The Diels-Alder Reaction Synthetic method for preparing compounds containing a cyclohexene ring

conjugated diene alkene (dienophile) cyclohexene + In general...

transition state via

concerted mechanism cycloaddition [4+2] cycloaddition pericyclic reaction a concerted reaction that proceeds through a cyclic transition state Mechanistic features Only the s-cis conformation of the diene can react

About 98% of the molecules are in the s-trans form. s-cis versus s-trans

diene dienophile transition state new  bond

What makes a reactive dienophile? The most reactive dienophiles have an electron-withdrawing group (EWG) directly attached to the double bond. Typical EWGs C O CN C CEWG

+ 100°C (100%) H2CH2CH2CH2C CHCH CH 2 H2CH2CH2CH2C CH CHO CHOExample

+ 100°C (100%) H2CH2CH2CH2C CHCH H2CH2CH2CH2C CH CHO CHOExample CHOvia:

+ 100°C (100%)OO O Example H2CH2CH2CH2C CHC CH 3 H3CH3CH3CH3COO O

+ benzene 100°C (100%)OO O Example H2CH2CH2CH2C CHC CH 2 CH 3 H3CH3CH3CH3COO O via: H3CH3CH3CH3C O O O

+ 100°C (98%) H2CH2CH2CH2C CHCH CH 2 Acetylenic Dienophile O CCOCH 2 CH 3 CH 3 CH 2 OCC O COCH 2 CH 3 OO

Stereospecific syn addition cis-trans relationship of substituents of alkene is retained in the product Diels-Alder Reaction The most reactive dienophiles have an electron-withdrawing group (EWG) directly attached to the double bond. The most reactive dienes have an electron- donating (releasing) group (ERG) directly attached to the double bond. Eg. -OR (ether)

Only product. But, is it enantiomeric? + H2CH2CH2CH2C CHCH CH 2 C C C6H5C6H5C6H5C6H5 COH HH OH C6H5C6H5C6H5C6H5 H COH O Only the s-cis conformation of the diene can participate in a Diels–Alder reaction Cis Cis Cis Cis (racemic)

Question Rank the compounds below in order of increasing rate of the Diels-Alder reaction. A)1 < 2 < 3B)3 < 1 < 2 C)3 < 2 < 1D)2 < 3 < 1

Answer Rank the compounds below in order of increasing rate of the Diels-Alder reaction. A)1 < 2 < 3B)3 < 1 < 2 C)3 < 2 < 1D)2 < 3 < 1

only product (racemic)+ H2CH2CH2CH2C CHCH CH 2 Trans Trans Trans Trans C C C6H5C6H5C6H5C6H5 COH H HO H C6H5C6H5C6H5C6H5H COH O

Question What is the product of the Diels-Alder reaction that occurs between the reactants shown here? A) B) C) D)

Answer What is the product of the Diels-Alder reaction that occurs between the reactants shown here? A) B) C) D)

Stereospecific, concerted, syn addition:

Predict the reaction products: 1. Consider the alignment of the reactants

2. Consider the charge distribution in each of the reactants

Question Select the correct starting materials to make the compound at the right through the Diels-Alder reaction. A) B) C)D)

Answer Select the correct starting materials to make the compound at the right through the Diels-Alder reaction. A) B) C)D)

Cyclic dienes yield bridged bicyclic Diels-Alder adducts.

Since only cis dienes can participate in Diels–Alder reactions: 5- & 6- membered rings are ideal

+ C C COCH 3 H HO CH 3 OC O H H COCH 3 O O

is the same as H H COCH 3 O O H H O O

The  Molecular Orbitals of Ethylene and 1,3-Butadiene

Orbitals and Chemical Reactions A deeper understanding of chemical reactivity can be modeled using frontier orbitals of the reactants. Electrons flow from the highest occupied molecular orbital (HOMO) of one reactant to the lowest unoccupied molecular orbital (LUMO) of the other.

We can illustrate HOMO-LUMO interactions by way of the Diels-Alder reaction between ethylene and 1,3-butadiene. We need only consider only the  electrons of ethylene and 1,3-butadiene. We can ignore the framework of  bonds in each molecule. Orbitals and Chemical Reactions

Reactants’ HOMO and LUMO

LUMO of ethylene (dienophile) HOMO of 1,3-butadiene HOMO of 1,3-butadiene and LUMO of ethylene are in phase with one another allows  bond formation between the alkene and the diene MO Analysis of Diels-Alder Reaction

Two Possible Configurations of Bridged Bicyclic Compounds

Secondary orbital overlap favors the endo product formation

diene dienophile transition state new  bond EndoExo

Electron withdrawing groups attached to dienophiles tend to occupy the ENDO position. Diels-Alder Reactions Major product Minor Product

The Diels-Alder transition state that produces the ENDO product benefits from favorable pi system interactions. Diels-Alder Reactions

Pericyclic reactions have several common features 1.The reaction mechanism is concerted. 2.The mechanism involves electrons moving in predictable patterns making and breaking bonds, which follow orbital theory and set rules. 3.The transition state is cyclic. 4.The reactions generally produce highly regioselective/ stereoselective results. 5.The polarity of the solvent generally has no effect on the reaction rate. Diels Alder: Pericyclic Reactions

Pericyclic Reactions Changes in the number of pi and sigma bonds distinguish pericyclic reactions from each other.

Electrocyclic Reactions Woodward-Hoffmann rules for thermal and photochemical electrocyclic reactions

Sigmatropic Rearrangements This is a [1,5] sigmatropic rearrangement.

A SIGMATROPIC REARRANGEMENT is a pericyclic reaction in which one sigma bond is replaced with another. Sigmatropic Rearrangements This is a [3,3] sigmatropic rearrangement.

Vinyl ethers undergo a [3,3] sigmatropic reaction in which one of the six atoms in the cyclic transition state is an OXYGEN. Sigmatropic Rearrangements

Two pericyclic reactions occur in the biosynthesis of vitamin D. Sigmatropic Rearrangements