Synthesis and biological activity of important phenolic mannich bases

Article abstract of DOI:10.14233/ajchem.2013.12580

A series of Mannich bases were synthesized by the condensation reaction of phenols and amines in the presence of formaldehyde. The newly synthesized Mannich bases were well characterized by FT-IR spectroscopy. All the synthesized compounds were tested for their antibacterial activity against Pasturella multocida and Staphylococcus aureus. The results have shown that most of the compounds are quite active against these pathogenic bacteria.

Full text of DOI:10.14233/ajchem.2013.12580

Asian Journal of Chemistry; Vol. 25, No. 1 (2013), 59-62
http://dx.doi.org/10.14233/ajchem.2013.12580
Synthesis and Biological Activity of Important Phenolic Mannich Bases
*
FAREEHA KOUSAR, SOFIA NOSHEEN , SAYEDA NIDA ZAHRA, SUMMAIRA KOUSAR and NAZISH JAHAN
Department of Chemistry and Biochemistry, University of Agriculture, Faisalabad-38040, Pakistan
*Corresponding author: E-mail: sofiakhan600@yahoo.com; nosheen.sofia@yahoo.com
(Received: 16 August 2011;
Accepted: 9 July 2012)
AJC-11820
A series of Mannich bases were synthesized by the condensation reaction of phenols and amines in the presence of formaldehyde. The
newly synthesized Mannich bases were well characterized by FT-IR spectroscopy. All the synthesized compounds were tested for their
antibacterial activity against Pasturella multocida and Staphylococcus aureus. The results have shown that most of the compounds are
quite active against these pathogenic bacteria.
Key Words: Mannich bases, Pasturella multocida, Staphylococcus aureus.
Synthesis of Mannich bases with different reactants:
Mannich bases were prepared according to the method given
by Ibrahim and Sharif8 with some modifications. It includes
the condensation reaction of aromatic amines (both substituted
and unsubstituted) with phenols (both substituted and
unsubstituted) and formaldehyde in the presence of acetic acid
as catalyst using ethanol as solvent.
INTRODUCTION
The Mannich base is an end product in the Mannich
reaction, which mainly consists of an amino alkylation of an
acidic proton placed next to a carbonyl functional group with
aldehyde and amine. The final product is a β-amino-carbonyl
compound also known as Mannich base1.
Procedure: One gram of each phenols were dissolved in
ethanol (20 mL) separately. After it, 4-5 mL formaldehyde
was added to the amine solution. Both the solutions were mixed
and 3-4 mL acetic acid was added. The reaction mixture was
stirred for 1 h. The stirring time could be varied depeneded
upon reactants. Crude product obtained after filteration was
recrystallized from DMSO and then characterized.
R
H
R
+
N
CH2
C
C
NH
C
O + CH
C
O
H
O
The Mannich-reaction is employed in the organic
synthesis of natural compounds such as peptides, nucleotides,
antibiotics and alkaloids (e.g. tropinone). Other applications
are in agro chemicals such as plant growth regulators2. Various
drugs obtained from Mannich reaction have proved to be more
effective and less toxic than their parent compounds3. They
have also been encountered with antibacterial, antimalarial
anticancer, analgesic, antiinflammatory, anticonvulsant, anti-
viral and CNS depressant activities4-7.
Antibacterial screening: In the third step, the antimi-
crobial e.g., antibacterial screening was performed using disc
diffusion method against pathogenic strains Staphylococcus
aureus and Pasturella multocida in comparison with standard
commercial antimicrobial agents.
RESULTS AND DISCUSSION
Due to the vast applications of Mannich bases in pharma-
ceutical products and other fields of life, this reaserch work
was conducted to synthesize some important phenolic Mannich
bases and evaluated its antibacterial activities.
The results revealed that both the partners having naphthyl
moiety expressed exellent activity in Mannich reaction as
among the phenols 2-naphthol and 1-naphthol and among the
amines 1-naphthylamine was given all condensation products
with all amines in high yields in the range 31.61-85.44 % and
59.34-76.07 %. Observations also indicated that electron with-
drawing and electron donating groups attached to phenolic
component did not expressed successful activity but presence
of electron withdrawing groups on the amines i.e., p-nitroaniline
EXPERIMENTAL
The experimental protocol consists three steps: (i) Synthesis
of Mannich bases with different reactants. (ii) Characterization
of Mannich bases, (iii)Application of Mannich bases for anti-
bacterial screening.

60 Kousar et al.
OH
Asian J. Chem.
O
OH
NH2
O
H3C
OH
NH
H
H
+
+
OH
OH
CH3
CH3
A1
Same reaction was carried out for other Mannich bases but with different phenols,
A2: o-Cresol, A3: 2-Naphthol, A4: 1-Naphthol and A5: p-Nitrophenol
Scheme-I: Condensation reaction of phenols and p-toluidine
NH2
O
OH
O
OH
H3C
OH
+
H
H
+
OH
OH
HN
B1
Same reaction was carried out for other Mannich bases but with different phenols,
B2: o-Cresol, B3: 2-Naphthol, B4: 1-Naphthol and B5: p-Nitrophenol
Scheme-II: Condensation reactions of phenols with 1-naphthylamine
NH2
O
OH
OH
H3C
OH
H2C
O
+
+
OH
+
NH
N
-
OH
O
O
+
N
-
O
O
C1
Same reaction was carried out for other Mannich bases but with different phenols,
C2: o-Cresol, C3: 2-Naphthol, C4: 1-Naphthol and C5: p-Nitrophenol
Scheme-III: Condensation reaction of phenols with p-nitroaniline
OH
O
NH2
OH
NH
H3C
OH
H2C
O
+
+
OH
OH
D1
Same reaction was carried out for other Mannich bases but with different phenols,
D2: o-Cresol, D3: 2-Naphthol, D4: 1-Naphthol and D5: p-Nitrophenol
Scheme-IV: Condensation reaction of phenols with aniline

Vol. 25, No. 1 (2013)
Synthesis and Biological Activity of Important Phenolic Mannich Bases 61
NH2
O
OH
OH
H3C
OH
H2C
O
+
+
OH
Br
OH
NH
Br
E1
Same reaction was carried out for other Mannich bases but with different phenols,
E2: o-Cresol, E3: 2-Naphthol, E4: 1-Naphthol and E5: p-Nitrophenol
Scheme-V: Condensation reaction of phenols and p-bromoaniline
OH
NH2
O
OH
H3C
OH
H2C
O
+
OH
+
OH
NH
O
S
O
OH
O
S
O
OH
F1
Same reaction was carried out for other Mannich bases but with different phenols,
F2: o-Cresol, F3: 2-Naphthol, F4: 1-Naphthol and F5: p-Nitrophenol
Scheme-VI: Condensation reaction of phenols and 1-Naphthylamine-4-SO3H
proved more active for Mannich reaction when compared11
to p-toluidine and p-bromoaniline. From 30 experiments,
sixteen products were obtained while thirteen were obtained
in good yields. The reactions did not occur (A4, A5, C1, E1,
E2, E5, D1-D4, F1, F2 and F5) which might be due to the
reason that both of the reactants were not miscible in same
solvent ethanol or may be reason behind is that the reaction
conditions i.e. shaking time, temperature provided were not
suitable for these reactions.
3200 cm-1 region arises due to intermolecular hydrogen bonding
of -OH functional group in phenols.
In the IR spectrum of Mannich base C3, a strong absor-
ption band at 1596 cm-1 could be attributed to -NH functional
group characteristic feature of Mannich base structure, while
the absorption bands at 1316 and 1326 cm-1 arising due to the
-C-N- stretching vibrations. The absorption bands appear at
1326 and 1516 cm-1 (due to stretching vibrations) and absor-
ption bands at around 808 cm-1 (due to -C-N- str. vibrations in
nitro benzenes) confirmed the presence of -NO2 group in
Mannich base C3. The absorption bands near 1200 cm-1
corresponded to the -C-O- functional group of phenolic
compounds.
The IR spectra of Mannich bases were found to be fully
consistent with the predicted structures. The IR spectrum of
Mannich base A2 showed a sharp absorption peak at 3516
cm-1 indicating the presence of -OH group in ortho substituted
phenols or may be due to the -NH str vibrations of secondary
aromatic amines. The sharp absorption band appears at 1616
cm-1 due to bending vibrations of -NH functional group and
absorption bands in the region of 1360-1250 cm-1 arising due
to the -C-N str vibrations confirmed the presence of -C-NH-C
group in Mannich base A2.
Biological activity:Antibacterial screening data expressed
that all the tested compounds showed moderate to good inhibi-
tion. Mannich base F3 derived from 1-naphthylamine-4-SO3H
showed maximum inhibition zones 33 mm against Pasturella
multocida and 38 mm against Staphylococcus aureus exact
near to reference compound (39 mm), respectively (Fig. 1).
Mannich bases B1, B5 and C3 showed good inhibition zones
in the range 21-26.5 mm and Mannich bases B2, B3, C4, E4
showed moderate inhibition zones (Fig. 1). All compounds of
B1-B5 (having 1-naphthylamine moiety) and F3 (derived from
Mannich base B1 showed absorption bands at ca. 1581
and 1398 cm-1, which could be attributed to the -NH (due to
bending vibrations) and -C-N- (due to stretching vibrations)
functional groups, respectively. The sharp broad band ca. 3400-

62 Kousar et al.
Asian J. Chem.
50
45
activity. So these results revealed that newly synthesized
Mannich bases have effective antibacterial potential and these
can be proved important drug intermediates for the synthesis
of antibacterial drugs.
P. multocida
S. aureus
40
35
30
25
20
15
10
5
REFERENCES
1. C. Mannich and Krosche, Arch. Pharm. 257, 247 (1912).
2. S. Mitsumori, H. Zhang, P.H.Y. Cheong, K. Houk, F. Tanaka and C.F.
Barbas, J. Am. Chem. Soc., 128, 1040 (2006).
0
3. S. Joshi, A.D. Manikpuri and P. Tiwari, Bioorg. Med. Chem. Lett., 17,
645 (2006).
Mannich bases
4. O. Bekircan and H. Bektas, Molecules, 13, 2126 (2008).
5. B. Lingappa, K.S. Girisha, B. Kalluraya, N.S. Rai and N.S. Kumari,
Indian J. Chem., 47B, 4448 (2008).
Fig. 1. Antibacterial activity of different Mannich bases
1-naphthylamine-4-SO3H) have showed maximum antibac-
terial activity than all other compounds which indicated that
Mannich bases derived from 1-naphthylamine and its deri-
vatives are the best compounds for the point of biological
6. A. Rajasekaran and S. Murugesan, Asian J. Chem., 16, 791 (2004).
7. J.T. Leonard, L. Jeyaseeli, O.S. Rajesh, K. Murugesh, R. Sivakumar
and V. Gunasekaran, Asian J. Chem., 18, 1104 (2006).
8. M.N. Ibrahim and S.A.E. Sharif, E-J. Chem., 4, 531 (2007).