An operationally simple and scalable approach to functionalized ionic liquids from phosphonium and N-heterocyclic halide salts

Article abstract of DOI:10.1055/s-0033-1338806

An approach toward the synthesis of N-heterocyclic anionic ionic liquids is described. The ionic liquids are readily obtained by the treatment of the sodium salt of the parent N-heterocycle with the halide salt of the desired cation. Good to excellent yie

Full text of DOI:10.1055/s-0033-1338806

1428▌
LETTER
lAettner Operationally Simple and Scalable Approach to Functionalized Ionic
Liquids from Phosphonium and N-Heterocyclic Halide Salts
Functionalized Ionic Liquid Synthesis
Christopher J. Meyer, Monika Vogt, James P. Catalino, Brandon L. Ashfeld*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46637, USA
Fax +1(574)6316652; E-mail: bashfeld@nd.edu
Received: 03.03.2013; Accepted after revision: 23.04.2013
phosphonium salts involves the acid–base neutralization
Abstract: An approach toward the synthesis of N-heterocyclic an-
of a protonated anion precursor and the appropriately li-
ionic ionic liquids is described. The ionic liquids are readily ob-
gated phosphonium hydroxide.10 Although generally ef-
fective for common ILs, obtaining the unsymmetrical
tained by the treatment of the sodium salt of the parent N-
heterocycle with the halide salt of the desired cation. Good to excel-
lent yields (62–99%) of the corresponding ionic liquids are obtained phosphonium hydroxide requires an anion exchange of
without the use of excessive materials and time associated with con-
ventional methods for synthesizing heterocyclic based ionic liquids.
the corresponding phosphonium halide that involves pro-
longed reaction times and excessive amounts of hydrox-
Key words: ionic liquids, heterocyclic anions, phosphonium salts,
imidazolium salts, triazolium salts
ide and solvents. Thus, a method that provides the desired
IL in a single synthetic operation from the protonated an-
ion precursor, without the need for chromatography, in
high levels of purity and without extended reaction times
The study of ionic liquids (ILs) constitutes one of the fast- that is readily scalable would facilitate the further devel-
est growing areas of research in academia and industry.1 opment of this increasingly important class of materials.
The interest in ILs is primarily due to their exceptional We speculated that a simple cation-exchange protocol in-
utility as a broad class of materials for a wide range of ap- volving metalation of the protonated heterocycle 1 with
plications. Characterized by a low vapor pressure, low either NaH or NaOMe, followed by addition of the desired
flammability, aqueous solubility, and high thermal stabil- phosphonium bromide 2 or imidazolium salt 3 directly,
ity, ILs have become increasingly important as materials would provide ILs 4 and 5, respectively after a simple
for phase-transfer catalysis,2 biocatalysis,3 liquid mem- aqueous workup (Scheme 1).11 Herein we report the suc-
branes,4 solar cell design, electrodeposition, lithium bat- cessful implementation of this method design in the syn-
teries,5 and chemical separations. Additionally, their use thesis of a wide assortment of N-heterocyclic anion-based
as polar solvents in synthetic transformations highlights ILs in a highly efficient and cost-effective manner that is
their potential as a green alternative to conventional or- readily amenable to large-scale production.
ganic solvents.6 In spite of these attractive characteristics,
the synthetic approach towards construction of ILs with
heterocyclic-based anions employs a method which re-
quires excessive amounts of solvent, reagents, and time.7
However, the benefits associated with the potential to tune
the physiochemical properties of ILs to optimize perfor-
mance parameters through the design of functionalized
heterocyclic frameworks, make the addressing of these is-
sues one of primary importance.7
(R2)3P(R3)
N
R1
X
(R2)3P(R3)
2
or
X
Z
H
N
Y
4
NaH, THF or
R1
or
X
R3
N
X
R2
Z
NaOMe/MeOH
Y
N
N
R3
N
1
R1
X
N
R2
Z
3
Y
5
anion
component
cations
component
ionic liquids
Our interest in the design and synthesis of ILs stems from
recent reports highlighting their use as working fluids for
the gas-phase separation of pre- and postcombustion
CO2.8 Although efforts in this area have focused on opti-
mizing the chemical and physical absorption properties of
CO2, there remains a need for an effective method for the
large-scale synthesis of ILs efficiently and rapidly, from a
variety of heterocyclic scaffolds. Most custom ILs de-
signed for these purposes contain an anionic component
with an unsymmetrical phosphonium or imidazolium
counterion to enhance the fluidic properties of the materi-
al.9 The most common method for the synthesis of the
Scheme 1 Cation exchange approach towards IL synthesis
In general, ILs 4 were obtained in good to excellent yields
by treatment of N-heterocycle 1 with either NaH (condi-
tions A12) or NaOMe (conditions B12) followed by the ad-
dition of phosphonium bromide 2a (Table 1). For
example, applying conditions A to 2-cyanopyrrole (1a)
and 2a yielded pyrrolide IL 4a in 91% (Table 1, entry 1).
The addition of one equivalent of NaOMe to bipyrrole 1b
provided IL 4b in 88% yield (Table 1, entry 2). Triazolide
IL 4c was readily obtained in 76% yield (Table 1, entry 3).
Pyrazoles 1d–f proved to be effective precursors for the
synthesis of IL 4d–f in excellent yields (Table 1, entries
4–6). The bisthiophene-substituted imidazole-based IL 4g
was obtained in 62% yield (Table 1, entry 7). These re-
SYNLETT 2013, 24, 1428–1432
Advanced online publication: 17.05.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338806; Art ID: ST-2013-R0194-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Functionalized Ionic Liquid Synthesis
1429
sults demonstrate the applicability of this cation-exchange lide salts 3 to NaH (Table 2). Cyanopyrrole 1a was readily
protocol for the generation of N-heterocyclic anion-based converted into IL 5a with N,N-bismesityl imidazolium
IL without the need for phosphonium hydroxide synthe- chloride 3a in 70% yield (Table 2, entry 1). The alkyl/al-
sis.
kyl, aryl/alkyl, and alkyl/benzyl imidazolium salts 3b–d
provided the corresponding triazolide ILs 5b–d, respec-
tively (Table 2, entries 2–4). Interestingly, the meth-
yl/MOM-substituted imidazolium salt 3e provided IL 5e
in 60% yield (Table 2, entry 5). It is noteworthy that in the
formation of ILs 5a–e only trace quantities of the corre-
sponding N-heterocyclic carbenes resulting from C2–H
abstraction by the heterocyclic anion were observed by 1H
NMR spectroscopy.14
Table 1 Heterocyclic Anionic Phosphonium Ionic Liquidsa
H
N
NaH, THF (method A)
or NaOMe/MeOH (method B)
P666(14)
N
Y
R
X
R
X
then BrP666(14) (2a)
Y
1
4
P666(14) = [Me(CH2)5]3P(CH3)13Me
Entry
1
4
Conditions Yield (%)b
Table 2 Heterocyclic Anionic Imidazolium Ionic Liquidsa
P666(14)
N
R1
N
N
R2
X
CN
R1
N
A
B
A
91
88
76
H
N
H
N
Y
3
N
4a
4b
CN
or
X
N
Z
NaH, THF
H
N
N
P666(14)
N
N
R2
1a
1h
5
2
3
Entry
1
3
5
Yield (%)b
P666(14)
N
N
Mes
N
N
CN
Cl
EtO2C
Mes
N
N
Mes
1
1a
70
N
N
4c
Mes
3a
P666(14)
N
5a
N
4
5
A
A
99
70
i-Pr
O2N
N
Cl
i-Pr
N
N
4d
i-Pr
N
N
2
3
4
5
1h
1h
1h
1h
96
72
81
60
N
N
P666(14)
N
N
i-Pr
3b
5b
NO2
n-Bu
N
Br
n-Bu
4e
N
N
N
Ph
N
N
TMS
P666(14)
N
N
N
Ph
3c
6
7
A
B
81
62
5c
CO2Et
Bn
N
4f
Br
Bn
N
N
Me
S
N
Me
N
N
N
Me
P666(14)
3d
N
N
5d
Me
MOM
N
Me
Cl
MOM
N
N
S
N
Me
Me
N
N
N
4g
Me
3e
a Conditions A: 1 (1.0 equiv), 2a (1.0 equiv), and NaH (1.0 equiv) in
THF (0.1 M), 18 h. Conditions B: 1 (1.0 equiv), 2a (1.0 equiv), and
NaOMe (1.0 equiv) in MeOH (0.1 M), 18 h.
5e
a Conditions: same as A, Table 1.
b Isolated yields
b Isolated yields.
Given the general utility of imidazolium-based ILs,13 we
next examined the formation of ILs 5 resulting from the
exposure of heterocycles 1a or 1h with imidazolium ha-
With a general approach established for the synthesis of
phosphonium and imidazolium ILs derived from readily
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1428–1432

1430
C. J. Meyer et al.
LETTER
Table 3 Cation Functional Variabilitya
obtained unsymmetrical tetraalkyl phosphonium and im-
idazolium halides, we turned our attention toward evalu-
ating this method with functionalized cation precursors. In
general, good to excellent yields of triazolide ILs 4 and 5
were obtained from the treatment of triazole (1i) and a di-
verse array of phosphonium and heterocyclic halide salts
with NaOMe in MeOH (Table 3). Based on a recent report
by Tsunashima and co-workers that the presence of phos-
phorus alkyl ether ligands decreased the viscosity of phos-
phonium bistriflamide ILs,15 we initially examined the
formation of methyl ether phosphonium triazolide ILs
employing this cation-exchange protocol. Treatment of
triazole (1i) with NaOMe in MeOH followed by the addi-
tion of MOM-substituted tributyl phosphonium chloride
provided ILs 4h in a respectable 72% yield (Table 3, entry
1). Truncating the straight alkyl chains on the phosphoni-
um cation to methyl did not hinder the formation of IL 4i
(Table 3, entry 2). Likewise, the length of alkyl substitu-
tion on the oxygen-bearing phosphonium ligand proved
inconsequential to IL synthesis (Table 3, entry 3). The
MEM-substituted phosphonium triazolides 4k and 4l
were obtained in 77% and 76% yields, respectively (Table
3, entries 4 and 5). Employing the corresponding SEM-
substituted phosphonium chloride provided the triazolide
IL 4m in 75% yield (Table 3, entry 6). Given the propen-
sity for imidazolium ILs to generate N-heterocyclic car-
benes in situ, we examined C2 alkyl-substituted
imidazolium halides to prohibit carbene formation.16
Thus, imidazolium ILs 5f and 5g bearing MOM- and
MEM-protected primary alcohols at C2 were obtained in
good yields (Table 3, entries 7 and 8). Finally, the triazo-
lium-based IL 5h was obtained in 91% yield (Table 3, en-
try 9).
H
cation
N
N
NaOMe/MeOH;
then X [cation]
N
N
N
N
4/5
1i
Entry
X
Ionic liquid
Yield (%)b
72
OMe
OMe
N
N
n-Bu3P
Me3P
Et3P
N
N
N
N
N
N
1
Cl
4h
4i
N
N
2
3
4
5
6
Cl
Cl
Cl
Cl
Cl
73
81
77
76
75
OEt
N
N
4j
4k
4l
N
N
OMe
Et3P
Me3P
O
O
N
N
OMe
TMS
N
N
n-Bu3P
O
4m
Me
N
Based on recent reports, most notably by Johnston and co-
workers, on the synthetic utility of phosphite anions,17 we
examined the application of this cation-exchange protocol
for the synthesis of phosphite anion-based ILs. Gratify-
ingly, treatment of diphenylphosphite 6 with NaH fol-
lowed by the unsymmetrical phosphonium bromide 2a or
imidazolium chloride 3a provided phosphite ILs 7 and 8
in 78% and 65% yield, respectively (Equation 1). Al-
though a relatively unexplored IL motif, phosphite-based
ILs offer a number of opportunities for performance opti-
mization through structural modification of the phosphite
precursor.
OMOM
OMEM
N
N
N
N
7
8
9
Br
Br
Br
81
73
91
N
N
n-Bu
5f
Me
N
N
N
N
n-Bu
5g
Me
N
N
N
N
N
O
O
cation
NaH, THF;
Ph2PH
Ph2P
then X [cation]
6
n-Bu
7:
cation =
P666(14)
78%
5h
a Conditions: same as B, Table 1.
b Isolated yields.
8: 65%
MesN
NMes
Equation 1
duction. Therefore, we examined the scalability of this
modified cation-exchange protocol using triazole (1i) in
the synthesis of the corresponding phosphonium-based
ILs (Table 4). Employing a series of unsymmetrical tet-
One challenge in applying functionalized ILs as working
fluids for industrial purposes is the development of a syn-
thetic method that is readily amenable to large-scale pro-
Synlett 2013, 24, 1428–1432
© Georg Thieme Verlag Stuttgart · New York

LETTER
Functionalized Ionic Liquid Synthesis
1431
Org. Chem. 2003, 68, 4281. (e) Wheeler, C.; West, K. N.;
Liotta, C. L.; Eckert, C. A. Chem. Commun. 2001, 887.
(3) (a) Garcia, S.; Lourenco, N. M. T.; Lousa, D.; Sequeira, A.
F.; Mimoso, P.; Cabral, J. M. S.; Afonso, C. A. M.;
Barreiros, S. Green Chem. 2004, 6, 466. (b) Chiappe, C.;
Leandri, E.; Lucchesi, S.; Pieraccini, D.; Hammock, B. D.;
Morisseau, C. J. Mol. Catal. B: Enzym. 2004, 27, 243.
(c) Persson, M.; Bornscheuer, U. T. J. Mol. Catal. B: Enzym.
2003, 22, 21. (d) Kim, K.-W.; Song, B.; Choi, M.-Y.; Kim,
M.-J. Org. Lett. 2001, 3, 1507.
(4) (a) Matsumoto, M.; Inomoto, Y.; Kondo, K. J. Membr. Sci.
2005, 246, 77. (b) Scovazzo, P.; Kieft, J.; Finan, D. A.;
Koval, C.; DuBois, D.; Noble, R. J. Membr. Sci. 2004, 238,
57. (c) Fortunato, R.; Afonso, C. A. M.; Reis, M. A. M.;
Crespo, J. G. J. Membr. Sci. 2004, 242, 197. (d) Branco, L.
C.; Crespo, J. G.; Afonso, C. A. M. Angew. Chem. 2002,
114, 2895.
(5) (a) Arce, A.; Earle, M. J.; Rodriguez, H.; Seddon, K. R. J.
Phys. Chem. B 2007, 111, 4732. (b) Visser, A. E.; Swatloski,
R. P.; Rogers, R. D. Green Chem. 2000, 2, 1. (c) Huddleston,
J. G.; Rogers, R. D. Chem. Commun. 1998, 1765.
(6) (a) Rogers, R. D.; Seddon, K. R. Science 2003, 302, 792.
(b) Baleizao, C.; Gigante, B.; Garcia, H.; Corma, A. Green
Chem. 2002, 4, 272. (c) Earle, M. J.; Seddon, K. R. Pure
Appl. Chem. 2000, 72, 1391.
(7) (a) Gurkan, B. E.; de la Fuente, J. C.; Mindrup, E. M.; Ficke,
L. E.; Goodrich, B. F.; Price, E. A.; Schneider, W. F.;
Brennecke, J. F. J. Am. Chem. Soc. 2010, 132, 2116.
(b) Gurkan, B.; Goodrich, B. F.; Mindrup, E. M.; Ficke, L.
E.; Massel, M.; Seo, S.; Senftle, T. P.; Wu, H.; Glaser, M. F.;
Shah, J. K.; Maginn, E. J.; Brennecke, J. F.; Schneider, W.
F. J. Phys. Chem. Lett. 2010, 1, 3494. (c) Anthony, J. L.;
Anderson, J. L.; Maginn, E. J.; Brennecke, J. F. J. Phys.
Chem. B 2005, 109, 6366.
(8) (a) Bara, J. E.; Gabriel, C. J.; Lessmann, S.; Carlisle, T. K.;
Finotello, A.; Gin, D. L.; Noble, R. D. Ind. Eng. Chem. Res.
2007, 46, 5380. (b) Bates, E. D.; Mayton, R. D.; Ntai, I.;
Davis, J. H. J. Am. Chem. Soc. 2002, 124, 926.
raalkyl phosphonium bromides, the corresponding tri-
azolide ILs 4n–p were obtained in yields ranging from
70–96% on 120 g scale (Table 4, entries 1–3).
Table 4 Large-Scale Production of Ionic Liquidsa
H
N
(R1)3P(R2)
NaOMe/MeOH
N
N
N
N
then Br[(R1)3P(R2)]
N
4n–p
1i
Entry
R1
R2
IL
Yield (%)b
1
2
3
CH3(CH2)5
CH3(CH2)3
CH3CH2
CH3(CH2)13
CH3(CH2)11
CH3(CH2)5
4n
4o
4p
93
96
70
a Conditions: 1i (2.0 equiv), 2 (1.0 equiv), and NaOMe (2.0 equiv) in
MeOH (1.0 M), 72 h.
b Isolated yields
In conclusion, we have developed a complementary meth-
od for the synthesis of functionalized phosphonium and
N-heterocyclic cation based ILs that relies on the ease of
Na+ ion cation exchange. The method described herein is
applicable to a diverse array of anionic and cationic com-
ponents containing an assortment of different functional
groups. This protocol allows for the direct use of phospho-
nium halides that obviates the conventional requirement
of phosphonium hydroxide synthesis and avoids the com-
plications associated with excessive solvent, reagents, and
extended reaction times. The reaction is amenable to
large-scale production and requires a simple aqueous
wash or filtration to obtain the desired ILs in high levels
of purity. Given the ever-increasing interest in functional-
ly diverse ILs, this method should facilitate the discovery
of new applications for this important class of materials.
(c) Brennecke, J. F.; Maginn, E. J. AlChE J. 2001, 47, 2384.
(9) (a) Cadena, C.; Anthony, J. L.; Shah, J. K.; Morrow, T. I.;
Brennecke, J. F.; Maginn, E. J. J. Am. Chem. Soc. 2004, 126,
5300. (b) Anthony, J. L.; Maginn, E. J.; Brennecke, J. F.
J. Phys. Chem. B 2002, 106, 7315.
(10) (a) Ohno, H.; Fukumoto, K. Acc. Chem. Res. 2007, 40, 1122.
(b) Fukumoto, K.; Yoshizawa, M.; Ohno, H. J. Am. Chem.
Soc. 2005, 127, 2398.
(11) (a) Smiglak, M.; Hines, C. C.; Wilson, T. B.; Singh, S.;
Vincek, A. S.; Kirichenko, K.; Katritzky, A. R.; Rogers, R.
D. Chem. Eur. J. 2010, 16, 1572. (b) Smiglak, M.; Bridges,
N. J.; Dilip, M.; Rogers, R. D. Chem. Eur. J. 2008, 14,
11314. (c) Katritzky, A. R.; Singh, S.; Kirichenko, K.;
Smiglak, M.; Holbrey, J. D.; Reichert, W. M.; Spear, S. K.;
Rogers, R. D. Chem. Eur. J. 2006, 12, 4630.
Acknowledgment
The authors thank Professor Joan F. Brennecke (University of Notre
Dame) for helpful discussions and the Department of Energy,
Advanced Research Projects-Energy, the University of Notre
Dame Sustainable Energy Initiative, and the Center for Sustainable
Energy at Notre Dame (cSEND) for support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(12) General Procedures for IL Synthesis
Method A: A clean, oven-dried round-bottom flask was
charged with NaH (1.0 equiv, 1.0 mmol), flushed with N2,
then suspended in THF (4 mL). A solution of 1 (1 equiv, 1.0
mmol) in THF (1 mL) was added dropwise over 30 min, then
stirred until evolution of H2 ceased. A solution of 2 or 3 (1
equiv, 1.0 mmol) in THF (5 mL) was added and the reaction
monitored by 1H NMR (DMSO-d6). The resulting mixture
was diluted with H2O (10 mL) and extracted with EtOAc (3
× 15 mL). The combined organic fractions were
concentrated under reduced pressure to afford the desired IL.
Method B: A clean, oven-dried round-bottom flask was
charged with NaOMe/MeOH (0.4 mL of 3.0 M, 1.2 mmol).
A solution of 1i (1.0 equiv, 1.2 mmol) in MeOH (5 mL) was
References and Notes
(1) (a) Tang, S.; Baker, G. A.; Zhao, H. Chem. Soc. Rev. 2012,
41, 4030. (b) Buzzeo, M. C.; Evans, R. G.; Compton, R. G.
ChemPhysChem 2004, 5, 1106. (c) Gordon, C. M. Appl.
Catal., A 2001, 222, 101. (d) Wasserscheid, P.; Keim, W.
Angew. Chem. Int. Ed. 2000, 39, 3772.
(2) (a) Kumar, V.; Talisman, I. J.; Bukhari, O.; Razzaghy, J.;
Malhotra, S. V. RSC Adv. 2011, 1, 1721. (b) Bender, J.;
Jepkens, D.; Hüsken, H. Org. Process Res. Dev. 2010, 14,
716. (c) Yadav, G. D.; Motirale, B. G. Ind. Eng. Chem. Res.
2008, 47, 9081. (d) Kim, D. W.; Song, C. E.; Chi, D. Y. J.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1428–1432

1432
C. J. Meyer et al.
LETTER
added over 10 min, then stirred at r.t. for 30 min. A solution
of 2l (1.0 equiv, 1.2 mmol) in MeOH (5 mL) was added,
whereupon NaCl precipitation was observed. Reaction
stirred for 12–18 h, monitored by 1H NMR (DMSO-d6).
Upon completion, MeOH was removed in vacuo, and EtOAc
was added (15 mL). Suspended salt was filtered off using
Celite and then rinsed with EtOAc (3 × 15 mL). Filtrate was
collected and concentrated in vacuo to afford IL 4l as an
orange-yellow oil, 77%. Residual halide content was
measured at 5–10% by ion chromatography for each sample.
4l: 1H NMR (400 MHz, DMSO-d6): δ = 7.26 (s, 2H), 4.38–
4.37 (d, J = 4 Hz, 2 H), 3.70–3.68 (m, 2 H), 3.48–3.46 (m, 2
H), 3.25 (s, 3 H), 1.87–1.83 (d, J = 16 Hz, 9 H). 13C NMR
(100 MHz, DMSO-d6): δ = 129.2, 73.2, 72.1, 71.2, 63.9,
63.2, 58.2, 5.3, 4.8. HRMS (ESI): m/z calcd for the
(13) (a) Bao, W.; Wang, Z.; Li, Y. J. Org. Chem. 2003, 68, 591.
(b) Huddleston, J. G.; Visser, A. E.; Reichert, W. M.;
Willauer, H. D.; Broker, G. A.; Rogers, R. D. Green Chem.
2001, 3, 156.
(14) (a) Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Huang, J.; Sun, D.
Green Chem. 2004, 6, 75. (b) Audic, N.; Clavier, H.;
Mauduit, M.; Guillemin, J.-C. J. Am. Chem. Soc. 2003, 125,
9248. (c) Xu, L.; Chen, W.; Xiao, J. Organometallics 2000,
19, 1123.
(15) Tsunashima, K.; Sugiya, M. Electrochem. Commun. 2007,
9, 2353.
(16) Struble, J. R.; Kaeobamrung, J.; Bode, J. W. Org. Lett. 2008,
10, 957.
(17) Nahm, M. R.; Linghu, X.; Potnick, J. R.; Yates, C. M.;
White, P. S.; Johnson, J. S. Angew. Chem. Int. Ed. 2005, 44,
2377.
C7H18O2P+: 165.1039; found: 165.1059; m/z calcd for
–
C2H2N3 : 68.0254; found: 68.0232.
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