Clinical advancements in nuclear medicine theranostics has excited a research interest in exploring novel radionuclides for medical use. The duo of the (3- emitter 67 Cu and the positron emitter 64 Cu, has advantages over the well-established clinical pair 68 Ga and 177 Lu in terms of capability for high-precision therapy. Low availability has hindered the use of 67 Cu whereas 64 Cu has become established at a limited number of sites through production in low-to-medium energy biomedical cyclotrons. Via the reaction 70 Zn(p,alpha) 67 Cu, 67 Cu can also be cyclotron produced, although data on the cross sections of this reaction are sparse. Our aim in this study was three-fold: 1) to establish cross sections for relevant beam energies (14-16 MeV) of the 70 Zn(p,alpha) 67 Cu reaction; 2) determine experimentally the thick target yield for 16.5 MeV proton beam; 3) establish a routine production of 67 Cu for radiochemical and preclinical research. Additionally, our work aims to explore the feasibility of using biomedical cyclotrons for developing of novel therapeutic radionuclides. Thin layers of enriched 70 Zn were electrodeposited onto silver foils to employ the stacked foils technique for assessing the cross section at six energies. The thick target yield was measured experimentally using a pressed [70Zn]ZnO target. Methods were developed for solid phase extraction separation of 67 Cu from the target material, as well as quality control of the product with regards to radionuclidic and radiochemical purity. Radiolabelling of PSMA-617 precursor was performed and the end product injected in a healthy mouse for a kinetic study. As a proof of concept for preclinical applications The animal was then SPECT imaged using the 185 keV gamma emission line. Summarizing, our data confirm that biomedical cyclotrons can contribute in developing novel radionuclides, even of low cross section, for preclinical research.

Increasing interest in 67Cu for targeted radionuclide therapy necessitates development of robust and validated analytical methods to ensure compliance with regulatory standards for clinical translation. We validated methods based on inductively coupled plasma optical emission spectroscopy (ICP-OES) and high-purity germanium (HPGe) γ-spectrometry. For ICP-OES, criteria were met for most elements, with Al and Ca, suffering matrix effects. Apparent molar activity calculated by ICP-OES was congruent with DOTA-titration-based effective molar activity when Al and Ca were excluded. HPGe γ-spectrometry was shown to enable accurate discrimination and quantification of co-produced radionuclides (67Ga, 66Ga, 69mZn) from 67Cu at 99.5

Phlorins have long remained underexplored relative to their fully conjugated counterparts, such as porphyrins, hydroporphyrins, and corroles. Herein, we have attempted to bridge that knowledge gap with a scalar-relativistic density functional theory (DFT) study of unsubstituted iridium and gold phlorin derivatives and a multitechnique experimental study of iridium-bispyridine and gold complexes of 5,5-dimethyl-10,15,20-tris(pentafluorophenyl)phlorin. Theory and experiments concur that the phlorin derivatives exhibit substantially smaller HOMO-LUMO gaps, as reflected in a variety of observable properties. Thus, the experimentally studied Ir and Au complexes absorb strongly in the near-infrared (NIR), with absorption maxima at 806 and 770 nm, respectively. The two complexes are also weakly phosphorescent with emission maxima at 950 and 967 nm, respectively. They were also found to photosensitize singlet oxygen formation, with quantum yields of 40 and 28%, respectively. The near-infrared (NIR) absorption and emission are consonants with smaller electrochemical HOMO-LUMO gaps of similar to 1.6 V, compared to values of similar to 2.1 V, for electronically innocent porphyrins and corroles. Interestingly, both the first oxidation and reduction potentials of the Ir complex are some 600 mV shifted to more negative potentials relative to those of the Au complex, indicating an exceptionally electron-rich macrocycle in the case of the Ir complex.

Clinical advancements in nuclear medicine theranostics has excited a research interest in exploring novel radionuclides for medical use. The duo of the β- emitter 67Cu and the positron emitter 64Cu, has advantages over the well-established clinical pair 68Ga and 177Lu in terms of capability for high-precision therapy. Low availability has hindered the use of 67Cu whereas 64Cu has become established at a limited number of sites through production in low-to-medium energy biomedical cyclotrons. Via the reaction 70Zn(p,α)67Cu, 67Cu can also be cyclotron produced, although data on the cross sections of this reaction are sparse. Our aim in this study was three-fold: 1) to establish cross sections for relevant beam energies (14-16 MeV) of the 70Zn(p,α)67Cu reaction; 2) determine experimentally the thick target yield for 16.5 MeV proton beam; 3) establish a routine production of 67Cu for radiochemical and preclinical research. Additionally, our work aims to explore the feasibility of using biomedical cyclotrons for developing of novel therapeutic radionuclides. Thin layers of enriched 70Zn were electrodeposited onto silver foils to employ the stacked foils technique for assessing the cross section at six energies. The thick target yield was measured experimentally using a pressed [70Zn]ZnO target. Methods were developed for solid phase extraction separation of 67Cu from the target material, as well as quality control of the product with regards to radionuclidic and radiochemical purity. Radiolabelling of PSMA-617 precursor was performed and the end product injected in a healthy mouse for a kinetic study. As a proof of concept for preclinical applications The animal was then SPECT imaged using the 185 keV gamma emission line. Summarizing, our data confirm that biomedical cyclotrons can contribute in developing novel radionuclides, even of low cross section, for preclinical research.

Soret-excited resonance Raman spectra (λex 413.1 nm) were acquired for manganese(III) and gold(III) tris(pentafluorophenyl)corrole, each as four different isotopomeric samples: natural abundance, fully pyrrole-15N-substituted, fully meso-13C-substituted, and fully pyrrole-15N-meso-13C-substituted. The spectra were modeled with density functional theory-based vibrational analyses, which in general did an excellent job of reproducing both the absolute frequencies and isotope shifts. The results led to the assignment and visualization of approximately 10 prominent Raman bands. A key finding was that the bands could be categorized into two broad classes: Class A, exhibiting large 15N isotope shifts, assignable to vibrations with predominant Cα-N character, and Class B, exhibiting large meso-13C isotope shifts, assignable to vibrations with predominant Cα-Cmeso character. Preliminary evidence suggests that the class A bands may serve as core size markers, while class B bands may correlate with the innocence or otherwise of the corrole macrocycle.

Conspectus Porphyrin chemistry is Shakespearean: over a century of study has not withered the field’s apparently infinite variety. Heme proteins continually astonish us with novel molecular mechanisms, while new porphyrin analogues bowl us over with unprecedented optical, electronic, and metal-binding properties. Within the latter domain, corroles occupy a special place, exhibiting a unique and rich coordination chemistry. The 5d metallocorroles are arguably the icing on that cake. New Zealand chemist Penny Brothers has used the word “misfit” to describe the interactions of boron, a small atom with a predilection for tetrahedral coordination, and porphyrins, classic square-planar ligands. Steve Jobs lionized misfits as those who see things differently and push humanity forward. Both perspectives have inspired us. The 5d metallocorroles are misfits in that they encapsulate a large 5d transition metal ion within the tight cavity of a contracted porphyrin ligand. Given the steric mismatch inherent in their structures, the syntheses of some 5d metallocorroles are understandably capricious, proceeding under highly specific conditions and affording poor yields. Three broad approaches may be distinguished. (a) In the metal–alkyl approach, a free-base corrole is exposed to an alkyllithium and the resulting lithio-corrole is treated with an early transition metal chloride; a variant of the method eschews alkyllithium and deploys a transition metal–alkyl instead, resulting in elimination of the alkyl group as an alkane and insertion of the metal into the corrole. This approach is useful for inserting transition metals from groups 4, 5, and, to some extent, 6, as well as lanthanides and actinides. (b) In our laboratory, we have often deployed a low-valent organometallic approach for the middle transition elements (groups 6, 7, 8, and 9). The reagents are low-valent metal–carbonyl or −olefin complexes, which lose one or more carbon ligands at high temperature, affording coordinatively unsaturated, sticky metal fragments that are trapped by the corrole nitrogens. (c) Finally, a metal acetate approach provides the method of choice for gold and platinum insertion (groups 10 and 11). This Account provides a first-hand perspective of the three approaches, focusing on the last two, which were largely developed in our laboratory. In general, the products were characterized with X-ray crystallography, electrochemistry, and a variety of spectroscopic methods. The physicochemical data, supplemented by relativistic DFT calculations, have provided fascinating insights into periodic trends and relativistic effects. An unexpected feature of many 5d metallocorroles, given their misfit character, is their remarkable stability under thermal, chemical, and photochemical stimulation. Many of them also exhibit long triplet lifetimes on the order of 100 μs and effectively sensitize singlet oxygen formation. Many exhibit phosphorescence in the near-infrared under ambient conditions. Furthermore, water-soluble ReO and Au corroles exhibit impressive photocytotoxicity against multiple cancer cell lines, promising potential applications as cancer phototherapeutics. We thus envision a bright future for the compounds as rugged building blocks for new generations of therapeutic and diagnostic (theranostic) agents.

Platinum L3-edge XAS and DFT calculations on three well-characterized Pt porphyrinoid complexes have provided detailed insights into metal- versus ligand-centered oxidation and ligand field effects.

Correction for ‘X-ray absorption spectroscopy of exemplary platinum porphyrin and corrole derivatives: metal- versus ligand-centered oxidation’ by Benjamin D. Matson et al., RSC Adv., 2021, 11, 32269–32274. DOI: 10.1039/D1RA06151H

Metallocorroles wherein the metal ion is Mn-III and formally Fe-IV are studied here using field- and frequency-domain electron paramagnetic resonance techniques. The Mn-III corrole, Mn(tpfc) (tpfc = 5,10,15-tris(pentafluorophenyl)corrole trianion), exhibits the following S = 2 zero-field splitting (zfs) parameters: D = 2.67(1) cm(-1), 1E1 = 0.023(5) cm-1. This result and those for other Mn-III tetrapyrroles indicate that when D = 2.5 0.5 cm(-1) for 4- or 5 coordinate and D 3.5 0.5 cm(-1) for 6-coordinate complexes, the ground state description is [Mn111(Cor3-)] or [Mn111(P2-)]+ (Cor = corrole, P = porphyrin). The situation for formally Few corroles is more complicated, and it has been shown that for Fe(Cor)X, when X = Ph (phenyl), the ground state is a spin triplet best described by [Few(Cor(3)(-))]+, but when X = halide, the ground state corresponds to [Fe-III(Cor(2)(-))]+, wherein an intermediate spin (S = 3/2) Fe-III is antiferromagnetically coupled to a corrole radical dianion (S = 1/2) to also give an S = 1 ground state. These two valence isomers can be distinguished by their zfs parameters, as determined here for Fe(tpc)X, X = Ph, Cl (tpc = 5,10,15 triphenylcorrole trianion). The complex with axial phenyl gives D = 21.1(2) cm(-1), while that with axial chloride gives D = 14.6(1) cm(-1). The D value for Fe(tpc)Ph is in rough agreement with the range of values reported for other Few complexes. In contrast, the D value for Fe(tpc)Cl is inconsistent with an Felv description and represents a different type of iron center. Computational studies corroborate the zfs for the two types of iron corrole complexes. Thus, the zfs of metallocorroles can be diagnostic as to the electronic structure of a formally high oxidation state metallocorrole, and by extension to metalloporphyrins, although such studies have yet to be performed.

Given that noninnocent and metalloradical-type electronic structures are ubiquitous among dipyrrin-bisphenolate (DPP) complexes, we synthesized the gold(iii) derivatives as potentially innocent paradigms against which the properties of other metallo-DPP derivatives can be evaluated. Electronic absorption spectra, electrochemical studies, a single-crystal X-ray structure, and DFT calculations all suggest that the ground states of the new complexes indeed correspond to an innocent Au-III-DPP3-, paralleling a similar description noted for Au corroles. Interestingly, while DFT calculations indicate purely ligand-centered oxidations, reduction of AuDPP is predicted to occur across both the metal and the ligand.

The elusive cis tautomer of free-base porphyrins has recently been isolated and structurally characterized in the form of a supramolecular complex. The question as to whether a suitable set of peripheral substituents might lead to a stable cis tautomer in the absence of supramolecular interactions, however, remains unanswered and is one we have attempted to address here by means of density functional theory calculations. The fact that many antipodally β-tetrasubstituted tetraphenylporphyrin derivatives exhibit localized central protons attached to the β-unsubstituted pyrrole rings led us to surmise that β-tetrasubstitution of adjacent pyrrole rings might lead to a porphyrin cis tautomer, an idea that proved fruitful. Indeed, for the "adjacently" substituted tetraphenylporphyrin derivative H2[adj-(CF3)4(CH3)4TPP], the global energy minimum proved to be a highly saddled cis tautomer, with the trans tautomer about 0.07 eV higher in energy. It is important to underscore, however, that the asymmetric β-substitution pattern is far from the only factor contributing to the stability of the cis tautomer for this porphyrin. A strongly saddled conformation resulting from meso-β steric interactions also helps alleviate the repulsion between the two central NH protons, thereby stabilizing the cis tautomer relative to the trans.

A combination of Cr K-edge XAS and DFT calculations have been performed on archetypal chromium porphyrinoid complexes CrIV[TMP]O (2) and CrV[TPC]O (3), and the results have been compared to the reference compound CrIII[TPP]Cl (1), where TPP2-, TMP2-, and TPC3- are the anions of meso-tetraphenylporphyrin, meso-tetramesitylporphyrin, and meso-triphenylcorrole, respectively. The intensity-weighted average energy position in 1 (5990.9 eV), 2 (5992.0 eV) and 3 (5992.6 eV) are consistent with increasing the metal oxidation state along the series. EXAFS and theoretical analysis of 2 and 3 reveal that the Cr-O bond is longer and weaker in 3 relative to 2, despite the structural similarity and increase in oxidation state in 3. This is also reflected in a comparison of the Cr K-pre-edge transitions. The roughly twenty-fold increase in intensity in the two oxo complexes is unsurprising and well-precedented for other first-row transition metals. However, although 3 had greater overall intensity, the intensity of transitions along the Cr-O bond is greater. EXAFS, DFT and TDDFT analyses show that the more contracted N4 core of the corrole results in a greater out-of-plane displacement of the Cr in 3 relative to 2, which in turn accentuates the lower local symmetry of the Cr in 3 relative to 2. This difference helps us to appreciate the TDDFT result that whereas two 1s→ 3d z 2 transitions make up the majority of the intensity in the pre-edge of 2, the pre-edge of 3 also includes fairly intense transitions to molecular orbitals with 3d xz , 3d yz and 3d z 2 character, thus accounting for the somewhat higher overall intensity for 3.

Single-crystal X-ray structures were obtained for the copper and μ-oxodiiron complexes of 2,3,7,8,12,13,17,18-octafluoro-5,10,15-triphenylcorrole, hereafter denoted as Cu[F8TPC] and {Fe[F8TPC]}2O. A comparison with the crystal structures of other undecasubstituted Cu corroles, including those with H, Ar, Br, I, and CF3 as β-substituents, showed that the degree of saddling increases in the order: H ≲ F < Ar ≲ Br ≲ I < CF3. In other words, Cu[F8TPC] is marginally more saddled than β-unsubstituted Cu triarylcorroles, but substantially less saddled than Cu undecaarylcorroles, β-octabromo-meso-triarylcorroles, and β-octaiodo-meso-triarylcorroles, and far less saddled than Cu β-octakis(trifluoromethyl)-meso-triarylcorroles. As for {Fe[F8TPC]}2O, the moderate quality of the structure did not allow us to draw firm conclusions in regard to bond length alternations in the corrole skeleton and hence also the question of ligand noninnocence. The Fe–O bond distances, 1.712(8) and 1.724(8), however, are essentially identical to those observed for {Fe[TPFPC]}2O, where TPFPC3– is the trianion of 5,10,15-tris(pentafluorophenyl)corrole, suggesting that a partially noninnocent electronic structural description may be applicable for both compounds.

A porphyrin cis tautomer, where the two central NH protons are on adjacent pyrrole rings, has long been invoked as an intermediate in porphyrin tautomerism. Only recently, however, has such a species been isolated and structurally characterized. Thus, single-crystal X-ray structure determinations of two highly saddled free-base porphyrins, β-heptakis(trifluoromethyl)-meso-tetrakis(p-fluorophenyl)porphyrin, H2[(CF3)7TFPP], and β-octaiodo-5,10,15,20-tetrakis(4′-trifluoromethylphenyl)porphyrin, H2[I8TCF3PP], unambiguously revealed cis tautomeric structures, each stabilized as a termolecular complex with a pair of ROH (R = CH3 or H) molecules that form hydrogen-bonded N–H···O–H···N straps connecting the central NH groups with the antipodal unprotonated nitrogens. The unusual substitution patterns of these two porphyrins, however, have left open the question how readily such supramolecular assemblies might be engineered, which prompted us to examine the much more synthetically accessible β-octabromo-meso-tetraphenylporphyrins. Herein, single-crystal X-ray structures were obtained for two such compounds, 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(4′-trifluoromethylphenyl)porphyrin, H2[Br8TCF3PP], and 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(4′-fluorophenyl)porphyrin, H2[Br8TFPP], and although the central hydrogens could not all be located unambiguously, the electron density could be convincingly modeled as porphyrin cis tautomers, existing in each case as a bis-methanol adduct. In addition, a perusal of the Cambridge Structural Database suggests that there may well be additional examples of porphyrin cis tautomers that have not been recognized as such. We are therefore increasingly confident that porphyrin cis tautomers are readily accessible via supramolecular engineering, involving the simple stratagem of crystallizing a strongly saddled porphyrin from a solvent system containing an amphiprotic species such as water or an alcohol.

The question of ligand noninnocence in Cu corroles has long been a topic of discussion. Presented herein is a Cu K-edge X-ray absorption spectroscopy (XAS) study, which provides a direct probe of the metal oxidation state, of three Cu corroles, Cu[TPC], Cu[Br8TPC], and Cu[(CF3)8TPC] (TPC = meso-triphenylcorrole), and the analogous Cu(II) porphyrins, Cu[TPP], Cu[Br8TPP], and Cu[(CF3)8TPP] (TPP = meso-tetraphenylporphyrin). The Cu K rising-edges of the Cu corroles were found to be about 0-1 eV upshifted relative to the analogous porphyrins, which is substantially lower than the 1-2 eV shifts typically exhibited by authentic Cu(II)/Cu(III) model complex pairs. In an unusual twist, the Cu K pre-edge regions of both the Cu corroles and the Cu porphyrins exhibit two peaks split by 0.8-1.3 eV. Based on time-dependent density functional theory calculations, the lower- and higher-energy peaks were assigned to a Cu 1s → 3d x2- y2 transition and a Cu 1s → corrole/porphyrin π* transition, respectively. From the Cu(II) porphyrins to the corresponding Cu corroles, the energy of the Cu 1s → 3d x2- y2 transition peak was found to upshift by 0.6-0.8 eV. This shift is approximately half that observed between Cu(II) to Cu(III) states for well-defined complexes. The Cu K-edge XAS spectra thus show that although the metal sites in the Cu corroles are more oxidized relative to those in their Cu(II) porphyrin analogues, they are not oxidized to the Cu(III) level, consistent with the notion of a noninnocent corrole. The relative importance of σ-donation versus corrole π-radical character is discussed.

X-ray structures of gold corroles, which are still rather uncommon, afford significant insights into intermolecular interactions involving Au(III), a subject that has been much less studied than aurophilic and metallophilic interactions involving Au(I). The X-ray structure of gold [Formula: see text]-octabromo-meso-tris(para-pentafluorosulfanylphenyl)corrole, reported herein, has revealed two Au···Br interactions (∼4.2 Å) per Au atom. We suggest that analogous but somewhat stronger Au···Br interactions are a key factor underlying the remarkable insolubility of gold octabromocorrole derivatives.

Halterman corroles have been synthesized for the first time from pyrrole and Halterman's aldehyde via Gryko's "water-methanol method". These were derivatized to the corresponding copper complexes and subsequently to the β-octabromo complexes. Electronic circular dichroism spectra were recorded for the enantiopure copper complexes, affording the first such measurements for the inherently chiral Cu corrole chromophore. Interestingly, for a given configuration of the Halterman substituents, X-ray crystallographic studies revealed both P and M conformations of the Cu-corrole core, proving that the substituents, even in conjunction with β-octabromination, are unable to lock the Cu-corrole core into a given chirality. The overall body of evidence strongly indicates a dynamic equilibrium between the P and M conformations. Such an interconversion, which presumably proceeds via saddling inversion, provides a rationale for our failure so far to resolve sterically hindered Cu corroles into their constituent enantiomers by means of chiral HPLC.

Electrochemical and acid-base properties of four free-base triarylcorroles were examined in nonaqueous media. These compounds are represented here as (tdcc)H[Formula: see text], (tpfc)H[Formula: see text], (Br[Formula: see text]tdcc)H[Formula: see text] and (Br[Formula: see text]tpfc)H[Formula: see text], where tdcc and tpfc are the trianions of tris(2,6-dichlorophenyl)corrole and tris(pentafluorophenyl)corrole, respectively. Different spectroscopic and electrochemical properties were observed for the [Formula: see text]-brominated corroles as compared to the non-brominated derivatives, due in part to the corrole ring distortion and in part to the strong electron-withdrawing properties of the Br groups. The brominated free-base corroles are easier to deprotonate than the non-brominated corroles in solution, which was confirmed by electrochemistry and spectroelectrochemistry as well as protonation/deprotonation reactions of the compounds with acid or base in PhCN. The electrochemistry of the protonated and deprotonated corroles is presented and comparisons made with previously published data for other protonated and deprotonated free-base corroles under the same solution conditions.