A Combined Experimental/Computational Study of the Mechanism of a Palladium-Catalyzed Bora-Negishi Reaction

Article abstract of DOI:10.1002/chem.201702703

Experimental and computational efforts are reported which illuminate the mechanism of a novel boron version of the widespread Negishi coupling reaction that offers a new protocol for the formation of aryl/acyl C?B bonds using a bulky boryl fragment. The role of nucleophilic borylzinc reagents in the reduction of the Pd^II pre-catalysts to Pd⁰ active species has been demonstrated. The non-innocent behavior of the PPh₃ ligands of the [Pd(PPh₃)₂Cl₂] pre-catalyst under activation conditions has been probed both experimentally and computationally, revealing the formation of a trimetallic Pd species bearing bridging phosphide (PPh₂^?) ligands. Our studies also reveal the monoligated formulation of the Pd⁰ active species, which led us to synthesize related (η³-indenyl)Pd-monophosphine catalysts which show improved catalytic performances under mild conditions. A complete mechanistic proposal to aid future catalyst developments is provided.

Full text of DOI:10.1002/chem.201702703

A Journal of
Accepted Article
Title: A Combined Experimental/Computational Study of the
Mechanism of a Palladium-Catalyzed Bora-Negishi Reaction
Authors: Jesus Campos, Ainara Nova, Eugene L Kolychev, and Simon
Aldridge
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201702703
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A Combined Experimental/Computational Study of the
Mechanism of a Palladium-Catalyzed Bora-Negishi Reaction
Jesús Camposa,b*, Ainara Novac*, Eugene L. Kolycheva, Simon Aldridgea*
Abstract: Experimental and computational efforts are reported
which illuminate the mechanism of a novel boron version of the
widespread Negishi coupling reaction that offers a new protocol for
the formation of aryl/acyl C-B bonds using a bulky boryl fragment.
The role of nucleophilic borylzinc reagents in the reduction of the
Pd(II) pre-catalysts to Pd(0) active species has been demonstrated.
The non-innocent behavior of the PPh3 ligands of the [Pd(PPh3)2Cl2]
pre-catalyst under activation conditions has been probed both
experimentally and computationally, revealing the formation of a
used class of reagent.4 These compounds in turn are typically
prepared by the borylation of C-halogen or C-H bonds using
diboron(4) esters of general formula B2(OR)4.1b
Very recently, we developed an alternative strategy for the
borylation of C-X (X = Br, Cl) bonds using polar, formally anionic,
borylzinc reagents,5 in the presence of simple and affordable
palladium pre-catalysts (Scheme 1).6 In effect, this approach
constitutes a novel boron version of the widelyapplied Negishi C-
C coupling reaction. Importantly, our method has allowed us to
develop the first efficient, systematic and catalytic route to
acylboranes,7,8,9 a rare class of organoboron compound with
high potential in synthetic organic chemistry.10
-
trimetallic Pd species bearing bridging phosphide (PPh2 ) ligands.
Our studies also reveal the monoligated formulation of the Pd(0)
active species, which led us to synthesize related (η3-indenyl)Pd-
monophosphine catalysts which show improved catalytic
performances under mild conditions.
A complete mechanistic
proposal to aid future catalyst developments is provided.
Introduction
Palladium-catalyzed cross-coupling reactions have revolu-
tionized synthetic organic chemistry since first breaking onto the
scene in the 1970s.1 Owing to their wide functional group
tolerance, and systematic tunability by rational ligand design,
these methods have been successfully transplanted from
academic laboratories to industrial finechemical, pharma-
ceutical and agrochemical production.2 The Suzuki-Miyaura
coupling, in which a C-C bond is formed using an organoboron
reagent, is arguably the most widely applied metal-mediated
cross-coupling transformation. Here, the choice of the boron-
containing component is known to be critical for the outcome of
the reaction,3 with boronic acid/esters being the most widely
Scheme 1. Palladium-catalyzed borylation of aryl bromides and acyl chlorides
using borylzinc reagent 1 (Dipp = 2,6-diisopropylphenyl).6
Many palladium-catalyzed cross coupling reactions are believed
to proceed through a common catalytic cycle involving oxidative
addition of the organic substrate at a Pd(0) centre, followed by
transmetalation of the coupling partner and reductive elimination
of the organic product, with concomitant catalyst regeneration
(Figure 1).1a,c,d The Pd(0) active species is usually generated via
in situ reduction of a Pd(II) pre-catalyst by one of a number of
potential routes. That said, it is apparent that the picture is often
more complicated than this simple mechanistic model would
imply, and subtle modifications to the reaction medium, for
example, can lead to drastic changes in reactivity,11 particularly
in processes involving highly polar zinc reagents.12 As a
consequence, detailed studies have proved to be crucial in
developing mechanistic understanding, which in turn can be
applied to the rational design of new catalysts with enhanced
performance, superior selectivity or broader applicability.
[a]
[b]
Prof. Simon Aldridge and Dr. Jesús Campos
Inorganic Chemistry Laboratory, South Parks Road, Oxford, UK,
OX1 3QR.
*simon.aldridge@chem.ox.ac.uk; *jesus.campos@iiq.csic.es
Instituto de Investigaciones Químicas (IIQ), Departamento de
Química Inorgánica and Centro de Innovación en Química
Avanzada (ORFEO-CINQA). Universidad de Sevilla and Consejo
Superior de Investigaciones Científicas (CSIC). Avenida Américo
Vespucio 49, 41092 Sevilla (Spain).
[c]
Dr. Ainara Nova
Centre for Theoretical and Computational Chemistry (CTCC),
Department of Chemistry, University of Oslo, P. O. Box 1033
Blindern, 0315 Oslo, Norway.
In the current contribution we present
a
joint experi-
*ainara.nova@kjemi.uio.no
mental/computational effort to elucidate the mechanism of the
novel bora-Negishi coupling which we believe may illuminate
future catalyst developments. A key mechanistic aspect in most
palladium-mediated organoboron reactions is the role of the
added base: potentially, this is required to access a transient
boron-centered nucleophile,13 although additional roles have
Details on the alternative one-step synthesis of borylzinc reagents,
crystallographic information, NMR spectra and computational details
and tables.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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also been suggested.14 One of the benefits of the bora-Negishi
system is that it allows this issue (and associated mechanistic
complexities derived from the presence of the base)15 to be
disregarded, since the intrinsic nucleophilicity of borylzinc
reagents removes the need for external additives of this type. In
addition, we report an alternative convenient one-step synthetic
protocol to access airstable borylzinc reagents directly from a
bromoborane, and thereby circumvent the need to use
the borylation of aryl bromides when compared to other Pd(II)
sources.6
Yamashita’s
highly
sensitive
boryllithium
complex
(thf)2Li{B(NDippCH)2}16 as
a
precursor (see Experimental
Section and Supporting Information for details). As such, this
simple development significantly enhances the convenience of
the bora-Negishi methodology in synthetic organic chemistry.
Scheme 2. Activation of [Ph(PPh3)2Cl2] (2a) with [(thf)2Zn2(Br)2{B(NDippCH)2}2]
(1) to form Pd(0) active species. [B] = [B(NDippCH)2]. [dvds = 1,1,3,3-
tetramethyldisiloxane]
Figure 1. General catalytic cycle for palladium-catalyzed cross-coupling
reactions (Ac = activation; OA = oxidative addition; Tr = transmetalation; RE =
reductive elimination).
Accordingly, the reaction of 2a with 2.5 equivalents of 1 under
catalytically relevant conditions (dioxane solvent, 80 °C) and in
the presence of ten equivalents of the trapping agent 1,3-divinyl-
1,1,3,3-tetramethyldisiloxane (dvds)27 results in the quantitative
formation of the stable Pd(0) monophosphine complex
[Pd(PPh3)(κ2-dvds)] (4) after 16 hours, with concomitant release
of one equivalent of PPh3 (Scheme 2). The reaction was
monitored by 1H and 31P{1H} NMR spectroscopy (showing 45
and 66% conversion after 2 and 4 h, respectively) and clean
formation of 4 was unambiguously confirmed by comparison
with previous literature data.28 Around 40% of the borylzinc
reagent 1 was converted into haloborane, in accordance with a
reduction stoichiometry which requires one boryl anion
equivalent per molecule of 2a. The haloborane generated is a ca.
1:6 ratio of chloroborane (5) and bromoborane (6), with the
mixture thought to result from halide exchange between 1 and
2a. This observation is supported by the fact that the same
reaction carried out over a period of 30 min, using variable
amounts of 1 (but in the absence of dvds) leads to a mixture of
products that includes [Pd(PPh3)2BrCl] (7) and [Pd(PPh3)2Br2] (8)
Results and Discussion
Catalyst pre-activation to generate Pd(0) species
Although systems based on Pd(II)/Pd(IV) pairs have been
reported,17 it is well known that LnPd(0) species are the active
catalysts in most palladium-mediated cross-coupling reactions.
Palladium nanoparticles and other heterogeneous forms of
palladium have shown outstanding catalytic properties.18
Nevertheless, according to poisoning experiments with CS2,
PPh3 and Hg carried out during our preliminary investigation,19
such species are not the active catalyst in our system.6
Alternative radical pathways related to those reported by
Marder20 for zinc-catalyzed borylation could also be ruled out
based on the borylation of organic substrates specifically
designed as radical probes.6
Active LnPd(0) species are typically generated via the in situ
reduction of Pd(II) salts by the action of phosphines,21 amines,22
hydride sources,23 other additives,24 or even by electrochemical
methods.25 However, despite the extensive use of air and
moisture stable [Pd(PAr3)2X2] pre-catalysts in cross-coupling
reactions, the pre-activation mechanisms by which the active
species LnPd(0) are generated are not fully understood.26 In the
bora-Negishi case, the strongly reducing nature of boryl
derivatives of main group metals prompted us to first examine
the ability of the borylzinc reagent 1 to give access to Pd(0)-
phosphine species, as well as the mechanism by which these
may be formed. In these and subsequent investigations we have
focused primarily on the pre-catalyst [Pd(PPh3)2Cl2] (2a), owing
to its superior performance and wider substrate applicability in
1
(Scheme 3). The nature of 7 and 8 was ascertained via H and
31P{1H} NMR spectroscopy by spiking with authentic samples
synthesized following literature procedures.29 Nonetheless,
under such conditions the major product (up to 95% using 10
equiv. of 1) was the expected species [Pd(0)(PPh3)2] (3a) (in any
of its related oligomeric forms or halide adducts)11a
,
characterized by a broad 31P{1H} NMR resonance at δP ca. 21
ppm.28,30 The formulation of the Pd(0) active species was further
confirmed by adding dvds or bromobenzene to these reaction
mixtures, which after 10 min at 25 °C resulted in quantitative
formation of the alkene adduct 4 or the oxidative addition
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Scheme 3. Reaction of pre-catalyst 2a with variable amounts of borylzinc 1 (31P{1H} NMR spectroscopic yields calculated relative to total phosphorus content).
[Pd]3 (11) = [(Ph3P)3Pd3(μ-PPh2)2(μ-Br)]+.
product [Ph(PPh3)2PhBr] (9a), respectively. These results
demonstrate that in the absence of any external additive,
borylzinc 1 is able to convert 2a into Pd(0) species (e.g. 3a)
under catalytically relevant conditions.
reagent 1 (vs. palladium precursor 2a), the Pd(0) species 3a
could comproportionate with asyet unreacted 2a to generate a
Pd dimer, which would evolve into products 9a, 10, 11 or 12
following a variety of elementary steps. In addition, the formation
of these products by initial comproportionation of Pd(0) and
Pd(II) is consistent with their non-observation in experiments
where 3a is trapped using dvds (Scheme 2). In contrast, under
higher concentrations of borylzinc reagent 1 (e.g. 10 equiv.)
Pd(II) precursor 2a would rapidly be consumed resulting in clean
and almost quantitative formation of 3a.
Another interesting aspect observed during reactions of 1 and
2a is the non-innocent character of the PPh3 ligands in
experiments performed under related conditions using fewer
equivalents of 1 (Scheme 3). Under such conditions, we could
identify [Pd(PPh3)2PhBr] (9a) and [PPh4]+ (10) even in the
absence of bromobenzene, as minor species in variable
amounts (the identities of which were confirmed by spiking with
authentic standards). Moreover, even in the absence of any
organic substrate to be borylated, phenylborane (12) is still
formed in yields of around 20 to 30% relative to 2a. Cleavage of
P-C bonds within phosphine ligands mediated by palladium has
precedent in the literature, and has been associated with
catalyst deactivation processes.31 One of the suggested
mechanisms involves the formation of multimetallic species
containing phosphide bridges after oxidative addition of a P-C
bond at an adjacent metal centre.32 A similar mechanism of this
kind (Scheme 4), which is also supported by calculations (vide
infra), would be consistent with the subsequent formation of
species 9a and 11. 10 could then be formed by reductive
elimination of [PPh4]+ from 9a.33 At low ratios of borylzinc
Interestingly,
during these
experiments
using lower
concentrations of 1 we could also observe a characteristic
pattern of 31P{1H} resonances due to an ABB'XX' spin system
(δX = 226.5, δB = 19.0 and δA = 12.3 ppm; JAX = 11, JAB = 91 Hz).
The species responsible (11) can be obtained in spectroscopic
yields of up to 60% by heating dioxane solutions of 1 and 2a (in
a 2:1 ratio) at 80 °C for 30 min. Increasing the amount of 1
relative to 2a decreases the amount of 11 produced in favour of
[Pd(0)(PPh3)2] (3a) (Scheme 3). Intense red crystals of 11 could
be grown from dichloromethane/hexane solutions and X-ray
diffraction studies reveal that the palladium-containing
component is the trinuclear bis-phosphide [(Ph3P)3Pd3(μ-
PPh2)2(μ-Br)]+ (Figure 2). The unit cell contains two of these tri-
palladium units co-crystallized with one [PPh4]+ cation (thus
further confirming its formation during pre-catalyst activation),
with charge balance being achieved via a rare [Zn6Cl15]3- anionic
cluster (see Supporting Information for details). The tripalladium
cluster might be seen as an intermediate state during pre-
catalyst reduction, with an average metal oxidation state of 4/3.
Scheme 4. Proposed mechanism for the activation of PPh3 by means of P-C
cleavage via formation of a Pd dimer.
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Figure 2. ORTEP diagram of cationic trinuclear component of 11 (thermal
Scheme 6. Mechanisms explored for the pre-catalyst activation of 2a by 1 with
free energies in kcal mol-1.
ellipsoids: 50% probability; H atoms, one of the two 11 cations present in the
3-
unit cell and [Zn6Cl15
]
counter-anion omitted and phenyl groups shown in
wireframe format for clarity).
In order to obtain further insight into the pathways involved in the
activation of the Pd pre-catalyst 2a, DFT calculations were
carried out using the M06L and M06 functionals and mixed
implicit-explicit models for THF solvation (see Computational
Details). The mechanism considered for the reduction of Pd(II)
to Pd(0) and formation of [B]-Cl (5) ([B] = [B(NDippCH)2]) was
transmetalation followed by reductive elimination (Scheme 6).
This mechanism is the one proposed for the reduction of Pd(II)
in most cross-coupling reactions from R-Pd-X intermediates11a,36
and it has been experimentally and computationally validated for
Negishi reactions using ZnMe2 and ZnMeCl.12e,l We additionally
considered the possibility of direct nucleophilic attack at chloride
by Zn[B]Br(thf)2 (itself generated by the fragmentation of 1),
which has been suggested for related systems.37 However, all
attempts to find a transition state were unsuccessful and lead us
to exclude this potential pathway (see Supporting Information for
more details).
It is noteworthy that an almost identical trinuclear palladium
phosphide (with the exception of the bridging halide ligand and
counter-anion) was reported by Dixon and co-workers to be
formed on prolonged heating of thf solutions of
[Pd(PPh3)3Cl][BF4].31,34 31P{1H} NMR spectroscopic and X-ray
diffraction data closely match those measured for 11. Despite
the extensive use of [Pd(PPh3)3Cl2] (2a) as a pre-catalyst, this is
to our knowledge the first time that such a palladium phosphide
cluster has been observed during a catalytic cross-coupling
reaction. Its potential role during catalysis will be further
discussed below.
Regarding the formation of phenylborane 12 during these
experiments, it is also important to note that the [PPh4]+ cation
generated as per Scheme 4 could serve as one of the sources
of 12, as has previously been reported for a related C-C cross-
coupling protocol.35 Indeed, we could demonstrate that 1 is able
to borylate [PPh4]+ (10) in the presence of 2a to form
phenylborane 12 and PPh3 in yields of around 10% (Scheme 5).
The low yield is attributed to catalyst poisoning by the released
PPh3, in agreement with control experiments discussed below.
Scheme 5. Borylation of the tetraphenylphosphonium cation using 1.
Figure 3: Geometries of TSA2 and T3a showing key distances. Hydrogen
atoms have been removed for clarity.
Coordination of Zn[B]Br(thf)2 was only found to be possible trans
to PPh3 due to the steric bulk of the boryl ligand [B] (Scheme 6).
Consistent with experimental observations (vide infra), this
necessarily implies dissociation of one of the phosphines from
2a, as suggested with other precatalysts of the type
[(R3P)2PdII(X)2] bearing bulky phosphines,38 and formation of
A1a. The substitution of one phosphine by the borylzinc
fragment is endoergic by 13.3 kcal mol-1. Substitution of one of
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the zinc-bound thf ligands by chloride has an energetic barrier of
7.9 kcal mol-1 (TSA1) and stabilizes this intermediate by 1.5 kcal
mol-1. Subsequent formation of the Pd-boryl bond in A3a (ΔG =
1.0 kcal mol-1) requires decomplexation of Br followed by
rotation of the Cl-Zn[B]Br(thf) bond. A transition state for this
process (TSA2, Figure 3) was located with a free energy of 29.0
kcal mol-1 above the initial reactants, which is consistent with the
high temperature (80 °C) required for catalyst activation. In A3a,
the boryl group is bound to both Pd and Zn, with Pd-B and B-Zn
distances of 2.09 and 2.81 Å, respectively. The latter interaction
is lost in the subsequent step, in which the boryl group is
displaced at zinc by an external thf molecule through TSA3 (ΔG
= 8.5 kcal mol-1). The overall transmetalation process is
exergonic by 5.2 kcal mol-1. Subsequent dissociation of
ZnBrCl(thf)2 yields the unsaturated Pd intermediate A6a, which
by reductive elimination forms [B]-Cl. This reaction has a low
energy barrier (3.6 kcal mol-1) and is exergonic by 4.9 kcal mol-1
if [B]-Cl remains bonded to Pd (A7a), and by 27.7 kcal mol-1 if
the chloroborane is displaced by PPh3 to give Pd(0)(PPh3)2.
To provide further evidence for the essential role of phosphine
dissociation during the transmetalation process that leads to
precatalyst activation, we additionally performed one of the
experiments described in Scheme 3 (2.5 equiv. of 1) in parallel
with an identical experiment in which 2.5 equiv. of PPh3 were
added to the mixture. While the former solution rapidly turned
dark red due to the formation of tripalladium compound 11, the
reaction containing additional PPh3 remained bright yellow even
after several hours at 80 ºC. Both reaction mixtures were
monitored by 1H and 31P{1H} NMR, revealing full consumption of
precatalyst 2a after ca. one hour at 80ºC in the absence of
added PPh3, but only 10% consumption (and 90% unchanged
2a) in the presence of PPh3.
Scheme 7. Mechanism for the oxidative addition of a P-Ph bond derived from
[Pd(0)(PPh3)2] and Pd(PPh3)2Cl2 via formation of a dinuclear Pd complex. Free
energies in kcal mol-1.
Oxidative addition
We previously observed that 2a was the catalyst of choice for
the borylation of bromobenzene (95% yield after 2 h reaction at
80 °C), while its tri(o-tolyl) phosphine counterpart [Pd(P(o-
Tol)3)2Cl2] (2b) was barely active (12% yield under identical
conditions), and rapidly decomposed to form Pd-black (Scheme
8).6 By contrast, the borylation of benzoyl chloride proceeded to
a similar extent with both systems.
Oxidative addition at [Pd(0)(PAr3)2] moieties is well known and
several experimental and computational studies have focused
on this process.35 We have experimentally observed that the
reactions of bromobenzene or benzoyl chloride with freshly
generated [Pd(0)(PPh3)2] (3a) proceed cleanly and extremely
rapidly (Scheme 2). Moreover, DFT calculations show that the
In addition, the dissociation of phosphine is consistent with the
reduced activity observed when using [Pd(dppf)Cl2] (dppf = 1,1'-
bis(diphenylphosphino)ferrocene) instead of [Pd(PPh3)2Cl2] (2a)
as the pre-catalyst,6 and with the formation of phosphonium salts
during the reaction of 2a with 1 (Scheme 3). As described above,
the formation of [PPh4]+ and 9a suggests the presence of facile
routes for the oxidative addition of P-Ph bonds. We found that
this reaction from the unsaturated Pd(II) and Pd(0) intermediates
A6a and A7a is either not feasible or endergonic by 17 kcal mol-
1, respectively. By contrast, an oxidative P-C bond cleavage
reaction at dimer D1a, (itself formed by coordination of 2a to
Pd(0)-PPh3 as proposed in Scheme 4) is exergonic (ΔG= -3.7
kcal mol-1) and has a low energy barrier (11.4 kcal mol-1 from
D2a). This reaction takes place in two consecutive steps
involving comproportionation, in which one Ph group of a
phosphine ligand assists the Pd(0) to Pd(II) oxidation, followed
by P-Ph oxidative addition involving the same Ph group.
Oxidative addition of C-X and Y-H bonds (X = halogen, and Y =
H, O, N) to Pd(I)-Pd(I) dimers has precedent in the literature.39
The formation of dimeric species D1a, D2a and D3a is
endergonic by 8.6, 5.8 and 4.9 kcal mol-1, respectively, and
indeed none of these species have ever been observed during
reactions of 1 and 2a. Instead, the products experimentally
characterized are 9a, 10, 11 and 12 (Scheme 3), presumably
formed by further reactions of D3a with ZnX2 and PPh3.
Scheme 8. Borylation of bromobenzene using pre-catalysts 2a and 2b.
oxidative addition of benzoyl chloride at either 3a or 3b is
favoured thermodynamically by 19.1 and 3.6 kcal mol-1,
respectively (Scheme 9). However, while the reaction of
bromobenzene and 3a is also exoergic (ΔG = -14.7 kcal mol-1)
the analogous process involving 3b is almost thermoneutral (ΔG
= 0.6 kcal mol-1), leading indeed to a bridging dipalladium
species with concomitant release of a phosphine ligand.35b This
is consistent with the reversible oxidative addition of
bromobenzene at 3b, with the differences compared to 3a
presumably being due to steric considerations. This equilibrium,
along with the fact that the subsequent transmetalation step
seems to be rate-limiting (vide infra) is presumably therefore
responsible for pre-catalyst decomposition to palladium black in
the system Ar-Br/3b. By contrast, the irreversible oxidative
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Scheme 9. Free energies in kcal mol-1 for the oxidative addition of (i) PhBr and
(ii) PhCOCl with L = PPh3 and L = P(o-Tol)3.
behaviour of intermediates 9a and 14a is almost identical to (or
even slightly superior than) that of pre-catalyst 2a, a finding
which clearly supports their roles as intermediates in the
catalytic cycle. We additionally assayed the trinuclear system 11
as a catalyst for the borylation of bromobenzene and found a
slightly diminished but comparable catalytic performance to that
of 2a and 9a. An induction period of around 10 min became
evident for 11 to become active, which we associate with its
break-up into active mononuclear Pd(0) species.
addition to 3a of bromobenzene stabilizes the Pd(II) component
in the form of 9a.40
Transmetalation of borylzinc reagents
Transmetalation is a critical step in cross-coupling reactions and
occurs via a variety of mechanisms owing to the broad variety of
nucleophiles employed.41 Following the commonly cited catalytic
cycle, transmetalation would be expected to take place at a
Pd(II) complex itself derived from the oxidative addition of
bromobenzene or benzoyl chloride to a [Pd(0)(PAr3)2] species.
From the intermediate Pd(II) complex, a mechanism analogous
to that shown in Scheme 6 might then be expected to be
responsible for introduction of the boryl ligand into the
coordination sphere of palladium, followed by B-C reductive
elimination. To probe this hypothesis, we performed
stoichiometric reactions between the previously synthesized
oxidative addition products 9a (from bromobenzene) or 14a
(from benzoyl chloride) and borylzinc reagent
1 under
catalytically relevant conditions (Scheme 10). As expected,
these reactions led efficiently to the formation of the borylated
organic
compounds
PhB(NDippCH)2
(12)
and
PhC(O)B(NDippCH)2 (13), as well as [Pd(0)(PPh3)2] (3a).
Notably, the ratio of 12 to 13 obtained from the stoichiometric
reaction of 14a with 1 (ca. 1.6:1) is identical to that obtained
from catalytic reactions using pre-catalyst [Pd(PPh3)3Cl2] (2a)
(see Scheme 8), thus suggesting that 14a is indeed a competent
intermediate during catalysis. In this reaction, 12 is potentially
formed via CO extrusion from 14a brought about by phosphine
ligand dissociation (see Supporting Information for details).
Figure 4. Reaction profiles for the borylation of bromobenzene (A) and benzoyl
chloride (B) using pre-catalyst 2a, oxidative addition intermediates 9a and 14a
and trimetallic-Pd 11. Reaction conditions: Reaction conditions: 1 (0.010
mmol), bromobenzene or benzoyl chloride (0.022 mmol), [Pd] (5 mol%),
solvent (0.5 mL; 1,4-dioxane (A) or thf (B)), 80 °C. Reaction monitoring by 1H
NMR spectroscopy using an internal standard. Lines drawn to guide the eye.
At first inspection, it seems likely that transmetalation is the rate
limiting step in the catalytic cycle since the stoichiometric
oxidative addition step is rapid, while no palladium boryl species
can be detected after transmetalation. At the very least, the
implication is that transmetalation must occur at a significantly
slower rate than subsequent reductive elimination in order that
the concentrations of palladium boryl intermediates never
accumulate to levels detectable by NMR. Given the trans
disposition of the aryl/acyl and halide ligands in 9a/14a we
therefore decided to investigate whether the change to a cis
disposition of aryl/acyl and boryl groups required for reductive
elimination was occurring during the transmetalation step via
ligand dissociation (as shown in Scheme 6). As an initial probe,
Scheme 10. Stoichiometric reactions between (a) 9a or (b) 14a and borylzinc
reagent 1.
The viability of 9a and 14a as intermediate species in the
catalytic cycle was further confirmed by comparison of their
catalytic profiles with that of pre-catalyst 2a for the borylation of
bromobenzene and benzoyl chloride, respectively. To do so, we
monitored the catalytic performance of the three palladium
1
species in parallel by H and 11B{1H} NMR spectroscopy: Figure
4 shows temporal profiles for each system (derived from 1H
NMR measurements) based on the consumption of the borylzinc
reagent 1 (see Experimental Section for details). The catalytic
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we examined the reactions towards borylzinc reagent 1 of
palladium complexes 15 and 16, which feature chelating
phosphines, and consequently cis oriented aryl/acyl and halide
ligands. Despite being electronically similar to 9a and 14a,
however, formation of the borylated products proceeded at a
considerably slower rate with 15/16 (Scheme 11). It seems likely
(given that 15 and 16 are stereochemically pre-organized with
respect to subsequent C-B reductive elimination), that it is a
slower rate of transmetalation for these chelating systems which
underpins this difference. This in turn can be ascribed to the
high steric encumbrance around the palladium centre which
would result from accommodating not only the two tertiary
phosphine co-ligands but also the massively hindered boryl
group. In the case of 9a/14a – featuring monodentate co-ligands
– the potential for phosphine dissociation during transmetalation
would reduce the degree of crowding in a manner less readily
accessible to 15 and 16 due to the chelate effect conferred by
the bisphosphine. Consistently, the necessity for phosphine
dissociation (which was also suggested for similar mechanistic
steps during pre-activation) is further implied by examining the
effects on the 9a + 1 temporal profile of the presence of two
additional equivalents of triphenylphosphine. Thus, the rate of
consumption of 1 is very clearly inhibited by the presence of
additional phosphine (Figure 5).
inferred from the considerably slower rates of borylation of ortho-
substituted aryl bromides compared to bromobenzene.6
Also consistent with the necessity for phosphine dissociation, is
the fact that in situ 31P{1H} NMR spectroscopic analyses during
catalytic runs using 2a reveal resonances at δP ca. 30 ppm
which we tentatively assign to mono-ligated species of general
formula [Pd(PPh3)PhX]2 (X = Cl, Br), based on literature
precedent ([Pd(PPh3)PhX]2, δP X = Cl {CD2Cl2: 31.6 ppm}, X =
Br {CD2Cl2: 30.4, C6D6: 30.7}; [Pd(PPh3)PhX2]-, δP X = Cl
{CD2Cl2: 30.9 ppm}, X = Br {CD2Cl2: 29.9, C6D6: 30.5}).43 These
species are only ever present in low concentration (< 20%) and
the associated NMR signals disappear after reaction completion.
Figure 5. Reaction profile for the reaction between [Pd(PPh3)2PhBr] (9a) and
borylzinc reagent 1 in the absence (blue circle) and the presence (orange
triangle) of added PPh3 (2 equiv). Reaction conditions: 1 (0.011 mmol),
bromobenzene (0.024 mmol), 2a (5 mol%), additional PPh3 (10 mol%), 1,4-
dioxane (0.5 mL), 80 °C. Reaction monitoring by 1H NMR spectroscopy using
an internal standard. Lines drawn to guide the eye.
In addition to these experiments, we also wanted to determine
by means of calculations the feasibility of a transmetalation
mechanism occurring via intermediates similar to those
proposed for the pre-catalyst activation step. With this in mind,
the structures/energies for species shown in Scheme 6 were
computed by replacing one of the chlorides by Ph (15Cl). The
relevant calculated energies are shown in Scheme 12. The free
energies of all intermediates in which zinc-containing species
are bound to Pd are higher with Ph (T1a-T5a) than with Cl (A1a-
A4a). This is consistent with the lower electrophilicity expected
for complexes of the type [PdL2RCl] compared to [PdL2Cl2],
together with the higher steric profile of Ph compared to Cl.
However, once ZnBrCl(thf)2 is dissociated from intermediate T5a,
direct formation of Ph-[B] takes place without any apparent
energy barrier and is strongly exergonic (ΔG= - 44.6 kcal mol-1).
Indeed a small gain in energy of 2.5 kcal mol-1 is observed by
replacing the Ph-[B] by PPh3. Attempts to calculate the transition
state for the bromide/boryl ligand exchange in Pd, which is
expected to be the one with the highest energy, were
unsuccessful. Indeed a similar geometry to that of TSA2, was
found to be a minimum with Ph instead of Cl (T3a, Figure 3)
probably due to an interaction between a π-CC bond of Ph with
Pd (which is not possible with Cl). The energy of this
intermediate is 24.5 kcal mol-1 above 15Cl and 1, and the
Scheme 11. Reaction of P(II) complexes 15 and 16 bearing chelating 1,2-
(diphenylphosphino)benzene with borylzinc 1.
These findings are in marked contrast with related studies
of Negishi C-C coupling reactions using organozinc reagents of
reduced steric demands compared to borylzinc 1, for which
phosphine dissociation is not a prerequisite for transmetalation
to occur.12e,l Moreover, it has been observed that transmetalation
with ZnMe2 is faster than with ZnMeCl in classic Negishi
reactions,12e while our studies reveal that bisboryl compound
Zn{B(NDippCH)2}2 is barely active for the borylation of aryl
bromides and acyl chlorides, most likely due to steric reasons.6
An additional advantage derived from the use of highly bulky
borylzinc reagents is that no B-B homocoupling is detected - as
often observed with organozinc reagents in Negishi reactions.42
The critical influence of sterics in our system can also be
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transition states connecting it with T2a and T4a (TST1f and TST2f
respectively) were estimated to be 27.2 and 26.4 kcal mol-1
above the reactants, respectively (see supporting information).
Scheme 12. Mechanism for the transmetalation pathway from E3 with the free
energies (kcal mol-1) obtained for intermediates. The energies for TST1f and
TST2f have been estimated by means of relaxed energy scan calculations (see
SI).
These energies suggest that
a transmetalation pathway
involving species T1a-T5a is reasonable for a reaction that takes
place at 80°C. It is also consistent with the fact that electron
deficient aryl rings are borylated at lower rates,6 which could be
understood in terms of higher energies for intermediates alike
T3a and their associated transition states. Moreover, the fact
that no boryl intermediates are observed at any point in the
reaction sequence is consistent with the effectively barrier-less
(or very low barrier) C-B reductive elimination step leading to
product formation.
electronically unsaturated and sterically unhindered [PdLRX]
intermediates facilitate cis-trans isomerization, leading
(reversibly) to trans-[PdL2RX] (9a, 14a) after phosphine re-
combination - species that are experimentally observed during
catalysis. Additionally, three-coordinate Pd compounds favor CO
elimination (Elim), which is evidenced during the borylation of
benzoyl chloride, particularly with the PPh3 system.
Transmetalation (Tr) from such three-coordinate Pd species
seems to be the rate-limiting step, yielding boryl Pd(II)
intermediates. This is followed by reductive elimination (RE),
which is expected to be almost barrierless and highly exoergic,
consistent with the non-observation of any Pd-[B] intermediates
Complete mechanistic cycle
Overall, the results obtained in this study together with existing
knowledge of Pd-catalyzed cross-coupling reactions are in
agreement with the mechanism shown in Scheme 13, in which
ligand dissociation plays a pivotal role in most of the steps.
During pre-catalyst activation (Ac), phosphine dissociation is
required to allow the transmetalation process that leads to
monoligated Pd(0) after reductive elimination of haloborane.
This Pd(0) species can either be stabilized with PPh3/P(o-Tol)3
(a), or react either with R-X (OA) or with unreacted pre-catalyst
(b). The latter is potentially the first step in a route yielding
trimetallic Pd species 11, which can be seen as a reservoir of
Pd(0), as well as a source of [PPh4]ZnX3 and trans-[PdL2PhX]
(which can enter into the catalytic cycle (c)) via P-Ph bond
activation. In addition to catalyst activation, oxidative addition of
R-X (OA) has been proposed in the literature to occur by mono-
ligated Pd species, even in the case of PPh3 co-ligands.40,44 The
Scheme 13. Proposed catalytic cycle for the borylation of aryl bromides and
acyl chlorides using borylzinc reagents and L2PdCl2 pre-catalysts.
Finally, taking into consideration the crucial role of mono-ligated
formulation of palladium during most steps of the catalytic cycle
we decided to examine the reactivity of related palladium
complexes bearing a single PPh3 co-ligand. We focused on
systems containing bulky η3-indenyl ligands, which have recently
been highlighted as convenient scaffolds that use steric factors
to avoid the formation of inactive Pd(I) dimers.45 We therefore
synthesized complexes [(η3-indenyl)Pd(PPh3)Cl] (17) and [(η3-1-
tBu-indenyl)Pd(PPh3)Cl] (18) from the reaction of PPh3 with
dimeric [(η3-indenyl)2Pd2Cl2] and [(η3-1-tBu-indenyl)2Pd2Cl2],
respectively (see Experimental Section for details). The catalytic
performance of 17 and 18 in the borylation of bromobenzene by
1
1 under our standard conditions was then monitored by H and
11B{1H} NMR spectroscopy (Figure 6). As expected, the initial
activity increases in the order 2a < 17 < 18. The initial induction
period evident in the case of 2a is consistent with that shown in
Figure
2
and is therefore ascribed to pre-catalyst
activation/formation of [Pd(0)(PPh3)2] (3a). The required
phosphine dissociation is circumvented in the monoligated
complexes 17 and 18 that apparently do not exhibit any
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significant induction periods. However, the indenyl pre-catalysts
seem to decompose at 3% catalyst loadings without reaching
reaction completion and are surpassed by the simpler and
affordable 2a, pointing to the successful stabilization of resting
states of catalyst by the second phosphine ligand. Lowering the
temperature to 50 ºC brings about improved yields for
bromobenzene borylation up to 85% using indenyl catalysts 17
and 18, while carrying out these reactions at 25 ºC clearly
demonstrates the superiority of the monoligated species under
milder conditions (Figure 6). Further catalyst design optimization
to balance the trade-off between activity and stability are
currently being investigated in our group and will be reported in
due course.
potential in synthetic organic chemistry.46 Experimentally, we
have analyzed the mechanism by which the Pd(II) pre-catalyst is
activated, isolated reaction intermediates and screened their
catalytic competence, demonstrated the pivotal role of ligand
dissociation and synthesized and tested alternative monoligated
systems. These studies have been complemented by theo-
retical investigations to obtain additional insight into each step of
the catalytic cycle, as well as to learn about the causes for the
divergent activity observed for related systems based on PPh3
and P(o-Tol)3 during the borylation of aryl bromides. This joint
experimental/computational effort has thus provided key
mechanistic information that we believe will pave the way toward
future catalyst developments for improved activity/selectivity,
and broader scope. These avenues and others are currently
being pursued in our laboratories.
Experimental Section
General methods and instrumentation. All manipulations were carried
out using standard Schlenk line or dry-box techniques under an
atmosphere of argon. Solvents were degassed with dinitrogen and dried
by passing through a column of the appropriate drying agent.47 THF was
refluxed over sodium/benzophenone and distilled. NMR spectra were
measured in benzene-d6 (dried over sodium or potassium and distilled
under reduced pressure) or CDCl3 (used as received). NMR samples
were prepared under argon in 5 mm Wilmad 507-PP tubes fitted with J.
Young Teflon valves. 1H, 13C{1H}, 11B{1H} and 19F{1H} NMR spectra were
recorded on a Varian Mercury-VX-300, a Bruker Mercury Avance III HD
NanoBay 400 or a Bruker Avance III 500 spectrometer at ambient
temperature, and referenced internally to residual protio-solvent (1H) or
solvent
(
13C) resonances, and are reported in ppm relative to
tetramethylsilane (δ = 0 ppm). Assignments were confirmed using two
dimensional HSQC and HMBC correlation experiments. Carbon signals
exhibiting significant line broadening due to quadrupolar relaxation
caused by the proximity of boron atoms were not reported. Chemical
shifts are quoted in ppm. Solid state and solution phase infrared spectra
were measured on a Nicolet iS5 FT-IR spectrometer using air sealed
KBr-discs or NaCl-cells. Elemental analyses were carried out at London
Metropolitan University.
Starting materials. Borylzinc reagent 16 and palladium complexes 9a,48
7,29 8,29 14a49 and 1750 were synthesized according to literature
procedures. Other palladium precursors and organic substrates were
obtained from commercial sources and used as received.
Figure 6. Reaction profile for the borylation of bromobenzene using
1
Zn{B(NDippCH)2}2 (19). In a glove box, metallic potassium (367 mg, 9.42
mmol) was cleaned to remove oxide coating and finely suspended by
vigorous stirring in 20 mL of refluxing absolute n-hexane under an argon
atmosphere. A mixture of ZnCl2 (582 mg, 4.28 mmol) and bromoborane
(Br{B(NDippCH)2}, 20) (1000 mg, 2.14 mmol) was prepared in a glove
box and removed in sealed glass vial. The mixture was then added to the
suspension of potassium sand at room temperature under a flow of argon.
The reaction mixture was vigorously stirred for 24 h to form a dark grey
suspension, filtered and dried in vacuo. NMR analysis of the crude
residue showed full conversion of 20 to 47% of 19 and 53% of
hydroborane (H{B(NDippCH)2}) 21. This mixture was dissolved in 9 mL
of refluxing absolute n-pentane, cooled to room temperature and kept in
a -26°C freezer for 48 h. Large colorless crystals of 19 formed at this
point which separated by filtration, washed with 0.5 mL of absolute n-
pentane and dried in vacuo. Yield: 280 mg, 31%. Analytical data is
identical to that reported previously.5a
catalyzed by 2a (blue circle), 17 (red diamond) and 18 (grey triangle) at 80 (A),
50 (B) or 25 ºC (B). Reaction conditions: 1 (0.010 mmol), bromobenzene
(0.022 mmol), [Pd] (3 mol%), 1,4-dioxane (0.5 mL). Reaction monitoring by 1H
NMR spectroscopy using an internal standard. Lines drawn to guide the eye.
Conclusions
In summary, we propose a complete mechanistic scheme
(Scheme 13) for a recently developed bora-Negishi reaction,
that allows the Pd-catalyzed borylation of a variety of organic
substrates. Importantly, it is the only method available for the
systematic and catalytic preparation of acylboranes, which
represent an unusual class of organoborane reagents of great
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t
2
[(Ph3P)3Pd3(μ-PPh2)2(μ-Br)]+ (11). A mixture of palladium precursor 2a
(50 mg, 0.071 mmol) and borylzinc reagent 1 (43 mg, 0.036 mmol) was
dissolved in dioxane (3 mL) and heated at 80 ºC for one hour under
argon atmosphere. The resulting dark red solution was filtered,
concentrated and compound 11 was obtained after precipitation with
1.65 (9 H, s, Bu). 13C{1H} NMR (CD2Cl2, 100 MHz): δ 137.2 (d, JCP = 2
Hz, Ind), 136.3 (d, 2JCP = 5 Hz, Ind), 134.0 (d, 2JCP = 12 Hz, PPh3), 132.1
(d, JCP = 45 Hz, PPh3), 130.8 (Ind), 130.6 (d, JCP = 3 Hz, PPh3), 128.4
(d, 3JCP = 11 Hz, PPh3), 126.2, 125.8, 120.4, 116.8 (Ind), 107.9 (d, 2JCP
7 Hz, Ind), 73.5 (d, JCP = 4 Hz, Ind), 34.7 (d, JCP = 5 Hz, C(CH3)), 29.5
(d, JCP = 5 Hz, C(CH3)). 31P{1H} NMR (CD2Cl2, 162 MHz): δ 28.9 .
1
4
=
2
3
-
4
pentane as a bright orange solid 11 (17 mg, 40%, assuming ZnBrCl2 as
the counteranion on the basis of elemental analysis). Crystals suitable for
X-Ray diffraction analysis were grown by layering the dioxane solution
with pentane and cooling the mixture at -23 ºC overnight. 1H NMR
(CD2Cl2, 400 MHz): δ 7.41 (6 H, t), 7.37 (4 H, t), 7.20 (12 H, t), 7.13 (3 H,
t), 7.09 (20 H, m), 6.80 (6 H, t), 6.75 (8 H, m), 6.59 (6 H, m). All aromatic
3JHH have values of around 7.5 Hz. 13C{1H} NMR (CD2Cl2, 100 MHz): δ
135.1 (vt, JCP = 13 Hz, Cipso), 134.0 (t, JCP = 6 Hz, CH), 133.0 (d, JCP = 13
Hz, CH), 132.8 (t, JCP = 8 Hz, CH), 132.5 (d, JCP = 22 Hz, Cipso), 131.5 (d,
JCP = 41 Hz, Cipso), 130.5 (d, JCP = 13 Hz, CH), 129.9 (d, JCP = 3 Hz),
128.3 (t, JCP = 5 Hz, CH), 128.2 (t, JCP = 5 Hz, CH), 127.9 (d, JCP = 10 Hz,
CH). 31P{1H} NMR (CD2Cl2, 162 MHz): ABB'XX' spin system (JAX = 11,
JAB = 91 Hz), δ 226.5 (2 P, m, PPh2 (PX)), 19.0 (2 P, m, PPh3 (PB)), 12.3
(1 P, m, PPh3 (PA)). Elemental analysis found: C 52.33, H 3.47 %,
calculated for C78H65Br2Cl2P5Pd3Zn C 52.85, H 3.70 %. Crystallographic
data: C156H130Br1.92Cl15.08P10Pd6Zn6, Mr = 4032.93, monoclinic, P21/n, a
= 29.2833 (3), b = 19.5660 (2), c = 33.5346 (5) Å, β = 96.388 (1)°, V =
19094.6 (4) Å3, Z = 4, ρc = 1.403 g cm-3, T = 150 K, λ = 0.71073 Å.
78158 reflections collected, 36679 independent [R(int) = 0.072], which
were used in all calculations. R1 = 0.1113, wR2 = 0.2427 for observed
unique reflections [I > 2σ(I)] and R1 = 0.0884, wR2 = 0.2308 for all
unique reflections. Max. and min. residual electron densities 4.00 and -
1.75 e Å-3.
Elemental analysis found: C 64.80, H 5.12 %, calculated for C31H31ClPPd
C 64.59, H 5.42 %.
Pre-activation experiments for trappig Pd(0) species. Two set of
experiments were carried out: (A) 2a (8 mg, 0.011 mmol), borylzinc
reagent 1 (16 mg, 2.5 equiv) and dvds (25 μL, 10 equiv) were placed in a
Young’s NMR tube inside a dry box and dissolved in dioxane (0.6 mL).
The tube was heated at 80 °C and conversion was monitored by 31P{1H}
analysis; (b) 2a (8 mg, 0.011 mmol) and borylzinc reagent 1 (66 mg, 10
equiv) were placed in a Young’s NMR tube inside a dry box and
dissolved in dioxane (0.6 mL). The tube was heated at 80 °C for 30 min
and then dvds (12 μL, 5 equiv) or bromobenzene (6 μL, 5 equiv) were
added inside a dry box. Conversion was monitored by 31P{1H} analysis.
Pre-activation experiments with variable amounts of 1. 2a (10 mg,
0.014 mmol) and variable amounts of borylzinc reagent 1 (0.5 to 10
equiv) were placed in a Young’s NMR tube inside a dry box and
dissolved in dioxane (0.6 mL). The tube was heated at 80 °C for 30 min.
Conversion and selectivity data were obtained by 1H and 31P{1H} NMR
analysis of the crude mixtures using
a capillary charged with
trimethoxybenzene and P(OPh)3 as internal standards.
General procedure for catalytic borylation. In a typical experiment
borylzinc reagent 1 (12 mg, 0.010 mmol) was placed in a Young’s NMR
Pd(DPPBz)PhBr (15) (DPPBz = 1,2-bis(diphenylphosphino)benzene). 9a
(250 mg, 0.318 mmol) and DPPBz (284 mg, 0.636 mmol) were
suspended in benzene (8 mL) and the reaction mixture stirred at room
temperature for 16 hours under N2 atmosphere. Pentane was added to
complete precipitation, and the product was isolated after filtration and
several washings with pentane giving a yellow powder (184 mg, 82%).
Spectroscopic details were identical to those previously reported for the
same compound synthesized by an alternative method.51
tube inside
a dry box, and the corresponding organic substrate
(bromobenzene or benzoyl chloride, 0.022 mmol, 1.1 equiv) then added.
Palladium pre-catalyst was transferred into the mixture as a stock
solution in dry 1,4-dioxane or thf (0.5 mL, 5 mol%) and the tube heated at
1
80 °C for up to 2 h, time during which H NMR data were obtained using
trimethoxybenzene as an internal standard to build the corresponding
reaction profiles.
Pd(DPPBz)(C(O)Ph)Cl
(16)
(DPPBz
=
1,2-
Stoichiometric experiments between 1 and Pd compounds. Borylzinc
reagent 1 (12 mg, 0.010 mmol) and the corresponding palladium
compound (9a, 16 mg, 0.020 mmol; 14a, 15 mg, 0.020 mmol; 15, 14 mg,
0.020 mmol; 16, 14 mg, 0.020 mmol) were placed in a Young’s NMR
tube inside a dry box and dissolved in thf-d8 or dioxane (0.6 mL). The
tube was heated at 80 °C for 3 h. Conversion and selectivity data were
bis(diphenylphosphino)benzene). 14a (150 mg, 0.194 mmol) and DPPBz
(172 mg, 0.389 mmol) were suspended in benzene (5 mL) and the
reaction mixture stirred at room temperature for 16 hours under N2
atmosphere. Pentane was added to complete precipitation, and the
product was isolated after filtration and several washings with pentane
giving a yellow powder (103 mg, 77 %). 1H NMR (CD2Cl2, 400 MHz): δ
7.03 – 7.59 (29 H, m). 13C{1H} NMR (CD2Cl2, 100 MHz): δ 134.3, 133.6
1
obtained by H and 31P{1H} NMR analysis of the crude mixtures using a
capillary charged with trimethoxybenzene and P(OPh)3 as internal
standards.
2
(d, JCP = 13 Hz), 133.3, 132.1, 131.7, 131.0, 130.6, 130.3, 129.7, 128.9
2
2
(d, JCP = 10 Hz), 128.6 (d, JCP = 11 Hz), 128.3, 127.7 (signals due to
quaternary carbon atoms were not observed). 31P{1H} NMR (CD2Cl2, 162
MHz): δ 39.8 (d, 2JPP = 42 Hz), 32.1 (d, 2JPP = 42 Hz). IR (CH2Cl2): ν(CO)
1590 cm–1. Elemental analysis found: C 63.93, H 4.16 %, calculated for
C37H29ClOP2Pd C 64.09, H 4.22 %.
Catalytic borylation of [PPh4][X]. Borylzinc reagent 1 (27 mg, 0.022
mmol) and [PPh4]Cl (16 mg, 0.044 mmol) were placed in a Young’s NMR
tube inside a dry box (in some experiments ZnBr2 (10 mg, 1equiv) was
-
also added to form ZnX3 in situ). Pd(PPh3)2Cl2 was transferred into the
mixture as a stock solution in dry dioxane (0.5 mL, 2.2 mM, 5 mol%) and
the tube heated at 80 °C for 2 h. Conversion and selectivity data were
obtained by 1H NMR analysis of the crude mixture after addition of
trimethoxybenzene as internal standard.
(η3-1-tBu-indenyl)Pd(PPh3)Cl (18). Dimer (η3-indenyl)2(μ-Cl)2Pd2 (80 mg,
0.130 mmol), prepared from a reported procedure,45 and PPh3 (68 mg,
0.260 mmol) were placed in a Schlenk flask and suspended in Et2O (8
mL) under argon atmosphere. The suspension was stirred for two hours
at room temperature, during which time the reaction mixture became
homogeneous. The solution was filtered, concentrated and cooled to -23
ºC overnight. Compound 18 was isolated as a brown crystalline powder
(106 mg) in 71% yield. 1H NMR (CD2Cl2, 400 MHz): δ 7.60 – 7.44 (15 H,
Computational details. Two different DFT functionals (M06L and M06)
and basis sets (BS1 and BS2) were selected for geometry optimization
and energy refinement, in order to optimize accuracy and computational
cost. All stationary points were fully optimized with the pure M06L
functional52 including dispersion, as implemented in the Gaussian09 soft-
ware package (Rev. D.01).53 Geometry optimizations were carried out on
m, PPh3), 7.59 (1 H, obscured with PPh3 singals, Ind), 7.15 (1 H, t, 3JHH
=
3
3
7.4 Hz, Ind), 6.93 (1 H, t, JHH = 7.4 Hz, Ind), 6.64 (1 H, d, JHH = 2.2 Hz,
3
3
Ind), 6.35 (1 H, d, JHH = 7.4 Hz, Ind), 4.33 (1 H, t, JHH = 2.2 Hz, Ind),
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10.1002/chem.201702703
Chemistry - A European Journal
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the full system including solvation by THF with the continuum SMD
model.54 Frequencies were computed with the aim of classifying all
stationary points as either minima or transition states and determining the
thermochemistry corrections, (G – E), which include the zero-point,
thermal and entropy energies. BS1 was used for geometry optimizations
and includes polarization functions and small-core pseudopotentials by
combining the double-ζ 6-31G** (C, N, O and H)55 and LANL2DZ (Pd)56
basis sets. Single point calculation on the optimized structures was
performed by using the hybrid M06 functional, including solvation and
using the triple-ζ BS2, in which Pd was described with the LANL2TZ(f)
basis set57 and C, N O and H were described with the 6-311+G** basis
set,58 including polarization and diffuse functions. The free energies
discussed in the text were obtained by adding the thermochemistry
corrections, (G – E), at the DFT(M06L)/SMD/BS1 level, to the potential
energies refined at the DFT(M06)/SMD/BS2 level. These energies were
corrected for a 1M standard state..
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