[4 + 2] cycloaddition reactions have been a valuable research topic for scientists for some time now. More specifically, the combination of dienes and carbonyl containing compounds have been studied primarily for their ability to combine together to form six membered oxygen heterocycles (1). The synthesis of oxygen heterocycles is a valuable tool, as these molecules are precursors to some natural products and they are also components in the synthesis of various carbohydrates (4). The general method utilized to form oxygen heterocycles was to combine an aldehyde as the heterodienophile and a diene in a hetero-Diels-Alder reaction. Extensive studies on this reaction have been completed. Huang and Rawal chose to study this reaction using hydrogen bond promoted ketones as the heterodienophile rather than aldehydes. This is the first time that unactivated ketones have been successfully utilized in a hetero-Diels-Alder reaction. This research is extremely valuable as it expands the extent by which oxygen heterocycles can be formed. This is extremely important to the biological chemists who study and utilize oxygen heterocycles frequently (1). Huang and Rawal began their study by observing the hetero-Diels Alder reaction rates between various aldehydes and the diene 1-amino-3-siloxybuadiene. They found that the reaction rate was siginificantly higher in polar protic solvents rather than polar aprotic solvents (2). They attributed this change in the reaction rate to the fact that the carbonyl oxygen in the aldehyde could readily hydrogen bond to the hydrogen in the polar protic solvents. This hydrogen bonding causes the carbonyl carbon to develop a partial positive charge, thus enabling the aldehyde to be a stronger heterodienophile. This in turn causes the hetero-Diels-Alder reaction to proceed at a faster rate. After seeing the effect of the solvent on the aldehydes, Huang and Rawal decided to extend their study to ketones. Similarly, these researchers found that the polar protic solvents also affected the ketones. The ketones also develop a partial positive charge at the carbonyl carbon, thus helping them to be more effective heterodienophiles (Figure 1). For the first time, it was proven experimentally that a simple ketone could be a starting material for a hetero-Diels-Alder reaction. Huang and Rawal studied hetero-Diels-Alder reactions between various simple ketones and 1-amino-3-siloxybuadiene in polar protic and polar aprotic solvents. After the completion of the hetero-Diels-Alder reaction and successive elimination of the amino group with acetyl chloride, they concluded that the product yield was the highest when a polar protic solvent containing a non-shielded alcohol group was utilized. 2-butanol was found to be the most efficient solvent for this reaction (1).
Figure 1. A simple ketone hydrogen bonded to the polar protic solvent. The carbonyl carbon develops a partial positive charge, thus helping it to be a more effective heterodienophile. The resulting hetero-Diels-Alder reaction is shown which is more effective than a ketone that does not participate in hydrogen bonding.

[pic] [pic]

Several mechanisms could be proposed for this reaction, and two are shown. The first is that of the concerted hetero-Diels-Alder reaction. The concerted mechanism involves the diene and the heterodienophile reacting together in one step to form a product. The amino group on the cyclic product is then protonated by the acetyl chloride. The acetyl chloride then removes the TBS group, thus causing the carbonyl to form and the electrons in the double bond to move to the next carbons, thus pushing out the amine as a leaving group (Figure 2).

Figure 2. The concerted hetero-Diels-Alder mechanism.

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A second possible mechanism would be a step-wise hetero-Diels-Alder mechanism. The diene first attacks the carbonyl carbon, forming a carbocation intermediate. The oxygen then attacks the remaining double bond in the diene forming the cyclic structure. The remainder of the mechanism is like that of the concerted hetero-Diels-Alder reaction (Figure 3).

Figure 3. The stepwise hetero-Diels-Alder mechanism.

[pic] Additional studies may be performed to determine which of the two mechanisms proposed is the actual mechanism for the hetero-Diels-Alder reaction. One study that could be completed would be to do a Curtain Hammett study with the simple ketone of interest added as a substituent on a benzene ring. The stepwise mechanism of these ketone substituted benzene rings involves a carbocation intermediate, whereas the concerted mechanism does not have such an intermediate. The stepwise mechanism should show a good correlation with sigma+ due to the presence of the carbocation intermediate. The ‘ρ’ for this Hammett study would be negative due to the TBSO and the double bond that is allylic to the carbocation. These are electron donating groups that stabilize the positively charged carbocation. The concerted mechanism will not show much of a correlation with sigma+ because there are no positive charged intermediates in the reaction; however the partial positive charge on the carbonyl carbon due to the polar protic solvent may exhibit a correlation with sigma+, but it will not be as pronounced as the correlation due to the carbocation in the stepwise mechanism. The kinetic isotope effect may also be utilized as a study to differentiate between the two mechanisms. In the starting material, the hydrogen adjacent to the amine group (circled in figures 2-3 in red) would first be exchanged with a deuterium (D). This Deuterium is attached to a sp2 hybridized carbon in the diene starting material and it is attached to a sp3 hybridized carbon in the first product in the concerted mechanism; whereas it is still attached to a sp2 carbon in the intermediate step in the stepwise mechanism. This difference will cause a Inverse Secondary Kinetic Isotope Effect to be seen for the concerted mechanism while no Kinetic Isotope Effect will be seen for the stepwise mechanism. The kH/kD for the deuterium in the concerted reaction will be less than 1, thus indicated an Inverse Secondary Kinetic Isotope Effect; whereas the kH/kD for the first step in the step-wise mechanism will be 1, thus indicating no Kinetic Isotope Effect. These are only a few potential studies that may be done to determine which mechanism the reaction proceeds by. Most likely the most efficient method for determining which mechanism this reaction follows is to do several of these studies until the data agrees on one mechanism and that should be the mechanism by which the reaction proceeds. The hetero-Diels-Alder reaction, like the Diels-Alder reaction, is most commonly explained and accepted as a concerted mechanism (3). Thus the expected outcome of the two suggested experiments would be to see only a small or no correlation with the sigma+ Hammett plot, as the carbocation is not formed in the concerted mechanism. The second experiment would show an Inverse Secondary Kinetic Isotope Effect, as the hybridization of the carbon of interest does change from sp2 to sp3 in the first step of the mechanism in the concerted mechanism.

Works Cited

1. Huang, Y. and Rawal, V. J. Am. Chem. Soc. 2002, 124, 9662-9663.
2. Huang, Y. and Rawal, V. Org. Lett. 2000, 2, 3321.
3. McMurry, J. McMurry Organic Chemistry Forth Edition.1995, p.512-513.
4. Schmidt, R. Acc. Chem. Res. 1986, 19, 250.

Case Study Proposal

Hydrogen-Bond-Promoted Hetero-Diels-Alder Reactions of Unactivated Ketones

By: Shannon Donley
CHEM 7240