Palladium on carbon-catalyzed Α-alkylation of ketones with alcohols as electrophiles: Scope and mechanism

Article abstract of DOI:10.1016/j.jcat.2019.01.034

The α-alkylation of ketones with alcohols represents a green strategy for the formation of crucial carbon–carbon bonds since it only produces water as byproduct. In terms of reaction mechanism, the evidence for homogeneous catalysis supports a catalytic hydrogen-borrowing pathway; however, the reaction mechanism has not been investigated for heterogeneous Pd/C catalysts. Here, we report an improved method for α-alkylation of ketones with alcohols using commercially available Pd/C, ubiquitous in organic synthesis labs, as catalyst. The reaction conditions are mild compared to state-of-the-art for both homo- and heterogeneous catalysts, and the developed conditions produces quantitative yields for most ketones and alcohols. A hot filtration experiment and recycling of the catalyst supports the heterogeneous nature of catalysis. Importantly, the reaction mechanism is studied for the first time by a combination of stoichiometric experiments and kinetic analyses by in-situ IR (React-IR).

Full text of DOI:10.1016/j.jcat.2019.01.034

Journal of Catalysis 371 (2019) 153–160
Contents lists available at ScienceDirect
Journal of Catalysis
journal homepage: www.elsevier.com/locate/jcat
Palladium on carbon-catalyzed
a
-alkylation of ketones with alcohols as
electrophiles: Scope and mechanism
⇑
⇑
Niklas R. Bennedsen, Rasmus L. Mortensen, Søren Kramer , Søren Kegnæs
Department of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
The a-alkylation of ketones with alcohols represents a green strategy for the formation of crucial carbon–
Received 21 November 2018
Revised 22 January 2019
Accepted 24 January 2019
carbon bonds since it only produces water as byproduct. In terms of reaction mechanism, the evidence for
homogeneous catalysis supports a catalytic hydrogen-borrowing pathway; however, the reaction mech-
anism has not been investigated for heterogeneous Pd/C catalysts. Here, we report an improved method
for a-alkylation of ketones with alcohols using commercially available Pd/C, ubiquitous in organic syn-
thesis labs, as catalyst. The reaction conditions are mild compared to state-of-the-art for both homo-
and heterogeneous catalysts, and the developed conditions produces quantitative yields for most ketones
and alcohols. A hot filtration experiment and recycling of the catalyst supports the heterogeneous nature
of catalysis. Importantly, the reaction mechanism is studied for the first time by a combination of stoi-
chiometric experiments and kinetic analyses by in-situ IR (React-IR).
Keywords:
Pd/C catalysis
Reaction mechanism
a-Alkylation
Heterogeneous catalysis
In-situ IR
Ó 2019 Elsevier Inc. All rights reserved.
Kinetics
CAC bond formation
1. Introduction
30,34,42]. The reaction is initiated by dehydrogenation of the alco-
hol forming the corresponding aldehyde, thus activating it as an
Methods for facile carbon–carbon bond formation are crucial for
the synthesis of organic molecules such as pharmaceuticals, agro-
chemicals, and functional materials [1–4]. Accordingly, the forma-
electrophile. Next, aldol condensation, which is typically catalyzed
by addition of base, reacts the produced aldehyde and the ketone
affording an a,b-unsaturated ketone. Finally, the CAC double bond
is hydrogenated by the hydrogen originally removed from the
alcohol, hence the term ‘‘hydrogen-borrowing”.
In contrast to the homogeneous reactions, limited mechanistic
evidence has been accumulated for a-alkylation of ketones with
tion of a new C(sp3)–C(sp3) bond to the
a
-carbon of carbonyl
-alkylation, is an important transformation
that has received considerable attention [5–10]. Conventional
methods for -alkylation reactions often have problems with unde-
compounds, termed
a
a
sired waste, e.g. salts from alkyl halides, and require strong metallic
bases and cryogenic temperatures. These aspects limit the indus-
trial implementation and decrease the atom efficiency and sustain-
ability of the methodologies [11,12]. Recently, a different strategy
where alcohols are used as masked electrophiles, leading to water
as the only byproduct, has attracted attention due to its potential
as a greener alternative [13–19]. A variety of transition-metals
alcohols using heterogeneous catalysis [37,39,41]. In particular,
no thorough mechanistic investigation including kinetics has been
performed on
a-alkylation of ketones with alcohols using palla-
dium on carbon catalysis. A reaction pathway similar to homoge-
neous catalysis is tempting to propose; however, it cannot
always be assumed that the pathways with homogeneous and
heterogeneous catalysts are the same [43,44]. A better understand-
ing of the operating pathways is pivotal for advancement of the
field and rational design of future reactions.
has been implemented as catalysts for the a-alkylation of ketones
with alcohols in both homogeneous [20–30] and heterogeneous
systems [31–41]. Typically, reaction temperatures above 100 °C
and 1–2 mol% catalyst loadings are required.
In 2005, Cho described the only existing methodology, which
includes substrate scope investigation, where commercially
For homogeneous systems, the reaction mechanism for
available Pd/C is used as catalyst for a-alkylation of ketones with
a
-alkylation of ketones with alcohols has been thoroughly
alcohols [31]. The catalytic system used for the reaction between
acetophenone and benzyl alcohol (2 equiv) was comprised of
5 mol% Pd/C, 3 equivalents KOH, and 4 equivalents 1-decene in
dioxane at 100 °C for 20 h and afforded 66% yield of the corre-
sponding 1,3-diphenylpropan-1-one. Albeit, the use of a commer-
cially available catalyst which is ubiquitous in organic synthesis
examined and the general consensus is that the reactions proceed
through
a hydrogen-borrowing pathway (Fig. 1) [19,23,26,
⇑
Corresponding authors.
E-mail addresses: sokr@kemi.dtu.dk (S. Kramer), skk@kemi.dtu.dk (S. Kegnæs).
https://doi.org/10.1016/j.jcat.2019.01.034
0021-9517/Ó 2019 Elsevier Inc. All rights reserved.

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N.R. Bennedsen et al. / Journal of Catalysis 371 (2019) 153–160
was obtained in a quantitative yield (Table 1, entry 1). The opti-
mized reaction conditions use 1 mol% Pd/C, 1.1 equivalents benzyl
alcohol, and 1.5 equivalents of K3PO4 in toluene at 80 °C for 6 h.
The reaction conditions are slightly milder, but otherwise very
similar to those recently reported for a custom-made palladium
on carbon catalyst.[38] Control experiments showed that no pro-
duct is formed in the absence of Pd/C and that activated carbon
without palladium leads to highly unselective conversion (entries
2–3). The weight percentage loading of palladium on the carbon
does not influence the reaction outcome (entry 4). However, the
reaction is sensitive to air and choice of base (entries 5–9). Finally,
variations to the K3PO4 equivalents, headspace, and concentration
were undertaken to ensure that changes to these parameters dur-
ing a mechanistic investigation was not detrimental to the reaction
outcome (entries 10–17).
2.2. Substrate scopes for alcohols and ketones
Fig. 1. Hydrogen-borrowing mechanism for a-alkylation of ketones with alcohols.
Having established optimized reaction conditions, the general-
ity of the transformation was assessed by a substrate scope inves-
tigation. To ensure one general procedure for all substrates, the
reaction time was increased to 24 h. First, acetophenone was
reacted with various alcohols (Table 2). Derivatives of benzyl alco-
hol bearing electron-withdrawing or -donating groups in the para-
position (Me, OMe, CF3, and F) provided excellent product yields
(entries 1–5). In contrast, the use of a secondary benzylic alcohol
did not lead to any product formation (entry 6), neither did a sec-
ondary aliphatic alcohol, pentan-3-ol (not shown). Although pri-
mary aliphatic alcohols reacted more sluggishly than benzylic
alcohols, an increase in temperature from 80 °C to 100 °C led to
good yields of the corresponding ketone for both heptanol and pro-
panol, respectively (entries 7–8).
laboratories is highly convenient, the moderate yield, high catalyst
loading, and need for strong base and an additive warrant
improvements. Furthermore, no investigation of the reaction
mechanism was performed.
Herein, we report a mechanistic investigation of a significantly
improved and simplified method for a-alkylation of acetophenones
with alcohols using commercially available Pd/C as the catalyst.
The individual reaction steps are examined by stoichiometric stud-
ies and reaction kinetics is thoroughly investigated by in-situ IR
measurements. In addition, the catalyst material is studied by
TEM and XPS, and the nature of catalysis is examined by hot filtra-
tion and recycling experiments. Finally, based on the mechanistic
investigation,
a rational solution for future optimization of
a-alkylations is suggested.
Next, a series of acetophenone derivatives were reacted with
benzyl alcohol (Table 3). Again, substrates bearing substituents
ranging from very electron-donating to very electron-
withdrawing (Me, OMe, CF3, and F) provided excellent yields and
selectivity towards the ketone product (entries 1–5). Substitution
2. Results and discussion
2.1. Optimization
on the
a-carbon of acetophenone decreased the activity but
maintained high selectivity towards the ketone product (entry 6).
Sterical hindrance in the ortho-position of the acetophenone was
well-tolerated (entry 7). Interestingly, under the same reaction
conditions, two aliphatic ketones also smoothly underwent
After an optimization of the reaction conditions on the reaction
between acetophenone and benzyl alcohol, the desired product
Table 1
Influence of various reaction parameters on the reaction outcome.
a-alkylation with excellent selectivity for the least substituted
-carbon (entries 8–9).
a
2.3. Recycling and heterogeneity
With regard to the nature of the hydrogen-borrowing catalysis,
there are two possibilities: (1) heterogeneous catalysis by palla-
dium nanoparticles or (2) leaching of catalytically active homoge-
neous species [45,46]. To distinguish between these possibilities, a
hot filtration experiment was performed (Scheme 1). In the exper-
iment, inhibition of the catalytic activity occurred when the solid
catalyst was removed from the reaction mixture despite the addi-
tion of fresh K3PO4 (1.5 equiv). This outcome of the hot filtration
experiment confirmed the heterogeneous nature of the
hydrogen-borrowing catalysis. Accordingly, the developed cat-
alytic system is appropriate for a reaction mechanism study of
Entry
Modifications
Conversion (%)a
Yield (%)a
1
2
3
4
5
6
7
8
–
100
6
100
0
No catalyst
Activated carbon
10 wt% Pd/C
In air
K2CO3
Li2CO3
43b
100
32
3b
100
7
0
0
66
0
100
100
100
99
97
100
100
100
0
0
66
0
100
100
100
99
Cs2CO3
Et3N
9
10
11
12
13
14
15
16
17
1.0 equiv K3PO4
2.0 equiv K3PO4
Headspace 3.0 mL
Headspace 2.5 mL
Headspace 2.0 mL
0.125 M
heterogeneous Pd/C-catalyzed a-alkylation.
Based on the established heterogeneity of the hydrogen-
borrowing catalysis, the possibility of catalyst recycling was exam-
ined. Facile catalyst separation and recycling is an advantage of
heterogeneous catalysis in comparison to homogeneous catalysis.
Indeed, the Pd/C catalyst was successfully recycled four times for
five consecutive reactions (Table 4; see supporting information
for procedure). Throughout all consecutive reactions, excellent
97
100
100
100
0.50 M
1.0 M
Based on 1H NMR using 0.5 equivalents of dibenzyl ether as standard.
Reaction time was 24 h.
a
b

N.R. Bennedsen et al. / Journal of Catalysis 371 (2019) 153–160
155
Table 2
Substrate scope with respect to the alcohol.
Entry
R1
R2
Conversion (%)a
Yield (%)a
1
2
3
4
5
6
7
H
H
H
H
H
H
Me
100
100
100
100
98
100
100
100
100
98
Me
MeO
F
CF3
F
0
72
0
72b
8
73
73b
Based on 1H NMR using 0.5 equivalents of dibenzyl ether as standard.
Reaction temperature was 100 °C.
a
b
Table 3
Substrate scope with respect to the ketone.
Entry
R1
R2
Conversion (%)a
Yield (%)a
1
2
3
4
5
6
7
H
H
H
H
H
H
Ph
100
100
100
100
100
67
100
100
100
100
100
52
Me
MeO
F
CF3
H
100
100
8
9
100
100
100b
100c
a
b
c
Based on 1H NMR using 0.5 equivalents of dibenzyl ether as standard.
Product is 2-cyclohexylethyl phenyl ketone.
Product is 1,5-diphenylpentan-3-one.
Scheme 1. Hot filtration experiment on the
a-alkylation of acetophenone with benzyl alcohol.
selectivity was maintained, but a decrease in activity was observed
at the fourth recycle (from 96% to 60%). The TEM images of the
fresh Pd/C catalyst and the Pd/C catalysts which had been recycled
four times appeared similar. Both contain Pd nanoparticles with a
size of 2–20 nm with a tendency of fewer smaller particles for the
recycled compared to the fresh catalyst but few to none larger
agglomerates (Fig. 2; additional images in supporting information).
Accordingly, particle agglomeration is unlikely to cause catalyst

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N.R. Bennedsen et al. / Journal of Catalysis 371 (2019) 153–160
Table 4
XPS analysis of palladium (3d) for the fresh and recycled cata-
Recycling of the commercial Pd/C catalyst.
lysts was performed (Fig. 3). The spectrum of palladium for the
fresh catalyst indicated the presence of two species with binding
energies consistent with Pd and PdO at 335.4 eV and 336.8 eV for
the 3d5/2 transition, respectively (Fig. 3, left) [47]. The same was
observed for the 3d3/2 signal at approximately 340 and 342 eV.
However, the signals for the PdO species were suppressed strongly
and Pd was primarily observed for the recycled catalyst. This
observation indicates that PdO was reduced under the reaction
conditions, possibly by hydrogen released from benzyl alcohol.
The composition of the carbon from the catalyst did not show
any difference between the fresh and recycled catalyst (Fig. 3,
right). Based on the observation made from XPS, TEM, and ICP,
we see a slight change in nanoparticle composition and size, and
no palladium is leached during the reaction. However, the effect
of change in composition and size of the nanoparticles relative to
the deactivation during the recycle study is still only speculative.
Entry
Number of recyclesa
Conversion (%)b
Selectivity (%)b
1
2
3
4
5
0
1
2
3
4
100
100
100
96
100
100
100
100
100
60
a
Recycling was performed by extracting the reaction mixture with toluene to
remove organic residues from the catalyst. 1.5 equiv fresh K3PO4 was added toge-
ther with a new batch of substrates.
Based on 1H NMR using 0.5 equivalents of dibenzyl ether as standard.
b
2.4. Mechanistic investigation
deactivation. The reaction liquid was analyzed by ICP-OES and the
palladium content in the reaction liquid was equal or below the
blank suggesting that palladium does not leach under our reaction
conditions (see supporting information for procedure).
Finally, we sought to identify the reaction pathway of the devel-
oped heterogeneous catalysis system. Potentially, a reaction mech-
anism similar to the one elucidated for the homogeneous
counterparts could be operating (Fig. 1). Accordingly, a series of
Fig. 2. (Left) TEM image of unused Pd/C catalyst. (Right) TEM image of recycled Pd/C that have been used for five consecutive reactions.
Fig. 3. XPS analysis of the fresh Pd/C catalyst and the recycled Pd/C catalyst. (Left) Pd 3d analysis and (right) C 1s analysis of both the fresh and the recycled catalyst.

N.R. Bennedsen et al. / Journal of Catalysis 371 (2019) 153–160
157
Scheme 2. Stoichiometric experiments conducted with Pd/C catalyst. (a) Test for alcohol dehydrogenation. (b) Chalcone formation from acetophenone and benzaldehyde
under standard reaction conditions. (c) Chalcone hydrogenation using benzyl alcohol as hydrogen donor. (d) Cross-over experiment demonstrating product formation from
both a benzylic alcohol and aldehyde under the reaction conditions. A control experiment demonstrated that the use of 2.4 equiv benzyl alcohol under the normal reaction
conditions also provides quantitative yield. For all reactions, the yields were determined by 1H NMR using 0.5 equiv dibenzyl ether as standard. aConversion and yield relative
to added benzyl alcohol.

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N.R. Bennedsen et al. / Journal of Catalysis 371 (2019) 153–160
O
O
OH
1 mol% Pd/C (5 wt%)
1.5 equiv K3PO4
Me
toluene (0.25 M), 80 °C, 3 h
1.2 equiv
1.25 mmol
Fig. 4. (top) Reaction conditions for React-IR. (bottom) Reaction profile monitored by React-IR.
Fig. 5. Reaction kinetics monitored by React-IR. (a) Same excess experiment. (b) Influence of catalyst loading on reaction rate. (c) First order plot for determination of overall
reaction order. (d) Variable time normalization analysis on two different acetophenone concentrations.
experiments were performed to establish the feasibility of the indi-
vidual steps (Scheme 2). Initially, it was demonstrated that Pd/C is
capable of dehydrogenating benzyl alcohol forming benzaldehyde,
independent of the presence of K3PO4 (Scheme 2a). Next, the quan-
titative formation of chalcone from acetophenone and benzalde-
hyde was established both under the standard catalytic
conditions and in the absence of Pd/C (Scheme 2b). Notably, the
chalcone is not reduced due to the lack of a hydrogen donor under

N.R. Bennedsen et al. / Journal of Catalysis 371 (2019) 153–160
159
these conditions. However, subjecting the chalcone to the reaction
conditions in the presence of benzyl alcohol as hydrogen donor
leads to facile reduction of the CAC double bond and oxidation of
likely that the slow aldol condensation is the reason that elevated
reaction temperatures are required for both homogeneous and
heterogeneous
vations indicate that it might be possible to lower the reaction
temperature in general for -alkylation of ketones with alcohols
a-alkylation of ketones with alcohols. These obser-
benzyl alcohol (Scheme 2c). Finally,
a cross-over experiment
between acetophenone, benzaldehyde, and CF3-labelled benzyl
alcohol demonstrated that both the benzylic alcohol substrate
and benzaldehyde can form product under the standard catalytic
conditions (Scheme 2d). In addition, the observation of significant
amounts of unlabeled benzyl alcohol indicates that the alcohol
dehydrogenation is reversible. Overall, these results are consistent
with the hydrogen-borrowing mechanism illustrated in Fig. 1, thus
such a reaction mechanism is also likely to be operating under the
heterogeneous catalytic conditions developed here.
After having demonstrated the feasibility of the individual steps
under the catalytic conditions, we investigated the reaction kinet-
ics using in-situ IR spectroscopy (React-IR). Initially, a 1.25 mmol
scale version of the reaction between acetophenone and benzyl
alcohol was monitored up to 90% conversion (Fig. 4). Supporting
the stoichiometric experiments, both benzaldehyde and chalcone
were observed during the reaction, albeit in low concentrations.
At 20 min and at 3 h, the yields of the compounds detected by
React-IR correspond to those detected by 1H NMR.
a
by addition of improved catalysts for the aldol condensation step.
Acknowledgments
The authors are grateful for funding from the Independent
Research Fund Denmark (grant no. 6111-00237), from Villum fon-
den (Grant No. 13158), from Haldor Topsøe A/S, and from Lund-
beck Foundation (grant no. R250-2017-1292). We thank Johannes
R. Dethlefsen for assistance with the React-IR, Simone L. Zacho
for assistance with TEM, and David Christensen for assistance with
XPS.
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.jcat.2019.01.034.
Based on the reaction profile, the system appeared well-
behaved and suitable for further kinetic analyses. The acetophe-
none consumption was chosen as a measure for the rate. First, a
same excess experiment was performed (Fig. 5a) [48]. The almost
perfect overlay of the time-adjusted same excess experiment indi-
cates that there is no product inhibition or deactivation in the rate-
limiting step. Interestingly, varying the Pd/C catalyst loading from
0.5 to 2.0 mol% had no influence on the reaction rate (Fig. 5b).
Accordingly, the hydrogen-borrowing cycle does not contain the
overall rate-limiting step, suggesting that the aldol condensation
is rate-limiting.
Plotting the acetophenone consumption in a first order plot pro-
duced a straight line up to 90% conversion (Fig. 5c). Thus, the over-
all reaction order is either first order or at least pseudo-first order.
Variable time normalization analysis at two different acetophe-
none concentrations clearly demonstrated a first order dependence
on acetophenone concentration (Fig. 5d; see supporting informa-
tion for fitting to other orders) [49]. This is again consistent with
the aldol condensation being rate-limiting. However, unless depro-
tonation of acetophenone is rate-limiting, generally, an overall sec-
ond order reaction would be expected. Nonetheless, the detected,
constant steady-state concentration of benzaldehyde (Fig. 4) could
lead to an observed overall pseudo-first order reaction, even if
addition of the enolate to the aldehyde is rate-limiting. In either
case, the rate of the reaction only depends on the concentration
of acetophenone with the experimental rate law being: rate = k
[ketone].
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