Design rules for optimization of photophysical and kinetic properties of azoarene photoswitches

Abstract

Azoarenes are an important class of molecular photoswitches that often undergo E → Z isomerization with ultraviolet light and have short Z-isomer lifetimes. Azobenzene has been a widely studied photoswitch for decades but can be poorly suited for photopharmacological applications due to its UV-light absorption and short-lived Z-isomer half-life (t_1/2). Recently, diazo photoswitches with one or more thiophene rings in place of a phenyl ring have emerged as promising candidates, as they exhibit a stable photostationary state (98% E → Z conversion) and E-isomer absorption (λ^max) in the visible light range (405 nm). In this work, we performed density functional theory calculations [PBE0-D3BJ/6-31+G(d,p)] on 26 hemi-azothiophenes, substituted with one phenyl ring and one thiophene ring on the diazo bond. We calculated the E-isomer absorption (λ^max) and Z-isomer t_1/2 for a set of 26 hemi-azothiophenes. We compared their properties to thiophene-based photoswitches that have been studied previously. We separated the 26 proposed photoswitches into four quadrants based on their λ^max and t_1/2 relative to past generations of hemi-azothiophene photoswitches. We note 8 hemi-azothiophenes with redshifted λ^max and longer t_1/2 than previous systems. Our top candidate has λ^max and a t_1/2 approaching 360 nm and 279 years, respectively. The results here present a pathway towards leveraging and optimizing two properties of photoswitches previously thought to be inversely related.

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Introduction

Azobenzene is the prototypical photoswitch; its photophysical and energy-storing properties are well-known, and it can be readily synthesized.^1–7 Azoarenes have been used for applications in materials science^8–12 and photopharmacology.^13–15 Azoarene photoswitches are a general class of azobenzene derivatives that offer considerable structural diversity and undergo light-promoted E → Z isomerization when irradiated with ultraviolet to infrared light.^9,16–18 Recent efforts in the field have focused on heteroarenes such as pyrazoles^19–23 and thiophenes,^24–26 because of their red-shifted absorption maximum (λ^max) and promising band separation in the E- and Z-isomers. There has been a broad effort to red-shift the absorption maximum (λ^max) of the azobenzene E-isomer (λ^max = 320 nm) into the visible-light range to minimize photodamage in living organisms.^27,28 This is especially true in photopharmacology, where the half-life (t_1/2) of the metastable Z-isomer needs to be on the order of days to establish a stable photostationary state.¹⁷ In 2019, Fuchter and co-workers synthesized a series of hemi-azopyrazole photoswitches showing UV-promoted photoswitching (80–93% Z-isomer population) and long-lived Z-isomer t_1/2 (up to 46 years).²⁹ In 2021, a set of bis-azopyrazoles discovered by Li and co-workers exhibited nearly complete E → Z photoconversion (94–98%) and a Z-isomer t_1/2 of up to 681 days.²² Our group recently reported the results of a high-throughput virtual screening (HTVS) where we observed significant differences in the λ^max and t_1/2 values for a set of positional isomers of bis-azofurans and bis-azothiophenes.³⁰ We showed that isomeric bis-azothiophenes and bis-diazofurans (2,2 vs. 3,3) increased the λ^max of the E-isomers by as much as 77 nm while simultaneously lowering the t_1/2 by six orders of magnitude. These changes resulted from the cross-conjugation vs. π-conjugation significantly increasing the activation free energies (ΔG^‡) and shorter λ^max wavelengths for the (3,3) isomers.

Wegner and Heindl showed that the λ^max and t_1/2 of hemi-2-thiophenes with a phenyl terminus can be tuned through functionalization on both aryl rings.²⁵ They synthesized a series of azothiophenes with substituents on the meta and para positions on the phenyl ring and at the 5-position on the thiophene ring. They determined the E-isomer λ^max and Z-isomer t_1/2 for each. They reported λ^max values approaching 405 nm (through substitution of the thiophene ring with a methoxy group) and high (>99%) E → Z photoconversion efficiencies (through substitution of the phenyl ring at the meta position with a CN functional group). Although the 2-hemi-thiophenes displayed red-shifted E-isomer λ^max values ranging from 45–85 nm compared to azobenzene, the t_1/2 lifetimes were shorter (maximum t_1/2 of 17.7 hours) than those of azobenzene (2 days in CH₃CN).

Past experimental and computational work on azoarenes has shown an empirical inverse relationship between the λ^max and t_1/2.^17,20,31 This leads to trade-offs during photoswitch design. This report describes how we have applied strategies to increase the λ^max and t_1/2 metrics to design photoswitches a priori for photopharmacological applications. We designed a new class of hemi-azothiophenes with the diazo group bound to a p-substituted-phenyl and thiophene substituted at the 3-position. This photoswitch was designed to maximize t_1/2 based on our recent discovery of the role of cross-conjugation on (3,3)-vs. (2,2)-bis-azothiophenes and similar experimental reports by Perry and co-workers.²⁶ We combined this powerful effect with known strategies to simultaneously increase λ^max (i.e., increasing π-conjugation length and substituent effects). To this end, we computed the λ^max and t_1/2 of 26 hemi-azothiophenes with quantum mechanical density functional theory calculations, enabled by our automated computational workflow, EZ-TS.³²

The EZ-TS code first generates a set of 12 transition state guess structures from an input Z-isomer geometry by rotating about the diazo bond. The 12 guess structures are then optimized using B3LYP-D3BJ/6-31G(d), and the lowest energy structure is subject to a conformational analysis with the Conformer Rotamer Ensemble Sampling Tool (CREST).³³ Next, a 5-step constrained relaxation using ORCA³⁴ is run on all conformers to ensure a smooth convergence for the final set of optimizations and frequency calculations, which are performed on the 10 lowest energy conformers using B3LYP-D3BJ/6-31G(d).^35–38 At the end of this final step, the 10 conformers are ranked by their energies. The lowest energy conformer with a vibrational frequency corresponding to the Z → E thermal isomerization reaction is determined to be the lowest energy transition state. We benchmarked this workflow for 11 azoarenes and 140 model chemistries. We found that the PBE0-D3BJ³⁹ with either the cc-pVDZ^40,41 or 6-31+G(d,p)³⁵ basis sets provide the best balance between computational cost and accuracy; the mean absolute error (MAE) for this model chemistry was 1.3 kcal mol⁻¹. This was the first comprehensive study that benchmarked DFT model chemistries for their accuracy in computing Z → E thermal isomerization barriers for azoarenes.

Past studies on the thermal mechanisms of azoarene photoswitches have determined three possible mechanisms for the Z → E isomerization reaction. These include rotation about the CNNC dihedral,^22,42,43 inversion of the π_NN bond, and a hula-twist mechanism where there is a twisting motion about the π-bond, and the aryl groups maintain their relative orientations.⁴⁴ Past experimental and computational work on azoarenes shows a preference for the inversion mechanism. Because photoswtiches with 3-substituted aryl rings (such as thiophenes and furans) have significantly increased t_1/2, we chose to study these further.

Scheme 1 shows all 26 azoarenes included in this study. We present 13 with an unsubstituted thiophene ring and 13 with 2,5-dimethoxy thiophenes. We substituted methoxy groups on the thiophene because Wegner observed longer t_1/2 values for azothiophenes with EDGs substituted at the 4-position.

Scheme 1 Parent structure for hemi-azothiophene and substituted hemi-azothiophene photoswitches tested for this work.

We hypothesize that adding π-donating groups (OMe) on the thiophene will red-shift the otherwise low E-isomer λ^max value for 3-substituted hemi-azothiophenes. We used a combination of electron donating groups (EDGs), including NH₂, OMe, and three vinyl dienes with OMe, Me, and CN terminal groups (Scheme 1). We also used seven electron-withdrawing groups (EWGs), including NO₂, CF₃, CN, COOH, COH, COMe, and Cl. Through aryl ring functionalization, we aim to find an optimal thiophene photoswitch with red-shifted λ^max and longer t_1/2 lifetimes than previously studied generation of hemi-azothiophene photoswitches.

Results and discussion

All transition structure calculations were performed in Gaussian 16⁴⁵ with the PBE0-D3BJ/6-31+G(d,p) method and the IEFPCM^water solvation model,⁴⁶ which we found to have an optimal balance of accuracy and computational cost.³² Next, we performed intrinsic reaction coordinate (IRC) calculations and optimized the reactive conformers corresponding to the E and Z isomers for a given thermal isomerization. The reactive Z-isomers were used to calculate the thermal barrier. For our set of 26 photoswitches, we confirmed that 17 underwent an inversion mechanism, while the remaining 9 underwent rotation. All systems that underwent a rotation mechanism were substituted with OMe groups on the thiophene ring, while all photoswitches with unsubstituted thiophene rings underwent an inversion mechanism. All transition state geometries are given in the ESI.†

The range of computed ΔG^‡ for was found to be 16.5 kcal mol⁻¹, corresponding to t_1/2 values ranging from 10⁻³ seconds to 10⁵ years (nearly 12 orders of magnitude). Fig. 1 shows the transition structures photoswitches with the smallest and largest t_1/2 values for the unsubstituted and substituted thiophene rings, respectively. The shortest lifetime was for photoswitches with nitro-substituted phenyl ring, and the longest lifetime was for the systems with an amine substituent on the phenyl ring.

Fig. 1 Transition state geometries corresponding to the systems with highest and lowest t_1/2 for the unsubstituted thiophenes (top) and methoxy substituted systems (bottom). NNC_Ph corresponds to the angle with the carbon atom in the phenyl ring, and NNC_Th corresponds to the angle including the carbon atom on the thiophene rings.

Fig. 1 shows the computed transition structures and t_1/2 for 3-TS, 13-TS, 3-OMe-TS, and 13-OMe-TS, representing the strongest EWG- and EDG-substituents (NH₂vs. NO₂, respectively). Our calculations show approximately 10 orders of magnitude difference in t_1/2. This increase in t_1/2 is observed for the unsubstituted thiophene (3-TS and 13-TS) and 2,5-dimethoxythiophenes (3-OMe-TS and 13-OMe-TS). Three of the four hemi-azothiophenes in Fig. 1 undergo inversion mechanisms (3, 13, and 3-OMe), while 13-OMe-TS isomerizes through a rotation mechanism. The mechanisms are differentiated based on the NNC angle about the diazo bond. For the inversion mechanism, one of the NNC angles is linear, whereas the other is nearly 120° (116°–118°), corresponding to an sp²-hybridized nitrogen atom. The rotation transition structures have non-linear CNN angles (128° and 118° for 13-OMe-TS for NNC_Ph and NNC_Th, respectively). We assessed the role of the EDGs and EWGs in delocalizing π_NN-electrons to explain the nearly 12 orders of magnitude range in t_1/2 for 1–13 and (1–13)-OMe. We plotted the ΔG^‡ for 20 of the 26 photoswitches against the Hammett (σ_para) parameters (there are no reported σ_para values for the methoxy diene groups in 11–13 and (11–13)-OMe). The Hammett parameter quantifies how much a given functional group stabilizes a developing negative charge in a transition structure. Venkataramani and König showed that azoarene Z → E thermal isomerization barriers decrease with the strength of EWGs at para-Ph positions.^20,21

Fig. 2 shows the linear relationship between the calculated (ΔG^‡) and σ_para for 1–3 and 7–13 (black line), and (1–3)-OMe and (7–13)-OMe (blue line). We used a broad range of EWG- and EDG-substituents (σ_para ranges from −0.66–0.81). The R² values are 0.89 and 0.78 for the unsubstituted and dimethoxy-thiophenes, respectively. The linear correlation suggests there is a moderately strong relationship between the ability of a substituent to delocalize the π_NN-electrons and the ΔG^‡. The slopes are −8.72 (black line) and −8.43 (blue line), which indicate that the unsubstituted thiophenes (1–13) are slightly more sensitive to the substituent effects than the 2,5-dimethoxy thiophenes [(1–13)-OMe]. We present our computed results for all 26 hemi-azothiophenes in the scatterplot in Fig. 3. We compared our computed λ^max and t_1/2 to those of hemi-azothiophene reported by Wegner in 2020 (λ^max of 365 nm and t_1/2 of 17.7 hours).⁴⁷ The scatterplot is organized into four quadrants; the red quadrant (bottom left) contains photoswitches where both λ^max and t_1/2 are lower relative to the past system, while the yellow quadrants (top left and bottom right) have a red-shifted λ^max and shorter t_1/2 (top-left) or a longer t_1/2 and a lower λ^max (bottom right) compared to the past system. The green quadrant (top right) contains eight photoswitches from our set with red-shifted λ^max and longer t_1/2 than hemi-azothiophene.

Fig. 2 Scatterplot showing the relationship between Hammett parameter σ_para and calculated activation barrier for unsubstituted (black) and dimethoxy (blue) hemi-thiophene systems. The linear correlation equation and R² are presented. The barriers are shown in kcal mol⁻¹. The “a” and “b” groups correspond to the carboxylic acid and ketone groups, respectively.

Fig. 3 Scatterplot showing 26 thermal Z/E isomerization t_1/2 plotted against the E-isomer λ^max (a). The eight azothiophenes in the green quadrant are presented (b). The λ^max values were computed using ωb97-XD/aug-cc-pVTZ and IEFPCM^water, and the t_1/2 were calculated using PBE0-D3BJ/6-31+G(d,p) and IEFPCM^water.

There are six hemi-azothiophenes contained in the red quadrant of the scatter plot in Fig. 3. All six of these structures have a lower λ^max and shorter t_1/2 than unsubstituted hemi-azothiophene (365 nm and 17.7 hours, respectively). The six photoswitches are 7, 8, 9, 10, 11, and 12, and are all substituted with EWGs (CN, COOH, COH, COMe, CF₃, and NO₂, respectively) at the phenyl ring para-position. These results and Fig. 2 suggest that substituting the phenyl ring with an EWG will significantly lower the Z-isomer t_1/2 of the hemi-azothiophene photoswitches; the energy of the transition state is lowered due to resonance stabilization from a strong EWG (the Hammett plot to show this trend is shown in Fig. 2). Hemi-azothiophenes 7–12 also have an unsubstituted thiophene ring bonded to the diazo bond, which suggests that functionalizing the thiophene in hemi-azothiophene red shifts λ^max.

The eight molecules (4, 5, 1-OMe, 2-OMe, 3-OMe, 5-OMe, 6-OMe, and 9-OMe) in Fig. 3b have computed λ^max values that range from 367–415 nm and t_1/2 values that range from 5–290 days. Six of the eight photoswitches (4, 5, 2-OMe, 3-OMe, 4-OMe, and 5-OMe) are substituted with an EDG at the para position on the phenyl ring, which increased the λ^max compared to an unsubstituted or EWG-substituted Ph group. 1-OMe has the lowest λ^max (367 nm) of the eight photoswitches in the green quadrant. Six of the eight photoswitches in the green quadrant are substituted on the thiophene ring with methoxy groups, consistent with EDGs red shifting the λ^max of azoarene photoswitches. We also observed that extending π-conjugation through a methoxy diene group significantly red-shifted the λ^max of the photoswitches while maintaining a relatively long-lived t_1/2 (as seen in 4, 5, and (4–5)-OMe). Our results show that all methoxy-substituted azothiophenes have lower ΔG^‡ than unsubstituted thiophene rings by 0.6–3.5 kcal mol⁻¹ and significantly increase the λ^max (an increase of 24–81 nm for the E-isomer). Due to the cross-conjugation of the thiophene ring, the dimethoxy-substituted photoswitches offer red-shifted λ^max and longer t_1/2 over previously reported azothiophenes.

Conclusion

We have used quantum mechanical calculations (TD-DFT and DFT) to calculate the λ^max and t_1/2 of a set of 26 hemi-azothiophene photoswitches. Our findings suggest it is possible to optimize these properties, generally thought to be inversely related. The 26 azoarenes have a t_1/2 range of nearly 12 orders of magnitude (10⁻³ seconds to 10⁵ years), and an E-isomer λ^max range of 107 nm (321–428 nm). We have also established a relationship between the Hammett parameters (σ_para) and the calculated thermal barriers for 20 of the hemi-azothiophene systems. We found that EWGs lower the energy of the TS geometry through the delocalization of the π-NN electrons. We are collaborating with experimentalists to validate these design principles and produce azoarenes of interest to photopharmacology.

Computational methods

We used DFT calculations to predict the activation free energies (ΔG^‡) and vertical excitation energies of 1–13 and 1-OMe–13-OMe. We computed the structures and energies of the Z-isomers, E-isomers, and transition structures for the 26 hemi-azothiophene isomerization reactions. After optimizing the transition state structures, we ran intrinsic reaction coordinate (IRC) calculations and optimized the endpoints corresponding to the E and Z-isomer reactive conformers. All calculations were performed using the Gaussian 16 software. We used the PBE0-D3BJ/6-31+G(d,p) model chemistry for the geometry optimizations and subsequent vibrational frequency calculations. Vertical excitation energies for all systems were calculated using TD-DFT with the ωB97X-D/6-311+G(d,p) model chemistry in IEFPCM^water. The lowest 10 singlet states were included in all TD-DFT calculations. The ΔG^‡ values presented in kcal mol⁻¹ were converted to t_1/2 (units of seconds) by using the Eyring equation at room temperature (293.15 K).

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

D. M. A. and S. A. L. acknowledge the National Science Foundation CAREER award (NSF-CHE-2144556) and Camille Dreyfus Teacher-Scholar Award for funding. All authors appreciate the assistance from the Northeastern Research Computing Team and the computing resources provided by the Massachusetts Life Science Center grant (G00006360).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3ob01298k

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