Reactivity in Cleavage of Dimethoxybenzenes
J . Org. Chem., Vol. 61, No. 23, 1996 8073
CCl4) δ 2.2 (s, 3H), 3.5 (m, 3H), 5.5 (broad s, 1H), 6.3 (m, 3H);
MS m/z 138 (M+). 4-Meth oxy-3-m eth ylp h en ol was prepared
from o-cresol by a method identical to that described above
for 4-methoxy-2-methylphenol. After distillation (bp 115-135
°C/4.5 Torr) and purification by flash chromatography, the
product, which solidified after a few minutes in the freezer,
was recrystallized three times from toluene and light petro-
leum ether; separation of an oil was avoided by chilling the
warm solution quickly by means of a salt/ice/water bath: small
white needles; yield 1.4%; mp 45-46 °C (lit.41 46-46.5 °C);
1H NMR (60 MHz, CCl4) δ 2.0 (s, 3H), 3.6 (s, 3H), 5.8 (broad
s, 1H), 6.3 (m, 3H). The δ 5.8 signal shrank on addition of
one drop of D2O and shifted upfield to δ 4.5. 3,4-(Meth ylen e-
d ioxy)tolu en e was synthesized from piperonal in a Huang-
Minlon-modified Wolff-Kishner reduction identical to that
described above for 3,4-dimethoxytoluene: yield 56%; bp 42
are the ones that break. A key difference between the
two substrates is that, whereas 3,4-dimethoxytoluene is
a true diether, the two oxygen atoms of 3,4-(methylene-
dioxy)toluene are in acetal functionality. Others12,33 have
observed that acetals of phenols, when cleaved by alkali
metals, tend to suffer rupture of aryl-oxygen bonds.
In seeking to understand this remarkable change, let
us note that change from alkyl-oxygen to aryl-oxygen
scission can also be caused by change of solvent.4 For
example, anisole is mainly cleaved to phenol in ammonia
(this work) and in hexamethylphosphorotriamide34 but
to phenylpotassium in heptane.35 The trend is for less
polar solvents more to favor aryl-oxygen scission. Mel-
loni and co-workers5,7 have made good use of the solvent
effect in synthesis.
A plausible interpretation is that two major factors
affect the sense of scission: (a) the basicity and (b)
solvation or ion-pairing of the oxyanion released. Release
of the less basic (aryloxide) anion is favored if solvation
is good, but if solvation is poor the exceptionally tight
ion-pairing of a highly basic (alkoxide) ion with an alkali
metal ion is energetically favored and alkyl-oxygen
scission occurs. For acetals, two influences of an R-alkoxy
substituent increase the likelihood of aryl-oxygen scis-
sion: it diminishes the basicity of an alkoxide ion (signifi-
cant for polar solvents) and probably increases ion-
pairing with an alkali metal cation (relevant especially
to nonpolar solvents). Lesser basicity for ROCH2O- is
suggested by the fact that pKa for HOCH2OH in water is
13.336 vs 15.5 for CH3OH.37 An R-alkoxy group may help
ion-pairing by chelation of the cation by the bridging
oxygen atom.
1
°C/4 Torr (lit.45 196 °C/740 Torr); H NMR (60 MHz, CCl4) δ
2.2 (s, 3H), 5.6 (s, 2H), 6.3 (m, 3H); MS m/z 136 (M+); >99%
pure by GC analysis. All other reagents used were purchased.
Sta n d a r d P r oced u r e for Clea va ge Exp er im en ts. Steps
1-4 were performed under an atmosphere of nitrogen and with
constant stirring. (1) Approximately 100 mL of ammonia was
distilled from sodium metal into a three-necked round-bottom
flask fitted with a well-type reflux condenser cooled by solid
carbon dioxide. For reactions in which THF was used as a
cosolvent, about 20 mL of THF, freshly distilled, was added.
(2) Approximately 6.7 mmol of substrate was added to the
flask. (3) Approximately 27 mmol of sodium metal was added
to the flask. (4) The mixture was allowed to react under reflux
for the specified length of time. (5) The reaction mixture was
quenched with a minimum amount of sodium benzoate (usu-
ally 1-2 g). A color change from blue to orange signaled
completion of this addition. (6) The excess base was neutral-
ized with ammonium nitrate (usually 1-2 g). A color change
from orange to colorless signaled completion of this addition.
(7) Approximately 3 mmol of an appropriate GC internal
standard was added to the flask. The internal standards found
to be most useful were, for anisole, m-dimethoxybenzene; for
m-dimethoxybenzene, phenol, o-dimethoxybenzene, or p-meth-
oxyphenol, or a combination thereof; for o-dimethoxybenzene,
m-dimethoxybenzene; for p-dimethoxybenzene, o-dimethoxy-
benzene and m-methoxyphenol; for 2,5-dimethoxytoluene, 3,4-
dimethoxytoluene; for 3,4-dimethoxytoluene, 2,5-dimethoxy-
toluene; for 3,4-(methylenedioxy)toluene, 2,5-dimethoxytoluene.
(8) After the addition of 100 mL of chilled diethyl ether and
with the condenser (from which all the carbon dioxide had
sublimed) left attached to the flask, the ammonia was allowed
to evaporate, a process that took approximately 3 h after the
carbon dioxide had all sublimed. The purpose of having
diethyl ether present was to reduce entrainment of more
volatile compounds, such as benzene, with the evaporating
ammonia. (9) Enough 5% aqueous sodium bicarbonate solu-
tion (usually 50-75 mL) was added to dissolve all solid
material. (CAUTION: If particles of sodium metal had clung
to the upper walls or necks of the flask, fire might result.) (10)
The ether and aqueous layers were separated, and the aqueous
phase extracted three times with 25 mL portions of diethyl
ether. All the ether extracts were combined and dried over
magnesium sulfate. (11) The ether solution was analyzed by
a Hewlett-Packard 5840A gas chromatograph (GC) equipped
with either a 10 m methyl silicone capillary column or a 20 m
carbowax capillary column. A reference solution of authentic
samples was used to calibrate the GC; product identifications
were by GC retention time analysis.
Exp er im en ta l Section
Ma ter ia ls. 3,4-Dim eth oxytolu en e was synthesized, ac-
cording to the Huang-Minlon-modified Wolff-Kishner
method,38 from 3,4-dimethoxybenzaldehyde: yield 46%, >99%
1
pure by GC analysis; n23 1.5263 (lit.39 n25 1.5257); H NMR
D
D
(60 MHz, CCl4) δ 2.2 (s, 3H), 3.6 (s, 6H), 6.3 (s, 3H); MS m/z
152 (M+). 4-Meth oxy-2-m eth ylp h en ol was prepared from
m-cresol by Elbs persulfate oxidation, methylation, and hy-
drolysis, after Baker and Brown.40 Distillation (95-127 °C/5
Torr) afforded the crude product (18.1%), which was purified
by flash chromatography (silica gel column, dichloromethane)
and recrystallization from toluene and hexanes: white
needles: yield 8.1%; mp 69-71 °C (lit.41 70.5-71.5 °C); 1H
NMR (60 MHz, CCl4) δ 2.2 (s, 3H), 3.6 (s, 3H), 5.2 (s, 1H), 6.4
(m, 3H). Shrinkage of the δ 5.2 signal on exposure to D2O
and broad IR absorbance at 3350 cm-1 both indicate a phenol.
2-Meth oxy-5-m eth ylp h en ol was prepared via diazotization
of 2-methoxy-5-methylaniline and ensuing hydroxydediazon-
iation;42 orange plates; >99% pure by GC analysis; yield 16.3%;
1H NMR (60 MHz, CCl4) δ 2.2 (s, 3H), 3.7 (s, 3H), 5.2 (broad
s, 1H), 6.4 (m, 3H); MS m/z 138 (M+). 2-Meth oxy-4-m eth yl-
p h en ol was prepared from vanillin according to Martin’s
modified Clemmensen reduction:43,44 yield 44%; bp 70-77 °C/
4-5 Torr (lit.44 105-106 °C/15 Torr); after redistillation, >99%
pure by GC analysis; bp 68-74 °C/4.5 Torr; 1H NMR (60 MHz,
(33) Cherkasov, A. N.; Pivnitskii, K. K. Zh. Org. Khim. 1972, 8, 211.
English translation: J . Org. Chem. USSR 1972, 8, 216.
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(35) Morton, A. A.; Lanpher, E. J . J . Org. Chem. 1958, 23, 1636.
(36) Bell, R. P. Adv. Phys. Org. Chem. 1966, 4, 15.
(37) Albert, A.; Serjeant, E. P. Ionization Constants of Acids & Bases;
Methuen & Co.: London, 1962; p 129.
(38) Bruce, J . M.; Sutcliffe, F. K. J . Chem. Soc. 1956, 3826.
(39) Handbook of Chemistry and Physics, 62nd ed.; Weast, R. C.,
Astle, M. J ., Eds.; CRC Press: Boca Raton, FL, 1981; p C-542.
(40) Baker, W.; Brown, N. C. J . Chem. Soc. 1948, 2303.
(41) Bamberger, E. J ustus Liebigs Ann. Chem. 1912, 390, 174.
(42) Goldberg, A. A.; Turner, H. S. J . Chem. Soc. 1946, 113.
(43) Martin, E. L. J . Am. Chem. Soc. 1936, 58, 1438.
Ackn owledgm en t. Preliminary experiments by Anne
De J arnatt were valuable in helping us organize our
work. This research was supported in part by National
Science Foundation Grant CHE-79-27119.
J O960148U
(44) Fletcher, J . H.; Tarbell, D. S. J . Am. Chem. Soc. 1943, 65, 1431.
(45) Lock, G. Monatsh. Chem. 1954, 85, 805.