Friedel-crafts benzoylation of anisole in ionic liquids: Catalysis, separation, and recycle studies

Article abstract of DOI:10.1021/op800134k

The comparison of three ionic liquid-mediated catalytic processes for the benzoylation of anisole with benzoic anhydride is presented. A detailed understanding of the mechanism by which the zeolite and metal triflate reactions in bis{trifluoromethanesulfonyl}imidebased ionic liquids has been reported previously, and these routes are considered together with an indium chloride-based ionic liquid system. Solvent extraction and vacuum/steam distillation have been assessed as possible workup procedures, and an overall preliminary economic evaluation of each overall process is reported. Although the predominant activity is associated with the in situ formation of a homogeneous acid catalyst, the low cost and facile separation of the zeolite-catalysed process leads to this route being the most economically viable overall option. The results of a continuous flow miniplant based on the zeolite catalyst are also presented and compared with the reaction using a small plug flow reactor.

Full text of DOI:10.1021/op800134k

Organic Process Research & Development 2008, 12, 1156–1163
Friedel-Crafts Benzoylation of Anisole in Ionic Liquids: Catalysis, Separation, and
Recycle Studies
Christopher Hardacre,* Paul Nancarrow, David W. Rooney,* and Jillian M. Thompson
QUILL Research Centre, School of Chemistry and Chemical Engineering, Queen’s UniVersity Belfast,
Belfast BT9 5AG, Northern Ireland
Abstract:
Friedel-Crafts alkylations and acylations were some of the
first synthetic reactions carried out in ionic liquids with the
4
The comparison of three ionic liquid-mediated catalytic processes
for the benzoylation of anisole with benzoic anhydride is presented.
A detailed understanding of the mechanism by which the zeolite
and metal triflate reactions in bis{trifluoromethanesulfonyl}imide-
based ionic liquids has been reported previously, and these routes
are considered together with an indium chloride-based ionic liquid
system. Solvent extraction and vacuum/steam distillation have been
assessed as possible workup procedures, and an overall prelimi-
nary economic evaluation of each overall process is reported.
Although the predominant activity is associated with the in situ
formation of a homogeneous acid catalyst, the low cost and facile
separation of the zeolite-catalysed process leads to this route being
the most economically viable overall option. The results of a
continuous flow miniplant based on the zeolite catalyst are also
presented and compared with the reaction using a small plug flow
reactor.
acylation of benzene, toluene, and chlorobenzene in a chloro-
aluminate system, where the ionic liquid behaves both as a
solvent and a catalyst. These reactions are catalysed by Lewis
3 3
acids, such as BF or AlCl , and various properties of ionic
liquids make them attractive from a reaction and process
engineering perspective. For example, their ability to dissolve
both metal catalysts and organic reagents allows improved
contact of substrates and catalysts, whilst their negligible vapour
5
pressure can aid the separation of products. However, in the
case of ionic liquid-mediated acylation reactions, the chloro-
aluminate-based systems also complex with the ketone product,
as found with the conventional AlCl
reactions offer no advantages for scale-up.
The issue of hydrolysis of the AlCl may be overcome by
3
process, and these
3
6
replacing the aluminium with indium. Recently, in our labora-
tory we reported an ionic liquid process for the benzoylation
7
of anisole using a chloroindate melt where the product isolation
was performed using an aqueous extraction and the ionic liquid
Introduction
shown to be recyclable. Metal triflate and bis{trifluoromethane-
The industrial manufacture of aryl ketones is conventionally
carried out by the aluminium trichloride-mediated Friedel-Crafts
acylation of aromatic substrates. The products of such reactions
are intermediates or final products in many important processes
such as the formation of pharmaceuticals Ibuprofen and (S)-
naproxen and in pesticides and fragrances; however, due to the
formation of a complex with the ketone product a stoichiometric
excess of aluminium trichloride is used which, following
hydrolysis required for product isolation, generates large quanti-
ties of metal salt waste. Alternatively, the reaction can be
catalysed by HF; however, its toxicity and corrosive nature
causes difficulties in the construction and operation of any plant.
In addition, current industrial acylation processes require the
use of large quantities of volatile organic compounds (VOCs)
as solvents, which are detrimental to the environment. Therefore,
much research is being conducted to develop a truly catalytic
reaction, where the catalyst does not form a complex with the
product, making it recyclable, while also minimising the use
of VOCs. Ionic liquids have been successfully used as alterna-
tive reaction media for a wide variety of reactions including
-
sulfonyl}imide ([NTf
2
] ) salts have also been shown to catalyse
8-11
Friedel-Crafts acylations in both organic solvents
and in
12,13
ionic liquids.
Importantly, recently it has been demonstrated
that, in ionic liquids, the metal triflate salt may not be the catalyst
but instead acts as a catalyst precursor which forms a Brønsted
14
acid, such as HOTf. Similar results were also found for solid
acid-catalysed Friedel-Crafts processes in ionic liquids using
15
16
heteropolyacids and zeolites. In this case, the acidic proton
(
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7) Earle, M. J.; Hakala, U.; Hardacre, C.; Karkkainen, J.; McAuley, B. J.;
Rooney, D. W.; Seddon, K. R.; Thompson, J. M.; Wahala, K. Chem.
Commun. 2005, 903, 905.
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(
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Friedel-Crafts, and their negligible volatility gives them an
environmental advantage over traditional molecular solvents.
2
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(
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*
Authors for correspondence: E-mail: c.hardacre@qub.ac.uk; d.rooney@
(14) Goodrich, P.; Hardacre, C.; Mehdi, H.; Nancarrow, P.; Rooney, D. W.;
Thompson, J. M. Ind. Eng. Chem. Res. 2006, 45, 6640–6647.
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A 2004, 212, 301.
qub.ac.uk.
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1) P aˆ rvulescu, V. I.; Hardacre, C. Chem. ReV. 2007, 107, 2615–2665.
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D. W.; Thompson, J. M. J. Catal. 2004, 227, 44–52.
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1
156
•
Vol. 12, No. 6, 2008 / Organic Process Research & Development
10.1021/op800134k CCC: $40.75  2008 American Chemical Society
Published on Web 10/15/2008

Scheme 1. Formation of 4-methoxybenzophenone and
benzoic acid from the benzoylation of anisole
in the zeolite, for example, undergoes cation exchange with the
ionic liquid 1-butyl-3-methyl imidazolium bis{trifluoromethane-
4 2
sulfonyl}imide ([C mim][NTf ]) resulting in the formation of
HNTf . In each system, the homogeneous acid formed acts as
2
the main catalyst for the reaction.
While there are a number of ionic liquid-mediated catalytic
routes, as discussed above, some facilitate product recovery and
ionic liquid recycle better than others. In addition, for the
purposes of process design the physical properties of the ionic
liquids must be considered. For example their relatively high
viscosities, when compared to typical organic solvents, will have
implications on heat-, mass-, and momentum-transport processes.
Therefore, it is only through optimisation of the combined
reaction and separation methods that the most effective overall
combination of catalyst and ionic liquid can be determined. A
range of separation methods are available for use with ionic
liquids such as liquid-liquid extractants, including supercritical
Figure 1. Effect of increasing the temperature after the initial
decrease in conversion on the zeolite-catalysed benzoylation of
anisole (A) using benzoic anhydride (B) to produce 4-methoxy-
benzophenone (4-MBP). Reaction conditions: residence time
0 s, 1.5 mol dm- limiting reactant, 0.85 mol dm [C
3
-3
mim]-
], temperature 90 °C for first 20 min (2:1 A:B, dashed
line) or 40 min (1:2 A:B solid line), followed by an increase to
50 °C.
1
2
[
NTf
2
1
23
it can be widely applied. Supercritical carbon dioxide extrac-
tion is a promising method due to the ability to dramatically
change the solubility of components in the supercritical fluid
by varying the pressure and temperature whilst the ionic liquid
17-22
23
24
2
CO ,
membrane separation, crystallisation, and distil-
lation. The latter is an obvious choice for removing volatile
components from the ionic liquid. However, the presence of
ionic liquid can significantly reduce the vapour pressures of
21
2
is insoluble in the CO phase. However, a significant barrier
to industrial uptake is the relatively high plant and equipment
costs associated with supercritical fluids. If ionic liquids are to
be used on a significant scale in industrial processes in the near
future, there is a need to apply well-established separation
technologies.
2
5,26
many components.
Together with the relatively high viscosi-
2
7
ties of ionic liquids which reduces the mass transfer rate from
the liquid to vapour phase, high energy costs and long workup
times are required to achieve adequate separation. An additional
problem is that many ionic liquids begin to decompose at around
In this current study, the results of a relatively large-scale
3
2
8
(500 cm reactor volume) zeolite-catalysed Friedel-Crafts
3
00 °C. It is, therefore, imperative that processing temperatures
benzoylation of anisole to form 4-methoxybenzophenone,
Scheme 1, in ionic liquids are reported. The zeolite-mediated
are kept well below the temperature at which decomposition is
initiated in order to prevent product contamination and loss of
the expensive ionic liquid. In such cases selective membrane
separation may offer the advantages of a relatively lower energy
input, and suitability for temperature-sensitive components.
While recent studies have shown membrane technology to be
a promising separation method for ionic liquid-based systems
the technology still requires significant development work before
16
process in the ionic liquids is compared with the reactions
14
7
catalysed by metal triflate salts and indium chloride as well
as with molecular solvent-based reactions. In addition, a
comparison of liquid-liquid extraction and steam distillation
separation techniques for zeolite-ionic liquid, metal salt-ionic
liquid, and chloroindate ionic liquid-catalysed systems is
provided for the first time. This shows the importance of
understanding the workup as well as the reaction in determining
the best comparator from which to benchmark the process
against molecular solvent processes.
(
17) Zhao, H.; Xia, S. Q.; Ma, P. S. J. Chem. Technol. Biotechnol. 2005,
8
0, 1089–1096.
(
(
18) Cole-Hamilton, D. J. AdV. Synth. Catal. 2006, 348, 1341–1351.
19) B o¨ smann, A.; Franci o` , G.; Janssen, E.; Solinas, M.; Leitner, W.;
Wasserschied, P. Angew. Chem., Int. Ed. 2001, 40, 2697–2699.
20) Kroon, M. C.; van Spronsen, J.; Peters, C. J.; Sheldon, R. A.; Witkamp,
G. J. Green Chem. 2006, 8, 246–249.
(
(
(
(
(
(
(
Results and Discussion
21) Blanchard, L. A.; Brennecke, J. F. Ind. Eng. Chem. Res. 2001, 40,
Catalysis Studies. From the initial studies of ionic liquid-
mediated zeolite-catalysed Friedel-Crafts acylation reactions,
the predominant catalyst was shown to be a homogeneous acid
formed by the cation exchange of the ionic liquid with the
2
87–292.
22) Zayed, F.; Greiner, L.; Schulz, P. S.; Lapkin, A.; Leitner, W. Chem.
Commun. 2008, 79–81.
23) Wong, H. T.; Pink, C. J.; Ferreira, F. C.; Livingston, A. G. Green
Chem. 2006, 8, 373–379.
16
surface protons of the zeolite. This effect is clearly illustrated
24) Reichert, W. M.; Holbrey, J. D.; Vigour, K. B.; Morgan, T. D.; Broker,
G. A.; Rogers, R. D. Chem. Commun. 2006, 4767.
25) Zhao, J.; Dong, C. C.; Li, C. X.; Meng, H.; Wang, Z. H. Fluid Phase
Equilib. 2006, 242, 147–153.
by the rapid reduction in activity of the catalyst with time-on-
stream at 90 °C, Figure 1, for both anisole-rich and benzoic
anhydride-rich reaction mixtures using a plug flow reactor. On
increasing the temperature to 150 °C, a significant increase in
activity was observed which also showed a subsequent loss in
conversion with reaction time albeit at a much slower rate than
26) Shiflett, M. B.; Yokozeki, A. J. Chem. Eng. Data 2006, 51, 1931–
1
939.
(
(
27) Wilkes, J. S. J. Mol. Catal. A 2004, 214, 11–17.
28) Ngo, H. L.; LeCompte, K.; Hargens, L.; McEwen, A. B. Thermochim.
Acta 2000, 357, 97–102.
Vol. 12, No. 6, 2008 / Organic Process Research & Development
•
1157

At temperatures below 70 °C, benzoic acid, a valuable byprod-
uct with applications as an additive in food and pharmaceuticals,
precipitated from the reaction mixture and could be removed
by vacuum filtration. However, it carried with it an orange
colour, thus making it undesirable for such industries. Recovery
of 4-methoxybenzophenone using similar precipitation or crys-
tallisation strategies was found to be more difficult due to its
high affinity for the ionic liquid. Such effects have been reported
21
4 6
by Blanchard and Brennecke for [C mim][PF ] where com-
pounds with high polarity and high aromaticity, in particular
aromatic ketones, favour the ionic liquid phase. At high
concentrations precipitation of the 4-methoxybenzophenone
product from a pure ionic liquid was possible; however, this
method was not successful when using typical reaction mixtures.
For each Friedel-Crafts system examined in detail previ-
16
14
7
ously, i.e. zeolite, metal triflate salts, and indium chloride -
mediated reactions, significant scale up issues associated with
ionic liquid/catalyst recycle and workup needed to be addressed.
The choice of workup is predominantly determined by the
mechanism by which the catalysts operate. The efficiency of
this process step significantly affects the viability of the ionic
liquid processes over those under solventless or molecular
solvent conditions, despite the fact that benchmarking the
activity in each system indicates that the addition of ionic liquid
increases the rate of reaction albeit with the reaction possibly
occurring via a different catalytic mechanism. Due to little
Figure 2. Effect of the anisole (A) to benzoic anhydride (B)
ratio on the outlet concentration of 4-methoxybenzophenone-
(
4-MBP) for the zeolite-catalysed benzoylation reaction. Reac-
-3
tion conditions: residence time 10 s, 1.5 mol dm limiting
reactant, solvent-free temperature 90 °C.
that found at 90 °C. At the higher temperature, it is possible
that the increase in activity may be due to further cation
exchange at sites which become accessible on expansion of the
zeolite framework. Previously we have reported that at 80 °C
16
only 49% of the zeolite sites were found to be exchangeable.
However, since the activity levels off to a point above zero, it
is likely that some heterogeneous catalytic activity of the zeolite
also contributes, even though this is a minor component.
The similarity of the time-on-stream profile for both anisole-
rich and benzoic anhydride-rich reaction mixtures in the ionic
liquid is in contrast with the behaviour under solventless
conditions, Figure 2. In the absence of solvent, lower initial
activity was observed compared with the reaction in the
presence of ionic liquid; however, neither a 2:1 or a 1:2 ratio
of anisole:benzoic anhydride showed the rapid initial decrease
in conversion observed with the ionic liquid system. Under the
solventless conditions, the zeolite behaves predominantly as a
heterogeneous catalyst with the slow decrease in activity
observed associated with surface deactivation through poisoning
of the catalyst. This effect is less pronounced for the anisole-
rich reaction mixtures where not only are higher conversions
obtained but also the activity remains approximately constant
with time-on-stream. In contrast, an excess of benzoic anhydride
results in a gradual decrease in 4-methoxybenzophenone yield.
These results are consistent with those reported by Derouane
-
-
reaction in hydrophilic ionic liquids based on [BF
4
] and [OTf]
] where high
anions, reactions were carried out in [C mim][NTf
4
2
conversions were obtained for all catalyst systems. Detailed
examination of both the zeolite and metal triflate routes indicates
that the major catalytic species is the highly active HNTf
2
when
-
reactions are performed in [NTf
2
] -based ionic liquids. In the
case of the chloroindate ionic liquids the catalytically active
species has not been determined unequivocally as, when the
4
ionic liquid is synthesised from combinations of [C mim]Cl and
InCl , a high-density, viscous suspension is formed. Two main
3
workup procedures have been evaluated for the acylation
reaction studied herein, namely, solvent extraction and distillation.
SolVent Extraction. Solvent extraction is a common strategy
employed for ionic liquids and is a mature separation technol-
ogy; however, a number of characteristics must be considered
when determining the most suitable solvent for an extraction
process, such as cost, toxicity, flammability, and freezing and
boiling points. Overall, the selectivity for the solute relative to
31
the carrier is normally given the highest priority. To determine
the most selective agents, a large number of organic solvents
were screened for use in the liquid-liquid extraction of
29,30
et al.
where anisole acts as a solvent and maintains a clean
surface, whereas at lower concentrations of anisole, there is a
buildup of products on the surface of the catalyst which slowly
deactivates the system.
Comparison of Workup Processes. Effective product
separation from ionic liquids, in general, still remains one of
the most significant drawbacks for their implementation within
industrial processes and, therefore, must also be taken into
consideration when developing an overall ionic liquid process.
2 2
4-methoxybenzophenone from [C mim][NTf ]. Table 1 shows
the percentage extraction of 4-methoxybenzophenone from the
ionic liquid into an equal volume of each solvent. All the
solvents chosen have relatively low miscibility with the ionic
liquids and are considered to be less harmful or polluting than
halogenated solvents. Aromatic solvents showed the highest
extraction ability compared with aliphatic solvents. In all cases
except hexane and cyclohexane, a small amount of the extractant
dissolved in the ionic liquid layer; however, in each case the
(
29) Derouane, E. G.; Dillon, C. J.; Bethell, D.; Derouane-AbdHamid, S. B.
J. Catal. 1999, 187, 209–218.
(
30) Derouane, E. G.; Crehan, G.; Dillon, C. J.; Bethell, D.; He., H.;
Derouane-AbdHamid, S. B. J. Catal. 2000, 194, 410–423.
(31) Seader, J. D.; Henley, E. J. Separation Process Principles; John Wiley
& Sons: New York, 1998.
1
158
•
Vol. 12, No. 6, 2008 / Organic Process Research & Development

Table 1. Comparison of various solvents for the extraction
of 4-methoxybenzophenone from [C mim][NTf
2
2
]
priceb
(relative
%
boiling
a
solvent
extraction point (°C) flammability to hexane)
hexane
21.3
79.8
73.4
73.7
75.6
70
27.2
32.3
35.9
48.5
33.6
68-69 high
1.00
1.00
3.74
1.81
2.34
0.69
0.75
0.41
0.48
0.74
0.35
mesitylene
163-165 medium
182-183 medium
172-173 medium
173-174 medium
167-168 medium
80-81 high
n-butylbenzene
isobutylbenzene
sec-butylbenzene
tert-butylbenzene
cyclohexane
o-xylene
p-xylene
tert-butyltoluene
dibutylether
143-145 medium
137-138 medium
189-192 medium
140-142 medium
a
Indicates the percentage of 4-methoxybenzophenone extracted from a standard
b
2 2
solution in [C mim][NTf ] into 5 mL of the solvent. Prices taken from Sigma
Aldrich for laboratory grade and used as an indication only.
ionic liquid content in the extractant layer was below the NMR
detection limit.
Mesitylene was chosen for further study as it is resistant to
Friedel-Crafts acylation preventing the formation of any
unwanted side products on recycle. Although the boiling point
is high, relative to those of other extractants such as hexane,
the added energy costs for solvent recovery would be balanced
by its superior product separation ability. Figure 3a shows the
2 2
ternary phase diagram of the [C mim][NTf ]/mesitylene/
4-methoxybenzophenone system at 20 °C. It is notable that the
points representing the extraction layer, i.e. mesitylene-rich, are
all on the left axis, showing that over a range of compositions
the contamination of this layer by ionic liquid is below detection
2 2
limits. Points A and B represent the solubility of [C mim][NTf ]
in mesitylene and mesitylene in [C mim][NTf ], respectively.
2
2
Figure 3. Ternary phase diagrams for the 4-methoxybenzophe-
none/[C mim][NTf ]/mesitylene system at (a) 20 °C, (b) 50 °C,
and (c) 80 °C.
With increasing concentration of 4-methoxybenzophenone the
system remains biphasic until point C where the system
becomes monophasic. Point C represents the limit of solubility
of 4-methoxybenzophenone in mesitylene.
2
2
It should be noted that, while solvent extraction proved to
be successful in recovering product from the ionic liquid
reaction mixture with a purity of >98% as determined by NMR
and HPLC, the product was coloured orange. It was observed
that, during reaction in the ionic liquid using the zeolite or the
metal triflates, the mixture became progressively more orange
with the catalyst remaining white (in the case of the zeolite).
In both cases this colour was transferred to the product during
extraction. Therefore, solvent extraction may not be suitable
when visual purity of the product is required. Interestingly, under
solventless conditions and in molecular solvents, the zeolite
becomes orange which has been attributed to formation of an
acyl complex with the zeolite during the heterogeneously
2 2
An examination of the [C mim][NTf ] layer, shows that in
contrast with the extraction phase, the points lie away from the
right axis, indicating that a significant amount of the mesitylene
is dissolved in this layer. This phenomenon becomes clearer
with increasing 4-methoxybenzophenone concentrations. From
this data we can estimate that >97% recovery of 1 kg of product
from ionic liquid (600 g) can be achieved using approximately
4
.8 kg of solvent over 3 extractions (1.6 kg of solvent per
extraction).
Diagrams b and c of Figure 3 show the ternary phase
equilibria experiments at 50 and 80 °C, respectively. Although
the temperature has very little effect on the shape or position
of the equilibrium curve, temperature does have a small effect
on the slope of the tie lines between equilibrium points. At 20
29,30
catalysed reaction.
In the case of the chloroindate reactions, the ionic liquid
can be extracted from the product mixture by the addition of
7
°C, the tie lines have a small positive gradient which becomes
water. In order to facilitate the separation of the water layer
more negative as the temperature is raised, indicating increased
extraction at higher temperatures. While this efficiency benefit
is small and therefore unlikely to outweigh the increased energy
costs associated with the higher operating temperatures if
beginning at room temperature, it would be more beneficial
during continuous operation where the reaction is already
operating at these higher temperatures.
from the organic, excess anisole, i.e. the reagent, was added to
decrease the viscosity of the organic layer. After at least five
washing procedures using an equal mass of water to ionic liquid,
the aqueous extracts were combined and concentrated in vacuo
to yield the original chloroindate ionic liquid. Recycling of the
anisole-benzoic anhydride reaction system was carried out in
this way, up to a total of 6 runs where the yield of 4-methoxy-
Vol. 12, No. 6, 2008 / Organic Process Research & Development
•
1159

Figure 5. Effect of high-vacuum treatment on the activity of
[C mim][NTf ] doped with HNTf as the catalyst system for
the benzoylation of anisole using benzoic anhydride. Reaction
Figure 4. Recycle studies on the 1-butyl-3-methyl imidazolium
chloroindate, [C mim]Cl-InCl (X(InCl ) ) 0.67), ionic liquid-
catalysed benzoylation reaction of anisole using benzoic anhy-
dride, showing the effect of the number of recycle runs on the
conversion and indium concentration of the product. Reaction
conditions: temperature 80 °C, anisole (9.95 g, 92.0 mmol),
2
2
2
4
3
3
-3
conditions: temperature 90 °C, 1.5 mol dm anisole, 3.1 mol
-3
dm benzoic anhydride.
2 2 2
To this end, a solution of HNTf in [C mim][NTf ], which is
known to be the major active catalyst in the zeolite reaction,
was heated to 150 °C under high vacuum for 3 h and its activity
re-examined. Figure 5 shows the comparison of the catalytic
activity of the solution before and after vacuum treatment. A
small decrease in the activity was observed, which was
benzoic anhydride (23 g, 102 mmol), 5 mol % free InCl
respect to anisole.
3
with
benzophenone obtained in general showed a slight decrease over
each recycle, Figure 4. As in the zeolite and metal triflate
reactions the colour of the reaction mixture turned from
colourless to deep orange. This disappeared almost completely
during the washing/extraction procedure, and although the
recovered ionic liquid was slightly coloured at the beginning
of successive runs, no significant change was observed for the
recycles. Despite the easier product extraction relative to the
mesitylene extraction in the zeolite and metal triflate reactions,
indium compounds are generally classified as toxic; therefore,
any catalyst leaching would be problematic when considering
scale up of this process. Samples of isolated product were tested
using ICP analysis where it was found that the indium content
was on average 0.36 ( 0.09 ppm per reaction over the 6 runs,
Figure 4, thereby necessitating further purification steps to
reduce the toxicity level.
surprising, given that the boiling point of HNTf is 90 °C under
2
atmospheric pressure. While this indicates that vacuum distil-
lation may be a useful method of separating the reaction
products from the ionic liquid, this was not the case, as further
studies showed that 4-methoxybenzophenone could not be easily
recovered under such conditions.
Steam distillation, via superheated steam, is used in a variety
of industries for the removal of organic material from waste-
water, soil, and carbon adsorption columns. Organic reagents
that are insoluble in water can be removed from the condensate
by decantation or filtration whilst those that are soluble are
isolated by further evaporation of the water. As the products
used in this reaction are insoluble in cold water, this system
was considered ideal for product isolation. In a setup similar to
that of the vacuum distillation experiment discussed above the
Distillation. Since ionic liquids are considered nonvolatile
32
unless operating under extreme conditions, evaporation or
distillation of the products is often considered to be an ideal
method for product recovery. As distillation relies on the ability
of the products to be volatilised rather than the solvent, this
can cause problems when the boiling point of the product is
high and therefore close to the thermal decomposition of the
activity of a HNTf solution was tested before and after contact
2
with superheated steam at 130 °C and 1 atm pressure for 3 h.
Figure 6 shows that in this case the catalyst is either destroyed
or removed from the ionic liquid as there is no activity in the
steam-distilled ionic liquid. However these small scale studies
did show that clean product recovery was possible.
ionic liquid. Here thermogravimetric analysis of [C
2
mim][NTf
2
]
Recycle and Scale Up Studies. A preliminary comparison
of the three methods indicated that the zeolite-catalysed reaction
was the least expensive in terms of catalyst cost (based on
September 2007 Sigma Aldrich prices). This is mostly due to
the high costs associated with the indium chloride and indium
indicated that the ionic liquid was stable up to 350 °C; however,
there was a significant loss of mass at 300 °C with almost 50%
lost after heating for 15 h, thus negating direct distillation of
the 4-methoxybenzophenone product (355 °C). In such cases
this type of problem is often mitigated by using vacuum or
steam distillation. Vacuum distillation was investigated as a
possible method of removing reaction products while preserving
the catalytic activity of the zeolite-acid-ionic liquid solution.
triflate salts as well as the high price of HNTf relative to that
2
of its lithium salt which is used in the production of the ionic
liquid. Of the product extraction strategies the steam distillation
proved to be the most effective for meeting the criteria in terms
of overall purity and colour.
Larger-scale studies on the recycle of both zeolite and ionic
liquid were carried out using the miniplant, Figure 7. Figure 8
(
32) Earle, M. J.; Esperan c¸ a, J. M. S. S.; Gilea, M. A.; Canongia Lopes,
J. N.; Rebelo, L. P. N.; Magee, J. W.; Seddon, K. R.; Widegren, J. A.
Nature 2006, 439, 831–834.
1
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32
to decomposition of the ionic liquid, vaporisation of the ionic
liquid, or mechanical loss due to entrainment in the high-velocity
steam.
Conclusions
There are a number of routes available for the benzoylation
of anisole when using ionic liquids when performed in batch
mode, with each route presenting increased rates when com-
pared to similar systems without the addition of the ionic liquid.
Our preliminary studies using chloroindate ionic liquid melts
2 2
as well as metal triflates and zeolites in [C mim][NTf ] indicated
that the zeolite process was the most cost-effective in terms of
the catalyst cost even though this resulted in the loss of ionic
liquid due to exchange with the catalyst surface. Previous studies
have shown that approximately 49% of the acid sites on the
Figure 6. Effect of steam distillation on the activity of
mim][NTf ] doped with HNTf as the catalyst system for
the benzoylation of anisole. Reaction conditions: temperature
2 2
zeolite were exchanged with [C mim] with 76.6 mg of HNTf
[
C
2
2
2
acid produced per gram of zeolite used. This translates to
approximately 12.9 g (0.033 mol) of ionic liquid consumed per
kg (4.71 mol) of product (based on a 90% conversion in a
typical batch experiment). It should be noted that much cheaper
cations could however be used for this exchange. While the
bulk of the activity stems from the generation of this acid there
is evidence that some heterogeneous activity remains although
the level of activity is considerably lower than nonionic liquid
system when excess anisole is used as the solvent.
-
3
-3
9
0 °C, 1.5 mol dm anisole, 3.1 mol dm benzoic anhydride.
shows the recycle of the zeolite using fresh batches of ionic
liquid for runs 1 and 2 and the recycle of the zeolite and ionic
liquid for run 3. In each case, the zeolite was regenerated
between reactions by first washing with acetonitrile and then
heating to 500 °C under air. Both the regenerated zeolite and
the ionic liquid show good recyclability.
As found for the small PFR, operation of the larger fixed
bed in the miniplant in continuous mode, Figure 9, shows that
there is a rapid decrease in conversion with time on stream,
demonstrating the exchange of the acidic proton on the surface
of the zeolite with the cation of the ionic liquid. However, even
after 1300 min on stream, some activity remains. The temper-
ature was then increased from 90 to 130 °C, and as expected,
the concentration of product in the outlet stream increased again
followed by a slower decrease in conversion than that observed
at 90 °C.
When considering continuous operation, where product
extraction and ionic liquid recycle are taken into account, the
normally quoted advantages of ionic liquids, in terms of low
volatility and high solubility of reactants, become disadvanta-
geous as they complicate product recovery and ionic liquid
recycle. Of the separation strategies investigated here i.e.
precipitation/crystallisation, solvent extraction, direct distillation
and vacuum/steam-distillation, only the latter method was able
to recover product of suitable quality. However, this too resulted
in additional losses of ionic liquid due either to its slight
volatility or more likely due to physical entrainment from the
steam-distillation vessel. It is interesting to note that the first
In the miniplant, the separator was operated at atmospheric
-1
33
pressure using a steam flow of approximately 32 g min where
it was shown that the anisole was removed at 130 °C, the
benzoic acid at 150 °C and 4-methoxybenzophenone at 250
commercial ionic liquid processes i.e. BASF’s BASIL process
is a two phase process where by the ionic liquid is the product
and phase separates from the reaction mixture. Similarly IFP’s
butenes dimerisation (Difasol) process uses a liquid-liquid
°C. The anisole was separated by simple decantation from the
34
separation tank, whereas the benzoic acid was soluble in the
hot condensed steam but was easily recovered by further cooling
and filtration. Within the distillation vessel any unreacted
benzoic anhydride was converted to benzoic acid under the
conditions of the separation. The 4-methoxybenzophenone was
recovered as an oily liquid which could be either decanted from
the hot water or if cooled isolated by filtration. This fraction
was then further purified by washing with 2 M sodium
hydroxide solution giving a pale-cream powder. In this way
biphasic reaction using an ionic liquid catalyst. Therefore one
could conclude that efficient and simple product separation is
the most significant factor for the commercial exploitation of
ionic liquids.
Despite the fact the ionic liquids have been shown not to be
as good as nonionic liquid routes for the Friedel-Crafts
benzoylation of anisole we have shown that such ionic liquid
processes can be scaled up effectively to >300 g/batch using
zeolite catalysts and that they can be recycled numerous times
with losses attributed to a mixture of exchange and mechanical
losses. It can also be noted that after 250 h of operation, between
batch and continuous operation no corrosion of the pump head
or valves was observed.
4
9
-methoxybenzophenone was isolated in 99.5% purity with
4.7% selectivity to the 4-isomer.
In contrast to the orange-coloured benzoic acid which was
filtered from the cooled reaction mixture, on using steam
distillation, white needlelike crystals were obtained. However,
some loss of the ionic liquid was observed (∼5% by weight
over the 2 h separation period), and it is unclear if this was due
(
(
33) Freemantle, M. Chem. Eng. News 2003, 81, 13–9.
34) Favre, F.; Forestiere, A.; Hugues, F.; Olivier-Bourbigou, H.; Chodorge,
J. A. Oil Gas-Eur. Mag. 2005, 31 (2), 83–87.
Vol. 12, No. 6, 2008 / Organic Process Research & Development
•
1161

Figure 7. Schematic diagram of the miniplant.
Figure 8. Batch recycle studies carried out on the miniplant.
Figure 9. Outlet concentration of 4-methoxybenzophenone
-3
Reaction conditions: temperature 90 °C, 1.6 mol dm anisole,
(4-MBP) from continuous reaction carried out on the miniplant.
-
3
-3
3
.3 mol dm benzoic anhydride, 9 g of zeolite, flow rate 500
Reaction conditions: temperature 90 °C, 1.6 mol dm anisole,
3
-1
-3
cm min
.
3.3 mol dm benzoic anhydride, 9 g of zeolite, flow rate 24
3
-1
cm h , residence time 30 min.
Experimental Section
size. The ionic liquids, 1-ethyl-3-methylimidazolium bis(tri-
Materials. Anisole (99%) and benzoic anhydride (98%)
were obtained from Lancaster. H-USY-29 zeolite samples were
provided from QUILL industrial partners and were calcined in
air at 500 °C overnight prior to use. The measured BET surface
area and pore volume of the catalyst were determined as 625.8
fluoromethylsulfonyl)imide ([C
methyl imidazolium chloroindate, ([C
fraction of InCl , X(InCl ) ) 0.67)), were synthesised according
2 2
mim][NTf ]) and 1-butyl-3-
4
mim]Cl-InCl
3
(mole
3
3
7,35
to a standard literature procedure. Prior to use ionic liquids
2
-1
3
-1
were dried in vacuo at 60 °C for more than 4 h and contained
m g and 0.396 cm g , respectively. Where required, the
zeolite pellets were formed from the powder by compression
to 6 tons crushed and then sieved to the appropriate particle
(
35) Bonh oˆ te, P.; Dias, A. P.; Papageorgiou, N.; Kalyanasundram, K.;
Gr a¨ tzel, M. Inorg. Chem. 1996, 1168, 1178.
1
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<
0.01 wt % water, determined by Karl Fischer analysis. The
in the fixed bed by first washing with acetonitrile to remove
excess ionic liquid and then by passing a slow stream of
compressed air through the system at 500 °C over the catalyst
bed.
densities of the ionic liquid and reagent mixtures, used to
calculate concentrations, were obtained using an Anton Parr
DMA4500 densitometer.
Small-Scale Reaction Procedure. The procedure for the
small-scale continuous flow experiments in a plug flow reactor
(
Catalytic reactions carried out using the ionic liquid, 1-
butyl-3-methyl imidazolium chloroindate ([C
4
mim]Cl-InCl
3
PFR) was as described previously.16
(X(InCl ) ) 0.67)) (3.50 g), were carried out in a round-
3
The miniplant (1.2 m × 1.5 m), Figure 7a, was accom-
bottomed flask equipped with a magnetic stirrer, at 80 °C, with
anisole (0.113 mol) and benzoic anhydride (0.124 mol), giving
a free indium content of 5 mol % with respect to anisole. The
system was recycled by adding excess anisole and removing
the ionic liquid by washing with water at least five times with
an equal mass of water to ionic liquid. The aqueous extracts
were combined and concentrated in vacuo to yield the original
chloroindate ionic liquid. Fresh anisole and benzoic anhydride
were added, and the system was recycled in this way, over 6
runs.
modated in a fume hood, and all pipe work, unions, and valves
were constructed from 1/4′′ stainless steel. Reagents [C
NTf ] (0.21 mol), anisole (0.39 mol), and benzoic anhydride
0.78 mol) were transferred from the feed tank to the holding
2
mim]-
[
(
2
tank using a peristaltic pump (Watson-Marlow, 101U) and a
gear pump (March May with a Fluid o Tech MGK209XPS17
gear head) was used to circulate reaction mixture at a flow rate
3
-1
of 500 cm min round the reaction loop. The holding tank
3
3
(
500 cm ) and steam-distillation vessel (1000 cm ) were
constructed from Pyrex glass with lids of mild steel lined with
PTFE to minimise corrosion. The catalyst bed (1/2′′ OD pipe)
and drying column were heated by Carbolite furnaces, and the
glass vessels were heated by band heaters. To prevent precipita-
tion of benzoic acid from the reaction mixture below 70 °C,
all pipe work in the reaction line was trace heated.
The catalyst bed was charged with 9 g of zeolite which had
a particle size in the range 650-800 µm. The drying column
was filled with 4 Å molecular sieve, and the carbon column
contained activated charcoal granules. Fine mesh was used to
keep the material in place.
Offline analysis was carried out using an Agilent HPLC
system with a diode array detector set at 224 nm. Samples of
known mass (∼30 mg) were removed over time and dissolved
3
in acetonitrile (10 cm ), an Eclipse XDB-C8 column with an
3
-1
eluent of methanol/water (60:40) at a flow rate of 1.0 cm min
was used. Quantification of the conversions was performed
using calibration curves for anisole and 4-methoxybenzophe-
none from known standards. In all cases conversions are
reported as the percentage conversion to 4-methoxybenzophe-
none. For all reactions, mass balances based on anisole and
4-methoxybenzophenone of greater than 95% were obtained.
Solvent Extraction. Screening of different solvents for
The miniplant was designed to be operable as a batch or
continuous system. When running as a batch process, a solution
of the reagents and solvent were placed in the feed tank and
passed round the heating loop until the required temperature
was reached. At this point the reaction mixture was passed over
the catalyst bed and round the reaction loop. On completion of
the reaction, the mixture was transferred to the steam-distillation
vessel for product isolation in batch mode. To operate the
system as a continuous process, the feedstock was fed into the
extracting the product, 4-methoxybenzophenone, from [C
2
mim]-
[NTf ] was performed by stirring a mixture of 4-methoxyben-
2
zophenone (1 g) and the ionic liquid (10 g) for approximately
1 h to ensure complete dissolution. An aliquot (1.1 g) was taken
to which the desired extraction solvent (3 g) was added. This
mixture was stirred in a sealed baffled vessel for 2 h at 1000
rpm (magnetic stirring) and 20 °C. The stirrer was stopped,
and the liquid was allowed to phase separate for a further 4 h.
Aliquots of known mass were taken from each layer and
3
-1
reactor via a piston pump at 24 cm h . In each case, samples
were taken from an additional sampling valve at the top of the
catalyst bed as a function of reaction time.
1
prepared for analysis by H NMR and HPLC by dissolution in
3
10 cm deuterated acetonitrile and protonated acetonitrile,
A schematic for the steam-distillation line is shown in Figure
respectively.
7
b. The superheater consists of two Watlow FIREROD cartridge
In a set of similar experiments, ternary equilibria data were
generated for the ionic liquid-mesitylene-4-methoxyben-
zophenone system. Initially 4-methoxybenzophenone was added
to a stirred solution (600 rpm) of ionic liquid and mesitylene
until the solution was observed to go cloudy, thereby indicating
the formation of a second liquid phase. Further addition of
product results in two distinct phases being formed. Tie lines
represent the equilibrium concentrations in each of the two
phases.
heaters and a series of four baffles housed in a custom-made
stainless steel vessel. Steam distillation was achieved by passing
wet steam, generated in a 4.5 dm 2.3 kW boiler at a flow of
3
-1
∼
64 g min through the superheater. The power to the cartridge
heaters was adjusted until the desired temperature was obtained.
In order to achieve temperatures in excess of 200 °C the power
to the boiler, and thus steam flow, was reduced to 50% of
maximum. The superheated steam flow was split into three,
two of which were introduced to the base of the steam-
distillation vessel and adjusted to facilitate suitable mixing and
the third was introduced via the top of the vessel. The exit steam
Acknowledgment
This work was supported by QUILL and a Portfolio
Partnership Grant from the EPSRC.
3
was condensed and stored in a modified 2 dm conical flask.
Once complete, the ionic liquid left in the steam-distillation
vessel was pumped through the drying column and the charcoal
column for purification before being stored in the reaction
holding tank for further reaction. The zeolite was reactivated
Received for review June 9, 2008.
OP800134K
Vol. 12, No. 6, 2008 / Organic Process Research & Development
•
1163