REVIEWS
Heteroaryl azo dyes as molecular
photoswitches
Stefano Crespi, Nadja A. Simeth and Burkhard König *
Abstract | We have known of azobenzene for over 150 years, the past 80 of which have seen the
study and application of its photochromism. Azobenzene derivatives are now considered
archetypical molecular switches, and their stability and reliability make them amenable to many
fields of modern chemistry, materials science, biology and photopharmacology. When
developing a photoswitch for a given application, a common approach is to tune the properties
of an azobenzene. It is also possible to instead use heteroaryl azo dyes — motifs that are less
popular even though their diversity offers distinct features. Despite the first discoveries of
switching behaviour in heteroaryl azos and azobenzenes being coincident, the former have only
recently begun to attract attention. This Review describes how the versatile and multifaceted
characteristics of these scaffolds make them serious alternatives to azobenzene derivatives in
molecular photoactuation. Heteroaryl azo photoswitches arguably deserve more consideration,
and our survey of these systems includes challenges to their successful deployment.
Photopharmacology
The use of light to control the
activity of biologically relevant
species used as molecular
tools, drugs or prodrugs.
Photoswitch
A molecule that can be
reversibly isomerized between
two (or more) states using light
irradiation. The return to the
first state, which is typically
more thermally stable, can
occur either photochemically
or thermally, depending on the
type of molecule.
Institute for Organic
Chemistry, Department of
Chemistry and Pharmacy,
University of Regensburg,
Regensburg, Germany.
*e-mail: burkhard.koenig@
chemie.uni-regensburg.de
https://doi.org/10.1038/
s41570-019-0074-6
The study of azo dyes can be traced back to 1858 to the
seminal work of Peter Grieß, the discoverer of diazonium
salts1,2. Diazonium chemistry has since enabled the synthesis of many azo compounds that have seen manifold
applications. Indeed, chemical modification of their
structure allows access to molecules having a vast chromatic range, from the pigment Yellow 12 to Trypan blue
(used on cotton)3,4. The tuneable absorption properties
of azo dyes enable them to be used for treating leather
and textiles, to be added to foods or to serve as pigments
in rubbers and plastics. The 1930s saw a particular azo
compound — sulfonamidochrysoïdine, also referred to as
prontosil — become the first antibiotic to be commercialized5, leading to a revolution in medicine. Interestingly, it
was only around this time that chemists learned that azo
compounds can exist in E and Z isomeric forms, of which
the former is typically more stable. These isomers can be
interconverted using light (Box 1), and it is in this way that
the first photochemical switches (photoswitches) were
accessed6–9. The switching mechanism involves a change
in molecular geometry and polarity that can be triggered
by irradiation at different wavelengths. This spatiotemporal control over molecular motion very quickly became
the basis of a wealth of research into azo compounds,
of which azobenzene (PhNNPh), owing to its stability,
reliability and tunability, emerged as the most archetypal
and popular motif10.
The performance of a switch can be evaluated according to four different parameters. The first of these is the
wavelength of maximum light absorption and the quantum yield for the ensuing isomerization. This quantum
NATuRe RevIeWS | ChemisTry
yield is directly related to the nature of the transition
triggered by the irradiation and the mecha­nistic pathways to the excited state. The tuneable light absorption
of azo compounds enables the preparation of species
that isomerize when exposed to visible or near-IR
light11,12, thereby enabling switching within a therapeutic
spectral window and applications in the nascent field of
photopharmacology13,14. The second performance parameter is the relative thermal stability of the two isomers,
a parameter that can vary greatly among different systems. Indeed, the Z isomers of some compounds rapidly
convert into their E forms15, while Z isomers in other
systems can have appreciable thermal stability16–19. The
lifetime of the Z form is important when considering
applications in materials science20 and medicine21 or in
technologies such as optical data storage22, logic gates23
or real-time information transfer24. Lifetimes (τ) or
half-lives (t1/2) of the Z isomer are usually measured in
solution. The nature of the solvent influences the stability of the metastable Z form10. The third characteristic
parameter of a photoswitch is the steady-state relative
abundance of E and Z isomers when the photoswitch is
exposed to a given light source (or none). Expressed as
an equilibrium constant or a ratio, this is also referred
to as the photostationary distribution (PSD) at the
photostationary state (PSS). The fourth parameter concerns the reproducibility of photochemical switching
over time25. Many azo compounds exhibit little to no
sign of fatigue after several cycles of irradiation, presumably owing to the absence of any side reactions26,27.
Collectively, the performance parameters of switching
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Box 1 | Photoisomerization of azobenzene
Azobenzene (PhNNPh) is the parent aromatic azo and can exist in E and Z
isomeric forms. The former is more stable and gives rise to a distinctive
absorption spectrum (see the figure below and Supplementary Fig. 1).
Excitation of E-PhNNPh from its S0 ground electronic state to its first
singlet excited state S1 is a weakly allowed nπ* transition in the visible
region (λ ≈ 450 nm), while populating the second excited state S2 is an
intense symmetry-allowed ππ* transition deep in the UV range
(λ ≈ 300 nm)10. The primary photochemical function of PhNNPh involves
isomerization of the N=N bond10, whereby the (quasi)planar E-PhNNPh is
converted into the metastable Z-PhNNPh (for certain molecules, such as
those in which an ArNNAr group is part of a macrocycle, it is actually the Z
isomer that is more stable25). Isomerization is accompanied by changes in
volume, polarity and light absorption, the latter in the form of an
intensification (and slight shift) of the nπ* band and attenuation (and
a
marked blue-shift) of the ππ* band10. Because isomerization can occur
from either the S1 or S2 states, each with its own quantum yield (the
number of isomerizations per photon absorbed by the system), we say
that PhNNPh violates Kasha’s rule38,116. The effect is promoted by a
non-productive S1→S0 conical intersection (CI) that is energetically
accessible only by excitation to the S2 state117–120. Population of both S1
and S2 eventually leads to funnelling through a CI that connects S1 and
S0 and promotes isomerization118,119. The photoisomerization of PhNNPh
proceeds by an inversion-assisted torsional pathway involving in-plane
motion and out-of-plane rotation121,122. If a derivative has restricted
rotation, isomerization is proposed to proceed by an in-plane inversion
with equal quantum yields from S1 and S2, satisfying Kasha’s rule123,124.
The isomerization is both photochemically reversible and thermally
reversible (Box 2).
b
20,000
ππ*
ππ*
S2
1,500
15,000
nπ*
ε (M–1 cm–1)
nπ*
S1
750
h
h
h
0
5,000
375
450
N
525
N
S1/S0 CI
N
0
h
E
10,000
300
400
500
600
‡
N
N
0˚
λ (nm)
N
180˚
CNNC dihedral angle
ε, molar absorptivity; λ, wavelength; hν, photon energy.
Kasha’s rule
A general rule that relates to
molecules that can be excited
to different states of the same
spin multiplicity. Of these
different states, it is the lower
state that emits a photon or
engages in reactivity. Thus, the
photophysical/photochemical
behaviour of a molecule is, to
some extent, independent of
the wavelength used to excite it
Photochromism
The light-triggered
interconversion between two
chemical species with different
absorption spectra. The two
species typically have distinct
structural and electronic
properties.
molecules can help us design systems in which the E→Z
and Z→E photoreactions are almost quantitative. This
quantitative bidirectionality is made possible by the
spectral separation of nπ* absorptions for the E and Z
forms of a species, and this separation is something one
can tune by selecting suitable substituents17,18,25.
The many potential applications of azoswitches have
spurred a continuing interest in these molecules over the
past decade. While the performance of azobenzenes can
be tuned only by introducing substituents to the aryls,
heteroaryl azoswitches offer broader structural diversity
that is reflected in their very different spectral properties. These properties include the positions of absorption
bands; presented here is a summary of data for some
typical heteroaryl azos28,29 (Fig. 1; Supplementary Fig. 1).
If we return to the PhNNPh archetype, simply introducing π-donors and π-acceptors, respectively, gives rise to
hypsochromic (lower λmax) and bathochromic (higher
λmax) shifts of the main absorption band30. In addition
to substituent effects, intramolecular and intermolecular interactions can also perturb the photophysics.
Replacing one or both aryls with a heteroaryl not only
preserves the photochromism but also introduces basic
sites for H-bonding or metal coordination — interactions that further affect the azo chromophore. Moreover,
systems featuring group 15 and/or 16 heteroatoms
afford access to five-membered aromatic rings. Thus,
134 | MARCH 2019 | volume 3
heteroaryl azo photoswitches have distinct photophysical and photochemical properties, along with different
steric profiles and molecular geometries28.
Covering the increasing interest in heteroaryl azo
photoswitches serves as motivation for this Review,
which describes the use of heteroaryl azos in a
non-comprehensive and qualitative fashion. This Review
does not cover preparations of these compounds, the
main routes to which include nucleophilic attack of an
aryl onto an aryl diazonium, dehydrative coupling of
an aryl nitrosyl with an aryl amine, and nucleophilic
substitution of an aryl halide with an aryl hydrazine
followed by oxidation (Supplementary Fig. 2). Here, we
begin by presenting the mechanistic features common to
hetero­aryl azoswitches, after which we provide individual sections on each different heteroaromatic core and its
derivatives, ordered according to the identity and number of heteroatoms in the aryl rings. The different hetero­
aromatics experience different amounts of popularity,
but we aim to provide coverage of each by highlighting
prominent applications of these underutilized motifs.
Common mechanistic features
Our picture of the photoinduced E→Z isomerization in
heteroaryl azoswitches is not as complete as it is for the
PhNNPh archetype, but it has nevertheless been proposed that the isomerization mechanisms are similar
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Reviews
ππ*: 310 (167)
nπ*: 442 (3.7)
PSD: 76:24
τ: 56 d
Me2SO
REF.29
HN
N N
N
N
N
ππ*: 321 (147)
nπ*: 448 (4.3)
PSD: 81:19
τ: 20 d
PhMe
REF.50
N
ππ*: 362 (180)
τ: 10 ms
PhMe
REF.32
N
N
N
NH2
ππ*: 366 (282)
nπ*: 457 (34)
PSD: 95:5
τ: 278 h
Me2SO
REF.34
N
N
N
N
MeO
OMe
N
N
N
S
N
S
+
ππ*: 413
τ: 150 µs
EtOH
REF.44
N
N
I
–
N
N
N
+
ππ*: 278 (251)
nπ*: 455 (50)
PSD: 0:100
MeCN
REF.47
N
N
2MeSO4–
N
N
ππ*: 336 (148)
PSD: 95:5
τ: 3.5 d
PhMe
REF.29
ππ*: 315 (225)
nπ*: 448 (4.1)
PSD: 80:20
τ: 69 h
C7H16
REFS10,30
N
ππ*: 372 (164)
τ: 6.5 s
Me2SO
REF.35
N
OH
N
N
N
ππ*: 444
τ: 19 ms
EtOH
REF.44
NH
N
+
N
N
N
N
N
HN
F
N
N
+
N
N
ππ*: 320 (146)
nπ*: 425 (7.8)
PSD: 98:2
τ: 107 d
Me2SO
REF.29
ππ*: 306 (150)
nπ*: 466 (2.3)
C7H16
REF.30
N
N
N
ππ*: 355 (184)
nπ*: 457 (15)
PSD: 92:8
τ: 2.3 d (Me2SO)
PhMe
REF.33
N
N
N
F
N
N
N
F
ππ*: 385 (221)
PSD: 84:16
τ: 17 h
MeCN
REF.29
F
N
ππ*: 477
τ: 48 s
Me2CO
REF.109
N
N
S
OMe
N
N
N
NH2
ππ*: 560
τ: 368 ns
EtOH
REF.44
NH
NH
N
N
I–
N
N
N
N
ππ*: 465 (306)
H2O (pH7)
REF.97
N
λ (nm)
N
N
+
ππ*: 283 (200)
nπ*: 455 (2.5)
PSD: 24:76
MeCN
REF.47
N
ππ*: 289 (200)
nπ*: 465 (3.2)
PSD: 0:100
MeCN
REF.47
N
N
S
N
N
MeSO4–
N
ππ*: 363 (193)
PSD: 77:23
τ: 5.3 h
MeCN
REF.29
N
N
ππ*: 377 (205)
τ: 2.9 h
PhMe
REF.32
N
N
N
S
N
ππ*: 544
τ: 70 µs
EtOH
REF.75
N
N
N
N
S
N
N
N
N
N+
ππ*: 323 (200) PF6–
nπ*: 445 (5.0)
PSD: 41:59
N
MeCN
REF.47
N
ππ*: 332 (115)
nπ*: 443 (6.1)
PSD: 90:10
τ: 55 d
PhMe
REF.60
N
ππ*: 349 (180)
τ: 9.7 h
PSD: 87:13
H2O
REF.103
N
N
N
N
N
N
NH2
ππ*: 360
nπ*: 437
τ: 2.9 h
PSD: 94:4
MeOH
REF.93
N
N
N
N
O
OH
OH
nπ*: 474
PSD: 42:58
τ: 66 min
Me2SO
REF.104
N
N
N
N N
ππ*: 328 (166)
nπ*: 417 (6.4)
PSD: >98:2
τ: >3.9 yr
Me2SO
REF.29
N
ππ*: 317 (390)
nπ*: 430 (3.2)
MeCN
REF.51
N
N
MeO
ππ*: 341 (162)
nπ*: 425 (6.8)
PSD: >98:2
τ: 16 d
MeCN
REF.29
N
N
N
N
N
N
N
ππ*: 405 (225)
τ: 23 s
H2O (pH 9)
REF.96
N
N
N
N
N
N
N
N
N
N
Fig. 1 | Photophysical and photochemical properties of heteroaryl azoswitches. A selection of heteroaryl azos,
organized according to the energy of their ππ* transition (or the nπ* transition if this is not available) to illustrate their
diverse properties (a broader range of examples can be found in Supplementary Fig. 3). When available, details of
the assignment and wavelength (λ, nm) of each transition are followed in parentheses by the molar absorptivity
(ε, 102 M−1 cm−1). In addition, the photostationary distribution (PSD, expressed as [Z]:[E]) at the photostationary state,
the lifetime (τ) of the Z isomer and the solvent are given.
Although quantum yields of the E→Z photoreaction are not known (or complete) for all heteroaryl
azoswitches, available data indicate weaker absorptions
when isomerization follows excitation to the brighter
S2 (ππ*) state instead of the weakly allowed S1 (nπ*)
state. This anti-Kasha behaviour, which is similar to
that of PhNNPh (refs28,29,31–34), is also supported by
(Box 1).
NATuRe RevIeWS | ChemisTry
computational studies35–38 that describe the presence of an
S1→S0 conical intersection (accessible only after population
of the S2 state) that converts the ππ* excited state of the E
isomer back into its electronic ground state (S0) instead
of triggering isomerization. The isomerization mecha­
nism across the S1 potential energy surface generally
involves an inversion-assisted rotation towards a conical
volume 3 | MARCH 2019 | 135
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Box 2 | Thermal isomerization of azobenzenes
While the E→Z isomerization of azobenzenes can be triggered photochemically, the reverse Z→E isomerization can be
induced both photochemically and thermally. Exceptions include molecules in which the ArNNAr group is part of a
macrocycle, for which the Z isomer can be more stable and opposite behaviour is possible25. The nature of the Ar
substituents, solvent and pressure influence which of the three isomerization mechanisms ArNNAr undergoes10,16.
The first of these is inversion, whereby the N=N–C angle opens along the molecular plane, reaching a maximum at ~180°
in the transition state (see the figure)16,111. Inversion is a relatively slow process that is typical of azobenzene (PhNNPh) and
the vast majority of substituted derivatives. The second mechanism is referred to as rotation, in which the CNNC
dihedral angle opens to a 90° dihedral angle in the transition state owing to motion in an out-of-plane coordinate16. This
mechanism is typical of push–pull azobenzenes — ArNNArʹ species with an electron-donating substituent (for example,
Ar = 4-aminophenyl) and an electron-withdrawing substituent (for example, Ar = 4-nitrophenyl) — in polar solvents16.
Indeed, access to a zwitterionic resonance structure featuring a single N–N bond can enable this fast isomerization
mechanism22. The third mechanism involves tautomerism, whereby intramolecular or intermolecular H+ transfer (usually
assisted by and favoured in protic solvents) converts the Z isomer into its hydrazone tautomer22. In the case of an
azobenzene bearing an –OH group, the equilibrium involves a net H+ transfer between the –OH group and the N=N moiety,
resulting in a single N–N bond, rotation around which enables fast Z→E kinetics22.
a
b
O
OH
Tautomerism
N
N
N
N
N
N
Tautomerism
Rotation
Z isomer
E isomer
N
Conical intersection
The crossing point between
two electronic states of the
same multiplicity. A polyatomic
species with N nuclei can thus
have two hypersurfaces of the
same spatial symmetry, which
cross in a (3N − 8)-dimensional
subspace of the (3N − 6)nuclear coordinate space.
N
intersection connecting the nπ* excited state of the E isomer to the ground state Z isomer35–37,39. The channel that
the excited state takes is typically substituent-dependent,
such that, for example, E-azoarylimidazoles decay to the
ground state of the Z form through bending, whereas
the E isomer of their N-methylated analogues relaxes
to the Z form from their S1 and S2 states by twisting and
bending, respectively40.
The thermal isomerization of metastable Z isomers
to their corresponding E isomers41 is the subject of a
substantial body of literature, and we summarize some
typical lifetimes here to put these systems in perspective10,24 (Fig. 1; Supplementary Fig. 3). This reaction in
heteroaryl azos follows the same canonical mechanisms
operative in azobenzenes and thus proceeds through
inversion, rotation or tautomerism (Box 2). The inversion pathway affords more stable Z forms than rotation or tautomerism. The choice of substituents and
solvents can bias which pathway ArNNAr undergoes,
and the introduction of heteroatoms can further shift
this prefe­rence24. Although the general principles for
thermal switching of heteroaryl azoswitches have yet
to be formalized, the following examples illustrate
how replacing an arene with a heteroarene can modify the properties of azobenzenes in terms of stability
of the Z form.
136 | MARCH 2019 | volume 3
N
s-cis-hydrazone
Z isomer
Inversion
N
HN
N
N
N
E isomer
OH
HN
N
O
s-trans-hydrazone
One particular tendency of heteroaryl dyes is that
an azo featuring an electron-rich five-membered
hetero­cycle bearing an NMe substituent typically has
an extremely long-lived Z isomer. This isomer converts into its E form by an inversion that is considerably slower than that for PhNNPh (ref.28) (Fig. 2a).
The reasonable thermal stability of heteroaryl azos
in their Z forms presumably arises because they
can assume a T-shaped conformation in which the
five-membered azaheterocycle engages in C–H···π
interactions. PhNNPh cannot exist in a similar conformation because its Ph rings are larger than these
five-membered rings 29. Another intui­t ive trend is
the fast isomerization (through rotation) characteristic of azos bearing an electron-poor pyridine or
pyrimidine on one side of the –N=N– group and an
electron-rich aryl on the other. The aryl, by virtue
of electron-releasing groups such as –OR or –NR2,
promotes a push–pull effect in conjunction with the
electron-withdrawing N-heterocycle10,42 (Fig. 2b). In
particular, one can draw charge-neutral and zwitterionic resonance structures. The latter features a single
N–N bond, rapid rotation around which enables rapid
isomerization43,44. This resonance is of course relevant
to both the E and Z forms, such that the latter has
very limited kinetic stability because rotation to give
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b
+
a
N
N
N
N
H
N
N
N
T-shaped Z isomer
stabilized by hydrogen bonding
N
N
N
Twisted Z isomer
destabilized by steric strain
N
N
N
+
N
Push–pull resonance enables rotation about the N–N bond
c
N
N
H
Ph
Intermolecular
H+ transfer
N
N
Ph
N
N
N
H
R
Ph
N
Ph
N
N
H
E isomer
Intermolecular
H+ transfer
N
N
H
Z isomer
H
H
s-cis-hydrazone
Z isomer
N
N
O R
H
O
N
H
Ph
N
Z or E isomer
N
N
s-trans-hydrazone
Fig. 2 | Thermal Z→E isomerization features in heteroaryl azoswitches. a | Five-membered electron-rich heterocycles
possessing an NMe substituent can exist in T-shaped Z isomers, in which the aryl groups are perpendicular to accommodate
C–H⋯π interactions29. These interactions and favourable π-conjugation between the heteroaromatic ring and the –N=N–
unit makes this Z form (relative to the E form) more stable than in the case of PhNNPh. b | Azoswitches with electron-donating
(for example, 4-(dimethylamino)phenyl) and electron-withdrawing (for example, 1-methyl-2-pyridiniumyl)44 substituents are
known as push–pull systems. The azo group has a single N–N bond character, rotation around which enables steric strain of
the Z form to be rapidly relieved by conversion into the E form. c | Heterocyclic azos bearing a protic group such as NH, when
in a protic solvent, can exist in equilibrium with their hydrazone tautomers, which feature single N–N bonds about which
rotation is relatively free35. Thus, Z isomers of these heterocyclic azos have short lifetimes, because they can convert, via
s-cis-hydrazone and s-trans-hydrazone, into E isomers. For several species, including (3-indolyl)NNPh, tautomerism involves
solvent-assisted intermolecular H+ transfer.
the more stable E isomer is fast even in the absence
of light. This behavi­our is enhanced if an endocyclic
N atom is quaternized (for example, by methylation) or
protonated, in which case the group exerts even more
of a pull on account of it being cationic43.
Distinct from resonance effects is the equilibrium
that exists between heteroaryl azos featuring hetero­
cyclic NH groups and their hydrazone tautomers, an
equilibrium that is also operative for azobenzenes with
–OH or –NH2 substituents (Box 2) . The hydrazone
tautomers have a N–N single bond, rotation around
which enables fast interconversion between s-trans
and s-cis conformers35. This tautomerization–rotation
mechanism is often suggested to be the origin of the
kinetic instability of the Z isomer of azoswitches with
heterocyclic NH groups28,29. Despite this sound logic,
these effects on E–Z isomerization have been confirmed only for azoimidazoles32 and azoindoles35 in
protic solvents. In both cases, the rate of isomerization
is dependent on both the concentration of the azoswitch
and the protic media32,35, with a computational study
confirming that intermolecular H+ transfer is involved
for azoindoles35 (Fig. 2c).
NATuRe RevIeWS | ChemisTry
Heteroaryl rings bearing one N atom
The following sections describe the photoisomerization
of azoswitches with heteroaryls bearing a single N atom,
such as pyridine, pyrrole or indole. Of these molecules,
azos with one or two pyridyl rings have been the most
studied in terms of fundamental and applied research,
with the first papers on these species already appearing in 1932 (refs6,8,9,45). By contrast, pyrrole and indole
derivatives, both of which have five-membered rings,
have only recently attracted attention as photoswitches,
such that their switching mechanisms and applications,
at least for now, remain largely unknown28,29.
Pyridine and pyridinium salts. Azopyridine (pyNNpy),
phenylazopyridine (PhNNpy) and their derivatives are
readily prepared and characterized. The Z isomers of the
parent compounds are accessible and sufficiently stable,
with detailed photochemical and theoretical characterizations of the E–Z isomerization having been carried
out30,37,46,47. The polarity of py differs from that of Ph,
such that the change in dipole moment upon switching between E and Z isomers is also different7,9. When
in a suitable isomer/conformation, a py group can bind
volume 3 | MARCH 2019 | 137
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metals48,49, while the azo group can efficiently quench
photogenerated triplet metal-to-ligand charge transfer
states, which are readily populated in complexes with
low-lying π* orbitals. Thus, light energy does not necessarily cause a M–(4-py)NNPh bond to break but can
instead excite the azo to its triplet state50. Following this,
intersystem crossing to the ground state is slow and often
favours the E isomer, such that E→Z switching is partially (for example, in the case of M = Iriii)51 or completely
(when M = Ruii, Rei)50,52 precluded. Isomerization is also
hindered when geometric or steric constraints are present, as in the case of the layered networks {Feii[(3-py)
NNPh]2Pd(CN)4}3– and {Feii[(4-py)NNPh]2Pd(CN)4}3–
(ref.53). A more interesting scenario is when switching
does occur, which can cause a change in the properties
of a ligated metal centre, such as that in the photoactive complex [Zn(tetraphenylporphyrinato)], the apical
sites of which are available to bind py groups54 (Fig. 3a).
A fine balance between steric and substituent effects,
basicity and relative position of the pyridyl N atom can
be manipulated to influence the fluorescence of the
[Zn(tetraphenylporphyrinato)]/[4-phenyl-2-pyridyl]
NNPh system31,55,56. In particular, E→Z photoisomerization makes the py group more sterically available for
coordination to Znii, whence the emission at 650 nm
is quenched by 50%55. Conversely, when the ligand is
replaced with either (4-py)NNPh or (3-py)NNPh,
emission is most quenched when the ligands are in
their E form, in which the N atom is most accessible to
the metal ion31,55,56.
The concept of E–Z switching leading to (de)coordination has been further developed in a porphyrinato­
nickel(ii) complex bearing a pendant (3-py)NN
group57,58 (Fig. 3b). When the azo group is in its E form,
the 3-py moiety is unavailable for coordination, and the
square-planar Niii assumes its typical S = 0 electronic
state. Photoisomerization of the azo group to the Z isomer
triggers coordination and affords a square-pyramidal
S = 1 Niii centre. Thus, a light stimulus directed at a
solution of the complex can affect bonding and afford
either diamagnetic or paramagnetic species at will59–61.
This complex, which resembles a molecular record
player, has outstanding fatigue resistance; the magnetic
bistability is efficiently controllable over thousands
of cycles by irradiation with green (500 nm, E→Z) or
violet (435 nm, Z→E) light. An improved system features a 4-MeO group on the pyridine ring, which boosts
its basicity and enables 85% conversion of the singlet
E isomer into the triplet Z complex. Overall, the paramagnetism of the entire solution can consequently be
regulated with high spatiotemporal precision62. The S = 0
and S = 1 forms are readily distinguishable inside a 7T
clinical magnetic resonance imaging instrument, such
that robust molecules such as this could serve as photo­
addressable contrast agents in medical diagnostics62.
Extending this photocontrolled magnetic bistability to
record player complexes of other metals ions such as
Feiii (as one might wish to do if a stronger paramagnet is
desired) has yet to be successful63.
We mentioned above that pyridinium groups serve
as strongly electron-withdrawing substituents in push–
pull systems, such that azo pyridiniums exhibit thermal
138 | MARCH 2019 | volume 3
Z→E isomerization lifetimes below the millisecond
range, down to the picosecond scale43,44,64. The absorptions of these derivatives are in the visible region and are
bathochromically shifted relative to non-push–pull analogues44,64 (Supplementary Fig. 3). Tethering a pyridinium
dye to an electron-rich azobenzene (Fig. 3c) affords a system in which the two azo groups can be easily isomerized to their Z forms using light of the same wavelength.
However, the rates of their thermal Z→E isomerization
differ by 15 orders of magnitude65. This system is notable
both as a blueprint for multifunctional light-addressable
materials and for the thermal isomerization lifetimes associated with the fast push–pull component. Apparently,
certain interactions see the latter component undergoing Z→E isomerization 1,000-fold faster than does the
analogous monoazo {(1-methyl-2-pyridiniumyl)NN
[4-(NMe2)C6H4)]}+. The lifetime of the fast component
is on the sub-nanosecond scale, making it the fastest
thermally isomerizing azobenzene derivative known65.
The spatiotemporal control we have over certain azopyridinium dyes makes them promising components in a
photo-driven oscillating system that transmits information in real time (or almost instantaneously) and reverts
back to its original state after the external stimulus is
removed43,44. In fact, azopyridine derivatives are superior to hydrocarbon azo analogues as fast-responding
liquid crystal dopants20,64. Liquid crystals doped with
azobenzene-derived mesogens have the propensity to
macroscopically bend upon irradiation, maintaining
their shape after removing the light source66. By contrast, heteroaryl azos can control the properties of a
liquid crystal mesophase, a film of which, doped with
an azo, experiences unidirectional wave motion when
under constant irradiation20 (Fig. 3d). In this case, the
mesogen 4-[(6-acryloxy)hexyl-1-oxy]benzoic acid is
doped (7 mol%) with an azo congener bearing a (4-py)
NNAr group that accepts a H-bond from the carboxylic
acid (Fig. 3e). This olefin group in the dopant undergoes
copolymerization with acrylate mesogen (a diacrylate
mesogen can also be used) to afford a persistent yet
photoresponsive structure. The H-bonding increases
the push–pull character of the azoswitch, leading to fast
thermal Z→E isomerization of the liquid crystal network. Thus, irradiating the film causes the azo groups
to adopt the Z form such that crests move on the surface,
casting shadows over some parts of the polymer film.
This remarkable macroscopic motion occurs because the
E→Z photoisomerization affords a liquid crystal region
whose glass transition temperature is below the ambient temperature. The illuminated region thus assumes a
glassy state, in which the azos undergo Z→E relaxation
much faster (t1/2 < 1 s). When both ends of the film are
fixed, self-shadowing occurs so as to generate a wave that
can be used to transport small macroscopic objects on
the film surface or to make oscillating materials20.
Pyrrole and indole. Despite being only a recent addition
to our library of known heteroaryl azos, arylazopyrroles
are efficient photoswitches that can have useful PSDs,
most of which have a Z isomer fraction greater than 80%.
Moreover, the Z isomer can persist for hours or even
days, provided the substituents in this isomer are not
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— is dependent on the concentration of H2O present,
which influences the rate of thermal isomerization. This
dependence has been attributed to bimolecular pathways
operative at high concentrations (>10−3 M)29, H-bond
located such that steric strain is present, in which case
the lifetime can drop to seconds28,29,41. The switching of
azopyrroles — and, as we discuss below, other hetero­
aryl azos like imidazoles29, indoles35 and indazoles33
a
Ph
N
N
Ph
N
= 315 nm
Ph
N
Ph
N
Zn
N
= 436 nm
N
N Ph
N
Ph
Ph
N
N
N
Zn
N
Ph
N
Ph
Ph
b
E
E
N
N
N
N
N
dx2- y2
N C6F5
C6F5
N
EF
N
Ni
= 500 nm
N
C6F5
N
C6F5
N
N
= 435 nm
or
Ni
N
N
C6F5
EF
C6F5
dx2 - y2
dz2
d z2
c
d
Non-responsive
plastic frame
N
N
N
N
N
5 mm
+
O
Glass plate
5 mm
N
Fast component
= 216 ps
t = 0.00 s
Slow component
= 86 h
e
t = 0.44 s
f
O
N
O
N
6
O
N
N
N
O
N
H
(4-py)NNPh core
R
O
O
O
6
O
4-[(6-Acryloxy)hexyl-1-oxy]benzoic acid
Solvent
PhMe
MeOH
Me2SO
Me2SO–H 2O (1:1) + DBU
τ (R = H)
47.5 ms
6.8 ms
6.5 s
31 ns
τ (R = Me)
17.1 min
2.4 h
2.6 d
–
Fig. 3 | Azos with aromatic rings containing one N atom. a | The fluorescence of [Zn(tetraphenylporphyrinato)] is
quenched upon coordination to Z-[4-phenyl-2-pyridyl]NNPh, which is photogenerated from E-[4-phenyl-2-pyridyl]NNPh,
whose coordination to Znii is sterically hindered55. b | A [Ni(porphyrinato)] derivative featuring a pendant (3-py)NN group
can undergo conversion from a diamagnetic into a paramagnetic form through photoinduced E→Z isomerization61.
c | The covalent linkage of two aryl azos, such as an alkylpyridinium-containing push–pull system and a classical
azobenzene, affords a molecule in which the Z isomers of both photoswitches can be formed simultaneously. In this case,
the two azo species exhibit vastly differing thermal back-isomerization lifetimes (τ)65. d | Isomerization can be translated
into movement on the macroscopic scale, such as in polymer films20. A photoactivated E→Z isomerization is accompanied
by the appearance of crests moving on the surface, shadowing some parts of the polymer, which then undergo fast
back-isomerization. e | The polymer film in part d is prepared by first doping an azo dye into a mesogen of comparable size.
These two components participate in intermolecular H-bonding, which removes electron density from the 4-pyridyl
group, increasing the thermal isomerization rates of the azoswitch20. Copolymerization of the liquid crystal components
affords a photoactivate polymer film. f | Varying the heterocyclic N-substituents and solvent for (3-indolyl)NNPh
enables one to tune the Z→E isomerization lifetime from days to nanoseconds35. Δ, heat; λ, wavelength; DBU,
1,8-diazabicyclo[5.4.0]undec-7-ene; EF, Fermi level; t, time. Part d is reproduced from ref.20, Springer Nature Limited.
NATuRe RevIeWS | ChemisTry
volume 3 | MARCH 2019 | 139
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formation67 and tautomerism to hydrazone forms35.
Thus, the reader should be aware of not only how to
design an azo compound but also how to manipulate
the concentration — of both the dye and H2O — to
have favourable effects on a given figure of merit. These
influences can be exploited to fine-tune the performance
of an azoswitch or can even be considered as a specific
strategy to design switches with properties (for example,
such as Z isomer half-life) that respond directly to the
environment around the switch68.
A series of [5-(2-thiopheneyl)pyrrole-2-yl]NNAr
compounds have been prepared in which the Ar
groups are electron-poor (hetero)aromatics69–73. The
extended π-system is such that the principal ππ* bands
of these molecules fall in the green region and confer second-order nonlinear optical properties to the
chromophores74. Moreover, the substituents promote
a push–pull effect comparable to that in azopyridinium dyes, enabling a rotational mechanism of thermal
isomerization and fast Z→E relaxation kinetics (second
to microsecond lifetimes)75,76. These dyes have impressive fatigue resistance and have been used as dopants in
liquid crystals, in which they participate in cooperative
interactions with mesogens to afford optical oscillators76.
The time taken for thermal Z→E isomerization of these
dyes matches the reorientation time of the liquid crystals,
increasing the frequency at which the system can operate.
Most studies of azopyrroles are conducted using
compounds with organic N-substituents. In general, the
choice of substituents and solvent can influence whether
an excited molecule undergoes inversion, rotation or
intermolecular hydrazone tautomerism. For azoindoles,
NMe derivatives have Z isomers with thermal lifetimes
on the order of days, whereas unsubstituted species
can have lifetimes down to nanoseconds35. As has been
described above, hydrazone tautomerism, unravelled
by spectroscopy, serves as a mechanism of fast Z→E
isomerization in heteroaryl azoswitches32,35 (see Fig. 3f).
Heteroaryl rings bearing two N atoms
We now describe azoswitches bearing heterocyclic substituents with two N atoms, namely, pyrimidine, pyrazole, indazole or imidazole. In contrast to the heteroaryl
azos with a single N in their rings, of which pyridine
derivatives are the most studied, the photochromism of
dyes with six-membered rings featuring two N atoms,
such as pyrimidine77, is the subject of only very few
reports. Of the heterocycles bearing two N atoms, it is
the five-membered derivatives, in particular arylazo­
pyrazoles, that have attracted the most attention28,29.
Nevertheless, the following sections describe examples
of each class.
Pyrimidine. The synthesis of azopyrimidines has long
been known77, and further motivation for their study
stems from their similarity to DNA nucleobases, especially regarding H-bonding. This makes them promising candidates for applications in photopharmacology
and biocompatible real-time information transmission34,42,78,79. Azopyrimidines are more electron deficient
than pyridines and thus are suitable substituents in azo
push–pull systems, with (4-phenolyl)NN(2-pyrimidinyl)
140 | MARCH 2019 | volume 3
undergoing thermal Z→E isomerization in as little as
40 ns (ref.42). This system exhibits high stability under
physiological conditions (it can experience more than
50,000 switching cycles in phosphate-buffered saline
solution at 37 °C) and good biocompatibility (69% at a
concentration between 0.1 and 1 μM in an Escherichia
coli culture), suggesting that the molecule is a viable
candidate for photobiological and photomedical applications42. Moreover, the distribution of rotamers of differently substituted (2-pyrimidinyl)NNAr species can be
controlled by exploiting intramolecular interactions such
as steric strain and H-bonding between an azo N atom
and an –NH2 group. In turn, the electronic demands of
substituents on both rings influence the formation and
stability of the Z isomer79.
Pyrazole and indazole. Azo compounds such as
(4-pyrazolyl)NNAr are some of the best understood
heteroaryl azoswitches aside from the pyridine and
imidazole archetypes. Several investigations into the
photo­chromic properties of this chromophore reveal
the importance of steric strain, solvent and concentration on the stability of the Z isomer and the associated
thermal lifetimes29,67. Additionally, substituents on the
Ar ring can be chosen so as to give azo-push–pull systems or enable hydrazone tautomerism (the latter would
be possible, for example, with an –OH substituent on the
Ar or if a pyrazole NH group is present). In this way, we
can prepare azo compounds that undergo a prescribed
thermal isomerization pathway or pathways and give us
access to a broad range of dye lifetimes67.
Certain pyrazole derivatives are particularly useful
in that they show excellent bidirectional photoswitching
and long thermal half-lives29. For example, the Z form
of (1-methyl-4-pyrazolyl)NNPh is stable for more than
1,000 days and can be photogenerated in high abundance28,29 (PSD > 98%; Fig. 4a). These characteristics are
comparable to those of the best performing azobenzene
derivatives and make azopyrazoles interesting motifs
for molecular data storage, an application in which
diarylethenes have traditionally been more popular27.
Moreover, computational analysis on a rotationally hindered azopyrazole (Fig. 4b) revealed the first example of
excited-state stereospecific relaxation80. In particular,
electronic structure and non-adiabatic dynamics calculations of the photochemical Z→E isomerization showed
that the population of the anticlockwise (M) atropochiral S1–S0 conical intersection of the Z isomer is favoured
relative to that of the clockwise (P) intersection, with a
97:3 M:P probability (a 22:77 M:P probability ratio was
found for PhNNPh)80,81.
Despite their promising properties, far fewer applications of azopyrazoles exist relative to azopyridine-based
switches. However, arylazopyrazoles have been recently
used as photoaddressable inhibitors of amidohydrolase,
a bacterial enzyme and a chemotherapeutic target82.
Azopyrazoles are stable in concentrated glutathione
solutions, a crucial requirement for the potential use
of the azo compounds in vivo83. Aside from biological
applications, this class of compounds have also seen
use in DNA nanotechnology84, as well as coordination85
and supramolecular chemistry86. An example of the
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a
N
= 355 nm
N
N
N
= 415 nm
N
N
N
N
PSD > 98% Z
Thermal half-life > 1,000 d
b
N
N
N
N
N
N
N
N
N
N
N
N
E isomer
S1 excited state
Favoured CI
Barrierless
N
N
N
M helicity
97%
N
*
N
N
N
Disfavoured CI
0.51 kcal mol-1 barrier
N
P helicity
3%
c
SH
O
N
N
N
N
H
N
N
Polyamine linker
HO
N
H
N
O
N
OH
=
7
N
Perthiolated -cyclodextrin
O
= 365 nm
= 520 nm
Aggregated state
De-aggregated state
d
N
N
N
(t1/2 = 16 s)
N
N
N
N
N
= 415 nm
N
N
N
H
–H+
–H+
H+
H+
N
H
N
+
N
N
N
N
N
pKa = 6.0
(t1/2 = 352 s)
N
N
N
H
H
= 415 nm
N
pKa = 4.7
Fig. 4 | Azos with aromatic rings containing two N atoms. a | (1-Methyl-4-pyrazolyl)NNPh exhibits excellent two-way
photoswitching and has a Z form with an extremely long thermal half-life (t1/2)28. b | Rotationally hindered phenylazopyrazoles
undergo stereospecific excited-state relaxation80. Indeed, the population of the first singlet excited state (S1)–ground
electronic state (S0) conical intersection (CI) leading to the anticlockwise (M) atropisomer of the Z pyrazole is overwhelmingly
favoured over that leading to the clockwise (P) atropisomer (97:3 M:P probability). c | A supramolecular system photoinduced
aggregation/disaggregation can be achieved87. Whereas the pyrazole linkers (guest) can interact with the immobilized
cyclodextrins (host) in a host–guest interaction in its E form, the Z form is sterically too demanding. d | E-(1-methyl-2-imidazolyl)
NN(1-methyl-2-imidazolyl) in a monodentate base (pKa = 4.7) that can undergo photoisomerization to its Z isomer, a stronger
bidentate base (pKa = 6.0) that is stabilized upon binding H+ (ref.95). Δ, heat; λ, wavelength; PSD, photostationary distribution.
NATuRe RevIeWS | ChemisTry
volume 3 | MARCH 2019 | 141
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latter is a system in which Au nanoparticles are decorated with cyclodextrins — hosts that bind a diaryl­
azo in its E form but not in its Z form87 (Fig. 4c). Thus,
a bivalent bis[(3-pyrazolyl)NNAr] guest can link two
cyclodextrins and induce aggregation in its bis(E) form.
Photoswitching to the bis(Z) form liberates the dye and
de-aggregates the decorated nanoparticles. Given their
immense potential, we consider azopyrazoles to be
understudied and predict that they will soon see more
use as rationally designed photoswitches.
As with azo dyes featuring pyrazoles, those of the
benzo analogue indazole have good-to-excellent photo­
isomerization characteristics and a Z isomer with
high thermal stability33 (lifetime on the order of a day;
Fig. 1). Interestingly, the Z→E isomerization is thought
to occur via a rotational transition state, in contrast to
the great majority of azos with long-lived Z forms, that
isomerize by an inversion mechanism10,16,29. Again, we
expect such species to attract more attention, particularly given developments in synthetic methods, such as
the high-yielding cyclization of C6F5-substituted formazans, through nucleophilic aromatic substitution, to
give (4,5,6,7-tetrafluoro-3-indazolyl)NNAr derivatives33.
In general, molecules that have enhanced photomediated acidity or basicity are useful agents to protonate or deprotonate a molecule of interest. The basicity of the simple compound (1-methyl-2-imidazolyl)
NN(1-methyl-2-imidazolyl) can be toggled upon
isomerization because its Z isomer can serve as a
bidentate base (pKa = 6.0 for the protonated form in an
aqueous phosphate–citrate buffer), whereas the E isomer is less easily protonated95 (pKa = 4.7; Fig. 4d). Such
a species could, in principle, be used to deprotonate
an acid with an intermediate pKa when stimulated by
light. Moreover, protonation stabilizes the Z isomer,
the thermal half-life of which increases from 16 seconds to 352 seconds95. The protonated forms are readily
observed by mass spectrometry, such that the photoisomerization (along with the PSD values) is readily
monitored 96. Azoimidazoles can also enable lighttriggered alteration of acidity in another way, namely,
through their control of the voltage-gated proton channel Hv1. Thus, (2-guanidino-5-benzoimidazolyl)NNAr
in its E isomer blocks the channel and native H+ currents in macrophages, whereas the Z isomer does not
bind the protein and allows H+ ions to flow through97.
Imidazole. Arylazoimidazoles are, after azopyridines, the
second most utilized and studied heteroaryl azoswitches
to date29,88. As is the case with azoindoles35, arylazoimidazoles have varying Z isomer stabilities, thermal Z→E
isomerization rates and mechanisms. Indeed, it was in a
study of (2- or 4-imidazolyl)NNAr species that the hydrazone tautomerism operative in the thermal isomerization
of NH-containing heteroaryl azos was first uncovered.
This seminal kinetic and computational study identified
the importance of the NH group and the accelerating
effect of protic solvents for tautomerization32. The formation of hydrazones is more prevalent at higher dye
and protic solvent concentrations, at which the thermal Z→E relaxation is on the millisecond timescale
(Fig. 1; Supplementary Fig. 2). By contrast, Z isomers of
N-substituted imidazoles have thermal half-lives of hours
to days, depending on the substituents, concentration
and presence of H2O in solution29,40,89.
Irradiating an E azoimidazole can cause it to exist
almost exclusively (>95%) in its Z state. The quantum
yields of isomerization and thermal lifetime of the
Z isomer are higher than those for PhNNPh (ref.90).
However, the PSDs for the back-isomerization of azoimidazole are limited owing to overlap of the ππ* and
nπ* bands29,89.
Azoimidazoles have found several applications,
including as components in liquid crystal copolymers
that show photoinduced birefringence91. When conjugated to a ribofuranose, azoimidazoles can serve as
photoswitchable nucleotides92, and when ligated to Cuii,
switching of E-(1-methyl-2-imidazolyl)NN(4-tolyl)
is inhibited because it is a good chelating ligand93. An
E-(1-methyl-5-imidazolyl)NNAr fragment has also been
incorporated into a record player porphyrinatonickel(ii)
complex analogous to the species described above that
features a (3-pyridyl)NNAr unit. In this case, 93% of the
complex could be converted into the pentacoordinated
form when in tetrahydrofuran (THF) solution94.
Heteroaryls bearing three or more N atoms
Azoswitches containing heterocycles with three or
more N atoms per ring are rare. (Triazolyl)NNPh and
(tetrazolyl)NNPh are known classes of compound, but
their photochromic properties have been described
only as part of a general study of five-membered heterocyclic azoswitches29. In general, these N-rich species
are challenging to prepare and may be thermodynamically unstable (for example, with respect to the loss
of N2)98–102. Despite these considerations, (1-tetrazolyl)
NN(1-tetrazolyl) — a compound containing ten contiguous N atoms — has been synthesized and even
photo­isomerized, although the latter was monitored
using only Raman spectroscopy 100. A much more
robust species is (1,2,3-triazol-1-yl)NN(1,2,3-triazol1-yl)99 (featuring eight contiguous N atoms; Fig. 5A),
which has been characterized using solid-state UV–
vis and Raman spectroscopy. Upon irradiation with
broad spectrum light (200–800 nm), the pale yellow
solid reversibly undergoes an atypical colour change
to deep blue species (λmax = 595 nm), proposed to be
the Z isomer99.
The incorporation of a pyrazolopyrimidine into
an azoswitch led to a photocontrollable inhibitor of
a transmembrane receptor tyrosine kinase (Fig. 5B), a
phosphorylating enzyme that is involved in cell signalling and overexpressed in cancer cells103. As with
all azos, the spatiotemporal control afforded over the
concentration of the active E isomer is relevant to conducting signal transduction studies in vivo. Research
towards another biological application in photopharmacology saw the synthesis of a small library of
6-azopurines104 (Fig. 5Ca) with high fatigue resistance
and tuneable visible-light-addressable nπ*-type absorptions (Fig. 5Cb). Overall, it becomes clear that purine
and related scaffolds are promising candidates in biological applications ranging from smart drugs to novel
photoswitchable nucleotides.
142 | MARCH 2019 | volume 3
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particularly pronounced for thiazoles ((thiazolyl)NNAr
derivatives are known but have not been studied as photo
switches108) and benzothia­zoles72,73,109. The latter are
more electron-withdrawing than are nitrophenyl
groups, such that the Z→E isomerization of a donor−
acceptor azo featuring one pyrrole is 23 times faster
when the other substituent is a benzo­thiazole instead
of nitrophenyl (see Supplementary Information)75,76. As
mentioned above, azo compounds that undergo rapid
thermal Z→E isomerization, when doped into liquid
crystals, are amenable for applications as molecular
photo-oscillators76 (Fig. 5D; see also the pyrrole section).
As with quickly oscillating PhNNpy derivatives, the less
well-studied arylazothiophenes and arylazo(benzo)thiazoles might also find use in visible-light-addressable
Heteroaryls bearing heteroatoms other than N
Only a few reports exist that describe azoswitches
with heteroatoms other than N in the aromatic ring.
Arylazothiophenes, arylazothiazoles and arylazobenzothiazoles have been studied for their nonlinear optical and
photochromic properties69,74,105,106. [5-(2,2ʹ-Bithiopheneyl)]
NNAr derivatives exhibit photochromic properties
addressable with visible light (35–50% E→Z isomerization,
t1/2 = 18–69 s), while 4-azobithiophenes do not107.
The thermal relaxation process of S-containing photochromic systems has been investigated in more detail, and
they do indeed exhibit fast thermal isomerization kinetics
(in the microsecond range) and extremely high fatigue
resistance (see the pyrrole section) when decorated with
electron-withdrawing rings75,76. This push–pull effect is
A
B
N
N
N
N
Xe lamp
N
N
N
N
N
N
N
N
N
= 503 nm
Ar
N
N
N
N
N
N
N
a
Ar =
b
F
428
420
F
CN
c
d
e
CO2H
CN
f
CO2H
Cl
6-Arylazoadenine (A)
g
Cb
OMe
N
N
N
6-Arylazo-2-aminoadenine (G)
Z isomer is inactive
N
N
N
N
N
E isomer is a RET kinase inhibitor
Ar
H2N
NH2
Z isomer is blue in the solid state
N
N
N
= 365 nm
N
E isomer undergoes thermal
decomposition at 193.8 °C
Ca
N
N
N
N
N
NH2
N
N
N
Ga
Gi
Ai,Gg
Gd
h
460 A 474
455
462
450
443
h
Ab,d,Ge
Aa,g,j
i
474
j
k
Af
max (nπ*)
467
480
Ae
Ak
(nm)
500
Da
N
S
N
N
N
N
S
S
N
N
S
S
S
F
Db
R
N
R = Et, nPr, nBu, heptyl
I52
ZLI-1695
Fig. 5 | Azophotoswitches based on arenes containing more than two heteroatoms. A | 1,1ʹ-Azobis-1,2,3-triazole
containing an N8-chain can be photoisomerized in the solid state, as presented in ref.99. The E→Z isomerization is
accompanied by an unusual colour change from yellow to blue. B | A pyrazolopyrimidine derivative functions as a
receptor tyrosine kinase (RET) inhibitor when in its E form but not in its Z form, as demonstrated in live-cell assays103.
Ca | Visible-light-responsive purine azoswitches are promising adenine and guanidine mimetics for photopharmacological applications. Cb | Most useful are those with Ar groups that give rise to longer wavelength (λ) absorptions104. Da | The
combination of electron-demanding (benzo)thiazoles with electron-rich pyrroles and thiophenes results in azo-push–pull
systems76. These compounds undergo rapid E→Z relaxation and are useful visible-light-sensitive dopants for liquid
crystals. Db | The liquid crystal hosts can be prepared from mesogens such as I52 or ZLI-1695. Δ, heat; λ, wavelength.
NATuRe RevIeWS | ChemisTry
volume 3 | MARCH 2019 | 143
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materials or in photopharmacology. Their utility arises
not only because they enable real-time transmission of
light but also because their extended π-systems enable
excitation using green light.
Conclusion and perspectives
Heteroaryl azo compounds have emerged as extremely
tuneable photoswitches. Relative to PhNNPh, the presence of one or more heteroatoms endows them with a
broader variety of photophysical and photochemical
properties. For instance, certain heteroaryl azos can
exist in metastable Z forms for anything from hundreds of picoseconds35,42 to more than 1,000 days29. This
spectrum of stability is available from compounds with
rela­tively simple or even no substituents attached to
the aromatic cores, which are selected according to the
desired excitation wavelength (Fig. 1; Supplementary
Fig. 3). Such moieties have already found applications
as photoaddressable Brønsted bases95, ligands that control luminescence and spin states of metal complexes55,61
and materials able to transform molecular motion into
macroscopic motion20. The tunability of light absorption
means we also have access to dyes that can be excited in
the near-IR region, a desirable aspect for photopharmacology104. The path towards real-world applications will
rely on novel theoretical approaches110 and more efficient
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Given the useful properties of heteroaryl azos, it is surprising that only a few azoheterocycles — principal among
them azopyridine, azopyrazole and azoimidazole — have
been thoroughly investigated. Many other heteroaryl azo
dyes, such as those featuring furan112, isoxazole113 and
quinoxaline114,115, are known but have not been the subject of publications describing photochromic properties.
In general, it appears that an understanding of the structure–property relationships of a broader number of
heteroaryl switches is lacking. Thus, the way in which different (and/or multiple) heteroatoms in a single scaffold
(on one or both sides of the –N=N– unit) influence electronic transitions, switching efficiency (quantum yield,
photostationary distribution and fatigue resistance) and
thermal stability has yet to be generalized. Furthermore,
the effect that changing the molecular environment
(including the solvent) has on these properties needs to be
verified. Several studies indicate that changing the polarity
of the solvent, altering the concentration of the chromophore or moving from the solution to a solid state markedly alters the performance of a photoswitch. Achieving
this understanding will require interdisciplinary study and
will bring together synthetic chemists, spectroscopists and
experts in computational chemistry in an effort that will
enable the truly rational design of heteroaryl azoswitches.
Published online 8 February 2019
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Acknowledgements
S.C. thanks D. Ravelli and R. Tinelli for fruitful discussions.
N.A.S. thanks the Studienstiftung des Deutschen Volkes for
a PhD scholarship.
Author contributions
S.C. and N.A.S. contributed equally to the preparation of this
manuscript. S.C. and N.A.S. researched data for the article
and contributed to the discussion of content and writing. B.K.
contributed to the discussion, writing, reviewing and editing
of the manuscript before submission.
Competing interests
The authors declare no competing interests.
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