Organocatalyzed Enantioselective [2 + 2] Cycloaddition of C,N-Cyclic Ketimines and Allenoates.

We report a novel enantioselective and regioselective [2 + 2] cycloaddition of allenoate and C,N-cyclic ketimine catalyzed by a quinidine derivative. The methodology enables the synthesis of fused tricyclic azetidines with a quaternary stereogenic center exhibiting high enantioselectivities. The broad range of substrates demonstrates the generality of the protocol, and the resulting functional products can be easily converted to a variety of valuable synthons. To elucidate the plausible reaction mechanism and how the catalyst affects absolute stereocontrol over the products, we conducted the corresponding density functional theory (DFT) calculations.

Mechanism and Selectivity of Copper-Catalyzed Bromination of Distal C(sp3)-H Bonds.

Unactivated C(sp3)-H bonds are the most challenging substrate class for transition metal-catalyzed C-H halogenation. Recently, the Yu group [Liu, T.; Myers, M. C.; Yu, J. Q. Angew. Chem., Int. Ed.2017, 56 (1), 306-309] has demonstrated that a CuII/phenanthroline catalyst and BrN3, generated in situ from NBS and TMSN3 precursors, can achieve selective C-H bromination distal to a directing group. The current understanding of the mechanism of this reaction has left numerous questions unanswered. Here, we investigated the mechanism of Cu-catalyzed C(sp3)-H bromination with distal site selectivity using density functional theory calculations. We found that this reaction starts with the Br-atom transfer from BrN3 to the Cu center that occurs via a small energy barrier at the singlet-triplet state seam of crossing. In the course of this reaction, the presence of the N-H bond in the substrate is critically important and acts as a directing group for enhancing the stability of the catalyst-substrate interaction and for the recruitment of the substrate to the catalyst. The required C-centered radical substrate formation occurs via direct C-H dehydrogenation by the Cu-coordinated N3 radical, rather than via the previously proposed N-H bond dehydrogenation and then the 1,5-H transfer from the γ-(C-H) bond to the N-radical center pathway. The C-H bond activation by the azide radical is a regioselectivity-controlling step. The following bromination of the C-centered radical by the Cu-coordinated bromine completes the product formation. This reaction step is the rate-limiting step, occurs at the singlet-to-triplet state seam of the crossing point, and is exergonic.

Stereospecific [3+2] Cycloaddition of Chiral Arylallenes with C,N-Cyclic Azomethine Imines.

A novel α,ß-regioselective [3+2] cycloaddition reaction of arylallene with C,N-cyclic azomethine imine is reported. The axial-to-central chirality transfer phenomenon has been disclosed with chiral allenes in the reaction. The wide substrate scope, including different functional groups and natural products, reveals the generality of the methodology. Both experiments and density functional theory calculations have been used to elucidate a plausible mechanism.

Correction: Mechanistic details of the cobalt-mediated dehydrogenative dimerization of aminoquinoline-directed benzamides.

[This corrects the article DOI: 10.1039/D0SC02066D.].

An Update on Formic Acid Dehydrogenation by Homogeneous Catalysis.

Formic acid (FA) has been extensively studied as one of the most promising hydrogen energy carriers today. The catalytic decarboxylation of FA ideally leads to the formation of CO2 and H2 that can be applied in fuel cells. A large number of transition-metal based homogeneous catalysts with high activity and selectivity have been reported for the selective FA dehydrogentaion. In this review, we discussed the recent development of C,N/N,N-ligand and pincer ligand-based homogeneous catalysts for the FA dehydrogenation reaction. Some representative catalysts are further evaluated by the CON/COF assessment (catalyst on-cost number)/(catalyst on-cost frequency). Conclusive remarks are provided with future challenges and opportunities.

Dehydrogenation of Formic Acid Catalyzed by a Ruthenium Complex with an N,N'-Diimine Ligand.

We report a ruthenium complex containing an N,N'-diimine ligand for the selective decomposition of formic acid to H2 and CO2 in water in the absence of any organic additives. A turnover frequency of 12 000 h-1 and a turnover number of 350 000 at 90 °C were achieved in the HCOOH/HCOONa aqueous solution. Efficient production of high-pressure H2 and CO2 (24.0 MPa (3480 psi)) was achieved through the decomposition of formic acid with no formation of CO. Mechanistic studies by NMR and DFT calculations indicate that there may be two competitive pathways for the key hydride transfer rate-determining step in the catalytic process.

The critical size of hydrogen-bonded alcohol clusters as effective Brønsted bases in solutions.

The alkyl oxonium ion, which is a protonated alcohol, has long been proposed as a key reaction intermediate in alcohol dehydration. Nonetheless, the dynamics and structure of this simple but important intermediate species have not been adequately examined due to the transient nature of the oxonium ion. Here, we devised a model system for the key step in the alcohol dehydration reaction, in which a photoacid transfers a proton to alcohols of different basicity in the acetonitrile solvent. Using time-resolved spectroscopy and computation, we have found that the linkage of at least two alcohol molecules via hydrogen bonding is critical for their enhanced reactivity and extraction of the proton from the acid. This finding addresses the cooperative role of the simplest organic protic compounds, namely alcohols, in nonaqueous acid-base reactions.

A potential role of a substrate as a base for the deprotonation pathway in Rh-catalysed C-H amination of heteroarenes: DFT insights.

The possibility of direct introduction of a new functionality through C-H bond activation is an attractive strategy in covalent synthesis. Here, we investigated the mechanism of Rh-catalysed C-H amination of the heteroaryl substrate (2-phenylpyridine) using phenyl azide as a nitrogen source by density functional theory (DFT). For the deprotocyclometallation and protodecyclometallation processes of the title reaction, we propose a stepwise base-assisted mechanism (pathway I) instead of the previously reported concerted mechanism (pathway II). In the new mechanism proposed here, 2-phenylpyridine acts as a base in the initial deprotonation step (C-H bond cleavage) and transports the proton towards the final protonation step. In fact, the N-H bond of the strong conjugate acid (formed during the initial C-H bond cleavage) considered in pathway I (via) is more acidic than the C-H bond of the neutral substrate considered in pathway II (via). The higher activation barrier of mainly originates from the ring strain of the four-membered cyclic transition state. The vital role of the base, as disclosed here, can potentially have broader mechanistic implications for the development of reaction conditions of transition metal-catalysed reactions.

A class of effective decarboxylative perfluoroalkylating reagents: [(phen)2Cu](O2CRF).

This article describes the invention of a class of effective reagents [(phen)2Cu](O2CRF) (1) for the decarboxylative perfluoroalkylation of aryl and heteroaryl halides. Treatment of copper tert-butyloxide with phenanthroline ligands, with subsequent addition of perfluorocarboxylic acids afforded air-stable copper(i) perfluorocarboxylato complexes 1. These complexes reacted with a variety of aryl and heteroaryl halides to form perfluoroalkyl(hetero)arenes in moderate to high yields. Computational studies suggested that the coordination of the second phen ligand may reduce the energy barrier for the decarboxylation of perfluorocarboxylate to facilitate perfluoroalkylation.

Remote C-H Activation of Quinolines through Copper-Catalyzed Radical Cross-Coupling.

Achieving site selectivity in carbon-hydrogen (C-H) functionalization reactions is a formidable challenge in organic chemistry. Herein, we report a novel approach to activating remote C-H bonds at the C5 position of 8-aminoquinoline through copper-catalyzed sulfonylation under mild conditions. Our strategy shows high conversion efficiency, a broad substrate scope, and good toleration with different functional groups. Furthermore, our mechanistic investigations suggest that a single-electron-transfer process plays a vital role in generating sulfonyl radicals and subsequently initiating C-S cross-coupling. Importantly, our copper-catalyzed remote functionalization protocol can be expanded for the construction of a variety of chemical bonds, including C-O, C-Br, C-N, C-C, and C-I. These findings provide a fundamental insight into the activation of remote C-H bonds, while offering new possibilities for rational design of drug molecules and optoelectronic materials requiring specific modification of functional groups.

Role of keto-enol tautomerization in a chiral phosphoric acid catalyzed asymmetric thiocarboxylysis of meso-epoxide: a DFT study.

The mechanism of a chiral phosphoric acid catalyzed thiocarboxylysis of meso-epoxide was investigated by density functional theory (DFT) calculations (M06-2X). The nucleophilic ring opening of epoxide by thiobenzoic acid was found to proceed via a concerted termolecular transition state with a simultaneous dual proton transfer to yield the ß-hydroxy thioester product. Electrostatic interactions together with the steric environment inside the chiral catalyst play an important role in determining the enantioselectivity of the reaction.

Hydrogen-bond-assisted controlled C-H functionalization via adaptive recognition of a purine directing group.

We have developed the Rh-catalyzed selective C-H functionalization of 6-arylpurines, in which the purine moiety directs the C-H bond activation of the aryl pendant. While the first C-H amination proceeds via the N1-chelation assistance, the subsequent second C-H bond activation takes advantage of an intramolecular hydrogen-bonding interaction between the initially formed amino group and one nitrogen atom, either N1 or N7, of the purinyl part. Isolation of a rhodacycle intermediate and the substrate variation studies suggest that N1 is the main active site for the C-H functionalization of both the first and second amination in 6-arylpurines, while N7 plays an essential role in controlling the degree of functionalization serving as an intramolecular hydrogen-bonding site in the second amination process. This pseudo-Curtin-Hammett situation was supported by density functional calculations, which suggest that the intramolecular hydrogen-bonding capability helps second amination by reducing the steric repulsion between the first installed ArNH and the directing group.

DFT prediction of multitopic N-heterocyclic carbenes using Clar's aromatic sextet theory.

Existence of several multitopic N-heterocyclic carbene (NHC) ligands with up to four carbene centers have been predicted on the basis of Clar's aromatic sextet theory. Assessment on stability and reactivity of NHCs was made by quantifying aromaticity, aromatic stabilization energy (E(aroma)), strength of carbene lone pair, proton affinity, and CuCl binding energy. On NICS(0) and HOMA scales of aromaticity, several NHCs showed high aromaticity, while E(aroma) (17.2-19.4 kcal/mol) indicated substantial stability for the N-heterocycle. Homodesmotic reactions suggested that heat of formation of most of the newly designed carbenes is very close to that of the existing bis-NHCs. Designing a multitopic ligand through branching via C(sp3) linkage was very effective as it improved the stability of the carbene. Electrostatic potential minimum (V(min)) at the carbene lone pair suggested that annelation of heterocycle to a benzenoid ring or branching through C(sp3) linkage can only marginally influence the electron donating power of the ligand. Hence, all multitopic NHCs showed proton affinity (252.3-267.4 kcal/mol) and CuCl binding energy (62.9-66.6 kcal/mol) very close to those of 1,3-dimethylimidazolidine-2-ylidene (1). It has also been demonstrated that branched multitopic 3-dimensional NHCs are attractive for designing metal-organic framework with narrow (1-1.5 nm) cage/pore size.

DPPH radical scavenging activity of tricin and its conjugates isolated from "Njavara" rice bran: a density functional theory study.

Structural, electronic, and energetic characteristics of tricin, tricin-4'-O-(erythro-ß-guaiacylglyceryl)ether (TEGE), and tricin-4'-O-(threo-ß-guaiacylglyceryl)ether (TTGE), isolated from "Njavara" rice bran have been studied using DFT to explain their experimentally determined radical scavenging activity (EC(50) values) in comparison with known standards such as quercetin, myricetin, and catechin. Among the three mechanisms proposed for explaining the antioxidant activity, proton coupled-electron transfer (PC-ET), sequential proton loss electron transfer (SPLET), and electron transfer-proton transfer (ET-PT), our results support the second one. The O-H bond dissociation enthalpy (BDE) and the spin density on the oxygen with the radical character are excellent descriptors of radical scavenging activity. BDE (in kcal/mol) increased in the order myricetin (74.6) < quercetin (78.1) < catechin (78.3) < tricin (81.5) < TTGE (90.6) < TEGE (91.1), while the EC(50) increased exponentially with increase in BDE, 20.51, 42.98, 45.07, 90.39, 208.01, and 352.04 µg/mL for myricetin, quercetin, catechin, tricin, TTGE, and TEGE, respectively.

Assessment of stereoelectronic factors that influence the CO2 fixation ability of N-heterocyclic carbenes: a DFT study.

The CO(2) fixation ability of N-heterocyclic carbenes (NHC) has been assessed on the basis of electronic and steric properties of the N- and C-substituents, measured in terms of molecular electrostatic potential minimum, observed at the carbene lone pair region of NHC (V(min1)) as well as at the carboxylate region of the NHC-CO(2) adduct (V(min2)). Both V(min1) and V(min2) are found to be simple and efficient descriptors of the stereoelectronic effect of NHCs. The V(min)-based analysis also proved that the stereoelectronic effect of N- and C-substituents is additive. When only C-substituents are present in NHC, its CO(2) affinity solely depends on the electronic effect, whereas if the N-center bears the substituents, the steric factor plays a major role in the carboxylation/decarboxylation process. For standard substituents, maximum CO(2) binding energy of 18.0 kcal/mol is observed for the most electron-donating combination of NMe(2) as the C-substituent and Me as the N-substituent. Introduction of ring strain through five-membered ring fusion at the NC bond slightly increased the electron-rich character of the carbene lone pair and also enhanced the CO(2) binding energy to 20.9 kcal/mol. To further improve the CO(2) fixing ability of NHCs, we have proposed the use of CH(2)OH, CH(2)NHCOMe, and CH(2)NHPh as N-substituents, as they participate in intramolecular hydrogen bond interaction with the carboxylate. With the new strategy, considerable improvement in the CO(2) binding energy (26.5 to 33.0 kcal/mol) is observed.

Mechanism of epoxide hydrolysis in microsolvated nucleotide bases adenine, guanine and cytosine: a DFT study.

Six water molecules have been used for microsolvation to outline a hydrogen bonded network around complexes of ethylene epoxide with nucleotide bases adenine (EAw), guanine (EGw) and cytosine (ECw). These models have been developed with the MPWB1K-PCM/6-311++G(3df,2p)//MPWB1K/6-31+G(d,p) level of DFT method and calculated S(N)2 type ring opening of the epoxide due to amino group of the nucleotide bases, viz. the N6 position of adenine, N2 position of guanine and N4 position of cytosine. Activation energy (E(act)) for the ring opening was found to be 28.06, 28.64, and 28.37 kcal mol(-1) respectively for EAw, EGw and ECw. If water molecules were not used, the reactions occurred at considerably high value of E(act), viz. 53.51 kcal mol(-1) for EA, 55.76 kcal mol(-1) for EG and 56.93 kcal mol(-1) for EC. The ring opening led to accumulation of negative charge on the developing alkoxide moiety and the water molecules around the charge localized regions showed strong hydrogen bond interactions to provide stability to the intermediate systems EAw-1, EGw-1 and ECw-1. This led to an easy migration of a proton from an activated water molecule to the alkoxide moiety to generate a hydroxide. Almost simultaneously, a proton transfer chain reaction occurred through the hydrogen bonded network of water molecules and resulted in the rupture of one of the N-H bonds of the quaternized amino group. The highest value of E(act) for the proton transfer step of the reaction was 2.17 kcal mol(-1) for EAw, 2.93 kcal mol(-1) for EGw and 0.02 kcal mol(-1) for ECw. Further, the overall reaction was exothermic by 17.99, 22.49 and 13.18 kcal mol(-1) for EAw, EGw and ECw, respectively, suggesting that the reaction is irreversible. Based on geometric features of the epoxide-nucleotide base complexes and the energetics, the highest reactivity is assigned for adenine followed by cytosine and guanine. Epoxide-mediated damage of DNA is reported in the literature and the present results suggest that hydrated DNA bases become highly S(N)2 active on epoxide systems and the occurrence of such reactions can inflict permanent damage to the DNA.

Role of stereoelectronic features of imine and enamine in (S)-proline catalyzed Mannich reaction of acetaldehyde: an in silico study.

A detailed mechanistic investigation of sixteen possible diastereomeric pathways for the C-C bond formation step in (S)-proline catalyzed Mannich reaction of acetaldehyde with N-acetyl protected benzaldimine in acetonitrile solvent has been carried out to understand how stereoelectronic features invoke enantioselectivity of the final product. Both kinetic and thermodynamic factors of the reaction obtained using various density functional theory methods point out that si-enantiofacial nucleophilic attack of anti-enamine on the iminium carbon of the E, s-cis N-acetyl protected imine is the stereoselective pathway. Structural features of the transition states predicted that enamine in anti conformation attacks the imine through a Burgi-Dunitz trajectory to yield the stereocenter. Computations at B3LYP-PCM/6-311++G(3df,2p)//B3LYP-PCM/6-31G(d,p) level showed a strong linear correlation between Burgi-Dunitz angle and activation energy when anti-enamine is used as nucleophile to react with all the configurations of the imine. Further, energy decomposition analysis has been carried out at B3LYP/TZ2P+ level for all the transition states, which revealed that the most dominant factor that control the enantioselectivity of the (S)-proline catalyzed Mannich reaction is steric effect. Though the less favored transition states showed high amount of stabilizing orbital interaction, the destabilizing steric effects from both Pauli repulsion and preparation energy for the reactant molecules are very high and overshadowed the stabilizing effects. However, in the most favored transition state, a balanced outcome of electronic and steric effects was observed. Solvation effect was nearly same for all the transition states and electrostatic effects showed no correlation to the rank order of the energy of the transition states.