R.I. Lerrick et al.
ISBN 978-979-18962-0-7
Proceeding of The International Seminar on Chemistry 2008 (pp. 194-198)
Jatinangor, 30-31 October 2008
The Synthesis of 4-Hydroxy-3-Methoxybenzonitrile from Vanillin:
a Precursor of Synthesis of 3′′-methoxydaidzein
Reinner Ishaq Lerrick1*, Bambang Purwono2, Sabirin Matsjeh2
1
Chemistry Department, Faculty of Sciences and Techniques, Nusa Cendana University,
Jl. Adi Sutjipto Kampus Baru Penfui Kupang NTT
2
Chemistry Department, Faculty of Mathematics and Natural Sciences,
Gadjah Mada University, Bulak Sumur, Yogyakarta
*
Corresponding author, tel: +6285239025326, email: i_lerrick@yahoo.com.sg
Abstract
Isoflavone and its derivates have attracted researchers’ interest in recent year. According to the
esterogen like properties, daidzein and others isoflavone derivates have been used as medicine in
treatment of degenerative diseases such as arteriosclerosis, hot flash symptoms, osteoporosis and even
for breast and prostate cancer. Daidzein has become as a molecular model in order to develop new
more active drugs. Due to its close chemical structure similarity to vanillin, based on retro-synthesis
approach, vanillin could be used as starting material for synthesis of 3′-methoxydaidzein i.e. as 4hydroxy-3-methoxybenzonitrile. The synthesis was carried out through two steps of reaction i.e.
reduction of vanillin becoming vanillyl alcohol with NaBH4 then halogenations which was followed
by nitrilization of the product with PBr3 and KCN, respectively. Yields of synthesis were 83 % of
white crystal of vanillyl alcohol and 36 % of yellow crystal of 4-hydroxy-3-methoxybenzonitrile.
Keywords: isoflavone, 3′-methoxydaidzein, vanillin, 4-hydroxy-3-methoxybenzonitrile
benzoin (2) as the important intermediate precursor.
This synthesis path needs a benzylcarboxylate (3) or a
benzonitrile (4) derivates as the starting material [7].
However, benzonitrile step of reaction (HoubenHoesch reaction) is the favour one according to
shorter step of reaction and even can be carried out in
one-pot reaction [8].
Vanillin (5) which its structure resembles to
benzonitrile (4), can be used as raw material in order
to synthesis one of daidzein derivates i.e. 3′methoxydaidzein (8). Hydroxyl group which has
oriented at para position through aldehyde, an ease
converting group, makes vanillin becomes favourable
material [9]. Furthermore, the present of additional
methoxy group hopes increasing the anti degenerative
effect as donating effect of that group.
Introduction
Isoflavones, which mostly contain in cereals
(Leguminoceae) especially in soy bean, have been
proven experimentally showing biological activities
related to degenerative diseases such as
arteriosclerosis, breast and prostate cancer [1-4], and
reduced hot flash symptoms suffered by women
menopausal phase. Furthermore, synthetic form of
daidzein (1), one of major constituent of isoflavone,
has been used as medicine in osteoporosis treatment
[5-6]. Daidzein has also used as molecular model for
developing new more active compounds in recent
years.
Synthesis of new daidzein derivates as well as all
isoflavones synthesis involves o-hydroxydeoxy
HO
O
OH
HO
O
OH
O
OH
2
1
HO
NC
OH
4
Figure 1. Retrosynthesis of Daidzein
194
O
OH
3
R.I. Lerrick et al.
Proceeding of The International Seminar on Chemistry 2008 (pp. 194-198)
Jatinangor, 30-31 October 2008
H
O
NC
OH
NaBH4
HO
(1) PBr3-ether
methanol
OMe
OMe
OH
OH
5
6
(2) KCN,
Tween 80
Benzene
O
OMe
OMe
OH
7
O
OH
8
Figure 2. The Synthesis Steps of Synthesis of 3′-methoxydaidzein
In this research, there were two steps of aldehyde
conversion into the target material. The synthesis
covered reduction of aldehyde using sodium
borohydrate (6) and brominating of the alcohol which
was followed with nitrilization of the product
becoming 4-hydroxy-3-methoxybenzonitrile (7).
Results and Discussion
Materials and Method
Synthesis of vanillyl alcohol
Materials
Vanillin, NaBH4, KCN, PBr3, methanol,
dichloromethane, ether, benzene, Na2SO4, and Tween
80. All reagents utilized were pro analysis quality
from Merck.
Direct reduction of vanillin produce 63% of white
crystal (m.p. = 112-113 oC, lit. = 112-115 oC) [10].
The gas chromatogram shows that the product is high
pure.
extracted with 3 x 20 ml of benzene. The organic
layer was collected and was dried using Na2SO4. The
organic solvent was evaporated and the product was
analysed using FT-IR and GC-MS.
Procedure
Synthesis of vanillyl alcohol
Vanillin (0.9 g, 6.0 mmol) was putted into 100 ml
of Erlenmeyer flask and diluted with 50 ml of
methanol. Sodium borohydrate (NaBH4) (0.3 g, 8.0
mmol) was added into the solution while shaking. The
solution was stirred for over night.
Methanol was evaporated using Büchii evaporator
and the white residue was diluted with 50 ml of water
and then extracted using 3 x 20 ml
of dichloromethane. The organic layer was collected
and dried over Na2SO4. The solvent was removed in
vaccuo and the white crystal was determined its
melting point. Structure analysis was characterized
using FT-IR, 1H-NMR and GC-MS.
Figure 3. Gas Chromatogram of Vanillyl Alcohol
Analysis of that white crystal using FT-IR gives
several characteristic absorptions. Lack of the
aldehyde absorption i.e. at 1730 cm-1 and the two
peaks at around 2850 and 2750 cm-1 indicates that the
product is no longer an aldehyde. Moreover, the
presence of strong intensity peak at 1434.9 cm-1
corresponded to methylene (-CH2-) group strengthens
that vanillin has been reduced. Other functional
groups that appear are hydroxyl at 3440.8 cm-1,
aromatic at 1604.7 and 1512.1 cm-1, ether at ca.
1265.2 -1126.4 cm-1 and methyl at 1373.2 cm-1.
Further analysis using 1 H-NMR is showed in
Figure 5. According to the spectrum, there are six
magnetic types of proton represented by six peaks.
Peak A is hydroxyl proton due to its singlet and one
proton integration. Peak B belongs to 3 protons of
aromatic laid in δ = 6-7 ppm. Besides that, peak C, D
and E correspond to 2 singlet proton of methylen (CH2-), 3 singlet proton of methyl (-CH3) and 1 singlet
proton of benzyl hydroxyl which absorbs more up
field then phenolic proton (6.5 - 8.5 ppm),
respectively.
Synthesis of 4-hydroxy-3-methoxybenzonitrile
Vanillyl alcohol (0.2 g, 1.2 mmol) in 15 ml of
ether was placed in ice bath until the temperature -5
o
C then added 0.5 g (1.8 mmol) of potassium bromide
with stirring drop wise. Then stood the mixing for 2
hours and further for 2 hours at room temperature.
The solution was poured 5 ml of cooled water and
then transferred the solution into separator funnel.
The solution then extracted with ether (3 x 10 ml).
The combine organic layers were collected and dried
with sodium sulphate. The solvent was evaporated
and then collected as an oily product.
Vanillyl bromide was immediately added
potassium cyanide (0.16 g, 2.5 mmol) solution in 5 ml
of water, 5 ml of benzene and 0.1 g of Tween 80. The
solution then refluxed for 6 hours. Into separatory
funnel, the cooled solution is poured was then
195
R.I. Lerrick et al.
Proceeding of The International Seminar on Chemistry 2008 (pp. 194-198)
Jatinangor, 30-31 October 2008
Wavenumber (1/cm)
Figure 4 FT-IR spectrum of vanillin reduction product (KBr-Disc)
Figure 5. 1H-NMR of Vanillyl Alcohol
m/z
Figure 6. Mass spectrum of Vanillyl Alcohol
196
Proceeding of The International Seminar on Chemistry 2008 (pp. 194-198)
Jatinangor, 30-31 October 2008
Intensity
R.I. Lerrick et al.
Time (min)
%T
Figure 7. Gas chromatogram of nitrilization product
Wavenumber (1/cm)
Figure 8. FT-IR spectrum of nitrilization product (KBr-Disc)
m/z
Figure 9. Mass spectrum of nitrilization product
197
R.I. Lerrick et al.
Proceeding of The International Seminar on Chemistry 2008 (pp. 194-198)
Jatinangor, 30-31 October 2008
According to FT-IR and NMR spectrum, the
product of vanillin reduction is vanillyl alcohol. This
is proved by the mass spectrometer analysis.
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Synthesis of 4-Hydroxy-3-methoxybenzonitrile
Synthesis of 4-hydroxy-3-methoxybenzonitrile is
carried out in two series of reaction i.e. bromination
of vanillyl alcohol and nitrilization the product using
NaCN. Bromination reaction produced high yield
(98%) of oily product whereas nitrilization only gives
36% of yellow crystal. The malting point of the
product is 55-57 oC corresponded to literature i.e. at
56-57oC [10].
Analysis of nitrilization product using FT-IR is
shown in Figure 8. According to the spectrum, the
presence of medium absorption at 2252.86 cm-1
caused of –C ≡ N stretch indicates strongly that the
product is a cyanide compound. This closes to nitrile
characteristic absorption, which is around 2200-2300
cm-1 in medium to weak intensity.
Other functional groups that still present are
alkene’s system which belongs to substituted aromatic
system, methyl and methylene, hydroxyl and ether
group. Further more, analysis of that yellow product
with mass spectrometer justifies that the product is 4hydroxy-3-methoxybenzonitrile due to its M+ and
fragmentation pattern.
Conclusions
The series of synthesis using vanillin as a raw
material in this research yields: 83 % of vanillyl
alcohol, 36 % of 4-hydroxy-3-methoxybenzonitrile.
Acknowledgements
This research is a very small part of big series
of synthesis funded by Indonesian Directorate
General of Higher Education, DIKTI.
References
1. Winarsi, H., 2005, Isoflavon Berbagai Sumber,
Sifat dan Manfaatnya Pada Penyakit Degenartif,
Gadjah Mada University Press, Yogyakarta, 3.
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