Dendritic molecular switch: Chiral folding and helicity inversion

Article abstract of DOI:10.1021/ja806723e

Appropriately designed chemical architectures can fold to adopt well-defined secondary structures without the need for structural motifs of biological origin. We have designed tris(N-salicylideneaniline)-based hyperbranched molecules that spontaneously collapse to compact three-blade propeller geometry of either (P)- or (M)-handedness. For a homologous series of compounds, a direct correlation was established between the absolute screw sense, either (P)- or (M)-, of this helical folding and the absolute configuration, either (R)- or (S)-, of the chiral alcohol groups introducing local asymmetric bias to the conformationally restricted molecular backbone. ¹H NMR and CD spectroscopic studies provided significant insights into structural folding and unfolding of these chiral molecules in solution, which proceed via reversible assembly and disassembly of the C ₃-symmetric hydrogen-bonding network. Notably, solvents profoundly influenced this dynamic process. A strong correlation between the solvent donor number (DN) or solvent basicity (SB) parameters and the change in the Cotton effects pointed toward specific O-H...solvent interactions that drive structural unfolding and eventual refolding to apparently opposite helicity. This unusual chirality inversion process could also be induced by installation of chemical protecting groups that simulate specific solvent-solute interactions. Removal of this covalent mimic of the solvent shell restored the original screw sense of the parent molecule, thus establishing the feasibility of covalently triggered helicity inversion as a new mode of operation for chiroptical molecular switches.

Full text of DOI:10.1021/ja806723e

Published on Web 11/11/2008
Dendritic Molecular Switch: Chiral Folding and Helicity
Inversion
Xuan Jiang, Young-Kwan Lim, Bong June Zhang, Elizabeth A. Opsitnick,
Mu-Hyun Baik, and Dongwhan Lee*
Department of Chemistry, Indiana UniVersity, 800 East Kirkwood AVenue,
Bloomington, Indiana 47405
Received August 25, 2008; E-mail: dongwhan@indiana.edu
Abstract: Appropriately designed chemical architectures can fold to adopt well-defined secondary structures
without the need for structural motifs of biological origin. We have designed tris(N-salicylideneaniline)-
based hyperbranched molecules that spontaneously collapse to compact three-blade propeller geometry
of either (P)- or (M)-handedness. For a homologous series of compounds, a direct correlation was
established between the absolute screw sense, either (P)- or (M)-, of this helical folding and the absolute
configuration, either (R)- or (S)-, of the chiral alcohol groups introducing local asymmetric bias to the
conformationally restricted molecular backbone. 1H NMR and CD spectroscopic studies provided significant
insights into structural folding and unfolding of these chiral molecules in solution, which proceed via reversible
assembly and disassembly of the C3-symmetric hydrogen-bonding network. Notably, solvents profoundly
influenced this dynamic process. A strong correlation between the solvent donor number (DN) or solvent
basicity (SB) parameters and the change in the Cotton effects pointed toward specific O-H · · · solvent
interactions that drive structural unfolding and eventual refolding to apparently opposite helicity. This unusual
chirality inversion process could also be induced by installation of chemical protecting groups that simulate
specific solvent-solute interactions. Removal of this covalent mimic of the solvent shell restored the original
screw sense of the parent molecule, thus establishing the feasibility of covalently triggered helicity inversion
as a new mode of operation for chiroptical molecular switches.
Introduction
handed (P)- or left-handed (M)-isomer of a three-bladed
propeller geometry (Scheme 1).6-8 Introduction of appropriate
Controlling the conformational bias of inherently flexible
chemical structures is a formidable challenge. Spontaneous
folding of biological macromolecules, however, proceeds with
an extraordinary degree of control over the spiral arrangement
of their linear sequences, as exemplified by the well-defined
secondary structures of R-helical polypeptides or polynucle-
otides.1 Exactly how the weak noncovalent interactions among
local carbon-centered chirality collectively translate to global
helicity of preferred handedness still remains to be elucidated.
During past decades, this important question of cooperativity2
has stimulated the design, synthesis, and application of helically
folding molecular and supramolecular structures.3,4
As was demonstrated by others, a delicate interplay of
noncovalent interactions promotes well-defined conformations
of linear foldamers.5 This conceptual framework should readily
be extended to dendritic structures, in which the making and
breaking of symmetrically positioned weak bonds can drive
addressable conformational switching.
chiral auxiliaries as part of R, however, can potentially bias
this dynamic process to increase the population of one helix-
sense over the other (Scheme 1).
(5) (a) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173–180. (b) Hill, D. J.;
Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. ReV.
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DeGrado, W. F. Chem. ReV. 2001, 101, 3219–3232. (e) Gong, B.
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Int. Ed. 2003, 42, 2448–2452. (g) Huc, I. Eur. J. Org. Chem. 2004,
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C. Angew. Chem., Int. Ed. 2006, 45, 4721–4723. (c) Gibson, S. E.;
Castaldi, M. P. Angew. Chem., Int. Ed. 2006, 45, 4718–4720.
(8) For conceptually related trinuclear coordination complexes undergoing
interconversion between the (P)- and (M)-isomers through concerted
tilting motions of bulky ligands or intramolecular ligand exchange,
see:(a) Ikeda, A.; Udzu, H.; Zhong, Z.; Shinkai, S.; Sakamoto, S.;
Yamaguchi, K. J. Am. Chem. Soc. 2001, 123, 3872–3877. (b) Hiraoka,
S.; Harano, K.; Tanaka, T.; Shiro, M.; Shionoya, M. Angew. Chem.,
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M.; Shionoya, M. J. Am. Chem. Soc. 2004, 126, 1214–1218.
Unidirectional tilting of three bulky aryl groups around a C3-
symmetric core can furnish with equal probability either a right-
(1) van Holde, K. E.; Johnson, W. C.; Ho, P. S. Principles of Physical
Biochemistry; 2nd ed.; Pearson Prentice Hall: Upper Saddle River,
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9
16812 J. AM. CHEM. SOC. 2008, 130, 16812–16822
10.1021/ja806723e CCC: $40.75
2008 American Chemical Society

Chiral Folding and Helicity Inversion
A R T I C L E S
Scheme 1. Unidirectional Tilting of Three Bulky Aryl Groups
Furnishes C3-Symmetric Structures of Either (P)- or (M)-Helicitya
and disruption of which might provide a means to control the
global helicity of the molecule.
In this paper, we describe the design of a homologous series
of tris(N-salicylideneamine)-based chiral dendritic molecules,
solution dynamics of their structural folding and unfolding, and
a highly unusual interconversion between conformations of
apparently opposite helicity. Notably, this new chiral switch14
can be operated either by interaction with solvent molecules or
by manipulation of scissile capping groups.
Results and Discussion
Design Principles for Chiral Induction. Crystallographically
characterized compound 1 (Figure 1)11d served as a useful design
template in our exploratory studies to develop chiral induction
models. In the solid state, 1 exists as a 1:1 mixture of right-
handed (P)- and left-handed (M)-conformers, in which a cyclic
array of three Ohydroxy-H· · ·Ohydroxy-H· · ·Oketo hydrogen bonds
assists unidirectional tilting of three bulky aryls propagating
from the C3-symmetric tris(N-salicylideneamine) core. We noted
that the methyl substituents on the six tertiary alcohol groups
of 1 are brought into distinctively different steric environments
upon structural folding, with three CH3 groups (in dotted circles)
pointing toward and the other three (in solid circles) pointing
away from the molecular core (Figure 1). As such, structural
modification at these positions to introduce chiral alcohol groups
was expected to induce sufficient steric bias to energetically
differentiate the diastereomeric (P)- and (M)-helixes.
a With achiral R groups (top), there is no bias toward either enantiomeric
conformer. Intimate contact between chiral R* groups (bottom), however,
can induce preferential structural folding to one diastereomer over the other.
(M)-helix is arbitrarily chosen for the schematic diagram shown at the
bottom.
We have recently shown that a three-fold symmetric branched
platform represented by tris(N-salicylideneamine)s9-11 can
readily be functionalized with hydroxy-terminated aryl-
groups.11d-g Multiple O-H· · ·O hydrogen bonds connecting
adjacent “wing-tip” groups of such molecules function as a
conformational lock and enforce overall helical arrangements
of the bulky aryls as shown in Scheme 1.12 We envisioned that
this cooperative folding process3-5,13 could potentially be driven
in asymmetric fashion by strategic placement of chiral groups
at aryl · · ·aryl contacts. In addition, the C3-symmetrically
disposed hydrogen-bonding network in such constructs can
function as a chirality transfer channel, the reversible formation
This intuitive chirality transfer model was evaluated quan-
titatively using density functional theory (DFT) calculations on
the model compound 2, which was constructed by replacing
the six “wing-tip” -C(CH3)2OH groups of
1
with
-C*H(C6H5)OH fragments. The two substituents, i.e., H and
C6H5, on these chiral alcohol groups were intentionally chosen
in order to maximize the steric differentiation and thus the
relative stability of one screw sense over the other. As shown
in Figure 1, the geometry optimized DFT model (S,S)3-2, having
(S)-chiral alcohol groups, adopted the (M)-helical structure as
the most stable conformation, in which bulky phenyl groups
pointed away from the sterically congested molecular core to
alleviate steric crowding (Figure 1). On the other hand, the
corresponding (P)-conformer with six phenyl groups pointing
toward the center of the molecule was energetically disfavored
by 12 kcal mol-1. The mirror-image isomer (R,R)3-2 with (R)-
chiral centers adopted the (P)-helical conformation which is
enantiomeric to (M)-(S,S)3-2, thereby establishing a direct
transfer of carbon-centered chiral information to the helical
screw sense of the dendritic molecular backbone.
(9) (a) Chong, J. H.; Sauer, M.; Patrick, B. O.; MacLachlan, M. J. Org.
Lett. 2003, 5, 3823–3826. (b) Sauer, M.; Yeung, C.; Chong, J. H.;
Patrick, B. O.; MacLachlan, M. J. J. Org. Chem. 2006, 71, 775–788.
(10) (a) Yelamaggad, C. V.; Achalkumar, A. S.; Rao, D. S. S.; Prasad,
S. K. J. Am. Chem. Soc. 2004, 126, 6506–6507. (b) Yelamaggad, C. V.;
Achalkumar, A. S.; Rao, D. S. S.; Prasad, S. K. J. Org. Chem. 2007,
72, 8308–8318. (c) Yelamaggad, C. V.; Achalkumar, A. S.; Rao,
D. S. S.; Prasad, S. K. J. Mater. Chem. 2007, 17, 4521–4529.
(11) (a) Riddle, J. A.; Bollinger, J. C.; Lee, D. Angew. Chem., Int. Ed.
2005, 44, 6689–6693. (b) Riddle, J. A.; Lathrop, S. P.; Bollinger, J. C.;
Lee, D. J. Am. Chem. Soc. 2006, 128, 10986–10987. (c) Lim, Y.-K.;
Wallace, S.; Bollinger, J. C.; Chen, X.; Lee, D. Inorg. Chem. 2007,
46, 1694–1703. (d) Jiang, X.; Bollinger, J. C.; Lee, D. J. Am. Chem.
Soc. 2006, 128, 11732–11733. (e) Lim, Y.-K.; Jiang, X.; Bollinger,
J. C.; Lee, D. J. Mater. Chem. 2007, 17, 1969–1980. (f) Jiang, X.;
Vieweger, M. C.; Bollinger, J. C.; Dragnea, B.; Lee, D. Org. Lett.
2007, 9, 3579–3582. (g) Riddle, J. A.; Jiang, X.; Huffman, J.; Lee, D.
Angew. Chem., Int. Ed. 2007, 46, 7019–7022.
Structural folding through hydrogen bonds brings into close
proximity multiple chiral centers that are remote in the
molecule’s branched backbone. Molecular C3-symmetry plays
a pivotal role here by maximizing the number of pairwise
contacts between bulky chiral groups and thereby effectively
amplifying local steric bias. This stereoinduction model was
subsequently tested for a homologous series of compounds with
systematic variations made in the number as well as in the
absolute configuration of the chiral centers.
Synthesis. As proof of principle, an enantiomeric pair of
compounds (R,R)3-3 and (S,S)3-3 were prepared in a high-
yielding (>90%) two-step synthesis using commercially avail-
able chiral alcohols (Scheme 2). As an isolated chiral arm model,
(S,S)-4 was prepared. Efficient cross-coupling protocols facili-
tated access to the chiral anilines 10 and 11, which were
subsequently incorporated into (S)3-5 and (S)3-6. These com-
(12) Opsitnick, E.; Lee, D. Chem. Eur. J. 2007, 13, 7040–7049.
(13) Riddle, J. A.; Jiang, X.; Lee, D. Analyst 2008, 133, 417–422.
(14) (a) Feringa, B. L.; van Delden, R. A.; Koumura, N.; Geertsema, E. M.
Chem. ReV. 2000, 100, 1789–1816. (b) Feringa, B. L.; van Delden,
R. A.; ter Wiel, M. K. J. In Molecular Switches; Feringa, B. L., Ed.;
Wiley-VCH: Weinheim, 2001; pp 123-163. (c) Kay, E. R.; Leigh,
D. A.; Zerbetto, F. Angew. Chem., Int. Ed. 2007, 46, 72–191.
(15) (a) Gilli, P.; Bertolasi, V.; Ferretti, V.; Gilli, G. J. Am. Chem. Soc.
2000, 122, 10405–10417. (b) Chin, J.; Kim, D. C.; Kim, H.-J.;
Panosyan, F. B.; Kim, K. M. Org. Lett. 2004, 6, 2591–2593. (c)
Sobczyk, L.; Grabowski, S. J.; Krygowski, T. M. Chem. ReV. 2005,
105, 3513–3560.
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A R T I C L E S
Jiang et al.
Figure 1. Capped-stick representation of the X-ray structure of 1 with O-H· · ·O-H· · ·O· · ·H-N hydrogen-bonding network represented as red dotted
lines,11d and space-filling representation of DFT models (S,S)3-2 and (R,R)3-2 constructed by formal asymmetric substitution of the gem-dimethyl groups of
1 (indicated by solid and dotted circles) with H and C6H5. The absolute screw sense, either (P)- or (M)-, of 2 is determined by the orientation of the three
aniline rings that are unidirectionally tilted with respect to the molecular C3-axis. For 1, the (P)- and (M)-helixes are isoenergetic, for which only the
(M)-isomer is shown here. See Scheme 1.
Scheme 2. Synthetic Routes to Chiral Tris(N-salicylideneaniline)s and N-Salicylideneaniline
pounds were specifically designed in order to introduce varia-
tions in the number of hydrogen bonds and the number of chiral
centers relative to (S,S)3-3. The mirror-image isomer (R)3-6 was
also prepared in a straightforward manner.
at the tris(N-salicylideneamine) core assist electronic conjugation
between carbonyl and alkenyl groups and facilitate π-orbital
overlap between the nitrogen lone pair electrons and the
peripheral phenyl rings.
UV-vis and CD Spectroscopy. In CHCl3 at 298 K, (R,R)3-3
and (S,S)3-3 displayed essentially identical UV-vis but dis-
played mirror-image CD spectra showing Cotton effects with
opposite signs (Figure 2). Time-dependent (TD) DFT studies
established that the longer-wavelength electronic transitions at
λmax ≈ 430 nm of (R,R)3- and (S,S)3-3 originate from molecular
orbitals that are associated with peripheral aryl groups conju-
gated to the tris(N-salicylideneamine) molecular core. As shown
by the frontier orbitals involved in the strong excitation of
(S,S)3-2 at λmax,calc ) 428 nm (Figure 3 and Figure S1
[Supporting Information]), resonance-assisted hydrogen bonds15
Quantitative predictions with TD-DFT further validated the
assignment of absolute screw sense shown in Figure 1. Using
the DFT model (S,S)3-2 (Figure 1), rotational strengths of the
60 lowest-energy electronic excitations were calculated and used
to simulate the CD spectrum. As shown in Figure 4, the CD
spectra of the (M)-helical conformer thus constructed using
either BP86/TZP or LB94/TZP DFT functionals consistently
predicted positive Cotton effects at >300 nm with intensity
patterns similar to those experimentally observed for (S,S)3-3
(Figure 2).
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Chiral Folding and Helicity Inversion
A R T I C L E S
Figure 4. CD spectrum of (S,S)3-2 calculated using DFT functionals (a)
BP86/TZP or (b) LB94/TZP. Vertical lines indicate rotatory strengths. The
spectrum was constructed using the Gaussian convolution and scaled by
empirically adjusting the linewidths.
Figure 2. (a) UV-vis and (b) CD spectra of (S,S)3-3 (solid line) and
(R,R)3-3 (dashed line) measured in CHCl3 at 298 K.
Figure 3. Isosurface plots (isodensity value ) 0.035 au) of HOMO,
Figure 5. CD spectra of chiral tris(N-salicylideneaniline)s and N-
salicylideneaniline measured in CHCl3 at 298 K.
HOMO-1, and LUMO+2 involved in the strong excitation at λmax,calc
428 nm of (S,S)3-2.
)
1D and 2D 1H NMR Studies: Hydrogen-Bonding Assisted
Structural Folding. In CDCl3 at 298 K, compounds (S,S)3-3,
(S)3-5, and (S)3-6 showed coupled (J ) 13.2 Hz) N-H and C-H
doublets at 14.01-13.34 and 9.64-8.78 ppm, respectively.
These features are in agreement with the keto-enamine, rather
than enol-imine, tautomer description of the tris(N-salicylide-
neamine) core.9a Notably, the simple spectral patterns with only
one set of Nenamine-H and Cvinyl-H proton resonances indicated
exclusive formation of only one isomer of C3-symmetry.11 The
significantly downfield-shifted OH proton resonances (5.24-6.25
ppm) of these compounds relative to that (3.05 ppm) of (S,S)-4
indicated hydrogen-bonding interactions involving wing-tip
alcohol groups,11d,e,g which prompted a further investigation of
solution structures.
As indicated by the frontier molecular orbital (FMO) plots
shown in Figure 3, a significant delocalization of electron
densities over the helically twisted molecular backbone is
responsible for the strong (∆ε ) 650-700 M-1 cm-1) positive
CD band observed for (S,S)3-2 at λ ≈ 430 nm. In support of
this notion, the CD spectrum of the isolated chiral arm model
(S,S)-4 (Scheme 2) showed only weak (∆ε < 300 M-1 cm-1
)
signal at λ < 285 nm with no features found in the longer
wavelength region (Figure 5).
As shown in Figure 5, a homologous series of compounds
(S,S)3-3, (S)3-5, and (S)3-6, all built with identical chiral alcohol
fragments, consistently showed positive Cotton effects in the
longer wavelength, thereby establishing a direct correlation
between the handedness of helical folding and the absolute
configuration of carbon-centered chirality. This trend is main-
tained regardless of the number of chiral centers such as (S,S)3-3
vs (S)3-5 and (S)3-6, or the number of alcohol groups such as
(S)3-5 vs (S)3-6.
The 2D-ROESY 1H NMR spectrum of (S)3-5 in CDCl3
(Figure 6a) revealed multiple cross-peaks associated with the
ethynyl-extended alcohol groups and the enamine skeleton at
the molecular core which are brought in close proximity through
structural folding. A strong ROE correlation between the two
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A R T I C L E S
Jiang et al.
1
Figure 7. (a) H NMR spectra (400 MHz) of (S,S)3-3 in CDCl3 showing
shifts of OH proton resonances as a function of temperature from -25 to
+55 °C. (b) Plots of δobs vs 1/T. Measured data points are denoted by square
markers for (S,S)3-3 and triangular markers for (S)3-6. Fits to the data by
the model are delineated by red (in toluene-d8) and blue (in CDCl3) curves.
See text for the thermodynamic parameters, ∆H and ∆S, derived from
nonlinear curve fitting.
Scheme 3. Binary Switching between the Folded (A) and Unfolded
(B) Conformer through the Assembly (r) and Disassembly (f) of
the Hydrogen-Bonding Network
Figure 6. (a) 2D ROESY spectrum of (S)3-5 in CDCl3 solution at T )
298 K. (b) Capped-stick representation of the DFT geometry optimized
model of (S)3-5 showing protons contributing to ROE and TOCSY-relayed
ROE cross peaks. Red dotted lines indicate hydrogen bonds. The tert-butyl
groups on the aniline rings have been omitted for clarity. A close-up view
of the chemical structure is shown next.
switching model shown in Scheme 3, this observable can be
deconvoluted into contributions from the folded A (δA) and
unfolded B (δB) conformers which exist in mole fractions of x
and 1 - x, respectively. A systematic downfield shift of δobs
with decreasing temperature (Figure 7) indicated an equilibrium
shift toward A with hydrogen-bonding-induced deshielding of
the O-H protons. In addition, the slower exchange kinetics at
lower temperature apparently led to significant line broadening.
These VT 1H NMR data were subsequently analyzed using eq
1 in order to derive the ∆H and ∆S parameters dictating the
thermodynamics of structural folding and unfolding.
alcohol OH protons was indeed in agreement with the relatively
short O · · ·O interatomic distance of ∼2.37 Å determined from
the DFT geometry optimized model (Figure 6b). In addition,
the OH-OH cross peaks have an opposite phase with respect
to those of CH-OH and NH-OH, which is consistent with
chemical exchange through O-H· · ·O-H contacts that are
maintained in solution.16 Collectively, these findings provided
compelling evidence that helical folding through the formation
of a cyclic hydrogen-bonding network, previously seen in crystal
structures,11e,f is an intrinsic propensity of the molecule, not an
artifact of solid-state packing interactions.
Energetics of Structural Folding and Unfolding: Temperature-
Dependent Studies. A reversible assembly and disassembly of
the hydrogen-bonding network can drive structural folding and
unfolding. The cooperative nature2,17 of this process could be
approximated by a simple two-state model (Scheme 3). The “all-
or-nothing” behavior of the molecule in this idealized situation
approaches a genuine switch,11g,13,18 which can be operated by
change in the temperature.
+ 1 -1 + δB
(1)
∆H
1
∆S
-
+
{
R (T)
}
[
]
δobs ) (δA - δB) exp
R
Initial fitting of the data obtained for (S,S)3-3 in CDCl3 within
the temperature range 248-328 K provided δB ) 2.28 ppm as
the OH proton resonance of the unfolded conformer B. This
value was close to the OH proton resonance at 2.35 ppm
experimentally determined for the free amine compound 8 (T
) 298 K), and thus supported the validity of our simplified two-
state model (Scheme 3). A nonlinear regression of the δobs vs
1/T data (Figure 7b) with δB fixed at 2.35 ppm furnished δA )
6.94 ( 0.02 ppm, ∆H ) 2.2 ( 0.1 kcal mol-1, and ∆S ) 4.2
( 0.1 cal mol-1 K-1. Comparable thermodynamic parameters
were obtained for (S,S)3-3 in toluene-d8 with ∆H ) 3.0 ( 0.1
kcal mol-1 and ∆S ) 6.4 ( 0.3 cal mol-1 K-1, and for (S)3-6
in CDCl3 with ∆H ) 2.0 ( 0.1 kcal mol-1 and ∆S ) 4.2 (
0.2 cal mol-1 K-1 (Figure 7), all consistently pointing toward
the endothermic nature of structural unfolding with positive
change in entropy.
The single OH proton resonance experimentally observed in
the 1H NMR spectrum of (S,S)3-3 indicated a fast exchange in
solution to provide a population averaged δobs value. With the
(16) Neuhaus, D.; Williamson, M. P. The Nuclear OVerhauser Effect in
Structural and Conformational Analysis, 2nd ed.; Wiley-VCH: New
York, 2000.
(17) Whitty, A. Nat. Chem. Biol. 2008, 4, 435–439.
(18) Shinkai, S.; Ikeda, M.; Sugasaki, A.; Takeuchi, M. Acc. Chem. Res.
2001, 34, 494–503.
Solvent-Induced Helicity Inversion. Solvent-solute interac-
tions profoundly affect the stability of conformationally flexible
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Chiral Folding and Helicity Inversion
A R T I C L E S
Figure 9. Solvent-dependent changes in the CD spectrum of (S)3-6
measured in benzene, toluene, nitrobenzene, dichloromethane, chloroform,
1,4-dioxane, ethyl acetate, THF, DMF, NMP, DMA, and DMSO at T )
298 K. Due to strong solvent absorption, data in nitrobenzene was obtained
only for >420 nm.
Figure 8. Changes in the CD spectrum of (S)3-6 with increasing volume
fraction of DMSO in CHCl3-DMSO mixed solvents at 298 K. CHCl3/
DMSO (v/v) ) 100:0, 90:10, 80:20, 70:30, 60:40, 40:60, 20:80, and 0:100
from top to bottom trace.
lack of correlated peaks, indicating disassembly of the O-H· · ·O
hydrogen-bonding network as a consequence of rapid chemical
exchange with solvent molecules. The loss of critical anchoring
contacts between the wing-tip OH groups and the core carbonyl
groups might trigger the experimentally observed solvent-
induced helicity switching. Alternatively, a preferential stabiliza-
tion of one screw sense over the other can be envisioned if the
molecule experiences a substantial change in solvent-accessible
surface upon structural unfolding and refolding. A significant
change in solvent dielectric from CHCl3 (ε ) 4.89) to DMSO
(ε ) 46.45)19 could enforce the molecule to adopt opposite
helicity in order to minimize contact between its poorly solvated
nonpolar aromatic surfaces and polar environment.21
Correlation with Solvent Parameters. In order to obtain a
better understanding of the role of solvents in helicity inversion,
the CD spectra of (S)3-6 were obtained in 12 different solvents
with varying degrees of polarity and hydrogen-bonding donor/
acceptor ability. As shown in Figure 9, (S)3-6 displayed strong
positive Cotton effects in benzene, toluene, nitrobenzene,
CH2Cl2, and CHCl3. The intensity of the positive band became
significantly diminished in 1,4-dioxane, ethyl acetate, and THF
and eventually reversed its sign in DMF, NMP, DMA, and
DMSO solution samples. The sign and magnitude of the CD
signal at 430 nm, ∆ε430, reflect the absolute screw sense and
stability of helical folding in this system and thus served as a
convenient experimental observable in our subsequent analysis.
The effect of solvent on structural folding was investigated
by plotting ∆ε430 of (S)3-6 against selected solvent parameters.
As shown in Figure 10, good correlations were observed
between ∆ε430 and donor number (DN),19,25,26 as a measure of
Lewis basicity, or solvent basicity (SB),19,17 as a measure of
molecules and their higher-order assemblies.4,5,19-21 With VT
1H NMR studies providing valuable insights into structural
folding and unfolding of (S)3-6, we initiated investigating the
feasibility of using molecule-solvent interactions to drive a
similar process. We reasoned that strong hydrogen-bond ac-
ceptor solvents would disrupt the O-H· · ·O hydrogen-bonding
network to trigger conformational transitions that can be
monitored directly.
As anticipated, the CD spectrum of (S)3-6 gradually lost the
intensity of its positive band with increasing volume fraction
of DMSO in CHCl3-DMSO mixed-solvent system and became
essentially featureless between 30 and 40% DMSO (v/v) at 298
K (Figure 8). Contrary to our intuitive prediction, however, a
further increase in the volume fraction of DMSO above this
critical ratio elicited an apparent “refolding” of the structure to
opposite helicity. This striking behavior was most effectively
demonstrated by the CD spectrum of (S)3-6 measured in 100%
DMSO, which displayed a pseudo mirror-image relationship to
that taken in 100% CHCl3 (Figure 8). Under identical conditions,
(R)3-6 showed an exactly opposite behavior, with negative-to-
positive sign change in Cotton effects upon changing solvent
from CHCl3 to DMSO (Figure S2 [Supporting Information]).
A similar solvent-dependent helicity inversion was observed also
for (S,S)3-3 or (R,R)3-3, although the magnitude of the Cotton
effects with reversed sign was smaller than that of (S)3-6 or
(R)3-6.
The UV-vis spectra of (S)3-6 in CHCl3-DMSO obtained with
varying volume ratio remained essentially invariant (Figure S1
[Supporting Information]), thus making aggregation or other
intermolecular interactions a less likely source for the experi-
mentally observed CD sign change. Chiral aggregation typically
accompanies evolution of exciton-coupled circular dichroism
(ECCD) from interchromophore interactions,22-24 which was
not observed in our case.
(24) (a) Imada, T.; Murakami, H.; Shinkai, S. J. Chem. Soc., Chem.
Commun. 1994, 1557–1558. (b) Kilbinger, A. F. M.; Schenning,
A. P. H. J.; Goldoni, F.; Feast, W. J.; Meijer, E. W. J. Am. Chem.
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H.; Wang, S.; Li, Y. Org. Lett. 2008, 10, 645–648.
1
The 1-D and 2-D H NMR spectrum of (S)3-6 in DMSO-d6
showed a significant broadening of OH proton resonances and
(19) Reichardt, C. SolVents and SolVent Effects in Organic Chemistry, 3rd
ed.; Wiley-VCH: Weinheim, 2003.
(20) Zhao, Y.; Zhong, Z.; Ryu, E.-H. J. Am. Chem. Soc. 2007, 129, 218–
225.
(25) (a) Gutmann, V. Coord. Chem. ReV. 1967, 2, 239–256. (b) Gutmann,
V. Coord. Chem. ReV. 1976, 18, 225–255. (c) Linert, W.; Fukuda,
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(21) Zhao, Y.; Moore, J. S. In Foldamers; Hecht, S., Huc, I., Eds.; Wiley-
VCH: Weinheim, 2007; pp 75-108.
(22) Circular Dichroism: Principles and Applications, 2nd ed.; Berova,
N.; Nakanishi, K., Woody, R. W., Eds.; VCH: New York, 2000.
(23) Wu¨rthner, F., Ed. Supramolecular Dye Chemistry; Springer-Verlag:
Berlin, Germany, 2005.
(26) DNλ estimated from spectral data of solvatochromic indicators was
used instead of DN for toluene, CH2Cl2, and CHCl3.25c
(27) Catala´n, J. In Handbook of SolVents; Wypych, G., Ed.; ChemTec
Publishing: Toronto, 2001.
9
J. AM. CHEM. SOC. VOL. 130, NO. 49, 2008 16817

A R T I C L E S
Jiang et al.
Figure 11. CD spectra of (S)3-7 in CH2Cl2 doped with H2O (0.1%, v/v)
measured prior to (red, solid line) and 30 min after (black, solid line) addition
of Bu4NF (10 equiv) at 298 K. The CD spectrum of (S)3-6 (blue, dotted
line) measured under identical conditions is shown for comparison.
Scheme 4. Covalently-Driven Helicity Switching Cycle
Figure 10. Plots of ∆ε430 ()∆ε at 430 nm in M-1 cm-1) of (S)3-6 vs (a)
donor number (DN), (b) solvent basicity (SB), (c) acceptor number (AN),
or (d) ET(30) for solvents including benzene (1), toluene (2), nitrobenzene
(3), dichloromethane (4), chloroform (5), 1,4-dioxane (6), ethyl acetate (7),
THF (8), DMF (9), NMP (10), DMA (11), and DMSO (12).
hydrogen-bond acceptor ability. In contrast, plots of ∆ε430 vs
acceptor number (AN),19,28 as a measure of Lewis acidity, or
ET(30),19,29 as a measure of solvent polarity, showed scattered
data points with no remarkable trends. These empirical findings
suggest that solvent, instead of functioning as a simple
macroscopic continuum exerting nondirectional forces, actively
participates in specific O-H· · ·solvent interactions to drive
structural unfolding and eventual helicity inversion.30 A con-
ceptually related mechanistic model was previously considered
for dipyrrinone derivatives that changed Cotton effect signs upon
changing solvent from CH2Cl2 to DMSO31 or addition of amine
cosolvents.32 It was proposed that the steric constraints imposed
by strong N-H· · ·OdS(CH3)2 hydrogen bonds or carboxylate · · ·
ammonium salt bridges trigger conformational twisting and
reorientation of the electronic transition dipoles.
Covalently-Triggered Helicity Inversion. A detailed mecha-
nistic understanding of this intriguing helicity switching awaits
precise solution structure analysis. We reasoned, however, that
chemical modification of the OH groups in (S)3-6 to simulate
solvent-induced disruption of the O-H· · ·O hydrogen-bonding
network could have essentially identical consequences in
structural dynamics.
reaction product was essentially superimposable on that of (S)3-
6. An HPLC analysis of the reaction mixture established
quantitative formation of (S)3-6.
One mechanistic model that is consistent with this experi-
mental observation is shown in Scheme 4, in which (S)3-7 adopts
a (P)-helical conformation in order to alleviate steric constraints
imposed by the bulky TMS wing-tip groups. Desilylation by
F- and subsequent protonation furnishes (S)3-6 and restores the
key O-H· · ·O network stabilizing the (M)-conformer to for-
mally complete the helicity switching cycle.
Summary and Outlook. Steric interactions between neighbor-
ing branches can collectively determine the screw sense of
helically folding dendritic molecules. This idea was implemented
with a series of C3-symmetric tris(N-salicylideneaniline)s having
chiral alcohol groups strategically placed around a cyclic
hydrogen-bonding network. Reversible assembly and disas-
This idea was tested in a straightforward manner using (S)3-
7, in which all the OH groups in (S)3-6 were protected with
TMS groups to mimic the O-H· · ·solvent interactions. In
CH2Cl2 at 298 K, (S)3-7 indeed displayed a negative Cotton
effect (Figure 11), similarly to the behavior of (S)3-6 in DMSO
(Figure 8). A facile protiodesilylation of (S)3-7 with 10 equiv
of TBAF at room temperature, however, induced helicity
switching. As shown in Figure 11, the CD spectrum of the final
(28) (a) Mayer, U.; Gutmann, V.; Gerger, W. Monatsh. Chem. 1975, 106,
1235–1257. (b) Mayer, U.; Gerger, W.; Gutmann, V. Monatsh. Chem.
1977, 108, 489–498. (c) Mayer, U. Pure Appl. Chem. 1979, 51, 1697–
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383.
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9
16818 J. AM. CHEM. SOC. VOL. 130, NO. 49, 2008

Chiral Folding and Helicity Inversion
A R T I C L E S
sembly of this key chirality transfer channel induced a highly
unusual helicity switching.
redox-52 or coordination-driven53-55 rearrangement of primary
metal coordination sphere, or solvent-induced chirality inversion
of dendrons,56 bis(porphyrin) tweezers,57 dipyrrinone deriva-
tives,32 or biaryl rotors.58
Our findings described in this paper suggest that covalently
triggered conformational transition can be a viable strategy to
achieve helicity inversion of stereodynamic small molecules.
Efforts are currently underway to unravel the molecular basis
of this intriguing phenomenon and to find technological ap-
plications of this emerging class of chiral switches.
Chirality inversion has previously been observed for supra-
molecularaggregates,30,33-35 polymers,14a,36-44 andfoldamers45-50
in which cooperative noncovalent interactions lead to an
effective amplification of locally introduced steric bias. For small
molecule systems with a limited number of weak bonds to
manipulate, chirality switching becomes a significant challenge.
Several small molecule systems do exist, however, which
undergo reversal in screw sense through photochemically driven
isomerization around a sterically overcrowded double bond,14a,51
Experimental Section
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General Considerations. All reagents were obtained from
commercial suppliers and used as received unless otherwise noted.
THF was saturated with nitrogen and purified by passage through
activated Al2O3 columns under nitrogen (Innovative Technology
SPS 400). Triethylamine was saturated with nitrogen and used
without further purification. Trimethylsilyl chloride was distilled
over CaH2 and stored under nitrogen. The compounds 1,3,5-
triformylphloroglucinol,9a 2-iodo-4-tert-butylaniline, and 2,6-diiodo-
4-tert-butylaniline59 were prepared according to literature proce-
dures. All air-sensitive manipulations were carried out under
nitrogen atmosphere in an M.Braun glovebox or by standard
Schlenk-line techniques.
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M.; Koe, J. R.; Motonaga, M.; Nakashima, H.; Terao, K.; Teramoto,
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Physical Measurements. 1H NMR and 13C NMR spectra were
recorded on a 400 MHz Varian Inova NMR Spectrometer. Chemical
shifts were reported versus tetramethylsilane and referenced to the
residual solvent peaks. High resolution chemical ionization (CI)
(using CH4 as CI reagent) and electrospray ionization (ESI) mass
spectra were obtained on a Thermo Electron Corporation MAT
95XP-Trap. FT-IR spectra were recorded on a Nicolet Avatar 360
FT-IR Spectrometer with EZ OMNIC ESP software. UV-vis
spectra were recorded on a Varian Cary 5000 UV-vis-NIR
spectrophotometer. Circular dichroism (CD) spectra were collected
on a Jasco J-715 circular dichroism spectropolarimeter. HPLC
analyses were carried out on a Waters Breeze HPLC System using
a chiral column (Regis Technologies Inc., Pirkle Covalent (S,S)-
Whelk-O 1 10/100 FEC, o.d. 0.46 cm × 25 cm).
(40) Tang, H.-Z.; Boyle, P. D.; Novak, B. M. J. Am. Chem. Soc. 2005,
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Reactions with Fluoride Ion. Stock solutions of tetrabutylam-
monium fluoride (TBAF) were prepared using TBAF ·3H2O and
anhydrous THF in the glovebox. Sample solutions of (S)3-6 and
(S)3-7 were prepared with CH2Cl2 doped with H2O (0.1%, v/v). In
order to minimize dilution effects, 10 µL aliquots of TBAF solutions
were delivered to sample solutions of (S)3-6 or (S)3-7 (3.5 mL)
using microsyringes prior to measurements.
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(1S,1′S)-3,3′-(2-Amino-5-tert-butyl-1,3-phenylene)bis(1-phenyl-
prop-2-yn-1-ol) (8). A round-bottom flask was charged with 4-tert-
butyl-2,6-diiodoaniline (1.03 g, 2.58 mmol), (R)-1-phenyl-2-propyn-
1-ol (750 mg, 5.67 mmol), Et3N (20 mL), Pd(PPh3)4 (60 mg, 0.052
mmol), and CuI (15 mg, 0.079 mmol) at room temperature. The
reaction mixture was purged with N2, stirred for 24 h at rt, and
concentrated under reduced pressure. Flash column chromatography
on SiO2 (hexanes/EtOAc ) 3:2, v/v) furnished 8 as a yellow solid
(1.05 g, 2.56 mmol, 99%). 1H NMR (400 MHz, CDCl3, 298 K): δ
7.62-7.55 (m, 4H), 7.41-7.33 (m, 6H), 7.32 (s, 2H), 5.75 (d, J )
5.6 Hz, 2H), 4.59 (bs, 2H), 2.35 (d, J ) 6.0 Hz, 2H), 1.25 (s, 9H);
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9
J. AM. CHEM. SOC. VOL. 130, NO. 49, 2008 16819

A R T I C L E S
Jiang et al.
13C NMR (100 MHz, CDCl3, 298 K): δ 147.1, 140.6, 140.2, 129.9,
128.6, 128.3, 126.6, 106.7, 94.2, 83.1, 65.0, 33.8, 31.2. FT-IR (thin
film on NaCl, cm-1): 3365, 2963, 2868, 2174, 1652, 1457, 1251,
1028, 698. HRMS (CI) calcd for C28H27NO2 [M]+ 409.2036, found
409.2032.
(S)-3-(2-Amino-5-tert-butyl-3-(3-hydroxyprop-1-ynyl)phenyl)-1-
phenylprop-2-yn-1-ol (10). This compound was prepared in
iterative two-step Sonogashira-Hagihara cross-coupling reac-
tions. Reaction of 4-tert-butyl-2,6-diiodoaniline (1.03 g, 2.57
mmol), (R)-1-phenyl-2-propyn-1-ol (310 mg, 2.35 mmol), Pd-
(PPh3)4 (60 mg, 0.052 mmol), and CuI (15 mg, 0.079 mmol) in
Et3N (15 mL) with a procedure analogous to that used to prepare
8 furnished (S)-3-(2-amino-5-tert-butyl-3-iodophenyl)-1-phe-
nylprop-2-yn-1-ol (650 mg, 1.60 mmol, 68%) as a yellow sticky
oil after flash column chromatography on SiO2 (hexanes/EtOAc
(2E,4E,6E)-2,4,6-Tris((4-tert-butyl-2,6-bis((S)-3-hydroxy-3-phe-
nylprop-1-ynyl)phenylamino)methylene)cyclohexane-1,3,5-trione
((S,S)3-3). A round-bottom flask was charged with 8 (1.05 g, 2.56
mmol), 1,3,5-triformylphloroglucinol (108 mg, 0.514 mmol), and
EtOH (20 mL) at room temperature. The reaction mixture was
heated at reflux for 30 h, concentrated under reduced pressure, and
purified by flash chromatography on SiO2 (CH2Cl2) to furnish
(S,S)3-3 as a yellow solid (0.70 g, 0.51 mmol, 99%). 1H NMR (400
MHz, CDCl3, 298 K): δ 13.34 (d, J ) 13.2 Hz, 3H), 9.43 (d, J )
13.6 Hz, 3H), 7.58-7.50 (m, 18H), 7.24-7.14 (m 18H), 6.13 (d,
J ) 8.8 Hz, 6H), 5.73 (d, J ) 8.4 Hz, 6H), 1.32 (s, 27H); 13C
NMR (100 MHz, CDCl3, 298 K): δ 184.8, 151.8, 148.5, 140.5,
138.1, 131.0, 128.3, 128.0, 126.6, 113.6, 106.1, 97.2, 81.9, 64.6,
34.5, 30.9; FT-IR (thin film on NaCl, cm-1): 3370, 2964, 2869,
1603, 1570, 1432, 1302, 1234, 1028, 986, 883. HRMS (ESI) calcd
for C93H81O9N3Na [M + Na]+ 1406.5865, found 1406.5814.
(1R,1′R)-3,3′-(2-Amino-5-tert-butyl-1,3-phenylene)bis(1-phenyl-
prop-2-yn-1-ol) (9). This compound was prepared with 4-tert-
butyl-2,6-diiodoaniline (414 mg, 1.03 mmol), (S)-1-phenyl-2-
propyn-1-ol (300 mg, 2.27 mmol), Et3N (20 mL), Pd(PPh3)4 (24
mg, 0.021 mmol), and CuI (6 mg, 0.03 mmol) by a procedure
analogous to that used to prepare 8. This product was isolated
as a yellow solid (418 mg, 1.02 mmol, 99%) after flash column
chromatography on SiO2 (hexanes/EtOAc ) 1:1). 1H NMR (400
MHz, CDCl3, 298 K): δ 7.64-7.60 (m, 4H), 7.44-7.33 (m, 6H),
7.32 (s, 2H), 5.75 (d, J ) 5.6 Hz, 2H), 4.59 (bs, 2H), 2.35 (d,
J ) 6.0 Hz, 2H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3,
298 K): δ 147.1, 140.6, 140.2, 129.9, 128.6, 128.3, 126.6, 106.7,
94.2, 83.1, 65.0, 33.8, 31.2. FT-IR (thin film on NaCl, cm-1):
3366, 2963, 2868, 2174, 1635, 1616, 1457, 1249, 1020, 699.
HRMS (CI) calcd for C28H27NO2 [M]+ 409.2036, found 409.2045.
1
) 3:1, v/v). H NMR (400 MHz, CDCl3, 298 K): δ 7.62 (d, J
) 2.4 Hz, 1H), 7.59 (d, J ) 7.0 Hz, 2H), 7.43-7.33 (m, 3H),
7.31 (d, J ) 2.4 Hz, 1H), 5.73 (bs, 1H), 4.53 (bs, 2H), 3.21 (bs,
1H), 1.25 (s, 9H); 13C NMR (100 MHz, CDCl3, 298 K): δ 145.7,
142.1, 140.6, 136.9, 129.4, 128.7, 128.4, 126.6, 106.4, 94.2, 83.4,
83.3, 65.0, 33.7, 31.2. A portion of this material (330 mg, 0.81
mmol) was carried on to the second coupling step by reacting
with propargyl alcohol (458 mg, 8.14 mmol), Pd(PPh3)4 (19 mg,
0.016 mmol), and CuI (5 mg, 0.03 mmol) in Et3N (10 mL) by
a procedure analogous to that used to prepare 8. A yellow sticky
oil of 10 (160 mg, 0.480 mmol, 59%) was isolated after flash
column chromatography on SiO2 (hexanes/EtOAc ) 1:1, v/v).
1H NMR (400 MHz, CDCl3, 298 K): δ 7.60-7.56 (m, 2H),
7.40-7.27 (m, 5H), 5.70 (bs, 1H), 4.73 (bs, 2H), 4.48 (s, 2H),
3.62 (bs, 1H), 3.01 (bs, 1H), 1.22 (s, 9H); 13C NMR (100 MHz,
CDCl3, 298 K): δ 147.0, 140.6, 140.3, 130.0, 129.8, 128.7, 128.4,
126.7, 106.9, 106.7, 94.2, 92.6, 83.2, 82.2, 65.0, 51.4, 33.8, 31.2.
FT-IR (thin film on NaCl, cm-1): 3363, 2962, 2867, 2172, 1616,
1457, 1252, 1029, 699. HRMS (CI) calcd for C22H23O2N [M]+
333.1723, found 333.1722.
(2E,4E,6E)-2,4,6-Tris((4-tert-butyl-2-((S)-3-hydroxy-3-phenylprop-
1-ynyl)-6-(3-hydroxypropynyl)phenylamino)methylene)cyclohexane-
1,3,5-trione ((S)3-5). This compound was prepared with 10 (150
mg, 0.45 mmol), 1,3,5-triformylphloroglucinol (19 mg, 0.090
mmol), and EtOH (10 mL) by a procedure analogous to that
used to prepare (S,S)3-3. This product was isolated as a yellow
solid (100 mg, 0.0865 mmol, 96%) after flash column chroma-
tography on SiO2 (CH2Cl2). 1H NMR (400 MHz, CDCl3, 298
K): δ 13.4 (d, J ) 13.2 Hz, 3H), 9.64 (d, J ) 13.2 Hz, 3H),
7.54 (d, J ) 7.2 Hz, 6H), 7.47 (d, J ) 6.4 Hz, 6H), 7.24-7.15
(m, 9H), 6.07 (d, J ) 7.6 Hz, 3H), 5.72 (d, J ) 7.2 Hz, 3H),
5.24 (t, J ) 5.6 Hz, 3H), 4.49 (d, J ) 4.8 Hz, 6H), 1.27 (s,
27H); 13C NMR (100 MHz, CDCl3, 298 K): δ 185.4, 152.2,
140.3, 138.2, 131.1, 130.9, 128.4, 128.0, 126.6, 113.8, 113.6,
106.3, 97.2, 95.9, 82.0, 81.3, 64.6, 51.1, 34.5, 31.0. FT-IR (thin
film on NaCl, cm-1): 3381, 2963, 2867, 2189, 1603, 1570, 1432,
1302, 1235, 1032, 986, 883. HRMS (ESI) calcd for
C75H69O9N3Na [M + Na]+ 1178.4926, found 1178.4917.
(S)-3-(2-Amino-5-tert-butylphenyl)-1-phenylprop-2-yn-1-ol (11).
This compound was prepared with 4-tert-butyl-2-iodoaniline (510
mg, 1.85 mmol), (R)-1-phenyl-2-propyn-1-ol (270 mg, 2.04
mmol), Et3N (10 mL), Pd(PPh3)4 (43 mg, 0.037 mmol), and CuI
(11 mg, 0.058 mmol) by a procedure analogous to that used to
prepare 8. This product was isolated as a yellow solid (510 mg,
1.83 mmol, 99%) after flash column chromatography on SiO2
(hexanes/EtOAc ) 2:1 to 1:1, v/v). 1H NMR (400 MHz, CDCl3,
298 K): δ 7.59 (d, J ) 7.2 Hz, 2H), 7.38-7.30 (m, 4H), 7.15
(dd, J ) 8.4, 2.0 Hz, 1H), 6.61 (d, J ) 8.4 Hz, 1H), 5.70 (s,
1H), 4.09 (bs, 2H), 3.35 (bs, 1H), 1.24 (s, 9H); 13C NMR (100
MHz, CDCl3, 298 K): δ 145.5, 140.9, 140.8, 128.7, 128.6, 128.2,
127.2, 126.6, 114.4, 106.8, 93.9, 83.7, 65.0, 33.8, 31.3. FT-IR
(thin film on NaCl, cm-1): 3367, 2961, 2902, 2866, 2172, 1623,
1500, 1263, 1015, 699. HRMS (CI) calcd for C19H21NO [M]+
279.1618, found 279.1609.
(2E,4E,6E)-2,4,6-Tris((4-tert-butyl-2,6-bis((R)-3-hydroxy-3-phe-
nylprop-1-ynyl)phenylamino)methylene)cyclohexane-1,3,5-trione
((R,R)3-3). This compound was prepared with 9 (250 mg, 0.61
mmol), 1,3,5-triformylphloroglucinol (26 mg, 0.12 mmol), and
EtOH (10 mL) by a procedure analogous to that used to prepare
(S,S)3-3. This product was isolated as a yellow solid (154 mg,
0.111 mmol, 93%) after flash column chromatography on SiO2
1
(CH2Cl2). H NMR (400 MHz, CDCl3, 298 K): δ 13.34 (d, J )
13.2 Hz, 3H), 9.43 (d, J ) 13.6 Hz, 3H), 7.58-7.50 (m, 18H),
7.24-7.14 (m, 18H), 6.13 (d, J ) 8.8 Hz, 6H), 5.73 (d, J ) 8.4
Hz, 6H), 1.32 (s, 27H); 13C NMR (100 MHz, CDCl3, 298 K): δ
184.8, 151.8, 148.5, 140.5, 138.1, 131.0, 128.3, 128.0, 126.6,
113.6, 106.1, 97.2, 81.9, 64.6, 34.5, 30.9. FT-IR (thin film on
NaCl, cm-1): 3372, 2963, 1603, 1569, 1432, 1301, 1234, 1028,
985, 883, 697. HRMS (ESI) calcd for C93H81O9N3Na [M + Na]+
1406.5865, found 1406.5890.
(1S,1′S)-3,3′-(5-tert-Butyl-2-((E)-2-hydroxybenzylidene-amino)-
1,3-phenylene)bis(1-phenylprop-2-yn-1-ol) ((S,S)-4). This com-
pound was prepared with 8 (50 mg, 0.12 mmol) and salicylal-
dehyde (5.00 g, 40.9 mmol) by a procedure analogous to that
used to prepare (S,S)3-3. This product was isolated as a yellow
solid (58 mg, 0.11 mmol, 94%) after flash column chromatog-
raphy on SiO2 (hexanes/EtOAc ) 20:1 to 4:1, v/v). 1H NMR
(400 MHz, CDCl3, 298 K): δ 14.0 (s, 1H), 9.02 (s, 1H),
7.55-7.52 (m, 6H), 7.38-7.26 (m, 7H), 7.00-6.97 (m, 2H),
6.84 (t, J ) 7.6 Hz, 1H), 5.67 (d, J ) 4.8 Hz, 2H), 3.05 (d, J )
5.2 Hz, 2H), 1.28 (s, 9H); 13C NMR (100 MHz, CDCl3, 298
K): δ 165.7, 161.2, 148.9, 147.6, 140.4, 133.6, 132.5, 130.6,
128.7, 128.4, 126.6, 119.2, 118.9, 117.5, 115.4, 93.8, 83.9, 65.1,
34.5, 31.0. FT-IR (thin film on NaCl, cm-1): 3377, 2963, 2190,
1653, 1457, 1224, 1103, 917, 698. HRMS (CI) calcd for
C35H31O3N [M]+ 513.2298, found 513.2280.
(2E,4E,6E)-2,4,6-Tris((4-tert-butyl-2-((S)-3-hydroxy-3-phenylprop-
1-ynyl)phenylamino)methylene)cyclohexane-1,3,5-trione ((S)3-6).
This compound was prepared with 11 (500 mg, 1.79 mmol),
1,3,5-triformylphloroglucinol (75 mg, 0.36 mmol), and EtOH
(20 mL) by a procedure analogous to that used to prepare (S,S)3-
9
16820 J. AM. CHEM. SOC. VOL. 130, NO. 49, 2008

Chiral Folding and Helicity Inversion
A R T I C L E S
3. The product was isolated as a yellow solid (354 mg, 0.356
mmol, 99%) after filtration and washing with EtOH. H NMR
ing the B3LYP/6-31G** level of theory.63,64 The energies of the
optimized structures were reevaluated by additional single-point
calculations on each optimized geometry using Dunning’s correla-
tion-consistent triple-ꢀ basis set cc-pVTZ(-f).65 Solvation energies
were calculated using a self-consistent reaction field (SCRF) method
and conductor-like screening model (COSMO) was employed.66,67
Empirical parameters such as dielectric constant (ε ) 4.806, CHCl3)
and atomic radii (H, 1.140 Å; C, 1.900 Å; O, 1.600 Å) were used
to construct the solute surface.
1
(400 MHz, CDCl3, 298 K): δ 14.01 (d, J ) 13.2 Hz, 3H), 8.78
(d, J ) 13.2 Hz, 3H), 7.71 (d, J ) 7.2 Hz, 6H), 7.43-7.31 (m,
12 H), 7.25-7.18 (m, 6H), 6.25 (d, J ) 5.2 Hz, 3H), 5.84 (d, J
) 5.2 Hz, 3H), 1.24 (s, 27H); 13C NMR (100 MHz, CDCl3, 298
K): δ 184.5, 148.1, 147.6, 141.2, 137.8, 128.6, 128.0, 127.8,
127.4, 126.9, 113.6, 113.0, 109.7, 106.6, 81.2, 64.8, 34.5, 31.1.
FT-IR (thin film on NaCl, cm-1): 2962, 1617, 1595, 1576, 1451,
1300, 1042, 816. HRMS (ESI) calcd for C66H63O6N3Na [M +
Na]+ 1016.4609, found 1016.4606.
The free energy in solution phase, Gsol, was calculated by
following standard protocol:
(R)-3-(2-Amino-5-tert-butylphenyl)-1-phenylprop-2-yn-1-ol (12).
This compound was prepared with 4-tert-butyl-2-iodoaniline (284
mg, 1.03 mmol), (S)-1-phenyl-2-propyn-1-ol (150 mg, 1.14 mmol),
Et3N (10 mL), Pd(PPh3)4 (24 mg, 0.021 mmol), and CuI (6 mg,
0.03 mmol) by a procedure analogous to that used to prepare 8.
This product was isolated as a yellow solid (285 mg, 1.02 mmol,
99%) after flash column chromatography on SiO2 (hexanes/EtOAc
Gsol ) Ggas + Gsolv
Ggas ) Hgas - TSgas
Hgas ) ESCF + ZPE
(2)
(3)
(4)
where Ggas ) free energy in gas phase; Gsolv ) free energy of
solvation as computed by using the continuum solvation model;
Hgas ) enthalpy in gas phase; T ) temperature () 298.15 K); Sgas
) entropy in the gas phase; ESCF ) self-consistent field energy,
i.e. “raw” electronic energy as computed from the SCF procedure;
ZPE ) zero point energy. Considering the energy difference of
∼12 kcal mol-1 computed for (M)-(S,S)3-2 and (P)-(S,S)3-2 (Table
S1 [SI]), the contribution of TSgas and ZPE terms are negligibly
small and thus approximated to be zero.
1
) 1:1, v/v). H NMR (400 MHz, CDCl3, 298 K): δ 7.59 (d, J )
7.2 Hz, 2H), 7.38-7.30 (m, 4H), 7.15 (dd, J ) 8.4, 2.4 Hz, 1H),
6.61 (d, J ) 8.4 Hz, 1H), 5.70 (s, 1H), 4.09 (bs, 2H), 3.35 (bs,
1H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3, 298 K): δ 145.5,
140.9, 140.8, 128.7, 128.6, 128.2, 127.2, 126.6, 114.4, 106.8, 93.9,
83.7, 65.0, 33.8, 31.3. FT-IR (thin film on NaCl, cm-1): 3362, 3062,
2962, 2903, 2867, 2172, 1635, 1576, 1499, 1264, 1015, 699. HRMS
(CI) calcd for C19H21NO [M]+ 279.1618, found 279.1607.
(2E,4E,6E)-2,4,6-Tris((4-tert-butyl-2-((R)-3-hydroxy-3-phenylprop-
1-ynyl)phenylamino)methylene)cyclohexane-1,3,5-trione ((R)3-6).
This compound was prepared with 12 (280 mg, 1.00 mmol), 1,3,5-
triformylphloroglucinol (42 mg, 0.20 mmol), and EtOH (20 mL)
by a procedure analogous to that used to prepare (S,S)3-3. This
product was isolated as a yellow solid (170 mg, 0.17 mmol, 86%)
after filtration and washing with EtOH. 1H NMR (400 MHz, CDCl3,
298 K): δ 13.92 (d, J ) 13.6 Hz, 3H), 8.76 (d, J ) 13.6 Hz, 3H),
7.71 (d, J ) 7.2 Hz, 6H), 7.43-7.31 (m, 12H), 7.11-7.00 (m,
6H), 6.31 (d, J ) 4.8 Hz, 3H), 5.84 (d, J ) 4.4 Hz, 3H), 1.21 (s,
27H); 13C NMR (100 MHz, CDCl3, 298 K): δ 184.5, 148.1, 147.6,
141.2, 137.8, 128.6, 128.0, 127.8, 127.4, 126.9, 113.6, 113.0, 109.7,
106.6, 81.2, 64.8, 34.4, 31.1. FT-IR (thin film on NaCl, cm-1):
2952, 2187, 1616, 1595, 1448, 1345, 1299, 815. HRMS (ESI) calcd
for C66H63O6N3Na [M + Na]+ 1016.4609, found 1016.4606.
(2E,4E,6E)-2,4,6-Tris((4-tert-butyl-2-((S)-3-phenyl-3-(trimethyl-
silyloxy)prop-1-ynyl)phenylamino)methylene)cyclohexane-1,3,5-tri-
one ((S)3-7). To a THF solution (5 mL) of (S)3-6 (21.1 mg, 0.021
mmol) and Et3N (0.20 mL, 1.4 mmol) under N2 atmosphere was
added TMSCl (0.20 mL, 1.6 mmol). The reaction mixture was
stirred at rt for 48 h. Volatile fractions were removed under reduced
pressure and the yellow residual material was extracted into hexanes,
filtered through glass wool, and concentrated under reduced pressure
to afford (S)3-7 as a yellow solid (25.7 mg, 100%). 1H NMR (400
MHz, CDCl3, 298 K): δ 13.69 (d, J ) 13.0 Hz, 3H), 8.76 (d, J )
13.6 Hz, 3H), 7.77 (d, J ) 7.6 Hz, 6H), 7.49 (d, J ) 2.0 Hz, 3H),
7.42-7.26 (m, 15H), 6.15 (s, 3H), 1.31 (s, 27H), 0.30 (s, 27H);
13C NMR (100 MHz, CDCl3, 298 K): δ 185.1, 147.8, 141.4, 138.7,
129.7, 128.4, 127.8, 127.1, 126.6, 114.0, 113.2, 107.6, 97.3, 81.0,
65.2, 34.5, 31.2, 0.3. FT-IR (thin film on NaCl, cm-1): 2961, 2903,
2869, 1613, 1587, 1445, 1344, 1289, 1266, 1251, 1230, 1088, 1064,
996, 874, 844, 752, 697. HRMS (ESI) calc for C75H88N3O6Si3 [M
+ H]+ 1210.5981, found 1210.5944.
In order to simulate the UV-vis and CD spectra, time-dependent
density functional theory (TD-DFT) was employed. The calculation
of individual excitation was carried out with the Amsterdam Density
Functional (ADF) software package68 using the generalized gradient
approximation (GGA) functional BP86/LB94 and the triple-ꢀ
polarized (TZP) standard ADF basis set on all atoms.64,69
The intensity of each electronic transition in calculated UV-vis
spectrum is represented by the oscillator strength, f, given in eq
5,70 where ε is the molar absorptivity and νj is the frequency in
wavenumbers.
f ) 4.315 × 10-9 ενj
(5)
∫
For the calculation of CD spectrum, rotatory strength, R, was
obtained by eq 6,71,72 where ∆ε (in M-1 cm-1) is the difference
in the molar absorptivity for the left- and right-handed circular
polarized light and νjo is the center of the band.
∆ ε (νj)
νj
22.94
R ) 22.94
dνj ≈
∆ ε (νj)dνj
(6)
∫
∫
νjo
Rotatory strengths in the calculated ECD spectra were reported
in the velocity representation of the electric transition dipole moment
and in centimeter ·gram·second (c.g.s) units of 10-40 esu cm
erg/G.71-73 Gaussian line shapes were assumed for individual
(63) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
(64) Becke, A. D. Phys. ReV. A 1988, 38, 3098–3100.
(65) Dunning, T. H., Jr J. Chem. Phys. 1989, 90, 1007–1023.
(66) Klamt, A.; Schu¨rmann, G. J. Chem. Soc., Perkin Trans. 2 1993, 799–
805.
(67) Pye, C. C.; Ziegler, T. Theor. Chem. Acc. 1999, 396–408.
(68) te Velde, G.; Bickelhaupt, F. M.; Baerends, E. J.; Guerra, C. F.; van
Gisbergen, S. J. A.; Snijders, J. G.; Ziegler, T. J. Comput. Chem. 2001,
22, 931–967.
(69) Perdew, J. P. Phys. ReV. B 1986, 33, 8822–8824.
(70) Drago, R. S. Physical Methods for Chemists, 2nd ed.; Surfside
Scientific Publishers: Gainesville, FL, 1992.
Density Functional Theory Calculations. All calculations were
performed using density functional theory (DFT). Initial structures
were constructed in Cerius60 and constrained with C3-symmetry
with Maestro.61 Geometry optimizations were performed using
Jaguar 6.0 suite62 of ab initio quantum chemistry program employ-
(71) Autschbach, J.; Ziegler, T.; van Gisbergen, S. J. A.; Baerends, E. J.
J. Chem. Phys. 2002, 116, 6930–6940.
(72) Dierksen, M.; Grimme, S. J. Chem. Phys. 2006, 124, 174301-1–
174301-12.
(60) Cerius2, v 4.8.1; Accelrys Inc.: San Diego, CA, 2003.
(61) Maestro, v 6.5.007; Schro¨dinger Inc.: Portland, OR, 2004.
(62) Jaguar, v 6.0; Schro¨dinger, Inc.: Portland, OR, 2003.
(73) Pulm, F.; Schramm, J.; Hormes, J.; Grimme, S.; Peyerimhoff, S. D.
Chem. Phys. 1997, 224, 143–155.
9
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A R T I C L E S
Jiang et al.
electronic excitations in the calculated CD spectra,74 which were
scaled by empirically adjusting the linewidths for a qualitative
comparison with the experimentally obtained spectrum.
Foundation. We thank Xiaofan Yang and Richard Lord of the Baik
group at Indiana University for helpful discussions on DFT studies.
This paper is dedicated to Professor Junghun Suh on the occasion
of his 60th birthday.
Acknowledgment. This work was supported by the National
Science Foundation (CAREER CHE 0547251), the U.S. Army
Research Office (W911NF-07-1-0533), and the Alfred P. Sloan
Supporting Information Available: Additional spectroscopic
data and DFT calculations. This material is available free of
charge via the Internet at http://pubs.acs.org.
(74) Harada, N.; Nakanishi, K. Circular Dichroic Spectroscopy: Exciton
Coupling in Organic Stereochemistry; University Science Books: Mill
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16822 J. AM. CHEM. SOC. VOL. 130, NO. 49, 2008