Advances in the synthesis of unsymmetrically
meso
substituted porphyrins are based on the development of new total syntheses and porphyrin functionalization methods. These methods have replaced ...earlier mixed condensation reactions and give synthetic access to almost any desired
meso
-substituted porphyrin. They include the complete series of porphyrin homologues and regioisomers of the A
x
-series with either alkyl or aryl residues, and numerous examples of ABCD-type chromophores. The syntheses are based on a combination of classic functionalization reactions, the use of organolithium reagents in S
N
Ar reactions, and organometallic reactions with Pd, Ni, Cr, Ru, B, and Sn catalysis. This feature article gives an account of our work in the past decade to develop synthetic methods for the A
x
- and ABCD-type porphyrins and their use as optical materials and photosensitizers.
Unsymmetrically substituted porphyrins are not that difficult to make! Advances made in recent years allow the synthesis of almost any desired
meso
substituted A
x
- or ABCD-type porphyrin.
Porphyrins feature prominently in nature, be it as enzymatic cofactors, electron and exciton shuffles, as photoactive dyes, or as signaling substances. Their involvement in the generation, storage ...and use of oxygen is pivotal to life, while their photochemical properties are central to the biochemical functioning of plants. When complexed to metals, porphyrins can engage in a multitude of contemporary applications ranging from solar energy generation to serving as catalysts for important chemical reactions. They are also able to function as useful theranostic agents, and as novel materials for a wide range of applications. As such, they are widely considered to be highly valuable molecules, and it almost goes without saying that synthetic organic chemistry has dramatically underpinned all the key advances made, by providing reliable access to them. In fact, strategies for the synthesis of functionalized porphyrins have now reached a state of refinement where pretty well any desired porphyrin can successfully be synthesized with the approaches that are available, including a cornucopia of related macrocycle-modified porphyrinoids. In this review, we are going to illustrate the development of this exciting field by discussing a number of classic syntheses of porphyrins. Our coverage will encompass the natural protoporphyrins and chlorophylls, while also covering general strategies for the synthesis of unsymmetrical porphyrins and chlorins. Various industrial syntheses of porphyrins will also be discussed, as will other routes of great practical importance, and avenues to key porphyrinoids with modified macrocycles. A range of selected examples of contemporary functionalization reactions will be highlighted. The various key syntheses will be described and analyzed from a traditional mechanistic organic chemistry perspective to help student readers, and those who are new to this area. The aim will be to allow readers to mechanistically appreciate and understand how many of these fascinating ring-systems are built and further functionalized.
The development of porphyrin synthesis is illustrated, using classic and modern-day examples, which attempt to provide insights, including mechanistic ones, into the most used methods for porphyrin ring-construction and selective functionalization.
The core N−H units of planar porphyrins are often inaccessible to forming hydrogen‐bonding complexes with acceptor molecules. This is due to the fact that the amine moieties are “shielded” by the ...macrocyclic system, impeding the formation of intermolecular H‐bonds. However, methods exist to modulate the tetrapyrrole conformations and to reshape the vector of N−H orientation outwards, thus increasing their availability and reactivity. Strategies include the use of porpho(di)methenes and phlorins (calixphyrins), as well as saddle‐distorted porphyrins. The former form cavities due to interruption of the aromatic system. The latter are highly basic systems and capable of binding anions and neutral molecules via N−H⋅⋅⋅X‐type H‐bonds. This Review discusses the role of porphyrin(oid) ligands in various coordination‐type complexes, means to access the core for hydrogen bonding, the concept of conformational control, and emerging applications, such as organocatalysis and sensors.
Porphyrins are tunable, multifunctional hydrogen bonding ligands. The flexibility and stereochemistry of porphyrin/porphyrinoid ligands is discussed with a special emphasis on conformational control through various means. Moreover, methods are presented that provide access to the “hidden” bifunctional core of porphyrins via molecular engineering and conformationally designed free base porphyrins are introduced as novel sensors and organocatalysts.
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Nonconjugated hydrocarbons, like bicyclo1.1.1pentane, bicyclo2.2.2octane, triptycene, and cubane are a unique class of rigid linkers. Due to their similarity in size and shape they are useful mimics ...of classic benzene moieties in drugs, so‐called bioisosteres. Moreover, they also fulfill an important role in material sciences as linear linkers, in order to arrange various functionalities in a defined spatial manner. In this Review article, recent developments and usages of these special, rectilinear systems are discussed. Furthermore, we focus on covalently linked, nonconjugated linear arrangements and discuss the physical and chemical properties and differences of individual linkers, as well as their application in material and medicinal sciences.
Rigid, linear, versatile, and increasingly in use are attributes of nonconjugating hydrocarbons, such as bicyclo1.1.1pentane, bicyclo2.2.2octane, triptycene, and cubane. This Review article details their fundamental properties, synthetic chemistry, and use as linker systems in materials sciences and drug development (see figure).
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Photodynamic therapy is a promising approach for cancer treatment that relies on the administration of a photosensitizer followed by tumor illumination. The generated oxidative stress may activate ...multiple mechanisms of cell death which are counteracted by cells through adaptive stress responses that target homeostasis rescue. The present renaissance of PDT was leveraged by the acknowledgment that this therapy has an immediate impact locally, in the illumination volume, but that subsequently it may also elicit immune responses with systemic impact. The investigation of the mechanisms of cell death under the oxidative stress of PDT is of paramount importance to understand how the immune system is activated and, ultimately, to make PDT a more appealing/relevant therapeutic option.
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This review follows the research, development and clinical applications of the photosensitizer 5,10,15,20‐tetra(m‐hydroxyphenyl)chlorin (mTHPC, temoporfin) in photodynamic (cancer) therapy (PDT) and ...other medical applications. Temoporfin is the active substance in the medicinal product Foscan® authorized in the EU for the palliative treatment of head and neck cancer. Chemistry, biochemistry and pharmacology, as well as clinical and other applications of temoporfin are addressed, including the extensive work that has been done on formulation development including liposomal formulations. The literature has been covered from 2009 to early 2022, thereby connecting it to the previous extensive review on this photosensitizer published in this journal Senge, M. O. and J. C. Brandt (2011) Photochem. Photobiol. 87, 1240–1296 which followed its way from initial development to approval and clinical application.
This review follows the research, development and clinical applications of the photosensitizer 5,10,15,20‐tetra(m‐hydroxyphenyl)chlorin (mTHPC, temoporfin) in photodynamic (cancer) therapy (PDT) and other medical applications for the period 2010 to 2022.
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Tetrapyrrole-containing proteins are one of the most fundamental classes of enzymes in nature and it remains an open question to give a chemical rationale for the multitude of biological reactions ...that can be catalyzed by these pigment-protein complexes. There are many fundamental processes where the same (i.e., chemically identical) porphyrin cofactor is involved in chemically quite distinct reactions. For example, heme is the active cofactor for oxygen transport and storage (hemoglobin, myoglobin) and for the incorporation of molecular oxygen in organic substrates (cytochrome P450). It is involved in the terminal oxidation (cytochrome c oxidase) and the metabolism of H2O2 (catalases and peroxidases) and catalyzes various electron transfer reactions in cytochromes. Likewise, in photosynthesis the same chlorophyll cofactor may function as a reaction center pigment (charge separation) or as an accessory pigment (exciton transfer) in light harvesting complexes (e.g., chlorophyll a). Whilst differences in the apoprotein sequences alone cannot explain the often drastic differences in physicochemical properties encountered for the same cofactor in diverse protein complexes, a critical factor for all biological functions must be the close structural interplay between bound cofactors and the respective apoprotein in addition to factors such as hydrogen bonding or electronic effects. Here, we explore how nature can use the same chemical molecule as a cofactor for chemically distinct reactions using the concept of conformational flexibility of tetrapyrroles. The multifaceted roles of tetrapyrroles are discussed in the context of the current knowledge on distorted porphyrins. Contemporary analytical methods now allow a more quantitative look at cofactors in protein complexes and the development of the field is illustrated by case studies on hemeproteins and photosynthetic complexes. Specific tetrapyrrole conformations are now used to prepare bioengineered designer proteins with specific catalytic or photochemical properties.
The nucleophilic substitution of aromatic moieties (SNAr) has been known for over 150 years and found wide use for the functionalization of (hetero)aromatic systems. Currently, several “types” of ...SNAr reactions have been established and notably the area of porphyrinoid macrocycles has seen many uses thereof. Herein, we detail the SNAr reactions of seven types of porphyrinoids with differing number and type of pyrrole units: subporphyrins, norcorroles, corroles, porphyrins, azuliporphyrins, N‐confused porphyrins, and phthalocyanines. For each we analyze the substitution dependent upon: a) the type of nucleophile and b) the site of substitution (α, β, or meso). Along with this we evaluate this route as a synthetic strategy for the generation of unsymmetrical porphyrinoids. Distinct trends can be identified for each type of porphyrinoid discussed, regardless of nucleophile. The use of nucleophilic substitution on porphyrinoids is found to often be a cost‐effective procedure with the ability to yield complex substituent patterns, which can be conducted in non‐anhydrous solvents with easily accessible simple porphyrinoids.
An up to date review regarding the SNAr of seven different types of porphyrinoids, each containing differing numbers and types of pyrrole rings and meso positions is presented. The reactivity and mechanistic analysis of subporphyrins, norcorroles, corroles, porphyrins, azuliporphyrins, N‐confused porphyrins, and phthalocyanines shows a bright future for the generation of unsymmetrical porphyrinoids via this reaction mechanism.
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This review traces the development and study of the second‐generation photosensitizer 5,10,15,20‐tetra(m‐hydroxyphenyl)chlorin through to its acceptance and clinical use in modern photodynamic ...(cancer) therapy. The literature has been covered up to early 2011.
5,10,15,20‐Tetra(m‐hydroxyphenylchlorin (mTHPC, Foscan®) is the first second‐generation photosensitizer that has reached clinical use. As such it presents an illuminating example for the use and development of tetrapyrroles in photodynamic therapy. The figure shows SKGT‐4 cells incubated with Foscan and stained for cytoplasmic membrane.
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