Mechanistic aspects of Submol % copper-catalyzed C-N cross-coupling

Article abstract of DOI:10.1002/cctc.201301088

Carbon-nitrogen bond formation can be catalyzed by copper in very low concentrations (≈100 ppm), with mechanistic features that are distinct from those in the high-concentration regime. The reaction was studied by initial rate kinetics, competitive Hammett studies, and DFT calculations. The deprotonation of the model nucleophile, pyrrole, is limited by mass transfer with the heterogeneous base. The positive reaction order in dimethylethylenediamine was explained by this reagent working not only as a ligand to Cu, but also as a facilitator for mass transfer. The selectivity-determining step in the competitive Hammett study is oxidative addition. Alternative mechanisms for this step, such as single-electron transfer, atom transfer, or σ-bond metathesis, can be excluded based on the observed Hammett behavior and DFT calculations. A dash of copper: The submol % copper catalyzed C-N bond formation has been studied by kinetic and DFT methods. DMEDA acts as a facilitator for mass transfer, as well as a ligand. Oxidative addition leads to a Cu ^III intermediate undergoing facile reductive elimination.

Full text of DOI:10.1002/cctc.201301088

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DOI: 10.1002/cctc.201301088
Mechanistic Aspects of Submol% Copper-Catalyzed CÀN
Cross-Coupling
Per-Fredrik Larsson,[a, b] Carl-Johan Wallentin,[a] and Per-Ola Norrby*[a, c]
CarbonÀnitrogen bond formation can be catalyzed by copper
in very low concentrations (ꢀ100 ppm), with mechanistic fea-
tures that are distinct from those in the high-concentration
regime. The reaction was studied by initial rate kinetics, com-
petitive Hammett studies, and DFT calculations. The deproto-
nation of the model nucleophile, pyrrole, is limited by mass
transfer with the heterogeneous base. The positive reaction
order in dimethylethylenediamine was explained by this re-
agent working not only as a ligand to Cu, but also as a facilita-
tor for mass transfer. The selectivity-determining step in the
competitive Hammett study is oxidative addition. Alternative
mechanisms for this step, such as single-electron transfer,
atom transfer, or s-bond metathesis, can be excluded based
on the observed Hammett behavior and DFT calculations.
Introduction
Since the 1970s, the area of cross-coupling reactions has been
dominated by palladium and nickel catalysts.[1] However, envi-
ronmental concerns together with economic factors have shift-
ed the scientific focus to alternative catalytic systems able to
perform these transformations with comparable or even
higher efficiency. These efforts have resulted in the develop-
ment of several improved procedures based on catalysts with
beneficial characteristics. Among these, copper-based systems
have proven effective for heteroatom (CÀN, CÀO, and CÀS)
cross-coupling reactions.[2–6] The early Ullmann chemistry is in
general known for being ineffective because of the limited
substrate scope and the necessity of using high catalytic load-
ings and high temperatures.[2] Since the revival of the Ullmann
chemistry by Buchwald[7–22] and others[23–43] during the late 90’s
and early 00’s, the field of cross-coupling catalysis centered on
CÀheteroatom bond formation has grown tremendously.[44–73]
Although much progress has been made, there are still unre-
solved issues related to the inherent properties of copper.
Turnover numbers and frequencies can be small, resulting in
slow reaction rates and/or the requirement of using high cata-
lyst loadings.
(DMEDA) as an additive, originally developed as a ligand in Cu
catalysis by Buchwald and co-workers,[9,11] CÀN couplings can
be performed with ppm levels of Cu.[74,75] The role of diamines
in formation of the Cu–Nuc (Nuc=nucleophile) complex has
been studied with both experimental and computational
methods.[40,76–82] The main conclusion from these studies is that
the diamines at high concentration prevent copper from form-
ing multiligated species that could otherwise hamper the cata-
lytic activity. Even though the concentration effect of the dia-
mines have been addressed partly, the details of the mecha-
nism for copper-catalyzed cross-coupling reactions is still not
understood to a satisfactory extent.[83]
Several proposals can be found in the literature, supported
by both experimental and computational investigations. A
recent study by Houk, Buchwald, and co-workers concluded
that the reacting species in CÀN coupling reactions between
aryl iodides and primary amines is a complex between ligand,
Cu, and the deprotonated nucleophile.[81] Depending on ligand
and nucleophile, the rate-determining step can be either
a single electron transfer or atom transfer between the L–Cu–
Nuc (L=ligand) complex and the aryl iodide, forming an aryl
radical that couples with the Cu-bound nucleophile (Figure 1).
However, Fu and co-workers revisited these specific calcula-
tions and could conclude that a polar mechanism involving
a classical oxidative addition/reductive elimination process
governed by a coordinative activation of the nucleophile ac-
tually is a viable mechanism.[84] In addition, Jutand, Ciofini, and
co-workers have shown that the coupling between primary
amines and aryl halides can be influenced by halogen bonding
(ArXÀN) between the aryl halide and the L–Cu–Nuc com-
plex.[78,82] Most relevant to the present work is perhaps the
conclusion drawn from a theoretical study by Zhang et al., in
which the authors convincingly showed that diamine-ligated
CuI complexes catalyze the coupling between aryl bromides
and amides through a three-centered oxidative addition/reduc-
tive elimination mechanism.[78] Clearly, the operating mecha-
Recently, in a collaborative effort our research group and the
Bolm group found that if using dimethylethylenediamine
[a] P.-F. Larsson, C.-J. Wallentin, P.-O. Norrby
Department of Chemistry and Molecular Biology
University of Gothenburg
Kemivꢀgen 10, SE-412 96, Gothenburg (Sweden)
E-mail: pon@chem.gu.se
[b] P.-F. Larsson
Akzo Nobel Functional Chemicals AB
Uddevallavꢀgen 17, SE-444 85 Stenungsund (Sweden)
[c] P.-O. Norrby
Pharmaceutical Development, Global Medicines Development
AstraZeneca, Pepparedsleden 1, SE-431 83 Mçlndal (Sweden)
per-ola.norrby@astrazeneca.com
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201301088.
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Figure 1. a) Present reaction studied. b) Intermediates achieved through dif-
ferent mechanisms proposed for various constellations of ligands and
nucleophiles.
nism or competing mechanisms for Cu-catalyzed CÀN cross
coupling are highly dependent on the nature of both ligand
and nucleophile. All mechanistic rationales are compatible
with the reaction orders measured for most reactants and re-
agents in the low-Cu regime,[75] but they do not explain the re-
action order observed for DMEDA. It is also difficult to recon-
cile the proposed single-electron-transfer (SET) and atom-trans-
fer (AT) mechanisms with the failure of radical clocks to detect
radical intermediates.[85]
Figure 2. Copper-catalyzed coupling of pyrrole with iodobenzene together
with initial rates measured for initiation of the reaction using different
reactants.
We present herein a kinetic investigation that together with
a computational study reveals additional functions of the dia-
mine additive. Also, the investigation clearly suggests that the
activation energies for the proposed traditional nonradical
mechanism are surprisingly low.
Scheme 1. Mass transfer for copper-catalyzed CÀN cross-coupling reactions.
Results and Discussion
This observation also points to a possible additional role of
DMEDA: as a mass-transfer catalyst assisting in solubilizing the
heterogeneous base (Scheme 1). This mechanism is further
supported by the observation that if DMEDA is used as a sol-
vent,[75] the base is fully dissolved at the end of the reaction, in
contrast to reactions run in aromatic hydrocarbons such as tol-
uene. Moreover, Buchwald and co-workers have shown that
with the high-[Cu] regime conditions, the corresponding cou-
pling displays zero-order kinetics with regards to the [diamine]
if the diamine/Cu ratio is 14:1 or higher. At lower ratios, the re-
action displays a first-order rate dependence on the [diamine].
A mechanistic model including a catalytically inactive resting
state of the catalyst was used to rationalize the observation.[80]
The present low-[Cu] conditions displays a positive non-zero
reaction order with regards to [diamine] at a diamine/Cu ratio
up to 1000:1.[75] Clearly, the role of diamine is, in part, different
in the submol% Cu-catalyzed coupling from that in the high-
Kinetic experiments
To broaden the understanding for the role of DMEDA and the
formation of the copper–amide complex, the initial rates for
the cross-coupling of pyrrole with iodobenzene was followed
by systematically excluding one essential reaction component,
then starting the pre-equilibrated reaction mixture (at 1358C)
by adding the missing reagent (Figure 2). Starting the reaction
with either CuCl2 or DMEDA gave curvatures similar to what
had previously been observed with pyrazole.[75] In fact, initiat-
ing the reaction using the CuII solution gave the highest initial
rate. The difference between starting with CuCl2 or DMEDA
may not be significant, but at least demonstrates that forma-
tion of the presumed CuI catalyst must be a very fast process.
In contrast, starting the reaction with pyrrole clearly had a lag
phase of approximately 60 min before the catalyst activated,
a qualitative difference from the curves for the other three
reactions.
[Cu]-regime conditions.
A mass-transfer-facilitating rational
The most probable explanation for this lag phase is mass-
transfer limitation for the deprotonation of pyrrole by the het-
erogeneous base (K3PO4). For all cases in which these two com-
ponents had a chance to equilibrate, the catalyst was immedi-
ately activated upon addition of the last reaction component.
does corroborate well with these differences.
To further gain insight into the mechanism behind the
submol% copper catalyzed cross-coupling reaction, a competi-
tive Hammett study was performed. The competitive condi-
tions have the distinct advantage that only the portion of the
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reaction path from the entry of aryl iodide up to the selectivi-
ty-determining transition state is probed. Thus, complications
from the unknown activity of the heterogeneous base and the
possible mass-transfer limitations affecting the deprotonation
are effectively avoided in this setup. The cross-coupling of pyr-
azole with iodobenzene was chosen as the standard reaction
(Figure 3). As can be seen in Figure 4, there is a good correla-
tion with the standard s values. The results are in close agree-
ment with a similar study by Taillefer in the high-[Cu]
C
Figure 4. Competitive Hammett correlation for s and s .
contaminations. Janiak and co-workers recently showed that
nanoparticles are easily deposited onto Teflon-coated magnetic
stirring bars.[87] This could be a potential source for trace metal
contaminations in many catalytic systems. However, in our
case, we were able to reproduce zero yields for the standard
reaction by using magnetic stirring bars with thicker Teflon
coating. To exclude the possibility of catalysis by palladium
traces in the submol%-copper-catalyzed reaction, PdOAc
(20 mL, 1 mm in dry THF, final loading 0.001 mol%) was added
instead of CuCl2. The reaction was run under standard reaction
conditions for 24 h without any product formation.
Figure 3. Competitive Hammett study using aryl iodide derivatives and pyra-
zole as nucleophiles.
regime,[40] but with an even lower 1 value. We note that there
C
is no correlation at all with s . This, together with the low
1 value, clearly shows that the reaction does not follow an SET
mechanism. It also casts doubt on the AT mechanism proposal,
because a rate limiting formation of an aryl radical would be
DFT calculations
C
expected to have some correlation with s , that is, both elec-
tron withdrawing and electron donating groups would be ex-
pected to stabilize a radical intermediate and increase the rate
The reaction mechanism was also investigated by computa-
tional methods, focusing on the fate of the already formed
DMEDA–Cu–pyrrolide complex reacting with PhI (Figure 5).
The results discussed above indicate that the rate-limiting step
may well be formation of this complex. Following the work of
C
of its formation. We note that the s scale was developed for
benzylic radicals,[86] and thus may not correlate well with for-
mation of a phenyl radical, but the observed survival of radical
clocks also argue against a radical
intermediate.[85]
During the course of the ex-
perimental work, using pyrazole
as a nucleophile, we encoun-
tered issues with reproduction
of a zero yield in “blank” reac-
tions, that is, reactions missing
only the Cu catalyst. The issue
was traced back to leaching
from the magnetic stirring bars
used in the reaction. By peeling
off the protective Teflon cover of
the stirring bars and running the
reaction under standard condi-
tions without added copper salt,
full conversion to the cross-cou-
pling product was observed.
This proves the great sensitivity
of the system towards metal Figure 5. Calculated free-energy profiles for CÀN formation, in kJmolÀ1
.
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Buchwald, Houk, and coworkers,[81] we first investigated the
possibility for SET and AT mechanisms, but also evaluated alter-
natives that would better rationalize the observed Hammett
behavior as well as the survival of radical clocks (see below).
The reaction paths were derived by calculation of free energies
by using dispersion-corrected DFT calculations as described in
the following.
and the high DMEDA concentration. The alternative, that for-
mation of the reactive complex in itself is rate-limiting, can be
excluded by the positive reaction order observed for the aryl
iodide.[75] We can thus conclude that the reactive complex de-
picted in Figure 5 partakes in an equilibrium with a resting
state, and that this equilibrium is facilitated by DMEDA even if
in 2000-fold excess. In addition to acting as a mass-transfer
mediator in this equilibrium process, we cannot exclude other
roles of DMEDA, such as promoting the displacement of deac-
tivating ligands on Cu (e.g., iodide or excess nucleophile).
In nonpolar solvents such as toluene, charge separation is
generally disfavored. Accordingly, we find the formation of ex-
pected intermediates resulting from a SET mechanism, a cation-
ic CuII complex, and a PhI anion radical, to be associated with
a highly endergonic reaction (291 kJmolÀ1). Thus, an SET
mechanism was discarded as a possible pathway. The direct
iodine atom transfer (AT, in Figure 1) results in a neutral CuII
complex and a phenyl radical, a process that is less dramatical-
ly uphill, endergonic by 102 kJmolÀ1. Recombination of the
two intermediates ultimately provide the new CÀN bond, a pro-
cess that is monotonously downhill on the potential energy
surface and, therefore, diffusion-controlled. Bimolecular diffu-
sion-controlled processes in general have a free-energy barrier
of approximately 20 kJmolÀ1.[88] The reverse reaction, from in-
termediates to starting materials, is also diffusion-controlled
and thus has also a barrier of approximately 20 kJmolÀ1. Both
transition states of the AT process can therefore be estimated
Conclusions
Cu-catalyzed C–N cross coupling utilizing “trace amounts” of
catalyst are to date restricted to aryl iodides and sp2-hybridized
N-containing substrates, such as pyrrols and amides. By careful
exclusion of contaminants, it was possible to show that the re-
action does not run in the complete absence of copper, but is
highly effective with only ppm levels of Cu salts. At these very
low loadings, it is highly unlikely that any other metal could be
present in amounts high enough to allow the observed cataly-
sis. One of the few metals that has been shown to work at
ppb levels is Pd,[89,90] which, however, was found to be incom-
petent under the present conditions in which Cu is hyperac-
tive. The specific reaction studied was found to be limited by
mass transfer of the heterogeneous base, possibly in combina-
tion with inadequate mass transfer of the potassium salt of the
deprotonated heteroaromatic substrate. The diamine additive
dimethylethylenediamine (DMEDA) is believed to act as
a mass-transfer promoter, accelerating the reaction rate even
at a 2000-fold excess. Liu and co-workers have shown that
using soluble organic bases and more polar solvents promotes
the reaction efficiently at room temperature utilizing high-[Cu]
regime conditions.[55] This observation not only lends support
to the conclusions presented here, but it also provides a start-
ing point for further development of the submol% Cu cata-
lyzed CÀN cross-coupling methodology.
to have energies of>120 kJmolÀ1
.
Interestingly, employing unrestricted open-shell singlet cal-
culations, we could identify a transition state (TS) for the direct
transfer of the phenyl group via a four-centered TS that elec-
tronically can by characterized as a concerted AT recombina-
tion or, alternatively, a “biradical s-bond metathesis”. The free
energy barrier of this process is higher than that of the AT,
144 kJmolÀ1, in part owing to the high entropic penalty associ-
ated with the more ordered TS. The more common closed-
shell s-bond metathesis has been excluded as a viable path-
way in the Buchwald–Houk study,[81] but for comparison, we
also calculated this more compact TS, which had an energy
barrier of 152 kJmolÀ1. However, a detailed comparison of
these paths became irrelevant when we next turned to investi-
gate the “standard” path of oxidative addition/reductive elimi-
nation. The oxidative addition of PhI to the DMEDA–Cu–pyrro-
lide complex proceeds with a low barrier of 68 kJmolÀ1. This
step was found to be effectively irreversible, with the reductive
elimination TS (in which the CÀN bond is formed) lying ap-
proximately 30 kJmolÀ1 lower on the free-energy surface. This
is a significant difference from the results in the Buchwald–
Houk study,[81] but in agreement with the work of Zhang
et al.,[78] as well as Lefꢁvre et al.[82]
From the Hammett study, we can exclude a single-electron-
transfer (SET) mechanism, and also cast severe doubts on the
atomic-transfer (AT) mechanism. The DFT results gives further
evidence against these proposals as well as the s-bond meta-
thesis mechanism, but instead supports a classical oxidative
addition/reductive elimination mechanism. The collective re-
sults indicate that the rate-limiting step of the reaction in-
cludes both the formation of the apparent reactive intermedi-
ate, a DMEDA-CuI-nucleophile complex, and the subsequent
oxidative addition, also found in previously published works
by Zhang et al.,[78] as well as Lefꢁvre et al.[82] As a final remark,
it is evident from this study, and in light of previous published
works by several research groups, that the reaction mechanism
is highly dependent on ligand, aryl halide, and nucleophile.
Most probably, the mechanism of these reactions does not in-
volve radical intermediates or biradical-type transition states.
The low calculated barrier obtained for the oxidative addi-
tion pathway is rather unexpected from an experimental view-
point. With such a low barrier, the reaction should proceed
rapidly even below room temperature, whereas the standard
protocol calls for a temperature of 1358C, and even our most
reactive system (in neat DMEDA) requires 658C.[75] To reconcile
the temperature requirement with our current computational
results, it is reasonable to assume that formation of the
DMEDA–Cu–pyrrolide complex constitute an unfavorable equi-
librium that necessitates both the high reaction temperatures
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Experimental Section
Acknowledgements
General
We are grateful to the Swedish Research Council for financial
support.
All the experiments were performed under inert atmosphere (nitro-
gen). CuCl2 (Aldrich, purity of 99.999% metal basis), K3PO4 (98%),
and pyrazole (98%) were stored under air- and moister-free condi-
tions. DMEDA, iodobenzene, and dodecane were distilled over cal-
cium hydride. The toluene was dried over calcium and stored
under nitrogen. A gas chromatograph with flame ionization detec-
tor and a 30 m–0.25 mm EQUITY-5 fused-silica capillary column
was used, with hydrogen as a carrier gas. General temperature pro-
gram: 1008C for 14 min, then up to 3008C at 508CminÀ1 for 4 min.
Dodecane was used as an internal standard.
Keywords: copper
· cross-coupling · density functional
calculations · kinetics · N ligands
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Procedure for starting the reaction with the reaction
components
The general reaction were as follows; pyrrole (140 mL, 2 mmol,
1 equiv.), K3PO4 (849 mg, 4 mmol, 2 equiv.), CuCl2 (40 mL, 5 mm in
dry THF, 0.01 mol%), toluene (2 mL), DMEDA (21.5 mL, 0.20 mmol,
10 mol%), iodobenzene (334 mL, 3 mmol, 1.5 equiv), and dodecane
(50 mL, 0.22 mmol). Starting with pyrrole: a microwave vial was
charged with K3PO4. The vial was sealed and the CuCl2 solution
was added. The THF was removed by three cycles of vacuum fol-
lowed by nitrogen, whereupon toluene, DMEDA, iodobenzene, and
dodecane were added. The vial was placed in a preheated alumi-
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time intervals, filtered through a small silica plug, and analyzed by
GC. The GC yield was determined by using dodecane as an internal
standard. The same starting procedure was repeated for iodoben-
zene, DMEDA, and CuCl2.
Procedure for the competitive Hammett study
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charged with CuCl2 (40 mL, 5 mm in dry THF, 0.01 mol%). The THF
was removed by three cycles of vacuum followed by nitrogen.
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Computational details
All geometries were optimized by using the dispersion-corrected
DFT functional B3LYP-D3[91–94] together with the LACVP* basis set
in Jaguar.[95] LACVP* uses 6-31G* for the light atoms, and the Hay–
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of stationary points, as well as for calculating free energy correc-
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the final geometries using the PBF continuum method[98,99] with
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A dash of copper: The submol%
copper catalyzed CÀN bond formation
has been studied by kinetic and DFT
methods. DMEDA acts as a facilitator for
mass transfer, as well as a ligand.
Oxidative addition leads to a CuIII
intermediate undergoing facile reduc-
tive elimination.
P.-F. Larsson, C.-J. Wallentin, P.-O. Norrby*
&& – &&
Mechanistic Aspects of Submol%
Copper-Catalyzed CÀN Cross-Coupling
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