Synthesis of meso -tetraarylthienylporphyrins by Suzuki-Miyaura cross-coupling reaction and studying their UV-Vis absorption spectra

meso -Tetra(5-arylthien-2-yl)porphyrins and their copper complexes were synthesized by two different approaches using Suzuki-Miyaura cross-coupling reactions. The first , involving the formation of 5-arylthien-2-yl carbaldehydes


Introduction
Since the first synthesis of meso-tetraphenylporphyrin (TPP) as a parent and most popular derivative of mesotetraarylporphyrins (TAP) in 1935 by Rothemund 1 and improved by Adler and Longo in 1967 2 and modified by Lindsey 3 , there have been ongoing interests in exploring their physical and chemical characters in addition to their potential applications.TPPs have a robust and versatile platform which give a different opportunity for substitution on the central and the peripheral positions; consequently permits tailoring required for variety of applications.Some of these applications include biomedical and pharmaceutical tenders, multimodal imaging, drug delivery, bio-sensing, phototherapy, probe design for selective anti-body sensors, and electrocatalytic activities can be improved by tuning the substituents on the main scaffold. 4he popularity of meso-tetraphenyl porphyrins [TPP] arises from their well established and straightforward methods of preparation.On the other hand, porphyrins with heteroaryl rings at mesopositions are a relatively unexplored class of porphyrins, and their synthesis is scarcely reported in the literature.For example, only few porphyrins with heteroaryl moieties at the meso-positions like pyrrolyl 5 furyl, 6 azulenyl, 7 pyrazolyl, 8,9 imidazoyl [10][11][12] were reported.Additionally, since the first report for the synthesis of meso-tetra(thien-2-yl)porphyrin by Triebs et al. in 1968, 13 as an important member of this class of compounds which demonstrated to have unique physical and thermal characters, therefore, it has been used in a diverse range of applications.For example, porphyrins with meso-tetrathienyl moieties were used in the light-harvesting and energy-transfer applications, [14][15][16] in building of ultrathin films of quasi-2D porphyrin materials, 17 organic semiconductor devices, 18 extended electronic systems for supramolecular architectures, 19 incorporated into dithiaporphyrins scaffold for phototoxins applications 20 and recently, it was used as electrocatalyst for water splitting reaction as one of the promising renewable energy sources. 21enerally, there are two possible approaches for the synthesis of meso-tetrathienylporphyrin compounds can be found in the literature.The first starts by tailoring and preparing the starting materials (either the pyrrole or the thienyl aldehyde derivatives) followed by regular condensation and oxidation in acidic medium. 21,22While the second involves the synthesis of the parent meso-tetrathienyl porphyrins followed by chemical transformations at the peripheral position of both pyrrole and aryl ring systems. 23n continuation to our work in designing and preparation of porphyrins for electrochemical and medicinal applications 21 , we present in this report synthesis of novel meso-tetraarylthien-2-ylporphyrins and its copper complexes via two different approaches using Suzuki-Miyaura cross-coupling (SMC), measuring, and studying the insertion of different aryl groups on the UV-Vis absorption spectra as well the aggregation behaviour in solution (DCM) of the synthesized porphyrins.The chemical structure of all the prepared compounds was delineated by spectroscopic techniques (FT-IR, NMR, MS and UV-Vis.)

Results and Discussion
Suzuki-Miyaura cross-coupling (SMC) is one of the powerful approaches to build sp 2 -sp 2 carbon-carbon bonds. 24,25][28] The work in this study started with the search for a suitable palladium catalyst for (SMC) to prepare the 5arylthiophene-2-carboxaldehydes (Scheme 1), which are required as building blocks in the synthesis of porphyrin scaffold.At the beginning phosphine-palladium catalyst Pd(PPh 3 ) 4 was used, but unfortunately, the coupling of the bromoaldehyde (1) with the arylboronic acids produced the desired product (2) in inferior yield (≤ 10 %).In order to overcome this problem, and after performing literature survey to find an alternative palladium-based catalyst for the SMC reaction, bis(acetonitrile)dichloro palladium(II) [PdCl 2 (CH 3 CN) 2 ] was found to be the catalyst of choice for this transformation.It was prepared in almost quantitative yield by boiling palladium (II)chloride (PdCl 2 ) in acetonitrile for 20-24 hours in Argon atmosphere. 29Now, the reaction started by coupling the 5-bromo-2-thiophenecarboxldehyde (1) with different arylboronic acid derivatives [ArB(OH) 2 ] in the presence of the prepared palladium catalyst [PdCl 2 (CH 3 CN) 2 ], sodium carbonate in water/ethanol mixture (2:1) at 45-50 o C. The coupling reaction was completed in one hour (the reaction was monitored by TLC) to give the desired 5-arylthiophene-2-carboxaldehydes (2a-e) in good to excellent yield (Scheme 1, Table 1).It was noticed that in some cases, a by-product was detected in the reaction medium.This byproduct was isolated and identified as bi-aryl derivatives (Ar-Ar). 29,30This byproduct was likely produced from the coupling of two aryl boronic acid units under the reaction conditions.The amount of this side product was minimized and prevented to some extent by adjusting the water/ethanol ratio (2:1 was the ideal ratio).Therefore, the desired products were isolated and obtained in pure forms by column chromatography and finally by regular purification with crystallization process (2a-e, Scheme 1-Table 1).
Scheme 1. Synthesis of 5-arylthienyl-2-carbaldehyde (2a-e) using SMC reaction.The chemical structure of the synthesized 5-arylthieyl-2-carboxaldehydes (2a-e) was confirmed by spectroscopic techniques (FT-IR, 1 H-NMR, 13 C-NMR and MS).The 1 H-NMR spectra of aldehydes 2a-e revealed a down-field singlet at = 9.90, 9.91, 9.91, 9.96, and 9.90 ppm respectively attributed to the formyl hydrogen alongside with the other multiplets of the aromatic protons.Additionally, the 13 C-NMR spectra of the syntheisized aldehydes (2a-e) showed a very deshielded signal at a range of = 184.9-182.5 ppm indorsed to the aldehydic carbon at position two of the thiophene ring.Furthermore, the FT-IR spectra revealed a sharp signal at a range of wave number 1665-1660 cm -1 attributed to the aldehyde carbonyl.
We now turn to construct the porphyrin scaffold, which was achieved by two approaches.Firstly, by the direct condensation of pyrrole with the synthesized 5-aryl thiophene-2-carboxaldehydes (2a-e) by modifying the previously reported method. 31.The modification includes using triethylamine (H 2 O/TEA 95: 5 v/v) in the work-up stage beside p-toluene sulphonic acid (PTSA) as an acidic catalyst and dimethylformamide (DMF) as a solvent.The meso-tetraarylthien-2-ylporphyrins (3a-e, M = H) were obtained in 28-37 % yield (Scheme 2 Table 2).Subsequently, the complexation reaction of the synthesized free-base porphyrins (3a-e, M = H) with copper acetate was readily performed when excess copper acetate Cu(OAc) 2 was heated with the mesotetraaryl(thien-2-yl)porphyrins (3a-e, M = H) at 90-100 o C in DMF.The porphyrin copper complexes were obtained in a good yield (60-70 %) (Scheme 2).
In addition to the synthesis route mentioned above, another direct approach for the synthesis of porphyrins 3a-e was investigated.The main aim of this direct approach is to enhance the yield and to shorten the long process of the porphyrin purifications process.Therefore, we have studied the possibility of using the direct coupling of the aryl boronic acids with the tetrabromo derivative the meso-tetra (thien-2-yl) porphyrin under Suzuki-Miyaura coupling condensations (SMC).3][34] Therefore, the free-base of meso-tetra(5bromothien-2-yl)porphyrin (4, M = H, Scheme 3) was prepared following the literature procedure 21 ,and the reactivity toward coupling with the arylboronic acids under SMC reaction conditions was explored.
At the beginning, the aforementioned mild SMC reaction conditions with water/ethanol mixture as a solvent was used (Scheme 3, Route I).The meso-tetraarylthienyllporphyrin (3) was not detected in the reaction medium even after twelve hours of reflux (aliquots were taken from the reaction mixture to monitor it by UV-Vis absorption spectra via observing the change on the values of Soret and Q bands of the mesotetra(5-bromothien-2-yl)porphyrin (4, M = H, Scheme 3, Route I).
Nevertheless, when water/ethanol mixture was replaced by toluene/water (9:1, v/v) as a solvent and the reaction mixture was refluxed for twelve hours, a dark mixture was obtained, and only traces of the mesotetraarylthienyllporphyrin was isolated (3a was taken as an example) (Scheme 3, Route II).Presumably, a mixture of different SMC products on the peripheral bromine atoms was formed.Also, the involvement of the palladium catalyst in another complexation reaction with free-base porphyrins instead of catalyzing the coupling reaction cannot be rolled out. 25Therefore, the copper complex of the meso-tetra (5-bromothien-2yl)porphyrin (4, M= Cu) was prepared 21 and used as porphyrin substrate in the SMC reaction instead of the free-base porphyrin (4, M= H) (Scheme 3, Route III).Under these reaction conditions, the copper complexes of the meso-tetraarylthien-2-ylporphyrins (3a-e, M = Cu) were obtained in better yield (40-50 %) compared to the other approaches.(Scheme 3, Route III, Table 3).The chemical structure of meso-tetraarylthien-2-yl porphyrins and their copper complexes (3a-e) were confirmed by spectroscopic techniques (FT-IR, NMR, MS, and UV-Vis.) and by comparing the spectral data of the porphyrins obtained in both approaches.
The 1 H-NMR spectra of the free-base porphyrins (3a-e, M = H) revealed a singlet signal at a very up-field and appeared at about -2.52 ppm attributed to the characteristic inner protons of the porphyrin ring (2NH).Which were exchanged by deuterium after adding D 2 O to the NMR tube and the signal was completely disappeared in the 1 H-NMR spectra.(Figure 1). 1 H-NMR shows the spectrum of porphyrin 3a after and before adding D 2 O).This signal was disappeared and was not detected in the 1 H-NMR spectra of the copper complexes of the meso-tetraarylporphyyrins (3a-e, M = Cu).Furthermore, all the 1 H-NMR spectra of the The free-base mesotetra-(5-arylthien-2-yl)porphyrins and their copper complexes (3a-e, M = H, Cu) exhibited multiplets in the range 8-7 ppm accredited to the other aromatic protons of the thienyl and the substituted aryl rings.Additionally, a downfield signal over 9 ppm recognized to the beta hydrogens of the porphyrin ring system.
The FT-IR spectra, of the free-base porphyrins (3a-e), revealed peaks at the range 3415-3400 cm -1 which can be attributed to the in-phase stretching vibration mode of the inner N-H bonds.Also, all the investigated porphyrins showed a very weak peak at about 3110 and 1600 cm -1 attributed to the stretching vibration mode of the C-H and C=C bonds of the aromatic ring systems respectively.

Measuring and studying the UV-Vis absorption spectra
The free-base meso-tetra-(5-arylthien-2-ylporphyrins and their copper complexes (3a-e, M = H, Cu) are symmetrical porphyrins.Therefore their UV-Vis absorption spectra revealed a typical pattern for the characteristic Soret and Q bands for such ring system. 34The UV-Vis absorption spectra for the meso-tetrathien-2-ylporphyrins (3a-e) were measured and compared with the reported values in the literature of the meso-tetrathien-2-ylporphyrins (3, Ar & M = H) 35 and meso-tetra-(5-bromothien-2-yl)porphyrins (4, M = H & Cu) and all the data are extracted in Table 4.The UV-Vis spectra are depicted in figure-2 (porphyrin 3b and its copper complex was taken as an example, and data reported for other synthesized porphyrins are provided in the supporting information).It was previously reported that, the presence of the 2-thienyl groups on the meso-positions of the porphyrin moiety alleviated the saddled conformation of the co-planar shape of the porphyrinoid scaffold when compared with the phenyl group on the meso-tetraphenylporphyrin (TPP). 35While the UV-Vis absorption spectrum of TPP gave  soret = 417 nm, the meso-tetrathien-2-yl (3, Ar & M = H) bathochromically shifted to longer wavelength and appeared at 426 nm. 35,36This shift was initially explained in terms of inductive effects 34 .However, Gupta et al. attributed the shift to the significant pi-localization effect of the thien-2-ylporphyrins due to a stronger resonance interaction between the porphyrin moiety and the thienyl groups at the meso positions when compared with the phenyl group. 37,38The insertion of the aryl substituents (Ar) on position five of the thiophene ring on the peripheral meso-positions of the porphyrinoid ring systems in the free base meso-tetraarylporphyrins (3a-e) has affected the values of both Soret and Q-bands compared to the parent meso-tetrathien-2-ylporphyrins (3, Ar & M = H).While, the later porphyrin with no substituent on the thiophene ring was previously reported to give Soret band with  soret = 426 nm 36 , the insertion of the aryl ring systems (4-Me-Ph,-Ph, 2-naphthyl, 1-naphthyl, and 6-MeO-2-naphthyl) in 3a, 3b, 3c, 3d, and 3e respectively enhanced this value by range of 15-9 nm (Figure 2 &Table 3).Additionally, the observed bathochromic shift in the UV-Vis for meso-tetraaryl-2-thienylporphyrins (3a-e) compared to the parent mesotetrathien-2-ylporphyrin (3, Ar & M=H) can be explained based on increment of the degree of conjugation.The insertion of aryl chromophoresat the thienyl ring at the meso-positions of the porphyrin moiety in 3a-e (4-Me-Ph,-Ph, 2-naphthyl, 1-naphthyl, and 6-MeO-2-naphthyl) would be extended the thienyl pi-electron, which would in turn efficiently increase the p-p overlap between the thienyl ring and the core 18 th pi-electron system of the porphyrin scaffold.Hence, extending the effective size of the pi-electron system which in turn led to the noticed red shift in the UV-Viv spectra of the studied porphyrins (3a-e).

Aggregation Studies by UV/Vis Spectroscopy
0][41][42][43] To assess the aggregation behavior of the synthesized porphyrins (3a-e) in solution, we studied this phenomenon by UV/Vis analysis in dichloromethane.It was observed that, firstly no change on the  max of the studied porphyrins, secondly, a linear increment in the absorption versus the concentration at the study concentration range (15-50 µm).(Figures 3, for compound 3b, M = H as an example, similar behaviour were obtained for other porphyrins and data are provided in the supporting information).These results indicate that, no aggregation behavior for any of the studied porphyrins were observed at the study concentration range (15-50 µm).

Conclusions
meso-Tetra(5-arylthien-2-yl)porphyrins and their copper complexes (3a-e M= H & Cu) were synthesized by two different approaches using Suzuki-Miyaura cross-coupling reactions (SMC).Either by two-step via tailoring the 5-arylthien-2-yl carbaldehydes followed by condensation with pyrrole in dimethylformamide (DMF) as a solvent and p-toluene sulphonic acid (PTSA) as a catalyst or by one-step-direct coupling of the meso-tetra(5bromothien-2-yl)porphyrins with the arylboronic acids.The yield of the second approach (40-50 %) was relatively better than the second (28-35 %).The UV-Vis absorption spectra of the synthesized porphyrins revealed bathochromic shifts in both Soret and Q bands (up to 15 nm), compared to the parent porphyrin (3, Ar & M = H) , as a result of extension of the pi-electron system of the core porphyrin moiety after insertion of the aryl chromophores as peripheral substituents.Additionally, the synthesized porphyrins showed no aggregation behavior in the DCM solution and gave a linear correlation of the absorption versus the concentration at the study concentration range (10-50 µm).

Experimental Section
General.All the reagents and solvents were purchased from commercial suppliers and used directly without further purification.Melting points were measured using a capillary tube with SANYO Gallen-Kamp instrument.The ultraviolet-visible (UV-Vis) spectra were measured on GENESYS 10S UV-VIS spectrophotometer.Infrared spectroscopy (IR) spectra were recorded using an Agilent Technologies Cary 630 FTIR spectrometer.The NMR spectra were measured with BRUKER nuclear magnetic resonance 850 MHT spectrometer in CDCl 3 as a solvent, and the chemical shift was given in  \ (ppm).EI-MS spectra were recorded on SHIMADZU QP-2010 PULS spectrometer.Chromatographic separations were performed either using palates (15x20 cm) or columns with silica gel ( 200) and (400) mesh, respectively.All the reactions were monitored by TLC using Merck silica gel 60 PF 245 cards and the compound were visualised by UV lamp (245-365 nm).

Figure 1 .
Figure 1. 1 H-NMR spectrum of the free base porphyrin (3a) in CDCl 3 after and before adding D 2 O and the disappearance of the signal for exchangeable inner 2NH at about -2.52 ppm.