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Twisted Cycloalkynes in Click Chemistry and Traceless Directing Groups in Radical Cascade Cyclizations

Title: Twisted Cycloalkynes in Click Chemistry and Traceless Directing Groups in Radical Cascade Cyclizations.

Inaccessible until Sep 27, 2020 due to copyright restrictions.

Name(s): Harris, Trevor Michael, author
Alabugin, Igor V., (Professor), professor directing dissertation
Ma, Teng, university representative
Hanson, Kenneth G., committee member
Kennemur, Justin Glenn, committee member
Florida State University, degree granting institution
College of Arts and Sciences, degree granting college
Department of Chemistry and Biochemistry, degree granting department
Type of Resource: text
Genre: Text
Doctoral Thesis
Issuance: monographic
Date Issued: 2017
Publisher: Florida State University
Place of Publication: Tallahassee, Florida
Physical Form: computer
online resource
Extent: 1 online resource (228 pages)
Language(s): English
Abstract/Description: This dissertation discloses the work of two research projects: the synthesis and study of twisted cycloalkynes for click chemistry and traceless directing groups used in radical cascade cyclizations. The structural design of the cycloalkynes incorporates a “twisted and bent” motif that disrupts the interaction between donor and acceptor groups. This accumulation of electronic energy in the twisted cycloalkyne is released in the transition state when the backbone structurally reorganizes and restores optimal conjugation at a remote location from the reacting alkyne center, providing a new way to control click reactivity through remote activation. An experimental confirmation of the proposed connection between structural changes and electronic effects was investigated by UV-Vis spectroscopy of the starting 2,2’-biaryl nucleophiles, cyclodecynes, and the triazole products. Furthermore, these twisted cycloalkynes make axial chirality a new molecular property that can be introduced by click chemistry. The synthesis of the cycloalkynes has been optimized to a gram-scale, one-step protocol that involves a strategically simple nucleophilic substitution reaction. The cyclization step avoids the use of alkyne protecting groups and six of the endogenous atoms come from commercially available 2,2’-biaryl sources and purification is accomplished through recrystallization. Because the cyclization proceeds without chiral racemization under basic conditions, synthesis of enantiopure cycloalkynes can be made from chiral starting materials. Circular dichroism spectroscopy demonstrated the biaryl backbone of the starting materials controls the chiroptical properties of the cycloalkynes. Several representative cyclodecynes were investigated to compare the reactivity with activated cyclononynes and seminal cyclooctyne. The click cycloaddition rate constants of cyclodecynes outcompete the smaller activated cyclononynes and even approach the reactivity of cyclooctyne. Rate enhancement in the cyclodecynes stems from the endocyclic heteroatoms that provide dual transition state (TS) stabilization via hyperconjugative (direct) and conjugative (remote) effects. Oligoalkynes are precursors that can be used for the preparation of carbon-rich polyaromatics. They can undergo radical cascade cyclizations in the presence of a Sn-radical source through chemo- and regioselective initiation. To assist the attack of the Sn-radical at the xii correct alkyne, a propargylic alkoxy group was installed. Through a sequence of exo-cyclizations that “zip up” the oligoalkyne backbone, the radical returns to the site of initial attack in a “boomerang” fashion. The key radical intermediate, the radical adjacent to the alkoxy group stabilized by an electron rich alkyltin group, furnishes the aromatized product through β-scission to form an alkoxy radical, rendering the directing group, traceless. Though computational analysis rendered the sequence of transformations favorable and a plausible mechanistic pathway, generation of an alkoxy radical is an unlikely scenario considering the barrier for C–O scission is relatively high. Because this pathway was a mechanistic ambiguity, a second termination step was considered: H-abstraction followed by elimination of an alcohol coupled with aromatization. This indirect route included an additional step in the overall cascade but avoids formation of the alkoxy radical intermediate. However, several key experiments and computational evidence demonstrated the direct route, formation of the alkoxy radical, is the preferred outcome. One experiment used a traceless directing group which was designed to incorporate a “weak-link” tether and radical stabilizing group to help facilitate β-scission of the alkoxy radical. This fragmentation generates formaldehyde and a radical that is finally quenched to a non-volatile product that is characterized by NMR spectroscopy. The alternative route does not occur because the alcohol product of the indirect path was not observed. Additionally, a separate trapping experiment used an electron rich vinyl silyl ether to trap the putative alkoxy radical.
Identifier: FSU_FALL2017_Harris_fsu_0071E_14198 (IID)
Submitted Note: A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Degree Awarded: Fall Semester 2017.
Date of Defense: November 13, 2017.
Keywords: click chemistry, cycloalkynes, radical cyclizations, traceless directing groups
Bibliography Note: Includes bibliographical references.
Advisory Committee: Igor V. Alabugin, Professor Directing Dissertation; Teng Ma, University Representative; Kenneth Hanson, Committee Member; Justin Kennemur, Committee Member.
Subject(s): Chemistry
Persistent Link to This Record:
Owner Institution: FSU

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Harris, T. M. (2017). Twisted Cycloalkynes in Click Chemistry and Traceless Directing Groups in Radical Cascade Cyclizations. Retrieved from