Porphyrin Atropisomerism as a Molecular Engineering Tool in Medicinal Chemistry, Molecular Recognition, Supramolecular Assembly, and Catalysis.

Porphyrin atropisomerism, which arises from restricted σ-bond rotation between the macrocycle and a sufficiently bulky substituent, was identified in 1969 by Gottwald and Ullman in 5,10,15,20-tetrakis(o-hydroxyphenyl)porphyrins. Henceforth, an entirely new field has emerged utilizing this transformative tool. This review strives to explain the consequences of atropisomerism in porphyrins, the methods which have been developed for their separation and analysis and present the diverse array of applications. Porphyrins alone possess intriguing properties and a structure which can be easily decorated and molded for a specific function. Therefore, atropisomerism serves as a transformative tool, making it possible to obtain even a specific molecular shape. Atropisomerism has been thoroughly exploited in catalysis and molecular recognition yet presents both challenges and opportunities in medicinal chemistry.

A Semiflexible Tetrahydrazone Macrocycle for Binding of Pyrophosphate and Smaller Anions.

Macrocyclization has proven to be a useful design strategy in the development of efficient anion receptors. In addition to the ring size, the overall preorganization due to structural rigidity is key. To explore this in the context of developing an efficient pyrophosphate receptor, three macrocycles featuring a 26-membered interior ring size and similar H-bonding motifs have been synthesized, and their anion binding ability has been investigated. Computational studies and nuclear magnetic resonance (NMR) data showed different degrees of preorganization as a result of differences in flexibility. The interaction of the three macrocycles with chloride, dihydrogen phosphate, and dihydrogen pyrophosphate was investigated in solution by NMR and ultraviolet-visible spectroscopy and in the solid state by X-ray crystallography. The tetrahydrazone-based macrocycle featuring intermediate flexibility exhibited the best affinity for all three anions investigated. Our results suggest that in addition to the proper preorganization of binding groups in a macrocycle a certain degree of flexibility is also required for an optimal affinity with the target guest.

Supramolecular Chirogenesis in a Sterically Hindered Porphyrin: A Critical Theoretical Analysis.

Invited for the cover of this issue are the groups of Irina Osadchuk at Tallinn University of Technology and Mathias Senge at Trinity College Dublin. The image depicts how a porphyrin with two guest molecules (R)-camphor sulfonic acid is irradiated with UV-visible light to measure and simulate ECD and UV-Vis spectra. Read the full text of the article at 10.1002/chem.202301408.

Transmembrane Transport of Inorganic Phosphate by a Strapped Calix[4]pyrrole.

Synthetic anion receptors are increasingly being explored for the transport of anions across lipid membranes because of their potential therapeutic applications. A considerable amount of research focuses on the transport of chloride, whereas the transmembrane transport of inorganic phosphate has not been reported to date, despite the biological relevance of this anion. Here we present a calix[4]pyrrole with a bisurea strap that functions as a receptor and transporter for H2PO4-, relying on the formation of eight hydrogen bonds and efficient encapsulation of the anion. Using a phosphate-sensitive lanthanide probe and 31P NMR spectroscopy, we demonstrate that this receptor can transport phosphate into vesicles by H2PO4-/Cl- antiport, H2PO4- uniport, and Cs+/H2PO4- symport mechanisms. This first example of inorganic phosphate transport by a neutral receptor opens perspectives for the future development of transporters for various biological phosphates.

Supramolecular Chirogenesis in a Sterically Hindered Porphyrin: A Critical Theoretical Analysis.

The determination of molecular stereochemistry and absolute configuration is an important part of modern chemistry, pharmacology, and biology. Electronic circular dichroism (ECD) spectroscopy is a widely used tool for chirality assignment, especially with porphyrin macrocycles employed as reporter chromophores. However, the mechanisms of induced ECD in porphyrin complexes are yet to be comprehensively rationalized. In this work, the ECD spectra of a sterically hindered hexa-cationic porphyrin with two camphorsulfonic acids in dichloromethane and chloroform were experimentally measured and computationally analyzed. The influence of geometric factors such as the position of chiral guest molecules, distortion of the porphyrin macrocycle, and orientation of aromatic and non-aromatic peripheral substituents on the ECD spectra was theoretically studied. Various potential pitfalls, such as a lack of significant conformations and accidental agreement of experimental and simulated spectra, are considered and discussed.

Importance of molecular symmetry for enantiomeric excess recognition by NMR.

Recently prochiral solvating agents (pro-CSA) came under the spotlight for the detection of enantiopurity by NMR. Chemical shift non-equivalency in achiral hosts introduced by the presence of chiral guests yields observable resonance signal splitting (Δδ) correlating to the enantiomeric excess (e.e.). In this work, symmetry is our lens to explain porphyrin-based supramolecular receptor activity in a chiral environment. Based on extensive NMR analyses of the atropisomeric receptors, the host symmetry is shown to be affected by porphyrin nonplanarity and further desymmetrized in the presence of a chiral guest. As such, the exposed porphyrin inner core (N-H), with its strong hydrogen bond abilities, for the first time, has been exploited in enantiomeric composition analysis. Our approach in e.e. detection by N-H signals appearing in a previously underutilized region of the spectrum (below 0 ppm) shows chemical shift splitting (Δδ) three times more sensitive to enantiomeric compositions than previously reported systems.

Steric Repulsion Induced Conformational Switch in Supramolecular Structures.

Inspired by the rigidified architecture of 'picket-fence' systems, we propose a strategy utilizing strain to impose intramolecular tension in already peripherally overcrowded structures leading to selective atropisomeric conversion. Employing this approach, tuneable shape-persistent porphyrin conformations were acquired exhibiting distinctive supramolecular nanostructures based on the orientation of the peripheral groups. The intrinsic assemblies driven by non-covalent bonding interactions form supramolecular polymers while encapsulating small molecules in parallel channels or solvent-accessible voids. The developed molecular strain engineering methodologies combined with synthetic approaches have allowed the introduction of the pivalate units creating a highly strained molecular skeleton. Changes in the absorption spectrum indicated the presence of severe steric repulsions between the peripheral groups which were confirmed by single crystal X-ray analysis. To release the steric strain introduced by the peripheral units, thermal equilibration strategies were used to selectively convert the most abundant atropisomer to the desirable minor one.

Strategic Synthesis of 'Picket Fence' Porphyrins Based on Nonplanar Macrocycles.

Traditional 'picket fence' porphyrin systems have been a topic of interest for their capacity to direct steric shielding effects selectively to one side of the macrocycle. Sterically overcrowded porphyrin systems that adopt macrocycle deformations have recently drawn attention for their applications in organocatalysis and sensing. Here we explore the combined benefits of nonplanar porphyrins and the old molecular design to bring new concepts to the playing field. The challenging ortho-positions of meso-phenyl residues in dodecasubstituted porphyrin systems led us to transition to less hindered para- and meta-sites and develop selective demethylation based on the steric interplay. Isolation of the symmetrical target compound [2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetrakis(3,5-dipivaloyloxyphenyl)porphyrin] was investigated under two synthetic pathways. The obtained insight was used to isolate unsymmetrical [2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetrakis(2-nitro-5-pivaloyloxyphenyl)porphyrin]. Upon separation of the atropisomers, a detailed single-crystal X-ray crystallographic analysis highlighted intrinsic intermolecular interactions. The nonplanarity of these systems in combination with 'picket fence' motifs provides an important feature in the design of supramolecular ensembles.

Elucidating Atropisomerism in Nonplanar Porphyrins with Tunable Supramolecular Complexes.

Atropisomerism is a fundamental feature of substituted biaryls resulting from rotation around the biaryl axis. Different stereoisomers are formed due to restricted rotation about the single bond, a situation often found in substituted porphyrins. Previously NMR determination of porphyrin atropisomers proved difficult, if not almost impossible to accomplish, due to low resolution or unresolvable resonance signals that predominantly overlapped. Here, we shed some light on this fundamental issue found in porphyrinoid stereochemistry. Using benzenesulfonic acid (BSA) for host-guest interactions and performing 1D, 2D NMR spectroscopic analyses, we were able to characterize all four rotamers of the nonplanar 5,10,15,20-tetrakis(2-aminophenyl)-2,3,7,8,12,13,17,18-octaethylporphyirin as restricted H-bonding complexes. Additionally, X-ray structural analysis was used to investigate aspects of the weak host-guest interactions. A detailed assignment of the chemical signals suggests charge-assisted complexation as a key to unravel the atropisomeric enigma. From a method development perspective, symmetry operations unique to porphyrin atropisomers offer an essential handle to accurately identify the rotamers using NMR techniques only.

Porphyrins as Colorimetric and Photometric Biosensors in Modern Bioanalytical Systems.

Advances in porphyrin chemistry have provided novel materials and exciting technologies for bioanalysis such as colorimetric sensor array (CSA), photo-electrochemical (PEC) biosensing, and nanocomposites as peroxidase mimetics for glucose detection. This review highlights selected recent advances in the construction of supramolecular assemblies based on the porphyrin macrocycle that provide recognition of various biologically important entities through the unique porphyrin properties associated with colorimetry, spectrophotometry, and photo-electrochemistry.

Conformational Re-engineering of Porphyrins as Receptors with Switchable N-H⋠⋠⋠X-Type Binding Modes.

The selectivity and functional variability of porphyrin cofactors are typically based on substrate binding of metalloporphyrins wherein the pyrrole nitrogen units only serve to chelate the metal ions. Yet, using the porphyrin inner core system for other functions is possible through conformational engineering. As a first step towards porphyrin "enzyme-like" active centers, a structural and spectroscopic study of substrate binding to the inner core porphyrin system shows that a highly saddle-distorted porphyrin with peripheral amino receptor groups (1, 2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetrakis(2-aminophenyl)porphyrin) coordinates analytes in a switchable manner dependent on the acidity of the solution. The supramolecular ensemble exhibits exceptionally high affinity to and selectivity for the pyrophosphate anion (2.26±0.021)×109 m-1 . 1 H NMR spectroscopic studies provided insight into the likely mode of binding and the characterization of atropisomers, all four of which were also studied by X-ray crystallography.

Synthesis of a Family of Highly Substituted Porphyrin Thioethers via Nitro Displacement in 2,3,7,8,12,13,17,18-Octaethyl-5,10,15,20-tetranitroporphyrin.

A series of highly substituted porphyrin thioethers was synthesized from 2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetranitroporphyrin (H2OETNP). The reactions proceeded via a SNAr mechanism with a broad range of aromatic thiols in the presence of a base. This is a rapid way to prepare a large variety of meso-substituted porphyrins from only one precursor. Single crystal X-ray analysis revealed that these new porphyrin thioethers are highly distorted, exhibiting conformational properties that are distinctive of both meso-sulfur substitution and steric overcrowding in general. Additionally, denitration of H2OETNP under basic conditions was investigated, yielding products of stepwise desubstitution. This allowed a comparative X-ray crystallographic study to delineate the successive structural effects of an increasing degree of nitro substitution in the complete series of nitro-substituted octaethylporphyrins.