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.

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.

The effect of solvation in torquoselectivity: ring opening of monosubstituted cyclobutenes.

The paradigmatic electrocyclic ring opening of monosubstituted cyclobutenes has been used to diagnose possible solvation effects tuning the torquoselectivity observed in these reactions. This kind of selectivity in electrocyclic reactions is mostly due to strong orbital interactions, particularly when they involve powerful electron donors and acceptors, which also combine with usually milder steric effects. Orbital interactions are established between the cleaving C-C bond and the HOMO/LUMO of the EDG/EWG substituent. This implies that the larger torquoselectivity-featuring substrates may also suffer stronger solvation effects due to the higher polarity imposed by the substituent. This premise is tested and the source of solvation effects as a consequence of substitution analyzed.

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.

Gold-Catalyzed Homogeneous (Cyclo)Isomerization Reactions.

Gold is currently one of the most used metals in organometallic catalysis. The ability of gold to activate unsaturated groups in different modes, together with its tolerance to a wide range of functional groups and reaction conditions, turns gold-based complexes into efficient and highly sought after catalysts. Natural products and relevant compounds with biological and pharmaceutical activity are often characterized by complex molecular structures. (Cyclo)isomerization reactions are often a useful strategy for the generation of this molecular complexity from synthetically accessible reactants. In this review, we collect the most recent contributions in which gold(I)- and/or gold(III)-catalysts mediate intramolecular (cyclo)isomerization transformations of unsaturated species, which commonly feature allene or alkyne motifs, and organize them depending on the substrate and the reaction type.

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 Synthesis of 1-(Indol-3-yl)carbazoles: Selective 1,2-Alkyl vs 1,2-Vinyl Migration.

Gold(III)-catalyzed cycloisomerization of α-bis(indol-3-yl)methyl alkynols selectively affords 1-(indol-3-yl)carbazoles, in a transformation that takes place through a selective 1,2-alkyl vs 1,2-vinyl migration step in the vinyl-gold intermediate generated from the initial 5-endo-spirocyclization. The reaction proceeds well with either tertiary or secondary starting alkynols as well as with a wide variety of alkyne substituents. The key role of the other indol-3-yl substituent for the unexpected selectivity in the 1,2 rearrangement has also been supported by DFT calculations that reveal a low barrier, two-step mechanism in the alkyl migration path where the second indole significantly stabilizes a carbocationic intermediate.

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.

Assessing the attractive/repulsive force balance in axial cyclohexane C-Hax ···Yax contacts: A combined computational analysis in monosubstituted cyclohexanes.

The interactions of axial substituents in monosubstituted cyclohexane rings are studied in this work using an array of different computational techniques. Additionally, the anomalous axial preference for some bulky substituents is related to stabilizing dispersion interactions. We find that the C-Hax ···Yax contacts for various substituents with distances ranging from 2 to ∼5 Å may include attractive dispersion forces that can affect the conformational equilibrium; these forces co-exist with Pauli repulsive forces effected by Yax group due to van der Waals sphere penetration. At distances between 2 and 3 Å stabilizing electron transfer interactions were calculated and the combination of natural bond orbital and QTAIM analysis showed that, in certain cases, Yax = t Bu, Cax -O or Cax = O or Sax = O or Cax = S this interaction can be characterized as an improper H-bond. DFT-D3 and non-covalent interactions calculations (NCIs) in cyclohexane derivatives with Yax = SiOR3 including HYax ···Hcy surfaces at distances ranging between 4 and 6 Å suggest that dispersion has a clear effect on the experimentally observed stabilization of the axial conformer. NCIs computed from the reduced density gradient help to visually identify and analyze these interactions. © 2016 Wiley Periodicals, Inc.

Exploring the Reactivity of α-Lithiated Aryl Benzyl Ethers: Inhibition of the [1,2]-Wittig Rearrangement and the Mechanistic Proposal Revisited.

By carefully controlling the reaction temperature, treatment of aryl benzyl ethers with tBuLi selectively leads to α-lithiation, generating stable organolithiums that can be directly trapped with a variety of selected electrophiles, before they can undergo the expected [1,2]-Wittig rearrangement. This rearrangement has been deeply studied, both experimentally and computationally, with aryl α-lithiated benzyl ethers bearing different substituents at the aryl ring. The obtained results support the competence of a concerted anionic intramolecular addition/elimination sequence and a radical dissociation/recombination sequence for explaining the tendency of migration for aryl groups. The more favored rearrangements are found for substrates with electron-poor aryl groups that favor the anionic pathway.

Normal-to-Abnormal NHC Rearrangement of Al(III) , Ga(III) , and In(III) Trialkyl Complexes: Scope, Mechanism, Reactivity Studies, and H2 Activation.

The present contribution reports experimental and theoretical mechanistic investigations on a normal-to-abnormal (C2-to-C4-bonded) NHC rearrangement processes occurring with bulky group 13 metal NHC adducts, including the scope of such a reactivity for Al compounds. The sterically congested adducts (nItBu)MMe3 (nItBu=1,3-di-tert-butylimidazol-2-ylidene; M=Al, Ga, In; 1 a-c) readily rearrange to quantitatively afford the corresponding C4-bonded complexes (aItBu)MMe3 (4 a-c), a reaction that may be promoted by THF. Thorough experimental data and DFT calculations were performed on the nNHC-to-aNHC process converting the Al-nNHC (1 a) to its aNHC analogue 4 a. A nItBu/aItBu isomerization is proposed to account for the formation of the thermodynamic product 4 a through reaction of transient aItBu with THF-AlMe3 . The reaction of benzophenone with (nItBu)AlMe3 afforded the zwitterionic species (aItBu)(CPh2 -O-AlMe3 ) (6), reflecting the unusual reactivity that such bulky adducts may display. Interestingly, the nItBu/Al(iBu)3 Lewis pair behaves like a frustrated Lewis pair (FLP) since it readily reacts with H2 under mild conditions. This may open the way to future reactivity developments involving commonly used trialkylaluminum precursors.

Brønsted Acid-Catalyzed Cascade Reactions Involving 1,2-Indole Migration.

A cascade reaction of indoles with propargylic diols involving an unprecedented metal-free 1,2-indole migration onto an alkyne was carried out. DFT calculations support a mechanism consisting of a concerted nucleophilic attack of the indole nucleus with loss of water, followed by the 1,2-migration and subsequent Nazarov cyclization. This Brønsted acid-catalyzed protocol affords indole-functionalized benzofulvene derivatives in high yields.

Noyori hydrogenation: aromaticity, synchronicity, and activation strain analysis.

By means of density functional theory calculations, we have computationally explored the intimacies of the crucial step of Noyori hydrogrogenation reactions of multiple bonds. This process can be considered analogous to the so-called double group transfer reactions. Both kinds of transformations proceed concertedly via the simultaneous migration of two hydrogen atoms/groups in a pericyclic [σ2s + σ2s + π2s] reaction through six-membered transition structures. Despite the structural resemblances of both types of saddle points, significant differences are found in terms of synchronicity and in-plane aromaticity. In addition, the activation strain model has been used to get quantitative insight into the factors which control the corresponding barrier heights. It is found that the presence of a heteroatom in the acceptor moiety is responsible for a remarkable increase of the interaction energy between the reactants which can compensate the destabilizing effect of the strain energy associated with the deformation of the initial reagents leading to low reaction barriers.

Computational study of gold-catalyzed homo- and cross-coupling reactions.

The role of gold as the organizing metal in homo- and cross-coupling reactions is explored in this paper combining DFT calculations with QTAIM, NBO, and the energetic span model analysis. For the gold(III) complex 7, a key intermediate in the experimental oxidative coupling scheme by Zhang et al., we describe the mechanisms corresponding to a cross-coupling after transmetalation with boron compounds and to a homocoupling after transmetalation with the original gold(I) complex 6, a new example of dual role of this metal in homogeneous catalysis. We predict for the first path a two-step transmetalation with a low energy rate-limiting step characterized by a four-center transition structure, where fluorine plays an essential role, followed by a reductive elimination where the C-C bond formation is coupled to the departure of fluorine from the gold center. The homocoupling path follows a similar mechanism, with a two-step transmetalation with interesting changes in bonding around the Au(I) center and a rate-limiting reductive elimination. Our findings on the competition between mechanisms, and the effect of ligands and solvent, agree with the experimental results and provide new insights into the mechanism of gold-catalyzed cross-coupling reactions.

Mechanistic and sterochemical insights on the Pt-catalyzed rearrangement of oxiranylpropargylic esters to cyclopentenones.

A mechanism for the rearrangement of oxiranylpropargylic esters to cyclopentenones catalyzed by PtCl(2) is proposed based on DFT calculations (M06/6-31++G(d,p)). Although the basic steps are coincidental with those proposed by Sarpong et al., who characterized a 2H-pyran as intermediate, calculations have revealed other intricate details of this complex rearrangement. The 2H-pyran is proposed to result from the ring-opening of a bicyclic oxonium ion that follows the nucleophilic capture by the epoxide of a platinum carbene generated by an initial Pt-mediated 1,2-propargylic rearrangement. The key steps in the evolution of this system are the electrocyclic ring-opening of the 2H-pyran to a α-methoxycarbonyl dienone and an iso-Nazarov ring closure. Prior to those, changes in hapticity and in the conformation of the dienone are required in order to produce the helical conformation needed to generate a single diastereomer of the cyclopentenone product obtained experimentally. The metal is needed well beyond the first step of the mechanism, and both electrocyclic reactions are favored by coordination to the metal when compared to their uncomplexed counterparts. Moreover, we have experimentally demonstrated that the rearrangement is stereoconvergent, a feature that is traced back to the initial configuration of the epoxide, which determines the somewhat counterthermodynamic placement of the metal syn to the methyl group of the stereogenic center in the 2H-pyran intermediate. Finally, starting from enantiopure oxiranylpropargylic ester 13, a racemate of cyclopentenone (R*,S*)-16 was obtained. Thus, the sequence does not proceed with memory of chirality, and the absolute stereochemical information is already lost at the stage of the 2H-pyran 14.

On the memory of chirality in gold(I)-catalyzed intramolecular carboalkoxylation of alkynes.

A computational study of the mechanism of the intramolecular carboalkoxylation of alkynes reported by Toste et al. allows the characterization of the chirality transfer process that makes this reaction enantioselective. Memory of chirality is preserved up until the stereocenter-generating iso-Nazarov cyclization through the synergy between the helicity of a pentadienyl cation intermediate and the control in the conformation of the allyl group, both elements defined upon alkoxy migration. The high barriers to conformational scrambling relative to those corresponding to chemical steps ensure the robustness of the chirality transfer mechanism and result in an unusual importance of conformational changes in reactivity that seems to be common in gold-catalyzed transformations.

Synthesis of diverse indole-containing scaffolds by gold(I)-catalyzed tandem reactions of 3-propargylindoles initiated by 1,2-indole migrations: scope and computational studies.

Similar to propargylic carboxylates and sulphides, 3-propargylindoles undergo 1,2-indole migrations under cationic gold(I) catalysis. The intermediate Au-carbenoid complex may evolve through different pathways depending on the substituents at the propargylic and terminal positions of the alkyne moiety. Thus, 3-indenylindole derivatives were easily obtained through formal iso-Nazarov or Nazarov cyclizations. DFT computations support the formation of an alkylidenecyclopropane intermediate that undergoes gold-iso-Nazarov or gold-Nazarov cyclizations upon torquoselective ring opening. In addition, 3-dienylindoles could be accessed when none of the referred pathways were accessible and so the intermediate Au-carbenoid complex evolved via a 1,2-C-H insertion reaction. We have also demonstrated that the final products can be obtained in a one-pot protocol from easily available propargylic alcohols and indoles.

Mechanism of the gold-catalyzed rearrangement of (3-acyloxyprop-1-ynyl)oxiranes: a dual role of the catalyst.

The three competing paths for the rearrangement of 1 (involving 1,2- and 1,3-ester migration with alkyne or oxirane activation) evidence the multifaceted character of gold as a catalyst. The most favorable mechanism for this useful synthetic transformation involves a cascade of more than eight steps. All the functional groups in the substrate play a crucial and synergistic role, and sequential gold coordination to both the pi-system and the lone pairs of oxygen is needed. Exploration of these three paths suggests the use of a nonalkynophilic Lewis acid (BF(3)) as a possible synthetic alternative for this transformation.