Porphyrin Macrocycle Modification: Pyrrole Ring-Contracted or -Expanded Porphyrinoids

In recent years, several synthetic strategies aiming at the peripheral functionalization of porphyrins were developed. Particularly interesting are those involving the modification of β-pyrrolic positions leading to pyrrole-modified porphyrins containing four-, five-, six- or seven-membered heterocycles. Azeteoporphyrins, porpholactones and morpholinoporphyrins are representative examples of such porphyrinoids. These porphyrin derivatives have recently gained an increasing interest due to their potential application in PDT, as multimodal imaging contrast agents, NIR-absorbing dyes, optical sensors for oxygen, cyanide, hypochlorite and pH, and in catalysis.


Introduction
Porphyrins and porphyrinoid compounds, including contracted and expanded porphyrin derivatives, are highly versatile compounds, both in terms of chemistry (which is extremely rich) and diversity of (potential) applications. These two strands have driven the continuous development of new routes to the synthesis of such compounds.
Porphyrin derivatives are being used in biomedical and environmental applications, in catalysis, and in a range of technical applications [1][2][3][4][5]. Most of these applications require compounds that display absorption bands in the 600-800 nm region. Since "simple" porphyrins hardly fulfill this requirement, chlorins, bacteriochlorins, π-extended porphyrins, pyrrole-modified porphyrins, and other porphyrinoids, are a better choice. Such compounds are typically prepared by: (i) the structural modification of already existing porphyrins via, for instance, cycloaddition reactions, electrophilic or nucleophilic aromatic substitutions, pyrrole ring-contraction or -expansion reactions; or (ii) by constructing the porphyrin macrocycle using adequate pyrrolic building blocks. Considering the last approach, the "3 + 1 method" was extensively used for the synthesis of chlorins and pyrrole-modified porphyrins. This subject has been reviewed recently [6][7][8][9] and will not be covered here. The metallation of porphyrinoids has also been covered in recent reviews [10][11][12].
Concerning the transformation of porphyrins into pyrrole-modified porphyrinoids, many pyrrole ring-contraction and -expansion reactions were reported during the last three decades. However, a substantial part of that work was published in recent years by the group of Brückner that, by using the "breaking and mending of porphyrins" approach [32], was able to produce an enormous diversity of pyrrole-modified porphyrins (some are exemplified in Figure 1). This review covers the reported methods for the modification of the porphyrin macrocycle and the potential applications of the resulting porphyrinoid compounds. This subject has already been discussed in recent reviews [33,34].

Chemistry
The conversion of a porphyrin, or a metalloporphyrin, into a pyrrole-modified porphyrinoid is frequently a multi-step process that requires the separation, purification and structural characterization of the intermediate compounds. However, in this article only the final steps of such transformations are discussed. The methods described below were organized according to the types of porphyrin derivatives used as immediate precursors of pyrrole-modified porphyrinoids.

From N-Substituted Porphyrins
The metallation of the N-substituted porphyrin 1 with nickel acetate in a refluxing CHCl3/MeOH mixture leads to the formation of two new porphyrinoids: the expanded porphyrin 2 and the pyriporphyrin 3 (Scheme 1) [35,36]. Compounds 2 and 3 result from the insertion of a C atom in an α-meso bond or in an α-β bond, respectively. This reaction, reported by Callott and Schaeffer in 1978, is one of the first examples of the direct conversion of a porphyrin into a pyrrole-modified porphyrin. This review covers the reported methods for the modification of the porphyrin macrocycle and the potential applications of the resulting porphyrinoid compounds. This subject has already been discussed in recent reviews [33,34].

Chemistry
The conversion of a porphyrin, or a metalloporphyrin, into a pyrrole-modified porphyrinoid is frequently a multi-step process that requires the separation, purification and structural characterization of the intermediate compounds. However, in this article only the final steps of such transformations are discussed. The methods described below were organized according to the types of porphyrin derivatives used as immediate precursors of pyrrole-modified porphyrinoids.
Brückner and co-workers [45,46] also used a 2,3-dihydroxychlorin as an intermediate in the synthesis of porphyrinoids in which one pyrrolic unit is formally replaced by a morpholine ring (Scheme 6). The 2,3-dihydroxy-meso-tetraphenylchlorin Ni16, obtained by osmium tetroxide-mediated dihydroxylation [47,48] of meso-tetraphenylporphyrin (TPP) and complexation with nickel acetate, was transformed into the secochlorin-2,3-dicarbaldehyde Ni17 by oxidation with lead tetraacetate. The dicarbaldehyde Ni17 undergoes intramolecular acetal formation when treated with alcohols in the presence of acid to produce a mixture of morpholinochlorins Ni18 and Ni19 (see also Scheme 11). Acid treatment of hydroxymorpholinochlorins Ni18 leads to the establishment of an intramolecular β-to-o-phenyl linkage resulting in the formation of the polycyclic-fused porphyrin system Ni20 [49,50]. Complexes of types Ni18, Ni19 and Ni20 (and most of their free-bases) exhibit a ruffled macrocycle with an inherent helical chirality. The resolution of the racemic mixtures can be achieved, both by classical methods via diastereomers or by HPLC on a chiral phase [49,50].
A electrochemical study of Ni(II) porphyrinoids showed that, upon electrochemical reduction, morpholinochlorins form ligand-based reduction products while the conformationally flexible chlorin and secochlorin complexes form Ni(I) complexes [51].
Brückner and co-workers [45,46] also used a 2,3-dihydroxychlorin as an intermediate in the synthesis of porphyrinoids in which one pyrrolic unit is formally replaced by a morpholine ring (Scheme 6). The 2,3-dihydroxy-meso-tetraphenylchlorin Ni16, obtained by osmium tetroxide-mediated dihydroxylation [47,48] of meso-tetraphenylporphyrin (TPP) and complexation with nickel acetate, Scheme 5. Routes to pyridone-and thiomorpholine-modified porphyrins [44]. was transformed into the secochlorin-2,3-dicarbaldehyde Ni17 by oxidation with lead tetraacetate. The dicarbaldehyde Ni17 undergoes intramolecular acetal formation when treated with alcohols in the presence of acid to produce a mixture of morpholinochlorins Ni18 and Ni19 (see also Scheme 11). Acid treatment of hydroxymorpholinochlorins Ni18 leads to the establishment of an intramolecular β-to-o-phenyl linkage resulting in the formation of the polycyclic-fused porphyrin system Ni20 [49,50]. Complexes of types Ni18, Ni19 and Ni20 (and most of their free-bases) exhibit a ruffled macrocycle with an inherent helical chirality. The resolution of the racemic mixtures can be achieved, both by classical methods via diastereomers or by HPLC on a chiral phase [49,50]. A electrochemical study of Ni(II) porphyrinoids showed that, upon electrochemical reduction, morpholinochlorins form ligand-based reduction products while the conformationally flexible chlorin and secochlorin complexes form Ni(I) complexes [51]. Scheme 6. Route to morpholinochlorins [45].
The group of Brückner also reported a variation of the previous method that allowed the synthesis of free-base morpholinochlorins and porpholactones (Scheme 7) [52]. Using the free-base dihydroxychlorin 16 and NaIO4 (heterogenized on silica gel) as the oxidant, this group was able to produce, isolate and characterize the unstable secochlorin-2,3-dicarbaldehyde 17. Reaction of 17 with MeOH, EtOH or i-PrOH under acid catalysis provided the stable morpholinochlorins 19a-c. The same compounds can be obtained directly from the reaction of 16 with NaIO4/silica under N2 in the presence of the corresponding alcohol. Treatment of methoxy derivative 19a with excess EtOH or i-PrOH under acid catalysis at 65 °C leads to alkoxy exchange and formation of 19b or 19c, respectively [52]. MnO4-induced cleavage of diol 16 under phase transfer catalysis (or using cetyltrimethylammonium permanganate, CTAP) affords porpholactone 5 in overall excellent yield (up to 80%). The formation of 5 probably involves the oxidation of the dicarbaldehyde 17 to the corresponding secochlorin-2,3dicarboxylate followed by decarboxylation and lactonization [52]. This methodology has been used for the synthesis of a range of porpholactones [53,54]. A similar approach has been used for the Scheme 6. Route to morpholinochlorins [45].
The group of Brückner also reported a variation of the previous method that allowed the synthesis of free-base morpholinochlorins and porpholactones (Scheme 7) [52]. Using the free-base dihydroxychlorin 16 and NaIO 4 (heterogenized on silica gel) as the oxidant, this group was able to produce, isolate and characterize the unstable secochlorin-2,3-dicarbaldehyde 17. Reaction of 17 with MeOH, EtOH or i-PrOH under acid catalysis provided the stable morpholinochlorins 19a-c. The same compounds can be obtained directly from the reaction of 16 with NaIO 4 /silica under N 2 in the presence of the corresponding alcohol. Treatment of methoxy derivative 19a with excess EtOH or i-PrOH under acid catalysis at 65˝C leads to alkoxy exchange and formation of 19b or 19c, respectively [52]. MnO 4 -induced cleavage of diol 16 under phase transfer catalysis (or using cetyltrimethylammonium permanganate, CTAP) affords porpholactone 5 in overall excellent yield (up to 80%). The formation of 5 probably involves the oxidation of the dicarbaldehyde 17 to the corresponding secochlorin-2,3-dicarboxylate followed by decarboxylation and lactonization [52]. This methodology has been used for the synthesis of a range of porpholactones [53,54]. A similar approach has been used for the conversion of meso-tetraphenylporphyrin N-oxide into pyrrole-modified porphyrin N-oxides [55].
Oxidative cleavage of the purple dihydroxychlorin 16 with NaIO4 heterogenized onto silica gel, in THF containing 1-2 vol % Et3N, converts it in essentially quantitative yields into the unstable free-base secochlorin-2,3-dicarbaldehyde 17 (a brown nonpolar compound) (Scheme 9) [59]. This dialdehyde can be purified by column chromatography (silica gel, CH2Cl2-0.1% Et3N) but in solution, particularly in acidic and/or wet solvents or on silica gel, it tends to decompose within several hours. However, evaporated to dryness and kept in a freezer at −18 °C, it is stable over several months [59]. When a solution of 17 in THF is treated with a large excess of a 30% aqueous solution of Et4NOH, three purple products are formed in varying yields (Scheme 9). The most polar compound (Rf = 0.41, silica-CH2Cl2) is the porpholactol 24, the one with intermediate polarity (Rf = 0.78, silica-CH2Cl2) is the Scheme 7. Route to free-base morpholinochlorins and porpholactones [52].
The group of Brückner demonstrated that Ag(II) can serve as a removable metal template in the oxidative cleavage of 2,3-dihydroxychlorins, allowing an easy access to free-base pyrrole-modified porphyrins [56].
Oxidative cleavage of the purple dihydroxychlorin 16 with NaIO4 heterogenized onto silica gel, in THF containing 1-2 vol % Et3N, converts it in essentially quantitative yields into the unstable free-base secochlorin-2,3-dicarbaldehyde 17 (a brown nonpolar compound) (Scheme 9) [59]. This dialdehyde can be purified by column chromatography (silica gel, CH2Cl2-0.1% Et3N) but in solution, particularly in acidic and/or wet solvents or on silica gel, it tends to decompose within several hours. However, evaporated to dryness and kept in a freezer at −18 °C, it is stable over several months [59]. When a solution of 17 in THF is treated with a large excess of a 30% aqueous solution of Et4NOH, three purple products are formed in varying yields (Scheme 9). The most polar compound (Rf = 0.41, Scheme 8. Routes to morpholinodithiachlorins and dithiaporpholactones [58]. Oxidative cleavage of the purple dihydroxychlorin 16 with NaIO 4 heterogenized onto silica gel, in THF containing 1-2 vol % Et 3 N, converts it in essentially quantitative yields into the unstable free-base secochlorin-2,3-dicarbaldehyde 17 (a brown nonpolar compound) (Scheme 9) [59]. This dialdehyde can be purified by column chromatography (silica gel, CH 2 Cl 2 -0.1% Et 3 N) but in solution, particularly in acidic and/or wet solvents or on silica gel, it tends to decompose within several hours. However, evaporated to dryness and kept in a freezer at´18˝C, it is stable over several months [59]. When a solution of 17 in THF is treated with a large excess of a 30% aqueous solution of Et 4 NOH, three purple products are formed in varying yields (Scheme 9). The most polar compound (Rf = 0.41, silica-CH 2 Cl 2 ) is the porpholactol 24, the one with intermediate polarity (Rf = 0.78, silica-CH 2 Cl 2 ) is the porpholactone 5 and the least polar one (Rf = 0.90, silica-CH 2 Cl 2 ) is the porpholactol dimer 25 (isolated in yields up to 11%). The authors proposed a mechanism to rationalize the formation of these products which involves an intramolecular Cannizzaro reaction in the dialdehyde 17 [59].
As shown in Scheme 6, the oxidative cleavage of 2,3-dihydroxy-meso-tetraphenylchlorin Ni16 with lead tetraacetate leads to the formation of morpholinochlorins (via the secochlorin-2,3-dicarbaldehyde Ni17). However, depending on the reaction conditions during the ring cleavage reaction, the formyl groups may react with the adjacent o-phenyl positions to establish direct o-phenyl-to-β-linkages [62,63]. The initially formed carbinols oxidize spontaneously to ketones, resulting in the formation of indaphyrin Ni31 in high yield (Scheme 11).
The Brückner group reported a new approach to pyrrole ring-contracted azeteoporphyrins (Scheme 14) [67]. It involves the oxidative cleavage of the dihydroxychlorin Ni16 to the secochlorin-2,3-dicarbaldehyde Ni17 (see Scheme 6) followed by a decarbonylation reaction with an excess of (Ph 3 P) 3 RhCl to afford a mixture of the chlorophins Ni39 (12% yield) and Ni40 (60% yield) [46,67]. The monoaldehyde Ni39 reacts with an excess of methylmagnesium bromide leading to the formation of the secondary alcohol Ni41. This alcohol reacts with an excess of TMSOTf to afford the azeteoporphyrin Ni42 in 60%-75% yield after purification by preparative TLC and crystallization. The role of TMSOTf in this cyclization reaction is to induce the removal of the hydroxyl group and generation of the corresponding carbocation. The azete ring is then formed by an intramolecular Friedel-Crafts reaction.
It is interesting to note that, under adequate experimental conditions, alcohol Ni41 is obtained in ca. 7% yield in the decarbonylation reaction of the dicarbaldehyde Ni17 [67]. The existence of alcohol Ni43 had been previously proposed as a side product in the Vilsmeier-Haack formylation of the chlorophin Ni40 [68].

From 2,3-Dioxochlorins
In 1984, Crossley and King reported that treatment of a CH2Cl2 solution of dione 44 (obtained in Scheme 13. Conversion of an indaphyrin into indachlorins [65].
It is interesting to note that, under adequate experimental conditions, alcohol Ni41 is obtained in ca. 7% yield in the decarbonylation reaction of the dicarbaldehyde Ni17 [67]. The existence of alcohol Ni43 had been previously proposed as a side product in the Vilsmeier-Haack formylation of the chlorophin Ni40 [68].
It is interesting to note that, under adequate experimental conditions, alcohol Ni41 is obtained in ca. 7% yield in the decarbonylation reaction of the dicarbaldehyde Ni17 [67]. The existence of alcohol Ni43 had been previously proposed as a side product in the Vilsmeier-Haack formylation of the chlorophin Ni40 [68].

From 2,3-Dioxochlorins
In 1984, Crossley and King reported that treatment of a CH 2 Cl 2 solution of dione 44 (obtained in quantitative yield by acidic hydrolysis of imino-oxochlorin 6) with an excess of NaH and exposed to air, followed by treatment with 3 M aqueous HCl, affords the morpholinoporphyrin 45 in 80% yield (Scheme 15). The ring-contracted azeteoporphyrin 46 is also formed in this reaction as a minor product [37]. Anhydride 45 can also be obtained in 64% yield by treatment of dione 44 with MCPBA [37]. Zaleski and co-workers [69] reported that the Cu(II) and Ni(II) complexes of 2,3-dioxochlorins react with benzeneselenic anhydride (BSA) leading to the formation of ring-contracted azetine derivatives M46 that further react with BSA to afford porpholactones M5 (Scheme 16). The yields of compounds M46 and M5 are highly dependent on the 2,3-dioxochlorin/BSA ratio and reaction time. When the reaction is carried out in a 1:2 ratio of M44 to BSA, the reaction proceeds very slowly and after 22 h both the ring-contracted azetine and the porpholactone are obtained in low yields while 59% of the unreacted dioxochlorin is recovered (Table 1). However, if a large excess of BSA is used (8-fold) all starting material is consumed within 5 h. The experimental results show that the isolated yield of the ring-contracted product is consistently low, suggesting that this species is an intermediate to the porpholactone M5. In fact, addition of 4 equivalents of BSA to a refluxing chlorobenzene solution of Cu46 generates Cu5 within 30 min; the reaction is complete after 16 h, resulting in 59% yield of Cu5.  The methyltrioxorhenium (MTO)-catalyzed H2O2 oxidation of the 2,3-dioxochlorin 44, in the presence of pyrazole, leads to the formation of four pyrrole-modified porphyrin derivatives (Scheme 17) Scheme 15. Route to 4-and 6-membered porphyrinoids [37].
Zaleski and co-workers [69] reported that the Cu(II) and Ni(II) complexes of 2,3-dioxochlorins react with benzeneselenic anhydride (BSA) leading to the formation of ring-contracted azetine derivatives M46 that further react with BSA to afford porpholactones M5 (Scheme 16). The yields of compounds M46 and M5 are highly dependent on the 2,3-dioxochlorin/BSA ratio and reaction time. When the reaction is carried out in a 1:2 ratio of M44 to BSA, the reaction proceeds very slowly and after 22 h both the ring-contracted azetine and the porpholactone are obtained in low yields while 59% of the unreacted dioxochlorin is recovered (Table 1). However, if a large excess of BSA is used (8-fold) all starting material is consumed within 5 h. The experimental results show that the isolated yield of the ring-contracted product is consistently low, suggesting that this species is an intermediate to the porpholactone M5. In fact, addition of 4 equivalents of BSA to a refluxing chlorobenzene solution of Cu46 generates Cu5 within 30 min; the reaction is complete after 16 h, resulting in 59% yield of Cu5. Zaleski and co-workers [69] reported that the Cu(II) and Ni(II) complexes of 2,3-dioxochlorins react with benzeneselenic anhydride (BSA) leading to the formation of ring-contracted azetine derivatives M46 that further react with BSA to afford porpholactones M5 (Scheme 16). The yields of compounds M46 and M5 are highly dependent on the 2,3-dioxochlorin/BSA ratio and reaction time. When the reaction is carried out in a 1:2 ratio of M44 to BSA, the reaction proceeds very slowly and after 22 h both the ring-contracted azetine and the porpholactone are obtained in low yields while 59% of the unreacted dioxochlorin is recovered (Table 1). However, if a large excess of BSA is used (8-fold) all starting material is consumed within 5 h. The experimental results show that the isolated yield of the ring-contracted product is consistently low, suggesting that this species is an intermediate to the porpholactone M5. In fact, addition of 4 equivalents of BSA to a refluxing chlorobenzene solution of Cu46 generates Cu5 within 30 min; the reaction is complete after 16 h, resulting in 59% yield of Cu5.  The methyltrioxorhenium (MTO)-catalyzed H 2 O 2 oxidation of the 2,3-dioxochlorin 44, in the presence of pyrazole, leads to the formation of four pyrrole-modified porphyrin derivatives (Scheme 17) [55,70]. During the reaction course it is observed the initial formation of compounds 45 and 5 while the corresponding N-oxides 47 and 48 are formed later in the reaction, and on the expense of the products formed initially [55]. The yield of each product depends on the reaction conditions, namely catalyst loading and reaction time. with diazomethane to give a mixture of three orange-brown bands that were identified as a mixture of two isomeric di(oxopyri)porphyrins: 53a/54a (18% yield), 53b/54b (31% yield), and 53c/54c (47% yield) (Scheme 19).
The reaction of 2,3-dioxoporphyrin metal complexes M44 (obtained by metallation of 44) with hydroxylamine hydrochloride affords the corresponding monooximes M55 in good yields (Scheme 20) [72]. When treated with p-toluenesulfonic acid (p-TSA) under forcing conditions, oximes M55 undergo a Beckmann rearrangement to produce the corresponding pyrazinoporphyrin imides M56 in moderate to good yields. Demetallation of pyrazinoporphyrin Ni56 affords the free-base pyrazinoporphyrin imide 56. The reaction of 56 with benzyl bromide in the presence of sodium hydride under nitrogen, at ambient conditions, leads to a mixture of the N-benzyl (22%) and O-benzyl (66%) derivatives 57 and 58, respectively.
Treatment of the free-base oxime 55 (M = 2H) with p-TSA in toluene at reflux leads to the formation of quinoline-annulated porphyrins [73,74].

From 2,3,12,13-Tetrabromoporphyrins
Nickel(II) 2,3,12,13-tetrabromo-5,10,15,20-tetraarylporphyrins Ni68a-d react with the anion of E-benzaldoxime, in the presence of CuBr, to provide the corresponding chlorophins Ni69-Ni71 and bacteriophins Ni72, resulting from the degradation of one or two pyrrolic units, respectively, and mono-or didebromination (Scheme 23) [42,83]. The yield of each product is highly dependent on the time and temperature of the reaction: the best yield of Ni72a (26%) is achieved after 2 h at a temperature fluctuating regularly between 80 °C and 160 °C. These chlorophins and bacteriophins display UV-vis spectra similar to those of metallated chlorin and bacteriochlorin systems but with more intense and bathochromically shifted Q-bands.

From 2,3,12,13-Tetrabromoporphyrins
Nickel(II) 2,3,12,13-tetrabromo-5,10,15,20-tetraarylporphyrins Ni68a-d react with the anion of E-benzaldoxime, in the presence of CuBr, to provide the corresponding chlorophins Ni69-Ni71 and bacteriophins Ni72, resulting from the degradation of one or two pyrrolic units, respectively, and monoor didebromination (Scheme 23) [42,83]. The yield of each product is highly dependent on the time and temperature of the reaction: the best yield of Ni72a (26%) is achieved after 2 h at a temperature fluctuating regularly between 80˝C and 160˝C. These chlorophins and bacteriophins display UV-vis spectra similar to those of metallated chlorin and bacteriochlorin systems but with more intense and bathochromically shifted Q-bands.
bacteriophins Ni72, resulting from the degradation of one or two pyrrolic units, respectively, and mono-or didebromination (Scheme 23) [42,83]. The yield of each product is highly dependent on the time and temperature of the reaction: the best yield of Ni72a (26%) is achieved after 2 h at a temperature fluctuating regularly between 80 °C and 160 °C. These chlorophins and bacteriophins display UV-vis spectra similar to those of metallated chlorin and bacteriochlorin systems but with more intense and bathochromically shifted Q-bands.

From β-Unsubstituted Porphyrins
Octaethylporphyrin (73) reacts with ozone at room temperature to afford the oxazolochlorin 74 (Scheme 24) [84]. This is probably the first reported example of a direct conversion of a porphyrin into a pyrrole-modified porphyrin. Scheme 24. Route to oxazolochlorins [84].

From β-Unsubstituted Porphyrins
Octaethylporphyrin (73) reacts with ozone at room temperature to afford the oxazolochlorin 74 (Scheme 24) [84]. This is probably the first reported example of a direct conversion of a porphyrin into a pyrrole-modified porphyrin.
E-benzaldoxime, in the presence of CuBr, to provide the corresponding chlorophins Ni69-Ni71 and bacteriophins Ni72, resulting from the degradation of one or two pyrrolic units, respectively, and mono-or didebromination (Scheme 23) [42,83]. The yield of each product is highly dependent on the time and temperature of the reaction: the best yield of Ni72a (26%) is achieved after 2 h at a temperature fluctuating regularly between 80 °C and 160 °C. These chlorophins and bacteriophins display UV-vis spectra similar to those of metallated chlorin and bacteriochlorin systems but with more intense and bathochromically shifted Q-bands. Scheme 23. Route to chlorophins and bacteriophins [83].

From β-Unsubstituted Porphyrins
Octaethylporphyrin (73) reacts with ozone at room temperature to afford the oxazolochlorin 74 (Scheme 24) [84]. This is probably the first reported example of a direct conversion of a porphyrin into a pyrrole-modified porphyrin. Scheme 24. Route to oxazolochlorins [84].

Scheme 24. Route to oxazolochlorins [84].
Gouterman and co-workers discovered, by serendipity, the direct conversion of free-base meso-tetraarylporphyrins into porpholactones using mild reagents [85]. While attempting to synthesize the silver complex of meso-tetrakis(pentafluorophenyl)porphyrin (AgF 20 TPP) by treatment of the corresponding free-base H 2 F 20 TPP 75 with AgNO 3 in glacial acetic acid at reflux, they obtained (in low yield) the corresponding porpholactone 76 (Scheme 25). These authors found that addition of oxalic acid to the reaction mixture allows the synthesis of porpholactone 76 in reproducible yields (ca. 15%) [85]. Later, the yield of this reaction was improved to 73% [86]. Porpholactone 79 can be converted into the corresponding Ni, Zn, Pd and Pt complexes by standard procedures [86]. Gouterman and co-workers discovered, by serendipity, the direct conversion of free-base meso-tetraarylporphyrins into porpholactones using mild reagents [85]. While attempting to synthesize the silver complex of meso-tetrakis(pentafluorophenyl)porphyrin (AgF20TPP) by treatment of the corresponding free-base H2F20TPP 75 with AgNO3 in glacial acetic acid at reflux, they obtained (in low yield) the corresponding porpholactone 76 (Scheme 25). These authors found that addition of oxalic acid to the reaction mixture allows the synthesis of porpholactone 76 in reproducible yields (ca. 15%) [85]. Later, the yield of this reaction was improved to 73% [86]. Porpholactone 79 can be converted into the corresponding Ni, Zn, Pd and Pt complexes by standard procedures [86]. Scheme 25. Route to meso-tetrakis(pentafluorophenyl)porpholactone [85,86].
Zhang and co-workers [87] found that heating a solution of H2F20TPP 75 and HAuCl4 (2 equiv.) in acetic acid at reflux affords a mixture of [Au(F20TPP)] + (20% yield), 2-chloro-H2F20TPP (25% yield) and the porpholactone 76 (6% yield). However, under similar conditions, TPP affords only the corresponding gold complex [AuTPP] + in 85% yield. Using 2-picolinic acid (Pic) as ligand, the porpholactone 76 is obtained in 63% yield (yield calculated based on the conversion (52%) of the starting porphyrin). A further improvement of the porpholactone yield is achieved by adding an oxidant to the reaction mixture. The highest yield of porpholactone 76 (80%) is obtained when two equivalents of Oxone ® are used, although the conversion of H2F20TPP was low (64%) (Scheme 26). Under these conditions, the complex [AuF20TPP] + is formed in very low yield (<2%). In the absence of [Au(Pic)Cl2], the reactivity of Oxone ® toward H2F20TPP is very low (<5%), confirming the catalytic effect of Au(III). Other fluorinated meso-tetraarylporphyrins can be converted into porpholactones by this gold-catalyzed approach. However, the electronic effect of the substituents of the porphyrins is very pronounced since the yield of the gold porphyrin complex increases and consequently the yield of the porpholactone reduces drastically in the order: meso-tetrakis(tetrafluorophenyl)-, mesotetrakis(trifluorophenyl)-, meso-tetrakis(difluorophenyl)-, and meso-tetrakis(p-fluorophenyl)porphyrin. The electronic effect of the substituents may be minimized if Ag + is used as a template metal ion. Starting from AgTPP, Ag(p-ClTPP) and Ag(p-FTPP) the corresponding free-base porpholactones are Scheme 25. Route to meso-tetrakis(pentafluorophenyl)porpholactone [85,86].
Zhang and co-workers [87] found that heating a solution of H 2 F 20 TPP 75 and HAuCl 4 (2 equiv.) in acetic acid at reflux affords a mixture of [Au(F 20 TPP)] + (20% yield), 2-chloro-H 2 F 20 TPP (25% yield) and the porpholactone 76 (6% yield). However, under similar conditions, TPP affords only the corresponding gold complex [AuTPP] + in 85% yield. Using 2-picolinic acid (Pic) as ligand, the porpholactone 76 is obtained in 63% yield (yield calculated based on the conversion (52%) of the starting porphyrin). A further improvement of the porpholactone yield is achieved by adding an oxidant to the reaction mixture. The highest yield of porpholactone 76 (80%) is obtained when two equivalents of Oxone ® are used, although the conversion of H 2 F 20 TPP was low (64%) (Scheme 26). Under these conditions, the complex [AuF 20 TPP] + is formed in very low yield (<2%). In the absence of [Au(Pic)Cl 2 ], the reactivity of Oxone ® toward H 2 F 20 TPP is very low (<5%), confirming the catalytic effect of Au(III). Other fluorinated meso-tetraarylporphyrins can be converted into porpholactones by this gold-catalyzed approach. However, the electronic effect of the substituents of the porphyrins is very pronounced since the yield of the gold porphyrin complex increases and consequently the yield of the porpholactone reduces drastically in the order: meso-tetrakis(tetrafluorophenyl)-, meso-tetrakis(trifluorophenyl)-, meso-tetrakis(difluorophenyl)-, and meso-tetrakis(p-fluorophenyl)porphyrin. The electronic effect of the substituents may be minimized if Ag + is used as a template metal ion. Starting from AgTPP, Ag(p-ClTPP) and Ag(p-FTPP) the corresponding free-base porpholactones are obtained in 23%, 17% and 10% isolated yields [87]. and the porpholactone 76 (6% yield). However, under similar conditions, TPP affords only the corresponding gold complex [AuTPP] + in 85% yield. Using 2-picolinic acid (Pic) as ligand, the porpholactone 76 is obtained in 63% yield (yield calculated based on the conversion (52%) of the starting porphyrin). A further improvement of the porpholactone yield is achieved by adding an oxidant to the reaction mixture. The highest yield of porpholactone 76 (80%) is obtained when two equivalents of Oxone ® are used, although the conversion of H2F20TPP was low (64%) (Scheme 26). Under these conditions, the complex [AuF20TPP] + is formed in very low yield (<2%). In the absence of [Au(Pic)Cl2], the reactivity of Oxone ® toward H2F20TPP is very low (<5%), confirming the catalytic effect of Au(III). Other fluorinated meso-tetraarylporphyrins can be converted into porpholactones by this gold-catalyzed approach. However, the electronic effect of the substituents of the porphyrins is very pronounced since the yield of the gold porphyrin complex increases and consequently the yield of the porpholactone reduces drastically in the order: meso-tetrakis(tetrafluorophenyl)-, mesotetrakis(trifluorophenyl)-, meso-tetrakis(difluorophenyl)-, and meso-tetrakis(p-fluorophenyl)porphyrin. The electronic effect of the substituents may be minimized if Ag + is used as a template metal ion. Starting from AgTPP, Ag(p-ClTPP) and Ag(p-FTPP) the corresponding free-base porpholactones are obtained in 23%, 17% and 10% isolated yields [87].

Scheme 30. Conversion of porpholactones into N-aminoporpholactams and porpholactams
Porpholactams can be further modified to imidazoloporphyrins, as shown in Scheme 31. In fact, treatment of porpholactam 87 with phosphoryl chloride (POCl3) in refluxing toluene gives access to the 3-chloroimidazoloporphyrin 89 in 97% yield. Subsequent reaction of a toluene solution of 89 with zinc dust and 2 N aq. H2SO4, at reflux for 5 h, affords a mixture of imidazoloporphyrin 81 (10% yield) and the starting porpholactam 87 (72%) [92].
Reduction of the porpholactone Zn5 with DIBAL-H affords the porpholactol Zn24 that, by demetallation, provides the free-base porpholactol 24 in almost quantitative yield (Scheme 32) [54,93,94]. The acid-catalyzed (BF 3¨O Et 2 or Amberlyst 15) deoxygenation of the porpholactol 24 affords the 2-oxachlorin 90 in near-quantitative yield. Over time, this compound undergoes (photo)oxidation back to porpholactol 24. Thus, it must be shielded from exposure to light or oxidizing conditions. Attempts at one-step reductions from Zn5 to Zn90 using LiAlH 4 or DIBAL-H under more forcing conditions failed, leading to the destruction of the porphyrinic macrocycle [54]. Reduction of the porpholactone Zn5 with DIBAL-H affords the porpholactol Zn24 that, by demetallation, provides the free-base porpholactol 24 in almost quantitative yield (Scheme 32) [54,93,94]. The acid-catalyzed (BF3·OEt2 or Amberlyst 15) deoxygenation of the porpholactol 24 affords the 2-oxachlorin 90 in near-quantitative yield. Over time, this compound undergoes (photo)oxidation back to porpholactol 24. Thus, it must be shielded from exposure to light or oxidizing conditions. Attempts at one-step reductions from Zn5 to Zn90 using LiAlH4 or DIBAL-H under more forcing conditions failed, leading to the destruction of the porphyrinic macrocycle [54].
The porpholactol 24 (an hemiacetal) reacts with a range of O-, N-, and S-nucleophiles, under mild acid-catalyzed conditions, providing access to a number of stable chlorin-like acetals, thioacetals, and aminals (Scheme 33) [54]. Acetals and aminals 95 can be prepared in a two-step, one-pot reaction directly from 2,3-dihydroxychlorins 91 (Scheme 34) [95]. The first step corresponds to the oxidation of 2,3-dihydroxychlorins 91 to secochlorin-2,3-dicarbaldehydes 92 (see Scheme 7) in the presence of a nucleophile (alcohol or secondary amine). The resulting crude mixture of morpholinochlorins 93 is then oxidized with CTAP. Depending on the nucleophile used in the first step, oxazolochlorin acetals or aminals are formed in good to acceptable isolated yields. The mechanism of the conversion of morpholinochlorins 93 into the oxazolochlorin derivatives 95 probably involves the formation of morpholinones 94 and extrusion of CO. Comparing this synthetic route to acetals and aminals with the previous one, the number of steps was reduced from 5 to 2 and the overall yields more than doubled: 73%-91% for the acetals and 33%-49% for the aminals.
Porpholactones react with alkyl-Grignard reagents to afford 3-alkyl-or 3,3-dialkyloxazolochlorins [96][97][98]. Addition of i-PrMgCl (15 equivalents) to the zinc complex of porpholactone Zn5, followed by an acid workup (that also removes the Zn(II)), affords the hemiketal 96 in 82% yield (Scheme 35). Reaction of 96 with an excess of Et3SiH, in the presence of BF3·OEt2, leads to the formation of the 3-isopropyloxazolochlorin 97 in 76% yield. Addition of an excess of i-PrMgCl to porpholactone Zn5 in the presence of BF3·OEt2 gives the diisopropyloxazolochlorin 98 in ca. 30% yield. Oxazolochlorins 96-98 can be further converted into bacteriochlorin-type compounds, such as 99 and 100 [96][97][98]. Oxazolochlorins Acetals and aminals 95 can be prepared in a two-step, one-pot reaction directly from 2,3-dihydroxychlorins 91 (Scheme 34) [95]. The first step corresponds to the oxidation of 2,3-dihydroxychlorins 91 to secochlorin-2,3-dicarbaldehydes 92 (see Scheme 7) in the presence of a nucleophile (alcohol or secondary amine). The resulting crude mixture of morpholinochlorins 93 is then oxidized with CTAP. Depending on the nucleophile used in the first step, oxazolochlorin acetals or aminals are formed in good to acceptable isolated yields. The mechanism of the conversion of morpholinochlorins 93 into the oxazolochlorin derivatives 95 probably involves the formation of morpholinones 94 and extrusion of CO. Comparing this synthetic route to acetals and aminals with the previous one, the number of steps was reduced from 5 to 2 and the overall yields more than doubled: 73%-91% for the acetals and 33%-49% for the aminals. Reaction of porpholactones 101a-d with an excess of Lawesson's reagent leads to the formation of the corresponding porphothionolactones 102a-d in good to excellent yields (Scheme 36) [99].
Reaction of porpholactones 101a-d with an excess of Lawesson's reagent leads to the formation of the corresponding porphothionolactones 102a-d in good to excellent yields (Scheme 36) [99]. The porphothionolactone 102a can be converted to the corresponding lactone 101a rapidly and quantitatively by addition of aqueous NaOCl (bleach). Since porpholactones are moderately fluorescent and the porphothionolactones are not, any reaction that induces the thionolactone-to-lactone conversion is accompanied by a strong fluorescence emission intensity enhancement. This process is the basis for the use of thionolactone 102a as a switch-on chemodosimeter for hypochlorite (see Section 3.4. Optical Sensors).
Reaction of porpholactones 101a-d with an excess of Lawesson's reagent leads to the formation of the corresponding porphothionolactones 102a-d in good to excellent yields (Scheme 36) [99]. The porphothionolactone 102a can be converted to the corresponding lactone 101a rapidly and quantitatively by addition of aqueous NaOCl (bleach). Since porpholactones are moderately fluorescent and the porphothionolactones are not, any reaction that induces the thionolactone-to-lactone conversion is accompanied by a strong fluorescence emission intensity enhancement. This process is the basis for the use of thionolactone 102a as a switch-on chemodosimeter for hypochlorite (see Section 3.4. Optical Sensors).
Reaction of porpholactones 101a-d with an excess of Lawesson's reagent leads to the formation of the corresponding porphothionolactones 102a-d in good to excellent yields (Scheme 36) [99]. The porphothionolactone 102a can be converted to the corresponding lactone 101a rapidly and quantitatively by addition of aqueous NaOCl (bleach). Since porpholactones are moderately fluorescent and the porphothionolactones are not, any reaction that induces the thionolactone-to-lactone conversion is accompanied by a strong fluorescence emission intensity enhancement. This process is the basis for the use of thionolactone 102a as a switch-on chemodosimeter for hypochlorite (see Section 3.4. Optical Sensors).
Reaction of secochlorin Ni103a with aqueous concentrated ammonia in THF, at room temperature, for 20 minutes, generates the pyrazinoporphyrin hemiacetal Ni104a in ca. 90% yield. Treatment of crude Ni104a with MeOH and catalytic quantities of THF generates the methoxy pyrazinoporphyrin Ni105a (Scheme 37) [100]. The free-base pyrazinoporphyrins 105a,b can be prepared in a similar way. Treatment of the secochlorins 103a,b under aerobic conditions with an excess of aqueous concentrated ammonia in pyridine at 40-50˝C, leads to the rapid formation of the pyrazinoporphyrin hemiacetals 104a,b. While the Ni(II) complex Ni105a is stable even under acidic conditions, the free-base analogues are very sensitive to decomposition, particularly under acidic or oxidative conditions. The extinction coefficients of the pyrazinoporphyrins are significantly smaller than those of TPP.
Ni105a (Scheme 37) [100]. The free-base pyrazinoporphyrins 105a,b can be prepared in a similar way. Treatment of the secochlorins 103a,b under aerobic conditions with an excess of aqueous concentrated ammonia in pyridine at 40-50 °C, leads to the rapid formation of the pyrazinoporphyrin hemiacetals 104a,b. While the Ni(II) complex Ni105a is stable even under acidic conditions, the free-base analogues are very sensitive to decomposition, particularly under acidic or oxidative conditions. The extinction coefficients of the pyrazinoporphyrins are significantly smaller than those of TPP.

Applications
Pyrrole-modified porphyrin derivatives have recently gained an increasing interest due to their potential application in photodynamic therapy (PDT), NIR-absorbing dyes, multimodal imaging contrast agents, catalysis, high pH sensors, optical sensors for cyanide, hypochlorite, and oxygen.

Photodynamic Therapy
Photodynamic therapy (PDT) is a promising strategy in cancer treatment. It uses a photosensitizer that, upon cellular internalization and light irradiation, generates reactive oxygen species (ROS) (mainly singlet oxygen) that kill the cancer cells leading to the eradication of the tumor. Porphyrin derivatives, namely chlorins and bacteriochlorins, due to their photophysical properties, such as strong absorption bands in the range of 650-800 nm, and appropriate triplet state to generate ROS, are particularly useful as photosensitizers. Pyrrole-modified porphyrins that display absorption spectra typical of chlorins or bacteriochlorins are also interesting compounds to be used as photosensitizers in PDT. Recent studies confirm the superior properties of such compounds.
In 2005, McCarthy and co-workers described the encapsulation of meso-tetraphenylporpholactol (24), a chlorin-type compound, into a poly(lactic-co-glycolic acid) (PLGA) matrix and the use of the resulting nanoparticles as photosensitizers in the PDT of tumors [94]. These authors found that the PLGA/porpholactol nanoparticles are unable to fluoresce or induce phototoxicity. However, upon cell internalization, the porpholactol is released from the nanoparticle, regains its ability to fluoresce and produce singlet oxygen, and becomes highly phototoxic. Irradiation with visible light results in cell-specific killing of several cancer cell lines. Importantly, in vivo experiments with this activatable PDT-nanoagent resulted in the complete eradication of cancers in mouse models.
Recently, Zhang and co-workers [101] reported the synthesis and evaluation of the potentialities of six porpholactol-type compounds (oxazolochlorin acetals) as PDT photosensitizers. The new compounds were prepared by chemical modification of porpholactol Zn78 (Scheme 38) and bear β-hydrophilic substituents terminated by glucosyl (neutral, Zn107a), sulfonic (anionic, Zn107b), zwitterionic (Zn107c), or ammonium (cationic, Zn107d-f) groups. It was shown that the terminal ionic groups influence significantly the cellular uptake of these conjugates that is higher for the compounds with positive charge. Importantly, their photocytotoxicity against cancer cells showed IC50 values down to the sub-micromolar range being the cationic compounds the most active ones. As revealed by cell imaging experiments, these compounds exert their photodynamic activity through apoptosis.

Applications
Pyrrole-modified porphyrin derivatives have recently gained an increasing interest due to their potential application in photodynamic therapy (PDT), NIR-absorbing dyes, multimodal imaging contrast agents, catalysis, high pH sensors, optical sensors for cyanide, hypochlorite, and oxygen.

Photodynamic Therapy
Photodynamic therapy (PDT) is a promising strategy in cancer treatment. It uses a photosensitizer that, upon cellular internalization and light irradiation, generates reactive oxygen species (ROS) (mainly singlet oxygen) that kill the cancer cells leading to the eradication of the tumor. Porphyrin derivatives, namely chlorins and bacteriochlorins, due to their photophysical properties, such as strong absorption bands in the range of 650-800 nm, and appropriate triplet state to generate ROS, are particularly useful as photosensitizers. Pyrrole-modified porphyrins that display absorption spectra typical of chlorins or bacteriochlorins are also interesting compounds to be used as photosensitizers in PDT. Recent studies confirm the superior properties of such compounds.
In 2005, McCarthy and co-workers described the encapsulation of meso-tetraphenylporpholactol (24), a chlorin-type compound, into a poly(lactic-co-glycolic acid) (PLGA) matrix and the use of the resulting nanoparticles as photosensitizers in the PDT of tumors [94]. These authors found that the PLGA/porpholactol nanoparticles are unable to fluoresce or induce phototoxicity. However, upon cell internalization, the porpholactol is released from the nanoparticle, regains its ability to fluoresce and produce singlet oxygen, and becomes highly phototoxic. Irradiation with visible light results in cell-specific killing of several cancer cell lines. Importantly, in vivo experiments with this activatable PDT-nanoagent resulted in the complete eradication of cancers in mouse models.
Recently, Zhang and co-workers [101] reported the synthesis and evaluation of the potentialities of six porpholactol-type compounds (oxazolochlorin acetals) as PDT photosensitizers. The new compounds were prepared by chemical modification of porpholactol Zn78 (Scheme 38) and bear β-hydrophilic substituents terminated by glucosyl (neutral, Zn107a), sulfonic (anionic, Zn107b), zwitterionic (Zn107c), or ammonium (cationic, Zn107d-f) groups. It was shown that the terminal ionic groups influence significantly the cellular uptake of these conjugates that is higher for the compounds with positive charge. Importantly, their photocytotoxicity against cancer cells showed IC 50 values down to the sub-micromolar range being the cationic compounds the most active ones. As revealed by cell imaging experiments, these compounds exert their photodynamic activity through apoptosis.
Porpholactones have also been studied as PDT photosensitizers. Zhang and co-workers compared the photophysical and biological properties of meso-tetrakis(pentafluorophenyl)porphyrin (75), the corresponding porpholactone 76 and their derivatives bearing thioglucosyl units [102]. This study demonstrated that the β-lactonization of the porphyrin lowers its lipophilicity and increases its binding affinity to low density lipoproteins facilitating its cellular uptake and selective localization within lysosomes. Lactonization also leads to enhanced singlet oxygen quantum yields, thus increasing the intracellular ROS levels. Porpholactones have also been studied as PDT photosensitizers. Zhang and co-workers compared the photophysical and biological properties of meso-tetrakis(pentafluorophenyl)porphyrin (75), the corresponding porpholactone 76 and their derivatives bearing thioglucosyl units [102]. This study demonstrated that the β-lactonization of the porphyrin lowers its lipophilicity and increases its binding affinity to low density lipoproteins facilitating its cellular uptake and selective localization within lysosomes. Lactonization also leads to enhanced singlet oxygen quantum yields, thus increasing the intracellular ROS levels.
The same research group also reported the photosensitizing properties of the two isomeric cis-(77) and trans-(77') porphodilactones (Scheme 27) and the corresponding Zn(II) complexes [89]. The electronic absorption spectra of the two isomers are similar to those of bacteriochlorins, with strong absorption bands in NIR region (>650 nm). However, the authors found that the relative orientation of the two β-lactone moieties has a significant influence on the electronic structures and photophysical properties of the porphodilactones. For example, the Qy band of trans-porphodilactone is red-shifted by 19 nm relative to that of the cis-isomer, and there is a 2-fold increase in the absorption intensity [89]. The orientation of the two lactone moieties also affects the singlet oxygen production of the two isomeric porphodilactones. The values obtained for the singlet oxygen quantum yields (ΦΔ) were 0.53 for the free-base trans-porphodilactone 77', 0.66 for Zn77', and 0.87 for Zn77. Surprisingly, the free-base cis-porphodilactone 77 shows no singlet oxygen production at all after irradiation by a 635 nm laser beam. Both porphodilactones, encapsulated into PLGA nanoparticles, showed no dark toxicity after incubation for 24 h in HeLa cells. However, after irradiation with a 671 nm laser for 60 s, porphodilactones 77' and Zn77' exhibited good phototoxicity with a IC50 value of 51 and 44 μg·mL −1 , respectively. The IC50 value of Zn77 was significantly larger (94 μg·mL −1 ), despite having a larger ΦΔ value, while the free-base cis-porphodilactone 77 showed nearly no photocytoxicity toward HeLa cells, which was consistent with the zero singlet oxygen production [89].

Multimodal Imaging Contrast Agents
Nowadays, there is a need to develop theranostic compounds for simultaneous cancer imaging, diagnosis and treatment interventions. In this context, and following the procedure indicated in Scheme 38. Porpholactol-type compounds studied as photosensitizers in PDT [101].
The same research group also reported the photosensitizing properties of the two isomeric cis-(77) and trans-(77') porphodilactones (Scheme 27) and the corresponding Zn(II) complexes [89]. The electronic absorption spectra of the two isomers are similar to those of bacteriochlorins, with strong absorption bands in NIR region (>650 nm). However, the authors found that the relative orientation of the two β-lactone moieties has a significant influence on the electronic structures and photophysical properties of the porphodilactones. For example, the Q y band of trans-porphodilactone is red-shifted by 19 nm relative to that of the cis-isomer, and there is a 2-fold increase in the absorption intensity [89]. The orientation of the two lactone moieties also affects the singlet oxygen production of the two isomeric porphodilactones. The values obtained for the singlet oxygen quantum yields (Φ∆) were 0.53 for the free-base trans-porphodilactone 77', 0.66 for Zn77', and 0.87 for Zn77. Surprisingly, the free-base cis-porphodilactone 77 shows no singlet oxygen production at all after irradiation by a 635 nm laser beam. Both porphodilactones, encapsulated into PLGA nanoparticles, showed no dark toxicity after incubation for 24 h in HeLa cells. However, after irradiation with a 671 nm laser for 60 s, porphodilactones 77' and Zn77' exhibited good phototoxicity with a IC 50 value of 51 and 44 µg¨mL´1, respectively. The IC 50 value of Zn77 was significantly larger (94 µg¨mL´1), despite having a larger Φ∆ value, while the free-base cis-porphodilactone 77 showed nearly no photocytoxicity toward HeLa cells, which was consistent with the zero singlet oxygen production [89].

Multimodal Imaging Contrast Agents
Nowadays, there is a need to develop theranostic compounds for simultaneous cancer imaging, diagnosis and treatment interventions. In this context, and following the procedure indicated in Scheme 38, the group of Zhang prepared two oxazolochlorin acetals bearing gadolinium(III) DOTA-type complexes (Zn108a,b, Figure 2) [103]. Both compounds can achieve cellular uptake, show no dark cytotoxicity and good photocytotoxicity on HeLa cells. Fluorescence and magnetic resonance imaging experiments showed that both compounds are suitable as bimodal imaging contrast agents. In addition, the photocytotoxicity results indicate that these compounds can also be exploited as photosensitizers for PDT. Scheme 38, the group of Zhang prepared two oxazolochlorin acetals bearing gadolinium(III) DOTA-type complexes (Zn108a,b, Figure 2) [103]. Both compounds can achieve cellular uptake, show no dark cytotoxicity and good photocytotoxicity on HeLa cells. Fluorescence and magnetic resonance imaging experiments showed that both compounds are suitable as bimodal imaging contrast agents. In addition, the photocytotoxicity results indicate that these compounds can also be exploited as photosensitizers for PDT.

Catalysis
The first report about the use of metalloporpholactones in catalysis dates back to 2005, when Cetin and Ziegler [104] demonstrated the catalytic activity of the manganese(III) complex of meso-tetraphenylporpholactone, Mn(TPPL)Cl (Mn5-Cl), in olefin epoxidation reactions. Comparing with the manganese(III) complex of meso-tetraphenylporphyrin, Mn(TPP)Cl, the Mn(TPPL)Cl is a slightly better catalyst for most alkene substrates. However, for the electron-poor substrate hex-1-ene, the turnover number is appreciably larger than the one observed for the manganese porphyrin.
Iron(III) and manganese(III) complexes of meso-tetraphenylporpholactone, Fe(TPPL)Cl and Mn(TPPL)CH3CO2, are efficient catalysts for the oxidation of sulfides with hydrogen peroxide [105]. Both aliphatic and aromatic sulfides are effectively oxidized to the corresponding sulfoxides and sulfones in yields of 80%-100%. The results show that the iron and manganese porpholactones catalyze the oxidation of sulfides with similar efficiency and are slightly better catalysts than the TPP analogues for most substrates.
The iron(III) complex of meso-tetrakis(pentafluorophenyl)porpholactone, Fe(F20TPPL)Cl (Fe76-Cl), is an effective catalyst for nitrogen atom transfer reactions such as aziridination of alkenes and amidation of alkanes using organic azides [106]. In contrast, the manganese(III) complex of the same porpholactone shows a low catalytic activity.
The palladium(II) complex of meso-tetraphenylporpholactone (Pd5) and other Pd(II)-porphyrin complexes were studied as catalysts for the light-induced aerobic oxidation of dibenzylamine to the corresponding imine [107]. The results showed that while PdF20TPP could furnish 100% substrate conversion (99% yield) within 1.5 h, the substrate conversion using Pd5 was only 75% (74% yield) for a similar reaction time. Still, this substrate conversion was higher than the observed for PdTPP (38%, 37% yield), indicating that the lactonization of the porphyrin macrocycle was beneficial for the photocatalysis.

Optical Sensors
Porphyrins and related macrocycles play a preeminent role in sensing applications involving chromophores [108]. Pyrrole-modified porphyrins are also becoming more frequent as chemo(sensors). For instance, the Pt(II) complexes of the meso-tetrakis(pentafluorophenyl)porphyrin (Pt75) and of the corresponding porpholactone (Pt76) have been extensively used as the O2-sensitive components of pressure sensitive paints [109][110][111][112][113]. The porphothionolactone 102a (Scheme 36) is another example. This compound is an effective fluorescent switch-on chemodosimeter for hypochlorite (OClˉ) [99]. In fact, this porphothionolactone is rapidly and quantitatively converted into the corresponding

Catalysis
The first report about the use of metalloporpholactones in catalysis dates back to 2005, when Cetin and Ziegler [104] demonstrated the catalytic activity of the manganese(III) complex of meso-tetraphenylporpholactone, Mn(TPPL)Cl (Mn5-Cl), in olefin epoxidation reactions. Comparing with the manganese(III) complex of meso-tetraphenylporphyrin, Mn(TPP)Cl, the Mn(TPPL)Cl is a slightly better catalyst for most alkene substrates. However, for the electron-poor substrate hex-1-ene, the turnover number is appreciably larger than the one observed for the manganese porphyrin.
Iron(III) and manganese(III) complexes of meso-tetraphenylporpholactone, Fe(TPPL)Cl and Mn(TPPL)CH 3 CO 2 , are efficient catalysts for the oxidation of sulfides with hydrogen peroxide [105]. Both aliphatic and aromatic sulfides are effectively oxidized to the corresponding sulfoxides and sulfones in yields of 80%-100%. The results show that the iron and manganese porpholactones catalyze the oxidation of sulfides with similar efficiency and are slightly better catalysts than the TPP analogues for most substrates.
The iron(III) complex of meso-tetrakis(pentafluorophenyl)porpholactone, Fe(F 20 TPPL)Cl (Fe76-Cl), is an effective catalyst for nitrogen atom transfer reactions such as aziridination of alkenes and amidation of alkanes using organic azides [106]. In contrast, the manganese(III) complex of the same porpholactone shows a low catalytic activity.
The palladium(II) complex of meso-tetraphenylporpholactone (Pd5) and other Pd(II)-porphyrin complexes were studied as catalysts for the light-induced aerobic oxidation of dibenzylamine to the corresponding imine [107]. The results showed that while PdF 20 TPP could furnish 100% substrate conversion (99% yield) within 1.5 h, the substrate conversion using Pd5 was only 75% (74% yield) for a similar reaction time. Still, this substrate conversion was higher than the observed for PdTPP (38%, 37% yield), indicating that the lactonization of the porphyrin macrocycle was beneficial for the photocatalysis.

Optical Sensors
Porphyrins and related macrocycles play a preeminent role in sensing applications involving chromophores [108]. Pyrrole-modified porphyrins are also becoming more frequent as chemo(sensors). For instance, the Pt(II) complexes of the meso-tetrakis(pentafluorophenyl)porphyrin (Pt75) and of the corresponding porpholactone (Pt76) have been extensively used as the O 2 -sensitive components of pressure sensitive paints [109][110][111][112][113]. The porphothionolactone 102a (Scheme 36) is another example. This compound is an effective fluorescent switch-on chemodosimeter for hypochlorite (OCl´) [99]. In fact, this porphothionolactone is rapidly and quantitatively converted into the corresponding porpholactone 101a by the addition of an aqueous solution of NaOCl (bleach). Since the thionolactone possesses only a very dim fluorescence emission but the lactone is brightly fluorescing, this reaction switches the fluorescence on (readily observed with the naked eye) within 10 min at ambient conditions. The conversion of the thionolactone to the lactone is highly selective for the oxidant hypochlorite and that is the basis for the use of this thionolactone as a switch-on chemodosimeter for this anion.
However, it must be taken into consideration that this reaction is pH-dependent and acidic to neutral conditions (pH between 1 and 7.4) are required for the conversion of 102a by OCl´ [99].
Cyanide is one of the most toxic and harmful anions to human health and environment but it is still widely used in mining, metallurgy, photographic processing, synthesis of nylon and other synthetic fibers, etc. Thus, it is very important to develop simple, selective, and sensitive methods to the detection of CN´, especially in water [114]. One interesting example of the potential applications of the pyrrole-modified porphyrins is their use as optical cyanide chemosensors. Recently, the group of Brückner demonstrated that the water-soluble PEGylated porpholactone 109 and its zinc(II), platinum(II), and gallium(III) complexes (Figure 3) behave as optical cyanide chemosensors in aqueous solutions, albeit these sensors possess only modest sensitivities [115]. It was shown that the optical response of the Zn109 complex to cyanide is totally different from that of the free-base, platinum, and gallium complexes. While for the Zn109 it can be attributed to axial ligation of the cyanide to the central metal, the sensing mechanism for 109, Pt109 and Ga109 relies on a nucleophilic addition of the cyanide to the lactone moiety. Incorporation of the gallium porpholactone complex (Ga109) in a Nafion®membrane resulted in a material that shows a reversible response to CN´and remains stable and transparent even after days in aqueous solutions [115]. porpholactone 101a by the addition of an aqueous solution of NaOCl (bleach). Since the thionolactone possesses only a very dim fluorescence emission but the lactone is brightly fluorescing, this reaction switches the fluorescence on (readily observed with the naked eye) within 10 min at ambient conditions. The conversion of the thionolactone to the lactone is highly selective for the oxidant hypochlorite and that is the basis for the use of this thionolactone as a switch-on chemodosimeter for this anion. However, it must be taken into consideration that this reaction is pH-dependent and acidic to neutral conditions (pH between 1 and 7.4) are required for the conversion of 102a by OClˉ [99]. Cyanide is one of the most toxic and harmful anions to human health and environment but it is still widely used in mining, metallurgy, photographic processing, synthesis of nylon and other synthetic fibers, etc. Thus, it is very important to develop simple, selective, and sensitive methods to the detection of CNˉ, especially in water [114]. One interesting example of the potential applications of the pyrrole-modified porphyrins is their use as optical cyanide chemosensors. Recently, the group of Brückner demonstrated that the water-soluble PEGylated porpholactone 109 and its zinc(II), platinum(II), and gallium(III) complexes ( Figure 3) behave as optical cyanide chemosensors in aqueous solutions, albeit these sensors possess only modest sensitivities [115]. It was shown that the optical response of the Zn109 complex to cyanide is totally different from that of the free-base, platinum, and gallium complexes. While for the Zn109 it can be attributed to axial ligation of the cyanide to the central metal, the sensing mechanism for 109, Pt109 and Ga109 relies on a nucleophilic addition of the cyanide to the lactone moiety. Incorporation of the gallium porpholactone complex (Ga109) in a Nafion® membrane resulted in a material that shows a reversible response to CNˉ and remains stable and transparent even after days in aqueous solutions [115].  A recent study demonstrated that β-lactonization of porphyrin ligands enhances the sensitization efficiency of the NIR luminescence of the ytterbium(III) complexes ( Figure 4) [116]. In addition, it was found that the NIR emission of the water-soluble Yb(porpholactone)-glucose conjugate Yb107 is specifically switched on in the presence of glucose oxidase and is switched off by addition of glucose. This experiment shows that ytterbium complex Yb110 may find application as a switchable probe emitting in the NIR region in which biological tissues and fluids are relatively transparent (900-1100 nm). The ability of meso-tetrakis(pentafluorophenyl)porpholactone (76) and its Pt(II) complex to function as optical high pH sensors was reported by the group of Brückner [53]. This group found A recent study demonstrated that β-lactonization of porphyrin ligands enhances the sensitization efficiency of the NIR luminescence of the ytterbium(III) complexes ( Figure 4) [116]. In addition, it was found that the NIR emission of the water-soluble Yb(porpholactone)-glucose conjugate Yb107 is specifically switched on in the presence of glucose oxidase and is switched off by addition of glucose. This experiment shows that ytterbium complex Yb110 may find application as a switchable probe emitting in the NIR region in which biological tissues and fluids are relatively transparent (900-1100 nm). porpholactone 101a by the addition of an aqueous solution of NaOCl (bleach). Since the thionolactone possesses only a very dim fluorescence emission but the lactone is brightly fluorescing, this reaction switches the fluorescence on (readily observed with the naked eye) within 10 min at ambient conditions. The conversion of the thionolactone to the lactone is highly selective for the oxidant hypochlorite and that is the basis for the use of this thionolactone as a switch-on chemodosimeter for this anion. However, it must be taken into consideration that this reaction is pH-dependent and acidic to neutral conditions (pH between 1 and 7.4) are required for the conversion of 102a by OClˉ [99]. Cyanide is one of the most toxic and harmful anions to human health and environment but it is still widely used in mining, metallurgy, photographic processing, synthesis of nylon and other synthetic fibers, etc. Thus, it is very important to develop simple, selective, and sensitive methods to the detection of CNˉ, especially in water [114]. One interesting example of the potential applications of the pyrrole-modified porphyrins is their use as optical cyanide chemosensors. Recently, the group of Brückner demonstrated that the water-soluble PEGylated porpholactone 109 and its zinc(II), platinum(II), and gallium(III) complexes (Figure 3) behave as optical cyanide chemosensors in aqueous solutions, albeit these sensors possess only modest sensitivities [115]. It was shown that the optical response of the Zn109 complex to cyanide is totally different from that of the free-base, platinum, and gallium complexes. While for the Zn109 it can be attributed to axial ligation of the cyanide to the central metal, the sensing mechanism for 109, Pt109 and Ga109 relies on a nucleophilic addition of the cyanide to the lactone moiety. Incorporation of the gallium porpholactone complex (Ga109) in a Nafion® membrane resulted in a material that shows a reversible response to CNˉ and remains stable and transparent even after days in aqueous solutions [115].  A recent study demonstrated that β-lactonization of porphyrin ligands enhances the sensitization efficiency of the NIR luminescence of the ytterbium(III) complexes ( Figure 4) [116]. In addition, it was found that the NIR emission of the water-soluble Yb(porpholactone)-glucose conjugate Yb107 is specifically switched on in the presence of glucose oxidase and is switched off by addition of glucose. This experiment shows that ytterbium complex Yb110 may find application as a switchable probe emitting in the NIR region in which biological tissues and fluids are relatively transparent (900-1100 nm). The ability of meso-tetrakis(pentafluorophenyl)porpholactone (76) and its Pt(II) complex to function as optical high pH sensors was reported by the group of Brückner [53]. This group found The ability of meso-tetrakis(pentafluorophenyl)porpholactone (76) and its Pt(II) complex to function as optical high pH sensors was reported by the group of Brückner [53]. This group found that these compounds behave as chemosensors for OH´and MeO´. When submitted to strong alkaline or high methoxide conditions their UV-vis spectra undergo dramatic and reversible red-shifts.
The dynamic range for the Pt76 in solution is from pH 11.5 to 13.2. This complex can also be used to coat optical fibers, allowing the construction of optical fiber-based pH sensors.
This study was extended to a range of metal complexes of other meso-tetraarylporpholactones, allowing to investigate the influence of the metal (M = Zn(II), Ni(II), Cu(II), Pd(II), Ag(II), Pt(II)), the aryl group (Ar = Ph, C 6 F 5 ), and the presence of a β-NO 2 group, on the pH sensing range [117]. The results showed that the optical response for the pentafluorophenyl-substituted derivatives is stronger than that of the nitrated phenyl-substituted analogues. However, β-nitration and pentafluorophenyl-substitution have additive effects. Since the metal has a minor influence on the optical response, the cheaper and easier to prepare zinc, copper and silver complexes of porpholactones are excellent alternatives to the platinum complexes [117].
PEGylated and fully water-soluble Pt(II)-and Ga(III)porpholactones behave as high pH sensors in purely aqueous solutions (pH between 10 and 12.5 and 8 and 11, respectively) [118]. Incorporation of these compounds into a Nafion ® optode membrane resulted in sensors suitable for a moderately rapid (response time in minutes) sensing of high concentrations of hydroxides (pH 11 and above).

Conclusions
As discussed above, the pyrrole-modified porphyrin chemistry is evolving quickly. Several methods to access these compounds, and new reactions for their conversion into other porphyrinoids, were already reported. Also, various (potential) applications have been suggested for these types of compounds and, in many cases, these porphyrinoids show a better performance than their porphyrin analogues. However, considering that these studies have been developed by a very restricted number of research groups, for a faster development of the pyrrole-modified porphyrins field (chemistry and applications) it is crucial that other research groups may become interested in this topic. Thus, we expect that this review contributes to motivate other researchers to embrace this subject.