Synthesis of p-hydroxy alkyl benzoates - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/9321/10/10_chapter 2.pdf · Synthesis of p-hydroxy alkyl benzoates Section A. Section

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Synthesis of p-hydroxy alkyl benzoates

Section A. Section A. Section A. Section A.

General introduction and literature survey of p-hydroxy alkyl

benzoates.

Section B.Section B.Section B.Section B.

Synthesis of p-hydroxy alkyl benzoates.

19

Section A:

General introduction and literature survey p-hydroxy

alkyl benzoates:

Introduction:

Parabens [Fig.2.1, 2.2, 2.3 and 2.4] have been attracting great

interest because of their importance in synthetic organic chemistry.

Parabens have been widely used as antimicrobial preservative

agents in foods, beverages, drugs and cosmetics for more than fifty

years due to their broad antimicrobial spectrum, [1]. Parabens are

very versatile in terms of food preservatives, differing from the

other preservatives such as benzoates, propionates and sorbates;

because they are not weak acid compounds but have a wide pH

range. The antimicrobial activity of parabens is directly dependent

on the chain length [2, 3].

In the plant world, 4-hydroxybenzoic acid and its

derivatives are commonly found in various vegetable foods, such as

barley, strawberries, black currants, peaches, carrots, onions, cocoa-

beans, vanilla; further in foods prepared from fruit plants such as

grapes and fruit juices, yeast extract, wine vinegar and also in

cheeses [4].

Methyl paraben found application in the synthesis of

dimethyl 4, 4 - (tetraphaioyldioxy) dibenzoates as a reactant for

monomer preparation [5]. Methyl and propyl p-hydroxybenzoate

are used in Rhamnolipid based formulation for fire suppression and

chemical and biological hazards [6] Methyl and propyl p-hydroxy

20

benzoates are used in collagen or gelatin based crumble as a

preservatives [7].Polyester is a manufactured fiber in which the

fiber-forming substance is any long-chain, synthetic polymer

composed of at least 85% of an ester of a substituted aromatic

carboxylic acid [8].

Paraben are esters of p-hydroxybenzoic acid, from which the name

is derived common parabens include methylparaben[Fig.2.1],

ethylparaben [Fig.2.2], propylparaben [Fig. 2.3] and butylparaben

[Fig. 2.4]

OH

O OCH3

OH

O OCH2CH3

OH

O OCH2CH2CH3O OCH2CH2CH2CH3

OH

Fig. 2.1. Fig. 2.2. Fig.2.3. Fig.2.4.

Phukan et al. [9] reported a synthesis of parabens using

montmorillonite K10 clay as heterogeneous catalyst. Methyl, ethyl,

and propyl parabens were synthesized by esterification of p-

hydroxy benzoic acid with corresponding alcohols [Fig. 2.5].

O OH

OH

ORO

OH

+ + H2OMontmorillonite K10 Clay

RefluxROH

Fig. 2.5.

21

Theodor et al. [10] reported an improved method for the

synthesis of 4-hydroxy methyl benzoate using p-hydroxy benzoic

acid through dipotasium salt of p-hydroxy benzoic acid and

esterification was carried out by dimethyl sulphate and adjusting

pH of reaction mass by sulphuric acid, NaOH, and ammonia.

Thereafter the crude product was purified by charcoal and sodium

dithionate to give p-hydroxy methyl benzoates [Fig.2.6].

O OH

OH

OKO

OK

CH3OO

OH

KOH Conc H2SO4 (pH=5)Dimethyl sulphate

33% NaOH(pH=6)Water,Liq NH3

Purification1. charcoal2.filter

3.Sodium dithionate4.H2SO4(pH=8.5)

OO

OH

CH3

Fig. 2.6.

John et al. [11] reported that a stream of dry oxygen was

passed through a solution of 1-(4-hydroxy phenyl)–2, 2, 2-trichloro

ethanol in methanol and a solution of sodium in methanol

containing cupric chloride dihydrate and 1,10 phenanthroline

hydrate was added and the reaction was allowed to continue for a

further 2h at room temperature and the reaction mixture was then

poured into dilute hydrochloric acid, extracted with ether and the

combined extracts washed with water. The dried MgSO4 extracts

was evaporated to dryness and the residue crystallized from

aqueous ethanol to give methyl 4-hydroxy benzoate (yield 66%)

[Fig. 2.7].

CH3O

O

OH

ClCl

Cl

OH

OH

Dry O2

Sodium in methanolCuCl2.2H2O

1,10 phenanthroline Hydrate25-30°C,Dil.HCl

Fig. 2.7.

22

Hosangadi et al. [12] reported treatment of variety of aromatic

carboxylic acids with alcohols in the presence of thionyl chloride

results in excellent yields of corresponding esters. This esterification

system is compatible with a wide assortment of functional groups

[Fig. 2.8].

O

OH SOCl2, ROH

O

ORX X

Fig. 2.8.

Schlater et al. [13] demostrated esterification of 4-hydroxy

benzoic acid under microwave irradiation with 42 % yield [Fig. 2.9].

O

OH

OH

O

OCH3

OH

H2SO4

+ CH3OHMW

Fig. 2.9.

Desmurs et al. [14] reported esterification of p-hydroxy benzoic acid

using N, N-diisopropyl ethyl amine with isopropyl bromide gives

isopropyl p-hydroxy benzoate with moderate yield [Fig. 2.10].

O OH

OH

+CH3

CH3

BrN,N diisopropyl ethyl amine

O O

CH3CH3

OH

+ CH3CH2N(C3H7)2.HBr

Fig. 2.10.

23

Shi Xiaobo Li Chungen [15] reported esterification of buty paraben

using Dodecatungstophosphoric acid gave moderate yield

[Fig. 2.11].

OH

OHO

HO

OH

OO

Dodecatungstophosphoric acid

Fig. 2.11.

Raghaven et al. [16] reported efficient synthesis method of n-butyl

parabens under microwave irradiation in the presence of an

inorganic salt Zinc chloride as a catalyst. The main advantages of

this methodology are better selectivity, rate enhancement and

reduction of thermal degradation and higher energy consumption

efficiency when compared to traditional heating. Yield is 43%

[Fig. 2.12].

O OH

OH

OCH2CH2CH2CH3O

OH

+ + H2OCH3CH2CH2CH2OHZnCl2

MW

Fig. 2.12.

M.Gorsd et al. [17] investigate that trifluoro methane sulphonic acid

immobilized on zirconium was found to be on effective catalyst for

esterification of 4-hydroxy benzoic acid with propyl alcohol gives

moderate yield [Fig. 2.13].

24

O OH

OH

OCH2CH2CH3O

OH

+ + H2OCH3CH2CH2OH

trifluoromethanesulphonic acid immobilised on Zirconium oxide

Fig. 2.13.

Lin Qi et al. [18] reported the synthesis of n-butyl p –hydroxy

benzoate with n-butanol and p-hydroxybenzoic acid as reactants

and solid super acid ZrO2/SO42- as catalysts has been studied. The

yield of butyl p-hydroxybenzoate was around 87% [Fig. 2.14].

O OH

OH

OCH2CH2CH2CH3O

OH

+ + H2OCH3CH2CH2CH2OHZrO2/SO4

2-

solid superacid supported

Fig. 2.14.

GAO Wen-yi et al. [19] The ethyl p-hydroxybenzoate was

synthesized by esterification of p-hydroxybenzoic acid with ethanol

using solid super acid S_2O~ (2-)_8/ZrO_2-Al_2O_3 as catalyst. The

yield of product reaches to 79.0% [Fig. 2.15].

O

OH

OH

O

OCH2CH3

OH

+ CH3CH2OHSolid Superacid

S-2O~(2-)-8 /ZrO- 2 -Al-2O-3

Fig. 2.15.

Alireza R. Sardarian et al. [20] reported aromatic carboxylic

acid esterification in the presence of triphenylphosphin dibromide

or triphenylphosphinediiodide and N,N-dimethylaminopyridine in

25

dichloromethane with 81% yield [Fig. 2.16].

R

O

OH

R = Alkyl, Aryl

Ph3PX3

- HX

X

PPh3 R

O

O

R'OH

- Ph3PO- HX

R' R

O

O

Fig. 2.16.

Jeum Jong kim et al. [21] reported esterification of carboxylic acid

with alcohol using 4,5-dichloro-2-[(4-nitrophenyl)

sulphonyl]pyridazine-3(2H)-one in the presence of 4-(N,N-

dimethylamino)pyridine in refluxing tetrahydrofuran gave the

corresponding ester in good yield. [Fig. 2.17].

C

O

OHR + R' OH

NO 2SNN

O

O

OCl

Cl

PyridineRCOOR'

Fig.2.17

26

Section B Synthesis of p-hydroxy alkyl benzoates Introduction

Azeotropic distillation is an essential unit operation in

today’s processes. Applications using azeotropic distillation are

readily apparent in the chemical process industry, specialty

chemicals and food industries.

The main advantages of azeotropic distillation are in allowing

the separation of chemicals that cannot feasibly be separated by

conventional distillation, such as systems containing azeotrope or

pinch points, and improving the economics of the separation by

saving energy and increasing recovery.

A minimum-boiling azeotrope can be formed by the

introduction of an azeotrope-forming compound (entrainer) to an

existing azeotropic mixture or close boiling mixture for which

separation by conventional distillation is not feasible. One example

is alcohol dehydration. Ethanol and water form a minimum-boiling

azeotrope with ethanol as the major component and therefore

ethanol cannot be completely dehydrated by conventional

distillation. Benzene forms a ternary azeotrope with ethanol and

water, which boils at a lower temperature and will therefore remove

the water with some ethanol overhead, leaving dry ethanol as a

bottoms product.

Similarly esters are produced by reacting alcohols with

organic acids. The reaction is reversible and therefore unless one of

the products is removed, the ester yield is limited. Assuming the

reaction is equilibrium-limited and not rate-limited, higher

conversions can be obtained by removing one of the products. For

instance, if during the reaction the water is removed, the reaction

27

will be driven by equilibrium to produce more ester product. High

purity esters can be produced with azeotropic distillation to

simultaneously remove water and alcohol from the esters using

aromatic and aliphatic hydrocarbons as entrainers.

There are distinct advantages to using azeotropic distillation,

including energy savings, increased recovery and ability to separate

components contained in close boiling, pinch point and azeotropic

mixtures. Azeotropic distillation will undoubtedly remains a viable

alternative for simplifying difficult separations found in industry

[22]. Parabens have synthetically important skeleton and possess

very potent pharmacological activities. Although many synthetic

protocols are reported for the preparation of parabens, most of these

suffer from one or more disadvantages such as harsh reaction

conditions, long reaction time, unsatisfactory yield, low purity,

multistep purification, hazardous catalyst, large quantity of effluent

and tedious workup.

Herein, we report the simple and efficient and economical

method of synthesis to get highly pure compound with short

reaction time and easy workup procedure for the synthesis of p-

hydroxybenzoic acid esters by azeotropic distillation technique

using toluene as azeotropic agent in presence of minimum amount

of concentrated sulphuric acid with corresponding alcohol

[Fig. 2.18].

O

OH

OH+ ROH

H2SO4/Toluene

Azeotropic distillation

RO

O

OH

Fig. 2.18.

28

The mechanism of esterification involves the following steps

OH

O

OH+

OH

OH

OH C+

OH

OH

OH C+

H

O R O+

OH

OH

OH R

H

O+

OH

OH

OH R

HHH

O

O+

OH

OH R

H

O

O

OH C+

R

H

O

O

OH C+

R O

O

OH R

H+

:+

+H+

HSO 4-

H2SO 4

H

H

O

O+

OH

OH R

1) Protonation of carboxyl group by H+ of the acid catalyst.This makes the carbonyl carbon more strongly electropositive

2) Attack By nucleophile

3) Transfer of proton to one of the -OH groups

4) The -OH group leaves as water molecule gives protonated ester

5) Elimination of Proton

-H2O

-H+

Fig. 2.19.

29

Experimental

Melting point was determined in open glass capillaries and is

uncorrected. 1H NMR spectra were recorded at room temperature

on Brucker “AVANCE 400” MHz spectrometer in CDCl3 using TMS

as an internal standard. Reaction was monitored by TLC on

aluminum sheet precoated with silica gel 60F254. p -hydroxybenzoic

acid and alcohols were purchased from Merck, India. Alcohols were

purified by distillation before use. Wave length was determined on

UV Spectrometer model Shimadzu 1601

Experimental procedure for the synthesis of p-hydroxy ethyl

benzoates

A 500 mL 4-necked round bottom flask fitted with overhead

mechanical stirrer, a dropping funnel, a thermometer and dean-

stark with condenser. Flask was charged with 100 mL Toluene, 2 mL

concentrated Sulphuric acid, p-hydroxybenzoic acid (50 gm, 0.362

mole) and ethanol (16.5 gm, 0.35 mole) and heated the reaction

mixture at 95-98°C and continuously added ethanol (28.0 gm, 0.6

mole) through dropping funnel within 5 h then performed

azeotropic distillation with continuous removal of water formed in

reaction mixture. The progress of reaction was monitored by TLC.

After completion of reaction, reaction mixture was cooled to 5°C.

Filtered the reaction mixture and washed with water (25mL x 3) and

dried in vacuo to afford the pure product. The purity of compound

was checked by HPLC [23,24] .The structures of compounds were

confirmed on the basis of IR, 1H NMR and mass spectra. Similarly

the compounds of the series shown in the Table-2.1 were

synthesized by using above procedure and characterization data is

given in Table 2.2.

30

Table 2.1

Efficient synthesis of p-hydroxy alkyl benzoates

Entery No.

Alcohol used

Temp. range (°C)

Reaction Time

(h) Product obtained

Yield (%)

Purity (%)

1 Methanol 90-95 5 p-hydroxy methyl

benzoate 94 99.96

2 Ethanol 95-98 5 p-hydroxy ethyl

benzoate 95 99.90

3 n-Propanol 90-105 6

p-hydroxy

n-propyl benzoate

95 99.90

4 n-Butanol 90-105 6

p-hydroxy

n-butyl benzoate

93 99.89

5 iso butanol 90-107 6 p-hydroxy

isobutyl benzoate 90 99.97

6 n-Pentanol 90-107 6

p-hydroxy

n-pentyl benzoate

88 99.80

31

Table 2.2

Characterization data of p-hydroxy alkyl benzoates

Sr.

No.

Substituents

‘R’

M.P./ B.P.

(°C)

Molecular

formula

Molecular

weights

λ Max.

(nm)

1 Methanol 121 – 123 C8H8O3 152 256

2 Ethanol 114 – 115 C9H10O3 166 256

3 n-Propanol 93 - 95 C10H12O3 180 256

4 n-Butanol 68 - 70 C11H14O3 194 257

5 Iso Butanol 68.5-69 C11H14O3 194 257

6 n-Pentanol 28-30 C12H16O3 208 258

Melting points of synthesized compounds were taken by open

capillary method and are uncorrected.

Spectral discussion [25, 26]

IR-Spectra

Synthesized compound were scanned for IR Spectra on Brucker FT-

IR (Alpha-P) using KBr. (Fig.2.20 and 2.21). Spectral results are

listed in Table 2.3 and spectra are included after table.

32

Table 2.3

IR Spectral data of p-hydroxy alkyl benzoates.

Sr. No.

Structure of Compounds

υO-H

cm-1

υC-

alkyl

cm-1

υC=O

cm-1

υC-H

aromatic

cm-1

υC-O

str.

cm-1

υC-X

para

disub.

cm-1

1.

OH

O OCH 3

3294 2850-

3000 1682

1514-

1432

1165

-

1118

850

2.

OH

O OCH 2CH 3

3222 2850-

3000 1672

1592-

1449

1169

-

1168

849

3.

OH

O OCH 2CH 2CH 3

3274 2980 1676 1518-

1440

1163

-

1125

849

4.

OH

O OCH2CH2CH2CH3

3383 2956 1678 1510-

1467

1165

-

1127

852

5. CH CH2 C O O

CH3

CH3

OH

3367 2962 1680 1513-

1479

116-

1127 846

33

34

35

1H NMR Spectra [Fig.2.22, 2.23 and 2.24]

Synthesized compounds were scanned for 1H NMR using CDCl3 and DMSO as a solvent on Bruker “AVANCE 400 “ MHz spectrometer using TMS as an internal standard. Spectral results are listed in Table 2.4 and spectra are included after table.

Table 2.4 1H NMR – Chemical Shifts in p- hydroxy alkyl benzoates.

Sr. No.

Structure of Compounds

Chemical Shifts in B ppm

1.

OH

O OCH 3

3.78(s,3H,-COOCH3) Protons 6.86(d,2H,3&5 Ar-H) Protons 7.82(d,2H,2&6 Ar-H) Protons 10.33(s,1H,Phenolic –OH) Proton

2.

OH

O OCH 2CH 3

1.28(t,3H,-COOCH2CH3) Protons 4.24(q,3H,-COOCH2CH3) Protons 6.85(d,2H,3&5 Ar-H) Protons 7.81(d,2H,2&6 Ar-H) Protons 10.33(s,1H,Phenolic –OH) Proton

3.

OH

O OCH 2CH 2CH 3

0.93(t,3H,-COOCH2CH2CH3) Protons 1.67(sextet,2H,-CH2CH2CH3) Protons 4.14(t,2H,-COOCH2CH2CH3) Protons 6.86(d,2H,3&5 Ar-H) Protons 7.82(d,2H,2&6 Ar-H) Protons 10.31(s,1H,Phenolic –OH) Proton

4.

OH

O OCH2CH2CH2CH3

0.91(t,3H,-COOCH2CH2CH2CH3) Protons 1.39(sextet,2H,-CH2CH2CH2CH3) Protons 1.64(quint,2H,- CH2CH2CH2CH3) Protons 4.19(t,2H,-CH2CH2CH2CH3) Protons 6.85(d,2H,3&5 Ar-H) Protons 7.82(d,2H,2&6 Ar-H) Protons 10.31(s,1H,Phenolic –OH) Proton

5.

CH CH 2 C O O

C H 3

C H 3

O H

0.94(d,6H,-CH-(CH3)2)Protons 1.97(m,,1H ,-CH-(CH3)2) Protons 3.98(d,2H,-CH2,-CH-(CH3)2) Protons 6.87(d,2H,3&5 Ar-H) Protons 7.82(d,2H,2&6 Ar-H) Protons 10.32(s,1H,Phenolic –OH) Proton

36

37

38

39

Mass spectrum [24, 25]

Synthesized compounds were scanned for mass spectrum on Shimadzu GCMS QP 5050A make Shimadzu Corporation Japan, mode EI. Spectral results are listed in Table 2.5 and spectra are included after table [Fig.2.25, 2.26].

Table 2.5 Mass fragmentation values of p-hydroxy alkyl benzoates.

Sr. No.

Structure of the Compounds

Molecular weight (Calcd.)

M/Z Values

1.

OH

O OCH 3

152 152,121,93,65,53,40.

2.

OH

O OCH 2CH 3

166 166,138,121,93,65,53,40.

3.

OH

O OCH 2CH 2CH 3

180 180,151,138,121,93,65,53,40

4.

OH

O OCH 2CH 2CH 2CH 3

194 194,165,138,121,177,93,65,

53,40

5.

CH CH 2 C O O

CH3

CH3

OH

194 194,177,138,121,93,65,43,41

.

40

41

42

Mass fragmentation pattern:

The mass fragmentation patterns of some p-hydroxy alkyl benzoate

are given the representative cases [Fig.2.27].

Mass fragmentation pattern of p-hydroxy butyl benzoate

O-CH 2-CH 2-CH 2-CH 3

C

O

OH

e-

70 ev

O-CH 2-CH 2-CH 2-CH 3

C

O

OH

- OH

O-CH 2-CH 2-CH 2-CH 3

C

O

+

+ .

m/z = 177

O-CH 2-CH 2

C

O

OH

-CH 2-CH 3

+

.

m/z = 165

m/z = 194

Molecular ion

+ .

CH 2-CH 3

H CH 2

CO

OH

O

CH

+ .

m/z = 138

COH

OH

O

CH 2 CH CH 2 CH 2.

OH

CO

+

-O-CH 2-CH 2-CH 2-CH 3

.+

m/z = 121

+

- CO.

m/z = 93

- CO.

+

m/z = 65

C4H5 C3H4

m/z = 53 m/z = 40

+ +-CH-CH. .

H O

.

Fig. 2.27

43

Results and discussion:

The development of environment friendly technologies is a

major goal of present research in chemistry. Synthetic esters are

generally prepared by reaction of alcohol with organic carboxylic

acid in presence of catalyst such as sulphuric acid, the reaction is

known as Fischer esterification. The Fischer esterification is a

reversible reaction. The equilibrium is pushed to the product side by

taking excess of a reactant by continuously removing the water

formed in the reaction.

We achieved simple and effective method for the synthesis

of p-hydroxybenzoic acid esters by azeotropic distillation technique

using Toluene as azeotropic agent in presence of minimum amount

of concentrated sulphuric acid with corresponding alcohol. This

method helps to avoid the etherification of free hydroxyl group and

polycondensation of phenol containing carboxylic acid as an

impurity. The product produced by this technique gives extremely

pure and further purification is not required.

Esterification of p-hydroxybenzoic acid with common

alcohols was carried out under similar conditions. Good to excellent

yields and perfect selectivity were obtained in all cases.

Azeotropic technique seems to be more effective, efficient and

economical to get highly pure compound with short reaction time

and easy workup procedure. Reaction and azeotropic distillation

can be carried out in same reaction vessel and as water formed in

the reaction, it can be removed continuously by ternary azeotropic

distillation and aqueous bottom phase separates out via phase

separator. Reaction will complete within 5-6 h with minimum

44

amount of alcohol. Recovered toluene can be used as such for next

batch and corresponding alcohol can be used after distillation.

CONCLUSION

In summary, a novel method for the synthesis of p-hydroxy alkyl

benzoates by azeotropic distillation technique using toluene as

azeotropic agent in presence of minimum amount of concentrated

sulphuric acid with corresponding alcohol was developed on high

yield with extremely high purity for the first time.

The main advantages of this methodology are

1) This novel method helps to avoid the etherification of free

hydroxy group and polycondensation of phenol containing

carboxylic acid as an impurity.

2) Extremely high purity product obtained with good yield

3) Easy synthetic procedure

4) For commercial point of view, process is economical

5) Toluene and excess alcohol can be recycled

6) Low energy consumption

(7) No additional purification required.

8) One pot synthesis.

45

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