The mechanism of the full catalytic cycle for Fe-chiral-bisphosphine-catalyzed cross-coupling reaction between alkyl halides and Grignard reagents (Nakamura and co-workers, J. Am. Chem. Soc. 2015, 137, 7128) was rationalized by using density functional theory (DFT) and multicomponent artificial force-induced reaction (MC-AFIR) methods. The computed mechanism consists of (a) C-Cl activation, (b) transmetalation, (c) C-Fe bond formation, and (d) C-C bond formation through reductive elimination. Our survey on the prereactant complexes suggested that formation of Fe(BenzP*)Ph and Fe(BenzP*)Ph complexes are thermodynamically feasible. Fe(BenzP*)Cl complex is the active intermediate for C-Cl activation. Fe(BenzP*)Ph complex can be formed if the concentration of Grignard reagent is high. However, it leads to biphenyl (byproduct) instead of the cross-coupling product. This explains why slow addition of Grignard reagent is critical for the cross-coupling reaction. The MC-AFIR method was used for systematic determination of transition states for C-Fe bond formation and C-C bond formation starting from the key intermediate Fe(BenzP*)PhCl. According to our detailed analysis, C-C bond formation is the selectivity-determining step. The computed enantiomeric ratio of 95:5 is in good agreement with the experimental ratio (90:10). Energy decomposition analysis suggested that the origin of the enantioselectivity is the deformation of Ph-ligand in Fe-complex, which is induced by the bulky tert-butyl group of BenzP* ligand. Our study provides important mechanistic insights for the cross-coupling reaction between alkyl halides and Grignard reagents and guides the design of efficient Fe-based catalysts for cross-coupling reactions.

Palladium complexes incorporating chiral N-heterocyclic carbene (NHC) ligands catalyze the asymmetric intramolecular α-arylation of amides producing 3,3-disubstituted oxindoles. Comprehensive DFT studies have been performed to gain insight into the mechanism of this transformation. Oxidative addition is shown to be rate-determining and reductive elimination to be enantioselectivity-determining. The synthesis of seven new NHC ligands is detailed and their performance is compared. One of them, L8, containing a tBu and a 1-naphthyl group at the stereogenic centre, proved superior and was very efficient in the asymmetric synthesis of fifteen new spiro-oxindoles and three azaspiro-oxindoles often in high yields (up to 99 %) and enantioselectivities (up to 97 % ee; ee=enantiomeric excess). Three palladacycle intermediates resulting from the oxidative addition of [Pd(NHC)] into the aryl halide bond were isolated and structurally characterized (X-ray). Using these intermediates as catalysts showed alkene additives to play an important role in increasing turnover number and frequency.

Take the right path: Comparison of the oxazolidinone and enamine pathways in enantioselective aldol reactions by using density functional and ab initio transition states reveals that the oxazolidinone route does not provide the correct stereochemical outcome (see picture), whereas the enamine pathway predicts the correct stereoselectivity.

The transition state models in two mechanistically distinct pathways, involving (i) an enamine carboxylic acid (path-A, 4) and (ii) an enamine carboxylate (path-B, 8), in the proline-catalyzed asymmetric α-amination have been examined using DFT methods. The path-A predicts the correct product stereochemistry under base-free conditions while path-B accounts for reversal of configuration in the presence of a base.

The stereocontrolling transition state (TS) models for C-C bond formation relying on hydrogen bonding have generally been successful in proline-catalyzed aldol, Mannich, α-amination, and α-aminoxylation reactions. However, the suitability of the hydrogen-bonding model in protic and aprotic conditions as well as under basic and base-free conditions has not been well established for Michael reactions. Through a comprehensive density functional theory investigation, we herein analyze different TS models for the stereocontrolling C-C bond formation, both in the presence and absence of a base in an aprotic solvent (THF). A refined stereocontrolling TS for the Michael reaction between cyclohexanone and nitrostyrene is proposed. The new TS devoid of hydrogen bonding between the nitro group of nitrostyrene and carboxylic acid of proline, under base-free conditions, is found to be more preferred over the conventional hydrogen-bonding model besides being able to reproduce the experimentally observed stereochemical outcome. A DBU-bound TS is identified as more suitable for rationalizing the origin of asymmetric induction under basic reaction conditions. In both cases, the most preferred approach of nitrostyrene is identified as occurring from the face anti to the carboxylic acid of proline-enamine. The predicted enantio- and diastereoselectivities are in very good agreement with the experimental observations.

We present mechanistic details of the formation of a NiFe hydride complex and provide information on its electron-and hydride-transfer processes on the basis of density functional theory calculations and artificial-forceinduced-reaction studies. The NiFe hydride complex conducts three transfer reactions: namely, electron transfer, hydride transfer, and proton transfer. In a NiFe hydride complex, the hydride binds to Fe, which is different from the Ni−R state in hydrogenase where the hydride is located between Ni and Fe. According to our calculations, in reaction with the ferrocenium ion, electron transfer occurs from the NiFe hydride complex to the ferrocenium ion, followed by a hydrogen atom transfer (HAT) to the second ferrocenium ion. The oxidation state of Fe varies during the redox process, different from the case of NiFe hydrogenase, where the oxidation state of Ni varies. A single-step hydride transfer occurs in the presence of a 10-methylacridinium ion (AcrH + ), which is more kinetically feasible than the HAT process. In contrast to the HAT and hydride-transfer process, the proton transfer occurs through a low barrier from a protonated diethyl ether. The revealed reaction mechanism guides the interpretation of the catalytic cycle of NiFe hydrogenase and leads to the development of efficient biomimetic catalysts for H 2 generation and an electron/hydride transfer.

Nowadays, computational studies are very important for the elucidation of reaction mechanisms and selectivity of complex reactions. However, traditional computational methods usually require an estimated reaction path, mainly driven by limited experimental implications, intuition, and assumptions of stationary points. However, the artificial force induced reaction (AFIR) method in the global reaction route mapping (GRRM) strategy can be used for unbiased and automatic reaction path searches for complex reactions. In this account, we highlight applications of the AFIR method to a variety of reactions (organic, organometallic, enzymatic, and photochemical) of complex molecular systems. In addition, the AFIR method has been successfully used to rationalise the origin of stereo- and regioselectivity. The AFIR method can be applied from small to large molecular systems, and will be a very useful tool for the study of complex molecular problems in many areas of chemistry, biology, and material sciences.

The mechanism, regioselectivity, and stereospecificity of Pd/NHC-catalyzed ring-opening cross-coupling of 2-arylaziridines with arylboronic acids (J. Am. Chem. Soc.136) is rationalized from density functional theory calculations. Pd(0)­SIPr complex, the active species, can be formed through the reduction of (η3-cinnamyl)­(Cl)­Pd­(II)­SIPr complex, where arylboronic acid in solution plays a key role. Then the Pd(0)­SIPr complex acts as the active species of the catalytic cycle that consists of the regioselective and stereospecific oxidative addition, proton transfer, rate-determining transmetalation, and reductive elimination. Transition states for the oxidative addition were systematically determined from a multicomponent artificial force induced reaction search and explained the regioselectivity and stereospecificity of the reaction. An energy decomposition analysis on the key transition states suggested that the interactions between Pd(0)­SIPr and 2-arylaziridines are important to the selectivity. The computed mechanism of the full catalytic cycle is consistent with the experimental data. Our detailed mechanistic survey provides important mechanistic insights for enantiospecific and regioselective ring-opening reactions of 2-arylaziridines.