β-Formyl- and β-Vinylporphyrins: Magic Building Blocks for Novel Porphyrin Derivatives †

Porphyrins bearing formyl or vinyl groups have been explored as starting materials to prepare new compounds with adequate features for different applications. In this review it is discussed mainly synthetic strategies based on the reaction of meso-tetraarylporphyrins bearing those groups at β-pyrrolic positions. The use of some of the obtained porphyrin derivatives for further transformations, namely via pericyclic reactions, is also highlighted.


Introduction
The role of tetrapyrrolic macrocycles like porphyrins and analogues ( Figure 1) in vital biological functions such as respiration and photosynthesis, and their unique properties responsible for important applications in different fields, explains why the scientific community maintains high interest in this type of macrocycle.
All these applications are strongly dependent on the availability of compounds with adequate and specific structural features. This explains the high number of studies related with the preparation and modification of natural and synthetic porphyrin derivatives or analogues ( Figure 2). In particular, synthetic porphyrins like meso-tetraarylporphyrins ( Figure 2) have been considered a good alternative All these applications are strongly dependent on the availability of compounds with adequate and specific structural features. This explains the high number of studies related with the preparation and modification of natural and synthetic porphyrin derivatives or analogues ( Figure 2). In particular, synthetic porphyrins like meso-tetraarylporphyrins ( Figure 2) have been considered a good alternative to the use of natural porphyrins due to their less complex structures and easy synthetic accessibility. The usefulness of this type of porphyrins can be improved through the adequate functionalization of β-pyrrolic positions or meso-aryl groups. In this review the manipulation of formyl and vinyl groups located at the β-pyrrolic positions to access new meso-tetraarylporphyrins will be mainly highlighted. Formyl porphyrins are being used with success in the construction of more elaborate systems using several approaches such as the Horner-Emmons, Wittig, Grignard, McMurry, Schiff's base, Knoevenagel and cycloaddition reactions [44][45][46][47]. The results reported here are mainly concerned with procedures involving reactions with methylene active compounds, amines and other nitrogen derivatives and with Wittig reagents. Further manipulation of some of the obtained derivatives, namely β-vinyl porphyrins, through pericyclic reactions will be also reported ( Figure 3). However, when considered appropriate, similar transformations involving porphyrins with natural type substitution patterns will also be discussed. All these applications are strongly dependent on the availability of compounds with adequate and specific structural features. This explains the high number of studies related with the preparation and modification of natural and synthetic porphyrin derivatives or analogues ( Figure 2). In particular, synthetic porphyrins like meso-tetraarylporphyrins ( Figure 2) have been considered a good alternative to the use of natural porphyrins due to their less complex structures and easy synthetic accessibility. The usefulness of this type of porphyrins can be improved through the adequate functionalization of β-pyrrolic positions or meso-aryl groups. In this review the manipulation of formyl and vinyl groups located at the β-pyrrolic positions to access new meso-tetraarylporphyrins will be mainly highlighted. Formyl porphyrins are being used with success in the construction of more elaborate systems using several approaches such as the Horner-Emmons, Wittig, Grignard, McMurry, Schiff's base, Knoevenagel and cycloaddition reactions [44][45][46][47]. The results reported here are mainly concerned with procedures involving reactions with methylene active compounds, amines and other nitrogen derivatives and with Wittig reagents. Further manipulation of some of the obtained derivatives, namely β-vinyl porphyrins, through pericyclic reactions will be also reported ( Figure 3). However, when considered appropriate, similar transformations involving porphyrins with natural type substitution patterns will also be discussed. In this review the manipulation of formyl and vinyl groups located at the β-pyrrolic positions to access new meso-tetraarylporphyrins will be mainly highlighted. Formyl porphyrins are being used with success in the construction of more elaborate systems using several approaches such as the Horner-Emmons, Wittig, Grignard, McMurry, Schiff's base, Knoevenagel and cycloaddition reactions [44][45][46][47]. The results reported here are mainly concerned with procedures involving reactions with methylene active compounds, amines and other nitrogen derivatives and with Wittig reagents. Further manipulation of some of the obtained derivatives, namely β-vinyl porphyrins, through pericyclic reactions will be also reported ( Figure 3). However, when considered appropriate, similar transformations involving porphyrins with natural type substitution patterns will also be discussed.
Since symmetric meso-tetraarylporphyrins play a special role in these chemical modifications, synthetic strategies providing access to these templates will be succinctly discussed, followed by the synthetic strategies used to introduce the formyl and the vinyl groups at the β-pyrrolic positions. The numbering of the porphyrinic nucleus (from 1 to 24) will follow the IUPAC recommendations [48].
However, the interpyrrolic positions and the peripheral pyrrolic positions will also be referred to as meso and β-pyrrolic positions, respectively ( Figure 2). Since symmetric meso-tetraarylporphyrins play a special role in these chemical modifications, synthetic strategies providing access to these templates will be succinctly discussed, followed by the synthetic strategies used to introduce the formyl and the vinyl groups at the β-pyrrolic positions. The numbering of the porphyrinic nucleus (from 1 to 24) will follow the IUPAC recommendations [48]. However, the interpyrrolic positions and the peripheral pyrrolic positions will also be referred to as meso and β-pyrrolic positions, respectively ( Figure 2).

General Considerations about the Synthesis and Properties of meso-Tetraarylporphyrins
The experimental conditions affording access to symmetric free-base 5,10,15,20-tetraarylporphyrins are in general based on the Rothemund reaction reported in 1935 (Scheme 1a) [49][50][51]. The strategy described by Rothemund involved the condensation of aliphatic, aromatic and heterocyclic aldehydes with pyrrole using a mixture of pyridine and methanol, at 145-155 °C in a sealed tube under anaerobic conditions. Under these conditions a series of 5,10,15,20-tetrasubstituted porphyrins were obtained in low yields and contaminated with chlorin [52,53]. An improvement of this method that merits mention is the condensation under aerobic acidic conditions (propionic or acetic acid) described later by Adler and Longo. This variation allows one to obtain the corresponding porphyrins in higher yields [54], but even under these improved conditions the chlorin is still present and, in order to minimize it, Smith recommended the treatment of the reaction mixture with 2,3dichloro-5,6-dicyanobenzoquinone (DDQ) [55]. Alternatively, as suggested by Gonsalves and coworkers [56], the condensation can be performed in a mixture of nitrobenzene and acetic acid. Under these conditions some porphyrins, namely 5,10,15,20-tetraphenylporphyrin (TPP, 1), can be obtained directly from the reactional medium by simple crystallization.
A two-step strategy can be used for labile aldehydes that cannot survive the refluxing acidic conditions, as reported by Gonsalves [57] and Lindsey [58][59][60] in the late eighties for the preparation of 5,10,15,20-tetraalkylporphyrins and 5,10,15,20-tetraarylporphyrins, respectively (Scheme 1b). The condensation of pyrrole with the aldehyde is performed at room temperature in the absence of oxygen and light and using trifluoroacetic acid (TFA) or BF3 as catalyst, in order to maximize the formation of the porphyrinogen. The oxidative step can be performed with DDQ or p-chloranil and yields between 30% and 40% can be attained. An efficient access to several 5,10,15,20-tetraarylporphyrins (in yields ranging between 20% and 65%) by condensation of pyrrole and aryl aldehydes at room temperature and using equimolar amount of PCl5 or CF3SO2Cl in the presence of air as an oxidant was reported by Sharghi and Nejad [61,62].

General Considerations about the Synthesis and Properties of meso-Tetraarylporphyrins
The experimental conditions affording access to symmetric free-base 5,10,15,20-tetraarylporphyrins are in general based on the Rothemund reaction reported in 1935 (Scheme 1a) [49][50][51]. The strategy described by Rothemund involved the condensation of aliphatic, aromatic and heterocyclic aldehydes with pyrrole using a mixture of pyridine and methanol, at 145-155 • C in a sealed tube under anaerobic conditions. Under these conditions a series of 5,10,15,20-tetrasubstituted porphyrins were obtained in low yields and contaminated with chlorin [52,53]. An improvement of this method that merits mention is the condensation under aerobic acidic conditions (propionic or acetic acid) described later by Adler and Longo. This variation allows one to obtain the corresponding porphyrins in higher yields [54], but even under these improved conditions the chlorin is still present and, in order to minimize it, Smith recommended the treatment of the reaction mixture with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) [55]. Alternatively, as suggested by Gonsalves and co-workers [56], the condensation can be performed in a mixture of nitrobenzene and acetic acid. Under these conditions some porphyrins, namely 5,10,15,20-tetraphenylporphyrin (TPP, 1), can be obtained directly from the reactional medium by simple crystallization.
A two-step strategy can be used for labile aldehydes that cannot survive the refluxing acidic conditions, as reported by Gonsalves [57] and Lindsey [58][59][60] in the late eighties for the preparation of 5,10,15,20-tetraalkylporphyrins and 5,10,15,20-tetraarylporphyrins, respectively (Scheme 1b). The condensation of pyrrole with the aldehyde is performed at room temperature in the absence of oxygen and light and using trifluoroacetic acid (TFA) or BF 3 as catalyst, in order to maximize the formation of the porphyrinogen. The oxidative step can be performed with DDQ or p-chloranil and yields between 30% and 40% can be attained. An efficient access to several 5,10,15,20-tetraaryl-porphyrins (in yields ranging between 20% and 65%) by condensation of pyrrole and aryl aldehydes at room temperature and using equimolar amount of PCl 5 or CF 3 SO 2 Cl in the presence of air as an oxidant was reported by Sharghi and Nejad [61,62].
Depending on the experimental conditions, the Rothemund reaction can also give access to inverted and expanded porphyrins. In particular, we discovered that the condensation of pyrrole with pentafluorobenzaldehyde in acetic acid and nitrobenzene, gives the expected 5,10,15,20-tetrakis (pentafluorophenyl) porphyrin (Ar = C6F5) and also stable mesohexakis(pentafluorophenyl) [26]hexaphyrin and - [28]hexaphyrin, respectively, with violet and blue colours ( Figure 4) [69]. Based on their colours, it was a real surprise when we found from spectroscopic and X-ray single crystal diffraction data that these compounds have aromatic features. Since then, expanded porphyrinoids have emerged as a well-recognized group due to their unique redox and metal coordination behaviors, conformational flexibility and chemical reactivities, as excellently reviewed by Tanaka and Osuka [70].  Due to their aromatic character porphyrins can undergo, among other reactions, electrophilic aromatic substitutions. In meso-tetraarylporphyrins this type of reaction usually occurs at the more sterically accessible β-pyrrolic positions, although depending on the experimental conditions, selective transformations on the aryl groups (e.g., nitration, sulfonation) can also be performed [44]. Without losing their aromatic character (the aromatic delocalization only requires 18 of the 22 Scheme 1. Conditions used to synthesize 5,10,15,20-tetrasubstituted porphyrins [60].
Depending on the experimental conditions, the Rothemund reaction can also give access to inverted and expanded porphyrins.
In particular, we discovered that the condensation of pyrrole with pentafluorobenzaldehyde in acetic acid and nitrobenzene, gives the expected 5,10,15,20-tetrakis (pentafluorophenyl) porphyrin (Ar = C 6 F 5 ) and also stable meso-hexakis(pentafluorophenyl) [26]hexaphyrin and - [28]hexaphyrin, respectively, with violet and blue colours ( Figure 4) [69]. Based on their colours, it was a real surprise when we found from spectroscopic and X-ray single crystal diffraction data that these compounds have aromatic features. Since then, expanded porphyrinoids have emerged as a well-recognized group due to their unique redox and metal coordination behaviors, conformational flexibility and chemical reactivities, as excellently reviewed by Tanaka and Osuka [70]. Depending on the experimental conditions, the Rothemund reaction can also give access to inverted and expanded porphyrins. In particular, we discovered that the condensation of pyrrole with pentafluorobenzaldehyde in acetic acid and nitrobenzene, gives the expected 5,10,15,20-tetrakis (pentafluorophenyl) porphyrin (Ar = C6F5) and also stable mesohexakis(pentafluorophenyl) [26]hexaphyrin and - [28]hexaphyrin, respectively, with violet and blue colours ( Figure 4) [69]. Based on their colours, it was a real surprise when we found from spectroscopic and X-ray single crystal diffraction data that these compounds have aromatic features. Since then, expanded porphyrinoids have emerged as a well-recognized group due to their unique redox and metal coordination behaviors, conformational flexibility and chemical reactivities, as excellently reviewed by Tanaka and Osuka [70].  Due to their aromatic character porphyrins can undergo, among other reactions, electrophilic aromatic substitutions. In meso-tetraarylporphyrins this type of reaction usually occurs at the more sterically accessible β-pyrrolic positions, although depending on the experimental conditions, selective transformations on the aryl groups (e.g., nitration, sulfonation) can also be performed [44]. Without losing their aromatic character (the aromatic delocalization only requires 18 of the 22 Due to their aromatic character porphyrins can undergo, among other reactions, electrophilic aromatic substitutions. In meso-tetraarylporphyrins this type of reaction usually occurs at the more sterically accessible β-pyrrolic positions, although depending on the experimental conditions, selective transformations on the aryl groups (e.g., nitration, sulfonation) can also be performed [44]. Without losing their aromatic character (the aromatic delocalization only requires 18 of the 22 conjugated π-electrons) porphyrins can undergo other reaction types at the β-pyrrolic positions like β,β -Diformyl-meso-tetraphenylporphyrins are also formed (in less than 4% yield) during the β-formylation of Ni(II)TPP (Ni1). Considering that these compounds could be potentially useful for further functionalization, and aiming at their syntheses, we decided to perform the Vilsmeier reaction in the presence of a larger excess of POCl 3 -DMF and using longer reaction times than employed in conventional conditions. Under these modified Vilsmeier conditions the diformyl compounds Ni6 or the corresponding free-bases (as discussed above, the demetallation was performed at the iminium stage) were obtained in ca. 30% yield (Scheme 3). It was also verified that the direct formylation of the mono-β-formyl derivative Ni3 can afford the five diformyl derivatives Ni6 in 71% yield [86]. It was realized that the first introduced formyl group does not exert a substantial effect on the introduction of the second one. β,β′-Diformyl-meso-tetraphenylporphyrins are also formed (in less than 4% yield) during the βformylation of Ni(II)TPP (Ni1). Considering that these compounds could be potentially useful for further functionalization, and aiming at their syntheses, we decided to perform the Vilsmeier reaction in the presence of a larger excess of POCl3-DMF and using longer reaction times than employed in conventional conditions. Under these modified Vilsmeier conditions the diformyl compounds Ni6 or the corresponding free-bases (as discussed above, the demetallation was performed at the iminium stage) were obtained in ca. 30% yield (Scheme 3). It was also verified that the direct formylation of the mono-β-formyl derivative Ni3 can afford the five diformyl derivatives Ni6 in 71% yield [86]. It was realized that the first introduced formyl group does not exert a substantial effect on the introduction of the second one. Mironov and co-workers also reported the diformylation of the Ni(II) complex of meso-tetrakis(pmethoxyphenyl)porphyrin and of its chlorin [87,88]. Their studies agree with our previous observation about the effect of the first introduced formyl group in the subsequent formylation. Also, the relative positions of the two formyl groups have a strong effect on the spectroscopic characteristics of the porphyrin derivatives. A different situation was observed for the chlorin derivative. In this case the first formyl group goes to the pyrrole ring adjacent to the reduced unit and the subsequent formylation is preferably directed into the pyrrole opposite to the reduced unit. In that work [88] it was also mentioned the access to β,β′-dicyano-meso-tetrakis(p-methoxyphenyl) porphyrins by treating the corresponding β,β′-diformylporphyrins with hydroxylamine in pyridine followed by dehydration of the oximes with acetic anhydride.
The use of MW irradiation to prepare β-formyl porphyrins was reported by Yaseen et al. in 2009 [89]. The authors found that the acidic Duff conditions had to be used in alternative to the standard Vilsmeier-Haack method. The β-formylated products were obtained in 50%-55% yields after irradiating the Zn(II) or Cu(II) complexes of the selected porphyrins in the presence of urotropine and acidified silica gel for a period of 18 min. However, Moura et al., demonstrated that it is possible to use microwave irradiation to formylate, under Vilsmeier-Haack conditions, the Ni(II) and Cu(II) Scheme 3. β,β -Diformylation of meso-tetraphenylporphyrin [86].
Mironov and co-workers also reported the diformylation of the Ni(II) complex of meso-tetrakis(p-methoxyphenyl)porphyrin and of its chlorin [87,88]. Their studies agree with our previous observation about the effect of the first introduced formyl group in the subsequent formylation. Also, the relative positions of the two formyl groups have a strong effect on the spectroscopic characteristics of the porphyrin derivatives. A different situation was observed for the chlorin derivative. In this case the first formyl group goes to the pyrrole ring adjacent to the reduced unit and the subsequent formylation is preferably directed into the pyrrole opposite to the reduced unit. In that work [88] it was also mentioned the access to β,β -dicyano-meso-tetrakis(p-methoxyphenyl) porphyrins by treating the corresponding β,β -diformylporphyrins with hydroxylamine in pyridine followed by dehydration of the oximes with acetic anhydride.
The use of MW irradiation to prepare β-formyl porphyrins was reported by Yaseen et al. in 2009 [89]. The authors found that the acidic Duff conditions had to be used in alternative to the standard Vilsmeier-Haack method. The β-formylated products were obtained in 50-55% yields after irradiating the Zn(II) or Cu(II) complexes of the selected porphyrins in the presence of urotropine and acidified silica gel for a period of 18 min. However, Moura et al., demonstrated that it is possible to use microwave irradiation to formylate, under Vilsmeier-Haack conditions, the Ni(II) and Cu(II) complexes of TPP and of 5,10,15,20-tetraarylporphyrins with electron-donating or electron-withdrawing substituents (Table 1) [90]. The authors reported that it is possible to reduce the reaction times from ca. 18 h (conventional heating method) to 30 min or less under MW radiation, but keeping the efficiency of the process or even improving the yields obtained (Table 1). In the same study it was confirmed that the yields were not affected by reaction scale-up. Another significant advantage is the small volume of solvent required which is five-fold lower than the used in the classical heating conditions. complexes of TPP and of 5,10,15,20-tetraarylporphyrins with electron-donating or electronwithdrawing substituents (Table 1) [90]. The authors reported that it is possible to reduce the reaction times from ca. 18 h (conventional heating method) to 30 min or less under MW radiation, but keeping the efficiency of the process or even improving the yields obtained (Table 1). In the same study it was confirmed that the yields were not affected by reaction scale-up. Another significant advantage is the small volume of solvent required which is five-fold lower than the used in the classical heating conditions.

Reactivity of β-Formyl-meso-tetraarylporphyrins with Methylene Active Compounds
The condensation of formyl porphyrins with methylene active compounds has not only been used in simple modifications of the porphyrin periphery, but also in the construction of more elaborate systems [44,45]. For instance, Ponomarev and co-workers [91] found that the reaction of β-CHOTPP 3, or of its copper(II) complex (Cu3), with nitromethane is dependent on the solvent used ( Figure 5). When the reactions were performed in a mixture of acetic acid and butylamine the 2-(2nitrovinyl)porphyrins 7 were isolated in moderate to excellent yields. However, when the reaction was carried out in a mixture of dimethylformamide (DMF) and butylamine the dinitro derivatives 8 were isolated (≥78% yield). When the reaction was carried out in liquid NH3 the nitroalcohols 9 were formed (≥90% yield). In the same publication it was also reported that the reaction of the Cu(II) complex of β-CHOTPP with malonic acid or with its methyl or ethyl esters led to the corresponding condensation products 10 in high yield (≥87%). The authors found that the demetallation of the copper complexes with POCl3 treated with water afforded the corresponding free-bases in excellent yields; it was highlighted that this protocol is a good alternative to the conventional treatment with concentrated H2SO4 which leads to a great decomposition of the porphyrin derivatives. Additionally, transformations of derivatives 10, namely reduction of the double bond, saponification and decarboxylation, were also reported. complexes of TPP and of 5,10,15,20-tetraarylporphyrins with electron-donating or electronwithdrawing substituents (Table 1) [90]. The authors reported that it is possible to reduce the reaction times from ca. 18 h (conventional heating method) to 30 min or less under MW radiation, but keeping the efficiency of the process or even improving the yields obtained (Table 1). In the same study it was confirmed that the yields were not affected by reaction scale-up. Another significant advantage is the small volume of solvent required which is five-fold lower than the used in the classical heating conditions.

Reactivity of β-Formyl-meso-tetraarylporphyrins with Methylene Active Compounds
The condensation of formyl porphyrins with methylene active compounds has not only been used in simple modifications of the porphyrin periphery, but also in the construction of more elaborate systems [44,45]. For instance, Ponomarev and co-workers [91] found that the reaction of β-CHOTPP 3, or of its copper(II) complex (Cu3), with nitromethane is dependent on the solvent used ( Figure 5). When the reactions were performed in a mixture of acetic acid and butylamine the 2-(2nitrovinyl)porphyrins 7 were isolated in moderate to excellent yields. However, when the reaction was carried out in a mixture of dimethylformamide (DMF) and butylamine the dinitro derivatives 8 were isolated (≥78% yield). When the reaction was carried out in liquid NH3 the nitroalcohols 9 were formed (≥90% yield). In the same publication it was also reported that the reaction of the Cu(II) complex of β-CHOTPP with malonic acid or with its methyl or ethyl esters led to the corresponding condensation products 10 in high yield (≥87%). The authors found that the demetallation of the copper complexes with POCl3 treated with water afforded the corresponding free-bases in excellent yields; it was highlighted that this protocol is a good alternative to the conventional treatment with concentrated H2SO4 which leads to a great decomposition of the porphyrin derivatives. Additionally, transformations of derivatives 10, namely reduction of the double bond, saponification and decarboxylation, were also reported. 57 50 Molecules 2017, 22, 1269 7 of 44 complexes of TPP and of 5,10,15,20-tetraarylporphyrins with electron-donating or electronwithdrawing substituents (Table 1) [90]. The authors reported that it is possible to reduce the reaction times from ca. 18 h (conventional heating method) to 30 min or less under MW radiation, but keeping the efficiency of the process or even improving the yields obtained (Table 1). In the same study it was confirmed that the yields were not affected by reaction scale-up. Another significant advantage is the small volume of solvent required which is five-fold lower than the used in the classical heating conditions.

Reactivity of β-Formyl-meso-tetraarylporphyrins with Methylene Active Compounds
The condensation of formyl porphyrins with methylene active compounds has not only been used in simple modifications of the porphyrin periphery, but also in the construction of more elaborate systems [44,45]. For instance, Ponomarev and co-workers [91] found that the reaction of β-CHOTPP 3, or of its copper(II) complex (Cu3), with nitromethane is dependent on the solvent used ( Figure 5). When the reactions were performed in a mixture of acetic acid and butylamine the 2-(2nitrovinyl)porphyrins 7 were isolated in moderate to excellent yields. However, when the reaction was carried out in a mixture of dimethylformamide (DMF) and butylamine the dinitro derivatives 8 were isolated (≥78% yield). When the reaction was carried out in liquid NH3 the nitroalcohols 9 were formed (≥90% yield). In the same publication it was also reported that the reaction of the Cu(II) complex of β-CHOTPP with malonic acid or with its methyl or ethyl esters led to the corresponding condensation products 10 in high yield (≥87%). The authors found that the demetallation of the copper complexes with POCl3 treated with water afforded the corresponding free-bases in excellent yields; it was highlighted that this protocol is a good alternative to the conventional treatment with concentrated H2SO4 which leads to a great decomposition of the porphyrin derivatives. Additionally, transformations of derivatives 10, namely reduction of the double bond, saponification and decarboxylation, were also reported. 41 36 Molecules 2017, 22, 1269 7 of 44 complexes of TPP and of 5,10,15,20-tetraarylporphyrins with electron-donating or electronwithdrawing substituents (Table 1) [90]. The authors reported that it is possible to reduce the reaction times from ca. 18 h (conventional heating method) to 30 min or less under MW radiation, but keeping the efficiency of the process or even improving the yields obtained (Table 1). In the same study it was confirmed that the yields were not affected by reaction scale-up. Another significant advantage is the small volume of solvent required which is five-fold lower than the used in the classical heating conditions.

Reactivity of β-Formyl-meso-tetraarylporphyrins with Methylene Active Compounds
The condensation of formyl porphyrins with methylene active compounds has not only been used in simple modifications of the porphyrin periphery, but also in the construction of more elaborate systems [44,45]. For instance, Ponomarev and co-workers [91] found that the reaction of β-CHOTPP 3, or of its copper(II) complex (Cu3), with nitromethane is dependent on the solvent used ( Figure 5). When the reactions were performed in a mixture of acetic acid and butylamine the 2-(2nitrovinyl)porphyrins 7 were isolated in moderate to excellent yields. However, when the reaction was carried out in a mixture of dimethylformamide (DMF) and butylamine the dinitro derivatives 8 were isolated (≥78% yield). When the reaction was carried out in liquid NH3 the nitroalcohols 9 were formed (≥90% yield). In the same publication it was also reported that the reaction of the Cu(II) complex of β-CHOTPP with malonic acid or with its methyl or ethyl esters led to the corresponding condensation products 10 in high yield (≥87%). The authors found that the demetallation of the copper complexes with POCl3 treated with water afforded the corresponding free-bases in excellent yields; it was highlighted that this protocol is a good alternative to the conventional treatment with concentrated H2SO4 which leads to a great decomposition of the porphyrin derivatives. Additionally, transformations of derivatives 10, namely reduction of the double bond, saponification and decarboxylation, were also reported. complexes of TPP and of 5,10,15,20-tetraarylporphyrins with electron-donating or electronwithdrawing substituents (Table 1) [90]. The authors reported that it is possible to reduce the reaction times from ca. 18 h (conventional heating method) to 30 min or less under MW radiation, but keeping the efficiency of the process or even improving the yields obtained (Table 1). In the same study it was confirmed that the yields were not affected by reaction scale-up. Another significant advantage is the small volume of solvent required which is five-fold lower than the used in the classical heating conditions.

Reactivity of β-Formyl-meso-tetraarylporphyrins with Methylene Active Compounds
The condensation of formyl porphyrins with methylene active compounds has not only been used in simple modifications of the porphyrin periphery, but also in the construction of more elaborate systems [44,45]. For instance, Ponomarev and co-workers [91] found that the reaction of β-CHOTPP 3, or of its copper(II) complex (Cu3), with nitromethane is dependent on the solvent used ( Figure 5). When the reactions were performed in a mixture of acetic acid and butylamine the 2-(2nitrovinyl)porphyrins 7 were isolated in moderate to excellent yields. However, when the reaction was carried out in a mixture of dimethylformamide (DMF) and butylamine the dinitro derivatives 8 were isolated (≥78% yield). When the reaction was carried out in liquid NH3 the nitroalcohols 9 were formed (≥90% yield). In the same publication it was also reported that the reaction of the Cu(II) complex of β-CHOTPP with malonic acid or with its methyl or ethyl esters led to the corresponding condensation products 10 in high yield (≥87%). The authors found that the demetallation of the copper complexes with POCl3 treated with water afforded the corresponding free-bases in excellent yields; it was highlighted that this protocol is a good alternative to the conventional treatment with concentrated H2SO4 which leads to a great decomposition of the porphyrin derivatives. Additionally, transformations of derivatives 10, namely reduction of the double bond, saponification and decarboxylation, were also reported. complexes of TPP and of 5,10,15,20-tetraarylporphyrins with electron-donating or electronwithdrawing substituents (Table 1) [90]. The authors reported that it is possible to reduce the reaction times from ca. 18 h (conventional heating method) to 30 min or less under MW radiation, but keeping the efficiency of the process or even improving the yields obtained (Table 1). In the same study it was confirmed that the yields were not affected by reaction scale-up. Another significant advantage is the small volume of solvent required which is five-fold lower than the used in the classical heating conditions.

Reactivity of β-Formyl-meso-tetraarylporphyrins with Methylene Active Compounds
The condensation of formyl porphyrins with methylene active compounds has not only been used in simple modifications of the porphyrin periphery, but also in the construction of more elaborate systems [44,45]. For instance, Ponomarev and co-workers [91] found that the reaction of β-CHOTPP 3, or of its copper(II) complex (Cu3), with nitromethane is dependent on the solvent used ( Figure 5). When the reactions were performed in a mixture of acetic acid and butylamine the 2-(2nitrovinyl)porphyrins 7 were isolated in moderate to excellent yields. However, when the reaction was carried out in a mixture of dimethylformamide (DMF) and butylamine the dinitro derivatives 8 were isolated (≥78% yield). When the reaction was carried out in liquid NH3 the nitroalcohols 9 were formed (≥90% yield). In the same publication it was also reported that the reaction of the Cu(II) complex of β-CHOTPP with malonic acid or with its methyl or ethyl esters led to the corresponding condensation products 10 in high yield (≥87%). The authors found that the demetallation of the copper complexes with POCl3 treated with water afforded the corresponding free-bases in excellent yields; it was highlighted that this protocol is a good alternative to the conventional treatment with concentrated H2SO4 which leads to a great decomposition of the porphyrin derivatives. Additionally, transformations of derivatives 10, namely reduction of the double bond, saponification and decarboxylation, were also reported. complexes of TPP and of 5,10,15,20-tetraarylporphyrins with electron-donating or electronwithdrawing substituents (Table 1) [90]. The authors reported that it is possible to reduce the reaction times from ca. 18 h (conventional heating method) to 30 min or less under MW radiation, but keeping the efficiency of the process or even improving the yields obtained (Table 1). In the same study it was confirmed that the yields were not affected by reaction scale-up. Another significant advantage is the small volume of solvent required which is five-fold lower than the used in the classical heating conditions.

Reactivity of β-Formyl-meso-tetraarylporphyrins with Methylene Active Compounds
The condensation of formyl porphyrins with methylene active compounds has not only been used in simple modifications of the porphyrin periphery, but also in the construction of more elaborate systems [44,45]. For instance, Ponomarev and co-workers [91] found that the reaction of β-CHOTPP 3, or of its copper(II) complex (Cu3), with nitromethane is dependent on the solvent used ( Figure 5). When the reactions were performed in a mixture of acetic acid and butylamine the 2-(2nitrovinyl)porphyrins 7 were isolated in moderate to excellent yields. However, when the reaction was carried out in a mixture of dimethylformamide (DMF) and butylamine the dinitro derivatives 8 were isolated (≥78% yield). When the reaction was carried out in liquid NH3 the nitroalcohols 9 were formed (≥90% yield). In the same publication it was also reported that the reaction of the Cu(II) complex of β-CHOTPP with malonic acid or with its methyl or ethyl esters led to the corresponding condensation products 10 in high yield (≥87%). The authors found that the demetallation of the copper complexes with POCl3 treated with water afforded the corresponding free-bases in excellent yields; it was highlighted that this protocol is a good alternative to the conventional treatment with concentrated H2SO4 which leads to a great decomposition of the porphyrin derivatives. Additionally, transformations of derivatives 10, namely reduction of the double bond, saponification and decarboxylation, were also reported. complexes of TPP and of 5,10,15,20-tetraarylporphyrins with electron-donating or electronwithdrawing substituents (Table 1) [90]. The authors reported that it is possible to reduce the reaction times from ca. 18 h (conventional heating method) to 30 min or less under MW radiation, but keeping the efficiency of the process or even improving the yields obtained (Table 1). In the same study it was confirmed that the yields were not affected by reaction scale-up. Another significant advantage is the small volume of solvent required which is five-fold lower than the used in the classical heating conditions.

Reactivity of β-Formyl-meso-tetraarylporphyrins with Methylene Active Compounds
The condensation of formyl porphyrins with methylene active compounds has not only been used in simple modifications of the porphyrin periphery, but also in the construction of more elaborate systems [44,45]. For instance, Ponomarev and co-workers [91] found that the reaction of β-CHOTPP 3, or of its copper(II) complex (Cu3), with nitromethane is dependent on the solvent used ( Figure 5). When the reactions were performed in a mixture of acetic acid and butylamine the 2-(2nitrovinyl)porphyrins 7 were isolated in moderate to excellent yields. However, when the reaction was carried out in a mixture of dimethylformamide (DMF) and butylamine the dinitro derivatives 8 were isolated (≥78% yield). When the reaction was carried out in liquid NH3 the nitroalcohols 9 were formed (≥90% yield). In the same publication it was also reported that the reaction of the Cu(II) complex of β-CHOTPP with malonic acid or with its methyl or ethyl esters led to the corresponding condensation products 10 in high yield (≥87%). The authors found that the demetallation of the copper complexes with POCl3 treated with water afforded the corresponding free-bases in excellent yields; it was highlighted that this protocol is a good alternative to the conventional treatment with concentrated H2SO4 which leads to a great decomposition of the porphyrin derivatives. Additionally, transformations of derivatives 10, namely reduction of the double bond, saponification and decarboxylation, were also reported. 88 41 Molecules 2017, 22, 1269 7 of 44 complexes of TPP and of 5,10,15,20-tetraarylporphyrins with electron-donating or electronwithdrawing substituents (Table 1) [90]. The authors reported that it is possible to reduce the reaction times from ca. 18 h (conventional heating method) to 30 min or less under MW radiation, but keeping the efficiency of the process or even improving the yields obtained (Table 1). In the same study it was confirmed that the yields were not affected by reaction scale-up. Another significant advantage is the small volume of solvent required which is five-fold lower than the used in the classical heating conditions.

Reactivity of β-Formyl-meso-tetraarylporphyrins with Methylene Active Compounds
The condensation of formyl porphyrins with methylene active compounds has not only been used in simple modifications of the porphyrin periphery, but also in the construction of more elaborate systems [44,45]. For instance, Ponomarev and co-workers [91] found that the reaction of β-CHOTPP 3, or of its copper(II) complex (Cu3), with nitromethane is dependent on the solvent used ( Figure 5). When the reactions were performed in a mixture of acetic acid and butylamine the 2-(2nitrovinyl)porphyrins 7 were isolated in moderate to excellent yields. However, when the reaction was carried out in a mixture of dimethylformamide (DMF) and butylamine the dinitro derivatives 8 were isolated (≥78% yield). When the reaction was carried out in liquid NH3 the nitroalcohols 9 were formed (≥90% yield). In the same publication it was also reported that the reaction of the Cu(II) complex of β-CHOTPP with malonic acid or with its methyl or ethyl esters led to the corresponding condensation products 10 in high yield (≥87%). The authors found that the demetallation of the copper complexes with POCl3 treated with water afforded the corresponding free-bases in excellent yields; it was highlighted that this protocol is a good alternative to the conventional treatment with concentrated H2SO4 which leads to a great decomposition of the porphyrin derivatives. Additionally, transformations of derivatives 10, namely reduction of the double bond, saponification and decarboxylation, were also reported. 83 19 Molecules 2017, 22, 1269 7 of 44 complexes of TPP and of 5,10,15,20-tetraarylporphyrins with electron-donating or electronwithdrawing substituents (Table 1) [90]. The authors reported that it is possible to reduce the reaction times from ca. 18 h (conventional heating method) to 30 min or less under MW radiation, but keeping the efficiency of the process or even improving the yields obtained (Table 1). In the same study it was confirmed that the yields were not affected by reaction scale-up. Another significant advantage is the small volume of solvent required which is five-fold lower than the used in the classical heating conditions.

Reactivity of β-Formyl-meso-tetraarylporphyrins with Methylene Active Compounds
The condensation of formyl porphyrins with methylene active compounds has not only been used in simple modifications of the porphyrin periphery, but also in the construction of more elaborate systems [44,45]. For instance, Ponomarev and co-workers [91] found that the reaction of β-CHOTPP 3, or of its copper(II) complex (Cu3), with nitromethane is dependent on the solvent used ( Figure 5). When the reactions were performed in a mixture of acetic acid and butylamine the 2-(2nitrovinyl)porphyrins 7 were isolated in moderate to excellent yields. However, when the reaction was carried out in a mixture of dimethylformamide (DMF) and butylamine the dinitro derivatives 8 were isolated (≥78% yield). When the reaction was carried out in liquid NH3 the nitroalcohols 9 were formed (≥90% yield). In the same publication it was also reported that the reaction of the Cu(II) complex of β-CHOTPP with malonic acid or with its methyl or ethyl esters led to the corresponding condensation products 10 in high yield (≥87%). The authors found that the demetallation of the copper complexes with POCl3 treated with water afforded the corresponding free-bases in excellent yields; it was highlighted that this protocol is a good alternative to the conventional treatment with concentrated H2SO4 which leads to a great decomposition of the porphyrin derivatives. Additionally, transformations of derivatives 10, namely reduction of the double bond, saponification and decarboxylation, were also reported. 87 26 a Not determined.

Reactivity of β-Formyl-meso-tetraarylporphyrins with Methylene Active Compounds
The condensation of formyl porphyrins with methylene active compounds has not only been used in simple modifications of the porphyrin periphery, but also in the construction of more elaborate systems [44,45]. For instance, Ponomarev and co-workers [91] found that the reaction of β-CHOTPP 3, or of its copper(II) complex (Cu3), with nitromethane is dependent on the solvent used ( Figure 5). When the reactions were performed in a mixture of acetic acid and butylamine the 2-(2-nitrovinyl)porphyrins 7 were isolated in moderate to excellent yields. However, when the reaction was carried out in a mixture of dimethylformamide (DMF) and butylamine the dinitro derivatives 8 were isolated (≥78% yield). When the reaction was carried out in liquid NH 3 the nitroalcohols 9 were formed (≥90% yield). In the same publication it was also reported that the reaction of the Cu(II) complex of β-CHOTPP with malonic acid or with its methyl or ethyl esters led to the corresponding condensation products 10 in high yield (≥87%). The authors found that the demetallation of the copper complexes with POCl 3 treated with water afforded the corresponding free-bases in excellent yields; it was highlighted that this protocol is a good alternative to the conventional treatment with concentrated H 2 SO 4 which leads to a great decomposition of the porphyrin derivatives. Additionally, transformations of derivatives 10, namely reduction of the double bond, saponification and decarboxylation, were also reported. The same type of strategy was used by Chen et al. to prepare the 2-substituted nickel mesotetraarylporphyrins 13 (Scheme 4) [92,93]. These derivatives were prepared by reacting the appropriate Ni(II) β-formylporphyrin 12 with diethyl malonate, ethyl cyanoacetate, malononitrile, and N,N′-diethylthiobarbituric acid in the presence of aluminum oxide. The formylporphyrins 12 were obtained from meso-tetrakis(4-isopropylphenyl)porphyrins (11, n = 0) by repeating the Wittig oxyprenylation procedure on the shorter aldehyde homolog 11 (Scheme 4). The unexpected perturbed absorption spectra found for some of these substituted porphyrins (splitting of the Soret and Q bands) were justified by considering the stronger interaction between the porphyrin π-system and the electronic acceptor unit through the olefin linkage in addition to their reduced symmetry. It was commented that the unperturbed absorption spectra observed for many β-substituted mesotetraphenylporphyrins can be justified by considering the weak electron accepting power of the substituent which can be an obstacle on the conjugation pathway or due to steric hindrance. Tandem mass spectrometry, namely electrospray tandem mass spectrometry (ESI-MS/MS) is a valuable tool for the rapid and sensitive analysis of porphyrins in mixtures and can also give important information about their structural characterization, namely of peripheral substituents [94]. This approach was considered to study the fragmentation pathways of β-nitroalkenyl-substituted meso-tetraphenylporphyrins 14a-c and of their Zn(II) complexes 15a-c ( Figure 6), obtained by the classic condensation reaction between an aldehyde and a nitroalkane bearing α-hydrogen atoms [95]. In addition to the common fragmentation pathway of nitro derivatives, whose relative abundances The same type of strategy was used by Chen et al. to prepare the 2-substituted nickel meso-tetraarylporphyrins 13 (Scheme 4) [92,93]. These derivatives were prepared by reacting the appropriate Ni(II) β-formylporphyrin 12 with diethyl malonate, ethyl cyanoacetate, malononitrile, and N,N -diethylthiobarbituric acid in the presence of aluminum oxide. The formylporphyrins 12 were obtained from meso-tetrakis(4-isopropylphenyl)porphyrins (11, n = 0) by repeating the Wittig oxyprenylation procedure on the shorter aldehyde homolog 11 (Scheme 4). The unexpected perturbed absorption spectra found for some of these substituted porphyrins (splitting of the Soret and Q bands) were justified by considering the stronger interaction between the porphyrin π-system and the electronic acceptor unit through the olefin linkage in addition to their reduced symmetry. It was commented that the unperturbed absorption spectra observed for many β-substituted meso-tetraphenylporphyrins can be justified by considering the weak electron accepting power of the substituent which can be an obstacle on the conjugation pathway or due to steric hindrance. The same type of strategy was used by Chen et al. to prepare the 2-substituted nickel mesotetraarylporphyrins 13 (Scheme 4) [92,93]. These derivatives were prepared by reacting the appropriate Ni(II) β-formylporphyrin 12 with diethyl malonate, ethyl cyanoacetate, malononitrile, and N,N′-diethylthiobarbituric acid in the presence of aluminum oxide. The formylporphyrins 12 were obtained from meso-tetrakis(4-isopropylphenyl)porphyrins (11, n = 0) by repeating the Wittig oxyprenylation procedure on the shorter aldehyde homolog 11 (Scheme 4). The unexpected perturbed absorption spectra found for some of these substituted porphyrins (splitting of the Soret and Q bands) were justified by considering the stronger interaction between the porphyrin π-system and the electronic acceptor unit through the olefin linkage in addition to their reduced symmetry. It was commented that the unperturbed absorption spectra observed for many β-substituted mesotetraphenylporphyrins can be justified by considering the weak electron accepting power of the substituent which can be an obstacle on the conjugation pathway or due to steric hindrance. Tandem mass spectrometry, namely electrospray tandem mass spectrometry (ESI-MS/MS) is a valuable tool for the rapid and sensitive analysis of porphyrins in mixtures and can also give important information about their structural characterization, namely of peripheral substituents [94]. This approach was considered to study the fragmentation pathways of β-nitroalkenyl-substituted meso-tetraphenylporphyrins 14a-c and of their Zn(II) complexes 15a-c ( Figure 6), obtained by the classic condensation reaction between an aldehyde and a nitroalkane bearing α-hydrogen atoms [95]. In addition to the common fragmentation pathway of nitro derivatives, whose relative abundances Scheme 4. Reaction between β-formylporphyrins and acceptors [92].
Tandem mass spectrometry, namely electrospray tandem mass spectrometry (ESI-MS/MS) is a valuable tool for the rapid and sensitive analysis of porphyrins in mixtures and can also give important information about their structural characterization, namely of peripheral substituents [94]. This approach was considered to study the fragmentation pathways of β-nitroalkenyl-substituted meso-tetraphenylporphyrins 14a-c and of their Zn(II) complexes 15a-c ( Figure 6), obtained by the classic condensation reaction between an aldehyde and a nitroalkane bearing α-hydrogen atoms [95].
In addition to the common fragmentation pathway of nitro derivatives, whose relative abundances are essentially controlled by the presence and absence of a metal and by the nature of the R substituent, it was found that losses of CH(NO 2 )R and HNO 2 plus C 2 H 2 are typical of free-base derivatives while the loss of OH, H 2 O, OH plus H 2 O and RCCH plus H 2 O were observed only for the complexes. It was also found that the nature of the R substituent affects the typical nitro group fragments. When CH 3 was replaced by Br, the main loss of HNO 2 changed to a combined elimination of the bromine atom with the typical nitro group fragments. Unusual fragmentations were also observed, namely the losses of RCNO, RCNO 2 and HNO 2 plus C 2 H 2 . This type of approach was explored by other groups to prepare dyads to be used in dye sensitized solar cells [96]. are essentially controlled by the presence and absence of a metal and by the nature of the R substituent, it was found that losses of CH(NO2)R and HNO2 plus C2H2 are typical of free-base derivatives while the loss of OH, H2O, OH plus H2O and RCCH plus H2O were observed only for the complexes. It was also found that the nature of the R substituent affects the typical nitro group fragments. When CH3 was replaced by Br, the main loss of HNO2 changed to a combined elimination of the bromine atom with the typical nitro group fragments. Unusual fragmentations were also observed, namely the losses of RCNO, RCNO2 and HNO2 plus C2H2. This type of approach was explored by other groups to prepare dyads to be used in dye sensitized solar cells [96]. One of our first studies concerning the use of β-CHOTPP 3 in aldol type condensations was based on the simple concept that 2-and 4-alkylpyridines can undergo aldol-like condensations with carbonyl compounds upon treatment with strong bases, but the use of N-alkylpyridinium salts would allow the reaction to occur under milder conditions, as a consequence of the electron withdrawing effect exerted on the ring by the presence of the positive charge [97]. In fact, it was verified that the condensation of β-CHOTPP with 1,2-or 1,4-dimethylpyridinium iodide in the presence of K2CO3 affords the cationic β-vinyl substituted meso-tetraphenylporphyrin derivatives 16a,b (Scheme 5). The synthesis of the neutral analogue of 16a starting from 3 has previously been reported in the literature, but the procedure described required the reduction of the carbonyl function, followed by halogenation of the resulting hydroxymethyl group, its conversion into the corresponding triphenylphosphonium salt and then reaction with pyridine-4-carbaldehyde. This strategy affords both E-and Z-isomers, while our method leads to the E-isomer only [98][99][100].
The in vitro activity of derivatives 16a,b against herpes simplex virus type I (HSV-1) was evaluated and although the two compounds displayed similar photocytotoxicity profiles, a striking difference was found in their photoinactivation efficiency. At the same concentration and after 5 min of irradiation, compound 16b was able to photoinactivate 97% of the viral population, while compound 16a, under the same conditions, displayed no virucidal effect [97]. Scheme 5. Aldol type condensation of β-CHOTPP 3 with 1,4-and 1,2-dimethylpyridinium iodides [97].
Interestingly, the two free-base isomers 16a and 16b were easily differentiated by ESI-MS and ESI-MS/MS studies [101]. Semi-empirical calculations allowed to conclude that the different electron density distribution was the responsible for the different gas phase behaviour of the two isomers and One of our first studies concerning the use of β-CHOTPP 3 in aldol type condensations was based on the simple concept that 2-and 4-alkylpyridines can undergo aldol-like condensations with carbonyl compounds upon treatment with strong bases, but the use of N-alkylpyridinium salts would allow the reaction to occur under milder conditions, as a consequence of the electron withdrawing effect exerted on the ring by the presence of the positive charge [97]. In fact, it was verified that the condensation of β-CHOTPP with 1,2-or 1,4-dimethylpyridinium iodide in the presence of K 2 CO 3 affords the cationic β-vinyl substituted meso-tetraphenylporphyrin derivatives 16a,b (Scheme 5). The synthesis of the neutral analogue of 16a starting from 3 has previously been reported in the literature, but the procedure described required the reduction of the carbonyl function, followed by halogenation of the resulting hydroxymethyl group, its conversion into the corresponding triphenylphosphonium salt and then reaction with pyridine-4-carbaldehyde. This strategy affords both E-and Z-isomers, while our method leads to the E-isomer only [98][99][100].
The in vitro activity of derivatives 16a,b against herpes simplex virus type I (HSV-1) was evaluated and although the two compounds displayed similar photocytotoxicity profiles, a striking difference was found in their photoinactivation efficiency. At the same concentration and after 5 min of irradiation, compound 16b was able to photoinactivate 97% of the viral population, while compound 16a, under the same conditions, displayed no virucidal effect [97]. are essentially controlled by the presence and absence of a metal and by the nature of the R substituent, it was found that losses of CH(NO2)R and HNO2 plus C2H2 are typical of free-base derivatives while the loss of OH, H2O, OH plus H2O and RCCH plus H2O were observed only for the complexes. It was also found that the nature of the R substituent affects the typical nitro group fragments. When CH3 was replaced by Br, the main loss of HNO2 changed to a combined elimination of the bromine atom with the typical nitro group fragments. Unusual fragmentations were also observed, namely the losses of RCNO, RCNO2 and HNO2 plus C2H2. This type of approach was explored by other groups to prepare dyads to be used in dye sensitized solar cells [96]. One of our first studies concerning the use of β-CHOTPP 3 in aldol type condensations was based on the simple concept that 2-and 4-alkylpyridines can undergo aldol-like condensations with carbonyl compounds upon treatment with strong bases, but the use of N-alkylpyridinium salts would allow the reaction to occur under milder conditions, as a consequence of the electron withdrawing effect exerted on the ring by the presence of the positive charge [97]. In fact, it was verified that the condensation of β-CHOTPP with 1,2-or 1,4-dimethylpyridinium iodide in the presence of K2CO3 affords the cationic β-vinyl substituted meso-tetraphenylporphyrin derivatives 16a,b (Scheme 5). The synthesis of the neutral analogue of 16a starting from 3 has previously been reported in the literature, but the procedure described required the reduction of the carbonyl function, followed by halogenation of the resulting hydroxymethyl group, its conversion into the corresponding triphenylphosphonium salt and then reaction with pyridine-4-carbaldehyde. This strategy affords both E-and Z-isomers, while our method leads to the E-isomer only [98][99][100].
The in vitro activity of derivatives 16a,b against herpes simplex virus type I (HSV-1) was evaluated and although the two compounds displayed similar photocytotoxicity profiles, a striking difference was found in their photoinactivation efficiency. At the same concentration and after 5 min of irradiation, compound 16b was able to photoinactivate 97% of the viral population, while compound 16a, under the same conditions, displayed no virucidal effect [97]. Scheme 5. Aldol type condensation of β-CHOTPP 3 with 1,4-and 1,2-dimethylpyridinium iodides [97].
Interestingly, the two free-base isomers 16a and 16b were easily differentiated by ESI-MS and ESI-MS/MS studies [101]. Semi-empirical calculations allowed to conclude that the different electron density distribution was the responsible for the different gas phase behaviour of the two isomers and Scheme 5. Aldol type condensation of β-CHOTPP 3 with 1,4-and 1,2-dimethylpyridinium iodides [97].
Interestingly, the two free-base isomers 16a and 16b were easily differentiated by ESI-MS and ESI-MS/MS studies [101]. Semi-empirical calculations allowed to conclude that the different electron density distribution was the responsible for the different gas phase behaviour of the two isomers and not the local distortion due to the presence of the β-vinylpyridyl substituents. It was also found that the different gas phase behaviour is less effective when the corresponding zinc(II) complexes were studied. The structural effects of the β-vinyl linker in the electronic properties of isomeric pyridinium porphyrins 16a and 16b were accessed later by steady state and transient spectroscopies both in organic solvents and in AOT reverse micelles, the biomimetic models of natural membranes [102]. Different contributions of the trans and quinoid resonance structures in the ground state were proposed for both isomers. Solvatochromic studies analysed for the Kamlet-Taft mutiparametric model showed that the solvatochromism of para isomer is ruled by solvent polarity, as expected for a charge transfer process in which an electron is transferred from the porphyrin to the pyridinium moiety, and being limited in the 2-substituted isomer 16b due to steric hindrance to rotation. Nevertheless, a specific interaction with protic solvents was revealed by the characteristic emission spectra of the 4-substituted isomer 16a in alcohols with increasing number of carbons. The spectroscopic behaviour of 16a and 16b isomers was also significantly different in AOT reverse micelles emphasizing the structural effect of the β-vinyl linker. While compound 16b, the cytotoxic compound, resides at the interface toward the organic phase, compound 16a, the non-cytotoxic one, does not interact with AOT reverse micelles. These different affinities towards membrane models may help to explain the higher virucidal effect of the 2-substituted isomer 16b. As an extension of the previous synthetic strategy, another condensation involving β-CHOTPP 3 or Zn3 with other N-alkyl derivatives of 2-and 4-methylpyridine and also of 2-and 4-methylquinoline gave rise to the cationic β-vinylpyridiniumand β-vinylquinolinium-meso-tetraphenylporphyrin derivatives 16c,d and 17 (Figure 7) [103]. not the local distortion due to the presence of the β-vinylpyridyl substituents. It was also found that the different gas phase behaviour is less effective when the corresponding zinc(II) complexes were studied. The structural effects of the β-vinyl linker in the electronic properties of isomeric pyridinium porphyrins 16a and 16b were accessed later by steady state and transient spectroscopies both in organic solvents and in AOT reverse micelles, the biomimetic models of natural membranes [102]. Different contributions of the trans and quinoid resonance structures in the ground state were proposed for both isomers. Solvatochromic studies analysed for the Kamlet-Taft mutiparametric model showed that the solvatochromism of para isomer is ruled by solvent polarity, as expected for a charge transfer process in which an electron is transferred from the porphyrin to the pyridinium moiety, and being limited in the 2-substituted isomer 16b due to steric hindrance to rotation. Nevertheless, a specific interaction with protic solvents was revealed by the characteristic emission spectra of the 4-substituted isomer 16a in alcohols with increasing number of carbons. The spectroscopic behaviour of 16a and 16b isomers was also significantly different in AOT reverse micelles emphasizing the structural effect of the β-vinyl linker. While compound 16b, the cytotoxic compound, resides at the interface toward the organic phase, compound 16a, the non-cytotoxic one, does not interact with AOT reverse micelles. These different affinities towards membrane models may help to explain the higher virucidal effect of the 2-substituted isomer 16b. As an extension of the previous synthetic strategy, another condensation involving β-CHOTPP 3 or Zn3 with other N-alkyl derivatives of 2-and 4-methylpyridine and also of 2-and 4-methylquinoline gave rise to the cationic β-vinylpyridinium-and β-vinylquinolinium-meso-tetraphenylporphyrin derivatives 16c,d and 17 (Figure 7) [103]. In this study it was verified that the condensations with 1,2-and 1,4-dimethylquinolinium iodides require slightly different conditions, namely being performed at 60 °C and using pyridine as solvent. The capability of this series of porphyrin derivatives to generate singlet oxygen was qualitatively estimated by measuring the absorption decay of 1,3-diphenylisobenzofuran (DPBF) and the results obtained showed that the best singlet oxygen producers were compounds 16b and 16da (with the sugar unit protected). Compounds with the quinolinium moiety did not produce singlet oxygen and the others showed an efficiency similar to TPP. The binding mode of the synthesized cationic derivatives with a short GC duplex oligonucleotide was evaluated by ESI-MS and the results Figure 7. β-Vinylpyridiniumand β-vinylquinolinium-meso-tetraphenylporphyrin derivatives [103].
In this study it was verified that the condensations with 1,2-and 1,4-dimethylquinolinium iodides require slightly different conditions, namely being performed at 60 • C and using pyridine as solvent. The capability of this series of porphyrin derivatives to generate singlet oxygen was qualitatively estimated by measuring the absorption decay of 1,3-diphenylisobenzofuran (DPBF) and the results obtained showed that the best singlet oxygen producers were compounds 16b and 16da (with the sugar unit protected). Compounds with the quinolinium moiety did not produce singlet oxygen and the others showed an efficiency similar to TPP. The binding mode of the synthesized cationic derivatives with a short GC duplex oligonucleotide was evaluated by ESI-MS and the results indicated the probable occurrence of an outside binding. The UV-vis spectroscopy data pointed also to a non-intercalation process.
The gas phase behavior of the cationic porphyrins 16d bearing the galactose unit was compared by ESI-MS and ESI-MS/MS with the behavior of other glycoporphyrins bearing the same sugar unit linked directly to a pyridine or to an aminophenyl group located at a meso-position [104]. For all derivatives, the electrospray mass spectra of the monocharged porphyrins showed the expected M + ions. It was also found from the fragmentation studies of these ions under ESI-MS/MS conditions that the elimination of the sugar residue as a radical is a common fragmentation pathway, but the loss of the sugar unit as a neutral fragment and cross-ring fragmentations typical of glyco-derivatives were only detected for the pyridinium glycoporphyrins, but not for ammonium glycoporphyrins. However, distinct fragmentations were observed for porphyrins 16d. For instance, for derivative 16db the major fragment in its MS/MS spectrum is due to loss of fragment C 5 H 8 O 5 corresponding to 148 Da (base peak at m/z 732) which was explained by the cleavage of the C5-C6 bond of the sugar unit with the migration of one hydrogen from that unit to the porphyrin residue (Scheme 6i). For porphyrin 16da, besides an abundant ion at m/z 732, due to the cleavage of the C5-C6 bond of the sugar unit as it was detected for the unprotected derivative 16db (in here only pathways (b) and (c) are possible), it was observed an important ion at m/z 625. This ion, corresponding to the combined losses of the protected galactose unit and of pyridyl unit was justified by considering the typical intramolecular cyclization between the double bond and the ortho position of the adjacent phenyl ring (Scheme 6ii). indicated the probable occurrence of an outside binding. The UV-vis spectroscopy data pointed also to a non-intercalation process.
The gas phase behavior of the cationic porphyrins 16d bearing the galactose unit was compared by ESI-MS and ESI-MS/MS with the behavior of other glycoporphyrins bearing the same sugar unit linked directly to a pyridine or to an aminophenyl group located at a meso-position [104]. For all derivatives, the electrospray mass spectra of the monocharged porphyrins showed the expected M + ions. It was also found from the fragmentation studies of these ions under ESI-MS/MS conditions that the elimination of the sugar residue as a radical is a common fragmentation pathway, but the loss of the sugar unit as a neutral fragment and cross-ring fragmentations typical of glyco-derivatives were only detected for the pyridinium glycoporphyrins, but not for ammonium glycoporphyrins. However, distinct fragmentations were observed for porphyrins 16d. For instance, for derivative 16db the major fragment in its MS/MS spectrum is due to loss of fragment C5H8O5 corresponding to 148 Da (base peak at m/z 732) which was explained by the cleavage of the C5-C6 bond of the sugar unit with the migration of one hydrogen from that unit to the porphyrin residue (Scheme 6i). For porphyrin 16da, besides an abundant ion at m/z 732, due to the cleavage of the C5-C6 bond of the sugar unit as it was detected for the unprotected derivative 16db (in here only pathways (b) and (c) are possible), it was observed an important ion at m/z 625. This ion, corresponding to the combined losses of the protected galactose unit and of pyridyl unit was justified by considering the typical intramolecular cyclization between the double bond and the ortho position of the adjacent phenyl ring (Scheme 6ii). The condensation of β-CHOTPP with methyl ketones has also been an important tool to functionalize the periphery of TPP giving access to new derivatives with potential applications in different fields. In 2003, Ishkov and co-workers reported the synthesis of porphyrin-chalcone-type derivatives 18 by reaction of β-CHOTPP or its Cu(II) complex with suitable ketones (acetone, 1,4diacetylbenzene, 2-acetylthiophene, acetylacetone and acetophenone) in the presence of piperidine ( Figure 8) [105,106]. These authors highlighted that the formation of the desired Claisen-Schmidt Scheme 6. Atypical fragmentations detected in the ESI-MS/MS spectra of porphyrins 16d [104].
The condensation of β-CHOTPP with methyl ketones has also been an important tool to functionalize the periphery of TPP giving access to new derivatives with potential applications in different fields. In 2003, Ishkov and co-workers reported the synthesis of porphyrin-chalcone-type derivatives 18 by reaction of β-CHOTPP or its Cu(II) complex with suitable ketones (acetone, 1,4-diacetylbenzene, 2-acetylthiophene, acetylacetone and acetophenone) in the presence of piperidine ( Figure 8) [105,106]. These authors highlighted that the formation of the desired Claisen-Schmidt condensation products in appreciable amounts only occurs with the addition of a few drops of perchloric acid. The condensation of 18b with β-CHOTPP or quinoxaline-6-carbaldehyde afforded the corresponding derivatives 19 and 20. The authors emphasized that in all cases the free-base reacted at a higher rate than the copper(II) complex.   Table 2). Scheme 7. Condensation of β-CHOTPP with aryl methyl ketones 21 [107]. Table 2. Yields of the products obtained in the reaction of β-CHOTPP 3 with ketones 21.  Table 2).
Depending on the ketone reactivity, and the reaction time, the porphyrin-chalcone-type derivatives 24 were also isolated. These compounds were considered to be the key intermediates for the formation of 22 and 23 [107].
The Kröhnke-type approach was selected as the key step to obtain the cationic porphyrin-terpyridine derivatives 25 and 26 (Scheme 8) [108]. The condensation of β-CHOTPP 3 with the adequate acetylpyridines afforded after a carefully selection of the experimental conditions the required neutral derivatives 22a, 22b and 22c as major products (yields between 45% to 48%) accompanied by the respective benzoporphyrins and porphyrin-chalcone-type derivatives. Interesting in this study, it was also isolated a new 2-(2,4-terpyridin-6-yl)-porphyrin 27 and the reduced compounds 28a and 28b (Figure 9). The quaternization of the pyridyl groups of 22a, 22b and 22c was performed in the presence of the adequate alkyl iodide affording the dicationic derivatives in excellent yields.  Table 2).
Depending on the ketone reactivity, and the reaction time, the porphyrin-chalcone-type derivatives 24 were also isolated. These compounds were considered to be the key intermediates for the formation of 22 and 23 [107].
The Kröhnke-type approach was selected as the key step to obtain the cationic porphyrinterpyridine derivatives 25 and 26 (Scheme 8) [108]. The condensation of β-CHOTPP 3 with the adequate acetylpyridines afforded after a carefully selection of the experimental conditions the required neutral derivatives 22a, 22b and 22c as major products (yields between 45% to 48%) accompanied by the respective benzoporphyrins and porphyrin-chalcone-type derivatives. Interesting in this study, it was also isolated a new 2-(2,4-terpyridin-6-yl)-porphyrin 27 and the reduced compounds 28a and 28b (Figure 9). The quaternization of the pyridyl groups of 22a, 22b and 22c was performed in the presence of the adequate alkyl iodide affording the dicationic derivatives in excellent yields.
The ESI-MS revealed to be a useful technique for the differentiation of these cationic derivatives through the formation of different diagnostic ions. The absence of the [M + H] 3+ ion and the formation of the monocharged [M − CH3] + ion allowed the differentiation of the ortho isomer 25a from the isomers 25b,c. On the other hand, formation of the [M + I − ] + adducts is a feature that is specific of the meta alkylated isomers 25b and 26b, enabling their differentiation from the para isomers 25c and 26c.
The efficiency of these dicationic derivatives to photoinactivate the bioluminescent E. coli was evaluated and the results show that their efficacy was dependent on the PS concentration, singlet oxygen efficiency, charge localisation in the porphyrin core and light irradiance [108]. A reduction in bacterial bioluminescence, up to 5.4 log, was obtained with the most efficient photosensitizer 25a. Scheme 8. Cationization of porphyrin-terpyridine derivatives [108].  The sensing ability of these compounds towards a series of mono-, di-and trivalent metals was evaluated in solution and solid state by absorption and fluorescence spectroscopy and in the gas phase using MALDI-TOF-MS. The most significant changes in the ground and excited states were observed in the presence of several di-and trivalent metals, although compound 24b was able to detect also the presence of Ag + . The results allowed to conclude that these probes can be analytically used to develop ratiometric molecular devices with high affinity and selectivity for Zn 2+ . Interestingly, from NMR titrations with Zn 2+ it was possible to conclude that compounds 24b and 24c lost the internal N-H protons while in the interaction of the other derivatives 24a, 24d and 24e the inner protons were maintained suggesting the formation of sitting-atop complexes as it was proposed by Fleischer [110,111]. The results showed also that these compounds when supported in polymethylmethacrylate (PMMA) films can detect and differentiate Zn 2+ and Hg 2+ . Additionally, the results obtained by MALDI-TOF-MS showed the gas phase sensing abilities of the compounds towards Zn 2+ , Cu 2+ , Hg 2+ , Cd 2+ and Ag + . The efficiency of these dicationic derivatives to photoinactivate the bioluminescent E. coli was evaluated and the results show that their efficacy was dependent on the PS concentration, singlet oxygen efficiency, charge localisation in the porphyrin core and light irradiance [108]. A reduction in bacterial bioluminescence, up to 5.4 log, was obtained with the most efficient photosensitizer 25a.
In order to avoid the hazards associated to the use of perchloric acid in Claisen-Schmidt condensations reported by Ishkov et al. [105,106] Moura et al. re-examined the condensation of β-CHOTPP 3 with ketones 21 in the presence of piperidine and La(OTf) 3 , known as an excellent Lewis acid even in the presence of water (Scheme 9) [109]. The reactions performed in refluxing toluene afforded the expected porphyrin-chalcone-type compounds 24 in yields between 52% to 71%, accompanied by minor amounts of the corresponding benzoporphyrins (1-3%). In order to avoid the hazards associated to the use of perchloric acid in Claisen-Schmidt condensations reported by Ishkov et al. [105,106] Moura et al. re-examined the condensation of β-CHOTPP 3 with ketones 21 in the presence of piperidine and La(OTf)3, known as an excellent Lewis acid even in the presence of water (Scheme 9) [109]. The reactions performed in refluxing toluene afforded the expected porphyrin-chalcone-type compounds 24 in yields between 52% to 71%, accompanied by minor amounts of the corresponding benzoporphyrins (1%-3%). The sensing ability of these compounds towards a series of mono-, di-and trivalent metals was evaluated in solution and solid state by absorption and fluorescence spectroscopy and in the gas phase using MALDI-TOF-MS. The most significant changes in the ground and excited states were observed in the presence of several di-and trivalent metals, although compound 24b was able to detect also the presence of Ag + . The results allowed to conclude that these probes can be analytically used to develop ratiometric molecular devices with high affinity and selectivity for Zn 2+ . Interestingly, from NMR titrations with Zn 2+ it was possible to conclude that compounds 24b and 24c lost the internal N-H protons while in the interaction of the other derivatives 24a, 24d and 24e the inner protons were maintained suggesting the formation of sitting-atop complexes as it was proposed by Fleischer [110,111]. The results showed also that these compounds when supported in polymethylmethacrylate (PMMA) films can detect and differentiate Zn 2+ and Hg 2+ . Additionally, the results obtained by MALDI-TOF-MS showed the gas phase sensing abilities of the compounds The sensing ability of these compounds towards a series of mono-, di-and trivalent metals was evaluated in solution and solid state by absorption and fluorescence spectroscopy and in the gas phase using MALDI-TOF-MS. The most significant changes in the ground and excited states were observed in the presence of several di-and trivalent metals, although compound 24b was able to detect also the presence of Ag + . The results allowed to conclude that these probes can be analytically used to develop ratiometric molecular devices with high affinity and selectivity for Zn 2+ . Interestingly, from NMR titrations with Zn 2+ it was possible to conclude that compounds 24b and 24c lost the internal N-H protons while in the interaction of the other derivatives 24a, 24d and 24e the inner protons were maintained suggesting the formation of sitting-atop complexes as it was proposed by Fleischer [110,111]. The results showed also that these compounds when supported in polymethylmethacrylate (PMMA) films can detect and differentiate Zn 2+ and Hg 2+ . Additionally, the results obtained by MALDI-TOF-MS showed the gas phase sensing abilities of the compounds towards Zn 2+ , Cu 2+ , Hg 2+ , Cd 2+ and Ag + . . It was reported that the best experimental conditions to obtain those compounds involve the reaction with phenylhydrazine in acetic acid at 60 °C followed by the oxidation of the porphyrinpyrazoline derivatives 29 with o-chloranil and then demetallation with H2SO4 in CHCl3.
The sensing ability of these porphyrin-pyrazole derivatives to detect a series of mono, di and trivalent metal ions was also evaluated by absorption and fluorescence spectroscopies and the most significant changes in the ground and excited states were observed in the presence of Cu 2+ , Zn 2+ , Cd 2+ , and Hg 2+ . The results from the titrations of the conjugates with Zn 2+ suggested complex formation in a stoichiometry of one metal ion per two ligands (M/L = 1:2), for ligands 30a,b,d, and two metals per ligand (M/L = 2:1) for ligand 30e; the lowest energy conformation for these two types of coordination determined through density functional theory (DFT) are shown in Figure 10. The same study showed that these probes have high selectivity towards Cu 2+ and Ag + in gas phase and when supported in poly (methyl methacrylate) towards Zn 2+ .

Reactivity of β-Formyl-meso-tetraarylporphyrins with Wittig Reagents
One efficient and simple procedure to introduce an alkenyl group at the porphyrin periphery of meso-tetraarylporphyrins involves the reaction of a β-formylporphyrin and a phosphorus ylide [44,85,113,114]. This approach was reported by Callot in 1973 [75] to prepare, for the first time, the β-vinylTPP 31, an important template in our studies. In that pioneer report, the reaction was performed between the Ni(II) complex of β-CHOTPP 3 and the adequate ylide generated from methyltriphenylphosphonium bromide and BuLi in THF at room temperature. The Ni(II) complex of β-vinylTPP (Ni31) is obtained in 52% yield (Scheme 11). This protocol is also efficient when the freebase or the copper or zinc complexes are used; NaH is a good alternative to BuLi [75,115].
A complementary strategy was reported by Officer and co-workers that selected the porphyrin . It was reported that the best experimental conditions to obtain those compounds involve the reaction with phenylhydrazine in acetic acid at 60 • C followed by the oxidation of the porphyrin-pyrazoline derivatives 29 with o-chloranil and then demetallation with H 2 SO 4 in CHCl 3 .
The sensing ability of these porphyrin-pyrazole derivatives to detect a series of mono, di and trivalent metal ions was also evaluated by absorption and fluorescence spectroscopies and the most significant changes in the ground and excited states were observed in the presence of Cu 2+ , Zn 2+ , Cd 2+ , and Hg 2+ . The results from the titrations of the conjugates with Zn 2+ suggested complex formation in a stoichiometry of one metal ion per two ligands (M/L = 1:2), for ligands 30a,b,d, and two metals per ligand (M/L = 2:1) for ligand 30e; the lowest energy conformation for these two types of coordination determined through density functional theory (DFT) are shown in Figure 10. The same study showed that these probes have high selectivity towards Cu 2+ and Ag + in gas phase and when supported in poly (methyl methacrylate) towards Zn 2+ . . It was reported that the best experimental conditions to obtain those compounds involve the reaction with phenylhydrazine in acetic acid at 60 °C followed by the oxidation of the porphyrinpyrazoline derivatives 29 with o-chloranil and then demetallation with H2SO4 in CHCl3.
The sensing ability of these porphyrin-pyrazole derivatives to detect a series of mono, di and trivalent metal ions was also evaluated by absorption and fluorescence spectroscopies and the most significant changes in the ground and excited states were observed in the presence of Cu 2+ , Zn 2+ , Cd 2+ , and Hg 2+ . The results from the titrations of the conjugates with Zn 2+ suggested complex formation in a stoichiometry of one metal ion per two ligands (M/L = 1:2), for ligands 30a,b,d, and two metals per ligand (M/L = 2:1) for ligand 30e; the lowest energy conformation for these two types of coordination determined through density functional theory (DFT) are shown in Figure 10. The same study showed that these probes have high selectivity towards Cu 2+ and Ag + in gas phase and when supported in poly (methyl methacrylate) towards Zn 2+ .

Reactivity of β-Formyl-meso-tetraarylporphyrins with Wittig Reagents
One efficient and simple procedure to introduce an alkenyl group at the porphyrin periphery of meso-tetraarylporphyrins involves the reaction of a β-formylporphyrin and a phosphorus ylide [44,85,113,114]. This approach was reported by Callot in 1973 [75] to prepare, for the first time, the β-vinylTPP 31, an important template in our studies. In that pioneer report, the reaction was performed between the Ni(II) complex of β-CHOTPP 3 and the adequate ylide generated from methyltriphenylphosphonium bromide and BuLi in THF at room temperature. The Ni(II) complex of β-vinylTPP (Ni31) is obtained in 52% yield (Scheme 11). This protocol is also efficient when the freebase or the copper or zinc complexes are used; NaH is a good alternative to BuLi [75,115].
A complementary strategy was reported by Officer and co-workers that selected the porphyrin

Reactivity of β-Formyl-meso-tetraarylporphyrins with Wittig Reagents
One efficient and simple procedure to introduce an alkenyl group at the porphyrin periphery of meso-tetraarylporphyrins involves the reaction of a β-formylporphyrin and a phosphorus ylide [44,85,113,114]. This approach was reported by Callot in 1973 [75] to prepare, for the first time, the β-vinylTPP 31, an important template in our studies. In that pioneer report, the reaction was performed between the Ni(II) complex of β-CHOTPP 3 and the adequate ylide generated from methyltriphenylphosphonium bromide and BuLi in THF at room temperature. The Ni(II) complex of β-vinylTPP (Ni31) is obtained in 52% yield (Scheme 11). This protocol is also efficient when the free-base or the copper or zinc complexes are used; NaH is a good alternative to BuLi [75,115].
A complementary strategy was reported by Officer and co-workers that selected the porphyrin derivative as the phosphonium salt partner. The procedure, as mentioned above, requires the reduction of the carbonyl function, halogenation of the resulting hydroxymethyl group and its conversion into the corresponding triphenylphosphonium salt. The condensation with aldehydes afforded a series of TPP derivatives bearing vinyl substituents [98][99][100]116]. Scheme 11. Synthesis of β-vinyl-meso-tetraarylporphyrins by Wittig reaction [75].
Interesting attempts to demetallate the Ni(II) complex of β-vinylporphyrins 31 (Ar = Ph or p-MeOC6H4) with strong acid conditions led to the isolation of the green naphthochlorins 32 (Figure 11) in excellent yields as a result of the acid catalysed intracyclization of the vinyl group with the neighbouring meso-aryl group [117]. Silva et al. showed that the Wittig reaction is also an excellent protocol to afford the β-butadienyl-34 and β,β′-di(butadienyl)porphyrins 35 from the corresponding β-formyl and β,β′-diformyl derivatives and allylic phosphorus ylide 33 (Scheme 12) [118]. Scheme 11. Synthesis of β-vinyl-meso-tetraarylporphyrins by Wittig reaction [75].
Interesting attempts to demetallate the Ni(II) complex of β-vinylporphyrins 31 (Ar = Ph or p-MeOC 6 H 4 ) with strong acid conditions led to the isolation of the green naphthochlorins 32 (Figure 11) in excellent yields as a result of the acid catalysed intracyclization of the vinyl group with the neighbouring meso-aryl group [117]. Scheme 11. Synthesis of β-vinyl-meso-tetraarylporphyrins by Wittig reaction [75].
Interesting attempts to demetallate the Ni(II) complex of β-vinylporphyrins 31 (Ar = Ph or p-MeOC6H4) with strong acid conditions led to the isolation of the green naphthochlorins 32 (Figure 11) in excellent yields as a result of the acid catalysed intracyclization of the vinyl group with the neighbouring meso-aryl group [117].  Silva et al. showed that the Wittig reaction is also an excellent protocol to afford the β-butadienyl-34 and β,β -di(butadienyl)porphyrins 35 from the corresponding β-formyl and β,β -diformyl derivatives and allylic phosphorus ylide 33 (Scheme 12) [118].
The reactivity of β-vinylporphyrins as dienes, dienophiles or dipolarophiles was also considered in our group as an important tool for further functionalization of meso-tetraarylporphyrins as shown below.

β-Vinylporphyrins as 4π Components in Cycloaddition Reactions
Johnson and co-workers described for the first time the addition of activated dienophiles, such as dimethyl acetylenedicarboxylate (DMAD) or tetracyanoethylene (TCNE), to the β-β′ double bond of protoporphyrin-IX dimethyl ester through Diels-Alder reaction [119,120]. In the later decades, Dolphin and co-workers reported an intensive study concerning the use of protoporphyrin-IX dimethyl ester and analogues as dienes in the reactions with TCNE or DMAD. However, these reactions were revealed to be more complex than had been previously reported. In the studies with TCNE the formation of mono-and bis-adducts from [2 + 2] and [4 + 2] cycloadditions was observed and the expected isobacteriochlorin was only isolated in minor amounts [121][122][123][124]. In the presence of DMAD only monoadducts like 36a were formed. These can be converted into the corresponding benzoporphyrins 36b by loss of the methyl group ( Figure 12) [122,124]. The possibility of βvinylporphyrins to act as dienes was also suggested by Inhoffen et al. [125] to justify the formation of photoproducts of type 38 obtained (via a [4 + 2] intermediate) in the reaction of protoporphyrin-IX dimethyl ester 37 with singlet oxygen (Figure 12). It was mentioned that the reaction only occurs in one vinyl group and not in both.
The Diels-Alder reaction between protoporphyrin-IX dimethyl ester and maleic anhydride was used for the synthesis of the amphiphilic chlorin derivatives 40-43 (Scheme 13) by ring-opening of the regioisomeric mono-adducts 39a and 39b with the adequate nucleophiles (alcohols or amines). The full characterization of the adducts 40-43 allowed to conclude that the final step in the process is highly regioselective and occurs at the carbonyl closer to the macrocycle. Additionally, the photophysical characterization showed that the compounds have adequate features for PDT applications [126,127].
The reactivity of β-vinylporphyrins as dienes, dienophiles or dipolarophiles was also considered in our group as an important tool for further functionalization of meso-tetraarylporphyrins as shown below.

β-Vinylporphyrins as 4π Components in Cycloaddition Reactions
Johnson and co-workers described for the first time the addition of activated dienophiles, such as dimethyl acetylenedicarboxylate (DMAD) or tetracyanoethylene (TCNE), to the β-β double bond of protoporphyrin-IX dimethyl ester through Diels-Alder reaction [119,120]. In the later decades, Dolphin and co-workers reported an intensive study concerning the use of protoporphyrin-IX dimethyl ester and analogues as dienes in the reactions with TCNE or DMAD. However, these reactions were revealed to be more complex than had been previously reported. In the studies with TCNE the formation of mono-and bis-adducts from [2 + 2] and [4 + 2] cycloadditions was observed and the expected isobacteriochlorin was only isolated in minor amounts [121][122][123][124]. In the presence of DMAD only monoadducts like 36a were formed. These can be converted into the corresponding benzoporphyrins 36b by loss of the methyl group ( Figure 12) [122,124]. The possibility of β-vinylporphyrins to act as dienes was also suggested by Inhoffen et al. [125] to justify the formation of photoproducts of type 38 obtained (via a [4 + 2] intermediate) in the reaction of protoporphyrin-IX dimethyl ester 37 with singlet oxygen (Figure 12). It was mentioned that the reaction only occurs in one vinyl group and not in both.
The Diels-Alder reaction between protoporphyrin-IX dimethyl ester and maleic anhydride was used for the synthesis of the amphiphilic chlorin derivatives 40-43 (Scheme 13) by ring-opening of the regioisomeric mono-adducts 39a and 39b with the adequate nucleophiles (alcohols or amines). The full characterization of the adducts 40-43 allowed to conclude that the final step in the process is highly regioselective and occurs at the carbonyl closer to the macrocycle. Additionally, the photophysical characterization showed that the compounds have adequate features for PDT applications [126,127].
The reaction of protoporphyrin-IX dimethyl ester with heterodienophiles was studied by us and other groups [63,128,129]. In particular, our studies were performed with nitrosobenzenes and only monoadducts such as 44a were formed; the use of an excess of the dienophile conducted to the formation of the formyl-monoadducts of type 44b (Figure 13). When the studies were extended to the centro-symmetric protoporphyrin-II dimethyl ester the chlorins and the expected bacteriochlorins 45 were identified by visible spectroscopy, NMR and MS; the bis-adducts (as a mixture of diastereoisomers) showed to be too unstable to support chromatography and gave rise to the formyl-monoadduct 46 [130]. The reaction of protoporphyrin-IX dimethyl ester with heterodienophiles was studied by us and other groups [63,128,129]. In particular, our studies were performed with nitrosobenzenes and only monoadducts such as 44a were formed; the use of an excess of the dienophile conducted to the formation of the formyl-monoadducts of type 44b (Figure 13). When the studies were extended to the centro-symmetric protoporphyrin-II dimethyl ester the chlorins and the expected bacteriochlorins 45 were identified by visible spectroscopy, NMR and MS; the bis-adducts (as a mixture of diastereoisomers) showed to be too unstable to support chromatography and gave rise to the formylmonoadduct 46 [130]. Scheme 13. Synthesis of amphiphilic chlorin derivatives [126]. Scheme 13. Synthesis of amphiphilic chlorin derivatives [126]. Scheme 13. Synthesis of amphiphilic chlorin derivatives [126]. The use of β-vinyl-meso-tetraarylporphyrins as dienes in Diels-Alder reaction was investigated for the first time in 1996 [131]. Faustino [132]. Similar results were reported by Matsumoto et al. [133]. Related reactions using 1,4-naphthoquinone and 1,4-benzoquinone as dienophiles did not afford the expected [4+2] chlorin adducts but the dehydrogenated derivatives 51 and 54 accompanied by a mixture of porphyrin-quinone derivatives with extended π-systems (compounds 52 and 55, Scheme 15) [134]. The authors found that the hydroxylated compound 53 also isolated, is converted into porphyrin 52 (85% yield) after treatment with 10% trifluoroacetic acid and the demetallation of 52 with 10% sulfuric acid in trifluoroacetic acid afforded the corresponding free-base porphyrin 51 (M = 2H) in quantitative yield. Knowing that quinones are excellent agents in the dehydrogenation of hydroaromatic compounds, a plausible mechanism was proposed to justify the formation of the various products. Related reactions using 1,4-naphthoquinone and 1,4-benzoquinone as dienophiles did not afford the expected [4+2] chlorin adducts but the dehydrogenated derivatives 51 and 54 accompanied by a mixture of porphyrin-quinone derivatives with extended π-systems (compounds 52 and 55, Scheme 15) [134]. The authors found that the hydroxylated compound 53 also isolated, is converted into porphyrin 52 (85% yield) after treatment with 10% trifluoroacetic acid and the demetallation of 52 with 10% sulfuric acid in trifluoroacetic acid afforded the corresponding free-base porphyrin 51 (M = 2H) in quantitative yield. Knowing that quinones are excellent agents in the dehydrogenation of hydroaromatic compounds, a plausible mechanism was proposed to justify the formation of the various products.
Related reactions using 1,4-naphthoquinone and 1,4-benzoquinone as dienophiles did not afford the expected [4+2] chlorin adducts but the dehydrogenated derivatives 51 and 54 accompanied by a mixture of porphyrin-quinone derivatives with extended π-systems (compounds 52 and 55, Scheme 15) [134]. The authors found that the hydroxylated compound 53 also isolated, is converted into porphyrin 52 (85% yield) after treatment with 10% trifluoroacetic acid and the demetallation of 52 with 10% sulfuric acid in trifluoroacetic acid afforded the corresponding free-base porphyrin 51 (M = 2H) in quantitative yield. Knowing that quinones are excellent agents in the dehydrogenation of hydroaromatic compounds, a plausible mechanism was proposed to justify the formation of the various products. Matsumoto and co-workers [135] also reported the reaction of porphyrin Ni31 with a range of dienophiles, including 1,4-naphthoquinone, and referred the formation of a single product in 76% yield that was identified as 51 (M = Ni). Matsumoto and co-workers [135] also reported the reaction of porphyrin Ni31 with a range of dienophiles, including 1,4-naphthoquinone, and referred the formation of a single product in 76% yield that was identified as 51 (M = Ni).
The reactivity of the β-butadienylporphyrin Ni34 with N-methylmaleimide, dimethyl fumarate and DMAD was also evaluated (Scheme 16) [118]. The reactions were performed in the presence of an excess of the dienophile (6 equiv.) in refluxing toluene and afforded the expected adducts 57-59 in moderate yields. In the same article it was reported that, in the absence of a dienophile, compound Ni34 undergoes electrocyclization followed by oxidation affording the benzoporphyrin 60 (Scheme 17). The extension of the studies to porphyrins Ni35a and Ni35b bearing two butadienyl groups in β-positions afforded respectively the opposite and adjacent dibenzoporphyrins 61 and 62 (Scheme 17). The authors found that the best solvent to perform these oxidative electrocyclizations is nitrobenzene. The single-crystal X-ray diffraction of the mono-and dibenzoporphyrin nickel complexes showed a strong distortion from the planarity of the porphyrin core [118]. The reactivity of the β-butadienylporphyrin Ni34 with N-methylmaleimide, dimethyl fumarate and DMAD was also evaluated (Scheme 16) [118]. The reactions were performed in the presence of an excess of the dienophile (6 equiv.) in refluxing toluene and afforded the expected adducts 57-59 in moderate yields. In the same article it was reported that, in the absence of a dienophile, compound Ni34 undergoes electrocyclization followed by oxidation affording the benzoporphyrin 60 (Scheme 17). The extension of the studies to porphyrins Ni35a and Ni35b bearing two butadienyl groups in βpositions afforded respectively the opposite and adjacent dibenzoporphyrins 61 and 62 (Scheme 17). The authors found that the best solvent to perform these oxidative electrocyclizations is nitrobenzene. The single-crystal X-ray diffraction of the mono-and dibenzoporphyrin nickel complexes showed a strong distortion from the planarity of the porphyrin core [118].

β-Vinylporphyrins As 2π Component in Cycloaddition Reactions
Porphyrins bearing a β-vinyl group can react as the dienophile in Diels-Alder reactions and as the dipolarophile in 1,3-dipolar cycloadditions. For example, the reactivity of the Zn(II) complex of β-vinylTPP (Zn31) was studied in the presence the ortho-quinone methides 63-65 generated in situ from the reaction of 2-hydroxy-1,4-naphthoquinone, 4-hydroxycoumarins or o-hydroxybenzyl alcohols with paraformaldehyde (Scheme 18). The reactions were performed in refluxing 1,4-dioxane or o-DCB until complete consumption of Zn31 and the resulting dyads were isolated in 50% (66), 22% (67), 88% (68a), 95% (68b), 49% (69a) and 86% (69b) yields. The site selectivity and regioselectivity observed in these reactions are in agreement with the ones described for similar systems. The sensing ability of these Zn(II) conjugates towards different types of anions was evaluated by UV-vis and fluorescence measurements and alterations in both absorption and emission spectra or only in the emission spectra were detected in the presence of Cl − , CN − and CH 3 COO − [136].
The sensing ability of the free-base conjugates 70a and 70b, obtained in excellent yield by demetallation of the corresponding Zn(II) complexes with a mixture of TFA/CHCl 3 (Scheme 18), was also evaluated but in the presence of different metal ions [137]. Both dyads showed a colorimetric effect (color change from purple to yellow) and an unprecedented selectivity for Hg(II), even in a mixture EtOH/H 2 O. The same colorimetric effect for Hg(II) was observed when the dyad 70a was incorporated in a cellulose support material. The same derivative, both in solution and in the solid support, showed also a colorimetric effect at different pH values.
The coumarin-porphyrin dyad 68a showed to be a potential probe towards the alkaloids caffeine, nicotine and cotinine, with a stoichiometry of one ligand per alkaloid [138]. Additionally, the interaction of 68a with cotinine was verified by MALDI-TOF-MS and it was evidenced that this probe can detect small amounts of cotinine (2.5 ± 0.3 µM) in dam water samples.
mixture EtOH/H2O. The same colorimetric effect for Hg(II) was observed when the dyad 70a was incorporated in a cellulose support material. The same derivative, both in solution and in the solid support, showed also a colorimetric effect at different pH values.
The coumarin-porphyrin dyad 68a showed to be a potential probe towards the alkaloids caffeine, nicotine and cotinine, with a stoichiometry of one ligand per alkaloid [138]. Additionally, the interaction of 68a with cotinine was verified by MALDI-TOF-MS and it was evidenced that this probe can detect small amounts of cotinine (2.5 ± 0.3 μM) in dam water samples.
The extension of this hetero-Diels-Alder approach to the zinc(II) complexes of chlorin e6 trimethyl ester and protoporphyrin-IX as dienophiles and the ortho-quinone methides 63, 64 and the ones generated from 4-hydroxy-N-methylquinolin-2-one and 2-hydroxy-1,4-naphthoquinone and paraformaldehyde, afforded the adequate dyads 71 and 72 in excellent yields (81%-91%) (Figure 14) [139]. These complexes and the corresponding free-bases obtained from demetallation were isolated as mixtures of diastereomers and their abundances and characterization were determined by NMR. Aiming to find potential applications for these derivatives, their photophysical and electrochemical properties were evaluated. The results showed that the fluorescence quantum yield of the chlorin e6 dyads are higher than the ones of protoporphyrin-IX dyads. All dyads were able to generate singlet oxygen but the free-base chlorin e6 dyads showed an unexpectedly higher ability to generate singlet Scheme 18. Reaction of Zn31 with a series of ortho-quinone methides [136].
The extension of this hetero-Diels-Alder approach to the zinc(II) complexes of chlorin e 6 trimethyl ester and protoporphyrin-IX as dienophiles and the ortho-quinone methides 63, 64 and the ones generated from 4-hydroxy-N-methylquinolin-2-one and 2-hydroxy-1,4-naphthoquinone and paraformaldehyde, afforded the adequate dyads 71 and 72 in excellent yields (81-91%) ( Figure 14) [139]. These complexes and the corresponding free-bases obtained from demetallation were isolated as mixtures of diastereomers and their abundances and characterization were determined by NMR. Aiming to find potential applications for these derivatives, their photophysical and electrochemical properties were evaluated. The results showed that the fluorescence quantum yield of the chlorin e 6 dyads are higher than the ones of protoporphyrin-IX dyads. All dyads were able to generate singlet oxygen but the free-base chlorin e 6 dyads showed an unexpectedly higher ability to generate singlet oxygen than the Zn(II) counterparts due to the higher tendency of the Zn(II) complexes to form aggregates. From the estimation of the intersystem crossing (ISC) quantum yield it was verified than the protoporphyrin-IX dyads have the highest ISC rates and that fact is in accordance with their higher singlet oxygen quantum yield when compared with the ones of the chlorin e 6 series. From the electrochemical studies it was found that the peripheral modification of the ring affected the redox processes involved when compared with the starting templates. oxygen than the Zn(II) counterparts due to the higher tendency of the Zn(II) complexes to form aggregates. From the estimation of the intersystem crossing (ISC) quantum yield it was verified than the protoporphyrin-IX dyads have the highest ISC rates and that fact is in accordance with their higher singlet oxygen quantum yield when compared with the ones of the chlorin e6 series. From the electrochemical studies it was found that the peripheral modification of the ring affected the redox processes involved when compared with the starting templates. Figure 14. Compounds obtained from the reaction of natural-type porphyrin derivatives with orthoquinone methides [139].

Figure 14.
Compounds obtained from the reaction of natural-type porphyrin derivatives with orthoquinone methides [139].
The synthesis of six coumarin-porphyrin dyads (73a-f) ( Figure 15) from porphyrin Zn31 and ortho-quinone methides (generated in situ from 4-hydroxycoumarin and suitable aromatic aldehydes) was also reported and recently reviewed [140,141]. The reactions were carried out in different experimental conditions, namely in water under ohmic heating (a process in which the reaction mixture behaving as an electrical ohmic heater, is The reactions were carried out in different experimental conditions, namely in water under ohmic heating (a process in which the reaction mixture behaving as an electrical ohmic heater, is heated by passing an AC electrical current) [142]. The study allowed to conclude that the use of ohmic heating leads to a reduction of the reaction time, higher yields, selectivity and an easier work-up when compared with traditional organic solvents. Additionally, it was confirmed the potentiality of ohmic heating to perform reactions with complex systems like porphyrins.
The reaction of Zn31 with nitrile imines generated in situ from the ethyl hydrazono-αbromoglyoxylates 74a-f gave access to the corresponding pyrazolines 75 in good to excellent yields (63-92%) (Scheme 19) [143]. Treatment of pyrazoline adducts with DDQ affords the corresponding pyrazole derivatives 76 with moderate to excellent yields (50-96%). When the hydrolysis in the pyrazoline ester derivatives was attempted, it was observed the concomitant oxidation of the heterocyclic unit, giving rise to porphyrin-pyrazole derivatives bearing a carboxylic group (79) in very good yields. The free-bases 77, 78 and 80 were obtained in excellent yields from the demetallation of the corresponding zinc(II) complexes with TFA. The photophysical properties of the pyrazoline-and pyrazole-porphyrin derivatives showed that the influence of the heterocyclic substituents is limited by the tendency of these molecules to aggregate. All other properties, and mainly the triplet kinetics, remain unaffected. The adducts with low tendency to aggregate showed very high singlet oxygen yield, and this makes these compounds interesting for their use as photosensitisers for PDT.
very good yields. The free-bases 77, 78 and 80 were obtained in excellent yields from the demetallation of the corresponding zinc(II) complexes with TFA. The photophysical properties of the pyrazoline-and pyrazole-porphyrin derivatives showed that the influence of the heterocyclic substituents is limited by the tendency of these molecules to aggregate. All other properties, and mainly the triplet kinetics, remain unaffected. The adducts with low tendency to aggregate showed very high singlet oxygen yield, and this makes these compounds interesting for their use as photosensitisers for PDT.

Reaction of β-Formyl-meso-tetraarylporphyrins with Amines and other Nitrogen Derivatives
The reaction of β-formylporphyrins with amines or other nitrogen derivatives was successfully explored by us and others to functionalize the β-pyrrolic positions of meso-tetraarylporphyrins [44,63].

Reaction of β-Formyl-meso-tetraarylporphyrins with Amines and Other Nitrogen Derivatives
The reaction of β-formylporphyrins with amines or other nitrogen derivatives was successfully explored by us and others to functionalize the β-pyrrolic positions of meso-tetraarylporphyrins [44,63].
Sharma and Nath reported that the condensation of the Ni(II) complex of β-CHOTPP with the adequate o-arylenediamines, o-aminophenols, o-aminothiophenol and 1-amino-2-naphthol in refluxing 1,2-dichlorobenzene gives access to the nickel(II) 2-benzazolo-5,10,15,20-tetraphenyl-porphyrins 81-84 in yields ranging from 75% to 95% (Scheme 20) [144]. A similar approach was used to synthesize the bis-benzimidazoloporphyrins 85 and 86 in 55% and 65% yields by reacting the Ni(II) complex of β-CHOTPP respectively with benzene-1,2,4,5-tetraamine tetrahydrochloride and 3,3 -diaminobenzidine ( Figure 16). The authors commented that these reactions seem to proceed through the initial formation of the iminoporphyrin intermediate, which is followed by an intramolecular oxidative cyclization in the presence of air.   [145]. The authors found that the best conditions for these Pictet-Spengler reactions is to perform the condensations in 1,4dioxane at temperatures between 25 to 40 °C, in the presence of p-dodecylbenzenesulfonic acid, followed by in-situ oxidation with potassium permanganate at room temperature. Using conventional protocols an efficient access to the corresponding free-bases and to the Zn(II) and Ni(II) complexes were also reported [145]. The red shift observed in the electronic absorption and in some emission spectra of the pyrrolo-and indolo [1,2-a]quinoxalinoporphyrins in comparison to the corresponding meso-tetraphenylporphyrins were justified as being due to the extended π-conjugation.
Giribabu and co-workers used the condensation between 1,2-diaminoanthraquinone and β-CHOTPP or its Zn(II) complex to prepare molecular bis(porphyrin)-anthraquinone triads having  [145]. The authors found that the best conditions for these Pictet-Spengler reactions is to perform the condensations in 1,4-dioxane at temperatures between 25 to 40 • C, in the presence of p-dodecylbenzenesulfonic acid, followed by in-situ oxidation with potassium permanganate at room temperature. Using conventional protocols an efficient access to the corresponding free-bases and to the Zn(II) and Ni(II) complexes were also reported [145]. The red shift observed in the electronic absorption and in some emission spectra of the pyrrolo-and indolo [1,2-a]quinoxalinoporphyrins in comparison to the corresponding meso-tetraphenylporphyrins were justified as being due to the extended π-conjugation.
Giribabu and co-workers used the condensation between 1,2-diaminoanthraquinone and β-CHOTPP or its Zn(II) complex to prepare molecular bis(porphyrin)-anthraquinone triads having azomethine bridges [146]. The same approach was used to couple the cutaneous leishmaniasis agents aminotriazole 91a, isoniazid (pyridine-4-carbohydrazide, 91b) and the aminothiadiazoles 91c and 91d with the β-formylporphyrins 3 and 3a (Ar = Ph and m-MeOC 6 H 4 ) as a strategy to obtain molecules with dual function potentialities (Schemes 22 and 23) [147]. The reactions performed in the presence of La(OTf) 3 afforded the expected imines 92a-d, but due to their instability to chromatographic purification, they were reduced to the corresponding amines 93; only imine 92b could be isolated in 88% yield (Scheme 22). The study showed that the reactivity of β-CHO-m-MeOTPP (3b) with those aminoheterocycles is more complex under the previous conditions (Scheme 23). Curiously, the reaction with 91a, but without La(OTf) 3 , afforded the double cyclized imine derivative 94 in 73% yield and the reaction with 91b afforded the stable imine 95 (Scheme 23).
The singlet oxygen generation studies showed that all β-substituted porphyrin derivatives are able to generate singlet oxygen but derivative 94 is the most efficient one. Additionally the preliminary leishmanicidal properties obtained by molecular modelling and docking calculations showed that all synthesized compounds have higher values of relative affinity to the leishmanial arginase than current drugs.
We also reported the reaction of the nickel(II) complex of β-CHOTPP (Ni3) with aniline and p-bromoaniline to obtain the β-iminoporphyrins 96 (Scheme 24) [148]. These imines react with electron-rich dienophiles such as 3,4-dihydro-2H-pyran and 2,3-dihydrofuran at room temperature and in the presence of La(OTf) 3 to give the expected β-(tetrahydroquinoline)porphyrins 97, 99 and 100 accompanied by the β-(arylaminomethyl)porphyrins 98. When the reaction was performed with the β-iminoporphyrins 96b and 2,3-dihydrofuran it was also observed the formation of the unexpected azetidine 101b. The reduction of the imine bond requires the presence of both the dienophile and the catalyst.
Further studies showed that the β-iminoporphyrin derivative 96b can react with ethyl diazoacetate in the presence of catalytic amounts of La(OTf) 3 affording a mixture of the isomeric E/Z β-amino-α,β-unsaturated esters 102 and the α,β-diamino ester 103 (Scheme 25) [149]. The probable pathway proposed to justify the formation of the isolated compounds was based on the mechanistic data found in the literature about the aziridation of imines with ethyl diazoacetate catalysed by Lewis acids. azomethine bridges [146]. The same approach was used to couple the cutaneous leishmaniasis agents aminotriazole 91a, isoniazid (pyridine-4-carbohydrazide, 91b) and the aminothiadiazoles 91c and 91d with the β-formylporphyrins 3 and 3a (Ar = Ph and m-MeOC6H4) as a strategy to obtain molecules with dual function potentialities (Schemes 22 and 23) [147]. The reactions performed in the presence of La(OTf)3 afforded the expected imines 92a-d, but due to their instability to chromatographic purification, they were reduced to the corresponding amines 93; only imine 92b could be isolated in 88% yield (Scheme 22). The study showed that the reactivity of β-CHO-m-MeOTPP (3b) with those aminoheterocycles is more complex under the previous conditions (Scheme 23). Curiously, the reaction with 91a, but without La(OTf)3, afforded the double cyclized imine derivative 94 in 73% yield and the reaction with 91b afforded the stable imine 95 (Scheme 23).
The singlet oxygen generation studies showed that all β-substituted porphyrin derivatives are able to generate singlet oxygen but derivative 94 is the most efficient one. Additionally the preliminary leishmanicidal properties obtained by molecular modelling and docking calculations showed that all synthesized compounds have higher values of relative affinity to the leishmanial arginase than current drugs. Scheme 21. Structures of pyrrolo-and indolo[1,2-a]quinoxalinoporphyrins [145].

Scheme 22.
Reaction of β-CHOTPP with cutaneous leishmaniasis agents [147]. 91d with the β-formylporphyrins 3 and 3a (Ar = Ph and m-MeOC6H4) as a strategy to obtain molecules with dual function potentialities (Schemes 22 and 23) [147]. The reactions performed in the presence of La(OTf)3 afforded the expected imines 92a-d, but due to their instability to chromatographic purification, they were reduced to the corresponding amines 93; only imine 92b could be isolated in 88% yield (Scheme 22). The study showed that the reactivity of β-CHO-m-MeOTPP (3b) with those aminoheterocycles is more complex under the previous conditions (Scheme 23). Curiously, the reaction with 91a, but without La(OTf)3, afforded the double cyclized imine derivative 94 in 73% yield and the reaction with 91b afforded the stable imine 95 (Scheme 23).
The singlet oxygen generation studies showed that all β-substituted porphyrin derivatives are able to generate singlet oxygen but derivative 94 is the most efficient one. Additionally the preliminary leishmanicidal properties obtained by molecular modelling and docking calculations showed that all synthesized compounds have higher values of relative affinity to the leishmanial arginase than current drugs. Scheme 21. Structures of pyrrolo-and indolo[1,2-a]quinoxalinoporphyrins [145].
We also reported the reaction of the nickel(II) complex of β-CHOTPP (Ni3) with aniline and pbromoaniline to obtain the β-iminoporphyrins 96 (Scheme 24) [148]. These imines react with electron-rich dienophiles such as 3,4-dihydro-2H-pyran and 2,3-dihydrofuran at room temperature and in the presence of La(OTf)3 to give the expected β-(tetrahydroquinoline)porphyrins 97, 99 and 100 accompanied by the β-(arylaminomethyl)porphyrins 98. When the reaction was performed with the β-iminoporphyrins 96b and 2,3-dihydrofuran it was also observed the formation of the unexpected azetidine 101b. The reduction of the imine bond requires the presence of both the dienophile and the catalyst. Scheme 24. Reaction of β-iminoporphyrins with electron-rich dienophiles [148].
Further studies showed that the β-iminoporphyrin derivative 96b can react with ethyl diazoacetate in the presence of catalytic amounts of La(OTf)3 affording a mixture of the isomeric E/Z β-amino-α,βunsaturated esters 102 and the α,β-diamino ester 103 (Scheme 25) [149]. The probable pathway proposed to justify the formation of the isolated compounds was based on the mechanistic data found in the literature about the aziridation of imines with ethyl diazoacetate catalysed by Lewis acids.
We also reported the reaction of the nickel(II) complex of β-CHOTPP (Ni3) with aniline and pbromoaniline to obtain the β-iminoporphyrins 96 (Scheme 24) [148]. These imines react with electron-rich dienophiles such as 3,4-dihydro-2H-pyran and 2,3-dihydrofuran at room temperature and in the presence of La(OTf)3 to give the expected β-(tetrahydroquinoline)porphyrins 97, 99 and 100 accompanied by the β-(arylaminomethyl)porphyrins 98. When the reaction was performed with the β-iminoporphyrins 96b and 2,3-dihydrofuran it was also observed the formation of the unexpected azetidine 101b. The reduction of the imine bond requires the presence of both the dienophile and the catalyst. Scheme 24. Reaction of β-iminoporphyrins with electron-rich dienophiles [148].
Further studies showed that the β-iminoporphyrin derivative 96b can react with ethyl diazoacetate in the presence of catalytic amounts of La(OTf)3 affording a mixture of the isomeric E/Z β-amino-α,βunsaturated esters 102 and the α,β-diamino ester 103 (Scheme 25) [149]. The probable pathway proposed to justify the formation of the isolated compounds was based on the mechanistic data found in the literature about the aziridation of imines with ethyl diazoacetate catalysed by Lewis acids. Scheme 24. Reaction of β-iminoporphyrins with electron-rich dienophiles [148].
The nickel(II) complex of β-CHOTPP (Ni3) reacts with N-methylglycine in refluxing toluene leading to the azomethine ylide 104 which can be trapped with dipolarophiles. Under this context, the reaction of 104 with fullerene was reported by Boyd and co-workers [150]. A related work, but involving other dipolarophiles, namely quinone, naphthoquinone, dimethyl fumarate, DMAD and N-phenylmaleimide was posteriorly described by our group (Scheme 26) [151]. The expected adducts (or their dehydrogenated derivatives) 105-109 were obtained in good yields.
Interestingly, during these studies it was found that the porphyrinic azomethine ylides 104a,b in the presence of a poor reactive dipolarophile or in its absence, undergoes 1,5-electrocyclic ring closure affording pyrrolo [3,4-b]porphyrins 110 in good yield (Scheme 27) [152]. This synthetic strategy to pyrrolo [3,4-b]porphyrins 110 is a good alternative to the one reported by Smith and co-workers to obtain similar compounds [153].
The nickel(II) complex of β-CHOTPP (Ni3) reacts with N-methylglycine in refluxing toluene leading to the azomethine ylide 104 which can be trapped with dipolarophiles. Under this context, the reaction of 104 with fullerene was reported by Boyd and co-workers [150]. A related work, but involving other dipolarophiles, namely quinone, naphthoquinone, dimethyl fumarate, DMAD and N-phenylmaleimide was posteriorly described by our group (Scheme 26) [151]. The expected adducts (or their dehydrogenated derivatives) 105-109 were obtained in good yields.
The nickel(II) complex of β-CHOTPP (Ni3) reacts with N-methylglycine in refluxing toluene leading to the azomethine ylide 104 which can be trapped with dipolarophiles. Under this context, the reaction of 104 with fullerene was reported by Boyd and co-workers [150]. A related work, but involving other dipolarophiles, namely quinone, naphthoquinone, dimethyl fumarate, DMAD and N-phenylmaleimide was posteriorly described by our group (Scheme 26) [151]. The expected adducts (or their dehydrogenated derivatives) 105-109 were obtained in good yields.
The reactivity of the exocyclic pyrrole unit in the pyrrolo [3,4-b]porphyrins 113 [154] and 115 [155] as diene was evaluated, respectively, by Knapp and Smith groups (Scheme 29). The studies were performed in the presence of acetylenedicarboxylates and afforded the expected adducts 114 and 116. Further studies by Smith and co-workers showed that the pyrroloporphyrin 115 (M = Ni), in the presence of excess DMAD, reacts through a Diels-Alder reaction and a Michael addition affording the bis-adducts 117 and 118. These adducts are converted into monobenzoporphyrins upon prolonged heating [156]. Interestingly, during these studies it was found that the porphyrinic azomethine ylides 104a,b in the presence of a poor reactive dipolarophile or in its absence, undergoes 1,5-electrocyclic ring closure affording pyrrolo [3,4-b]porphyrins 110 in good yield (Scheme 27) [152]. This synthetic strategy to pyrrolo [3,4-b]porphyrins 110 is a good alternative to the one reported by Smith and coworkers to obtain similar compounds [153].
The reactivity of the exocyclic pyrrole unit in the pyrrolo[3,4-b]porphyrins 113 [154] and 115 [155] as diene was evaluated, respectively, by Knapp and Smith groups (Scheme 29). The studies were performed in the presence of acetylenedicarboxylates and afforded the expected adducts 114 and 116. Further studies by Smith and co-workers showed that the pyrroloporphyrin 115 (M = Ni), in the presence of excess DMAD, reacts through a Diels-Alder reaction and a Michael addition affording the bis-adducts 117 and 118. These adducts are converted into monobenzoporphyrins upon prolonged heating [156]. Interestingly, during these studies it was found that the porphyrinic azomethine ylides 104a,b in the presence of a poor reactive dipolarophile or in its absence, undergoes 1,5-electrocyclic ring closure affording pyrrolo [3,4-b]porphyrins 110 in good yield (Scheme 27) [152]. This synthetic strategy to pyrrolo [3,4-b]porphyrins 110 is a good alternative to the one reported by Smith and coworkers to obtain similar compounds [153].
The new imide was used as a template to obtain other 1,3-dioxopyrrolo[3,4-b]porphyrins 121 and 123 by reaction, respectively, with pentylamine and 2-aminoethanol, followed by ring-closure of the corresponding open counterparts Ni120 and Ni122 (Scheme 31) [157]. The UV-vis absorption spectra of the new compounds show significant red-shifts when compared with those of the nonsubstituted analogues. The ring-opening of imide Ni119 in the presence of KOH afforded the corresponding 3-(methylcarbamoyl)-2-carboxylic acid in 84% yield. When this compound was heated in refluxing DMSO a decarboxylation occurred affording the corresponding amide derivative in 52% yield. Scheme 30. Reaction of N-methylpyrrolo [3,4-b]porphyrin Ni110a with singlet oxygen [157].
The new imide was used as a template to obtain other 1,3-dioxopyrrolo[3,4-b]porphyrins 121 and 123 by reaction, respectively, with pentylamine and 2-aminoethanol, followed by ring-closure of the corresponding open counterparts Ni120 and Ni122 (Scheme 31) [157]. The UV-vis absorption spectra of the new compounds show significant red-shifts when compared with those of the nonsubstituted analogues. The ring-opening of imide Ni119 in the presence of KOH afforded the corresponding 3-(methylcarbamoyl)-2-carboxylic acid in 84% yield. When this compound was heated in refluxing DMSO a decarboxylation occurred affording the corresponding amide derivative in 52% yield. A protocol to convert the pyrrolo [3,4-b]porphyrin Ni110a into the corresponding benzoporphyrin-2 2 ,2 3 -dicarboxylic anhydride 127 was also developed (Scheme 32) [158]. The first step involved the reaction of Ni110a with an excess of DMAD in refluxing toluene for 1 h, affording the bisadduct 124, which after thermal decomposition in refluxing 1,2,4-TCB originated the benzoporphyrin-2 2 ,2 3 -dicarboxylic ester 125 (53% yield). The hydrolysis of the ester groups to the "phthalic" acid 126 (90% yield) followed by dehydration in refluxing 1,2,4-trichlorobenzene afforded the anhydride 127.
The reaction of anhydride 127 in the presence of adequate alkylamines and arylamines afforded the corresponding "phthalimides" 128-131 in moderate to excellent yields (Scheme 33) [158].
As an extension of the previous studies on cycloaddition reactions with porphyrins, it was showed that the porphyrinyl nitrone 137, isolated from the reaction of β-CHOTPP 3 with N-methyl-hydroxylamine hydrochloride, reacts with dimethyl fumarate, DMAD and ethyl propiolate to give the corresponding cycloadducts (Scheme 36) [159].
All reactions were performed in toluene at 60 • C and afforded the expected isoxazolidine and isoxazoline cycloadducts 138-142. The best yield was obtained when dimethyl fumarate was used as the dipolarophile and the separation of the two diastereoisomeric adducts was possible after their metalation to Ni138 and Ni139.
As an extension of the previous studies on cycloaddition reactions with porphyrins, it was showed that the porphyrinyl nitrone 137, isolated from the reaction of β-CHOTPP 3 with N-methylhydroxylamine hydrochloride, reacts with dimethyl fumarate, DMAD and ethyl propiolate to give the corresponding cycloadducts (Scheme 36) [159]. All reactions were performed in toluene at 60 °C and afforded the expected isoxazolidine and isoxazoline cycloadducts 138-142. The best yield was obtained when dimethyl fumarate was used as the dipolarophile and the separation of the two diastereoisomeric adducts was possible after their metalation to Ni138 and Ni139.
The condensation of Ni3 with glycine methyl ester hydrochloride, followed by reduction and hydrolysis afforded the N-(porphyrin-2-ylmethyl)glycine Ni145 which after reaction with paraformaldehyde gave the azomethine ylide Ni146 (Scheme 37) [160]. This 1,3-dipole reacted with dimethyl fumarate to give the expected adduct 147 while with 1,4-benzo-and 1,4-naphthoquinones only the dehydrogenated adducts 149 and 150/151 were isolated (Scheme 38). The reaction of the same ylide with meso-tetrakis(pentafluorophenyl)porphyrin and the tetraazaporphyrin gave access to the porphyrin-chlorins 152 and porphyrin-tetraazachlorin 153 dyads (Scheme 39). The N-(porphyrin-2-ylmethyl)glycine Ni145 was also used to generate phthalocyaninesubstituted azomethine ylides that could be trapped with fullerene C60 to afford, in one step, the fullerene-phthalocyanine-porphyrin triads or pentads Ni154 and Ni155 ( Figure 17) [161]. Demetallation and metalation of the porphyrin units with Zn(OAc)2 afforded the corresponding freebases and Zn(II) complexes. These triads and pentads, upon excitation of their porphyrin components, give rise to a sequence of energy and charge transfer reactions yielding radical ion pair states. The N-(porphyrin-2-ylmethyl)glycine Ni145 was also used to generate phthalocyanine-substituted azomethine ylides that could be trapped with fullerene C 60 to afford, in one step, the fullerenephthalocyanine-porphyrin triads or pentads Ni154 and Ni155 ( Figure 17) [161]. Demetallation and metalation of the porphyrin units with Zn(OAc) 2 afforded the corresponding free-bases and Zn(II) complexes. These triads and pentads, upon excitation of their porphyrin components, give rise to a sequence of energy and charge transfer reactions yielding radical ion pair states.
The N-(porphyrin-2-ylmethyl)glycine Ni145 was also used to generate phthalocyaninesubstituted azomethine ylides that could be trapped with fullerene C60 to afford, in one step, the fullerene-phthalocyanine-porphyrin triads or pentads Ni154 and Ni155 (Figure 17) [161]. Demetallation and metalation of the porphyrin units with Zn(OAc)2 afforded the corresponding freebases and Zn(II) complexes. These triads and pentads, upon excitation of their porphyrin components, give rise to a sequence of energy and charge transfer reactions yielding radical ion pair states.

Final Remarks
As shown in this review, porphyrin macrocycles containing simple substituents like the formyl one at pyrrolic positions provide versatile building blocks for the preparation of new significant derivatives through easy synthetic strategies. Examples of the latter are the reactions with methylene active compounds, amines and other nitrogen derivatives and with Wittig reagents. Further manipulation of some of the obtained derivatives, namely those bearing chalcone, imine/amine and vinyl units allows thee expansion to a plethora of new compounds. Other transformations like the 1,5-electrocyclic ring closure of porphyrinic azomethine ylides can give rise to pyrrolo [3,4b]porphyrins and these can afford efficiently 1,3-dioxopyrrolo [3,4-b]porphyrins and anhydrides. The

Final Remarks
As shown in this review, porphyrin macrocycles containing simple substituents like the formyl one at pyrrolic positions provide versatile building blocks for the preparation of new significant derivatives through easy synthetic strategies. Examples of the latter are the reactions with methylene active compounds, amines and other nitrogen derivatives and with Wittig reagents. Further manipulation of some of the obtained derivatives, namely those bearing chalcone, imine/amine and vinyl units allows thee expansion to a plethora of new compounds. Other transformations like the 1,5-electrocyclic ring closure of porphyrinic azomethine ylides can give rise to pyrrolo [3,4-b]porphyrins and these can afford efficiently 1,3-dioxopyrrolo [3,4-b]porphyrins and anhydrides. The cycloaddition avenue can also lead to several derivatives with potential biological applications. The discovery of a simple access to Kröhnke type porphyrins and their potential as chemo-responsive materials deserves further exploration of their use, particularly in the construction of supramolecular systems. Finally the synthetic methodologies established with simple porphyrins can be extended to other tetrapyrrolic macrocycles; a wide range of new derivatives can be envisaged as well as their potential applications in solving many problems to the mankind.