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U of M CHEM 211 - MWrite 2 - Final

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Grant Proposal Using the Base-Free Wittig Reaction to Synthesize Anticancer CompoundsAs you know, my research group’s goal is to develop anticancer compounds and, as the organic chemist expert, I would like to introduce our base-free Wittig reaction that synthesizes benzoxepine analogs with anticancer properties. This reaction is quite innovative and can have a large impact if we are able to share our discoveries and further our research. But first, it is key to understand how the reaction works and why it is selective in order to prove it’s significance.As an organic chemist, I am quite familiar with the general Wittig reaction and even morefamiliar with my group’s specific base-free Wittig reaction that synthesizes a benzoxepine analog, as shown below. (Watts, 2020)This scheme shows the successful Wittig reaction that does not require an external baseand uses a maleate as starting material. For this scheme, we must form an ylide to carry out thereaction. First, the lone pair that is on the phosphorus in PBu3 attacks a carbon in the carbon-carbon double bond in the maleate. Then the electrons in the double bond move to form a new carbon-carbon double bond and the electrons from the carbon-oxygen double bond push to form a negative charge on oxygen. The oxygen reforms the double bond and the electrons from the carbon-carbon double bond deprotonate the carbon that was initially attacked by the phosphorus. This forms the ylide which also exists in an important resonance form that does not contain charges as it creates a double bond between the carbon and phosphorus.Next, cycloaddition occurs between this ylide and the aldehyde meaning that they react to form a ring. The electrons in the carbon-phosphorus double bond attack the carbon in the carbon-oxygen double bond in the aldehyde. As that occurs, the carbon-oxygen double bond simultaneously attacks the phosphorus to form a four membered ring. In the final step, cycloreversion occurs to break the ring and give our final products. The oxygen and PBu3 form a double bond with the electrons from the carbon-oxygen bond to create one product then the phosphorus-carbon bond breaks and uses its electrons to form the other product that is seen in the scheme above.The reason these starting materials and reagents allow the reaction to be successful without any external base, like the traditional reaction, is due to the electron withdrawing groups.The double bond between the carbons in maleate allows only one hydrogen to be attached to each carbon meaning that when PBu3 attacks a carbon, the electrons in the double bond transfer to the other carbon and form a negative charge. This allows that carbon to then deprotonate the other carbon intramolecularly in order to form a double bond between the carbon and phosphorus through resonance, resulting in a perfect ylide to react with the aldehyde. This last step is important to why the reaction is significant and innovative as the traditional Wittig reaction does not have these electron withdrawing groups, so in order to pushforward the deprotonation that leads to the ylide, the presence of a strong base is needed. This is uniquely innovative while also reducing reagents due to the lack of a need for a strong external base for the deprotonation and formation of the ylide compared to the traditional reaction. The maleate scheme allows for the reaction to follow through but a similar compound with a similar structure and carbon-carbon double bond called acrylate, seen in the scheme below, did not synthesize the desired product as it lacks specific characteristics that maleate has. There is no symmetry in the acrylate like with maleate which creates selectivity with which carbon the PBu3 attacks. This leads to the PBu3 attacking the less substituted carbon or the carbon with two hydrogens. This will shift the electrons from the double bond onto the other carbon and create a negative charge. In the maleate reaction the next step would be intramolecular deprotonation, however, the hydrogens on the other carbon are not acidic enough in this scheme to deprotonate successfully. It is not resonance stabilized and thus, with itsformal charges, it is unstable and will not react. This causes the specific resonance structure with a double bond to be unable to form to create the needed ylide, preventing the reaction from proceeding. (Watts, 2020)Our researched base-free Wittig reaction has the potential to be extremely important in future research as there are major benefits over the traditional Wittig reaction. Using fewer reactants reduces hazardous chemicals for both chemists and the planet and also allows for cheaper production on the industrial end. This also means easier manufacturing as there are less chemicals and steps needed to carry out the reaction which will be beneficial in terms of both cost and time. There are also fewer waste byproducts, and no initial hazardous base, which can be beneficial for the previous reasons and also beneficial for patients receiving this anticancer compound as it will likely have fewer impurities. Overall, the modified base-free Wittig is more efficient, especially for large-scale applications.References:Watts, F. (2020, March 7). Wittig Reaction (W20 ed.).pdf. Retrieved from


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