Photoswitches beyond azobenzene: a beginner’s guide

Introduction

Photophysical properties and switching mechanism

Key learning points

Before introducing the different photoswitch classes in this review, we familiarise ourselves with different photophysical properties. A photochromic molecule can switch reversibly between a stable and a metastable state, which are shown in an energetic profile as two local minima (Figure 1). Shining light will bring the molecule to a generic excited state (which is different for different photoswitch classes and substitution patterns and will not be treated in detail), which can then relax back to the ground state in either of the two wells. In cases where the two absorption spectra of the two isomers do not overlap, only one isomer is excited by the irradiation wavelength, enriching the other isomer until an equilibrium is reached. This equilibrium is called a photostationary state (PSS) [1]. The isomeric distribution at equilibrium can also be called photostationary distribution (PSD). It must be noted, though, that in literature both PSS and PSD are used to indicate the photostationary distribution [2]. We will use the PSS notation throughout the review. Often, the two absorption spectra overlap, and both isomers are excited to different extents at the same time. The extent of excitation depends on the molar extinction ε of each isomer. It is the absorbance A normalised by the concentration c and the path length l, calculated according to the Beer–Lambert law:

For this reason, careful choice of the excitation wavelength is important, as it affects how well one isomer can be switched to another. To achieve the best PSS, a wavelength with minimum spectral overlap should be chosen, which may not correspond to the maximum absorption wavelength (Figure 2) [3]. Positive photochromism is observed when the stable isomer has a maximum absorption at the lower wavelength (i.e., UV), and it is switched to one that absorbs at a higher wavelength (i.e., blue). The opposite phenomenon is called negative or inverse photochromism [3]. A shift towards higher energies is called hypsochromic or blue shift, while a shift towards lower energies is called bathochromic or red shift.

When working with a photoswitch, several factors must be considered: substituents, temperature, and solvent strongly affect the photophysical properties. For instance, the presence of electron-withdrawing (for instance -Cl, -Br, -CN, -NO₂) and electron-donating groups (-alkyl, -OR, -NR₂), which are directly conjugated with the chromophore structure, will influence its absorption spectrum and stability [4]. The solvent will also affect the properties, as it can stabilise or destabilise either the ground or the excited state, resulting in a red- or blue shift of the spectra. The thermal half-life (t_1/2) measures the time within 50% of the metastable isomer is thermally converted to the stable one [3]. It depends on the photoswitch class, solvent, substitution pattern, and temperature. For some photoswitch classes, proton exchange and intramolecular hydrogen bonds are known to accelerate the thermal relaxation of the metastable isomer [5-7], thus they are also important factors to consider when choosing the solvent and the concentration of the solution. The half-life can be extrapolated by monitoring the photoswitch in the metastable form over time by various spectroscopic methods (UV–vis, NMR) in the absence of light. Apart from some special cases where more competing mechanisms are operating [5], the thermal isomerisation typically is a first-order decay:

Where I is the monitored signal at the time t, I₀ the initial signal, and k the kinetic constant. Once k is known, the thermal half-life t_1/2 can be easily calculated. According to the thermal half-life, photoswitches are usually classified in P-type (thermally stable, with long half-life) and T-type (thermally unstable) [3]. The quantum yield Φ measures the efficiency of the switching, and it relates the number of photons absorbed n_x to the number of irradiated photons n_tot:

Quantum yields vary in the range 0 ≤ Φ ≤ 1 and can be calculated by spectroscopic methods [8]. The calculation, however, is not trivial because irradiation can trigger various photochemical events. For instance, if the spectra of the two isomers strongly overlap, both forward and backward isomerisation can occur simultaneously. Moreover, some unwanted photochemical side reactions Φ_S can occur, as shown in the Equation 4:

A is one state of the photoswitch, B the second state, and B’ a generic degradation product. Fatigue resistance measures how many times the photoswitch can be switched before it is degraded by side reactions. It is typically reported as cyclability Z₅₀, which “is the number of cycles required to reduce the initial absorbance at a specific wavelength by 50%” [3]. The quantum yield Φ_S of these side reactions determines the resistance to fatigue of the photoswitch. Examples of photogenerated side reactions can be oxidation or irreversible rearrangements.

In the following sections, seven classes of photoswitches beyond the classic azobenzene are introduced and discussed (Scheme 1). Each of them shows unique photophysical behaviour and has individual features that may render them more suitable for applications than azobenzenes. This review, particularly for those new to the field, aims to summarise the classes of azoheteroarenes, diazocines, indigoids, arylhydrazones, diarylethenes, fulgides, and spiropyrans concerning their photophysical properties and tuneability while also outlining the most common synthetic methods for these compounds. Additionally, each chapter presents exemplary applications of the illustrated photoswitch classes, highlighting their practical relevance while inspiring the reader with new ideas in this field. For a more detailed view on photoswitches, such as in-depth analysis of photoswitching processes [9], their application into smart materials and biological systems [10], and the application in aqueous environments [2], we refer the interested reader to further reviews on these topics.

Review

Azoheteroarenes

Azoheteroarenes are azoswitches of which at least one aromatic ring is a heteroarene (Figure 3).

The variety of heterocycles and substitution patterns that can be used gives rise to a considerable number of variants covering all the UV and visible spectrum and with thermal Z-isomer lifetimes that span from picoseconds to several years. The presence of heteroatoms also introduces H-bond donors and acceptors and metal coordination sites [11]. Like azobenzenes, E–Z isomerisation of azoheteroarenes can be triggered by light irradiation, while Z–E isomerisation proceeds through irradiation with a different wavelength (P-type) or through thermal back isomerisation (T-type). As a general rule, the absorption can be red-shifted by the choice of electron-donating rings (pyrrole, thiophene), while electron-withdrawing rings (pyridine, pyrimidine, pyrazole, imidazole, thiazole) give the opposite effect [12]. Absorption red-shift is usually correlated to the shortening of the thermal lifetime [13]. To understand and to predict the thermal lifetime of these photoswitches, it is important to have a closer look at the thermal Z–E isomerisation, for which three main mechanisms have been found to take place: inversion (usually associated with longer lifetimes), rotation (usually associated to shorter lifetimes) and tautomerism (fast), shown in Scheme 2. The tendency between inversion and rotation depends on the degree of single-bond character of the N=N azo bond as well as the geometry of the Z-isomer [14]. Hydrazone tautomerism is an intermolecular process that depends not only on the choice of aryl rings and substituents but also on concentration, solvent polarity, and the presence of proton sources [5,15]. In conclusion, the choice of aryl rings, substituents, and substitution position are all crucial to determine the photophysical properties of this photoswitch class. The vast possibility of combinations and the straightforward syntheses make these compounds extremely attractive, however, somewhat difficult to strictly categorise: among the azoheteroarenes we find mainly nitrogen-based heterocycles such as pyrazole, pyrrole, pyridine, and indole, alongside with less common oxygen and sulphur-based heterocycles such as thiophene, thiazole, oxazole. At the end of the section, we will also briefly discuss heteroarylimines which, although not being azo-switches, resemble the geometry of azo-compounds and possess similar photophysical properties.

Push–pull systems, where a combination of an electron-donating group on one side of the azo bond (push) and an electron-withdrawing one on the other side (pull) decreases the double bond character of the N=N motif, are characterised by rotational thermal relaxation (Scheme 3) [16]. Due to the strong electron conjugation, these compounds usually show much shorter thermal lifetime, alongside with strong bathochromic shifts [17-26]. They are useful when fast responsive T-type photoswitches are needed. Moreover, some compounds show interesting non-linear optical properties, switching with two-photon absorption of near-IR wavelengths [3,27]. This could open the way to laser-storage devices and to application in biological systems, where longer wavelengths are preferred due to improved tissue penetration [28].

When the push–pull character is not so strong as in the previous examples, a deeper analysis is usually needed to predict the photophysical properties of the azoheteroarenes. While the Z-isomer of 6-membered rings is always in a twisted conformation, it was discovered in the case of 5-membered rings that also a T-shaped conformation could be achieved in virtue of the reduced steric clash [29]. A systematic study on different azoheteroarenes with 5-membered rings demonstrated that the shape of the Z-isomer was responsible for the thermal lifetime of the photoswitch and for the PSS of the photoinduced Z–E isomerisation (Figure 4A) [14]. In case of T-shaped 8a and 9a the Z-isomer was more thermally stable thanks to the weak interaction between the hydrogen and the π-system. However, the high symmetry weakens the intensity of the nπ* absorption band, which is the excitation band for the Z–E isomerisation, resulting in a lower E-PSS. Basic nitrogen in “ortho” position (according to the nomenclature in the original paper) [14] also gives slightly twisted Z-isomers 10a and 10b. Moreover, a rough approximation of the thermal lifetime could be made considering the nature and connectivity of the heterocycle as either “complete” or “partial” conjugation (Figure 4B). The “complete” conjugation implies shorter lifetimes, due to the ability to rearrange the electrons more efficiently, thus showing a stronger push character.

A follow-up study showed that di-ortho-fluorination (9c and 9d) and di-ortho-methoxylation (9e) of the phenyl moiety of 4-phenylazopyrazoles notably increased the half-lives with respect to the unsubstituted ones, probably a result of favourable weak interactions between the pyrazole ring and the ortho-substituents in the Z-form [30]. Despite the high intensity of the nπ* absorption band, the absorption spectra of the two isomers are strongly overlapped, resulting in a less efficient switching. Conversely, di-ortho-chlorinated 9f has lower thermal stability because of the steric clash with the bulky chlorine substituents (Figure 5).

An interesting study shows how the Z-isomer thermal lifetime changes between two phenylazoindole photoswitches (Figure 6) [5]. N-Methylation of indole 2b increases the lifetime due to a preference for the inversion with respect to the rotation mechanism. Interestingly, the isomerisation of the non-methylated 2a is also strongly influenced by protic solvents, by the pH of the solution, and by the concentration of the photoswitch in solution: when MeOH or water are present, the lifetimes drop significantly, and particularly at pH 4, as consequence of more favourable intermolecular proton transfer. Calculations show that water molecules bridging between two Z-isomers favour the formation of hydrazone and thus rapid conversion to the E-isomer.

A follow-up study calculated the activation energies of inversion, rotation, and tautomerisation of a number of previously reported and newly synthesised heteroaryl azo-switches, correlating the preferred mechanism of thermal back isomerisation to the reported lifetimes with great accuracy [7]. In summary, the more extended the conjugation of the heterocycle with the N=N bond, the more feasible the inversion mechanism (which does not involve the rupture of the double N=N bond). The less conjugated switches, however, would undergo rotation around the (instant) single bond N–N. The hydrazone pathway in protic solvents could be ruled out in cases when the energy of the s-cis-hydrazone was superior to the energy of the other two transition states. For further substituent effects on azoheteroarenes, we refer the readers to the following reports by Venkataramani, Corminboeuf, Samanta, and König [6,31-35].

Although they do not possess an azo bond, heterocyclic imines are worth mentioning in this chapter due to their similarity to the azo-compounds and their straightforward synthesis. Substitution of the azo bond with an imine bond gives rise to heterocyclic imines [36-38]. The Z-isomers of the unsubstituted derivatives adapt different conformations: T-shaped for the N-phenyl and twisted for the N-pyrazoles. The half-lives follow the same trends already discussed beforehand. In contrast with the azopyrazoles, mono- and di-ortho-amination of the aryl ring of 11a and 11b yield iminopyrazoles with longer half-lives and negative photochromism (Figure 7, top). This unusual behaviour can be explained by the absence of adjacent non-bonding lone pairs in the imine bond [37]. Conversely, in the case of N-phenyl derivatives 11c and 11d (Figure 7, bottom), the thermal lifetimes drop significantly [38]. It is thus crucial to take into account the asymmetric nature of the imine bond and the steric hindrance of the substituents in the design of these photoswitches. For a detailed analysis of the structure–property relationship of these compounds we direct to recent literature [37,38].

Synthesis

Many synthetic approaches have been developed for the synthesis of azoheteroarenes. Typically, synthesising this kind of photoswitches is rather straightforward and one can usually obtain azoheteroarenes with low synthetic effort. Symmetrical compounds can be synthesised through oxidation of aminoheteroarenes 12 (Scheme 4A) or reduction of nitroheteroarenes 13 (B). Bayer–Mills coupling (Scheme 4C) is suitable for both symmetric and asymmetric targets, usually in acidic conditions. Basic conditions [14] are more effective with very electron-poor aromatic amines.

Another strategy for both symmetric and asymmetric targets is the azo coupling of a diazonium salt 15 (Scheme 5A) with a nucleophile, which can be a (hetero)aromatic 16 [29] (B), a lithiated ring 19 [39] (C), or a precursor 20a,b [29,32,40] (D). In case of more than one reactive position, the synthesis can be directed towards the desired target with the use of protecting groups [41].

For the synthesis of azothiazoles 25, the addition of phenylhydrazine (22) to ammonium thiocyanate followed by ring closure and oxidation was recently proposed (Scheme 6A) [42]. Heteroarylazo-1,2,3-triazoles 28 can be obtained by click chemistry (Scheme 6B) via one-pot deprotection of 26 and Cu(I)-catalysed reaction with an azide [43,44].

Heteroarylimines 31a,b can be easily obtained by condensation of a (hetero)aromatic aldehyde 30a,b with a (hetero)aromatic amine 29a,b [36-38] (Scheme 7). The choice of aldehyde and amine will determine the direction of the imine bond and the geometry of the Z-isomer.

Examples

Non-ionic bithienylpyrrole push–pull azo dye 32 was successfully introduced in liquid-crystalline matrices with thermal relaxation in the µs order, making them among the fastest liquid crystalline optical oscillators (Figure 8) [45].

The Herges group reported a photoinduced magnetic spin change of a Ni(II) porphyrine. The spin change was caused by the reversible coordination of azopyridine 33 to the Ni(II), which was only possible in the E-isomer (Scheme 8) [46].

The Han group reported a series of compounds 34a–c (Scheme 9) which melt upon irradiation with UV light in the solid phase. Upon irradiation with green light, the compounds isomerise back to the solid phase. The large depth of light penetration of these compounds (>1400 µm for both UV and vis light) and the high capacity for heat storage (>300 J/g) makes these compounds suitable for molecular solar thermal energy storage (MOST) [47].

Diazocines

Diazocines are bridged azobenzenes (Figure 9).

The added strain renders the E-isomer metastable, favouring the more stable Z-isomer. In the planar E-azobenzene, the nπ* transition is symmetry-forbidden, which reflects in a low intensity of this band, while the Z-isomer is bent, giving rise to a higher intensity nπ* band [48]. The distorted nature of both Z- and E-isomers of diazocine makes the nπ* transition symmetry-allowed: as a consequence, the absorbance and the separation of the nπ* bands, which are used in the photoswitching process, are increased, leading to higher PSSs and higher excitation wavelengths, alongside with an excellent quantum yield in both directions. The bridge is also accountable for the much faster response to irradiation with respect to azobenzene [49]. The metastable E-diazocine exists in two conformers that can interconvert and have different absorption spectra (Scheme 10): twist (generally more stable) and chair (less stable). The spectrum of the chair conformer overlaps with the Z-isomer. Thus, to obtain better PSSs, the right conditions should be chosen to favour the twist conformer [50]. Each form exists in two enantiomers. The E-enantiomers cannot interconvert directly without first converting to the other conformer [51].

Regarding the substitutions on the aromatic rings, it has been reported that electron-donating groups tend to red-shift the absorption of the ππ* absorption band, which overlaps with the nπ*, resulting in a decrease in the PSS (Scheme 11), while they are well tolerated when separated from the chromophore backbone [50,52-54]. Electron-withdrawing groups seem not to perturb much the absorption spectra [55]. There is one known report of diazocines with heteroaromatic rings: an electron-rich aromatic ring (thiophene) gives a similar effect to what is shown for electron-rich substituents with a very poor 385 nm PSS (18%), while an electron-poor aromatic as pyridine does not affect the absorption properties much [55].

Several diazocines with heteroatoms in the bridge have been reported (Figure 10) [50,51,53]. Oxygen-containing heterodiazocine exhibits high PSS in both directions but has a short half-life, whereas the sulphur derivative has a significantly longer half-life but a slightly reduced E-PSS. This is likely due to the spectral overlap between the E-chair isomer and the Z-boat isomer [53]. Nitrogen-containing heterodiazocines were also reported. Alkyl substitution on N gave the highest bathochromic shifts. However, the E-PSS is generally low, again a probable consequence of the presence of the E-chair isomer [51]. All the compounds show excellent resistance to fatigue.

The behaviour of some (hetero)diazocines was also studied in water and solvent mixtures [50,51]. Interestingly, N-acetyl-diazocine possesses overall comparable properties and a longer thermal half-life, and it is also soluble in water. For C- and S-diazocine, the absorption band separation of the two isomers is lower in polar solvents, resulting in worse PSS. In particular, for the S-diazocine it was found that the E-chair conformer was bathochromically shifted with increasing polarity of the solvent until completely overlapping with the Z-boat conformer, making it impossible to switch it any further (42% E in H₂O/MeCN 9:1). A diazonine was also synthesised, which exhibits a UV–vis spectrum of the E-isomer very similar to that of E-azobenzene and an unusually long E–Z thermal half-life [54].

Synthesis

The synthesis of symmetrical diazocines is more demanding compared to classical azobenzenes since the two aromatic rings are not only connected via an azo-bond, but also have to be linked by an alkyl chain first. For that, more synthetic effort is required. It can be performed through oxidative dimerisation of o-nitrotoluene (37) followed by reduction with Zn/Ba(OH)₂ and partial re-oxidation (Scheme 12A) [52]. They can also be obtained from o-halogenated benzyl bromides 40 by lithium–halogen exchange followed by nucleophilic substitution and a second lithium–halogen exchange with iodine (Scheme 12B) or by nickel-catalysed reductive cross-coupling of benzyl halides when substituents prone to reduction (CN, esters) are present (Scheme 12C). The Ullman–Goldberg coupling of 41b with Boc-hydrazine followed by deprotection and oxidation then affords 35 [55].

Asymmetric diazocines can be synthesised by Sonogashira cross-coupling and subsequent reduction of 45 (if substrates 43 and 44 contain a NO₂ group, this will also be reduced, Scheme 13A) [54], or by Wittig reaction and reduction of the isomeric mixture of alkenes 48 (Scheme 13B) [57]. Oxidation of 49 with oxone [58] or m-chloroperbenzoic acid [54] yields 35. Wittig reaction can also be used to prepare precursors for the Ullman–Goldberg coupling (Scheme 12B and 12C); however, in the presence of halogens, an alternative reduction pathway of the alkene with tosylhydrazine and NaOAc must be used [55].

Hetereodiazocines 35b and 35c are synthesised by coupling of o-nitrobenzyl bromide (47) with 50 or with 52, after its reduction with NaBH₄. The intermediate products are then treated with lead in a buffered basic environment to get the final product in low yield accompanied by two by-products, 54a,b. For the O-heterodiazocine, reduction with triphenylphosphine and a molybdenum catalyst allows partial conversion of the recovered by-product to the final product 35b, while for the S-heterodiazocine lead was used for the reduction in neat conditions (Scheme 14) [53].

N-Heterodiazocines (Scheme 15) can be synthesised by coupling of monoprotected diamine 55 with benzyl bromide 47, followed by Fmoc protection of 56, Boc deprotection of 57, reduction of the NO₂ group to NO and intramolecular Mills coupling to form 35h. Removal of the Fmoc protecting group under basic conditions affords the unsubstituted product 35d which, after N-alkylation or acylation affords the substituted products 35e–g [51].

Examples

Because of their red-shifted absorption and inverse stability, diazocines are suitable substitutes for azobenzenes in biological environments. Light with longer wavelengths can penetrate biological media, such as tissue, more effectively, and is less harmful to living organisms than UV irradiation, for example. The inversion of E/Z-isomer stability compared to azobenzenes creates the opportunity to “invert” the mode of action in a biological context. Indeed, with azobenzene-based photopharmacophores, it is mostly the case that the least bulky E-isomer is a better fit in the protein-binding site than the bent Z-isomer. However, it would be more desirable to have an inactive molecule in its most stable state which can be activated by irradiation [51,59]. Hernando and co-workers were able to design photoswitchable neurotransmitters of ionotropic kainate receptors by replacing the azobenzene moiety of the already established partial agonist GluAzo with a diazocine unit. While both photochromic ligands show biological activity in the E form, the E-isomer is the thermodynamically more stable one for the azobenzene analog, whereas for the diazocine-modified neurotransmitter it is the Z form. Hence, GluAzo would permanently show biological activity in the dark (E-isomer), whereas the diazocine analog (Z-isomer) would be inert and only gets activated upon irradiation [58]. The Trauner group synthesised a puromycin diazocine 59 that shows higher affinity to the ribosome pocket in its (metastable) trans-isomer, inhibiting RNA translation (Scheme 16). In contrast, the azo-puromicin did not show significant change in activity between the two isomers [60].

Indigoids

Indigoid photoswitches are characterised by switching in both directions with visible light (Figure 11).

The main representatives are shown in Figure 12. The relative stability of the isomers is generally E for indigo and thioindigo and Z for the other indigoids, but there are a few exceptions that depend on the substitution pattern [61-64]. Due to the very different properties, each subclass should be treated separately.

Indigo and thioindigo possess an intrinsic push–pull character, giving them extremely red-shifted spectra without the need for additional substituents [65]. The E-isomer is planar and conjugated, while the Z-isomer is not. The rupture of conjugation causes a hypsochromic shift, which characterises this subclass with negative photochromism. Unsubstituted indigo (60) does not undergo photochemical isomerisation, due to much faster relaxation through excited-state proton transfer 60* followed by tautomerisation 60’ (Scheme 17). The first proof of the existence of Z-indigo was provided by Wyman and Zenhäusern, who isolated derivative 61, which is sterically constrained to the Z form, and compared the absorption spectrum to the spectra of already reported Z-indigoids (Figure 13) [66].

The Hecht group rationalised the role of N-substitution on the photophysical properties of indigos [67]. In general, electron-donating substituents red-shift the absorption and decrease the thermal half-life, and vice versa for the electron-withdrawing ones. Phenyl rings with electron-withdrawing p-substituents allow a better fine-tuning of the spectral separation between the two isomers (thus, giving better PSSs) and improved the half-lives without interfering too much with the absorption of the E-indigo (Figure 14). Diarylated indigos like 60g showed the presence of the Z-isomer in the dark, possibly due to the stabilisation energy given by the π–π interaction between the aryl rings (Figure 14, box) and repulsion between the aryl and the carbonyl group in the E-isomer.

Some studies on N-acylindigo derivatives reported, besides the expected spectral blue-shift, also a decrease in the fatigue resistance due to photochemical rearrangements [68,69]. Dube and co-workers reported a series of mono-N-substituted indigos which were also able to isomerise, despite the presence of one hydrogen atom, capable of proton transfer. Only rather electron-neutral substituents show photoswitching to some extent, and the thermal half-lives are, in general, very short. Interestingly, low amounts of water led to a strong decrease in the thermal half-life, suggesting water is also involved in the Z–E thermal isomerisation process [70]. Bridged indigos have also been reported for which the Z-isomers are unstable. By bridging the two nitrogen atoms, these compounds show planar chirality and can be racemised upon irradiation. For further details about bridged indigos, we refer the reader to the work of Tsubaki and co-workers [71]. Although less pronounced, substituents in the phenyl ring also change the absorption properties of indigos. Considering only the resonance structures that involve the phenyl ring (in Scheme 18), one can conclude that electron-withdrawing groups in positions 4 and 6 and electron-donating groups in positions 5 and 7 decrease the energy of the excited state, resulting in a bathochromic shift. Conversely, electron-donating groups in positions 4 and 6 and electron-withdrawing groups in positions 5 and 7 destabilise the excited state and give hypsochromic shifts [72,73]. Positions 4 and 7 also have some steric effects [65].

The impossibility of proton transfer in thioindigo makes it readily switchable without the need for any substituents on the sulphur atom. The same effects of ring substitution as indigo are observed (Scheme 18) [73,74]. A complete quench of thioindigo isomerisation was obtained by the addition of OH groups in the 4-position [75]. Upon excitation of 62, it is believed a similar deactivation mechanism to the unsubstituted indigo is operative (Scheme 19). By exchanging both OH groups with methoxy, the switching properties are fully restored.

Preliminary studies on hemiindigo reported dimerisation as a side reaction of irradiation with UV light during their synthesis. This was particularly evident in substrates with electron-donating substituents on the stilbene fragment [76]. Recently, hemiindigos with electron-donating substituents were rediscovered by the Dube group, which reported all-vis photoswitches with very high PSS in both ways and good to excellent thermal stabilities. Lower absorption coefficients of the Z-isomers in the derivatives with bulky N-substitution suggest that the conformation is twisted, with reduced conjugation. Steric hindrance at the indoxyl nitrogen also provides higher thermal stability of the E-isomer, with mixtures of E and Z found at thermal equilibrium [77]. Heteroaromatic substitution in hemiindigo generates interesting results: in the case of derivative 63 containing pyrrole, capable of hydrogen bonding with the carbonyl oxygen (Scheme 20, left) [61,62], the E form is obtained almost quantitatively upon irradiation. In the case of pyridine-containing derivative 64 (Scheme 20, right) no photoswitching is observed as a consequence of a deactivation pathway similar to that of indigo [62].

The effect of substituents in hemithioindigo has been extensively studied. The presence of electron-donating groups in the o- and p-position of the phenyl ring generates hemithioindigos with very fast response to irradiation, but very strong electron donors were found to slow down the isomerisation, which was also complemented by a strong red-shift of the absorption spectrum [78]. Moreover, the thermal stability is also affected. To obtain red-shifted photoswitches, which are also thermally stable, electron-donating groups can be added to the thioindigo fragment in p-position to the sulphur atom (Figure 15) [79].

Substituents in the o-position generate twisted hemithioindigos, which do not switch in polar solvents, due to an alternative deexcitation pathway [80]. Heteroaryl substituents are also reported: a pronounced red-shift of the E-isomer was observed for the pyrrole derivative 66 [81], showing that the hydrogen bond between pyrrole and carbonyl also plays a role (Scheme 21, left). The band separation also provides almost quantitative PSS in both directions. The imidazole derivative 67 (Scheme 21, right) can interchange between tautomers to make a chalcogen bond with sulphur in the Z-isomer and a hydrogen bond in the E-isomer [64]. Extension of the conjugation with additional electron-rich arenes enables isomerisation with wavelengths up to >700 nm, with high PSS and high quantum yield. Electron-poor heterocycles generally possess strongly overlapped spectra with low PSS and low resistance to fatigue [64,82]. The hydrogen bond was also recently used to generate photobases [83].

Hemithioindigos with fully substituted double bonds have also been reported: more rigid stiff stilbene moieties have been explored [84,85], as well as alkyl and aryl groups [86,87]. The diaryl hemithioindigos 68 offer the most interesting properties, namely improved thermal half-lives, red-shifted absorption spectra, and higher molar extinction coefficients, with a combination of electron-withdrawing substituents on one side and electron-donating substituents on the other side giving the best performance (Figure 16, left). These peculiar compounds also showed increased stability and red-shift with increasing solvent polarity [87]. Oxidation of the sulphur atom to sulphoxide 69 introduces a sulphur-based stereocentre, which, combined with additional steric hindrance to the stilbene moiety and on the double bond, induces a helical twisting around the double bond in 71, thus generating a molecular motor, capable of unidirectional movement upon photoswitching (Figure 16, right) [84,85]. Sulphone hemithioindigos 70 have also been explored. Unlike sulphoxides, sulphones are not chiral. Both sulphone and sulphoxide are more electron-deficient than hemithioindigo, which induces a blue-shift of the absorption spectrum (Figure 16, centre) [88].

The photophysical properties of iminothioindoxyl 72 (Scheme 22, top), although already known as dye [89] have only been studied very recently. Exchanging the C=C bond for a C=N bond gives a new subclass of extremely short-lived T-type photoswitches with visible light activation, thermal half-lives in the µs range, and very large spectral separation. The study of iminothioindoxyl with different substituents on the phenyl 4-position shows that electron-donating groups generate bathochromic shifts as well as increase the absorption coefficient. This is explained by the increased electron density of the phenyl ring, which tends to planarise and to extend the conjugation to the rest of the molecule. The transition state for the thermal back-isomerisation of 72 is planar in case of electron-donating groups and twisted for electron-withdrawing groups; the latter isomerise faster than the former (Scheme 23, top). The planar transition state is also favoured in polar and protic solvents, causing a slower thermal isomerisation. The photoswitch is suitable for aqueous buffers and biological environments and is resistant to glutathione oxidase [90]. Phenyliminoindolinone 73 was designed to improve the features of iminothioindoxyl [63]. Substitution at the indole nitrogen of phenyliminoindolinone with an acetyl group destabilises the Z-isomer due to the steric hindrance of the substituent, giving negative photochromism (Scheme 22, bottom). Bulkier substituents at the indole nitrogen do not influence much the photophysical properties, while electron-withdrawing groups in the phenyl 4-position give hypsochromic shifts and shorten the thermal half-life by stabilising the transition state 73’ (Scheme 23, bottom) [63].

Synthesis

The classic synthesis of indigo is achieved via Baeyer–Drewsen synthesis reacting 2-nitrobenzaldehyde (74) and acetone in basic medium (Scheme 24, top) [91]. Since indigo is a well-known commercial product, we will not focus on other synthetic pathways, which can be found in a review by Hecht and co-workers [65], and instead discuss the N-functionalisation (Scheme 24, bottom). N-Alkylation in 76 can be achieved with alkyl halides and base. There are different methods for N-arylation depending on the aryl type: electron-rich and electron-neutral substituents are introduced via Chan–Lam coupling with an arylboronic acid, electron-poor aromatics via Cu(I)-catalysed cross-coupling with aryliodonium salts, and monosubstitution is achieved via Ullman–Goldberg coupling with aryl iodides. The monosubstituted product 78 can be further functionalised with any of the previous methods [67].

Hemiindigos 81 and 82 are synthesised by generation of 80 via reaction with (diacetoxyiodo)benzene (PIDA) in the presence of base, followed by reaction with the corresponding aldehyde and, if required, N-functionalisation via nucleophilic substitution (for aliphatic substituents) or palladium-catalysed cross-coupling (for aromatic substituents) (Scheme 25) [77].

Hemithioindigo can be synthesised by treating phenylthioacetic acid (83) with triflic acid. Then, the product is condensed with a (hetero)aromatic aldehyde in the presence of a base to yield 86 (Scheme 26) [81]. Iminothioindoxyl can be synthesised in the same way, using nitrosoarenes instead of aldehydes [90]. For several other synthetic methods, we refer to the excellent reviews by Konieczny and Konieczny [92] and Wiedbrauk and Dube [93].

Double-bond-substituted hemithioindigos 93 are synthesised by functionalising 87 with an aliphatic or aromatic 88 and subsequent intramolecular aldol reaction to 90. Treatment with SOCl₂ and with the aromatic nucleophile or a cross-coupling partner of choice affords 93 (Scheme 27) [86,87].

Phenyliminoindolinone is synthesised by N-acetylation of 80 with acetic anhydride catalysed by DMAP, then 94 is treated with sodium sulphite to give 95. Base-assisted coupling with a nitrosoarene finally yields N-acetylphenyliminoindolinone 97 (Scheme 28) [63].

As each subclass shown in this chapter requires individual synthetic pathways, it is difficult to simply classify the synthetic accessibility of indigoids in general. For example, while it is straightforward to get N-functionalised indigos, it requires more synthetic effort for double-bond-substituted hemithioindigos. Hence, depending on the desired indigoid photoswitch, synthesis may show varying levels of difficulty. Nevertheless, if compared to diarylethenes or fulgides, indigoids are typically easier to obtain.

Examples

The chiral hemithioindigo sulphoxide 98 has been demonstrated to have unidirectional rotation upon photoisomerisation, making it an all-visible example of a molecular motor (Scheme 29) [85]. Irradiation at 470 nm of 98-A leads to the thermally unstable 98-B, which immediately converts to the less sterically hindered 98-C. Further irradiation leads to the thermally unstable 98-D, which again converts quickly to the starting point 98-A. The unstable isomers were observed at low temperatures. Besides that, hemithioindigos have been used to operate as structural switches in peptides. Upon irradiation, the photoisomerisation of the hemithioindigo moiety is triggered, leading to an overall structural change of the peptide chain [94].

Arylhydrazones

Arylhydrazones are a class of extremely versatile photoswitches, with good fatigue resistance and thermal half-lives that span from a few hours to years (Figure 17).

The common feature of arylhydrazones is the presence of a H-bond acceptor in the rotor, which stabilises one of the two isomers via the formation of a hydrogen bond (Scheme 30) [95]. This peculiarity makes this photoswitch class extremely susceptible to solvent polarity [96-98], pH [98-101], and metal coordination [102-104].

With such variability, predicting which is the most stable isomer is not always intuitive, and several early studies focused on this aspect [96,105,106]. For small substituents (H, Me, CN) in aprotic solvents and in the absence of other external factors, the equilibrium is usually shifted towards the least hindered configuration, regardless of the presence of H-bond acceptors [102,104,107]. The presence and the nature of the H-bond can be identified by ¹H NMR spectroscopy since the N–H proton has a characteristic chemical shift depending on the H-bond acceptor [101]. Arylhydrazones based on pyridine have been intensively studied since the H-bond between hydrazone and pyridine can be broken by protonation with an acid and even by metal coordination, rendering these compounds photo- and acidochromic (Scheme 31) [102]. The equilibrium can also be modulated by introducing hydrogen-bond acceptors in R¹ [107] or by introducing substituents to the stator [95].

The photoswitching of arylhydrazones was first reported in 1976 by the group of Courtot [96,105], and the structure–property relationships were thoroughly studied by the Aprahamian group [108]. Electron-donating groups generally give a red-shifted spectrum, while electron-withdrawing groups (with the exception of NO₂) do not change the absorption significantly with respect to unsubstituted derivatives. It is important to note that, unlike the azo-bond, the hydrazone bond is not symmetric, which means that not only the type of substituent but also the position will strongly influence the physical properties. Combining p-NO₂ on the stator with a p-NMe₂ group at the rotor affords the red-shifted hydrazone 101 with almost a quantitative PSS in both directions, while not affecting the thermal stability much (Scheme 32A). Conversely, the presence of an electron-donating group (NMe₂ or OMe) in the stator shortens the thermal half-life due to a change in mechanism, from inversion to rotation around the C=N bond (Scheme 32B). Due to the direct conjugation of NMe₂ with the hydrazone core, both isomers of 102 are red-shifted, resulting in strong spectral overlap which gives only 27% of the E form upon photoswitching and no suitable wavelength was found for E–Z photoisomerisation. Compound 103 with an electron-withdrawing group on the rotor also has a shorter half-life. However, the effect is mitigated by the fact that the rotor is not perfectly planar with respect to the hydrazone, which leads to a less effective conjugation (Scheme 32C). The lower degree of conjugation also reflects in a less pronounced red-shift and spectral overlap compared to 102, and a better PSS (Z–E 92%, E–Z 52%).

This hypothesis was further supported by forcing the planarity of the rotor phenyl by ring strain (Scheme 33) [110]. The direct consequence of the planar 104 is the enhanced conjugation, which gives a red-shift in the absorption and favours the rotation mechanism (as seen in Scheme 32). The forced steric interaction of the aryl ring with the hydrazone moiety destabilises 105-E even further, decreasing the thermal stability from hundreds of years to a few days.

The addition of a further hydrogen-bond acceptor on the stator led to the discovery of hydrazones with a thermal stability of thousands of years (Scheme 34, left) [111]. The extra H-bond in 106-E and 107-E raises the energy of the linear transition state E-inversion (Scheme 32A). The addition of ring strain between the stator and the rotor (Scheme 34, right) was found to affect the thermal half-life depending on the ring size [109]. Too small (n = 3) 108a and too large rings (n > 5) 108d–f force the E-isomer in a less stable conformation and weaken the hydrogen bonds between N–H and the ester moieties of the rotor and the stator.

The Cigáň group focused on the synthesis of benzoylpyridine hydrazones with different substitutions in the rotor benzene [97]. The p-NMe₂ group causes red-shift of both absorption maxima of the E- and Z-isomer, however, it leads to a poor Z–E PSS and poor resistance to fatigue. This is most likely due to internal relaxation processes prevailing over photoswitching. One interesting finding was the strong dependency of the thermal half-life on concentration in DMSO. The authors hypothesised the aggregation of 109-E (Figure 18) that leads to a weakening of the C=N bond and consequent rotation mechanism (similar to 103 in Scheme 32C). This hypothesis was corroborated by the same trend in the presence of the base Et₃N.

Acylhydrazones 110 are also worth mentioning in this section for their structural and synthetic similarity to arylhydrazones. Their structure–property relationships were thoroughly studied by the Hecht group, focusing in particular on the maximum absorption of the E-isomer, on the band separation between E and Z, and on the thermal half-life [112]. Electron-rich substituents in R¹ (Figure 19) result in slight bathochromic shifts of the spectra, while substitution of hydrogen for methyl in R² has a slight hypsochromic effect on the absorption maximum of the E-isomer, and the thermal half-life is generally shorter. Methylation of N (R⁴) causes the destabilisation of the E-isomer and increased thermal stability of the Z-isomer. The most interesting effects were found by variation of R³: increasing the conjugation with large aromatic moieties shifts the absorption maximum of the E-isomer to lower energies with respect to the Z-isomer, giving negative photochromism, and also increases the thermal half-life. Substitution with heteroaromatics affords changes in the absorption maxima and in the band separation, but no clear trend was observed. The introduction of an H-bond acceptor (2-pyridine) increases the lifetime of the Z-isomer when R⁴ is a hydrogen atom.

Synthesis

In general, aryl- and acylhydrazones are accessible with comparatively low synthetic effort, especially compared to diarylethenes and fulgides. The synthesis of arylhydrazones is usually performed through condensation between a carbonyl 112 and a hydrazine 111 (Scheme 35A) [109]. Alternatively, one can perform an azo-coupling between a diazonium salt 113 and a nucleophile 114 (Scheme 35B) [113] or a Grignard/aryllithium reagent 115 and a diazo compound 116 (Scheme 35C) [108].

Acylhydrazones 110 can be synthesised by reaction of hydrazine with 118 and subsequent acid-catalysed condensation of 119 with carbonyl 120 (Scheme 36) [112].

Examples

The Aprahamian group reported hydrazone 121, which is emissive in its Z-isomer. The fluorescence can be switched on and off by irradiation with 442 nm and 340 nm, respectively (Scheme 37) [114]. The photophysical and emissive properties were also maintained in bovine serum, in the solid state, and in the presence of glutathione, opening the possibility for applications in a biological environment.

Some interesting isatin-based arylhydrazones were reported [115-117]. Compound 122H is a P-type hydrazone photoswitch. The addition of tetrabutylammonium fluoride (TBAF) deprotonates the hydrazone, affording the T-type azo-switch 122-E⁻ (Scheme 38).

Diarylethenes

Diarylethenes are a fascinating class of robust photoswitches. Their main features include thermal stability, a high quantum yield of cyclisation, excellent resistance to fatigue, and a picosecond-range response to irradiation [118] (Figure 20).

The primary example of a diarylethene is stilbene: it was discovered that upon irradiation, stilbene would not only switch between the E- (I) and Z-configuration (II) but also, in its Z-configuration, it would undergo a 6π-electrocyclisation (III) (see Scheme 39) [119]. However, this form is not stable, and it easily undergoes irreversible oxidation under air to give phenanthrene (IV).

This challenge was addressed by substituting the hydrogen atoms with methyl groups in 124-II. Moreover, the E–Z isomerisation could be avoided by adding a ring to the central double bond, thus destabilizing the E-isomer 124-I due to the ring strain (Scheme 40).

According to the Woodward–Hoffmann rule [120], the excited state electrocyclisation of a 4n + 2 conjugated system proceeds in a conrotatory fashion. For steric reasons, the excited state ring closure is only possible when o-125 is in antiparallel conformation (Scheme 41). However, open-ring diarylethenes usually consist of an equilibrium between a parallel conformation (not active) and antiparallel (active). For some examples, the equilibrium was also found to be affected by the polarity of the solvent: polar solvents could stabilise the parallel excited state because of the larger dipole moment [121]. To enrich the population of the antiparallel (and thus increasing the quantum yield of cyclisation), bulky substituents on the 2,2’ positions of benzothiophene were added [122], also the antiparallel conformation could be fixed by introduction of intramolecular interactions [123]; other solutions are the incorporation in polymers [124] or the confinement in supramolecular cages [125,126].

The thermal stability was found to depend primarily on the nature of the aryl rings: the high aromatic stabilisation energy of phenyl is correlated to a low activation energy barrier for the ground-state ring-opening [127]. Heterocycles with lower aromatic stabilisation energies are less susceptible to thermal ring-opening (Figure 21). The substituent nature of the aromatic groups was also demonstrated to influence the thermal stability. Strongly electron-withdrawing groups can weaken the photogenerated C–C bond, thus making the diarylethene thermally unstable, as in the case of c-126b and c-126c (Figure 22) [128,129]. Moreover, electron-withdrawing groups were also found to improve the fatigue resistance by avoiding the irreversible rearrangement 127 (Scheme 42) [130]. Besides influencing the thermal stability, the presence of substituents also increases the conjugation, typically giving a red-shifted closed-ring isomer. Electron-donating substituents were also found to have a strong red-shift effect and to increase the molar absorption coefficient of the closed form [131].

Regarding the ethene bridge, several cyclic and acyclic solutions have been extensively reported and reviewed [132,133]. Some of the most common bridges are pentene, perfluoropentene, maleic anhydride, and maleimide. An interesting study correlated the ring size of the bridge to the photophysical properties of four different perfluoroalkenylated diarylethene derivatives [134]. Unsurprisingly, the acyclic 128a turned out to be the worst-performing in terms of fatigue resistance due to the competing E–Z photoisomerisation reaction. The fatigue resistance of the cyclic ones is comparable. However, a decrease in the ring size leads to more rigidity of the closed isomer, and thus major conservation of planarity, eventually resulting in a bathochromic shift of the closed-ring isomer (Figure 23). The absorption of the open-ring isomer is also influenced by the nature of the bridge: maleimide and maleic anhydride bridges are more red-shifted than perfluoroalkenes [129].

Nakatani and co-workers synthesized dithienylethene 129 with a peculiar bridge that confers an extremely long thermal half-life and high resistance to fatigue (Scheme 43) [135]. The low aromaticity of the bridge results in an increased stabilisation upon ring closure, and the electron-withdrawing nature makes it more resistant to fatigue.

Synthesis

The synthetic procedures for diarylethenes are various, and they strongly depend on the nature of the bridge. Typically, diarylethenes require some synthetic effort to be obtained, especially compared to azoheteroarenes or spiropyrans. Working with strong bases such as n-BuLi or using Pd-catalysed coupling methods requires handling under inert conditions by skilled synthetic organic chemists, which may not be suitable for every lab. Here, we list a few of the most common synthetic procedures. For less common derivatives, we refer the readers to an excellent review on the specific topic [132]. Perfluoroalkylated diarylethenes can be prepared by addition–elimination of perfluorocyclopentenes 132 [131] or perfluoroglutarates 133 [136] with a heteroarene 131 previously halogenated and treated with n-butyllithium. Cyclisation of the intermediate 134 to 135 is performed through McMurry coupling (Scheme 44). Variation of the reactant ratio gives access to symmetric and asymmetric diarylethenes.

The same strategy can be used for diarylcyclopentenes 139 (Scheme 45A) [137], starting from a Friedel–Crafts acylation of 136 with 137. Homo-coupling of 140 (Scheme 45B) followed by McMurry coupling yields the 2,5-dihydrothiophene derivative 142 [138].

Suzuki–Miyaura coupling (Scheme 46) with arylboronates 143 and dihaloalkenes 144 has also been reported for the synthesis of diarylethenes, however, the mono-coupling is not selective, thus it is more indicated for symmetrical derivatives [139,140].

Acyclic derivatives 148 can be synthesised by homo-coupling of 147, while an extra step of basic hydrolysis can give the maleic anhydride derivative 149 (Scheme 47). Reaction of 152 with oxalyl chloride and aminoacetonitrile, followed by condensation with 151 yields maleimide derivatives 154 (Scheme 47) [129]. The Rⁿ substituents can be modified in a later stage through palladium coupling [141].

Examples

Upon isomerisation, diarylethenes undergo both geometrical and electronic changes. The versatility contributed to the popularity of this photoswitch. An interesting application is found in the photoswitchable activity of a gramicidin S derivative where amino acids forming the β-hairpin of the cyclic peptide 155a were substituted by a diarylethene moiety 155b (Figure 24) [142]. The more rigid closed isomer c-155b influences the secondary structure of the gramicidin S derivatives, decreasing the antimicrobial activity, while the open form o-155b resembles more the original and keeps very similar activity. In a follow-up report, the hydrazide linker was substituted with a ketone, which provided c-155c with a red-shifted absorption spectrum [143].

The pyridoxal 5´-phosphate cofactor mimic reported by Branda and co-workers is an elegant example of photoswitchable electronic properties [144]. The diarylethene mimic o-159 (Scheme 48) is inactive because the electron-withdrawing pyridinium ion is insulated from the aldehyde reactive site. Upon ring closure, the pyridinium becomes conjugated with the aldehyde, which can react with an amino acid, yielding 160. The difference in activity between the isomers was measured by monitoring the racemisation rate of enantiopure ʟ-alanine.

Fulgides

Fulgides are a class of photoswitches first reported by Stobbe in 1905, which are named after the Latin word fulgere (to shine) due to their bright colours [145] (Figure 25).

The name refers to the original bismethylenesuccinic anhydrides in Scheme 49, while more derivatives have been subsequently synthesised, among which we find fulgimides, fulgenolides, and fulgenates. They are thermally stable, resistant to fatigue, and have fast response to irradiation. As in the case of diarylethene, fulgides can also undergo E–Z isomerisation (Scheme 49). The Z-isomer Z-o-161 cannot undergo ring closure to c-161 without converting to the E-isomer first E-o-161.

Similarly to what was already discussed for diarylethenes, the excited-state ring closure is conrotatory (see Scheme 41). In order to avoid irreversible oxidation of the closed isomer, all the hydrogen atoms of the hexatriene backbone must be substituted for bulkier groups. It was reported that the presence of hydrogen substituents generates irreversible side products of elimination (164), disrotatory ring-opening (o-162’), thermal (163), and photoinduced sigmatropic hydrogen shifts (165) (Scheme 50) [146-148]. Moreover, it was reported that substitution of the phenyl ring for a furan would decrease the spectral overlap between the open and the closed isomer, thus improving the PSS [149].

Many other heteroaromatics have been employed ever since. A systematic study showed that the absorption maximum red-shifts with increasing electron-donating character of the heteroaromatic ring and of the substituents, while electron-withdrawing substituents cause a hypsochromic shift (Figure 26). The effect is stronger in the closed isomer [150,151].

Some fused heterocycles and sterically hindered substituents were also reported. However, it was proposed that such substituents lead to a loss in coplanarity in the closed form and/or a higher stability of the heteroaromatic, thus lowering the quantum yield of ring closure and the ratio of C to E-isomer at the PSS. A methoxy substituent in 6-position of an indolinefulgide was proven to increase the absorption coefficient of the closed form [152]. Another study reports a bathochromic shift for an indolinefulgide with methoxy substitution in the 5-position and an unusually low ring-opening quantum yield for 167 with a dimethylamino substituent [153]. The proposed hypothesis is that with such a strong electron-donating group, an electron displacement in the excited state c-167* occurs (Scheme 51) that eventually returns to c-167. This is in accordance with the general observation that electron-withdrawing groups improve the ring-opening process and disfavour the ring closure, while for the electron-donating groups, it works the other way round [151]. A similar explanation can be used to justify the solvent dependence on the ring-opening quantum yield of thionylfulgide observed in Tomoda’s group: The quantum yield of ring-opening was lower in ethyl acetate than toluene, thanks to the better stabilisation of the polar excited state by the more polar solvent [154].

As already mentioned, the open form of fulgide can exist as E- and Z-isomer, for which the former one is the only one active for the 6π-electrocyclisation. The effect of bulky substituents in 168 was studied, and it was demonstrated to inhibit dramatically the E–Z isomerisation due to the increasing steric hindrance (Figure 27) [155]. A report of indolylfulgide with a trifluoromethyl group instead of methyl showed higher thermal stability of the closed form and higher resistance to fatigue. The authors explain that this is due to the absence of allylic hydrogens that can undergo abstraction in the excited state [156].

It must be noted that, given the helical nature of the open fulgide, it presents two couples of enantiomers (right-helical P and left-helical M), which can thermally interconvert [157]. Besides the photoinduced E–Z isomerisation, the thermal rotation at room temperature of the furyl moiety (belly-roll) leads to the E_β conformer, which is unable to cyclise (Scheme 52, left). Changing the furan to a benzofuran shifts the equilibrium towards the active E_α conformer, however, to fully suppress E–Z isomerisation and the thermal isomerisation to the inactive E_β conformer, the bicyclic derivative 169 was reported (Scheme 52, right) [158].

Furylfulgide 170b [159] and thiophenfulgide 171b [160] with an adamantyl group were correlated with their isopropyl derivatives, and they both show a net increase in the ring-opening quantum yield, however, associated with a slight increase in E–Z isomerisation (Scheme 53).

Fulgimides have in general very similar properties to fulgides, but they offer a few advantages like improved resistance to hydrolysis in protic solvents and easy functionalisation on the maleimide nitrogen (see next section "Synthesis"). Thus, they are preferred, especially for biological applications [161]. Fulgenates have diesters instead of the anhydride. They are also easier to functionalise and are resistant to hydrolysis. However, the freedom of rotation around the bond between the two esters makes them less appealing in terms of photophysical properties. Substitution of the maleic anhydride with a lactone (fulgenolides) or with other heteroatoms was also reported [151].

Synthesis

Fulgides, fulgenates, and fulgimides require some synthetic effort, especially when compared to azoheteroarenes and spiropyrans. The classic synthetic pathway [146], shown in Scheme 54, is through a Stobbe condensation of 172 and 173 followed by esterification, a second Stobbe condensation of 175 and 176 and saponification. At this point, through acidic esterification of 177 one can obtain fulgenates 178. Fulgides 179 are obtained through condensation with acetic anhydride, acetyl chloride, or dicyclohexylcarbodiimide (DCC) [162]. Further amidation and condensation by base or by means of coupling agents [163] yields fulgimides 181.

Due to the low yields of the Stobbe condensation, another pathway was designed specifically for sterically demanding substituents (Scheme 55) [164,165]. Reaction of the lithiated alkyne 182 with the heteroarylketone 176 yields the precursor 183, which is then carbonylated via palladium catalysis.

Slanina and co-workers recently developed an improved synthetic strategy to yield fulgimides via a sequential one-pot procedure (Scheme 56). For this purpose, they start with cyclic lactone 185 which under basic conditions opens to intermediate 186. Treatment with HATU and an amine source converts the carboxylic acid moiety to the corresponding amide 187 which then can cyclise again to the target fulgimide 181 upon treatment with NaH. This synthesis is not only faster compared to classical procedures, but also does not require the purification of intermediates, overall increasing the accessibility of fulgimides [166].

Examples

Fulgimide 188 was used as a bridge between a fluorescence resonance energy transfer (FRET) donor (anthracene) and an acceptor (coumarin) (Scheme 57). The open form o-188 allows intramolecular energy transfer between anthracene and coumarin, resulting in fluorescence emission of the coumarin. However, in the closed isomer c-188 the fluorescence is quenched. The closed isomer acts like an energy trap, dissipating the energy through radiationless pathways and inhibiting the FRET [167].

Slanina and co-workers developed a three-state fulgimide photoswitch (Scheme 58). Irradiation of Z-o-189 with UV light leads to c-189, while a combination of UV and red light leads to the open E-o-189. The least stable Z-isomer can be accessed quantitatively through triplet-state sensitization (with addition of anthracene as a sensitizer and by removal of oxygen from the solution) and dual irradiation with UV and red light [166].

Spiropyrans

Another important and versatile class of photoswitches are spiropyrans, named after their spirocyclic carbon atom centrally located in the molecular structure, which plays a crucial role in switching [168] (Figure 28).

They are well known for their drastic change in geometry and polarity when switched from the closed spiropyran form (SP) to the open merocyanine isomer (MC) [169]. Besides that, they show a broad spectrum of responsiveness to external influences other than light, reaching from solvato- to acidochromism, high quantum efficiencies for direct and back photoinitiated rearrangements, and very high cross sections of two-photon light absorption of ring-opened and ring-closed forms [170-172]. Apart from classical spiropyrans, there are the related classes of spirooxazines and spironaphthopyrans. As they share some common features, they are also briefly discussed within this section. The first feature to be described was their thermochromic behaviour [173]. Some years later, Fischer and Hirshberg observed that SPs are not only thermochromic but by irradiating with UV light, one can generate the same colourful species as upon heating [174]. For both the thermal and photochemical cases, decolourisation was observed after a certain time, indicating that the switching process is, in principle, reversible. Scheme 59 shows the ring-opening mechanisms for the photochemical and thermal cases. While in the photochemical case, the C_spiro–O bond gets cleaved in the excited state 190-SP*, the thermal process can be described as 6π-electrocyclic ring-opening of the pyran ring. In both cases, the open 190-MC isomer is formed, which can be zwitterionic or quinoidal and thermally re-isomerises back to the closed spiropyran form [169].

A total of eight different MC isomers can be formed (Figure 29), the TTC and TTT being the most stable ones [170,175,176]. In most organic solvents, the rather non-polar closed SP form is predominant under thermal conditions. Upon irradiation with UV light (or NIR light in the case of two-photon absorption) [171,175,176], one can switch it to the ring-opened merocyanine isomer, which thermally re-isomerises back to the closed SP form with a particular lifetime (depending on the photoswitch itself, the temperature, and the conditions of the system) [177].

This low energy barrier for re-isomerisation classifies spiropyrans as a T-type photoswitch [3]. Interestingly, since the colourless SP gets interconverted to the intensely coloured MC form by light, positive (or direct) photochromism can be observed in organic solvents [2]. In aqueous conditions, however, the open merocyanine isomer is sufficiently stabilised due to its zwitterionic character (dipole moment µ = 14–18 D, in contrast with µ ≈ 4 D for SP) [169,178]. As a result, a noteworthy amount of MC is present at thermal equilibrium, which can be interconverted to the colourless SP form upon irradiation with light in the visible regime. In this case, the spiropyran photoswitch shows negative (or inverse) photochromism [3,179]. The degree of stabilisation of either MC or SP depends on the polarity of the solvent and on the substitution pattern [2,180,181].

Besides that, the MC form can be reversibly protonated in aqueous conditions, as illustrated in Scheme 60. Thereby, the absorbance spectra of the non-protonated 191-MC and the protonated merocyanine 191-MCH⁺ differ notably, and a pH-dependent colour change can be observed, referred to as acidochromism. The degree of protonation also plays an essential role in the ring-closing to 191-SP since only the non-protonated merocyanine isomers 191-MC can convert to 191-SP. In contrast, for the protonated ones 191-MCH⁺, this process is not feasible anymore [175]. Hence, this opens the opportunity for pH-gated E/Z-isomerisation of the 191-MCH⁺ isomers by visible or UV light under very acidic conditions without converting them to 191-SP [175]. Further, by the addition of acid with its pK_a higher than the pK_a of 191-Z-MCH⁺ and lower than the one of 191-E-MCH⁺, one can create a photoacid generator. Photochemical conversion of 191-E-MCH⁺ to 191-Z-MCH⁺ re-protonates the used acid, followed by ring-closure to 191-SP, which can again be photochemically opened to form the 191-E-MC. Re-protonation to 191-E-MCH⁺ by the present acid closes the cycle [175].

A study by Andréasson and co-workers reported that substitution at R² with alkyl chains bearing a terminal amine group allows photoswitchable behaviour of spiropyrans in aqueous buffer also at acidic conditions (Scheme 61) [180]. The acidity of the phenol can be fine-tuned by the choice of R¹ (Scheme 61, box), with electron-withdrawing groups stabilising the 192-MC at lower pH [180,182]. The positively charged substituent probably avoids further protonation of the indoline nitrogen in the 192-SP isomer, which would slow down isomerisation. Indeed, the authors attribute the lower rate to the presence of the species 192-SPH⁺, which cannot isomerise to 192-MC directly but only through equilibrium with 192-SP (Scheme 61) [180]. It must be noted that the observations are done in an aqueous buffer and that the solvent and the environment play a crucial role, especially for this photoswitch class. It is noteworthy also that 192-E-MCH⁺ in aqueous media switches to 192-SP with visible light upon proton release, while 192-E-MC switches to 192-SP thermally [183]. For a detailed analysis of spiropyrans in water, we invite you to read the excellent review by Berton and Pezzato [183].

While the pH-responsive behaviour of spiropyrans, in principle, enables their use for various applications where pH plays a crucial role, one also has to deal with their tendency to hydrolyse, especially in aqueous media. It was found that the phenolic oxygen atom of the non-protonated merocyanine (MC) is crucial for the hydrolysation to proceed, coordinating to water molecules acting as nucleophiles. Changing the pK_a of the phenol moiety slows down the hydrolysis rate, but only apparently, as it will also shift the thermal equilibrium towards the spiropyran form [180]. A later report proposes a different hydrolysis mechanism that rules out the role of phenolate (Scheme 62, left) [184]. A strategy to slow down the nucleophilic attack of water is to introduce electron-donating groups directly conjugated with the ene–iminium core in order to decrease the electrophilicity of the system (Scheme 62, right) [183-185].

Louie and co-workers investigated the effects different substitution patterns have on the photophysical behaviour of spiropyrans and spirooxazines more closely [178]. Therefore, they tuned the electron-withdrawing effect on the chromene and indoline moiety by combinations various functional groups at position 5’ on the methylene indoline moiety and position 6 on the chromene unit. While for 5’-OMe spiropyrans the photoconversion process SP → MC is drastically enhanced the more electron-withdrawing the substituent on the chromene unit is, there is no direct trend for varying substituents on the indoline moiety, given a fixed NO₂ group on the 6-position of the chromene unit. By increasing the electron-withdrawing effect even more by incorporating a positively charged tertiary nitrogen atom in the chromene ring, the photochemical response was enhanced, together with the thermal stability. Interestingly, spirothiopyrans were also reported, where the oxygen atom is substituted by a sulphur atom, resulting in a strong red-shift of the open form up to the infrared region. However, the compound shows photochromic behaviour only below 0 °C [186]. It was found that by simple addition of a nitro group in p-position to the sulphur, the open form was stable up until 80 °C, and the absorption could be further tuned by introducing several substituents in various positions [187]. Similar to spiropyrans, naphthopyrans 194 can also be switched between closed and open forms TC (transoid–cis) and TT (transoid–trans) upon irradiation (Scheme 63, top). The metastable TC isomer thermally reverts back to the closed form within seconds to minutes, while the TT isomer takes minutes to hours for the ring closure. Like in the case of spiropyrans, the behaviour of thermal re-isomerisation renders naphthopyrans T-type photoswitches, and their absorption properties, as well as their lifetimes, can be tuned with different substituents [188]. This subclass, however, does not possess zwitterionic character in either form. A further class of spiropyran-related photoswitches are spirooxazines 195. They contain a nitrogen atom in the 6-membered ring of the spiro junction and can also undergo reversible cyclisation. Driven by light, the C_spiro–O bond gets cleaved, leading to the open form (Scheme 63, bottom), which can be switched back to the closed one either by light of another wavelength or thermally. Spironaphtooxazines, analogues of spirooxazines, have been more extensively studied due to synthetic availability [189].

Synthesis

One big advantage of spiropyrans is their synthetic accessibility. Compared to other photoswitch classes presented in this review, the synthetic effort to obtain spiropyrans is relatively low. The most common synthesis of spiropyran is the condensation of a Fischer indoline base 196 with a salicylaldehyde 197a, in basic media, as shown in Scheme 64 [170]. However, this synthetic route can give a dicondensation by-product 199, due to the high reactivity of indoline. To avoid this, it is possible to use a less reactive quaternary indolenylium salt 200 (Scheme 65) [190]. The same synthetic pathway can be used for the synthesis of spirooxazine 198b, substituting the salicyladehyde 197a with o-hydroxynitrosobenzene 197b [189].

Another way to obtain spiropyrans is the reaction of an acylated methylene indoline species 201 with a phenol 202 upon the addition of POCl₃ and subsequent treatment with NaOH. By that, it is possible to install a substituent R⁴ (Scheme 66).

Naphtopyrans 210 can be synthesised by acid-catalysed condensation of naphthols 206 and diarylpropargyl alcohols 204. The reaction proceeds in one pot via multiple steps, which are shown in Scheme 67. To facilitate the electrocyclisation step in cases where o-210 is stabilised, it is recommended to irradiate the reaction mixture with visible light [191].

Examples

Spiropyrans have been extensively used in materials science to design smart materials [192]. For example, the decoration of polymers with spiropyrans can alter their macroscopic properties, such as surface wettability, conductivity, and mechanical properties with light [193]. A spiropyran polymer brush 211 induced a difference in surface wettability upon irradiation, due to the major affinity of the zwitterionic 211-MC to water (Scheme 68) [194].

Spiropyrans have also demonstrated applicability in the biological environment: Feringa and co-workers were able to modify the naturally occurring channel protein MscL (mechanosensitive channel of large conductance) from Escherichia coli by covalently connecting a spiropyran photoswitch to the cysteine residues of the channel protein. Photochemical ring opening of the spiropyran with 366 nm light leads to weakening of the hydrophobic forces that keep the channel in its closed state, resulting in channel opening, while visible-light irradiation restores the initial state [195].

Conclusion

In the field of photoswitches, many alternatives to azobenzenes remain underrepresented. While these alternatives may not be as well-known, they possess intriguing photophysical and mechanical properties. This review describes the synthesis, structure–property relationships, and examples of applications for seven important classes of photoswitches. The authors hope this review serves as a guide and inspiration for researchers approaching the topic, helping them design the most suitable photoswitch for their research and keep the field vibrant and growing (Figure 30).