March 2020MWrite 2 — Wittig ReactionBenzoxepine is a molecule composed of a benzene ring and a seven-membered oxepinring. Benzoxepine analogs are very useful in inhibiting types of cancers as well as tuberculosisby inducing activation of the apoptosis pathway.1 Benzoxepine analogs can be synthesized usinga base-free Wittig reaction, which can be utilized on an industrial scale while also producing fewwaste byproducts. A traditional Wittig reaction is the reaction between an aldehyde or a ketonewith an ylide.2 An ylide is a molecule that contains a negatively charged carbon atom directlybonded to a positively charged atom of sulfur, phosphorus, nitrogen, or another element.3 Thisreaction ends with two products: One being the originally negatively charged phosphorus orother atom double bonded to the oxygen from the carbonyl, and the other product being analkene with the R-group substituents bonded to the middle carbons.This base-free Wittig reaction is one that includes a maleate, an aldehyde with a phenylgroup, and PBu3. In order for the Wittig reaction to begin, an ylide needs to form. The ylide isformed with the PBu3 nucleophile attacking the double bond in the maleate, making thephosphorus positively charged. While this happens, the electrons from the C=C double bond arethen pushed to create a new double bond between the original double bonded carbon and thecarbon in the carbonyl, pushing the electrons in the C=O double bond up to the oxygen, makingit negatively charged. This structure is in resonance with the structure that occurs if the carbonylis reformed, and the electrons from the C=C double bond are pushed onto the carbon, making itnegatively charged. Though this molecule has a negative charge on a carbon and a positivecharge on a phosphorus, it is not an ylide because the two charged atoms are not bonded to eachother.4 So, in order for an ylide to be created, the carbon bonded to the phosphorus needs anegative charge. In order for this to occur, an intramolecular deprotonation — the removal of ahydrogen atom — occurs, with the negatively charged carbon deprotonating the carbon bondedto the phosphorus, switching the negative charges, and creating the ylide. This carbon beingnegative is favored over the other, because molecules with both a positive and negative chargeare more stable when those charges are closer to one another. Once the ylide is created, theelectrons on the carbon attack the carbon in the carbonyl of the aldehyde, pushing the electronsin the double bond off of the carbon to attack the phosphorus. This creates a 4-membered ring,with the oxygen of the original carbonyl bonded to the phosphorus and the carbon of the originalcarbonyl bonded to the previously negatively charged carbon of the ylide. To complete the1 MWrite 2 assignment explanation and rubric2“Wittig Reaction.” Wikipedia. Wikimedia Foundation, January 17, 2020. https://en.wikipedia.org/wiki/Wittig_reaction.3“Ylid: Definition of Ylid by Lexico.” Lexico Dictionaries | English. Lexico Dictionaries. Accessed March 9, 2020. https://www.lexico.com/en/definition/ylid.4Nacsa, Eric. Princeton University. Novel Applications of Phosphorus in Catalysis for Organic Synthesis, June 22, 2017, 37–38. http://chemlabs.princeton.edu/macmillan/wp-content/uploads/sites/6/EDN-P-catalysis.pdf.reaction, the O-C and P-C bonds break, with those electrons moving to form C=C and O=Pdouble bonds, forming the two products.5The difference between the traditional Wittig Reaction (scheme 1) and the base-freeWittig reaction (scheme 2)6 is that in order to createthe ylide in scheme 1, a strong base is needed. Theylide formation in scheme 2 does not require a base because the R group substituents on themaleate in scheme 2 are electron withdrawing groups. Because of the -COOEt electronwithdrawing group, electron density is pulled towards that group. This, in turn, pulls electrondensity away from the hydrogen bonded to the carbon, making the C-H bond weaker, whichmakes the hydrogen more acidic. Because of this, that hydrogen can be more easily deprotonatedby the negatively charged carbon, resulting in the formation of the more stable ylide. Thetraditional 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. Because of this difference between the two types of reactions, it is important thatresearchers focus on the base-free Wittig reaction over the traditional Wittig reaction. This is dueto the fact that the base-free reaction is much more efficient than the traditional one. All itrequires is the reagents necessary for the final product, no extra base is needed to push thereaction forward. This means that the base-free reaction can be done efficiently in larger scaleresearch studies without the need for adding a strong base, as it will deal with the protonationsand deprotonations intramolecularly. This base-free Wittig reaction occurs with a maleate, but it will not occur with an acrylate(scheme 3).7 This is because electron withdrawing groups are needed on both ends of themolecule. In the maleate, one electron withdrawing group is necessary to pull electrons up when5 “ChemDraw 18.2.” CambridgeSoft Corp., 2020. 6 From figure 4 in the MWrite 2 assignment explanation and rubric7 From figure 4 in the MWrite 2 assignment explanation and rubricthe phosphorus is bonding to the carbon, and the other electron withdrawing group is needed topull electron density away from the hydrogen so that it can be deprotonated. Without bothelectron withdrawing groups, the deprotonation step would not be able to occur without a strongbase, which means that for the reaction to proceed it would not be base-free anymore. Therefore,a base-free Wittig reaction would be impossible with an acrylate while it will work perfectly witha maleate.Ultimately, it is important for futureresearch to utilize the base-free Wittigreaction over the traditional Wittig reaction. It ismuch more efficient and has fewer wastebyproducts, meaning that it will have asignificant impact in the efficiency ofresearching Wittig synthesis and its relation to anticancer