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TUTORIAL REVIEW

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www.rsc.org/csr

Continuous reactions in supercritical carbon dioxide: problems, solutions

and possible ways forwardw
Xue Han and Martyn Poliako
Received 18th November 2011
DOI: 10.1039/c2cs15314a
This Tutorial Review focuses on supercritical carbon dioxide (scCO2), and discusses some of the
problems that have frustrated its wide use on an industrial scale. It gives some recent examples
where strategies have been developed to reduce the energy requirements, including sequential
reactions and gas-expanded liquids. It then describes a number of cases where scCO2 oers real
chemical advantages over more conventional solvents, for example by controlled phase
separation, tunable selectivity, oxidation and on-line analysis and self-optimisation. Overall, this
review indicates where scCO2 could deliver value in the future.

Introduction
Ever since the birth of Green Chemistry, solvents have occupied
a central place in the eort to make chemical processes greener.
This is because solvents often contribute a disproportionately
large amount to the waste generated in a given process,
particularly if that process involves many purication steps.
Solvents are not normally incorporated into nal products and,
although recycle is possible, the solvents are eventually lost to
the environment or require disposal as waste. Furthermore,
since most of the solvents in current use are derived directly or
indirectly from petroleum, there are signicant drivers to nd
replacements which have a greener life cycle and reduced
environmental impact.14

The School of Chemistry, The University of Nottingham, Nottingham,

NG7 2RD, UK. E-mail: Martyn.Poliako@nottingham.ac.uk
w Part of a themed issue covering the latest developments in green
chemistry.

Xue Han

1428

Born in Hebei, China, Xue Han

received her BSc degree in
Chemistry at Peking University
in 2007. She then started working on photochemical reactions
in scCO2 at the University of
Nottingham under the supervision of Prof. Michael W. George
and Prof. Martyn Poliako and
obtained her PhD degree in
Chemistry in 2010. She is now
a postdoctoral researcher at
Nottingham, studying the phase
behaviour of high pressure
systems for delivering new
processes.

Chem. Soc. Rev., 2012, 41, 14281436

There are several contenders for these replacements including

water,57 renewable solvents derived from biomass,810 and the
so-called advanced solvents such as ionic liquids1113 and
supercritical uids.1416 In reality, these dierent solvents are
not in direct competition but rather are complementary, each
with its own advantages and drawbacks. The purpose of this
Review is to focus on supercritical CO2, scCO2, to discuss some
of the problems that have frustrated its widespread use on an
industrial scale and to highlight research which indicates where
scCO2 should deliver value in the future.
scCO2 is potentially attractive as a solvent. It displays
properties which are a mixture of those normally associated
with gases or liquids (e.g. diusivity approaching that of a gas
combined with the solvent power of a light liquid alkane).17
Such properties are especially useful in reactions involving
gaseous reagents, hydrogenation with H2, oxidation with O2
or hydroformylation with syngas. scCO2 is easily obtained in
high purity as a by-product from many processes including the
fermentation of biomass, potentially a very large scale source

Martyn Poliako was born in

London. After studying in
Cambridge, he spent 7 years at
the University of Newcastle
upon Tyne. Since 1979, he has
worked at Nottingham where he
is currently Research Professor
in Chemistry. He is Chair of the
Editorial Board of the journal
Green Chemistry and Foreign
Secretary of the Royal Society,
the UK academy of sciences. He
is also one of the presenters of
the YouTube chemistry channel,
www.periodicvideos.com.

Martyn Poliako

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of CO2 with the use of bioethanol increasing as a transport

fuel. Furthermore, scCO2 is totally non-ammable and its
properties can be manipulated by varying the applied
pressure.18
There has been one outstandingly successful application of
scCO2, the decaeination of coee beans which has become
one of the most popular decaeination processes.18 A number
of other processes have also been implemented in the food
industry probably because of the attraction of a completely
non-toxic solvent and the relatively high value of the products,
at least compared to typical ne chemicals. A key factor in the
success of the decaeination process is that the caeine can be
recovered from the high pressure CO2 by extraction with water
rather than by releasing the pressure. This has a positive
impact on the energy costs of the process.
Although there has been a considerable volume of basic
research19,20 on chemical reactions in scCO2, the need to work
with high pressures has kept the eld small compared to the use
of ionic liquids21,22 which can be used as drop-in replacements for conventional solvents in standard laboratory glassware. In addition, much of the supercritical research has been
carried out on batch reactions in sealed autoclaves, processes
which do not have obvious routes to commercial scale-up
because of the high cost of large pressure vessels. Our research
group in Nottingham is one of relatively few worldwide that has
concentrated on continuous reactions14 in scCO2.
In the early days of Green Chemistry, it was hoped that one
could exploit the rapid change in physical properties very close to
the critical point of CO2 (Tc 31.1 1C, pc 7.38 MPa). Several
promising examples of unusual selectivity were reported on the
small-scale.2325 However it was quickly realised that such reactions
would be very dicult to reproduce on a commercial scale because
these eects were usually observed in dilute solution and required
very precise control of temperature and pressure.
There have been two successful industrial-scale hydrogenation
processes in scCO2. The rst was part of the synthesis of vitamins
by Homan la Roche (later DSM Vitamins)2628 and the other
was a multi-purpose plant built by Thomas Swan & Co Ltd. in
collaboration with our research group.29 The Thomas Swan plant
was a technical successin the hydrogenation of isophorone,
Scheme 1, the product trimethylcyclohexanone, TMCH, was
obtained suciently pure that it could be sold without any
downstream purication.
Unlike the caeine in decaeination, the TMCH was recovered
by depressurisation of the CO2 which was then recompressed and
recycled. However, the plant went on stream at a time of rising
energy costs and quickly became too expensive to be used on a
hydrogenation as simple as that of isophorone. Nevertheless, the
plant has provided an extremely valuable test-bed for large scale
implementation of scCO2 for chemical reactions.29

In the past few years, there have been several reviews of

reactions in scCO2 including some that focus on continuous
reactions,14,30,31 and there is a recent, helpful introduction to
continuous reactions32 which highlights some of their advantages particularly in the context of Green Chemistry. The aim of
this review is to give some recent examples where strategies have
been developed to reduce the energy requirements and then, in
the second part, we describe some cases where scCO2 oers real
chemical advantages over more conventional solvents.

Scheme 1 Hydrogenation of isophorone to TMCH,29 one of the few

reactions to be carried out on a commercial scale in scCO2.

Fig. 1 Schematic diagram of a typical continuous ow apparatus for

reactions in scCO2.

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The basics
Before going into the detailed examples of continuous ow
reactions in scCO2, we rst describe a general setup for such
processes, Fig. 1.
CO2 is delivered from cylinder usually by a chilled pump
because CO2 is too compressible at room temperature to be
pumped easily. The substrate stream contains pure starting
materials, mixed with a catalyst and co-solvent as necessary.
Gaseous reactants, such as hydrogen and oxygen, are introduced into the system separately via a dosing unit or mass-ow
controller (not illustrated). Static mixers are often included to
ensure complete mixing before the reactants pass into the
reactor. The size and shape of the reactor is varied to suit
the particular reaction, but tubular reactors are commonly
used because of their ease of construction. Nevertheless, there
are many examples of custom designed reactors for specic
experiments. For heterogeneous catalysis, the catalyst can be
packed to form a xed bed, and usually a heating block is
attached to the catalyst bed to control the reaction temperature.
After the mixture has passed through the reactor, the product
stream can be collected by releasing the system pressure, usually
via a back pressure regulator. A number of on-line analytical
techniques have also been developed, including on-line gas
chromatography,33 see below. Finally, it is worth noticing that
the pressure in this system is controlled by the back pressure
regulator. Therefore reactions can, if necessary, be run under
pressure without CO2 merely by switching o the CO2 pump.

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Reducing the energy requirement

The major energy consumption of a supercritical apparatus
comes from the compression of CO2 to its supercritical
pressure. The most straightforward approach would be to
use CO2 which has already been compressed elsewhere as part
of a dierent process, thereby removing the energy burden of
compression completely. Until now such an approach has
seemed extremely unlikely. However as plans for Carbon
Capture and Storage (CCS)34 become more denite, it
is becoming clear that there is a real possibility of CO2
compressed to >100 bar becoming an extremely abundant
material.35,36 The problem is that such CO2 is likely to be
impure with N2, H2O and possibly CO present in CO2.
Recently, our group published a study37 showing that the
presence of N2 (up to 10 mol%) has a marginal eect on the
hydrogenation of isophorone, Scheme 1. CO and H2O had
some eect but the eciency of the reaction could be largely
restored by increasing the temperature of the catalyst bed.
Since the reaction is highly exothermic, running at a higher
temperature does not necessarily increase the energy consumption
of the process. Of course, this is only one reaction but it does raise
the possibility that chemistry in scCO2 could advantageously be
coupled to CCS.
Sequential reactions
In the absence of CCS, one of the simplest ways to mitigate the
energy requirements of a given reaction in scCO2 is to run two
or more reactions sequentially without depressurisation
between them. In this way, the energy cost of compressing
the CO2 can be spread over several reactions. For example,
Amandi et al. used this approach for the alkylation of phenol
to make cyclohexyl phenol.38 The alkylation worked well with
cyclohexene but it is an expensive alkylating reagent. In terms
of starting materials, it is much cheaper to use cyclohexanol
and to dehydrate it to cyclohexene over the same g-alumina
catalyst as is used for the alkylation reaction itself, Scheme 2.
The cyclohexene generated in this fashion gave comparable
yields in the alkylation reaction to those achieved when using
commercially available cyclohexene. There was, however, a
complication because the H2O, produced in the dehydration
step, deactivated the catalyst towards alkylation. Therefore
the reactions were run using two separate catalyst beds, with a
moisture trap in between, to collect the water generated in the
rst step.38
A chemically more complex example39,40 comes from Seki and
co-workers in Zurich who used a customised bifunctional
palladium-acid catalyst, to carry out sequentially an aldol
condensation followed by a hydrogenation in a single reactor,
Scheme 3. With the high activity, selectivity and long lifetime of
the catalyst, this route aords the ecient production of the
industrially important compounds A and B, which can in
principle be easily separated by distillation.
Stevens et al. then showed that using two separate catalysts in
separate reactors gave considerable advantages.41 The combined
aldol condensation and hydrogenation could be carried out with
improved yield but one could also obtain the unsaturated aldol
addition product, Scheme 4.
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Chem. Soc. Rev., 2012, 41, 14281436

Scheme 2 Sequential reactions to reduce energy costs; dehydration of

cyclohexanol to form cyclohexene, followed by alkylation of phenol
with the cyclohexene.38

Scheme 3 Sequential reactions in scCO2: an aldol condensation

followed by a hydrogenation.39

Stevens et al. then explored further the potential of carrying

out sequential reactions in separate but linked continuous ow
reactors in scCO2. By packing the two reactors with dierent
catalysts and controlling the reactor temperatures separately,42
no fewer than ve dierent products could be obtained from a
single feedstock (furfural) with high yield and selectivity, Fig. 2.
This example of real-time switching between dierent products
not only demonstrated the advantages of ow reactions over
the traditional batch processes, but also potentially enables
chemical manufacture to respond more rapidly to changing
market demands for products, enhancing protability and
reducing reactor downtime.
A rather special case of sequential reaction involves decomposing
a pressurised liquid to generate high pressure CO2 without the
pressurisation of the gaseous CO2 itself, hence reducing the energy
consumption of such processes. For example, Hyde et al. developed
an approach for hydrogenation reactions in which the supercritical
uid mixture was generated by the catalytic decomposition of liquid
formic acid, HCO2H, over a preheated Pt catalyst bed.43,44 The
CO2 and H2 generated in this way could be used directly as both the
supercritical solvent and the reagent gas. The hydrogenation of
several organic substrates, including alkenes, ketones and aldehydes

Scheme 4 Sequential reactions in scCO2 in separate reactors;41 the

self aldol condensation of propionaldehyde showing both the aldol
intermediate and the unsaturated dehydration product.

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and provides, in principle at least, a versatile and convenient

methodology for non-specialist chemists.

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Gas expanded liquids

Fig. 2 Real-time switching of the reactions of furfural in scCO2 to

give ve dierent products42 simply by varying the temperature of the
two catalyst beds, R1 and R2.

was successfully performed using this gasless method. Since,

however, the concentration of H2 is often a key parameter in
obtaining a selective reaction,45 the authors controlled the H2
concentration by the parallel decomposition of a second liquid
precursor, such as ethyl formate HCO2Et, which can produce
C2H6 + CO2. Because the ow rates of the two liquid precursors
could be controlled separately and the liquids could be decomposed
over the same catalyst, a mixture of H2 + CO2 + C2H6 with the
desired partial pressure of H2 could be produced without increasing
the complexity of the apparatus unduly. Yields from hydrogenation
reactions performed in this way were similar to those obtained in
previously reported reactions with pure scCO2. Compared to the
other examples of sequential reactions in scCO2 described above,
this without gases approach to supercritical uid chemistry
removes the need of using gas cylinders and specialised CO2 pumps,

Although it is an appealing idea to run two reactions sequentially to achieve higher energy eciency of scCO2 processes,
sequential reactions always require careful planning of the
experiments to match the rates of the production. Probably
this is why only a few examples of sequential reactions have
been reported. Another more general solution for tackling the
energy costs of scCO2 processes is to use lower pressures of
CO2 merely to expand liquid reactants or solvents, to form
so-called gas-expanded-liquids (GXLs). This method not
only reduces the energy requirement but also greatly enhances
solubility of polar reactants and catalysts compared to pure
scCO2. Furthermore, expansion by CO2 renders gaseous
reactants, such as H2 and O2, more soluble than in neat organic
solvents.46 An extensive review of GXLs has been published by
Jessop and Subramaniam47 and more recently Akien and
Poliako gave a critical look at the reactions in CO2 expanded
liquids.48 Because of the many advantages of using CO2 for the
reactions involving H2, a large number of the published papers
involve hydrogenation reactions in GXLs, and there is an
extensive review of this area by Seki et al.49
Although batch and semi-batch reactors are more often
used for reactions in GXLs, several examples of continuous
ow reactions using xed bed reactors have also been
reported.5052 The higher solvent power of GXLs compared
to scCO2 oers an opportunity for reactions with higher
molecular complexity. This aspect of GXLs has been exploited
to dissolve homogeneous catalysts or substrates which have
only poor solubility in pure CO2. For example, Clark et al.
carried out the hydrogenation with H2 of the complex
pharmaceutical intermediate sertraline, using a Pd/CaCO3
catalyst in THF/CO2, Scheme 5.53 The reaction showed superior
selectivity towards the cis products compared to the published

Scheme 5 Diastereoselective hydrogenation of sertraline imine53 in gas expanded THF, the rst example of a pharmaceutical intermediate being
hydrogenated in CO2.

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Scheme 6

Debenzylation of 1,4-debenzyloxybenzene.55

industrial process,54 possibly due to the heat transfer properties

of CO2 helping to remove excess heat from the catalyst surface.
The same Pd/CaCO3 was also used by Akien et al. to
catalyse the selective debenzylation of 1,4-dibenzyloxybenzene,55
Scheme 6. In the presence of CO2 good selectivity (86%) towards
the monodebenzylated product was achieved, suggesting that the
reaction has potential applications for desymmetrisation of such
molecules.

The way forward

In the previous sections, we introduced a number of strategies
for reducing the energy requirements of CO2 processes, such as
running sequential reactions, generating scCO2 uid from
liquid precursors, and using lower pressure GXLs. Here, we
give some examples where scCO2 oers real processing
advantages over more conventional solvents.
Controlled phase separation
In some cases, the miscibility of two liquids decreases rather than
increases when expanded with CO2. This eect, rst reported by
Lazzaroni et al.,56 typically occurs when one liquid is water and
the other is a water-miscible organic. In such cases, the expansion
with CO2 can promote the separation of organic and water-rich
phases. For example, Bourne et al. reported57 that, in the
hydrogenation of levulinic acid, Scheme 7, pure g-valerolactone
product could be separated from the coproduced water by using
the pressure of CO2 already present inside the reactor. In this
way, the product could be separated without any additional
input of energy, Fig. 3. This was achieved by combining the use
of water as a co-solvent, and of CO2 to manipulate the phases.

Fig. 4 In the continuous ow reaction,57 the pressure of CO2

generates a triphasic mixture (gases, CO2 + GVL and aqueous phase).
The aqueous phase can be collected in the separator (S), the GVL-rich
phase passes through S and to the back pressure regulator (BPR) for
recovery of pure GVL. The aqueous phase, containing any unreacted
LA continues to accumulate in S and can periodically be drained via a
ball valve, without signicant loss of the system pressure. (Reproduced
from ref. 57, copyright the Royal Society of Chemistry).

The result was reaction and separation integrated into a single

process, completely avoiding the conventional separation of H2O
and GVL by distillation.
Another elegant example of integrating reaction and separation
into a single operation was demonstrated by Harwardt et al.,58
who designed a reactor with two temperature zones to exploit the
change in solvent properties of CO2 with temperature, Fig. 5.
A homogeneous mixture of the substrates, catalyst and CO2 was
formed in the lower, cooler zone, allowing reaction to occur under
single phase conditions. When, however, the reaction mixture
owed to the hotter, upper zone, the solubility of the metalphosphine catalyst was signicantly reduced due to the dramatic
decrease of CO2 density. The catalyst therefore precipitated and
fell back into the lower zone where it redissolved allowing the
continuous recycle of catalyst. By contrast, the reaction products
had sucient solubility in the hotter zone to stay in solution and
to ow out of the reactor with the CO2. Successful operation was
demonstrated on the catalytic isomerisation of allylic alcohols,
Scheme 8.

Scheme 7 The hydrogenation of levulinic acid57 where phase separation

can be used to recover pure GVL.

Fig. 3 CO2-promoted phase separation57 of GVL from water and

residual LA. (see Fig. 4).

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Fig. 5 Integrated reaction and catalyst separation58 based on the fact

that, at constant pressure, CO2 has lower density and, hence, a lower
solvent power at higher temperatures. (Redrawn from ref. 58).

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Scheme 8 The isomerisation of allylic alcohols, carried out using the

reactor in Fig. 5.

the authors could achieve minimal catalyst leaching and reaction

rates comparable to current industrial processes.
Hintermair et al. then applied this concept further to the
asymmetric hydrogenation of dimethyl itaconate by using a
chiral Rh catalyst,64 and obtained >99% ee enantiomerically
pure product for periods of up to 10 h, Scheme 9.
Tunable selectivity

Fig. 6 Continuous ow reactions in IL/CO2 systems; the ionic

catalyst is immobilised in the IL phase, and the CO2 is used as a
transport vector for organic substrates. (Redrawn from ref. 63).

Scheme 9 Asymmetric hydrogenation of dimethyl itaconate using a

chiral Rh catalyst immobilised in an IL/CO2 system.64

Although not observed in this case, high temperatures can also

lead to the decomposition of expensive catalysts. Therefore,
another approach is interesting because it achieves easy catalyst
separation without heat in a continuous ow process by using an
ionic liquid (IL)/CO2 combination. The method relies on
Brenneckes important observation59 that CO2 is highly soluble
in ILs, but ILs are generally not soluble in CO2. This means that
CO2 can be used to extract a wide range of organics from ILs
while the IL phase is completely retained in the reactor. Following
the pioneering work of Cole-Hamilton,6063 many examples of
reactions using CO2/IL have been reported, but particularly
hydroformylation reactions of alkenes have been demonstrated.63
The process involves dissolving an ionic Rh catalyst in an IL and
using CO2 as a transport vector for both the starting materials
(H2 and 1-octene) and the product (aldehyde), Fig. 6. By careful
choice of the IL, the catalyst and the other reaction parameters,

The high enantioselectivity achieved in the example above was

largely due to the superior properties of the chiral catalyst rather
than to the CO2 itself. Interestingly, however, CO2 can sometimes
enhance the selectivity of a reaction. For example Licence et al.,65
showed that the selectivity of the reaction of 1,6-hexanediol with
MeOH in scCO2 could be almost completely switched from 1 : 20
in favour of the bis-ether to 9 : 1 in favour of the desymmetrised
mono-ether merely by changing the system pressure from 50 to
200 bar, Scheme 10.
This switch in selectivity was closely linked to the phase
behaviour of the reaction mixture which can be tuned by CO2
pressure.65 Pressure tuning of the selectivity of reactions is
clearly an appealing aspect of CO2 chemistry compared to
more conventional solvents. For example, Oakes et al.
reported66 that the acidcatalysed diastereoselective oxidation
of cysteine and methionine derivatives in scCO2 proceeds with
reaction selectivity above 95%, whereas the same reaction
carried out in conventional solvent showed no selectivity,
Scheme 11.
However, replacing a conventional solvent with scCO2, does
not necessarily lead to an improvement, as demonstrated by
Parrott et al. in continuous etherication reactions.67 Comparable yield and selectivity could be obtained in high pressure
CO2 and in the reactions at ambient pressure where no
additional solvent was used. More interestingly, when the
reaction was conducted without CO2, a dramatic decrease in
yield was observed with the increasing pressure. This sends an
important message, namely that, whenever possible, control
experiments should be carried out to assess the value of using
high pressures.

Scheme 10 The methylation of 1,6-hexanediol with MeOH over a

g-alumina catalyst in scCO2, which shows a dramatic switch in
selectivity as the pressure is increased.65

Scheme 11 The selective acidcatalysed diastereoselective oxidation66 of methionine derivatives observed only at 180 bar pressure in scCO2.

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Oxidation
Apart from reaction selectivity, a strong dependence of reaction rate on pressure has also been found in some cases where
CO2 has been used as solvent. For example Caravati et al.,
reported68 that in the catalytic oxidation of benzyl alcohol to
benzaldehyde in CO2 (0.8% toluene), the conversion rose from
25% to 75% when the pressure was increased from 140 to 150
bar, Fig. 7.
This increase in conversion was again closely linked to the
phase behaviour of the reaction mixture; the authors believed

Fig. 7 Conversion of benzyl alcohol to benzylaldehyde in scCO2/

toluene as a function of pressure, showing the sudden increase in
conversion close to 140 bar. (Reproduced with permission from
ref. 68; Copyright 2006 Elsevier).

Fig. 8 Schematic of the continuous photo-oxidation76 using immobilised

photocatalysts in scCO2, the use of LEDs is much more energy ecient
than conventional light sources.

that a single phase condition was essential for achieving high

catalytic activity.68 Because of the full miscibility of scCO2
with permanent gases, such as H2 and O2, and its ability to
dissolve organic compounds, especially with the aid of co-solvent,
single phase reaction mixtures often show exceedingly high rates
that are rarely achievable in conventional liquid solvents due to
inherent gas-liquid mass transport limitations. However there are
cases where reactions under single phase conditions can be slower
because the reactants are more dilute.69,70
CO2 has an added attraction in oxidation reactions using O2
as oxidant, because CO2 is fully oxidised and hence safe and
inert. Numerous authors have reported studies of catalytic
oxidations of a variety of organic substrates using O2 with
homogenous or heterogeneous catalysts in scCO2, and an
extensive review of this eld has also been published by
Seki and Baiker.71 More recently, Bourne et al. further
exploited CO2 for photo-catalytic oxidation reactions by
singlet oxygen,72 Scheme 12. With the long lifetime in scCO2
of the excited singlet oxygen73,74 and the homogeneous
conditions in CO2, more rapid conversion of the substrate
was found than in the conventional solvents such as CCl4. The
reactions in scCO2 have also been scaled up by conducting
continuous ow photochemistry.75 The reactions were initially
carried out with a CO2 soluble photocatalyst, 5,10,15,
20-tetrakis(pentauorophenyl)porphyrin, under homogenous
conditions in a sapphire tube reactor, where signicantly
enhanced space-time yields were achieved compared to more
conventional photochemical reactors. Then, several immobilised
photocatalysts were developed to remove the need for downstream purication of the products, Fig. 8. With the most
promising system,76 a porphyrin analogue immobilised on PVC
beads, the photo-oxidation reactions of both a-terpinene and
citronellol were successfully performed with consistently high
yields over a period of 6 h.
On-line analysis and automation

Scheme 12 Photo-catalytic oxidation reactions by singlet O2 in

scCO2.72,75,77

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This nal section describes recent advance in on-line analysis

and automation of continuous reactions using scCO2. The aim
of work in this area is to reduce the time needed for optimising
supercritical uid experiments. Optimisation is time-consuming
because the high compressibility of scCO2 adds a whole extra
dimension to the parameter space to be optimised, and even a
rough optimisation often requires many control and repeat
experiments to acquire enough data. One solution lies in automation which can remove much of the tedium of optimisation.
For example, an automated high pressure reactor was developed
by Walsh et al., in which the heterogeneous acid catalysed
etherication reactions in scCO2 were monitored by on-line
gas-liquid chromatography.33 This automation allowed
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statistically useful amounts of data to be obtained whilst decreasing the amount of manual control and monitoring required during
an experiment. Furthermore, the on-line sampling system
permitted quantication of all products, including those volatile
compounds, such as dimethyl ether (bp: 24.8 1C), that would
evaporate during the expansion stage of a non-automated reactor.
This technique has then been applied to a range of dierent
reactions, such as hydrogenation,42 aldol condensation,41 and
methylation.65
However, this automated reactor varies only a single parameter
at a time during an experiment and, because it does not account for
interactions between parameters, a large amount of unnecessary
data must be collected for every possible parameter combination to
cover all the potential reaction environments. Recently, Parrott
et al. developed a reactor capable of self-optimisation;78 it combines
the use of an automated reactor with feedback generated by an
evolutionary search algorithm, Fig. 9. All the data of reaction
parameters such as pressure, temperature, the ow rates of CO2
and organic substrates are used as inputs for the control algorithm,
which is based on the super modied simplex (SMSIM)
algorithm.79 This algorithm then outputs control signals to change
the temperature, pressure, and the ow rates of the pumps to new
values calculated to improve the yield of desired product. Two
reactions, the dehydration of ethanol and the carboxymethylation
reaction of dimethylcarbonate, Scheme 13, were chosen to validate
this self-optimising reactor. Three parameters of the reactions
(pressure, temperature and CO2 ow rate) were varied at the same
time. This greatly improved the eciency of the optimisation;
maximising the yield of 2b or 2c. Each optimisation took
ca. 35 h to complete, far less than the time required to cover the

Scheme 13 Reactions optimised using the reactor in Fig. 9, the

dehydration of ethanol, 1, and the carboxymethylation reaction of
primary alcohols, 2, with dimethylcarbonate78 (Reproduced from
ref. 78, copyright Wiley).

same volume of parameter space with Walshs automated

reactor.33
This work represents a signicant step forward in the use of
optimisation algorithms for scCO2 reactors. However, it is not
merely the maximum yield of a product, which can be optimised.
The conditions could also be optimised for dierent criteria, such
as maximising or minimising the ratio of two products, minimising
the production of an unwanted by-product, or even minimising
the E factor (kg waste/kg product) of the reaction, which is
particularly interesting in the context of Green Chemistry.80

Conclusions
This review has considered some of the problems associated with
continuous reactions in scCO2. By far the most serious problem is
the energy cost associated with compressing CO2. In the long
term, it may well be possible to oset this energy burden by
exploiting CO2, already compressed in Carbon Capture and
Storage. However, large scale implementation of CCS is still
some years o. Therefore in the short term, the most promising
strategy will be to deploy CO2 in applications where there is a
genuine chemical advantage to be gained by its use. The most
obvious area is oxidation where the chemical inertness of CO2
cannot be matched by other common solvents apart from water.
The use of singlet oxygen in scCO2 is particularly promising
because 1O2 has a very short lifetime in water. In addition, there
are now sucient examples to suggest that scCO2 can give
unusual or improved selectivity in a range of reactions compared
to more conventional solvents. Overall, the current surge in
interest among organic chemists in ow chemistry makes it likely
that continuous reactions in scCO2 will nd an increasing number
of applications in the coming years.

Fig. 9 The self-optimising reactor78 has two pumps, one to supply

CO2 and the other to supply reactants which pass through the reactor.
The temperature is controlled by proportional-integral-derivative (PID)
heating controller and monitored by thermocouples. The reaction
pressure is controlled by a back pressure regulator, BPR, and monitored
by pressure transducers. The product composition is analysed by on-line
GLC. This automated supercritical reactor is equipped with software
for a controlled feedback loop. The left-hand side indicates the control
paths and the right-hand side the reactor monitoring. (Reproduced with
permission from ref. 78, copyright 2011 Wiley).

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The Royal Society of Chemistry 2012

Acknowledgements
We thank Professor M. W. George, Dr R. A. Bourne and all
our colleagues and collaborators whose work is included in
this review, as well as our technical sta for their invaluable
support. We also thank those organisations that have funded
our research including EPSRC, Thomas Swan & Co Ltd.,
AstraZeneca, Johnson Matthey, Shasun, the EU SYNFLOW
project and the University of Nottingham.
Chem. Soc. Rev., 2012, 41, 14281436

1435

Published on 16 January 2012. Downloaded by Universitat de Valncia on 17/11/2015 09:33:05.

References
1 M. Poliako and P. Licence, Nature, 2007, 450, 810812.
2 D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey,
J. L. Leazer Jr., R. J. Linderman, K. Lorenz, J. Manley,
B. A. Pearlman, A. Wells, A. Zaks and T. Y. Zhang, Green Chem.,
2007, 9, 411420.
3 P. J. Dunn, S. Galvin and K. Hettenbach, Green Chem., 2004, 6,
4348.
4 R. K. Henderson, C. Jimenez-Gonzalez, D. J. C. Constable,
S. R. Alston, G. G. A. Inglis, G. Fisher, J. Sherwood,
S. P. Binks and A. D. Curzons, Green Chem., 2011, 13, 854862.
5 M. Raj and V. K. Singh, Chem. Commun., 2009, 66876703.
6 C. J. Li and L. Chen, Chem. Soc. Rev., 2006, 35, 6882.
7 C. J. Li, Chem. Rev., 2005, 105, 30953165.
8 R. A. Sheldon, Catal. Today, 2011, 167, 313.
9 J. C. Serrano-Ruiz, R. M. West and J. A. Durnesic, in Annual
Review of Chemical and Biomolecular Engineering, ed.
J. M. Prausnitz, M. F. Doherty and M. A. Segalman, Annual
Reviews, Palo Alto, 2011, vol. 1, pp. 79100.
10 U. Biermann, U. Bornscheuer, M. A. R. Meier, J. O. Metzger and
H. J. Schaefer, Angew. Chem., Int. Ed., 2011, 50, 38543871.
11 T. Welton, Chem. Rev., 1999, 99, 20712083.
12 K. R. Seddon, Nat. Mater., 2003, 2, 363365.
13 M. J. Earle and K. R. Seddon, Pure Appl. Chem., 2000, 72,
13911398.
14 J. R. Hyde, P. Licence, D. Carter and M. Poliako, Appl. Catal.,
A, 2001, 222, 119131.
15 A. Baiker, Chem. Rev., 1999, 99, 453473.
16 P. G. Jessop, T. Ikariya and R. Noyori, Chem. Rev., 1999, 99,
475493.
17 M. Skerget, Z. Knez and M. Knez-Hrncic, J. Chem. Eng. Data,
2011, 56, 694719.
18 Mark McHugh and V. Krukonis, Supercritical uid Extraction
Principle and Practice, Butterworth-Hernemann, 1994.
19 C. M. Rayner, Org. Process Res. Dev., 2007, 11, 121132.
20 W. Leitner, Acc. Chem. Res., 2002, 35, 746756.
21 T. Jiang and B. X. Han, Curr. Org. Chem., 2009, 13, 12781299.
22 S. Q. Hu, Z. F. Zhang, Y. X. Zhou, J. L. Song, H. L. Fan and
B. X. Han, Green Chem., 2009, 11, 873877.
23 B. J. Hrnjez, A. J. Mehta, M. A. Fox and K. P. Johnston, J. Am.
Chem. Soc., 1989, 111, 26622666.
24 A. A. Cliord, K. Pople, W. J. Gaskill, K. D. Bartle and
C. M. Rayner, J. Chem. Soc., Faraday Trans., 1998, 94, 14511456.
25 R. S. Oakes, T. J. Heppenstall, N. Shezad, A. A. Cliord and
C. M. Rayner, Chem. Commun., 1999, 14591460.
26 Roche. Mag., 1992, 41, 2.
27 L. Devetta, A. Giovanzana, P. Canu, A. Bertucco and
B. J. Minder, Catal. Today, 1999, 48, 337345.
28 L. Devetta, P. Canu, A. Bertucco and K. Steiner, Chem. Eng. Sci.,
1997, 52, 41634169.
29 P. Licence, J. Ke, M. Sokolova, S. K. Ross and M. Poliako,
Green Chem., 2003, 5, 99104.
30 D. J. Cole-Hamilton, Adv. Synth. Catal., 2006, 348, 13411351.
31 R. Ciriminna, M. L. Carraro, S. Campestrini and M. Pagliaro,
Adv. Synth. Catal., 2008, 350, 221226.
32 C. Wiles and P. Watts, Green Chem., 2012, DOI: 10.1039/
c1gc16022b.
33 B. Walsh, J. R. Hyde, P. Licence and M. Poliako, Green Chem.,
2005, 7, 456463.
34 R. S. Haszeldine, Science, 2009, 325, 16471652.
35 H. Chen, C. Zhao, Y. Li and X. Chen, Energy Fuels, 2010, 24,
57515756.
36 J. Davison and K. Thambimuthu, Proc. Inst. Mech. Eng., Part A,
2009, 223, 201212.
37 J. G. Stevens, P. Gomez, R. A. Bourne, T. C. Drage, M. W. George
and M. Poliako, Green Chem., 2011, 13, 27272733.
38 R. Amandi, K. Scovell, P. Licence, T. J. Lotz and M. Poliako,
Green Chem., 2007, 9, 797801.
39 T. Seki, J.-D. Grunwaldt and A. Baiker, Chem. Commun., 2007,
35623564.
40 T. Seki, J.-D. Grunwaldt, N. van Vegten and A. Baiker, Adv.
Synth. Catal., 2008, 350, 691705.
41 J. G. Stevens, R. A. Bourne and M. Poliako, Green Chem., 2009,
11, 409416.

1436

Chem. Soc. Rev., 2012, 41, 14281436

42 J. G. Stevens, R. A. Bourne, M. V. Twigg and M. Poliako,

Angew. Chem., Int. Ed., 2010, 49, 88568859.
43 J. R. Hyde and M. Poliako, Chem. Commun., 2004, 14821483.
44 J. R. Hyde, B. Walsh, J. Singh and M. Poliako, Green Chem.,
2005, 7, 357361.
45 M. G. Hitzler, F. R. Smail, S. K. Ross and M. Poliako, Org.
Process Res. Dev., 1998, 2, 137146.
46 Z. Z. Xie, W. K. Snavely, A. M. Scurto and B. Subramaniam,
J. Chem. Eng. Data, 2009, 54, 16331642.
47 P. G. Jessop and B. Subramaniam, Chem. Rev., 2007, 107,
26662694.
48 G. R. Akien and M. Poliako, Green Chem., 2009, 11, 10831100.
49 T. Seki, J.-D. Grunwaldt and A. Baiker, Ind. Eng. Chem. Res.,
2008, 47, 45614585.
50 J. C. Chan and C. S. Tan, Energy Fuels, 2006, 20, 771777.
51 A. C. Frisch, P. B. Webb, G. Zhao, M. J. Muldoon, P. J. Pogorzelec
and D. J. Cole-Hamilton, Dalton Trans., 2007, 55315538.
52 R. Tschan, R. Wandeler, M. S. Schneider, M. M. Schubert and
A. Baiker, J. Catal., 2001, 204, 219229.
53 P. Clark, M. Poliako and A. Wells, Adv. Synth. Catal., 2007, 349,
26552659.
54 G. P. Taber, D. M. Psterer and J. C. Colberg, Org. Process Res.
Dev., 2004, 8, 385388.
55 G. R. Akien, J.-C. Legeay, A. Wells and M. Poliako, Org. Process
Res. Dev., 2010, 14, 12021208.
56 M. J. Lazzaroni, D. Bush, R. Jones, J. P. Hallett, C. L. Liotta and
C. A. Eckert, Fluid Phase Equilib., 2004, 224, 143154.
57 R. A. Bourne, J. G. Stevens, J. Ke and M. Poliako, Chem.
Commun., 2007, 46324634.
58 T. Harwardt, G. Francio and W. Leitner, Chem. Commun., 2010,
46, 66696671.
59 L. A. Blanchard, D. Hancu, E. J. Beckman and J. F. Brennecke,
Nature, 1999, 399, 2829.
60 U. Hintermair, G. Zhao, C. C. Santini, M. J. Muldoon and
D. J. Cole-Hamilton, Chem. Commun., 2007, 14621464.
61 T. E. Kunene, P. B. Webb and D. J. Cole-Hamilton, Green Chem.,
2011, 13, 14761481.
62 M. F. Sellin, P. B. Webb and D. J. Cole-Hamilton, Chem. Commun.,
2001, 781782.
63 P. B. Webb, M. F. Sellin, T. E. Kunene, S. Williamson, A. M.
Z. Slawin and D. J. Cole-Hamilton, J. Am. Chem. Soc., 2003, 125,
1557715588.
64 U. Hintermair, T. Hoefener, T. Pullmann, G. Francio and
W. Leitner, ChemCatChem, 2010, 2, 150154.
65 P. Licence, W. K. Gray, M. Sokolova and M. Poliako, J. Am.
Chem. Soc., 2005, 127, 293298.
66 R. S. Oakes, A. A. Cliord, K. D. Bartle, M. T. Petti and
C. M. Rayner, Chem. Commun., 1999, 247248.
67 A. J. Parrott, R. A. Bourne, P. N. Gooden, H. S. Bevinakatti,
M. Poliako and D. J. Irvine, Org. Process Res. Dev., 2010, 14,
14281434.
68 M. Caravati, J. D. Grunwaldt and A. Baiker, Appl. Catal., A, 2006,
298, 5056.
69 M. N. da Ponte, J. Supercrit. Fluids, 2009, 47, 344350.
70 Z. S. Hou, B. X. Han, L. Gao, Z. M. Liu and G. Y. Yang, Green
Chem., 2002, 4, 426430.
71 T. Seki and A. Baiker, Chem. Rev., 2009, 109, 24092454.
72 R. A. Bourne, X. Han, A. O. Chapman, N. J. Arrowsmith,
H. Kawanami, M. Poliako and M. W. George, Chem. Commun.,
2008, 44574459.
73 M. Okamoto, T. Takagi and F. Tanaka, Chem. Lett., 2000,
13961397.
74 D. R. Worrall, A. A. Abdel-Sha and F. Wilkinson, J. Phys.
Chem. A, 2001, 105, 12701276.
75 R. A. Bourne, X. Han, M. Poliako and M. W. George, Angew.
Chem., Int. Ed., 2009, 48, 53225325.
76 X. Han, R. A. Bourne, M. Poliako and M. W. George, Chem.
Sci., 2011, 2, 10591067.
77 X. Han, R. A. Bourne, M. Poliako and M. W. George, Green
Chem., 2009, 11, 17871792.
78 A. J. Parrott, R. A. Bourne, G. R. Akien, D. J. Irvine and
M. Poliako, Angew. Chem., Int. Ed., 2011, 50, 37883792.
79 R. A. Bourne, R. A. Skilton, A. J. Parrott, D. J. Irvine and
M. Poliako, Org. Process Res. Dev., 2011, 15, 932938.
80 R. A. Sheldon, Green Chem., 2007, 9, 12731283.

This journal is

The Royal Society of Chemistry 2012