Inorganica Chimica Acta
Note
Reservoir catalysis: Rationalization of anomalous reaction orders
in Pd-catalyzed amination of aryl halides
Antonio C. Ferretti a,b, Colin Brennan c, Donna G. Blackmond a,b,d,
⇑
a Department of Chemistry, Imperial College, London SW7 2AZ, United Kingdom
b Department of Chemical Engineering and Chemical Technology, Imperial College, London SW7 2AZ, United Kingdom
c Process Studies Group, Syngenta, Jealott’s Hill Research Centre, Bracknell, Berkshire RG42 6EY, United Kingdom
d Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 31 January 2011
Reversible partitioning of a portion of the catalyst away from the active cycle provides a mechanistic
rationalization of the anomalous reaction orders observed in the presence of additives. The concept of
stable reservoir species leads to a practical protocol for maintaining a robust catalyst system that may
be particularly useful for development of reactions under harsh conditions likely to lead to catalyst deac-
tivation and incomplete turnover. Probing Pd-catalyzed amination reactions in the presence of compet-
itive binding events reveals the key role that reservoir species connected reversibly to the catalytic cycle
can play.
Dedicated to Prof. Robert G. Bergman
Keywords:
Catalysis
Amination
Kinetics
Ó 2011 Elsevier B.V. All rights reserved.
Reservoir catalysis
1. Introduction
the product to complete the catalytic cycle. For reaction of primary
aliphatic amines such as 2a, oxidative addition is rate-determining
The Pd catalyzed amination of aryl halides has rapidly become
one of the most viable methods to synthesize substituted aryl-
amines [1], important molecules for pharmaceuticals and agro-
chemicals. Mechanistic studies have revealed much about the
rich chemistry of the catalytic cycle [2], but a challenge remains
to develop systems that can operate to high turnover for less reac-
tive substrates under demanding conditions. Competitive amina-
tion reactions have helped to rationalize the origin of selectivity
in terms of amine binding strengths and nucleophilicity [3]. We re-
cently reported investigations of the reactions of Scheme 1 carried
out with amines 2a and 2b both in separate reactions and in com-
petition to gain insight into the relative importance of the stability
and the reactivity of intermediate species [4]. This work led us to
probe the effects of competitive binding of non-reacting additives.
Here we report how these studies help to rationalize anomalous
reaction orders, understand catalyst stability, and design effective
reaction protocols for robust processes.
and the reaction has been shown to give first- and zero-order
kinetics in [1] and [2a], respectively [2,4]. Intriguingly, Fig. 1 shows
that when the reaction of Scheme 1 is carried out in the presence of
hydrazone 3b, the steady-state rate of reaction of 1 + 2a is first or-
der in amine concentration [2a], not zero order as expected, and
zero order in aryl halide concentration [1], not first order as
expected.
To understand how the presence of 3b affects the reaction, we
compared conversion profiles of the reaction of aryl halide 1 with
amine 2a in the presence and absence of amine 3b obtained by
reaction calorimetry.1 Fig. 2a shows that rate is suppressed in the
presence of 3b; however, the overlay of rate curves in ‘‘same excess’’
[5] reactions of 1 + 2a shown in Fig. 2b confirms steady-state cata-
lytic behavior, indicating that no irreversible loss of Pd from the cy-
cle occurs over the course of the reaction in the presence of 3b.
While the secondary amine 3b is not reactive under the condi-
tions of the experiments of Figs. 1 and 2, in the absence of primary
amine 2a arylation of 3b with 1 can occur to form 3c at a rate
nearly tenfold slower than arylation of 2a (Scheme 2). If this reac-
tion proceeds mechanistically as a typical Pd-catalyzed amination,
amine 3b adds to the oxidative addition complex of 1 to form a Pd
species containing both 1 and 3b, which we term 6b, that is a com-
petent intermediate for transmetallation and reductive elimination
of the biarylated product.
2. Results and discussion
The currently accepted mechanism for this reaction involves
oxidative addition of the aryl halide to Pd0 followed by reaction
with amine, deprotonation by base, and reductive elimination of
⇑
Corresponding author at: Department of Chemistry, The Scripps Research
Institute, La Jolla, CA 92037, United States.
1
Arylation of 3b with 1 occurs only under large excess of 1 and at a rate ca. tenfold
slower than arylation of 2a.
0020-1693/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.