Aryl Azocyclopropeniums: Minimalist, Visible-Light Photoswitches

Abstract

We report convenient syntheses of aryl azocyclopropeniums and a study of their photochemical properties. Incorporation of the smallest arene leads to pronounced redshift of the π–π* absorbance band, compared to azobenzenes. Photoisomerization under purple or green light irradiation affords Z- or E-isomers in ratios up to 94% Z or 90% E, and the switches proved stable over multiple irradiation cycles. Thermal half-lives of metastable Z-isomers range from minutes to hours in acetonitrile and water. These properties together with the concise, versatile syntheses render aryl azocyclopropeniums exciting additions to the tool kit of readily available molecular photoswitches for wide ranging applications.

Azobenzenes have been used as dyes for almost 200 years.¹ Only recently light-controlled isomerization² has sparked the development of photopharmacology³⁻⁵ and photoresponsive materials.^6,7 These studies are leading to a deeper understanding of the physical chemistry of azoarene photoisomerization. Variation of substituents on phenyl rings or their replacement with heteroarenes enables tuning photoswitching properties, such as E/Z-ratios,⁸ thermal stability of the metastable isomer,^9,10 and absorbance wavelength.¹¹⁻¹³ Numerous azo photoswitches have been designed, synthesized, and studied that encompass a large variety of arenes, most commonly incorporating 6 π- and less prevalently 10 π-electron systems. Interestingly, the smallest 2 π-electron system, the cyclopropenium cation,¹⁴ has not been studied in azoarenes. Herein, we report two versatile synthetic approaches to azo photoswitches that incorporate cyclopropenium cations (Scheme 1). Their photophysical properties are investigated, and fully reversible, high-yielding photoisomerization under visible-light irradiation is presented.

Scheme 1. Aryl Azocyclopropenium Photoswitches.

Photopharmacology has fueled the search for azoarenes that undergo high-yielding bidirectional switching, display red-shifted absorbance, or have Z-isomers with long thermal half-lives (Figure 1). Azoarenes featuring five-membered heteroarenes have enjoyed considerable attention. Herges and Fuchter showed that aryl azoimidazoles and azopyrazoles undergo near-quantitative isomerization and display remarkable bistability.^8,9,15 Most aryl azoheteroarenes require UV irradiation for photoswitching,^8,9,16−18 which can limit applications in biology and material sciences.^19,20 Bistable tetra-ortho-substituted azobenzenes, as introduced by Woolley^13,21 and Hecht,¹⁰ allow for visible-light photoswitching at longer irradiation times via excitation of the weakly absorbing n−π* transitions. Switches featuring 10 π-arenes have also been studied. As an example, König reported aryl azoindoles with tunable thermal half-lives.²² Interestingly, azoarenes featuring 2 π systems remain elusive.

Figure 1.

Development of azoarene photoswitches.

Triphenylcyclopropenium tetrafluoroborate was described by Breslow in 1957 and constitutes the first isolable arene with 2 π-electrons.²³ However, Breslow noted the decomposition of the cation over prolonged storage in methanol. Because strong π-donors elicit stabilizing effects, applications of amine-substituted cyclopropeniums have subsequently dominated.^24,25 In recent years, the use of cyclopropeniums in materials science and catalysis has been disclosed.^25,26 For example, Sanford described the application of cyclopropenium-based anolytes in redox flow batteries.^27,28 Tris(dialkylamino)cyclopropenium salts were employed by Lambert in electrophotocatalytic C–H bond oxidation reactions.²⁹

Recently, we have been interested in applying azoarenes to gain spatiotemporal control of biological processes and identifying novel azoarenes and their synthesis.^17,30−32 To expand the scope of visible-light photoswitches, we envisioned that the electron-accepting character of cyclopropenium would lead to electronic push–pull systems displaying a redshift of the strongly absorbing π–π* bands.³³ Additionally, we sought to study the stability and photochromism of these 2 π-electron azoarenes that have not been previously examined.

For a synthesis of aryl azocyclopropeniums, we chose chloro bis(dialkylamino)cyclopropenium salts as suitable precursors, which are readily prepared from tetrachlorocyclopropene and dialkylamines.³⁴ Feringa has reported access to azoarenes from organolithium reagents and aryl diazonium salts.³⁵ Chloro bis(diisopropylamino)cyclopropenium salt 1a has previously been shown to react with n-BuLi, affording carbene 2 (Scheme 2).³⁶⁻³⁸ It was unclear whether 2 would be sufficiently nucleophilic to add onto ArN₂⁺. Employing literature conditions afforded deeply red phenyl azocyclopropenium tetrafluoroborate 3a in 20% yield.^17,35 We surmised that the poor outcome resulted from low nucleophilicity of 2, compared to organolithiums, compounded by the low solubility of ArN₂⁺ salt in tetrahydrofuran (THF). Accordingly, chlorocyclopropenium 1a was treated with n-BuLi in THF at −78 °C, and the resulting solution was added to PhN₂BF₄ in MeCN, affording 3a in 60% yield. Under these conditions, 3b–d were prepared (Scheme 2).

Scheme 2. Carbene Addition to Diazonium Salts.

Reaction conditions: (a) 1a (1.0 equiv), n-BuLi (1.0 equiv), THF, −78 °C; (b) ArN₂BF₄ (1.0 equiv), MeCN, −45 °C.

The isolated aryl azocyclopropeniums 3a–d proved stable toward moisture and air, aqueous workup, and column chromatography. Analysis of the X-ray structure of cationic 3a (Scheme 2) revealed a N=N bond distance of 1.27 Å, matching that of azobenzenes (1.26–1.27 Å).³⁹ The C–C bonds within the cyclopropenium are of comparable length (1.37–1.39 Å).⁴⁰

Next, when bisdimethylamino-substituted chlorocyclopropenium 1b was treated with n-BuLi and PhN₂BF₄, only decomposition was observed. We concluded that accessing sterically less shielded aryl azocyclopropeniums would necessitate different approaches.

Chlorocyclopropenium cations undergo S_NAr with pyridine to form dicationic adducts.^41,42 We envisioned harnessing this reactivity to activate chlorocyclopropeniums for coupling with Boc-hydrazides 4a–r (Scheme 3).⁴³⁻⁴⁵

Scheme 3. Synthesis of Aryl Azocyclopropenium Salts through S_NAr.

Reaction conditions: (a) 1a or 1b (1.0–1.3 equiv), 4a or 4b (1.0 equiv), py (1.2 equiv), CHCl₃ or DCE, 50–80 °C; (b) BQ (2.0 equiv), CHCl₃ or DCE/TFA (1:1), rt.

Treatment of 1b with 4a (Ar = Ph) in the presence of pyridine gave 5b. Without purification, subjecting 5b to deprotection (TFA) and in situ oxidation with benzoquinone (BQ) furnished 6a (63%). 3a could be prepared from chlorodiisopropylaminocyclopropenium 1a under modified conditions (Scheme 3) in 60% yield, highlighting the method’s generality. The S_NAr approach tolerates substrates bearing nucleophilic groups, such as phenol (6d) as well as carboxylic acid (6i), allowing the synthesis of a variety of different aryl- and heteroaryl-substituted aryl azocyclopropeniums. Hydrazine hydrochlorides were also competent substrates, leading to the formation of 6p-r bearing two ortho-substituents. The stability of 6o in D₂O was monitored by ¹H NMR spectroscopy, and it retained ∼95% purity after seven months at ambient temperature (see SI).

With a variety of aryl azocyclopropeniums, we set out to investigate their photophysical properties (Figure 2, Table 1). The compounds synthesized (3a–f, 6a–r) displayed λ_max = 380–510 nm (Figure 2, SI). Comparing the dominant π–π* absorption of 3a in DMSO (λ_max = 401 nm, see SI) to azobenzene (λ_max = 323 nm)⁴⁶ and phenyl azopyrazolium MeOSO₃^– (λ_max = 320 nm)⁴⁷ reveals that phenyl azocyclopropenium 3a is redshifted by ∼80 nm. para-Substitution of the phenyl with electron-donating substituents, as in 3b or 6b–d, augmented the bathochromic shift for λ_max (see SI). No hypsochromic shift was observed for compounds incorporating a phenyl ring substituted with electron-withdrawing groups (6j).

Figure 2.

Photochromism of 3a. (A) Time-dependent UV/vis absorbance of 3a (100 μM, MeCN) under irradiation at 385 nm; (B) UV/vis absorption spectra of 3a (100 μM, water) before (dark) and after irradiation at 340–530 nm for at least 20 min.

Table 1. Photophysical Properties of Selected Aryl Azocyclopropenium Salts.

	λmax (nm) MeCN | H2O	t1/2a (min) MeCN | H2O	PSS385 nmc % Z MeCN | H2O	PSS505 nmc % E MeCN | H2O
3a	393 | 392	4 | 13	90d | 90d	88d | 90d,f
6a	386 | 386	73 | 452	92 | 91	90 | 85
6c	412 | 410	16 | 93b	81e | 80e	82f | 81f
6e	392 | 392	5 | 361	88d | 90	82d | 84
6l	387 | 385	17 | 309	83 | 86	87 | 86
6n	387 | 388	170 | 340	94 | 92	87 | 87
6o	393 | 394	337 | 223b	90d | 90	90d,f | 81

^aDetermined at 25 °C.

^bDetermined in water at 37 °C.

^cDetermined by HPLC analysis.

^dEstimated based on absorbance spectra; for details see SI.

^ePSS_415 nm.

^fPSS_530 nm.

The photochromism of prototypical aryl azocyclopropenium 3a was investigated by irradiating a solution in MeCN (λ_LED = 385 nm, 100 μM) close to λ_max. Within 90 s, the photostationary state (PSS) was reached (Figure 2). Performing this procedure at different wavelengths (340–530 nm), we observed reversible changes in absorption intensity and band position, indicative of E/Z-isomerization. Photophysical properties of a collection of (hetero)aryl azocylopropeniums can be found in Table 1 (for additional examples and photophysical characterization, see SI).

Generally, irradiation at 385 nm in MeCN afforded PSSs displaying the highest Z-isomer content (% Z, Table 1). Most efficient switching was observed for thiophenyl azocyclopropenium 6n, affording 94% Z, as determined by HPLC analysis. Electron-rich arene 6c (p-OMe), displaying red-shifted absorbance (λ_max = 412 nm), gives the highest % Z under violet light irradiation (81%, 415 nm). Z-6c and Z-6n are switched to 80–90% E, using green light irradiation (505–530 nm). Importantly, no solvatochromism was observed for any of the structures studied (Δλ_max < 10 nm, water vs MeCN), and PSS-E/Z-ratios remained largely unaffected. We did not detect photochromism for highly red-shifted 6b and 6m (λ_max > 500 nm).^48,49

Thermal half-lives of the photochemically generated Z-isomers, measured in MeCN or water, range from minutes to hours (Table 1 and SI). The values were solvent-dependent, and in all cases, longer thermal half-lives were observed in water. The largest solvent effect was measured for Z-6e (MeCN: 5 min vs water: 361 min). Electron-rich azocyclopropenium 6c displayed a reduced thermal half-life compared to phenyl-substituted 6a (MeCN: 16 min vs 73 min; H₂O: 93 min vs 452 min). The same trend was observed when comparing NMe₂- with N(i-Pr)₂-substituted aryl azocyclopropeniums, as can be seen for 3a and 6a (MeCN: 4 min vs 73 min; H₂O: 13 min vs 452 min).

Dreuw and Wachtveitl have reported that Z-2-thiophenylazobenzene adopts a perpendicular disposition between phenyl and thiophene.⁵⁰ Such T-shaped arrangement features a S-lone pair−π interaction that impacts the photoisomerization time scale. We synthesized pyrazol-4-yl-, indazol-3-yl-, and triazol-4-yl-azocyclopropeniums 6s–u to examine potential interactions between the N-lone pair and the cyclopropenium cation in the Z-isomer (Scheme 4).

Scheme 4. Photochemically Induced Reactivity.

Reaction conditions: (a) 1b (1.3 equiv), 4a (1.0 equiv), pyridine (1.2 equiv), CHCl₃, 50 °C; (b) BQ (2.0 equiv), CHCl₃/TFA (1:1), rt.

Irradiation of a sample of 6s with green light (505 nm) in DMSO caused the disappearance of the yellow color (see SI). When the reaction was performed on a preparative scale, we isolated α-keto amide 8a, as determined by NMR spectroscopy and X-ray analysis (Scheme 4). We hypothesize that formation of 8a involves E/Z-isomerization, skeletal rearrangement, and oxidation by DMSO solvent (for the detailed mechanism see SI). When the reaction was performed in water, α-amino amide 8b was isolated. Similar reactivity was observed for indazole- and triazole-substituted cyclopropenium azo arenes 6t and 6u, resulting in the formation of heteropentalenes 8c and 8d, respectively. To showcase that this reactivity is highly dependent on the presence of nitrogen substitution as found in 6s, photostability of 3a, 6a, 6c, and 6o was investigated and validated (see SI).⁵¹

We extended our study on the stability of aryl azocyclopropeniums in PBS buffer and bacterial growth medium, wherein 3a and 6c displayed good stability. Half-lives in the presence of 1–10 mM glutathione ranged from minutes to >2 h. Photophysical properties of 6o (100 mM, PBS buffer) were not affected by other ions in the buffer (see SI).⁵²

Application of aryl azocyclopropeniumss in probes requires handles for further manipulation. We demonstrate that alkyne 3c and carboxylic acid 3f undergo Cu-catalyzed click reaction⁵³ and T3P-mediated amide bond formation,⁵⁴ respectively (Scheme 5). Thus, aryl azocyclopropeniums can be synthetically manipulated by employing routinely applied transformations in chemical biology.

Scheme 5. Aryl Azocyclopropenium Derivatization.

Reaction conditions: (a) 3c (1.0 equiv), azide (1.0 equiv), sodium ascorbate (4.0 equiv), CuSO₄ (10 mol %), MeCN/water, rt; (b) 3f (1.0 equiv), H-l-PheOMe·HCl (1.5 equiv), T3P (2.0 equiv), NEt₃ (5.1 equiv), MeCN, rt.

We turned our attention to the introduction of a handle for derivatization of the cyclopropenium. Ideally, this would require an unsymmetrically substituted chloro bisaminocyclopropenium bearing a selectively addressable functional group, which has not been reported to date. With the protocol we developed, multigram quantities of 1b are synthesized, which we envisioned as a suitable precursor to access unsymmetrically substituted chloro bisaminocyclopropeniums.

Accordingly, 1b was treated with L-HProOt-Bu, and the condensation product was observed, as determined by NMR analysis. Treatment of the unpurified material with KOH (2 M in water, 70 °C) led to 10 in 70% yield. Chlorocyclopropenium 1c was accessible in 87% yield from 10. Subsequent condensation of 1c with Boc-hydrazide followed by deprotection and oxidation afforded 11a and 11b (Scheme 6). Analysis of the photophysical characteristics of 11a revealed λ_max and PSS-E/Z-ratios comparable to those of 6c (see SI). Incorporation of the N-prolinyl substituent allows for an increase in structural complexity without affecting the beneficial photophysical properties of the underlying switch.

Scheme 6. Chlorocyclopropenium Derivatization.

Reaction conditions: (a) 1b (1.0 equiv), H-l-ProOt-Bu (1.1 equiv), NaHCO₃ (2.0 equiv), rt; (b) KOH (2 M), H₂O, 70 °C; (c) (COCl)₂ (3.0 equiv), DMF (cat.), 0 °C to rt; (d) EtOH, rt; (e) 1c (1.2 equiv), 4a (1.0 equiv), py (1.2 equiv), CHCl₃, 50 °C; then BQ (2.0 equiv), CHCl₃/TFA (1:1), rt.

We have presented two protocols to access a variety of (hetero)aryl azocyclopropeniums. Analysis of their photochemical properties revealed high-yielding photoisomerism under visible-light irradiation with thermal half-lives in the range of minutes to hours. Additional interesting aspects of these new switches include the absence of solvatochromism and longer thermal half-lives in water than in MeCN. Owing to their beneficial photophysical properties, unique geometry, and readily available functionalization protocols, aryl azocyclopropeniums are set to serve as a useful expansion to the scope of water-soluble photoswitches.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.4c01786.

• Details on the syntheses and analyses of presented compounds, NMR spectra, crystallographic data, and photophysical measurements, including Figures S1–S177, Schemes S1 and S2, as well as Tables T1–T5 (PDF)

E.M.C. is grateful to ETH Zürich for financial support. M.F. is an awardee of the Scholarship Fund of the Swiss Chemical Industry (SSCI).

The authors declare no competing financial interest.