Introduction

Tetrapyrrolic macrocycles are a class of cyclic compounds that contain four pyrrolic units in their ring. Examples of these are porphyrins, chlorins, porphyrazines, bacteriochlorins, corroles, calix[4]pyrroles, and phthalocyanines. One of the major differences between these pyrrolic macrocycles is how the adjacent pyrrole rings are connected. The most widely studied tetrapyrrolic macrocycles are typically π‐conjugated (aromatic) organic heterocyclic systems, excluding calix[4]pyrroles, which are colorless and non-aromatic, as well as norcorroles, isophlorins, and the 16π oxidized form of porphyrin that exhibits anti-aromatic character (Figure 1a). Calix[4]pyrroles possess a nonplanar structure and a high degree of conformational flexibility, allowing them to adopt four key conformations: 1,3-alternate, cone, partial cone, and 1,2-alternate . Calix[4]pyrroles are one of the most studied hosts in supramolecular chemistry, finding use in applications of molecular recognition and extraction, drug delivery, ion transport and separation technology . Conversely, porphyrins are connected via methine (=CH-) bridges, resulting in an 18 π-electron macrocyclic system affording macrocyclic planarity as well as unique photophysical and electrochemical properties (Figure 1b). While corroles share similarities with porphyrins, the direct linkage between their pyrrole units leads to a more contracted cavity compared to that of porphyrins. Similar to calix[4]pyrroles, synthetic metallo- and free-base (metal-free) porphyrins find various applications in the fields of medicine, energy, catalysis, molecular recognition, and supramolecular assemblies . There are numerous examples of using metalloporphyrins as artificial photosynthesis models, enzyme mimics, and catalysts for various organic transformations, where a metal center acts as an active site . However, metal-free (or free-base) macrocycles have not been explored as much in terms of catalysis, even though they are starting compounds for the preparation of their metallated analogues that are commonly used as catalysts.

Figure 1: Chemical structures of the main tetrapyrrolic macrocycles studied in this review for their role as catalyst. a) calix[4]pyrrole 1 and b) porphyrin 2a and corrole 2b. The 18 π-electron aromatic system of porphyrin and corrole is highlighted by the red colour.

In contrast with a calix[4]pyrrole macrocycle with four NHs (from four pyrrole units), a metal-free porphyrin macrocycle contains two Ns and two NHs (from two pyrrolenine and two pyrrole units), both of which can act as supramolecular H-bond donor and acceptors and can promote metal-free catalysis. Additionally, due to their synthetic versatility, these macrocycles can be further functionalized to add other binding sites required for substrate binding and/or promotion of the catalytic activity. Past studies have shown that modifying the porphyrin core with urea functionalities and amino acid substituents leads to the formation of ureaporphyrins, which significantly enhance sugar binding in non-polar solutions . Similarly, Burns and co-workers reported di- and tetra-urea picket porphyrins highlighting, the impact of buried solvent molecules, such as DMSO, on the selectivity, affinity, and stoichiometry of anion binding . Iron complexes of tetra-urea picket porphyrins further demonstrate how second-sphere interactions with a multipoint hydrogen-bonding pattern enhance CO2 reduction in organic solvents, improving stability, facilitating proton transfer, reducing energy barriers, and increasing selectivity . Apart from advances in synthetic methodologies , the exploration of these macrocyclic catalysts is in a very nascent stage. In this review, the recent advancement in the field of metal-free macrocycles for catalysis will be summarized; mainly focused on porphyrins and calix[4]pyrroles and in the field of organocatalysis, photocatalysis, and electrocatalysis.

Review 1 Metal-free tetrapyrrolic macrocycles as supramolecular organocatalysts

Supramolecular organocatalysis has recently attracted emerging attention as a green alternative to metal-based catalysis . Organocatalysis using macrocyclic scaffolds such as crown ethers, cyclodextrins, cucurbiturils, and calixarenes has been extensively studied using both enzyme mimics and non-biomimetic systems, due to the presence of an internal cavity (binding sites) and nearby functional groups (catalytic sites) . Tetrapyrrolic macrocycles contain an internal cavity with multiple inner –N/NH groups that function as hydrogen-bond donors and acceptors. Additionally, the nitrogen atoms in the pyrrole units of the porphyrin structure can also act as Lewis bases, capable of donating electron pairs. These properties enable tetrapyrrolic macrocycles to act as effective binding sites or catalytically active groups for a variety of substrates, making their use as supramolecular organocatalysts based on bifunctional activation mechanism (hydrogen-bonding/Lewis basicity) highly promising. At the same time, additional functional groups that are required for the catalysis can be easily installed on the periphery of tetrapyrrolic macrocycles using well established methodologies. This section focuses on examples where tetrapyrrolic macrocycles serve as organocatalysts. Firstly, various applications of calix[4]pyrroles as organocatalysts will be examined, followed by a discussion on organocatalysis using metal-free porphyrins.

1.1 Calix[4]pyrrole macrocycles as organocatalysts

Calix[4]pyrroles act as versatile ligands in supramolecular chemistry and have been widely studied as binding hosts for various guests such as anions, ion pairs, or neutral compounds , ligands for p-block elements, as well as transition and rare-earth metals . There are many comprehensive reviews covering these two areas along with the connection of these ligands to supramolecular and medicinal chemistry . In addition, calix[4]pyrroles, due to the presence of four accessible inner NHs and well-defined binding pockets, offer a preorganized arrangement of functional groups as a suitable microenvironment for organocatalysis.

In 2008, Kohnke, Soriente and co-workers first reported the H-bonding organocatalytic activity of calix[4]pyrrole derivatives 3 and 4 and acyclic dipyrromethane 5 for the hetero-Diels–Alder reaction of Danishefsky's diene 6 with p-nitrobenzaldehyde (7, Figure 2). The reaction can provide three products depending on the reaction conditions; either a Mukaiyama aldol (8) or products of Diels–Alder cycloaddition (9 and 10). Out of the three screened catalysts, only calix[4]pyrrole α,β-isomer 4 was found to be catalytically active providing a 57% conversion to 10, suggesting a concerted cycloaddition mechanism. Calix[4]pyrrole α,α-isomer 3 and dipyrromethane 5 were catalytically inactive. The authors concluded that the catalytic inactivity of 3 is caused by the parallel orientation of p-nitrophenyl units, due to the shielding of the bound aldehyde substrate from the incoming diene. The catalytic inactivity of 5 demonstrated the requirement of macrocyclic character for the potential catalysts.

Figure 2: Calix[4]pyrroles 3 and 4 and an their acyclic analogue 5 used for the transformation of Danishefsky's diene 6 and p-nitrobenzaldehyde (7) to the respective Mukayama aldol (8) and products of a hetero-Diels–Alder reaction (9 and 10); p-nitrophenyl units in red and blue, pointing upwards and downwards, respectively. Adapted from .

Later in 2009, the same group reported an organocatalyzed diastereoselective aldol addition of furan-based silyloxydiene synthons to a variety of achiral aldehydes using four different calix[4]pyrrole macrocycles (3, 4, 11, and 12) as organocatalysts (Figure 3) . These calixpyrrole macrocycles acted as hydrogen-bond donors, activating substrate aldehydes through hydrogen-bonding interactions and accelerating aldol reactions. In the absence of a catalyst, no reaction between 2-(trimethylsilyloxy)furan (TMSOF, 13) and benzaldehyde (14) was observed, whereas all the tested macrocyclic compounds were found catalytically active, with 11 being the most efficient providing erythro/threo (15/16) aldol products with up to 82% yield in a 70:30 diastereoisomeric ratio.

Figure 3: Calixpyrrole-based organocatalysts 11 and 12 for the diastereoselective addition reaction of TMSOF 13 and benzaldehyde (14) providing the respective erythro 15 and threo 16 aldol product. Adapted from .

A decade after, Ema, Maeda and co-workers investigated using of calix[4]pyrrole macrocyclic organocatalysts for the synthesis of cyclic carbonates 21 from epoxides 20 (1,2-epoxyhexane) and CO2. For this purpose, they used three different types of macrocycles: calix[4]pyrroles 11, 17a–c, porphyrin 18, and calix[4]arene 19 (Figure 4a). Despite the presence of –OH and –NH binding sites, both calix[4]arene 19 and porphyrin 18 showed only a negligible activity compared to calix[4]pyrroles (11, 17a–c), which provided, with TBAI as a co-catalyst, up to 74% yields (Table 1). The inactivity of porphyrin 18 was attributed to the inaccessibility of the inner core imine due to its planar structure. The mechanism of the epoxide ring-opening reaction was elucidated by DFT calculations, which suggested that the macrocycle adopts a 1,3-alternate conformation and binds simultaneously to the epoxide O-atom and iodide anion via (NH···O and NH···I) hydrogen-bonding interactions. The TBA countercation is bound to the O-atom of the epoxide ring with hydrogen bonds and is situated away from the I− anion. This crucial transition state stabilizes the anionic species generated during the reaction pathway and facilitates a backside attack of I− on the epoxide thus resulting in the initial ring opening (Figure 4b).

Figure 4: (a) Chemical structures of macrocyclic organocatalysts used for the synthesis of cyclic carbonates from epoxides and CO2; (b) Structure of the DFT-calculated transition state in the 11/TBAI-catalysed reaction of 1,2-epoxyhexane 20 with CO2. Adapted from .

Table 1: Organocatalytic activity of calix[4]pyrrole macrocycles 11, 17a–c for CO2 insertion into the epoxide 20 leading to the cyclic carbonate 21.

Catalyst Yield (%) – 21 11 74 11a 0 17a 28 17b 40 17c 41 18b 9 19b 9

aWithout TBAI; bcat. (0.5 mol %), TBAI (1 equiv to cat.), 75 °C, 6 h.

Apart from acting as an organocatalyst, calix[4]pyrrole 11 has been used for the promotion of cuprous chloride-catalyzed aziridination of styrene (22) by chloramine-T (23, NaCl=NTs) as a source of nitrene in acetonitrile (Figure 5) . No aziridine product was formed either without any source of copper or in the presence of a different copper salt, such as CuCl, CuCl2·2H2O, or CuOTf. Calix[4]pyrrole itself is catalytically inactive, but the mixture of CuCl (7 mol %) and calix[4]pyrrole (14 mol %) resulted in a 74% yield of 1-tosyl-2-phenylaziridine (24). Considering the significant shift (from 7.48 to 9.98) in the N–H signal of calix[4]pyrrole after the addition of CuCl, the authors suggested that calix[4]pyrrole activates the Cu–Cl bond via chloride···calixpyrrole (N–H···Cl) hydrogen-bonding interactions toward the formation of the nitrene intermediate from chloramine-T (NaCl=NTs). Additionally, calix[4]pyrrole served as a phase-transfer catalyst in this reaction. Since chloramine-T had low solubility in acetonitrile, calix[4]pyrrole enhanced its solubility, contributing to its indirect activation. Various control experiments, such as using CuI with and without calix[4]pyrrole and using dipyrromethane as another potential co-catalyst, have confirmed the role of calix[4]pyrrole as a promoter.

Figure 5: Cuprous chloride-catalyzed aziridination of styrene (22) by chloramine-T (23) providing 1-tosyl-2-phenylaziridine (24) (top); suggested structure of a catalytically active intermediate of CuCl and calix[4]pyrrole 11 (below). Adapted from .

Recently, Ballester and co-workers reported on the preparation of an octapyridinium-based water-soluble superaryl-extended calix[4]pyrrole molecular container and used it as a capsule for desymmetrization reactions , where the reported compound acts both as sequestering and supramolecular protecting group.

All of the examples mentioned above indicate that calix[4]pyrroles can be used as organocatalysts. Despite major advancements in synthetic methodologies to synthesize functionalized calix[4]pyrrole macrocycles, not much progress has been done in this area in recent years. One of the major challenges of using calix[4]pyrroles as catalysts may be related to their conformational flexibility, that leads to less preorganized binding and catalytic sites. Calix[4]pyrroles in solution exist in four-different conformations (cone, partial cone, 1,3-alternate, and 1,2-alternate); this macrocyclic flexibility arises due to the sp3-linkage between the pyrrole units that allows their inversion through the plane of the macrocycle and could inhibit the organocatalytic activity.

1.2 Porphyrin macrocycles as organocatalysts

Porphyrins can coordinate almost any metal from the periodic table , they offer high functional versatility , and many of these resulting metal complexes are catalytically active . These synthetic metalloporphyrins take inspiration from biological systems, such as hemes (iron complexes), chlorophylls (magnesium complexes), and vitamin B12 (cobalt complex).

Contrary to metalloporphyrins that are easily accessible for the incoming substrates, pyrrole –N/NH moieties inside the core of metal-free porphyrins are mostly hidden and unavailable for any kind of intermolecular hydrogen-bonding interactions or molecular recognition as they are 'shielded' by the planar macrocyclic system . Therefore, most of the work involving metal-free porphyrins is limited to investigations on N–H tautomerization and protonation–deprotonation studies . However, there are several chemical tools to convert the planar geometry of porphyrins to nonplanar, such as functionalization at β- and meso-positions, N-alkylation, arylation or protonation, interruption of the conjugated system, reduction/oxidation of the macrocycle and/or strapping of the macrocycle via covalent linkage of the meso- or β-pyrrole positions . These alternations can significantly affect the optical and electronic properties, as well as the reactivity of porphyrins, mainly introducing non-planarity with easier access to the inner pyrrolic –NHs and –N-lone pairs. Additionally, these alterations potentially increase Lewis basicity that further improves interactions with substrates. Changes in the reduction or oxidation state can alter redox behavior, thereby affecting catalytic activity. For example, it has been reported that 2,3,5,7,8,10,12,13,15,17,18,20-dodecasubstituted free-base porphyrins and their mono/diprotonated derivatives are highly distorted with a good access to the pyrrolic N/N–H moieties . Overall, these alterations provide a versatile toolkit for tailoring porphyrin properties for various applications.

In 2017, Senge and co-workers, reported the first example of using metal-free tetrapyrrolic porphyrins as bifunctional organocatalysts, confirming that the distortion/nonplanarity of the macrocycle and the resulting availability of pyrrolic protons is necessary for catalytic activity . A set of 18 different metal-free porphyrins (non-alkylated, neutral alkylated, and cationic alkylated) with varying degrees of distortion from planarity as well as different electronic properties (18, 25–41, Figure 6) were screened as catalysts for the sulfa-Michael addition of tert-butyl benzylmercaptan 42 to phenyl vinyl sulfone (43). Without the addition of a porphyrin, no product was formed. Among the non-alkylated porphyrins (18, 25–32) only the ones containing ethyl groups at the β-position and C6H5 or 4-Me-C6H4 at the meso-position (26 and 28) were catalytically active, giving more than 98% conversion, whereas the planar derivatives; H2OEP (2,3,7,8,12,13,17,18-octaethylporphyrin (25)), H2TPP (5,10,25,20-tetraphenylporphyrin (18)) and all the compounds with electron-withdrawing substituents at the meso- and/or β-positions and highly saddle-distorted geometry (27, 29–31) are inactive (Table 2). Mono-N-alkylation of the macrocycles resulted in a slight improvement of activity giving up to 50–62% conversion for 34 and 37, both of which are alkylated versions of an inactive tetraarylporphyrin 18, by increasing the porphyrin basicity and distortion. On the other hand, di-N-alkylation of 18 (providing compound 38) reduced the catalytic activity to only 5% conversion. The authors also screened cationic N-alkylated macrocycles (39–41) and found that only 39 with one remaining –NH group is catalytically active while both tri- and tetraalkylated analogues 40 and 41, without an –NH unit, are not. Further, the authors performed 1H NMR experiments with a different substrate:macrocycle ratio and suggested a bifunctional reaction mechanism involving both inner amine and imine groups (Figure 7).

Figure 6: Chemical structures of the various porphyrin macrocycles (18, 25–41) screened as potential catalysts of the sulfa-Michael addition reaction between thiol 42 and phenyl vinyl sulfone (43). Adapted from .

Table 2: Organocatalytic activity of porphyrins 18, 25–41 for the synthesis of 44 from 42 and 43.

Catalyst Yield (%)a – 0 18, 25, 27, 29-32 0 26 >98 28 >98 33 <5 34 50 35 >98 36 3 37 62 38 5 39 >98 40, 41 0

aDetermined by 1H NMR spectroscopy using an internal standard.

Figure 7: Organocatalytic activity of distorted porphyrins explored by Senge and co-workers. Planar macrocycle 18 is unable to bind/activate small molecules. With the increase in distortion, the macrocycle’s core becomes available for intermolecular interactions. Figure 7 was adapted from , M. Kielmann et al., ‘’Incremental Introduction of Organocatalytic Activity into Conformationally Engineered Porphyrins’’, Eur. J. Org. Chem., with permission from John Wiley and Sons. Copyright © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This content is not subject to CC BY 4.0.

Later the same group synthesized a series of five macrocycles derived from tetraphenylporphyrin (H2TPP) with a different number of ethyl substituents at the β-positions; H2EtxTPPs (x = 0, 2, 4, 6, 8; 18, 45–47, 26, Figure 8) to explore the effect of electronic and steric factors on the organocatalytic performance in the same reaction as before (Table 2) . Among the tested compounds, the highly nonplanar macrocycle 26 with a good accessibility of both pyrrolic –N/N–H moieties turned out to be the best candidate, giving an 80% conversion yield, whereas the other compounds (18, 45–47) provided only a trace amount of the product.

Figure 8: Chemical structures of H2EtxTPP (x = 0, 2, 4, 6, 8) compounds with incrementally increasing nonplanarity used to explore effect of electronic and steric factors on the organocatalytic activity. Figure 8 was adapted from , M. Kielmann et al., ‘’Incremental Introduction of Organocatalytic Activity into Conformationally Engineered Porphyrins’’, Eur. J. Org. Chem., with permission from John Wiley and Sons. Copyright © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. This content is not subject to CC BY 4.0.

Considering the nonplanarity of a metal-free porphyrin as an essential requirement for its catalytic activity, Hill and co-workers explored the use of oxidized porphyrin macrocycles, also known as oxoporphyrinogens (OxPs), 48 and 49 for the 1,4-conjugate addition (Michael addition) of 2,4-pentanedione (51) to β-nitrostyrene (50) (Figure 9) . The OxP-macrocycles turned out to combine the advantages of porphyrins and calix[4]pyrroles. Due to their nonplanar geometry, OxPs have easily accessible inner –NH groups, similarly to calix[4]pyrroles, and at the same time their conformation is rigid due to the presence of sp2-hybridized carbon bridges between the pyrrole units and alkyl groups on two of the inner N atoms of the macrocycle . Among the OxP derivatives tested for organocatalysis (48a–i and 49a–i), only N-dialkylated ones with secondary amine side arm (48d, 48g, h) were catalytically active for Michael additions, providing 60–71% yields (Table 3), whereas tetraalkylated analogues (49a–g) and dialkylated OxPs without a secondary amine side arm (48a–c, 48e and 48i) were not. Based on these results, the authors have concluded that both the presence of hydrogen-bond donor moieties (pyrrolic –NH groups) and a basic β-substituent are necessary to make the compound catalytically active. Further, authors have performed 1H NMR binding and kinetic studies and suggested that the reaction mechanism involves a simultaneous activation of both substrates via hydrogen-bonding interactions. Additionally, these macrocycles showed excellent activity for sulfa-Michael additions, as well as a moderate activity for Henry and aza-Henry reactions. These results are consistent with the observation reported by Senge and co-workers, establishing that nonplanarity and the presence of both basic Ns and NHs capable of hydrogen bonding are necessary for making metal-free tetrapyrrolic macrocycles catalytically active.

Figure 9: Chemical structures of OxP macrocycles tested as potential organocatalysts for the conjugate addition of 2,4-pentanedione (51) to β-nitrostyrene (50). Adapted from .

Table 3: Organocatalytic activity of tetrapyrrolic macrocycles 48a–i and 49a–i for the synthesis of 52 (Michael addition product) from 50 and 51.

Catalyst Catalyst loading (mol %) Conversion (%) – – 0 48a, 48b, 49a, 49b 1.0 0 48c 1.0 10 48d 0.5 71 49d, 48e, 49h, 48i 0.5 0 48f 0.5 <5 48g 0.5 63 48h 0.5 60

An alternative approach for making metal-free porphyrins catalytically active is based on using amphiphilic macrocycles and their aggregates. Moyano, Crusats and co-workers have done an extensive work on the development of supramolecular organocatalysts containing an amphiphilic metal-free porphyrin meso-(4-sulfonatophenyl)porphyrin and its J-aggregates . In acidic (pH < 4.8) aqueous solutions, the central pyrroleninic core of the porphyrin is diprotonated, which induces the formation of supramolecular aggregates, stabilized by ion-pair contacts (electrostatic interactions) between the cationic porphyrin centers and anionic sulfonate groups of the periphery (Figure 10a). In 2018, the group reported heterogeneous catalysis of Diels–Alder reaction in aqueous environment catalyzed by TPPS353 supramolecular aggregates . The Diels–Alder reaction between cinnamaldehyde (55) and cyclopentadiene (56) proceeds via iminium activation by the zwitterionic hetero-aggregates derived from TPPS3 molecules 53 and a cyclic secondary amine 57. They have hypothesized that the organocatalytic activity of the aggregates is based on two types of interactions, i.e., electrostatic interactions of α,β-unsaturated iminium cations derived from cinnamaldehyde and the cyclic secondary amine with anionic sulfonate groups and π–π interactions between phenyl groups and cyclopentadiene. Due to the presence of both types of moieties on the aggregate surface, the two reacting species can get into proximity and form the desired product (Figure 10b).

Figure 10: a) Fundamental structure of the J-aggregates of diprotonated TPPS353 and b) its use as a catalyst of Diels–Alder reaction. Figure 10 was reproduced from (© 2018 A. Arlegui et al., published by MDPI, distributed under the terms of the Creative Commons Attribution 4.0 International, https://creativecommons.org/licenses/by/4.0).

Later, an analogous system was used for catalysis of an asymmetrical Diels–Alder reaction. Although meso-tetrakis(4-sulfonatophenyl)porphyrin (TPPS4, 54) is an achiral molecule, the respective J-aggregates reveal supramolecular chirality caused by spontaneous mirror symmetry breaking (SMSB) during the aggregation process in an aqueous acidic solution. Using of these aggregates led to enantiomeric excess (ee) up to 5.5% . Related catalytic systems based on amphiphilic 5-(cyclic-secondary-amine)-10,15,20-tris(4-sulfonatophenyl)porphyrin macrocycles 58–61 act as switchable organocatalysts for Michael and aldol reactions in water . The macrocycles 58–61 containing different chiral or achiral cyclic secondary amine moieties oscillate between the aggregated and non-aggregated state depending on pH (Figure 11). The diprotonated species generated at lower pH forms supramolecular aggregates whereas the metal-free macrocycle is unable to aggregate and remains in the solution as a monomer. Since the aggregates were found catalytically inactive, while the monomers in the solution were active, the system acts as a pH-switchable ‘ON–OFF’ organocatalyst. In the case of the enamine-mediated addition of cyclohexanone (62) to 4-nitrobenzaldehyde (7), using 10 mol % of 58 provided up to 99% yield with a 93:7 ratio of the anti:syn aldol product (63a:63b) and no enantioselectivity at pH 6.7, whereas at pH 3.6 the catalyst was completely inactive (Table 4). Although the supramolecular system composed of a porphyrin macrocycle and a secondary amine organocatalyst operated through the reversible formation of covalent enamine intermediates, it also leveraged the supramolecular behavior of the porphyrinic component. In acidic aqueous media, the porphyrin macrocycle formed supramolecular H- and J-aggregates stabilized by hydrophobic interactions between the π-systems of the aromatic regions, along with electrostatic and hydrogen-bonding interactions. This behavior not only allowed for the selective activation and deactivation of organocatalytic activity but also facilitated efficient catalyst recovery at the end of the catalytic reaction. Notably, control experiments supported the hypothesis that the reaction would work in acidic environment using catalysts insensitive to pH-induced aggregation.

Figure 11: Chemical structures of amphiphilic porphyrin macrocycles used as pH-switchable catalysts based on in situ aggregation/dissociation. Adapted from .

Table 4: Organocatalytic activity of amphiphilic porphyrins 58–61 for aqueous aldol reaction of cyclohexanone (62) with 4-nitrobenzaldehyde (7).

Catalyst pH Yield (%)a 63a:63b (dr)b % eec 58 3.6 0 – – 58 6.7 99 93:7 – 59 3.6 0 – – 59 4.0 0 – – 59 6.7 100 66:34 – 60 6.7 96 63:37 1.9 (2S)/0 61 6.7 89 70:30 16.7 (2S)/11.8 (2S)

aIsolated yield of racemic aldol (63a + 63b) after chromatographic purification. bDetermined by 1H NMR (400 MHz) of the crude reaction mixture before chromatographic purification. cDetermined by chiral HPLC for 63a (anti) and 63b (syn), respectively.

In the same aldol reaction, using of macrocycles 60 and 61 containing chiral secondary amine moieties provided not only good yields, but also good diastereoselectivities; chiral HPLC analysis of the aldol product mixture showed that the reaction mixture contained only a negligible amount (1.9% ee) of the anti-isomer 63a and syn-diastereomer 63b was obtained in the racemic form when 60 was used as an organocatalyst. On the other hand, when using 61, both diastereomers were obtained in optically active form with 16.7% ee for 63a and 11.8% ee for 63b, respectively (Table 4). The pH-induced aggregation does not only enable to control the catalytic activity, but it also allows a straightforward separation and recovery of the catalyst from the reaction mixture by acidification and centrifugation.

In the same way as a calix[4]pyrrole was used as organocatalyst for cyclic carbonate synthesis from epoxide and CO2, as discussed in section 1.1, Gallo and co-workers investigated the organocatalytic activity of porphyrin/TBACl binary catalytic systems for the regioselective cycloaddition of CO2 to N-alkyl/arylaziridines providing N-alkyl/aryloxazolidin-2-ones .

They used seven different planar tetraarylporphyrin organocatalysts; H2TPP (tetraphenylporphyrin, 18), H24-t-BuTPP (tetrakis(4-tert-butylphenyl)porphyrin, 64), H24-CF3TPP (tetrakis(4-trifluoromethylphenyl)porphyrin, 65), H24-COOHTPP (tetrakis(4-carboxyphenyl)porphyrin, 66), H2F20TPP (meso-tetrakis(pentafluorophenyl)porphyrin, 67), H2F5TPP (5-(pentafluorophenyl)-10,15,20-triphenylporphyrin, 68) and H2OEP (octaethylporphyrin, 25) (Figure 12a), all of which were found catalytically active under optimized reaction conditions (catalyst/TBACl/aziridine 1:5:100 and 1.2 CO2 MPa at 125 °C) . Out of all the used macrocycles, the unsubstituted H2TPP (18)/TBACl system turned out to be the best, giving up to 95% yield for the both N-alkyl/arylaziridine substrates with regioisomeric ratios up to 95:5 (70b:71b) for R = n-Bu and 87:13 (70a:71a) for R = 3,5-(CF3)2C6H3. It was found out that increasing the steric features on the catalyst skeleton resulted in only marginally lower yields, suggesting that the electronic and steric features of the employed porphyrin have only a limited influence on the catalytic performances (Table 5). DFT calculations predicted that the catalytically active species is the adduct of porphyrin and TBACl (18-I), which forms an activated complex (18-II) with the substrate followed by a ring-opening nucleophilic attack of Cl−. The electron-rich nitrogen atom in 18-III further activates electrophilic CO2, leading to the formation of 18-IV. The negatively charged oxygen in 18-IV is then responsible for removing the chloride atom leading to the major isomer as a final product.