Examining the Importance of Hydrogen Bonding and Proton Transfer in Iron Porphyrin-Mediated Carbon Dioxide Upconversion.

ConspectusThe title should give a sense of the "big picture" of this Account, but what is it really about? An unexpected change in research direction? A series of courageous and creative students? A team taking on challenging problems in chemistry? The answer is a definite "yes" to all of the above. More specifically, the problem in which we are interested is the upconversion or valorization of carbon dioxide. This problem has captured the attention of a great many chemists in earnest following the gas crisis of the 1970s and more recently galvanized due to climate concerns arising from the ongoing release of anthropogenic carbon. Addressing the problem of atmospheric carbon accumulation requires effort in two very broad areas: capture and conversion. Storage is an alternative to conversion, but this eliminates the opportunity to use what might be otherwise a waste product. Our group has investigated a series of modified versions of iron(III)-5,10,15,20-tetraphenylporphyrin (FeTPP) that can convert CO2 to carbon monoxide, which is a versatile and useful precursor for other syntheses. Following pioneering work from Savéant and his colleagues in the 1990s and thereafter, we started with a simple question: how many pendent ancillary groups that can donate H-bonds or protons are needed to support efficient CO2-to-CO conversion? Using a molecule with only one 2-hydroxylphenyl group, we demonstrated that the single prepositioned -OH group gave rise to efficient turnover, but only when experiments were carried out in a weakly H-bond-accepting solvent system. In other words, the ability of a solvent to accept H-bonds can impede CO2 reduction. We followed up with a deeper investigation of the influence of H-bonding interactions with external acids in FeTPP-mediated CO2 reduction. Savéant's framework mechanism appears to be independent of solvent, and rate differences can be approximated by considering H-bonding equilibria. Following that work, we sought to better understand the minimum catalyst design requirements with respect to internal H-bond/proton donors. To that end, we produced all possible isomers of tetraarylpoprhyrins with 2,6-dihydroxyphenyl + phenyl groups. All else being equal, the complexes with a formally trans orientation of the 2,6-dihydroxyphenyl groups performed the best. Most recently, we surveyed the roles of internal and external Brønsted acids with different pKa values. Surprisingly, the best-performing catalysts have more weakly acidic internal groups. Overall, our work has demonstrated that CO2 reduction mediated by porphyrin catalysts can be improved by considering solvent H-bonding, the orientation of internal H-bonding groups, and the balance of the pKa values of internal and external acids. The future for molecular electrocatalysts is promising as more ideas emerge about how to design molecules and conditions for CO2 reduction.

Dramatic Improvement of Homogeneous Carbon Dioxide and Bicarbonate Electroreduction Using a Tetracationic Water-Soluble Cobalt Phthalocyanine.

Electrochemical conversion of carbon dioxide (CO2) offers the opportunity to transform a greenhouse gas into valuable starting materials, chemicals, or fuels. Since many CO2 capture strategies employ aqueous alkaline solutions, there is interest in catalyst systems that can act directly on such capture solutions. Herein, we demonstrate new catalyst designs where the electroactive molecules readily mediate the CO2-to-CO conversion in aqueous solutions between pH 4.5 and 10.5. Likewise, the production of CO directly from 2 M KHCO3 solutions (pH 8.2) is possible. The improved molecular architectures are based on cobalt(II) phthalocyanine and contain four cationic trimethylammonium groups that confer water solubility and contribute to the stabilization of activated intermediates via a concentrated positive charge density around the active core. Turnover frequencies larger than 103 s-1 are possible at catalyst concentrations of down to 250 nM in CO2-saturated solutions. The observed rates are substantially larger than the related cobalt phthalocyanine-containing catalysts. Density functional theory calculations support the idea that the excellent catalytic properties are attributed to the ability of the cationic groups to stabilize CO2-bound reduced intermediates in the catalytic cycle. The homogeneous, aqueous CO2 reduction that these molecules perform opens new frontiers for further development of the CoPc platform and sets a greatly improved baseline for CoPc-mediated CO2 upconversion. Ultimately, this discovery uncovers a strategy for the generation of platforms for practical CO2 reduction catalysts in alkaline solutions.

Inducing ring distortions in unsubstituted metallophthalocyanines using axial N-heterocyclic carbenes.

A series of metallophthalocyanine (PcM) complexes with axial N-heterocyclic carbene ligands (NHC; 1,3-diisopropylimidazol-2-ylidene (DIP) and 1,3-dimethylbenzimidazol-2-ylidene (DMB)) were prepared and structurally characterized. PcCoII(DIP), PcZnII(DIP), and PcZnII(DMB) are five-coordinate complexes with mild dome-type Pc-ring distortions, while PcFeII(DIP)2 is six-coordinate and has a very large ruffle-type ring-distortion with respect to typical PcM(L)2 systems. The distortion is induced by the highly steric axial DIP ligands. The distortions were quantified and classified by their bond lengths and torsion angles, and according to the normal-coordinate structural decomposition (NSD) analysis. Upon ligation of the NHC, the insoluble PcM materials were solublized in common organic solvents, with typical UV-visible Q-band maxima observable between 658 and 677 nm; the increased solubility is rationalized in terms of the reduced solid-state aggregation of the complexes, attributable to the axial ligation.

Understanding the Interplay of the Brønsted Acidity of Catalyst Ancillary Groups and the Solution Components in Iron-porphyrin-Mediated Carbon Dioxide Reduction.

The rapid and efficient conversion of carbon dioxide (CO2) to carbon monoxide (CO) is an ongoing challenge. Catalysts based on iron-porphyrin cores have emerged as excellent electrochemical mediators of the two proton + two electron reduction of CO2 to CO, and many of the design features that promote function are known. Of those design features, the incorporation of Brønsted acids in the second coordination sphere of the iron ion has a significant impact on catalyst turnover kinetics. The Brønsted acids are often in the form of hydroxyphenyl groups. Herein, we explore how the acidity of an ancillary 2-hydroxyphenyl group affects the performance of CO2 reduction electrocatalysts. A series of meso-5,10,15,20-tetraaryl porphyrins were prepared where only the functional group at the 5-meso position has an ionizable proton. A series of cyclic voltammetry (CV) experiments reveal that the complex with -OMe positioned para to the ionizable -OH shows the largest CO2 reduction rate constants in acetonitrile solvent. This is the least acidic -OH of the compounds surveyed. The turnover frequency of the -OMe derivative can be further improved with the addition of 4-trifluoromethylphenol to the solution. In contrast, the iron-porphyrin complex with -CF3 positioned opposite the ionizable -OH shows the smallest CO2 reduction rate constants, and its turnover frequency is less enhanced with the addition of phenols to the reaction solutions. The origin of this effect is rationalized based on kinetic isotope effect experiments and density functional calculations. We conclude that catalysts with weaker internal acids coupled with stronger external acid additives provide superior CO2 reduction kinetics.

An Investigation of the Influence of Tyrosine Local Interactions on Electron Hopping in a Model Protein.

Multi-step electron transfer reactions are important to the function of many cellular systems. The ways in which such systems have evolved to direct electrons along specific pathways are largely understood, but less so are the ways in which the reduction-oxidation potentials of individual redox sites are controlled. We prepared a series of three new artificial variants of Pseudomonas aeruginosa azurin where a tyrosine (Tyr109) is situated between the native Cu ion and a Ru(II) photosensitizer tethered to a histidine (His107). Arginine, glutamine, or methionine were introduced as position 122, which is near to Tyr109. We investigated the rate of CuI oxidation by a flash-quench generated Ru(III) oxidant over pH values from 5 to 9. While the identity of the residue at position 122 affects some of the physical properties of Tyr109, the rates of CuI oxidation are only weakly dependent on the identity of the residue at 122. The results highlight that more work is still needed to understand how non-covalent interactions of redox active groups are affected in redox proteins.

Further Understanding the Roles of Solvent, Brønsted Acids, and Hydrogen Bonding in Iron Porphyrin-Mediated Carbon Dioxide Reduction.

Improving our understanding of how molecules and materials mediate the electrochemical reduction of carbon dioxide (CO2) to upgraded products is of great interest as a means to address climate change. A leading class of molecules that can facilitate the electrochemical conversion of CO2 to carbon monoxide (CO) is iron porphyrins. These molecules can have high rate constants for CO2-to-CO conversion; they are robust, and they rely on abundant and inexpensive synthetic building blocks. Important foundational work has been conducted using chloroiron 5,10,15,20-tetraphenylporphyrin (FeTPPCl) in N,N-dimethylformamide (DMF) solvent. A related and recent report points out that the corresponding perchlorate complex, FeTPPClO4, can have superior function due to its solubility in other organic solvents. However, the importance of hydrogen bonding and solvent effects was not discussed. Herein, we present a detailed kinetic study of the triflate (CF3SO3-) complex of FeTPP in DMF and in MeCN using a range of phenol Brønsted acid additives. We also detected the formation of Fe(III)TPP-phenolate complexes using cyclic voltammetry experiments. Importantly, our new analysis of apparent rate constants with different added phenols allows for a modification to the established mechanistic model for CO2-to-CO conversion. Critically, our improved model accounts for hydrogen bonding and solvent effects by using simple hydrogen bond acidity and basicity descriptors. We use this augmented model to rationalize function in other reported porphyrin systems and to make predictions about operational conditions that can enhance the CO2 reduction chemistry.

Contemporary Strategies for Immobilizing Metallophthalocyanines for Electrochemical Transformations of Carbon Dioxide.

Metallophthalocyanine (PcM) coordination complexes are well-known mediators of the electrochemical reduction of carbon dioxide (CO2). They have many properties that show promise for practical applications in the energy sector. Such properties include synthetic flexibility, a high stability, and good efficiencies for the reduction of CO2 to useful feedstocks, such as carbon monoxide (CO). One of the ongoing challenges that needs to be met is the incorporation of PcM into the heterogeneous materials that are used in a great many CO2-reduction devices. Much progress has been made in the last decade and there are now several promising approaches to incorporate PcM into a range of materials, from simple carbon-adsorbed preparations to extended polymer networks. These approaches all have important advantages and drawbacks. In addition, investigations have led to new proposals regarding CO2 reduction catalytic cycles and other operational features that are crucial to function. Here, we describe developments in the immobilization of PcM CO2 reduction catalysts in the last decade (2013 to 2023) and propose promising avenues and strategies for future research.

Proximal Methionine Amino Acid Residue Affects the Properties of Redox-Active Tryptophan in an Artificial Model Protein.

Redox-active amino acid residues are at the heart of biological electron-transfer reactions. They play important roles in natural protein functions and are implicated in disease states (e.g., oxidative-stress-associated disorders). Tryptophan (Trp) is one such redox-active amino acid residue, and it has long been known to serve a functional role in proteins. Broadly speaking, there is still much to learn about the local features that make some Trp redox active and others inactive. Herein, we describe a new protein model system where we investigate how a methionine (Met) residue proximal to a redox-active Trp affects its reactivity and spectroscopy. We use an artificial variant of azurin from Pseudomonas aeruginosa to produce these models. We employ a series of UV-visible spectroscopy, electrochemistry, electron paramagnetic resonance, and density functional theory experiments to demonstrate the effect that placing Met near Trp radicals has in the context of redox proteins. The introduction of Met proximal to Trp lowers its reduction potential by ca. 30 mV and causes clear shifts in the optical spectra of the corresponding radicals. While the effect may be small, it is significant enough to be a way for natural systems to tune Trp reactivity.

Ferrocene-appended anthraquinone and coumarin as redox-active cytotoxins.

Appending of ferrocene (Fc) to biologically-active organic backbones can generate novel multi-functional species for targeting bacteria and cancer. In this work Fc was linked to coumarin and anthraquinone with the goal of harnessing the redox-active Fc centre to generate new compounds that exhibit cytoxicity through the generation of toxic reactive oxygen species (ROS). A Cu(I)-catalyzed azide-alkyne cycloaddition "click" reaction was used to connect the organic and Fc components via a triazole linker. Cyclic voltammetry shows that the Fc potentials are suitable for oxidation by biological hydrogen peroxide to give reactive ferrocenium (Fc+) species, which can then generate hydroxyl radicals. The ability of the compounds to generate hydroxyl radicals in the presence of hydrogen peroxide was shown directly using EPR spin-trapping experiments. Furthermore, in vitro studies in MCF-7 breast cancer cells show significant increases in ROS following incubation with the Fc-functionalized compounds. Screening for antibacterial activity produced negative results for all of the Fc compounds, consitent with low levels of hydrogen peroxide typically found in bacteria. By contrast, Fc-coumarin showed cytotoxicity against A549 lung cancer and SKOV3 ovarian cancer cell lines, whereas the parent compound was inactive. This is consistent both with the cytoxic potential of the Fc group and the elevated hydrogen peroxide levels found in many cancers. Interestingly, the anthraquinone compounds showed the opposite effect with the parent compounds showing modest activity against A549 cells, but the Fc compounds being inactive. This demonstrates other potential negative impacts of including Fc, such as significantly increased lipophilicity.

Cofactor Dynamics Couples the Protein Surface to the Heme in Cytochrome c, Facilitating Electron Transfer.

Electron transport through biomolecules and in biological transport networks is of great importance to bioenergetics and biocatalysis. More generally, it is of crucial importance to understand how the pathways that connect buried metallocofactors to other cofactors, and to protein surfaces, affect the biological chemistry of metalloproteins. In terms of electron transfer (ET), the strongest coupling pathways usually comprise covalent and hydrogen bonded networks, with a limited number of through-space contacts. Herein, we set out to determine the relative roles of hydrogen bonds involved in ET via an established heme-to-surface tunneling pathway in cytochrome (cyt) c (i.e., heme-W59-D60-E61-N62). A series of cyt c variants were produced where a ruthenium tris(diimine) photooxidant was placed at position 62 via covalent modification of the N62C residue. Surprisingly, variants where the H-bonding residues W59 and D60 were replaced (i.e., W59F and D60A) showed no change in ET rate from the ferrous heme to Ru(III). In contrast, changing the composition of an alternative tunneling pathway (i.e., heme-M64-N63-C62) with the M64L substitution shows a factor of 2 decrease in the rate of heme-to-Ru ET. This pathway involves a through-space tunneling step between the heme and M64 residue, and such steps are usually disfavored. To rationalize why the heme-M64-N63-C62 is preferred, molecular dynamics (MD) simulations and Pathways analysis were employed. These simulations show that the change in heme-Ru ET rates is attributed to different conformations with compressed donor-acceptor distances, by ∼2 Å in pathway distance, in the M64-containing protein as compared to the M64L protein. The change in distance is correlated with changes in the electronic coupling that are in accord with the experimentally observed heme-Ru ET rates. Remarkably, the M64L variation at the core of the protein translates to changes in cofactor dynamics at the protein surface. The surface changes identified by MD simulations include dynamic anion-π and dipole-dipole interactions. These interactions influence the strength of tunneling pathways and ET rates by facilitating decreases in through-space tunneling distances in key coupling pathways.

On the roles of methionine and the importance of its microenvironments in redox metalloproteins.

The amino acid residue methionine (Met) is commonly thought of as a ligand in redox metalloproteins, for example in cytochromes c and in blue copper proteins. However, the roles of Met can go beyond a simple ligand. The thioether functional group of Met allows it to be considered as a hydrophobic residue as well as one that is capable of weak dipolar interactions. In addition, the lone pairs on sulphur allow Met to interact with other groups, inluding the aforementioned metal ions. Because of its properties, Met can play diverse roles in metal coordination, fine tuning of redox reactions, or supporting protein structures. These roles are strongly influenced by the nature of the surrounding medium. Herein, we describe several common interactions between Met and surrounding aromatic amino acids and how they affect the physical properties of both copper and iron metalloproteins. While the importance of interactions between Met and other groups is established in biological systems, less is known about their roles in redox metalloproteins and our view is that this is an area that is ready for greater attention.

The Impact of Second Coordination Sphere Methionine-Aromatic Interactions in Copper Proteins.

The interplay between the primary and secondary coordination spheres in biological metal sites plays an essential role in controlling their properties. Some of the clearest examples of this are from copper sites in blue and purple copper proteins. Many such proteins contain methionine (Met) in the primary coordination sphere as a weakly bound ligand to Cu. While the effects of replacing the coordinated Met are understood, less so is the importance of its second-sphere interactions. In this combined informatics and experimental study, we first present a bioinformatics investigation of the second-sphere environments in biological Met-Cu motifs. The most common interaction is between the Met-CH3 and the π-face of a phenylalanine (Phe) (81% of surveyed structures), tyrosine (Tyr) (11%), and tryptophan (Trp) (8%). In most cases, the Met-CH3 also forms a contact with a π-face of one of a Cu-ligating histidine-imidazole. Such interactions are widely distributed in different Cu proteins. Second, to explore the impact of the second-sphere interactions of Met, a series of artificial Pseudomonas aeruginosa azurin proteins were produced where the native Phe15 was replaced with Tyr or Trp. The proteins were characterized using optical and magnetic resonance spectroscopies, X-ray diffraction, electrochemistry, and an investigation of the time-resolved electron-transfer kinetics of photosensitizer-modified proteins. The influence of the Cu-Met-Aro interaction on azurin's physical properties is subtle, and the hallmarks of the azurin blue copper site are maintained. In the Phe15Trp variant, the mutation to Phe15 induces changes in Cu properties that are comparable to replacement of the weak Met ligand. The broader impacts of these widely distributed interactions are discussed.

Free Energies of Proton-Coupled Electron Transfer Reagents and Their Applications.

We present an update and revision to our 2010 review on the topic of proton-coupled electron transfer (PCET) reagent thermochemistry. Over the past decade, the data and thermochemical formalisms presented in that review have been of value to multiple fields. Concurrently, there have been advances in the thermochemical cycles and experimental methods used to measure these values. This Review (i) summarizes those advancements, (ii) corrects systematic errors in our prior review that shifted many of the absolute values in the tabulated data, (iii) provides updated tables of thermochemical values, and (iv) discusses new conclusions and opportunities from the assembled data and associated techniques. We advocate for updated thermochemical cycles that provide greater clarity and reduce experimental barriers to the calculation and measurement of Gibbs free energies for the conversion of X to XHn in PCET reactions. In particular, we demonstrate the utility and generality of reporting potentials of hydrogenation, E°(V vs H2), in almost any solvent and how these values are connected to more widely reported bond dissociation free energies (BDFEs). The tabulated data demonstrate that E°(V vs H2) and BDFEs are generally insensitive to the nature of the solvent and, in some cases, even to the phase (gas versus solution). This Review also presents introductions to several emerging fields in PCET thermochemistry to give readers windows into the diversity of research being performed. Some of the next frontiers in this rapidly growing field are coordination-induced bond weakening, PCET in novel solvent environments, and reactions at material interfaces.

Photo-initiated oxidation of C-H bonds by diimine complexes of vanadium(V).

The photochemical activation of carbon-hydrogen bonds by vanadium(v)-dioxo and vanadium(v)-oxo-peroxo diimine complexes is described. Reactions were carried out using a selection of organic substrates with C-H bond dissociation free energy values between 70 and 97 kcal mol-1. The ability to activate C-H bonds using vanadium(v)-dioxo and vanadium(v)-oxo-peroxo diimine complexes varies with different bond dissociation free energy. Compounds with weaker C-H bonds are oxidized in minutes, rather than in days for thermal oxidations by the corresponding complexes. Dioxygen is necessary for substrate consumption, which suggests that the electronically excited V complexes are radical reaction initiators via H-atom abstraction from the organic substrate.

A heme•DNAzyme activated by hydrogen peroxide catalytically oxidizes thioethers by direct oxygen atom transfer rather than by a Compound I-like intermediate.

Hemin [Fe(III)-protoporphyrin IX] is known to bind tightly to single-stranded DNA and RNA molecules that fold into G-quadruplexes (GQ). Such complexes are strongly activated for oxidative catalysis. These heme•DNAzymes and ribozymes have found broad utility in bioanalytical and medicinal chemistry and have also been shown to occur within living cells. However, how a GQ is able to activate hemin is poorly understood. Herein, we report fast kinetic measurements (using stopped-flow UV-vis spectrophotometry) to identify the H2O2-generated activated heme species within a heme•DNAzyme that is active for the oxidation of a thioether substrate, dibenzothiophene (DBT). Singular value decomposition and global fitting analysis was used to analyze the kinetic data, with the results being consistent with the heme•DNAzyme's DBT oxidation being catalyzed by the initial Fe(III)heme-H2O2 complex. Such a complex has been predicted computationally to be a powerful oxidant for thioether substrates. In the heme•DNAzyme, the DNA GQ enhances both the kinetics of formation of the active intermediate as well as the oxidation step of DBT by the active intermediate. We show, using both stopped flow spectrophotometry and EPR measurements, that a classic Compound I is not observable during the catalytic cycle for thioether sulfoxidation.

Recent Developments in Metalloporphyrin Electrocatalysts for Reduction of Small Molecules: Strategies for Managing Electron and Proton Transfer Reactions.

Porphyrins are archetypal ligands in inorganic chemistry. The last 10 years have seen important new advances in the use of metalloporphyrins as catalysts in the activation and reduction of small molecules, in particular O2 and CO2 . Recent developments of new molecular designs, scaling relationships, and theoretical modeling of mechanisms have rapidly advanced the utility of porphyrins as electrocatalysts. This Minireview focuses on the summary and evaluation of recent developments of metalloporphyrin O2 and CO2 reduction electrocatalysts, with an emphasis on contrasting homogeneous and heterogeneous electrocatalysis. Comparisons for proposed reaction mechanisms are provided for both CO2 and O2 reduction, and ideas are proposed about how lessons from the last decade of research can lead to the development of practical, applied porphyrin-derived catalysts.

Clustering of Aromatic Amino Acid Residues around Methionine in Proteins.

Short-range, non-covalent interactions between amino acid residues determine protein structures and contribute to protein functions in diverse ways. The interactions of the thioether of methionine with the aromatic rings of tyrosine, tryptophan, and/or phenylalanine has long been discussed and such interactions are favorable on the order of 1-3 kcal mol-1. Here, we carry out a new bioinformatics survey of known protein structures where we assay the propensity of three aromatic residues to localize around the [-CH2-S-CH3] of methionine. We term these groups "3-bridge clusters". A dataset consisting of 33,819 proteins with less than 90% sequence identity was analyzed and such clusters were found in 4093 structures (or 12% of the non-redundant dataset). All sub-classes of enzymes were represented. A 3D coordinate analysis shows that most aromatic groups localize near the CH2 and CH3 of methionine. Quantum chemical calculations support that the 3-bridge clusters involve a network of interactions that involve the Met-S, Met-CH2, Met-CH3, and the π systems of nearby aromatic amino acid residues. Selected examples of proposed functions of 3-bridge clusters are discussed.

Controlling the Oxygen Reduction Selectivity of Asymmetric Cobalt Porphyrins by Using Local Electrostatic Interactions.

The development and improvement of electrocatalysts for the 4H+/4e- reduction of O2 to H2O is an ongoing challenge. The addition of ancillary groups (e.g., hydrogen bonding, Brønsted acid/base) near the active site of metal-containing catalysts is an effective way to improve selectivity and kinetics of the oxygen reduction reaction (ORR). In this regard, iron porphyrins are among the most researched ORR catalysts. Closely related cobalt porphyrin ORR catalysts can function closer to the O2/H2O thermodynamic potential, but they tend to be less selective and follow a different mechanism than for the iron porphyrins. Herein, we explore strategies to extend the ideas about ancillary groups that have been developed for iron porphyrin ORR electrocatalysts to improve the performance of the corresponding cobalt complexes. We describe a series of porphyrin electrocatalysts that are modified versions of Co(5,10,15,20-tetraphenylporphyrin), where the 2-position of one of the phenyl groups contains -NH2, -N(CH3)2, and -N(CH3)3+. Investigations using cyclic voltammetry and hydrodynamic electrochemistry show that the presence of a cationic ancillary group gives rise to a catalyst that is selective for the conversion of O2 to H2O across a wide pH range. In contrast, the other catalysts are selective for reduction of O2 to H2O at pH 0, but produce H2O2 at higher pH. The ORR rate (∼106 M-1 s-1) and selectivity of the -N(CH3)3+-modified catalyst are invariant between pH 0 and 7. Quantum chemical calculations support the hypothesis that the enhancement of selectivity can be attributed to the distinct mechanism of O2 reduction by Co-porphyrins. Specifically, the mechanism relies on anionic, peroxide-bound intermediates. While protic ancillary groups are important in the performance of iron porphyrin ORR catalysts, we suggest that electrostatic stabilizers of O2-bound intermediates are more crucial for cobalt porphyrin ORR catalysts.