Synthesis of sequentially deuterated 1-n-Butyl-3-methylimidazolium ionic liquids

Article abstract of DOI:10.1002/jlcr.1884

Deuterium isotopologues of the ionic liquid (IL) 1-n-butyl-3- methylimidazolium chloride ([C₄mim]Cl) sequentially labeled on the C-1″, C-1′, C-2′, C-3′, and C-4′ positions of the N-alkyl groups were prepared following a strategy that minimizes

Full text of DOI:10.1002/jlcr.1884

Research Article
Received 20 January 2011,
Accepted 22 February 2011
Published online 25 April 2011 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1884
Synthesis of sequentially deuterated
1-n-Butyl-3-methylimidazolium ionic liquids
Ã
Alexander Khrizman, Hiu Yan Cheng, and Guillermo Moyna
Deuterium isotopologues of the ionic liquid (IL) 1–n-butyl-3-methylimidazolium chloride ([C4mim]Cl) sequentially labeled
on the C-100, C-10, C-20, C-30, and C-40 positions of the N-alkyl groups were prepared following a strategy that minimizes the
number of distinct reactions through the use of analogous synthetic routes. In several cases, good yields after the initial
deuterium incorporation reaction were achieved by combining well-established chemical transformations into efficient
single-step processes.
Keywords: deuteration; deuterium isotope effects; imidazolium cations; ionic liquids
Introduction
Experimental
Arbitrarily defined as organic salts with melting points below Deuterated starting materials were purchased from Sigma-
1001C, ionic liquids (ILs) have gained considerable notoriety in Aldrich, Inc. (St. Louis, MO, USA) and Cambridge Isotopes, Inc.
the past decade. Owing to their negligible vapor pressure, (Andover, MA, USA), and used as received. THF and diethyl ether
thermal stability, and tunable solvent properties, these materials were distilled from sodium benzophenone ketyl prior to use.
have found applications in a wide range of laboratory and 1-Methylimidazole used in N-alkylation reactions was freshly
industrial processes.1 As part of efforts aimed at better under- distilled through a Vigreux column at ꢁ20 mm Hg. Flash
standing the liquid structure of imidazolium-based ILs, we have column chromatography was carried out using 230–450 mesh
shown that intraionic hydrogen-bonding (H-bonding) inter- silica gel. Melting points were determined on a Thomas Hoover
actions in 1-n-butyl-3-methylimidazolium chloride ([C4mim]Cl capillary melting point apparatus and are uncorrected. IR
(1), Figure 1) are evidenced by sizable deuterium isotope effects spectra were recorded on a Thermo Electron Nicolet Avatar
on the chloride ion 35/37Cl NMR signal (i.e. D35/37Cl(H,D)).2 370 DTGS FT-IR spectrophotometer. NMR experiments were
Measurements obtained on the [C4mim]Cl isotopologues performed on a Bruker AVANCE 400 spectrometer operating at
[2-d1]-[C4mim]Cl and [2,4,5-d3]-[C4mim]Cl led to D35/37Cl(H,D) 1H and 13C frequencies of 400.13 and 100.61 MHz, respectively,
values of up to 2 ppm, and corroborated the presence of using CDCl3 as solvent. Chemical shifts (d) are in ppm relative to
H-bonds between the anion and the imidazolium cation protons the residual solvent signal (7.28 ppm), and coupling constants (J)
on the C-2, C-4, and C-5 positions.
Recent theoretical studies indicate that H-bonding between Varian Saturn 2100 T and Thermo Scientific Exactive Orbitrap
are reported in Hz. MS and HR-MS spectra were recorded on
the anion and protons along the N-alkyl groups could also have mass spectrometers using EI and ASAP ionization,5 respectively.
an impact on the structure and dynamics of this class of ILs.3,4
[10,10,10-d3]-1-Methylimidazole (2): To a round-bottom flask
Based on our previous results, these anion–cation interactions containing a solution of imidazole (10.6 g, 0.16 mol) in diethyl
could be detected experimentally by measurement of deuter- ether (200 mL) was added 18-crown-6 (4.1 g, 16 mmol) and
ium isotope effects on the 35/37Cl NMR signal of the chloride ion. potassium tert-butoxide (19.3 g, 0.17 mol) under an argon
For this purpose, we decided to synthesize a series of [C4mim]Cl atmosphere. The resulting slurry was stirred for 20 min, and a
deuterium isotopologues sequentially labeled along the N-alkyl solution of [d3]-iodomethane (23.8 g, 0.16 mmol) in diethyl ether
group carbons (Figure 1a–e). These could also be easily (100 mL) was added dropwise over 30 min at 01C. After an
converted by metathesis to the corresponding tetrafluoroborate additional 4 h, the reaction mixture was filtered and the solid
and hexafluorophosphate imidazolium salts (i.e. [C4mim]BF4 and residue was washed with diethyl ether (5 ꢂ 100 mL). The
[C4mim]PF6), which would be suitable for the study of interionic combined organic phases were concentrated in vacuo, and the
H-bonds through analysis of deuterium isotope effects on the
31
10/11B, 19F, and P signals of the BF4ꢀ and BFꢀ6 anions. In this
manuscript we describe a strategy which uses similar routes to
Department of Chemistry and Biochemistry, University of the Sciences in
minimize the number of distinct reactions needed to prepare Philadelphia, 600 South Forty-Third Street, Philadelphia, PA 19104, USA
these compounds. As detailed below, good yields after the
*Correspondence to: Guillermo Moyna, Department of Chemistry and Biochem-
initial deuterium incorporation reaction were achieved in several
istry, University of the Sciences in Philadelphia, 600 South Forty-Third Street,
Philadelphia, PA 19104, USA.
E-mail: g.moyna@usp.edu
cases through the combination of well-established chemical
transformations into efficient single-step processes.
J. Label Compd. Radiopharm 2011, 54 401–407
Copyright r 2011 John Wiley & Sons, Ltd.

A. Khrizman et al.
done slowly to avoid layer separation and to maintain the
temperature below 101C. The resulting mixture was diluted with
diethyl ether (300 mL), and extracted with 3 M HCl (3 ꢂ 60 mL),
1 M NaOH (30 mL), 3 M HCl (30 mL), and brine (20 mL). The
organic layer was dried over MgSO4 and concentrated in vacuo
to yield the title compound as white solid (46.3 g, 94%). M.p.:
40–431C. IR (KBr disc, cmꢀ1): 3068, 3002, 2984, 2960, 2936, 1751,
1597, 1436, 1366, 1348, 1272, 1191, 1177, 1079, 1019, 897, 732,
659, 575, 556. 1H NMR: d 7.81 (2H, d, J = 8.3, Ar), 7.36 (2H, d,
J = 8.3, Ar), 4.98 (1H, bq, J = 6.4, H3), 3.61 (3H, s, OCH3), 2.47 (3H,
s, Ar-CH3), 1.37 (3H, d, J = 6.4, H4). 13C NMR: d 169.7 (C1), 144.7
(Ar), 134.0 (Ar), 129.8 (Ar), 127.8 (Ar), 75.7 (C3), 51.8 (OCH3), 40.7
a
b
b d d
a
a
e
e
1"
N
N
2
1'
3'
H3C
c
c
e
N
N
CH3
4'
Cl
2'
1a - a = D; b = c = d = e = H
1b - b = D; a = c = d = e = H
1c - c = D; a = b = d = e = H
1d - d = D; a = b = c = e = H
1e - e = D; a = b = c = d = H
Cl
4
5
1
Figure 1. Structure and numbering of [C4mim]Cl (1) and its deuterium
isotopologues (1a–e).
crude product was distilled through a Vigreux column at (quin, 1JCD = 19.8, C2), 21.6 (Ar-CH3), 20.9 (C4). HR-MS (ASAP): m/z
ꢁ20 mm Hg to yield 2 as a colorless oil (11.8 g, 84%). IR (NaCl calcd for C12H15D2O5S ([M1H]1): 275.0917, found: 275.0908.
plate, cmꢀ1): 3392, 3106, 2136, 2078, 1508, 1286, 1233, 1118,
[2,2-d2]-1-Butanol (3b): THF (300 mL) and LiAlH4 (7.4 g,
1076, 910, 818, 743, 664. 1H NMR: d 10.53 (1H, bdd, J = 1.2, 0.20 mmol) were carefully combined in an argon-flushed two-
J = 1.0, H2), 7.64 (1H, dd, J = 1.2, J = 1.0, H4), 7.47 (1H, dd, J = 1.2, neck round-bottom flask. A solution of compound 6 (46.2 g,
J = 1.2, H5). 13C NMR: d 137.7 (C2), 129.3 (C5), 120.0 (C4), 32.5 0.20 mmol) in THF (100 mL) was then added dropwise over
1
(hep, JCD = 21.4, C10). HR-MS (ASAP): m/z calcd for C4H4D3N2 30 min at 01C. The resulting slurry was warmed to room
([M1H]1): 86.0793, found: 86.0809.
temperature, stirred for 1 h, and heated to reflux for an
[1,1-d2]-1-Butanol (3a): THF (50 mL) and LiAlD4 (4.5 g, 0.11 mol) additional 15 min. The reaction was then quenched with 6 M
were carefully combined in an argon-flushed 2-neck round- HCl (130 mL), and extracted with diethyl ether (3 ꢂ 400 mL). The
bottom flask. Methyl butyrate (22.2 mL, 0.20 mol) was added combined organic layers were concentrated in vacuo, re-
dropwise over 10 min at 01C, and the resulting slurry was dissolved in dichloromethane, and washed with brine (60 mL).
refluxed for 1 h. The mixture was cooled to room temperature The organic layer was dried over MgSO4 and the solvent was
and diluted with diethyl ether (200 mL), and the reaction was removed under reduced pressure to yield 3b as a pale yellow oil
then quenched with 1 M HCl (100 mL). After 30 min the mixture (7.8 g, 61%). IR (NaCl plate, cmꢀ1): 3344, 2960, 2933, 2874, 2191,
was filtered, and the filtrate was extracted with diethyl ether 2131, 1465, 1379, 1049, 1027, 982. 1H NMR: d 3.66 (2H, quin,
(2 ꢂ 200 mL). The combined organic layers were dried over 3JHD = 1.0, H1), 1.58 (1H, bs, OH), 1.39 (1H, qquin, J = 7.4,
MgSO4 and concentrated in vacuo to yield the title compound 3JHD = 1.1, H3), 0.95 (3H, t, J = 7.4, H4). 13C NMR: d 62.6 (C1),
1
as a colorless oil (12.2 g, 82%). IR (NaCl plate, cmꢀ1): 3351, 2960, 33.9 (quin, JCD = 19.2, C2), 18.7 (C3), 13.8 (C4). MS (EI): m/z
2932, 2875, 2197, 2100, 1465, 1380, 1081, 1067, 968. H NMR: d (rel. int.): 57 (100, [M-HDO]1), 42 (72).
1
1.56 (2H, tquin, J = 7.5, 3JHD = 0.9, H2), 1.41 (2H, tq, J = 7.5, J = 7.3,
4-(tert-Butyldimethylsilyloxy)-2-butanone (7): 4-Hydroxy-2-buta-
H3), 1.27 (1H, bs, OH), 0.96 (3H, t, J = 7.3, H4). 13C NMR: d 61.9 none (10.0 g, 0.11 mol) and imidazole (9.3 g, 0.13 mol) were
(quin, 1JCD = 21.6, C1), 34.6 (C2), 18.8 (C3), 13.8 (C4). MS (EI): m/z dissolved in dichloromethane (500 mL) in an argon-flushed
(rel. int.): 58 (100, [M-H2O]1), 43 (45).
round-bottom flask. tert-Butyldimethylsilyl chloride (18.0 g,
(7)-[2,2-d2]-Methyl-3-hydroxybutyrate (5): Methyl acetoacetate 0.11 mol) was quickly added and the resulting mixture was
(30.0 g, 0.27 mol) and D2O (30 mL) were combined in a round- stirred at room temperature for 1.5 h. The reaction mixture was
bottom flask and stirred under argon for 10 min at 701C. The then extracted with saturated aqueous NH4Cl (3 ꢂ 100 mL), and
solution was then cooled to room temperature and solid NaCl the organic layer was dried over MgSO4 and concentrated
(9 g) was added. The mixture was extracted with D2O-saturated in vacuo. The crude oil was purified by flash chromatography
diethyl ether (300 mL), and the solvent evaporated in vacuo. using hexanes-EtOAc (95:5) as eluting solvent to yield the title
After repeating this process twice, the crude product was compound as a colorless oil (21.6 g 94%). IR (NaCl plate, cmꢀ1):
redissolved in D2O (60 mL) at 701C, cooled to ꢀ51C, and treated 2957, 2930, 2885, 2858, 1717, 1473, 1361, 1257, 1104, 867, 837,
1
with a chilled solution of NaBH4 (3.3 g, 88 mmol) in D2O (30 mL) 778. H NMR: d 3.89 (2H, t, J = 6.4, H4), 2.62 (2H, t, J = 6.4, H3),
added in one portion. Stirring was continued for 30 min at 01C, 2.18 (3H, s, H1), 0.88 (9H, s, SiC(CH3)3), 0.05 (6H, s, Si(CH3)2). 13C
1 M HCl (60 mL) and NaCl (40 g) were then added, and the NMR: d 207.8 (C2), 58.8 (C4), 46.5 (C3), 30.7 (C1), 25.8 (SiC(CH3)3),
mixture was extracted with chilled dichloromethane (300 mL). 18.1 (SiC(CH3)3), ꢀ5.6 (Si(CH3)2). HR-MS (ASAP): m/z calcd for
The organic layer was dried over MgSO4 and the solvent was C10H23O2Si ([M1H]1): 203.1462, found: 203.1456.
removed under reduced pressure to yield 5 as a colorless oil
(7)-[2-d1]-4-(tert-Butyldimethylsilyloxy)-2-butanol (8a): NaBD4
(24.9 g, 80%). IR (NaCl plate, cmꢀ1): 3435, 2972, 2957, 2932, 2240, (2.4 g, 58 mmol) was added to a solution of compound 7 (21.6 g,
1736, 1437, 1270, 1118, 1064, 1028, 921. 1H NMR: d 4.20 (1H, 0.11 mol) in methanol (200 mL), and the resulting mixture was
tquin, J = 6.4, 3JHD = 1.2, H3), 3.73 (3H, s, OCH3), 2.94 (1H, bs, OH), refluxed for 15 min. The reaction mixture was then concentrated
1.24 (3H, d, J = 6.4, H4). 13C NMR: d 173.3 (C1), 64.2 (C3), 51.7 in vacuo, redissolved in dichloromethane (300 mL), washed with
(OCH3), 42.0 (quin, 1JCD = 19.6, C2), 22.4 (C4). HR-MS (ASAP): m/z saturated aqueous NH4Cl (75 mL), and brine (75 mL). The organic
calcd for C5H9D2O3 ([M1H]1): 121.0829, found: 121.0827.
layer was dried over MgSO4 and the solvent removed under
(7)-[2,2-d2]-Methyl-3-(p-toluenesulfonyloxy)butyrate (6): Com- reduced pressure to yield 8a (21.7 g, 99%). IR (NaCl plate, cmꢀ1):
pound 5 (21.5 g, 0.18 mol) was dissolved in anhydrous pyridine 3403, 2957, 2930, 2885, 2858, 2134, 1473, 1361, 1257, 1154,
1
(72 mL, 0.90 mol) in a round-bottom flask and cooled to 01C. 1104, 837, 776. H NMR: d 3.91 (1H, ddd, J = 10.2, J = 4.8, J = 4.6,
p-Toluenesulfonyl chloride (51.1 g, 0.27 mol) was then added, H4), 3.83 (1H, ddd, J = 10.2, J = 8.5, J = 4.4, H4), 3.05 (1H, bs, OH),
3
and the solution was stirred under argon for 22 h at 01C. The 1.69 (1H, dddt, J = 14.3, J = 8.5, J = 4.6, JHD = 1.2, H3), 1.64
reaction was quenched by addition of water (10 mL), which was (1H, ddd, J = 14.3, J = 4.8, J = 4.4, H3), 1.21 (3H, t, JHD = 0.8, H1),
3
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Copyright r 2011 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2011, 54 401–407

A. Khrizman et al.
1
0.92 (9H, s, SiC(CH3)3), 0.10 (6H, bs, Si(CH3)2). 13C NMR: d 67.8 1473, 1257, 1098, 964, 837, 776. H NMR: d 3.83 (2H, td, J = 5.6,
(t, 1JCD = 21.6, C2), 62.7 (C4), 39.9 (C3), 25.8 (SiC(CH3)3), 23.2 (C1), J = 0.4, H3), 3.79 (2H, td, J = 5.6, J = 0.4, H1), 2.69 (1H, bs, OH), 1.77
18.1 (SiC(CH3)3), ꢀ5.5 & ꢀ5.6 (Si(CH3)2). HR-MS (ASAP): m/z calcd (2H, quin, J = 5.6, H2), 0.92 (9H, s, SiC(CH3)3), 0.10 (6H, s, Si(CH3)2).
for C10H24DO2Si ([M1H]1): 206.1682, found: 206.1707.
13C NMR: d 62.7 (C3), 62.2 (C1), 34.2 (C2), 25.8 (SiC(CH3)3), 18.2
(SiC(CH3)3), ꢀ5.5 (Si(CH3)2). HR-MS (ASAP): m/z calcd for
(7)-[2-d1]-4-(tert-Butyldimethylsilyloxy)-2-(p-toluenesulfonylox-
y)butane (9a): Compound 8a (21.5 g, 0.10 mol) and anhydrous C9H23O2Si ([M1H]1): 191.1462, found: 191.1487.
pyridine (25 mL, 0.30 mol) were dissolved in dichloromethane
3-(tert-Butyldimethylsilyloxy)propanal (11): Dimethylsulfoxide
(50 mL) in a round-bottom flask. p-Toluenesulfonyl chloride (32.7 mL, 0.46 mol) was added over 20 min to a stirred solution
(29.9 g, 0.16 mol) was then added, and the solution was stirred of oxalyl chloride (19.5 mL, 0.23 mol) in dichloromethane
under argon at room temperature for 20 h. The mixture was (250 mL) at ꢀ781C. A solution of compound 10 (29.2 g,
subsequently cooled to 01C, and the reaction was quenched by 0.14 mol) in dichloromethane (150 mL) was then added over
addition of water (10 mL), which was done slowly to avoid layer 40 min, and the mixture was stirred for an additional 15 min.
separation and to maintain the temperature below 101C. The Triethylamine (106 mL, 0.77 mol) was then added dropwise
resulting mixture was diluted with dichloromethane (350 mL) over 10 min, and the resulting slurry diluted with dichloro-
and extracted with 3 M HCl (3 ꢂ 40 mL), 1 M NaOH (20 mL), 3 M methane (200 mL). After stirring for 15 min, the reaction mixture
HCl (20 mL), and brine (20 mL). The organic layer was dried over was allowed to warm to room temperature and water (150 mL)
MgSO4 and concentrated in vacuo to yield the title compound was added. The aqueous layer was extracted with dichloro-
as a pale yellow oil (36.7 g, 98%). IR (NaCl plate, cmꢀ1): 2955, methane (100 mL), and the combined organic layers were
2929, 2884, 2857, 2194, 1472, 1361, 1257, 1189, 1093, 910, 839, washed with brine (100 mL), concentrated in vacuo, diluted with
1
777, 664. H NMR: d 7.80 (2H, d, J = 8.4, Ar), 7.34 (2H, d, J = 8.4, diethyl ether (100 mL), extracted with water (3 ꢂ 100 mL), and
Ar), 3.55 (1H, ddd, J = 10.4, J = 6.1, J = 6.1, H4), 3.50 (1H, ddd, dried over MgSO4. The solvent was removed under reduced
J = 10.4, J = 6.8, J = 5.9, H4), 2.45 (3H, s, Ar-CH3), 1.85 (1H, ddd, pressure to afford 11 as a yellow oil that was used in the
J = 14.2, J = 6.1, J = 5.9, H3), 1.67 (1H, ddd, J = 14.2, J = 6.8, J = 6.1, next step without further purification. IR (NaCl plate, cmꢀ1):
H3), 1.32 (3H, s, H1), 0.86 (9H, s, SiC(CH3)3), 0.00 & ꢀ0.00 (6H, s, 2657, 2930, 2885, 2857, 2728, 1729, 1475, 1389, 1256, 1098,
1
Si(CH3)2). 13C NMR: d 144.4 (Ar), 134.6 (Ar), 129.7 (Ar), 127.7 (Ar), 814, 778. H NMR: d 9.82 (1H, t, J = 2.1, H1), 4.01 (2H, t, J = 6.0,
77.8 (t, 1JCD = 22.9, C2), 58.8 (C4), 39.4 (C3), 25.8 (SiC(CH3)3), 21.6 H3), 2.62 (2H, td, J = 6.0, J = 2.1, H2), 0.90 (9H, s, SiC(CH3)3),
(Ar-CH3), 20.9 (C1), 18.1 (SiC(CH3)3), ꢀ5.5 & ꢀ5.6 (Si(CH3)2). 0.09 (6H, s, Si(CH3)2). 13C NMR: d 202.1 (C1), 57.40 (C3), 46.6 (C2),
HR-MS (ASAP): m/z calcd for C17H30DO4SSi ([M1H]1): 360.1770, 25.80 (SiC(CH3)3), 18.2 (SiC(CH3)3), ꢀ5.5 (Si(CH3)2). HR-MS
found: 360.1815.
[3,3-d2]-1-Butanol (3c): Diethyl ether (150 mL) and LiAlD4 (7.3 g, 189.1330.
(ASAP): m/z calcd for C9H21O2Si ([M1H]1): 189.1306, found:
0.17 mol) were carefully combined in an argon-flushed two-neck
(7)-[1,1,1-d3]-4-(tert-Butyldimethylsilyloxy)-2-butanol (8b): Mag-
round-bottom flask. A solution of compound 9a (56.5 g, nesium turnings (4.0 g, 0.17 mol) were added to an argon-
0.15 mol) in diethyl ether (60 mL) was added dropwise over flushed two-neck round bottom flask containing a solution of
5 min, and the resulting slurry was refluxed for 4 h. The reaction [d3]-iodomethane (24.0 g, 0.17 mol) in anhydrous diethyl ether
was then quenched slowly by addition of 6 M HCl (200 mL). The (400 mL) at 01C. The mixture was allowed to warm to room
organic solvent was distilled off under vacuum, and the temperature, refluxed for 30 min, and cooled to 01C. A solution
remaining aqueous solution was stirred for an additional of compound 11 (27.9 g, 0.15 mol) in diethyl ether (100 mL) was
30 min at room temperature. The solution was then extracted then added dropwise over 15 min, and the resulting mixture
with diethyl ether (3 ꢂ 500 mL), and the combined organic layers was refluxed for an additional 15 min. After cooling to room
were concentrated in vacuo, redissolved in diethyl ether temperature, the reaction was quenched with saturated
(150 mL), and washed with water (10 mL). The organic layer aqueous NH4Cl (50 mL) and diluted with water (250 mL). The
was dried over MgSO4 and the solvent was removed under aqueous layer was extracted with diethyl ether (150 mL), the
reduced pressure to yield 3c as a pale yellow oil (8.3 g, 69%). IR organic layers were combined and dried over MgSO4, and
(NaCl plate, cmꢀ1): 3345, 2957, 2931, 2873, 2179, 2115, 1457, the solvent evaporated in vacuo. The remaining crude oil was
1
1378, 1061, 1042, 991. H NMR: d 3.67 (2H, t, J = 6.7, H1), 3.20 purified by flash chromatography using hexanes-EtOAc (95:5) as
(1H, bs, OH), 1.56 (2H, tquin, J = 6.7, JHD = 1.1, H2), 0.93 eluting solvent to yield the title compound as a colorless oil
3
3
(3H, quin, JHD = 1.1, H4). 13C NMR: d 62.5 (C1), 34.3 (C2), 18.1 (40.0 g, 65% from 10). IR (NaCl plate, cmꢀ1): 3393, 2956, 2929,
1
(quin, JCD = 19.1, C3), 13.6 (C4). MS (EI): m/z (rel. int.): 58 2885, 2858, 2223, 1472, 1361, 1257, 1141, 1095, 836, 776. 1H
(100, [M-H2O]1), 43 (74).
NMR: d 4.02 (1H, bdd, J = 8.4, J = 2.6, H2), 3.90 (1H, ddd, J = 10.3,
3-(tert-Butyldimethylsilyloxy)-1-propanol (10): 1,3-Propanediol J = 4.7, J = 4.7, H4), 3.82 (1H, ddd, J = 10.3, J = 8.7, J = 4.0, H4), 3.28
(13.9 g, 0.18 mol) was added dropwise over 15 min to a stirred (bs, OH), 1.68 (1H, ddd, J = 14.3, J = 8.7, J = 4.7, H3), 1.64 (1H,
suspension of NaH (4.4 g, 0.18 mol) in THF (300 mL) under argon. dddd, J = 14.3, J = 8.4, J = 4.7, J = 4.0, H3), 0.91 (9H, s, SiC(CH3)3),
After 45 min, tert-butyldimethylsilyl chloride (25.0 g, 0.17 mol) 0.09 (6H, bs, Si(CH3)2). 13C NMR: d 68.1 (C2), 62.8 (C4), 39.9 (C3),
1
was added over 15 min and stirred for an additional 45 min. The 25.8 (SiC(CH3)3), 22.5 (hep, JCD = 19.2, C1), 18.1 (SiC(CH3)3),
reaction was quenched by slow addition of 10% aqueous ꢀ5.5 & ꢀ5.6 (Si(CH3)2). HR-MS (ASAP): m/z calcd for C10H22D3O2Si
Na2CO3 (40 mL), and water (80 mL). The clear aqueous phase was ([M1H]1): 208.1807, found: 208.1799.
extracted with diethyl ether (100 mL), and the combined organic
(7)-[1,1,1-d3]-4-(tert-Butyldimethylsilyloxy)-2-(p-toluenesulfony-
layers were concentrated in vacuo, redissolved in dichloro- loxy)butane (9b): Obtained from 8b in 94% yield following the
methane (150 mL), and washed with water (3 ꢂ 20 mL). The procedure described for the preparation of 9a. IR (NaCl plate,
organic layer was dried over MgSO4 and concentrated under cmꢀ1): 2956, 2929, 2884, 2857, 2231, 1472, 1363, 1257, 1189,
reduced pressure to yield the title compound as a colorless oil 1098, 918, 837, 777, 662. 1H NMR: d 7.81 (2H, d, J = 8.3, Ar),
(30.3 g, 96%). IR (NaCl plate, cmꢀ1): 3352, 2955, 2929, 2985, 2858, 7.24 (2H, d, J = 8.3, Ar), 4.77 (1H, bdd, J = 7.2, J = 5.5, H2), 3.54
J. Label Compd. Radiopharm 2011, 54 401–407
Copyright r 2011 John Wiley & Sons, Ltd.
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A. Khrizman et al.
(1H, ddd, J = 10.4, J = 6.2, J = 6.0, H4), 3.50 (1H, ddd, J = 10.4, the top layer, consisting mainly of unreacted 1-chlorobutane,
J = 6.8, J = 5.9, H4), 2.46 (3H, s, Ar-CH3), 1.86 (1H, dddd, J = 14.1, was decanted. The remaining residue was washed with EtOAc
J = 7.2, J = 6.2, J = 5.9, H3), 1.68 (1H, dddd, J = 14.1, J = 6.8, J = 6.0, (3 ꢂ 5 mL), discarding the solvent after each wash. The residual
J = 5.5, H3), 0.86 (9H, s, SiC(CH3)3), 0.00 & ꢀ0.00 (6H, s, Si(CH3)2). EtOAc was removed under reduced pressure to yield the
13C NMR: d 144.4 (Ar), 134.5 (Ar), 129.7 (Ar), 127.7 (Ar), 78.0 (C2),
different 1-n-butyl-3-methylimidazolium chloride isotopologues
58.8 (C4), 39.5 (C3), 25.8 (SiC(CH3)3), 21.6 (Ar-CH3), 20.1 (hep, as pale yellow viscous oils.
1JCD = 19.8, C1), 18.2 (SiC(CH3)3), ꢀ5.5 & ꢀ5.6 (Si(CH3)2). HR-MS
[10,10,10-d3]-1-n-Butyl-3-methylimidazolium chloride (1a): Ob-
(ASAP): m/z calcd for C17H28D3O4SSi ([M1H]1): 362.1895, found: tained from 2 and 1–chlorobutane in quantitative yield. IR (NaCl
362.1903.
plate, cmꢀ1): 3384, 3130, 3052, 2959, 2935, 2874, 2257, 2129,
[4,4,4-d3]-1-Butanol (3d): Obtained from 9b in 60% yield by 2076, 1564, 1466, 1174. 1H NMR: d 10.53 (1H, bdd, J = 1.8, J = 1.7,
reduction of 9b with LiAlH4 following the procedure described H2), 7.64 (1H, dd, J = 1.8, J = 1.7, H4), 7.47 (1H, dd, J = 1.8, J = 1.8,
for the preparation of 3c. IR (NaCl plate, cmꢀ1): 3351, 2934, 2867, H5), 4.25 (2H, t, J = 7.4, H10), 1.82 (2H, tt, J = 7.6, J = 7.4, H20), 1.29
2220, 2124, 2076, 1461, 1380, 1051, 1020, 951. H NMR: d 3.67 (2H, tq, J = 7.6, J = 7.4, H30), 0.87 (3H, t, J = 7.4, H40). 13C NMR: d
1
(2H, t, J = 6.7, H1), 1.66 (bs, 1H, OH), 1.57 (2H, tt, J = 7.6, J = 6.7, 137.8 (C2), 123.7 (C4), 122.0 (C5), 49.7 (C10), 35.8 (hep, 1JCD = 22.0,
H2), 1.38 (2H, thep, J = 7.6, JHD = 1.1, H3). 13C NMR: d 62.7 (C1), C100), 32.1 (C20), 19.4 (C30), 13.4 (C40). HR-MS (ASAP): m/z calcd for
3
34.4 (C2), 18.6 (C3), 12.9 (hep, JCD = 19.1, C4). MS (EI): m/z (rel. C8H12D3N2 ([M-Cl]1): 142.1419, found: 142.1437.
1
int.): 59 (100, [M-H2O]1), 41 (48).
[10,10-d2]-1-n-Butyl-3-methylimidazolium chloride (1b): Ob-
tained from 1-methylimidazole and 4a in quantitative yield. IR
(NaCl plate, cmꢀ1): 3385, 3132, 3052, 2959, 2934, 2873, 2237,
Chlorination of 1-butanol isotopologues
1
2146, 2117, 1571, 1467, 1182. H NMR: d 10.58 (1H, bdd, J = 1.8,
To a solution of the appropriate 1-butanol isotopologue (15 g,
0.20 mol) and anhydrous pyridine (0.02 eq), thionyl chloride
(1.1 eq) was added dropwise over 30 min at 01C. The mixture
was refluxed until gas ceased to evolve for at least 15 min. The
solution was then cooled to room temperature and the reaction
was quenched with water (5 mL). The organic layer was washed
with saturated aqueous NaHCO3 (5 mL), dried over MgSO4, and
distilled through a Vigreux column to yield the different
1-chlorobutane isotopologues as colorless oils.
[1,1-d2]-1-Chlorobutane (4a): Obtained from 3a in 77% yield. IR
(NaCl plate, cmꢀ1): 2963, 2935, 2876, 2251, 2244, 2161, 1466. 1H
NMR: d 1.76 (2H, tquin, J = 7.5, 3JHD = 1.1, H2), 1.48 (2H, tq, J = 7.5,
J = 7.4, H3), 0.95 (3H, t, J = 7.4, H4). 13C NMR: d 44.2 (quin,
1JCD = 22.8, C1), 34.4 (C2), 20.0 (C3), 13.3 (C1). MS (EI): m/z (rel.
int.): 58 (100, [M-HCl]1), 43 (30).
J = 1.8, H2), 7.64 (1H, dd, J = 1.8, J = 1.8, H4), 7.48 (1H, dd, J = 1.8,
J = 1.8, H5), 4.06 (3H, s, H10), 1.82 (2H, bt, J = 7.6, H20), 1.31 (2H, tq,
J = 7.6, J = 7.4, H30), 0.89 (3H, t, J = 7.4, H40). 13C NMR: d 137.8 (C2),
123.7 (C4), 122.0 (C5), 49.1 (quin, 1JCD = 21.6, C10), 36.5 (C100), 31.9
(C20), 19.3 (C30), 13.4 (C40). HR-MS (ASAP): m/z calcd for
C8H13D2N2 ([M-Cl]1): 141.1356, found: 141.1352.
[20,20-d2]-1-n-Butyl-3-methylimidazolium chloride (1c): Obtained
from 1-methylimidazole and 4b in quantitative yield. IR (NaCl
plate, cmꢀ1): 3385, 3138, 3052, 2959, 2933, 2873, 2201, 2135,
2109, 1572, 1465, 1175. 1H NMR: d 10.54 (1H, bdd, J = 1.8, J = 1.7,
H2), 7.64 (1H, dd, J = 1.8, J = 1.7, H4), 7.47 (1H, dd, J = 1.8, J = 1.8,
H5), 4.25 (2H, bs, H10), 4.05 (3H, s, H10), 1.28 (2H, bt, J = 7.4, H30),
0.88 (3H, t, J = 7.4, H40). 13C NMR: d 137.6 (C2), 123.7 (C4), 122.0
(C5), 49.5 (C10), 36.4 (C100), 31.3 (quin, 1JCD = 19.6, C20), 19.1 (C30),
13.3 (C40). HR-MS (ASAP): m/z calcd for C8H13D2N2 ([M-Cl]1):
141.1356, found: 141.1352.
[30,30-d2]-1-n-Butyl-3-methylimidazolium chloride (1d): Ob-
tained from 1-methylimidazole and 4c in quantitative yield. IR
(NaCl plate, cmꢀ1): 3383, 3137, 3046, 2957, 2933, 2870, 2178,
2137, 2110, 1572, 1459, 1172. 1H NMR: d 10.42 (1H, bdd, J = 1.8,
J = 1.8, H2), 7.62 (1H, dd, J = 1.8, J = 1.8, H4), 7.45 (1H, dd, J = 1.8,
J = 1.8, H5), 4.18 (2H, t, J = 7.4, H10), 3.98 (3H, s, H10), 1.74 (2H,
dt, J = 7.4, H20), 0.78 (3H, bs, H40). 13C NMR: d 137.6 (C2), 123.7
(C4), 122.0 (C5), 49.7 (C10), 36.4 (C100), 31.9 (C20), 18.6 (quin,
1JCD = 19.3, C30), 13.1 (C40). HR-MS (ASAP): m/z calcd for
C8H13D2N2 ([M-Cl]1): 141.1356, found: 141.1355.
[2,2-d2]-1-Chlorobutane (4b): Obtained from 3b in 63% yield. IR
(NaCl plate, cmꢀ1): 2962, 2935, 2875, 2203, 2130, 2107, 1460. 1H
3
NMR: d 3.55 (2H, quin, JHD = 1.0, H1), 1.47 (2H, qquin, J = 7.4,
3JHD = 1.1, H3), 0.95 (3H, t, J = 7.4, H4). 13C NMR: d 44.7 (C1), 33.8
(quin, JCD = 19.5, C2), 19.8 (C3), 13.3 (C4). MS (EI): m/z (rel. int.):
1
57 (100, [M-DCl]1), 42 (42).
[3,3-d2]-1-Chlorobutane (4c): Obtained from 3c in 54% yield. IR
(NaCl plate, cmꢀ1): 2969, 2932, 2874, 2217, 2184, 2116, 1459. 1H
3
NMR: d 3.56 (2H, t, J = 6.7, H1), 1.76 (2H, tquin, J = 6.7, JHD = 1.1,
H2), 0.94 (3H, quin, 3JHD = 1.1, H4). 13C NMR: d 44.8 (C1), 34.4 (C2),
19.3 (quin, JCD = 19.3, C3), 13.1 (C4). MS (EI): m/z (rel. int.): 58
1
(100, [M-HCl]1), 43 (33).
[40,40,40,-d3]-1-n-Butyl-3-methylimidazolium chloride (1e): Ob-
tained from 1-methylimidazole and 4d in quantitative yield. IR
(NaCl plate, cmꢀ1): 3385, 3138, 3052, 2983, 2935, 2865, 2220,
[4,4,4-d3]-1-Chlorobutane (4d): Obtained from 3d in 74% yield.
IR (NaCl plate, cmꢀ1): 2957, 2935, 2869, 2216, 2126, 2078, 1463.
1H NMR: d 3.56 (2H, t, J = 6.8, H1), 1.77 (2H, tt, J = 7.4, J = 6.8, H2),
1
2124, 2075, 1571, 1460, 1170. H NMR: d 10.62 (1H, bdd, J = 1.8,
3
1.46 (2H, thep, J = 7.4, JHD = 1.0, H3). 13C NMR: d 44.9 (C1), 34.5
J = 1.8, H2), 7.64 (1H, dd, J = 1.8, J = 1.8, H4), 7.47 (1H, dd, J = 1.8,
J = 1.8, H5), 4.28 (2H, t, J = 7.4, H10), 4.07 (3H, s, H10), 1.84
(2H, J = 7.7, J = 7.4, H20), 1.30 (2H, bt, J = 7.7, H30). 13C NMR: d
137.9 (C2), 123.7 (C4), 122.0 (C5), 49.7 (C100), 36.5 (C10), 32.1 (C20),
1
(C2), 19.8 (C3), 12.4 (hep, JCD = 19.2, C4). MS (EI): m/z (rel. int.):
59 (100, [M-HCl]1), 41 (32).
1
19.2 (C30), 12.5 (hep, JCD = 19.2, C40). HR-MS (ASAP): m/z calcd
Alkylation of 1-methylimidazole isotopologues
for C8H12D3N2 ([M-Cl]1): 142.1419, found: 142.1417.
The appropriate 1-methylimidazole (5 g, 60 mmol) and
1-chlorobutane (1.2 eq) isotopologues were combined in a
20 mL scintillation vial and sealed with a Teflon-lined cap. The
Results and discussion
vial was then immersed in an oil bath at 951C, and the solution Our previous deuterium isotope effect studies employed
was stirred vigorously for 16–20 h. The resulting biphasic [C4mim]Cl labeled on the C-2 or C-2,4,5 positions. Given the
mixture was subsequently cooled to room temperature and labile nature of the imidazolium protons, the preparation of
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J. Label Compd. Radiopharm 2011, 54 401–407

A. Khrizman et al.
these isotopologues only requires an H/D exchange of the IL chloride. A slight excess of 4a was then used to N-alkylate
with D2O, either pure or in the presence of a weak base.2,6 In 1-methylimidazole and obtain the desired product in 63%
order to use established literature methods,6,7 the synthesis of overall yield (Scheme 1).
[C4mim]Cl bearing sequential labels along the N-alkyl groups
The preparation of 1c required a 1-chlorobutane isotopolo-
requires suitable deuterated 1-chlorobutane precursors. While gue deuterated in the C-2 position. An appropriately labeled
similar compounds have been reported in the literature, their precursor of this chloroalkane could be easily and inexpensively
preparation employed relatively low-yielding reactions and obtained by successive H/D exchange reactions on methyl
expensive starting materials which are no longer commercially acetoacetate. Owing to the labile nature of the C-2 protons of
available.8 Furthermore, an approach that uses analogous the b-ketoester,12 the final deuterium content at this position is
transformations to obtain the different 1-chlorobutane isotopo- higher than 98% after three exchange cycles. Furthermore, the
logues was desirable.
ketone in the C-3 position of the deuterated intermediate can
As shown in Scheme 1, the preparation of 1a and 1b was be reduced to alcohol 5 using NaBH4 without isolation from the
straightforward. The former involved N-methylation of imidazole D2O solution after the last H/D exchange step (Scheme 2). The
with [d3]-iodomethane using potassium tert-butoxide as base resulting b-hydroxyester was treated with p-toluenesulfonyl
and
a
catalytic amount of 18-crown-6,9,10 followed by chloride to afford 6, which after simultaneous reduction of the
N-alkylation of 2 with 1-chlorobutane to afford the imidazolium ester and tosylate functionalities with LiAlH4 produced alcohol
salt in 84% combined yield. In the case of 1b, methylbutyrate 3b.13 The next steps in the preparation of imidazolium chloride
was first reduced to alcohol 3a with LiAlD4,11 which was then 1c, which was obtained from 5 in 36% overall yield, were
converted to the corresponding chloroalkane with thionyl identical to those used in the synthesis of 1b.
a
b
D3C
D3C
Cl
HN
N
N
N
N
N
CH3
2
1a
D D
O
D D
c
e
H3C
Cl
N
N
CH3
X
CH3
H3CO
CH3
3a (X = OH)
4a (X = Cl)
d
1b
Scheme 1. (a) CD3I, tBuOK, 18-crown-6, Et2O (84%); (b) 1-Chlorobutane (quantitative); (c) LiAlD4, THF (82%); (d) SOCl2 (77%); and (e) 1-Methylimidazole (quantitative).
O
OH
CH3
O
OTs
CH3
O
d
O
a,b
c
H3CO
H3CO
H3CO
CH3
D D
D D
5
6
H3C
Cl
f
X
e
CH3
N
N
CH3
D D
D D
3b (X = OH)
4b (X = Cl)
1c
Scheme 2. (a) D2O; (b) NaBH4, D2O (84% over both steps); (c) TsCl, pyridine (94%); (d) LiAlH4, THF (61%); (e) SOCl2 (63%); and (f) 1-Methylimidazole (quantitative).
X
O
O
a
b
TBSO
c
CH3
HO
CH3
TBSO
CH3
D
7
8a (X = OH)
9a (X = OTs)
D D
CH3
D D
CH3
d,e
g
H3C
N
N
X
Cl
3c (X = OH)
4c (X = Cl)
f
1d
Scheme 3. (a) TBDMSCl, imidazole (94%); (b) NaBD4, MeOH (99%); (c) TsCl, pyridine, CH2Cl2 (98%); (d) LiAlD4, Et2O; (e) HCl/H2O (69% over both steps); (f) SOCl2 (54%);
and (g) 1-Methylimidazole (quantitative).
J. Label Compd. Radiopharm 2011, 54 401–407
Copyright r 2011 John Wiley & Sons, Ltd.
www.jlcr.org

A. Khrizman et al.
The synthesis of the 1-chlorobutane isotopologue needed to intermediate was converted into tosylate 9a, which was reduced
obtain 1d started with the reduction of TBDMS-protected with LiAlD4 and deprotected under acidic conditions to afford 3c
ketone 7 with NaBD4 to yield monodeuterated alcohol 8a. This (Scheme 3). After this point, the same transformations described
O
a
b
TBSO
OH
HO
c
OH
TBSO
H
10
11
X
e,f
h
H3C
Cl
N
N
CD3
X
g
CD3
TBSO
d
CD3
3c (X = OH)
4c (X = Cl)
8b (X = OH)
9b (X = OTs)
1e
Scheme 4. (a) TBDMSCl, NaH, THF (96%); (b) (COCl)2, DMSO, Et3N, CH2Cl2; (c) CD3I, Mg, Et2O (65% over both steps); (d) TsCl, pyridine, CH2Cl2 (94%); (e) LiAlH4, Et2O; (f) HCl/
H2O (60% over both steps); (g) SOCl2 (74%); and (h) 1-Methylimidazole (quantitative).
Figure 2. Aliphatic region of the 1H NMR spectra of 1(a) and its deuterium isotopologues 1a–e (b–f).
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J. Label Compd. Radiopharm 2011, 54 401–407

A. Khrizman et al.
for the preparation of the previous imidazolium salts were reagents (D2O, LiAlD4, NaBD4, and CD3I). As a result, we have
employed to obtain 1d in 36% combined yield following the been able to obtain the deuterated ILs in sufficient quantities to
initial deuterium incorporation reaction.
carry out a variety of D(H,D) measurements at a moderate cost.
It is important to mention that the choice of solvent for the The results from these ongoing studies will be reported
reduction of 9a with LiAlD4 is critical. While using either THF or elsewhere in due course.
diethyl ether leads to the elimination of the tosylate group
almost quantitatively, performing the reaction in the former Acknowledgements
generates a 2:1 mixture of [3,3-d2]-1-butanol and [4-d1]-1-butanol
after removal of the TBDMS protecting group. Interestingly,
this apparent scrambling of the deuterium label is not observed
in the reduction of butyrate 6 with LiAlH4 in THF described earlier.
Based on these results and on other preliminary experiments
(data not shown), we believe that the formation of the side
product is due to reductive cleavage of the THF ring by the
metal hydride with participation of the silyl group present in
compound 9a.14
The last [C4mim]Cl isotopologue in the series was prepared
using singly protected propanediol 10 as a precursor. This
alcohol was oxidized using standard Swern conditions to afford
TBDMS-protected aldehyde 11,15 which was then converted to
alcohol 8b by treatment with [d3]-methylmagnesium iodide
(Scheme 4). The remaining steps were analogous to those
detailed above for the preparation of 1d, and led to imidazolium
salt 1e in 42% overall yield following the Grignard reaction.
Funding from the National Science Foundation is acknowledged
(Awards DUE-9952264 and CHE-0845026).
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Conclusions
To summarize, we described the preparation of deuterium
isotopologues of [C4mim]Cl sequentially labeled along the
N-alkyl groups. The aliphatic region of their 1 H NMR spectra is
presented in Figure 2.
As stated earlier, the approach employs a limited number of
distinct reactions, and in several cases combines them efficiently
into single-step processes. This is best exemplified in the
preparation of imidazolium salt 1c, which combines an H/D
exchange reaction with a reduction in aqueous media as well as
the reduction of tosylate and ester functionalities into single
steps. It is also worth noting that all deuterium incorporation
reactions were carried out using few and relatively inexpensive
J. Label Compd. Radiopharm 2011, 54 401–407
Copyright r 2011 John Wiley & Sons, Ltd.
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