A convenient synthesis of quaternary ammonium gemini surfactants from long-chain alkyldimethylamines and epichlorohydrin

Article abstract of DOI:10.1055/s-2002-34876

Aqueous micellar systems proved to be an excellent reaction medium for the selective synthesis of bis-quaternary ammonium salts 5a-c from epichlorohydrin 2 and long-chain alkyldimethylamines 1a-c, in the presence of the corresponding amine chlorohydrates

Full text of DOI:10.1055/s-2002-34876

LETTER
1811
A Convenient Synthesis of Quaternary Ammonium Gemini Surfactants from
Long-Chain Alkyldimethylamines and Epichlorohydrin
S
C
ynthesis of
Q
ua
.
y
A
mm
G
onium
G
emini Su
.
rfactants Ricci, M. I. Cabrera, J. A. Luna, R. J. Grau*
Instituto de Desarrollo Tecnológico para la Industria Química, Universidad Nacional del Litoral and CONICET, Güemes 3450, 3000 Santa
Fe, Argentina
Fax +54(342)4550944; E-mail: cqfina@ceride.gov.ar
Received 25 June 2002
two-step process involving nucleophilic substitution with
Abstract: Aqueous micellar systems proved to be an excellent re-
the amine hydrochloride 3a–c assistance to open the ep-
oxide ring affording the intermediate mono-ammonium
salt 4a–c, followed by amine attack on the chlorine-sub-
action medium for the selective synthesis of bis-quaternary ammo-
nium salts 5a–c from epichlorohydrin
2 and long-chain
alkyldimethylamines 1a–c, in the presence of the corresponding
amine chlorohydrates 3a–c as functional surfactants. Unlike alcohol stituted carbon of 4a–c yielding bis-ammonium salt 5a–c
or alcohol–water mixtures as reaction medium, mono-quaternary (Scheme 1). So far described syntheses of 5a–c from
ammonium salts 4a–c were formed, if any, in very small amounts
1
a–c and 2 proceed through 4a–c in the presence of protic
under micellar conditions, allowing a more direct and rapid access
to these quaternary ammonium gemini surfactants.
5
polar solvents, such as alcohols, or alcohol–water
mixtures able to solubilize all reactants, especially the
long-chain tri-alkylamine.
6
Key words: gemini surfactants, bis-quaternary ammonium com-
pounds, epichlorohydrin, quaternization, micellar system
The fast selective synthesis of 5a–c and the use of inex-
pensive solvents are especially attractive for production
purposes. In this connection, we report herein that the sub-
stitution reaction in aqueous micellar medium enables
more facile and cheaper access to bis-quaternary ammoni-
um salts from long-chain alkyldimethylamines and epi-
chlorohydrin. The key feature of this process can be found
in the ability of micellar media to influence rates of
Bis-quaternary ammonium salts are the most common cat-
ionic gemini surfactants. They possess at least two hy-
1
drophobic chains and two cationic groups connected with
a spacer group, typically a polyethylene or polyoxyethyl-
ene group. They have better surface-active and micelle-
forming properties than corresponding conventional sur-
7
2
substitution reactions. Yields and selectivity for hydroal-
factants of equivalent chain length. These remarkable
coholic and aqueous micellar systems are compared in or-
der to have a better assessment of the advantages of this
method.
properties give them excellent properties as cationic sur-
factants, good extractive abilities as phase transfer cata-
3
lysts, and good antimicrobial activity.
5
Following a previous report, the preparation of the
Quaternization reactions of long-chain tri-alkylamines
have been very extensively studied, largely with dihaloge-
bis-quaternary ammonium salts from 1a–c and 2 in the
presence of the corresponding amine hydrochlorides 3a–c
and ethanol as reaction medium, was corroborated to be
unfeasible at 50 °C because the conversion of 4a–c into
4
nated substrates to provide the spacer group. Another at-
tractive variant involves the reaction between tertiary
amines and an alkylene oxide substrate, such as an epiha-
lohydrin, because alkylene oxides have shown to be more
5
a–c does not take place in appreciable extension at low
5
temperature (entries 1, 5 and 9 in Table 1). However,
the quaternization reaction provided the bis-quaternary
reactive than dihalogenated substrates. The reaction of a
long-chain tri-alkylamine 1a–c and epichlorohydrin 2 is a
Scheme 1
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1811,1814,ftx,en;S01002ST.pdf.
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Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1
812
C. G. Ricci et al.
LETTER
ammonium salts 5a–c in 84%, 92% and 76% yields, re- tems. Another argument to support this suggestion arises
spectively, after conversion of the mono-quaternary am- from the low availability of amine hydrochlorides 3a–c to
monium salts 4a–c, at 80 °C (entries 1, 5 and 9 in assist the epoxide opening since they are forming mi-
8
Table 2). All reactions have been followed by combined celles. A plausible mechanism of formation of 5a–c from
9
HPLC and colorimetric methods.
1a–c and 2 in cationic micelles is depicted in Scheme 2.
The reaction appears to proceed via a ring-opening step
leading to the zwitterion I, which by further arrangement
involving C–Cl bond breaking affords the epoxide II as
intermediate. Then, another molecule of 1a–c attacks the
epoxide carbon with ease to give the intermediate III.13
Finally, 5a–c can be formed by proton attacking the
alkoxide group of III. Protons and chloride anions are
provided by a fast and partial dissociation of 3a–c in wa-
ter. The reaction between II and 3a–c to give 5a–c is un-
likely since it is probably diffusion-controlled. Micellar
recognition studies are currently under investigation in
our laboratory.
In another set of experiments, the use of ethanol–water
mixtures was examined to find better reaction condi-
tions. The convenient effect of adding water to ethanol
is remarkable (entries 2, 3; 6, 7; 10, 11 in Tables 1 and 2).
A significant enhancement of the rate of production of the
mono-quaternary ammonium salts 4a–c was observed at
1
0
5
0 °C, but the yields of 5a–c did not improve enough be-
cause only a small increase took place by increasing the
water in the binary mixture (entries 2, 3; 6, 7; 10, 11 in
Table 1). Nevertheless, the rates of production of 5a–c
were significantly improved. In fact, in the ethanol–water
(
50:50) mixture the yield of 5a rises up to 91% in only 2.5
h, at 80 °C (entries 2, 3 in Table 2). Under these reaction
conditions, the results were also much better for com-
pounds 5b and 5c (entries 6, 7; 10, 11 in Table 2).
Encouraged by these results, we tried to increase the rate
of production of 5a–c still further, conducting the quater-
nization reaction directly in aqueous solution by taking
advantage of the ability of 3a–c to solubilize both 1a–c
1
1
and 2 in water. Upon varying the amine–epichlorohy-
drin–amine hydrochloride molar ratio within a wide
range, micellization occurred abruptly over a small con-
centration range, which was different for each system.
The amount of amine hydrochloride needed to be lower as
the alkyl chain length increased. Even though the solution
appeared homogeneous, the formation of cationic mi-
celles was detected by measuring the viscosity and con-
ductivity of the reaction mixture. It was found that the rate
of quaternization reaction was enhanced as expected, but
there was another remarkable finding. To our surprise, the
bis-quaternary ammonium salts 5a–c were formed in high
yields and good to excellent selectivity from the begin-
ning of the reaction, even at 50 °C (entries 4, 8 and 12 in
Tables 1 and 2). It should be noted that the desired prod-
ucts 5a–c could not be obtained in aqueous ethanol medi-
um at this temperature (entries 1–3, 5–7 and 9–11 in
Scheme 2
In summary, the bis-quaternary ammonium salt was di-
rectly obtained in good yield (greater than 86%) and ex-
cellent selectivity (greater than 97%), under micellar and
mild conditions. This synthetic approach is believed to be
cost-effective and facile on an industrial scale, offering an
alternative method for the synthesis of quaternary ammo-
nium gemini surfactants from long-chain alkyldimethy-
lamines and epichlorohydrin.
Table 1), in agreement with the fact of that micelles do not
form in solvents containing ethanol.12
The lack of an appreciable formation of mono-quaternary
ammonium salts suggests that the reaction mechanism
shown in Scheme 1 is unlikely for cationic micellar sys-
Table 1 Comparison of the Quaternization Reaction of Long-Chain Tri-alkylamines 1a–c with Epichlorohydrin 2 and the Corresponding
Amine Hydrochlorides 3a–c in Homogeneous and Micellar Media, at 50 °C
Entry
Amine
Solvent
EtOH:H O
Yield of Bis-quaternary Ammonium Salt
(%)a
Selectivity of Bis-quaternary Ammonium Salt Reaction
b
(%)
Medium
2
(
% v/v)
2.0 h
<1
1
4.0 h
<1
2
6.0 h
8.0 h
2.0 h
4.0 h
6.0 h
8.0 h
1
2
3
1a
100:0
80:20
50:50
1
3
5
2
7
9
2
1
2
2
2
4
5
2
7
9
homog.c
homog.c
homog.c
3
2
2
1.6
Synlett 2002, No. 11, 1811–1814 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Quaternary Ammonium Gemini Surfactants
1813
Table 1 Comparison of the Quaternization Reaction of Long-Chain Tri-alkylamines 1a–c with Epichlorohydrin 2 and the Corresponding
Amine Hydrochlorides 3a–c in Homogeneous and Micellar Media, at 50 °C (continued)
Entry
Amine
Solvent
EtOH:H O
Yield of Bis-quaternary Ammonium Salt
(%)a
Selectivity of Bis-quaternary Ammonium Salt Reaction
b
(%)
Medium
2
(
% v/v)
2.0 h
25
4.0 h
63
6.0 h
90
8.0 h
88
2.0 h
4.0 h
94
6.0 h
99
8.0 h
97
4
5
0:100
100:0
90
2
micellard
homog.e
1b
<1
<1
1
2
2
2
3
6
7
8
9
80:20
50:50
0:100
100:0
80:20
50:50
0:100
2
1
2
2
3
4
4
5
6
3
3
3
3
4
4
4
homog.e
homog.e
micellarf
homog.g
homog.g
homog.g
micellarh
22
1
40
1
53
1
87
<1
<1
<1
86
92
1
91
1
97
1
97
1
1c
1
1
1
0
1
2
1
<1
<1
56
<1
<1
81
4
2
<1
<1
100
<1
1
1
2
1
30
98
99
100
a
b
c
d
e
f
Quantitatively determined by combined techniques.9
Selectivity is defined as the percentage of the consumed epichlorohydrin that forms the bis-quaternary ammonium salt.
a:2:3a (2:1:1).
a:2:3a (2:1:3.1).
1
1
1
b:2:3b (2:1:1).
1
b:2:3b (2:1:1.5).
g
h
1
1
c:2:3c (2:1:1).
b:2:3b (2:1:1.3).
Table 2 Comparison of the Quaternization Reaction of Long-Chain Tri-alkylamines 1a–c with Epichlorohydrin 2 and the Corresponding
Amine Hydrochlorides 3a–c in Homogeneous and Micellar Media, at 80 °C
Entry
Amine
Solvent
Yield of Bis-quaternary Ammonium Salt
Selectivity of Bis-quaternary Ammonium Salt Reaction
EtOH:H O (%)a
(%)
b
Medium
2
(
% v/v)
2.0 h
10
16
76
89
19
34
51
76
6
4.0 h
31
47
91
90
61
71
84
86
18
42
74
85
6.0 h
54
76
92
89
82
91
89
89
41
74
85
85
8.0 h
84
87
92
90
92
91
91
90
76
89
89
87
2.0 h
4.0 h
38
50
96
99
63
78
89
95
22
43
73
99
6.0 h
64
78
96
98
83
93
93
94
44
83
92
97
8.0 h
93
90
96
99
95
93
97
97
83
96
96
99
1
2
3
4
5
6
7
8
9
1a
100:0
80:20
50:50
0:100
100:0
80:20
50:50
0:100
100:0
80:20
50:50
0:100
13
15
64
99
21
36
58
95
16
17
29
95
homog.c
homog.c
homog.c
micellard
homog.e
homog.e
homog.e
micellarf
homog.g
homog.g
homog.g
micellarh
1b
1c
1
1
1
0
1
2
12
32
64
a
b
c
Quantitatively determined by combined techniques.9
Selectivity is defined as the percentage of the consumed epichlorohydrin that forms the bis-quaternary ammonium salt.
d
e
f
g
h
1
a:2:3a (2:1:1). 1a:2:3a (2:1:3.1). 1b:2:3b (2:1:1). 1b:2:3b (2:1:1.5). 1c:2:3c (2:1:1). 1b:2:3b (2:1:1.3).
Synlett 2002, No. 11, 1811–1814 ISSN 0936-5214 © Thieme Stuttgart · New York

1
814
C. G. Ricci et al.
LETTER
HPLC was not successful due to the unacceptable
Acknowledgement
reproducibility. We overcame these difficulties by
We thank the Consejo Nacional de Investigaciones Científicas y
Técnicas (CONICET) and the Universidad Nacional del Litoral (U.
N. L.) of Argentina for financial support.
combining reversed-phase ion-pair HPLC using sodium p-
toluen-sulfonate as UV-absorbing ion-pair reagent, and UV
quantification of quaternary ammonium-bromophenol blue
complexes extracted with chloroform from a mixture of a
suitable aliquot of the reaction mixture in alkaline solution
References and Notes
(10% sodium carbonate) and bromophenol blue (0.001 N).
After comparison with standard mixtures, the experimental
error was found to be about 2–3%. (b) The HPLC method
was based on that of: Dowle, C. J.; Campbell, W. C. Analyst
(
1) Menger, F. M.; Keiper, J. S. Angew. Chem. Int. Ed. 2000, 39,
906.
2) (a) Menger, F. M.; Mbadugha, N. A. J. Am. Chem. Soc.
001, 123, 875. (b) Menger, F. M.; Keiper, J. S.; Mbadugha,
B. N. A.; Caran, K. L.; Romsted, L. S. Langmuir 2000, 16,
095. (c) Kim, T.-S.; Kida, T.; Nakatsuji, Y.; Hirao, T.;
1
(
1989, 114, 883. (c) The colorimetric determination method
2
was based on that of: van Steveninck, J.; Maas, M. In
Cationic Surfactants, Surfactant Science Series, Vol. 4;
Jungermann, E., Ed.; Marcel Dekker, Inc.: New York, 1970,
Chap. 13.
9
Ikeda, I. J. Am. Oil Chem. Soc. 1996, 73, 907. (d) De, S.;
Aswal, V. K.; Goyal, P. S.; Bhattacharya, S. J. Phys. Chem.
(
10) A typical procedure was as follows. A stirred solution of
N,N-dimethyloctylamine(1a) (1.26 g, 8 mmol) and N,N-
dimethyloctylamine hydrochloride (3a, 0.78g, 4 mmol) in of
ethanol–water (80:20, 5 mL) mixture was heated until
complete dissolution at 50 °C. The epichlorohydrin (2,
1
996, 100, 11664. (e) Hirata, H.; Hattori, N.; Ishida, M.;
Okabayashi, H.; Frusaka, M.; Zana, R. J. Phys. Chem. 1995,
9, 17778. (f) Danino, D.; Talmon, Y.; Zana, R. J. Colloid
9
Interface Sci. 1997, 185, 84. (g) Pisarcik, M.; Dubnickova,
M.; Devinsky, F.; Lacko, I.; Skvarla, J. Colloids and
Surfaces A: Physicochem. Eng. Aspects 1998, 143, 69.
3) (a) Rosen, M. J. CHEMTECH 1993, 23, 30. (b) Alami, E.;
Beinert, G.; Marie, P.; Zana, R. Langmuir 1993, 9, 1465.
0.37g, 4 mmol) was then added under vigorous agitation.
After being stirred for 8–10 hours, the reaction mixture was
immediately cooled and the solvent was removed under
vacuum at room temperature. The residue was washed with
acetone, and the quaternary ammonium salts were isolated
by recrystallization from acetone. It afforded the mono-
quaternary ammonium salt 4a (0.96 g, 84% isolated yield,
(
(
c) Beger, J.; Jacobi, R.; Sü mitt, U.; Müller, T.; Stöhr, A.;
Schmidt, V. Tenside Surf. Det. 1992, 29, 4, 271.
d) Devínsky, F.; Lacko, I.; Mlynarcik, D.; Racansky, V.;
(
Krasnec, L. Tenside Detergents 1985, 22, 10. (e) Devisnky,
F.; Lacko, I. Acta Fac. Pharm. Univ. Comenianae 1990, 44,
90% analytical yield). The bis-quaternary ammonium salt 5a
(
1.53 g, 87% isolated yield, 92% analytical yield), was
119. (f) Devisnky, F.; Masarova, L.; Lacko, I.; Mlynarcik,
obtained by performing the reaction with the same amount of
reagents and solvent, at 80 °C.
D. Collect. Czech. Chem. Commun. 1984, 49, 2819.
(
4) (a) Menger, F. M.; Littau, A. C. J. Am. Chem. Soc. 1991,
(
11) A typical procedure was as follows. A stirred solution of
N,N-dimethyloctylamine hydrochloride (3a, 2.36 g, 12.4
mmol) in water (5 mL) was heated until complete dissolution
at 50 °C. A mixture of N,N-dimethyloctylamine (1a, 1.26 g
113, 1451. (b) Merians, J. J. ISP Invenstments Inc. USA
Patent WO 93 07251-A1, 1993.
(
(
(
5) Kim, T.-S.; Hirao, T.; Ikeda, I. J. Am. Oil Chem. Soc. 1996,
7
3, 67.
6) (a) Login, R. B. United States Patent 4,734,277, 1988.
b) Login, R. B. United States Patent 4,812,263, 1989.
8
mmol) and epichlorohydrin (2, 0.37 g, 4 mmol) was then
added at once under vigorous agitation, with spontaneous
micellization. The solution was stirred for 6–8 hours. After
evaporation of the solvent under vacuum at room
temperature, the residue was washed with acetone and the
quaternary ammonium salts were isolated by
(
7) (a) Bunton, C. A.; Gillitt, N. D.; Mhala, M. M.; Moffat, J. R.;
Yatsimirsky, A. K. Langmuir 2000, 16, 8595. (b) Romsted,
L. S.; Bunton, C. A.; Yao, J. J. Curr. Opin. Colloid Interface
Sci. 1997, 2, 622. (c) Bunton, C. A. J. Mol. Liq. 1997, 72,
recrystallization from acetone. It afforded the bis-quaternary
ammonium salt 5a (1.48 g, 84% isolated yield, 88%
analytical yield), instead of the mono-quaternary ammonium
2
31. (d) Fendler, J. H.; Fendler, E. J. Catalysis in Micellar
and Macromolecular Systems; Academic Press: New York,
975. (e) Bunton, C. A. Catal. Rev. Sci. Eng. 1979, 20, 1.
8) Compounds 4a–c and 5a–c have been isolated in a pure
1
9
salt 4a, as described in ref. There was no problem to
(
(
1
13
separate the surfactants 5a–c from the excess of 3a–c
because these amine hydrochlorides are soluble in cold
acetone, while the bis-quaternary ammonium salts are
insoluble ones.
analytical form and their spectral data ( H NMR and
NMR) were consistent with the structure. Spectral data for
b and 5b are in full agreement with those previously
C
4
5
reported in ref. Isolated yields were slightly lower (6–8%)
than those obtained by the combined technique based on the
(
12) Hartley, G. S. Q. Rev. (London) 1948, 2, 152.
(13) McKelvey, J. B.; Benerito, R. R.; Ward, T. L. I and EC
Product Research and Development 1967, 6, 115.
9
combined HPLC and colorimetric methods described in ref.
9) (a) Simultaneous determination of mono- and bis-quaternary
salts 4a–c and 5a–c from crudes of reaction by ion-exchange
Synlett 2002, No. 11, 1811–1814 ISSN 0936-5214 © Thieme Stuttgart · New York