Linear Selective Isomerization/Hydroformylation of Unsaturated Fatty Acid Methyl Esters: A Bimetallic Approach

Article abstract of DOI:10.1021/acscatal.7b00249

Herein, we report about the development of an isomerization/hydroformylation tandem reaction to selectively convert fatty acid methyl esters into asymmetric α,ω-functionalized aldehyde esters. An orthogonal tandem catalytic system consisting of a palladium-based isomerization catalyst and a rhodium-based hydroformylation catalyst was developed, using methyl 3-hexenoate as a model substrate. Using this catalyst, high yields (81% at 99% conversion) and regioselectivities (l/b-ratio of 98/2) toward the desired terminal hydroformylation product are obtained in the conversion of methyl 3-hexenoate under mild conditions. Ethyl 4-decenoate was subsequently applied as a second model substrate to identify challenges associated with the longer chain length of the unsaturated ester. Finally, methyl oleate was converted using the developed catalyst system. High aldehyde yields of 74% (at 99% conversion) with an l/b-ratio of 91/9 are obtained.

Full text of DOI:10.1021/acscatal.7b00249

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Article
Linear selective isomerization / hydroformylation of
unsaturated fatty acid methyl esters – A bimetallic approach
Tom Gaide, Jonas Bianga, Kim Elisabeth Schlipkoeter, Arno Behr, and Andreas Johannes Vorholt
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Page 1 of 22
ACS Catalysis
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Linear selective isomerization / hydroformylation of unsaturated fat-
ty acid methyl esters – A bimetallic approach
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Tom Gaide, Jonas Bianga, Kim Schlipköter, Arno Behr, Andreas. J. Vorholt*.
*andreas.vorholt@bci.tu-dortmund.de
Technische Universität Dortmund, Emil-Figge-Straße 66 G5.12, 44227 Dortmund.
ABSTRACT: Herein we report about the development of an isomerization / hydroformylation tandem reaction to selec-
tively convert fatty acid methyl esters into asymmetric α,ω-functionalized aldehyde esters. An orthogonal tandem catalyt-
ic system consisting of a palladium-based isomerization catalyst and a rhodium-based hydroformylation catalyst was
developed using methyl 3-hexenoate as a model substrate. Using this catalyst high yields (81% at 99% conversion) and
regioselectivities (l/b-ratio of 98/2) towards the desired terminal hydroformylation product are obtained in the conversion
of methyl 3-hexenoate under mild conditions. Ethyl 4-decenoate was subsequently applied as a second model substrate to
identify challenges associated with the longer chain length of the unsaturated ester. Finally, methyl oleate was converted
using the developed catalyst system. High aldehyde yields of 74% (at 99% conversion) with an l/b-ratio of 91/9 are ob-
tained.
KEYWORDS hydroformylation, isomerization, tandem reactions, α,ω-functionalization, fatty acids, homogeneous
catalysis
tion of the complete carbon chain of the fatty acid for the
synthesis of potential polymer precursors.
INTRODUCTION
Fatty acids and their derivatives are very interesting re-
newable feedstocks for the chemical industry since they
naturally contain both a carboxyl function and a long
carbon chain. Consequently, they are widely used as start-
ing material in the chemical industry, e.g., in surfactant
synthesis.1
Especially the conversion of unsaturated fatty compounds
like methyl oleate (1) into an α,ω-functionalized long
chained molecules (Scheme 1) is of great interest in terms
of synthesizing new bio based polymer precursors.2–5
Unfortunately, these are very challenging reaction se-
quences that place high demands on the applied catalysts.
To reach high yields and high selectivities towards the
desired products, a catalyst has to be extremely active in
double-bond isomerization since the double bond has to
be isomerized over many carbon atoms to the end of the
chain. High chemoselectivity for the desired functionali-
zation and high regioselectivity towards functionalization
in the terminal position are also required. The transfor-
Scheme 1: Isomerization /
methyl oleate (1).
ω-functionalization of
The isomerization / methoxycarbonylation (Scheme 2) of
fatty acid methyl esters (FAMEs) first described by Cole-
Hamilton et al. is a very successful example for this kind
of transformation.9 Yields of >85% and selectivities of
>95% towards the linear product are achieved using a
Pd/dtbx catalyst (Scheme 2). Detailed mechanistic studies
have been conducted by Mecking et al.7,10 and Köckritz et
al.11 Recently, successful approaches to recycle the
Pd/dtbx catalyst using ionic liquids and thermomorphic
solvent systems were also reported by Riisager et al.12 and
our group.13,14 The conversion of FAMEs via alkoxycar-
bonylation leads directly to symmetric α,ω-functionalized
diesters with potential applications as AA-type mono-
mers.
mation of unsaturated fatty compounds into α,ω
-
functionalized long chained molecules is made even more
difficult because internal double bonds are thermody-
namically favored over terminal ones.6 In the case of me-
thyl oleate, only 0.2% of all isomers contain a terminal
double bond in the equilibrium mixture.7 Mecking et al.
recently published a detailed review of this topic.8
For the selective synthesis of valuable asymmetric α,ω
-
functionalized molecules, which are potential AB-type
monomers, via isomerizing alkoxycarbonylation at a rea-
sonable reaction time and with high selectivities, FAMEs
have to be derivatized prior reaction (e.g. to amides).15,16
Of particular interest in this context are isomerization /
carbonylation tandem reactions such as alkoxycarbonyla-
tions or hydroformylations. They enable the incorpora-
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Page 2 of 22
Isomerizing hydroformylation provides a more straight-
forward way of synthesizing asymmetric α,ω
1
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-
functionalized molecules from FAMEs (Scheme 2). The
isomerizing hydroformylation is well described for simple
internal olefins and short chained unsaturated esters such
as methyl 3-pentenoate.17,18 Unfortunately, all catalysts
applied in the isomerizing hydroformylation of FAMEs
lead to low yields, chemo- and/or regioselectivities.
8
9
Nozaki et al. described the synthesis of C19-alcohols from
methyl oleate (1) via an isomerization / hydroformylation
/ hydrogenation tandem reaction. The resulting alde-
hydes from the rhodium catalyzed hydroformylation are
directly converted into corresponding alcohols by a se-
cond ruthenium catalyst. The yield of the linear alcohol is
53% with a l/b-ratio of 82/18.19 Direct synthesis of alcohols
may either be desired or not, since they already are an
AB-type monomer. On the other hand, the aldehyde, as
the more versatile intermediate, can be easily converted
into different products (e.g., alcohols, amines, carboxylic
acids).
Scheme 3. Isomerizing hydroformylation of methyl
oleate: This work compared with literature.
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In order to overcome the limitations mentioned above,
we decided to develop an orthogonal tandem reaction
using two different catalysts: one catalyst for the isomeri-
zation and one catalyst for the linear selective hydro-
formylation of the terminal double bond. This strategy
allows the reaction to proceed at mild reaction condi-
tions, enabling the highest yields and the highest regiose-
lectivity towards the linear aldehyde in the hydroformyla-
tion of methyl oleate (1) described in the literature today
(Scheme 3).
If the aldehyde itself is targeted, yields of the linear prod-
uct described in the literature regarding the isomerizing
hydroformylation of methyl oleate (1) are even lower. A
yield of 26% of the linear aldehyde can be achieved by
applying a Rh/biphephos (Scheme 2) catalyst complex.
The yield is slightly higher (34%) using ethyl linoleate as
substrate. These are the highest yields yet reported in the
literature. The ratio of linear to branched (l/b) aldehydes
is about 75/25 in both reactions, which is unusually low
for a Rh/biphephos catalyst.20 The application of ligand L1
(Scheme 2) leads to similar l/b-ratios. The yield of the
desired linear product cannot be improved with this cata-
lyst either.21 The main problems this kind of transfor-
mation presents are that the hydrogenation of the start-
ing material and the formation of branched aldehydes
lead to low chemo- and regioselectivities if the known
catalysts are applied.
RESULTS AND DISCUSSIONS
In order to identify a suitable orthogonal catalyst system
as well as suitable reaction conditions, we started our
investigation of isomerizing hydroformylation using me-
thyl 3-hexenoate (2, Scheme 4) as a model substrate. Sub-
strate 2 has an internal double bond and an ester moiety
such as the targeted substrate methyl oleate (1). In prin-
ciple, the same qualitative problems as in the conversion
of 1 occur. The model substrate 3-methyl hexenoate with
its shorter carbon chain provides crucial analytical ad-
vantages since isomers can be separated and quantified
via gas chromatography.
In order to identify problems that occur in connection
with the elongation of the substrates carbon chain, we
decided to apply the developed catalyst systems and reac-
tion conditions to ethyl 4-decenoate (3, Scheme 4) as a
second model substrate, before optimizing the conditions
for the isomerizing hydroformylation of methyl oleate.
Scheme 4 summarizes the approach for the development
of the tandem reaction.
Consequently, developing a new catalytic system that
catalyzes the double bond isomerization from the 9 posi-
tion to the carbon chains end and the linear selective
hydroformylation in an efficient manner is of high inter-
est.
O
isomerizing
methoxycarbonylation
isomerizing
hydroformylation
O
methyl oleate (1)
CO/MeOH
[cat.]
CO/H2
[cat.]
O
O
O
O
Scheme 4: Approach for development of the isomer-
izing hydroformylation of FAMEs.
O
methyl 19-oxononadecanoate
O
O
(l-C19al)
dimethyl nonadecanedioate
Catalyst development. To develop a new orthogonal
tandem catalytic system for the isomerization / hydro-
formylation tandem reaction, we determined several se-
lection criteria for both the hydroformylation and the
isomerization catalyst. The hydroformylation catalyst
needs to be very selective for functionalization in the
terminal position. The activity in double bond hydrogena-
tion needs to be as low as possible. We decided to use a
Rh/biphephos catalyst, which is well known for linear
selective hydroformylation and also provides the highest
yields of the linear aldehyde in the hydroformylation of
O
O
O
P
O
P
R
R
O
O
R
O
R
O
O
P
O
P
(t-Bu)2
P
P(t-Bu)2
dtbx
O
O
O
O
L1
R=
biphephos
Scheme 2: Isomerizing hydroformylation and meth-
oxycarbonylation.
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ACS Catalysis
methyl oleate described in the literature.20 This catalyst
also has some activity in double bond isomerization that
1
2
is helpful in view of the tandem reaction.
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The isomerization catalyst, on the other hand, has to be
highly active in double bond isomerization in a synthesis
gas atmosphere. Activity in hydrogenation and (non-
selective) hydroformylation are highly undesirable. In
order to find a suitable isomerization catalyst, we investi-
gated several transition metal catalyst precursors based
on Pd, Rh, Ru, Ir, Pt Co and Ni in the isomerization of
methyl 3-hexenoate (2) under hydroformylation condi-
tions (15 bar CO/H2, 90 °C, most promising results are
shown in Table 1, all tested precursors can be found in
Table S1 and S2, supporting information). The most prom-
ising candidate was the palladium-dimer C1 (Table 1,
Entry 1.2; Scheme 6). This catalyst precursor was first
synthesized by Vilar et al.22 and described by Gooßen et
al. as very effective in double bond isomerization of long
chained olefins and oleocompounds in their work regard-
ing the isomerizing metathesis tandem reaction.23–25
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Scheme 5: Reaction network of the isomerizing hy-
droformylation of 2.
When 0.5 mol% of C1 was added, much better results
were obtained (Entry 2.2). The yield of l-C7al increased to
68% with a high l/b-ratio of 95/5. Also, substrate hydro-
genation was slightly suppressed with 10% of C6an ob-
tained. The C1 amount added had strong influence on the
outcome of the reaction (Entries 2.2 – 2.4). When the
amount of C1 was decreased to 0.25 mol%, yield of l-C7al
was comparable (65%), but the l/b-ratio decreased drasti-
cally to 82/18 while the yield of hydrogenated C6an was
17%. On the other hand, when 1 mol% C1 was added, the
l/b-ratio was even higher (98/2) but the activity of the
Rh/biphephos catalyst was inhibited and only 45% of
l-C7al were formed.
Table 1: Isomerization catalyst screening
High
No hydro-
formyla-
tion
No Hy-
drogena-
tion
isomeri-
zation
rate
Entry
Catalyst
Pd(t-Bu3P)2
C1
ꢀ
ꢀ
ꢀ
•
ꢀ
ꢀ
ꢀ
•
1.1
1.2
1.3
1.4
1.5
•
ꢀ
•
PdCl2(PPh3)2
Rh2(OAc)2
ꢀ
Shvo’s cata-
lyst
ꢀ
ꢀ
•
Conditions: 2.1 g toluene, 3.5 mmol 2, 1 mol% metal, 15 bar
synthesis gas (absolute pressure; CO/H2 = 1/1/), 16 h, 90 °C,
batch reaction in 20 mL autoclave, stirrer speed 500 rpm.
ꢀ= Meets criterion fully, •= Meets criterion in an acceptable
manner; ꢁ= does not meet criterion
Scheme 6: Synthesis of C1 and likely catalytically
active species according to Gooßen et al.26,27
Isomerization, hydroformylation and hydrogenation are
detected by GC-FID.
However, in light of these first promising results, we de-
cided to study this orthogonal catalyst system in greater
detail. We were first interested in the role of the Pd-dimer
C1. According to Gooßen et al. this compound can be
synthesized via comproportionation of PdBr2 and Pd(t-
Bu3P)2 (Scheme 6).26 We wondered if precursor C1 is nec-
essary to form the catalytically active isomerization spe-
cies or if it could be formed merely by adding PdBr2 and
Pd(t-Bu3P)2 to the reaction mixture under the given con-
ditions. The latter would be advantageous since addition-
al effort and costs would be avoided if the synthesis of C1
is not required. A comparison of the results of the reac-
tion using C1 as isomerization catalyst precursor (Entry
2.2) with the use of PdBr2 and Pd(t-Bu3P)2 (Entry 2.5)
showed that the yield of the linear aldehyde l-C7al was
slightly higher (73% vs 68%) when the active isomeriza-
tion catalyst was formed directly from
We began developing an orthogonal tandem catalytic
system consisting of Rh/biphephos as the hydroformyla-
tion catalyst and C1 as the isomerization catalyst in the
isomerizing hydroformylation of 2. Scheme 5 shows the
reaction network of this reaction. The desired linear alde-
hyde (l-C7al) can only be formed from the isomer con-
taining the terminal double bond. Branched aldehydes
(b-C7al) and the hydrogenated substrate (C6an) can be
formed from any isomer of 2. Especially the α,β
-
unsaturated isomer of 2 is very prone for hydrogenation.20
If the Rh/biphephos catalyst was applied without the
addition of C1 (Table 2, Entry 2.1), the yield of the linear
aldehyde (l-C7al) is 59% under the given conditions. The
l/b-ratio is 81/19, which is relatively low for this catalyst
compared to the results obtained if the internal olefins
are converted (>90/10) and the yield of the hydrogenated
substrate (C6an) is 15%.
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Table 2: Catalyst development for the isomerizing hydroformylation of methyl 3-hexenoate (2).
1
2
3
4
5
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8
Conversiona l-aldehyde b-aldehyde Hydrogenated l/b-ratio
9
Entry
Isomerization Isomerization
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catalyst A
catalyst B
(l-C7al) [%] (b-C7al)
[%]
substrate
[%]
(C6an) [%]
2.1
2.2
2.3
2.4
2.5
-
-
-
-
-
87
81
59
68
65
45
73
13
3
15
10
17
8
81/19
95/5
0.5 mol% C1
0.25 mol% C1
1 mol% C1
96
54
98
14
1
82/18
98/2
88/12
0.5
PdBr2
mol% 0.5 mol%
Pd(t-Bu3P)2
10
15
2.6
2.7
2.8
-
1 mol%
68
49
60
81
9
10
21
17
84/16
82/18
98/2
Pd(t-Bu3P)2
0.5
PdCl2
mol% 0.5 mol%
Pd(t-Bu3P)2
94
13
2
0.5 mol%
PdI2
0.5 mol%
Pd(t-Bu3P)2
-
>99
2.9
1 mol% PdI2
<1
15
-
-
-
-
2.10
1 mol% LiI
0.5 mol%
Pd(t-Bu3P)2
1 mol%
12
<1
2
97/3
2.11
1 mol% LiI
>99
78
2
19
98/2
Pd(t-Bu3P)2
Conditions: 2.1 g toluene, 3.5 mmol 2, 0.4 mol% Rh(CO)2acac, 1.6 mol% biphephos, 15 bar synthesis gas (absolute pressure,
CO/H2 = 1/1/), 16 h, 90 °C, batch reaction in 20 mL autoclave, stirrer speed 500 rpm. Conversion yields and l/b-ratios were deter-
mined by GC-FID.
a Double bond isomerization not considered in the conversion
PdBr2 and Pd(t-Bu3P)2, but selectivity was slightly lower
(l/b: 88/12 vs 95/5; yield C6an 15% vs. 10%).In principle,
both precursors caused similar results in the tandem
reaction, which led us to the assumption that the catalyti-
cally active isomerization species is the same in both
cases. DFT studies made by Gooßen et al. in their investi-
gations regarding the isomerization of allylic esters sug-
gest that the catalytically active isomerization species is
C1*, formed from precursor C1 (Scheme 6).27 We assume
this could also be the active isomerization catalyst in this
case.
We further investigated how the nature of the halide
influences the tandem reaction (Entries 2.5, 2.7, 2.8). It
turned out that the catalytic activity as well as the selec-
tivity towards desired l-C7al increases strongly from chlo-
ride to iodide. When PdCl2/Pd(t-Bu3P)2 was used as pre-
cursor (Entry 2.7), the yield of l-C7al was 60% and the l/b-
ratio was 82/18, which again is quite similar to the results
obtained without an additional isomerization catalyst
(Entry 2.1). In contrast, by using PdI2/Pd(t-Bu3P)2, a very
high yield of l-C7al (81%) and an excellent l/b-ratio of
98/2 were obtained. One possible explanation for this
effect is that the nature of the halide influences the for-
mation of the catalytically active, three-coordinated Pd-
isomerization species from a four-coordinated, halide-
bridged dimeric resting state of the catalyst. Also a direct
influence of the halide on isomerization activity of the
catalytically active species cannot be excluded at this
point.
In order to get more information about the isomerization
catalyst we conducted an experiment in which only Pd(t-
Bu3P)2 was added as a precursor (Entry 2.6). The results
(yield of l-C7al 49%, l/b = 84/16) obtained were more or
less comparable with the reaction without introducing
any isomerization catalyst (Entry 1.1), although the activi-
ty in hydroformylation and hydrogenation was slightly
lower. We also screened the Pd(t-Bu3P)2 precursor in the
isomerization of 2 without Rh/biphephos and only rela-
tively small amounts of isomers were formed (Entry 1.1,
Table 1).
However, when PdI2 was used as precursor without Pd(t-
Bu3P)2 no hydroformylation or hydrogenation was ob-
served and only traces of isomers were formed (Entry 2.9).
We assume that the iodide coordinates to the rhodium
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Table 3: Double bond isomer distribution of 2 in the
complex in the absence of palladium leading to a com-
1
2
plete deactivation of the rhodium catalyst.
equilibrium and distribution of branched aldehydes
after reaction.
Investigations on the halide source (use of LiI instead of
PdI2) showed that the cations nature does not influence
the outcome of the tandem reaction (comparing Entries
2.8 and 2.11) but, as mentioned above, the amount of Pal-
ladium (and therefore the ratio of Pd/I-) is crucial (com-
paring Entries 2.8, 2.10 and 2.11) to prevent catalyst deacti-
vation. A Pd/I--ratio of 1/1 led to excellent yields of l-C7al
(~80%) and l/b-ratios (98/2) whereas an excess of iodide
led to catalyst deactivation. These results also show that
the oxidation state of the Pd precursor is not crucial and
both the Pd(0) and the Pd(II) are converted into the ac-
tive isomerization catalyst under the given conditions.
3
4
5
6
7
8
9
Equilibrium
distribution of branched alde- branched alde-
double bond hydes using only hydes using
isomers (at room Rh/biphephos orthogonal
Distribution of Distribution of
temperature) 7
catalyst
Rh/Pd catalyst a
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Branched alde-
Branched alde-
hydes exclusive- hydes exclusive-
ly formed from
internal double
bonds: 67%
ly formed from
internal double
bonds: 37%
We also were interested in the distribution of the isomer-
ic unsaturated C6-esters in the equilibrium and the dis-
tribution of the branched C7-aldehydes (b-C7al) (Table
3).
Studies of Mecking et al. regarding the isomerization of
methyl 5-hexenoate showed that the a,ß-unsaturated
isomers are the most abundant ones in the thermody-
namic equilibrium (54.4% at room temperature). The
equilibrium mixture contains only 0.9% of the terminal
unsaturated isomers.7 Consequently, high yield and high
selectivity towards the desired linear aldehyde can only be
achieved if mainly terminal unsaturated isomers are hy-
droformylated and therefore are selectively removed from
the equilibrium. These isomers can then be regenerated
by isomerization of the internal unsaturated isomers.
Reaction conditions: Conditions: 2.1 g toluene, 3.5 mmol 2,
0.4 mol% Rh(CO)2acac, 1.6 mol% biphephos, 15 bar synthesis
gas (absolute pressure, CO/H2 = 1/1/), 16 h, 90 °C, batch reac-
tion in 20 mL autoclave, stirrer speed 500 rpm. Distribution
of aldehyde isomers was determined by GC-FID. Identifica-
tion of the formyl groups position was done by GC-MSD.
The distribution of the branched aldehydes formed if
Rh/biphephos is applied as the only catalyst (Table 3)
shows that in principle also internal double bonds can be
hydroformylated under given conditions, if they coordi-
nate to the Rh-center. 67% of all branched aldehydes are
formed exclusively by hydroformylation of an internal
double bond. Only 33% of the branched aldehydes con-
tain the formyl group in position 5 of the carbon chain.
This aldehyde can either be formed by hydroformylation
of the terminal unsaturated C6-ester or from the unsatu-
rated C6-ester with the double bond in position 4.
a Addition of 0.5 mol% PdI2 and 0.5 mol% Pd(t-bu3P)2
both catalysts. Therefore, experiments with the orthogo-
nal
tandem
catalytic
system
consisting
of
Rh/biphephos/PdI2/Pd(t-Bu3P)2 (Figure 1a) were com-
pared with experiments using only the Rh/biphephos
catalyst at different temperatures (Figures 1b – 1c).
When the orthogonal catalyst was used (Figure 1a), isom-
erization of methyl 3-hexenoate (2) was extremely fast.
After ten minutes the mixture contained only 16% of the
starting material and 74% isomers. At this point the iso-
mers seem to be in equilibrium since the concentrations
of 2 and its isomers decreased at the same rate. The for-
mation of the linear aldehyde also started instantly (9%
after 10 minutes).
In contrast, application of the orthogonal Rh/Pd-catalyst
strongly shifts this distribution towards formation of the
branched aldehyde with the formyl group in position 5
(63% of all branched aldehydes; Table 3). One possible
explanation for this observation is that the coordination
of the terminal unsaturated substrate to the
Rh/biphephos complex, which is supposed to be the rate
determining step in the hydroformylation using this cata-
lyst28, is strongly favored over coordination of isomers
with an internal double bond. If the terminal unsaturated
isomers are generated by an additional isomerization
catalyst, mainly these isomers will coordinate to the Rh-
complex and undergo hydroformylation. This leads to an
very high l/b-ratio (98/2).
During the first four hours, remarkably, no formation of
branched aldehydes was observed. Consequently, only
isomers containing a terminal double bond were con-
sumed via hydroformylation and regenerated from the
remaining isomers via isomerization. Hydrogenated sub-
strate was also detected from the start of the reaction (1%
after 0.5 h). Based on the results described in previous
studies20, it can be assumed that mainly the
α,β−unsaturated isomer is hydrogenated. When only
Rh/biphephos (Figure 1b) was applied as a catalyst at
90 °C, the isomerization rate drastically decreased. The
formation of the targeted linear aldehyde l-C7al was
slower (3% after 0.5 h) and also the formation of
After investigating the reaction parameters temperature,
synthesis gas pressure and synthesis gas composition
(Figure S1 –S3) and slightly adjusting (100 °C and 10 bar)
the reaction conditions, we also studied the kinetics of
the reaction to better understand the interplay between
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isomers of 2
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isomers of 2
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Figure 1a. Rh/biphephos/PdI2/Pd(t-Bu3P)2 at 100 °C
time [h]
Figure 1b. Rh/biphephosat 90 °C
time [h]
Figure 1c. Rh/biphephos at 100 °C
Figure 1. Reaction kinetics of the isomerizing hydroformylation of 2.
Figure 1a. Conditions: 48 g toluene, 70 mmol 2, 0.4 mol% Rh(CO)2acac, 1.6 mol% biphephos, 0.5 mol% PdI2, 0.5 mol Pd(t-Bu3P)2
10 bar synthesis gas (absolute pressure, CO/H2 = 1/1/), 100 °C, batch reaction in 300 mL autoclave, stirrer speed 1000 rpm. Yields
were determined by GC-FID.
Figure 1b. Conditions: 48 g toluene, 70 mmol 2, 0.4 mol% Rh(CO)2acac, 1.6 mol% biphephos, 15 bar synthesis gas (absolute pres-
sure, CO/H2 = 1/1/), 90 °C, batch reaction in 300 mL autoclave, stirrer speed 1000 rpm. Yields were determined by GC-FID.
Figure 1c. Conditions: 48 g toluene, 70 mmol 2, 0.4 mol% Rh(CO)2acac, 1.6 mol% biphephos, 10 bar synthesis gas (absolute pres-
sure, CO/H2 = 1/1/), 100 °C, batch reaction in 300 mL autoclave, stirrer speed 1000 rpm. Yields were determined by GC-FID.
undesired branched aldehydes was detected from the
start of the reaction (1% after 0.5 h). Undesired hydro-
genation of the substrate was more than two times faster
(7% after 2 h instead of 3%) compared to the application
of the orthogonal catalyst.
However, interactions between the transition metals and
their ligands cannot be excluded at this point. For exam-
ple, as shown in Table 2 (Entry 2.9 and Entry 2.10), cata-
lytic activity is strongly inhibited if more iodide than
palladium is present in the reaction mixture. This demon-
strates that components of the isomerization catalyst
precursor may potentially interact with the rhodium cata-
lyst.
When the temperature was increased to 100 °C (Figure
1c), the reaction rates of all partial reactions increased as
well. After two hours, aldehyde yield of 52% (l/b=90/10)
and 14% of the hydrogenated substrate C6an were ob-
tained.
After successfully developing a promising orthogonal
tandem catalytic system, the next step was to apply this
system in the isomerizing hydroformylation of ethyl 4-
deceneoate (3) as a second model substrate bearing a
longer carbon chain.
The selectivity towards the linear aldehyde in the hydro-
formylation also increased with temperature. Compared
to the orthogonal catalyst system, the isomerization of 2
was still much slower, though the hydroformylation
(branched) and hydrogenation reaction rates were higher.
Isomerizing hydroformylation of ethyl 4-decenoate
(3). In order to identify limitations that occur when using
a long chained unsaturated ester as a substrate, we tested
the catalyst system in the isomerizing hydroformylation
of ethyl 4-decenoate (3) (Figure 2). The results show that
reaction rates for hydroformylation and hydrogenation
were slower compared to the conversion of 2. Aldehyde
formation (1% l-C11al) was observed after two hours. The
hydrogenation of the starting material was observed after
four hours (1% yield of C10an). This was the case because
it took more time to reach the equilibrium of the double
bond isomers (Figure S4). Ratios of the isomers were
unchanged after two hours. Afterwards, the reaction pro-
ceeded similar to the isomerizing hydroformylation of 2,
albeit more slowly due to the lower equilibrium concen-
tration of the terminal unsaturated ester. The l/b-ratio of
the resulting aldehydes was also slightly lower (95/5). As
The use of the orthogonal catalyst inhibits the most im-
portant side reactions (hydrogenation and formation of
branched aldehydes). The results show that selectivity
towards the linear hydroformylation product correlates
with the isomerization rate. As outlined above, this could
be traced back to a higher coordination affinity of the
terminal unsaturated substrates to the Rh/biphephos
complex. If an additional isomerization catalyst is pre-
sent, the “supply” of the terminal unsaturated isomers via
isomerization of internal unsaturated ones is very fast,
resulting in a higher l/b-ratio in the hydroformylation.
This could also explain the higher chemoselectivity when
the orthogonal tandem catalyst is applied, especially con-
sidering that the α,β-unsaturated isomer is very prone to
hydrogenation.20
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Figure 2. Isomerizing hydroformylation of 4-ethyl decenoate (3).
Conditions: 48 g toluene, 40 mmol 3, 0.4 mol% Rh(CO)2acac, 1.6 mol% biphephos, 0.5 mol% PdI2, 0.5 mol Pd(t-Bu3P)2 10 bar
synthesis gas (absolute pressure, CO/H2 = 1/1/), 100 °C, batch reaction in 300 mL autoclave, stirrer speed 1000 rpm. Yields were
determined by GC-FID.
discussed before, this could also be attributed to the low-
er concentration of the terminal unsaturated isomer of 3.
For the conversion of long chained fatty acid methyl es-
ters such as methyl oleate, the isomerization rate has to
be increased in order to reach reasonable yields and l/b-
ratios.
methyl oleate (1) (Table 4, entries 4.3-4.8). The results
show that the best yields of l-c19al were obtained when
the PdI2 concentration was reduced to 0.33 mol% (Pd/I-
ratio of 3.5, Entry 4.6). The yield of the desired linear
aldehyde l-C19al was 44% with an l/b-ratio of 88/12.
Higher iodide concentrations led to lower catalyst activity
while lower iodide concentrations also led to a strongly
decreased l/b-ratio. After this investigation we set the
Pd/I—ratio to 3.5 and varied the total amount of the isom-
erization catalyst precursor. It seems that a total palladi-
um concentration of 2.33 mol% is sufficient to allow for a
high isomerization rate (Entry 4.6). Higher amounts do
not lead to higher yields of desired l-C19al (Entry 4.9 and
4.10). Lower concentrations (Entry 4.11) lead to decreased
catalytic activity (conversion 40%, yield of l-C19al 19%
and regioselectivity (l/b 70/30), indicating that the “sup-
ply” of terminal unsaturated esters for the rhodium cata-
lyst is not fast enough. Longer reaction times lead to a
higher conversion and higher yields of the desired prod-
uct l-C19al. After 40h, the yield of l-C19al was 62% (Entry
4.12), after 72 h full conversion was reached, yielding in
67% l-C19al and a l/b-ratio of the aldehydes of 91/9 (Entry
4.13). These are the highest yields and selectivities de-
scribed in the literature thus far.
Isomerizing hydroformylation of methyl oleate (1).
As discussed above, a high isomerization rate is required
for an efficient conversion of long chained unsaturated
esters such as methyl oleate (1). When the developed
reaction conditions are applied directly in the isomerizing
hydroformylation of methyl oleate, almost no reaction
was observed (Table 4, Entry 4.1). A higher isomerization
rate can be achieved by increasing the temperature or the
isomerization catalyst concentration. Studies on model
substrate (2) showed that increasing the temperature led
to high yields of the undesired hydrogenation product
and low l/b-ratios (Figure S1). The same observation was
made in the hydroformylation of methyl oleate (Entry
4.2). The yield of the hydrogenated substrate (C18an) was
15%, whereas the yield of the targeted linear aldehyde
(13% l-19al) and also the l/b-ratio (55/45) of the resulting
aldehydes were low. By contrast, higher palladium con-
centrations led to more promising results (Entry 4.3).
When 2 mol% of both Pd-precursors are used at 100 °C,
the yield of l-C19al was still low (15%) but the l/b-ratio of
the aldehydes was 83/17. Investigations on model sub-
strate 2 showed that the ratio of Pd/I- strongly influences
the activity and selectivity of the reaction (Table 2, entries
2.10 and 2.11). Therefore we examined the Pd/I- ratio in
greater detail for the isomerizing hydroformylation of
In the absence of the isomerization catalyst (Entry 4.14),
yield of the linear aldehyde (3%) and l/b-ratio (20/80)
were drastically lower, clearly demonstrating the benefit
of the developed orthogonal tandem catalytic system. It
allows for the generation of high aldehyde yields (74%)
and regioselectivities (l/b 91/1) in the hydroformylation.
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Table 4: Catalyst development for the isomerizing hydroformylation of methyl oleate (1).
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4
5
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9
Entry
T [°C]
t [h]
PdI2
Pd(t-Bu3P)2 Conv.a
l-ald.
(l-C19al) (b-C19al)
b-ald.
Hydrogenated
substrate
l/b-ratio
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[%]
[%]
[%]
(C18an) [%]
4.1b
4.2b
4.3
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0.5 mol%
0.5 mol%
2 mol%
1 mol%
0.5 mol%
0.33 mol%
0.2 mol%
-
0.5 mol%
0.5 mol%
2 mol%
2 mol%
2 mol%
2 mol%
2 mol%2
2.3 mol%
6 mol%
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1 mol%
3 mol%
3 mol%
-
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-
-
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-
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87/13
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70/30
91/9
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17
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37
31
3
4.4
45
55
72
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3
4.5
5
4.6
4.7
6
7
4.8
14
5
4.9
4.10
4.11
4.12
4.13
4.14
1 mol%
0.5 mol%
0.17 mol%
0.5 mol%
0.5 mol%
-
45
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62
67
3
76
40
93
>99
21
6
9
7
88/12
70/30
89/11
91/9
7
12
20/80
Conditions: 2.05 g toluene, 1.3 mmol 1, 0.8 mol% Rh(CO)2acac, 3.2 mol% biphephos, 10 bar synthesis gas (absolute pressure,
CO/H2 = 1/1/), batch reaction in 20 mL autoclave, stirrer speed 500 rpm. Yields were determined by GC-FID.
a Double bond isomerization not considered in the conversion.
b 0.4 mol% Rh(CO)2acac, 1.6 mol% biphephos
However, the hydrogenation of the substrate is still an
issue using the bimetallic catalyst. In order to arrive at a
better understanding of the interplay of the orthogonal
catalyst system, in situ spectroscopic measurements com-
bined with DFT studies should be conducted.29 This could
lead to insights that may prove to be very helpful in the
design of new, more efficient orthogonal catalysts.
methyl 3-hexenoate (Acros Organics, >95%), ethyl 4-
decenoate (TCI Chemicals, >98%) were purchased from
different commercial suppliers. Methyl oleate (>89%) was
donated by Dako Aktiengesellschaft Chemical Products.
Biphephos (>95%) was synthesized from Molisa GmbH.
Rh(CO)2acac was donated by Umicore AG & Co. Kg. Pal-
ladium precursors, tri-tert-butylphosphine and Lithi-
umiodid were purchased from ABCR. All chemicals were
degassed before use and stored under argon. CO (2.0) and
H2 (5.0) were purchased from Messer Industriegase
GmbH.
CONCLUSION
In this paper we describe the successful development of
an orthogonal tandem catalytic system for the linear se-
lective isomerizing hydroformylation of methyl oleate.
The isomerization catalyst consists of the palladium pre-
cursors Pd(t-Bu3P)2 and PdI2 at a ratio of 6/1, while a
Rh/biphephos complex is used as the hydroformylation
catalyst. The use of this catalyst system leads to an alde-
hyde yield of 74% and an l/b-ratio of 91/9 for the resulting
aldehydes. These are the highest yields and selectivities
described for this reaction in the literature thus far.
Hydroformylation reactions
Rh(CO)2acac, Pd(t-bu3P)2, PdI2 and biphephos were
weighted either in a homemade 20 ml autoclave or in a
300 ml autoclave (Parr Instruments). The autoclave was
closed, evacuated and flushed with argon three times.
Degassed toluene and the substrate were subsequently
transferred into the reactor via cannula using the stand-
ard Schlenk technique. The reactor was pressurized with
synthesis gas and heated while stirring to reaction tem-
perature. In cases of time-resolved experiments, samples
were taken from the reactor and analyzed via GC-FID.
After the reaction time the reactor was put into an ice
EXPERIMENTAL
Chemicals
Toluene (Acros Organics, >99%), ethyl acetate (Acros
Organics, >99%), cyclohexane (Acros Organics, >99%)
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(10) Roesle, P.; Caporaso, L.; Schnitte, M.; Goldbach, V.;
Cavallo, L.; Mecking, S. J. Am. Chem. Soc. 2014, 136, 16871–
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Jiao, H.; Bentrup, U.; Brückner, A.; Martin, A.; Köckritz, A. J.
Catal. 2013, 297, 44–55.
bath and the pressure was carefully released. The reaction
mixture was analyzed via GC-FID.
Supporting Information.
Additional results regarding the influence of the reaction
conditions
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8
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(12) García-Suárez, E. J.; Khokarale, S. G.; van Buu, O. N.;
Fehrmann, R.; Riisager, A. Green Chem. 2013, 16, 161–166.
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Used chemicals
Details about analytical procedures
Product isolation and characterization
NMR and MS spectra
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Exemplary chromatograms
ACKNOWLEGMENTS
We gratefully acknowledge the financial support of the
German Science Foundation (Project SFB/TRR 63:
”InPROMPT – Integrated Chemical Processes in Multi-
Phase Fluid Systems”) for this work (Subproject A1). We
would also like to express our gratitude to Umicore AG &
Co. KG for supplying the catalyst precursors and to Dako
Aktiengesellschaft Chemical Products for supplying the
methyl oleate.
REFERENCES
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isomers of 2
l-C7al
b-C7al
C6an
2
isomers of 2
l-C7al
b-C7al
C6an
2
isomers of 2
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time [h]
Figure 1a. Rh/biphephos/PdI2/Pd(t-Bu3P)2 at 100 °C
time [h]
time [h]
Figure 1c. Rh/biphephos at 100 °C
Figure 1b. Rh/biphephos at 90 °C
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Scheme 1: Isomerization / -functionalization of methyl oleate (1).
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Scheme 2: Isomerizing hydroformylation and meth-oxycarbonylation.
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ACS Catalysis
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Scheme 3. Isomerizing hydroformylation of methyl oleate: This work compared with literature.
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Scheme 4: Approach for development of the isomer-izing hydroformylation of FAMEs.
173x39mm (300 x 300 DPI)
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ACS Catalysis
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Scheme 5: Reaction network of the isomerizing hy-droformylation of 2.
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Scheme 6: Synthesis of C1 and likely catalytically active species according to Gooßen et al.
146x91mm (300 x 300 DPI)
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ACS Catalysis
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ACS Catalysis
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TOC
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