pH-dependent concatenation of an inorganic complex results in solid state helix formation.

Growth of the library of tetraaza macrocyclic pyridinophane ligands is a result of the potential to treat neurodegenerative diseases by binding unregulated redox active metal-ions, scavenging radicals, and reducing oxidative stress. As part of this work, the copper complex of OH PyN 3 Cu (3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-trien-13-ol) was previously identified as a discrete molecule in the solid state when isolated at lower pH values. However, here we report that OH PyN 3 Cu forms a helical structure upon crystallization around pH 6.5. Several properties of the ligand and complex were evaluated to understand the driving forces that led to the concatenation and formation of this solid-state helix. DFT studies along with a comparison of keto/enol tautomerization stability and bond lengths were used to determine the keto-character of the C=O within each subunit. This pH dependent keto-enol tautomerization is responsible for the solid state intermolecular C=O···Cu bonds observed in this metallohelix (Cu1 H ) when produced around pH 6.5. Perchlorate templating that occurs through hydrogen bonding between perchlorate counter ions and each Cu1 H unit is the primary driving factor for the twist that leads to the helix structure. Cu1 H does not exhibit the typical factors that stabilize the formation of helices, such as intra-strand hydrogen bonding or π-stacking. The helix structure further highlights the diversity of inorganic metallohelices and demonstrates the importance of tautomerization and pH that occurs with the pyridinophane ligand used in this study. To our knowledge and although these phenomenon have been observed individually, this is the first example of a pH dependent keto-enol tautomerization in an azamacrocycle being the driving force for the formation of a metallohelix solid state structure and is a particularly unique observation for pyridinophane complexes.

Light-Driven Hydrodefluorination of Electron-Rich Aryl Fluorides by an Anionic Rhodium-Gallium Photoredox Catalyst.

An anionic Rh-Ga complex catalyzed the hydrodefluorination of challenging C-F bonds in electron-rich aryl fluorides and trifluoromethylarenes when irradiated with violet light in the presence of H2 , a stoichiometric alkoxide base, and a crown-ether additive. Based on theoretical calculations, the lowest unoccupied molecular orbital (LUMO), which is delocalized across both the Rh and Ga atoms, becomes singly occupied upon excitation, thereby poising the Rh-Ga complex for photoinduced single-electron transfer (SET). Stoichiometric and control reactions support that the C-F activation is mediated by the excited anionic Rh-Ga complex. After SET, the proposed neutral Rh0 intermediate was detected by EPR spectroscopy, which matched the spectrum of an independently synthesized sample. Deuterium-labeling studies corroborate the generation of aryl radicals during catalysis and their subsequent hydrogen-atom abstraction from the THF solvent to generate the hydrodefluorinated arene products. Altogether, the combined experimental and theoretical data support an unconventional bimetallic excitation that achieves the activation of strong C-F bonds and uses H2 and base as the terminal reductant.

Mechanistic Insights into Iron-Catalyzed C-H Bond Activation and C-C Coupling.

Iron-catalyzed C-C coupling reactions of pyrrole provide a unique alternative to the traditional Pd-catalyzed counterpart. However, many details regarding the actual mechanism remain unknown. A series of macrocyclic iron(III) complexes were used to evaluate specifics related to the role of O2, radicals, and µ-oxodiiron-complex participation in the catalytic cycle. It was determined that the mononuclear tetra-azamacrocyclic complex is a true catalyst and not a stoichiometric reagent, while more than one equivalent of a sacrificial oxidant is needed. Furthermore, the reaction does not proceed through an organic radical pathway. µ-Oxodiiron complexes are not involved in the main catalytic pathway, and the dimers are, in fact, off-cycle species that decrease catalytic efficiency.

Correction: Functionalized pyridine in pyclen-based iron(iii) complexes: evaluation of fundamental properties.

[This corrects the article DOI: 10.1039/D0RA05756H.].

Synthesis of 12-Membered Tetra-aza Macrocyclic Pyridinophanes Bearing Electron-Withdrawing Groups.

The number of substituted pyridine pyridinophanes found in the literature is limited due to challenges associated with 12-membered macrocycle and modified pyridine synthesis. Most notably, the electrophilic character at the 4-position of pyridine in pyridinophanes presents a unique challenge for introducing electrophilic chemical groups. Likewise, of the few reported, most substituted pyridine pyridinophanes in the literature are limited to electron-donating functionalities. Herein, new synthetic strategies for four new macrocycles bearing the electron-withdrawing groups CN, Cl, NO2, and CF3 are introduced. Potentiometric titrations were used to determine the protonation constants of the new pyridinophanes. Further, the influence of such modifications on the chemical behavior is predicted by comparing the potentiometric results to previously reported systems. X-ray diffraction analysis of the 4-Cl substituted species and its Cu(II) complex are also described to demonstrate the metal binding nature of these ligands. DFT analysis is used to support the experimental findings through energy calculations and ESP maps. These new molecules serve as a foundation to access a range of new pyridinophane small molecules and applications in future work.

Electronic influence of substitution on the pyridine ring within NNN pincer-type molecules.

Pincer molecules are of increasing interest due to the modular nature of modification and range of reactivity observed when coordinated to metal ions. A subset within the family of pincer molecules use a pyridine group to bridge the outer two arms as well as provide a N-donor atom for metal binding. While the arm appendages have been studied extensively, little research has been conducted on the electronic effects of the central, substituted pyridine systems. Therefore, a series of NNN pincer-type ligands with substitution on the 4-position of the pyridine ring with -OH, -OBn, -H, -Cl, and -NO2 functional groups were synthesized and characterized through NMR spectroscopy and ESI-HRMS. Each pincer was metalated with Cu(ii) salts and evaluated through X-ray diffraction analysis, cyclic voltammetry, and density functional theory analysis. The results indicate that the relatively unstudied -OBn group demonstrates both electron-withdrawing (XRD bond lengths) and electron-donating (NMR spectroscopy) properties. The -NO2 pincer ligand shows a redox event within experimental windows evaluated, in contrast to the other congeners studied. In addition, electron-donating groups increase the electron density around the Cu(ii) center based on DFT studies and cyclic voltammetry. These findings can be applied to other pyridine-based pincer systems when considering ligand design and warrants future characterization of 4-position substituted pyridines.

Functionalized pyridine in pyclen-based iron(iii) complexes: evaluation of fundamental properties.

The use of tetra-aza pyridinophanes is of increasing interest in the fields of bioinorganic modeling, catalysis, and imaging. However, a full study of how modifications to the pyridyl moiety affect the characteristics of the daughter metal complexes, has not been explored. In this study, six tetra-aza macrocyclic ligands were metalated with Fe(iii) and were characterized for the first time. The pyridyl functional groups studied include: 4-hydroxyl (L1), 4-H (L2), 4-chloro (L3), 4-trifluoromethyl (L4), 4-nitrile (L5), and 4-nitro (L6) modified pyridyl on a pyclen base structure. The resulting iron complexes were characterized by X-ray diffraction analysis, cyclic voltammetry, and metal-binding affinities (log ß) were determined. Analysis of these results indicate that such functionalizations introduce a handle by which electrochemical properties and thermodynamic stability of daughter complexes with transition metal ions can be tuned, which in turn, could potentially impact the reactivity of these complexes in future studies.

Enhancement of the Antioxidant Activity and Neurotherapeutic Features through Pyridol Addition to Tetraazamacrocyclic Molecules.

Alzheimer's and other neurodegenerative diseases are chronic conditions affecting millions of individuals worldwide. Oxidative stress is a consistent component described in the development of many neurodegenerative diseases. Therefore, innovative strategies to develop drug candidates that overcome oxidative stress in the brain are needed. To target these challenges, a new, water-soluble 12-membered tetraaza macrocyclic pyridinophane L4 was designed and produced using a building-block approach. Potentiometric data show that the neutral species of L4 provides interesting zwitterionic behavior at physiological pH, akin to amino acids, and a nearly ideal isoelectric point of 7.3. The copper(II) complex of L4 was evaluated by X-ray diffraction and cyclic voltammetry to show the potential modes of antioxidant activity derived, which was also demonstrated by 2,2-diphenyl-1-picrylhydrazyl and coumarin carboxylic acid antioxidant assays. L4 was shown to have dramatically enhanced antioxidant activity and increased biological compatibility compared to parent molecules reported previously. L4 attenuated hydrogen peroxide (H2O2)-induced cell viability loss more efficiently than precursor molecules in the mouse hippocampal HT-22 cell model. L4 also showed potent (fM) level protection against H2O2 cell death in a BV2 microglial cell culture. Western blot studies indicated that L4 enhanced the cellular antioxidant defense capacity via Nrf2 signaling activation as well. Moreover, a low-cost analysis and high metabolic stability in phase I and II models were observed. These encouraging results show how the rational design of lead compounds is a suitable strategy for the development of treatments for neurodegenerative diseases where oxidative stress plays a substantial role.