Aryl-phenyl scrambling in intermediate organopalladium complexes: A gas-phase study of the mizoroki-heck reaction

Article abstract of DOI:10.1002/chem.201400115

The intramolecular aryl-phenyl scrambling reaction within palladium-DPPP-aryl complex (DPPP=1,3-bis(diphenylphosphino)propane) ions was analyzed by state-of-the-art tandem MS, including gas-phase ion/molecule reactions. The Mizoroki-Heck cross-coupling reaction was performed in the gas phase, and the intrinsic reactivity of important intermediates could be examined. Moreover, linear free-energy correlations were applied, and a mechanism for the scrambling reaction proceeding via phosphonium cations was assumed.

Full text of DOI:10.1002/chem.201400115

DOI: 10.1002/chem.201400115
Communication
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Mass Spectrometry
Aryl–Phenyl Scrambling in Intermediate Organopalladium
Complexes: A Gas-Phase Study of the Mizoroki–Heck Reaction
Lukas Fiebig, Nils Schlçrer, Hans-Gꢀnther Schmalz, and Mathias Schꢁfer*[a]
Abstract: The intramolecular aryl–phenyl scrambling reac-
tion within palladium–DPPP–aryl complex (DPPP=1,3-bis-
(diphenylphosphino)propane) ions was analyzed by state-
of-the-art tandem MS, including gas-phase ion/molecule
reactions. The Mizoroki–Heck cross-coupling reaction was
performed in the gas phase, and the intrinsic reactivity of
important intermediates could be examined. Moreover,
linear free-energy correlations were applied, and a mecha-
nism for the scrambling reaction proceeding via phospho-
nium cations was assumed.
The palladium-catalyzed Mizoroki–Heck reaction is well-estab-
Scheme 1. Scrambling of aryl moieties leading to unwanted by-products
lished as an important CÀC bond-forming process in modern
found in palladium-mediated cross-coupling reactions.[4b,d,i,13]
organic synthesis.[1] In this reaction, a large variety of mono-
and bidentate phosphine ligands is commonly used to control
the regio- and stereochemistry of the transformation.[2] It is as-
studied in the gas phase, in which solvent effects, counterions
sumed that the reaction is initiated by an oxidative addition of
[Pd0(L2)] (L2 =(PR3)2 or R2P-(CH2)n-PR2; n=2, 3) with ArX (X=I,
Br, Cl) either forming [Pd(L2)(Ar)(X)], following a neutral mecha-
nism, or [Pd(L2)(Ar)(S)]+XÀ (S=solvent) by an ionic mecha-
nism.[1d,3] However, before the insertion of the olefin (carbopal-
ladation) as the CÀC bond-forming step, the aryl palladium(II)
complexes tend to undergo exchange reactions between the
phosphorus- and palladium-bound aryl moieties. This leads to
unwanted product mixtures, similar to the case of other promi-
nent palladium-mediated cross-coupling or polymerization re-
actions (Scheme 1).[4]
and aggregation processes are fully eliminated or can be care-
fully controlled. Hence, intrinsic structure–reactivity relation-
ships of organometallics can be investigated.[5] Electrospray
ionization (ESI)[6] mass spectrometry has proved to be very
useful for this analytical approach, because even labile species
can be transferred intact from a complex reaction solution into
a mass spectrometer,[7,8] in which the exact ion mass and the
isotopic distribution can be measured.[9] Once the ions of inter-
est reach the mass analyzer, for example, a quadrupole-ion
trap (QIT),[5e] individual precursor ions can be selected for
tandem MS experiments, in which they are activated by colli-
sions with an inert He-buffer gas, leading to collision-induced
dissociation (CID) reactions and product-ion spectra exhibiting
characteristic fragmentation patterns.[10] Also, reactive colli-
sions, that is, ion/molecule reactions (IMRs) of selected precur-
sor ions with neutral reagents can be conducted in the gas
phase, when volatile reagents are fed into the QIT through the
buffer-gas flow.[5c,11] IMRs are especially appropriate to establish
a relative-affinity order of different ionic organometallic com-
plexes towards typical substrates, to study reaction kinetics or
to stepwise examine even complete catalytic cycles by the
combination of sequential IMR and CID experiments.[5c,11b,12]
Recently, Guo and co-workers and Schrçder and co-workers
extensively studied the gas-phase fragmentation reactions of
collision-activated [Pd(PPh3)2(Ar)]+ complexes and found evi-
dence for intramolecular aryl–aryl migrations there.[14] However,
Schrçder and co-workers worked in the absence of olefinic
coupling-reaction substrates, the respective coupling reaction
was not conducted, and hence the extent of aryl scrambling
Novak and co-workers and Grushin extensively studied the
aryl–aryl scrambling process of different [Pd(L2)(Ar)(X)] com-
1
plexes (X=I, Br, Cl) by H and 31P NMR techniques and report-
ed that the presence of electron-rich aryl groups facilitates the
aryl migration, whereas electron-poor aryl moieties or the addi-
tion of excess phosphine ligand reduces or even suppresses
the exchange reaction.[4g,h] Hence, the aryl–aryl scrambling was
proposed to proceed via an intermolecular reductive-elimina-
tion/oxidative-addition mechanism forming an intermediate
phosphonium salt.[4d,g–i]
Alternatively, the nature, identity, and reactivity of transient
species of transition-metal-catalyzed reactions can also be
[a] L. Fiebig, Dr. N. Schlçrer, Prof. H.-G. Schmalz, Priv.-Doz. Dr. M. Schꢀfer
Department of Chemistry, University of Cologne
Greinstrasse 4, 50939 Kçln (Germany)
E-mail: mathias.schꢀfer@uni-koeln.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400115.
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could only be investigated on an early and preliminary stage
and not on the level of products.
Herein, we studied the [Pd0(dppp)] (DPPP=1,3-bis(diphenyl-
phosphino)propane)-catalyzed Mizoroki–Heck coupling of dif-
ferent aryl iodides with dimethylbutadiene (DMB) by gas-phase
IMRs and simultaneously monitored the extent of intramolecu-
lar aryl scrambling in intermediate [PdII(dppp)] complex cations
as a function of different aryl moieties used.[15] Moreover, linear
free-energy correlations were applied to enlighten details of
the aryl–phenyl scrambling mechanism.
To gain access to gaseous cationic [Pd(dppp)(Ar)]+ (2) spe-
cies, different aryl iodides were reacted with bis(dibenzyli-
deneacetone)palladium ([Pd(dba)2]) and DPPP in acetonitrile at
room temperature (Scheme 2). A 31P NMR analysis of the reac-
Scheme 2. Oxidative addition of aryl iodides 1 on Pd0 in acetonitrile and
transfer of [Pd(dppp)(Ar)]+ (2) and [Pd(dppp)(I)]+ (3) into the gas phase by
ESI-MS.
Figure 1. a) (+)ESI-MS spectrum of a reaction solution of p-iodotoluene (1a;
1.0 equiv), [Pd(dba)2] (2.0 equiv), and DPPP (1.5 equiv) in acetonitrile at room
temperature under inert gas atmosphere (inset: experimental and calculated
isotopic distribution of 2a, showing good agreement). b) Aryl migration
during isolation of complex ion 2a and IMR of 2a/2a’ (m/z 609) with DMB
giving a mixture of 4a and 4a’ (m/z 691; reaction time 30 ms, ca. 1012 mole-
cules DMB vs. 104 ions inside the ion trap).
tion solution clearly proved that [Pd(dppp)(Ar)(I)] was the only
Pd–phosphine species present next to [Pd(dppp)(dba)] and
phosphonium aryl salts (Figure S1 in the Supporting Informa-
tion). Dilution and ESI-MS analysis of the same reaction mixture
gave the gaseous complex ions [Pd(dppp)(Ar)]+ (2) and [Pd-
(dppp)(I)]+ (3), which were characterized by exact mass mea-
surement, comparison of experimental and theoretical isotopic
patterns and indicative fragmentation behavior obtained from
MS2 and MS3 product ion experiments that are in line with the
results of Schrçder and co-workers (Figure 1a and Figures S2
and S3 in the Supporting Information).[14b]
To probe the gas-phase Mizoroki–Heck coupling, complex
ions [Pd(dppp)(Ar)]+ (2) were mass selected in the ion trap
and reacted with dimethylbutadiene (DMB) introduced into
the trap by the gas flow of the helium-background
gas.[5c,11b,12b,16] The IMRs of all complex ions [Pd(dppp)(Ar)]+ (2)
with DMB led exclusively to the formation of isobaric product
ions 4/4’ with a characteristic mass shift of 82 Da (DMB: C6H10,
ions 4a and 4a’ in Figure 1b). The complex ions 4 represent
[Pd(dppp)(aryl–butenyl)]+ species formed after DMB carbopal-
ladation. This assumption is based on the fact that CID prod-
uct-ion spectra of the ions 4/4’ (see, for example, 4a and 4a’
in Figure 2) give only two hydride complex ions 5 and 6 as
product ions formed by neutral loss matching the respective
Mizoroki–Heck products (in Figure 2 losses of C13H16 and
C12H14, respectively).[17] DMB loss and reformation of respective
[Pd(dppp)(Ar)]+ (2) ions was not observed upon CID ruling out
the possibility of 4 being Pd–DMB p-complex ions (Figure 2).
The structure of hydride complex ion 5 was strongly supported
Figure 2. CID of Pd complex ions 4a and 4a’ (m/z 691) enabling ß-H elimi-
nation. We noted that both formed hydride complex ions 5 (m/z 519) and
6a (m/z 533) underwent new IMRs with DMB still present in the LTQ giving
the adduct ions 5·DMB (m/z 601) and 6a·DMB (m/z 615). The precursor ion
is marked with an asterisk and was selected with an isolation width of 8 Da.
by its CID pattern, which exhibited the loss of PPh2H (Fig-
ure S4a in the Supporting Information). As can be seen in
Figure 2, 5 instantly underwent anew IMR with DMB still pres-
ent in the LTQ forming the p-complex ion 5·DMB.[12b] CID of
5·DMB (m/z 601) gave 5 as the only fragment ion, evidencing
the presence of a Pd–olefin p complex (Scheme 3).
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Scheme 3. Gas-phase Mizoroki–Heck reaction initialized by a combination of IMR and CID and scrambling mechanism via phosphonium ion 7 or 8 consistent
with the experimental findings.[4d,g,i,14b]
Similar to the product ion 5, ions 6 also form DMB adduct
ions 6·DMB via subsequent IMR, observed in the product-ion
spectra of 4/4’. Fragment ion 6a formally differs from 5 in one
CH2 unit and can be rationalized assuming an interchange be-
tween the palladium-bound aryl moiety and a phosphorus-
bound phenyl group (in this case, tolyl vs. phenyl). Accordingly,
each CID experiment of 4b–k gave exclusively two hydride
complex ions 5 and 6b–k exhibiting a mass difference, which
correlates with the aryl moieties used. In a control experiment,
CID of [Pd(dppp)(Ph)]+ (4l) gave 5 as the only hydride-com-
plex ion (Figures S5 and S6 in the Supporting Information).
Novak and co-workers reported that no aryl–phenyl ex-
change was observed in a diluted chloroform solution of [Pd-
(dppp)(p-tolyl)(I)] at ambient temperature.[4g] According to this
finding and proven by our own NMR measurements, including
1H{31P}, 31P{1H}, nuclear Overhauser effect spectroscopy
(NOESY), total correlation spectroscopy (TOCSY), and 1H–31P
heteronuclear multiple quantum coherence (HMQC) 2D-NMR
analyses, no aryl–phenyl interchange took place in the reaction
solution prior to ESI-MS analysis, indicating that the observed
intramolecular aryl–phenyl scrambling is an exclusive gas-
phase phenomenon taking place before CID (Figure S1 in the
Supporting Information).
To further scrutinize the aryl–phenyl interchange mecha-
nism, the logarithm of (6+6·DMB)/(5+5·DMB) ratios were plot-
ted as a function of the Hammett sP parameter of the corre-
sponding substituted aryl moieties (Figure 3).[20] Linear free-
energy correlations can be employed in gas-phase ionic sys-
tems,[21] and McIndoe and co-workers recently applied this
concept to the reductive elimination of cross-coupling prod-
ucts from Pd-complex ions.[7e] The slope of the linear fit (1=
À0.90) in Figure 3 indicates that the scrambling reaction is fa-
vored for aryl ligands with electron-donating para-substitu-
ents.[22] This result is consistent with the proposed mechanism
for the scrambling reaction proceeding via the formation of
In analogy to condensed-phase NMR studies,[4a–i] the extent
of aryl–phenyl scrambling in the gas phase increases with en-
hanced electron density of the Pd-bound aryl group indicated
by CID spectra of 4a–k (Figure S5 in the Supporting Informa-
tion). However, while in the condensed phase little or no ex-
change of electron-deficient aryl groups was observed,[18] we
found gas-phase aryl migrations also in complexes with deacti-
vated aryl ligands (para-substituents F, COMe, CF3, NO2, and
complexes 2h–k). This result documents an elevated reactivity
in the gas phase in the absence of solvent molecules and
counterions, leading to a higher aryl–phenyl scrambling effi-
ciency.[19] Furthermore, the higher sensitivity of mass spectrom-
etry compared with NMR might also be relevant.
Figure 3. log10-Plot of (6+6·DMB)/(5+5·DMB) as a function of the Hammett
sP parameter (reaction time of IMRs with DMB 100 ms).[20] Because the
extent of aryl–phenyl scrambling of [Pd(dppp)(Ph)]+ (2i, p-H in the Hammett
plot) could not be determined directly by this method, [Pd(dppp)(C6D5)]+
(2h) was measured instead, assuming that no significant kinetic isotope
effect was present in the scrambling reaction.
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a phosphonium ion,[4d, g–i] which is one of different aryl–aryl
scrambling mechanisms reported in literature.[14]
Experimental Section
The oxidative addition of iodides was carried out in a flame-dried
Schlenk flask charged with the respective iodide (0.02 mmol,
1.0 equiv), bis(dibenzylideneacetone) palladium (0.04 mmol,
2.0 equiv), and 1,3-bis(diphenylphosphino)propane (0.03 mmol,
1.5 equiv) and diluted in dry acetonitrile (8 mL). The resulting solu-
tion was stirred at RT under argon atmosphere until oxidative addi-
tion, that is, formation of 2, was observed in the ESI mass spectrum
(0.5–4 h). Ion/molecule reactions (IMRs) were performed in the
linear ion trap (LTQ) of a Thermo Fisher LTQ-Orbitrap XL (Bremen,
Germany)[27] hybrid instrument, which was modified as described
elsewhere.[5c,11,12b] In brief, the helium-buffer gas supply of the LTQ
was upgraded with an extra septum inlet, which allowed the injec-
tion of dimethylbutadiene (DMB) by using a pump-driven Hamilton
syringe. This way, a gaseous mixture of helium and DMB was intro-
duced into the LTQ with a helium partial pressure of approximately
2.5 mTorr, and an olefin partial pressure of approximately 2.5ꢃ
10À3 mTorr inside the ion trap (Figure S9 in the Supporting infor-
mation). To quantify the extent of gas-phase aryl–phenyl scram-
bling, the ratio of the hydride complex ions (6+6·DMB)/(5+5·
DMB), formed during CID of 4/4’, was determined by adding up
the intensities of the two most intense isotopes of each complex
ion. A more detailed description is given in the Supporting Infor-
mation.
Scheme 3 outlines the reversible aryl–phenyl interchange
mechanism via phosphonium ions 7 or 8 and summarizes the
performed gas-phase Mizoroki-Heck reactions: After transfer
from solution to the gas phase by ESI-MS, complex ion 2 un-
dergoes intramolecular aryl–phenyl exchange giving a mixture
of 2/2’, only due to their internal energy related to the initial
electrospray ionization process[23] and the storage of the ions
in a linear ion trap.[24] Subsequently, IMR with DMB and the car-
bopalladation reaction follows. Upon CID, ß-H elimination, si-
multaneous formation, and release of the coupling product
was afforded, and anew olefin addition to the resulting hydride
complex was observed.
Alternatively, complexes 2.DMB with the DMB p bonded to
palladium can be formed by IMR prior to the scrambling pro-
cess. Subsequently, the Ar/Ph-scrambling proceeds in the pres-
ence of the p-bonded DMB via the intermediate phosphonium
ion 8 giving 2’.DMB, benefiting from the association enthalpy
of the IMR and the additional stabilization of the palladium
metal by DMB ligation in complex ion 8.[12b,25]
The gas-phase approach proved to be well suited to study
the extent of aryl–phenyl exchange in [Pd(dppp)(Ar)]+ com-
plexes (2) as a function of the aryl moities used and especially
to distinguish even between aryl–phenyl interchanges of deac-
tivated aryl groups, all of which did not show significant
scrambling in solution. In addition, the aryl–phenyl exchange
reaction was investigated under defined conditions, because
aryl migrations take place either in [Pd(dppp)(Ar)]+ species (2)
during isolation in the quasi-thermal environment of the ion
trap or in complexes 2.DMB after IMR association of the
DMB.[26] After the DMB carbopalladation, an aryl–phenyl ex-
change can no longer occur, because in the resulting com-
plexes 4/4’, no Pd-bound aryl ligand is present anymore
(Scheme 3). Additionally, the gas-phase reactions, that is, the
carbopalladation (Figure 1b) and ß-H elimination (Figure 2),
proceed chemoselective, because as no other complex species
were observed (apart from the subsequent formation of DMB
adduct ions).
Acknowledgements
This work was generously supported by a doctoral fellowship
of the “Cusanuswerk” to L.F. We thank Daniela Naumann for as-
sistance in NMR measurements.
Keywords: cross-coupling · linear free-energy correlations ·
mass spectrometry · NMR spectroscopy · reaction mechanisms
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Received: January 10, 2014
Revised: February 21, 2014
Published online on && &&, 0000
[16] P. S. D. Robinson, G. N. Khairallah, G. da Silva, H. Lioe, R. A. J. O’Hair,
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Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
5
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
Ion–molecule reactions: The intramo-
lecular aryl–phenyl scrambling reaction
within palladium–DPPP–aryl complex
(DPPP=1,3-bis(diphenylphosphino)pro-
pane) ions was analyzed by state-of-the-
art tandem MS, including gas-phase
ion/molecule reactions. The Mizoroki–
Heck cross-coupling reaction was per-
formed in the gas phase, and the intrin-
sic reactivity of important intermediates
could be examined. Moreover, linear
free-energy correlations were applied,
and a mechanism for the scrambling re-
action proceeding via a phosphonium
cation was assumed (see scheme).
&
Mass Spectrometry
L. Fiebig, N. Schlçrer, H.-G. Schmalz,
M. Schꢀfer*
&& – &&
Aryl–Phenyl Scrambling in
Intermediate Organopalladium
Complexes: A Gas-Phase Study of the
Mizoroki–Heck Reaction
&
&
Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!