Use of diethoxymethane as a solvent for phase transfer-catalyzed O -alkylation of phenols

Article abstract of DOI:10.1021/op900324p

The effectiveness of diethoxymethane (DEM) as a solvent for O-alkylation of a variety of phenols under phase transfer conditions has been examined and evaluated. The reaction between 4-methoxy phenol and benzyl chloride was selected to compare reaction rates in various solvents and the efficiency of various PTCs. This reaction was further studied to develop a commercially amenable process complete with recycle streams and efficient product isolation. DEM is a good solvent for these types of phase transfer-catalyzed reactions and can be considered as an alternative solvent for dichloromethane and toluene.

Full text of DOI:10.1021/op900324p

Organic Process Research & Development 2010, 14, 732–736
Use of Diethoxymethane as a Solvent for Phase Transfer-Catalyzed O-Alkylation of
Phenols
,†
‡
M. Todd Coleman* and Gabriel LeBlanc
FutureFuel Chemical Company, P.O. Box 2357, BatesVille, Arkansas 72501, U.S.A., and Lyon College, 2300 Highland Road,
BatesVille, Arkansas 72501, U.S.A.
Abstract:
Scheme 1. Alkylation of phenols
The effectiveness of diethoxymethane (DEM) as a solvent for
O-alkylation of a variety of phenols under phase transfer condi-
tions has been examined and evaluated. The reaction between
4-methoxy phenol and benzyl chloride was selected to compare
reaction rates in various solvents and the efficiency of various
PTCs. This reaction was further studied to develop a commercially
amenable process complete with recycle streams and efficient
product isolation. DEM is a good solvent for these types of phase
transfer-catalyzed reactions and can be considered as an alterna-
tive solvent for dichloromethane and toluene.
these facts in mind, we report O-alkylation reactions amenable
to phase transfer catalysis which have been investigated using
DEM as the reaction solvent, a comparison to traditional
solvents, and a process development example complete with
stream recycling.
O-Alkylation of Phenols. O-Alkylation of phenols is a well-
known reaction in which PTC excels and was first reported by
4
McKillop using dichloromethane as solvent. A more recent
Introduction
5
report by Yadav utilizes an engineered three-phase liquid-
The use of phase transfer catalysis in organic synthesis
liquid-liquid PTC system to prepare aromatic ethers in which
toluene was selected as the solvent. This engineered system
uses a 25% sodium chloride aqueous phase and 100 mol % of
the phase transfer catalyst in order to obtain the three-phase
system.
1
became an area of active research in the mid-1970s. Nucleo-
philic displacement reactions, strong base condensations, alky-
lations, dehydrohalogenations as well as oxidations, reductions
and polymerizations were all thoroughly investigated. Typical
solvents used in these reactions included chloroalkanes such
as dichloromethane, aromatic solvents such as toluene and
ketones such as methyl isobutyl ketone. Despite its recent
commercial availability, very few examples have been reported
where diethoxymethane (DEM) is utilized as a solvent for phase
Several of the experiments reported in these papers, as well
as others, were performed in which the solvents, either dichlo-
romethane or toluene, were replaced with DEM according to
4
Scheme 1. The conditions reported by McKillop are repre-
sented by Method A in which the phenol was prepared as a
2
transfer catalyzed reactions. The physical properties of DEM
2.0 M solution in DEM and treated with 2.0 equiv of the
make it an excellent candidate for these type of reactions.
DEM’s boiling point of 88 °C provides a temperature range
for the majority of PTC reactions (typically 25-80 °C) while
not requiring too high a temperature for solvent recovery. DEM
is stable in the presence of strong base, making it amenable to
the majority of typical commercial phase-transfer catalysis
conditions. Its low water solubility allows for a simplified, single
solvent workup strategy. Since DEM has a heterogeneous
azeotrope with water, this allows for reaction mixture drying
by distillation and direct recycling to subsequent batches. From
a safety standpoint, preliminary laboratory data suggests DEM
electrophile, 1.5 equiv of 25% NaOH, and 10 mol % tetrabu-
tylammonium bromide (TBAB) at 55 °C. Method B consisted
of treating a 2.0 M solution of the phenol in DEM with 1.5
equiv of alkyl halide and 10 mol % TBAB. This mixture was
exposed to a 25% solution of NaCl containing 1.5 equiv 50%
NaOH at 90 °C. It should be noted that the amount of phase
transfer catalyst used in Method B was reduced to 10 mol %
from 100 mol % as reported in the literature in order to reflect
conditions more appropriate for a commercial process. All target
compounds were easily prepared in good yields when using
DEM as the reaction solvent by either of the previously
referenced methods (Table 1). Unreacted phenol was removed
as the phenoxide with the aqueous waste streams. Little to no
byproduct was detected by gas chromatographic analysis,
although some C-alkylation most likely occurred. DEM was
easily removed by vacuum distillation to isolate the target
product. If the product were a solid, in most cases it could be
isolated by crystallization from DEM.
3
is resistant to the formation of peroxides upon exposure to air.
Regulatory issues are limited since DEM is currently not on
the SARA 313 list and is considered a non-HAP solvent. With
*
Author to whom correspondence may be sent. E-mail: toddcoleman@
ffcmail.com.
†
FutureFuel Chemical Company.
Lyon College.
‡
(
1) (a) Starks, C. M.; Liotta, C. Phase Transfer Catalysis: Principles and
Techniques; Academic Press: New York, 1978. (b) Weber, W. P.; Gokel,
G. W. Phase Transfer Catalysis in Organic Synthesis; Springer-Verlag:
Berlin, 1977.
(4) McKillop, A.; Fiaud, J. C.; Hug, R. P. Tetrahedron 1974, 30, 1379–
1382.
(
(
2) Boaz, N. W.; Venepalli, B. Org. Process Res. DeV. 2001, 5, 127–131.
3) Coleman, M. T. Chem. Today 2009, 27, 19–21.
(5) Yadav, G. D.; Desai, N. M. Org. Process Res. DeV. 2005, 9, 749–756.
7
32
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Vol. 14, No. 3, 2010 / Organic Process Research & Development
10.1021/op900324p  2010 American Chemical Society
Published on Web 03/05/2010

Table 1. Phenolic ethers using DEM as PTC reaction
the combination of selected TBA salts as the phase transfer
catalyst and DEM as the reaction solvent. In experiments 2-4,
the amount of “virgin” TBAB was reduced by 50% while still
obtaining excellent yields. In experiments 5-7, no “virgin”
TBAB was added, and yields remained good. This demonstrates
that a wide range of “virgin” catalyst can be used while still
obtaining high process yields. A cost-benefit analysis would
be required to determine the optimum scenario for the process
under investigation. The increase in yield between certain
experiments can be attributed to recovery of product from the
middle third phase. The recycle experiments described in Table
2 demonstrate that an engineered three-phase system as reported
solvent
entry method
R
1
R
2
R
3
X
yield (%)
Aa
1
2
3
4
5
6
7
8
9
1
1
H
H
H
H
H
H
H
H
Bn
Bu
Cl
Br
81
82
91
83
85
81
65
86
86
85
81
A
A
H
MeO
MeO
MeO
t-Bu
t-Bu
H
MeO
t-Bu
H
allyl Cl
b
B
Bu
Bn
Bu
Br
Cl
Br
A
B
A
B
A
A
A
allyl Cl
Br
Ac Bu
H
H
Me
Me
OSO
OSO
OSO
3
Me
3
Me
3
Me
0
1
Ac Me
5
by Yadav is not required in order to obtain a phase transfer
a
Method A - 2.0 M in DEM; 1.5 equiv 25% NaOH; 2.0 equiv electrophile; 10
b
catalyst system suitable for recycle. These conditions can be
obtained by the proper selection of the phase transfer catalyst
and solvent system.
mol % TBAB; 4 h @ 55 °C. Method B - 2.0 M in DEM; 25% aq NaCl; 1.5
equiv 50% NaOH; 1.5 equiv alkyl halide; 10 mol % TBAB; 2 h @ 90 °C.
Table 2. Recycle of middle third phase
Comparison Studies. A model system of 4-methoxy phenol
and benzyl chloride to prepare 4-benzyloxy anisole was selected
to compare reaction rate and yield in various solvents and the
effect of different PTCs in DEM.
Chart 1 compares the relative reaction rate in DEM,
dichloromethane and toluene and plots the concentration of
product vs the reaction time. The data demonstrates that the
studied reaction is much faster (<1 h) in dichloromethane than
either DEM or toluene (3 h) while yields were comparable at
yielda
(%)
TBAB
(mol %)
recycled third
phase (g)
exp #
1
2
3
4
5
6
7
5.0
2.5
2.5
2.5
0.0
0.0
0.0
0.0
4.7
5.7
6.5
7.5
5.7
4.7
85
95
106
100
93
99
91
∼
90%. As would be predicted, the absence of a catalyst in DEM
a
A yield of >100% likely reflects the redistribution of product from the middle
third phase of the previous run into the product phase.
results in a very sluggish reaction with low yield. The fact that
the reaction rate in dichloromethane is much faster than DEM
and that no middle third phase containing the PTC is present
suggests the PTC-phenoxide complex is much more soluble in
dichloromethane than either DEM or toluene.
Of interest was the observation that in some reactions, upon
initially settling the reaction mixture, three liquid phases were
detected. An NMR analysis of the smaller middle phase
6
While dichloromethane is an excellent solvent for laboratory
PTC reactions at temperatures up to its boiling point, its use in
large scale industrial applications is often limited by compliance
with environmental regulations. At the same time, while toluene
may be used in many large scale commercial PTC applications,
DEM offers easier recovery, is not a SARA 313 listed chemical,
and is a non-HAP solvent.
revealed the presence of product and phase transfer catalyst.
This phenomenon was dependent on the phase transfer catalyst
selected as well as the electrophile. This middle third phase
was observed with TBAB and tetrabutylammonium hydrogen
sulfate, but not with benzytriethylammonium chloride (BTEAC).
The middle third phase was not observed with either tetrabu-
tylammonium hydrogen sulfate (TBA salt) when using dimethyl
sulfate (DMS) as the electrophile. The lack of a middle phase
when using DMS as the electrophile most likely can be
attributed to the solubility of the TBA-methyl sulfate salt that
results as a byproduct from the desired reaction. Thus, a
potential advantage of DEM as a solvent for selected phase
transfer-catalyzed reactions is the recovery and reuse of certain
phase transfer catalysts.
The impact on yield with several phase transfer catalysts
was evaluated using the aforementioned model system (Table
3). The PTCs were selected across a wide range of “C #”s.
The “C #” has been defined as the total number of carbons in
a PTC and provides a representation of the solubility of the
7
catalyst in an organic solvent. A higher “C #” generally
designates a higher solubility in an organic solvent.
The trend from the study demonstrates that the tetrabutyl
cations with either bromide or sulfate anion are most effective
in this model system as yields are excellent and the workup is
straightforward. The use of tetrabutylammonium iodide resulted
in a moderate yield, and the workup was complicated by an
early precipitation of solids. The product in this case was
isolated by crystallization. The use of Aliquat 336 provided a
good yield with a straightforward workup and no middle third
phase, which is typical in PTC reactions using this highly
organophilic catalyst. Cetylpyridinium chloride (CPC) resulted
in a thick emulsion at the end of the 4-h reaction time. CPC is
To investigate the recovery and reuse of the middle third
phase, a series of recycle experiments were performed in which
either 2.5 mol % or no TBAB was added in addition to the
recovered middle phase. This procedure was evaluated on the
reaction between 4-methoxy phenol and benzyl chloride using
TBAB as the phase transfer catalyst using Method A (Table
2).
The data demonstrate the feasibility of phase transfer catalyst
recovery and recycle from the middle third phase when using
(
6) (a) Wang, D. H.; Weng, H. S. J. Chin. Inst. Chem. Eng. 1996, 27,
129–139. (b) Weng, H. S.; Wang, D. H. J. Chin. Inst. Chem. Eng. 1996,
27, 419–426. (c) Wang, D. H.; Weng, H. S. J. Chin. Inst. Chem. Eng.
1995, 26, 147–56. (d) Wang, D. H.; Weng, H. S. J. Eng. Sci. 1995, 50,
3477–86.
(7) The definition of “C #” can be found at www.phasetransfer.com/
suppliers/catdir.htm.
Vol. 14, No. 3, 2010 / Organic Process Research & Development
•
733

Chart 1. Relative reaction rate in various solvents
Table 3. Comparison of various PTCs in the reaction of
Table 4. Raw material and yield data for process
development study
4
-methoxy phenol and benzyl chloride in DEM
yield
(%)
DEM
(mL)
BnCl
(g)
TBAB
(g)
recycled
midphase (g)
yield
(%)
catalyst
tetrabutylammonium bromide
tetrabutylammonium hydrogensulfate 16 yes
C # midphase
batch
16 yes
90
1
2
3
4
5
500
100
0
50
50
126.5
72.5
75.0
90.3
85.0
16
8
-
29
31
40
74
103
100
86
93
63
83
88
tetrabutylammonium iodide
Aliquat 336
Aliquat 175
16 no
27 no
13 yes
8
0
4
32.8
80
cetylpyridium chloride
tetraethylammonium chloride
benzyltriethylammonium chloride
butylmethylimidazolium chloride
21 emulsion emulsion
8
no
13 no
no
44
51
76
clarification to eliminate the precipitated salts, the ionic liquid
is of sufficient purity for recycle. Butyl methylimidazolium
chloride ([bmim]Cl) is a commercially available ionic liquid
and was evaluated in the model system. The byproduct sodium
chloride precipitated, the dense ionic liquid was decanted, and
the desired product was easily recovered by crystallization in
76% yield. After removal of water by distillation, the ionic liquid
would be ready for recycle. In addition, some additional product
could be recovered upon recycling of the ionic liquid. A
recycling protocol with the ionic liquid was not pursued.
Application of DEM as an Industrial Process Solvent;
Demonstration of a Model. We have demonstrated that DEM
may be used as a solvent for the alkylation of phenols utilizing
phase transfer catalysis, but a larger-scale trial and the use of
recycling would provide more confidence for the use of DEM
as a solvent for commercial-scale phase transfer catalyzed
reactions. The preparation of 4-benzyloxy anisole at 1 L scale
was chosen as a model. The objective of the study was to (a)
recycle the middle PTC phase, (b) distill and recycle DEM, (c)
crystallize the product from DEM, and (d) recycle the filtrate
containing dissolved product, benzyl chloride, and DEM. Five
total batches with four batches using recycled streams were
executed. The reaction conditions were 1.0 M in DEM, 2.0 mol
equiv of benzyl chloride, 1.5 equiv of 25% sodium hydroxide,
and TBAB as the PTC at 10 mol % (initial batch) for 4 h at
50-55 °C. Upon completion of the hold time, the layers were
allowed to settle to produce three distinct phases. The middle
phase was collected and saved for recycling. The upper phase
was washed with water, concentrated, and cooled to crystallize
8
a well-known surfactant and is not a recommended phase
transfer catalyst due to emulsion formation. The reaction mixture
using CPC was not evaluated for conversion since the process
would not be amenable to commercial production. Benzyltri-
ethylammonium chloride resulted in a moderate yield with no
middle third phase, with a reasonable workup. The very
hydrophilic phase-transfer catalysts typically do not form a
6
middle third phase since they dissolve readily in water.
The effects observed of catalyst structure on reactivity are
consistent with this etherification being an “I-Reaction”
intrinsic reaction rate-controlled reaction) that is commonly
enhanced by more organophilic quarternary PTCs (quats) such
as Aliquat 336 and is less reactive in the presence of very
hydrophilic quats such as tetraethylammonium chloride. When
a middle third phase is observed, reaction rates are almost
always higher than when the third phase is not observed. That
may explain the lower reactivity of Aliquat 336 relative to that
of TBAB.
8
(
Ionic liquids have been reported to enhance reaction rates
9
due to their ability to support a charged transition state and
may be considered as phase transfer catalysts. They are easily
recovered due to the fact that they are insoluble in most organic
solvents, including DEM. Generally, after water removal and
(
8) Starks, C.; Liotta, C.; Halpern, M. Phase Transfer Catalysis: Funda-
mentals, Applications and Industrial PerspectiVes; Chapman and Hall:
New York, 1994.
7
34
•
Vol. 14, No. 3, 2010 / Organic Process Research & Development

Scheme 2. Model system 4-benzyloxy anisole
reactions were performed using a mechanical stirrer with a
banana-shaped blade. The agitation speed was set at 250 ( 25
rpm. Liquid products were purified by Kugelrohr distillation at
<
1 mmHg at 125-150 °C and analyzed using a Varian 300
MHz NMR. Weight percent assays were determined using
either benzyl benzoate or dimethoxybenzene as an internal
standard.
the product. The product was filtered, washed with heptane,
and vacuum-dried (Table 4). Batches 2-5 were performed by
recycling the DEM distillate, product filtrate, and fresh DEM
to equal the volume of DEM used in the initial batch. Additional
benzyl chloride was charged in order to equal 2.0 equiv. The
PTC was introduced by addition of the recycled middle third
phase, and fresh TBAB. The amount of fresh TBAB was varied
to in order observe the effect on the conversion and yield of
the process.
Several trends can be observed from the data collected during
the process of recycling streams. The increased yield in the
recycled batches can be attributed to recovering product from
the recycled filtrate. The highest yields and best benzyl chloride
usage factors were obtained in Batches 2 and 3 when 5 mol %
of TBAB was added to the recycled middle third phase. A
reduction in the amount of TBAB added in the recycled middle
third phase in Batches 4 and 5 resulted in a rather large drop in
the isolated yield and increases in the amount of benzyl chloride
added to the next batch. Further experiments would be required
to determine if the observed yield loss was due to the reduction
in TBAB addition amount or other process parameters such as
catalyst decomposition or impurity buildup in the filtrate.
Experiments would also need to be designed to investigate a
purge level for both the middle third phase and the product
filtrate. However, the unoptimized results from this short recycle
study demonstrate the feasibility of recycling the DEM distillate,
the DEM filtrate, and the middle third phase streams. A starting
point for future process development efforts reguarding reactions
of this type has been established.
Alkylation of Phenols (Method A). The phenol (0.1 mol)
was dissolved in DEM (50 mL). The alkyl halide or DMS (0.2
mol) was added followed by tetrabutylammonium bromide (3.2
g, 0.01 mol). Water (15 mL) and 50% caustic (12 g, 0.15 mol)
were thoroughly mixed and added to the DEM solution. The
temperature increased to 30-35 °C. The temperature was
adjusted to 50-55 °C and held for 4 h. The layers were allowed
to settle, and the lower aqueous phase, and the middle third
phase (if present) were removed. The organic phase was washed
with a saturated NaHCO
saturated NaCl solution (25 mL). The organic phase was dried
over MgSO and concentrated by rotary evaporation. The crude
3
solution (25 mL) followed by a
4
sample was purified by short-path distillation and analyzed by
NMR.
Alkylation of Phenols (Method B). Sodium chloride (87.5
g, 1.50 mol) and 50% caustic (12 g, 0.15 mol) were dissolved
in water (200 mL). Tetrabutylammonium bromide (3.2 g, 0.01
mol) was added to the solution. The phenol (0.1 mol) was
dissolved in DEM (50 mL) and added to the solution. The alkyl
halide (0.15 mol) was added and the mixture heated to reflux
(
85-90 °C) and held for 2 h. The reaction mixture was cooled
to <50 °C, and the phases were allowed to settle. The organic
phase was washed with a saturated NaHCO solution (25 mL)
followed by a saturated NaCl solution (25 mL). The organic
phase was dried over MgSO and concentrated by rotary
3
4
evaporation. The crude sample was purified by short-path
distillation and analyzed by NMR.
4-Benzyloxy Anisole - Recycling of DEM, Middle Phase,
Conclusions
and Filtrate Streams - Initial Batch. 4-Methoxy phenol (62
g, 0.5 mol), benzyl chloride (126.5 g, 1.0 mol), and TBAB (16
g, 0.05 mol) were dissolved in DEM (500 mL). Water (60 mL)
and 50% caustic (60 g, 0.75 mol) were thoroughly mixed and
added over 30 min to the reaction mixture. The contents were
then heated to 50-55 °C and held for 4 h. The layers were
allowed to settle, and the middle third phase was removed,
weighed, and saved for recycle. The organic phase was washed
with water (100 mL) and then heated to 105 °C to remove
residual amounts of water and DEM. The amount of distillate
collected was approximately 250 mL. The distillate was saved
for future recycle. The pot contents were cooled to 30 °C and
seeded with a small amount of 4-benzyloxy anisole to crystallize
the product. The slurry was further cooled to 0-5 °C, filtered,
and washed with heptanes (100 mL). The filtrate was saved,
weighed, and analyzed for benzyl chloride. The product was
vacuum-dried at 50 °C and assayed by NMR.
DEM has proven to be a good solvent for O-alkylation
phenols under PTC conditions. Yields are good to excellent,
and product workup is straightforward. Selected combinations
of DEM and catalyst provided a reaction system in which the
catalyst can be easily recovered and recycled. Recovery and
recycle of DEM and the phase transfer catalyst were demon-
strated in a model example that should be applicable to scale
up. The physical properties of DEM and the lack of current
regulatory restrictions make DEM an excellent candidate to
replace dichloromethane or aromatic solvents in commercial
phase transfer catalyzed reactions. Application of DEM in other
classifications of PTC reactions are currently under investigation.
Experimental Section
Diethoxymethane (DEM) was obtained and used without
further purification from FutureFuel Chemical Company. All
(
9) (a) Sharma, Y. O.; Degani, M. S. J. Mol. Cat. A: Chem. 2007, 277,
2
15–220. (b) Jorapur, Y. R.; Chi, D. Y. Bull. Korean Chem. Soc. 2006,
4-Benzyloxy Anisole - Recycling of DEM, Middle Phase,
and Filtrate Streams - Recycle Batch. The analysis of the
filtrate was used to calculate the amount of virgin benzyl
chloride. The amount of benzyl chloride in the filtrate was
subtracted from 126.5 g and charged to the reaction flask. The
filtrate from the previous batch was added followed by the
27, 345–354. (c) Man, B. Y. W.; Hook, J. M.; Harper, J. B. Tetrahedron
Lett. 2005, 46, 7641–7645. (d) Kim, D. W.; Hong, D. J.; Seo, J. W.;
Kim, H. S.; Kim, H. K.; Song, C. E.; Chi, D. Y. J. Org. Chem. 2004,
6
2
9, 3186–3189. (e) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Org. Chem.
003, 68, 4281–4285. (f) Li, Y. X.; Bao, W. L.; Wang, Z. M. Chin.
Chem. Lett. 2003, 14, 239–242. (g) Judeh, Z. M. A.; Shen, H.; Chi,
B. C.; Feng, L.; Selvasothi, S. Tetrahedron Lett. 2002, 43, 9381–9384.
Vol. 14, No. 3, 2010 / Organic Process Research & Development
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735

distillate from the previous batch. TBAB (0-8 g, 0-0.025 mol)
was added followed by the middle third phase from the previous
batch. 4-Methoxy phenol (62 g, 0.5 mol) was dissolved in the
reaction mixture. Water (60 mL) and 50% caustic (60 g, 0.75
mol) were thoroughly mixed and added over 30 min to the
reaction mixture. The contents were heated to 50-55 °C and
held for 4 h. The layers were allowed to settle, and the middle
third phase was removed, weighed, and saved for recycle. The
organic phase was washed with water (100 mL) and then heated
to 105 °C to remove residual amounts of water and DEM. The
amount of distillate collected was approximately 250 mL. The
distillate was saved for future recycle. The pot contents were
cooled to 30 °C and seeded with a small amount of 4-benzyloxy
anisole to crystallize the product. The slurry was further cooled
to 0-5 °C, filtered, and washed with heptanes (100 mL). The
filtrate was saved, weighed, and analyzed for benzyl chloride.
The product is vacuum-dried at 50 °C and assayed by NMR.
Acknowledgment
We thank the FutureFuel Chemical Company Analytical
Department for NMR and GC support.
Received for review December 14, 2009.
OP900324P
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Vol. 14, No. 3, 2010 / Organic Process Research & Development