A catalytic symmetrical etherification

Article abstract of DOI:10.1039/a808980i

A novel, catalytic, thermal etherification produces minimal waste and can be carried out under almost neutral conditions.

Full text of DOI:10.1039/a808980i

A catalytic symmetrical etherification
Laurence Bagnell, Teresa Cablewski and Christopher R. Strauss*
CSIRO Molecular Science, Bag 10, Clayton South,Victoria 3169, Australia. E-mail: chris.strauss@molsci.csiro.au
Received (in Cambridge, UK) 17th November 1998, Accepted 5th January 1999
A novel, catalytic, thermal etherification produces minimal
waste and can be carried out under almost neutral condi-
tions.
corresponding oxonium ion as a better leaving group.1,2 The
reaction then can proceed through substitution by another
molecule of the alcohol or by elimination of water, followed by
acid-catalysed addition of the alcohol to the resulting olefin.
Although the overall reaction is also satisfied by eqn. (3), the
solution would remain acidic throughout.
By contrast, the present process requires participation by the
counterion X2 and utilises ostensibly neutral conditions. For it
to operate efficiently, X2 should be a good leaving group [to
satisfy eqn. (1)], an effective nucleophile [to accommodate eqn.
(2)] and a weak base to minimise competing elimination
reactions.12 Bromide and iodide possess these properties.13 To
the best of our knowledge, a critical participatory role for the
counterion of the acid has not previously been envisaged or
recognised.
Most methods for etherification use either strongly acidic or
basic conditions.1–3 Their disadvantages have been summarised
by Lemaire and co-workers, who explored hydrogenolysis of
hemiacetals as an alternative.4 The long-established Williamson
synthesis5 is still the most common procedure. It involves
substitution of an alkyl halide (RX) by a strongly basic alkoxide
or phenoxide (e.g. KOR or NaOR) and so is unsuitable if base
catalysed elimination of HX from RX can compete.6,7
A
stoichiometric amount of waste salt (KX or NaX) is also
produced. Importantly, inorganic salts account for the bulk of
industrial chemical wastes.7 Besides polluting soil and ground
water, salts can lower the pH of atmospheric moisture and have
been implicated in the formation of acid-dew.8 Hence, their
minimisation is essential.
Our research is directed toward technologies and method-
ologies for environmentally benign organic chemistry.6,9 We
now report a catalytic etherification that produces minimal
organic waste and that can be carried out without the addition of
acid or base.10
For a symmetrical ether, an excess of alcohol (ROH) and a
catalytic amount of RX are heated. A solvolytic displacement
reaction11a between RX and ROH affords R2O along with HX
or its elements [hereafter referred to as HX; eqn. (1)]. The
liberated HX reacts with another molecule of ROH to form
water and to regenerate RX [eqn. (2)]. If the rates of these
forward reactions are comparable, the concentration of HX will
be low throughout and that of RX will remain relatively
constant. Although HX and RX are stoichiometric reactants or
products in eqn. (1) and (2), they do not appear in the sum [eqn.
(3)]. The net process involves condensation of two molecules of
ROH to give R2O plus water.
The examples presented in Table 1 were obtained by heating
the reactants in glass-lined pressure vessels without water
removal. Conversions rather than yields have been quoted,
owing to the catalytic nature of the systems, and by-product
formation was negligible in all cases. Neat BunOH was
unreactive at 200 °C (entry 1), but in the presence of a catalytic
amount of BunBr it afforded Bun O without significant
2
consumption of the haloalkane (entry 2). A comparable result
was obtained with PhCH2CH2OH at 220 °C (entries 4 and 5).
Styrene or 1-phenylethyl derivatives, that might have been
anticipated through mechanisms involving elimination, were
not detected. Cyclopropylmethanol, although highly acid-
labile,14 was stable at reflux (entry 6), but in the presence of a
catalytic amount of cyclopropylmethyl bromide, it condensed to
form bis(cyclopropylmethyl) ether, without significant deple-
tion of the bromide or rearrangement (entry 7), until the
conversion was approximately 50%. This result indicated that
the concentration of acid was not sufficiently high to affect the
cyclopropylmethyl group.
As the reaction further progressed though, phase separation
occurred and HBr accumulated in the aqueous medium.
Consequently, the rate of etherification slowed and the
unreacted alcohol and the product ether were decomposed by
the acid to give cyclobutyl and homoallyl alcohols along with
mixtures of ethers containing cyclopropyl, cyclobutyl and
homoallyl functionalities.14
RX
HX
+
+
ROH
ROH
R2O
RX
+
HX
(1)
(2)
+
H2O
2 ROH
R2O + H2O (3)
A widely accepted mechanism of etherification catalysed by
strong acids (commonly, sulfuric acid is used) involves
protonation of the hydroxy function of an alcohol to give the
Nonetheless, the examples in Table 1 demonstrated the
process, its applicability for base- or acid-labile compounds
(entries 5 and 7, respectively) and the catalytic role of RX.
Table 1 Example reactions and conditions
Entry Starting material(s)
T /°C t/h Major product(s)
Conversion(%)
1
BunOH
200
200
200
220
220
120
2
1
1
no reaction
Bun2O
—
26
54
< 1
76
2
BunOH (10 ml) + BunBr (1 mol)
BunOH (10 mol) + BunBr (1 mol) + LiBr (1 mol
PhCH2CH2OH
3a
4
Bun2O
22 (PhCH2CH2)2O
21 (PhCH2CH2)2O
24 no reaction
24 bis(cyclopropylmethyl) ether
5
5
5a
6
PhCH2CH2OH (10 mol) + PhCH2CH2Br (1 mol)
Cyclopropylmethanol
Cyclopropylmethanol (10 mol) + cyclopropylmethyl bromide (0.9 mol) 115
7a,b
51
8
8a,c,d,e BusOH (10 mol) +BusBr (1 mol)
150
150
Bus2O(1:1 mixture of diastereoisomers)
Bus2O(1:1 mixture of diastereoisomers) 18
9a,c,d,e BusOH (10 mol) +BusBr (1 mol) +LiBr (1 mol)
a Concentration of bromo derivative essentially unchanged after the reaction. b Extended heating led to acid catalysed decomposition. See text. c Optically
d
e
pure BusOH also afforded a 1:1 mixture of diastereoisomers, suggestive of an SN1 mechanism. Prolonged heating led to some evolution of gas. Neat
BusOH did not react at 150 °C for 5 h.
Chem. Commun., 1999, 283–284
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The pathway was investigated by heating PhCH2CH2OH
with Bu4NBr (not entered in Table 1). After 20 h at 200 °C,
(PhCH2CH2)2O was not detected (but PhCH2CH2OBun was
produced by Hoffmann degradation, in low conversion).
PhCH2CH2Br and (PhCH2CH2)2O formed only after a few
drops of acid (HOAc) were added to the reaction mixture,
followed by further heating. This experiment indicated that the
presence of X2 was insufficient to drive the reaction and that
HX was required. We have also found that the process can be
started from eqn. (2). In an example, HBr (9 mol%) was heated
with PhCH2CH2OH at 200 °C. After 3 h, the product mixture
was no longer acidic and contained PhCH2CH2Br (9%) and
(PhCH2CH2)2O (6%) along with unreacted PhCH2CH2OH.
These results were all consistent with the pathway in eqn.
(1)–(3) and indicated that mechanisms proposed for acid-
catalysed etherification1,2 may in some cases need to accom-
modate possible participatory roles of the counterion.
As mentioned above, although hydroxy and alkoxy functions
are not readily displaced from carbon atoms, protonation in
strong acid greatly facilitates their leaving.1,2 Indeed, HBr and
HI have been employed as cleavage agents for ethers for well
over a century.15 Conversely, the rate of solvolytic displace-
ment of alkyl halides by alcohols [the forward reaction in eqn.
(1)] can be accelerated by a small amount of water.11b However,
excess water would shift unfavourably the position of equilib-
rium in eqn. (2) and promote the reverse reaction in eqn. (3).
These opposing factors indicate that, for etherification, deple-
tion of water should be beneficial but complete removal may be
detrimental. Also, when the concentration of alcohol is 10–50
times larger than that of RX, the first order rate constant of eqn.
(1) can rise considerably.16 Thus the rate and extent of reaction
in eqn. (1) will depend on the relative concentrations of RX and
ROH as well as on the concentration of water present. Entries 3
and 9 were consistent with reports that the addition of alkaline
metal salts also can accelerate solvolytic processes,17 including
the rate of ionisation of RX.18 Our results and published
data11,16–18 indicate that the catalytic process would operate
most effectively at low to moderate conversions and should be
amenable to continuous processing. This aspect and the
preparation of unsymmetrical and polyethers will be discussed
elsewhere.
Notes and references
1 H. Feuer and J. Hooz, The Chemistry of the Ether Linkage, ed. S. Patai,
Interscience, London, 1967, ch. 10, pp. 445–498.
2 N. Baggett, Comprehensive Organic Chemistry, series ed. D. Barton
and W. D. Ollis, vol. ed., J. F. Stoddart, Pergamon, Oxford, 1979, vol.
1, pp. 799–852.
3 O. Mitsunobu, Comprehensive Organic Synthesis, series ed. B. M. Trost
and I. Fleming, vol. ed., E. Winterfeldt, Pergamon, New York, 1991,
vol. 6, pp. 1–31.
4 V. Bethmont, F. Fache and M. Lemaire, Tetrahedron Lett., 1995, 36,
4235.
5 A. W. Williamson, J. Chem. Soc., 1852, 4, 229.
6 T. Cablewski, A. F. Faux and C. R. Strauss, J. Org. Chem., 1994, 59,
3408; K. D. Raner, C. R. Strauss, R. W. Trainor and J. S. Thorn, J. Org.
Chem., 1995, 60, 2456.
7 R. A. Sheldon, Chem. Ind. (London), 1997, 12.
8 H. Okochi, T. Kajimoto, Y. Arai and M. Igawa, Bull. Chem. Soc. Jpn.,
1996, 69, 3355.
9
C. R. Strauss and R. W. Trainor, Aust. J. Chem., 1995, 48, 1665; J. Li,
A. W.-H. Mau and C. R. Strauss, Chem. Commun., 1997, 1275; L.
Bagnell, M. Bliese, T. Cablewski, C. R. Strauss and J. Tsanaktsidis,
Aust. J. Chem., 1997, 50, 921; J. An, L. Bagnell, T. Cablewski, C. R.
Strauss and R. W. Trainor, J. Org. Chem., 1997, 62, 2505.
10 A patent application has been filed.
11 (a) A. Streitwieser Jr., Solvolytic Displacement Reactions, McGraw-
Hill, New York, 1962, p. 2; (b) pp. 34–38.
12 C. K. Ingold, Structure and Mechanism in Organic Chemistry, 2nd edn.,
Cornell University Press, 1969, ch. 7, pp. 418–561.
13 E. S. Gould, Mechanism and Structure in Organic Chemistry, Holt,
Rinehart and Winston, New York, 1959, ch. 8, pp. 250–313.
14 C. C. Lee and A. J. Cessna, Can. J. Chem., 1980, 58, 1075 and
references cited therein.
15 E. Staude and F. Patat, The Chemistry of the Ether Linkage, ed. S. Patai,
Interscience, London, 1967, ch. 2, pp. 21–80.
16 E. Gelles, E. D. Hughes and C. K. Ingold, J. Chem. Soc., 1954, 2918.
17 S. Winstein, E. Clippinger, A. H. Fainberg and G. C. Robinson, J. Am.
Chem. Soc., 1954, 76, 2597.
18 J. F. Bunnett and D. L. Eck, J. Org. Chem., 1971, 36, 897; L. C. Manege,
T. Ueda and M. Hojo, Bull. Chem. Soc. Jpn., 1998, 71, 589.
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