Driving an equilibrium acetalization to completion in the presence of water

Article abstract of DOI:10.1039/c4ra07116f

Formation of an acetal from a carbonyl substrate by condensation with an alcohol is a classical reversible equilibrium reaction in which the water formed must be removed to drive the reaction to completion. A new method has been developed for acetalization of carbonyl substrates by diols in the presence of water. Complexation of poly(4-styrenesulfonic acid) with poly(4-vinylpyridine) generates a catalytic membrane of polymeric acid at the interface between two parallel laminar flows in a microchannel of a microflow reactor. The catalytic membrane provides a permeable barrier between the organic layer and water-containing layer in the reaction, and permits discharge of water to the outlet of the microreactor to complete the acetalization. Condensation of a variety of carbonyl substrates with diols proceeded in the presence of water in the microflow device to give the corresponding acetals in yields of up to 97% for residence times of 19 to 38 s. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra07116f

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Driving an equilibrium acetalization to completion
in the presence of water†
Cite this: RSC Adv., 2014, 4, 36864
a
a
ab
*
Maki Minakawa, Yoichi M. A. Yamada and Yasuhiro Uozumi
Received 15th July 2014
Accepted 13th August 2014
DOI: 10.1039/c4ra07116f
www.rsc.org/advances
Formation of an acetal from a carbonyl substrate by condensation with from cyclohexanone (1a) and ethylene glycol (2a) described in
an alcohol is a classical reversible equilibrium reaction in which the Organic Syntheses involves performing the reaction in the
water formed must be removed to drive the reaction to completion. A presence of 4-toluenesulfonic acid as an acid catalyst in
new method has been developed for acetalization of carbonyl reuxing benzene for six hours with azeotropic removal of water
substrates by diols in the presence of water. Complexation of poly(4- by means of a Dean–Stark condenser; this procedure gives the
styrenesulfonic acid) with poly(4-vinylpyridine) generates a catalytic acetal, 1,4-dioxaspiro[4.5]decane (3a), in 75–85% yield (Fig. 2b).4
membrane of polymeric acid at the interface between two parallel This is the most basic method for acetal formation. When this
laminar flows in a microchannel of a microflow reactor. The catalytic reaction is performed at 50 ꢀC under equilibrium conditions
membrane provides a permeable barrier between the organic layer and without the use of the Dean–Stark condenser, the product 3a is
water-containing layer in the reaction, and permits discharge of water obtained in a low yield (see below). Therefore, even in classical
to the outlet of the microreactor to complete the acetalization. organic transformations, there are serious problems that need
Condensation of a variety of carbonyl substrates with diols proceeded to be overcome conceptually to permit equilibrium and revers-
in the presence of water in the microflow device to give the corre- ible reactions to proceed to completion.
sponding acetals in yields of up to 97% for residence times of 19 to 38 s.
Recently, microchannel systems that offer many funda-
mental and practical advantages have been developed for
organic transformations.7–15 By using our molecular convolu-
tion methodology, we have been able to fabricate a range of
palladium-containing polymeric membrane catalysts inside
microchannel reactors at the laminar ow interfaces in the
channels.16–19 A catalytic membrane is formed along the center
of a microchannel and then two reactants are introduced from
opposite sides of the membrane and ow through the divided
channel in contact with the large-area interfacial surfaces of the
membrane from the front and the rear, thereby realizing an
instantaneous chemical reaction. We surmised that a catalytic
membrane inside a microow reactor might provide a phase
barrier between a layer of a solution of a carbonyl compound in
an organic solvent and a layer of a diol in an acetalization
reaction.20–24 The dehydrative condensation reaction should
proceed under the inuence of the driving force of permeation
of the reactants through the catalytic membrane, so that the
resulting product and water are separated from one another and
taken up into the organic solvent and diol layers, respectively.
Eventually, water is discharged in the diol layer emerging from
the outlet of the catalytic membrane-containing microow
reactor, driving the equilibrium in the direction of completion
of the acetalization reaction (Fig. 1, le). We developed a novel
microchannel reactor containing a catalytic polymer acid
Introduction
It is widely accepted in the chemical and biochemical literature
that equilibrium constants for reversible catalytic, noncatalytic,
and enzymatic chemical reactions all have constant values.
Under equilibrium conditions, the concentrations of the prod-
ucts reach steady values that are determined by entropy.1
The acetalization of a carbonyl substrate by an alcohol is a
representative example of a reversible reaction that reaches
equilibrium.2,3 This reaction is one of the most basic and clas-
sical reversible reactions in organic chemistry in which the
products and reactants are in equilibrium. In the case of the
reversible reaction of a carbonyl substrate with a diol, the only
products are the corresponding acetal and water. To drive the
reaction toward completion by shiing the equilibrium, the
water that is formed must be removed by physical4 or chemical
methods.5,6 For example, the standard preparation of the acetal
aRIKEN Center for Sustainable Resource Science, Hirosawa, Wako, Saitama 351-0198,
Japan. E-mail: uo@riken.jp; Fax: +81 48 467 1423; Tel: +81 48 467 9406
bInstitute for Molecular Science, Myodaiji, Okazaki, Aichi 444-8787, Japan. E-mail:
uo@ims.ac.jp; Fax: +81 564 95 5574; Tel: +81 564 59 5571
† Electronic supplementary information (ESI) available: Materials, Methods, NMR
and GC Charts. See DOI: 10.1039/c4ra07116f
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Fig. 1 Schematic showing the preparation of the polymeric acid catalyst membrane-containing microchannel reactor (top left) and its appli-
cation in acetal formation by a flow reaction (bottom left), together with an optical micrograph of the microreactor (top right) and a scanning
electron micrograph of the polymeric acid membrane (bottom right).
acid) and a 1.0 mM solution of poly(4-vinylpyridine) in
propan-2-ol were continuously injected from syringe pumps
into the opposite branches of the Y-shaped microchannel of the
microreactor at 24 ꢀC at equal ow rates of 10 mL minÀ1. A two-
phase parallel laminar ow formed in the central microchannel,
and a polymeric membrane precipitated at the interface
between the two phases. Optical micrographs showed that a
sheet of polymeric membrane 20 mm thick, 40 mm high, and 20–
40 mm long was formed at the interface between the laminar
ows in the microchannel (Fig. 1, right top). A high-resolution
scanning electron micrograph revealed that the membrane
Fig. 2 Formation of the acetal in the microreactor and in batch
experiments.
had a mesoporous structure that provided a large surface area
(Fig. 1, right bottom). Elemental analysis indicated that the
ratio of poly(4-styrenesulfonic acid) to poly(4-vinylpyridine) in
the membrane was 1.75 : 1. Attenuated total reectance
infrared spectroscopic studies showed that, whereas the C]N
stretching absorption of the pyridine ring in poly(4-
vinylpyridine) is normally observed at 1470 cmÀ1, the poly-
meric membrane showed a new absorption peak at 1550 cmÀ1
and no peak at 1470 cmÀ1. This indicated that the pyridine
moiety in poly(4-vinylpyridine) had reacted with the poly(4-
styrenesulfonic acid) to give the corresponding pyridinium
sulfonate salt. The membrane in the microreactor contained
0.02 mmol per 10 mm of sulfonate. When water at neutral pH
was introduced from the inlet and passed through the micro-
ow reactor, the water at the outlet remained at a pH of 7.
Having prepared the polymeric acid membrane-containing
microreactor, we proceeded to investigate the formation of an
acetal in a ow reaction (Fig. 2).29–34 Ethylene glycol (2a) and a
4.8 M solution of cyclohexanone (1a) in toluene were introduced
from the opposite branches of the Y-shaped channel into the
central membrane-separated channel at 50 ꢀC and a ow rate of
0.2 mL minÀ1 for the cyclohexanone and 0.1 mL minÀ1 for
ethylene glycol. The two parallel laminar layers were passed
through the membrane-separated channel with a residence
membrane at the interface between two parallel laminar layers
of reactant and we applied it in the acetalization of a number of
carbonyl substrates with several diols in the presence of water to
give the corresponding acetal products in yields of up to 93%
within residence times of 19–38 s.
Results and discussion
The preparation of the polymeric acid membrane in the
microchannel is shown schematically in Fig. 1. Whitesides and
co-workers originally reported the deposition of a polymer
membrane at a laminar interface between solutions of a sulfo-
nate salt and a polymeric ammonium salt.25–27 However, to the
best of our knowledge, apart from our previous studies,16–19
there have been no reports in the literature on interfacial
deposition of membranes with the aim of using them as cata-
lytic membranes. We formed a catalytic acid membrane inside a
glass microchannel reactor with a Y-junction and a channel
pattern measuring 100 mm wide, 40 mm deep, and 20 or 40 mm
long.28 A 60 mM aqueous solution of poly(4-styrenesulfonic
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time of 19 s. The organic/ethylene glycol microstream that
emerged from the channel was collected at the outlet.
The chemical conversion and the structure of the products
were determined by gas chromatography and 1H NMR spec-
troscopy, respectively. We were pleased to nd that the micro-
channel reactor with the poly(4-styrenesulfonic acid)–poly(4-
vinylpyridine) membrane successfully promoted the catalytic
reaction of ketone 1a with diol 2a at 50 ꢀC to give acetal 3a with
80% yield within a residence time of 19 s.33,34 A 0.1 M solution of
1a similarly afforded the acetal in 97% yield. Furthermore, the
polymeric acid catalyst-containing microchannel reactor
showed superior performance in acetal formation without any
additional mechanism for removal of water. The catalytic
membrane in the microow device provides a phase barrier
between the organic solvent and water-containing diol layers, so
that the water that forms is discharged from the outlet of the
microreactor, driving the formation of the acetal toward
completion. In contrast, the formation of the acetal from ketone
ꢀ
1a with diol 2a without separation of water in toluene at 50 C
under batch conditions gave 3a in 36% and 42% yield in 6 and
24 hours, respectively.
Fig. 3 Formation of acetals from aldehydes or ketones with diols in
the polymeric acid catalyst-containing microchannel reactor. Reac-
tion conditions: 1 (0.1 M, toluene, flow rate: 0.1 mL minÀ1), 2 (neat, flow
We then used the polymeric acid-containing microchannel
reactor to prepare acetals from a range of aldehydes and
ketones with various diols. The formation of acetals from the
aliphatic aldehydes hexanal (1b), heptanal (1c), and octanal (1d)
with 2a, carried out under similar conditions, gave 2-pentyl-1,3-
dioxolane (3b; 86%), 2-hexyl-1,3-dioxolane (3c; 85%), and 2-
heptyl-1,3-dioxolane (3d; 97%), respectively, within a residence
time of 19 s (Fig. 3); no polymerization side reactions were
observed. (2E)-Hex-2-enal (1e) was converted into acetal 3e in
68% yield at 80 ꢀC and a residence time of 38 s; decomposition
of the acid-labile substrate and product as well as deconjuga-
tion of the olen were not detected. The reaction of the aromatic
aldehydes benzaldehyde (1f) and 4-bromobenzaldehyde (1g)
with 2a in the microchannel reactor at 80 ꢀC gave the corre-
sponding 1,3-dioxolanes 3f and 3g in 84% and 90% yield,
respectively. Hetaryl aldehydes 1h and 1i similarly reacted with
2a to give acetals 3h and 3i in 86% and 73% yield, respectively.
The reaction of 2-methylcyclohexan-1-one (1j) with diol 2a gave
6-methyl-1,4-dioxaspiro[4.5]decane (3j) in 77% yield, and the
corresponding reaction of tert-butyl 4-oxopiperidine-1-
carboxylate (1k) gave the 1,3-dioxolane 3k in 86% yield
without damage to the acid-sensitive tert-butoxycarbonyl group.
The reaction of bicyclic octahydronaphthalen-1(2H)-one (1l)
gave acetal 3l in 88% yield. The monoacetal from the Wieland–
Miescher ketone 1m gave the corresponding monoacetal 3m in
64% yield in which no deconjugation of the alkene was
observed. The reaction of cyclohexanone (1a) with propane-1,3-
diol (2b) gave the corresponding 1,3-dioxane 3n in 87% yield.
The collected stream emerging from the outlet automatically
separated to permit isolation of the acetal product with high
purity. The upper layer of the collected sample, which consisted
of a toluene phase containing the acetal, was decanted by
continuous pumping (Fig. 4). Therefore, a desired acetal can be
readily and automatically obtained by using our microdevice
(a)
rate: 0.1 mL minÀ1);
microchannel reactor (length: 20 mm), 50 ꢀC;
(b)
(c)
microchannel reactor (length: 40 mm), 80 ꢀC;
reactor (length: 40 mm), 100 ꢀC.
microchannel
Fig. 4 Automatic separation of the product stream from the micro-
flow acetalization reaction in the microreactor.
Conclusions
In conclusion, we have developed a novel catalytic system for
equilibrium and reversible reactions. A novel polymeric acid
membrane was prepared inside a microchannel reactor at the
interface between two laminar ows through ionic interaction
of poly(4-styrenesulfonic acid) with poly(4-vinylpyridine). The
microchannel reactor was used to form acetals from various
aldehydes and ketones, without additional separation of water,
to give the corresponding acetal products. The ow acetaliza-
tion system permitted automatic separation of the products
(which were present in the toluene layer) and water (which was
present in the diol layer). Attempts are underway to apply this
novel concept to a variety of equilibrium and reversible
reactions.
Acknowledgements
system without the need to consider any equilibrium and Partial nancial support was provided by the JSPS (Grant-in-Aid
reversible reactions.
for Scientic Research #20655035; Grant-in-Aid for Scientic
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Research on Innovative Area #2105), the JST (CREST and ACT-C) 17 Y. M. A. Yamada, T. Watanabe, K. Torii and Y. Uozumi,
and the RIKEN Advanced Science Institute (Fund for Seeds of Chem. Commun., 2009, 5594–5596.
Collaborative Research). We thank Ms. A. Ohno of our project 18 Y. M. A. Yamada, T. Watanabe, T. Beppu, N. Fukuyama,
team for the SEM observations. We are also grateful to the
RIKEN ASI Advanced Technology Support Division for
elemental analysis (Dr Yoshio Sakaguchi).
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