Nickel Catalyzed Carbonylation/Carboxylation Sequence via Double CO2 Incorporation.

A carbonylation-carboxylation synthetic sequence, via double CO2 fixation, is described. The productive merger of a Ni-catalyzed cross-electrophile coupling manifold, with the use of AlCl3, triggered a cascade reaction with the formation of three consecutive C-C bonds in a single operation. This strategy traces an unprecedented synthetic route to ketones under Lewis acid assisted carbon dioxide valorization. Computational insights revealed a unique double function of AlCl3, and labeling (13CO2) experiments validate the genuine incorporation of CO2 in both functional groups.

PIDA-mediated Oxidative Decarboxylation of Oxamic Acids. The Role of Radical Acidity Enhancement.

The PIDA-mediated oxidative decarboxylation of oxamic acids in the presence of alcohols is shown to afford the corresponding urethanes under thermal conditions. Computational and experimental mechanistic exploration allows to rationalize the different reactivity of PIDA as compared to related cyclic BI-OAc and highlights the importance of the enhanced acidity of the proton in the carbamoyl radical intermediate.

On the mechanism of the dyotropic expansion of hydrindanes into decalins.

A combined computational/experimental approach has revealed key mechanistic aspects in a recently reported dyotropic expansion of hydrindanes into decalins. While computer simulations had already anticipated the need for acid catalysis for making this reaction feasible under the mild conditions used in the laboratory, this work places the dyotropic step not into the reaction flask but at a later step, during the work up instead. With this information in hand the reaction has been optimized by exploring the performance of different activating agents and shown to be versatile, particularly in steroid related chemistry due to the two scaffolds that this reaction connects. Finally, the scope of the reaction has been significantly broadened by showing that this protocol can also operate in the absence of the fused six-member ring.

Accessible triplet excited states in the photoisomerization of allenes with extended conjugation.

A series of bidentate allene- and enyne-containing ligands have been synthesized and the photochemical properties of their rhenium(I) complexes have been studied. These complexes exhibit facile isomerization of the conjugated double bonds upon ambient light exposure. Simulations unveiled a very efficient intersystem crossing and the consequent key role of the triplet states in the observed photochemistry of these substrates upon rhenium(I) complexation.

Enantioselective CO2 Fixation Via a Heck-Coupling/Carboxylation Cascade Catalyzed by Nickel.

A novel asymmetric nickel-based procedure has been developed in which CO2 fixation is achieved as a second step of a truncated Heck coupling. For this, a new chiral ligand has been prepared and shown to achieve enantiomeric excesses up to 99 %. The overall process efficiently furnishes chiral 2,3-dihydrobenzofuran-3-ylacetic acids, an important class of bioactive products, from easy to prepare starting materials. A combined experimental and computational effort revealed the key steps of the catalytic cycle and suggested the unexpected participation of Ni(I) species in the coupling event.

Experimental and Computational Study of the 1,5-O → N Carbamoyl Snieckus-Fries-Type Rearrangement.

The reactions of o-lithiated O-aryl N,N-diethylcarbamates with different C-N multiple bond electrophiles have been thoroughly studied. A 1,5-O → N carbamoyl shift, a new variation of the anionic Fries-type rearrangement, takes place when nitriles, imines, or alkylcarbodiimides are employed. In these cases, the carbamoyl group plays a dual role as a directing group, building up a variety of functional groups through the 1,5-O → N carbamoyl migration. On the other hand, the use of iso(thio)cyanates and arylcarbodiimides led to non-rearranged o-functionalized O-arylcarbamates. This reactivity was further computationally explored, and the governing factor could be traced back to the relative basicity of the alternative products (migrated vs nonmigrated substrates). This exploration also provided interesting insights about the degree of complexation of the lithium cations onto these substrates. A new access to useful 2-hydroxybenzophenone derivatives has also been developed.

Site-selective synthesis of 1,3-dioxin-3-ones via a gold(i) catalyzed cascade reaction.

A novel gold(i)-catalyzed protocol for the synthesis of 4H-1,3-dioxin-3-ones is presented. The protocol exploits a metal induced cascade sequence involving a [3,3]-sigmatropic rearrangement followed by regioselective O-annulation reactions. A wide range of oxygen-based heterocyclic scaffolds (21 examples) were achieved in excellent yield (up to 80%) and a detailed computational investigation as well as deuterium-labelling investigations enabled all the plausible reaction pathways to be mapped and the rationalization of the recorded regioselectivity.

Gold(i)-catalyzed nucleophilic cyclization of ß-monosubstituted o-(alkynyl)styrenes: a combined experimental and computational study.

The stereospecific gold(i)-catalyzed nucleophilic cyclization of ß-monosubstituted o-(alkynyl)styrenes to produce C-1 functionalized 1H-indenes including challenging substrates and nucleophiles, such as ß-(cyclo)alkyl-substituted o-(alkynyl)styrenes and a variety of alcohols as well as selected electron-rich aromatics, is reported. DFT calculations support the stereochemical outcome of the process that involves the formation of a key cyclopropyl gold carbene intermediate through a regiospecific 5-endo cyclization.

On the Use of Popular Basis Sets: Impact of the Intramolecular Basis Set Superposition Error.

The magnitude of intramolecular basis set superposition error (BSSE) is revealed via computing systematic trends in molecular properties. This type of error is largely neglected in the study of the chemical properties of small molecules and it has historically been analyzed just in the study of large molecules and processes dominated by non-covalent interactions (typically dimerization or molecular complexation and recognition events). In this work we try to provide proof of the broader prevalence of this error, which permeates all types of electronic structure calculations, particularly when employing insufficiently large basis sets.

Phosphine-Catalyzed Stereoselective Dearomatization of 3-NO2-Indoles with Allenoates.

The stereoselective phosphine-catalyzed (( pMeOC6H4)3P, 10-20 mol %) dearomatization of 3-NO2-indoles with allenoates is described. A range of densely functionalized indolines (18 examples) is obtained in high yields (up to 96%) under mild reaction conditions (rt, air, reagent-grade solvent). Computational simulations and labeling experiments revealed a stepwise [3 + 2]-type mechanism involving a water-assisted hydrogen shift and accounted for the diastereoselection recorded.

Pushing the limits of concertedness. A waltz of wandering carbocations.

Among the array of complex terpene-forming carbocation cyclization/rearrangement reactions, the so-called "triple shift" reactions are among the most unexpected. Such reactions involve the asynchronous combination of three 1,n-shifts into a concerted process, e.g., a 1,2-alkyl shift followed by a 1,3-hydride shift followed by a second 1,2-alkyl shift. This type of reaction so far has been proposed to occur during the biosynthesis of diterpenes and the sidechains of sterols. Here we describe efforts to push the limits of concertedness in this type of carbocation reaction by designing, and characterizing with quantum chemical computations, systems that could couple additional 1,n-shift events to a triple shift leading, in principle to quadruple, pentuple, etc. shifts. While our designs did not lead to clear-cut examples of quadruple, etc. shifts, they did lead to reactions with surprisingly flat energy surfaces where more than five chemical events connect reactants and plausible products. Ab initio molecular dynamics simulations demonstrate that the formal minima on these surfaces interchange on short timescales, both with each other and with additional unexpected structures, allowing us a glimpse into a very complex manifold that allows ready access to great structural diversity.

Nitrogen doped nanohoops as promising CO2 capturing devices.

The impact of climate change in the face of steady or increasing emissions has made the capture and storage of CO2 a priority issue. Supramolecular chemistry is one of the tools that can be used for this task, due to the possibility of tuning intermolecular interactions for the capture of this gas in a selective and efficient way. In this context, this work presents a novel approach for the capture of CO2 based on n-cycloparaphenylenes ([n]-CPPs) doped with nitrogen atoms. This is the first time that the potential of these structures for the capture of polluting gases has been evaluated. Among all the structures analysed, the one yielding the best results (complexation energy of -32.80 kJ mol-1) contains 4 nitrogen atoms per monomer. The topology of the electron density of the host-guest complex and the nature of its non-covalent interactions have been analyzed in this work in order to explain this high binding energy and identify potential structural modifications to improve it. The capability of this system to be used as a sensing device for CO2 using vibrational spectroscopy is also explored.

Gold-Catalyzed Dearomatization of 2-Naphthols with Alkynes.

The site-selective dearomatization of naphthols is realized in a straightforward manner through a gold(I)-catalyzed [3,3]-sigmatropic rearrangement/allene functionalization cascade sequence. The method employs readily available naphthylpropargyl ethers as starting materials. A range of densely functionalized dihydrofurylnaphthalen-2(1H)-ones are obtained in high yields (up to 98 %) and extremely mild reaction conditions (reagent grade solvent, air, 10 minute reaction time). A complete theoretical elucidation of the reaction machinery is also proposed, providing a rationale for important issues such as regio- and chemoselectivity.

Governing effects in the mechanism of the gold-catalyzed cycloisomerization of allenic hydroxylamine derivatives.

The formation of chiral heterocycles via cycloisomerization reactions of allene derivatives has gained relevance due to their associated efficiency and atom-economy. The only drawback that keeps these reactions away from being routine synthetic strategies is the control in the regioselectivity (most often 5-endo vs. 6-endo). In this work, we computationally explore the experimental chemistry reported by Krause using N-hydroxy-α-aminoallenes and hydroxylamine ethers as substrates and provide a rationale for the different reactivity observed. The drastic effects observed experimentally when changing the nature of the gold catalyst have also been studied mechanistically. These results are expected to help in the design of improved regioselective protocols for the formation of medium sized chiral heterocycles from allene substrates.

Cycloreversion of the CO2 trimer: a paradigmatic pseudopericyclic [2 + 2 + 2] cycloaddition reaction.

Very recently, the CO2 trimer has been experimentally synthesized, isolated and characterized. This process opens new ways for the withdrawal and storage of this greenhouse gas. The trimer is reported to be stable up to -40 °C, with a lifetime of about 40 min at this temperature. At these or under harsher thermal conditions it reverts to the three monomers. The mechanism of this reaction has been theoretically studied and the electronic character of the associated transition state has been analyzed from a variety of perspectives (energetic, magnetic, electron localization and delocalization functions) which indicate that it has paradigmatic pseudopericyclic character. To allow for a comparative study, the isoelectronic fragmentations of cyclohexane into three units of ethylene and of benzene into three units of acetylene have been included in this work. The study of a similar series of formally forbidden-four-centered [2 + 2] cycloreversions confirmed the pseudopericyclic nature of these reactions when the CO2 dimer or trimer is involved.

A Radical Mechanism for the Vanadium-Catalyzed Deoxydehydration of Glycols.

We propose a novel mechanism for the deoxydehydration (DODH) reaction of glycols catalyzed by a [Bu4N][VO2(dipic)] complex (dipic = pyridine-2,6-dicarboxylate) using triphenylphosphine as a reducing agent. Using density functional theory, we have confirmed that the preferred sequence of reaction steps involves reduction of the V(V) complex by phosphine, followed by condensation of the glycol into a [VO(dipic)(-O-CH2CH2-O-)] V(III) complex (6), which then evolves to the alkene product, with recovery of the catalyst. In contrast to the usually invoked closed-shell mechanism for the latter steps, where 6 suffers a [3+2] retrocycloaddition, we have found that the homolytic cleavage of one of the C-O bonds in 6 is preferred by 12 kcal/mol. The resulting diradical intermediate then collapses to a metallacycle that evolves to the product through an aromatic [2+2] retrocycloaddition. We use this key change in the mechanism to propose ways to design better catalysts for this transformation. The analysis of the mechanisms in both singlet and triplet potential energy surfaces, together with the location of the MECPs between them, showcases this reaction as an interesting example of two-state reactivity.

Rational Design in Catalysis: A Mechanistic Study of ß-Hydride Eliminations in Gold(I) and Gold(III) Complexes Based on Features of the Reaction Valley.

ß-Hydride eliminations for ethylgold(III) dichloride complexes are identified as reactions with an unusually long prechemical stage corresponding to the conformational preparation of the reaction complex and spanning six phases. The prechemical process is characterized by a geared rotation of the L-Au-L group (L = Cl) driving methyl group rotation and causing a repositioning of the ligands. This requires more than 28 kcal/mol of the total barrier of 34.0 kcal/mol, according to the unified reaction valley approach, which also determines that the energy requirements of the actual chemical process leading to the ß-elimination product are only about 5.5 kcal/mol. A detailed mechanistic analysis was used as a basis for a rational design of substrates (via substituents on the ethyl group) and/or ligands, which can significantly reduce the reaction barrier. This strategy takes advantage of either a higher trans activity of the ligands or a tuned electronic demand of the ethyl group. The ß-hydride elimination of gold(I) was found to suffer from strong Coulomb and exchange repulsion when a positively charged hydrogen atom enforces a coordination position in a d(10)-configured gold atom, thus triggering an unassisted σ-π Au(I)-C conversion.

Solving the Pericyclic-Pseudopericyclic Puzzle in the Ring-Closure Reactions of 1,2,4,6-Heptatetraene Derivatives.

The ongoing controversy whether cyclization reactions of conjugated allenes or ketenes follow a pericyclic or a pseudopericyclic mechanism has triggered dozens of investigations, which have led to new valuable synthetic routes. In this work, the mechanism of 10 representative cyclization reactions of hepta-1,2,4,6-tetraenes with different terminal groups is investigated utilizing the unified reaction valley approach that registers all electronic structure changes of the target molecule along the entire reaction pathway. A clear differentiation between a purely pericyclic and a purely pseudopericyclic mechanism is established. Additionally, it is found that, by using suitable functional groups, a pericyclic mechanism can be converted into a pseudopericyclic one, which is associated with a steady decrease of the reaction barrier and a continuous change from one mechanism to the other. The energetics of the reaction are confirmed by coupled cluster calculations of the CCSD(T) type. The mechanistic insight gained is used to design new pseudopericyclic reactions with low or no barrier, which will open new synthetic avenues.

Accounting for Diradical Character through DFT. The Case of Vinyl Allene Oxide Rearrangement.

The transformation of vinyl allene oxides into cyclopentenones is key to the biosynthesis of a number of hormone-like molecules in plants. Two competitive paths are generally accepted for this transformation: a concerted SN2-like mechanism and a stepwise path with a diradical oxyallyl intermediate. Recently, a new stepwise closed-shell path has been proposed that circumvents the key oxyallyl intermediate. In this work, we conduct a thorough computational investigation, including dynamic effects, to identify the most likely mechanism for this transformation.

Computational approaches to homogeneous gold catalysis.

Homogenous gold catalysis has been exploding for the last decade at an outstanding pace. The best described reactivity of Au(I) and Au(III) species is based on gold's properties as a soft Lewis acid, but new reactivity patterns have recently emerged which further expand the range of transformations achievable using gold catalysis, with examples of dual gold activation, hydrogenation reactions, or Au(I)/Au(III) catalytic cycles.In this scenario, to develop fully all these new possibilities, the use of computational tools to understand at an atomistic level of detail the complete role of gold as a catalyst is unavoidable. In this work we aim to provide a comprehensive review of the available benchmark works on methodological options to study homogenous gold catalysis in the hope that this effort can help guide the choice of method in future mechanistic studies involving gold complexes. This is relevant because a representative number of current mechanistic studies still use methods which have been reported as inappropriate and dangerously inaccurate for this chemistry.Together with this, we describe a number of recent mechanistic studies where computational chemistry has provided relevant insights into non-conventional reaction paths, unexpected selectivities or novel reactivity, which illustrate the complexity behind gold-mediated organic chemistry.