A Redox Isomerization Strategy for Accessing Modular Azobenzene Photoswitches with near Quantitative Bidirectional Photoconversion

Article abstract of DOI:10.1021/acs.orglett.9b03387

Photoswitches capable of accessing two geometric states are highly desirable, especially if their design is modular and incorporates a pharmacophore tethering site. We describe a redox isomerization strategy for synthesizing p-formylazobenzenes from p-nit

Full text of DOI:10.1021/acs.orglett.9b03387

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Redox Isomerization Strategy for Accessing Modular Azobenzene
Photoswitches with Near Quantitative Bidirectional
Photoconversion
Jie S. Zhu,† Julio M. Larach,† Robert J. Tombari,† Phillip W. Gingrich,† Stanley R. Bode,†
Jeremy R. Tuck,† Hunter T. Warren,† Jung-Ho Son,† Whitney C. Duim,† James C. Fettinger,†
Makhluf J. Haddadin,‡ Dean J. Tantillo,† Mark J. Kurth,*,† and David E. Olson*,†,§,∥
†Department of Chemistry, University of California, Davis, One Shields Avenue, Davis, California 95616, United States
‡Department of Chemistry, American University of Beirut, Beirut 1107 2020, Lebanon
§Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, 2700 Stockton Boulevard,
Suite 2102, Sacramento, California 95817, United States
∥Center for Neuroscience, University of California, Davis, 1544 Newton Court, Davis, California 95618, United States
S
* Supporting Information
ABSTRACT: Photoswitches capable of accessing two geo-
metric states are highly desirable, especially if their design is
modular and incorporates a pharmacophore tethering site. We
describe a redox isomerization strategy for synthesizing p-
formylazobenzenes from p-nitrobenzyl alcohol. The resulting
azo-aldehydes can be readily converted to photoswitchable
compounds with excellent photophysical properties using
simple hydrazide click chemistry. As a proof of principle, we
synthesized a photoswitchable surfactant enabling the photocontrol of an emulsion with exceptionally high spatiotemporal
precision.
Challenges associated with azobenzene design often require
he optical control of systems can be achieved by exploiting
Tthe photoisomerization of functional groups such as these tools to be engineered on a case-by-case basis using
azologization or azoextention strategies.6 This lack of modu-
larity limits the ability of non-experts to design photoswitchable
technologies. Therefore, we sought to design an azobenzene
chromophore that could be conjugated to any pharmacophore
or functional group through simple, robust chemistry to produce
completely bidirectional photoswitches. We envisioned that an
aldehyde would be an ideal handle for introducing moieties of
interest via hydrazide click chemistry.7 However, access to azo-
aldehydes is not straightforward as most azobenzenes are
constructed via the Mills reaction following nitroarene reduction
or aniline oxidation (Figure 1B) to nitroso compounds,
conditions not tolerated by redox-labile aldehydes. Alternatively,
at the expense of step economy, p-nitrosobenzaldehyde can be
synthesized via nitrosation of potassium trifluoroborates.8
Inspired by the Davis−Beirut reaction (DBR), we envisioned
a redox isomerization strategy for accessing p-formylazoben-
zenes from p-nitrobenzyl alcohol (1) (Figure 1C). The DBR
delivers 2H-indazoles9 by in situ generation of an o-nitro-
sobenzaldehyde, primary amine condensation, and N−N bond-
forming heterocyclization. Thus, we hypothesized that p-
nitrosobenzaldehyde could be formed by treating p-nitrobenzyl
stilbenes, spiropyrans, diarylethenes, and fulgides.1,2 Of these,
azobenzenes are prominent due to their large and rapid change
in geometry, fatigue resistance, and tunability (Figure 1A).1b,3
The greatest challenge associated with designing biologically
relevant azobenzene photoswitches is ensuring that the two
wavelengths of light used to induce photoisomerization are
sufficiently red-shifted to maximize light penetration and
minimize tissue damage, while achieving complete E and Z
isomer conversion. Typically, irradiation of the E isomer with
UV light induces isomerization to the Z isomer via a π → π*
transition, while visible light promotes Z → E conversion via an
n → π* transition.4 The Z isomer n → π* transition is
symmetry-allowed and more intense than that of the E isomer.
However, the E and Z isomer n → π* bands tend to overlap,
making it challenging to achieve complete conversion to the E
isomer, though strategies for separating the n → π* bands of the
two isomers have been reported.5 Another approach to
obtaining high Z → E conversion relies on rapid thermal
relaxation of push−pull azobenzenes, so-called “pseudo-
stilbenes”.3a The advantage is that their π → π* transitions are
red-shifted; however, this usually results in significant overlap of
the π → π* and n → π* transitions, making it difficult to
selectively irradiate one isomer and achieve highly enriched
photostationary states (PSSs).
Received: September 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03387
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Letter
a
Table 1. Synthesis and PSSs of Modular Photoswitches
Figure 1. (A) Azobenzenes toggle between two PSSs depending on the
irradiation wavelength. (B) Azobenzenes are traditionally synthesized
via Mills reaction between an aniline and a nitrosoarene − derived by
either reduction of a nitroarene or oxidation of an aniline. (C) Our
redox isomerization strategy for preparing modular photoswitches.
Figure 2. (A) A variety of p-formylazobenzenes can be accessed from p-
nitrobenzyl alcohol. The X-ray structures of one such product (8) and
the associated azoxy byproduct (7) are shown. (B) The nitroso-
aldehyde can be trapped via a Diels−Alder reaction. (C) Proposed
mechanism for redox isomerization of 1.
alcohol with a base. Subsequent aniline condensation with the
nitroso-aldehyde would furnish azo-imines that could be
hydrolyzed to the desired azo-aldehydes. Herein, we report
the synthesis of p-formylazobenzenes through a redox isomer-
ization strategy, their chromatography-free coupling to
hydrazides, and the unique photophysical properties of the
resulting modular photoswitches.
a
Photostationary states measured via 1H NMR in DMSO-d6 are
reported at various wavelengths (nanometers). Quantification of a
photostationary state consisting of >95% of a single isomer is
challenging due to the signal-to-noise ratio of H NMR. Therefore, a
1
Treatment of p-nitrobenzyl alcohol (1) with KOH and an
excess of commercially available anilines in a MeOH/H2O
95:5 ratio represents a maximally enriched photostationary state.
Upon sequential illumination from short to long wavelengths, 470
b
B
DOI: 10.1021/acs.orglett.9b03387
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Letter
Table 1. continued
c
nm light induces the largest change in the Z:E ratio. Half-life (t1/2) of
316 min at room temperature as determined by 1H NMR in DMSO-
d
d6. Rotomers observed.
Figure 4. Calculated differential electron density surfaces (excited−
ground state) predict localization of electron density changes over the
azo functionality rather than the acylhydrazone. Red and blue indicate
increased and decreased electron density, respectively, in the excited
compared to the ground states. Density calculations were performed for
the lowest-energy π → π* and n → π* transitions for 13E and 13Z,
respectively.
mixture yields azo-imines. Electron-rich anilines exhibit greater
reactivity toward the transiently formed nitroso intermediate as
compared to electron-deficient anilines. Selective imine to
aldehyde hydrolysis is accomplished using aqueous acid. This
procedure yields the desired p-formylazobenzenes in reasonable
yields [∼65% per step (Figure 2A); see the Supporting
Information for a detailed discussion (Figure S1)]. Experimental
evidence supports the intermediacy of a nitroso-aldehyde. Azoxy
compound 7 was often observed,10 and a Diels−Alder reaction
with 1,3-cyclohexadiene can trap nitroso-aldehyde intermediate
2 producing 9 [20% yield (Figure 2B)].
ation,14 we characterized the PSSs of these modular photo-
switches (Table 1). In general, moving from blue to red light
resulted in PSSs more highly enriched in the E isomers. The half-
life (t1/2) for thermal isomerization of 13Z was 316 min at room
temperature in DMSO-d6. When a Z-enriched sample of 13 was
illuminated sequentially from long to short wavelengths,
photoisomerization was first observed at 625 nm, suggesting
that the PSSs at 656 nm reported in Table 1 might be slightly
impacted by thermal relaxation occurring during measurement
of the PSSs.
While the isomeric enrichment of most azobenzene PSSs are
typically only 70−80%, many compounds described here
exhibited near quantitative bidirectional photoconversion
regardless of what hydrazide was appended to the p-
formylazobenzene. Our results suggest that the appended
substrate does not influence the photophysical properties of
the chromophore; thus, this chromophore can incorporate a
variety of warheads without suppressing the photoswitching
performance. While individual photoswitches capable of
A proposed mechanism for the formation of nitroso-aldehyde
2 is shown in Figure 2C. The pKa of p-nitrotoluene is 20.4 in
DMSO,11 so benzylic deprotonation of p-nitrobenzyl alcohol
(1) is a reasonable first step. Proton transfer yields 12, and
hydroxide elimination furnishes 2. While redox isomerization of
o-nitrobenzyl alcohol has a strong precedent,12 we report for the
first time this transformation has been achieved using p-
nitrobenzyl alcohol. However, p-nitrobenzyl alcohol is known to
undergo redox isomerization following irradiation with light,
generating the dimer of p-nitrosobenzaldehyde.13
Using hydrazide click chemistry,7 we were able to convert 8
into a variety of photoswitchable compounds in excellent yields
[65−95% (Table 1)]. The simplicity of this procedure is of
particular importance as it allows others without synthetic
expertise to readily prepare novel photoswitchable tool
1
compounds. Using H NMR under constant sample irradi-
Figure 3. (A) Acylhydrazone-containing modular photoswitch 13 exhibits improved bidirectional photoconversion relative to that of parent aldehyde
8 or constitutional isomer 25. Photostationary states measured via 1H NMR in DMSO-d6 are reported at various wavelengths (nanometers). The
maximally enriched states for the Z and E isomers are colored blue and orange, respectively. Quantification of a photostationary state consisting of
1
>95% of a single isomer is challenging due to the signal-to-noise ratio of H NMR. Therefore, a 95:5 ratio represents a maximally enriched
photostationary state. (B) UV−vis spectra of 8, 13, and 25 (50 μM DMSO) after illumination with the indicated wavelengths for 10 min.
C
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Letter
acylhydrazone containing 13 can achieve more highly enriched
PSSs (Figure S2).
While 13 was derived from the reaction of an azoaldehyde
with a hydrazide, we reasoned that modular photoswitches could
also be prepared by reacting an azohydrazide with an aldehyde.
Therefore, we synthesized 25, a constitutional isomer of 13
resulting from the transposition of the acylhydrazone atoms.
Surprisingly, 25 was unable to achieve highly enriched
photostationary states (Figure 3), suggesting that it is not
simply an increased level of conjugation but rather the specific
array of atoms in the acylhydrazide that endows 13 with unique
photophysical properties.
These photoswitches contain two potential photoswitchable
groups, the azobenzene and the acylhydrazone.17 However, at
biologically relevant wavelengths, we observe photoisomeriza-
tion of only the azo group, not the acylhydrazone, even after
extended irradiation. Time-dependent density functional theory
(see SI for details) was used to predict differences in electron
densities between ground and excited states for 13E and 13Z
(Figure 4). Differential electron density surfaces depict electron
density primarily over the azo motif, with far less observed over
the acylhydrazone motif.
This difference potentially explains why the E acylhydrazone
configuration is retained during visible light-induced photo-
isomerization of the azo group. Furthermore, independent
switching of two photoswitchable motifs is often not observed
when the two functional groups are electronically coupled, as in
13. However, through careful molecular design, photoswitch-
able functional groups within the same molecule can be
electronically decoupled from each other to achieve independ-
ent photoswitching.18
Finally, we used our modular strategy to engineer 24 (see
Table 1), a compound with a polar cationic headgroup and a
hydrophobic azobenzene tail capable of serving as a photo-
switchable surfactant (Figure 5). A number of photoswitchable
surfactants have been developed,19 as they enable colloidal
system control, coordinated drug delivery, and the study of
biological processes occurring at membranes. However, most
photoswitchable surfactants have not demonstrated quantitative
photoswitching and require long irradiation times (minutes to
hours) to induce phase separation.
Compound 24 is a unique high-performance photoswitchable
surfactant. First, 24 achieves PSSs highly enriched in either the E
or Z isomer in both DMSO-d6 (93% E or 94% Z) and D2O (88%
E or 80% Z) (Figure 5A) with Z → E half-lives of 435 and 434
min, respectively. Dissolving 24 in water prior to addition of
benzene gives an emulsion that can be readily controlled by light.
Under 350 nm light, 24E photoisomerizes to the more polar 24Z,
resulting in droplet fusion and increased phase separation within
2 s (Figure 5B, left). To ensure that this was not due to heating
upon irradiation, we used a nonphotoswitchable cationic
surfactant (cetrimonium bromide) as a control. Irradiation of
a benzene/water emulsion containing cetrimonium bromide did
not lead to increased phase separation or changes in droplet
morphology (Figure 5B, right). While light-induced phase
separation is unidirectional, we demonstrated temporal control
of this process by illuminating the edge of a benzene droplet with
two distinct wavelengths of light. Under 350 nm irradiation, the
benzene droplet begins to expand into the aqueous layer; this
process can be instantly halted by switching to 560 nm light
(Movie S1). Phase separation is initiated and halted by toggling
between these two wavelengths. The rapidity of this process is
remarkable and contrasts sharply with the speed of other
Figure 5. (A) Photoswitchable surfactant 24 can achieve PSSs in both
DMSO-d6 and D2O that are highly enriched in either the E or Z isomers
depending on the wavelength. (B) Light-induced phase separation
occurs only in the presence of a photoswitchable surfactant (24) and
not in the presence of a surfactant lacking a photoswitchable functional
group (cetrimonium bromide). White arrows indicate areas of
photoinduced droplet fusion. (C) Fluorescence microscopy reveals
that light-induced phase separation occurs at sites where the density of
24 is highest (indicated by a white arrow). Scale bars in panels B and C
are 50 μm.
achieving near quantitative bidirectional photoconversion are
known,5,15 most are not modular photoswitchable scaffolds.
Ravoo and co-workers attempted to solve this problem by
attaching a functionalizable carboxylic acid to the pyrazole
nitrogen of an arylazopyrazole.16 However, flexible sp3-
hybridized atoms between the tethering group and the
photoswitch are not ideal as they increase the degree of
conformational freedom tempering the stark structural differ-
ences between photoisomers.
While 13 undergoes nearly quantitative bidirectional photo-
conversion, its parent p-formylazobenzene 8 does not (Figure
3A). Inspection of their UV−vis spectra reveals that more
conjugated 13 absorbs more light at all wavelengths and exhibits
a red-shifted λmax for the π → π* transition. Calculations predict
a greater difference between the UV−vis spectra of the E and Z
isomers of modular photoswitch 13 than for p-formylazoben-
zene 8 at all wavelengths; this possibly explains why
D
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Letter
photoswitchable surfactants that require irradiation for minutes
to hours for noticeable changes in emulsion properties.
resolution mass spectrometry experiments. J.C.F. and J.-H.S.
performed the X-ray crystallography experiments. W.C.D.
assisted R.J.T. with the photoswitchable surfactant microscopy.
M.J.K. and D.E.O. supervised experiments and wrote the
manuscript with input from all authors.
To demonstrate spatial control, we sought to visualize the
distribution of 24 in the emulsion. 24 is fluorescent upon being
irradiated at 470 nm. As expected, the surfactant is localized to
the benzene−water interface, with some areas possessing more
surfactant than others. When the entire field of view was
illuminated at 350 nm, regions of high surfactant density
underwent the most drastic phase separation, which occurred in
<2 s (Figure 5C and Movie S2). This is the first time a
photoswitchable surfactant has been visualized at the interface
between two immiscible liquids using fluorescence microscopy
and highlights the importance of surfactant geometry for
controlling surface tension.
In conclusion, we have developed a redox isomerization
strategy inspired by the DBR. Our p-formylazobenzenes are
easily functionalized with a variety of groups in high yields to
produce modular photoswitches capable of achieving PSSs
highly enriched in either the E or Z isomer depending on the
wavelength of light employed. As a proof of principle, we
developed a high-performance photoswitchable surfactant
enabling control of an emulsion with high spatial and temporal
precision. The ease of this chemistry coupled with the
exceptional photophysical properties of these modular photo-
switches greatly expands the use of photoswitchable tools for
applications in biology, materials science, and beyond.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by funds from the National Institutes
of Health (NIH) (Grants DK072517 to M.J.K., DK067003 to
M.J.K., and R01GM128997 to D.E.O.). The authors thank the
NSF XSEDE program (CHE030089 to D.J.T.) for computa-
tional support. Funding for NMR spectrometers was provided
by the National Science Foundation (Grants DBIO722538 and
CHE9808183) and National Institute of Environmental Health
Sciences (Grant ES00570713). Funding for the Dual Source X-
ray diffractometer was provided by the National Science
Foundation (Grant CHE0840444). J.S.Z. is supported by the
UC Davis Tara K. Telford CF Fund, the UC Davis Dissertation
Year Fellowship, and the R. Bryan Miller Graduate Fellowship.
J.M.L. is supported by the UC LEADS program. R.J.T. is
supported by NIH Training Grant T32GM113770. The authors
thank J. T. Shaw (UC Davis) for helpful discussions.
REFERENCES
■
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b03387.
■
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*E-mail: mjkurth@ucdavis.edu.
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Jie S. Zhu: 0000-0003-3009-4135
James C. Fettinger: 0000-0002-6428-4909
Dean J. Tantillo: 0000-0002-2992-8844
Mark J. Kurth: 0000-0001-8496-6125
David E. Olson: 0000-0002-4517-0543
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DOI: 10.1021/acs.orglett.9b03387
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