Electrophilic Aromatic Substitution Part 1

1. Generic reaction: Electrophilic Aromatic SubstitutionPart 1 Optional reading: OCATSA email for access: harding@chem.ucla.edu

2. Nucleophile (pi bond) Electrophile (induced dipole) d- d+ d- d+ Introduction • Fact: Alkenes undergo electrophilic addition • Addition reaction: Increases the number of groups attached to the substrate at the expense of a pi bond How is the Br-Br dipole induced? DEN = 0 No bond dipole Weak C=C/Br-Br repulsion Weak Br-Br polarization Strong Br-Br polarization

3. Addition to Benzene Pi Bonds? Question: Benzene has pi bonds...also adds Br2? X No reaction occurs (NR) • Why NR? What is special about benzene? • Is benzene a nucleophile? Benzene has pi electrons  Benzene is a nucleophile • Is Eact too large? Benzene + Br2 gives a stable intermediate  Eact probably ok Resonance-stabilized carbocation

4. Not aromatic e- acceptor Permanent d+ Electrophile = e- deficient Therefore take e- away from Br So What It Up With Benzene? How else is benzene different from an alkene? Aromatic • Aromaticity - worth 36 kcal mol-1 of stabilization • Loss of aromaticity = large increase in Eact = mechanism step too expensive • How to solve this problem? • Make Br2 more electrophilic FeBr3 More electrophilic than Br2 alone

5. Useful reminder Arenium ion Reaction and Mechanism Mechanism? Arenium ion resonance hybrid:

6. Arenium Ion Fate? Arenium ion = a carbocation, so carbocation fates apply Capture a nucleophile: Aromaticity not restored • Be deprotonated; form pi bond: • Weak base adequate Aromaticity restored

7. Electrophilic aromatic substitution (EAS) Reaction Name and Kinetics Overall reaction Mechanism Kinetics: Which is rds? • Carbocation formed • Aromaticity lost • Rate-determining step • Carbocation quenched • Aromaticity restored Reaction rate depends on: Nucleophilicity of benzene ring Arenium ion stability Strength of electrophile

8. Benzene + + What If Benzene Ring Has Substituent(s)? Only one product possible 2-Bromotoluene Ortho-bromotoluene 3-Bromotoluene Meta-bromotoluene 4-Bromotoluene Para-bromotoluene Toluene

9. Which Product is Major? Number of positions (probability) Steric hindrance to electrophilic attack Ortho attack (between CH3 and H) More hindered Two ortho positions Two meta positions One para position Meta attack (between H and H) Less hindered Product ratio conclusion: 40% ortho, 40% meta, 20% para Para attack (between H and H) Less hindered Product ratio conclusion: meta, para > ortho

10. Which Product is Major? Arenium ion stability More stable Ortho attack: 3o 2o 2o Less stable Meta attack: 2o 2o 2o More stable Para attack: 2o 2o 3o Product ratio conclusion: ortho, para > meta

11. Reversed when steric effects are large enough Which Product is Major? • Summary • Number of positions: ortho, meta > para • Steric effects: meta, para > ortho • Arenium ion stability: ortho, para > meta Which factor dominates? Ask Mother Nature... 60% <1% 40% Conclusion: arenium ion stability >>> number of positions > steric effects

12. } Electron donation (resonance) outweighs electron withdrawing (induction) Directing Effects • CH3 is an ortho/para director • Why? Arenium ion stability • CH3 stabilizes adjacent carbocation by electron-donating inductive effect Extension: Any carbocation stabilizing group = ortho/para director Ortho/para directors Alkyl groups (-CH3, -CH2CH3, etc.) Pi bonds: alkene, alkyne, aromatic rings Lone pairs (-X:) -OH, -OR -NH2, -NHR, -NR2 -F, -Cl, -Br, -I Others... In general... If it stabilizes a carbocation it is an ortho/para director.

13. Nucleophilicity: Arenium ion stability: Substituent Effects: Kinetics ? or Which reacts faster with Br2/FeBr3: • Rate-determining step: electrophile + nucleophile  arenium ion • Electrophile: same in both cases • Nucleophile: CH3 is electron-donating group (EDG) • H is neither EDG or EWG > • Arenium ion: CH3 is electron-donating group • H is neither EDG or EWG > Conclusion: Br2/FeBr3 reacts faster with toluene than with benzene

14. Electron donation (resonance) outweighs electron withdrawing (induction) } Activating Effects CH3 is an EAS activator • Why? Relative to H... • CH3 enhances benzene ring nucleophilicity • CH3 increases arenium ion stability • CH3 is electron-donating group; stabilizes adjacent carbocation • Extension: Any carbocation-stabilizing group is an activator • EAS Activating Groups • Alkyl groups (-CH3, -CH2CH3, etc.) • Pi bonds: alkene, alkyne, aromatic rings • Lone pairs (-X:) -OH, -OR • -NH2, -NHR, -NR2 Better electron donors = more powerful activators

15. Activating Effects: An Exception Are all ortho/para directors also activators? Yes, except F, Cl, Br, and I Why? Balance of electron-donation versus electron-withdrawal Does transition state look more like benzene ring or arenium ion? Net effect: F, Cl, Br, I are ortho/para directors, but deactivators Example: • OCH3 is ortho/para director • OCH3 is activator • Reaction faster than benzene + Br2/FeBr3 • F is ortho/para director • F is deactivator • Reaction is slower than benzene + Br2/FeBr3

16. Nitro group Substituent Effects: the Nitro Group (NO2) Predict major product: Nitro group structure?

17. Electrophilic Aromatic SubstitutionPart 2

18. Example: arenium ion Part 1 Summary Electrophilic aromatic substitution (EAS): electrophilic attack on aromatic ring leads to hydrogen atom replacement ortho meta para Mechanism: rds Substituent effects: CH3 is an ortho/para director and activator

19. Nitro group Substituent Effects: the Nitro Group (NO2) Predict major product: Nitro group structure?

20. Bad ! Substituent Effects: the Nitro Group (NO2) Arenium ion stability Ortho attack: 2o 2o 2o Meta attack: 2o 2o 2o Para attack: 2o 2o 2o Product ratio conclusion: meta > ortho > para

21. Directing Effects • NO2 is an meta director • Why? Arenium ion stability • NO2 destabilizes adjacent carbocation by electron-withdrawing inductive effect • Extension: Any carbocation destabilizing group = meta director • Meta directors • -NO2 • -+NH3, -+NH2R, -+NHR2, -+NR3 • -C=O (ketone, aldehyde, ester, carboxylic acid, etc.) • -CN • -CF3 • -SO3H sulfonic acid • Others... In general: If it destabilizes a carbocation it is a meta director.

22. Nucleophilicity: Arenium ion stability: Substituent Effects: Kinetics ? or Which reacts faster with Br2/FeBr3: • Rate-determining step: electrophile + nucleophile  arenium ion • Electrophile: same in both cases • Nucleophile: NO2 is electron-withdrawing group (EWG) • H is neither EDG or EWG < • Arenium ion: NO2 is electron-withdrawing group • H is neither EDG or EWG < Conclusion: Br2/FeBr3 reacts more slowly with nitrobenzene than with benzene

23. o/p director Other Electrophiles: BrominationAr-H  Ar-Br Origin of electrophile: --or-- : Example: Write out the complete mechanism for yourself

24. more hindered * * o/p director * * * * Other Electrophiles: ChlorinationAr-H  Ar-Cl Origin of electrophile: --or-- EDG Example: major minor Write out the complete mechanism for yourself

25. + electrophile + + What is the Electrophile? A useful pattern for remembering EAS reactions... comes from Bromination: comes from Chlorination: General EAS: comes from

26. o/p director Other Electrophiles: NitrationAr-H  Ar-NO2 Electrophile: +NO2 Origin of electrophile: --or-- : Example: Write out the complete mechanism for yourself

27. ortho/para director meta director director Just Who Is In Charge Here? Nitration of bromobenzene: Bromination of nitrobenzene: Generic EAS reaction:

28. meta director Other Electrophiles: SulfonationAr-H  Ar-SO3H (sulfonic acid) Electrophile: +SO3H Origin of electrophile: --or-- EWG Example: Write out the complete mechanism for yourself

29. How? Other Electrophiles: Friedel-Crafts AlkylationAr-H  Ar-R (R = alkyl group) Electrophile: R+ (a carbocation) Origin of electrophile: Less stable carbocations More stable carbocations • Carbocation rearrangements possible Example: Electrophile = +C(CH3)3 Write out the complete mechanism for yourself

30. (a ketone) How? Electrophile = Other Electrophiles: Friedel-Crafts Acylation Electrophile: Acylium ion Origin of electrophile: Example: Write out the complete mechanism for yourself

31. Other Electrophiles: Diazo Coupling Electrophile: Diazonium cation Origin of electrophile: • Mechanism? An OWLS problem Example: Write out the complete mechanism for yourself

32. Ar-N=N-Ar suggests synthesis via diazo coupling Strawberry soda colored with Allura Red AC EAS Application Example:Synthesis of Allura Red C • Allura Red AC (an azo dye) • Color due to extensive conjugation • Many dyes are diazo compounds

33. EWG Nucleophile Electrophile Deactivated Activated * EDG * Synthesis of Allura Red C o/p director Allura Red AC