Real-Time Mass Spectrometric Investigations into the Mechanism of the Suzuki-Miyaura Reaction

Article abstract of DOI:10.1021/acs.organomet.8b00705

Real-time monitoring of the Suzuki-Miyaura reaction using mass spectrometry during sequential addition of the various reaction components suggests that a dynamic series of equilibria exist in these solutions. Depending on conditions, the boronic acid can

Full text of DOI:10.1021/acs.organomet.8b00705

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Real-Time Mass Spectrometric Investigations into the Mechanism of
the Suzuki−Miyaura Reaction
Lars P. E. Yunker,† Zohrab Ahmadi,† Jessamyn R. Logan,† Wenzhao Wu,† Tengfei Li,† A. Martindale,†
Allen G. Oliver,‡ and J. Scott McIndoe*,†
†Department of Chemistry, University of Victoria, P.O. Box 3065, Victoria, BC V8W 3V6, Canada
‡Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: Real-time monitoring of the Suzuki−Miyaura reac-
tion using mass spectrometry during sequential addition of the
various reaction components suggests that a dynamic series of
equilibria exist in these solutions. Depending on conditions, the
boronic acid can be dehydrated, deprotonated, hydroxylated (or
alkoxylated), or fluorinated. Palladium−phosphine species present
include Pd(0) (to which the aryl iodide rapidly oxidatively adds), the
Pd(II) aryl iodide complex, a cationic Pd(II) species formed by
dissociation of the iodide ligand, and the Pd(II) bisaryl complex that
ultimately extrudes the product through reductive elimination. No
fluorinated or hydr(alk-)oxylated palladium complexes were
observed under catalytic conditions. Several transmetalation
combinations were excluded as reactive partners, but several
possibilities remain, and more than one mechanism is likely to be
operative, even under similar conditions.
mechanism proceeds through the reaction of boronate
[RB(OR)3]− and L2Pd(aryl)X, but they also note that the
mechanism is likely highly dependent on reaction conditions,
and both or either mechanism may be active depending on the
conditions.21 Denmark and co-workers have employed low
temperature nuclear magnetic resonance (NMR) to determine
the structures of pretransmetalation intermediates bearing Pd−
O−B−aryl linkages.24,25 They note that the formation of this
pretransmetalation species does not require formation of
LnPd(aryl)(OH), and instead the intermediate may be
approached by more than one mechanism (Scheme 1, both
A and B). The Carrow group has recently found evidence for a
palladium cation-mediated transmetalation pathway ([LPd-
(aryl)]+ where L is PAd3); Scheme 1D),26 and the Braun group
found evidence implying a fluoride-mediated cationic trans-
metalation pathway.27
For the most part, characterization of the LnPd(aryl)(OH)
monomer species has relied on 31P NMR and cyclic
voltammetry,14−17,28 and only the L = Cy3P or i-Pr3P
monomer species have been isolated.13,16,19,20,29−32 The
related bridged dimeric species, L2Pd2(aryl)2(μ-OH)2, has
been well-characterized by solid-state NMR and X-ray
crystallography for a range of L = phosphine.33 Electrospray
ionization mass spectrometry (ESI-MS) studies have pre-
viously observed the presence of cationic [L2Pd(aryl)]+, but
INTRODUCTION
■
The Suzuki−Miyaura (SM) reaction is the most commonly
used cross-coupling protocol in organic chemistry.1 It has been
performed countless times under the influence of catalysts that
are extraordinarily active, including an array of challenging
substrates such as aryl chlorides and sterically encumbered
boronic acids.2−7 The mechanism is thought to proceed via
three main steps: oxidative addition of the aryl halide to a
Pd(0) species, transmetalation of the other coupling partner
from boron to palladium, and reductive elimination of the two
coupling partners from palladium while forming a new C−C
bond.8,9 The number of phosphines coordinating the
palladium species undergoing oxidative addition varies
according to ancillary ligand and electrophile,10−12 but the
step that generates most debate is transmetalation. There have
been a variety of mechanisms mooted for this part of the
Suzuki−Miyaura reaction, and many have been whittled away
by a plethora of studies to leave two popular mechanisms. One
involves a ligand exchange of X− for HO−, and the reaction of
L2Pd(aryl)(OH) with the neutral boronic acid (Scheme
1A),13−17 and the other involves the reaction between a
boronate [RB(OR)3]− and L2Pd(aryl)X (Scheme 1B).18−22
These two possibilities are summarized nicely by Buchwald,23
as well as Lennox and Lloyd-Jones,20 and the weight of
evidence seems to point toward involvement of an
intermediate species of the type LnPd(aryl)(OH). However,
recent work by Lima and co-workers has suggested that in
typical Suzuki−Miyaura reaction conditions, the major
Received: September 27, 2018
© XXXX American Chemical Society
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reaction, it may be included on either the boronic acid or the
aryl halide (also, charged spectator ligands can be used to
interrogate the catalyst directly).46,48 In this study, we focused
on the aryl iodide (Ar+I), as it highlights post oxidative
addition intermediate species (as oxidative addition is not
turnover-limiting for aryl iodides), where the Ar+B(OH)2 only
shows post-transmetalation species (additionally complicated
by the zwitterionic aryl-boronate that forms in the presence of
base; see Supporting Information). The phosphonium tag is
sufficiently bulky and surface-active that it dominates the ESI
mass spectrum to such an extent that the total ion current
remains approximately constant throughout the reaction
(providing good mass balance throughout), and the inclusion
of a noncoordinating anion ensures aggregate ions do not
complicate the spectra and that ion pairing does not diminish
intensity. Additionally, the phosphonium no longer bears the
lone pair of electrons necessary for involvement as an L-type
ligand, avoiding the complication of mixed-ligand systems. We
have previously employed this charge tag to study the
Sonogashira reaction and found that PSI-ESI-MS reaction
progress traces agree well with ultraviolet/visible spectroscopy
and NMR data, indicating that the relative intensity of species
bearing this moiety can represent the overall progress of
reaction.49
Scheme 1. Various Mechanisms for the Transmetalation
Step of Suzuki Cross-Coupling of Aryl Iodides
a
RESULTS AND DISCUSSION
■
Experiments with a Positively Charged Aryl Iodide.
As a first step in order to verify that the charge tag does not
significantly affect the overall chemistry, a laboratory scale
Suzuki reaction was conducted that yielded the expected
coupled biaryl product (Figure 1). The reaction can also be
a
Ar, Ar′ = aromatic groups, L = PPh3, X = halide.
did not find LnPd(aryl)(OH) species.34−37 One of these
studies suggested that the transmetalation was between
cationic [LPd(aryl)]+ and RB(OR)2,34 and the other suggested
that the observed [L2Pd(aryl)]+ was generated via dissociation
of an anionic ligand from the L2Pd(aryl)(X) species.35
Computational approaches have also been extensively
employed to probe the various possibilities, and where
mechanistic pathways were compared, these studies found
that the most feasible path is the reaction between L2Pd-
(aryl)(X) and the anionic [ArB(OH)3]−.2,11,18,38
We set out to study the Suzuki−Miyaura reaction using
pressurized sample infusion electrospray ionization mass
spectrometry (PSI-ESI-MS),39 with the aim of gathering
evidence for one (or more) transmetalation mechanisms. PSI
is a simple method of transferring reacting solution
continuously from the reaction flask directly into a mass
spectrometer, akin to a cannula transfer. PSI-ESI-MS allows
the straightforward measurement of the abundances of
reactants, products, byproducts, intermediates, resting states,
and decomposition products in a catalytic reaction, with the
caveat that only the ionic species are observable by this
technique.40 Cooks has used a slightly different setup to
examine a variety of catalytic reactions; however, no catalyst-
containing species were observed.41 We alter the substrate
(natively neutral) by the use of charged tags,42−47 and in this
instance the aryl group was appended with a phosphonium tag
in the para position, [-C6H4−CH2−PPh3]+[PF6]−, denoted
“Ar+”. The phosphonium group conveys a positive charge to all
species incorporating it, and in the case of the Suzuki−Miyaura
Figure 1. X-ray crystal structure of [4,4′-MeC6H4C6H4CH2PPh3]-
[PF6]. The new C−C bond is between C5 and C8. The angle
between the benzyl and tolyl rings is 26.76(8)°, and the bond angles
and lengths were similarly ordinary.
studied using the uncharged version (to enable the detection of
charged species that appear without the involvement of a
charged tag) and in the negative ion mode (to detect any
possible anionic catalyst species or boronate species).
Perhaps the most informative perspective our approach
(real-time analysis with mass spectrometry of a catalytic
reaction using a charged tag) can provide is through direct
observation of the intermediates, noting how their abundance
changes over the course of the reaction, and their dynamic
response to the addition of various reaction components. This
information is generally difficult to obtain with other
techniques, at least in a way that provides unambiguous
identification of potential intermediates. Our initial results
were promising: we found conditions in which the reaction
proceeded quickly, under which our charged tag was stable,
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and where ESI-MS response factors between product and
starting material were very similar (demonstrable by the
consistency of the total ion current over the course of
reaction). We could observe the charge-tagged aryl iodide
starting material (Ar+I), the coupled biaryl product (Ar+Ar′),
and a possible palladium-bearing intermediate (Figure 2). If
Information). The pseudo-first-order behavior of the traces is
demonstrated in Figure 3A, inset, where the natural logarithm
of Ar+I intensity is linear with time to 5 half-lives (∼97%
consumption), indicating that the intensity is a good
representation of the relative amount of Ar+I in solution,
thus allowing for reliable kinetic analysis. The stable ion
current during these experiments is diagnostic of the
homogeneity of the solution (phase separation or insolubility
manifests as irregularities in the spray, and the traces become
very noisy).
In methanol, the two intermediates visible to ESI-MS are
[L2Pd(Ar+)I] and [L2Pd(Ar+)]+ (where L = PPh3). The bis-
cationic [L2Pd(Ar+)]+ is likely the product of halide
dissociation (eq 1):
[L2Pd(Ar+)]+ exists in solution as the solvent stabilized
adduct (see Supporting Information); it is doubly charged as it
both bears the phosphonium-tagged aryl moiety and is an
ML2X species with a palladium(II) center and so is inherently
cationic even without the charged tag. [L2Pd(aryl)]+ species
have been detected before by ESI-MS, but in those cases, it
was thought they appeared because halide loss was the most
facile mechanism by which a charged complex could be
produced for detection by ESI-MS.35,50 In the absence of a
charged tag, ionization can occur through a variety of different
mechanisms including association with a cation or oxidation,51
but the inherent efficiency of a permanent charge tends to
render these processes relatively unimportant. In this case,
[L2Pd(Ar+)]+ forms despite the fact that the electrospray
ionization process would disfavor its appearance (separation of
an anion from a dication is energetically prohibitive in the gas
phase), confirming that it is indeed formed in solution. Both
[L2Pd(Ar+)I] and [L2Pd(Ar+)]+ are pretransmetalation spe-
cies, indicating that transmetalation is turnover-limiting under
these conditions. Once the cation is formed, any X-type ligand
available in solution may coordinate to the palladium, with the
equilibria between these X-type ligands being governed by the
nucleophilicity of the ligand as well as the donor ability of the
solvent. We frequently observe low levels of [L2Pd(Ar+)(Cl)]
in our reaction solutions due to the ubiquity of chloride ions
and the sensitivity of the ESI-MS technique.
Figure 2. Summed ESI(+) mass spectrum of a Suzuki reaction run in
methanol (40 °C). Ar+I = [IC6H4CH2PPh3]+, Ar′ = p-CH3C6H4B-
(OH)2. [Ar+I][PF6] 0.6 mM, ArB(OH)2 1.2 equiv, Cs2CO3 17 equiv
in 10 mL of MeOH.
the abundances of these species were tracked over time, we
observed the expected pseudo-first-order kinetics of Ar+I and
Ar+Ar′ (Figure 3A), as well as the behavior of observed
palladium intermediates (Figure 3B), and the traces showed
good reproducibility across replicates (see Supporting
Under our conditions, the reaction is first order in boronic
acid with constant base concentration (see Supporting
Information) and is known to be first order in catalyst.15
The reaction is complete within a few minutes in refluxing
methanol, but takes hours at room temperature. The reaction
was monitored at 30, 40, 50, and 65 °C, and the entropy and
enthalpy of activation for the overall reaction were determined
from an Eyring plot as ΔS⧧ = 20 20 J·mol−1 and ΔH⧧ = 104
6 kJ·mol−1, respectively (Figure 4). The variable effect of
temperature on reaction rate in this plot clearly demonstrates
that the reaction is taking place in solution as opposed to being
an artifact of the ESI-MS process.52,53
A variety of boronic acids (para-substituted −H, −CH3, -Cl,
−CN, −COOCH3, −OCH3, and −CF3) were subjected to our
reaction conditions to probe the relative substituent effects.
The resulting Hammett plot (Figure 5) gave ρ = −2.1, a trend
that indicated that electron-donating groups on the boronic
acid resulted in rate enhancement, which is in agreement with
Figure 3. Relative species intensity over time for reactant and product
(A) and palladium intermediates (B) using the same conditions as
Figure 2. Inset: natural log of the intensity of Ar+I over time showing
well-behaved pseudo-first-order kinetics out to 5 half-lives.
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Figure 4. Relative species intensity over time of several Suzuki
reactions monitored at 30, 40, 50, and 65 °C in methanol with Ar+I
(0.5 mM), solid Na2CO3 (10 equiv), p-tolylboronic acid (1.2 equiv),
and 5 mol % Pd(PPh3)4. Reactions are first-order. Inset: Eyring plot
constructed from the consumption rates of Ar+I.
Figure 6. Relative species intensity over time for (A) abundant
species and (B) palladium intermediate in a sequential addition of
Pd(PPh3)4 (5 mol %, at 9 min) and MeOH (excess, at 22 min) to a
MeCN solution of Ar + I (0.15 mM), p-tolylboronic acid (1.1 equiv),
and solid Na2CO3 (10 equiv) monitored by PSI-ESI(+)-MS.
Even with all reaction components present in MeCN except
for a protic solvent (aryl halide, boronic acid, Na2CO3 base,
Pd(PPh3)4 catalyst), no reaction occurred. [L2Pd(Ar+)I] and
[L2Pd(Ar+)]+ both formed, but they did not react to form any
product until an aliquot of methanol was added (Figure 6).
The logical roles of the MeOH could be formation of
[L2Pd(Ar+)(OMe)], formation of the boronate [Ar′B(OR)3]−
(R = H or Me), or as a phase transfer catalyst for boronic acid
or boronate. The latter can be can be excluded because both
boronic acid and boronate are soluble in MeCN to
concentrations much higher than those employed. This
experiment would seem to exclude mechanisms involving
direct transmetalation between [L2Pd(Ar)I] and Ar′B(OH)2,
and between [L2Pd(Ar)]+ and Ar′B(OH)2, because under
these conditions, all these components are present and they do
not result in catalytic turnover.
Experiments in the Negative Ion Mode. We decided to
examine the speciation in the negative ion mode, to see if the
changes were consistent with what was happening in the
positive ion mode. An experiment was set up where an MeCN
solution containing Ar′B(OH)2 (Ar′ = p-C6H4OMe) and
Na2CO3 was examined, while adding first MeOH, then Ar+I,
then the Pd(PPh3)4 catalyst (the order of addition was
modified to observe the changes in boron speciation). The
speciation changes were rapid (Figure 7).
The boronic acid does not appear in these traces because it
is neutral, but weak signals were observed for boroxine species
[(BOAr′)n + OH]− (n = 3 or 4).59 These however disappeared
instantly upon addition of methanol, to be replaced by the
[Ar′B(OMe)3]− boronate species, which achieved a stable
intensity within 10 min. Addition of aryl halide (Ar+I) did not
affect the equilibrium significantly (all boronate species
remained unchanged, though the signal was partially sup-
pressed by the addition of [PF6]−). However, addition of
catalyst caused a precipitous drop in aryl boronate concen-
Figure 5. A Hammett plot showing the effect of the para-substituent57
of the boronic acid on the rate of reaction. The trend indicates that
electron-donating para-substituents enhance the reaction rate under
our conditions. Ar+I 0.32 mM, ArB(OH)2 1.1 equiv, Cs2CO3 20
equiv, 8 mol % Pd for all reactions.
previous findings in other studies in methanol and
dimethylformamide21,54,55 but is in contrast with another
study on aryl boronic acids, which found a small positive
correlation in 1,4-dioxane.56
These kinetic experiments illustrate that PSI-ESI-MS can be
used to obtain the expected kinetic behavior of the Suzuki−
Miyaura reaction, but does not provide insight into the
transmetalation mechanism. If consumption of [L2Pd(Ar+)I]
was turnover-limiting, what was it reacting with? Based on the
currently accepted mechanism, we assumed that halide
dissociation and methoxide coordination was occurring to
form [L2Pd(Ar+)(OMe)], which is rapidly consumed by
boronic acid to form [L2Pd(Ar+)(Ar′)]. As such, we needed
to conduct experiments in a nonprotic solvent, so we could
examine directly the effect of adding methoxide. We repeated
our reactions in dry acetonitrile, which is an excellent solvent
for ESI-MS and one in which the coupling reactions proceeded
readily (Figure 6).34,55,58 Interestingly, [L2Pd(Ar+)]+ was the
most prominent palladium species in the spectrum, with
[L2Pd(Ar+)I] lost in the noise. Clearly, acetonitrile is a better
donor for the stabilization of I− displacement from palladium
than methanol.
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acetonitrile. With no source of protic solvent present (water or
methanol), we could determine whether boronates are
important transmetalation partners. We prepared a Miyaura
caged triesterboronate and characterized it fully as the
tetraethylammonium salt (Figure 8).61
Figure 8. X-ray crystal structure of [NEt4][PhB(O3C5H9)]. The
tetraethylammonium cation and solvent of crystallization have been
excluded for clarity. The compound was characterized crystallo-
graphically as the dihydrate, but all samples used in the MS studies
1
were dried until no water was observable in the H NMR spectrum
(see Supporting Information). Key bond lengths and angles: B1−C6
1.6142(16) Å; B1−Oaverage 1.494 Å; C6−B1−Oaverage 110.5°; B1−O−
Caverage 111.2°.
The triesterboronate was soluble and stable in acetonitrile
solutions, and 11B studies indicated that a single boronate
species exists in aprotic solvents on the NMR time scale (see
Supporting Information). In the presence of stoichiometric
amounts of water or methanol, only trace amounts of
hydrolysis (or methanolysis) products were observed, and a
large excess of water or methanol resulted in more extensive
reaction (see Supporting Information). However, without
additional water or methanol, no other boronate species are
observed, and the intensity remains constant.
Figure 7. Relative species intensity over time in a sequential addition
of MeOH (excess, at 3 min), Ar+I (1 equiv., at 11 min), and
Pd(PPh3)4 (5 mol %, at 16 min) to a MeCN solution of
MeOC6H4B(OH)2 (0.7 mM) and solid Na2CO3 (14 equiv). Traces
are shown for all abundant anions except PF6 (the counterion for Ar+I
which is not involved in the reaction). Due to changes in the spray
conditions with each addition, each species is normalized to its
maximal intensity value.
The charged aryl iodide (Ar+I) and catalyst precursor were
combined in acetonitrile in the absence of base, and as before,
the [L2Pd(Ar+)]+ and [L2Pd(Ar+)(I)] complexes appear with
good intensity (indicating that the base does not significantly
affect the oxidative addition reaction). A solution of the
triesterboronate was injected to instant effect: the intensity of
both intermediates plummeted into the baseline, and product
was rapidly formed (Figure 9). An identical reaction tracked in
the negative ion mode showed pseudo-first-order disappearance
of the caged boronate (see Supporting Information).
tration down to a low steady-state concentration, and
[B(OMe)4]− byproduct was steadily generated (significant
changes in the ESI spray are likely to blame for the exaggerated
drop in arylboronate intensity).
The prominence of the boronate species in the spectrum,
and especially their appearance only after methanol was added,
led us to consider the possibility that perhaps it was the
boronate that was the coupling partner rather than the boronic
acid. This observation is consistent with a mechanism
involving L2Pd(aryl)X and [(aryl)B(OR)3]−. A 1994 paper
by Smith et al. pointed out that the transmetalation reactivities
of aryl bromide and iodotoluene are about the same, so they
assumed from this that a dissociative transmetalation involving
[L2Pd(Ar)]+ and [ArB(OH)3]− was unlikely.58 However, it is
not completely clear to us why this should be the case; the
iodide ligand may be less strongly bound to palladium, but the
degree of solvation of the bromide anion is likely to be higher,
and exactly how these effects compare to each other deserves
further investigation.
Experiments with Premade Boronates. Given that aryl
boronates have been previously shown to undergo Suzuki−
Miyaura couplings in the absence of added base or
nucleophile,60 an experiment was devised to determine the
extent of the participation of boronates. Miyaura introduced
caged triesterboronates as effective coupling partners that do
not require added base,8 and we were interested to see if these
reacted directly with either [L2Pd(Ar+)I] or [L2Pd(Ar+)]+ in
In this case, the possibility of an [L2Pd(Ar+)(OR)]
intermediate forming is greatly reduced, as no ROH (R = H
or Me) is present, but it is possible that one of the alkoxy arms
of the triesterboronate dissociates from the boron and
coordinates to palladium. ESI-MS cannot distinguish to
which atoms each oxygen is bonded, but the dissociation of
oxygen from boron should be suppressed by the chelate effect.
Despite this transformation being disfavored, L2Pd(aryl)(OR)
has been shown to rapidly transmetalate, so this is still a
possible reaction pathway.16 Given that we did not observe any
of these L2Pd(aryl)(OR) species in any of our reactions, we
entertained the possibility that there could be a direct reaction
between [L2Pd(Ar+)(I)] and [Ar′B(OR)3]− or between
[L2Pd(Ar+)]+ and [Ar′B(OR)3]−. While the data show that
[L2Pd(Ar+)]+ disappears very rapidly upon addition of
triesterboronate, it is possible that this process could simply
be a fast recoordination of I− driven by consumption of
[L2Pd(Ar+)(I)].62 We could eliminate this possibility by
adding AgNO3 to efficiently remove any free iodide from
solution,14 and when this reaction is carried out, the reaction
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boronate was performed, but upon boronate addition,
precipitate immediately formed in the reaction flask, and no
coupled product was observed (presumably the silver formed
an insoluble salt with the boronate).
Locating the Hydroxyl-Palladium Species. We were
particularly concerned that we had never observed the
L2Pd(aryl)(OR) intermediate (or its respective dimer) in
any of our reaction solutions, where so many other studies had
assigned electrochemical or 31P signals to this species.
Accordingly, we set up an experiment that optimized
conditions for its formation, namely, charge-tagged aryl iodide
Ar+I, Pd(PPh3)4, Na2CO3 base, and methanol. No source of
boronic acid or boronate was added. Under these conditions,
we expect the formation of the dimer species L2Pd2(Ar+)2(μ-
OR)2, as it is should be preferably formed (with R = Me or H,
L = PPh3).17 We collected data for 15 min, accumulating 1019
scans under conditions where the signal-to-noise ratio for
[L2Pd(Ar+)I] was ∼7500 to 1. Under such conditions, we
could detect no [L2Pd(Ar+)(OMe)], [L2Pd(Ar+)(OH)], or the
dimers [L2Pd2(Ar+)2(μ-OR)2] (R = H or Me), suggesting that
if any of these species do form, the equilibrium between
[L2Pd(Ar+)I] and [L2Pd(Ar+)(OR)] (or between [L2Pd-
(Ar+)]+ and [L2Pd(Ar+)(OR)]) lies a long way to the former
(Scheme 2; see Supporting Information).
Figure 9. Relative species intensity over time in a sequential addition
of Pd(PPh3)4 (5 mol % at 10 min) and [NEt4][PhB(O3C5H9)] (1
equiv at 18 min) to an acetonitrile solution of Ar+I (2.6 mM)
monitored by PSI-ESI(+)-MS. Intermediate intensity is multiplied by
a factor of 800.
still proceeds rapidly despite the complete absence of any
detectable L2Pd(Ar)(I) (Figure 10). Note the disappearance of
Scheme 2. Equilibria between L2Pd(aryl)(I) and
a
L2Pd(aryl)(OH)
a
The L2Pd(aryl)(X) (X = I or OH) have the potential to dimerize to
the form [L2Pd2(aryl)2(μ-X)2].
We reasoned that perhaps Na2CO3 was too weak a base to
generate the hydroxyl-palladium species in detectable amounts,
so we adjusted our conditions to resemble the conditions used
by others for preparation of L2Pd(aryl)(OH). This species can
be isolated if a dichloromethane solution of L2Pd(aryl)I is
treated with sodium hydroxide,17 so we tried those conditions
with our charge-tagged aryl iodide, and [L2Pd(Ar+)(OH)]
appeared with excellent intensity. The MS/MS spectrum
(Figure 11) of this species is entirely consistent with the
assignment, first losing a PPh3 ligand, then another, after which
a species corresponding to [Ar+OH] was seen in addition to
[PPh4]+. The fact that we can observe this species given the
correct conditions (noncoordinating solvent and strong base)
suggests that the observed [L2Pd(Ar+)]+ is a separate species
from [L2Pd(Ar+)(OH)] and is not an artifact of the ESI
process. It is important to note that [L2Pd(Ar+)]+ is not part of
the CID fragmentation pathway of [L2Pd(Ar+)(OH)], adding
weight to the assertion that the dication is a distinct species.
Under similarly forcing conditions, that is, excess sodium
methoxide in CH2Cl2, [L2Pd(Ar+)(OMe)] and the dimer
species [L2Pd2(Ar+)2(μ-OMe)2] could be readily observed
(see Supporting Information). Sequential reactions with the
boronic acid were attempted in CH2Cl2, but addition of the
boronic acid to the strongly basic solution generated a large
Figure 10. Relative species intensity over time for (A) reactant and
product, and (B) palladium intermediates in a sequential addition
reaction of Pd(PPh3)4 (8 mol % at 1 min), AgNO3 (1.5 equiv at 4
min), and p-tolylboronic acid (1.1 equiv at 7 min) to a methanol
solution of Ar+I (0.5 mM) and solid Na2CO3 (9 equiv) monitored by
PSI-ESI(+)-MS. Spray instability was observed after the addition of
AgNO3, which is likely due to clogging of the PEEK tubing by AgI
particles.
[L2Pd(Ar+)I] and the boost in abundance of [L2Pd(Ar+)]+
upon addition of AgNO3. Subsequent introduction of ArB-
(OH)2 resulted in the [L2Pd(Ar+)]+ disappearing in favor of
product Ar+−Ar′. This observation is curious, as this does not
appear to agree with either of the popular transmetalation
mechanisms (Scheme 1A,B). A similar reaction using the caged
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Figure 11. ESI(+)-MS/MS of (PPh3)2Pd(Ar+)(OH) at m/z 999.2 generated from a mixture of Pd(PPh3)4, Ar+I (1 equiv relative to Pd(PPh3)4),
and NaOH (excess) in dichloromethane. Inset: the predicted isotope pattern (bars) overlaid on the experimental mass spectrum (line) of
(PPh3)2Pd(Ar+)(OH).
amount of precipitate (presumably insoluble boronates), and
no product formed.
We found it difficult to reconcile our results with the popular
mechanisms. We could not detect any amounts of [L2Pd-
(Ar+)(OR)] in any reaction that resulted in product formation,
which does not agree with the hydroxyl-palladium mechanism.
However, it is of course possible that even though the
equilibrium resulting in L2Pd(aryl)(OR) lies a long way toward
[L2Pd(Ar)]+ (as evidenced by abundance below the detection
limit of ESI-MS), the brief formation of this species and direct
reaction with the arylboronic acid is a viable transmetalation
process. At this stage, it seemed our results gave evidence for
transmetalation through L2Pd(aryl)X, except that trans-
metalation with arylboronate is preceded by halide dissocia-
tion. Some transmetalation mechanisms have been tested
Figure 12. Species intensity over time in a sequential addition of
computationally, and the reaction of [ArB(OH)3]− with
iodobenzene (1.8 mM, 2.2 min), Pd(PPh3)4 (5 mol % at 5.6 min),
L2Pd(Ar)X (Scheme 1B) should be favored over the reaction
and phenylboronic acid (1.4 equiv at 8.7 min) to methanol and solid
of ArB(OH)2 with L2Pd(Ar)(OH) (Scheme 1A).11,18,38,63 To
Na2CO3 (5 equiv). Reaction was monitored by ESI(+)-MS and was
our knowledge, no one has tried to calculate the [L2Pd(Ar)]+
plotted as raw counts due to changes in spray behavior of the species
and [ArB(OH)3]− pathway (Scheme 1D).
with each addition.
Experiments without a Charged Tag. We are conscious
of criticism of the fact that we invoke charged intermediates
(because we use a technique that can only detect ions), but in
this case, a cationic intermediate is observed despite the
positively charged tag. We can make some predictions about
what we ought to see when examining the reaction with
reactants that are not charge-tagged if a cation is involved. For
the untagged system, we would expect to see only [LnPd(Ar)]+
in the positive ion mode, and perhaps only if the trans-
metalation is a relatively slow step. In the negative ion mode,
we would expect to see boronate replaced by iodide as the
reaction proceeds. Both of these predictions play out (Figures
12 and 13). The only Pd-containing intermediate observed in
the positive ion mode is [L2Pd(Ar)]+, and it disappears quickly
upon addition of the boronic acid. In the negative ion mode, a
small steady amount of iodide immediately appears upon
addition of the catalyst to the phenyl iodide. Addition of the
boronic acid results in the appearance of boronate species in
the mass spectrum, which slowly goes away to be replaced by
iodide (which appears with much lower intensity than the
boronate species due to its much lower surface activity).
Aggregate species are also noted in both ion modes and
provide evidence that the reaction taking is place, even in the
absence of a deliberately added charged tag.
If we charge-tag the boron species with a positively charged
tag, we would expect this to be in equilibrium with the
zwitterionic charge-tagged boronate, but the product biaryl
compound will experience no such complication. The only
possible Pd-containing intermediates should be [LnPd(Ar)]+
and [LnPd(Ar)(Ar′+)] (the latter charged now via Ar′ rather
than Ar). Again, the speciation and reactivity is consistent with
these predictions (see Supporting Information).
Reactivity of Cationic Palladium Complexes. Cationic
palladium complexes are known and can be readily prepared in
a form close to [L2Pd(Ar)]+ by stabilizing the complex with a
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Figure 15. Relative species intensity in a sequential addition reaction
of [(Ph3P)2Pd(Ph)][OTf] (0.8 equiv at 5 min) and methanol (excess
at 33 min) to a solution of [NEt4][PhB(O3C5H9)] (0.5 mM) in dry
acetonitrile monitored by PSI-ESI(+)-MS. The apparent jump in
intensity upon addition of methanol arises from changes in spray
conditions rather than through a change in abundance.
Figure 13. Species intensity over time for the sequential addition of
iodobenzene (1.8 mM at 2.7 min), Pd(PPh3)4 (5 mol % at 4.8 min),
and phenylboronic acid (1 equiv at 7.8 min) to methanol and solid
Na2CO3. Reaction was monitored by ESI(−)-MS and was plotted as
raw counts due to changes in spray behavior of the species with each
addition. The large difference in intensity of [PhB(OMe)3]− (starting
material) and [B(OMe)4]− (products) is due to the starting material
being much more surface active.
The Role of Water and Fluoride. Since the boronate is
clearly not interacting directly with the palladium cation, the
question then arose as to why we observed reactivity in Figure
9 (triesterboronate plus Ar+I in acetonitrile, no added base).
The reaction in Figure 9 was repeated, each time showing
similar traces, and through adjustment of a variety of
conditions, we found that the reactivity was likely due to
catalytic concentrations of water present in the acetonitrile
(see Supporting Information). This result indicates that the
caged arylboronate must first be hydrolyzed prior to reaction,
and does not directly react with the palladium cation, or that
trace water is responsible for the formation of very reactive
[L2Pd(Ar+)(OH)]. Additionally, the binding strength of
triflate anion used for isolation may have inhibited the
dissociation to a sufficient extent as to prevent reaction (a
phenomenon noted in the recent work of the Carrow group).26
Instead, we turned our attention to the recent work from the
Denmark group, who had observed Pd−O−B−aryl structures
using low temperature NMR (Figure 16).24,25 The proposed
weakly bound donor ligand.64 Accordingly, an untagged
palladium cation complex was independently synthesized and
isolated as the 4-methylpyridine adduct (Figure 14).
Figure 14. X-ray crystal structure of [(Ph3P)2Pd(Ph)(C6H7N)]-
[OTf]. The triflate anion, solvent of crystallization (CH2Cl2), and
hydrogens have been excluded for clarity. Key bond lengths and
angles: Pd1−C7 2.0196(19) Å, Pd1−N1 2.1244(16) Å, C7−Pd1−N1
176.46(7)°, N1−Pd1−P2 89.85(4)°, N1−Pd1−P1 92.81(4)°, C7−
Pd1P2 86.77(6)°, C7−Pd1−P1 90.45(6)°.
Figure 16. Intermediate structure determined by Denmark and co-
workers.24,25
structure of this species effectively contained two subunits: the
palladium cation [L2Pd(aryl)]+ and a deprotonated arylboronic
acid [O(HO)B(aryl)]−. We had observed in other work an
arylboron species of mass corresponding to that of the
deprotonated boronic acid, and considered that perhaps
these two could exist separately in solution and interact to
form the pretransmetalation intermediate.
When the isolated palladium cation and arylboronic acid
were dissolved in the presence of added base (NEt3), no
reaction was observed, again requiring the addition of
If the cationic mechanism were operative, we would expect
that combining it with the caged boronate would result in
transmetalation. However, when this reaction was performed
in dry acetonitrile, no consumption of the [LnPd(Ar)(4-
methylpyridine)]+ was observed, instead requiring an aliquot
of methanol to facilitate reaction (Figure 15). The lack of
reactivity may be due to the difficulty of displacing pyridine,
but the ease of displacing this ligand in the ESI process
suggests it is much more labile than PPh3.
H
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methanol for reaction to occur (see Supporting Information).
The negative ion mode indicated that the intended
deprotonated arylboronic acid was not formed, and instead
the base promoted the formation of arylboroxine species,
which appear to be unreactive in Suzuki−Miyaura reactions
(Figures 6 and 7). The arylboron speciation was studied in a
titration experiment, and it was found that the arylboroxine
species hydrolyze quickly and are mostly converted to other
species by the addition of an excess of water (see Supporting
Information). Several other bases were tested (K2CO3,
Cs2CO3, DBU), but none resulted in the observation of the
deprotonated arylboronic acid. We turned to the work of
Amatore and Jutand, who found that the presence of fluoride
ions could facilitate the reaction between L2Pd(aryl)(I) and
PhB(OH)2 in DMF and asserted that transmetalation occurred
between L2Pd(aryl)(F) and the boronic acid (Scheme
1C).32,65 We reasoned that this could also be facilitated by
fluoride deprotonating boronic acid (as the pKa of strong acids
is increased significantly in nonaqueous conditions).66 In that
work, the authors used [NBu4][F] as a fluoride source, so we
prepared a reaction to promote formation of the posited
L2Pd(aryl)(F) using our charged aryl halide. Despite increasing
the catalyst loading to 25 mol %, no trace of [L2Pd(Ar+)(F)]
was observed (see Supporting Information). It appears that
fluoride is insufficiently nucleophilic to coordinate to
palladium under these conditions, but perhaps in more weakly
coordinating solvents (such as DMF), this coordination could
occur. Despite the lack of observation of the putative
intermediate, when arylboronic acid was added to the reaction
solution, slow product formation was observed (Figure 17).
with the formula Ar′B(OMe)n(F)m(OH)o (n + m + o = 3)
being observed in addition to several other boron species, all of
which eluded assignment (the CID spectra of these species
provided no additional information). Additionally, an ion with
mass corresponding to the deprotonated [Ar′BO2H]− was
observed only after the addition of water. The presence of both
it and the palladium cation in solution simultaneously indicates
that the direct reaction of these two components does not
occur, and the Denmark intermediate must be approached
from a different combination (perhaps the anionic oxygen is
not nucleophilic enough to facilitate this coordination) or our
structural assignment of [Ar′BO2H]− is not an accurate
representation of the ion in solution.
The halting of turnover is curious, as it appears that there is
slow turnover in the presence of minimal water and fluoride
(presumably fluoride-mediated), but turnover is halted when
the conditions involve more water. Interestingly, this suggests
that there must be at least two mechanisms that can
accomplish Suzuki−Miyaura couplings (this fluoride-mediated
mechanism cannot be active under most Suzuki−Miyaura
conditions, as the majority contain large amounts of water).
We were unable to detect any species under these conditions
that provide evidence for a particular mechanism.
EXPERIMENTAL SECTION
■
[4-IC6H4(CH2)PPh3][PF6] was prepared through a previously
published synthesis.67 All other chemicals were used as obtained
from Sigma-Aldrich. Solvents were purified on an MBraun solvent
purification system. All gases used were obtained from Airgas. Mass
spectra were processed with the assistance of ProteoWizard,68 and
species assignments were in part assisted by ChemCalc.69 The
Supporting Information contains more details including conditions for
the various experiments described, additional mass spectra, NMR
data, additional reaction traces, X-ray crystal structures, and structural
data.
Synthesis of [4-(B(OH)2)C6H4(CH2)PPh3][PF6]. Triphenylphos-
phine (0.22 g, 1 mmol) and 4-(B(OH)2)C6H4CH2Br (0.40 g, 1.5
mmol) were dissolved in toluene (10 mL). The reaction mixture was
stirred at room temperature for 16 h. The resulting white precipitate
was filtered and washed with toluene to remove excess PPh3, leaving
the product [4-(B(OH)2)C6H4(CH2)PPh3][Br] (yield 0.3 g, 65%). A
salt metathesis was performed with [Na][PF6] (0.55 g, 2 mmol)
giving [4-(B(OH)2)C6H4(CH2)PPh3][PF6] (yield 0.100 g, 50%) after
stirring for 1 h in methanol. 1H NMR (300 MHz, CD2Cl2) δ 4.35 (d,
2H, J = 14 Hz), 6.83 (dd, 2H, J = 3, 8 Hz), 7.30−7.65 (m, 6H), 7.80
(td, 8H, J = 2, 8 Hz). 31P NMR (300 MHz, CD2Cl2) δ 22.38 (s).
ESI(+)-MS: m/z 425.2 in MeOH (both OH groups are substituted
with OMe).
Synthesis of [4,4′-MeC6H4C6H4CH2PPh3][PF6]. Compound 1
(0.896 g, 1.6 mmol), p-tolylboronic acid (0.240 g, 1.8 mmol), sodium
carbonate (1.67 g, 16 mmol), and tetrakis(triphenylphosphine)-
palladium(0) (0.094 g, 0.4 mmol) were dissolved in MeCN (30 mL)
and water (2 mL). The solution was refluxed for 1 h resulting in a pale
yellow precipitate. The product was pumped to dryness in vacuo. A
salt metathesis was performed with [Na][PF6] (0.795 g, 3 mmol) in
methanol (5 mL) with stirring for 2 h (yield 0.300 g, 40%). 1H NMR
(300 MHz, CD2Cl2) δ 2.36 (s, 3H), 4.59 (d, 2H, J = 9 Hz), 6.93 (dd,
2H, J = 2, 8 Hz), 7.20 (d, 2H, J = 2 Hz), 7.34−7.40 (m, 4H), 7.49−
7.56 (m, 6H), 7.60−7.67 (m, 6H), 7.76−7.79 (m, 3H). 31P NMR
(300 MHz, CD2Cl2) δ 22.70 (s). ESI(+)-MS: m/z 443.2. Crystals
suitable for X-ray analysis (Figure 1) were prepared by dissolving the
product in hot ethanol and allowing slow crystallization at room
temperature.
Figure 17. Relative species intensity over time in a sequential addition
of p-tolylboronic acid (1 equiv, 4 min) and water (excess, 22 min) to
a solution of [Ar+I][PF6] (0.3 mM), [NBu4][F] (2 equiv), and
Pd(PPh3)4 (25 mol % total) in methanol.
Since the [NBu4][F] was added as the trihydrate, we reasoned
that the slow product formation was a result of low
concentrations of water, so an aliquot of water was added,
curiously halting the reaction. The palladium intermediate
[L2Pd(Ar+)(I)] was still observed after water addition, and the
reaction solution remained clear and colorless, indicating that
the catalyst had not decomposed.
If this reaction is followed by ESI-MS in the negative ion
mode, a series of aggregates of the formula Ar′B(OMe)n(F)m
(n + m = 3, Ar′ = p-tolyl) were observed after the addition of
[NBu4]F. The spectrum became significantly more compli-
cated after the addition of water, with a series of aggregates
I
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conditions to produce detectable quantities of the fluoride
complex. As the addition of protic solvent to these mixtures
affects both the palladium and boron speciation simulta-
neously, we were unable to distinguish which speciation
changes are ultimately responsible for reactivity.
CONCLUSIONS
■
Ultimately, what was intended to be a relatively simple
investigation into the transmetalation step in the Suzuki
reaction ended up being a broad survey of possible coupling
partners. Despite combining a wide range of potential reactants
(Scheme 3), we did not find a pair that could both be present
Complexes of the type [L2Pd(Ar)]+ were similarly treated
with different boron-containing substrates, including in a
stoichiometric reaction between [L2Pd(Ph)(pyridine)]+, and
proved unreactive toward all candidates. This result suggested
that the role of [L2Pd(Ar)]+ is to serve as an intermediary
between L2Pd(Ar)(I) and the unidentified pretransmetalation
palladium intermediate.
Scheme 3. Proposed Set of Equilibria Resulting from the
Various Palladium and Boron-Containing Species
a
Considered Herein
Complexes of the type L2Pd(Ar)(OH) and L2Pd(Ar)(OMe)
were not detectable under normal catalytic conditions, though
both were readily observed as the most abundant species when
generated via the addition of very strong base in nonpolar
solvents.
In every case where the reaction turns over, the presence of
H2O or MeOH is required. What is the ROH (R = Me or H)
doing? ROH perturbs the speciation of the boronic acid,
especially in the presence of base, by facilitating the formation
of [ArB(OR)3]−, but independent testing of preformed
boronates of this type suggest that they are no more prone
to react than boronic acids. ROH also provides a source of an
alkoxide ligand. While we do not see any species of the type
L2Pd(Ar)OR, it is most likely in low concentration but in rapid
equilibrium with some other Pd−Ar species such that its
abundance never rises to detectable levels under catalytic
conditions, even when those detectable limits are those of a
technique as sensitive as mass spectrometry.
ASSOCIATED CONTENT
* Supporting Information
■
a
L = phosphine ligand, R = H or Me, and R′ = OR or F.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00705.
in detectable quantities in separate solutions and produce
immediate reactivity. However, we can offer suggestions about
what is needed to enable rapid reaction to occur.
Additional mass spectra, reaction monitoring, synthetic
The boronic acid speciation is dynamic and greatly affected
by reaction conditions (Scheme 3, right-hand side). Arylbor-
onic acid ArB(OH)2 is dehydrated to boroxine [ArBO]m (m =
3, 4) in anhydrous conditions. It may also be deprotonated to
give [ArBO2H]−, which was unreactive with any palladium
species, indicating that the intermediate proposed by Denmark,
4, is likely not formed by the direct interaction of [L2Pd(Ar)]+
and [ArBO2H]−. In basic conditions, ArB(OH)2 is in
equilibrium with boronate [ArB(OR)3]− (R = H or Me). In
the presence of fluoride ions, the OR groups may be
substituted for F. Given the variety of boronic species
accessible via these equilibria, it is likely that many of these
are simultaneously accessible under a given set of conditions
and that the key for transmetalation lies in the palladium
speciation.
The L2Pd(Ar)I complex showed no apparent reactivity with
the boron containing species Ar′B(OH)2, [ArB(OR)3]−, and
[ArBO]n (n = 3,4). The addition of a protic solvent was
required for reaction to occur in each of these cases. The
behavior of L2Pd(Ar)Cl mirrored that of the I analogue,
suggesting that in polar solvents at least, these species are in
equilibrium with each other, probably via the cationic
[L2Pd(Ar)]+, which is found contemporaneously in the same
solutions. L2Pd(Ar)F was not observed even under conditions
that ought to have favored its appearance (excess fluoride), but
F− was not competitive enough with I− even under these
details, NMR spectra, and X-ray crystallographic data
(PDF)
Dynamic visualization of the data depicted in Figure 3A
(AVI)
Accession Codes
CCDC 1875028−1875029 and 967677 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
*Fax: (+1) 250-7217147. E-mail: mcindoe@uvic.ca.
ORCID
Tengfei Li: 0000-0002-8378-7130
J. Scott McIndoe: 0000-0001-7073-5246
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
J.S.M. thanks NSERC for operational funding (Discovery
Grants and Discovery Accelerator Supplements), and CFI,
■
J
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DOI: 10.1021/acs.organomet.8b00705
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