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 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.

Activation of H2 using ansa-aminoboranes: solvent effects, dynamics, and spin hyperpolarization.

Spin hyperpolarization generated upon activation of parahydrogen, the spin-0 isomer of H2, by ansa-aminoboranes (AABs) constitutes a rare but interesting example of applied metal-free catalysis in parahydrogen-induced polarization (PHIP). AAB molecular moieties made of light elements would be useful in important areas of NMR, such as chemosensing and the production of hyperpolarized substances, or generally in NMR sensitivity enhancement. At the same time, little is known about the detailed mechanistic aspects of underlying chemical processes. Herein, we present a joint experimental-computational study of the kinetic and thermodynamic aspects of H2 activation by AABs, for the first time providing molecular-level details and results of PHIP experiments with AABs in various solvents. Specifically, a large number of kinetic and thermodynamic parameters are measured experimentally for H2 activation by 2-aminophenylboranes of variable steric bulkiness of the boryl site. A clear correlation between the experimental and DFT-predicted thermochemical parameters is observed. PHIP effects in toluene, dichloromethane, and acetonitrile are characterized and rationalized based on the use of the kinetic and nuclear spin relaxation parameters. Altogether, the obtained results provide valuable information for the further rational design of efficient AAB catalysts for metal-free PHIP based on frustrated Lewis pair (FLP) chemistry.

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.

Late-Stage Formal Double C-H Oxidation of Prenylated Molecules to Alkylidene Oxetanes and Azetidines by Strain-Enabled Cross-Metathesis.

Prenylation is a ubiquitous late-stage modification in nature that often confers significantly improved bioactivity for secondary metabolites. While this lipophilic modification renders enhanced potency, the lipophilic tag(s) can diminish bioavailability and adversely alter drug transportation and metabolism. Thus, a functional-group-tolerant, mild, and selective late-stage C-H functionalization of prenyl tags would present a great potential in drug discovery programs but could also impact other fields, such as agrochemistry and chemical biology. Herein we report an exocyclic-strain-driven cross-metathesis reaction of prenyl tags, a formal double C-H oxidation protocol, that can be used for the selective late-stage derivatization of prenylated compounds and natural products. This methodology avoids the need for prefunctionalization of target molecules and affords ready access to an unprecedented library of oxo- and aza-prenylated complex molecules. Thus, in a broader context, this methodology extends late-stage functionalization beyond that available to nature.

Carboxylate Catalyzed Isomerization of ß,γ-Unsaturated N-Acetylcysteamine Thioesters.

We demonstrate herein the capacity of simple carboxylate salts - tetrametylammonium and tetramethylguanidinium pivalate - to act as catalysts in the isomerization of ß,γ-unsaturated thioesters to α,ß-unsaturated thioesters. The carboxylate catalysts gave reaction rates comparable to those obtained with DBU, but with fewer side reactions. The reaction exhibits a normal secondary kinetic isotope effect (k1H /k1D =1.065±0.026) with a ß,γ-deuterated substrate. Computational analysis of the mechanism provides a similar value (k1H /k1D =1.05) with a mechanism where γ-reprotonation of the enolate intermediate is rate determining.

The Influence of Secondary Interactions on the [N-I-N]+ Halogen Bond.

[Bis(pyridine)iodine(I)]+ complexes offer controlled access to halonium ions under mild conditions. The reactivity of such stabilized halonium ions is primarily determined by their three-center, four-electron [N-I-N]+ halogen bond. We studied the importance of chelation, strain, steric hindrance and electrostatic interaction for the structure and reactivity of halogen bonded halonium ions by acquiring their 15 N NMR coordination shifts and measuring their iodenium release rates, and interpreted the data with the support of DFT computations. A bidentate ligand stabilizes the [N-I-N]+ halogen bond, decreasing the halenium transfer rate. Strain weakens the bond and accordingly increases the release rate. Remote modifications in the backbone do not influence the stability as long as the effect is entirely steric. Incorporating an electron-rich moiety close by the [N-I-N]+ motif increases the iodenium release rate. The analysis of the iodine(I) transfer mechanism highlights the impact of secondary interactions, and may provide a handle on the induction of stereoselectivity in electrophilic halogenations.

Are bis(pyridine)iodine(I) complexes applicable for asymmetric halogenation?

Enantiopure halogenated molecules are of tremendous importance as synthetic intermediates in the construction of pharmaceuticals, fragrances, flavours, natural products, pesticides, and functional materials. Enantioselective halofunctionalizations remain poorly understood and generally applicable procedures are lacking. The applicability of chiral trans-chelating bis(pyridine)iodine(I) complexes in the development of substrate independent, catalytic enantioselective halofunctionalization has been explored herein. Six novel chiral bidentate pyridine donor ligands have been designed, routes for their synthesis developed and their [N-I-N]+-type halogen bond complexes studied by 15N NMR and DFT. The chiral complexes encompassing a halogen bond stabilized iodenium ion are shown to be capable of efficient iodenium transfer to alkenes; however, without enantioselectivity. The lack of stereoselectivity is shown to originate from the availability of multiple ligand conformations of comparable energies and an insufficient steric influence by the chiral ligand. Substrate preorganization by the chiral catalyst appears a necessity for enantioselective halofunctionalization.

Catalytic Activity of trans-Bis(pyridine)gold Complexes.

Gold catalysis has become one of the fastest growing fields in chemistry, providing new organic transformations and offering excellent chemoselectivities under mild reaction conditions. Methodological developments have been driven by wide applicability in the synthesis of complex structures, whereas the mechanistic understanding of Au(III)-mediated processes remains scanty and have become the Achilles' heel of methodology development. Herein, the systematic investigation of the reactivity of bis(pyridine)-ligated Au(III) complexes is presented, based on NMR spectroscopic, X-ray crystallographic, and DFT data. The electron density of pyridines modulates the catalytic activity of Au(III) complexes in propargyl ester cyclopropanation of styrene. To avoid strain induced by a ligand with a nonoptimal nitrogen-nitrogen distance, bidentate bis(pyridine)-Au(III) complexes convert into dimers. For the first time, bis(pyridine)Au(I) complexes are shown to be catalytically active, with their reactivity being modulated by strain.

Metal-Free C-H Borylation of N-Heteroarenes by Boron Trifluoride.

Organoboron compounds are essential reagents in modern C-C coupling reactions. Their synthesis via catalytic C-H borylation by main group elements is emerging as a powerful tool alternative to transition metal based catalysis. Herein, a straightforward metal-free synthesis of aryldifluoroboranes from BF3 and heteroarenes is reported. The reaction is assisted by sterically hindered amines and catalytic amounts of thioureas. According to computational studies the reaction proceeds via frustrated Lewis pair (FLP) mechanism. The obtained aryldifluoroboranes are further stabilized against destructive protodeborylation by converting them to the corresponding air stable tetramethylammonium organotrifluoroborates.

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.

Mechanochemical Synthesis of Corannulene-Based Curved Nanographenes.

It is shown that corannulene-based strained π-surfaces can be obtained through the use of mechanochemical Suzuki and Scholl reactions. Besides being solvent-free, the mechanochemical synthesis is high-yielding, fast, and scalable. Therefore, gram-scale preparation can be carried out in a facile and sustainable manner. The synthesized nanographene structure carries positive (bowl-like) and negative (saddle-like) Gaussian curvatures and adopts an overall quasi-monkey saddle-type of geometry. In terms of properties, the non-planar surface exhibits a high electron affinity that was measured by cyclic voltammetry, with electrolysis and in situ UV/vis spectroscopy experiments indicating that the one-electron reduced state displays a long lifetime in solution. Overall, these results indicate the future potential of mechanochemistry in accessing synthetically challenging and functional curved π-systems.

Mechanism of Au(III)-Mediated Alkoxycyclization of a 1,6-Enyne.

Gold-mediated homogeneous catalysis is a powerful tool for construction of valuable molecules and has lately received growing attention. Whereas Au(I)-catalyzed processes have become well established, those mediated by Au(III) have so far barely been explored, and their mechanistic understanding remains basic. Herein, we disclose the combined NMR spectroscopic, single-crystal X-ray crystallographic, and computational (DFT) investigation of the Au(III)-mediated alkoxycyclization of a 1,6-enyne in the presence of a bidentate pyridine-oxazoline ligand. The roles of the counterion, the solvent, and the type of Au(III) complex have been assessed. Au(III) is demonstrated to be the active catalyst in alkoxycyclization. Alkyne coordination to Au(III) involves decoordination of the pyridine nitrogen and is the rate-limiting step.

Dynamic Refolding of Ion-Pair Catalysts in Response to Different Anions.

Four distinct folding patterns are identified in two foldamer-type urea-thiourea catalysts bearing a basic dimethylamino unit by a combination of X-ray crystallography, solution NMR studies, and computational studies (DFT). These patterns are characterized by different intramolecular hydrogen bonding schemes that arise largely from different thiourea conformers. The free base forms of the catalysts are characterized by folds where the intramolecular hydrogen bonds between the urea and the thiourea units remain intact. In contrast, the catalytically relevant salt forms of the catalyst, where the catalyst forms an ion pair with the substrate or substrate analogues, appear in two entirely different folding patterns. With larger anions that mimic the dialkyl malonate substrates, the catalysts maintain their native fold both in the solid state and in solution, but with smaller halide anions (fluoride, chloride, and bromide), the catalysts fold around the halide anion (anion receptor fold), and the intramolecular hydrogen bonds are disrupted. Titration of catalyst hexafluoroacetylacetonate salt with tetra-n-butylammonium chloride results in dynamic refolding of the catalyst from the native fold to the anion receptor fold.

Halogen Bonding Helicates Encompassing Iodonium Cations.

The first halonium-ion-based helices were designed and synthesized using oligo-aryl/pyridylene-ethynylene backbones that fold around reactive iodonium ions. Halogen bonding interactions stabilize the iodonium ions within the helices. Remarkably, the distance between two iodonium ions within a helix is shorter than the sum of their van der Waals radii. The helical conformations were characterized by X-ray crystallography in the solid state, by NMR spectroscopy in solution and corroborated by DFT calculations. The helical complexes possess potential synthetic utility, as demonstrated by their ability to induce iodocyclization of 4-penten-1-ol.

Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,ß-Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas.

Carboxylic acids and their corresponding carboxylate anions are generally utilized as Brønsted acids/bases and oxygen nucleophiles in organic synthesis. However, a few asymmetric reactions have used carboxylic acids as electrophiles. Although chiral thioureas bearing both arylboronic acid and tertiary amine were found to promote the aza-Michael addition of BnONH2 to α,ß-unsaturated carboxylic acids with moderate to good enantioselectivities, the reaction mechanism remains to be clarified. Detailed investigation of the reaction using spectroscopic analysis and kinetic studies identified tetrahedral borate complexes, comprising two carboxylate anions, as reaction intermediates. We realized a dramatic improvement in product enantioselectivity with the addition of 1 equiv of benzoic acid. In this aza-Michael reaction, the boronic acid not only activates the carboxylate ligand as a Lewis acid, together with the thiourea NH-protons, but also functions as a Brønsted base through a benzoyloxy anion to activate the nucleophile. Moreover, molecular sieves were found to play an important role in generating the ternary borate complexes, which were crucial for obtaining high enantioselectivity as demonstrated by DFT calculations. We also designed a new thiourea catalyst for the intramolecular oxa-Michael addition to suppress another catalytic pathway via a binary borate complex using steric hindrance between the catalyst and substrate. Finally, to demonstrate the synthetic versatility of both hetero-Michael additions, we used them to accomplish the asymmetric synthesis of key intermediates in pharmaceutically important molecules, including sitagliptin and α-tocopherol.

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.

Expanding the Boundaries of Water-Tolerant Frustrated Lewis Pair Hydrogenation: Enhanced Back Strain in the Lewis Acid Enables the Reductive Amination of Carbonyls.

The development of a boron/nitrogen-centered frustrated Lewis pair (FLP) with remarkably high water tolerance is presented. As systematic steric tuning of the boron-based Lewis acid (LA) component revealed, the enhanced back-strain makes water binding increasingly reversible in the presence of relatively strong base. This advance allows the limits of FLP's hydrogenation to be expanded, as demonstrated by the FLP reductive amination of carbonyls. This metal-free catalytic variant displays a notably broad chemoselectivity and generality.

Metal-Free sp(2)-C-H Borylation as a Common Reactivity Pattern of Frustrated 2-Aminophenylboranes.

C-H borylation is a powerful and atom-efficient method for converting affordable and abundant chemicals into versatile organic reagents used in the production of fine chemicals and functional materials. Herein we report a facile C-H borylation of aromatic and olefinic C-H bonds with 2-aminophenylboranes. Computational and experimental studies reveal that the metal-free C-H insertion proceeds via a frustrated Lewis pair mechanism involving heterolytic splitting of the C-H bond by cooperative action of the amine and boryl groups. The adapted geometry of the reactive B and N centers results in an unprecedentently low kinetic barrier for both insertion into the sp(2)-C-H bond and intramolecular protonation of the sp(2)-C-B bond in 2-ammoniophenyl(aryl)- or -(alkenyl)borates. This common reactivity pattern serves as a platform for various catalytic reactions such as C-H borylation and hydrogenation of alkynes. In particular, we demonstrate that simple 2-aminopyridinium salts efficiently catalyze the C-H borylation of hetarenes with catecholborane. This reaction is presumably mediated by a borenium species isoelectronic to 2-aminophenylboranes.

Nuclear spin hyperpolarization with ansa-aminoboranes: a metal-free perspective for parahydrogen-induced polarization.

The parahydrogen-induced polarization (PHIP) phenomenon, observed when parahydrogen is used in H2 addition processes, provides a means for substantial NMR signal enhancements and mechanistic studies of chemical reactions. Commonly, noble metal complexes are used for parahydrogen activation, whereas metal-free activation is rare. Herein, we report a series of unimolecular metal-free frustrated Lewis pairs based on an ansa-aminoborane (AAB) moiety in the context of PHIP. These molecules, which have a "molecular tweezers" structure, differ in their substituents at the boryl site (-H, -Ph, -o-iPr-Ph, and -Mes). PHIP effects were observed for all the AABs after exposing their solutions to parahydrogen in a wide temperature range, and experimental measurements of their kinetic and thermodynamic parameters were performed. A theoretical analysis of their nuclear spin polarization effects is presented, and the roles of chemical exchange, chemical equilibrium and spin dynamics are discussed in terms of the key dimensionless parameters. The analysis allowed us to formulate the prerequisites for achieving strong polarization effects with AAB molecules, which can be applied for further design of efficient metal-free tweezers-like molecules for PHIP. Mechanistic (chemical and physical) aspects of the observed effects are discussed in detail. In addition, we performed quantum chemical calculations, which confirmed that the J-coupling between the parahydrogen-originated protons in AAB-H2 molecules is mediated through dihydrogen bonding.