Understanding of Cu-catalysed coupling reactions for C-N bond formation
File(s)
Author(s)
Sung, Simon
Type
Thesis
Abstract
The rate of reaction for the copper-catalysed coupling reactions to form C–N bonds between
aryl halides and amines can be significantly improved in the presence of various bidentate
ligands. This improved reaction is often referred as the modified Ullmann amination reaction.
However the intermediates and steps involved in the mechanism and the role of the ligand are
not fully understood. In this work, mechanistic studies have been carried out in order to improve
the current understanding of this reaction. The role of copper(I) alkylamide complexes as potential intermediates in the modified
Ullmann reaction between aryl halides and alkylamines is discussed in Chapter 2. A series of
copper(I) alkylamide complexes have been synthesised and shown using single crystal X-ray
crystallography to exist as tetramers in the solid state. The structures of these complexes in
benzene-d6 were determined by 1H DOSY NMR spectroscopy which revealed equilibrating
aggregates, where the equilibrium rate could be faster or slower than the NMR time scale,
with average aggregation numbers between the dimeric and tetrameric forms. The complexes
have been shown to react stoichiometrically with iodobenzene to give arylamine products, both
in the absence and presence of 1,10-phenanthroline as an ancillary ligand.The influence of
1,10-phenanthroline on the solution structures in benzene-d6 and DMSO-d6 is also discussed
and can be related to the stoichiometric and catalytic reactivity. Overall these results highlight
the role of copper(I) alkylamide complexes as potential intermediates and show the significance
of 1,10-phenanthroline in modulating the reactivity of the system. Chapter 3 describes the improvement in product yield from utilising O,O- and N,O-chelating
ligands over N,N-chelating ligands in the copper-catalysed C–N cross-coupling reaction between
piperidine and iodobenzene. A kinetic study of this reaction using 2-acetylcyclohexanone as
the added ligand demonstrated that the poorly soluble potassium phosphate base caused
the reaction rate to be limited by mass transfer effects. The results provide insights into the
qualitative rate dependences in the reactants and also the role of the ligand in the catalyst
deactivation pathway by disproportionation. A mechanistic study of the copper-catalysed C–N cross-coupling reaction between piperidine
and iodobenzene using bis(tetra(n-butyl)phosphonium) malonate as a soluble base is presented in Chapter 4. A detailed kinetic study using reaction calorimetry and the reaction progress
kinetic analysis (RPKA) methodology reveals first order rate dependences in the substrates
and copper catalyst concentration, and negative first order kinetics in the base concentration.
NMR spectroscopic evidence suggests the malonate base simultaneously functions as an
ancillary ligand and coordinates to give an off-cycle unstable species. Catalyst deactivation by
disproportionation was found to be an important consequence of malonate ligand coordination,
with the piperidine substrate playing a key role in mitigating the rate of catalyst deactivation.
The absence of aryl radical formation suggests that the aryl halide activation mechanism occurs
by an oxidative addition process. The experimental data has been successfully modelled to the proposed mechanism to give approximate equilibrium and rate constants for each step.
aryl halides and amines can be significantly improved in the presence of various bidentate
ligands. This improved reaction is often referred as the modified Ullmann amination reaction.
However the intermediates and steps involved in the mechanism and the role of the ligand are
not fully understood. In this work, mechanistic studies have been carried out in order to improve
the current understanding of this reaction. The role of copper(I) alkylamide complexes as potential intermediates in the modified
Ullmann reaction between aryl halides and alkylamines is discussed in Chapter 2. A series of
copper(I) alkylamide complexes have been synthesised and shown using single crystal X-ray
crystallography to exist as tetramers in the solid state. The structures of these complexes in
benzene-d6 were determined by 1H DOSY NMR spectroscopy which revealed equilibrating
aggregates, where the equilibrium rate could be faster or slower than the NMR time scale,
with average aggregation numbers between the dimeric and tetrameric forms. The complexes
have been shown to react stoichiometrically with iodobenzene to give arylamine products, both
in the absence and presence of 1,10-phenanthroline as an ancillary ligand.The influence of
1,10-phenanthroline on the solution structures in benzene-d6 and DMSO-d6 is also discussed
and can be related to the stoichiometric and catalytic reactivity. Overall these results highlight
the role of copper(I) alkylamide complexes as potential intermediates and show the significance
of 1,10-phenanthroline in modulating the reactivity of the system. Chapter 3 describes the improvement in product yield from utilising O,O- and N,O-chelating
ligands over N,N-chelating ligands in the copper-catalysed C–N cross-coupling reaction between
piperidine and iodobenzene. A kinetic study of this reaction using 2-acetylcyclohexanone as
the added ligand demonstrated that the poorly soluble potassium phosphate base caused
the reaction rate to be limited by mass transfer effects. The results provide insights into the
qualitative rate dependences in the reactants and also the role of the ligand in the catalyst
deactivation pathway by disproportionation. A mechanistic study of the copper-catalysed C–N cross-coupling reaction between piperidine
and iodobenzene using bis(tetra(n-butyl)phosphonium) malonate as a soluble base is presented in Chapter 4. A detailed kinetic study using reaction calorimetry and the reaction progress
kinetic analysis (RPKA) methodology reveals first order rate dependences in the substrates
and copper catalyst concentration, and negative first order kinetics in the base concentration.
NMR spectroscopic evidence suggests the malonate base simultaneously functions as an
ancillary ligand and coordinates to give an off-cycle unstable species. Catalyst deactivation by
disproportionation was found to be an important consequence of malonate ligand coordination,
with the piperidine substrate playing a key role in mitigating the rate of catalyst deactivation.
The absence of aryl radical formation suggests that the aryl halide activation mechanism occurs
by an oxidative addition process. The experimental data has been successfully modelled to the proposed mechanism to give approximate equilibrium and rate constants for each step.
Version
Open Access
Date Issued
2015-05
Date Awarded
2015-08
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Davies, Robert
Braddock, Chris
Armstrong, Alan
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)