Use of a switchable-hydrophilicity solvent as both a solvent and a catalyst in aldol condensation

Article abstract of DOI:10.1039/c9gc02593f

A switchable-hydrophilicity solvent, N,N-dimethylcyclohexylamine, was used as a recyclable catalyst and solvent for aldol condensation, giving >97% pure product in 94% isolated yield without the need for purification or additional solvents. CO₂-triggered separation produced yields greater than conventional workup and allowed facile recycling of the amine.

Full text of DOI:10.1039/c9gc02593f

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Use of a switchable-hydrophilicity solvent as both
a solvent and a catalyst in aldol condensation†
Cite this: Green Chem., 2019, 21,
6263
Hailey Poole,a Jeremy Gauthier,a Jesse R. Vanderveen, b Philip G. Jessop b and
Received 25th July 2019,
Accepted 6th November 2019
a
Roland Lee
*
DOI: 10.1039/c9gc02593f
rsc.li/greenchem
A
switchable-hydrophilicity solvent, N,N-dimethylcyclohexyl- tiple uses.6 Kantam et al. (1998) used a solid base Mg–Al
amine, was used as a recyclable catalyst and solvent for aldol con- hydrotalcite catalyst to catalyse aldol condensations.6 With this
densation, giving >97% pure product in 94% isolated yield without catalyst they showed ≥98% yield for the reaction of various
the need for purification or additional solvents. CO2-triggered sep- aldehydes with acetone.6
aration produced yields greater than conventional workup and
As an alternative to solid heterogeneous catalysis, there has
been other work looking at the use of CO2 as a readily-remova-
ble acid catalyst in a number of dehydration and aldol conden-
sation reactions.7–9 For example, Lee et al. (2016) used CO2 as
a catalyst in the production of bio-jet fuel precursors by an
aldol reaction of acetone with sugar-derived 5-hydroxymethyl
furfural (5-HMF).7
In many reaction systems, none of the starting material
and/or catalyst can be recycled and are thus considered wastes;
there is therefore a need for alternative methods that facilitate
post-reaction separations in a way that permits recycling of as
many materials as possible.10 There has been recent research
looking into alternative separation systems such as the use of
CO2 switchable solvents, catalysts, and other materials.11–13
For example, Groβeheilmann and Kragl (2017) used CO2-trig-
gered separation after a Henry reaction through the use of
switchable organocatalysts.12 Su et al. (2018) showed the
post-polymerization purification of ATRP polymers through
the use of CO2 switchable solvents; this allows the removal of
the copper catalyst in addition to recovery and reuse of the
ligand.13 Furthermore, reversible ionic liquids have demon-
allowed facile recycling of the amine.
Introduction
Aldol reactions are effective C–C bond forming reactions.1
These reactions have been studied extensively for the pro-
duction of various pharmaceutical compounds and precursors,
in addition to fragrances and synthetic flavonoids.1,2 The cata-
lyst for most industrial aldol reactions is typically a strong,
soluble inorganic base such as sodium hydroxide or potassium
hydroxide.1 In many of the industries that utilize aldol conden-
sation as a process step, the strong base catalyst can impact
downstream processes and has to be removed or neutralized,
thereby increasing the energy consumption of the process and
generating inorganic waste.1 Isolation of the products typically
requires volatile solvents, which add to the environmental
impacts and pose flammability and inhalation risks to the
workers.1,3,4 In addition, waste treatment adds to both process
complexity and costs.5
strated the ability to have
a built-in separation system
In order to lower the environmental impact of the aldol
reaction, researchers have looked at alternative catalysts or
promoters.1,6–9 For example, a solid heterogeneous catalyst is
easily removed from the product mixture, allowing it to be
reused, lowering the energy costs of post-reaction separations
and amortizing the harm from catalyst preparation over mul-
for recovery of products and catalysts and recycling of sol-
vents.14 Hart et al. (2010) demonstrated Claisen-Schmidt con-
densations using
a
guanidine-based switchable-polarity
solvent (SPS).14 In this case, product isolation was accom-
plished by switching the polarity of the solvent by adding
methanol and CO2; the products were then extracted with
octane.
aMacEwan University, Department of Physical Sciences, Canada.
E-mail: leer86@macewan.ca
bQueen’s University, Department of Chemistry, Canada
Switchable solvents are solvents that can switch between
two forms by a simple change in the system.15 For example,
switchable hydrophilicity solvents (SHS) have a hydrophobic
neutral form that is poorly miscible with water and a charged,
hydrophilic form that is completely miscible with water.15
†Electronic supplementary information (ESI) available: Materials and methods;
1H NMR spectroscopy of aldol condensation products from Tables 1 and 2;
qHNMR calculation. See DOI: 10.1039/c9gc02593f
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Table 1 Aldol condensation of acetone (34.4 mmol, 2.0 ml) and
various aromatic aldehydes catalysed by DMCHA and isolated using
either a conventional hydrochloric acid workup (method A) or CO2 sep-
aration (method B)
SHSs have been shown to serve as both solvent and catalyst for
the transesterification of soybean oil.16 Viner et al. (2019) used
2-(dibutylamino)ethanol as a catalyst for transesterification.
Carbonated water was used to extract the SHS from the biodie-
sel produced. Viner et al. obtained an 85% product yield and
92% recovery of SHS.16
The work presented here looks at the use of an SHS, in
combination with water, as an alternative solvent/catalyst
system for aldol condensation. N,N-Dimethylcyclohexylamine
(DMCHA) is an SHS that can switch hydrophilicity upon
addition or removal of CO2 from the system. Thanks to this
switching ability it is possible to recover and recycle the SHS,
with the aldol condensation product being filtered off, elimi-
nating the need for further purification steps.
Entry
Method workup
Aldehyde
Yield (%)
1
2
A
A
A
A
B
B
B
B
B
B
B
B
B
B
Benzaldehyde
HMF
29
38
15
0
84
83
83
92
75
83
94
0
3
p-Anisaldehyde
p-Anisaldehyde
3-Methoxybenzaldehyde
4-Bromobenzaldehyde
4-Hydroxybenzaldehyde
Benzaldehyde
o-Anisaldehyde
p-Anisaldehyde
p-Anisaldehyde
p-Anisaldehyde
p-Anisaldehyde
p-Anisaldehyde
4a
5
6
7
8
9
10
11b
12c
13d
14a
79
0
Results and discussion
Reaction conditions: (Method A) aldehyde, 0.10 g; ketone, 2.0 ml;
DMCHA 1.0 ml; water, 2.0 ml; reflux 70 °C 24 h hydrochloric acid
workup. Column chromatography purification, hexane : ethyl acetate,
9 : 1 for entries 1 and 3, and 1 : 1 for entry 2. (Method B) aldehyde,
0.10 g; ketone, 2.0 ml; DMCHA 1.0 ml; water, 2.0 ml; reflux 70 °C 24 h
CO2 separation. a Negative control; no DMCHA present. b Aldehyde,
10.0 g. c Instead of DMCHA used 1.0 ml of 2-(dibutylamino)ethanol.
d Instead of DMCHA used 1.0 ml of triethylamine.
An SHS, DMCHA, is proposed for use as both an alternative
catalyst and solvent for aldol condensation, with the expec-
tation that this choice should facilitate post-reaction separ-
ation of the product from SHS and the recycling of the latter.
Aldehydes capable of aldol condensation range from simple
to complex aromatic structures. Aliphatic aldehydes were
initially tested, but self-condensation was observed. Aromatic
aldehydes were then chosen based on their ability to be separ-
ated, as many small molecule aldehydes are soluble in water,
we assumed that unreacted aldehyde would remain in the
aqueous phase while the product, being more hydrophobic in
most cases, would be water-insoluble. The products made are
of interest because they can be found in industrial processes
as precursors to bio-jet fuel, sunscreens, fragrances and
flavonoids.1,2,7,17
Fig. 1 depicts two protocols for the aldol condensation of
acetone with an aldehyde catalysed by DMCHA. Method A
used a conventional work up protocol with HCl to neutralize
the base, while method B used a CO2-triggered separation
protocol.
The aldol condensation was performed using a number of
different aldehydes (shown in Table 1), plus acetone, DMCHA
and water. After the reaction takes place, the product has to be
extracted. In method A, hydrochloric acid was used to proto-
nate the DMCHA, making the SHS water-soluble. However,
this process leads to salt formation of the DMCHA and HCl,
making the catalyst non-recyclable. Additional solvents such as
ethyl acetate are incorporated in order to isolate the product.
Once the product is isolated it is then purified using column
chromatography. The additional solvents used to isolate and
purify the product add to the overall waste generated by the
process. In method B, CO2 is sparged through the system for
30 minutes converting DMCHA into a water-soluble bicarbon-
ate salt, causing it to partition into the carbonated water layer
along with any water-soluble starting material. The product
can then be removed by decantation/filtration. CO2 can be
removed from the carbonated water by refluxing to restore the
hydrophobic form of the DMCHA, which phase separates from
the water, facilitating the recycling of both the amine and the
water.
Table 1 shows the aldehydes that were reacted with acetone
in the DMCHA facilitated aldol condensation using both
method A and method B workups. The aldol condensation of
acetone with benzaldehyde, HMF, and p-anisaldehyde had
moderate to low isolated yields of the mono-aldol conden-
sation product, ranging from 15–38% using the conventional
workup procedure (Table 1). Although the yields are low, they
demonstrate that DMCHA can be used as a catalyst in aldol
condensation.
The advantage of using an SHS for aldol condensation is
that we can manipulate the system using CO2. By using CO2 we
are able to make the SHS water-soluble and extract it, along
with any water-soluble starting material, from the product into
carbonated water. This benign separation system eliminates
Fig. 1 Two protocols for the DMCHA facilitated aldol condensation
using
a traditional hydrochloric acid and organic solvent workup
(method A) or CO2 separation workup (method B).
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Table 2 Aldol condensation product yield of p-anisaldehyde and
acetone using recycled DMCHA recovered by CO2 separation. Trial 1
involved 24 h reaction times and no replenishment of solvent losses at
the end of each cycle. Trial 2 involved 48 h reaction times and no
replenishment of solvent losses at the end of each cycle. Trial 3 involved
24 h reaction times with replenishment of solvent losses at the end of
each cycle. Trial 4 involved 24 h reaction times in a sealed glassware
water bath and no replenishment of solvent losses at the end of each
cycle
the need to introduce any additional organic solvents or purifi-
cation steps. It is important to note that this methodology
would not be effective for separating the amine from water
soluble products.
The isolated yields after the CO2 workup were significantly
greater than those after the conventional hydrochloric acid
workup. The isolated yield was 5X greater when the CO2
workup was used (entry 10) than when the hydrochloric acid
workup was used (entry 3). This increase in yield is attributed
to the simplicity of the CO2 separation as there is no need for
additional solvent extractions or purification and therefore
fewer opportunities for product loss.
Cycle 1
Trial yield (%)
Cycle 2
yield (%)
Cycle 3
yield (%)
Cycle 4
yield (%)
Cycle 5
yield (%)
1
2
3
4
83
76
77
83
4
1
0
0
76
66
69
83
1
4
0
0
66
66
73
77
4
1
4
4
62
62
66
76
2
2
4
2
57
0
61
73
5
When the reaction is performed on a larger scale the iso-
lated yield increased from 83% to 94% (entries 10 and 11 in
Table 1, Fig. S1 and S2†). This increase in the yield is due to
reduced loss of sample during sample work up procedure.
qHNMR was used to analyse purity of the final product
9
1
Reaction conditions: (1) aldehyde, 0.10 g; ketone, 2.0 ml; DMCHA
1.0 ml; water, 2.0 ml; reflux 70 °C 24 h. (2) aldehyde, 0.10 g; ketone,
2.0 ml; DMCHA 1.0 ml; water, 2.0 ml; reflux 70 °C 48 h. (3) aldehyde,
0.10 g; ketone, 2.0 ml; DMCHA 1.0 ml; water, 2.0 ml; reflux 70 °C 24 h.
(4) aldehyde, 0.10 g; ketone, 2.0 ml; DMCHA 1.0 ml; water, 2.0 ml;
sealed glassware 70 °C 24 h.
1
(entry 11).18 The only impurity observed in the H NMR spec-
trum was water (Fig. S3†). qHNMR does not take into consider-
ation water as an impurity making the purity >99%. However,
if we take into consideration water as an impurity we obtain
>97% purity of our final product (Fig. S3†).
recycled DMCHA recovered at the end of the previous batch,
Additional aldehydes were tested to further demonstrate without any fresh DMCHA to make up for losses. Water was
the ability of DMCHA to catalyse the aldol condensation as also recycled from the previous batch to reduce SHS losses and
well as the ability of CO2 to facilitate the subsequent product reduce water consumption.
separation (Table 1). 1H NMR spectroscopy showed that high
The initial trial was performed with 24 h reflux demonstrat-
selectivity to the mono-addition product was found with no ing that DMCHA can be recycled, albeit with slowly decreasing
double-addition detected in any of the products formed yields (trial 1 of Table 2). The decrease in yield was thought to
(Fig. S2†). HMF was not reacted using CO2 separation, as the be due to the loss of DMCHA due to evaporation during reflux.
product appeared to be water-soluble and could not therefore 1H NMR spectroscopy of the products produced through trial 1
be recovered using the CO2 workup protocol.
indicated significant amounts of starting material left in the
Other SHSs were used to test their effectiveness to catalyse product mixture of all the subsequent cycles (Fig. S4†). From
the aldol condensation in comparison to DMCHA. In entry 12, this it is noted that the synthesis is not as efficient as
the aldol condensation of acetone and p-anisaldehyde was cat- envisioned.
alysed by 2-(dibutylamino)ethanol (2-DBAE), but no product
A second trial was conducted, using prolonged reaction
was formed (Table 1), presumably because 2-DBAE (pKa 9.67) times of 48 h reflux to enhance completion of the product.
is a weaker base than DMCHA (pKa 10.48). In entry 13, the However that change also increased the amount of DMCHA
aldol condensation of acetone and p-anisaldehyde was cata- lost during the reflux so that insufficient DMCHA was left in
lysed by triethylamine (pKa 10.68), an SHS with similar basicity the last cycle to promote the reaction (trial 2 of Table 2,
as DMCHA, giving yields similar to that obtained with DMCHA Fig. S5†). This problem was corrected in the third trial, where
(Table 1).19 These results demonstrate the importance of SHS the total amount of DMCHA used in each cycle was kept con-
basicity when performing aldol condensations.
stant by supplementing the recycled DMCHA with fresh
The recyclability of DMCHA was assessed over four different DMCHA equivalent to the amount lost in the previous cycle.
experimental trials of 5 cycles each, with a cycle being defined This resulted in more consistent yields over the five cycles
as the entire process depicted in Fig. 1 using method B. The (trial 3 of Table 2, Fig. S6†).
product formed from the aldol condensation of p-anisaldehyde
Given that DMCHA is a volatile SHS, a fourth trial was con-
and acetone is a pale-yellow precipitate, which can be easily ducted inside sealed glassware in a water bath rather than
removed from the carbonated water/SHS liquid mixture by fil- allowing reflux. This method would prevent DMCHA evapor-
tration. We therefore used this reaction to test the recyclability ation out of the system. In this trial the catalyst remained in
of DMCHA. The yield of the aldol condensation product of the system and was able to be fully recycled in order to
p-anisaldehyde and acetone over the different trials is shown produce substantial yields with each recycled experiment
in Table 2.
without need for supplemental DMCHA (trial 4 of Table 2).
1
Recycling the SHS may result in some losses of SHS in each The H NMR spectrum of trial 4 further confirmed the main-
cycle. When a sequence of five cycles was performed with SHS tenance of the DMCHA in the system as no indications of
recycling, cycle 1 used fresh DMCHA from the reagent bottle, impurities or starting material were observed in the products
but the DMCHA used in subsequent cycles was only the of the later cycles. The peak at 1.56 ppm is water, which is not
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hydrolysis of the CvN bond and by formation of a bicarbonate
salt, both of which interfere with the switching of the SPS.14
Switchable amine SHS can be used in the presence of water.
Conclusions
This work presents successful examples of aldol condensation
using DMCHA as both solvent and catalyst for aldol conden-
sation. The simple process of using a CO2 switchable catalyst,
DMCHA, allows for recyclability of the solvent and catalyst,
with minimal organic waste. The recyclability of the catalyst
has major environmental advantages with respect to solvent/
catalyst reuse leading to less chemical waste. Clean separation
of products can be achieved without the need for additional
solvents or purification. An environmental disadvantage to
this procedure is that DMCHA is a fairly volatile organic com-
pound; future work will explore the use of non-volatile SHSs.19
Fig. 2 1H NMR spectra of the filtered product after DMCHA-promoted
aldol condensation of p-anisaldehyde with acetone using repeatedly
recycled DMCHA and the CO2-triggered separation protocol. Trial 4
cycle 1 (top) – cycle 5 (bottom).
considered an impurity (Fig. 2).18 The peaks assigned to the
aldol condensation products were comparable to literature
Conflicts of interest
data. This indicates that selectivity to the mono-aldol product PGJ is an inventor on patent applications for the SHS
is high with no double addition products noted (Fig. 2).20,21 technology.
The overall loss of DMCHA was 25% following the five cycles
in trial 4.
This work demonstrates the use of an SHS as both a solvent
and a catalyst for aldol condensation. Conventionally the aldol
Acknowledgements
condensation is performed using a strong inorganic base cata- The authors gratefully acknowledge financial support from
lyst.1 The major drawback of these catalysts is their non-recycl- MacEwan University’s internal project grant.
ability due to conventional acid workup leading to generation
of inorganic waste.1 Further purification of the product is gen-
erally required, the common purification processes are recrys-
tallization; and column chromatography, both of which
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