The synthesis of symmetrical peripheral and non-peripheral octa-substituted metal-free phthalocyanines: simpler, better, faster, cheaper

Phthalocyanines are important not only as industrial pigments, but also in photodynamic cancer therapy, catalysis and various other fields. Despite the huge demand, synthetic routes to Pcs are tedious and the yields poor. In this paper, we report on modifications to the syntheses of symmetrical octa-substituted metal-free phthalocyanines (H 2 Pc). H 2 Pcs with peripheral or non-peripheral alkyl substituents were prepared in less steps and in higher yields than previously reported, whereas the yields of H 2 Pcs with alkoxy substituents (peripheral or non-peripheral) were improved considerably


Introduction
With applications in dyes, photodynamic cancer therapy, photochemical and photovoltaic cells, laser printing, optical communication and catalysis, 1 phthalocyanines (Pcs) are of considerable industrial importance. The Pc pigment market alone was valued at $1.4 billion in 2019. 2 The phthalocyanine skeleton (1) (Figure 1) is a tetraazatetrabenzoporphyrin (TABP) consisting of four isoindoline units linked by four meso nitrogen bridges. The resulting conjugated 18 π electron system, which can host more than 95 metals/metalloids in the central cavity, is responsible for the appealing photophysical, photochemical and electrochemical properties of Pcs. 3,4 Pcs are commonly modified by (i) substituents on the peripheral (β) and/or non-peripheral (α, bay) positions, (ii) by changing the central metal/metalloid or (iii) axial ligands (depending on the oxidation state of the metal and a preference for hexa-coordination over tetracoordination). Substituents not only have an effect on π-stacking and thus aggregation and solubility, but also on the electronic properties of the Pc. Metal-free Pcs (H2Pc) may be obtained from the corresponding phthalonitrile (1,2-dicyanobenzene) 4 (2) by alkali-induced cyclotetramerization according to the Tomada method, 5 reductive cyclotetramerization at elevated temperatures (>180 °C), 6 template cyclotetramerization with metal alkoxides according to the Linstead method and displacement of the metal cation by acidification, 4 or treatment with ammonia and subsequent cyclotetramerization of the 1,3-diiminoisoindoline. 7 However, despite being critical to numerous industries, synthetic routes to Pcs are elaborate and time-consuming, and the yields are often poor (vide infra). In this paper, we thus report on improvements to the syntheses of octa-substituted metal-free phthalocyanines (H2Pcs). H2Pcs with alkyl substituents in the peripheral or non-peripheral positions could be prepared in less steps and in higher yields than previously reported, whereas the yields of H2Pcs with alkoxy substituents (peripheral or non-peripheral) could be improved considerably.

Results and Discussion
We started our investigations with improvements to the synthesis of 3,6-and 4,5-disubstituted phthalonitriles with alkyl, alkoxy and aryloxy substituents. Reagents and conditions: 3, K2CO3, KI and RX in solvent were kept at the temperature as indicated.

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By disrupting the aromaticity of thiophene through oxidation of the sulphur atom, it may function as a diene in Diels-Alder reactions. 36 The Diels-Alder reaction of thiophene 1,1-dioxide (24) with fumaronitrile is very sluggish, though. 23,28,30,31 A theoretical study by Jursic 36 indicated the HOMO energy of thiophene 1-oxide to be higher than that of thiophene 1,1-dioxide, thus confirming it to be more electron-rich than the latter. In this regard, Thiemann and co-workers 37-39 reported a one-pot oxidation-cycloaddition procedure wherein BF3.OEt2 by coordinating to the S-monoxide oxygen and decreasing the nucleophilicity of the sulphur atom, prevents over-oxidation to the dioxide in the presence of meta-chloroperbenzoic acid (mCPBA). 37,39 The Lewis acid may, in addition, decrease the energy of the dienophile LUMO. 37 By applying this concept in a novel oxidation -Diels-Alder reaction of substituted thiophene (23) with fumaronitrile, the crude 2,3-dicyano-1,4-dihexyl-7thiabicyclo[2.2.1]hept-5-ene S-oxide (26) could be obtained within 1 hour (as opposed to days reported for the S-dioxide method). The intermediate substituted S-oxide (26) could furthermore be converted into the desired 1,4-dialkylphthalonitrile (21) within an hour via a microwave irradiation process (Scheme 3c).
Cyclotetramerization to H2Pc. The Linstead method 40 for the tetramerization of phthalonitriles by lithium alkoxides, which dates back to 1934, is still commonly used. 4,34,35 Modifications of this method increased the yield of H2Pc octasubstituted in the non-peripheral position with octyloxy substituents from 8 to 47% yield, for example. Following the procedure reported by McKeown and co-workers, 26.27 3,6-dioctyloxyphthalonitrile (4a) was exposed to lithium metal in pentan-1-ol at reflux for 2 hours to afford the desired H2Pc (27a), after treatment with acetic acid to exchange the lithium ions with hydrogens, in low yield (ca. 8%) ( Table 3, entry 1). As only two equivalents of base are required according to the commonly accepted mechanism for tetramerization, 41-43 the Li equivalents were reduced to 2.5. This resulted in the desired octaoctyloxy Pc (27a), which were accompanied by Pcs where some of the octyloxy groups were substituted by pentoxy groups, to be obtained in 34% yield after 3 hours (Table 3, entry 2). The next logical choice was to form the lithium alkoxide prior to the introduction of the phthalonitrile, which afforded the desired H2Pc (27a) in 47% yield (Table 3, entry 3). The optimized method was extended to the preparation of non-peripherally octasubstituted H2Pc with pentoxy (27b) and butoxy substituents (27c), as well hexyl substituents (27d), in 56, 64 and 34% yield, respectively.  Similarly, peripherally octa-substituted H2Pc with hexyl (28a), pentoxy (28b) and 2,4-t-butylphenoxy substituents (27c) could be obtained in yields of 37, 57 and 38%, respectively (Table 4).

Experimental Section
General. NMR-spectroscopy was performed on a Bruker AM 600 FT-spectrometer at 293 K (unless specified to the contrary) with either CDCl3 (deuterochloroform), (CD3)2CO (deuterated acetone) or C6D6 (deuterobenzene) as solvent. Chemical shifts are reported in parts per million (ppm) with the solvent peak at 7.26 ppm for CDCl3, 2.05 ppm for (CD3)2CO or 7.16 ppm for C6D6 in 1

Standardization of BuLi and Grignard reagents
Triphenylmethane or 2,2'-bypiridine (8-10 mg) was dissolved in dry 1,4-dioxane (4 mL). A double-burette titration was performed with BuLi or Grignard and dry 1-pentanol (0.05 mL). The endpoint of the titration was presented with a colour change from colourless to red or orange. All titrations were performed in triplicate. and octyl bromide (1.2 mL, 6.9 mmol, 3.0 eq.) in dry DMF (25 mL) was kept at 80 °C overnight. The reaction mixture was allowed to cool to ambient temperature prior to acidification with 3 M HCl (1 L/100 mL DMF
The reaction mixture was cooled to room temperature, diluted with dry THF (180 mL) and cooled to -20 °C. Hexyl bromide (32 mL, 228.0 mmol, 3.0 eq.) was added dropwise over 5 min. and the reaction mixture allowed to reach room temperature. After stirring for 1 hour, the reaction mixture was transferred to ice water (500 mL) and extracted with Et2O (  The organic phase was washed with H2O (2 x 100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude product and o-toluic acid (spatula tip) was dissolved in DCE (7 mL) and the solution exposed to microwave irradiation (60 power cycles). Recrystallization (EtOH) afforded 3,6-dihexylphthalonitrile (21a) as white needles (0.46 g, 39%): mp 38-40 °C (lit. 26  Preparation of metal-free phthalocyanines Standard cyclotetramerization procedure Lithium metal (3 eq.) was added to 1-alcohol (4 mL/mmol) and the solution heated to 140 °C until no solid lithium could be observed. Appropriately substituted solid phthalonitrile was added and heating continued for another 4 h. The reaction mixture was then cooled to ambient temperature and transferred to acetic acid (40 mL/mmol). All solvent was removed in vacuo and the crude product dissolved in DCM. The solution was washed with 3M HCl (20 mL/mmol), H2O (20 mL/mmol), saturated aqueous NaHCO3 (2 x 20 mL/mmol) and brine (20 mL/mmol). The organic phase was dried over Na2SO4 and evaporated to dryness. 3 mmol, 2.9 eq.) was added to 1-pentanol (5 mL) and the solution heated to 140 °C until no solid lithium could be observed. 3,6-Dipentoxyphthalonitrile (4b) (0.45 g, 1.5 mmol) was added and heating continued for another 45 min. The reaction mixture was then cooled to ambient temperature and transferred to acetic acid (160 mL). All solvent was removed in vacuo and the crude product dissolved in DCM. The solution was washed with 3M HCl (160 mL), H2O (160 mL), saturated aqueous NaHCO3 (160 mL) and brine (160 mL). The organic phase was dried over Na2SO4 and evaporated to dryness. 2,3,9,10,16,17,23,24-Octapentoxyphthalocyanine (28b). Lithium metal (0.10 g, 14.28 mmol, 10 eq.) was added to 1-pentanol (15 mL) and the solution heated to 140 °C until no solid lithium could be observed. 4,5-Dipentoxyphthalonitrile (6c) (1.52 g, 1.26 mmol) was added and heating continued for 8 h. The reaction mixture was then cooled to ambient temperature and transferred to acetic acid (40 mL). All solvent was removed in vacuo and the crude product dissolved in DCM. The solution was washed with 3M HCl (40 mL), H2O (40 mL), saturated aqueous NaHCO3 (40 mL) and brine (40 mL). The organic phase was dried over Na2SO4 and evaporated to dryness. Trituration (