Organic Synthetic Chemistry
My research interests are in the area of synthetic organic chemistry. I am presently exploring ipso substitutions of difluoro arenes with various antitumor ligands.
Anthracene-9,10-diones, such as Ametantrone and Mitoxantrone, are presently prescribed to patients for the effective treatment of leukemia, lymphomas, and breast cancer. Their side-arm ligands attach to the phosphate portion of the nucleic acid backbone through hydrogen bonding. Exploration of a variety of diamino ethyl derivatives produced a number of ideal candidates for anticancer testing. The significance of these ligands by themselves is deemed worthy of investigation.
The preparation of bi-ligand molecules with an arene backbone has proved to be a challenging task. Activation of the ring to afford disubstitution with the nucleophilic ligands tend to yield a variety of regioselective products that are difficult to purify. Research has been initiated which could lead to specific ring substitution with halo arenes without ring activation.
Halo arenes with chloro, bromo or iodo leaving groups generally yield elimination-addition reactions through the generation of benzyne intermediates. The abstraction of the hydrogen adjacent to the halide affords benzyne molecule which can undergo nucleophilic attack on either carbon center. The 1,4 dihalobenzene consequently produce a mixture of meta and para substituted products.
Difluro arenes have been studied sparsely in comparison with their fellow halide analogs. Experiments utilizing the larger, softer halides found the rate limiting step to be the proton removal. However, when fluoride is the leaving group, cleavage of the C-F bond is considered the rate limiting step. The fact that the order of halide reactivity is Br>I>Cl>> F (when the reaction is performed with KNH2 in NH3) shows that the SNAr mechanism is not operating for larger halides.(Bunnett; Kearley J. Org. Chem. 1971, 36, 184.) The low reactivity of fluoro arenes has left this class of compounds relatively unexplored.
Initial experiments of 1,4 difluorobenezene reacted with sodium ethylenediamide salts afforded high yields of one product. Instrumental analysis of this compound found it to be the para substitituted derivative.
Subsequently, similar experiments were performed utilizing 1,3-difluorobenzene. Once again, a single product was isolated. Analysis showed it to be the meta-substituted product in excellent yields. Both 1,4-dichloro and dibromobenzene analogs provided a mixture of meta and para byproducts. Further investigation into the mechanism of the difluoro arenes reacting with metal amides is warranted.
38. W. Langenaeker, F. De Proft and P. Geerlings,
"Ab Initio and Density Functional Theory Study of the Geometry and Reactivity of Benzyne, 3-Fluorobenzyne, 4-Fluorobenzyne and 4,5-Didehydropyrimidine".
Journal of Physical Chemistry A102, 5944 (1998).
48. "Diels-Alder Reactions of 3-Fluorobenzyne and Substituted Furans," S.E. Branz, G.W. Gribble, and D.J. Keavy, Invited Poster Presentation at the Heterocycles Gordon Conference, New Hampton, New Hampshire, July 10-15, 1988.
"Unexpected Regioselective Diels-Alder Cycloaddition Reactions Between 3-Fluorobenzyne and 2-Alkylfurans"; Gribble, G.W.; Keavy, D.J.; Branz, S.E.; Kelly, W.J.; Pals, M.A., Tetrahedron Lett., 1988, 29, 6227.
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