Structure-selectivity Relationships Research Articles

Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics

AbstractJanus Kinases (JAKs) play a crucial role as therapeutic targets for various cancers. However, the current JAK inhibitors (JAKi) available have limited therapeutic benefits due to their lack of selectivity. This review focuses on the structural analysis to elucidate the molecular determinants of JAKs specificity and the discovery and design of selective JAKi. It includes descriptions and comparison of different JAK structures and their binding sites, a comparative analysis of JAKi and their binding modes, detailed interaction fingerprints (IFPs), and an extensive structure‐selectivity relationship (SSRs). Moreover, the review also explores the challenges and possibilities of using computational structure‐based methods for discovering and designing selective JAKi. Other structure‐based approaches, such as targeting the pseudokinase domain, as well as covalent and allosteric designs, are also covered. Based on this analysis, key determinants corresponding to JAK specificity and rational medicinal chemistry strategies are proposed to facilitate the development of highly selective JAKi. Overall, we aim to enhance the understanding of JAK specificity and explore strategies that can lead to the discovery of effective and selective JAKi in cancer therapy, thus improving the prognosis for cancer patients.

Electrochemical Dearomatizing Methoxylation of Phenols and Naphthols: Synthetic and Computational Studies.

The electrochemical oxidative dearomatizing methoxylation of phenols and naphthols was developed. It provides an alternative route for the preparation of methoxycyclohexadienones, important and versatile synthetic intermediates, that eliminates the need for stoichiometric high-energy chemical oxidants and generates hydrogen as a sole by-product. The reaction proceeds in a simple constant current mode, in an undivided cell, and it employs standardized instrumentation. A collection of methoxycyclohexadienones derived from various 2,4,6-tri-substituted phenols and 1-substituted-2-naphthols was obtained in moderate to excellent yields. These include a complex derivative of estrone, as well as methoxylated dearomatized 1,1'-bi-2-naphthols (BINOLs). The mechanism of the reaction was subject to profound investigations using density functional theory calculations. In particular, the reactivity of two key intermediates, phenoxyl radical and phenoxenium ion, was carefully examined. The obtained results shed light on the pathway leading to the desired product and rationalize experimentally observed selectivities regarding a side benzylic methoxylation and the preference for the functionalization at the para over the ortho position. They also uncover the structure-selectivity relationship, inversely correlating the steric bulk of the substrate with its propensity to undergo the side-reaction. Moreover, the loss of stereochemical information from enantiopure BINOL substrates during the reaction is rationalized by the computations.

A step forward in unraveling the lanthanide discrimination puzzle: structure–selectivity relationship based on phenanthroline diimide ligands towards europium and terbium detection in water

Unveiling the lanthanides selectivity in aqueous media from the molecular structures bias was demonstrated which could potentially contribute to establish the structure-function relationship for intragroup lanthanides discrimination and extractions.

Gas-Phase CuPd Bimetallic Cluster-Modified Electrodes as Model Electrocatalysts for CO2 Conversion

Copper-based electrocatalysts possess the unique ability to convert CO2 to multicarbon products such as ethylene – a precursor in many industrial processes. However, their stability and product selectivity remain insufficient. A promising approach to overcome these shortcomings and design better CO2RR electrocatalysts is to tune Cu selectivity by forming bimetallic Cu-M systems [1] while establishing their detailed structure-selectivity relationship. To achieve this, we used laser ablation Cluster Beam Deposition (CBD) [2] to produce well-defined bimetallic cluster-modified electrodes [2]. More specifically, CuPd clusters with an original average size of 2.5 nm and mass loadings of 1-3 µg cm-2 were deposited onto a carbon support. To produce a model catalyst which allows the independent investigation of the electronic and geometric structural effects induced to Cu by the second element, a Cu0.9Pd0.1 composition was selected [3]. CuPd cluster-decorated electrodes were tested for CO2 electrolysis and methane (C1), and ethylene (C2) were found among the products. Observed from the electrocatalytic activity trends, the evolution of C2 products is correlated with the cluster mass loading. In addition, the cluster coverage has an effect on the onset of the competitive H2 evolution (HER); with the lowest cluster-loaded electrodes presenting more intense HER due to limited cluster coverage of the carbon substrate. High resolution (Scanning) Transmission Electron Microscopy ((S)TEM) coupled with Energy-dispersive X-ray spectroscopy (EDX), and X-ray Photoelectron Spectroscopy (XPS) analyses of the as-prepared cluster-modified electrodes, show that the clusters feature some degree of CuPd alloying in the ambient. CuPd cluster-based systems will then be investigated in-situ using X-ray absorption spectroscopy to unravel their structure-catalytic performance relationship.

Unveiled the Structure-Selectivity Relationship for Carbon Dioxide Reduction Triggered by Bi-Doped Cu-Based Nanocatalysts.

To investigate synergistic effect between geometric and electronic structures on directing CO2RR selectivity, water phase synthetic protocol and surface architecture engineering strategy are developed to construct monodispersed Bi-doped Cu-based nanocatalysts. The strongly correlated catalytic directionality and Bi3+ dopant can be rationalized by the regulation of [*COOH]/[*CO] adsorption capacities through the appropriate doping of Bi3+ electronic modulator, resulting in volcano relationship between FECO/TOFCO and surface EVBM values. Spectroscopic study reveals that the dual-site binding mode ([Cu─μ─C(═O)O─Bi3+]) enabled by Cu1Bi3+ 2 motif in single-phase Cu150Bi1 nanocatalyst drives CO2-to-CO conversion. In contrast, the study of dynamic Bi speciation and phase transformation in dual-phase Cu50Bi1 nanocatalyst unveils that the Bi0-Bi0 contribution emerges at the expense of BOC phase, suggesting metallic Bi0 phase acting as [H]˙ formation center switches CO2RR selectivity toward CO2-to-HCOO- conversion via [*OCHO] and [*OCHOK] intermediates. This work provides significant insight into how geometric architecture cooperates with electronic effect and catalytic motif/phase to guide the selectivity of electrocatalytic CO2 reduction through the distinct surface-bound intermediates and presents molecular-level understanding of catalytic mechanism for CO/HCOO- formation.

Valorization to hydrogen of bio-oil aqueous fractions from lignocellulosic biomass pyrolysis by aqueous phase reforming over Pt/C catalyst

Aqueous phase reforming was studied for the valorization to hydrogen of the aqueous fraction of bio-oil from lignocellulosic biomass pyrolysis. Aqueous phase reforming was carried out at 220 °C with a 3 % wt. Pt/carbon catalyst and an aqueous fraction of bio-oil feed containing 1 % wt. of organic matter. Binary and multicomponent mixtures representing aqueous fractions of bio-oil were studied. Strong hydrogen production dependence on aqueous fraction of bio-oil composition was evidenced. Higher processability was obtained for aqueous fractions of bio-oil rich in levoglucosan and hydroxyacetone, reaching a hydrogen production close to 40 mmol per gram of organic carbon, whereas furfural and acetic acid hampered reforming. A significant influence of minority components such as methanol and, particularly, formic acid, was observed. These components improved reforming of the whole multicomponent mixture, showing that blending with biorefinery fractions rich in them can improve the applicability of aqueous phase reforming. The catalyst exhibited stable activity and hydrogen production after 5 reaction cycles and more than 20 h. An increase in selectivity was observed during cycles 2 and 3, which was studied by characterization of fresh and used catalysts to show structure-selectivity relationships. No significant variation of Pt2+/Pt0 and metal particle mean diameter were observed, but Pt nanoparticles underwent morphological changes leading to higher prevalence of low coordination sites, in particular step-edge sites on the particle surface, resulting in higher hydrogen production. Temperature programmed desorption and oxidation analysis showed a cumulative deposition of reaction byproducts on the catalyst surface that contributed to loss of activity.

Computational workflow for steric assessment using the electric field-derived size

Molecular structure plays an important role in the selectivity and performance of catalysts. Understanding the impact of structural differences on catalyst performance via quantitative structure-selectivity relationships is key to developing high-performing catalytic systems. There are several methods that have been introduced to quantify steric contributions, including Tolman cone angles, Charton parameters, and A-values. While these have shown promise in predicting selectivity, they access similar, general steric contributions and are largely empirically derived. Alternatively, Sterimol parameters offer a specific multi-directional measure of steric bulk in the form of three vectors in units of distance. Recently, these parameters revealed strong correlations between structure and selectivity in asymmetric catalysis. Yet, despite their demonstrated performance, Sterimol parameters are commonly derived using van der Waals radii, which approximate molecular size using hard-spheres. This method may not accurately describe highly polarized systems. Recently, a new chemical system size metric based on the electric-field of a molecule was developed, which accesses the occupied space of a molecule. Here, we demonstrate that the electric field-derived Sterimol parameters reveal similar structure-selectivity relationships in asymmetric catalysis as conventional Sterimol parameters. Specifically, we present a computational workflow for calculating Sterimol parameters based on the size of a molecule’s electric field, and validate our method using several asymmetric catalysis reactions.

Surface solid frustrated Lewis pair constructed on alumina for selective hydrogenation reaction

The design of solid frustrated Lewis pairs (FLPs) in heterogeneous systems is crucial to achieve the desired catalytic behavior in vital heterogeneous processes such as hydrogenation reactions. Herein, we report a synthesis approach for FLPs via calcination of AlOOH under different atmospheres (air and N2 atmospheres), in which unsaturated Al sites near OH vacancies and surface O atoms act as Lewis acidic sites and Lewis basic sites, respectively. A study combining 1H nuclear magnetic resonance (NMR), 27Al NMR, and electron paramagnetic resonance (EPR) demonstrates the presence of different types of OH vacancies, which results in spatial hindrance in generating various FLP sites. Notably, the selectivity of the hydrogenation of unsaturated aldehydes can be switched depending on the catalyst: the Al2O3–air catalyst with AlⅣ–O FLP sites exhibits over 90% selectivity to unsaturated alcohols via CO hydrogenation, while the Al2O3–N2 catalyst with AlⅤ–O FLP sites shows a unique selectivity toward saturated alcohols via hydrogenation of CC and CO bonds with a yield above 90%. Structure–property relationship studies based on in situ Fourier transform infrared spectroscopy (FT-IR) and density functional theory (DFT) calculations reveal that the different adsorption modes, i.e., vertical adsorption configuration at the AlⅣ–O FLP sites and flat adsorption configuration at the AlⅤ–O FLP sites, are responsible for the different selectivity in the hydrogenation reactions. This in-depth study on the structure–selectivity relationship provides new insights for the development of selective hydrogenation reactions heterogeneously catalyzed by solid FLPs.

Catalytic Asymmetric Hydrogen Atom Transfer: Enantioselective Hydroamination of Alkenes.

We report a highly enantioselective radical-based hydroamination of enol esters with sulfonamides jointly catalyzed by an Ir photocatalyst, Brønsted base, and tetrapeptide thiol. This method is demonstrated for the formation of 23 protected β-amino-alcohol products, achieving selectivities up to 97:3 er. The stereochemistry of the product is set through selective hydrogen atom transfer from the chiral thiol catalyst to a prochiral C-centered radical. Structure-selectivity relationships derived from structural variation of both the peptide catalyst and olefin substrate provide key insights into the development of an optimal catalyst. Experimental and computational mechanistic studies indicate that hydrogen-bonding, π-π stacking, and London dispersion interactions are contributing factors for substrate recognition and enantioinduction. These findings further the development of radical-based asymmetric catalysis and contribute to the understanding of the noncovalent interactions relevant to such transformations.

Pharmacological insights emerging from the characterization of a large collection of synthetic cannabinoid receptor agonists designer drugs

Synthetic cannabinoid receptor agonists (SCRAs) constitute the largest and most defiant group of abuse designer drugs. These new psychoactive substances (NPS), developed as unregulated alternatives to cannabis, have potent cannabimimetic effects and their use is usually associated with episodes of psychosis, seizures, dependence, organ toxicity and death. Due to their ever-changing structure, very limited or nil structural, pharmacological, and toxicological information is available to the scientific community and the law enforcement offices. Here we report the synthesis and pharmacological evaluation (binding and functional) of the largest and most diverse collection of enantiopure SCRAs published to date. Our results revealed novel SCRAs that could be (or may currently be) used as illegal psychoactive substances. We also report, for the first time, the cannabimimetic data of 32 novel SCRAs containing an (R) configuration at the stereogenic center. The systematic pharmacological profiling of the library enabled the identification of emerging Structure-Activity Relationship (SAR) and Structure-Selectivity Relationship (SSR) trends, the detection of ligands exhibiting incipient cannabinoid receptor type 2 (CB2R) subtype selectivity and highlights the significant neurotoxicity of representative SCRAs on mouse primary neuronal cells. Several of the new emerging SCRAs are currently expected to have a rather limited potential for harm, as the evaluation of their pharmacological profiles revealed lower potencies and/or efficacies. Conceived as a resource to foster collaborative investigation of the physiological effects of SCRAs, the library obtained can contribute to addressing the challenge posed by recreational designer drugs.

Structure-Selectivity Relationship Prediction of Tau Imaging Tracers Using Machine Learning-Assisted QSAR Models and Interaction Fingerprint Map.

Protein aggregates composed of tau fibrils are major pathologic findings in different tauopathies. An ideal agent for imaging tau fibrils must be highly selective. The molecular basis for the binding of current available compounds to tau aggregates is not well understood. Herein, we provide insights into previously studied positron emission tomography tracers using various computational methods, including machine learning-based quantitative structure-activity relationship (QSAR) classification, docking, and molecular dynamics (MD) simulations to investigate the structural basis of selective tau aggregate binding for potential compounds. The QSAR classification model based on the Random Forest algorithm with an accuracy of 96.6% for the selective and 97.6% for the nonselective class of compounds revealed essential selective moieties. The combination of molecular docking, MD simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free-energy calculation showed superior binding energy of ligand 63 toward tau and PHF6, a key hexapeptide in tau aggregation, as the most selective compound in the data set. Dissecting the binding properties of ligand 63 and ligand 8 (the least selective compound) within tau and Aβ structures confirmed that these two compounds favor different binding sites of tau; however, the preferential binding site in Aβ was similar for both with lower binding energies calculated for ligand 8. Results revealed that the number of N-heterocycles, the position of nitrogen atoms, and the presence of tertiary amine are important components of selective binding moieties, and they should be maintained in molecules for selective binding to tau aggregates. The predicted structure-selectivity relationship will facilitate the rational design and further development of selective tau imaging agents.

Toward Understanding Base-Catalyzed Isomerization of Saccharides

This Perspective addresses recent advances in isomerization of aldoses into ketoses catalyzed by bases. In recent years, catalytic activity of a number of bases was reported, but the structure–performance correlations are typically missing or remain poorly understood. In this Perspective, the reaction mechanism and kinetics of the base-catalyzed isomerization are discussed. An overview of products obtained via base-catalyzed transformations of d-glucose (Glc), d-lactose (Lac), d-galactose (Gal), and aldopentoses d-ribose (Rib), d-arabinose (Ara), d-xylose (Xyl), and d-lyxose (Lyx) is provided. Side reactions that occur under base conditions are summarized. Catalysis by soluble metal hydroxides and general bases is considered. Moreover, structure–selectivity relationships observed for soluble bases as well as methods for stabilization of ketoses via complexation are discussed. Influences of organic (co-)solvents on reaction kinetics and acceleration of the reaction rate in aqueous phase in the presence of soluble salts–also referred to as salt effect–are addressed. Next, solid bases applied as catalysts for isomerization are considered with a focus on contributions of homogeneous and heterogeneous catalysis into the isomerization processes. The applicability of a filtration test and a contact test as tools to estimate impact of leached species onto catalysis is critically discussed.

Mechanism-Guided Design of Robust Palladium Catalysts for Selective Aerobic Oxidation of Polyols

The palladium complex [(L1)Pd(μ-OAc)]2[OTf]2 (L1 = neocuproine) is a selective catalyst for the aerobic oxidation of vicinal polyols to α-hydroxyketones, but competitive oxidation of the ligand methyl groups limits the turnover number and necessitates high Pd loadings. Replacement of the neocuproine ligand with 2,2'-biquinoline ligands was investigated as a strategy to improve catalyst performance and explore the relationship between ligand structure and reactivity. Evaluation of [(L2)Pd(μ-OAc)]2[OTf]2 (L2 = 2,2'-biquinoline) as a catalyst for aerobic alcohol oxidation revealed a threefold enhancement in turnover number relative to the neocuproine congener, but a much slower rate. Mechanistic studies indicated that the slow rates observed with L2 were a consequence of precipitation of an insoluble trinuclear palladium species─(L2Pd)3(μ-O)22+─formed during catalysis and characterized by high-resolution electrospray ionization mass spectrometry. Density functional theory was used to predict that a sterically modified biquinoline ligand, L3 = 7,7'-di-tert-butyl-2,2'-biquinoline, would disfavor the formation of the trinuclear (LPd)3(μ-O)22+ species. This design strategy was validated as catalytic aerobic oxidation with [(L3)Pd(μ-OAc)]2[OTf]2 is both robust and rapid, marrying the kinetics of the parent L1-supported system with the high aerobic turnover numbers of the L2-supported system. Changes in ligand structure were also found to modulate regioselectivity in the oxidation of complex glycoside substrates, providing new insights into structure-selectivity relationships with this class of catalysts.

Catalytic asymmetric indolization by a desymmetrizing [3 + 2] annulation strategy.

A new catalytic asymmetric indolization reaction by a desymmetrizing [3 + 2] annulation strategy is developed. The reaction proceeds via a rhodium-catalyzed enantioposition-selective addition/5-exo-trig cyclization/dehydration cascade between ortho-amino arylboronic acids and 2,2-disubstituted cyclopentene-1,3-diones to produce N-unprotected cyclopenta[b]indoles bearing an all-carbon quaternary stereocenter in high yields with good enantioselectivities. A quantitative structure-selectivity relationship (QSSR) model was established to identify the optimal chiral ligand, which effectively controlled the formation of the stereocenter away from the reaction site. Density functional theory (DFT) calculations, non-covalent interaction analysis, and Eyring analysis were performed to understand the key reaction step and the function of the ligand.

Steric evaluation of Pyox ligands for asymmetric intermolecular Heck-Matsuda reaction

A structure selectivity relationship was established by systematically increasing the steric of the ligands from phenyl substituent to mesityl on the pyridine ring of Pyox and isopropyl to tert-butyl group on the oxazoline ring. The ligand 6MesPyoxsBu bearing a sterically demanding mesityl group at position 6 of the pyridine ring showed optimum catalytic activity for Heck-Matsuda desymmetrization reaction of non-activated cyclopentene using Pd(tfa)2 as the catalyst. A wide range of arenediazonium salts bearing electronically distinct substituents was evaluated in Heck-Matsuda coupling, which resulted in good to excellent isolated yields (67–92 %), excellent enantio- and diastereoselectivity (up to 96 % ee, >20:1 dr).

Constructing Interfacial Boron‐Nitrogen Moieties in Turbostratic Carbon for Electrochemical Hydrogen Peroxide Production

AbstractThe electrochemical oxygen reduction reaction (ORR) provides a green route for decentralized H2O2 synthesis, where a structure–selectivity relationship is pivotal for the control of a highly selective and active two‐electron pathway. Here, we report the fabrication of a boron and nitrogen co‐doped turbostratic carbon catalyst with tunable B−N−C configurations (CNB‐ZIL) by the assistance of a zwitterionic liquid (ZIL) for electrochemical hydrogen peroxide production. Combined spectroscopic analysis reveals a fine tailored B−N moiety in CNB‐ZIL, where interfacial B−N species in a homogeneous distribution tend to segregate into hexagonal boron nitride domains at higher pyrolysis temperatures. Based on the experimental observations, a correlation between the interfacial B−N moieties and HO2− selectivity is established. The CNB‐ZIL electrocatalysts with optimal interfacial B−N moieties exhibit a high HO2− selectivity with small overpotentials in alkaline media, giving a HO2− yield of ≈1787 mmol gcatalyst−1 h−1 at −1.4 V in a flow‐cell reactor.

Constructing Interfacial Boron-Nitrogen Moieties in Turbostratic Carbon for Electrochemical Hydrogen Peroxide Production.

The electrochemical oxygen reduction reaction (ORR) provides a green route for decentralized H2O2 synthesis, where a structure–selectivity relationship is pivotal for the control of a highly selective and active two‐electron pathway. Here, we report the fabrication of a boron and nitrogen co‐doped turbostratic carbon catalyst with tunable B−N−C configurations (CNB‐ZIL) by the assistance of a zwitterionic liquid (ZIL) for electrochemical hydrogen peroxide production. Combined spectroscopic analysis reveals a fine tailored B−N moiety in CNB‐ZIL, where interfacial B−N species in a homogeneous distribution tend to segregate into hexagonal boron nitride domains at higher pyrolysis temperatures. Based on the experimental observations, a correlation between the interfacial B−N moieties and HO2 − selectivity is established. The CNB‐ZIL electrocatalysts with optimal interfacial B−N moieties exhibit a high HO2 − selectivity with small overpotentials in alkaline media, giving a HO2 − yield of ≈1787 mmol gcatalyst −1 h−1 at −1.4 V in a flow‐cell reactor.

Shaping Copper Nanocatalysts to Steer Selectivity in the Electrochemical CO2 Reduction Reaction.

The carbon-neutral production of fuels and chemical feedstocks is one of the grand challenges for our society to solve. The electrochemical conversion of CO2 is emerging as a promising technology contributing to this goal. Despite the huge amount of progress made over the past decade, selectivity still remains a challenge. This Account presents an overview of recent progress in the design of selective catalysts by exploiting the structural sensitivity of the electrochemical CO2 reduction reaction (CO2RR). In particular, it shows that the accurate and precise control of the shape and size of Cu nanocatalysts is instrumental in understanding and in discovering the structure-selectivity relationships governing the reduction of CO2 to valuable hydrocarbons, such as methane and ethylene. It further illustrates the use of faceted Cu nanocatalysts to interrogate catalytic pathways and to increase selectivity toward oxygenates, such as ethanol, in the framework of tandem schemes. The last part of the Account highlights the role of well-defined nanocatalysts in identifying reconstruction mechanisms which might occur during operation. An outlook for the emerging paradigms which will empower the design of novel catalysts for CO2RR concludes the Account.

Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists.

We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A1AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarilly evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure–activity and structure–selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R4 and R6 of the pyrimidine core but most importantly the prominent role to the unprecedented A1AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure–activity relationship trends on both A1 and A2AARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series.

Selectivity in Electrochemical CO2 Reduction.

The electrocatalytic CO2 reduction reaction (CO2RR) to generate fixed forms of carbons that have commercial value is a lucrative avenue to ameliorate the growing concerns about the detrimental effect of CO2 emissions as well as to generate carbon-based feed chemicals, which are generally obtained from the petrochemical industry. The area of electrochemical CO2RR has seen substantial activity in the past decade, and several good catalysts have been reported. While the focus was initially on the rate and overpotential of electrocatalysis, it is gradually shifting toward the more chemically challenging issue of selectivity. CO2 can be partially reduced to produce several C1 products like CO, HCOOH, CH3OH, etc. before its complete 8e-/8H+ reduction to CH4. In addition to that, the low-valent electron-rich metal centers deployed to activate CO2, a Lewis acid, are prone to reduce protons, which are a substrate for CO2RR, leading to competing hydrogen evolution reaction (HER). Similarly, the low-valent metal is prone to oxidation by atmospheric O2 (i.e., it can catalyze the oxygen reduction reaction, ORR), necessitating strictly anaerobic conditions for CO2RR. Not only is the requirement of O2-free reaction conditions impractical, but it also leads to the release of partially reduced O2 species such as O2-, H2O2, etc., which are reactive and result in oxidative degradation of the catalyst.In this Account, mechanistic investigations of CO2RR by detecting and, often, chemically trapping and characterizing reaction intermediates are used to understand the factors that determine the selectivity in CO2RR. The spectroscopic data obtained from different intermediates have been identified in different CO2RR catalysts to develop an electronic structure selectivity relationship that is deemed to be important for deciding the selectivity of 2e-/2H+ CO2RR. The roles played by the spin state, hydrogen bonding, and heterogenization in determining the rate and selectivity of CO2RR (producing only CO, only HCOOH, or only CH4) are discussed using examples of both iron porphyrin and non-heme bioinspired artificial mimics. In addition, strategies are demonstrated where the competition between CO2RR and HER as well as CO2RR and ORR could be skewed overwhelmingly in favor of CO2RR in both cases.