Mechanistic Studies on the Copper-Catalyzed N

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Research Article
pubs.acs.org/acscatalysis
Mechanistic Studies on the Copper-Catalyzed N‑Arylation of
Alkylamines Promoted by Organic Soluble Ionic Bases
Simon Sung,† David Sale,‡ D. Christopher Braddock,† Alan Armstrong,† Colin Brennan,‡
and Robert P. Davies*,†
†
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom
Process Studies Group, Syngenta, Jealott’s Hill Research Centre, Bracknell, Berkshire RG42 6EY, United Kingdom
‡
S Supporting Information
*
ABSTRACT: Experimental studies on the mechanism of
copper-catalyzed amination of aryl halides have been undertaken for the coupling of piperidine with iodobenzene using a
Cu(I) catalyst and the organic base tetrabutylphosphonium
malonate (TBPM). The use of TBPM led to high reactivity
and high conversion rates in the coupling reaction, as well as
obviating any mass transfer effects. The often commonly
employed O,O-chelating ligand 2-acetylcyclohexanone was
surprisingly found to have a negligible effect on the reaction
rate, and on the basis of NMR, calorimetric, and kinetic
modeling studies, the malonate dianion in TBPM is instead
postulated to act as an ancillary ligand in this system. Kinetic profiling using reaction progress kinetic analysis (RPKA) methods
show the reaction rate to have a dependence on all of the reaction components in the concentration range studied, with firstorder kinetics with respect to [amine], [aryl halide], and [Cu]total. Unexpectedly, negative first-order kinetics in [TBPM] was
observed. This negative rate dependence in [TBPM] can be explained by the formation of an off-cycle copper(I) dimalonate
species, which is also argued to undergo disproportionation and is thus responsible for catalyst deactivation. The key role of the
amine in minimizing catalyst deactivation is also highlighted by the kinetic studies. An examination of the aryl halide activation
mechanism using radical probes was undertaken, which is consistent with an oxidative addition pathway. On the basis of these
findings, a more detailed mechanistic cycle for the C−N coupling is proposed, including catalyst deactivation pathways.
KEYWORDS: copper, Ullmann Reaction, C−N bond coupling, amination, RPKA, catalyst deactivation, organic bases
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INTRODUCTION
and complementary method to palladium-catalyzed Buchwald−
Hartwig amination.6 As highlighted in recent reports, these
advantages have allowed the modified Ullmann reaction to have
a key role in the total synthesis of a number of natural products
and other compounds with biological activity.7
Although computationally derived mechanisms for the
copper-catalyzed C−N cross coupling between aryl halides
and amines have been proposed in the literature, 8,9
experimentally obtained mechanistic information is still scarce.
Nevertheless a number of experimental studies have probed the
structures and behavior of intermediates in the catalytic cycle,
and the three-coordinate copper(I) amide catalyst resting state
(Complex I, Scheme 2) has been proposed as a key catalytic
intermediate in a number of literature reports.9,10 In addition,
reactivity studies have shown aryl halide activation likely
proceeds via direct oxidative addition of the aryl halide with this
catalyst resting state.9,10b Kinetic studies on the coppercatalyzed C−N cross coupling reaction have also been used
The classic copper-mediated cross-coupling reaction between
aryl halides and amines to form C−N bonds, as first reported
by Ullmann, has many drawbacks including high (often
stoichiometric) copper loadings, high reaction temperatures,
and long reaction times.1 Recently, protocols that employ
bidentate nitrogen- and oxygen-based ancillary ligands, such as
1,10-phenanthroline,2 1,3-diketones,3 and amino acids,4 have
overcome some of these issues and enabled the cross-coupling
reactions to be carried out under milder reaction temperatures
(≤110 °C) with lower copper loadings (≤10%) (Scheme 1).5
The relatively low cost and low toxicity of copper, the use of
cheap and low molecular weight ancillary ligands, and good
functional group tolerance have made this reaction an attractive
Scheme 1. Modified Ullmann Reaction
Received: February 19, 2016
Revised: April 28, 2016
Published: May 23, 2016
© 2016 American Chemical Society
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Research Article
RESULTS AND DISCUSSION
1. Modified Ullmann Amination Reaction. The C−N
cross-coupling of piperidine (1) and iodobenzene (2) to give
N-phenylpiperidine (3) using 10.0 mol % catalytic loadings of
CuI was chosen as the model reaction in this work, following
on previously published results from our group involving
similar systems.16 First the catalytic reactivity of this reaction
using either fully soluble TBPM base or poorly soluble K3PO4
base, both in dimethyl sulfoxide solvent at room temperature
and with 20.0 mol % 2-acetylcyclohexanone (L) as the ancillary
ligand, were compared (Figure 1). In agreement with Liu’s
Scheme 2. Proposed Catalytic Cycle for the Modified
Ullmann Amination Reaction
to confirm the intermediacy of this copper(I) amide
species.11,12 However, the exact roles played by the ligand,
solvent, and base, and the presence and impact of off-cycle
equilibria remain a matter of debate. A more detailed kinetic
profiling would allow the currently proposed general catalytic
cycle, as shown in Scheme 2, to be further developed to include
other potential reaction steps and solution equilibria such as
catalyst deactivation and inhibition. In addition, it would
improve fundamental understanding of the mechanism and in
turn allow a more rational approach to the development of new
catalysts as well as the improvement of existing systems.
However, the attainment of accurate kinetic data for coppercatalyzed amination reactions is challenging. Commonly
employed inorganic bases, such as K3PO4, NaOtBu, or
Cs2CO3, exhibit low solubility in the reaction media.5 As a
result, mass transfer effects can arise. These significantly affect
the rate of deprotonation and therefore also the overall rate of
reaction.13 This complicates the attainment of an accurate
chemical kinetic profile. As a result, detailed kinetic studies of
copper-catalyzed N-arylation reactions to date have been
limited to low pKa substrates such as amide nucleophiles (as
reported by Buchwald and co-workers).14
In this work, experimental studies on the mechanism of
copper-catalyzed C−N cross coupling between aryl iodides and
alkylamine substrates are reported using tetra(n-butyl)phosphonium malonate (TBPM) as the base. This organic
ionic base has been previously shown by Liu and co-workers15
to be highly effective in copper-catalyzed protocols, capable of
operating at reaction temperatures as low as 0 °C for the
amination of aryl iodides or room temperature for aryl bromide
substrates. In addition to the benefits associated with its high
reactivity in modified-Ullmann protocols, TBPM is fully soluble
in various polar solvents.15 Thus, the homogeneous nature of
the reaction solutions eliminates undesired mass transfer effects
that are present using alternative inorganic bases. As a result,
kinetic analysis of the cross coupling reaction can be simplified,
which allows full determination of the rate dependences in
reactants and provides additional insights into possible catalytic
intermediates and catalyst deactivation pathways. Kinetic
modeling has also been used to support the experimental data.
Figure 1. Profiles of [3] over time produced using TBPM or K3PO4 as
the base in the presence or absence of 2-acetylcyclohexanone (L) for
the reaction shown. Product concentrations were determined by GC
using naphthalene as an internal standard.
work on soluble organic bases,15 the reaction rate was observed
to be significantly faster with TBPM compared to K3PO4 (red
and green curves, respectively, Figure 1). Furthermore, 97%
yield of product 3 was obtained after only 3 h using TBPM,
whereas the yield of 3 using K3PO4 plateaued at the lower value
of 77% after 22 h.
The influence of the commonly used ancillary diketone (L)
on the reaction rate was also assessed. Surprisingly, the [3] over
time profiles produced in the presence and absence of L with
TBPM are very similar (red and blue curves, Figure 1). In
marked contrast, only 7% yield of 3 was observed in the
absence of L with K3PO4 after 18 h (not shown in Figure 1).
Hence, while the diketone significantly improves the overall
reactivity with K3PO4, it does not seem to influence the
reactivity at all with TBPM as the base. One possible
explanation for this observation is that TBPM, unlike K3PO4,
is not basic enough to deprotonate L to give the active 1,3diketonate ligand. In order to test this theory, a 1H NMR
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spectrum of a mixture of L and TBPM together in DMSO-d6
was obtained.17 However, this revealed that TBPM is indeed
sufficiently basic in DMSO to deprotonate L (which is present
predominantly in its enol tautomer form), as evidenced by the
loss of its acidic enol O−H proton resonance at 15.92 ppm.
Alternative explanations are that the excess of malonate anion
(present in TBPM) coordinates more strongly to the copper(I)
catalyst center than the 1,3-diketonate ligand, or that the
accelerating effect of L is solely due to its role in improving
mass transfer of the base with K3PO4, which is not relevant
when dealing with soluble bases such as TBPM.
Reaction profiles using the ancillary ligands N,N-dimethylglycine, 2-picolinic acid, or 1,10-phenanthroline15 (all with
TBPM base) showed similar reactivity to the 1,3-diketone and
ligand free systems.17 Hence, in order to simplify the system as
much as possible, while still maintaining high reactivity and
conversion rates, it was decided to perform the reactions in the
kinetic study using ligand-free conditions.
In order to further verify the suitability of the model reaction
for kinetic profiling, the system was further analyzed for mass
transfer effects and for the presence of any competing sidereactions. In contrast to the heterogeneous reaction mixture
obtained with K3PO4 as the base, employing soluble TBPM led
to an entirely homogeneous reaction solution. Moreover, very
similar [2] over time profiles for unstirred and stirred reactions
verify that mass transfer effects are not present.17
Although the C−N coupling reaction proceeds to give 97%
yield of the target arylamine with TPBM as the base (Figure 1),
GC monitoring of the reaction revealed 100% conversion of
phenyl iodide (2). The missing mass balance was investigated
using 1H NMR analysis of the completed reaction mixtures.
These studies revealed a 3% yield of benzene was also present,
presumably arising due to hydrodehalogenation of 2. Hydrodehalogenation side reactions of aryl halides have been reported
in other copper-mediated reactions in the literature.11,18,19
However, given the very small quantity of benzene generated
during the reaction, it was thought unlikely to significantly
affect the interpretation of any kinetic data. Further 1H NMR
studies show the amine proton to be the most likely source of
the hydrogen atom in the hydrodehalogenation reaction.17
2. Kinetic Analysis Using RPKA. Reaction progress kinetic
analysis (RPKA), as described by Blackmond,20,21 was used to
explore the rate dependence in each reactant and identify
possible catalyst deactivation and inhibition pathways. RPKA
involves analyzing experimental data collected by continuously
monitoring reactions performed under synthetically relevant
conditions. By utilizing a parameter called the “excess” ([e]),
which is defined as the difference in the initial substrate
concentrations (eq 1), kinetic information can be obtained
from same excess and different excess experiments.20 The
experimental data can then be plotted as reaction rate functions
against substrate concentration to extract kinetic information.
These plots are commonly referred to as graphical rate
equations. RPKA has been demonstrated by numerous reports
in the literature to be an effective method for elucidating
reaction mechanisms for catalytic processes.22
[e] = [amine]0 − [aryl halide]0
Figure 2. (a) Graphical rate equation for the reaction shown. (b)
Comparison between [2] determined from calorimetry heat flow and 1
H NMR spectroscopy measurements.
equations to exclude any rate effects caused by heat transfer
effects and also to limit inaccuracies as the limiting substrate
concentration approaches zero (see the Supporting Information
for the full plots).21 Validation of the reaction calorimetry data
was confirmed by the excellent correlation between the
conversion calculated from the detected heat flow and the
conversion determined by 1H NMR analysis (Figure 2b). In
addition, the calculated enthalpy of reaction, ΔHrxn, for all
calorimetric experiments obtained in this study over all the
various initial reactant concentrations was consistent within a
2% margin (ΔHrxn = 172.5 ± 3.5 kJ mol−1).
Monitoring of the reaction rate against [2] with CuI loadings
of either 2.50 or 5.00 mol % gives overlaying plots when the
reaction rate is normalized by [Cu]total0.9 (Figure 3). This
indicates that the copper-catalyzed coupling reaction between 1
and 2 is approximately first order in [Cu]total.23
For the same excess experiments, the reaction rates at any
given value of [2] would be expected to be equal in each
experiment when the concentration of the active catalyst (or
on-cycle catalyst) is constant (i.e., no catalyst activation or
deactivation processes are present). However, at any given [2],
the rate in an experiment with lower initial reactant
concentrations (red curve, Figure 4) was found to be higher
than that in the experiment with higher initial concentrations
(blue curve). This indicates a drop in [Cu]active in the higher
concentration experiment, which can be due to either catalyst
inhibition or deactivation. To determine if catalyst inhibition by
reaction products or byproducts was the cause of the decreased
(1)
The model copper-catalyzed C−N cross-coupling reaction,
as defined in the previous section and shown in Figure 2, was
monitored in situ by reaction calorimetry to produce the
graphical rate equation also shown in Figure 2. Only the data
between 20−80% conversion is displayed in the graphical rate
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The rate vs [2] curve produced with these added
components overlays with the previous same excess experiment
and therefore indicates that catalyst inhibition by processes
such as product coordination, protonation of 1 by 4, or solution
conductivity changes caused by ionic species 5 can all be
discounted. Because catalyst inhibition can be ruled out,
catalyst deactivation is implied (see discussion later for analysis
of catalyst decomposition routes).
The rate dependences in [TBPM], [1], and [2] were next
determined using the different excess protocol. Two reactions
were conducted using either 0.1500 or 0.2000 M [1]0, so that at
any given time, the concentrations of all the reactants except 1
are the same in both experiments. An overlay of the curves
produced by normalizing the reactions rates by [1]1 (Figure 5)
Figure 3. Normalized graphical rate equation (from dividing rate by
[Cu]total0.9) of experiments using concentrations listed in the table.
Figure 5. Normalized graphical rate equations (from dividing rate by
[1]1) of experiments using concentrations listed in the table.
shows the reaction is first-order in [1]. Similarly, the graphical
rate equations of the two different excess experiments shown in
Figure 6 reveal a first-order dependence in [2] on the reaction
rate.
The graphical rate equations produced from different excess
experiments using varied [TBPM]0 unexpectedly revealed that
Figure 4. Graphical rate equations from standard and same excess
experiments using concentrations stated in the table.
reactivity, the same excess experiment was repeated but with
the added reaction products/byproducts N-phenylpiperidine
(3), tetra(n-butyl)phosphonium monoanionic malonic acid (4),
and tetra(n-butyl)phosphonium iodide (5), each at 0.0500 M
concentration (green curve, Figure 4).
Figure 6. Normalized graphical rate equations (from dividing rate by
[2]1) of experiments using concentrations listed in the table.
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higher [TBPM]0 led to slower reaction rates. This indicates a
negative rate dependence in [TBPM]. When the reaction rates
are normalized by dividing [TBPM]−1, the curves overlay
moderately well (Figure 7), suggesting that the order in
Figure 7. Normalized graphical rate equations (from dividing rate by
[TBPM]−1) using concentrations listed in the table.
[TBPM] is approximately negative first-order in this concentration regime. As far as we are aware, this is the first time a
negative order in base has been implied in copper-catalyzed
amination reactions.
Thus, overall under these conditions, the reaction rate was
found to have a first order dependence in [1], [2], and [Cu]total
and negative order dependence in [TBPM]. In addition, the
same excess experiments revealed the catalyst to deactivate over
the course of the reaction. As the reaction rate can be
influenced by a large number of factors, the initial visual fit to a
straightforward system exhibiting overall-second order kinetics,
as suggested by the linearity and overlay of the normalized rate
curves in Figure 5 and Figure 6, is likely misleading. The
reduction in rate over time caused by decreasing [Cu]total as a
result of catalyst deactivation, is likely offset by an
approximately equal increase in rate caused by the continually
decreasing [TBPM] as it is consumed in the reaction. These
findings highlight the important role kinetic profiling using
RPKA can play in uncovering the many different influences on
reaction rate which might otherwise remain hidden or
obscured.
3. Studies on Catalyst Deactivation. Decreases in rate
between sequential reactions using the same catalyst solution
were monitored using calorimetry in order to confirm catalyst
deactivation was occurring. A reaction between 1.000 mmol
piperidine (1) and 0.500 mmol iodobenzene (2) in DMSO and
2.000 mmol TBPM was initiated by addition of 0.050 mmol
CuI with a total solution volume of 10 mL (Figure 8a and b,
blue curve). After the heat flow from the first reaction became
negligible, indicating the reaction had completed, a mixture of
piperidine (1) and iodobenzene (2) (0.500 mmol each in 200
μL DMSO solution) was injected to start another reaction cycle
using the same catalyst. Thus, the approximately same initial
concentrations of 1 and 2 were regenerated, but now with a
lower 0.1500 M [TBPM]. It was expected that the second
Figure 8. (a) Profiles of heat flow over time after sequential additions
of 1 and 2 (0.0500 M each); (b) Graphical rate equations for each
sequential reaction.
reaction would be faster due to the lower [TBPM]. However,
the peak heat flow was lower in the second reaction (Figure
8a), and the reaction rate was slower (red curve, Figure 8b)
(reaction rate at [2] = 0.040 M decreased by 16% between
runs). Furthermore, after a second 0.500 mmol portion of 1
and 2 was added, the reaction rate decreased even further (by
an additional 21%) and only 85% conversion was achieved
(green curve, Figure 8b). The total solvent volume increased by
only 2% with each portion of additional 1 and 2, and as a result,
[Cu]total was diluted by the same percentage. As the decrease in
reaction rate between the sequential reactions is significantly
greater than 2%, catalyst deactivation can be shown to be
occurring.
To identify the catalyst deactivation pathway, a series of
experiments was carried out in which all but one of the
reactants were stirred together for 60 min before addition of the
final reactant to initiate the reaction. The conversion of
iodobenzene (2) over time was monitored for each of these
experiments, as shown in Figure 9. The reaction rate remained
approximately unchanged when either CuI (blue curve, Figure
9), TBPM (red curve), or 2 (orange curve) were used to
initiate the reaction. However, when the amine 1 was used to
initiate the reaction (purple curve), the observed rate was much
slower than the other experiments, and moreover, the
conversion of 2 was significantly curtailed at just 14%. In
addition, the reaction solution in this experiment visibly
changed appearance from colorless to blue within 15 min,
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Scheme 3. Proposed Catalyst Deactivation Pathway and the
Competitive Coordination of Piperidine (1) to [CuIMal]−
(6)a
Figure 9. Conversion of 2 over time where the reagent(s) shown was
used to initiate the reaction after a delay of 60 min. Conversions were
determined by GC using naphthalene as an internal standard.
a
indicative of the formation of copper(II) species. When both 1
and TBPM were added together to initiate the reaction (green
curve), the rate and overall conversion of 2 once more
resembled the values seen with CuI, TBPM, or 2 initiation.
These results suggest that the catalyst is stable in the absence of
TBPM, or when TBPM and amine 1 are both present, but
becomes unstable when TBPM is present in the absence of the
amine.
A simple qualitative experiment in which CuI in DMSO was
treated with TBPM further verified this finding, with the
solution rapidly changing from colorless to blue in appearance.
A similar color change is observed in the final reaction solutions
produced in the kinetic experiments discussed previously and
has also been reported in the literature for Ullmann couplings
using inorganic bases.24,25 In the later cases, this was attributed
to disproportionation of a (as yet unidentified) copper(I)
species.24,25 These results now pinpoint a copper(I)−base
complex as the most likely candidate to undergo this
disproportionation reaction. It is noteworthy that isolated
solutions of copper(I) carboxylate complexes without stabilizing coligands, such as phosphines or alkenes, have previously
been reported to be unstable and prone to disproportionation
at room temperature even under inert atmospheres.26 In
addition, all isolated copper(I) malonate complexes to date
contain PPh 3 coligands, presumably to prevent such
disproportionation.27
The results also demonstrate how amine 1 can act as a
stabilizing coligand to reduce the degree of disproportionation
of the copper(I) malonate intermediate. Scheme 3 shows this in
the context of the reaction mechanism where 1 competitively
coordinates to the copper(I) malonate complex 6 to give
heteroleptic complex 7, whereas coordination of another
malonate dianion would give the homoleptic complex 9.
Complex 7 can subsequently undergo N−H deprotonation to
give the malonate-ligated copper(I) piperidine complex 8,
which is a commonly accepted intermediate in the catalytic
cycle (I, Scheme 2). However, complex 9 would be susceptible
to disproportionation to give Cu(0) and Cu(II) species. In the
literature, copper(I) disproportionation has been shown to
occur from copper(I) complexes ligated by two 1,3-diketonate,
Tetra(n-butyl)phosphonium counter cations are not shown.
1,3-keto ester enolate, or 1,3-keto amide enolate ancillary
ligands.24,28 In agreement with these other studies, disproportionation is proposed to occur from the copper(I) dimalonate
species 9 in Scheme 3.
In order to confirm the proposed stabilizing effect of the
amine on the catalyst, a multiple addition experiment was
performed in which the reaction rates of sequential reactions
were monitored over successive additions of aryl iodide 2 to a
reaction solution that contained a large excess of amine 1
(Figure 10). In accordance with the mechanism proposed in
Scheme 3, a large excess of 1 would favor the formation of the
piperidine-ligated copper(I) intermediate 7 over the off-cycle
dimalonate complex 9. This in turn would effectively remove
the negative rate dependence in [TBPM] and prevent catalyst
deactivation. In addition, the negligible effect of addition of
monoanionic malonic acid (4) on the reaction rate (see Figure
4) indicates that the N−H deprotonation of 7 is highly favored,
thus leading to saturation of the catalyst as the malonate-ligated
copper(I) piperidide complex 8. As a result, the rate equation in
the presence of a large excess of 1 can be estimated as being
dependent only on [2] and [Cu]total (eq 2).
rate = k[Cu]total [2]
(2)
Figure 10 shows that the rate vs [2] profiles from this
experiment are linear and overlay, thus confirming that [Cu]total
is constant and catalyst deactivation has been prevented at high
[1]0. The amine has therefore been shown to have an
important role in minimizing catalyst deactivation. As the
graphical rate equations were in agreement with eq 2, the rate
constant for iodobenzene activation could be calculated using
the gradients of the linear least-squares fits to the plots in
Figure 10 to be 18.0 ± 0.7 M−1 min−1.
4. Identification of Aryl Halide Activation Mechanism.
In order to investigate the aryl halide activation mechanism, the
overall catalytic reaction between piperidine (1) and
iodobenzene (2) with TBPM was performed in the dark.
Product 3 was still obtained in excellent yield (97%) after 3 h,
similar to when the reaction was performed under ambient
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compound with the nucleophile bonded to the pendant methyl
moiety.
The copper-catalyzed reaction of piperidine (1) and radical
probe 10 produced the arylamine product in 45% yield and
hydrodehalogenation side product allyl phenyl ether in 2%
yield, while no detectable amount of either cyclized side
products were observed by 1H NMR spectroscopy or GC-MS
(Scheme 4). Therefore, it is likely that the copper-catalyzed aryl
amination and hydrodehalogenation reactions do not proceed
via aryl radical intermediates under these conditions. This result
is in agreement with the absence of biphenyl formation from
phenyl radical homocoupling when iodobenzene (2) was used
as the substrate in the kinetic study.19 Furthermore, it is also in
agreement with a previous report by Hartwig and co-workers
who found that the copper-catalyzed N-arylation of diarylamines was unlikely to involve free aryl radicals and that the
aryl halide activation involved oxidative addition to copper(I).10b The aryl halide activation in the copper-catalyzed Narylation of alkylamines studied in this work can therefore be
considered to progress via an oxidative addition mechanism as
opposed to a single-electron transfer process.
5. Proposed Mechanistic Cycle and Kinetic Modeling.
Based on the results from the kinetic and other mechanistic
studies herein, Scheme 5 shows our proposed reaction
Figure 10. Graphical rate equations using sequential additions of 2
(0.585 mmol) to the same solution after reaction completion. Linear
least-squares fit to y = mx + c gave the following parameters to three
significant figures: 1st reaction: m = 0.0348 ± 1.66 × 10−4 min−1, c =
9.51 × 10−5 ± 3.94 × 10−6 M min−1, r2 = 0.984; 2nd reaction: m =
0.0360 ± 1.59 × 10−4 min−1, c = 1.61 × 10−4 ± 4.32 × 10−6 M min−1,
r2 = 0.988; 3rd reaction: m = 0.0374 ± 1.01 × 10−4 min−1, c = 1.02 ×
10−4 ± 2.72 × 10−6 M min−1, r2 = 0.995.
Scheme 5. Proposed Reaction Mechanism, Including
Catalyst Deactivation Pathway, For the Copper-Catalyzed
Cross-Coupling Reaction between Piperidine and
Iodobenzene with TBPM as the Basea
light. This control experiment confirmed that the aryl halide
activation is not photochemically induced; however, it does not
omit aryl radicals as potential reaction intermediates.
To determine if aryl radicals are formed during the reaction,
the radical probe 2-(allyloxy)iodobenzene (10) was used as a
substrate (Scheme 4). If the reaction proceeds via a nonradical
Scheme 4. Employment of the Radical Probe 10 Reveals Aryl
Halide Activation Is Unlikely To Occur via a Radical-Based
Mechanisma
a
a
Yields were determined by 1H NMR spectroscopy using naphthalene
as an internal standard.
Tetra(n-butyl)phosphonium counter cations are not shown.
mechanism for the copper-catalyzed C−N cross coupling
reaction. This mechanism is also supported by detailed 1H
NMR spectroscopic studies.17 As dianionic malonate can adopt
a large number of coordination modes to copper(I),30 the
mode of malonate coordination is not defined in the proposed
mechanism.
Malonate coordination to the initially formed copper(I)
malonate (6) is proposed to give an off-cycle copper(I)
di(malonate) species (9). Catalyst deactivation via copper(I)
disproportionation to give copper(II) and copper(0) is then
based mechanism, the expected C(sp2)−N bond formation
would occur. In comparison, if the mechanism involves the
formation of aryl radicals, the allyloxy aryl radical intermediate
would rapidly ring-close via a 5-exo-trig process (k = 9.6 × 109
s−1 at 25 °C in DMSO).29 The subsequent methyl radical could
then react to give 3-methyl-2,3-dihydrobenzofuran or a
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suggested to occur from this off-cycle complex 9. As piperidine
(1) was found to stabilize the copper catalyst from deactivation,
it is proposed to competitively coordinate against malonate to
complex 6 to give the malonate and piperidine heteroleptic
copper(I) intermediate 7. The next step involves N−H
deprotonation of the coordinated piperidine ligand by malonate
to give the malonate-ligated copper(I) piperidide complex 8.
Complex 8 has a 1:1:1 ratio of ancillary ligand (malonate),
copper(I), and deprotonated nucleophile, which is in
accordance with the general structure of proposed catalytic
resting state species in other copper-catalyzed C−N crosscoupling reactions.9a,10a,b,14b,25b As the radical probe 10 had no
effect on the aryl amination reaction, aryl halide activation of
iodobenzene (2) is proposed to occur via an oxidative
addition/reductive elimination mechanism to give arylamine
product 3 and regenerate complex 6.
On account of the dianionic malonate from TBPM acting as
both the ancillary ligand and base, the general structure of the
on-cycle species in the proposed mechanism in Scheme 5 are
similar to those in the general catalytic cycle shown in Scheme
2. The experimental studies herein therefore provide further
support for the identity of the on-cycle intermediates. The
proposed mechanism in Scheme 5 also incorporates for the first
time a catalyst deactivation pathway which proceeds via an offcycle copper(I)-base complex (9).
The steady-state rate law for the proposed catalytic cycle
shown in Scheme 5 (including all steps proposed as reversibly
connected to the cycle, but neglecting the irreversible
deactivation step) is shown in eq 3 and derived in the
Supporting Information.
rate =
k4K 2K3[1][2][mal][Cu]total
1 + K 2[1] + K 2K3[1][mal] + K1[mal]
Figure 11. Simulated concentrations of complexes 6, 7, 8, 9, and
[Cu(II)] + [Cu(0)] (a) over the course of the reaction in Figure 2 and
(b) under the same conditions but using an excess of amine 1 (2.000
M). Produced in COPASI using optimized kinetic parameters.17
(3)
In order to obtain the first order kinetics in both [1] and [2]
(as observed in the experimental RPKA studies), either the free
catalyst (the “1” term) or the K1[mal] term must dominate the
denominator; the latter being the most likely (as backed up by
the calculations below). This therefore implies that the intrinsic
steady-state dependence of [mal] is zero-order. It is the
irreversible draining of catalyst out of the system (which is not
considered in the steady-state rate law) which allows the order
in [mal] to manifest itself as negative in the RPKA experiments.
In order to further access the viability of our proposed
mechanistic cycle, the reaction simulation and data-fitting
program COPASI31 was employed to model the experimental
calorimetric data.17 A number of different mechanistic scenarios
were investigated including changes in the order of piperidine
and malonate coordination, disproportionation from copper(I)
malonate (6) instead of copper(I) di(malonate) (9),
disproportionation from an equivalent of 6 and 9 each, and
formation of a di(piperidido)cuprate off-cycle complex.
However, the best-fit model, being both consistent with the
experimental reaction calorimetry data and displaying low
standard deviations on the rate constants, was the mechanism
shown in Scheme 5. The simulated concentrations of all copper
containing species over the course of the reaction under
standard conditions and also in the presence of a large excess of
amine are shown in Figure 11.
Since K1 is predicted to be large, malonate coordination to
copper(I) malonate (6) to give copper(I) di(malonate) (9)
occurs readily leading to a high [9] over the course of the
reaction, and in particular in the early stages (Figure 11a).
Hence a significant quantity of catalyst is predicted to reside
(under these conditions) in an inactive off-cycle form (9).
However, increasing the initial concentration of amine 1
(Figure 11b) drives the amine coordination and deprotonation
steps forward to the catalyst resting state 8, which is now
predicted to be the predominate copper containing species.
This suppresses formation of 9 and inhibits catalyst
deactivation, and is in agreement with the experimental kinetic
studies (vide supra). A consequence of an unfavorable
equilibrium in the reverse direction from catalyst resting state
8, through intermediates 7 and 6, back to unstable off-cycle
copper(I) dimalonate complex 9 is that solutions of CuI, amine
1, and TBPM together are relatively stable against immediate
complete catalyst deactivation. This is also in agreement with
the experimental observations presented in this manuscript that
showed solutions of CuI and TBPM are stable to
disproportionation in the presence of 1 and is also supported
by the multiple addition experiments (Figure 8 and 10).
The modeling also predicts kdeact to be lower but of a similar
magnitude to k4. Hence, the relative magnitudes of the rate and
equilibrium constants in the other equilibrium reaction steps
(both on- and off-cycle) can significantly influence the reaction
outcome. A better understanding of these positive and negative
influences on the catalytic cycle will undoubtedly benefit further
optimization of the copper(I) amination process.
■
CONCLUSION
In order to build a better understanding of the mechanism of
copper catalyzed amination reactions, experimental mechanistic
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studies have been undertaken on the representative C−N crosscoupling reaction between piperidine (1) and iodobenzene (2)
using a Cu(I) catalyst. On the basis of initial screenings,
tetrabutylphosphonium malonate (TBPM) was employed as
the base with no additional ligands present. In contrast to
poorly soluble inorganic bases, such as K3PO4, the high
solubility of TBPM in the reaction media was shown to obviate
all base mass transfer effects, thus permitting the collection of
more reliable and precise kinetic data.
Kinetic profiling reveals the reaction rate to have a
dependence on all of the reaction components in the
concentration range studied. First-order kinetics are observed
with respect to [1], [2], and [Cu]total, and unexpectedly
negative-order kinetics in [Base]. The negative rate dependence
in [Base] can been attributed to the formation of an off-cycle
copper(I) dimalonate species (9), in which the malonate
dianion is acting as a ligand in addition to its role as the base.
This off-cycle species is then postulated to undergo
disproportionation and is thus responsible for catalyst
deactivation. A new catalytic scheme incorporating this offcycle catalytic deactivation step has been proposed (Scheme 5),
with similar deactivation processes likely common to all
copper(I)-catalyzed Ullmann reactions. Modeling of the kinetic
experimental data using COPASI is shown to be congruent
with the proposed scheme. The key role of the amine 1 in
minimizing catalyst deactivation has also been highlighted by
the kinetic studies, and it is demonstrated how a high
concentration of amine can ensure excellent catalyst stability
and improve the observed TON. In addition, an examination of
the aryl halide activation mechanism using radical probes is
consistent with an oxidative addition pathway.
Existing studies on the Ullmann amination reaction rarely
acknowledge the negative effect ligands (ancillary or base
derived) can have on the reaction rate, for example, by causing
the introduction of off-cycle equilibria and reduced catalyst
stability. The results presented in this work suggest that ligand
(and base) choice for these catalytic systems should not only
focus on improving the rate of the on-cycle steps but also aim
to minimize or eliminate these detrimental off-cycle processes.
To this end, we are currently investigating a range of existing
and new ancillary ligand systems using similar experimental
mechanistic studies. It is anticipated that building a better
understanding of the various positive and negative influences
on these complex reaction kinetics will lead to the development
of better performing and more robust copper-catalyzed
amination protocols.
■
■
ACKNOWLEDGMENTS
■
REFERENCES
This work was supported by Syngenta and the UK EPSRC
(Grant EP/J500239/1). We thank the reviewers for their
suggested improvements to the modelling studies, which have
been implemented in the final version of the manuscript.
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ASSOCIATED CONTENT
S Supporting Information
*
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.6b00504.
Experimental procedures, experimental and spectroscopic data, full graphs related to the kinetic studies,
and details of the kinetic modeling using COPASI (PDF)
■
Research Article
AUTHOR INFORMATION
Corresponding Author
*E-mail: [email protected]. Tel: +44 (0)207 5945754.
Notes
The authors declare no competing financial interest.
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