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Authors: Buzdygon, Ryan Scott
Advisors: Groves, John T
Contributors: Chemistry Department
Keywords: Artemisinin
Radical Clocks
Subjects: Chemistry
Organic chemistry
Inorganic chemistry
Issue Date: 2012
Publisher: Princeton, NJ : Princeton University
Abstract: As models for cytochrome P450, cationic manganese porphyrin complexes were used to study oxygen atom transfer reactions in non-aqueous solvents. Typically water-soluble, cationic metalloporphyrins when converted to a hexafluorophosphate (PF<super>6</super>) salt are soluble in organic solvents affording catalysts for epoxidation and hydroxylation of olefins and hydrocarbons. Of the catalysts tested, MnTM-4-PyP[PF<super>6</super>]4, manganese(III) [(5,10,15,20-tetrakis(N-methylpyridinium-4-yl) porphyrin)] yielded the highest conversion of cyclooctene to cyclooctene epoxide in dry acetonitrile with iodosylbenzene. The effect of electron withdrawing groups on the porphyrin macrocycle was investigated by chlorination of the TM-4-PyP ligand. MnOCTM-4-PyP[PF<super>6</super>]4, manganese(III) &beta;-octa-chlorinated tetrakis(N-methylpyridinium-4-yl)porphyrin was synthesized with sulfuryl chloride via a nickel porphyrin intermediate for the complete &beta;-chlorination of the porphyrin macrocycle. &beta;-chlorination led to destabilization of the porphyrin macrocycle and subsequent bleaching of the ligand, resulting in lower turnover for epoxidation compared to un-chlorinated MnTM-4-PyP[PF<super>6</super>]4. The reactivity of oxo-manganese porphyrins toward C-H abstraction and oxygen atom transfer has been studied using three radical clocks substrates. Products from the manganese porphyrin oxidation of bicyclohexane, norcarane and bicyclopentane, substrates with krearr ranging from 2 x 10<super>7</super> s<super>-1</super> to 2 x 10<super>9</super> s<super>-1</super>, demonstrated a hydrogen abstraction and radical rebound mechanism for hydroxylation. From the observed ratio of unrearranged to rearranged products from the manganese porphyrin oxidation of bicyclohexane, norcarane and bicyclopentane, the rebound rate (kreb) was determined for hydroxylation by MnTM-4-PyP ranging from 10<super>9</super> to 10<super>11</super> s<super>-1</super>. In addition to hydroxylated products, bicyclohexane and norcarane yielded products by desaturation. Desaturation arises from the regioselective oxidation at an alternative C-H bond, generating a carbon-centered radical beta to a cyclopropyl followed by a second hydrogen abstraction from a hydroxo-manganese(IV) intermediate generating an olefin. For the oxidation of more structurally complex substrates, manganese, iron and ruthenium porphyrin catalysts were successful in preparing metabolites of the anti-malarial drug artemisinin. The hydroxylation of artemisinin demonstrates the utility of a metalloporphyrin screen for late-stage C-H activation of drug molecules affording substrate diversification. In summary, metalloporphyrin model systems have been shown to be efficient catalysts for modeling a variety of reactions undertaken by cytochrome P450 including hydroxylation, epoxidation and desaturation.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Chemistry

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