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A study of the physical chemistry of acyl radicals : formation and reactions

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Amos, R (2010) A study of the physical chemistry of acyl radicals : formation and reactions. PhD thesis, University of Tasmania.

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Abstract

Aryl hydrazides (including isoniazid - an antibiotic used for the treatment of Tuberculosis) are oxidized to acyl radicals through a mechanism involving diimide intermediates that are prone to nucleophilic acyl substitution. This oxidation occurs regardless of the oxidant involved; however the radical formed does not undergo further oxidation to the corresponding acylium ion, even in the presence of strong oxidants. This mechanistic information adds to the knowledge base providing clarification of conflicting mechanistic information present within the literature. It also provides potential insight into isoniazid resistance in Mycobacterium tuberculosis.
Through DFT calculations the nucleophilic acyl substitution of the diimide intermediate formed by the oxidation of isoniazid (and other aryl hydrazides) was found to most likely involve two methanol molecules in a six membered cyclic transition state. Calculations were performed in the gas phase and solvation effects were included both explicitly and implicitly using CPCM. These results reflected those found in the experimental oxidation of isoniazid.
The addition of an acetyl radical at the various positions in both pyridine and the pyridinium ion has been investigated computationally using DFT calculations. The energy barrier for attack at the nitrogen atom in pyridine is calculated to be lower than for the analogous attack at any other atom in pyridine, or at any position in the pyridinium ion. Simultaneous SOMO -> π*, LPN -> SOMO and LPN -> π*c=o interactions are responsible for this preference.
The addition of an acetyl radical to benzene, aniline, trifluorobenzene and naphthalene has also been investigated computationally using DFT calculations. Addition to benzene is calculated to have an energy barrier which is similar to that for attack at a carbon in pyridine but higher than for the attack at the nitrogen in pyridine. This difference is due to the involvement of the nitrogen lone pair in the latter process. In the case of benzene, this reaction is associated with simultaneous SOMO -> π* and π -> SOMO interactions with the latter interaction dominating, suggesting that acetyl radicals react predominantly as electrophilic radicals in the interaction with benzene.
An investigation of the McFadyen-Stevens rearrangement was performed as this rearrangment was proposed to occur through the same intermediate as the oxidation of hydrazides. The proposed mechanism for this conversion from an arylsulfonylhydrazide to an aldehyde upon reflux in alkaline solution, was found to be implausible and a more reasonable radical mechanism is proposed. The results are inconclusive; however a radical mechanism is certainly at play when the reaction is performed under oxidative conditions.

Item Type: Thesis (PhD)
Keywords: physical organic chemistry, radical, McFadyen-Stevens, mechanism
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Copyright 2010 the Author

Additional Information:

Chapter 2 appears to be the equivalent of a pre-print version of an article published as: Amos, R. I. J.; Gourlay, B. S.; Schiesser, C. H.; Smith, J. A.; Yates, B. F., 2008, A mechanistic study on the oxidation of hydrazides: application to the tuberculosis drug isoniazid. Chemical communications, 14, 1695-1697.

Chapter 3 appears to be the equivalent of a pre-print version of an article published as: Amos, R. I. J.; Schiesser, C. H.; Smith, J. A.; Yates, B. F., 2009, Nucleophilic acyl substitution of acyl diimides. Journal of organic chemistry, 74(15), 5707-5710

Chapter 4 appears to be the equivalent of a pre-print version of an article published as: Amos, R. I. J.; Smith, J. A.; Yates, B. F.; Schiesser, C. H., 2009, Acyl radical addition to pyridine: multiorbital interactions. Tetrahedron, 65(36), 7653-7657

Chapter 5 appears to be the equivalent of a pre-print version of an article published as: Amos, R. I. J.; Smith, J. A.; Yates, B. F.; Schiesser, C. H., 2010, Acyl radical addition to benzene and related systems – a computational study. Tetrahedron, 66(38), 7600-7604.

Date Deposited: 01 Jul 2011 06:11
Last Modified: 05 Dec 2016 02:07
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