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A site‐selective C(3)/C(4)‐alkylation of N‐pyridylisoquinolones is achieved by employing C−C bond activation of cyclopropanols under Ru(II)‐catalyzed/Cu(II)‐mediated conditions. The regioisomeric ratios of the products follow directly from the electronic nature of the cyclopropanols and isoquinolones used, with electron‐withdrawing groups yielding predominantly the C(3)‐alkylated products, whereas the electron‐donating groups primarily generate the C(4)‐alkylated isomers. Density functional theory calculations and detailed mechanistic investigations suggest the simultaneous existence of the singlet and triplet pathways for the C(3)‐ and C(4)‐product formation. Further transformations of the products evolve the utility of the methodology thereby yielding scaffolds of synthetic relevance. [ABSTRACT FROM AUTHOR]

We report a detailed experimental and theoretical analysis of through‐space arene activation with halogens, tetrazoles and achiral esters and amides. Contrary to previously assumed direct activation through σ‐complex stabilization, our results suggest that these reactions proceed by a relay mechanism wherein the lone pair‐containing activators form exothermic π‐complexes with electrophilic nitronium ion before transferring it to the probe ring through low barrier transition states. Noncovalent interactions (NCI) plots and Quantum Theory of Atoms in Molecules (QTAIM) analyses depict favorable interactions between the Lewis base (LB) and the nitronium ion in the precomplexes and the transition states, suggesting directing group participation throughout the mechanism. The regioselectivity of substitution also comports with a relay mechanism. In all, these data pave the way for an alternate platform of electrophilic aromatic substitution (EAS) reactions. [ABSTRACT FROM AUTHOR]

The template‐directed C−H insertion of α,β‐unsaturated esters into quinoline was interrogated by using computational quantum chemistry. An energetically viable mechanism for this complex multistep transformation was elucidated, with attention paid throughout to conformational flexibility and alternative ligand binding modes. The selectivity was found to correlate with distortion from a tetrahedral geometry for the carbon atom involved in C−H insertion, a parameter that can be applied to future template design. [ABSTRACT FROM AUTHOR]

Reported herein is a reactivity of propargyl alcohols as "Three‐Carbon Synthons" in a Rh(III)‐catalyzed C−H functionalization of acetanilides, leading to the synthesis of core structures of isocryptolepine, γ‐carbolines, dihydrochromeno[2,3‐b]indoles, and diindolylmethanes (DIM) derivatives. The transformation involves a rhodium(III)‐catalyzed C−H functionalization and heteroannulation to yield indoles followed by a cascade cyclization with both external and internal nucleophiles to afford diverse products. The role of the hydroxy group, the key function of the silver additive, the origin of the reverse regioselectivity and the rate‐determining step, are rationalized in conformity with the combination of experimental, noncovalent interaction analysis and DFT studies. This protocol is endowed with several salient features, including one‐pot multistep cascade approach, exclusive regioselectivity, good functional group tolerance and synthesis of variety of molecular frameworks. [ABSTRACT FROM AUTHOR]

Gold‐catalyzed dehydro‐Diels‐Alder reactions of ynamide derivatives allow efficient access to a variety of N‐containing aromatic heterocycles. A dual gold catalysis mechanism was postulated for transformations involving the formation of C−C bonds by reaction between a terminal alkyne and an enynamide fragment. In this article, complete experimental and computational investigations into the mechanism of such a transformation are reported. Support for a dual gold catalysis was found and it was shown that the concerted or stepwise nature of the cyclization event depends on the substitution of the ynamide moiety. The reaction was found to proceed in three stages: 1) formation of a σ,π‐digold complex from the terminal alkyne, 2) cyclization to produce a gem‐diaurated aryl complex, and 3) catalyst transfer to free the product and regenerate the σ,π‐digold complex. [ABSTRACT FROM AUTHOR]

In the early 1960s, as part of R. B. Woodward's isoxazole route to vitamin B12, Subramania Ranganathan uncovered two coupled sets of stereospecific reactions, a thermal set and a photochemical set. These four reactions illustrated the alternating configurations that were the major data points that prompted the solution of the no‐mechanism problem. Though Ranganathan's reactions played a major role, according to Woodward, in the development of the Woodward–Hoffmann rules, they were published only as part of the documentation of a lecture given by Woodward in 1966. The authors of this paper have uncovered Subramania Ranganathan's 1964 postdoctoral report and have used modern quantum chemical theory to predict the 1H NMR spectra for Ranganathan's key compounds, providing support for the structure assignments made by Woodward and Ranganathan. A similar set of alternating, stereospecific reactions was observed by E. J. Corey and Alfred Hortmann in their 1963 total synthesis of dihydrocostunolide. We also have applied the computational process used for Ranganathan's compounds to Hortmann's compounds, now also including the calculation of coupling constants, and find computational support for Corey and Hortmann's structure assignments. [ABSTRACT FROM AUTHOR]

The harmful impact caused by pesticides on human health and the environment necessitates the development of efficient degradation processes and control of prohibited stocks of such substances. Organophosphates (OPs) are among the most used agrochemicals in the world and their degradation can proceed through several possible pathways. Investigating the reactivity of OPs with nucleophilic species allows one to propose new and efficient catalyst scaffolds for use in detoxification. In light of the remarkable catalytic activity of imidazole (IMZ) at promoting dephosphorylation processes of OPs, the reactivity of 4(5)‐hydroxymethylimidazole (HMZ) with diethyl‐2,4‐dinitrophenylphosphate (DEDNPP) and Paraoxon are evaluated by combining experimental and theoretical approaches. It is observed that HMZ is an efficient and regiospecific catalyst with reactivity modulated by competing tautomers. To propose an optimal IMZ‐based catalyst, quantum chemical calculations were performed for monosubstituted 4(5)IMZ derivatives that might cleave DEDNPP. Both inductive effects and hydrogen bonding by the substituents are shown to influence barriers and mechanisms. [ABSTRACT FROM AUTHOR]

C-H functionalization, mechanism, Pd catalysts, quantum chemistry, templates Keywords: C-H functionalization; mechanism; Pd catalysts; quantum chemistry; templates EN C-H functionalization mechanism Pd catalysts quantum chemistry templates 1 1 1 05/16/23 20230511 NES 230511 B Like an octopus b trapping its prey with wriggling arms, a palladium catalyst binds its quinoline substrate through multiple conformations en route to selective activation of a particular C-H bond. Cover Feature: Mechanism and Origins of Site-Selectivity of Template-Directed C-H Insertion of Quinolines (Chem. Eur. J. 27/2023). [Extracted from the article]

Medium-sized rings, particularly the corresponding cyclic peptides, are challenging synthetic targets. In the present study, we report an approach to medium-sized cyclic peptides through targeted formation and collapse of cyclol intermediates. This methodology operates on β-amino imides derived from 2,5-diketopiperazines and offers a straightforward transition from frequently examined scaffolds in drug discovery to a rarely visited class of medium-sized rings. [ABSTRACT FROM AUTHOR]

Metal carbenes appended with two electron-donating groups, known as 'donor/donor' carbenes, undergo diastereo- and enantioselective rhodium-catalyzed C−H insertion reactions with ether substrates to form benzodihydrofurans. Unlike the reactions of metal carbenes with electron-withdrawing groups attached, the attenuated electrophilicity enables these reactions to be conducted in Lewis basic solvents (e.g., acetonitrile) and in the presence of water. The diazo precursors for these species are prepared in situ from hydrazone using a mild and chemoselective oxidant (MnO2). Although this sequence often can be performed in one-pot, control experiments have elucidated why a 'two-pot' process is often more efficient. A thorough screening of achiral catalysts demonstrated that sterically encumbered catalysts are optimal for diastereoselective reactions. Although efficient insertion into allylic and propargylic C−H bonds is observed, competing dipolar cycloaddition processes are noted for some substrates. The full substrate scope of this useful method of benzodihydrofuran synthesis, mechanisms of side reactions, and computational support for the origins of stereoselectivity are described. [ABSTRACT FROM AUTHOR]

Imidazole (IMZ) rings catalyze many biological dephosphorylation processes. The methyl positioning effect on IMZs reactivity has long intrigued scientists and its full understanding comprises a promising tool for designing highly efficient IMZ-based catalysts. We evaluated all monosubstituted methylimidazoles (xMEI) in the reaction with diethyl 2,4-dinitrophenyl phosphate by kinetics studies, NMR analysis and DFT calculations. All xMEI showed remarkable rate enhancements, up to 1.9×105 fold, compared with spontaneous hydrolysis. Unexpectedly, the electron-donating methyl group acts to decrease the reactivity of the xMEI compared to IMZ, except for 4(5)methylimidazole, (4(5)MEI). This behavior was attributed to both electronic and steric effects. Moreover, reaction intermediates were monitored by NMR and surprisingly, the reactivity of the two different 4(5)MEI tautomers was distinguished. [ABSTRACT FROM AUTHOR]

Terpene synthases, as key enzymes of terpene biosynthesis, have garnered the attention of chemists and biologists for many years. Their carbocationic reaction mechanisms are responsible for the huge variety of terpene structures in nature. These mechanisms are amenable to study by using classical biochemical approaches as well as computational analysis, and in this study we combine quantum-chemical calculations and deuterium-labeling experiments to elucidate the reaction mechanism of a triquinane forming sesquiterpene synthase from chamomile. Our results suggest that the reaction from farnesyl diphosphate to triquinanes proceeds through caryophyllyl and presilphiperfolanyl cations and involves the protonation of a stable (−)-( E)-β-caryophyllene intermediate. A tyrosine residue was identified that appears to be involved in the proton-transfer process. [ABSTRACT FROM AUTHOR]

DFT (both B3LYP and M06-2X), CASSCF, and CASPT2 calculations were used to investigate competing [3, 3] and [3, 5] sigmatropic shifts and intramolecular [4+2] cycloaddition of 1,3,7-octatriene. In accord with previous results on 1,5-hexadiene, CASSCF calculations found both stepwise and concerted pathways for the [3, 3] rearrangement. For the competing [3, 5] sigmatropic rearrangement, CASSCF and CASPT2 calculations revealed three stepwise pathways with similar barriers. UB3LYP and UM06-2X calculations predicted a different potential energy landscape: no stepwise [3, 3] pathway, only two competing [3, 5] sigmatropic shifts, and an intramolecular Diels-Alder cycloaddition/homolytic ring-opening pathway. Significant lowering of barriers for all rearrangements was predicted for some 1,3,7-octatrienes with substituents at the 4- and 7-positions. [ABSTRACT FROM AUTHOR]