Dissertation Defense: Abolghasem Bakhoda

Candidate Name: Abolghasem Bakhoda

Major: Chemistry

Advisor: Timothy H. Warren, Ph.D.

Title: Mechanistic Studies of Copper and Nickel Catalyzed sp3 C−H Functionalization

sp3 C−H functionalization represents a paradigm shift from the conventional rationality of organic synthesis. Classical organic synthesis relies on the manipulation of functional groups while the new logic of C−H functionalization focuses on the direct installation of functional groups using supposedly “unreactive” C−H bonds even in the presence of more reactive functional groups. This paradigm has the potential to change the synthetic organic chemistry strategy for creating new molecules. This way, light aliphatic hydrocarbons can be converted into value−added chemicals such as amines. Alternatively, complex molecules with one or more functional groups may be converted into more functionalized chemicals for industrial purposes such as drug discovery.

Recent advances in the field of organotransition metal chemistry have offered opportunities to achieve activation and functionalization of C−H bonds. Seminal work in this area focused on the reaction development for relatively simple hydrocarbons. Over the past few years, however, several C−H functionalization methods have been discovered and established for the synthesis of complex target molecules. Nowadays, the field has moved from an organometallic challenge with the goal of simply cleaving C−H bonds to form metal−carbon bonds to the development of new synthetic methods for efficient organic synthesis.

Despite all the aforementioned advances, the development of site−selective C−H functionalization is still in its infancy. Although several catalyst sytems have been established and many mechanisms have been proposed for transition metal catalyzed C−H functionalization, only a handful of examples are well understood and are mechanistically deriven for resolving the site−selectivity issue. Therefore, more detailed mechanistic studies are needed towards the goal of creating a wide range of reactions suitable for the practical synthesis of both simple and complex molecules by C−H bond functionalization.

Herein decribes a series of mechanistic studies that employ −diketiminato copper(I) and nickel(I) complexes in catalytic intermolecular sp3 C−H functionaliztion. Initially, the successful isolation of a terminal copper−nitrene for nitrene group tranfer into nucleophiles such as isocyanides and phosphines as well as the benzylic C−H bonds is discussed (Chapter 1). Reactivity studies showed a dicopper(II) ketimide complex can be considered as a “masked” terminal copper−arylnitrene complex [Cu]=NAr (Ar = 2,6−iPr2C6H3) for successful nitrene transfer into isocyanides, phosphines and C−H bond of ethylbenzene.

Learning from the isolation of the masked arylnitrene complex, several bulky −diketiminate ligands were designed and synthesized to stabilize transient copper−acylnitrene [Cu]=NC(O)Ar species for site−selective hydrogen atom abstraction (HAA) of R−H substrate to form primary and secondary organoradicals R• (chapter 2). Radical capture (RC) of this alkyl radical by the sterically congested [CuII]−NHC(O)Ar furnished primary and secondary amidated products R−NHC(O)Ar. This is the first example of the site−selective primary and secondary functionalization of aliphatic C−H bonds via transition−metal nitrenes. This primary site−selectivity completes that of the previously reported C−H functionalization by our laboratory for the tertiary selective C−H functionalization.

Recent studies from our laboratory have discovered that C−H functionalization with unactivated amines, anilines or acyl−protected phenols with tBuOOtBu as an oxidant can take place at CuI −diketiminates under a radical−relay mechanism. Mechanistic studies revealed that while in some cases the copper(II) alkylamide [CuII]−NHR′ is capable of HAA, the principle role of the copper intermediates [CuII]−NHR′ or [CuII]−OAr is to capture an alkyl radical R• (generated in the HAT of R−H substrate via tBuO• radical) to form R−NHR’ or R’OAr, respectively.

We sought to extend this protocol to Ni−catalysis to expand the scope of functional groups that can be installed via radical relay approaches to C−H functionalization (chapter 3). Besides potentially offering access to a wider range of functional groups, a radical−relay approach that employs [NiII]−FG species more stable than their [CuII]−FG could potentially offer different site−selectivities comparing to the established Cu system. Hence, mild activation of tBuOOtBu at [NiI] center was shown and the resulted {[NiII]}2(μ−OtBu)2 complex was shown to be a suitable precursor to prepare several [NiII]−FG complexes were prepared where FG = nitromethanoato, enolato, amido or phenolato ligands. These complexes were carefully characterized and their radical capture behavior was studied to assess the capability of this system for catalytic reactions.

The Glaser coupling reaction, an oxidative cross−coupling of alkynes to form 1,3−diynes is an important reaction in synthetic chemistry and material sciences. This transformation was discovered by Carl Glaser in 1869 with the use of cuprous chloride as catalyst and aqueous ammonia as the base under an oxygen atmosphere. Since discovery of this oxidative coupling, chemists have been synthesizing molecules by this means featuring conjugated C≡C bonds, yet its mechanism is unclear up to date. Although several mechanisms have been proposed, the most currently accepted one has been reported by Bohlmann and coworkers in 1964 and relies on dimeric copper acetylides as intermediates in the oxidative acetylenic coupling. Herein, transalkynylation of a sterically encumbered copper(II) tert−butoxide with and sterically bulky, electron−deficient terminal arylakyne allows for isolation of the first three-coordinate, terminal copper(II) alkynyl species [CuII]-C≡CArCl2 (Cl2Ar = 2,6−Cl2C6H3) (chapter 4). Facile reduction of [CuII]−C≡CArCl2 (E1/2 = −645 mV vs Cp2Fe+/Cp2Fe) to the copper(I) alkynide complex {[CuII]−C≡CArCl2} − was achieved using cobaltocene. This reduction triggers redox disproportionation upon coordination of the Lewis base, such as MeCN, 2,4−lutidine, or an alkynylate anion to provide [CuII]−C≡CArCl2(LB), which reductively eliminates 1,3−diyne Cl2ArC≡C−C≡CArCl2. This new mechanistic findings provide insight into the mechanism of C−C coupling in the Glaser coupling and support a redox disproportionation pathway involving CuI, CuII, and CuIII organometallic intermediates.

Wednesday, May 29 at 11:00am to 3:00pm

Regents Hall, 451
3700 O St. NW

Event Type

Academic Events, Dissertation Defense


Georgetown College, Chemistry, Graduate School of Arts and Sciences



Open to the public and the press?


Event Contact Name

Muhammad Itani

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