2,4-Bis(arylethynyl)-9-chloro-5,6,7,8-tetrahydroacridines: synthesis and photophysical properties

Acridine derivatives have attracted considerable interest in numerous areas owing to their attractive physical and chemical properties. Herein, starting from readily available anthranilic acid, an efficient synthesis of 2,4-bis(arylethynyl)-9-chloro-5,6,7,8-tetrahydroacridine derivatives was accomplished via a one-pot double Sonogashira cross-coupling method. The UV-visible absorption and emission properties of the synthesized molecules have been examined. Additionally, theoretical studies based on density functional theory (DFT/B3LYP/6-31G(d)) were carried out.

Tetrahydroacridine, containing a partially hydrogenated ring, is another privileged scaffold which showed interesting biological activities [48][49][50][51][52][53][54]. As a typical example, 9-amino-1,2,3,4tetrahydroacridine or tacrine was the first drug approved for the treatment of Alzheimer's disease [55][56][57]. Surprisingly, photophysical properties of tetrahydroacridines have, to the best of our knowledge, not been studied so far. Recently, our research group reported the synthesis of a large variety of acridine derivatives which showed promising fluorescence properties and high quantum yields [58][59][60]. In continuation of our previous studies and as a part of our interest in discovering new organic materials applications [61][62][63], we herein report the synthesis of new 2,4-bis(arylethynyl)-9-chloro-5,6,7,8-tetrahydroacridine derivatives. The investigation of their photophysical properties and theoretical DFT studies were achieved aiming to understand the influence of substituents at introduced arylethynyl groups.
Tetrahydroacridine 2 represents a novel synthetic building block for Pd catalysis. With this precursor in hand, we intended to expand the π-conjugation by introducing two arylethynyl groups by Sonogashira reactions [66][67][68][69]. For the optimization, we studied the reaction of 2 with phenylacetylene (3a) and we obtained the desired product 4a in up to 72% as best yield using 0.6 mol % of tetrakis(triphenylphosphine)palladium(0) and 1.2 mol % of copper iodide (Scheme 2, Table 1). Scheme 2: Synthesis of 2,4-bis(arylethynyl)-9-chloro-5,6,7,8-tetrahydroacridines 4a-g. The reaction proceeded chemoselectively at the two carbon-bromine bonds giving 2,4-bis(phenylethynyl)-9-chloro-5,6,7,8-tetrahydroacridine (4a). This result was not entirely predictable, as the chlorine atom is located at the more reactive electron-poor pyridine moiety of the heterocyclic core structure. In fact, the chlorine position proved to be quite unreactive and all attempts to isolate 2,4,9-tris(phenylethynyl)-5,6,7,8-tetrahydroacridine failed even after using an excess of phenylacetylene and prolonging the reaction time. In order to study the regioselectivity of the reaction, a series of experiments were carried out with decreasing amounts of phenylacetylene. Although we used one equivalent of phenylacetylene, we were not able to isolate the mono coupling product.
Concerning the catalyst performance, Pd(PPh 3 ) 4 was found to be a suitable catalyst. In contrast, PdCl 2 (PPh 3)2 was slightly less effective and gave lower yields. The replacement of dioxane by toluene or DMF did not lead to any significant improvement of the yields ( The best result for the Sonogashira coupling reaction between intermediate 2 and phenylacetylene (3a) was obtained using 0.6 mol % of Pd(PPh 3 ) 4 , 1.2 mol % of CuI in DIPEA at 80 °C for three hours. With the optimized conditions in hand, we examined the scope of the coupling reaction of 2 with different phenylacetylenes 3b-g. As shown in Table 2, tetrahydroacridine derivatives 4a-g were obtained in moderate to good yields. The yields were better for acetylenes containing electron-donating substituents. For example, arylacetylene 3g, bearing a methoxy group, gave the best chemical yield of 93%. However, in case of the electron-attracting trifluoromethyl group (3e), we obtained a somewhat lower, but still good yield of 75%.

Photophysical properties
As a prominent blue fluorescence was observed for the prepared tetrahydroacridine derivatives, their photophysical properties were investigated. Absorption and emission spectra were measured at room temperature in diluted dichloromethane solu- tion and are depicted in Figure 2 and Figure 3. All spectroscopic data, including the maximum of absorption and emission, fluorescence quantum yield, stokes shift, onset of the absorption wavelengths and optical band gap are summarized in Table 3. Aiming to understand the impact of substituents at arylethynyl groups, spectra of diversely substituted tetrahydroacridines were compared with unsubstituted derivative 4a taken as reference. The UV-vis absorption was measured in a spectral rang of 300 nm to 600 nm. The optical absorption spectra of all compounds spread over the UV range and showed wide absorption bands. These bands are assigned to a π→π* electronic transitions of the quinoline core and its two arylethynyl groups. As shown in Figure 2, the unsubstituted derivative 4a exhibited wide bands with two maxima at 346 and 365 nm. A methyl group at the ortho position have a minor impact and derivative 4b showed similar optical transitions with a slight red shift. While, derivatives 4e and 4f bearing an electron-deficient fluoro or trifluoromethyl group show a hyperchromic shift of their bands located between 340 and 380 nm. In case of the electron-donating methoxy substituent (4g), a bathochromic shift was observed. Besides, a new band appeared at 321 nm which may be attributed to intermolecular charge transfer between the oxygen lone pair electrons and the quinoline core. The unsubstituted derivative 4a presents an onset of absorption (λ onset ) at 389 nm and its optical band gap was deduced to be around 3.18 eV. Tetrahydroacridines 4e and 4f showed approximately the same optical band gaps. However, the optical band gaps of 4b and 4g are lower (3.05 eV and 2.98 eV, respectively).  [71].  Emission spectra of synthesized tetrahydroacridine derivatives were measured in dichloromethane solutions under UV-laser excitation of 325 nm. The emission spectrum of compound 4a presents a profile with two transitions located at 386 and 400 nm. Methyl-substituted derivative 4b gave a slight red shift of 10 nm as compared to 4a. In contrast, fluorine and trifluoromethyl-substituted derivatives 4e and 4f show nearly the same emission. However, derivative 4g containing an electron-donating methoxy substituent exhibits a larger red shift of around 40 nm. Based on the absorption and emission spectra, the prepared tetrahydroacridine derivatives possess stokes shifts (wavenumber) ranging from 2400 to 4300 cm −1 . Their fluorescence quantum yields range from 0.1 to 0.2 as measured according to a relative method using quinine sulfate [70]. Tetrahydroacridine derivative 4g containing an electron-donating methoxy substituent gave the highest fluorescence intensity as shown in Figure 3 and a quantum yield of 20%.

DFT studies
The arylethynyl substituents showed an impact on the absorption and emission. In order to elucidate these experimental observations, quantum chemical calculations based on density functional theory (DFT) methodology were performed. The estimated visualization of highest occupied and lowest unoccupied molecular orbitals, as well as the molecular electrostatic potential (MEP) of prepared products are given in Table 4.
For phenylethynyl-substituted product 4a, the blue colored surface, located mainly at the cyclohexane ring, visualizes the electron deficiency. While the red region, localized essentially at the nitrogen atom and its closer ethynyl group, show the electron abundance. Due to their low donating effect, the methyl group in product 4b induce an addition of yellow regions into the external phenyl rings. However, the electron-deficient fluorine atom in derivative 4e results in a decrease of the electron density of the tetrahydroacridine core and the external phenyl rings. For product 4f, the high electron-deficient effect of the trifluoromethyl groups induces the appearance of blue surfaces around the tetrahydroacridine core, the ethynyl groups and the external phenyl rings, indicating a significant decrease of their electronic densities. However, a yellow-red region is added to the electrostatic map of compound 4g, due to the positive mesomeric effect of the π-donating methoxy substituent. Accordingly, we conclude that substituents at the introduced arylethynyl groups can communicate electronically with the central tetrahydroacridine core via the ethynyl group. Consequently, they influence the electronic situation of the prepared tetrahydroacridines and are expected to change their structural proprieties. Hence, some structural parameters including gap (E g ), ionization potential (IP), electron affinity (EA) and dipole moments (µ) were deduced on the ground state from the optimized chemical structure of obtained molecules ( Table 5).
The calculated permanent dipole moments µ (D) have considerably increased values for 4f and 4g, which show significant changes in their experimental emission properties. The presence of six fluorine atoms induces a large polarity difference. In fact, derivative 4f shows the highest dipole moment of 4.276 D as compared to 4a (0.698 D). As shown in Table 5, the ionization potential (IP) and electron affinity (EA) of tetrahydroacridines are almost identical. In addition, E HOMO and E LUMO do not change notably and the calculated E g values vary only slightly from 3.26 to 3.55 eV. Although, the HOMO energy level of 4g with −5.055 eV is higher than −5.887 eV of 4e, both compounds have close band gap values of 3.36 eV and 3.53 eV, respectively.

Conclusion
In summary, we have reported a facile synthesis of 2,4bis(arylethynyl)-9-chloro-5,6,7,8-tetrahydroacridine derivatives via a double Sonogashira cross-coupling method. The arylethynyl groups expand the π-conjugation of the tetrahydroacridine core. The substituents located at the aryl group influenced the photophysical properties of the prepared molecules. In particular, the methoxy derivative shows promising fluorescence properties.

Experimental Materials and measurements
All reactions were carried out under an inert argon atmosphere. Anhydrous solvents and chemicals were purchased from Sigma-Aldrich and used without further purification. All reactions were monitored by thin-layer chromatography (TLC) using commercial silica-gel plate 60 coated with a fluorescence indicator and the visualization was performed by UV (254 nm). Organic compounds were purified using Merck Silica gel 60 (0.043-0.06 mm). Solvents for work-up and column chromatography were distilled before use.
NMR data were recorded on Bruker ARX 300 instruments in CDCl 3 with tetramethylsilane as the internal standard (signals due to the solvent; CHCl 3 : δ 7.26 for 1 H and δ 77.16 for 13 C). The 1 H NMR chemical shifts and coupling constants were determined assuming first-order behavior. Peak characterization of 1 H NMR spectra: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. Chemical shifts were given in ppm (δ) relative to tetramethylsilane (SiMe 4 ). Photophysical studies were carried out in freshly prepared dichloromethane solutions with concentrations of 1 × 10 −5 M. UV-vis spectra were recorded on a Shimadzu 2401 PC spectrophotometer in quartz cuvettes with a path length of 1 cm. Emission spectra were recorded on a Perkin-Elmer LS50B spectrofluorimeter.

Theoretical calculations
Theoretical studies were realized in vacuum with Gaussian 09 program [72]. The geometry of the equilibrium conformer at ground state was first found at AM1 level. Then, further optimizations through density functional theory (DFT) approach [73] at the restricted Becke3-Lee-Yang-Parr hybrid functional (B3LYP) with standard basis set 6-31G were carried out.