High pressure CO2-controlled reactors: Enzymatic chiral resolution in emulsions

Article abstract of DOI:10.1039/c4ra02131b

In this work we have reported the formulation of a CO₂-based micelle stabilized by nontoxic TMN series surfactants. Enantioselection of racemic ibuprofen catalyzed by Candida antarctica lipase B (CALB) was used as a model reaction. The effect of reactive parameters, such as temperature, pH, pressure, and water content on reactive environment and conversion has been discussed. For the resolution of racemic ibuprofen in CO₂-based micelles, the enzymatic activity reached a high level at 45 °C, with pressure 250 bar, pH 7.4, and water to surfactant ratio W₀ 25. In addition, the relatively long-chain length in TMN-10 could help the esterification and trans-esterification processes, which resulted in an efficient reaction rate in a CO₂-based micelle system. Enzymatic catalysis has been conducted in a CO₂-based system rather than in the conventional media to make the enzyme reaction greener. The better resolution efficiency in high pressure CO₂-based micelles could be achieved within a relatively short period of time compared with other traditional reactive systems. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c4ra02131b

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High pressure CO2-controlled reactors: enzymatic
chiral resolution in emulsions
Cite this: RSC Adv., 2014, 4, 24083
*
Wenting Shang, Xiaogang Zhang, Xiaoxi Yang and Shujuan Zhang
In this work we have reported the formulation of a CO2-based micelle stabilized by nontoxic TMN series
surfactants. Enantioselection of racemic ibuprofen catalyzed by Candida antarctica lipase B (CALB) was
used as a model reaction. The effect of reactive parameters, such as temperature, pH, pressure, and
water content on reactive environment and conversion has been discussed. For the resolution of
racemic ibuprofen in CO2-based micelles, the enzymatic activity reached a high level at 45 ꢀC, with
pressure 250 bar, pH 7.4, and water to surfactant ratio W0 25. In addition, the relatively long-chain length
in TMN-10 could help the esterification and trans-esterification processes, which resulted in an efficient
reaction rate in a CO2-based micelle system. Enzymatic catalysis has been conducted in a CO2-based
system rather than in the conventional media to make the enzyme reaction greener. The better
resolution efficiency in high pressure CO2-based micelles could be achieved within a relatively short
period of time compared with other traditional reactive systems.
Received 11th March 2014
Accepted 20th May 2014
DOI: 10.1039/c4ra02131b
www.rsc.org/advances
high interfacial area, with the enzyme anchoring on the
aqueous side of the surfactant interface.
1 Introduction
The water content which is necessary to favour synthesis
reactions in organic media can be achieved by micro-encapsu-
lation of the biocatalyst within reverse micelles. For reverse
micelle system, its challenge is recovering the product from
reverse micelles at large scale due to the presence of the surfac-
tant and other components of the system, making the separation
and purication of the product be more difficult, especially when
it is to be used in foods, pharmaceuticals or other products that
require either non-toxic or highly pure products.
High pressure carbon dioxide has been identied as a ‘green’
solvent with its potential applications for industrial use as it
provides a clean, non-toxic, non-ammable and tunable solvent
system which is easily removed to leave reaction products free
from undesirable organic residues. Therefore, the combination
of biocatalysis and carbon dioxide is extremely attractive. Enzy-
matic catalysis has been conducted in CO2-based system rather
thaninthe conventional mediatomakeenzymereactiongreener.
The rst report on enzyme catalyzed reactions in high pres-
sure CO2 was in 1985 by Randolph et al.,16 Hammond et al.,17
and in 1986 by Nakamura et al.18 Recently, a number of groups
have explored the use of enzymes in high pressure CO2.19–24
However, it was reported that native enzymes were easily deac-
tivated in CO2-based medium because CO2 molecules could
react with 3-amino groups of lysine residues placed on the
enzyme surface to form inhibitory carbamates.25 One attempt to
prevent this phenomenon has been made by using reverse
micelles to stabilize the enzyme in a water pool, and meantime
maintain the benet of high mass diffusivity of high pressure
CO2. For the CO2-based systems, their applications are probably
With the growing demand for environmentally friendly
processes working at ambient conditions, the use of bio-
catalysts in organic synthesis has become an interesting alter-
native to conventional chemical methods.1,2 Enzymes are eco-
friendly biocatalysts that can catalyze chemical reactions under
mild conditions, such as ambient temperature, pressure, and
neutral pH.3,4 The use of enzymes generally circumvents the
need for functional group activation and avoids protection and
deprotection steps required in traditional organic syntheses.5
From a biotechnological viewpoint, conducting enzymatic
reactions in nonaqueous solvents offer new possibilities for
producing valuable chemicals. Their versatility would be further
expended if the enzymatic reactions could be performed in
reverse micelles. Reverse micelles are thermodynamically stable
water droplets dispersed in an organic phase by means of a
surfactant. One of the most important properties of reverse
micelles is their ability to entrap enzymes and other biomole-
cules in their water droplets. In addition, the micelles are
dynamic structures, the substrates and products can be
exchanged between water droplets and bulk organic solvent.
Reverse micelles have wide applications in a variety of elds
including chemical reactions,6–8 material synthesis,9–11 protein
delivery,12–14 drug release15 and so on. A reversed micellar system
is especially suitable for lipases, which are activated in the
presence of a water–oil interface. These systems can provide a
Department of Chemistry, Renmin University of China, Beijing, 100872, P.R. China.
E-mail: zhang_xg@ruc.edu.cn; Fax: +86-10-62515601; Tel: +86-10-62515601
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hindered by the weak solubility for many hydrophiles and by thin-layer chromatography (TLC). Candida antarctica lipase B
proteins of interest.26 Recently, many of amphiphiles have been (CALB) (1000 units per mg solid) was purchased from Sigma
shown to form micelle in carbon dioxide media. For general (China). CALB was used as received. Non-ionic surfactants
case, the reactive rate in high pressure, especially supercritical Tergitol®TMN-3 (99% 5b-C12E3, n ¼ 2.98, Mw ¼ 335), Tergi-
uid system is faster than that performed at atmospheric tol®TMN-6 (90% 5b-C12E8, 10 wt% water, n ¼ 8.32, Mw ¼ 552),
pressure because of the reduced mass-transfer.27,28 The extra Tergitol®TMN-10 (90% 5b-C12E12, 10 wt% water, n ¼ 11.55, Mw
advantages associated with use of CO2 as media for enzymatic ¼ 694) were purchased from Sigma-Aldrich and were used as
reactions are not only related to its low environmental impact received. The chemicals were of G.R. grade and used without
but also due to its chemical properties such as high diffusivity, further purication. Carbon dioxide (99.995% purity) was
tunable solubility with CO2 density, and easy separation of purchased from Beijing Analytical Instruments Inc. Double
solvent from products.
distilled water was used throughout.
There is an increasing trend towards the use of optically pure
enantiomers for drugs and agrochemicals because they are
more effective and have fewer side effects compared with their
racemic mixtures. Ibuprofen, 2-(4-isobutylphenyl)propionic
acid, is a racemic carboxylic acid, is a widely used nonsteroidal
anti-inammatory drug that belongs to the family of 2-arylpro-
pionic acid derivatives. Due to its high medical activity and low
toxicity, ibuprofen is one of the most popular non-prescription
medicines in the world. The pharmaceutical activity of
ibuprofen is dependent on the chirality of the compound. Only
the S-isomer exhibits an anti-inammatory property and is
valuable.29 Enzyme kinetic separation was reported as one of the
best ways to obtain pure (S)-ibuprofen.30 Utilization of lipase in
the resolution of ibuprofen received great interests because of
the mild reaction condition, high enantioselectivity, less side
reactions and environment pollution of enzyme-catalyzed
reactions. However, the biological catalytic processes for chiral
separation oen taken a very long reaction time, and stability
could not be a good guarantee, recycling and reuse were also
encountered many challenges.
In this paper, the CO2-based micelles with the TMN series
surfactants, which were related to poly(ethylene glycol)-2,6,8-
trimethyl-4-nonyl ethers, were used as reactive medium. Enan-
tioselection of racemic ibuprofen catalyzed by Candida antarc-
tica lipase B (CALB) was used as a model reaction. The better
resolution efficiency in high pressure CO2-based micelles could
be achieved within a relatively shorter period of time comparing
with other reactive systems. The effect of reactive parameters,
such as temperature, pH, pressure, and water content on reac-
tive environment and conversion has been discussed.
2.2 Enzymatic dynamic kinetic resolution in CO2-based
micelle system
The apparatus in which the chiral resolution of racemic
ibuprofen catalyzed by CALB (shown in Scheme 1) in CO2-based
micelle was carried out was shown in Fig. 1. In typical experi-
ments, racemic ibuprofen (20.6 mg), propanol (18 ml), sodium
phosphate buffer (25 ml, pH ¼ 7.4) mixed with surfactant TMN-
10 (35 ml) and 3 mg CALB solution were loaded in a high-pres-
sure cell with a working volume of 8 ml. The cell was sealed and
ꢀ
then heated to 45 C with stirring. CO2 was introduced slowly
into the cell until to desired pressure. The mixture was stirred at
600 rpm during the reaction, carried out for 36 hours. Aer
reaction, the cell was cooled to 0 ꢀC and the gas stream was then
vented slowly to ambient pressure through the traps containing
10 ml n-hexane. Thereaer, the cell was opened, and the
remaining residue was extracted with another 20 ml of n-
hexane. The mixture of the two solutions was then ltered
through a water-soluble membrane in order to remove the
lipase. The resulting solution was conducted by HPLC spec-
troscopy analysis. All experiments were performed three times
to calculate the mean x, stand deviation s, and condence
interval of mean Dx of 95%.
2.3 HPLC analysis
The analysis of both enantiomers of ibuprofen was conducted
by an Agilent 1100 high performance liquid chromatography
(HPLC) instrument equipped with a OD-H chiral column (5 mm,
4.6 mm ꢁ 250 mm) and a UV detector. The wavelength of the
detector and the environment of the column oven were set up at
254 nm and 40 ꢀC respectively during the measurement. The
column is capable of separating the (R)- and (S)-enantiomers of
both acid and ester derivatives. The HPLC was performed with
n-hexane–isopropyl alcohol (98/2, HPLC grade, Fisher Scientic
2 Materials and method
2.1 Materials
Racemic ibuprofen was supplied by Xian Lang Hong Biotech-
nology Co. Ltd. Propanol was supplied by Sinopharm Chemical
Reagent Co., Ltd. The standard reference of (S)- and (R)-
ibuprofen were purchased from Sigma. Ibuprofen propyl ester
was synthesized using the method of Patricia de et al.31 in our
lab. Racemic(R,S)-ibuprofen and propanol were dropped into a
round-bottom ask containing hydrochloric acid as the catal-
ysis and the solution was reuxed for 6 hours. Aer the reaction,
ibuprofen propyl ester was leached by adding right amount of
n-hexane. From the reaction mixture ibuprofen propyl
ester was extracted and puried by repeated extraction with
Scheme 1 Kinetic resolution of ibuprofen catalyzed by CALB in CO2-
n-hexane; ibuprofen could be detected in the product as tested based micelle.
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Table 1 Comparison of the chiral resolution of racemic ibuprofen in
different reactive systems
Time
Conversion ees
Entry
Lipase
Solvent
[hour] [%]
[%]
1 (ref. 35) Aspergillus niger Isooctane
168
60
96
>48
>20
>50
62
>70
>70
>90
83
2 (ref. 31) Mucor miehel
SC CO2
3 (ref. 36) APE1547
n-Heptane
CO2-based
micelle
4a
CALB
36
a
The data in this work.
Fig. 1 Schematic diagram of reaction apparatus. (1) CO2 reservoir
tank; (2) high pressure syringe pump; (3) reaction vessel, pressure and
temperature control system; (4) cooling water.
clearly demonstrated that the CO2-based micelle stabilized by
TMN-10 could be used as a suitable reaction medium for the
resolution of racemic ibuprofen. Fig. 2 also showed that the ees
levelled out in CO2-based micelle aer 36 h. The reaction time
was designated as 36 h in following experiments.
Co.) as the mobile phase at a ow rate of 0.5 ml minꢂ1. The
concentration of the (R)- and (S)-ibuprofen ester was deter-
mined periodically, and the ees of the substrate was calculated
by eqn (1).
The dependence of enzymatic activity on the different EO
chain length in the TMN surfactant series were studied also
(Fig. 3). For the TMN series surfactants, the ees values were
increased with an increase in the chain length of EO in TMN.
Possibly, the EO groups in TMN surfactant were favourable for
stabilization of the enzymes. In addition, the relative long-chain
length in TMN-10 could help the esterication and trans-
esterication processes, which resulted in efficient reactive rate
in micelle system.
Temperature, pH, pressure and water content were the most
important environmental factors affecting enzymatic catalysis
in CO2-based micelle system, particularly their activity, enan-
tioselectivity and stability. The effects of these factors on the
chiral resolution of racemic ibuprofen in CO2-based micelle
were systematically investigated.
½Sꢃ ꢂ ½Rꢃ
ees ¼
(1)
½Rꢃ þ ½Sꢃ
3 Results and discussion
The asymmetric synthesis of esters was the most active area of
research; the several lipases combined with the unique prop-
erties of high pressure CO2 have successfully permitted the
chiral resolution of a large number of racemates.32–35
In this study, we compared the chiral resolution of racemic
ibuprofen catalyzed by CALB performed in CO2-based and
hexane-based micelle reactive systems. Fig. 2 showed that in the
case of resolution of racemic ibuprofen catalyzed by enzyme,
reactive equilibrium could be easily achieved in high pressure
CO2-based than in atmosphere hexane-based micelle. The
reason might be attributed to the faster mass transfer effects in
high pressure CO2-based micelle. From the comparison results
of enantio-separation for racemic ibuprofen in different reactive
systems shown in Table 1, we saw that the better resolution
efficiency in high pressure CO2-based micelles could be ach-
ieved within a relatively shorter period of time. The results
3.1 The effect of temperature
The reactive temperature was an important factor that affects
conversion of the substrate and the enzyme activity. For
different reaction systems, the optimum reactive temperature
was determined by experiment. In the CO2-based reverse
micelle system, the dependence of temperature on the yield was
Fig. 2 ees values of the chiral resolution of racemic ibuprofen in Fig. 3 ees values of the chiral resolution of racemic ibuprofen in CO2-
hexane-based and CO2-based micellar systems.
based micelle involved TMN surfactants with different EO chain length.
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solubilized in the micelles. In fact, the buffer solution played a
great role in pH control for the CO2-based micelle.40 The results
for the pH prole were shown in Fig. 5. It is observed that the
pH prole would no longer be bell-shaped fashion; the catalytic
activity of CALB was relatively low in a pH 7 buffer solution. The
enzymatic activity increased to a maximum value at pH 7.4 and
quickly dropped with an increase in the pH value.
3.3 The effect of pressure
The effect of pressure on enantioselection was investigated by
the lipase-catalyzed resolution of ibuprofen at pressures
ranging from 70 to 300 bar with maintaining the temperature at
45 ꢀC. As shown in Fig. 6, the ees values decreased from 66% to
52% when pressure was increased from 70 to 120 bar, and then
increased from 52% to the maximum value 78% with the
pressure increasing from 120 to 250 bar. A further raise of
pressure started to decline the ees. The conversion proles fol-
lowed similar trends with the ees changes with pressure, just a
small rise at 80 bar.
Fig. 4 The conversion and ees values of the chiral resolution of
racemic ibuprofen in CO2-based micelle with TMN-10 at different
temperatures.
measured at 250 bar. Fig. 4 showed the conversion and ees
values of racemic ibuprofen ester under the temperature range
of 25–50 ꢀC at 36 hour of the reaction. The results demonstrated
that the conversion of the substrate and ees increased as the
reaction temperature increased until it reached an optimum
reaction temperature of 45 ꢀC. The ees and conversion of the
racemic ibuprofen obtained at this temperature were 85% and
55% respectively. However, the ees and conversion decreased
rapidly when the temperature was further elevated. A sharp
decay in conversion and ees at 50 ꢀC was mainly due to the
exposure of the enzyme above its optimum temperature for a
long time. The accumulated heat could result in partial deac-
tivation and denaturation of enzyme structure. Temperature
had a positive effect on kinetics, but it had also a negative effect
on enzyme activity. Both effects could be counteracted each
other, and resulted in the optimum temperature. This result
agreed with other reported ndings that the stability of enzyme
decreased with the elevated temperatures, although the initial
reaction rate was high.37 Therefore, based on the results
obtained, the reactive temperature of 45 ꢀC was selected for the
resolution of racemic ibuprofen, for which both rapid reactive
rate and high enzyme activity were essential for an optimum
operation. The actual desired temperature for a reaction was a
temperature at which the enzyme exhibited a constant activity
over a period of time.
Generally, density change with pressure was very sensitive
near the critical region for CO2-based systems. A large change in
density signicantly changed the interactions between CO2 and
Fig. 5 The conversion and ees values of the chiral resolution of
racemic ibuprofen in CO2-based micelle with TMN-10 at different pH.
3.2 The effect of pH
In the enzymatic reaction, the pH effect on lipase activity was
also carefully investigated. In most enzymatic resolution
processes, it has been suggested that the variation in pH of
buffer solution might inuence the chiral selectivity, since the
conformation of an enzyme depended on its ionization
state.38,39 For general case, the lipase might contain both posi-
tively and negatively charged groups, these ionizable groups
constituted part of the active sites and oen involved in acid–
base catalysis. For the CO2-based micelle system, the measure-
ment of pH inside the water pool was difficult; the values of pH
Fig. 6 The conversion and ees values of the chiral resolution of
racemic ibuprofen in CO2-based micelle with TMN-10 at different
mentioned here referred to that of the buffer before it was pressure ranges.
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enzyme, causing the formation of carbamates from CO2 and
free amine groups on the surface of the enzyme.25 The interac-
tions might gradually change the conformation of the enzyme
in response to pressure, and further resulting in a continuous
change in enantioselectivity.41–43 The effect of pressure on
enzymatic reaction in CO2-based systems had been the subject
of investigation in several studies. However, the inuence of
pressure on the biocatalysis reactions was still not fully under-
stood due to contradictory results.44,45 The rising pressure was
accompanied by an increase of the solvating power of high
pressure CO2, which meant the increase of the solubility of the
substrates in CO2. Due to this solvation effect, the partitioning
of the substrates between the high pressure CO2 phase of the
reverse micelle and the immediate vicinity of the enzyme was
changed. The enzyme environment was depleted with regard to
the substrates, which caused a decline in the reaction rate.46
When the partitioning of the substrates shied to the super-
critical phase, a further increase of pressure could no longer
result in a further depletion in the enzyme environment, i.e. the
reactive rate could no longer be affected by the rise of pressure.
For micelle reactive system, the extent of interfacial area offered
more reactive opportunity with the forming of the micelles. The
solubility of water in high pressure CO2 is raised drastically
when the pressure is larger than 100 bar.47 According to the
phase diagrams of water–CO2 microemulsion formed by TMN
series surfactants in the domain of CO2,48 the reactive system
tended to form microheterogeneous CO2-based micelles with
the pressure increasing from 150 to 300 bar. Signicantly
increased interfacial areas favored the substrates approached
the interfacial regions in the micelles, accelerating the reaction
rate. Therefore, the ees values and conversion increased when
the pressure was larger than 150 bar. The ees and conversion
reached a maximum at 250 bar, where the interfacial areas of
the microreactors reached a steady state. With further increase
of the pressure at constant volume, the diluting effect caused a
decrease in conversion at higher CO2 pressure. A common rule
could not be found to identify how pressure affected the activity
of enzyme. From a standpoint of reaction rate, pressure could
affect the reaction rate by changing the rate constant directly.
An increase in pressure resulted in enhancing uid density, and
improved solvating power of the uid.
Fig. 7 The conversion and ees values of the chiral resolution of
racemic ibuprofen in CO2-based micelle with TMN-10 at different
water contents.
Fig. 7 demonstrated that increasing the amount of water was
expected to increase the enzymatic activity of the lipase in the
CO2-based micelle. The ees values and conversion gradually
decreased as the W0 was increased up to 25, aer which further
increasing the W0 could result in the decrease of the ees and
conversion. Generally, a minimum amount of water in the
enzyme vicinity was necessary for maintaining catalytic activity,
i.e. the enzyme needed to be sufficiently hydrated in micelles. If
the water content in micelle was too high, the micelle system
might be separated two phases; the increased humidity might
lead to enzyme deactivation.
4 Conclusions
The chiral resolution of racemic ibuprofen catalyzed by CALB in
CO2-based micelle was explored. The experimental results
demonstrated that CO2-based micelle was used instead of the
conventional oil micelle to improve the greenness of the enzyme
reactions. For the CO2-based micelle with surfactant TMN
series, the ees was enhanced with an increase in the chain
length of EO in TMN. The effects of reaction parameters such as
temperature, pH, pressure, and water content on the reactive
behavior were discussed. The combination of enzyme with high
pressure CO2 represented a promising “green” reaction system
for bioconversions. In such combination, the amount of less
green substances such as surfactants was very small. Studies
along these are now in progress.
3.4 The effect of water
Water concentration was a key factor which played a signicant
role in the enzyme-catalyzed reactions in CO2-based micelles.
Control of the water content was important for optimizing the
activity in enzymatic systems. The amount of water required to
retain catalytic activity was enzyme dependent and varied for
different reactive systems. The size of the water pool could be
tailored by controlling the W0 value (water to surfactant ratio) to
make the micelle mimic a biological system or any other
restricted environment. In common with many micelles, water-
in-CO2 micelle showed a spherical droplet structure for which
the droplet radius was directly proportional to W0 value,49 and
the microenvironment around the enzyme could be tuned
directly by simply changing the W0 value. The results shown in
Acknowledgements
The authors are grateful to the National Nature Science Foun-
dation of China (Grant no. 20876169) for nancial support.
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