Reversible heterochiral aggregation/dissociation of bis(2-hydroxyphenyl) diamides driven by UV/Vis irradiation

Article abstract of DOI:10.1002/anie.201106832

Light to dissolve: (R)- and (S)-diamides bearing a hydrogen-bonding framework (red in picture) and a trans-azobenzene unit (blue) form an insoluble heterochiral aggregate, which can be dissolved by photoisomerization of the azobenzene unit to the cis conformation by UV irradiation (365-nm). The insoluble aggregate was formed again by subsequent irradiation with visible light (>422-nm). The precipitation and dissolution is manifestly reversible. Copyright

Full text of DOI:10.1002/anie.201106832

Angewandte
Chemie
DOI: 10.1002/anie.201106832
Photoisomerization
Reversible Heterochiral Aggregation/Dissociation of
Bis(2-hydroxyphenyl)diamides Driven by UV/Vis Irradiation**
Akihiro Nojiri, Naoya Kumagai,* and Masakatsu Shibasaki*
The dynamic self-assembly of molecules into supramolecular
ensembles is the basis for a vast array of living systems and has
inspired chemists to design and construct molecular architec-
tures with dynamic and responsive properties.[1] Because
molecular assembly is often exerted by the integration of
various noncovalent interactions, such as hydrogen bonding,
p–p interactions, and solvophobic effects, programmed per-
turbation of these interactions with external stimuli gives rise
to a dynamic supramolecular system.[2] For example, a hydro-
gen-bonding pattern can be modified by temperature,[3] pH
value,[4] metal cations,[5] and light,[6] leading to stimuli- and
environment- responsive materials. Among these external
stimuli, light offers a particularly effective noncontact method
for perturbation, because wavelength and intensity can be
finely tuned and the response is both rapid and reversible.[7]
Indeed, considerable efforts have been devoted to the
development of smart molecular materials exhibiting a photo-
responsive dynamic assembly.[6,7] Chirality is an additional
factor used to control molecular assembly.[8] Heterochiral
assembly is ubiquitous in nature, as exemplified by proteino-
genic amino acids,[9] and has attracted particular attention as
a possible rationale for the evolution of homochirality in
a prebiotic environment.[10] Remarkable differences in the
assembly properties of homochiral and heterochiral samples
have been observed in some cases and exploited for
significant enantiomeric amplification.[11] The heterochiral
assembly is a viable target for perturbation with external
stimuli, producing a new dynamic self-assembly system.
Herein, we report low-molecular-weight bis(2-hydroxyphe-
nyl)diamides armed with a light-responsive azobenzene unit
that exhibit a reversible heterochiral aggregation/dissociation
capability driven by irradiation with ultraviolet (UV) and
visible light (Vis). Multiple alignments of hydrogen-bond
donors and acceptors allowed for efficient aggregation and
dissociation with high fidelity. X-ray crystallographic analysis
of the heterochiral aggregate provides clues to the molecular
basis of the aggregation and dissociation properties.
Recently, we reported a solvent-dependent heterochiral
aggregation of low-molecular-weight bis(2-hydroxyphenyl)-
diamide 1a.[12,13] (R)-1a forms insoluble heterochiral aggre-
gates in halogenated solvents upon the addition of (S)-1a, and
the aggregation is highly dependent on the arrangements of
the hydrogen-bond donor and acceptor (Scheme 1a). Based
on these studies, we hypothesized that the arrangement of
phenol and amide functionalities in 1a is essential for the
aggregation properties of low-molecular-weight compounds
so that they exhibit significant solubility differences between
the homochiral and racemic samples. We envisioned that this
unique aggregation property could be applied to a dynamic
system, allowing for arbitrary control of aggregation and
dissociation by light as a non-accumulative and noncontact
external trigger.[7] Exploitation of the trans–cis isomerism of
[*] A. Nojiri, Dr. N. Kumagai, Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry, Tokyo
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
E-mail: nkumagai@bikaken.or.jp
mshibasaki@bikaken.or.jp
Homepage: http://www.bikaken.or.jp/research/group/shibasaki/
shibasaki-lab/index_e.html
A. Nojiri
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
[**] This work was financially supported by a Grant-in-Aid for Scientific
Research on Innovative Areas (NK) from MEXT. A.N. thanks the
JSPS for a predoctral fellowship. Akinobu Matsuzawa is gratefully
acknowledged for X-ray crystallographic analysis of the heterochiral
aggregate of 3b.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106832.
Scheme 1. a) A static heterochiral aggregation system and b) a
dynamic heterochiral aggregation system.
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azobenzenes for perturbing intermolecular hydrogen-bond
interactions was anticipated to offer an effective method for
regulating aggregation properties (Scheme 1b).
The design of bis(2-hydroxyphenyl)diamides bearing the
azobenzene unit is depicted in Scheme 2. Initially, preserving
the isopropyl group derived from valine as well as the
preferred hydrogen-bond donor/acceptor arrangement
Figure 1. a) Impact of the amino acid residue on heterochiral precip-
itation. b) High fidelity in the formation of insoluble heterochiral
aggregates from the ensemble of three diamides bearing different
amino acid residues.
Scheme 2. Design of bis(2-hydroxyphenyl)diamides 2 and 3 bearing an
azobenzene unit.
suitable for perturbing the intermolecular interaction by
trans–cis photoisomerization and induce reversible hetero-
chiral precipitation and dissolution.
(shown in red), we attached the azobenzene unit (shown in
blue) of diamide 2 to the salicylic acid moiety (Scheme 2a).
We anticipated that the trans and cis configurations of
azobenzene, which are interconverted by UV and Vis
irradiation, would have an impact on the aggregation
capability, thus allowing us to control aggregation and
dissociation by external light irradiation. Unexpectedly, 2
afforded few insoluble heterochiral aggregates and photo-
isomerism of 2 was not efficient.[14,15] This finding led us to
focus on the amino acid residue in the diamide framework, to
which the azobenzene unit is installed. As a preliminary study,
“cross” heterochiral aggregation was examined, where heter-
ochiral diamides bearing different amino acid residues were
mixed to test the precipitation capability. Whereas the
mixture of [(S)-1a + (R)-1a] derived from valine or the
mixture of [(S)-1b + (R)-1b] derived from phenylalanine
underwent heterochiral precipitation in CHCl3,[16] the “cross”
mixture of [(S)-1a + (R)-1b] did not produce insoluble
heterochiral aggregate, and the resulting mixture remained
homogeneous even after 24 h (Figure 1a). For the ensemble
of three molecules of [(S)-1a + (R)-1a + (R)-1b], no forma-
tion of a heterochiral aggregate with a “cross” pair was
observed, but the insoluble heterochiral aggregate of [(S)-
1a + (R)-1a] was formed exclusively, and (R)-1b was not
recognized and remained in the solution phase (Figure 1b).
These results indicated that the amino acid residue had
a significant impact on the aggregation to form precipitates,
and the uniformity of the residue is essential to the
precipitation.[17] Therefore, we anticipated that the installa-
tion of the azobenzene unit at the residue part would be
Based on the above assumption, we next designed
diamides 3 bearing a pendant azobenzene unit at the residue
part (Scheme 2b).[18] Although the solubility of diamide (S)-
3a was too low in most of the common organic solvents to
conduct further studies, (S)-3b and (S)-3c exhibited suitable
solubility to allow for the preparation of a homochiral
solution in CHCl3 or CH3CN. (S)-3b was easy to handle and
the heterochiral aggregation of 3b was examined next. When
0.05m solutions of trans-(S)-3b and trans-(R)-3b in CH3CN
were mixed, an insoluble heterochiral aggregate was pro-
duced immediately; approximately 70% of 3b was precipi-
tated within three minutes (Figure 2a).[19] Aggregation
reached completion after approximately three hours, and
87% of 3b was precipitated.[20] Subsequently, the resulting
suspension was irradiated with UV light at 365 nm for six
hours with stirring to isomerize the pendant trans- to the cis-
azobenzene unit. The isomerization resulted in the gradual
disappearance of precipitates to increase the concentration of
3b in the solution phase (Figure 2b). Eventually, a clear
homogeneous solution of 3b developed, and over 95% of 3b
went back into solution, probably because the bent cis
configuration of the azobenzene moiety disturbed the effi-
ciency of the intermolecular hydrogen-bond interactions
between the preferred framework of (S)-3b and (R)-3b.[21,22]
To dissect the origin of the heterochiral precipitation, we
performed an X-ray crystallographic analysis of a single
crystal obtained from the heterochiral aggregate of 3b
(Figure 3).[23] Similar to the heterochiral aggregate of
1a,[12,24] we observed a zig-zag tight packing of (S)-3b and
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Figure 2. a) Formation of insoluble heterochiral aggregates of trans-3b. CH3CN solutions of trans-(S)-3b and trans-(R)-3b (both 0.05m) were
mixed and the content of the solution phase was analyzed by HPLC. b) Dissolution of insoluble heterochiral aggregates by UV irradiation
(365 nm). As the fraction of cis-(S)-3b and cis-(R)-3b increased, the concentration of diamides (S)-3b and (R)-3b in the solution phase increased
to form a clear orange solution after six hours. The white object in the photograph is a teflon-coated magnetic stir bar. Ar=3,5-(CF3)2C6H3.
leading to dissociation
and dissolution of the
insoluble
heterochiral
aggregate.
The reversible nature
of trans–cis photoisomer-
ism can be exploited to
produce reversible heter-
ochiral precipitation and
dissolution in the present
diamide
system
(Figure 4). After the ini-
tial formation of the
insoluble
heterochiral
aggregate (point (A) in
Figure 4), UV irradiation
at 365 nm was used to
produce a clear solution
(point (B) in Figure 4).
The thus-formed homo-
geneous heterochiral so-
Figure 3. X-ray crystal structure of the heterochiral aggregate of 3b represented in a tube model. a) Tight hydrogen-
bond packing in an R/S alternating array along the amide functionalities of trans-(S)-3b and trans-(R)-3b. b) A close
offset p–p contact (3.58 ꢀ) was observed between azobenzene units. The electron-deficient (CF3)2C6H3 group and
C6H4 group were paired. H white, C gray, N blue, O red, F light blue.
(R)-3b through hydrogen bonding between amide functions
(Figure 3a). Furthermore, azobenzene units lined up in
parallel and offset p–p stacking was operative as a secondary
interaction (Figure 3b). Although the crystal structure could
not directly reflect the packing pattern of the insoluble
heterochiral aggregate, isomerization of the trans-azobenzene
unit to cis-azobenzene might attenuate the heterochiral
association through the preferred hydrogen-bond framework,
lution of cis-configured 3b was irradiated with visible light at
a wavelength above 422 nm for three hours to re-isomerize to
trans-azobenzene, and subsequent stirring again resulted in
the formation of insoluble heterochiral aggregate (point (C)
in Figure 4). When the mixture was left in the dark, the trans/
cis ratio of 3b remained stable, and the precipitation persisted
(point (D) in Figure 4). This precipitation/dissolution process
can be repeated at least five times.[25] Furthermore, in contrast
to the [(S)-1a + (R)-1b] mixture, for which no “cross”
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from the preferred hydrogen-bonding framework and favor-
able p–p interaction and hydrogen bonding were achieved
without attenuating each other. Introduction of a functional
group to endow a specific catalytic function to these dynamic
precipitation/dissolution systems would be possible and will
be examined in future studies.[26,27]
In conclusion, we demonstrated the reversible formation
of insoluble heterochiral aggregate of low-molecular-weight
diamides bearing an azobenzene unit. Trans–cis isomerism of
the azobenzene unit had a significant impact on the precip-
itation properties, allowing us to control precipitation and
dissolution of the diamides by UV/Vis irradiation, which can
be repeated reproducibly. The concentration of the diamides
in the solution phase can be manipulated by this reversible
precipitation/dissolution, and the introduction of catalytic
functional groups to the diamides would foster the develop-
ment of a smart catalyst, the catalytic efficiency of which is
controlled by an external signal.[26] Further exploration of
diamides to exploit this aggregation/dissociation property in
molecular catalysis is underway.
Figure 4. Iterative formation of an insoluble heterochiral aggregate of
diamide 3b driven by UV/Vis irradiation. CH3CN solutions of trans-(S)-
3b and trans-(R)-3b (both 0.04m) were mixed and the content of the
solution phase was monitored by HPLC analysis.
Received: September 26, 2011
Revised: November 28, 2011
Published online: January 19, 2012
Keywords: azobenzene · dynamic aggregation ·
hydrogen bonds · photochromism · self-assembly
aggregation occured (Figure 1), the “cross” aggregation
proceeded with a [(R)-3b + (S)-3c] combination to form
heterochiral precipitate (Figure 5), presumably because the
positions of distinct substituents were sufficiently far apart
.
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[17] As described in the last section, diamides 3 exhibited “cross”
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[18] Synthesis of diamide (S)-3a–c is described in the Supporting
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[19] The mixture was stirred with a magnetic stirrer. At each point,
the mixture was centrifuged and a small aliquot of the resultant
supernatant was subjected to HPLC analysis to determine the
content in the solution phase. Salicylamide was used as an
internal standard for HPLC analysis. See the Supporting
Information for details.
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was left standing at room temperature to grow a single crystal of
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and stirring were different from the conditions for Figure 2, in
which immediate precipitation was observed. CCDC 843843
(trans-3b) contains the supplementary crystallographic data for
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[14] Synthesis of diamide 2 is described in the Supporting Informa-
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