School of Chemistry - Theses
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ItemMechanistic studies on radical reactions initiated by oxidative electron transfer( 2017)This thesis is concerned with intermolecular radical addition reactions to alkynes. The objective of this work was to explore the generation of azidyl radicals by oxidation of inorganic azide and the reaction of azidyl radicals with C≡C triple bonds. Preliminary experiments revealed cerium (IV) ammonium nitrate is a good oxidation source to generate azidyl radicals from sodium azide. Reactions of azidyl radicals with terminal aromatic alkynes led to three unique chemical conversions, which were identified through a combination of characterisation techniques, such as X-ray crystallography. Electronic effects appear to play a role in the outcome of the functionality at the C≡C triple bond. Reaction of an azidyl radical with electron rich alkyne 65 results in the formation of acyl cyanide 69. In contrast, reaction of an azidyl radical with electron poor alkyne 66 provides nitrile 93. Following investigation of the reaction using experimental and computational studies, the azidyl radical appears to undergo intermolecular radical addition to terminal aromatic alkyne 94 to form a cyclic radical intermediate 98, which then undergoes oxidation to form cyclic cation intermediate 99. Addition of a nitrate ligand at the or position to the aryl ring, followed by ring opening can account for the structurally different products. Acyl cyanide 69 may undergo post-reaction oxygen exchange with water, to account for the incorporation of oxygen-18 labeled water in 69 through isotopic labeling experiments. Aryl alkyne 111, with a para-ethyl substituent, afforded isoxazole 112 and acyl cyanide 113 as major products. Formation of isoxazole 112 may occur via a cyclisation reaction between acyl cyanide and azido-nitrate intermediates, followed by expulsion of NO2– and loss of N3+. Finally, reactions of azidyl radicals with internal aromatic alkynes resulted in the formation of diketones. The persulfate radical anion, generated photochemically or thermally from potassium peroxydisulfate, was investigated as an oxidant. Persulfate radical anions were also found to be an efficient oxidation source, generating azidyl radicals from azide anions. Reaction of azidyl radicals with terminal aromatic alkyne 65 in the presence of potassium peroxydisulfate afforded NH-1,2,3-triazole 162 as the major product, along with nitrile 163 and isoxazole 164. Formation of NH-1,2,3-triazole 162 supported the computational studies, indicating azidyl radical addition to alkynes occurs to form a cyclic radical intermediate. Further calculations indicated that the cyclic radical intermediate could undergo reduction by an azide anion for subsequent triazole formation. Reactions performed with potassium peroxydisulfate as the oxidant were more efficient when initiated thermally than photochemically to generate persulfate radical anions. Reaction of internal aromatic alkyne 27 with azidyl radicals resulted in 2H-1,2,3-triazole 179 and 2-substituted-1,2,3-triazole 180, in the presence of potassium peroxydisulfate. Numerous other oxidants were investigated at length to generate azidyl radicals from inorganic azide. Experiments with these oxidants resulted in complex mixtures, low yielding products and/or no reaction. No reactions were observed between azidyl radicals and aliphatic alkynes.
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ItemThiyl radical reactions with alkynes in the absence and presence of oxygen( 2009)This thesis is concerned with the reactions of sulfur-centred radicals and alkynes. The first objective of this work was to extend the scope of “self-terminating radical cyclisations” to sulfur-centred radicals, such as thiyl radicals. Preliminary experiments revealed that the reaction of thiyl radicals with alkynes was sensitive to residual oxygen. In the absence of oxygen, the reactions of photochemically generated phenylthiyl radicals with cyclodecyne (1) resulted in three isomeric sulfides, which were identified through a combination of techniques. (1S,6S)-2-phenylthiobicyclo[4.4.0]decane (trans-49a, unknown stereochemistry at C2) was identified by synthesis of an authentic sample, while the structure of (1S,2R,6S)-2-phenylthiobicyclo[4.4.0]decane (cis-49a1) was determined by X-ray analysis of the corresponding crystalline sulfone, cis-69. The third sulfide, (1S,2S,6S)-2-phenylthio-bicyclo[4.4.0]decane (cis-49a2), was assigned based on computational studies. In addition, the reactions of benzylthiyl, tert-butylthiyl and allylthiyl radicals with cyclodecyne (1) were investigated. Various sources of thiyl radical generation were utilized, such as the photolysis of disulfides and thiols, hydrogen atom abstraction of thiols using radical initiators, as well as thiol autoxidation in the presence of oxygen. The radical cascade initiated by the addition of thiyl radicals to alkyne 1 was typically terminated by either reduction or disproportionation, whereas “self-termination” was only observed in one particular instance where the tert-butylthiyl radical was generated by autoxidation. However, this was only a minor pathway. The second objective of this work was to investigate the reactions of thiyl radicals with alkynes in the presence of oxygen. For this purpose, phenylthiyl radicals were generated in the presence of diphenylacetylene (89) and molecular oxygen. Benzil (91), an α-diketone, and 1,2-diphenyl-2-(phenylthio)ethanone (93), an α-ketosulfide, were formed. The novel thiyl radical-mediated oxidation of diphenylacetylene to benzil mediated proceeds under mild and metal-free conditions, using various methods of thiyl radical generation. The product ratio of diketone to ketosulfide varied with the reaction conditions. Under photochemical conditions, benzil was formed but its photodegradation was also observed. Using autoxidation, moderate to good yields of both diketone 91 and ketosulfide 93 were obtained, although the product ratios varied with solvent and reaction conditions. Diketone 91 was the major product when the thiyl radical was generated electrochemically. Following investigation of the reaction mechanism using experimental and computational studies, the phenylthiyl peroxyl radical was identified as the key reactive intermediate. This represents the first synthetic application of thiyl peroxyl radicals. Using autoxidation conditions, the oxidation was explored using substituted aromatic thiyl radicals, e.g. 2,6-dimethylbenzene, 2,4,6-tri-tert-butylbenzene, 4-methoxybenzene and 4-nitrobenzene thiyl radicals. Except for the case of 4-methoxybenzene thiyl radicals, where generation of the thiyl radicals was inefficient, diketone 91 was formed as the dominant product. This oxidation of alkynes to ketones, via thiyl radical-mediated activation of oxygen, was then applied to cyclodecyne (1). Bicyclic ketones 7/8 were found as the major products under photochemical conditions, while sulfides 152/trans-49a were the dominant products under autoxidation conditions. Bicyclic ketones 7/8 were formed due to the intramolecular radical processes directed by the transannular strain of the ten-membered carbon framework. Only trace amounts of the cyclic α-diketone 151 were detected under autoxidation conditions.