Olefins and carboxylic acids are among the most important feedstock compounds. They are commonly found in natural products and drug molecules. We report a new reaction of nickel-catalyzed decarboxylative olefin hydroalkylation, which provides a novel practical strategy for the construction of C(sp³)−C(sp³) bonds. This reaction can tolerate a variety of synthetically relevant functional groups and shows good chemo- and regioselectivity. It enables cross-coupling of complex organic molecules containing olefin groups and carboxylic acid groups in a convergent fashion.

Conversion of biomass-derived ethyl levulinate to γ-valerolactone is realized by using homogeneous iron-catalyzed transfer hydrogenation (CTH). By utilizing Casey's catalyst and cheap isopropanol as hydrogen source, γ-valerolactone can be generated in 95% yield. Addition of catalytic amount of base is important to achieve good yield.

An unprecedented Pd-catalyzed regioselective activation of gem-difluorinated cyclopropanes induced by CC bond cleavage is reported. It provides a general and efficient access to a variety of 2-fluoroallylic amines, ethers, esters, and alkylation products in high Z-selectivity, which are important skeletons in many biologically active molecules. In addition, the transformation represents the first general application of gem-difluorinated cyclopropanes as reaction partners in transition-metal-catalyzed cross-coupling reaction.

An unprecedented Pd-catalyzed regioselective activation of gem-difluorinated cyclopropanes induced by CC bond cleavage is reported. It provides a general and efficient access to a variety of 2-fluoroallylic amines, ethers, esters, and alkylation products in high Z-selectivity, which are important skeletons in many biologically active molecules. In addition, the transformation represents the first general application of gem-difluorinated cyclopropanes as reaction partners in transition-metal-catalyzed cross-coupling reaction.

A copper-catalyzed reductive cross-coupling reaction of nonactivated alkyl tosylates and mesylates with alkyl and aryl bromides was developed. It provides a practical method for efficient and cost-effective construction of aryl–alkyl and alkyl–alkyl CC bonds with stereocontrol from readily available substrates. When used in an intramolecular fashion, the reaction enables convenient access to various substituted carbo- or heterocycles, such as 2,3-dihydrobenzofuran and benzochromene derivatives.

The development of new catalytic systems for the conversion of biomass-derived molecules into liquid fuels has attracted much attention. We propose a non-noble bimetallic catalyst based on nickel–tungsten carbide for the conversion of the platform molecules 5-(hydroxymethyl)furfural into the liquid-fuel molecule 2,5-dimethylfuran (DMF). Different catalysts, metal ratios and reaction conditions have been tested and give rise to a 96% yield of DMF. The catalysts have been characterized and are discussed. The reaction mechanism is also explored through capture of reaction intermediates. The analysis of the reaction mixture over different catalysts is presented and helps to understand the role of nickel and tungsten carbide during the reaction.

The recent development of Au-catalyzed reactions has greatly enriched the methods of organic synthesis. The phosphine or phosphate-coordinated Au complexes have shown high efficiency in catalyzing various CC and CH activations. In many of these reactions, the AuP bond strength was found to play an important role in determining the catalytic efficiency. In the present study, the accuracy of different theoretical methods for prediction of AuP strengths has been examined on basis of the experimental enthalpy changes between different ClAu(PR₃) and ClAu(THT) (THT=tetrahydrothiophene). By comparing the different DFT functionals (e.g. B3LYP, TPSS, M06), different basis sets (including the different effective core potentials on Au and the total electron basis sets on all other atoms), and different solution phase single point calculations, we found that the TPSS/(CPE-121G+f:6-311+G(d,p)(SMD)//TPSS/(CPE-121G:6-31G(d) (M1) method gives the best correlations with the available experimental results. Meanwhile, the calculations with B3LYP//TPSS and M05//TPSS also give comparable calculation results. Finally, the specified method (M1) is used to calculate the AuP bond dissociation enthalpies and energies of different ClAu(PR₃)/ClAu(P(OR)₃) complexes. By accurately reproducing the available experimental results, we believe that the method (M1) is reliable for the theoretical analysis of Au-P systems.

Density functional theory (DFT) calculations have been performed to study the mechanism of the recently reported Co-catalyzed ligand-controlled hydroarylation of styrenes as a means of preparing 1,1- or 1,2-diarylalkanes. The present study corroborates the previously proposed three-step mechanism, comprising CH activation (CH oxidative addition), styrene insertion, and reductive elimination. In the CH activation and reductive elimination steps, our calculations suggest that styrene does not coordinate to the Co center. In the insertion step, styrene is inserted into the CoH bond rather than the CoC bond. Furthermore, the rate- and regiodetermining step is found to be CC reductive elimination. It is significant that the regioselectivity observed experimentally has been successfully reproduced by our calculations. More importantly, in analyzing the origin of the ligand-controlled regioselectivity, we have found that the steric effects of different ligands mainly determine the observed regioselectivity. Both the shape (i.e., “umbrella-up” or “umbrella-down”) and bulkiness of the ligand contribute to the steric effect.

The palladium-catalyzed decarboxylative benzylation of α-cyano aliphatic carboxylate salts with benzyl electrophiles was discovered. This reaction exhibits good functional group compatibility and proceeds under relatively mild conditions. A diverse range of quaternary, tertiary and secondary β-aryl nitriles can be conveniently prepared by this method.

Mechanistic studies have been performed for the recently developed, Ni-catalysed selective cross-coupling reaction between aryl and alkyl aldehydes. A mono-carbonyl activation (MCA) mechanism (in which one of the carbonyl groups is activated by oxidative addition) was found to be the most favourable pathway, and the rate-determining step is oxidative addition. Analysing the origin of the observed cross-coupling selectivity, we found the most favourable carbonyl activation step requires both coordination of the aryl aldehyde and oxidative addition of the alkyl aldehyde. Therefore, the stronger π-accepting ability of the aryl aldehyde (relative to alkyl aldehyde) and the ease of oxidative addition of the alkyl aldehyde (relative to aryl aldehyde) are responsible for the cross-coupling selectivity.

The Pd-catalyzed decarboxylative allylation of α-(diphenylmethylene)imino esters (1) or allyl diphenylglycinate imines (2) is an efficient method to construct new C(sp³)C(sp³) bonds. The detailed mechanism of this reaction was studied by theoretical calculations [ONIOM(B3LYP/LANL2DZ+p:PM6)] combined with experimental observations. The overall catalytic cycle was found to consist of three steps: oxidative addition, decarboxylation, and reductive allylation. The oxidative addition of 1 to [(dba)Pd(PPh₃)₂] (dba=dibenzylideneacetone) produces an allylpalladium cation and a carboxylate anion with a low activation barrier of +9.1 kcal mol⁻¹. The following rate-determining decarboxylation proceeds via a solvent-exposed α-imino carboxylate anion rather than an O-ligated allylpalladium carboxylate with an activation barrier of +22.7 kcal mol⁻¹. The 2-azaallyl anion generated by this decarboxylation attacks the face of the allyl ligand opposite to the Pd center in an outer-sphere process to produce major product 3, with a lower activation barrier than that of the minor product 4. A positive linear Hammett correlation [ρ=1.10 for the PPh₃ ligand] with the observed regioselectivity (3 versus 4) supports an outer-sphere pathway for the allylation step. When Pd combined with the bis(diphenylphosphino)butane (dppb) ligand is employed as a catalyst, the decarboxylation still proceeds via the free carboxylate anion without direct assistance of the cationic Pd center. Consistent with experimental observations, electron-withdrawing substituents on 2 were calculated to have lower activation barriers for decarboxylation and, thus, accelerate the overall reaction rates.

Ni-catalyzed cross-coupling of unactivated secondary alkyl halides with alkylboranes provides an efficient way to construct alkyl–alkyl bonds. The mechanism of this reaction with the Ni/L1 (L1=trans-N,N′-dimethyl-1,2-cyclohexanediamine) system was examined for the first time by using theoretical calculations. The feasible mechanism was found to involve a Ni^I–Ni^III catalytic cycle with three main steps: transmetalation of [Ni^I(L1)X] (X=Cl, Br) with 9-borabicyclo[3.3.1]nonane (9-BBN)R₁ to produce [Ni^I(L1)(R₁)], oxidative addition of R₂X with [Ni^I(L1)(R₁)] to produce [Ni^III(L1)(R₁)(R₂)X] through a radical pathway, and CC reductive elimination to generate the product and [Ni^I(L1)X]. The transmetalation step is rate-determining for both primary and secondary alkyl bromides. KOiBu decreases the activation barrier of the transmetalation step by forming a potassium alkyl boronate salt with alkyl borane. Tertiary alkyl halides are not reactive because the activation barrier of reductive elimination is too high (+34.7 kcal mol⁻¹). On the other hand, the cross-coupling of alkyl chlorides can be catalyzed by Ni/L2 (L2=trans-N,N′-dimethyl-1,2-diphenylethane-1,2-diamine) because the activation barrier of transmetalation with L2 is lower than that with L1. Importantly, the Ni⁰–Ni^II catalytic cycle is not favored in the present systems because reductive elimination from both singlet and triplet [Ni^II(L1)(R₁)(R₂)] is very difficult.

An efficient catalytic system for biomass oxidation to form formic acid was developed. The conversion of glucose to formic acid can reach up to 52 % yield within 3 h when catalyzed by 5 mol % of H₅PV₂Mo₁₀O₄₀ at only 373 K using air as the oxidant. Furthermore, the heteropolyacid can be used as a bifunctional catalyst in the conversion of cellulose to formic acid (yield=35 %) with air as the oxidant.

The method of native chemical ligation between an unprotected peptide α-thioester and an N-terminal cysteine–peptide to give a native peptide in aqueous solution is one of the most effective peptide ligation methods. In this work, a systematic theoretical study was carried out to fully understand the detailed mechanism of ligation. It was found that for the conventional native chemical ligation reaction between a peptide thioalkyl ester and a cysteine in combination with an added aryl thiol as catalyst, both the thiol-thioester exchange step and the transthioesterification step proceed by an anionic concerted S_N2 displacement mechanism, whereas the intramolecular rearrangement proceeds by an addition–elimination mechanism, and the rate-limiting step is the thiol-thioester exchange step. The theoretical method was then extended to study the detailed mechanism of the auxiliary-mediated peptide ligation between a peptide thiophenyl ester and an N-2-mercaptobenzyl peptide in which both the thiol-thioester exchange step and intramolecular acyl-transfer step proceed by a concerted S_N2-type displacement mechanism. The energy barrier of the thiol-thioester exchange step depends on the side-chain steric hindrance of the C-terminal amino acid, whereas that of the acyl-transfer step depends on the side-chain steric hindrance of the N-terminal amino acid.

The use of ligands to control regioselectivity in transition-metal-catalyzed CH activation/functionalization is a highly desirable but challenging task. Recently, Itami et al. reported an important finding relating to Pd-catalyzed ligand-controlled α/β-selective CH arylation of thiophenes. Specifically, the use of the 2,2′-bipyridyl ligand resulted in α-arylation, whereas the use of the bulky fluorinated phosphine ligand P[OCH(CF₃)₂]₃ resulted in β-arylation. Understanding of this surprising ligand-controlled α/β-selectivity could provide important insights into the development of more efficient catalyst systems for selective CH arylation, and so we carried out a detailed computational study on the problem with use of density functional theory methods. Three mechanistic possibilities—S_EAr and migration, metalation/deprotonation, and Heck-type arylation mechanisms—were examined. The results showed that the S_EAr and migration mechanism might not be plausible, because the key Wheland intermediates could not be obtained. On the other hand, our study indicated that the metalation/deprotonation and Heck-type arylation mechanisms were both involved in Itami’s reactions. In the metalation/deprotonation pathway the α-selective product (C5-product) was preferred, whereas in the Heck-type arylation mechanism the β-selective product (C4-product) was favored. The ligands played crucial roles in tuning the relative barriers of the two different pathways. In the 2,2′-bipyridyl-assisted system, the metalation/deprotonation pathway was energetically advantageous, leading to α-selectivity. In the P[OCH(CF₃)₂]₃-assisted system, on the other hand, the Heck-type arylation mechanism was kinetically favored, leading to β-selectivity. An interesting finding was that P[OCH(CF₃)₂]₃ could produce a CH⋅⋅⋅O hydrogen bond in the catalyst system, which was crucial for stabilization of the Heck-type transition state. In comparison, this CH⋅⋅⋅O hydrogen bond was absent with the other phosphine ligands [i.e., P(OMe)₃, PPh₃, PCy₃] and these phosphine ligands therefore favored the metalation/deprotonation pathway leading to α-selectivity. Furthermore, in this study we have provided theoretical evidence showing that the Heck-type arylation reaction could proceed through an anti-β-hydride elimination process.

Several 1-benzyl-1,4-dihydronicotinamide derivatives, which are important NADH model compounds were studied theoretically in acetonitrile. The performances of various DFT methods including B3LYP, B1B95, B3PW91, MPW1B95, MPWKCIS, and M06 were tested to calculate the redox potentials. The first theoretical protocol to predict the redox potentials of these derivatives is B1B95, whose reliability has been tested against almost all the available experimental data. Strikingly, the mean absolute derivations (MAD) and root mean square (RMS) error of the current theoretical model equal 0.015 and 0.017, respectively. By using this method, the important thermodynamic properties of BNAHs were investigated and the mechanisms of hydride transfer progress were explained. Besides, para-substituents that have a big effect on these redox potentials of BNAH were systematically studied and carefully demonstrated.

Quantitative nucleophilicity scales are fundamental to organic chemistry and are usually constructed on the basis of Mayr’s equation [log k=s(N+E)] by using benzhydrylium ions as reference electrophiles. Here an ab initio protocol was developed for the first time to predict the nucleophilicity parameters N of various π nucleophiles in CH₂Cl₂ through transition-state calculations. The optimized theoretical model (BH&HLYP/6-311++G(3df,2p)//B3LYP/6-311+G(d,p)/PCM/UAHF) could predict the N values of structurally unrelated π nucleophiles within a precision of ca. 1.14 units and therefore may find applications for the prediction of nucleophilicity of compounds that are not readily amenable to experimental characterization. The success in predicting N parameters from first principles also allowed us to analyze in depth the electrostatic, steric, and solvation energies involved in electrophile–nucleophile reactions. We found that solvation does not play an important role in the validity of Mayr’s equation. On the other hand, the correlations of the E, N, and log k values with the energies of the frontier molecular orbitals indicated that electrostatic/charge-transfer interactions play vital roles in Mayr’s equation. Surprising correlations observed between the electrophile–nucleophile CC distances in the transition state, the activation energy barriers, and the E and N parameters indicate the importance of steric interactions in Mayr’s equation. A method is then proposed to separate the attraction and repulsion energies in the nucleophile–electrophile interaction. It was found that the attraction energy correlated with N+E, whereas the repulsion energy correlated to the s parameter.

The homolytic C–C and C–H bond dissociation enthalpyies (BDE) of highly crowded alkanes were calculated by using an ONIOM-G3B3 method. Geometric parameters such as bond length, bond angle and molecular volume were carefully investigated, as most of the acyclic alkanes in this study were not yet synthesized. These parameters reflect the influence of steric effect on BDE. Good correlations were found between the rapid decrease of BDE and the increase of molecular volumes. The correlations can be applied to the prediction of the possible existence of many highly strained compounds.

Six density function theory methods (B3LYP, B3P86, MPWB1K1, MPWPW91, PBEPBE, TPSS1KCIS3) were used to calculate bond dissociation enthalpies of nitro compounds, where the B3P86 method was found to give the most accurate predictions. Using the B3P86 method meta- and para-substituted nitroaromatics were systematically studied for the first time. The remote substituent effects, Hammett relationships, and the origin of the substituent effects were discussed on the basis of the calculated results. Both meta- and para-substituted nitromethyl-benzenes showed significant substituent effects and a fair correlation against substituent constants σ_p⁺ The ground state effects were found to play the major role in determining the overall substituent effects. Meanwhile, nitroamino- benzenes showed irregular substituent effects and a poorer Hammett correlation, where both ground and radical state effects contributed to the overall substituent effects.

The available experimental αC-H BDEs of a variety of amine-containing molecules were examined by using the G3B3 and CBS-Q methods. The verified values were employed to benchmark and calibrate the density functional theory methods. It was found that the (U)BHandH/6-311++G(2df, 2p)//(U)B3LYP/6-31G(d) method was a fast and accurate method for calculating C–H BDEs at nitrogen α-positions. By using the newly benchmarked BHandH method, the αC–H BDEs in a number of nitrogen-containing drug molecules were calculated, where a dramatic variation of the αC–H BDEs was discovered. To understand this variation, the effects of mono- and double-substitution at both carbon and nitrogen atoms on the αC-H BDEs were systematically studied. The origin of the substitution effects was thoroughly discussed in terms of four categories of substituents.

A computational study with the B3PW91 density functional theory was carried out on the activation process of palladacycles as catalysts in the Heck reaction. Two possible pathways (i.e. anion reductive cleavage of the Pd–C bond, and olefin insertion into the Pd–C bond followed by β-H elimination) were taken into consideration. Computational results indicate that the palladacycles are activated via olefin insertion into the Pd–C bond followed by β-H elimination in the reaction conditions.