-M/88

53.OOi.00
0 1988PcrgsmonPrrsspk

7-w&-&cm Vol.44No.21.Pp.6617
~06680.
1988
Printed
inGreatBritain.

SYNTHETICAPPLICATIONOF MICELLARCATALYSIS.
WILLIAMSONSSYNTHESISOF ETHERS

BRANKOJURSIC

Laboratory
University

of Organic
of Zagreb,

Chemistry and Biochemistry,

Faculty
Strossmayerov
trg 14, 41000 Zagreb,

(Received

in UK

of Science,
Yugoslavia

16 August1988)

procedure for the preparation

of
Abstract - A simple, rapid and efficient
di-alkyl,
simple phenyl-alkyl
and hindered phenyl-alkyl
ethers has been developed.
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 rcverse 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
has been developed
is

still
1

ethers.

the best

general

However,

this

of eliminations
catalysis
tic

the last

method for

of &cellar

of this

technique

the initial

the most widely

used is the direct

these

formation

phenols

alcohols

methods can be considered

synthesis
is

in controlling

of ethers

of procedures

discovered

as well

in 1850,

as symmetrical

ethers

the conversion

alkylation

of ethers.
of phenols

of the obnoxious
6
dialkyl

esters,

into

or alkoxide

or diazoalkane5
nature
oxalate

the preparation

ions.

ethers

which

Among these

which is mostly

of the reagent.
9

li-

Alkylation

onium salts,

esters,?

of dicyclohexylcarbodiimide.

method for

to achieve

or alcohols

phenoxide

with diazomethane

in the presence

as a general

the aromatic

performed

for

of the corresponding

In our work we used aqueous micelles

and succeeded

reaction,

of unsymmetrical

to the synthesis

for

with orthocarbonate

with

which a wide variety

low yields

and seldom used because

been accomplished

by treating

groups

procedures

do not comprise

to methyl ethers

for

The Williamson

containing
a tertiary
group (because
2
By the use of phase-transfer
are obtained.
the Williamson reaction
was achieved. 3 A number of very useful synthe4
catalysis
has been reported,
but to our knowledge, no detailed
stu-

an improvement of

There are few available

has also

reaction

the preparation

with secondary

on the application

mited

synthetic

hundred years.

method is not satisfactory

while

applications

dies

is an important

during

a and

However, none of

of ethers.

perturbations
which are synthetically
favourable
11
10
and enone reduction.
In this paper a new

brominativn

under mild conditions

in the presence

of normal and reverse

micellea

reported.
RESULTSAND DISCUSSION

As already
synthesis
of

100-1000

mentioned
of phenyl

cationie
ethers

micelles
(see

than in CTAB micelle.

cetyltrimethylammonium
**sodium dodecyl

Table

fCTAB)* are more effective

1).

So the alkylation

Cetyltrimethyl

rate

than anionic

ammonium phenvxide.

bromide

sulfate
6677

vnes (SDS)**

in the

of phenol in SDS is lower by a factor

formed by the reaction

of CTAB

8. JURSIC

6678

Table 1. Yields of alkyl phenyl ethers PhOR preparedfrom phenoland alkyl

halide in the presenceof CTAB as micelle

RX

PhOR

Yield,%"

RX

PhOR

Yield, %'

CH31

PhOCH3

97

CH2=CH-CH2Cl

PhOCH2CWH2

96

CH3Cti2Br

PhOCH2CH3

93

PhCH2Cl

PhOCH2Ph

95

CH3CH2CH2Br

PhOCH2CH2CH3

95

PhCH2CH2Cl

PhOCH2CH2Ph

87

t+,HQCl

PhOCIiHg

87

Cl(CH212Cl

PhOfCH212OPh

n-C5H,,Cl

PhOC5H1,

91

Cl(CH2$Cl

PhO(CH&OPh

89
86

n-C10H2,Cl

PbC10H21

89

Cl(CH2)ACl

PhO(CH~)~OP~

91

86

Cl(CH215Cl

PhOlCH2)50Ph

93

63

Er(CH2)6Br

PhO(CH2160Ph

90

n-C,2H25Cl
n-C,6H33Br

PhCV25
PhoC16H33

'Refers to isolatedmaterial.
and sodium phenolatein water is a surfaceactive compoundwhich dissolvesalkyl halides.The phe12
noxy ion, as evidencedby 1H NMR spectroscopy, resideson the Stern layer of the normalmicelle80

the nucleophilicdisplacementof phenoxy ion on primaryalkyl chloridetakes place on the interface

of micelle fFigureIf.
Table 2. Etherification
of hinderedphenolswith
butyl chloridein the presenceof CTAB as micelle

ArOH
2,6-Dimethylphenol

95

2,6-Dimethyl-4-t-butylphenol

82

2,&Dimethoxyphenol

91
80

Z,d-Di-t-butylphenol

Figure 1

Yield,%"

aRefer to isolatedmaterial.
It was of interestto examinethe applicabilityof the presentedmethod to the esterification
11
of highly hinderedphenols,where generationof the phenoxideions was reportedto be difficult.*"
A number of highly hinderedphenol8were thereforetreatedwith butyl chlorideunder miceilarconaryl butyl ethers were
ditionswith 20% sodium hydroxide.Excellentyields of the corresponding
obtained (Table2). As expected,there was no reactionin the absenceof CTAB, which was confirmed
(by gas chromatography)
for the etherification
of 2,6-dimethylphenol
with butyl chloride.
This synthesisof aryl ethersis very convenientbecausethe work-upis simple and involvessaturationof the reactionmixturewith sodium chloride,filtration,extractionand purification
The productsobtainedare 98% pure as determinedby gas
either by distillationor crystallization.
chromatography
and 'H NMR analysis.
Preparationof mixed n-alkylether8 from the correspondingalcoholsand n-alkylchloridesin
20% or 50% aqueous sodium or potassiumhydroxidein the presenceof normal micellesis not 80 effective,rather low yields were obtainedand a certainamount of symmetricether was formed (40%).
This yield was raised to 40% when a large axce88 of alkyl chloride~83 used. The reactionof benzyl alcoholwith a two-foldexcess of I-pentylchloridein 50% potassiumhydroxidein the presence of CTAB resultedin a very poor yield (30%) of the expectedbenzyl ether: the major product
was diphenylether. However,the desiredbenzyl pentyl ether was obtainedin an excellentyield
74
when the reactionwas performedunder the liquid-solid reverse&cellar conditions.The experimental conditionsfor the solid-liquidreversemicellar ("water-pool")
processare exceedingly
simple.Etherification
is

usually

carried

out in tbe presenceof the organicphase talky1chloride

and alcohol1and with a two-foldexoess of sodium or potassiumhydroxideas the solid phase.In cases
where solid productswere formeda tetrahydrofuran
solutionof alkyl chlorideand alcohol was used
as a liquid phase.The resultsare presentedin Table 3. The amountof water plays an important

Synthetic application
ofmicetlar
catalysis

6679

role in the solid-liquidreversemlcellarcatalysis:in the absenceof water no nucleophilicdisplacementreaction(etherification)

takes place. This findingis similarto that valid for phase
15
transfersystems.
Table 3. Yields of dfalkyl ethers preparedfrom alkyl halidesand alcohols
in the presence
of CTAB as reversemfcelle
R'OH

RX

CH30H

n-C5H,,Cl

C2H5OH

n-C5HIIC1

n-C3H70H

n-C5H,,Cl

n-C5H,,0H

n-C3H.,Br

(CH~)~CHOH

n-C5H11C1

n-C4H90H

n-C5H,,Cl

n-C5H,,OH

n-C4H9Cl

CH3CH2CH(CH3)OH

n-C5H,,C1

C4H90c5Hll
~H3CH~CH(CH3)OC~H,,

(CH3)3COH

CH31

KH313COCH3

a5

1CH313COH

CH3CH2Br

KH313COCH2CH3

a3

(CH~)~COH

n-C3H7Br

(CH3)3COC3H7

87

(CH3j3C0H

n-C4H9Cl

(CH313COC4H9

86

(CH~)~COH

n-C5H,,C1

fCH313COC5H1,

87

PhCH?OH

CH2sCH-CH2Cl

PhCH20CH2CHzCH2

91

n-C4H9OH

CH2=CH-CH2C1

C4H90CH2CH.CH2

95

n-C5H,,0H

CH2=CH-CH2C1

C5H,,0CH2CH=CH2

96

n-C,2H250H

CH2= CH-CH2Cl

C,2H250CH2CH=CH2

90

R'OR
cH30C5Hll
C2H50C5H11
c3H70c5Hll
C3H70c5Hll
(CH3)$HOC5H,,
C4H90C5Hll

CH31

c>a

Yield,%'

OCH

5
OH

n-C4H9Cl

C4H9

a2

a5
86
81
91
a7
a5
a2

81

87

aRefers to isolatedmaterial.
With an excess of water two non-miscibleliquid-phases
are formed and the yield of the reactionis
decreased.The schematicpresentationof the proposedcatalysisis given in Figure 2. The reverse
micelledissolvessodium hydroxideand removesit from the solid state to the organicbulk; the
hydroxideion is a very strong base and forms alkoxideion thus enablingthe displacementreaction
with alkyl chlorideon the interfaceof the reversemicelle.

(surfactant
A

(water)

Figure 2. Schematicpresentationof "water-pool"(reversemicelle)catalysisin

the esterification
of alcoholswith alkyl chlorides

6680

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" internal 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 Model 920 gas chromatograph with standard Carbowax20M columns,Commerciallyavailable
(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 procedurefor the preparationof phenolicethers

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 solution. After drying with sodium sulfate, the solvent was evaporated and the residual ether purified 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 procedurefor the preparationof unsymmetrical alkyl ethers

A mixture of alkyl chloride (0.2 mol), alcohol (0.2 mol), water (1.0 mL), cetyltrimethylammonium 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 reaction 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 combined and dried over anhydrous sodium sulfate. Ether or tetrahydrofuran was carefully evaporated
and the oily residue purified by distillation or crystallization.
REFERENCES
l.a) A.W. Williamson, J. Chem. Sot., ", 229 (1952).
b1O.C. Dermer, Chem. Revs., 2, 409 (1934).
c)J. March, Advanced Organic Chemistry, McGraw-Hill, New York, 1968 and 1985.
d1I.G.
Vasi and R.K. Desai,
J. Inst. Chem. Calcuta 43 (1971); C.A. 2, 63024e (19711.
2. B. Sj8berg
and K. Sjl)berg,
Acta Chem. Stand., 26 275 (19721.
3. a) A. McKillop, J.C. Fiand, and R-P. Hug, Tetrahedron, 30, 1379 (1974).
bl H.H. Freedom and R.A. Dubois, Tetrahedron Lett., 3351 (1975).
cl A. Merz, Angew. Chem.. 85, 868 (1973).
d) R.M. Nouquier and M. Mchich, J. Org. Chem., 50, 3296 (1985).
e) B.C. ZupanfiE and M. SopEiE, Synthesis, 123 (1979).
4. a) J.A. Nikles and C.N. Sukenik, Tetrahedron Lett., 4, 4211 (1982).
b) J.K. Sutter
and C.N. Sukenik, J. Org. Chem., 9, 1295 (1984).
c) A. Natrajan, J.D. Ferrara, W.J. Youngs, and C.N. Sukenik, J. Am. Chem. Sot., 109, 7477 (1987).
d) M. Livnek, J.K. Sutter, and C.N. Sukenik, J. Org. Chem., 52, 5039 (1987).
ef R.B. Lennox and R.A. McClelland, J. Am. Chem. Sot., s,
3771 (19861.
5. a) See e.g. C.A. Buehler and D.E. Pearson, Survey of Organic Synthesis, pp. 285-382,
Wiley-Interscience, New York, 1970.
b) H. Zollinger, Azo and Diazo Chemistry, Interscience, New York, 1961.
6. 8. Smith, Acta Chem. Stand., 2,
1006 (1956).
7. E.E. Smissan, M.D. Corbett,
S. Et-Antably,
and K.C. Kroboth,
J. Org. Chem., 37, 3944 (1972).
8. O.C. Dermer and G.E. Ham, Ethylenimine
and other
Aziridines,
Academic Press,
New York, 1969.
9. E. Vowinkel,
Chem. Ber., 99, 1479 (1966).
10. B. Ju&i&, Tetrahedron, 44, 1553 (1988).
11. B. JurLif and D.E. Sunko, J. Chem. Research, 000 (1988).
12.a) C.J. Suckling and A.A. Wilson, J. Chem.Soc., Chem. Comm., 613 (1981).
b) C.J. Suckling and A.A. Wilson, J. Chem. Sot., Perkin Trans., 2, 1616 (1981).
C)
J-J. Jacobs, R.A. Anderson, and T.R. Watson, J. Pharm. Pharmac., 23, 149 (19711.
13.L.A. Cohen, J. Org. Chem., g, 1333 (1957).
14. Applicability of liquid-solid reverse micellar catalysis to the preparation of many organic
compounds has been recently described:
a) B. Jurgid, J. Chem. Research, 000 (1988).
b) 8. Jurgid, J. Chem. Sot., Chem. Comm., submitted for publication.
15. a) H.A. Zahalka and Y. Sasson, J. Chem. Sot., Chem. Comm., 1652 ($984).
b) 0. Arral and Y. Sasson, J. Am. Chem. Sot., 110, 185 (1988).