Study of Lewis acid accelerated palladium catalyzed C[sbnd]H activation

Article abstract of DOI:10.1016/j.molcata.2016.09.018

Acceleration of palladium catalyzed C[sbnd]H activation by various Lewis Acids was demonstrated on the directed ortho-alkenylation and acylation of acetanilide and urea derivatives. The universality of this effect was investigated by the study of differen

Full text of DOI:10.1016/j.molcata.2016.09.018

Accepted Manuscript
Title: Study of Lewis Acid Accelerated Palladium Catalyzed
C-H Activation
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Author: Orsolya Tischler Szabolcs Kovacs Gabor Ersek Peter
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Kralln Janos Daru Andras Stirling Zoltan Novak
PII:
S1381-1169(16)30390-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2016.09.018
MOLCAA 10042
To appear in:
Journal of Molecular Catalysis A: Chemical
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30-5-2016
7-9-2016
14-9-2016
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Please cite this article as: Orsolya Tischler, Szabolcs Kovacs, Gabor Ersek, Peter
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Kralln, Janos Daru, Andras Stirling, Zoltan Novak, Study of Lewis Acid Accelerated
Palladium Catalyzed C-H Activation, Journal of Molecular Catalysis A: Chemical
http://dx.doi.org/10.1016/j.molcata.2016.09.018
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Study of Lewis Acid Accelerated Palladium Catalyzed C-H Activation
Orsolya Tischler,a Szabolcs Kovács, a Gábor Érsek, a Péter Králl, a János Daru,b András
Stirling,b* Zoltán Nováka*
aMTA-ELTE “Lendület” Catalysis and Organic Synthesis Research Group, Institute of Chemistry. Eötvös Loránd University, Pázmány Péter
stny. 1/a, Budapest, 1117, Hungary
bMTA TTK Research Centre for Natural Sciences of the Hungarian Academy of Sciences, Department of Theoretical Chemistry, Magyar
Tudósok körútja 2. H-1117 Budapest, Hungary
E-mail addresses: stirling.andras@ttk.mta.hu, novakz@elte.hu.
1

Graphical abstract
Highlights
 Amide and urea directed ortho-acylation and ortho-olefination on aromatic cores is
accelerated by Lewis acidic additives.
 Lewis acidic additives afford more electrophilic transition metal center, favoring C-H
activation.
 The efficiency of several palladium(II) catalysts is raised.
 KIE experiments and calculations suggests a rate-determining C-H activation step.
Keywords: C-H activation, palladium, Lewis acid, DFT studies
This paper is dedicated to Professor Georgiy B. Shul’pin on the occasion of his 70th birthday
Abstract
Acceleration of palladium catalyzed C-H activation by various Lewis Acids was demonstrated
on the directed ortho-alkenylation and acylation of acetanilide and urea derivatives. The
universality of this effect was investigated by the study of different palladium catalysts,
directing groups in the aromatic substrates and versatile Lewis acids. Experiments were carried
out to monitor the reactions and to compare the behavior and activity of different types of Lewis
acids. Kinetic investigation revealed a rate determining C-H activation step, and DFT studies
were performed for the explanation of Lewis acid effect on C-H activation.
1. Introduction
Over the past decade the palladium catalyzed regioselective direct functionalization of arenes
has been extensively utilized in organic chemistry. The mechanistic studies of the transition
metal catalyzed C-H bond breaking [1-3] constitute an important part of this research field.
Thus, throughout the past decade(s) several theories[4-11] have been elaborated regarding the
2

elementary steps of the key transformation. Some reagents of the reaction mixtures have well-
defined role, others are still in the phase of empirical inquiry. Certain substituents and functional
groups with heteroatom ensure the proximity of the transition metal to the substrate by
coordination and enable the C-H activation[12-16]. In the field of mild transformations [17, 18]
different additives, mainly inorganic metal salts are generally applied. The exact role of each
reactants in the catalytic transformation [19-21] is not always clear. Brønsted acids have proven
accelerating effect on the C-H activation reactions via enhancing ligand dissociation/exchange
on the transition metal, generating a more electrophilic metal center [22-27]. However, the
beneficial effect of protic media cannot be omitted. We experienced accelerating effect of Lewis
acids on palladium catalyzed ortho-acylation of acetanilide derivatives and hypothesize that
Lewis acidic triarylboranes may act as effective accelerators in palladium catalyzed C-H
activation [28]. In this paper we present the studies of the catalytic system to find out the scope
of applicable Lewis acids and their role in the C-H activation processes.
2. Experimental
2.1. General
Anhydrous dichloromethane was distilled from sodium under N2 and stored on
molecular sieves, 4Å. Isotope labelled compounds were synthesized. All other solvents and
reagents
were
purchased
from
commercial
sources,
including
B(C6F5)3.
Tris(pentafluoro)phenyl borane was stored and handled inside a glove box. BBr3 was applied in
the form of a stock solution: 0.25 M in anh. DCM. BCl3 was applied in the form of a stock
solution: 1 M in anh. DCM. Conversions are determined by gas chromatography: Agilent 5890
Gas Chromatograph (30 m x 0.25 mm column with 0.25 µm HP-5MS coating, He carrier gas)
with FID detector and mass spectrometry was obtained on an Agilent 6890N Gas
Chromatograph (30 m x 0.25 mm column with 0.25 µm HP-5MS coating, He carrier gas) and
Agilent HP 5973N Mass Spectrometer (Ion source: EI+, 70eV, 230 °C interface 300 °C).
2.2. General procedure of the reactions
A screw capped 4 mL vial with a stirring bar was charged with acetanilide (0.1 mmol, 13.5
mg, 1 equiv.) and Pd catalyst (0.005 mmol, 5 mol%). The solids were dissolved in anh.
dichloromethane (0.2 mL). Lewis acid (0.0072 mmol, 7.2 mol%), 4-fluoro-benzaldehyde (0.2
mmol, 21 µL, 2 equiv.) and tBuOOH solution (5.5M in C10H22, 4Å M.S.) (0.2 mmol, 40 µL, 2
3

equiv.) were added and the vial was closed with septum screw cap. The reaction mixture was
magnetically stirred at 30°C for 24 hours. During 24 hours samples for GC analysis were taken.
A screw capped 4 mL vial with a stirring bar was charged with N-aryl, N, N-dimethyl urea
(0.1 mmol, 1 equiv.) and Pd catalyst (0.005 mmol, 5 mol%). The solids were dissolved in
dichloromethane (0.2 mL). Lewis acid (0.0072 mmol, 7.2 mol%), acrylic ester (0.15 mmol, 1.5
equiv.) and tBuOOH solution (5.5M in C10H22, 4Å M.S.) (0.15 mmol, 30 µL, 1.5 equiv.) were
added and the vial was closed with septum screw cap. The reaction mixture was magnetically
stirred at 30°C for 24 hours. During 24 hours samples for GC analysis were taken.
2.3. Computational protocol
The reaction mechanism has been investigated by density functional theory based
calculations employing the M06 exchange-correlation functional [29] as implemented in G09.
The Kohn-Sham orbitals have been expanded in a double-zeta basis set (6-31+G* basis set for
main group elements and LANL2DZ basis set with additional set of diffuse and polarization
functions). Solvent effects have been introduced by the SMD solvent model using DCM as a
solvent[30]. The contributions to the Gibbs free energies have been calculated by assuming
30 °C and 1 mol/L concentration. Kinetic isotope effect has been calculated through the
Bigeleisen-Mayer theory [31, 32] with the QUIVER code[33]. Scaling factors have been
obtained from Ref. [29].
3. Results and discussion
Amide moiety is a versatile directing group on aromatic cores. Several examples can be
found in recent literature, including mild, palladium catalyzed ortho-functionalization of
acetanilides. The successfully applied common acylating agents are α-oxo-carboxylic acids[34,
35] and aldehydes[36-43], but the coupling reaction has already been achieved with benzylic
alcohols [44-46] and even from toluene derivatives[47-50].
We have recently identified Lewis acidic triaryl boranes as co-catalyst of palladium (II)
compounds in the directed ortho-acylation of acetanilide derivatives at ambient temperature by
in situ generated acyl radicals. [28] In further investigations we examined the universality of
this beneficial effect regarding the types of suitable directing groups, coupling partners,
transition metal catalysts and the applicable Lewis acids.
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3.1. Study of the efficiency of different palladium sources
The ortho-acylation of acetanilide by 4-fluoro-benzaldehyde was chosen as test
reaction. Different kinds of palladium (II) catalysts (5 mol% palladium-acetate, palladium-
trifluoroacetate, palladium acetylacetonate) were applied in the presence of boron trifluoride
diethyl etherate (7.2 mol%) to see the specific activity of Lewis acidic additive and to compare
the reaction rates. (Fig. 1.).
We found that Pd(acac)2 itself was not a suitable catalyst for the reaction and the
additional Lewis acid did not enhance the transformation. The more electrophilic metal center
in palladium-acetate and trifluoroacetate ensured better conversions compared to Pd(acac)2.
Complete consumption of the starting material was observed in case of both latter palladium
catalysts in the presence of 7.2 mol% Lewis acidic BF3•Et2O. However, in the absence of Lewis
acid the conversions were only 50% (Pd(TFA)2) and 15% (Pd(OAc)2) respectively after 24
hours. The reaction rate acceleration was significant in the initial period of the transformation
on the basis of the conversions measured after 2 hours reaction time. In case of Pd(OAc)2 the
conversion increased from 1% to 41% by the influence of catalytic amount of BF3•Et2O, while
the conversion of Pd(TFA)2 catalyzed reaction was increased from 7% to 96% when 7.2 mol%
Lewis acid was added to the reaction mixture. The results of these comparative studies suggest
that the more electrophilic catalyst is more beneficial for the reaction, and the rate acceleration
effect of Lewis acidic additive is general for all the studied palladium catalysts.
3.2. Scope of Lewis acids
Our earlier studies with electron deficient tris(pentafluoro)phenyl borane revealed an
unexpected induction period of the palladium acetate catalyzed coupling of anilides and
aldehydes [28]. In continuation of our studies, we monitored the same coupling reaction
utilizing silver tetrafluoroborate as inorganic Lewis acidic additive (Fig. 2.). The aim of the
experiments was to explore the generality of the previously observed unusual kinetics of the
Lewis acid accelerated coupling reaction. When acetanilide was coupled with 4-
fluorobenzaldehyde in the absence of any Lewis acid additive with Pd(OAc)2 at 30°C in DCM,
we observed only 4% conversion in the reaction. Significant rate acceleration was observed
when 7.2 mol% B(C6F5)3 or AgBF4 was added to the reaction mixture. After 24 hours, the
reaction reached 64% and 94% conversion respectively. In comparison, amongst the studied
5

Lewis acids the silver salt has more pronounced rate acceleration effect, and induction period
was observed only in case of the triaryl borane.
Later, we examined the progress of the same reaction catalyzed by the more electrophilic
palladium trifluoroacetate in the presence of tris-pentafluorophenyl borane or silver
tetrafluoroborate. The monitoring of the reactions showed no induction period of the
transformation, and similar conversions were measured to the case of Pd(OAc)2 (Fig. 3.).
Next, we studied the influence of other inorganic Lewis acidic additives on the palladium
catalyzed couplings. We have applied halides of aluminium, silver, indium and iron(III) in the
palladium catalyzed coupling. The presence of these salts completely inhibited the
transformation (not depicted), most likely because of the strong coordination of the halide
anions to the palladium center, disabling C-H activation. Zinc and copper sulfate, sodium and
iron(II) tetrafluoroborate and ammonium and potassium hexafluorophosphate salts proved to
be inert additives and their presence did not change the conversion of the transformation
compared to the reactions carried out in the absence of Lewis acid (not depicted). Sulfate salts
of iron, aluminum, nickel and lead evolved the conversion 2-2.5 times higher than it was
observed in case of Lewis acid free transformations (not depicted). In our further studies we
found that the most beneficial additives for the coupling reaction, besides the previously tested
AgBF4, are silver zinc and copper salts with weakly coordinating counterions such as triflate or
perchlorate. (Fig. 4.). With their application the reaction rate of the transformation can be
significantly increased. Boron trifluoride, contrary to the chloro and bromo trihaloborane
analogues, also enhances the reaction and almost complete conversion can be reached after 24
hours reaction time.
3.3. Mechanistic studies
Similar transformations are usually explained by catalytic pathways involving palladacycles
as intermediates and the corresponding C-H bond breaking is considered to be rate limiting[30,
31]. In order to understand the catalytic effect of the BF3• Et2O additive we have performed
DFT based calculations for the assumed rate-determining step. Since our experimental
evidences suggested the existence of a fast pre equilibrium, the mechanism of the active
catalytic complex formation has not been investigated in details (Fig. 5.)
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Path A (Fig. 5., blue) represents our lowest energy pathway in the absence of BF3• Et2O
with the overall activation energy of 23.8 kcal/mol. This path features a neutral transition state.
We note that the mechanism where an acetate ion dissociates before the C-H activation requires
very high activation energy (50 kcal/mol) therefore it has been excluded from discussion.
Path B (Fig. 5., red) shows that in the presence of Lewis acid, OEt2 - acetate ligand exchange
can be assumed between Pd and the boron center. This mechanism is overall 3.4 kcal/mol more
favorable than the previous pathway. Even more favorable path can be obtained if only neutral
species are assumed (Path C, Fig. 5., green). Coordination of BF3 to the trans acetate ligand
(relative to the aryl ring) can further enhance the reaction by increasing the charge on the Pd
atom without providing ionic substances. The overall activation free energy of the path is 14.5
kcal/mol. It is important to note that the presented barrier heights are calculated assuming the
presence of Pd(OAc)2 in the solvent. However, its di- and trimerization on nonpolar solvents
can be assumed, which may further increase the barrier by the stability of the dimer or trimer.
We have calculated the kinetic isotope effect for path C. Our approximate KIE calculation based
on the Back-of-an-envelope TST theory yielded kH/kD=5.17.
Beside the calculation results, we performed simple experimental kinetic studies. First,
coupling reactions of H5-acetanilide and D5-acetanilide with 4-fluorobenzaldehyde in the
presence of 7.2 % BF3•Et2O under the previously used reaction conditions were performed in
separate vessels, to determine the time-conversion curves (Fig. 6.). We found difference in the
reaction rates: with the replacement of hydrogen atoms to deuterium in the aromatic core the
reaction rate decreased, ie. the coupling took place faster in case of H5-acetanilide. These
findings suggest hydrogen atom preference in the C-H activation in perfect accord with the
primary kinetic isotope effect predicted by the calculations.
Kinetic isotope effect was also examined by intermolecular competition studies. The
palladium catalyzed coupling reactions of the anilides and aldehyde were performed under the
previously used catalytic conditions with simultaneous addition of acetanilide and its D5
analogue into the same reaction mixture in 1:1 ratio (Error! Reference source not found. 7.).
In these studies strong isotope effect has been experienced by NMR monitoring. The protium
isotopomer has been converted to the product significantly faster than the deutero analogue.
Based on our experimental estimate, the kH/kD is in the range of 3.4 ±1.1 considering the
accuracy of integration of the peaks in the NMR spectra.
7

The measured isotope effect obtained in the intermolecular competition experiment, the
results of the parallel reactions of H5 and D5-acetanilides in separate vessels and the calculation
results suggests that the C-H activation takes place in the rate determining step as it was found
earlier for similar systems experimentally [36] and by calculation [37].
3.4. Application of Lewis acids in other C-H activation reactions
In continuation of our studies we wished to expand the Lewis acid acceleration to other
palladium catalyzed C-H activation processes. (Fig. 8) Aryl amides and N-aryl ureas are often
reported in ortho-olefination since the discovery of the Fujiwara-Moritani reaction[51-54].
These transformations usually prefer benzoquinone as oxidant, but there are available examples
for mild methods using tBuOOH instead, which we have applied previously.
Acetanilide was subjected to palladium acetate catalyzed Fujiwara-Moritani type
coupling reaction with several alkene reactants in the presence and absence of Lewis acidic
AgBF4 additive at 30°C in DCM. Unactivated olefins such as isoprene did not afford any C-H
activation product, but the coupling reaction with styrene was accelerated by the silver salt, and
37% conversion was reached after 24 hours. Significant Lewis acid acceleration was observed
in case of methyl acrylate. The coupling of acetanilide with methyl acrylate without Lewis
acidic additive did not yield the desired product, but in the presence of AgBF4 the conversion
increased up to 74%. Butyl acrylate was an effective coupling partner even in the absence of
Lewis acid, but together with AgBF4 the conversion was increased from 50% to 82%.
Based on recent literature[25, 55, 56] ureas can be used as directing groups in mild
transformations leading to ortho-olefinated products. We examined several additives to explore
the scope of Lewis acid activation. N-(4-methyl)phenyl, N,N-dimethyl urea was reacted with
methyl and butyl acrylate in the presence of catalytic amount of Lewis acids (see Table 1.).
Without any additive (entries 9,18) no product formation was observed. Among the metal salts
that were tested, copper and zinc triflate resulted in the highest conversion (entries 3,4), silver
triflate and tetrafluoroborate were less efficient (entries 1,2) and the borane derivatives were
also ineffective (entries 7,8). Butyl acrylate (entries 10-18.), was more reactive than methyl
acrylate but only slight conversion increase was seen in all cases and maximum of 39%
conversion was reached with Zn(OTf)2.
For the sake of better conversions, we replaced the TBHP oxidant with benzoquinone, which is
8

a usual, common oxidant utilized in Fujiwara-Moritani type reactions [57, 58]. An elevated
amount of the Lewis acids was applied imitating the usual conditions with Brønsted acids as
co-catalysts in C-H activation processes (Table 2).
Acrylic esters did not react with N-phenyl, N, N-dimethyl urea under the applied catalytic
conditions in the absence of Lewis acid (entries 8,15). If the Lewis acidic additives were added,
good to excellent conversions were reached. Silver tetrafluoroborate and perchlorate were the
most effective, leading to 91 and 70% conversion (entries 6, 7), boron trifluoride in this case
resulted in 45% conversion (entry 3) and copper triflate provided similar results (48%, entry 5).
However, zinc triflate did not accelerate the reaction at all. The same substrate with the more
reactive butyl acrylate showed similar tendencies. Silver tetrafluoroborate afforded 88%, silver
perchlorate 77% conversion (entries 13, 14). Interestingly, copper triflate was inactive but zinc
triflate gave 87% conversion (entries 11,12). Boron trifluoride enabled 62% conversion (entry
10). The more electron rich N-(3-MeO)phenyl, N, N-dimethyl urea alone reacted with methyl
acrylate in the absence of any additive, and the desired product was formed in 15% conversion
(entry 15). In the presence of tris(pentafluoro)phenyl borane, the formation of the coupled
product was not observed. Finally, we found that the addition of boron trifluoride, silver
tetrafluoroborate, silver perchlorate or copper triflate resulted full conversion of the
transformation (entries 17, 19-21). In these experiments we established that the Fujiwara-
Moritani reaction can be achieved efficiently in the presence of benzoquinone oxidant in the
presence of Lewis acidic additives.
4. Conclusion
In summary, we examined the beneficial effect of different types of Lewis acidic
additives on palladium catalyzed C-H activation reactions. Ortho-acylation by aldehydes and
ketocarboxylic acids and ortho-olefination by acrylic esters and styrene was achieved using
acetanilide and aromatic urea derivatives as substrates. When anilides were coupled with
aldehydes the activity of palladium acetate and trifluoroacetate, was increased with catalytic
amount of BF3•Et2O additive. We demonstrated that Lewis acidic electron deficient triaryl
borane, trihalo boranes and inorganic metal salts are suitable for the acceleration of C-H
activation reactions. Amongst the inorganic Lewis acids silver, copper and zinc salts with
weakly coordinating anions proved to be applicable additives for rate acceleration of the
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palladium catalyzed process. With the aid of DFT calculations we explained the catalytic effect
of Lewis acids on the direct coupling and determined primary kinetic isotope effect.
Additionally, KIE experiments also showed light atom preference in C-H activation and suggest
that being the rate determining step. In conclusion, the palladium catalyzed C-H activation
reaction of aromatic amide and urea derivatives can be accelerated with catalytic amount of
Lewis acidic additives.
Acknowledgements
This work was supported by the “Lendület” Research Scholarship, HAS (LP2012-48/2012).
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11

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[58] P. Roffia, F. Conti, G. Gregorio, G.F. Pregaglia, R. Ugo, J. Organomet. Chem. 56 (1973) 391-394.
12

Fig.1. Accelerating effect of BF3•Et2O on the palladium catalyzed C-H activation reaction
(conversion based on GC FID results).
13

Fig. 2. Monitoring of the coupling reactions catalyzed by Pd(OAc)2 with GC FID analysis.
14

Fig.3. Monitoring of the coupling reactions catalyzed by Pd(TFA)2 with GC FID analysis.
15

Fig. 4. Profiles of the conversions at the initial stage of the reaction with different Lewis acidic
additives.
16

Fig. 5. Free energy profile and relevant structures along three postulated C-H activation
mechanisms. Pathways A, B and C are depicted with blue, red and green lines, respectively.
Values in parentheses are Gibbs free energies in kcal/mol units.
17

Fig. 6. Pd(OAc)2 catalyzed ortho-acylation reactions of H5 and D5-acetanilide in the presence
of boron trifluoride.
18

Fig. 7. Intermolecular Kinetic Isotope Effect in the ortho-acylation of acetanilides.
19

Fig. 8. Silver tetrafluoroborate as activating additive in the catalytic ortho-directed olefination
of acetanilide. Conversions measured by GC FID analysis.
20

Table 1. Different Lewis acids in catalytic quantity for the ortho-olefination of aryl urea
derivatives with acrylic esters
conversion
#
R
R’
additive
(24 h)
7.5%
11%
19%
22%
0%
1
2
3
4
5
6
7
8
9
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
AgBF4
AgOTf
Cu(OTf)2
Zn(OTf)2
Zn(ClO4)2
BCl3
0%
BF3•Et2O
B(C6F5)3
-
13%
4%
0%
10 4-Me
11 4-Me
12 4-Me
13 4-Me
14 4-Me
15 4-Me
16 4-Me
17 4-Me
18 4-Me
AgBF4
AgOTf
Cu(OTf)2
Zn(OTf)2
Zn(ClO4)2
BCl3
15%
18%
22%
39%
35%
3%
BF3•Et2O
B(C6F5)3
-
36%
4%
0%
21

Table 2. Different Lewis acids in equimolar quantity in the ortho-olefination of aryl urea
derivatives with acrylic esters
#
R
R’
additive
-
conversion (24 h)
0%
1
H
Me
Me
Me
Me
Me
Me
Me
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Me
Me
Me
Me
Me
Me
Me
2
H
B(C6F5)3
BF3•Et2O
Zn(OTf)2
Cu(OTf)2
AgClO4
AgBF4
0%
3
H
45%
0%
4
H
5
H
48%
70%
91%
0%
6
H
7
H
8
H
-
9
H
B(C6F5)3
BF3•Et2O
Cu(OTf)2
Zn(OTf)2
AgClO4
AgBF4
0%
10
11
12
13
14
15
16
17
18
19
20
21
H
62%
4%
H
H
87%
77%
88%
15%
0%
H
H
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
-
B(C6F5)3
BF3•Et2O
Zn(OTf)2
AgBF4
100%
32%
100%
100%
100%
AgClO4
Cu(OTf)2
22