Helimeric porphyrinoids: Stereostructure and chiral resolution of meso -tetraarylmorpholinochlorins

The synthesis and chiral resolution of free-base and Ni(II) complexes of a number of derivatives of meso-tetraphenylmorpholinochlorins, with and without direct β-carbon-to-o-phenyl linkages to the flanking phenyl groups, is described. The morpholinochlorins, a class of stable chlorin analogues, were synthesized in two to three steps from meso-tetraphenylporphyrin. The conformations and the relative stereostructures of a variety of free-base and Ni(II) complexes of these morpholinochlorins were elucidated by X-ray diffractometry. Steric and stereoelectronic arguments explain the relative stereoarray of the morpholino-substituents, which differ in the free-base and Ni(II) complexes, and in the monoalkoxy, β-carbon-to-o-phenyl linked morpholinochlorins, and the dialkoxy derivatives. The Ni(II) complexes were all found to be severely ruffled whereas the free-base chromophores are more planar. As a result of the helimeric distortion of their porphyrinoid chromophores, the ruffled macrocycles possess a stable inherent element of chirality. Most significantly, resolution of the racemic mixtures was achieved, both by classical methods via diastereomers and by HPLC on a chiral phase. Full CD spectra were recorded and modeled using quantum-chemical computational methods, permitting, for the first time, an assignment of the absolute configurations of the chromophores. The report expands the range of known pyrrole-modified porphyrins. Beyond this, it introduces large chiral porphyrinoid π-systems that exist in the form of two enantiomeric, stereochemically stable helimers that can be resolved. This forms the basis for possible future applications, for example, in molecular-recognition systems or in materials with chiroptic properties. © 2011 American Chemical Society

Pyrrolic pigments

Part 1 presents studies aimed at the synthesis of novel aromatic tetra- and pentapyrrolic pigments with meso-phenyl substituents and with long wavelengths of absorption. Such compounds are potential photosensitizers for use in photodynamic therapy (PDT). Several approaches are described: 1. The osmium tetroxide mediated dihydroxylation of variously substituted mesotetraphenylporphyrins (TPP) to provide novel stable chlorins such as 129 and bacteriochlorins such as 141 and 146 is reported. The directing effect of the central metal zinc in the stereo- and regiochemical outcome of the dihydroxylation of meso-tetraphenylchlorins is outlined. The resulting 8,6'-dihydroxylated amphiphilic chlorins are characterized by spectroscopic and analytical techniques. Preliminary in vitro biological results of their potency as drugs in PDT have been encouraging. One side-product of the osmylation reaction, the 2-oxa-3-oxochlorin 163, was structurally characterized by X-ray crystallography. [Model not included] Some unique physical (observable rotation of the phenyl groups) and chemical properties of the 6,6'-diolchlorins are reported. For instance, me,«?-tetraphenyl-2,3-vjcdihydroxy- 2,3-chlorinato)nickel(II) can be converted oxidatively into the corresponding 2,3- secochlorin-2,3-dialdehyde 167. This compound can ring-close to the novel double ketal 175. This severely distorted pigment has been structurally characterized by X-ray crystallography and is without precedent. [Model not included] 2. A directed synthesis of N-confused porphyrin 104 was developed. The key step in the synthesis was a 2+2-type condensation of dipyrromethane 197 with the novel a,6-linked dipyrromethane 190. Although the goal of producing 104 in high yields could not be met, this study provided valuable insight into the chemistry of dipyrromethanes and provided through fortuitous circumstance tripyrrane 180. [Model not included] 3. Tripyrrane 180 is the key reagent in the directed high-yield synthesis of meso-phenylsapphyrins such as 200. As inferred from spectroscopic properties, the protonation dependent conformation of 200 is described. 4. Studies towards the elucidation of the mechanism of formation of porphycyanines via the lithium aluminum hydride (LAH) reduction pathway of 2-cyanodipyrromethanes are presented. To this end, variously substituted 2-cyanopyrroles were prepared and reduced by LAH. It was found that imine linked dimers such as 204 are directly formed during this reduction. A mechanistic proposal for this outcome is presented. A unique reaction of 204 with nickel(II) to form the tripyrrolic complex 236 is described. The complex was structurally characterized by X-ray crystallography and its mode of formation has been rationalized. [Model not included] Part 2 describes the synthesis of 5-phenyldipyrromethane (20) and the conversion into the corresponding raeso-phenyldipyrrins (11). Their ability to complex to transition metals is described and the optical spectra of the resulting dipyrrinato complexes of nickel(II), copper(II), and zinc(II) are discussed in depth, compared to known alkyldipyrrinato complexes and correlated to their structure. The special steric properties of the novel me so -phenyl dipyrrins are highlighted by the structural characterization of two unusual complexes, namely the square planar diamagnetic nickel(II) complex 27 and octahedral copper(III) complex 48. [Model not included] Part 3 describes the improved preparation of dipyrromethane 2 by direct hydrodesulfurization of thione 7 with Raney-nickel/H2- It was also found that 2-pyrrolylthiones chelate in an N,S-bidentate fashion to a variety of transition metals. The preparation of, for instance, the square planar nickel(II) (29), octahedral copper(III) (33, two isomers) and tetrahedral mercury(II) (32) chelates of 7 are described and their spectroscopic properties are correlated to their structures. The steric requirements for the dipyrrolylthione ligand were determined. These complexes as well as the free base 7 were structurally characterized by X-ray crystallography. Furthermore, the synthesis of the 2-thioacetylpyrrole and 2-thiobenzoylpyrrole and their nickel(II) and cobalt(III) complexes is described. This is the first report of the complexing ability of the 2-pyrrolyl moiety. [Model not included]Science, Faculty ofChemistry, Department ofGraduat

Origin of the Regioselective Reduction of Chlorins

The reduction of a free-base chlorin generally forms a bacteriochlorin (BC), while the reduction of the corresponding metallochlorin forms a metalloisobacteriochlorin (M-iBC). This regioselectivity has been long known but was never fully rationalized. In the free-base case, this regioselectivity can be explained using resonance arguments, but the explanations for the regioselectivity in the metallochlorin reactions requires a more sophisticated approach. A combination of DFT-calculated average local ionization energies (ALIEs), thermodynamics of the products, and the transition-state trajectories of reduction reactions of <i>meso</i>-tetraaryl- and β-octaethylchlorins, as their free bases and zinc complexes, now fully delineate the theoretical basis of the reduction regioselectivity. The reactions are kinetically controlled. Steric effects originating in the conformational flexibility of the chlorin macrocycle direct the reactions toward the formation of iBCs. Only when electronic effects are strong enough to override the steric effects are BCs formed. Depending on the substituents present on the chlorin, this regioselectivity may change, but ALIE calculations provide reliable guidelines to predict this. The practical value of this work lies in the presentation of a simple predictive method toward synthetic tetrahydroporphyrins by reduction of chlorins

<i>meso</i>-Tetrakis(pentafluorophenyl)porphyrin-Derived Chromene-Annulated Chlorins

The synthesis of mono- and bis-chromene-annulated <i>meso</i>-(pentafluorophenyl)­chlorins from <i>meso</i>-tetrakis­(pentafluorophenyl)­porphyrins by an OsO₄-mediated dihydroxylation reaction, followed by an intramolecular nucleophilic aromatic substitution reaction, is described. The reaction sequence is applicable to the free base systems as well as their Zn­(II), Ni­(II), Pd­(II), and Pt­(II) complexes. The optical properties (UV–vis and fluorescence spectra) of the (metallo)­chlorin-like chromophores that possess slightly red-shifted optical spectra compared to the corresponding 2,3-dihydroxychlorins are reported. Molecular modeling and ¹H–¹⁹F-HOESY NMR spectroscopy provide indications for the conformation of the chromene-annulated chromophores. Using ¹H–¹H COSY and ¹⁹F–¹⁹F QF-COSY NMR spectra, we interpret the ¹H and ¹⁹F NMR spectra of the porphyrins and chlorins, thus providing a refined reference point for the use of ¹⁹F NMR spectroscopy as a diagnostic tool in the analysis of <i>meso</i>-pentafluorophenyl-substituted porphyrinoids

Reaching across the Divide: How Monometalation of One Binding Pocket Affects the Empty Binding Pocket in a Siamese-Twin Porphyrin Palladium Complex

Siamese-twin porphyrin is a pyrazole-containing expanded porphyrin incorporating two porphyrin-like binding pockets. The macrocycle, however, does not possess an aromatic π system but rather two separated conjugation pathways that are isolated by the pyrazole junctions. Mono- and bimetallic complexes of the Siamese-twin porphyrin are known. This work addresses in detail the electronic consequences that monometalation (with Pd^II) has on the electronic properties of the nonmetalated binding pocket by studying the solid-state structure, acid/base, and electrochemical properties of the monopalladium twin-porphyrin complex. Specifically, metalation leads to a switch of the protonation sites of the free-base pocket. The unusual location of the protons at adjacent pyrrolic nitrogen atoms was revealed using X-ray diffraction and 1D/2D NMR spectroscopy. The one-electron oxidation and reduction events are both ligand-centered, as derived by spectroelectrochemical and electron paramagnetic resonance measurements, but are located on different halves of the molecule. Single-electron oxidation (−0.32 V vs Fc/Fc⁺) generated an organic radical centered on the metal-coordinating side of the ligand, while single-electron reduction (−1.59 V vs Fc/Fc⁺) led to the formation of an organic radical on the free-base side of the macrocycle. Density functional theory calculations corroborated the redox chemistry observed. The possibility of selectively preparing the monometallic complexes carrying two distinct redox sitesa metal-containing oxidation site and a metal-free reduction sitefurther expands the potential of Siamese-twin porphyrins to serve as an adjustable platform for multielectron redox processes in chemical catalysis or molecular electronics applications

Fusion and Desulfurization Reactions of Thiomorpholinochlorins

An unusually nonplanar, ruffled structure that had been suspected for the previously reported [2,3-bismethylene­thio­morpholino­chlorinato]­nickel­(II) complex was confirmed by determination of its crystal structure. Treatment of this thiomorpholinochlorin with acid converts the exocyclic double bonds to direct links to the <i>ortho</i>-positions of both adjacent <i>meso</i>-phenyl groups. The crystal structure of this product indicated that the introduction of these linkages did not change the overall conformation of the macrocycle. The reactivity of the bis-linked thiomorpholine moiety with respect to Raney-nickel-induced (hydro)­desulfurization reactions was probed, forming a bis-phenyl-linked 2,3-dimethylchlorin, also characterized by X-ray diffraction, and a bis-indene-annulated porphyrin. We also report on the synthesis of the oxygen analogue to the bis-linked thiomorpholine by reaction of a secochlorin bisketone nickel complex with Woollins’ reagent. We thus introduce novel methodologies toward the synthesis of porphyrinoids carrying β-to-<i>ortho</i>-phenyl fusions and expand on the scope and limits of the chemistry and interconversion of pyrrole-modified porphyrins

Reaching across the Divide: How Monometalation of One Binding Pocket Affects the Empty Binding Pocket in a Siamese-Twin Porphyrin Palladium Complex

Siamese-twin porphyrin is a pyrazole-containing expanded porphyrin incorporating two porphyrin-like binding pockets. The macrocycle, however, does not possess an aromatic π system but rather two separated conjugation pathways that are isolated by the pyrazole junctions. Mono- and bimetallic complexes of the Siamese-twin porphyrin are known. This work addresses in detail the electronic consequences that monometalation (with Pd^II) has on the electronic properties of the nonmetalated binding pocket by studying the solid-state structure, acid/base, and electrochemical properties of the monopalladium twin-porphyrin complex. Specifically, metalation leads to a switch of the protonation sites of the free-base pocket. The unusual location of the protons at adjacent pyrrolic nitrogen atoms was revealed using X-ray diffraction and 1D/2D NMR spectroscopy. The one-electron oxidation and reduction events are both ligand-centered, as derived by spectroelectrochemical and electron paramagnetic resonance measurements, but are located on different halves of the molecule. Single-electron oxidation (−0.32 V vs Fc/Fc⁺) generated an organic radical centered on the metal-coordinating side of the ligand, while single-electron reduction (−1.59 V vs Fc/Fc⁺) led to the formation of an organic radical on the free-base side of the macrocycle. Density functional theory calculations corroborated the redox chemistry observed. The possibility of selectively preparing the monometallic complexes carrying two distinct redox sitesa metal-containing oxidation site and a metal-free reduction sitefurther expands the potential of Siamese-twin porphyrins to serve as an adjustable platform for multielectron redox processes in chemical catalysis or molecular electronics applications

Mono- and Bisquinoline-Annulated Porphyrins from Porphyrin β,β′‑Dione Oximes

An acid-induced reaction of <i>meso</i>-tetraphenyl-2-hydroxyimino-3-oxoporphyrin leads, with concomitant loss of water, to a formal electrophilic aromatic substitution of the ortho-position of the phenyl group adjacent to the oxime, forming a quinoline moiety. Owing in part to the presence of a π-extended chromophore, the resulting <i>meso</i>-triphenylmonoquinoline-annulated porphyrin (λ_max = 750 nm) possesses a much altered optical spectrum from that of the starting oxime (λ_max = 667 nm). An oxidative DDQ-induced ring-closure process is also possible, generating the corresponding <i>meso</i>-triphenylmonoquinoline-annulated porphyrin quinoline <i>N</i>-oxide, possessing a slightly shifted and sharpened UV–vis spectrum (λ_max = 737 nm). The connectivity of the chromophores was conclusively shown by NMR spectroscopy. Both ketone functionalities in <i>meso</i>-tetraphenyl-2,3-dioxoporphyrin can be converted, via the oxime and using the acid- or oxidant-induced reaction pathways, either in one step or in a stepwise fashion, to bisquinoline-annulated porphyrin (λ_max = 775 nm) and its <i>N</i>-oxide (λ_max = 779 nm), respectively. This process is complementary to a previously established pathway toward bisquinoline-annulated porphyrins. Their zinc­(II), nickel­(II), and palladium­(II) complexes are also described. Several examples of the quinoline-annulated porphyrins were crystallographically characterized, proving their connectivity and showing their conformations that are extremely distorted from planarity. The work presents a full account on the synthesis, structure, and spectroscopic properties of these classes of NIR-absorbing dyes

Fusion and Desulfurization Reactions of Thiomorpholinochlorins

An unusually nonplanar, ruffled structure that had been suspected for the previously reported [2,3-bismethylene­thio­morpholino­chlorinato]­nickel­(II) complex was confirmed by determination of its crystal structure. Treatment of this thiomorpholinochlorin with acid converts the exocyclic double bonds to direct links to the <i>ortho</i>-positions of both adjacent <i>meso</i>-phenyl groups. The crystal structure of this product indicated that the introduction of these linkages did not change the overall conformation of the macrocycle. The reactivity of the bis-linked thiomorpholine moiety with respect to Raney-nickel-induced (hydro)­desulfurization reactions was probed, forming a bis-phenyl-linked 2,3-dimethylchlorin, also characterized by X-ray diffraction, and a bis-indene-annulated porphyrin. We also report on the synthesis of the oxygen analogue to the bis-linked thiomorpholine by reaction of a secochlorin bisketone nickel complex with Woollins’ reagent. We thus introduce novel methodologies toward the synthesis of porphyrinoids carrying β-to-<i>ortho</i>-phenyl fusions and expand on the scope and limits of the chemistry and interconversion of pyrrole-modified porphyrins

Octaethyl-1,3-oxazinochlorin: A β‑Octaethylchlorin Analogue Made by Pyrrole Expansion

Treatment of the oxime of octaethyloxochlorin <b>4</b>, available from octaethylporphyrin <b>3</b>, under Beckmann conditions provided not the expected lactam, but octaethyl-1,3-oxazinochlorin <b>8</b>, in which a pyrrole moiety of the parent oxochlorin was expanded by an oxygen atom to an 1,3-oxazinone moiety. Its mechanism of formation was demonstrated to occur along an “abnormal Beckmann” pathway, followed by intramolecular ring closure and hydrolysis. The work expands the methodologies known to convert octaethylporphyrin to pyrrole-modified porphyrin analogues