Benzylidene-oxazolones as molecular photoswitches

Article abstract of DOI:10.1021/ol301741g

The synthesis and photochemical study of a family of molecular switches inspired by the green fluorescent protein (GFP) chromophore is presented. These compounds can be easily synthesized, and their photophysical properties may be tuned. Due to their effi

Full text of DOI:10.1021/ol301741g

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4334–4337
Benzylidene-Oxazolones as Molecular
Photoswitches
Marina Blanco-Lomas, Pedro J. Campos, and Diego Sampedro*
´
Departamento de Quımica, Centro de Investigacion en Sıntesis Quımica (CISQ),
Universidad de La Rioja, Madre de Dios, 51, E-26006, Logrono, La Rioja, Spain
ꢀ
´
´
~
diego.sampedro@unirioja.es
Received June 25, 2012
ABSTRACT
The synthesis and photochemical study of a family of molecular switches inspired by the green fluorescent protein (GFP) chromophore is
presented. These compounds can be easily synthesized, and their photophysical properties may be tuned. Due to their efficient
photoisomerization and high stability, these compounds can be switched on/off by using light and heat or light with different wavelengths.
Different stimuli have been used recently to induce a
mechanical movement at the molecular level.1 In particu-
lar, the use of light has been extensively used to provide a
rapid and noninvasive way to control movement.2,3 Dif-
ferent types of systems capable of E/Z photoisomerization
have been already used as molecular switches in order to
control diverse properties.4À6 Among the several photo-
chemicalswitchesdeveloped, systemsbased on azobenzene
have been extensively used in biological applications7 and
photomodification of polymers8 and to induce photome-
chanical movements in liquid crystals,9 just to mention
some examples. Azobenzene derivatives feature very inter-
esting properties such as strong light absorption, efficient
photoisomerization, and a great change in the distance
between the extremes of the molecule after isomerization.
Moreover, a vast diversity of azobenzene derivatives are
synthetically accessible and a detailed knowledge of the
relation between substitution and properties is available.
Chiral diarylidenes, which provide very different struc-
tures and properties, have been also extensively studied.10,11
In these compounds, a single isomerizable bond allows for a
preferential direction of isomerization. Thus, these com-
pounds can act as molecular rotors or motors. In spite of
these appealing properties as effective switches, azobenzene
derivatives or chiral diarylidenes are just examples of a
whole family of compounds capable of performing con-
trolled E/Z isomerization. Consequently, the preparation of
switches that differ from these structures in properties such
as size, shape change, wavelength of absorption, polarity,
and isomerization mechanism represent an attractive re-
search target. This could, in turn, expand the applicability of
the switch concept to different and increasingly complex
molecular environments.
(1) Molecular Switches; 2nd ed.; Feringa, B. L.; Browne, W. R., Eds.;
Wiley-VCH: Weinheim, 2011.
(2) Balzani, V.; Credi, A.; Venturi, M. Molecular Devices and Ma-
chines: Concepts and Perspectives for the Nanoworld; Wiley-VCH Verlag,
Germany: Weinheim, 2008.
(3) Bossi, M. L.; Aramendıa, P. F. J. Photochem. Photobiol. C 2011,
12, 154.
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Allain, M.; Richomme, P.; Levillain, E.; Roncali, J. J. Am. Chem. Soc.
2003, 125, 2888.
To help in the development of new prototypes, inspira-
tion from Nature can provide useful insights. For instance,
the retinal protonated Schiff base (PSB) chromophore of
rhodopsins12 constitutes an example of a very efficient E/Z
switch shaped by biological evolution. In fact, several
families of Rh-based photoswitches have already been
(6) Shinkai, S.; Minami, T.; Kusano, Y.; Manabe, O. J. Am. Chem.
Soc. 1983, 105, 1851.
(10) Feringa, B. L. Acc. Chem. Res. 2001, 34, 504.
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(8) Natansohn, A.; Rochon, P. Chem. Rev. 2002, 102, 4139.
(9) Yu, Y.; Nakano, M.; Ikeda, T. Nature 2003, 425, 145.
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Physics; Stavenga, D. G., de Grip, W. J., Pugh, E. N., Eds.; Elsevier:
Amsterdam, 2000; Vol. 3, p 56.
r
10.1021/ol301741g
Published on Web 08/09/2012
2012 American Chemical Society

synthesized and their properties as photoswitches have
been reported.13À19 These systems have been also used to
photocontrol peptide conformations.20À22
and photochemical study of oxazolone analogs of the GFP
chromophore to test their ability to act as efficient mole-
cular photoswitches.
Another example of biomolecules that undergo photo-
induced Z/E isomerizations is the chromophore of the
green fluorescent protein (GFP), from Aequorea victoria
jellyfish. GFPs are intrinsically fluorescent molecules
whose optical properties are determined by a photoexci-
table green-light emitter chromophore.23 However, several
studies have revealed that the GFP chromophore also
undergoes nonradiative processes when irradiated with
light, such as a Z/E photoisomerization, which contributes
to reducing the luminescence quantum yield.24À27 Also,
different modifications of the imidazoline GFP chromo-
phore have been also reported to show photophysical and
photochemical relevant processes.25,28,29 Interestingly,
well-known intermediates in the synthesis of GFP deriva-
tives such as the oxazolone analogs have been only slightly
explored in terms of their photoswitching ability. Although
the photoisomerization of benzylidene lactones has been
known for some time,30,31 only recently have some re-
ports on the photophysical properties of these com-
pounds appeared, with a focus on the fluorescence and
its applications.32À34 Thus, we report herein the synthesis
The general structure of synthesized compounds is
shown in Figure 1, together with the GFP chromophore.
The main difference between them is that the GFP chro-
mophore and its derivatives present an amide function in
the five-membered ring (dihydroimidazolone), while the
compounds that we have studied have an ester function
instead (5(4H)-oxazolones). The structure of the GFP
chromophore can be easily achieved from the synthesized
structures through a single reaction step.25 The synthesis of
the new photoswitches with the structure based on the
GFP chromophore takes place under the classical condi-
tions for the formation of azalactones,35 which is repre-
sented in Scheme 1. Using this methodology a number of
photoswitches can be easily synthesized (Table 1). In all
cases, the Z isomer was the only product detected in the
reaction crude. The configuration assigment was made on
the basis of X-ray diffraction data for 2d (see Supporting
Information (SI) for details).
(13) Sampedro, D.; Migani, A.; Pepi, A.; Busi, E.; Basosi, R.;
Latterini, L.; Elisei, F.; Fusi, S.; Ponticelli, F.; Zanirato, V.; Olivucci,
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Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 17642.
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Zanirato, V.; Olivucci, M. J. Org. Chem. 2009, 74, 4666.
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Sinicropi, A.; Parisi, M. L.; Martin, E.; Ryazantsev, M.; Ding, W. J.;
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2010, 29, 3117.
Figure 1. GFP chromophore (a) and oxazolone derivatives (b).
Scheme 1. Synthesis for GFP-Based Photoswitches
(19) Rivado-Casas, L.; Blanco-Lomas, M.; Campos, P. J.; Sampedro,
D. Tetrahedron 2011, 67, 7570.
(20) Andruniow, T.; Fantacci, S.; De Angelis, F.; Ferre, N.; Olivucci,
M. Angew. Chem., Int. Ed. 2005, 44, 6077.
(21) Blanco-Lomas, M.; Samanta, S.; Campos, P. J.; Woolley, G. A.;
Sampedro, D. J. Am. Chem. Soc. 2012, 134, 6960.
(22) Sinicropi, A.; Bernini, C.; Basosi, R.; Olivucci, M. Photochem.
Photobiol. Sci. 2009, 8, 1639.
(23) Heim, R.; Prasher, D. C.; Tsien, R. Y. Proc. Natl. Acad. Sci. U.S.
A. 1994, 91, 12501.
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G. J. Phys. Chem. A 2011, 115, 13733.
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Viappiani, C.; Beltram, F. J. Phys. Chem. B 2008, 112, 10714.
(26) Yang, J.-S.; Huang, G.-J.; Liu, Y.-H.; Peng, S.-M. Chem.
Commun. 2008, 1344.
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J.-S.; Kranz, C.; Tolbert, L. M. J. Am. Chem. Soc. 2010, 132, 5845.
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(29) Kikuchi, A.; Fukumura, E.; Karasawa, S.; Mizuno, H.; Miyawaki,
A.; Shiro, Y. Biochemistry 2008, 47, 11573.
Although this methodology can be used to prepare a
wide range of products, the use of certain benzaldehyde
derivatives, such as 2-carboxy- or 2-cyanobenzaldehyde,
and ketones is prevented. Next, the UVÀvis spectra for all
the synthesized compounds were measured. The values for
the maximum wavelengths and the extinction coefficients
of the bands found for each compound in acetonitrile are
displayed in Table S1. Interestingly, these compounds
(30) Baumann, N.; Sung, M.-T.; Ullman, E. F. J. Am. Chem. Soc.
1968, 90, 4157.
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Org. Lett., Vol. 14, No. 17, 2012
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Table 1. Synthesized Molecular Switches
Table 2. Photostationary State
entry
R1
R2
switch
ratio Z/E
1
2
3
4
5
6
7
Ph
Ph
Ph
Me
Me
Me
Me
Ph
2a
2b
2c
2d
2e
2f
75/25
83/17
75/25
64/36
80/20
83/17
83/17
p-MeOPh
p-BrPh
o-MeOPh
Ph
p-NO2Ph
2g
samples were performed every 3 min with the aim of
tracking the isomerization process of the compounds
Z-2e and E-2e. Representing the isomer ratio vs the
irradiation time, we obtained the two graphs that are
shown in Figure 2, (a) corresponding to the sample with
100% of Z-2e isomer at the beginning of the reaction, and
(b) corresponding to the sample with 100% of E-2e isomer
at tirrad = 0 min.
show a maximum of absorption around 350 nm, though
the presence of electron-donating groups provokes a red
shift of the band. Thus, 2b absorbs in the visible. This is
indeed a very useful feature for a photoswitch, as low-
energy light compatible with complex environments such
biological media could be used. Besides, the UVÀvis
spectra of the compounds were measured in diverse sol-
vents with varying polarity. Acetonitrile and chloroform
were used to test if there was any solvent effect. The
spectrum for 2e is shown in Figure S1. It should be noted
that the maximum absorption wavelength of the band only
suffers a slight (5 nm) red shift when changing from a polar
(acetonitrile) to a nonpolar (chloroform) solvent. How-
ever, in general terms, we can consider that the UV
spectrum of these compounds remains almost the same,
so they can be used in different environments without large
modifications in the photophysical properties.
Analysis of the UVÀvis spectra of the photoswitches
showed that, for irradiating the different compounds, a
Pyrex filter can be used to avoid radiation below 290 nm.
Thus, as the light source, a 125-W medium-pressure Hg
lamp was used. The results for the irradiation in an
immersion well reactor of 0.01 M solutions of a selection
of photoswitches in acetonitrile are shown in Table 2. The
irradiation process of each compound was followed by 1H
NMR, at different time intervals, until the photostationary
state (PSS) was reached, since Z and E isomers have
1
distinctive H NMR signals (see SI). Integration of the
1H NMR signals corresponding to each isomer allowed us
to know the isomer ratio at a given irradiation time.
Depending on the absorption bands, the irradiated mix-
ture took from 1 to 3 h to reach the PSS. The resulting
mixture of isomers could be separated by flash chromato-
graphy on silica gel, using hexane/ethyl acetate (10:1) as
eluent.
Then, we studied the kinetics of the isomerization reac-
tion. For this purpose, wepreparedin two distinctivePyrex
NMR tubes two 0.07 M solutions in CDCl3, one for each
isomer of 2e. Afterward, both NMR tubes were irradiated
in a 125-W medium-pressure Hg lamp and a Pyrex filter,
until both solutions reached the PSS. As the samples were
directly dissolved in CDCl3, it was easy to follow the
photoisomerization reaction by 1H NMR at short irradia-
Figure 2. Isomers ratio vs the irradiation time starting from the
(a) Z isomer and (b) E isomer of compound 2e after irradiation
with a 125-W medium-pressure Hg lamp and a Pyrex filter.
As can be seen, the PSS is rapidly reached (ca. 30 min)
and the isomer ratio is independent from the starting
isomer (Z or E). On the other hand, from the linear
1
tion intervals. Therefore, H NMR spectra of the two
4336
Org. Lett., Vol. 14, No. 17, 2012

relationship between the first points of each graph of
Figure 2 (representing ln [A0]/[A] vs irradiation time with
a linear fit), we can calculate the values for the kinetic
constants of each process and, therefore, the value of the
relative kinetic constant that relates the speed of both
processes. In this particular case, if k ZfE = 1, then kEfZ
≈ 4.5, which means that the EfZ isomerization process is
4.5 times faster than the ZfE reaction. Besides, when both
samples reached the PSS, we proceeded to heat them at
50 °C in the dark for several hours, to see if the isomer ratio
was altered. By studying the 1H NMR spectra oftheheated
samples, we deduced that at that temperature the isomer
ratio remained unchanged. This implies that these photo-
switches are thermally stable at 50 °C and can be operated
by light without the interference of thermal processes.
Using deuterated toluene, we warmed up the samples at
100 °C. This way, we observed that the Z isomer remained
unchanged whenheatedforlongperiods oftime. However,
the E isomer slowly reverted to the Z isomer, and after
heating for 776 h, this reversion was fully achieved. Con-
sequently, we can use this property to tune the switch
behavior, obtaining mixtures of isomers rich in one isomer
or another depending on whether we use light or heat.
We then explored the effect of the wavelength of irradia-
tion in the switching process. Figure 3 shows the UV
spectra for both isomers of 2e.
was reached. As shown in Figure 3, at 330 nm the Z isomer
has a stronger absorption. Consequently, a PSS richer in
the E isomer was expected. The progress of the reaction
was followed by 1H NMR, and the isomer ratio at the PSS
was found to be 43% (Z)/57% (E) independently of the
starting isomer. Then we selected an irradiation wave-
length from the end of the band (370 nm). At this wave-
length, the E isomer presented stronger absorption than
the Z isomer. The equilibrium was displaced toward the
formation of Z, being the main isomer at the PSS, with a
value of 83% (Z)/17% (E). Finally, we selected a wave-
length from the beginning of the band (260 nm). At this
wavelength, the E isomer absorbed more than the Z, but
the absorption for both isomers was really low. This means
that the EfZ isomerization was favored over the ZfE
reaction. Consequently we found a mixture of isomers rich
in Z, although we were not able to reach the PSS due to low
reaction rates. Therefore, we can obtain mixtures of iso-
mers rich in Z at the beginning and end of the absorption
band (260 and 370 nm), while mixtures of isomers rich in E
are afforded when irradiating at the maximum of the band
(330 nm).
Tocheck the photoisomerization efficiencywemeasured
the quantum yield of the reaction using the two isomers of
2e to determine the photoisomerization quantum yield for
both the ZfE reaction and the EfZ process. Using trans-
azobenzene36 as the actinometer (SI), we obtained 0.25 (
0.01 for the ZfE process and 0.11 ( 0.02 and for the EfZ
isomerization. Thus, these prototypes of molecular
switches can be considered quite efficient, as the measured
Φ valuesfor the two isomers of thisswitchare similartothe
values obtained for the photoisomerization of analogous
compounds based on the GFP chromophore.37
We have shown that an efficient photoswitching process
can be achieved by using oxazolone analogs of the GFP
chromophore. The easy and versatile synthesis allows for
the preparation of derivatives with a different substitution
pattern that can be used to tune the photophysical proper-
ties. The main isomer can be controlled not only by using
light or heat as the stimulus but also through careful
selection of the wavelength of irradiation. Further efforts
to fully understand the photophysics of the process and to
use these switches in a complex system are currently
underway.
Figure 3. UVÀvisspectrafortheZand Eisomers of compound 2e.
Acknowledgment. This research has been supported by
the Spanish MICINN (CTQ2011-24800). M.B.-L. thanks
the Spanish MEC for her grant. The authors thank
Fernando Rodriguez (Universidad de La Rioja) for his
assistance in solving the X-ray diffraction structure.
It can be seenthat there are slight differences in the shape
of their absorption bands. Thanks to this effect, we could
selectively irradiate in different regions of the absorption
spectrum of each isomer with monochromatic light to
obtain different isomer ratios at the PSS depending on
the irradiation wavelength (SI). We first irradiated a
solution of each isomer of 2e at 330 nm until the PSS
Supporting Information Available. Synthetic proce-
dures, characterization data and CIF file for 2d. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(36) Kuhn, H. J.; Braslavsky, S. E.; Schmidt, R. Pure Appl. Chem.
2004, 76, 2105.
ꢁ
(37) Abbandonato, G.; Signore, G.; Nifosi, R.; Voliani, V.; Bizzarri,
The authors declare no competing financial interest.
R.; Beltram, F. Eur. Biophys. J. 2011, 40, 1205.
Org. Lett., Vol. 14, No. 17, 2012
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