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

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.Junta de Castilla y León and FEDER (BU076U16) and Ministerio de Economía y Competitividad (MINECO) (CTQ2016-75023-C2-1-P and CTQ2016-75023- C2-2-P

On the mechanism of the Au(I)‐mediated addition of alkynes to anthranils to furnish 7‐acylindoles

Indole is a very common structural motif in alkaloids with a remarkable history in pharma industry. In the continuous search for more direct and efficient access to these valuable structures, a new and rather elegant approach was found by Jin and coworkers, which involved a gold(I)-mediated addition of alkynes onto anthralins. This approach selectively furnishes 7-acylindoles in a rather expeditious way, and it has been shown to be compatible with a large range of decorated reactants, both at the alkyne side and at the anthralin side. We studied the mechanism of this reaction with a set of different alkynes, including disubstituted ones, to establish similarities and differences between them and to aid in the elucidation of key steps in the reaction pathway. The observed regioselectivity seems to be connected to the irreversible formation of a key α-imino gold carbene intermediate, common to all reaction profiles, through the initial regioselective nucleophilic attack of the anthranil N atom onto the alkyne fragment.Xunta de Galicia | Ref. ED431C 2021/41Agencia Estatal de Investigación | Ref. PID2020‐115789GB‐C22Financiado para publicación en acceso aberto: Universidade de Vigo/CISU

Rational Design of Efficient Environmental Sensors: Ring-Shaped Nanostructures Can Capture Quat Herbicides

The viability of using [n]-cycloparaphenylenes (CPPs) of different sizes to encapsulate diquat (DQ) pesticide molecules has been tested analyzing the origin of the host–guest interactions stabilizing the complex. This analysis provides rational design capabilities to construct ad hoc capturing systems tailored to the desired pollutant. All CPPs considered (n = 7–12) are capable of forming remarkably stable complexes with DQ, though [9]-CPP is the best candidate, where a fine balance is established between the energy penalty due to the deformation + repulsion of the pesticide molecule inside the cavity (larger in smaller CPPs) and the maximization of the favorable dispersion, electrostatic and induction contributions (which also decrease in larger rings). These encouraging results prompted us to evaluate the potential of using Resonance Raman spectroscopy on nanohoop complexes as a tool for DQ sensing. The shifts observed in the vibrational frequencies of DQ upon complexation allow us to determine whether complexation has been achieved. Additionally, a large enhancement of the signals permits a selective identification of the vibrational modesThe authors thank the Centro de Supercomputación de Galicia (CESGA) for the generous allocation of computer time. Ministerio de Economía y Competitividad (MINECO, PCTQ2016-75023-C2-2-P) and Consellería de Cultura, Educación e Ordenación Universitaria e da Consellería de Economía, Emprego e Industria (Axuda para Consolidación e Estruturación de unidades de investigación competitivas do Sistema Universitario de Galicia, Xunta de Galicia ED431C 2017/17) are also acknowledged. Á.V.V. is grateful to the Universidade de Vigo for a predoctoral fellowshipS

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 is here described. DFT calculations support a mechanism consisting in 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.Junta de Castilla y León(BU237U13) and Ministerio de Economía y Competitividad (MINECO) and FEDER (CTQ2013-48937-C2-1P and 2-P

Au(III) Catalyzes the Cross-Coupling Between Activated Methylenes and Alkene Derivatives

In the last decade substantial efforts were devoted towards the exploitation of the Au(I) as a promising tool to promote C[sbnd]C bond formation reactions via the activation of unsaturations. Among these efforts, Au(I)/Au(III) cross couplings mediated by a co-oxidant or by photoactivation sit at a privileged position. Au(III) has also shown a rich chemistry but, due to its hardness and lower affinity for unsaturations, it is less often the catalyst of choice in C[sbnd]C bond forming strategies. Surprisingly, we have recently found two examples of cross-coupling reactions in which the authors report to be adding Au(III) to the reaction flask while claiming that Au(I) is the species responsible for the catalytic events. One of such cases even occurs under oxidizing conditions. Here we present a detailed computational study in which we explore the mechanism behind these C[sbnd]C forming reactions. Our results suggest that Au(III) can efficiently catalyze these transformations, thus invoking this exotic reduction is not only unnecessary but also energetically unfavourable

Computational and experimental studies on Cu/Au-catalyzed stereoselective synthesis of 1,3-disubstituted allenes

Cu- and Au-mediated formation of allenes from terminal alkynes and aldehydes via propargylamine intermediates is hampered by reversibility in the propargylamine formation. The use of a stable Au(I) catalyst in the reaction using a chiral propargylamine provided clues to disentangle the mechanism of the whole process that would have been otherwise hidden. Additionally, the process was observed to be stereoselective when an enantiomerically pure chiral propargylamine was used as starting substrate providing the corresponding 1,3-disubstituted allenes with high enantiomeric ratio.Agencia Estatal de Investigación | Ref. CTQ2017-85919-RAgencia Estatal de Investigación | Ref. CTQ2016-75023-C2-2-PXunta de Galicia | Ref. ED431C 2017/7

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.Xunta de Galicia and Ministerio de Economiá y Competitividad for funding through Projects EM2014/040 and CTQ2013-48937-C2-1-P and CTQ2013-48937-C2-2-P, respectively. R.S. thanks the Junta de Castilla y León for funding through projects BU237U13 and BU076U16

Three cycles in the dioxomolybdenum-catalyzed reduction of nitrobenzenes to anilines with pinacol. A computational study towards the valorization of biomass subproducts.

In this work, we use density functional theory to unravel the mechanism of the nitrobenzene to aniline reduction, catalyzed by dioxomolybdenum (VI) dichloride. The use of pinacol as an oxoaccepting reagent and the production of only acetone and water as byproducts, signals a novel and environmentally friendly way to add value to the oxygen-rich biomass-derived polyols. The reaction proceeds through three consecutive cycles, each one responsible for one of the three reductive steps needed to yield nitroaniline from nitrobenzene, with nitrosobenzene and benzylnitrene as intermediates. Each cycle regenerates the Mo(VI) catalyst and releases two acetone molecules. The mechanism involves singlet/triplet state crossings, a feature that has been found to be key in related polyoxomolibdate catalyzed processes. The role of the Mo-coordinated water, product of the reduction of pinacol, as the provider of the mysterious protons needed to reduce the nitro group, was revealed. The disclosure of this challenging mechanism and its rate limiting step can contribute to the design of more effective Mo(VI) catalysts