CHEM 330 Topics Discussed on Oct 16 Deprotonation of α,β-unsaturated (= conjugated) carbonyl compounds Important: bases cannot abstract protons connected to the olefinic α-position of a conjugated carbonyl compound, because resonance interactions force the C=O and C=C π-systems to be coplanar As a result, the dihedral angle θ between the axis of the olefinic α-C–H s bond and the axis of the lobes of the π*C=O orbital is ca. 90°. There is no overlap between σC–H and π*C=O orbitals à no deprotonation is possible axis of the bases cannot abstract these protons dihedral angle large lobe θ ≈ 90° of the * O no overlap! π C=O H orbital H O Me O H axis of the OEt C–H bond Definition of α, β, γ, … carbons of an α,β-unsaturated carbonyl compound β O generic α,β-unsaturated R1 carbonyl compound R2 γ α Principle of vinylogy (= "vinyl analogy"): the interposition of a C=C unit between the components of a functional group generates a new chemical entity, which retains the chemical characteristics of the original Examples: an enolizable carbonyl a vinylog of the original: compound: deprotonation : B B : resonance delocalization is possible because of O H O H of (–) charge on the O resonance delocalization C CH C C=C–CH atom still possible through of (–) charge on the 2 2 the C=C bond: can undergo eletronegative O atom deprotonation O + O an ester: it undergoes hydrolysis to H3O an acid and an alcohol when treated C OR C OH + HOR with, e.g. aqueous HCl O + O a vinylogous ester: reacts with aq. H3O HCl like the original C C=C–OR C C=C–OH + HOR Deprotonation of α,β-unsaturated esters: conversion of, e.g., ethyl crotonate into a dienolate O O O a base (e.g, LDA) can H OEt H remove one of these H OEt OEt protons, because .... H H : B the anion is resonance-stabilized, a dienolate just like an ordinary enolate lecture of Oct 16 p. 2 Normal O-reactivity of dienolates of conjugated esters with, e.g., TMS-Cl: O LDA O–Li TMS-Cl O–SiMe3 OEt –78 °C OEt OEt dienolate Definition of α, β, γ, etc., positions of a dienolate: β OLi dienolate of a generic , -unsaturated R1 α β R2 carbonyl compound γ α Potential C-reactivity of a dienolate at the α-carbon or at the γ-carbon, e.g.: OLi O β O β β γ R1 + CH I could R1 α R1 2 3 form 2 & / or R2 γ α R γ R α prod. of α-alkylation prod. of γ-alkylation Principle: the nucleophilic C-reactivity of dienolates is expressed selectively at the α-carbon. This is true both for alkylation and for protonation. E.g.: • α-alkylation of dienolates: O β O Br β Br β OLi 1 α 1 γ R R R1 R2 R2 2 γ α γ α R actual product • α-protonation of dienolates: formation of deconjugated carbonyl compounds: β O β O H O+ + 3 β OLi H O 1 α 1 γ 3 R R R1 R2 R2 2 γ α γ α R actual product Molecular orbital based rationale for selective α-carbon reactivity of dienolates: greater electronic density at the α-carbon relative to the γ-carbon, and consequent greater α- nucleophilicity relative to γ- nucleophilicity Principle of least motion: a reaction that could theoretically lead to multiple products tends to form preferentially the product that requires the least amount of internal motion due to the repositioning / displacement of atoms during rehybridization. lecture of Oct 16 p. 3 Invoking the principle of least motion to rationalize the selective α-carbon reactivity of dienolates: C, C remain C, C remain singly bonded: doubly bonded: ≈ no relative motion ≈ no relative motion β O C, O go from singly bonded R1 to doubly bonded: they move smaller extent R2 closer to each other of internal motion γ α favored E C, C go from doubly bonded to singly bonded: they move farther from each other α β OLi E+ 1 R 2 C, C go from singly bonded α R γ γ to doubly bonded: they move closer to each other β O C, O go from singly bonded 1 γ to doubly bonded: they move greater extent R 2 of internal motion α R closer to each other disfavored E C, C go from doubly bonded to singly bonded: they move farther from each other Deprotonation of α,β-unsaturated ketones (= enones), e.g., cyclohexenone: potential formation of two regioisomeric dienolates: O O O deprotonation α' α deprotonation of the α' position β of the γ position γ thermordynamically favored: thermordynamically disfavored: cyclohexenone: a typical enone resonance disperses charge resonance disperses charge over the α and γ carbons only over the α' carbon Deprotonation of, e.g., cyclohexenone under kinetic (non-equilibrating) conditions (slight excess of LDA, THF, –78 °C): deprotonation occurs selectively at the α' position: • proper representation of the half-chair conformation of cyclohexene and of cyclohexenone: H H H H H H H H H H H H H H H H H H H H H H H H H H H H O O H H H H H H H H lecture of Oct 16 p. 4 • formation and fate of the enone-LDA complex: only this H • is properly • N O O aligned for OLi kinetic enone deprotonation H Li dienolate. The LDA H (–) charge is H H delocalized over O (excess) H one C=C bond H H H Normal O- and C-reactivity of kinetic dienolates of enones O–TMS O-reactive E+ O OLi e.g., TMS-Cl LDA O (excess) C-reactive E+ Me kinetic enone enolate e.g. CH3–I Deprotonation of enones under thermodynamic (equilibrating) conditions: deprotonation occurs selectively at the γ position: O appropriate OLi thermodynamic O O conds. (e.g., enone dienolate: slight defect The (–) charge is delocalized over of LDA (notes two C=C bonds of Oct 14) Selective α-alkylation and protonation of thermodynamic enone dienolates: O OLi O α Br Br α α γ β β β γ γ actual product O OLi O + + H3O H3O α α α β β β γ γ γ actual product lecture of Oct 16 p. 5 Soft enolization of enones such as cyclohexenone leading directly to regiochemically defined silyl enol ethers O TMS-OTf O–TMS kinetic silyl enol ether faster-forming, but N thermodynamically disfavored isomer Et non-equilibrating conds. O TMS-OTf O–TMS thermodynamically Me3Si–NH–SiMe3 favored isomer equilibrating conds. .