R.I. Lerrick et al.

Proceeding of The International Seminar on Chemistry 2008 (pp. 194-198)

Jatinangor, 30-31 October 2008

194

The Synthesis of 4-Hydroxy-3-Methoxybenzonitrile from Vanillin:

a Precursor of Synthesis of 3′′′′-methoxydaidzein

Reinner Ishaq Lerrick

1*, Bambang Purwono

2, Sabirin Matsjeh

2

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 4-

hydroxy-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

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

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 (Houben-

Hoesch 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.

O

O

OH

O

O

HO

2

HOHO

1

OHOH

OH

3

OH

4

NC

Figure 1. Retrosynthesis of Daidzein

ISBN 978-979-18962-0-7

R.I. Lerrick et al.

Proceeding of The International Seminar on Chemistry 2008 (pp. 194-198)

Jatinangor, 30-31 October 2008

195

OH OH

OH

OH

OH

OMe

NC

OMeOMe

5 6

OH

OMe

HO O

O

78

NaBH4

methanol

(1) PBr3-ether

(2) KCN, Tween 80 Benzene

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).

Materials and Method

Materials Vanillin, NaBH4, KCN, PBr3, methanol,

dichloromethane, ether, benzene, Na2SO4, and Tween

80. All reagents utilized were pro analysis quality

from Merck.

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.

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 oC 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

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.

Results and Discussion

Synthesis of vanillyl alcohol

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.

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 1H-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.

R.I. Lerrick et al.

Proceeding of The International Seminar on Chemistry 2008 (pp. 194-198)

Jatinangor, 30-31 October 2008

196

Figure 4 FT-IR spectrum of vanillin reduction product (KBr-Disc)

Figure 5. 1H-NMR of Vanillyl Alcohol

Figure 6. Mass spectrum of Vanillyl Alcohol

Wavenumber (1/cm)

m/z

R.I. Lerrick et al.

Proceeding of The International Seminar on Chemistry 2008 (pp. 194-198)

Jatinangor, 30-31 October 2008

197

Figure 7. Gas chromatogram of nitrilization product

Figure 8. FT-IR spectrum of nitrilization product (KBr-Disc)

Figure 9. Mass spectrum of nitrilization product

Time (min)

Inte

nsity

Wavenumber (1/cm)

% T

m/z

R.I. Lerrick et al.

Proceeding of The International Seminar on Chemistry 2008 (pp. 194-198)

Jatinangor, 30-31 October 2008

198

According to FT-IR and NMR spectrum, the

product of vanillin reduction is vanillyl alcohol. This

is proved by the mass spectrometer analysis.

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 4-

hydroxy-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.

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