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Computational Models for Reactivity and Selectivity in Catalytic Olefin Functionalization

Award Number: R35GM128779
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Computational Models for Reactivity and Selectivity in Catalytic Olefin Functionalization - Abstract Transition metal- and enzyme-catalyzed reactions of alkenes are among the most powerful approaches to synthesize functionalized organic compounds for biomedical research. Recent experimental advancements have enabled promising catalytic methods for various alkene functionalization reactions with different mechanistic features and distinct types of bond formations. However, it remains a significant challenge to effectively control regio- and stereoselectivity in reactions with readily available, unactivated alkenes. Due to the lack of theoretical understanding of reaction mechanisms and origins of catalyst effects on reactivity and selectivity, experimental developments of new catalytic reactions often rely on trial-and-error screening. A general strategy to investigate catalytic reaction mechanisms and to utilize mechanistic information to guide catalyst discovery is warranted. The overall goal of this proposal is to develop and apply computational tools to obtain mechanistic insights and predictive models to guide experimental development of catalytic functionalizations of alkenes. We will use a series of computational tools, including density functional theory (DFT) and ab initio molecular dynamics (AIMD) simulations, to model reaction pathways and identify rate- and selectivity-determining transition states. We will utilize energy decomposition analysis (EDA) calculations to analyze covalent and non-covalent interactions between catalyst and substrate and provide quantitative and straightforward prediction of dominant catalyst– substrate interactions that control reactivity and selectivity. We will apply these computational tools to investigate mechanistically complex catalytic systems, including reactions involving conformationally flexible catalysts, solvent cage effects in radical-mediated reactions, and cooperative effects in multicomponent reactions. We will use computational tools to perform detailed studies of new-to-nature reactions catalyzed by engineered enzymes. These studies will reveal the mechanisms of enantioinduction and the roles of key active site residues on reactivity and selectivity. The proposed research program is significant and innovative because it aims to address general challenges in computational studies of a broad range of catalytic reactions, rather than to simply explain existing results for specific experimental systems. Our studies will establish computational approaches to investigate complex, yet important phenomena in catalysis, including the roles of non-covalent interactions, solvent, and catalyst flexibility. These mechanistic insights can provide new principles and strategies in rational catalyst design to improve reactivity, selectivity, and substrate scope. Our research is highly unique in collaborating with many prominent experimental groups. These fruitful collaborations allowed us to progress in not only the understanding of many specific examples of alkene functionalization reactions, but also the development of general rules of regio- and stereoselectivity in these processes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $334,519 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	8	1/7/2026	NON-COMPETING CONTINUATION	$334,519
														Subtotal = $334,519

Issue Date FY: 2025 ( Subtotal = $371,688 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	003	7	8/8/2025	NON-COMPETING CONTINUATION	$37,169
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	002	7	12/3/2024	NON-COMPETING CONTINUATION	$334,519
2025	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	6	11/5/2024	COMPETING CONTINUATION	$0
2025	2022	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	001	5	11/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $371,688

Issue Date FY: 2024 ( Subtotal = $362,690 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	6	12/7/2023	COMPETING CONTINUATION	$362,690
														Subtotal = $362,690

Issue Date FY: 2022 ( Subtotal = $369,498 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	5	8/16/2022	NON-COMPETING CONTINUATION	$369,498
														Subtotal = $369,498

Issue Date FY: 2021 ( Subtotal = $369,498 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Biomedical Research and Research Training	000	4	8/27/2021	NON-COMPETING CONTINUATION	$369,498
														Subtotal = $369,498

Issue Date FY: 2020 ( Subtotal = $369,498 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	3	8/19/2020	NON-COMPETING CONTINUATION	$369,498
														Subtotal = $369,498

Issue Date FY: 2019 ( Subtotal = $369,498 )
2019	2019	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	2	8/7/2019	NON-COMPETING CONTINUATION	$369,498
														Subtotal = $369,498

Issue Date FY: 2018 ( Subtotal = $348,404 )
2018	2018	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Biomedical Research and Research Training	000	1	8/23/2018	NEW	$348,404
														Subtotal = $348,404

Grand Total All Awards = $2,895,293

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Computational Models for Reactivity and Selectivity in Catalytic Olefin Functionalization

Award Number: R35GM128779

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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