Revisiting the Rearrangement of Dewar Thiophenes

Gómez, Sara; Osorio, Edison; Dzib, Eugenia; Islas, Rafael; Restrepo, Albeiro; Merino, Gabriel

doi:10.3390/molecules25020284

Cited by 10 publications

(10 citation statements)

References 32 publications

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“…The energetic picture is not altered in any sensitive way after the inclusion of the continuum solvent or after improving the basis set to aug–cc-pVTZ, whose largest DLPNO–CCSD(T) energy difference with respect to I in the gas phase is ≈1.8 kcal/mol. These numbers indicate that, given the accuracy of computational methods, and since

kcal/mol at room conditions, all methyl groups should either act as free rotors or exhibit fluxional behavior [ 39 ]. Indeed, internal rotational barriers for M1, M2, M3 have been reported on the order of 0.25, 0.15, 0.45 kcal/mol, respectively [ 62 ], furthermore, interconversion paths calculated in this work also afford very small barriers, the smallest one being 0.8 kcal/mol under Gibbs energies for I→III→I , similarly, 1.1 kcal/mol are obtained for I→II→I .…”

Section: Resultsmentioning

confidence: 99%

“…In this scenario, honoring Frank Weinhold on occasion of his 80th birthday, we resort to NBO and other analysis methods to resolve this structural conundrum. NBO, developed over the last few decades in the group of Frank Weinhold [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ], is a widely used and highly successful strategy in the analysis of a large body of chemical problems [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ]. Specifically, for the conformational problem in caffeine, for each methyl rotation, we study hyperconjugation, electron delocalization involving the methyl groups, NBO donor–acceptor interactions, and the effect of all these factors on geometrical variables.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Conformational Preferences in Caffeine

2022

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High level DLPNO–CCSD(T) electronic structure calculations with extended basis sets over B3LYP–D3 optimized geometries indicate that the three methyl groups in caffeine overcome steric hindrance to adopt uncommon conformations, each one placing a C–H bond on the same plane of the aromatic system, leading to the C–H bonds eclipsing one carbonyl group, one heavily delocalized C–N bond constituent of the fused double ring aromatic system, and one C–H bond from the imidazole ring. Deletion of indiscriminate and selective non-Lewis orbitals unequivocally show that hyperconjugation in the form of a bidirectional –CH3 ⇆ aromatic system charge transfer is responsible for these puzzling conformations. The structural preferences in caffeine are exclusively determined by orbital interactions, ruling out electrostatics, induction, bond critical points, and density redistribution because the steric effect, the allylic effect, the Quantum Theory of Atoms in Molecules (QTAIM), and the non-covalent interactions (NCI), all predict wrong energetic orderings. Tiny rotational barriers, not exceeding 1.3 kcal/mol suggest that at room conditions, each methyl group either acts as a free rotor or adopts fluxional behavior, thus preventing accurate determination of their conformations. In this context, our results supersede current experimental ambiguity in the assignation of methyl conformation in caffeine and, more generally, in methylated xanthines and their derivatives.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Analysis of Conformational Preferences in Caffeine

2022

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“…A discussion of the merits and shortcomings of both methods is out of place in this manuscript; we explicitly state that we use them as well established analysis tools once the molecular problem has been solved. The interested reader is directed to the specialized literature , for details as to how those descriptors are related to bonding. − In addition, the synchronicity of each step was studied using the GGR index …”

Section: Methodsmentioning

confidence: 99%

Role of Substrate Substituents in Alkene Metathesis Mediated by a Ru Alkylidene Catalyst

et al. 2021

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Quantum mechanical calculations on the mechanism of olefin metathesis with a variety of substituents mediated by a Ru alkylidene catalyst reveal multistep processes along the general reactants → adduct → coordination complex → metallacycle → decoordination complex → products pathway for two consecutive turnovers. Net energy barriers in solution do not exceed 12 kcal mol −1 during the [Ru]The complex series of steps is initially driven by the evolution of the Ru(catalyst)•••C(olefin) contact. Dissection of bonding interactions using the tools provided by the natural bond orbitals and by the quantum theory of atoms in molecules methods indicate that each contact in the Ru(catalystcyclic reactive center undergoes the following series of transformations in different orders: no interaction → long range → σ → → π. Every single contact in this reactive center gains/loses an entire σ bond during the •••TS → metallacycle → TS••• interval. The lowest point in the potential energy surface is usually the metallacycle. For the first turnover, cycloreversion and final elimination of the products exhibit late transition states leading to higher relative energy barriers. Conversely, for the second turnover, it is the metallacycle to decoordination complex transformation step which leads to the highest barriers, constituting the rate-determining step for the entire process. Each step of the reaction is best described as a highly asynchronous process. Electron-withdrawing groups exhibit the largest overall barriers by virtue of destabilizing the emerging π bond in the final R 1 R 2 CCR 1 R 2 olefin during the second turnover.

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“…As an initial effort to elucidate the reaction mechanism, equilibrium geometries for all reactants, transition states, intermediates, and products were obtained using the popular B3LYP/6-31G(d) model chemistry, which has proven very efficient and accurate for closely related problems. − All stationary points were characterized as true minima or as transition states by harmonic vibrational analysis at the same level. Intrinsic reaction coordinate (IRC) paths were calculated for every single step with two goals in mind: first, to establish connectivity along the minimum energy path between reactants, intermediates, and products via the corresponding transition states and, second, to produce accurate potential energy surfaces (PES) used to carefully analyze the evolution of bonding along the entire chemical transformation. ,,− In addition to purely electronic energies and to zero-point-corrected electronic energies (ZPEs), activation and reaction energies are reported using Gibbs free energies at room conditions (298.15 K and 1 atm). We undertook the following steps to refine our calculations: First, all stationary points within a given reaction path were reoptimized using the more demanding 6-311++G(d,p) basis set.…”

Section: Methodsmentioning

confidence: 99%

Double-Ring Epimerization in the Biosynthesis of Clavulanic Acid

et al. 2020

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All reaction steps during the biosynthesis of suicidal clavulanic acid (coformulated with β-lactam antibiotics and used to fight bacterial infections) are known, except for the crucial 3S,5S → 3R,5R double epimerization needed to produce a biologically active stereoisomer, for which mechanistic hypothesis is subject to debate. In this work, we provide evidence for a reaction channel for the double inversion of configuration that involves a total of six reaction steps. When mediated by an enzyme with a terminal S–H bond, this highly complex reaction is spontaneous in the absence of solvents. Polarizable continuum models introduce reaction barriers in aqueous environments because of the strong destabilization of the first transition state. Molecular geometries and electronic structures in both cases indicate that solvent-free spontaneity and aqueous medium barriers are both firmly rooted in a substantial reorganization of the electron density right at the onset of the reaction, mostly involving a cyclic evolution/involution of large regions of π delocalization used to stabilize the excess charge left after the initial proton abstraction.

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Revisiting the Rearrangement of Dewar Thiophenes

Cited by 10 publications

References 32 publications

Analysis of Conformational Preferences in Caffeine

Analysis of Conformational Preferences in Caffeine

Role of Substrate Substituents in Alkene Metathesis Mediated by a Ru Alkylidene Catalyst

Double-Ring Epimerization in the Biosynthesis of Clavulanic Acid

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