Origins of high catalyst loading in copper(i)-catalysed Ullmann-Goldberg C-N coupling reactions

Article abstract of DOI:10.1039/c7sc02859h

A mechanistic investigation of Ullmann-Goldberg reactions using soluble and partially soluble bases led to the identification of various pathways for catalyst deactivation through (i) product inhibition with amine products, (ii) by-product inhibition with inorganic halide salts, and (iii) ligand exchange by soluble carboxylate bases. The reactions using partially soluble inorganic bases showed variable induction periods, which are responsible for the reproducibility issues in these reactions. Surprisingly, more finely milled Cs₂CO₃ resulted in a longer induction period due to the higher concentration of the deprotonated amine/amide, leading to suppressed catalytic activity. These results have significant implications on future ligand development for the Ullmann-Goldberg reaction and on the solid form of the inorganic base as an important variable with mechanistic ramifications in many catalytic reactions.

Full text of DOI:10.1039/c7sc02859h

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2017, DOI: 10.1039/C7SC02859H.
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Origins of High Catalyst Loading in Copper(I)-Catalysed Ullmann-
Goldberg C-N Coupling Reactions
Received 00th January 20xx,
Accepted 00th January 20xx
a
b
a
b
b
Grant J. Sherborne, Sven Adomeit, Robert Menzel, Jabor Rabeah, Angelika Brückner, Mark R.
c
a
a
Fielding, Charlotte E. Willans, and Bao N. Nguyen
DOI: 10.1039/x0xx00000x
Mechanistic investigation of Ullmann-Golberg reactions using soluble and partially soluble bases led to identification of
various pathways for catalyst deactivation through (i) product inhibition with amine products, (ii) byproduct inhibition with
inorganic halide salts, and (iii) ligand exchange by soluble carboxylate bases. Reactions using a partially soluble inorganic
bases showed variable induction periods, which is responsible for reproducibility issues in these reactons. Surprisingly,
www.rsc.org/
2 3
more finely milled Cs CO resulted in longer induction period due to higher concentration of deprotonated amine/amide,
leading to suppressed catalytic activity. These results have singificant implications on future ligand development for
Ullmann-Goldberg reaction, and on the solid form of the inorganic bases as an important variable with mechanistic
ramifications in many catalytic reactions.
between this complex
product and completes the catalytic cycle.
different types of mechanism, e.g. oxidative addition, SET,
I and the aryl halide releases the amine
3
1, 32
Introduction
Several
Metal catalysed C-N couplings are amongst the most
important types of catalytic reactions in modern synthetic
2
5, 26, 33, 34
atom transfer,
have been proposed for this rate-
1
chemistry. These reactions are often catalysed by palladium
determining-step. The overall rate law of the reaction at high
ligand loading is showed in equation (1).
2
-10
catalysts.
reactions, also known as Ullmann-Goldberg reactions,
However, copper(I)-catalysed C-N coupling
1
1, 12
have gained significant attention from industry and academia
alike. A contemporary drive for cheaper and more sustainable
catalysts, combined with improvements of the Ullmann-
Goldberg reaction to lower the required temperature and to
broaden the range of substrates, have made this a viable
1
3-15
alternative to the palladium-catalysed reactions.
Since the pivotal work by Buchwald group on ligand-
1
6-19
assisted Ullmann-Goldberg coupling,
a variety of effective
1
chelating ligands such as ethylene glycol, L-proline, N,N-
8
20
2
0
21
dimethyl glycine, and N,N-diethylsalicylamide have been
reported for N-arylation of both aliphatic and aryl amines.
Mechanistic studies of Ullmann-Goldberg reactions have been
carried out using diamines and diketones as ligands by
Scheme 1. Currently accepted mechanism of Ullmann-Goldberg reaction.
2
2, 23
22
24-26
27, 28
Buchwald,
2
Davies,
Blackmond, Hartwig,
Norrby,
and
9, 30
and the mechanism is summarised in Scheme 1.
rate
≈
kobs[CuL][ArI][HNR
2
]
(1)
The reaction starts with coordination of the N-partner,
followed by its deprotonation by the mild base. Reaction
22, 3522, 3522, 3522, 3522, 3522, 3522, 35
Importantly, equilibrium A
results in a need for high ligand loading to protect the active
2
2, 35
catalytic species.
More recent studies by Davies and co-
workers identified even more nuances on the role of O,O-
chelating ligand 2-acetylcyclohexanone, which is easily
displaced by malonate anion (included as base), and formation
2
9, 30
of di-, tri-, tetrameric Cu(I)-amido species.
The high
catalyst/ligand loading (typically 10 mol% of Cu(I) precursor
and 20 mol% of ligand, reactions with catalyst loading below 1
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6, 37
38
its poor reproducibility, and the need for The formation of 4-hydroxyanisole could be explained by the
mol% are rare),
aryl iodide/bromide substrates remain important challenges in presence of trace amount of water in the highly hygroscopic
these reactions.
TBAA. Hydrodehalogenation product such as anisole was also
2
4, 26, 43
observed by Hartwig and co-workers.
hydrodehalogenation by Cu(I)-catalysts
demonstrated under acidic conditions, or in the presence of
In addition,
has been
In this paper, we report the results of our experimental
investigations into the origin of high catalyst loading and poor
reproducibility, which are crucial in improving catalytic
performance and substrate scope, in Ullmann-Goldberg
reactions. In particular, the role of the bases, products and
halide salts as byproducts on the speciation of catalytic species
and reaction mechanisms were evaluated in details. These also
led to identification of the origin of the poor reproducibility in
these reactions and a counter-intuitive relationship between
the particle size of the inorganic base and reaction rate. These
mechanistic insights form the basis for future development of
more effective Ullmann-Goldberg catalytic systems and
highlight the need to consider the solid form of the inorganic
base as an important variable in many catalytic reactions.
44
4
5, 46
a proton source.
Thus, the formation of anisole in our
reaction could be attributed to generation of soluble mono- or
diprotonated adipate as by-products.
1
Evaluation of the effect of [
L
] showed little changes to the
5%, Figure
a, Figure 1b and Figure 1f). This is consistent with suggestions
kinetics (within error margin of the technique, i.e.
±
1
from Davies and co-workers that their diketone ligand is
replaced by the malonate or amido anion, and that the
2
9, 30
reaction proceeds in a predominantly ‘ligandless’ manner.
Doubling [ ] led to a non-linear increase in initial rate as
expected due to its triple role as substrate, ligand and
2
2
2
inhibitor. On the other hand, doubling [TBAA] led to a small
0
decrease in initial reaction rate (Figure 1b). This can be
1
attributed to ligand exchange between
L
and TBAA, which
Results and discussion
results in a less active catalyst. Reaction performed without
1
L gave 18% conversion after 5 hours, compared to 80%
ligand
Homogeneous reactions
1
conversion obtained in the presence of 20 mol% of
L
H at the
Low turnover numbers and reproducibility issues are often
3
same reaction time. Importantly, the difference in initial rate
quickly gave way to very similar kinetic profile after 50 minutes
and about 40-50% conversion under standard conditions
0
associated with catalyst deactivation. However, little data
can be found on catalyst deactivation data in these reactions.
Thus, an Ullmann-Goldberg reaction between 4-iodoanisole (
1)
(Figure 1b), suggesting a change in the reaction dominant
and piperidine (2), using soluble tetrabutylammonium adipate
mechanism to a slower pathway.
3
TBAA) as base, was selected for our study. This system
9
(
Similar kinetic behaviours and reaction rates were also
observed with reactions performed in d3-acetonitrile as
solvent under similar conditions (Figure 1c). The most
significant change when replacing d -DMF with d -MeCN is a
simplifies phasic behaviours and allows us to focus on any
intrinsic catalyst deactivation (Scheme 2). The reaction was
found to be extremely air-sensitive and unsuitable for
7
3
1
sampling. Thus, in situ H NMR was used to monitor the
decrease in side products to ~ 7%. This is likely due to a less
side reactions associated with hydrolysis/acyl transfer of DMF.
The decrease in reaction rate after approximately 50
minutes led us to profile a ‘same excess’ experiment starting at
reaction kinetics. A key advantage of this over the often
reported calorimetry-based kinetics of Ullmann-Goldberg
reaction is that it allows quantification of side products which
may be present in small quantities and easily removed during
[
1] = 62.5 mM and [
2] = 125 mM instead of 125 mM and 187.5
2
2, 23, 30
workup.
These were determined to be anisole, 4-
mM, respectively, and without added (by)-products (Figure
47, 48
methoxy-N,N-dimethylaniline, through hydrolysis/ acyl
4
1d).
The d[3]/dt vs [1] plot for this experiment against the
0, 41
transfer of DMF,
and 4-methoxyphenol (see ESI for
reaction under standard conditions showed strong evidence of
a catalyst deactivation process as the reaction progresses. The
plot did not go through origin point (0,0) under standard
characterization of side products). While each of these was
present in small quantity, their combined yield (up to 15%) can
create significant error in the rate of formation of
3 if this was
conditions, and the difference in reaction rates at [1] = 62.5
only measured by calorimetry. A small quantity (~1%) of 4-
chloroanisole was also identified. This product was attributed
to chloride contamination in tetrabutylammonium hydroxide,
mM can only be explained by catalyst deactivation.
Deactivation was similarly observed with the reaction using
30
malonate as base, and was attributed to a possible Cu(I) to
4
2
which was used to prepare the TBAA base.
Scheme 2. Reaction scheme and general conditions of in situ H NMR kinetic
study.
Cu(0/II) disproportionation process reported by Lei et. al with
1
L and adipate base
1
4
acetylacetonate as ligand. As our ligand
9
3
0
are quite different to those in that study, we probed a more
obvious deactivation pathway through product inhibition.
Product [
3] = 77.0 mM (0.62 eq.) was included in a standard
reaction at t = 0 minute and the reaction rate vs [
1] data were
plotted against that of the standard reaction in Figure 1e. This
led to approximately 2 times decrease in initial reaction rate,
confirming the inhibitive effect of the product
reaction.
3 on this
2
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