Recycling of two molecular catalysts in the hydroformylation/aldol condensation tandem reaction using one multiphase system

Article abstract of DOI:10.1039/d0gc03392h

Tandem reactions are of great importance to efficiently execute multiple conversions in one synthesis step. Herein we present a multiphase system for the hydroformylation/aldol condensation, which is able to recycle both optimized catalysts multiple times. The system consists of an organometallic rhodium/sulfoXantphos hydroformylation catalyst and basic NaOH as aldol condensation initiator, which are both immobilized in a polyethylene glycol phase. Under reaction conditions, NaOH is converted to sodium formate, which is still able to catalyse the aldol condensation. The reaction and recycling are demonstrated by the conversion of 1-pentene to the corresponding aldol product in a recycling experiment. During nine consecutive runs, no significant loss of activity is found with an overall TON of 8700 in regard to the rhodium catalyst and an average rhodium leaching of only of 0.07% per run is observed.

Full text of DOI:10.1039/d0gc03392h

View Article Online
View Journal
Green
Chemistry
Cutting-edge research for a greener sustainable future
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Strohmann, J.
T. Vossen, A. J. Vorholt and W. Leitner, Green Chem., 2020, DOI: 10.1039/D0GC03392H.
Volume 20
This is an Accepted Manuscript, which has been through the
Number
May 2018
Pages 1919-2160
9
7
Royal Society of Chemistry peer review process and has been
accepted for publication.
Green
Chemistry
Cutting-edge research for a greener sustainable future
rsc.li/greenchem
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1463-9262
PAPER
Paul T. Anastas et al.
The Green ChemisTREE: 20 years after taking root with the 12
principles
rsc.li/greenchem

Please do not adjust margins
Page 1 of 8
Green Chemistry
View Article Online
DOI: 10.1039/D0GC03392H
ARTICLE
Recycling of Two Molecular Catalysts in the Hydroformylation/
Aldol Condensation Tandem Reaction Using One Multiphase
System
Received 00th January 20xx,
Accepted 00th January 20xx
Marc Strohmann,a Jeroen T. Vossen,a Andreas J. Vorholt* a and Walter Leitner a,b
DOI: 10.1039/x0xx00000x
Tandem reactions are of great importance to efficiently execute multiple conversions in one synthesis step. Herein we
present a multiphase system for the hydroformylation/aldol condensation, which is able to recycle both optimized catalysts
multiple times. The system consists of an organometallic rhodium/sulfoXantphos hydroformylation catalyst and basic NaOH
as aldol condensation initiator, which are both immobilized in a polyethylene glycol phase. Under reaction conditions, NaOH
is converted to sodium formate, which is still able to catalyse the aldol condensation. The reaction and recycling are
demonstrated by the conversion of 1-pentene to the corresponding aldol product in a recycling experiment. During nine
consecutive runs, no significant loss of activity is found with an overall TON of 8700 in regard to the rhodium catalyst and
an average rhodium leaching of only of 0.07% per run is observed.
hydroformylation is the first reaction step, followed by,
Introduction
hydrogenation
(hydrohydroxymethylation),
reductive
amination (hydroaminomethylation), acetalization, acyloin
reaction or aldol condensation (Scheme 1).10, 11, 14-17
Tandem catalysis provides a powerful tool for improving
molecular transformations, as it allows a reduction in energy
and material and saves overall process time. Therefore, it is not
surprising to see tandem catalysis as a growing field in current
research.1-6 In comparison to one-pot reactions, tandem
systems are characterized by having all components present at
the beginning of the reaction. Furthermore, tandem reactions
differ from domino or cascade reactions as such that more than
one catalyst cycle is involved. Tandem catalysis can be further
subdivided into auto-tandem and orthogonal tandem catalysis,
depending on weather only one or multiple catalyst species are
used.7, 8
The hydroformylation/aldol condensation tandem reaction
allows the formation of α,ß-unsaturated aldehydes, which are
an important molecule class for cosmetics, agrochemicals and
pharmaceuticals.18 Nevertheless, it has received less attention
compared to hydrohydroxymethylation or hydroamino-
methylation. One reason might be the increased complexity of
this reaction sequence because of the additional catalyst
required for the aldol condensation step. In 2014 Beller and
coworkers presented a homogeneous catalyst system for the
hydroformylation/aldol condensation tandem reaction.19 The
group
took
advantage
of
a
rhodium/phosphine
Hydroformylation is the reaction of olefins with hydrogen and
carbon monoxide (synthesis gas) to linear and branched
aldehydes. It has been well investigated and is nowadays one of
the largest homogeneously catalysed processes in industry.9
The produced aldehydes are usually not the final products, but
are further converted in subsequent reaction steps.
Additionally, aldehydes are very versatile and can be
transformed in many ways. Therefore, the hydroformylation
reaction is particularly suitable as a part of a tandem catalysis
network.10, 11 One possible tandem sequence is a double bond
isomerization followed by hydroformylation, since terminal
olefins are hydroformylated much faster than internal ones.12,
hydroformylation catalyst in combination with a pyrrolidine-
based organocatalyst for the aldol step. With this system, they
were able to convert a variety of olefins to the corresponding
aldol products with high conversions and selectivity.
Additionally, they showed cross aldol condensation with
aromatic aldehydes. Ethyl acetate or N-Methyl-2-pyrrolidon
13
However, more common are tandem reactions in which
a. Max-Planck-Institut für Chemische Energiekonversion, Stiftstraße 34-36, 45470
Mülheim an der Ruhr, Germany. E-mail: andreas-j.vorholt@cec.mpg.de
b. Institut für Technische und Makromolekulare Chemie (ITMC), RWTH Aachen
University, Worringer Weg 1, 52074 Aachen, Germany
† Electronic
DOI: 10.1039/x0xx00000x
Supplementary
Information
(ESI)
available.
See
Scheme 1 Possible tandem reactions involving hydroformylation.
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 8
ARTICLE
Journal Name
(NMP) were used as solvent in the tandem reactions. For this
homogeneous reaction system, no recycling of the catalysts was
discussed.
A different strategy to approach the hydroformylation/aldol
condensation reaction was presented by Jasra and
coworkers.20-22 They prepared multifunctional catalysts by
immobilizing the organometallic species RhH(CO)(PPh3)3 onto a
Results and Discussion
Catalysis in Water
View Article Online
DOI: 10.1039/D0GC03392H
The conversion of 1-pentene served as model reaction for our
investigation of the multiphase hydroformylation/aldol
condensation tandem reaction. 1-pentene is first
hydroformylated to n-hexanal and then undergoes self-aldol
condensation to form the desired aldol product 4-butyloctenal
(Scheme 2). Also displayed are typical side reactions including
the hydrogenation of pentene to pentane, of hexanal to
hexanol and of the aldol product to the saturated aldehyde 4-
butyloctanal (saturated aldol). Another side product is the iso-
basic
carbonate,
a
hydrotalcite
of
the
form
2-
[Mg1-xAlx(OH2)x+(CO3
)
x/n·m H2O]. This catalyst was able to
convert linear olefins from ethylene to 1-decene to the
corresponding aldol derivatives in one-pot. However, with
increasing length of the olefin substrates the selectivity to the
aldol product decreases as side reactions such as isomerization
and hydrogenation of the starting material took place.
Additionally, hydrogenation of the aldol product to the
saturated aldehyde was observed. As a heterogeneous catalyst,
it could be separated from the product mixture by simple
filtration. Unfortunately, the basic support loses its activity for
the aldol condensation during catalysis because of structural
hexanal
(2-methylpentanal)
which
forms
during
hydroformylation but does not undergo self-condensation
because of its branching. In order to achieve a high conversion
towards the aldol product, a good n:iso ratio as well as a low
hydrogenation activity are necessary. For our biphasic reaction
system, we initially chose water as catalyst phase and
[Rh(acac)(CO)2] with sulfoXantphos (4,5-Bis(diphenylphosphi-
no)-9,9-dimethyl-2,7-disulfoxanthene disodium salt) as in situ
hydroformylation catalyst system. Xantphos and its sulfonated,
water-soluble variation sulfoXantphos are well known
hydroformylation ligands that give high linear to branched
ratios due to their wide bite angle (111 °) and were successfully
applied for hydroformylation reactions in the past.32-34 We then
changes, thus not allowing
a successful reuse of the
multifunctional catalyst over multiple runs.
The difficulty of catalyst removal and especially catalyst
recycling is one of the major hurdles to bring homogeneous
catalysed reactions into application. The presence of two
different catalysts increases the difficulty level of recycling in
tandem reactions in general and thus also that of the
hydroformylation/aldol condensation tandem reaction.
Multiphase systems present an elegant way of recycling
molecular catalysts by immobilizing the catalyst in one of the
liquid phases, while the product forms the other phase. This
recycling strategy has found application in industry for example
in the oligomerization of ethylene (Shell Higher Olefine
Process)23 or the hydroformylation of propene (Ruhrchemie/
Rhône-Poulenc process).24 Water is the most common choice
for the polar catalyst phase in multiphase catalysis, but other
polar solvents such as 1,4-butanediol, methanol,25 polyethylene
glycol (PEG),26 ionic liquids27, 28 or deep eutectic solvents29 have
been applied in industry and academia, as well. Among these,
focussed on finding
a suitable catalyst for the aldol
condensation step. Inorganic bases, such as sodium or
potassium hydroxide are the most common catalysts in aldol
reactions. However, the reaction also proceeds via enamine
catalysis. In terms of enamine catalysis, amines such as
pyrrolidine or amino acids can be used. A couple of different
bases and organocatalysts have been selected and tested in the
biphasic aldol condensation of hexanal (Fig. 1).
The basic catalyst NaOH gave a moderate conversion of 62%
after the reaction time of 1.5 h, whereas no conversion was
observed for the less basic Na2CO3. Although NaOH seems to be
a suitable catalyst for the aldol condensation, it is known that
the rate of hydroformylation is reduced with increasingly basic
pH-values.[14] Additionally, in the work by Fang et al. NaOH
turned out to be an ineffective aldol catalyst, when used under
hydroformylation conditions.[6] In the same work, the authors
found a combination of pyrrolidine and benzoic acid to be the
especially water and polyethylene glycol are widely considered
31
as green solvents.30,
Furthermore, aqueous multiphase
catalysis has been successfully used for catalyst recycling in the
hydroaminomethylation tandem reaction.32
While hydroformylation and aldol condensation alone have
often been studied in liquid/liquid systems, to our knowledge,
the tandem reaction has not been demonstrated in such a
manner. In this work, we therefore set out to apply multiphase
catalysis to perform the hydroformylation/aldol condensation
tandem reaction with special focus on recycling of both
catalysts simultaneously. 1-pentene was chosen as model
substrate. Water and polyethylene glycol are investigated as
solvents for the catalyst phase and the recyclability of the
orthogonal catalyst system is demonstrated in recycling
experiments.
O
iso-hexanal
O
+
O
+ hexanal, - H2O
[base or amine]
+ H2/CO
[Rh/P]
n-hexanal
1-pentene
aldol product
+H2 [Rh/P]
+H2 [Rh/P]
OH
+H2 [Rh/P]
O
pentane
hexanol
saturated aldol
Scheme 2 Desired conversion of 1-pentene to the C12-aldol product by
hydroformylation/aldol condensation tandem reaction and typical side products that
occur.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 8
Green Chemistry
Please do not adjust margins
Journal Name
ARTICLE
The low activity of these two amino acids might be a result of
View Article Online
DOI: 10.1039/D0GC03392H
their high solubility in water and therefore low tendency to shift
to the organic phase for the catalysis. In a work by Ostrowski
et al. all 20 proteinogenic amino acids were compared for their
catalytic activity in aldol condensations of aldehydes in
ethanol.36 L-Tryptophan and L-phenylalanine performed best
and tryptophan was successfully applied in a water system, too.
Similarly, in our biphasic system both amino acids performed
excellently with hexanal conversions of 95% and 94%,
respectively. NaOH, pyrrolidine/benzoic acid and tryptophan
were selected for further investigation, since they were the
most active of each of the three catalyst types.
We continued by searching for suitable reaction conditions for
the hydroformylation step, before adding the aldol catalysts.
Table 1 summarizes the results of the hydroformylation of
1-pentene with and without the selected aldol catalysts. A low
temperature of 65 °C was not enough for the hydroformylation
step, as no conversion of pentene was observed. Increasing the
temperature to 100 °C and 120 °C then lead to conversions of
18% and 58%, respectively (Table 1, entries 1-3). Next, we
added the different aldol catalyst to investigate the whole
tandem reaction at 120 °C. In presence of NaOH less pentene
(48%) was converted compared to the reaction without NaOH
(entry 4). In addition, no aldol product was observed after the
reaction. It turned out that NaOH is deactivated under reaction
Fig. 1 Hexanal conversion in the aqueous biphasic aldol condensation using different
catalysts. Conditions: Hexanal (8.2 mmol, 1 mL), H2O (0.4 mL), catalyst (5 mol%), 65 °C,
1.5 h. Conversions were determined by GC-FID.
conditions by
a reaction with CO to sodium formate
(Scheme 3a), which was confirmed by the presence of the
formate peak at around 8.5 ppm in the 1H-NMR spectrum (see
Fig. S1). With a pKa-value of only 3.8 (acidity constant of formic
acid), the basicity of sodium formate does not seem to be
enough to catalyse the aldol condensation itself. The formation
of formate was also observed at a lower temperature of 100 °C
and a lower pressure of 10 bar and proceeds faster than the
hydroformylation. Since CO is essential for the tandem reaction
and cannot be replaced, this deactivation excluded NaOH as
possible aldol catalyst in the water system. When
pyrrolidine/benzoic acid or tryptophan were used as catalyst,
higher pentene conversions (92% and 93%) were reached
compared to the 58% conversion in the reaction without
additional aldol catalyst (entries 5-6).In addition, the formation
of aldol product was observed in these cases, however, less
than what was expected from the previous experiments. The
higher pentene conversions are probably due to the amphiphilic
most successful aldol catalyst for their reaction system. The
pyrrolidine enables enamine catalysis, while the benzoic acid
accelerates the enamine formation. Thus, pyrrolidine in
combination with different organic acids was tried for our
system, as well. A good conversion of 82% was reached in the
case of benzoic acid, confirming the suitability of this
organocatalytic system. In comparison, pyrrolidine alone only
gave 59% conversion. With catalyst recycling in mind, we
attempted the reaction with acetic acid and the sulfonated
benzoic acid (sodium 3-sulfobenzoate) as acidic additive in
combination with pyrrolidine. Due to the higher solubility of the
named acids in water, they are more likely to remain
immobilized in the water phase after the reaction.
Unfortunately, both acidic additives lead to lower conversions
compared to pyrrolidine without additives, 52% in the case of
acetic acid and only 5% in the case of sulfonated benzoic acid. It
is assumed, that the reaction proceeds slower with these
catalysts, because the aldol reaction takes place in the organic
phase. If an acidic additive is added to the reaction, it will form
an adduct with pyrrolidine and depending on the water
solubility of the acid, the adduct will be solvated mostly in the
water phase with barely any transition of pyrrolidine to the
organic phase.
Table 1 Hydroformylation of 1-pentene and consecutive aldol condensation in water
using different aldol catalysts.a
hexanal [%]
(n:iso)
aldol [%]
Entry
aldol catalyst
T [°C]
X [%]
1
2
3
4
5
6
-
-
-
65
0
0
0
0
0
0
10
29
100
120
120
120
120
18
58
48
92
93
18 (60:40)
57 (97:3)
48 (83:17)
71 (97:3)
59 (97:3)
The amino acid L-proline combines the functionalities of the
pyrrolidine ring and a carboxylic acid and is known for
asymmetric aldol condensations.35 However, only 3% of hexanal
was converted by proline under the chosen reaction conditions.
Sarcosine, also bearing a secondary amine and a carboxylic acid
group, showed even less activity with less than 1% conversion.
NaOH
PyH/PhCOOHb
L-tryptophan
a Conditions: Pentene (8.2 mmol, 0.9 mL), H2O (0.4 mL), [Rh(acac)(CO)2] (0.1 mol%),
sulfoXantphos (0.2 mol%), aldol catalyst (5 mol%), H2/CO (25 bar each), 16 h. b PyH
= pyrrolidine.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 8
ARTICLE
Journal Name
O
CO
Therefore, the tandem reaction was attempted again with the
View Article Online
(a)
NaOH
same aldol catalysts as before in PEDGO-2I:0100.10(T3a9/bDle0GC2)0.33T9h2He
reaction was indeed accelerated by the solvent change, as
pentene conversions of ≥ 97% were achieved within the same
reaction time of 16 h in all cases. For pyrrolidine/benzoic acid as
aldol catalyst, a similar aldol product yield of 12% as for the
water system was observed, despite the higher pentene
conversion (Table 2, entry 1). This is because pyrrolidine is fully
deactivated in a similar manner as in the water system
(Scheme 3b). Lowering the temperature to 100 °C lead to a
slightly higher yield of 31% but could not prevent the
deactivation (entry 2). In the case of tryptophan 73% of the
formed hexanal undergoes aldol condensation, however, 41%
of the aldol product is further hydrogenated to the saturated
aldol (entry 3). In order to reduce the formation of the saturated
aldol, the experiment was repeated at a lower temperature.
Indeed, at 100 °C, only 6% of the saturated aldol were formed
and the yield of the aldol product reached 76% (entry 4).
Unfortunately, the use of tryptophan caused an increased
miscibility of the two phases, which was evident from the fact
that the catalyst phase was smaller after the reaction and the
product phase turned yellow. The associated loss of PEG and
catalyst inevitably prevents successful recycling of the catalyst
phase (see Fig. S4).
H
ONa
N
O
R
[Rh]
H2
N
H
(b)
N
R
R
Scheme 3 Deactivation pathways of NaOH (a) and pyrrolidine (b) under
hydroformylation conditions.
nature of these catalysts. With similar structures, they may act
in the same way as surfactants and accelerate the
hydroformylation by forming micelles, which increase the
surface area between the two phases.37 While in the case of
pyrrolidine/benzoic acid a pentene conversion of 92% was
reached, only 10% of aldol product were formed. The low yield
could again be traced back to catalyst deactivation. During
catalysis pyrrolidine forms an enamine with hexanal which can
be irreversibly hydrogenated to the corresponding amine by the
rhodium catalyst (Scheme 3b). The presence of the amine was
observed by GC with a yield of around 5%, which equals the
amount used as catalyst, hence indicating that pyrrolidine was
fully deactivated during the reaction. In the reaction with
tryptophan, 29% aldol product was observed, which is the
highest yield of the three selected aldol catalyst, but still most
hexanal formed during the reaction did not react further. It is
In contrast to the water-based system, NaOH showed a good
activity for the aldol condensation in PEG. At 120 °C most
hexanal underwent aldol condensation, giving 69% of aldol
product and 18% of saturated aldol (entry 5). At 100 °C the yield
of aldol product could be further increased to 80%, however,
more hexanal remained unreacted in the product mixture, as
well (entry 6). These results raised the question whether there
is less or no deactivation of NaOH in the PEG system. The
formation of the formate anion was found by 1H-NMR analysis
of the catalyst phase after the reaction repeatedly, indicating
the deactivation of NaOH at both temperatures (see Fig. S2). In
order to find a way to avoid deactivation, we took a more
detailed look at the temperature dependence of the tandem
reaction by varying the reaction temperature between 75 °C
and 135 °C (Fig. 2). At 75 °C, a pentene conversion of 80% was
reached after the reaction time of 16 h. It was confirmed by 1H-
NMR that even at 75 °C deactivation of NaOH takes place in
PEG-200, which is why no improvement could be achieved by
lowering the reaction temperature. With increased
not certain, weather tryptophan undergoes
a similar
deactivation as pyrrolidine, as the corresponding amine could
not be observed during the reaction. However, the low yields of
aldol product compared to the preliminary experiments
indicate that tryptophan is at least partially deactivated.
Catalysis in polyethylene glycol
Since none of the three aldol catalysts showed promising results
in water, we decided to alter the reaction system by switching
the catalyst phase to polyethylene glycol (PEG) which is known
as a green alternative polar phase for multiphase catalysis.38, 39
The work by Zhao et al. demonstrated that multiphase
hydroformylation can be performed with PEG as catalyst phase
and that a successful catalyst recycling is also possible.26
A
comparison of different chain lengths showed that the shortest
PEG with an average molecular weight of 200 g mol-1 (PEG-200)
gave the best results. Furthermore, all catalysts are soluble in
PEG-200, which makes it a possible alternative to water.
Table 2 Hydroformylation/aldol condensation of 1-pentene in PEG-200 using different
aldol catalysts.a
T
X
hexanal
[%] (n:iso)
60 (97:3)
51 (97:3)
15 (96:4)
12 (98:2)
7 (98:2)
aldol
[%]
12
31
32
76
69
80
sat. aldol
[%]
4
entry
aldol catalyst
[°C] [%]
1
2
3
4
5
6
PyH/PhCO2Hb
PyH/PhCO2Hb
L-tryptophan
L-tryptophan
NaOH
120
100
120
100
120
100
99
98
98
97
97
97
2
41
6
18
2
NaOH
12 (98:2)
a Conditions: Pentene (8.2 mmol, 0.9 mL), PEG-200 (0.4 mL), [Rh(acac)(CO)2]
(0.1 mol%), sulfoXantphos (0.2 mol%), aldol catalyst (5 mol%), H2/CO (25 bar each),
16 h. b PyH = pyrrolidine.
Fig. 2 Temperature variation in the hydroformylation/aldol condensation reaction of
1-pentene in PEG-200 with Rh/SulfoXantphos and NaOH. Side products include pentane
and alcohols. Conditions: Pentene (8.2 mmol, 0.9 mL), PEG-200 (0.4 mL), [Rh(acac)(CO)2]
(0.1 mol%), sulfoXantphos (0.2 mol%), NaOH (5 mol%), H2/CO (25 bar each), 16 h.
This journal is © The Royal Society of Chemistry 20xx
4 | J. Name., 2012, 00, 1-3
Please do not adjust margins

Page 5 of 8
Green Chemistry
Please do not adjust margins
Journal Name
ARTICLE
temperature, the conversion also increases up to 98% at 130 °C.
While at low temperatures hexanal is the main product, with
increasing temperatures more aldol product is formed. The
maximum of aldol product yield is obtained at 100 °C with 80%.
Above 100 °C the aldol yield drops again, as the further
hydrogenation to the saturated aldehyde becomes more and
more significant. The yield of additional side products, mostly
pentane and hexanol, stays low, at around 5% at all
temperatures up to 120 °C. Above 120 °C side product
formation increases strongly reaching up to 31% at 135 °C. The
data indicates that 100 °C is the best temperature to maximize
the aldol product yield, since the consecutive reaction to the
saturated aldehyde is still mostly suppressed. The sum of aldol
product and saturated aldol is high with 88% at 125 °C.
To foster the aldol reaction a closer look was given to the
deactivation of the base catalyst. Different bases were
employed and examined whether they react to formates during
the reaction. Therefore, we looked at a series of catalysts with
similar or slightly lower basic strength as NaOH (Table 3). KOH
showed a similar reactivity as NaOH and was also deactivated
(Table 3, entry 2). KOSiMe3 is less basic than NaOH with a pKa of
11. However, a comparable result was achieved with this
catalyst, even reaching a slightly higher aldol yield of 82%
(entry 3). Unfortunately, the formation of the formate anion
was also observed when using KOSiMe3. We assumed that
formate is formed from water in this case, CO and the basic
catalysts as illustrated in Scheme 4. This reaction sequence can
be generalized for all strong bases, as the presence of water
cannot be avoided since it is a by-product in the aldol
condensation. Surprisingly, a reaction with sodium methoxide
resulted in much less aldol product in comparison to the
previously tested bases, with only 35%, although it is also
deactivated by the reaction to the corresponding formate in the
same way (entry 4). Trimethylamine also performed worse than
NaOH with 54% yield of aldol product, but it was the only base
investigated that did not show the formation of formates during
the reaction (entry 5). Both results are probably connected to
the fact, that triethylamine is a neutral and not an ionic base
O
O
B
View Article Online
H2O
+
CO
+
+
B
B
H
DOI: 10.1039/D0GC03392H
H
OH
H
O
Scheme 4 Deactivation pathway of strong bases in presence of CO and H2O.
monophasic after the reaction when using triethylamine as a
base. We also wanted to verify that sodium formate is not active
as a catalyst in the aldol condensation, which was concluded for
the water system. Nevertheless, sodium formate lead exactly to
the same product distribution as NaOH (entry 6). This indicated
that sodium formate is the actual catalyst in the reaction and
not remaining NaOH. Consequently, recycling and reuse of the
aldol catalyst should be possible. We suspect that the aldol
condensation is catalysed by formate in PEG but not in water,
because formate is more basic in PEG. The pKa value for
formate in the comparable solvent 1,2-Ethanediol is much
higher with 7.3 than in water.40, 41Given that 1,2-Ethanediol and
PEG have similar functionalities, it is likely that a higher basicity
is found in PEG, too. Finally, we also tested lithium and caesium
formate to see the influence of the counterion. While lithium
formate performed worse with only 56% aldol product, caesium
formate resulted in the same aldol product yield as sodium
formate with 80% (entries 7-8).
After understanding the current catalysis system better, it was
tested for catalyst recycling. In order to verify the recyclability
of both catalysts, we therefore performed recycling
experiments over multiple runs with NaOH as initiator for the
aldol reaction. After each run the product phase separated from
the catalyst phase which was then extracted with pentane and
treated with high vacuum to remove any remaining product
traces. Afterwards new substrate was added for the next run.
After each run the product phase was analysed via GC-FID for
conversion and yields. The results for a nine-run experiment
with NaOH at 100 °C are displayed in Fig. 3. As it can be seen,
the pentene conversion stays constant between 96% and 97%
throughout all nine runs. Only in run 8, it drops slightly to 94%,
but increases to 97% in the final run again. A similar behaviour
is found for the yields of the products. The amount of aldol
Table 3 Comparison of different base catalysts in the hydroformylation/aldol
condensation reaction.a
base
catalyst
NaOH
KOH
KOSiMe3
NaOMe
NEt3
X
hexanalc aldol
Deacti-
vation?
b
Entry
pKa
[%]
97
98
97
98
99
97
97
97
[%]
12
13
11
56
43
12
37
13
[%]
80
78
82
35
54
80
56
80
1
2
3
4
5
6
7
8
14
14
11
15
10
3.8
3.8
3.8
yes
yes
yes
yes
no
-
d
NaHCO2
LiHCO2
CsHCO2
d
-
-
d
a Conditions: Pentene (8.2 mmol, 0.9 mL), PEG-200 (0.4 mL), [Rh(acac)(CO)2]
(0.1 mol%), sulfoXantphos (0.2 mol%), base (5 mol%), H2/CO (25 bar each), 100 °C,
16 h. b Acidity constant of the corresponding acid in water. c Both isomers, n:iso =
98:2 d Metal formate. Lithium formate was used as monohydrate.
Fig. 3 Recycling experiment of the hydroformylation/aldol condensation of 1-pentene in
PEG-200 with NaOH. For conditions see Table 3, entry 1. Side products include pentane
and alcohols.
product drops slightly from 81% in the first to 79% in the second
run but then only decreases one additional percentage point to
78% in the final run. In contrast, the hexanal yield increases
and intensifies the mixing of the two phases instead of
supporting their separation. In fact, the reaction mixture was
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 6 of 8
ARTICLE
Journal Name
from 9% to 12% in the first two runs and varies between 11% gases were conducted in 10 mL stainless steel high-pressure
View Article Online
DOI: 10.1039/D0GC03392H
and 13% afterwards. The amount of additional side products, autoclaves with glass inserts.
including pentane and hexanol, fluctuates between 2% and 4%.
Aldol Condensation Reactions in Water
The data clearly indicates the recyclability of this catalyst
system, as catalytic activity is maintained over nine experiments
for both reactions. All nine runs considered a total turnover
number of almost 8700 was reached regarding rhodium
compared to the 970 for a single run. The total turnover number
regarding sodium formate also increased from 16 to 150 due to
the recycling. In addition, we analysed the rhodium leaching by
In general, the aldol catalyst (5 mol%) was dissolved in water
(0.4 mL). The catalyst solution was heated to 65 °C and the
reaction was started by the addition of hexanal (1.0 mL,
8.2 mmol). The mixture was then stirred for 1.5 h, cooled down
and the organic phase was separated and analysed by GC-FID.
conducting ICP-MS measurements of the product phase after Hydroformylation/Aldol Condensation Tandem Reaction
each run. On average, a low rhodium leaching of only 800 ppb
In general, the aldol catalyst (5 mol%) was weighed into a glass
was observed, which equals a rhodium loss of 0.07% of the
insert, which was transferred to a 10 mL autoclave. The
initial rhodium amount per run. As far as we are aware, our
autoclave was filled with argon before adding the catalyst
system features the first successful recycling concept of the
solution consisting of [Rh(acac)(CO)2] (2.1 mg, 0.1 mol%) and
sulfoXantphos (12.8 mg, 0.2 mol%) in 0.4 mL water or PEG-200.
hydroformylation/aldol condensation tandem reaction.
After the addition of 1-pentene (0.9 mL, 8.2 mmol) the
autoclave was pressurized with CO (25 bar) and H2 (25 bar). The
mixture was stirred at 100 °C or 120 °C for a reaction time of
Conclusions
An orthogonal, multiphase catalyst system was developed for
the hydroformylation/aldol condensation tandem reaction with
the possibility to recycle both catalysts present in the reaction
mixture. Rhodium/sulfoXantphos initiates hydroformylation
and NaOH aldol condensation, using polyethylene glycol as
polar phase. The applicability of this system was demonstrated
in the conversion of 1-pentene to 2-butyloctenal with multiple
reuse of the catalysts. Besides NaOH, pyrrolidine and amino
acids were also tested as aldol catalysts, but they all suffered
from irreversible deactivation under hydroformylation
conditions. NaOH, too, is transformed under the conditions by
a reaction with CO to the less basic sodium formate.
Nevertheless, and despite being not active in water, formate is
able to catalyse the aldol condensation when polyethylene
glycol is used as catalyst phase. Therefore, it was possible to
reuse the catalyst system. In nine consecutive runs, the
recyclability was shown and a total turnover number regarding
rhodium of 8700 was achieved, with an average rhodium
leaching of 0.07% of the initial rhodium amount per run.
For future investigations, the substrate scope of the tandem
reaction will be expanded. Furthermore, in order to enable
cross aldol reactions, the aldol condensation must be
accelerated to be faster in comparison to the hydroformylation
step. Additionally, the reaction could be transferred to a
continuous flow set-up in which the long-term stability of the
catalyst can be investigated. For this, a solution must be
established to continuously remove the water, which is formed
as side-product, for example by membrane techniques.
16 h, before the autoclave was cooled down to room
temperature and vented carefully after the reaction. Then the
product phase was separated and analysed via GC-FID. Products
were not isolated, instead GC-Yields are presented in the text.
Recycling Experiments
The tandem reaction was conducted as described before. After
separation of the product phase, the catalyst phase was washed
with pentane to remove remaining product. Afterwards, the
catalyst solution was treated with high vacuum to remove the
rest of pentane. Then new 1-pentene was added, and the
mixture was pressurized with CO and H2 for the next run. After
each run, the product phase was analysed via GC-FID and ICP-
MS to determine the product distribution and the Rh-leaching,
respectively.
Analytics
Gas chromatography measurements were performed on a
Shimadzu Chromatograph Nexis GC-2030 equipped with a
CP Wax 52 CB column and an FID detector. Samples were
prepared by diluting 0.1 mL of product solution with 1 mL
heptane. The response factors of all compounds either were
determined by calibration or estimated using Sternberg’s
effective carbon method.42
1H-NMR spectra were recorded on a Bruker AV400 (400.2 MHz)
spectrometer using CDCl3 or D2O as solvent.
ICP-MS measurements were performed on a Shimadzu ICPMS-
2030. The measurement provided the Rh-content in mg per L of
product solution.
Experimental Section
General
Conflicts of interest
All reactions were carried out under argon inert gas atmosphere
by using standard Schlenk-techniques or a glovebox. Chemicals
were degassed before use and air-sensitive substances were
stored under argon. Hydrogen (5.0) and carbon monoxide were
supplied by Westfalen. All experiments including the use of
“There are no conflicts to declare”.
Acknowledgements
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 8
Green Chemistry
Please do not adjust margins
Journal Name
ARTICLE
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
J. Esteban, H. Warmeling and A. J. Vorholt, Catal. Commun.,
We gratefully acknowledge basic support and Open Access
funding by the Max Planck Society. We also would like to thank
the SusChemSys initiative for financial support.
View Article Online
2019, 129, 105721.
DOI: 10.1039/D0GC03392H
M. Vafaeezadeh and M. M. Hashemi, J. Mol. Liq., 2015,
207, 73-79.
J. Chen, S. K. Spear, J. G. Huddleston and R. D. Rogers,
Green Chem., 2005, 7, 64-82.
T. A. Faßbach, F. O. Sommer and A. J. Vorholt, Adv. Synth.
Catal., 2018, 360, 1473-1482.
P. W. N. M. van Leeuwen and P. C. J. Kamer, Catal. Sci.
Technol, 2018, 8, 26-113.
B. Hamers, P. S. Bäuerlein, C. Müller and D. Vogt, Adv.
Synth. Catal., 2008, 350, 332-342.
S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem.
Rev., 2007, 107, 5471-5569.
K. A. Ostrowski, D. Lichte, M. Stuck and A. J. Vorholt,
Tetrahedron, 2016, 72, 592-598.
T. Rösler, T. A. Faßbach, M. Schrimpf, A. J. Vorholt and W.
Leitner, Ind. Eng. Chem. Res., 2019, 58, 2421-2436.
V. S. Shende, V. B. Saptal and B. M. Bhanage, Chem. Rec.,
2019, 19, 2022-2043.
Notes and references
1.
2.
3.
H. Pellissier, Adv. Synth. Catal., 2016, 358, 2194-2259.
J. E. Camp, Eur. J. Org. Chem., 2017, 2017, 425-433.
J. A. Mata, F. E. Hahn and E. Peris, Chem. Sci., 2014, 5, 1723-
1732.
4.
5.
A. Behr, A. J. Vorholt, K. A. Ostrowski and T. Seidensticker,
Green Chem., 2014, 16, 982-1006.
R. Kourist and J. González-Sabín, ChemCatChem, 2020, 12,
1903-1912.
6.
7.
H. Pellissier, Org. Prep. Proced. Int., 2019, 51, 311-344.
D. E. Fogg and E. N. dos Santos, Coord. Chem. Rev., 2004,
248, 2365-2379.
8.
9.
T. L. Lohr and T. J. Marks, Nat. Chem., 2015, 7, 477-482.
R. Franke, D. Selent and A. Börner, Chem. Rev., 2012, 112,
5675-5732.
39.
40.
Á. Molnár and A. Papp, Coord. Chem. Rev., 2017, 349, 1-65.
A. Kütt, S. Selberg, I. Kaljurand, S. Tshepelevitsh, A.
Heering, A. Darnell, K. Kaupmees, M. Piirsalu and I. Leito,
Tetrahedron Lett., 2018, 59, 3738-3748.
J.-D. Yang, http://ibond.nankai.edu.cn
J. T. Scanlon and D. E. Willis, J. Chromatogr. Sci., 1985, 23,
333-340.
10.
11.
B. P. Bondžić, J. Mol. Catal. A: Chem., 2015, 408, 310-334.
P. Eilbracht, L. Bärfacker, C. Buss, C. Hollmann, B. E. Kitsos-
Rzychon, C. L. Kranemann, T. Rische, R. Roggenbuck and A.
Schmidt, Chem. Rev., 1999, 99, 3329-3366.
T. Gaide, J. Bianga, K. Schlipköter, A. Behr and A. J. Vorholt,
ACS Catal., 2017, 7, 4163-4171.
M. Vilches-Herrera, L. Domke and A. Börner, ACS Catal.,
2014, 4, 1706-1724.
P. Kalck and M. Urrutigoity, Chem. Rev., 2018, 118, 3833-
3861.
P. Eilbracht and A. M. Schmidt, in Catalytic Carbonylation
Reactions, ed. M. Beller, Springer Berlin Heidelberg, Berlin,
Heidelberg, 2006, DOI: 10.1007/3418_017, pp. 65-95.
C. Plass, A. Hinzmann, M. Terhorst, W. Brauer, K. Oike, H.
Yavuzer, Y. Asano, A. J. Vorholt, T. Betke and H. Gröger, ACS
Catal., 2019, 9, 5198-5203.
41.
42.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
K. A. Ostrowski, T. A. Faßbach, D. Vogelsang and A. J.
Vorholt, ChemCatChem, 2015, 7, 2607-2613.
T.-S. Jiang and J.-H. Li, Chem. Commun., 2009, DOI:
10.1039/B917782E, 7236-7238.
X. Fang, R. Jackstell, R. Franke and M. Beller, Chem. Eur. J.,
2014, 20, 13210-13216.
S. K. Sharma, P. A. Parikh and R. V. Jasra, J. Mol. Catal. A:
Chem., 2009, 301, 31-38.
S. K. Sharma, V. K. Srivastava, R. S. Shukla, P. A. Parikh and
R. V. Jasra, New J. Chem., 2007, 31, 277-286.
V. K. Srivastava, S. K. Sharma, R. S. Shukla and R. V. Jasra,
Catal. Commun., 2006, 7, 879-884.
23.
24.
W. Keim, Angew. Chem. Int. Ed., 2013, 52, 12492-12496.
C. W. Kohlpaintner, R. W. Fischer and B. Cornils, Appl.
Catal., A, 2001, 221, 219-225.
25.
Y.-l. Liu, J.-g. Zhao, Y.-j. Zhao, H.-M. Liu, H.-y. Fu, X.-l. Zheng,
M.-l. Yuan, R.-x. Li and H. Chen, RSC Adv., 2019, 9, 7382-
7387.
26.
27.
28.
Y. Zhao, Y. Liu, J. Wei, H. Fu, X. Zheng, M. Yuan, R. Li and H.
Chen, Catal. Lett., 2018, 148, 438-442.
X. Jin, J. Feng, Q. Ma, H. Song, Q. Liu, B. Xu, M. Zhang, S. Li
and S. Yu, Green Chem., 2019, 21, 3267-3275.
S. Wesselbaum, U. Hintermair and W. Leitner, Angew.
Chem. Int. Ed., 2012, 51, 8585-8588.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Green Chemistry
Page 8 of 8
View Article Online
DOI: 10.1039/D0GC03392H
TOC
80x39mm (300 x 300 DPI)