Corroles and Hexaphyrins: Synthesis and Application in Cancer Photodynamic Therapy

molecules

Review Corroles and Hexaphyrins: Synthesis and Application in Cancer Photodynamic Therapy

Susana M. M. Lopes , Marta Pineiro and Teresa M. V. D. Pinho e Melo *

Coimbra Chemistry Centre and Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal; [email protected] (S.M.M.L.); [email protected] (M.P.) * Correspondence: [email protected]; Tel.: +351-239-854-475

Academic Editors: M. Amparo F. Faustino, Carlos J. P. Monteiro and Catarina I. V. Ramos Received: 25 June 2020; Accepted: 27 July 2020; Published: 29 July 2020

Abstract: Corroles and hexaphyrins are porphyrinoids with great potential for diverse applications. Like porphyrins, many of their applications are based on their unique capability to interact with light, i.e., based on their photophysical properties. Corroles have intense absorptions in the low-energy region of the uv-vis, while hexaphyrins have the capability to absorb light in the near-infrared (NIR) region, presenting photophysical features which are complementary to those of porphyrins. Despite the increasing interest in corroles and hexaphyrins in recent years, the full potential of both classes of compounds, regarding biological applications, has been hampered by their challenging synthesis. Herein, recent developments in the synthesis of corroles and hexaphyrins are reviewed, highlighting their potential application in photodynamic therapy.

Keywords: corroles; hexaphyrins; photodynamic therapy (PDT); photosensitizer dye

1. Introduction Corroles are tetrapyrrolic macrocycles containing 4 pyrrole units, 3 methine bridges and a direct pyrrole–pyrrole linkage (Figure1). Therefore, corroles are contracted porphyrinoids with one methine (=CH–) bridge less than porphyrins, which leads to lower symmetry, higher fluorescence quantum yields, lower oxidation potentials and more intense absorption in the low-energy region of the visible spectrum. Despite being less studied than porphyrins over the years, probably due to their challenging synthesis, there was a significant change in this scenario after the synthetic breakthroughs by Gryko, Gross and Paolesse [1–3]. In fact, many efforts have been devoted to the synthesis of corroles in recent years [4–7]. Their free-bases and metal complexes have been explored in a wide range of applications [8,9], namely as promising drug candidates for prevention and treatment of diverse diseases, such as diabetes, neurodegenerative diseases and cancer [10–14], as antibacterial agents [15] as well as bio-imaging agents [16]. Corroles also found application in the photodynamic inactivation of microorganisms (PDI) [17], sonodynamic therapy [18] and photodynamic therapy (PDT) [19–21]. Expanded porphyrins [7,22–24] have gained remarkable attention due to their interesting and versatile features, such as diverse π-conjugation pathways owing to flexible structures [25], near- infrared (NIR) absorption/emission [26], facile interconversion between multiple redox states [27], and multi-metal coordination cavities for various divalent and trivalent metal ions (Figure1)[ 22,28]. Beyond the study of these unique properties and their applications, the interest in expanded porphyrins has been focused on exploring the limits to which the classic Hückel definition of aromaticity may be applied. The goal has been to understand what factors endow a fully conjugated macrocycle with characteristics that can be considered aromatic or antiaromatic. Among the known expanded porphyrins that can combine from 5 to 12 pyrrole rings and diverse meso-bridges, hexaphyrins stand-out because these six-pyrrole macrocycles can adopt various conformations and electronic states such

Molecules 2020, 25, 3450; doi:10.3390/molecules25153450 www.mdpi.com/journal/molecules Molecules 2020, 24, x 2 of 39 electronic states such as Hückel aromatic, Hückel antiaromatic, Möbius aromatic, Möbius antiaromatic and stable radical states [29,30]. [26]Hexaphyrins(1.1.1.1.1.1) and [28]hexaphyrins(1.1.1.1.1.1), having six meso-bridges, are attractive molecules in view of aromaticity/antiaromaticity with a 26 and 28 π-electronic system, respectively, intense uv-vis absorption and a small HOMO-LUMO gap (Figure 1). [26]Hexaphyrins(1.1.1.1.1.1) can adopt a double-sided rectangular ring conformation with Hückel aromaticity while [28]hexaphyrins(1.1.1.1.1.1) adopt a single-sided twisted ring conformation with Möbius aromaticity. The unique uv-vis-NIR absorption/emission properties of these expanded π conjugatedMolecules 2020 , 25molecular, 3450 systems offer useful optical nonlinear properties such as two-photon2 of 39 absorption (TPA) [31], which make them a promising class of two-photon absorption chromophores, with potential for a wide range of applications including microscopy, microfabrication, three- dimensionalas Hückel aromatic, data-storage, Hückel optical antiaromatic, power limiting, Möbius up-converted aromatic, Möbius lasing, antiaromatic localized release and stable of bio-active radical species,states [29 as,30 well]. as application in photodynamic therapy [32].

N N H N NH HN NH H N N H N N HN 2+ NH HN N H HN NH H N HN NHHN N N

Corrole Cyclo[6]pyrrole Amethyrin Rosarin [18]Tetraphyrin(1.1.1.0) [22]Hexaphyrin(0.0.0.0.0.0) [24]Hexaphyrin(1.0.0.1.0.0) [24]Hexaphyrin(1.0.1.0.1.0)

H N N N N H HN NH H N N NH N NH N

N HN NH N HN N N H HN H N N N N H Rubyrin Hexaphyrin Bronzaphyrin [26]Hexaphyrin(2.0.0.2.0.0) [26]Hexaphyrin(1.1.0.1.1.0) [26]Hexaphyrin(1.1.1.1.1.1) [28]Hexaphyrin(1.1.1.1.1.1) Figure 1. ChemicalChemical structures structures of corrole and hexaphyrins.

2. Synthesis[26]Hexaphyrins(1.1.1.1.1.1) of New Corrole Derivatives and [28]hexaphyrins(1.1.1.1.1.1), having six meso-bridges, are attractive molecules in view of aromaticity/antiaromaticity with a 26 and 28 π-electronic system,In recent respectively, decades, intense the synthesis uv-vis of absorption corroles and and metallocorroles a small HOMO-LUMO had attracted gap considerable (Figure1). attention[26]Hexaphyrins(1.1.1.1.1.1) from the scientific cancommunity adopt a double-sidedand some reviews rectangular have ringbeen conformation published [4,6,7,9,33,34]. with Hückel Nevertheless,aromaticity while the [28]hexaphyrins(1.1.1.1.1.1)relevance of corroles’ applicat adoptions a single-sidedhas driven the twisted development ring conformation of interesting with approachesMöbius aromaticity. to construct The macrocycles unique uv-vis-NIR with new absorption moieties,/emission via classical properties and novel of these methodologies, expanded π collectedconjugated herein. molecular systems offer useful optical nonlinear properties such as two-photon absorption (TPA) [31], which make them a promising class of two-photon absorption chromophores, with potential 2.1. Classical Synthetic Methodologies for a wide range of applications including microscopy, microfabrication, three-dimensional data-storage, opticalOne power of the limiting, most explored up-converted routes lasing, to meso localized-substituted release corroles of bio-active relies species, on the assynthesis well as applicationof bilanes, obtainedin photodynamic from the therapy condensation [32]. of dipyrromethanes (DPs) with aldehydes, followed by oxidative macrocyclization. This strategy was applied to the synthesis of new corroles to be used in diverse applications.2. Synthesis of New Corrole Derivatives LiuIn recent and decades,coworkers the synthesisdescribed of corrolesthe synthesis and metallocorroles of trans-A had2B attractedcorroles considerablemeso-substituted attention by phenothiazinefrom the scientific (PTZ) community and 2,3-di(2-pyridyl)qui and some reviews havenoxaline been published(DPQ) groups. [4,6,7, 9,33The,34 ].HCl-catalyzed Nevertheless, condensationthe relevance ofof corroles’ PTZ and applications DPQ formyl has derivatives driven the 2 development and 4 with 5-pentafluorophenyldipyrromethane of interesting approaches to construct (macrocycles1) followed withby 2,3-dichloro-5,6-dicyano-1,4-benzo new moieties, via classical and novelquinone methodologies, (DDQ)-promoted collected macrocyclization herein. gave the target corroles 3 and 5 in 31 and 34% yield, respectively (Scheme 1) [35]. Corroles 3 and 5 are 2.1. Classical Synthetic Methodologies One of the most explored routes to meso-substituted corroles relies on the synthesis of bilanes, obtained from the condensation of dipyrromethanes (DPs) with aldehydes, followed by oxidative macrocyclization. This strategy was applied to the synthesis of new corroles to be used in diverse applications. Liu and coworkers described the synthesis of trans-A2B corroles meso-substituted by phenothiazine (PTZ) and 2,3-di(2-pyridyl)quinoxaline (DPQ) groups. The HCl-catalyzed condensation of PTZ and DPQ formyl derivatives 2 and 4 with 5-pentafluorophenyldipyrromethane (1) followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-promoted macrocyclization gave the target corroles Molecules 2020, 25, 3450 3 of 39

Molecules 2020, 24, x 3 of 39 3 and 5 in 31 and 34% yield, respectively (Scheme1)[ 35]. Corroles 3 and 5 are novel donor-acceptor novelsystems, donor-acceptor in which the systems, corrole scain whichﬀold is the an corrole acceptor scaffold and PTZ is an or acceptor DPQ moiety and PTZ is an or energy DPQ moiety/electron is andonor. energy/electron The absorption donor. spectra The absorption of both dyads spectra are ofa both superposition dyads are a of superposition the absorption of the spectra absorption of the spectramonomers, of the indicating monomers, a weak indicating electronic a weak interaction electron betweenic interaction the corrole between and the either corrole PTZ and or DPQ either groups, PTZ orwhich DPQ was groups, corroborated which was by the corroborated observed electrochemical by the observed properties. electrochemical A detailed properties. study of A the detailed excited studystate deactivation of the excited of bothstate dyadsdeactivation shows thatof both the singlet–singletdyads shows that energy the transfersinglet–singlet from PTZ energy to the transfer corrole fromunit isPTZ the to main the corrole process unit in is the the case main of process dyad 3 ,in while the case in theof dyad case 3, of while5 a reductive in the case electron of 5 a reductive transfer, electronfrom the transfer, ground from state the of DPQ ground to the state excited of DPQ state to th ofe theexcited corrole, state is of the the main corrole, process. is the Therefore,main process. one Therefore,dyad mimics one the dyad primary mimics process the primary and the process other mimics and the the other reaction mimics center the eventsreaction in center photosynthesis. events in photosynthesis.The proton-triggered The proton-trigger emission studiesed emission of dyad 5 studiesand OFET of dyad studies 5 and indicate OFET that studies they indicate can be applied that they in canthe DNAbe applied photocleavage. in the DNA photocleavage.

F O PTZ F F H PTZ F F F F 2 N HN F F 1. HCl, H2O/MeOH F F 2. DDQ NHHN NH HN F F F F N 1 3 31%

S O DPQ PTZ H DPQ F F F F 4 N HN

1. HCl, H2O/MeOH F F 2. DDQ NHHN N F F F F N N 5 34% N

DPQ

SchemeScheme 1. Synthesis 1. of Synthesistrans-A2B-corroles of bearingtrans-A 2phenothiazineB-corroles bearingand 2,3-di(2-pyridyl)quinoxaline phenothiazine and substituents.2,3-di(2-pyridyl)quinoxaline substituents.

TheThe synthesis of 10-(4-methyl-bipyridyl)-5,15-di(pentafluoropheny)corrole10-(4-methyl-bipyridyl)-5,15-di(pentafluoropheny)corrole ( (77)) was was achieved throughthrough Gryko’sGryko’s methodology, methodology, i.e., i.e., the th condensatione condensation of dipyrromethane of dipyrromethane1 with 1 the with bipyridyl-aldehyde the bipyridyl- aldehyde6 in a mixture 6 in a of mixture H2O/MeOH of H2O/MeOH using HCl using as catalyst. HCl as Oxidationcatalyst. Oxidation with DDQ with aff ordedDDQ afforded corrole 7 corrolein 17% 7yield in 17% (Scheme yield2 (Scheme)[ 36]. The 2) uv-vis[36]. The spectrum uv-vis exhibitsspectrum a strongexhibits Soret a strong band Soret at approximately band at approximately 400 nm and 400the Qnm bands and the appear Q bands between appear 500 between and 700 500 nm; and a single 700 nm; emission a single band emission is observed band inis theobserved fluorescence in the fluorescencespectrum. The spectrum. photophysical The photophysical properties studied properties in dichloromethane studied in dichloromethane (DCM) showed (DCM) that showed corrole that7 fluorescence corrole 7 fluorescence quantum yield quantum is 0.04, yield the internalis 0.04, the conversion internal conversion quantum yield quantum is 0.45 yield and is the 0.45 triplet and thequantum triplet yieldquantum formation yield isformation about 0.54. is about The singlet 0.54. The oxygen singlet quantum oxygen yield, quantum a measure yield, of a the measure ability of of thethe ability photosensitizer of the photosensitizer to generate cytotoxic to generate singlet cyto oxygentoxic singlet and anoxygen important and an parameter important to parameter evaluate the to evaluatecapability the of thecapability molecules of the to actmolecules as photosensitizers to act as photosensitizers for PDT, was measured for PDT, as was 0.47, measured indicating as a 0.47, high indicatingefficiency ina high energy efficiency transfer in from energy the corroletransfer triplet from the state. corrole triplet state. Molecules 2020, 25, 3450 4 of 39 MoleculesMolecules 20202020,, 2424,, xx 44 ofof 3939

NN NN FF OHCOHC FF FF N N 1.1. HCl, HCl, H H2O/MeOHO/MeOH + 2 FF FF + 2.2. DDQ, DDQ, NEt NEt3 FF FF FF FF NN 3 NN HNHN FF FF NHNH HNHN NHNHHNHN 11 66 FF FF FF FF 7 17% 7 17% SchemeScheme 2.2. SynthesisSynthesisSynthesis ofof of 10-(4-methyl-bipyridyl10-(4-methyl-bipyridyl 10-(4-methyl-bipyridyl)-5,15-di(pentaﬂuorophenyl)corrole.)-5,15-di(pentafluorophenyl)corrole.)-5,15-di(pentafluorophenyl)corrole.

TheThe trifluoroacetictrifluoroacetictrifluoroacetic acid (TFA)-catalyzedacidacid (TFA(TFA)-catalyzed)-catalyzed condensation condensationcondensation of meso-pentafluorophenyl-dipyrromethane ofof mesomeso-pentafluorophenyl--pentafluorophenyldipyrromethane(dipyrromethane1) with 8-hydroxyquilonine-2-carboxaldehyde ((11)) withwith 8-hydroxyquiloni8-hydroxyquilonine-2-carboxaldehydene-2-carboxaldehyde (8) gave the low-symmetric ((88)) gavegave Athethe2B-type low-symmetriclow-symmetric corrole 9 in AA 16%22B-B- typeyield.type corrolecorrole Free base 99 inin corrole 16%16% yield.yield.9 was FreeFree treated basebasewith corrolecorrole an excess99 waswas oftreatedtreated GaCl 3withwithin refluxing anan excessexcess pyridine ofof GaClGaCl to33 in producein refluxingrefluxing the pyridinepyridineGa(III) corrole toto produceproduce10 in 40% thethe Ga(III)Ga(III) yield (Scheme corrolecorrole 3 1010)[ inin37 40%].40% According yieldyield (Scheme(Scheme to the fluorescence3)3) [37].[37]. AccordingAccording studies, toto Ga(III)thethe fluorescencefluorescence corrole 10 studies,wasstudies, a good Ga(III)Ga(III) “off -on-ocorrolecorroleff” 1010 pH waswas sensor aa goodgood in 1–14 “off-on-off”“off-on-off” pH range. pHpH The sensorsensor Ga(III) inin complex 1–141–14 pHpH presents range.range. TheThe a fluorescence Ga(III)Ga(III) complexcomplex band presentswithpresents maximum aa fluorescencefluorescence at 603 nm, bandband fluorescence withwith maximummaximum quantum atat 603603 yield nm,nm, of fluorescencefluorescence 11.7% and a quantum fluorescencequantum yieldyield lifetime ofof 11.7%11.7% of2.42 andandns aa fluorescencefluorescencein DCM solution. lifetimelifetime The ofof intensity 2.422.42 nsns of inin fluorescence DCMDCM solutionsolution decreases.. TheThe intensityintensity gradually ofof with fluorescfluoresc theence acidityence decreasesdecreases of the solution graduallygradually and withwithincreases thethe acidityacidity when theofof thethe solution solutionsolution is more andand increasesincreases basic. whenwhen thethe solutionsolution isis moremore basic.basic.

OHOH OHOH NN NN 1.1. DPDP 11 GaCl TFA,TFA, DCMDCM GaCl33 FF FF FF FF NN NN OHCOHC NN 2. DDQ F F F F PyPy 2. DDQ F F F F Ga OHOH NN HNHN FF Ga FF 8 N N 8 FF FF N N F F NHNHHNHN FF FF F F N FF FF FF FF N

99 16%16% 10 40% 10 40%

SchemeScheme 3. 3. SynthesisSynthesisSynthesis ofof of aa a 8-hydroxyquinoline-substituted8-hydroxyquinoline-substituted 8-hydroxyquinoline-substituted AA A22B-type2B-typeB-type freefree free basebase base corrolecorrole corrole andand the the correspondingcorresponding Ga(III) Ga(III) corrole. corrole.

TheThe condensation condensation ofofof 5-(4-nitrophenyl)dipyrromethane5-(4-nitrophenyl)dipyrromethane5-(4-nitrophenyl)dipyrromethane ( 11 ((1111)) with) withwith aromatic aromaticaromatic aldehydes, aldehydes,aldehydes, followed followedfollowed by oxidation with p-chloranil allowed the isolation of trans-A B corroles 12 in 29–38% yield (Scheme4)[ 38]. byby oxidationoxidation withwith pp-chloranil-chloranil allowedallowed thethe isolationisolation ofof transtrans2 -A-A22BB corrolescorroles 1212 inin 29–38%29–38% yieldyield (Scheme(Scheme 4)The4) [38].[38]. photophysical TheThe photophysicalphotophysical properties propertiesproperties in toluene inin toluenetoluene show characteristicshshowow characteristiccharacteristic absorption absorption/emissionabsorption/emission/emission spectra spectraspectra with Soretwithwith SoretSorettype bandstypetype bandsbands between betweenbetween 420 and 420420 450 andand nm, 450450 Q-type nm,nm, Q-typeQ-type bands around bandsbands aroundaround 590–655 590–655590–655 nm and nm thenm fluorescenceandand thethe fluorescencefluorescence bands in bandsbandsthe range inin the ofthe 673–690 rangerange ofof nm. 673–690673–690 The fluorinated nm.nm. TheThe corrolesfluorinatefluorinate presentdd corrolescorroles fluorescence presentpresent quantum fluorescencefluorescence yields quantumquantum higher than yieldsyields the higherhighercarboxymethyl thanthan thethe derivative, carboxymetcarboxymet 0.76hylhyl for derivative,derivative,12a, 0.80 for0.760.7612b forforand 12a12a 0.77,, 0.800.80 for forfor12c 12b12b. Corroles andand 0.770.7712a forfor–d 12c12cshowed.. CorrolesCorroles an excellent 12a12a––dd showedshowedaffinity for anan excellenttheexcellent fluoride affinityaffinity ions, for allowingfor ththee fluoridefluoride for an ions, unusualions, allowingallowing selectivity forfor anan for unusualunusual fluoride selectivityselectivity ions. The forfor quenching fluoridefluoride of ions.ions. the TheThefluorescence quenchingquenching emission ofof thethe fluorescencefluorescence with the addition emissionemission of fluorine withwith thth ionee additionaddition indicates ofof that fluorinefluorine these ionion corroles indicatesindicates can bethatthat used thesethese as corrolescorrolesfluorine can ioncan be sensors.be usedused asas fluorinefluorine ionion sensors.sensors. Molecules 2020, 2425, x 3450 5 of 39 Molecules 2020, 24, x 5 of 39

Scheme 4. Synthesis of trans-A2B corroles [where A = 4-nitrophenyl and B = pentafluorophenyl, 2,6- Schemedifluorophenyl, 4. 4. SynthesisSynthesis 3,4,5-trifluorophenyl of of transtrans-A-A2B2 Bcorroles corroles and 4-(methoxycarbonyl)phenyl[where [where A = A 4-nitrophenyl= 4-nitrophenyl and groups]. and B = Bpentafluorophenyl, = pentafluorophenyl, 2,6- difluorophenyl,2,6-difluorophenyl, 3,4,5-trifluorophenyl 3,4,5-trifluorophenyl and and 4-(methoxycarbonyl)phenyl 4-(methoxycarbonyl)phenyl groups]. groups]. Liang and coworkers developed the synthesis of three low-symmetry A2B type manganese(III) meso-triarylcorrolesLiang and coworkers providing developed a push–pull the synthesis electronic of three system low-symmetry (Scheme A 5).2BB type typeThe manganese(III) manganese(III)acid-catalyzed mesocondensation-triarylcorroles-triarylcorroles of dipyrromethane providing a 13 push–pullpush–pull with the electronicappropriateelectronic systemsystem aldehyde (Scheme(Scheme followed5 ).5). by TheThe oxidation acid-catalyzedacid-catalyzed with p- condensationchloranil gave of ofcorroles dipyrromethane dipyrromethane 14. The reaction1313 withwith ofthe the these appropriate appropriate macrocycles aldehyde aldehyde with followed manganese followed byby oxidationchloride oxidation inwith DMF with p- chloranilaffordedp-chloranil metallocorrolesgave gave corroles corroles 14 15a14. .The– Thec inreaction reactionhigh yields of of these these (63–90%) macrocycles macrocycles [39]. The with with fluorescence manganese manganese studies chloride chloride reveal in in DMF that affordedMn(III)afforded corroles metallocorrolesmetallocorroles 15a–c strongly15a 15a–c–inc interactin high high yields with yields (63–90%) the (63–90%) cell-free [39]. circulating[39]. The fluorescenceThe fluorescence tumor studiesDNA studiesin reveal solution reveal that and Mn(III) that the Mn(III)abilitycorroles of corroles15a this–c interactionstrongly 15a–c strongly interact increases withinteract with the with cell-freethe electron-donatingthe cell-free circulating circulating tumor character DNA tumor inof solutionDNAthe 10-substituent in andsolution the ability and of the of abilitytriarylcorrole.this interaction of this interactionThis increases interaction withincreases the with electron-donating withDNA the can electron-donating be used character for tumor of characterdetection the 10-substituent andof the targeting 10-substituent of the drug triarylcorrole. delivery of the triarylcorrole.Thisin vivo. interaction This with interaction DNA can with be used DNA for can tumor be used detection for tumor and detection targeting and drug targeting delivery drug in vivo. delivery in vivo.

Scheme 5. SynthesisSynthesis of of Mn(III) Mn(III) transtrans-A-A2B2 Btriarylcorroles triarylcorroles [where [where A A= =3-nitrophenyl3-nitrophenyl and and B = B 4-= Schememethoxphenyl,4-methoxphenyl, 5. Synthesis 4-(dimethylamino)p 4-(dimethylamino)phenyl of Mn(III) transhenyl-A 2andB andtriarylcorroles 4-(trifluoromethyl) 4-(trifluoromethyl) [where2phenyl2 phenylA = groups].3-nitrophenyl groups]. and B = 4- methoxphenyl, 4-(dimethylamino)phenyl and 4-(trifluoromethyl)2phenyl groups]. Triaryl corrolescorroles with with a meso a meso-iodoaryl-iodoaryl substituent substituent were preparedwere prep andared their and photophysical their photophysical properties werepropertiesTriaryl studied were corroles in order studied towith evaluate in ordera meso their to-iodoaryl evaluate capabilities theirsubstituent as capabilities photosensitizers were as prep photosensitizers forared PDT. and A2 B-typetheir for PDT.photophysical triaryl A corroles2B-type properties17triarylwere corroles synthesized were studied17 were through in synthesized order the TFA-catalyzedto evaluate through their the condensation capabilities TFA-catalyzed as of photosensitizers DP condensation1 with 2-hydroxybenzaldehyde forof PDT.DP 1 A with2B-type 2- triarylhydroxybenzaldehydeand m -iodinatedcorroles 17 2-hydroxybenzaldehydes, were and synthesized m-iodinated through 2-hydroxybenzaldehydes,16 ,the followed TFA-catalyzed by oxidation 16condensation, followed with DDQ byof (Scheme oxidationDP 1 with6)[ with 402-]. hydroxybenzaldehydeTheDDQ presence (Scheme of 6) iodine [40]. The atomsand presencem did-iodinated not of significantly iodine 2-hydroxybenzaldehydes, atoms influence did not the signif absorption icantly16, followed influence spectra by and oxidationthe only absorption a slightwith DDQspectradecrease (Scheme and in theonly 6) absorption a[40]. slight The decrease coepresencefficient in of ofthe iodine the absorpti Soret atoms bandon coefficientdid (ca. not 420 signif nm)of theicantly was Soret observed influence band (ca. with the 420the absorption nm) increase was spectraobservedin the number and with only the of iodinea increase slight atoms. decrease in the However, number in the ofabsorpti the iodi fluorescenceneon atoms. coefficient However, quantum of the the yield Soret fluorescence and band fluorescence (ca. quantum 420 nm) lifetime yield was observedandare stronglyfluorescence with influenced the lifetimeincrease by are in the thestrongly iodine number atom.influenced of iodi Corrolene byatoms. 17athe, However,iodine without atom. iodine the Corrolefluorescence atoms, 17a, has withoutquantum a fluorescence iodine yield andquantumatoms, fluorescence has yield a fluorescence of 0.143lifetime that arequantum decreases strongly yield to influenced 0.031 of 0.143 in the thatby case the decreases of iodine mono-iodo-corrole atom.to 0.031 Corrole in the17b 17a,caseand withoutof to 0.023mono-iodo- iodine for the atoms,corroledi-iodo-corrole has17b aand fluorescence17c to .0.023 The decreasefor quantum the di-iodo-corrole in theyield fluorescence of 0.143 17c that. quantumThe decreases decrease yield toin is 0.031the accompanied fluorescence in the case by quantumof the mono-iodo- decrease yield in corroleisthe accompanied fluorescence 17b and to lifetimeby 0.023 the andfordecrease the a slight di-iodo-corrole in increase the fluorescence in the17c triplet. The lifetime decrease quantum and in yields thea slight fluorescence showcasing increase thequantum in heavythe triplet yield atom isquantumeff ect.accompanied Despite yields the showcasingby increase the decrease in the the heavy einffi ciencythe atom fluorescence of effect. the triplet Despite lifetime state the formation, increaseand a slight in the the singlet increaseefficiency oxygen in of the the quantum triplet quantumyieldstate formation, (Φ∆ )yields decreased, showcasingthe singlet going oxygen fromthe heavy mono-iodo-corrole quantum atom effect.yield ( ΦDespiteΔ17b) decreased,(Φ the∆ = increase0.9) going to di-iodo-corrole infrom the mono-iodo-corroleefficiency17c of( theΦ∆ triplet= 0.4).17b state(ΦΔ = formation, 0.9) to di-iodo-corrole the singlet oxygen 17c (Φ Δquantum = 0.4). yield (ΦΔ) decreased, going from mono-iodo-corrole 17b (ΦΔ = 0.9) to di-iodo-corrole 17c (ΦΔ = 0.4). Molecules 2020, 25, 3450 6 of 39 Molecules 2020, 24, x 6 of 39

Y X Y X Molecules 2020, 24, x F 6 of 39 F F OH OH Y X Y CHO X16 F F F F F F F F F 1. TFA, DCM N HNOH OH 2. NEt3, DDQ CHO 16 F F F F F F F F NH HN 1. TFA, DCM N NHHNHN 2. NEt , DDQ F F F F 1 3 F F NH HN NHHN 17a X = Y = H F F F F 1 17b X = I, Y = H 17a17c X X = =Y Y= H= I 17b X = I, Y = H Scheme 6. Iodine-containingIodine-containing A A22B-typeB-type triaryl triaryl corroles corroles synthesized synthesized17c X = Y = to toI evaluate evaluate the the influence influence of iodine atoms on the photophysical properties. Scheme 6. Iodine-containing A2B-type triaryl corroles synthesized to evaluate the influence of iodine atoms on the photophysical properties. During thethe synthesissynthesis of of the the bulky bulky bis-pocket bis-pocket corrole corrole20a, Chang20a, Chang and coworkers and coworkers identified identified another anothergreen compound greenDuring compound the as synthesis being as the being ofβ the-chlorinated the bulky β-chlorinated bis-pocket corrole corrolecorrole20b, fully 20b20a,, supported Changfully supported and bycoworkers characterization by characterization identified data, data,including anotherincluding X-ray green X-ray crystallography compound crystallography as being analysis the analysis β (Scheme-chlorinated (Scheme7)[ 41 corrole]. 7) The [41]. 20bβ-chloro-corrole, Thefully β supported-chloro-corrole20b by wascharacterization 20b formed was throughformed throughthe mono-chlorinationdata, the including mono-chlorination X-ray of crystallography corrole of 20acorrolein analysis which 20a in (Scheme DDQwhich acted 7)DDQ [41]. as actedThe both β -chloro-corroleas oxidant both oxidant and 20b chlorinating and was chlorinating formed agent. agent.The presencethrough The presence the of a mono-chlorination chlorine of a atomchlorine at the ofatom corroleβ-position at the20a βin of-position which corrole DDQ20b of corroleinducedacted as 20bboth a slight induced oxidant red shift and a slight inchlorinating the red absorption shift in agent. The presence of a chlorine atom at the β-position of corrole 20b induced a slight red shift in theand absorption fluorescence and emission fluorescence spectra, emission together spectra, with together a significant with a significant decrease in decrease fluorescence in fluorescence intensity. the absorption and fluorescence emission spectra, together with a significant decrease in fluorescence intensity.Fluorescence Fluorescence lifetimes, aslifetime well ass, theas well fluorescence as the fluorescence quantum yields, quantum are yields, shorter are for shorterβ-chloro-corrole for β-chloro-20b intensity. Fluorescence lifetimes, as well as the fluorescence quantum yields, are shorter for β-chloro- (2.5 ns) than for corrole 20a (4.2 ns). However, the decrease in the fluorescence did not promote the corrolecorrole 20b 20b(2.5 (2.5ns) ns)than than for for corrole corrole 20a 20a (4.2 (4.2 ns).ns). However, the the decrease decrease in inthe the fluorescence fluorescence did notdid not 20a promoteincreasepromote inthe the increasethe capability increase in thein to the generatecapability capability singlet to to genera genera oxygen,tete singlet since oxygen, non-chlorinatedoxygen, since since non-chlorinated non-chlorinated corrole demonstratedcorrole corrole 20a 20a a demonstratedhigherdemonstrated ability toa higher generate a higher ability singletability to togenerate oxygen generate than singlet singlet the oxygenβ-chlorinated than than the the corroleβ -chlorinatedβ-chlorinated20b. corrole corrole 20b .20b .

PhPh PhPh

Ph Ph + Ph Ph Ph Ph Ph Ph CHO CHO NH HN 19 NH 18HN 19 18 1. TFA, DCM Ph Ph 1.2. TFA, NEt3, DCM DDQ Ph Ph 2. NEt3, DDQ Ph Ph Ph Ph Ph Ph Ph Ph + Ph Ph Ph Ph N HN N HN + Ph Ph Ph Ph Ph N HN Ph Ph N HN Ph NHHN NHHN Ph Ph Ph Ph Ph Ph Ph Ph NHHN NHHN Ph Cl Ph Ph 20a 3.9% Ph 20b 5.7% Scheme 7. Synthesis of bulky bis-pocket corroles. Cl 20aScheme 3.9% 7. Synthesis of bulky bis-pocket corroles.20b 5.7%

TheThe three three component component one-potScheme one-po reaction7.t reaction Synthesis ofof ofpyrrole,pyrrole, bulky bis-pocketpp-trifluoromethylbenzaldehyde-triﬂuoromethylbenzaldehyde corroles. and andazulene azulene (21), catalyzed by TFA, followed by oxidation with DDQ, allowed the isolation of novel meso- (21), catalyzed by TFA, followed by oxidation with DDQ, allowed the isolation of novel Thetriarylazulicorrole three component 22 (Scheme one-po t8) reaction [42]. Despite of pyrrole, the poor p-trifluoromethylbenzaldehyde yield (<1%), carbacorrole 22 could and azulenebe meso-triarylazulicorrole 22 (Scheme8)[ 42]. Despite the poor yield (<1%), carbacorrole 22 could (21), convertedcatalyzed into by theTFA, corresponding followed Cu(III)by oxidation and Au(III) with complexes. DDQ, allowed Single-crystal the isolationX-ray structures of novel were meso - be converted into the corresponding Cu(III) and Au(III) complexes. Single-crystal X-ray structures triarylazulicorroleobtained for the 22 free-base (Scheme and 8) Cu(III) [42]. derivatives,Despite the uncovering poor yield detailed (<1%), structural carbacorrole information 22 could on be werethese obtained novel for macrocyles. the free-base The andmeso Cu(III)-triarylazulicorroles derivatives, show uncovering absorption detailed spectra structural with absorption information converted into the corresponding Cu(III) and Au(III) complexes. Single-crystal X-ray structures were on thesefeatures novel extending macrocyles. into the The NIRmeso region,-triarylazulicorroles opening the way showto their absorption application spectra in bioimaging with absorption and obtained for the free-base and Cu(III) derivatives, uncovering detailed structural information on featuresphotodynamic extending therapy. into the NIR region, opening the way to their application in bioimaging and these novel macrocyles. The meso-triarylazulicorroles show absorption spectra with absorption photodynamic therapy. features extending into the NIR region, opening the way to their application in bioimaging and photodynamic therapy. Molecules 2020, 25, 3450 7 of 39 Molecules 2020, 24, x 7 of 39 Molecules 2020, 24, x 7 of 39

SchemeScheme 8. Synthesis8. Synthesis of ofmeso meso-tri-(-tri-(p-trifluoromethyl)phenylazulicorrole.-trifluoromethyl)phenylazulicorrole. Scheme 8. Synthesis of meso-tri-(p-trifluoromethyl)phenylazulicorrole. 2.2. New2.2. New Synthetic Synthetic Methodologies Methodologies 2.2.The NewThe above-described Synthetic above-described Methodologies syntheses syntheses of of corroles corroles werewere based based on on classical classical methodologies methodologies involving involving acid-catalyzed condensation of pyrroles or meso-substituted dipyrromethanes and aldehydes, acid-catalyzedThe above-described condensation ofsyntheses pyrroles of or corrolesmeso-substituted were based dipyrromethanes on classical methodologies and aldehydes, involving followed followed by oxidation. Recently, Pinho e Melo et al. described an innovative synthesis of A2B-type by oxidation.acid-catalyzed Recently, condensation Pinho e Meloof pyrroles et al. describedor meso-substituted an innovative dipyrromethanes synthesis of and A B-type aldehydes, corroles, corroles, bearing an oxime functionality, by exploring the reactivity of dipyrromethanes2 toward followed by oxidation. Recently, Pinho e Melo et al. described an innovative synthesis of A2B-type bearingnitrosoalkenes an oxime functionality, (Scheme 9) [43]. by In exploring situ dehydrohalogenation the reactivity of dipyrromethanesof the α,α-dihalo-oximes toward 23nitrosoalkenes generates corroles, bearing an oxime functionality, by exploring the reactivity of dipyrromethanes toward (Schemetransient9)[ 43α-chloro-nitrosoalkenes,]. In situ dehydrohalogenation which react with of dipyrromethanes the α,α-dihalo-oximes either via23 hetero-Dielsgenerates−Alder transient α-chloro-nitrosoalkenes,nitrosoalkenes (Scheme which 9) [43]. react In situ with dehydrohalogenation dipyrromethanes either of the via α,α hetero-Diels-dihalo-oximesAlder 23 generates reaction or reaction or conjugated addition to give the corresponding alkylated dipyrromethanes.− The side conjugatedtransientchains of addition α these-chloro-nitrosoalkenes, DPs to giveundergo the another corresponding which dehydrohalog react alkylatedwith enationdipyrromethanes dipyrromethanes. to afford new either nitrosoalkenes, via The hetero-Diels side chains allowing−Alder of these DPsreaction undergothe synthesis or another conjugated of the dehydrohalogenation target addition bilanes to give24 (16–40%) the to a ffcorrespondingord upon new nitrosoalkenes,reaction alkylated with adipyrromethanes. allowingsecond molecule the synthesis The of theside of the chains of these DPs undergo another dehydrohalogenation to afford new nitrosoalkenes, allowing targetdipyrromethane. bilanes 24 (16–40%) The oxidative upon reaction macrocyclization with a second with moleculeDDQ affords of thethe dipyrromethane.corresponding corroles The 25 oxidative in the synthesis of the target bilanes 24 (16–40%) upon reaction with a second molecule of the macrocyclization40–84% yields. with These DDQ are the affords first theexamples corresponding of meso-substituted corroles corroles25 in 40–84% with an yields. oxime Thesefunctionality. are the first dipyrromethane. The oxidative macrocyclization with DDQ affords the corresponding corroles 25 in examples of meso-substituted corroles with an oxime1 functionality. 1 40–84% yields. These are the first examples of mesoR-substitutedNOH corroles with anR oximeNOH functionality.

2 NOH R 1 1 Na2CO3 R NOH DDQ R NOH X NH HN N HN R1 + H O/DCM 2 2 THF, rt, 3 h NOH R2 2 R R R2 R2 X NH HN rt,Na 20 COmin 23 2 3 NH HN DDQ NHHN 1 X + NH HN N HN R R2 = Aryl X = Br, Cl H2O/DCM 2 2 THF, rt, 3 h 2 X R R R2 R 1 NH HN rt, 20 min 24 16-40% R =23 Me, Aryl NH HN 25 NH40-84%HN 2 X = Br, Cl R = Aryl trans-A2B-corroles R1 = Me, Aryl 24 16-40% R2 R2 25 40-84% Conjugate trans-A2B-corroles Addition NOH [1,5]H NOH - HX DP N RHN2 NH RHN2 R1 R1 NOH ConjugateO H N Addition [1,5]H E:Z mixture X Na2CO3 NOHX NOHX - HX 1 DP R - HX 1 N HN NH HN R R1 2 R1 2 NOHX O H R R N X E:Z mixture 23 X Na2CO3 X X 1 DP R - HX 1 O OH - HX R 2 NH HN2 X Hetero-Diels-Alder N NHRHN 1,2-Oxazine N R X 23 Reaction H ring-opening DP R1O X reaction R1OH X Anti Oxime - HX NH HN Hetero-Diels-Alder N NH HN 1,2-Oxazine N Reaction H ring-openingHON R1 2 R R1 X reaction R1 X Anti Oxime

DP O HONNH HNR1 NHR2HN N via Conjugate Addition or R2 R2 Hetero-Diels-Alder NH HN R1 DPReaction O HN NH HN NH N via Conjugate Addition or R2 24 R2 Hetero-Diels-Alder NH HN R1 Reaction Scheme 9. Synthesis of oxime-containing trans-A2B-corroles based on the reactivity of nitrosoalkenes toward dipyrromethanes. 24

SchemeScheme 9. Synthesis 9. Synthesis of oxime-containingof oxime-containingtrans trans-A-A22B-corroles based based on on the the reac reactivitytivity of ofnitrosoalkenes nitrosoalkenes towardtoward dipyrromethanes. dipyrromethanes. Molecules 2020, 25, 3450 8 of 39 Molecules 2020, 24, x 8 of 39

3. Functionalization Functionalization at at the the Inner Inner Core and Peripheral Positions of Corroles In addition addition to to the the synthesis synthesis of of new new corrole corrole deriva derivatives,tives, the the functionalization functionalization of ofthe the basic basic core core of corrolesof corroles is another is another aspect aspect that that has has been been largely largely us useded for for the the modulation modulation of of their properties. This includes the the introduction introduction of of different different metals and li ligandsgands in the internal cavity of the corrole or the introduction of functionalities, side chains oror heterocycles,heterocycles, onon thethe corrole’scorrole’s periphery.periphery. Gross and and coworkers coworkers explored explored the the influence influence of ofthe the presence presence of trifluoromethyl of trifluoromethyl groups groups in the in structurethe structure of phosphorus of phosphorus corroles corroles as photocatalysts as photocatalysts [44]. The [ 44authors]. The develope authorsd several developed strategies several to functionalizestrategies to functionalizethe phosphorus(V) the phosphorus(V) tri(pentafluorop tri(pentafluorophenyl)corrolehenyl)corrole (26) in order (to26 )obtain in order a library to obtain of complexesa library of with complexes different with numbers different of CF numbers3 substitutions. of CF3 substitutions. Mixtures of monosubstituted Mixtures of monosubstituted corroles were obtainedcorroles werevia direct obtained electrophilic via direct electrophilicCF3 incorporation CF3 incorporation using FSO2CF using2CO2 FSOMe 2andCF 2copperCO2Me iodide. and copper The mono-CFiodide.3 The-substituted mono-CF corrole3-substituted 27 could corrole also27 becould obtained alsobe in obtained 50% yield in 50%carrying yield carryingout the trifluoromethylationout the trifluoromethylation with 5-(trifluorometh with 5-(trifluoromethyl)dibenzothiopheniumyl)dibenzothiophenium tetrafluoroborate tetrafluoroborate and andN- methylmorpholineN-methylmorpholine (NMM) (NMM) (Scheme (Scheme 10). The10). reaction The reaction of corrole of corrole 27 with27 FSOwith2CF2 FSOCO22Me/CuICF2CO afforded2Me/CuI theafforded bis-CF the3-substituted bis-CF3-substituted derivative derivative 28 in 10%28 yield.in 10% On yield. the Onother the hand other, the hand, synthesis the synthesis of corroles of corroles with morewith morethan thantwo twoCF3 CFgroups3 groups required required initial initial bromination bromination leading leading to to 2,3,8,17,18-pentabrominated derivatives, followed followed by by treatment treatment with with the the trifluoromethylating trifluoromethylating reagent reagent (FSO (FSO2CF22COCF2Me/CuI).CO2Me/CuI). The DFTThe DFTanalysis, analysis, electrochemistry electrochemistry and and photophysical photophysical measurements measurements reveal reveal that that compounds compounds with with a β 3 higher number of β-CF-CF33 groupsgroups are are the the best photocatalysts fo forr the bromination of phenol, toluene and benzene.

CF3 BF4 CF3 C6F5 4 + C6F5 C6F5 6 5 S+ 6 5 6 5

F FSO CF CO Me N F N N F N FSO2CF2CO2Me N F N P C F NMM, DMF C F P C F CuI, DMF C F P C F C6F5 C6F5 C6F5 C6F5 C6F5 C6F5 6 5 6 5 rt F 100 ˚C, 10 h 6 5 F N F N rt N F N 100 ˚C, 10 h N F N

F3C F3C CF F3C F3C CF3 26 27 50% 28 10% 26 27 50% 28 10% β Scheme 10.10. IntroductionIntroduction of ofCF CF3 3 substituentssubstituents at at β-positions-positions of of phosphorus(V) tri(pentafluorophenyl)corrole.tri(pentaﬂuorophenyl)corrole.

The same authors described the synthesis of tris- (30a) and tetra-CF3 substituted (30b) gallium The same authors described the synthesis of tris- (30a) and tetra-CF3 substituted (30b) gallium corrole complexes bearing four bromine atoms at beta-positions (Scheme 11)[45]. A red shift was corrole complexes bearing four bromine atoms at beta-positions (Scheme 11) [45]. A red shift was observed in the uv-vis absorption and emission spectra going from the non-brominated corroles to observed in the uv-vis absorption and emission spectra going from the non-brominated corroles to the tetra-brominated derivatives. Moreover, an increased reduction potential was observed, resulting the tetra-brominated derivatives. Moreover, an increased reduction potential was observed, resulting 30 30b in an enhancement performance of of corroles corroles 30, especially corrole 30b,, regarding the photocatalyticphotocatalytic bromide-to-bromine conversion when comparedcompared withwith octabrominated galliumgallium corroles.corroles.

Scheme 11. Tetra-bromination of tris- and tetra-CF3 substituted galium corrole complexes. Scheme 11. Tetra-brominationTetra-bromination of tris- and tetra-CF3 substitutedsubstituted galium galium corrole corrole complexes.

Gross and Zhao also described the synthesis and photophysical properties of fluorinated phosphorus corrole complexes 32 and the corresponding β-iodo-substituted derivatives 34 [46]. The preparation of complexes 32 was achieved in quantitative yield by the axial hydroxyl ligand exchange Molecules 2020, 25, 3450 9 of 39

Gross and Zhao also described the synthesis and photophysical properties of fluorinated Molecules 2020, 24, x 9 of 39 phosphorus corrole complexes 32 and the corresponding β-iodo-substituted derivatives 34 [46]. Theof complexes preparation 31 ofwith complexes fluorides,32 uponwas achievedreaction with in quantitative aqueous hydrofluoric yield by the acid axial (Scheme hydroxyl 12). ligand The exchangesynthesis of complexescorrole complexes31 with fluorides,34 required upon the reactioniodination with of aqueouscomplexes hydrofluoric 31 with N-iodosuccinimide acid (Scheme 12). The(NIS) synthesis to give of corroletetra-iodo complexes corrole34 complexesrequired the 33 iodination, whose ofsubsequent complexes 31treatmentwith N-iodosuccinimide with aqueous (NIS)hydrofluoric to give tetra-iodoacid afforded corrole the complexestarget molecules33, whose in high subsequent yields (85–90%). treatment The with presence aqueous of hydrofluoric the iodine acidatoms aff ordedred-shifts the targetthe absorption molecules inby high 16–19 yields nm, (85–90%). and the absorption The presence of of the the Q iodine band atoms (589 red-shiftsnm) is more the absorptionintense. Corrole by 16–19 complexes nm, and 32 the exhibit absorption emission of the bands Q band between (589 nm) 525 is more and intense.700 nm, Corrole while complexesthe iodine 32complexesexhibit emission34 have emission bands between bands 525at ca. and 796 700 nm nm, indica whileting the that iodine these complexes emit phosphorescence.34 have emission The bandsfluorescence at ca. 796 quantum nm indicating yields and that lifetimes these emit decrease phosphorescence. drastically with The fluorescencethe addition quantumof iodine yieldsatoms. andOn lifetimesthe other decrease hand, the drastically singlet oxygen with the quantum addition yields of iodine of the atoms. iodine-containing On the other hand, complexes the singlet 34 (60–71%) oxygen quantumwere higher yields than of those the iodine-containing observed for the complexesnon-iodinated34 (60–71%) complexes were 32 higher(46–49%). than These those experimental observed for theresults non-iodinated are in agreement complexes with32 DFT(46–49%). and TDDFT These experimentalcomputational results calculations are in agreement [47,48] performed with DFT with and TDDFTnon-substituted computational and iodine calculations substituted [47 phosphorus,48] performed corrole with complexes. non-substituted The results and iodinedemonstrated substituted that phosphorusiodine-substituted corrole phosphorus complexes. Thecorrole results complexes, demonstrated such that as iodine-substituted34, are good candidates phosphorus to corroleact as complexes,photosensitizers such asin 34photodynamic, are good candidates therapy. to act as photosensitizers in photodynamic therapy.

Scheme 12. Axial ligand exchange and iodina iodinationtion of phosphorus corroles.

Catalytic water splitting via oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) are are electrochemical electrochemical processes processes that that produce produce oxygen oxygen (O2 (O) and2) and hydrogen hydrogen (H2), (H respectively,2), respectively, and andconstitute constitute an interesting an interesting strategy strategy for the for conversi the conversionon of renewable of renewable energy energy into chemical into chemical energy energy with withapplications applications in fuel in fuelcells cells and and metal–air metal–air batteries. batteries. In Inthis this context, context, the the bis-aminophenyl-substituted bis-aminophenyl-substituted cobalt(III) corrole corrole 3636 waswas synthesized synthesized in in order order to to evaluate evaluate its its capability capability to toact act as an as anelectrocatalyst electrocatalyst for forOER OER and HER and HER(Scheme (Scheme 13) [49]. 13 Corrole)[49]. 12a Corrole was synthesized12a was synthesized in high yield in (51%) high via yield HCl-catalyzed (51%) via HCl-catalyzedcondensation of condensation dipyrromethene of dipyrromethene 11 with pentafluorobenzaldehyde11 with pentafluorobenzaldehyde and converted and convertedinto bis- intoaminophenyl-corrole bis-aminophenyl-corrole 35 through35 throughthe SnCl2 the/HCl SnCl reduction2/HCl reduction in the nitro in thegroups. nitro Reacting groups. the Reacting free-base the free-basecorrole 35 corrole with Co(OAc)35 with2·4H Co(OAc)2O in refluxing4H O in pyridine, refluxing cobalt(III) pyridine, corrole cobalt(III) complex corrole 36 complexwas obtained36 was in 2· 2 obtained81% yield. in It 81% was yield. demonstrated It was demonstrated that this aminop that thishenyl-substituted aminophenyl-substituted cobalt(III) cobalt(III)corrole acts corrole as a actsbifunctional as a bifunctional electrocatalyst electrocatalyst for the oxygen for the and oxygen hydrogen and hydrogen evolution evolution reactions. reactions. The strong The electron- strong electron-withdrawingwithdrawing pentafluorophenyl pentafluorophenyl group present group on present the corrole on the ring corrole was ring associated was associated with the with shift the in shiftthe redox in the process redox process towards towards the anodic the anodic direction direction and and being being responsible responsible for for the the HER HER performance, performance, whereas the increase in basicity due to the amin aminophenylophenyl group was associated with the improvement in the OER activity. Molecules 2020, 25, 3450 10 of 39

Molecules 2020, 24, x 10 of 39

F F F F F F F F 1. F CHO

F F F F SnCl2/HCl F F HCl, H O/MeOH MeCN/DCM (2:1) DP 11 2 2. DDQ, CHCl 3 N HN reflux, 3 h N HN

O2N NO2 H2N NH2 NHHN NHHN

12a 51% 35 55% F F F

Co(OAc)2 4H2O F F Py, 100 ºC 15 min Py N N Co H2N NH2 N N Py

36 81%

SchemeScheme 13. SynthesisSynthesis of ofbis-aminophe bis-aminophenyl-substitutednyl-substituted Co(III) Co(III) transtrans-A2-AB 2corroleB corrole (where (where A A= p=- aminophenylp-aminophenyl and and B = B pentafluorophenyl).= pentaﬂuorophenyl).

TheThe introduction introduction of ofaryl aryl and andalkyl alkyl groups groups in the β in-position the β-position of the meso of-triarylcorrole the meso-triarylcorrole complexes iscomplexes a topic of interest, is a topic since of it interest, can lead since to significant it can lead changes to signiﬁcant in their spectroscopic changes in and their electrochemical spectroscopic properties.and electrochemical Thus, Paolesse, properties. Smith Thus,and coworkers Paolesse, Smithapplied and the coworkersStille reaction applied to introduce the Stille aryl reaction and ethynylto introduce groups aryl at β and-positions ethynyl of silver groups corrole at β-positions complex 37 of [50]. silver Thus, corrole the reaction complex of 37corrole[50]. 37 Thus,with tributylphenylthe reaction of corroletin or37 withtributylethynyl tributylphenyl tin tin orderivatives tributylethynyl in tinpres derivativesence of inpalladium presence tetrakis(triphenylof palladium tetrakis(triphenylphosphine)phosphine) gave β-aryl silver gave corroleβ-aryl complex silver corrole 38 incomplex high yields,38 in as high well yields, as 3,17- as diethynyl-substitutedwell as 3,17-diethynyl-substituted and 3,17-di(arylethynyl)-substituted and 3,17-di(arylethynyl)-substituted silver corrole silver complexes corrole complexes39 (54–92%)39 (Scheme(54–92%) 14). (Scheme The introduction 14). The introduction of acetylenic of moieties acetylenic is moietiesparticularly is particularly interesting interestingsince it opens since the it possibilityopens the possibilityto explore to “click” explore reactions “click” reactions as a route as a routeto corrole-based to corrole-based materials/conjugates. materials/conjugates. β- Ethynyl/arylethynylβ-Ethynyl/arylethynyl silver silver corrole corrole complexes complexes 39 39exhibitexhibit red red shifts shifts (ca. (ca. 20 20nm) nm) of the of the B and B and Q bands Q bands in thein the absorption absorption spectra spectra when when compared compared with with the the co correspondingrresponding unsubstituted unsubstituted or or halogenated halogenated silver silver corroles.corroles. DFT calculations cancan assignassign thethe clearclear impact, impact, especially especially on on the the Q Q bands, bands, of of the the conjugation conjugation of ofthe theβ-ethynyl β-ethynyl/arylethynyl/arylethynyl units units with thewith corrole the corroleπ-system, π-system, made possible made bypossible the coplanar by the orientation coplanar orientationof the acetylenic of the groupsacetylenic at thegroups beta-positions at the beta-pos withitions the corrole with the macrocycle. corrole macrocycle. The shift The in the shift B andin the Q Bbands and Q towards bands lowertowards energies lower wasenergies more was pronounced more pronounced for p-nitrophenylethynyl for p-nitrophenylethynyl derivative derivative39a. This 39aincrease. This in increase the absorption in the withinabsorption the therapeuticwithin the windowtherapeutic (650–800 window nm) (650–800 points to thenm) applicability points to the of applicabilitythis compound of this in photodynamic compound in therapy.photodynamic therapy. Molecules 2020, 25, 3450 11 of 39

Molecules 2020, 24, x 11 of 39

Scheme 14. 14. SynthesisSynthesis of 3,17- of 3,17-diphenyldiphenyl silver silver meso-mesoarylcorrole-arylcorrole complex complex and 3,17-di and 3,17-diethynyl-ethynyl- 3,17- di(arylethynyl)3,17-di(arylethynyl) silver silver meso-mesoarylcorrole-arylcorrole complexes. complexes.

Truxene-corrole 41 and the truxene-bridged BODIPY-corrole dyad 42 were obtained from the reaction of corrole 40 with a truxenetruxene derivative or with the truxene-BODIPYtruxene-BODIPY derivative, as outlined in Scheme 15 [[51].51]. Truxene-bridged Truxene-bridged BODIPY-corrole BODIPY-corrole dyad dyad 42 shows strong and broad absorption between 300 and 676 nm, i.e., the combination of the BODIPY and corrole chromophores allowed to improve the uv-vis absorption characteristics of the corrole core, with their use as photosensitizers in mind. The The dyad showed fast singlet–singlet energy energy transfer transfer from from BODIPY to to corrole, resulting in a triplet state with characteristics (energy (energy and and lifetime) that that are are more adequate to achieve an efficient eﬃcient energy transfer transfer to to oxygen, oxygen, which which results results in in a higher a higher singlet singlet oxygen oxygen photosensi photosensitizingtizing ability ability (70% (70% for 42for) when42) when compared compared with with the corresponding the corresponding corrole corrole (58%). (58%). Moreover, Moreover, when whenthe dy thead is dyad used is as used triplet as triplet photosensitizer for triplet triplet annihilation upconversion, with red excitation at 589 nm, photosensitizer for triplet−triplet− annihilation upconversion, with red excitation at 589 nm, the upconversionthe upconversion emission emission intensity intensity is higher is higher than thanthe corrole the corrole itself itselfand the and upconversion the upconversion quantum quantum yield yield(2.57%) (2.57%) increases increases by ca. by 2-fold. ca. 2-fold. The Thecombination combination of BODIPY of BODIPY and and corrole corrole results results in in a a dyad dyad with improved photophysical properties toto bebe usedused asas aa photosensitizerphotosensitizer forfor PDT.PDT. Molecules 2020, 25, 3450 12 of 39 Molecules 2020, 24, x 12 of 39

CHO Br F F F CHO O O B F F

NH N Br

Pd(PPh3)4 NH HN F F F F Na CO N HN 2 3 THF, Ar F F F F Br NHHN F F F F F F 41 24% 40 F F F F CHO

F F Truxene-BODIPY derivative N Pd(PPh3)4 NH Na2CO3 THF, Ar NH HN

F F

F F F 42 32% N N B F F

SchemeScheme 15. 15. SynthesisSynthesis of of a a truxene-corrole truxene-corrole derivative derivative and and a a truxene-bridged truxene-bridged BODIPY-corrole BODIPY-corrole dyad. dyad.

GhoshGhosh andand coworkerscoworkers described described the synthesisthe synthesis of meso of-pyrrole–appended meso-pyrrole–appended isocorroles isocorroles via oxidative via oxidativecoupling ofcoupling corroles of with corroles pyrrole. with The pyrrole. treatment The of treatment triarylcorroles of triarylcorroles43 with an excess 43 with of pyrrolean excess in theof pyrrolepresence in of the DDQ presence gave 5-isocorroles of DDQ gave44 and5-isocorroles 10-isocorroles 44 and45 (Scheme10-isocorroles 16)[52 45]. 5-(Scheme Isocorroles 16) 44[52].were 5- Isocorrolesisolated in higher44 were yields isolated (30–56%) in higher than yields the isomeric(30–56%) 10-isocorroles than the isomeric45 (2–5%). 10-isocorroles The pyrrole-appended 45 (2–5%). The pyrrole-appendedisocorroles could be isocorroles further complexed could be with further Cu(II) comple in moderatexed with yield Cu(II) by reactingin moderate with yield copper(II) by reacting acetate. withSingle-crystal copper(II) X-ray acetate. structures Single-crystal were reported X-ray struct for twoures of were these reported interesting for macrocycles.two of these interesting The uv-vis macrocycles.spectra of free The base uv-vis isocorroles spectra (44 ofand free45 base) and isocorroles the corresponding (44 and 45 Cu(II)-complexes) and the corresponding (46 and 47 Cu(II)-) show complexesabsorption ( in46 theand NIR 47) region.show absorption The Cu(II) in complexes the NIR region. exhibit The more Cu(II) signiﬁcant complexes red-shifted exhibit spectra, more significantrelatively, tored-shifted the free bases spectra, for both relatively, Soret and to Qthe bands. free bases The most for bo signiﬁcantth Soret shiftand wasQ bands. observed The for most the significantstrong Q bands, shift was which observed appear for broad the and strong double-humped Q bands, which at about appear 650–725 broad nm and in double-humped the case of the free at aboutbases, 650–725 whereas nm the in Cu the complexes case of the alsofree bases, exhibit wh double-humpedereas the Cu complexes Q bands also but exhibit sharper double-humped and red-shifted Qbands bands into but the sharper near-infrared and red-shifted (800–855 bands nm). Theseinto the features near-infrared make the (800–855 free base nm). isocorroles These features and their make Cu thecomplexes free base potential isocorroles agents andfor their biological Cu complexes applications, potential namely, agents as for photodynamic biological applications, agents. namely, as photodynamic agents. Molecules 2020, 25, 3450 13 of 39 Molecules 2020, 24, x 13 of 39 Molecules 2020, 24, x 13 of 39

Ar Ar Ar Ar Ar NH Ar NH N HN DDQ (1 equiv) NH NH N N HN + DDQ (1 equiv) NH NH N + N HN + N + N HN Ar Ar NH DCM Ar Ar Ar H DCM Ar Ar Ar NHHN Ar N HN Ar Ar NHHN 10 equiv Ar N HN NH N 10 equiv NH N X 43 X 43 Ar = 44 30-56% 45 2-5% Ar = X = CF , F, H 44 30-56% 45 2-5% X = CF 3, F, H 5-isocorrole 10-isocorrole Me,3 OMe 5-isocorrole 10-isocorrole Me, OMe Cu(OAc) .H O Cu(OAc) 2.H 2O CHCl /MeOH2 2 CHCl 3/MeOH reflux3 or rt reflux or rt Ar Ar Ar NH Ar NH NH N N NH N N Cu N N Cu Ar N N Ar Ar Ar Cu Ar Ar N N Ar Cu Ar N N N N N N 46 46 47 48-77% 47 48-77% ~5% ~5% Scheme 16. Synthesis of pyrrole-appended meso-triarylisocorroles and the corresponding copper(II) SchemeScheme 16. 16. SynthesisSynthesis of pyrrole-appended of pyrrole-appended meso-triarylisocorrolesmeso-triarylisocorroles and the corresponding and the corresponding copper(II) complexes. complexes.copper(II) complexes.

Ghosh andand coworkers coworkers also also described described the ethefficient efficient synthesis, synthesis, single-crystal single-crystal X-ray structure X-ray structure analyses Ghosh and coworkers also described the efficient synthesis, single-crystal X-ray structure andanalyses photophysical and photophysical properties of properties rhenium(V)-oxo of rhenium(V)-oxo triarylcorroles 48 triarylcorroles(Scheme 17). Macrocycles 48 (Scheme48 were17). analyses and photophysical properties of rhenium(V)-oxo triarylcorroles 48 (Scheme 17). isolatedMacrocycles in high 48 were yields isolated (61–84%) in high by oxidative yields (61–84%) metalation by oxidative of meso-triarylcorroles metalation of meso43 with-triarylcorroles dirhenium Macrocycles 48 were isolated in high yields (61–84%) by oxidative metalation of meso-triarylcorroles decacarbonyl43 with dirhenium in refluxing decacarbonyl decalin (Scheme in refluxing 17)[53 ].decalin The di ff(Schemeerent metallo-triarylcorrole 17) [53]. The different derivatives metallo-48 43 with dirhenium decacarbonyl in refluxing decalin (Scheme 17) [53]. The different metallo- exhibittriarylcorrole very similar derivatives uv-vis spectra48 exhibit despite very bearing similardi uv-visfferent spectrameso-aryl-substituents. despite bearing Rheniumdifferent complexesmeso-aryl- triarylcorrole derivatives 48 exhibit very similar uv-vis spectra despite bearing different meso-aryl- 48substituents.show moderate Rhenium near-infrared complexes phosphorescence 48 show moderate (from near-infraλem =red770 phosphorescence to λem = 788 nm) (from with lifetimesλem = 770 substituents. Rhenium complexes 48 show moderate near-infrared phosphorescence (from λem = 770 betweento λem = 788 56 nm) and with 74 µs lifetimes and quantum between yields 56 and ranging 74 μs fromand quantum 1.07 to 1.52%. yields The ranging dyes from were 1.07 evaluated to 1.52%. as to λem = 788 nm) with lifetimes between 56 and 74 μs and quantum yields ranging from 1.07 to 1.52%. potentialThe dyes opticalwere evaluated oxygen sensors as potential and as sensitizersoptical oxygen in triplet–triplet-annihilation-based sensors and as sensitizers in triplet–triplet- upconversion. The dyes were evaluated as potential optical oxygen sensors and as sensitizers in triplet–triplet- Itannihilation-based was demonstrated upconversion. that ReO corroles It was are demonstrated viable sensitizers that ReO for corroles triplet–triplet-annihilation-based are viable sensitizers for annihilation-based upconversion. It was demonstrated that ReO corroles are viable sensitizers for upconversion,triplet–triplet-annihilation-based covering the orange upconversion, part of the co electromagneticvering the orange spectrum part of (λthe electromagnetic= 590 nm and triplet–triplet-annihilation-based upconversion, covering the orange part of theabs electromagnetic upconversionspectrum (λabs = quantum 590 nm and yield upconversion= 0.16). These quantum features yieldand = 0.16). the These excellent features photostability and the excellent of the spectrum (λabs = 590 nm and upconversion quantum yield = 0.16). These features and the excellent rhenium(V)-oxophotostability of corrolesthe rhenium(V)-oxo48 make them corroles good 48 candidates make them to good be used candidates as sensitizers to be used in photodynamic as sensitizers photostability of the rhenium(V)-oxo corroles 48 make them good candidates to be used as sensitizers therapyin photodynamic [54]. therapy [54]. in photodynamic therapy [54].

Ar Ar Ar Ar

N HN [Re2(CO)10] N O N N HN [Re2(CO)10] N O N Ar Ar decalin, reflux, 12 h Ar Re Ar Ar Ar decalin, reflux, 12 h Ar Re Ar NHHN N N NHHN N N

X 43 X 48 43 Ar = 48 Ar = X = CF3, F, H 61-84% X = CF3, F, H 61-84% Me, OMe Me, OMe Scheme 17. Synthesis of Re(V)-oxo triarylcorroles. SchemeScheme 17. 17. SynthesisSynthesis of of Re(V)-oxo Re(V)-oxo triarylcorroles. triarylcorroles.

Cobalt(III) corroles 50, substituted at the 10-meso-phenyl position by an electron-withdrawing or Cobalt(III)Cobalt(III) corroles corroles 5050,, substituted substituted at at the the 10- 10-mesomeso-phenyl-phenyl position position by by an an electron-withdrawing electron-withdrawing or or electron-donating group, were prepared in high yields (62–70%) by metalation of the corresponding electron-donatingelectron-donating group, group, were were prepared prepared in in high high yi yieldselds (62–70%) (62–70%) by by metalation metalation of of the the corresponding corresponding free base corroles 49 with cobalt acetate in the presence of triphenylphosphine (Scheme 18) [55]. These freefree base base corroles corroles 4949 withwith cobalt cobalt acetate acetate in the in presence the presence of triphenylphosphine of triphenylphosphine (Scheme (Scheme 18) [55]. 18 These)[55]. corroles act as electrocatalysts in hydrogen evolution reactions. Showing high stability under corrolesThese corroles act as actelectrocatalysts as electrocatalysts in hydrogen in hydrogen evolution evolution reactions. reactions. Showing Showing high high stability stability under under electrolysis conditions, complex 50a was more active than 50b and 50c. This suggests that the electrolysis conditions, complex 50a was more active than 50b and 50c. This suggests that the Molecules 2020, 25, 3450 14 of 39

Molecules 2020, 24, x 14 of 39 electrolysis conditions, complex 50a was more active than 50b and 50c. This suggests that the introductionintroduction of suitablesuitable peripheralperipheral substituents is a wayway toto modulatemodulate thethe catalyticcatalytic performanceperformance ofof Co(III) corroles.

X X

Co(OAc)2.4H2O Co(OAc)2.4H2O F F F F F F F F PPh3, DCM F F N N F F N HN F F PPh3, DCM N N N HN rt, 2 h rt, 2 h F Co F F F F Co F F F N N NHHN N N NHHN F F F F F F F F F F F F PPh3 49 3 50a X=CN 50a X=CN 70% 50b 50b X=H 66% 50c X=NMe2 62% 50c X=NMe2 62% Scheme 18. Synthesis of Co(III) trans-A2B triarylcorrole complexes (where A = pentafluorophenyl and Scheme 18. Synthesis of Co(III) trans-A2B triarylcorrole triarylcorrole complexes (where A = pentafluorophenylpentaﬂuorophenyl and B = phenylphenyl or pp-substitutedphenyl).-substitutedphenyl).

Aiming to develop photocatalysts, the synthesissynthesis of antimony(III) corrole complexes 51 and (oxo)antimony(IV)(oxo)antimony(IV) corrolecorrole complexes complexes52 was52 was described described by the by group the ofgroup Kar[ 56of]. Kar The Sb(III)[56]. The complexes Sb(III) 51complexeswere obtained 51 were in obtained good yields in good (85–86%) yields by(85–86%) the metalation by the metalation of the corresponding of the corresponding free base free corroles base withcorroles antimony(III) with antimony(III) chloride in pyridine.chloride Thein oxidationpyridine. with The iodoxobenzene oxidation with in dichloromethane iodoxobenzene gave in thedichloromethane (oxo)antimony(IV) gave complexes the (oxo)antimony(IV)52 (Scheme 19 ).complexes The uv-vis 52 spectra (Scheme of complexes 19). The 51uv-visshow spectra split Soret of bandscomplexes at 440–462 51 show nm, split while Soret complexes bands at52 440–462exhibit nm, a single while Soret complexes band at 52 408–413 exhibit nm, a single which Soret indicates band thatat 408–413 complexes nm, which51 are lessindicates symmetric that complexes than 52. Corrole 51 are less complexes symmetric51 and than52 52show. Corrole weak complexes emission 51 at 630–649and 52 show nm and weak a shoulder emission at at 688–711 630–649 nm. nm and a shoulder at 688–711 nm.

Scheme 19.19. Synthesis of corrole antimony(III)antimony(III) complexes via metalation of triarylcorroles and their oxidation into corrole (oxo)antimony(V)(oxo)antimony(V) complexes.complexes.

The A A33-type-type chromyl(V) chromyl(V) triarylcorrole triarylcorrole complexes complexes 53 53werewere prepared prepared from from the corresponding the corresponding free The A3-type chromyl(V) triarylcorrole complexes 53 were prepared from the corresponding free free base corroles in moderate yields by metalation with chromium oxide in refluxing toluene base corroles in moderate yields by metalation with chromium oxide in refluxing toluene (Scheme (Scheme 20)[57]. Even though having high similarity in electronic and structural properties, complexes 20) [57]. Even though having high similarity in electronic and structural properties, complexes 53 53 show some differences in redox potentials, which were associated with the inductive effect of the show some differences in redox potentials, which were associated with the inductive effect of the substituents at the 4 position of the aryl groups. substituents at the 4 position of the aryl groups. MoleculesMolecules 20202020,, 2524,, 3450x 1515 ofof 3939 Molecules 2020, 24, x 15 of 39

Scheme 20. Synthesis of Cr(V) meso-triarylcorrole complexes. Scheme 20. Synthesis of Cr(V) meso-triarylcorrole complexes. Axial ligand exchange is another way to modulate the properties of phosphorus corrole complexes.Axial ligand ligandThe treatment exchange exchange isof anotheris corrole another way dihydroxophosphorus way to modulate to modu thelate properties the (V) propertiescomplex of phosphorus 54of withphosphorus corrole the appropriate complexes. corrole Thecomplexes.alcohol treatment in presence The of treatment corrole of TFA, dihydroxophosphorus of at corrole room temperatdihydroxophosphorusure (V)during complex 10 min,(V)54 complex affordedwith the 54corrole appropriate with complexesthe appropriate alcohol 55 inin presencealcoholhigh yields in of presence TFA,(80–95%) at roomof (Scheme TFA, temperature at 21)room [58]. temperat duringThis acid-cure 10 min, atalyzedduring aﬀorded 10 ligand min, corrole exchangeafforded complexes corrolewas followed 55complexesin high by yieldsuv-vis 55 in 31 (80–95%)highand 31yieldsP-NMR (Scheme (80–95%) spectroscopy 21)[ (Scheme58]. This analyses. 21) acid-catalyzed [58]. The This absorption acid-c ligandatalyzed exchange and emission ligand was exchange followed spectra ofwas by corrole uv-vis followed andcomplexes byP-NMR uv-vis 54 spectroscopyand 5531P-NMR were very analyses.spectroscopy similar. The Fluorescence analyses. absorption The quantum and absorption emission yields and spectra for emission complexes of corrole spectra 55 complexes(28–30%) of corrole are54 slightlycomplexesand 55 lowerwere 54 veryandthan 55 similar.the were ones very Fluorescence observed similar. Fluorescence quantumfor complex yields quantum 54 for (32%). complexes yields This for 55decrease complexes(28–30%) was are 55 slightlyaccompanied(28–30%) lower are slightly thanwith theshorter lower ones observedthanfluorescence the forones complexlifetimes. observed54 The(32%). for study complex This of decreasesix-coordinate 54 (32%). was accompanied Thisphosphorus decrease withcorroles was shorter accompanied included ﬂuorescence derivatives with lifetimes. shorter with Thefluorescenceaxial study ligands of six-coordinatelifetimes.containing The terminal study phosphorus of halides, six-coordinate corroles thiols included and phosphorus alkenyl derivatives groups, corroles with which included axial are ligands derivativesvery containinginteresting with terminalaxialfunctionalities ligands halides, containing since thiols they and terminal alkenylopen thehalides, groups, way whichthiols for arefuandrther very alkenyl interestingfunctionalization groups, functionalities which in areorder very since to interesting they enhance open thefunctionalitiesphotophysical way for further propertiessince functionalization they and open applicability. the in orderway tofor enhance further photophysical functionalization properties in order and applicability.to enhance photophysical properties and applicability.

Scheme 21.21. Acid-catalyzed axial ligand exchange in phosphorus corrolecorrole complexes.complexes. Scheme 21. Acid-catalyzed axial ligand exchange in phosphorus corrole complexes. AA series of of tetragonal tetragonal phosphorus(V) phosphorus(V) cations cations (e.g., (e.g., 57)57 have) have been been prepared, prepared, characterized characterized and andtheir theirAability series ability to of act tetragonal as to Lewis act as acidphosphorus(V) Lewis catalysts acid catalystsin cationsselected in(e.g., chemical selected 57) have transformations chemical been prepared, transformations evaluated characterized (Scheme evaluated and 22) (Schemetheir[59]. Theability 22cationic)[ to59 act]. phosphoracorrolesas The Lewis cationic acid catalysts phosphoracorroles 57 were in selected prepared chemical57 inwere two transformations preparedsteps, starting in two from evaluated steps, the free starting (Scheme base meso- from 22) the[59].triphenylcorrole. free The base cationicmeso phosphoracorroles-triphenylcorrole.Treatment of corrole 57 Treatment were prepared43 ofwith corrole inphenyl two43 steps,with tetrachlorophosphorane phenylstarting tetrachlorophosphorane from the free base or meso-3,5- ortriphenylcorrole.bis(trifluoromethyl)phenyl 3,5-bis(trifluoromethyl)phenyl Treatment tetrac of tetrachlorophosphanehlorophosphanecorrole 43 with in presencephenyl in presence tetrachlorophosphoraneof oftrimethylamine, trimethylamine, followed followed or 3,5- by additionbis(trifluoromethyl)phenyladdition ofof tetrabutylammoniumtetrabutylammonium tetrac triacetoxyborohydride, hlorophosphanetriacetoxyborohy dride,in presence aff ordedafforded theof the hexacoordinatetrimethylamine, hexacoordinate corroles followed corroles56a and56aby 56badditionand, 56b respectively., ofrespectively. tetrabutylammonium The second The second step was triacetoxyborohystep the was treatment the treatmentdride, of corroles ofafforded corroles56 with the 56 [Ph hexacoordinate with3C][B(C [Ph36C][B(CF5)4] whichcorroles6F5)4] which led 56a to tetragonalandled to56b tetragonal, respectively. phosphorus(V) phosphorus(V) The cations second 57 cationsstep. These was 57 cationicthe. These treatment phosphoracorrolescationic of corrolesphosphoracorroles 56 demonstrated with [Ph demonstrated3C][B(C high6F5 tolerance)4] which high towardledtolerance to tetragonal hydroxylic toward hydroxylicphosphorus(V) functionalities functionalities cations and proved 57 .and These to proved be cationic very to e ffibe phosphoracorrolescient very Lewis efficient acid Lewis catalysts demonstrated acid forcatalysts carbonyl high for hydrosilylation, C –H bond functionalization and carbohydrate deoxygenation reactions. tolerancecarbonyl hydrosilylation,toward hydroxylicsp3 Csp 3functionalities–H bond functionalization and proved andto be carb veryohydrate efficient deoxygenation Lewis acid catalysts reactions. for carbonyl hydrosilylation, Csp3–H bond functionalization and carbohydrate deoxygenation reactions. Molecules 2020,, 2524,, 3450x 16 of 39 Molecules 2020, 24, x 16 of 39 R R Ph R R R R Ph R R Ph Ph N HN B(C F ) i Ph ii Ph 6 5 4 Ph N HN Ph N i N ii N N B(C6F5)4 NHHN P Ph Ph Ph N N PN Ph Ph N Ph N NHHN N P Ph N N Ph Ph P N N Ph N 43 X = H H N 43 X = H 56a R = H 20% 57a R = H 74% 56a56b RR == HCF 3 20%24% 57a57b RR == HCF 3 74%86% 56b R = CF3 24% 57b R = CF3 86% i. a) PhPCl4 or 3,5-(CF3)2C6H3PCl4,Et3N, toluene, Δ, 1 h; b) [Bu N][BH(OAc) ], toluene, rt, overnight; i. a) PhPCl4 4 or 3,5-(CF3 3)2C6H3PCl4,Et3N, toluene, Δ, 1 h; ii. [Ph C][B(C F ) ], DCM, rt, 5 min. b) [Bu3 4N][BH(OAc)6 5 4 3], toluene, rt, overnight; ii. [Ph3C][B(C6F5)4], DCM, rt, 5 min. Scheme 22. Synthesis of tetragonal phosporus(V) cations. SchemeScheme 22. 22. SynthesisSynthesis of of tetragonal tetragonal phosporus(V) phosporus(V) cations. cations. The synthesis of iron(II) corrolate 59 has been described, as well as its reactivity towards molecularTheThe synthesissynthesis oxygen ofofand iron(II) iron(II) organic corrolate corrolate electrophiles59 has59 beenhas (Scheme been described, described, 23) as [60]. well asThe as well its reaction reactivity as its ofreactivity towards corrolemolecular towards58 with molecularoxygenstoichiometric and oxygen organic quantities and electrophiles organic of KCelectrophiles (Scheme8 in tetrahydrofuran 23 )[(Scheme60]. The 23) reaction [60].afforded The of corrole reactionthe iron(II)58 withof corrole stoichiometriccorrolate 58 with 59, stoichiometricquantities of KC8 quantities in tetrahydrofuran of KC affinorded tetrahydrofuran the iron(II) corrolateafforded59, K(THF)2[Fe(TPC)]. the iron(II) corrolate This corrole 59, K(THF)2[Fe(TPC)]. This corrole complex8 of divalent iron could be isolated and crystallographically complex of divalent iron could be isolated and crystallographically characterized. Corrole 59 reacts K(THF)characterized.2[Fe(TPC)]. Corrole This 59 corrole reacts complex with carbon of divalent monoxide iron couldto generate be isolated the anion and crystallographically 60, with molecular with carbon monoxide to generate the anion 60, with molecular oxygen, giving the Fe(III) corrole 61, characterized.oxygen, giving Corrole the Fe(III) 59 reactscorrole with 61, andcarbon with monoxide methyl iodine, to generate affording the theanion Fe(IV)-methyl 60, with molecular complex and with methyl iodine, affording the Fe(IV)-methyl complex 62. oxygen,62. giving the Fe(III) corrole 61, and with methyl iodine, affording the Fe(IV)-methyl complex 62. Corrole OC Ph Ph Corrole43 K(THF) OC O Ph Ph 2 Ph 43 N O Ph KC8, THF N N K(THF)CO2 N N Ph Ph Fe N KC8, THF N Fe N N Ph Fe N Ph CDCO3CN N Ph N Ph N N Ph Fe N N N Ph Fe CD CN Ph Ph FeN N Ph 3 N N Ph N 60 N N 59 88% Fe(II) 58 60 CH3I 59 88% Fe(II) O2 58 CHCH3CNI O 3 THFO O H3C CH CN 2 Ph Ph 3 THF O O H3C Ph Ph N N N N Ph Fe Ph Fe N N Ph N Ph N N N Ph Fe N Ph Fe N Ph Ph N N N N 61 62 Fe(III)61 Fe(IV) 62 Fe(III) Fe(IV) Scheme 23. Synthesis of iron corrole anions. Scheme 23. Synthesis of iron corrole anions.

Liang and coworkers described the synthesis and the optical and redoxredox propertiesproperties ofof AA22B type Liang and coworkers described the synthesis and the optical and redox properties3 of A2B type Ir(III) triaryl corroles 64 containingcontaining mesomeso-substituents-substituents with push–pullpush–pull eeffectffect andand AA3 typetype triphenyltriphenyl Ir(III) triaryl corroles 64 containing meso-substituents with push–pull effect and A3 type triphenyl corroles 65,, didifferingffering inin thethe axialaxial pyridinepyridine ligandsligands (Scheme(Scheme 2424))[ [61].61]. TheThe metalationmetalation ofof thethe AA22B type corroles 65, differing in the axial pyridine ligands (Scheme 24) [61]. The metalation of the A2B type corroles 6363 leadingleading toto iridium(III)iridium(III) triaryl triaryl corroles corroles64 64was was carried carried out out upon upon reaction reaction with with [Ir(cod)Cl] [Ir(cod)Cl]2 in2 corroles 63 leading to iridium(III) triaryl corroles 64 was carried out upon reaction with [Ir(cod)Cl]2 thein the presence presence of potassiumof potassium carbonate carbonate in refluxingin refluxin THF,g THF, followed followed by theby the addition addition of pyridine. of pyridine. The The A3 intypeA 3the type Ir(III) presence Ir(III) triphenyl triphenyl of potassium corroles corroles carbonate65 were65 were prepared in preparedrefluxin byg a byTHF, similar a similar followed metalation meta bylation the procedure addition procedure startingof pyridine. starting from from The the Atriphenylthe3 type triphenyl Ir(III) corrole corroletriphenyl43, 43 using ,corroles usingp-substituted p -substituted65 were prepared pyridines pyridines by in a in thesimilar the last last step.meta step.lation The The Ir(III) procedureIr(III) corrolescorroles starting 6464 andand from 65 thedemonstrated triphenyl corrole similar 43 optical, using and p-substituted redox properties, pyridines showingshowing in the interestinglast step. The electrocatalytic Ir(III) corroles properties 64 and 65 in demonstrated similar optical and redox properties, showing interesting electrocatalytic2 properties in oxygen reductionreduction reactions. reactions. The The nature nature of theof themeso meso-substituents-substituents of the of A the2B typeA B corrolestype corroles and the and nature the oxygen reduction reactions. The nature of the meso-substituents of the A2B type corroles and the ofnature the axial of the pyridine axial pyridine ligands ligands of the A of3 typethe A Ir(III)3 type triarylcorroles Ir(III) triarylcorroles modulates modulates their reactivity. their reactivity. nature of the axial pyridine ligands of the A3 type Ir(III) triarylcorroles modulates their reactivity. Molecules 2020, 25, 3450 17 of 39 Molecules 2020, 24, x 17 of 39

R Corrole 43 N HN 1. [Ir(cod)Cl] , K CO F3C CF3 2 2 3 NHHN reflux, N2 2. X-Py 63 X 1. [Ir(cod)Cl]2, K2CO3 reflux, N2 2. Py N Ph N R N Ph N I F3C r N N N N Ph Ir N N N CF3 N

64 7-33% X 65 25-30%

R = C6H5, C6F5, p-MeOC6H4 X = H, CN, OCH 3

2 3 Scheme 24. Synthesis of A2BB type type Ir(III) Ir(III) triarylcorroles and A 3 typetype Ir(III) Ir(III) triarylcorroles. triarylcorroles.

Photophysical studies of six-coordi six-coordinatednated Ir(III) triarylcorroles showed that regardless of the aryl substituent (phenyl, p-methoxyphenyl, p-methylphenyl,-methylphenyl, pp-fluorophenyl-fluorophenyl or or p-trifluoromethylphenyl)-trifluoromethylphenyl) and axial ligand (pyridine,(pyridine, trimethylamine,trimethylamine, isoquinoline,isoquinoline, p-dimethylaminopyridine-dimethylaminopyridine or p-picolinic acid) these complex exhibit low phosphorescence at room temperature. Remarkably, Remarkably, Ir(III) complex of 5,10,15-tris(p-trifluorophenyl)corrole-trifluorophenyl)corrole were were found to be singletsinglet oxygenoxygen sensitizers.sensitizers. The ability to produce singlet oxygen was found to be dependent on the axial coordination.coordination. The complex bearing p-dimethylaminopyridine as as an an axial axial ligand presents a singletsinglet oxygen formation quantum yield of 0.38, while the complex with pyridine as an axial li ligandgand shows a significant significant increase in singlet oxygen formation quantum yield to 0.71. Thus, Thus, iridium iridium corrol corroleses show adequate characteristics to be used as PDT sensitizers [[62].62]. Phosphorus ( (6666--PP),), gallium gallium (66 (66-Ga-Ga) and) and tin tin (66 (-66Sn-Sn) complexes) complexes were were prepared prepared in high in high yields yields (85– (85–87%)87%) by the by reaction the reaction of tri(4-pyridyl)corrole of tri(4-pyridyl)corrole 66 with66 POClwith3 or POCl the3 appropriateor the appropriate metal source metal (Scheme source (Scheme25) [63]. These 25)[63 corrole]. These derivatives corrole derivatives exhibit sharper exhibit and sharper stronger and Soret stronger bands Soretthat the bands free thatbase thecorrole free 66base, the corrole major66 red-shift, the major being red-shift observed being for observed corroles for 66 corroles-Sn and 6666--SnGaand. High66- Gafluorescence. High fluorescence quantum quantumyields were yields found were for complexes found for complexes66-P (0.41) and66-P 66(0.41)-Ga (0.31) and 66 while-Ga (0.31)complex while 66-Sn complex has a fluorescence66-Sn has a quantumfluorescence yield quantum lower than yield that lower observed than that for observed free base for corrole free base 66 (0.12). corrole Complex66 (0.12). 66 Complex-Sn has the66- lowestSn has fluorescencethe lowest fluorescence lifetime (0.2 lifetime ns) and (0.2 free ns) andbase free corrole base 66 corrole the highest66 the highest (3.2 ns), (3.2 whereas ns), whereas complexes complexes 66-P and66-P 66and-Ga66 have-Ga have similar similar fluorescence fluorescence decays, decays, 2.3 2.3and and 2.1 2.1 ns, ns, respectively. respectively. Complex Complex 6666--SnSn hashas the highest singlet oxygen quantum yield (0.71) which, to togethergether with its great great photostability, photostability, makes it an interesting photosensitizer. Molecules 2020, 25, 3450 18 of 39 Molecules 2020, 24, x 18 of 39 Molecules 2020, 24, x 18 of 39 N N N N

POCl3 POCl N HN Py, reflux3 N N N HN 40Py, minreflux N N N N N HO P OH N 40 min HO P OH N NHHN N N N N N NHHN N N

66 66-P 85% 66 N 66-P 85% SnCl2.2H2O GaCl3 N DMF,SnCl reflux2.2H2O Py,GaCl reflux3 DMF, reflux Py,2 hreflux N 2 h N N N N N N Ga N Ga N N N N N Cl N N N N Cl N N Sn N Sn N N N N 66-Ga 87% N N 66-Ga 87%

66-Sn 87% 66-Sn 87% Scheme 25. Synthesis of phosphorus, gallium and tin complexes of meso-tri(4-pyridyl)corrole. SchemeScheme 25.25. SynthesisSynthesis ofof phosphorus,phosphorus, galliumgallium andand tintin complexescomplexes ofofmeso meso-tri(4-pyridyl)corrole.-tri(4-pyridyl)corrole. 4.4. New New Materials Materials Containing Containing Corroles Corroles 4. New Materials Containing Corroles InIn recent recent years, years, new new materials materials co containingntaining the the corrole corrole motif, motif, such such as as nanoparticles, nanoparticles, metal metal organic organic In recent years, new materials containing the corrole motif, such as nanoparticles, metal organic frameworksframeworks (MOFs), (MOFs), covalent covalent organic organic framework framework (COF) (COF) and and porous porous organic organic polymers polymers (POPs), (POPs), have have frameworks (MOFs), covalent organic framework (COF) and porous organic polymers (POPs), have attractedattracted the the interest interest of of the the scientific scientiﬁc community. community. attracted the interest of the scientific community. LuLu and and coworkers describeddescribed thethe synthesis synthesis of of 10-( 10-(p-hydroxyphenyl)corrolep-hydroxyphenyl)corrole copper copper complex complex69 and 69 Lu and coworkers described the synthesis of 10-(p-hydroxyphenyl)corrole copper complex 69 andits corresponding its corresponding self-assembled self-assembled nanostructure nanostructure [64]. [64]. The The free free base base corrole corrole68 was 68 was prepared prepared in 22% in and its corresponding self-assembled nanostructure [64]. The free base corrole 68 was prepared in 22%yield yield by condensation by condensation of 5-phenyldipyrromethane of 5-phenyldipyrromethane (67) and (67p-hydroxybenzaldehyde) and p-hydroxybenzaldehyde in the presence in the 22% yield by condensation of 5-phenyldipyrromethane (67) and p-hydroxybenzaldehyde in the presenceof HCl, followedof HCl, followed by oxidation by oxidation with p-chloranil with p-chloranil (Scheme 26(Scheme). Metalation 26). Metalation of the free of base the corrolefree base68 presence of HCl, followed by oxidation with p-chloranil (Scheme 26). Metalation of the free base corrolewith copper(II) 68 with copper(II) acetate gave acetate theexpected gave the complexexpected69 complexin good 69 yield in good (50%). yield The (50%). copper The corrole copper69 corrole 68 with copper(II) acetate gave the expected complex 69 in good yield (50%). The copper corroleself-assembled 69 self-assembled into large-scale, into large-sc needle-likeale, needle-like nanostructures, nanostructures, with H-aggregate with H-aggregate nature and nature relevant and corrole 69 self-assembled into large-scale, needle-like nanostructures, with H-aggregate nature and relevantintermolecular intermolecularπ-π interactions. π-π interactions. These nanostructures These nanostructures revealed high revealed electric high conductivity, electric conductivity, acting as gas relevant intermolecular π-π interactions. These nanostructures revealed high electric conductivity, actingsensors as with gas se highnsors selectivity with high for selectivity NO2 gas. for NO2 gas. acting as gas sensors with high selectivity for NO2 gas. OH OH OH OH

HO CHO HO CHO Cu(OAc)2 Cu(OAc) 1. HCl, H O/MeOH CHCl /MeOH2 2 N HN 3 N N 2.1. p -ChloranilHCl, H2O/MeOH CHCl3/MeOH N HN N NH HN 2. p-Chloranil NCu NH HN Cu 67 NHHN N N 67 NHHN N N

68 22% 69 50% 68 22% 69 50% SchemeScheme 26.26. SynthesisSynthesis of transof trans-A2B-A corrole2B corrole copper copper complex complex (where A(where= phenyl A and = Bphenyl= p-hydroxyphenyl). and B = p- Scheme 26. Synthesis of trans-A2B corrole copper complex (where A = phenyl and B = p- hydroxyphenyl). Contraryhydroxyphenyl to porphyrins,). where aggregates have been deeply investigated, the aggregation of corrolesContrary has been to porphyrins, less explored. where Nevertheless, aggregates it have has beenbeen demonstrated deeply investigated, that in aqueousthe aggregation media and of Contrary to porphyrins, where aggregates have been deeply investigated, the aggregation of corrolesin biological has been conditions, less explored. hydrophobic Nevertheless, corroles it and has metallocorroles been demonstrated form that nanoparticles in aqueous (NPs) media due and to corroles has been less explored. Nevertheless, it has been demonstrated that in aqueous media and inaggregation biological conditions, processes. Inhydrophobic fact, stable corroles nanoparticles and metallocorroles were prepared form by rapidnanoparticles injection (NPs) of DMSO due to or in biological conditions, hydrophobic corroles and metallocorroles form nanoparticles (NPs) due to aggregationpyridine solutions processes. of tris-pentaﬂuorophenyl In fact, stable nanoparticle corroles were complexes prepared70 (Mby =rapidGa, Alinjection and Au) of inDMSO aqueous or aggregation processes. In fact, stable nanoparticles were prepared by rapid injection of DMSO or pyridine solutions of tris-pentafluorophenyl corrole complexes 70 (M = Ga, Al and Au) in aqueous pyridine solutions of tris-pentafluorophenyl corrole complexes 70 (M = Ga, Al and Au) in aqueous Molecules 2020, 24, x 19 of 39

media (Figure 2). The analysis of uv-vis, IR spectra and DFT calculations of these NPs showed only small changes in comparison to the corresponding monomer, which was attributed to very weak intermolecular interactions in these nanoparticles [65]. Gross and coworkers studied the correlation between the lipophilicity/hydrophilicity of corroles and their metal complexes and their capability to act as anticancer agents. The authors found high affinity of corroles with the very-low-density lipoprotein fraction (VLDL) of human serum and high photocytotoxicity [66]. It was observed that the cytotoxicities increased in the order Ga < Fe < Al < Mn < Sb < Au for the studied corroles [67]. They studied assemblies of NPs of corroles with native serum proteins, soluble in aqueous media, to act as controlled release drug delivery systems. The formulation of NPs using specific proteins enables the targeting cells in which the corresponding Moleculesreceptors2020 are, 25 overexpressed,, 3450 and therefore increases the selectivity of corroles for the targeted 19tissue. of 39 The cellular uptake in DU-145 prostate cancer cells, followed by optical imaging, reveals that transferrin/corrole 70 nanoparticles were internalized, with distribution into the endoplasmic mediareticulum (Figure and2 ).lysosomes, The analysis to ofa greater uv-vis, IRextent spectra by andthe DFTtransferrin-receptor-r calculations of theseich DU-145 NPs showed cells, onlythan smallalbumin/corrole changes in comparison70 NPs. Moreover, to the corresponding the stability monomer, and whichenhanced was attributeduptake properties to very weak of intermoleculartransferrin/corrole interactions 70 NPs indicate in these that nanoparticles these can [be65 applied]. as imaging agents (Figure 2) [67].

F F F F F F F F F F F F F F F F F F N N N N F M F M F F N N N N F F F F F F F F SO3 SO3 70 71 M = 3H, Al, Ga, Mn, Fe, Sb, Au FigureFigure 2.2. Structure ofof metallometallo mesomeso-tri(pentaﬂuorophenyl)corroles.-tri(pentafluorophenyl)corroles.

GrossGallium and corrole-coated coworkers studied zinc oxide the correlation (ZnO) nanopartic betweenles the were lipophilicity prepared/ hydrophilicityby the addition of of corroles corrole and73 to their an metalethanol complexes solutionand of theirzinc capabilityacetate (nanoparticle to act as anticancer precursor). agents. Knoevenagel The authors reaction found highwith acyanoaceticﬃnity of corroles acid was with used the very-low-densityto introduce a monodentate lipoprotein fractionanchoring (VLDL) group of into human acrolein-substituted serum and high photocytotoxicitygallium corrole complex [66]. It was72, leading observed tothat the thetarget cytotoxicities corrole 73 in increased high yield in the (94%) order (Scheme Ga < Fe 27)< Al[68].< TheMn

CH33

O py N N CN N py HO Ga N N H33C CH33 piperidine, CH CN Ga 33 N N H33C CH33 reflux,reflux, 3030 minmin N N

O CN O 72 HO 73 94%94% SchemeScheme 27. 27. KnoevenagelKnoevenagel reaction reaction to introduce to introduce a monode a monodentatentate anchoring anchoring group into group an acrolein- into an acrolein-substitutedsubstitutedsubstituted galliumgallium corrole galliumcorrole complex.complex. corrole complex.

trans meso 75 TangTang and and coworkers coworkers synthesized synthesized-A 2tBransrans-A-A-(4-chlorophenyl)-corrole22B meso-(4-chlorophenyl)-corrole-(4-chlorophenyl)-corroleand the corresponding75 andand thethe cobalt(III)corresponding complex cobalt(III)76 (Scheme complex 28) 76 which (Scheme(Scheme was 28)28) incorporated whichwhich waswas onto incorporatedincorporated graphene ontoonto oxide graphenegraphene (GO) through oxideoxide (GO)(GO)π-π interactions.throughthrough π--π interactions. Theinteractions. gas sensing TheThe ability gasgas sensingsensing of corroles abilityability75 , ofof76 corrolescorrolesand the 75 corrole-functionalized,, 76 andand thethe corrole-functionalizedcorrole-functionalized GO was evaluated. GOGO 76 75 Cobalt(III)was evaluated. complex Cobalt(III)exhibits complex better 76 NO exhibitsexhibits2 gas sensitivity betterbetter NONO than22 gasgas thesensitivitysensitivity corresponding thanthan thethe free-base correspondingcorresponding corrole free-free- ( ), duebase to corrole the presence (75),), duedue of to theto thethe coordination presencepresence ofof metal. thethe coordinationcoordination Likewise, the metal.metal. Co(III)corrole Likewise,Likewise, complex thethe Co(III)corrole functionalized complex GO alsofunctionalizedfunctionalized demonstrated GOGO higheralso demonstrated gas sensitivity higher [69]. gas sensitivity [69].

CH33

Cl Cl

NH HN Co(OAc)22.4H.4H22O 74 1. HCl, H22O/MeOH PPh33,, DCM/MeOHDCM/MeOH + 2. p-Chloranil-Chloranil reflux,reflux, 22 hh N N Cl N HN Co H C CH 3 H C CH 33 3 H33C 33 N N NHHN

CHO PPh33 75 75 76

Scheme 28. Synthesis of trans-A22B 10-(4-chlorophenyl)-5,15-di(4-methylphenyl)-corrole and its Scheme 28.28. Synthesis of transtrans-A-A2B 10-(4-chlorophenyl)-5,15-di(4-methylphenyl)-corrole10-(4-chlorophenyl)-5,15-di(4-methylphenyl)-corrole and itsits cobalt(III)cobalt(III)cobalt(III) complex.complex.complex.

AA simplesimple methodmethod forfor thethe regioselectiveregioselective thiocyanationthiocyanation ofof 5,10,15-triphenylcorrole5,10,15-triphenylcorrole ((4343))) waswaswas developeddeveloped by by Kar’s Kar’s group. group. The The treatment treatment of a solution of a solution of corrole of corrole 43 inin carboncarbon43 in disulfidedisulfide carbondisulfide withwith anan excessexcess with anof excessammonium of ammonium thiocyanate thiocyanate (NH44SCN) (NH at4 SCN)reflux, at gave reflux, the gave β-thiocyanate-thiocyanate the β-thiocyanate corrolecorrole corrole77 inin 40%40%77 in yieldyield 40% yield(Scheme(Scheme (Scheme 29)29) [70].[70]. 29)[ GoldGold70]. Gold nanoparticlesnanoparticles nanoparticles coatedcoated coated withwith with thethe β the-thiocyanate-thiocyanateβ-thiocyanate corrole,corrole, corrole, Au--Au77,- were77were, were preparedprepared prepared byby bythethethe additionaddition addition ofof ofsodiumsodium sodium borohydrideborohydride borohydride tototo aa apremixedpremixed premixed mixturemixture mixture ofof of corrolecorrole and and tetrachloroaurictetrachloroauric acidacidacid (HAuCl(HAuCl(HAuCl44).). TheThe The formationformation formation ofof of AuAu--77-77 waswaswas monitoredmonitored monitored byby by uv-visuv-vis uv-vis spectroscopy,spectroscopy, spectroscopy, startingstarting starting fromfrom from aa solutionsolution a solution ofof ofcorrole corrole 7777 inin in DMF,DMF, DMF, withwith with nono no significantsignificant significant changeschanges changes uponupon upon additionaddition addition ofof of NaBHNaBH NaBH444 butbutbut bothboth both thethe Soret Soret andand QQ bandsbands ofof corrolecorrole underwentunderwent drasticdrastic changeschanges inin intensityintensity uponupon thethe additionaddition ofof thethe HAuClHAuCl44 solution.solution. TheThe finalfinal absorptionabsorption spectraspectra ofof AuAu---7777 showshowshow thethethe presencepresencepresence ofofof thethethe characteristiccharacteristiccharacteristic SoretSoret bandbandband fromfromfrom thethethe corrolecorrole 7777,,, aaa strongstrongstrong plasmonplasmonplasmon resonanceresonanceresonance bandbandband ofofof goldgoldgold nanoparticlesnananoparticles (525(525 nm)nm) andand thethe presencepresence ofof QQ bandsbands (655(655 nm),nm), despitedespite beingbeing significantlysignificantly reduced.reduced. TheThe intensityintensity ofof emissionemission bandsbands isis significantlysignificantlysignificantly reduced,reduced,reduced, goinggoinggoing fromfromfrom corrolecorrolecorrole 7777 tototo AuAu---7777,,, thethethe samesamesame trendtrendtrend observedobservedobserved forforfor thethethe fluorescencefluorescencefluorescence lifetime,lifetime,lifetime, fromfromfrom 3.693.69 toto 1.19 1.19 ns, ns, respectively. respectively. A plausibleA plausible structure structure of gold-corrole of gold-corrole nano-assemblies nano-assemblies was proposed was proposed based based on a face-off binding mode of corrole, which would be possible due to pyrrole–pyrropyrrole–pyrrolele linkagelinkage (lack(lack ofof oneone meso-carbon).-carbon). TheThe Au--77 nanoparticlenanoparticle sizesize isis aboutabout 6.56.5 nmnm andand theythey areare stablestable underunder Molecules 2020, 25, 3450 21 of 39

Molecules 2020, 24, x 21 of 39 onMolecules a face-o 2020ﬀ, 24binding, x mode of corrole, which would be possible due to pyrrole–pyrrole linkage21 (lack of 39 of one meso-carbon). The Au-77 nanoparticle size is about 6.5 nm and they are stable under ambient ambientambient conditions,conditions, whichwhich makesmakes thethe corrolecorrole frframeworkamework anan excellentexcellent stabilizerstabilizer forfor goldgold conditions, which makes the corrole framework an excellent stabilizer for gold nanoparticles. nanoparticles.nanoparticles.

CS , NH SCN CS22, NH44SCN NN HNHN NN HNHN Py,Py, reflux, reflux, 3 3 h h

NHNHHNHN NHNHHNHN NCSNCS SCNSCN 4343 7777 40% 40% NaBH , HAuCl NaBH44, HAuCl44 DMF,DMF, 2.5 2.5 h h

NN HNHN

NHNHHNHN SS SS

Au-77Au-77 AuAu

SchemeScheme 29.29. 29. ThiocyanationThiocyanationThiocyanation ofof mesomeso of-triphenylcorrole-triphenylcorrolemeso-triphenylcorrole andand schematicschematic and schematicrerepresentationpresentation representation ofof gold-corrolegold-corrole of nano-assemblies.gold-corrolenano-assemblies. nano-assemblies.

The synthesis of an organic–inorganic photocatalyst to promote the photodegration of the TheThe synthesissynthesis ofof anan organic–inorganicorganic–inorganic photocatphotocatalystalyst toto promotepromote thethe photodegrationphotodegration ofof thethe pollutantpollutant di-anionicdi-anionic azo-dyeazo-dye AcidAcid BlackBlack 11 waswas describeddescdescribedribed byby ZhuZhu andand coworkers.coworkers.coworkers. ThisThis photocatalystphotocatalyst consists of corrole 78 linked to glycidoxypropyltrimethoxysilane (GPTMS)-modiﬁed TiO2 nanoparticles consistsconsists ofof corrolecorrole 7878 linkedlinked toto glycidoxypropyltrimethoxysilaneglycidoxypropyltrimethoxysilane (GPTMS)-modified(GPTMS)-modified TiOTiO22 (Scheme 30). The corrole-GPTMS/TiO2 nanoparticles 79 demonstrated high photodegradation eﬃciency nanoparticlesnanoparticles (Scheme(Scheme 30).30). TheThe corrole-GPTMS/TiOcorrole-GPTMS/TiO22 nanoparticlesnanoparticles 7979 demonstrateddemonstrated highhigh photodegradationandphotodegradation reusability [71 ]. efficiencyefficiency andand reusabilityreusability [71].[71].

NH NH22

OHOH OO OO TiO Si O ++ HOHO TiO22 OO Si O NN HNHN OO OH HH2NN NHNH2 OH 2 2 GPTMS/TiOGPTMS/TiO2 NHNHHNHN 2

7878 NHNH2 DCMDCM 2 7878 ºC, ºC, 5 5 h h

OHOH NN HNHN O OH HH O OH N NH N NH22 HO TiOTiO2 O Si O HO 2 O Si O NHNHHNHN OO OH OH 7979 Corrole-GPTMS/TiO Corrole-GPTMS/TiO22

Scheme 30. Design of the photocatalyst corrole-GPTMS/TiO2 nanoparticles. SchemeScheme 30.30. DesignDesign ofof thethe photocatalystphotocatalyst corrole-GPTMScorrole-GPTMS/TiO/TiO22 nanoparticles.nanoparticles.

Metal–organicMetal–organic frameworksframeworks (MOF(MOFs)s) areare porousporous crystallinecrystalline materialsmaterials composedcomposed ofof aa three-three- dimensionaldimensional (3D)(3D) networknetwork ofof metal,metal, heldheld inin placeplace byby multidentatemultidentate organicorganic molecules.molecules. ZhangZhang andand coworkerscoworkers developeddeveloped robustrobust corrole-basedcorrole-based MOFsMOFs (e.g.,(e.g., 8484)) usingusing 9-connected9-connected ZrZr66 oror HfHf66 andand corrolecorrole Molecules 2020, 25, 3450 22 of 39

Metal–organic frameworks (MOFs) are porous crystalline materials composed of a

Moleculesthree-dimensional 2020, 24, x (3D) network of metal, held in place by multidentate organic molecules. Zhang22 of and 39 coworkers developed robust corrole-based MOFs (e.g., 84) using 9-connected Zr6 or Hf6 and corrole as the organic linker (Scheme 31)31)[ [72].72]. The The free free base corrole 8181 was prepared in 21% by the reaction of pyrrole pyrrole with with methyl methyl pp-formylbenzoate-formylbenzoate (80 (80) )in in the the presence presence of of HCl, HCl, followed followed by by oxidation oxidation with with p- chloranil.p-chloranil. The The metalation metalation with with FeCl FeCl2 and2 and hydrolysis hydrolysis of of the the ester ester group group afforded aﬀorded the the corrole corrole (e.g., (e.g., 8383)) in good yield. Polycrystalline Polycrystalline [corrole-MOF(Fe)Cl] [corrole-MOF(Fe)Cl] 8484 waswas isolated isolated in in 84% 84% yield from the reaction of corrole 83 with ZrCl 4 inin DMF DMF at at 120 120 °C◦C in in the the presence presence of of acetic acetic acid. acid. This This procedure procedure was was also also applied applied to synthesize other corrole-MOFs, namely, namely, using HfCl 4 asas metal metal source source or or the the free base corrole as a linker. [Corrole-MOF(Fe)Cl][Corrole-MOF(Fe)Cl]84 84was was successfully successfully used used as aas heterogeneous a heterogeneous catalyst catalyst in hetero-Diels-Alder in hetero-Diels- Alderreactions reactions of dienes of dienes with inactivated with inactivated aldehydes. aldehydes.

CO2Me CO2Me

FeCl2.4H2O DMF, reflux, 2 h

N HN N Cl N Fe MeO2C CO2Me MeO2C CO2Me NHHN N N

81 21% 82 80%

1. HCl, H2O/MeOH 2. DCM, p-chloranil KOH 1.3 M THF/MeOH CHO 40 ºC, 24 h N + MeO2C H 80 CO2H

ZrCl4 AcOH, DMF, 120 ºC N Cl N 72 h Fe HO2C CO2H 84 84% N N [Corrole-MOF(Fe)]Cl 83 87% 9-c Zr6 Cluster Corrole linker SchemeScheme 31. SynthesisSynthesis of of a a heterogenous heterogenous catalyst catalyst corrole-metal–organic corrole-metal–organic framework (MOF).

Many of the porous solids, such as MOFs, are notnot stable enough for some applications, due to their being built built through through coordina coordinationtion bonds between the organic ligand and the the metal metal donors. donors. Thus, Thus, to overcome some instability, Porous Organic Polymers (POPs) emerged as as a new class of porous materials, which are built by covalent bonding betweenbetween organic building blocks [[73].73]. The synthesis of POP-CorCo POP-CorCo 8888 andand 9090 cancan be be made made following following two two strate strategies,gies, having having di-iodophenyl di-iodophenyl corrole corrole 86 86as theas the starting starting point point (Scheme (Scheme 32) 32 [74].)[74 ].Corrole Corrole 8686 waswas prepared prepared in in 26% 26% yield yield by by the acid-catalyzed condensation of meso-(p-iodophenyl)dipyrromethane ( 85) with benzaldehyde, followed by oxidation with pp-chloranil.-chloranil. TheThe ﬁrstfirst strategy strategy (via (via 1) 1) to to prepare prepare POP-CorCo POP-CorCo88 is88 the is the reaction reaction between between the freethe basefree basedi-iodophenyl di-iodophenyl corrole corrole86 and 86 the and tetrahedral-shaped the tetrahedral-shaped87 through 87 through the copper-free the copper-free palladium-catalyzed palladium- catalyzedSonogashira Sonogashira cross-coupling, cross-coupling, followed by followed cobalt complexation, by cobalt complexation, leading the leading target POP the intarget 78% POP overall in 78%yield. overall The second yield. methodologyThe second methodology (via 2) involves (via the 2) involves preparation the ofpreparation cobalt corrole of cobalt complex corrole89, protected complex 89by, twoprotected amine by ligands, two amine followed ligand bys, followed the coupling by the reaction coupling to givereaction the to POP-CorCo give the POP-CorCo90 in 70% yield.90 in 70%The POP-CorCoyield. The POP-CorCo90 prepared by90 theprepared two pathways by the two exhibits pathways similar exhibits high permanent similar high porosity permanent and the porosity and the ability to selectively capture or sense carbon monoxide, even in the presence of other gases, such as CO2, O2 and N2. Molecules 2020, 25, 3450 23 of 39 ability to selectively capture or sense carbon monoxide, even in the presence of other gases, such as COMolecules2,O2 2020and, 24 N, 2x. 23 of 39

I Co(OAc)2 NH DMSO 3 MeOH/NH Ph CHO 3 N N N HN 1. H2O, HCl I Co I 2. p-Chloranil I I N N NH HN NHHN 85 H3N 86 26% 89 80%

PdCl2(PPh3)2 PdCl2(PPh3)2 THF/Et N THF/Et N 87 3 87 3 70 ºC 70 ºC Via 1 78% overall Via 2 70%

NH3

H3N Co(OAc)2, DMSO 87 MeOH/NH3

90 88 82% Scheme 32. Synthetic routes to porous organic polymers (POP)-CorCo.

5. Corroles as PDT Agents in Cancer Treatment The chemical, physical and photophysical prop propertieserties of corroles make them valuable photosensitizers for PDT. Therefore,Therefore, the developmentdevelopment of photosensitizers based on the corrole macrocycle hashas attractedattracted the the attention attention of of several several research research groups groups and and some some review review articles articles on this on topic this havetopic beenhave publishedbeen published [9,19, 20[9,19,20,75].,75]. Herein, Herein, the compilation the compilation of the of latest the latest advances advances is presented. is presented. Mack and coworkers described the synthesis and characterization of two Sn(IV) corroles with thien-2-yl (92) and phenyl (93) substituents at meso-positions and their photodynamic activity against breast cancercancer cells cells (MCF-7) (MCF-7) [76 [76].]. The The condensation condensation of pyrrole of pyrrole withthe with appropriate the appropriate aldehyde aldehyde in presence in ofpresence HCl followed of HCl followed by oxidation by oxidation with p-chloranil with p-chloranil gave corroles gave corroles91 and 43 91. and Sn(IV) 43. triarylcorrolesSn(IV) triarylcorroles92 and 9392 andwere 93 obtained were obtained via metalation via metalation with SnCl with2 SnClin reﬂuxing2 in refluxing DMF DMF (Scheme (Scheme 33). Sn(IV)33). Sn(IV) tris-thyen-2-yl tris-thyen- corrole2-yl corrole92 shows 92 shows an absorptionan absorption spectrum spectrum red red shift shif comparedt compared with with the the phenyl phenyl analogue analogue 9393,, whichwhich leads to aa betterbetter absorptionabsorption inin thethe therapeutictherapeutic window.window. Along with the absence of aggregationaggregation in solution, tin(IV) complexes 92 and 93 have high values of singletsinglet oxygen quantum yields (0.87 and 0.54, respectively) and triplet state lifetimes of 31 and 50 µμs, respectively. The cellular uptake of both corrole complexescomplexes in in MCF-7 MCF-7 cancer cancer cells reachedcells reached a peak a after peak 24 hafter of incubation, 24 h of withincubation, the concentration with the ofconcentration92, two times of higher 92, two than times93 .higher The photocytotoxicity than 93. The photocytotoxicity assays of Sn(IV) assays corroles of 92Sn(IV)and corroles93 show 92 values and of93 ICshow50 of values 3.2 and of IC 13.150 ofµM 3.2 against and 13.1 MCF-7 μM against cancer MCF-7 cells after cancer irradiation cells after and irradiation non-toxicity and non-toxicity in the dark. Thein the higher dark. photocytotoxicity The higher photoc of corroleytotoxicity complex of corrole92 was complex attributed 92 towas its highattributed singlet to oxygen its high quantum singlet yieldoxygen and quantum lipophilicity. yield and lipophilicity.

Molecules 2020, 24, x 24 of 39 Molecules 2020, 25, 3450 24 of 39 Molecules 2020, 24, x 24 of 39 R R

CHO R R R 1. HCl, H2O/MeOH N HN SnCl2.2H2O, DMF N Cl N CHO+ R 2. p-Chloranil R reflux, 1 h R Sn R 1. HCl, H2O/MeOH R N HN SnCl2.2H2O, DMF N Cl N + NHHN 70-80% N N 2. p-Chloranil reflux, 1 h Sn N R R R R H NHHN 70-80% N N N H 91 R = 92 R = S S 9143 RR == Ph 9293 RR == Ph S S Scheme 33. Synthesis43 R = Ph of Sn(IV) meso-triarylcorroles. 93 R = Ph Scheme 33. Synthesis of Sn(IV) meso-triarylcorroles. Mono-hydroxyphenyl metallocorroles 95a–c have been prepared from the corresponding free 95a c baseMono-hydroxyphenyl corroles 94a–c by complexation metallocorroles metallocorroles with 95airon(III),– –havec have beenmangan been prepared preparedese(III) from and from the copper(III) correspondingthe corresponding in high free yields basefree 94a c corrolesbase(Scheme corroles 34)– andby94acomplexation –theirc by DNA-bindingcomplexation with iron(III), abilitywith iron(III),manganese(III) and phot manganodynamic andese(III) copper(III) antitumor and copper(III) in activity high yields were in (Schemehigh evaluated yields 34) and(Scheme[77]. their The 34) DNA-bindingDNA and binding their DNA-binding abilitystudies and indicate photodynamic ability that andmetallocorroles phot antitumorodynamic activity94a –antitumorc bind were to evaluated CT-DNAactivity were [77by]. an evaluated The external DNA binding[77].binding The studiesmode, DNA indicatewithbinding the thatstudiesortho metallocorroles-hydroxyphenyl indicate that94a metallocorroles metallocorroles–c bind to CT-DNA 94a (95a–c by) bindbeing anexternal to the CT-DNA ones binding with by less mode,an externalbinding with thebindingaffinity.ortho -hydroxyphenylmode,Cytotoxicity with the assays ortho metallocorroles -hydroxyphenylwere performed (95a) metallocorroles beingusing thecarcinoma ones with(95a A549) less being (lung), binding the onesHepG2 aﬃ nity.with (liver), Cytotoxicityless binding MCF-7 assaysaffinity.(breast), were CytotoxicityDU145 performed (prostate) assays using cell were carcinoma lines performed and A549 one normal (lung),using HepG2carcinomacell line, (liver), GES-1 A549 MCF-7 (gastric (lung), (breast), epithelial).HepG2 DU145 (liver), Under (prostate) MCF-7 dark cell(breast),or light lines conditions,DU145 and one (prostate) normal all thecell cellmetallocorroles line, lines GES-1 and one (gastric are normal non-toxic epithelial). cell forline, the UnderGES-1 normal dark(gastric cells or lightGES-1epithelial). conditions, and onlyUnder Cu all dark-95b the metallocorrolesorwas light slightly conditions, cytotoxic are non-toxicall against the metallocorroles for DU the145 normal cells. Onare cells thenon-toxic GES-1 other and hand, for only the manganese(III) Cunormal-95b wascells slightlyGES-1 and copper(III) and cytotoxic only corrolesCu against-95b DU145wasrevealed slightly cells. weak cytotoxic On cytotoxicity the other against hand, against DU manganese(III)145 A549, cells. HepG2 On the and otherand copper(III) MCF-7 hand, manganese(III)when corroles compared revealed and with copper(III) weak iron(III) cytotoxicity corroles,corroles againstrevealedin the absence A549, weak HepG2 orcytotoxicity presence and MCF-7 ofagainst light. when A549,In addition, compared HepG2 Fe an with-95cd MCF-7 iron(III)shows when a corroles, significant compared in theph otocytotoxicitywith absence iron(III) or presence corroles, against of µ light.inA549 the Incellsabsence addition, with or IC presenceFe50 -of95c 30shows μ ofM, light. being a signiﬁcant In noncytotoxic addition, photocytotoxicity Fe -in95c the shows dark. a againstThe significant studies A549 phdemonstrated cellsotocytotoxicity with IC50 thatof against 30Fe-95cM, being noncytotoxic in the dark. The studies demonstrated that Fe-95c induced the A549 cell apoptosis A549induced cells the with A549 IC50 ofcell 30 apoptosis μM, being and noncytotoxic necrosis, inhigh the dark.cellular The ROS studies level demonstrated and disruption that Feof -95cthe andinducedmitochondrial necrosis, the highA549 membrane cellular cell apoptosis potential. ROS level and and necrosis, disruption high of the cellular mitochondrial ROS level membrane and disruption potential. of the mitochondrial membrane potential. OH OH

OH OH FeCl2, DMF, 130 ˚C, 4 h or Mn(OAc) , MeOH, 60 ˚C, 4 h F F F F 2 F F F F N HN FeCl2, DMF, 130 ˚C, 4 h or Cu(OAc)2, DCM/MeOH, rt, 4 h N N or Mn(OAc)2, MeOH, 60 ˚C, 4 h F F F F F F F F M F F F N HN or Cu(OAc) , DCM/MeOH, rt, 4 hF N N NHHN 2 N N F M F F F F F F F F F F F NHHN N N F F 94a ortho-OH F F F 95aF ortho-OH M = Fe, Mn,F CuF 94b meta-OH 95b meta-OH 55-90% 94a ortho-OH 95a ortho-OH 94c para-OH 95c para-OH M = Fe, Mn, Cu 94b meta-OH 95b meta-OH 55-90% 94c para-OH 95c para-OH SchemeScheme 34.34. Synthesis ofof mono-hydroxymono-hydroxy metallocorroles.metallocorroles. Scheme 34. Synthesis of mono-hydroxy metallocorroles. Tri-hydroxyTri-hydroxy corrole corrole96 96was was prepared prepared in high in yieldhigh (79%) yield from (79%) corrole from94c corroleby aromatic 94c by nucleophilic aromatic substitutionnucleophilicTri-hydroxy usingsubstitution corrole 2-aminoethanol using96 was 2-aminoethanol asprepared the nucleophile, in ashigh the followed yieldnucleophile, (79%) by complexation fromfollowed corrole by withcomplexation 94c gallium(III) by aromatic with to producenucleophilicgallium(III) the metallocorroletosubstitution produce the using97 metallocorrolein 2-aminoethanol 85% yield (Scheme 97 inas 85%the 35 )[ nucleophile,yield78]. Similarly(Scheme followed to35) mono-hydroxy [78]. by Similarlycomplexation complexes to mono- with 95gallium(III)hydroxy, corroles complexes 96to andproduce97 95established, corroles the metallocorrole 96 outside and 97 bindingestablished 97 in with85% outside yield DNA. (Schemebind Corrolesing with35)96 and [78].DNA.97 Similarly showedCorroles moderate to96 mono-and 97 cytotoxicityhydroxyshowed moderatecomplexes in the dark, cytotoxicity 95, corroles with corrole in96 theand complex dark, 97 established with97 being corrole outside more complex cytotoxic bind ing97 thanbeingwith theDNA. more free Corrolescytotoxic base 96, 96 andthan and both the 97 exhibitedshowedfree base moderate 96 high, and photocytotoxicity both cytotoxicity exhibited in high againstthe photocytotoxicitydark, lung with cancer corrole cells ag complexainst A549, lung hepatoma97 cancer being cellmore cells A549, HepG2cytotoxic hepatoma and than breast cellthe μ cancerfreeHepG2 base cell and 96 MCF-7, breastand both (IC cancer50 exhibited= 0.3 cellµ M).MCF-7 high The photocytotoxicity(IC PDT50 treatment= 0.3 M). ofThe HepG2ag PDTainst treatment cells lung with cancer96 of orHepG2cell97s inducesA549, cells hepatoma with the potential 96 or cell 97 destruction of the mitochondrial membrane and, consequently, tumor cell apoptosis. HepG2induces and the breast potential cancer destruction cell MCF-7 of (IC the50 =mitochondrial 0.3 μM). The PDT membrane treatment and, of HepG2consequently, cells with tumor 96 or cell 97 inducesapoptosis.Water-soluble the potential sodium destruction salts of of sulfonated the mitochondrial corrole 98 andmembrane its metal and, complexes consequently, of copper tumor (99- Cucell), ironapoptosis. (99-Fe ) and manganese (99-Mn) were prepared and their photodynamic anti-cancer activity against human tumor cell lines, namely lung carcinoma (A549), hepatocellular cancer (HepG2) and cervical cancer (HeLa), was evaluated (Figure3)[ 79]. Photocytotoxicity studies demonstrated that all the tested cell lines are sensitive to the presence of corrole 98, especially A549 cells (IC50 = 5.0 µM), while no dark toxicity was observed with the studied corroles. Similar behavior was already found Molecules 2020, 24, x 25 of 39

OH OH

OH Molecules 2020, 25, 3450 H2N 25 of 39 F F F F DMSO, reflux F F F F N HN N HN for corrole–cyclodextrinF conjugates whenF compared withHN the corrole-free base 70 [80]. TheNH studies to NHHN NHHN clarify theF mechanismF of PDTF activityF of corrole HO98 evidencedF aF large productionF of reactiveF oxygenOH species (ROS), which could induce A549 cell apoptosis and activate the mitochondrial apoptosis, with 94c OH 96 79% the SIRT1 protein degradation being crucial for the process. The PDT activity of corrole 98 in vivo was also assessed and a signiﬁcant decrease in tumor growth (A549 xenografted tumor), without obvious GaCl3, py loss of mice body weight, was observed. Molecules 2020, 24, x reflux 25 of 39

F F Py F F OH N N Py = OH N HN Ga NH N N HO F F OHF F OH H2N 97 85% F F F F DMSO, reflux F F F F N HN N HN Scheme 35. Synthesis of a tri-hydroxy corrole and the corresponding gallium complex. F F HN NH NHHN NHHN Water-solubleF F sodium saltsF ofF sulfonated corroleHO 98 andF itsF metal complexesF of copperF (99OH-Cu), iron (99-Fe) and manganese94c (99-Mn) wereOH prepared and their photodynamic96 79% anti-cancer activity against human tumor cell lines, namely lung carcinoma (A549), hepatocellular cancer (HepG2) and cervical cancer (HeLa), was evaluated (Figure 3) [79]. PhotocytotoxicityGaCl3, py studies demonstrated that all the tested cell lines are sensitive to the presence of corrole 98, especiallyreflux A549 cells (IC50 = 5.0 μM), while no dark toxicity was observed with the studied corroles. Similar behavior was already found F F Py F F for corrole–cyclodextrin conjugates whenN comparedN with the corrole-freePy = base 70 [80]. The studies to N clarify the mechanism ofHN PDT activity ofGa corrole 98 evidencedNH a large production of reactive oxygen species (ROS), which could induce A549N cellN apoptosis and activate the mitochondrial apoptosis, with HO F F F F OH the SIRT1 protein degradation being crucial for the process. The PDT activity of corrole 98 in vivo 97 85% was also assessed and a significant decrease in tumor growth (A549 xenografted tumor), without obvious lossScheme of mice 35. body Synthesis weight, of a was tri-hydroxy observed. corrole and the corresponding galliumgallium complex.complex.

Water-soluble sodium saltsF of sulfonated corrole 98 and its metalF complexes of copper (99-Cu), iron (99-Fe) and manganeseF (99-MnF ) were prepared and theirF photodynamicF anti-cancer activity against human tumor cell lines, namely lung carcinoma (A549), hepatocellular cancer (HepG2) and F F F F cervical cancer (HeLa), was evaluated (Figure 3) [79]. Photocytotoxicity studies demonstrated that all the tested cell linesF areF sensitive to theF presenceF of corroleF 98F , especially A549F cellsF (IC50 = 5.0 μM), N HN N N while no dark toxicity was observed with the studied corroles. SimilarM behavior was already found F F F F for corrole–cyclodextrin conjugatesNHHN when compared with the corrole-freeN N base 70 [80]. The studies to clarify the mechanismF F of PDT activity ofF corroleF 98 evidencedF F a large productionF ofF reactive oxygen species (ROS), which could induce A549SO cell3Na apoptosis and activate the mitochondrialSO3Na apoptosis, with NaO3S NaO3S the SIRT1 protein degradation98 being crucial for the process. The PDT 99-Cu activityM = Cu of corrole 98 in vivo was also assessed and a significant decrease in tumor growth (A54999-Fe xenografted M = Fe tumor), without 99-Mn M = Mn obvious loss of mice body weight, was observed. Figure 3. Molecular structure of a sodium salts of sulfonated corrole and its metal complexes.complexes. F F ReVO 5,10,15-tris(F meta-methoxycarbonylphenyl)corrole,F F ReF VO 5,10,15-tris(para- ReVO 5,10,15-tris(meta-methoxycarbonylphenyl)corrole, ReVO 5,10,15-tris(para- methoxycarbonylphenyl)corrole and their corresponding carboxylic acids were evaluated as F F F F sensitizers forfor PDT.PDT. This This metallocorroles metallocorroles present present a high a high singlet singlet oxygen oxygen formation formation quantum quantum yield (0.72)yield regardless of the ester or acid functionalities at the phenyl rings. The ReVO carboxylic acids were (0.72) regardless Fof theF ester or acid functionalitiesF F at Fthe phenylF rings. The FReVOF carboxylic acids found to exhibit high photocytotoxicityN HN against rat bladder cancerN cellsN (AY27) and human colon were found to exhibit high photocytotoxicity against rat bladder cancerM cells (AY27) and human colon F F F F carcinoma cells (WiDr), achievingachieving 50% cellcell deathdeath withinwithin 5–75–7 minmin ofof blueblue lightlight exposure.exposure. CellCell deathdeath rates for WiDr cell line in theNH absenceHN of light are much lower (23%N cellN death after 24 h incubation F F F F F F F F with a 10 µM concentration of sensitizer)SO3 [Na81]. SO3Na Recently, the synthesisNaO3S of a two-dimensional corrole-basedNaO covalent3S organic framework (COF) was 98 99-Cu M = Cu developed. The corrole-based COF-100 with desymmetrized structure99-Fe was M isolated = Fe in 86% yield from 99-Mn M = Mn Figure 3. Molecular structure of a sodium salts of sulfonated corrole and its metal complexes.

ReVO 5,10,15-tris(meta-methoxycarbonylphenyl)corrole, ReVO 5,10,15-tris(para- methoxycarbonylphenyl)corrole and their corresponding carboxylic acids were evaluated as sensitizers for PDT. This metallocorroles present a high singlet oxygen formation quantum yield (0.72) regardless of the ester or acid functionalities at the phenyl rings. The ReVO carboxylic acids were found to exhibit high photocytotoxicity against rat bladder cancer cells (AY27) and human colon carcinoma cells (WiDr), achieving 50% cell death within 5–7 min of blue light exposure. Cell death Molecules 2020, 24, x 26 of 39 rates for WiDr cell line in the absence of light are much lower (23% cell death after 24 h incubation withMolecules a 102020 μM, 25 concentration, 3450 of sensitizer) [81]. 26 of 39 Recently, the synthesis of a two-dimensional corrole-based covalent organic framework (COF) was developed. The corrole-based COF-100 with desymmetrized structure was isolated in 86% yield fromthe [3 +the2] imine[3 + condensation 2] imine reactioncondensation of the approximatelyreaction of T-shapedthe approximately tris(p-aminophenyl)corrole T-shaped tris( (78p-) aminophenyl)corrolewith the linear terephthaldehyde (78) with the (Scheme linear terephthaldehyde 36)[82]. COF-100 (Schemedemonstrated 36) [82]. high COF chemical-100 demonstrated stability and highpermanent chemical porosity, stability with and a sphere-like permanent morphology porosity, with and a Brunauer–Emmett–Tellersphere-like morphology (BET)and a surfaceBrunauer– area 2 Emmett–Tellerof 745 m /g. The (BET) uv-vis surface absorption area of spectrum 745 m2/g. shows The uv-vis an absorption absorption intensity spectrum in theshows entire an visibleabsorption and intensityNIR regions in the with entire a Soret visible band and at 399NIR nm, regions which with is redshifted a Soret band by7 at nm 399 relative nm, which to corrole is redshifted78. COF by-100 7 nmexhibits relative a high to capabilitycorrole 78 to. COF generate-100 exhibits oxygen singleta high (90%capability efficiency to generate of 1,3-diphenylisobenzofuran oxygen singlet (90% efficiency(DPBF) degradation, of 1,3-diphenylisobenzofuran whereas monomeric (DPBF) corrole degradation, showed sharply whereas decreased monomeric activity corrole for degrading showed sharplyDPBF with decreased a low conversion activity for of degrading 56%), weaker DPBF fluorescence with a low intensity conversion and aof shorter 56%), weaker fluorescence fluorescence lifetime 2 intensityof 0.082 nsand compared a shorter withfluorescence78 (0.19 lifetime ns). Laser of 0.082 irradiation ns compared (0.18 W with cm −78) (0.19 of MCF-7 ns). Laser cells irradiation incubated µ (0.18with COFW cm-100−2) of(50 MCF-7g/mL), cells at incubated 635 nm for with 10 min,COF led-100 to (50 the μg/mL), death ofat 85%635 ofnm the for cancer 10 min, cells. led to These the deathresults of clearly 85% of demonstrated the cancer cells. that COF These-100 resultsis a promising clearly demonstrated candidate to bethat used COF as- a100 photosensitizer is a promising in candidatephotodynamic to be therapy.used as a photosensitizer in photodynamic therapy.

Scheme 36. SynthesisSynthesis a a two-dimensional two-dimensional corrolecorrole-basedbased covalent organic framework.

In summary, the eeffortsfforts to develop new corrole-basedcorrole-based entities useful as a photosensitizer for photodynamic therapy have followed didifferentfferent strategies:strategies: (i) (i) optimization of the photophysical parameters through through halogenation halogenation at at mesomeso oror betabeta positionspositions of of the the corrole corrole core, core, where where the the iodination iodination at 3-positionat 3-position of the of the mesomeso-phenyl-phenyl ring ring and and beta-pyrrolic beta-pyrrolic positions positions stand stand out, out, leading leading to the to the increase increase in singletin singlet oxygen oxygen quantum quantum yield; yield; (ii) modification (ii) modification of the of inner the core inner through core through complexation complexation with metals, with namelymetals, Fe, namely Sn, Ir Fe,and Sn,Re complexes, Ir and Re which complexes, proved which to be provedmore efficient to be singlet more e oxygenfficient sensitizers singlet oxygen than thesensitizers free-base than corroles, the free-base with the corroles, Ga complexes with the also Ga being complexes more alsophotocytotoxic; being more (iii) photocytotoxic; solubility issues (iii) havesolubility been issuesovercome have through been overcome the introduction through of the polar introduction groups (SO of3 polarNa or groups COOH), (SO by3Na the or formation COOH), ofby themacrostructures formation of macrostructuressuch MOF or nanoparticles; such MOF or nanoparticles;iv) the modification (iv) the modificationof uv-vis-NIR of uv-vis-NIRabsorption characteristicsabsorption characteristics was achieved was by achieved extending by the extending π-conjugated the π-conjugated system. system.

6. Hexaphyrins: Hexaphyrins: Synthesis Synthesis and and Applications Applications Gossauer et et al. al. described, described, in in 1983, 1983, the the first first synthesis synthesis of ofhexaphyrins hexaphyrins with with six sixmesomeso-bridges,-bridges, β- substitutedβ-substituted aromatic aromatic macrocycles macrocycles with with 26-electron 26-electron conjugation, conjugation, following following a “3 a + “3 3”+ approach,3” approach, i.e., throughi.e., through the thecondensation condensation of oftwo two tripyrromethanes tripyrromethanes [83]. [83 ].Following Following this this work, work, meso-substituted [28]hexaphyrins were were synthetized using using the the classica classicall methodologies methodologies for for the the synthesis synthesis of of porphyrins, porphyrins, such asas Lindsey Lindsey and and Rothemund Rothemund synthetic synthetic approaches approaches [84,85]. [84,85]. Although Although these methods these aremethods convenient are convenientand effective, and when effective, stabilized when with stabilized electron-withdrawing with electron-withdrawing groups at the groupsmeso-position, at the meso the-position, simultaneous the simultaneousformation of everyformation size ofof expanded every size porphyrins, of expanded at porphyrins, least up to dodecamer, at least up to inevitably dodecamer, causes inevitably serious causesseparation serious diffi culties.separation Therefore, difficulties. more ring-sizeTherefore, selective more synthesesring-size usingselective dipyrromethanes syntheses using and dipyrromethanestripyrromethanes and as the tripyrromethanes starting materials as werethe starting developed materials [86,87 were]. developed [86,87]. More recently, Osuka and coworkers described the synthesis of hexaphyrins bearing two benzoyl groups at meso-positions and their complexes [88]. [28]Hexaphyrin 103 was synthesized as a stable compound in 12% overall yield by p-toluenesulfonic acid catalyzed cross-condensation of tripyrrane Molecules 2020, 24, x 27 of 39

MoleculesMore2020 recently,, 25, 3450 Osuka and coworkers described the synthesis of hexaphyrins bearing27 oftwo 39 benzoyl groups at meso-positions and their complexes [88]. [28]Hexaphyrin 103 was synthesized as a stable compound in 12% overall yield by p-toluenesulfonic acid catalyzed cross-condensation of 101tripyrranewith phenylglyoxal 101 with phenylglyoxal monohydrate monohydrate (102), at 0 ◦ C(102 under), at 0 N °C2 atmosphere under N2 atmosphere with protection with fromprotection room lightfrom forroom 1.5 light h, followed for 1.5 byh, followed oxidation by with oxidation DDQ (Scheme with DDQ 37). (Scheme X-Ray di 37).ffraction X-Ray analysis diffraction has revealedanalysis thathas 103revealedadopts that a dumbbell-like 103 adopts a conformation, dumbbell-like held conformation, by effective intramolecularheld by effective hydrogen intramolecular bonding betweenhydrogen the bonding pyrrolic between NH protons the pyrrolic and benzoyl NH proton carbonyls and groups. benzoyl Oxidation carbonyl of groups.103 with Oxidation MnO2 aff oforded 103 [26]hexaphyrinwith MnO2 afforded104, quantitatively.[26]hexaphyrin However,104, quantitatively. hexaphyrin However,104 is easily hexaphyrin reduced 104 back is easily to 103 reducedunder ambientback to conditions,103 under indicatingambient conditions, that [28]hexaphyrin indicating is morethat stable[28]hexaphyrin than [26]hexaphyrin is more stable despite than its distinct[26]hexaphyrin antiaromatic despite character. its distinct The complexation antiaromatic ofcharacter.103 with Au(III)The complexation afforded two of bis-Au(III) 103 with isomeric Au(III) complexesafforded two105a bis-Au(III)and 105b isomericin 32% complexes and 3%, respectively 105a and 105b (Scheme in 32% 37 and). X-Ray 3%, respectively crystal analysis (Scheme showed 37). thatX-Ray both crystal complexes analysis present showed rectangular that both conformations complexes with present hydrogen rectangular bonding betweenconformations the benzoyl with groupshydrogen and bonding the outer between NH protons. the benzoyl groups and the outer NH protons.

Ar O

NH HN H . H2O Ar + O NH 102 101 F F

1. p-TsOH.H2O, CH2Cl2, 0 ºC, 1.5 h Ar = F 2. DDQ, 30 min F F Ph Ar Ar O Ar Ar N N Ar N N NH N H H O Ph NH N O Ph N MnO2 N Ph O + Ar Ar CH Cl H H 2 2 Ph HN O HN N N N N Ar Ar N N 103 12% Ar Ar 104a Ar Ph O 104b

Na AuCl4 .2H2O (102a/102b ratio = 1:2.6) NaOAc Ag2CO3 MeOH, 24 h, rt

O Ph Ar Ar Ar N N

N N N N O Ph Au Au + Ar Au Au Ar N Ph N N O N

N N Ar Ar 105a 3% Ar 105b 32% Ph O Scheme 37. Synthesis of isomeric 5,20-dibenzoyl [28]hexaphyrins and their Gold(III) complexes.

Complex 105b was quantitatively reduced toto [26]hexaphyrin[26]hexaphyrin Au(II)Au(II) complexcomplex 106106 withwith NaBHNaBH44 at room temperature,temperature, which which could could oxidize oxidize back back to 105bto 105bwithout without signiﬁcant significant degradation degradation by treatment by treatment with MnOwith 2MnO. The2 benzoyl. The benzoyl substituents substituents and pyrrolic and NH-protons pyrrolic NH of-protons the bis-Au(III) of the complex bis-Au(III) of [28]hexaphyrin complex of 106[28]hexaphyrinwere used as106 peripheral were used bidentate as peripheral coordination bidentate sites coor todination prepare sites the to boron(II) prepare complexthe boron(II)107. Thecomplex complexation 107. The complexation was achieved was in90% achieved yield in by 90% heating yield a by mixture heating of a 106mixture, BF3-OEt of 1062 and, BF3 DIPEA-OEt2 and in dichloromethaneDIPEA in dichloromethane at 40 ◦C for at 24 40 h °C (Scheme for 24 h38 (Scheme)[88]. 38) [88]. The absorption spectrum of the [28]hexaphyrin 103 in CH2Cl2 shows a Soret band at 516 nm and a Q band (without fine structure) between 700–900 nm. The absorption spectra of gold complexes 105a and 105b are similar, showing Soret-like bands around 670 nm and Q-like bands in the NIR Molecules 2020, 24, x 28 of 39

region at ca. 822, 930 and 1195 nm, supporting their 26π aromaticity. The absorption spectrum of the reduced complex 106 shows broad absorption bands at 544, 603, and 738 nm and weak absorption in NIR region, reflecting its antiaromaticity. The absorption spectrum of 107 is red-shifted by ca. 100 nm Moleculesand sharper2020, 25 than, 3450 that of 106, probably due to structural rigidity and the presence of electron28 of 39 withdrawing BF2-moieties.

Ph O Ph O Ar H Ar N N NaBH4 N N CH2Cl2/MeOH N N 5 min, rt Ar Au Au Ar Ar Au Au Ar N N N N

N N Ar Ar H Ph O 105b Ph O 106 95%

BF3.OEt2 DIPEA CH2Cl2 40 ºC, 24 h F O B Ph F Ar N

N N Ar Au Au Ar N N

N Ar F B O Ph F 107 90% SchemeScheme 38.38. Synthesis of a [26]hexaphyrin[26]hexaphyrin bis-gold(III)bis-gold(III) complexcomplex andand thethe correspondingcorresponding exocyclicexocyclic boronboron complex.complex.

The5,20-Bis(ethoxycarbonyl)-[28]hexaphyrin absorption spectrum of the [28]hexaphyrin 109 was103 insynthesized CH2Cl2 shows using a Soret meso band-pentafluorophenyl at 516 nm and atripyrrane Q band (without 101 and fine ethyl structure) 2-oxoacetate between ( 700–900108) as nm.starting The absorptionmaterials and spectra the of previously gold complexes described105a andmethodology105b are similar, to promote showing the cross-condensation, Soret-like bands around followed 670 nmby oxidation and Q-like with bands DDQ in the(Scheme NIR region 39) [89]. at ca.X-Ray 822, crystallographic 930 and 1195 nm, analysis supporting revealed their that 26π aromaticity.109 presents The a dumbbell-like absorption spectrum conformation of the reducedheld by complexeffective 106intramolecularshows broad hydrogen absorption bonding bands between at 544, 603,the pyrrolic and 738 NH nm protons and weak and absorption carbonyl oxygen in NIR region,of ethoxycarbonyl reflecting its group. antiaromaticity. The uv-vis Thespectrum absorption of 109 spectrum displayed of characteristic107 is red-shifted features by ca.of antiaromatic 100 nm and sharperporphyrinoids than that with of 106 a, probablybroad Soret-like due to structural band at rigidity 514 nm, and and the presencerelatively of electronweak Q-like withdrawing bands. BF[28]Hexaphyrin2-moieties. 109 can serve as a bis-NNNO ligand to form square planar bis-Ni(II) and bis-Cu(II) complexes.5,20-Bis(ethoxycarbonyl)-[28]hexaphyrin The reaction of 109 with 20 equiv. of109 nickel(II)was synthesized acetylacetonate using (Ni(acac)meso-pentafluorophenyl2) in dry toluene tripyrraneat 100 °C for101 48 andh afforded ethyl 2-oxoacetatea bis-Ni(II) complex (108) as 110 starting in 48% materialsyield. X-Ray and crystallographic the previously analysis described has methodologyconfirmed that to 110 promote has a the square cross-condensation, planar geometry followed formed by through oxidation the with coordination DDQ (Scheme of the 39 )[three89]. X-Raynitrogen crystallographic atoms inner and analysis the carbonyl revealed oxygen that 109atompresents to the Ni(II) a dumbbell-like ion, and that conformation this bis-complex held kept by etheffective dumbbell-like intramolecular conformation. hydrogen The bonding comp betweenlexation thewith pyrrolic a large NH excess protons of CuCl and carbonyl2 in the presence oxygen ofof ethoxycarbonylNaOAc in CH2Cl group.2, at room The temperature, uv-vis spectrum for 24 of h,109 yieldsdisplayed the bis-Cu(II) characteristic complex features 111 in 79% of antiaromatic yield, which porphyrinoidsalso takes on a with dumbbell-like a broad Soret-like conformation band at and 514 nm,square and planar relatively geometry. weak Q-like The absorption bands. [28]Hexaphyrin spectrum of 109110 canin CH serve2Cl2 showed as a bis-NNNO a broad Soret- ligandlike to band form at square 508 and planar 621 nm, bis-Ni(II) Q-like band and bis-Cu(II)at 830 nm and complexes. a weak Theabsorption reaction tail of 109up towith 1700 20 nm. equiv. The of complexation nickel(II) acetylacetonate with copper (Ni(acac) modified2) the in dry absorption toluene atspectrum 100 ◦C for of 48111, h anarrowingfforded a bis-Ni(II)the Soret-like complex band110 at 520in 48% and yield.635 nm X-Ray, blue-shifting crystallographic the Q-like analysis bands hasto 814 confirmed nm and thatalso 110thehas very a squareweak planarabsorption geometry tail up formed to ca. through 1500 nm the. coordinationOxidation of of 5,20-bis(ethoxycarbonyl)- the three nitrogen atoms inner[28]hexaphyrin and the carbonyl 109 with oxygen a large atom excess to the of Ni(II) PbO2 ion, in CH and2Cl that2 at this room bis-complex temperature kept for the 3 dumbbell-like min afforded conformation.[26]hexaphyrin The 112 complexationin 73% yield. withThis ahexaphyrin large excess was of CuCleasily2 reducedin the presence back to of 109 NaOAc with NaBH in CH42 Clin 2,a at room temperature, for 24 h, yields the bis-Cu(II) complex 111 in 79% yield, which also takes on a dumbbell-like conformation and square planar geometry. The absorption spectrum of 110 in CH2Cl2 showed a broad Soret-like band at 508 and 621 nm, Q-like band at 830 nm and a weak absorption tail up to 1700 nm. The complexation with copper modified the absorption spectrum of 111, narrowing the Molecules 2020, 25, 3450 29 of 39

Soret-like band at 520 and 635 nm, blue-shifting the Q-like bands to 814 nm and also the very weak absorptionMolecules 2020 tail, 24, upx to ca. 1500 nm. Oxidation of 5,20-bis(ethoxycarbonyl)-[28]hexaphyrin 109 with29 of 39 a large excess of PbO2 in CH2Cl2 at room temperature for 3 min aﬀorded [26]hexaphyrin 112 in 73% yield. Thismixture hexaphyrin of CH2Cl was2/MeOH easily at reduced room temperature back to 109 forwith 10 NaBHmin (Sch4 ineme a mixture 39). Interestingly, of CH2Cl2/ MeOHthe hexaphyrin at room temperature112 was the forsole 10 product, min (Scheme in contrast 39). Interestingly, with the formation the hexaphyrin of two112 isomericwas the sole[26]hexaphyrins product, in contrast in the withoxidation the formation of 5,20-dibenzoyl-[28]hexaphyrin of two isomeric [26]hexaphyrins with MnO in the2 [88]. oxidation The uv-vis-NIR of 5,20-dibenzoyl-[28]hexaphyrin absorption spectrum of with112 showed MnO2 [88 a ].sharp The uv-vis-NIR Soret-like absorptionband at 562 spectrum nm and of Q-like112 showed bands a at sharp 712, Soret-like 770, 892,band and at1022 562 nm, nm andcharacteristic Q-like bands features at 712, of 770,aromatic 892, and porphyrinoids. 1022 nm, characteristic features of aromatic porphyrinoids.

Ar O

NH HN H . H2O EtO Ar + O NH 108 101 F F

1. p-TsOH.H2O, CH2Cl2, 0 ºC, 1.5 h Ar = F 2. DDQ, 30 min F F

Ar Ar N N H H O OEt N N EtO O H H N N Ar Ar PbO2 109 9% CH Cl (rt, 30 min) Ni(acac)2 2 2 Toluene, NaBH4 100 ºC, 48 h CuCl2, NaOAc CH2Cl2/MeOH CH2CH2, rt 24 h rt,10 min Ar Ar N Ar Ar Ar Ar N N N N NH N O OEt O OEt Ni O OEt N Cu N N EtO O N EtO O Ni Cu HN O N EtO N N N N Ar Ar Ar Ar N Ar Ar 110 48% 111 79% 112 73%

SchemeScheme 39.39. Synthesis of a 5,20-bis(ethoxycarbonyl)-[28]hexaphyrin,5,20-bis(ethoxycarbonyl)-[28]hexaphyrin, its its bis-Ni(II) and bis-Cu(II) complexescomplexes andand thethe correspondingcorresponding 5,20-bis(ethoxycarbonyl)-[26]hexaphyrin.5,20-bis(ethoxycarbonyl)-[26]hexaphyrin.

FollowingFollowing studiesstudies onon thethe complexationcomplexation ofof aromaticaromatic electron-deficientelectron-deficient mesomeso-pentafluorophenyl-pentafluorophenyl [26]hexaphyrin[26]hexaphyrin and electronelectron richrich mesomeso-pentafluorophenyl-pentafluorophenyl [28]hexaphyrin with Möbius aromaticity, OsukaOsuka andand coworkers coworkers reported reported the the synthesis synthesis of ofπ-ruthenium π-ruthenium complexes complexes [90 ].[90]. The The treatment treatment of mono of mono-- and bis-gold(III)and bis-gold(III) complexes comple ofxes [28]hexaphyrin of [28]hexaphyrin113a and 113a113b andwith 113b five equivalentswith five equivalents of [RuCl2(p -cymene)]of [RuCl2( inp- thecymene)] presence in ofthe NaOAc presence in a mixtureof NaOAc of toluenein a mixtur/DMFe atof 100 toluene/DMF◦C for 65 h aatfforded 100 °Cπ-ruthenium for 65 h afforded complexes π- 114arutheniumand 114b complexesin 45% 114a and 56%and 114b yield, in respectively 45% and 56% (Scheme yield, respectively 40). When the(Schememeso-pentafluorophenyl 40). When the meso- [26]hexaphyrinpentafluorophenyl was submitted[26]hexaphyr to thein samewas reactionsubmitted conditions, to the onlysame decomposition reaction conditions, products wereonly obtained,decomposition suggesting products that were the formationobtained, suggesting of ruthenium thatπ the-complexes formation might of ruthenium need an electron-richπ-complexes hexaphyrin.might need an The electron-rich absorption spectrum hexaphyrin. of 114b The showsabsorption two intense spectrum bands of 114b at 490 shows and 656 two nm intense and two bands less intenseat 490 and and 656 more nm broad and bandstwo less at 1066intense and and 1250 more nm. Thebroad treatment bands at with 1066 TFA and yielded 1250 nm. the trifluoroacetate The treatment 115with, with TFA the yielded absorption the trifluoroacetate spectrum of this 115 salt, with presenting the absorption the same spectrum bands, and of bluethis salt shifted presenting to 455, 609,the 1066same and bands, 1097 and nm. blue shifted to 455, 609, 1066 and 1097 nm. Molecules 2020, 25, 3450 30 of 39 Molecules 2020, 24, x 30 of 39 Molecules 2020, 24, x 30 of 39

SchemeScheme 40. 40. SynthesisSynthesis of of Ru(II) Ru(II) complexes complexes of mesoof mesopentafluorophenyl-[28]hexaphyrin-pentaﬂuorophenyl-[28]hexaphyrin mono- mono- and bis- and Scheme 40. Synthesis of Ru(II) complexes of meso-pentafluorophenyl-[28]hexaphyrin mono- and bis- bis-Au(III)Au(III) complexes. complexes. Au(III) complexes. Ru-metalationRu-metalation of of [26]hexaphyrin [26]hexaphyrin bis-Pd(II)bis-Pd(II) complex 116,116 ,a a unique unique complex complex with with a characteristic a characteristic Ru-metalation of [26]hexaphyrin bis-Pd(II) complex 116, a unique complex with a characteristic conjugatedconjugated aromatic aromatic circuit circuit andand relativelyrelatively acidic outer pyrrolic pyrrolic NH NH protons protons [27,91], [27,91 ],was was achieved achieved conjugated aromatic circuit and relatively acidic outer pyrrolic NH protons [27,91], was achieved through a reaction with [RuCl2(p-cymene)] in the presence of NaOAc in a mixture of toluene/DMF through a reaction with [RuCl2(p-cymene)] in the presence of NaOAc in a mixture of toluene/DMF (4:1) (4:1)through at 100 a reaction °C for 12with h [90].[RuCl The2(p-cymene)] [26]hexaphyrin in the bis-Pd(II)-bis-Ru(II)presence of NaOAc complexin a mixture 117 ,of a toluene/DMFtriple-decker at 100(4:1)◦ Cat for100 12 °C h for [90 ].12 The h [90]. [26]hexaphyrin The [26]hexaphyrin bis-Pd(II)-bis-Ru(II) bis-Pd(II)-bis-Ru(II) complex complex117, a triple-decker117, a triple-decker complex withcomplex both thewith [( pboth-cymene)Ru(II)] the [(p-cymene)Ru(II)] moieties located moieties above located and ab belowove and the below center the of thecenter hexaphyrin of the hexaphyrincomplex with framework, both the was[(p- cymene)Ru(II)]obtained in 57% moieties yield (Scheme located 41). ab Theove absorptionand below spectrum the center of of117 the in framework,hexaphyrin was framework, obtained inwas 57% obtained yield (Scheme in 57% yi 41eld). The(Scheme absorption 41). The spectrum absorption of 117spectrumin CH 2ofCl 1172 shows in CH2Cl2 shows two Soret-like bands at 461 and 650 nm and a Q-like band at 829 nm. twoCH Soret-like2Cl2 shows bands two Soret-like at 461 and bands 650 nmat 461 and and a Q-like 650 nm band and ata Q-like 829 nm. band at 829 nm.

Scheme 41. Synthesis of Ru(II) complexes of meso-pentafluorophenyl-[28]hexaphyrin bis-Pd(II) Schemecomplex.Scheme 41. 41. SynthesisSynthesis of Ru(II) of Ru(II)complexes complexes of meso-pentafluorophenyl-[28]hexaphyrin of meso-pentafluorophenyl-[28]hexaphyrin bis-Pd(II) bis-Pd(II)complex. complex. Hexaallyloxy-appended hexaphyrin 119 prepared through nucleophilic aromatic substitution reactionHexaallyloxy-appendedHexaallyloxy-appended of 5,10,15,20,25,30-hexakis hexaphyrinhexaphyrin(pentafluorophenyl)-[26]hexaphyrin 119 prepared through through nucleophilic nucleophilic (118) with aromatic aromatic allyl alcohol,substitution substitution [92] reactionwasreaction subjected of of 5,10,15,20,25,30- 5,10,15,20,25,30- to olefin metathesishexakishexakis(pentafluorophenyl)-[26]hexaphyrin reaction(pentafluorophenyl)-[26]hexaphyrin using the improved Hoveyda–Grubbs (118) (118 with) with catalyst. allyl allyl alcohol, alcohol,When [92]the [92 ] wasreactionwas subjected subjected was toconducted to olefin olefin metathesis metathesis at room temperature, reaction reaction usingusing on lythe peripherally improved HoHoveyda–Grubbs strappedveyda–Grubbs [26]hexaphyrin catalyst. catalyst. monomerWhen When the the reaction120reaction was was wasobtained conducted conducted in a at 37% at room room yield. temperature, temperature, Decreasing only onthely peripherally amperipherallyount of strappedcatalyst strapped and [26]hexaphyrin [26]hexaphyrin increasing the monomer monomer reaction120 wastemperature120 obtained was obtained in to a 40 37% °Cin yield. leda 37% to Decreasingthe yield. formation Decreasing the of amount 120 the as a ofam minor catalystount productof and catalyst increasing (9% andyield) increasing the and reaction cyclophane-type the temperature reaction temperature to 40 °C led to the formation of 120 as a minor product (9% yield) and cyclophane-type to[26]hexaphyrin 40 ◦C led to the dimer formation 121 in of 21%120 yieldas a minor(Scheme product 42). The (9% treatment yield) and of dimer cyclophane-type 121 with NaBH [26]hexaphyrin4 at room [26]hexaphyrin dimer 121 in 21% yield (Scheme 42). The treatment of dimer 121 with NaBH4 at room dimertemperature121 in 21% for 10 yield min (Scheme afforded 42[28]hexaphyrin). The treatment dimer of 122 dimer in 30%121 yield,with which NaBH could4 at room be transformed temperature temperature for 10 min afforded [28]hexaphyrin dimer 122 in 30% yield, which could be transformed for 10 min afforded [28]hexaphyrin dimer 122 in 30% yield, which could be transformed back into Molecules 2020, 25, 3450 31 of 39

Molecules 2020, 24, x 31 of 39 121 by oxidation with MnO2 (Scheme 42)[93]. The uv-vis-NIR absorption spectrum of aromatic

[26]hexaphyrinback into 121120 by showsoxidation a typical with MnO sharp2 (Scheme Soret-like 42) [93]. band The at uv-vis-N 569 nmIR and absorption Q-like bands spectrum at 718, of 908, and 1031aromatic nm. [26]hexaphyrin Dimer 121 shows 120 shows split a Soret-liketypical sharp bands Soret-like at 543 band and at 569 577 nm nm, and attributed Q-like bands to theat 718, exciton coupling908, and of the 1031 two nm. hexaphyrin Dimer 121 shows cores split in a Soret-like stacked geometry,bands at 543 [94 and] and 577 Q-likenm, attributed bands 724,to the 899, exciton and 1031 nm. Thecoupling absorption of the two spectrum hexaphyrin of 122 coresexhibits in a stacked characteristics geometry, [94] of anti-aromatic and Q-like bands [28]hexaphyrins, 724, 899, and 1031 smaller absorptionnm. The bands absorption at 490, spectrum 526, and of 571122 exhibits nm and characteristics a weak absorption of anti-aromatic at the near-infrared [28]hexaphyrins, region. smaller absorption bands at 490, 526, and 571 nm and a weak absorption at the near-infrared region.

SchemeScheme 42. 42.Synthesis Synthesis of of monomericmonomeric and and dimeric dimeric strapped strapped hexaphyrins. hexaphyrins. Molecules 2020, 25, 3450 32 of 39 Molecules 2020, 24, x 32 of 39

Following the pioneer work of Osuka and coworker coworkerss on regioselective nucl nucleophiliceophilic substitution reactions of mesomeso--hexakis(pentafluorophenyl)-substituted(pentafluorophenyl)-substituted [26]hexaphyrin [26]hexaphyrin with with an alkoxides and isopropyl amineamine [95 ],[95], Wiehe Wiehe and coworkersand coworkers achieved ac thehieved synthesis the of hexa-glycosylatedsynthesis of hexa-glycosylated [28]hexaphyrin 124[28]hexaphyrinin high yield 124 (Scheme in high 43yield)[96 (Scheme]. [28]Hexaphyrin 43) [96]. [28]Hexaphyrin123, obtained 123 in 96%, obtained yield in through 96% yield a reduction through ina reduction [26]hexaphyrin in [26]hexaphyrin118 with NaBH 1184 within methanol NaBH4 in at methanol room temperature at room temperature for 20 min, was for transformed20 min, was intotransformed the hexa-glycosilated into the hexa-glycosilated derivative in derivative 78% yield in by78% nucleophilic yield by nucleophilic substitution substitution of the para offluorine the para substituentfluorine substituent of all six pentafluorophenylof all six pentafluorophenyl units, using 1-thio-units, βusing-D-glucose 1-thio- sodiumβ-D-glucose salt as sodium nucleophile, salt as in drynucleophile, DMF overnight in dry DMF at room overnight temperature. at room Attempts temperat toure. promote Attempts the glycosylationto promote the of glycosylation [26]hexaphyrin of 118[26]hexaphyrindelivered a complex118 delivered mixture a complex with traces mixture of the expectedwith traces product of the and expected evidence product for the and formation evidence of thefor the corresponding formation of reduced the corresponding form, [28]hexaphyrin reduced form,123. [28]hexaphyrin 123.

Scheme 43. Synthesis of a hexa-glycosylated [28]hexaphyrin.

To createcreate well-defined well-defined NIR-II NIR-II dyes, dyes, chemical chemical modification modification of the hexapyrrolicof the hexapyrrolic core is an core alternative is an viablealternative approach. viable Recently,approach. SesslerRecently, and Sessler coworkers and reportedcoworkers the reported synthesis the of synthesis a new hexaphyrin, of a new pyrihexaphyrinhexaphyrin, pyrihexaph (0.1.0.0.1.0)yrin125 (0.1.0.0.1.0), (Figure4 )125 that,, (Figure upon uranyl 4) that, dication upon uranyl complexation, dication undergoes complexation, ring contraction,undergoes ring affording contraction, 22 π-electron affording aromatic 22 π-electron contracted aromatic pyrihexaphyrin contracted pyrihexaphyrin (0.0.0.0.1.0)-uranyl (0.0.0.0.1.0)- complex, 126uranyl, which complex, displays 126 Hückel, which typedisplays aromatic Hückel features. type aromatic In fact, uv-visfeatures. spectroscopic In fact, uv-vis analysis spectroscopic revealed markedanalysis direvealedfferences marked in comparison differences to the in precursor. comparison A relativelyto the precursor. weak Soret-like A relatively band wasweak observed Soret-like at 549band nm was along observed with Q-type at 549 bands nm atalong 734 and with 1003 Q-type nm [97 bands]. A robust at 734 bis-rhodium(I) and 1003 nm complex [97]. A of πrobust-extended bis- planar,rhodium(I) anti-aromatic complex mesoof π-pentafluorophenyl--extended planar, βanti-aromatic,β-phenylene-bridged meso-pentafluorophenyl- hexaphyrin [1.0.1.0.1.0],β,β-phenylene- rosarin 127bridged, was hexaphyrin synthesized [1.0.1.0.1.0], in 60% yield rosarin from the 127 corresponding, was synthesized free-base in 60% (Figure yield4). from Both the ligandcorresponding and the bis-Rh(I)free-base complex(Figure 4). show Both uv-vis the ligand spectra and in CHthe 2bis-Rh(I)Cl2 with broadcomplex bands show between uv-vis 400–700spectra in nm CH [982Cl]. 2 with broad bands between 400–700 nm [98]. Molecules 2020, 24, x 33 of 39

The synthesis of doubly N-confused dioxohexaphyrins 128a,b as well as their Zn and Cu complexes, was also reported (Figure 4). These are interesting small molecule-based photoacoustic agents that respond to NIR-II light excitation and constitute a promising platform for deep-tissue NIR-II photoacoustic imaging applications [99]. Hexaphyrin (2.1.2.1.2.1), also known as rubyrins, 129a and b and their rhodium, zinc and copper metal complexes, were obtained to explore the control of aromaticity and cis-/trans-isomeric structure of non-planar hexaphyrins (Figure 4). While the free-base and Zn complex exhibit uv-vis spectra similar to the ones observed for porphyrins, the copper complex has a significant red-shifted bands with Q-like bands at 859 and 947 nm. The rhodium complex displayed a sharp, intense Soret-like band, and a weak Q-like band in the NIR region [100,101]. The incorporation of chalcogenic elements into five-membered rings (i.e., furan and thiophene) significantly affects the dipole vector and charge displacement. This causes a reversal in the direction of the dipole moment between the furan/thiophene and pyrrole [102]. The change in the polarization results in electronic perturbations of the π conjugation. In this regard, chalcogen-substituted hexaphyrins have been synthesized [103–108], some of them having been explored as NIR photodynamic therapy agents [109], and others such as dithiabronzaphyrin 130 [108] show intense Moleculesabsorption2020 , and25, 3450 fluorescence in the NIR region, opening the way for their use in biological33 of 39 applications.

C F C F N N 6 5 N N 6 5 OC CO NH HN N O N Rh Rh U N OC CO N N O N H N N N N N HN

C6F5 125 126 127

C6F5 Ar Ar N N Rh R R S N HN HN OC CO O NH N R R R R O NH N NH N CO OC N Rh Rh CO OC N HN Ar R S Ar C6F5 N N C6F5

128a R = Ar = C6F5 R 130 128b R = Si Ar = C6F5 129a R = H 129b R = Ph

Figure 4. Other hexaphyrins derivatives and anal analogsogs synthesized in recent years.

7. ConclusionsThe synthesis of doubly N-confused dioxohexaphyrins 128a,b as well as their Zn and Cu complexes, was also reported (Figure4). These are interesting small molecule-based photoacoustic The efforts of several research groups to develop the synthesis of corroles and hexaphyrins agents that respond to NIR-II light excitation and constitute a promising platform for deep-tissue followed three main strategies: (a) improvement in classical methodologies for the synthesis of the NIR-II photoacoustic imaging applications [99]. macrocycle; (b) development of methodologies for the functionalization of the peripheral positions Hexaphyrin (2.1.2.1.2.1), also known as rubyrins, 129a and b and their rhodium, zinc and copper and (c) improvement in complexation methods to modify the inner core. In addition to the above, a metal complexes, were obtained to explore the control of aromaticity and cis-/trans-isomeric structure few novel methodologies have been developed and all, together, opened the way to corroles and of non-planar hexaphyrins (Figure4). While the free-base and Zn complex exhibit uv-vis spectra hexaphyrins with new substitution patterns. The resulting modulation of the photophysical similar to the ones observed for porphyrins, the copper complex has a significant red-shifted bands properties lays the foundation for the development of further applications. with Q-like bands at 859 and 947 nm. The rhodium complex displayed a sharp, intense Soret-like band, and a weak Q-like band in the NIR region [100,101]. The incorporation of chalcogenic elements into five-membered rings (i.e., furan and thiophene) significantly affects the dipole vector and charge displacement. This causes a reversal in the direction of the dipole moment between the furan/thiophene and pyrrole [102]. The change in the polarization results in electronic perturbations of the π conjugation. In this regard, chalcogen-substituted hexaphyrins have been synthesized [103–108], some of them having been explored as NIR photodynamic therapy agents [109], and others such as dithiabronzaphyrin 130 [108] show intense absorption and fluorescence in the NIR region, opening the way for their use in biological applications.

7. Conclusions The eﬀorts of several research groups to develop the synthesis of corroles and hexaphyrins followed three main strategies: (a) improvement in classical methodologies for the synthesis of the macrocycle; (b) development of methodologies for the functionalization of the peripheral positions and (c) improvement in complexation methods to modify the inner core. In addition to the above, a few novel methodologies have been developed and all, together, opened the way to corroles and Molecules 2020, 25, 3450 34 of 39 hexaphyrins with new substitution patterns. The resulting modulation of the photophysical properties lays the foundation for the development of further applications.

Author Contributions: S.M.M.L., M.P. and T.M.V.D.P.eM. contribute to the bibliography search, analysis and writing of the manuscript. T.M.V.D.P.eM. supervised the project. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Coimbra Chemistry Centre (CQC) is supported by Fundação para a Ciência e a Tecnologia (FCT) through project UIDB/00313/2020 and UIDP/00313/2020, co-funded by COMPETE2020-UE. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References

1. Paolesse, R.; Jaquinod, J.; Nurco, D.J.; Mini, S.; Sagone, F.; Boschi, T.; Smith, K.M. 5,10,15-Triphenylcorrole: A product from a modiﬁed Rothemund reaction. Chem. Commun. 1999, 14, 1307–1308. [CrossRef] 2. Gross, Z.; Galili, N.; Saltsman, I. The First Direct Synthesis of Corroles from Pyrrole. Angew. Chem. Int. Ed. 1999, 38, 1427–1429. [CrossRef]

3. Gryko, D.T.; Jadach, K. A Simple and Versatile One-Pot Synthesis of meso-Substituted trans-A2B-Corroles. J. Org. Chem. 2001, 66, 4267–4275. [CrossRef] 4. Barata, J.F.B.; Neves, M.G.P.M.S.; Faustino, M.A.F.; Tomé, A.C.; Cavaleiro, J.A.S. Strategies for Corrole Functionalization. Chem. Rev. 2017, 117, 3192–3253. [CrossRef][PubMed] 5. Ghosh, A. Electronic Structure of Corrole Derivatives: Insights from Molecular Structures, Spectroscopy, Electrochemistry, and Quantum Chemical Calculations. Chem. Rev. 2017, 117, 3798–3881. [CrossRef] [PubMed] 6. Orłowski, R.; Gryko, D.; Gryko, D.T. Synthesis of Corroles and Their Heteroanalogs. Chem. Rev. 2017, 117, 3102–3137. [CrossRef] 7. Sarma, T.; Panda, P.K. Annulated Isomeric, Expanded, and Contracted Porphyrins. Chem. Rev. 2017, 117, 2785–2838. [CrossRef][PubMed] 8. Habermeyer, B.; Guilard, R. Some activities of PorphyChem illustrated by the applications of porphyrinoids in PDT, PIT and PDI. Photochem. Photobiol. Sci. 2018, 17, 1675–1690. [CrossRef][PubMed] 9. Nardis, S.; Mandoj, F.; Stefanelli, M.; Paolesse, R. Metal complexes of corrole. Coord. Chem. Rev. 2019, 388, 360–405. [CrossRef] 10. Haber, A.; Angel, I.; Mahammed, A.; Gross, Z. Combating diabetes complications by 1-Fe, a corrole-based catalytic antioxidant. J. Diabetes Complicat. 2013, 27, 316–321. [CrossRef] 11. Haber, A.; Gross, Z. Catalytic antioxidant therapy by metallodrugs: Lessons from metallocorroles. Chem. Commun. 2015, 51, 5812–5827. [CrossRef][PubMed] 12. Haber, A.; Mahammed, A.; Fuhrman, B.; Volkova, N.; Coleman, R.; Hayek, T.; Aviram, M.; Gross, Z. Amphiphilic/Bipolar Metallocorroles at Catalyze the Decomposition of Reactive Oxygen and Nitrogen Species, Rescue Lipoproteins from Oxidative Damage, and Attenuate Atherosclerosis in Mice. Angew. Chem. Int. Ed. 2008, 47, 7896–7900. [CrossRef] 13. Kupershmidt, L.; Okun, Z.; Amit, T.; Mandel, S.; Saltsman, I.; Mahammed, A.; Bar-Am, O.; Gross, Z.; Youdim, M.B.H. Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration. J. Neurochem. 2010, 113, 363–373. [CrossRef][PubMed] 14. Soll, M.; Bar Am, O.; Mahammed, A.; Saltsman, I.; Mandel, S.; Youdim, M.B.H.; Gross, Z. Neurorescue by a ROS Decomposition Catalyst. ACS Chem. Neurosci. 2016, 7, 1374–1382. [CrossRef][PubMed] 15. Cardote, T.A.F.; Barata, J.F.B.; Amador, C.; Alves, E.; Neves, M.G.P.M.S.; Cavaleiro, J.A.S.; Cunha, A.; Almeida, A.; Faustino, M.A.F. Evaluation of meso-substituted cationic corroles as potential antibacterial agents. An. Acad. Bras. Cienc. 2018, 90, 1175–1185. [CrossRef][PubMed] 16. Liang, X.; Mack, J.; Zheng, L.-M.; Shen, Z.; Kobayashi, N. Phosphorus(V)-Corrole: Synthesis, Spectroscopic Properties, Theoretical Calculations, and Potential Utility for in Vivo Applications in Living Cells. Inorg. Chem. 2014, 53, 2797–2802. [CrossRef] 17. Bornhütter, T.; Shamali, N.; Saltsman, I.; Mahammed, A.; Gross, Z.; Däschlein, G.; Röder, B. Singlet oxygen luminescence kinetics under PDI relevant conditions of pathogenic dermatophytes and molds. J. Photochem. Photobiol. B 2018, 178, 606–613. [CrossRef] Molecules 2020, 25, 3450 35 of 39

18. Sharma, V.K.; Mahammed, A.; Soll, M.; Tumanskii, B.; Gross, Z. Corroles and corrole/transferrin nanoconjugates as candidates for sonodynamic therapy. Chem. Commun. 2019, 55, 12789–12792. [CrossRef] 19. Teo, R.D.; Hwang, J.Y.; Termini, J.; Gross, Z.; Gray, H.B. Fighting Cancer with Corroles. Chem. Rev. 2017, 117, 2711–2729. [CrossRef] 20. Jiang, X.; Liu, R.-X.; Liu, H.-Y.; Chang, C.K. Corrole-based photodynamic antitumor therapy. J. Chin. Chem. Soc. 2019, 66, 1090–1099. [CrossRef] 21. Mahammed, A.; Gross, Z. Corroles as triplet photosensitizers. Coord. Chem. Rev. 2019, 379, 121–132. [CrossRef] 22. Alka, A.; Shetti, V.S.; Ravikanth, M. Coordination chemistry of expanded porphyrins. Coord. Chem. Rev. 2019, 401, 213063. [CrossRef] 23. Brewster, J.T.; Zafar, H.; Root, H.D.; Thiabaud, G.D.; Sessler, J.L. Porphyrinoid f-Element Complexes. Inorg. Chem. 2020, 59, 32–47. [CrossRef][PubMed] 24. Jasat, A.; Dolphin, D. Expanded Porphyrins and Their Heterologs. Chem. Rev. 1997, 97, 2267–2340. [CrossRef] 25. Basumatary, B.; Ramana Reddy, R.V.; Rahul Sankar, J. The Curious Case of a Parasitic Twin of the Corroles. Angew. Chem. Int. Ed. 2018, 57, 5052–5056. [CrossRef] 26. Saito, S.; Osuka, A. Expanded Porphyrins: Intriguing Structures, Electronic Properties, and Reactivities. Angew. Chem. Int. Ed. 2011, 50, 4342–4373. [CrossRef] 27. Inoue, M.; Osuka, A. Redox-Induced Palladium Migrations that Allow Reversible Topological Changes between Palladium(II) Complexes of Möbius Aromatic [28]Hexaphyrin and Hückel Aromatic [26]Hexaphyrin. Angew. Chem. Int. Ed. 2010, 49, 9488–9491. [CrossRef][PubMed] 28. Rao, Y.; Kim, T.; Park, K.H.; Peng, F.; Liu, L.; Liu, Y.; Wen, B.; Liu, S.; Kirk, S.R.; Wu, L.; et al. π-Extended “Earring” Porphyrins with Multiple Cavities and Near-Infrared Absorption. Angew. Chem. Int. Ed. 2016, 55, 6438–6442. [CrossRef][PubMed] 29. Stepien, M.; Sprutta, N.; Latos-Grazynski, L. Figure Eights, M bius Bands, and More: Conformation and Aromaticity of Porphyrinoids. Angew. Chem. Int. Ed. 2011, 50, 4288–4340. [CrossRef] 30. Szyszko, B.; Białek, M.J.; Pacholska-Dudziak, E.; Latos-Gra˙zy´nski,L. Flexible Porphyrinoids. Chem. Rev. 2017, 117, 2839–2909. [CrossRef] 31. Ahn, T.K.; Kwon, J.H.; Kim, D.Y.; Cho, D.W.; Jeong, D.H.; Kim, S.K.; Suzuki, M.; Shimizu, S.; Osuka, A.; Kim, D. Comparative Photophysics of [26]- and [28]Hexaphyrins(1.1.1.1.1.1): Large Two-Photon Absorption Cross Section of Aromatic [26]Hexaphyrins(1.1.1.1.1.1). J. Am. Chem. Soc. 2005, 127, 12856–12861. [CrossRef] [PubMed] 32. Pawlicki, M.; Collins, H.A.; Denning, R.G.; Anderson, H.L. Two-Photon Absorption and the Design of Two-Photon Dyes. Angew. Chem. Int. Ed. 2009, 48, 3244–3266. [CrossRef] 33. Mondal, S.; Naik, P.K.; Adha, J.K.; Kar, S. Synthesis, characterization, and reactivities of high valent metal–corrole (M = Cr, Mn, and Fe) complexes. Coord. Chem. Rev. 2019, 400, 213043. [CrossRef] 34. Ooi, S.; Yoneda, T.; Tanaka, T.; Osuka, A. meso-Free Corroles: Syntheses, Structures, Properties, and Chemical Reactivities. Chem. Eur. J. 2015, 21, 7772–7779. [CrossRef][PubMed]

35. Kandhadi, J.; Yan, W.C.; Cheng, F.; Wang, H.; Liu, H.Y. trans-A2B-corrole bearing 2,3-di(2-pyridyl)quinoxaline (DPQ)/phenothiazine moieties: Synthesis, characterization, electrochemistry and photophysics. New J. Chem. 2018, 42, 9987–9999. [CrossRef] 36. Pivetta, R.C.; Auras, B.L.; Souza, B.d.; Neves, A.; Nunes, F.S.; Cocca, L.H.Z.; Boni, L.D.; Iglesias, B.A. Synthesis, photophysical properties and spectroelectrochemical characterization of 10-(4-methyl-bipyridyl)-5,15-(pentafluorophenyl)corrole. J. Photochem. Photobiol. A 2017, 332, 306–315. [CrossRef] 37. Cai, F.; Xia, F.; Guo, Y.; Zhu, W.; Fu, B.; Liang, X.; Wang, S.; Cai, Z.; Xu, H. “Off–on–off” type of selectively pH-sensing 8-hydroxyquinoline-substituted gallium(iii) corrole. New J. Chem. 2019, 43, 18012–18017. [CrossRef]

38. Yadav, O.; Varshney, A.; Kumar, A.; Ratnesh, R.K.; Mehata, M.S. A2B corroles: Fluorescence signaling systems for sensing ﬂuoride ions. Spectrochim. Acta A Mol. Biomol. Spectrosc. 2018, 202, 207–213. [CrossRef] 39. Liang, X.; Fang, J.J.; Li, M.Z.; Chen, Q.Y.; Mack, J.; Molupe, N.; Nyokong, T.; Zhu, W.H. Push-pull type manganese(III)corroles: Synthesis, electronic structures and tunable interactions with ctDNA. J. Porphyr. Phthalocyanines 2017, 21, 751–758. [CrossRef] Molecules 2020, 25, 3450 36 of 39

40. Zhao, F.; Zhan, X.; Lai, S.-H.; Zhang, L.; Liu, H.-Y. Photophysical properties and singlet oxygen generation of meso-iodinated free-base corroles. RSC Adv. 2019, 9, 12626–12634. [CrossRef] 41. Ali, A.; Cheng, F.; Wen, W.-H.; Ying, X.; Kandhadi, J.; Wang, H.; Liu, H.-Y.; Chang, C.-K. Case synthesis of a β-chloro bulky bis-pocket corrole: Crystallographic characterization and photophysical properties. Chin. Chem. Lett. 2018, 29, 1888–1892. [CrossRef] 42. Larsen, S.; McCormick-McPherson, L.J.; Teat, S.J.; Ghosh, A. Azulicorrole. ACS Omega 2019, 4, 6737–6745. [CrossRef] 43. Lopes, S.M.M.; Pinho e Melo, T.M.V.D. Meso-Substituted Corroles from Nitrosoalkenes and Dipyrromethanes. J. Org. Chem. 2020, 85, 3328–3335. [CrossRef][PubMed] 44. Zhan, X.; Teplitzky, P.; Diskin-Posner, Y.; Sundararajan, M.; Ullah, Z.; Chen, Q.C.; Shimon, L.J.W.; Saltsman, I.; Mahammed, A.; Kosa, M.; et al. Maximizing Property Tuning of Phosphorus Corrole Photocatalysts through a Trifluoromethylation Approach. Inorg. Chem. 2019, 58, 6184–6198. [CrossRef][PubMed] 45. Zhan, X.; Zini, Y.; Fridman, N.; Chen, Q.-C.; Churchill, D.G.; Gross, Z. “Hetero-Multifunctionalization” of Gallium Corroles: Facile Synthesis, Phosphorescence, Redox Tuning, and Photooxidative Catalytic Improvement. ChemPlusChem 2020, 85, 163–168. [CrossRef] 46. Mahammed, A.; Chen, K.P.; Vestfrid, J.; Zhao, J.Z.; Gross, Z. Phosphorus corrole complexes: From property tuning to applications in photocatalysis and triplet-triplet annihilation upconversion. Chem. Sci. 2019, 10, 7091–7103. [CrossRef] 47. Alberto, M.E.; De Simone, B.C.; Liuzzi, S.; Marino, T.; Russo, N.; Toscano, M. Iodine substituted phosphorus corrole complexes as possible photosensitizers in photodynamic therapy: Insights from theory. J. Comp. Chem. 2020, 41, 1395–1401. [CrossRef] 48. Alberto, M.E.; De Simone, B.C.; Mazzone, G.; Russo, N.; Toscano, M. Photophysical Properties of Nitrated and Halogenated Phosphorus Tritolylcorrole Complexes: Insights from Theory. Molecules 2018, 23, 2779. [CrossRef] 49. Kumar, A.; Sujesh, S.; Varshney, P.; Paul, A.; Jeyaraman, S. Aminophenyl-substituted cobalt(III) corrole: A bifunctional electrocatalyst for the oxygen and hydrogen evolution reactions. Dalton Trans. 2019, 48, 11345–11351. [CrossRef] 50. Stefanelli, M.; Ricci, A.; Chiarini, M.; Lo Sterzo, C.; Berionni Berna, B.; Pomarico, G.; Sabuzi, F.; Galloni, P.; Fronczek, F.R.; Smith, K.M.; et al. β-Arylethynyl substituted silver corrole complexes. Dalton Trans. 2019, 48, 13589–13598. [CrossRef] 51. Che, Y.; Yuan, X.; Cai, F.; Zhao, J.; Zhao, X.; Xu, H.; Liu, L. Bodipy Corrole dyad with truxene bridge: − Photophysical Properties and Application in Triplet Triplet Annihilation upconversion. Dyes Pigment. 2019, − 171, 107756. [CrossRef] 52. Larsen, S.; McCormick, L.J.; Ghosh, A. Rapid one-pot synthesis of pyrrole-appended isocorroles. Org. Biomol. Chem. 2019, 17, 3159–3166. [CrossRef][PubMed] 53. Einrem, R.F.; Gagnon, K.J.; Alemayehu, A.B.; Ghosh, A. Metal–Ligand Misfits: Facile Access to Rhenium–Oxo Corroles by Oxidative Metalation. Chem. Eur. J. 2016, 22, 517–520. [CrossRef][PubMed] 54. Borisov, S.M.; Einrem, R.F.; Alemayehu, A.B.; Ghosh, A. Ambient-temperature near-IR phosphorescence and potential applications of rhenium-oxo corroles. Photochem. Photobiol. Sci. 2019, 18, 1166–1170. [CrossRef] 55. Lin, H.; Hossain, M.S.; Zhan, S.-Z.; Liu, H.-Y.; Si, L.-P. Electrocatalytic hydrogen evolution using triaryl corrole cobalt complex. Appl. Organomet. Chem. 2020, 34, e5583. [CrossRef] 56. Mondal, S.; Garai, A.; Naik, P.K.; Adha, J.K.; Kar, S. Synthesis and characterization of antimony(V)-oxo corrole complexes. Inorg. Chim. Acta 2020, 501, 119300. [CrossRef] 57. Schweyen, P.; Kleeberg, C.; Körner, D.; Thüsing, A.; Wicht, R.; Zaretzke, M.-K.; Bröring, M. Ruffling and doming: Structural and redox studies on meso-aryl and β-alkyl chromyl(V)corroles. J. Porphyr. Phthalocyanines 2020, 24, 303–313. [CrossRef] 58. Chen, Q.-C.; Xiao, Z.-Y.; Fite, S.; Mizrahi, A.; Fridman, N.; Zhan, X.; Keisar, O.; Cohen, Y.; Gross, Z. Tuning Chemical and Physical Properties of Phosphorus Corroles for Advanced Applications. Chem. Eur. J. 2019, 25, 11383–11388. [CrossRef] 59. Gilhula, J.C.; Radosevich, A.T. Tetragonal phosphorus(v) cations as tunable and robust catalytic Lewis acids. Chem. Sci. 2019, 10, 7177–7182. [CrossRef] 60. Caulfield, K.P.; Conradie, J.; Arman, H.D.; Ghosh, A.; Tonzetich, Z.J. Iron(II) Corrole Anions. Inorg. Chem. 2019, 58, 15225–15235. [CrossRef] Molecules 2020, 25, 3450 37 of 39

61. Zhang, X.; Wang, Y.; Zhu, W.; Mack, J.; Soy, R.C.; Nyokong, T.; Liang, X. Meso- and axially-modified IrIIItriarylcorroles with tunable electrocatalytic properties. Dyes Pigment. 2020, 175, 108124. [CrossRef] 62. Thomassen, I.K.; McCormick-McPherson, L.J.; Borisov, S.M.; Ghosh, A. Iridium Corroles Exhibit Weak Near-Infrared Phosphorescence but Efficiently Sensitize Singlet Oxygen Formation. Sci. Rep. 2020, 10, 1–9. [CrossRef][PubMed] 63. Lai, S.-H.; Wang, L.-L.; Wan, B.; Lu, A.-W.; Wang, H.; Liu, H.-Y. Photophysical properties, singlet oxygen generation and DNA binding affinity of Tris(4-pyridyl)corrole and its phosphorous, gallium and tin complexes. J. Photochem. Photobiol. A 2020, 390, 112283. [CrossRef] 64. Lu, G.; Sun, Q.; Zhang, T.; Kong, X.; Wang, Q.; He, C. Preparation of new semiconducting corrole nanostructures and their application as gas sensor. Synth. Met. 2019, 252, 69–75. [CrossRef] 65. Oppenheim, J.; Gray, M.H.B.; Di Bilio, A.J.; Brennan, B.J.; Henling, L.M.; Lim, P.; Soll, M.; Termini, J.; Virgil, S.C.; Gross, Z.; et al. Structures and Spectroscopic Properties of Metallocorrole Nanoparticles. Inorg. Chem. 2019, 58, 10287–10294. [CrossRef][PubMed] 66. Agadjanian, H.; Ma, J.; Rentsendorj, A.; Valluripalli, V.; Hwang, J.Y.; Mahammed, A.; Farkas, D.L.; Gray, H.B.; Gross, Z.; Medina-Kauwe, L.K. Tumor Detection and Elimination by a Targeted Gallium Corrole. Proc. Natl. Acad. Sci. USA 2009, 106, 6105–6110. [CrossRef][PubMed] 67. Soll, M.; Goswami, T.K.; Chen, Q.C.; Saltsman, I.; Teo, R.D.; Shahgholi, M.; Lim, P.; Di Bilio, A.J.; Cohen, S.; Termini, J.; et al. Cell-Penetrating Protein/Corrole Nanoparticles. Sci. Rep. 2019, 9, 2294. [CrossRef] 68. Berionni Berna, B.; Savoldelli, A.; Pomarico, G.; Zurlo, F.; Magna, G.; Paolesse, R.; Fronczek, F.R.; Smith, K.M.; Nardis, S. Grafting Copper and Gallium Corroles onto Zinc Oxide Nanoparticles. ChemPlusChem 2019, 84, 154–160. [CrossRef] 69. Tang, J.; Chen, B.; Zhang, Y.; Lu, J.; Zhang, T.; Guo, Q.; Zhang, J. Synthesis and gas sensitivity properties of novel metallocorroles and functionalized graphene oxide. Funct. Mater. Lett. 2019, 12, 1940001. [CrossRef] 70. Sahu, K.; Mondal, S.; Patra, B.; Pain, T.; Patra, S.K.; Dosche, C.; Kar, S. Regioselective thiocyanation of corroles and the synthesis of gold nanoparticle–corrole assemblies. Nanoscale Adv. 2020, 2, 166–170. [CrossRef] 71. Lu, G.; Bao, L.; Hu, X.; Liu, X.; Zhu, W. Synthesis, spectroscopic characterization and photocatalytic properties

of corrole modified GPTMS/TiO2 nanoparticles. Inorg. Chem. Commun. 2018, 98, 165–168. [CrossRef] 72. Zhao, Y.; Qi, S.; Niu, Z.; Peng, Y.; Shan, C.; Verma, G.; Wojtas, L.; Zhang, Z.; Zhang, B.; Feng, Y.; et al. Robust Corrole-Based Metal—Organic Frameworks with Rare 9-Connected Zr/Hf-Oxo Clusters. J. Am. Chem. Soc. 2019, 141, 14443–14450. [CrossRef][PubMed] 73. Waller, P.J.; Gándara, F.; Yaghi, O.M. Chemistry of Covalent Organic Frameworks. Acc. Chem. Res. 2015, 48, 3053–3063. [CrossRef][PubMed] 74. Brandès, S.; Quesneau, V.; Fonquernie, O.; Desbois, N.; Blondeau-Patissier, V.; Gros, C.P. Porous organic polymers based on cobalt corroles for carbon monoxide binding. Dalton Trans. 2019, 48, 11651–11662. [CrossRef][PubMed] 75. Gomes, A.; Neves, M.; Cavaleiro, J.A.S. Cancer, Photodynamic Therapy and Porphyrin-Type Derivatives. An. Acad. Bras. Cienc. 2018, 90, 993–1026. [CrossRef] 76. Babu, B.; Prinsloo, E.; Mack, J.; Nyokong, T. Synthesis, characterization and photodynamic activity of Sn(iv) triarylcorroles with red-shifted Q bands. New J. Chem. 2019, 43, 18805–18812. [CrossRef] 77. Sun, Y.-M.; Akram, W.; Cheng, F.; Liu, Z.-Y.; Liao, Y.-H.; Ye, Y.; Liu, H.-Y. DNA interaction and photodynamic antitumor activity of transition metal mono-hydroxyl corrole. Bioorg. Chem. 2019, 90, 103085. [CrossRef] 78. Chen, X.; Wang, H.H.; Akram, W.; Sun, Y.M.; Liao, Y.H.; Si, L.P.; Liu, H.Y.; Chang, C.K. Tri-hydroxyl Corrole and Its Gallium(III) Complex: DNA-Binding, Photocleavage and in Vitro Photodynamic Antitumor Activities. Chin. J. Inorg. Chem. 2019, 35, 1687–1697. [CrossRef] 79. Zhang, Z.; Yu, H.J.; Huang, H.; Wan, B.; Wu, S.; Liu, H.Y.; Zhang, H.T. The photocytotoxicity effect of cationic sulfonated corrole towards lung cancer cells: In vitro and in vivo study. Lasers Med. Sci. 2019, 34, 1353–1363. [CrossRef] 80. Barata, J.F.B.; Zamarrón, A.; Neves, M.G.P.M.S.; Faustino, M.A.F.; Tomé, A.C.; Cavaleiro, J.A.S.; Röder, B.; Juarranz, Á.; Sanz-Rodríguez, F. Photodynamic effects induced by meso-tris(pentafluorophenyl)corrole and its cyclodextrin conjugates on cytoskeletal components of HeLa cells. Eur. J. Med. Chem. 2015, 92, 135–144. [CrossRef] Molecules 2020, 25, 3450 38 of 39

81. Einrem, R.F.; Alemayehu, A.B.; Borisov, S.M.; Ghosh, A.; Gederaas, O.A. Amphiphilic Rhenium-Oxo Corroles as a New Class of Sensitizers for Photodynamic Therapy. ACS Omega 2020, 5, 10596–10601. [CrossRef] [PubMed] 82. Zhao, Y.; Dai, W.; Peng, Y.; Niu, Z.; Sun, Q.; Shan, C.; Yang, H.; Verma, G.; Wojtas, L.; Yuan, D.; et al. A Corrole-Based Covalent Organic Framework Featuring Desymmetrized Topology. Angew. Chem. Int. Ed. 2020, 59, 4354–4359. [CrossRef][PubMed] 83. Carbon-linked HexapyrrolicSystems and Heteroatom Analogs. In Expanded, Contracted & Isomeric Porphyrins; Jonathan, L.; Sessler, S.J.W. (Eds.) Tetrahedron Organic Chemistry Series; Elsevier: Amsterdam, The Netherlands, 1997; volume 15, pp. 329–367. 84. Neves, M.G.P.M.S.; Martins, R.M.; Tomé, A.C.; Silvestre, A.J.D.; Silva, A.M.S.; Félix, V.; Drew, M.G.B.; Cavaleiro, J.A.S. meso-Substituted expanded porphyrins: New and stable hexaphyrins. Chem. Commun. 1999, 385–386. [CrossRef] 85. Shin, J.-Y.; Furuta, H.; Yoza, K.; Igarashi, S.; Osuka, A. meso-Aryl-Substituted Expanded Porphyrins. J. Am. Chem. Soc. 2001, 123, 7190–7191. [CrossRef][PubMed] 86. Taniguchi, R.; Shimizu, S.; Suzuki, M.; Shin, J.-Y.; Furuta, H.; Osuka, A. Ring size selective synthesis of meso-aryl expanded porphyrins. Tetrahedron Lett. 2003, 44, 2505–2507. [CrossRef] 87. Suzuki, M.; Osuka, A. Improved Synthesis of meso-Aryl-Substituted [26]Hexaphyrins. Org. Lett. 2003, 5, 3943–3946. [CrossRef] 88. Ishida, S.-I.; Soya, T.; Osuka, A. A Stable Antiaromatic 5,20-Dibenzoyl [28]Hexaphyrin(1.1.1.1.1.1): Core AuIII Metalation and Subsequent Peripheral BIII Metalation. Angew. Chem. Int. Ed. 2018, 57, 13640–13643. [CrossRef] 89. Nakai, A.; Kim, J.; Kim, D.; Osuka, A. 5,20-Bis(ethoxycarbonyl)-Substituted Antiaromatic [28]Hexaphyrin and Its Bis-NiII and Bis-CuII Complexes. Chem. Asian J. 2019, 14, 968–971. [CrossRef] 90. Nakai, A.; Ishida, S.-I.; Soya, T.; Osuka, A. π-Ruthenium Complexes of Hexaphyrins(1.1.1.1.1.1): A Triple-Decker Complex Bearing Two Ruthenoarene Units. Angew. Chem. Int. Ed. 2019, 58, 8197–8200. [CrossRef] 91. Yoneda, T.; Osuka, A. Synthesis of a [26]Hexaphyrin Bis-PdII Complex with a Characteristic Aromatic Circuit. Chem. Eur. J. 2013, 19, 7314–7318. [CrossRef] 92. Yoneda, T.; Kim, T.; Soya, T.; Neya, S.; Oh, J.; Kim, D.; Osuka, A. Conformational Fixation of a Rectangular Antiaromatic [28]Hexaphyrin Using Rationally Installed Peripheral Straps. Chem. Eur. J. 2016, 22, 4413–4417. [CrossRef][PubMed] 93. Nakai, A.; Yoneda, T.; Ishida, S.-i.; Kato, K.; Osuka, A. Aromatic and Antiaromatic Cyclophane-type Hexaphyrin Dimers. Chem. Asian J. 2019, 14, 256–260. [CrossRef][PubMed] 94. Kasha, M.; Rawls, H.R.; El-Bayoumi, M.A. The exciton model in molecular spectroscopy. Pure Appl. Chem. 1965, 11, 371–392. [CrossRef] 95. Suzuki, M.; Shimizu, S.; Shin, J.-Y.; Osuka, A. Regioselective nucleophilic substitution reaction of meso-hexakis(pentaﬂuorophenyl) substituted [26]hexaphyrin. Tetrahedron Lett. 2003, 44, 4597–4601. [CrossRef] 96. Klingenburg, R.; Stark, C.B.W.; Wiehe, A. Nucleophilic Thioglycosylation of Pentaﬂuorophenyl-Substituted Porphyrinoids: Synthesis of Glycosylated Calix[n]phyrin and [28]Hexaphyrin Systems. Org. Lett. 2019, 21, 5417–5420. [CrossRef][PubMed] 97. Brewster, J.T.; Root, H.D.; Mangel, D.; Samia, A.; Zafar, H.; Sedgwick, A.C.; Lynch, V.M.; Sessler, J.L. 2+ UO2 -Mediated ring contraction of pyrihexaphyrin: Synthesis of a contracted expanded porphyrin-uranyl complex. Chem. Sci. 2019, 10, 5596–5602. [CrossRef] 98. Samala, S.; Dutta, R.; He, Q.; Park, Y.; Chandra, B.; Lynch, V.M.; Jung, Y.M.; Sessler, J.L.; Lee, C.-H. A robust bis-rhodium(I) complex of π-extended planar, anti-aromatic hexaphyrin[1.0.1.0.1.0]. Chem. Commun. 2020, 56, 758–761. [CrossRef] 99. Shimomura, K.; Kai, H.; Nakamura, Y.; Hong, Y.; Mori, S.; Miki, K.; Ohe, K.; Notsuka, Y.; Yamaoka, Y.; Ishida, M.; et al. Bis-Metal Complexes of Doubly N-Confused Dioxohexaphyrins as Potential Near-Infrared-II Photoacoustic Dyes. J. Am. Chem. Soc. 2020, 142, 4429–4437. [CrossRef] 100. Xue, S.; Kuzuhara, D.; Aratani, N.; Yamada, H. Control of Aromaticity and cis-/trans-Isomeric Structure of Non-Planar Hexaphyrin(2.1.2.1.2.1) and Metal Complexes. Angew. Chem. Int. Ed. 2019, 58, 12524–12528. [CrossRef] Molecules 2020, 25, 3450 39 of 39

101. Xue, S.; Kuzuhara, D.; Aratani, N.; Yamada, H. [30]Hexaphyrin(2.1.2.1.2.1) as Aromatic Planar Ligand and Its Trinuclear Rhodium(I) Complex. Inorg. Chem. 2018, 57, 9902–9906. [CrossRef] 102. Laidig, K.E.; Speers, P.; Streiwieser, A. Origin of depressed dipole moments in fivemembered, unsaturated heterocycles. Can. J. Chem. 1996, 74, 1215–1220. [CrossRef] 103. Ajay, J.; Shirisha, S.; Ishida, M.; Ito, K.; Mori, S.; Furuta, H.; Gokulnath, S. Planar Antiaromatic Core-Modified 24π Hexaphyrin(1.0.1.0.1.0) and 32π Octaphyrin(1.0.1.0.1.0.1.0) Bearing Alternate Hybrid Diheterole Units. Chem. Eur. J. 2019, 25, 2859–2867. [CrossRef][PubMed] 104. Abdisa Kerayu, B.; Ching, W.-M.; dela Cruz, J.-a.; Hung, C.-H. 2,5-Thienylene-Strapped Bicyclic and Tricyclic Expanded Porphyrins. ChemPlusChem 2019, 84, 810–815. [CrossRef][PubMed] 105. Ambhore, M.D.; Basavarajappa, A.; Anand, V.G. A wide-range of redox states of core-modified expanded porphyrinoids. Chem. Commun. 2019, 55, 6763–6766. [CrossRef][PubMed] 106. Dash, S.; Ghosh, A.; Srinivasan, A.; Suresh, C.H.; Chandrashekar, T.K. Protonation-Triggered Hückel and Möbius Aromatic Transformations in Nonaromatic Core-Modified [30]Hexaphyrin(2.1.1.2.1.1) and Annulated [28]Hexaphyrin(2.1.1.0.1.1). Org. Lett. 2019, 21, 9637–9641. [CrossRef][PubMed] 107. Gaur, R.; Ambhore, M.D.; Anand, V.G. Non-planar core-modified dibenzi expanded isophlorin. J. Porphyr. Phthalocyan. 2020, 24, 298–302. [CrossRef] 108. Kishore, M.V.N.; Panda, P.K. Revisiting the intense NIR active bronzaphyrin, a 26-π aromatic expanded porphyrin: Synthesis and structural analysis. Chem. Commun. 2018, 54, 13135–13138. [CrossRef] 109. Tian, J.; Ding, L.; Xu, H.-J.; Shen, Z.; Ju, H.; Jia, L.; Bao, L.; Yu, J.-S. Cell-Specific and pH-Activatable Rubyrin-Loaded Nanoparticles for Highly Selective Near-Infrared Photodynamic Therapy against Cancer. J. Am. Chem. Soc. 2013, 135, 18850–18858. [CrossRef]

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).