Near-Infrared Photoswitching of Azobenzenes under Physiological Conditions

Article abstract of DOI:10.1021/jacs.7b06471

Biological tissue exhibits an absorbance minimum in the near-infrared between 700 and 900 nm that permits deep penetration of light. Molecules that undergo photoisomerization in this bio-optical window are highly desirable as core structures for the development of photopharmaceuticals and as components of chemical-biological tools. We report the systematic design, synthesis, and testing of an azobenzene derivative tailored to undergo single-photon photoswitching with near-infrared light under physiological conditions. A fused dioxane ring and a methoxy substituent were used to place oxygen atoms in all four ortho positions, as well as two meta positions, relative to the azobenzene N=N double bond. This substitution pattern, together with a para pyrrolidine group, raises the pK_a of the molecule so that it is protonated at physiological pH and absorbs at wavelengths >700 nm. This azobenzene derivative, termed DOM-azo, is stable for months in neutral aqueous solutions, undergoes trans-to-cis photoswitching with 720 nm light, and thermally reverts to the stable trans isomer with a half-life near 1 s.

Full text of DOI:10.1021/jacs.7b06471

Subscriber access provided by UNIVERSITY OF ADELAIDE LIBRARIES
Article
Near-infrared photoswitching of azobenzenes under physiological conditions
Mingxin Dong, Amirhossein Babalhavaeji, Catherine Collins,
Kareem Jarrah, Oleg Sadovski, Qiuyun Dai, and G. Andrew Woolley
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b06471 • Publication Date (Web): 08 Sep 2017
Downloaded from http://pubs.acs.org on September 8, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
Near-infrared photoswitching of azobenzenes under physio-
logical conditions
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1,2
1
1
1
Mingxin Dong , Amirhossein Babalhavaeji , Catherine V. Collins , Kareem Jarrah , Oleg Sa-
1
2
1
dovski , Qiuyun Dai , & G. Andrew Woolley *
1
2
Department of Chemistry, 80 St. George St., University of Toronto, Toronto, M5S 3H6 Canada. Beijing Institute of
Biotechnology, Beijing 100071, China
KEYWORDS azobenzene, photopharmacology, photoswitch, optochemical genetics.
ABSTRACT: Biological tissue exhibits an absorbance minimum in the near-infrared between 700-900 nm that permits
deep penetration of light. Molecules that undergo photoisomerization in this bio-optical window are highly desirable as
core structures for the development of photopharmaceuticals and as components of chemical-biological tools. We report
the systematic design, synthesis, and testing of an azobenzene derivative tailored to undergo single-photon photoswitch-
ing with near-infrared light under physiological conditions. A fused dioxane ring and a methoxy substituent were used to
place oxygen atoms in all four ortho positions, as well as two meta positions, relative to the azobenzene N=N double
bond. This substitution pattern, together with a para pyrrolidine group raises the pK of the molecule so that it is proto-
a
nated at physiological pH and absorbs at wavelengths >700 nm. This azobenzene derivative, termed DOM-azo, is stable
for months in neutral aqueous solutions, undergoes trans-to-cis photoswitching with 720 nm light, and thermally reverts
to the stable trans isomer with a half-life near 1 s.
INTRODUCTION
light under physiological conditions (i.e. aqueous solu-
tions at neutral pH).
Photoswitching between different conformational states
of a molecule provides an exquisite means for external
spatial and temporal control of molecular function. This
fact is of central importance for the nascent field of pho-
topharmacology in which the action of a photoswitchable
bioactive molecule is spatially restricted to desired target
areas and can be temporally modulated. Photoswitchable
bioactive molecules have now been developed that modu-
late retinal responses, glucose homeostasis, ion channel
Among organic chromophores, donor-acceptor Stenhouse
adducts (e.g. 1) can be tuned to absorb in near-IR ranges
9
but show complex solvent dependent photochemistry
that has so far prevented effective photoswitching in wa-
10
ter. A variety of azobenzene derivatives show absorbance
11
in the near-IR region (e.g. 2) but undergo very rapid
(<μs) thermal back isomerization meaning that the cis
isomer content is vanishingly small unless very bright
light sources are used. BF2-adducts of azobenzenes (e.g.
1-
12
function, and the activity of G-protein coupled receptors.
3
3
) absorb in the near-IR and have slower thermal relaxa-
13
tion (seconds) but hydrolyze in water. Bridged azoben-
zenes (e.g. 4, 5) absorb near-IR wavelengths to produce
the thermally more stable isomer. For photopharmaco-
For applications in vivo, photoswitching in the bio-optical
window is desirable, i.e. at wavelengths between 700 and
12,14
900 nm, to enable effective tissue penetration without the
logical applications in vivo, production of the thermally
less stable isomer by near-IR light is desirable, otherwise
thermal relaxation will lead to bioactivity outside the
zone of irradiation. The rate of the thermal back reaction
to the stable isomer should be slow enough to permit ac-
cumulation of the cis isomer under constant near-IR illu-
mination, but fast enough that spatial targeting is not
lost. Based on MRI and PET measurements of mean trans-
it times for blood in the cerebral vasculature, for example,
need for fiber optics. This can be achieved using two-
photon photoswitching but requires specialized high in-
tensity light sources and molecules with built-in anten-
4
,5
nae. Upconverting nanoparticles provide another means
to drive isomerization using multiple, long-wavelength
6,7
photons but the size of nanoparticles places constraints
8
on their applications. It would therefore be highly desir-
able to identify a molecular structure that undergoes sin-
gle photon photoswitching with near-infrared (near-IR)
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 10
the appropriate time constant for thermal relaxation solubility in a variety of solvents so that further derivati-
1
5,16
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
should be in the range of 0.1-10 s.
zation proved impractical. The substitution pattern
shown in compound 10, in which there is one meta oxy-
gen substituent per ring, was then considered. Computa-
tional modeling indicated that para amino substituted
derivatives of 10 would exhibit the twisted trans neutral
state, as well as a planar trans azonium ion expected for
tetra-ortho substituted methoxy azobenzenes (Fig. 1). Due
to the asymmetry of the compound, distinct confor-
mations exist with the dioxane rings on the same side or
on different sides of the molecule. For the trans azonium
form of the compound, these conformations were calcu-
lated to differ by less than 1 kcal/mol in energy (see SI);
the lowest energy conformation is shown in Figure 1b
with a stabilizing H-bond indicated. TD-DFT calculations
gave a predicted absorbance maximum for this species
near 600 nm, i.e. 50 nm further red-shifted than 6, so that
substantial absorbance >700nm was expected (see SI).
CN
N
N+
N
F
O
N
O
N
B
OH
S
N
N
N
N
N
F
N
N
N
1
O
2
3
S
N
4
O
O
N
H
O
H
N+
O
N+
N
N
H
2
N
NH
2
N
N
N
N
O
O
N
N
O
7
O
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Here we present the systematic design, synthesis, and
testing of an azobenzene derivative that is tailored to un-
dergo single photon photoswitching with near-IR light
under physiological conditions and that thermally reverts
to the stable trans isomer with a half-life near 1 s. The
design was based on extensive azobenzene literature, pre-
vious studies on substituted azobenzenes that form
azonium ions, as well as computational modeling.
RESULTS and DISCUSSION
Previous work on azobenzene derivatives bearing four
methoxy substituents showed that when all four substitu-
ents were in ortho positions relative to the azo unit, and
there was an amino group in the para position (e.g. 6), the
thermal half-life of the cis isomer was appropriate (~20 s)
but the wavelength maximum was too short so that ab-
1
7
sorbance at wavelengths >700 nm was minimal. An or-
tho-meta arrangement of the methoxy groups (7), in con-
trast, produced a substantial red-shift, but led to a very
Figure 1. DFT-calculated low energy conformations of a p-
pyrrolidine derivative of 10 in the (a) neutral trans form
(b) trans azonium form, (c) neutral cis form, (d) cis
azonium form.
short (μs) cis isomer thermal half-life and a pK for the
a
1
8
azonium ion too low for use at pH 7.0.
The neutral trans form of tetra-ortho substituted azo
compounds such as 6, exhibits highly twisted
a
Synthesis
1
7,19
geometry,
derivative.
a feature that is absent in the ortho-meta
The steric hindrance that produces this
1
8
The synthetic route to the para-Br derivative of 10, (des-
ignated 11), which serves as a precursor for para-amino
derivatives is shown in Scheme 1. This employs a key or-
tho-lithiation step to convert 13 to 14. A similar approach
has been exploited recently by Feringa to develop general
approaches for the synthesis of ortho substituted azoben-
twisting may also increase the thermal energy barrier for
cis-to-trans isomerization. Thus, to obtain slow thermal
relaxation together with absorbance in the bio-optical
window, both tetra-ortho substitution and meta-methoxy
substitution would appear necessary, for example as in 8,
which bears methoxy substituents at all ortho and all me-
ta positions. Computational modeling showed that steric
clash of the methyl groups in 8 would lead to loss of con-
jugation between methoxy oxygen lone pairs and the ring
systems. Locking the conformation of the methoxy groups
by creating dioxane rings (compound 9) solves this prob-
lem.
2
zenes. The structure of the final compound was con-
firmed by X-ray crystallography (Fig. 2).
Br
O
O
OH
O
O
O
1) nBuLi, TMEDA, THF
2) CF BrCF Br
O
O
O
CH
3
I, K
2
CO
3
NH
3
, Cu
DMF
2
2
DMF
12
13
14
NH
2
NH
2
O
N
Br
O
O
O
O
CuBr, pyridine
toluene
O
O
O
Br
2
, K
2
CO
3
O
N
O
CHCl
3
O
O
Br
Br
15
16
11
O
O
O
O
O
N
R
O
O
N
R
O
O
N
R
O
Scheme 1. Synthesis of the dioxane-methoxy-azobenzene
(DOM-azo) core.
O
O
O
O
O
O
R
N
O
O
R
N
O
O
R
N
O
O
As had been observed with the related tetra-ortho meth-
1
9
oxy substituted compound, compound 11 can co-
crystallize with chloroform with the acidic proton of the
CHCl3 molecule making H-bond interactions with the
methoxy oxygen atoms and the azo nitrogen atoms (Fig.
2a). Spectra of trans and cis isomers of the non-
8
9
10
Chart 1.
Computational analysis indicated that para amino substi-
tuted derivatives of 9 would have the desired red shift
see SI). However, precursors to 9 had extremely poor
(
ACS Paragon Plus Environment

Page 3 of 10
Journal of the American Chemical Society
1
8
protonated form of 11 in organic solvents (Fig. 2b) show
the separation of n-π* transitions expected for a tetra-
ortho substituted azobenzene derivative (see SI).
ing. The diethylamino-substituted derivative 19 exhibit-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ed a substantially higher pK (7.1), but had an unexpected-
ly elevated second pK for the ammonium species (6.2).
a
1
9,20
a
This species absorbs at shorter wavelengths (see SI) and
the coexistence of azonium and ammonium species at
physiological pH means that absorbance at far-red wave-
lengths is diminished. The azetidine-substituted com-
pound 20 and the pyrrolidinesubstituted compounds 21,
and 22 exhibited pK values close to neutral and strongly
a
red-shifted maximal absorbance. Compound 21 was prone
to aggregation, however, especially in pH ranges near the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. (a) X-ray structure of 11, co-crystallized with
CHCl3 (b) UV-Vis spectra of dark-adapted (solid line) and
irradiated (540 nm, dashed line) in toluene.
pK . This observation suggests that aggregation may in-
a
volve sharing of protons between molecules. Of course,
the solubility properties are likely to be different when
the photoswitch is part of a larger bioactive molecule.
Since the nature of the amine in the para position can
Compound 22, in which the para substituent is a pyrroli-
dine group bearing a solubilizing sulfone moiety, proved
much less prone to self-association. The compound also
exhibited the longest wavelength absorbance tail, togeth-
tune the wavelength maximum and also the azonium pKa,
a variety of derivatives of 10 were then prepared using
Buchwald-Hartwig coupling to link various amines to the
para-Br compound 11 (see SI). The structures of these are
shown in Table 1. Polar groups were included to promote
water solubility.
er with a pK near neutral. Figure 3 shows the acid-base
a
titration of this compound, which was designated DOM-
azo (for dioxane-methoxy-azobenzene). The observed pKa
of 6.7 (Fig. 3b) means that ~25% of the molecules are pro-
tonated at a physiological pH of 7.2. The molar absorptiv-
O
O
O
17
18
19
, R=
,
R=
, R=
N
N
O
O
N
R
N
O
-1
-1
N
O
ity of the azonium ion is high (138,000 M cm at 600
nm)(see SI) so that strong absorbance is seen at wave-
lengths >700 nm at physiological pH.
N
O
S
O
O
R
20, R=
21, R=
22, R=
O
N
N
N
We then tested the ability of DOM-azo to photoswitch
upon exposure to near-IR light. A high intensity LED (17
Table 1. Properties of trans azonium ions formed by p-
amino substituted derivatives of 10
2
mW/cm ) with a maximum emission at 720 nm was used
Structure
λmax
569
560
580
595
575
597
pKa
to irradiate a solution of DOM-azo at pH. 7.2, and a 540
nm LED source was used as a measuring beam (the spec-
tra of these LED sources is shown in Fig. 3a for reference).
A photomultiplier tube was used to monitor changes in
absorbance over time. Figure 3c shows photoswitching
time courses in response to 720 nm irradiation interleav-
ed with periods of thermal relaxation in the dark. Clear,
rapid photoswitching is seen (τon = 0.9 ± 0.1 s) together
with thermal relaxation (τoff 0.7 ± 0.1 s). These time cours-
es are rapid enough to permit spatial localization of the
cis isomer in vivo.
1
1
7
4.5
8
5.5, 3.5*
7.1, 6.2*
6.4
19
20
21
~7
22
6.7
*
Second pK due to formation of ammonium species.
a
Spectra of trans isomers in aqueous solutions and pKas
Finally, we tested the stability of DOM-azo in water by
measuring absorbance scans over extended periods of
time and found no significant changes over >6 h (see SI).
Thin layer chromatography of solutions of DOM-azo
stored in aqueous buffer at physiological pHs showed the
compound was intact after 3 months at room temperature
Acid-base (pH) titrations in aqueous solutions were car-
ried out for the thermally stable trans isomeric forms of
the compounds shown in Table 1 (see SI for details). The
pK of 17 was found to be well below the physiological
a
range. Compound 18 gave a higher pK , consistent with
a
(
see SI). We then tested stability to glutathione, the pri-
mary intracellular reducing agent. A slow loss of colour
τ1/2 ~3 h) was observed when DOM-azo was exposed to 10
mM reduced glutathione (see SI), the highest concentra-
better donating ability of the p-amino substituent, but
this was still below 7 and below the corresponding tetra-
ortho methoxy compound (i.e. the compound without a
(
1
8
substituent in the meta position). The low pK is thus
a
21
tion expected intracellularly. This sensitivity to reduc-
tion is similar to that observed for related azonium ions
likely due to steric clash between H-atoms on the 6-
membered p-amino substituent and the benzodioxane
ring leading to twisting of the 6-membered N-containing
ring relative to the aromatic ring and diminished delocal-
ization of the nitrogen lone pair into the azo system.
Twisting of the 6-membered N-containing ring relative to
the aromatic ring is confirmed by computational model-
1
7
previously and may limit these photoswitches to extra-
cellular applications, for example as blood borne photo-
pharmaceuticals interacting with extracellular receptors.
ACS Paragon Plus Environment

Journal of the American Chemical Society
AUTHOR INFORMATION
Page 4 of 10
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Corresponding Author
* Prof. G.A. Woolley, Dept. of Chemistry, University of To-
ronto; awoolley@chem.utoronto.ca
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
Funding Sources
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
This work was supported by the Natural Sciences and Engi-
neering Research Council of Canada.
ABBREVIATIONS
DOM, dioxane-methoxy; IR, infrared; LED, light emitting
diode; MRI, magnetic resonance imaging, PET, positron
emission tomography; TLC, thin layer chromatography; UV,
ultraviolet.
Figure 3. (a) UV-Vis spectra of DOM-azo (22) as a func-
tion of pH. The solid black line is the limiting spectrum of
the azonium ion at low pH (<pH 5.0); the dotted black
line is the spectrum of the neutral trans isomer obtained
at pH 10.0. Spectra at intermediate pHs are shown in gray.
REFERENCES
(
1)
Res. 2015, 48, 1947.
2) Hansen, M. J.; Lerch, M. M.; Szymanski, W.; Feringa, B.
L. Angew. Chem. Int. Ed. Engl. 2016, 55, 13514.
(3) Mehta, Z. B.; Johnston, N. R.; Nguyen-Tu, M. S.;
Broichhagen, J.; Frank, J. A.; Trauner, D. Acc. Chem.
(
(
b) Absorbance (680 nm) plotted vs. pH from the data in
part (a); the fitted pK = 6.7. (c) Photoswitching with
a
near-IR light under physiological conditions (aqueous
buffer solution (20% DMSO), pH 7.2). Absorbance at 540
nm was monitored vs. time while the sample was exposed
to 720 nm near-IR light (indicated by red bars above the
trace) or left in darkness (black bars). On and off time
constants were extracted from exponential fits (two such
fits are indicated). The spectral outputs of the near-IR
LED used for switching (red line) and the green LED used
to monitor absorbance (green line) are shown (red line)
in part (a).
Broichhagen, J.; Schultz, P.; Larner, D. P.; Leclerc, I.; Trauner, D.;
Rutter, G. A.; Hodson, D. J. Sci. Rep. 2017, 7, 291.
(4)
Gascon-Moya, M.; Pejoan, A.; Izquierdo-Serra, M.; Pit-
tolo, S.; Cabre, G.; Hernando, J.; Alibes, R.; Gorostiza, P.; Busque,
F. J. Org. Chem. 2015, 80, 9915.
(5)
Izquierdo-Serra, M.; Gascon-Moya, M.; Hirtz, J. J.; Pit-
tolo, S.; Poskanzer, K. E.; Ferrer, E.; Alibes, R.; Busque, F.; Yuste,
R.; Hernando, J.; Gorostiza, P. J. Am. Chem. Soc. 2014, 136, 8693.
(6)
Liu, J.; Bu, W.; Pan, L.; Shi, J. Angew. Chem. Int. Ed.
Engl. 2013.
(7)
Moller, N.; Hellwig, T.; Stricker, L.; Engel, S.; Fallnich,
C.; Ravoo, B. J. Chem. Commun. 2016, 53, 240.
(8)
Desai, N. AAPS J. 2012, 14, 282.
CONCLUSION
(9)
Hemmer, J. R.; Poelma, S. O.; Treat, N.; Page, Z. A.; Do-
linski, N.; Diaz, Y. J.; Tomlinson, W.; Clark, K. D.; Hooper, J. P.;
Hawker, C. J.; Read de Alaniz, J. J. Am. Chem. Soc. 2016, 138,
By tailoring the structure of an azobenzene with appro-
priate substituents, trans-to-cis photoswitching was
achieved with near-IR light (720 nm) from a continuous
LED source under physiological conditions. The core pho-
toswitch structure developed here may form a basis for
future photopharmaceuticals. It could directly enable
near-IR responses in current photoswitchable tethered
1
3960.
10)
ga, B. L. J. Am. Chem. Soc. 2016, 138, 6344.
(11) Salvador, M. A.; Almeida, P.; Reis, L. V.; Santos, P. F.
Dyes Pigm. 2009, 82, 118.
12) Dong, M.; Babalhavaeji, A.; Samanta, S.; Beharry, A. A.;
Woolley, G. A. Acc. Chem. Res. 2015, 48, 2662.
(13) Yang, Y.; Hughes, R. P.; Aprahamian, I. J. Am. Chem.
Soc. 2014, 136, 13190.
14) Hammerich, M.; Schutt, C.; Stahler, C.; Lentes, P.;
Rohricht, F.; Hoppner, R.; Herges, R. J. Am. Chem. Soc. 2016, 138,
3111.
(15)
(
Lerch, M. M.; Wezenberg, S. J.; Szymanski, W.; Ferin-
(
22
ligands for ion channels and receptors, in photoswitcha-
ble cross-linkers or in azobenzene -based drug delivery
23
(
24
systems.
1
Ibaraki, M.; Ito, H.; Shimosegawa, E.; Toyoshima, H.;
Ishigame, K.; Takahashi, K.; Kanno, I.; Miura, S. J. Cereb. Blood
Flow Metab. 2007, 27, 404.
ASSOCIATED CONTENT
Supporting Information. Details of computational model-
ing of structure and absorbance properties, details of synthe-
ses, acid base titrations, and photoswitching experiments.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16)
Carrera, E.; Jones, P. S.; Iglesias, S.; Guadagno, J. V.;
Warburton, E. A.; Fryer, T. D.; Aigbirhio, F. I.; Baron, J. C. J.
Cereb. Blood Flow Metab. 2011, 31, 1027.
(17)
Samanta, S.; Babalhavaeji, A.; Dong, M. X.; Woolley, G.
A. Angew. Chem. Int. Ed. Engl. 2013, 52, 14127.
ACS Paragon Plus Environment

Page 5 of 10
Journal of the American Chemical Society
(
18)
Woolley, G. A. Chem. Commun. 2015, 51, 12981.
(19) Samanta, S.; Beharry, A. A.; Sadovski, O.; McCormick,
Dong, M.; Babalhavaeji, A.; Hansen, M. J.; Kalman, L.;
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
T. M.; Babalhavaeji, A.; Tropepe, V.; Woolley, G. A. J. Am. Chem.
Soc. 2013, 135, 9777.
(
20) Beharry, A. A.; Sadovski, O.; Woolley, G. A. J. Am.
Chem. Soc. 2011, 133, 19684.
21) Jiang, X.; Yu, Y.; Chen, J.; Zhao, M.; Chen, H.; Song, X.;
(
Matzuk, A. J.; Carroll, S. L.; Tan, X.; Sizovs, A.; Cheng, N.; Wang,
M. C.; Wang, J. ACS Chem. Biol. 2015, 10, 864.
(22) Rullo, A.; Reiner, A.; Reiter, A.; Trauner, D.; Isacoff, E.
Y.; Woolley, G. A. Chem. Commun. 2014, 50, 14613.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
23) Martin-Quiros, A.; Nevola, L.; Eckelt, K.; Madurga, S.;
Gorostiza, P.; Giralt, E. Chem. Biol. 2015, 22, 31.
24) Wang, D.; Wu, S. Langmuir 2016, 32, 632.
(
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 10
SYNOPSIS TOC
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
By tailoring the structure of an azobenzene with appropriate substituents, trans-to-cis photoswitching was achieved
with near-IR light (720 nm) under physiological conditions
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
ACS Paragon Plus Environment

Page 7 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(a)
(c)
(b)
(d)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 10
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
1
0
0
0
.4
.2
.0
.8
.6
.4
0.2
0.0
(
a)
(b)
300
400
500
600
Wavelength (nm)
ACS Paragon Plus Environment

Page 9 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
.5
.0
.5
0
0
0
0
0
.8
.6
.4
.2
.0
1
0
4
6
8
10
(
a)
0.0
(
b)
pH
3
00 400 500 600 700 800
Wavelength (nm)
720 720
720
720
720
0
0
0
0
.5
(
c)
.4
.3
.2
0
10
20
30
40
50
Time (s)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 10
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
20 nm
t1 s
1/2
ACS Paragon Plus Environment