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SYNTHETICAPPLICATIONOF MICELLARCATALYSIS.

WILLIAMSONSSYNTHESISOF ETHERS

BRANKO URSIC

Laboratory of Organic Chemistry and Biochemistry, Faculty of Science,

University of Zagreb, Strossmayerov trg 14, 41000 Zagreb, Yugoslavia

Received

in UK 16

August1988)

Abstract

- A simple, rapid and efficient procedure for the preparation of

di-alkyl, simple phenyl-alkyl and hindered phenyl-alkyl ethers has been de-

veloped. Based on the principle of micellar catalysis the method involves

alkylation of the alkoxide or the phenoxide ion with an alkyl chloride at

80C in the presence of cationfc mieelles. For the preparation of phenyl-

-alkyl ethera normal micelles ware used, while for the di-alkyl ethers rc-

verse micelles were more effective. By increasing the ionic strength of the

solution the rate of formation of phenyl-alkyl ethers could be increased.

Preparation of ethers is an important synthetic reaction for which a wide variety of procedures

has been developed during the last hundred years.

The Williamson reaction, discovered in 1850,

is still the best general method for the preparation of unsymmetrical as well as symmetrical

ethers.

1

However, this method is not satisfactory for ethers containing a tertiary group (because

of eliminations while with secondary groups low yields are obtained.

2

By the use of phase-transfer

catalysis an improvement of the Williamson reaction was achieved.

3

A number of very useful synthe-

tic applications of cellar catalysis has been reported,

4

but to our knowledge, no detailed stu-

dies on the application of this technique to the synthesis of ethers.

There are few available procedures for the conversion of phenols or alcohols into ethers which

do not comprise the initial formation of the corresponding phenoxide or alkoxide ions. Among these

the most widely used is the direct alkylation with diazomethane or diazoalkane5

which is mostly li-

mited to methyl ethers and seldom used because of the obnoxious nature of the reagent. Alkylation

has also been accomplished with orthocarbonate esters,

6

dialkyl oxalate esters,?

onium salts,

and

by treating phenols with alcohols in the presence of dicyclohexylcarbodiimide.

9

However, none of

these methods can be considered as a general method for the preparation of ethers.

In our work we used aqueous micelles to achieve perturbations which are synthetically favourable

and succeeded in controlling the aromatic brominativn

10

and enone reduction.

11

In this paper a new

synthesis of ethers performed under mild conditions in the presence of normal and reverse micellea

is reported.

RESULTSAND DISCUSSION

As already mentioned cationie micelles fCTAB)* are more effective than anionic vnes (SDS)** in the

synthesis of phenyl ethers (see Table 1).

So the alkylation rate of phenol in SDS is lower by a factor

o

100 1000

than in CTAB micelle. Cetyltrimethyl ammonium phenvxide.

formed by the reaction of CTAB

cetyltrimethylammonium bromide

**sodium dodecyl sulfate

6677

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78

8.

JURSIC

Table 1. Yields f alkyl phenyl thers hOR prepared rom phenol nd alkyl

halide n the presence f CTAB as micelle

RX

CH31

CH3Cti2Br

CH3CH2CH2Br

t+,HQCl

n-C5H,,Cl

n-C10H2,Cl

n-C,2H25Cl

n-C,6H33Br

PhOR

Yield, RX PhOR

Yield, '

PhOCH3 97 CH2=CH-CH2Cl PhOCH2CWH2 96

PhOCH2CH3

93

PhCH2Cl PhOCH2Ph

95

PhOCH2CH2CH3

95

PhCH2CH2Cl PhOCH2CH2Ph

87

PhOCIiHg

87

Cl(CH212Cl PhOfCH212OPh

89

PhOC5H1,

91

Cl(CH2$Cl PhO(CH&OPh

86

PbC10H21

89

Cl(CH2)ACl PhO(CH~)~OP~

91

PhCV25

86

Cl(CH215Cl

PhOlCH2)50Ph

93

PhoC16H33

63

Er(CH2)6Br PhO(CH2160Ph

90

'Refers to isolated aterial.

and sodium henolate n water is a surface ctive ompound hich dissolves lkyl halides. he phe-

noxy ion, as evidenced y

1

H NMR spectroscopy,

2

resides n the tern layer of the normal icelle 0

the nucleophilic isplacement f phenoxy on on primary lkyl chloride akes place on the inter-

f ce

of micelle

fFigure f.

Figure 1

It was of interest o examine he

Table 2. Etherificationf hindered henols ith

butyl chloride n the presence f CTAB as micelle

ArOH

Yield,

2,6-Dimethylphenol

95

2,6-Dimethyl-4-t-butylphenol 82

2,&Dimethoxyphenol

91

Z,d-Di-t-butylphenol 80

aRefer to isolated aterial.

applicability f the presented ethod to the esterification

11

of highly indered henols,

here generation f the phenoxide onswas reported o be difficult.*

A number f highly hindered henol8 ere therefore reated ith butyl chloride nder miceilar on-

ditions ith 20% sodium ydroxide. xcellent ields f the corresponding ryl butyl ethers ere

obtained Table ). As expected, here was no reaction n the absence f CTAB, which was confirmed

(by gas chromatography) or the etherification f 2,6-dimethylphenolith butyl chloride.

This synthesis f aryl ethers

s very

convenient ecause he work-up

s

simple nd involves

a

turation f the reaction ixture ith sodium hloride,

iltration, xtraction nd purification

either by distillation r crystallization.

he products btained re 98% pure as determined y

gas

chromatography nd 'H NMR analysis.

Preparation f mixed n-alkyl ther8 from the corresponding lcohols nd n-alkyl hlorides n

20% or 50% aqueous odium r potassium ydroxide n the presence f normal icelles s not 80 ef-

fective, ather low yields ere obtained nd a certain mount f symmetric ther was formed (40%).

This yield was raised to 40% when a large axce88 f alkyl chloride 83 used. The reaction f ben-

zyl alcohol ith a two-fold xcess f I-pentyl hloride n 50% potassium ydroxide n the pre-

sence of CTAB resulted n a very poor yield (30%) f the expected enzyl ther: he major product

was diphenyl ther. owever,

he desired enzyl entyl ther was obtained n an excellent ield

when the reaction as performed nder the liquid-solid

4

reverse cellar conditions. he experi-

mental conditions or the solid-liquid everse icellar water-pool )rocess re exceedingly

simple. therification s usually carried out in tbe presence f the organic hase talky1 hloride

and alcohol1 nd with a two-fold xoess f sodium r potassium ydroxide s the solid hase. n cases

where solid products ere formed tetrahydrofuranolution f alkyl chloride nd alcohol as used

as a liquid hase. he results re presented n Table 3. The amount f water plays an important

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yntheticapplicationfmicetlaratalysis

6679

role in the solid-liquid everse lcellar atalysis:

n the absence f water no nucleophilic is-

placement eaction etherification)akes place.

his finding s similar o that valid for phase

transfer ystems.

5

Table 3. Yields of dfalkyl thers repared rom alkyl halides nd

alcohols

in

the

presence of

CTAB as reverse fcelle

R'OH

RX R'OR

Yield, '

CH30H

C2H5OH

n-C3H70H

n-C5H,,0H

(CH~)~CHOH

n-C4H90H

n-C5H,,OH

CH3CH2CH(CH3)OH

(CH3)3COH

1CH313COH

(CH~)~COH

(CH3j3C0H

(CH~)~COH

PhCH?OH

n-C4H9OH

n-C5H,,0H

n-C,2H250H

c>a

H

OH

n-C5H,,Cl

n-C5HIIC1

n-C5H,,Cl

n-C3H.,Br

n-C5H11C1

n-C5H,,Cl

n-C4H9Cl

n-C5H,,C1

CH31

CH3CH2Br

n-C3H7Br

n-C4H9Cl

n-C5H,,C1

CH2sCH-CH2Cl

CH2=CH-CH2C1

CH2=CH-CH2C1

CH2= CH-CH2Cl

CH31

n-C4H9Cl

cH30C5Hll

C2H50C5H11

c3H70c5Hll

C3H70c5Hll

(CH3)$HOC5H,,

C4H90C5Hll

C4H90c5Hll

~H3CH~CH(CH3)OC~H,,

KH313COCH3

KH313COCH2CH3

(CH3)3COC3H7

CH313COC4H9

fCH313COC5H1,

PhCH20CH2CHzCH2

C4H90CH2CH.CH2

C5H,,0CH2CH=CH2

C,2H250CH2CH=CH2

5

OCH

3

0

C4H9

a

a

86

81

91

a7

a5

a2

a5

a3

87

86

87

91

95

96

90

81

87

aRefers to isolated aterial.

With an excess f water two non-miscible iquid-phases re formed nd the yield of the reaction s

decreased. he schematic resentation f the proposed atalysis s given in Figure . The reverse

micelle issolves odium ydroxide nd removes t from the solid state to the organic ulk; the

hydroxide on is a very strong ase and forms alkoxide on thus enabling he displacement eaction

with alkyl chloride n the interface f the reverse icelle.

surfactant

A

water)

Figure . Schematic resentation f

water-pool reverse icelle) atalysis n

the esterification f alcohols ith alkyl chlorides

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B JURW

EXPERIMENTAL

Melting points were determined on a Kofler hot-stage microscope apparatus and are uncorrected.

IR spectra were recorded on a Perkin-Elmer Model 257 grating infrared spectrophotometer using a

standard liquid film and Nujol mull techniques.

Nuclear magnetic resonance spectra were recorded on

a JEOL 90 FXQ spectrometer, as solutions in deuteriochloroform, using tetramethylsilane as a in-

ternal standard. Where possible, the identity of products was confirmed by comparing their IR and

NMR spectra with those of commercial samples.

Analytical gas-liquid chromatography was done on a

Vsrian odel 920 gas

chromatograph with standard

Carbowax 0M columns, ommercially vailable

(Fluka) sodium dodecyl sulfate (SDS) and cetyltrimethylammonium bromide (CTAB) were used without

further purification.

Starting phenols,

alcohols, and alkyl chloride were purchased commercially and, where necessary

purified before use. Analytical and spectral data for the product ether8 were consistent,with the

assigned structures. The products were 98% pure as determined by gas chromatography and H NMR

analysis.

General rocedure or the preparation f phenolic thers

To a 20 aqueous solution of sodium hydroxide (1000 mL1 the corresponding phenol (0.1 molf and

cetyltrimethylammonium bromide (3.2 g; 0.1 mol) were added.

The mixture was heated to 60C for 0.5

hr and then allowed to cool to ambient temperature, after which the corresponding alkyl halide (0.12

mol) wa8 added with stirring. After re-heating to 8O*C for 5 hrs,

the reaction mixture was saturated

with sodium chloride and the aqueous layer separated by filtration from the solid sodium chloride.

The aqueous solution was extracted with diethyl ether (x31. The ethereal extract was washed twice

with 20% sodium hydroxide to remove unreacted phenol,

and then with saturated sodium chloride so-

lution. After drying with sodium sulfate, the solvent was evaporated and the residual ether puri-

fied by distillation or crystallization.

When methyl iodide was used as an alkylation agent, due to hydrolysis a notable excess of

methyl iodide (x5) was required.

General

procedure or the preparation f

unsymmetrical alkyl ethers

A mixture of alkyl chloride (0.2 mol),

alcohol (0.2 mol), water (1.0 mL), cetyltrimethylammo-

nium bromide (3.64 g; 0.01 mol), sodium hydroxide 516 g; 0.4 mol), and, in the case of solid

products, tetrahydrofuran (50 mL) was heated to 70 C and stirred vigorously overnight. The reac-

tion suspension was then allowed to cool and the solid residue was separated by filtration. The

residue was washed several times with ether or tetrahydrofuran, the organic solutions were com-

bined and dried over anhydrous sodium sulfate.

Ether or tetrahydrofuran was carefully evaporated

and the oily residue purified by distillation or crystallization.

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