Arylation of sensitive 1-(Pyrrolidin-1-yl)-diazen-1-ium-diolate in ionic liquids

Article abstract of DOI:10.1080/00397910903074079

The purpose of this research was to investigate the stability and reactivity of 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (PYRRO/NO) in dimethylformamide (DMF, as the reference solvent) and compare them to those obtained using different ionic liquids. The results of our experiments showed that PYRRO/NO is more stable (based on reactivity) in ionic liquid [EMIM][Ms] (with reaction yields up to 52%) than in DMF, that substitution products can be separated directly and quantitatively from the ionic liquid using a single flash-column separation, and that the ionic liquids can also be recovered and reused in a second iteration of the same reaction to achieve similar yields.

Full text of DOI:10.1080/00397910903074079

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Arylation of Sensitive 1-(Pyrrolidin-1-yl)-
diazen-1-ium-diolate in Ionic Liquids
Carlos A. Velázquez a , Geoffrey M. Lynn a , Vineet Kumar b , Larry K.
Keefer a & Sanjay V. Malhotra b
a Chemistry Section, Laboratory of Comparative Carcinogenesis,
National Cancer Institute at Frederick , Frederick, Maryland, USA
b Laboratory of Synthetic Chemistry, SAIC–Frederick Inc., National
Cancer Institute at Frederick , Frederick, Maryland, USA
Published online: 07 Apr 2010.
To cite this article: Carlos A. Velázquez , Geoffrey M. Lynn , Vineet Kumar , Larry K. Keefer & Sanjay
V. Malhotra (2010) Arylation of Sensitive 1-(Pyrrolidin-1-yl)-diazen-1-ium-diolate in Ionic Liquids,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:9, 1322-1332, DOI: 10.1080/00397910903074079
To link to this article: http://dx.doi.org/10.1080/00397910903074079
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Synthetic Communications1, 40: 1322–1332, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903074079
ARYLATION OF SENSITIVE 1-(PYRROLIDIN-1-
YL)-DIAZEN-1-IUM-DIOLATE IN IONIC LIQUIDS
1
1
2
´
Carlos A. Velazquez, Geoffrey M. Lynn, Vineet Kumar,
Larry K. Keefer,1 and Sanjay V. Malhotra2
1Chemistry Section, Laboratory of Comparative Carcinogenesis, National
Cancer Institute at Frederick, Frederick, Maryland, USA
2Laboratory of Synthetic Chemistry, SAIC–Frederick Inc., National Cancer
Institute at Frederick, Frederick, Maryland, USA
The purpose of this research was to investigate the stability and reactivity of
1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (PYRRO/NO) in dimethylformamide (DMF,
as the reference solvent) and compare them to those obtained using different ionic liquids.
The results of our experiments showed that PYRRO/NO is more stable (based on
reactivity) in ionic liquid [EMIM][Ms] (with reaction yields up to 52%) than in DMF,
that substitution products can be separated directly and quantitatively from the ionic liquid
using a single flash-column separation, and that the ionic liquids can also be recovered and
reused in a second iteration of the same reaction to achieve similar yields.
Keywords: Diazeniumdiolate; ionic liquid; nitric oxide donor; nucleophilic displacement
INTRODUCTION
N-Diazen-1-ium-1,2-diolates are some of the most useful nitric oxide donors
employed in a wide variety of research fields to study the biological roles of nitric
oxide (NO). The physicochemical properties of zwitterionic diazeniumdiolates allows
them to spontaneously generate NO when dissolved in physiologically relevant
media.[1] The unprompted release of NO from N-diazeniumdiolates can be modu-
lated by O2 alkylation or O2 arylation, depending upon the nature of the alkyl or aryl
substituent attached; O2 derivatives can be metabolized selectively by a wide variety
of different enzymes.[2–7] N-Diazeniumdiolates are prepared by direct reaction of NO
(gas) with a primary or secondary amine in the presence of an added base, usually
sodium methoxide. However, the synthesis of O2-alkyl or O2-aryl N-diazeniumdio-
lates is not always straightforward and often gives poor yields and the corresponding
N-nitrosamine as the major by-product. A typical O2-alkylation or O2-arylation
reaction for N-diazeniumdiolates involves the reaction of its sodium salt with an
electrophile bearing a good leaving group, using polar solvents such as dimethylfor-
mamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoramide (HMPA),
Received November 19, 2008.
Address correspondence to Sanjay V. Malhotra, SAIC–Frederick Inc., National Cancer Institute
at Frederick, DTP, 1050 Boyles Street, Frederick, MD 21702, USA. E-mail: malhotrasa@mail.nih.gov
1322

ARYLATION OF 1-(PYRROLIDIN-1-YL)-DIAZEN-1-IUM-DIOLATE
1323
Figure 1. Representative synthesis, O2 alkylation or O2 arylation (protection), and enzymatic metabolism
of N-diazen-1-ium-1,2-diolates.
tetrahydrofuran (THF), or acetonitrile. The poor solubility of sodium N-diazenium-
diolates in organic solvents, and the relative rate between competing reactions (SN2
or SNAr vs. nitric oxide release; see Figure 1), are probably the most important
causes associated with poor-yielding O2-alkylation or O2-arylation reactions.
Given the importance of O2-substituted N-diazeniumdiolates as intermediates in
the synthesis of drugs and prodrugs, and considering the limitations associated with
their chemical synthesis using conventional solvents, we decided to carry out a system-
atic study to compare the stability and reactivity of N-diazeniumdiolates in DMF (as
the reference solvent) with those obtained using different ionic liquids (ILs). ILs
possess many advantages such as negligible vapor pressure, high thermal stability,
and recyclability, which make them prominent candidates to replace conventional
volatile organic compound (VOC) solvents. The possibilities of structural variation
offer the flexibility to design the most idealized solvent suitable for the needs of any
particular process.[8,9] Apart from tunable physical and chemical properties of ILs,
their immiscibility with various organic solvents enables the easy biphasic separation
of the desired products and recycling of expensive catalysts.[10] Furthermore, their abil-
ity to dissolve complex molecules such as nucleosides and amino acids helps the che-
mists to perform efficient modification on these biologically active compounds.[11–13]
With these advantages, the ILs have created increased interest in synthetic chemistry
in recent years, specifically because of their use as suitable solvents for nucleophilic
displacement reactions.[14–18] To the best of our knowledge, this is the first report
describing the use of ILs to dissolve and react N-diazeniumdiolates.
We hypothesized that highly polar ILs would favor the nucleophilic substi-
tution over the decomposition reaction, mainly by increasing the solubility of the
N-diazeniumdiolate ion. Once in solution, N-diazeniumdiolate should react faster
with electrophilic aryl halides to give better yields of the O2-arylation product. To
test this hypothesis, we used the aromatic nucleophilic substitution reaction between
sodium 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (PYRRO=NO) and 2,4-dinitro-
fluorobenzene (1) (Scheme 1). This reaction is one of the many nucleophilic
substitution reactions frequently used by our group to obtain O2-aryl N-diazenium-

´
C. A. VELAZQUEZ ET AL.
1324
Scheme 1. Representative aromatic nucleophilic substitution between PYRRO=NO and 2,4-dinitrofluor-
obenzene (1), yielding O2-(2,4-dinitrophenyl) 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (2).
diolates with important biological activities, such as the anti-cancer prodrugs
JS-K[6,19] and PABA=NO.[20]
RESULTS AND DISCUSSION
A wide range of ILs having different cations and anions were screened for this
reaction (Table 1). The first series of reactions carried out in ILs afforded very poor
yields of product 2 (less than 10%) regardless of stir time (1–24 h). For example,
reaction of PYRRO=NO with compound 1 in commercial [EMIM][MS] (Table 1,
entry 9) gave only 8% yield of product 2. In this regard, it has been described in
the literature during the acid-catalyzed decomposition of N-diazeniumdiolates,[21,22]
so before the next reactions were set up, we made sure all the ILs (including the
eutectic mixture of urea–choline) were not only dry (1H NMR) but also free of acid
residues as monitored by pH paper.
After purification and neutralization of ILs (see the Experimental section), the
reaction between PYRRO=NO and compound 1 in neutralized [EMIM][MS]
afforded product 2 in 46.9% yield (Table 2, entry 9). The amount of 2 was quantified
by high-performance liquid chromatography (HPLC), based on a calibration curve
using a pure sample of the product; results are shown in Table 2. In general, the ILs
having triflate, methanesulfonate, or trifluoroacetate anions afforded the product in
moderate yields (33–47%) (Table 2, entries 2–5 and 9–11) as compared to the ILs
with bis(triflic)imide anion (9–18%) (Table 2, entries 6–8). The best results were
obtained in ILs [EtPy][Tf] and [EMIM][MS] with 44% and 47% yields, respectively
(Table 2, entries 4 and 9). On the other hand, some of the ILs (entries 6–8) were
too viscous (a bit more than usual, probably due to the drying and neutralization
procedures) to allow stirring at 25ꢀC, and this may be why we obtained poor yields
with such solvents. Using DMF as the reference solvent, we were able to get product
2 in 53% yield (Table 2, entry 13). The greatest yield (54%) was obtained with a 2:1
mixture of urea=choline (Ur-Ch, entry 1). Even though this solvent is a eutectic mix-
ture[23–25] and not a typical IL per se, we were interested to study its fundamental
nature (2 equivalents of urea) and the presence of a positively charged nitrogen
(choline moiety) along with its primary alcohol group. These features offered a polar
medium suitable for dissolving PYRRO=NO almost quantitatively after a few min-
utes of stirring. Interestingly, we also carried out a neat reaction by stirring the
reagents without solvent (entry 12), obtaining product 2 in 39% yield.

ARYLATION OF 1-(PYRROLIDIN-1-YL)-DIAZEN-1-IUM-DIOLATE
1325
Table 1. Common abbreviations and chemical structures of ILs used in this work
Ionic liquid
Entry
1
Abbreviation
Cation
Aniona
Ur-Chb
2
3
[EMIM][Tf]
[BMIM][Tf]
4
5
[EtPy][Tf]
[MeOEMIM][Tf]
[EMIM][Tf2N]
[BMIM][Tf2N]
[MeOEMIM][Tf2N]
[EMIM][MS]
6
7
8
9
10
[MeOEMIM][MS]
11
[EMIM][TFA]
aExcept urea.
bPhysical mixture of 2 equivalents of urea to 1 equivalent of choline chloride.
We also wanted to study the effect of stir time on product yield. This was an
important issue because the N-diazeniumdiolate is often stirred for long periods of
time (more than 24 h), presumably to increase reaction yield. For this purpose, we
compared the amount of product obtained after 1 h and 24 h of stirring at 25ꢀC in
three different solvents (DMF, [EMIM][MS], and [BMIM][Tf2N]). According to
our results (see Table 2), there was no significant difference between 1 and 24 h of
stirring, which strongly suggests that most of the PYRRO=NO reacts within 1 h
and that there is no need to prolong the stir time. To support this idea, we also quan-
tified the amount of product (2) obtained by adding the electrophile (1) at different
times; in other words, we stirred PYRRO=NO for 15, 60, 360, and 1,260 min before
adding compound 1 (Results are presented in Fig. 2).
As can be observed in Fig. 2, the reactivity of PYRRO=NO decreased rapidly
in DMF as compared to [EMIM][MS] over time, probably because of its rapid
decomposition. There is
a clear difference (different slopes) between the

´
C. A. VELAZQUEZ ET AL.
1326
Table 2. Yield of O2-(2,4-dinitrophenyl) 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (2) obtained from
PYRRO=NO and 2,4-dinitrofluorobenzene (1), using different solvents
Entry
Solvent
Yielda (%, 1 h)
Yieldb (%, 24 h)
1
2
Ur-Ch
[EMIM][Tf]
54 ꢁ 4.3
32.9 ꢁ 3.5
38.1 ꢁ 0.7
44.3 ꢁ 3.0
39.7 ꢁ 1.0
9.1 ꢁ 1.3
ndc
ndc
3
[BMIM][Tf]
[EtPy][Tf]
ndc
4
ndc
5
[MoEMIM][Tf]
[EMIM][Tf2N]
[BMIM][Tf2N]
[MoEMIM][Tf2N]
[EMIM][MS]
[MoEMIM][MS]
[EMIM][TFA]
ndc
6
ndc
7
17.2 ꢁ 3.6
18.4 ꢁ 1.3
46.9 ꢁ 3.3
40.5 ꢁ 1.9
36.6 ꢁ 4.0
38.9 ꢁ 4.0
53.0 ꢁ 2.6
14.3 ꢁ 3.6
8
ndc
9
48.0 ꢁ 6.0
ndc
10
11
12
13
ndc
ndc
d
—
DMF
54.4 ꢁ 2.3
aAverage yield determined by HPLC (ꢁstandard deviation, n ¼ 4) relative to a known concentration of
pure compound 2, after 1 h of stirring at 25 ꢀC.
bAverage yield determined by HPLC (ꢁstandard deviation, n ¼ 4) relative to a known concentration of
pure compound 2, after 24 h of stirring at 25 ꢀC.
cNot determined.
dNo solvent was added (neat reaction).
time-dependent decomposition of PYRRO=NO in DMF and that obtained by using
[EMIM][MS]; the zero-order decline in the yield of 2 resulting from decomposition
of PYRRO=NO in the IL shows a better stability pattern than in DMF. Further-
more, it is reasonable to assume an increased stability of the transition state involved
in the nucleophilic displacement when the reaction takes place in a polar IL com-
pared to in DMF. In this regard, previous NO-release studies with N-diazeniumdio-
lates in phosphate buffer solutions (different pH values) showed the release of up to
2 equivalents of NO and the corresponding free secondary amine[1]; nevertheless, in
our experiment we did not detect (by HPLC) the presence of N-(2,4-dinitrophenyl)
pyrrolidine, which would have been the product between free pyrrolidine (from
PYRRO=NO decomposition) and compound 1.
Finally, it was important for us to assess the applicability of ILs in terms of
isolated yields of product 2; therefore, we carried out three reactions using Ur-Ch,
[EtPy][Tf], and [EMIM][MS], in which we scaled up the reaction to 200 mg of
PYRRO=NO; results are shown in Table 3. Product 2 was isolated using two differ-
ent methods. In method 1, which is similar to the conventional methods used to work
up these reactions, the reaction was quenched with water, and the product was
extracted with ethyl acetate, dried over sodium sulfate, and purified using flash chro-
matography (hexane=ethyl acetate) (41 to 52% yields). In method 2, the reaction
mixture was directly transferred into a column prepacked with silica and eluted with
hexane=ethyl acetate (gradient from 10–50%) to obtain the pure product. Once the
product was obtained, the column was eluted with ethyl acetate=methanol (10–
50%) to recover the ILs. This is another attractive feature of this methodology: it
eliminates the additional steps of quenching, extraction, and drying in workup

ARYLATION OF 1-(PYRROLIDIN-1-YL)-DIAZEN-1-IUM-DIOLATE
1327
Figure 2. Correlation between stir time and reaction yield, by adding 2,4-dinitrofluorobenzene (1) to
PYRRO=NO at different time points. Reaction conditions: 10–14 mg of PYRRO=NO were dissolved in
0.5 mL of DMF or EMIM-MS with stirring for different times before 1.25 equivalents of 1 were added.
Reactions were quenched after 1 h of stirring at 25 ꢀC by adding 3.5 mL of 0.1% v=v formic acid in a
2:1 mixture of acetonitrile=water. Then 50 mL were diluted to 1 mL with 0.1% v=v formic acid in 2:1
mixture of acetonitrile=water. The amount of product 2 was quantified by HPLC using a calibration curve
with a sample of pure compound 2.
procedure and gives the final product in similar yields as those obtained in method 1
(Table 3). Furthermore, the ILs used in method 2 were also successfully recovered
and used again (recycled) to repeat the procedure described in method 1 (Table 3,
method 3), which constitutes another advantage of ILs over DMF or other polar
organic solvents. Samples of product 2 obtained with these procedures showed
physicochemical features identical to those reported previously.[26]
Table 3. Yield of O2-(2,4-dinitrophenyl) 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (2) obtained from
PYRRO=NO and 2,4-dinitrofluorobenzene (1), using three ILs
Entry
Ionic liquida
Yieldb (%, method 1)
Yieldc (%, method 2)
Yieldd (%, method 3)
1
2
3
Ur-Ch
[EtPy][Tf]
[EMIM][MS]
41.3
44.6
52.4
40.8
43.1
47.6
nde
40.8
46.2
aReaction conditions: 200 mg of PYRRO=NO, 5 mL of ionic liquid, 1.25 eq. of 2,4-dinitrofluoroben-
zene, 1 h, 25ꢀC.
bIsolated yield of product 2 after quenching, extraction and flash chromatography.
cIsolated yield of product 2 after direct purification by flash chromatography.
dIsolated yield of product 2 after quenching, extraction, and flash chromatography using the IL
recovered from method 2.
eNot determined.

´
C. A. VELAZQUEZ ET AL.
1328
CONCLUSION
To put the results obtained in this work in the context of previous reports,
even though product 2 (as well as similar O2-aryl N-diazeniumdiolates) had been
obtained in moderate yields (18–67%) using a wide variety of polar aprotic organic
solvents including (but not limited to) DMSO, HMPA, and THF, as well as protic
solvents such as mixtures of water and t-butyl alcohol in basic conditions,[27–29] the
use of DMF was preferred because, in the case of PYRRO=NO, it offered better
yields of O2-arylation products compared to DMSO or THF. On the other hand,
the use of protic solvents is limited by a narrow pH window (it has to be basic enough
to stabilize the O2-sodium N-diazeniumdiolate but not so basic as to induce decompo-
sition of the electrophilic products). Like many other IL-assisted nucleophilic sub-
stitutions reported in the literature, the synthetic method described in this work
offers proof-of-concept supporting the use of ILs to dissolve, stabilize, and react
N-diazeniumdiolates.
EXPERIMENTAL
General
1H NMR (400-MHz) analysis was acquired using a Varian Unity Inova
spectrometer. Ultraviolet (UV) spectra were recorded using an Agilent 8453 spectro-
photometer (Agilent Technologies). Flash-column chromatography was performed
using SiliaSep HP (silica gel 25, 40, and 80g). Nitric oxide gas was purchased from
Matheson Gas Products (Montgomeryville, PA). 2,4-Dinitrofluorobenze, [EMIM][Cl],
[BMIM][Cl], and [EMIM][MS] were purchased from Sigma-Aldrich Chemical Co.
(Milwaukee, WI); [EtPy][Br] was purchased from Acros Organics. They were used
without further purification. Sodium 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
(PYRRO=NO),[2] [MoEMIM][Cl],[13] [EMIM][Tf],[29] [BMIM][Tf],[29] [EtPy][Tf],
[MoEMIM][Tf],[30] [EMIM][Tf2N],[13] [BMIM][Tf2N],[31] [MoEMIM][Tf2N],[13] [MoE-
MIM][MS],[13] and [EMIM][TFA][32] were prepared according to literature procedures
(a brief description of their synthesis is given here). Diethylamine-derivatized silica
(40–63mm, loading ¼ 1.32mmol=g) was purchased from Silicycle Chemical Division,
QC, Canada.
General Procedure for the Reaction of PYRRO/NO with
2,4-Dinitrofluorobenzene (1)
Pulverized PYRRO=NO (10–14 mg) was reacted with commercial 2,4-dinitro-
fluorobenzene (1.25 eq) in 0.5 mL of solvent (DMF or the corresponding IL), stir-
ring at 25ꢀC for 1 h. Knowing that O2-sodium N-diazeniumdiolates decomposes
rapidly in the presence of acid, reactions were quenched by adding 3.5 mL of
0.1% v=v formic acid in 2:1 acetonitrile=methanol, and then an aliquot of 50 mL
was diluted with 950 mL of 0.1% formic acid in acetonitrile=methanol (2:1). Differ-
ent volumes of these (final) solutions were used to calculate the amount of product
2 by HPLC.

ARYLATION OF 1-(PYRROLIDIN-1-YL)-DIAZEN-1-IUM-DIOLATE
1329
Representative Procedure for the Reaction of PYRRO/NO with
2,4-Dinitrofluorobenzene in [EMIM][Ms] and Product Isolation
PYRRO=NO (1.31 mmol, 200 mg) was mixed with ionic liquid [EMIM][Ms]
(3 mL) in a 15-ml vial followed by the addition of 2,4-dinitrofluorobenzene
(1.96 mmol, 365 mg). After 1 h, the reaction mixture was directly transferred into a
column prepacked with silica and eluted with hexane=ethyl acetate (gradient
10–50%) to obtain the pure product in 52.4% yield (203 mg) with melting point
1
94–95ꢀC (lit. mp 94–95ꢀC[26]). The spectral data (i.e., H NMR, 13C NMR) and
elemental analysis of the product were identical to those reported previously.[26]
Once the product was obtained, the column was eluted with ethyl acetate=methanol
(10–50%) to recover the IL.
Synthesis of Ur-Ch
Urea (20 g, 0.33 mol) and choline chloride (23.2 g, 0.16 mol) were vigorously
mixed in a big mortar. After a few minutes, the solid mixture turned slushy, then
semiliquid, and finally (after about 30 min) liquid. This mixture was transferred into
an Erlenmeyer flask to continue stirring for 1 h; it was used after drying in a vacuum
oven at 80ꢀC under reduced pressure (ꢂ25 to ꢂ30 in. Hg) for 24 h.
General Synthesis of [EMIM][Tf], [BMIM][Tf], [EtPy][Tf], and
[MoEMIM][Tf]
A solution of [EMIM][Cl], [BMIM][Cl], [MoeMIM][Cl], or [EtPy][Br] (0.1 M,
150 mL) was added to a solution of silver trifluoromethanesulfonate (0.1 M,
150 mL, prepared by mixing equimolar amounts of silver oxide and trifluorometha-
nesulfonic acid in water) under stirring. After stirring for 3 h at 25ꢀC, the solids were
filtered off, and the filtrate was checked for residual halide by adding a few drops of
0.01 M solution of silver trifluoromethanesulfonate until no further silver halide
precipitation was observed. The aqueous solution was then filtered off, and the fil-
trate was concentrated under vacuum to afford the corresponding ILs [EMIM][Tf],
[BMIM][Tf], [EtPy][Tf], and [MoEMIM][Tf].
[EtPy][Tf]
1H NMR (400 MHz, CD3CO) d 9.22 (d, J ¼ 5.6 Hz, 2H), 8.73 (tt, J ¼ 1.3 and
7.8 Hz, 1H), 8.27 (t, J ¼ 7.0 Hz, 2H), 4.89 (q, J ¼ 7.3 Hz, 2H), 1.74 (t, J ¼ 7.3 Hz,
3H); 13C NMR (101 MHz, CD3CO)
d 145.92, 144.95, 128.72, 121.62 (q,
J ¼ 323.09 Hz), 57.54, 16.11.
General Synthesis of [EMIM][Tf2N], [BMIM][Tf2N], and
[MoEMIM][Tf2N]
A solution of [EMIM][Cl], [BMIM][Cl], or [MoEMIM][Cl] (0.1 M, 125 mL) in
distilled water was added to lithium bis(triflic)imide (0.12 M, 125 mL) under stirring.
After stirring for 3 h at 25ꢀC the bottom layer was separated, washed with distilled

´
C. A. VELAZQUEZ ET AL.
1330
water (3 ꢃ 50 mL) and concentrated under vacuum to give the corresponding ILs
[EMIM][Tf2N], [BMIM][Tf2N], or [MoEMIM][Tf2N].
Synthesis of [MoEMIM][MS]
This was prepared from [MoEMIM][Cl] (0.1 M) and silver methanesulfonate
(0.1 M, prepared by mixing equimolar amount of silver oxide and methanesulfonic
acid in water) using the procedure described for [MoEMIM][Tf].
Synthesis of [EMIM][TFA]
This was prepared from [EMIM][Cl] (0.1 M) and silver trifluoroacetate (0.1 M,
prepared by mixing equimolar amount of silver oxide and trifluoroacetic acid in
water) using the procedure described for [EMIM][Tf].
General Procedure to Purify and Neutralize
Commercial or ‘‘In House’’ ILs
The corresponding IL was dissolved in methanol (10% v=v), mixed with
charcoal (2% w=w), and refluxed for 5 min; the black solids were filtered off. The
solvent was partly removed (by about half) under vacuum. Diethylamine-derivatized
silica gel (0.5 g of silica per 25 mL of IL) was added. This mixture was stirred for
15 min, and then the silica gel was filtered off. The remaining solvent was evaporated
in a rotavapor first, and the residue was dried in a vacuum oven at 80ꢀC under
reduced pressure (ꢂ25 to ꢂ30 in. Hg) for 12–24 h. This procedure afforded pure,
dry, and acid-free ILs.
ACKNOWLEDGMENTS
This work was supported by federal funds from the National Cancer Institute,
National Institutes of Health (NIH) under contract HHSN261200800001E with
SAIC–Frederick Inc. as well as by the Intramural Research Program of the NIH,
National Cancer Institute, Center for Cancer Research.
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