IJPRD, 2014; Vol 6(06):August-2014 (019 - 025) International Standard Serial Number 0974 9446

Available online on www.ijprd.com

19

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A GREEN APPROACH TO THE SYNTHESIS OF -SUBSTITUTED CHLOROACETAMIDES FROM
CHLOROACETYL CHLORIDE USING WATER AS A SOLVENT

Amruta S.Patil
1*
, Bindurani Ram
1

1
Siddhant College of Pharmacy , Sudumbare, Pune , India.


ABSTRACT
A main objective of the present research study is Green
chemistry, that uses water as a solvent which has recently
received great attention in organic synthesis. Here we report
an efficient synthesis of biologically important acetamides
from chloroacetyl chloride and amines using water, where
water is used as the only solvent in the reactions. The
remarkable features of this green methodology include
high product yields, wide tolerance of various functional
groups as substrates, and excellent region /site-specificities,
thus rendering this methodology a highly versatile and eco-
friendly alternative to the existing methods for synthesizing
acetamides. All synthesized compounds were characterized
by FT-IR,
1
H NMR,
13
C NMR and are well supported by
spectroscopic data.

Keywords- Green chemistry, Acetamides, Chloroacetyl
chloride.












INTRODUCTION
Green chemistry involves the development
of chemical products and synthetic procedures,
which are environmentally friendly and have
reduced health risks with the search for more
efficient methods to do chemistry. Its roots stem
back ten years from a simple idea to a prominent
concept which permeates all areas of modern
chemistry. [1] Chemistry is undeniably a very
prominent part of our daily lives. However,
additional chemical developments also bring new
environmental problems and harmful unexpected
side effects, which result in the need for greener
chemical products. [2]
Arylacetamides are pharmaceutically
interesting as they show various biological
activities such as analgesic, local anesthetic,
antiarthritic, antiarrhythmic activities, etc.[3]
Where,
Ar
H
N
O
R / Ar'

Ar = Aryl, substituted aryl, heteroaryl
R / Ar = H, alkyl, aryl, substituted aryl, heteroaryl
Correspondence Author

Amruta S.Patil

Siddhant College of Pharmacy,
Sudumbare, Pune . 412109, MH, India

International Journal of Pharmaceutical Research & Development ISSN: 0974 9446

Available online on www.ijprd.com
20
In arylacetamides the nature of aromatic ring and
its substituent is primary determinant for its
activity. The trifluoromethyl substituted
arylacetamide, 2-(4-(trifluoromethyl) phenyl)-N-
methyl-N-((S)-1-phenyl-2-(pyrrolidin-1-yl) ethyl)
acetamide [4] (A) possesses high lipophilicity, and
indeed shows far greater peripheral analgesia than
central analgesia.
N
O
N
F
3
C

(A)
(B)
N
N
H
3
C
O
Cl
Cl
CH
3
OH
HBr

Benzeneacetamide,3,4-dichloro-N-[(1-(3-
hydroxyphenyl)-1-(1-methyl-2-piperidinyl methyl)]-
N-methyl-, hydrobromide [5] (B) is also an
analgesic agent. 2-(4,5-dicarbomethoxy-1,2,3-
triazol-1-yl)-N-(2-methoxy phenyl) acetamide (C)
shows Antimicrobial, analgesic anti-inflammatory,
local anaesthetic activity [6].


O
H
N
O
N
N N
O O
O
O

(C)
The wide pharmacological profile of
arylacetamides have attracted us for designing the
newer analogues from this series, during literature
survey of this chemical class we have found the
drug molecules like heteroaryl acetamide e.g. 2-
(4,5-dicarbomethoxy-1,2,3-triazol-1-yl)-N-(2-
methoxy phenyl) acetamide (C) having distinct
pharmacological activities.

The present study involves the synthesis,
purification and characterization of various N-
substituted chloroacetamide derivatives. The
chloroacetyl chloride treated with various aliphatic
and aromatic amines at room temperature with
stirring for few hours with monitoring reaction by
thin layer chromatography gave 2-chloro-N-
alkyl/aryl acetamide as solid compounds. We
checked the melting point of synthesized
compounds with an open ended capillary tube
method. The spectral techniques like Infra red and
GC-MS have been used for characterization and
establishment of structure of synthesized
compounds. The antimicrobial screening of the
synthesized chloroacetamides have shown
excellent antibacterial and antifungal.

The reaction between chloroacetyl chloride
and mono- or bis-aliphatic or aromatic amines in
water under basic or neutral conditions gives rise
to the formation of a variety of functionalized -
chloroamides. The resulting products were
obtained as solids in moderate to good yields, upon
precipitation and isolation by filtration. This
method was particularly effective for the formation
of functionalized aromatic -chloroamides. . [7]


MATERIALS AND METHODS

All chemicals used were of Laboratory Reagent (LR)
Grade. The synthesized derivatives were
characterized by melting point, TLC, FT-IR, GC-MS
and NMR. Thin Layer Chromatography was
performed using Silica Gel - G coated on glass
plates and the spots were visualized by exposure to
International Journal of Pharmaceutical Research & Development ISSN: 0974 9446

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21
iodine. Melting points were taken in open glass
capillary tubes in liquid paraffin bath and were
uncorrected. IR spectra were recorded on FTIR-
8400S SHIMADZU spectrophotometer. GC-MS
spectra & chromatogram were recorded on GCMS-
QP 2010 SHIMADZU instrument.
Synthetic Scheme
Overnight Stirring
0C to RT
Cl
N
O
R/Ar
Cl
Cl
O
+
H
N
R/Ar
H
H
(1)
(3)
(2)

Experimental:
General procedure
Four equivalents of chloroacetyl chloride (1) was
added drop wise over one hour to the aqueous
amine (2) solution. Then the solution was left to
stir overnight.The desired product was isolated as
precipitate after pouring reaction mixture to an ice-
cold water. Precipitate was filtered, washed with
cold water and dried. Recrystalised using 95%
ethanol. Different chloroacetamides were obtained
using amines listed in following table.

Table 1: List of amines & Physical characterization
of 2-chloro-N- Alkyl/Aryl acetamide derivatives.
Table 1: List of amines & Physical characterization of 2-chloro-N- Alkyl/Aryl acetamide derivatives

Sr.
No.
Name of amine Structure R/Ar

code
Melting
point
(
0
C)
Yield
(%)
R
f

value
1.
Aniline
H
2
N



3a
140-142 82.77 0.62
2.
m-toluidine
H
2
N
CH
3
CH
3


3b
86-91 21.55 0.63
International Journal of Pharmaceutical Research & Development ISSN: 0974 9446

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3.
m-chloroaniline
H
2
N
Cl
Cl


3c
98-99 70.32 0.66
4.
o-chloroaniline
H
2
N
Cl

C l


3d
65-67 82.14 0.59
5.
o-anisidine
H
2
N
H
3
CO
H
3
CO


3e

40-42

59.62

0.56
6.
p- anisidine
H
2
N OCH
3

OCH
3


3f

118-120

38.17

0.71
7.
Benzylamine
H
2
N

CH
2


3g
91-93 40.77 0.72
8.
N-methyl
aniline

HN
H
3
C

N
CH
3



3h
66-68 25.80 0.57
9.
p-nitroaniline
H
2
N NO
2

NO
2


3i 180-183 23.90 0.68
10.
Alpha-
naphthylamine
NH
2



3j
155-158 61.02 0.40
11.
p-fluoroaniline
H
2
N F

F



3k
127-130 53.07 0.52



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RESULTS
1. Phenyl Chloroacetamide (3a)
It was obtained from (1) with aniline in crystalline
form. Yield 82.77%, mp 140-142
0
C, and IR
3277.17cm-1(NH-stretch: 2 amide),1688.48 (C=O
stretch:2 amide), 1533.46 (NH-bend:2 amide),
1273.06 (C-N stretch), 744.55 (C-Cl stretch) ,Mass
spectrum [M
+
], m/z 169 (100%) ,[M
+1
] 169, [M
+2
]
120, [M
+3
] 93.

2. 2-chloro-N-m-tolyacetamide (3b)
It was obtained from (1) with m-toludine in
crystalline form. Yield 21.55%, mp 86-91
0
C, and IR
3294.53cm-1(NH-stretch: 2 amide) , 1672.34 (C=O
stretch:2 amide), 1550.82 (NH-bend:2 amide),
1417.73 (C-N stretch), 895.00 (C-Cl stretch) ,Mass
spectrum [M
+
], m/z 183(100%) [M
+1
] 183, [M
+2
]
120, [M
+3
] 107.

3. 2-chloro-N-(3-chlorophenyl)acetamide (3c)
It was obtained from (1) with aqueous m-chloro
aniline in crystalline form. Yield 70.32%, mp 98-
100
0
C, and IR 3282.95cm-1(NH-stretch: 2 amide) ,
1666.55 (C=O stretch:2 amide), 1600.97 (NH-
bend:2 amide), 1442.80 (C-N stretch), 1091.75 (C-
Cl stretch) , 898.96(Meta-disubstituted benzene
ring),Mass spectrum [M
+
], m/z 203(100%), [M
+
]
207, [M
+1
] 203, [M
+2
] 154, [M
+4
] 127.

4. 2-chloro-N-(2-chlorophenyl)acetamide (3d)
It was obtained from (1) with aqueous o-chloro
aniline in crystalline form Yield 82.14%, mp 65-
67
0
C, and IR 3259.81cm-1(NH-stretch: 2 amide) ,
1658.84 (C=O stretch:2 amide), 1543.10 (NH-
bend:2 amide), 1435.09 (C-N stretch), 1045.45 (C-
Cl stretch) , 690.54 (Ortho-disubstituted benzene
ring),Mass spectrum [M
+
], m/z 203(100%), [M
+
]
207, [M
+1
]203, [M
+2
] 168.

5. 2-chloro-N-(2-methoxyphenyl)acetamide (3e)
It was obtained from (1) with aqueous o-methoxy
aniline in crystalline form. Yield 59.62%, mp 40-
42
0
C, and IR 3271.38cm-1(NH-stretch: 2 amide) ,
1668.48 (C=O stretch:2 amide), 1543.10 (NH-
bend:2 amide), 1475.59 (C-N stretch), 785-540 (C-
Cl stretch) , 759.98 (Ortho-disubstituted benzene
ring),Mass spectrum [M
+
], m/z 199(100%),
[M
+1
]199, [M
+2
] 150 [M
+3
] 122.

6. 2-chloro-N-(4-methoxyphenyl)acetamide (3f)
It was obtained from (1) with aqueous p-methoxy
aniline in crystalline form. Yield 38.17%, mp 118-
120
0
C, and IR 3286.81cm-1(NH-stretch: 2 amide) ,
1658.84 (C=O stretch:2 amide), 1531.53 (NH-
bend:2 amide), 1438.94 (C-N stretch), 785-540 (C-
Cl stretch) , 810.13 (Para-disubstituted benzene
ring), Mass spectrum [M
+
], m/z 199(100%), [M
+1
]
199, [M
+2
] 122, [M
+3
] 108.

7. N-benzyl-2-chloroacetamide (3g)
It was obtained from (1) with benzylamine in
crystalline form. Yield 40.77%, mp 91-93
0
C, and IR
3275.24cm-1(NH-stretch: 2 amide) , 1624.12 (C=O
stretch:2 amide), 1543.10 (NH-bend:2 amide),
1438.94 (C-N stretch), 785-540 (C-Cl stretch) ,
567.03 (Monosubstituted benzene ring), Mass
spectrum [M
+
], m/z 183(100%), [M
+1
] 183, [M
+2
]
148.

8. 2-chloro-N-methyl-N-phenylacetamide (3h)
It was obtained from (1) with N-methyl aniline in
crystalline form. Yield 25.80%, mp 66-68
0
C, and IR
1670.41 (C=O stretch:3 amide), 3049.56 (C-
Nstretch: 3 amide), 785-540 (C-Cl stretch) , 563.23
(Monosubstituted benzene ring), Mass spectrum
[M
+
], m/z 183(100%), [M
+1
] 183, [M
+2
] 148, [M
+3
]
106.
9. 2-chloro-N-(4-nitrophenyl)acetamide (3i)
It was obtained from (1) with aqueous p-nitro
aniline in crystalline form. Yield 23.90%, mp 180-
183
0
C, and IR 3279.10cm-1(NH-stretch: 2 amide) ,
1670.41 (C=O stretch:2 amide), 1591.33 (NH-
bend:2 amide), 1502.60 (C-N stretch), (C-Cl
stretch) , 850.64 (Para-disubstituted benzene ring),
850.64 (NO
2
-Asymmetric stretch), Mass spectrum
[M
+
], m/z 214(100%), [M
+
] 216, [M
+1
] 214, [M
+2
]
166, [M
+3
] 138.

10. 2-chloro-N-(naphthalen-2-yl)acetamide (3j)
It was obtained from (1) with 2-naphthalene in
crystalline form. Yield %, mp 155-158
0
C, and IR
3252.09cm-1(NH-stretch: 2 amide) , 1660.77 (C=O
International Journal of Pharmaceutical Research & Development ISSN: 0974 9446

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24
stretch:2 amide), 1562.75 (NH-bend:2 amide),
1404.22 (C-N stretch), 752.26 (1,2 disubstituted
benzene ring) , 856.42 (Meta-disubstituted
benzene ring), Mass spectrum [M
+
], m/z 147(100%)
[M
+
] 219, [M
+1
] 184, [M
+2
] 170, [M
+3
] 143

11. 2-chloro-N-(4-flurophenyl)acetamide (3k)
It was obtained from (1) with aqueous p-fluro
aniline in crystalline form. Yield %, mp 127-130
0
C,
and IR 3271.38 cm-1(NH-stretch: 2 amide) ,
1651.12 (C=O stretch:2 amide), 1535.39 (NH-
bend:2 amide), 1502.60 (C-N stretch), (C-Cl
stretch) , 825.56 (Para-disubstituted benzene ring),
1219.05 (C-F stretch), Mass spectrum [M
+
], m/z
199(100%).

CONCLUSION
The study involves the synthesis,
purification and characterization of various -
substituted chloroacetamide derivatives. We have
synthesized -substituted chloroacetamides
derivatives by using water as a solvent, due to
which the yield of product was increased from 60%
to 85% as compared to other organic solvents and
Also eliminated formation of the waste and
byproduct . It is simple ecofriendly method and
can be used as an alternative to the existing
methods which uses harmful organic solvents. We
have choosen water as a green solvents because
of its non-volatility and nonflammability,
The choice for one specific green solvent in
which carrying out a process depends on
economical and technical aspects as well as on the
intrinsic characteristics of a given reaction and/or
solvent. It is important to emphasize that the ideal
green solvent, suitable for each application, does
not exist, but it is possible to find from time to time
a suitable option for a specific need that will
reduce the impact of that application on the health
of humans and environment. Use of green
solvents in a flexible and pragmatic way, where
each improvement, also the least important, could
be a benefit for the scientific community and for
the entire society.


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International Journal of Pharmaceutical Research & Development ISSN: 0974 9446

Available online on www.ijprd.com
25
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