Informing Molecular Design by Stereoelectronic Theory: The Fluorine Gauche Effect in Catalysis

Accounts of Chemical Research, Journal Year: 2018, Volume and Issue: 51(7), P. 1701 - 1710

Published: June 12, 2018

The axioms of stereoelectronic theory constitute an atlas to navigate the contours molecular space. All too rarely lauded, advent and development has been one organic chemistry's greatest triumphs. Inevitably, however, in absence a comprehensive treatise, many field's pioneers do not receive veneration that they merit. Rather their legacies are pillars persist teaching research. This ubiquity continues afford practitioners chemistry with abundance opportunities for creative endeavor reaction design, conceiving novel activation modes, preorganizing intermediates, or stabilizing productive transition states products. Antipodal steric governance, which mitigates destabilizing nonbonding interactions, control allows well-defined, often complementary, conformations be populated. Indeed, prevalence hyperconjugative interactions biosynthetic processes renders this approach preorganization decidedly biomimetic and, by extension, expansive. In Account, evolution application simple donor-acceptor model based on fluorine gauche effect is delineated. Founded reinforcing involving C(sp3)-H bonding orbitals C(sp3)-X antibonding [σC-H → σC-X*], general stratagem used conjunction array secondary noncovalent achieve acyclic conformational (ACC) structures interest. These effects range from 1,3-allylic strain (A1,3) through electrostatic charge-dipole cation-π interactions. Synergy between these ensures rotation about strategic C(sp3)-C(sp3) bonds subject requirement antiperiplanarity (180°). Logically, generic [X-CH2-CH2-Y] system (X, Y = electron withdrawing groups) two synclinal (i.e., gauche) significantly As such, models didactically predictively powerful achieving topological preorganization. case effect, low demand remaining substituents at C(sp3) hybridized center placed predictable area space: An exit vector analogy thus appropriate. Furthermore, intrinsic chemical stability C-F bond advantageous, it may considered as inert steering group: juxtaposition size electronegativity fluorinated molecules unique among organo-halogen series. Cognizant replacement atom difluoroethylene motif another group preserves conformation, was reasoned β-fluoroamines would intriguing candidates investigation. burgeoning field Lewis base catalysis, particularly via iminium ion activation, provided timely platform explore postulated fluorine-iminium effect. Necessarily, requires process intramolecularization generate deficient neighboring Examples include protonation, condensation salts, acylation. process, akin substrate binding, obvious parallels enzymatic since perturbs dynamics [ synclinal-endo, antiperiplanar, synclinal-exo]. Account details conformationally small [X-Cα-Cβ-F] logical design illustrates synthetic value enantioselective catalysis.

Language: Английский

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Interacting Quantum Atoms—A Review

Molecules, Journal Year: 2020, Volume and Issue: 25(17), P. 4028 - 4028

Published: Sept. 3, 2020

The aim of this review is threefold. On the one hand, we intend it to serve as a gentle introduction Interacting Quantum Atoms (IQA) methodology for those unfamiliar with it. Second, expect act an up-to-date reference recent developments related IQA. Finally, want highlight non-exhaustive, yet representative set showcase examples about how use IQA shed light in different chemical problems. To accomplish this, start by providing brief context justify development real space alternative other existent energy partition schemes non-relativistic molecules. We then introduce self-contained algebraic derivation methodological ecosystem well overview these formulations vary level theory employed obtain molecular wavefunction upon which procedure relies. several applications examined research groups worldwide investigate wide variety

Language: Английский

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Non-covalent interactions from a Quantum Chemical Topology perspective

Journal of Molecular Modeling, Journal Year: 2022, Volume and Issue: 28(9)

Published: Aug. 25, 2022

Abstract About half a century after its little-known beginnings, the quantum topological approach called QTAIM has grown into widespread, but still not mainstream, methodology of interpretational chemistry. Although often confused in textbooks with yet another population analysis, be it perhaps an elegant somewhat esoteric one, been enriched about dozen other research areas sharing main mathematical language, such as Interacting Quantum Atoms (IQA) or Electron Localisation Function (ELF), to form overarching Chemical Topology (QCT). Instead reviewing latter’s role understanding non-covalent interactions, we propose number ideas emerging from full consequences space-filling nature atoms, and discuss how they (will) impact on interatomic including ones. The architecture force field FFLUX, which is based these ideas, outlined. A new method Relative Energy Gradient (REG) put forward, able, by computation, detect fragments given molecular assembly govern energetic behaviour this whole assembly. This can offer insight typical balance competing atomic energies both covalent case studies. brief discussion so-called bond critical points given, highlighting concerns their meaning, mainly arena interactions.

Language: Английский

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A relative energy gradient (REG) study of the planar and perpendicular torsional energy barriers in biphenyl

Theoretical Chemistry Accounts, Journal Year: 2018, Volume and Issue: 138(1)

Published: Dec. 10, 2018

Biphenyl is a prototype molecule, the study of which important for proper understanding stereo-electronic effects. In gas phase it has an equilibrium central torsion angle ~ 45° and shows both planar (0°) perpendicular (90°) torsional energy barrier. The latter analysed first time. We use newly proposed REG method,

Language: Английский

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Pentafluorocyclopropanation of (Hetero)arenes Using Sulfonium Salts: Applications in Late‐Stage Functionalization

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(35)

Published: July 4, 2023

The evaluation of the pentafluorocyclopropyl group as a chemotype in crop protection and medicinal chemistry has been hampered past by lack suitable methodologies that enable practical incorporation this moiety into advanced synthetic intermediates. Herein, we report gram-scale synthesis an unprecedented sulfonium salt, 5-(pentafluorocyclopropyl)dibenzothiophenium triflate, its use versatile reagent for photoinduced C-H pentafluorocyclopropylation broad series non-previously functionalized (hetero)arenes through radical mediated mechanism. scope potential benefits protocol developed are further demonstrated late-stage introduction unit biologically relevant molecules widely used pharmaceuticals.

Language: Английский

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Can Combined Electrostatic and Polarization Effects Alone Explain the F···F Negative-Negative Bonding in Simple Fluoro-Substituted Benzene Derivatives? A First-Principles Perspective

Computation, Journal Year: 2018, Volume and Issue: 6(4), P. 51 - 51

Published: Sept. 20, 2018

The divergence of fluorine-based systems and significance their nascent non-covalent chemistry in molecular assemblies are presented a brief review the field. Emphasis has been placed to show that type-I -II halogen-centered F···F long-ranged intermolecular distances viable between entirely negative fluorine atoms some fluoro-substituted dimers C6H6 can be regarded as consequence significant attractive interactions. Such interactions observed solid-state structures C6F6 other similar fluorine-substituted aromatic compounds have frequently underappreciated. While these often ascribed crystal packing effects, we using first-principles level calculations much more fundamental nature. stability reliability supported by binding energies emerge from supermolecular procedure MP2 (second-order Møller-Plesset perturbation theory), Symmetry Adapted Perturbation Theory, which latter does not determine interaction energy computing total monomers or dimer. Quantum Theory Atoms Molecules Reduced Density Gradient Non-Covalent Index charge-density-based approaches confirm contacts attraction unified bond path (and critical point) isosurface charge density topologies, respectively. These explained neither so-called electrostatic surface potential (MESP) model approach demonstrates sites opposite means Coulomb’s law electrostatics, nor purely effect polarization. We provide evidence against standalone use this overlooking approaches, former allow for calculation on surfaces overlapping equilibrium geometry complex. This study thus provides unequivocal limitation MESP its gaining insight into nature reactivity overlapped interacting involved.

Language: Английский

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Does the Intra‐Atomic Deformation Energy of Interacting Quantum Atoms Represent Steric Energy?

ChemistryOpen, Journal Year: 2019, Volume and Issue: 8(5), P. 560 - 570

Published: Feb. 8, 2019

Abstract We show that the mutual, through‐space compression of atomic volume experienced by approaching topological atoms causes an exponential increase in intra‐atomic energy those atoms, regardless approach orientation. This insight was obtained using modern partitioning method called interacting quantum (IQA). behaviour is consistent for all except hydrogen, which can behave differently depending on its environment. Whilst experience charge transfer when they interact, hydrogen atom more vulnerable to these changes than larger atoms. The difference found be due hydrogen's lack a core electrons, which, heavier consistently provide repulsion compressed. As such, do not always steric hindrance. In accounting unusual and demonstrating character other we evidence IQA's as quantitative description energy.

Language: Английский

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Engaging α-Fluorocarboxylic Acids Directly in Decarboxylative C–C Bond Formation

ACS Catalysis, Journal Year: 2020, Volume and Issue: 10(7), P. 4451 - 4459

Published: March 24, 2020

Fluorine-containing organic molecules, particularly those that bear (sp3)C–F bonds, are rapidly gaining prominence in modern chemical synthesis. Although extensive studies have been devoted to the preparation of secondary and tertiary fluorides, crucial shortcomings remain: for example, lengthy substrate synthesis, contrived installation difficult-to-remove directing/activating units, excessive waste generation and/or limited functional group compatibility. Here, we show readily accessible α-monofluoro carboxylic acids, which conventionally difficult substrates cross-coupling, undergo direct decarboxylative cross-coupling with sp2- sp3-hybridized organohalides afford a wide assortment fluorinated products. Reactions typically promoted by combination 1 mol % an Ir-based photocatalyst 2–15 bipyridine–Ni complex, delivering products up 86% yield under blue LED light irradiation. Concise synthesis key therapeutic candidates underscores utility, complementarity, distinct advantages compared existing methods. DFT calculations used rationalize reactivity α-fluoro acid (vs nonfluorinated parent acids) decarboxylation conditions.

Language: Английский

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A molecular electron density theory study of hydrogen bond catalysed polar Diels–Alder reactions of α,β-unsaturated carbonyl compounds

Tetrahedron Chem, Journal Year: 2024, Volume and Issue: 10, P. 100064 - 100064

Published: Feb. 22, 2024

Language: Английский

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Using the Relative Energy Gradient Method with Interacting Quantum Atoms to Determine the Reaction Mechanism and Catalytic Effects in the Peptide Hydrolysis in HIV‐1 Protease

Chemistry - A European Journal, Journal Year: 2018, Volume and Issue: 24(43), P. 11200 - 11210

Published: May 26, 2018

The reaction mechanism in an active site is of the utmost importance when trying to understand role that enzyme plays biological processes. In a recently published paper [Theor. Chem. Acc. 2017, 136, 86], we formalised Relative Energy Gradient (REG) method for automating Interacting Quantum Atoms (IQA) analysis. Here, REG utilised determine peptide hydrolysis aspartic HIV-1 Protease. Using along with IQA approach without employing any arbitrary parameters and remarkable ease (albeit at large computational cost: system contains 133 atoms, which means there are 17 689 individual terms be calculated). When work together it possible atomistic resolution from data directly derived quantum calculations, parameters. Moreover, determined by this novel gives concrete insight into how residues catalyse hydrolysis.

Language: Английский

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