# Tuning the Thermal Stability of Tetra - o- chloroazobenzene Derivatives by Transforming Push-Pull to Push-Push Systems

Nawel Goual, Rémi Métivier, Guillaume Laurent, Pascal Retailleau, Keitaro Nakatani, Juan Xie

► To cite this version:

Nawel Goual, Rémi Métivier, Guillaume Laurent, Pascal Retailleau, Keitaro Nakatani, et al. Tuning the Thermal Stability of Tetra - o- chloroazobenzene Derivatives by Transforming Push-Pull to Push-Push Systems. Chemistry - A European Journal, 2024, 30 (53), pp.e202401737. 10.1002/chem.202401737. hal-04797043

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# Tuning the Thermal Stability of Tetra-o-chloroazobenzene Derivatives by Transforming Push-Pull to Push-Push Systems

Nawel Goual,[a] Rémi Métivier,[a] Guillaume Laurent,[a] Pascal Retailleau,[b] Keitaro Nakatani,[*a] and Juan Xie*[a]

Molecular photoswitches provide interesting tools to reversibly control various biological functions with light. Thanks to its small size and easy introduction into the biomolecules, azobenzene derivatives have been widely employed in the field of photopharmacology. All visible-light switchable azobenzenes with controllable thermostability are highly demanded. Based on the reported tetra-o-chloroazobenzenes, we synthesized push-pull systems, by introducing dialkyl amine and nitro groups as strong electron-donating and electron-withdrawing groups on the para-positions, and then transformed to push-pull systems by a simple reduction step. The developed push-pull

and push-pull tetra-o-chloroazobenzene derivatives displayed excellent photoswitching properties, as previously reported. The half-life of the Z-isomers can be tuned from milliseconds for the push-pull system to several hours for the push-pull system. The n-$\pi^*$ and $\pi-\pi^*$ transitions have better resolution in the push-pull molecules, and excitation at different wavelengths can tune the E/Z ratio at the photostationary state. For one push-pull molecule, structure and absorption spectra obtained from theoretical calculations are compared with experimental data, along with data on the push-pull counterpart.

## Introduction

As photochromic molecules, azobenzenes have been widely used to reversibly photomodulate chemical, biological or pharmacological activities or properties of molecules. This is due to their small size, ease of synthesis, facile azologization of relevant biomolecules, good photophysical properties as well as the possibility of thermal isomerization.[1] With the advent of photopharmacology,[1a,b,d,2] the development of azobenzenes which could be fully photoswitched with visible light has enhanced enabled light penetration into the tissues and reduced cellular toxicity.[3] For these purposes, azoheteroarene and diazocine photoswitches have been developed.[3,4] Other strategies include protonation of the azo linkage,[5] ortho-substitution with alkoxy groups,[6] halogen or chalcogen atoms,[7] and more.[3] For example, tetra-o-chlorination of azobenzene allows for E→Z photoisomerization under green or red light irradiation, and Z→E back photoisomerization occurs under violet or blue light illumination.[6a,7b-d,g-l,k,l] Modulating the thermostability of the Z-azobenzene is also an important issue in order to enable the thermal re-isomerization to the thermodynamically stable form within the relevant timescale for intended biological applications. This includes ultra-fast thermal return for neurological applications and longer thermostability for other biological applications. Different electron-donating groups (EDG) as well as electron-withdrawing groups (EWG) have been introduced in *p*-position of tetra-o-chloroazobenzene (Scheme 1a) to tune their photophysical properties. The *mono-*(*p*-substituted derivatives showed a decreased half-life of the Z-isomer compared to the unsubstituted one (t₁/₂ = 4.4 to 32.4 days for compounds B–G compared to t₁/₂ = 38.1 days for A).[7g] However, *p*-substitution with a strong EDG (–NMe₂, compound H, t₁/₂ = 16.8 h) or EWG group (–NO₂, compound I, t₁/₂ = 1.1 h) drastically reduced the thermostability of the corresponding Z-isomers.[7g] A few *p*,*p'*-disubstituted tetra-o-chloroazobenzenes have also been reported (ex. compounds J–M, Scheme 1a), with the thermostability of the Z-isomers declining from the symmetrical compound J (t₁/₂ = 6.6 days) to the push-pull system (t₁/₂ = 13.8 and 8.3 h for *p*-methoxy-substituted K and L, and t₁/₂ = 8.1 min for *p*-dimethylamino-substituted M).[7g,l,l] Due to the strong electronic effect observed on the thermostability of Z-tetra-o-chloroazobenzenes with nitro or dimethylamino groups, we were wondering the possibility to obtain even faster thermal return by introducing both nitro and dialkylamino groups in *p*-position, despite the presence of four chlorine atoms in *o*-position of azo bond. Furthermore, this push-pull system can be readily transformed into a push-pull system by reducing the nitro group into an amine function. As a continuing interest in the development of molecular photoswitches and their applications,[8] we have

<footnote>[a] N. Goual, R. Métivier, G. Laurent, K. Nakatani, J. Xie *Photophysique et Photochimie Supramoléculaires et Macromoléculaires*, ENS Paris-Saclay, CNRS, University Paris-Saclay, Gif-sur-Yvette 91190, France
E-mail: keitaro.nakatani@ens-paris-saclay.fr
joanne.xie@ens-paris-saclay.fr</footnote>

<footnote>[b] P. Retailleau
University Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, Gif-sur-Yvette 91198, France</footnote>

<footnote>Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202401737</footnote>

<footnote>© 2024 The Author(s). Chemistry - A European Journal published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.</footnote>
<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

b) This work

<figure><img src="image_5.png" /></figure>

1 R₃ = Me, R₄ = CH₂CH₂OH

2 R₃ = Et, R₄ = CH₂CH₂OH

3 R₃ = Me, R₄ = CH₂CH₂Ph

4 R₃, R₄ = CH₂CH=CH₂

5 R₃, R₄ = CH₂CH₂OCH₂CH₂

6 R₃, R₄ = CH₂CH₂CH₂CH₂

$t_{1/2} < 10$ ms

reduction

<figure><img src="image_6.png" /></figure>

7 R₃ = Me, R₄ = CH₂CH₂OH

8 R₃ = Et, R₄ = CH₂CH₂OH

9 R₃ = Me, R₄ = CH₂CH₂Ph

10 R₃, R₄ = CH₂CH=CH₂

11 R₃, R₄ = CH₂CH₂OCH₂CH₂

12 R₃, R₄ = CH₂CH₂CH₂CH₂

$t_{1/2} > 4$ h

<caption>**Scheme 1.** (a) Reported tetra-*o*-chloroazobenzenes and the half-life of the Z-isomers at rt; (b) General structure of tetra-*o*-chloroazobenzenes presented in this work.</caption>

synthesized *p*,*p'*-disubstituted tetra-*o*-chloroazobenzenes bearing strong EDG and EWG groups (1–6) and carried out their conversion into push-push systems (7–12) (Scheme 1b). These molecules can be reversibly photoswitched with full-visible light and exhibit high fatigue resistance. Furthermore, the half-life can be tuned from few milliseconds to several hours simply by reducing the nitro group.

## Results and Discussion

### Synthesis

We designed a library of *p*,*p'*-disubstituted tetra-*o*-chloroazobenzenes bearing strong EDG and EWG groups for further functionalization. For the EDG, we have chosen (i) acyclic amine with hydroxyl function (1–2), diallylamine (4) offering facile functionalization, and dialkyl amine (3); or (ii) cyclic amine such as morpholine (5) and pyrrolidine (6). For the EWG, we have selected a nitro function, which can be easily reduced to an amine function (7–12).

The synthesis of tetra-*o*-substituted azobenzenes is challenging due to the high steric hindrance around the central N=N double bond, induced by the four substituents. In our synthesis, we tried first the late-stage C–H chlorination developed by Trauner’s group[7b] of the commercial Disperse Red 13 to produce compound 2 (Scheme 2). However, the

<figure><img src="image_7.png" /><figcaption>**Scheme 2.** Tentative *o*-chlorination of Disperse Red 13.</figcaption></figure>

reaction led to several unidentified decomposition products. Lindhorst and collaborators have observed that the presence of a hydroxy group in the substrate reduced the yield of *o*-chlorination.[7d] Direct attachment of the OH group to the aromatic system of azobenzene hindered the reaction, probably due to the competition between the ortho-directing effect of the hydroxy group and the azo group.[7d] We then tried to replace the OH group with azide, acetate, or *O*-propargyl groups ($R = N₃$, OAc or OCH₂C≡CH). However, all the reactions also failed, probably due to the complexation of palladium with the dialkylamine group. We finally decided to perform azo-coupling reactions starting from chlorinated substrates.

We started by the amination of the commercially available 1,3-dichloro-5-iodobenzene through Ullman-Golberg coupling catalysis with copper iodide and sodium hydroxide as base at 90 °C[9] to obtain the substrates S1 and S2 (50% yield in both cases) (Scheme 3). Since the conditions mentioned above were not suitable for substrates S3–S6, Buchwald-Hartwig amination was performed.[10] This reaction was catalyzed by tris-(dibenzylideneacetone)dipalladium, using XantPhos ligand and cesium carbonate in 1,4-dioxane at 100 °C. Under these conditions, substrates S3–S6 were isolated with good yields ranging from 58% to 73%. For the next step, we carried out a diazotization reaction of the commercially available 2,6-dichloro-4-nitroaniline. The diazonium salt was sequentially coupled with substrates S1–S6 via an azo-coupling reaction to give the push-pull azobenzenes 1–6 with acceptable to excellent isolated yields (41% to 98%). Finally, the push-push azobenzenes 7–12 were obtained by reduction with sodium sulfide in a mixture of THF/H₂O at reflux.[11] The reduced azobenzenes were isolated

<figure><img src="image_8.png" /><figcaption>**Scheme 3.** Synthetic pathway of the tetra-*o*-chloroazobenzenes 1–12.</figcaption></figure>
<figure><img src="image_9.png" /></figure>

with moderate yields (30–49%), in line with the literature.[⁶⁵] The targeted push-pull azobenzenes **1–6** and push-push azobenzenes **7–12** have been fully characterized by NMR, UV-vis spectroscopy and additionally X-ray crystallography for **5**.

## Photophysical Characterisation

We recorded the UV-vis absorption spectra of the newly synthesized derivatives in DMSO solution. For the *E*-isomers of the push-pull series (compounds **1–6**), we observed a broad band with a maximum absorption wavelength ranging from 414 nm (5) to 434 nm (2 and 6), which would represent the prominent *π*-*π*\* band. The corresponding molar absorption coefficients are comprised between 18600 M⁻¹ cm⁻¹ (for 5 and 6) and 21700 M⁻¹ cm⁻¹ (for 3). The positions of the absorption maxima and the molar absorption coefficients values are reported in Table 1. We notice an extended tail up to 700 nm for all the compounds (see SI, Figures S4–S9), attributed to the presence of an overlapping *n*-*π*\* band.

For the push-push compounds **7–12**, the *E*-isomers feature a *π*-*π*\* band peaking between 403 nm (for **11**) and 421 nm (for **12**), with absorption coefficients ranging from 17000 M⁻¹ cm⁻¹ (for **11**) to 20800 M⁻¹ cm⁻¹ (for **8**) (see Table 1). Although still visible as a shoulder of the *π*-*π*\* band, the *n*-*π*\* band appears clearly (see SI, Figures S10–S15), providing differentiation between both series of molecules. This will be illustrated in the next paragraph using pair **5** and **11**, and further discussed along with theoretical calculations.

To highlight the contrasting properties between push-pull and push-push azobenzenes, we then compare compounds **5** and **11** as illustrative examples, both bearing morpholine as an EDG. The UV-vis absorption spectra of *E*-5 and *E*-11 shown in Figure 1 point out the differences in spectral features between the two categories of azobenzene compounds mentioned earlier. The *π*-*π*\* band of **11** has a blue-shift of 11 nm compared to **5**, and a better resolved *n*-*π*\* band in the former. Photoisomerization was investigated by UV-vis absorption spectroscopy in DMSO solutions. For compound **5**, upon irradiation, no change was detected using steady-state absorption spectroscopy due to its very fast thermal Z-to-*E* isomerization, and transient absorption measurements turned to be necessary to evidence the photoisomerization (see below). In contrast, compound **11** exhibits considerable absorption variations related to *E*-to-Z photoswitching upon visible light irradiation, with an isosbestic point at 358 nm (Figure 2).

During the *E*-to-Z reaction, the *π*-*π*\* band decreases in intensity and is blue-shifted by 14 nm, while the *n*-*π*\* band becomes slightly less intense. To get more quantitative information, we monitored the *E*-11-to-Z-11 and the reverse Z-to-*E* photoisomerizations in DMSO-d₆ combining UV–vis absorption and NMR spectroscopy (Figures 2A and B). Under irradiation at 405 nm, close to the absorption maximum, the pure *E*-11 form switches to the Z-11 isomer, reaching a photostationary state (PSS) with a Z/E ratio as high as 73:27. Other PSS were obtained at longer wavelengths, showing, for instance, a Z/E ratio of 52:48 under irradiation in the *n*-*π*\* band

<table><caption>Table 1. Absorption maxima (λ<sub>max</sub>) of the π-π* and n-π* bands, molar absorption coefficient at λ<sub>max</sub> (ε) and half-life (t<sub>1/2</sub>) at room temperature in DMSO solution.</caption><thead><tr><th>Comp.</th><th>R<sub>3</sub></th><th>R<sub>4</sub></th><th>λ<sub>max</sub><br>π-π*<br>[nm]</th><th>ε<br>[M<sup>-1</sup> cm<sup>-1</sup>]</th><th>t<sub>1/2</sub> [ms]</th><th>Comp.</th><th>R<sub>3</sub></th><th>R<sub>4</sub></th><th>λ<sub>max</sub><br>π-π*<br>[nm]</th><th>ε<br>λ<sub>max</sub><br>n-π*<br>[nm]</th><th>t<sub>1/2</sub> [h]</th></tr></thead><tbody><tr><td>1</td><td>Me</td><td>CH<sub>2</sub>CH<sub>2</sub>OH</td><td>431</td><td>20320</td><td>1.2</td><td>7</td><td>Me</td><td>CH<sub>2</sub>CH<sub>2</sub>OH</td><td>419</td><td>485</td><td>18460</td><td>5.3</td></tr><tr><td>2</td><td>Et</td><td>CH<sub>2</sub>CH<sub>2</sub>OH</td><td>434</td><td>19150</td><td>1.9</td><td>8</td><td>Et</td><td>CH<sub>2</sub>CH<sub>2</sub>OH</td><td>420</td><td>481</td><td>20800</td><td>5.5</td></tr><tr><td>3</td><td>Me</td><td>CH<sub>2</sub>CH<sub>2</sub>Ph</td><td>430</td><td>21700</td><td>nd</td><td>9</td><td>Me</td><td>CH<sub>2</sub>CH<sub>2</sub>Ph</td><td>418</td><td>484</td><td>19050</td><td>7.3</td></tr><tr><td>4</td><td>CH<sub>2</sub>CH=CH<sub>2</sub></td><td>CH<sub>2</sub>CH=CH<sub>2</sub></td><td>417</td><td>21200</td><td>nd</td><td>10</td><td>CH<sub>2</sub>CH=CH<sub>2</sub></td><td>CH<sub>2</sub>CH=CH<sub>2</sub></td><td>414</td><td>483</td><td>18500</td><td>6.9</td></tr><tr><td>5</td><td>CH<sub>2</sub>CH<sub>2</sub>OCH<sub>2</sub>CH<sub>2</sub></td><td></td><td>414</td><td>18600</td><td>9.3</td><td>11</td><td>CH<sub>2</sub>CH<sub>2</sub>OCH<sub>2</sub>CH<sub>2</sub></td><td>CH<sub>2</sub>CH<sub>2</sub>OCH<sub>2</sub>CH<sub>2</sub></td><td>403</td><td>488</td><td>17000</td><td>12.4</td></tr><tr><td>6</td><td>CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub></td><td></td><td>434</td><td>18600</td><td>nd</td><td>12</td><td>CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub></td><td>CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub>CH<sub>2</sub></td><td>421</td><td>483</td><td>18200</td><td>5.5</td></tr></tbody><tfoot><tr><td colspan="13">nd = not determined</td></tr></tfoot></table>

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>
<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /><figcaption>Figure 1. UV-vis absorption spectra of E-5 and E-11 in DMSO</figcaption></figure>

<figure><img src="image_14.png" /><figcaption>Figure 2. (a) Photoisomerisation reaction and photoconversion yield of 11 in DMSO-d₆; (b) PSS determination (Z:E ratio) at different irradiation wavelengths in DMSO (c = 3.06.10⁻⁵ M); (c) Fatigue resistance of 11 after 50 cycles of alternate irradiations at 406 nm (120 s; P₄₀₆ = 35.47 mW cm⁻²) and 340 nm (180 s; P₃₄₀ = 14.12 mW cm⁻²) in degassed DMSO.</figcaption></figure>

at 575 nm. The values for the other PSS are reported in Figure 2B, demonstrating the possibility to tune the Z/E ratio as well as to control the reaction forward or backward. Indeed, after irradiation at 405 nm, the azobenzene Z-11 underwent reverse isomerization to E-11 at 340 nm or 485 nm, resulting in a Z/E ratio of 17:83 or 33:67, respectively. The quantum yield of the E-11-to-Z-11 photoisomerization reaction was determined to be 0.23 under 405 nm irradiation, whereas the value corresponding to the Z-11-to-E-11 reverse reaction under 340 nm light was found to be almost twice higher (0.51). Moreover, the azobenzene 11 demonstrated high fatigue resistance under alternating visible (405 nm) and UV (340 nm) irradiations in DMSO. Almost no photodegradation was observed after 50 successive irradiations cycles (Figure 2C). The thermal reversion of Z-11→E-11 was monitored at room temperature in the dark by recording the UV-vis absorption spectra. The half-life time of the Z-11 isomer was estimated to be 10.1 hours (608 min) at room temperature in DMSO, based on a numerical fit (Figure 3A).

After that, the kinetics of the thermal Z-to-E isomerization process for compound 5 was studied by means of nanosecond laser flash photolysis (pump at 430 nm and probe at 414 nm). A

<figure><img src="image_15.png" /><figcaption>Figure 3. (a) Absorption spectra of 11 during the thermal Z-to-E reversion after irradiation at 405 nm, and determination of the t₁/₂ of Z-11 in DMSO at room temperature from the absorbance at 403 nm. (b) Absorption change under nanosecond laser flash photolysis (pump at 430 nm and probe at 414 nm) and determination of the t₁/₂ of Z-5 in DMSO at room temperature from nanosecond laser flash photolysis (pump at 430 nm and probe at 414 nm).</figcaption></figure>

numerical fit estimated the half-life of the Z-5 isomer to be 9 ms in DMSO at room temperature (Figure 3B). The same order of half-lives has also been observed for compounds 1 and 2 (t₁/₂ = 1.2 ms and 1.9 ms respectively, Table 1). Compared to the tetra-o-chloroazobenzene M (t₁/₂ = 8.1 min, Scheme 1), the introduction of a strong electron-withdrawing nitro group accelerated the kinetics of the thermal return by ~5×10⁴ times. However, the reduction of the nitro group to an amine function led to the Z-11 isomer, which is ~4×10⁶ times more thermostable than the corresponding Z-5.

## X-ray Crystallography and Computational Studies

The compound E-5 has been also characterized by X-ray crystallography. ORTEP (Oak Ridge Thermal Ellipsoid Plot) view is displayed in Figure 4 with selected bond distances and

<figure><img src="image_16.png" /><figcaption>Figure 4. ORTEP drawings for compound E-5. Selected bond lengths (Å) and angles (deg): N1–N2 = 1.241; N1–C1 = 1.420; C1–C2 = 1.405; N2–C7 = 1.412; C7–C8 = 1.406; N1–N2–C7 = 115.33; N2–C7–C8 = 128.37; N2–N1–C1 = 115.38; N1–C1–C6 = 127.49. $\Phi_1$ = C6–C1–N1–N2 = 34.6°; $\Phi_2$ = C8–C7–N2–N1 = 34.0°; $\Psi$ = C1–N1–N2–C7 = 178.9°.</figcaption></figure>
<figure><img src="image_17.png" /></figure>

angles. The asymmetric unit of the centrosymmetric triclinic crystal contains two molecules of E-5 with minor variations in their conformations (four in total, see SI). For instance, the N–N bond distance measures 1.227 Å in the first conformer and 1.241 Å in the second one, Φ₁, Φ₂, and Ψ dihedral angles are 22.2°, 23.9°, 179.2° and 34.6°, 34.0°, 178.9°, respectively. This means that, for both conformers, the two phenyl rings lie in almost parallel planes, although the steric bulk of the ortho-chlorine atoms twists the two aryl rings of E-5 out of the C–N=N–C plane. This is to be compared to the unsubstituted parent azobenzene in which the N–N bond distance measures 1.249 Å, the Φ dihedral angles are 9.7°, and the Ψ dihedral angle 180.0°.[7e] However, the distortion between the two phenyl rings is much less prominent in E-5 than in the tetrachlorinated parent azobenzene (E-A) in which the Φ₁ and Φ₂ have very different values (respectively 35.2° and 79.7°) for one of the conformers. [7e]

To shed more light on the experimental results and to correlate molecular structure and spectral properties, we performed theoretical calculations on E-5 and E-11. Geometry optimization was performed by DFT calculations from X-ray crystallography data as a starting point for the atom coordinates (for E-5). Contrary to the X-ray data geometry, the optimization shows that the E-5 adopts a twisted geometry, where the two aromatic rings belong to different planes, in accordance with an important difference between the dihedral angles Φ₁ and Φ₂ (55.2° and 22.4°). Distortion around the N–N bond slightly increases, and Ψ takes the value of 176.0° after optimization. Such difference between the crystal structure and the optimized structure stems from multiple intermolecular close contacts in crystals, which maintain the E-5 molecules in a layered structure, with an interplanar distance of 3.444 Å (see SI). The E-11 adopts a similar computational geometry, with Φ dihedral angles of 35.6° and 38.0°, and the Ψ dihedral angle of 175.9°. The computational geometry is more in accordance with the E-A structure, which is more twisted.[7e] Previous studies from literature on symmetrical tetra-o-chloroazobenzenes (e.g. A) show that these angles, especially Φ, can significantly affect the n→π* transition energy (more than the π→π*).[7e] Then, TD-DFT calculations were performed to determine the transition energies with either B3LYP or CAM–B3LYP functional using an implicit IEF-PCM solvent model for DMSO, according to the push-pull or push-pull character of the molecules. The position of the first transition was compared to the maximum of the first experimental absorption band. For the charge-transfer molecule E-5, with the CAM–B3LYP functional, the first vertical transition has a weak oscillator strength (471 nm, f=0.1373), followed by a more intense transition (348 nm, f=0.998). The B3LYP functional gives less consistent results with two first weak bands. Natural Transition Orbitals (NTO) were computed with CAM–B3LYP and it was revealed that the hole is located on a non-bonding orbital (n-type) for the first transition and on a π-type orbital for the second transition, while the electron is located on a π*-type orbital for both, which is respectively consistent with the n→π* and π→π* nature of these transitions. For the push-pull compound E-11, the functional B3LYP gives a better simulation of the UV-vis absorption spectrum than

CAM–B3LYP, with an intense transition at 390 nm (f=0.6611) and a moderately intense band at 529 nm (f=0.2789) akin to experimental spectrum. Again, the NTO analysis confirms that the first transition is n→π* type and the second transition is a π→π*. The calculations demonstrate both a longer wavelength gap between these transitions, and a higher n→π* vs π→π* oscillator strength ratio for 11 compared to 5. This provides a rationale for the difference in shapes of the absorption spectra.

## Conclusions

In summary, a series of push-pull tetra-o-chloroazobenzenes have been efficiently synthesized in two steps, incorporating dialkyl amine and nitro groups as strong electron-donating and electron-withdrawing moieties, in para-position of the azobenzene core. These original push-pull tetra-o-chloroazobenzenes exhibit reversible photoisomerization upon visible light irradiation and demonstrate rapid thermal Z-to-E isomerization in DMSO, occurring in less than 10 milliseconds. Moreover, the push-pull architecture enables facile conversion to push-push systems via a simple reduction step. The tunability of the Z-isomers half-life from milliseconds to several hours enhances their versatility. Furthermore, the extended tail corresponding to the n-π* band provides the possibility of exciting and tuning the E-Z photoisomerisation with longer wavelengths light. These derivatives exhibit excellent photoswitching capabilities under visible light illumination. These results are interesting for the versatile design of tetra-o-chloroazobenzene derivatives with strong push-pull systems, characterized by extremely short half-life, making them suitable for brain investigations.[12] They can also be easily converted into push-push systems for other applications requiring metastable photoswitches. The amino-functionalized tetra-o-chloroazobenzenes could be readily incorporated into biomolecules to modulate their bioactivity through full visible light photoswitching.

## Experimental Section

### General Information

Reagent-grade chemicals were obtained from diverse commercial suppliers and used as received. Anhydrous solvents were dried and purified using alumina columns. Reactions were monitored by thin-layer chromatography on Merck silica gel plates (60 F254 aluminum sheets). All separations were carried out under flash-chromatographic conditions on silica gel (Redi Sep Bronze or Gold prepacked column, 230–400 mesh) at medium pressure (20 psi) with use of a CombiFlash Companion Rf or NextGen 300+. Melting point (m.p) were determined using a Kofler bench. ¹H NMR (400 MHz) and ¹³C NMR (101 MHz) spectra were recorded on JEOL JMS ECS 400 MHz spectrometer at 298 K unless otherwise stated. Absorption spectra and experiments realized under light irradiations were performed in spectroscopic grade dimethylsulfoxide (Carlo Erba Reagents from DASIT Group). UV-vis absorption spectra were recorded on Cary 100 or Cary 5000 spectrophotometer from Agilent Technologies. High-resolution mass spectra (HRMS) were performed on a Bruker maXis mass spectrometer by the SALSA platform from ICOA laboratory.
<figure><img src="image_18.png" /></figure>

**General procedure I (GP-I) for azobenzenes synthesis by azo-coupling reaction:** 2,6-Dichloro-4-nitroaniline (1.2 eq.) was dissolved in acetic acid (0.37 M) and cooled using an ice bath (~5 °C). Then, 0.1 mL of sulfuric acid was added, followed by the addition of sodium nitrite (1.4 eq.) in water solution (2.3 M). After 30 min of stirring in the ice bath (~5 °C), this solution was then transferred in a dropping funnel and added dropwise to ice cooled solution of substrates **S1–S6** (1 eq.) dissolved in acetone (0.82 M). After the addition was complete, the cooling was removed and the resulting reaction mixture was stirred at room temperature for 3 hrs. Then, the mixture was quenched with a saturated NaHCO₃ aqueous solution and extracted with ethyl acetate thrice. The combined organic layer was dried over MgSO₄ and the organic solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to give the desired product.

**Azobenzene 1:** Starting from 2,6-dichloro-4-nitroaniline (197 mg, 0.95 mmol, 1.2 eq.) and 3,5-dichloro-*N*-methyl-*N*-phenethylaniline **S1** (175 mg, 0.80 mmol, 1.0 eq.) and following the **GP-I**, compound **1** was obtained as a dark red solid (175 mg, 50% yield). R<sub>f</sub> = 0.16 (30% AcOEt in petroleum ether); m.p.: 162 ± 2 °C; ¹H NMR (400 MHz, CDCl<sub>3</sub>) δ 8.22 (s, 2H), 6.73 (s, 2H), 3.84 (t, J = 5.7 Hz, 2H), 3.56 (t, J = 5.5 Hz, 2H), 3.09 (s, 3H); ¹³C NMR (CDCl<sub>3</sub>, 101 MHz) δ 153.6 (C), 151.4 (C), 145.8 (C), 135.1 (C), 133.6 (C), 127.9 (C), 124.5 (CH), 112.7 (CH), 60.3 (CH<sub>2</sub>), 54.34 (CH<sub>2</sub>), 39.5 (CH<sub>3</sub>); UV/vis (DMSO): λ<sub>max</sub> (ε) = 431 nm (20320 M<sup>-1</sup> cm<sup>-1</sup>); HRMS (ESI) calcd. for C<sub>15</sub>H<sub>13</sub>Cl<sub>4</sub>N<sub>4</sub>O<sub>3</sub> [M + H]<sup>+</sup>: 438.9708, found: 438.9706.

**Azobenzene 2:** Starting from 2,6-dichloro-4-nitroaniline (106 mg, 0.51 mmol, 1.2 eq.) and 2-(3,5-dichlorophenyl)(ethyl)amino)ethan-1-ol **S2** (100 mg, 0.43 mmol, 1.0 eq.) and following the **GP-I**, compound **2** was obtained as a dark red solid (111 mg, 57% yield). R<sub>f</sub> = 0.20 (30% AcOEt in Petroleum Ether); m.p.: 143 ± 2 °C; ¹H NMR (400 MHz, CDCl<sub>3</sub>) δ 8.28 (s, 2H), 6.76 (s, 2H), 3.90 (t, J = 5.8 Hz, 2H), 3.58 (t, J = 5.8 Hz, 2H), 3.53 (q, J = 7.0 Hz, 2H), 1.26 (t, J = 7.0 Hz, 3H); ¹³C NMR (CDCl<sub>3</sub>, 101 MHz) δ 153.6 (C), 150.4 (C), 145.7 (C), 134.9 (C), 133.9 (C), 127.9 (C), 124.5 (CH), 112.5 (CH), 60.2 (CH<sub>2</sub>), 52.3 (CH<sub>2</sub>), 46.2 (CH<sub>2</sub>), 12.1 (CH<sub>3</sub>); UV/vis (DMSO): λ<sub>max</sub> (ε) = 434 nm (19150 M<sup>-1</sup> cm<sup>-1</sup>); HRMS (ESI) calcd. for C<sub>16</sub>H<sub>15</sub>Cl<sub>4</sub>N<sub>4</sub>O<sub>3</sub> [M + H]<sup>+</sup>: 452.9865, found: 452.9866.

**Azobenzene 3:** Starting from 2,6-dichloro-4-nitroaniline (49 mg, 0.24 mmol, 1.2 eq.) and 3,5-dichloro-*N*-methyl-*N*-phenethylaniline **S3** (55 mg, 0.20 mmol, 1.0 eq.) and following the **GP-I**, compound **3** was obtained as a dark red solid (96 mg, 98% yield). R<sub>f</sub> = 0.22 (5% AcOEt in petroleum ether); m.p.: 144 ± 2 °C; ¹H NMR (400 MHz, CDCl<sub>3</sub>) δ 8.30 (s, 2H), 7.37–7.31 (m, 2H), 7.29–7.24 (m, 1H), 7.22–7.17 (m, 2H) 6.71 (s, 2H), 3.68 (t, J = 7.2 Hz, 2H), 2.94 (t, J = 7.2 Hz, 2H), 2.93 (s, 3H); ¹³C NMR (101 MHz, CDCl<sub>3</sub>, 101 MHz) δ 153.7 (C), 150.7 (C), 145.7 (C), 138.4 (C), 134.8 (C), 133.8 (C), 129.0 (CH), 128.9 (CH), 127.9 (C), 127.0 (CH), 125.4 (CH), 124.5 (CH), 112.4 (CH), 54.6 (CH<sub>2</sub>), 39.3 (CH<sub>3</sub>), 33.5 (CH<sub>2</sub>); UV/vis (DMSO): λ<sub>max</sub> (ε) = 430 nm (21700 M<sup>-1</sup> cm<sup>-1</sup>); HRMS (ESI) calcd. for C<sub>21</sub>H<sub>17</sub>Cl<sub>4</sub>N<sub>4</sub>O<sub>2</sub> [M + H]<sup>+</sup>: 499.0073, found: 499.0069.

**Azobenzene 4:** Starting from 2,6-dichloro-4-nitroaniline (99 mg, 0.48 mmol, 1.2 eq.) and N,*N*-diallyl-3,5-dichloroaniline **S4** (97 mg, 0.40 mmol, 1.0 eq.) and following the **GP-I**, compound **4** was obtained as a dark red solid (126 mg, 68% yield). R<sub>f</sub> = 0.32 (5% AcOEt in petroleum ether); m.p.: 123 ± 2 °C; ¹H NMR (CDCl<sub>3</sub>, 400 MHz) δ 8.28 (s, 2H), 6.74 (s, 2H), 5.92–5.78 (m, 2H), 5.28 (dd, J = 10.7, 1.0 Hz, 2H), 5.20 (dd, J = 17.0, 1.0 Hz, 2H), 4.07–3.95 (m, 4H); ¹³C NMR (CDCl<sub>3</sub>, 101 MHz) δ 153.7 (C), 150.9 (C), 145.8 (C), 135.3 (C), 133.6 (C), 131.4 (C), 127.7 (C), 124.5 (CH), 117.5 (CH<sub>2</sub>), 112.9 (CH), 53.0 (CH<sub>2</sub>); UV/vis (DMSO): λ<sub>max</sub> (ε) = 417 nm (21200 M<sup>-1</sup> cm<sup>-1</sup>); HRMS (ESI) calcd. for C<sub>18</sub>H<sub>15</sub>Cl<sub>4</sub>N<sub>4</sub>O<sub>2</sub> [M + H]<sup>+</sup>: 460.9916, found: 460.9921.

**Azobenzene 5:** Starting from 2,6-dichloro-4-nitroaniline (75 mg, 0.36 mmol, 1.2 eq.) and 4-(3,5-dichlorophenyl)morpholine **S5** (70 mg, 0.3 mmol, 1.0 eq.) and following the **GP-I**, compound **5** was obtained as a dark red solid (56 mg, 41% yield). R<sub>f</sub> = 0.42 (20% AcOEt in petroleum ether); m.p.: 252 ± 2 °C; ¹H NMR (CDCl<sub>3</sub>, 400 MHz) δ 8.30 (s, 2H), 6.92 (s, 2H), 3.93–3.81 (m, 4H), 3.43–3.31 (m, 4H); ¹³C NMR (CDCl<sub>3</sub>, 101 MHz) δ 153.3 (C), 152.2 (C), 145.9 (C), 136.8 (C), 132.8 (C), 127.6 (C), 124.4 (CH), 114.4 (CH), 66.2 (CH<sub>2</sub>), 47.0 (CH<sub>2</sub>); UV/vis (DMSO): λ<sub>max</sub> (ε) = 414 nm (18600 M<sup>-1</sup> cm<sup>-1</sup>); HRMS (ESI) calcd. for C<sub>16</sub>H<sub>13</sub>Cl<sub>4</sub>N<sub>4</sub>O<sub>3</sub> [M + H]<sup>+</sup>: 450.9708, found: 450.9715.

**Azobenzene 6:** Starting from 2,6-dichloro-4-nitroaniline (267 mg, 1.29 mmol, 1.2 eq.) and 1-(3,5-dichlorophenyl)pyrrolidine **S6** (231 mg, 1.07 mmol, 1.0 eq.) and following the **GP-I**, compound **6** was obtained as a dark red solid (381 mg, 88% yield). R<sub>f</sub> = 0.22 (5% AcOEt in petroleum ether); m.p.: 224 ± 2 °C; ¹H NMR (CDCl<sub>3</sub>, 400 MHz) δ 8.28 (s, 2H), 6.62 (s, 2H), 3.46–3.37 (m, 4H), 2.14–2.04 (m, 4H); ¹³C NMR (CDCl<sub>3</sub>, 101 MHz) δ 153.7 (C), 149.5 (C), 145.6 (C), 134.5 (C), 133.9 (C), 128.0 (C), 124.5 (CH), 112.7 (CH), 48.1 (CH<sub>2</sub>), 25.5 (CH<sub>2</sub>); UV/vis (DMSO): λ<sub>max</sub> (ε) = 434 nm (18600 M<sup>-1</sup> cm<sup>-1</sup>); HRMS (ESI) calcd. for C<sub>16</sub>H<sub>13</sub>Cl<sub>4</sub>N<sub>4</sub>O<sub>2</sub> [M + H]<sup>+</sup>: 434.9759, found: 434.9761.

For substrates **S1–S6**, synthetic procedures and physical data are given in the supporting information.

**General procedure II (GP-II) for azobenzenes reduction; Azobenzene derivative 1–6 (1.0 eq.) was dissolved in a mixture of THF:H<sub>2</sub>O 3:1 (0.08 M). Then, Na<sub>2</sub>S (3.0 equiv) was added. The reaction mixture was then stirred at reflux for around 3 hrs. After completion of the reaction, the reaction mixture was cooled to room temperature and the THF was removed under reduced pressure. The remaining water was diluted with EtOAc and 1 M NaOH. The organic phases were washed with 1 M NaOH aqueous solution, aqueous sat. NaHCO₃ and brine. The organic phases were dried over MgSO₄, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (eluent DCM) to give the desired product.

**Azobenzene 7:** Starting from azobenzene **1** (50 mg, 0.11 mmol, 1.0 eq.) and sodium sulfide (26 mg, 0.33 mmol, 2.0 eq.) and following the **GP-II**, compound **7** was obtained as a dark red solid (22 mg, 49% yield). R<sub>f</sub> = 0.27 (50% AcOEt in petroleum ether); m.p.: 179 ± 2 °C; ¹H NMR (400 MHz, acetone-d<sub>6</sub>) δ 6.86 (s, 2H), 6.63 (s, 2H), 5.65 (br s, 2H), 3.98 (t, J = 5.4 Hz, 1H), 3.81 (q, J = 5.4 Hz, 2H), 3.62 (t, J = 5.4 Hz, 2H), 3.14 (s, 3H); ¹³C NMR (101 MHz, acetone-d<sub>6</sub>) δ 151.1 (C), 137.8 (C), 136.6 (C), 131.3 (C), 130.9 (C), 115.2 (CH), 113.1 (CH), 60.1 (CH<sub>2</sub>), 55.3 (CH<sub>2</sub>), 39.4 (CH<sub>3</sub>); UV/vis (DMSO): λ<sub>max</sub> (ε) = 419 nm (18460 M<sup>-1</sup> cm<sup>-1</sup>), 485 nm; HRMS (ESI) calcd. for C<sub>15</sub>H<sub>15</sub>Cl<sub>4</sub>N<sub>4</sub>O [M + H]<sup>+</sup>: 408.9966, found: 408.9968.

**Azobenzene 8:** Starting from azobenzene **2** (100 mg, 0.22 mmol, 1.0 eq.) and sodium sulfide (52 mg, 0.66 mmol, 3.0 eq.) and following the **GP-II**, compound **8** was obtained as a dark red solid (36 mg, 39% yield). R<sub>f</sub> = 0.31 (50% AcOEt in petroleum ether); m.p.: 185 ± 2 °C; ¹H NMR (400 MHz, acetone-d<sub>6</sub>) δ 6.86 (s, 2H), 6.83 (s, 2H), 5.63 (br s, 2H), 4.00 (t, J = 5.8 Hz, 1H), 3.80 (t, J = 5.8 Hz, 2H), 3.62–3.53 (m, 4H), 1.23 (t, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, acetone-d<sub>6</sub>) δ 151.0 (C), 149.9 (C), 137.8 (C), 136.6 (C), 131.5 (C), 130.8 (C), 115.1 (CH), 112.9 (CH), 60.1 (CH<sub>2</sub>), 53.3 (CH<sub>2</sub>), 46.2 (CH<sub>2</sub>), 12.2 (CH<sub>3</sub>); UV/vis (DMSO): λ<sub>max</sub> (ε) = 420 nm (20800 M<sup>-1</sup> cm<sup>-1</sup>), 481 nm; HRMS (ESI) calcd. for C<sub>16</sub>H<sub>17</sub>Cl<sub>4</sub>N<sub>4</sub>O [M + H]<sup>+</sup>: 423.0123, found: 423.0120.

**Azobenzene 9:** Starting from azobenzene **3** (96 mg, 0.19 mmol, 1.0 eq.) and sodium sulfide (45 mg, 0.58 mmol, 3.0 eq.) and following the **GP-II**, compound **9** was obtained as a dark red solid (43 mg, 48% yield). R<sub>f</sub> = 0.24 (20% AcOEt in petroleum ether); m.p.: 132 ± 2 °C; ¹H NMR (400 MHz, CDCl<sub>3</sub>) δ 7.32 (t, J = 7.7 Hz, 2H), 7.24 (t, J = 7.7 Hz, 2H), 7.19 (d, J = 7.7 Hz, 2H), 6.71 (s, 2H), 6.68 (s, 2H), 3.95 (br s, 2H), 3.61 (t, J = 7.7 Hz, 2H), 2.89 (t, J = 7.7 Hz, 2H), 2.87 (s, 2H);
$^{13}$C NMR (101 MHz, CDCl$_{3}$) δ 149.1 (C), 147.2 (C), 139.2 (C), 138.8 (C), 136.2 (C), 131.3 (C), 130.0 (C), 128.92 (CH), 128.87 (CH), 126.8 (CH), 54.5 (CH$_{2}$), 39.0 (CH$_{3}$), 33.3 (CH$_{2}$); UV/vis (DMSO): λ$_{max}$ (ε) = 418 nm (19050 M$^{-1}$ cm$^{-1}$), 484 nm; HRMS (ESI) calcd. for C$_{21}$H$_{19}$Cl$_{4}$N$_{4}$ [M + H]$^{+}$ : 469.0331, found: 469.0336.

**Azobenzene 10:** Starting from azobenzene 4 (97 mg, 0.22 mmol, 1.0 eq.) and sodium sulfide (51 mg, 0.65 mmol, 3.0 eq.) and following the **GP-II**, compound 10 was obtained as a dark red solid (40 mg, 43% yield). R<sub>f</sub> = 0.29 (20% AcOEt in petroleum ether); m.p.: 102 ± 2 °C, ¹H NMR (400 MHz, CDCl<sub>3</sub>) δ 6.69 (s, 2H), 6.68 (s, 2H) 5.89–5.74 (m, 2H), 5.283 (dd, *J* = 10.5, 1.5 Hz, 2H), 5.17 (dd, *J* = 17.2, 1.5 Hz, 2H), 4.03–3.88 (m, 6H); <sup>13</sup>C NMR (101 MHz, CDCl<sub>3</sub>) δ 149.2 (C), 147.2 (C), 139.2 (C), 136.6 (C), 132.1 (CH), 131.03 (C), 131.02 (C), 117.0 (CH<sub>2</sub>), 115.3 (CH), 112.9 (CH), 52.8 (CH<sub>2</sub>); UV/vis (DMSO): λ<sub>max</sub>(ε) = 414 nm (18500 M<sup>-1</sup> cm<sup>-1</sup>), 483 nm; HRMS (ESI) calcd. for C<sub>18</sub>H<sub>17</sub>Cl<sub>4</sub>N<sub>4</sub> [M + H]<sup>+</sup>: 431.0174, found: 431.0168.

**Azobenzene 11:** Starting from azobenzene 5 (86 mg, 0.19 mmol, 1.0 eq.) and sodium sulfide (45 mg, 0.572 mmol, 3.0 eq.) and following the **GP-II**, compound 11 was obtained as a dark red solid (24 mg, 30% yield). R<sub>f</sub> = 0.12 (20% AcOEt in petroleum ether); m.p.: 209 ± 2 °C; ¹H NMR (CDCl<sub>3</sub>, 400 MHz) δ 6.90 (s, 2H), 6.72 (s, 2H), 4.02 (br s, 2H), 3.89–3.83 (m, 4H), 3.28–3.23 (m, 4H); <sup>13</sup>C NMR (CDCl<sub>3</sub>, 101 MHz) δ 151.0 (C), 147.7 (C), 139.2 (C), 138.8 (C), 130.6 (C), 130.2 (C), 115.3 (CH), 115.2 (CH), 66.6 (CH<sub>2</sub>), 47.9 (CH<sub>3</sub>); UV/vis (DMSO): λ<sub>max</sub> (ε) = 403 nm (17000 M<sup>-1</sup> cm<sup>-1</sup>), 488 nm; HRMS (ESI) calcd. for C<sub>16</sub>H<sub>15</sub>Cl<sub>4</sub>N<sub>4</sub>O [M + H]<sup>+</sup>: 420.9966, found: 420.9964.

**Azobenzene 12:** Starting from azobenzene 6 (80 mg, 0.18 mmol, 1.0 eq.) and sodium sulfide (43 mg, 0.55 mmol, 3.0 eq.) and following the **GP-II**, compound 12 was obtained as a dark red solid (25 mg, 34% yield). R<sub>f</sub> = 0.27 (20% AcOEt in petroleum ether); m.p.: 192 ± 2 °C; ¹H NMR (CDCl<sub>3</sub>, 300 MHz) δ 6.70 (s, 2H), 6.57 (s, 2H), 3.93 (br s, 2H), 3.38–3.30 (m, 4H), 2.08–2.00 (m, 4H); <sup>13</sup>C NMR (CDCl<sub>3</sub>, 101 MHz) δ 148.1 (C), 146.9 (C), 139.5 (C), 135.7 (C), 131.5 (C), 129.9 (C), 115.3 (CH), 112.3 (CH), 47.9 (CH<sub>2</sub>), 25.6 (CH<sub>3</sub>); UV/vis (DMSO): λ<sub>max</sub> (ε) = 421 nm (18200 M<sup>-1</sup> cm<sup>-1</sup>), 483 nm; HRMS (ESI) calcd. for C<sub>16</sub>H<sub>15</sub>Cl<sub>4</sub>N<sub>4</sub> [M + H]<sup>+</sup>: 405.0017, found: 405.008.

## Theoretical Calculations

From the obtained coordinates of crystallographic data, the geometry optimizations were realized by the DFT (Density Functional Theory) method using the B3LYP or CAMBLYP functional and the 6-311++G (d,p) basis set, as implemented in the Gaussian16 software package. The absence of imaginary frequencies was checked on all calculated structures to confirm they are true minima. Franck-Condon energy transitions were calculated by the time-dependent DFT formalism (TD-DFT) with the B3LYP or CAMBLYP functional and the 6-311++G (d,p) basis set. The solvent effect (DMSO) has been included using the IEF-PCM model. The simulated spectra were plotted using a broadening Gaussian of 0.33 eV (FWHM = 2685 cm<sup>-1</sup>).

## Supporting Information Summary

The authors have cited additional references within the Supporting Information.<sup>[13–17]</sup> Experimental details (including NMR spectra, X-ray structure determination, photochemical and photophysical characterisations and DFT, TD-DFT and NTO calculations) are given in the supporting information.

## Acknowledgements

The authors acknowledge the support of the French "Agence Nationale de la Recherche" (ANR) as part of the "Investissements d'Avenir" program (Labex NanoSaclay, reference: ANR-10-LABX-0035) and "PHOTOMIC" project (ANR-21-CE24-0027), and the Centre National de la Recherche Scientifique (CNRS). The authors would like to thank Cyril Colas from the "Fédération de Recherche" ICOA/CBM (FR2708) for HRMS analysis. This work was performed by using HPC resources from the "Mésocentre" computing center of Université Paris-Saclay, CentraleSupélec and École Normale Supérieure Paris-Saclay supported by the CNRS and the Région Ile-de-France (http://mesocentre.centrale-supelec.fr/).

## Conflict of Interests

The authors declare no conflict of interest.

## Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.

**Keywords:** Azobenzene · Push-pull · Push-push · Photoswitch · Thermostability

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Manuscript received: May 2, 2024

Version of record online: September 3, 2024