Diels-Alder Reaction: Preparation of cis-Norbornene-5,6-endo-dicarboxylic Anhydride

(University of Colorado, Boulder, Dept of Chem and Biochem.)

The Diels-Alder reaction is an important addition reaction in organic chemistry. It is named for its primary developers, the German chemists Otto Diels and Kurt Alder, who received the Nobel Prize in chemistry in 1950 for their work. The reaction involves the cycloaddition of a conjugated diene with an alkene to form a compound containing a six-membered ring. It takes place in a single step, with a cyclic flow of electrons:

The conjugated diene, referred to simply as the diene, supplies 4 electrons; the alkene, or the dienophile, supplies 2 electrons. The Diels-Alder product contains two new sigma bonds and one new pi bond; the new pi bond ends up between where the two double bonds were on the diene. Reaction is facilitated by electron withdrawing groups (e.g., C=O and CN) on the dienophile and electron-donating groups (e.g.,R and OR) on the diene. Also, the diene must be capable of achieving an s-cis conformation in order to give the necessary cis double bond in the cyclohexene product. A diene with s-trans conformation would yield a trans double bond which is geometrically impossible in six-membered rings.

Many compounds exist primarily in the s-transconformation due to steric reasons. However, since at any given time there is a small amount of s-cis form in equilibrium with the s-trans , the compound will be capable of reacting with the dienophile in the Diels-Alder reaction. Cyclic dienes (e.g., cyclopentadiene) which are locked into the s-cis form are particularly reactive.

A unique type of stereoselectivity is observed in Diels-Alder reactions when the diene is cyclic. In the reaction of maleic anhydride with cyclopentadiene, for example, the endo isomer is formed (the substituents from the dienophile point to the larger bridge) rather than the exo isomer (the substituents from the dienophile point away from the larger bridge). (You should try the following reaction with your molecular models!) The preference for endostereochemistry is observed in most Diels-Alder reactions. The fact that the more hindered endo product is formed puzzled scientists until Woodward, Hoffmann, and Fukui used molecular orbital theory to explain that overlap of the p orbitals on the substituents on the dienophile with p orbitals on the diene is favorable, helping to bring the two molecules together. Hoffmann and Fukui shared the 1981 Nobel Prize in chemistry for their molecular orbital explanation of this and other organic reactions. In the illustration below, notice the favorable overlap (matching light or dark lobes) of the diene and the substituent on the dienophile in the formation of the endo product:

Oftentimes, even though the endo product is formed initially, an exo isomer will be isolated from a Diels-Alder reaction. This occurs because the exo isomer, having less steric strain than the Endo , is more stable, and because the Diels-Alder reaction is often reversible under the reaction conditions. In a reversible reaction, the product is formed, reverts to starting material, and forms again many times before being isolated. The more stable the product, the less likely it will be to revert to the starting material. The isolation of an exo product from a Diels-Alder reaction is an example of an important concept: thermodynamic vs kinetic control of product composition. The first formed product in a reaction is called the kinetic product. If the reaction is not reversible under the conditions used, the kinetic product will be isolated. However, if the first formed product is not the most stable product and the reaction is reversible under the conditions used, then the most stable product, called the thermodynamic product, will often be isolated. The Diels-Alder reaction also exhibits another form of stereoselectivity. Note that the diene and dienophile approach each other in parallel planes: the diene undergoes a syn addition to the dienophile. Therefore, groups that are cis in the dienophile are also cis in the product. Thus, reaction of 1,3-butadiene with maleic acid (cis) gives only the cis -diacid, while reaction with fumaric acid (trans) gives only the trans -diacid.

You will react cyclopentadiene with maleic anhydride to form the Diels-Alder product below. This Diels-Alder reaction produces almost solely the endo isomer upon reaction at ambient temperature.

The cyclopentadiene needed for this experiment cannot be purchased since even at room temperature it readily dimerizes in a Diels-Alder reaction with itself to form dicyclopentadiene. Fortunately, the dimerization may be reversed simply by distilling. At the boiling point of dicyclopentadiene, equilibration with the monomer is rapid; the monomer, being more volatile, may be drawn off at the top of a fractionating column, according to the procedure below.

If time allows, you should run an NMR spectrum of your product. The NMR spectrum of cis-5-norbornene-2,3-endo-dicarboxylic anhydride is given below:

Safety Precautions Dicyclopentadiene is both extremely flammable and toxic. It also has a very unpleasant odorkeep it in the hood as much as possible. Maleic anhydride is corrosiveavoid skin contact. Hexanes and ethyl acetate are flammable. Wear gloves and protective clothing throughout the lab. Procedure Section Because dicyclopentadiene has a noxious odor, it will be converted to cyclopentadiene in a single apparatus in the main fume hood for all the students in the lab. Your TA will supervise this procedure, which is outlined in the following paragraph: Dicylopentadiene is cracked in an apparatus for fractional distillation. A vigruex column is used as the fractionating column. Dicyclopentadiene and a boiling chip are placed in a round bottom flask under the fractionating column and the flask is fitted with a heating mantle. A one-piece distillation apparatus is fitted to the top of the fractionating column. A threenecked round bottom flask is used as the receiving flask. One of the necks is fitted with a septum to allow your TA to use a syringe to remove cyclopentadiene. The Variac is set to 90 to produce brisk boiling (the head temperature should be about 65C). As the cyclopentadiene collects in the receiving flask, it is dispensed to students (each student needs 1.5mL). Use the cyclopentadiene as soon as possible. While the distillation is in progress, each student should dissolve 1.5 g of maleic anhydride in 7 mL of ethyl acetate in a 50 mL Erlenmeyer flask. Heat gently (approximately to body temperature) to get all of the maleic anhydride into solution, then add 7 mL of hexanes. Add 1.5 mL of the freshly prepared cyclopentadiene to the maleic anhydride solution. Swirl the mixture just until the exothermic reaction is complete, and then set it down on your benchtop. Crystals of product will appear in a few minutes. Collect on a Bchner funnel. To recrystallize the product, place it in an Erlenmeyer flask and add 6 mL of toluene. Heat on a steam/sand bath. Unreacted starting material and side-products will not go into solution. Hot filter the solution to remove these undesired compounds. Add about 3 mL of hexanes to the filtered solution. Cool the flask in an ice bath, and the cis-norbornene-5,6-endodicarboxylic anhydride crystals should appear after a few minutes. Collect the crystals on a Bchner funnel. The melting point of these crystals should be sharp and in the range of 160C and 165C. Optional: Run an NMR of your product.

Study Questions 1) Given the following reaction sequence and information, draw an energy diagram (Energy vs Reaction Coordinate) illustrating the major energetic features of the following reaction: C A B Thermodynamic product Starting Product Kinetic product 2) Provide the products for the following Diels-Alder reactions. Be sure to indicate the stereochemistry of the products where applicable.