Chiral Translation and Cooperative Self-Assembly of Discrete Helical Structures Using Molecular Recognition Dyads

Article abstract of DOI:10.1021/ja064554z

Complementary diaminopyridine (DAP) and flavin derivatives self-assemble into discrete helically stacked tetrads in hydrocarbon solvents. The self-assembled structure was demonstrated through induced circular dichroism using DAPs with chiral side-chains a

Full text of DOI:10.1021/ja064554z

Published on Web 10/28/2006
Chiral Translation and Cooperative Self-Assembly of Discrete
Helical Structures Using Molecular Recognition Dyads
Hiroshi Nakade,† Brian J. Jordan,† Hao Xu,† Gang Han,† Sudhanshu Srivastava,†
Rochelle R. Arvizo,† Graeme Cooke,‡ and Vincent M. Rotello*,†
Contribution from the Department of Chemistry, UniVersity of Massachusetts, 710 North
Pleasant Street, Amherst, Massachusetts 01003, and WestCHEM Centre for Supramolecular
Electrochemistry, Department of Chemistry, Joseph Black Building, UniVersity of Glasgow,
Glasgow G12 8QQ, United Kingdom
Received June 27, 2006; E-mail: rotello@chem.umass.edu
Abstract: Complementary diaminopyridine (DAP) and flavin derivatives self-assemble into discrete helically
stacked tetrads in hydrocarbon solvents. The self-assembled structure was demonstrated through induced
circular dichroism using DAPs with chiral side-chains and flavin with achiral side-chains. Flavin derivatives
with chiral side-chains were synthesized; cooperativity in the self-assembly was established through circular
dichroism (CD) profiles and melting curves. It was found that placing stereocenters in both recognition
units resulted in a strong bisignated profile and enhancement of complex stability, indicative of cooperative
self-assembly.
versatile liquid crystalline materials.7 Discrete self-assembly,
in contrast, provides monodisperse and well-defined structures
Introduction
displaying useful properties.8 Examples include molecular
capsulation,9 chiral amplification10 and memory,11 and selective
Molecular self-assembly presents access to ordered aggregates
in materials science.1 Extended self-assemblies provide three-
dimensional networks, which have led to the development of
materials for sensing,2 optoelectronic devices,3 transporting-
channels,4 gels,5 and nanotube materials,6 as well as highly
(7) (a) Kato, T.; Matsuoka, T.; Nishii, M.; Kamikawa, Y.; Kanie, K.; Nishimura,
T.; Yashima, E.; Ujiie, S. Angew. Chem., Int. Ed. 2004, 43, 1969-1972.
(b) Hirschberg, J.; Koevoets, R. A.; Sijbesma, R. P.; Meijer, E. W. Chem.-
Eur. J. 2003, 9, 4222-4231. (c) van Gorp, J. J.; Vekemans, J.; Meijer, E.
W. J. Am. Chem. Soc. 2002, 124, 14759-14769. (d) Barbera, J.; Puig, L.;
Romero, P.; Serrano, J. L.; Sierra, T. J. Am. Chem. Soc. 2005, 127, 458-
464. (e) Kato, T.; Mizoshita, N.; Kishimoto, K. Angew. Chem., Int. Ed.
2005, 45, 38-68. (f) Kamikawa, Y.; Nishii, M.; Kato, T. Chem.-Eur. J.
2004, 10, 5942-5951. (g) Bushey, M. L.; Nguyen, T. Q.; Zhang, W.;
Horoszewski, D.; Nuckolls, C. Angew. Chem., Int. Ed. 2004, 43, 5446-
5453. (h) Bushey, M. L.; Hwang, A.; Stephens, P. W.; Nuckolls, C. Angew.
Chem., Int. Ed. 2002, 41, 2828-2831. (i) Giorgi, T.; Lena, S.; Mariani,
P.; Cremonini, M. A.; Masiero, S.; Pieraccini, S.; Rabe, J. P.; Samori, P.;
Spada, G. P.; Gottarelli, G. J. Am. Chem. Soc. 2003, 125, 14741-14749.
(8) Mateos-Timoneda, M. A.; Crego-Calama, M.; Reinhoudt, D. N. Chem. Soc.
ReV. 2004, 33, 363-372.
(9) (a) Rivera, J. M.; Martin, T.; Rebek, J. Science 1998, 279, 1021-1023.
(b) Rivera, J. M.; Craig, S. L.; Martin, T.; Rebek, J. Angew. Chem., Int.
Ed. 2000, 39, 2130. (c) Kerckhoffs, J.; ten Cate, M. G. J.; Mateos-Timoneda,
M. A.; van Leeuwen, F. W. B.; Snellink-Ruel, B.; Spek, A. L.; Kooijman,
H.; Crego-Calama, M.; Reinhoudt, D. N. J. Am. Chem. Soc. 2005, 127,
12697-12708. (d) Nuckolls, C.; Hof, F.; Martin, T.; Rebek, J. J. Am. Chem.
Soc. 1999, 121, 10281-10285. (e) Palmer, L. C.; Zhao, Y. L.; Houk, K.
N.; Rebek, J. Chem. Commun. 2005, 3667-3669.
(10) (a) Mateos-Timoneda, M. A.; Crego-Calama, M.; Reinhoudt, D. N.
Supramol. Chem. 2005, 17, 67-79. (b) Prins, L. J.; Huskens, J.; de Jong,
F.; Timmerman, P.; Reinhoudt, D. N. Nature 1999, 398, 498-502. (c)
Ishida, Y.; Aida, T. J. Am. Chem. Soc. 2002, 124, 14017-14019. (d)
Takeuchi, M.; Imada, T.; Shinkai, S. Angew. Chem., Int. Ed. 1998, 37,
2096-2099. (e) ten Cate, A. T.; Dankers, P. Y. W.; Kooijman, H.; Spek,
A. L.; Sijbesma, R. P.; Meijer, E. W. J. Am. Chem. Soc. 2003, 125, 6860-
6861. (f) Shi, X. D.; Fettinger, J. C.; Davis, J. T. J. Am. Chem. Soc. 2001,
123, 6738-6739. (g) Prins, L. J.; Timmerman, P.; Reinhoudt, D. N. J.
Am. Chem. Soc. 2001, 123, 10153-10163.
(11) (a) Ziegler, M.; Davis, A. V.; Johnson, D. W.; Raymond, K. N. Angew.
Chem., Int. Ed. 2003, 42, 665-668. (b) Ikeda, C.; Yoon, Z. S.; Park, M.;
Inoue, H.; Kim, D.; Osuka, A. J. Am. Chem. Soc. 2005, 127, 534-535. (c)
Terpin, A. J.; Ziegler, M.; Johnson, D. W.; Raymond, K. N. Angew. Chem.,
Int. Ed. 2001, 40, 157-160. (d) Prins, L. J.; De Jong, F.; Timmerman, P.;
Reinhoudt, D. N. Nature 2000, 408, 181-184. (e) Ishi-i, T.; Crego-Calama,
M.; Timmerman, P.; Reinhoudt, D. N.; Shinkai, S. J. Am. Chem. Soc. 2002,
124, 14631-14641. (f) Ishi-i, T.; Crego-Calama, M.; Timmerman, P.;
Reinhoudt, D. N.; Shinkai, S. Angew. Chem., Int. Ed. 2002, 41, 1924-5.
† University of Massachusetts.
‡ University of Glasgow.
(1) Typical reviews: (a) Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.;
Sijbesma, R. P. Chem. ReV. 2001, 101, 4071-4097. (b) Hoeben, F. J. M.;
Jonkheijm, P.; Meijer, E. W.; Schenning, A. Chem. ReV. 2005, 105, 1491-
1546. (c) Elemans, J.; Rowan, A. E.; Nolte, R. J. M. J. Mater. Chem. 2003,
13, 2661-2670.
(2) Fenniri, H.; Deng, B. L.; Ribbe, A. E. J. Am. Chem. Soc. 2002, 124, 11064-
11072.
(3) (a) Wurthner, F.; Chen, Z. J.; Hoeben, F. J. M.; Osswald, P.; You, C. C.;
Jonkheijm, P.; von Herrikhuyzen, J.; Schenning, A.; van der Schoot, P.;
Meijer, E. W.; Beckers, E. H. A.; Meskers, S. C. J.; Janssen, R. A. J. J.
Am. Chem. Soc. 2004, 126, 10611-10618. (b) Schenning, A.; Meijer, E.
W. Chem. Commun. 2005, 3245-3258. (c) Schenning, A.; Jonkheijm, P.;
Peeters, E.; Meijer, E. W. J. Am. Chem. Soc. 2001, 123, 409-416. (d)
Jonkheijm, P.; Hoeben, F. J. M.; Kleppinger, R.; van Herrikhuyzen, J.;
Schenning, A.; Meijer, E. W. J. Am. Chem. Soc. 2003, 125, 15941-15949.
(e) Thalacker, C.; Wurthner, F. AdV. Funct. Mater. 2002, 12, 209-218.
(f) Jeukens, C.; Jonkheijm, P.; Wijnen, F. J. P.; Gielen, J. C.; Christianen,
P. C. M.; Schenning, A.; Meijer, E. W.; Maan, J. C. J. Am. Chem. Soc.
2005, 127, 8280-8281.
(4) (a) Percec, V.; Dulcey, A. E.; Balagurusamy, V. S. K.; Miura, Y.; Smidrkal,
J.; Peterca, M.; Nummelin, S.; Edlund, U.; Hudson, S. D.; Heiney, P. A.;
Hu, D. A.; Magonov, S. N.; Vinogradov, S. A. Nature 2004, 430, 764-
768. (b) Percec, V.; Dulcey, A. E.; Peterca, M.; Ilies, M.; Sienkowska, M.
J.; Heiney, P. A. J. Am. Chem. Soc. 2005, 127, 17902-17909. (c) Percec,
V.; Dulcey, A. S. E.; Peterca, M.; Ilies, M.; Ladislaw, J.; Rosen, B. M.;
Edlund, U.; Heiney, P. A. Angew. Chem., Int. Ed. 2005, 44, 6516-6521.
(d) Kaucher, M. S.; Harrell, W. A., Jr.; Davis, J. T. J. Am. Chem. Soc.
2006, 128, 38-39.
(5) (a) Hirst, A. R.; Smith, D. K.; Feiters, M. C.; Geurts, H. P. M. Chem.-Eur.
J. 2004, 10, 5901-5910. (b) Kim, H. J.; Zin, W. C.; Lee, M. J. Am. Chem.
Soc. 2004, 126, 7009-7014.
(6) (a) Moralez, J. G.; Raez, J.; Yamazaki, T.; Motkuri, R. K.; Kovalenko, A.;
Fenniri, H. J. Am. Chem. Soc. 2005, 127, 8307-8309. (b) Miyauchi, M.;
Takashima, Y.; Yamaguchi, H.; Harada, A. J. Am. Chem. Soc. 2005, 127,
2984-2989. (c) Raez, J.; Moralez, J. G.; Fenniri, H. J. Am. Chem. Soc.
2004, 126, 16298-16299.
9
14924
J. AM. CHEM. SOC. 2006, 128, 14924-14929
10.1021/ja064554z CCC: $33.50 © 2006 American Chemical Society

Chiral Translation and Cooperative Self-Assembly
A R T I C L E S
ionophores.12 In many cases, the development of sophisticated
self-assembled materials will require reliable methods to control
the aggregation.
Chiral translation is ubiquitous in self-assembled materials
and provides a tool for characterization of dynamic self-
assembled structures. These self-assemblies generally feature
helical structures consisting of racemic mixtures of right- and
left-handed self-assembled structures. Installation of stereo-
centers into building blocks give rise to favored handedness of
the aggregation, allowing us to modulate chiroptical properties,
and thus three-dimensional structures of self-assemblies.7f,13
Molecular capsulation featuring chiral cavities formed through
chiral translation provides a platform for chiral discrimination
of a targeted guest molecule,9 offering novel methodologies for
the creation of chiral sensors.14 Thus, installment of stereocenters
in building blocks generates a new strategy toward the control
of chiral translation within self-assembled structures. The
consequence of the interplay of chiral translation will create
frustrated and cooperative systems, provided that the delicate
interplay of stereocenters is substantial in the formation of self-
assembled structures.
In previous studies, we15 and others16 have established specific
molecular recognition through three-point hydrogen bonding
using diaminopyridine (DAP) and flavin. The DAP-flavin dyad
provides an effective platform for the demonstration of chiral
translation: specific hydrogen bonding and long wavelength
absorption of the flavin should enable us to detect chiral self-
assembled structures. Herein, we report the design and char-
acterization of discrete self-assembly of specific hydrogen-
bonded dyads based on DAP and flavin (Figure 1a). These
systems demonstrate (1) chiral translation to an achiral flavin
from a chiral DAP due to the self-assembled structure and (2)
the cooperative self-assembly system using chirality in both
components of the DAP-flavin dyad. Chiral translation occurs
through formation of a discrete tetramolecular complex, as
established using light scattering. Induced CD (ICD) of the
achiral flavin demonstrates the self-assembly of the complex
in a helical sense. Finally, combination of chiral DAPs with
the chiral flavin provides insight into the interplay of stereo-
centers and demonstrates the formation of cooperative and
frustrated systems.
Figure 1. (a) Molecular structures of specific hydrogen-bonding dyad based
on diaminopyridine-flavin. (b) Illustrative representation of right-handed
(P) and left-handed (M) stacking structures for the complexes (1S-2, 1R-
2, and 1S-2S); achiral flavin 2 can be CD active due to the formation of
self-assembled structure based on biased helical stacking of dyads, and the
1S-2S system provides the cooperative self-assembly.
to demonstrate cooperative assembly in combination with 1S-
R. N-Methyl flavin 3 was employed to provide a non-hydrogen-
bonding control.
Chiral Translation in Self-Assembled Structures. Binding
affinity between 1 and 2 through specific hydrogen bonding
1
was quantified using H NMR titration in CDCl3, resulting in
an association constant (Ka) of 1050 M-1 at 23 °C. CD spectra
of achiral flavin 2 with 1S and 1R were recorded in a variety
of solvents to probe ICD17 in DAP-flavin systems. No
significant Cotton effect was observed in solvents such as
toluene and halomethanes (CH2Cl2 and CHCl3), where DAP-
flavin hydrogen bonding occurs. This lack of ICD indicates that
formation of the DAP-flavin dyad does not result in efficient
translation of chirality. In contrast, strong ICD was observed
in less polar hydrocarbon solvents such as hexanes, cyclohex-
anes, and dodecane, indicative of the formation of helical self-
assembled structures. As expected from the self-assembled
nature of these systems, significant temperature dependence of
ICD was observed. A 1:1 mixture of DAP 1S and flavin 2 (1S-
2) showed induced Cotton effect in the range of -10 to 20 °C
°C (Figure 2), whereas at elevated temperatures (30-50 °C)
the Cotton effect completely disappeared. This dependence was
completely thermally reversible (Figure 2a). The consistency
and lack of hysteresis of the two curves obtained upon heating
and cooling cycles reflect the reversible formation of discrete
Results and Discussion
Synthesis. We prepared three DAP hosts (1, 1S, and 1R)
and flavin guests (2, 2S, and 3) (Figure 1a) to provide a system
for discrete self-assembly. Enantiomerically pure tails, (S) and
(R)-citronellols, were installed in DAP 1S and 1R, respectively,
to demonstrate chiral translation into the achiral flavin guest 2,
resulting in evidence for discrete self-assembled structures
(Figure 1b). Flavin 2S featuring (S)-citronellol was synthesized
(12) (a) Van Leeuwen, F. W. B.; Miermans, C. J. H.; Beijleveld, H.;
Tomasberger, T.; Davis, J. T.; Verboom, W.; Reinhoudt, D. N. EnViron.
Sci. Technol. 2005, 39, 5455-5459. (b) van Leeuwen, F. W. B.; Verboom,
W.; Shi, X. D.; Davis, J. T.; Reinhoudt, D. N. J. Am. Chem. Soc. 2004,
126, 16575-16581.
(13) Prins, L. J.; Jolliffe, K. A.; Hulst, R.; Timmerman, P.; Reinhoudt, D. N. J.
Am. Chem. Soc. 2000, 122, 3617-3627.
(14) Nonokawa, R.; Yashima, E. J. Am. Chem. Soc. 2003, 125, 1278-1283.
(15) (a) Breinlinger, E.; Niemz, A.; Rotello, V. M. J. Am. Chem. Soc. 1995,
117, 5379-5380. (b) Deans, R.; Niemz, A.; Breinlinger, E. C.; Rotello, V.
M. J. Am. Chem. Soc. 1997, 119, 10863-10864.
(16) (a) Tamura, N.; Mitsui, K.; Nabeshima, T.; Yano, Y. J. Chem. Soc., Perkin
Trans. 2 1994, 2229-2237. (b) Cooke, G. Angew. Chem., Int. Ed. 2003,
42, 4860-4870.
(17) (a) Yashima, E.; Maeda, K.; Nishimura, T. Chem.-Eur. J. 2004, 10, 43-
51. (b) Sakai, R.; Satoh, T.; Kakuchi, R.; Kaga, H.; Kakuchi, T.
Macromolecules 2004, 37, 3996-4003.
9
J. AM. CHEM. SOC. VOL. 128, NO. 46, 2006 14925

A R T I C L E S
Nakade et al.
Figure 2. Variable-temperature CD spectra of 1S-2 in n-hexane (total
concentration: 4 × 10-4 M, -10 to 50 °C, 10 mm path). Inset (a) shows
the reversibility of the Cotton effect at 490 nm upon temperature control
between -10 and 50 °C. Arrows indicate changes upon decreasing
temperature. Inset (b) shows variable-temperature CD spectra of DAP 1S
and N-methyl flavin 3 in cyclohexane (total concentration: 4 × 10-4 M,
10-40 °C, 10 mm path).
Figure 3. CD spectra of 1S-2 and 1R-2 recorded at -10 °C in n-hexanes
(total concentration: 3 × 10-4 M, 10 mm path); mirror-image Cotton effects
were observed for 1S-2 and 1R-2.
self-assembled structures. A 1:1 mixture of DAP 1S and
N-methyl flavin 3 (1S-3) in cyclohexane18 displayed no Cotton
effect even at reduced temperatures (Figure 2b), whereas
substantial ICD was observed with the DAP 1S and flavin 2 in
the same solvent.19 This contrasting behavior demonstrates the
requirement for three-point hydrogen bonding in the chiral
translation process.
Figure 4. 1H NMR spectra of 1S (top) and 1S-2 (bottom) recorded at 25
°C in n-hexane-d14 (total concentration: 1 × 10-3 M). DAP amide peak
(7.38 ppm) completely disappeared, and DAP aromatic peak (7.74 ppm)
was broadened upon mixing with flavin 2. Flavin peaks for aromatic core
protons were significantly broadened due to the aggregation of flavins inside
of the self-assembled structure.
Mirroring Cotton effects were observed upon self-assemblies
of 1S-2 and 1R-2 (Figure 3). Given that the sign of coupling
and the direction of dipole moments are established, the coupling
in the flavin visible region allows the determination of the
chirality of stacking using semiempirical methods.20 In general,
CD spectra featuring bisignate Cotton effects showing positive
features at longer wavelength and negative ones at shorter
wavelength indicate that the chirality of the dipole moments is
right-handed, so-called “positive chirality”. In the DAP-flavin
assembly, UV absorption at 450 nm results exclusively from
π-π* transition across the flavin ring with the directionality
shown in Figure 1a.21 This absorption showed bisignated Cotton
effects centered at 450 nm in CD; negative (negative first and
positive second) and positive (likewise positive first and negative
second) chiralities were observed for 1S-2 and 1R-2, respec-
tively. The negative chirality induced by the (S)-configuration
in the peripheral chains corresponds to a left-handed stacking,
and the positive chirality induced by the (R)-configuration
indicates a right-handed stacking in the self-assembled structures
(Figure 1b).
With ICD demonstrated in the DAP-flavin system, we
focused on determining the structure of the DAP-flavin
assembly. Variable-temperature UV experiments were per-
formed to demonstrate interactions between dyads. Absorption
at 450 nm showed a 4 nm hypochromic effect upon decrease
of temperature (50 to 20 °C), indicative of solvophobic π-π
1
stacking.19 Further structural insight was obtained using H
NMR in n-hexanes-d14 (Figure 4). Addition of flavin 2 to DAP
1S resulted in the disappearance of the DAP amide peak, and
peak broadening and upfield shift of the aromatic protons of
DAP branching group. Significantly, resonances arising from
flavin 2 were extremely broad. The observed line-broadening
and upfield shifts were typical for self-assembled structures
resulting from close contact of aromatics and restricted mobility
of flavins in the self-assembled structures.3c,4a,22 The upfield
shifts in DAP support the stacked structures of self-assemblies.
Given that the loss of mobility increases the relaxation time in
NMR, resulting in line-broadening or even disappearance of
the peaks for flavins, we can conclude that flavins are stacked
in the self-assembled structures with low mobility. The contrast-
ing behavior of the DAP and flavin resonances is indicative of
(18) Cyclohexane was required for the mixture of 1S and 3 due to the solubility
in n-hexanes.
(19) See Supporting Information.
(20) (a) Berova, N.; Nakanishi, K.; Woody, R. Circular Dichroism: Principles
and Applications, 2nd ed.; Wiley-VCH: New York, 2000; pp 337-382.
(b) Balaz, M.; Holmes, A. E.; Benedetti, M.; Rodriguez, P. C.; Berova,
N.; Nakanishi, K.; Proni, G. J. Am. Chem. Soc. 2005, 127, 4172-4173.
(c) Borovkov, V. V.; Lintuluoto, J. M.; Fujiki, M.; Inoue, Y. J. Am. Chem.
Soc. 2000, 122, 4403-4407. (d) Hofacker, A. L.; Parquette, J. R. Angew.
Chem., Int. Ed. 2005, 44, 1053-1057.
(22) (a) Kraft, A.; Osterod, F.; Frohlich, R. J. Org. Chem. 1999, 64, 6425-
6433. (b) Brunsveld, L.; Zhang, H.; Glasbeek, M.; Vekemans, J.; Meijer,
E. W. J. Am. Chem. Soc. 2000, 122, 6175-6182.
(21) Song, P. S. Ann. N.Y. Acad.Sci. 1969, 158, 410-423.
9
14926 J. AM. CHEM. SOC. VOL. 128, NO. 46, 2006

Chiral Translation and Cooperative Self-Assembly
A R T I C L E S
Figure 5. Variable-concentration DLS and CD experiments of 1S-2,
recorded at 20 °C (DLS (blue), CD (red), total concentration: 5 × 10-5 to
5 × 10-3 M). Inset (a) is the DLS result at 5 × 10-3 M showing essentially
monodisperse assembly.
a complex where flavins are stacked atop one another, where
the stacking is more rigid than the stacking of the DAPs atop
each other.
An important issue with the DAP-flavin assembly is whether
discrete assemblies or extended aggregates are formed. The size
of self-assembled structures was determined using variable-
concentration dynamic light scattering (DLS). An increase in
the hydrodynamic diameter was observed with increasing total
concentration, reaching a limiting value of 3.2 nm. In the range
of 5 × 10-4 to 5 × 10-3 M, DLS profiles showed narrow
monomodal distributions (over 90% is in the range of 2-5 nm)
(Figure 5a). The limiting value accompanied with the narrow
monomodal distribution in the concentration-dependent DLS
demonstrates the formation of discrete self-assembly rather than
extended self-assembly. This profile was strongly correlated with
the concentration-normalized induced Cotton effect (Figure 5).
No detectable aggregation was observed with DLS in solvents
that do not induce ICD such as CH2Cl2 and toluene.
Because of the broadening within the NMR and lack of
crystallinity of the complexes, direct determination of the
structure of the complex was not possible. From the CD data
(vide supra), we could conclude that dyad formation was
required for transduction based on the lack of ICD when using
N-methyl flavin 3. Moreover, on the basis of the lack of ICD
in halogenated solvents where nonaggregating dyads were
formed, we could conclude that more than one dyad was
required in the assembly. NMR provides further information
on the structure. From the selective broadening of the flavin in
the complex, we can infer that the flavins are stacked atop each
other. Finally, DLS provides an approximate diameter for the
complex of 3.2 nm.
Figure 6. (a) Energy-minimized models of self-assembled dyad-dimer.
Surrounding aliphatic tails preclude further aromatic stacking within the
dyad-dimer structure. (b) Aromatic core of tetramolecular structure (trans-
flavin over flavin arrangement is shown, and side-chains are omitted for
clarification).
agreement with the 3.2 nm obtained using DLS results (Figure
6a). From these simulations, it was clear that the aliphatic tails
surrounding aromatic cores prevented further stacking within
the dyad-dimer structure, preventing extended aggregation.
These results were consistent with the discrete structures that
were observed experimentally (Figure 6). Modeling also pro-
vided further insight into the arrangement of specific hydrogen-
bonding units in the self-assembled structure. Given that the
1H NMR spectrum of the DAP 1S and flavin 2 assembly
indicated flavin-flavin stacking, two possible arrangements
were considered: trans- and cis-arrangements relative to the
direction of side-chains on the flavin-flavin stacked system.19
The trans-flavin over flavin complex shown in Figure 6 was
found to be 2.7 kcal/mol (11.4 kJ/mol) more stable than the
cis, indicating that the trans structure is the most likely one
found in solution.
To provide a possible structure for the assembly, Monte Carlo
conformation analysis using Amber* force field23 was used to
provide structures based on the above experimental observations.
We found that two dyads stacked one upon the other provided
a structure with an average diameter of 3.4 nm, in excellent
Cooperative Self-Assembly. Chiral flavin 2S was synthesized
to further understand the effect of side tails on chiral translation.
Considering the stereocenters of the side-chains in the dyad,
three unique systems were explored: 1-2S, 1S-2S, and 1R-
2S. The 1-2S in contrast to 1S-2 complex has the stereocenter
on the flavin, revealing the effect of stereocenter location on
(23) Macro Model v.7.0: Mohamadi, F.; Richards, N. G. J.; Guida, W. C.;
Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still,
W. C. J. Comput. Chem. 1990, 11, 440-467.
9
J. AM. CHEM. SOC. VOL. 128, NO. 46, 2006 14927

A R T I C L E S
Nakade et al.
Figure 7. CD spectra of 1-2S recorded in the range of -10 to 50 °C in
n-hexanes (total concentration: 6 × 10-4 M, 10 mm path). The arrow
indicates changes upon decreasing temperature.
Figure 8. CD spectra of 1R-2S recorded in the range of -10 to 60 °C in
n-hexanes (total concentration: 6 × 10-4 M, 10 mm path). The arrow
indicates changes upon decreasing temperature.
the self-assembly. CD spectra of 1-2S were recorded in hexanes
and CH2Cl2. As expected, the 1-2S complex also provided
chiroptical properties associated with flavin due to the formation
of the self-assembled structures; 1-2S showed a temperature-
dependent Cotton effect in hexanes (Figure 7), and no Cotton
effect was observed in CH2Cl2 in the given temperature range.
The relatively complicated signature observed in hexanes (Figure
7) is in contrast to that observed in the 1S-2 and 1R-2 systems
(Figures 2 and 3). This difference clearly shows the effect of
location of the stereocenters on chiral translation; chiral flavin
2S provides remote control of self-assembly distinct from that
of chiral DAPs (1S and 1R). This discrepancy is presumably
due to the distance from assembly center and heterogeneity of
hydrogen-bonding units.
As demonstrated in Figures 2, 3, and 7, stereocenters on the
side-chains on each recognition unit provide differing self-
assembly properties. To determine if there is cooperativity based
on the interplay of side-chain chirality in the recognition process,
hybridized self-assemblies (1R-2S and 1S-2S) were prepared
in hexanes and CD spectra were recorded. The 1R-2S system
that has (R)-citronellols on DAP and (S)-citronellols on flavin
showed weak Cotton effects indicative of frustrated self-
assembly for 1R-2S (Figure 8). In sharp contrast, the 1S-2S
system that has (S)-citronellols in both recognition units showed
a strong bisignate Cotton effect indicative of cooperative process
(Figure 9). Ellipticity at 458 nm for three systems (1S-2S,
1-2S, and 1R-2S) was recorded in the temperature range of
-10 to 60 °C to provide preliminary insight of cooperative and
frustrated translations (Figure 10). From melting curves, it was
clear that the stability of 1S-2S was greatly improved in
comparison to other systems (1-2S and 1R-2S). A sigmoidal
curve was observed for 1S-2S, and simple slopes were observed
for 1-2S and 1R-2S in the given temperature range. The
observed sigmoidal curve evidently supports the cooperative
self-assembly for 1S-2S, resulting in the stabilization of the
structures.
Figure 9. CD spectra of 1S-2S recorded in the range of -10 to 60 °C in
n-hexanes (total concentration: 6 × 10-4 M, 10 mm path). Arrows indicate
changes upon decreasing temperature.
Figure 10. Melting curves for 1-2S, 1S-2S, and 1R-2S recorded in the
range of -10 to 60 °C in n-hexanes (total concentration: 6 × 10-4 M, 10
mm path). Ellipticity at 458 nm was monitored. Solid lines present heating
profiles, and dotted lines present cooling profiles.
Interestingly, swapping achiral tails to (S)-citronellyl tails on
flavin unit promotes dramatic chiroptical switching in the
cooperative self-assembly (Figure 11). The observed bisiganted
Cotton effects for 1S-2 and 1S-2S are almost mirror-image,
providing evidence for opposite sense of stacking: (M)-stacking
for 1S-2 and (P)-stacking for 1S-2S. Considering that the
1S-2 system has the (S)-citronellyl tails on DAP 1S and 1S-
2S has the (S)-citronellol tails on both DAP and flavin for the
chiral translation, the switching was triggered by conferring the
same configuration of (S)-citronellyl tails on the recognition
9
14928 J. AM. CHEM. SOC. VOL. 128, NO. 46, 2006

Chiral Translation and Cooperative Self-Assembly
A R T I C L E S
Figure 12. CD response changes in variable mole fraction of 2S in the
mixture of 1S-2 and 1S-2S.
12 shows chiroptical response as a function of the mole fraction
of 2S. The distinctive nonlinear behavior at 425 nm indicates
that flavin 2S can direct achiral 2 to follow the preorganized
helical structures in a “Sergeants and Soldiers” fashion; a dyad
with 80% of the chiral building block 2S provides essentially
the same chiroptical property as a dyad prepared with 100% of
the chiral building block.
Figure 11. CD spectra of 1S-2S and 1S-2 recorded at -10 °C in
n-hexanes (total concentration: 7 × 10-4 M, 10 mm path).
dyads. The results clearly suggest that the location and combi-
nation of chiral tails dictate chiroptical property and coopera-
tivity in the DAP-flavin self-assembly.
Given that 1S-2S provides the cooperative translation, we
focused on chiral amplification effects in the DAP-flavin self-
assembly, the “Sergeants and Soldiers” effect.24 This effect
demonstrates the ability of chiral building blocks to guide the
achiral components in effect of the helicity induced by chiral
blocks, apparent in dynamic helical polymers25 and self-
assemblies.7c,26 Observation of this phenomena would reflect
the control of achiral unit 2 by chiral unit 2S in the self-
assembled structures. To provide preliminary insight of this
effect, hybridized experiments of 1S-2 and 1S-2S solutions
were performed at a fixed total concentration of flavin (2 and
2S), and chiroptical responses at 425 nm were monitored. Figure
Conclusions
We demonstrated the chiral translation in a DAP-flavin self-
assembled structure using ICD. Specific three-point hydrogen
bonding triggers the formation of a tetrameric complex that
exhibits chiral translation. The combination of the same ste-
reocenters on both recognition units provides cooperative self-
assembly resulting in improvement of stability and efficient
chiroptical switching. The observed location and cooperative
effects provide new directions of molecular design for self-
assembly. Ongoing studies are focused on bulk and surface
properties of the discrete self-assembly as well as the electronic
control of the properties.
(24) (a) Green, M. M.; Park, J. W.; Sato, T.; Teramoto, A.; Lifson, S.; Selinger,
R. L. B.; Selinger, J. V. Angew. Chem., Int. Ed. 1999, 38, 3139-3154. (b)
Green, M. M.; Peterson, N. C.; Sato, T.; Teramoto, A.; Cook, R.; Lifson,
S. Science 1995, 268, 1860-1866. (c) Hirschberg, J.; Brunsveld, L.; Ramzi,
A.; Vekemans, J.; Sijbesma, R. P.; Meijer, E. W. Nature 2000, 407, 167-
170.
(25) (a) Nakano, T.; Okamoto, Y. Chem. ReV. 2001, 101, 4013-4038. (b) Green,
M. M.; Reidy, M. P.; Johnson, R. J.; Darling, G.; Oleary, D. J.; Willson,
G. J. Am. Chem. Soc. 1989, 111, 6452-6454. (c) Nagai, K.; Maeda, K.;
Takeyama, Y.; Sakajiri, K.; Yashima, E. Macromolecules 2005, 38, 5444-
5451. (d) Wilson, A. J.; Masuda, M.; Sijbesma, R. P.; Meijer, E. W. Angew.
Chem., Int. Ed. 2005, 44, 2275-2279. (e) Schlitzer, D. S.; Novak, B. M.
J. Am. Chem. Soc. 1998, 120, 2196-2197.
Acknowledgment. This research was supported by the NSF
[CHE-0518487] and MRSEC (DMR 0213695). G.C. thanks
EPSRC. We acknowledge Cambridge Isotope Laboratories, Inc.
for the donation of a series of deuterated solvents. B.J.J.
acknowledges the NSF [DUE-044852] for an IGERT fellowship,
and R.R.A. thanks the NIH for a CBI fellowship (T32
GM008515).
Supporting Information Available: Experimental details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(26) (a) Mateos-Timoneda, M. A.; Crego-Calama, M.; Reinhoudt, D. N. Chem.-
Eur. J. 2006, 12, 2630-2638. (b) Ishi-i, T.; Kuwahara, R.; Takata, A.;
Jeong, Y.; Sakurai, K.; Mataka, S. Chem.-Eur. J. 2006, 12, 763-776. (c)
Brunsveld, L.; Schenning, A.; Broeren, M. A. C.; Janssen, H. M.;
Vekemans, J.; Meijer, E. W. Chem. Lett. 2000, 292-293.
JA064554Z
9
J. AM. CHEM. SOC. VOL. 128, NO. 46, 2006 14929