Novel ammonium ionic liquids as scavengers for aromatic and heterocyclic amines: Conversion into new pharmacological agents

Article abstract of DOI:10.1016/j.molliq.2016.09.042

The aim of our protocol is to develop new simple, economic and efficient scavengers for primary amines, due to their substantial adverse impacts on environment and human health. In this endeavor, we have designed, successfully synthesized and structurally characterized new salicylaldehyde-tri-ⁿbutylammonium ionic liquids which were investigated as scavengers for diverse aromatic and heterocyclic primary amines in the synthesis of new pharmacologically relevant candidates, imines scavenging product, via Schiff-base-scavenging reaction. The new scavengers exhibited good capture efficiency and can be easily regenerated and reused. The advantages of our scavengers over polymer-supported scavengers are the simplicity, shorter reaction time and real-time monitoring of a model reaction. The biocidal and antitumor activities of the scavenging products revealed a moderate to excellent broad-spectrum antibacterial efficacy, low activity or inactivity as fungicides and different levels of cytotoxicity (weak to excellent) against human breast carcinoma (MCF-7) cells.

Full text of DOI:10.1016/j.molliq.2016.09.042

Journal of Molecular Liquids 223 (2016) 1123–1132
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Novel ammonium ionic liquids as scavengers for aromatic and
heterocyclic amines: Conversion into new pharmacological agents
b
b
Reda F.M. Elshaarawy a, , Wafaa A. Mokbel , Emtithal A. El-Sawi
⁎
a
Faculty of Science, Suez University, Suez, Egypt
b
Department of Chemistry, Faculty of Women for Arts, Science and Education, Ain Shams University, Heliopolis, Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 August 2016
Received in revised form 14 September 2016
Accepted 15 September 2016
Available online 17 September 2016
The aim of our protocol is to develop new simple, economic and efficient scavengers for primary amines, due to
their substantial adverse impacts on environment and human health. In this endeavor, we have designed, suc-
cessfully synthesized and structurally characterized new salicylaldehyde-tri-nbutylammonium ionic liquids
which were investigated as scavengers for diverse aromatic and heterocyclic primary amines in the synthesis
of new pharmacologically relevant candidates, imines scavenging product, via Schiff-base-scavenging reaction.
The new scavengers exhibited good capture efficiency and can be easily regenerated and reused. The advantages
of our scavengers over polymer-supported scavengers are the simplicity, shorter reaction time and real-time
monitoring of a model reaction. The biocidal and antitumor activities of the scavenging products revealed a mod-
erate to excellent broad-spectrum antibacterial efficacy, low activity or inactivity as fungicides and different
levels of cytotoxicity (weak to excellent) against human breast carcinoma (MCF-7) cells.
Keywords:
Ammonium ionic liquids
Schiff bases
Scavengers
Antibacterial
Anticancer
© 2016 Elsevier B.V. All rights reserved.
1. Introduction
the polymer ratio. (ii) Carrying out the polymer-based scavenging
protocol in a biphasic system which diminishes the rate of scavenging
Aromatic and heterocyclic amines, notorious environmental pollut-
ants, are often released into the environment as industrial effluents
from epoxy and polyurethane polymers [1], textile, leather and dye-
stuffs, plastics, pesticides, photographic and pharmaceutical industries
[2] or as the breakdown products of herbicides [3]. Skin contact, inges-
tion and inhalation exposure to aromatic amines even at very low
doses is suspected to result in carcinogenicity [4]. Moreover, aromatic
amines become a source of serious social and hygienic problems as
notorious environmental pollutants [5]. Therefore, the scavenging of ar-
omatic amines from industrial effluents for both healthcare reasons and
reducing their emissions into the environment is a topic of great
concern.
Scavengers are designed materials that can effectively sweep or
quench particular undesirable substances or byproducts form the reac-
tion mixture and industrial effluents. Polymer-supported materials are
the most commonly used scavengers due to simplicity and ease of
their removing from scavenging area by simple filtration process to ob-
tain pure product, thus avoiding tedious chromatography purification
[6]. However, these traditional polymer-supported scavengers suffer
from several drawbacks, including; (i) using excessive amount of scav-
enger due to its lower functional groups (responsible for scavenging) to
process, due to imine formation on solid phase, as compared to that per-
formed in a monophasic system. (iii) Depletion excessive amount of a
suitable solvent as a scavenging medium to fulfill the swelling require-
ment of polymer-based scavengers. These obstacles limit the wide ap-
plications of traditional polymer-supported scavengers. Thus, various
alternatives such as PEG-anchored [7], silica-based [8], fluorous-phase
[9,10] and aqueous-phase [11] scavengers have been developed to re-
place them.
The unrivaled physicochemical features of ionic liquids (ILs) such as
low melting point (mp b 100 °C) which give them a wide liquid range,
negligible vapor pressure, nonflammability, excellent thermal and
chemical stability, wide electrochemical window, high dual solubility
in both polar and nonpolar solvents [12], have attracted the attention
of many analytical chemists. These peculiar properties endow ILs sever-
al analytical applications like separation process, MALDI-MS matrix,
quartz crystal microbalance sensors and designer solvent in liquid/liq-
uid extractions, purification processes, and synthetic organic chemistry
as well as electroanalysis [13]. Recently, amine- [14] and pH-sensing ap-
plications [15] of ILs-based architectures have been addressed.
However, to the best of our knowledge, scavengers based on
salicylaldehyde ionic liquids (Sal-ILs) with amine-dependent morpho-
logical response have not yet been reported.
In the last two decades, a great attention has been paid to the devel-
opment of new Schiff bases due to their facile synthesis, marvelous
structural and electronic features and they have been well documented
as smart materials for potential applications in many fields including
⁎
Corresponding author.
E-mail addresses: reda_elshaarawi@science.suez.edu.eg,
Reda.El-Shaarawy@uni-duesseldorf.de (R.F.M. Elshaarawy), elsawi_e@yahoo.com
(E.A. El-Sawi).
http://dx.doi.org/10.1016/j.molliq.2016.09.042
0167-7322/© 2016 Elsevier B.V. All rights reserved.

1124
R.F.M. Elshaarawy et al. / Journal of Molecular Liquids 223 (2016) 1123–1132
pharmaceutical [16], magnetism [17], luminescence [18], optical [19]
and catalysis [20]. Interestingly, based on our previous work, Schiff
bases bearing ionic liquids compartments exhibited significant antimi-
crobial [21], anticancer [21c,22] and antibiofouling [23] efficacies so
that they may offer promising pharmacological candidates. Moreover,
ionic o-aminothiophenol-based Schiff base demonstrated a remarkable
fluorescence sensing of Ca(II) ions [24].
Inspired by this literature survey, we aimed herein to investigate the
efficacy of new Sal-ILs probes (see Fig. 1) in hope that we develop new
promising simple and efficient amine scavengers smart materials. The
preference of our proposed salicylaldehyde ammonium ionic liquid-
based scavenger over other imidazolium and pyridinium ionic liquid-
functionalized scavengers stems also from an economic point of view,
as ammonium-based ionic liquids (AILs) are less expensive than
imidazolium and pyridinium ones. Furthermore, the dual function of
o-hydroxy group in: (i) Stabilization of imines scavenging products via
intramolecular hydrogen bonding, as a result of which enhancement
of scavenging efficacy. (ii) Promoting the hydrolysis of scavenging prod-
ucts under either acidic or basic conditions to regenerate the parent
scavenger, and thus ease of scavenger recovery.
mode for positive ions on UHR-QTOF maXis 4G (Bruker Daltonics) and
BRUKER Ultraflex MALDI-TOF instrument equipped with a 337 nm nitro-
gen laser pulsing at a repetition rate of 10 Hz. The 2+ charge assign-
ment of ions in ESI-MS was confirmed by the m/z = 0.5 difference
between the isotope peaks (x, x + 1, x + 2). Peaks with chlorine
showed the isotope ratio 35/37Cl = 75.8:24.2. For the mass spectral as-
signment: Peaks are based on 12C with 12.0000 Da, 35Cl with
34.968 Da. All instruments are available in the lab of Prof. Dr. Christoph
Janiak, Institut für Anorganische Chemie und Strukturchemie, Heinrich-
Heine Universität Düsseldorf.
2.3. Synthesis of 5-chloromethyl-3-chloro-2-hydroxybenzaldehyde
(CM(Cl)Sal, 1)
Compound 1 was synthesized from the corresponding ClSal accord-
ing to the modified chloromethylation procedure [21a]. It was isolated
as white needles (65% yield). FTIR (ATR, cm−1): 3240 (m, br, ν(O\\H)),
3120 (m, br, ν(C\\H)asym, Ar), 3050 (m, br, ν(C\\H)sym, Ar), 2876 (m, sh,
ν
(CH2)), 1659 (vs, sh, ν(C=O)), 1578, 1489, 1437 (s, sh, ν(C=CAr+ C-
Hbend)), 1252 (s, sh, ν(C\\Cl), CH2Cl), 1150 (s, sh, ν(HC=C), Ar), 770 (vs,
sh, ν(C\\Cl), Ar\\Cl). 1H NMR (200 MHz, CDCl3) δ (ppm): 11.07 (s, 1H)
9.90 (s, 1H), 7.65 (s, H), 7.38 (s, 1H), 4.63 (s, 2H). 13C NMR (126 MHz,
CDCl3) δ (ppm): 193.58, 161.32, 137.14, 134.26, 131.48, 129.47,
126.58 and 47.77.
2. Experimental
2.1. Materials
Chemicals were obtained from the following suppliers and used
without further purification: 3-chlorosalicylaldehyde (ClSal), tri-n-
butylamine (nBu3N), hexafluoro-phosphoric acid aqueous solution
~55 wt.% (HPF6) 3-methyl-2-aminopyridine (AP), 2-aminothiophenol
2.4. Synthesis of formyl-chloro-hydroxybenzyl)-tri-nbutylammonium ionic
liquids (ClSal-(nBu3N+X−), 2a,b)
A solution of CM(Cl)Sal (1) (4.01 g, 19.55 mmol) in dry toluene
(100 mL) was added dropwise by syringe pump to a vigorously stirred
solution of nBu3N (4.63 mL, 19.50 mmol) in dry toluene (25 mL) at
room temperature was over 30 min under nitrogen atmosphere. Then,
the resulting solution was stirred under nitrogen atmosphere at 60 °C
for 24 h. After cooling, the isolated product was washed intensively
with dry toluene (5 × 10 mL), several with ether (5 × 5 mL) to remove
the unreacted materials, and dried under vacuum to give 3-(3-formyl-
5-chloro-4-hydroxybenzyl)-tri-nbutylammonium chloride (2a) which
used for the following preparations without further purification. It was
obtained as a yellowish white solid, Yield (93%), mp: 66–67 °C. FTIR
(KBr, cm−1): 3421 (m, br, ν(O\\H)), 2850 (m, sh, ν(C\\H), aldehyde),
1678 (vs, sh, ν(C=O)), 1612, 1444, 1373 (s, sh, ν(C=CAr+ C-Hbend)), 1278
(s, sh, ν(Ar\\O)), 772 (vs, sh, ν(C\\Cl), Ar\\Cl). 1H NMR (200 MHz, DMSO-
d6) δ (ppm): 10.74 (s, 1H), 10.08 (s, 1H), 7.81 (s, 1H), 7.48 (s, 1H),
4.57 (s, 2H), 3.85 (t, J1 = J2 = 7.06 Hz, 6H), 1.98–1.87 (m(5), 6H),
1.51–1.38 (m(6), 6H), 1.07 (t, J1 = J2 = 6.8 Hz, 9H). 13C NMR
(125 MHz, DMSO-d6) δ (ppm): 194.56, 162.97, 140.21, 136.32, 131.68,
129.73, 127.24, 66.11, 59.48, 24.12, 20.34 and 14.06. Positive mode
ESI-MS: m/z calcd for C20H33Cl2NO2 (390.39), found 354.90, [M - Cl−
(ATP), p-toluidine (p-Tol), anthranilic acid (Anth) and
2 6-
diisopropylaniline (DIPA) (Sigma–Aldrich), paraformaldehyde
((CH2O)n) (Roth)) and anhydrous zinc chloride (ZnCl2) (GRÜSSING
GmbH).
2.2. Instrumentation
Melting points were measured using a BÜCHI Melting point B-540
apparatus; all melting points were measured in open glass capillaries
and are uncorrected. FT-IR spectra were recorded on a BRUKER Ten-
sor-37 FT-IR spectrophotometer in the range 400–4000 cm−1 as KBr
disc in the 4000–550 cm−1 region with 2 cm−1 resolution. For signal in-
tensities the following abbreviations were used: br (broad), sh (sharp),
w (weak), m (medium), s (strong), vs (very strong). NMR-spectra were
obtained with a Bruker Avance DRX200 (200 MHz for 1H) or Bruker
AvanceDRX500 (125, 202 and 470 MHz for 13C, 31P and 19F respectively)
spectrometer with calibration to the residual proton solvent signal in
DMSO-d6 (1H NMR: 2.52 ppm, 13C NMR: 39.5 ppm), CDCl3 (1H NMR:
7.26 ppm, 13C NMR: 77.16 ppm) against TMS (δ = 0.00 ppm) for 1
H
and 13C, 85% phosphoric acid (δ = 0.00 ppm) for 31P and CFCl3 (δ =
0.00 ppm) for 19F NMR. Multiplicities of the signals were specified as s
(singlet), d (doublet), t (triplet), q (quartet) or m (multiplet). The
mass spectra of the synthesized Sal-ILs were acquired in the linear
]
+a.m.u.
2.5. Anion metathesis: synthesis of 3-(3-formyl-5-chloro-4-
hydroxybenzyl)-tri-nbutylammonium hexafluorophosphates (2b)
An aqueous solution of HPF6 (~55 wt.%, 2.7 mL, 17.62 mmol) was
added portionwise to a solution of 2a (4.59 g, 11.75 mmol) in milli-Q
water (100 mL) with vigorous stirring, while the reaction mixture was
cooled in an ice-bath, over 1 h. After the HPF6 addition was completed,
the reaction mixture was stirred at room temperature for 24 h. Then, the
isolated solid product was filtered, washed with milli-Q water (to re-
move excess HPF6 solution and any water-soluble impurities) until
the washing effluent becomes neutral. The final product (2b) was
dried under vacuum at 40 °C for 24 h. 2b was obtained as a white
solid, Yield (90%), mp: 95–97 °C. FTIR (KBr, cm−1): 3427 (m, br,
ν
(O\\H)), 2850 (m, sh, ν(C\\H), aldehyde), 1656 (vs, sh, ν(C_O)), 1580,
1452, 1393 (s, sh, ν(C_CAr + C\\Hbend)), 1276 (s, sh, ν(Ar\\O)) 821 (vs, sh,
−
Fig. 1. Chlorosalicylaldehyde ionic liquids ClSal-(nBu3N+X−) (2a,b) used in this work.
ν(PF6 )str), 760 (vs, sh, ν(C\\Cl), Ar\\Cl), 556 (s, sh, δ(P\\F)). 1H NMR

R.F.M. Elshaarawy et al. / Journal of Molecular Liquids 223 (2016) 1123–1132
1125
(200 MHz, DMSO-d6) δ (ppm): 10.68 (s, 1H), 10.16 (s, 1H), 7.71 (s, 2H),
N,N,N-tri-nbutyl-N-(5-chloro-4-hydroxy-3-((p-tolylimino)methyl)-
benzyl)ammonium chloride (3d): Faint yellow needles from
methanol, Yield (85%), mp: 258 °C. FTIR (KBr, cm−1): 3450 (vs, br,
7.56 (m, 1H), 7.43 (d, J = 12.9 Hz, 1H), 4.37 (s, 2H), 3.86 (t, J1 = J2
=
7.02, 6H), 1.99–1.89 (m(5), 6H), 1.53–1.42 (m(6), 6H), 1.09 (t, J1
=
J2 = 6.8 Hz, 9H). 13C NMR (125 MHz, DMSO-d6) δ (ppm): 190.23,
166.20, 157.52, 138.91, 132.16, 130.03, 128.33, 126.87, 125.45, 66.78,
59.13, 24.23, 20.02 and 14.10. 31P NMR (202 MHz, DMSO-d6):
ν
ν
(O\\H)), 1621 (s, sh, ν(C_N), azomethine), 1478, 1443, 1398 (s, sh,
(C_CAr + C\\Hbend)), 1289 (s, sh, ν(Ar\\O)), 767 (vs, sh, ν(C\\Cl), Ar\\Cl).
1H NMR (300 MHz, DMSO-d6) δ (ppm): 13.08 (s, 1H), 10.65 (s, 1H),
7.69 (t, J = 7.6 Hz, 1H), 7.25 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.97–
6.94 (m, 2H), 4.57 (s, 2H), 3.83 (t, J1 = J2 = 7.00 Hz, 6H), 1.91–1.83
(m(5), 6H), 1.50–1.40 (m(6), 6H), 1.01 (t, J1 = J2 = 6.9 Hz, 9H). 13C
NMR (75 MHz, DMSO-d6) δ (ppm): 160.91, 158.08, 150.23, 144.84,
137.20, 133.31, 130.56, 129.92, 127.15, 124.06, 123.13, 122.65, 119.99,
65.25, 57.73, 23.99, 20.10 and 14.03. Positive mode ESI-MS: m/z calcd
for C27H40Cl2N2O (479.53), found 444.07, [M-Cl−]+a.m.u.
2
−159.41 to −117.34 ppm (septet, JPF = 711.17 Hz). 19F NMR
1
(470 MHz, DMSO-d6): −67.83 to −64.80 ppm (doublet, JPF
=
711.26 Hz). Positive mode ESI-MS: m/z calcd. for C20H33ClF6NO2P
(499.90), found 354.90, [M-PF−6 ]+a.m.u.
2.6. General procedure for scavenging of primary amine into ionic liquid-
supported imines (3a–l)
N-(3-((2-carboxy-5-chlorophenylimino)methyl)-4-hydroxybenzyl)-
N,N,N-tri-nbutylammon-ium chloride (3e): Yellowish orange powder
from ethanol, yield (71%), mp: 150–151 °C. FTIR (KBr, cm−1): 3434
(vs, br, ν(O\\H)), 1659 (s, sh, ν(C_O), carbonyl), 1625 (s, sh, ν(C_N),
azomethine), 1577, 1449, 1397 (s, sh, ν(C_CAr + C\\Hbend)), 1281 (s, sh,
Generally, a mixture of an ethanolic solution (30 mL) containing
(9 mmol) of target amine and (10 mmol) of 2a,b in the presence of cat-
alytic amount of 0.1% acetic acid (0.5 mL) (pH = 5.78, which in the rang
optimum pH for imine formation, 5.63–7.00 [25]) into a 100 mL round-
bottomed (RB) flask was stirred for 5 h at 60 °C (the reaction progress
was monitored by TLC). After completion of the reaction, the reaction
mixture was cooled to room temperature and then allowed to stand
for 30 min. Thereafter, the separated solid product was isolated by filtra-
tion, washed with ether (3 × 5 mL) and dried under vacuum. Samples of
the isolated solids were recrystallized from proper solvent and charac-
terized as follows;
ν
(Ar\\O)), 768 (vs, sh, ν(C\\Cl), Ar\\Cl). 1H NMR (300 MHz, DMSO-d6) δ
(ppm): 10.76 (s, 1H), 10.25 (s, 1H), 8.88 (s, 1H), 8.21–8.02 (m, 2H),
7.83 (dt, J = 24.8, 7.7 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.39 (s, 1H),
7.11 (s, 1H), 4.39 (s, 2H), 3.25 (t, J1 = J2 = 7.3 Hz, 6H), 1.80–1.69
(m(5), 6H), 1.39–1.27 (m(6), 6H), 0.92 (t, J1 = J2 = 7.1 Hz, 9H). 13C
NMR (75 MHz, DMSO-d6) δ (ppm): 191.02, 169.91, 159.92, 150.48,
135.26, 134.32, 133.65, 131.64, 131.09, 130.22, 128.72, 126.81, 122.12,
117.57, 67.13, 59.75, 24.98, 20.02 and 14.21. Positive mode ESI-MS: m/
z calcd for C27H38Cl2N2O3 (509.51), found 474.00, [M-Cl−]+a.m.u.
N-(3-((5-chloro-2,6-diisopropylphenylimino)methyl)-4-
N,N,N-tri-nbutyl-N-(5-chloro-4-hydroxy-3-((3-methylpyridin-2-
ylimino)methyl)benzyl)-ammonium chloride (3a): Yellow needles from
methanol, Yield (82%), mp: 158–160 °C. FTIR (KBr, cm−1): 3403 (vs,
br, ν(O\\H)), 1617 (s, sh, ν(C_N), azomethine), 1568, 1443, 1398 (s, sh,
hydroxybenzyl)-N,N,N-tri-nbutyl ammonium chloride (3f): Yellow crys-
tals from ethanol, Yield (69%), mp: 270–271 °C. FTIR (KBr, cm−1):
3426 (vs, br, ν(O\\H)), 1625 (s, sh, ν(C_N), azomethine), 1479, 1444,
ν(C_CAr + C\\Hbend)), 1277 (s, sh, ν(Ar\\O)), 763 (vs, sh, ν(C\\Cl), Ar\\Cl).
1H NMR (300 MHz, DMSO-d6) δ (ppm): 14.06 (s, 1H), 10.42 (s, 1H),
7.91 (s, br, 2H), 7.57 (s, 1H), 7.48 (s, 1H), 6.87–6.78 (m, 1H), 4.58 (s,
2H), 3.81 (t, J1 = J2 = 7.03 Hz, 6H), 1.87–1.79 (m(5), 6H), 1.49–1.38
(m(6), 6H), 0.98 (t, J1 = J2 = 7.0 Hz, 9H). 13C NMR (75 MHz, DMSO-
d6) δ (ppm): 162.39, 158.07, 153.55, 151.05, 146.62, 142.52, 140.65,
133.57, 130.87, 129.13, 126.92, 123.04, 114.15, 66.03, 59.13, 24.08,
19.99 and 14.11. Positive mode ESI-MS: m/z calcd for C26H39Cl2N3O
(480.51), found 445.00, [M - Cl−]+a.m.u.
1398 (s, sh, ν(C_CAr
ν
C\\Hbend)), 1290 (s, sh, ν(Ar\\O)), 768 (vs, sh,
+
(C\\Cl), Ar\\Cl). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 10.75 (s, 1H),
10.01 (s, 1H), 7.66 (t, J1 = J2 = 7.1 Hz, 1H), 7.51 (s, 1H), 7.21–7.11 (m,
2H), 7.00 (s, 1H), 4.44 (s, 2H), 3.31 (t, J1 = J2 = 7.2 Hz, 6H), 2.96–2.83
(m(7), 6H), 1.79–1.68 (m(5), 6H), 1.41–1.30 (m(6), 6H), 1.23 (d, J =
6.8 Hz, 6H), 0.93 (t, J1 = J2 = 6.9 Hz, 9H). 13C NMR (75 MHz, DMSO-
d6) δ (ppm): 161.78, 159.83, 148.94, 136.98, 133.51, 132.23, 130.54,
128.43, 126.56, 123.74, 122.52, 67.25, 59.81, 30.01, 24.55, 23.79, 19.68
and 14.03. Positive mode ESI-MS: m/z calcd for C32H50Cl2N2O
(549.66), found 514.20, [M-Cl−]+a.m.u.
N,N,N-tri-nbutyl-N-(5-chloro-4-hydroxy-3-((2-mercaptophenylimino)-
methyl)benzyl)-ammonium chloride (3b): Brown powder from methanol,
Yield (25%), mp: 188–189 °C. FTIR (KBr, cm−1): 3407 (vs, br, ν(O\\H)),
2610 (s, br, ν(S\\H)), 1611 (s, sh, ν(C_N), azomethine), 1476, 1443, 1397
N,N,N-tri-nbutyl-N-(5-chloro-4-hydroxy-3-((3-methylpyridin-2-
ylimino)methyl)benzyl)-ammonium hexafluorophosphate (3g): Light yel-
low needles from methanol, Yield (85%), mp: 112–114 °C. FTIR (KBr,
cm−1): 3412 (vs, br, ν(O\\H)), 1618 (s, sh, ν(C_N), azomethine), 1557,
1444, 1398 (s, sh, ν(C_CAr + C\\Hbend)), 1278 (s, sh, ν(Ar\\O)), 826 (vs, sh,
(s, sh, ν(C_CAr + C\\Hbend)), 1283 (s, sh, ν(Ar\\O)), 766 (vs, sh, ν(C\\Cl)
,
Ar\\Cl). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 12.96 (s, 1H), 10.41 (s,
1H), 7.58–7.35 (m, 2H), 7.27 (s, 1H), 7.15–6.96 (m, 2H), 6.74 (d, J =
7.6 Hz, 1H), 6.44 (d, J = 7.6 Hz, 1H), 5.45 (s, 2H), 4.07 (s, 1H), 3.88 (t,
J1 = J2 = 7.03 Hz, 6H), 1.90–1.80 (m(5), 6H), 1.51–1.39 (m(6), 6H), 1.05
(t, J1 = J2 = 7.0 Hz, 9H). 13C NMR (75 MHz, DMSO-d6) δ (ppm): 162.97,
161.65, 158.29, 145.59, 143.38, 139.03, 134.35, 131.07, 129.58, 126.63,
122.03, 121.13, 117.99, 65.98, 59.01, 24.24, 20.04 and 13.99. Positive
mode ESI-MS: m/z calcd. for C26H38Cl2N2OS (497.56), found 462.10, [M-
Cl−]+a.m.u.
−
ν(PF6 )str), 768 (vs, sh, ν(C\\Cl), Ar\\Cl), 558 (s, sh, δ(P\\F)). 1H NMR
(300 MHz, DMSO-d6) δ (ppm): 13.43 (s, 1H), 10.39 (s, 1H), 7.93 (s, br,
2H), 7.56 (s, 1H), 7.43 (s, 1H), 7.15–6.94 (m, 1H), 4.59 (s, 2H), 3.83 (t,
J1 = J2 = 7.1 Hz, 6H), 1.88–1.79 (m(5), 6H), 1.41–1.29 (m(6), 6H), 0.97
(t, J1 = J2 = 6.9 Hz, 9H). 13C NMR (75 MHz, DMSO-d6) δ (ppm):
161.89, 158.66, 153.56, 151.05, 145.92, 143.33, 140.65, 134.21, 131.12,
129.13, 125.23, 123.25, 117.13, 66.03, 59.28, 24.10, 19.76 and 13.98.
31P NMR (202 MHz, DMSO-d6): −159.42 to −117.35 ppm (septet,
2JPF = 711.14 Hz). 19F NMR (470 MHz, DMSO-d6): −67.79 to
−64.75 ppm (doublet, 1JPF = 711.22 Hz). Positive mode ESI-MS: m/z
calcd for C26H39ClF6N3OP (590.02), found 445.00, [M - PF−6 ]+a.m.u.
N,N,N-tri-nbutyl-N-(5-chloro-4-hydroxy-3-((2-
N-(3-((2-aminophenylthio)(hydroxy)methyl)-5-chloro-4-hydroxy-
benzyl)-N,N,N-triethyl-ammonium chloride (3c): Yellowish brown pow-
der from chloroform, Yield (71%), mp: 68–69 °C. FTIR (KBr, cm−1):
3476, 3433 (s, br, ν(NH2)), 3353 (s, br, ν(O\\H)), 1543, 1463, 1390 (s, sh,
ν(C_CAr + C\\Hbend)), 1279 (s, sh, ν(Ar\\O)), 765 (vs, sh, ν(C\\Cl), Ar\\Cl),
605 (m, sh, ν(C\\S)). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 10.21 (s,
1H), 7.24–6.93 (m, 2H), 6.73 (dd, J = 8.1, 1.3 Hz, 2H), 6.43 (ddd, J =
7.7, 7.1, 1.3 Hz, 2H), 6.28 (s, 2H), 5.65 (s, 1H), 4.04 (s, 1H), 3.76 (t,
J1 = J2 = 7.01 Hz, 6H), 1.83–1.73 (m(5), 6H), 1.40–1.38 (m(6), 6H),
0.98 (t, J1 = J2 = 6.9 Hz, 9H). 13C NMR (75 MHz, DMSO-d6) δ (ppm):
156.29, 149.19, 139.13, 132.28, 130.89, 129.45, 128.91, 128.13, 125.72,
119.78, 116.01, 114.74, 78.35, 68.03, 60.12, 23.93, 21.11 and 14.76. Pos-
itive mode ESI-MS: m/z calcd for C26H40Cl2N2O2S (515.58), found
480.10, [M - Cl−]+a.m.u.
mercaptophenylimino)methyl)benzyl)-ammonium hexafluorophosphate
(3h): Canary yellow powder from ethanol, Yield (25%), mp: 260–
261 °C. FTIR (KBr, cm−1): 3409 (vs, br, ν(O\\H)), 1618 (s, sh, ν(C_N),
azomethine), 1479, 1445, 1399 (s, sh, ν(C_CAr + C\\Hbend)), 1279 (s, sh,
−
ν
δ
(Ar\\O)), 823 (vs, sh, ν(PF6 )str), 761 (vs, sh, ν(C\\Cl), Ar\\Cl), 557 (s, sh,
(P\\F)). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 12.84 (s, 1H), 10.39 (s,
1H), 7.61–7.49 (m, 2H), 7.37 (s, 1H), 7.20 (s, 1H), 7.08 (d, J = 7.4 Hz,
1H), 6.93 (d, J = 7.1 Hz, 1H), 4.93 (s, 2H), 3.98 (s, 1H), 3.76 (t, J1
=

1126
R.F.M. Elshaarawy et al. / Journal of Molecular Liquids 223 (2016) 1123–1132
J2 = 7.1 Hz, 6H), 1.88–1.76 (m(5), 6H), 1.49–1.38 (m(6), 6H), 0.98 (t,
J1 = J2 = 7.0 Hz, 9H). 13C NMR (75 MHz, DMSO-d6) δ (ppm): 162.05,
160.21, 158.13, 145.48, 143.38, 139.00, 133.97, 131.07, 129.36, 128.10,
(t, J1 = J2 = 7.1 Hz, 1H), 7.56 (s, 1H), 7.28–7.18 (m, 2H), 7.01 (s, 1H),
4.45 (s, 2H), 3.33 (t, J1 = J2 = 7.2 Hz, 6H), 2.97–2.85 (m(7), 6H), 1.81–
1.72 (m(5), 6H), 1.41–1.30 (m(6), 6H), 1.25 (d, J = 7.0 Hz, 6H), 0.96 (t,
J1 = J2 = 6.9 Hz, 9H). 13C NMR (75 MHz, DMSO-d6) δ (ppm): 161.34,
159.84, 149.11, 136.98, 134.21, 132.22, 130.89, 129.55, 125.98, 123.75,
123.31, 121.13, 118.12, 66.78, 59.49, 24.24, 19.91 and 12.14. 31P NMR
2
(202 MHz, DMSO-d6): −159.39 to −117.33 ppm (septet, JPF
=
711.16 Hz). 19F NMR (470 MHz, DMSO-d6): −67.81 to −64.79 ppm
(doublet, JPF = 711.25 Hz). Positive mode ESI-MS: m/z calcd for
122.31, 67.27, 59.81, 29.89, 24.54, 23.79, 19.67 and 13.99. 31P NMR
1
2
(202 MHz, DMSO-d6): −159.39 to −117.32 ppm (septet, JPF
=
C26H38ClF6N2OPS (507.07), found 462.10, [M-PF−6 ]+a.m.u.
711.16 Hz). 19F NMR (470 MHz, DMSO-d6): −67.82 to −64.79 ppm
(doublet, JPF = 711.25 Hz). Positive mode ESI-MS: m/z calcd for
1
N-(3-((2-aminophenylthio)(hydroxy)methyl)-5-chloro-4-
hydroxybenzyl)-N,N,N-triethyl ammonium hexafluorophosphate (3i)):
Orange powder from chloroform, Yield (74.00%), mp: 89–91 °C. FTIR
(KBr, cm−1): 3432, 3377 (s, br, ν(NH2)), 3298 (s, br, ν(O\\H)), 1471,
C32H51F6N2OP (659.17), found 514.20, [M-PF−6 ]+a.m.u.
2.7. General procedure for regeneration of Sal-(nBu3N+ X−) (2a,b)
scavengers
1443 (s, sh, ν(C_CAr
C\\Hbend)), 1280 (s, sh, ν(Ar\\O)), 829 (vs, sh,
+
−
ν(PF6 )str), 765 (vs, sh, ν(C\\Cl), Ar\\Cl), 615 (m, sh, ν(C\\S)), 556 (s, sh,
(P\\F)). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 10.36 (s, 1H), 7.42 (s,
1H), 7.31 (m, 1H), 7.23 (s, 1H), 7.14–7.01 (m, 2H), 6.83 (dd, J = 8.3,
1.4 Hz, 2H), 6.29 (s, br, 2H), 5.68 (s, 1H), 3.99 (s, 1H), 3.76 (t, J1
δ
2 N HCl (3.0 mL) was added to the ionic liquid-supported imines
(3a–l) (100 mg) and the mixture was stirred vigorously for 4 h. While
the reaction progressed, the color of the imine scavenging products so-
lution was changed to yellowish or colorless. After a completion of the
reaction, the reaction mixture was neutralized with NaHCO3 and the
isolated scavenger was extracted with DCM (3 × 3.0 mL). The organic
layer was dried with sodium sulfate and evaporated and extracted
with a hexane/ethyl acetate mixture (1:1, v/v) to remove amine deriva-
tive. After removal of amino component, the residue was dried under
reduced pressure to yield the chlorosalicylaldehyde-functionalized am-
monium ionic liquids Sal-(nBu3N+ X−) (2a,b) in a yield of the range
(70–95%).
=
J2 = 7.10 Hz, 6H), 1.85–1.73 (m(5), 6H), 1.41–1.30 (m(6), 6H), 1.11 (t,
J1 = J2 = 7.2 Hz, 9H). 13C NMR (75 MHz, DMSO-d6) δ (ppm): 157.21,
149.48, 140.17, 133.03, 130.29, 129.15, 128.45, 127.82, 125.76, 120.12,
116.31, 115.10, 77.89, 68.43, 59.49, 24.20, 19.91 and 12.14. 31P NMR
2
(202 MHz, DMSO-d6): −159.38 to −117.33 ppm (septet, JPF
=
711.16 Hz). 19F NMR (470 MHz, DMSO-d6): −67.83 to −64.81 ppm
(doublet, JPF = 711.24 Hz). Positive mode ESI-MS: m/z calcd for
1
C26H40ClF6N2O2PS (625.09), found 480.10, [M – PF−6 ]+a.m.u.
N,N,N-tri-nbutyl-N-(5-chloro-4-hydroxy-3-((p-
tolylimino)methyl)benzyl)ammonium hexa-fluorophosphate (3j): Pale
yellow powder from methanol, Yield (93%), mp: 270–271 °C. FTIR
(KBr, cm−1): 3449 (vs, br, ν(O\\H)), 1623 (s, sh, ν(C_N), azomethine),
1477, 1448, 1399 (s, sh, ν(C_CAr + C\\Hbend)), 1287 (s, sh, ν(Ar\\O)), 829
2.8. Antimicrobial assays
2.8.1. Reagents
−
(vs, sh, ν(PF6 )str), 767 (vs, sh, ν(C\\Cl), Ar\\Cl), 560 (s, sh, δ(P\\F)). 1H
Dimethylsulphoxide (DMSO), ampicillin antibiotic (C16H19N3O4S,
349.41 g mol−1) and amphotericin B (C47H73NO17, 923.49 g mol−1), an-
tifungal drug, were obtained from Sigma Chemical Co. (St. Louis, MO,
USA).
NMR (300 MHz, DMSO-d6) δ (ppm): 12.86 (s, 1H), 10.51 (s, 1H), 7.69
(s, 1H), 7.34 (s, 1H), 7.15 (d, J = 8.1 Hz, 2H), 7.08–6.97 (m, 2H), 4.56
(s, 2H), 3.85 (t, J1 = J2 = 7.00 Hz, 6H), 1.89–1.77 (m(5), 6H), 1.49–1.37
(m(6), 6H), 1.00 (t, J1 = J2 = 7.1 Hz, 9H). 13C NMR (75 MHz, DMSO-
d6) δ (ppm): 161.11, 158.23, 150.73, 145.21, 136.99, 133.42, 131.03,
129.93, 124.15, 122.91, 122.35, 120.03, 66.10, 57.75, 23.86, 19.90 and
14.01. 31P NMR (202 MHz, DMSO-d6): −159.39 to −117.32 ppm (sep-
2.8.2. Microbial cultures
Strains used in this study were provided by the National Organiza-
tion for Drug Control and Research (NODCAR), Cairo, Egypt. The tested
strains are Staphylococcus aureus (S. aureus, ATCC-25923 as a represen-
tative Gram-positive bacterial strain, Escherichia coli (E. coli, ATCC-
25922) as the most important Gram-negative pathogenic bacterium as
well antifungal species, Aspergillus flavus (A. flavus) and Candida albicans
(C. albicans, NCIM No. 3100). Stock cultures were grown aerobically on
nutrient broth (NB) agar slants (Hi-Media) at 37 °C and then main-
tained at 4 °C. Pre-cultures containing 105 CFU/mL (CFU = colony
forming units), grown aerobically in Mueller Hinton (MH) liquid medi-
um (Hi-Media) at 37 °C for 5 h, were used as inoculum for all
experiments.
2
tet, JPF = 711.15 Hz). 19F NMR (470 MHz, DMSO-d6): −67.83 to
−64.81 ppm (doublet, 1JPF = 711.25 Hz). Positive mode ESI-MS: m/z
calcd for C27H40ClF6N2OP (589.04), found 444.07, [M-PF−6 ]+a.m.u.
N-(3-((2-carboxy-5-chloro-phenylimino)methyl)-4-hydroxybenzyl)-
N,N,N-tri-nbutylamm-onium hexafluorophosphate (3k): Brownish pow-
der from methanol, Yield (81%), mp: 168–169 °C. FTIR (KBr, cm−1):
3436 (vs, br, ν(O\\H)), 1660 (s, sh, ν(C_O), carbonyl), 1625 (s, sh, ν(C_N),
azomethine), 1579, 1446, 1398 (s, sh, ν(C_CAr + C\\Hbend)), 1283 (s, sh,
−
ν
δ
(Ar\\O)), 825 (vs, sh, ν(PF6 )str), 771 (vs, sh, ν(C\\Cl), Ar\\Cl), 555 (s, sh,
(P\\F)). 1H NMR (300 MHz, DMSO-d6) δ (ppm): 11.34 (s, 1H), 10.29 (s,
1H), 8.88 (s, 1H), 8.25–8.13 (m, 2H), 7.81 (d, J = 7.7 Hz, 1H), 7.73–
7.63 (m, 1H), 7.55 (s, 1H), 7.25 (s, 1H), 7.11 (d, J = 8.1 Hz, 1H), 4.43
(s, 2H), 3.26 (t, J1 = J2 = 7.1 Hz, 6H), 1.80–1.69 (m(5), 6H), 1.40–1.28
(m(6), 6H), 0.96 (t, J1 = J2 = 7.0 Hz, 9H). 13C NMR (75 MHz, DMSO-
d6) δ (ppm): 190.68, 169.13, 159.90, 149.97, 135.26, 134.32, 132.89,
131.63, 131.09, 129.88, 126.74, 123.42, 119.57, 117.58 67.09, 59.77,
24.81, 20.22 and 14.23. 31P NMR (202 MHz, DMSO-d6): −159.41 to
−117.34 ppm (septet, 2JPF = 711.17 Hz). 19F NMR (470 MHz, DMSO-
2.8.3. Antimicrobial susceptibility
Antimicrobial susceptibility of the microbial strains was carried out
by agar well diffusion method [24] for the target compounds as well
as standard drugs, ampicillin and amphotericin B. The diameter of the
zone of inhibition (ZOI, mm) was measured accurately as indicative of
antimicrobial activity.
1
d6): −67.83 to −64.80 ppm (doublet, JPF = 711.26 Hz). Positive
2.8.4. Determination of MIC90
mode ESI-MS: m/z calcd for C27H38ClF6N2O3P (619.02), found 474.00,
As parameters of the antibacterial efficacy, the minimum inhibitory
concentration of the target compounds which inhibit the growth of
90% of tested microorganisms as compared to a control, MIC90, was de-
termined against infection isolates using the macro-dilution broth sus-
ceptibility test. Stationary–phases for tested microbial species were
prepared at 37 °C and used to inoculate fresh 5.0 mL of bacterial cultures
to an OD600 of 0.05. These 5.0 mL cultures were then incubated at 37 °C
until an OD600 of 0.10 was achieved from which standardized bacterial
suspensions were prepared with a final cell density of 6 × 105 CFU/mL.
[M-PF−6 ]+a.m.u.
N-(3-((2,6-diisopropylphenylimino)methyl)-5-chloro-4-
hydroxybenzyl)-N,N,N-tri-nbutyl ammonium hexafluorophosphate (3l):
Yellow crystals from methanol, Yield (77%), mp: 280–282 °C. FTIR
(KBr, cm−1): 3425 (vs, br, ν(O\\H)), 1623 (s, sh, ν(C_N), azomethine),
1479, 1446, 1397 (s, sh, ν(C_CAr + C\\Hbend)), 1286 (s, sh, ν(Ar\\O)), 823
−
(vs, sh, ν(PF6 )str), 769 (vs, sh, ν(C\\Cl), Ar\\Cl), 557 (s, sh, δ(P\\F)). 1H
NMR (300 MHz, DMSO-d6) δ (ppm): 10.83 (s, 1H), 10.19 (s, 1H), 7.71

R.F.M. Elshaarawy et al. / Journal of Molecular Liquids 223 (2016) 1123–1132
1127
Different concentrations from the tested samples (0–320 mg/mL) were
prepared and mixed with 5.0 mL of the standardized bacterial suspen-
sion then added to the plates and incubated for 24 h at 37 °C. The CFU
were counted for each dilution and compared to the growth of untreat-
ed controls.
pipette. The micro-titer plates were incubated at 37 °C in a humidified
incubator with 5% CO2 for 48 h. Three wells were used for each sample
concentration. A control of untreated cells was cultured in absence of
tested sample. A positive control containing doxrubcine® drug was
used for comparison. An infinitesimal amount of DMSO exist in the
wells (maximal 0.1%) has no significant effect on the experiment.
After incubation of the cells for 24 h at 37 °C, various concentrations
(5–50 μg/mL) of sample were added, and the incubation was continued
for further 48 h then the viable cells yield was determined by a colori-
metric method. After the end of the incubation period, media were aspi-
rated and the crystal violet solution (1%) was added to each well for at
least 30 min. The stain was removed and the plates were rinsed using
tap water until all excess stain was removed. Glacial acetic acid (30%)
was then added to all wells and mixed thoroughly, and then the absor-
bance of the plates were measured after gently shaken on Micro plate
reader (TECAN, Inc.), using a wavelength of 490 nm. All results were
corrected for background absorbance detected in wells without stain.
All experiments were carried out in triplicate and the average values
were calculated. The number of viable cells was determined using
ELISA reader as previously mentioned before and the percentage of via-
bility was calculated as {(1 − (ODt / ODc)) × 100} where ODt is the
mean optical density of wells treated with the tested sample and ODc
is the mean optical density of untreated cells [26]. The 50% inhibitory
concentration (IC50), the concentration required to cause toxic effect
in 50% of intact cells, was estimated from graphic plots.
2.9. In vitro anticancer (antitumor) activity
2.9.1. Reagents
Dimethylsulphoxide (DMSO), crystal violet and trypan blue dye
were purchased from Sigma Chemical Co. (St. Louis, Mo, USA).
Dulbecco's modified Eagle's medium (DMEM), Roswell Park Memorial
Institute medium (RPMI-1640), fetal bovine serum (FBS), 4-(2-
hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES) buffer solu-
tion, L-glutamine, gentamycin and 0.25% trypsin–EDTA were obtained
from Lonza.
Crystal violet stain was prepared as 0.5% crystal violet solution by
dissolving 0.5 g of crystal violet stain in 50 mL methanol, then the solu-
tion was completed to 100 mL with deionized water, filtered through
Whatmann No.1 and stored at room temperature.
2.9.2. Cell cultures
Human tumor cell lines, MCF-7 (breast adenocarcinoma) was ob-
tained from the VACSERA Tissue Culture Unit and cultured in either
RPMI-1640 or DMEM media supplemented with 10% heat-inactivated
FBS, 1% L-glutamine, HEPES buffer and 50 μg/mL gentamycin. All cells
were maintained at 37 °C in a humidified atmosphere with 5% CO2
and sub-cultured two times a week. Cell toxicity was monitored by de-
termining the effect of the tested samples on cell morphology and cell
viability. The effect of the vehicle solvent (DMSO) on the growth of
these cell lines was evaluated in all the experiments by exposing un-
treated control cells to the maximum concentration (0.5%) of DMSO
used in each assay.
3. Results and discussion
3.1. Synthesis protocol
A stepwise synthetic route for fabrication of chlorosalicylaldehyde-
functionalized ammonium ionic liquids (ClSal-(nBu3N+X−), 2a,b) is
depicted in Scheme 1. This synthetic route began with chloromethylation
of ClSal, an inexpensive material, with paraformaldehyde/HClaq as co-
chloromethylating agent in the presence of catalytic amount of ZnCl2
under HClg stream to give CM(Cl)Sal (1) in excellent yield. Thereafter,
quaternization of tri-nbutylamine (nBu3N) using CM(Cl)Sal (1) as
quaternizing agent afford the desired (ClSal-(nBu3N+Cl−), 2a) which
subsequently underwent anion metathesis with HPF6(aq) to yield the cor-
responding hexafluorophosphate salt (ClSal-(nBu3N+PF6−), (2b). Note-
worthy that ClSal-(nBu3N+Cl−) (2a) is hydrophilic and soluble in water
and wide range of polar organic solvents (such as MeOH, EtOH, CHCl3,
… etc.) while (ClSal-(nBu3N+PF6−), (2b) is hydrophobic and insoluble in
water and EtOH but soluble in MeOH.
2.9.3. Antitumor assay
The in vitro antitumor activity of the most potent biocidal scaveng-
ing products was evaluated according to the procedure adopted by the
Regional Center for Mycology & Biotechnology, Egypt. Briefly, MCF-7
cells were seeded in 96-well cell-culture plate at a cell concentration
of (1 × 104) cells per well in 100 μL of growth medium. Fresh medium
containing different concentrations of the tested sample was added
after 24 h of seeding. Serial two-fold dilutions of the tested compound
were added to confluent cell mono layers dispensed into 96-well, flat-
bottomed microtiter plates (Falcon, NJ, USA) using a multichannel
Scheme 1. Schematic diagram for the synthesis of chlorosalicylaldehyde-functionalized ammonium ionic liquids (ClSal-(nBu3N+X−), 2a,b).

1128
R.F.M. Elshaarawy et al. / Journal of Molecular Liquids 223 (2016) 1123–1132
Scheme 2. Capture of aromatic and heterocyclic amines by 2a,b.
The structures of ClSal-(nBu3N+ X−) (2a,b) were proposed based
Schiff-base-scavenging reaction of five different aromatic and heterocy-
clic amines by scavengers (2a,b) to yield the corresponding scavenging
products, ionic liquid-supported imines (3a–l), was depicted in Scheme
2. Interestingly that the reaction between 2-aminothiophenol (ATP)
and scavengers (2a,b), under the scavenging conditions, has been
found to yield not only the expected imines (3b,h) as scavenging prod-
ucts but also hemimercaptals (3c,i) as co-scavenging products. These
scavenging products were dismissed from the homogeneous solution
as ethanol-insoluble products which removed by filtration. Thus, simple
filtration and washing with appropriate solvents is the stepwise proto-
col followed to remove imine scavenging products.
Changes in the physicochemical properties of the scavenging prod-
ucts in comparison to reaction entries (such as color, solubility and
melting points; check experimental section) coupled with the structural
characterization of these products based on spectral analysis (FTIR, 1H
NMR and 13C NMR) give very strong evidences for the successful
Schiff-base-scavenging strategy.
upon spectral analysis (FTIR, NMR (1H, 13C, 19F, 31P) and ESI-MS).
3.2. Characterizations of ClSal-(nBu3N+X−) (2a,b)
The collected spectral data reveals a success of our protocol in
achieving the synthesis of new ClSal-functionalized ammonium ionic
liquids ClSal-(nBu3N+X−) (2a,b). Where the FTIR spectroscopic signa-
tures of ClSal-(nBu3N+X−) (2a,b) highlighted the following markers;
(i) an intense broad absorption band with a maxima at the range of
3424 7 cm−1 is characteristic for the stretching vibration of phenolic
hydroxyl (Ar-OH) involved into an intramolecular hydrogen bonding.
(ii) An extremely sharp band around 1667 cm−1 coupled with a medi-
um peak around 2850 cm−1 are assignable to the carbonyl (C_O) and
aldehydic proton stretching vibrations of salicylaldehyde fragment. (iii)
A set of versatile peaks around 3000, 2980 cm−1, due to aliphatic chain;
950, 750 cm−1 which are characteristic for antisymmetric and symmet-
ric vibration of quaternary nitrogen (R4N+) coupled with PF6− vibration
bands noticed at 821 and 556 cm−1 are typical for tri-nbutylammonium
ionic liquid terminals.
FTIR spectra of all scavenging products (3a–l) evinced; demise of
two stretches around 3300 and 3400 cm−1, characteristic for NH2
stretching modes, and the aldehyde carbonyl stretch in ClSal-
(nBu3N+X−) (2a,b) at the range of 1678 11 cm−1 along with the emer-
1H/13C NMR spectra of Sal-nBu3N+X− (2a,b) are dominated by com-
mon spectral peculiarities represented in; (i) The two low-field singlets,
around 10.70 and 10.16 ppm, are attributable to an intramolecular hy-
drogen-bonded phenolic proton (this further confirmed by notice of a
maxima of (C\\O)phenol resonance peak in 13C NMR at ca. 160 ppm)
and the aldehydic proton (which in agreement with observation of
13C NMR carbonyl peak at ~190 ppm). (ii) A set of peaks at the ranges
of δ 7.81–7.02 and δ 3.86–1.00 ppm are originating from the resonances
of aromatic and nbutyl protons, respectively, which confirm the success-
ful quaternization of nBu3N with CM(Cl)Sal. (iii) 31P/19F NMR spectra of
ClSal-(nBu3N+ PF−6 ) (2b) provide an evidence for the success of chloride
metathesis with hexafluorophosphate as revealed from a septet cen-
tered at −142.28 ppm (2JPF = 711.17 Hz) and doublet centered at
−66.32 ppm (1JPF = 711.26 Hz) those observed in its 31P and 19F
NMR spectra, respectively.
gence of two new peaks at the range of 1618
7 cm−1 and 1283
7 cm−1 assignable to the stretching vibrations of azomethine (HC_N)
and aryl-oxygen (Ar\\O), respectively, belonging to salicylidene core
[21]. These FTIR spectral data provide a significant preliminary evidence
for a successful Schiff-base-scavenging process and formation of ionic liq-
uid-functionalized imines as scavenging products. Moreover, FTIR
3.3. Primary amines scavenging with ClSal-(nBu3N+X−) (2a,b) scavengers
The primary amine scavenging efficiency of newly synthesized
chlorosalicylaldehyde-tri-nbutylammonium ionic liquids (2a,b) was in-
vestigated by reacting them, initially, with p-toluidine under different
conditions for determination of the optimum scavenging conditions.
Only 58% and 63% of p-toluidine was captured from its ethanolic solu-
tion by 2a and 2b, respectively, under reflux conditions for 6 h. Whilst,
an addition of a catalytic amount of acetic acid to the reaction mixture
provides synergistic effects that dramatically increases the p-toluidine
scavenging efficiency of 2a and 2b up to 85% and 93%, respectively,
and accelerates the scavenging process even at ambient temperature.
Fig. 2. FTIR segment for comparison of the stretching vibrations and splitting patterns of
ATP-based scavenging products (3b,c) with scavengers (2a).

R.F.M. Elshaarawy et al. / Journal of Molecular Liquids 223 (2016) 1123–1132
1129
Table 1
Scavenging of primary amines into ionic liquid-based imines.
Entry Sal-(nBu3N+X−
)
Ar/Het (abbrev.)
Imines
Conversion %
82
1
2
3
4
5
6
7
8
9
Sal-(nBu3N+Cl−) (2a) 3-CH3C5H3N (AP)
Sal-(nBu3N+Cl−) (2a) 2-HSC6H4(ATP)
Sal-(nBu3N+Cl−) (2a) 4-CH3C6H4 (p-Tol)
Sal-(nBu3N+Cl−) (2a) 2-COOHC6H4 (Anth)
3a
(3b + c)a 95
3d
3e
85 (58)b
71
69
85
Sal-(nBu3N+Cl−) (2a) 2,6-(isoPr)2C6H3 (DIPA) 3f
Sal-(nBu3N+PF6−) (2b) 3-CH3C5H3N (AP)
Sal-(nBu3N+PF6−) (2b) 2-HSC6H4 (ATP)
Sal-(nBu3N+PF6−) (2b) 2-CH3C6H4 (o-Tol)
Sal-(nBu3N+PF−6 ) (2b) 2-COOHC6H4 (Anth)
3 g
(3 h + i)a 99
3j
3 k
93 (63)b
81
77
10
Sal-(nBu3N+PF−6 ) (2b) 2,6-(isoPr)2C6H3 (DIPA) 3 l
a
Co-scavenging products, imines and hemimercaptals.
Isolated yield in the absence of acetic acid.
b
spectroscopic markers (Fig. 2) may provide a powerful tool for validation
of mixed-scavenging products in the case of capture of 2-
aminothiophenol with scavengers (2a,b). Whereas, notice of an intense
sharp stretches around 2610 and 1623 cm−1, in the FTIR spectra of
3b,h, attributable to the stretching vibrations of azomethine (HC_N)
and aryl-thiol (Ar\\SH) moieties, respectively, confirms the formation
of imines (3b,h), as aminothiophenol scavenging product, via Schiff-
base-scavenging reaction. On the other hand, observation of two strong
peaks around 3400 cm−1, characteristic for NH2 stretching vibrations,
coupled with the absence of vibration bands assignable to HC_N and
Ar\\SH fragments proves the formation of hemimercaptals (3c,i)), as
aminothiophenol co-scavenging product, through nucleophilic-addition-
scavenging pathway.
Further evidences confirm successful anchoring of aromatic and het-
erocyclic amines onto the salicylaldehyde-tri-nbutylammonium ionic
liquids (2a,b) scaffolds are the common features of the 1H/13C NMR
spectra which are dominated by common peculiarities represented in:
(i) A low-field singlet in the region of δ 14.00–11.00 ppm assignable
to the resonance of phenolic proton involved in internal hydrogen-
bonded environment (which agree with a notice of maxima for
(C\\O)phenol resonance peak in 13C NMR around 159 ppm). (ii) More-
over, a deshielded singlet due to azomethine proton signal was ob-
served around 10.50 ppm (which is consistent with the 13C NMR
imine peak in the region of 169–161 ppm).
Scheme 3. schematic representation for possible tautomeric forms and H-bonded six-
membered chelate ring in ionic imine scavenging products (3a–l).
heterocyclic amines depends on the structural features and substitution
pattern of scavenger, amino component and scavenging products. The
essential requirement for effective Schiff-base scavenging is an en-
hancement of the nucleophile-electrophile interaction between a nucle-
ophilic nitrogen atom from amino component and electrophilic
carbonyl group of a scavenger. Nature of the substituents on scavenger
and aromatic or heterocyclic amine play crucial roles in refinement this
interaction. Data from scavenging experiment is collected in Table 1 and
depicted in Fig. 3. These data revealed that the presence of ortho or para
electron-donating group (EDG) in aniline derivatives such SH and CH3
was significantly increased the nucleophilicity of amino group and pro-
moted the ClSal-(nBu3N+X−) scrubbing for amine capture. However,
ortho or para electron-withdrawing group (EWG) such as COOH in en-
tries 4 and 9 (Table 1, Fig. 2) reduces the nucleophilicity of amino group
and amine capture accordingly.
Noteworthy, an ortho bulky substituent, isopropyl group, entries 5
and 10 (Table 1, Fig. 3) hinders nucleophile-electrophile interaction
and amine-imine conversion leading to a drop in the scavenging effi-
ciency. Interestingly, as shown in Fig. 3, hexafluorophosphate salt (2b)
in more efficient than the corresponding chloride salt (2a) for Schiff-
base scavenging of aromatic and heterocyclic amines from ethanolic
media.
3.4. Scavenging efficiency of ClSal-(nBu3N+X−) (2a,b) scavengers
The Schiff-base-scavenging efficiency of primary amine with ClSal-
(nBu3N+X−) (2a,b) is demonstrated by the rate of capture of amine
and yield conversion of entries in Scheme 2 into imines scavenging
products. Generally, Schiff-base scavenging efficiency of aromatic and
Fig. 3. ClSal-(nBu3N+X−) (2a,b) scrubbing for primary amine capture.

1130
R.F.M. Elshaarawy et al. / Journal of Molecular Liquids 223 (2016) 1123–1132
Table 2
Scavenging of p-toluidine by our scavengers in comparison to literature ones.
1° Amine
Scavenger
Scavenging protocol
Imine yield (%)
Ref.
4- CH3C6H4 (p-Tol)
ClSal-(nBu3N+Cl−) (2a)
ClSal-(nBu3N+PF−6 ) (2b)
Wang aldehyde resin
Polyacrolein aldehyde resin
IL-based aldehyde
EtOH/60 °C/5 h
EtOH/60 °C/5 h
DCM/reflux/24 h
DCM/r.t/24 h
85
93
59
84
82
This work
This work
[27]
[28]
[29]
EtOH/60 °C/6 h
Furthermore, the strong electron-withdrawing nature cationic ter-
minal and chloro group of scavenger enhances the electrophilicity of
carbonyl moiety and the reactivity of scavenger, accordingly, for
Schiff-base condensations with primary amines. Moreover, stabilization
of imines scavenging products via formation H-bonded six-membered
chelate ring, through intramolecular hydrogen bonding interaction be-
tween o-hydroxy group of salicyl fragment and azomethine group
(see Scheme 3), leads to an enhancement of the scavenging efficacy.
Shorter reaction time and real-time monitoring are the major prefer-
able advantages for our proposed scavengers over polymer-supported
scavenger for amine. For example, in previous work [27] (see Table 2),
using of Wang aldehyde resin as scavenger for a series of primary
amines revealed scavenging efficacies, using reflux/ 24 h as a scavenging
protocol, of the value in the range of 59–82%. On the other hand, our
ionic liquid scavengers exhibited scavenging efficacies of 69–99%
using shorter scavenging protocol, stirring at 60 °C/5 h. Moreover, alter-
ations of the physical properties of the scavenging products in compar-
ison to reaction entries open window for real-time monitoring of
scavenging process.
4.1. Antimicrobial activity profile and antibacterial efficacy
The scavengers ClSal-(nBu3N+X−) (2a,b) and scavenging products
(3a–l) were in vitro assessed for their antimicrobial efficacies in com-
parison to standard antibiotics (antibacterial, ampicillin; antifungal,
amphotericin B) against common clinically significant pathogenic mi-
crobial strains including Staphylococcus aureus (S. aureus) as a Gram-
positive (G+) bacterium, Escherichia coli (E. coli), as a Gram-negative
(G−) one, and Aspergillus flavus (A. flavus) as well Candida albicans (C.
albicans, NCIM No. 3100), as fungal pathogens. Zone of inhibition
(ZOI) assay (Fig. 4) demonstrates that the imine scavenging products
(3a–l) are more effective for fighting microbial infections than the par-
ent scavengers (2a,b). These antimicrobial efficacies are comparable to/
or exceed that of standard drugs. This boost in biopotency of scavenging
products in comparison to scavengers may be ascribed to merging of di-
verse potent pharmacophores into a single molecular structure, (3a–l),
which exerts overall additive antimicrobial effects. Primarily, hydrogen
bond donor (HBD) and acceptor (HBA) pharmacophores belonging to
salicylidene fragment of 3a–l such as azomethine group (H\\C_N)
and phenolic OH offer significant targets for H-bonding with the active
sits of the microbial cell constituents leading to an interference with
their normal functions [30]. Moreover, tri-nbutylammonium ionic liquid
terminal provide further effective pharmacophore which exert its anti-
microbial action via direct electrostatic and hydrophobic interactions
[31]. Whereas, the outer cellular membrane which acts as a formidable
barrier especially against hydrophobic pharmacological agents can be
easily attacked by biomolecules bearing cationic terminals, such as
3a–j which bear cationic tri-nbutylammonium, that enable them to
readily bind to their anionic targets in the cellular membrane, lipopoly-
saccharide (LPS) (a major constituent of G− bacterial surface)or
lipoteichoic acid (LTA) through an electrostatic interaction with the
negatively charged phosphate groups of the LPS and LTA resulting in
the disruption of the bacterial outer membrane and failure of its barrier
function [32].
3.5. Recovery of ClSal-(nBu3N+X−) (2a,b) scavengers
Schiff-base hydrolysis is the followed protocol for recovering of
ClSal-(nBu3N+X−) (2a,b) scavengers from imines scavenging products
(3a–l). This hydrolysis is carried out in water–alcohol mixtures and
has established the susceptibility to readily precede under acid catalysis
conditions. The proposed mechanism for this acid catalysis Schiff-base
hydrolysis involves the addition of water to the azomethine (HC_N)
moiety to form the carbinolamine intermediate which underwent fur-
ther hydrolysis to regenerate the desired ClSal-(nBu3N+X−) (2a,b)
scavengers (see Scheme 4) in excellent yield and pure state.
4. Pharmacology of imine scavenging products
Additionally, the hydrophobic pharmacophores (butyl and isopropyl
terminals) help new pharmacological agents (3g,l) in penetration and
diffusion across the lipid bilayer of the microbial cell wall to the cell in-
terior which may leads to a disruption of the cytoplasmic membrane, re-
leasing of cell constituents and inducing DNA damage [33].
Many trials to explore new pharmacologically active ingredient
(PAI) ended in failure because of its low efficacy associated with its lim-
ited bioavailability or solubility. Anchoring of this PAI to ionic liquid ter-
minals may offer synergistic effects of improving its water solubility and
enhancing the pharmacological action.
Scheme 4. Proposed mechanism for regeneration of ClSal-(nBu3N+X−) (2a,b) scavengers.

R.F.M. Elshaarawy et al. / Journal of Molecular Liquids 223 (2016) 1123–1132
1131
Fig. 4. Graph of zone of inhibition (ZOI, mm) for assaying compounds against different microbial species.
Noteworthy, as revealed from ZOIs data in Fig. 4, scavenging prod-
ucts are more effective than scavengers in inducing antibacterial effect
with a slight preferable efficacy in fighting staphylococcal more than
the E. coli infection.
Noticeable that, as shown in Fig. 4, imine scavenging products exhib-
ited limited potency or inactive as fungicidal agents. This limited or lack
of antifungal activities may be ascribed to either rigidity of the fungal
outer-wall that composed predominately of chitin, mannan and pro-
teins [34] which function as an impermeable barrier that limits or pre-
vents a diffusion of pharmacological agent through it, or complexity of
the mode of fungal drug-resistance which may proceeds via much
more complicated mechanisms than bacterial conflict.
Among assaying compounds, thiophenol-based scavenging
products, (3c,i) were found to exhibit excellent antibacterial action
(MIC90 = 56.23, 34.18 μg/mL against S. aureus; MIC90 = 88.32,
101.32 μg/mL against C. albicans, respectively) in comparison to other
scavenging products and standard drug. Thus, further structural refine-
ment coupled with more microbiological assessments may offer new
promising antibiotic candidates that play critical role in fighting staphy-
lococcal and C. albicans infections.
pronounced inhibitory effects on proliferation of MCF-7 cell lines, with
a structure-activity relationship (SAR) profile. Noteworthy, the surviv-
ing fraction assays and IC50 values demonstrated that the tested scav-
enging products exhibited different levels of cytotoxic activities (weak
to excellent) against MCF-7 cells. For example, aminothiophenol-
based tri-nbutylammonium hexafluorophosphate (3h) (IC50
=
8.03 μg/mL) was ca. 6-fold more cytotoxic than its chloride analogue
(3b) (IC50 = 44.80 μg/mL). Lipophilicity and/or vulnerability to hydro-
lytic cleavage seem to be the key structural features leading to the ob-
served anion-dependent cytotoxicity. Interestingly, strong hydrogen
bonding interactions between hexafluorophosphate, PF−6 , and DNA
nucleobases [35] is the expected key factor for exponential efficiency
of hexafluorophosphate salt, 3h,i, over chloride analogues, 3b,c. Fur-
thermore, electrostatic interactions promoted association of hydrophil-
ic cationic segments, tri-nbutylammonium, with terminal phosphate
groups of DNA provide further reason from enhanced antitumor activity
of assayed compound.
5. Conclusion
Novel chlorosalicylaldehyde-tri-nbutylammonium ionic liquids have
been designed, successfully synthesized and structurally characterized.
Thereafter, these ionic liquids were evaluated as scavengers for diverse
aromatic and heterocyclic primary amines in the synthesis of new phar-
macologically relevant candidates, imines scavenging products. The
most plausible proposed mechanism for this scavenging process is a tra-
ditional simple Schiff-base condensation reaction between scavengers
and target primary amines except in case of 2-aminothiophenol scav-
enging for which two different strategies, Schiff-base and nucleophilic
addition, are involved for its capture to yield co-scavenging products,
imines and hemimercaptals. The new scavengers exhibited good cap-
ture efficiency as revealed from yields of scavenging products (69–
99%). The advantages of our protocol over that based on polymer-sup-
ported aldehyde scavenger are the simplicity, shorter reaction time, ho-
mogeneity of reaction medium, real-time monitoring of a model
reaction, characterization of scavenging products and feasibility of re-
generation and reuse of scavengers.
4.2. Preliminary in vitro anticancer assay
The preliminary in vitro antitumor studies of representative scav-
enging products such as 3b,c and 3h,i were in vitro evaluated in relation
to the standard anticancer drug doxorubicin® (C27H29NO11, 543.52 g/
mol) against human breast carcinoma (MCF-7). The surviving fraction
assays (Fig. 5) demonstrated that all selected compounds exert
The biocidal and antitumor activities of the scavenging products
have been investigated against common bacterial and fungal pathogens
and human breast carcinoma (MCF-7) cell lines, respectively. Both the
ZOIs and MIC values revealed that the designed scavenging products ex-
hibited moderate to excellent broad-spectrum antibacterial efficacy in
comparison to the parent scavengers and standard antibiotic with an
ability to inhibit the growth of A. flavus b C. albicans b E. coli b S. aureus.
The surviving fraction assays and IC50 values demonstrated that the
tested scavenging products exhibited different levels of cytotoxic activ-
ities (weak to excellent) against MCF-7 cells. For example,
aminothiophenol-based tri-nbutylammonium hexafluorophosphate
(3h) (IC50 = 8.03 μg/mL) was ca. 6-fold more cytotoxic than its chloride
analogue (3b) (IC50 = 44.80 μg/mL).
Fig. 5. Concentration-dependent antitumor efficacy assessment and IC50 of representative
scavenging products (3b,c and 3h,i) against human MCF-7 cell lines.

1132
R.F.M. Elshaarawy et al. / Journal of Molecular Liquids 223 (2016) 1123–1132
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