Ch.16 Chemistry of Benzene: Electrophilic Aromatic Substitution Electrophilic aromatic substitution: E + E + + Some electrophilic aromatic substitution: X N 2 S 3 R C R alogenation Nitration Sulfonation Alkylation Acylation
16.1 Bromination of Aromatic Rings Bromination: Br Br 2 FeBr 3 + Br electrophilic addition mechanism: - - similar first electrophilic addition mechanism but aromatic rings are less reactive (more stable) than alkenes
- need catalyst for aromatic electrophilic substitution δ - δ + - FeBr 3 + Br Br Br Br Br FeBr + Br + 3 Fe or 4 a strong electrophile Br + Br Br Br allylic carbocation three resonance forms : stable but, much less reactive than the aromatic reactant endothermic, high E a, slow reaction
- electrophilic aromatic substitution need higher activation energy than alkene does E E a, alkene Energy alkene + E + E E a, benzene benzene + E + Reaction progress
overall substitution: addition + rearomatization Br + slow Br nonaromatic intermediate FeBr 4 - X fast aromatic product Br addition Br Br + Br + FeBr 3 nonaromatic product
electrophilic bromination E Energy E a Br Br benzene + Br 2 Br + Br Reaction progress
16.2 ther Aromatic Substitutions Chlorination 3 C N 2 cat Fe 3 + N 86% Diazepam (tranquilizer)
Iodination l + 2 Cu 2+ 2 2 I + + 2 Cu + l 2 I cat Cu 2 65%
Nitration : N 3 + 2 S 4 (cat) N + N N 2 + + 2 C 3 N 3 N 2 cat 2 S 4 85% 2 N N 2 N 2 Trinitrotoluene (TNT)
reduction of nitro to aniline N 2 1. Sn 2, 3 + N 2 2. -
Sulfonation : fuming sulfuric acid, S 3 + 2 S 4 (cat) S + S S 3 N 2 S 3 cat 2 S 4 95% S 2 N 2 sulfanilimide (a sulfa drug)
alkali fusion reaction S 3 1. Na, 300 o C 2. 3 + p-cresol (72%) C 3 C 3
16.3 Alkylation of Aromatic Rings: The Friedel-Craft Reactions Friedel-Craft Alkylation - Al 3 + 3 C C 3 Al 4 3 C C + 3 + 3 C C 3 Al 3 + Cumene (85%)
Limitation: - only useful for R not for Ar or vinyl chloride - aromatic rings with electron-withdrawing groups are unreactive - aromatic rings with amino group are unreactive: amines under go acid-base reaction with Al 3 Y + Al 3 R X N reaction Y = NR 3 +, N 2, CN, S 3, C, CR, C, CR = N 2, NR, NR 2
polyalkylation problem + (C 3 ) 3 C Al 3 C(C 3 ) 3 C(C 3 ) 3 + minor C(C 3 ) 3 major - use excess of benzene for mono alkylation
skeleton rearrangement: carbocation Al 3 + + 65% 35%
carbocations: skeleton rearrangement to a more stable cation C 2 ydride shift 3 C C Alkyl shift 2 3 C 3 C C 3 C 3 C 3 + Al 3
16.4 Acylation of Aromatic Rings Friedel-Craft Acylation C 3 + C 3 Al 3 80 o C + Acetophenone (95%) - Al 3 + C + Al 4 R R C R - no polyacylation: less reactive acyl product
16.5 Substituent Effects in Substituted Aromatic Rings 1. Reactivity N 2 relative rate of nitration 6 x 10-8 0.033 1 1000
2. rientation N 3 2 S 4, 25 o C N 2 + + N 2 N 2 o-nitrophenol m- p- 50% 0% 50% CN N 3 2 S 4, 25 o C CN N 2 CN CN + + N 2 N 2 o-nitrobenzonitrile m- p- 17% 81% 2%
Substituent Effects in Electrophilic Aromatic Substitution electron-poor electron-rich -N 2 -S 3 -C -C -Br -F -Ph -Me - -NR 3 + -CN -CC 3 -CC 3 -I - - -C 3 alkyl -NCC 3 -N 2 meta-directing deactivators ortho- and paradirecting deactivators ortho- and paradirecting activators no meta-directing activators
Two factors in activating/deactivating effect: inductive effect: electronegativity differences resonance effect: lone pair electrons, double bond Inductively withdrawing groups - positive charges at the neighboring atom inductively withdrawing δ + δ X δ C δ + R δ C δ + R C N δ δ + N δ + δ X= F,, Br, I inductively donating R
Resonance effect: withdraw or donate electrons through a π-bond - the effect is greatest at the ortho and para positions electron withdrawing resonance effect C R C R C R C R δ Z Y δ + δ C δ + R δ C N δ + N δ + δ
Electron donating resonance effect - the effect is greatest at the ortho and para positions Y N 2 R X X= halogen - inductive effect and resonance effect don't necessary act in the same direction ; -X, -, -N atoms are inductively withdrawing groups but electrondonating resonance effect
16.6 An Explanation of Substituent Effects Activating/deactivating effect Activating groups: donate electrons to the ring - stabilize carbocation intermediate - lower the activation energy for carbocation formation Deactivating groups: withdraw electrons from the ring - destabilize carbocation intermediate - raise the activation energy for carbocation formation
Y Y > > E + E + E + Y Y E E E stabilized destabilized carbocation carbocation
rientating Effect ortho, para directors: - lone pair electrons - stabilize carbocation intermediate by resonance N 2 R Br halogens: - inductively deactivating - but ortho, para directing by resonance stabilization
alkyl group: ortho, para activator C 3 C 3 C 3 + N N 2 2 N 2 N 2 ortho 63% Most stable C 3 C 3 C 3 C 3 meta 3% N 2 N 2 N 2 C 3 C 3 C 3 para 34% N 2 N 2 N 2 Most stable
, N 2 group: ortho, para activator + N N 2 N 2 2 N 2 N 2 ortho 50% Most stable meta 0% N 2 N 2 N 2 para 50% N 2 N 2 N 2 N 2 Most stable - stabilizing resonance interactions for ortho and para additions
halogen group: ortho, para adectivator + N N 2 N 2 2 N 2 N 2 ortho 35% Most stable meta 1% N 2 N 2 N 2 para 64% N 2 N 2 N 2 N 2 Most stable - inductively deactivating - stabilizing resonance interactions for ortho and para additions
EWG group: meta deactivator δ + C C C + ortho δ C δ + 19% Least stable C C C meta 72% C C C para 9% Least stable destabilizing inductive interactions for ortho and para additions
A Summary of Substituent Effects in Aromatic Substitution Substituents Reactivity rientation Inductive Effect Resonance Effect -C 3 activating ortho para weak; electrondonating none -, -N 2 activating ortho para weak; electronwithdrawing strong; electrondonating -F,, Br, I deactivating ortho para strong; electronwithdrawing weak; electrondonating -N + (C 3 ) 3 deactivating meta strong; electronwithdrawing none -N 2, -CN, - C, -C 2 Me, - CC 3, -C deactivating meta strong; electronwithdrawing strong; electronwithdrawing
16.7 Trisubstituted Benzenes: Additivity of Effects 1. two groups reinforce each other: C 3 C 3 N 3 N 2 2 S 4 N 2 N 2
2. two groups oppose each other: more powerful directing group wins, but mixture of products often result C 3 C 3 Br 2 Br
3. sterically hindered site: further substitution rarely occurs between the two groups in a metadisubstituted compound C 3 too hindered 2 Fe 3 C3 + C 3 C 3 NT formed - alternative preparation 1,2,3-trisubstituted compound C 3 C 3 C 3 N 2 N 2 N 3 N 2 + N 2 2 S 4 N 2
16.8 Nucleophilic Aromatic Substitution nucleophilic aromatic substitution: no S N 1, S N 2 mechanism 2 N N 2 1. Na 2 N N 2 2. 3 + + - N 2 N 2 100%
X + - sp 2 orbital (unstable) no S N 1 reaction - X no S N 2 reaction
addition/elimination mechanism - - + N 2 N 2 N 2 Meisenheimer complex - nucleophilic aromatic substitution occurs only if the aromatic ring has electron withdrawing group(s) in ortho or para position to the halogen - meta substituent has no resonance stabilization
nucleophilic aromatic substitution: need ortho or para EWG - ortho N 2 N 2 - para 2 N 2 N N N meta - X no stabilization of charge by nitro group N 2 N 2
16.9 Benzyne nucleophilic aromatic substitution of non-activated system ; need high temperature and high pressure 1. Na, 2, 340 o C, 2500psi + Na 2. 3 + benzyne intermediate; elimination/addition mechanism - 2 - elimination Benzyne addition
evidence for benzyne mechanism: 14 C labeling at C1 N 3 * KN 2 N3 * * * N + 3 addition Benzyne 50% 50% symmetrical N 3
trapping benzyne intermediate Br KN 2 N 3 Benzyne dienophile Diels-Alder adduct C C C C C C
16.10 xidation of Aromatic Compounds xidation of Alkylbenzene Side Chains aromatic rings; inert to KMn 4 benzylic C 2 : oxidized to -C by KMn 4, Na 2 Cr 2 7 industrial procedure C 3 KMn 4 2 C C C 3 2 C 3 Co (III) C
attack benzylic C- bonds 3 C C 3C3 C KMn 4 2 N reaction
Bromination of Alkylbenzene Side Chains NBS (PhC 2 ) 2 C 4 Br + N
radical mechanism R Br R Br 2 Br R + Br Br Br + N Br Br 2 + N
resonance stabilized benzylic radical
16.11 Reduction of Aromatic Compounds Catalytic ydrogenation of Aromatic Rings aromatic rings; inert to normal hydrogenation conditions 2, Pd Et
but, at high pressure of 2 and high temperature or use reactive rhodium catalyst ; reduced to cycloalkanes C 3 2 (2000 psi) C 3 C 3 Pt Et 25 o C 100% C 3 2 (1 atm) Rh/C Et 25 o C 100%
Reduction of Aryl Alkyl Ketones ; neighboring carbonyl groups are reactive under reducing condition Al 3 2, Pd Et Al 3 +
nitro groups are reduced under the reaction conditions 2 N 2, Pd 2 N Et
synthesis of complex molecules starting from simple precursors; - pharmaceutical industry: new drugs - chemical industry: economical routes to known compounds - academic: applications + pure challenges planning synthesis needs - knowledge about organic reactions - practical ability: any problems retrosynthetic analysis: design reaction schemes backward in case complex molecules
16.12 Synthesis of Trisubstituted Benzenes N 2?... N 2 N 2 N 3 2, Fe 2 S 4 3 X N 3 2 S 4
Br? C Br KMn 4 Br C 3 Al 3 Br Br 2, FeBr 3 C C 3 Br 2, FeBr 3 Br 2, FeBr 3 C 3, Al 3 C C 3
2, Pd/C N 2 N 2 deactivated ring will not undergo Friedel-Craft rxn ; N 3 2 S 4 no correct isomer N 2
Chemistry @ Work Combinatorial Chemistry R 1 R 4 N N R 3 Benzodiazepine library (R 1 -R 4 are various substituents) R 2
Chemistry @ Work 2,180,106 compounds
Problem Sets Chapter 16 28, 33, 35, 40, 54, 64, 70