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Computational Studies of Catalytic Organic and Bioorganic Reactions

Fu, Yue (2022) Computational Studies of Catalytic Organic and Bioorganic Reactions. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Understanding reaction mechanisms, rationalizing reactivity and selectivity, and predicting new catalytic transformations are long-standing challenges for synthetic organic chemistry. To provide molecular level understanding of reaction mechanisms and catalyst effects, computational study has emerged as an effective approach. The use of computational methods in mechanistic studies is especially valuable in systems involving complex reaction pathways, reactive intermediates, strong solvent effects, and open-shell transition metal complexes, where experimental techniques for mechanistic investigations are relatively limited.
I applied various computational methods to investigate reaction mechanisms and factors controlling reactivity and selectivity in glycosylation reactions, silver catalyzed C−H amination reactions, and P450-catalyzed bioorganic reactions. In this dissertation (Chapter 2), I use the combination of AIMD metadynamics and BOMD trajectory simulations to provide metrics (energy, geometry, and timing) to describe the continuum of glycosylation mechanisms (SN2, SN2-like, SNi, SN1-like, and SN1). In Chapter 3, I apply systematic studies to evaluate the sensitivity of regioselectivity to different substrate properties (BDE, tether length, electronic effects, etc) in silver catalyzed C–H amination reactions. Finally, I report a computational study on the mechanism, reactivity, and enantioselectivity in the P450-catalyzed atom transfer radical cyclization (ATRC) (Chapter 4). I discovered a bifunctional biocatalyst, with the heme cofactor enabling atom transfer activity and the Q263 residue introduced in directed evolution serving as a critical hydrogen bond donor, activating the substrate, and enhancing enantioselectivity.
Computational insights derived from these studies were used to facilitate the synthesis of functionalized organic compounds and guide reaction design.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Fu, Yueyuf40@pitt.eduyuf400000-0003-3085-7817
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairLiu, Pengpengliu@pitt.edupengliu
Committee MemberJordan, Kennethjordan@pitt.eduJORDAN
Committee MemberIslam, Kabirulkai27@pitt.edukai27
Committee MemberIsayev,
Date: 30 September 2022
Date Type: Publication
Defense Date: 2 August 2022
Approval Date: 30 September 2022
Submission Date: 19 July 2022
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 167
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: Ligands,Organic compounds, Organic reactions, Selectivity, Transition states, Noncovalent interactions, Organic reactions, QM/MM, Stereoselectivity, Surface interactions
Date Deposited: 30 Sep 2022 19:00
Last Modified: 30 Sep 2022 19:00


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