An improved Balz-Schiemann reaction enabled by ionic liquids and continuous processing

Article abstract of DOI:10.1016/j.tet.2019.05.020

A Balz-Schiemann reaction was developed to convert 2-cyano-5-aminopyridine to 2-cyano-5-fluoropyridine. The use of an ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate, BMIMBF₄) as a solvent was found to be critical in achieving high assay yields and high selectivity for the fluorination vs. protonation. A process was developed to recycle and reuse the ionic liquid enabling its cost-effective use as a solvent. Finally, the optimal conditions were demonstrated under as a continuous process to address process safety risks associated with diazonium intermediates and the product was used to access a key intermediate in the synthesis of β-amyloid cleaving enzyme 1 inhibitor, verubecestat.

Full text of DOI:10.1016/j.tet.2019.05.020

Accepted Manuscript
An improved Balz-Schiemann reaction enabled by ionic liquids and continuous
processing
David R. Snead, Francois Levesque, William J. Morris, John R. Naber
PII:
S0040-4020(19)30559-9
https://doi.org/10.1016/j.tet.2019.05.020
TET 30341
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 April 2019
Revised Date: 5 May 2019
Accepted Date: 10 May 2019
Please cite this article as: Snead DR, Levesque F, Morris WJ, Naber JR, An improved Balz-Schiemann
reaction enabled by ionic liquids and continuous processing, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.05.020.
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ACCEPTED MANUSCRIPT
An Improved Balz-Schiemann Reaction
Leave this area blank for abstract info.
Enabled by Ionic Liquids and Continuous
Processing
David R. Snead, Francois Levesque*, William J. Morris, and John R. Naber
Process Research and Development, Merck & Co., Inc., P.O. Box 2000, Rahway, NJ 07065 USA

ACCEPTED MANUSCRIPT
An Improved Balz-Schiemann Reaction Enabled by
Ionic Liquids and Continuous Processing
David R. Snead, François Lévesque*, William J. Morris, and John R. Naber
AUTHOR ADDRESS
Process Research and Development, Merck & Co., Inc., P.O. Box 2000, Rahway, NJ 07065 USA
Corresponding author. e-mail: francois.levesque@merck.com
KEYWORDS
Active Pharmaceutical Ingredient (API), Continuous Flow, Ionic Liquids (IL), Balz-Schiemann
ABSTRACT
A Balz-Schiemann reaction was developed to convert 2-cyano-5-aminopyridine to 2-cyano-5-fluoropyridine. The
use of an ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate, BMIMBF4) as a solvent was found to be
critical in achieving high assay yields and high selectivity for the fluorination vs. protonation. A process was
developed to recycle and reuse the ionic liquid enabling its cost-effective use as a solvent. Finally, the optimal
conditions were demonstrated under as a continuous process to address process safety risks associated with
diazonium intermediates and the product was used to access a key intermediate in the synthesis of β-amyloid
cleaving enzyme 1 inhibitor, verubecestat.
Figure 1: Synthesis of verubecestat (1) from 5-amino-
2-cyanopyridine (2) and 3.
INTRODUCTION
Verubecestat (1) is an inhibitor of the β-
amyloid cleaving enzyme 1, and was recently
Our efforts to identify new chemistry to 2
began from 2-cyano-5-aminopyridine. This starting
material was readily available, and we reasoned the
aryl amine could be readily converted to the aryl
fluoride using Balz-Schiemann3 conditions followed
by amide hydrolysis (Figure 2). We established at the
outset of this work that the most pressing challenges
with this approach would be achieving acceptable
levels of selectivity4 during the Balz-Schiemann
reaction and identifying a solution to address the
handling of the intermediate diazonium salts upon
scale up. Study of this transformation was initially
performed in batch and was later optimized in flow.
evaluated for its
potential to treat Alzheimer’s
disease.1 Our laboratories disclosed a synthetic route to
1 that utilizes a copper-catalyzed C-N amidation
reaction between 5-fluoro-picolinamide 2 and aryl
bromide 3 to forge the aryl-nitrogen bond of 1 (Figure
1).2 Commercial sources of
2 are prohibitively
expensive for a commercial manufacturing process so
we sought to identify a synthetic strategy to prepare 2
in a more cost efficient manner.
1

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F
H2N
XN2
Balz-
Table 1: Diazotization solvent screen.a
N
5
CN
N
4
CN
N
CN
Schiemann
diazonium
intermediate
F
Amide
NH2
N
2
Hydrolysis
O
5 (%)b
Entry
1
Solvent
MeCN
iPrCN
PhCN
6 (%)
3.6
5/6
19.4
12.4
13.7
6.3
7.6
9.6
7.4
5.5
10.3
3.8
-
Figure 2: Proposed synthesis plan for the preparation
of 2.
69.7
58.5
61.6
72.1
31.9
52.9
63.9
24.7
69.3
36.0
6.5
2
4.7
3
4.5
RESULTS AND DISCUSSION
4
nBuOAc
MeOH
EtOH
11.4
4.2
The Balz-Schiemann reaction involves initial
conversion of an aryl amine to an intermediate
diazonium salt followed by fluorination5 to yield aryl
fluorides. Our goal was to develop a through-process
to directly convert 4 to 5, overcoming any safety
hazard related to the handling or isolation of
diazonium salts.
5
6
5.5
7
iPrOH
AmOH
TFEc
8.6
8
4.5
9
6.7
10
11
12
13
14
HFIP
9.4
We began evaluating this strategy by conducting a
solvent screen of the initial diazotization reaction
which revealed that MeCN gave the most favorable
combination of yield and selectivity for the desired
product relative to the reduced arene (Table 1). Under
every reaction conditions, toluene was used to promote
decomposition of the diazonium intermediate and
fluorination. Alcohol solvents were also competent in
the reaction showing a favorable balance between yield
and selectivity. The solvent screen showed more
highly substituted nitrile and alcohol solvents led to
decreased levels of selectivity between 5 and 6. Non-
polar solvents such as toluene showed insufficient
solvation of the starting material, precluding a single
solvent composition for the diazotization and diazo
decomposition transformations.
MTBE
iPrNO2
Pyridine
Lutidine
ND
14.7
15.7
16.3
32.2
ND
2.2
-
ND
-
a tBuONO (0.600 mmol) added to solution of amino-2-cyanopyridine
(0.500 mmol), LiBF4 (4.50 mmol), and TFA (0.500 mmol) in solvent
(5 mL total volume) at 20 °C. After 1 min, 200 ꢀL was transferred
and added to a mixture of toluene (1 mL) and LiBF4 (0.169 g) and
heated at 95 °C for 10 min. bAssay yield determined using HPLC.
cThermal decomposition run in trifluorotoluene rather than toluene.
While the preliminary selectivities shown in Table 1
were encouraging, additional optimization was
necessary to meet the strict purity specification
established for 5. Unsurprisingly, 5 and 6 displayed
similar solubilities in all solvents evaluated, limiting
our capacity to remove 6 by crystallization. To further
optimize our reaction a screen was conducted to
evaluate the impact of co-solvent on the conversion of
the intermediate diazonium salt to 5 (Table 2). We
used MeCN for the initial diazotization reaction and
varied the solvent used for the diazonium
decomposition step. The solvent chosen for the
diazonium decomposition showed minimal impact to
both yield and selectivity with minor improvements to
yield observed when trifluorotoluene was employed.
The diazonium decomposition was complete in 10
minutes at 95 °C. Decreasing the temperature of the
2

ACCEPTED MANUSCRIPT
reaction resulted in longer reaction times without
Additional reaction optimization revealed that the
concentration of 4 was able to be increased from 0.1 to
0.5 M with only limited effect on the reaction outcome.
Changes to TFA stoichiometry had minimal impact on
reaction performance, as did additives such as LiPF6,
nitrosonium salts, 12-crown-4, nBu4NBF4, and
HF·pyridine. The mass balance of the reaction was
made up of by-products formed through nucleophilic
substitution of the diazonium salt. Weak anions such as
trifluoroacetate participated in SNAr replacement of the
diazonium salt as did the water formed during nitrite
decomposition to yield the hydroxylated aromatic ring.
improving the yield or selectivity. We next considered
the possibility that the ratio of solvents used in the
diazonium decomposition might influence the reaction
outcome. To that end, changing the ratio of MeCN:
toluene from 1:5 to 1:10 by doubling the volume of
toluene used afforded
a
70% yield with an
improvement to selectivity to nearly 26:1 (Table 2,
Entry 12). While the influence of concentration on
selectivity was an exciting development this result
presented a new challenge to our reaction design.
Using flow chemistry for diazonium formation
followed by diazonium decomposition in batch would
not be suitable for our system as the constantly
changing composition of solvent would result in
deleterious selectivity changes over time.
The highly electrophilic nature of the intermediate
rendered it susceptible to multiple non-productive side
reactions even in the presence of poor nucleophiles. A
Ritter reaction with the MeCN solvent was
a
Table 2: Diazonium decomposition solvent screen.a
prominent side reaction in addition to dimerization of
pyridine rings, and hydration of the nitrile across all
the products formed. To address this, we considered
strategies aimed at increasing the fluoride
concentration but were limited by the poor solubility of
most fluoride sources in our desired solvents. Given
this limitation we shifted our investigation to
imidazolium-based ionic liquids with fluorous counter-
ions postulating these solvents could address the
solubility limitations of fluoride salts.6 Running the
diazonium decomposition reaction in 1-butyl-3-
methylimidazolium tetrafluoroborate (BMIMBF4) led
to an improved yield (84%) with excellent selectivity
(40:1) (Figure 3).
5 b
(%) (%)
6
Entry
Solvent
5/6
1
2
trifluorotoluene
toluene
71.9
69.7
4.0
3.6
18.0
19.4
1,2-
3
4
73.3
70.4
5.4
6.8
13.6
10.4
difluorobenzene
1,4-
difluorobenzene
5
6
fluorobenzene
HFIP
36.3
20.1
13.4
4.8
3.4
8.6
7.6
5.9
1.6
-
7
MeCN
Figure 3: Improved yield and selectivity imparted by
ionic liquid as a solvent for diazonium decomposition.
8
THF
ND 94.2
13.2 77.1
ND 98.3
40.8 54.1
9
Dioxane
DMF
0.2
-
A solvent screen of ionic liquids showed a
general improvement in yield without sacrificing
selectivity. (Table 3).7 ILs with the PF6 counterion
tended to produce slightly higher levels of reduced
arene 5 than their tetrafluoroborate counterparts, and a
slight reduction in selectivity was observed when
incorporating SbF6 anion (Entry 5). The PF6 anion
increased the hydrolysis of the cyano group to amide 2,
likely due to the tendency to form acidic by-products
from the PF6 group.8 Similarly, use of MIM·H2SO4
leads to very high levels of 2 (>50%, entry 13). 1,3
substituted ionic liquids gave higher yields than
analogous ionic liquids with incorporation of a methyl
group at the 2-position (entries 9-12), and benzyl
substitution also decreased yield (entry 8). A brief
10
11
12
DMC
Toluenec
0.8
25.9
70.0
2.7
a tBuONO (0.600 mmol) added to solution of amino-2-cyanopyridine
(0.500 mmol), LiBF4 (4.50 mmol), and TFA (0.500 mmol) in MeCN
(5 mL total volume) at 20 °C. After 1 min, 200 ꢀL was transferred
and added to a mixture of solvent (1 mL) and LiBF4 (0.169 g) and
heated at 95 °C for 10 min. bAssay yield determined using HPLC
ctBuONO (0.600 mmol) added to solution of amino-2-cyanopyridine
(0.500 mmol), LiBF4 (4.50 mmol), and TFA (0.500 mmol) in MeCN
(5 mL total volume) at 20 °C. After 1 min, 200 ꢀL was transferred
and added to a mixture of toluene (2 mL) and LiBF4 (0.169 g) and
heated at 95 °C for 10 min
3

ACCEPTED MANUSCRIPT
examination of pyridinium and pyrrolidinium salts was
not promising (entries 14-16).
Table 3: Ionic liquid solvent screen.a
5 (%)b
6 (%)
5/6
Ionic Liquid
Entry
Counter-Ion Temp. (°C)
1
2
EMIM
BF4
PF6
95
95
85.2
92.1b
83.7
68.1
85.0
93.1
89.0b
68.2
71.6
84.8
70.4
78.9
64.2b
77.5
76.4
65.8
2.5
3.1
2.1
25.7
4.1
3.5
5.7
ND
2.5
5.3
9.6
5.9
2.6
7.0
2.6
5.6
34.4
29.8b
39.9
2.7
EMIM
3
BMIM
BF4
PF6
95
4
BMIM
95
5
BMIM
SbF6
BF4
PF6
95
20.6
26.8
15.5b
ND
6
OMIM
OMIM
95
7
95
8
BnMIM
PF6
130
130
95
9
EDMIM
BF4
BF4
PF6
29.1
16.1
7.3
10
11
12
13
14
15
16
BDMIM
BDMIM
95
BDMIM
PF6
130
95
13.3
25.1c
11.0
29.0
11.7
MIM
H2SO4
BF4
BF4
BF4
N-Butyl-4-methyl pyridinium
N-Ethyl pyridinium
N-Butyl-N-methyl pyrrolidinium
130
95
130
a tBuONO (2.40 mmol) added to solution of amino-2-cyanopyridine (2.00 mmol), LiBF4 (18.0 mmol), and TFA (2.00 mmol) in MeCN (5 mL
total volume) at 20 °C. After 1 min, 50 ꢀL was transferred and added to a mixture of ionic liquid (0.5 mL) and LiBF4 (0.500 g) and heated for 10
min. bAssay yield determined using HPLC. cCombined yield of picolinamide 2 and picolinonitrile 5.
Though the use of ionic liquids as solvent for
this reaction provided a favorable outcome with
respect to yield and selectivity, the isolation of product
was not some trivial endeavor as ionic liquids are non-
volatile and excellent solvents for organic compounds.
Gratifyingly, we found that isolation of 5 from
BMIMBF4 via extraction using a co-solvent mixture of
toluene and ethyl acetate (6.7:1) was effective. We
were also pleased to observe that the extractive workup
resulted in an improved ratio between 5 and 6 after the
extraction (>70:1) with simultaneous removal of
impurities resulting from side reactions between
MeCN and the diazonium salt intermediate (Figure
4a). Analysis of the residual ionic liquid showed an
enrichment of the reduced arene 6. After solvent
removal the isolated yield of 5 was 77%.
We next sought to develop a protocol to
purify and recycle the ionic liquid to render its use
cost-effective on scale.9 The boiling point of 6 and 5
are 230 and 240 °C respectively. These compounds
can be distilled from BMIMBF4 along with water and
MeCN used in the process to purify the ionic liquid to
a suitable point for reuse (Figure 4b). Application of
this methodology demonstrated effective removal of
product from the reaction mixture via vacuum
distillation at temperatures below 175 °C.
At
distillation temperatures exceeding 180 °C,
decomposition products were generated, and they
4

ACCEPTED MANUSCRIPT
remained in the ionic liquid. The purified ionic liquid
Figure 5: Performance of recycled ionic liquid in 7
was successfully recycled in the reaction for seven
reaction cycles (Figure 5). First, the diazotization was
run in MeCN followed by thermal decomposition in
BMIMBF4. Then, product was isolated via three
extractions with organic solvent, and the ionic liquid
was purified by distillation at 150 °C under vacuum.
The reaction was subsequently repeated for 7 cycles,
where the average isolated yield across the 7 reactions
was 74% with a selectivity of 66:1 for 5 over 6.
reactions
With an optimized reaction in place, as well as a
protocol to recycle the ionic liquid solvent, we next
turned our attention to addressing the hazardous nature
of the reaction. We considered flow chemistry10 to be
one possible solution to this challenge as the dye
industry, as well as the broader synthetic community,
has used continuous operations to address safety
concerns surrounding build-up and isolation of these
high energy intermediate diazonium salts.11,12,13 Use of
the diazonium salts formed in situ have been applied to
a number of different reactions14 including the Balz-
Schiemann reaction.15,16
We developed
diazotization
a
and
procedure to run both the
diazonium decomposition
continuously since maintaining the ratio of the two
solvents was shown to impact the reaction profile
(Figure 6). The reactor setup consists of a t-mixer to
combine tert-butyl nitrate with a solution of 4, LiBF4
and TFA in MeCN, followed by a PFA loop to age the
reaction mixture for 1 minute at room temperature.
Upon exiting the first reactor, BMIMBF4 and LiBF4
were combined with the reaction stream using a second
t-mixer. The resulting solution was pushed into a PFA
reactor heated to 95 °C to yield the desired product
after a 10 minutes residence time. To minimize the
impact of gas evolution (N2) on residence time, the
entire reactor was pressurized to 100 psi with the aid of
a back-pressure regulator. It is worth noting that we
observed slightly diminished levels of selectivity when
running the reaction under continuous conditions but
the work up procedure enabled an upgrade to
Figure 4: Scheme for ionic liquid reuse including a)
Selective extraction of product from BMIMBF4. b)
Strategy for recycle of ionic liquid.
100%
80%
60%
40%
20%
0%
10.0%
8.0%
6.0%
4.0%
2.0%
0.0%
78%
76%
76% 74%
76%
73%
66%
selectivity
as
described
earlier.
1.5%
1.2% 1.3% 1.5%
1.4%
0.8%
0.2%
1
2
3
4
5
6
7
ArF Yield (%)
ArH Yield (%)
Number of Uses of IL
Figure 6: Continuous flow synthesis of 5.
5

ACCEPTED MANUSCRIPT
Finally, 5 was converted to 2 using hydrolysis
4.928 mL. The orange solution was transferred to a 6
mL scintillation vial equipped with a magnetic stir bar
and temperature was controlled via a water batch held
at 20 °C. tBuONO (71.5 ꢀL, 0.600 mmol) was added
to the rapidly stirred solution to form the diazonium
salt, and after 1 minute, 200 ꢀL was transferred and
added to a 1 mL mixture of trifluorotoluene and LiBF4
conditions described by Shimizu and co-workers
(Figure 7).17,18 The 2-step procedure to convert 2-
cyano-5-aminopyridine
to
5-fluoro-2-
pyridinecarboxamide proceeded in 79% overall yield.
(0.169 g, 1.8 mmol) heated at 95 °C.
After 10
minutes, the reaction mixture was removed from heat
and diluted to 5 mL to make a homogeneous solution.
The reaction was analyzed by HPLC as described
above.
Figure 7: Hydration of 5.
CONCLUSION
2-Cyano-5-fluoropyridine (5, Ionic Liquid Recycle):
Amino-2-cyanopyridine (0.238 g, 2.00 mmol, 0.4 M),
LiBF4 (1.69 g, 18.0 mmol), and TFA (154 ꢀL, 2.00
mmol) were combined with MeCN to reach a volume
of 4.714 mL. The orange solution was transferred to a
6 mL scintillation vial equipped with a magnetic stir
bar and temperature was controlled via a water batch
held at 20 °C. tBuONO (286 ꢀL, 2.40 mmol) was
added to the rapidly stirred solution to form the
diazonium salt, and after 1 minute, 50.0 ꢀL was
transferred and added to a mixture of BMIMBF4 (0.5
mL) and LiBF4 (0.500 g, 5.33 mmol) heated at 95 °C.
After 10 minutes, the reaction mixture was removed
from heat, and a 1 mL mixture of 6.6:1 toluene to ethyl
acetate was added. A vortex mixer stirred the mixture
for 30 seconds, and then the organic and ionic liquid
phases were allowed to settle. The organic phase was
collected, the extraction was repeated twice more, and
the organic fractions were combined, diluted to 5 mL
and analyzed by HPLC as described above. The vial
containing ionic liquid was capped with a septum,
placed under vacuum, and heated for 10 minutes at 150
°C to remove residual solvent and product. The ionic
liquid was returned to 95 °C under an atmosphere of
air, and freshly prepared diazonium solution was
added. The cycle was repeated six times after the
initial run.
The use of an ionic liquid as solvent enabled
improvements to yield and selectivity for the
conversion of 4 to 5. The purity of the Balz-Schiemann
adduct could be further enhanced through an extractive
process which lowered the levels of the reduced arene
6. The extraction was followed by a distillation to
purify and recycle the ionic liquid. The robust
performance of the recovered ionic liquid was
demonstrated for 7 iterations with negligible impact to
the reaction profile. Finally, the reaction was
demonstrated under continuous flow conditions to
address process safety concerns related to build-up of
unstable diazonium salts.
EXPERIMENTAL
General Remarks: Solvents, reagents and starting
materials were purchased from commercial sources
and used as received. Reactions were analyzed using
an Agilent 1100 Series HPLC and quantified through
calibration curves developed for 2-cyano-5-
fluoropyridine,
2-cyanopyridine,
and
5-
fluoropicolinamide. A C18 reversed-phase analytical
column (Ascentis Express C18, 10 cm x 4.6 mm, 2.7
ꢀm particle size) was used for separations with mobile
phases A (water + 0.1% H3PO4) and B (MeCN)
flowing at a rate of 1.25 mL/min. 2 ꢀL of sample was
injected, and the following gradient was applied: hold
at 90:10 ratio of A to B for 1 min then linearly increase
to 95% B from 10% B over 6 min. Hold at 5:95 A to
B for 3 min. 1H-NMR was collected on a Bruker 500
MHz spectrometer, and chemical shifts (δ) are
expressed in part per million. Spectra were obtained
using MeCN-d3 as solvent with MTBE used as an
external standard.
2-Cyano-5-fluoropyridine (5, Continuous Flow):
Plug-flow reactors were constructed from 1/16” PFA
tubing (0.03” ID, Upchurch Scientific) and reagents
and reaction streams were joined through connections
with PEEK tee-mixers (0.04” ID, Upchurch Scientific).
Pressure was regulated with a 100 psi backpressure
regulator cartridge from Upchurch Scientific. Reagent
streams were pumped with Harvard Apparatus PhD
Ultra syringe pumps. A 20 ꢀL (4.4 cm, 1 min tR)
segment of PFA air-cooled tubing was used as a
reactor for diazonium formation, and a 2.2 mL (482
cm, 10 min tR) coil of PFA tubing heated at 95 °C in an
oil bath was used for the thermal dediazoniation. 5-
Amino-2-cyanopyridine (0.238 g, 2.00 mmol, 0.4 M),
2-Cyano-5-fluoropyridine
(4,
Representative
procedure for batch screening): Amino-2-
cyanopyridine (0.0600 g, 0.500 mmol, 0.1 M), LiBF4
(0.422 g, 4.50 mmol), and TFA (38.6 ꢀL, 0.500 mmol)
were combined with MeCN to reach a total volume of
6

ACCEPTED MANUSCRIPT
LiBF4 (0.562 g, 6.00 mmol), and TFA (154 ꢀL, 2.00
T. H. Chem. Eng. Technol., 2016, 39, 66-80.
c) Noël, T.; Maimone, T. J.; Buchwald, S. L.
Angew. Chem. Int. Ed. Engl., 2011, 50, 8900-
8903.
mmol) were combined in a 5 mL volumetric flask and
MeCN was added to reach a total volume of 5 mL.
The orange solution was transferred to an 8 mL
stainless steel syringe and pumped at 18.92 ꢀL/min.
tBuONO (8.41 M) was added to a 2.5 mL glass syringe
with luer lock adapter and pumped at 1.08 ꢀL/min. A
solution of LiBF4 (1.00 g, 10.7 mmol) in BMIMBF4
was made to 10 mL, added to a stainless-steel syringe,
and pumped at 200 ꢀL/min. After passing 5 residence
volumes (1.10 mL) sample was collected for 2 minutes
and 38 seconds (0.579 mL), diluted to 5 mL in MeCN,
and analyzed by HPLC as described above.
6) a) Laali, K.K.; Gettwert, V.J. J. Fluor. Chem.
2001, 107, 31-34. b) Heredia-Moya, J.; Kirk,
K.L. J. Fluor. Chem. 2007, 128, 674-678. c)
Marsh, K.N.; Deev, R.; Wu, A.C.-T.; Tran,
E.; Klamt, A. Korean J. Chem. Eng. 2002, 19,
357-362. b) Plechkova, N.V.; Seddon, K.R.
Chem. Soc. Rev. 2008, 37, 123-150. d)
García-Verdugo, E.; Altava, B.; Burguete,
M.I.; Lozano, P.; Luis, S.V. Green Chem.
2015, 17, 2693-2713.
7) a) Rutherford, K.G.; Redmond, W.A. J. Org.
Chem. 1963, 28, 568-571. b) Sellers, C.;
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ACKNOWLEDGEMENTS
The authors would also like to thank Jonathan McMullen,
Micheal Di Maso and Douglas Otte for proofreading the
manuscript
.
8) Freire, M.G.; Neves, M.S.S.; Marrucho, I.M.;
Coutinho, J.A.P.; Fernandes, A.M. J. Phys.
Chem. A 2010, 114, 3744-3749.
SUPPLEMENTARY MATERIAL
Supplementary data to this article can be found online.
9) a) Dhingra, S.R.; Nag, P.; Saxena, R.; Chem.
Sci. Trans. 2015, 4, 1149-1155. b) Wu, B.;
Liu, W.; Zhang, Y.; Wang, H. Chem. Eur. J.
2009, 15, 1804-1810. c) Abu-Eishah, S.I.
“Ionic Liquids Recycling for Reuse” in Ionic
Liquids – Classes and Properties, ed. Handy,
S.T. InTech, 2011, 239-268. c) Lan Mai, N.;
Ahn, K.; Koo, Y.-M. Proc. Bio. 2014, 49,
872-881
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