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Introduction of the trifluoromethyl (CF3) group into organic compounds has garnered substantial interest because of its significant role in pharmaceuticals and agrochemicals. Here, we report a hydroxylamine‐mediated radical process for C(sp2)−H trifluoromethylation of terminal alkenes. The reaction shows good reactivity, impressive E/Z selectivity (up to >20 : 1), and broad functional group compatibility. Expansion of this approach to perfluoroalkylation and late‐stage trifluoromethylation of bioactive molecules demonstrates its promising application potential. Mechanistic studies suggest that the reaction follows a radical addition and subsequent elimination pathway. [ABSTRACT FROM AUTHOR]

Transition metal intermediates bearing M−X σ‐bonds are ubiquitous in metal‐mediated C−X bond transformations. Thermodynamic knowledge of M−X bond cleavage is crucial to explore relevant reactions; but little was accumulated till present due to lack of suitable determination methods. We here report the first systematic study of the Pd−X bond homolysis dissociation free energies [BDFE(Pd−X)] of representative [(tmeda)Pd(4‐F−C6H4)X] (tmeda=N,N,N′,N′‐tetramethylethylenediamine, X=OR or NHAr) in DMSO on the basis of reliable measurement of their bond heterolysis energies (ΔGhet(Pd−X)). Despite ΔGhet(Pd−O)s of palladium‐phenoxides are generally found about 8 kcal/mol smaller than ΔGhet(Pd−N)s of palladium‐amidos, their BDFE(Pd−X)s are observed comparable. The structure‐property relationship was investigated to disclose an enhancement effect of electron‐withdrawing groups on BDFE(Pd−X)s. Linear free energy relationship analysis revealed that Pd−X bonds are more sensitive than X−H bonds to structural variation. The energetic propensity of reductive elimination from arylpalladium complexes was evaluated by combinatorial use of BDFE(Pd−X)s and BDFE(C−X)s, indicating an overall thermodynamic bias to C−N bond formation. [ABSTRACT FROM AUTHOR]

The enantioselective aza‐Diels–Alder reaction is efficient for constructing chiral tetrahydropyridines, but the catalytic asymmetric aza‐Diels–Alder reaction of ketimines with unactivated dienes is still a challenging topic. Herein, guided by computational screening, a highly enantioselective aza‐Diels–Alder reaction of 2‐aryl‐3H‐indol‐3‐ones with unactivated dienes was realized by using a B(C6F5)3/chiral phosphoric acid catalyst system under mild conditions. The reaction has a broad scope with respect to both aza‐Diels–Alder reaction partners and hence offers rapid access to an array of tetrahydropyridine derivatives with pretty outcomes (up to 99 % yield, >20:1 dr and 98:2 er). The reaction is very efficient: lowering catalyst loadings for the model reaction to 0.1 mol %, enantioselectivity is still maintained. The synthetic utility was confirmed by transformations of the products. DFT calculations provide convincing evidence for the interpretation of stereoselection. [ABSTRACT FROM AUTHOR]

Fluorine incorporation into organic molecules is expected to lower the pKa of neighboring functionality via its strong electron‐withdrawing effect, and this strategy has been widely exploited in diverse disciplines. Herein, we report a striking anomalous α‐fluorine substitution effect on the α‐Csp3‐H acidity. We have experimentally measured the pKa values of a series of popular nucleophilic monofluoromethylating reagents α‐fluoro(phenylsulfonyl)methane derivatives as well as their C‐H analogues by Bordwell's overlapping indicator method in dimethyl sulfoxide solution. Contrary to expectations, we found that α‐fluorine substituent does not generally enhance but rather weaken the α‐Csp3‐H acidity of most (phenylsulfonyl)methane derivatives. DFT computations reproduce and provide insight into the anomalous α‐fluorine effect. A correlation was identified between the C‐H pKa of (phenylsulfonyl)methane derivatives and Mayr's nucleophilicity parameter (N) of the corresponding carbanions. [ABSTRACT FROM AUTHOR]

Thermodynamic knowledge of the metal–ligand (M−L) σ‐bond strength is crucial to understanding metal‐mediated transformations. Here, we developed a method for determining the Pd−X (X=OR and NHAr) bond heterolysis energies (ΔGhet(Pd−X)) in DMSO taking [(tmeda)PdArX] (tmeda=N,N,N′,N′‐tetramethylethylenediamine) as the model complexes. The ΔGhet(Pd−X) scales span a range of 2.6–9.0 kcal mol−1 for ΔGhet(Pd−O) values and of 14.5–19.5 kcal mol−1 for ΔGhet(Pd−N) values, respectively, implying a facile heterolytic detachment of the Pd ligands. Structure‐reactivity analyses of a modeling Pd‐mediated X−H bond activation reveal that the M−X bond metathesis is dominated by differences of the X−H and Pd−X bond strengths, the former being more influential. The ΔGhet(Pd−X) and pKa(X−H) parameters enable regulation of reaction thermodynamics and chemoselectivity and diagnosing the probability of aniline activation with Pd−X complexes. [ABSTRACT FROM AUTHOR]

While many approaches to predict aqueous pKa values exist, the fast and accurate prediction of non‐aqueous pKa values is still challenging. Based on the iBonD experimental pKa database (39 solvents), a holistic pKa prediction model was established using machine learning. Structural and physical‐organic‐parameter‐based descriptors (SPOC) were introduced to represent the electronic and structural features of the molecules. The models trained with a neural network or the XGBoost algorithm showed the best prediction performance with a low MAE value of 0.87 pKa units. The approach allows a comprehensive mapping of all possible pKa correlations between different solvents and it was validated by predicting the aqueous pKa and micro‐pKa of pharmaceutical molecules and pKa values of organocatalysts in DMSO and MeCN with high accuracy. An online prediction platform was constructed based on the current model, which can provide pKa prediction for different types of X−H acidity in the most commonly used solvents. [ABSTRACT FROM AUTHOR]

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The enantioselective ketimine–ene reaction is one of the most challenging stereocontrolled reaction types in organic synthesis. In this work, catalytic enantioselective ketimine–ene reactions of 2‐aryl‐3H‐indol‐3‐ones with α‐methylstyrenes were achieved by utilizing a B(C6F5)3/chiral phosphoric acid (CPA) catalyst. These ketimine–ene reactions proceed well with low catalyst loading (B(C6F5)3/CPA=2 mol %/2 mol %) under mild conditions, providing rapid and facile access to a series of functionalized 2‐allyl‐indolin‐3‐ones with very good reactivity (up to 99 % yield) and excellent enantioselectivity (up to 99 % ee). Theoretical calculations reveal that enhancement of the acidity of the chiral phosphoric acid by B(C6F5)3 significantly reduces the activation free energy barrier. Furthermore, collective favorable hydrogen‐bonding interactions, especially the enhanced N−H⋅⋅⋅O hydrogen‐bonding interaction, differentiates the free energy of the transition states of CPA and B(C6F5)3/CPA, thereby inducing the improvement of stereoselectivity. [ABSTRACT FROM AUTHOR]

Summary of main observation and conclusion: Electrophilic trifluoromethylthiolation has emerged as an important and efficient methodology for installing the SCF3 moiety onto an array of organic molecules. Due to the low reactivities of trifluoromethylthiolating reagents, these transformations often require activation through an exogenous Lewis/Brønsted acid. We report herein the quantification of the activation capabilities of Lewis/Brønsted acids for trifluoromethylthiolating reagents through computing the difference in trifluoromethylthio cation donor ability (Tt+DA) between the "activated" and "unactivated" reagent. A moderate correlation is found to exist between the activation capability and Lewis acidity. [ABSTRACT FROM AUTHOR]

Nucleophilicity parameters (N, sN) of a group of representative diazaphospholenium hydrides were derived by kinetic investigations of their hydride transfer to a series of reference electrophiles with known electrophilicity (E) values, using the Mayr equation log k2=sN(N+E). The N scale covers over ten N units, ranging from the most reactive hydride donor (N=25.5) to the least of the scale (N=13.5). This discloses the highest N value ever quantified in terms of Mayr's nucleophilicity scales reported for neutral transition‐metal‐free hydride donors and implies an exceptional reactivity of this reagent. Even the least reactive hydride donor of this series is still a better hydride donor than those of many other nucleophiles such as the C−H, B−H, Si−H and transition‐metal M−H hydride donors. Structure–reactivity analysis reveals that the outstanding hydricity of 2‐H‐1,3,2‐diazaphospholene benefits from the unsaturated skeleton. P−H superhydrides: The unexpected philicity of P−H bonds in diazaphospholenes has made their applications to catalytic reductions a burgeoning field. A three‐parameter kinetic equation was used to evaluate their nucleophilicity parameters (N), which cover over ten N units. Kinetic studies imply their much superior hydricity over commonly used hydrides, with 2‐H‐1,3,2‐diazaphospholene being the strongest nucleophilic donor ever quantified by the Mayr equation. [ABSTRACT FROM AUTHOR]

Abstract: The electrophilicity parameters (E) of some trifluoromethylthiolating and difluoromethylthiolating reagents were determined by following the kinetics of their reactions with a series of enamines and carbanions with known nucleophilicity parameters (N, sN), using the linear free‐energy relationship log k2=sN(N+E). The electrophilic reactivities of these reagents cover a range of 17 orders of magnitude, with Shen and Lu's reagent 1 a being the most reactive and Billard's reagent 1 h being the least reactive electrophile. While the observed electrophilic reactivities (E) of the amido‐derived trifluoromethylthiolating reagents correlate well with the calculated Gibbs energies for heterolytic cleavage of the X−SCF3 bonds (Tt+DA), the cumol‐derived reagents 1 f and 1 g are more reactive than expected from the thermodynamics of the O−S cleavage. The E parameters of the tri/difluoromethylthiolating reagents derived in this work provide an ordering principle for their use in synthesis. [ABSTRACT FROM AUTHOR]

Free energy relationship (FER) studies to correlate steric parameters with the enantiocatalytic performance of bifunctional tertiary-amine hydrogen-bonding catalysts, including ( S, S)-cyclohexane-1,2-diamine-derived thioureas, Cinchona alkaloid derived thioureas, and ( S, S)-cyclohexane-1,2-diamine-derived squaramides, in Michael reactions revealed that the reactions are much favored by catalysts with less bulky N-substituents. The observed FERs are independent of the chiral scaffold and hydrogen-bond donor, and deepen the understanding of current bifunctional hydrogen-bonding catalysts. Moreover, DFT calculations were performed to interpret the observed high reactivities of thioureas with less bulky substituents. In particular, the computations demonstrated the advantage of a benzyl thiourea catalyst, in which an extra CH ⋅⋅⋅π interaction between catalyst and substrate is the key factor. [ABSTRACT FROM AUTHOR]

Identifying the ability of traditional electrophilic trifluoromethylating reagents as CF3· radical sources offers a great opportunity for developing new radical trifluoromethylation reactions. Herein, we report the first extensive assessment of the propensity of these reagents to donate a CF3· radical by computing X−CF3 bond homolytic dissociation enthalpies. Single electron reduction has a substantial effect on activating the X−CF3 bond, thereby significantly facilitating a CF3 radical release. The quantitative information provided here could be valuable for mechanistic understanding and the rational design of new radical trifluoromethylation reactions. [ABSTRACT FROM AUTHOR]

A highly predictive model to correlate the steric and electronic parameters of tertiary amine thiourea catalysts with the stereoselectivity of Michael reactions of 3-substituted benzofuranones and alkyl 2-phthalimidoacrylates is described. As predicted, new 3,5-bis(trifluoromethyl)benzyl- and methyl-substituted tertiary amine thioureas turned out to be highly suitable catalysts for this reaction and enabled the synthesis of enantioenriched α-amino acid derivatives with 1,3-nonadjacent stereogenic centers. [ABSTRACT FROM AUTHOR]

An asymmetric 1,6-conjugate addition of thioacetic acid with para-quinone methides has been developed by using chiral phosphoric acid catalysis in the presence of water. A series of sulfur-containing compounds were thus obtained in high yields with good to excellent enantioselectivities. Theoretical studies indicated that the water-bridged proton transfer is a potentially favorable reaction pathway. An unprecedented O−H⋅⋅⋅π interaction between water and the aromatic nucleus of chiral phosphoric acid was discovered to contribute significantly to the stereocontrol in the catalysis. [ABSTRACT FROM AUTHOR]

A visible-light-mediated, organic photocatalytic stereoselective radical cascade cyclization of polyprenoids is described. The desired cascade cyclization products are achieved in good yields and high stereoselectivities with eosin Y as photocatalyst in hexafluoro-2-propanol. The catalyst system is also suitable for 1,3-dicarbonyl compounds, which require only catalytic amounts of LiBr to promote the formation of the corresponding enols. [ABSTRACT FROM AUTHOR]

A highly enantioselective b-isocupreidine (b-ICD) catalyzed synthesis of dihydropyran-fused benzofurans through [4+2] cycloaddition of allenoates and benzofuranone alkenes was developed. Switchable chirality inversion of cycloaddition products was achieved by replacing the phenolic proton of the catalyst with a methyl, demonstrating an amazing effect of minimal structural variation on inverting enantioselectivity. DFT calculations were utilized to elucidate the origin of the observed phenomena. Computation also provided a clue for a rational design in which the multi-hydrogen bond with the alcohol additive was found to improve the enantioselectivity of the cycloaddition. Finally, the substrate scope was examined, in which a number of functionalized dihydropyran-fused benzofurans could be obtained in high yields (up to 97%) with very good regio- (>20:1) and enantioselectivities (up to 98:2 e.r.). [ABSTRACT FROM AUTHOR]

Electrocatalytic water oxidation using the oxidatively robust 2,7-[bis(2-pyridylmethyl)aminomethyl]-1,8-naphthyridine ligand (BPMAN)-based dinuclear copper(II) complex, [Cu2(BPMAN)(μ-OH)]3+, has been investigated. This catalyst exhibits high reactivity and stability towards water oxidation in neutral aqueous solutions. DFT calculations suggest that the OO bond formation takes place by an intramolecular direct coupling mechanism rather than by a nucleophilic attack of water on the high-oxidation-state CuIVO moiety. [ABSTRACT FROM AUTHOR]

We described herein a catalyst-free visible-light photolytic protocol for the imidation of arenes and heteroarenes. N-Bromosaccharin was identified as a viable and chemoselective nitrogen radical precursor that undergoes controllable homolytic cleavage under ambient light irradiation. The reaction can be applied to a number of arenes and heteroarenes with good chemo- and regioselectivity. Mechanistic studies revealed that radical chain termination by electron transfer-proton transfer (ET-PT) is the leading productive pathway for the reaction. [ABSTRACT FROM AUTHOR]

A simple and direct α-allylic alkylation of unmodified aldehydes with allylic alcohols catalyzed by primary amine/Br⊘nsted acid has been developed. The N, N-dimethylethylenediamine/TfOH was identified as the optimal catalyst to promote this transformation via an enamine process in high yields (up to 88%) and with good diastereoselectivities (up to 9:1). [ABSTRACT FROM AUTHOR]

We report the first example of the enantioselective conjugate addition of alkenes (aromatic enamines) to enones catalyzed by chiral primary amines. The reactions encompass a plethora of α,β-enones including difficult α-substituted vinyl ketones to give vinylation adducts in high yields with good enantioselectivity. The methodology is of synthetic potential in accessing chiral functional materials. [ABSTRACT FROM AUTHOR]

The chiral benzofuranone structural motif is a prominent feature in many natural products, which exhibit a broad range of biological and pharmaceutical activities. In the past few years, a survey of chiral benzofuranone derivatives based on asymmetric catalysis reveals an increasing number of papers, which reflects the latest achievements to facilitate the synthesis of sufficient quantities of related compounds as potential medicinal agents and biological probes. Recent advances in this area are summarized and classified according to the structure of the starting substrate. [ABSTRACT FROM AUTHOR]

Enantioselective protonation with a catalytic enamine intermediate represents a challenging, yet fundamentally important process for the synthesis of α-chiral carbonyls. We describe herein chiral primary-amine-catalyzed conjugate additions of indoles to both α-substituted acroleins and vinyl ketones. These reactions feature enamine protonation as the stereogenic step. A simple primary-tertiary vicinal diamine 1 with trifluoromethanesulfonic acid (TfOH) was found to enable both of the reactions of acroleins and vinyl ketones with good activity and high enantioselectivity. Detailed mechanistic studies reveal that these reactions are rate-limiting in iminium formation and they all involve a uniform H2O/acid-bridged proton transfer in the stereogenic steps but divergent stereocontrol modes for the protonation stereoselectivity. For the reactions of α-branched acroleins, facial selections on H2O-bridged protonation determine the enantioselectivity, which is enhanced by an OH⋅⋅⋅π interaction with indole as uncovered by DFT calculations. On the other hand, the stereoselectivity of the reactions with vinyl ketones is controlled according to the Curtin-Hammett principle in the CC bond-formation step, which precedes a highly stereospecific enamine protonation. [ABSTRACT FROM AUTHOR]

The article discusses a study on an asymmetric binary acid catalysis of hetero-Diels-Alder reaction of simple olefins with electron-deficient enones. It says that achieving a catalytic asymmetric version with simple olefins remains elusive despite the advances in Diels-Alder chemistry. It mentions the examination of Lewis acids and chiral phosphoric acids in the model reaction of styrene 2a with ketoester 3a.

Aromatic enamines: para‐Vinylanilines were identified as unique nucleophiles, closely resembling enamines, to undergo CC coupling with aldehydes catalyzed by a simple primary–tertiary diamine/Brønsted acid. The resulting bis(allylic) adducts, which have potential as functional materials, were obtained in high yields under rather mild conditions (see scheme). [ABSTRACT FROM AUTHOR]

A highly enantioselective catalytic double-Michael addition reaction of substituted benzofuran-2-ones with divinyl ketones promoted by readily accessible tertiary amine-thiourea Cinchona alkaloids has been developed. A number of optically enriched spirocyclic benzofuran-2-ones were prepared in very good yields (up to 99 %), diastereoselectivities (up to 19:1 d.r.), and very good enantioselectivities (up to 92 % ee). Density functional theory (DFT) calculations were performed to investigate the origin of stereoselectivity. [ABSTRACT FROM AUTHOR]

A mechanistic study of the tert-aminocyclization reaction was performed by using DFT calculations and labeling experiments. The results showed that the reaction proceeded through a rate-limiting-, stereospecific-, and suprafacial 1,5-H-transfer pathway, followed by a barrier-less CC bond formation. The mode of stereocontrol for facial selection could be ruled out owing to the high activation energy of CN bond rotation. The intrinsic feature of this Lewis acid activation was found to be the activation of the LUMO, as well as an intermediate-stabilization effect. The catalytically active species was believed to be a 1:1 complex of phosphoric acid and MgCl2, which was stabilized by a H⋅⋅⋅Cl hydrogen bond. The chiral catalytic complex selectively recognizes and activates one of the two helical conformations of substrate A, required for 1,5-suprafacial H-transfer, which dictates the stereoselectivity of the forming products. [ABSTRACT FROM AUTHOR]

Prediction of protein-folding rates follows different rules in two-state and multi-state kinetics. The prerequisite for the prediction is to recognize the folding kinetic pathway of proteins. Here, we use the logistic regression and support vector machine to discriminate between two-state and multi-state folding proteins. We find that chain length is sufficient to accurately recognize multi-state proteins. There is a transition boundary between two kinetic models. Protein folds with multi-state kinetics, if its length is larger than 112 residues. The logistic prediction from amino acid composition shows that the kinetic pathway of folding is closely related to amino acid volume. Small amino acids make two-state folding easier, and vice versa. However, cysteine, alanine, arginine, lysine, histidine, and methionine do not conform to this rule. Proteins 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Folding kinetics of proteins is governed by the free energy and position of transition states. But attempts to predict the position of folding transition state on reaction pathway from protein structure have been met with only limited success, unlike the folding-rate prediction. Here, we find that the folding transition-state position is related to the secondary structure content of native two-state proteins. We present a simple method for predicting the transition-state position from their α-helix, turn and polyproline secondary structures. The method achieves 81% correlation with experiment over 24 small, two-state proteins, suggesting that the local secondary structure content, especially for content of α-helix, is a determinant of the solvent accessibility of the transition state ensemble and size of folding nucleus. Proteins 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

We present a simple method for determining the folding rates of two- and three-state proteins from the number of residues in their secondary structures (secondary structure length). The method is based on the hypothesis that two- and three-state foldings share a common pattern. Three-state proteins first condense into metastable intermediates, subsequent forming of α-helices, turns, and β-sheets at slow rate-limiting step. The folding rate of such proteins anticorrelate with the length of these β-secondary structures. It is also assumed that in two-state folding, rapidly folded α-helices and turns may facilitate formation of fleeting unobservable 'intermediates' and thus show two-state behavior. There is an inverse relationship between the folding rate and the length of β-sheets and loops. Our study achieves 94.0 and 88.1% correlations with folding rates determined experimentally for 21 three- and 38 two-state proteins, respectively, suggesting that protein-folding rates are determined by the secondary structure length. The kinetic kinds are selected on the basis of a competitive formation of hydrophobic collapse and α-structure in early intermediates. Proteins 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]