A Cost-Efficient Method for Unsymmetrical Meso-Aryl Porphyrin Synthesis Using NaY Zeolite as an Inorganic Acid Catalyst

Herein we report the synthesis of unsymmetrical meso-aryl substituted porphyrins, using NaY zeolite as an inorganic acid catalyst. A comparative study between this method and the several synthetic strategies available in the literature was carried out. Our method presented a better, more cost-efficient rationale and displayed a significantly lower environmental impact. Furthermore, it was possible to verify the scalability of the process as well as the reutilization of the inorganic catalyst NaY (up to 6 times) without significant yield decrease. In addition, this method was applied to the synthesis of several other unsymmetrical porphyrins, from a low melting point porphyrin to mono-carboxylated halogenated unsymmetrical porphyrins, in yields higher than those found in the literature. Additionally, for the first time, two acetamide functionalized halogenated porphyrins were prepared in high yields. This methodology opens the way to the preparation of high yielding functionalized porphyrins, which can be easily immobilized for a variety of applications, either in catalysis or in biomedicine.


S3.1. NaY method
An amount of 1.0 g of NaY zeolite (0.08 mmol) was introduced into a 50 mL round flask, containing a mixture of 4-hydroxybenzaldehyde (0.625 mmol, 76.3 mg), benzaldehyde (1.875 mmol, 0.19 mL) in a glacial acetic acid/nitrobenzene mixture (7 mL/5 mL). Addition of equimolar amount of pyrrole (2.5 mmol, 0.17 mL) was carried out dropwise under stirring and heating (≈120 °C). After complete addition (ca. 3 min), the suspension was heated further till reflux temperature (≈130 °C) and maintained at this temperature for ca. 2 hours. The hot suspension was filtered and the resulting solid material washed with tetrahydrofuran (THF) until no coloured material was collected on the supernatant (250 mL). As alternative Soxhlet extraction with THF can be performed, but in our case we found washing sufficient. The volume of solution was then reduced by rotoevaporation (enough volume to remove the added washing solvent). To induce precipitation, n-hexane (ca. 50 mL) was added. The Erlenmeyer flask containing the statistical porphyrin mixture was left overnight in the refrigerator and the deposited solid was collected by filtration and then purified by column chromatography using silica gel as stationary phase, starting with n-hexane:CH2Cl2 (1:3) to collect the first fraction (5,10,15,20-tetraphenyl porphyrin) and then with CH2Cl2 to collect the second band. As this fraction was identified as the porphyrin 1, other following bands were discarded. Fraction 2 was evaporated to dryness and the resulting solid was dried under vacuum and weighed to give 60 mg (0.0938 mmol) of 1 (16% yield).
Characterization data is in accordance with the literature [3]. 3

S3.2. Adler-Longo method [4] 4
A mixture of 4-hydroxybenzaldehyde (3.75 mmol, 0.458 g) and benzaldehyde (11.25 mmol, 1.13 mL) was introduced into a 250 mL round flask containing propionic acid (100 mL). Addition of equimolar amount of pyrrole (15 mmol, 1.03 mL) was carried out dropwise under stirring and heating (≈130 °C). After complete addition (ca. 10-12 min), the suspension was heated further till reflux temperature (≈150 °C) and maintained at this temperature for ca. 2 hours. The flask condenser was substituted by a distillation apparatus and the solvent mixture was removed by vacuum, under heating. The obtained solid was redissolved in CH2Cl2 (30 mL) and the solution washed with saturated NaHCO3 solution (3 x 25 mL). The solution was concentrated to dryness in a rotoevaporator and purified by column chromatography using silica gel as stationary phase, starting with n-hexane:CH2Cl2 (1:3) to collect the first fraction (5,10,15,20-tetraphenyl porphyrin) and finally with CH2Cl2 to collect the second band, contaminated with the corresponding chlorin (close Rf). Other following bands were discarded. Fraction 2 was evaporated to dryness and the resulting solid was dried under vacuum and weighed to give 142 mg (0.225 mmol) of 1 plus its corresponding chlorin (~10%), in an approximated 6% yield.

S3.3. Gonsalves-Pereira method [5] 5
A mixture of 4-hydroxybenzaldehyde (3.75 mmol, 0.458 g) and benzaldehyde (11.25 mmol, 1.13 mL) was introduced into a 100 mL round flask containing a glacial acetic acid/nitrobenzene mixture (50 mL/25 mL). Addition of equimolar amount of pyrrole (15 mmol, 1.03 mL) was carried out dropwise under stirring and heating (≈120 °C). After complete addition (ca. 10-12 min), the suspension was heated further till reflux temperature (≈130 °C) and maintained at this temperature for ca. 1 hour. The flask condenser was substituted by a distillation apparatus and the solvent mixture was removed by vacuum, under heating. The deposited solid was purified by column chromatography using silica gel as stationary phase, starting with n-hexane to remove nitrobenzene traces, then n-hexane:CH2Cl2 (1:3) to collect the first fraction (5,10,15,20-tetraphenyl porphyrin) and finally with CH2Cl2 to collect the second band. As this fraction was identified as the porphyrin 1, other following bands were discarded. Fraction 2 was evaporated to dryness and the resulting solid was dried under vacuum and weighed to give 166 mg (0.263 mmol) of 1 (7% yield).

S3.4. Lindsey method [6] 6
A mixture of pyrrole (0.25 mL, 3.75 mmol), 4-hydroxybenzaldehyde (114 mg, 0.938 mmol) and benzaldehyde (0.275 mL, 2.75 mmol) in CHCl3 (250 ml) was bubbled with N2 for 30 min, and TFA (0.13 mL, 2.0 mmol) was added. The mixture was stirred at room temperature under N2 for 1 hr. DDQ (625 mg, 3.75 mmol) was added and the mixture was stirred for 12 hr with protection from light. Triethylamine (2.5 ml, 19 mmol) was added and stirred for 30 min, and the solvent was removed by rotary evaporation. The residue was then suspended in CH2Cl2, placed on the top of a dry column of Al2O3, and eluted with CH2Cl2. The eluted solution was evaporated and then purified by chromatography on silica gel, starting with n-hexane:CH2Cl2 (1:4) to collect the first fraction (5,10,15,20-tetraphenyl porphyrin) and finally with CH2Cl2 to collect the second band. As this fraction was identified as the porphyrin 1, other following bands were discarded. Fraction 2 was evaporated to dryness and the resulting solid was dried under vacuum and weighed to give 89 mg (0.14 mmol) of 1 (15% yield).

S4. Porphyrin yield as function of the amount of zeolite NaY used
Ratio was calculated as the quotient between the number of moles of NaY used per sum of moles of pyrrole and aldehydes (reagents). For instance, when the reaction (see above, point 2) was performed using 1 g NaY (0.08 mmol) per 5 mmol reagents, the ratio was 0.032 i.e., NaY was present in 3.2% of all reagents. When ratio was 0.032, the yield obtained was ca. 16 %. The yields obtained using different ratios of NaY per amount of reagents is presented in Table S1 and Figure   S2. Table S1. Isolated yields of 5-(4-hydroxyphenyl)-10,15,20-tris(phenyl) porphyrin (1)

Figure S2
Isolated yields of porphyrin 1 vs NaY amount. Note: when amount NaY = 0, it represents the isolated yields using the nitrobenzene method.

S5. Catalyst recycling
The catalyst zeolite NaY was tested in successive cycles to evaluate the reutilisation process in the synthesis of 5-(4-hydroxyphenyl)-10,15,20-tris(phenyl) porphyrin 1. Using the best determined conditions, after the first cycle, the selected catalyst was collected by filtration and washed with chloroform and tetrahydrofuran, following drying of the solid overnight, at 150 ºC under vacuum. The second, third, fourth and fifth and sixth cycles were carried out with the recovered solid and reactivation procedure was followed for each reutilisation.  NaY method** 784 g nitrobenzene + 641 g acetic acid + 2000 g silica + 9410 g dichloromethane + 1970 g n-hexane)/

S7. Price evaluation related to the synthesis of porphyrin 1
Notes: Market prices were calculated on basis of laboratory scale acquisition at Sigma-Aldrich company and available at www.sigmaaldrich.com, excluding NaY, whose prices were calculated from Zeolyst International company. Prices do not reflect reagents and solvents acquisitions on a large scale, but at a laboratory scale, just following Sigma-Aldrich website prices. Amounts of solvents and reagents used for the preparation of 10 mmol product were calculated simply by multiplying the amounts used in preparations according to the experimental above, considering obtained yields.

S9.1. General procedure
An amount of 1.0 g of NaY zeolite (0.08 mmol) was introduced into a 50 mL round flask, containing a 1:3 mixture of aldehydes (0.625 mmol:1.875 mmol) in a glacial acetic acid/nitrobenzene mixture (7 mL/5 mL). Addition of equimolar amount of pyrrole (2.5 mmol, 0.17 mL) was carried out dropwise under stirring and heating (≈120 °C). After complete addition (ca. 3 min), the suspension was heated further till reflux temperature (≈130 °C) and maintained at this temperature for ca. 2 hours. The hot suspension was filtered and the resulting solid material washed with tetrahydrofuran (THF) until no coloured material was collected on the supernatant (250 mL). As alternative Soxhlet extraction with THF can be performed, but in our case we found washing sufficient. The volume of solution was then reduced by rotoevaporation (enough volume to remove the added washing solvent). To induce precipitation, n-hexane (ca. 50 mL) was added. The Erlenmeyer flask containing the statistical porphyrin mixture was left overnight in the refrigerator and the deposited solid was collected by filtration and then purified by column chromatography using silica gel as stationary phase, starting with n-hexane:CH2Cl2 (1:3) and then increasing polarity using appropriate gradients of n-hexane:CH2Cl2, then pure CH2Cl2 and finally CH2Cl2:ethanol gradients if necessary to collect fraction 2 (the target compound). This fraction was then evaporated to dryness and the resulting solid was dried under vacuum and weighed.