Oxidative addition of haloheteroarenes to palladium(0): Concerted versus SNAr-type mechanism

Article abstract of DOI:10.1002/chem.201406210

The kinetics of the oxidative additions of haloheteroarenes HetX (X=I, Br, Cl) to [Pd⁰(PPh₃)₂] (generated from [Pd⁰(PPh₃)₄]) have been investigated in THF and DMF and the rate constants have been determined. In contrast to the generally accepted concerted mechanism, Hammett plots obtained for substituted 2-halopyridines and solvent effects reveal a reaction mechanism dependent on the halide X of HetX: an unprecedented S_NAr-type mechanism for X=Br or Cl and a classical concerted mechanism for X=I. These results are supported by DFT studies.

Full text of DOI:10.1002/chem.201406210

DOI: 10.1002/chem.201406210
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Reaction Mechanisms
Oxidative Addition of Haloheteroarenes to Palladium(0):
Concerted versus SNAr-Type Mechanism
Bert U. W. Maes,*[a] Stefan Verbeeck,[a] Tom Verhelst,[a] Audrey Ekomiꢀ,[b] Niklas von Wolff,[b]
Guillaume Lefꢁvre,[c] Emily A. Mitchell,[a] and Anny Jutand*[b]
Abstract: The kinetics of the oxidative additions of halohe-
teroarenes HetX (X=I, Br, Cl) to [Pd0(PPh3)2] (generated from
[Pd0(PPh3)4]) have been investigated in THF and DMF and
the rate constants have been determined. In contrast to the
generally accepted concerted mechanism, Hammett plots
obtained for substituted 2-halopyridines and solvent effects
reveal a reaction mechanism dependent on the halide X of
HetX: an unprecedented SNAr-type mechanism for X=Br or
Cl and a classical concerted mechanism for X=I. These re-
sults are supported by DFT studies.
Introduction
means of cross-coupling of 5-(tributylstannyl)-1-methylimida-
zole with 7-chloro-2-iodothieno[3,2-b]pyridine under standard
Stille reaction conditions. Remarkably, this was the only Pd-cat-
alyzed cross-coupling reaction that proved to be robust and
scalable (Kumada, Suzuki–Miyaura, or Hiyama reactions all
failed on the same substrate and a Negishi reaction proved un-
reliable on a larger scale). This example clearly illustrates the
sensitivity of Pd-catalyzed cross-coupling reactions when heter-
oatoms are present in the coupling partners. In sharp contrast
to the widespread application of Pd-catalyzed cross-coupling
reactions on haloheteroarenes, experimental data regarding
the effect of the heteroatoms on the fundamental steps (oxida-
tive addition, transmetalation, reductive elimination) of the cat-
alytic cycle are scarce.[5] Surprisingly, no kinetic data for the oxi-
dative addition of haloheteroarenes to Pd0 complexes have
been reported and the mechanism remains unknown.[6] Data
for haloheteroarenes are, however, important to gain insight
into factors governing their reactivity. This provides a tool to
predict the regioselectivity of Pd-catalyzed cross-coupling reac-
tions in multihalogenated heteroaromatic systems, when the
oxidative addition determines the selectivity.[7] When the halo-
gen atoms present are identical (e.g., Cl), both the position of
the heteroatom(s) and the substituent(s) can govern the regio-
selectivity. Regioselective Pd-catalyzed cross-coupling reactions
have recently received a great deal of attention as they pro-
vide a particularly attractive strategy to functionalize heteroar-
omatic scaffolds for library synthesis.[8] Based on the impor-
tance of heteroarenes to the fine chemicals industry, and con-
sidering the paucity of data concerning their oxidative addi-
tion, we report herein our study of the kinetics and mecha-
nisms of oxidative additions of haloheteroarenes to Pd0
complexes.
Palladium-catalyzed cross-coupling reactions have had an un-
paralleled impact on synthetic organic chemistry. Indeed, the
2010 Nobel Prize in Chemistry awarded to this field reflects its
impact on our society. These synthetic tools are now widely
used to prepare fine chemicals (pharmaceuticals, agrochemi-
cals, and materials) and complex natural products, and are ap-
plied in both discovery and process chemistry.[1,2] For example,
the large-scale production of the biaryl unit of the fungicide
Boscalid employs a Suzuki–Miyaura reaction as a key step.[2] Al-
though cross-coupling reactions have historically been devel-
oped for haloarene substrates, they are now widely applied to
haloheteroarenes as well.[1a] This is not surprising, given the im-
portance of heterocyclic motifs in commercial fine chemicals.[3]
However, the application of catalyst systems, originally devel-
oped for carbocyclic coupling partners, to their heterocyclic
analogues is not always straightforward. A striking example is
the synthesis of a vascular endothelial growth factor receptor
(VEGFR) kinase inhibitor ({2-(3-methyl-3H-imidazol-4-yl)thie-
no[3,2-b]pyridin-7-yl}-2-(methyl-1H-indol-5-yl)amine) developed
by Pfizer.[4] The 2-(3-methyl-3H-imidazol-4-yl)thieno[3,2-b]pyri-
dine biaryl unit was synthesized on a multikilogram scale by
[a] Prof. B. U. W. Maes, Dr. S. Verbeeck, Dr. T. Verhelst, Dr. E. A. Mitchell
Organic Synthesis, Department of Chemistry
University of Antwerp, 2020 Antwerpen (Belgium)
E-mail: bert.maes@uantwerpen.be
[b] A. Ekomiꢀ, N. von Wolff, Prof. A. Jutand
Ecole Normale Supꢀrieure-PSL Research University
Dꢀpartement de Chimie, Sorbonne Universitꢀs
UPMC Univ Paris 06, CNRS UMR 8640 PASTEUR
24 Rue Lhomond, 75231 Paris Cedex 5 (France)
E-mail: Anny.Jutand@ens.fr
[c] Dr. G. Lefꢁvre
CEA-Saclay, IRAMIS Institute, SIS2M/NIMBE/LCMCE
91191 Gif Sur Yvette, Cedex (France)
Results and Discussion
[Pd0(PPh3)4] was selected as a model catalytic system based on
its widespread use in Pd-catalyzed cross-coupling reactions in-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406210.
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volving heteroaromatic substrates (HetX). It is known that
[Pd0(PPh3)4] fully dissociates to [Pd0(PPh3)3] in solution.[6a–d] The
latter is unreactive, but in equilibrium with [Pd0(PPh3)2], which
is the active complex involved in oxidative additions (Sche-
me 1).[6a–d] Consequently, the rate of the oxidative addition is
controlled by the thermodynamic concentration of [Pd0(PPh3)2]
Table 1. koa KL values for the oxidative addition of 2-halopyridines and
halobenzenes to [Pd0(PPh3)4] in DMF and THF at 258C.
Entry
Substrate
k
oa KL [sꢀ1
DMF
]
koa KL [sꢀ1
]
THF
1
2
3
4
5
6
1a
2a
3a
2.5ꢃ10ꢀ6
no reaction
3.3ꢃ10ꢀ3
3.0ꢃ10ꢀ6[a]
1.3
4.1ꢃ10ꢀ7
no reaction
1.3ꢃ10ꢀ3
n.m.[b]
Scheme 1. Oxidative addition of HetX to [Pd0(PPh3)2] generated from
[Pd0(PPh3)4].
1.13
7.5ꢃ10ꢀ2[a]
8.7ꢃ10ꢀ2[a]
in the equilibrium (equilibrium constant KL) and its intrinsic re-
activity in the oxidative addition (rate constant koa; Scheme 1).
The overall reactivity of the Pd0 complex in the oxidative addi-
tion is therefore characterized by the product koa KL expressed
in sꢀ1 (see the Supporting Information for more details on the
kinetic laws).
[a] See ref. [6a]; [b] n.m.=not measured.
The kinetics of the oxidative
addition were investigated by
chronoamperometry at a gold
rotating disk electrode (RDE, d=
2 mm, w=105 radsꢀ1) polarized
on the plateau of the oxidation
wave of [Pd0(PPh3)3] (+0.35 V in
DMF, +0.45 V in THF versus a sa-
turated calomel electrode (SCE)).
The decrease of the oxidation
plateau current of [Pd0(PPh3)3]
(proportional to its concentra-
tion at any time) in the presence
of HetX was recorded versus
time in DMF and in THF at
258C.[6a] 2-Chloro- (1a), 2-bromo-
(2a), and 2-iodopyridine (3a)
were selected as initial sub-
strates (2-PyX). 2-PyI was the
most reactive and the kinetics of
its oxidative addition were inves-
tigated for
a
stoichiometric
amount of 2-PyI (3a) and [Pd0L4]
(C0 =2 mm). The reaction was
performed in the presence of an
excess
amount
of
PPh3
(10 equiv) to sufficiently slow the
reaction to record the decay of
the oxidation current of [Pd0L3]
versus time. The kinetic law 1/
Figure 1. a) Kinetics of the oxidative addition of 2-PyI (3a; 2 mm) to [Pd0(PPh3)4] (C0 =2 mm) in the presence of
x=1+koa KL C0t/[PPh3]0
(molar PPh3 (20 mm) in THF at 258C. Plot of 1/x versus time: 1/x=1+koa KL C0 t/[PPh3]0. b) Kinetics of the oxidative addi-
tion of 2-PyBr (2a; 80 mm) to [Pd0(PPh3)4] (C0 =2 mm) in DMF at 258C. Plot of 2lnxꢀx+1 versus time:
2lnxꢀx+1=ꢀkoa KL [2-PyBr]t/C0. c) Kinetics of the oxidative addition of 2-PyCl (1a; 160 mm) to [Pd0(PPh3)4]
(C0 =2 mm) in DMF at 258C. Plot of 2lnxꢀx+1 versus time: 2lnxꢀx+1=ꢀkoa KL [2-PyCl]t/C0. d) Determination of
the reaction order for the oxidative addition of 2-PyBr (2a) to [Pd0(PPh3)4] (C0 =2 mm) in THF at 258C. Plot of kobs
fraction
x=[Pd0]t/[Pd0]0 =it/i0)
was used to determine the value
of koa KL from the slope of the
linear plot (Figure 1a, Table 1 versus [2-PyBr]/C0 (kobs =koa KL [2-PyBr]/C0).
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entry 5). Oxidative addition of the less reactive 2-PyBr (2a) and
2-PyCl (1a) was performed with a large excess of substrate (>
10C0) and in the absence of extra PPh3. In these cases the ki-
netic law 2lnxꢀx+1=ꢀkoa KL [2-PyX]t/C0 is applicable (Fig-
ure 1b, Table 1 entry 3; Figure 1c, Table 1 entry 1) and was
used to determine the koaKL value. The kinetic laws take into
account the variation of the concentration of PPh3 all along
the reaction (see the Supporting Information).[6g]
All reactions were found to be first order in both Pd0 and 2-
PyX by means of a pseudo-first-order plot (see Figure 1d for 2-
PyBr) allowing the determination of koa KL (Table 1). A reactivity
order was established both in DMF and THF: 2-PyI>2-PyBr>
2-PyCl (3a>2a>1a). This reactivity order is similar to that
previously established for PhX (PhI>PhBr@PhCl; Table 1).[6a] 2-
PyX were always found to be more reactive than PhX for the
same X (compare entries 1 and 2, 3 and 4, 5 and 6 in Table 1).
The imine moiety in the pyridine core clearly exerts an acceler-
ating effect on the oxidative addition. The activation energy
differences between azine and arene in DMF are 17.3 and
7.0 kJmolꢀ1 for X=Br and I, respectively. The lower reactivity
of 1a in the series is reflected in the high activation energy de-
termined from oxidative addition experiments performed at
several temperatures in DMF (69.8 kJmolꢀ1, Figure S5 in the
Supporting Information). Interestingly, a rate decrease was ob-
served for the oxidative addition of 2-PyCl (1a) when changing
from DMF to THF. No significant difference in rate was ob-
served for 2-PyI (3a) and the solvent effect for 2-PyBr (2a) was
moderate (Table 1, entries 1, 3, 5).
Figure 3. Hammett plots for the oxidative addition of 5-Z-2-PyCl to
[Pd0(PPh3)2] generated from [Pd0(PPh3)4] in THF (a) and DMF (b) at 258C.
Next, a series of experiments was conducted in THF and
DMF for the oxidative addition of 5-substituted-2-halopyridines
(5-Z-2-PyX) to [Pd0(PPh3)2] to determine the influence of the
substituents Z on the kinetics by means of Hammett plots
(Table 2–4, Figures 2–4).[9] Electron-withdrawing substituents Z
Figure 4. Hammett plots for the oxidative addition of 5-Z-2-PyBr to
[Pd0(PPh3)2] generated from [Pd0(PPh3)4] in THF (a) and DMF (b) at 258C.
in the 5-position of 2-halopyridines exerted a significant rate
increase versus the unsubstituted 2-halopyridine, while the re-
verse effect was observed for electron-donating substituents.
Hammett plots of log(kZoaKL/kHoaKL) (=log(koZa/koHa)) versus sp of
the substituent Z revealed linear correlations with positive
1 values: log(koZa/koHa)=1.sp (Figures 2–4).[10] The rates of the ox-
idative additions of 5-Z-2-PyI with [Pd0(PPh3)2] were not signifi-
cantly affected by the solvent (DMF or THF) with low 1 values
of +2.8 and +3.0, respectively (Figure 2, Figures S31–S38 in
Figure 2. Hammett plots for the oxidative addition of 5-Z-2-PyI to
[Pd0(PPh3)2] generated from [Pd0(PPh3)4] in THF (a) and DMF (b) at 258C.
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the Supporting Information). These data indicate that the
charge buildup during oxidative addition is very low, which im-
plies the involvement of an uncharged transition state. A com-
parably low value (1= +2 in THF)[6b,c] was also observed for
the oxidative addition of 4-Z-C6H4-I to [Pd0(PPh3)2], as was the
lack of any significant solvent effect.[6d]
Table 2. koa KL values for the oxidative addition of [Pd0(PPh3)4] to 5-Z-2-io-
dopyridines in DMF and THF at 258C.
Entry
Z
koa KL [sꢀ1
]
DEa[a] [kJmolꢀ1
]
koa KL [sꢀ1
]
DMF
DMF
THF
1
2
3
4
5
Me (3b)
H (3a)
Cl (3c)
CO2Me (3d)
NO2 (3e)
n.m.[b]
1.3
5.3
23.5
217
–
0
0.25
1.13
5.9
22.2
237
For substituted 5-Z-2-PyCl (Figures S9–S16 in the Supporting
Information), 1 values were found to be much higher than for
the related iodopyridines (see above): +3.9 and +4.3 in DMF
and THF, respectively (Figure 3).[11] Moreover, for all substitu-
ents in the 5-position, a higher value of kZoaKL was obtained in
DMF compared to THF (Table 4). The high positive 1 values
and the significant solvent effect clearly indicate the buildup
of negative charge in the pyridine ring during the reaction. A
smaller 1 value (+3.3) was obtained for 4-Z-2-PyCl in DMF (Fig-
ure S19 in the Supporting Information).[12] This is in agreement
with a lower electronic effect of a 4-Z versus a 5-Z substituent
on the 2-chloropyridine. An identical series of experiments was
also performed for 5-Z-2-PyBr (Figure 4, Figure S21–S30), which
reveals similarly high 1 values, +4.1 (DMF) and +4.4 (THF), as
well as a significant solvent effect (Table 3). This suggests an
oxidative addition mechanism similar to that for 5-Z-2-PyCl.
The data for 5-Z-2-PyBr are in sharp contrast with the low
1 value and the absence of a solvent effect observed for the
oxidative addition of 4-Z-C6H4Br to [Pd0(PPh3)2] (1= +2.1 DMF)
for which a concerted mechanism was proposed.[6e]
ꢀ3.5
ꢀ7.2
ꢀ12.7
[a] Relative to 3a. [b] n.m.: not measured.
Table 3. koa KL values for the oxidative addition of [Pd0(PPh3)4] to 5-Z-2-
bromopyridines in DMF and THF at 258C.
Entry
Z
koa KL [sꢀ1
]
DEa[a] [kJmolꢀ1
]
koa KL [sꢀ1
]
DMF
DMF
THF
1
2
3
4
5
6
Me (2b)
H (2a)
Cl (2c)
CO2Me (2d)
CHO (2e)
NO2 (2 f)
7.2ꢃ10ꢀ4
3.3ꢃ10ꢀ3
9.8ꢃ10ꢀ3
24.3ꢃ10ꢀ2
0.526
+3.7
0
ꢀ2.7
ꢀ10.7
ꢀ12.6
ꢀ17.7
1.5ꢃ10ꢀ4
1.3ꢃ10ꢀ3
5.9ꢃ10ꢀ3
9.1ꢃ10ꢀ2
0.16
4.1
3.7
[a] Relative to 2a.
Table 4. koa KL values for the oxidative addition of [Pd0(PPh3)4] to 5-Z-2-
chloropyridines in DMF and THF at 258C.
Given the solvent effect on koa KL values, as well as the high
1 values observed, one can postulate that the mechanism for
oxidative addition of 2-chloro- and 2-bromopyridines might
proceed by means of a SNAr-type pathway. Such a mechanism
has been proposed for 4-Z-C6H4Cl and [Pd0(PPh3)2] by Fitton
and Rick.[13a] The first experimental evidence for an SNAr-type
oxidative addition pathway was provided by Portnoy and Mil-
stein using a very nucleophilic [Pd0(dippp)] complex and 4-Z-
C6H4Cl.[13b] However, based on DFT calculations for both ArX
and HetX, oxidative addition with Pd0 complexes has always
been thought to proceed by means of a concerted mecha-
nism, which does not involve charged species.[14,15a–f,h–j] This
might well be due to the fact that previous DFT studies have
not taken into account solvent effects[15g] and are often based
on simplified model ligands such as PH3.[14a] To support our ex-
perimental findings, we decided to perform DFT[16a] calcula-
tions for 2-PyX and [Pd0(PPh3)2] by taking into account the ef-
fects of solvent and the full ligand. The structural and energet-
ic properties of the complexes described herein were thus de-
termined. All theoretical calculations were performed using
Gaussian 09 code.[16b] The 6-31+G(d) basis set[16c,d] was used for
atoms C, H, and N; Pd was treated by using the Stuttgart pseu-
dopotential and associated basis set,[16e] and halides (Cl, I) were
treated by using a 6-311+G(d) basis set.[16f,g] The hybrid ex-
change correlation functional PBE0 was also used.[16h] It mixes
25% of Hartree–Fock exchange into the gradient-corrected
PBE exchange and correlation functional[16i] and yields accurate
and reliable thermochemistry data for reactions involving tran-
sition-metal compounds.[16j] All structures were calculated with-
out geometrical constraints, and all stationary points were
characterized as minima or transition states by frequency cal-
Entry
Z
koa KL [sꢀ1
]
DEa[a] [kJmolꢀ1
]
koa KL [sꢀ1
]
DMF
DMF
THF
1
2
3
4
5
H (1a)
Cl (1b)
CO2Me (1c)
CN (1d)
2.5ꢃ10ꢀ6
6.1ꢃ10ꢀ6
1.97ꢃ10ꢀ4
6.8ꢃ10ꢀ4
3.9ꢃ10ꢀ3
0
4.1ꢃ10ꢀ7
4.2ꢃ10ꢀ6
1.50ꢃ10ꢀ5
1.9ꢃ10ꢀ4
1.86ꢃ10ꢀ3
ꢀ2.2
ꢀ10.8
ꢀ13.9
ꢀ18.2
NO2 (1e)
[a] Relative to 1a.
culations (i.e., only one negative frequency for a transition
state, no negative frequencies for minima). Solvent effects
(here DMF) were included in all structure-optimization and fre-
quency calculations using the polarizable continuum model
(PCM) implicit solvation model of Tomasi and co-workers, as
implemented in the Gaussian code.[16k,l] All charges were com-
puted by using an natural bond orbital (NBO) partition analy-
sis.[16m] As recent contributions highlighted the crucial effect of
dispersion forces on computed oxidative addition reactions for
similar systems,[16n] Grimme’s DFT-D3 correction was added to
the computed free energies.[16o]
A classical three-center mechanism for the oxidative addition
of 2-PyCl (1a) to [Pd0(PPh3)2] was first computed (Figure 5).
This oxidative addition proceeds in three steps. A pre-complex
ACl is formed by complexation of the C=C double bond adja-
cent to the Cl atom (d(PdꢀC2)=2.27 ꢄ; d(PdꢀC3)=2.31 ꢄ; C5-
C2-Cl=159.88). A more stable second complex BCl is then
formed by torsion of the C5-C2-Cl angle, which becomes
155.78. This leads to a stronger C=C/Pd ligation by increasing
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ride migrates from the ring to the PdII center is slightly easier
with a free-energy barrier of 29.72 kJmolꢀ1 for TS3Cl (Figure 6).
The overall barrier for the SNAr-type mechanism is
53.84 kJmolꢀ1, which means that this pathway is preferred to
the three-center oxidative addition depicted in Figure 5. No
transition state corresponding to a SNAr-type mechanism could
be found for the oxidative addition of 2-PyI (3a) to
[Pd0(PPh3)2]. Only the classical three-center mechanism could
be computed (Figure 7). The process essentially follows the
Figure 5. Computed classical concerted mechanism for the oxidative addi-
tion of 2-chloropyridine to [Pd0(PPh3)2] in DMF
the backbonding from the Pd center to the C=C p* system
(d(PdꢀC2)=2.11 ꢄ; d(PdꢀC3)=2.19 ꢄ). BCl is finally transformed
to the PdII product CCl by means of the three-center TS1Cl. In-
terestingly, TS1Cl does not exhibit any charge delocalization
onto the pyridinyl ring. Indeed, the overall charge borne by
the Py ring is q(Py)=ꢀ0.08jej. The overall computed barrier
for this three-center oxidative addition is 59.86 kJmolꢀ1. No co-
ordination of the C=N bond to [Pd0(PPh3)2] could be character-
ized for a three-center oxidative addition. All attempted struc-
tures for this complex led to a Meisenheimer-type complex
(DCl) supporting an oxidative addition by means of a SNAr-type
mechanism (Figure 6).
Figure 7. Computed classical concerted mechanism for the oxidative addi-
tion of 2-iodopyridine to [Pd0(PPh3)2] in DMF
same steps as depicted for 2-chloropyridine in Figure 5. The p
complex formed prior to the oxidative addition transition state
is weak and has been located 2.30 kJmolꢀ1 below the non-in-
teracting reactants (Figure 7). The low energy barrier of
12.25 kJmolꢀ1 for oxidative addition is in agreement with the
fast reactions observed for 2-iodopyridines with [Pd0(PPh3)2]
(Table 2). This fast process overrides the SNAr-type pathway,
which leads to a less stable intermediate due to the weaker
electron-accepting power of 2-PyI (3a), unable to stabilize par-
tial negative charge as effectively as 2-PyCl (1a). These kinetics
and DFT results on the reaction of substituted 2-halopyridines
with [Pd0(PPh3)2] thus illustrate for the first time that the mech-
anism of the oxidative addition depends on the leaving group
X, that is, concerted (X=I) versus SNAr-type mechanism (X=Br,
Cl; Scheme 2). Faster oxidative additions with 2-bromo- than
with 2-chloropyridines suggest that the second step in the
SNAr-type mechanism (CꢀX bond cleavage) is rate determining,
as supported by the DFT calculation on 2-PyCl (1a; Figure 6).
Both the dispersion-corrected and dispersion-free free-
Figure 6. Computed SNAr-type mechanism for the oxidative addition of 2-
chloropyridine to [Pd0(PPh3)2] in DMF
Formation of DCl via TS2Cl requires a computed barrier of
48.03 kJmolꢀ1 and exhibits a complexation between the partly
negatively charged nitrogen (q(N)=ꢀ0.54jej) and the partly
positively charged [PdIIL2] center (q= +0.32jej) with d(Pdꢀ energy profiles show that the ionic SNAr-type mechanism is fa-
N)=2.18 ꢄ. DCl is therefore not a classical Meisenheimer com-
plex (as was proposed by Fitton and Rick for ArCl)[13a] with
a large negative charge on the N atom and a large positive
charge on the PdII center, but involves PdꢀN bonding. This is
probably due to the low nucleophilicity of the [Pd0(PPh3)2]
moiety compared to that of the nucleophiles involved in classi-
cal SNAr reactions. DCl also exhibits a strong charge delocaliza-
tion: q(Py)=ꢀ0.27jej. The angle C5-C2-Cl (150.28) is smaller
than that in 2-chloropyridine, which attests that the halogenat-
ed carbon acquired a sp3 character during the reaction. This is
also supported by the C2ꢀCl distance: d(C2ꢀCl)=1.82 ꢄ versus
1.75 ꢄ in 2-chloropyridine. The second step in which the chlo-
vored over the neutral three-center oxidative addition pathway
in the case of 2-PyCl (the SNAr-type mechanism being more fa-
vored by 10.46 kJmolꢀ1 in a dispersion-free model; see the
Supporting Information). However, dispersion-free computa-
tions seem to provide a better quantitative fit for the compari-
son of the relative activation barriers of 2-PyCl and 2-PyI in the
oxidative addition process. Experimentally, a difference of
DDEꢀexp =32.61 kJmolꢀ1 is obtained for the oxidative addition
activation barriers of [Pd0(PPh3)4] to 2-PyCl and 2-PyI (Table 1,
entries 1, 5; and the Supporting Information). This barrier dif-
ference is well estimated by the computed dispersion-free en-
thalpies (DDHcꢀalc =28.81 kJmolꢀ1) and free energies (DDGꢀcalc
=
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plified for 1-chloroisoquinoline (6; 11.8 kJmolꢀ1
; Table 5,
entry 4; Figure S42 in the Supporting Information).
To obtain an estimate of the difference in reactivity of azine-
versus azole-type substrates in oxidative additions, 2-chloro-
thiazole (8; Figures S45 and S46 in the Supporting Information)
was also examined. In comparison with 1a, a lowering of the
activation energy of 16.6 kJmolꢀ1 was obtained, which corre-
sponds to a rate increase by a factor of 815 (Table 5,
entry 6).[18] Interestingly, benzoannelation through the C4ꢀC5
bond has a much smaller effect on the activation energy in the
azole (9.5 kJmolꢀ1) series than in the azines (ꢁ12–15 kJmolꢀ1
;
Table 5, compare entries 6 and 8).
Finally, the effect of a change in solvent polarity on the rate
of the oxidative addition was investigated for some of the sub-
strates in Table 5. The data reveal that a decrease in solvent
polarity, upon substituting DMF for THF, has a similar deceler-
ating rate effect as observed for 2-PyCl (1a). A decelerating
factor of 7.7 and 6.4 was observed for 2-chloropyrazine (4) and
2-chloroquinoline (7), respectively (Table 5, entries 2 and 5).
The azole-type substrates 2-chlorothiazole (8) and 2-chloroben-
zothiazole (10) also showed a decrease in rate upon changing
to the less polar solvent (Table 5, entries 6 and 8). These decel-
erations were, however, much larger—55 and 19 times, respec-
tively—than those found in the azine series. This is in accord-
ance with the ionic character in the transition state, which is
higher for azole than for azine derivatives. This can be rational-
ized if one considers the delocalization of negative charge
over a smaller five-membered ring as compared to a six-mem-
bered heteroaromatic ring system, as is described for SNAr re-
actions with classical nucleophiles.[19]
Scheme 2. Different mechanistic pathways for the oxidative addition of sub-
stituted 2-chloro-, 2-bromo-, and 2-iodopyridines to [Pd0(PPh3)2].
35.69 kJmolꢀ1), but the dispersion-corrected computed barriers
reveal an overestimation of the latter (DDGdꢀisp, calc
=
41.59 kJmolꢀ1). The entropic effects roughly counterbalance
the dispersion correction (see the Supporting Information) as
the dispersion-corrected free energies are close to the disper-
sion-free enthalpies. The main effect of the dispersion correc-
tion in the calculation is therefore a shift of the free-energy
profile towards lower values, as reported by Maron and co-
workers.[16p]
Experiments using chronoamperometry were also performed
to determine the effect of a second nitrogen atom in the 2-
chloropyridine skeleton, as well as benzoannelation, on the ki-
netics of oxidative addition. Both C(sp2)ꢀH to N(sp2) replace-
ments in C4 and C6 were explored (Table 5, entries 2
and 3; Figures S40 and S41 in the Supporting Infor-
Table 5. koa KL values for the oxidative addition of halo(hetero)arenes to [Pd0(PPh3)4] in
DMF and THF at 258C.
mation). Although these replacements are both in
a meta position relative to the C2ꢀCl bond, a different
effect on the activation energy of the reaction was
observed. Both chlorodiazine substrates 4 and 5 re-
acted significantly faster than 1a at comparable con-
centrations, which reflects their more electrophilic
nature. The decrease in activation energy for 2-chlor-
opyrazine (4), relative to 1a, was 11.1 kJmolꢀ1, while
a value of 7.7 kJmolꢀ1 was determined for 3-chloro-
pyridazine (5).[17] The influence of benzoannelation of
(di)azine substrates was also investigated. 2-Chloro-
quinoline (7; Table 5, entry 5; Figures S43 and 44 in
the Supporting Information) as well as 2-chloroqui-
noxaline (9; Table 5, entry 7; Figure S47 in the Sup-
porting Information) gave a lower activation energy
of 15.0 and 14.5 kJmolꢀ1, respectively, in comparison
with 1a and 2-chloropyrazine (4; Table 5, compare
entries 1 and 5, 2 and 7). This indicates that the
effect of benzoannelation by means of the C5ꢀC6
bond of a (di)azine on oxidative addition is quite in-
dependent of its specific structure. Benzoannelation
through C3ꢀC4 gives a slightly lower value as exem-
Entry
Substrate
koa KL [sꢀ1
DMF (THF)
]
DEa DMF
[kJmolꢀ1
]
1
2
3
1a
4
2.5ꢃ10ꢀ6 (4.1ꢃ10ꢀ7
)
)
–
2.2ꢃ10ꢀ4 (2.8ꢃ10ꢀ5
5.6ꢃ10ꢀ5
ꢀ11.1[a]
ꢀ7.7[a]
5
4
6
2.9ꢃ10ꢀ4
1.1ꢃ10ꢀ3
ꢀ11.8[a]
5
6
7
8
7
8
ꢀ15.0[a]
ꢀ16.6[a]
ꢀ14.5[b]
ꢀ9.5[c]
(1.7ꢃ10ꢀ4
)
)
2.0ꢃ10ꢀ3
(3.7ꢃ10ꢀ5
9
7.5ꢃ10ꢀ2
9.5ꢃ10ꢀ2
(5.1ꢃ10ꢀ3
10
)
[a] Relative to 1a; [b] relative to 4; [c] relative to 8.
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Conclusion
Acknowledgements
Kinetic data for the oxidative addition of haloheteroarenes to
[Pd0(PPh3)2] (rate constant koa), generated from [Pd0(PPh3)4]
(equilibrium constant KL), have been collected for the first
time. koa KL values were determined in THF and DMF at 258C.
Hammett plots and solvent effects supported by DFT studies
unequivocally indicate that the mechanism of the oxidative ad-
ditions of 2-halopyridines to [Pd0(PPh3)2] depends on the
halide. The oxidative additions of 2-chloro- and 2-bromopyri-
dines involve charged intermediates and transition states
(SNAr-type mechanism). Consequently, solvent effects and large
1 values were experimentally observed for 5-Z-2-PyX (X=Br,
Cl). In contrast, 2-iodopyridines involve a neutral intermediate
and transition state (concerted mechanism) without any signifi-
cant solvent effect and a smaller 1 value was experimentally
observed for 5-Z-2-PyI. Based on the solvent effects seen in all
HetCl studied, a SNAr-type mechanism is generally occurring.
Practical applications of this study are the ability to increase
the rate of cross-coupling reactions with HetX (X=Cl, Br;
which have a rate-determining oxidative addition step) by
simply selecting a solvent with a higher polarity. Secondly,
given that chlorinated heteroarenes are less expensive and
have a better availability in comparison to their brominated
and iodinated counterparts, the DEa values determined for
these desirable substrates (substituted chloropyridines and
chloroheteroarenes) quantify the effect of structural modifica-
tion (substituents and heteroarene core) on the activation
energy of the oxidative addition, which provides a useful tool
to predict regioselectivities in polychlorinated systems.
This work was financially supported by the University of Ant-
werp (BOF), the Hercules foundation, the Research Foundation
- Flanders (FWO), the CNRS (Centre National de la Recherche
Scientifique) and ENS (Ecole Normale Supꢀrieure).
Keywords: arenes
· homogeneous catalysis · kinetics ·
oxidative addition · reaction mechanisms
[1] a) Palladium in Heterocyclic Chemistry (Eds.: J. J. Li, G. W. Gribble), Perga-
mon, Amsterdam, 2006; b) J. P. Corbet, G. Mignani, Chem. Rev. 2006,
106, 2651–2710; c) K. C. Nicolaou, S. A. Snyder, Classics in Total Synthesis
II, Wiley-VCH, Weinheim, 2003; d) Science of Synthesis: Cross coupling
and Heck-Type Reactions Vol. 1–3 (Eds.: G. A. Molander, J. P. Wolfe, M.
Larhed), Thieme, Stuttgart, 2013.
[2] A. M. Rouhi, Chem. & Eng. News 2004, 82, 49–58.
[3] a) T. A. Unger, Pesticide Synthesis Handbook, Noyes, Park Ridge 1996;
b) A. Kleemann, J. Engel, B. Kutscher, D. Reichert, Pharmaceutical Sub-
stances: Syntheses, Patents, Applications Of The Most Relevant APIs,
Thieme, Stuttgart, 2009.
[4] J. A. Ragan, J. W. Raggon, P. D. Hill, B. P. Jones, R. E. McDermott, M. J.
Munchhof, M. A. Marx, J. M. Casavant, B. A. Cooper, J. L. Doty, Y. Lu, Org.
Process Res. Dev. 2003, 7, 676–683.
[5] For transmetalation rates involving [(Het)PdII(X)] complexes, see: S. Ver-
beeck, C. Meyers, P. Franck, A. Jutand, B. U. W. Maes, Chem. Eur. J. 2010,
16, 12831–12837; for reductive elimination rates involving [(Het)P-
dII(NR’R’’)] complexes, see: a) M. W. Hooper, J. F. Hartwig, Organometal-
lics 2003, 22, 3394–3403; b) M. Yamashita, J. F. Hartwig, J. Am. Chem.
Soc. 2004, 126, 5344–5345; c) Q. Shen, J. F. Hartwig, J. Am. Chem. Soc.
2007, 129, 7734–7735.
[6] For rate constants of oxidative additions of (pseudo)haloarenes to
[Pd0Ln] (L=PPh3), see: a) A. Jutand, Chem. Rev. 2008, 108, 2300–2347;
b) J. Fauvarque, F. Pflꢅger, M. Troupel, J. Organomet. Chem. 1981, 208,
419–427; c) C. Amatore, F. Pflꢅger, Organometallics 1990, 9, 2276–
2282; d) C. Amatore, A. Jutand, F. Khalil, M. A. M’Barki, L. Mottier, Orga-
nometallics 1993, 12, 3168–3178; e) A. Jutand, B. Noverges, unpublish-
ed work; f) A. Kurbangalieva, D. Carmichael, K. K. (Mimi) Hii, A. Jutand,
Chem. Eur. J. 2014, 20, 1116–1125; g) It is known that in the absence of
added phosphine, some trans-[Het-PdX(PPh3)2] complexes generated in
the oxidative addition of heteroaromatic halides are in equilibrium with
a binuclear form [{Het-PdX(PPh3)}2], which releases PPh3 upon forma-
tion (see: T. A. Anderson, R. J. Barton, B. E. Robertson, K. Venkatasubra-
manian, Acta Crystallogr. Sect. C 1985, 41, 1171–1174; R. Bertani, A.
Berton, F. Di Bianca, B. Crociani, J. Organomet. Chem. 1986, 303, 283–
299; K. Isobe, K. Nanjo, Y. Nakamura, S. Kawaguchi, Bull. Chem. Soc. Jpn.
1986, 59, 2141–2149). This additional PPh3 may intervene in the equi-
librium yielding [Pd0L2] with a retarding effect on the oxidative addi-
tion. The equations used in this work (see Supporting Information) do
not take this dimerization into account. As in most cases the equilibri-
um is in favor of the monomeric oxidative addition complex; the equa-
tions are a very good approximation. Indeed, in many cases, even in
the absence of added PPh3, a perfect straight line was obtained for
a conversion of up to 80% (e.g., Figure 1b; Figures S12–S14, S16, S21,
S23, S24, S43 in the Supporing Information), which shows that the re-
lease of PPh3 from the monomeric [Het-PdX(PPh3)2] is a slow process
that did not affect the rate of the oxidative addition, even for the slow-
est reactions as those involving 2-chloropyridines (e.g., Figures S12–
S14, S16, S43 in the Supporting Information). However, to avoid any
significant influence of the released PPh3, koa KL values were calculated
using data between 0 and 50% conversion. In this way, the amount of
PPh3 released in the dimerization remained small and did not affect the
rate of the oxidative addition. The high R2 values obtained for the Ham-
mett plots for the substituted 2-chloro- and 2-bromopyridines indicate
that this approximation is justified.
Experimental Section
General procedure for kinetic measurements of the oxidative addi-
tion of HetX to [Pd0(PPh3)2] generated from [Pd0(PPh3)4] by means
of chronoamperometry at a rotating disk electrode (RDE)
All experiments were performed in a thermostatted (258C) three-
electrode cell connected to a Schlenk line under argon. The coun-
ter electrode was a platinum wire of approximately 1 cm2 apparent
surface area. The reference was a saturated calomel electrode sep-
arated from the solution by a bridge filled with DMF (2 mL) con-
taining nBu4NBF4 (0.3m). Distilled and degassed DMF (18 mL) con-
taining nBu4NBF4 (0.3m) was poured into the cell followed by
[Pd0(PPh3)4] (41.6 mg, 0.036 mmol, C0 =2 mm). The kinetic measure-
ments were performed at a rotating gold disk electrode (d=2 mm)
with an angular velocity of 105 radsꢀ1 (Radiometer controvit). The
RDE was polarized at +0.35 V versus SCE on the plateau of the oxi-
dation wave of [Pd0(PPh3)3] (the major species generated in solu-
tion from [Pd0(PPh3)4]) allowing measurement of the initial oxida-
tion current io0x, which is proportional to the initial concentration of
[Pd0(PPh3)3] (C0). Substrate HetX (X=Cl, Br, I) was then added into
the cell. The decrease of the oxidation current iot x (proportional to
[Pd0(PPh3)3] at t) was recorded versus time. The same procedure
was employed in THF except that the RDE was polarized at
+0.45 V versus SCE. All plotting of data and linear regression was
performed using Kaleidagraph version 4.5 and MSExcel. Hammett
plots and associate 1 values were obtained by forcing through
(0,0).
[7] Only in cases with reversible oxidative addition will the transmetalation
become important as a selectivity governing step: a) G. Espino, A. Kur-
bangalieva, J. M. Brown, Chem. Commun. 2007, 1742–1744; b) A. Aria-
Chem. Eur. J. 2015, 21, 1 – 9
www.chemeurj.org
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fard, Z. Lin, I. J. S. Fairlamb, Organometallics 2006, 25, 5788–5794; for
examples dealing with the role of reversible oxidative addition in selec-
tive Pd0-catalyzed intramolecular cross-couplings of polyhalogenated
substrates, see: c) S. G. Newman, M. Lautens, J. Am. Chem. Soc. 2010,
132, 11416–11417; d) D. A. Petrone, M. Lischka, M. Lautens, Angew.
Chem. Int. Ed. 2013, 52, 10635–10638; Angew. Chem. 2013, 125, 10829–
10832.
[15] Theoretical studies of the oxidative addition of aryl halides to mono-
and bis-ligated Pd0 point towards a concerted mechanism. For some
recent examples, see: a) M. Ahlquist, P. Fristrup, D. Tanner, P.-O. Norrby,
Organometallics 2006, 25, 2066–2073; b) A. Ariafard, Z. Lin, Organome-
tallics 2006, 25, 4030–4033; c) R. Fazaeli, A. Ariafard, S. Jamshidi, E. S.
Tabatabaie, K. A. Pishro, J. Organomet. Chem. 2007, 692, 3984–3993;
d) K. C. Lam, T. D. Marder, Z. Lin, Organometallics 2007, 26, 758–760;
e) M. Ahlquist, P.-O. Norrby, Organometallics 2007, 26, 550–553; f) J. D.
Hicks, A. M. Hyde, A. M. Cuezva, S. L. Buchwald, J. Am. Chem. Soc. 2009,
131, 16720–16734; Only when solvent was incorporated in the DFT
study involving aryl halides was a SNAr mechanism predicted, see:
g) H. M. Senn, T. Ziegler, Organometallics 2004, 23, 2980–2988. For re-
views and an account, see h) M. Garcꢆa-Melchor, A. A. C. Braga, A.
Lledꢇs, G. Ujaque, F. Maseras, Acc. Chem. Res. 2013, 46, 2626–2634; i) L.
Xue, Z. Lin, Chem. Soc. Rev. 2010, 39, 1692–1705; j) K. J. Bonney, F.
Schoenebeck, Chem. Soc. Rev. 2014, 43, 6609–6638.
[16] a) R. G. Parr, W. Yang, Density-Functional Theory of Atoms and Molecules,
Oxford University Press, Oxford, 1989; b) GAUSSIAN 09, (Revision D.01),
M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Na-
katsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G.
Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Ha-
segawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven,
J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E.
Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Ra-
ghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N.
Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo,
J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakr-
zewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Dan-
iels, ꢈ. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox,
Gaussian Inc. Wallingford CT, 2009; c) R. Krishnan, J. S. Binkley, R. Seeger,
J. A. Pople, J. Chem. Phys. 1980, 72, 650–654; d) T. Clark, J. Chandrase-
khar, G. W. Spitznagel, R. V. R. Schleyer, J. Comput. Chem. 1983, 4, 294–
301; e) L. von Szentpꢉly, P. Fuentealba, H. Preuss, H. Stoll, Chem. Phys.
Lett. 1982, 93, 555–559; f) M. N. Glukhovtsev, A. Pross, M. P. McGrath, L.
Radom, J. Chem. Phys. 1995, 103, 1878–1885; g) J. P. Perdew, K. Burke,
M. Ernzerhof, Phys. Rev. Lett. 1996, 77, 3865–3868; h) C. Adamo, V. J.
Barone, J. Chem. Phys. 1999, 110, 6158–6170; i) J. P. Blaudeau, M. P.
McGrath„ L. A. Curtiss, L. Radom, J. Chem. Phys. 1997, 107, 5016; j) R.
Coquet, M. Tada, Y. Iwasawa, Phys. Chem. Chem. Phys. 2007, 9, 6040–
6046; k) S. Miertus, E. Scrocco, J. Tomasi, Chem. Phys. 1981, 55, 117; l) G.
Scalmani, M. J. Frisch, B. Mennucci, J. Tomasi, R. Cammi, V. Barone, J.
Chem. Phys. 2006, 124, 094107; m) J. P. Foster, F. Weinhold, J. Am. Chem.
Soc. 1980, 102, 7211–7218; n) It has been shown that dispersion effects
were closely related to entropic factors and were therefore crucial for
the comparison of associative and dissociative pathways in oxidative
additions of Pd complexes to aryl halides and triflates. For recent exam-
ples, see: E. Lyngvi, I. A. Sanhueza, F. Schoenebeck, Organometallics
2015, 34, 805–812; C. L. McMullin, J. Jover, J. N. Harvey, N. Fey, Dalton
Trans. 2010, 39, 10833–10836 and references cited; o) S. Grimme, J.
Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 2010, 132, 154104; p) L.
Castro, E. Kirillov, O. Miserque, A. Welle, L. Haspeslagh, J.-F. Carpentier,
L. Maron, ACS Catal. 2015, 5, 416–425.
[8] For reviews dealing with regioselective cross-coupling reactions, see:
a) I. J. S. Fairlamb, Chem. Soc. Rev. 2007, 36, 1036–1045; b) S. Schrçter,
C. Stock, T. Bach, Tetrahedron 2005, 61, 2245–2267; c) R. Rossi, F. Bellina,
M. Lessi, Adv. Synth. Catal. 2012, 354, 1181–1255; d) Z. Hassan, T. Pato-
nay, P. Langer, Synlett 2013, 412–423; e) J. R. Wang, K. Manabe, Synthe-
sis 2009, 1405–1427; f) A. R. Kapdi, D. Prajapati, RSC Adv. 2014, 4,
41245. For selected examples, see: g) S.-Y. Lin, C.-L. Chen, Y.-J. Lee, J.
Org. Chem. 2003, 68, 2968–2971; h) I. C. Christoforou, P. A. Koutentis,
Org. Biomol. Chem. 2006, 4, 3681–3693; i) R. Pereira, A. Furst, B. Iglesias,
P. Germain, H. Gronemeyer, A. R. de Lera, Org. Biomol. Chem. 2006, 4,
4514–4525; j) S. T. Handy, T. Wilson, A. Muth, J. Org. Chem. 2007, 72,
8496–8500; k) E. Maerten, M. Sauthier, A. Mortreux, Y. Castanet, Tetrahe-
dron 2007, 63, 682–689; l) J. Liu, A. E. Fitzgerald, N. S. Mani, J. Org.
Chem. 2008, 73, 2951–2954; m) A. Seggio, A. Jutand, M. G. Priem, F.
Mongin, Synlett 2008, 2955–2960; n) H. Hikawa, Y. Yokoyama, Tetrahe-
dron 2010, 66, 9552–9559; o) B. Noverges, C. Mollar, M. Medio-Simon,
G. Asensio, Adv. Synth. Catal. 2013, 355, 2327–2342; p) T. H. M. Jonckers,
B. U. W. Maes, G. L. F. Lemiꢁre, R. Dommisse, Tetrahedron 2001, 57,
7027–7034;.q) B. U. W. Maes, K. T. J. Loones, T. H. M. Jonckers, G. L. F. Le-
miꢁre, R. A. Dommisse, A. Haemers, Synlett 2002, 1995–1998; r) J. T.
Kuethe, A. Wong, I. W. Davies, J. Org. Chem. 2004, 69, 7752–7754;
s) K. T. J. Loones, B. U. W. Maes, C. Meyers, J. Deruytter, J. Org. Chem.
2006, 71, 260–264; t) C. S. Bryan, M. Lautens, Org. Lett. 2010, 12, 2754–
2757; u) X. Dai, Y. Chen, D. Garrell, H. Liu, L. Zhang, S. Palani, G. Hughes,
R. Nargund, J. Org. Chem. 2013, 78, 7758–7763; v) L. M. Recnik, M. A. El
Hameid, M. Haider, M. Schnꢅrch, M. D. Mihovilovic, Synthesis 2013, 45,
1387–1405; w) S. Reimann, P. Ehlers, A. Petrosyan, S. Kohse, A. Span-
nenberg, A. E. Surkus, T. V. Ghochikyan, A. S. Saghyan, S. Lochbrunner,
O. Kꢅhn, R. Ludwig, P. Langer, Adv Synth. Catal. 2014, 356, 1987–2008.
For a prediction of regioselectivity in cross-coupling reactions based on
1H NMR chemical shift values, see: x) S. T. Handy, Y. Zhang, Chem.
Commun. 2006, 299–301.
[9] For comparative purposes (with previously reported 1 values),[6] the sp
values were used for Hammett analysis. For similar 1 values in classical
SNAr reactions, see: A. M. Porto, L. Altieri, A. J. Castro, J. A. Brieux, J.
Chem. Soc. B 1966, 963–972.
[10] E. V. Anslyn, D. A. Dougherty, Modern Physical Organic Chemistry, Univer-
sity Science Books, Sausalito, 2006.
[11] Electron-donating substituents could not be investigated for 2-chloro-
pyridine as their rate of oxidative addition was extremely slow at 258C.
[12] A 4-chloro substituent could not be investigated in this case due to
a potential competitive oxidative addition reaction at C4.
[13] a) A SNAr-type mechanism was proposed by Fitton and Rick for the oxi-
dative addition of halobenzenes to [Pd0(PPh3)2] with the cleavage of
the CꢀX bond as RDS. The proposal was based on the effect of sub-
stituents in ArCl on the rate of the oxidative addition. P. Fitton, E. A.
Rick, J. Organomet. Chem. 1971, 28, 287–291; b) A SNAr-type mecha-
nism was proposed by Portnoy and Milstein for the oxidative addition
of 4-Z-C6H4Cl to [Pd0(dippp)], generated from [Pd0(dippp)2] in dioxane
(dippp=1,3-bisdiisopropylphosphinopropane). The mechanistic propos-
al is based on a Hammett plot featuring a high 1 value of +5.2. How-
ever, the study was not extended to bromo- and iodobenzenes. M.
Portnoy, D. Milstein, Organometallics 1993, 12, 1665–1673.
[14] For theoretical studies of the oxidative addition of heteroaryl halides to
[Pd0L2] revealing a concerted mechanism, see: a) C. Y. Legault, Y. Garcia,
C. A. Merlic, K. N. Houk, J. Am. Chem. Soc. 2007, 129, 12664–12665; b) Y.
Garcia, F. Schoenebeck, C. Y. Legault, C. A. Merlic, K. N. Houk, J. Am.
Chem. Soc. 2009, 131, 6632–6639; c) W. A. Herrebout, N. Nagels, S. Ver-
beeck, B. Van der Veken, B. U. W. Maes, Eur. J. Org. Chem. 2010, 3152–
3158.
[17] This is in accordance with SNAr reactions with p-nitrophenoxide in
which chloropyrazine possesses a 3.4-fold increased rate constant com-
pared with that of 3-chloropyridazine, see: T. L. Chan, J. Miller, Aust. J.
Chem. 1967, 20, 1595–1600.
[18] In classical SNAr reactions a higher reactivity of 2-chlorothiazole versus
2-chloropyridine was also found, see: T. L. Gilchrist, Heterocyclic Chemis-
try, Pitman Publishing, London, 1985, p. 211.
[19] M. Bosco, L. Foriani, V. Liturri, P. Riccio, P. E. Todesco, J. Chem. Soc. B
1971, 1373–1376.
Received: November 24, 2014
Published online on && &&, 0000
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Chem. Eur. J. 2015, 21, 1 – 9
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8
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Full Paper
FULL PAPER
X changes everything: Kinetics of the
oxidative additions of HetX (X=I, Br, Cl)
to [Pd0(PPh3)2] generated from
&
Reaction Mechanisms
B. U. W. Maes,* S. Verbeeck, T. Verhelst,
A. Ekomiꢀ, N. von Wolff, G. Lefꢁvre,
E. A. Mitchell, A. Jutand*
[Pd0(PPh3)4] and DFT calculations reveal
a mechanism that, contrary to the gen-
erally accepted concerted mechanism,
depends on the nature of X. The data
point to an unprecedented SNAr-type
mechanism for X=Br or Cl, whereas
a classical concerted mechanism is at
play for X=I (see scheme).
&& – &&
Oxidative Addition of
Haloheteroarenes to Palladium(0):
Concerted versus SNAr-Type
Mechanism
Chem. Eur. J. 2015, 21, 1 – 9
www.chemeurj.org
9
ꢂ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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&
These are not the final page numbers! ÞÞ