Biomass derived ionic liquids: Synthesis from natural organic acids, characterization, toxicity, biodegradation and use as solvents for catalytic hydrogenation processes

Article abstract of DOI:10.1016/j.tet.2013.05.054

Ionic liquids with natural organic derived anions (l-lactate, l-tartrate, malonate, succinate, l-malate, pyruvate, d-glucuronate, d-galacturonate) were easily prepared from tetrabutylammonium hydroxide and an excess of the corresponding acid with good yields. Their characterization was realized through classical NMR, IR, and elemental analysis techniques; their viscosity and TGA (thermogravimetric analysis) parameters were also determined. These ionic liquids showed good performance and recyclability in the selective catalytic hydrogenation of 1,5-cyclooctadiene (1,5-COD) into cyclooctene (COD) at room temperature under atmospheric H₂ pressure. Antimicrobial toxicity assays toward a large panel of bacteria and fungi strains were also completed and biodegradation studies (Closed Bottle test, 28 days) were also performed.

Full text of DOI:10.1016/j.tet.2013.05.054

Tetrahedron 69 (2013) 6150e6161
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Biomass derived ionic liquids: synthesis from natural organic acids,
characterization, toxicity, biodegradation and use as solvents for
catalytic hydrogenation processes
a
b
a
c
d
Nad eꢀ ge Ferlin , Matthieu Courty , Sylvain Gatard , Marcel Spulak , Brid Quilty ,
e
e
f
f
Ian Beadham , Mukund Ghavre , Annette Haiß , Klaus K u€ mmerer ,
e,
a,
*
*
Nicholas Gathergood , Sandrine Bouquillon
Institut de Chimie Mol ꢁe culaire de Reims UMR CNRS 7312, Universit ꢁe de Reims Champagne-Ardenne, Boîte n 44, B.P. 1039, F-51687 Reims, France
Laboratoire de R ꢁe activit ꢁe et de Chimie des Solides, Universit ꢁe de Picardie Jules Verne, UFR des Sciences, 33, rue Saint Leu, 80039 Amiens Cedex 1,
a
ꢀ
b
France
c
Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovsk ꢁe ho 1203, CZ-500 03 Hradec Kr aꢁ lov ꢁe , Czech
Republic
d
School of Biotechnology and National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
School of Chemical Sciences and National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland
e
f
Institute of Sustainable and Environmental Chemistry, Leuphana University L u€ neburg, DE-21335 L u€ neburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Ionic liquids with natural organic derived anions (L-lactate, L-tartrate, malonate, succinate, L-malate,
Received 28 March 2013
Received in revised form 8 May 2013
Accepted 14 May 2013
pyruvate, D-glucuronate, D-galacturonate) were easily prepared from tetrabutylammonium hydroxide
and an excess of the corresponding acid with good yields. Their characterization was realized through
classical NMR, IR, and elemental analysis techniques; their viscosity and TGA (thermogravimetric anal-
ysis) parameters were also determined. These ionic liquids showed good performance and recyclability
in the selective catalytic hydrogenation of 1,5-cyclooctadiene (1,5-COD) into cyclooctene (COD) at room
Available online 18 May 2013
Keywords:
Ionic liquids
Synthesis
Characterization
Hydrogenation
Toxicity
2
temperature under atmospheric H pressure.
Antimicrobial toxicity assays toward a large panel of bacteria and fungi strains were also completed and
biodegradation studies (Closed Bottle test, 28 days) were also performed.
Ó 2013 Elsevier Ltd. All rights reserved.
Biodegradation
1
. Introduction
applications11 or for separations and extractions.12 A number of
detailed reviews have expounded the advantages of using ionic
liquids as new ‘greener’ solvent types.
9
,13
Ionic liquids (ILs) consist of an organic cation associated with an
1
anion that may be either organic or inorganic. They are liquids
below 100 C and many of them are liquids at room temperature
Concerning the catalysis domain and especially the hydroge-
nation field, numerous examples of the use of organometallic
complexes in hydrogenation processes including the production of
useful products and intermediates are already reported.1 Catalytic
reactions involving metal complexes in ionic liquids have been
actively investigated, with many ionic liquids screened (nearly
300). The majority of these ionic liquids contain heterocyclic de-
rivatives as cations, such as pyridinium, imidazolium, poly-
alkylammonium and recently synthesized guanidinium,
piperidinium, pyrrolium, pyrrolidinium, morpholinium, cholinium,
piperazinium, thiazolium, polycyclic examples, ionic liquids with
bridged structures, binuclear or polynuclear, zwitterionic, hydro-
ꢀ
(
RTILs, Room Temperature Ionic Liquids). The rising interest
4
attracted by ILs in the last two decades is due to their properties: low
vapor pressure,2 high thermal stability, and excellent solvation of
3
a wide range of compounds. Consequently, ILs have been consid-
4
e7
ered as an alternative tovolatile solvents in catalytic applications,
biocatalysis8 synthetic chemistry, electrochemistry, analytical
9
10
*
Corresponding authors. Tel.: þ33 (0) 3 26 91 89 73; fax: þ33 (0) 3 26 91 31 66
S.B.); tel.: þ353 (0) 17007860; fax: þ353 (0) 170005503 (N.G.); e-mail addresses:
nick.gathergood@dcu.ie (N. Gathergood), sandrine.bouquillon@univ-reims.fr
S. Bouquillon).
(
15
phobic (fluorinated), and chiral derivatives. The unsaturated
(
substrates in hydrogenation reactions in ionic liquids include:
0
040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.054

N. Ferlin et al. / Tetrahedron 69 (2013) 6150e6161
6151
cyclohexene, cyclohexadiene, pent-1-ene, aromatic hydrocarbons
e.g., styrene and phenylacetylene), sorbic acid, copolymers of ac-
containing oxygenated chains and/or tetrabutylammonium cations
3
,28
(
are less toxic toward many strains.
rylonitrile, and butadiene as well as many other alkenes with more
complex structures.16 P.J. Dyson described in 2002 the use of clas-
sical ionic liquids for synthesis of organometallics and catalytic
However data about IL biodegradation29 and their bio-
30
accumulation are still lacking for many of the ionic liquids pre-
pared, in particular ammonium salts. Specific imidazolium and
pyridinium based ionic liquids have already been shown to be
‘readily biodegradable’ according to OECD (Organisation for Eco-
1
7a
hydrogenations
and extended its studies to kinetics and recy-
cling in 2005.1 Next, Wasserscheid and co-workers showed in
7b
31
2
007 the capability of ionic liquids to assure superior catalytic
nomic Co-operation and Development) rules. Since 2002, Gath-
4
,18
29
systems for transition metal catalyzed hydrogenation.
In 2007,
ergood, Scammells and co-workers developed some biodegradable
19
Keglevich and co-workers reviewed data accumulated in recent
years on the synthesis and use of phosphorous containing ionic
liquids. Reactions studied included catalytic hydrogenations,
transfer hydrogenations, oxidations, and hydroformylations. Recent
papers in the field of catalysis, especially hydrogenation catalysis in
ionic liquids, closely associated with principles of green chemis-
try include using electroreduction, microwave, and sonochemical
irradiation processes with organometallic complexes or nano-
particles.1
ILs by modifying the structure of the imidazolium cation by adding
esterorether function groups. An alternative strategy is changing the
nature of the anions as Davis and co-workers in 2002 or Keglevich
and co-workers in 2011 with imidazolium or phosphonium cations
(see examples in Fig. 1). It is reasonable to propose that an IL com-
posed of a biodegradable anion and cation will be biodegradable as
long as the IL compound is non-toxic under the test conditions.
Where an IL contains a ‘persistent’ ion paired with a biodegradable
counterion, it is possible to meet the requested threshold values
established in the OECD biodegradation tests and for the salt to be
classified as readily biodegradable. Under such circumstances the IL
2
0
4c, 21
As the selective hydrogenation of fatty compounds can modify
their physical properties for many application fields (e.g., cos-
metics, agri-food, pharmacy), the selective hydrogenation of
3
2a,b,d
could not be called green nor sustainable.
Fig. 1. Examples of biodegradable phosphonium, imidazolium and pyridinium ionic liquids.
polyunsaturated compounds remains a constant challenge.22 In
000, Dupont and co-workers described the selective Pd-catalyzed
hydrogenation of butadiene to but-1-ene or but-2-ene in
BMIM$BF or BMIM$PF (BMIM: 1-butyl-3-methylimidazolium)
and showed the possibility of recycling the catalytic system.
Other metal salts, such as Co(acac) , Co(acac) , Fe(acac) , and
Ni(acac) have also shown activities for this reaction. Since this
study, more selective conditions involving Pd(0) nanoparticles
induced from Pd(acac) in [bmim][BF ] have been found. A 72%
yield of but-1-ene could be attained with a constant pressure of
Although limited, some data is available about biodegradability
3
3
2
of ammonium based ionic liquids. When mono, di and tri (2-
hydroxyethyl)ammonium lactate ionic liquids were tested for bio-
3
4
4
6
degradability using BOD (Biochemical Oxygen Demand) method,
2
3
35
all were found to be readily biodegradable (60e95%) (Fig. 2).
Similarly, interesting results were obtained when NAILs (naph-
thenic acid ILs) were screened for biodegradation. Carboxylates of
various cores were chosen as anions in ILs. Eight out of ten ILs were
2
3
3
2
2
4
ꢀ
24
0
.4 MPa of hydrogen at 40 C. More recently, we studied the
hydrogenation of phenyloctadiene in presence 0.03 equiv of
Pd(acac) in biodegradable ILs and these solvents allowed recy-
clability of the catalytic species and also a better selectivity in the
2
2
5
formation of the phenyloct-2-ene.
Concerning now the green aspect of these solvents, whereas ILs
have very low toxicity in air because of their very low vapor pres-
17
sure and low flammability, many lipophilic ILs are toxic in aque-
ous media.3
,26
This problem has become a real challenge for IL development
and a great number of publications are dealing with their IL toxicity
19,27
(
inc. antibacterial and antifungal),
Furthermore, toxicity studies
involving the nature of the cation and the anion have been already
performed on a large number of ILs and showed that anions
Fig. 2. Hydrogenation of 1-5-cyclooctadiene in water with TBA L-lactate 1.

6152
N. Ferlin et al. / Tetrahedron 69 (2013) 6150e6161
found to be ‘readily biodegradable’ (60e83%), when tested using
formation of ILs accordingly to the method developed by Ohno and
co-workers. Tetrabutylammonium hydroxide (TBAOH) could be
36
41
Closed Bottle test.
Pretti et al.37 investigated the toxicity and biodegradation of
cyclic ammonium based ILs. Both DABCO (1,4-diazabicyclo[2.2.2]
octane) and morpholine based ILs containing bromide anion
prepared from tetrabutylammonium bromide (TBABr) by reaction
3
8
of an excess of acid in the presence of an ion exchange resin, but
traces of bromide (classical measurement of bromide traces in the
presence of silver salt) detected in the final ILs indicated that the
exchange with the resin was not complete. As a consequence, the
synthesis from cheap commercial TBAOH was therefore preferred
(Scheme 1). Starting with sustainable acids obtained available from
the biomass, corresponding ILs were prepared in refluxing water
for 24 h with an excess of the corresponding acid required (Scheme
1, pathway a) and obtained with excellent yields (93e97%, Table 1).
ILs from sugar acids were synthesized in absolute ethanol for 24 h
at room temperature (Scheme 1, pathway b) with good yields
(77e80%, Table 1).
2
showed low biodegradability when measured by CO headspace
test. DABCO based ILs lied in the range of 5e30% whereas mor-
pholinium ILs showed 22e40% biodegradation. Out of these results
ethyl substituted ILs (for both DABCO and morpholinium) degraded
better than decyl derivatives as expected. Above-mentioned results
3
8
were corroborated by the work of Pernak and co-workers, where
benzylmorpholinium cation in ionic liquids did not biodegrade.
Authors suggested that functionalised side chain instead of benzyl
3
9
group would improve biodegradation. Wells and co-workers
studies have already shown that the long alkyl or glycol chain ILs
Scheme 1. Formation of TBA ILs.
show poor or no biodegradability. Recently a temperature study has
been performed to enhance the biodegradability of a tetrabuty-
lammonium IL, which was successful and biodegradation was en-
hanced from 23% at 30 C to 64% at 45 C From other compounds it
is known that biodegradation is accelerated when temperature is
increased.40
Synthesis of compounds (1, 2, and 5) has already been de-
41,42
scribed,
however the characterization of the physicochemical
properties of a majority have not been performed. So viscosity was
ꢀ
ꢀ
ꢀ
ꢀ
determined at two different temperatures (25 C and 80 C) with
a viscometer (Table 2). For ionic liquids 1 and 6, the viscosity at
ꢀ
25 C is quite different (respectively, 409.1 cP and 220 cP), whereas
ꢀ
Of note, however the majority of biodegradation studies has
focused on the effect of substitution of the cation of the ionic liq-
at 80 C a value between 17 and 18 cP was found for both 1 and 6. At
ꢀ
25 C, TBA
L-tartrate 2 was too viscous to permit the measurement
2
9
uid. While toxicity studies of a series of ionic liquids with the
and TBA
L-malate 5 has also a high viscosity at room temperature,
2
7
same cation and varying the anion are widely reported almost all
of these investigations do not include biodegradation data. That is
an obvious lack of knowledge on biodegradability and greenness of
due to its gel aspect. The more hydroxyl groups the anion had, the
ꢀ
more viscous the compound at 25 C. For these compounds, the
number of carbons also seemed to play a role on the viscosity at
room temperature, because the less viscous ILs (1 and 6) had 3
carbons, and the more viscous ones (2 and 5) had 4 carbons. At
3
2d
IL.
As ILs are often used as solvent or co-solvent, their synthesis in
ꢀ
a quick and efficient manner is required. In addition, making ILs
from bio-resources, such as acids derived from biomass, could lead
to easily obtained biodegradable and low toxicity ILs. Toxicity
screening is thus included in this investigation so any undesirably
high toxicity ionic liquids can be identified at an early stage. When
combined with biodegradation and catalysis performance data, an
assessment of an ionic liquid as ‘fit for purpose’ can be made.
80 C, compound 2 still remained very viscous with a viscosity
measured at more than 3600 cP. However the viscosity of the ionic
liquid 5 decreased to 266 cP on raising the temperature. Hydrogen
bonds, governed by the nature of the anions, can influence the
physicochemical properties including the viscosity of compounds 1,
2, 5, and 6.
For compounds 3, 4, 7, and 8, viscosity values unfortunately
ꢀ
could not be determined at 80 C, because of their waxy aspect (3,
ꢀ
ꢀ
4
) or their melting points situated between 80 C and 100 C (7, 8).
The glass transition temperature (T ) was determined by Dif-
ferential Scanning Calorimetry (DSC). Respectively, for ILs 1 and 6,
2
2
2
. Results and discussion
g
.1. Syntheses
and ILs 2e5, T
g
values were similar. T
g
values for glycosidic acid
ꢀ
derived ILs were higher and surprisingly above 0 C for compound
.1.1. Synthesis of ILs with tetrabutylammonium (TBA) as cati-
8.
on. Although anion metathesis is the most widely used method to
Next, thermogravimetric analyses were performed to determine
the decomposition temperature (Tdec) of the different compounds.
With the exception of compound 3, the decomposition
1
form ionic liquids, the Br o€ nsted acid character of the reactants as
well as the unavailability of certain mono-sodium (or mono-
potassium) salts led us to prefer the acid-base pathway for the

N. Ferlin et al. / Tetrahedron 69 (2013) 6150e6161
6153
Table 1
Table 2
Synthesis of TBA ILs
TBA ILs: viscocity, glass transition temperature, decomposition temperature
ꢀ
dec ( C)a
ꢀ
T
ReCOOH
ILs
Pathway Aspect Yield
%)
IL
Viscosity (cP)
T
g
( C)
(
ꢀ
ꢀ
C
25
C
80
1
2
3
4
5
6
7
8
409.1
Nd
Nd
17.9
3689
Nd
106
266
17.2
Nd
ꢁ59.0
ꢁ31.0
ꢁ34.8
ꢁ38.6
ꢁ34.4
ꢁ59.3
ꢁ20.5
18.3
201.4
212.6
170.1
212.6
230
Nd
136
Nd
a
Oil
97
Nd
>40 000
220
Nd
L-lactic acid
Nd
Nd
Nd: not determined.
a
The values reported on Table 2 correspond to the onset temperature found by
a
Oil
98
ꢀ
ꢀ
ꢁ1
heating the compounds from 30 C to 500 C with a heating rate of 10 K min .
L -tartaric acid
improve the ability of our ionic liquids to be ‘selective’ solvents and
appropriate ones for the recycling process. Indeed, few examples
dealing with selective hydrogenation of 1,5-COD describe selective
a
a
Wax
Wax
99
98
hydrogenation processes conducted under harsh conditions
Malonic acid
Succinic acid
ꢀ
(
5e50 bar, 50e100
BMIM$PF /Na [Ru
BMIM$C
In our study, the hydrogenation of 1,5-COD was realized by us-
ing PdCl as without additional ligands in distilled water (5 mass
C and 4e6 h) with different systems
4
4
6
H
2
6
C(CO)16],
Ni
catalyst
coated
with
4
5
23
8
17SO
4
and BMIM$BF
4
/Pd(acac) .
2
2
equivalent compared to the IL) under 1 atm of hydrogen during 18 h
at room temperature (Scheme 2). First attempts with cyclooctene
(COE) and styrene showed that hydrogenation of carbonecarbon
double bonds in these conditions was possible; COE and styrene
were completely converted into cyclooctane (COA) and ethyl-
benzene, respectively, with water as solvent. The use of another
solvent was required because of the high viscosity of the studied
ILs. Among the available solvents, two were tested: propan-2-ol,
a common co-solvent for hydrogenation with ionic liquids and
distillated water, a green solvent. But only hydrogenation of 1,5-
COD performed in water gave a majority of COE.
In the absence of an ionic liquid, complete conversion of 1,5-
COD into COA was obtained in water in the first run. Recycling
the Pd catalyst led to the formation of COE until 87% was attained
for the fourth and fifth runs (Table 3, entries 1aee). In commercial
TBABr or TBACl, the first runs led to mixtures of COE and COA, but
also gave isomerization into 1,4-cyclooctadiene (1,4-COD). This
isomerization had already been observed in presence of other
a
a
Gelly 97
L-malic acid
Pyruvic acid
4
6
Oil
93
b
b
Solid
Solid
80
77
2 3 2 2 3
metallic catalysts (CuOeAl O , CuOeSiO or ZnOeAl O ) via water
47
gas shift reaction. Furthermore, the first recycling in both ILs
D-glucuronic acid
D-galacturonic acid
showed a large decrease in conversion as well as isomerization into
1
,3-cyclooctadiene (1,3-COD) observed during the second cycle
with TBACl (entry 3a).
With TBA -lactate 1, the conversion of 1,5-COD to COE pro-
L
ceeded with high selectivity until the sixth recycling where the
conversion dropped. Isomerization product, 1,4-COD, was observed
in all of the runs (Fig. 2).
Similar results were obtained with TBA
L-tartrate 2, TBA malo-
nate 3, and TBA -malate 5 (See Figs. S5, S6, and S8 in ESD) but lower
L
conversion and selectivity were observed by using the TBA pyru-
vate 6 (Fig. 3).
ꢀ
temperatures of ILs derived from bioacids were above 200 C and
ꢀ
under 250 C, which is low for ionic liquids. In fact, the thermal
stability of ionic liquids is limited by the strength of hetero-
atomeheteroatom associations and carbonehydrogen bonds
what could explain the low Tdec values for compounds 7 and 8
The highest conversions and selectivities were found with TBA
succinate 4, TBA
D
-glucuronate 7, and TBA -galacturonate 8 (Fig. 4).
D
4
3
IL 8 gave excellent conversion of 1,5-COD into COE with low
amounts of isomerized products, even after 10 cycles.
derived from osidic acids.
As BMIM ILs have previously been reported as appropriate sol-
vents/additives in selective hydrogenation processes, under harsh
conditions, using different metallic based catalysts (Pd, Fe, Ni, W, Ru
2
.2. Catalytic hydrogenation
2
3,44,45
etc.)
we compared the activity and selectivity between
commercial BMIM ILs and the TBA ILs 1e8 under our hydrogenation
conditions described herein. Conversion of 1,5-COD was very low in
In the present study, the selective hydrogenation of the 1,5-
cyclooctadiene (1,5-COD) was chosen as a model reaction to

6154
N. Ferlin et al. / Tetrahedron 69 (2013) 6150e6161
Scheme 2. Selective hydrogenation of 1,5-cyclooctadiene in presence of ILs.
Table 3
Using our mild conditions, ionic liquids 1e8 derived from TBA
were more suitable than BMIM ILs. Furthermore, the use of a Pd-
based catalyst in TBA ILs is novel because in general hydrogena-
tion of alkenes or dienes in ILs are largely performed with Ru or Rh
Hydrogenation of cyclooctadiene in water and in mixtures water/commercial TBABr
or TBACl
Entry IL
Conv. (%)a COE (%)a COA (%)a 1,4-COD (%)a 1,3-COD (%)a
4
8
1
1
1
1
1
2
2
3
3
a
d
100
100
99
d
100
35
17
13
6
d
d
d
d
d
d
d
d
catalysts in imidazolium IL derivatives. In all cases herein, results
with ILs (neat or as additive) were different to those obtained in
only water. The presence of IL shade an effect on the hydrogenation
of 1,5-COD and could inhibit the reaction (e.g., Table 4, entry 1a) as
well as permit the selective formation of COE (Table 4, entries 8aej),
due to the hydrogenation of the second carbonecarbon double
b
b
65
82
87
87
55
63
75
62
b
c
1
b
d
e
a
b
a
b
100
93
d
b
7
TBABr 100
17
45
6
4
d
b
31
21
29
TBACl
66
26
d
49
bond of COD requiring more energy. It is well known that the
b
5
4
4
solubility of gases in ILs is lower than in common organic solvents.
a
Determined by GC.
Recycling experiments.
To our knowledge, there are few studies dealing with the solubility
of gases in ILs/solvents mixtures [4], and no study for the solubility
of hydrogen in our conditions, i.e., a mixture of TBA ILs and water
b
(
1:5). Considering the different results (Tables 3 and 4), the solu-
Table 4
Hydrogenation of 1,5-cyclooctadiene in BMIM ILs
bility of hydrogen in an aqueous medium containing ILs/H O seems
2
to be lower than the solubility of hydrogen in water alone. These
hypotheses could be reinforced by the fact that the starting solu-
tions with or without ILs were generally orange-red due to the
Entry IL
Conv. (%)a COE (%)a COA (%)a 1,4-COD (%)a 1,3-COD (%)a
1
1
2
2
3
3
3
3
3
a
b
a
b
a
b
BMIMBr
26
17
96
18
53
61
90
71
28
50
55
45
41
4
3
5
24
72
50
45
55
59
45
32
5
d
4
b
b
b
2
dispersion of PdCl in them. After the introduction of the hydrogen
BMIMCl
d
d
d
d
d
d
d
5
atmosphere, the solution without ILs becomes black more quickly
than experiments containing an IL. This could signify a more rapid
reduction of the Pd(II) into Pd(0) and consequently a higher re-
activity with hydrogen.
BMIM
L-lactate 100
d
d
d
d
d
100
100
100
100
b
c
b
d
b
e
a
Determined by GC.
Recycling experiments.
2.3. Antimicrobial toxicity screening study
b
For the antifungal studies, compounds were screened against
the following yeast strains: Candida albicans ATCC 44859, C. albi-
cans ATCC 90028, Candida parapsilosis ATCC 22019, Candida krusei
ATCC 6258, C. krusei E28, Candida tropicalis 156, Candida glabrata
20/I, Candida lusitaniae 2446/I, Trichosporan asahii 1188 and fila-
mentous fungi (Aspergillus fumigatus 231, Absidia corymbifera 272,
Trichophyton mentagrophytes 445). MIC values for antifungal study
were defined as 80% inhibition (IC80) of the control growth for yeast
and 50% inhibition (IC50) of the control growth for filamentous
fungi (Table S1, See ESD). The MIC values for most fungi were
recorded after 24 h and 48 h except for the dermatophytic strain (T.
mentagrophytes 445), which was determined after 72 h and 120 h.
The results show that all ionic liquids were non-toxic to all 12
fungi strains up to 1 mM concentration.
Fig. 3. Hydrogenation of 1,5-cyclooctadiene in water with TBA pyruvate 6.
BMIMBr (Table 5, entries 1a and 1b) and the formation of iso-
merized products was significantly high. In BMIMCl, although
a high conversion and selectivity for COE in the first run was
demonstrated (entry 2a), the conversion of the substrate decreased
drastically in the second run to 18%. With BMIM L-lactate, which
was also commercially available, quantitative conversion of 1,5-
COD was observed during the 5 runs but yielded a majority of COA.
Next, bacteria were screened against four Gram positive or-
ganisms Staphylococcus aureus ATCC 6538, S. aureus MRSA HK5996/
08, Staphylococcus epidermidis HK6966/08, Enterococcus sp.
HK14365/08 and four Gram negative organisms Escherichia coli
ATCC 8739, Klebsiella pneumoniae HK11750/08, K. pneumoniae-ESBL
positive HK14368/08 and Pseudomonas aeruginosa ATCC 9027
(Table S2, see ESD). MIC values for the antibacterial study were
defined as 95% inhibition (IC95) of the control growth. These results

N. Ferlin et al. / Tetrahedron 69 (2013) 6150e6161
6155
Fig. 4. Hydrogenation of 1,5-cyclooctadiene in water with TBA succinate 4, TBA D-glucuronate 7, and TBA D-galacturonate 8.
Table 5
IC50 determination
Entry
Compound
IC50 value (mM)
E. coli
B. subtilis
P. fluorescens
P. putida (CP1)
P. putida (KT2440)
1
2
3
4
5
6
7
8
9
TBABr
TBAOH$30H O
2
03.13e06.25
06.25e12.50
12.50e25.00
06.25e12.50
12.50e25.00
12.50e25.00
06.25e12.50
12.50e25.00
06.25e12.50
12.50e25.00
25.00e50.00
12.50e25.00
06.25e12.50
03.13e06.25
06.25e12.50
03.13e06.25
03.13e06.25
06.25e12.50
25.00e50.00
25.00e50.00
06.25e12.50
12.50e25.00
12.50e25.00
03.13e06.25
06.25e12.50
12.50e25.00
03.13e06.25
06.25e12.50
25.00e50.00
25.00e50.00
25.00e50.00
12.50e25.00
06.25e12.50
03.13e06.25
06.25e12.50
06.25e12.50
03.13e06.25
06.25e12.50
25.00e50.00
25.00e50.00
12.50e25.00
12.50e25.0
12.50e25.00
12.50e25.00
12.50e25.00
12.50e25.00
03.13e06.25
12.50e25.00
25.00e50.00
25.00e50.00
1
2
3
4
5
6
7
8
10
show that all ionic liquids, TBABr, TBACl, and 1e8, were non-toxic to
all 8 bacteria strains up to 1 mM concentration. Table S1 and S2 (See
ESD) combined demonstrate that the ionic liquids do not exhibit
high antimicrobial toxicity to a wide range of bacteria and fungi.
Finally, IC50 values for the ionic liquids were also determined
after 18 h against a screen of 5 bacteria (Table 5).
toxic than 7 to E. coli (12.5e25 mM vs 6.25e12.5 mM, Table 5, entry
10 vs 9).
The C3 carboxylate ILs TBA -lactate 1 and TBA pyruvate 6 have
L
similar toxicity. The IC50 values for E. coli (12.5e25 mM), B. subtilis
(6.25e12.5 mM), P. putida (CP1) (6.25e12.5 mM), and P. putida
(KT2440) (12.5e25 mM) are the same for both 1 and 6, while TBA
Table 5 shows the IC50 values for 5 bacteria. The effect of
changing the anion can be observed by comparing TBA salts (Table
pyruvate 6 is more toxic than TBA -lactate 1 to P. fluorescens
L
(6.25e12.5 mM vs 12.5e25 mM, entry 8 vs 3). Ionic liquids with
anions containing only a carboxylic acid and a carboxylate group
(TBA malonate 3 and TBA succinate 4) have the same IC50 values for
E. coli (12.5e25 mM), P. putida (CP1) (6.25e12.5 mM) and P. putida
(KT2440) (12.5e25 mM). However, while TBA succinate 4 is more
5
, entries 2e10) to TBABr (Table 5, entry 1). The highest antibac-
terial toxicity was found for TBA salts containing carboxylic acid,
carboxylate, and hydroxyl groups. TBA -malate 5 has IC50 values for
the 5 bacteria strains between 3.13 and 12.5 mM (Table 5, entry 7)
and TBA -tartrate 2 IC50 values in the range 3.12e25 mM (Table 5,
entry 4). The lowest antibacterial toxicity ionic liquids were the
sugar carboxylate derivatives TBA -glucuronate 7 and TBA -gal-
acturonate 8. Both ionic liquids have IC50 values between 25 and
0 mM for the 4 bacteria (B. subtilis, Pseudomonas fluorescens,
Pseudomonas putida (CP1) and P. putida (KT2440)) while 8 is less
L
L
toxic than malonate 3 to B. subtilis (3.12e6.25 mM vs
6.25e12.5 mM, Table 5, entry 6 vs 5), 3 is more toxic than 4 to P.
fluorescens (6.25e12.5 mM vs 12.5e25 mM, Table 5, entry 5 vs 6).
Comparing the IC50 values for the halide salt, TBABr with the bio-
mass derived ILs the following trends are apparent. ILs 1e8 are less
D
D
5
toxic to the Gram negative bacteria E. coli. Sugar derivatives TBA D-

6156
N. Ferlin et al. / Tetrahedron 69 (2013) 6150e6161
glucuronate 7 and TBA
to all 5 bacteria strains (Gram positive and negative) screened.
Changing from a halide to -lactate, -tartrate, malonate, succinate,
-malate or pyruvate increased the toxicity of the ionic liquid to the
Gram positive bacteria B. subtilis and Gram negative P. putida (CP1).
For P. fluorescens, only TBA -tartrate 2 and -malate 5 were more
toxic than TBABr. TBA -malate 5 was also more toxic to P. putida
D
-galacturonate 8 are less toxic than TBABr
hydroxide and an excess of the corresponding acid with good
yields. Their characterization was realized through routine NMR, IR,
elemental analysis, viscosity, and ATG techniques. These ionic liq-
uids derived from TBA show good performance and recyclability in
catalytic selective hydrogenation of 1,5-cyclooctadiene into cyclo-
octene at room temperature under atmospheric H pressure. They
2
are more suitable for selective hydrogenation of 1,5-COD into COE
under milder conditions than commercial BMIM ILs.
L
L
L
L
L
L
(
KT2440) than TBABr.
Toxicity assays toward a large panel of bacterial and fungal
strains were also performed. Ionic liquids containing
or -galacturonate anions were the least toxic to the strains
screened, and TBA -tartrate and TBA -malate the most toxic bio-
D-glucuronate
3
. BiodegradationdClosed Bottle test
D
L
L
The biodegradability of the tetraalkylammonium salts was in-
mass derived examples prepared (antibacterial activity). All ionic
liquids (1e8) were less toxic to E. coli than TBABr, however this
trend did not apply to all ionic liquids for other Gram negative
bacteria in the study (e.g., P. putida). None of the tetrabuty-
lammonium salts, containing biomass derived anions (1e8) passes
the Closed Bottle test nor tetrabutylammonium, tetraethylammo-
nium or tetramethylammonium bromide. Thus these ions are
classified as not readily biodegradable components of ILs according
to this test. While none of the ionic liquids can be prioritized for
further catalysis study based on passing Closed Bottle test (all
failed), positively the series of ILs (1e8) all did not exhibit high
antimicrobial toxicity. On-going investigations tackle the problem
of low biodegradability, while maintaining good performance in
the catalytic hydrogenation studies.
vestigated in the Closed Bottle test. The test was valid according to
the test guideline since sodium acetate was biodegraded up to 82%
within 14 days (demand of at least 60%) and oxygen concentrations
ꢁ1
in all bottles did not fall below 0.5 mg L at any time. Oxygen
ꢁ
1
depletion in the inoculum blanks after 28 days was 0.82 mg L and
ꢁ1
therefore less than 1.5 mg L . The difference of extremes in rep-
licate values of the removal of the test compound was less than 20%
in all tests except for TBA succinate 4 where this validity criterion
was not met.
The results of the biodegradation of the tetraalkylammonium
salts are presented in Table 6. Of all the compounds tested, the
sugar acid derivatives 7 and 8 had the highest biodegradabilities
(
18.6 and 22.6%, respectively), which were within the range of the
variation of the results for the same compound in repeated tests
that are due to differences in the composition of inoculum and
number of bacteria present. None of the test compounds 1e8
passed the Closed Bottle test (pass level: 60%). Tetraethylammo-
nium and tetramethylammonium bromide were also included in
the study to investigate the effect of alkyl chain length on bio-
degradation. Both these bromide salts also failed the Closed Bottle
test (OECD 301D) and are not classed readily biodegradable.
5
5
. Experimental
.1. General
All reagents were commercially available and used as received
(
L
-lactic acid 90% from ACROS, TBAOH$30H
acid 98% from Aldrich, -tartaric acid from Prolabo, malonic acid
99% from Jansen, succinic acid 99%, -malic acid 99%, pyruvic acid
8%, and -glucuronic acid 98% from Alfa Aesar). H and C NMR
spectra were recorded on an AC 250 Bruker in CDCl , CD OD or
with TMS as reference for H spectra and CDCl 77.0),
30.6) for C spectra. The infrared
2
O and D-galacturonic
L
Table 6
L
Biodegradation studies (Closed Bottle test OECD 301D)
1
13
9
D
Entry
Compound
Biodegradation in % ThOD
theoretical oxygen demand)
3
3
1
(
acetone-d
MeOD (
3
(d
6
13
1
2
3
4
5
6
7
8
9
TBABr
TBAOH$30H
TEABr
TMABr
1
2
3
4
5
6
7
8
7.9
3.8
0
2.6
15.5
15.5
9.9
d
6
49.9) or acetone-d (d
2
O
spectra were recorded with Spectrafile IRÔ Plus MIDAC. C, H, and N
analyses were performed on a Perkin Elmer 2400 CHN equipment.
GC was recorded on a HewlettePackard HP-6890 gas chromato-
graph, fitted with DB-1 capillary column (25 m, 0.32 mm), a flame
ionization detector and HP-3395 integrator;
Nd
Thermogravimetric analyses coupled with a mass spectrometer
14.2
12.2
18.6
22.8
ꢀ
ꢀ
were performed between 30 C and 500 C under a constant flow of
dry argon (50 mL/min) using a Simultaneous Thermal Analyzer STA
449C Jupiter from Netzsch, and a heating rate of 10 K/min. The
1
1
1
0
1
2
isothermal drift and sensitivity values are 0.6 mg/h and 0.1 mg, re-
NdeNot determined due to failing one of the validation requirements for the test.
spectively. Alumina crucibles were loaded with 10e20 mg of sample
powder.
There is no clear trend between the effect of the anion structure
and biodegradability. Low biodegradation was observed for TBA
bromide (7.9%), slightly higher for 1, 2, 3, 5, and 6 (9.9e15.5%).
According to the standard method, all tetraalkylammonium
salts under investigation were not toxic since after 14 days the
degradation was more than 25% in the toxicity control containing
The mass spectrometer is a quadrupole QMS 403 A e€ olosÒ with
a stainless steel capillary and a SEV detector (Channeltron). The
counting time for mass spectrometer is of 20 ms per m/z values
(scanning width: m/z¼10e150 amu) with a resting time of 1 s.
The DSC experiments were carried out on a Netzsch DSC 204F1
heat flux differential calorimeter at a heating/cooling rate of 10 K/
min under a constant argon flow with 200 mL/min. The crucibles
were loaded with 10e20 mg of sample powder/liquid. Samples
were weighed in aluminum sample pans covered with a pierced lid.
An empty aluminum sample pan with a pierced lid was used as
a reference.
substance and sodium acetate each in
5
a
concentration of
ꢁ
2
mg O L . None of the examined compounds proved to be ef-
1
fective against the growth of the degrading bacteria present in the
test vessels.
4
. Conclusion
The viscosities measurements in cP (or mPa s) were performed
with a Brookfield LV-DVIIþ PRO viscometer using a CP51 cone
spindle. The instrument was connected to a HUBER-ministat cir-
culation-type thermo-regulated water bath, and measures were
Ionic liquids with natural organic acid derived anions (L-lactate,
L
-tartrate, malonate, succinate,
L-malate, pyruvate,
D-glucuronate,
D
-galacturonate) were easily prepared from tetrabutylammonium

N. Ferlin et al. / Tetrahedron 69 (2013) 6150e6161
6157
realized between 298.15 and 353.15 K. The repeatability of the
viscometer was of 0.20% with an uncertainty in the viscosity
measurements of 1.00% of the full scale range, declared by the
manufacturer.
were no higher than the nearest concentration value up and down
the dilution scale.
5.4. Toxicity studies
IC50 values for the compounds were determined at The School of
5
.2. Antifungal activity
Biotechnology, Dublin City University using a modification of the
5
3
broth microdilution method described by Amsterdam. Strains
were grown in nutrient broth overnight, washed with 0.01 M so-
dium phosphate buffer and the cell number adjusted to give an
optical density reading of 0.07 at 660 nm. The antimicrobial activity
In vitro antifungal activities of the compounds were evaluated
on a panel of four ATCC strains (C. albicans ATCC 44859, C. albicans
ATCC 90028, C. parapsilosis ATCC 22019, C. krusei ATCC 6258) and
eight clinical yeast isolates (C. krusei E28, C. tropicalis 156, C. glab-
rata 20/I, C. lusitaniae 2446/I, T. asahii 1188) and filamentous fungi
of the ILs were tested in 96 well microplates. 180
Hinton broth was pipetted into column 1 of the wells and 100
into the other wells. 20 L of the chemical solution was transferred
into column 1 giving a concentration of 200 mM. 100 L of the
mL of Mueller-
m
L
(A. fumigatus 231, A. corymbifera 272, T. mentagrophytes 445) from
m
the collection of fungal strains deposited at the Department of Bi-
ological and Medical Sciences, Faculty of Pharmacy, Charles Uni-
versity, Hradec Kr aꢁ lov eꢁ , Czech Republic. Three ATCC strains were
used as the quality control strains. All of the isolates were main-
tained on Sabouraud dextrose agar prior to being tested.
Minimum inhibitory concentrations (MICs) were determined
by modified CLSI standard of microdilution format of the M27-A3
and M38-A2 documents.
a diluent for all compounds; the final concentration did not ex-
ceed 2%. RPMI 1640 (Sevapharma, Prague) medium supplemented
with L-glutamine and buffered with 0.165 M morpholinepropa-
nesulfonic acid (Serva) to pH 7.0 by 10 M NaOH was used as the
test medium. The wells of the microdilution tray contained
m
solution from column 1 was then transferred to the next column
and mixed. The procedure was repeated to give a series of twofold
dilutions. Each well was inoculated with 5 mL of bacterial culture.
Wells containing medium only were used as blanks and wells
containing medium and culture only were used as positive controls.
ꢀ
The microplates were incubated overnight at 37 C for E. coli and
5
0,51
Dimethyl sulfoxide (100%) served as
ꢀ
3
0 C for all other bacteria. The presence or absence of growth was
determined by measuring the optical density of the wells at
a wavelength of 405 nm using a plate reader. The IC50 values were
determined as the concentration or range of concentrations that
caused a 50% reduction in growth.
2
00
the compounds (1000e0.244
and 10 L of inoculum suspension. Fungal inoculum in RPMI
m
L of the RPMI 1640 medium with 2-fold serial dilutions of
5
.5. Closed Bottle test (CBT)
m
mol/L for the new compounds)
m
The CBT is one of six test methods described in the OECD Test
1640 was prepared to give
a
final concentration of
5
4
Guidelines to determine the ready biodegradability of organic
chemicals. With a low nutrient content and a low bacterial density
the CBT simulates the conditions of environmental surface water.
One can assume that substances classified as ‘readily biodegrad-
able’ are biodegradable in sewage treatment plants and therefore
are not expected to reach or accumulate in the aquatic
environment.
3
ꢁ1
ꢀ
5
ꢂ10 ꢃ 0.2 cfu mL . The trays were incubated at 35 C and MICs
were read visually after 24 h and 48 h. The MIC values for the
dermatophytic strain (T. mentagrophytes) were determined after
72 h and 120 h. The MICs were defined as 80% inhibition (IC80) of
the control growth for yeasts and as 50% inhibition (IC50) of the
control growth for filamentous fungi. MICs were determined
twice and in duplicate. The deviations from the usually obtained
values were no higher than the nearest concentration value up
and down the dilution scale.
The test was performed in the dark at a room temperature of
ꢀ
2
0ꢃ1 C in the laboratories of the Institute of Sustainable and En-
vironmental Chemistry at Leuphana University L u€ neburg as de-
5
5
scribed in details elsewhere. It consisted of four different test
series. All series were run as duplicates. The ‘blank series’ contained
only mineral medium and inoculum. The ‘quality control’ was
prepared additionally with readily biodegradable sodium acetate to
monitor the activity of the microorganisms. The ‘test series’ in-
cluded besides medium and inoculum the test compound as only
organic compound while the ‘toxicity control’ series contained
additionally sodium acetate. The amount of sodium acetate and of
each test compound corresponded to a theoretical oxygen demand
(ThOD) of 5 mg L . All test vessels contained the same mineral salt
solution and were inoculated with two drops of inoculum from the
effluent of the municipal sewage treatment plant in L u€ neburg
(Abwasser, Gr u€ n und L u€ neburger Service GmbH, Germany; 250.000
5
.3. Antibacterial activity
In vitro antibacterial activities52 of the compounds were eval-
uated on a panel of three ATCC strains (S. aureus ATCC 6538, E. coli
ATCC 8739, P. aeruginosa ATCC 9027) and five clinical isolates (S.
aureus MRSA HK5996/08, S. epidermidis HK6966/08, Enterococcus
sp. HK14365/08, K. pneumoniae HK11750/08, K. pneumoniae-ESBL
HK14368/08) from the collection of fungal strains deposited at the
Department of Biological and Medical Sciences, Faculty of Phar-
macy, Charles University, Hradec Kr ꢁa lov eꢁ , Czech Republic. The
above-mentioned ATCC strains also served as the quality control
strains. All the isolates were maintained on Mueller-Hinton agar
prior to being tested.
ꢁ1
population equivalents).
Dimethyl sulfoxide (100%) served as a diluent for all com-
pounds; the final concentration did not exceed 2%. Mueller-Hinton
agar (MH, HiMedia, Cadersky-Envitek, Czech Republic) buffered to
According to the guidelines, at least 60% decomposition of the
reference substance sodium acetate is required within 14 days.
Toxicity was assessed by comparing oxygen consumption as mea-
sured in the toxicity control bottles with the predicted level com-
puted from the oxygen consumption in the quality control and in
the test vessel containing only the test compound, respectively. A
compound is labeled toxic if the difference between the predicted
amount of oxygen consumption and the measured one exceeds
ꢂ
pH 7.4 (ꢃ0.2) was used as the test medium. The wells of the
microdilution tray contained 200 L of the Mueller-Hinton medium
with 2-fold serial dilutions of the compounds (1000e0.244 mmol/L)
and 10 L of inoculum suspension. Inoculum in MH medium was
prepared to give a final concentration of 0.5 McFarland scale
8
ꢁ1
ꢀ
54
(
1.5ꢂ10 cfu mL ). The trays were incubated at 37 C and MICs
were read visually after 24 h and 48 h. The MICs were defined as
5% inhibition of the control growth. MICs were determined twice
and in duplicate. The deviations from the usually obtained values
25%.
The process of aerobic biodegradation was monitored by mea-
suring the biological oxygen demand of the microorganisms in
9
5
6
accordance with international standard methods at day 0, 0 (after

6158
N. Ferlin et al. / Tetrahedron 69 (2013) 6150e6161
1
3
h), 1, 7, 14, 21 and 28 using sensor spots in the bottles and an
1069 (
n
CO or
n
CN); H NMR (250 MHz, CD
3
eCOeCD
3
):
d
¼4.60 (large
0
0
oxygen electrode (Oxi 196 with EO 196-1.5 WTW Weilheim,
Germany).
s, 2H, H-2 , H-3 ), 3.44 (m, 8H, H-1), 1.79 (quint, 8H, H-2,
J
(
d
1e2¼7.7 Hz, J2e3¼7.4 Hz), 1.47 (hex, 8H, H-3, J2e3¼J3e4¼7.4 Hz), 1.07
13
t, 12H, H-4, J3e4¼7.4 Hz); C NMR (63 MHz, CD
3
eCOeCD
¼173.3 (C]O), 72.9 (C-2 , C-3 ), 59.2 (C-1), 24.4 (C-2), 20.5 (C-3),
3.8 (C-4); Calcd C20 , 0.7H O C: 59.44%, H: 10.57%; N: 3.47%,
Found C: 59.33%, H: 9.95%; N: 3.45% MS (ESIþ) 242.2 MS (ESIꢁ)
48.8.
3
):
0
0
5
.6. General procedure for ILs using acids obtained from
1
H41NO
6
2
biomass
1
The acid (0.74 mmol) was dissolved in distilled water (5 mL)
note: slight warming is necessary with succinic acid). Then, an
aqueous solution of TBAOH$30H O (0.62 mmol in 10 mL of distilled
(
5.6.3. Tetrabutylammonium malonate 3.
2
water) was added dropwise. After addition, the mixture was stirred
ꢀ
at 100 C during 24 h. After cooling, the solvent was evaporated and
the crude product washed with diethyl ether (3ꢂ25 mL) and dried
ꢀ
in vacuo at 60 C for 2 days.
5.6.1. Tetrabutylammonium
L
-lactate 1.
3
General procedure with malonic acid (73 mg, 0.76 mmol) and
TBAOH$30H
onate (217.0 mg, 0.627 mmol) was obtained as a white wax. Yield:
9%.
IR (film): 3600e3100 (
2
O (502.1 mg, 0.63 mmol). Tetrabutylammonium mal-
9
1
n
OH
,
n
Nþ), 2966 (nCH), 2939 (nCH), 2877
(
n
n
CH), 1738 (
n
COOH), 1645 (
n
COOꢁ), 1485, 1471, 1376, 1352, 1192 (
n
CO or
1
CN), 1054 (
n
CO or
n
CN), 1062; H NMR (250 MHz, CD
3
eCOeCD
3
):
General procedure with
TBAOH$30H O (497 mg, 0.62 mmol). Tetrabutylammonium
tate 1 (200.1 mg, 0.60 mmol) was obtained as a colorless oil. Yield:
L
-lactic acid (61
m
L, 0.74 mmol) and
0
d
¼3.39 (m, 8H, H-1), 2.77 (s, 2H, H-2 ), 1.75 (quint, 8H, H-2,
2
L-lac-
J
1e2¼8.2 Hz, J2e3¼7.3 Hz), 1.38 (sext, 8H, H-3, J2e3¼7.3 Hz,
13
J3e4¼7.2 Hz), 0.95 (t, 12H, H-4, J3e4¼7.2 Hz); C NMR (63 MHz,
9
7%.
0
IR (film) cmꢁ1: 3600e3000 (
CD
3
eCOeCD
3
):
d¼173.7 (C]O), 60.0 (C-1), 40.2 (C-2 ), 25.2 (C-2),
n
OH
,
n
Nþ), 2963 (nCH), 2952 (
n
CH),
CN),
2
4 2
1.1 (C-3), 14.8 (C-4); C19H39NO $0.8H O Calcd C: 63.40%, H: 11.37%;
2
1
876 (
093 (
CD eCOeCD
n
CH), 1606 (
CO or
n
COOꢁ), 1489, 1464, 1381, 1345, 1117 (
n
CO or
n
1
N: 3.89%, Found C: 63.65%; H: 11.03%; N: 3.80%. MS (ESIþ) 242.2 MS
n
n
CN), 1033 (
n
CO or
n
CN); H NMR (250 MHz,
¼6.8 Hz), 3.37 (m, 8H, H-
0
(ESIꢁ) 103.0.
3
3
):
d
¼4.00 (q, 1H, H-2 , J
2
0
e3
0
1
3
4
6
C
6
), 1.75 (quint, 8H, H-2, J1e2¼8.3 Hz, J2e3¼7.3 Hz), 1.40 (sext, 8H, H-
0
5.6.4. Tetrabutylammonium succinate 4.
, J2e3¼J3e4¼7.3 Hz), 1.27 (d, 3H, H-3 , J
2
0
e3
0
¼6.8 Hz), 0.95 (t, 12H, H-
13
, J3e4¼7.3 Hz); C NMR (63 MHz, CD
3
eCOeCD
3
):
d
¼179.8 (C]O),
0
0
8.6 (C-2 ), 60.1 (C-1), 25.2 (C-2), 22.1 (C-3 ), 21.1 (C-3), 14.8 (C-4);
19
H
20NO3.2H
2
O Calcd C: 62.09%, H: 12.34%; N: 3.81%, Found C:
2.36%; H: 12.15%; N: 3.42%. MS (ESIþ) 242.1 MS (ESIꢁ) 89.
5.6.2. Tetrabutylammonium
L
-tartrate 2.
4
General procedure with succinic acid (88.9 mg, 0.75 mmol) and
TBAOH$30H
cinate (218.6 mg, 0.61 mmol) was obtained as a white wax. Yield:
8%.
IR (film): 3500e3200 (
CH), 1727 (
250 MHz, CD
2
O (498.2 mg, 0.62 mmol). Tetrabutylammonium suc-
9
2
n
OH
,
n
Nþ), 2956 (
n
CH), 2932 (
n
CH), 2871
1
(n
n
COOH), 1553, 1400, 1335, 1304, 1127, 1069; H NMR
(
3
eCOeCD
3
):
d
¼3.42 (m, 8H, H-1), 2.44 (large s, 4H, H-
0
0
General procedure with
L
-tartaric acid (112.3 mg, 0.74 mmol)
and TBAOH$30H O (498.4 mg, 0.62 mmol). Tetrabutylammonium L-
tartrate (238.5 mg, 0.609 mmol) was obtained as a very viscous
light yellow oil. Yield: 98%.
2 , H-3 ) 1.77 (quint, 8H, H-2, J1e2¼7.6 Hz, J2e3¼7.3 Hz), 1.40 (sext,
8H, H-3, J2e3¼7.3 Hz, J3e4¼7.2 Hz), 0.96 (t, 12H, H-4, J3e4¼7.2 Hz);
2
1
3
C NMR (63 MHz, CD
3
eCOeCD
3
):
d
¼177.1 (C]O), 60.1 (C-1), 33.3
0
0
4
(C-2 , C-3 ), 25.1 (C-2), 21.2 (C-3), 14.8 (C-4). Calcd C20H41NO C:
IR (film): 3600e3000 (
n
OH
,
n
Nþ), 2973 (
CO or
n
CH), 2874 (
n
CH), 1734
66.81%, H: 11.49%; N: 3.90%, Found C: 65.85%; H: 10.98%; N: 4.02%;
MS (ESIþ) 242.2 MS (ESIꢁ) 117.1.
(n
COOH), 1652 ( COOꢁ), 1468, 1379, 1120 (
n
n
n
CN), 1082 (
n
CO or CN),
n

N. Ferlin et al. / Tetrahedron 69 (2013) 6150e6161
6159
5.6.5. Tetrabutylammonium
L
-malate 5.
absolute ethanol (100 mL) was added dropwise at room tempera-
ture and the resulting dispersion was stirred at room temperature
during 24 h (solution became clear). After evaporation of the sol-
vent under reduced pressure, 150 mL of acetone was added. A white
solid formed almost immediately and was separated from the
remaining liquid by filtration. The filtrate was evaporated and ac-
etone added one more time to form a white solid. The two solids
were combined and gave 1.749 g of tetrabutylammonium
D-glu-
curonate (3.98 mmol) as a white solid. Yield 80%.
ꢀ
ꢁ1
T
f
: 95 C. IR (KBr) cm : 3500e3000 (
CH), 2731, 1611 (
065, 1024 ( CO or
n
OH
,
n
Nþ), 2963 (
nCH), 2871
(
1
d
n
n
COOꢁ), 1475, 1431, 1349, 1318, 1291, 1158, 1117,
CN), 949, 885 H NMR (250 MHz, CD
5
1
n
n
3
OD):
0
0
¼5.03 (d, 1H, H-1
a
,
J
1
0
a
e2
a
0
a
¼3.4 Hz), 4.37 (d, 1H, H-1
b
a
,
,
General procedure with
TBAOH$30H O (501 mg, 0.63 mmol). Tetrabutylammonium L
2
L
-malic acid (101.9 mg, 0.75 mmol) and
-malate
229.6 mg, 0.61 mmol) was obtained as a colorless gel. Yield: 97%.
0
0
J
J
1
0
0
b
e2
e4
0
b
¼7.7 Hz), 3.96 (d, H-5
, J
4
0
a
e5
0
a
¼10 Hz), 3.57 (t, 1H, H-3
0
0
¼8.6, J
0
0
¼9.1 Hz), 3.36 (d, 1H, H-5
b
, J
4
0
0
0
¼8.7 Hz),
(
3
3
a
a
2
a
e1
a
b
e5
a
0
0
0
.26 (m, 3H, H-2
a
, H-2
b, H-3
b
), 3.14 (m, 9H, H-1; H-4 a), 3.07 (t,
IR (film): 3500e3200 (
CH), 1721 (
250 MHz, CD
n
OH
,
n
Nþ), 2963 (
n
CH), 2935 (
n
CH), 2874
1
0
0
0
0
0
1
H, H-4
b
,
J
3
b
e4
¼J
b 4
b
e5
b
¼8.6 Hz), 1.55 (quint, 8H, H-2,
(
(
(
(
n
n
COOH), 1594, 1489, 1461, 1379, 1263, 1168, 1069; H NMR
0
J1e2¼8.0 Hz, J ¼7.3 Hz), 1.32 (sext, 8H, H-3, J ¼7.3 Hz,
eCOeCD
3
):
d
¼4.28 (t, 1H, H-2 , J
2
0
e3
ae3
0
¼6.4 Hz), 3.30
2e3
2e3
3
13
0
J3e4¼7.2 Hz), 0.91 (t, 12H, H-4, J ¼7.2 Hz); C NMR (63 MHz,
m, 8H, H-1), 2.57 (m, 2H, H-3 , J
2
0
e3
0
¼6.4 Hz, J
3
0
0
b
¼16 Hz), 1.66
3e4
0
0
0
0
CD
7
3
OD):
d
¼177.5 (C-6
a
), 176.2 (C -6
b
), 98.4 (C-1
b), 93.9 (C-1
a),
quint, 8H, H-2, J1e2¼8.2 Hz, J2e3¼7.4 Hz), 1.29 (hex, 8H, H-3,
13
0
0
0
0
0
7.8 (C-3
b
), 76.2 (C-4
b
), 76.1 (C-5
), 71.3 6 (C-2
b
), 74.6 (C-3
), 59.4 (C-1), 24.8 (C-2), 20.7 (C-3),
a
), 74.1 (C-4
a
), 73.7
J
2e3¼7.4 Hz, J3e4¼7.3 Hz), 0.84 (t, 12H, H-4, J3e4¼7.3 Hz); C NMR
0
0
0
0
0
0
(C-2
b
), 73.6 (C-5
a
a
(
6
0
63 MHz, CD
3
eCOeCD
3
):
0.2 (C-1), 41.4 (C-3 ), 25.4 (C-2), 21.3 (C-3), 14.8 (C-4); C20
.5H O Calcd C: 62.47%, H: 11.01%; N: 3.64%, Found C: 62.00%; H:
d
¼176.9 (C-1 ), 173.6 (C-4 ), 68.7 (C-2 ),
0
14.1 (C-4); C23H47NO Calcd C: 60.66%, H: 10.41%; N: 3.22%, Found
H41NO
5
,
6
C: 59.68%; H: 10.11%; N: 3.30%. MS (ESIþ) 242.2, MS (ESIꢁ) 193.0.
2
10.57%; N: 3.40%. MS (ESIþ) 242.2 MS (ESIꢁ) 133.0.
5.6.8. Tetrabutylammonium
D
-galacturonate 8.
5.6.6. Tetrabutylammonium pyruvate 6.
8
6
D
-Galacturonic acid mono hydrate (1.312 g, 6 mmol) was dis-
persed in absolute ethanol (150 mL). A solution of TBAOH$30H
4.0027 g, 5 mmol) in absolute ethanol (150 mL) was added drop-
wise at room temperature and the resulting dispersion was stirred
at room temperature during 24 h. After evaporation of the solvent
General procedure with pyruvic acid (52
mL, 0.73 mmol) and
2
O
TBAOH$30H
vate (191.0 mg, 0.58 mmol) was obtained as a yellow oil. Yield: 93%.
2
O (500.9 mg, 0.63 mmol). Tetrabutylammonium pyru-
(
IR (film): 3500e3100 (
721 ( COOH), 1461, 1375, 1338 (
CD eCOeCD ):
n
OH
,
n
Nþ), 2959 (
n
CH), 2935 (
n
CH), 2871 (
n
CH),
1
1
n
n
CO or
n
CN), 1059; H NMR (250 MHz,
under reduced pressure, acetone was added and the solution was
0
3
3
d
¼3.40 (m, 8H, H-1), 2.25 (s, 3H, H-3 ),1.77 (quint, 8H,
ꢀ
kept at 4 C for 2 days to precipitate the remaining
D
-galacturonic
H-2, J1e2¼8.2 Hz, J2e3¼7.3 Hz), 1.63 (sext, 8H, H-3, J2e3¼J3e4¼7.3 Hz),
acid. The solid was then eliminated by precipitation and the filtrate
13
1
d
.22 (t, 12H, H-4, J3e4¼7.3 Hz); C NMR (63 MHz, CD
3
eCOeCD
¼200.5 (C-1 ),168.7 (C-2 ), 60.1 (C-1), 25.3 (C-2), 21.1 (C-3),14.8 (C-4);
MS (ESIþ) 242.2C19 ,1H O Calcd C: 65.66%, H: 11.89%; N: 4.03%,
Found C: 65.80%; H: 11.46%; N: 3.98% MS (ESIþ) 242.2 MS (ESIꢁ) 87.1.
3
):
ꢀ
kept at 4 C for 2 days. After elimination of the solid, the filtrate was
0
0
evaporated under reduced pressure. Tetrabutylammonium D-gal-
acturonate (1.6793 g, 3.86 mmol) was obtained as a white solid.
Yield: 77%.
H39NO
3
2
ꢀ
ꢁ1
T
f
: 98 C. IR (KBr) cm : 3500e3000 (
n
OH
,
n
Nþ), 2959 (
nCH), 2874
5.6.7. Tetrabutylammonium
D-glucuronate 7.
(
1
(
4
n
CH), 2737, 1605 (
106, 1024 (
d, 1H, H-1
.37 (m, 1H, H-4
n
COOꢁ), 1468, 1417, 1379, 1335, 1267, 1158, 1140,
CN), 977, 881. H NMR (250 MHz, CD
1
n
CO or
n
3
OD)
d
¼5.15
0
0
a
, J
1
0
a
e2
a
0
¼3.3 Hz), 5.05 (d, 1H, H-1
b
, J
1
0
b
e2
0
b
¼6.4 Hz),
0
a
), 4.24 (dd, 1H, H-4
b
,
J
3
0
be4
0
b
¼5.9 Hz,
0
0
J
J
4
0
b
e5
0
b
¼2.8 Hz), 4.17 (m, 1H, H-3
a
), 4.03 (t, 1H, H-3
b
,
0
0
0
b
¼J
0
0
¼5.9 Hz), 3.92 (d, 1H, H-5
b
, J
0
0
b
¼2.8 Hz), 3.74
2
b
e3
3
b
e4
b
4
b
e5
0
0
a,
(
dd, 1H, H-2
a
, J
1
0
a
e2
0
a
¼3.3 Hz, J
2
0
a
e3
0
a
¼6.9 Hz), 3.44 (d, 1H, H-5
J
J
4
0
a
e5
0
a
¼4 Hz), 3.17 (m, 8H, H-1), 1.62 (quint, 8H, H-2 J1e2¼8.2 Hz,
2e3¼7.4 Hz), 1.37 (sext, 8H, H-3, J2e3¼7.4 Hz, J3e4¼7.3 Hz), 0.99 (t,
13
0
0
1
1
8
(
2H, H-4, J3e4¼7.3 Hz); C NMR (63 MHz, CD
3
OD):
d
¼176.8 (C-6
a
a
),
),
0
0
0
0
76.6 (C -6
b
), 104.4 (C-1
b
), 97.7 (C-1
a
), 86.3 (C-4
b
), 84.7 (C-4
0
0
0
0
0
3.1 (C-3
b
), 79.4 (C-2
b
), 79.3 (C-2
a
), 77.7 (C-3
a), 74.3 (C-5
a), 73.6
7
0
C-3
b
), 59.6 (C-1), 24.9 (C-2), 20.8 (C-3), 14.6 (C-4); C23
H47NO
6
2
$H O
D-Glucuronic acid (1.193 g, 6.0 mmol) was dispersed in absolute
Calcd C: 58.25%, H: 10.44%; N: 3.09%, Found C: 57.99%; H: 10.18%; N:
ethanol (150 mL). A solution of TBAOH$30H O (4.02 g, 5.0 mmol) in
2
3.13%. MS (ESIþ) 242.2, MS (ESIꢁ) 193.0.

6
160
N. Ferlin et al. / Tetrahedron 69 (2013) 6150e6161
12. (a) Baltus, R. E.; Counce, R. M.; Culbertson, B. H.; Luo, H. D.; DePaoli, W.; Dai, S.;
5
.7. General procedure for catalyses
Duckworth, D. C. Sep. Sci. Technol. 2005, 40, 525e541; (b) Han, X.; Armstrong,
D. W. Acc. Chem. Res. 2007, 40, 1079e1086; (c) Arce, A.; Earle, M. J.; Katdare, S. P.;
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5
.7.1. Catalysis experiments. A Schlenk tube was charged with the
ionic liquid (c.a. 400 mg) and the catalyst (3.5 mg, 0.02 mmol,
.01 equiv/substrate) and left for 10 min under vacuum. Next, 1,5-
cyclooctadiene (250 L, 2 mmol, 1 equiv) and distilled water
2 mL, 5 equiv Mass compared to IL) were added under argon. The
0
m
1
3. (a) P a^ rvulescu, V. I.; Hardacre, C. Chem. Rev. 2007, 107, 2615e2665; (b) Plech-
kova, N. V.; Seddon, K. R. Chem. Soc. Rev. 2008, 37, 123e150; (c) Beadham, I.;
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GmbH & KGaA: 2012; Vol. 9, pp 137e158.
(
argon atmosphere was then replaced by hydrogen through a gas
bag and the mixture was vigorously stirred for 18 h at room tem-
perature. The aqueous phase was next extracted with Et
2
O
14. (a) Sheldon, R. A.; Arends, I.; Hanefeld, U. Green Chemistry and Catalysis; Wiley-
VCH: Weinheim, Germany, 2007; (b) Augustine, R. L. Heterogeneous Catalysis for
the Synthetic Chemist; CRC: New York, NY, 1995; (c) Beletskaya, I. P.; Kustov, L.
M. Russ. Chem. Rev. 2010, 79, 441e461.
(
3ꢂ5 mL) and the combined organic layers were dried over MgSO
4
and then filtered through cotton (1
mL was injected into GC to
evaluate the conversion). The aqueous phase was kept in the
Schlenk tube to be reused.
15. Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3772e3789.
1
6. (a) Kustov, L. M.; Vasina, T. V.; Ksenofontov, V. A. Ross. Khim. Zh. 2004, 48,
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1
4
5.7.2. Recycling experiments. After a short vacuum/argon sequence
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(
three times), the 1,5-cyclooctadiene (250 L, 2 mmol, 1 equiv) was
m
18. Wasserscheid, P.; Schulz, P. In Handbook of Homogeneous Hydrogenation; De
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This work was supported by the Fondation du Site Paris Reims
(
post doctoral fellowship for N.F.) and the FEDER for material funds.
2
2
2
2
2
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versit eꢁ de Picardie Jules Verne for their help in viscosity
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Supplementary data
Results from catalysis studies (conversion, ratio of products,
recycling) for hydrogenation of 1,5-cyclooctadiene in water Fig S1,
and in water and IL (Figs. S2eS11) are provided in ESI. Antimicrobial
screening data antifungal Table S1 and antibacterial Table S2 are
also included. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2013.05.054.
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