Introduction

Porphyrins are tetrapyrrolic macrocycles that perform essential processes in nature, such as oxygen transport in hemoglobin and photosynthesis . Porphyrins are often described as planar 18π aromatic macrocycles; however, molecular structure analysis frequently reveals nonplanar ring distortion . In fact, porphyrins with nonplanar ring distortions are vital for many natural processes to occur, e.g., nonplanarity can alter oxygen affinity of the metal iron core . Nonplanar porphyrins offer a marked difference in chemical and physical properties when compared to their planar compatriots , with relatively smaller HOMO–LUMO gaps resulting in an observed bathochromic shift in the UV–vis absorption spectrum . The phenomenon of nonplanarity results from the porphyrin ring deforming from the mean porphyrin plane either by steric repulsion in the core of the macrocycle or by bulky substituents at the porphyrin periphery . This affords four principle distortion modes, saddle, dome, ruffle or wave , which can be quantified by the normal-coordinate structural decomposition (NSD) method developed by Shelnutt and co-workers and further implemented and visualized by us . Of the four main quantifiable distortion modes, saddle-shaped porphyrins can be afforded by peri-interactions between β-substituents and the meso-substituents , or alternatively by core protonation, whereby all four-core nitrogen atoms are protonated to produce the diacid ; these diacids can tilt the pyrrole rings 20–40° from the mean-porphyrin plane. Norvaiša et al. showed that a saddle-shaped porphyrin as a dodecasubstituted diacid can bind anions via two independent faces and trap anions such as pyrophosphate . Saddle-shaped porphyrins have also been exploited by researchers for the use in organocatalysis as bifunctional system . Dodecasubstitution of porphyrin, as seen in Figure 1, often results in saddle-shaped distortion; however, ruffled and almost planar dodecasubstituted porphyrins have been reported.

Figure 1: (A) Structures of tetrasubstituted 5,10,15,20-tetraphenylporphyrin (TPP, 1), dodecasubstituted 2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetraphenylporphyrin (OETPP, 2), and octasubstituted 2,3,7,8,12,13,17,18-octaethylporphyrin (OEP, 3). (B) Aim of this work, the arm extension of the meso-phenyl position of dodecasubstituted porphyrins.

Despite the increasing interest in the chemical and physical properties of nonplanar porphyrins only limited synthetic methods are available for the functionalization of these macrocycles . An attractive approach to accomplish further substitution directly on the meso- or a meso-phenyl ortho/meta/para positions of a porphyrin, is the introduction of C–C bond forming chemistry. This is typically achieved using palladium and/or another transition-metal catalyst . Sonagashira , Suzuki–Miyaura , Heck , Stille , Negishi , and Kumada coupling reactions, as well as modern iridium and rhodium-based coupling techniques , are just some examples of the C–C bond formations that have been implemented to achieve complex substitution patterns and functional arrangements on porphyrins.

Of these named coupling reactions, Suzuki–Miyaura couplings are known to be a robust tool when functionalizing porphyrins . Many complex porphyrinoid architectures have been synthesized in this manner, from functional porphyrin arrays to sterically challenging meso-substituted aryl bis-pocket porphyrins and tetrabromoanthracenyl porphyrins . In general, the halogen atom needed for the Suzuki coupling reaction resides on the porphyrin; however, Suzuki–Miyaura reactivity has also been shown to be reversed whereby the synthesis of borolanylporphyrins leads to a different approach to reactivity . Borolanylporphyrins can be synthesized by Miyaura-borylation of the halogenated porphyrin . There are also reported instances of borolanylporphyrins being synthesized under condensation conditions . Despite the many synthetic advancements for the decoration of porphyrins, many of these strategies are utilized only with planar porphyrins. Apart from the arylation of the β-position of 2,3,5,7,8,10,12,13,15,17,18,20-dodecaarylporphyrins, developed by Smith and co-workers few reports on synthetic techniques for dodecasubstituted nonplanar porphyrins can be found in literature. In light of the promise of appropriately designed nonplanar porphyrins as receptors and catalysts we report here on our efforts to use the Suzuki–Miyaura reaction for the modification of the o,m,p-phenyl positions in 5,10,15,20-tetraryl-2,3,7,8,12,13,17,18-octaethylporphyrins.

Results and Discussion Investigation of the Suzuki coupling reaction at the meso-phenyl position of dodecasubstituted porphyrins Synthesis of porphyrin precursors

To investigate the Suzuki coupling at the ortho-, meta- and para-position of a dodecasubstituted saddle-shaped porphyrin, first the precursor porphyrins 11, 12, and 13 had to be synthesized (Scheme 1). The synthetic route to achieve OET-xBrPPs (2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetra(x-bromo)phenylporphyrin, where x = ortho/meta/para) pyrrole 7 was synthesized through literature procedures . Pyrrole 7 was then subjected to condensation with aldehydes 8, 9, and 10 under Lindsey conditions utilizing BF3·OEt2 and DDQ to achieve porphyrins 4, 5, and 6, which were not isolated and instead reacted immediately.

Scheme 1: Reaction scheme for the synthesis of OET-xBrPPs and subsequent Ni(II) metalation.

Ni(II)porphyrins 11, 12, and 13 were prepared by reacting porphyrins 4, 5, and 6 in toluene for 18 hours using Ni(II)(acac)2 under an inert atmosphere attaining a 18%, 28%, and 29% yield for porphyrins 11, 12, and 13, respectively, over two steps. Porphyrins 6 and 13 had previously been described in literature .

Coupling at the meso-para-phenyl position

The exploration of aryl substitution of OET-xBrPPs using the Suzuki coupling began with investigating first the Suzuki reaction compatibility of boronic acid 14 with porphyrin 13. Porphyrin 13 and phenylboronic acid (14) were subjected to coupling at 85 °C for 48 hours using Pd2dba3/SPhos as a catalyst/ligand giving porphyrin 26 in a 32% yield, based on a literature procedure . With initial success in the synthesis porphyrin 26, this Suzuki coupling reaction was performed on 13, for a range of boronic acids/esters as shown in Figure 2 and Scheme 2. Boronic acids/esters were chosen based on their electronic properties (activating/deactivating) as well as their steric bulk (e.g., 9-anthracenylboronic acid (15)). Table 1 lists all attempts at the meso-para-phenyl position.

Figure 2: Substrates used for the investigations for the Suzuki–Miyaura coupling reactions.

Scheme 2: Scope of arm-extended dodecasubstituted porphyrins synthesized via modification of the meso-para-phenyl position of porphyrin 13.

Table 1: Optimization table for the Suzuki–Miyaura coupling reactions with porphyrin 13.

Entry Catalyst/ligand
SPhos (1 equiv) Cat. mol % per C–Br Base
(24 equiv) Temperature Time Boronic acid/ester
(3 equiv per C–Br) Yield %
(porphyrin) 1 Pd2dba3/Sphos 6.25% K3PO4 85 °C 48 h 14 32% (26) 2 Pd2dba3/Sphos 6.25% K3PO4 85 °C 48 h 15 trace 3 Pd2dba3/SPhos 6.25% K3PO4 110 °C 48 h 15 39% (27) 4 Pd2dba3/Sphos 6.25% K3PO4 85 °C 48 h 16a 0 5 Pd2dba3/Sphos 6.25% Cs2CO3 85 °C 48 h 16a 0 6 Pd2dba3/SPhos 6.25% Cs2CO3 85 °C 48 h 16b 8% (30) 7 Pd2dba3/SPhos 6.25% K3PO4 110 °C 48 h 17 48% (28) 8 Pd2dba3/SPhos 12.5% K3PO4 110 °C 48 h 18a 0 9 Pd2dba3/SPhos 6.25% Cs2CO3 85 °C 48 h 18b 72% (29) 10 Pd2dba3/Sphos 6.25% K3PO4 85 °C 48 h 19 0 11 Pd2dba3/SPhos 6.25% K3PO4 110 °C 48 h 19a trace 12 Pd2dba3/SPhos 12.5% K3PO4 110 °C 24 h 20 25% (34) 13 Pd2dba3/SPhos 6.25% Cs2CO3 110 °C 24 h 21 56% (33) 14 Pd2dba3/SPhos 6.25% K3PO4 110 °C 48 h 23 trace 15 Pd2dba3/SPhos 6.25% Cs2CO3 85 °C 48 h 23 trace 16 Pd(PPh3)4 10% Na2CO3 100 °C 1 h 23b 0 17 Pd2dba3/SPhos 6.25% Cs2CO3 85 °C 24 h 23 trace 18 Pd2dba3/SPhos 6.25% Cs2CO3 110 °C 24 h 23 trace 19 Pd2dba3/SPhos 25% Cs2CO3 110 °C 24 h 23 16% (31) 20 Pd2dba3/SPhos 12.5% Cs2CO3 110 °C 24 h 24 58% (35) 21 Pd2dba3/SPhos 6.25% Cs2CO3 85 °C 24 h 25 47% (32)

a5 equiv of boronic acid used in this reaction per C–Br. bMicrowave irradiation instead of conventional heating was used.

When attempting the synthesis of tetra(p-phenylanthracene)porphyrin (27) the conditions used before (Table 1, entry 1) resulted only in trace amounts of porphyrin 27 (Table 1, entry 2).

The reaction temperature was increased to 110 °C, affording the desired porphyrin 27 in a 39% yield (Table 1, entry 3). A temperature of 110 °C was also used for the synthesis of terphenylporphyrin 28 using boronic acid 17, affording terphenylporphyrin 28 in 48% yield (Table 1, entry 7).

Boronic acids with heteroatoms and activating/deactivating electronic properties were investigated next. Attempts to introduce electron-withdrawing groups at the para-position with substrate boronic acid 16a (Table 1, entries 4 and 5) yielded no tetracoupled product. Similarly, coupling with 18a resulted in most of the starting material porphyrin 13 being left unreacted. On switching the substrate from boronic acid to the boronic acid ester and opting for the weaker base Cs2CO3 instead of K3PO4, a significant difference in reactivity was observed with a 72% yield accomplished in the synthesis of porphyrin 29 (Table 1, entry 9), bearing a methoxycarbonyl electron-withdrawing group utilizing boronic acid pinacol ester 18b. Following on from these results porphyrin 30 was synthesized in an 8% yield, when switching to weaker base Cs2CO3 using pinacol ester 16b (Table 1, entry 6). Switching the base to a weaker one, may have slowed down the protodeboronation process, as substrates with electron-withdrawing groups are postulated to increase the Lewis acidity of the boronic acid, which may allow an increased incidence of protodeboronation to occur. It is also known that aryl–B(Pin) complexes have a greater stability than boronic acids and other employed esters as the four methyl groups protect the boron center from attack of water , preventing protodeboronation from the hydrolysis route. However, protodeboronation can be complex when it comes to pKa considerations, for example, 3,5-dinitrophenylboronic acid has a marginally lower pKa than pentafluorophenyl boronic acid ; however, it undergoes protodeboronation, several orders of magnitude slower .

The synthesis of porphyrin 31 with a benzothiophene moiety, proved challenging (Table 1, entries 14–19). Use of a microwave-assisted procedure , switching catalyst to Pd(PPh)3, and base to Na2CO3 (Table 1, entry 16) gave no product.

Ultimately, an increased catalyst loading of 25 mol % per C–Br bond gave the desired porphyrin in a 16% yield when using Cs2CO3 as base. The synthesis of other heterocycle-appended dodecasubstituted porphyrins, achieved porphyrins 32 and 33 in a 47% and 56% yield, respectively (Table 1, entries 13 and 21), using Cs2CO3 as the base. Electron-withdrawing sulfur-containing heterocyclic substrates 21 and 23 do not readily undergo protodeboronation even at high pH making the yields of porphyrins 31 and 33 higher than expected considering the electronic similarities between substrates 4-nitrophenylboronic acid and 3-thiaphenylboronic acid (16a and 21) and the yields obtained when coupling. The weakly electron-withdrawing boronic acid 24 when coupled with porphyrin 13, resulted in porphyrin 35 in a 58% yield (Table 1, entry 20). Reactivity with the electron-donating 4-methylphenylboronic acid (34) was established using K3PO4 at 110 °C (Table 1, entry 12). No product was obtained in the coupling of electron-donating (4-(dimethylamino)phenyl)boronic acid (19), even upon increasing the number of equivalents of boronic acid (Table 1, entries 10 and 11).

Coupling at the meso-meta-phenyl position

Optimization of conditions for OET-meta-BrPPs 12 (Scheme 3) were investigated next. Table 2 summarizes the reaction conditions used to synthesize a library of OET-meta-arylPPs as shown in Scheme 3. As a starting point initial conditions used in the synthesis for porphyrin 26 were used (Table 1, entry 1). This gave biphenylporphyrin 36 in a 16% yield (Table 2, entry 1). The lower yield is expected due to the increased steric demand at the meta-positions. Coupling of sterically bulky 9-anthracenylboronic acid (15) and porphyrin 12 gave no conversion when the base was switched from K3PO4 to Cs2CO3 (Table 2, entry 2). K3PO4 was reimplemented in the reaction and trace reactivity was observed by TLC (Table 2, entry 3). Next, the catalyst loading was increased to 12.5 mol % (Table 2, entry 4). Formation of palladium black was observed but product formation was also indicated by TLC and 1H NMR. For a final attempt at establishing reactivity with boronic acid 15 the temperature was increased to 110 °C and gave the desired anthracenylporphyrin 37 in a 32% yield. In the case of boronic acids with larger π-systems, e.g., 15, K3PO4 was required to achieve the tetra-coupled product. This trend is consistent in reactivity observed with porphyrins 12 and 13. Similarly, no terphenyl product was formed in the coupling reaction between 12 and 17 (Table 2, entry 6) when using Cs2CO3. Similar to the reactivity observed with 9-anthracenylboronic acid (15), no conversion to the desired product was established. Increasing the temperature and catalyst loading (Table 2, entry 5) gave the terphenylporphyrin 38 in a 7% yield (Table 2, entry 7).

Scheme 3: Scope of arm-extended dodecasubstituted porphyrins synthesized via reaction at the meso-meta-phenyl position of porphyrin 12.

Table 2: Optimization table for the Suzuki-coupling reaction on porphyrin 12.

Entry Catalyst/ligand
SPhos (1 equiv) Cat. mol % per C–Br Base
(24 equiv) Temp. Time Boronic acid/ester
(3 equiv per C–Br) Yield % (porphyrin) 1 Pd2dba3/SPhos 6.25% K3PO4 85 °C 48 h 14 16% (36) 2 Pd2dba3/SPhos 6.25% Cs2CO3 85 °C 48 h 15 0 3 Pd2dba3/SPhos 6.25% K3PO4 85 °C 48 h 15 trace 4 Pd2dba3/SPhos 12.5% K3PO4 85 °C 48 h 15 trace 5 Pd2dba3/SPhos 12.5% K3PO4 110 °C 48 h 15 32% (37) 6 Pd2dba3/SPhos 6.25% Cs2CO3 85 °C 48 h 17 0 7 Pd2dba3/SPhos 12.5% K3PO4 110 °C 24 h 17 7% (38) 8 Pd2dba3/SPhos 6.25% Cs2CO3 85 °C 48 h 18b 0 9 Pd2dba3/SPhos 12.5% Cs2CO3 85 °C 48 h 18b 23% (39) 10 Pd2dba3/SPhos 12.5% Cs2CO3 85 °C 24 h 16b 4% (40) 11 Pd2dba3/SPhos 6.25% Cs2CO3 85 °C 48 h 20 0 12 Pd2dba3/SPhos 12.5% K3PO4 110 °C 24 h 20 30% (44) 13 Pd2dba3/SPhos 12.5% Cs2CO3 110 °C 24 h 21 10% (43) 14 Pd2dba3/SPhos 25% Cs2CO3 110 °C 24 h 23 4% (41)