Second Comes First: Switching Elementary Steps in Palladium-Catalyzed Cross-Coupling Reactions

Article abstract of DOI:10.1002/chem.202001041

The electron-poor palladium(0) complex L₃Pd (L=tris[3,5-bis(trifluoromethyl)phenyl]phosphine) reacts with Grignard reagents RMgX and organolithium compounds RLi via transmetalation to furnish the anionic organopalladates [L₂PdR]

Full text of DOI:10.1002/chem.202001041

Accepted Article
Accepted Article
Title: Second Comes First: Switching Elementary Steps in Palladium-
Catalyzed Cross-Coupling Reactions
Authors: Marlene Kolter and Konrad Koszinowski
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202001041
Link to VoR: https://doi.org/10.1002/chem.202001041
01/2020

10.1002/chem.202001041
Chemistry - A European Journal
FULL PAPER
Second Comes First: Switching Elementary Steps in Palladium-
Catalyzed Cross-Coupling Reactions
Marlene Kolter and Konrad Koszinowski*[a]
Abstract: The electron-poor palladium(0) complex L3Pd (L = tris(3,5-
bistrifluoromethylphenyl)phosphine) reacts with Grignard reagents
RMgX and organolithium compounds RLi via transmetalation to
furnish the anionic organopalladates [L2PdR]−, as shown by negative-
ion mode electrospray-ionization mass spectrometry. These
palladates undergo oxidative additions of organyl halides R'X (or
related SN2-type reactions) followed by further transmetalation. Gas-
phase fragmentation of the resulting heteroleptic palladate(II)
complexes results in the reductive elimination of the cross-coupling
products RR'. This reaction sequence corresponds to a catalytic cycle,
in which the order of the elementary steps of transmetalation and
oxidative addition is switched relative to that of palladium-catalyzed
cross-coupling reactions proceeding via neutral intermediates. An
attractive feature of the palladate-based catalytic system is its ability
Scheme 1. Canonical catalytic cycle of a Pd-catalyzed cross-coupling reaction
to mediate challenging alkyl-alkyl coupling reactions. However, the
poor stability of the phosphine ligand L against decomposition
reactions so far prevents its successful use in practical applications.
between an organyl halide R’X and an organometallic reagent RM.
An intriguing way to overcome these difficulties makes use of
anionic organopalladate(0) complexes. As Kambe and coworkers
have shown, the nucleophilicity of these palladates exceeds that
of conventional neutral palladium(0) complexes such that they
readily react with alkyl halides.[11] The catalyst used by Kambe
and coworkers included 1,3-dienes as additives, which play an
essential role in stabilizing the anionic organopalladate(0)
complexes. 1,3-Dienes have the advantage of being cheap, but
they do not offer the same flexibility as phosphines for fine-tuning
the catalytic activity. We therefore wondered whether phosphine-
containing palladium complexes could also participate in a
catalytic cycle, in which the elementary step of the transmetalation
precedes that of the oxidative addition.
Introduction
Palladium-catalyzed cross-coupling reactions provide an
extremely efficient means for the formation of new carbon-carbon
bonds. These reactions are known to proceed via a common
catalytic cycle characterized by the elementary steps of oxidative
addition, transmetalation, and reductive elimination (Scheme 1).[1]
This sound mechanistic understanding has proven invaluable for
the rational design of new phosphine and N-heterocyclic carbene
ligands, without which cross-coupling reactions would not have
reached their current level of reliability and versatility.[2–7]
As we have shown previously, electron-poor phosphines, such as
L and, to a lesser extent LPh1 (Chart 1) stabilize anionic
palladate(0) complexes of the type LnPdX−, X = Cl, Br, I, OAc.[12,13]
Despite the power of modern palladium-catalyzed cross-coupling
reactions, shortcomings of these transformations remain. One of
the most pressing problems is the difficulty of alkyl-alkyl coupling.
These reactions are hindered by the reluctance of conventional
palladium catalysts to undergo oxidative additions of alkyl halides.
Even if such oxidative reactions take place, the resulting
intermediates are prone to β-hydrogen elimination if the
palladium-bound organyl group bears a hydrogen atom in β
position, as is the case for most alkyl residues.[8–10]
[a]
Dr. M. Kolter, Prof. Dr. K. Koszinowski
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstraße 2, 37077 Göttingen (Germany)
E-mail: konrad.koszinowski@chemie.uni-goettingen.de
Chart 1. Phosphine ligands used for the generation of palladate complexes.
Supporting information for this article is given via a link at the end of
the document
This article is protected by copyright. All rights reserved.

10.1002/chem.202001041
Chemistry - A European Journal
FULL PAPER
Here, we investigate whether these ligands also stabilize anionic
organopalladates formed upon the reaction of L3Pd with RMgX
and other organometallic reagents and whether such anionic
complexes react with alkyl halides to afford cross-coupling
products. To identify palladate intermediates, we use negative-ion
mode electrospray-ionization (ESI) mass spectrometry. This
method has proven well suitable for the detection of these and
other anionic organometallate complexes.[12,14–18] By combining
ESI mass spectrometry with gas-phase experiments on mass-
selected species, we can also determine the microscopic
reactivity of species of interest and directly probe their catalytic
competence.
When the Grignard reagent was changed from BuMgCl to
PhMgCl, the transmetalation product [L2PdPh]− (or possibly its
[LPd(ArF PPh)ArF]− isomer) formed in analogy to the previous
2
experiment, although only in rather low abundance, whereas
palladates bearing fragments of the phosphine L predominated in
the resulting negative-ion mode ESI mass spectrum
(Figures S11-S15). Upon the reaction of L3Pd with BnMgCl, the
expected organopalladate(0) [L2PdBn]− was not detected
(Figures S16-S18). Instead, palladate(II) complexes, such as
[LPdArFBn2]− and [LPdBn3]− were observed and pointed to the
operation of oxidation processes. Such oxidation processes could
possibly involve traces of O2 or residual BnCl as a contaminant of
the BnMgCl reagent.[22]
We next examined whether other organometallic reagents also
brought about the transmetalation of L3Pd. The reaction of the
latter with BuLi afforded [L2PdBu]−, but at the same time furnished
more ligand decomposition products as well as palladate(II)
complexes (Figure S19). The reaction with BuZnCl∙LiCl gave
Results
Transmetalation of L3Pd
Negative-ion mode ESI mass-spectrometric analysis of solutions
of L3Pd and BuMgCl in tetrahydrofuran (THF) showed the
organopalladate(0) anion [L2PdBu]− as base peak (Figure 1 and
Table 1 as well as Figures S1-S10 in the Supporting Information).
In addition, several other palladate species were present, which
contained fragments of the phosphine ligand. The transfer of aryl
substituents from the phosphine ligand onto the palladium center
has been observed before for the case of triphenylphosphine-
palladium complexes.[19–21] We cannot rule out that even some of
the ions assigned as [L2PdBu]− actually correspond to
[L3PdCl]− and [L2Pd(PArF )]− as main products together with
2
several heterobimetallic complexes, such as [L3PdZnBuCl2]−
(Figures S20-S26). As it is not immediately obvious whether the
butyl substituent of this species was bound to the Pd or Zn center,
we defer the answer to this question to the analysis of its gas-
phase fragmentation behavior (see below).
We went on to probe the influence of the phosphine ligand on the
formation and stability of the organopalladate(0) anions. The
treatment of [Pd(PPh3)4] with BuMgCl did not yield any anionic
palladates detectable by ESI mass spectrometry. When to a
palladium complex of LPh1 (formed in situ by the reaction of
Pd(dba)2 with 4 equiv. of LPh1) was added BuMgCl, the main anion
[LPd(ArF PBu)ArF]−, in which an exchange of the palladium-bound
2
butyl group with the aryl substituent of the phosphine ligand has
taken place (see below). Among the detected ions, the dinuclear
complex [L2Pd2(PArF )Bu]2− was remarkable because it is a rare
example of a dianionic organometallic complex detectable by ESI
mass spectrometry.
2
observed
was
[LPh1PdArF Bu]−
along
with
further
2
organopalladate(II) and minor -palladate(0) species, but no
[LPh12PdBu]− (Figures S27-S36). Apparently, neither PPh3 nor LPh1
was effective in stabilizing alkylpalladate(0) complexes.
To obtain additional information on the organopalladate(0) anions,
we also investigated their gas-phase fragmentation behavior
(Table S2). Both [L2PdBu]− and [L2PdPh]− preferentially afforded
[LPdArF]− upon collision-induced dissociation (CID), eq. (1) with
R = Bu and Ph, respectively (Figures S37 and S38).
[L2PdR]−
→
[LPdArF]− + [P,ArF ,R]
(1)
2
It is not clear whether the neutral fragments of these reactions
corresponded to a phosphine PArF R or to separate entities. The
2
former possibility would be in accordance with the facile
transformation of the reactant ion into its [LPd(ArF2PR)ArF]−
isomer (see above). Further fragmentation reactions of interest
resulted in the loss of a ligand L, either alone or in combination
with the product of a putative β-hydrogen elimination, eq. (2) and
(3), respectively. These reactions clearly demonstrate that at least
part of the reactant complexes did not undergo isomerization and
contained the intact ligand L.
Figure 1. Negative-ion mode ESI mass spectrum of a solution of [Pd(PArF3)3]
(L3Pd, 3 mM) and BuMgCl (12 mM) in THF (a = [L2Pd2(PArF2)Bu]2−
b = [LPd(PArF2)BuH], c = [L2PdH]).
,
[L2PdPh]−
[L2PdBu]−
→
→
[LPdPh]− + L
(2)
(3)
[LPdH]− + C4H8 + L
This article is protected by copyright. All rights reserved.

10.1002/chem.202001041
Chemistry - A European Journal
FULL PAPER
For determining the connectivity of the [L3PdZnBuCl2]− complex
formed from L3Pd and BuZnCl∙LiCl (see above), we analyzed its
gas-phase fragmentation. CID of this complex mainly gave
[L2PdZnBuCl2]−, eq. (4a), but also [L3PdCl]−, eq. (4b), which
suggests that the butyl group had not been transferred from Zn to
Pd, or at least that such a transfer, if occurring, must be easily
reversible (Figure S39). This assumption is further supported by
and S61). In contrast, no reaction took place with PrCl
(Figure S62). With the sterically more hindered iPrBr, the
i
[LPdBu2 Pr]− product ion could be observed, but only in very low
signal intensities (Figure S63). The addition of (2-phenyl)ethyl
bromide also led to the expected product ion when L was used as
a ligand (Figures S64-S66). In contrast, no oxidative addition
reaction could be observed upon treatment of in-situ formed
palladium complexes of the less electron-withdrawing LPh1 with
BuMgCl and (2-phenyl)ethyl bromide.
the observation that the related anion [L2PdZnBuCl(PArF )]−
2
showed the elimination of BuZnCl as main fragmentation pathway
(Figure S40).
When allyl bromide was added to solutions of [L2PdBu]−, the
yellow reaction mixture rapidly turned colorless, thus, suggesting
the occurrence of a chemical reaction. However, the resulting
negative-ion mode ESI mass spectrum displayed only poor signal
intensities and did not show the expected allyl-containing
heteroleptic palladate(II) ions, possibly due to the operation of fast
consecutive reactions (Figure S67). Analogous experiments with
ethyl 4-bromobenzoate (ArBr) as substrate afforded the
heteroleptic product ions [LPdBu2Ar]− and [LPdArFBuAr]− together
with further ligand decomposition products, which again exhibited
the highest signal intensities (Figures S68-S80).
[L3PdZnBuCl2]−
[L3PdZnBuCl2]−
→
→
[L2PdZnBuCl2]− + L
[L3PdCl]− + BuZnCl
(4a)
(4b)
Reactions of organopalladates with organyl halides
When solutions of [L2PdBu]− and [L2PdPh]− palladates formed in
situ were treated with alkyl iodides R'I, R' = Et and Pr, small
amounts of the heteroleptic organopalladate(II) complexes
[LPdBu2R']− and [LPdPh2R']− (or possibly isomers thereof) were
observed together with the organyl-free palladate(0) anion
[L3PdI]− and various ligand decomposition products (Figure 2,
Table S3, and Figures S41-S59).
In a different type of experiment, we subjected mass-selected
[L2PdBu]− ions to gas-phase reactions with different organyl
iodides R'I (R' = Me, Et, allyl, vinyl, Ph) for times of up to 2 s. In
no case, the product of an oxidative addition could be observed,
which implies that such reactions, if proceeding at all, were
relatively inefficient and slower than the time scale of our
experiment (Figure S81 for the example of vinyl iodide).
Alternatively, the [L2PdBu]− ions might also react with the R'I
substrates in an SN2-type fashion to afford neutral heteroleptic
palladium(II) complexes along with I−. Although we did not
observe the formation of I−, this negative result does not rigorously
rule out the occurrence of SN2-type reactions because the low-
mass cut-off of the used quadrupole-ion trap mass spectrometer
renders the detection of light product ions (relative to the
precursor ion) notoriously difficult.
For comparison, we also analyzed the bimolecular gas-phase
reactivity of [Pd(PArF )]−, a species detected among the various
2
ions originating from the decomposition of the phosphine ligand L.
[Pd(PArF )]− underwent a fast oxidative addition of PhI, eq. (5)
2
(Figures S82 and S83). Due to the relatively low signal intensity
of the precursor ion and a competing reaction with residual traces
of O2 present in the vacuum system of the mass spectrometer, no
reliable determination of the rate constant of this reaction was
feasible.
Figure 2. Negative-ion mode ESI mass spectrum of a solution of [Pd(PArF3)3]
(L3Pd, 3 mM), PhMgCl (12 mM), and EtI (12 mM) in THF.
[Pd(PArF )]− + PhI
→
[PhPd(PArF )I]−
(5)
2
2
In a control experiment, the reaction of L3Pd with EtI was probed
in the absence of any Grignard reagent and was found to furnish
no detectable heteroleptic palladate complexes. The addition of
LiI to the sample solution ensured that any formed neutral
heteroleptic palladium(II) products would have been readily
ionized by the coordination of I−.[12]
Gas-phase fragmentation of heteroleptic organopalladates
Upon CID, the putative heteroleptic organopalladate anions
[LPdR2R']− (for the possible involvement of different isomers, see
below) produced inter alia [LPdR]− fragment ions (Figure 3, Table
S4, Figures S84-S97). Most likely, the neutral byproduct of this
reaction corresponded to the cross-coupling product RR', eq. (6),
and not to separate R• and R'• radicals. The stepwise release of
such radicals would not only be energetically strongly disfavored,
but should also give rise to intermediates resulting from the loss
We then examined the reactions of [L2PdBu]− with further
substrates. With PrBr, the heteroleptic product complex
[LPdBu2Pr]− was formed again, although more slowly than in the
reaction with PrI as a comparison of the signal intensity of the
product ion relative to that of [L2PdBu]− indicated (Figures S60
This article is protected by copyright. All rights reserved.

10.1002/chem.202001041
Chemistry - A European Journal
FULL PAPER
of only a single organyl radical, which in no case were detected,
however. Likewise, the liberation of the homo-coupling product R2
was not observed either.
and Ph, or the organolithium compound BuLi furnish the anionic
transmetalation products [L2PdR]−; these species resemble the
previously observed organyl-free palladates [LnPdX]−, X = Cl, Br,
I, OAc.[12] The fact that the organozinc reagent BuZnCl∙LiCl failed
to afford the corresponding organopalladate(0) complex suggests
that only highly reactive organometallics, such as RMgCl and RLi,
are capable of transferring their organyl group to the palladium(0)
center of L3Pd. This behavior resembles the transmetalation of
palladium diene complexes,[14b] but contrasts that of typical
palladium(II) complexes, whose reactivity toward organozinc
compounds and even milder transmetalation reagents is well
known and forms the basis of synthetically most useful
transformations, e.g., Negishi and Suzuki-Miyaura cross-coupling
reactions.[24,25]
[LPdR2R']−
→
[LPdR]− + RR'
(6)
Further fragmentation reactions, several of which were quite
prominent, again involved the decomposition of the phosphine
ligand as well as the loss of alkanes RH and R’H. In addition, the
observation of oxygen-containing product ions once more pointed
to the operation of reactions with traces of O2 present in the mass
spectrometer.
Besides the organometallic reagent, the phosphine ligand is also
of crucial importance for the formation and stabilization of anionic
alkylpalladate(0) complexes. These complexes could only be
observed for the particularly electron-poor phosphine L, but not
for the less electron-poor LPh1 or for PPh3. Apparently, only the
former sufficiently stabilizes the anionic palladium(0) by a π back
donation from the occupied d orbitals of the metal center into the
empty σ* orbitals of the C−P bonds of the phosphine. In this
context,
a comparison with the organyl-free palladate(0)
complexes [(phosphine)nPdX]−, X = Cl, Br, I, n = 1 – 3, is of
interest. These species proved to be stable not only for
phosphine = L, but also for phosphine = LPh1. This behavior is
indicative of the organyl-free palladate(0) complexes
[(phosphine)nPdX]− having an electron density at the palladium
center not quite as high as that of their organopalladate(0)
counterparts. Indeed, it appears plausible that the binding of a
carbanion R− raises the electron density of a palladium center
more than that of a halide X− does. Moreover, the organyl-free
palladates typically bear three phosphine ligands instead of the
two observed for the organopalladates. The coordination of the
additional electron-poor phosphine supposedly further stabilizes
the anionic palladium(0) center by abstracting more electron
density. The different coordination numbers found for [L2PdR]− on
the one hand and for [L3PdX]− on the other presumably reflect the
larger size of the carbanion R− in comparison to the halide X−,
which renders the coordination of an additional ligand unfavorable.
Figure 3. Mass spectrum of mass-selected [LPdBu2Pr] and its fragment ions
produced upon collision-induced dissociation (ELAB = 15 eV, a = unknown,
b = [Pd,ArF,O2], c = [PdArFPrH]).
Analysis of neutral reaction products
For obtaining further insight, we used gas chromatography to
analyze the neutral products formed in the reactions of Grignard
reagents with alkyl halides in the presence of 2 mol% of the
palladium catalyst L3Pd under synthetic conditions. In the
reactions of BuMgCl with decyl iodide and (2-phenyl)ethyl iodide
as well as that of HexMgCl with ethyl bromide, we did observe the
cross-coupling products. However, control experiments showed
that these products also formed in the absence of the palladium
catalyst. In contrast, no cross-coupling product could be detected
for the reaction of BuMgCl with (2-phenyl)ethyl bromide, not even
when the more reactive so-called turbo-Grignard reagent
BuMgCl∙LiCl was used.[23] In all experiments with the L3Pd
catalyst, we observed decomposition products of the electron-
poor phosphine ligand, such as the cleaved-off arene moiety 1,3-
bis(trifluoromethyl)benzene.
Differences between the organopalladates(0) and their organyl-
free counterparts also manifested themselves in their
unimolecular reactivity. The former reacted mainly via ligand
decomposition whereas the latter preferentially lost intact
phosphine ligands L. This comparison again shows the stronger
binding of the phosphine L to the palladium center in the [L2PdR]−
than in the [L3PdX]− complexes. Moreover, it specifically points to
the importance of the π back donation in the organopalladates,
which transfers electron density from the metal-centered d
orbitals into the anti-bonding C−P σ* orbital of the ligand. In this
way, the C−P bond of the phosphine is activated for its
dissociation.
Discussion
Oxidative addition
Transmetalation
The observation of heteroleptic organopalladates [LPdR2R']−
formed in the reactions of [L2PdR]− with alkyl halides R'X (for the
As our experiments have shown, the reactions between the
palladium complex L3Pd and Grignard reagents RMgCl, R = Bu
This article is protected by copyright. All rights reserved.

10.1002/chem.202001041
Chemistry - A European Journal
FULL PAPER
possible involvement of different isomers, see below) points to
the occurrence of an oxidative addition or related process
followed by a second transmetalation along with a ligand
dissociation (Scheme 2).
formed I− ions again prevent an unambiguous mechanistic
assignment.
Reductive elimination
The
gas-phase
fragmentation
of
the
heteroleptic
organopalladate(II) complexes [LPdR2R']− afforded evidence for
the formation of the cross-coupling products RR'. These reactions
correspond to reductive eliminations, which regenerate the
palladium(0) catalyst. However, the occurrence of several
competing reactions results in a rather low selectivity of the
reductive eliminations.
Scheme 2. Oxidative addition of an alkyl halide to [L2PdR] with subsequent
transmetalation.
A remarkable feature of the reductive elimination from the putative
[LPdBu2R']− complexes, R' = Et and Pr, is the non-occurrence of
homo-coupling reactions. Given the electronic similarities of the
alkyl groups, it is not clear how the catalyst could differentiate
between them. A possible explanation of this behavior could be
the involvement of a different isomer. If the reactant palladate(0)
complex did not correspond to [L2PdBu]−, but to the isomerized
The dissociation of one of the two phosphine ligands reflects the
relatively low stability of penta-coordinated palladium(II)
complexes.[26–28]
The absence of an analogous heteroleptic palladium(II) complex
in the control experiment without added Grignard reagent
indicates that the latter is required for the reaction. Apparently, the
electron-poor neutral L3Pd complex is not sufficiently nucleophilic
to undergo oxidative additions of substrates R'X, but becomes
activated by its transformation into an anionic palladate [L2PdR]−.
Likewise, organyl-free palladates [L2PdX]− do not appear to react
with alkyl halides efficiently.
species [LPd(ArF PBu)ArF]− (see above), its reaction with the
2
substrates R'X and subsequent transmetalation would afford
[LPd(ArF PBu)ArFBuR']−. In these heteroleptic complexes, the
2
electronic properties of the palladium-bound ArF group on the one
hand and of the alkyl residues on the other strongly differ, which
could rationalize the selectivity of the gas-phase fragmentation
with the exclusive formation of the BuR' cross-coupling product.
In solution, heteroleptic organopalladate products form both for
sp3- and sp2-hybridized organic halides R'X. The latter, but not the
former are typical substrates for classical oxidative additions. The
situation is just the opposite for SN2-type reactions, which Kambe
and coworkers proposed to occur for diene-containing
palladate(0) anions.[11] Hence, the observed reactivity pattern
does not allow for a straightforward distinction between the two
mechanistic pathways in the present case. The higher efficiency
of the reactions with R'I than of those with R'Br does not permit a
differentiation either because this result is expected for both
pathways. In general, the two pathways could be distinguished by
analyzing the stereochemical outcome of a cross-coupling
reaction with an enantiopure chiral substrate R'X. Inversion of the
stereochemistry at the reactive center would point to the operation
of an SN2-type reaction, whereas retention would be consistent
with a classical oxidative addition. However, such experiments
would be rather difficult in the present case owing to the
occurrence of the uncatalyzed background reaction.
Catalytic cycle and catalyst stability
The present results demonstrate that anionic organopalladate
complexes can react in a catalytic cycle that differs from that of
conventional palladium-catalyzed cross-coupling reactions in that
the order of the transmetalation and oxidative addition is reversed
(Scheme 3). For the product-forming step of the reductive
elimination, we consider two different possibilities: (i) The
reductive elimination occurs for [LnPdRR'], i.e., the same type of
The failure of the gaseous [L2PdR]− complexes to react with
various substrates R'I at measureable rates implies that these
gas-phase reactions must be rather slow. Addition processes,
such as classical oxidative additions, often proceed only
sluggishly in the diluted gas phase because the exothermicity of
these reactions cannot be efficiently carried away by third-body
collisions, but remains in the formed adducts and causes them to
re-dissociate easily. In contrast, SN2 reactions in the gas phase
do not suffer from this constraint because the exothermicity can
be effectively released as kinetic energy of the two reaction
products.[29] Indeed, SN2 reactions are commonly found to
proceed much faster in the gas phase than in solution.[30,31] In the
present case, the technical difficulties of detecting the possibly
Scheme 3. Alternative catalytic cycle of a Pd-catalyzed cross-coupling reaction:
formation of an organopalladate(0) intermediate by transmetalation with an
organometallic reagent RM, subsequent oxidative addition of an organyl halide
R'X, and reductive elimination of the cross-coupling product from the resulting
neutral intermediate or after a further transmetalation.
This article is protected by copyright. All rights reserved.

10.1002/chem.202001041
Chemistry - A European Journal
FULL PAPER
complex also invoked in the conventional catalytic cycle. (ii)
present in the reaction mixture. Thus, the practical utilization of
the new catalytic pathway requires the development of
phosphines that combine an electron-poor character with a high
stability.
Alternatively, this complex may first undergo
a
further
transmetalation to afford an anionic palladate(II) species, which
then can release the cross-coupling product in a reductive
elimination and, thus, directly regenerates the reactive
organopalladate(0) intermediate. Presumably, the two alternative
modes of reductive elimination compete with each other, with their
relative weights depending on the reaction conditions (e.g., nature
and concentration of the transmetalating reagent).
Experimental Section
General
All experiments were carried out under standard Schlenk conditions to
exclude moisture and oxygen. THF was dried over sodium/benzophenone
and freshly distilled before use. LPh1 was synthesized according to
literature procedures (see the Supporting Information).[12,34] BnMgCl was
synthesized according to standard procedures. BuZnCl∙LiCl was prepared
in situ from ZnCl2 and BuLi. All other organometallic reagents as well as
the palladium complexes PdL3, Pd(PPh3)4, and Pd(dba)2 were purchased.
The concentrations of the organometallic reagents were determined by
iodometric titration.[35]
Although the separate elementary steps of this cycle are all
feasible, the overall cross-coupling reaction proceeds only very
sluggishly. The low efficiency of the catalyzed reactions results
from the facile decomposition of the electron-poor ligand L, which
opens up competing processes and, even more importantly,
reduces the concentration of the active catalyst. The degradation
of phosphine ligands in palladium-catalyzed reactions has
previously been observed in numerous instances.[20,21,32,33]
However, the combination of
phosphine with a highly nucleophilic organometallic reagent in the
present case severely aggravates this problem.
a particularly electron-poor
Sample solutions were prepared by dissolving the palladium catalyst and,
if necessary, an additional phosphine ligand in dry THF. The
organometallic reagent and, in some experiments, the organyl halide were
added at 195 K. The resulting solutions were analyzed immediately.
ESI mass spectrometry
Conclusions
Sample solutions were fed into the ESI source of a micrOTOF-Q II mass
spectrometer (Bruker Daltonik) with gas-tight syringes at typical flow rates
of 8 µL min1. The ESI source was operated at a voltage of 3500 V. N2 was
used as nebulizer gas (flow rate of 5 L min−1) and drying gas (0.7 bar
backing pressure, temperature of 333 K). In simple MS1 experiments, all
generated ions with 50 ≤ m/z ≤ 3000 were allowed to pass the quadrupole
mass filter of the instrument. In gas-phase fragmentation experiments,
ions of interest were mass-selected in the quadrupole-mass filter,
subjected to a kinetic energy ELAB, and allowed to collide with N2 gas.
Residual precursor ions and fragment ions were then detected after
passage through the TOF analyzer. An external calibration with a mixture
of CF3COOH and phosphazenes in H2O/CH3CN allowed for typical
accuracies of the measured m/z ratios of ≤ 25 ppm. In some cases, an
additional internal calibration had to be applied. To this end, the m/z scale
was adjusted to match the theoretical m/z ratio of an ion, whose identity
could be independently established with certainty (indicated for each
experiment). Theoretical exact m/z ratios and isotope patterns were
calculated with the Compass DataAnalysis software package (Bruker
Daltonik).
The use of negative-ion mode ESI mass spectrometry permits the
observation of organopalladates(0) [L2PdR]− formed from the
electron-poor palladium complex [L3Pd] and Grignard or
organolithium reagents, RMgX or RLi, respectively. Thus, the
present study extends the scope of known palladate(0) anions.
The fact that reactions with less electron-poor phosphines or with
RZnX as milder transmetalation reagents do not afford the
analogous palladates points to the considerable reluctance, with
which the very electron-rich [L2PdR]− complexes form.
The high electron density and, thus, nucleophilicity of the [L2PdR]−
palladates can be exploited for their reaction with organyl halides
and, in particular, alkyl halides R'X. As gas-phase fragmentation
experiments show, the resulting heteroleptic organopalladate(II)
complexes undergo reductive eliminations and release cross-
coupling products R'R. Overall, this reaction sequence
corresponds to a catalytic cycle, in which the elementary step of
transmetalation precedes that of oxidative addition and which
therefore differs from that of conventional palladium-catalyzed
cross-coupling reactions. An analogous mechanism has
previously been found for reactions catalyzed by palladate anions
containing dienes, but not for those mediated by phosphine-
coordinated palladium complexes.
Ion-molecule reactions in the gas phase were analyzed by means of a HCT
quadrupole-ion trap mass spectrometer (Bruker Daltonik). Defined
mixtures of neutral reactants and helium were prepared and introduced
into the three-dimensional quadrupole ion trap using a mixing device,
which has been described in detail previously.[36]
GC analysis
Despite the potential of the present organopalladates for
catalyzing challenging alkyl-alkyl cross-coupling reactions and the
significant interest in these transformations, these systems
themselves are not suited for practical applications because of the
facile catalyst degradation under the reaction conditions. This
problem arises from the electron-poor character of the phosphine,
which is needed for stabilizing the electron-rich palladate center
by a π back donation to the ligand. The partial occupation of the
anti-bonding C−P orbital weakens this bond and activates it for
degradation reactions with the highly reactive organometallics
The Grignard reagent (1.5 mmol) and the organyl halide (1.0 mmol) were
added dropwise to solutions of L3Pd (0.02 mmol) in THF (5 mL) held at
195 K. After warming up, the resulting mixtures were stirred for reaction
times ranging from 3 h to 48 h before they were treated with brine (2 mL)
and extracted with THF (3 × 2 mL). The combined organic layers were
dried over Na2SO4 and filtrated through silica gel. The resulting solutions
were analyzed by GC-MS with a Trace DSQ instrument (Thermo Finnigan)
equipped with a VF-5ms column (Agilent).
This article is protected by copyright. All rights reserved.

10.1002/chem.202001041
Chemistry - A European Journal
FULL PAPER
[24] a) J. A. Casares, P. Espinet, B. Fuentes, G. Salas, J. Am. Chem. Soc.
2007, 129, 3508–3509. b) B. Fuentes, M. García-Melchor, A. Lledós, F.
Maseras, J. A. Casares, G. Ujaque, P. Espinet, Chem. Eur. J. 2010, 16,
8596–8599. c) M. García-Melchor, B. Fuentes, A. Lledós, J. A. Casares,
G. Ujaque, P. Espinet, J. Am. Chem. Soc. 2011, 133, 13519–13526.
[25] J. Li, L. Jin, C. Liu, A. Lei, Org. Chem. Front. 2014, 1, 50–52.
[26] L. J. Gooßen, D. Koley, H. Hermann, W. Thiel, Chem. Commun. 2004,
2141–2143.
Acknowledgements
We thank Mr. Marius Deuker for carrying out some of the ESI-
mass spectrometric experiments and the anonymous reviewers
for helpful comments. We gratefully acknowledge funding from
the CaSuS (Catalysis for Sustainable Synthesis) program
(scholarship for M.K.).
[27] M. Bröring, C. D. Brandt, Chem. Commun. 2003, 2156–2157.
[28] S. Hansson, P.-O. Norrby, M. P. T. Sjögren, B. Åkermark,
Organometallics 1993, 12, 4940–4948.
[29] a) J. I. Brauman, W. N. Olmstead, C. A. Lieder, J. Am. Chem. Soc. 1974,
96, 4030–4031. b) W. N. Olmstead, J. I. Brauman, J. Am. Chem. Soc.
1977, 99, 4219–4228.
Keywords: Cross-coupling • Mass spectrometry • Palladium •
Phosphines • Reactive intermediates
[30] a) D. K. Bohme, L. B. Young, J. Am. Chem. Soc. 1970, 92, 7354–7358.
b) D. K. Bohme, A. B. Raksit, J. Am. Chem. Soc. 1984, 106, 3447–3452.
[31] J. K. Laerdahl, E. Uggerud, Int. J. Mass Spectrom. 2002, 214, 277–314.
[32] a) W. A. Herrmann, C. Broβmer, K. Öfele, M. Beller, H. Fischer, J.
Organomet. Chem. 1995, 491, C1–C4. b) W. A. Herrmann, C. Broßmer,
K. Öfele, M. Beller, H. Fischer, J. Mol. Cat. A 1995, 103, 133–146.
[33] S. A. Macgregor, Chem. Soc. Rev. 2006, 36, 67–76.
[34] A. Jakab, Z. Dalicsek, T. Holczbauer, A. Hamza, I. Pápai, Z. Finta, G.
Timári, T. Soós, Eur. J. Org. Chem. 2015, 60–66.
[35] A. Krasovskiy, P. Knochel, Synthesis 2006, 890–891.
References
[1] A. de Meijere, S. Bräse, M. Oestreich, Metal-Catalyzed Cross-Coupling
Reactions and More, Wiley-VCH, Weinheim, 2014.
[2] E. R. Strieter, D. G. Blackmond, S. L. Buchwald, J. Am. Chem. Soc. 2003,
125, 13978–13980.
[3] E. A. B. Kantchev, C. J. O’Brien, M. G. Organ, Angew. Chem. 2007, 119,
2824–2870; Angew. Chem. Int. Ed. 2007, 46, 2768–2813.
[4] G. C. Fu, Acc. Chem. Res. 2008, 41, 1555–1564.
[36] T. Parchomyk, K. Koszinowski, J. Mass Spectrom. 2019, 54, 81–87.
[5] N. Marion, S. P. Nolan, Acc. Chem. Res. 2008, 41, 1440–1449.
[6] C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot, V. Snieckus,
Angew. Chem. 2012, 124, 5150–5174; Angew. Chem. Int. Ed. 2012, 51,
5062–5085.
[7] N. Hazari, P. R. Melvin, M. M. Beromi, Nat. Rev. Chem. 2017, 1, 1–16.
[8] T.-Y. Luh, M. Leung, K.-T. Wong, Chem. Rev. 2000, 100, 3187–3204.
[9] A. C. Frisch, M. Beller, Angew. Chem. 2005, 117, 680–695; Angew.
Chem. Int. Ed. 2005, 44, 674–688.
[10] R. Jana, T. P. Pathak, M. S. Sigman, Chem. Rev. 2011, 111, 1417–1492.
[11] a) J. Terao, H. Watanabe, A. Ikumi, H. Kuniyasu, N. Kambe, J. Am. Chem.
Soc. 2002, 124, 4222–4223. b) J. Terao, Y. Naitoh, H. Kuniyasu, N.
Kambe, Chem. Lett. 2003, 32, 890–891. c) J. Terao, Y. Naitoh, H.
Kuniyasu, N. Kambe, Chem. Commun. 2007, 0, 825–827. d) J. Terao, N.
Kambe, Acc. Chem. Res. 2008, 41, 1545–1554. e) N. Kambe, T. Iwasaki,
J. Terao, Chem. Soc. Rev. 2011, 40, 4937–4947.
[12] M. Kolter, K. Böck, K. Karaghiosoff, K. Koszinowski, Angew. Chem. 2017,
129, 13427–13431; Angew. Chem. Int. Ed. 2017, 56, 13244–13248.
[13] For early reports on anionic palladate complexes with triphenylphosphine
ligands, see: a) C. Amatore, M. Azzabi, A. Jutand, J. Am. Chem. Soc.
1991, 113, 8375–8384. b) C. Amatore, A. Jutand, Acc. Chem. Res. 2000,
33, 314–321.
[14] a) M. Kolter, K. Koszinowski, Chem. Eur. J. 2016, 22, 15744–15750. b) M.
Kolter, K. Koszinowski, Chem. Eur. J. 2019, 25, 13376–13384.
[15] a) A. Putau, H. Brand, K. Koszinowski, J. Am. Chem. Soc. 2012, 134,
613–622. b) C. Schnegelsberg, S. Bachmann, M. Kolter, T. Auth, M. John,
D. Stalke, K. Koszinowski, Chem. Eur. J. 2016, 22, 7752–7762. c) F.
Kreyenschmidt, S. E. Meurer, K. Koszinowski, Chem. Eur. J. 2019, 25,
5912–5921. d) T. Parchomyk, S. Demeshko, F. Meyer, K. Koszinowski,
J. Am. Chem. Soc. 2018, 140, 9709–9720.
[16] B. H. Lipshutz, J. Keith, D. J. Buzard, Organometallics 1999, 18, 1571–
1574.
[17] a) K. L. Vikse, M. A. Henderson, A. G. Oliver, J. S. McIndoe, Chem.
Commun. 2010, 46, 7412–7414. b) T. K. Trefz, M. A. Henderson, M. Y.
Wang, S. Collins, J. S. McIndoe, Organometallics 2013, 32, 3149–3152.
c) H. S. Zijlstra, A. Joshi, M. Linnolahti, S. Collins, J. S. McIndoe, Eur. J.
Inorg. Chem. 2019, 2019, 2346–2355.
[18] J. Váňa, T. Terencio, V. Petrović, O. Tischler, Z. Novák, J. Roithová,
Organometallics 2017, 36, 2072–2080.
[19] R. Qian, Y.-X. Liao, Y.-L. Guo, H. Guo, J. Am. Soc. Mass Spectrom. 2006,
17, 1582–1589.
[20] D. Agrawal, E.-L. Zins, D. Schröder, Chem. Asian J. 2010, 5, 1667–1676.
[21] V. V. Grushin, Organometallics 2000, 19, 1888–1900.
[22] T. Gärtner, W. Henze, R. M. Gschwind, J. Am. Chem. Soc. 2007, 129,
11362–11363.
[23] A. Krasovskiy, P. Knochel, Angew. Chem. 2004, 116, 3396–3399; Angew.
Chem. Int. Ed. 2004, 43, 3333–3336.
This article is protected by copyright. All rights reserved.

10.1002/chem.202001041
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
The electron-poor palladium(0)
complex L3Pd (L = tris(3,5-
M. Kolter, K. Koszinowski*
Page No. – Page No.
bistrifluoro-methylphenyl)phosphine)
first undergoes transmetalation with
RMgCl or RLi before it reacts with
alkyl halides in an oxidative addition.
Thus, the order of these elementary
steps is reversed in comparison to
conventional palladium-catalyzed
cross-coupling reactions.
Second Comes First: Switching
Elementary Steps in Palladium-
Catalyzed Cross-Coupling Reactions
This article is protected by copyright. All rights reserved.