The Integration of Computational and

Preparative Techniques to Demonstrate Concepts

in Synthetic Organic Chemistry Using the Diels-
Alder Reaction

ABSTRACT

Chemical reactions can yield entirely different product distributions depending on

the reaction conditions. Generally high temperatures and long reaction times favor the
most stable (thermodynamic) products, while low temperatures and short reaction times
yield the most easily formed (kinetic). In this study the molecular model program Spartan
was used to predict the formation of the endo and exo stereochemical Diels-Alder
products of N-phenylmaleimide with furan under kinetic and thermodynamic conditions.
After the theoretical calculations are done, the results were tested in the laboratory.

The experimental part involved a two-step synthesis. First the N-phenylmaleimide

was prepared from maleic anhydride and aniline. The N-phenylmaleimide was used in
the Diels-Alder reaction with furan under the following kinetic and thermodynamic
condition- 0 degree Celsius for 7 days, room temperature for 7 days, room temperature
for 21 days, 0 degree Celsius for seven days then heated at 60 degree Celsius for 5 hours.

The NMR spectra will be used to identify the exo and endo stereoproducts. A
comparison of experimental data with that of the theoretical predictions will be done.It is
expected that the results of this study can be incorporated into an organic chemistry
laboratory since the exo and endo selectivity of Diels-Alder reactions bridges the gap
from the concept to the bench and demonstrate clearly the integration between
computational and synthesis experiment.
AIM

Spartan Calculations are used to predict the formation of the most stable products in the
Diels-Alder reaction.
The calculations are compared with the experimental data to determine the efficacy of
the program.

The program Spartan is commercially available at , www.wavefun.com.

It is user friendly – point and click. It is an educational tool that can be use for building
and viewing complicated molecules.
The Diels-Alder reaction is a useful synthesis tool to expand rings.
Furan + N-phenylmaleimide reaction is used in this study because it s easy to study in
the laboratory and stereo specific products are formed under conditions that are contrary
to expectations.

INTRODUCTION/BACKGROUND

In 1928, otto Diels ans Kurt Alder discovered the Diels-Alder reaction. They received the
Nobel prise for this work in 1950.

The Diels-Alder reaction is a conjugate addition reaction of a conjugated diene to an

alkene (the dienophile) to produce a cyclohexene. The simplest example is the reaction of
1,3-butadiene with ethene to form cyclohexene as shown bellow:

The analogous reaction of 1,3-butadiene with ethyne to form 1,4-cyclohexadiene is also

known as shown bellow:
Since the reaction forms a cyclic product, via a cyclic transition state, it can also be
described as a "cycloaddition". The reaction is a concerted process. Bonds are broken in
1,3 diene and cyclohexene is formed. this reaction is shown below. The arrow identifies
the bonds that are broken and the bonds that are formed in the forward reaction.

Due to the high degree of regio- and stereoselectivity (due to the concerted mechanism),
the Diels-Alder reaction is a very powerful reaction and is widely used in synthetic
organic chemistry. The reaction usually thermodynamically favorable due to the
conversion of 2 π-bonds into 2 new stronger σ-bonds.
The two reactions shown above require harsh reaction conditions, but the normal Diels-
Alder reaction is favored by electron withdrawing groups on the electrophilic dienophile
and by electron donating groups on the nucleophilic diene.

The Diels-Alder reaction is stereospecific with respect to both the diene and the
dienophile.
Addition is syn on both components (bonds form from same species at the same time)
This is shown by the examples below:

cis-dienophile gives cis-

substituents in the
product.
trans-dienophile gives
trans-substituents in
the product.
If both substituents on
the diene are Z, then
both end up on the
same face of the
product

If substituents on the
diene are E and Z, then
they end up on
opposite faces of the
product

www.chem.ucalgary.ca Figure 1: Addition of diel-alder reaction

Cyclic dienes can give stereoisomeric products depending on whether the
dienophile lies under or away from the diene in the transition state. The endo
product is usually the major product (due to kinetic control)

Diene and dienophile aligned directly Diene and dienophile staggered with
over each other gives the endo respect to each other gives the exo
product product

Figure2: Stereoisomeric products of cyclic dienes

www.chem.ucalgary.ca www.chem.ucalgary.ca

Diels-Alder Reaction studied in this work are shown bellow:

Figure3: Diels-Alder reaction for our study.

PROCEDURE

The experiment involved several steps. First, N-phenylmaleimide was synthesized from
maleic anhydride and aniline. After isolation of N-phenylmaleimide, it was left
undisturbed in presence of furan to undergo a Diels-Alder cycloaddition. The two Diels-
Alder adducts: the exo and endo products will be analyzed by NMR.

Maleanic acid synthesis

Adding 1.9810 g of maleic anhydride to 25-ml of ether at 0 C in a 50- ml Erlenmeyer

flask containing a magnetic bar and immerged in iced bath. Meanwhile, another solution
of 1.8814 g of aniline at 0 degree Celsius with 10 ml of ether was prepared. After proper
cooling of the solution, aniline was added slowly to the maleic anhydride while stirring at
0C. After the complete addition of the aniline solution, stirring for one hour at 0 C. The
resulting product was filtered using dry filtration and washed by 10 ml of ether for 30
minute. The solid mass was measured and left over night to completely air dry. A small
portion of maleanilic acid was left for the NMR test and 2.1412 g of it was used for the
synthesis of N-phenymaleimide.

N-phenylmaleimide

Adding 2.1412 of maleinic acid to 0.43 g of anhydride sodium acetate and 4.23 of acetic
anhydride in a 50 round bottom flask. Placing a condenser with water running from
bottom to top and heating the solution using a beaker containing water boiling at 70
degree celsius and stirring gently with magnetic stirrer for 1 hour. When the solution
turned light yellow, the resulting product is poured into a beaker containing 20 ml of
water-iced mixture and stirred until the solid appeared. The solid is collected using dry
filtration and is left to air dry over night. Once the solid is dry, it was recrystallized from
50 ml hot cyclohexane and collected by dry filtration. This pure solid is the dienophile to
be used in the diels-alder reaction. A 0.5g of N-phenymaleimide was dissolved in 5 ml of
furan in a small Erlenmeyer flask sealed with Para film. This mixture was left for a week
under the four following conditions:

•At 0 degree Celsius

•At room temperature in the drawer
•At room temperature for 21days
•At 0C for one week, then heated to 60 degree Celsius for 5 hour.

The N-phenylmaleimide amount was not enough to run the 4 conditions. Therefore the
experiment was repeated for 3 times in order to run all the samples for the Diels-Alder
reaction under different conditions.
 The final product from each condition will be purified using column chromatography,
and NMR spectra will be used to identify the exo and endo stereoproducts.A comparison
of the experimental data with that of the theoretical predictions will be done.
Using the Spartan program to build the substituted endo or exo addition products and
calculate the activation energies of the transition state. A lower activation energy
indicates a more stable compound.
The activation energy of the transition states were compared under two reaction
conditions:
-the thermodynamically control product (high temperature,long reaction time)
-the kinetic control product (low temperature, short reaction time)
-For the calculations we optimized the transition state at the AM1 level and calculate the
activation energy.

RESULTS

*% Exo Endo E.act E.act

Time Temp yield % % Exo Endo
(Exp) (Exp) (Exp) (Cal) (Cal)
7 days 0 C 75.5% 36 49 NA NA

7 days RT 54% 48 41 NA NA
33.7
35.17
21 2
RT 25.2 68 23 Kcal/
days Kcal/
mol
mol
7
8Kca 9Kcal
days+ 0 C 13.59 43 21
l/mol /mol
5h
*This data will be further analyzed to define the percentage of NMR Conclusion

CONCLUSION

These results illustrate that the program is useful for predicting the product of the Diels-
Alder reactions.This is therefore a useful molecular modeling tool for predicting the
products of a reaction.
The reaction at high temperature and long reaction time(thermodynamically
favored)shows larger % of the exo product , this correlates with the lower Energy of
activation as calculated using Spartan.
Reaction at law temperature, short reaction time (kinetic control product) also shows a
dominance of the exo product which correlates with the lower Energy of activation.
Reaction at law temperature, short reaction time (kinetic control product)
Also shows a dominance of the exo product which correlates with the lower Energy of
activation.

ACKNOWLEDGEMENTS

Prof.Shani Rywkin: assistant professor, chemistry

Claune Braithwaite: LSAMP, project administrator CCNY
Vaughn Clai March: LSAMP, project coordinator BMCC

REFERENCES

1. A Guide to Molecular Mechanics and Quantum Chemical Calculations. Warren J.

Hehre. Wavefunction Inc., Irving, CA. 2003.
2. Organic Chemistry. Maitland Jones, Jr. W.W Norton & Company. New York. 1997.
3. A PC Spartan Plus Tutorial version 2.0. Warren J. Hehre, Bernard J. Deppmeier and
Phipip E. Kluzinger. Wavefunction Inc. Irving CA.1999.
4. Endo- and exo- Stereochemistry in the Diels-Alder Reaction: Kinetic versus
Thermodynamic control. Cooley J. H and Williams R.V. J. Chem Ed. 74 (5), 1997.