Multistep Synthesis Preparation of 4,4-Diphenyl-3-buten-2-one This experiment illustrates several important concepts in organic synthesis. It is a multistep synthesis, in which the product of one reaction becomes the starting material of the next. This process is very common in industry and requires careful attention to yields and techniques. The experiment also illustrates the use of the ethylene ketal protecting group used here to mask one carbonyl group from reaction while the other is permitted to react with Grignard reagent. Multistep synthesis can be challenging. You can calculate the overall yield of a sequence by multiplying the yield found for each step. For example, a two-step synthesis with a yield of 0.48 at step one and 0.92 at step two would have an overall yield of (0.48 * 0.92 * 100) = 44.90%. In this synthesis, one functional group molecule undergoes a protecting group reaction while another undergoes a protecting group reaction. To be useful, the protecting group must be capable of being introduced under mild conditions and in very high yield. It must also be highly resistant to the conditions employed for subsequent reaction of the unmasked group, yet not be so obtrusive as to interfere with the desired transformation. Finally, the protecting group must be easily removed by a mild, high yield reaction that will restore the masked functionality to its original state. This is the desired product for this multistep synthesis. Given the starting material product on the left of the figure below (ethyl acetoacetate), simply adding the Grignard reagent shown below will not give the desired intermediate. This is because the ketone is more reactive as an electrophile than the ester carbonyl group. Thus, the use of a protecting group leads to synthetic sequences that would not have been possible otherwise. MgBr H2O OCH2CH3 Anar This product does not form under these conditions. Therefore, this multistep synthesis must incorporate a protecting group to protect the ketone carbonyl from reaction with the nucleophilic Grignard reagent. One of the most widely accepted protecting groups is that of the ethylene ketal, used to mask the carbonyl group and protect it from reaction. Step 1: Protection of the carbonyl group The present procedure involves the preparation of the ethylene ketal of ethyl acetoacetate by the reaction of the ketoester with ethylene glycol in the presence of p-toluenesulfonic acid.
The Correct Answer and Explanation is:
In the multistep synthesis of 4,4-Diphenyl-3-buten-2-one, the protection of the ketone carbonyl group is essential to ensure selective reactivity during the Grignard addition. The primary challenge in this synthesis is that the ketone carbonyl group is more reactive toward the Grignard reagent than the ester carbonyl group, which could lead to unwanted side reactions. To address this, a protecting group is used to mask the ketone and prevent it from reacting with the Grignard reagent.
The protection of the ketone carbonyl group is achieved by forming an ethylene ketal, which is a common and effective protecting group. The procedure involves reacting the ketoester (ethyl acetoacetate) with ethylene glycol in the presence of p-toluenesulfonic acid (p-TsOH) as a catalyst. Ethylene glycol, a simple diol, reacts with the carbonyl group of the ketone to form a cyclic structure, which shields the carbonyl from further reactions. The acidic environment provided by p-TsOH facilitates the formation of the ethylene ketal, as it promotes the condensation reaction between the ethylene glycol and the ketone.
Once the ethylene ketal is formed, the ketone is effectively “protected,” allowing the ester carbonyl group to undergo reaction with the Grignard reagent in subsequent steps of the synthesis. The protection ensures that only the ester group reacts with the Grignard reagent, leading to the formation of the desired intermediate. This approach is crucial in selective organic synthesis, where functional group manipulation must be controlled precisely.
The final step involves removing the ethylene ketal protection group under mild conditions to restore the original ketone functionality. The protection and deprotection steps are carefully chosen to maintain high yields and avoid unwanted side reactions, making the process efficient for large-scale synthesis in both industrial and academic settings.
