Proton Relay Research Articles

Across the Board: Rui Cao on Electrocatalytic CO2 Reduction.

In this series of articles, the Board Members of ChemSusChem review recent research articles that they consider of exceptional quality and importance for sustainability. This entry features Prof. Rui Cao, who discusses how tuning the second-sphere environments of Fe porphyrins can improve the activity and selectivity for CO2 reduction. Substituents with proton relay capability, hydrogen-bonding, and electrostatic features have significant impact on the efficiency of Fe porphyrins for the electrocatalytic CO2 reduction reaction.

Depicting the proton relay network in human aromatase: New insights into the role of the alcohol-acid pair.

Human aromatase is the cytochrome P450 catalyzing the conversion of androgens into estrogens in a three steps reaction essential to maintain steroid hormones balance. Here we report the capture and spectroscopic characterization of its compound I (Cpd I), the main reactive species in cytochromes P450. The typical spectroscopic transitions indicating the formation of Cpd I are detected within 0.8 s when mixing aromatase with meta‐chloroperoxybenzoic acid. The estrogen product is obtained from the same reaction mixture, demonstrating the involvement of Cpd I in aromatization reaction. Site‐directed mutagenesis is applied to the acid‐alcohol pair D309 and T310 and to R192, predicted to be part of the proton relay network. Mutants D309N and R192Q do not lead to Cpd I with an associated loss of activity, confirming that these residues are involved in proton delivery for Cpd I generation. Cpd I is captured for T310A mutant and shows 2.9‐ and 4.4‐fold faster rates of formation and decay, respectively, compared to wild‐type (WT). However, its activity is lower than the WT and a larger amount of H2O2 is produced during catalysis, indicating that T310 has an essential role in proton gating for generation of Cpd 0 and Cpd I and for their stabilization. The data provide new evidences on the role of threonine belonging to the conserved “acid‐alcohol” pair and known to be crucial for oxygen activation in cytochromes P450.

Proton Relay Effects on Oxygen Reduction Reaction Catalyzed by Dinuclear Cobalt Polypyridyl Complexes with OH Groups on Bipyridine Ligands

Abstract Four-electron oxygen reduction reaction (4e−-ORR) is the foundation of both natural and artificial energy conversion systems. Mechanism studies and catalysis improvements of 4e−-ORR are important research for the actualization of a sustainable society. In this study, we present a dinuclear cobalt complex containing mono-deprotonated forms of 6,6′-dihydroxy-2,2′-bipyridine (6DHBP-H+), [Co2(OH)2(6DHBP–H+)2(btpyxa)](PF6)2 (2) is a highly active 4e−-ORR catalyst in a low acid concentration solution. When ferrocene (Fe(Cp)2) was used as a reductant in PhCN containing a low concentration of perchloric acid (1.0 mmol L−1), 2 showed higher selectivity (99%) and reaction rate (kcat = 6.0 × 103 M−1 s−1) for 4e−-ORR than the bpy analog 1 (kcat = 6.2 × 10 M−1 s−1) and 4DHBP analog 3 (kcat = 1.5 × 102 M−1 s−1). A high catalytic current in the cyclic voltammetry (CV) of 2 indicates a high reaction rate for electrochemical ORR under low acid concentration conditions. Moreover, X-ray crystallography of the corresponding monomeric analog [Co(OH2)(6DHBP–2H+)(trpy)](PF6) (4, 6DHBP–2H+: a doubly deprotonated form of 6DHBP) suggests that OH groups of 2 can form hydrogen bonds with a μ-O2 ligand. Hydroxy groups at the 6,6′-position of bpy would deliver protons to the μ-O2 ligand of the intermediate, thereby promoting O–O bond cleavage in the proton-coupled electron transfer (PCET) process.

Bioinspired Molecular Electrocatalysts for H2Production: Chemical Strategies

The environmentally friendly production of H2 is one of the major challenges that society has to face in the next decades, as H2 is considered as a promising energy carrier. By taking inspiration from nature, and especially from the two enzymes [NiFe] and [FeFe] hydrogenases, capable of producing H2 catalytically with high rate, efforts have been focused on mimicking the structural and/or functional properties of their active site, i.e., organometallic NiFe and FeFe complexes, respectively. This perspective gives an update on families of bioinspired FeFe and NiFe (electro)catalysts with the aim of emphasing the features that seem to be critical for optimal perfomances: the presence of a (i) nearby electron reservoir or (ii) potential proton relay or (iii) hydride species with specific structural and electronic properties.

Electroreduction of Carbonyl Compounds Catalyzed by a Manganese Complex

Chemical conversions are nowadays evaluated not only according to their functionality and originality but also regarding their atom and redox economy. Excess energy consumption, the origin of that energy, and waste production are becoming increasingly important factors in chemical synthesis development. This led to a re-emerging of electroorganic synthesis after decades of dormancy. Inspired by this, we combined organometallic catalysis and electrochemistry to develop a versatile and broadly applicable method for hydrogenation of ketones and aldehydes by electrons and trifluoroethanol as proton source under ambient conditions. Aromatic, aliphatic, and further functionalized ketones and aldehydes were converted to the corresponding alcohols in decent to excellent yields, with a catalyst loading of only 1%. The protocol is selective toward ketones and aldehydes over non-conjugated C═C bonds, esters, and carboxylic acids. As a base metal catalyst, we utilized a manganese complex with a proton relay, which was previously shown to electrohydrogenate CO2 via an Mn–H species. Mechanistic analysis showed that this hydride is also pivotal for the electrohydrogenation of C═O bonds in organic scaffolds and fosters ionic hydrogenations over radical-type PCET reactions, which leads to the observed selectivity toward polar substrates. Further mechanistic analysis shed light on the pKa of the metal hydride species, the kinetic rate of its formation, as well as the all-over catalysis. Chemical formation of the MnH species via H2 splitting under ambient conditions failed, which emphasizes that merging electrochemistry and organometallic catalysis can open different pathways for chemical catalysis under mild conditions.

A Porous π-π Stacking Framework with Dicopper(I) Sites and Adjacent Proton Relays for Electroreduction of CO2 to C2+ Products.

Crystalline porous materials sustained by supramolecular interactions (e.g., π-π stacking interactions) are a type of molecular crystals showing considerable stability, but their applications are rarely reported due to the high difficulty of their construction. Herein, a stable π-π stacking framework formed by a trinuclear copper(I) compound [Cu3(HBtz)3(Btz)Cl2] (CuBtz, HBtz = benzotriazole) with pyrazolate-bridged dicopper(I) sites is reported and employed for electrochemical CO2 reduction, showing an impressive performance of 73.7 ± 2.8% Faradaic efficiency for C2+ products [i.e., ethylene (44%), ethanol (21%), acetate (4.7%), and propanol (4%)] with a current density of 7.9 mA cm-2 at the potential of -1.3 V versus RHE in an H-type cell and a Faradic efficiency (61.6%) of C2+ products with a current density of ≈1 A cm-2 and a reaction rate of 5639 μmol m-2 s-1 at the potential of -1.6 V versus RHE in a flow cell device, representing an impressive performance reported to date. In-situ infrared spectroscopy, density functional theory calculations, and control experiments revealed that the uncoordinated nitrogen atoms of benzotriazolates in the immediate vicinity can act as proton relays and cooperate with the dicopper(I) site to promote the hydrogenation process of the *CO intermediate and the C-C coupling, resulting in the highly selective electroreduction of CO2 to C2+ products.

Electrocatalytic hydrogen evolution of a cobalt A2B triaryl corrole complex containing –N=PPh3 group

A new cobalt 5,15-bis(perfluorophenyl)-10-(4-N-(triphenylphosphoranylidene)-2,3,5,6-tetrafluorophenyl) corrole complex (Co-BPNC-PPh3) containing –N=PPh3 group has been prepared by Staudinger reaction and characterized by the single-crystal X-ray structure determination. The electrocatalytic hydrogen evolution reaction (HER) of Co-BPNC-PPh3 by using acetic acid (AcOH), trifluoroacetic acid (TFA) and p-toluenesulfonic acid (TsOH) as proton sources in N, N-dimethylformamide (DMF) solvent had been investigated. The turn-over frequency (TOF) value of Co-BPNC-PPh3 was observed 450 h−1 at an overpotential of 838 mV in neutral aqueous solution, showing excellent electrocatalytic HER activity. This Co-BPNC-PPh3 exhibited excellent durability and stability in the 5-hours electrolysis. Its activity is also better than cobalt 5, 10, 15-(tris-pentatfulorophenyl) corrole (Co-TPFC-PPh3), which may be ascribed to the –N=PPh3 proton relay effect in the electrocatalytic HER.

Gliding on Ice in Search of Accurate and Cost-Effective Computational Methods for Astrochemistry on Grains: The Puzzling Case of the HCN Isomerization.

The isomerization of hydrogen cyanide to hydrogen isocyanide on icy grain surfaces is investigated by an accurate composite method (jun-Cheap) rooted in the coupled cluster ansatz and by density functional approaches. After benchmarking density functional predictions of both geometries and reaction energies against jun-Cheap results for the relatively small model system HCN···(H2O)2, the best performing DFT methods are selected. A large cluster containing 20 water molecules is then employed within a QM/QM′ approach to include a realistic environment mimicking the surface of icy grains. Our results indicate that four water molecules are directly involved in a proton relay mechanism, which strongly reduces the activation energy with respect to the direct hydrogen transfer occurring in the isolated molecule. Further extension of the size of the cluster up to 192 water molecules in the framework of a three-layer QM/QM′/MM model has a negligible effect on the energy barrier ruling the isomerization. Computation of reaction rates by the transition state theory indicates that on icy surfaces, the isomerization of HNC to HCN could occur quite easily even at low temperatures thanks to the reduced activation energy that can be effectively overcome by tunneling.

Role of Water in Proton-Coupled Electron Transfer between Tyrosine and Cysteine in Ribonucleotide Reductase.

Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to deoxyribonucleotides and is critical for DNA synthesis and repair in all organisms. Its mechanism requires radical transfer along a ∼32 Å pathway through a series of proton-coupled electron transfer (PCET) steps. Previous simulations suggested that a glutamate residue (E623) mediates the PCET reaction between two stacked tyrosine residues (Y730 and Y731) through a proton relay mechanism. This work focuses on the adjacent PCET reaction between Y730 and a cysteine residue (C439). Quantum mechanical/molecular mechanical free energy simulations illustrate that when Y730 and Y731 are stacked, E623 stabilizes the radical on C439 through hydrogen bonding with the Y730 hydroxyl group. When Y731 is flipped away from Y730, a water molecule stabilizes the radical on C439 through hydrogen bonding with Y730 and lowers the free energy barrier for radical transfer from Y730 to C439 through electrostatic interactions with the transferring hydrogen but does not directly accept the proton. These simulations indicate that the conformational motions and electrostatic interactions of the tyrosines, cysteine, glutamate, and water strongly impact the thermodynamics and kinetics of these two coupled PCET reactions. Such insights are important for protein engineering efforts aimed at altering radical transfer in RNR.

Crystallographic snapshots of ternary complexes of thermophilic secondary alcohol dehydrogenase from Thermoanaerobacter pseudoethanolicus reveal the dynamics of ligand exchange and the proton relay network.

Three-dimensional structures of I86A and C295A mutant secondary alcohol dehydrogenase (SADH) from Thermoanaerobacter pseudoethanolicus were determined by x-ray crystallography. The tetrameric structure of C295A-SADH soaked with NADP+ and dimethyl sulfoxide (DMSO) was determined to 1.85 Å with an Rfree of 0.225. DMSO is bound to the tetrahedral zinc in each subunit, with ligands from SG of Cys-37, NE2 of His-59, and OD2 of Asp-150. The nicotinamide ring of NADP is hydrogen-bonded to the N of Ala-295 and the O of Val-265 and Gly-293. The O of DMSO is connected to a network of hydrogen bonds with OG of Ser-39, the 3'-OH of NADP, and ND1 of His-42. The structure of I86A-SADH soaked with 2-pentanol and NADP+ contains (R)-2-pentanol bound in each subunit, ligated to the tetrahedral zinc, and connected to the proton relay network. The structure of I86A-SADH soaked with 3-methylcyclohexanol and NADP+ has alcohol bound in three subunits. Two of the sites have the alcohol ligated to the zinc in an axial position, with OE2 of Glu-60 in the other axial position of a trigonal bipyramidal complex. One site has 3-methylcyclohexanol bound noncovalently, with the zinc in an inverted tetrahedral geometry with Glu-60. The fourth site also has the zinc in a trigonal bipyramidal complex with axial Glu-60 and water ligands. These structures demonstrate that ligand exchange of SADH involves pentacoordinate and inverted zinc complexes with Glu-60. Furthermore, we see a network of hydrogen bonds connecting the substrate oxygen to the external solvent that is likely to play a role in the mechanism of SADH.

The crystal structure of the S154Y mutant carbonyl reductase from Leifsonia xyli explains enhanced activity for 3,5-bis(trifluoromethyl)acetophenone reduction

Carbonyl reductase from Leifsonia xyli (LXCAR, UniProtKB - T2FLN4) can stereoselectively catalyze the reduction of 3,5-bis(trifluoromethyl)acetophenone (BTAP) to its corresponding alcohol, (R)-[3,5-bis(trifluoromethyl)phenyl]ethanol ((R)-BTPE), which is a valuable chiral intermediate for the synthesis of antiemetic drugs, Aprepitant and Fosaprepitant. Moreover, this protein was found to have a broad spectrum of substrate specificity and can asymmetrically catalyze the reduction of a variety of ketones and keto esters. Even though molecular modelling of this protein was done by Wang et al. (2014), a crystal structure has not yet obtained. In this study, a single mutant, S154Y, which was shown to have higher catalytic activity toward BTAP than that of the wild type, was overexpressed in Escherichia coli BL21 (DE3), purified, and crystallized. The crystal structure of LXCAR-S154Y explains how the mutant enzyme can work with BTAP more efficiently than wild type carbonyl reductase. Furthermore, the structure explains why LXCAR-S154Y can use either NADH or NADPH efficiently as a cofactor, as well as elucidates a proton relay system present in the enzyme.

Structural analysis of P450 AmphL from Streptomyces nodosus provides insights into substrate selectivity of polyene macrolide antibiotic biosynthetic P450s

AmphL is a cytochrome P450 enzyme that catalyzes the C8 oxidation of 8-deoxyamphotericin B to the polyene macrolide antibiotic, amphotericin B. To understand this substrate selectivity, we solved the crystal structure of AmphL to a resolution of 2.0 Å in complex with amphotericin B and performed molecular dynamics (MD) simulations. A detailed comparison with the closely related P450, PimD, which catalyzes the epoxidation of 4,5-desepoxypimaricin to the macrolide antibiotic, pimaricin, reveals key catalytic structural features responsible for stereo- and regio-selective oxidation. Both P450s have a similar access channel that runs parallel to the active site I helix over the surface of the heme. Molecular dynamics simulations of substrate binding reveal PimD can “pull” substrates further into the P450 access channel owing to additional electrostatic interactions between the protein and the carboxyl group attached to the hemiketal ring of 4,5-desepoxypimaricin. This substrate interaction is absent in AmphL although the additional substrate -OH groups in 8-deoxyamphotericin B help to correctly position the substrate for C8 oxidation. Simulations of the oxy-complex indicates that these -OH groups may also participate in a proton relay network required for O2 activation as has been suggested for two other macrolide P450s, PimD and P450eryF. These findings provide experimentally testable models that can potentially contribute to a new generation of novel macrolide antibiotics with enhanced antifungal and/or antiprotozoal efficacy.

Role of High-Spin Species and Pendant Amines in Electrocatalytic Alcohol Oxidation by a Nickel Phosphine Complex

The development of active and efficient electrocatalysts for oxidation of alcohols using earth-abundant metals will aid progress toward a renewable energy economy. Here, we present a detailed mechanistic study of electrocatalytic benzyl alcohol oxidation by a molecular nickel complex containing pendant amines using a combination of kinetic studies, nuclear magnetic resonance spectroscopy, and density functional theory. The catalyst preferentially binds alcohol in a high-spin octahedral geometry, but this complex is not readily deprotonated by an exogenous base and inhibits catalysis. Dissociation of one or more solvent ligands returns the complex to a low-spin state that can be deprotonated. Kinetic modeling indicates that the off-cycle high-spin intermediate lowers the catalytic turnover frequency by a factor of 8, suggesting that substantial gains in activity can be attained by improvements to the catalyst coordination geometry. In a second finding, we demonstrate that the pendant amine of the catalyst only functions as a proton relay for the potential-determining step, oxidation of a nickel hydride intermediate, but does not have a substantial impact on the overall rate for oxidation of benzyl alcohol to benzaldehyde. This result contradicts the common expectation for pendant amines to participate in rate-limiting proton transfer reactions.

Direct Observation of Ultrafast Proton Rocking in the BLUF Domain

AbstractWe present direct observation of ultrafast proton rocking in the central motif of a BLUF domain protein scaffold. The mutant design has taken consideration of modulating the proton‐coupled electron transfer (PCET) driving forces by replacing Tyr in the original motif with Trp, in order to remove the interference of a competing electron transfer pathway. Using femtosecond pump–probe spectroscopy and detailed kinetics analysis, we resolved an electron‐transfer‐coupled Grotthuss‐type forward and reverse proton rocking along the FMN–Gln–Trp proton relay chain. The rates of forward and reverse proton transfer are determined to be very close, namely 51 ps vs. 52 ps. The kinetic isotope effect (KIE) constants associated with the forward and reverse proton transfer are 3.9 and 5.3, respectively. The observation of ultrafast proton rocking is not only a crucial step towards revealing the nature of proton relay in the BLUF domain, but also provides a new paradigm of proton transfer in proteins for theoretical investigations.

Direct Observation of Ultrafast Proton Rocking in the BLUF Domain

We present direct observation of ultrafast proton rocking in the central motif of a BLUF domain protein scaffold. The mutant design has taken consideration of modulating the proton-coupled electron transfer (PCET) driving forces by replacing Tyr in the original motif with Trp, in order to remove the interference of a competing electron transfer pathway. Using femtosecond pump-probe spectroscopy and detailed kinetics analysis, we resolved an electron-transfer-coupled Grotthuss-type forward and reverse proton rocking along the FMN-Gln-Trp proton relay chain. The rates of forward and reverse proton transfer are determined to be very close, namely 51 ps vs. 52 ps. The kinetic isotope effect (KIE) constants associated with the forward and reverse proton transfer are 3.9 and 5.3, respectively. The observation of ultrafast proton rocking is not only a crucial step towards revealing the nature of proton relay in the BLUF domain, but also provides a new paradigm of proton transfer in proteins for theoretical investigations.

Considering the Influence of Polymer-Catalyst Interactions on the Chemical Microenvironment of Electrocatalysts for the CO2 Reduction Reaction.

The electrochemical CO2 reduction reaction (CO2RR) is an attractive method for capturing intermittent renewable energy sources in chemical bonds, and converting waste CO2 into value-added products with a goal of carbon neutrality. Our group has focused on developing polymer-encapsulated molecular catalysts, specifically cobalt phthalocyanine (CoPc), as active and selective electrocatalysts for the CO2RR. When CoPc is adsorbed onto a carbon electrode and encapsulated in poly(4-vinylpyridine) (P4VP), its activity and reaction selectivity over the competitive hydrogen evolution reaction (HER) are enhanced by three synergistic effects: a primary axial coordination effect, a secondary reaction intermediate stabilization effect, and an outer-coordination proton transport effect. We have studied multiple aspects of this system using electrochemical, spectroscopic, and computational tools. Specifically, we have used X-ray absorption spectroscopy measurements to confirm that the pyridyl residues from the polymer are axially coordinated to the CoPc metal center, and we have shown that increasing the σ-donor ability of nitrogen-containing axial ligands results in increased activity for the CO2RR. Using proton inventory studies, we showed that proton delivery in the CoPc-P4VP system is controlled via a proton relay through the polymer matrix. Additionally, we studied the effect of catalyst, polymer, and graphite powder loading on CO2RR activity and determined best practices for incorporating carbon supports into catalyst-polymer composite films.In this Account, we describe these studies in detail, organizing our discussion by three types of microenvironmental interactions that affect the catalyst performance: ligand effects of the primary and secondary sphere, substrate transport of protons and CO2, and charge transport from the electrode surface to the catalyst sites. Our work demonstrates that careful electroanalytical study and interpretation can be valuable in developing a robust and comprehensive understanding of catalyst performance. In addition to our work with polymer encapsulated CoPc, we provide examples of similar surface-adsorbed molecular and solid-state systems that benefit from interactions between active catalytic sites and a polymer system. We also compare the activity results from our systems to other results in the CoPc literature, and other examples of molecular CO2RR catalysts on modified electrode surfaces. Finally, we speculate how the insights gained from studying CoPc could guide the field in designing other polymer-electrocatalyst systems. As CO2RR technologies become commercially viable and expand into the space of flow cells and gas-diffusion electrodes, we propose that overall device efficiency may benefit from understanding and promoting synergistic polymer-encapsulation effects in the microenvironment of these catalyst systems.

Multiple Proton-Coupled Electron Transfers at a Tricopper Cluster: Modeling the Reductive Regeneration Process in Multicopper Oxidases.

Metal clusters in enzymes carry out the life-sustaining reactions by accumulating multiple redox equivalents in a narrow potential range. This redox potential leveling effect commonly observed in Nature has yet to be reproduced with synthetic metal clusters. Herein, we employ a fully encapsulated synthetic tricopper complex to model the three-electron two-proton reductive regeneration of fully reduced trinuclear copper cluster CuICuICuI(μ2-OH2) (FR) from native intermediate CuIICuIICuII(μ3-O) (NI) in multicopper oxidases (MCOs). The tricopper cluster can access four oxidation states (I,I,I to II,II,II) and four protonation states ([Cu3(μ3-O)]LH, [Cu3(μ3-OH)]L, [Cu3(μ3-OH)]LH, and [Cu3(μ3-OH2)]L, where LH denotes the protonated ligand), allowing mechanistic investigation of proton-coupled electron transfer (PCET) relevant to MCOs. Seven tricopper complexes with discrete oxidation and protonation states were characterized with spectroscopy or X-ray single-crystal diffraction. A stepwise electron transfer-proton transfer (ET-PT) mechanism is established for the reduction of CuIICuIICuII(μ3-O)LH to CuIICuIICuI(μ3-OH)L, while a stepwise PT-ET mechanism is determined for the reduction of CuIICuICuI(μ3-OH)LH to CuICuICuI(μ2-OH2)L. The switch-over from ET-PT to PT-ET mechanism showcases that the tricopper complex can adopt different PCET mechanisms to circumvent high-barrier proton transfer steps. Overall, three-electron two-proton reduction occurs within a narrow potential range of 170 mV, exemplifying the redox potential leveling effect of secondary proton relays in delivering multiple redox equivalents at metal clusters.

Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps

Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump.

Electrocatalytic reduction of protons to dihydrogen by the cobalt tetraazamacrocyclic complex [Co(N4H)Cl2]+: mechanism and benchmarking of performances.

The cobalt tetraazamacrocyclic [Co(N4H)Cl2]+ complex is becoming a popular and versatile catalyst for the electrocatalytic evolution of hydrogen, because of its stability and superior activity in aqueous conditions. We present here a benchmarking of its performances based on the thorough analysis of cyclic voltammograms recorded under various catalytic regimes in non-aqueous conditions allowing control of the proton concentration. This allowed a detailed mechanism to be proposed with quantitative determination of the rate-constants for the various protonation steps, as well as identification of the amine function of the tetraazamacrocyclic ligand to act as a proton relay during H2 evolution.

Electrocatalyst decomposition pathways: torsional strain in a second sphere proton relay shuts off CO2RR in a Re(2,2'-bipyridyl)(CO)3X type electrocatalyst.

Group 7 tris(carbonyl) bipyridine complexes have been well explored as important CO2 reduction reaction (CO2RR) electrocatalysts and now represent an excellent platform for catalyst design. Recent synthetic focus has been on the installation of proton sources/relays within the primary/secondary coordination sphere. These proton sources have been implicated in directly assisting catalysis by acting as shuttles for proton transfer or through the stabilization of transition states through hydrogen bonding. Herein, we report a new ligand system for CO2RR electrocatalysts, which features an aryl amine appended to a quinoline-bipyridine core. While the geometrical arrangement of the aryl amine seems amenable to assisting CO2RR electrocatalysis, we find, through spectroelectrochemical and chemical reduction studies, the torsional strain imposed on the ligand induces a structural reorganization through loss of a hydrogen atom radical. This new complex, which utilizes the anionic nitrogen as a donor atom, and other Re complexes with the same coordination motif, have been found to be entirely inactive for CO2RR. Subsequent reduction yields hydrogenation of the complex through dearomatization of the quinoline backbone concomitant with decomposition products. While the electrocatalytic capability of the reported complexes is moderate, the study represents an important investigation into the deactivation of CO2RR electrocatalysts as a consequence of typical proton shuttle moieties and guides future ligand design by highlighting an oft overlooked structural parameter.