A synthetic toolbox for sustainable methods in porphyrin chemistry

Abstract

Greener synthesis for red dyes. As the days of chlorinated organic solvents are numbered, we propose a sustainable synthetic protocol for porphyrin synthesis to facilitate the transition into a more viable, safer and greener lab. Here we present a facile flow-assisted method for the sustainable synthesis of 40 meso-substituted planar porphyrins of the A₄-, A₂-, and trans-A₂B₂-type, including 10 examples of dodecasubstituted nonplanar porphyrins. We set forth a sustainable approach towards porphyrin synthesis, saving up to 90% of chlorinated solvents and drastically limiting waste generation by merging a flow synthesis process via a continuous stirred tank reactor (CSTR) with a traditional batch oxidation method.

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Sustainability spotlight

“A synthetic toolbox for sustainable methods in porphyrin chemistry” falls into goal 12 of the UN Sustainable Development Goals (Sustainable consumption and production patterns). One of the targets of chapter 20 of Agenda 21 is preventing or minimizing the generation of hazardous waste. In porphyrin chemistry, the bulk of hazardous waste generated during porphyrin synthesis consists of chlorinated solvents. We aim to limit the generation of hazardous waste in porphyrin synthesis by reducing the volume of solvent required for the synthesis. This is enabled by continuous flow; merging a flow synthesis process via a continuous stirred tank reactor (CSTR) with a traditional batch oxidation step, we reduced the volume of chlorinated solvent required for the synthesis by up to 90%.

Introduction

Minimising solvent use in chemical reactions is one of the twelve principles of green chemistry¹ and the ten objectives of green and sustainable chemistry, proposed by the United Nations.² Specifically, seeking alternatives to chlorinated solvents was identified as one of the key green chemistry research areas by the ACS Green Chemistry Institute in 2005.³ While a suitable drop-in replacement for dichloromethane (DCM) and its homologues has not yet been identified,⁴ limiting their use is strongly encouraged. This is exemplified by the restriction for specific industrial applications of DCM in the European Union since 2010 (ref. 5) and most uses of DCM introduced in the United States by the Environmental Protection Agency in 2024.⁶

Macrocycles constitute a class of functional molecules applied in sensing, catalysis, medicine, cosmetics, agriculture and nanotechnology.⁷ Their synthesis requires high dilution to promote cyclisation over formation of linear products.⁸ This is called the high dilution principle, and its implications can be circumvented by experiment design,⁹ pseudodilution¹⁰ and catalysis.¹¹

Porphyrins are aromatic tetrapyrrolic macrocycles. meso-Substituted porphyrins, such as 5,10,15,20-tetraphenylporphyrin (H₂TPP, Fig. 1) are artificial dyes, counterparts to naturally occurring porphyrinoids, like heme B, chlorophyll a, or vitamin B12 (Fig. 1).¹² Due to the ease of their synthesis and versatile chemical and physical properties, meso-substituted porphyrins are highly sought after as feasible targets for research areas including catalysis,¹³ quantum technologies,¹⁴ molecular probes¹⁵ and supramolecular assemblies,¹⁶ applications in dye-sensitised solar cells,¹⁷ remediation,¹⁸ imaging, photodynamic therapy,¹⁹ and other areas of biomedicine.²⁰

Fig. 1 Structures of chlorophyll a, heme B, 5,10,15,20-tetraphenylporphyrin (H₂TPP) and vitamin B12.

Perhaps the most thoroughly studied and certainly most frequently applied method for porphyrin synthesis is a two-step protocol involving a condensation of aldehydes with pyrroles under acidic conditions, followed by an oxidation of the tetrapyrrolic macrocycle.²¹ The first general method toward porphyrin synthesis was initially reported by Rothemund²² and further developed by Adler,²³ and called for harsh conditions, such as high temperatures and acidic or basic solvents (Table 1).

Table 1 Comparison of synthetic methods in porphyrin synthesis

Protocol	Rothemund	Adler–Longo	Lindsey
Steps	1	1	2
Concentration	High 3.6 M	High 0.1–0.3 M	Low 0.001–0.1 M
Temperature	220 °C	140 °C	20 °C
Solvent	Pyridine	Propionic acid	Chlorinated
Catalyst	None	cat. = solvent	BF3·Et2O, TFA
Conditions	sealed vessel	Aerobic	Inert
Oxidant	None	Nitrobenzene	Quinone
Yields	<10%	<30%	35–60%

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Porphyrins synthesised via either Rothemund or Adler protocols were contaminated with the corresponding chlorins (<10%); this could be evaded by treatment with a strong quinone oxidant, such as 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). In Lindsey's method, oxidation is an inherent step following the mild, room temperature cyclisation carried out in acidified chlorinated solvents, at low concentrations.²⁴ Currently, the Lindsey protocol is the mildest and most effective method for the synthesis of meso-substituted porphyrins, both A₄ 5,10,15,20-tetra-^25,26 (Fig. 2) and 2,3,5,7,8,10,12,13,15,17,18,20-dodecasubstituted.^27,28 The higher yields and wider functional group tolerance are related to the mild reaction conditions.

Fig. 2 meso-Substitution patterns in 5,15- and 5,10,15,20-substituted porphyrins.

The Lindsey protocol is currently the standard method for porphyrin synthesis in academia and industry.²⁹ One major drawback of this method is the requirement for large volumes of chlorinated solvents for the reaction, which calls for 1–100 mM reactant concentrations to promote macrocyclisation over formation of linear side products.^30,31 This constitutes a sustainability issue and improvements to the current methods or development of new protocols for porphyrin synthesis are needed to overcome this problem.

Protocols employing microwave irradiation and mechanochemistry, as well as the use of ionic liquids as solvents, have been developed over the past two decades to increase the sustainability of meso-substituted porphyrin synthesis.³² Recently, two contributions describing the use of continuous flow in porphyrin synthesis were reported. These involve the Gonsalves protocol,^33,34 and a process for Lindsey synthesis of meso-substituted porphyrins.³⁵ Both articles constitute landmarks in porphyrin synthesis in continuous flow; however, there is still room for improvement in the sustainability-related aspects of porphyrin synthesis. Reduction of solvent volume required for the synthesis, application of green solvents and finally, generalisation of solventless methods are green directions in porphyrin synthesis. In this contribution we build up on the preliminary studies reported for application of continuous flow in porphyrin synthesis to achieve improved sustainability (E-factor) and propose a universal method for porphyrin synthesis. We present a semi-continuous protocol for porphyrin synthesis under Lindsey conditions, incorporating a continuous stirred tank reactor (CSTR) at the condensation step. In this approach, we show that a significant (10×) increase in reactant concentration is not only beneficial for the reaction yield, but it also allows reduction in the volume of chlorinated solvents required for macrocyclisation by up to 90%.

Experimental

Materials and methods

Dipyrromethanes 5c and 5d (Scheme 4) were purchased from Frontier Scientific. Column chromatography was carried out using Supelco Silica Gel (pore size 60 Å, 230–400 mesh; Merck). CSTR-assisted synthesis was carried out using Asynt fReactor with five 2 mL modules (total reactor volume 10 mL). Detailed description of the experimental setup, including photographs, is provided in SI (page S6). Full compound characterisation data and ¹H NMR, ¹³C NMR, ¹⁹F NMR, HRMS, IR, UV/vis spectra are provided in SI.

Synthetic procedures

Dipyrromethanes 5a, 5b, 5e, 5f (Scheme 4) and 3,4-diethylpyrrole 9 (Scheme 5) were prepared according to literature procedures.^36–38

General procedure A: flow-assisted synthesis of A₄ porphyrins. A solution of pyrrole 1 (155 µL, 2.25 mmol, Scheme 1) and aldehyde 2a–af (2.25 mmol, Fig. S1, SI) in DCM (15 mL) and a solution of trifluoroacetic acid (TFA, 170 µL, 2.25 mmol) in DCM (15 mL) were taken up in syringes and injected into fReactor at equal flow rate of 1 mL min⁻¹. After injection was completed, an additional 10 mL of DCM was pumped through the reactor to wash fully wash out the crude porphyrinogen 3a–af (Scheme 2) into a round bottom flask equipped with a stir bar and shielded from light. DDQ (450 mg, 2.00 mmol) was added to the crude mixture as powder and the mixture was stirred at RT for 1 h, neutralised with triethylamine (TEA, 300 µL, 2.25 mmol) and poured onto a short silica gel plug. Porphyrins 4a–af (Scheme 2) were eluted with DCM (50 mL) and precipitated with n-hexane or methanol to afford purple crystals. The yields were determined based on two experiments.

Scheme 1 CSTR-assisted synthesis of 4a.

Scheme 2 Scope and limitations of CSTR-assisted synthesis of A₄ porphyrins. Yields in grey were reported in literature for batch syntheses.^{44 a}Literature yield for Alder–Longo method.

General procedure B: flow-assisted synthesis of A₂ and trans-A₂B₂ porphyrins. A solution of dipyrromethane 5a–f (0.75 mmol, Scheme 4) and aldehyde 2a–af (0.75 mmol, Fig. S1, SI) in DCM (15 mL) and a solution of TFA (57 µL, 0.75 mmol) in DCM (15 mL) were taken up in syringes and injected into fReactor at equal flow rate of 1 mL min⁻¹. After injection was completed, an additional 10 mL of DCM was pumped through the reactor to wash fully wash out the crude porphyrinogen 6a–af (Scheme 4) into a round bottom flask equipped with a stir bar and shielded from light. DDQ (136 mg, 0.60 mmol) was added to the crude as powder and the mixture was stirred at RT for 1 h, neutralised with TEA (100 µL, 0.75 mmol) and poured onto a short silica gel plug. Porphyrins 7a–af, and 8c–e (Scheme 4) eluted with DCM (30 mL) and precipitated with n-hexane to afford purple crystals. The yields were determined based on two experiments.

General procedure C: flow-assisted synthesis of 2,3,5,7,8,10,12,13,15,17,18,20-dodecasubstituted porphyrins. A solution of 3,4-diethylpyrrole 9 (135 mg, 1.10 mmol, Scheme 5) and aldehyde 2a–af (1.10 mmol, Fig. S1, SI) in DCM (10 mL) and a solution of p-toluenesulfonic acid (TSA, 209 mg, 1.10 mmol) in DCM/MeOH (10 mL, 99 : 1, v/v) were taken up in syringes and injected into fReactor at equal flow rate of 1 mL min⁻¹. After injection was completed, an additional 10 mL of DCM was pumped through the reactor to wash fully wash out the crude porphyrinogen 10a–af (Scheme 6) into a round bottom flask equipped with a stir bar and shielded from light. DDQ (750 mg, 3.30 mmol) was added to the crude mixture as powder and the mixture was stirred at RT for 1 h, then neutralised with TEA (150 µL, 1.1 mmol). The crude porphyrins 11a–s (Scheme 6) were isolated as green solids by precipitation with methanol. Recrystallisation from KOH/EtOH 0.4% w/v afforded ‘free base’ dodecasubstituted porphyrins as brown/purple crystals. Porphyrin 11d (Scheme 6) was isolated as a dication salt, in the form of a green solid. The yields were determined based on two experiments.

Results and discussion

A₄ porphyrins

With the goal to limit the volume of chlorinated solvents required for porphyrin synthesis, we envisioned a semi-continuous process, aided by a CSTR reactor (continuous stirred tank reactor). In the first step, an in-flow condensation of aldehydes 2a–af (Fig. S1) with pyrrole 1 was performed. Due to the poor solubility of DDQ in chlorinated solvents, in-line oxidation would be counterproductive to the goal of limiting the need for chlorinated solvents in porphyrin synthesis.³⁹ DDQ was selected as the oxidant for this method (rather than its weaker tetrachlorinated derivative p-chloranil) in order to eliminate the need for heat supply during the oxidation step⁴⁰ and to comply with principle 6 of green chemistry (“design for energy efficiency”).¹ Hence, both the oxidation and neutralisation steps were conducted in-batch.

Optimisation. The model reaction selected for optimisation was a condensation of pyrrole 1 with benzaldehyde 2a, catalyzed by TFA, followed by an oxidation with DDQ and neutralisation with TEA, to yield ‘free base’ 5,10,15,20-tetraphenylporphyrin (4a, Scheme 1). The reagents (pyrrole 1 and aldehyde 2a) were used in 1 : 1 molar ratio. The optimisation of in-flow condensation conditions involved the flow rate and the concentration of the reactants. The concentration range investigated started at 0.02 M, (a typical concentration for in-batch condensation)²⁴ and was increased up to c = 1.00 M (50 times more concentrated). For each concentration, we examined four different flow rates to assess the influence of residence time on the yield. Isolated yields listed in Table 2 were determined for the pure isolated product of condensation, oxidation and neutralisation (i.e., ‘free base’ porphyrin 4a).

Table 2 Optimisation of CSTR-assisted synthesis of 4a

Entry	Conc. [M]	Flow rate [mL min^−1]	Yield [%]
1	0.02	0.5	15
2	0.02	1.0	12
3	0.02	1.5	10
4	0.02	2.0	9
5	0.05	0.5	22
6	0.05	1.0	16
7	0.05	1.5	15
8	0.05	2.0	11
9	0.10	0.5	27
10	0.10	1.0	24
11	0.10	1.5	23
12	0.10	2.0	20
13	0.15	0.5	30
14	0.15	1.0	30
15	0.15	1.5	29
16	0.15	2.0	29
17	0.20	0.5	28
18	0.20	1.0	28
19	0.20	1.5	27
20	0.20	2.0	25
21	0.30	0.5	27
22	0.30	1.0	26
23	0.30	1.5	24
24	0.30	2.0	24
25	0.50	0.5	22
26	0.50	1.0	20
27	0.50	1.5	20
28	0.50	2.0	19
29	1.00	0.5	12
30	1.00	1.0	12
31	1.00	1.5	13
32	1.00	2.0	13

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Overall, the yields obtained in this optimisation varied from 9 to 30% (Table 2, entry 4 and entries 13 and 14, respectively). Interestingly, increasing the concentration of the reactants from standard batch conditions (c = 0.02 M) up to 10 times (c = 0.15, 0.20 M) returned best results; the highest yield recorded for c = 0.02 M was 15% (entry 1), and the best yield overall was 30% (c = 0.15 M, entries 13, 14). No further improvement was observed increasing the reactant concentration to c = 1.00 M – unsurprisingly, a gradual drop in isolated yields to 28% (0.20 M, entry 17), 27% (0.30 M, entry 21), 22% (0.50 M, entry 25) and 13% (1.00 M, entries 31, 32) was observed. The optimal concentration of reactants for the in-flow condensation reaction was 0.15 M.

The impact of flow rate and residence time on the yield of 5,10,15,20-tetraphenylporphyrin 4a was well-pronounced at low concentrations (0.02–0.10 M, entries 1–12, Table 2). Here, decreasing the flow rate from 2.0 mL min⁻¹ to 0.5 mL min⁻¹ contributed to 6, 12 and 7% yield increase at 0.02, 0.05 and 0.10 M, respectively. The maximum yields obtained for this range of concentrations were 15, 22 and 27%, increasing with the reactant concentration and residence time (entries 4, 8, 12). The influence of residence time on the isolated yield of H₂TPP (4a) was negligible in more concentrated reaction mixtures (0.15–1.00 M), with 3–8% differences in isolated yields. At the most effective reagent concentration of 0.15 M, both 0.5 mL min⁻¹ and 1.0 mL min⁻¹ returned the same highest yield of 30%. Thus, we concluded that the optimal flow rate for in-flow condensation of aldehydes and pyrroles under acid catalysis is 1.0 mL min⁻¹, translating to 15 min residence time.

Having established the optimal concentration and flow rate of the reactants for condensation, we examined other solvents commonly used in porphyrin synthesis – acetonitrile (MeCN), as a non-chlorinated alternative, and CHCl₃ (Table 3). The reactions were carried out at c = 0.3 M concentrations at 1.0 mL min⁻¹ flow rate. No product was detected in the reaction in MeCN (entry 1), and in CHCl₃ the yield was 10% – over 2.5 times lower than in DCM (entries 2 and 3, respectively). While DCM is more volatile than CHCl₃, the latter is classified as significantly more hazardous for health according to the CLP Regulation.^41,42 Thus, we selected DCM as the more promising choice of solvent for this synthetic method.

Table 3 Solvent screening for 4a synthesis

Entry	Conc. [M]	Flow rate [mL min^−1]	Solvent	Yield [%]
1	0.30	1.0	MeCN	0
2	0.30	1.0	CHCl3	10
3	0.30	1.0	DCM	26

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Next, we carried out experiments with other acids used as catalysts in the Lindsey method of porphyrin synthesis, i.e., boron trifluoride diethyl etherate (BF₃·Et₂O) and p-toluenesulfonic acid (TSA). Both acids promoted the condensation, however neither performed as well as TFA: BF₃·Et₂O yielded 17% of H₂TPP (entry 1, Table 4) and TSA 25% (entry 2). Additionally, we examined the influence of the amount of acid catalyst used on the yield, on the example of TFA. Reducing the amount of acid to 0.5 eq. resulted in a yield decrease to 8% (entry 4), while using 2.0 eq. of TFA only slightly increased the yield from 30 to 34% (entry 5). This result is in line with the 31% yield of 4a reported by Parveen et al.³⁵ Given the modest improvement in yield triggered by the 100% increase in TFA quantity (entry 5), we concluded that TFA in 1.0 eq. is the optimal catalyst for condensation of aldehydes with pyrrole in a CSTR reactor. Taken together, the optimised conditions used for the determination of scope of flow-assisted synthesis of porphyrins under Lindsey conditions at high concentrations were a c = 0.15 M concentration of reagents in DCM with 1.0 eq. of TFA, at 1.0 mL min⁻¹ flow rate. These optimised conditions require 7.5 times less DCM for porphyrin synthesis (c = 0.15 M). Additionally, a further decrease in solvent requirement is possible with a negligible drop in yield (from 30 to 28%), to 10 times less DCM than in batch conditions (using c = 0.20 M).

Table 4 Optimisation for acid

Entry	Conc. [M]	Flow rate [mL min^−1]	Acid	Acid eq.	Yield [%]
1	0.15	1.0	BF3·Et2O	0.1	17
2	0.15	1.0	TSA	1.0	25
3	0.15	1.0	TFA	1.0	30
4	0.15	1.0	TFA	0.5	8
5	0.15	1.0	TFA	2.0	34

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Scope and limitations. With the optimised conditions in hand, we moved on to scope determination. We selected a broad range of mono-, oligo- and per substituted benzaldehydes bearing electron donating and withdrawing groups, as well as polyaromatic, heterocyclic and aliphatic aldehydes (Fig. S1, Scheme 2).

The best yields were obtained for condensations involving activated benzaldehydes, 4-tert-butylbenzaldehyde 2d (4d, 43%), 4-tolualdehyde 2b (4b, 33%) and 3,5-di-tert-butylbenzaldehyde 2q (4q, 33%). 4a was obtained in 31% yield from 2a. Condensations with isomeric anisaldehyde 2e and 2i yielded 5,10,15,20-tetrakis(4-methoxyphenyl)porphyrin (4e, 26%) and 5,10,15,20-tetrakis(3-methoxyphenyl)porphyrin (4i, 24%). The presence of a bulky substituent in the ortho position of a benzaldehyde negatively impacts the yield,⁴³ as evidenced by 5,10,15,20-tetrakis(2-methoxyphenyl)porphyrin 4l and 5,10,15,20-tetrakis(2,6-dimethoxyphenyl)porphyrin 4n, which were formed in low yields of 8 and 4%, from aldehydes 2l and 2n, respectively. While p-bromobenzaldehyde 2c gave 20% yield of the corresponding porphyrin 4c, meta and ortho isomers both yielded 7% yield of porphyrins 4h and 4k, respectively. Interestingly, 4f and 4g were not isolated despite moderate yields reported in literature for batch synthesis of these porphyrins under Adler–Longo and Lindsey conditions, respectively.^44j,k ortho-Substituted 2,6-difluorobenzaldehyde 2m and 2,4,6-trifluorobenzaldehyde 2t produced porphyrins (4m, 13%) and (4t, 11%) in yields lower than reported in literature for batch synthesis. The low yields of condensation observed for benzaldehydes bearing bulky substituents at the ortho-positions in comparison to H₂TPP result directly from the steric hindrance caused by bromine and fluorine atoms and methoxy groups, compared to a hydrogen atom.⁴³ Porphyrins 4k and 4l were obtained as mixtures of atropisomers.⁴⁵

Polycyclic aromatic aldehydes, naphthaldehyde 2y, 4-methoxynaphthaldehyde 2z, 9-phenantrenecarbaldehyde 2ab, 9-antracenecarbaldehyde 2aa and 1-pyrenecarbaldehyde 2ac were subjected to condensations with pyrrole to yield π-rich porphyrins which have previously found applications in two-photon absorption⁴⁶ and nanomaterials,⁴⁷ with moderate results. 5,10,15,20-Tetrakis(1-naphthyl)porphyrin 4y and 5,10,15,20-tetrakis(4-methoxy-1-naphthyl)porphyrin 4z were isolated in 27 and 20% yields, while phenanthrene and pyrene carbaldehydes 2ab and 2ac produced porphyrins 4ab and 4ac in 16% and 8% yields, respectively. Not surprisingly, the sterically hindered 5,10,15,20-tetrakis(9-anthryl)porphyrin 4aa was not isolated out of the reaction mixture. Previous efforts to synthesise this porphyrin resulted in only 0.2% yield for Rothemund conditions,⁴⁸ 0.4% for modified Rothemund conditions (in pyridine and glacial acetic acid)⁴⁹ and 2.6% and 4% for the carbinol route.^50,51 Among heterocyclic derivatives, tetrakis(2-furyl)porphyrin 4w was obtained in 14% yield, while 5,10,15,20-tetrakis(1-methyl-2-imidazolyl)porphyrin 4x was not isolated. To further demonstrate the wide applicability of this method, three aliphatic aldehydes were included in the scope. These typically produce lower yields than their aromatic counterparts.⁵² Valeraldehyde 2ad and iso-butylaldehyde 2ae formed porphyrins 4ad and 4ae in 8% yields, but pivaldehyde 2af did not produce the 5,10,15,20-tetrakis(tert-butyl)porphyrin 4af. Porphyrins 4d, 4w, 4z and 4ae (Scheme 2, framed) were isolated in yields surpassing those reported in literature for batch methods.^53–55 Yields determined for 4b, 4i, 4q, 4ab and 4ac were comparable with those reported in literature for conventional methods of porphyrin synthesis according to the Lindsey protocol.^56–59 The detailed comparison of the yields obtained with this method and those reported previously in literature is presented in Scheme 2.

The limitations of this method correspond with those observed in traditional porphyrin synthesis. Bulky substituents installed near the formyl group of the aldehyde can hamper or preclude condensation.⁴³ This was observed for mesitylaldehyde 2u, 2,6-dimethylbenzaldehyde 2o, 2,6-dichlorobenzaldehyde 2p and 2,4,6-trimethoxybenzaldehyde 2v as corresponding porphyrins 4u, 4o, 4p and 4v were not isolated.

In summary, we prepared 21 5,10,15,20-tetrasubstituted porphyrins in 4–43% yields. The yield range in this library is in line with that reported by Parveen et al., albeit exact comparison of numerical values cannot be made due to negligible overlap in scopes.³⁵

A₂ and trans-A₂B₂ porphyrins

Optimisation. A₂B₂ porphyrins (including A₂ porphyrins, Fig. 2) are highly sought after for their applications in nonlinear optics,⁶⁰ dye-sensitised solar cells⁶¹ and photodynamic therapy.⁶² The reduced symmetry of A₂B₂ porphyrins compared to A₄ enables incorporation of substituents and functional groups with distinct chemical character, leading to remarkable properties. This comes at the cost of more laborious, multi-step synthesis. trans-A₂B₂ porphyrins are synthesised in a [2 + 2] condensation, known as MacDonald condensation, in which meso-free or meso-substituted dipyrromethane (e.g., 5a in Scheme 3) undergoes an acid catalyzed condensation with an aldehyde to form porphyrinogen 6a, which is then oxidised to porphyrin 7a.⁶³ We tested the applicability of our flow-assisted method, developed for A₄ porphyrins, for the synthesis of a model A₂ porphyrin, 5,15-diphenylporphyrin (7a, H₂DPP). Without deviation from the optimised conditions (c = 0.15 M, flow rate 1 mL min⁻¹, cat. 1.0 eq. TFA) we isolated H₂DPP 7a in 27% yield (Scheme 3).

Scheme 3 CSTR-assisted synthesis of 7a (H₂DPP).

As [2 + 2] condensations are typically carried out at higher dilutions,⁶⁴ we anticipated an improvement in the isolated yield of H₂DPP upon decreasing the reagent concentration. Indeed, at concentrations c = 0.10, c = 0.07 and c = 0.05 M the recorded yields gradually increase to 29, 31 and 35%, respectively (Table 5, entries 2, 3 and 4). Further dilution to c = 0.03 and c = 0.01 M resulted in yield drop to 19 and 17%, respectively (entries 5 and 6). Similarly to the case of A₄ porphyrins described above, deviation from 1.0 eq. of TFA brought no improvement to the yield, as 0.5 eq. of acid produced 26% of H₂DPP (entry 7), and 2.0 eq. of TFA yielded only 9% of the porphyrin (entry 8). Taken together, under the best yielding conditions for [2 + 2] condensation of meso-unsubstituted dipyrromethane 5a and benzaldehyde 2a, catalyzed by TFA, at c = 0.05 M concentration in dichloromethane, at 1.0 mL min⁻¹ flow rate, H₂DPP 7a was isolated in 35% yield. These conditions were used for scope determination for [2 + 2] condensations producing A₂ and trans-A₂B₂ porphyrins. While the isolated yield of H₂DPP is lower than that obtained under traditional batch conditions, our optimised CSTR-assisted method uses only 10% of the DCM volume, comprising a significant reduction of the environmental cost of porphyrin synthesis.

Table 5 Optimisation of 7a (H₂DPP) synthesis

Entry	Conc. [M]	Flow rate [mL min^−1]	TFA eq.	Yield [%]
1	0.15	1.0	1.0	27
2	0.10	1.0	1.0	29
3	0.07	1.0	1.0	31
4	0.05	1.0	1.0	35
5	0.03	1.0	1.0	19
6	0.01	1.0	1.0	17
7	0.05	1.0	0.5	26
8	0.05	1.0	2.0	9

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Scope and limitations. The conditions optimised for flow-assisted variant of MacDonald [2 + 2] condensation of dipyrromethanes and aldehydes were used in the synthesis of two libraries of porphyrins with distinct substitution patterns: A₂ porphyrins, obtained through a condensation of aldehydes with meso-free dipyrromethane 5a, and trans-A₂B₂ porphyrins, formed from meso-substituted dipyrromethanes 5b–f (Scheme 4).

Scheme 4 Scope and limitations of CSTR-assisted synthesis of A₂ and trans-A₂B₂ porphyrins. Yields in grey were reported in literature for batch syntheses.^{65 a}Literature yield for Alder–Longo method. ^bYield not reported in literature.

Similarly to Lindsey condensations, 3,5-di-tert-butylbenzaldehyde 2q produced porphyrin 7q in the highest yield, 42%, close to the yield reported for batch synthesis (48%).⁶⁴ This was the only A₂ porphyrin obtained with higher yield than H₂DPP 7a, which was formed in 35%. p-Tolualdehyde 2b and p-tert-butylbenzaldehyde 2d yielded 7b and 7d in 20 and 18%, respectively, while for p-nitrobenzaldehyde 2f, a significant drop in yield was observed (3%). iso-Butyraldehyde 2ae was selected as an aliphatic example and yielded 16% of porphyrin 7ae. 5,15-Bis(2,6-difluorophenyl)porphyrin 7m was formed in 26% yield, but condensations with more hindered ortho-aldehydes, mesitylaldehyde 2u and 2,6-dimethoxybenzaldehyde 2n, did not produce the anticipated porphyrins 7u and 7n. In contrast to the A₄ porphyrin 4w, the heterocyclic 5,15-bis(2-furyl)porphyrin 7w was not formed. Formation of A₂ porphyrins substituted with polycyclic aromatic hydrocarbons was also impeded, as neither the naphthalene porphyrin 7y, nor the anthracene derivative 7aa were isolated.

In the second part of the scope, benzaldehyde 2a was subjected to [2 + 2] MacDonald condensations with a small library of meso-substituted dipyrromethanes, i.e. 5-phenyldipyrromethane 5b, 5-(4-bromophenyl)dipyrromethane 5c, 5-(4-nitrophenyl)dipyrromethane 5d, 5-(4-carboxymethylphenyl)dipyrromethane 5e and 5-(4-acetamidophenyl)dipyrromethane 5f. However, under the optimised conditions (Table 5), the crude mixtures contained unreacted dipyrromethanes. Thus, flow rate was adapted to 0.5 mL min⁻¹ to allow longer residence time, and to drive the reactions to completion. Gratifyingly, this modification helped achieve full consumption of starting materials. Utilising aryl substituted dipyrromethanes 5b–f the tetrarylporphyrins 4a, 8c, 8f and 8g were formed in 28, 20, 11 and 5% yields, respectively. These values are lower than those reported previously for batch synthesis of the respective porphyrins 4a, 8c, 8f and 8g.^59,66 8ag was not formed under flow conditions. No scrambling was observed in these experiments.⁵⁹

Dodecasubstituted porphyrins

Recognising the unique properties arising from the shape of dodecasubstituted porphyrins, and their potential for applications in sensing,⁶⁷ organocatalysis⁶⁸ and photocatalysis⁶⁹ we focused on the third library of interest – 5,10,15,20-tetraaryl-2,3,7,8,12,13,17,18-octaethylporphyrins (H₂OETAP). To the best of our knowledge, this is the first flow-assisted method for the synthesis of dodecasubstituted porphyrins.

Optimisation. We optimised the synthetic and process conditions for condensation of benzaldehyde 2a and 3,4-diethylpyrrole 9, followed by in-batch oxidation of the porphyrinogen 10a and neutralisation (Scheme 5). Following the incremental differences in yield of 4a observed at different flow rates within the optimal concentration range (Table 6), here we applied a constant flow rate of 1.0 mL min⁻¹. The synthetic methods for dodecasubstituted porphyrins are significantly less studied than their tetra substituted counterparts.⁷⁰ Interestingly, BF₃·Et₂O, which is the standard acid catalyst used for H₂OETAP synthesis,⁷¹ did not promote macrocyclisation to form the desired porphyrinogen 10a under continuous flow, as evidenced by 0% yield obtained using 0.1 and 0.5 eq. BF₃·Et₂O at reagent concentrations c = 0.01 and c = 0.1 M (Table 6, entries 1–3). We then turned our attention to trifluoroacetic acid (TFA); attempts carried out at c = 0.01, c = 0.05 and c = 0.1 M did not result in the formation of the macrocycle (entries 4–6). Gratifyingly, p-toluenesulfonic acid (TSA) was found a suitable catalyst for this condensation (entries 7–13).

Scheme 5 CSTR-assisted synthesis of 11a (H₂OETPP).

Table 6 Optimisation of CSTR-assisted synthesis of 11a

Entry	Acid	MeOH [%v/v]	Conc. [M]	Yield [%]
a 0.1 eq. of BF3·Et2O was used.b 0.5 eq. of BF3·Et2O was used.
1^a	BF3·Et2O	0	0.010	0
2^a	BF3·Et2O	0	0.100	0
3^b	BF3·Et2O	0	0.010	0
4	TFA	0	0.010	0
5	TFA	0	0.050	0
6	TFA	0	0.100	0
7	TSA	0	0.010	0
8	TSA	0	0.050	6
9	TSA	0	0.100	16
10	TSA	0.1	0.050	10
11	TSA	1.0	0.050	20
12	TSA	1.0	0.100	30
13	TSA	1.0	0.200	21

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Using 1.0 eq. of TSA, we observed formation of porphyrin 11a with 6% isolated yield at c = 0.05 M concentration (Table 6, entry 8) and 16% at c = 0.1 M (Table 6, entry 9); at c = 0.01 M (typical batch concentration) porphyrin 11a was not isolated (entry 9). The low solubility of TSA in DCM was a significant limitation in these experiments. Hence, we examined the influence of methanol as a solubilising additive. A significant increase in isolated yield, from 6 to 10%, was observed when 0.1% (v/v) of MeOH was used (entries 8 and 10). The yield was increased 2-fold when 1% of MeOH was used (20%, entry 11). With these satisfactory results, we assessed the effect of the concentration of reactants on the yield, keeping in mind our aim to reduce the volume of chlorinated solvents required for porphyrin synthesis. Pleasingly, at c = 0.1 M porphyrin 11a was isolated in 30% yield (entry 12), but at c = 0.2 M the yield dropped to 21% (entry 13). Hence, the optimised conditions for the synthesis of dodecasubstituted porphyrins involve TSA as acid catalyst, c = 0.1 M in DCM/MeOH, 99 : 1, v/v and 1.0 mL min⁻¹ flow rate. As p-toluenesulfonic acid has not been used in the synthesis of dodceca substituted porphyrins to date, we carried out batch experiments using TSA for formation of 2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetraphenylporphyrin (11a, H₂OETPP); however no macrocycle was isolated at low (c = 0.01 M) or high (c = 0.1 M) concentrations.

Scope and limitations. In comparison to their planar counterparts, dodecasubstituted nonplanar porphyrins are relatively underexplored in terms of synthesis, functionalisation and applications.⁷⁰ Additionally, achieving a significant nonplanar distortion in a porphyrin greatly augments the porphyrins basicity.^72,73 This ring contortion makes the pyrrolic imine nitrogen atoms extremely susceptible to core protonation. In practical terms, H₂OETAPs are typically isolated as dication salts, and strong bases are required for isolation of ‘free base’ ligands.^74,75

Following the TSA-catalyzed condensation, we synthesised a library of ten dodecasubstituted porphyrins from a range of aldehydes and 3,4-diethylpyrrole 9 (Scheme 6). The highest yield in this library was observed for porphyrin 11e (45%), 2% higher than previously reported in literature^76a and 19% higher than the corresponding planar porphyrin 4e (26%, Scheme 2) under flow conditions. Electronically similar H₂OETPP 11a and octaethyltetra-p-tolylporphyrin 11b were isolated in 30 and 29% yields, respectively, with the latter having no comparable value in literature.^76b Both meta-disubstituted 3,5-dimethoxybenzaldehyde 2r and 3,5-dibromobenzaldehyde 2s produced the corresponding porphyrins 11r and 11s in good yields (29 and 35%, respectively). However, the condensation yield determined for the reaction with 3,5-di-tert-butylbenzaldehyde 2q was only 6% for 11q, a yield 10% lower than reported for batch synthesis.^76c Similarly, p-tert-butylbenzaldehyde 2d only produced 4% of the dication salt of porphyrin 11d. 11d was the only porphyrin in this series isolated as a dication, possibly due to an increased basicity of the porphyrin core due to activating electronic effects. p- And m-bromobenzaldehydes 2c and 2h yielded 20% and 19% of 11c and 11h, respectively the nonplanar meta-derivative was once again obtained in a higher yield than the planar 4h (7%, Scheme 2); the para-derivative with an isolated with a yield 13% lower than reported for batch conditions.^76d On the other hand, o-bromobenzaldehyde 2k was the poorest starting material in this library, with only a 2% isolated yield for 11k. This is likely due to the increased steric hindrance near the reacting atoms.³⁹ Alkyl groups substituting pyrrole C_β positions may augment this effect significantly; 11k was the only porphyrin isolated out of five ortho-substituted aldehydes investigated. Alkyl aldehydes 2ad and 2ae, furfural 2w and p-nitrobenzaldehyde 2f, and ortho-hindered benzaldehydes 2m, 2n, 2p failed to produce the corresponding porphyrins 11f, 11m, 11n, 11p, 11w, 11ad and 11ae (Scheme 6), contrary to the results reported for batch synthesis.⁷²

Scheme 6 Scope and limitations of CSTR-assisted synthesis of dodecasubstituted porphyrins. Yields in grey were reported in literature for batch syntheses.^{76 a}Yield not reported in literature. ^bCompound isolated as a dication salt. ^cFor porphyrins 11a and 11k, single crystal X-ray structures were obtained, full refinement details and analysis are provided in the SI (CCDC: 2521006 and 2521007).

E-Factors

To validate our methods as sustainable, we calculated E-factor (environmental impact factor)⁷⁷ for the protocols presented in this manuscript and compare them with corresponding values determined for batch protocols. E-Factor is one of the key descriptors used to assess the sustainability of a chemical reaction, considering the effectiveness in product formation over waste produced in the process. We selected E-factor as a measure of success in achieving our goal, which was to develop a sustainable and versatile flow-assisted protocol for porphyrin synthesis, reducing the volume of chlorinated solvent required for cyclisation.

In eqn (1) below, waste includes unreacted starting materials, catalysts, solvents, side products formed over the course of the reaction and materials and chemicals used in the work-up. Detailed analysis of waste contributions is disclosed in SI (Table S1).

Table 7 presents a comparison of E-factors calculated for protocols developed in this project and the corresponding values obtained for literature batch protocols. All values are presented for 4a (H₂TPP), 7a (H₂DPP) and 11a (H₂OETPP) syntheses as examples. The range of E-factor values for fine chemicals in industry is 5–50.^77a In porphyrin chemistry, the E-factor values for traditional synthesis of 4a (H₂TPP) range between 158 for Alder–Longo method and 2252 for Lindsey method.⁷⁸ Porphyrin synthesis is an environmentally taxing process, which is in part due to high dilutions required for macrocyclisation, combined with the side reactions predominant in acidic conditions.⁷⁹ We circumvented some of the problems associated with the synthesis of meso-substituted porphyrins. By incorporating flow chemistry at the condensation step, we successfully accessed higher global concentration of reactants, which directly translates to lower demand for chlorinated solvents, and decreasing the volume of waste produced in the process. This effect is quantified by E-factor. The comparison of E-factors for H₂TPP 4a, H₂DPP 7a and H₂OETPP 11a synthesis in flow and in batch shows significant improvement for all three methods presented in this contribution. The E values were reduced by 48% for 4a (from 2252 to 1180), 38% for 7a (from 2282 to 1416) and 35% for 11a (from 2015 to 1314). The reaction yield, type of acid catalyst, oxidant and possible additives have negligible influence on the E-factor (Table S1); the major contribution comes from the mass of solvents used for the synthesis and purification. Hence, the 90% decrease in solvent volume required for porphyrin synthesis in our method directly translates to significant improvements in sustainability parameters.

Table 7 E-Factors for compounds, 4a (H₂TPP), 7a (H₂DPP) and 11a (H₂OETPP)

Porphyrin	4a		7a		11a
Method	Flow	Batch	Flow	Batch	Flow	Batch
Scale [mmol]	2.25		0.75		1.10
Waste [g]	130	495	85	251	92	262
Product [g]	0.11	0.22	0.06	0.11	0.07	0.13
E-Factor^77

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Crystallography

Many examples of X-ray crystal structures of dodecasubstituted nonplanar porphyrins are found in the literature.^74,76,80 However, many H₂OETAP derivatives are often reported in their dicationic form with just one other example of a ‘free base’ OETAP being previously reported (11a, crystallised from ethanolic KOH).⁸¹ Here, the X-ray crystal structures of the ‘free base’ dodecasubstituted porphyrins 11a (from deuterated benzene) and 11k are reported, with 11k adopting the α₃β atropisomeric conformation (Fig. 3).⁸²

Fig. 3 (Left) View of the molecular structure of 11a in the crystal, depicting the hydrogen bond interactions in the porphyrin core. Deuterated benzene solvent molecules are omitted for clarity. (Right) View of the molecular structure of 11k in the crystal, showing the α₃β atropisomer and hydrogen bond interactions in the porphyrin core. Solvent molecules and hydrogen atoms on the porphyrin periphery are omitted for clarity.

Analysis of the view of the molecular structures in the crystal of 11a and 11k reveals the expected saddled shaped (B_2u) nonplanar distortion. For porphyrin 11k intramolecular hydrogen bonding interactions (2.29–2.34 Å) between both opposing enamine hydrogen atoms (N-21 and N-23) and the adjacent imine nitrogen atoms (N-22) are observed. A preferential hydrogen bonding of N-24 with the hydrogen atom of the CHCl₃ solvate is noted (Fig. 3). This solvent binding event is not observed in the case of 11a where enamine hydrogen atoms (N-21 and N-23) hydrogen bond (2.29–2.31 Å) to both adjacent imine nitrogen's (N-22 and N-24).

In contrast to the X-ray crystal structure of 11k, porphyrin 11a by when analyzed by NSD analysis has 3.4° greater tilt in the pyrroles from the mean porphyrin plane. Additionally, the total Δ_oop distortion of the ‘free base’ analogue (defined as the average deviation of the 24-atom macrocycle with respect to the mean porphyrin plane, Δz = 0)⁸³ is 3.48 Å in porphyrin 11a compared to 3.13 Å in 11k.

Comparing the crystal structure of ‘free base’ 11k with the analogous Ni(II) metalated cis-α₂β₂ atropisomeric derivative of 11k from literature^76e is difficult as conformationally these two porphyrins are quite different, nonetheless, the pyrrole tilt angle for the ‘free base’ 11k is 26° almost 3° less than the Ni(II) derivative. The total Δ_oop distortion of the ‘free base’ analogue is 0.64 Å less compared to the Ni(II) counterpart with a total Δ_oop distortion of 3.77 Å. Nevertheless, it is very difficult to make a direct comparison between the two structures due to disparate atropisomeric conformations as well differing crystallisation^76d and crystal packing effects.⁸⁴

Conclusions

In conclusion, we designed and optimised flow-based synthetic methods for meso-substituted porphyrin synthesis and demonstrated their applicability to three libraries of porphyrins: A₄, trans-A₂B₂ (including A₂) and dodecasubstituted A₄ porphyrins. These sustainable methods were optimised to operate at significantly higher reactant concentrations than traditional batch methods, leading to a dramatic decrease in the volume of chlorinated solvents required for porphyrin synthesis (up to 90% solvent saving), and a significant improvement in E-factors over batch conditions (up to 48% reduction of E values). The synthesis of 40 porphyrins is disclosed, alongside their structural details. We hope that this contribution proves useful to porphyrin chemists across the globe and prompts the use of sustainable protocols in porphyrin and other chemical laboratories.

Author contributions

Karolina Urbańska – conceptualisation, funding acquisition, methodology, investigation, project administration, writing – original draft; Liam Cribbin – conceptualisation, funding acquisition, investigation, writing – original draft; Brendan Twamley – investigation, formal analysis; Fiach O Ceallaigh – investigation; Mathias O. Senge – resources, supervision, writing – review & editing.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article is included as part of the supplementary information (SI) (compound characterisation, NMR, HRMS, UV/vis and IR spectra and refinement details). References cited in the SI (ref. 85–118) are listed in the article reference list. Supplementary information: compound characterisation data, spectra, CIF files, E-factor calculation. See DOI: https://doi.org/10.1039/d6su00176a.

CCDC 2521006 (11a) and 2521007 (11k) contain the supplementary crystallographic data for this paper.^119a,b

Acknowledgements

This project has received funding from Royal Society of Chemistry under Sustainable Laboratories Grant (award L23-8636817163) and from Taighde Éireann – Research Ireland (award 21/FFP-A/9469, PORPHYSHAPE).

Notes and references

1. P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, New York, 1998.
2. A. Halpaap, Green and Sustainable Chemistry: Framework Manual, The United Nations, 2020.
3. D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. J. L. Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A. Wells, A. Zak and T. Y. Zhang, Green Chem., 2007, 9, 411–420.
4. A. Jordan, P. Stoy and H. F. Sneddon, Chem. Rev., 2021, 121, 1582–1622.
5. Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC.
6. United States Environmental Protection Agency, Fed. Regist., 2024, 89, 39254.
7. F. Davis and S. Higson, Macrocycles: Construction, Chemistry, and Nanotechnology Applications, John Wiley & Sons, 2011.
8. A. K. Yudin, Chem. Sci., 2015, 6, 30–49.
9. A. C. Bédard, S. Régnier and S. K. Collins, Green Chem., 2013, 15, 1962–1966.
10. Q. Fan, T. Wang, J. Dai, J. Kuttner, G. Hilt, J. M. Gottfried and J. Zhu, ACS Nano, 2017, 11, 5070–5079.
11. F. Garnes-Portolés and A. Leyva-Pérez, ACS Catal., 2023, 13, 9415–9426.
12. P. J. Brothers and M. O. Senge, Fundamentals of Porphyrin Chemistry, Wiley, 2022.
13. L. Feng, K. Y. Wang, E. Joseph and H. C. Zhou, Trends Chem., 2020, 2(6), 555–568.
14. H. Lee, K.-I. Hong and W.-D. Jang, Coord. Chem. Rev., 2018, 354, 46–73.
15. (a) F. Santanni and A. Privitera, Adv. Opt. Mater., 2024, 12(18), 2303036; (b) D. Ranieri, A. Privetera, F. Santanni, K. Urbanska, G. J. Strachan, B. Twamley, E. Salvadori, Y. K. Liao, M. Chiesa, M. O. Senge, F. Totti, L. Sorace and R. Sessoli, Angew. Chem., Int. Ed., 2023, 62(48), e202312936.
16. H. Lee, H. Park, D. Y. Ryu and W. D. Jang, Chem. Soc. Rev., 2023, 52, 1947–1974.
17. W. M. Campbell, A. K. Burrell, D. L. Officer and K. W. Jolley, Coord. Chem. Rev., 2004, 248, 1363–1379.
18. R. Das, P. Kumar Verma and C. M. Nagaraja, Coord. Chem. Rev., 2024, 514, 215944.
19. D. Xu, Q. Duan, H. Yu and W. Dong, J. Mater. Chem. B, 2023, 11, 5976–5989.
20. J. Chen, Y. Zhu and S. Kaskel, Angew. Chem., Int. Ed., 2021, 60(10), 5010–5035.
21. D. Dolphin, J. Heterocycl. Chem., 1970, 7, 275–283.
22. P. Rothemund and A. R. Menotti, J. Am. Chem. Soc., 1941, 63, 267–270.
23. A. D. Adler, F. R. Longo and W. Shergalis, J. Am. Chem. Soc., 1964, 86, 3145–3149.
24. J. S. Lindsey, H. C. Hsu and I. C. Schreiman, Tetrahedron Lett., 1986, 27, 4969–4970.
25. K. M. Smith, New J. Chem., 2016, 40, 5644–5649.
26. M. O. Senge, N. N. Sergeeva and K. J. Hale, Chem. Soc. Rev., 2021, 50, 4730–4789.
27. T. Ishizuka, N. Grover, C. J. Kingsbury, H. Kotani, M. O. Senge and T. Kojima, Chem. Soc. Rev., 2022, 51, 7560–7630.
28. M. O. Senge, Chem. Commun., 2006, 243–256.
29. B. Habermeyer and R. Guilard, Photochem. Photobiol. Sci., 2018, 17, 1675–1690.
30. P. Ruggli, Adv. Cycloaddit., 1912, 392, 92–100.
31. K. Ziegler, H. Eberle and H. Ohlinger, Adv. Cycloaddit., 1933, 504, 94–130.
32. S. M. A. Pinto, C. A. Henriques, V. A. Tomé, C. S. Vinagreiro, M. J. F. Calvete, J. M. Dąbrowski, M. Piñeiro, L. G. Arnaut, M. M. Pereira and J. Porphyrins, Phthalocyanines, 2016, 20, 45–60.
33. A. M. d'A Rocha Gonsalves, J. M. T. B. Varejão and M. M. Pereira, J. Heterocycl. Chem., 1991, 28, 635–640.
34. P. B. Momo, B. S. Bellete, T. J. Brocksom, R. O. M. A. de Souza and K. T. de Oliveira, RSC Adv., 2015, 5, 84350–84355.
35. F. Parveen, H. J. Morris, H. West and A. G. Slater, J. Flow Chem., 2024, 14, 23–31.
36. T. E. O. Screen, K. B. Lawton, G. S. Wilson, N. Dolney, R. Ispasoiu, T. Goodson III, S. J. Martin, D. D. C. Bradley and H. L. Anderson, J. Mater. Chem., 2001, 11, 312–320.
37. O. Yadav, A. Varshney and A. Kumar, Inorg. Chem. Commun., 2017, 86, 168–171.
38. S. D. Roth, T. Shkindel and D. A. Lightner, Tetrahedron, 2007, 63, 11030–11039.
39. In a recent paper by Parveen et al. (ref. 35), the authors designed a fully continuous process with the steps of condensation, oxidation and neutralisation arranged in three consecutive coil reactors.
40. J. S. Lindsey, I. C. Schreiman, H. C. Hsu, P. C. Kearney and A. M. Marguerettaz, J. Org. Chem., 1987, 52, 827–836.
41. Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006.
42. (a) Merck Life Sciences Ltd, Chloroform, Safety Data Sheet, Version 8.9, Revision date 25.12.2025, https://www.sigmaaldrich.com/IE/en/sds/SIAL/288306; (b) Merck Life Sciences Ltd, Dichloromethane, Safety Data Sheet, Version 8.12, Revision date 23.12.2025, https://www.sigmaaldrich.com/IE/en/sds/SIAL/270997.
43. (a) J. B. Kim, J. J. Leonard and F. R. Longo, J. Am. Chem. Soc., 1972, 94, 3986–3992; (b) J. S. Lindsey and R. W. Wagner, J. Org. Chem., 1989, 54, 828–836.
44. (a) G. J. Capitosti, C. D. Guerrero, D. E. Binkley Jr, C. S. Rajesh and D. A. Modarelli, J. Org. Chem., 2003, 68, 247–261; (b) I. Yslas, M. G. Alvarez, C. Marty, G. Mori, E. N. Durantini and V. Rivarola, Toxicology, 2000, 149, 69–74; (c) C. A. Hunter, M. C. Misuraca and S. M. Turega, J. Am. Chem. Soc., 2011, 133, 582–594; (d) D. J. Walaszek, K. Maximova, K. Rybicka-Jasińska, A. Lipke and D. Gryko, J. Porphyrins Phthalocyanines, 2014, 18, 493–505; (e) Y. Ishimizu, Z. Ma, M. Hada and H. Fujii, Inorg. Chem., 2021, 60, 17687–17698; (f) M. Blanco, M. Lunardon, M. Bortoli, D. Mosconi, L. Girardi, L. Orian, S. Agnoli and G. Granozzi, J. Mater. Chem. A, 2020, 8, 11019–11030; (g) D. Oulmi, P. Maillard, J.-L. Guerquin-Kern, C. Huel and M. Momenteau, J. Org. Chem., 1995, 60, 1554–1564; (h) A. C. Kaelin and G. D. Zanelli, J. Labelled Compd. Radiopharm., 1990, 28, 343–354; (i) L. Huang, Y. Chen, G.-Y. Gao and X. P. Zhang, J. Org. Chem., 2003, 68, 8179–8184; (j) D. Yadav, A. Kumar, J. Y. Kim, N.-J. Park and J.-O. Baeg, J. Mater. Chem. A, 2021, 9, 9573–9580; (k) R. Soman, D. Raghav, S. Sujatha, K. Rathinasamy and C. Arunkumar, RSC Adv., 2015, 5, 61103–61117.
45. J. W. Dirks, G. Underwood, J. C. Matheson and D. Gust, J. Org. Chem., 1979, 44, 2551–2555.
46. N. Sheng, B. Gu, B. Ren, J. Zhang, Y. Wang, J. Wang and J. Sha, Dyes Pigm., 2017, 142, 116–120.
47. I. Radivojevic, I. Likhtina, X. Shi, S. Singh and C. M. Drain, Chem. Commun., 2010, 46, 1643–1645.
48. J. M. Cense and R.-M. Le Quan, Tetrahedron Lett., 1979, 3725–3728.
49. A. Treibs and N. Häberle, Liebigs Ann. Chem., 1968, 718, 183–207.
50. H. Volz and G. Herb, Z. Naturforsch., B: Anorg. Chem., Org. Chem., 1984, 39, 1393–1398.
51. M. Baljozović, J. Pijeat, S. Campidelli and K.-H. Ernst, J. Am. Chem. Soc., 2024, 146, 34600–34608.
52. M. O. Senge, I. Bischoff, N. Y. Nelson and K. M. Smith, J. Porphyr. Phthalocyanines, 1999, 3, 99–116.
53. M. M. Martin, C. Oleszak, F. Hampel and N. Jux, Eur. J. Org Chem., 2020, 2020, 6758–6762.
54. I. Gupta and M. Ravikanth, Tetrahedron, 2003, 59, 6131–6139.
55. T. Ema, M. O. Senge, N. Y. Nelson, H. Ogoshi and K. M. Smith, Angew. Chem., Int. Ed., 1994, 33, 1879–1881.
56. V. V. Borovkov, M. Anikin, K. Wasa and Y. Sakata, Photochem. Photobiol., 1996, 63, 477–482.
57. S. Banfi, E. Caruso, S. Caprioli, L. Mazzagatti, G. Canti, R. Ravizza, M. Gariboldi and E. Monti, Bioorg. Med. Chem., 2004, 12, 4853–4860.
58. G. D. Carlo, A. O. Biroli, M. Pizzotti, F. Tessore, V. Trifiletti, R. Ruffo, A. Abbotto, A. Amat, F. De Angelis and P. R. Mussini, Chem.–Eur. J., 2013, 19, 10723–10740.
59. G. R. Geier III, B. J. Littler and J. S. Lindsey, J. Chem. Soc., Perkin Trans. 2, 2001,(5), 701–711.
60. K. S. Suslick, C. T. Chen, G. R. Meredith and L. T. Cheng, J. Am. Chem. Soc., 1992, 114, 6928–6930.
61. M. J. A. Reis, A. M. V. M. Pereira, N. M. M. Moura and M. G. P. M. S. Neves, ACS Omega, 2024, 9, 31196–31219.
62. D. Pan, P. Liang, X. Zhong, D. Wang, H. Cao, W. Wang, W. He, Z. Yang and X. Dong, ACS Appl. Bio Mater., 2019, 2, 999–1005.
63. G. P. Arsenault, E. Bullock and S. F. MacDonald, J. Am. Chem. Soc., 1960, 82, 4384–4389.
64. J. Jökel, F. Schwer, M. von Delius and U. P. Apfel, Chem. Commun., 2020, 56, 14179–14182.
65. (a) X. Jiang, T. Zhang and F. Gou, Mol. Catal., 2024, 555, 113865; (b) S. Arrechea, A. Molina-Ontoria, A. Aljarilla, P. de la Cruz, F. Langa and L. Echegoyen, Dyes Pigm., 2015, 121, 109–117; (c) C. Schissler, E. K. Schneider, S. Lebedkin, P. Weis, G. Niedner-Schatteburg, M. M. Kappes and S. Bräse, Chem.–Eur. J., 2021, 27, 15202–15208; (d) M. C. Kuo, H. F. Chen, J. J. Shyue, D. M. Bassani and K. T. Wong, Chem. Commun., 2012, 48, 8051–8053; (e) M. Handayani, S. Gohda, D. Tanaka and T. Ogawa, Chem.–Eur. J., 2014, 20, 7655–7664; (f) S. M. S. Ló, D. R. B. Ducatti, M. E. R. Duarte, S. M. W. Barreira, M. D. Noseda and A. G. Gonçalves, Tetrahedron Lett., 2011, 52, 1441–1443; (g) R. Elliott, A. A. Ryan, A. Aggarwal, N. Zhu, F. W. Steuber, M. O. Senge and W. Schmitt, Molecules, 2021, 26, 2955; (h) Y. Xie, F. Zhang, P. Liu, F. Hao and H. a. Luo, Can. J. Chem., 2014, 92, 49–53; (i) S. M. Kuzmin, S. A. Chulovskaya and V. I. Parfenyuk, J. Electroanal. Chem., 2023, 943, 117594; (j) J. Deyerling, B. Berionni Berna, D. Biloborodov, F. Haag, S. Tömekce, M. G. Cuxart, C. Li, W. Auwärter and D. Bonifazi, Angew. Chem., Int. Ed., 2025, 64, e202412978.
66. Y. B. She, H. Y. Fu, Z. L. Zhang, X. F. Song and Z. C. Sun, Heterocycles, 2014, 89, 503–514.
67. K. Norvaiša, K. J. Flanagan, D. Gibbons and M. O. Senge, Angew. Chem., Int. Ed., 2019, 58, 16553–16557.
68. M. Roucan, M. Kielmann, S. J. Connon, S. S. R. Bernhard and M. O. Senge, Chem. Commun., 2018, 54, 26–29.
69. T. Ishizuka, S. Ohkawa, H. Ochiai, M. Hashimoto, K. Ohkubo, H. Kotani, M. Sadakane, S. Fukuzumi and T. Kojima, Green Chem., 2018, 20, 1975–1980.
70. Only 434 Records Found for “Nonplanar Porphyrin” in a Scopus Search, Compared to 82,358 Records for the Keyword “Porphyrin”, Making up <1% of the Field, (accessed January 2026).
71. B. Evans, K. M. Smith and J. H. Fuhrhop, Tetrahedron Lett., 1977, 18, 443–446.
72. (a) A. Neuberger and J. J. Scott, Proc. R. Soc. London, Ser. A, 1952, 213, 307–326; (b) O. S. Finikova, A. V. Cheprakov, P. J. Carroll, S. Dalosto and S. A. Vinogradov, Inorg. Chem., 2002, 41, 6944–6946.
73. M. Kielmann and M. O. Senge, Angew. Chem., Int. Ed., 2019, 58, 418–441.
74. M. O. Senge, T. P. Forsyth, L. T. Nguyen and K. M. Smith, Angew. Chem., Int. Ed., 1995, 33, 2485–2487.
75. M. O. Senge and W. W. Kalisch, Z. Naturforsch., 1999, 54b, 943–959.
76. (a) Yu. B. Ivanova, N. Zh. Mamardashvili, A. V. Glazunov and A. S. Semeikin, Russ. J. Gen. Chem., 2014, 84, 1404–1410; (b) E. I. Sagun and E. I. Zenkevich, Opt. Spectrosc., 2013, 115, 727–738; (c) K. Norvaiša, K. Yeow, B. Twamley, M. Roucan and M. O. Senge, Eur. J. Org Chem., 2021, 2021, 1871–1882; (d) K. J. Flanagan, B. Twamley and M. O. Senge, Inorg. Chem., 2019, 58, 15769–15787; (e) L. Cribbin, B. Twamley, N. Buga, J. E. O'Brien, R. Bühler, R. A. Fischer and M. O. Senge, Beilstein J. Org. Chem., 2025, 20, 2784–2798; (f) K. M. Barkigia, M. D. Berber, J. Fajer, C. J. Medforth, M. W. Renner and K. M. Smith, J. Am. Chem. Soc., 1990, 112, 8851–8857; (g) K. M. Kadish, M. Lin, E. V. Caemelbecke, G. De Stefano, C. J. Medforth, D. J. Nurco, N. Y. Nelson, B. Krattinger, C. M. Muzzi, L. Jaquinod, Y. Xu, D. C. Shyr, K. M. Smith and J. A. Shelnutt, Inorg. Chem., 2002, 41, 6673–6687; (h) A. Hoshino, Y. Ohgo and M. Nakamura, Tetrahedron, 2005, 46, 4961–4964.
77. (a) R. A. Sheldon, Chem. Ind., 1992, 903–906; (b) R. A. Sheldon, J. Chem. Technol. Biotechnol., 1997, 68, 381–388.
78. C. A. Henriques, S. M. A. Pinto, G. L. B. Aquino, M. Pineiro, M. J. F. Calvete and M. M. Pereira, ChemSusChem, 2014, 7(10), 2821–2824.
79. H. Hölzel, M. Muth, D. Lungerich and N. Jux, Chem.:Methods, 2021, 1, 142–147.
80. C. J. Kingsbury, M. Kielmann, B. Twamley and M. O. Senge, Molecules, 2022, 27, 7060.
81. A. Regev, T. Galili, C. J. Medforth, K. M. Smith, K. M. Barkigia, J. Fajer and H. Levanon, J. Phys. Chem., 1994, 98, 2520–2526.
82. S. Maguire, G. Strachan, K. Norvaiša, C. Donohue, L. Gomes-da-Silva and M. O. Senge, Chem.–Eur. J., 2024, 30, e202401559.
83. W. Jentzen, X.-Z. Song and J. A. Shelnutt, J. Phys. Chem. B, 1997, 101, 1684–1699.
84. W. R. Scheidt and Y. J. Lee, in Structure and Bonding, ed. J. W. Buchler, Springer-Verlag, Berlin, 1987, vol. 64, p. 1.
85. R. A. W. Johnstone, M. L. P. G. Nunes, M. M. Pereira, A. M. d'A, R. Gonsalves and A. C. Serra, Heterocycles, 1996, 43, 1423–1437.
86. F. Liu, L. Duan, Y. Wang, Q. Zhang and J. Wang, Synth. Commun., 2009, 39, 3990–3998.
87. O. V. Malkova, V. G. Andrianov, B. D. Berezin, A. S. Semeikin and I. I. Zhilina, Zh. Org. Khim., 1988, 24, 1546–1550.
88. G. Mele, R. D. Sole, G. Vasapollo, E. Garcia-Lopez, L. Palmisano and M. Schiavello, J. Catal., 2003, 217, 334–342.
89. Y. Naruta, F. Tani, N. Ishihara and K. Maruyama, J. Am. Chem. Soc., 1991, 113, 6865–6872.
90. M. Yaseen, M. Ali, M. N. Ullah, M. A. Munawar and I. Khokbar, J. Heterocycl. Chem., 2009, 46, 251–255.
91. H. Lv, B. Yang, J. Jing, Y. Yu, J. Zhang and J. L. Zhang, Dalton Trans., 2012, 41, 3116–3118.
92. I. Gupta and M. Ravikanth, Tetrahedron Lett., 2002, 43, 9453–9455.
93. C. H. da Silveira, E. N. Garoforo, O. A. Chaves, P. F. B. Goncalves, L. Streit and B. A. Iglesias, Inorg. Chim. Acta, 2018, 482, 542–553.
94. P. Kus, G. Knerr and L. Czuchjakowski, J. Heterocycl. Chem., 1990, 27(4), 1161–1166.
95. T. Zoltan, F. Vargas, C. Rivas, V. Lopez, J. Perez and A. Biasutto, Sci. Pharm., 2010, 78, 767–790.
96. N. Sheng, P. H. Zhu, C. Q. Ma and J. Z. Jinag, Dyes Pigm., 2009, 81, 91–96.
97. R. Plamont, Y. Kikkawa, M. Takasahi, M. Kanesato, M. Giorgi, A. C. K. Shun, C. Roussel and T. S. Balaban, Chem.–Eur. J., 2013, 19, 11293–11300.
98. A. Auger, A. J. Muller and J. C. Swarts, Dalton Trans., 2007, 33, 3623–3633.
99. J. S. Manka and D. S. Lawrence, Tetrahedron Lett., 1989, 30, 6989–6992.
100. C. Ryppa, M. O. Senge, S. S. Hatscher, E. Kleinpeter, P. Wacker, U. Schilde and A. Wiehe, Chem.–Eur. J., 2005, 11, 3427–3442.
101. D. Bonifazi, G. Accorsi, N. Armaroli, F. Song, A. Palkar, L. Echegoyen, M. Scholl, P. Seiler, B. Jaun and F. Diedrich, Helv. Chim. Acta, 2005, 88(7), 1839–1884.
102. R. Shediac, M. H. B. Gray, H. T. Uyeda, R. C. Johnson, J. T. Hupp, P. J. Angiollo and M. J. Therien, J. Am. Chem. Soc., 2000, 122, 7017–7033.
103. X. Z. Song, W. Jentzen, S. L. Jia, L. Jaquinod, D. J. Nurco, C. J. Medforth, K. M. Smith and J. A. Shelnutt, J. Am. Chem. Soc., 1996, 118, 12975–12988.
104. B. Temelli and C. Unaleroglu, Tetrahedron, 2009, 65, 2043–2050.
105. W. Anannarukan, S. Tantayanon, D. Zhang, E. A. Alemán, D. A. Modarelli and F. W. Harris, Polymer, 2006, 47, 4936–4945.
106. M. B. Bakar, M. Oelgemöller and M. O. Senge, Tetrahedron, 2009, 65, 7064–7078.
107. N. Rana, S. Kumari and M. Sankar, Chem.–Asian J., 2025, 20, e202400719.
108. C. R. Jen, R. J. Cheng, C. C. Chen, G. H. Lee, S. M. Peng and P. P. Y. Chen, Inorg. Chem., 2014, 53, 8848–8850.
109. H. Hope, in Progress in Inorganic Chemistry, ed. K. D. Karlin, John Wiley & Sons, 1994, vol. 41, pp. 1–19.
110. Bruker, SAINT, v8.41B, Bruker AXS SE, Karlsruhe, Germany, 2004.
111. L. Krause, R. Herbst-Irmer, G. M. Sheldrick and D. Stalke, J. Appl. Crystallogr., 2015, 48, 3–10.
112. G. M. Sheldrick, Acta Crystallogr., 2015, A71, 3–8.
113. G. M. Sheldrick, Acta Crystallogr., 2015, C71, 3–8.
114. O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard and H. J. Puschmann, J. Appl. Crystallogr., 2009, 42, 339–341.
115. C. J. Kingsbury and M. O. Senge, Coord. Chem. Rev., 2021, 431, 213760.
116. C. J. Kingsbury and M. O. Senge, Angew. Chem., Int. Ed., 2024, 63, e202403754.
117. C. R. Groom, I. J. Bruno, M. P. Lightfoot and S. C. Ward, Acta Crystallogr., 2016, B72, 171–179.
118. D. Kratzert, FinalCif., https://dkratzert.de/finalcif.html.
119. (a) CCDC 2521006: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2qm9sg; (b) CCDC 2521007: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2qm9th.

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