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304

CHAPTER

25 Diels-Aider Reaction

Prefab Exercise: Describe in detail the laboratory operations, reagents, and sol­vents you would employ to prepare

Otto Diels and his pupil Kurt Alder received the Nobel Prize in 1950 for their discovery and work on the reaction that bears their names . Its great usefulness lies in its high yield and high stereospecificity. A cycloaddition reaction, it involves the 1 ,4-addition of a conjugated diene in the s-cis conformation to an alkene in which two new a (sigma) bonds are formed from two 7T (pi) bonds.

s-trans s-cis

The adduct is a six-membered ring alkene. The diene can have the two conjugated bonds contained within a ring system, as with cyclopentadiene or cyclohexadiene, or the molecule can be an acyclic diene that must be in the cis conformation about the single bond before reaction can occur.

0 H ~ H

' '

C._CH 3.

H 3C : Hi

® -H

_nts, and sol-

1950 for their reat usefu!nes Jn reaction , it ormation o an rr (pi) bonds.

[ti: H H

NO conjugated clohexadiene, conformation

Chapter 25 Die!s-A!der Reaction 305

The reaction works best when there is a marked difference between the electron densities in the diene and the alkene with which it reacts, the dienophile . Usually the dienophile has electron-attracting groups attached to it, while the diene is electron rich, for example, as in the reaction of methyl vinyl ketone with 1 ,3-butadiene.

-Methyl vinyl ketone 1,3-Butadiene

Retention of the configurations of the reactants in the products implies that both new a- bonds are formed almost simultaneously. If not , then the intermediate with a single new bond could rotate about that bond before the second a- bond is formed , thus destroying the stereospecificity of the reaction. -

~)fCOOCH, H-NcoocH3 -

~ H

Dimethyl maleate +

1 ,3-butadiene

This does not happen:

H ~COOCH,

H i ~OCH, H¥COOCH3

. H--{.1~ __:.. + ~CH3

~ -_______/

H 3COOC

trans Isomer

cis Isomer

0 •

'I

!Ill

,, ' \/ ..

I ' I

306

A highly stereospec · eaction

Woodward's Diels-Alder adduct

Macroscale and Microscale Organic Experiments

This reaction is not polar in that no charged intermediates are formed. Neither is it a radical reaction because no unpaired electrons are involved. It is instead known as a concerted reaction, or one in which several bonds in the transition state are simultaneously made and broken. When a cyclic diene and a cyclic dienophile react with each other as in the present reaction, more than one stereoisomer may be formed. The isomer that predominates is the one that involves maximum overlap of 1r electrons in the transition state. The transition state for the formation of the endo isomer in the present reaction involves a sandwich with the diene directly above the dienophile. To form the exo isomer, the diene and dienophile would need to be arranged in a stair-step fashion .

Maximum overlap of '" electrons

..

..

'" electron overlap not so large

0

eru/Q Isomer predominant product

H

exo Isomer

0

The Diels-Alder reaction has been used extensively in the synthesis of complex natural products · because it is possible to exploit the formation of a number of chiral centers in one reaction and also the regioselectivity of the reaction. For example, the first step in R. B. Woodward's synthesis of cortisone was the formation of a Diels-Alder adduct.

But the reaction is also subject to steric hindrance, especially when the difference between the electron-withdrawing and -donating characters of the two reactants is not great. When Woodward tned to synthesize cantharidin, the active ingredient in Spanish fly, by the Diels-Alder condensation of furan with dimeth· ylmaleic anhydride, the reaction did not work. The reaction possesses - L1 V*

.ed. FIG. 25.1 1 H NMR spectru It is dicyclopentadiene (250 z) .

m the ,ne and

.ore than t one that

e transition J involves a

.e exo isomer, cp fashion.

=0

synthesis of rmation of a :tivity of the ; of cortisone

Jy when the

i~, ~~::c:v~ J with dimeth· j[ !Sses - .JV*

0

Cantharidin

Chapter 25 Diels-Aider Reaction 307

10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 PPM(Ii)

(it proceeds with a net decrease in volume). High pressure should overcome this problem, but this reaction will not proceed even at 600,000 lb/in2 (4.1 x 1010

dynes/cm2). A closely related reaction will proceed at 300,000 lb/in2 and has

been used to synthesize this molecule. 1 Cantharidin is a powerful vesicant (blister­former).

R. B. Woodward and Roald Hoffmann formulated the theoretical rules involving the correlation of orbital symmetry, which govern the Diels-Alder and other electrocyclic reactions.

Cyclopentadiene is obtained from the light oil from coal tar distillation but exists as the stable dimer , dicyclopentadiene, which is the Diels-Alder adduct from two molecules of the diene. Thus generation of cyclopentadiene by pyrolysis of the dimer represents a reverse Diels-Alder reaction. See Figs. 25.1 and 25.2 for NMR and IR spectra of dicyclopentadiene.

In the Diels-Alder addition of cyclopentadiene and maleic anhydride, the two molecules approach each other in the orientation shown in the top drawing on the previous page, since this orientation provides maximal overlap of 7r bonds of the two reactants and favors formation of an initial "' complex and then the final endo product. Dicyclopentadiene also has the endo configuration.

1. W. G. Dauben, C. R. Kessel ,:and K. H. Takemura, J. Am. Chern. Soc. 102, 6893, 1980.

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"I .,

:I

I

i,

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c:JI: !·.H ·1·;1\'i'

"':,

3 8

) .

Macroscale and Microscale Organic Experiments

~ 0

Q:> u !':

£l '§ "' !':

"' .... E-<

2.5 I

I 4000

3.0

3046 cm_1 j

3500

Microns (~Lml

3.5 4 .0 5.0 6.0

~ ( 1438 cm-1

I I 2500 2000 1500

Wavenumber (cm- 1 )

8 10 15

~ 1340 cm-1

7( CI

1000

Experiments ____ _ _ ________ _ _

In Experiment 1 , unique apparatus for the microscale cracking of dicyclo: tadiene is used . The dicyclopentadiene is dispensed from a septum-capped • tainer into a syringe so the vile odor of dicyclopentadiene is not detected ir laboratory .

Gas chromatography reveals that cyclopentadiene is 8% dimerized in and 50% dimerized in 24 h at room temperature . It should be kept on ice used as soon as possible after being prepared.

u 1. krosca le Cracking of Dicyclopentadiene

Dicyclopentadiene den 0.98

MW 132.20 bp 170°C n281.5100

-160"C room

temperature

Cyclopentadiene bp 4l °C, den 0.80

MW 66.10

Half fill with mineral oil the short-necked 5-mL round-bottomed flask equi: with an addition port bearing a septum on the sidearm and topped with a tillation head and thermometer (Fig . 25.3) . Heat the flask on a sand bath . , the heating with the thermometer -down in the oil. Heat it to about 250°C,

:; ., '

370 scale and Microsca/e Organic Experiments

FIG. 25 . :: -- -- - - ·-

dicyclope ta ·:: - =

_--:! you are sure n-L of product.

Reverse Diels-Alder

Check old dicvclopentadiene for peroxides .

200 100 80

PPM [o]

the yield will be lower. Once the dicyclopentadiene has all been added, remove the syringe, and weigh the product after closing the vial. Rinse the syringe with acetone in the hood. Calculate the percentage yield of cyclopentadiene. If the product is cloudy , add a small quantity of anhydrous calcium chloride pellets to dry it if the maleic anhydride experiment is being done next. It need not be dry to make ferrocene. Keep this cyclopentadiene on ice, and use it the same day it is prepared.

Cleaning Up Place the mineral oil from the reaction flask and any unused dicyclopentadiene in the organic solvents container. If calcium chloride was used, it should be-freed of cyclopentadiene by evaporation in the hood and then placed in the nonhazardous solid waste container.

~ 2. Macroscale Cracking of Dicyclopentadiene

The infrared spectrum of dicyclopentadiene appears in Fig . 25 .2 . Measure 20 mL of dicyclopentadiene into a 100 mL flask , and arrange for

fractional distillation into an ice-cooled receiver (Fig. 21.2). Heat the dimer with an electric flask heater until it refluxes briskly and at such a rate that the mon­omeric diene begins to distill in about 5 min and soon reaches a steady boiling point in the range 40-42°C. Apply heat continuously to promote rapid distillation without exceeding the boiling point of 42°C. Distillation for 45 min should 'provide the 12 mL of cyclopentadiene required for two preparations of the adduct; continued distillation for another half hour gives a total of about 20 mL of monomer.

Cleaning Up Pour the pot residue of dicyclopentadiene and unused cyclo­pentadiene into the recovered dicyclopentadiene container. This recovered ma- f terial can, despite its appearance, be cracked in the future to give cyclopentadiene-If the pot residue is not to be recycled , place it in the organic solvents container.

20 0

ded, remove syringe with diene. If the ide pellets to :d not be dry he same day

any unused :hloride was >od and then

l arrange for e dimer with 1at the mon­eady boiling d distillation min should

f the adduct; t 20 mL of

msed cyclo­:overed ma­>pentadiene. ts container.

• Mixing of .-,e .-~:;;. - :;s :s l'ery . D - - • tmportanl. , :..; _ ~ 2 e"'c-on mixture in~o :;;. - i ~e . and rh en expel ir ir.~o -·:e reaction tube or blow : _.:..om a piperte hrougl: : r.== re c 'on mixture .

311

. cis-Norbornene-5,6-endo-dicarboxylic Anhydride

Maleic anhydride mp 53°C, MW 98.06

Microscale Procedure

cis-Norbornene-5,6-endo-dicarboxylic anhydride mp 165°C, MW 164.16

Dissolve 0 .20 g of powdered maleic anhydride in 1 mL of ethyl acetate in a tared 10 x 100 mm reaction tube and then add 1 mL bp 60-80°C ligroin. This combination of solvents is used because the product is too soluble in pure ethyl acetate and not soluble enough in pure ligroin. To the solution of maleic anhydride add 0.20 mL (0 . 160 g) of dry cyclopentadiene, mix the reactants , and observe the reaction. Allow the tube to cool to room temperature, during which time crystallization of the product should occur. If crystallization does not occur, scratch the inside of the test tube with a stirring rod at the liquid-air interface. The scratch marks on the inside of the tube often form the nuclei on which crystallization starts. Should crystallization occur very rapidly at room temper­ature , the crystals w~be very small. If so, save a seed crystal, heat the mixture until the product dissolves, seed it, and allow it to cool slowly to room tem­perature . You will be rewarded with large platelike crystals. Remove the solvent from the crystals with a Pasteur pipette that is forced to the bottom of the tube, wash the crystals with one portion of cold ligroin, and remove the solvent (see Fig. 3. 19) . Scrape the product onto a piece of filter paper, allow the crystals to dry in air, determine their weight, and calculate the yield of the product. De­termine the melting point of the product and tum in any material not used in the next experiment. Thin-layer chromatography of the product is hardly necessary; it is quite pure (Figs. 25.5 and 25.6).

Cleaning Up Place the crystallization solvent mixture in the organic solvents cont~iner. It contains a very small quantity of the product.

Macroscale Procedure

Place 6 g of maleic anhydride in a 125-mL Erlenemeyer flask and dissolve the anhydride in 16 mL of ethyl acetate by heating on a hot plate or steam bath. Add 16 mL of ligroin (bp 60-90°C) or hexane, c'ool the solution thoroughly in an ice-water bath, and leave it in the bath (some anhydride may crystallize).

I · '

1.

I,' '

312

FIG. 25.5 1 H NMR spe cis-norbornene-5-6,-e do­dicarboxylic anhyd ride ( 5 MHz).

Cyclopentadiene is flammable.

Rapid addirion at 0°C

FIG. 25.6 Infrared spectrum of cis-norbornene-5, 6-endo­dicarboxylic anhydride.

M acroscale and Microscale Organic Experiments

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 PPM (o)

The distilled cyclopentadiene may be slightly cloudy because of the con­densation of moisture in the cooled receiver and water in the starting material. Add about 1 g of calcium chloride to remove the moisture. It will redimerize in a few hours; use it immediately . Measure 6 mL of dry cyclopentadiene, and add it to the ice-cold solution of maleic anhydride. Swirl the solution in the ice bath for a few minutes until the exothermic reaction is over and the adduct separates as a white solid . Then heat the mixture on a hot plate or steam bath until the solid is all di-ssolved. 2 If you let the solution stand undisturbed, you will be

~ 0

4000

3.0 I

3.5

3000

Microns (fLm)

2500 2000 1500

Wavenumber (cm-1 )

8 10 I I

I 1000 500

2. In case moisture has gotten into the system, a little of the corresponding diacid may remain undissolved at this point and should be removed by filtration of the hot solution.

0

of the con­ng material. ~dimerize in :ne , and add the ice bath 1ct separates 1th until the you will be

500

I may remain

FIG. 25.7 13C NMR spectru o cis-norbornene-5,6-endo­dicarboxylic anhydride (22.6 MHz).

' cp~er 25 Diets-Alder Reaction 313

200 140 120 100 80 60 40 20 0

PPM [.S]

rewarded with a beautiful display of crystal formation. The anhydride crystallizes in long spars (mp 164-165°C); a typical yield is 8.2 g (Fig. 25.7). 3

Cleaning Up Place the crystallization solvent mixture in the organic solvents container. It contains a very small quantity of the product. Aliow the organic material to evaporate from the drying agent (in the hood) and then place it in the nonhazardous solid waste container.

4. cis-Norbornene-5,6-endo-dicarboxylic Acid

-H

COOH endo,cis-Diacid

D Microscale Procedure

To 0,.2 g (200 mg) of the anhydride from the preceding experiment, add 2.5 mL of water and a boiling stick in a 10 X 100 mm reaction tube. Heat the mixture

3. The student need not work up the mother liquor but may be interested in learning the result. Concentration of the solution to a small volume is not satisfactory because of the presence of dicyclopentadiene, formed by dimerization of excess monomer; the dimer has high solvent power. Hence the bulk of the solvent is evaporated on the steam bath, and the flask is connected to the water pump with a rubber stopper and glass tube and heated under vacuum on the steam bath until dicyclopentadiene is removed and the residue solidifies. Crystallization from 1:1 ethyl acetate-ligroin affords 1.3 g adduct (mp 156-158°C); total yield is 95%.