Bài giảng Organic Chemistry - Chapter 14 Delocalized Pi Systems

Chemistry 3BThe (a) view of your existence.In the News: A Cure for Hepatitis CSyllabusSofosbuvir (Sovaldi) by Gilead Sciences (Foster City) approved by FDA December 2013: already a blockbuster drug >$ 5 billion in 2014~200 Million affected; leads to liver cirrhosis and cancer; 350,000 deaths (20,000 US) annuallyThe phosphate serves as a defective nucleotide substrate for the viral RNA polymerase, and thus inhibits viral RNA synthesis.“Prodrug”I, too, started small..Peter VollhardtUniversity of California at BerkeleyThe Fun of Organic ChemistryTigre Delta, Buenos Aires, 1952Chapter 14 Delocalized Pi SystemsTrigonalThe π bond is e-rich: E+ attack, R∙ add The lobes of the p-orbitals: Perpendicular to the sigma frame and parallel to each other.Recall the double bondEtheneF2-Propenyl (Allyl)Question: What about adding a third p-orbital adjacent to the double bond?Is there something special?Or: Is there any special reactivity at the carbons adjacent to a double bond?Ha.b.c.SN1 reactivity of allylic carbon like that of RsecX, even though it is primary!pKa ~ 40: Acidic!50SN187 kcal mol-1: Weak!101 kcal mol-1Replacing one of the hydrogens in ethene with another sp2-hybridized carbon gives a propenylic or allylic system.Allylic positionObservations:HLHBBHHClearly: Allylic · are stabilized.-+Short notation: Dotted linesWhy? Resonance!Reactivity of Allylic PositionA. Radical HalogenationCH2 CHCH3+Br2CH2 CH CH2Br+HBrFaster than addition!Low conc.Mechanism:1.2.Br22 Br.hυ or ΔInitiation:Propagation:CH2 CHCH3+Br.CH2 CH CH2.CH2 CH CH2.+HBrCH2 CH CH2.CH2 CH CH2.Br2CH2 CH CH2Br +Br.or ROOR radical initiatorTermination:3.Br.+.CH2CH CH2BrCH2CH CH2Br.Br.+Br2CH2CH CH2.2CH2CH CH2CH2 CHCH2Anything that traps radicals, including the “dirt” on the walls of the flask, contributes to termination.Catalytic traces,always present in NBSLow conc.A convenient solid brominating agent: N-Bromosuccinimide, NBSMechanism?Electronegativity N and Br = 3.0, but carbonyl pullsδ+δ-AllylicF11Stoichiometry: Br2 does not show up, but is the actual brominating sbpecies! Propene generates a symmetrical allylic radical and only one product. For unsymmetrical systems: mixtures. Ratios depend on % radical character on each carbon and TSs leading to products. B. SN1: The Allylic Cation is StabilizedCH3CH CHCH2ClH2O- Cl-CH3CH CH CH2+CH3CH CH CH2+CH3CH CHCH2OHCH3CHCH CH2OHH+ ++ H+Two productsC. SN2: Fast! The allylic TS is stabilized and the allylic carbon is relatively electrophilic.CH3CH CHCH2ClNaICH3CH CH CClI..+‡CH3CH CHCH2I+Cl-100 times faster than....δ-δ-δ+sp2 = e-withdrawingTS delocalizedD. Allylic Organometallics+Alternative preparation: allylic Grignard reagentsMg+We shall encounter neutral analogs of allylic anions:X = OR, SR, NR2H2CCCH3CH2LiH2CCCH3CH2CHRMgBrX:isoelectronic toOOHRCHConjugated Double BondsWhat about Nomenclature: Cis/trans; E/Z. Review Chapter 11?Does Conjugation Impart Stability? Heats of hydrogenation (kcal mol-1)CH3(CH2)3CH CH2H2+1,5-Hexadiene1,3-ButadieneBut:Resonance energy of butadiene ~ 3.5 kcal mol-1ΔH˚-30.3-60.5-57.12 H2+2 H2+Seems small, but has profound effect on equilibria. Recall ΔGRT0 = -1.36 log K (Table 2.1); hence K = 10-ΔG/1.36 Short relative to an alkane C―C single bond (1.54 Å). FastStructure“s” Refers to single bondAcceptable: s-cis = syn, s-trans = antiConjugation stabilizes thermodynamically, but it also increases reactivity, for example in electrophilic additions (review Chapter 12).1,2-Addition (faster “kinetic”)Reason: Intermediate cation is also stabilized+HClCl-1,4-Addition (slower but leads to more stable product “thermodynamic”)CH3ClCH3ClCH3CH3Cl-+ cisHClAddnF11FastTerminal alkene less stable than internalMarkovnikov addition with a twist:Less stableMore stableBoth reversible by SN1Kinetic vs Thermodynamic ControlKineticThermodynamicKinetic vs Thermodynamic ControlWhat is happening at 40°C? The kinetic products start dissociating by SN1, setting up an equilibrium with the intermediate allylic cation. Thus the initial kinetic ratio of 70%:30% changes to the thermodynamic ratio of 15%:85%.Ratio reflects the relative thermodynamic stability: more substituted double bond more stable.SN1 of products slowSN1 of products fastXStronger contributorWeaker contributorLet us look at the allylic cation “relay”:Extended Conjugation+HBrBr-Three productsCH3CH3CH3Quite reactive, even thoughstabilized by conjugationThermodynamic stability does not always equal lack of reactivityCation also stabilized by conjugationCyclohexatriene is Special - BenzeneCyclic array of six electrons has special stability, called aromaticity (Chapter 15).Benzene is relatively inert to H2-cat, electrophiles, oxidants, in comparison with hexatriene.Extended Conjugation in Natural and Unnatural ProductsOrange color of carrotsBiological degradationVisionOrganic ConductorsHeeger, MacDiarmid, Shirakawa, Nobel Prize 2000(based on discoveries made in 1970, 1976)~AgHCCHTi catalystLight emitting diodes (LEDs)Conjugated Systems Undergo Special Transformations: Pericyclic ReactionsThe conjugated π system can react as a unit, involving both ends. For example,1. Cycloadditions: The Diels-Alder reaction, a [4+2] cycloaddition+Δ4π-4C Diene2π-2C Dienophile20%CycloadductHCHCCH2CH2H2CCH2HCCH2HCCH2CH2CH2Otto Diels1876-1954Kurt Alder1902-1958Nobel Prize 1950Diels-Alder reactions work best when we pair ane-rich (push) diene with an e-poor (pull) dienophile,(or an e-poor diene with an e-rich dienophile)The Diels-Alder Reaction is ChemoselectiveDepends on substituents:e-Donating: Alkyl, alkoxy, alkylthioCH3,CH3O, CH3CH2SInduction and HyperconjugationResonanceEven though O is e-negative (inductive effect), resonance wins out.OCH3OCH3OCH3e-Withdrawing: CF3, CR, C N, NO2OResonance:Example:Inductive:Does not compete with dienophile: relatively e-rich.90%+ΔCFFFH2CCCRHOH2CCCRHOH2CCCRHOCROCROSome Examples of the Trend in Reactivity of Dienophiles and Dienes +ΔOrbital description:sp3Mechanism: Concertedsp2sp2Diels-Alder reaction requires accessing the less stable s-cis conformation When s-cis form is impossible, the reaction does not occur. When diene is constrained s-cis, the transformation is accelerated.When s-cis form is hindered, the reaction slowsConsequences of ConcertednessStereospecific: Retention of Dienophile Stereochemistry (new C—C bonds green)++CisCis (racemic)TransTrans (racemic)80%90%Retention of Diene Stereochemistry++Trans,trans (same for cis,cis-diene)Cis,trans“Endo rule” determines their preferred approachWhat happens when both partners are stereochemically defined?EndoExoEndo/Exo AdditionDAF11Usually faster, even though product less stable: Kinetic controlGenerally:+Another example:EndoWalbaCtFReasons for endo rule are complex. of Organic Reactions and RearrangementsEricAlkynes as DienophilesGenerate 1,4-cyclohexadienes+Can react again75%Δ, Ea = 32.9 kcal mol-1 hυExothermic (ring strain released)Light driven: Can beat thermodynamics. Wavelength dependent (can go either way).ΔH ° = -9.7 kcal mol-1 2. Electrocyclic Reactions: Intramolecular ring closure and openingsThe Cyclobutene  1,3-Butadiene Equilibrium Immel AltEnterEndothermic(C C better than C C, and no ring strain present) Δ, Ea = 29.9 kcal mol-1 Light driven: Can beat thermodynamics. Wavelength dependent (can go either way).The 1,3-Cyclohexadiene  1,3,5-Hexatriene Equilibrium ΔH ° = +14.7 kcal mol-1 Immel AltEnterhυElectrocyclic Reactions are StereospecificΔcis–3,4-DimethylcyclobuteneTransOnly!Only!cis,trans–2,4-HexadieneTrans,transΔMovement of SubstituentsConrotatoryConrotatory: They rotate in the same directionΔImmelBoth either clockwise or counterclock- wise: Same product.Conrotatory (clockwise)Counterclockwise conrotation in principle possible but sterically prohibited:ΔΔdisdisFascinatingly, hυ goes disrotatory (rotation in opposite directions)Ring openingRing closureΔ = disEven more startling: The hexatriene/cyclohexadiene interconversion is also stereospecific, but follows the opposite rules of sense of rotation, compared to the butadiene/cyclobutene system:Immelhυ = con Robert B. Woodward1917-1979NP 1965Roald Hoffmannb. 1937; NP 1981