Bài giảng Organic Chemistry - Chapter 16 Electrophilic Attack on Derivatives of Benzene

Electrophilic Attack on Derivatives of Benzene What are the effects of the substituent?Reactivity of the benzene ring b. Regiochemistry of EAS: ortho, meta, paraDonors and AcceptorsDonors activateAcceptors deactivateActivators: Send electrophile to the ortho and para positionsDeactivators: Send electrophile to the meta positionsInduction and ResonanceInductive effect:Occurs through the σ framework- Tapers off rapidly with distance -Governed by hyperconjugation and electronegativity of atoms and resulting polarization of bondsBoth can operate, not always in the same direction, but resonance usually winsResonance effect: Usually overrides inductive effect when in competition.-Takes place through π bonds -Longer range-Strong in chargedsystemsSpecialdeactivateA. InductionSame results with HNO3, SO3, Friedel-Crafts reagents: Mainly ortho and para substitution (less ortho, because of sterics). Why ortho-para ?1. Donors: R = alkyl, activate by induction and hyperconjugation, ortho/para directingFaster than benzeneNo further bromination, because Br deactivatesMechanism:Steric effect larger with large alkyl group: tert-Bu gives only paraFriedel-Crafts reactions with deactivated arenes are too slow, but other E+ work. Why meta?2. Acceptors: R = -CF3, -CCl3, -C(OR)3, deactivate by electronegativity, meta directingSlower than benzeneMechanism:Wins by default: Least bad optionB. Resonance1. Donors: R = -NH2, -NR’R”, -NHCR’, -OR,activate by resonating lone pairs, ortho/para-directing. Do not even need catalyst in halogenations!OWhy ortho/para? Resonance wins over inductionMechanism:EASNH2Octet!!Octet!!Reminder: Friedel-Crafts reagents too slow. Why meta?2. Acceptors: R = COOH, CR, NO2, SO3H, C N, deactivate by resonance, meta-directingOMechanism:EASCO2H3. Exception: R = X (halogen), deactivate (slightly) by electronegativity. Here: Induction wins over resonance in the starting arene.Nevertheless: ortho/para-directing! Why? Resonance wins over induction in charged intermediate.Mechanism:Octet!!Octet!!Summary of Substituent Effects(rates relative to benzene)~105~103~10~10-2~10-3~10-5~10-8Disubstituted Benzenes-Higher SubstitutionSubstituent Effects are AdditiveThe Strongest Activator WinsGUIDELINE 1. The most powerful activator controls the position of attackGUIDELINE 2.Three classes of substituents in the order of diminishing control when in competition: 1. Best: resonance activators NR2, OR;2. Second: halogens X and inductive activators, e.g., R3. Last: deactivators CO2R < CF3 < NO2When there is competition for regioselectivity between members of the same group, outcome is difficult to predict (unless they both point to the same position).GUIDELINE 3. When product mixtures are predicted on the basis ofguidelines 1 and 2, products from ortho attack tobulky groups or between two substituents are disfavored (dashed lines): sterics!GUIDELINE 4. Guidelines 1 through 3 apply to even more highly substituted benzenes. Remember: The strongest activator is in control! Note: Higher substitution in the starting material reduces the number of possible products: I.e., life gets easier....... -NO2 -NH2Reduction: Zn(Hg), HCl; or H2, Pd; or H2, Ni; or Fe, HCl OOxidation: CF3 COOHStrategies in EASWe can change the sense of the directing power of substituents(meta director) (ortho/para director) ReductionOxidationExamples:Retrosynthesis: Think of any N substituent as derived from NO2, which you can introduce by nitration.H2, Pd,2. –CR -CH2RReducing agents: H2, Pd, CH3CH2OH (hydrogenates carbonyl to alcohol, then cleaves the benzylic OH) or Clemmensen Reduction Zn(Hg), HCl, ΔOxidizing agents:CrO3, H2SO4, H2OO(meta director) (ortho/para director) ReductionOxidationRetrosynthesis: Think of any alkyl substituent RCH2- as derived from RCO-, which you can introduce by acylation.Direct butylation gives lots of (1-methylpropyl)benzene and overalkylation.3. Friedel-Crafts reactions do not work with strongly deactivated benzenes (i.e., no activating substituents present):But: Friedel-Crafts reactions are OK with halobenzenes (weakly deactivated) or with additional, activating substituents (cancel effect of deactivating group: back to guideline 1) 4. Use reversible sulfonation for blocking certain positions5. EAS in polycyclic benzenoids: An exercise in resonance. Example: NaphthaleneThe molecule is activated and selective for attack at C1:?Why?Let us look at resonance in the respective intermediate cations: Five resonance structures! = ActivationTwo resonance forms with intact benzene ringsAttack at C1Three resonance forms with disrupted cyclic conjugationAttack at C2Only one resonance form with an intact benzene ringEAS on Substituted NaphthalenesActivators: -Direct electrophile to the same ring -Ortho/paraExample: Deactivators: -Direct electrophile away (to other ring) and to α-positions (C5 and C8)Generally: Always write out the complete set of resonance forms of attack at all possible unique positions.StericsExam1