Biologically active aprotic (2-hydroxyethyl)ammonium ionic liquids. Choline derivatives

Full text of DOI:10.1007/s11172-012-0173-8

Russian Chemical Bulletin, International Edition, Vol. 61, No. 6, pp. 1262—1163, June, 2012
1262
Biologically active aprotic (2ꢀhydroxyethyl)ammonium ionic liquids.
Choline derivatives
S. N. Adamovich, R. G. Mirskov, A. N. Mirskova, and M. G. Voronkov
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
1 ul. Favorskogo, 664033 Irkutsk, Russian Federation.
Eꢀmail: mir@irioch.irk.ru
Scheme 2
Some drugs such as choline chloride (vitamin B4),
phosphatidylcholine (neuroprotective agent), choline
salicylate (antiinflammatory, sedative, and antipyretic
agent),1 and gallium (67Ga) choline citrate (marker for
brain, prostate, and breast cancer diagnostics)2 have
structures of typical alkylated ionic liquids (IL)3
[Me3N+CH2CH2OH]X–. Starting from choline iodide (1)
or choline hydroxide (2) and biologically active acetic acid
derivatives,4 here we obtained novel choline derivatives
(3—9) as potential biologically active aprotic (2ꢀhydrꢀ
oxyethyl)ammonium ionic liquids (Scheme 1).
R = Me, n = 1 (10); R = Me, n = 2 (11); R = 2ꢀMeC6H4OCH2,
n = 1 (12)
(2ꢀHydroxyethyl)trimethylammonium iodide (1) was prepared
from N,Nꢀdimethylethanolamine and iodomethane. Colorless
powder, decomp. >250 C. 1H NMR, : 4.03 (t, 2 H, OCH2);
3.58 (t, 2 H, NCH2); 3.29 (s, 9 H, NMe). 13C NMR, : 68.96
(OCH2); 57.05(NCH2); 55.00 (NMe).
Scheme 1
(2ꢀHydroxyethyl)trimethylammonium hydroxide (2) was preꢀ
pared by treating compound 1 with a solution of NaOH. Hygroꢀ
1
scopic powder. H NMR, : 3.99 (t, 2 H, OCH2); 3.56 (t, 2 H,
NCH2); 3.27 (s, 9 H, NMe). 13C NMR, : 67.98 (OCH2); 56.55
(NCH2); 55.09 (NMe).
(2ꢀHydroxyethyl)trimethylammonium 2ꢀmethylphenoxyacetꢀ
ate (3). A 1 : 1 mixture of compound 1 and 2ꢀmethylphenoxyꢀ
acetic acid in MeOH was heated at 50 C for 8 h with slow
concentration to 1/3 of the initial volume and cooled to 5 C.
The resulting solution was added dropwise to anhydrous diethyl
ether (50 mL). The precipitate that formed was filtered off and
dried in vacuo (0.1 Torr). The yield of compound 3 was 1.56 g
(58%), colorless powder, m.p. 107 C. 1H NMR, : 7.12—6.77
(m, 4 H, C6H4); 4.41 (s, 2 H, C6H4OCH2); 4.00 (t, 2 H, OCH2);
3.54 (t, 2 H, NCH2); 3.26 (s, 9 H, NMe). 13C NMR, : 171.52
(C=O); 130.39—110.94 (C6H4); 68.00 (C6H4OCH2); 67.38
Ar = 2ꢀMeC6H4, M = H (3); Ar = 4ꢀClC6H4, M = Na (4);
Ar = 2ꢀHOC6H4, M = K (5); Ar = Ph, M = SiMe3 (6);
Ar = 4ꢀClC6H4, Y = S (7); Ar = 4ꢀClC6H4, Y = SO2 (8);
Ar = 3ꢀindolyl, Y = S (9)
(OCH2); 55.66 (NCH2); 53.56 (NMe); 14.93 (Me). IR, /cm–1
:
1599 (C=O); 3333 (OH). Found (%): C, 62.73; H, 8.31; N, 5.19.
C14H23NO4. Calculated (%): C, 62.43; H, 8.60; N, 5.20.
(2ꢀHydroxyethyl)trimethylammonium 4ꢀchlorophenoxyacetꢀ
ate (4). A mixture of compound 1 and sodium 4ꢀchlorophenoxyꢀ
acetate in MeOH was heated at 65 C for 1 h and then kept at
0 C for 72 h. The precipitate of NaI was filtered off. The solvent
was removed and the residue was washed with diethyl ether and
dried in vacuo. The yield of compound 4 was 94%, powder, m.p.
200 C (decomp.). 1H NMR, : 7.20—6.88 (m, 4 H, C6H4); 4.35
(s, 2 H, C6H4OCH2); 3.97 (t, 2 H, OCH2); 3.51 (t, 2 H, NCH2);
3.22 (s, 9 H, NMe). 13C NMR, : 176.09 (C=O); 138.81—117.20
(C6H4); 69.00 (C6H4OCH2); 68.65 (OCH2); 57.05 (NCH2);
54.87 (NMe). IR, /cm–1: 1606 (C=O); 3340 (OH). Found (%):
Zinc is an essential microbioelement found in 300 enꢀ
zymes and hormones, which actively affects the structuraꢀ
tion of more than 200 proteins.5,6 With the aim of preparꢀ
ing novel Znꢀcontaining IL (10—12), we carried out reacꢀ
tions of compound 1 with zinc derivatives7 (Scheme 2).
IR spectra were recorded on a Varian 3100FTꢀIR75 spectroꢀ
photometer. 1H and 13C NMR spectra (CD3OD, D2O) were
recorded on a DPXꢀ400 spectrometer (400.13 (1H) and 101.62
MHz (13C)) with HMDS as the internal standard.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1248—1249, June, 2012.
1066ꢀ5285/12/6106ꢀ1262 © 2012 Springer Science+Business Media, Inc.

Cholineꢀbased ionic liquids
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 6, June, 2012
1263
C, 54.17; H, 6.65; N, 4.80. C13H20ClNO4. Calculated (%):
C, 53.88; H, 6.95; N, 4.83.
(2ꢀHydroxyethyl)trimethylammonium zinc bis(2ꢀmethylphenꢀ
oxyacetate) iodide (12). A 1 : 1 mixture of compound 1 and zinc
bis(2ꢀmethylphenoxyacetate) in ethanol was kept at 20 C for
10 h. The precipitate that formed was filtered off, washed with
diethyl ether, and dried in vacuo. The yield of compound 10 was
94%, colorless powder, m.p. 50 C. The powder is soluble in
water but is insoluble in ethanol. 1H NMR (D2O), : 7.07—6.66
(m, 4 H, C6H4); 4.33 (s, 2 H, C6H4OCH2); 3.86 (t, 2 H, OCH2);
3.31 (t, 2 H, NCH2); 3.19 (s, 9 H, NMe); 2.09 (s, 6 H, Me).
13C NMR, : 176.64 (C=O); 155.55—111.35 (C6H4); 66.93
(C6H4OCH2); 66.64 (OCH2); 55.12 (NCH2); 53.42 (NMe);
15.04 (Me). IR, /cm–1: 1595 (C=O); 3332 (OH). Found (%):
C, 43.89; H, 5.14; N, 2.35; I, 20.54; Zn, 8.04. C23H32INO7Zn.
Calculated (%): C, 44.07; H, 5.14; N, 2.23; I, 20.24; Zn, 8.34.
(2ꢀHydroxyethyl)trimethylammonium zinc diacetate iodide
(10) was obtained as described for complex 12. Yield 92%, hygroꢀ
scopic powder, m.p. 25—28 C. 1H NMR (D2O), : 3.92 (t, 2 H,
OCH2); 3.39 (t, 2 H, NCH2); 3.07 (s, 9 H, NMe); 1.81 (s, 6 H,
Me). 13C NMR, : 181.55 (C=O); 67.39 (OCH2); 55.60 (NCH2);
53.92 (NMe); 22.66 (Me). IR, /cm–1: 1548 (C=O); 3333 (OH).
Found (%): C, 24.15; H, 4.70; N, 3.35; Zn, 16.51. C9H20INO5Zn.
Calculated (%): C, 23.86; H, 5.00; N, 3.47; Zn, 16.24.
(2ꢀHydroxyethyl)trimethylammonium 2ꢀhydroxyphenoxyꢀ
acetate (5) was obtained as described for compound 4 from comꢀ
pound 1 and potassium 2ꢀhydroxyphenoxyacetate. The yield of
compound 5 was 91%, colorless powder, m.p. 160—170 C (deꢀ
1
comp.). H NMR, : 7.18—6.95 (m, 4 H, C6H4); 4.34 (s, 2 H,
C6H4OCH2); 4.09 (t, 2 H, OCH2); 3.49 (t, 2 H, NCH2); 3.19
(s, 9 H, NMe). 13C NMR, : 177.19 (C=O); 131.81—117.00
(C6H4); 69.01 (C6H4OCH2); 68.65 (OCH2); 56.89 (NCH2);
54.83 (NMe). IR, /cm–1: 1600 (C=O); 3335 (br, OH). Found (%):
C, 57.84; H, 7.53; N, 5.20. C13H21NO5. Calculated (%): C, 57.55;
H, 7.80; N, 5.16.
(2ꢀHydroxyethyl)trimethylammonium phenoxyacetate (6).
A 1 : 1 mixture of compound 1 and trimethylsilyl phenoxyacetꢀ
ate in MeOH was heated at 65 C for 8 h. The solvent and
Me3SiI were removed and the residue was washed with diethyl
ether and dried. The yield of compound 6 was 85%, light yellow
1
powder, m.p. 130 C. H NMR, : 7.11—6.77 (m, 5 H, C6H4);
4.65 (s, 2 H, C6H4OCH2); 4.00 (t, 2 H, OCH2); 3.54 (t, 2 H,
NCH2); 3.24 (s, 9 H, NMe). 13C NMR, : 180.00 (C=O);
130.49—111.02 (C6H4); 67.68 (C6H4OCH2); 64.91 (OCH2);
55.76 (NCH2); 53.67 (NMe). IR, /cm–1: 1596 (C=O); 3350
(OH). Found (%): C, 61.44; H, 8.00; N, 5.40. C13H21NO4. Calꢀ
culated (%): C, 61.15; H, 8.29; N, 5.48.
Bis[(2ꢀhydroxyethyl)trimethylammonium] zinc diacetate diꢀ
iodide (11) was obtained as described for complex 12. Yield 93%,
1
hygroscopic powder, m.p. 24—27 C. H NMR, : 3.94 (t, 4 H,
(2ꢀHydroxyethyl)trimethylammonium 4ꢀchlorophenylsulfanylꢀ
acetate (7) was obtained from compound 2 (1.21 g, 0.01 mol)
and 4ꢀchlorophenylsulfanylacetic acid (2.02 g, 0.01 mol) in
MeOH (20 mL) (20 C, 15 min). The solvent and water were
removed and the residue was dried in vacuo over P2O5. The yield
of compound 7 was 3.05 g (95%), colorless powder, m.p. 142 C.
1H NMR (D2O), : 7.72—7.38 (m, 4 H, C6H4); 3.27 (t, 2 H,
OCH2); 2.72 (s, 2 H, SCH2); 2.68 (t, 2 H, NCH2); 2.37 (s, 9 H,
NMe). 13C NMR, : 178.79 (C=O); 136.82—127.00 (C6H4);
67.65 (OCH2); 56.05 (NCH2); 54.07 (NMe); 40.21 (SCH2). IR,
/cm–1: 1613 (C=O); 3341 (OH). Found (%): C, 51.34; H, 6.30;
N, 4.40. C13H20ClNO3S. Calculated (%): C, 51.05; H, 6.59;
N, 4.58.
(2ꢀHydroxyethyl)trimethylammonium 4ꢀchlorophenylsulfonylꢀ
acetate (8) was obtained as described for salt 7 from compound 2
and 4ꢀchlorophenylsulfonylacetic acid. The yield of compound 8
was 95%, colorless powder, m.p. 165 C. 1H NMR (D2O),
: 7.96—7.65 (m, 4 H, C6H4); 4.57 (s, 2 H, SO2CH2); 3.73 (t, 2 H,
OCH2); 3.20 (t, 2 H, NCH2); 2.57 (s, 9 H, NMe). 13C NMR,
: 177.79 (C=O); 135.23—125.07 (C6H4); 69.21 (SO2CH2); 66.45
(OCH2); 56.55 (NCH2); 54.87 (NMe). IR, /cm–1: 1114, 1324
(SO2); 1610 (C=O); 3332 (OH). Found (%): C, 46.49; H, 5.68;
N, 4.23. C13H20ClNO5S. Calculated (%): C, 46.21; H, 5.96;
N, 4.14.
(2ꢀHydroxyethyl)trimethylammonium 3ꢀindolylsulfanylacetate
(9) was obtained as described for salt 7 from compound 2 and
3ꢀindolylsulfanylacetic acid. The yield of compound 9 was 95%,
pink powder, m.p. 155 C. 1H NMR (D2O), : 7.11—6.58
(m, 5 H, Ind); 3.27 (t, 2 H, OCH2); 2.77 (s, 2 H, SCH2); 2.66
(t, 2 H, NCH2); 2.37 (s, 9 H, NMe). 13C NMR, : 177.53 (C=O);
135.77—102.67 (Ind); 66.89 (OCH2); 55.10 (NCH2); 53.34
(NMe); 41.20 (SCH2). IR, /cm–1: 1576 (C=O); 3332 (OH).
Found (%): C, 58.29; H, 6.88; N, 8.80. C15H22N2O3S. Calculatꢀ
ed (%): C, 58.03; H, 7.14; N, 9.02.
OCH2); 3.41 (t, 4 H, NCH2); 3.09 (s, 18 H, NMe); 1.82 (s, 6 H,
Me). 13C NMR, : 181.53 (C=O); 67.40 (OCH2); 55.62 (NCH2);
53.96 (NMe); 22.82 (Me). IR, /cm–1: 1553 (C=O); 3329 (OH).
Found (%): C, 26.33; H, 5.00; N, 4.55; Zn, 10.40. C14H34I2N2O6Zn.
Calculated (%): C, 26.04; H, 5.30; N, 4.33; Zn, 10.12.
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Received November 28, 2011;
in revised form March 22, 2012