Twisted perylene stereodimers reveal chiral molecular assembly codes

Article abstract of DOI:10.1021/ja7111959

Unique perylene diastereomeric linear and cyclic dimers were synthesized from twisted perylene monomers, revealing that π-stacking stereoisomerism imparted specific intermolecular self-assembly and intramolecular folding. Only the homochiral twisted tetrachloroperylene monomers cyclized via a cooperative reaction, forming the homochiral diastereomers. The heterochiral tetrachloroperylene monomers proceeded through a stepwise reaction and yielded a linear heterochiral dimer, which equilibrated with the linear homochiral dimers. The linear homochiral dimers cyclized to produce the same cyclic homochiral diastereomers. These results demonstrated that homochiral and heterochiral self-assemblies were two distinct molecular codes, directing two specific chemical pathways. The homochiral cyclic dimers remain isomerically pure at -20°C but can be interconverted to the heterochiral cyclic dimer meso compound at room temperature. The diastereomers were readily separated by HPLC. While driven by solvophobic forces, foldable linear dimers synthesized from the same twisted monomers using phosphoramidite chemistry folded into homodimer and heterodimer, confirming the inherent molecular codes, which were dictated by the perylene chirality, ultimately gauged the weak π-stack forces, and directed self-assembly and folding.

Full text of DOI:10.1021/ja7111959

Published on Web 06/10/2008
Twisted Perylene Stereodimers Reveal Chiral Molecular
Assembly Codes
Wei Wang, Andrew D. Shaller, and Alexander D. Q. Li*
Department of Chemistry, Washington State UniVersity, Pullman, Washington 99164
Received December 20, 2007; E-mail: dequan@wsu.edu
Abstract: Unique perylene diastereomeric linear and cyclic dimers were synthesized from twisted perylene
monomers, revealing that π-stacking stereoisomerism imparted specific intermolecular self-assembly and
intramolecular folding. Only the homochiral twisted tetrachloroperylene monomers cyclized via a cooperative
reaction, forming the homochiral diastereomers. The heterochiral tetrachloroperylene monomers proceeded
through a stepwise reaction and yielded a linear heterochiral dimer, which equilibrated with the linear
homochiral dimers. The linear homochiral dimers cyclized to produce the same cyclic homochiral
diastereomers. These results demonstrated that homochiral and heterochiral self-assemblies were two
distinct molecular codes, directing two specific chemical pathways. The homochiral cyclic dimers remain
isomerically pure at -20 °C but can be interconverted to the heterochiral cyclic dimer meso compound at
room temperature. The diastereomers were readily separated by HPLC. While driven by solvophobic forces,
foldable linear dimers synthesized from the same twisted monomers using phosphoramidite chemistry folded
into homodimer and heterodimer, confirming the inherent molecular codes, which were dictated by the
perylene chirality, ultimately gauged the weak π-stack forces, and directed self-assembly and folding.
Introduction
approach utilizes molecular templates to modulate the effective
molarity of reactive groups, providing a bias for certain
While covalent bonds establish the primary molecular struc-
tures, weak intra- and intermolecular forces govern molecular
recognition and determine the folded or self-assembled su-
pramolecular architecture. When the delicate balance of weak
forces is reached, molecular assemblies such as DNA duplex
and globular proteins establish their structure, gaining exquisite
functionality. These weak forces typically include dispersion
forces, hydrogen bonding, solvophobic effects, and Coulombic
interactions.1 Recently, however, more and more reports are
focusing on the often overlooked weak π-π stacking force,
resulting from the molecular overlap of π-orbitals between
planar aromatic systems.2
pathways over competing ones by increasing the proximity
between reaction centers.4,5 However, with molecular self-
assemblies, no template is needed, as the reactants undergo the
assembly process by self-templating.6
In our recent reports, the role of the π-π stacking force
driving dynamic intermolecular self-assembly and intramolecular
folding has been elucidated with a series of architecturally
diverse nanostructured foldamers (folded polymers) using planar
perylenetetracarboxylic diimides (PDIs) as the building block.6,7
We first demonstrated that the planar monomers with minimally
steric but highly solubilizing flexible tetraethylene glycol (TEG)
side chains will spontaneously self-assemble above a critical
self-assembly concentration, even in the absence of solvophobic
Molecular assemblies allow the capacity to mimic nature by
directing specific reaction pathways that are otherwise difficult
to achieve. Such assemblies have been successfully demon-
strated to form cyclic and/or concatenated rings.3 A popular
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2008 American Chemical Society
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A R T I C L E S
Wang et al.
Scheme 1. Synthesis of Chiral, Twisted Monomers as the Starting Material for Diastereomeric Dimersa
a Only the R isomer is shown for clarity.
effects.8,9 We also demonstrated linear perylene oligomers from
dimer through 11-mer spontaneously fold and remain folded in
π-stacks, even at nanomolar concentrations.7,8,10 Next, we
exhibited that dynamic self-assembly (DSA) effectively directs
and enhances specific reaction pathways, employing weak
π-stacking interactions to self-template specific covalent bond
formation.6
spectrophotometer. Fluorescence spectra were recorded with a
SPEX Fluorolog-3-21 spectrofluorometer with excitation at 489 nm.
Reactions were monitored by thin-layer chromatography (TLC) on
a precoated plate of silica gel 60 F254 (EM Science). Column
chromatography was performed on silica gel 60 (230-400 mesh,
EM Science). HPLC was performed with an Agilent 1100 series
instrument using a normal-phase column and CH2Cl2/MeOH eluent.
In this paper, we expand the self-assembly and folding
knowledge base by examining the role of molecular recognition
between chiral aromatic systems. Known highly twisted (37°),11
chiral,12 bay-substituted tetrachloro-PDI monomers were used
as the building blocks to synthesize diastereomeric linear and
cyclic dimers. The cyclic diastereomeric dimers are separable
by HPLC and stable at low temperatures, but they slowly
interconvert at room temperature. Dimer characterization reveals
that the preferred self-assembly, hereafter called the molecular
code, effectively directs the coupling reaction pathway, favoring
distinct homochiral and heterochiral structures. Solvophobic-
driven folding is distinguished between the unique dimers,
deciphering an inherent chiral molecular code between twisted
PDIs that directs the resulting molecular architectures.
Results and Discussion
Monomer Synthesis. We incorporated flexible TEG chains
to provide the linkages between the rigid perylene cores, in
contrast to numerous other PDI derivatives reported with various
imide functional groups.12–14 More rigid or sterically demanding
groups such as 2,6-diisopropylaniline, swallowtail alkyl chains,
or 3,4,5-trialkyl-substituted aniline groups are designed in part
to prevent aggregation, an obvious advantage for design of
highly fluorescent pigments, light havesting arrays, and highly
fluorescent dendrimers. However, these diminish the desired
unique self-assembly properties responsible for molecular codes.
The TEG chains afford high solubility in common chlorinated
solvents while minimally retarding the π-π stacking properties
of the perylene core. They also facilitate simple, robust, and
high-yield coupling reactions such as the disulfide and phos-
phoramidite strategies applied here.
Scheme 1 outlines the synthesis of the monomeric starting
material for the diastereomeric cyclic dimers. Tetrachloro-
substituted perylenetetracarboxylic acid was synthesized ac-
cording to a literature procedure,15 as were the amino-
functionalized TEG chains,10 which were attached to both ends
of the twisted perylene core as imides 1. The significantly
increased solubility of the highly twisted core allows the reaction
to proceed in the easily removed solvent pyridine rather than
higher boiling point solvents such as dimethylsulfoxide or
quinoline required for the planar unsubstituted perylene. The
chain-end hydroxyl groups in 1 were tosylated to yield 2,
Experimental Procedures
The syntheses of the cyclic and linear dimers and their
intermediates are detailed in the Supporting Information. Solvents
and reagents were purified where necessary using literature methods.
MALDI-TOF mass spectra were obtained with an ABVS-2025
spectrometer. Electrospray ionization (ESI) mass spectra were
obtained with an API-4000 triple-quadrupole spectrometer. 1H, 13C,
and 31P NMR spectra were recorded with a Mercury 300 (300 MHz)
spectrometer in CDCl3 (CD3OD) solutions. Bruker 500 and 600
MHz NMR spectrometers were also used whenever necessary.
Absorbance spectra were recorded with a Varian Cary 100
(8) Wang, W.; Han, J.; Wang, L.-Q.; Li, L.-S.; Shaw, W.; Li, A. D. Q.
Nano Lett. 2003, 3, 455–458.
(9) Li, A. D. Q.; Wang, W.; Wang, L. Q. Chem. Eur. J. 2003, 9, 4594–
4601.
(10) Wang, W.; Li, L.-S.; Helms, G.; Zhou, H.; Li, A. D. Q. J. Am. Chem.
Soc. 2003, 125, 1120–1121.
(13) Zhang, X.; Chen, Z.; Wurthner, F. J. Am. Chem. Soc. 2007, 129, 4886–
4867.
(11) Chen, Z.; Debiji, M.; Debaerdemaeker, T.; Osswald, P.; Wurthner, F.
Chem. Phys. Chem. 2004, 5, 137–140.
(14) Klok, H.-A.; Becker, S.; Schuck, F.; Pakula, T.; Mullen, K. Macromol.
Biosci. 2003, 3, 729–741.
(12) Osswald, P.; Wurthner, F. J. Am. Chem. Soc. 2007, 129, 14319–14326.
(15) Rogovik, V.; Gutnik, L. Zh. Org. Khim. 1988, 24, 635–639.
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Twisted Perylene Stereodimers
A R T I C L E S
Scheme 2. Synthesis of Diastereromeric Cyclic Dimersa
a Conditions: NaOMe/MeOH, open to air at room temperature; H+ quench to stop the reaction. The chiral monomer 3 (R or S enatiomer) creates two
molecular codes: the homochiral assembly (R-R or S-S) and the heterochiral assembly (R-S). These dynamic self-assemblies effectively direct the formation
of cyclic dimer product 5Homo (R,R or S,S enatiomers) and intermediate heterochiral linear dimer 4Hetero. No heterochiral cyclic dimer is formed. The
homochiral cyclic dimer 5Homo, however, slowly interconverts to the meso heterochiral cyclic dimer 5Hetero (R,S) at room temperature, until reaching a
50/50 mixture.
followed by substitution of the tosyl groups with thiol acetate
groups to form the dithioaceate 3, the cylization reaction starting
material.
monomer-ring compounds were detected. Interestingly, very
little heterochiral cyclic dimer 5Hetero was detected during the
reaction. Upon standing, however, 5Homo spontaneously, albeit
slowly, equilibrated with its heterochiral diastereomer 5Hetero
at room temperature, until their ratio reached 1:1 after 24 h.
It is instructive to compare the achiral planar molecules to
the twisted chiral monomers. The planar perylene readily
π-stacks with other planar monomers, forming a self-assembled
structure favorable for cooperative disulfide-bond formation and
cyclic products. This hypothesis was validated previously
because no reactive intermediates were observed, regardless of
how fast the reaction was quenched. The twisted chiral
molecules, however, have two options: homo template (R-R or
S-S π-stack) or hetero template (R-S π-stack). Obviously, the
homo template and the hetero template have different self-
assembled structures and thus control the reaction pathway
differently, although both reactions are accelerated by the self-
assembly effect.
Diastereomeric Cyclic Dimers. Disulfide chemistry was used
to form the cyclic dimers, a recognized ring-closure strategy
where disulfide linkages are readily triggered by air oxidation
under basic deacetylation conditions.2d,5 We have reported this
chemistry in detail previously, demonstrating that various ring
structures are formed from planar perylene monomers, resulting
in dimer rings, concatenated tetramer rings, or monomeric rings,
depending on the monomer concentration and reaction time.6
Since twisting the perylene core imparts chirality, dynamic self-
assembly effectively sorts out and directs enatiomerically pure
organization. This indicates that molecular size, shape, and
electric potential distributions function like specific codes that
can be exploited to benefit specific products.
The strategy to form cyclic dimers is outlined in Scheme 2.
Deacetylating a racemic mixture of the twisted chiral monomer
3 initially yielded the homochiral cyclic product 5Homo and
the heterochiral linear dimer 4Hetero, as indicated by TLC.
Quenching the reaction early captured these two products, which
were separated by column chromatography and characterized
by NMR and mass spectrometry. When the reaction was allowed
to proceed to completion, 5Homo was the only main product.
Unlike the achiral planar monomers, no concatenated or
Our experimental results reveal that the homo template directs
cooperative disulfide-bond formation, yielding a cyclic dimer,
5Homo, whereas the hetero template endures a stepwise
reaction, first producing a linear heterodimer, 4Hetero. This
linear heterodimer equilibrates with its counterpart, the linear
homodimer 4Homo, which then folds according to the homo
template molecular code rather than hetero template molecular
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A R T I C L E S
Wang et al.
Figure 1. NMR spectra recorded during the isomerization reaction. (Top)
5Homo exhibits one peak for all eight identical aromatic protons (left, red)
and only one triplet for protons adjacent to the disulfide bonds (right, blue).
(Bottom) 5Homo interconverts to 5Hetero, reaching a 50/50 diastereomeric
mixture in about 24 h. The mixture then exhibits two equally integrated
perylene peaks and two equal triplets for protons adjacent to the disulfide.
Solvent: CDCl3.
Figure 2. Normal-phase HPLC spectra of 5Homo and 5Hetero, showing
that 5Hetero elutes first. The fractions collected were immediately
characterized by ESI. Inset: Nearly identical mass spectra were obtained
for 5Hetero (left) and 5Homo (right), closely matching the calculated
isotopic pattern, with the exact m/z for [5Homo + NH4]+ ) [5Hetero +
NH4]+ ) 1834.1.
code. Since homo template molecular code favors the reaction
pathway toward homocyclic formation, 4Homo is converted to
the cyclic homodimer 5Homo. The cyclization of the ho-
modimer effectively removes it from the equilibrium, causing
more 4Hetero to convert to 4Homo (Le Chatelier’s principle).
Thus, the conversion rate is greatly increased when compared
to cyclic dimer interconversion.
adjacent protons (Figure 1, top). However, upon allowing the
purified 5Homo solution to equilibrate in CH2Cl2 for >24 h,
two aromatic peaks with equal integration were apparent, and
the disulfide-adjacent protons displayed two equal-sized over-
lapping triplets concomitantly (Figure 1, bottom). The first
reaction product generates the higher field aromatic peak, has
a lower chromatographic Rf, and has a lower A0-0/A0-1
absorbance ratio (vide infra), consistent with greater π-π
overlap. Modeling shows the homo structure has a larger overlap
than the hetero one; thus, we assign the product as 5Homo.
To determine if the two compounds were truly interconverted
diastereomers, we used normal-phase HPLC to separate and
purify the suspected isomers. The compounds separated surpris-
ingly well, with 5Hetero eluting before 5Homo because of the
more steric and soluble hetero structure (Figure 2). The separate
fractions were collected and immediately characterized by ESI
mass spectrometry; each compound exhibited almost identical
mass and isotopic distributions, consistent with the cyclic dimer
containing eight chlorine atoms (Figure 2).
We then performed HPLC monitoring, starting with each
purified compound at room temperature, to examine if the
diastereomers truly interconvert, or if the conversion proceeds
in only one direction (Figure 3). Convincingly, the reaction
proceeded in both directions until reaching a 50/50 mixture in
about 24 h, after which no further change in ratio occurred.
Noticing the relative slow interconversion rate, we next
examined the temperature dependence of the isomerization
reaction rate. When a solution of 5Hetero in CDCl3 was
maintained at -20 °C for 24 h, NMR proved that no noticeable
isomerization occurred (Figure 4). These results are consistent
with our own studies16 and the recently reported free energy
barrier of 87 kJ/mol for interconverting chiral twisted tetra-
chloroperylene enatiomers.11
Why did the twisted-monomer reaction yield no measurable
concatenated rings? According to our concatenation mechanism,
the cyclic dimer and linear monomer template reacting with
another linear monomer simultaneously produced concatenated
rings. Planar perylene derivatives have identical intercomple-
mentary molecular codes. The twisted perylene derivatives,
however, are different: the racemic mixture creates two mo-
lecular codes. A concatenated tetramer prefers R,R,R,R or S,S,S,S
configurations sterically. The probability of forming such a
homochiral tetramer is only 1/8 of planar concatenated rings
because homodimers and linear monomers have only 1/2
probability of participating in the reaction for a racemic mixture.
In addition, steric hindrance probably further discourages the
formation of such a template in twisted structures that leads to
concatenated rings. These analyses reduce the theoretical yield
of the concatenated rings to less than a few percent, a level
difficult to isolate.
1
Cyclic Homo- and Heterodimer Equilibrium. H NMR first
revealed the equilibrium between the homo- and heterochiral
dimers, which are diastereomers. On the NMR time scale,
5Homo exists as a pair of enatiomers (R,R and S,S) with D2
symmetry, while 5Hetero is a meso compound (R,S) with C2h
symmetry (Figure 1, Supporting Information). Thus, both
diastereomers have a single peak representing all eight aromatic
protons, although the peaks are slightly different for the two
compounds. Similarly, the TEG chain protons also experience
slightly different chemical shifts between the diastereomeric pair;
the protons directly adjacent to the disulfide bonds are conve-
niently well resolved from other peaks and particularly sensitive
to isomerization. Immediately following reaction quenching,
5Homo was purified and characterized by NMR, showing
mainly one aromatic peak and a single triplet for the disulfide-
Self-Assembly Functions as Molecular Codes. The absence
of concatenated rings suggests that the twisted tetrachlorop-
(16) Wang, W.; Bain, A. D.; Wang, L.-Q.; Exarhos, G. J.; Li, A. D. Q. J.
Phys. Chem. A 2008, 112, 3094–3103.
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Twisted Perylene Stereodimers
A R T I C L E S
Figure 3. HPLC spectra recorded during the isomerization reaction. Pure 5Homo (left) or 5Hetero (right) interconverts to its isomers at room temperature
in CH2Cl2. The reaction proceeds in both directions until reaching a 1:1 equilibrium in about one day. Inset: Longer reaction time monitoring still showed
1:1 mixtures after several days (peaks shift to longer elution times due to change in solvent polarity).
perylenes are probably rotated 30° from each other, separated
by 3.5 Å.17 Thus, alternating stack members may be rotated
60° from each other or oriented in parallel, perfect for
cooperative catenation. The twisted tetrachloro units apparently
preclude this rotational ambiguity, forcing thiol group orientation
to be unfavorable for disulfide-bond formation between any units
other than those directly adjacent to each other.
At low concentrations (and thus limited self-assembly tem-
plate effect), the planar perylene forms a monocyclic ring,6
while the highly twisted monocyclic tetrachloroperylene does
not. One possible explanation for the absence of twisted
monocyclic tetrachloroperylene ring formation is that the twist
angle separates the two thiol groups unfavorably for intramo-
lecular disulfide-bond formation. As the two naphthalene planes
are twisted closer to perpendicular, the idealized zigzag TEG
chains also become perpendicular to each other, rendering lower
intramolecular reaction probability between the two sulfur atoms.
Experimentally, NMR has shown that the ethylene unit con-
nected to the diimide is relatively more rigid than the other
ethylene units,16 and therefore twisting the perylene core coupled
to the first rigid ethylene unit abates the probability of forming
an intramolecular disulfide bond. The added steric hindrance
of the four chlorine atoms is not likely responsible, as the much
bulkier, moderately twisted tetraphenoxyperylene (θ ≈ 25°)
readily forms the monocyclic structure.16 Unless there are
distinguishing electronic effects between the reactive thiol
groups and the Cl4-perylene core, the orientation steering is a
reasonable explanation.
Figure 4. (Top) NMR spectra recorded after a solution of 5Hetero in
CDCl3 was maintained at -20 °C for 24 h. No noticeable isomerization
occurred. (Bottom) NMR spectra recorded after a solution of 5Homo was
left at room temperature for 24 h. A significant amount of 5Hetero was
formed. Triplets for disulfide adjacent protons are inset for each sample.
The most remarkable result of the twisted cyclization reaction
is that only homochiral cyclic dimers form directly and
exclusively from the monomer racemic mixture. The perylene
units first undergo molecular recognition, dynamically self-
assembling conducive to subsequent disulfide-bond formation.
Homochiral assembly directs nearly simultaneous disulfide-bond
formation leading directly to cyclic 5Homo, whereas hetero-
chiral assembly directs stepwise disulfide coupling via inter-
mediate linear 4Hetero, precluding heterocyclization.
If instead the first disulfide bond formed primarily by random
intermolecular collision without self-assembly directing effects,
the second disulfide bond must similarly form by random
intramolecular collision. Generally, intramolecular reactions are
greatly accelerated over intermolecular reactions due to reduced
activation entropy. However, 4Hetero never directly cyclizes,
while 4Homo is never isolated because it rapidly proceeds to
5Homo. What prevents 4Hetero from cyclizing? In the absence
Figure 5. Absorbance (solid lines) and fluorescence (dashed lines) spectra
recorded in CH2Cl2 for 5Homo (blue) and 5Hetero (red) compared to the
monomer 1 (black). A lower A0-0/A0-1 ratio for the homochiral dimer (1.18)
than for the heterochiral dimer (1.28) indicates a slight difference in packing
structures. Fluorescence Fl0-0/Fl0-1 ratios corroborate the absorbance
Franck-Condon factors.
erylene units impart an effect on reaction pathways, favoring
disulfide-bond formation leading exclusively to cyclic dimers.
Conversely, planar monomers do not have such an effect, and
the reaction proceeds to concatenation in high yield.6 Thus, if
stacks greater than two twisted monomers form, they must be
oriented in such a way that only disulfide bonds between
adjacent monomers are favorable. The planar perylene, however,
was oriented in such a way that alternating members of the stack
could react, forming concatenated rings. Ab initio and DFT
calculations consistently predict that stacked adjacent planar
(17) Clark, A.; Qin, C.; Li, A. D. Q. J. Am. Chem. Soc. 2007, 129, 7586–
7595.
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A R T I C L E S
Wang et al.
Scheme 3. Synthesis Route to the Foldable Dimera
a Conditions: (i) benzoyl chloride/py; (ii) 4,4′-dimethoxytrityl chloride, DMAP/py; (iii) 2-cyanoethyl-N,N-diisopropylchlorophosphoramidite, diisopro-
pylethylamine/DCM; (iv) NPhIMT, DCM, then I2 (DCM/Py/H2O 1:3:1), room temperature; (v) TCA/DCM, room temperature.
ratio of 5Homo to 5Hetero. Because 5Hetero is not a reaction
product, intramolecular assembly must precede cyclization,
where the folded 4Hetero structure unfavorably orients the
remaining thiols, effectively blocking the reaction. Thus, mo-
lecular codes control such reactions. The same code responsible
for intramolecular folding must also direct intermolecular self-
organization, as the molecular code is not selectively turned on
and off. What hetero configuration could cause such an
unfavorable orientation? Modeling shows that longitudinally
offset stacking or perpendicular cofacial rotation could greatly
reduce the likelihood of the 90°-90° offset elbow C-S-S-C
bond formation. Regardless, the appearance of strictly hetero-
chiral linear dimers and homochiral cyclic dimers elucidates
unique molecular codes.
The code phenomenon can be explained as follows: Weak,
π-stacking force brings the monomers together via dynamic self-
Figure 6. (Left) Comparison of dimer absorbance and monomer absorbance
assembly. (The self-assembly enthalpy ∆HSA was determined
to be -3-7 kcal/mol in the planar units8,9 and smaller in the
twisted units.) Negative ∆HSA helps compensate the self-
assembly entropy ∆SSA (also negative), thus bringing some
perylene units within 3.5 Å of each other, a favorable reaction
environment. The efficaciously reduced assembly entropy pays
at least partially the disulfide-bond activation entropy penalty,
∆SqS-S. The perylene template locates the TEG chain ends near
each other so that the thiol reactive intermediates can react
favorably to form disulfide bonds. Thus, the reaction rate is
greatly increased, resulting in the kinetically favored homochiral
cyclic dimer when the self-assembled monomers have comple-
mentary molecular codes. Heterochiral monomers also have a
complementary molecular code; however, the heterochiral
molecular code directs a different self-assembled structure,
which leads to formation of the linear dimer rather than the
cyclic dimer. If the molecular code is noncomplementary, such
a specific reaction rate enhancement is absent.
in pure chloroform. The dimer is slightly vertically off-set for clarity. (Right)
Absorbance spectra monitoring the linear dimer folding in chloroform/
methanol gradient. Methanol increases the solvophobicity, causing the dimer
to fold, resulting in a diagnostic increase in the ratio A0-0/A0-1 of the
vibronic bands. In pure chloroform the ratio is 1.43, while in pure MeOH
the ratio is 1.15. This ratio for the monomer does not change even in pure
methanol (not shown).
of molecular codes, steric hindrance between heterochiral
perylene units could conceivably discourage favorable S-S
contact. However, modeling shows minimal differences between
4Homo and 4Hetero in intramolecular steric resistance, leaving
many other available configurations with likely intramolecular
thiol collision probability. This is supported by a nearly
temperature independent Keq ≈ 1 for the interconversion
between 5Homo and 5Hetero, revealing that the hetero template
is similarly favored thermodynamically over the homo template.
Had the cyclization been mainly governed by the free energy
difference between hetero and homo perylene stacking, 4Homo
and 4Hetero would equally cyclize to yield 5Homo and
5Hetero, respectively, because they have the same free energy
in the stacked states (G5Homo ) G5Hetero). Thus, a random
intramolecular collision between thiols would be nearly equally
favored in each case, and the reaction product would be a 1:1
Equation 1 shows the activation free energy that controls the
reaction rate. To increase the rate, it is desired to make the
disulfide-bond activation entropy ∆Sq as close to zero as
S-S
possible. ∆SqS-S contains translational and orientation terms (eq
2), each of which the perylene self-assembly contributes to
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8276 J. AM. CHEM. SOC. VOL. 130, NO. 26, 2008

Twisted Perylene Stereodimers
A R T I C L E S
Figure 7. Merck Molecular Force Field (MMFF94) energy-minimized models, contrasting possible folded configurations in the heterochiral dimer (top)
and the homochiral dimer (bottom) with increasing solvophobicity. As solvophobic forces drive the dimer to fold, molecular recognition codes different
homo- and heterochiral structures. Ultimately, the homochiral dimer stacks with greater π-π overlap. All atoms except for the perylene core are omitted for
clarity.
improving. The translational entropy penalty, T∆Sq
,
probability of proceeding to the disulfide.20 Regardless of
explanation, the self-assembly molecular code is significant,
orchestrating unambiguous reaction pathways that yield distinct
products.
S-S,translation
depends on the concentration but typically is -(8-10) kcal/
mol at 1 M, while the orientation penalty, T∆SqS-S,orientation, is
typically -(3-8) kcal/mol.18 Dynamic self-assembly reduces
the number of independent molecules, with a consequent loss
of three translational and up to three rotational degrees of
freedom, albeit partially compensated by residual degrees of
freedom in the self-assembled structure, especially in the flexible
TEG chains. The perylene encounter complex likely provides
catalytic factors of 2.4-6.0 kcal/mol, typical of other enzymic
or chelate rate accelerations.18a Thus, self-assembly-induced
Spectroscopic Analysis. We have previously demonstrated that
perylene folding or self-organizing has a diagnostic indicator
and changes the vibronic band ratio A0-0/A0-1 in the absorbance
spectrum.8,10 Likewise, the Franck-Condon factor changes, as
observed in the fluorescence spectrum, can also indicate similar
interaction.8–10 We have shown that planar cyclic and linear
oligomers, when excited, form delocalized excited states, which
have typical π-stack red emission, a tell-tale sign of π
interactions.7,21
diminishment in ∆Sq significantly favors coded structure
S-S
formation over random collision products.
The 5Homo and 5Hetero absorbance and fluorescence
spectra further reveal the nuance in the chiral molecular
recognition code (Figure 5). The normalized spectra show that
∆GqS-S ) ∆HqS-S - T∆Sq
(1)
(2)
S-S
∆SqS-S ) ∆SqS-S,translation + ∆Sq
S-S,orientation
the diastereomers have a clear, noticeable difference in the A0-0
/
The self-assembly-directed disulfide-bond formation is quasi-
catalytic, but there is no catalyst by definition, as dynamic self-
assembly is a phenomenon, not a substance. Catalysts are
frequently associated with lowering the activation enthalpy,
while activation entropy is often overlooked. The importance
of activation enthalpy vs entropy is still highly debated; evidence
supports that either entropy or enthalpy dominates the catalytic
effect in many enzymes.19 A popular alternative explanation is
that self-assembly stabilizes the encounter complex, holding the
transition-state thiol intermediates long enough to improve the
A
0-1 ratio. As expected, the homodimer ratio is lower than the
heterodimer ratio because the homochiral rings have a larger
π-stack area and a tighter fit, and thus they experience a greater
displaced harmonic oscillator. The 5Homo ratio is 1.18, while
the 5Hetero ratio is 1.28. Both cyclic dimers exhibit lower ratios
than the monomer and the linear dimer; the monomer and linear
dimer have a ratio of 1.43, indicating that the cyclic architecture
imposes a considerable influence on the folding equilibrium.
Interestingly, our previous report demonstrated that the linear
and cyclic planar dimers were similarly folded, exhibiting A0-0
A
/
0-1 ratios of 0.84 and 0.73, respectively.7 The highly twisted
(18) (a) Page, M.; Jencks, W. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1678–
1683. (b) Jenks, W. P. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 4046–
4050. (c) Sugimura, T.; Hagiya, K.; Sato, Y.; Tei, T.; Tai, A.;
Okuyama, T. Org. Lett. 2001, 3, 37–40. (d) Janin, J. Proteins: Struct.,
Funct. Genet. 1997, 28, 153–161.
cores are reluctant to fold in the linear dimer but are architectur-
ally forced to fold in the more structurally restrained cyclic
dimers. The cyclic dimer λmax are slightly hypsochromatically
(19) (a) Wolfenden, R.; Snider, M.; Ridgway, C.; Miller, B. J. Am. Chem.
Soc. 1999, 121, 7419–7420. (b) Bruice, T.; Lightstone, F. Acc. Chem.
Res. 1999, 32, 127–136. (c) Strajbl, M.; Sham, Y.; Villa, J.; Chu, Z.;
Warshel, A. J. Phys. Chem. B 2000, 104, 4578–4584.
(20) Frisch, C.; Fersht, A.; Schreiber, G. J. Mol. Biol. 2001, 308, 69–77.
(21) Han, J. J.; Wang, W.; Li, A. D. Q. J. Am. Chem. Soc. 2006, 128,
672–673.
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A R T I C L E S
Wang et al.
Figure 9. 1H NMR spectra of a control experiment in which the dimer
concentration was varied from 27.8 µM to 1.389 mM (limit of solubility)
while maintaining a constant 67% methanol concentration. The high-
concentration sample shifted by only 0.03 ppm upfield when compared to
the low-concentration sample, demonstrating that most chemical resonance
shifts are due to intramolecular folding effects and not intermolecular self-
assembly.
twisted dimers, indicating no delocalized excited states. Thus,
while the vibronic band ratios indicate ground-state interaction,
the excited-state coupling strength between adjacent chro-
mophores must be too weak to establish delocalization.
Foldable Linear Dimer. To complement the cyclic ring
chemistry, the twisted tetrachloro-perylene and its chirality-
responsive folding were investigated using a different approach.
The new approach uses a phosphostriester linkage to replace
the exchangeable disulfide bond to form a linear foldable dimer.
Scheme 3 outlines the synthesis strategy.
The dynamic folding equilibrium constant Kfold for the dimer
10 remains small in chlorinated solvents such as chloroform
because the highly twisted perylene has tuned down the
π-stacking force, apparent in the absorbance spectra where the
A
0-0/A0-1 vibrational peak ratio remains nearly the same as
for the monomer (Figure 6, left). This is in contrast to the more
architecturally restrained cyclic dimer, which exhibits consider-
able folding in chlorinated solvents. However, increasing the
methanol concentration generates solvophobicity, and Kfold
increases as the diagnostic A0-0/A0-1 vibronic band ratio grows
(Figure 6, right). In pure chloroform the ratio is 1.43, while in
pure MeOH the ratio is 1.15. The monomer ratio does not
change at these low concentrations prepared for absorbance
measurements, even in pure methanol (,critical concentration).
Although not apparent from the UV/vis spectrum, the
diastereomers begin to differentiate themselves as their molec-
ular recognition codes begin to enforce compatibility (Figure
7). The homochiral dimers (R,R and S,S) are not as sterically
frustrated as the heterochiral dimers (R,S and S,R), and thus
they experience a slightly more negative enthalpy of folding.
As hinted early, the homo molecular code has a different
structure than the hetero molecular code; NMR should be able
to distinguish the linear folded homodimer and heterodimer.
Ultimately, the homochiral dimer is able to fold with a greater
π-π overlap for a given solvent composition and can be
detected by NMR. The cyclic tetrachloro perylene R,R (S,S) or
R,S compound has only one equivalent aromatic proton due to
symmetric configurations, each showing a distinct chemical shift
(Vide supra). However, the linear foldable dimer has a benzoyl
anchor on one end and a hydroxyl group on the other and
Figure 8. (Top) Scheme showing solvent-dependent folding equilibrium
for the heterochiral linear dimer. (Bottom) 1H NMR spectra of the foldable
linear dimer recorded while varying the CDCl3/CD3OD gradient; CD3OD
percentage is listed for each spectrum. Increasing the solvophobicity with
methanol causes the dimer equilibrium to increase, resulting in a stronger
ring-current effect and a concomitant upfield chemical shift. The homochiral
dimers (R,R and S,S) and heterochiral dimers (R,S and S,R) have distinct
folded structures, as evidenced by different chemical resonances. The first
four spectra are taken at 1.4 mM; the last spectrum is recorded at 278 µM
to maintain solubility. Maintenance of symmetric peak structure limited to
upfield chemical shift emphasizes that the folding equilibrium is dynamic
and fast on the NMR time scale.
shifted from that of the free monomer, a further indication of
folding interactions.
The fluorescent spectrum also shows subtle differences in the
Franck-Condon factors, which again indicates a more slightly
displaced harmonic oscillator in the homochiral dimer. Unlike
the planar dimers, π-stack red emission is not observed in the
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Twisted Perylene Stereodimers
A R T I C L E S
therefore has four separate aromatic protons for each of the
homodimers and the heterodimers. The unfolded linear dimer
chemical shifts have aromatic proton resonances similar to that
of 4Hetero (∼8.67 ppm) as long as the concentration is below
the critical self-assembly concentration (about 10 mM).
However, increasing the solvophobicity forces the dimers to
fold, inducing an upfield chemical shift of the aromatic protons.
As the methanol concentration increases, homochiral dimer
folding has a larger π-contact area, and the aromatic protons
experience a greater upfield chemical shift as a result of the
ring current. Thus, similar to those of the cyclic dimers, the
linear homodimer peaks are farther upfield than the linear
heterodimer peaks.
The homo- and heterochiral dimer mixtures were diluted to
the same concentration (1.4 mM) using various ratios of
deuterated chloroform and methanol. The NMR spectra were
recorded at room temperature and the perylene core aromatic
proton chemical shifts compared (Figure 8). At 11% methanol
(v/v), the homo- and heterodimers, adopting mostly the unfolded
configuration, exhibit identical chemical shifts, both displaying
four sharp peaks in a narrow 0.020-ppm region. As the
concentration of methanol is increased to 33%, the peaks begin
to differentiate. At just over 50% methanol concentration, the
diastereomers are completely resolved, and eight sharp peaks
are clearly visible. At 66% methanol, the high-field steroisomer
and the low-field steroisomer are separated by as much as 0.099
ppm.
To see how far the diastereomers could be differentiated, a
lower concentration (278 µM) was prepared, allowing solubility
in 78% methanol. In this case, the difference between the
isomers increased to 0.120 ppm, clearly separating the proton
groups belonging to homodimers from those of heterodimers.
Since increasing the solvophobicity can also decrease the
critical self-assembly concentration and ultimately lead to
intermolecular interactions, a control experiment was performed
at a constant 67% methanol concentration while varying the
dimer concentration from 28 µM to 1.4 mM (limit of solubility).
Over this broad concentration range, the two isomers produce
a chemical shift difference of only ∼0.03 ppm (Figure 9),
demonstrating that most of the chemical shift differentiation is
due to intramolecular folding effects and not intermolecular self-
assembly.
a stepwise reaction, leading to one disulfide-bond formation and
the corresponding linear dimer, 4Hetero. These observations
provide convincing insight into how self-assembly can function
as molecular codes that direct reaction pathways. Only homo-
chiral cyclic dimers are formed from twisted chiral monomers,
providing strong evidence that self-assembly precedes ring
formation and there is a preferred molecular homochiral
recognition code. The self-assembly template directs ring
formation, likely by reducing the disulfide-bond activation
entropy penalty and favorably orienting the free-standing thiol
groups into juxtaposed positions to increase the kinetic rate of
disulfide-bond formation.
The homochiral cyclic dimers spontaneously interconvert to
the heterchiral cyclic dimer at room temperature, reaching a
1:1 equilibrium in ∼24 h. However, heterochiral cyclic dimer
cannot be synthesized directly from the racemic monomer
mixture because of forbidden molecular codes. To summarize,
the homocyclic dimer is kinetically favored; however, the kinetic
product eventually reaches a 1:1 equilibrium with its thermo-
dynamically equally favored diastereomer.
A complementary diastereomeric linear dimer was synthe-
sized using phosphoramidite chemistry to study the solvent-
dependent folding equilibrium. In contrast to the previously
studied planar perylene dimer that was mostly folded in
chlorinated solvents, Kfold in the twisted perylene dimer was
much smaller in similar solvents because the highly twisted
π-system tuned down the π-stacking force. Increasing solvent
polarity shifted the equilibrium toward the folded states and
revealed that the folded homochiral dimer and heterochiral dimer
have distinct structures. These folded nanostructures were
apparent by absorbance and NMR spectroscopy, while it was
determined that intramolecular folding dominated over inter-
molecular assembly.
The cyclic and linear twisted dimers presented here reveal
an inherent chiral molecular assembly code, directing self-
assembly, folding, and chemical reactions. The implications are
important and will undoubtedly expand the field of self-
assembly-directed chemistry. We envision that reactions utilizing
temporary π-π stacking bonds will become commonplace in
supramolecular synthesis.
Acknowledgment. The authors acknowledge the support of
National Institute of General Medicine Sciences (Grant GM065306).
A.D.Q.L. was a Beckman Young Investigation (BYI).
Conclusion
We have synthesized both cyclic and linear diastereomeric
dimers using highly twisted tetrachloroperylene monomers to
impart chirality and molecular codes. The homochiral self-
assembly directs a cooperative reaction, resulting in both
disulfide bonds forming nearly simultaneously to yield the cyclic
dimer, 5Homo, whereas the heterochiral self-assembly directs
Supporting Information Available: Synthesis and character-
ization of the cyclic and linear dimers and their intermediates.
This material is available free of charge via the Internet at http://
pubs.acs.org.
JA7111959
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