Synthesis and microbiological activities of novel acyclic nitrones

Article abstract of DOI:10.14233/ajchem.2016.19576

In this article, the synthesis, antibacterial and antifungal activities of α-(5-(R)-2-thiophyl)-N-(4-R′) phenyl nitrones are reported. The synthesis was achieved by the condensation of N-substituted hydroxylamine [4-R′-phenylhydroxylamine] with 5-R-2-thiophenecarboxaldehyde in boiling absolute ethanol. The chemical structure of this nitrones was identified by spectroscopic techniques (IR and NMR). The antibacterial and antifungal activities were evaluated against bacteria: B. substilis, S. aureus, E. coli, S. enterica and fungus: M. ramannianus and F. oxysporium f.sp. albedinis. The reactivity of this reaction was making clear according the director condition.

Full text of DOI:10.14233/ajchem.2016.19576

Asian Journal of Chemistry; Vol. 28, No. 5 (2016), 1027-1030
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19576
Synthesis and Microbiological Activities of Novel Acyclic Nitrones
*
CHERIFA MAHIEDDINE , MOHAMED SALAH BOUKHECHEM, SAID ZERKOUT and ABDELGHANI ZITOUNI
Laboratoire de Recherche sur les Produits Bioactifs et la Valorisation de la Biomasse, Ecole Normale Supérieure-Vieux Kouba, B.P.: 92,
16038 Kouba, Alger, Algeria
*
Corresponding author: E-mail: mahieddinec@gmail.com
Received: 24 August 2015;
Accepted: 12 October 2015;
Published online: 30 January 2016;
AJC-17740
In this article, the synthesis, antibacterial and antifungal activities of α-(5-(R)-2-thiophyl)-N-(4-R’) phenyl nitrones are reported. The
synthesis was achieved by the condensation of N-substituted hydroxylamine [4-R’-phenylhydroxylamine] with 5-R-2-thiophene-
carboxaldehyde in boiling absolute ethanol. The chemical structure of this nitrones was identified by spectroscopic techniques (IR and
NMR). The antibacterial and antifungal activities were evaluated against bacteria: B. substilis, S. aureus, E. coli, S. enterica and fungus:
M. ramannianus and F. oxysporium f.sp. albedinis. The reactivity of this reaction was making clear according the director condition.
Keywords: Antibacterial, Antifungal, Nitrones, Thiophene.
2-thiophene carboxaldehyde 98 % (Fluka), 5-nitro-2-thiophene
INTRODUCTION
carboxaldehyde 98 % (Fluka), 4-nitophenol (Fluka), 4-chloro
nitro benzene m.p. 78 °C (lit. 80-83 °C) and 4-bromo nitro-
benzene m.p. 122 °C (lit. 124-126 °C) were prepared according
the method of nitration of aromatic cycle [11] using chloro-
benzene (Merck) and bromobenzene (Merck) respectively.
Ammonium chloride (BDH), zinc dust (Prolabo) were
purchased from market.
The syntheses of acyclic and cyclic nitrones are considered
as intermediary molecules for the preparation of therapeutic
products [1-4] because of their easiness preparation which are
more stable and reactive than other compounds containing
C=N group [5]. They have an effect of carbonyl group and
exhibit geometric isomerism [6]. They also contribute well in
1
,3-dipolar cycloaddition reactions, nucleophilic additions
IR spectra were measured with a FTIR-8300 Shimadzu.
and synthetic utility [7]. Previous work also showed that the
nitrones was used as spin traps, antioxidants in biological
systems and antibacterial [8].
1
13
H and C NMR spectra were obtained in CDCl
3
solution at
300 MHz with a Bruker Nanobay. Melting points were measured
on traditional methods and are uncorrected.
The method for synthesis of nitrone was selected accor-
ding to chemical structure of nitrone which is synthesized,
chemical and physical properties of initial substances, the
catalyst and the solvent or reactions conditions that will be
affected in the course of interaction in addition by Torssell
et al. [4] and Coutts et al. [9]. The general synthetic method
of the acyclic nitrones was from the condensation reaction
between the N-substituted hydroxylamine and aldehyde that
is used as a direct synthetic method of many acyclic nitrones
Preparation of nitrone
Preparation of β-phenylhydroxylamine: To a magneti-
cally stirred solution of nitrobenzene (12.5 g, 0.101 mol) in
aqueous solution of ammonium chloride (6.25 g, 0.126 mol)
was added zinc dust partly (14.25 g, 21.79 mmol). The reaction
mixture was stirred at 60-65 °C for 15 min after the stir was
completed for another 15 min without heating. At this time,
the reaction mixture was filtered and then was extracted with
diethyl ether. Also, diethyl ether was evaporated on a rotary
evaporator that gave a yellow crystalline solid. Recrystalli-
zation of this solid from petroleum ether (40-60°) gave (7.56
g) colourless needles crystalline of β-phenyl-hydroxylamine
[12].
[
4,6,10].
EXPERIMENTAL
Ethanol (Merck), butanol (Merck), diethyl ether (Reidel
de Haën), ethyl acetate (Reidel de Haën), dichloromethane
(
(
Reidel de Haën), petroleum ether (Fluka), nitrobenzene
Merck), 2-thiophene carboxaldehyde 98 % (Fluka), 5-methyl-
Preparation of 4-R′-phenylhydroxylamine: To a magne-
tically stirred solution of 4-R′-nitrobenzene (12.5 g, 10.1

1
028 Mahieddine et al.
Asian J. Chem.
mmol) in alcoholic solution (ethanol) of ammonium chloride
1 g, 18.6 mmol) was added zinc dust partly (4.5 g, 68.8 mmol).
The reaction mixture was stirred at a cold (12-16 °C) for 2h.
At this time the reaction mixture filtered. The filtrate was used
directly for the second stage of the synthesis of α-(2-thiophyl)-
N-(4-R′-phenyl)nitrone.
α-(2-Thiophenyl)-N-phenyl nitrone (4a): A mixture of
β-phenylhydroxylamine (3 g, 27.4 mmol) in (40 mL) of absolute
ethanol and 2-thiophene carboxaldehyde (3.08 g, 27.4 mmol)
in (50 mL) of ethanol was refluxed for 3 h leaving the mixture
under room temperature for the whole night. Evaporation of
solvent on the rotary evaporator gave brown oil, which was
triturated with petroleum ether (60-80°) to give crystals. Recry-
stallization from buthanol gave pistachio green crystals.Yield:
acetate to give (2.97 g) of yellow needles. Yield: 50.69 %;
m.p.: 207 °C; UV (EtOH) λmax (log ε): 364.5 (3.75), 292.5
(3.56), 270.5 (3.52), 238.0 (3.40), 201.0 (3.88) nm; IR (KBr,
(
-1
ν
max, cm ): 3052.08 (N=C-H), 1593.7 (C=N), 1050.0 (N→O),
1
841.6, 805.2; H NMR (CDCl
3
, 300 MHz): δ (ppm) 9.10 (s,
1H, OH); 8.52 (s, 1H, N=C-H); 7.40 (2H, 3, 4, CH, Ar); 7.05
(dd, 3H, o, 5, CH, Ar); 6.76 (dd, 2H, m, CH, Ar); C NMR
(CDCl
13
3
, 300 MHz): δ (ppm) 151.28, 142.64, 131.62, 130.04,
127,69, 122.44, 111.58, 105.79, 103.92.
α-(2-Thiophenyl)-N-(4-chlorophenyl)nitrone (4e). A
mixture of the filtrate of 4-chlorophenyl hydroxylamine (3.86
g, 26.7 mmol) in (70 mL) of ethanol and 2-thiophene carboxal-
dehyde (3 g, 26.7 mmol) in (50 mL) of ethanol was refluxed
for 3 h, leaving the mixture under room temperature for the
whole night. Removal of the solvent gave yellow solid. Recrys-
tallization from ethyl acetate gave (3 g) of yellow needles.
Yield: 58.00 %; m.p.: 170 °C; UV (EtOH) λmax (log ε): 358.5
6
2
2.47 %; m.p.: 75 °C; UV (EtOH) λmax (log ε): 343.0 (4.39),
60.5 (3.78), 222.5 (4.05), 203.0 (4.28) nm; IR (KBr, νmax
,
-
1
cm ): 3057.3 (N=C-H), 1557.3 (C=N), 1067.7 (N→O),
1
-1
7
1
7
70.83, 757.3. H NMR (CDCl
3
, 300 MHz): δ (ppm) 8.49 (s,
(4.06), 261.5 (3.50), 203.0 (4.08) nm; IR (KBr, νmax, cm ):
H, N=C-H); 7.84 (2H, 3, 4, CH, Ar); 7.62 (m, 1H, CH, Ar);
.57(m, 1H, CH, Ar); 7.48 (3H, o, p, CH, Ar ); 7.22 (1H, 5,
3058.7 (N=C-H), 1570.4 (C=N), 1091.3 (N→O), 723.4, 710.4;
1
H NMR (CDCl , 300 MHz): δ (ppm) 8.63 (s, 1H, N=C-H);
3
13
CH,Ar); C NMR (CDCl
31.60, 130.74-130.55, 129.89-129.47, 127.66, 121.73.
α-[5-(Methyl)-2-thiophenyl]-N-phenylnitrone (4b): A
3
, 300 MHz): δ (ppm) 147.19, 133.75,
8.59 (1H, 5, CH, Ar); 8.03-7.93 (d, 2H, 3, 4, CH, Ar); 7.73
(2H, o, CH, Ar); 7.31 (2H, m, CH, Ar); C NMR (CDCl , 300
13
1
3
MHz): δ (ppm) 149.72, 145.69, 136.01, 132.62-132.31,
131.96-129.37, 127.61, 124.94, 118.23, 115.64.
mixture of β-phenylhydroxylamine (3 g, 27.4 mmol) in (40
mL) of absolute ethanol and 5-methyl-2-thiophene carboxal-
dehyde (3.46 g, 27.4 mmol) in (50 mL) of ethanol was refluxed
for 3 h, leaving the mixture under room temperature for the
whole night. Evaporation of solvent on the rotary evaporator
gave yellow oil which was triturated and recrystallized with
petroleum ether (60-80°) to give (5.73 g) of yellow needles.
Yield: 95.98 %; m.p.: 139 °C; UV (EtOH) λmax (log ε): 348.5
α-(2-Thiophenyl)-N-(4-bromophenyl)nitrone (4f): A
mixture of the filtrate of 4-bromo-phenyl hydroxylamine (5.04
g, 26.7 mmol) in (70 mL) of ethanol and 2-thiophenecarboxal-
dehyde (3 g, 26.7 mmol) in (50 mL) of ethanol was refluxed
for 3 h, leaving the mixture under room temperature for the
whole night. A green yellow plates separated, which was
recrystallized from ethyl acetate to give (6.14 g) of yellow
plates.Yield: 81.18 %; m.p.: 193 °C; UV (EtOH) λmax (log ε):
347.0 (4.32), 265.0 (3.78), 245.0 (3.85), 222.5 (3.98), 203.0
-
1
(
4.14), 205.0 (4.31) nm; IR (KBr, νmax, cm ): 3062.7 (N=C-
1
H), 1554.5 (C=N), 1068.5 (N→O), 779.2, 752.2; H NMR
CDCl , 300 MHz): δ (ppm) 8.39 (s, 1H, N=C-H); 7.84 (d,
H, 3, 4, CH, Ar); 7.49 (4H, o, m, CH, Ar); 7.04 (d, 1H, p,
); C NMR (CDCl
ppm) 165.13, 146.57, 145.24, 138.64, 133.82, 130.91, 126.52.
-
1
(
2
3
(4.25) nm; IR (KBr, νmax, cm ): 3071.7 (N=C-H), 1535.2
1
(C=N), 1078.2 (N→O), 758.7, 745.6; H NMR (CDCl , 300
3
13
CH, Ar); 2.48 (s, 3H, CH
(
3
3
, 300 MHz): δ
MHz): δ (ppm) 8.51 (s, 1H, N=C-H); 7.83 (dd, 2H, 3, 4, CH,
Ar); 7.64 (dd, 2H, o, CH, Ar); 7.49 (2H, m, CH, Ar); 7.27 (d,
1H, 5, CH,Ar); C NMR (CDCl , 300 MHz): δ (ppm) 149.75,
13
α-(5-(Nitro)-2-thiophenyl)-N-phenylnitrone (4c): A
3
mixture of β-phenylhydroxylamine (1.74 g, 15.9 mmol) in
145.71, 136.02, 132.60, 132.33, 131.97, 129.35, 127.60,
124,96, 118.23, 115.66.
(40 mL) of absolute ethanol and 5-nitro-2-thiophene carboxal-
dehyde (2.5 g, 15.9 mmol) in (60 mL) of ethanol was refluxed
for about 1 h, shiny orange plates separated, recrystallization
from dichloromethane afforded (3.09 g) of 4c. Yield: 78.17
RESULTS AND DISCUSSION
In this study, we have studied the efficacy of the presence
of thiophene ring in the acyclic nitrone molecular, that we
have prepared six types of acyclic nitrones 4 which contained
a heterocyclic ring [11,13] of thiophene by the condensation
of the β-phenyl-hydroxyl-amine derivatives 2 and the
commercially available 5-R-2-thiophene carboxaldehyde 3.
Before that one, we have prepared β-phenylhydroxylamine
derivatives by the reduction of 4-R′-nitrobenzene 1 with zinc
dust in aqueous or alcoholic solution of ammonium chloride
%
; m.p.: 228 °C; UV (EtOH) λmax (log ε): 403.5 (4.25), 275.0
-1
(
4.21), 204.0 (4.34) nm; IR (KBr, νmax, cm ): 3052.08 (N=C-
1
H), 1551.6 (C=N), 1072.9 (N→O), 772.9, 762.5; H NMR
CDCl , 300 MHz): δ (ppm) 8.59 (s, 1H, N=C-H); 7.99 (d,
H, 4, CH, Ar) ; 7.84 (dd, 2H, m, CH, Ar); 7.55 (t, 3H, o, p,
(
1
3
13
CH,Ar); 7.46 (d, 1H, 3, CH,Ar); C NMR (CDCl
δ (ppm) 145.90, 138.56, 131.10, 129.5-127.90-127.84-127.55,
21.09.
α-(2-Thiophenyl)-N-(4-hydroxyphenyl)nitrone (4d):A
mixture of the filtrate of 4-hydroxyphenyl hydroxylamine
3.34 g, 26.7 mmol) in (70 mL) of ethanol and 2-thiophene
3
, 300 MHz):
1
NH Cl (the weak acid) to count of substituent R′ [4,12] without
4
making it under the nitrogen gas and to take in the consideration
of the instability of β-phenyl hydroxylamine derivatives [3]
that we have achieved the synthesis of β-phenylhydroxylamine
and the condensation reaction successively.All that were clari-
fied in Scheme-I [13], substituents and yield were illustrated
in Table-1.
(
carboxaldehyde (3 g, 26.7 mmol) in (50 mL) of ethanol was
refluxed for 3 h, leaving the mixture under room temperature
for the whole night. Removal of the solvent gave a dark violet
crystalline solid. This solid was recrystallized from ethyl

Vol. 28, No. 5 (2016)
Nitrone
Synthesis and Microbiological Activities of Novel Acyclic Nitrones 1029
TABLE-1
NITRONES, SUBSTITUENT AND INFRARED DATA
-
1
Substituent
Reaction
time (h)
Frequency (cm )
Yield (%)
m.p. (°C)
R
R'
N→O
C=N
4
a
H
Me
NO2
H
H
H
H
H
H
OH
Cl
Br
62.47
95.98
78.17
50.69
58.00
81.18
75
3
3
2-3
3
3
3
1067.7
1068.5
1072.9
1050.0
1091.3
1078.2
1557.3
1554.5
1554.6
1593.7
1570.4
1535.2
4
b
139
228
207
170
193
4
c
4
d
4
4
e
f
H
2
O
than 5-methyl-2-thiophene carboxaldehyde which indicates
that the electophilicity strength of the molecular entity (5-R-
R'
R'
60-65 °C
2
-thiophenecarboxaldehyde) is greater in the state of methyl
group that justifies the high value of yield.
EtOH / H
2
O
NHOH
1
NO
2
Infrared and H NMR spectra: The infrared spectra of
2
1
14-16 °C
the synthesized nitrones characteristic an absorption bands of
the (N→O) group and (C=N) group and their stretching are
listed in Table-1. which according to results of precedent study
S
OHC
R
[
14,15] about α,N-diphenylnitrone that the (N→O) stretching
EtOH, reflux
-1
frequencies were assigned to, respectively, 1088 and 1172 cm
and the (C=N) stretching frequencies were assigned to,
R'
3
-1
respectively, 1587 and 1548 cm [6]. Through these results
the change of the benzene nucleus by thiophene nucleus in
the α-position (C-position) of the molecule α-(5-(R)-2-
thiophyl)-N-(4-R′) phenyl nitrone 4 (Scheme-I) caused a blue
shift of frequencies values of (N→O) and (C=N) groups
because of the increases of the µ values and also the change of
the benzene nucleus by thiophene led to a weakening of
resonance energy of the α,N-diphenylnitrone compared with
the molecule 4 which decreased the value of the bond constant
of Hook law.
-
O
+
N
4
C
S
R
H
Scheme-I: Synthesis of nitrones [α-(5-(R)-2-thiophyl)-N-(4-R′)phenyl
nitrone]
The reactivity of the condensation of the N-substituted
hydroxylamine (4-R′-phenylhydroxylamine) and aldehyde (5-
R-2-thiophenecarboxaldehyde) in boiling ethanol as a polar
protic solvent to produce nitrones [α-(5-(R)-2-thiophyl)-N-
1
On the other hand, the H NMR spectra of nitrones [16]
prepared in this study attribute single signals of the CH proton
of azomethine N-oxide group (N=CH) that is observed in the
region 8.39-8.63 ppm, while the multiple signals of the CH
proton of aromatic rings (thiophenyl and phenyl) are shifted
at 6.76-8.46 ppm.According to results of previous study about
acyclic nitrones in particular α,N-diphenylnitrone [13,15-17].
The chemical shift of the carbon atom of the nitrone group in
(
4-R′)phenyl nitrone] depended on the nucleophilicity of 4-
R′-phenylhydroxylamine or the electrophilicity of 5-R-2-
thiophene carboxaldehyde and also the effect of the substituents
(
electron-donating or withdrawing) on the aromatic rings.
The electron donating substituent located in the 4-position of
benzene nucleus imposes a positive mesomeric depending on
the electro-negativity of –OH, –Cl and –Br which is diminishing
as well as the reaction solvent is a polar protic solvent, the
basicity of the molecular entity (4-R′-phenylhydroxylamine)
is decreased respectively for these substituents this means that
the nucleophilicity strength of this molecular entity was best
in the state of bromo the less electro negativity resulting in the
best and acceptable yield (Table-1). The other hand, the presence
of the methyl group (electron-donating) located at the 5-
position of the thiophene ring of the aldehyde reactive (5-R-
13
the C NMR spectra [18] of α-(5-(R)-2-thiophenyl)-N-(4-R′)
phenyl nitrone 4 is located in the range of 117 to 152 ppm and
depends on the electrophilic character of substituent in posi-
tion 5 and 4' of the aromatic ring of thiophene and benzene
(
Table-2).
TABLE-2
PROTON AND CARBON CHEMICAL SHIFT OF NITRONES
δ (ppm)
Nitrone
Hα
8.49
8.39
8.59
8.52
8.63
8.51
α-C
4
a
–
147.19
165.13
145.90
151.28
149.72
149.75
2
-thiophene carboxaldehyde) imposes a positive mesomeric
4b
2.48 (CH3)
effect on contrary to the nitro group which imposes a negative
mesomeric effect, it was expected that the reactivity of the
reaction was better in the case of nitro group than methyl group
but the high electro negativity of the nitrogen atom in nitro
group (electron-withdrawing) in compared the carbon atom
of methyl made us conclude that the basicity of 5-nitro-2-
thiophene carboxaldehyde in a polar protic solvent was better
4
c
–
4d
9.10 (OH)
4e
4f
–
–
Antibacterial and antifungal activities: To uncover the
biological properties of the synthesized nitrones 4, we have

1
030 Mahieddine et al.
Asian J. Chem.
TABLE-3
MICROBIAL ACTIVITY OF NITRONES (THE DIAMETER OF THE ZONE OF INHIBITED MICROBIAL GROWTH AROUND A DISC)
Zone of inhibition (mm)
Microorganism tested
4
a
4b
–
4c
–
4d
4e
7
4f
–
Escherichia coli
4
–
Salmonella enterica
Staphylococcus aureus
Bacillus substilis
11
–
–
–
11
–
8
–
8
12
–
16 (11N)
–
10
–
7
–
–
b
Fusarium oxysporium f.sp. albedinis
12
–
12
8
–
16
–
11
–
–
14
9
Mucor ramannianus
b
Diameter of clear zone, –No zone of inhibition
accredited the Kirby-Bauer [19] that is assimilated to grow a
sterilized paper disc (5 mm), which was impregnated with
ACKNOWLEDGEMENTS
The authors are indebted to Pr. N. Sabaou and Dr.A. Badji
for their assistance in microbial activity test and to O. Fabre
and A. Addou for the measurements of NMR spectra. Thanks
are also due to Pr. A. Nedjmi and Mr. A. Chouchane for their
useful discussions.
nitrone solution (0.25 mg per a disk) in ISP [20] medium of
2
cultivation in petri dish.All this was accomplished at an isolated
milieu. The culture medium contained bacteria: Gram-positive
(
(
Bacillus substilis, Staphylococcus aureus), Gram-negative
Escherichia coli, Salmonella enterica) and fungus: Fusarium
oxysporium f.sp. albedinis and Mucor ramannianus. Once
reading the diameter of the zone of inhibition, the results
obtained are summarized in Table-3.
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8. J.G. Millar and K.F. Haynes, Methods in Chemical Ecology: Bioassay
Methods, Kluwer Academic Publishers, First Printed, vol. 2, pp. 432-
433 (1998).
Conclusion
In conclusion, the successful preparation of α-(5-(R)-2-
thiophyl)-N-(4-R′) phenyl nitrone as an acyclic nitrones possess
heterocyclic ring of thiophene, that was confirmed by the IR
1
1
13
spectrum, H NMR and C NMR spectrum of the synthesized
compounds. On the other hand this nitrones obvious an activity
in opposition to certain microbe chosen (bacteria and fungus).
Further the preparation of other acyclic nitrones and their
activity are currently underway in our laboratory.
1
2
9. B. Badji,A. Zitouni, F. Mathieu,A. Lebrihi and N. Sabaou, Can. J. Microbiol.,
5
2, 373 (2006).
0. (a) P. Laszlo and P. Pennetreau, J. Org. Chem., 52, 2407 (1987); (b) A.W.
Johnson, Invitation to Organic Chemistry, Jones and Bartlett Publishers,
Sudbury, MA, USA (1999).