Synthesis of acyclic quaternary ammonium compounds containing ω-alkoxyethyl and 2-hydroxyethyl substituents at the nitrogen atom

Article abstract of DOI:10.1007/s11172-015-1209-7

A series of acyclic symmetric quaternary ammonium chlorides Me₂(HOCH₂CH₂)N⁺(CH₂CH₂O)_nR Cl^– (n = 1, R = n-C₉H₁₉; n = 2, R = n-C₆H₁₃; n = 3, R = n-C₃H₇) was synthesized by alkylation of the corresponding tertiary amines Me₂N(CH₂CH₂O)_nR with ethylene chlorohydrin in a two-phase system, using water as a solvent. The tertiary amines were synthesized in a heterogeneous system organic phase—aqueous phase, using an aqueous solution of Me₂NH and a solid alkali. The intermediate monoethers of ethylene, diand triethylene glycol were obtained in high yield via a phase-transfer alkylation in dioxane, using solid KOH. The proton and carbon atom signals in the NMR spectra of the synthesized amines and ammonium chlorides were assigned based on the data of heteronuclear correlations (¹H, ¹³C).

Full text of DOI:10.1007/s11172-015-1209-7

Russian Chemical Bulletin, International Edition, Vol. 64, No. 11, pp. 2697—2701, November, 2015
2697
Synthesis of acyclic quaternary ammonium compounds containing
ωꢀalkoxyethyl and 2ꢀhydroxyethyl substituents at the nitrogen atom*
K. V. Tcarkova,a S. K. Belus´,a O. I. Artyushin,b A. V. Kharlamov,a and N. A. Bondarenkoa
aState ScientificꢀResearch Institute of Chemical Reagents and High Purity Substances,
3 Bogorodsky val, 107076 Moscow, Russian Federation.
Eꢀmail: bond039@mail.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Eꢀmail: oleg.artyushin@gmail.com
A
series
of
acyclic
symmetric
quaternary
ammonium
chlorides
Me2(HOCH2CH2)N+(CH2CH2O)nR Cl– (n = 1, R = nꢀC9H19; n = 2, R = nꢀC6H13; n = 3,
R = nꢀC3H7) was synthesized by alkylation of the corresponding tertiary amines
Me2N(CH2CH2O)nR with ethylene chlorohydrin in a twoꢀphase system, using water as a solvent.
The tertiary amines were synthesized in a heterogeneous system organic phase—aqueous phase,
using an aqueous solution of Me2NH and a solid alkali. The intermediate monoethers of
ethylene, diꢀ and triethylene glycol were obtained in high yield via a phaseꢀtransfer alkylation
in dioxane, using solid KOH. The proton and carbon atom signals in the NMR spectra of the
synthesized amines and ammonium chlorides were assigned based on the data of heteronuclear
correlations (1H, 13C).
Key words: polyethylene glycol monoethers, phaseꢀtransfer alkylation, polyethylene glycols,
ωꢀalkoxyethyl chlorides, tertiary amines, quaternary ammonium compounds.
Earlier, it was shown1 that the introduction of ethylꢀ
ene or diethylene glycol fragments between the nitrogen
atom and the dodecyl substituent in the Katinol molecule,
Me2N+(nꢀC12H25)CH2CH2OH Cl–, possessing bacteriꢀ
cidal properties leads to a significant increase in the activꢀ
ity of such compounds against St. aureus. In the case of
E. coli, their activity remains virtually on the same level.
In this connection, we carried out the investigations of
the relationship between bactericidal properties of such
molecules and the number of ethylene glycol units in the
12ꢀmembered fragment at the nitrogen atom. For this purꢀ
pose, we synthesized a series of ammonium chlorides 1a—c
analogues to Katinol molecule by a sequential replaceꢀ
ment of each third methylene unit counting from the
nitrogen atom in the Nꢀdodecyl fragment with an oxyꢀ
gen atom.
Note that compounds containing such groups in the
molecule possess a decreased toxicity to warmꢀblooded
organisms.2—4
Results and Discussion
Ammonium chlorides 1a—c were synthesized by a traꢀ
ditional conversion of secondary amines to the tertiary
ones 2a—c and their subsequent reaction with ethylene
chlorohydrin (Scheme 1). It is known that the most effiꢀ
cient order of the introduction of substituents to the nitroꢀ
gen atom suggests an initial NHꢀalkylation of secondary
amines with the less active alkylating agents, ωꢀalkoxyꢀ
ethyl chlorides, while more active reagent is used for the
Nꢀalkylation of tertiary amines.5
The tertiary amines 2a—c were synthesized in 77—85%
yield by the reaction of Me2NH (used as a 38% aqueous
solution) with ωꢀalkoxyethyl chlorides 3a—c in the heteroꢀ
geneous system "organic phase—aqueous phase" in the
presence of NaOH (110—115 °C, 15 h, a sealed tube) and
in the absence of a solvent and a phaseꢀtransfer catalyst
(Table 1). N,NꢀDimethylꢀNꢀ(2ꢀnonyloxyethyl)amine (2a)
obtained by a similar method was described earlier.5
Compound
X(4)
X(7)
X(10)
Katinol
1a
1b
CH2
CH2
CH2
O
CH2
CH2
O
CH2
O
O
1c
O
O
* To 90th birthday anniversary of the Corresponding Member of the
Russian Academy of Sciences T. A. Mastryukova (1925—2006).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2697—2701, November, 2015.
1066ꢀ5285/15/6411ꢀ2697 © 2015 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 64, No. 11, November, 2015
Tcarkova et al.
1
assigned based on the 2D H, 13C correlation spectra
(HSQC and HMBC). Thus, the HSQC (1H, 13C) spectral
data allowed us to reliably assign the signals for the carbon
atoms of methyl groups 1 and 14, 15, methylene groups 8
and 9 in amine 2a, 5 and 6 in amine 2b, and 2 and 3 in
amine 2c, as well as that for the αꢀcarbon atom 12 in all
the amines. Chemical shifts of other signals for carbon
atoms were assigned based on the crossꢀpeaks in the
HMBC spectra (see Table 1).
Scheme 1
1—3
R
n
1
2
3
a
b
c
nꢀC9H19
nꢀC6H13
nꢀC3H7
Ammonium chlorides 1a—c were obtained in 67—88%
(Table 2) yield by Nꢀalkylation of tertiary amines 2a—c
with ethylene chlorohydrin in the twoꢀphase system using
water as a solvent (see Scheme 1). Their structure was
Reagents and conditions: i. Cl(CH2CH2O)nR (3a—c), NaOH,
110—115 °C, 15 h; ii. ClCH2CH2OH, H2O, 90—95 °C, 4 h.
1
confirmed by H and 13C NMR spectroscopy and high
The structure and composition of amines 2a—c were
resolution mass spectrometry (ESI) (see Table 2). The
1H NMR spectra contain the proton characteristic signals
of the alkoxy and Me2N groups, as well as the ethylene
glycol fragments, and four proton multiplets of the methylꢀ
ene units 11, 12, 16, 17 in the region δH 3.68—4.18, which
are attributed to the two structurally similar 2ꢀalkoxyꢀ and
2ꢀhydroxyethyl substituents at the nitrogen atom. These
signals were assigned in a separate study6 based on the 2D
confirmed by 1H and 13
C NMR spectroscopy (see Table 1),
as well as by high resolution mass spectrometry (ESI). The
1H NMR spectra correspond to the structure of these comꢀ
pounds and contain proton characteristic signals for the
alkyl and ethylene glycol fragments of the molecules
(δH 0.79—1.62 and δH 3.31—3.69, respectively). The sigꢀ
nals in the 13C NMR spectra of tertiary amines 2a—c were
Table 1. Yields and 1H and 13C{1
H} NMR spectra (CDCl3) of tertiary amines R(OCH2CH2)nNMe2 2a—c
Comꢀ
pound
X(4)
CH2
X(7)
CH2
Yielda
(%)
δ (J/Hz)
1H
13C{1
H}
3
2а
2b
2с
81
0.83 (t, 3 Н, H3C(1), JH,H = 6.7); 1.15—1.35
(m, 12 Н, H2C(2)—H2C(7)); 1.53 (quint, 2 Н,
H2C(5), 3JH,H = 6.9); 2.22 (s, 6 Н, H3C(14),
H3C(15)); 2.45 (t, 2 Н, H2C(12), JH,H = 5.9);
3.38 (t, 2 Н, Н2C(9), JH,H = 6.8); 3.47 (t, 2 Н,
14.30 (C(1)); 22.86d (C(2), C(3));
26.33 (C(7)); 29.46, 29.68, 29.75
(C(4), C(5), C(6)); 29.80 (C(8));
32.07d (C(2), C(3)); 46.05 (C(14),
C(15)); 59.08 (C(12));
(
oilb,c
)
3
3
Н2C(11), 3JH,H = 5.9)
69.97 (C(11)); 71.62 (C(9))
3
CH2
O
O
77
(oilc)
0.87 (t, 3 Н, H3C(1), JH,H = 6.9); 1.20—1.40
(m, 6 Н, H2C(2)—H2C(4)); 1.52 (quint, 2 Н,
H2C(5), 3JH,H = 7.0); 2.25 (s, 6 Н, H3C(14),
H3C(15)); 2.50 (t, 2 Н, H2C(12), JH,H = 5.9);
3.44 (t, 2 Н, Н2C(6), 3JH,H = 6.8); 3.55—3.60
14.00 (C(1)); 22.58 (C(2));
25.74 (C(4)); 29.57 (C(5));
31.66 (C(3)); 45.86 (C(14), C(15));
58.82 (C(12)); 69.36 (C(11));
70.05 (C(8)); 70.40 (C(9));
71.49 (C(6))
3
(m, 6 Н, H2C(8), H2C(9), H2C(11))
O
85
(oilc)
0.87 (t, 3 Н, H3C(1), 3JH,H = 7.4);
1.47 (sext, 2 Н, Н2C(2), JH,H = 7.1);
10.09 (C(1)); 22.14 (C(2));
46.03 (C(14), C(15)); 58.98 (C(12));
69.49 (C(11)); 70.17 (C(5));
70.53 (C(6)); 70.71 (C(8), C(9));
73.23 (C(3))
3
2.22 (s, 6 Н, H3C(14), H3C(15)); 2.47 (t, 2 Н,
H2C(12), 3JH,H = 5.9); 3.38 (t, 2 Н, Н2C(3),
3JH,H = 6.8); 3.52—3.62 (m, 10 Н,
Н2C(5), Н2C(6), Н2C(8), Н2C(9), Н2C(11))
a Yield of analytically pure products.
b Described earlier.5
c Compounds are very hygroscopic, purified by column chromatography.
d According to the HMBC (1H, 13C) spectrum, the signals belong only to atoms C(2) or C(3).

Synthesis of quaternary ammonium compounds
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 11, November, 2015 2699
homoꢀ (1H, 1H) and heterocorrelation procedure (1H, 13
C
field. Positions of signals for other hydrogen atoms did
not change.
and H, 15N), using the gsꢀCOSY, gsꢀHSQC, and gsꢀ
HMBC pulse field gradients. The data obtained allowed
us to reliably assign the signals in the lowꢀfield part of the
1H NMR spectra to the methylene protons in the followꢀ
ing sequence: 16, 12, 11, 17. The most downfield multiꢀ
plet at δH 4.05—4.18 belongs to the protons of the hyꢀ
droxymethyl group 17 (see Table 2). Note that the conꢀ
version of tertiary amines 2a—c to the corresponding
ammonium chlorides 1a—c leads to a noticeable downꢀ
field shift of the signals for the protons of the αꢀmethylene
groups 12 and the methyl groups 14 and 15 by 1.4 and
1.2 ppm, respectively. The signal for the protons of the
methyl groups 14 and 15 at the nitrogen atom overlaps
with one of the components of the triplet belonging to the
protons of the CH2O methylene groups 9, 6, 3 in comꢀ
pounds 1a, 1b, and 1c, respectively. The signals for the
βꢀmethylene protons at position 11 (NCH2CH2O) are
only insignificantly (by ~0.4 ppm) shifted toward the low
1
The assignment of the 13C signals given in Table 2 is
based on the data of heteronuclear (1H, 13C) HSQC and
HMBC correlation spectra.6 The signals for the carbon
atoms of the Nꢀ2ꢀoxyꢀ and Nꢀ2ꢀhydroxyethyl substituents
were found in the following sequences: 17, 11, 12, 16 in
the spectrum of salt 1a with a nonyloxy group and 17, 12,
11, 16 in the spectrum of hexyloxy and propyloxy derivaꢀ
tives 1b and 1c (see Fig. 1). The signals for the carbon
atoms of the ethylene glycol units in the spectra of salts 1b
and 1c have the following sequence: 8, 9, 6 and 5, 8, 6, 9.
The most downfield signal belongs to the carbon atoms 9,
6 and 3 bonded to the oxygen atom in the OR fragments
(see Table 2).
ωꢀAlkoxyethyl chlorides 3a—c were obtained in two
steps:5 first, the reaction of phaseꢀtransfer monoalkylaꢀ
tion of ethylene, diꢀ and triethylene glycol with nonyl,
hexyl, and propyl bromide in the presence of KOH withꢀ
Table 2. Yields and 1H and 13C{1
R(OCH2CH2)nN+(CH2CH2OH)Me2 Cl– 1a—c
H} NMR spectra (CDCl3) of quaternary ammonium compounds
Comꢀ
pound
X(4)
CH2
X(7)
CH2
Yielda
(%)
δ (J/Hz)
1H
13C{1
H}
3
1a
67
(oilb)
0.85 (t, 3 Н, H3C(1), JH,H = 6.6); 1.15—1.33
(m, 12 Н, Н2C(2)—Н2C(7)); 1.52 (quint, 2 Н,
14.14 (C(1)); 22.68d (C(2), C(3));
26.16 (C(7)); 29.28 29.42, 29.46,
29.52 (C(4), C(5), C(6), C(8));
31.86d (C(2), C(3)); 53.02 (C(14),
C(15)); 56.04 (C(17)); 64.67 (C(11));
64.82 (C(12)); 67.26 (C(16));
71.86 (C(9))
Н2C(8), JH,H = 6.6); 3.39c (s, 6 Н,
3
H3C(14), H3C(15)); 3.42c (t, 2 Н, Н2C(9),
3JH,H = 6.6); 3.68—3.80 (m, 3 Н,
Н2C(16) + OH); 3.85 (br.m, 4 Н,
Н2C(12) + Н2C(11)); 4.05—4.18 (m, 2 Н,
Н2C(17))
1b
CH2
O
73
(oilb)
0.86 (t, 3 Н, H3C(1), 3JH,H = 6.9); 1.20—1.35
14.26 (C(1)); 22.82 (C(2));
25.95 (C(3)); 29.79 (C(5));
(m, 6 Н, Н2C(2)—Н2C4)); 1.52 (quint
,
2 Н, Н2C(5), 3JH,H = 7.0); 3.39c (s, 6 Н,
H3C(14), H3С(15)); 3.40c (t, 2 Н, Н2C(6),
3JH,H = 6.8); 3.49—3.55 (m, 2 Н, Н2C(8));
3.61—3.66 (m, 2 Н, Н2C(9)); 3.70—3.78
(m, 2 Н, Н2C(16)); 3.83—3.92 (m, 2 Н,
Н2C(12));3.93—3.99 (m, 2 Н, Н2C(11));
4.08—4.16 (m, 3 Н, Н2C(17) + OH)
31.84 (C(4)); 53.36 (C(14), C(15));
56.28 (C(17)); 64.89 (C(12));
65.25 (C(11)); 67.41 (C(16));
69.85 C(8); 70.72 C(9); 71.74 (C(6))
1c
O
O
88
(oilb)
0.90 (t, 3 Н, H3C(1), 3JH,H = 7.4); 1.58
10.65 (C(1)); 22.91 (C(2));
53.17 (C(14), C(15)); 56.15 (C(17));
64.72 (C(12)); 65.19 (C(11));
(
sext, 2 Н, Н2C(2), 3JH,H = 7.1);
3.39c (s, 6 Н, H3C(14), H3C(15));
3.40c (t, 2 Н, Н2C(3), 3JH,H = 6.6);
3.52—3.70 (m, 8 Н, Н2C(5), Н2C(6), Н2C(8),
Н2C(9)); 3.73—3.81 (m, 2 Н, Н2C(16));
3.83—3.92 (m, 2 Н, Н2C(12)); 3.94—4.04
(m, 2 Н, Н2C(11)); 4.07—4.18 (m, 2 Н,
Н2C(17)); 4.71 (s, 1 Н, OH)
67.27 (C(16)); 70.09 (C(5)); 70.35 (C(8));
70.49 (C(6)); 70.65 (C(9)); 73.18 (C(3))
a Yields of analytically pure products.
b Compounds are very hygroscopic, purified by column chromatography.
c Overlapped singlet and triplet.
d According to the HMBC (1H, 13C) spectrum, the signals belong only to atoms C(2) or C(3).

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Russ.Chem.Bull., Int.Ed., Vol. 64, No. 11, November, 2015
Tcarkova et al.
hydrin (0.3 g, 4.1 mmol), and H2O (3 mL). The salt 1b (1.0 g)
was purified by column chromatography on silica gel, eluent
chloroform—methanol (2 : 1). The yield of product 1b was 0.8 g
(73%) (see Table 2). Found, m/z: 262.2366 [M]+. C14H32NO3.
Calculated: M = 262.2377.
out a phaseꢀtransfer catalyst gave monoethers 4a—c
(70—75%); in the second step, they were treated with thioꢀ
nyl chloride in the presence of pyridine (Scheme 2).
Nꢀ(2ꢀHydroxyethyl)ꢀN,NꢀdimethylꢀNꢀ{2ꢀ[2ꢀ(2ꢀpropyloxyꢀ
ethoxy)ethoxy]ethyl}ammonium chloride (1c) was obtained simiꢀ
larly to compound 1a from amine 2c (0.6 g, 2.7 mmol), ethylene
chlorohydrin (0.2 g, 3.0 mmol), and H2O (3 mL). The salt 1c
(0.8 g) was purified by column chromatography on silica gel,
eluent chloroform—methanol (5 : 1). The yield of product 1c
was 0.7 g (88%) (see Table 2). Found, m/z: 264.2170 [M]+.
C13H30NO4. Calculated: M = 264.2169.
Scheme 2
Nꢀ[2ꢀ(2ꢀHexyloxyethoxy)ethyl]ꢀN,Nꢀdimethylamine (2b).
A mixture of 0.86 g of 38% aqueous solution of Me2NH (0.32 g,
7.1 mmol), 1ꢀ[2ꢀ(2ꢀchloroethoxy)ethoxy]hexane (3b) (2.00 g,
9.6 mmol), and solid NaOH (0.4 g, 10.5 mmol) was heated
in a sealed tube at 110—115 °C for 15 h. Then, the content of
the tube was diluted with benzene (15 mL) and water (10 mL).
The organic layer was separated, washed with water (3×10 mL),
dried with Na2SO4, and concentrated in vacuo. The residue
(1.70 g) was purified by column chromatography on silica gel,
eluent chloroform—methanol (4 : 1). The yield of amine 2b was
1.60 g (77%) (see Table 1). Found, m/z: 218.2107 [M + H]+.
C12H27NO2. Calculated: M = 218.2115.
3, 4
a
b
R
n
1
2
3
nꢀC9H19
nꢀC6H13
nꢀC3H7
c
Reagents and conditions: i. RBr, KOH, dioxane, 100—105 °C,
5—10 h; ii. SOCl2, PhMe, Py, –5 °C→100 °C, 2 h.
Thus, we synthesized a series of ammonium chlorides
with Nꢀωꢀalkoxyethyl and Nꢀ2ꢀhydroxyethyl substituents
by the alkylation of Nꢀ(ωꢀalkoxyethyl)ꢀN,Nꢀdimethylꢀ
amines with ethylene chlorohydrin in the twoꢀphase
system using water as a solvent. The compounds obtained
are of interest as bactericidal agents, as well as for the
study of the structure—activity relationship.
N,NꢀDimethylꢀNꢀ{2ꢀ[2ꢀ(2ꢀpropyloxyethoxy)ethoxy]ethyl}ꢀ
amine (2c) was obtained similarly to amine 2b from 0.86 g of 38%
aqueous solution of Me2NH (0.32 g, 7.1 mmol), 1ꢀ{2ꢀ[2ꢀ(2ꢀ
chloroethoxy)ethoxy]ethoxy}propane (3c) (2.00 g, 9.5 mmol),
and solid NaOH (0.42 g, 10.4 mmol). The product (1.90 g) was
purified by column chromatography on silica gel, eluent chloroꢀ
form—methanol (4 : 1). The yield of amine 2c was 1.80 g (85%)
(see Table 1). Found, m/z: 220.1917 [M + H]+. C11H25NO3.
Calculated: M = 220.1907.
1ꢀ[2ꢀ(2ꢀChloroethoxy)ethoxy]hexane (3b) was obtained acꢀ
cording to the described procedure5 from monoether 4b
(6.8 g,
Experimental
36 mmol), anhydrous pyridine (3.5 mL, 3.4 g, 43 mmol), SOCl2
(3.1 mL, 5.1 g, 43 mmol), and anhydrous toluene (20.0 mL). The
product (6.8 g) was distilled in vacuo to obtain chloride 3b (6.4 g,
84%) with b.p. 126—128 °C (13—14 Torr) (cf. Ref. 8: b.p. 126 °C
1
H and 13C NMR spectra of compounds in CDCl3 were reꢀ
corded on a Bruker Avance III NanoBay spectrometer (300.28 MHz),
using signals of residual protons (δ 7.28) and carbon atoms
(δ 77.20) of the solvent as a internal reference. 2D Correlation
1
3
(14 Torr)). H NMR, δ: 0.84 (t, 3 H, Me, JH,H = 6.9 Hz);
COSY {1H; H}, HSQC, and HMBC{1H; 13C} spectra were reꢀ
1.20—1.39 (m, 6 H, C3H6Me); 1.55 (quint, 2 H, CH2Bu, 3JH,H
=
1
corded using a standard Bruker procedure. High resolution mass
spectra (ESI) were recorded on a Bruker micrOTOF II instruꢀ
ment. Aldrich silica gel (130—270 mesh, 60 Å) was used for
column chromatography. Solvents were purified and dried acꢀ
cording to the known procedures.7 The syntheses of N,Nꢀdiꢀ
methylꢀNꢀ(2ꢀnonyloxyethyl)amine (2a), 1ꢀ(2ꢀchloroethoxy)ꢀ
nonane (3a), and ethylene glycol monononyl ether (4a) were
described earlier.5
= 7.1 Hz); 3.42 (t, 2 H, OCH2C5H11, 3JH,H = 6.8 Hz); 3.53—3.65
3
(m, 6 H, CH2OCH2CH2OC6H13); 3.72 (t, 2 H, ClCH2, JH,H
=
= 5.8 Hz). 13C NMR, δ: 14.18 (Me); 22.77 (CH2Me); 25.92
(CH2Et); 29.75 (CH2Pr); 31.84 (CH2Bu); 42.82 (ClCH2); 70.23
(ClCH2CH2O); 70.88 (CH2OC6H13); 71.54 (CH2CH2OC6H13);
71.75 (OCH2C5H11).
1ꢀ{2ꢀ[2ꢀ(2ꢀChloroethoxy)ethoxy]ethoxy}propane (3c) was
obtained similarly to chloride 3b from monoether 4c (2.3 g,
Nꢀ(2ꢀHydroxyethyl)ꢀN,NꢀdimethylꢀNꢀ(2ꢀnonyloxyethyl)ꢀ
ammonium chloride (1a) was obtained according to the described
12 mmol), anhydrous pyridine (1.2 mL, 1.2 g, 14 mmol), SOCl2
(1.0 mL, 1.6 g, 14 mmol), and anhydrous toluene (8.0 mL). The
product (1.8 g) was purified by column chromatography on silica
gel, eluent chloroform—methanol (49 : 1). The yield of product
3c was 1.6 g (63%). 1H NMR, δ: 0.87 (t, 3 H, Me, 3JH,H = 7.4 Hz);
1.56 (sext, 2 H, CH2Me, 3JH,H = 7.1 Hz); 3.37 (t, 2 H, OCH2CH2Me,
3JH,H = 6.7 Hz); 3.52—3.63 (m, 10 H, CH2OCH2CH2OCH2ꢀ
procedure5 from amine 2a
(1.2 g, 5.6 mmol), ethylene chloroꢀ
hydrin (0.5 g, 6.1 mmol), and H2O (3 mL). The salt 1a (1.5 g)
was purified by column chromatography on silica gel, eluent
chloroform—methanol (2 : 1). The yield of product 1a was 1.1 g
(67%) (see Table 2). Found, m/z: 260.2573 [M]+. C15H34NO2.
Calculated: M = 260.2584.
3
CH2OPr); 3.71 (t, 2 H, ClCH2, JH,H = 5.8 Hz). 13C NMR,
Nꢀ[2ꢀ(2ꢀHexyloxyethoxy)ethyl]ꢀNꢀ(2ꢀhydroxyethyl)ꢀN,Nꢀ
dimethylammonium chloride (1b) was obtained similarly to comꢀ
pound 1a from amine 2b (0.8 g, 3.7 mmol), ethylene chloroꢀ
δ: 10.63 (Me); 22.94 (CH2Me); 42.83 (ClCH2); 70.17 (CH2OPr);
70.75 (OCH2CH2OPr); 70.83 (ClCH2CH2OCH2CH2O); 71.49
(ClCH2CH2O); 73.21 (OCH2Et).

Synthesis of quaternary ammonium compounds
Russ.Chem.Bull., Int.Ed., Vol. 64, No. 11, November, 2015 2701
Diethylene glycol monohexyl ether (4b) was obtained accordꢀ
ing to the described procedure5 from diethylene glycol (19.1 g,
179 mmol), KOH (3.4 g, 60 mmol), hexyl bromide (9.0 g,
55 mmol), and anhydrous dioxane (19 mL). The product (9.3 g)
was distilled in vacuo to obtain ether 4b (7.0 g, 68%) with b.p.
134—135 °C (9 Torr) (cf. Ref. 8: b.p. 140—141 °C (16 Torr)).
1H NMR, δ: 0.85 (t, 3 H, Me, 3JH,H = 7.0 Hz); 1.20—1.40 (m, 6 H,
C3H6Me); 1.56 (quint, 2 H, CH2Bu, 3JH,H = 6.8 Hz); 2.66 (s, 1 H,
References
1. A. V. Kharlamov, Abstract of the Ph.D Thesis (Chem.), State
ScientificꢀResearch Institute of Chemical Reagents and High
Purity Substances, Moscow, 2011, 25 pp. (in Russian).
2. V. E. Limanov, A. E. Épshtein, E. K. Skvortsova, L. I.
Aref´eva, S. E. Gleiberman, A. P. Volkova, Pharm. Chem.
J. (Engl.Transl.), 1976, 10, 55 [Khim. Farm. Zh., 1976, 10, 63].
3. A. E. Épshtein, V. E. Limanov, M. Yu. Telegin, E. K. Skvortsꢀ
ova, T. I. Maksimova, Pharm. Chem. J. (Engl.Transl.), 1980,
14, 292 [Khim. Farm. Zh., 1980, 14, 23].
3
OH); 3.42 (t, 2 H, OCH2C5H11, JH,H = 6.8 Hz); 3.53—3.59
(m, 4 H, OCH2CH2OC6H13); 3.61—3.65 (m, 2 H, HOCH2CH2O);
3.67—3.70 (m, 2 H, HOCH2). 13C NMR, δ: 14.19 (Me); 22.76
(CH2Me); 25.90 (CH2Et); 29.70 (CH2Pr); 31.82 (CH2Bu); 61.98
(HOCH2); 70.32 (HOCH2CH2O); 70.64 (CH2OC6H13); 71.77
(CH2CH2OC6H13); 72.71 (OCH2C5H11).
4. C. J. Marasco, Jr., C. Piantadosi, K. L. Meyer, S. Morrisꢀ
Natschke, K. S. Ishaq, G. W. Small, L. W. Daniel, J. Med.
Chem., 1990, 33, 985.
Triethylene glycol monopropyl ether (4c) was obtained simiꢀ
larly to ether 4b from triethylene glycol (20.0 g, 133 mmol),
KOH (2.7 g, 49 mmol), propyl bromide (5.5 g, 44 mmol), and
anhydrous dioxane (22 mL). The product (8.0 g) was purified by
column chromatography on silica gel, eluent nꢀhexane—aceꢀ
tone (4 : 1) to obtain ether 4c (7.0 g, 71%). 1H NMR, δ: 0.82 (t, 3 H,
Me, 3JH,H = 7.4 Hz); 1.46 (sext, 2 H, CH2Me, 3JH,H = 7.2 Hz);
5. A. V. Kharlamov, O. I. Artyushin, N. A. Bondarenko, Russ.
Chem. Bull.
Khim., 2014, 2445].
6. A. S. Peregudov, O. I. Artyushin, K. V. Tcarkova, N. A. Bondꢀ
arenko, Russ. Chem. Bull. Int. Ed. , 2015, 64, 2702 [ Izv. Akad.
Nauk, Ser. Khim., 2015, 2702].
(Int. Ed.), 2014, 63, 2445 [Izv. Akad. Nauk, Ser.
(
)
7. A. J. Gordon, R. A. Ford, in The Chemists Companion:
A Handbook of Practical Date, Techniques and References,
Wiley, New York, 1972].
3
2.91 (br.s, 1 H, OH); 3.33 (t, 2 H, OCH2Et, JH,H = 6.8 Hz);
3.48—3.53 (m, 4 H, OCH2CH2OPr); 3.55—3.57 (m, 2 H,
HOCH2CH2O); 3.58 (s, 4 H, HOCH2CH2OCH2CH2O); 3.65
8. B. A. Mulley, J. Chem. Soc., 1958, 2065.
3
(t, 2 H, HOCH2, JH,H = 4.0 Hz). 13C NMR, δ: 10.64 (Me);
22.93 (CH2Me); 61.91 (HOCH2); 70.16 (HOCH2CH2O); 70.54
(OCH2CH2OPr); 71.79 (HOCH2CH2OCH2CH2O); 72.68
(CH2OPr); 73.29 (OCH2Et).
Received June 29, 2015