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Investigating the reactivity of small nucleophilic scaffolds is a strategic approach for the design of new catalysts aiming at effective detoxification processes of organophosphorus compounds. The drug methimazole (MMZ) is an interesting candidate featuring two non‐equivalent nucleophilic centers. Herein, phosphoryl transfer reactions mediated by MMZ were assessed by means of spectrophotometric kinetic studies, mass spectrometry (MS) analyses, and density functional theory (DFT) calculations using the multi‐electrophilic compound O,O‐diethyl 2,4‐dinitrophenyl phosphate (DEDNPP). MMZ anion acts primarily as an S‐nucleophile, exhibiting a nucleophilic activity comparable to that of certain oximes featuring alpha‐effect. Selective nucleophilic aromatic substitution was observed, consistent with the DFT prediction of a low energy barrier. Overall, the results bring important advances regarding the mechanistic understanding of nucleophilic dephosphorylation reactions, which comprises a strategic tool for neutralizing toxic organophosphates, hence promoting chemical security. [ABSTRACT FROM AUTHOR]

This review describes unexpected dynamical behaviors of rearranging carbocations and the modern computational methods used to elucidate these aspects of reaction mechanisms. Unique potential energy surface topologies associated with these rearrangements have been discovered in recent years that are not only of fundamental interest, but also provide insight into the way Nature manipulates chemical space to accomplish specific chemical transformations. Cautions for analyzing both experimental and theoretical data on carbocation rearrangements are included throughout.

Density functional theory was used to elucidate the mechanism and the pericyclicity of chromium‐catalyzed bicyclization reactions that purportedly involve 8‐electron electrocyclization steps. Our computational results indicate that these reactions do indeed proceed via 8‐electron electrocyclization rather than an alternative pathway involving 4‐electron electrocyclization followed by Cope rearrangement. The role of C=[M] groups on the electrocyclization, specifically its pericyclicity, was examined in detail using modern theoretical tools. [ABSTRACT FROM AUTHOR]

Nitrogen heterocycles play a vital role in pharmaceuticals and natural products, with the six‐membered aromatic and aliphatic architectures being commonly used. While synthetic methods for aromatic N‐heterocycles are well‐established, the synthesis of their aliphatic functionalized analogues, particularly piperidine derivatives, poses a significant challenge. In that regard, we propose a stepwise dearomative functionalization reaction for the construction of highly decorated piperidine derivatives with diverse functional handles. We also discuss challenges related to site‐selectivity, regio‐ and diastereoselectivity, and provide insights into the reaction mechanism through mechanistic studies and density functional theory computations. [ABSTRACT FROM AUTHOR]

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]

Stereoselective Zweifel olefination using boronate complexes carrying two different reactive π‐systems was achieved to synthesize vinyl heteroarenes and conjugated 1,3‐dienes in good yield and up to 100 % stereoselectivity, which remains unexplored until now. Most importantly, we report the unprecedented formation of E vs. Z‐vinyl heteroarenes for different heteroarenes under identical conditions. Density functional theory (DFT) investigations unveil the mechanistic dichotomy between olefin and heteroarene activation followed by 1,2‐migration, leading to E or Z‐vinyl heteroarenes respectively. We also report a previously unknown reversal of stereoselectivity by using 2,3‐Dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ) as an electrophile. The Zweifel olefination using a boronate complex that carries two different olefins was previously unexplored due to significant challenges associated with the site‐selective activation of olefins. We have solved this problem and reported the site‐selective activation of olefins for the stereoselective synthesis of 1,3‐dienes. [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 [3s,5s]‐sigmatropic shift is an example of an orbital‐symmetry forbidden pericyclic reaction that is outcompeted by the allowed [3s,3s]‐sigmatropic shift. Density functional theory calculations are used to show that PdII‐complexed systems with strategically placed substituents engaging in key stereoelectronic effects can select for the [3s,5s] process, thereby outcompeting both orbital‐symmetry‐allowed [3s,3s]‐ and [3s,5a]‐shifts. [ABSTRACT FROM AUTHOR]

The calculation of hydrogen atom transfer (HAT) barriers within the cytochrome P450 catalytic cycle is of central importance for the prediction of metabolites formed from medicinally relevant compounds. We report the accurate estimation of hydrogen atom transfer barriers using inexpensive descriptors computed for a panel of 21 compounds. By a simple univariate linear regression between barriers previously computed using density functional theory (DFT) and newly computed "frozen radical" bond dissociation energies using the GFN2‐xTB method, a mean absolute error of 1 kcal mol−1 is achieved. Other affordable levels of theory are studied to assess differences in performance and computational cost. Multiple linear regression incorporating additional descriptors using GFN2‐xTB is shown to predict HAT barriers with mean absolute errors of 0.82 kcal mol−1. With computing times in milliseconds on modest computing hardware, this systematic approach is accessible and extensible to large scale screening workflows. [ABSTRACT FROM AUTHOR]

The fundamental challenge of C−F bond formation by reductive elimination has been met by compounds of select transition metals and fewer main group elements. The work detailed herein expands the list of main group elements known to be capable of reductively eliminating a C−F bond to include tellurium. Surprising and novel modes of both sp2 and sp3 C−F bond formation were observed alongside formation of TeIV cations during two separate attempts to synthesize/characterize fluorinated organotellurium(VI) cations in superacidic media (SbF5/SO2ClF). Following detailed low‐temperature NMR experiments, the mechanisms of the two unique reductive elimination reactions were probed and investigated using density functional theory (DFT) calculations. Ultimately, we found that an "indirect" reductive elimination pathway is likely operative whereby Sb plays a key role in fluoride abstraction and C−F bond formation, as opposed to unimolecular reductive elimination from a discrete TeVI cation. [ABSTRACT FROM AUTHOR]

[Display omitted] Both concerted [4 + 2] cycloadditions and stepwise carbocation-alkene cyclizations have been proposed as means to construct the complex polycyclic cores of the artatrovirenols and daphenoid natural products during their biosyntheses. Here the energetic feasibility of each of these reactions is assessed using density functional theory calculations. While none of the previously proposed processes can be ruled out, an alternative process with a lower barrier is proposed. This process would allow for formation of a key C C bond during the cyclase phase of terpenoid biosynthesis. [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]

Between 1910 and 1947, Robert Robinson (primarily), among others, published numerous proposed structures for strychnine. Robinson published 17 of his strychnine papers with his doctoral advisor William Henry Perkin, Jr. though all but two appeared after Robinson had taken his first permanent academic position. This Essay analyzes 20 key publications leading up to Robinson's (correct, then incorrect, then correct again though not definitively) proposal and Woodward's assignment of the actual structure of strychnine. We subjected the assignment of the strychnine structure to a modern computational quantum chemistry workflow. By computing, with density functional theory, 1H and 13C NMR chemical shifts for the literature‐proposed strychnine structures, we were able to rule out most incorrect structures. 13C NMR predictions were better at this, but 1H NMR chemical shifts were helpful. A comparison is made between the consequences of publishing erroneous ideas in the first half of the 20th century and doing so in the 21st century. [ABSTRACT FROM AUTHOR]

The effects of including (a) implicit solvent in geometry optimizations, (b) conformationally flexible molecules in test sets, and (c) empirical dispersion D3(BJ) on scaling factors for predicting 1H and 13C NMR chemical shifts were explored. Scaling factors with optimizations performed in the gas phase and with a Polarizable Continuum Model (PCM) solvent model were obtained for 12 organic solvents, including 2,2,2‐trifluroethanol and chlorobenzene, for which scaling factors have been developed for the first time. Scaling factors for aromatic solvents were split into primary and secondary scaling factors to account for CH–π effects. Including empirical dispersion D3(BJ) did not lead to significant improvement. [ABSTRACT FROM AUTHOR]

Quantum chemical methods are useful for probing the energetic viability of chemical mechanisms involved in natural product biosynthesis. Typical computational approaches are described and representative examples of mechanistic studies on radical, pericyclic, and carbocation rearrangement reactions that lead to polycyclic skeletons of complex natural products showcase the utility of such methods in providing understanding and shaping future experimental studies. The importance of inherent substrate reactivity is highlighted and cautions for interpreting computational results are discussed. This article is categorized under:Structure and Mechanism > Reaction Mechanisms and CatalysisTheoretical and Physical Chemistry > Reaction Dynamics and KineticsStructure and Mechanism > Computational Biochemistry and Biophysics [ABSTRACT FROM AUTHOR]

Second order Jahn–Teller (SOJT) effects arise from interactions between filled and empty molecular orbitals of like symmetry. These interactions often lead to structural distortions whose extent is inversely proportional to the energy difference between the interacting orbitals. The main objectives of the work described here are (1) the calculation (using density functional theory methods) of the energies of the valence molecular orbitals in the species EH3 (E = N, P, As or Sb), HEEH (E = C, Si, Ge or Sn), and H2EEH2, (E = C, Si, Ge or Sn) and (2) the correlation of these energies with barriers for planarization or linearization. The calculations suggest an upper limit of about 12 eV energy separation of the interacting levels for SOJT effects to be significant, which is considerably larger than previously thought and implies that SOJT effects may be more common than currently realized. [ABSTRACT FROM AUTHOR]

With the help of chemical shifts computed with density functional theory (DFT), it is demonstrated that the reported experimental 13C NMR data of acremolin C are incompatible with the claimed structure of an N2,3-ethenoguanine with an isopropyl group at C-1'. An alternative structure, which is in agreement with both experimental and computed data, presents an isopropyl group at the C-2' position of an N2,3-ethenoguanine and leads to the conclusion that acremolin C is identical with acremolin B. [ABSTRACT FROM AUTHOR]

Meroterpenes derived from dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate have attracted much biosynthetic attention, yet only recently have synthetic solutions to any family members appeared. A key point of divergence in DMOA-derived meroterpene biosynthesis is the protoaustinoid A carbocation, which can be diverted to either the berkeleyone, andrastin, or terretonin structural classes by cyclase-controlled rearrangement pathways. Shown herein is that the protoaustinoid bicyclo[3.3.1]nonane nucleus can be reverted to either andrastin or terretonin ring systems under abiotic reaction conditions. The first total syntheses of members of these natural product families are reported as their racemates. [ABSTRACT FROM AUTHOR]

An energetically viable (on the basis of results from density functional theory computations) pathway to the diterpene variediene is described. Only one of the three secondary carbocations along this pathway is predicted to be a minimum on the potential energy surface. [ABSTRACT FROM AUTHOR]

Caryolene formation occur asynchronously in a concerted way through carbocationic rearrangements involving the generation of a secondary or a tertiary carbocation whether the reaction proceeds in the absence or in the presence of NH3, respectively. Both caryolene formation mechanisms are analyzed within the general framework of the reaction force; the reaction force constant is used to gain insights into the synchronicity of the mechanisms and the reaction electronic flux helps to characterize the electronic activity taking place during the reaction. DFT calculations at the B3LYP/6-31+G(d,p) level show a clear difference in the mechanisms of the base promoted or base free caryolene formation reactions. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

In this work, covalent hydration energies for a variety of azanaphthalenes and purine analogs have been calculated using a variety of quantum chemical methods. On the basis of these results, we recommend the CPCM(UA0)-B3LYP/6-31+G(d,p) level for rapid prediction of covalent hydration energies. However, we caution the use of this methodology for computing covalent hydration energies for fluorine-containing compounds. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010 [ABSTRACT FROM AUTHOR]

Density functional theory calculations were carried out in order to determine the viability of putative mechanistic pathways for formation of the diterpenoid (+)-chatancin. It was found that a cycloaddition involving a pyrylium ion would have a lower energetic barrier than previously proposed cycloadditions involving a 2H-pyran or furan. All three reactions are predicted to be concerted. [ABSTRACT FROM AUTHOR]

Herein we describe our exploration, using density functional theory calculations, of a conjugate addition-rearrangement sequence that leads to medium-ring cyclic amines. On the basis of the results of our calculations, we conclude that the rearrangement step is rate determining. In addition, we analyze the role of a carbanion lone pair in the rearrangement step, concluding that it functions as a substituent on a [3,3] sigmatropic shift, rather than a nucleophile; thus, the Woodward-Hoffmann rules are not circumvented in this reaction via involvement of orthogonal orbitals on an atom involved in the rearrangement. [ABSTRACT FROM AUTHOR]

Gold(I) catalysts effectively promote the Cope rearrangement of acyclic 1,5-dienes bearing a terminal cyclopropylidene. When this methodology is applied to cyclic substrates an unexpected transformation occurs, resulting in the formation of a tricyclic compound incorporating a bicyclo[4.2.0]oct-1-ene core, a portion of which is found in a number of natural products. Density functional theory calculations (M06 and M06-2X) reveal insight into the mechanism and thermodynamics of this unique transformation. [ABSTRACT FROM AUTHOR]

A heterocycle-to-heterocycle strategy is presented for the preparation of highly fluorescent and solvatochromic dibenzonaphthyridinones (DBNs) via methodology that leads to the formation of a tertiary, spiro-fused carbon center. A linear correlation between the results of photophysical experiments and time dependent density functional theory calculations was observed for the λmax of excitation for DBNs with varying electronic character. [ABSTRACT FROM AUTHOR]

Quantum chemical calculations coupled to experiments were used to predict covalent hydration propensities of biologically relevant α-ketoamides. Experimentally determined hydration equilibrium constants for related ketones and aldehydes were compared to computationally determined values to develop a method for predicting hydration equilibrium constants. This method was used on six newly synthesized α-ketoamides to experimentally verify computational predictions. A correlation between calculation and experiment was observed and applied to models of several pertinent APIs. Our results indicate that the keto form is favored for practically all α-ketoamides in biological environs. [ABSTRACT FROM AUTHOR]

Abstract: Metal complexation to aryl (Ph, Cp, cyclobutadienyl) methylium cations, radicals, and anions was investigated using hybrid density functional theory methods (B3LYP/LANL2DZ), with a focus on the effects of substituents. The results of these calculations, in which both geometric and energetic consequences of adding substituents were examined, indicate that metal–methylium interactions are most sensitive to substituent effects for complexed cations. [Copyright &y& Elsevier]