Diel Alder Report

The Integration of Computational and Preparative Techniques to Demonstrate Concepts in Synthetic Organic Chemistry Using the DielsAlder 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 DielsAlder 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 cissubstituents 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 over each other gives the endo product

Diene and dienophile staggered with respect to each other gives the exo 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 DielsAlder 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

Time

*% Temp yield (Exp)

Exo Endo E.act E.act % % Exo Endo (Exp) (Exp) (Cal) (Cal)

7 days 0 C

75.5% 36

49

NA

NA

7 days RT

54%

41

NA 33.7 2 Kcal/ mol

NA

21 days

RT

7 days+ 0 C 5h

25.2

13.59

48 68

43

23

21

35.17 Kcal/ mol

8Kca 9Kcal l/mol /mol

*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 DielsAlder 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.