Recently, Jiao and co-workers reported an unprecedented gold-catalyzed nitrogenation of alkynes with trimethylsilyl azide through C–C and C≡C bond cleavages. In this reaction, the acidic additive controls the chemoselectivity for the formation of either carbamides or aminotetrazoles from an internal alkyne. In this study, density functional theory calculations were performed to clarify the mechanism and origin of this chemoselectivity. A systematic search shows that the acidities of CH3SO3H and CF3SO3H determine which of the two reaction pathways is followed and, thus, the chemoselectivity. CH3SO3H favors the hydroxylation step and eventually leads to carbamide production. In contrast, CF3SO3H, which is a stronger acid than CH3SO3H, favors trimethylsilyl removal and eventually generates aminotetrazoles. This acid-dependent chemoselectivity also applies to terminal alkynes and is consistent with the corresponding experimental results. Both CH3SO3H and CF3SO3H form carbamides preferentially because the hydrogen atom in a terminal alkyne promotes nucleophilic hydration more effectively than the n-butyl group in an internal alkyne.

Rh-Catalyzed alkyne–isatin decarbonylative coupling provides an effective method for cleavage of C–C bonds in unstrained five-membered ring compounds. The challenge in this transformation is activation of the less-strained C–C bond, while avoiding competitive C–H activation. We performed DFT calculations to clarify this process to facilitate expansion of this strategy. The calculations show that chemoselectivity switching (C–C versus C–H functionalization) depends on the substituent on the phenyl ring of isatin. The coordination properties of the ligand significantly affect the alkyne insertion step. Dissociation of a strong σ-donor phosphine ligand from the Rh center to enable alkyne coordination is unfavorable, therefore the subsequent alkyne insertion step has a high energy barrier. Our calculations also explain the experimentally observed regioselectivity, which mainly arises from the interaction energy.

Martin and co-workers recently developed a strategy for Ni(0)-complex-catalyzed [4 + 4] annulation of primary benzocyclobutenones (BCBs) and 1,3-dienes. A density functional theory study was performed to clarify the catalytic mechanism. The results provide insights into the origins of the chemo-, regio-, and diastereoselectivity. The calculation results explain why only P(C6H5CF3)3, among several candidates, performed well and why the [4 + 4] annulation of BCB with a 1,3-diene was achieved with a Ni(0) but not with a Rh(I) catalyst.

The efficient construction of 2,4,5-trisubstituted imidazoles, through a copper-mediated three-component reaction involving ketones, aldehydes, and Me3SiN3, has been developed. During the process, 4 C–N bonds were formed sequentially. Experimental results and DFT calculations suggested that azidation of the alpha methylene group of the ketone was the key C–N bond-forming step.

A systematic density functional theory study has been conducted to examine the mechanisms involved in the rhodium(III)-catalyzed alkenylation of N-phenoxyacetamide with two different substrates (i.e., styrene and N-tosylhydrazone). The density functional theory calculations indicated that the reaction of the N-tosylhydrazone substrate resulted in the formation of a Rh(V)–nitrene intermediate via the cleavage of the O–N bond of N-phenoxyacetamide, whereas the styrene substrate resulted in an Rh(I) species through consecutive β-H elimination and H migration steps to the internal oxidant. The differences observed between the N-tosylhydrazone and styrene systems were attributed to differences in the reactivity of their Rh(V)–nitrene intermediates. For example, the N-tosylhydrazone formed a five-membered Rh(V)–nitrene intermediate, which was readily reduced to a Rh(III) species by tautomerization, whereas this pathway was energetically unfavorable for the styrene substrate.

A one-pot multicomponent approach was established for site selective synthesis of novel 1,3,6-trisubstituted 3,6-diunsaturated (3Z,6Z)-2,5-diketopiperazine derivatives with high stereoselectivity. The computational studies revealed that the steric hindrances between the 2-hydrogen atoms on the aromatic rings and the carbonyl, as well as the steric repulsions between the hydrogen atoms of the CH group in the benzylidene and the CH2 group in the N-alkylative part might be responsible for the Z/E selectivity. Compound (3Z,6Z)-3h (IC50=11 nM) has a close activity to the positive compound plinabulin (IC50=15 nM) against the cancer cell line HL60.

The Rh(III)-catalyzed cyclopropanation reaction using N-enoxyphthalimides and alkenes developed by Rovis group [J. Am. Chem. Soc.2014, 136, 11292−11295] provided an efficient method for the constructions of trans 1,2-disubstituted cyclopropanes in which an elegant control of the diastereoselectivities was achieved. In the current report we aimed at uncovering the mechanism and diastereoselectivity of the reactions using density functional theory (DFT) calculations. By comparing the energies of all possible pathways, we found that a novel mechanism involving a four-membered Rh(V) species is the energetically most favorable one. In this pathway, the four-membered Rh(V) intermediate is formed by sequential CH activation, alkene insertion and NO bond cleavage steps, and the final cyclopropane product is formed via an reductive elimination process. The NO bond cleavage was found to be the diastereoselectivity-determining, which was reproduced well the experimentally observed selectivity. By analyzing using the distortion/interaction model, it was found that the distortion energy plays a main role in determining the diastereoselectivity.

A density functional theory (DFT) study has been conducted to elucidate the mechanism of the rhodium(III)-catalyzed C–H activation of O-substituted N-hydroxybenzamides and cyclohexadienone-containing 1,6-enynes. The impact of different O-substituted internal oxidants (OPiv versus OMe) on the arylative cyclization (i.e., Ⓝ-Michael addition versus Ⓒ-Michael addition) has been evaluated in detail. The Ⓝ-Michael addition pathway proceeded via a Rh(I) species, while Rh(III) remained unchanged throughout the Ⓒ-Michael addition pathway. The Rh(III)/Rh(I) catalytic cycle in the Ⓝ-Michael addition pathway was different from those reported previously where the Rh(III)/Rh(V) catalytic cycle was favored for the Rh(III)-catalyzed C–H activation of O-substituted N-hydroxybenzamides. The first three steps were similar for the OPiv- and OMe-substituted substrates, which involved sequential N–H deprotonation, C–H activation (a concerted metalation–deprotonation process), and 1,6-enyne insertion steps. Starting from a seven-membered rhodacycle, the alternative mechanism would be controlled by the OR substituent. When the substituent was OMe, the unstable seven-membered rhodacycle was readily coordinated by a double bond of the cyclohexadienone which enabled the Ⓒ-Michael addition reaction. However, the presence of an N-OPiv moiety stabilized the seven-membered rhodacycle through a bidentate coordination which facilitated the Ⓝ-Michael addition process.

Succession of C–H activation and C–C activation was achieved by using a single rhodium(III) catalyst. Vinylcyclopropanes were used as versatile coupling partners. Mechanistic studies suggest that the olefin insertion step is rate-determining and a facile β-carbon elimination is involved, which represents a novel ring opening mode of vinylcyclopropanes.

The Pd-catalyzed functionalization of Csp2–H bonds using a 1,2,3-triazole directing group has been investigated by density functional theory calculations at the B3LYP level. The results of these calculations showed that the substitution pathway was kinetically favored over the cyclization pathway for the N2-pyridine-1,2,3-triazole-4-carboxylic acid (TAPy)-directed functionalization of Csp2–H bonds, while the cyclization pathway was kinetically favored over the substitution pathway for the N1-aryl-1,2,3-triazole-4-carboxylic acid (TAA)-directed Csp2–H functionalization. The kinetic preference of the TAPy directing group for the substitution reaction can be attributed the reduced level of bond cleavage in the transition structure of the substitution step because the pyridine moiety of the TAPy directing group can act as a ligand for the Pd center.

A density functional theory (DFT) study has been conducted to elucidate the mechanism of the rhodium(III)-catalyzed C–H activation of N-phenoxyacetamide, where the amido component of an internal oxidant serves as a leaving group. The impact of different substrates (alkynes versus cyclopropenes) on the reaction mechanism has been discussed in detail. The pathway for cyclopropene substrate proceeded via a Rh(V) nitrene, while Rh(III) remained unchanged throughout the pathway for alkyne substrate. The C–O bond-forming reductive elimination and O–N bond cleavage steps simultaneously occurred for the alkyne substrate. However, the C–O bond was formed by an electrocyclization from a Rh(III) intermediate for the cyclopropene substrate. The energy profiles for the cyclopropene substrate were accompanied by a change in spin-state because the triplet spin state of a Rh(V) nitrene complex is lower than that of the singlet spin state.

A systematic DFT study was performed to examine the isomerization of 2-aryl-2H-azirines to 2,3-disubstituted indoles by FeCl2 and Rh2(O2CCF3)4. The results indicate that the isomerization of 2-aryl-2H-azirines mainly proceeds through a stepwise mechanism and the Rh2(O2CCF3)4 exhibits higher catalytic performance than FeCl2. Investigation of the magnetic properties suggests that the C–N bond formation step is pseudoelectrocyclization for the FeCl2-catalyzed system. The calculations show that a water-catalyzed 1,2-H shift for the FeCl2-catalyzed system adopts a proton-transport catalysis strategy, in which chlorine atom coordination to the iron center is critical because it acts as a proton acceptor. When a molecule of water is involved in the Rh2(O2CCF3)4-catalyzed reaction, the 1,2-H shift is significantly promoted, so that the rate-determining step becomes the ring opening of 2-aryl-2H-azirine. In addition, we studied the catalytic activity of Fe(OAc)2 and CuCl.

DFT calculations have been performed to study the reaction mechanism of N–N bond formation from aryl azide catalyzed by the copper(I) iodide complex. We studied various activation modes for the azide group, and found that the azide group is activated by the Cu(μ-I)2Cu(TMEDA) dimer coordinating to the N-atom of phenyl imine and the internal N-atom of azide.

In this study, the Cu(OAc)2- and [PdCl2(PhCN)2]-catalyzed syntheses of benzimidazoles from amidines were theoretically investigated using density functional theory calculations. For the Cu-catalyzed system, our calculations supported a four-step-pathway involving C–H activation of an arene with Cu(II) via concerted metalation–deprotonation (CMD), followed by oxidation of the Cu(II) intermediate and deprotonation of the imino group by Cu(III), and finally reductive elimination from Cu(III). In our calculations, the barriers for the CMD step and the oxidation step are the same. The results are different from the ones reported by Fu et al. in which the whole reaction mechanism includes three steps and the CMD step is rate determining. On the basis of the calculation results for the [PdCl2(PhCN)2]-catalyzed system, C–H bond breaking by CMD occurs first, followed by the rate-determining C–N bond formation and N–H deprotonation. Pd(III) species is not involved in the [PdCl2(PhCN)2]-catalyzed syntheses of benzimidazoles from amidines.

Density functional theory calculations have been carried out to study the reaction mechanism of the [FeIII(F20TPP)Cl] catalyzed C–H amination reaction. The calculations show that the classical three-step mechanism for other metals (Ru, Rh, Ir and Zn), including N2 liberation, C–N bond formation and 1,2-hydrogen shift, does not fit the iron(III)-catalyzed system. After N2 liberation, the favorable reaction pathway for the iron(III)-catalyzed system is a 1,2-hydrogen shift preceding C–N bond formation, i.e., a H-abstraction/radical rebound mechanism.

A systematic DFT study was performed to examine how catalysts with different metals influence the C–H amination mechanism of biaryl azides. The mechanisms of (cod)Ir(OMe), RuCl3(DME) (DME = CH3OCH2CH2OCH3, a solvent molecule), Rh2(O2CCF3)4, and ZnI2 were investigated in our study. The calculations indicated that the C–H amination reactions mainly proceeded through a stepwise mechanism regardless of the metal center (Ru, Ir, Rh, or Zn). The energetic span (δE) model proposed by Shaik et al. has been applied to reveal the kinetic behavior of the four catalytic cycles. The results indicate that the ruthenium species exhibits a higher catalytic performance than the other three. The investigation of magnetic properties suggests that no matter what the metal center was—Ir, Ru, Rh, or Zn—the C–N bond formation step is pseudoelectrocyclization with an orbital disconnection on the nitrogen atom (N1) in the pseudopericyclic transition structure.

An efficient synthesis of 2- or 4-iododibenzofurans through CuI-mediated sequential iodination/cycloetherification of two aromatic C–H bonds in o-arylphenols has been developed. Both the preexisting electron-withdrawing groups (NO2, CN, and CHO) and the newly introduced iodide are readily modified for a focused dibenzofuran library synthesis. Mechanistic studies and DFT calculations suggest that a Cu(III)-mediated rate-limiting C–H activation step is involved in cycloetherification.

DFT calculations have been carried out to study the reaction mechanism on N–O or N–N bond formation from aryl azide catalyzed by iron(II) bromide complex. A favorable reaction pathway is proposed to account for the construction of the core structure of 2H-indazoles or 2,1-benzisoxazoles.

DFT calculations have been performed to study the reaction mechanism of N–N bond formation from aryl azide catalyzed by the copper(I) iodide complex. We studied various activation modes for the azide group, and found that the azide group is activated by the Cu(μ-I)2Cu(TMEDA) dimer coordinating to the N-atom of phenyl imine and the internal N-atom of azide.

Density functional theory calculations have been carried out to study the reaction mechanism of the [FeIII(F20TPP)Cl] catalyzed C–H amination reaction. The calculations show that the classical three-step mechanism for other metals (Ru, Rh, Ir and Zn), including N2 liberation, C–N bond formation and 1,2-hydrogen shift, does not fit the iron(III)-catalyzed system. After N2 liberation, the favorable reaction pathway for the iron(III)-catalyzed system is a 1,2-hydrogen shift preceding C–N bond formation, i.e., a H-abstraction/radical rebound mechanism.

A systematic density functional theory study has been conducted to examine the mechanisms involved in the rhodium(III)-catalyzed alkenylation of N-phenoxyacetamide with two different substrates (i.e., styrene and N-tosylhydrazone). The density functional theory calculations indicated that the reaction of the N-tosylhydrazone substrate resulted in the formation of a Rh(V)–nitrene intermediate via the cleavage of the O–N bond of N-phenoxyacetamide, whereas the styrene substrate resulted in an Rh(I) species through consecutive β-H elimination and H migration steps to the internal oxidant. The differences observed between the N-tosylhydrazone and styrene systems were attributed to differences in the reactivity of their Rh(V)–nitrene intermediates. For example, the N-tosylhydrazone formed a five-membered Rh(V)–nitrene intermediate, which was readily reduced to a Rh(III) species by tautomerization, whereas this pathway was energetically unfavorable for the styrene substrate.

In this study, the Cu(OAc)2- and [PdCl2(PhCN)2]-catalyzed syntheses of benzimidazoles from amidines were theoretically investigated using density functional theory calculations. For the Cu-catalyzed system, our calculations supported a four-step-pathway involving C–H activation of an arene with Cu(II) via concerted metalation–deprotonation (CMD), followed by oxidation of the Cu(II) intermediate and deprotonation of the imino group by Cu(III), and finally reductive elimination from Cu(III). In our calculations, the barriers for the CMD step and the oxidation step are the same. The results are different from the ones reported by Fu et al. in which the whole reaction mechanism includes three steps and the CMD step is rate determining. On the basis of the calculation results for the [PdCl2(PhCN)2]-catalyzed system, C–H bond breaking by CMD occurs first, followed by the rate-determining C–N bond formation and N–H deprotonation. Pd(III) species is not involved in the [PdCl2(PhCN)2]-catalyzed syntheses of benzimidazoles from amidines.

Rh-Catalyzed alkyne–isatin decarbonylative coupling provides an effective method for cleavage of C–C bonds in unstrained five-membered ring compounds. The challenge in this transformation is activation of the less-strained C–C bond, while avoiding competitive C–H activation. We performed DFT calculations to clarify this process to facilitate expansion of this strategy. The calculations show that chemoselectivity switching (C–C versus C–H functionalization) depends on the substituent on the phenyl ring of isatin. The coordination properties of the ligand significantly affect the alkyne insertion step. Dissociation of a strong σ-donor phosphine ligand from the Rh center to enable alkyne coordination is unfavorable, therefore the subsequent alkyne insertion step has a high energy barrier. Our calculations also explain the experimentally observed regioselectivity, which mainly arises from the interaction energy.

A systematic DFT study was performed to examine the isomerization of 2-aryl-2H-azirines to 2,3-disubstituted indoles by FeCl2 and Rh2(O2CCF3)4. The results indicate that the isomerization of 2-aryl-2H-azirines mainly proceeds through a stepwise mechanism and the Rh2(O2CCF3)4 exhibits higher catalytic performance than FeCl2. Investigation of the magnetic properties suggests that the C–N bond formation step is pseudoelectrocyclization for the FeCl2-catalyzed system. The calculations show that a water-catalyzed 1,2-H shift for the FeCl2-catalyzed system adopts a proton-transport catalysis strategy, in which chlorine atom coordination to the iron center is critical because it acts as a proton acceptor. When a molecule of water is involved in the Rh2(O2CCF3)4-catalyzed reaction, the 1,2-H shift is significantly promoted, so that the rate-determining step becomes the ring opening of 2-aryl-2H-azirine. In addition, we studied the catalytic activity of Fe(OAc)2 and CuCl.

The efficient construction of 2,4,5-trisubstituted imidazoles, through a copper-mediated three-component reaction involving ketones, aldehydes, and Me3SiN3, has been developed. During the process, 4 C–N bonds were formed sequentially. Experimental results and DFT calculations suggested that azidation of the alpha methylene group of the ketone was the key C–N bond-forming step.

Succession of C–H activation and C–C activation was achieved by using a single rhodium(III) catalyst. Vinylcyclopropanes were used as versatile coupling partners. Mechanistic studies suggest that the olefin insertion step is rate-determining and a facile β-carbon elimination is involved, which represents a novel ring opening mode of vinylcyclopropanes.