Microwave synthesis of quaternary ammonium salts

Article abstract of DOI:10.3390/molecules13092107

The microwave synthesis of several quaternary ammonium salts is described. The synthesis provides comparable or better yields than published methods with reduced reaction times and in the absence of solvent.

Full text of DOI:10.3390/molecules13092107

Molecules 2008, 13, 2107-2113; DOI: 10.3390/molecules13092107
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molecules
ISSN 1420-3049
www.mdpi.org/molecules
Article
Microwave Synthesis of Quaternary Ammonium Salts
Angela J. Winstead *, Nicole Fleming , Krystal Hart and Deveine Toney
Morgan State University, Department of Chemistry, 1700 E Cold Spring Lane, Baltimore, MD 21251,
U.S.A.
* Author to whom correspondence should be addressed; E-mail: angela.winstead@morgan.edu.
Received: 12 August 2008; in revised form: 27 August 2008 / Accepted: 1 September 2008 /
Published: 3 September 2008
Abstract: The microwave synthesis of several quaternary ammonium salts is described.
The synthesis provides comparable or better yields than published methods with reduced
reaction times and in the absence of solvent.
Keywords: Quaternary ammonium salts, Microwave synthesis, Heterocycles.
Introduction
Fluorescence spectroscopy has become a key technique for the detection and elucidation of
biological processes. In particular, cyanine dyes see widespread application as fluorescent probes.
They have been used in DNA sequencing, immunoassays, agarose gel and capillary electrophoresis
staining [1], DNA analysis in polymerization chain reactions [2, 3], in flow cytometry [4], or as
fluorescent probes for membrane fluidity [5, 6] and membrane potential studies [7]. However, common
problems associated with cyanine dyes include their tendency to undergo photobleaching [8], and self-
aggregation [9]. This has prompted the development of novel cyanine dyes with increased
photostability, Stokes’ shift, and quantum yield for use in bio-applications.
Cyanine dyes have traditionally been prepared from a condensation of an N-alkyl heterocyclic
quaternary ammonium salt and a bisimine or bisaldehyde (Scheme 1) [9]. N-Alkyl quaternary
ammonium salts are used extensively as precursors of near-IR spiropyrans [10] and various cyanine

Molecules 2008, 13
2108
dyes [11]. The salts are synthesized by refluxing reagents with solvents such as chloroform, o-
dichloro-benzene, acetonitrile and ethanol for 6 – 48h. One example requires refluxing in acetonitrile
for 24 h, then treatment with diethyl ether followed by filtration. The combined filtrates are
concentrated and refluxed for an additional 24 h, treated with diethyl ether and filtered [12]. This
process was repeated 1-3 times to achieve the published yields (25 – 78%). Another method heats the
reagents at 80οC for 21 h in an ampule tube sealed with a torch [10]. Purification of the salts range
from Soxhlet extraction with benzene for 24 h [13] to filtration with cold ether [12].
Scheme 1. General synthesis of heptamethine cyanine dyes.
Cl
Z
Cl
Z
Z
NHPh
PhN
N
N
X
N
R
R
X
R
Z = O, S, C(CH3)2
R = alkyl, Bn, (CH2)4SO3
A simple efficient microwave synthesis of N-alkyl quaternary ammonium salts has now been
developed. Reaction times are measured in minutes as opposed to hours and all of the experiments are
performed under solvent-free conditions.
Results and Discussion
The reaction of 2,3,3-trimethylindolenine with an array of alkyl halides with varied functionality
were studied. The reactions were performed by charging each microwave reaction vial with of 2,3,3-
trimethylindolenine and an alkyl halide (Scheme 2). Our previously published reaction of ethyl iodide
with 2,3,3-trimethylindolenine served as the model system [14]. The microwave reaction conditions
were determined using a single-mode microwave system. The temperature was monitored throughout
each reaction. The optimized reaction condition was 130οC, ramp time: 2:50 min, reaction time: 5:00
min giving a 95% yield.
The scope of the reaction was examined with the coupling of 2,3,3-trimethylindolenine and
benzothiazole with iodomethane, iodopropane, bromoethanol, and bromohexanoic acid. The hold time,
ramp time, and temperature for each electrophile was studied. The optimized reaction conditions are
presented in Table 1. In most cases, the yields were comparable or exceeded the published yields.
Most significant is the substantially decreased reaction time and simplicity of the reaction procedure.
The yields presented are the yields without resubjection of the filtrates.
Scheme 2. General synthesis of quaternary salts.
Z
Z
RX
M icrowave
N
N
X
R

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Table 1. Microwave synthesis of quaternary ammonium salt derivatives.
Lit.
Yield
(%)
59
Lit Time
(h)
Temp Time Yield
Entry
Z
R
(οC)
(min)
(%)
1
2
C(CH3)2
C(CH3)2
C(CH3)2
C(CH3)2
Et
Me
130
110
110
110
110
170
120
170
100
170
5:00
2:30
95
93
83
73
59
83
85
65
58
51
48 [13]
21 [11]
24 [15]
24 [16]
12 [15]
48 [13]
7 [17]
75
3
Pr
7:00
44
4
-(CH2)2OH
7:00
69
5
C(CH3)2 -(CH2)5CO2H
7:00
67
6
S
S
S
S
S
Et
Me
20:00
20:00
20:00
35:00
35:00
48
7
60
8
Pr
5
7 [17]
9
-(CH2)2OH
-(CH2)5CO2H
N/A
61
6 [18]
10
48 [19]
Work up and purification
Alkyl salts 1, 2, 3, 6, and 7 were simply filtered and washed with cold ether. The products were
pure by NMR analysis and no further purification was necessary. Salts 4, 5, 9 and 10, which all
contain hydroxyl groups, did not crystallize right away. The reaction solution containing 4 was
concentrated followed by the addition of hexanes. The solution was heated until crystals formed and
then filtered. Similarly, salt 5 was recrystallized from acetone. Reaction vials containing 9 and 10 were
allowed to sit at room temperature for 2-4 h, after which time crystals formed and could be filtered.
Conclusions
The single mode microwave system has provided substantially decreased reaction times, simplicity
of reaction procedure, and comparable or increased reaction yields observed for reactions conducted.
Experimental
General
All microwave reactions were conducted using the single-mode Biotage Initiator 2.0
1
(www.Biotage.com). H- and 13C-NMR spectra were obtained in DMSO-d6 using a Bruker Avance
400 MHz NMR and were recorded at 400 MHz and 100 MHz, respectively. All reagents and
chemicals were obtained from Aldrich Chemical Company (USA) and Alfa Aesar and were used as
received.
2,3,3-Trimethyl-1-ethyl-3H-indolium iodide (1): Iodoethane (1.76 mL, 0.0218 moles) and 2,3,3-
trimethylindolenine (0.76 mL, 0.0218 moles) were added to a reaction vial via syringe and heated at

Molecules 2008, 13
2110
130oC in the microwave system for 5 min and a ramp time of 4 min. The crystals were filtered and
1
washed with cold ether and dried under vacuum for a yield of 95%. H-NMR: δ 7.99-7.97 (m, 1H),
7.86-7.84 (m, 1H), 7.64-7.62 (m, 2H), 4.5 (q, J = 7.3 Hz, 2H), 2.8 (s, 3H), 1.5 (s, 6H), 1.4 (t, J = 7.3
13
Hz, 3H); C-NMR: δ 196.0 (C), 141.8 (C), 140.6 (C), 129.3 (CH), 128.8 (CH), 123.4 (CH), 115.2
(CH), 54.0 (C), 42.9 (CH2), 21.8 (CH3), 13.7 (CH3), 12.5 (CH3).
1,2,3,3-Tetramethyl-3H-indolium iodide (2): Iodomethane (0.44 mL, 0.00709 moles) and 2,3,3-
trimethylindolenine (0.22 mL, 0.00142 moles) were added to a reaction vial via syringe and heated at
110oC in the Explorer microwave system for 2:30 min and a ramp time of 2 min. Crystals were washed
1
with cold ether and dried under vacuum for a yield of 93%. H-NMR: δ 7.9-7.6 (m, 4H), 3.9 (s, 3H),
3.3 (s, 3H), 1.5 (s, 6H); 13C-NMR: δ 195.8 (C), 141.9 (CH), 141.4 (CH), 129.1 (CH), 128.6 (CH),
123.1 (CH), 115.0 (CH), 53.8 (CH3), 34.6 (CH2), 21.5 (C(CH3)2), 14.15 (CH3).
2,3,3-Trimethyl-1-propyl-3H-indolium iodide (3): Iodopropane (0.60 mL, 0.1639 moles) and 2,3,3-
trimethylindolenine (0.19 mL, 0.0329 moles) were added to a reaction vial via syringe and heated at
110oC in the microwave system for 5 min and a ramp time of 2 min. Crystals were washed with cold
1
ether and dried under vacuum for a yield of 83%. H-NMR: δ 8.01-7.9 (m, 1H), 7.86-7.84 (m, 1H),
7.64-7.62 (m, 2H), 4.44 (t, J = 7.3 Hz, 2H), 2.85 (s, 3H), 1.88 (m, 2H), 1.55 (s, 6H), 0.99 (t, J=7.4Hz,
13
3H); C-NMR: δ 196.5 (C), 141.8 (C), 141.0 (C), 129.4 (CH), 128.9 (CH), 123.5 (CH), 115.5 (CH),
54.1 (C), 48.8 (CH2), 22.0 (CH3), 20.7 (CH2), 14.0 (CH3), 10.7 (CH3).
1-(2-Hydroxyethyl)-2,3,3-trimethyl-3H-indolium bromide (4): 2-Bromoethanol (0.52 mL, 0.008 moles)
and 2,3,3-trimethylindolenine (0.60 mL, 0.004 moles) were added to a reaction vial via syringe and
heated at 110oC in the microwave system for 9 min and a ramp time of 4 min. The liquid was
concentrated using CH2Cl2. The residue was suspended in hexanes and heated, the solid scraped and
1
filtered, then re-crystallized in chloroform. Crystals were dried under vacuum for a yield of 73%. H-
NMR: δ 8.02-8.00 (m, 1H), 7.88-7.86 (m, 2H), 7.63-7.62 (m, 2H), 4.26 (t, J=5.0 Hz, 2H), 3.8 (t, J=5.0
Hz, 2H), 2.8 (s, 3H), 1.5 (s, 6H); 13C-NMR: δ 197.7 (C), 141.8 (C), 141.1 (C), 129.2 (CH), 128.7 (CH),
123.4 (CH), 115.6 (CH), 57.7 (CH2), 54.2 (C), 50.3 (CH2) 22.0 (CH3), 14.6 (CH3).
1-(5-Carboxypentyl)-2,3,3-trimethyl-3H-indolium bromide (5): 6-Bromohexanoic acid (0.67 g, 0.0034
moles) and 2,3,3-trimethylindolenine (0.54 mL, 0.0034 moles) were added to a reaction vial via
syringe and heated at 160oC for 1200 s and a ramp of 150 s in the Explorer microwave system.
Crystals were washed with acetone and dried under vacuum for a yield of 42%. 1H-NMR: δ 7.87-8.01
(m, 1H), 7.78-7.87 (m, 1H), 7.26-7.64 (m, 2H) 4.45 (t, J = 7.6 Hz, 2H), 2.87 (s, 3H), 2.24 (t, J = 7.2
13
Hz, 2H), 1.85-1.81 (m, 2H), 1.6-1.5 (m, 8H), 1.44 (m, 3H); C-NMR: δ 196.5 (C), 174.2 (C), 141.8
(C), 141.0 (C), 129.3 (CH), 128.9 (CH), 123.5 (CH), 115.4 (CH), 54.1 (C), 47.4 (CH2), 33.3 (CH2),
26.9 (CH2), 25.4 (CH2), 24.0 (CH2), 22.0 (CH3), 14.0 (CH3).
3-Ethyl-2-methylbenzothiazole iodide (6): Iodoethane (0.248 mL, 0.0031 moles) and 2-methylbenzo-
[d]thiazole (0.20 mL, 0.0015 moles) were added to a reaction vial via syringe and heated at 170 oC in
the 20 min and a ramp time of 4 min. The resulting white solid was washed with cold ether and dried

Molecules 2008, 13
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under vacuum for a yield of 83%. 1H-NMR: δ 8.0-7.9 (m, 1H), 7.87-7.84 (m, 1H), 7.65-7.63 (m, 1H),
13
4.51 (q, J = 7.3 Hz, 2H), 2.85 (s, 3H), 1.54 (s, 6H), 1.46 (t, J = 7.3 Hz, 3H); C-NMR: δ 176.7 (C),
140.4 (C), 129.3 (CH), 129.1 (C), 128.0 (CH), 124.7 (CH), 116.7 (CH), 44.8 (CH2), 17.1 (CH3), 13.3
(CH3).
2,3-Dimethylbenzothiazoleiodide (7): Iodomethane (0.37 mL, 0.006 moles) and 2-methylbenzo[d]-
o
thiazole (0.40 mL, 0.003 moles) were added to a reaction vial via syringe and heated at 120 C in the
microwave system for 20 min and a ramp time of 2 min. The white solid was washed with cold ether
1
and dried under vacuum for a yield of 85%. H-NMR: δ 7.9-7.6 (m, 4H), 3.9 (s, 3H), 3.3 (s, 3H), 1.5
(s, 6H); 13C-NMR: δ 176.23 (C), 140.60 (C), 128.27 (CH), 127.72 (C), 127.08 (CH), 123.55 (CH),
115.81 (CH), 35.39 (CH3), 16.36 (CH3).
3-Propyl-2-methylbenzothiazole iodide (8): Iodopropane (0.75 mL, 0.007 moles) and 2-methylbenzo-
[d]thiazole (0.20 mL, 0.0015 moles) were added to a reaction vial via syringe and heated at 170 oC in
the microwave system for 30 min and a ramp time of 4 min. The tan solid was washed with cold ether
and dried under vacuum. The product was recrystallized from acetonitrile to produce a white solid in
1
65% yield. H-NMR: δ 8.01-7.9 (m, 1H), 7.86-7.84 (m, 2H), 7.64-7.62 (m, 1H), 4.44 (t, J = 7.3 Hz,
2H), 2.85 (s, 3H), 1.88 (m, 2H), 1.55 (s, 6H), 0.99 (t, J=7.4Hz, 3H); 13C-NMR: δ 177.0 (C), 140.8 (C),
129.3 (CH), 129.0 (C), 128.0 (CH), 124.6 (CH), 116.9 (CH), 50.4 (CH2), 21.3 (CH2), 17.1 (CH3), 10.7
(CH3),
3-(2-Hydroxyethyl)-2-methylbenzothiazole bromide (9): 2-Bromoethanol (0.44 mL, 0.006 moles) and
2-methylbenzo[d]thiazole (0.4 mL, 0.003 moles) were added to a reaction vial via syringe and heated
at 100 oC in the microwave system for 35 min and a ramp time of 2 min. After 4 h, a light purple tinted
solid forms. The solid was recrystallized from acetonitrile and the white solid was dried under vacuum
for a 57% yield. 1H-NMR: δ 7.62-7.28 (m, 4H), 4.2 (q, J = 7.2 Hz, 2H), 3.0 (s, 3H), 1.2 (s, 6H), 1.1 (t,
13
J = 7.2 Hz, 3H); C-NMR: δ 178.0 (C), 141.0 (C), 129.1 (CH), 128.9 (C), 127.9 (CH), 124.5 (CH),
117.0 (CH), 58.5 (CH2), 51.9 (CH2), 17.3 (CH3).
3-(5-Carboxypentyl)-2-methylbenzothiazole bromide (10): 6-Bromohexanoic acid (2.9 g, 0.015 moles)
and 2-methylbenzo[d]thiazole (0.40 mL, 0.003 moles) were added to a reaction vial via syringe and
heated at 170oC for 35 min and a ramp of min in the microwave system. The solid was washed with
1
cold ether, recrystallized from acetonitrile, and dried under vacuum for a yield of 51%. H-NMR: δ
7.87-8.01 (m, 1H), 7.78-7.87 (m, 1H), 7.26-7.64 (m, 1H) 4.45 (t, J = 7.6 Hz, 2H), 2.87 (s, 3H), 2.24 (t,
13
J= 7.2 Hz, 2H), 1.85-1.81 (m, 2H), 1.6-1.5 (m, 8H), 1.44 (m, 3H); C-NMR: δ 177.0 (C), 174.2 (C),
140.8 (C), 129.3 (CH), 129.0 (CH), 128.0 (CH), 124.6 (CH), 116.8 (CH), 49.0 (CH), 33.4 (CH2), 27.4
(CH2), 25.4 (CH2), 24.0 (CH2), 16.8 (CH3).
Acknowledgements
This study was supported by the following grants: DOE ER63580 and NSF HRD-0627276.

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Sample Availability: Samples of compounds 1-10 are available from the authors
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