Indigoid Photoswitches: Visible Light Responsive Molecular Tools

Article Cite This: Acc. Chem. Res. 2018, 51, 1153−1163

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Indigoid Photoswitches: Visible Light Responsive Molecular Tools Christian Petermayer and Henry Dube* Ludwig-Maximilians-Universität München, Department für Chemie and Munich Center for Integrated Protein Science (CIPSM), D-81377 Munich, Germany CONSPECTUS: Indigoid photoswitches comprise a class of chromophores that are derived from the parent and well-known indigo dye. Different from most photoswitches their core structures absorb in the visible region of the spectrum in both isomeric states even without substitutions, which makes them especially interesting for applications not tolerant of highenergy UV light. Also different from most current photoswitching systems, they provide highly rigid structures that undergo large yet precisely controllable geometry changes upon photoisomerization. The favorable combination of pronounced photochromism, fast and efficient photoreactions, and high thermal bistability have led to a strongly increased interest in indigoid photoswitches over the last years. As a result, intriguing applications of these chromophores as reversible triggering units in supramolecular and biological chemistry, the field of molecular machines, or smart molecules have been put forward. In this Account current developments in the synthesis, mechanistic understanding of light responsiveness, advantageous properties as phototools, and new applications of indigoid photoswitches are summarized with the focus on hemithioindigo, hemiindigo, and indigo as key examples. Many methods for the synthesis of hemithioindigos are known, but derivatives with a fourth substituent at the double bond could not easily be prepared because of the resulting increased steric hindrance in the products. Recent efforts in our laboratory have provided two different methods to prepare these highly promising photoswitches in very efficient ways. One method is especially designed for the introduction of sterically hindered ketones while the second one allows rapid structural diversification in only three high-yielding synthetic steps. Given the lesser prominence of indigoid photoswitches, mechanistic understanding of their excited state behavior and therefore rational design opportunities for photophysical properties are also much less developed compared to, for example, azobenzenes or stilbenes. By testing different substitution patterns, we were able to produce strongly beneficial property combinations in hemithioindigo, hemiindigo, or indigo photoswitches, for example, red-light responsiveness together with very high thermal bistability of the switching states. This is of particular importance for photopharmacological and biological applications of these switches to reduce the damage from high-energy light and to enable deep penetration of the light into tissues. An additional ground state twisting in hemithioindigo allowed us to control the type of light-induced bond rotation simply by the polarity of the solvent. With the aid of time-resolved spectroscopy and quantum yield measurements, we could show that in apolar cyclohexane exclusive double bond rotation takes place while in polar DMSO sole single bond rotation is observed. Such precise control over geometrical changes is of great interest for the construction of future sophisticated molecular machinery. In this field, we have introduced hemithioindigo photoswitches as novel core structure for molecular motors providing very fast directional motions upon irradiation with visible light. The mechanism of the directional rotation adheres to a four-step process, which could directly be observed in situ with a slower second-generation motor. Further applications of indigoid photoswitches were made in our laboratory in the realms of photocontrolled folding and host−guest chemistry as well as in molecular digital information processing showcasing the great versatility and enormous future promise of indigoid photoswitches.

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INTRODUCTION

efficiencies, and high photostabilities enabling robust photoswitching over many cycles. Last but not least synthetic access and functionalization is usually simple and requires only a few steps so that implementation of these structures as photoactive tools is chemically straightforward. Despite these many advantages indigoid photoswitches are still being largely overlooked, and their potential has only started being tapped. In this Account, we focus on the three most prominent representatives of indigoid photoswitches: hemithioindigo (HTI), hemiindigo (HI), and indigo itself highlighting exciting

Indigoid photoswitches are derived from the parent indigo compound (Figure 1) and have been known for more than a century as chromophores and dyes.1,2 Their potential use as photoswitches had however not been advanced until much later, when it became clear that many derivatives show reversible photochromism in the visible region of the electromagnetic spectrum.3 This property alone makes them highly interesting for applications, as damaging UV-light is not needed to induce their photoswitching processes. But indigoid photoswitches have more to offer: rigid and predictable geometry changes upon switching, very high thermal stabilities of the metastable states in many cases, good quantum © 2018 American Chemical Society

Received: December 27, 2017 Published: April 25, 2018 1153

DOI: 10.1021/acs.accounts.7b00638 Acc. Chem. Res. 2018, 51, 1153−1163

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Accounts of Chemical Research

effort can be reduced by omitting purification of intermediates. This method allows one to introduce a variety of substituents in the vicinity of the double bond, even ones with considerable steric hindrance. Recent work in our lab have also shown high functional group tolerance for this synthetic approach as alkyl amines or halogen atoms can be introduced as well. Another recent effort of our lab has resulted in a synthetic method for the rapid and very versatile construction of doublebond substituted HTIs, I (Scheme 1B).19 In only three steps, a great structural diversity of novel HTI photoswitches can be generated from commercially available starting materials with carbon- or heteroatom-based groups as fourth substituents at the central double bond instead of the proton. In this way, 25 derivatives with different aliphatic, aromatic, acetylenic, or heterocyclic substituents were prepared in high yields. Heteroatom substituents could easily be installed by the addition of amines, alcohols, or thiols. A further interesting case is the construction of HTIs via the concomitant establishment of two carbon−sulfur bonds starting from 2-nitrochalcones.20 Kitzig and Rück-Braun recently reported on the synthesis of new HTI-peptides via a native chemical ligation approach.21 Photochemistry and Photophysics

One key property that makes HTIs very interesting for application is their visible light responsiveness in both switching directions. This favorable sensitivity to low energy light is already present in the core chromophore without any substituents. However, for applications in biological or photopharmacological contexts, it is highly desirable to shift the absorption further to the red part of the spectrum toward the biooptical window (650−1350 nm). The easiest approach uses strengthening of the donor−acceptor character of the central double bond: the carbonyl acceptor remains unchanged, and strong donor groups are attached in the conjugated paraposition of the stilbene fragment.7 Significantly red-shifted absorptions are observed in this case but at the same time the thermal stability of the metastable E isomer is strongly reduced (see HTI 10 versus HTI 11 in Figure 2A as example). We were able to circumvent this problem by introduction of a strong electron donating substituent in the para-position of the sulfur atom at the thioindigo part. The resulting HTI 12 can be photoisomerized with green and red light (up to 625 nm) while maintaining high thermal stability (ΔG* = 26.5 kcal/mol, that is, half-life of 30 days at 25 °C) of the E isomer (Figure 2A).22 High yields of each isomer (>80%) were obtained in the respective photostationary state (pss). Zweig and Newhouse have used very strong electron-donor substituents with hydrogen-bonding capacity as the stilbene part to shift the absorption wavelengths of HTIs even further to the red. In this case, high switching viability and thermal bistabilities are maintained via intramolecular hydrogen bonding in the E isomers.23 When studying the photoreaction of HTIs, double-bond isomerization has been identified as the reaction coordinate of choice responsible for geometry changes of the excited molecule. However, there is another degree of freedom in the molecule, which could potentially undergo light induced rotation: the single bond connecting the stilbene part to the central double bond. In a recent work, we were able to construct HTI photoswitches (13 and 14) capable of using this rotation axis for light induced motions (Figure 2B). We showed that pretwisting of an electron rich stilbene fragment in the

Figure 1. Indigoid chromophores indigo (1), thioindigo (2), hemiindigo (3), and hemithioindigo (4). The photoswitching between the Z and E isomers is shown for HI 3 and HTI 4.

new developments in their syntheses, photochemistry, and photophysics, as well as diverse applications put forward in our group over the past few years.

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HEMITHIOINDIGO Hemithioindigo is a hybrid chromophore in which a central photoisomerizable double bond connects a thioindigo part with a stilbene part. Its basic photochemistry and substituent effects on the photoisomerization rates are rather well understood4−7 and were summarized in a 2015 review from our group.8 At that time, about a dozen different applications were reported for hemithioindigo switches ranging from photoswitching of lipids,9,10 gramicidin channels,11 or enzyme inhibition12 to photomodulation of peptide folding13,14 and molecular recognition.15,16 In the meantime, the field has progressed significantly and intriguing new properties and applications of hemithioindigo have literally come to light, justifying the high expectations that we had articulated back then. Synthesis

Many syntheses have been reported for the construction of HTIs8,17 the most prevalent of which rely on simple condensation reactions between a benzothiophenone precursor and aldehydes. However, for some of the more interesting applications, available synthetic schemes failed, a problem most pressing when steric hindrance needs to be increased significantly in the molecule. Recently we have developed a new synthesis for sterically encumbered HTIs that provides high yields for structural motifs not accessible by other methods.18 This method increases the steric hindrance in the molecule stepwise using a novel sulfur heterocyclization reaction as key step and therefore does not require extremely powerful bond-formation reactions or harsh reaction conditions. The synthesis is shown in Scheme 1A. In this sequence, high individual and overall yields are obtained and synthetic 1154


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Scheme 1. New High Yielding HTI Syntheses: (A) Synthetic Access to Sterically Hindered HTIs; (B) Rapid and Versatile Synthetic Access to Double Bond Substituted HTI Derivatives

the same time, we showed that unambiguous identification of TICT states requires multiple independent experimental techniques, most importantly measurements of solvent effects on (i) the quantum yields of different photoprocesses (fluorescence, isomerization, etc.), (ii) absorption and fluorescence energies, (iii) occurrence of dual fluorescence, and (iv) occurrence of different excited state species and their lifetimes. In a related study published 2017, Wang and Rück-Braun describe N,N-diarylamine-substituted HTIs in which the donor character of diarylamine-substituted stilbene fragments was modulated by additional substituents.25 In this case, electron acceptors at the diarylamine improve E isomer content in the pss and increase thermal stability of this metastable state. Electron donating substituents lead to opposite behavior. A possible TICT-like behavior was suggested for the methoxysubstituted derivative based on the occurrence of dual fluorescence in polar solvents.

ground state allows the molecule to populate a twisted intramolecular charge-transfer (TICT) state after photoexcitation. This TICT state establishes a 90° torsion angle around the mentioned single bond, which was identified as rotation axis via the chemically locked derivative 14 possessing only this one bond with rotational freedom (Figure 2B). As TICT states are highly polar, the polarity of the surrounding solvent influences their stability greatly. This sensitivity allowed us to choose the axis of light induced rotation of 13 and 14 simply by changing the nature of the solvent. In apolar cyclohexane, extremely efficient double-bond photoisomerization is found (quantum yields of up to 56%), while no TICT formation takes place at all. In very polar DMSO, the TICT state is not only populated almost exclusively but can now also de-excite directly back to the ground state. As a result, doublebond isomerization does not take place in this solvent showing mutual exclusiveness of these two pathways. We have further scrutinized the electronic and geometric preconditions for this unusual TICT behavior in HTI chromophores and found them to be surprisingly narrow and specific.24 Only the combination of very strong electron donors and a strong pretwisting in the ground state lead to this complex photoresponsive behavior. At

Applications

Since 2015, a variety of new applications for HTI photoswitches have been developed in our laboratory. Two different types can be distinguished: applications making use of the 1155


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Figure 2. HTI chromophores with unusual photochemical and photophysical properties and behaviors. (A) HTIs with red-shifted absorptions and strongly different thermal bistabilities. (B) HTIs 13 and 14 undergo efficient photoisomerization of the double bond in cyclohexane because in this solvent the TICT state is too high in energy to be available. In polar solvents such as DMSO, very efficient TICT formation via rotation around the single bond takes place.

of the system. A binary logic system can be set up with just protonation and irradiation at a single wavelength as input 1 and input 2, respectively, while the absorption at a suitable wavelength provides the corresponding output. With this setup, we were able to realize 14 of the 16 theoretically possible output structures for a 2-bit system.22 A combination of gates is also possible leading to molecular half adders or half subtractors. In this case, the absorption at 470 and 410 nm provide output 1 (carry digit) and output 2 (sum digit). Even a different type of logical operation, that is, sequential logical behavior, can be realized with HTI 12. In this case, the sequence in which three different inputs are given, protonation as input A, deprotonation as input B, and irradiation at 420 nm as input C, can be distinguished by HTI 12. In this advanced keypad lock only one sequence of inputs, that is, BAC, leads to the unlocking of a strong absorption at 480 nm. Because this absorption belongs to the thermally unstable E-12-H+, the keypad lock erases its unlocked state after a short while and therefore represents a novel “high-security” version for this advanced logical behavior (Figure 3C). Although the overall geometry changes between the different isomers are not very pronounced for the HTI core chromophore, the relative positions of different substituents at the different molecular fragments can nevertheless be

different stable isomeric states, and therefore employing HTI as a classical photoswitch, and molecular machines, which use the trajectories and mechanical motion of directional light-induced rotations. For the first type, we have provided two different examples, a smart molecule application for digital information processing and a visible light responsive supramolecular receptor whose folding and affinity for aromatic guest molecules can be altered by irradiation and heating. HTI 12 was found to be susceptible to protonation with trifluoroacetic acid (TFA) (Figure 3A), which altered its absorption spectrum significantly and allowed for reversible photoswitching at shorter wavelengths (400 nm for Z to E and 470 nm for E to Z photoisomerization, Figure 3B). However, the thermal stability of the protonated E isomer E-12-H+ was significantly reduced (half-life of ca. 45 s at 25 °C). Base addition leads to deprotonation and restoration of the initial green and red light responsiveness as well as high bistability. We used this reversible alteration of the photophysical and physical properties of 12 via acid and base addition for advanced molecular digital information processing. For this purpose protonation, base addition, and irradiation at a certain wavelength represent three different and independent inputs to the system. The thresholded absorption intensities at different selected wavelengths serve as outputs for reading out the state 1156


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Figure 3. Applications of HTI for photoswitchable property changes. (A) Four different states can be established reversibly for HTI 12 using protonation, deprotonation, and irradiation at different wavelengths. (B) Protonation leads to blue-shifted absorption of HTI 12-H+, which can be photoisomerized with shorter wavelengths. (C) Using protonation, deprotonation, and irradiation at 420 nm as input signals A, B, and C, respectively, a reversible “high-security” molecular keypad-lock can be realized with HTI 12. Absorption at 480 nm is unlocked (blue bar) after the input sequence BAC for only a short time (gray bar). (D) The folding and affinity for electron-poor aromatic guest molecules of bis-HTI 15 can be altered by visible light and heat. (E) Signal changes observed in the 1H NMR spectra of bis-HTI 9 upon binding of 27DDF (green signals).

structure is helical leading to a close proximity of the electronrich 1,3-benzenediamines. The helical structure exhibits substantial binding affinity for electron-poor aromatic guest molecules (Figure 3D,E), which are now bound in a 1:1 stoichiometry. Upon heating, the bis-HTI reverts quantitatively to the thermodynamically stable Z,Z isomer and releases the guest. Although the main driving force for binding in E,Z-15 is polar aromatic interactions, as suggested by the sandwich-type binding mode, we observed astonishing guest selectivity. While 9-dicyanomethylene-2,7-dinitrofluorene (27DDF) was bound as a guest, its regioisomer 9-dicyanomethylene-2,5-dinitrofluorene (25DDF) did not show any affinity for the helical receptor E,Z-15. We expect such minimal foldamer to be especially useful in the context of smart responsive polymers, sensors, or artificial muscles to alter, for example, their properties and reporting abilities. Molecular motors 27 have gained great attention as prototypical molecular machines28,29 because of their ability to carry out directional motions against the equilibrating force of Brownian motion. Currently a number of molecular motor setups exists using different energy supplies, but light is arguably the most direct, convenient, and waste-free source.30−33 However, the majority of light-powered molecular motors need UV-light, which is a result of their core chromophore absorption properties.31,34−36 For applications such as in the material sciences37,38 or biology,39 it is therefore of great interest to shift the absorption profile to the visible region of the electromagnetic spectrum to alleviate the

changed significantly upon photoswitching. Since only one freely rotatable bond is present, the aforementioned single bond connecting to the stilbene fragment, HTI represents in fact a quite rigid structural scaffold offering precise photocontrol over molecular geometry. We used the strong geometric differences between two stable isomeric states of a novel bis-HTI motif (15) to effectively control folding of the molecular structure as well as its binding affinity for electron poor aromatic guests.26 The bis-HTI structure consists of a central unit with two thioindigo fragments fused to the same benzene ring in a nonsymmetrical fashion (Figure 3D). Two biphenyl units are attached as stilbene fragments bearing electron-rich 1,3-benzenediamines at their respective ends. nPentyl chains were attached in para-position to the biphenyl axis, that is, ortho to the rotatable single bond. These latter substituents serve two purposes: enhancing solubility in organic solvents and preventing population of conformer structures in which the electron-rich biphenyls are rotated by 180°. This negative preorganization therefore leads to only one isomeric structure out of 4 possible for the thermodynamically most stable Z,Z-double bond configuration as shown by crystal structure and NMR spectroscopic analysis. After irradiation of bis-HTI Z,Z-15 with blue light (420 nm), a highly selective photoreaction takes place where only one of the two double bonds photoisomerizes leading to E,Z-15 in 94% yield. In the E,Z isomeric form, the same negative preorganization takes place again reducing the conformer space to only one prevalent conformation in solution. In this conformation, the overall 1157


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Figure 4. Applications of HTI in visible-light driven molecular motors. (A) Structure in the crystalline state of the first generation HTI molecular motor (Z-(S)-(P) isomer) capable of unidirectional rotation with speeds up to 1 kHz at ambient temperature. (B) Ground state energy profile of HTI motor 16. (C) Structure in the crystalline state of the second generation HTI molecular motor 17 (E-(S)-(P) isomer). (D) Direct observation of the sequence in which the four different states of HTI motor 17 are interconverted under irradiation conditions via 1H NMR spectroscopy at −105 °C. Spectra were recorded in 8 s intervals while the sample was irradiated inside the NMR spectrometer with a glass fiber coupled 470 nm LED.

providing direct experimental scrutiny of the first photoequilibrium. The full thermal conversion of this intermediate into exclusively E-(S)-(P)-16 proved complete directionality of the first 180° rotation and provided the kinetics of the slowest step. When irradiating the second stable isomer, that is, E-(S)(P)-16 at low temperatures (down to −100 °C) the expected fourth isomeric state was not observed but rather conversion to the most stable Z-(S)-(P)-16 instead. The apparent contradiction of two separated photoequilibria for Z-(S)-(P)-16, one with E-(S)-(M)-16 and one with E-(S)-(P)-16, gave indirect evidence for the four-step motor mechanism and complete unidirectionality. To prove the proposed four-step process, we therefore set out to develop a next generation system with slower motion to capture the elusive fourth intermediate and deliver experimental evidence for its existence. For this purpose, it was necessary to increase the steric hindrance of the stilbene fragment beyond the size of the methoxy group implemented in the first generation system. However, the initially employed simple condensation reaction between benzothiophenone and an indanone derivative proved completely ineffective if indanones with increased steric demand were used. For this reason, we established a new synthesis for efficient construction of

damaging effect of UV irradiation on the motor surroundings. At the moment, a comparatively small number of molecular motors respond to visible light, providing rather slow rotation speeds at ambient temperatures.30,40−42 In 2015, we have reported on a new molecular motor, 16, employing the HTI chromophore as visible-light responsive core structure.43 HTI 16 can be set in motion with wavelengths up to 500 nm and provides very fast rotations at ambient temperatures, that is, a maximum possible speed of about 1 kHz at 20 °C. At the same time, its motion is completely unidirectional (Figure 4A,B) and proceeds in a four-step process similar to the Feringa motor system,31 where two independent photoequilibria are ratcheted by intervening thermal steps. In our case the thermal steps are very fast with associated barriers of 13.1 kcal/mol and 90%) obtained in the pss at shorter wavelengths.50−53 The authors proposed stabilization of the E isomeric form via an intramolecular hydrogen bond as mechanistic explanation for these findings. An analogous explanation was given for the beneficiary effects of pyrrole1159


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Figure 6. Mono- and bis-arylated indigo photoswitches with red-light responsiveness. (A) Molecular structures of indigos 23−25. (B) Structures of trans-24 and trans-25 in the crystalline state. (C) Color changes upon photoisomerization of indigos 24 (top) and 25 (bottom) in THF solution. (D) Dependence of the thermal half-lives of cis-24 (black) and cis-25 (red) on small amounts of added water.

substitution in the related HTI chromophore leading to increased photoisomerization yields.23 Ikegami and Arai could further demonstrate the interaction of pyrrole-substituted hemiindigo with bovine serum albumin (BSA) in aqueous media hinting directly at possible biological applications, despite nonideal high-energy light responsiveness.52 Addition of BSA led to significant increase of fluorescence (fluorescence lifetimes of 4.2 ns) for the E isomer indicating direct interactions with the protein. The nonfluorescing state, associated with unbinding from the protein, could be restored by irradiation with 558 nm light leading to photoswitchable fluorescence as sensory output for the presence of BSA in aqueous solution. In light of the already discussed necessity for red-shifted absorption of photoswitches, we became interested in scrutinizing HI as a new photoswitchable core structure. For this purpose, we have added strong electron donor substituents on the benzene ring of the stilbene moiety to establish a significant push−pull character across the photoisomerizable double bond. In this case, the carbonyl group of the indigo fragment serves as acceptor. We studied five different derivatives of HI either with no further substitution at the indoxyl nitrogen atom (HIs 18 and 19) or introducing n-propyl (HIs 20 and 21) or p-tolyl (HI 22) groups at that position (Figure 5A). The resulting absorption profiles were quite promising with maxima at high extinctions beyond 500 nm for the Z isomers and beyond 550 nm for the E isomers and pronounced photochromism allowing distinction of the isomers by the naked eye (Figure 5B,C,E).54 Irradiation with either blue or green light effected the Z to E photoisomerization and gave very high yields of the E isomers (typically >90%) in solvents of low (toluene), intermediate (THF), or very high (DMSO) polarity. Likewise the E to Z photoisomerization was found to be highly efficient yielding back the corresponding Z isomers to typically >95% after irradiation with yellow or red light regardless of the solvent. Examination of the photostability of HI 20 in DMSO showed only 3% degradation after 50 cycles of alternating irradiations to the respective pss at 470 and 590 nm (Figure 5D). This prolific photoswitching behavior was even

found in aqueous solutions with small amounts of THF, DMF, or DMSO mixed in for solubility (Figure 5C). Sizable photoisomerization quantum yields of about 20% for the Z/E and about 10% for the E/Z direction were found for the HI derivatives, which are comparable to the ones of HTIs with similar donor substitution at their stilbene fragments. The high isomeric yields in the pss at different wavelengths are therefore clearly dominated by the pronounced photochromism and less so by the quantum yields of the individual photoreactions. Calculations at the TD-B3LYP-GD3BJ/6-311+G(d,p) PCM (DMSO) level of theory revealed the main transition to be a HOMO−LUMO excitation with π−π* character, thus labilizing the double bond character and allowing its rotation in the excited state. When scrutinizing their thermal stability, we found that the Z and E isomers of HI derivatives bearing substituents at the nitroxyl nitrogen atom possess very similar energies (ΔG°(E/ Z) = 0.00−0.46 kcal/mol). It is therefore not possible to convert one isomer completely back to the other by simple heating. Different from most HTIs for which the Z isomer is clearly the most stable state, for the HI derivatives studied thermally stable compositions between 1:1 and 2:1/1:2 are found after equilibrating at 100 °C. The increased steric demands of the N-substituents are most likely responsible for raising the energy of the Z isomer. However, as almost quantitative isomer photoconversion is achieved by light irradiation, the thermal equilibrium ground-state compositions are not hampering or affecting the photoswitching. Another surprise was the extraordinarily high thermal stability of all HI isomers leading to thermal half-lives of up to 83 years at 25 °C. Again, this high bistability was scarcely impaired by changing the solvent polarity. Only in protic solvents like water and in solvents prone to proton dissociation like CH2Cl2 did we find the bistability reduced. With these properties, donor substituted HIs represent novel photoswitches with a unique property profile, that is, solvent independent photoswitching with green and red light, extraordinarily high isomeric ratios in the pss, very high thermal bistabilities, and good quantum yields (for a 1160


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studies revealed how unusual geometrical changes can be induced as de-excitation pathways or how red-shifting of their absorption can be decoupled from influencing the thermal stability of metastable states. New and very efficient synthetic accesses have been developed for the construction of sterically hindered derivatives as well as diverse double-bond substituted HTIs, enlarging the chemical space as well as functionalizations available for these photoswitches. Hemiindigo has been introduced as nearly perfect chromophore for bistable photoswitching near the biooptical window and with a highly advantageous property profile unaltered by the surrounding medium’s nature. Likewise, also the parent dye indigo has entered the stage and can be rendered into a red-light responsive photoswitch if at least one proton at the indoxylN atoms is replaced by substituents. It is evident that with the herein described progress indigoid photoswitches now represent a well-developed and valuable alternative to commonly used chromophores offering precise and effective photocontrol over large geometrical changes by low-energy visible light. Notwithstanding the already many examples for their successful use as molecular tools, we are confident that this is just the beginning.

comparison of the different photophysical properties, we refer the reader to refs 8 and 54). Together with their easy synthetic access and functionalizability this makes HIs nearly perfect photoswitches for applications in biology, chemistry, and pharmaceutical or materials sciences. We hope for exciting new applications and developments with this type of photoswitch in the near future.

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INDIGO Indigo is one of the most prominent chromophores known to man, its vivid blue color and high photostability being the main reasons for worldwide use as a dye. Adolf von Baeyer completed its structural assignment in 1883,1 and since that time countless derivatives and related motifs have been developed and studied in detail. Only much later, the reason for its extraordinarily high photostability was explained: an ultrafast and highly efficient excited state proton transfer (ESPT), which prevents destructive side reactions and quickly regenerates the original ground state after light absorption.55−57 Because of this efficient excited state pathway, indigo does not undergo photoisomerization. This situation changes, however, if the NH protons are replaced by carbon-based alkyl58,59 or acetyl substituents60 resulting in blue or red/orange indigo photoswitches, respectively. The main problem for applicability in these cases are very short thermal half-lives of the metastable cis-isomers, which barely reached second time scales at ambient temperature. Hecht and co-workers61 recently found that bisaryl substituted indigo62 exhibits significantly higher thermal stability with half-lives reaching up to hours at 22 °C. Easy onestep preparation starting from the cheap parent indigo allows for very convenient access to a variety of blue photoswitches. In the indigo field, we have made an interesting discovery recently, that is, that monoarylated indigos such as 23 or 24 do also undergo photoisomerization despite the presence of one NH proton suitable for ESPT (Figure 6A,B,C).63 Up to 40% cis isomer can be obtained by red light illumination (>620 nm) of the thermodynamically stable trans isomer. Higher cis content (72%) is possible if both N atoms are substituted with aryl residues (e.g., indigo 25 or ref 61). First mechanistic insights showed that ESPT is indeed operational in monoarylated indigos and is most likely the reason for their limited photoswitching efficiencies. As the photochromism of monoarylated indigos is quite sizable, cis enriched solutions can be distinguished by the naked eye from solutions containing only the trans isomer (Figure 6C). Additionally we found an extraordinary sensitivity of the thermal cis to trans isomerization of monoarylated indigo 24 towards the presence of water (Figure 6D). Upon addition of minute amounts of water, this dark reaction can be accelerated up to a factor of 300, thus enabling a simple option for finetuning of thermal bistability. Applications of this chromophore as a new type of water sensor using absorption changes in the red part of the spectrum as readout are therefore an interesting possibility.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Henry Dube: 0000-0002-5055-9924 Funding

We thank the “Fonds der Chemischen Industrie” for a Liebig (Li 188/05) and a Chemifonds stipend (Do 199/53) and the Deutsche Forschungsgemeinschaft (DFG) for an Emmy Noether fellowship (DU 1414/1-1). We further thank the collaborative research center (SFB 749, A12) and the Cluster of Excellence “Center for Integrated Protein Science Munich” (CIPSM) for financial support. Notes

The authors declare no competing financial interest. Biographies Christian Petermayer received his bachelor’s degree in Chemistry and Biochemistry from LMU München in 2011 and his master’s degree in Chemistry in 2014. He started his Ph.D. in the same department with Dr. Henry Dube in June 2015 and focuses his research on indigoid photoswitches and machines. Henry Dube received his intermediate Diploma in Chemistry from the Philipps-University Marburg in 2000, his Diploma in Chemistry from the LMU München in 2004, and his Ph.D. from the ETH Zürich in 2008 with Prof. François Diederich. He then did postdoctoral studies at The Scripps Research Institute with Prof. Julius Rebek, Jr. At the end of 2011, he started his independent career with a LiebigFellowship of the FCI at the LMU München. Since the end of 2014, he leads an Emmy Noether Independent Junior Research Group at the same institution. His research focuses on photochemistry, supramolecular chemistry, and molecular machines.

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SUMMARY In summary, indigoid photoswitches have gained a considerable track record over the last years and have matured into sophisticated and highly valuable light responsive molecular tools as evidenced by a steeply increasing amount of different applications in supramolecular chemistry, molecular machinery, or the field of smart molecules. Comprehensive mechanistic

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ACKNOWLEDGMENTS We thank all of our current and past co-workers and collaboration partners who have contributed to our research on indigoid chromophores. 1161


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Indigoid Photoswitches: Visible Light Responsive Molecular Tools

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