Aqueous intramolecular Mizoroki-Heck reaction of (2-iodophenyl)(3-methyl-1H-indol-1-yl)methanone: A model reaction for the in situ performance evaluation of Pd catalysts

Article abstract of DOI:10.1039/c4nj01921k

The regiospecific 5-exo intramolecular Mizoroki-Heck reaction of (2-iodophenyl)(3-methyl-1H-indol-1-yl)methanone is presented as a catalytic model reaction for the in situ performance evaluation of Pd catalysts for C-C cross-coupling reactions in aqueous medium. The reaction produces a conjugated cyclic compound which can be easily detected and quantified by UV-vis spectroscopy. Therefore, the reaction progress can be easily monitored and the catalytic parameters determined. The model reaction was tested using molecular and nanoparticulate catalysts, based on the Pd(OAc)₂ salt.

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Aqueous Intramolecular Mizoroki-Heck Reaction
of (2-iodophenyl)(3-methyl-1H-indol-1-
Cite this: DOI: 10.1039/c3nj00000x
yl)methanone: A Model Reaction for the in Situ
Performance Evaluation of Pd Catalysts
Received 00th XXXXX 2013,
Accepted 00th XXXXX 2013
Aline M. Signori, Eloah Latocheski, Brunno L. Albuquerque, Deonildo
Faggion Jr., Tula B. Bisol, Lidiane Meier and Josiel B. Domingos*
DOI: 10.1039/c3nj00000x
www.rsc.org/njc
dissolving organic compounds or isolating the reaction product,
there has been increasing interest in its use in the past two
decades, which is related to environmental and economic
aspects.10
Taking into consideration that a model reaction should be a
straightforward chemical reaction, the rate of which can be
measured with high precision allowing full kinetic analysis, we
propose the use of the 5-exo regiospecific cyclization reaction
of (2-iodophenyl)(3-methyl-1H-indol-1-yl)methanone (1),
Scheme 1.
The regiospecific 5-exo intramolecular Mizoroki-Heck
reaction
of
(2-iodophenyl)(3-methyl-1H-indol-1-
catalytic model
yl)methanone is presented as
a
reaction for the in situ performance evaluation of Pd
catalysts for C-C cross-coupling reactions in aqueous
medium. The reaction produces a conjugated cyclic
compound which can be easily detected and quantified
by UV-vis spectroscopy. Therefore, the reaction
progress can be easily monitored and the catalytic
parameters determined. The model reaction was tested
with molecular and nanoparticulate catalysts, based on
the Pd(OAc)2 salt.
Palladium-based catalysts are undoubtedly the most versatile
and ever-present catalysts in modern organic synthesis.1,2 They
are applied to a plethora of organic transformations and in this
context palladium-catalyzed C-C bond formation is by far the
most important process. The development of this process
transformed the construction of new molecules and continues to
attract the attention of researchers worldwide.3-6 In the quest for
new methods to perform C-C bond formation reactions,
progress in relation to novel approaches for catalyst research
and development is fundamental. From traditional methods to
Scheme
yl)methanone (1).
1
Cyclization reaction of (2-iodophenyl)(3-methyl-1H-indol-1-
This is an intramolecular Mizoroki-Heck reaction, catalyzed
by Pd catalysts in the presence of a base.11 The product (2) of
this reaction is a conjugated cyclic compound which can be
easily detected and quantified by UV-vis spectroscopy.
Consequently, one can monitor the reaction progress and
determine the catalytic parameters for the in situ evaluation of
the catalyst performance. As shown in Fig. 1, product 2 of this
reaction has a distinct absorbance band centered at 364 nm,
thus allowing the reaction to be monitored by measuring the
UV-vis absorption intensity due to its appearance.
high-throughput
screening
techniques
for
catalyst
synthesis/testing, the most important point to be addressed at
the primary screening level is the evaluation of the catalytic
performance, and in this regard studies on the reaction kinetics
are an indispensable step.7,8 However, this step is commonly
difficult, time-consuming and labor-intensive. In this context,
we investigated a catalytic model reaction to assess in situ the
activity of Pd catalysts for C-C cross-coupling reactions,
specifically for the Mizoroki-Heck reaction in aqueous
medium. The Mizoroki-Heck reaction is one of the most
popular C-C bond formation processes9 and it has been
speculated that this is the best model process for the
development of new catalytic systems for palladium-catalyzed
reactions.3 While water has not been the solvent of choice for
many organic reactions, due to difficulties associated with
In this study we verified the applicability of the proposed
model reaction to three different catalytic protocols, all based
on the use of Pd(OAc)2 salt: (A) addition of Pd(OAc)2 to an
aqueous reaction medium containing a base; (B) addition of as
-
prepared Pd nanoparticles (Pd-NPs), synthesized from
Pd(OAc)2 and a pyridinium salt (Scheme 2), to an aqueous
reaction medium containing a base; and (C) addition of
Pd(OAc)2 to an aqueous reaction medium containing a base and
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the same pyridinium salt used to synthesized the NPs in absorption intensity can also be used to directly determine the
protocol (B) (namely, Pd(OAc)2-PS).
amount of product produced in the reaction, applying the Beer-
Lambert equation and using a molar absorption coefficient of
5,328 L mol-1 cm-1, determined by UV-vis spectroscopy and
confirmed by high performance liquid chromatography (Fig.
S3, ESI†). Using the amount of product yielded, the
productivity and catalytic parameters were calculated. The
turnover number (TON) was calculated from the number of
moles of product yielded per mol of soluble metal catalyst. The
catalytic activity parameter used in this study were the
maximum turnover frequency (TOFMAX
)
obtained by
normalizing TON to time at each point of the reaction (see inset
of Fig. 1).
The applicability of the reaction model was tested in the
screening of the reaction conditions, for instance, the influence
of the reaction medium, type and concentration of base, and
catalyst concentration, by comparing the activity (TOFMAX) of
all three catalytic systems. The first experiment was focused on
the need to add an organic cosolvent to the reaction. In our
case, the addition of 10 vol % of an organic solvent (CH3CN)
was found to be necessary to guarantee the solubilization of the
reactants and reach the best conditions for the reaction to
proceed, for all catalytic systems. The addition of less than 10
vol % of CH3CN gave a turbid solution and the reaction was
much slower, as well with the addition of more than 10 vol %,
as shown representatively in Fig. 2 for the reaction with
Pd(OAc)2. The same behavior was observed for the other two
systems.
Fig. 1 Variation in UV-vis absorption spectra over time used to monitor the
appearance of product 2 in the cyclization reaction of 1 catalyzed by Pd-NPs. ([1]
= 0.1 mmol L-1; [Pd-NPs] = 10 mol %; [Et3N] = 0.2 mmol L-1; H2O/CH3CN (9/1,
v/v); 80 °C). The inset shows the time dependence of the absorption of 2 at 364
nm (black spheres) and TOF at each point of the reaction (red spheres).
The as-prepared Pd-NPs were synthesized using a novel
approach by simply mixing an aqueous solution of Pd(OAc)2
with
the
pyridinium
salt
1-methyl-2-
(propionamidomethyl)pyridinium iodide [PS-Me(I)], in the
ambient atmosphere at room temperature (Scheme 2), in a 1:2
ratio.
R4N+
R4N+
I-
R4N+
I-
I-
I-
H
R4N+
Pd(OAc)2
H2O
N
Pd-NP
N
I-
R4N+
I
I-
R4N+
O
I-
R4N+
PS-Me(I)
I-
R4N+
Scheme 2 Pd nanoparticles obtained by reduction of Pd(OAc)2 in the presence of
the pyridinium salt PS-Me(I), in water and in the ambient atmosphere at room
temperature.
Fig. 2 TOF as a function of the amount of CH3CN (vol %) in the aqueous reaction
medium, for the cyclization reaction of 1 catalyzed by Pd(OAc)2. ([1] = 0.1 mmol
L-1; [Et3N] = 0.1 mmol L-1; [Pd] = 10 mol %; 80 °C).
The formation of NPs is practically instantaneous and the
optimized conditions led to
nanoparticles synthesis method, with no addition of an extra
reducing agent. Particles of 1.9 nm ( = 16%) average diameter
a
reproducible palladium
No rationale for the effect of water on the intramolecular
Heck reaction has as yet been given.9 However, these results
demonstrate that the rate enhancement mainly comes from the
hydrophobic effect of water, as expected for more compact
transition states, such as in intramolecular Heck
cyclizations.18,19 The increase in the amount of CH3CN
diminishes the hydrophobic interactions in the transition state
of the reaction and consequently reduces the reaction rate, in a
way similar to the well-known effect of water in Diels-Alder
reactions and the Claisen rearrangement.3 Moreover, the
aqueous reaction medium with 10 vol % of CH3CN presented
an additional positive feature, that is, by only cooling down the
reaction system, the cyclic product precipitates and it could be
σ
were observed by transmission electron microscopy (TEM)
analysis (Fig. S1, ESI†). Additional energy-dispersive X-ray
spectroscopy (EDS) analysis of the Pd-NPs identified the
characteristic palladium lines at 2.83 and 2.97 keV and iodide
lines at 3.94 and 4.22 keV (Fig. S2, ESI†), indicating that the
iodide counteranion of the pyridinium salt interactes with the
NP surface, probably providing the electrostatic stabilization of
the NPs (Scheme 2), as previously reported for other iodide
quaternary ammonium salts.12-15
The full kinetic profile was obtained for all three catalytic
systems, as representatively shown in Fig. 1 for the reaction
with Pd-NPs. Since only 2 absorbs at this wavelength, the
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easily recovered by filtration. This behavior increases the showed the same concentration profile as K2CO3. While for
applicability of the reaction model, if the isolation of the Pd(OAc)2 there was a decrease in the catalytic activity with an
product is required.
increase in the bases concentration, the other two catalytic
In the next experiment the reaction dependence on the base systems presented a maximum TOFMAX for an optimal base
was investigated. It is generally accepted that the base in concentration. When the reaction was performed in the absence
Mizoroki-Heck reactions is involved in the reductive of a base, catalysis still occurred but the conversion was very
elimination step to regenerate Pd(0), the active species in the low (Fig. S4, ESI†). In this respect, the addition of small
catalytic cycle, from Pd(II). However, it has also been amount of base can increase the productivity (TON and yield)
suggested that the equilibrium between XPdH and Pd(0) is of all catalytic systems, without significant decrease in their
reached quickly and may not require the addition of a base, so catalytic activity. For the Pd(OAc)2 catalyst, for example, the
the main function of the base would be the prevention of addition of 0.1 mmol L-1 of Et3N increases the product yield
accumulated protic acids in the reaction medium.9
In this context, we investigated the influence of two bases % in the TOFMAX (Fig. 3a).
from 23 % to 61 % (Fig. S4a, ESI†) with only a reduction of 18
commonly employed in Heck reactions, Et3N and K2CO3, on
Fig. 4 shows the dependence of the TOFMAX value on the Pd
the intramolecular cyclization of 1. As represented in Fig. 3a concentration, which is stronger for the protocols using the
and 3b, the use of a base was found to be important for all Pd(OAc)2 salt (protocols A and C) and weaker for the Pd-NPs
catalytic systems.
(protocol B). For all protocols, the “homeopathic” effect was
not observed and no product formation was observed between
0.1 mol % and 0.01 mol % of Pd.15
Fig. 4 TOF as a function of Pd loading (mol %) for the cyclization reaction of 1
catalyzed by Pd-NPs (orange bars), Pd(OAc)2 (grey bars) or Pd(OAc)2-PS (green
bars) in H2O/CH3CN (9/1, v/v). ([1] = 0.1 mmol L-1; [Et3N] = 0.1 mol %; 80 °C).
These results reveal a bell-like dependence of TOFMAX and
TON (Fig. S5, ESI†) on the initial palladium loading, typical of
substrates in which the rate of oxidative addition is low and the
build-up of Pd(0) leads to the inactivation of the catalyst.
However, on considering the product yield as a function of the
initial palladium loading (Fig. S5, ESI†), it can be observed that
the decrease in the TOFMAX and TON values is manly
associated with the amount of Pd and not with a reduction in
the product formation. This decrease in catalytic activity with
increasing Pd loading, in ligand-free approaches, is generally
attributed to the formation of insoluble palladium black, which
leads to the withdrawal of all palladium from the catalytic
cycle. Visible Pd black was only observed for the Pd(OAc)2
system at 20 mol %, but the presence of clusters was observed
by TEM for all protocols (Fig. 5).
The TEM analysis revealed that NPs were present from the
beginning of the reaction for all catalytic systems, and after 20
h of reaction the largest clusters were observed for protocol A,
which were of different shapes and sizes (Fig. 5a). For the
system with the as-prepared Pd-NPs catalyst (protocol B), the
average diameter increased from 5.5 nm at the beginning of the
reaction to 8.5 nm after 20 h (Fig. 5b). For protocol C, where
Fig. 3 TOF as a function of (a) Et3N concentration and (b) K2CO3 concentrations,
for the cyclization reaction of 1 catalyzed by Pd-NPs (orange bars), Pd(OAc)2
(grey bars) or Pd(OAc)2-PS (green bars) in H2O/CH3CN (9/1, v/v). ([1] = 0.1
mmol L-1; [Pd] = 10 mol %; 80 °C).
Although Et3N is most commonly used in nonpolar solvents
and ligand-assisted protocols, the reaction in its presence
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the pyridinium salt was present in the reaction vessel before the the analysis, since they are normally used in very low
addition of Pd(OAc)2, NPs of 3.5 nm ( = 17%) were formed at concentrations and constant during the reaction.
the beginning of the reaction (Fig. 5c), and after 20 h the The performance of this model reaction can be further
diameter showed a small variation with the formation of even extended to applications involving different organic cosolvents,
σ
smaller NPs of 2.5 nm (
σ
= 32%).
exploring the effect of the reactant solubility, type of base,
reactant concentration and the recovery of the product from the
reaction medium, significant parameters when screening
techniques for catalyst synthesis/testing are performed in large-
scale and in more commercially relevant situations.
Experimental
The kinetics experiments were carried out in a quartz cell with
3.0 mL of final volume. All reactions were followed by UV-vis
single wavelength spectral kinetics at 364 nm at 80 ºC. The
samples for TEM were prepared on a carbon-coated Cu grid
and carried out in JEM-1011 equipment. The average particle
diameter was determined by analyzing at least 200 particles.
Acknowledgements
We are grateful to CNPq, CAPES and the Central Laboratory
of Electron Microscopy (LCME) at UFSC.
Notes and references
1
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Springer Berlin Heidelberg, 2012, pp. 1.
2
J. Tsuji, Palladium reagents and catalysts: new Perspectives for the 21st
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4
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7
A. de Meijere and F. Diederich, eds., MetalꢀCatalyzed CrossꢀCoupling
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A. Hagemeyer, P. Strasser and J. Volpe, Anthony F. , eds., Highꢀ
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E. G. Derouane, V. Parmon, F. Lemos and F. R. Ribeiro, eds., Principles
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Science+Business Media Dordrecht 2002; p 521.
M. Oestreich, ed., The MizorokiꢀHeck reaction, John Wiley & Sons, Ltd,
Chichester, 2009.
Fig. 5 TEM micrographs at the beginning of the reaction and after 20 h catalyzed
by (a) Pd(OAc)2, (b) Pd-NPs and (c) Pd(OAc)2-PS, in H2O/CH3CN (9/1, v/v) ([1]
= 0.1 mmol L-1; [Et3N] = 0.1 mmol L-1; [Pd] = 5 mol %; 80 °C).
Of the three protocols investigated in this study, protocol A
is the most catalytic and productive. However, since the
utilization of Pd(OAc)2 without any type of extra stabilization
led to the formation of large aggregates and even palladium
black at the end of the reaction, its applicability in large-scale
reactions would be compromised. On the other hand, the
protocol C, with the in situ stabilization of the formed Pd-NPs
by the pyridinium salt, proved to be an simple and efficient
approach to protect Pd(0) against inactivation and still provides
good catalytic and productivity results. Thus, this protocol
should be further explored in future studies.
In summary, despite the different natures of the catalysts
tested in this study, the 5-exo regiospecific cyclization reaction
of (2-iodophenyl)(3-methyl-1H-indol-1-yl)methanone (1) was
found to be a very efficient model reaction. In an easy and
quick manner it allows a complete kinetic analysis of the
reaction, the determination of the catalytic parameters for the
catalyst applied and the obtainment of further information on
the mode of action. It is important to note that no other products
were observed in addition to the cyclic product 2, which means
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that no potential side reactions have occurred, as
a
LaCBio – Chemistry Department, Universidade Federal de Santa
Catarina, Campus Trindade, Florianópolis ꢀ SC, 88040ꢀ900, Brazil. Eꢀ
mail: josiel.domingos@ufsc.br
homocoupling of the substrate 1. Even if this occurs, the
homocoupling reaction product presents a different UV-vis
spectrum, with no absorption interference for the cyclic product
quantification. Moreover, even screening of ligands that could
have similar UV profiles to the product 2 would not interfere in
† Electronic Supplementary Information (ESI) available: Synthetic,
reaction kinetics and characterization procedures, as well additional
data for the catalytic tests. See DOI: 10.1039/c000000x/
4 | J. Name., 2012, 00, 1-3
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Table of Contents (TOC)
GRAPHIC
TEXT
The activity of Pd catalysts for C-C coupling reactions is evaluated by using UV-vis spectroscopy
and a Heck model reaction.