Organic Chemistry - City University of New York

Organic Chemistry - City University of New York

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-Butadiene3-Buten-2-one (a diene) (a dienophile) Diels-Alder adduct 24-1 Diels-Alder Reaction Alkynes also function as dienophiles. COOEt

COOEt + COOEt 1,3-butadiene Diethyl (a diene) 2-butynedioate (a dienophile) COOEt Diels-Alder adduct Cycloaddition reaction: A reaction in which two reactants add together in a single step to form a cyclic product. 24-2 Diels-Alder Reaction We write a Diels-Alder reaction in the following way: Diene Dienophile Adduct

The special value of D-A reactions are that they: 1. form six-membered rings. 2. form two new C-C bonds at the same time. 3. are stereospecific and regioselective. Note the reaction of butadiene and ethylene gives only traces of cyclohexene. 24-3 Diels-Alder Reaction The conformation of the diene must be s-cis. s-trans conformation (lower in energy) s-cis conformation (higher in energy) 24-4 Diels-Alder Reaction Steric Restrictions (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 closer than allowed by van der Waals radii s-trans conformation s-cis conformation (lower energy) (higher energy) (2Z,4Z)-2,4-Hexadiene 24-5 Diels-Alder Reaction Reaction is facilitated by a combination of electronwithdrawing substituents on one reactant and electron-releasing substituents on the other. 200 C pressure + 1,3-Butadiene

Ethylene Cyclohexene O O 140 C + 1,3-Butadiene 3-Buten-2-one O O + 30C 2,3-Dimethyl3-Buten-2-one 1,3-butadiene

24-6 Diels-Alder Reaction Electron-ReleasingElectron-Withdrawing Groups Groups -CH3, alkyl groups -CHO (aldehyde, ketone) -OR (ether) -COOH (carboxyl) -OOCR (ester) -COOR (ester) -NO2 (nitro) -C N (cyano) 24-7

Diels-Alder Reaction The Diels-Alder reaction can be used to form bicyclic systems. + room temperature Diene Dienophile 170C H H Dicyclopentadiene (endo form) 24-8 Diels-Alder Reaction Exo and endo are relative to the double bond derived from the diene. the double bond

derived from the diene exo (outside) relative to the double endo (inside) bond 24-9 Diels-Alder Reaction For a Diels-Alder reaction under kinetic control, endo orientation of the dienophile is favored. O + OCH3 Cyclopentadiene Methyl propenoate 7 COOCH3

H redraw6 5 4 1 2 3 COOCH3 Methyl bicyclo[2.2.1]hept-5-enendo-2-carboxylate (racemic) 24-10 Diels-Alder Reaction The configuration of the dienophile is retained. COOCH3 COOCH3 + COOCH3

A cis dienophile) H3 COOC COOCH3 Dimethyl cis-4-cyclohexene1,2-dicarboxylate COOCH3 + COOCH3 A trans dienophile) COOCH3 Dimethyl trans4-cyclohexene1,2-dicarboxylate (racemic) 24-11 Diels-Alder Reaction The configuration of the diene is retained.

CH3 O + CH3 CH3 + CH3 H3 C H O O O H3 C O

H3 C O O O H O H O Check that this is endo. O H O H3C 24-12

Diels-Alder Reaction Mechanism No evidence for the participation of either radical of ionic intermediates. Chemists propose that the Diels-Alder reaction is a concerted pericyclic reaction. Pericyclic reaction: reaction A reaction that takes place in a single step, without intermediates, and involves a cyclic redistribution of bonding electrons. Concerted reaction: All bond making and bond breaking occurs simultaneously. 24-13 Diels-Alder Reaction

Mechanism of the Diels-Alder reaction 24-14 Aromatic Transition States Hckel criteria for aromaticity: The presence of (4n + 2) pi electrons in a ring that is planar and fully conjugated. Just as aromaticity imparts a special stability to certain types of molecules and ions, the presence of (4n + 2) electrons in a cyclic transition state imparts a special stability to certain types of transition states. Reactions involving 2, 6, 10, 14.... electrons in a cyclic transition state have especially low activation energies and take place particularly readily. 24-15 Aromatic Transition States, Examples

Decarboxylation of -keto acids and -dicarboxylic acids. O H O O H O C O O O + CO2 (A cyclic six-membered enol of transition state)

a ketone Cope elimination of amine N-oxides. C H C CH3 heat N+ O CH3 A cyclic six-membered transition state C C An alkene + H

O N CH3 CH3 N,N-dimethylhydroxylamine 24-16 Aromatic Transition States the Diels-Alder reaction Diene Dienophile Adduct pyrolysis of esters (Problem 22.42) We now look at examples of two more reactions that proceed by aromatic transition states:

Claisen rearrangement. Cope rearrangement. 24-17 Claisen Rearrangement Claisen rearrangement: A thermal rearrangement of allyl phenyl ethers to 2-allylphenols. O OH 200-250C Allyl phenyl ether 2-Allylphenol 24-18 Claisen Rearrangement O

O heat Allyl phenyl ether Transition state O H keto-enol tautomerism A cyclohexadienone intermediate OH o-Allylphenol 24-19 Cope Rearrangement

Cope rearrangement: A thermal isomerization of 1,5-dienes. heat 3,3-Dimethyl1,5-hexadiene 2-Methyl-2,6heptadiene 24-20 Cope Rearrangement Example 24.8 Predict the product of these Cope rearrangements. 350C (a) OH 320C (b) H

24-21 Synthesis of Single Enantiomers We have stressed throughout the text that the synthesis of chiral products from achiral starting materials and under achiral reaction conditions of necessity gives enantiomers as a racemic mixture. Nature achieves the synthesis of single enantiomers by using enzymes, which create a chiral environment in which reaction takes place. Enzymes show high enantiomeric and diastereomeric selectivity with the result that enzyme-catalyzed reactions invariably give only one of all possible stereoisomers. 24-22 Synthesis of Single Enantiomers How do chemists achieve the synthesis of single

enantiomers? The most common method is to produce a racemic mixture and then resolve it. How? the different physical properties of diastereomeric salts. the use of enzymes as resolving agents. chromatographic on a chiral substrate. 24-23 Synthesis of Single Enantiomers In a second strategy, asymmetric induction, induction the achiral starting material is placed in a chiral environment by reacting it with a chiral auxiliary. auxiliary Later it will be removed. E. J. Corey used this chiral auxiliary to direct an asymmetric Diels-Alder reaction. 8-Phenylmenthol was prepared from naturally occurring enantiomerically pure menthol. Me HO Me

several steps Me Menthol (enantiomerically pure) Ph Me Me HO Me 8-Phenylmenthol (an enantiomerically pure chiral auxillary) 24-24 Synthesis of Single Enantiomers The initial step in Coreys prostaglandin synthesis was a Diels-Alder reaction. By binding the achiral acrylate with enantiomerically pure 8-phenylmenthol, he thus placed the dienophile

in a chiral environment. The result is an enantioselective synthesis. Me OBn Ph Me O + O Achiral Me Enantiomerically pure Diels-Alder 89% BnO OBn

+ O 97% OR RO O 3% 24-25 Synthesis of Single Enantiomers A third strategy is to begin a synthesis with an enantiomerically pure starting material. Gilbert Stork began his prostaglandin synthesis with the naturally occurring, enantiomerically pure Derythrose. This four-carbon building block has the R configuration at each stereocenter. With these two stereocenters thus established, he then used well understood reactions to synthesize his target molecule in enantiomerically pure form. OH O HO

OH D-Erythrose H 24-26

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