JOURNAL OF THE CHINESE

CHEMICAL SOCIETY

Article

Mohrs Salt Hexahydrate: A Novel, Cheap and Powerful Reagent for Green Synthesis
of Biscoumarins on Water
Saeed Khodabakhshi* and Mojtaba Baghernejad
Young Researchers Club, Gachsaran Branch, Islamic Azad University, Gachsaran, Iran
(Received: Sept. 11, 2012; Accepted: Dec. 21, 2012; Published Online: Feb. 1, 2013; DOI: 10.1002/jccs.201200489)

A new and convenient method for the synthesis of biscoumarins based on the condensation of 4-hydroxycoumarin and aromatic aldehydes in the presence of Mohrs salt hexahydrate (ferrous ammonium sulfate
hexahydrate) as a novel catalyst on water is developed. This method has advantages such as the use of inexpensive and available reagent, avoidance of organic solvents, short reaction times, and high product
yields.
Keywords: Mohrs salt; Biscoumarin; On-water; Aldehyde; Ferrous ammonium sulfate
hexahydrate.
INTRODUCTION
Coumarins have attracted the attention of chemists
because they are biologically active so that they reduce the
HIV activity and some coumarins have shown cytostatic
activity and therefore can be considered as potential candidates for anti-cancer therapy.1 Biscoumarins, the bridge
substituted dimers of 4-hydroxycoumarin, have enormous
potential as anticoagulants.2 Dicoumarol is also an anticoagulant that functions as a vitamin K antagonist.3 It is the
hemorrhagic agent responsible for the sweet clover disease
of cattle,4 and has also been employed for the prevention
and treatment of thrombosis.5 There are some methods described in the literature for the synthesis of bis-4-hydroxycoumarins using different catalysts or reagents in various
conditions.6-12 Bis-4-hydroxycoumarins have been generally synthesized by refluxing 4-hydroxycoumarin and various aldehydes in ethanol for several hours. However, some
of the reported methods suffer from drawbacks, such as the
use of expensive or synthetic reagents and organic solvents.6,8 Also, some of them require harsh conditions,10 tedious work-up in certain cases12 and long reaction times to
complete.11
With an objective to develop environmentally benign
reaction conditions and media for organic transformations
with excellent efficiency and selectivity, water has been
shown to be a useful solvent or media.13 Recently, organic
synthesis on water was reviewed by Fokin and co-workers.14 In this context, we report the use of Mohrs salt hexahydrate (ferrous ammonium sulfate hexahydrate) as an
eco-friendly and readily available reagent for the synthesis
of substituted biscoumarins on water.

RESULTS AND DISCUSSION

As a part of our continual efforts toward the development of novel, efficient, and green procedures for organic
reactions,15-18 we turned our attention toward the condensation of 4-hydroxycoumarin (1) and aromatic aldehydes 2 in
the presence of Mohrs salt hexahydrate as catalyst to produce bis-4-hydroxycoumarin derivatives 3 (Scheme I).19
Scheme I Synthesis of biscoumarins using Mohrs
salt under reflux in water
O
HO

OH

Fe2+

H
2

S O
O
O

H2O, Reflux
25-40 min.

O
2

O
OH HO
3

X
2

To identify the suitable reaction conditions for the

synthesis of 3 using Mohrs salt, the reaction of 4-hydroxycoumarin (1) and benzaldehyde (2a) was selected as a
model (Scheme II).
As can be seen in Table 1, we found that in the absence of the catalyst, the reaction was not completed, even
at long reaction times in several solvents (Entry 1-3). In another experiment, in order to show the effect of solvent or
media on the reaction progress, we employed several solvents which the results have been shown in Table 1. It can
be concluded that protonic solvents such as EtOH, MeOH,
and H2O can accelerate the condensation reaction. It should
be also noted that 4-hydroxycoumarin is soluble in alcohol,
acetone and ether, but it has low solubility in water.

* Corresponding author. Tel: +98 742 333923; Fax: +98 742 3332003; E-mail: saeidkhm@yahoo.com
J. Chin. Chem. Soc. 2013, 60, 495-498

2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Article

Khodabakhshi and Baghernejad

Scheme II Reaction of benzaldehyde with 4-hydroxycoumarin in various conditions

Table 2. Synthesis of biscoumarin derivatives in the presence of

Mohr's salt under reflux in water
Entry

Through screening, we found that this reaction was

completed with Mohrs salt (5 mol%) under refluxing H2O
about 30 min (Entry 6). Higher loadings of catalyst did not
affect a marked influence on the product yield or reaction
rate (Entry 8). After optimization of the reaction conditions, to prove the general applicability of this method, different aldehydes and 4-hydroxycoumarin were examined
(Table 2).
The nature of X group on the aldehydes showed no
significant effect on the reaction rate or product yield. It
should be mentioned that our efforts for the synthesis of
biscoumarins using aliphatic aldehydes were unsuccessful.
The problem with alkyl aldehydes is likely due to their
enolization during the reaction.
In order to show the merit of present method in comparison with other methods used for the similar reaction,
we have tabulated some of the results in Table 3. As it is evidence from the results, the use of Mohrs salt as catalyst
and water as a media can be considerable from the environmental and economic aspects.
Although so many different reagents and catalysts
Table 1. Optimization of the reaction conditions through various
solvents and temperatures
Conditions

Time
(min)

Yield
(%)

1
2
3
4
5
6
7
8
9
10
11
12

Catalyst-free/EtOH/reflux
Catalyst-free/EtOH:H2O/reflux
Catalyst-free/H2O/reflux
Mohr's salt (5 mol%)/EtOH/reflux
Mohr's salt (5 mol%)/EtOH:H2O/reflux
Mohr's salt (5 mol%)/H2O/reflux
Mohr's salt (2 mol%)/H2O/reflux
Mohr's salt (10 mol%)/H2O/reflux
Mohr's salt (5 mol%)/MeOH/reflux
Mohr's salt (5 mol%)/THF/reflux
Mohr's salt (5 mol%)/CH2Cl2/reflux
Mohr's salt (5 mol%)/solvent-free/100 C

300
300
300
45
40
30
70
35
40
60
120
120

25
25
25
85
95
98
90
95
90
85
75
50

496

www.jccs.wiley-vch.de

Entry

3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l

Time (min) Yield [a] (%) M.p. (C)Ref.

X
H
4-F
4-Cl
4-Br
4-NO2
4-OMe
4-PhCH2O
2-Cl
4-Me
4-iPr
4-Cl-3-NO2
3,4,5-(OMe)3

30
25
35
40
20
25
25
30
35
40
25
25

98
90
98
90
97
95
90
95
90
85
90
90

229-2316
267-2696
253-2556
265-2676
232-2346
241-2436
227-2297
226-2286
268-2706
245-24720
265-2677
243-2457

[a] Yields of isolated products.

Table 3. Comparison of our method with other methods for the

synthesis of 3a
Entry
1
2
3
4
5
6
7

Time/Yield (%)Ref.

Conditions
NaHSO4.SiO2/toluene/100

C
Indion 190 resin/toluene/100 C
Silica-supported Preyssler
nanoparticles/EtOH/r.t.
SO3H-functionalized ILs/70 C
H6[PMo9V3O40]/EtOH:H2O
Catslyst-free/microwave/H2O/150 W,
150 C
Mohr's salt/H2O/reflux

30 min/896
30 min/926
30 min/928
2 h/959
15 h/3010
9 min/ 8511
30 min/98 [a]

[a] This work.

have been reported for this type of condensation, the use of

Mohrs salt seems to be attractive and provides another
valuable option for chemists because it is a safe and easily
accessible reagent. Besides, the use of water instead of organic solvents is more reasonable because of its safety and
cheapness. All of these factors are in accord with green
chemistry principles. The structures and purity of the obtained products were deduced from their IR, elemental
analysis, and NMR spectral data.
CONCLUSION
In summary, we have introduced a condensation reaction leading to biscoumarin derivatives starting from simple and readily available precursors. This reaction can be
regarded as a new approach for the preparation of synthetically and pharmaceutically relevant heterocyclic systems.
This approach includes some important aspects such as
high yields, short reaction times, simple work-up proce-

2013 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

J. Chin. Chem. Soc. 2013, 60, 495-498

JOURNAL OF THE CHINESE

CHEMICAL SOCIETY

Mohrs Salt Catalyzed Synthesis of Biscoumarins

dures, and use of water as a clean media, which make this

protocol a useful and an attractive procedure for the synthesis of biscoumarin derivatives.

124.98, 124.41, 116.87, 116.68, 116.39, 115.63, 115,41, 105.49,

103.95, 35.68. Anal. Calcd. for C25H15NO8: C, 65.65; H, 3.31; N,
3.06. Found: C, 65.89; H, 3.24; N, 3.17.

Compound 3g
1

EXPERIMENTAL
General

H NMR (DMSO-d6, 400 MHz) d ppm: 11.59 (b, 2H),

7.93-7.81 (m, 2H), 7.63-7.58 (m, 2H), 7.44-7.31 (m, 5H), 7.22-

All chemicals were purchased from Merck and Aldrich.

7.06 (m, 2H), 6.90 (d, 2H, J = 8.8 Hz), 6.31 (s, 2H), 5.04 (s, 2H).

The reactions were monitored by thin layer chromatography

13

C NMR (DMSO-d6, 100 MHz) d ppm: 164.97, 164.78, 156.44,

(TLC; silica-gel 60 F254, n-hexane: ethyl acetate). IR spectra were

152.13, 137.21, 132.68, 131.90, 131.77, 128.48, 128.35, 127.84,

recorded on a FT-IR JASCO-680 and the 1H NMR spectra were

127.75, 127.71, 127.64, 123.90, 123.83, 123.76, 123.16, 117.76,

obtained on a Bruker-Instrument DPX-400 MHz Avance 2 model.

116.34, 115.95, 115.23, 114.31, 104.32, 90.96, 69.09, 35.21.

The varioEl CHNS Isfahan Industrial University was used for ele-

Anal. Calcd. for C32H22O7: C, 74.12; H, 4.28. Found: C, 74.29; H,

mental analysis. All products were characterized by comparison

4.15.

of their spectra and physical data with those reported in the literature.6,7

Preparation of bis-4-hydroxycoumarins
A mixture of 4-hydroxycoumarin 1 (2 mmol), aromatic aldehydes 2 (1 mmol) and Mohrs salt (5 mol%) in water (10 mL)
was refluxed for the appropriate time mentioned in Tables 2. The

ACKNOWLEDGEMENTS
The authors are very grateful to Haj Khodadad
Taghipour (the head of Young Researchers Club, Islamic
Azad University of Gachsaran, Iran) for his kind cooperation.

progress of reaction was monitored by TLC. After completion of

reaction, the solid compound obtained was filtered off and the

REFERENCES

crude products were purified by recrystallization from EtOH.

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Selected spectral data

Compound 3a
1

H NMR (CDCl3, 400 MHz) d ppm: 11.41 (b, 2H), 8.08 (d,

J = 6.8 Hz, 1H), 8.00 (d, J = 7.2 Hz, 1H), 7.42 (m, 2H), 7.63 (m,
2H), 7.33 (m, 2H), 7.38 (m, 2H), 7.23 (m, 2H), 7.27 (m, 1H), 6.11
(s, 1H). 13 C NMR (CDCl 3 , 100 MHz) d ppm: 169.30, 166.88,
165.81, 164.62, 152.51, 152.29, 135.19, 132.83, 128.65, 126.88,
126.59, 124.81, 124.38, 116.99, 116.63, 105.60, 103.92, 36.15.
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3.79.

Compound 3c
1

H NMR (DMSO-d6, 400 MHz) d ppm: 10.70 (b, 1H), 9.99

(s, 1H), 7.89 (d, 2H, 8 Hz), 7.58 (t, 2H, J = 8 Hz), 7.40-729 (m,
6H), 7.12 (d, 2H, J = 8.4 Hz), 6.28 (s, 1H). 13C NMR (DMSO-d6,
100 MHz) d ppm: 165.89, 164.55, 152.26, 140.22, 132.69,
132.28, 131.72, 131.22, 130.74, 129.08, 123.93, 123.53, 123.16,
118.31, 116.35, 115.84, 103.60, 90.95, 35.72. Anal. Calcd. for
C25H15ClO6: C, 67.20; H, 3.38. Found: C, 67.35; H, 3.29.

Compound 3e
1

H NMR (CDCl3, 400 MHz) d ppm: 11.57 (s, 1H), 11.35 (s,

1H), 8.08 (d, 1H, J = 8 Hz), 8.03 (d, 1H, J = 8 Hz), 7.68-7.64 (m,
2H), 7.44 (d, 4H, J = 8 Hz), 7.21 (dd, 2H, J = 8 Hz, 5.2 Hz), 7.03
(t, 2H, J = 8 Hz), 6.07 (s, 1H).

13

C NMR (CDCl3, 100 MHz) d

ppm: 169.23, 166.86, 165.93, 164.63, 162.94, 160.50, 152.54,

152.29, 133.01, 130.87, 130.84, 128.22, 128.14, 124.98, 128.14,
J. Chin. Chem. Soc. 2013, 60, 495-498

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