Basicity and stability of urea deep eutectic mixtures

Article abstract of DOI:10.1039/c5ra24558c

The stability and basicity origin of some common urea based deep eutectic mixtures/solvents (DES) were studied. We have observed an unexpected Hantzsch dihydropyridine reaction in sorbitol/urea DES, where the source of ammonia was found not to be originated from the individual ingredients of the DES. Our results showed that decomposition of urea occurs in DES at lower than expected temperatures, namely below 100 °C and is enhanced in diol DES by the formation of carbonates causing their unexplained basicity. Carbohydrates and choline chloride (ChCl) DES exhibit lower rates of decomposition, while no decomposition was observed from neat urea or MeOH and EtOH urea solutions.

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Basicity and Stability of the Urea Deep Eutectic Mixtures
S. P. Simeonova* and C. A. Afonsob*
Received 00th January 20xx,
Accepted 00th January 20xx
The stability and the basicity origin of some common urea based deep eutectic mixtures/solvents
(DES) were studied. We have observed an unexpected Hantzsch dihydropyridine reaction in
sorbitol/urea DES, where the source of ammonia was found not to be originated from the individual
ingredients of the DES. Our results showed that decomposition of urea occur in DES at lower than
DOI: 10.1039/x0xx00000x
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expected temperatures, namely below 100°C and is enhanced in diols DES by the formation of
carbonates causing their unexplained basicity. Carbohydrates and Choline chloride (ChCl) DES exhibit
lower rates of decomposition, while no decomposition was observed from neat urea or MeOH and
EtOH urea solutions.
and valorisation of biorenewable resources.21-22 Many of these
transformations require reaction temperatures up to 100°C
and although some of them could proceed at lower
temperatures the initial formation of the DES is usually
Introduction
During the last decades immerged considerable scientific
interest on more green and sustainable approaches in organic
synthesis.1-2 Ionic liquids (ILs) were intensively studied as
promising green solvents and catalysts for diverse organic
transformations.3-5 They are considered green mainly due to
their low vapour pressure, high thermal stability and
recyclability but despite that there are some serious doubts
about their real greenness when their all life cycle and the
toxic and environmental effects during the synthesis,
application and deposal are considered.6-7 More recently, after
performed by heating the ingredients till homogeneous
mixture is formed. Herein are provided some insides on the
stability of choline chloride (ChCl), polyalcohols and
carbohydrates DES with urea under heating and the origin of
their already observed basicity23 and catalytic activity in base
catalysed reactions.16-17, 19-20
Results and Discussion
the pioneer and systematic research of Abbott et al.8-10 a new In our research we were interested on the possible application
class of ionic fluids emerged namely deep eutectic of chiral DES in asymmetric synthesis and in particular
mixtures/solvents (DES), which exhibit similar properties as the asymmetric Biginelli reactions. Such an alternative would be
traditional ILs but being much more eco-friendly and cheap are highly attractive because DES can be easily accessed from
of a growing interest.11-12
cheap and environmental friendly natural compounds like
DES are typically formed by two or three components which carbohydrates or derived polyols.
interact each other mainly via hydrogen bond interactions to The Biginelli reaction is an acid-catalysed, three-component
form an eutectic mixture, which has melting point lower than reaction between an aldehyde, ß-ketoester and urea providing
each of the individual ingredients. Most of them are liquid at dihydropyrimidones,24
compounds
with
interesting
temperatures below 70°C and even at RT, and can be used as pharmacological properties associated with their heterocyclic
safe and inexpensive solvents for diverse applications. Usually scaffold25 (Scheme 1).
DES are obtained by mixing quaternary ammonium salts with
metal salts or hydrogen bond donors (HBD).13-15 Among all the
R2
O
Ar
O
O
O
HBD, urea is one of the most widely used because it is cheap,
readily available and non-toxic. Urea based DES are already
applied as solvents for various classical organic reactions13, 16-20
H+
O
NH
R2
Ar
O
H2N
NH2
R1
O
R1
N
H
O
Scheme 1
Initially we carried out classical Biginelli reaction between
ethyl acetoacetate and p-tolyl aldehyde catalysed by p-toluene
sulfonic
acid
(p-TSA)
at
90°C
in
sorbitol/urea
(47mol%/53mol%) DES. The resulting dihydropyrimidone
1
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was obtained in 95% yield after 12h, with no enantiomeric The unexpected formation of 1,4-dihydropyridine derivatives
excess. Surprisingly when the same reaction was repeated in raises the question about the origin of ammonia in the
absence of p-TSA instead of
1 we observed a new product in reaction mixture. We used standard Nestler reagent test,
41% yield, which was determined to be diethyl 2,4,6-trimethyl- which gives yellow colour in presence of ammonia (Figure 1).
1,4-dihydropyridine-3,5-dicarboxylate
2
(Scheme 2).
The blank tests of pure urea and sorbitol water solutions were
negative (Table 1), thereby proving that ammonia is not
originated as an impurity in the individual ingredients of the
DES. Positive result was observed only for aqueous solution of
sorbitol/urea DES (Table 1, Figure 1), which is somehow
unexpected since the significant thermal urea decomposition
requires higher temperatures, above 150°C.27 However, this
observation leads to the idea that partial decomposition of
urea to ammonia occurs during the heating and formation of
urea based DES and is responsible for their basicity.23
Ammonia could also be the catalyst in the reported base
catalysed reactions, such as Perkin17 and Knovenagel
condensations.19
O
O
O
O
O
p-TSA
O
H2N
NH2
O
90°C
NH
N
H
O
1
H
N
no catalyst
90°C
EtOOC
COOEt
2
Scheme 2
Obviously the formation of was a result of Hantzsch
2
dihydropyridine synthesis26 that proceed via initial Knovenagel
condensation between 1 equiv. ethyl acetoacetate and p-tolyl
aldehyde to form intermediate 3, which further reacts with
ester enamine
4, produced by the condensation of a second
equivalent of ethyl acetoacetate with ammonia. The formed
intermediate
5
undergo cyclization to give 2 (Scheme 3).
NH4+ + 2[HgI4]2ꢀ + 4OHꢀ
HgO·Hg(NH3)I + 7Iꢀ + 3H2O
yellowcolor
O
O
O
NH2
O
O
O
O
Base
O
O
Figure 1. Observed positive Nestler test (aqueous solution) for
3
4
sorbitol/urea (3 h, 80°C)
O
HN
H
N
Table 1. Nestler reagent test results.
Entry
Tested mixture
Result
positive
negative
negative
Sorbitol/Urea (47mol%/53mol%)a
Urea aqueous solutionb
EtOOC
COOEt
EtOOC
COOEt
1
2
3
Sorbitol aqueous solutionb
a Prepared by heating sorbitol and urea mixture for 3h at 80°C. b 0.1g
solution in 4 mL of distilled water.
5
2
Scheme 3
The synthesis of
2 was later used as a clock reaction for the
decomposition of urea in different alcohols. The reactions
were monitored by TLC (Table 2).
Different aryl aldehydes were screened under the same
conditions and 1,4-dihydropyridine derivatives 7a-c were
4
obtained in moderate yields of up to 50% (Scheme
O
).
Table 2 Screening of the effect of the alcohol structure on the
formation of 2.a
H
N
H2N
NH2
O
H
EtOOC
COOEt
O
O
O
N
sorbitol-urea DES
80°C
NH3
O
O
alcohol/urea
O
EtOOC
COOEt
2eq.
O
R
80 ºC, overnight
R
2eq.
7a-c
7a
, R = OMe, 48% yield
7b, R= OH, 38% yield
7c, R=NO2, 50% yield
2
Scheme 4
2 | J. Name., 2012, 00, 1-3
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Entry
Alcohol
Methanol
Ethanol
ChCl
Sorbitol
Glycerol
Resultb
No reaction
No reaction
Traces
Product
Product
1
2
3
4
5
a Each reaction was performed overnight at 80°C using 1:1 w/w ratio of the
alcohol and urea.. b Product detected by TLC
The formation of
2 was found to be enhanced in presence of
poly alcohols (2, entries 4 and 5), while no product was
detected in presence of mono alcohols (Table 2, entries 1 and
2), thereby bringing to the idea that the formation of ammonia
is not a result of a simple urea thermal decomposition.
According to the results, the most rationalized explanation of
the ammonia origin is the possible formation of cyclic
carbonates and their related intermediates from the reaction
of urea with poly alcohols (Scheme 5) that can proceed at
20140318_eutecticDMSO
28000
26000
24000
22000
20000
18000
16000
14000
12000
10000
8000
O
8
4
O
O
3
5
1
2
moderate temperatures, even below 100°C.
O
HO
7
6
6
-2NH3
O
O
OH
Glycerol
O
R
HO
R
H2N
NH2
H2N
OH
O
O
-H2O
-NH3
NH
R
6
N
H
O
R
R
6
6000
and/or
and/or
O
4000
O
O
R
2000
H2N
N
H
0
HN
OH
-2000
82
81
80
79
78
77
76
75
74
73
72
f1 (ppm)
71
70
69
68
67
66
65
64
63
62
Scheme 5
Figure 3. 13C NMR of glycerol:urea mixture (5:2 molar ratio, 80°C, 3
The formation of cyclic carbonates has been confirmed in a
test reaction where a mixture of glycerol and urea (5:2 molar
ratio) was heated at 80°C with steering for 3 weeks to form
weeks), in DMSO-d6
Our results could also explain the basicity of one of the most
commonly used ChCl/urea (1:2), in which some urea
glycerol carbonate
6
(Scheme 6).
O
decomposition occurred and traces of product
2 were
O
OH
80°C
O
O
observed by TLC (Table 2, entry 3). We speculate that the
lower amount of formed ammonia is due to the fact that ChCl,
being mono alcohol, cannot form cyclic carbonates via
favourable intermolecular cyclization (Scheme 7).
HO
OH
H2N
NH2
HO
6
Scheme 6
Cl
O
The reaction mixture was analysed by MS (Figure 2) and 13C
NMR (Figure 3). The formation of together with other minor
-NH3
Cl
OH
O
NH2
N
N
H2N
NH2
6
O
side products, which were not assigned, was confirmed..
Scheme 7
Having these results in hands, we explored the stability of
some already reported DES in a systematic way. The liberated
ammonia during the formation of DES was trapped in an
aqueous acid solution and after titration with a base, in
presence of an indicator, the amount of ammonia was
determinedand could be directly related to the urea
decomposition rate. The temperature of 80°C was chosen for
our study because it can mimic commonly used by many
researchers conditions for the formation of DES. A scale of
2.4g of urea or dimethylurea (DMU) was used for the synthesis
of DES and the other ingredients were recalculated as they are
Figure 2. MS spectra of glycerol urea mixture (5:2 molar ratio, 80°C,
3 weeks)
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reported in the literature. In a standard experiment DES was Scientific High Resolution Magnetic Sector MS DFS by chemical
heated at 80°C for 7h and continuously flashed with N2, which ionization.
was then bubbled trough 10mL 0.05M water solution of H2SO4.
At the end, the solution was titrated with 0.05M solution of Preparation of Sorbitol-Urea DES: 13.96 g of urea and 49.8 g
KOH using phenolphthalein as indicator, the results are of sorbitol were mixed and stirred at 80°C for 3h till
summarized in Table 3.
homogeneous liquid mixture was formed.
Table 3. Results from the titration of the captured ammonia in 10
mL 0.05M water solution of H2SO4 after 7h at 80°C.
Ethyl
6-methyl-2-oxo-4-(p-tolyl)-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (1).28
NH3/CH3NH2
0.05M KOH NH3/ CH3NH2
Entry DES/molar ratio
yield
mL.a
mmol
c,d
%
18 ChCl/Urea 1:2
18.5
9.3
20
0.075
0.535
0.000
0.09
0.66
0
2b Sorbitol/Urea 5.2:4
3
Urea
Glucose/Urea/CaCl2
1.6:4:0.5
418
19
0.005
0.006
5g of sorbitol/urea DES were placed in a round bottom flask
then p-tolyl aldehyde (1mmol, 120mg), ethyl acetoacetate
(1mmol, 130mg) and p-TsOH (0.2mmol, 34mg) were added
and stirred overnight at 90°C. The reaction was dissolved in 10
mL of water. After complete dissolution, the product was
5
Glycerol/Urea 10:4
4.9
19.5
19.5
19.3
18
0.755
0.025
0.025
0.035
0.100
0.94
0.03
0.03
0.04
0.12
68 ChCl/DMU 1:2
7
8
Glycerol/DMU 10:4
Sorbitol/DMU 5.2:4
918 Fructose/Urea 3:2
a Theoretical volume of 0.05M KOH aqueous solution needed for complete extracted with ethyl acetate 2x25 mL. The organic phase was
b
neutralization of H2SO4 solution (10mL, 005M) is 20mL. urea/sorbitol DES
was previously prepared in this molar ratio in our laboratory. c Calculated as
a percent from the theoretical yield of ammonia considering full urea
decomposition. d The ammonia/CH3NH2 which may have remained dissolved
in the DES is not taken into account and the actual yields are expected to be
higher.
dried over Na2SO4, evaporated and the crude was purified with
automatic flash chromatography machine -CombiFlash using
gradient mixing of hexane and ethylacetate to give 260.4 mg
(95%)
Reported M.p 170-172 °C; found: 171-172ºC.
The spectral data (1H and 13C NMR) is identical with the
reported.29
The obtained results were in agreement with our previous
observation that the urea decomposition is enhanced in
presence of poly alcohols. As it was expected, pure urea was
complete stable at 80°C and no ammonia was detected (Table
3, entry 3). The highest amount of ammonia was observed in
case of glycerol (Table 3, entry 5) and sorbitol (Table 3, entry
2), while only small amount was observed for ChCl (Table 2,
entry 1). When carbohydrates such as glucose and fructose
were used only minor amounts of ammonia were detected
(Table 3, entries 4 and 9). However, after 7 hours at 80°C the
colour of these DES turns brown, probably due to
carbohydrates decomposition and formation of humins, which
also should be taken into account when they are used as a
reaction media at high temperatures. Switching from urea to
dimethylurea DMU resulted in more stable DES and only traces
of methylamine were observed, even with glycerol and
sorbitol (Table 3, entries 7 and 8).
1H NMR (300 MHz, DMSO-d6) δ (ppm) 9.16 (s, 1H, NH), 7.68
(br s, 1H, NH), 7.12 (s,4H), 5.10 (d, 1H, J=3.3 Hz), 3.36 (q, 2H,
J=7.1 Hz), 2.49 (s, 3H), 2.24 (s, 3H), d 1.10 (t, 3H, J=7.1 Hz)
13C NMR (100 MHz, DMSO-d6) δ (ppm), 166.3, 152.9, 148.9,
142.8, 137.3, 129.7, 126.8, 100.2, 59.9, 54.5, 21.4, 18.5, 14.8.
Synthesis of Nessler reagent: A saturated solution of HgCl2
(~2.2g in 35 mL of distilled water) was added to a solution of
5g of KI in 5 mL of distilled water until the excess is indicated
by the formation of a precipitate. Then 20mL of 5N NaOH were
added and the mixture diluted to 100 mL with distilled water.
The solution was left to settle and the clear liquid was draw
off.
Nessler test: To a solution of 0.1g sorbitol/urea DES, urea or
sorbitol in 4 mL of distilled water were added several drops of
the Nessler reagent. The appearance of yellow colour was
followed as a sign for the presence of ammonia.
Experimental
General procedure for the synthesis of 1,4 dihydropyridine
derivatives: 5g of sorbitol/urea DES were placed in a round
bottom flask then 1mmol of the corresponding aromatic
aldehyde and 2 mmol of ethyl acetoacetate were added and
stirred overnight at 90°C. The reaction was dissolved in 10 mL
of water. After complete dissolution, the product was
extracted with ethyl acetate 2x25 mL. The organic phase was
dried over Na2SO4, evaporated and the crude was purified with
automatic flash chromatography machine (CombiFlash) using
gradient mixing of hexane and ethyl acetate.
General: All the reagents were purchased from Sigma-Aldrich
or Merck and were used without further purification. The
reaction evolution was followed by TLC using silica Merck
Kieselgel 60 F254 plates, and revealed by ultraviolet light at
254 nm and 325 nm. NMR spectra were recorded at room
temperature in a Bruker AMX 300 or Bruker AMX 400 using
CDCl3 or DMSO-d6 as solvents. The MS spectra of the glycerol
urea mixture (5:2 molar ratio) was recorded using Thermo
4 | J. Name., 2012, 00, 1-3
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°
C;32
Diethyl
dicarboxylate (2).30
2,6-dimethyl-4-(p-tolyl)-1,4-dihydropyridine-3,5-
Yellow solid, yield: 131mg, 38%. Reported M.p: 230-231
found: 219-220 C.
°
1H NMR (400 MHz, DMSO) δ (ppm) 9.07 (s, 1H), 8.70 (s, 1H),
6.92 (d, J = 8.5 Hz, 2H), 6.57 (d, J = 8.5 Hz, 2H), 4.74 (s, 1H),
4.00 – 3.96 (m, 4H), 2.23 (s, 6H), 1.13 (t, J = 7.1 Hz, 6H).
13C NMR (101 MHz, DMSO) δ (ppm) 167.11, 155.44, 144.77,
138.92, 128.29, 114.52, 102.29, 58.89, 37.87, 18.21, 14.21
ESI-MS: calculated for [C19H23NO5 + H]+/z: 346.40; found:
(M+H)/z: 346.02
IR (KBr, cm-1): 3346.50 (N-H), 2985.81 (Ar-H), 2937.59 (CH),
1662.64 (C=O), 1442.75 (C-OH).
Light yellow solid, yield: 140mg, 41%. Reported M.p: 136–
137°C;30 found: 140-142
°C.
1H NMR (300 MHz, CDCl3) δ (ppm) 7.17 (d, J = 7.6 Hz, 2H), 7.01
(d, J = 7.6 Hz, 2H), 5.74 (s, 1H), 4.95 (s, 1H), 4.08 (q, J = 7.0 Hz,
4H), 2.31 (s, 6H), 2.27 (s, 3H), 1.22 (t, J = 7.1 Hz, 6H).
13C NMR (75 MHz, CDCl3) δ (ppm) δ 167.70, 144.89, 143.81,
135.50, 128.56, 127.83, 104.23, 59.70, 39.10, 21.05, 19.56,
14.26.
Diethyl
2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydropyridine-3,5-
dicarboxylate (7c).31
ESI-MS: calculated for [C20H25NO4 + H]+/z: 344.24; found:
(M+H)/z: 344.15
IR (KBr, cm-1): 3342.64 (NH), 2982.11 (Ar-H), 2936.77 (CH),
1693.65 (C=O).
Yellow solid, yield: 189mg, 50%. Reported M.p: 118–127°C;31
Diethyl 4-(4-methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (7a).31
found: 129-130°C.
1H NMR (400 MHz, CDCl3) δ (ppm) 8.07 (d, J = 8.8 Hz, 2H), 7.44
(d, J = 8.8 Hz, 2H), 5.84 (s, 1H), 5.08 (s, 1H), 4.11 – 4.05 (m, J =
7.1, 3.1 Hz), 2.34 (s, 6H), 1.21 (t, J = 7.1 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ (ppm) 167.10, 155.14, 146.34,
144.70, 128.92, 123.30, 103.18, 60.02, 40.14, 19.65, 14.27.
ESI-MS: calculated for [C19H22N2O6 + H]+/z: 375.40, found:
(M+H)/z: 375.06
IR (KBr, cm 1): 3319.49 (NH), 2926.01 (Ar-H), 2852.72 (CH),
1701.22 (C=O).
Light yellow solid, yield: 160mg, 48%. Reported M.p: 148–
153°C;31 found: 156-157
°C.
1H NMR (400 MHz, CDCl3) δ (ppm) 7.19 (d, J = 8.7 Hz, 2H), 6.74
(d, J = 8.7 Hz, 2H), 5.62 (s, 1H,), 4.92 (s, 1H), 4.21 – 3.99 (m,
4H,), 3.75 (s, 3H,), 2.32 (s, 6H), 1.22 (t, J = 7.1 Hz, 6H).
13C NMR (101 MHz, CDCl3) δ (ppm) 167.83, 158.00, 143.66,
140.46, 129.10, 113.31, 104.54, 59.84, 55.27, 38.86, 19.74,
14.41.
Conclusions
The reported unusual basicity of urea based DES17, 19, 23 can be
explained by the urea decomposition and liberation of
ammonia, even at lower than the expected temperatures. The
presence of ammonia was detected during unexpected
formation of dihydropyridines via Hantzsch synthesis in
sorbitol/urea DES and further confirmed with Nesstler reagent
tests. The formation of ammonia was not caused by simple
thermal urea decomposition and was enhanced in presence of
poly alcohols via the formation of cyclic carbonates. Neat or
mono alcohols solutions of urea were observed to be
completely stable under heating up to 80°C for at least 7h.
ChCl was found to be an exception and although being mono
alcohol, low rate of urea decomposition was also detected at
80°C for 12h. DMU based DES were more stable since DMU is
less prompt to react with alcohols forming carbonates and
insignificant amounts of methylamine were detected. Besides
the extremely useful and high potential of DES clearly
demonstrated for different applications after the pioneer
discovery of Abbott et al.,8-10 this study provides some
guidelines about their use for long time under high
temperature in which for some specific DES combination,
ESI-MS: calculated for [C20H25NO5 + H]+/z: 360.42; found:
(M+H)/z: 360.08
IR (KBr, cm-1): 3342.64 (NH), 2983.88 (Ar-H), 2956.87 (CH),
1689.64 (C=O).
Diethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylate (7b).32
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25. Kappe, C. O., Eur. J. Med. Chem., 2000, 35, 1043.
26. Saini, A. K., Sanjay Sandhu, Jagir S, J. Sci. Ind. Res., 2008, 67
95.
27. Schaber, P. M.; Colson, J.; Higgins, S.; Thielen, D.; Anspach,
B.; Brauer, J., Thermochim. Acta, 2004, 424, 131.
28. Jing, X.; Li, Z.; Pan, X.; Shi, Y.; Yan, C., JICS, 2009, 6, 514.
29. Liberto, N. A.; de Paiva Silva, S.; de Fátima, Â.; Fernandes, S.
A., Tetrahedron, 2013, 69, 8245.
namely urea/polyalcohols occurs some ammonia liberation.
These observations could be of importance for applications
using urea based DES in different areas such as organic
synthesis since, as we have shown, ammonia could be a
,
catalyst or
a reactive nucleophile in organic reactions
performed in this reaction media.
30. Bandyopadhyay, D.; Maldonado, S.; Banik, B. K., Molecules,
2012, 17, 2643.
Acknowledgements
31. Affeldt, R. F.; Benvenutti, E. V.; Russowsky, D., New J. Chem.,
2012, 36, 1502.
32. Koukabi, N.; Kolvari, E.; Khazaei, A.; Zolfigol, M. A.;
The authors acknowledge Fundação para a Ciência e a
Tecnologia (FCT) (ref. SFRH/BD/67025/2009, PTDC/QUI-
QUI/119823/2010 and UID/DTP/04138/2013) and European
Research Area Network; ERANet LAC (ref. ELAC2014/BEE-
0341) for financial support and REDE/1518/REM/2005 (FF-UL)
for the mass service.
Shirmardi-Shaghasemi, B.; Khavasi, H. R., Chem. Commun., 2011
47, 9230.
,
Notes and references
1. Anastas, P. T., Chem. Rev., 2007, 107, 2167.
2. Horváth, I. T.; Anastas, P. T., Chem. Rev., 2007, 107, 2169.
3. Hallett, J. P.; Welton, T., Chem. Rev., 2011, 111, 3508.
4. Park, S.; Kazlauskas, R. J., Curr. Opin. Biotechnol., 2003, 14
,
432.
5. van Rantwijk, F.; Sheldon, R. A., Chem. Rev., 2007, 107, 2757.
6. Renner, R., Environ. Sci. Technol., 2001, 35, 410A.
7. Thuy Pham, T. P.; Cho, C.-W.; Yun, Y.-S., Water Res., 2010
44, 352.
,
8. Abbott, A. P.; Capper, G.; Davies, D. L.; Rasheed, R. K.;
Tambyrajah, V., Chem. Commun., 2003, 70.
9. Abbott, A. P.; Boothby, D.; Capper, G.; Davies, D. L.; Rasheed,
R. K., J. Am. Chem. Soc., 2004, 126, 9142.
10. Smith, E. L.; Abbott, A. P.; Ryder, K. S., Chem. Rev., 2014, 114
11060.
,
11. Zhang, Q.; De Oliveira Vigier, K.; Royer, S.; Jerome, F., Chem.
Soc. Rev., 2012, 41, 7108.
12. Dai, Y.; van Spronsen, J.; Witkamp, G.-J.; Verpoorte, R.; Choi,
Y. H., J. Nat. Prod., 2013, 76, 2162.
13. Imperato, G.; Hoger, S.; Lenoir, D.; Konig, B., Green Chem.,
2006, 8, 1051.
14. Maugeri, Z.; Dominguez de Maria, P., RSC Adv., 2012, 2, 421.
15. Abbott, A. P.; Barron, J. C.; Ryder, K. S.; Wilson, D., Chem.
Eur. J., 2007, 13, 6495.
16. Phadtare, S. B.; Shankarling, G. S., Green Chem., 2010, 12
458.
,
17. Pawar, P. M.; Jarag, K. J.; Shankarling, G. S., Green Chem.,
2011, 13, 2130.
18. Imperato, G.; Eibler, E.; Niedermaier, J.; Konig, B., Chem.
Commun., 2005, 1170.
19. Sonawane, Y. A.; Phadtare, S. B.; Borse, B. N.; Jagtap, A. R.;
Shankarling, G. S., Org. Lett., 2010, 12, 1456.
20. Singh, B.; Lobo, H.; Shankarling, G., Catal. Lett., 2011, 141
178.
,
21. Vigier, K. D. O.; Benguerba, A.; Barrault, J.; Jerome, F., Green
Chem., 2012, 14, 285.
22. Ilgen, F.; Ott, D.; Kralisch, D.; Reil, C.; Palmberger, A.; Konig,
B., Green Chem., 2009, 11, 1948.
23. Li, W.; Zhang, Z.; Han, B.; Hu, S.; Song, J.; Xie, Y.; Zhou, X.,
Green Chem., 2008, 10, 1142.
24. Suresh; Sandhu, J. S., Arkivoc, 2012, 66.
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5RA24558C
Some decomposition occurs below 100°C for urea based deep eutectic mixtures/solvents (DES)
liberating ammonia and is enhanced for diols by formation of carbonates.