Selective and sequential photorelease using molecular switches

Article abstract of DOI:10.1002/anie.200601584

(Chemical Equation Presented) Effective release mechanism: Low-energy visible light is used to convert thermally stable cyclic dithienylethene derivatives 1 into thermally unstable forms 2 that undergo spontaneous fragmentation. The photoresponsive archit

Full text of DOI:10.1002/anie.200601584

Communications
DOI: 10.1002/anie.200601584
Molecular Switches
Selective and Sequential Photorelease Using Molecular
Switches**
Vincent Lemieux, Simon Gauthier, and Neil R. Branda*
Angewandte
Chemie
6820
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Chemie
L
ight is an effective trigger for the release of active
chemical and biological species from masked, innocuous
forms.[1] It offers the precise temporal and spatial control
needed to deliver therapeutics,[2] agents to initiate biological
phenomena,[3] and designer reagents for chemical transfor-
mations,[4] as well as for photolithography.
[4]
The number of classes of molecular structures that can be
photochemicallycleaved to free a species of interest is
relativelysmall. Most existing ssytems are based on the
photochemical redox reactions of the 2-nitrobenzyl group,
with others based on 7-nitroindoline, coumarin, hydroxyphe-
nacyl, and benzoin chromophores.[1,5] Widespread use of these
systems in practical applications is limited by a number of
factors such as the generation of reactive side products, the
need for high-energyradiation sources (200–400 nm), which
maylead to undesirable side reactions, and most significantly,
the inabilityto selectivelystimulate photocleavable groups in
the presence of others due to their absorbing light in the same
general spectral range.[1,3,5]
Our goal is to develop a universal photorelease system by
using a common photoresponsive molecular scaffold that
1) can be easilytailored to fine-tune its electronic properties
without adverselyaffecting its performance, 2) strongly
absorbs long-wavelength light to minimize cellular damage,
3) generates photoreleased products which absorb at wave-
lengths that are shifted out of the spectral region that triggers
the photorelease to minimize side reactions, and 4) is
modified using synthetic methods tolerant to a wide range
of chemistries.[6] A system that fits this description will offer a
means to sequentiallyrelease different species byusing light
of different wavelengths. Here, we report our success in
developing a versatile approach to the selective and sequen-
tial light-initiated release of an easilyfunctionalized chemical
species byusing two different thermallybistable dithienyl-
ethene (DTE) photoswitches and low-energyvisible light of
two different wavelengths.
Scheme 1. Photochemical reactions of the dithienylethene (DTE) archi-
tecture. The absorption properties attainable in the ring-closed forms
1b can be fine-tuned by modifying the groups R1 and R2 at the ends of
the p-conjugated backbone.
[8]
photoreactions of multicolored, multifrequencyssytems.
The same feature makes compounds based on the DTE
architecture appealing for use in photodeliveryapplications.
Our use of the DTE architecture as a photocleavable
group combines two approaches to integrate chemical
reactivitywith light (reactivit-ygated photoswitching and
photogated reactivity) and is based on the Diels–Alder
reaction between photostable dienes and a small dienophile
to generate photoswitchable DTE derivatives (Scheme 2).[9]
In reactivity-gated photoswitching, light does not induce a
molecular transformation unless it is preceded bya chemical
reaction between two or more species.[9] For example,
dithienylfulvenes 2 and 3 are not photoswitchable as they
lack the required hexatriene functionality. However, the
butadiene portions of the compounds (highlighted in bold)
spontaneouslyundergo thermal Diels–Alder cycloadditions
with an electron-deficient alkene 4 to result in the formation
of racemic 5a and 6a.[10] The rearrangement of the p bonds
creates the DTE architecture and renders 5a and 6a photo-
active. UV light can now be used to convert both DTE
derivatives into their thermallystable ring-closed forms, 5b
and 6b. Thus, the thermal reaction has gated the photo-
chemistry.
Dithienylethenes are molecular switches, which contain
hexatriene architectures, that undergo reversible ring-closing
and ring-opening reactions (1aÐ1b in Scheme 1) when
In photogated reactivity, light triggers a structural change
in the molecule and imparts chemical reactivityunique to
each form of the compound. This approach is also illustrated
in Scheme 2, where the reverse Diels–Alder reactions can
proceed onlyfrom the ring-open forms of the compounds
because 5b and 6b lack the cyclohexene structures required
for the fragmentation reactions. UV light has effectively
locked the systems in their “armed” states which removes all
molecules from the initiallyestablished Diels–Alder equi-
libria. The ring-closed forms can be considered to act as
phototriggers as visible light regenerates the cyclohexenes in
5a and 6a and allows the thermal Diels–Alder equilibria to be
reestablished, spontaneouslyreleasing the dienophile. Thus,
the photochemistryhas gated the thermal reaction.
[7]
irradiated with UV and visible light, respectively.
Scheme 1 also illustrates how the optical properties of the
ring-closed forms (1b) can be fine-tuned byrationally
decorating the two heterocycles on the DTE backbone; an
attribute that is central in reports that describe the selective
[*] V. Lemieux, S. Gauthier, Prof. N. R. Branda
4D LABS
Department of Chemistry
Simon Fraser University
8888 University Drive, Burnaby, BC V5A 1S6 (Canada)
Fax: (+1)604-291-3765
E-mail: nbranda@sfu.ca
Because the release mechanism is thermallydriven and
independent of the photochemistry, the photochemical trig-
gers can be tailored to harness a wide range of wavelengths to
release the small auxiliaryagent, thus offering a relatively
universal approach to photorelease technology. Also, the light
absorbed bythe ring-open isomers, the fulvenes, and the
dienophile is significantlyhigher in energyand lies far outside
[**] This work was supported by the Natural Sciences and Engineering
Research Council of Canada (PGS-A and PGS-D to V.L.), the Canada
Research Chair Program, and Simon Fraser University. We thank
Philippe Reutenauer for helpful guidance about the use of the
fumarate dienophiles.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 2. Reversible Diels–Alder reactions of fulvenes 2 and 3 with dienophile 4 to generate racemic DTEs 5a and 6a, which undergo cyclization
when irradiated with UV light. The thermally stable “armed” states, 5b and 6b, are unlocked with visible light to induce ring-opening, regenerating
the cyclohexene necessary for fragmentation. Note that the stereochemistry of 5a, 6a, 5b, and 6b is arbitrary and does not imply the formation of
specific stereoisomers.
the region used to trigger the photochemistry, thus minimiz-
ing photochemical side reactions. Another appealing feature
is that the two photoisomers of DTE derivatives displaya
wide range of properties unique to their structure, offering a
means to “release and report”,[11] that is, to quantifythe extent
and location of discharge bymonitoring a readout signal
(color, refractive index, luminescence, or redox chemistry).[12]
We chose the fulvene structure as the Diels–Alder diene
component because it undergoes both forward and reverse
cycloaddition reactions[13] under milder conditions than those
required for other dienes.[14] Dithienylfulvenes 2 and 3 can be
prepared from two known DTE derivatives (R1,R2 = Ph;[15]
R1,R2 = Cl[16] in Scheme 1).[17] As anticipated, compounds 2
and 3 show good photostabilityand their irradiation with UV
or visible light results in minimal degradation.
Dithienylfulvenes 2 and 3 readilyundergo Diels–Alder
reactions when treated with electron-deficient dienophiles
such as maleic anhydride (7) and maleimide (8; Scheme 2) to
afford the bicyclic products in nearly quantitative yields as
1
observed by H NMR spectroscopy. The products of these
reactions show excellent photoresponsive activity, and irradi-
Figure 1. Partial 1H NMR spectra (500 MHz, CD2Cl2) showing the
ating them at l = 313 nm[17] leads to an immediate decrease in
peaks corresponding to the aromatic protons in a) fulvene 2, b) a 1:1
the intensities of the high-energyabsorptions with simulta-
mixture of 2 and diethyl dicyanofumarate (4) measured when the
equilibrium with racemic 5a has been reached, c) the isolated mixture
neous appearance of absorptions in the visible region as is
typical for DTE derivatives. These changes are a result of the
ring-closing reactions of the compounds, and the solutions are
transformed from colorless to pink (when 2 is used) and
yellow (when 3 is used). Irradiation of the colored solutions
with visible light (l > 434 nm) results in ring-opening, regen-
eration of the original absorption spectra, and bleaching of
the solutions.
Although the Diels–Alder products formed using 7 or 8
show excellent photoactivityand are ideal models to charac-
terize the photochemistryof the cycloaddition products, they
are not suitable for photorelease applications as their cyclo-
addition reactions are not significantlyreversible at room
temperature. The esters of dicyanofumarate are more suitable
and establish equilibrating mixtures of starting materials and
products under much milder conditions.[18] When solutions of
fulvenes 2 and 3 in CD2Cl2 are treated with diethyl
dicyanofumarate (4), reversible reactions are immediately
observed and the equilibria between the fulvenes and the
racemic, bicyclic products 5a and 6a stabilize within
20 minutes (Figure 1a and b) and contain 40–45% of the
ring-open products.[19] Equilibrium constants at 228C were
of the ring-closed stereoisomers of 5b, and d) a solution of 5b
periodically irradiated with visible light (l>490 nm) showing the
disappearance of the ring-closed compound 5b (*) and the appear-
ance of fulvene 2 (°).
determined to be 16mꢀ1 for 2 + 4Ð5a and 13mꢀ1 for 3 +
1
4Ð6a from the H NMR spectra.
The reverse cycloaddition reactions to generate com-
pounds 2, 3, and 4 can be prevented bylocking the structures
in their ring-closed, “armed” forms 5b and 6b. Irradiation of
solutions containing the fulvenes and fumarate 4 with 313-nm
light produces compounds that are thermallystable and can
be isolated bycolumn chromatography(Figure 1c). As long
as theyare kept in the dark, both 5b and 6b can be stored with
no observable degradation in solution and in the solid state at
room temperature. Irradiation of the solutions with light of
the appropriate wavelength in the visible range (l > 557 nm
for 5b and l > 434 nm for 6b) triggers the ring-opening
reactions and subsequent release of dienophile 4 (Figure 1d).
In the case of 5b, onlythe two starting materials ( 2 and 4)
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Chemie
1
could be observed by H NMR spectroscopybythe time a
irradiated at l = 430 nm (Figure 2 f). Repeating the irradi-
spectrum could be acquired.[20] Under the conditions used to
monitor the release reactions by H NMR spectroscopy(3 ”
ation with lower energylight ( l > 557 nm) selectivelyring-
opens 5b (Figure 2c) and releases the fumarate 4 from 5a
(Figure 2g) without affecting 6b. Both compounds can be
triggered to release the dienophile when irradiated at l >
434 nm (Figure 2d and h).
1
10ꢀ3 m) and UV/Vis absorption spectroscopy(3 ” 10 ꢀ5 m),
there is quantitative release of the fumarate dienophile
within the first 3 minutes of irradiation. When the release
experiment using compound 5b is repeated at lower temper-
atures (ꢀ10 to 08C), the ring-open isomer 5a can be briefly
observed before it undergoes the rapid thermal fragmentation
reaction, illustrating that the photorelease mechanism pro-
ceeds through the ring-open isomer 5a and not bya direct
photochemical reaction.
In summary, we have presented a new approach to deliver
chemical species based on combining reactivity-gated photo-
chemistryand photogated reactivity. The light used to trigger
the release reaction is in the visible range, leading to the dual
advantages of limiting biological damage and increasing the
penetration depth. In addition, the DTE substructure will
facilitate the monitoring of the release events byusing a wide
range of physical properties, such as the absorbance or
emission of light, or electrochemical properties which are
unique to the “armed” and “released” systems. The economical
size and chemistryof the fumarate auxiliaryimplies that it can
be modified with various chemical species without significantly
interfering with the role of the component of interest, thus
offering a great potential for practical applications.
Because 5b and 6b absorb different types of visible light,
selective and sequential release can be achieved bytuning the
light source to trigger the ring-opening reaction of onlyone of
the ring-closed compounds. Figure 2 demonstrates the success
of the selective ring-opening using UV/Vis absorption spec-
troscopy(Figure 2a–d) and the selective release using
1H NMR spectroscopy(Figure 2e–h).
An equimolar mix-
[22]
ture of compounds 5b and 6b could be irradiated at l =
430 nm to selectivelyring-open onlyderivative 6b (Fig-
Received: April 21, 2006
Published online: July20, 2006
ure 2b), as it absorbs more significantlyin this spectral region.
Derivative 5b is more effective at absorbing lower energy
light and is virtuallyunaffected during this irradiation.
Keywords: cycloaddition · molecular devices · photochromism ·
Fulvene 3 and fumarate 4 are the onlynew products observed
.
1
retro reactions · UV/Vis spectroscopy
by H NMR spectroscopywhen the 1:1 mixture in CD Cl2 is
2
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pounds (h).
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[19] To obtain measurable equilibria at the concentrations used for
the experiment (1–7 ” 10ꢀ2 m), 4 equivalents of 4 were added to
the solutions of the fulvenes. The same results were obtained
when dimethyl dicyanofumarate was used.
[20] The thermal release of 3 and 4 was significantlyslower, and
appreciable amounts of the ring-open isomer 6a could be
observed by 1H NMR spectroscopy.
[21] Derivative 5b was purified as a mixture of stereoisomers by
column chromatography. Derivative 6b was further purified by
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[22] Selective ring-opening was pushed almost to completion using
different samples (Figure 3a–d) to demonstrate the high level of
selectivity. In the case of the release experiments (Figure 3e–h),
the same NMR sample was used to show sequential release.
Irradiation of each compound was stopped after partial release
for easycomparison of the spectra.
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