Acidic Α-hydrogen Research Articles

Redox-Neutral, Iron-Mediated Directed C-H Activation: General Principles and Mechanistic Insights.

Experimental and computational studies have been conducted and established the general principles for enabling redox-neutral C-H activation by iron(II) complexes. The idealized octahedral iron(II) dimethyl complex, (depe)2Fe(CH3)2 (depe = 1,2-bis(diethylphosphino)ethane) promoted the directed, regioselective ortho C(sp2)-H methylation of pivalophenone. The rate of the iron(II)-mediated C(sp2)-H functionalization depended on the lability of L-type phosphine ligands, the spin state of the iron center, and the size of the X-type ligands (halide, hydrocarbyl) in P4FeIIX2 complexes. The C(sp2)-H alkylation reaction proved general among multiple substrates with directing groups including carbonyl, imines and pyridines. Among these, ketones and aldehydes were identified as optimal and were compatible with various steric environments and presence of acidic α-hydrogens. With stronger nitrogen donors, higher barriers for product-forming reductive elimination were observed. The effect of orbital hybridization on the chemoselectivity of C-H activation through a σ-CAM pathway by dn>0 transition metals was also established by studying the stoichiometric reactivity of the differentially substituted (depe)2Fe(Me)R complexes (R = alkyl, aryl), where the Fe-R bond with greater s-character preferentially promoted selective C-H activation. Deuterium labeling and kinetic studies, coupled with computational analysis, supported a pathway involving phosphine dissociation and rate-determining C-H bond activation, leading to the observed products.

Eutectic Mixtures As Highly Concentrated and Molten Electrolytes with Nearly Single-Ion Conducting Behavior

Today's state-of-the-art liquid electrolytes in lithium ion batteries (LIBs) have a high ionic conductivity and good performance regarding their cycle life. (1) However, they pose a safety risk due to their high vapor pressures and low thermal stability. (1) Furthermore, due to the limited electrochemical stability of the solvent, liquid electrolytes are not suitable for the application in high-voltage LIBs. (2) Molten salts, also called ionic liquids (IL), or highly concentrated electrolytes (HCE) have high lithium ion concentrations, where nearly every solvent molecule is coordinated. Due to this, there are strong ion interactions and the formation of ion clusters that lead to an increased lithium ion transference number of >0.5. (3) Therefore, they can represent an alternative in the field of liquid electrolytes. Additionally, HCE exhibit a higher thermal and electrochemical stability compared to dilute electrolytes and can improve the cycle performance in lithium metal batteries. (4, 5)McOwen et al. reported the coordination of lithium ions and crystalline structures in HCE of the binary mixtures of ethylene carbonate (EC) and lithium bis(trifluoromethane sulfonyl)imide (LiTFSI) with molar ratio up to 1:1. (6) Based on the concept of melting point depression as known from thermodynamics, room-temperature molten, highly concentrated electrolytes of a carbonate-based solvent with lithium sulfonyl imides were investigated. Instead of EC, the solvent pinacol carbonate (PIC) without acidic α-hydrogen atoms, but four bulky methyl groups was synthesized and used for eutectic mixtures, as the melting point of PIC is with 187 °C far above room-temperature. The physicochemical properties of these electrolytes are studied with respect to the different influence of lithium bis(fluorosulfonyl)imide and LiTFSI despite their same basic molecule structure. The focus will be on the electrochemical analysis by the means of the ionic conductivity, transference number and the electrochemical stability.In comparison to dilute liquid electrolytes the molten electrolytes show extremely high transference numbers, especially for the PIC-LiTFSI mixtures nearly a single-ion conducting behavior (0.9) is observed. This behavior can be explained by the formation of a 2D polymeric network within the HCE electrolyte as determined by crystallographic measurements in the solid state. Combined with the high electrochemical stability, a stable long-term cycling and dendrite suppression in symmetric lithium cells could be shown. Cycling in full cells with high-voltage cathode materials such as LiNi0.6Mn0.2Co0.2O2 (NMC622) or LiMn4O2 (LMO) against lithium metal anodes is applicable. References K. Xu, Chemical Reviews, 104(10), 4303–4417 (2004).J. Li, C. Ma, M. Chi, C. Liang and N. J. Dudney, Advanced Energy Materials, 5(4) (2015).K. M. Diederichsen, E. J. McShane and B. D. McCloskey, ACS ENERGY LETTERS, 2(11), 2563–2575 (2017).G. Jiang, F. Li, H. Wang, M. Wu, S. Qi, X. Liu, S. Yang and J. Ma, Small Struct., 2(5), 2000122 (2021).V. Nilsson, A. Kotronia, M. Lacey, K. Edstrom and P. Johansson, ACS Applied Energy Materials, 3(1), 200–207 (2020).D. W. McOwen, D. M. Seo, O. Borodin, J. Vatamanu, P. D. Boyle and W. A. Henderson, Energy & Environmental science, 7(1), 416–426 (2014).

Lactone-Based Li+/F- Hybrid Liquid Electrolytes for Room-Temperature Fluoride Shuttle Batteries

The fluoride shuttle batteries (FSBs) represent one of the potentially promising beyond-lithium-ion innovative battery systems, operating with a redox-active fluoride-ion transporting electrolyte. The low-weight, anion-based, multi-electron-transfer reactions at the anode and cathode, with a wide range of options on metals and their fluoride counterparts as the active materials, offer the opportunity to hopefully breakthrough the energy density limitation of the state-of-the-art lithium ion batteries.Of the two options of FSBs, all-solid type and liquid-type cells, we have focused on the latter format that would probably enable a much easier room-temperature operation than does the all-solid based cell, if only we could succeed in the development of a redox-active fluoride-ion (or its complexed forms) transporting liquid electrolyte that concomitantly ensures a high electrochemical stability over a widest possible potential window. To this end, we have recently established a novel method to fabricate a plain fluoride-ion electrolyte in a high boiling lactone solvent (γ-butyl lactone; GBL), denoted as CsF(KF)/GBL, where either CsF or KF is dissociated without the help of any extra addenda. This is believed to be by virtue of the acidic α-hydrogen atoms next to the carbonyl group of GBL. As shown in Figure 1, F- ions in GBL may be stabilized in the configuration where they are coordinated by two GBL molecules via the interactions with α-hydrogens on both sides. This structure prevents the formation of HF (by the α-hydrogen abstraction by the F- ion), thus resulting in the sufficient stability and the long (many months or even years) shelf-life of CsF(KF)/GBL as the liquid electrolyte for room-temperature FSBs.Nevertheless, we subsequently realized that while the high reactivity of the GBL-solvated F- ions brought about good reversible fluorination and defluorination reactions for almost arbitrary metals from Ag down to Zn in the redox series, it also caused a highly irreversible reductive sub-reaction that could never be traced back to the simple electrochemical reduction of GBL on its own. What we then came up with is the Li+/F- hybrid liquid electrolyte, where the Li+ ions mixed in a large excess of an equimolar composition with respect to the F- ions form some complexes, Li x F( x -1)+, that are soluble in GBL, and thus prevent the precipitation of LiF.The lactone-based Li+/F- hybrid liquid electrolyte prepared in the above-noted manner largely extended, especially, the high negative potential window to or beyond the standard redox potential of Li+/Li. The Li+/F- hybrid liquid electrolyte was also accompanied by a unique function as an AA (anion acceptor) that facilitates a very minor but yet substantial dissolution of various metal fluorides as the active materials in the proximity of the electrodes under the respective redox operations. This, together with the expanded potential window, greatly improved the charge/discharge capacities and reversibility of both positive and negative electrodes in the practical composite forms employing nano-scale or sub-nanoscale particles of the relevant active materials. We are demonstrating the charge/discharge behaviors of some typical electrodes in the Li+/F- hybrid electrolyte, such as Cu/CuF2, Bi/BiF3, Al in combination with a highly disordered phase of AlF3, and so forth. Acknowledgement:This work was supported by the Research and Development Initiative for Scientific Innovation of New Generation Battery 2 (RISING2), financially supported by New Energy and Industrial Technology Development Organization (NEDO). Figure 1

Synthesis of poly-substituted thiophenes in the realm of sulfonylketenimines chemistry

ABSTRACT An efficient synthesis of highly substituted thiophenes was developed by means of sulfonylketenimines in a multi-step reaction including heterocumulene system containing sulfur and nitro-alkanes with acidic α-hydrogen. The speed and ease of conducting this four-component reaction under mild conditions and using available materials makes it an ideal method to synthesize high purity substituted thiophenes with sulfonamide moiety. All structures synthesized are confirmed by the instrumental analysis (EI-MS, IR and 1H /13C-NMR).

1,1-Bis(dimethylamino)-2,2-difluoroethene, a diverse building block for the preparation of difluoroalkyl molecules. Acylation and condensation reactions

1,1-Bis(dimethylamino)-2,2-difluoroethene has been shown to be a diverse and highly effective building block for the preparation of a variety of fluorinated compounds. Reported here are preliminary results of its use for acylation reactions with acyl chlorides to form 2,2-difluoroketoacetamides as well as for its direct condensation with various acidic α-hydrogen carbon compounds to form a variety of functionalized difluoromethyl enamines.

ChemInform Abstract: Recent Advances in α‐Alkylation Reactions Using Alcohols with Hydrogen Borrowing Methodologies

AbstractReview: 142 refs.

Recent Advances in α-Alkylation Reactions using Alcohols with Hydrogen Borrowing Methodologies

This paper summarizes recent advances in α-alkylation reactions based on hydrogen borrowing methodologies using alcohol as an alkylating agent. This review provides a summary of recent progress toward the α-alkylation of carbonyl substrates, as well as relatively unactivated substrates bearing fewer acidic α-hydrogens, such as acetonitriles, acetamides, esters, methylpyrimidines, and methylquinolines. A summary of recent improvements in α-methylation strategies based on hydrogen borrowing methodologies has also been provided. Particular emphasis has been placed on highly practical and green chemistry approaches involving modified catalytic systems, including metal-supported heterogeneous catalysts and nanoparticle-based catalysts, as well as reactions conducted in the absence of a transition-metal catalyst. A review of recent achievements in methylation strategies using methanol as a methyl source, and their application to the α-methylation of ketones using transition-metal catalyzed hydrogen borrowing me...

ChemInform Abstract: Carbohydrate Derived Bicyclic Azetidin‐3‐ones as Scaffolds for Highly Functionalized Azetidines.

Abstract Bicyclic azetidin-3-ones with no acidic α-hydrogens, prepared in good yields via cis -2,4-di- O -triflates of pyranosides, are stable divergent intermediates for the synthesis of highly substituted azetidines, as illustrated by the synthesis of (2 R ,3 R ,4 R )-3-hydroxy-4-(hydroxymethyl)-3-methylazetidine-2-carboxylic acids. Preliminary studies on the reactions of bicyclic azetidinones indicate their potential as scaffolds for novel complex azetidines.

Carbohydrate derived bicyclic azetidin-3-ones as scaffolds for highly functionalized azetidines

Bicyclic azetidin-3-ones with no acidic α-hydrogens, prepared in good yields via cis-2,4-di-O-triflates of pyranosides, are stable divergent intermediates for the synthesis of highly substituted azetidines, as illustrated by the synthesis of (2R,3R,4R)-3-hydroxy-4-(hydroxymethyl)-3-methylazetidine-2-carboxylic acids. Preliminary studies on the reactions of bicyclic azetidinones indicate their potential as scaffolds for novel complex azetidines.

Déficience mitochondriale et résistance à l’insuline

β-Arylation of thiophenes might proceed through the Heck mechanism, but in this system the syn-βH elimination of conventional Heck mechanism could not take place. To understand the H elimination in Heck reactions of substituted thiophenes without syn-βH, three mechanistic possibilities, i.e. isomerization and syn-βH elimination (Mechanism A), αH elimination and 1,2-H shift (Mechanism B), and anti-βH elimination (Mechanism C), were carefully examined by DFT methods. More importantly, various factors (substrates, ligands and bases) on these βH elimination processes were systematically analyzed, as they might control the barriers of different hydrogen elimination. Based on the calculations, we found that base-assisted anti-βH elimination is the most energetically favored in the Heck hydrogen elimination mechanisms in substituted thiophenes systems as well as other heterocycles (i.e. thiophene, furan and N-methylpyrrole). Moreover, isomerization and syn-βH elimination (Mechanism A) may also be taken into account on the condition that the substrate has a weakly acidic α-hydrogen and no substituent on the heteroatom. In addition, the phosphine ligands with different electron-donating abilities have no effect on the preferred anti-βH elimination mechanism. Finally, carbonate as the base employed in Heck reaction is more beneficial for the anti-βH elimination than the amine. These results could not only offer a more comprehensive understanding of the Heck mechanism, but also provide helpful insights to the development of Heck-type arylation reactions of heterocyclic substrates.

Theoretical study on β-H elimination in Heck reactions of heterocyclic substrates

β-Arylation of thiophenes might proceed through the Heck mechanism, but in this system the syn-βH elimination of conventional Heck mechanism could not take place. To understand the H elimination in Heck reactions of substituted thiophenes without syn-βH, three mechanistic possibilities, i.e. isomerization and syn-βH elimination (Mechanism A), αH elimination and 1,2-H shift (Mechanism B), and anti-βH elimination (Mechanism C), were carefully examined by DFT methods. More importantly, various factors (substrates, ligands and bases) on these βH elimination processes were systematically analyzed, as they might control the barriers of different hydrogen elimination. Based on the calculations, we found that base-assisted anti-βH elimination is the most energetically favored in the Heck hydrogen elimination mechanisms in substituted thiophenes systems as well as other heterocycles (i.e. thiophene, furan and N-methylpyrrole). Moreover, isomerization and syn-βH elimination (Mechanism A) may also be taken into account on the condition that the substrate has a weakly acidic α-hydrogen and no substituent on the heteroatom. In addition, the phosphine ligands with different electron-donating abilities have no effect on the preferred anti-βH elimination mechanism. Finally, carbonate as the base employed in Heck reaction is more beneficial for the anti-βH elimination than the amine. These results could not only offer a more comprehensive understanding of the Heck mechanism, but also provide helpful insights to the development of Heck-type arylation reactions of heterocyclic substrates.

Chiral Silver Amides as Effective Catalysts for Enantioselective [3+2] Cycloaddition Reactions

Asymmetric [3+2] cycloaddition of α-aminoester Schiff bases with substituted olefins is one of the most efficient methods for the preparation of chiral pyrrolidine derivatives in optically pure form. In spite of its potential utility, applicable substrates for this method have been limited to Schiff bases that bear relatively acidic α-hydrogen atoms. Here we report a chiral silver amide complex for asymmetric [3+2] cycloaddition reactions. A silver complex prepared from silver bis(trimethylsilyl)amide (AgHMDS) and (R)-DTBM-SEGPHOS worked well in asymmetric [3+2] cycloaddition reactions of α-aminoester Schiff bases with several olefins to afford the corresponding pyrrolidine derivatives in high yields with remarkable exo- and enantioselectivities. Furthermore, α-aminophosphonate Schiff bases, which have less acidic α-hydrogen atoms, also reacted with olefins with high exo- and enantioselectivities. The stereoselectivities of the [3+2] cycloadditions with maleate and fumarate suggested that the reaction proceeded by means of a concerted mechanism. An NMR spectroscopic study indicated that complexation of AgHMDS with the bisphosphine ligand was not complete, and that free AgHMDS, which did not show any significant catalytic activity, existed in the catalyst solution. This means that significant ligand acceleration occurred in the current reaction system.

Mild Conversion of Esters Lacking Acidic α-Hydrogens into Amides via Samarium(III) Tris[hexamethyldisilazide] and Amines

Samarium(III) tris[hexamethyldisilazide] (Sm[(Me3Si)2N]3 = Sm[HMDS]3) promotes the direct conversion of an ester admixed with an amine into the corresponding carboxamide under exceptionally mild conditions (≤0 ˚C) and in high yields. Only a slight excess of amine and the lanthanide complex are required to effect complete conversion of the ester into the amide. Esters with acidic α-hydrogens undergo a competing Claisen-like condensation along with the desired conversion into amides.

Does intermolecular SO⋯H–C–SO hydrogen bonding in sulfoxides and sulfones provide a robust supramolecular synthon in the solid state?

Hydrogen bonding between the sulfur oxygens and the acidic α-hydrogens in sulfoxides and sulfones is proposed as a supramolecular synthon in crystal engineering. A systematic analysis of supramolecular interactions in the solid state of a series of structurally related aryl benzyl sulfides, sulfoxides and sulfones was undertaken to establish the extent to which such hydrogen bonds persist as a structure determining feature in the solid state. The impact of the level of oxidation at sulfur, steric and electronic effects of substituents on the aryl rings and methyl substitution α to the sulfur functional group on the solid state structure of the compounds have been explored. The impact of stereochemical features, including relative and absolute stereochemistry, is also discussed.

Synthesis, Electrochemistry, and Reactivity of Half-Sandwich Ruthenium Complexes Bearing Metallocene-Based Bisphosphines

The bimetallic complexes CpRu(P−P)X [Cp = η5-C5H5; X = Cl, H; P−P = dppf (1,1′-bis(diphenylphosphino)ferrocene), dppr (1,1′-bis(diphenylphosphino)ruthenocene), dppo (1,1′-bis(diphenylphosphino)-osmocene), dippf (1,1′-bis(diisopropylphosphino)ferrocene), dcpf (1,1′-bis(dicyclohexylphosphino)ferrocene)], Cp*Ru(P−P)X [Cp* = η5-C5Me5; X = Cl, H; P−P = dppf, dippf, dppomf (1,1′-bis(diphenylphosphino)octamethylferrocene), dppc (1,1′-bis(diphenylphosphino)cobaltocene)], [Cp*Ru(P−P)X]+ (X = H, CCPh; P−P = dppc+), and [Cp*Ru(P−P)L]2+ (L = CH3CN, t-BuCN; P−P = dppc+) have been synthesized. Most of the chloride and hydride complexes have been studied by cyclic voltammetry. The X-ray structures of [Cp*Ru(dppc)CH3CN][PF6]2 and [Cp*Ru(dppc)CCPh][PF6] have been determined. Protonation of [Cp*Ru(dppc)CCPh]+ gives the vinylidene complex [Cp*Ru(dppc)CCHPh]2+. The Co(III/II) potential of the dppc+ ligand undergoes a cathodic shift upon coordination in [Cp*Ru-(dppc)H]+ and an anodic shift upon coordination in [Cp*Ru(dppc)CH3CN]2+. The 1H NMR spectrum of Cp*Ru(dppc)H is consistent with its formulation as a Co(II)/Ru(II) complex. As gauged by their reactivity toward iminium cations, the hydride complexes are poor hydride donors; proton and electron transfer are dominant. CpRu(dippf)H and CpRu(dcpf)H deprotonate iminium cations with acidic α-hydrogens. Cp*Ru(dppc)H is oxidized by the N-(benzylidene)pyrrolidinium cation, giving [Cp*Ru-(dppc)H]+ and the vicinal diamine 1,2-bis(N-pyrrolidino)-1,2-diphenylethane. Most of the hydride complexes give trans-dihydride cations upon protonation; an exception is [Cp*Ru(dppc)H]+, which forms a dihydrogen complex [Cp*Ru(dppc)(H2)]2+ with surprising kinetic stability. This dihydrogen complex is more acidic and less thermodynamically stable than its dihydride isomer. The H2 ligand in [Cp*Ru(dppc)-(H2)]2+ is readily replaced by nitriles; the reaction with t-BuCN occurs by a dissociative mechanism.

A new method for the synthesis of 1,4,5-oxadiazocines and its application in the structure modification of natural products

A new method for the synthesis of eight-membered heterocyclic 1,4,5-oxadiazocines has been described from β-diketone and β,β,β-triketone with an acidic α-hydrogen. The method entails the reaction of a di- or triketone with 2-hydroxyethylhydrazine and an aldehyde in the presence of acetic acid providing respectable yield.

Transacetalization with gaseous carboxonium and carbosulfonium ions

Primary carboxonium (H 2CO +–R) and carbosulfonium (H 2CS +–R) ions (R = CH 3, C 2H 5, Ph) and the prototype five-membered cyclic carboxonium ion are found to react in the gas phase with cyclic acetals and ketals by transacetalization to form the respective O-alkyl-1,3-dioxolanium and S-alkyl-1,3-oxathiolanium ions. The reaction, which competes mainly with proton transfer and hydride abstraction, initiates by O-alkylation and proceeds by ring opening and recyclization via intramolecular displacement of the carbonyl compound previously protected in its ketal form. As indicated by product ion mass spectra, and confirmed by competitive reactions, carbosulfonium ions are, by transacetalization, much more reactive than carboxonium ions. For acyclic secondary and tertiary carboxonium ions bearing acidic α-hydrogens, little or no transacetalization occurs and proton transfer dominates. This structurally related reactivity distinguishes primary from both secondary and tertiary ions, as exemplified for the two structural isomers H 2CO +–C 2H 5 and CH 3C(H)O +–CH 3. The prototype five- and six-membered cyclic carboxonium ions react mainly by proton transfer and adduct formation, but the five-membered ring ion also reacts by transacetalization to a medium extent. Upon CID, the transacetalization products of the primary ions often dissociate by loss of formaldehyde, and a +44 u neutral gain/−30 u neutral loss MS 3 scan is shown to efficiently detect reactive carboxonium and carbosulfonium ions. Transacetalization with either carboxonium or carbosulfonium ions provides a route to 1,3-oxathiolanes and analogs alkylated selectively either at the sulfur or oxygen atom.

Hetero Diels-Alder reaction of aldimines derived from 3-indoleacetaldehyde and 3-indolecarboxaldehyde

Aldimines derived from 3-indoleacetaldehyde and 3-indolecarboxaldehyde undergo Lewis acid catalyzed Diels-Alder reactions. We found that Zn(OTf) 2 is an excellent promoter of hetero Diels-Alder reactions of imines with acidic α-hydrogens. Higher yields were obtained with aldimines from 3-indolecarboxaldehyde which does not have the acidic α-hydrogens.

An Improved Method for the One-Carbon Homologation of Ketones with Acidic α-Hydrogens

An Improved Method for the One-Carbon Homologation of Ketones with Acidic α-Hydrogens

Synthesis of the fluorine-18 labeled inhalation anesthetics

Fourteen compounds (fluoroalkanes and fluoroethers), including the two most utilized inhalation anesthetics Isoflurane (CF 3CHClOCF 2H) and Halothane (CF 3CHBrCl), have been labeled with fluorine-18 via a facile 18F-for- 19F exchange reaction. The compounds include ten inhalation anesthetics which span a ten-fold range in potency and four structurally related non-anesthetics. All the compounds possess a trifluoromethyl group ( CF 3 ) adjoining a carbon atom with an acidic α-hydrogen and at least one halogen or a strong electron withdrawing group ( X), { CF 3CHXR }. We postulate the isotopic fluoride exchange reaction proceeds through a carbanion transition state resulting from α-proton transfer to base. The carbanion stability is attributed to the inductive effect of the CF 3 group and the electron withdrawing capability of X. Compounds labeled in dimethyl sulfoxide (DMSO) at 125°C in 15 min include Isoflurane-CF 3CHClOCF 2H ( 1) (97% [ 18F]fluorine incorporation, 99% radiochemical purity, respectively), Sevoflurane-CF 3CHCF 3OCFH 2 ( 2) [98%, 99%], CF 3CHBrOCF 2H ( 3) [85%, 80%], Desflurane-CF 3CHFOCF 2H ( 4) [50%, 99%], Fluroxene-CF 3CH 2OCHCH 2 ( 5) [25%, 99%], Fluothyl-CF 3CH 2OCH 2CF 3 ( 6) [60%, 10% at a temperature of 175°C], Halothane-CF 3CHBrCl ( 7) [98%, 95%], CF 3CH 2I ( 8) [99%, 98%], CF 3CH 2Br ( 9) [18%, 98%], CF 3CH 2Cl ( 10) [95%, 98%], CF 3CHCl 2 ( 11) [90%, 20%], CF 3CHClCF 3 ( 12) [95%, 99%], (CF 3) 3CH ( 13) [99%, 99%] and HF-134a-CF 3CFH 2 ( 14) (15%, 93% at a temperature of 175°C).