Omer, Humair
(2020)
Exploring C−H Functionalization Reactions with Theory and Experiment.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
C−H bond functionalization reactions are powerful, efficient, and potentially step-economic strategy for the construction of carbon−carbon and carbon−heteroatom bonds in organic synthesis. In recent years, novel Ni-catalyzed C−H bond functionalization reactions using N,N bidentate directing groups have been developed to selectively activate inert C−H bonds. However, the reaction mechanisms and origins of reactivity and selectivity of many of these organic transformations remain unclear. A detailed understanding of the molecular processes involved is essential for understanding and developing more efficient and diverse C−H functionalization reactions. Density functional theory (DFT) has emerged as a powerful tool to elucidate reaction mechanisms and intricate details of the elementary steps involved, and divergent reaction pathways in transition metal-catalyzed reactions. In this dissertation, the mechanisms of Ni-catalyzed C–H oxidative annulation, arylation, alkylation, benzylation and sulfenylation with N,N-bidentate directing groups are investigated using DFT calculations.
Ni-catalyzed C–H functionalization reactions can be broadly divided into two distinct mechanistic steps: (i) C–H metalation (ii) C–C or C–heteroatom bond formation steps. Specifically, the C–H metalation may occur via either the concerted metalation-deprotonation (CMD) or σ-complex-assisted metathesis (σ-CAM) mechanism. The subsequent C–C and C–heteroatom bond formation steps may occur via closed-shell Ni(II) or Ni(IV) intermediates. Alternatively, radical pathways involving Ni(III) complexes are also possible. Our studies indicated that the reaction mechanism of Ni-catalyzed C–H functionalization is substrate-dependent. The mechanistic insights gained from the computational studies were employed to investigate a number of experimental phenomena including substituent effects on reactivity, chemo- and regioselectivity, ligand and directing group effects, and the effects of oxidants.
Furthermore, a novel C(sp3)−H functionalization methodology was developed to synthesize biologically relevant vinyl sulfone-containing compounds of pharmacologically prevalent picolyl amides with allenic sulfones. The reaction conditions are mild. The starting materials can be prepared from readily available sources. The reaction has a broad functional group tolerance. Mechanistic studies suggested that the reaction likely operates via a rare pyridine-initiated and p-toluenesulfinate anion-mediated activation analogous to phosphine-triggered reactions and Padwa’s allenic sulfone chemistry.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
8 June 2020 |
| Date Type: |
Publication |
| Defense Date: |
27 January 2020 |
| Approval Date: |
8 June 2020 |
| Submission Date: |
14 January 2020 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
351 |
| 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: |
C-H functionalization, Nickel catalysis, vinyl sulfones, allenyl sulfones, reaction mechanism, pyridine-intiated |
| Date Deposited: |
08 Jun 2020 16:52 |
| Last Modified: |
08 Jun 2020 16:52 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/38137 |
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