Understanding Precatalyst Activation in Cross-Coupling Reactions: Alcohol Facilitated Reduction from Pd(II) to Pd(0) in Precatalysts of the Type (η3-allyl)Pd(L)(Cl) and (η3-indenyl)Pd(L)(Cl)

Article abstract of DOI:10.1021/acscatal.5b01291

Complexes of the type (η³-allyl)Pd(L)(Cl) (L = PR₃ or NHC), have been used extensively as precatalysts for cross-coupling and related reactions, with systems containing substituents in the 1-position of the η³-allyl ligand, such as (η³-cinnamyl)Pd(L)(Cl), giving the highest activity. Recently, we reported a new precatalyst scaffold based on an η³-indenyl ligand, (η³-indenyl)Pd(L)(Cl), which typically provides higher activity than even η³-cinnamyl supported systems. In particular, precatalysts of the type (η³-1-^tBu-indenyl)Pd(L)(Cl) give the highest activity. In cross-coupling reactions using this type of Pd(II) precatalyst, it is proposed that the active species is monoligated Pd(0), and the rate of reduction to Pd(0) is crucial. Here, we describe detailed experimental and computational studies which explore the pathway by which the Pd(II) complexes (η³-allyl)Pd(IPr)(Cl) (IPr = 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene), (η³-cinnamyl)Pd(IPr)(Cl), (η³-indenyl)Pd(IPr)(Cl) and (η³-1-^tBu-indenyl)Pd(IPr)(Cl) are reduced to Pd(0) in alcoholic solvents, which are commonly used in Suzuki-Miyaura and α-arylation reactions. The rates of reduction for the different precatalysts are compared and we observe significant variability based on the exact reaction conditions. However, in general, η³-indenyl systems are reduced faster than η³-allyl systems, and DFT calculations show that this is in part due to the ability of the indenyl ligand to undergo facile ring slippage. Our results are consistent with the η³-indenyl systems giving increased catalytic activity and provide fundamental information about how to design systems that will rapidly generate monoligated Pd(0) in the presence of alcohols.

Full text of DOI:10.1021/acscatal.5b01291

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Article
Understanding Precatalyst Activation in Cross-Coupling
Reactions: Alcohol Facilitated Reduction from Pd(II) to Pd(0) in
Precatalysts of the type (#3-allyl)Pd(L)(Cl) and (#3-indenyl)Pd(L)(Cl)
Patrick R Melvin, David Balcells, Nilay Hazari, and Ainara Nova
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b01291 • Publication Date (Web): 17 Aug 2015
Downloaded from http://pubs.acs.org on August 23, 2015
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Understanding Precatalyst Activation in Cross-Coupling Reactions: Alcohol
Facilitated Reduction from Pd(II) to Pd(0) in Precatalysts of the Type (3-
allyl)Pd(L)(Cl) and (3-indenyl)Pd(L)(Cl)
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Patrick R. Melvin,a David Balcells,b Nilay Hazaria,* and Ainara Novab,*
aThe Department of Chemistry, Yale University, P. O. Box 208107, New Haven, Connecticut, 06520,
USA, bCentre for Theoretical and Computational Chemistry (CTCC) and The Department of
Chemistry, University of Oslo, P.O. Box 1033 Blindern, 0315 Oslo, Norway. E-mail:
nilay.hazari@yale.edu or ainara.nova@kjemi.uio.no.
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Abstract
Complexes of the type (3-allyl)Pd(L)(Cl) (L = PR3 or NHC), have been used extensively as precatalysts
for cross-coupling and related reactions, with systems containing substituents in the 1-position of the 3-
allyl ligand, such as (3-cinnamyl)Pd(L)(Cl), giving the highest activity. Recently, we reported a new
precatalyst scaffold based on an 3-indenyl ligand, (3-indenyl)Pd(L)(Cl), which typically provides higher
activity than even 3-cinnamyl supported systems. In particular, precatalysts of the type (3-1-tBu-
indenyl)Pd(L)(Cl) give the highest activity. In cross-coupling reactions using this type of Pd(II) precatalyst,
it is proposed that the active species is monoligated Pd(0) and the rate of reduction to Pd(0) is crucial. Here,
we describe detailed experimental and computational studies which explore the pathway by which the
Pd(II) complexes (3-allyl)Pd(IPr)(Cl) (IPr = 1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-
ylidene), (3-cinnamyl)Pd(IPr)(Cl), (3-indenyl)Pd(IPr)(Cl) and (3-1-tBu-indenyl)Pd(IPr)(Cl) are reduced
to Pd(0) in alcoholic solvents, which are commonly used in Suzuki-Miyaura and -arylation reactions. The
rates of reduction for the different precatalysts are compared and we observe significant variability based
on the exact reaction conditions. However, in general, 3-indenyl systems are reduced faster than 3-allyl
systems, and DFT calculations show that this is in part due to the ability of the indenyl ligand to undergo
facile ring slippage. Our results are consistent with the 3-indenyl systems giving increased catalytic
activity and provide fundamental information about how to design systems that will rapidly generate
monoligated Pd(0) in the presence of alcohols.
Keywords
Cross-coupling, catalysis, palladium, precatalyst, Suzuki-Miyaura reaction, catalyst activation, DFT
calculations.
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Introduction
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Palladium-catalyzed cross-coupling is an area of intense research interest because it has numerous
applications in the synthesis of pharmaceuticals, fine chemicals, and materials.1 The most effective
cross-coupling catalysts, especially for challenging substrates such as aryl chlorides, are supported by
strongly electron-donating and sterically bulky phosphine or N-heterocyclic carbene (NHC) ancillary
ligands.1f,1g The enhanced reactivity of these ligands is attributed to the formation of highly reactive
monoligated Pd(0) species.2 In recent years a number of well-defined Pd(I) and Pd(II) precatalysts
(Figure 1), which are bench stable and readily form monoligated Pd(0) have been developed.3 A key
feature in the effectiveness of these Pd(I) and Pd(II) precatalysts is the rate and efficiency of their
conversion into the monoligated Pd(0) active species under the reaction conditions.1b,1f,1h Studies of the
mechanism of activation of the Mingos/Hartwig,4 Buchwald3d and Organ precatalysts3g,5 have had
important implications for the design of improved precatalyst systems.
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Figure 1: A selection of popular well-defined precatalyst scaffolds with a 1:1 Pd to ligand ratio that are
commercially available.
Recently, it was demonstrated that the efficiency of both Nolan type (3-allyl)Pd(NHC)(Cl) and
Colacot/Shaughnessy type (3-allyl)Pd(PR3)(Cl) precatalysts is related to two factors: (a) The rate of
activation of the ligated Pd(II) precatalyst scaffold to form the catalytically active L-Pd(0) species; and
(b) Comproportionation between L-Pd(0) and the starting precatalyst, which forms a Pd(I) μ-allyl
dimer of the form (μ-allyl)(μ-Cl)Pd2(L)2 and removes L-Pd(0) from the reaction mixture.3m,3o,6 Colacot
used these results to develop improved precatalysts featuring a 1-methylallyl ligand,3o while our group
used this information to design a new precatalyst scaffold featuring an 3-indenyl ligand.3p In
particular, precatalysts based on the (3-1-tBu-indenyl)Pd(L)(Cl) scaffold were highly active because
Pd(I) dimer formation was effectively suppressed. However, surprisingly, given the utility and
popularity of catalysts of the type (3-allyl)Pd(L)(Cl)1b,1g,3m-o (L = NHC or PR3), the mechanism by
which Pd(II) is activated to Pd(0) under catalytic conditions is not well understood.3j,6a,7 In preliminary
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studies several different reduction pathways have been proposed on the basis of the olefin by-product
observed (Scheme 1): (i) Nucleophilic addition of the base (Nu) to the 3-allyl ligand, which ultimately
generates an olefin of the type CH2(Nu)-CH=CH(R).3j,7c (ii) Transmetallation with the nucleophilic
coupling partner such as an aryl (Ar) organoborane in the Suzuki-Miyaura reaction followed by
reductive elimination, yielding a CH2=CH-CH(R)(Ar) olefin;7b and (iii) Hydrogen transfer from the
alcohol solvents commonly used in Suzuki-Miyaura and -arylation reactions, yielding a CH2=CH-
CH2(R) olefin. The latter reaction may be either stepwise (A), by sequential -H and reductive
eliminations,6a,7a or concerted (B), by hydrogen shift, as shown by us in this work.
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Scheme 1: Mechanisms proposed for the reduction of Pd(II) 3-allyl systems with the experimentally
observed by-products highlighted in red.
These data suggest that small variations in the nature of the system, including the allyl ligand, the base
and the solvent, may result in different reaction mechanisms. In this scenario, it is unclear how the
highly active precatalysts based on the 3-indenyl scaffold are activated. Here, we describe the first
comprehensive study, including both experiment and theory, on the activation of (3-allyl)Pd(IPr)(Cl)
and (3-indenyl)Pd(IPr)(Cl) type precatalysts to Pd(0) in the presence of alcoholic solvents. We
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demonstrate that 3-indenyl containing precatalysts activate significantly faster than 3-allyl systems
(Figure 2) and provide a rationalization for these rates on the basis of the hydrogen shift mechanism
calculated using DFT.
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Figure 2: Rates of activation to monoligated Pd(0) for different precatalysts determined experimentally in
alcoholic solvents in this work. The pathways of activation which involve a key hydrogen shift are elucidated
using DFT calculations.
Results and Discussion
Experimental Studies of Activation of Pd(II) to Pd(0)
The highly active IPr supported precatalysts for the Suzuki-Miyaura reaction All, Cin, Ind and tBuInd
were synthesized using literature methods.3i,3l,3p The rates of conversion of the Pd(II) complexes into
Pd(0) were studied by treating these compounds with base in the presence of ten equivalents of 1,3-
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divinyl-1,1,3,3-tetramethyldisiloxane (dvds) and following the reaction using H NMR spectroscopy
(Table 1). These reactions model the activation of Pd(II) to Pd(0) in catalysis, where oxidative addition
to the unstable monoligated Pd(0) complex subsequently occurs to start the catalytic process. In all
cases, the products of these reactions are the Pd(0) complex (IPr)Pd(dvds),8 along with various
different organic by-products. Three different types of reaction conditions, which are relevant to
catalysis, were examined. The first set of conditions, which used KOtBu as the base and d8-iPrOH as
the primary solvent,9 is similar to the catalytic reaction conditions utilized by Nolan and co-workers.3l
The second set of conditions using K2CO3 and d4-MeOH as the solvent is related to catalytic reaction
conditions that we recently reported.6a Under these conditions K2CO3 is not soluble and 1,4,7,10,13,16-
hexaoxacyclooctadecane (18-crown-6) was used as a solubilizing agent. The third set of reactions,
which used KOtBu as the base and d4-MeOH as the solvent, was performed as a point of comparison
with both the first and second sets of experiments to probe the effect of both solvent and base on the
rate of precatalyst activation.
The indenyl complexes Ind and tBuInd were activated the fastest in all cases. In many instances, the
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activation was so fast that only a minimum rate could be estimated at 25°C using H NMR
spectroscopy. A series of reactions analogous to those described in Table 1 at 0°C, allowed us to
establish that tBuInd activates slightly faster than Ind. This is in agreement with the relative catalytic
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performance of these two complexes3p and indicates that modification of the substituent on the indenyl
ligand can be used to increase the rate of activation. The cinnamyl species Cin was relatively
efficiently activated using KOtBu as the base in d8-iPrOH, consistent with the excellent catalytic
performance of this precatalyst under related reaction conditions.3l Although, under these conditions
Cin activated faster than All, All was more efficiently activated than Cin in both of the reactions
conducted in d4-MeOH. These results indicate that the choice of solvent directly affects the rate of
activation and that the optimal solvent for one precatalyst may not be the same as for another
precatalyst, even when the precatalysts and solvents are closely related. Finally, the effect of adding
phenylboronic acid was also explored and it was observed that it slowed down the rate of activation in
all cases. Using K2CO3 as the base in d4-MeOH, in the presence of phenylboronic acid, tBuInd activates
slightly faster than Ind.
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Table 1: Rates of activation of All, Cin, Ind or tBuInd under different conditions in the presence of dvds.a
Rate of activation kobs (s-1)e
PhB(OH)2
present
Base
KOtBu
Solvent
d8-iPrOHb
All
Cin
Ind
tBuInd
No
5.6 ± 0.1 * 10-4 3.80 ± 0.03 * 10-3
> 7.7 * 10-3
> 7.7 * 10-3
(4.8 ± 0.1 * 10-3)f (5.3 ± 0.2 * 10-3)f
KOtBu
K2CO3
K2CO3
d4-MeOH
d4-MeOHc
d4-MeOHc
No
No
1.80 ± 0.02 * 10-3 5.1 ± 0.1 * 10-4
> 7.7 * 10-3
> 7.7 * 10-3
(5.3 ± 0.2 * 10-3)f (5.7 ± 0.1 * 10-3)f
9.6 ± 0.2 * 10-4
2.4 ± 0.1 * 10-4
4.2 ± 0.1 * 10-4
1.4 ± 0.2 * 10-4
> 7.7 * 10-3
> 7.7 * 10-3
(4.7 ± 0.1 * 10-3)f (5.0 ± 0.2 * 10-3)f
7.2 ± 0.1 * 10-4 7.6 ± 0.1 * 10-4
Yesd
aReaction conditions: 0.0087 mmol All, Cin, Ind or tBuInd, 0.087 mmol of base, 0.087 mmol of dvds in 500 L of
solvent. b100 L of d8-THF was added along with only 400 L of iPrOH. cTwo equivalents of 18-crown-6 (relative
to K2CO3) were added to solubilize the K2CO3. d0.0087 mmol precatalyst, 0.087 mmol phenylboronic acid, 0.096
e
mmol base, 0.087 mmol dvds in 500 L d4-MeOH. All rates are the average of at least two runs and were
measured using 1H NMR spectroscopy. fExperiments performed at 0°C.
To gain information about the role of dvds in the activation, reactions were performed in the absence
of dvds using the precatalysts All, Cin and Ind (Table 2). In this case, the Pd containing products of
the activation of All, Cin and Ind are Pd(I) dimers with bridging allyl or indenyl ligands, which we
have previously synthesized and characterized.6,10 However, the Pd(I) dimers are not soluble under the
reaction conditions, which precluded careful kinetic analysis of the data, due to difficulties associated
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with accurate integration of the H NMR spectra. Nevertheless, qualitative analysis indicates that
activation experiments performed in the absence of dvds give the same trends as those in the presence
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of dvds, with the indenyl complex Ind, always activating significantly faster than either All or Cin
under all conditions. This suggests that conclusions made about the rate of activation in the presence of
dvds are relevant to the true catalytic system which does not contain dvds. It should be noted that the
corresponding reactions with tBuInd did not give clean reactivity, presumably because the Pd(I) dimer
with a bridging 1-tBu-indene ligand is not accessible,3p which resulted in a mixture of products being
observed.
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Table 2: Rates of activation of All, Cin or Ind under different conditions in the absence of dvds.a
Time to completion (minutes)d
Base
Solvent
All
150
120
160
Cin
90
150
180
Ind
40
30
40
KOtBu
d8-iPrOHb
d4-MeOH
d4-MeOH
KOtBu
c
K2CO3
aReaction conditions: 0.0087 mmol All, Cin or Ind, 0.087 mmol of base in 500 L of solvent. b100 L of d8-THF
i
c
was added along with only 400 L of PrOH. Two equivalents of 18-crown-6 (relative to K2CO3) were added to
solubilize the K2CO3. dAll times to completion are the average of at least two runs and were measured using 1H
NMR spectroscopy.
It was possible to identify the organic by-products of activation in the presence of dvds using either 1H
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or C NMR spectroscopy (Table 3).11 Under all conditions, propene, allylbenzene, indene and 1-tBu-
indene were observed as by-products in activation studies using All, Cin, Ind and tBuInd, respectively.
These species were formed in > 95% yield as determined using 1H NMR spectroscopy. In addition, for
i
all reactions performed in PrOH, acetone was formed in high yield as determined using 13C NMR
spectroscopy. It is proposed that in reactions performed in MeOH, formaldehyde is a by-product,
although it was not directly observed using NMR spectroscopy. Instead resonances consistent with
oligomers of the type HO(CH2O)iCH3 (i > 1) were detected,12 regardless of the choice of base,
consistent with the formation of formaldehyde as the initial by-product in these reactions. The
reactions in the presence of phenylboronic acid exhibited the same by-products, indicating that the T-
RE mechanism illustrated in Scheme 1 (ii), which involves initial transmetallation of the boronic acid,
followed by reductive elimination, is not the major activation pathway. In agreement with this
conclusion the expected by-products from this alternative pathway (for example allylbenzene in the
case of All) were not detected. For the same reason, the nucleophilic addition mechanism, (i) in
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Scheme 1, is also excluded. Given that activation is 1st order in base (see Figure 3, for a representative
experiment using All), we believe that phenylboronic acid inhibits activation by reducing the effective
concentration of the base, but does not play a direct role in activation.
Table 3: Organic by-products from activation of All, Cin, Ind or tBuInd under different conditions in the presence
of dvds.a
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By-products from activation
PhB(OH)2
present
No
Base
Solvent
All
propene,
acetone
Cin
Ind
tBuInd
KOtBu d8-iPrOH
KOtBu d4-MeOH
K2CO3 d4-MeOH
K2CO3 d4-MeOH
allylbenzene,
acetone
indene,
acetone
indene,
1-tBu-indene,
acetone
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No
propene,
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formaldehydeb
allylbenzene,
formaldehydeb
allylbenzene,
formaldehydeb
1-tBu-indene,
formaldehydeb
propene,
formaldehydeb formaldehydeb
indene,
formaldehydeb formaldehydeb
indene,
1-tBu-indene,
1-tBu-indene,
formaldehydeb
propene,
Yes
formaldehydeb
formaldehydeb formaldehydeb
aThe same reaction conditions described in Table 1 were utilized, with the exception that a mixture of protio and
b
deuterated solvents was utilized to determine the organic by-products originating from the solvent. Proposed
product based on the formation of oligomers of the type HO(CH2O)iCH3 (i > 1).12
0.0025
0.002
R² = 0.9862
0.0015
0.001
0.0005
0
0
5
10
15
20
25
Number of equivalents of K2CO3
Figure 3: Plot of observed rate constant versus number of equivalents of base for the activation of All in
d4-MeOH with K2CO3 in the presence of dvds and 18-crown-6 ether measured using 1H NMR
spectroscopy.
DFT Studies of Activation of Pd(II) to Pd(0)
Our experimental studies provide the rates of activation of the four systems and the by-product formed.
This allows us to discard mechanisms i and ii in Scheme 1. However, our mechanistic studies do not
provide information about whether the pathway iii in is A or B (Scheme 1). Therefore, DFT
calculations were performed to study the elementary steps in the mechanism of activation of All, Cin,
Ind and tBuInd in detail. The calculations were performed using OMe- as the base, which is equivalent
to experiments using KOtBu as the base in MeOH (Table 1). A number of different pathways were
calculated for the activation of all four systems (see Supporting Information). The key intermediates
and TS energies for All are shown in Schemes 2 and 3, while those for Cin and tBuIn are shown in
Scheme 4. Results for Ind are not shown in Schemes but described in the text. Initial substitution of Cl-
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by OMe- can take place via dissociative (INT1 = 13.8 kcal mol-1) or associative (TS1 = 15.7 kcal
mol-1) substitution (Scheme 2). The lower energy barrier for the former process is in agreement with
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n
previous experimental studies showing that the addition of excess Bu4NCl inhibits activation.6a
Similar results were obtained for Cin, Ind and tBuInd, with larger energy differences between both
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pathways; 5.3, 5.0 and 9.7 kcal mol-1, respectively, in favor of the dissociative mechanism in all cases.
Scheme 2: Calculated pathway for the dissociative and associative ligand substitution of Cl- by OMe- in
the All system. Relative energies are given in kcal mol-1.
Scheme 3: Calculated pathways for the activation of All from INT2. Energies are relative to All (Scheme 2)
and given in kcal mol-1.
After the coordination of MeO-, formation of the olefin observed experimentally requires migration of
a proton from the OMe- group to the allyl ligand. A plausible stepwise mechanism involves -H
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elimination followed by reductive elimination of propene (mechanism iii, pathway A in Scheme 1). In
order to generate the vacant site required for -H elimination, a change in coordination mode of the
allyl ligand from 3 (INT2) to 1 (INT3) is needed (Scheme 3). This change in coordination mode is
endoergic by 10.1 kcal mol-1. The -H elimination transition state (TS3) involves an energy barrier of
24.0 kcal mol-1 and connects to a 2-formaldehyde complex (INT4) through a transient agostic
intermediate (see Supporting Information). The decoordination of formaldehyde requires a 2 → 1
rearrangement, which involves the highest energy transition state found in this pathway; i.e., TS4, 28.5
kcal mol-1 above reactants. After 1 → 3 isomerization of the allyl ligand, reductive elimination takes
place through a low energy barrier of 15.1 kcal mol-1 (TS5) and yields propene. The formation of this
product from INT3 is also possible through the HS mechanism, (iii, B) in Scheme 1, in which one
proton migrates from the MeO- ligand to the allyl in a single concerted step involving TS2, with an
energy barrier of 20.5 kcal mol-1. The relaxation of this transition state yields formaldehyde and the
Pd(0)-propene complex. The relative energy of TS2, which is 8.0 kcal mol-1 lower than that of TS4,
strongly suggests that the HS mechanism is kinetically more favorable than the HE-RE pathway.
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Scheme 4: Calculated pathways for the activation of Cin and tBuInd from INT2. Relative energies are given in
kcal mol-1 (blue for Cin and red for tBuInd).
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The relative energies of TS2 and TS4 were also computed for Cin, Ind and tBuInd (see Scheme 4 and
S3) and the former is lower in energy in all cases by 5.3, 3.9 and 5.3 kcal mol-1, respectively, showing
the same preference for the HS mechanism over the HE-RE found for All. In addition, by computing
the reductive elimination step for the unsymmetrical systems Cin and tBuInd, it was found that two
transition states (TS5a and TS5b) are feasible, each one yielding a different Pd(0)-olefin complex with
either olefin1 (terminal; observed) or olefin2 (internal; not observed). The lower energy of TS5b and
Pd(0)-olefin2 with both Cin and tBuInd indicates that olefin2 would be observed if the HE-RE
pathway was preferred.13 The HS mechanism is thus supported by both its lower energy barrier and the
predicted reaction product, which matches the one observed experimentally.
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The energy profiles for the HS mechanism with All, Cin, In and tBuInd are given in Scheme 5,
showing the rate-limiting barriers; i.e., 24.5, 25.2, 21.7 and 19.8 kcal mol-1, respectively. The barriers
correspond to the energy difference between TS2 and the most stable reactant, which is the starting
material for Cin and INT2 for all other systems. Overall, these values are consistent with the
experimental trend observed for precatalyst activation rates in MeOH (see Table 1), i.e. tBuInd > Ind >
All > Cin.
Scheme 5: Free energy profiles (in kcal mol-1) for the activation of All (black), Cin (red), Ind (green) and
tBuInd (blue) by a HS type mechanism. Structures of Indenyl type ligands and energies for All and Ind have
been omitted for clarity.
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The structures of the key transition states for activation of All, Cin, Ind and tBuInd are shown in
Figure 4. The structures of the four transition states are similar. In all cases a seven-membered ring
facilitates proton transfer and the Pd is essentially only bound to one carbon atom of the allyl,
cinnamyl, indenyl or 1-tBu-indenyl ligand. The lowering of the hapticity of those ligands in the
transition state is already apparent in INT3. Indeed the energy differences between All, Cin, Ind and
tBuInd systems are greater when moving along the reaction coordinate from INT2 to INT3 (10.1, 7.3,
5.5, 0.5 kcal mol-1, respectively) than from INT3 to TS2 (14.1, 17.1, 16.2 and 17.9 kcal mol-1,
respectively). The M-L donor-acceptor interactions in INT2 and INT3 were investigated by means of
natural bond orbital analysis (NBO version 6).14 These calculations showed that all systems are
stabilized by -donation, L() → Pd(d), between the ligand and the metal center (L = allyl, cinnamyl,
indenyl and 1-tBu-indenyl) in INT2. However this interaction is highly reduced in INT3, in agreement
with the lowering of the hapticity of L. The natural localized molecular orbitals (NLMOs) associated
with this interaction are depicted in Figure 5. In addition to the ligand -donation to the metal, the
NLMOs for Ind and tBuInd show some delocalization of the allyl -system over the phenyl ring.
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Second-order perturbation analysis was carried out to calculate the stabilization energy (SE) of the
L() → Pd(d) donation for allyl, cinnamyl, indenyl and 1-tBu-indenyl ligands in both INT2 and
INT3.15 In line with the different shape of the NLMOs, different SE values for L() → Pd(d) were
obtained. For INT2, SE = 59.3 (All), 48.3 (Cin), 39.6 (Ind) and 22.5 (tBuInd) kcal mol-1 (Figure 5 in
blue), whereas for INT3, SE = 8.4 (All), 9.4 (Cin), 8.2 (Ind) and 8.6 (tBuInd) kcal mol-1 (Figure 5 in
red). The decrease in the SE values when moving from All and Cin to Ind and tBuInd in INT2 is
consistent with the nature of its NLMOs. The increase in the allyl delocalization by allyl-phenyl
conjugation in indenyl type ligands weakens the L() → Pd(d) donation in INT2. Consequently, the
loss in energy expected for the hapticity change from INT2 to INT3 is lower for these systems
compared to All and Cin. This result is in agreement with previous studies, which indicate that ring
slippage of indenyl ligands coordinated to Pd is facile.16 The graphic representation of the SE
differences for the L() → Pd(d) donation in INT2 and INT3 versus the energy difference between
these two intermediates shows a strong correlation in a linear regression (y = 3.83x + 11.4; r2 = 0.997).
This supports that the stability of INT2 relative to INT3 is largely controlled by the L() → Pd(d)
donor interaction.
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a)
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c)
d)
t
Figure 4: Calculated transition state (TS2) structures for activation of a) All, b) Cin, c) Ind and d) BuInd.
Selected hydrogen atoms are omitted for clarity. Selected bond distances (Å): a) Pd(1)-C(1) 2.14, Pd(1)-C(2)
2.67, C(1)-C(2) 1.41, C(2)-C(3) 1.41, C(3)-H(1) 1.36, H(1)-C(4) 1.34, C(4)-O(1) 1.30, Pd(1)-O(1) 2.13, Pd(1)-
C(5) 2.02. b) Pd(1)-C(1) 2.18, Pd(1)-C(2) 2.71, C(1)-C(2) 1.40, C(2)-C(3) 1.43, C(3)-H(1) 1.30, H(1)-C(4)
1.38, C(4)-O(1) 1.29, Pd(1)-O(1) 2.13, Pd(1)-C(5) 2.03. c) Pd(1)-C(1) 2.20, Pd(1)-C(2) 2.74, C(1)-C(2) 1.41,
C(2)-C(3) 1.43, C(3)-H(1) 1.33, H(1)-C(4) 1.37, C(4)-O(1) 1.29, Pd(1)-O(1) 2.12, Pd(1)-C(5) 2.05. d) Pd(1)-
C(1) 2.21, Pd(1)-C(2) 2.75, C(1)-C(2) 1.40, C(2)-C(3) 1.44, C(3)-H(1) 1.33, H(1)-C(4) 1.37, C(4)-O(1) 1.29,
Pd(1)-O(1) 2.13, Pd(1)-C(5) 2.05.
Although our DFT calculations on activation were performed using OMe- as the base, which is
experimentally equivalent to using KOtBu as the base in MeOH, they can also be related to reactions
using K2CO3 as the base in MeOH. In this case, K2CO3 which is a weak base, is not sufficiently strong
to deprotonate MeOH and generate a free MeO- anion. Therefore, when All, Cin, Ind and tBuInd are
activated in MeOH, we propose that MeOH initially coordinates to Pd (INT1a) (via dissociative ligand
substitution of the Cl- ligand, INT1), which increases its acidity. The coordinated MeOH is
subsequently deprotonated by K2CO3 to form INT2. This pathway is shown for All in Scheme 6. We
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expect that the intermediate INT1a and K2CO3 are slightly higher in energy than either All, Cin, Ind
and tBuInd, MeOH and K2CO3, given that no intermediate is observed experimentally. Thus, the
energy profile for this reaction will be similar to that calculated for activation using OMe- as the base,
where the energies of the starting materials, INT2 and TS2 are crucial. This is consistent with what is
observed experimentally where the by-products and relative rates of activation of All, Cin, Ind and
tBuInd using KOtBu as the base in MeOH are the same as those observed for activation using K2CO3 as
the base in MeOH.
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Figure 5: NBO6 analysis: a) Stabilization energies (x) vs. L (y) for INT2 (blue) and INT3 (red); b) Correlation
between differences in INT2/INT3 relative energies (x) and stabilization energies (y); natural localized molecular
orbitals (NLMOs) for c) INT2 (All), d) INT3 (All), e) INT2 (Ind; side view) and f) INT2 (Ind; top view). All energies
are given in kcal mol-1.
Scheme 6: Proposed pathway for activation of All with K2CO3 in MeOH. Analogous pathways are proposed for
Cin, Ind and tBuInd.
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Experimentally, activation of Cin using KOtBu in PrOH is faster than activation of All. Under these
conditions the primary base in solution is OiPr-. Given the relatively small calculated difference in
energy between G‡ for activation of All and Cin using OMe-, it is reasonable that changing the base
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materials, INT2 or TS2 to result in Cin being easier to activate than All. Alternatively, it is possible
that there is a different mechanism of activation using OiPr-. However, given the similar kinetic profile
of the reaction and the observation of related by-products to those found for OMe-, this seems unlikely.
Conclusions
In this work we use both experiment and theory to unambiguously establish the pathway for the
activation of the highly active cross-coupling precatalysts All, Cin, Ind and tBuInd in alcoholic
solvents, which are commonly used for Suzuki-Miyaura and -arylation reactions. To our knowledge
this study represents the first comprehensive comparative investigation of precatalyst activation in
systems containing allyl and/or indenyl ligands and the mechanistic understanding gained should help
with the rational design of improved precatalysts. We show that one reason for the excellent activity of
the tBuInd precatalyst is due to its rapid reduction from Pd(II) to Pd(0) under catalytic conditions
involving alcoholic solvents. In fact, under these conditions we estimate that the tBuInd precatalyst
activates at least an order of magnitude faster than state of the art All and Cin precatalysts. This
complements previous work which demonstrated that the improved activity of the tBuInd precatalyst
compared to All and Cin precatalysts is in part related to its inability to form a less reactive Pd(I)
dimer during catalysis.6a DFT calculations suggest that the key step in the activation of tBuInd, as well
as the related All and Cin systems, involves a concerted proton abstraction from a coordinated
alkoxide, generated from the alcoholic solvent, by the nucleophilic indenyl or allyl ligand. This process
is faster for indenyl ligands compared to allyl ligands primarily due to the ability of the indenyl ligand
to undergo facile ring slippage, as evidenced by detailed DFT calculations. The rate of the activation
reaction is influenced both by the choice of base and solvent and these variables should be carefully
optimized in catalytic reactions. We believe that the results described in this work with IPr-supported
systems will be generalizable to the activation of precatalysts supported by phosphine ligands in
alcoholic solvents and in future work we will explore complexes of this type. However, the mechanism
of activation of 1-tert-butylindenyl scaffolds under conditions which do not involve an alcoholic
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solvent, such as those used for the Buchwald-Hartwig reaction, remains unclear, and studies are still
required to elucidate the pathway of reduction in these cases.
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Experimental Section
General methods
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Experiments were performed under a dinitrogen atmosphere in an M-Braun dry box or using standard
Schlenk techniques unless otherwise stated. Under standard glovebox conditions purging was not
performed between uses of pentane, benzene and toluene; thus when any of these solvents were used,
traces of all these solvents were in the atmosphere and could be found intermixed in the solvent bottles.
Moisture- and air-sensitive liquids were transferred by stainless steel cannula on a Schlenk line or in a
dry box. THF was dried by passage through a column of activated alumina followed by storage under
dinitrogen. All commercial chemicals were used as received except where noted. MeOH (J. T. Baker)
and iPrOH (Macron Fine Chemicals) were not dried but were degassed by sparging with dinitrogen for
1 hour and stored under dinitrogen. Potassium tert-butoxide (99.99%, sublimed) was purchased from
Aldrich. 2,6-dimethylboronic acid (98%), 1-naphthaleneboronic acid (97%) were purchased from
Fisher
Scientific.
Potassium
carbonate
was
purchased
from
Mallinckrodt.
1,3-
divinyltetramethyldisiloxane was purchased from TCI. Potassium carbonate was ground up with a
mortar and pestle and stored in an oven at 130ºC prior to use. Deuterated solvents were obtained from
Cambridge Isotope Laboratories. d4-MeOH, d8-iPrOH, and d8-THF were not dried but were degassed
prior to use through three freeze-pump-thaw cycles. NMR spectra were recorded on Agilent-400, -500
and -600 spectrometers and Varian-300, -500 spectrometers at ambient probe temperatures unless
noted. For variable temperature NMR, the sample temperature was calibrated by measuring the
distance between the OH and CH2 resonances in ethylene glycol (99%, Aldrich). Literature procedures
were used to prepare the following compounds: (3-allyl)Pd(IPr)(Cl)3i (All), (3-cinnamyl)Pd(IPr)(Cl)
(Cin),3l (3-indenyl)Pd(IPr)(Cl)3p (Ind) and (3-tBu-indenyl)Pd(IPr)(Cl)3p (tBuInd).
Computational details
All stationary points were fully optimized at the DFT level with the hybrid meta-GGA M06
functional15 including dispersion, as implemented in the Gaussian09 software package (Rev. D.01).16
Geometry optimizations were carried out on the full system including solvation by MeOH with the
continuum SMD model.17 Frequencies were computed with the aim of classifying all stationary points
as either minima (reactants, intermediates and products, with all real frequencies) or saddle points
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(transition states, with a single imaginary frequency). These calculations were also used to determine
the thermochemistry corrections, (G – E), which include the zero-point energies, thermal contributions
and entropies. In addition, vibrational data were used to relax the transition states towards the reactants
and products connected to them. Two different basis sets were used, BS1, for geometry optimizations
and frequency calculations, and BS2, for single-points. BS1 includes polarization functions and small-
core pseudopotentials by combining the double- 6-31G** (C, N, O and H)18 and triple- LANL08*
(Pd)19 basis sets. With BS2, Pd was described at the same level, whereas C, N O and H were described
with the triple- 6-311+G** basis set20 , including polarization and diffuse functions. The single-point
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calculations
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level
on
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DFT(M06)/SMD(MeOH)/BS1-optimized geometries with the aim of refining the potential energies
(Esol). The energies discussed in the text, Gsol, were obtained by adding the thermochemistry
corrections to the refined potential energies (Eq 1). The energy correction for a 1M standard state was
also included; i.e. + or –1.9 kcal mol-1 for a bimolecular dissociative or associative step, respectively.
Gsol = Esol + (G – E) +/– 1.9 kcal mol-1
(Eq 1)
Donor-acceptor interactions were explored by means of natural bond orbital calculations (NBO6
version).14 The nature of these interactions was determined by computing the associated natural
molecular orbitals (NLMO). Second order perturbation analysis was performed to calculate the
stabilization energies (SE), which allow for quantifying the relative strength of these interactions.
Experiments on Activation of Pd(II) to Pd(0):
Experimental details for Table 1: Rates of activation of All, Cin, Ind and tBuInd under different
conditions in the presence of dvds
d8-iPrOH / KOtBu experiments:
KOtBu (9.8 mg, 0.087 mmol) was dissolved in 300 L of d8-iPrOH along with 100 L of a 0.87 M
solution of dvds in d8-iPrOH. All (5.0 mg), Cin (5.6 mg), Ind (5.6 mg), or tBuInd (6.0 mg, 0.0087
mmol) was dissolved in 100 L of d8-THF. These solutions were combined in a J. Young NMR tube at
-78°C. The reaction mixture was degassed on a Schlenk line, after which dinitrogen was introduced
1
into the NMR tube. An array of H NMR spectra was taken at 25°C (or 0°C for the cases of Ind and
tBuInd) over the course of 3 hours. During this time, the growth of the methyl protons of the
(IPr)Pd(dvds)8 product were monitored.
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d4-MeOH / KOtBu experiments:
4
KOtBu (9.8 mg, 0.087 mmol) was dissolved in 300 L of d4-MeOH along with 100 L of a 0.87 M
solution of dvds in d4-MeOH. All (5.0 mg), Cin (5.6 mg), Ind (5.6 mg), or tBuInd (6.0 mg, 0.0087
mmol) was dissolved in 100 L of d4-MeOH. These solutions were combined in a J. Young NMR tube
at -78°C. The reaction mixture was degassed on a Schlenk line, after which dinitrogen was introduced
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into the NMR tube. An array of H NMR spectra was taken at 25°C (or 0°C for the cases of Ind and
tBuInd) over the course of 3 hours. During this time, the growth of the methyl protons of the
(IPr)Pd(dvds)8 product were monitored.
d4-MeOH / K2CO3 experiments:
K2CO3 (12.0 mg, 0.087 mmol) and 18-crown-6 ether (46.0 mg, 0.174 mmol) were dissolved in 300 L
of d4-MeOH along with 100 L of a 0.87 M solution of dvds in d4-MeOH. All (5.0 mg), Cin (5.6 mg),
Ind (5.6 mg), or tBuInd (6.0 mg, 0.0087 mmol) was dissolved in 100 L of d4-MeOH. These solutions
were combined in a J. Young NMR tube at -78°C. The reaction mixture was degassed on a Schlenk
line, after which dinitrogen was introduced into the NMR tube. An array of 1H NMR spectra was taken
at 25°C (or 0°C for the cases of Ind and tBuInd) over the course of 3 hours. The strong –CH2 peak
from the 18-crown-6 ether was suppressed by presaturating its signal during the experiment. During
this time, the growth of the methyl protons of the (IPr)Pd(dvds)8 product were monitored.
d4-MeOH / K2CO3 / PhB(OH)2 experiments:
KOtBu (10.8 mg, 0.096 mmol) and phenylboronic acid (10.6 mg, 0.087 mmol) were dissolved in 300
L of d4-MeOH along with 100 L of a 0.87 M solution of dvds in d4-MeOH. All (5.0 mg), Cin (5.6
mg), Ind (5.6 mg), or tBuInd (6.0 mg, 0.0087 mmol) was dissolved in 100 L of d4-MeOH. These
solutions were combined in a J. Young NMR tube at -78°C. The reaction mixture was degassed on a
1
Schlenk line, after which dinitrogen was introduced into the NMR tube. An array of H NMR spectra
was taken at 25°C over the course of 3 hours. During this time, the growth of the methyl protons of the
(IPr)Pd(dvds)8 product were monitored.
Experimental details for Table 2: Rates of activation of All, Cin and tBuInd under different conditions
in the absence of dvds
d8-iPrOH / KOtBu experiments:
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KOtBu (9.8 mg, 0.087 mmol) was dissolved in 400 L of d8-iPrOH. All (5.0 mg), Cin (5.6 mg), or Ind
(5.6 mg, 0.0087 mmol) was dissolved in 100 L of d8-THF. These solutions were combined in a J.
Young NMR tube at -78°C. The reaction mixture was degassed on a Schlenk line, after which
dinitrogen was introduced into the NMR tube. An array of 1H NMR spectra was taken at 25°C over the
course of 3 hours. Due to the insolubility of the products, the disappearance of starting Pd(II)
precatalyst was monitored to determine the time to completion.
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d4-MeOH / KOtBu experiments:
KOtBu (9.8 mg, 0.087 mmol) was dissolved in 400 L of d4-MeOH. All (5.0 mg), Cin (5.6 mg), or
Ind (5.6 mg, 0.0087 mmol) was dissolved in 100 L of d4-MeOH. These solutions were combined in a
J. Young NMR tube at -78°C. The reaction mixture was degassed on a Schlenk line, after which
dinitrogen was introduced into the NMR tube. An array of 1H NMR spectra was taken at 25°C over the
course of 3 hours. Due to the insolubility of the products, the disappearance of starting Pd(II)
precatalyst was monitored to determine the time to completion.
d4-MeOH / K2CO3 experiments:
K2CO3 (12.0 mg, 0.087 mmol) and 18-crown-6 ether (46.0 mg, 0.174 mmol) were dissolved in 400 L
of d4-MeOH. All (5.0 mg), Cin (5.6 mg), or Ind (5.6 mg, 0.0087 mmol) was dissolved in 100 L of
d4-MeOH. These solutions were combined in a J. Young NMR tube at -78°C. The reaction mixture
was degassed on a Schlenk line, after which dinitrogen was introduced into the NMR tube. An array of
1H NMR spectra was taken at 25°C over the course of 3 hours. The strong –CH2 peak from the 18-
crown-6 ether was suppressed by presaturating its signal during the experiment. Due to the insolubility
of the products, the disappearance of starting Pd(II) precatalyst was monitored to determine the time to
completion
Experimental details for Table 3: By-products from precatalyst activation of All, Cin, Ind or tBuInd
under different conditions in the presence of dvds
Identifying propene, allylbenzene, indene or 1-tBu-indene as by-products after activation experiments
using different reaction conditions
K2CO3 (12.0 mg, 0.087 mmol) and 18-crown-6 ether (46.0 mg, 0.174 mmol) were dissolved in 300 L
of d4-MeOH along with 100 L of a 0.87 M solution of dvds in d4-MeOH. All (5.0 mg, 0.0087 mmol),
Cin (5.6 mg, 0.0087 mmol) Ind (5.6 mg), or tBuInd (6.0 mg, 0.0087 mmol) was dissolved in 100 L of
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d4-MeOH. These solutions were combined in a J. Young NMR tube at -78°C. The reaction mixture
was degassed on a Schlenk line, after which dinitrogen was introduced into the NMR tube. The
reaction was allowed to continue at room temperature for 2 hours to ensure complete activation of the
1
precatalyst. At this time, a H NMR spectrum was recorded. Peaks corresponding to the appropriate
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by-product were found; a second H NMR spectrum was recorded following the addition of a known
quantity of the by-product into the reaction mixture to verify the identity of the organic products
produced.
Analogous reactions using d8-iPrOH as the solvent and KOtBu as the base and d4-MeOH as the solvent
and KOtBu as the base were performed using the same method.
Identifying acetone as a byproduct after activation when using iPrOH
KOtBu (9.8 mg, 0.087 mmol) was dissolved in 200 L of d8-iPrOH and 200 L of protio-iPrOH. All
(5.0 mg, 0.0087 mmol), Cin (5.6 mg, 0.0087 mmol) Ind (5.6 mg), or tBuInd (6.0 mg, 0.0087 mmol)
was dissolved in 100 L of d8-THF. These solutions were combined in a J. Young NMR tube at -78°C.
The reaction mixture was degassed on a Schlenk line, after which dinitrogen was introduced into the
NMR tube. The reaction was allowed to continue at room temperature for 2 hours to ensure complete
activation of the precatalyst. At this time, the volatiles were transferred to a new J. Young NMR tube
via vacuum transfer using a Schlenk line. A 1H NMR spectrum was recorded and peaks with chemical
shifts corresponding to acetone were identified.
Identifying formaldehyde as a byproduct after activation using MeOH
K2CO3 (12.0 mg, 0.087 mmol) and 18-crown-6 ether (46.0 mg, 0.174 mmol) were dissolved in 200 L
of d4-MeOH and 200 L of protio-MeOH. All (5.0 mg, 0.0087 mmol), Cin (5.6 mg, 0.0087 mmol) Ind
(5.6 mg), or tBuInd (6.0 mg, 0.0087 mmol) was dissolved in 100 L of d4-MeOH. These solutions were
combined in a J. Young NMR tube at -78°C. The reaction mixture was degassed on a Schlenk line,
after which dinitrogen was introduced into the NMR tube. The reaction was allowed to continue at
room temperature for 2 hours to ensure complete activation of the precatalyst. At this time, the
volatiles were transferred to a new J. Young NMR tube via vacuum transfer using a Schlenk line.
Peaks corresponding to the hemiacetal products reported by Hahnenstein et al for formaldehyde in
MeOH were observed.12
Acknowledgements
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AN and DB acknowledge support from the Norwegian Research Council through the Center of
Excellence for Theoretical and Computational Chemistry (CTCC) (Grant No. 179568/V30) and the
Norwegian Metacenter for Computational Science (NOTUR; Grant nn4654k). DB also thanks the EU
REA for a Marie Curie Fellowship (Grant CompuWOC/618303). PRM thanks the NSF for support as
NSF Graduate Research Fellows. NH is a fellow of the Alfred P. Sloan Foundation and a Camille and
Henry-Dreyfus Foundation Teacher Scholar.
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Supporting information available
Further experimental details and details of DFT calculations are available free of charge via the
internet at http://pubs.acs.org.
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