Diels-Alder Reaction

Organic Lecture Series

ConjugatedConjugated SystemsSystems && PericyclicPericyclic ReactionsReactions

Organic Lecture Series Conjugated Dienes from heats of hydrogenation-relative stabilities of conjugated vs unconjugated dienes can be studied:

0 Structural ΔH Name Formula kJ (kcal)/mol

1-Butene -127 (-30.3) 1-Pentene -126 (-30.1)

cis-2-Butene -120 (-28.6)

trans-2-Butene -115 (-27.6)

1,3-Butadiene -237 (-56.5) conjugated trans-1,3-Pentadiene -226 (-54.1) 1,4-Pentadiene -254 (-60.8) 2 Organic Lecture Series Conjugated Dienes

conjugation of the double bonds in 1,3-butadiene gives an extra stability of approximately 17 kJ (4.1 kcal)/mol

catalyst 0 22+ 2H2 ΔH = 2(-127 kJ/mol) = -254 kJ/mol)

catalyst ΔH0 = -237 kJ/mol + 2H2

Organic Lecture Series Conjugated Dienes The π systems of the 2 olefins overlap H H C C

H2C CH2

C C C C

S-cis conformer 4 Organic Lecture Series Conjugated Dienes

CH2 H C C H

H2C C

C C C

S-Trans conformer 5

Organic Lecture Series Summary of C—C Bond Reactions

Nucleophilic displacement of a leaving group by “R - ” Gilman & Grignard additions Alkyne and -CN anions Alkylation of enolates Alkylation of enamines 6 Organic Lecture Series Nucleophilic addition To carbonyl & carboxyl groups Gilman, Grignard & organolithium Alkyne and CN anions Aldol reactions Claisen & Dieckmann Enamine acylations Wittig & variations 7

Organic Lecture Series Conjugate addition to α,β- unsaturated carbonyls Michael reaction

Carbene / carbenoid additions Simmons-Smith cyclopropanations

Electrophilic Aromatic Substitutions Friedel Crafts alkylation & acylations

Diazonium with CN 8 Organic Lecture Series Conjugated Systems

– systems containing conjugated double bonds, not just those of dienes, are more stable than those containing unconjugated double bonds O O

2-Cyclohexenone 3-Cyclohexenone (more stable) (less stable)

Most significant are α,β-unsaturated carbonyl 9

Organic Lecture Series 1,2 vs 1,4-Addition OH Nu 1,2 Addition KineticProduct O 1 RLi and RMgBr

2 3

O 1,4 Addition Thermodynamic Product R 2 CuLi and RMgBr/Cu

Nu 10 Organic Lecture Series Simple Rxn Coordinate Diagram

Δ H is (-)

e.g. an Sn2 Mechanism 11

Organic Lecture Series A Two Step Mechanism:

≠ ≠

Δ H is (-)

e.g. an Sn1 Mechanism 12 Organic Lecture Series 1,2 vs 1,4-Addition • Addition of 1 mol of HBr to butadiene at -78°C gives a mixture of two constitutional isomers: -78°C CH2 = CH- CH= CH2 + HBr 1,3-Butadiene BrH Br H CH2 = CH- CH- CH2 + CH2 - CH= CH- CH2 3-Bromo-1-butene 1-Bromo-2-butene 90% 10% (1,2-addition) (1,4-addition)

– these products can be explained by the following two-step mechanism 13

Organic Lecture Series 1,2- and 1,4-Addition the key intermediate is a resonance-stabilized allylic carbocation:

2 2 2 2

14 Organic Lecture Series

2 2 2 2

90% 10%

Organic Lecture Series Kinetic vs Thermodynamic Control

90% 10%

Δ Go = Δ Ho –T ΔSo Gibbs Free energy

For transition states: Δ G≠ = Δ H ≠–T ΔS≠ 16 Organic Lecture Series DielsDiels--AlderAlder ReactionReaction

Diene Dienophile Cycloadduct

Dienophile is an alkene which is a reactant in the Diels-Alder reaction.

Organic Lecture Series Diels-Alder Reaction • Diels-Alder reaction: a cycloaddition reaction of a conjugated diene and certain types of double and triple bonds – dienophile: “diene-loving” – Diels-Alder adduct: the product of a Diels- Alder reaction O O

1,3-Butadiene 3-Buten-2-one Diels-Alder adduct (a diene) (a dienophile) 18 Organic Lecture Series

– alkynes also function as dienophiles

COOEt COOEt + COOEt COOEt 1,3-butadiene Diethyl Diels-Alder adduct (a diene) 2-butynedioate (a dienophile)

– cycloaddition reaction: a reaction in which two reactants add together in a single step to form a cyclic product

Organic Lecture Series

– the Diels-Alder reaction is shown in the following way:

Cyclohexene products

Diene Dieno- Adduct phile

• the special value of D-A reactions are that they (1) form six-membered rings (2) form 2 new C-C bonds at the same time (3) are stereospecific and regioselective

20 Organic Lecture Series

• Mechanism – no evidence for the participation of either radical or ionic intermediates – the Diels-Alder reaction is a pericyclic reaction • Pericyclic reaction:reaction a reaction that takes place in a single step, without intermediates, and involves a cyclic redistribution of bonding electrons

Organic Lecture Series

– the conformation of the diene must be s-cis

s-trans s-cis conformation con formation (lower in energy) (higher in energy)

22 Organic Lecture Series

–(2Z,4Z)-2,4-hexadiene is unreactive in Diels- Alder reactions because nonbonded interactions prevent it from assuming the planar s-cis conformation

methyl groups forced clos er th an allowed by van der Waals radii

s-trans conformation s-cis conformation (lower energy) (higher energy) (2Z,4Z)-2,4-Hexadiene 23

Organic Lecture Series reaction is facilitated by a combination of electron- withdrawing substituents on the dienophile and electron-releasing substituents on the diene

200°C + pressure 1,3-Butadiene Ethylene Cyclohexene O O 140°C +

1,3-Butadiene 3-Buten-2-one O O

+ 30°C

2,3-Dimethyl- 3-Buten-2-one 1,3-butadiene 24 Organic Lecture Series

Electron-Releasing Electron-Withdrawing Groups Groups

-CH3, alkyl groups -CHO (aldehyde, ketone) -OR (ether) -COOH (carboxyl) -OOCR (ester) -COOR (ester) -NO2 (nitro) -C N (cyano)

Use these to activate the diene Use these to activate the dienophile ERG EWG

Organic Lecture Series Stereochemistry of the Dienophile

the configuration of the dienophile is retained

COOCH3 COOCH3 +

COOCH3 COOCH3 A cis Dimethyl cis-4-cyclohexene- dienophile) 1,2-dicarboxylate

H3 COOC COOCH3 +

COOCH3 COOCH3 A trans Dimethyl trans-4-cyclohexene- dienophile) 1,2-dicarboxylate

cis-alkene gives cis products 26 Stereochemistry of the DieneOrganic Lecture Series the configuration of the diene is retained:

CH3 O H C 3 H O

+ O O

H O H C O CH3 3

O H3 C O CH3 H

+ O O CH 3 H O H C O 3 27

Stereochemistry of the DieneOrganic Lecture Series

The diene’s substitutents are turned “inside out”

28 Organic Lecture Series

B C

B D A C A D

π bond B rotates counterclockwise C rotates clockwise B C This is called: Disrotation

A D

2 σ bonds 29

Organic Lecture Series Summary

30 Organic Lecture Series Summary