Synthesis of Pyridazine Derivatives by Suzuki-Miyaura Cross-Coupling Reaction and Evaluation of Their Optical and Electronic Properties through Experimental and Theoretical Studies

A series of π-conjugated molecules, based on pyridazine and thiophene heterocycles 3a–e, were synthesized using commercially, or readily available, coupling components, through a palladium catalyzed Suzuki-Miyaura cross-coupling reaction. The electron-deficient pyridazine heterocycle was functionalized by a thiophene electron-rich heterocycle at position six, and different (hetero)aromatic moieties (phenyl, thienyl, furanyl) were functionalized with electron acceptor groups at position three. Density Functional Theory (DFT) calculations were carried out to obtain information on the conformation, electronic structure, electron distribution, dipolar moment, and molecular nonlinear response of the synthesized push-pull pyridazine derivatives. Hyper-Rayleigh scattering in 1,4-dioxane solutions, using a fundamental wavelength of 1064 nm, was used to evaluate their second-order nonlinear optical properties. The thienylpyridazine functionalized with the cyano-phenyl moiety exhibited the largest first hyperpolarizability (β = 175 × 10−30 esu, using the T convention) indicating its potential as a second harmonic generation (SHG) chromophore.


Introduction
Few reactions have contributed to enhancing the efficiency of organic synthesis as much as the palladium-catalyzed cross-couplings. The reactions are used in research worldwide as well as in the commercial production of pharmaceuticals and a variety of molecules are utilized in the electronics industry, amongst other examples.
Among a diverse number of palladium-catalyzed cross couplings, the Suzuki-Miyaura cross-coupling reaction offers, at present, one of the most efficient ways to prepare π-conjugated heterocyclic systems through the formation of carbon-carbon bonds. Suzuki coupling is a versatile method of synthesis, possessing a large number of advantages. It employs readily available reagents (about 1800 compounds: Boronic acids, boronate esters, etc.) that are commercially available, it occurs under mild reaction conditions, it is largely unaffected by the presence of water, it tolerates a wide variety of functional groups, it generally proceeds regio-and stereoselectively, while the inorganic a 3-bromo-6-(thiophen-2-yl)pyridazine [51] derivative and several hetero(aromatic) boronic acids as coupling components. The new pyridazine NLOphores were functionalized with an electron-rich thiophene heterocycle as electron donor group/π-spacer, and a hetero(aryl) moiety functionalized with several groups with different electron ability. This research was conducted with the purpose of studying the relationship between their structure and second harmonic generation efficiency.
The low yields of compounds 3a-e might be explained by the possible homocoupling of the brominated thienylpyridazine precursor 2, or the competitive hydrolytic deboronation of the hetero(aryl) boronic acids, especially because the hetero(aryl)boronic acids bears electron-attracting groups [43,45]. Due to instability, the hydrolysis of the C-Br bond of the thienylpiridazine 2 could also occur, giving the precursor pyridazinone 1 [51]. The novel compounds were characterized by standard spectroscopic techniques.
Molecules 2018, 23, x 3 of 12 derivatives which were synthesized through palladium catalyzed Suzuki-Miyaura coupling, using a 3-bromo-6-(thiophen-2-yl)pyridazine [51] derivative and several hetero(aromatic) boronic acids as coupling components. The new pyridazine NLOphores were functionalized with an electron-rich thiophene heterocycle as electron donor group/π-spacer, and a hetero(aryl) moiety functionalized with several groups with different electron ability. This research was conducted with the purpose of studying the relationship between their structure and second harmonic generation efficiency.
The low yields of compounds 3a-e might be explained by the possible homocoupling of the brominated thienylpyridazine precursor 2, or the competitive hydrolytic deboronation of the hetero(aryl) boronic acids, especially because the hetero(aryl)boronic acids bears electron-attracting groups [43,45]. Due to instability, the hydrolysis of the C-Br bond of the thienylpiridazine 2 could also occur, giving the precursor pyridazinone 1 [51]. The novel compounds were characterized by standard spectroscopic techniques.

Study of the Optical (Linear and Nonlinear) Properties
The linear optical properties of thienylpyridazines 3a-e were studied in ethanol at room temperature (Table 1, Figure 1). All compounds exhibited a strong and broad absorption band with high molar extinction coefficients in the range of 24,100 to 29,800 M −1 ·cm −1 with maximum absorption peaks found between 314 and 357 nm. The variation of the maximum absorption wavelength amongst the thienylpyridazine derivatives depended on the electronic nature of the spacer and the electron withdrawing moieties, thus bathochromic shifts were found when substituting the phenyl ring for the furan (22 nm) or thiophene (25 nm) heterocycles due to the increase in the electron donating ability, and when substituting the nitro group in the meta position for the cyano (9 nm) or formyl (18 nm) groups in the para position. This was due to the electron withdrawing strength of these groups.
The fluorescence properties of thienylpyridazines 3a-e were studied by exciting the compounds at the wavelength of maximum absorption, at room temperature ( Table 1). All thienylpyridazines showed very weak emissive properties; with relatively low quantum yields in the range of 0.003 to 0.006. Given that the molar extinction coefficients are all greater than 24,000 M −1 ·cm −1 , indicating that the transitions have reasonable oscillator strength, the low quantum yields are likely to be an indication of strong quenching, perhaps induced by hydrogen bonding of the solvent with the nitrogen atoms [68]. However, the molar extinction coefficients of compounds 3d and 3e were identical whether dissolved in ethanol (Table 1) or 1,2-dioxane (Table 2). Furthermore, any strong excited state quenching is unlikely to affect greatly the second order nonlinear response of these molecules, which is produced dominantly by virtual transitions, at least in the absence of any multiphoton absorption. The linear optical properties of thienylpyridazines 3a-e were studied in ethanol at room temperature (Table 1, Figure 1). All compounds exhibited a strong and broad absorption band with high molar extinction coefficients in the range of 24,100 to 29,800 M −1 ·cm −1 with maximum absorption peaks found between 314 and 357 nm. The variation of the maximum absorption wavelength amongst the thienylpyridazine derivatives depended on the electronic nature of the spacer and the electron withdrawing moieties, thus bathochromic shifts were found when substituting the phenyl ring for the furan (22 nm) or thiophene (25 nm) heterocycles due to the increase in the electron donating ability, and when substituting the nitro group in the meta position for the cyano (9 nm) or formyl (18 nm) groups in the para position. This was due to the electron withdrawing strength of these groups.
The fluorescence properties of thienylpyridazines 3a-e were studied by exciting the compounds at the wavelength of maximum absorption, at room temperature ( Table 1). All thienylpyridazines showed very weak emissive properties; with relatively low quantum yields in the range of 0.003 to 0.006. Given that the molar extinction coefficients are all greater than 24,000 M −1 ·cm −1 , indicating that the transitions have reasonable oscillator strength, the low quantum yields are likely to be an indication of strong quenching, perhaps induced by hydrogen bonding of the solvent with the nitrogen atoms [68]. However, the molar extinction coefficients of compounds 3d and 3e were identical whether dissolved in ethanol (Table 1) or 1,2-dioxane (Table 2). Furthermore, any strong excited state quenching is unlikely to affect greatly the second order nonlinear response of these molecules, which is produced dominantly by virtual transitions, at least in the absence of any multiphoton absorption. The hyper-Rayleigh scattering (HRS) technique was used to determine the first hyperpolarizabilities β of thienylpyridazines 3a-e, at a fundamental wavelength of 1064 nm [69,70]. The hyperpolarizabilty β values were measured against a reference solution of p-nitroaniline (pNA), using 1,4-dioxane as a solvent [71,72]. Proper care was taken to account for possible fluorescence of the thienylpyridazines 3a-e [73].
The static hyperpolarizabilty β0 values [74][75][76] for the thienylpyridazines 3a-e showed the same trend as the measured values, however these values are only indicative and should be treated with discretion, as they were calculated using a simple two-level model neglecting damping.
The data in Table 2 show an enhancement of the SHG response with an increase of the auxiliary electron donating ability of the spacer upon changing the phenyl ring (β = 54 × 10 −30 esu for 3c) with furan heterocycle (β = 100 × 10 −30 esu for 3b), and then for a thiophene moiety (β = 155 × 10 −30 esu for 3a). For compound 3e, with the nitro group at the meta position, it was not possible to quantify the SHG signal due to interference resulting from competing fluorescence from multiphoton absorption. The highest measured hyperpolarizability value was achieved by thienylpyridazine 3d having a phenyl ring substituted at position four with a cyano group (β = 175 × 10 −30 esu). The hyper-Rayleigh scattering (HRS) technique was used to determine the first hyperpolarizabilities β of thienylpyridazines 3a-e, at a fundamental wavelength of 1064 nm [69,70]. The hyperpolarizabilty β values were measured against a reference solution of p-nitroaniline (pNA), using 1,4-dioxane as a solvent [71,72]. Proper care was taken to account for possible fluorescence of the thienylpyridazines 3a-e [73]. The static hyperpolarizabilty β 0 values [74][75][76] for the thienylpyridazines 3a-e showed the same trend as the measured values, however these values are only indicative and should be treated with discretion, as they were calculated using a simple two-level model neglecting damping.
The data in Table 2 show an enhancement of the SHG response with an increase of the auxiliary electron donating ability of the spacer upon changing the phenyl ring (β = 54 × 10 −30 esu for 3c) with furan heterocycle (β = 100 × 10 −30 esu for 3b), and then for a thiophene moiety (β = 155 × 10 −30 esu for 3a). For compound 3e, with the nitro group at the meta position, it was not possible to quantify the SHG signal due to interference resulting from competing fluorescence from multiphoton absorption. The highest measured hyperpolarizability value was achieved by thienylpyridazine 3d having a phenyl ring substituted at position four with a cyano group (β = 175 × 10 −30 esu).

Theoretical Calculations
Density functional theory (DFT) calculations were performed to understand the structural differences and the variation of the electronic properties of these thienylpyridazines, and to establish a comparative computational basis for this series. The dipole moments and hyperpolarizabilities β were calculated for thienylpyridazines 3a-e, as well as the energy levels and the respective electron density maps that were computed in a polarized solvent continuum of 1,4-dioxane. The results are shown in Table 3 and Figure 2.

Materials and Methods
Phosphorous (V) oxybromide and boronic acids were procured from Aldrich, Acros Organics, and Fluka. All commercial reagents and solvents were used without further purification. The progress of the reaction was checked by means of thin layer chromatography on 0.25 mm thick precoated silica plates (Merck Fertigplatten Kieselgel 60 F254); and the spots were visualized using UV light. Silica gel column chromatography (Merck Kieselgel, 230 to 400 mesh) was used in the purification of the compounds. NMR spectra were performed on a BruckerG Avance II 400 (working frequency of 400 MHz for 1 H and 100.6 MHz for 13 C), and the solvent peak was used as internal Each thienylpyridazine derivative can exist as several different conformers, depending on the relative arrangement of their components. We present the lowest energy forms, which are responsible for the calculated properties. Coplanarity was observed between the three rings in molecules 3a and 3b, while the replacement of a substituted thiophene by a functionalized phenyl ring reduced the planarization of the conjugated system in molecules 3c-e.
The maps of frontier orbitals showed diffuse and overlapping highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) densities, the HOMO density slightly more concentrated on the thiophene donor group and the LUMO density slightly more concentrated on the (hetero)aromatic acceptor moiety, except in chromophore 3e. In 3e the LUMO was essentially localized on the meta-nitrophenyl acceptor group. No significant correlation was observed between HOMO-LUMO gaps and maxima of absorption spectra.
The estimated dipole moments for the five molecules range between 4.3 and 8.9 Debye (in 1,4-dioxane), and exhibit a higher correlation with the experimentally determined hyperpolarizabilities than the calculated hyperpolarizabilities. However, the moderate experimental β values are in good agreement with their calculated small values.

Materials and Methods
Phosphorous (V) oxybromide and boronic acids were procured from Sigma Aldrich Chemie, Steinheim, Germany and Acros Organics, Geel, Belgium. Other commercial reagents (NaCl, NaOH, quinine sulfate, ammonia, MgSO 4 , Na 2 CO 3 , Pd(PPh 3 ) 4 ), and solvents (dimethoxyethane, ethanol, dichloromethane, chloroform, n-hexane, dioxane, light petroleum (40-60 • C), acetone-d 6 ) were obtained from Panreac Quimica S.L.U., Barcelona, Spain) and were used without further purification. The progress of the reaction was checked by means of thin layer chromatography on 0.25 mm thick precoated silica plates (Merck Fertigplatten Kieselgel 60 F254; Merck, Darmstadt, Germany); and the spots were visualized using UV light. Silica gel column chromatography (Merck Kieselgel, 230 to 400 mesh; Merck, Darmstadt, Germany) was used in the purification of the compounds. NMR spectra were performed on a BruckerG Avance II 400 (Bruker Daltonics, Bremen, Germany), working frequency of 400 MHz for 1 H and 100.6 MHz for 13 C, and the solvent peak was used as internal reference. The solvents are specified in parenthesis before the chemical shifts values (δ relative to tetramethylsilane (TMS)-tetramethylsilane). Peak assignments were obtained by comparison of chemical shifts, peak multiplicities, and J values, and were sustained by spin decoupling-double resonance and bidimensional heteronuclear HMBC (Heteronuclear Multiple Bond Correlation) and HMQC (Heteronuclear Multiple-Quantum Correlation) techniques. Infrared spectra were obtained on a BOMEM MB 104 spectrophotometer (BOMEM, Québec, QC, Canada). UV-vis absorption spectra were recorded with a Shimadzu UV/2501PC spectrophotometer (Shimadzu Coorporation, China). Fluorescence spectra were obtained with a FluoroMax-4 spectrofluorometer (Horiba Jobin Yvon, Edison, New Jersey, USA). Luminescence quantum yields were obtained in comparison with a solution of quinine sulfate in 0.05 M H 2 SO 4 as standard and corrected for the refraction index of the solvents [66,67]. Melting points were determined on a Gallenkamp machine (Gallenkamp, UK). Mass spectrometry analyses were performed at the C.A.C.T.I.-Unidad de Espectrometria de Masas of the University of Vigo, Spain (Bruker Daltonics, Bremen, Germany).

Procedure for the Synthesis of Thienylpyridazine Precursor 2
A mixture of 6-(thiophen-2-yl)pyridazin-3(2H)-one 1 (2.8 mmol, 0.5 g) and POBr 3 (5.5 mmol, 1.6 g) was heated for 6 h at 110 to 120 • C. The mixture was cooled till room temperature and then poured onto ice-water, basified with a solution of ammonia (2 M), and stirred for 30 min to give a brown solid. The suspension was filtered and the solid washed with water and light petroleum to give the pure thienylpyridazine 2 as brown solid (76%). 1

General procedure for the Synthesis of Thienylpyridazines 3a-e through Suzuki-Miyaura Cross Coupling
3-Bromo-6-(thiophen-2-yl)pyridazine 2 (0.5 mmol) was coupled with the appropriate (hetero)aromatic boronic acids (0.6 mmol) in a mixture of DME (8 mL), ethanol (2 mL), aqueous 2 M Na 2 CO 3 (1 mL), and Pd(PPh 3 ) 4 (5 mol %) at 80 • C, under nitrogen. The reaction time (48 h) was determined by thin layer chromatography (TLC). The reaction mixture was extracted, after cooling, with chloroform (3 × 20 mL) followed by extraction with a saturated solution of NaCl (20 mL). After the separation of the phases, the organic layer was washed with water (3 × 10 mL) and with a solution of NaOH (10%) (10 mL). The organic phase obtained was dried (MgSO 4 ), filtered, and the solvent removed, giving a crude mixture which was purified using silica gel column chromatography and mixtures of dichloromethane in light petroleum (40-60 • C) of increasing polarity. Evaporation of the solvent gave the coupled products as solids that were recrystallized from dichloromethane/hexane giving the pure pyridazines 3a-e.

Nonlinear Optical Measurements
Hyper-Rayleigh scattering (HRS) was used to measure the orientationally averaged first hyperpolarizability β of the push-pull chromophores 3a-e. The experimental set-up for HRS measurements is identical to that described in detail in reference [73].
Following reference [72] we have chosen to report our values using the so-called T (Taylor expansion) convention. Taking into account the most recent hyper-Rayleigh scattering measurement from CCl 4 signal which was used as a reference [77], the corrected reference value for the first hyperpolarizatibity tensor element β 333 of pNA in dioxane at 1064 nm is 40 × 10 −30 esu. The standard two-level model, that ignores damping, was used to estimate the magnitude of the static first-order hyperpolarizability β 0 [74][75][76]. Given the model's simplicity, these extrapolated values should be viewed with caution.

Theoretical Calculations
All theoretical calculations were performed in Gaussian 09 (Gaussian, Inc., Wallingford CT, USA, 2010) [78]. The geometry of individually molecule was optimized by the density functional theory (DFT) at the B3LYP level by employing the 6-311G** basis set and using polarizable continuum model using dioxane as the solvent. [keyword: SCRF = (PCM, Solvent = 1,4-Dioxane)]. Frequency calculations were achieved in order to ensure the absence of negative frequencies. Hyperpolarizability factors were estimated at the same level of theory using an incident wavelength of 1064 nm (keywords: freq = raman, cphf = rdfreq, polar) and with a polarized solvent continuum model using dioxane as the solvent.

Conclusions
A series of novel thienylpyridazines were prepared through palladium catalyzed Suzuki-Miyaura cross-coupling in low yields due to the possibility of competitive secondary reactions. The new molecules were functionalized with different electron acceptor groups, and the structures were confirmed by standard spectroscopic techniques.
All compounds exhibited strong and broad absorption bands that showed bathochromic shifts with the increase of the electron donating and electron accepting abilities of the donor/π-bridge and the electron-withdrawing group, respectively. All thienylpyridazines showed very weak emissive properties.
The potential of the synthesized thienylpyridazines as second harmonic generators was evaluated by hyper-Rayleigh scattering showing an enhancement of the hyperpolarizability β with the increase of the auxiliary electron donating ability of the donor group/π-spacer, with highest measured hyperpolarizability value being achieved by the thienylpyridazine functionalized with 4-cyanophenyl group (β = 175 × 10 −30 esu).
DFT calculations were also carried out, showing coplanarity between the thienylpyridazine part of the molecule with the formyl-thiophene or furan end-cap, reduced planarization with the phenyl-based substituents, and generally diffuse and overlapping HOMO and LUMO densities. The estimated dipole moments for the five molecules range between 4.3 and 8.9 Debye (in 1,4-dioxane), and exhibit a higher correlation with the experimentally determined hyperpolarizabilities than the calculated hyperpolarizabilities.