Experimental study of the [ZnCl2(THF)2] catalyzed cis/trans-isomerization of [Pd(C6Cl2F3)Me(PPh3)2] and of the transmetalation of trans-[PdCl(C6Cl2F3)(PPh3)2] with [ZnMeCl(THF)2]

Article abstract of DOI:10.1016/j.ica.2020.120206

The kinetics of the transmetalation reaction between trans-[PdCl(C₆Cl₂F₃)(PPh₃)₂] and [ZnMeCl(THF)₂] shows a complex dependence on [PPh₃] for the rate of formation of different reaction products: cis and trans-[Pd(C₆Cl₂F₃)Me(PPh₃)₂], trans-[PdClMe(PPh₃)] (which further reacts with [ZnClMe(THF)₂]), and [Zn(C₆Cl₂F₃)Cl(THF)₂]. To better understand the system the reactions between cis and trans-[Pd(C₆Cl₂F₃)Me(PPh₃)₂] and [ZnCl₂(THF)₂] (the retro-transmetalation reactions) and their kinetic dependence on [PPh₃] were studied. These reactions lead to the formation of trans-[PdClMe(PPh₃)] and [Zn(C₆Cl₂F₃)Cl(THF)₂] as main products. Additionally, the experiments show that the isomerization of cis to trans-[Pd(C₆Cl₂F₃)Me(PPh₃)₂] is catalyzed by [ZnCl₂(THF)₂]. In this catalyzed isomerization the concentration of PPh₃ is involved in two ways: It modulates the concentration of the organozinc [Zn(C₆Cl₂F₃)Cl(THF)₂], and also it shifts a ligand substitution equilibrium in the palladium complex, producing an anomalous dependence of the reaction rate on the concentration of triphenylphosphine.

Full text of DOI:10.1016/j.ica.2020.120206

Inorganica Chimica Acta 517 (2021) 120206
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Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Research paper
Experimental study of the [ZnCl2(THF)2] catalyzed cis/trans-isomerization
of [Pd(C6Cl2F3)Me(PPh3)2] and of the transmetalation of trans-[PdCl
(C6Cl2F3)(PPh3)2] with [ZnMeCl(THF)2]
*
´
Desire Carrasco, Juan A. Casares
´
IU CINQUIMA/Química Inorganica, Facultad de Ciencias, Universidad de Valladolid, 47071-Valladolid, Spain
A R T I C L E I N F O
A B S T R A C T
The kinetics of the transmetalation reaction between trans-[PdCl(C6Cl2F3)(PPh3)2] and [ZnMeCl(THF)2] shows a
complex dependence on [PPh3] for the rate of formation of different reaction products: cis and trans-[Pd
(C6Cl2F3)Me(PPh3)2], trans-[PdClMe(PPh3)] (which further reacts with [ZnClMe(THF)2]), and [Zn(C6Cl2F3)Cl
(THF)2]. To better understand the system the reactions between cis and trans-[Pd(C6Cl2F3)Me(PPh3)2] and
[ZnCl2(THF)2] (the retro-transmetalation reactions) and their kinetic dependence on [PPh3] were studied. These
reactions lead to the formation of trans-[PdClMe(PPh3)] and [Zn(C6Cl2F3)Cl(THF)2] as main products. Addi-
tionally, the experiments show that the isomerization of cis to trans-[Pd(C6Cl2F3)Me(PPh3)2] is catalyzed by
[ZnCl2(THF)2]. In this catalyzed isomerization the concentration of PPh3 is involved in two ways: It modulates
the concentration of the organozinc [Zn(C6Cl2F3)Cl(THF)2], and also it shifts a ligand substitution equilibrium in
the palladium complex, producing an anomalous dependence of the reaction rate on the concentration of
triphenylphosphine.
Dedicated to Prof. Maurizio Peruzzini on the
occasion of his retirement.
Keywords:
Cross-coupling
Fluoroaryls
Palladium
Transmetalation
Negishi reaction
1. Introduction
organozinc species involved change during the reaction course; for
instance when a diorganozinc [ZnR2(solv)2] reagents are used, the halo-
The Negishi reaction is a palladium or nickel catalyzed cross
coupling in which an aryl halide reacts with an organozinc nucleophile
(Scheme 1). The reaction is one of the most successful cross-coupling
systems and its utility has been widely recognized [1–3]. Although
most of the time the reaction works nicely using palladium catalysts, for
specific pairs of reagents the homocoupling products are competitively
formed. This happens when the transmetalation reactions, that are fast
and reversible, lead to an exchange of aryls between zinc and palladium
by a transmetalation/retro-transmetalation sequence or, alternatively,
by the direct aryl-by-aryl exchange between palladium and zinc
(Scheme 2
organozinc [ZnRX(solv)2] is produced during the reaction leading to a
different transmetalation reaction [6]. The speciation also depends on
reagents from which organozinc compounds are synthesized. The most
effective routes to form organozinc halides and diorganozinc com-
pounds involve transmetalation reactions between ZnX2 and LiR or
organomagnesium reagents, and the final solutions of the organozinc
compound contain significant amounts of LiX or MgX2 that can react
with the organozinc reagents [7–9]. The coordination of anions to the
organozinc species leads to anionic species “zincates”, whose exact
composition is not always easily established, and whose reactivity dif-
fers substantially from neutral organozinc reagents [7–25]. Finally, the
halogen coordinated to the zinc in halo-organozinc reagents, (whose
halogen may proceed from any of the reagents used in its synthesis), also
plays a relevant role. A. Lei et al. carried out mechanistic studies using in
situ IR and X-Ray absorption spectroscopy [26–28]. They found that in
phenylzinc derivatives the Zn-C bond distance increases upon changing
the halide anion from chloride to bromide and to iodide and that a
higher transmetalation rate occurs when organozinc with longer Zn-C
bond distances are employed.
The study of the transmetalation is important because sometimes it is
the rate limiting step, and because of its relevance to the selectivity of
the reaction. Unfortunately, it is not an easy task, not only because the
high reaction rate of this step, but also because of the difficulties
regarding the speciation of zinc reagents that complicates the compu-
tational modeling of the systems [4]. First of all, the consideration or not
of solvent molecules coordinated to the zinc may change the energy and
the geometry of intermediate states of the reaction [5]. In addition, the
* Corresponding author.
E-mail address: juanangel.casares@uva.es (J.A. Casares).
https://doi.org/10.1016/j.ica.2020.120206
Received 25 September 2020; Received in revised form 8 December 2020; Accepted 13 December 2020
Available online 18 December 2020
0020-1693/Published by Elsevier B.V.

D. Carrasco and J.A. Casares
Inorganica Chimica Acta 517 (2021) 120206
isomerization of isolated [PdR1R2L2] complexes is through three-
coordinated species [PdR1R2L] (Scheme 3). This mechanism seems to
be quite general for palladium(II) and platinum(II) organometallics
[34–38]. However the catalysis is often carried out under an excess of
phosphine in order to prevent the decomposition of Pd(0) intermediates,
so this pathway becomes inaccessible under catalytic conditions.
Fortunately for the cross-coupling reaction, organozinc, as other or-
ganometallics, catalyze the trans-cis isomerization (Scheme 3)
[32,33,39–41].
Scheme 1. General scheme of the Negishi reaction.
As stated above, in transmetalation reactions organozinc reagents
are able to exchange their organic group for a halogen, but also for
another organic group from the organopalladium complex. The first
example of an aryl-for-aryl exchange was observed in 1994 on the re-
action between p-tolylzinc chloride and the complex [PdBzBr(ArBIAN)]
(Bz = benzyl; ArBIAN = bis(aryliminio)acenaphthene), reported by
Elsevier et al. [29]. A similar reaction takes place in the C(sp3)-C(sp2)
cross-coupling with alkylzinc reagents: On the study of the trans-
metalation of trans-[PdRfCl(PPh3)2] (1) (Rf = 3,5-dichloro-2,4,6-tri-
oorophenyl), with [ZnMe2(solv)2] and [ZnMeCl(solv)2], we found the
formation of fluoroaryl-zinc species resulting from the exchange of Rf by
Me groups between metals [6]. The exchange of non-fluorinated aryls by
alkylzinc is also a fast process that often hinders the analysis or the re-
action products [30]. In the aryl-aryl cross coupling reaction this
problem can be overcome by a judicious choice of the organozinc and
haloaryl groups. In this sense A. Lei et al. analyzed the factors that
produced the aryl by aryl exchange in the cross-coupling reaction of aryl
iodides Ar1X with arylzinc halides [ZnAr2Cl(solv)2], catalyzed by
[PdCl2(dppf)]. Depending on the substituents in the ArI group the re-
action yields the cross-coupling product or the exchange products
[ZnAr1X(solv)2] and “Ar2PdAr2” that eventually render the homocou-
pling product [31].
The lack of stereochemical selectivity in the transmetalation was
discussed in experimental and computational mechanistic studies of the
reaction between trans-[PdRClL2] (R = Me or Rf, L PPh2Me or PPh3) and
[ZnMeCl(solv)2] or [ZnMe2(solv)2], [4,32,33,42] and is a consequence
of the excellent nucleophilicity of the C-Zn bond, that allows its behavior
as donor ligand instead of the phosphine ligand opening a pathway of
phosphine substitution that competes with the direct substitution of the
halogen. But even if the ligand L is inert to the substitution, organozinc
reagents are able to find a relatively “flat” reaction surface connecting
different transition states that allows the fast equilibria between in-
termediates that lead to different isomers. This, along with the small ΔH
associated to the exchange between C-Zn and C-Pd bonds, is the reason
by which organozinc catalyze the cis-trans isomerization of [PdR1R2L2]
complexes. The isomerization catalyzed by poor nucleophiles, such as
[ZnCl2(solv)2] remains unproven until now, although the role of zinc
halides in other steps of the Negishi reaction has been reported [25].
In this work we study the effect of the ligand in solution on the
transmetalation between trans-[PdRfCl(PPh3)2] (1) and [ZnMeCl
(THF)2] and on the retro-transmetalation system formed by
[ZnCl2(THF)2] and the complexes cis and trans-[PdRfMe(PPh3)2] (2 and
3). We chose these systems because the Rf-Me coupling step is slow, the
initial transmetalation isomers, 2 and 3, are stable, and also because the
use of fluorinated ligands provides a useful label in 19F NMR spectros-
copy allowing the monitoring of the reaction [43].
When complexes with monodentate ligands, such as phosphines, are
used as catalysts the stereochemistry of the transmetalation is also an
issue. The transmetalation of complexes of the type [PdXR1L2] with
reagents [ZnER2(THF)2] (E = halogen or R2) in THF (THF: tetrahydro-
furan) produces mixtures of cis and trans-[PdR2R1L2] [6,32,33]. This
point is relevant in catalytic systems because the reductive elimination
step can only take place from the cis isomer, thus the formation of the
trans isomer means that a fraction of the catalyst is accumulated in a
relatively inert form. The most accessible pathway for the trans-cis
2. Experimental
All the manipulations were performed under N2 or Ar atmosphere,
using standard Schlenk techniques unless otherwise stated. Solvents
were dried using a solvent purification system SPS PS-MD-5 or distilled
from appropriate drying agents under nitrogen according to literature
[44], and stored over 3 A zeolites for a week. The residual amount of
water (in the range 1–5 ppm) was measured with a Metler Toledo C20KF
Karl Fischer instrument. Prior to their use, solvents were degassed by
three freeze–pumpthaw cycles. NMR spectra were recorded on Bruker
AV 400 or Agilent 500-MR instruments equipped with variable-
temperature probes. Chemical shifts are reported in ppm from tetra-
methylsilane (1H and 13C), CCl3F (19F), at 298 K unless otherwise stated.
The temperature for the NMR probe was calibrated with an ethylene
glycol standard (high temperature) and with a methanol standard (low
Scheme 2. Processes that lead to homocoupling products in the Negishi reac-
tion: (a) through a transmetalation/retro-transmetalation sequence, (b) and (c)
through aryl-by-aryl exchange and transmetalation reactions.
Scheme 3. Trans-cis isomerization routes.
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D. Carrasco and J.A. Casares
Inorganica Chimica Acta 517 (2021) 120206
halide, a solution of [ZnRfCl(THF)2] in THF was prepared reacting in
THF [ZnCl2(THF)2] with the stoichiometric amount of Ag(C6Cl2F3). A
[ZnMeCl(THF)2] solution was prepared by mixing a solution of
[ZnCl2(THF)2] (9.4 mL, 1.1 mol⋅Lꢀ 1) in THF with a solution of ZnMe2
(5.0 mL, 2.0 mol⋅Lꢀ 1) in toluene, under argon. 1H NMR (THF, acetone‑d6
capillary, 298 K): δ ꢀ 0.65 ppm (s, 3H).
Table 1
Chemical shifts (ppm) of the nuclei of F2,6 of the organometallic compounds used
for the quantification of their concentration in THF solutions.
trans-[PdRfCl
cis-[PdRfMe
trans-[PdRfMe
[ZnRfCl
(THF)2]
Rf–CH3
(PPh3)2]
(PPh3)2]
(PPh3)2]
ꢀ 91.9
ꢀ 90.6
ꢀ 91.0
ꢀ 92.1
ꢀ 117.4
(t, 4JF-P = 7
Hz)
(d, 4JF-P = 10
Hz)
(t, 4JF-P = 3 Hz)
(s)
(s)
2.1. Kinetic experiments. Typical procedure
In a standard experiment an NMR tube cooled to 193 K was charged
with the palladium compound (9.9 × 10ꢀ 3 mmol), zinc compound (0.20
mmol), and THF until a volume of 0.60 mL. When the mixture was
dissolved in the THF, a coaxial capillary containing acetone‑d6 was
added and the sample was placed into the NMR probe that had been
previously thermostated at 298 K. The evolution of the reaction was
monitored by 19F NMR spectroscopy without the use of internal stan-
dard. 128 scan spectra were recorded employing 33,768 complex points
temperature) [45]. In the 19F NMR spectra recorded in non-deuterated
THF, a coaxial tube containing acetone-d6 was used to maintain the
lock to 2H signal, and the chemical shifts in 19F NMR are reported
relative to 1,3,5-trichloro 2,4,6-trifluorobencene (δ = ꢀ 115.1 ppm) as
internal standard. Complexes cis-[PdRfMe(PPh3)2] [6], trans-[PdRfMe
(PPh3)2] [6], trans-[PdRfCl(PPh3)2] [46], cis-[PdMe2(PPh3)2] and
trans-[PdClMe(PPh3)2] [47], and Ag(C6Cl2F3) [48], were prepared and
characterized as reported in the literature. In order to identify the
chemical shift of the complex [ZnRfCl(THF)2] in the absence of residual
using a π/8 pulse length. The delay between spectra was of 20 s so that
one spectrum was recorded every five minutes. No significative varia-
tion of the overall integral values during the reaction course was noticed
in the experiments. Concentration-time data were obtained by integra-
tion of the 19F NMR signals corresponding to the fluorine nuclei in po-
sition ortho to the palladium whose chemical shirts are collected in
Table 1. The kinetic order was obtained by the initial rates method, and
kinetic rate constants were obtained by non-linear minimum square
fitting of the experimental data points to kinetic models, with the aid of
the software “COPASI” [49].
3. Results and discussion
In a previous work we have shown that, under a large excess of
[ZnMeCl(THF)2] that resembles catalytic conditions, the reaction be-
tween trans-[PdRfCl(PPh3)2] and [ZnMeCl(THF)2] produces preferen-
tially cis-[PdRfMe(PPh3)2] that isomerizes to the trans isomer [6]. The
reaction also produces [ZnRfCl(THF)2] and trans-[PdMeCl(PPh3)2]
which further reacts with [ZnMeCl(THF)2] to give cis-[PdMe2(PPh3)2].
Fig. 1 shows the typical reaction profile monitored by 19F NMR of the
reaction of 1 with [ZnClMe(THF)2] and compares it with the same
experiment in which an excess of PPh3 has been added.
The most obvious difference between the reactions with and without
added phosphine is the reaction rate. The half-life of 1 is about 30 min in
the first case and about five hours in the second. The kinetic experiments
under different concentrations of PPh3 (Table S1 in supplementary
material) show that the reaction is strongly retarded by the addition of
free PPh3, the kinetic order on [PPh3] for the disappearance of trans-
[PdRfCl(PPh3)2] has been measured by the initial rates method, giving
roughly a value of ꢀ 1. This suggests a transmetalation mechanism that
involves the substitution of a phosphine ligand by [ZnMeCl(THF)2] as
first step. But there is also a significant difference in the ratio of the
products of the reaction: In the absence of added phosphine [ZnRfCl
(THF)2] is formed very quickly, reaching in a few minutes the equilib-
rium concentration that then changes slightly with the composition of
the reaction mixture, the cis isomer 2 is formed quickly at the beginning
of the reaction and the trans isomer 3 is formed at an slower pace,
however under added PPh3 the concentration of [ZnRfCl(THF)2] re-
mains in “quasi steady-state” concentration, and 2 and 3 are formed in
their equilibrium ratio.
The role of [ZnRfCl(THF)2] in the reaction is not clear, and several
mechanisms may be invoked to explain its formation. This organozinc
could be just an unwanted by-product formed by a transmetalation retro-
transmetalation sequence, or it could be formed in a direct methyl-by-
aryl exchange between palladium and zinc. The system includes
several competitive pathways and reversible reactions and is too com-
plex to allow the obtention of a detailed picture or quantitative values
for rate constants. Additional information about the equilibria involved
in this system was obtained from the study of the reverse reaction.
Fig. 1. Concentrations time plot of the reactions between trans-[PdRfCl
(PPh3)2] and [ZnMeCl(THF)2] ([trans-[PdRfCl(PPh3)2] = 1.6*10ꢀ 2 M, [ZnMeCl
(THF)2]0 = 0.33 mol⋅Lꢀ 1). Upper plot: T = 293 K, no phosphine added; lower
plot T = 298 K; [PPh3] = 0.0174 mol⋅Lꢀ 1
.
3

D. Carrasco and J.A. Casares
Inorganica Chimica Acta 517 (2021) 120206
formation of [ZnRfCl(THF)2] is particularly informative. Starting from 2
(Fig. 3) [ZnRfCl(THF)2] is formed very fast at the beginning of the re-
action, its concentration reaches a maximum and then gently declines.
The initial reaction rate of formation of ZnRfCl(THF)2 is not sensitive to
[PPh3], and it is possible to obtain a common value of about 1.8⋅10ꢀ 6
molLꢀ 1sꢀ 1 for all the experiments, however, the maximum concentra-
tion of [ZnRfCl(THF)2] increases with the concentration of phosphine.
The same behavior is obtained starting from complex trans-[PdRfMe
(PPh3)2] (3) (Fig. 4) although the formation of [ZnRfCl(THF)2] from the
trans isomer is about one order of magnitude slower than from the cis,
and as consequence of the isomerization 3 to 2, the formation of [ZnRfCl
(THF)2] do not stop as suddenly as when starting from 2. To explain this
behavior, the reactions shown in Scheme 5 were proposed.
Scheme 4. Retro-transmetalation products formed in the reaction between cis-
[PdRfMe(PPh3)2] (2) or trans-[PdRfMe(PPh3)2] (3) with [ZnCl2(THF)2] in THF.
The formation of cationic species [PdMeL3]+ induced by Lewis acids,
such as organozinc derivatives, has been demonstrated previously [42],
and is not unexpected in the presence of a strong acid as [ZnCl2(THF)2].
In an attempt to detect the formation of [PdMeL3]+, the reaction of cis-
[PdRfMe(PPh3)2] (2) with [ZnCl2(THF)2] in the presence of PPh3 was
stopped after one hour by cooling the solution to ꢀ 20 ◦C. The 19F
spectrum shows the partial conversion of 2 to trans-[PdRfMe(PPh3)2]
(3), and the formation of [ZnRfCl(THF)2]. Accordingly, the 31P{1H}
spectrum shows the presence of 2, 3 and also [PdMeL3]+, characterized
by its AX2 spin system, in an amount that matches the amount of [ZnRfCl
(THF)2] observed in the 19F NMR spectrum (Fig. 5).
3.1. Retro-transmetalation experiments
The reactions between cis-[PdRfMe(PPh3)2] (2) or trans-[PdRfMe
(PPh3)2] (3) with [ZnCl2(THF)2] were studied. These mixtures form an
exchange system in which, in addition to the known cis/trans-[PdRfMe
(PPh3)2] isomerization equilibrium,[41] other products are formed such
as [ZnRfCl(THF)2] (4) and minor amounts of the trans-[PdRfCl(PPh3)2]
(1) (Scheme 4), as well as small amounts of the reductive elimination
product RfMe. Transmetalation equilibria are shifted to the formation of
[PdRfMe(PPh3)2] and [ZnCl2(THF)2], so that the reactions required a
large excess of [ZnCl2(THF)2] to be studied. The formation of the com-
pound [PdCl2(PPh3)2] was not observed even under a large excess of
[ZnCl2(THF)2].
Thus, the reaction shown in equilibrium 3, removes [PdMeCl
(PPh3)2] from the reaction medium shifting equilibria 1 and 2 to the
right so that a larger amount of [ZnRfCl(THF)2] is produced for higher
concentrations of PPh3.
The main effect of the addition of [ZnCl2(THF)2] to 2 or 3 is on the
cis/trans isomerization rate. In Fig. 2 the experimental graphics of the
isomerization with [ZnCl2(THF)2] are compared to the reaction without
added [ZnCl2(THF)2] (simulated course from experimental kinetic pa-
rameters), showing that the isomerization from cis- to trans-[PdRfMe
(PPh3)2] is faster in the presence of [ZnCl2(THF)2]. Note that at equi-
librium both complexes reach a concentration that can be measured by
NMR, therefore the isomerization rate can be measured starting from
either the cis or from the trans isomer. It is also clear from the graphics
that, irrespectively of the chosen starting system, the fastest reaction is
the formation of [ZnRfCl(THF)2]. It is worth noting that an induction
period was observed for the isomerization process that is coincident with
the time required for the formation of the maximum amount of [ZnRfCl
(THF)2].
Scheme 5 also explains the increase on the isomerization rate between
2 and 3 in the presence of [ZnCl2(THF)2], that is implicit in equations 1
and 2, but does not explain satisfactorily the dependence on [PPh3] of the
isomerization rates: the formation of trans-[PdRfMe(PPh3)2] (3) when
starting from cis-[PdRfMe(PPh3)2] (2) (Fig. 3) or the formation of 2 when
starting from 3 (Fig. 4). The shape of these curves is a sigmoid suggesting
an induction period, coincident with the formation of [ZnRfCl(THF)2] (4).
To explain this behavior another isomerization route, catalyzed by
[ZnRfCl(THF)2] was proposed (Scheme 6). This reaction is similar to that
studied for the isomerization of 2 and 3 in the presence of ZnMe2, and
involves the substitution of one phosphine ligand by the incoming
[ZnRfCl(THF)2] [32]. During this reaction the aryl group is exchanged
between the organozinc and the organopalladium.
The experimental data fit nicely with this complex scheme (see
supplementary information) in a wide interval of values for Keq(4), the
values of k5 and Keq(5) being dependent on this parameter. Thus,
although a good qualitative interpretation of the results is possible, the
obtention of a complete energy profile for the reaction system is not
possible with a reasonable number of experiments.
The dependence of the reaction on the concentration of PPh3 is not
identical for the different species involved. Figs. 3 and 4 show the
concentration–time plots for the reactions between [ZnCl2(THF)2] with
cis-[PdRfMe(PPh3)2] (2) (Fig. 3) and [ZnCl2(THF)2] with trans-[PdRfMe
(PPh3)2] (3) (Fig. 4). The disappearance of the starting complex, 2 or 3 is
almost insensitive to the concentration of PPh3. However, the plots
showing the formation of [ZnRfCl(THF)2] and the isomerization product
on each case (3 and 2 respectively) change noticeably with [PPh3]. The
Another interesting feature of this set of experiments is the behavior
of the species trans-[PdRfCl(PPh3)2] (1). This product is formed very
Fig. 2. Concentration/time plots for the reactions: a) 3 + [ZnCl2(THF)2] ([3]0 = 0.0165 mol⋅Lꢀ 1, [ZnCl2(THF)2]0 = 0.66 mol⋅Lꢀ 1, and [PPh3]0 = 0.0165 mol⋅Lꢀ 1), b)
2 + [ZnCl2(THF)2] ([2]0 = 0.0165 mol⋅Lꢀ 1, [ZnCl2(THF)2]0 = 0.66 mol⋅Lꢀ 1 and [PPh3]0 = 0.0158 mol⋅Lꢀ 1), and c) Simulated cis- to trans-[PdRfMe(PPh3)2]
isomerization reaction with [PPh3]0 = 0.0165 mol⋅Lꢀ 1. The simulation was done by using the data taken from Ref. [41].
4

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Inorganica Chimica Acta 517 (2021) 120206
Fig. 3. Concentration-time plots for the reactions between [ZnCl2(THF)2] and cis-[PdRfMe(PPh3)2] (2) at 298 K under different concentrations of PPh3 in THF. The
values on the table represent the initial concentration of PPh3 in molLꢀ 1. Starting conditions: [2]0 = 0.0160 mol⋅Lꢀ 1, [ZnCl2(THF)2]0 = 0.66 mol⋅Lꢀ 1. Note that the
vertical scale is different for each plot.
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D. Carrasco and J.A. Casares
Inorganica Chimica Acta 517 (2021) 120206
Fig. 4. Concentration/time plot for the reaction between [ZnCl2(THF)2] and trans-[PdRfMe(PPh3)2] (3) at 298 K under different concentrations of PPh3 in THF. The
values on the table represent the initial concentration of PPh3 in mol⋅Lꢀ 1. ([3]0 = 0.0160 mol⋅Lꢀ 1, [ZnCl2(THF)2]0 = 0.66 mol⋅Lꢀ 1). Note that the vertical scale is
different for each plot.
slowly in both systems, either starting from 2 or from 3, and is the
product of the retro-transmetalation of 1 with [ZnCl2(THF)2]. Equations
7 and 8 were introduced to account for this result (Scheme 7). A close
inspection of the experiments starting from trans-[PdRfMe(PPh3)2] (3)
in Fig. 4 shows that the initial rate of formation of trans-[PdRfCl(PPh3)2]
(1) is close to zero and that 1 is only formed when the reaction has
produced a significant amount of the isomer 2, so that k8 is assumed to
be negligible.
triphenylphosphine (Scheme 8). It should be pointed out that under a
large excess of [ZnMeCl(THF)2] the product [PdMeCl(PPh3)2] reacts to
produce cis and trans-[PdMe2(PPh3)2], but these complexes also ex-
change the methyl groups for fluoroaryls when reacting with fluoroar-
ylzinc derivatives, as shown previously in reactive systems with
[ZnMe2(THF)2] [32].
Finally, when the whole system is considered it is clear that the
number of kinetic parameters involved (rate and equilibrium constants)
is too large to allow the extraction of their actual values within the
desirable statistical validity. The rates of transmetalation are affected by
the concentration of PPh3 because this ligand affects the equilibria in
equations 4, 6, 9 and 10 involved in the transmetalation pathways, but
also because the concentration of the key complex [PdClMe(PPh3)2]
depends on the equilibrium 3. Since the actual equilibrium constant of
the equation 3 (Scheme 5) in unknown, the concentration of the inter-
mediate [PdClMe(PPh3)2] cannot be univocally stablished, and this af-
fects the values of the other rate constants. Additionally, other reactions
may be considered; for instance, the above mentioned transmetalation
of [PdClMe(PPh3)2] with [ZnMeCl(THF)2], which for the sake of clarity
has not been included in the schemes. This reaction has been previously
studied in systems with PPh2Me instead of PPh3 showing that the
complexes react very fast to give trans and cis-[PdMe2(PPh2Me)], but
the exact values for these rate constants on the system with PPh3 are not
available. In spite of these limitations, the reaction scheme depicted in
Scheme 9, provides a sound qualitative interpretation of the complex
system of the transmetalations related to the Negishi cross-coupling
reactions.
Turning back to the reaction between trans-[PdRfCl(PPh3)2] (1) and
[ZnMeCl(THF)2], the above described set of equations with their values
was used to simulate the behavior of this system. Starting from 1, the fast
formation of [ZnRfCl(THF)2] cannot be explained merely as result of the
reactions 1 and 2, since the amount of cis and trans-[PdRfMe(PPh3)2]
and of [ZnCl2(THF)2] at the beginning of the reaction is very small. The
dependence on [PPh3] is satisfactorily explained by introducing a pre-
equilibrium
in
which
[ZnClMe(THF)2]
substitutes
one
4. Conclusions
The study of the system formed by trans-[PdRfCl(PPh3)2], [ZnMeCl
(THF)2], and their products of reaction, shows some interesting features
of the transmetalation reactions with organozinc derivatives and palla-
dium complexes, such as: i) The almost complete absence of
Scheme 5. Retro-transmetalation of complexes 2 and 3 with [ZnCl2(THF)2] to
form [ZnRfCl(THF)2]. The capture of trans-[PdClMe(PPh3)2] by [ZnCl2(THF)2]
(eq. 3) shifts to the right equilibria 1 and 2.
6

D. Carrasco and J.A. Casares
Inorganica Chimica Acta 517 (2021) 120206
Scheme 7. Retro-transmetalation of complexes 2 and 3 with [ZnCl2(THF)2] to
form [ZnMeCl(THF)2] and complex 1.
Scheme 8. Scheme for the ligand dependent exchange of Rf and Me between
Fig. 5. 19F (F(2) and F(6) only) and 31P{1H} NMR of the reaction of 2 with
[ZnCl2(THF)2] in the presence of PPh3 showing the signals due to the cation
[PdMeL3]+. The spectra have been recorded at ꢀ 20 ◦C in THF.
complexes 1 and [ZnMeCl(THF)2].
stereoselectivity of the transmetalation reaction. As shown also in pre-
vious works the transmetalation lead to the cis or to the trans isomer
with a small difference on the reaction rates [33]. ii) The reaction is
reversible and the equilibrium is only slightly shifted towards the
products. Thus, mechanistic proposals that include transmetalation of
organozinc reagents should consider this step as a reversible reaction.
And iii) as shown in the studied system, the reactions of organometallic
species of palladium complexes containing halides as ligands with zinc
Scheme 6. Chemical equations that account for the cis- trans isomerization 2
Scheme 9. Set of equilibria that occur as a consequence of the reaction of
to 3 catalyzed by [ZnRfCl(THF)2].
complexes 1, 2 and 3 with [ZnCl2(THF)2] and with [ZnClMe(THF)2].
7

D. Carrasco and J.A. Casares
Inorganica Chimica Acta 517 (2021) 120206
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organometallics often produce the exchange of aryl or alkyl groups
competitively with the exchange of the organic group for the halogen.
Additionally, this work provides information about the reactions in
which zinc chloride participates, which is relevant not only because zinc
halides are formed during the Negishi reaction but also because they are
occasionally used as “additives”. It has been found that [ZnCl2(THF)2]
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action of complexes [PdRfMe(PPh3)2]. The isomerization occurs
through the exchange of Rf fluoroaryls between the cis or trans-[PdRfMe
(PPh3)2] complex and the organozinc [ZnRfCl(THF)2] formed in situ by
a retro-transmetalation reaction.
´
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´
Desire Carrasco: Investigation, Software, Writing - original draft.
Juan A. Casares: Conceptualization, Methodology, Software, Writing -
review & editing.
¨
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Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
[21] M.G. Organ, S. Avola, I. Dubovyk, N. Hadei, E.A.B. Kantchev, C.J. O’Brien,
C. Valente, A user-friendly, all-purpose Pd–NHC (NHC=N-heterocyclic carbene)
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Acknowledgments
[22] P. Eckert, M.G. Organ, A path to more sustainable catalysis: the critical role of LiBr
in avoiding catalyst death and its impact on cross-coupling, Chem. Eur. J. 26
(2020) 4861–4865, https://doi.org/10.1002/chem.202000288.
The authors thank the Spanish MINECO (project CTQ2016-80913-P),
[23] L.C. McCann, M.G. Organ, On the remarkably different role of salt in the cross-
coupling of arylzincs from that seen with alkylzincs, Angew. Chem. Int. Ed. 53 (17)
(2014) 4386–4389, https://doi.org/10.1002/anie.201400459.
´
Ministerio de Ciencia e Innovacion (project PID2019-111406GB-100),
´
and the Junta de Castilla y Leon (projects VA051P17 and VA062G18),
for financial support.
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K. Bohme, M.G. Organ, Identification of a higher-order organozincate intermediate
involved in Negishi cross-coupling reactions by mass spectrometry and NMR
spectroscopy, Chem. Eur. J. 17 (28) (2011) 7845–7851, https://doi.org/10.1002/
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Appendix A. Supplementary data
[25] P. Eckert, M. G. Organ. The role of LiBr and ZnBr2 on the cross-coupling of aryl
bromides with Bu2Zn or BuZnBr. Chem. – A Eur. J. 25 (2019), 15751–15754, doi:
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Supplementary data to this article can be found online at https://doi.
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