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Deoxygenation of phosphine oxides is of great significance to synthesis of phosphorus ligands and relevant catalysts, as well as to the sustainability of phosphorus chemistry. However, the thermodynamic inertness of P═O bonds poses a severe challenge to their reduction. Previous approaches in this regard rely primarily on a type of P═O bond activation with either Lewis/Brønsted acids or stoichiometric halogenating reagents under harsh conditions. Here, we wish to report a novel catalytic strategy for facile and efficient deoxygenation of phosphine oxides via successive isodesmic reactions, whose thermodynamic driving force for breaking the strong P═O bond was compensated by a synchronous formation of another P═O bond. The reaction was enabled by PIII/P═O redox sequences with the cyclic organophosphorus catalyst and terminal reductant PhSiH3. This catalytic reaction avoids the use of the stoichiometric activator as in other cases and features a broad substrate scope, excellent reactivities, and mild reaction conditions. Preliminary thermodynamic and mechanistic investigations disclosed a dual synergistic role of the catalyst.

Hydroxylamines, represented by 1-hydroxy-2,2,6,6-tetramethylpiperidine (TEMPOH), are widely involved as active species in various chemical and electrochemical oxidations. The electrochemical behavior of TEMPOH is crucial to understanding the mechanisms of TEMPO-mediated redox sequences. However, compared to abundant studies on TEMPOH electrochemistry in aqueous solutions, the sole value of its oxidation potential Eox(TEMPOH) in organic solutions was reported to be 0.7 V (vs Fc in acetonitrile), seemingly conflicting with experimentally observed facile oxidation of TEMPOH. Herein, the electrochemistry of TEMPOH derivatives in acetonitrile was revisited, featuring much smaller oxidation potentials (about 0 V) than literature ones. Acid/base effects and kinetic studies lent credibility to these new values. Such a 0.7 V energy discrepancy impelled us to review the thermodynamic properties and oxidation mechanisms of TEMPOH deduced from the old value.

Electrostatic interaction, especially electrostatic attraction, usually plays critical roles in controlling the reactivity and selectivity in catalytic transformations; however, the like-charge repulsion, which is ubiquitous in physical systems, is rarely applied in reaction control. Herein we disclosed an unexpected like-charge repulsion induced enantio-control mode in primary aminecatalyzed fluorination reactions with 1-fluoro-2,4,6-trimethylpyridinium triflate. The ionic reaction works favorably in both highly polar (methanol) and non-polar (hexane) solvents, a seldom observed phenomenon in asymmetric catalysis. Erying plot analysis showed that an inversion temperature existed in MeOH, which was explained by the solvent-solute cluster model under different temperatures. Density functional theory (DFT) study and energy decomposition analysis (EDA) verified that the like-charge repulsion takes effect in polar solvent methanol, while in nonpolar solvents, the steric repulsion associated with ion-pair was found to be the major effect for the observed enantioselectivity.

The Vilsmeier–Haack reaction is a powerful tool to introduce formyl groups into electron-rich arenes, but its wide application is significantly restricted by stoichiometric employment of caustic POCl3. Herein, we reported a catalytic version of the Vilsmeier–Haack reaction enabled by a P(III)/P(V)═O cycle. This catalytic reaction provides a facile and efficient route for the direct construction of C1-deuterated indol-3-carboxaldehyde under mild conditions with stoichiometric DMF-d7 as the deuterium source. The products feature a remarkably higher deuteration level (>99%) than previously reported ones and are not contaminated by the likely unselective deuteration at other sites. The present transformation can also be used to transfer other carbonyl groups. Further downstream derivatizations of these deuterated products manifested their potential applications in the synthesis of deuterated bioactive molecules. Mechanistic insight was disclosed from studies of kinetics and intermediates.

The metal-free catalytic C–F bond activation of polyfluoroarenes was achieved with diazaphospholene as the catalyst and phenylsilane as the terminal reductant. Density functional theory calculations suggested a concerted nucleophilic aromatic substitution mechanism.

An efficient kinetic resolution of sulfinamides via an asymmetric N-allylic alkylation reaction was realized using hydroquinine as a catalyst under mild conditions. The kinetic resolution of a range of Morita–Baylis–Hillman adducts and N-aryl tert-butylsulfinamides was highly effective. In addition, the synthetic utility of the protocol was demonstrated by a scaled-up reaction. Density functional theory calculations provide convincing evidence for the interpretation of stereoselection.

Herein, access to axially and centrally chiral sulfinamides via asymmetric allylic alkylation was reported. A series of sulfinamides were obtained with good outcomes (up to 99% yield, >19:1 dr, and 98:2 er). The synthetic utility of the reaction was demonstrated by scaled-up synthesis, product transformation, and application as a catalyst in asymmetric catalysis.

The sources of asymmetric induction in the photoinduced phase-transfer-catalytic perfluoroalkylation of β-ketoesters were interpreted by density functional theory calculations. The calculations indicated that multiple hydrogen-bonding interactions mode rather than π–π stacking interactions model better described the transition structure of the reaction. The quantitative estimation of these noncovalent interactions within the key transition states identified that the O–H···O and specific C–H···O hydrogen bonds play key roles for the stereocontrol.

A series of novel N-tert-butyl sulfinyl squaramide receptors have been designed and synthesized. Their interactions with a range of inorganic anions were studied in solution by 1H NMR spectroscopy. This new type of squaramide displayed better anion-binding abilities over conventional diphenyl squaramides. The single crystal analysis and DFT calulations implied the role of the tert-butyl C–H protons in binding Cl–. The energies of C–H···Cl–interactions were estimated to be 1.4–1.6 kcal/mol in solution.

An acidity scale of triazolium-based N-heterocyclic carbene precursors was established by measuring 25 compounds’ (10a–15b) equilibrium acidities in dimethyl sulfoxide (DMSO) solution using overlapping indicator method. The pKavalues ranged from 12.08 to 15.5, responding not only to the N-aryl motif, but also to the core structure. Excellent correlation was observed between the pKavalues and the Hammett substituent constants (σp).

N-tert-Butyl sulfinyl squaramides were used for chiral discrimination of α-hydroxyphosphonates using 31P NMR. A free energy relationship study indicates that both steric and the electronic effects influence the chiral recognition of the donors.

Controlling product selectivity in successive reactions of the same type is challenging owing to the comparable thermodynamic and kinetic properties of the reactions involved. Here, the synergistic interaction of the two phosphoryl groups in bisphosphine dioxides (BPDOs) with a bromo-phosphonium cation was studied experimentally to provide a practical tool for substrate–catalyst recognition. As the eventual result, we have developed a phosphonium-catalyzed monoreduction of chiral BPDOs to access an array of synthetically useful bisphosphine monoxides (BPMOs) with axial, spiro, and planar chirality, which are otherwise challenging to synthesize before. The reaction features excellent selectivity and impressive reactivity. It proceeds under mild conditions, avoiding the use of superstoichiometric amounts of additives and metal catalysts to simplify the synthetic procedure. The accessibility and scalability of the reaction allowed for the rapid construction of a ligand library for optimization of asymmetric Heck-type cyclization, laying the foundation for a broad range of applications of chiral BPMOs in catalysis.

The recent recognition of the novel application of a few traditional electrophilic trifluoromethylthiolating reagents as SCF3radical sources offers a remarkable new opportunity for the development of radical trifluoromethylthiolation reactions. Herein, the first trifluoromethylthio radical donating ability (Tt•DA) scale of electrophilic SCF3-transfer reagents has been developed. This scale is based on Y-SCF3bond dissociation energies, which were obtained by density functional calculations (M06-2X). Single electron transfer is revealed to exhibit a substantial Y-SCF3bond-weakening effect, thus significantly facilitating the SCF3radical (•SCF3) release. The results may aid in future novel radical SCF3-transfer reagent design and new reaction development.

A Brönsted basicity scale comprising nine representative N-heterocyclic olefins (NHOs) was established by measuring the equilibrium acidities of their corresponding precursors in DMSO using an ultraviolet–visible spectroscopic method. The basicities (pKaHs) of the investigated NHOs cover a range from 14.7 to 24.1. The basicities of unsaturated NHOs are stronger than those of their N-heterocyclic carbene (NHC) analogues; however, the basicities for the saturated ones are much weaker than those of their NHC analogues, which is largely due to the aromatization effect that intrinsically influences the acidic dissociations of NHC and NHO precursors. The nucleophilicities of four NHOs were measured photometrically by monitoring the kinetics of reactions of these NHOs with common reference electrophiles for quantifying nucleophilic reactivities. In general, the nucleophilicity of the NHOs is much stronger than that of commonly used Lewis bases such as Ph3P or DMAP [4-(dimethylamino)pyridine] but weaker than that of their NHC analogues; however, caution should be taken when generalizing this conclusion to a wide range of electrophiles with distinctively electronic and structural properties.

The equilibrium acidities for several series of structural and electronic different organic acids were measured in 3-pyrrolidinium-based aprotic and protic ionic liquid (IL) analogues, that is, [Bmpy][NTf2], [BpyH][NTf2], and [PyH2][NTf2], by the UV–Vis method. The acidities of neutral acids are found to be much stronger in the protic ILs (PILs) than aprotic ILs (AILs), and the acidifying effect in the two PILs roughly increases proportionally to the number of protons in the cation of the PIL. On the other hand, interestingly, the cationic N+–H acids exhibit similar acidities in [Bmpy][NTf2] and [BpyH][NTf2] but much weaker than those in [PyH2][NTf2]. The Hammett ρ values for the acidic dissociation of para-substituted benzoic acids in two PILs are about the same as that in water (1.00) but significantly smaller than that in the AIL [Bmpy][NTf2] (2.66). The correlations between the acidities in the PILs and water show double-linear relationships with different slopes and intercepts for the neutral and cationic acids. These, together with previous observations in the PILs [DBUH][OTf] (DBU = 1,5-diazabicyclo(5.4.0)-5-undecene) and EAN (ethylammonium nitrate), clearly indicate that the structure of the cation plays a subtle but a crucial role on sensing the electronic nature of solutes and strongly affects the solvation behaviors of PILs.

Because of their unique biological, physical, and chemical properties, organofluorine compounds play an increasingly important role in numerous areas of chemistry and everyday life. However, although fluorine is the most abundant halogen in the earth’s crust and ranks 13th in abundance among all elements, naturally occurring organofluorine compounds are rare. Consequently, there is a growing demand for the development of safe and efficient reagents and selective synthetic methodologies for the introduction of fluorine or fluorine-containing groups into organic compounds. A wide variety of shelf-stable electrophilic fluorinating and fluoroalkylating reagents have been developed in the past decades. Some of them have also been shown to act as radical sources. These versatile reagents have promoted revolutionary advances in synthetic fluorine chemistry.

The work of Kita et al. on asymmetric oxidative dearomatization of naphthol carboxylic acids to spirolactones mediated/catalyzed by a novel, conformationally rigid μ-oxo-bridged hypervalent iodine(III) species is a landmark discovery in enantioselective iodine(III) catalysis [Kita, Y.; et al. Angew. Chem., Int. Ed.2008, 47, 3787. DOI: 10.1002/anie.200800464; J. Am. Chem. Soc.2013, 135, 4558. DOI: 10.1021/ja401074u]. We have investigated the detailed mechanism of this important transformation using density functional theory. Calculations revealed that proton transfer from the pendant carboxylic acid of naphthols to the bridging oxygen atom or the ligand of iodine(III) species, which enhances the nucleophilicity of the carboxylic oxygen and the nucleofugality of the iodoarene, is crucial for the dearomatizing spirolactonization. Halogen bonding between the resulting carboxylate and the electron-deficient iodine(III) center further stabilizes the dearomatizing spirolactonization transition states. Calculations also revealed a long-neglected cleaved μ-oxo iodine(III) species that is more reactive but less selective than the μ-oxo-bridged hypervalent iodine(III) species itself for the oxidative dearomatization of naphthols. The coexistence of two sequential dearomatizing spirolactonization processes in the reaction system results in a lower enantioselectivity. A new stereochemical model that is able to reproduce and rationalize the observed apparent enantioselectivities is proposed.

Axially chiral amides are usually found in many biologically active compounds and are useful ligands in asymmetric catalysis. Herein, by using the dynamic kinetic resolution approach, an asymmetric allylic alkylation reaction of racemic amide naphthols is disclosed, which leads to generation of the axially chiral naphthamides in good to excellent yields (up to 97%) and enantioselectivities (up to 96:4 e.r.). Density functional theory was used to gain a theoretical understanding of the enantioselectivities in this reaction.

Green and efficient C–C bond cleavage/cyanoalkylation of quinoxalin-2(1H)-ones and other heteroarenes under visible light or sunlight irradiation is described. The reaction proceeds under mild conditions at room temperature without transition-metal catalysts and extra bases. Notably, the products enable facile transformations to various significant organic compounds.

Cyanoalkylated diarylmethanes with biological and pharmacological potentials were synthesized from para-quinone methides and cyanoalkylating reagents through a photocatalytic process. This protocol is operationally simple and mild and has high efficiency, which gave the corresponding products in moderate to good yields. The synthetic utility of this work has been illustrated in the efficient synthesis of GPR40 agonists, which play an important role in FA-induced glucose-sensitive insulin secretion.

A highly diastereoselective and enantioselective Michael addition/desymmetrization reaction of maleimides with prochiral 3- substituted phthalides catalyzed by quinine-derived bifunctional thiourea was realized. A broad range of the 3,3′-disubstituted phthalides bearing vicinal quaternary-tertiary stereogenic centers were synthesized in moderate to good yields (up to 96%) with high diastereoselectivities (up to >19:1 dr) and enantioselectivities (up to 96:4 er).

The acidity ladder scale in [BMPY][NTf2] was successfully expanded toward the weak acidity region for about five more pKunits compared to the previously established one. This allows the acidities of a series of 13 aliphatic and aromatic nitroalkanes to be determined accurately by the UV–vis spectroscopic method. The acidity of nitroalkane in [BMPY][NTf2] covers ∼8 pKunits and is significantly weaker than those in DMSO and water. The Hammett plot for 4-substituted phenylnitromethanes shows an excellent linearity with a slope of 2.06, which is rather close to that in DMSO but significantly larger than that in water (0.80). The regression analyses reveal that the solvation behavior of [BMPY][NTf2] on the acidic dissociations of C–H acids is similar to that of DMSO.

A highly efficient method to access axially chiral anilides through asymmetric allylic alkylation reaction with achiral Morita–Baylis–Hillman carbonates by using a biscinchona alkaloid catalyst was reported. Through the atroposelective approach, a broad range of axially chiral anilide products with different acyl groups, such as substituted phenyl, naphthyl, alkyl, enyl, styryl, and benzyl, were generated with very good yields, moderate to excellent cis:transratios, and good to excellent enantioselectivities. The reaction can be scaled up, and the synthetic utility of axially chiral anilides was proved by transformations. Moreover, the linear free energy relationship analysis was introduced to investigate the reaction.

Most organic transformation involves cleavage and formation of various covalent bonds, and naturally, can be regarded as a process of bond reorganization, which should be intrinsically related to bond energies (e.g., pKa, BDE, etc.). However, in many cases such as in C–H bond activation/functionalization, direct correspondence between the bond energy and reaction rate or other relevant properties is only occasionally observed when applying the bond data by simple rules like the Linear Free-Energy Relationships (LFERs) in handling intricate reaction systems. In this Perspective, we present examples to argue that the above-mentioned situation is not a consequence of a diminishing role of the bond energetics in research, but most likely, comes from an improper use of energetic strategy, or simply due to a faulty selection of the data from unsuitable sources. Some advisable applications of bond energies in unscrambling the problems in modern day chemistry are exemplified through representative recent advances of the researches in this connection. Some of the possible directions of future research endeavors in the field of bond energetics and its prudent applications are recommended.

Highly enantioselective catalytic conjugate additions of 3‐substituted benzofuran‐2(3H)‐ones to 1,1‐bis(phenylsulfonyl)ethylene in the presence of catalysts based on Cinchonaalkaloids and containing tertiary amine and thiourea groups have been developed. Good to excellent stereoselectivities (up to 99 % ee) could be achieved. An interesting effect of substituent positions on stereoselectivities was observed, and a theoretical study to explain this phenomenon was undertaken.

Remote F effect: Unprecedented hetero‐Diels–Alder reactions of mono‐ and bis‐substituted cyclopentadienes have been realized by an asymmetric binary‐acid catalyst that synergistically combines a chiral phosphoric acid 1 h/InBr3with good periselectivity, high regioselectivity, and excellent stereoselectivity. Substituent mapping of the chiral phosphoric acid indicates a dramatic remote ortho‐fluoro effect on the stereocontrol (see scheme).

Enamine protonation: A chiral diamine catalyzes an asymmetric Friedel–Crafts reaction through catalytic enantioselective protonation of an enamine. This process can be applied to a range of α‐substituted acroleins and indoles with high yields of products and high enantioselectivity (up to 94 % ee). An OH/π interaction between H2O and the indole ring was found to play an important role in the transition state (see scheme).

Ein chirales Diaminkatalysiert asymmetrische Friedel‐Crafts‐Reaktionen über die enantioselektive Protonierung eines Enamins. Dieser Prozess verknüpft eine Reihe von α‐substituierten Acroleinen und Indolen in hohen Ausbeuten und mit Enantioselektivitäten bis 94 % ee.Eine O‐H/π‐Wechselwirkung zwischen H2O und dem Indolring spielt im Übergangszustand eine wichtige Rolle (siehe Schema).

Auf das Anion ist Verlass: Der Austausch des Anions einer Indium‐Lewis‐Säure bewirkt einen bemerkenswerten Regioselektivitätswechsel bei asymmetrischen 1,2‐ und 1,4‐Additionen. N‐geschützte Indole und β,γ‐ungesättigte α‐Ketoester lieferten die Addukte mit ausgezeichneter Enantioselektivität (siehe Schema).

You can count on the anion: Simply swapping the anions of an indium Lewis acid leads to a remarkable regioselectivity switch between asymmetric 1,2‐ and 1,4‐addition reactions. N‐protected indoles and β,γ‐unsaturated α‐keto esters gave adducts with excellent enantioselectivity (see scheme).

The immobilization of organocatalysts is one of the most explored approaches to overcome the limitations associated with organocatalytic systems such as high catalyst loading, difficult product separation and catalyst recycling. When compared with the commonly used covalent immobilization methods, which usually involve tedious synthetic manipulations, the non-covalent attachment of organocatalysts to supports offers facile and modular construction of immobilized chiral catalysts with maintained or even improved activity and stereoselectivity. This review summarizes the successful application of non-covalent interactions, such as acid–base interaction, ion–pair interaction, hydrophobic interaction and so on, in assembling recoverable and reusable organocatalysts.

The first primary aminocatalytic direct cross‐aldol reaction of acetaldehyde is presented. Among the various vicinal diamines screened, the L‐tert‐leucine derivative 1cin conjunction with (H4SiW12O40)0.25was identified as the optimal catalyst; good catalytic activity (up to 99 % yield in 4 h), and high enantioselectivities (up to 92 % ee) were achieved for a range of donors, including aromatic aldehydes and isatin derivatives. Aqueous acetaldehyde solution and paraldehyde can be conveniently applied in this system.

Chiral pyrroloindoles: A highly enantioselective catalytic conjugate addition of 3‐substituted oxindoles with 2‐chloroacrylonitrile has been developed with a readily accessible alkyl bifunctional tertiary amine thiourea catalyst. Excellent stereoselectivity of up to >30:1 diastereomeric ratio and 99 % enantiomeric excess was achieved. The obtained Michael products could be easily converted to chiral pyrroloindole structures, which are widely distributed in natural indole alkaloids (see scheme).

One stone four birds: A single chiral primary amine was found to catalyze unprecedented asymmetric retro‐aldol and transfer‐aldol reactions, leading to four different chiral aldol adducts from one common chiral source with up to 99:1 d.r. and 99 % ee(see scheme).

Ionic liquid works better: The first intermolecular asymmetric α‐alkylation of cyclic ketones was realized by using functionalized chiral ionic liquids as catalysts. The reaction proceeded with good to excellent yields and high ee.Highly stereoselective desymmetrization of 4‐substituted cyclohexanones with >99:1 d.r. and up to 87 % eewere achieved by using this protocol.

Acidity effect: Correlations of pKawith catalytic activity and stereoselectivity were determined and linear free energy relationships (LFERs) were observed for both pKa−log (k) and pKa−log (R/S) correlations in meta‐ and/or para‐substituted aromatic thioureas (see figure). These results provided a basis for new catalyst development and several improved catalysts were identified in our initial attempts.

By judiciously anchoring functional groups onto chiral ionic liquids, functionalized chiral ionic liquids (FCILs) are emerging as a new type of asymmetric organocatalysts and nonclassical chiral ligands. This Focus Review highlights the applications of FCILs from the viewpoint of asymmetric catalysis. We focus mainly on the de novo designed and synthesized FCILs which likely still maintain the typical ionic liquids properties, and in a few cases relevant ionic liquid immobilized chiral catalysts are briefly discussed.

A new strategy for the immobilization of asymmetric organocatalysts by combining polystyrene (PS)/sulfonic acids and chiral amines in situ through acid–base interactions is presented. The PS/sulfonic acids play a dual role as catalyst anchors and modulators for activity and stereoselectivity. Different types of polymeric sulfonic acids were examined and 1 % divinylbenzene (DVB) cross‐linked PS/sulfonic acid 1 ewith a medium loading of sulfonic acid moieties was found to be the optimal support. Furthermore, the noncovalency of this system allows combinatorial screening of optimal catalysts for the targeted reactions. In this regard, highly efficient and enantioselective heterogeneous catalysts were identified for the asymmetric direct aldol and Michael addition reactions. The catalysts could be easily recovered by filtration and reused for six cycles with similar stereoselectivity but slightly decreased activity. Significantly, the deactivated catalysts could be regenerated following an acidic washing/amine recharging procedure.

A magnetic nanoparticle-supported quinuclidine was prepared and evaluated as a recoverable Morita–Baylis–Hillman catalyst. The supported catalyst 2 demonstrated comparable activity with that of DABCO and could be simply recycled with the assistance of an external magnet. The thus recycled catalyst could be reused for 7 times without significant loss of activity.

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Three pseudo-polymorphs of N, N′-bis(4-nitrophenyl)-2,6-pyridinedicarboxamide 1were characterized by X-ray crystallography. The C–H ⋅sO hydrogen bond was found to contribute significantly to the assembly of this host. With the variation of the guest, the host changed the molecular conformation and the supramolecular synthons. In all three cases concerned, the solvent guests were bonded through direct host-guest interaction and accommodated in the voids formed by the assembly of the host.

With the advent of green chemistry, the importance of environmentally benign synthesis has been increasingly recognized. This review summarizes recent progresses in this field, covering mainly the organocatalysis, lanthanide triflate catalysis, and our recent related works. Emphasis will be paid on synthetic applications and their significance to green technology by using environmentally friendly reagents and solvents such as water and ionic liquids. In addition, some new trends in the related areas such as chemoenzymatic catalysis and organic synthesis in ionic liquid will be discussed.

Five 1‐(p‐substituted phenyl)‐1,4‐dihydronicotinamides (GPNAH‐1,4‐H2) and five 1‐(p‐substituted phenyl)‐1,2‐dihydronicotinamides (GPNAH‐1,2‐H2) were synthesized, which were used to mimic NAD(P)H coenzyme and its 1,2‐dihydroisomer reductions, respectively. When the 1,4‐dihydropyridine (GPNAH‐1,4‐H2) and the 1,2‐dihydroisomer (GPNAH‐1,2‐H2) were treated with p‐trifluoromethylbenzylidenemalononitrile (S) as a hydride acceptor, both reactions gave the same products: pyridinium derivative (GPNA+) and carbanion SH−by a hydride one‐step transfer. Thermodynamic analysis on the two reactions shows that the hydride transfer from the 1,2‐dihydropyridine is much more favorable than the hydride transfer from the corresponding 1,4‐dihydroisomer, but the kinetic examination displays that the former reaction is remarkably slower than the latter reaction, which is mainly due to much more negative activation entropy for the former reaction. When the formed pyridinium derivative (GPNA+) was treated with SH−, the major reduced product was the corresponding 1,4‐dihydropyridine along with a trace of the 1,2‐dihydroisomer. Thermodynamic and kinetic analyses on the hydride transfer from SH−to GPNA+all suggest that the 4‐position on the pyridinium ring in GPNA+is much easier to accept the hydride than the 2‐position, which indicates that when the 1,4‐dihydropyridine is used the hydride donor to react with S, the formed pyridinium derivative GPNA+may return to the 1,4‐dihydropyridine by a hydride transfer cycle; but when the 1,2‐dihydropyridine is used as the hydride donor, the formed pyridinium derivative can not return to the 1,2‐dihydropyridine by the hydride reverse transfer from SH−to GPNA+. These results clearly show that the hydride‐transfer cycle is favorable for the 1,4‐dihydronicotinamides, but unfavorable for the corresponding 1,2‐dihydroisomers.

Five 1-(p-substituted phenyl)-1,4-dihydronicotinamides (GPNAH-1,4-H2) and five 1-(p-substituted phenyl)-1,2-dihydronicotinamides (GPNAH-1,2-H2) were synthesized, which were used to mimic NAD(P)H coenzyme and its 1,2-dihydroisomer reductions, respectively. When the 1,4-dihydropyridine (GPNAH-1,4-H2) and the 1,2-dihydroisomer (GPNAH-1,2-H2) were treated with p-trifluoromethylbenzylidenemalononitrile (S) as a hydride acceptor, both reactions gave the same products: pyridinium derivative (GPNA⁺) and carbanion SH⁻ by a hydride one-step transfer. Thermodynamic analysis on the two reactions shows that the hydride transfer from the 1,2-dihydropyridine is much more favorable than the hydride transfer from the corresponding 1,4-dihydroisomer, but the kinetic examination displays that the former reaction is remarkably slower than the latter reaction, which is mainly due to much more negative activation entropy for the former reaction. When the formed pyridinium derivative (GPNA⁺) was treated with SH⁻, the major reduced product was the corresponding 1,4-dihydropyridine along with a trace of the 1,2-dihydroisomer. Thermodynamic and kinetic analyses on the hydride transfer from SH⁻ to GPNA⁺ all suggest that the 4-position on the pyridinium ring in GPNA⁺ is much easier to accept the hydride than the 2-position, which indicates that when the 1,4-dihydropyridine is used the hydride donor to react with S, the formed pyridinium derivative GPNA⁺ may return to the 1,4-dihydropyridine by a hydride transfer cycle; but when the 1,2-dihydropyridine is used as the hydride donor, the formed pyridinium derivative can not return to the 1,2-dihydropyridine by the hydride reverse transfer from SH⁻ to GPNA⁺. These results clearly show that the hydride-transfer cycle is favorable for the 1,4-dihydronicotinamides, but unfavorable for the corresponding 1,2-dihydroisomers.

Heterolytic and homolytic bond dissociation energies of the C4&bond;H bonds in ten NADH models (seven 1,4-dihydronicotinamide derivatives, two Hantzsch 1,4-dihydropyridine derivatives, and 9,10-dihydroacridine) and their radical cations in acetonitrile were evaluated by titration calorimetry and electrochemistry, according to the four thermodynamic cycles constructed from the reactions of the NADH models with N,N,N',N'-tetramethyl-p-phenylenediamine radical cation perchlorate in acetonitrile (note: C9&bond;H bond rather than C4&bond;H bond for 9,10-dihydroacridine; however, unless specified, the C9&bond;H bond will be described as a C4&bond;H bond for convenience). The results show that the energetic scales of the heterolytic and homolytic bond dissociation energies of the C4&bond;H bonds cover ranges of 64.2–81.1 and 67.9–73.7 kcal mol⁻¹ for the neutral NADH models, respectively, and the energetic scales of the heterolytic and homolytic bond dissociation energies of the (C4&bond;H)^.+ bonds cover ranges of 4.1–9.7 and 31.4–43.5 kcal mol⁻¹ for the radical cations of the NADH models, respectively. Detailed comparison of the two sets of C4&bond;H bond dissociation energies in 1-benzyl-1,4-dihydronicotinamide (BNAH), Hantzsch 1,4-dihydropyridine (HEH), and 9,10-dihydroacridine (AcrH2) (as the three most typical NADH models) shows that for BNAH and AcrH2, the heterolytic C4&bond;H bond dissociation energies are smaller (by 3.62 kcal mol⁻¹) and larger (by 7.4 kcal mol⁻¹), respectively, than the corresponding homolytic C4&bond;H bond dissociation energy. However, for HEH, the heterolytic C4&bond;H bond dissociation energy (69.3 kcal mol⁻¹) is very close to the corresponding homolytic C4&bond;H bond dissociation energy (69.4 kcal mol⁻¹). These results suggests that the hydride is released more easily than the corresponding hydrogen atom from BNAH and vice versa for AcrH2, and that there are two almost equal possibilities for the hydride and the hydrogen atom transfers from HEH. Examination of the two sets of the (C4&bond;H)^.+ bond dissociation energies shows that the homolytic (C4&bond;H)^.+ bond dissociation energies are much larger than the corresponding heterolytic (C4&bond;H)^.+ bond dissociation energies for the ten NADH models by 23.3–34.4 kcal mol⁻¹; this suggests that if the hydride transfer from the NADH models is initiated by a one-electron transfer, the proton transfer should be more likely to take place than the corresponding hydrogen atom transfer in the second step. In addition, some elusive structural information about the reaction intermediates of the NADH models was obtained by using Hammett-type linear free-energy analysis.

Heterolytic and homolytic bond dissociation energies of the C4H bonds in ten NADH models (seven 1,4‐dihydronicotinamide derivatives, two Hantzsch 1,4‐dihydropyridine derivatives, and 9,10‐dihydroacridine) and their radical cations in acetonitrile were evaluated by titration calorimetry and electrochemistry, according to the four thermodynamic cycles constructed from the reactions of the NADH models with N,N,N′,N′‐tetramethyl‐p‐phenylenediamine radical cation perchlorate in acetonitrile (note: C9H bond rather than C4H bond for 9,10‐dihydroacridine; however, unless specified, the C9H bond will be described as a C4H bond for convenience). The results show that the energetic scales of the heterolytic and homolytic bond dissociation energies of the C4H bonds cover ranges of 64.2–81.1 and 67.9–73.7 kcal mol−1for the neutral NADH models, respectively, and the energetic scales of the heterolytic and homolytic bond dissociation energies of the (C4H).+bonds cover ranges of 4.1–9.7 and 31.4–43.5 kcal mol−1for the radical cations of the NADH models, respectively. Detailed comparison of the two sets of C4H bond dissociation energies in 1‐benzyl‐1,4‐dihydronicotinamide (BNAH), Hantzsch 1,4‐dihydropyridine (HEH), and 9,10‐dihydroacridine (AcrH2) (as the three most typical NADH models) shows that for BNAH and AcrH2, the heterolytic C4H bond dissociation energies are smaller (by 3.62 kcal mol−1) and larger (by 7.4 kcal mol−1), respectively, than the corresponding homolytic C4H bond dissociation energy. However, for HEH, the heterolytic C4H bond dissociation energy (69.3 kcal mol−1) is very close to the corresponding homolytic C4H bond dissociation energy (69.4 kcal mol−1). These results suggests that the hydride is released more easily than the corresponding hydrogen atom from BNAH and vice versa for AcrH2, and that there are two almost equal possibilities for the hydride and the hydrogen atom transfers from HEH. Examination of the two sets of the (C4H).+bond dissociation energies shows that the homolytic (C4H).+bond dissociation energies are much larger than the corresponding heterolytic (C4H).+bond dissociation energies for the ten NADH models by 23.3–34.4 kcal mol−1; this suggests that if the hydride transfer from the NADH models is initiated by a one‐electron transfer, the proton transfer should be more likely to take place than the corresponding hydrogen atom transfer in the second step. In addition, some elusive structural information about the reaction intermediates of the NADH models was obtained by using Hammett‐type linear free‐energy analysis.