Understanding the Influence of Donor-Acceptor Diazo Compounds on the Catalyst Efficiency of B(C6 F5 )3 Towards Carbene Formation.

Diazo compounds have been largely used as carbene precursors for carbene transfer reactions in a variety of functionalization reactions. However, the ease of carbene generation from the corresponding diazo compounds depends upon the electron donating/withdrawing substituents either side of the diazo functionality. These groups strongly impact the ease of N2 release. Recently, tris(pentafluorophenyl)borane [B(C6 F5 )3 ] has been shown to be an alternative transition metal-free catalyst for carbene transfer reactions. Herein, a density functional theory (DFT) study on the generation of carbene species from α-aryl α-diazocarbonyl compounds using catalytic amounts of B(C6 F5 )3 is reported. The significant finding is that the efficiency of the catalyst depends directly on the nature of the substituents on both the aryl ring and the carbonyl group of the substrate. In some cases, the boron catalyst has negligible effect on the ease of the carbene formation, while in other cases there is a dramatic reduction in the activation energy of the reaction. This direct dependence is not commonly observed in catalysis and this finding opens the way for intelligent design of this and other similar catalytic reactions.

Discovery of Periodinane Oxy-Assisted (POA) Oxidation Mechanism in the IBX-Controlled Oxidative Dearomatization of Pyrroles Mediated by Acetic Acid.

The 2-iodoxybenzoic acid (IBX)-controlled oxidative dearomatization of pyrroles occurs very slowly (or not all) in many organic solvents, including DMSO in which IBX is soluble. Interestingly, although IBX is only partially soluble in acetic acid, this solvent mediates the pyrrole oxidative dearomatization. With the aid of density functional theory (DFT) calculations, we have discovered a new mode of reactivity, termed the periodinane oxy-assisted (POA) oxidation mechanism, which explains this observation.

Site-Selective Csp3-Csp/Csp3-Csp2 Cross-Coupling Reactions Using Frustrated Lewis Pairs.

The donor-acceptor ability of frustrated Lewis pairs (FLPs) has led to widespread applications in organic synthesis. Single electron transfer from a donor Lewis base to an acceptor Lewis acid can generate a frustrated radical pair (FRP) depending on the substrate and energy required (thermal or photochemical) to promote an FLP into an FRP system. Herein, we report the Csp3-Csp cross-coupling reaction of aryl esters with terminal alkynes using the B(C6F5)3/Mes3P FLP. Significantly, when the 1-ethynyl-4-vinylbenzene substrate was employed, the exclusive formation of Csp3-Csp cross-coupled products was observed. However, when 1-ethynyl-2-vinylbenzene was employed, solvent-dependent site-selective Csp3-Csp or Csp3-Csp2 cross-coupling resulted. The nature of these reaction pathways and their selectivity has been investigated by extensive electron paramagnetic resonance (EPR) studies, kinetic studies, and density functional theory (DFT) calculations both to elucidate the mechanism of these coupling reactions and to explain the solvent-dependent site selectivity.

Oxidation of Electron-Deficient Phenols Mediated by Hypervalent Iodine(V) Reagents: Fundamental Mechanistic Features Revealed by a Density Functional Theory-Based Investigation.

Hypervalent iodine (HVI) compounds are efficient reagents for the double oxidative dearomatization of electron-rich phenols to o-quinones. We recently reported that an underexplored class of iodine(V) reagents possessing bidentate bipyridine ligands, termed Bi(N)-HVIs, could dearomatize electron-poor phenols for the first time. To understand the fundamental mechanistic basis of this unique reactivity, density functional theory (DFT) was utilized. In this way, different pathways were explored to determine why Bi(N)-HVIs are capable of facilitating these challenging transformations while more traditional hypervalent species, such as 2-iodoxybenzoic acid (IBX), cannot. Our calculations reveal that the first redox process is the rate-determining step, the barrier of which hinges on the identity of the ligands bound to the iodine(V) center. This crucial process is composed of three steps: (a) ligand exchange, (b) hypervalent twist, and (c) reductive elimination. We found that strong coordinating ligands disfavor these elementary steps, and, for this reason, HVIs bearing such ligands cannot oxidize the electron-poor phenols. In contrast, the weakly coordinating triflate ligands in Bi(N)-HVIs allow for the kinetically favorable oxidation. It was identified that trapping in situ-generated triflic acid is a key role played by the bidentate bipyridine ligands in Bi(N)-HVIs as this serves to minimize the decomposition of the ortho-quinone product.

Tris(pentafluorophenyl)borane-Catalyzed Carbenium Ion Generation and Autocatalytic Pyrazole Synthesis-A Computational and Experimental Study.

In recent years, metal-free organic synthesis using triarylboranes as catalysts has become a prevalent research area. Herein we report a comprehensive computational and experimental study for the highly selective synthesis of N-substituted pyrazoles through the generation of carbenium species from the reaction between aryl esters and vinyl diazoacetates in the presence of catalytic tris(pentafluorophenyl)borane [B(C6 F5 )3 ]. DFT studies were undertaken to illuminate the reaction mechanism revealing that the in situ generation of a carbenium species acts as an autocatalyst to prompt the regiospecific formation of N-substituted pyrazoles in good to excellent yields (up to 81 %).

DFT-Based Comparison between Mechanistic Aspects of Amine and Alcohol Oxidation Mediated by IBX.

Density functional theory was utilized to investigate plausible mechanisms for amine and alcohol oxidation by an iodine(V) hypervalent reagent (IBX). In this contribution, we found that amine and alcohol oxidation both proceed by similar mechanisms. The reactions initiate from ligand exchange to give four coordinate intermediates followed by a redox process giving an iodine(III) species and oxidized substrates. Interestingly, for both the ligand-exchange and the redox steps a hypervalent twist is required for the reaction to proceed via an energetically more accessible route. The ligand-exchange process was found to be mediated by a proton-shuttling agent such as water, a second IBX, or a second substrate. While the ligand-exchange step for both amine and alcohol occurs with almost identical activation energy (particularly when water is considered as the shuttling agent), the redox step for the amine takes place with much lower activation energy than that for the alcohol. Finally, we ascertained that five coordinate amide iodine(V) complexes are unreactive toward redox reactions due to the fact that in such cases two electrons from the coordinated amide are required to occupy a 3c-4e σ* orbital which is too high in energy to be reachable.

Gold-Catalyzed Regiospecific Annulation of Unsymmetrically Substituted 1,5-Diynes for the Precise Synthesis of Bispentalenes.

Precise control of the selectivity in organic synthesis is important to access the desired molecules. We demonstrate a regiospecific annulation of unsymmetrically substituted 1,2-di(arylethynyl)benzene derivatives for a geometry-controlled synthesis of linear bispentalenes, which is one of the promising structures for material science. A gold-catalyzed annulation of unsymmetrically substituted 1,2-di(arylethynyl)benzene could produce two isomeric pentalenes, but both electronic and steric effects on the aromatics at the terminal position of the alkyne prove to be crucial for the selectivity; especially a regiospecific annulation was achieved with sterically blocked substituents; namely, 2,4,6-trimetyl benzene or 2,4-dimethyl benzene. This approach enables the geometrically controlled synthesis of linear bispentalenes from 1,2,4,5-tetraethynylbenzene or 2,3,6,7-tetraethynylnaphthalene. Moreover, the annulation of a series of tetraynes with a different substitution pattern regioselectively provided the bispentalene scaffolds. A computational study revealed that this is the result of a kinetic control induced by the bulky NHC ligands.

Dual Gold-Catalyzed Cycloaromatization of Unconjugated (E)-Enediynes.

A synthesis of unconjugated (E)-enediynes from allenyl amino alcohols is reported and their gold-catalyzed cascade cycloaromatization to a broad range of enantioenriched substituted isoindolinones has been developed. Experimental and computational studies support the reaction proceeding via a dual-gold σ,π-activation mode, involving a key gold-vinylidene- and allenyl-gold-containing intermediate.

A Computational Mechanistic Investigation into Reduction of Gold(III) Complexes by Amino Acid Glycine: A New Variant for Amine Oxidation.

Density functional theory (DFT) was utilized to explore the reduction of gold(III) complexes by the amino acid glycine (Gly). Interestingly, when the nitrogen atom of Gly coordinates to the gold(III) center, its Cα -hydrogen atom becomes so acidic that it can be easily deprotonated by a mild base like water. The deprotonation converts the amino acid into a potent reductant by which gold(III) is reduced to gold(I) with a moderate activation energy. To our knowledge, this is the first contribution suggesting that primary amines are oxidized to imines via direct α-carbon deprotonation. This finding may provide new insights into the mechanistic interpretation of amine oxidations catalyzed/mediated by a center with high cathodic reduction potential. This work also provides a rationalization behind why gold(III) complexes with amine-based polydentate ligands are reluctant to undergo a redox process. Gold(III) reduction occurs most efficiently if the Cα proton leaves in the plane of the Cα , N and Au atoms. Chelation prevents this alignment, resulting in the gold(III) complex being unreactive toward reduction. It has been experimentally found that gold(III) is capable of oxidizing Gly to glyoxylic acid (GA) as the initial product. The latter, in the presence of another gold(III) complex, has been reported to undergo oxidative decarboxylation to afford CO2 and HCOOH. This process is found to be mediated by formation of a geminal diol intermediate produced by reaction of water with the aldehyde functional group of the coordinated GA.

Nazarov cyclisations initiated by DDQ-oxidised pentadienyl ether: a mechanistic investigation from the DFT perspective.

The Nazarov cyclisation is an important and reliable reaction for the synthesis of cyclopentenones. Density functional theory (DFT) has been utilised to study the mechanism of Nazarov cyclisations initiated by oxidation of pentadienyl ethers by a benzoquinone derivative (DDQ), as recently reported by West et al. (Angew. Chem., Int. Ed., 2017, 56, 6335). We determined that the reaction is most likely initiated by a hydride transfer from the pentadienyl ether to an oxygen of DDQ through a concerted pathway and not a single electron transfer mechanism. This oxidation by hydride abstraction leads to the formation of a pentadienyl cation from which the 4π electrocyclisation occurs, giving an alkoxycyclopentenyl cation. The ensuing cation is subsequently deprotonated by the reduced DDQ to afford an enol ether product. Consistent with experimental results, the hydride transfer is calculated to be the rate determining step and it can be accelerated by using electron donating substituents on the pentadienyl ether substrate. Indeed, the electron donating substituents increase the HOMO energy of the ether, making it more reactive toward oxidation. It is predicted that an unsubstituted benzoquinone, due to having a higher lying LUMO, shows much less reactivity than DDQ. Interestingly, we found an excellent correlation between the hydride transfer activation energy and the gap between the ether HOMO and the benzoquinone LUMO. From this correlation, we propose a predictive formula for reactivity of different types of substrates in the corresponding reaction.

A Mechanistic Investigation of the Gold(III)-Catalyzed Hydrofurylation of C-C Multiple Bonds.

The gold-catalyzed direct functionalization of aromatic C-H bonds has attracted interest for constructing organic compounds which have application in pharmaceuticals, agrochemicals, and other important fields. In the literature, two major mechanisms have been proposed for these catalytic reactions: inner-sphere syn-addition and outer-sphere anti-addition (Friedel-Crafts-type mechanism). In this article, the AuCl3-catalyzed hydrofurylation of allenyl ketone, vinyl ketone, ketone, and alcohol substrates is investigated with the aid of density functional theory calculations, and it is found that the corresponding functionalizations are best rationalized in terms of a novel mechanism called "concerted electrophilic ipso-substitution" (CEIS) in which the gold(III)-furyl σ-bond produced by furan auration acts as a nucleophile and attacks the protonated substrate via an outer-sphere mechanism. This unprecedented mechanism needs to be considered as an alternative plausible pathway for gold(III)-catalyzed arene functionalization reactions in future studies.

Sulfur dioxide activation: a theoretical investigation into dual S═O bond cleavage by three-coordinate molybdenum(III) complexes.

Cummins et al. have observed that 3 equiv of Mo(N[R]Ar)3 (R = C(CD3)2CH3, Ar = 3,5-C6H3Me2) are required for dual S═O bond cleavage within a SO2 molecule. Using density functional theory calculations, this theoretical study investigates a mechanism for this SO2 cleavage reaction that is mediated by MoL3, where L = NH2 or N[(t)Bu]Ph. Our results indicate that an electron transfers into the SO2 ligand, which leads to Mo oxidation and initiates SO2 coordination along the quartet surface. The antiferromagnetic (AF) nature of the (NH2)3Mo-SO2 adduct accelerates intersystem crossing onto the doublet surface. The first S═O bond cleavage occurs from the resulting doublet adduct and leads to formation of L3Mo═O and SO. Afterward, the released SO molecule is cleaved by the two remaining MoL3, resulting in formation of L3Mo═S and an additional L3Mo═O. This mononuclear mechanism is calculated to be strongly exothermic and proceeds via a small activation barrier, which is in accordance with experimental results. An additional investigation into a binuclear process for this SO2 cleavage reaction was also evaluated. Our results show that the binuclear mechanism is less favorable than that of the mononuclear mechanism.

Formation of ethane from mono-methyl palladium(II) complexes.

This article describes the high-yielding and selective oxidatively induced formation of ethane from mono-methyl palladium complexes. Mechanistic details of this reaction have been explored via both experiment and computation. On the basis of these studies, a mechanism involving methyl group transmetalation between Pd(II) and Pd(IV) interediates is proposed.

Decarboxylative-coupling of allyl acetate catalyzed by group 10 organometallics, [(phen)M(CH3)]+.

Gas-phase carbon-carbon bond forming reactions, catalyzed by group 10 metal acetate cations [(phen)M(O2CCH3)](+) (where M = Ni, Pd or Pt) formed via electrospray ionization of metal acetate complexes [(phen)M(O2CCH3)2], were examined using an ion trap mass spectrometer and density functional theory (DFT) calculations. In step 1 of the catalytic cycle, collision induced dissociation (CID) of [(phen)M(O2CCH3)](+) yields the organometallic complex, [(phen)M(CH3)](+), via decarboxylation. [(phen)M(CH3)](+) reacts with allyl acetate via three competing reactions, with reactivity orders (% reaction efficiencies) established via kinetic modeling. In step 2a, allylic alkylation occurs to give 1-butene and reform metal acetate, [(phen)M(O2CCH3)](+), with Ni (36%) > Pd (28%) > Pt (2%). Adduct formation, [(phen)M(C6H11O2)](+), occurs with Pt (24%) > Pd (21%) > Ni(11%). The major losses upon CID on the adduct, [(phen)M(C6H11O2)](+), are 1-butene for M = Ni and Pd and methane for Pt. Loss of methane only occurs for Pt (10%) to give [(phen)Pt(C5H7O2)](+). The sequences of steps 1 and 2a close a catalytic cycle for decarboxylative carbon-carbon bond coupling. DFT calculations suggest that carbon-carbon bond formation occurs via alkene insertion as the initial step for all three metals, without involving higher oxidation states for the metal centers.

Theoretical investigation into the mechanism of 3'-dGMP oxidation by [Pt(IV)Cl4(dach)].

The mechanism for the oxidation of 3'-dGMP by [PtCl(4)(dach)] (dach = diaminocyclohexane) in the presence of [PtCl(2)(dach)] has been investigated using density functional theory. We find that the initial complexation, i.e., the formation of [PtCl(3)(dach)(3'-dGMP)], is greatly assisted by the reaction of the encounter pair [PtCl(2)(dach)···3'-dGMP] with [PtCl(4)(dach)], leading to migration of an axial chlorine ligand from platinum(IV) to platinum(II). A dinuclear platinum(II)/platinum(IV) intermediate could not be found, but the reaction is predicted to pass through a platinum(III)/platinum(III) transition structure. A cyclization process, i.e., C8-O bond formation, from [PtCl(3)(dach)(3'-dGMP)] occurs through an intriguing phosphate-water-assisted deprotonation reaction, analogous to the opposite of a proton shuttle mechanism. Followed by this, the guanine moiety is oxidized via dissociation of the Pt(IV)-Cl(ax) bond, and the cyclic ether product is finally formed after deprotonation. We have provided rationalizations, including molecular orbital explanations, for the key steps in the process. Our results help to explain the effect of [PtCl(4)(dach)] on the complexation step and the effect of a strong hydroxide base on the cyclization reaction. The overall reaction cycle is intricate and involves autocatalysis by a platinum(II) species.

Mechanistic investigation of the oxidation of hydrazides: implications for the activation of the TB drug isoniazid.

Aryl hydrazides are oxidised to acyl radicals through a mechanism involving diimide intermediates that are prone to nucleophilic acyl substitution. This oxidation occurs regardless of the oxidant involved, however there is no evidence that the acyl radical formed undergoes further oxidation to the corresponding acylium ion, even in the presence of strong oxidants. This study may provide insight into the mechanism of isoniazid resistance in Mycobacterium tuberculosis.

Chemical kinetics of a bipalladium complex.

A theoretical model is presented, for reductive elimination in a bipalladium complex, based on the model of Ariafard et al. (2011). This reaction is of particular interest due to the novel Pd(III) intermediate. A thermo-kinetic model is proposed for this reaction scheme, and the rate laws and energy balance are given as a system of ordinary differential equations. A simplified model is then derived that only involves two key variables, so that the system can be analyzed completely in a phase plane. It is shown that kinetic oscillations do not occur, but that there are multiple steady states for the reaction. These new features are confirmed by a numerical analysis of the full model scheme. The predictions provide a mechanism to test the model and the underlying computational chemistry.

Theoretical investigation into the mechanism of Au(I)-catalyzed reaction of alcohols with 1,5 enynes.

Density functional theory has been used to investigate the reactions of 1,5 enynes with alcohols in the presence of a gold catalyst. We have compared the mechanism of the alcohol addition reaction for the enyne with that of the enyne where the carbon at position 3 is replaced with silicon. We find that different intermediates are present in both cases, and in the case of the silicon analogue, the intermediate that we find from the calculations is different from any that have previously been proposed in the literature. For the silicon analogue we have been able to rationalize the observed effects of alcohol concentration and nucleophilicity on the product distribution. For the carbon-based enyne we have shown why different products are observed depending on the substitution at position 3 of the enyne. Overall, we have provided for the first time a consistent explanation and rationalization of several different experiments that have been previously published in the literature. Our mechanism will assist in predicting the outcome of experimental reactions involving different alcohols, reagent concentrations, and substitution patterns of the 1,5 enynes.

Connecting binuclear Pd(III) and mononuclear Pd(IV) chemistry by Pd-Pd bond cleavage.

Oxidation of binuclear Pd(II) complexes with PhICl(2) or PhI(OAc)(2) has previously been shown to afford binuclear Pd(III) complexes featuring a Pd-Pd bond. In contrast, oxidation of binuclear Pd(II) complexes with electrophilic trifluoromethylating ("CF(3)(+)") reagents has been reported to afford mononuclear Pd(IV) complexes. Herein, we report experimental and computational studies of the oxidation of a binuclear Pd(II) complex with "CF(3)(+)" reagents. These studies suggest that a mononuclear Pd(IV) complex is generated by an oxidation-fragmentation sequence proceeding via fragmentation of an initially formed, formally binuclear Pd(III), intermediate. The observation that binuclear Pd(III) and mononuclear Pd(IV) complexes are accessible in the same reactions offers an opportunity for understanding the role of nuclearity in both oxidation and subsequent C-X bond-forming reactions.

Density functional theory studies on the oxidation of 5'-dGMP and 5'-dAMP by a platinum(IV) complex.

Density functional theory has been used to investigate the oxidation of a guanine nucleotide by platinum(IV), a process that can be important in the degradation of DNA. For the first time, we have provided a comprehensive mechanism for all of the steps in this process. A number of intermediates are predicted to occur but with short lifetimes that would make them difficult to observe experimentally. A key step in the mechanism is electron transfer from guanine to platinum(IV), and we show that this is driven by the loss of a chloride ligand from the platinum complex after nucleophilic attack of 5'-phosphate to C8 of guanine. We have investigated several different initial platinum(IV) guanine adducts and shown that the adduct formed from replacement of an axial chlorine ligand in the platinum(IV) complex undergoes oxidation more easily. We have studied adenine versus guanine adducts, and our results show that oxidation of the former is more difficult because of disruption of the aromatic π system that occurs during the process. Finally, our results show that the acidic hydrolysis step to form the final oxidized product occurs readily via an initial protonation of N7 of the guanine.