Copper(I) Complexes of Amide Functionalized Bisphosphine: Proximity Enhanced Metal-Ligand Cooperativity and Its Catalytic Advantage in C(sp3)-H Bond Activation of Unactivated Cycloalkanes in Dehydrogenative Carboxylation Reactions.

The reactions of amide functionalized bisphosphine, o-Ph2PC6H4C-(O)N(H)C6H4PPh2-o (1) (BalaHariPhos), with copper salts is described. Treatment of 1 with CuX in a 1:1 molar ratio yielded chelate complexes of the type [CuX{(o-Ph2PC6H4C(O)N(H)C6H4PPh2-o)}-κ2-P,P] (X = Cl, 2; Br, 3; and I, 4), which on subsequent treatment with KOtBu resulted in a dimeric complex [Cu(o-Ph2PC6H4C(O)(N)C6H4PPh2-o)]2 (5). Interestingly, complexes 2-4 showed weak N-H···Cu interactions. These weak H-bonding interactions are studied in detail both experimentally and computationally. Also, CuI complexes 2-5 were employed in the oxidative dehydrogenative carboxylation (ODC) of unactivated cycloalkanes in the presence of carboxylic acids to form the corresponding allylic esters. Among complexes 2-5, halide-free dimeric CuI complex 5 showed excellent metal-ligand cooperativity in the oxidative dehydrogenative carboxylation (ODC) in the presence of carboxylic acids to form the corresponding allylic esters through C(sp3)-H bond activation of unactivated cycloalkanes. Mechanistic details of the catalytic process were established by isolating the precatalyst [Cu{(o-Ph2PC6H4C(O)(NH)C6H4PPh2-o)-κ2-P,P}(OOCPh)] (6) and fully characterized by mass spectrometry, NMR data, and single-crystal X-ray analysis. Density functional theory-based calculations further provided a quantitative understanding of the energetics of a series of H atom transfer steps occurring in the catalytic cycle.

Orthorhombic charge density wave on the tetragonal lattice of EuAl4.

EuAl4 possesses the BaAl4 crystal structure type with tetragonal symmetry I4/mmm. It undergoes a charge density wave (CDW) transition at T CDW = 145 K and features four consecutive antiferromagnetic phase transitions below 16 K. Here we use single-crystal X-ray diffraction to determine the incommensurately modulated crystal structure of EuAl4 in its CDW state. The CDW is shown to be incommensurate with modulation wave vector q = (0,0,0.1781 (3)) at 70 K. The symmetry of the incommensurately modulated crystal structure is orthorhombic with superspace group Fmmm(00σ)s00, where Fmmm is a subgroup of I4/mmm of index 2. Both the lattice and the atomic coordinates of the basic structure remain tetragonal. Symmetry breaking is entirely due to the modulation wave, where atoms Eu and Al1 have displacements exclusively along a, while the fourfold rotation would require equal displacement amplitudes along a and b. The calculated band structure of the basic structure and interatomic distances in the modulated crystal structure both indicate the Al atoms as the location of the CDW. The tem-per-ature dependence of the specific heat reveals an anomaly at T CDW = 145 K of a magnitude similar to canonical CDW systems. The present discovery of orthorhombic symmetry for the CDW state of EuAl4 leads to the suggestion of monoclinic instead of orthorhombic symmetry for the third AFM state.

RuII complexes of 1,2,3-triazole appended tertiary phosphines, [P(Ph){(o-C6H4)(1,2,3-N3C(Ph)CH}2] and [P(Ph){o-C6H4(CCH)-(1,2,3-N3-Ph)}2]: highly active catalysts for transfer hydrogenation of carbonyl/nitro compounds and for α-alkylation of ketones.

The synthesis of two new 1,2,3-triazole appended monophosphines [P(Ph){(o-C6H4)(1,2,3-N3C(Ph)CH}2] (1) and [P(Ph){o-C6H4(CCH)(1,2,3-N3-Ph)}2] (2) and their RuII complexes is described. The reactions of 1 and 2 with [Ru(PPh3)3Cl2] in a 1 : 1 molar ratio produced cationic complexes 3 and 4, respectively. Both the complexes showed very high catalytic activity towards transfer hydrogenation, nitro reduction, and α-alkylation reactions and afforded the corresponding products in good to excellent yields. The free energy of ß-hydride elimination from the respective Ru-alkoxide intermediates, a key mechanistic step common to all the three catalytic pathways, was calculated to be close to ergoneutral by density functional theory-based calculations, which is posited to rationalize the catalytic activity of 3. The reduction of aromatic nitro compounds was found to be highly chemoselective and produced the corresponding amines as major products even in the presence of a carbonyl group. The triazolyl-N2 coordinated RuII-NPN complex 3 showed better catalytic activity compared to the triazolyl-N3 coordinated complex 4.

Knowledge Graph-Based Approaches to Drug Repurposing for COVID-19.

The COVID-19 pandemic has motivated researchers all over the world in trying to find effective drugs and therapeutics for treating this disease. To save time, much effort has focused on repurposing drugs known for treating other diseases than COVID-19. To support these drug repurposing efforts, we built the CAS Biomedical Knowledge Graph and identified 1350 small molecules as potentially repurposable drugs that target host proteins and disease processes involved in COVID-19. A computer algorithm-driven drug-ranking method was developed to prioritize those identified small molecules. The top 50 molecules were analyzed according to their molecular functions and included 11 drugs in clinical trials for treating COVID-19 and new candidates that may be of interest for clinical investigation. The CAS Biomedical Knowledge Graph provides researchers an opportunity to accelerate innovation and streamline the investigative process not just for COVID-19 but also in many other diseases.

TbVps41 regulates trafficking of endocytic but not biosynthetic cargo to lysosomes of bloodstream forms of Trypanosoma brucei.

The bloodstream stage of Trypanosoma brucei, the causative agent of African trypanosomiasis, is characterized by its high rate of endocytosis, which is involved in remodeling of its surface coat. Here we present evidence that RNAi-mediated expression down-regulation of vacuolar protein sorting 41 (Vps41), a component of the homotypic fusion and vacuole protein sorting (HOPS) complex, leads to a strong inhibition of endocytosis, vesicle accumulation, enlargement of the flagellar pocket ("big eye" phenotype), and dramatic effect on cell growth. Unexpectedly, other functions described for Vps41 in mammalian cells and yeasts, such as delivery of proteins to lysosomes, and lysosome-related organelles (acidocalcisomes) were unaffected, indicating that in trypanosomes post-Golgi trafficking is distinct from that of mammalian cells and yeasts. The essentiality of TbVps41 suggests that it is a potential drug target.

Deletion of a Golgi protein in Trypanosoma cruzi reveals a critical role for Mn2+ in protein glycosylation needed for host cell invasion and intracellular replication.

Trypanosoma cruzi is a protist parasite and the causative agent of American trypanosomiasis or Chagas disease. The parasite life cycle in its mammalian host includes an intracellular stage, and glycosylated proteins play a key role in host-parasite interaction facilitating adhesion, invasion and immune evasion. Here, we report that a Golgi-localized Mn2+-Ca2+/H+ exchanger of T. cruzi (TcGDT1) is required for efficient protein glycosylation, host cell invasion, and intracellular replication. The Golgi localization was determined by immunofluorescence and electron microscopy assays. TcGDT1 was able to complement the growth defect of Saccharomyces cerevisiae null mutants of its ortholog ScGDT1 but ablation of TcGDT1 by CRISPR/Cas9 did not affect the growth of the insect stage of the parasite. The defect in protein glycosylation was rescued by Mn2+ supplementation to the growth medium, underscoring the importance of this transition metal for Golgi glycosylation of proteins.

Definition of Redox Centers in Reactions of Lithium Intercalation in Li3RuO4 Polymorphs.

Cathodes based on layered LiMO2 are the limiting components in the path toward Li-ion batteries with energy densities suitable for electric vehicles. Introducing an overstoichiometry of Li increases storage capacity beyond a conventional mechanism of formal transition metal redox. However, the role and fate of the oxide ligands in such intriguing additional capacity remain unclear. This reactivity was predicted in Li3RuO4, making it a valuable model system. A comprehensive analysis of the redox activity of both Ru and O under different electrochemical conditions was carried out, and the effect of Li/Ru ordering was evaluated. Li3RuO4 displays highly reversible Li intercalation to Li4RuO4 below 2.5 V vs Li+/Li0, with conventional reactivity through the formal Ru5+-Ru4+ couple. In turn, it can also undergo anodic Li extraction at 3.9 V, which involves O states to a much greater extent than Ru. This reaction competes with side processes such as electrolyte decomposition and, to a much lesser extent, oxygen loss. Although the associated capacity is reversible, reintercalation unlocks a different, conventional pathway also involving the formal Ru5+-Ru4+ couple despite operating above 2.5 V, leading to chemical hysteresis. This new pathway is both chemically and electrochemically reversible in subsequent cycles. This work exemplifies both the challenge of stabilizing highly depleted O states, even with 4d metals, and the ability of solids to access the same redox couple at two very different potential windows depending on the underlying structural changes. It highlights the importance of properly defining the covalency of oxides when defining charge compensation in view of the design of materials with high capacity for Li storage.

Extended Interfacial Stability through Simple Acid Rinsing in a Li-Rich Oxide Cathode Material.

Layered Li-rich Ni, Mn, Co (NMC) oxide cathodes in Li-ion batteries provide high specific capacities (>250 mAh/g) via O-redox at high voltages. However, associated high-voltage interfacial degradation processes require strategies for effective electrode surface passivation. Here, we show that an acidic surface treatment of a Li-rich NMC layered oxide cathode material leads to a substantial suppression of CO2 and O2 evolution, ∼90% and ∼100% respectively, during the first charge up to 4.8 V vs Li+/0. CO2 suppression is related to Li2CO3 removal as well as effective surface passivation against electrolyte degradation. This treatment does not result in any loss of discharge capacity and provides superior long-term cycling and rate performance in comparison to as-received, untreated materials. We also quantify the extent of lattice oxygen participation in charge compensation ("O-redox") during Li+ removal by a novel ex situ acid titration. Our results indicate that the peroxo-like species resulting from O-redox originate on the surface at least 300 mV earlier than the activation plateau region at around 4.5 V. X-ray photoelectron spectra and Mn L-edge X-ray absorption spectra of the cathode powders reveal a Li+ deficiency and a partial reduction of Mn ions on the surface of the acid-treated material. More interestingly, although the irreversible oxygen evolution is greatly suppressed through the surface treatment, O K-edge resonant inelastic X-ray scattering shows that the lattice O-redox behavior is largely sustained. The acidic treatment, therefore, only optimizes the surface of the Li-rich material and almost eliminates the irreversible gas evolution, leading to improved cycling and rate performance. This work therefore presents a simple yet effective approach to passivate cathode surfaces against interfacial instabilities during high-voltage battery operation.

Random Global and Local Optimal Search Algorithm Based Subset Generation for Diagnosis of Cancer.

BACKGROUND: Data mining algorithms are extensively used to classify the data, in which prediction of disease using minimal computation time plays a vital role. OBJECTIVES: The aim of this paper is to develop the classification model from reduced features and instances. METHODS: In this paper we proposed four search algorithms for feature selection the first algorithm is Random Global Optimal (RGO) search algorithm for searching the continuous, global optimal subset of features from the random population. The second is Global and Local Optimal (GLO) search algorithm for searching the global and local optimal subset of features from population. The third one is Random Local Optimal (RLO) search algorithm for generating random, local optimal subset of features from the random population. Finally the Random Global and Optimal (RGLO) search algorithm for searching the continuous, global and local optimal subset of features from the random population. RGLO search algorithm combines the properties of first three stated algorithm. The subsets of features generated from the proposed four search algorithms are evaluated using the consistency based subset evaluation measure. Instance based learning algorithm is applied to the resulting feature dataset to reduce the instances that are redundant or irrelevant for classification. The model developed using naïve Bayesian classifier from the reduced features and instances is validated with the tenfold cross validation. RESULTS: Classification accuracy based on RGLO search algorithm using naïve Bayesian classifier is 94.82% for Breast, 97.4% for DLBCL, 98.83% for SRBCT and 98.89% for Leukemia datasets. CONCLUSION: The RGLO search based reduced features results in the high prediction rate with less computational time when compared with the complete dataset and other proposed subset generation algorithm.

Mapping free energy regimes in electrocatalytic reductions to screen transition metal-based catalysts.

The free energy landscape of catalytic intermediates in the two-electron reduction of proton donors and/or CO2 to H2, CO and HCO2 - is mapped with density functional theory to screen catalyst candidates from a library of different transition metals and ligands. The goal is to minimize the free energy corrugations between reactants, catalytic intermediates and each desired product, simultaneously screening against intermediates with low free energy that would be traps, and against necessary intermediates with high free energy. Catalysts are initially screened for those with: (a) standard state free energy of the metal hydride intermediate ergoneutral with HCO2 -, which is the lowest energy product with weak proton donors, and (b) standard free energy of the metal carbonyl intermediate sufficiently high to avoid trapping. The design method is tested on a diverse range of ligands including cyclopentadienyl, polypyridyl, amino, phosphino and carbonyl ligands, around three earth-abundant d6 transition metal ions, Mn(i), Fe(ii) and Co(iii), using the BP86 density functional, the double-zeta 6-31+G* basis, LANL2DZ effective core potential on the metals and SMD polarizable continuum model for acetonitrile as solvent, which have previously provided chemically accurate values of several redox potentials, pK a's and ligand exchange equilibria for transition metal complexes. Among the 36 complexes screened, an Fe(ii) center ligated to two bipyridines and a pyridine with a solvent-bound sixth coordination site for hydride formation from phenol as the proton donor is identified as a promising candidate for ergoneutral hydride formation without trapping by CO. The redox-active bipyridine ligands are predicted to provide near ergoneutral sites for accumulating the two electrons needed to form the hydride. To test the predictions, an Fe(ii) complex was prepared with the desired ligand environment using a pentadentate ligand to prevent ligand exchange. The synthesized complex was indeed found to be active towards electrocatalytic proton reduction as well as CO2 reduction at the predicted redox potentials with no trapping by CO. However, contrary to the in silico predictions, we found electrochemical evidence of CO2 binding after the first reduction leading to CO production. Mapping the free energies of key catalytic intermediates such as the metal hydride and metal carbonyl species by using density functional theory (DFT) serves as a first step in catalyst screening spanning large libraries of metals and ligands. In order to screen against all the intermediates in the catalytic pathway, such as reduced metal-bound CO2 intermediates, further refinement and validation of the DFT methods are needed.

Prediction of cancer using customised fuzzy rough machine learning approaches.

This Letter proposes a customised approach for attribute selection applied to the fuzzy rough quick reduct algorithm. The unbalanced data is balanced using synthetic minority oversampling technique. The huge dimensionality of the cancer data is reduced using a correlation-based filter. The dimensionality reduced balanced attribute gene subset is used to compute the final minimal reduct set using a customised fuzzy triangular norm operator on the fuzzy rough quick reduct algorithm. The customised fuzzy triangular norm operator is used with a Lukasiewicz fuzzy implicator to compute the fuzzy approximation. The customised operator selects the least number of informative feature genes from the dimensionality reduced datasets. Classification accuracy using leave-one-out cross validation of 94.85, 76.54, 98.11, and 99.13% is obtained using a customised function for Lukasiewicz triangular norm operator on leukemia, central nervous system, lung, and ovarian datasets, respectively. Performance analysis of the conventional fuzzy rough quick reduct and the proposed method are performed using parameters such as classification accuracy, precision, recall, F-measure, scatter plots, receiver operating characteristic area, McNemar test, chi-squared test, Matthew's correlation coefficient and false discovery rate that are used to prove that the proposed approach performs better than available methods in the literature.

Protonation of a Cobalt Phenylazopyridine Complex at the Ligand Yields a Proton, Hydride, and Hydrogen Atom Transfer Reagent.

Protonation of the Co(I) phenylazopyridine (azpy) complex [CpCo(azpy)] 2 occurs at the azo nitrogen of the 2-phenylazopyridine ligand to generate the cationic Co(I) complex [CpCo(azpyH)]+ 3 with no change in oxidation state at Co. The N-H bond of 3 exhibits diverse hydrogen transfer reactivity, as studies with a variety of organic acceptors demonstrate that 3 can act as a proton, hydrogen atom, and hydride donor. The thermodynamics of all three cleavage modes for the N-H bond (i.e., proton, hydride, and hydrogen atom) were examined both experimentally and computationally. The N-H bond of 3 exhibits a p Ka of 12.1, a hydricity of Δ G°H- = 89 kcal/mol, and a bond dissociation free energy (BDFE) of Δ G°H• = 68 kcal/mol in CD3CN. Hydride transfer from 3 to the trityl cation (Δ G°H- = 99 kcal/mol) is exergonic but takes several hours to reach completion, indicating that 3 is a relatively poor hydride donor, both kinetically and thermodynamically. Hydrogen atom transfer from 3 to 2,6-di- tert-butyl-4-(4'-nitrophenyl)phenoxyl radical (tBu2NPArO·, Δ G°H• = 77.8 kca/mol) occurs rapidly, illustrating the competence of 3 as a hydrogen atom donor.

Evolutionary sequential genetic search technique-based cancer classification using fuzzy rough nearest neighbour classifier.

Cancer is one of the deadly diseases of human life. The patient may likely to survive if the disease is diagnosed in its early stages. In this Letter, the authors propose a genetic search fuzzy rough (GSFR) feature selection algorithm, which is hybridised using the evolutionary sequential genetic search technique and fuzzy rough set to select features. The genetic operator's selection, crossover and mutation are applied to generate the subset of features from dataset. The generated subset is subjected to the evaluation with the modified dependency function of the fuzzy rough set using positive and boundary regions, which act as a fitness function. The generation and evaluation of the subset of features continue until the best subset is arrived at to develop the classification model. Selected features are applied to the different classifiers, from the classifiers fuzzy-rough nearest neighbour (FRNN) classifier, which outperforms in terms of classification accuracy and computation time. Hence, the FRNN is applied for performance analysis of existing feature selection algorithms against the proposed GSFR feature selection algorithm. The result generated from the proposed GSFR feature selection algorithm proved to be precise when compared to other feature selection algorithms.

Membrane Proteins in Trypanosomatids Involved in Ca2+ Homeostasis and Signaling.

Calcium ion (Ca2+) serves as a second messenger for a variety of cell functions in trypanosomes. Several proteins in the plasma membrane, acidocalcisomes, endoplasmic reticulum, and mitochondria are involved in its homeostasis and in cell signaling roles. The plasma membrane has a Ca2+ channel for its uptake and a plasma membrane-type Ca2+-ATPase (PMCA) for its efflux. A similar PMCA is also located in acidocalcisomes, acidic organelles that are the primary Ca2+ store and that possess an inositol 1,4,5-trisphosphate receptor (IP3R) for Ca2+ efflux. Their mitochondria possess a mitochondrial calcium uniporter complex (MCUC) for Ca2+ uptake and a Ca2+/H⁺ exchanger for Ca2+ release. The endoplasmic reticulum has a sarcoplasmic-endoplasmic reticulum-type Ca2+-ATPase (SERCA) for Ca2+ uptake but no Ca2+ release mechanism has been identified. Additionally, the trypanosomatid genomes contain other membrane proteins that could potentially bind calcium and await further characterization.

Acidocalcisome-Mitochondrion Membrane Contact Sites in Trypanosoma brucei.

Membrane contact sites are regions of close apposition between two organelles, typically less than 30 nanometers apart, that facilitate transfer of biomolecules. The presence of contact sites has been demonstrated in yeast, plants, and mammalian cells. Here, we investigated the presence of such contact sites in Trypanosoma brucei. In mammalian cells, endoplasmic reticulum-mitochondria contact sites facilitate mitochondrial uptake of Ca2+ released by the ER-located inositol 1,4,5-trisphosphate receptor (InsP3R). However, the InsP3R in trypanosomes localizes to acidocalcisomes, which serve as major Ca2+ stores in these parasites. In this work, we have used super-resolution structured illumination microscopy and electron microscopy to identify membrane contact sites that exist between acidocalcisomes and mitochondria. Furthermore, we have confirmed the close association of these organelles using proximity ligation assays. Characterization of these contact sites may be a necessary starting point towards unraveling the role of Ca2+ in regulating trypanosome bioenergetics.

A Riboswitch-based Inducible Gene Expression System for Trypanosoma brucei.

Generation of conditional mutants in Trypanosoma brucei can be done by the use of RNA interference (RNAi). However, RNAi frequently produces off target effects. Here, we present an alternative strategy in which the glmS ribozyme is inserted in the C-terminal region of one allele of a GOI and effectively knocks it down in response to the presence of glucosamine in the culture medium. Using several endogenous genes, we show that the glmS ribozyme cleaves the mRNA in vivo leading to reduction in mRNA and protein expression following glucosamine treatment in both T. brucei procyclic and bloodstream forms. Glucosamine-induced ribozyme activation can be rapidly reversed by removing the inducer. In summary, the glmS ribozyme could be used as a tool to study essential genes in T. brucei.

Initiation of the Electrochemical Reduction of CO2 by a Singly Reduced Ruthenium(II) Bipyridine Complex.

The one-electron reduction of [CpRu(bpy)NCCH3]PF6 (Cp = cyclopentadienyl; bpy = 2,2'-bipyridine), abbreviated as [Ru-S]+, where S = CH3CN, in CO2-saturated acetonitrile initiates a cascade of rapid electrochemical and chemical steps (ECEC) at an electrode potential of ca. 100 mV positive of the first reduction of the ruthenium complex. The overall two-electron process leads to the generation of a CO-bound ruthenium complex, [Ru-CO]+, and carbonate, as independently confirmed by NMR spectroscopy. Simulations of the cyclic voltammograms using DigiElch together with density functional theory based calculations reveal that the singly reduced ruthenium complex [Ru-S]0 binds CO2 at a rate of ca. 105 M-1 s-1 at almost zero driving force. Subsequent to CO2 binding, all of the steps leading up to deoxygenation are highly exergonic and rapid. A model of the potential energy profile of the CO2 approach to the Ru center in the singly reduced manifold reveals a direct correlation between the reactivity toward CO2 and the nucleophilicity at the metal center influenced by different ligand environments. Through the binding of CO2 after the first reduction, overpotentials associated with consecutive electrochemical reductions are avoided. This work therefore provides an important design principle for engineering transition-metal complexes to activate CO2 under low driving forces.

Multielectron Transfer at Cobalt: Influence of the Phenylazopyridine Ligand.

The dicationic complex [CpCo(azpy)(CH3CN)](ClO4)2 1 (azpy = phenylazopyridine) exhibits a reversible two-electron reduction at a very mild potential (-0.16 V versus Fc0/+) in acetonitrile. This behavior is not observed with the analogous bipyridine and pyrazolylpyridine complexes (3 and 4), which display an electrochemical signature typical of CoIII systems: two sequential one-electron reductions to CoII at -0.4 V and CoI at -1.0 to -1.3 V versus Fc0/+. The doubly reduced, neutral complex [CpCo(azpy)] 2 is isolated as an air-stable, diamagnetic solid via chemical reduction with cobaltocene. Crystallographic and spectroscopic characterization together with experimentally calibrated density functional theory calculations illuminate the key structural and electronic changes that occur upon reduction of 1 to 2. The electrochemical potential inversion observed with 1 is attributed to effective overlap between the metal d and the low-energy azo π* orbitals in the intermediary redox state and additional stabilization of 2 from structural reorganization, leading to a two-electron reduction. This result serves as a key milestone in the quest for two-electron transformations with mononuclear first-row transition metal complexes at mild potentials.

Mass-tag labeling reveals site-specific and endogenous levels of protein S-fatty acylation.

Fatty acylation of cysteine residues provides spatial and temporal control of protein function in cells and regulates important biological pathways in eukaryotes. Although recent methods have improved the detection and proteomic analysis of cysteine fatty (S-fatty) acylated proteins, understanding how specific sites and quantitative levels of this posttranslational modification modulate cellular pathways are still challenging. To analyze the endogenous levels of protein S-fatty acylation in cells, we developed a mass-tag labeling method based on hydroxylamine-sensitivity of thioesters and selective maleimide-modification of cysteines, termed acyl-PEG exchange (APE). We demonstrate that APE enables sensitive detection of protein S-acylation levels and is broadly applicable to different classes of S-palmitoylated membrane proteins. Using APE, we show that endogenous interferon-induced transmembrane protein 3 is S-fatty acylated on three cysteine residues and site-specific modification of highly conserved cysteines are crucial for the antiviral activity of this IFN-stimulated immune effector. APE therefore provides a general and sensitive method for analyzing the endogenous levels of protein S-fatty acylation and should facilitate quantitative studies of this regulated and dynamic lipid modification in biological systems.

Experimental and Theoretical Study of CO2 Insertion into Ruthenium Hydride Complexes.

The ruthenium hydride [RuH(CNN)(dppb)] (1; CNN = 2-aminomethyl-6-tolylpyridine, dppb = 1,4-bis(diphenylphosphino)butane) reacts rapidly and irreversibly with CO2 under ambient conditions to yield the corresponding Ru formate complex 2. In contrast, the Ru hydride 1 reacts with acetone reversibly to generate the Ru isopropoxide, with the reaction free energy ΔG°(298 K) = -3.1 kcal/mol measured by (1)H NMR in tetrahydrofuran-d8. Density functional theory (DFT), calibrated to the experimentally measured free energies of ketone insertion, was used to evaluate and compare the mechanism and energetics of insertion of acetone and CO2 into the Ru-hydride bond of 1. The calculated reaction coordinate for acetone insertion involves a stepwise outer-sphere dihydrogen transfer to acetone via hydride transfer from the metal and proton transfer from the N-H group on the CNN ligand. In contrast, the lowest energy pathway calculated for CO2 insertion proceeds by an initial Ru-H hydride transfer to CO2 followed by rotation of the resulting N-H-stabilized formate to a Ru-O-bound formate. DFT calculations were used to evaluate the influence of the ancillary ligands on the thermodynamics of CO2 insertion, revealing that increasing the π acidity of the ligand cis to the hydride ligand and increasing the σ basicity of the ligand trans to it decreases the free energy of CO2 insertion, providing a strategy for the design of metal hydride systems capable of reversible, ergoneutral interconversion of CO2 and formate.