{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/78714"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/78714","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"C(sp3)-H aminations under first row transition metal catalysis","abstract":"Nitrogen functionality is ubiquitous in biologically active molecules, from naturally occurring alkaloids and peptides to synthetic pharmaceuticals. However, due to its promiscuous reactivity, nitrogen can be challenging to incorporate into molecules and carry through synthetic sequences. Traditional methods to introduce nitrogen (e.g. Mannich, reductive amination) often rely on pre-existing functionality and require additional transformations such as oxidation state changes and/or protecting group maniuplations. C—H amination represents a powerful alternative synthetic strategy. This approach involves the direct functionalization of highly robust sp3 C—H bonds, which allows for the introduction of nitrogen functionality at late stages in synthetic sequences, both obviating the requirement for lengthy functional group manipulation strategies and enabling rapid access to a diversity of structures. Although small molecule iron and manganese catalysts were first explored for metallonitrene-mediated C—H amination reactions, the majority of synthetic advances in the field have been with noble metal dirhodium carboxylate catalysts. These catalysts are highly reactive and have collectively displayed the ability to efficiently aminate benzylic, ethereal, and aliphatic C—H bonds. However, they are poorly chemoselective in the presence of π-functionality such as olefins and alkynes, and direct addition to these π-bonds is often competitive with desired C—H amination reactivity. It is likely that rhodium’s concerted asynchronous C—H insertion mechanism, which favors functionalization at more electron-rich sites, is responsible for this lack of chemoselectivity. Conversely, first row transition metal catalysts like iron and manganese are thought to react through a stepwise homolytic C—H abstraction/rebound mechanism. We hypothesized that this different mechanism would lead to orthogonal reactivity under first row transition metal catalysis, including the ability to functionalize allylic C—H bonds with high chemoselectivity. In addition, iron and manganese are highly abundant and non-toxic base metals that have been relatively unexplored. The first chapter of this dissertation describes the development of the first synthetically useful C—H amination method under iron catalysis. This reaction, which employs the bulk commodity complex [FeIIIPc], confirms our initial hypothesis, displaying excellent chemoselectivity (generally >20:1 ins./azir.) for allylic C—H amination over a range of olefin classes and exhibiting site-selectivity trends that are orthogonal to those observed under rhodium catalysis. In addition, this bulky, electrophilic catalyst is able to differentiate between allylic C—H bonds in polyolefinic substrates on the basis of their electronic and steric nature. Mechanistic studies support a stepwise mechanism involving discrete electrophilic intermediates. In seeking to expand the scope of this C—H amination methodology, we were struck by a clear divergence in the literature between reactivity and selectivity. Existing catalysts for C(sp3)—H amination, including our [FeIIIPc] catalyst, are either highly reactive or highly selective, but not both. We sought to exploit the exquisite chemoselectivity of first row transition metals in order to develop a small molecule C—H amination catalyst that was truly general. The second chapter of this dissertation describes the discovery and development of [Mn(tBuPc)], a novel manganese catalyst that for the first time is able to effectively functionalize all types of sp3 C—H bonds with preparative product yields (>50%) even for very strong 2° and 1° aliphatic C—H bonds, while maintaining excellent chemoselectivity for C—H amination (>20:1) in the presence of readily oxidizable π-bonds. We conduct mechanistic studies to investigate the often drastic reactivity differences between [Mn(tBuPc)] and our previous [FeIIIPc], finding subtle changes in the C—H cleavage step that suggest attenuated radical behavior with manganese relative to iron. The generality of this method and versatility of the oxathiazinane C—H amination product lend it well for application to the diversification of topologically and functionally complex bioactive molecules. This is demonstrated for picrotoxinin and isosteviol derivatives, which maintain (or magnify) the reactivity and selectivity trends observed with the corresponding simple substructural units.","abstract_html":"Nitrogen functionality is ubiquitous in biologically active molecules, from naturally occurring alkaloids and peptides to synthetic pharmaceuticals. However, due to its promiscuous reactivity, nitrogen can be challenging to incorporate into molecules and carry through synthetic sequences. Traditional methods to introduce nitrogen (e.g. Mannich, reductive amination) often rely on pre-existing functionality and require additional transformations such as oxidation state changes and/or protecting group maniuplations. C—H amination represents a powerful alternative synthetic strategy. This approach involves the direct functionalization of highly robust sp3 C—H bonds, which allows for the introduction of nitrogen functionality at late stages in synthetic sequences, both obviating the requirement for lengthy functional group manipulation strategies and enabling rapid access to a diversity of structures. Although small molecule iron and manganese catalysts were first explored for metallonitrene-mediated C—H amination reactions, the majority of synthetic advances in the field have been with noble metal dirhodium carboxylate catalysts. These catalysts are highly reactive and have collectively displayed the ability to efficiently aminate benzylic, ethereal, and aliphatic C—H bonds. However, they are poorly chemoselective in the presence of π-functionality such as olefins and alkynes, and direct addition to these π-bonds is often competitive with desired C—H amination reactivity. It is likely that rhodium’s concerted asynchronous C—H insertion mechanism, which favors functionalization at more electron-rich sites, is responsible for this lack of chemoselectivity. Conversely, first row transition metal catalysts like iron and manganese are thought to react through a stepwise homolytic C—H abstraction/rebound mechanism. We hypothesized that this different mechanism would lead to orthogonal reactivity under first row transition metal catalysis, including the ability to functionalize allylic C—H bonds with high chemoselectivity. In addition, iron and manganese are highly abundant and non-toxic base metals that have been relatively unexplored. The first chapter of this dissertation describes the development of the first synthetically useful C—H amination method under iron catalysis. This reaction, which employs the bulk commodity complex [FeIIIPc], confirms our initial hypothesis, displaying excellent chemoselectivity (generally >20:1 ins./azir.) for allylic C—H amination over a range of olefin classes and exhibiting site-selectivity trends that are orthogonal to those observed under rhodium catalysis. In addition, this bulky, electrophilic catalyst is able to differentiate between allylic C—H bonds in polyolefinic substrates on the basis of their electronic and steric nature. Mechanistic studies support a stepwise mechanism involving discrete electrophilic intermediates. In seeking to expand the scope of this C—H amination methodology, we were struck by a clear divergence in the literature between reactivity and selectivity. Existing catalysts for C(sp3)—H amination, including our [FeIIIPc] catalyst, are either highly reactive or highly selective, but not both. We sought to exploit the exquisite chemoselectivity of first row transition metals in order to develop a small molecule C—H amination catalyst that was truly general. The second chapter of this dissertation describes the discovery and development of [Mn(tBuPc)], a novel manganese catalyst that for the first time is able to effectively functionalize all types of sp3 C—H bonds with preparative product yields (>50%) even for very strong 2° and 1° aliphatic C—H bonds, while maintaining excellent chemoselectivity for C—H amination (>20:1) in the presence of readily oxidizable π-bonds. We conduct mechanistic studies to investigate the often drastic reactivity differences between [Mn(tBuPc)] and our previous [FeIIIPc], finding subtle changes in the C—H cleavage step that suggest attenuated radical behavior with manganese relative to iron. The generality of this method and versatility of the oxathiazinane C—H amination product lend it well for application to the diversification of topologically and functionally complex bioactive molecules. This is demonstrated for picrotoxinin and isosteviol derivatives, which maintain (or magnify) the reactivity and selectivity trends observed with the corresponding simple substructural units.","abstract_has_math":false,"creators":["Paradine Tschirhart, Shauna"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Chemistry","degree_department":null,"school":null,"contributors":["White, Maria C.","Denmark, Scott E.","van der Donk, Wilfred A.","Katzenellenbogen, John A."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-07-22T22:45:03Z","date_published":"2015-07-22T22:45:03Z","updated_at":"2026-07-22T22:26:12Z","subjects":["C-H amination","transition metal catalysis","organic chemistry"],"languages":[],"rights":["Copyright 2015 Shauna Paradine Tschirhart"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2142/78714","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["White, Maria C.","Denmark, Scott E.","van der Donk, Wilfred A.","Katzenellenbogen, John A."]},{"key":"dc:creator","label":"Author","values":["Paradine Tschirhart, Shauna"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2015-07-22T22:45:03Z","2017-07-23T09:15:22Z","2015-05","2015-03-04","2015-5"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Chemistry"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["C-H amination","transition metal catalysis","organic chemistry"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2015 Shauna Paradine Tschirhart"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/78714"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Nitrogen functionality is ubiquitous in biologically active molecules, from naturally occurring alkaloids and peptides to synthetic pharmaceuticals. However, due to its promiscuous reactivity, nitrogen can be challenging to incorporate into molecules and carry through synthetic sequences. Traditional methods to introduce nitrogen (e.g. Mannich, reductive amination) often rely on pre-existing functionality and require additional transformations such as oxidation state changes and/or protecting group maniuplations. C—H amination represents a powerful alternative synthetic strategy. This approach involves the direct functionalization of highly robust sp3 C—H bonds, which allows for the introduction of nitrogen functionality at late stages in synthetic sequences, both obviating the requirement for lengthy functional group manipulation strategies and enabling rapid access to a diversity of structures. Although small molecule iron and manganese catalysts were first explored for metallonitrene-mediated C—H amination reactions, the majority of synthetic advances in the field have been with noble metal dirhodium carboxylate catalysts. These catalysts are highly reactive and have collectively displayed the ability to efficiently aminate benzylic, ethereal, and aliphatic C—H bonds. However, they are poorly chemoselective in the presence of π-functionality such as olefins and alkynes, and direct addition to these π-bonds is often competitive with desired C—H amination reactivity. It is likely that rhodium’s concerted asynchronous C—H insertion mechanism, which favors functionalization at more electron-rich sites, is responsible for this lack of chemoselectivity. Conversely, first row transition metal catalysts like iron and manganese are thought to react through a stepwise homolytic C—H abstraction/rebound mechanism. We hypothesized that this different mechanism would lead to orthogonal reactivity under first row transition metal catalysis, including the ability to functionalize allylic C—H bonds with high chemoselectivity. In addition, iron and manganese are highly abundant and non-toxic base metals that have been relatively unexplored. The first chapter of this dissertation describes the development of the first synthetically useful C—H amination method under iron catalysis. This reaction, which employs the bulk commodity complex [FeIIIPc], confirms our initial hypothesis, displaying excellent chemoselectivity (generally >20:1 ins./azir.) for allylic C—H amination over a range of olefin classes and exhibiting site-selectivity trends that are orthogonal to those observed under rhodium catalysis. In addition, this bulky, electrophilic catalyst is able to differentiate between allylic C—H bonds in polyolefinic substrates on the basis of their electronic and steric nature. Mechanistic studies support a stepwise mechanism involving discrete electrophilic intermediates. In seeking to expand the scope of this C—H amination methodology, we were struck by a clear divergence in the literature between reactivity and selectivity. Existing catalysts for C(sp3)—H amination, including our [FeIIIPc] catalyst, are either highly reactive or highly selective, but not both. We sought to exploit the exquisite chemoselectivity of first row transition metals in order to develop a small molecule C—H amination catalyst that was truly general. The second chapter of this dissertation describes the discovery and development of [Mn(tBuPc)], a novel manganese catalyst that for the first time is able to effectively functionalize all types of sp3 C—H bonds with preparative product yields (>50%) even for very strong 2° and 1° aliphatic C—H bonds, while maintaining excellent chemoselectivity for C—H amination (>20:1) in the presence of readily oxidizable π-bonds. We conduct mechanistic studies to investigate the often drastic reactivity differences between [Mn(tBuPc)] and our previous [FeIIIPc], finding subtle changes in the C—H cleavage step that suggest attenuated radical behavior with manganese relative to iron. The generality of this method and versatility of the oxathiazinane C—H amination product lend it well for application to the diversification of topologically and functionally complex bioactive molecules. This is demonstrated for picrotoxinin and isosteviol derivatives, which maintain (or magnify) the reactivity and selectivity trends observed with the corresponding simple substructural units.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2017-05-01","The student, Shauna Paradine Tschirhart, accepted the attached license on 2015-03-03 at 12:51.","The student, Shauna Paradine Tschirhart, submitted this Dissertation for approval on 2015-03-03 at 12:56.","This Dissertation was approved for publication on 2015-03-04 at 10:17.","DSpace SAF Submission Ingestion Package generated from Vireo submission #7732 on 2015-07-22 at 14:24:08","Made available in DSpace on 2015-07-22T22:45:03Z (GMT). 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However, due to its promiscuous reactivity, nitrogen can be challenging to incorporate into molecules and carry through synthetic sequences. Traditional methods to introduce nitrogen (e.g. Mannich, reductive amination) often rely on pre-existing functionality and require additional transformations such as oxidation state changes and/or protecting group maniuplations. C—H amination represents a powerful alternative synthetic strategy. This approach involves the direct functionalization of highly robust sp3 C—H bonds, which allows for the introduction of nitrogen functionality at late stages in synthetic sequences, both obviating the requirement for lengthy functional group manipulation strategies and enabling rapid access to a diversity of structures. Although small molecule iron and manganese catalysts were first explored for metallonitrene-mediated C—H amination reactions, the majority of synthetic advances in the field have been with noble metal dirhodium carboxylate catalysts. These catalysts are highly reactive and have collectively displayed the ability to efficiently aminate benzylic, ethereal, and aliphatic C—H bonds. However, they are poorly chemoselective in the presence of π-functionality such as olefins and alkynes, and direct addition to these π-bonds is often competitive with desired C—H amination reactivity. It is likely that rhodium’s concerted asynchronous C—H insertion mechanism, which favors functionalization at more electron-rich sites, is responsible for this lack of chemoselectivity. Conversely, first row transition metal catalysts like iron and manganese are thought to react through a stepwise homolytic C—H abstraction/rebound mechanism. We hypothesized that this different mechanism would lead to orthogonal reactivity under first row transition metal catalysis, including the ability to functionalize allylic C—H bonds with high chemoselectivity. In addition, iron and manganese are highly abundant and non-toxic base metals that have been relatively unexplored. The first chapter of this dissertation describes the development of the first synthetically useful C—H amination method under iron catalysis. This reaction, which employs the bulk commodity complex [FeIIIPc], confirms our initial hypothesis, displaying excellent chemoselectivity (generally >20:1 ins./azir.) for allylic C—H amination over a range of olefin classes and exhibiting site-selectivity trends that are orthogonal to those observed under rhodium catalysis. In addition, this bulky, electrophilic catalyst is able to differentiate between allylic C—H bonds in polyolefinic substrates on the basis of their electronic and steric nature. Mechanistic studies support a stepwise mechanism involving discrete electrophilic intermediates. In seeking to expand the scope of this C—H amination methodology, we were struck by a clear divergence in the literature between reactivity and selectivity. Existing catalysts for C(sp3)—H amination, including our [FeIIIPc] catalyst, are either highly reactive or highly selective, but not both. We sought to exploit the exquisite chemoselectivity of first row transition metals in order to develop a small molecule C—H amination catalyst that was truly general. The second chapter of this dissertation describes the discovery and development of [Mn(tBuPc)], a novel manganese catalyst that for the first time is able to effectively functionalize all types of sp3 C—H bonds with preparative product yields (>50%) even for very strong 2° and 1° aliphatic C—H bonds, while maintaining excellent chemoselectivity for C—H amination (>20:1) in the presence of readily oxidizable π-bonds. We conduct mechanistic studies to investigate the often drastic reactivity differences between [Mn(tBuPc)] and our previous [FeIIIPc], finding subtle changes in the C—H cleavage step that suggest attenuated radical behavior with manganese relative to iron. The generality of this method and versatility of the oxathiazinane C—H amination product lend it well for application to the diversification of topologically and functionally complex bioactive molecules. This is demonstrated for picrotoxinin and isosteviol derivatives, which maintain (or magnify) the reactivity and selectivity trends observed with the corresponding simple substructural units.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2017-05-01","The student, Shauna Paradine Tschirhart, accepted the attached license on 2015-03-03 at 12:51.","The student, Shauna Paradine Tschirhart, submitted this Dissertation for approval on 2015-03-03 at 12:56.","This Dissertation was approved for publication on 2015-03-04 at 10:17.","DSpace SAF Submission Ingestion Package generated from Vireo submission #7732 on 2015-07-22 at 14:24:08","Made available in DSpace on 2015-07-22T22:45:03Z (GMT). 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