ESI-MS detection of proposed reaction intermediates in the air-promoted and ligand-modulated oxidative heck reaction

Article abstract of DOI:10.1021/jo061437d

Electrospray ionization mass spectrometry (ESI-MS) and subsequent MS/MS analyses were used to directly detect palladium-containing cationic reaction intermediates in a ligand controlled palladium(II)-catalyzed oxidative Heck arylation. All potential intermediates were observed as dmphen-ligated palladium(II) species, suggesting that the dmphen bidentate ligand is attached to the metal center during the entire catalytic cycle. The study supports previous mechanistic propositions and provides new information regarding the composition of aryl-containing Pd(II) complexes in an ongoing oxidative Heck reaction. In addition, sodium acetate was found to be a useful base alternative to previously used tertiary amines.

Full text of DOI:10.1021/jo061437d

ESI-MS Detection of Proposed Reaction Intermediates in the
Air-Promoted and Ligand-Modulated Oxidative Heck Reaction
,
†
Per-Anders Enquist, Peter Nilsson, Per Sj o¨ berg,* and Mats Larhed*
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center,
Uppsala UniVersity, P. O. Box 574, SE-751 23 Uppsala, Sweden, and Department of Physical and
Analytical Chemistry, Analytical Chemistry, Uppsala Biomedical Center, Uppsala UniVersity,
P.O. Box 599, SE-751 24 Uppsala, Sweden
mats@orgfarm.uu.se; per.sjoberg@kemi.uu.se
ReceiVed July 11, 2006
Electrospray ionization mass spectrometry (ESI-MS) and subsequent MS/MS analyses were used to directly
detect palladium-containing cationic reaction intermediates in a ligand controlled palladium(II)-catalyzed
oxidative Heck arylation. All potential intermediates were observed as dmphen-ligated palladium(II)
species, suggesting that the dmphen bidentate ligand is attached to the metal center during the entire
catalytic cycle. The study supports previous mechanistic propositions and provides new information
regarding the composition of aryl-containing Pd(II) complexes in an ongoing oxidative Heck reaction. In
addition, sodium acetate was found to be a useful base alternative to previously used tertiary amines.
7
Introduction
synthesis. Major advantages with this catalytic process include
the high tolerance of functional groups and the possible control
Since the early 1970s when R. F. Heck and T. Mizoroki
independently discovered the palladium(0)-catalyzed vinylic
substitution with aryl halides, a process which later came to be
known as the Heck reaction, this transformation has been a
topic for extensive research.3 The Heck methodology has
proven to be a versatile tool for the formation of carbon-carbon
bonds and has found applications, in for example, the industrial
5
8
of both regio- and stereoselectivity. In the palladium(II)-
catalyzed version of the Heck arylation, recently named the
oxidative Heck reaction, the aryl halide is replaced as the
coupling partner by an arylboronic acid
organometallic reactant.
a large commercial availability, are less toxic, and generate
easily removable byproducts compared to alternative transmeta-
lation substrates. In order to further improve the oxidative Heck
1
,2
9
,10
or an alternative
-5
11-13
Importantly, arylboronic acids have
6
production of fine chemicals and complex natural product
9
*
To whom correspondence should be addressed. (M.L.) Phone: +46-18-
4
714667. Fax: +46-18-4714474.
(7) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945-2963.
(8) Shibasaki, M.; Vogl, E. M.; Ohshima, T. AdV. Synth. Catal. 2004,
346, 1533-1552.
†
Department of Analytical Chemistry.
1) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320-2322.
(9) Jung, Y. C.; Mishra, R. K.; Yoon, C. H.; Jung, K. W. Org. Lett.
2003, 5, 2231-2234.
5
3
2
81.
(
3) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100,
(10) Andappan, M. M. S.; Nilsson, P.; Larhed, M. Mol. DiV. 2003, 7,
97-106.
(11) Parrish, J. P.; Jung, Y. C.; Shin, S. I.; Jung, K. W. J. Org. Chem.
2002, 67, 7127-7130.
(12) Hirabayashi, K.; Ando, J.; Kawashima, J.; Nishihara, Y.; Mori, A.;
Hiyama, T. Bull. Chem. Soc. Jpn. 2000, 73, 1409-1417.
(13) Inoue, A.; Shinokubo, H.; Oshima, K. J. Am. Chem. Soc. 2003,
125, 1484-1485.
009-3066.
(4) De Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. 1994, 33, 2379-
411.
5) Larhed, M.; Hallberg, A. In Handbook of Organopalladium Chemsitry
in Organic Synthesis; Negishi, E.-i., Ed.; Wiley & Sons Inc.: New York,
002; Vol. 2001, pp 1133-1178.
6) Tucker, C. E.; De Vries, J. G. Top. Catal. 2002, 19, 111-118.
(
2
(
1
0.1021/jo061437d CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/14/2006
J. Org. Chem. 2006, 71, 8779-8786
8779

Enquist et al.
reaction the stable and cheap bidentate 2,9-dimethyl-1,10-
phenanthroline ligand (dmphen), previously investigated by
Cabri in the classical Heck reaction,14 was found to allow vinylic
1
5
substitutions with only 2 mol % of palladium catalyst. The
Pd(OAc)2/dmphen combination provided the first examples of
16
Pd(II)-catalyzed internal (R-) arylations of electron-rich olefins,
and in addition, dmphen was found to promote the essential
regeneration of active Pd(II) species even under atmospheric
1
7
air.
The analytical technique electrospray ionization (ESI)18,19 has,
since its development in the mid-1980s, significantly increased
the utility of mass spectrometry (MS).2
0,21
It is considered a
soft ionization technique in the sense that it yields little, if any,
fragmentation products and has therefore proven to be an
22
FIGURE 1. Plausible catalytic cycle of the phenanthroline ligand-
modulated oxidative Heck reaction with an electron-rich olefin. The
different types of cationic intermediates in the catalytic cycle are
excellent tool for analyzing fragile biomolecules and different
9
kinds of organometallic complexes.2
3-26
Electrospray ionization
is not an ionization technique in the sense that neutral molecules
become charged; instead, ions are transferred from solution to
the gas phase in a smooth manner that is ideal for observation
of short-lived molecular ions directly from a reaction medium.
ESI-MS has been used previously to probe the mechanism of
assigned letters from A-D and catalytic steps are named I-VI.
Results and Discussion
The overall aim of this investigation was to detect existing
cationic palladium complexes present during a productive
oxidative Heck reaction between an arylboronic acid and an
enamide and to explore the composition of suggested intermedi-
ates in the catalytic cycle (A-D, Figure 1). Step I in the catalytic
cycle corresponds to the starting point, where different Pd(II)
species of class A participates in a transmetalation process and
arylpalladium(II) complexes of class B are formed. In step II,
the metal center coordinates to the olefin, generating a π-com-
plex of type Cπ. Thereafter, the Cπ species undergoes a
migratory insertion process forming a σ-complex (Cσ, step III).
After the subsequent â-elimination (step IV), a palladium
hydride is formed which is believed to first coordinate to the
arylated olefin (D) before dissociating, forming free Heck
product and a palladium hydride (E, step V). For multiple
turnovers, active palladium(II) species must be regenerated (step
VI). The dmphen ligand and related 1,10-phenanthroline deriva-
tives are believed to play an important role in this process,
allowing the direct use of molecular oxygen as a Pd(0)
27-29
different palladium(0)-catalyzed reactions like the Heck
and
3
0
the Suzuki reaction. The tandem version, ESI-MS/MS, is a
valuable tool for identification and structural assignments of
charged complexes because of the possibility to use the first
mass analyzer to “fish out” species with a certain m/z ratio and
thereafter to subject them for fragmentation (CID) in the
collision cell. The generated fragments can then be analyzed
with the second mass analyzer.
This technique should also be well suited for an on-line
31
monitoring of reaction intermediates in the palladium(II)-
catalyzed oxidative Heck reaction since it is believed to proceed
via cationic intermediates (and only charged complexes can be
observed by MS-detection). Although there is a proposed general
catalytic cycle for the oxidative Heck reaction9 (Figure 1),
there are presently no noncomputational studies of the mecha-
nistic aspects supporting these assumptions.
,32
(
14) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J. Org. Chem. 1993,
8, 7421-7426.
15) Andappan, M. M. S.; Nilsson, P.; Larhed, M. Chem. Commun. 2004,
18-219.
16) Andappan, M. M. S.; Nilsson, P.; von Schenck, H.; Larhed, M. J.
Org. Chem. 2004, 69, 5212-5218.
17) Enquist, P.-A.; Lindh, J.; Nilsson, P.; Larhed, M. Green Chem. 2006,
, 338-343.
18) Whitehouse, C. M.; Dreyer, R. N.; Yamashita, M.; Fenn, J. B. Anal.
3
3,34
5
reoxidant.
A number of other bidentate ligands, such as
(
bipyridine and dppp (1,3-bis(diphenylphosphino)propane), are
also productive, although they provide slow reactions and lower
2
(
1
7
yields.
(
Regarding the exact nature of step VI in Figure 1, Stahl and
co-workers recently presented an aerobic Pd(II)-catalyzed oxida-
tion reaction where molecular oxygen is believed to directly
react with a palladium hydride to generate active Pd(II) and
8
(
Chem. 1985, 57, 675-679.
(
19) Yamashita, M.; Fenn, J. B. J. Phys. Chem. 1984, 88, 4451-4459.
(20) Cole, R. B., Ed. Electrospray Ionization Mass Spectrometry:
3
5
complete the catalytic cycle. Thus, the issue whether Pd(0)
species are involved or not in dioxygen coupled Pd(II)-catalyzed
reactions is at present not fully understood, although the essential
reoxidant is commonly referred to as a “Pd(0) reoxidant”.
Palladium hydrides are, however, not stable under basic
conditions (yielding Pd(0) and HX in the classic Heck reaction)
and are very seldom detected during the course of a palladium-
Fundamentals, Instrumentation, and Applications; Wiley: New York, 1997.
21) Santos, L. S.; Knaack, L.; Metzger, J. O. Int. J. Mass Spectrom.
005, 246, 84-104.
22) Fenn, J. B.; Mann, M.; Meng, C. K.; Wong, S. F.; Whitehouse, C.
(
2
(
M. Science 1989, 246, 64-71.
(
23) Plattner, D. A. Top. Curr. Chem. 2003, 225, 153-203.
(24) Henderson, W.; Nicholson, B. K.; McCaffrey, L. J. Polyhedron 1998,
1
7, 4291-4313.
(
25) Chevrin, C.; Le, Bras, J.; Henin, F.; Muzart, J.; Pla-Quintana, A.;
2
7,36
catalyzed reaction.
Roglans, A.; Pleixats, R. Organometallics 2004, 23, 4796-4799.
(
26) Traeger, J. C. Int. J. Mass Spectrom. 2000, 200, 387-401.
A possible byproduct might be observed if complex B
undergoes a competing second transmetalation with a free
(27) Sabino, A. A.; Machado, A. H. L.; Correia, C. R. D.; Eberlin, M.
N. Angew. Chem., Int. Ed. 2004, 43, 2514-2518.
28) Ripa, L.; Hallberg, A. J. Org. Chem. 1996, 61, 7147-7155.
(33) Stahl, S. S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am.
Chem. Soc. 2001, 123, 7188-7189.
6
6
57-659.
(
30) Aliprantis, A. O.; Canary, J. W. J. Am. Chem. Soc. 1994, 116, 6985-
(34) Thiel, W. R. Angew. Chem., Int. Ed. 1999, 38, 3157-3158.
(35) Konnick, M. M.; Gandhi, B. A.; Guzei, I. A.; Stahl, S. S. Angew.
Chem., Int. Ed. 2006, 45, 2904-2907.
986.
(
31) Fabris, D. Mass Spectrom. ReV. 2005, 24, 30-54.
(32) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400-3420.
(36) Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 13178-13179.
8780 J. Org. Chem., Vol. 71, No. 23, 2006

ESI-MS Detection of Reaction Intermediates in the Heck Reaction
SCHEME 1. Investigated Oxidative Heck Reactions and Subsequent Hydrolysis
TABLE 1. Productivity from the Catalytic Systems Using Selected
ate R-arylated products (4a-c) were hydrolyzed with HCl (aq)
a
Reaction Components at Room Temperature
and isolated as the corresponding aryl methyl ketones (5a,b).
Acetonitrile is a polar solvent that also works well in ESI-MS
analysis. Accordingly, the labile organometallic reaction inter-
mediates, which might only exist under specific conditions, were
believed to remain unaffected when removed from the reaction
mixture and injected into the ESI-MS for analysis. In order to
improve the signal-to-noise ratio in the ESI-MS-(+) detection,
sodium acetate was evaluated as an alternative base to N-
methylmorpholine. Unexpectedly, this weak inorganic base
furnished a faster reaction, with full internal selectivity but with
a slightly reduced yield (63% of product 5a after 24 h, Table
b
no.
ArB(OH)2
olefin
ligand
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
EtCN
yield (%)
1
2
3
4
5
6
7
1a
1a
1b
1a
1a
1a
1a
2a
2a
2a
2a
2b
2a
2a
3a
3a
3a
3b
3a
3a
3a
5a, 63
5a, 72c
5b, 76
5a, 55
5a, 59d
5a, 69
5a, 50e
MeCN/H2O
a
Arylboronic acid (1, 2 equiv), olefin (2, 1 mmol, 1 equiv), ligand (3,
.024 equiv), NaOAc (2 equiv), Pd(II) salt (0.02 equiv) in 3 mL of solvent
was stirred in an open vessel for 24 h. In all entries, except entry 4, 1-4%
biaryl formation was observed. Isolated yield of the corresponding aryl
methyl ketone 5 after acidic hydrolysis. >95% pure according to GC-
MS. Palladium propionate instead of palladium acetate and increased
reaction time to 30 h. Increased reaction time to 7 days. Acetonitrile/
water, 50:50.
0
b
1
, entry 1) compared to the corresponding reaction with
16
N-methylmorpholine (71% 5a after 48 h). Additional reactions
with arylboronic acid 1b, enamide 2b, ligand 3b, and propi-
onitrile as solvent also proceed smoothly with sodium acetate
c
d
e
(entries 2-6). In order to test whether or not water had an impact
on the reaction outcome, the solvent in the standard reaction
was changed to a 50:50 acetonitrile/water solution, furnishing
only slightly lower yield of isolated 5a (50% instead of 63%,
entries 7 and 1). The amount of biaryl, formed through a
competing Suzuki-like pathway varied between 1 and 4%.
Competing protodeboronation and phenol formation were also
found to consume arylating agents 1a,b, although these pro-
cesses did not affect the yield of the oxidative Heck reaction
because of the excess (2 equiv) of arylboronic acid.3
8-40
Next, we decided to initiate the mechanistic investigation,
attempting to probe the plausible catalytic cycle of the reaction
presented in Scheme 1 with 1a, 2a, and 3a through the use of
ESI-MS analysis. An aliquot was withdrawn from the reaction
mixture after 3 h and was directly diluted 10 times with
FIGURE 2. ESI-MS-(+) spectrum of palladium complex B2 (C23
22 3
H N -
Pd, m/z 446), solid line, and theoretical isotopic pattern, dotted line.
41-43
acetonitrile.
After sample injection, ESI-MS-(+) traces were
arylboronic acid before the migratory insertion takes place (step
37
III). According to this competing Suzuki-like reaction pathway,
a symmetric biaryl product (G, not shown in Figure 1) will be
formed after an aryl-aryl reductive elimination process.
The ligand-mediated oxidative Heck protocol previously
developed in our laboratory proceeds under air at room
(
38) Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini, H. J. Am.
Chem. Soc. 2006, 128, 6829-6836.
39) Yamamoto, Y.; Suzuki, R.; Hattori, K.; Nishiyama, H. Synlett 2006,
027-1030.
40) Abarca, B.; Ballesteros, R.; Blanco, F.; Bouillon, A.; Collot, V.;
(
1
(
Dominguez, J.-R.; Lancelot, J.-C.; Rault, S. Tetrahedron 2004, 60, 4887-
temperature with a base (2.0 equiv) and dmphen (3a, 0.024
4893.
equiv) as the ligand.17 p-Tolylboronic acid (1a, 2.0 equiv) and
(41) All reported ESI-MS and ESI-MS/MS signals were obtained after
3
h based on an investigation at different time intervals (see Figure 5 or
the electron-rich enamide 2a (1.0 equiv) with Pd(OAc)2 (0.02
equiv) as palladium(II) source were chosen as the standard
reaction system for ESI-MS analysis (Scheme 1). The rationale
behind the employment of an electron-rich olefin was that if
an internally arylated product was isolated, the regioselective
outcome would support a Heck process proceeding via cationic
the Supporting Information, S33-36). Interestingly, in the standard reaction
between 1a and 2a using dmphen and Pd(OAc)2, all detected palladium
complexes were already present after 10 min. To allow the detected
palladium(II) species to describe a productive catalytic cycle, the selected
time of analysis was set to 3 h, corresponding to around 50% conversion
of the yield-determining starting material (2a) in the standard reaction. Two
additional graphs are included on pp S39-40 (Supporting Information). In
the first graph, the plotted intensity of the standard reaction is corrected
for detector saturation by utilizing isotopic peak intensity. In the second
graph, accumulated ion intensities from detected adducts are presented.
(42) Enke, C. G. Anal. Chem. 1997, 69, 4885-4893.
5
Pd(II) σ- and π-intermediates. After full conversion, intermedi-
(37) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359-1469.
(43) Tang, L.; Kebarle, P. Anal. Chem. 1993, 65, 3654-3668.
J. Org. Chem, Vol. 71, No. 23, 2006 8781

Enquist et al.
FIGURE 3. ESI-MS-(+) spectrum for the standard reaction, using 1a, 2a, 3a, NaOAc, and MeCN under air at room temperature after 3 h (entry
1
, Table 1). Palladium complexes depicted according to Table 2.
recorded by scanning the first quadrupole of an API III+ triple-
quadrupole instrument. Various groups of m/z signals corre-
sponding to the characteristic isotopic distribution pattern of
palladium-containing complexes were detected (Figure 2). The
m/z separation between adjacent peaks revealed that only
monocharged cationic species were observed. The full ESI-MS
scan of the reaction mixture from the standard reaction is
depicted in Figure 3. The largest peaks came from sodium
adducts of arylated olefins (monomers, dimers, and even
trimers), but also olefin adducts or even solvent species could
be observed. By utilizing the power of tandem mass spectrom-
etry (MS/MS), a structural proposition of each of the palladium
complexes could be deduced. The ion with strongest intensity
in each complex (the ion from 1 Pd, which is the palladium
isotope with highest natural abundance) was selected for further
MS/MS-(+) analysis. A daughter ion spectrum was recorded
with the collision energy and collision gas thickness set to 20
sole proton scavenger. An intriguing feature of the MS/MS
spectrum of complex A1 (Supporting Information) is that the
dissociation of an acetate ion should render a +2 charged
palladium-ligand species and consequently not gives a fragment
with a m/z ratio of 314. The recording of the m/z ) 314 signal
suggests a single-electron transfer. Such unexpected charge
transfers are, however, not unheard of. Reduction processes can
occur in the collision cell for transition metals in higher
z+
oxidation states (M with z > 1) when colliding with residual
4
4
gas molecules.
Table 2. Aryl-Pd(II) Complexes (B). The principal trans-
metalation product recorded was the fully ligated B2. Impor-
tantly, MS/MS-(+) experiments afforded further support to the
suggested structures, confirming the presence of the chelating
dmphen in B1-3 (see the Supporting Information). In the MS/
MS spectrum for, e.g., potential intermediate B2 (Figure 4), the
neutral dissociation of acetonitrile and toluene could be estab-
lished and a relatively large signal (m/z 313), matching the mass
of a charged Pd-dmphen complex, was also observed. The
elimination of toluene from tolyl-containing B-type ions is not
a surprising process with benzylic hydrogens in the near
06
13
-2
eV and 200 × 10 molecules‚cm , respectively (see the
Supporting Information).
Table 2. Starting Pd(II) Complexes (A). Three different
dmphen-coordinated single-charged cationic complexes were
detected. Of those, derivative A1 was the predominant type A
species, according to the ESI-MS intensity. The 16-electron bis-
dmphen complex A3 is thought to provide A1 by up-front
2
1
proximity of the metal center. The fragmentation of complex
B1 was almost identical to B2 with the difference that the
solvent molecule (MeCN) first dissociated from the mother ion
20
45
fragmentation. MS/MS-(+) data supported the assigned com-
position of A3 by establishing loss of monocoordinated dmphen
from the coordination sphere of the metal. A clear difference
between species of class A compared to all other detected
organopalladium compounds are that they all have acetate
associated to the Pd(II) center. Clearly, after transmetalation
B2 when exposed to MS/MS-(+) analysis.
Table 2. Pd(II) Complexes (C). In the case of C1, a
structural assignment by MS/MS-(+) was ambiguous. The m/z
ratio (516) corresponds either to an aryl-Pd(II) species π-bonded
to the olefin (Cπ) or the corresponding 1,2-inserted σ-complex
(
(
Cσ). The observation of dissociation of both free enamide 2a
m/z 405) and â-elimination product 4a (m/z 315), from the C1
(step I, Figure 1) monocharged aryl containing moieties cannot
bind yet another counterion like the acetate anion and still be
visible in ESI-MS-(+). To assess if the metal still carried one
of its two originally bonded acetate ions in complex A1-3,
Pd(OAc)2 from the standard reaction was replaced with pal-
ladium propionate. The reaction with palladium propionate
proceeded somewhat slower, although providing a 72% yield
of 3a after 30 h (Table 1, entry 2). In the presence of the sodium
acetate anion, ions of A1-3 were again observed, supporting
the role of the acetate as a palladium(II) ligand and not as a
complex, suggest an equilibrium between the π-complex and
the σ-complex, but since the conditions in Q2 are quite different
from actual oxidative Heck reaction conditions, no definite
conclusions can be made. Although the m/z ratio 516 also fits
a π-complex of class D (Figure 1), the information from MS/
(44) Blades, A. T.; Jayaweera, P.; Ikonomou, M. G.; Kebarle, P. J. Chem.
Phys. 1990, 92, 5900-5906.
(45) Bruins, A. P. Electrospray Ioniz. Mass Spectrom. 1997, 107-136.
8782 J. Org. Chem., Vol. 71, No. 23, 2006

ESI-MS Detection of Reaction Intermediates in the Heck Reaction
TABLE 2. Single Charged Cationic Palladium(II) Complexes
Detected in the Standard Oxidative Heck Reaction with 1a, 2a, and
points toward a dmphen-Pd(II)-hydride complex (see the Sup-
porting Information, p S26) probably formed via a CID-induced
â-elimination from the σ-bonded C1 complex and loss of prod-
uct 4a. The intensive C1 MS/MS fragment ion m/z 355 was a
more bothersome discovery. We have at present no explanation
for this signal (see the Supporting Information, p S26).
Table 2. Pd(II) Complex (F). Detection of the biaryl
intermediate F1 was challenging because of overlapping peaks.
Rewardingly, via mass-selection and CID-induced fragmenta-
tion, the spectrum, after loss of a toluene fragment, displayed
dissociation chemistry very similar to B2, supporting the
presented cis structure or the alternative trans isomer.
3
a Using ESI-MS-(+) Analysis
Importantly, all potential intermediates listed in Table 2 do
not necessarily originate from the reaction cocktail. This holds
especially true for electronically unsaturated complex A1 and
B1, which are most likely formed during the desolvation step
in the ion source and/or by up-front collision-induced dissocia-
tion from intermediates A3 and B2-3, respectively.2 Alter-
natively, they might function as reactive intermediates in
dissociative catalytic processes.
7,45
An interesting feature during the investigation at different
time intervals (Figure 5) was how the intensity of the proposed
intermediates varied between the different sampling times, e.g.,
complexes A1 and A3 were increasing over the whole reaction,
while all three complexes of class B were showing decreased
intensity. A possible explanation for this behavior could be that
the transmetalation step (step I, in Figure 1) becomes slower with
time due to the continuous consumption of arylboronic acid 1a,
yielding not only product 4a but also side products, such as
38
39
40
bitolyl, p-methylphenol, and toluene (from protodeborona-
tion). However, interpretation of the different ion intensities is
somewhat hampered as the response factor for the detected Pd
complexes probably varies depending on the degree of competi-
tion for excess charge between different species in the generated
42,43
ESI droplets.
Even in cases where intensities can be directly
correlated to concentrations, caution should be exerted when
drawing conclusions based on a specific species concentration.
The resting state for Ar-Pd species may be altered when the rel-
ative concentration of a substrate is changed during a reaction.47
The proposed identity of the observed complexes in the
standard reaction (Table 2) was further supported by a series
of additional reactions where the reaction components, one at
a time, were exchanged to deliver analogous and chemically
equivalent palladium(II) intermediates (Table 1). For each
homologous replacement, an electrospray mass spectrum was
recorded for the specific reaction. Novel palladium-containing
cations were further analyzed by MS/MS (Table 3).
Table 3. Starting Pd(II) Complexes (A). The presented
structure of complex A1 was validated by using the related but
1
52 g/mol heavier bathocuproine (3b) instead of 3a as ligand.
Both 3a and 3b furnished product 4a in similar yields (Table
, 63% (entry 1) and 55% (entry 4), respectively) with more
1
than 99% internal selectivity (GC-MS). The MS patterns were
almost identical except that the trace from A1′, as expected,
had its peaks positioned 152 m/z units higher. Intermediate A2,
containing a monoligated bidentate ligand, could not be observed
among the derivatized ions in the MS-spectrum when ligand or
solvent was exchanged to 3b or propionitrile (Table 1, entries
4 and 6). The presence of A3′ was detected in the ESI-MS-(+)
scan. The subsequent MS/MS-(+) fragmentation process started
a
Reported m/z values are based on 106Pd. b Structures supported by MS-
MS-(+) analysis.
MS-(+) reduces that possibility by detecting elimination of non-
arylated 2a (the insertion-elimination, step III-IV in Figure 1, is
considered irreversible).4 Another interesting observation in
the MS/MS-(+) spectrum of C1 was that the signal of m/z 315
,46
(
46) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009-
(47) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. ReV. 2005, 105, 2527-
2571.
3
066.
J. Org. Chem, Vol. 71, No. 23, 2006 8783

Enquist et al.
FIGURE 4. MS/MS-(+) spectrum for palladium complex B2 m/z 446, (B2-MeCN) m/z 405, (B2-[toluene + MeCN]) m/z 313. The large signal
at m/z 224 is not believed to originate from the B2 mother ion since when the MS/MS spectrum was recorded for other palladium isotopes than
106
Pd, it was not observed.
FIGURE 5. Intensity vs reaction time for ESI-MS detected palladium complexes in the standard reaction using 1a, 2a, 3a, NaOAc, and MeCN
entry 1, Table 1).
(
with a loss of the extra nitrogen ligand and thereafter followed
the same dissociation pattern as for A1 and A1′.
To further establish the structure for the reaction intermediates
of class B, a different arylpalladium precursor was needed. The
choice fell on homologous p-(n-butyl)phenylboronic acid (1b),
an arylating agent with similar properties as p-tolylboronic acid
(1a) but with a higher molecular weight (Table 1, entry 3). When
1a was exchanged to 1b and the reaction mixture analyzed with
mass spectrometry, the m/z ratio of the mother ions B1′′, B2′′,
and B3′′ agreed with expectation. Subsequent dissociation of
daughter ions in MS/MS-(+) of mass-selected ions also followed
the anticipated pattern.
Table 3. Pd(II) Complexes (C). The intriguing complex C1
was investigated in a similar way as described above. Arylating
agent 1b and ligand 3b were successfully exploited as chemical
equivalents, but an olefin analogue of N-vinylpyrrolidinone (2a)
was needed. Thus, the slightly larger enamide N-vinylcapro-
lactam (2b) was selected. This reactant furnished 5a via 4c with
almost identical yield and selectivity in the oxidative Heck reac-
tion as with 2a (Table 1, entry 5). Even though there was a
large difference in reaction time, it did not prevent the detection
of intermediates and the ESI-MS-(+) analysis produced antici-
pated results, including a complex of type C1′′ (Table 3).
Table 3. Aryl-Pd(II) Complexes (B). The previously
utilized ligand 3b was again used to directly validate the
proposed structures in Table 2. As expected, when ligand 3b
was used, the corresponding m/z ratios for the new cationic
complexes of type B could be observed in the mother scan
(Table 3). The following MS/MS-(+) analysis of the ions further
supported the structures by illustrating a dissociation pattern
matching that of the parent B complexes (see the Supporting
Information). Complex B2′, for example, possesses some
specific MS/MS-(+) easily distinguished features like toluene
and acetonitrile dissociations and a dominating palladium-
bathocuproine signal. The applicability of the chemical verifica-
tion process of complex B3 through B3′ was a bit more
demanding since the signal was weak in the ESI-MS-(+) scan
and the presence of isobaric ions complicated the task when
ligand 3b was used. In any case, the cleavage of the neutral
ligand and the dissociation of toluene, leaving the charged
palladium center bonded to bidentate 3b, was distinguishable
by MS/MS-(+) analysis, manifesting the proposed structure.
8784 J. Org. Chem., Vol. 71, No. 23, 2006

ESI-MS Detection of Reaction Intermediates in the Heck Reaction
TABLE 3. ESI-MS-(+)-Detected Single Charged Cationic Complexes in Oxidative Heck Reactions Using Homologous Reaction Components
Table 3. Pd(II) Complex (F). Last, we investigated the
proposed structure of byproduct intermediate F1 by the same
replacing strategy. The variable components in the complex were
one-at-a-time switched to equivalent replacements, such as
ligand 3b, aryl group 1b and propionitrile as solvent. Interest-
ingly, no bitolyl product or bitolyl complex of type F1 was ob-
served when bulky ligand 3b was used (Table 1, entry 4). Unfor-
tunately, this did not increase the yield of 4a (Table 1, entries
1 and 4) since the olefin and not the arylboronic acid was yield
determining. The MS/MS-(+) dissociation pattern of the F
J. Org. Chem, Vol. 71, No. 23, 2006 8785

Enquist et al.
complexes was easily interpreted due to the quick loss of
coordinating aryl and solvent molecule, leaving the characteristic
daughter ion of Pd(II)-N,N-ligand.
CH
2
Cl
2
, concentrated and purified on silica gel using a mixture of
iso-hexane and ethylacetate (20:1) to give the pure aryl methyl
ketones 5a,b in 50-76% yield.
Mass Spectrometry. An API III+ triple-quadrupole mass
spectrometer equipped with an articulated IonSpray interface was
used in this study. The reaction mixture was diluted 10 times with
acetonitrile after 3 h of stirring in an open vessel at room
temperature and introduced by continuous infusion with the aid of
a syringe pump at a flow-rate of 5 µL/min through a fused silica
capillary (50 µm inner diameter and 184 µm outer diameter). The
fused silica capillary was centered in a stainless steel capillary
counter assembly, which also served as the ESI high voltage contact.
The nebulizer gas flow was set to 0.5 L/min. The flow rate of dry
nitrogen counter-current curtain gas (heated to 60 °C) was 1.2 L/min
over the sampling orifice. The mass spectrometric parameters were
as follows: ion spray voltage (ISV) 3500 V, interface plate voltage
(IN) 650 V, orifice lens voltage (OR) 50 V, and AC entrance rod
Conclusion
Potential oxidative Heck intermediates including starting
palladium(II) catalysts, transmetalation complexes, and insertion
intermediates were observed directly in the reaction mixture by
ESI-MS-(+) analysis. The detected organopalladium intermedi-
ates were found to be in good agreement with the generally
suggested catalytic cycle of an oxidative Heck reaction. The
structures of the detected ions were validated by MS/MS and
by stepwise replacement of reaction components. The bidentate
nitrogen ligand 2,9-dimethyl-1,10-phenanthroline (dmphen) was
ubiquitous in all detected complexes and appeared to play an
essential role not only for regeneration of active Pd(II) but for
the whole reaction process. The sensitivity, speed, direct assay,
and versatility of the ESI-MS methodology suggest applications
as a tool for mechanistic studies also in related reaction systems.
(R0) 30 V. Mass spectral data were typically recorded by scanning
the 100-800 u region with a dwell time of 1-2 ms and a step size
of 0.1 u in multichannel acquisition mode (MCA summation of
10-20 scans). Mass scale calibration was performed using a
polypropylene glycol solution (PPG). During the MS/MS experi-
ments the collision energy was set to 20 eV. The collision gas was
argon with 99.9999% purity. The collision gas thickness was 2 ×
Experimental Section
15
-2
1
0 molecules‚cm .
General Procedure of Reaction Preparation. Oxidative Heck
reactions were run under air in room temperature from arylboronic
acid (1a,b, 2 equiv), olefin (2a,b, 1.00 mmol, 1 equiv), sodium
acetate (2 equiv, 164 mg) as base, ligand (3a,b, 0.024 equiv), and
palladium(II) precursor (0.020 mol) in 2 mL of solvent. Acetonitrile,
propionitrile, or a 50:50 acetonitrile/water system served as solvent.
The reaction mixture was vigorously stirred for 1-7 days. After
completion, the reaction mixture was interrupted, and intermediate
R-arylated enamides 4a-c were hydrolyzed in situ using 5 mL of
Acknowledgment. We express our sincere gratitude to Knut
and Alice Wallenberg’s Foundation and to the Swedish Research
Council. We also thank Shane Peterson for linguistic advice
and Prof. Anders Hallberg for fruitful discussions.
Supporting Information Available: Text giving full details of
experimental procedures, spectrometric data, and spectra. This mater-
ial is available free of charge via the Internet at http://pubs.acs.org.
2
M HCl, generating the corresponding aryl methyl ketones (5a,b).
The crude product was extracted from the reaction mixture with
JO061437D
8786 J. Org. Chem., Vol. 71, No. 23, 2006