24-1 Diels-Alder Reaction  Diels-Alder reaction:  Diels-Alder reaction: A cycloaddition reaction of a conjugated diene and certain types of double and triple bonds. dienophile:dienophile: Diene-loving. Diels-Alder adduct:Diels-Alder adduct: The product of a Diels-Alder reaction.

24-2 Diels-Alder Reaction Alkynes also function as dienophiles. Cycloaddition reaction:Cycloaddition reaction: A reaction in which two reactants add together in a single step to form a cyclic product.

24-3 Diels-Alder Reaction We write a Diels-Alder reaction in the following way: 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.

24-4 Diels-Alder Reaction The conformation of the diene must be s-cis.

24-5 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.

24-6 Diels-Alder Reaction Reaction is facilitated by a combination of electron- withdrawing substituents on one reactant and electron-releasing substituents on the other.

24-7 Diels-Alder Reaction

24-8 The Diels-Alder reaction can be used to form bicyclic systems.

24-9 Diels-Alder Reaction Exo and endo are relative to the double bond derived from the diene.

24-10 Diels-Alder Reaction For a Diels-Alder reaction under kinetic control, endo orientation of the dienophile is favored.

24-11 Diels-Alder Reaction The configuration of the dienophile is retained.

24-12 Diels-Alder Reaction The configuration of the diene is retained. Check that this is endo.

24-13 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  Pericyclic 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.

24-14 Diels-Alder Reaction Mechanism of the Diels-Alder reaction

24-15 Aromatic Transition States  Hückel criteria for aromaticity:  Hückel 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, electrons in a cyclic transition state have especially low activation energies and take place particularly readily.

24-16 Aromatic Transition States, Examples Decarboxylation of  -keto acids and  -dicarboxylic acids. Cope elimination of amine N-oxides.

24-17 Aromatic Transition States the Diels-Alder reaction 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.

24-18 Claisen Rearrangement  Claisen rearrangement:  Claisen rearrangement: A thermal rearrangement of allyl phenyl ethers to 2-allylphenols.

24-19 Claisen Rearrangement

24-20 Cope Rearrangement  Cope rearrangement:  Cope rearrangement: A thermal isomerization of 1,5-dienes.

24-21 Cope Rearrangement Example 24.8 Example 24.8 Predict the product of these Cope rearrangements.

24-22 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.

24-23 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.

24-24 Synthesis of Single Enantiomers asymmetric induction chiral auxiliaryIn a second strategy, asymmetric induction, the achiral starting material is placed in a chiral environment by reacting it with a chiral 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.

24-25 Synthesis of Single Enantiomers The initial step in Corey’s 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.

24-26 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 D- erythrose. 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.