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Homolytic Aromatic Substitution, Conformational Dynamics of Dihydrophenanthridines, and High-Throughput Synthesis of Amides with Fluorous Technology: Methodologies in Reaction, Analysis, and Separation

Keller, Adam I. (2007) Homolytic Aromatic Substitution, Conformational Dynamics of Dihydrophenanthridines, and High-Throughput Synthesis of Amides with Fluorous Technology: Methodologies in Reaction, Analysis, and Separation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Homolytic aromatic substitution encompasses a wide range of synthetic transformations based on inter- and intramolecular additions of radicals to arenes. Additions of radicals derived from aryl iodides to arenes are promoted by tris(trimethylsilyl)silane and occur under exceptionally mild conditions in non-degassed benzene. Experimental observations led to a proposed mechanism involving reaction of the intermediate cyclohexadienyl radical with dioxygen to generate the aromatic product and the hydroperoxy radical. This methodology was extended to the synthesis of biaryl and heterocyclic compounds.N-Acetyldihydrophenanthridines exhibit remarkable conformational dynamics that are observable on the NMR timescale. Semiempirical calculations were performed to understand their conformational preferences. The predictions derived from the calculated structures were verified by x-ray crystallography, two-dimensional exchange and variable temperature NMR spectroscopy. The rate constants for conformational switching were calculated by a matrix-based routine with data extracted from the two-dimensional exchange spectra.A fluorous equivalent of diisopropylcarbodiimide (FDIC) was synthesized to overcome the separation problems encountered when conducting solution-phase, carbodiimide mediated acyl couplings. The reactivity of the fluorous analog was not greatly affected by the presence of a fluorous domain, and was equally as effective as diisopropylcarbodiimide in facilitating amide bond formation. Coupled with a reverse F-SPE strategy, FDIC mediated couplings were conducted to provide the target amides in high-purities (95-99%). A small library of amides was prepared in a high-throughput fashion to demonstrate the utility of this approach.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Keller, Adam
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairCurran, Dennis Pcurran@pitt.eduCURRAN
Committee MemberDay, Billybday@pitt.eduBDAY
Committee MemberWilcox, Craigdaylite@pitt.eduDAYLITE
Committee MemberFloreancig, Paulflorean@pitt.eduFLOREAN
Date: 21 June 2007
Date Type: Completion
Defense Date: 2 March 2007
Approval Date: 21 June 2007
Submission Date: 12 April 2007
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: 2DEXSY; AM1; amide rotamer; aryl bromide; aryl halide; aryl iodide; aryl radical; biphenyl; cartridge; chem3D; control reaction; Curran; D2DNMR; DIC; energy barrier; energy minimization; EXSY; fluorous carbodiimide; fluorous technologies; fluorous urea; FTI; GC; GC-MS; incorporated; internal standard; mixing time; molecular modeling; N-acylurea; nOe; oxygen; phenanthridine; pulse sequence; radical mechanism; rotational barrier; silica gel; silicon NMR; SPE; tributyltin hydride; TTMSS; twisted amide; vinyl radical; VTNMR
Other ID:, etd-04122007-142347
Date Deposited: 10 Nov 2011 19:36
Last Modified: 15 Nov 2016 13:39


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