janssen, H. M.; Peeters, E.; van Zundert, M. F.; van Genderen, M.
H. P.; Meijer, E. W. Macromolecules 1997, 9, 22815.
(13) Palmans, A. R. A.; Vekemans, J. A. J. M.; Fischer, H.; Hikmet, R.
A.; Meijer, E. W. Chem. Eur. J. 1997, 3, 300.

Growth of Chiral Structures in Protic Media
J. Am. Chem. Soc., Vol. 122, No. 26, 2000 6177
Figure 3. Temperature-dependent UV-vis spectra of 2 in n-butanol (2.7 × 10-5 M), showing the two transitions. Top: the increase of the temperature
from -10 to 30 °C. Bottom: increase of the temperature from 30 to 100 °C. Inset: the absorbance at 385 nm at different temperatures.
Scheme 2. Synthesis of Disk-Shaped Molecule 2
for all low molecular weight alcohols). The higher boiling point
of n-butanol enables the use of temperature as a tool for
denaturation of the self-assembled structures.
indicating the molecularly dissolved nature of 2. A similarly
resolved spectrum was obtained for a 1.5 wt % solution of 2 in
n-butanol-d10 at 100 °C. However, cooling of the n-butanol-d10
solution to 35 °C gave rise to a gradual broadening of the signals
with a concomitant significant shielding of the aromatic protons
(Figure 4). Both processes are indicative of aggregation via π-π
stacking and reveal the order within the stacks. Lowering the
temperature from 35 to 30 °C resulted in a sudden and complete
loss of the signals attributed to the aromatic protons. Lowering
the temperature even further did not change the spectrum
anymore. This phenomenon is due to the total loss of freedom
of movement within the self-assembly. This process is highly
cooperative as can be deduced from the sharp S-curve observed
with the temperature-dependent UV-vis spectroscopy and the
UV-Vis and NMR Spectroscopy. Temperature-dependent
ultraviolet-visible (UV-vis) absorption (Figure 3) and NMR
spectroscopy (Figure 4) measurements were performed in order
to investigate the self-assembling of 2 in dilute solution. In
chloroform, 2 is molecularly dissolved, as concluded from the
shape of the UV spectrum.3 In polar solvents such as acetonitrile,
methanol, ethanol, and n-butanol, these molecules aggregate as
indicated by the red shift of about 10 nm in the UV spectrum.
Raising the temperature of a solution of 2 (10-5 M) in n-butanol
from -10 to 100 °C resulted in two transitions as concluded
from the UV spectra (Figure 3). Whereas between -10 and 15
°C the UV spectrum is constant, a highly cooperative transition
takes place around 20 °C, resulting in a spectrum that is red-
shifted. Further heating gives, above 30 °C, rise to the second
transition as evidenced by a gradual blue shift of the spectra.
At 100 °C a UV spectrum was obtained which featured the same
band shape as that of 2 in chloroform at room temperature. 1H
NMR and 13C NMR spectra of compound 2 in deuterated
chloroform at room temperature showed clearly resolved spectra
1
sudden sharp transition observed by H NMR spectroscopy.
Time-Resolved Fluorescence Spectroscopy. Time-resolved
fluorescence experiments were performed to study the nature
of the species in the molecularly dissolved state as well as in
the self-assembled structures. To characterize the fluorescence,
a comparative study of disk-shaped molecule 2 with model
compounds 18a-c (diacylated 2,2′-bipyridine-3,3′-diamines)
was performed (Scheme 3). Analogous to disk-shaped molecule

6178 J. Am. Chem. Soc., Vol. 122, No. 26, 2000
BrunsVeld et al.
Figure 6. Fitted fluorescence transients of 2 in chloroform (- - -) and
in n-butanol at different temperatures (s); λfl ) 520 nm; concentration
10-6 M. The increase of the transients after ∼600 ps is due to the system
response and is taken into account with the fitting.
state refers to a protonated form (obtained after intramolecular
proton transfer from the amide to the nitrogen of the heterocycle
upon excitation). The dynamic Stokes shift, in typically 3 ps,
is representative of the solvation of the photoexcited protonated
molecule dissolved in chloroform.17
1
Figure 4. Aromatic region of the H NMR spectrum (n-butanol-d10,
5 × 10-3 M, 400 MHz) at different temperatures.
Lifetime measurements were performed using the picosecond
fluorescence setup described previously.18 The excited-state
lifetime of the molecularly dissolved compounds in chloroform
was found to be dependent on the size of the substituents on
the amides. The lifetime of the excited state of compound 18a
is 10 ps; replacement of the Boc group by a phenyl (18b) results
in an increase of the lifetime to 50 ps. A further enlargement
of the steric bulk by attachment of long ethylene oxide chains
(18c) increases the lifetime to 150 ps.19 The results thus show
that when rigidity is imposed on to the molecules, the non-
radiative decay of the excited state is suppressed.
In analogy with these results for compounds 18a-c, it was
found that the lifetime of compound 2 had increased from 300
ps in chloroform (molecularly dissolved) to ∼5 ns in the self-
assembled state, i.e., an increase by about 1 order of magnitude,
due to the decreased motion of the molecules within the
aggregate. Some typical fluorescence transients fitted to a
biexponential function at various temperatures of 2 in chloro-
form and n-butanol (10-6 M) are displayed in Figure 6. One of
the two characteristic time constants has a magnitude similar
to the lifetime for 2 in the molecularly dissolved molecules in
chloroform, whereas the second lifetime component is about 1
order of magnitude longer. This finding shows the simultaneous
presence of two forms of 2 in solution, i.e., 2 in its molecularly
dissolved form and in an aggregated form. It proved impossible
to detect the dynamic Stokes shift in the aggregates of 2 in an
accurate way. As a result, the time-resolved fluorescence data
are focused on the equilibrium between the molecularly dis-
solved and aggregated forms only (the transition lies between
30 and 90 °C as was already established from UV-vis and
NMR spectroscopy, vide supra).
Figure 5. Fluorescence transients of 18c dissolved in chloroform at
room temperature at different detection wavelengths (open circles) with
their fits (lines); concentration ) 10-5 M.
Scheme 3. Model Compounds 18a-c
2, all the model compounds showed a large Stokes shift of the
fluorescence emission (λmax-fluor ∼513 nm) under all experi-
mental conditions. Measurements with our femtosecond fluo-
rescence upconversion technique15 with the detection of emission
at different wavelengths, for 18c in the molecularly dissolved
state (in chloroform), showed a dynamic Stokes shift typical of
the intramolecular charge transfer; the characteristic time was
approximately 3 ps (Figure 5). In analogy with the previously
studied 2,2′-bipyridyl-3,3′-diol,16 it is likely that its fluorescent
(16) (a) Prosposito, P.; Marks, D.; Zhang, H.; Glasbeek, M. J. Phys.
Chem. A 1998, 102, 8894. (b) Eyal, M.; Reisfeld, R.; Chernyak, V.;
Kaczmarek, L.; Grabowska, A. Chem. Phys. Lett. 1991, 176, 531. (c) Bulska,
H. Chem. Phys. Lett. 1983, 98, 398.
(17) Horng, M. L.; Gardecki, J. A.; Papazyan, A.; Maroncelli, M. J. Phys.
Chem. 1995, 99, 17311.
(18) Middelhoek, E. R.; van der Meulen, P.; Verhoeven, J. W.; Glasbeek,
M. Chem. Phys. 1995, 198, 373.
(15) van der Meulen, P.; Zhang, H.; Jonkman, A. M.; Glasbeek, M. J.
Phys. Chem. 1996, 100, 5367.
(19) Transients were found to be independent of the detection wavelength
(520, 570, and 620 nm).

Growth of Chiral Structures in Protic Media
J. Am. Chem. Soc., Vol. 122, No. 26, 2000 6179
Figure 7. Top: fraction of aggregated molecules (circles) and
molecularly dissolved molecules (squares) in a 10-6 M n-butanol
solution at different temperatures. Bottom: lifetimes of the two species,
aggregated (circles) and single molecules (squares), as a function of
temperature in the same solution.
Figure 8. Temperature-dependent CD spectra of 2 in n-butanol (10-5
M).
Figure 7 displays the ratios of compounds being molecularly
dissolved and self-assembled at different temperatures. The data
reveal that at 80 °C all molecules 2 are molecularly dissolved.
Lowering the temperature to 20 °C results in the formation of
small aggregates and below 20 °C almost all molecules
participate in aggregates. The lifetime of the aggregated species
increases rapidly upon lowering the temperature to 20 °C (Figure
7). The increase of the lifetime is due to the formation of
aggregates in which the flexibility of the molecules is decreased.
Circular Dichroism and Differential Scanning Calorim-
etry Studies. Circular dichroism (CD) spectroscopy measure-
ments were performed in order to investigate the expression of
chirality and thus the order in the self-assemblies of 2 in dilute
solution. Since 2 is molecularly dissolved in chloroform
solutions, no well-defined order exists and the side chains cannot
interact cooperatively to transfer their chirality to the aromatic
core; hence, no detectable CD effect is observed. In polar
solvents, however, these molecules do aggregate, which allows
intermolecular side-chain interactions to occur. Surprisingly, a
significant Cotton effect in the π-π* transition is observed at
temperatures below 20-30 °C. Apparently the molecules have
a high degree of order within the self-assembly which, together
with the ordered side chains, results in the formation of a chiral
superstructure. To investigate the degree of order during self-
assembly, we studied the CD effect for a solution of 2 in
n-butanol as a function of temperature (Figure 8). Raising the
temperature from -10 to 90 °C in steps of 2 °C with ample
time to equilibrate resulted in a highly cooperative transition at
20 °C, i.e., the same temperature as the low-temperature
Figure 9. Normalized intensities of the CD spectra of 2 in n-butanol
at 337 nm at three different concentrations (10-6, 10-4, and 10-2 M).
1
transition observed with UV-vis and H NMR spectroscopy.
At temperatures below the transition, the chirality within the
self-assembly is constant, but during the transition the self-
assembly totally loses its supramolecular chirality, as concluded
from the rapid disappearance of the Cotton effect at 20 °C. These
results show that in the self-assembly at low temperatures the
molecules are locked in position and nearly all molecules
participate in the self-assembly. Consequently, the side chains
interact in a cooperative fashion and transfer their chirality to
the aromatic core of the disks. At temperatures above this
transition, the molecules have lost their positional order, because
the intermolecular interactions accounting for that are not
operative. The temperature window over which the chirality is
lost is only slightly concentration dependent (Figure 9); over a
concentration range from 10-6 to 10-2 M the transition
Figure 10. DSC thermodiagram of 3 × 10-5 M of 2 in n-butanol.
temperature only changes by 10 °C (around 20 °C at 10-6
M
to 30 °C at 10-2 M), in agreement with the transitions observed
with UV-vis and 1H NMR spectroscopy. The cooperativity of
the transition increases significantly at higher concentrations
as deducible from the increase of the sharpness of the transition
(Figure 9).
The transition around 25 °C could also be detected using an
ultrasensitive differential scanning calorimeter (DSC) (Figure
10). At 10-2 M in n-butanol, a melting endotherm could be
detected with the melting point at 30 °C and a melting enthalpy
of approximately 50 kJ/mol. The transition shifts to lower

6180 J. Am. Chem. Soc., Vol. 122, No. 26, 2000
BrunsVeld et al.
Figure 11. A tentative picture displaying the molecules packed in a chiral column with a pitch of nine molecules (a); the chiral side chains have
been omitted for clarity. Structure b shows the same column, but for the colored molecules one of the outer benzene rings and one of the bipyridine
groups have been left out, enabling a look into the core of the column. Highlighted are the intermolecular hydrogen bonds that are proposed to lock
the molecules in the column. Structure c shows one of the molecules in which parts have been omitted; the arrows indicate the CdO and N-H
involved in hydrogen bonding. Structure d is the aromatic core of 2 without chiral side chains. The three bipyridine wedges are tilted, similar to
the situation in columns a and b.
temperatures upon lowering the concentration (26.5 °C at 5 ×
10-4 M); the energy of the transition remains constant over the
concentration range in which measurements could be performed
(10-2 to 10-4 M). These results show the high cooperativity of
the transition, while the large energy involved reveals that very
strong and specific interactions between the molecules are
present. The large energy of the transition also shows that a
highly significant growth of the aggregates occurs during the
transition, concomitant with the occurrence of the directional
intermolecular interactions.
The UV-vis and CD signal near the transition midpoint
around 20 °C can be modeled as a linear combination of the
signals from the two limiting states (at 10 and 30 °C).
Furthermore, the UV-vis and CD data show coinciding
sigmoidal transition curves. These results together with the
observation of a melting endotherm indicate that the transition
from chiral to achiral self-assembly has a two-state behavior.20
The two limiting states are both present and interconvert. The
second transition at higher temperature seems to be less
cooperative and follows isodesmic behavior.9
The Hierarchical Growth. The dynamic behavior of 2 in
n-butanol with two different kinds of self-assemblies sharply
contrasts with that of apolar analogue 1 in hexane and
supramolecular architectures in apolar solvents in general. Upon
heating the hexane solution of 1, optical activity and stacking
are lost simultaneously over a broad temperature range (0-
100 °C). Hence, aggregation and expression of chirality of the
self-assembled stacks of 1 are strongly interrelated. This is due
to the apolar solvent, which does not differentiate between
ordering secondary interactions (like hydrogen bonding) and
the other interactions (like π-π stacking and hydrophobic
interactions) that account for the aggregation. In polar solvents,
however, the solvent is capable of preferentially interfering with
certain secondary interactions. Owing to its polar nature,
n-butanol is capable of destroying the structuring secondary
interactions between the molecules that account for the positional
order in the chiral supramolecular self-assembly. At the low
temperatures where this interference starts to take place (∼20
°C), the solubilizing power of n-butanol is not sufficient to
overcome the hydrophobic π-π interactions between the
aromatic cores. Therefore, the expression of chirality is lost prior
to the loss of aggregation and two unique self-assembled states
exist, one that expresses its chirality in the supramolecular
assembly and one that does not. On the basis of the results
presented here, it is proposed that the former is a rigid-rod
extended stack, while the disordered aggregate is of small
dimensions. Theoretical studies and detailed small-angle neutron
scattering (SANS) measurements will be performed to elucidate
this in a comprehensive way; notwithstanding, a tentative picture
displaying the unique chiral columnar self-assembly is displayed
in Figure 11. Preliminary SANS measurements confirm the
results above and show the presence of rigid columnar archi-
tectures at temperatures below 20 °C.
The hierarchical growth of the self-assembly of 2 contrasts
with the behavior of the R,ω-disubstituted sexithiophenes, which
only show one unique self-assembly that is proposed to melt
upon increasing the temperature.10 This different behavior is
due to the additional intermolecular interactions between
molecules of 2 not present in the R,ω-disubstituted sexithiophene.
The aggregation of the latter is basically the result of only
hydrophobic interactions, whereas 2 has the possibility for extra,
solvent dependent, interactions. A two-step process, however,
was observed for a series of oligo(m-phenylene ethynylene)s.5
Similar to that for 2, two different types of interactions account
for the hierarchical growth, of which one arises earlier than the
other because of differences in sensitivity for hydrophobicity.
The locking of the disks in a fixed chiral conformation is
proposed to be governed by intra- and intermolecular hydrogen
bonding with the consecutive molecules mutually twisted in such
a way that self-assembled, highly regular chiral columnar stacks
are formed. Self-assembly a in Figure 11 shows how these
molecules can pack into chiral columns. The three wedges on
the central core are twisted out of the plane due to steric
hindrance, thus providing a scaffold for the packing of the
molecules. The second helix (b) in Figure 11, in which part of
the outer groups are omitted, shows the possibility for the
formation of intermolecular hydrogen bonds: due to the rotation
of the subsequent molecules and the twist of the wedges (ship
screw packing of the molecules),3 linear intermolecular hydrogen
bonding is possible, thus enabling positional locking of the
molecules. As has been shown previously,3,21 intermolecular
hydrogen bonding between similar C3-symmetrical disks is
(21) (a) Brunsveld L.; Schenning, A. P. H. J.; Broeren, M. A. C.; Janssen,
H. M.; Vekemans, J. A. J. M.; Meijer, E. W. Chem. Lett. 2000, 292. (b)
Yasuda, Y.; Iishu, E.; Inada, H.; Shirota, Y. Chem. Lett. 1996, 575. (c)
Yasuda, Y.; Takebe, Y.; Fukumoto, M.; Inada, H.; Shirota, Y. AdV. Mater.
1996, 8, 740.
(20) Chan, H. S.; Bromberg, S.; Dill, K. A. Philos. Trans. R. Soc. London
B 1995, 348, 61.

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J. Am. Chem. Soc., Vol. 122, No. 26, 2000 6181
luminescence spectrometer. The femtosecond fluorescence upconversion
transients were measured using the setup (time resolution: ∼ 150 fs)
described previously.15 Fluorescence transient measurements with
picosecond time resolution were conducted using time-correlated single-
photon-counting detection.18 The syntheses of 2,2′-bipyridine-3,3′-
diamine (5),22 (2S)-ethyl-2-(tetrahydropyran-2-yloxy)propionate (10),23
(2S)-2-(tetrahydropyran-2-yloxy)propan-1-ol (11),23 and compounds
18a-c24 have been described previously.
highly cooperative and directional and locks the subsequent
molecules on top of each other. The creation of a hydrophobic
microenvironment by the π-π stacking of the aromatic cores
allows for operation of these secondary interactions in polar
media, similar to the way the hydrophobic microenvironment
in proteins, which is created by a hydrophobic collapse, allows
for the expression of hydrogen bonds.7 The molecularly dis-
solved molecules first aggregate into small self-assembled
species via hydrophobic interactions. When such self-assemblies
are formed, the polar solvent cannot penetrate into the core any
longer, resulting in a hydrophobic microenvironment around the
inner molecules. With the occurrence of the microenvironment,
the native state of the helical structure can be created via the
intermolecular hydrogen bonds.
N,N′,N′′-Tris{3[3′-(3,4,5-tris{(2S)-2-(2-{2-[2-(2-methoxyethoxy)-
ethoxy]ethoxy}ethoxy)propyloxy})benzoylamino]-2,2′-bipyridyl}-
benzene-1,3,5-tricarbonamide (2). To an ice-cooled solution of 4 (1.00
g, 0.92 mmol) and triethylamine (0.14 mL, 1.0 mmol) in dry methylene
chloride (10 mL) was added a solution of trimesic chloride (3) (79
mg, 0.30 mmol) in dry methylene chloride (5 mL) dropwise at room
temperature. The resulting mixture was stirred at room temperature
overnight, and the solvents were evaporated in vacuo. The crude product
was purified by column chromatography (silica; 5% methanol in
methylene chloride) and preparative size exclusion chromatography
(methylene chloride) to give 2 as an off-white wax (0.87 g, 0.247 mmol,
Conclusions
In conclusion, we have demonstrated the creation of well-
defined chiral self-assembled structures in protic media invoking
a variety of secondary interactions. These interactions occur in
a hierarchical fashion, thus giving rise to a stepwise growth of
the discotic molecules into chiral columns via intermediates
lacking supramolecular chirality. The created hydrophobic
microdomain in the achiral aggregates allows the expression
of the more sensitive polar interactions. The reversible chiral
assemblage and its importance for the hierarchical growth
resemble the folding and assembly of proteins and polynucleo-
tides and together with the differences observed for superstruc-
ture formation between apolar and polar media gives valuable
information for a better understanding of supramolecular
architecture formation in protic media.
1
82%): Tcl ) 270 °C; H NMR (CDCl3) δ ) 15.52 (s, 3H), 14.42 (s,
3H), 9.60 (dd, J ) 8.5 and 1.2 Hz, 3H), 9.40 (dd, J ) 8.5 and 1.4 Hz,
3H), 9.30 (s, 3H), 9.07 (dd, J ) 4.6 and 1.4 Hz, 3H), 8.53 (dd, J ) 4.4
and 1.3 Hz, 3H), 7.58 (m, 6H), 7.32 (s, 6H), 4.18-4.15 (m, 9H), 4.05-
3.90 (m, 18H), 3.90-3.72 (m, 27H), 3.71-3.60 (m, 99H), 3.59-3.52
(m, 18H), 3.37 (m, 27H), 1.33 (m, 27H); 13C NMR (CDCl3) δ ) 165.8,
164.0, 152.6, 142.2, 141.6, 141.5, 140.6, 137.4, 137.3, 136.0, 130.4,
130.0, 129.8, 129.5, 124.6, 124.2, 107.5, 76.3, 75.0, 74.3, 73.1, 71.8,
70.8, 70.7, 70.5 (3×), 70.4 (2×), 68.8, 68.5, 89.9, 17.5; MALDI-TOF
[M + Na+] ) calcd 3428.7 Da, obsd 3428.1 Da.
3′-{3,4,5-Tris[(2S)-2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-
ethoxy)propy1oxy]benzoylamino}-2,2′-bipyridine-3-amine (4). To a
solution of 8 (2.6 g, 2.8 mmol) and two drops of dry dimethylformamide
in dry methylene chloride (10 mL) was added a solution of oxalyl
chloride (0.39 g, 3.1 mmol) in methylene chloride (5 mL) dropwise.
The mixture was stirred overnight at room temperature in the absence
of light, and subsequently the solvent was removed by evaporation in
vacuo and the compound (7) was dried under vacuum (1 mbar) for 2
h. The product was dissolved in dry methylene chloride (20 mL) and
added dropwise via a syringe to an ice-cooled, magnetically stirred
solution of 2,2′-bipyridine-3,3′-diamine (5) (0.521 g, 2.8 mmol) and
triethylamine (0.38 mL, 2.8 mmol) in dry methylene chloride (25 mL).
Stirring was continued for another 2 h at 0 °C and subsequently
overnight at room temperature. The solution was diluted with methylene
chloride, washed with water (2×) and brine (1×), and dried over sodium
sulfate, and the solvents were evaporated in vacuo. The crude product
was purified by column chromatography (silica; 5% methanol in
methylene chloride) and preparative size exclusion chromatography
(methylene chloride) to yield the title compound as a yellow oil (2.2
g, 2.03 mmol, 78%). The product was thoroughly dried in vacuo over
P2O5: 1H NMR (CDCl3) δ ) 14.40 (s, 1H), 9.21 (dd, J ) 8.5 and 1.7
Hz, 1H), 8.33 (dd, J ) 4.6 and 1.5 Hz, 1H), 8.03 (dd, J ) 3.9 and 1.8
Hz, 1H), 7.33 (m, 3H), 7.15 (m, 2H), 6.57 (s, 2H), 4.12-4.05 (m, 3H),
3.98-3.53 (m, 54H), 3.38 (s, 3H), 3.37 (s, 6H), 1.32 (m, 9H); 13C
NMR (CDCl3) δ ) 165.7, 152.4, 145.1, 143.6, 141.2, 140.8, 138.4,
135.9, 134.8, 130.7, 128.5, 125.2, 124.2, 122.7, 106.7, 76.3, 75.0, 74.3,
72.9, 71.8, 70.7, 70.4, 70.3, 68.8, 68.5, 58.9, 17.4.
Experimental Section
General. All starting materials were obtained from commercial
suppliers and used as received. All moisture-sensitive reactions were
performed under an atmosphere of dry argon. Dry and ethanol-free
dichloromethane were obtained by distillation from P2O5, dry tetra-
hydrofuran was obtained by distillation from Na/K/benzophenone,
dimethylformamide was dried over BaO, and triethylamine was dried
over potassium hydroxide. Analytical thin-layer chromatography was
performed on Kieselgel F-254 precoated silica plates. Visualization was
accomplished with UV light. Column chromatography was carried out
on Merck silica gel 60 (70-230 mesh) or on Merck aluminum oxide
90 (70-230 mesh, activity II-III). Preparative size exclusion chro-
matography was performed on BIO RAD Bio Beads S-X1 swollen in
methylene chloride. 1H NMR and 13C NMR spectra were recorded on
a 400 MHz 4-nucleus NMR (Varian Mercury Vx) (400.13 MHz for
1H NMR and 100.62 MHz for 13C NMR). Proton chemical shifts are
reported in ppm downfield from tetramethylsilane (TMS) and carbon
chemical shifts in ppm downfield of TMS using the resonance of the
deuterated solvent as internal standard. Matrix-assisted laser desorption/
ionization mass spectra were obtained using indole acrylic acid as the
matrix on a PerSeptive Biosystems Voyager-DE PRO spectrometer.
IR spectra were measured on a Perkin-Elmer 1600 FT-IR. Optical
properties and melting points were determined using a Jeneval
polarization microscope equipped with a Linkam THMS 600 heating
device with crossed polarizers. DSC spectra were obtained on a Perkin-
Elmer Pyris 1 DSC. Ultrasensitive differential scanning microcalorim-
eter measurements were recorded on a VP-DSC from Heath Scientific.
X-ray diffraction patterns were recorded using a multiwire area detector
X-1000 coupled with a graphite monochromator. GPC measurements
were carried out using a column with PL gel and chloroform as eluent
and a flow rate of 1 mL min-1; detection was carried out on a UV
detector at a wavelength of 254 nm. GC-MS measurements were
performed on a Shimadzu GCMS QP5000. UV-vis spectra were
recorded on a Perkin-Elmer Lambda 900 UV/vis/NIR spectrometer.
CD spectra were recorded on a Jasco J-600 spectropolarimeter.
Fluorescence emission spectra were recorded on a Perkin-Elmer LS50B
3,4,5-Tris[(2S)-2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}ethoxy)-
propyloxy]benzoic Acid (8). A solution of 9 (2.80 g, 3.0 mmol) and
KOH (85%) (0.53 g, 9.0 mmol) in ethanol (20 mL) and water (20 mL)
was heated under reflux overnight. Subsequently, the solution was
acidified to pH ) 2 with concentrated hydrochloric acid under reflux
and then the solution was poured onto an water/ice mixture. The
aqueous layer was extracted with methylene chloride (2×). The
(22) Kaczmarek, L.; Nantka-Namirski, P. Acta Polon. Pharm. 1979, 6,
629.
(23) (a) Perkins, M. V.; Kitching, W.; Ko¨nig, W. A.; Drew, R. A. I. J.
Chem. Soc., Perkin Trans. 1 1990, 2501. (b) Cowie, J. M. G.; Hunter, H.
W. Makromol. Chem. 1990, 191, 1393. (c) Chiellini, E.; Galli, G.;
Carrozzino, S. Macromolecules 1990, 23, 2106.
(24) Palmans, A. R. A.; Vekemans, J. A. J. M.; Meijer, E. W. Recl.
TraV. Chim. Pays-Bas 1995, 114, 277.

6182 J. Am. Chem. Soc., Vol. 122, No. 26, 2000
BrunsVeld et al.
combined organic layers were washed with brine (pH ) 2) and dried
over magnesium sulfate, and evaporation of the solvent in vacuo
afforded pure 8 as a colorless oil (2.7 g, 2.95 mmol, 98%): 1H NMR
(CDCl3) δ ) 7.33 (s, 2H), 4.12-4.05 (m, 3H), 3.98-3.88 (m, 9H),
3.86-3.53 (m, 45H), 3.38 (s, 3H), 3.37 (s, 6H), 1.32 (m, 9H); 13C
NMR (CDCl3) δ ) 168.9, 152.0, 142.3, 124.5, 108.6, 76.0, 74.9, 74.2,
72.5, 71.7, 70.7, 70.6, 70.4, 70.3, 70.2, 68.7, 68.4, 58.8, 17.3.
Methyl 3,4,5-Tris[(2S)-2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-
ethoxy)propyloxy]benzoate (9). A mixture of 17 (5.60 g, 13.3 mmol),
methyl 3,4,5-trihydroxybenzoate (0.73 g, 4.0 mmol), and K2CO3 (5.5
g, 40 mmol) in dimethylformamide (40 mL) was stirred overnight at
70 °C. After cooling, the mixture was poured into water (200 mL, pH
) 2) and extracted with methylene chloride. The organic layer was
washed with water (3×) and brine (1×) and dried over magnesium
sulfate, and the solvent was evaporated in vacuo. The crude product
was purified by column chromatography (alumina; 1% ethanol in
methylene chloride) to yield the pure compound as a viscous colorless
oil (2.9 g, 3.1 mmol, 78%): 1H NMR (CDCl3) δ ) 7.30 (s, 2H), 4.12-
4.05 (m, 3H), 3.98-3.85 (m, 6H), 3.89 (s, 3H), 3.84-3.50 (m, 48H),
3.37 (s, 3H), 3.36 (s, 6H), 1.32 (m, 9H); 13C NMR (CDCl3) δ ) 166.6,
152.2, 142.0, 124.9, 108.2, 76.3, 75.0, 74.3, 72.6, 71.9, 70.8, 70.5, 70.4,
68.8, 68.5, 59.0, 52.2, 17.5.
(2S)-1-Benzyloxy-2-(tetrahydropyran-2-yl-oxy)propane (12). A
solution of t-BuOK (78.5 g, 0.70 mol) in tert-butyl alcohol (570 g)
was added dropwise to 11. The solution was stirred for 2 h,
concentrated, and subsequently diluted with dioxane (400 mL). A
catalytic amount of tetrabutylammonium chloride (2 g) was added after
which benzyl chloride (88.6 g, 0.70 mol) was added dropwise at room
temperature. The mixture was heated at 80 °C overnight. After reaction,
water was added, and the mixture was extracted with diethyl ether (3×).
The organic layers were combined and back-washed with water and
brine, subsequently dried over magnesium sulfate, and concentrated in
vacuo, leaving a yellow oil. Distillation (118 °C, 5 × 10-2 mbar) gave
the pure title compound as a colorless oil (99.3 g, 0.40 mol, 64%): 1H
NMR (400 MHz, CDCl3) δ ) 7.40-7.20 (m, 5H), 4.78 (dt, 1H), 4.56
(d, 2H), 4.07-3.90 (m, 2H), 3.62-3.42 (m, 3H), 1.90-1.80 (m, 1H),
1.80-1.68 (m, 1H), 1.65-1.50 (m, 4H), 1.27-1.15 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ ) 138.5, 138.4, 128.3, 128.2, 127.5, 127.4, 127.4,
98.8, 96.1, 74.3, 74.2, 73.2, 73.1, 71.9, 70.4, 62.7, 62.2, 31.0, 31.0,
25.5, 19.9, 19.5, 18.6, 16.6.
extracted with methylene chloride (3 × 100 mL), and the combined
organic layers were washed with water (pH ) 1) (2×) and with brine
(1×). After drying over magnesium sulfate, the solvent was evaporated
in vacuo to yield the pure compound as a colorless oil (60.7 g, 0.167
mol, 97%): 1H NMR (400 MHz, CDCl3) δ ) 7.79 (d, 2H), 7.35 (d,
2H), 4.15 (t, 2H), 3.68 (t, 2H), 3.67-3.58 (m, 10H), 3.54 (t, 2H), 3.36
(s, 3H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ ) 144.6, 132.7,
129.5, 128.0, 71.8, 70.6 (2×), 70.4 (2×), 70.3, 69.1, 68.5, 58.8, 21.4.
(2S)-1-Benzyloxy-2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-
ethoxy)propane (15). A solution of 13 (19.9 g, 0.120 mol) 14 (50.0 g,
0.138 mol) and KOH (26.6 g, 0.404 mol) in tetrahydrofuran (350 mL)
was stirred under reflux for 12 h under an argon atmosphere.
Subsequently water (50 mL) was added to hydrolyze the excess of 14
to the corresponding alcohol. Water/diethyl ether extraction, drying of
the collected organic layers with magnesium sulfate, and evaporation
of the solvent gave the crude yellow product. Kugelrohr distillation
(225 °C, 5 × 10-2 mbar) gave the pure title compound as a colorless
oil (37.6 g, 0.105 mol, 88%): 1H NMR (400 MHz, CDCl3) δ ) 7.35-
7.22 (m, 5H), 4.53 (d, 2H), 3.71-3.37 (m, 19H), 3.35 (s, 3H), 1.15 (d,
3H); 13C NMR (100 MHz, CDCl3) δ ) 138.3, 128.3, 127.5, 127.4,
75.0, 74.0, 73.2, 71.8, 70.8, 70.5 (3×), 70.4, 68.5, 59.0, 17.2.
(2S)-2-(2-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}ethoxy)propan-
1-ol (16). The benzyl-protected precursor 15 (37.0 g, 0.104 mol) was
dissolved in ethanol (96%) (100 mL) and acidified with hydrochloric
acid (0.1 mL, 37%). A catalytic amount of Pd/C (10%) was added to
the solution, and hydrogenation at 50 psi H2-overpressure was carried
out during 4 h. Filtration, evaporation of the solvents, and Kugelrohr
distillation (175 °C, 5 × 10-2 mbar) gave the pure title compound as
a colorless oil (26.4 g, 0.099 mol, 95%): 1H NMR (400 MHz, CDCl3)
δ ) 3.85-3.78 (m, 1H), 3.69-3.43 (m, 18H), 3.36 (s, 3H), 2.99 (bs,
1H) 1.12 (d, 3H); 13C NMR (100 MHz, CDCl3) δ ) 76.7, 71.8, 70.7,
70.5 (3×), 70.4, 68.0, 66.2, 58.9, 16.2. [R]20 (c ) 0.88; chloroform)
D
) +13.3°.
(2S)-2-(2-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}ethoxy)propane-
1-p-tosylate (17). NaOH (0.92 g, 0.023 mol) and 16 (4.0 g, 0.015 mol),
in a two-phase system of water (4 mL) and tetrahydrofuran (4 mL),
was cooled via an ice bath with magnetic stirring. p-Toluenesulfonyl
chloride (3.3 g, 0.017 mol) in tetrahydrofuran (4 mL) was added
dropwise to the mixture, while maintaining the temperature below 5
°C. The solution was stirred at 0 °C for another 3 h and then poured
into ice-water (25 mL). The mixture was extracted with methylene
chloride (3 × 25 mL), and the combined organic layers were washed
with water (pH ) 1) (2×) and with brine (1×). After drying over
magnesium sulfate, the solvent was evaporated in vacuo to yield the
pure compound as a colorless oil (5.7 g, 0. 013 mol, 89%): 1H NMR
(400 MHz, CDCl3) δ ) 7.81 (d, 2H), 7.36 (d, 2H), 4.00-3.88 (m,
(2S)-1-Benzyloxypropan-2-ol (13). To an ice-cooled solution of 12
(98 g, 0.39 mol) in methanol (500 mL) was added p-TsOH‚H2O (3 g,
18 mmol). The solution was subsequently stirred at room temperature
overnight. NaHCO3 was added to quench the reaction. The methanol
was evaporated, and additional coevaporation with methanol was
performed to make sure that all dihydropyran (DHP) was also removed.
Water/diethyl ether extraction, drying of the collected organic layers
with magnesium sulfate, and evaporation of the solvent gave the crude
yellow product. Distillation (91 °C, 8 × 10-1 mbar) gave the pure title
compound as a colorless oil (56.0 g, 0.34 mol, 86%): 1H NMR (400
MHz, CDCl3) δ ) 7.37-7.24 (m, 5H), 4.54 (s, 2H), 4.00-3.95 (m,
1H), 3.46-3.25 (m, 2H), 1.13 (d, 3H); 13C NMR (100 MHz, CDCl3)
δ ) 137.9, 128.4, 127.7 (2×), 75.8, 73.2, 66.4, 18.6.
2H), 3.70-3.50 (m, 17H), 3.36 (s, 3H), 2.45 (s, 3H), 1.14 (d, 3H); 13
C
NMR (100 MHz, CDCl3) δ ) 144.5, 132.7, 129.6, 127.7, 73.4, 72.5,
71.8, 70.6, 70.5 (2×), 70.4 (3×), 68.8, 58.9, 21.6, 16.7.
Acknowledgment. The National Research School Combina-
tion: Catalysis is thanked for funding. We thank Joost van
Dongen for MALDI-TOF/MS measurements. Koen Pieterse is
kindly acknowledged for creation of Figure 11.
2-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}ethyl p-Tosylate (14).
NaOH (9.9 g, 0.25 mol) and 2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-
ethanol (36.0 g, 0.173 mol), in a two-phase system of water (50 mL)
and THF (400 mL), was cooled via an ice bath with magnetic stirring.
p-Toluenesulfonyl chloride (36.2 g, 0.190 mol) in tetrahydrofuran (50
mL) was added dropwise to the mixture, while maintaining the
temperature below 5 °C. The solution was stirred at 0 °C for another
3 h and then poured into ice-water (100 mL). The mixture was
Supporting Information Available: 1H and 13C NMR of
compounds 2, 4, 7-9, and 15-17. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA0005237