Exploration of Vitamin B6-Based Redox-Active Pyridinium Salts towards the Application in Aqueous Organic Flow Batteries.

Pyridoxal hydrochloride, a vitamin B6 vitamer, was synthetically converted to a series of diverse redox-active benzoyl pyridinium salts. Cyclic voltammetry studies demonstrated redox reversibility under basic conditions, and two of the most promising salts were subjected to laboratory-scale redox flow battery tests involving galvanostatic cycling at 10 mM in 0.1 M NaOH. In these tests, the battery was charged completely, corresponding to the transfer of two electrons to the electrolyte, but no discharge was observed. Both CV analysis and electrochemical simulations confirmed that the redox wave observed in the experimental voltammograms corresponds to a two-electron process. To explain the irreversibility in the battery tests, we conducted bulk electrolysis with the benzoyl pyridinium salts, affording the corresponding benzylic secondary alcohols. Computational studies suggest that the reduction proceeds in three consecutive steps: first electron transfer (ET), then proton-coupled electron transfer (PCET) and finally proton transfer (PT) to give the secondary alcohol. 1H NMR deuterium exchange studies indicated that the last PT step is not reversible in 0.1 M NaOH, rendering the entire redox process irreversible. The apparent reversibility observed in CV at the basic media likely arises from the slow rate of the PT step at the timescale of the measurement.

N-Alkylated Pyridoxal Derivatives as Negative Electrolyte Materials for Aqueous Organic Flow Batteries: Computational Screening.

N-functionalized pyridinium frameworks derived from the three major vitamers of vitamin B6, pyridoxal, pyridoxamine and pyridoxine, have been screened computationally for consideration as negative electrode materials in aqueous organic flow batteries. A molecular database including the structure and the one-electron standard reduction potential of related pyridinium derivatives has been generated using a computational protocol that combines semiempirical and DFT quantum chemical methods. The predicted reduction potentials span a broad range for the investigated pyridinium frameworks, but pyridoxal derivatives, particularly those involving electron withdrawing substituents, have potentials compatible with the electrochemical stability window of aqueous electrolytes. The stability of radicals formed upon one-electron reduction has been analyzed by a new computational tool proposed recently for large-scale computational screening.

Unveiling a key catalytic pocket for the ruthenium NHC-catalysed asymmetric heteroarene hydrogenation.

The chiral ruthenium(ii)bis-SINpEt complex is a versatile and powerful catalyst for the hydrogenation of a broad range of heteroarenes. This study aims to provide understanding of the active form of this privileged catalyst as well as the reaction mechanism, and to identify the factors which control enantioselectivity. To this end we used computational methods and in situ NMR spectroscopy to study the hydrogenation of 2-methylbenzofuran promoted by this system. The high flexibility and conformational freedom of the carbene ligands in this complex lead to the formation of a chiral pocket interacting with the substrate in a "lock-and-key" fashion. The non-covalent stabilization of the substrate in this particular pocket is an exclusive feature of the major enantiomeric pathway and is preserved throughout the mechanism. Substrate coordination leading to the minor enantiomer inside this pocket is inhibited by steric repulsion. Rather, the catalyst exhibits a "flat" interaction surface with the substrate in the minor enantiomer pathway. We probe this concept by computing transition states of the rate determining step of this reaction for a series of different substrates. Our findings open up a new approach for the rational design of chiral catalysts.

Two Faces of the Two-Phase Thermodynamic Model.

The quantum harmonic model and the two-phase thermodynamic method (2PT) are widely used to obtain quantum-corrected properties such as isobaric heat capacities or molar entropies. 2PT heat capacities were calculated inconsistently in the literature. For water, the classical heat capacity was also considered, but for organic liquids, it was omitted. We reanalyzed the performance of different quantum corrections on the heat capacities of common organic solvents against experimental data. We have pointed out serious flaws in previous 2PT studies. The vibrational density of states was calculated incorrectly causing a 39% relative error in diffusion coefficients and 45% error in the 2PT heat capacities. The wrong conversion of isobaric and isochoric heat capacities also caused about 40% error but in the other direction. We have introduced the concept of anharmonic correction (AC), which is simply the deviation of the classical heat capacity from that of the harmonic oscillator model. This anharmonic contribution is around +30 to 40 J/(mol K) for water depending on the water model and -8 to -10 J/(mol K) for hydrocarbons and halocarbons. AC is unrealistically large, +40 J/(K mol) for alcohols and amines, indicating some deficiency of the OPLS force field. The accuracy of the computations was also assessed with the determination of the self-diffusion coefficients.

Enantioselective Acetalization by Dynamic Kinetic Resolution for the Synthesis of γ-Alkoxybutenolides by Thiourea/Quaternary Ammonium Salt Catalysts: Application to Strigolactones.

Although acetalization is a fundamental transformation in organic synthesis, intermolecular asymmetric acetalization remains an unsolved problem. In this study, a thiourea-ammonium hybrid catalyst was shown to promote the O-alkylation of enols with a racemic γ-chlorobutenolide through dynamic kinetic resolution to give chiral acetals with good enantioselectivity. The catalyst simultaneously activates both the nucleophile and electrophile in a multifunctional manner. This method was applied to the asymmetric synthesis of several strigolactones. DFT calculations suggest that hydrogen-bonding interactions between the chlorine atom of the γ-chlorobutenolide and the tosylamide hydrogen atom of the catalyst, as well as other types of noncovalent catalyst-substrate interactions, are crucial for achieving high stereoselectivity.

RuBisCO-Inspired CO2 Activation and Transformation by an Iridium(I) Complex.

The synthesis of a new iridium(I) complex containing an enamido phosphine anion (dbuP- ) and its unique reactivity with CO2 is reported. The complex binds two equivalents of CO2 and initiates a highly selective reaction cascade. The reaction leads to the reversible cleavage of CO2 and the enamido ligand as well. Computational analysis points to the existence of a relatively stable Ir-CO2 complex as a reaction intermediate prior to CO2 cleavage, which was confirmed experimentally. The observed transformation resembles several aspects of enzymatic CO2 fixation by RuBisCO.

Stereocontrol in Diphenylprolinol Silyl Ether Catalyzed Michael Additions: Steric Shielding or Curtin-Hammett Scenario?

The enantioselectivity of amine-catalyzed reactions of aldehydes with electrophiles is often explained by simple steric arguments emphasizing the role of the bulky group of the catalyst that prevents the approach of the electrophile from the more hindered side. This standard steric shielding model has recently been challenged by the discovery of stable downstream intermediates, which appear to be involved in the rate-determining step of the catalytic cycle. The alternative model, referred to as the Curtin-Hammett scenario of stereocontrol, assumes that the enantioselectivity is related to the stability and reactivity of downstream intermediates. In our present computational study, we examine the two key processes of the catalytic Michael reaction between propanal and ß-nitrostyrene that are relevant to the proposed stereoselectivity models, namely the C-C bond formation and the protonation steps. The free energy profiles obtained for the pathways leading to the enantiomeric products suggest that the rate- and stereodetermining steps are not identical as implied by the previous models. The stereoselectivity can be primarily controlled by C-C bond formation even though the reaction rate is dictated by the protonation step. This kinetic scheme is consistent with all observations of experimental mechanistic studies including those of mass spectrometric back reaction screening experiments, which reveal a mismatch between the stereoselectivity of the back and the forward reactions.

Folding Patterns in a Family of Oligoamide Foldamers.

A series of small, unsymmetrical pyridine-2,6-dicarboxylamide oligoamide foldamers with varying lengths and substituents at the end groups were synthetized to study their conformational properties and folding patterns. The @-type folding pattern resembled the oxyanion-hole motifs of enzymes, but several alternative folding patterns could also be characterized. Computational studies revealed several alternative conformers of nearly equal stability. These folding patterns differed from each other in their intramolecular hydrogen-bonding patterns and aryl-aryl interactions. In the solid state, the foldamers adopted either the globular @-type fold or the more extended S-type conformers, which were very similar to those foldamers obtained computationally. In some cases, the same foldamer molecule could even crystallize into two different folding patterns, thus confirming that the different folding patterns are very close in energy in spite of their completely different shapes. Finally, the best match for the observed NOE interactions in the liquid state was a conformation that matched the computationally characterized helix-type fold.

Mukaiyama-Michael reactions with trans-2,5-diarylpyrrolidine catalysts: enantioselectivity arises from attractive noncovalent interactions, not from steric hindrance.

The scope of the enantioselective Mukaiyama-Michael reactions catalyzed by trans-2,5-diphenylpyrrolidine has been expanded to include both α- and ß-substituted enals. However, the rationalization of the observed enantioselectivity is far from obvious since the catalyst is not very sterically hindered. DFT calculations were carried out to rationalize the observed stereoselectivities. Transition states of the C-C bond formation between iminium intermediates and silyloxyfurans were located and their relative energies were used to estimate the stereoselectivity data. We find excellent agreement between the predicted and observed stereoselectivities. The analysis of intermolecular forces reveals that the enantioselectivity is mostly due to stabilizing noncovalent interactions between the reacting partners, not due to steric hindrance. The role of attractive noncovalent interactions in enantioselective catalysis may be underappreciated.

On the mechanism of bifunctional squaramide-catalyzed organocatalytic Michael addition: a protonated catalyst as an oxyanion hole.

A joint experimental-theoretical study of a bifunctional squaramide-amine-catalyzed Michael addition reaction between 1,3-dioxo nucleophiles and nitrostyrene has been undertaken to gain insight into the nature of bifunctional organocatalytic activation. For this highly stereoselective reaction, three previously proposed mechanistic scenarios for the critical CC bond-formation step were examined. Accordingly, the formation of the major stereoisomeric products is most plausible by one of the bifunctional pathways that involve electrophile activation by the protonated amine group of the catalyst. However, some of the minor product isomers are also accessible through alternative reaction routes. Structural analysis of transition states points to the structural invariance of certain fragments of the transition state, such as the protonated catalyst and the anionic fragment of approaching reactants. Our topological analysis provides deeper insight and a more general understanding of bifunctional noncovalent organocatalysis.

Reactivity models of hydrogen activation by frustrated Lewis pairs: synergistic electron transfers or polarization by electric field?

Two alternative qualitative reactivity models have recently been proposed to interpret the facile heterolytic cleavage of H2 by frustrated Lewis pairs (FLPs). Both models assume that the reaction takes place via reactive intermediates with preorganized acid/base partners; however, they differ in the mode of action of the active centers. In the electron transfer (ET) model, the hydrogen activation is associated with synergistic electron donation processes with the simultaneous involvement of active centers and the bridging hydrogen, showing similarity to transition-metal-based and other H2-activating systems. In contrast, the electric field (EF) model suggests that the heterolytic bond cleavage occurs as a result of polarization by the strong EF present in the cavity of the reactive intermediates. To assess the applicability of the two conceptually different mechanistic views, we examined the structural and electronic rearrangements as well as the EFs along the H2 splitting pathways for a representative set of reactions. The analysis reveals that electron donations developing already in the initial phase are general characteristics of all studied reactions, and the related ET model provides qualitative interpretation for the main features of the reaction pathways. On the other hand, several arguments have emerged that cast doubt on the relevance of EF effects as a conceptual basis in FLP-mediated hydrogen activation.

Copper(II)-binding ability of stereoisomeric cis- and trans-2-aminocyclohexanecarboxylic acid-L-phenylalanine dipeptides. A combined CW/pulsed EPR and DFT study.

With the aim of an improved understanding of the metal-complexation properties of alicyclic ß-amino acid stereoisomers, and their peptides, the complex equilibria and modes of coordination with copper(II) of L-phenylalanine (F) derivatives of cis/trans-2-aminocyclohexanecarboxylic acid (c/tACHC), i.e. the dipeptides F-c/tACHC and c/tACHC-F, were investigated by a combination of CW and pulsed EPR methods. For the interpretation of the experimental data, DFT quantum-chemical calculations were carried out. Simulation of a pH-dependent series of room-temperature CW-EPR spectra revealed the presence of EPR-active complexes ([Cu(aqua)](2+), [CuL](+), [CuLH(-1)], [CuLH(-2)](-), and [CuL(2)H(-1)](-)), and an EPR-inactive species ([Cu(2)L(2)H(-3)](-)) in aqueous solutions for all studied cases. [CuLH](2+) was included in the equilibrium model for the c/tACHC-F-copper(II) systems, and [CuL(2)], together with two coordination isomers of [CuL(2)H(-1)](-), were also identified in the F-tACHC-copper(II) system. Comparison of the complexation properties of the diastereomeric ligand pair F-(1S,2R)-ACHC and F-(1R,2S)-ACHC did not reveal significant differences. Considerably lower formation constants were obtained for the trans than for the cis isomers for both the F-c/tACHC and the c/tACHC-F pairs in the case of [CuLH(-1)] involving tridentate coordination by the amino, the deprotonated peptide, and the carboxylate groups. A detailed structural analysis by pulsed EPR methods and DFT calculations indicated that there was no significant destabilization for the complexes of the trans isomers. The lower stability of their complexes was explained by the limitation that only the conformer with donor groups in equatorial-equatorial ring positions can bind to copper(II), whereas both equatorial-axial conformers of the cis isomers are capable of binding. From a consideration of the proton couplings obtained with X-band (1)H HYSCORE, (2)H exchange experiments, and DFT, the thermodynamically most stable cyclohexane ring conformer was assigned for all four [CuLH(-1)] complexes. For the F-cACHC case, the conformer did not match the most stable conformer of the free ligand.

Stereoelectronic requirements for optimal hydrogen-bond-catalyzed enolization.

Protein crystallographic analysis of the active sites of enolizing enzymes and structural analysis of hydrogen-bonded carbonyl compounds in small molecule crystal structures, complemented by quantum chemical calculations on related model enolization reactions, suggest a new stereoelectronic model that accounts for the observed out-of-plane orientation of hydrogen-bond donors (HBDs) in the oxyanion holes of enolizing enzymes. The computational results reveal that the lone-pair directionality of HBDs characteristic for hydrogen-bonded carbonyls is reduced upon enolization, and the enolate displays almost no directional preference for hydrogen bonding. Positioning the HBDs perpendicular to the carbonyl plane induces strain in the catalyst-substrate complex, which is released upon enolization, resulting in more favorable kinetics and thermodynamics than the in-plane arrangement of HBDs.

Rationalizing the reactivity of frustrated Lewis pairs: thermodynamics of H(2) activation and the role of acid-base properties.

The acid-base strengths of recently reported frustrated Lewis pairs and their relation with the thermodynamic feasibility of heterolytic hydrogen splitting reactions are analyzed in terms of quantum chemical calculations. Reaction free energies of hydrogenation processes are computed, and an energy partitioning scheme is introduced, which involves quantitative measures of the acidity and basicity of the reacting Lewis centers. Additional terms are also included that account for possible dative bond formation between the active sites and for stabilizing electrostatic interactions occurring in the product species. For intermolecular combinations of donor-acceptor components, the calculated reaction free energies are found to correlate well with the cumulative acid-base strengths. Product stabilization for these systems represents a notable contribution to the overall energetics; however, it generally shows only a slight variation for the investigated series. The reactivity of linked donor-acceptor pairs is primarily governed by acid-base properties as well, but the magnitude of stabilizing effects arising from acid-base cooperativity of active sites is also of significant importance in determining the thermodynamic feasibility of the reactions.

On the mechanism of B(C6F5)3-catalyzed direct hydrogenation of imines: inherent and thermally induced frustration.

The reaction mechanism for the transition metal free direct hydrogenation of bulky imines catalyzed by the Lewis acid B(C6F5)3 is investigated in detail by quantum chemical calculations. A recently introduced mechanistic model of heterolytic hydrogen splitting that is based on noncovalent association of bulky Lewis acid-base pairs is shown to account for the reactivity of imine-borane as well as amine-borane systems. Possible catalytic cycles are examined, and the results provide solid support for the imine reduction pathway proposed from experimental observations. In addition, the feasibility of an autocatalytic route initiated by amine-borane hydrogen cleavage is demonstrated. Conceptual issues regarding the notion of frustration are also discussed. The observed reactivity is interpreted in terms of thermally induced frustration, which refers to thermal activation of strained dative adducts of bulky Lewis donor-acceptor pairs to populate their reactive frustrated complex forms.

Concerted attack of frustrated Lewis acid-base pairs on olefinic double bonds: a theoretical study.

A computational approach reveals cooperative action of the preorganized acidic and basic centers of the frustrated P(t-Bu)(3)/B(C(6)F(5))(3) Lewis pair on olefinic bonds as the key to the observed regioselective addition reaction.

Computing reliable energetics for conjugate addition reactions.

The performance of various density functionals along with second-order perturbation treatments has been tested for a set of conjugate addition reactions relevant to stereoselective organocatalysis. It is shown that B3LYP predictions seriously underestimate the reaction energies, whereas two newly designed functionals (M05-2X and M06-2X) and the SCS-MP2 method provide very accurate data. These new methods represent promising alternative approaches in future mechanistic studies.

Theoretical studies on the bifunctionality of chiral thiourea-based organocatalysts: competing routes to C-C bond formation.

The mechanism of enantioselective Michael addition of acetylacetone to a nitroolefin catalyzed by a thiourea-based chiral bifunctional organocatalyst is investigated using density functional theory calculations. A systematic conformational analysis is presented for the catalyst, and it is shown that both substrates coordinate preferentially via bidentate hydrogen bonds. The deprotonation of the enol form of acetylacetone by the amine of the catalyst is found to occur easily, leading to an ion pair characterized by multiple H-bonds involving the thiourea unit as well. Two distinct reaction pathways are explored toward the formation of the Michael product that differ in the mode of electrophile activation. Both reaction channels are shown to be consistent with the notion of noncovalent organocatalysis in that the transition states leading to the Michael adduct are stabilized by extensive H-bonded networks. The comparison of the obtained energetics for the two pathways allows us to propose an alternative mechanistic rationale for asymmetric C-C bond forming reactions catalyzed by bifunctional thiourea derivatives. The origin of enantioselectivity in the investigated reaction is also discussed.