Continuous flow oxidation of alcohols and aldehydes utilizing bleach and catalytic tetrabutylammonium bromide

Article abstract of DOI:10.1021/op200118h

We report a method for the oxidation of a range of alcohols and aldehydes utilizing a simple flow system of alcohols in EtOAc with a stream of 12.5% NaOCl and catalytic Bu₄NBr. Secondary alcohols are oxidized to ketones, aldehydes are oxidized directly to methyl esters in the presence of methanol, and benzylic alcohols are oxidized to either benzaldehydes or methyl esters, depending on the conditions used. The reaction conditions are mild and generally provide complete conversion in 5-30 min.

Full text of DOI:10.1021/op200118h

ARTICLE
pubs.acs.org/OPRD
Continuous Flow Oxidation of Alcohols and Aldehydes Utilizing
Bleach and Catalytic Tetrabutylammonium Bromide
Andrew B. Leduc and Timothy F. Jamison*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S Supporting Information
b
ABSTRACT: We report a method for the oxidation of a range of alcohols and aldehydes utilizing a simple flow system of alcohols in
EtOAc with a stream of 12.5% NaOCl and catalytic Bu NBr. Secondary alcohols are oxidized to ketones, aldehydes are oxidized
4
directly to methyl esters in the presence of methanol, and benzylic alcohols are oxidized to either benzaldehydes or methyl esters,
depending on the conditions used. The reaction conditions are mild and generally provide complete conversion in 5ꢀ30 min.
’
INTRODUCTION
surface-area-to-volume ratios between solvent plugs. Scalability
thus becomes an issue of increasing reactor length and flow rates
to increase throughput while maintaining the necessary contact
between reagents. With these benefits in mind we endeavored to
develop an environmentally friendly flow method utilizing the
Stevens oxidation as inspiration.
There exist numerous and varied methods for oxidation of
1
alcohols including methods utilizing stoichiometric (Jones, Collins,
PCC, PDC, and others) and catalytic (TPAP and others) metal
2
3
species, hypervalent iodine reagents (IBX, DessꢀMartin peri-
4
odinane and derivatives), stable N-oxyl radicals (TEMPO and
Oxidations carried out in flow have been performed utilizing
derivatives) or proceeding by way of alkoxysulfonium inter-
1
3a
13b
5
a wide variety of reagents including KMnO
ozone, DMSO/
4,
mediates (MoffattꢀSwern, MoffattꢀPfitzner, CoreyꢀKim, Parikhꢀ
13c
6
trifluoroacetic anhydride, and immobilized ruthenium com-
Doering), hydride transfer from metal alkoxides (Oppenauer,
13dꢀf
7
plexes.
Oxidation methods have also been developed utiliz-
14
Mukaiyama), and the Stevens oxidation, which utilizes a con-
ing immobilized versions of TEMPO, the stationary phase
typically being silica- or polystyrene-based. Utilizing these
immobilized reagents poses several possible disadvantages in
flow. The primary concern with polymer-immobilized reagents
involves the swelling/shrinking properties of the stationary phase,
which can lead to clogging and high system pressures. Although
essentially immune to swelling, silica can lead to chromato-
graphic effects, resulting in not only increased residence times,
but also increased residence time distribution.
centrated solution of NaOCl as oxidant and acetic acid as solvent
and generally oxidizes secondary alcohols in preference to primary.
Variations of the Stevens method, utilizing cosolvents such as
8
acetonitrile, have also been reported. The use of phase-transfer
9
catalysis (PTC) has also been investigated although we have
only found one example utilizing ethyl acetate and tetrabutylam-
9a
monium bromide (TBAB) as the sole catalyst with limited
examples and only secondary alcohols investigated.
The majority of the oxidations mentioned above possess
limitations affecting their practicality. In recent years continuous
flow methods for organic synthesis have increased in popularity
’ RESULTS AND DISCUSSION
1
0
and variety. Key advantages include the precise control of
reaction time and temperature. The very high surface-area-to-
volume ratio results in exceptional heat transfer, which in turn
enables very fast heating and cooling and reduces the occurrence
of uncontrolled exothermic reactions. The small reaction volumes
employed provide both significant leverage—a small reactor can
produce large amounts of desired material over time—and more
importantly, greatly enhanced safety. Recent demonstrations of
Using these flow reactions as inspiration we began to inves-
tigate the use of other traditional oxidants catalytically via
reoxidation by a stoichiometric oxidant. Ideally, we wished to
perform the oxidations in the presence of an immobilized catalyst
to ease purification as well as prevent leaching of metals in certain
cases; however, leaching was often unavoidable.
In the course of studying the oxidation of secondary alcohols
to ketones utilizing various immobilized catalysts we performed a
control experiment in the absence of the catalyst and only the
stoichiometric reoxidant, a 12.6% solution of sodium hypochlor-
ite, present with a catalytic amount of PTC, TBAB. The condi-
tions utilized in the control experiment proved more than capable
of oxidizing secondary alcohols without the need for an addi-
tional catalyst. The literature contains few examples of similar
11
12
this last point include publications by our group, and others,
demonstrating the ability to utilize sodium azide or hydrazoic
acid at high temperatures in flow.
In batch, scaling of multiphasic reactions presents significant
challenges as varying reactor size, shape, and stirring rate can all
have an effect on the rate and reproducibility of reactions. On
small scale thorough mixing can be readily achieved by magnetic
or overhead stirrers, but on larger scales this becomes harder to
accomplish and often requires further optimization. Performing
biphasic reactions in flow could be extremely beneficial as efficient
mixing and small reactor inner diameters ensure consistent high
Special Issue: Continuous Processing 2012
Received: April 26, 2011
Published: June 15, 2011
r 2011 American Chemical Society
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Figure 1. Schematic representation of the flow apparatus utilized for the oxidation of alcohols and aldehydes.
Scheme 1. Optimized reaction conditions for the oxidation
of benzylic and aliphatic secondary alcohols
Table 1. The oxidation of secondary benzylic and aliphatic
alcohols to ketones
7,9
7
oxidations under batch conditions, the Stevens oxidation
being among the most well-known.
Our initial investigations in batch translated well into flow,
utilizing simple and readily available equipment including a single
syringe pump, 10-mL glass syringes, and a coil of 0.5 mm id PFA
1
5
tubing (Figure 1), and the reaction was optimized utilizing
-octanol. All reactions were screened by offline GC analysis.
2
Residence times (t ) were varied by adjusting flow rates, and
R
optimal times were determined on the basis of the GC conver-
sion and yield data obtained from run samples. Early criteria for
the reaction were set so as to ensure complete conversion within
3
0 min.
An initial investigation of catalysts for this oxidation demon-
strated that neither an alternative PTC, tetrabutylammonium
acetate, nor a simple bromide salt, NaBr, was capable of catalyz-
ing the reaction under our conditions; however, the addition
of both reagents rescued the reaction and produced the expected
products. Optimal catalyst loading for the oxidation of secondary
aliphatic alcohols was 15 mol % TBAB. As expected, the oxidation
of benzylic secondary alcohols was faster and thus could be
performed with lower loading of the catalytic bromide, generally
requiring 7.5 mol %. The use of two equivalents of bleach was
optimal, and the reaction was best performed at an initial substrate
concentration of approximately 0.8 M. Heating the reaction was
not beneficial, and the above optimized conditions thus consti-
tute our continuous oxidation system.
With the reaction thus optimized (Scheme 1), we began to
examine the scope of the oxidation (Table 1). Initial screening
focused on the substitution of the aromatic portion of the benzylic
alcohols. Electron-donating and moderately withdrawing groups
were well tolerated. Cyclic benzylic alcohols were also suitable
substrates for reaction. Entry 4 is notable as the somewhat
sensitive cyclopropyl ketone generated is stable to the reaction
conditions. The presence of olefins or alkynes was not tolerated
in any substrate that was investigated.
a
Reactions were run as outlined in Figure 1: A 0.818 M solution of
alcohol containing 0.075 equivalents of TBAB (benzylic alcohols) or
0
solution of NaOCl at a mixing Y and flowed through a reactor coil for the
indicated time. Products were isolated by flash chromatography. Re-
sidence times (t ) were obtained by variation of the total flow rates using
a 750 μL reactor loop Conversion and Yield were obtained by offline
.15 equivalents of TBAB (aliphatic alcohols) was mixed with a 1.64 M
b
R
c
We next examined the oxidation of a series of aliphatic alcohols
and found that most provided good to excellent conversion. With
regards to the presence of tertiary centers, 6-methyl-2-heptanol
GC analysis of aliquots of reaction mixture standardized with dodecane.
(
(
entry 13) was readily oxidized; however 5-methyl-2-hexanol
entry 12) was not efficiently oxidized. It would appear that
conversion. Upon oxidation of menthol only one diastereomer
was observed, with no sign of epimerization to isomenthone,
indicating that base-induced epimerization was not occurring.
the catalyst is less effective in this case, producing only low
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Scheme 2. Optimized reaction conditions for the oxidation
of benzaldehydes and aliphatic aldehydes to methyl esters
Table 2. Oxidation of aromatic and aliphatic aldehydes to esters
Isomenthol was also subjected to the reaction conditions;
however, the oxidation was very sluggish, and only low conver-
sion (∼5%) was obtained. The product observed by GC analysis
of the reaction mixture, nevertheless, was isomenthone with no
sign of epimerization to menthone. Overall, isolated yields
agreed well with yields obtained by GC analysis with an internal
standard, the exceptions being ketone products of appreciable
vapor pressure and thus subject to loss of material during
purification.
During our initial batch experiments we had discovered that
the oxidation of primary alcohols produced very little aldehyde,
but did produce significant amounts of an ester obtained from
two molecules of the original alcohol, likely via formation of a
16
hemiacetal that was then further oxidized. While the oxida-
17
tion of aldehydes directly to esters is known it is frequently
substrate-specific and, in practice, it is much more common to
oxidize to the acid under various conditions followed by ester-
ification. With this point and our previous results in hand, we set
out to determine whether it would be possible to develop a general
continuous processing method for the oxidation of an aldehyde,
in the presence of an appropriate alcohol, to an ester without
requiring the intermediacy of the acid. An initial experiment with
benzaldehyde and EtOH demonstrated that this reaction was
possible, although only moderate conversion and low yield
were observed in initial experiments. Increasing the amount of
EtOH utilized from 2 to 10 equivalents while using 10 mol % of
tetrabutylammonium bromide was found to be optimal.
While our initial experiments utilized ethanol, it was discov-
ered that the reaction was more prone to the formation of reactor-
clogging precipitates when 10 or more equivalents, relative to
aldehyde, were used. This problem could be mitigated through
the use of a diluted solution of aldehyde; though decreasing the
concentration below ∼0.5 M slowed the reaction and led to
incomplete conversion within our desired 30 min target reaction
time. Ultimately, this problem was overcome by switching to
MeOH. Thus, the optimized reaction conditions (Scheme 2)
utilize 10 eq. of MeOH and 10 mol % TBAB, and were found
to be appropriate for the majority of benzaldehydes (Table 2,
entries 4ꢀ17) which were moderately to highly electron deficient
and aliphatic aldehydes (entries 18ꢀ21).
Electron-rich benzaldehydes (entries 1ꢀ3), however, were
more resistant to oxidation. This result would seem to indicate that
it is the electrophilicity of the aldehyde that is most important
with regard to the rate of oxidation. At least one electron poor
heteroaromatic aldehyde was also a suitable substrate for oxida-
tion (entry 7). While the reaction appears to be quite general,
substitution ortho to the aldehyde moiety generally decreased
the rate of oxidation, the exception being when a suitably strong
electron-withdrawing group is present. This effect, while pronounced
when a single ortho substituent is present, can drastically slow
oxidation to the ester when both ortho-positions are substituted
a
Reactions were run as outlined in Figure 1: A 0.818 M solution of alcohol
containing 0.1 equiv of TBAB and 10 equiv of methanol was mixed with a
1.64 M solution of NaOCl at a mixing Y and flowed through a reactor coil
for the indicated time. Products were isolated by flash chromatography.
b
Residence times (t ) were obtained by variation of the total flow rates
R
c
using a 750-μLreactor loop. Conversion and yield were obtained by offline
GC analysis of aliquots of reaction mixture standardized with dodecane.
(entry 15). The smaller, more electron-deficient fluorine equiva-
lent (entry 16) did, however, undergo oxidation, albeit with low
conversion. Interestingly, while secondary alcohols containing an
olefin did not undergo oxidation, 10-undecenal was oxidized
quite smoothly under these conditions, providing a 75% isolated
yield of methyl 10-undecenoate (entry 20).
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Scheme 3. Optimized reaction conditions for the oxidation of benzylic alcohols to methyl benzoates
With these results in hand and the notion that a benzylic
alcohol should be oxidized more quickly than methanol, we also
investigated the possibility of oxidizing a benzylic alcohol in
the presence of methanol directly to the methyl ester without
needing to isolate an intermediate aldehyde. Lending credence to
this idea, the one-step oxidation of alcohols to methyl esters is
Table 3. Oxidation of benzylic alcohols to esters
1
8
known; however, the conditions used typically involve either
catalytic or stoichiometric metals or the use of elemental halogens.
Certain examples, in a manner similar to our method, utilize a
18aꢀc
halide salt and stoichiometric oxidant to achieve the oxidation.
When utilizing 1,2-benzenedimethanol under the reaction
conditions that were used previously in the oxidation of alde-
hydes omitting the added methanol, we were pleased to observe
the formation of phthalide with full conversion and 90% isolated
yield. Optimization of the general oxidation of benzylic alcohols
to methyl esters simply required an increase to 3 equiv of NaOCl
and 20 mol % of catalyst (Scheme 3).
Once again electron-deficient benzylic alcohols were the most
suitable in this reaction (Table 3) as the second oxidation occurs
much more quickly. Electron-rich benzylic alcohols would form
the desired products, albeit in lower yield. While conversion of
the electron rich benzylic alcohols was complete, the majority of
the oxidized material stalled at the aldehyde oxidation state. Attempts
were made to increase yield, but none provided consistent im-
provements. Interestingly, as in the Stevens oxidation, aliphatic
primary alcohols appear to undergo oxidation more slowly than
secondary and benzylic alcohols. This result explains why the
oxidation of aldehydes and benzylic alcohols in the presence of vast
excesses of methanol and ethanol is possible. It also implies that
the reaction as described may be able to oxidize secondary and
benzylic alcohols selectively in the presence of primary aliphatic
alcohols in a similar manner to that of the Stevens oxidation.
When we initially investigated the oxidation of benzylic alcohols
to methyl esters, we envisioned that the second oxidation would
be faster than the first, and the aldehyde would quickly form a
hemiacetal with methanol (rather than with another molecule of
benzylic alcohol as we had observed previously), and then oxidize
to the methyl ester. Our early experiments with electron-deficient
benzylic alcohols demonstrated this type of reactivity with only
small amounts of aldehyde present at any given time; however,
when we utilized electron-rich alcohols, we were intrigued by the
formation of significant quantities of the benzaldehydes. In fact,
the low yield of the esters obtained with electron-rich benzylic
alcohols is mostly attributable to the remainder of the reaction
products being stalled at the aldehyde oxidation state. With this
result in mind, and the apparent stability of the aldehydes used in
the initial oxidations to methyl esters, we decided to examine the
selective oxidation of benzylic alcohols to aldehydes under the
same conditions (Scheme 4).
a
Reactions were run as outlined in Figure 1: A 0.55 M solution of alcohol
containing 0.2 equiv of TBAB and 10 equiv of methanol was mixed with
a 1.64 M solution of NaOCl at a mixing Y and flowed through a reactor
coil for the indicated time. Residence times (t ) were obtained by
variation of the total flow rates using a 750-μL reactor loop. Conversion
and yield were obtained by offline GC analysis of aliquots of reaction
mixture standardized with dodecane. The formation of phthalide was
performed with 2 equiv of NaOCl and 0.1 equiv of TBAB. Yield (%) is
representative only of the esters of interest. Low yield is the result of
large amounts of product stalled at the aldehyde oxidation state and not
due to side reactions or decomposition.
b
R
c
d
e
Benzylic alcohols possessing strongly and weakly electron-
donating groups were oxidized very quickly, providing the
desired aldehydes in good yield (Table 4). In the case of benzylic
alcohols with pendant electron-withdrawing groups (entries
desired aldehydes. These decreased yields are attributable to
the high electrophilicity of the aldehydes produced. Their
5
ꢀ8) the reactions produced only low to moderate yield of the
1
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Scheme 4. Optimized reaction conditions for the oxidation
of benzylic alcohols to aldehydes
benzylic alcohols bearing an ortho-substituent (entries 9ꢀ13).
We hoped to utilize the decreased reactivity observed in the
oxidation of aldehydes with an ortho-substituent that we had
encountered previously.
As can be seen when comparing entry 7 to 12, moving the
nitro group from the meta- to the ortho-position increases the
yield from 10% to 55% and comparing entry 7 to 13 demon-
strated that the addition of a methyl group in the ortho position
increases the yield from 10% to 50%. Clearly the presence of
an ortho substituent can be used to increase the yield of aldehyde
in this reaction via suppression of overoxidation in the case of
electron-poor benzylic alcohols.
Table 4. Oxidation of benzylic alcohols to aldehydes
’
SCALE UP
Following the completion of the investigation of substrate
scope, we sought to demonstrate the ability to easily scale up the
reaction. Towards this end we utilized a Uniqsis FlowSyn commer-
19
cial flow system fitted with a 14-mL reactor coil. In order to
avoid any risk associated with the use of concentrated bleach with
stainless steel components and seals, the bleach solution was
pumped with the use of two glass 50-mL syringes and a syringe
pump plugged into the mixing T-joint. The experiment utilized
5
2
-nitro-2-furaldehyde as substrate and prepared methyl 5-nitro-
-furoate in the same manner as on small scale. In total, the
flow system was allowed to run for 75 min and generated 11.0 g
(
75% yield) of methyl 5-nitro-2-furoate. This rate of throughput
translates to 211 g of product per day. This experiment repre-
sented a 20-fold increase in scale, utilized tubing with a different
inner diameter, required no further optimization, and provided
the desired product with only a slight decrease in isolated yield
from previous experiments, a testament to the simplicity of scale
up in flow systems.
’
CONCLUSION
We have developed a continuous flow oxidation method utilizing
a 12.6% aqueous solution of sodium hypochlorite as stoichiometric
oxidant. Theprocesswasfoundtobecapableofoxidizingsecondary
alcohols to ketones, aldehydes directly to methyl esters, and
benzylic alcohols to aldehydes and esters in moderate to high
conversion and yield in most cases. The conditions utilized for
oxidation have proven relatively mild and are well tolerated by a
wide range of substrates. The use of continuous flow reactors
greatly reduced the challenges inherent to performing biphasic
reactions in batch, most notably the strict control of reaction
time, the ability to continuously quench small volumes of bleach
without the associated heating, and the ability to greatly increase
scale and throughput without further optimization.
a
Reactions were run as outlined in Figure 1: An 0.82 M solution of
’ EXPERIMENTAL SECTION
alcohol containing 0.2 equiv of TBAB was mixed with a 1.64 M solution
of NaOCl at a mixing Y and flowed through a reactor coil for the
indicated time. Products were isolated by flash chromatography. Re-
sidence times (t ) were obtained by variation of the total flow rates using
a 750-μL reactor loop. Conversion and yield were obtained by offline
GC analysis of aliquots of reaction mixture standardized with dodecane.
1
Materials and Methods. H NMR spectra were obtained at
b
500 MHz. All spectra were obtained in deuterated chloroform
and referenced to residual chloroform at 7.26 ppm. Solvents and
starting materials were used as received from the supplier without
further purification. Flash chromatography was performed using
R
c
2
30ꢀ400 mesh silica gel obtained from SiliCycle. Reactions were
electrophilic nature likely leads to formation of hemiacetals with
a second benzylic alcohol and subsequent oxidation to an ester.
In these cases the ester products could be isolated, and in the case
of entry 8, observed by GC. In an effort to prevent the over-
oxidation to esters we attempted the oxidation of electron-poor
monitored offline by GC. GC samples were prepared by collect-
ing a 40-μL sample of the reaction mixture (20 μL organic and
20 μL aqueous) which was diluted to 5 mL in a volumetric flask
with EtOAc and a known amount of dodecane as an internal
standard. One-microliter injections of sample were run according
1
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1
to one of the following methods. GC Method A: Samples were
run on an Agilent DB-WAX column (30 m ꢁ 0.32 mm i.d., 25 μm
film thickness) with a flow rate of 1 mL/min. Oven temperature
was held at 50 °C for 10 min and then increased linearly to
H NMR (500 MHz): 7.97 (m, 2H), 7.57 (m, 1H), 7.47 (m, 2H),
2.61 (s, 3H).
General Procedure for the Oxidation of Aldehydes to
Methyl Esters. An aldehyde and TBAB (132 mg, 0.1 equiv)
were dissolved in 1.65 mL of methanol (10 equiv) in a 5-mL
volumetric flask. Upon complete dissolution the volume was
brought to 5 mL with EtOAc to obtain a final concentration of
0.818 M. This solution was then added to a glass airtight syringe.
An equal volume of an approximately 1.64 M solution of sodium
hypochlorite was taken up in a second syringe.
2
50 °C over 10 min with a final hold of 2 min. GC Method B:
Samples were run on an Agilent HP-5 column (30 m ꢁ 0.32 mm
i.d., 25 μm film thickness) with a flow rate of 1 mL/min. Oven
temperature was held at 50 °C for 10 min and then was increased
linearly to 250 °C over 10 min with a final hold of 2 min. GC
yields and conversions were determined using standard curves
generated from a series of known standards referenced to the
internal standard dodecane.
Flow Apparatus. Syringes of reagents were loaded into a
syringe pump and connected to a Y-mixer and the reaction coil
with the use of Upchurch Super Flangeless fittings and Luer Lock
adapters. The reaction coil was composed of a 750-μL (3.88 m)
piece of 0.02 in. (0.5 mm) inner diameter PFA tubing connected
to the Y-mixer using Upchurch Super Flangeless fittings. Reac-
tions were run at appropriate flow rates to obtain the desired
retention time which had been previously determined. The
effluent was collected in a separation funnel containing a
saturated aqueous solution of sodium sulfite. Upon completion
of the reaction the organic layer was separated and the aqueous
layer washed twice with EtOAc. Purification was performed via
flash column chromatography.
Methyl Benzoate. As described in the General Procedure for
the Oxidation of Aldehydes to Methyl Esters, 435 mg of benzal-
dehyde was dissolved and processed. The solutions of reagents
flowed for 91 min at a total flow rate of 75 μL/min with a
residence time of 10 min. A total volume of 3.41 mL of organic
phase was collected, providing a theoretical yield of 379 mg of
methyl benzoate. Purification was accomplished by flash column
chromatography with 2% EtOAc in hexanes. Obtained was 175 mg
of pure methyl benzoate (44% yield). GC (Method A) Standard:
0 0
t = 16.258 ; reaction: t = 16.259 ; H NMR (500 MHz): 8.04
R R
(m, 2H), 7.56 (m, 2H), 7.44 (m, 2H), 3.92 (s, 3H).
1
General Procedure for the Oxidation of Benzylic Alcohols
to Methyl Esters. A benzylic alcohol and TBAB (175 mg, 0.2 equiv)
were dissolved in 1.10 mL of methanol (10 equiv) in a 5-mL
volumetric flask. Upon complete dissolution the volume was brought
to 5 mL with EtOAc to obtain a final concentration of 0.547 M. This
solution was then added to a glass airtight syringe. An equal volume
of an approximately 1.64 M solution of sodium hypochlorite was
taken up in a second syringe.
Methyl 3-Nitro-2-methylbenzoate. As described in the General
Procedure for the Oxidation of Benzylic Alcohols to Methyl
Esters, 455 mg of 3-nitro-2-methylbenzyl alcohol was dissolved
and processed. The solutions of reagents flowed for 166 min at
a total flow rate of 25 μL/min with a residence time of 30 min.
A total volume of 2.08 mL of organic phase was collected, providing
a theoretical yield of 223 mg of methyl 3-nitro-2-methylbenzoate.
Purification was accomplished via flash column chromatography
with 2.5% EtOAc in hexanes. Obtained was 168 mg of pure
methyl 3-nitro-2-methylbenzoate (75% yield). GC (Method B)
0
1
reaction: t = 18.255 ; H NMR (500 MHz): 8.00 (dd, J = 8 Hz,
R
1
3
Hz, 1H), 7.85 (dd, J = 8 Hz, 1 Hz, 1H), 7.39 (t, J = 8 Hz, 1H),
.94 (s, 3H), 2.63 (s, 3H).
General Procedure for the Oxidation of Benzylic Alcohols
General Procedure for the Oxidation of Secondary Alcohols
to Ketones. A secondary alcohol and TBAB (100 mg, 0.075 equiv
for benzylic alcohols; 200 mg, 0.15 equiv for aliphatic alcohols) were
dissolved in a minimal amount of EtOAc in a 5-mL volumetric flask.
Upon complete dissolution the volume was brought to 5 mL with
EtOAc to obtain a final concentration of 0.818 M. This solution was
then added to a glass airtight syringe. An equal volume of an
approximately 1.64 M solution of sodium hypochlorite was taken up
in a second syringe.
to Aldehydes. A benzylic alcohol and TBAB (265 mg, 0.2 equiv)
were dissolved in a minimal amount of EtOAc in a 5-mL volumetric
flask. Upon complete dissolution the volume was brought to
5 mL with EtOAc to obtain a final concentration of 0.818 M. This
solution was then added to a glass airtight syringe. An equal volume
of an approximately 1.64 M solution of sodium hypochlorite was
taken up in a second syringe.
2-Iodobenzaldehyde. 2-Iodobenzyl alcohol (955 mg) was dis-
solved and processed as described in the General Procedure for
the Oxidation of Benzylic Alcohols to Aldehydes. The solutions
of reagents flowed for 180 min at a total flow rate of 16.67 μL/min
with a retention time of 15 min. A total volume of 1.50 mL of
organic phase was collected, providing a theoretical yield of
324 mg of 2-iodobenzaldehyde. Purification was accomplished
by filtration through a plug of silica with EtOAc; 241 mg of pure
2-iodobenzaldehyde (74% yield) was obtained. GC (Method B)
Acetophenone. As described in the General Procedure for
the Oxidation of Secondary Alcohols to Ketones, 500 mg of
1
-phenylethanol was dissolved and processed. The solutions of
reagents flowed for 165 min at a total flow rate of 25 μL/min with
a retention time of 30 min. A total volume of 2.06 mL of organic
phase was collected, providing a theoretical yield of 202 mg
of acetophenone. Purification was accomplished via flash
column chromatography with 5% EtOAc in hexanes; 153 mg
of pure acetophenone (76% yield) was obtained. GC
0
1
reaction: t = 17.096 ; H NMR (500 MHz): 10.07 (s, 1H), 7.96
R
(ddd, J = 8 Hz, 1 Hz, 0.5 Hz, 1H), 7.88 (ddd, J = 7.5 Hz, 1.5 Hz,
0.5 Hz, 1H), 7.47 (m, 1H), 7.29 (ddd, J = 7.5 Hz, 7 Hz, 2 Hz, 1H).
0 0
Method A) Standard: t = 17.079 , reaction: t = 17.071 ;
R R
(
1
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Large-Scale Synthesis of Methyl 5-Nitro-2-furoate. Twenty-
three grams of 5-nitro-2-furaldehyde, 66 mL of MeOH, and 5.2 g
of TBAB were dissolved in EtOAc, and the solution was brought
to a final volume of 200 mL. The solution of reagents and ∼12.5%
NaOCl flowed for 75 min at a total flow rate of 2.8 mL/min and a
residence time of 5 min and was stopped once the syringes of
bleach were exhausted. Unlike previous examples, the reaction
was flowed through a 14-mL coil of 0.04” (1 mm) inner diameter
PTFE tubing using a Uniqsis FlowSyn commercial flow unit. As a
preventative measure to protect the valves and pumps of the unit,
the bleach solution was delivered via a syringe pump outfitted
with two 50-mL syringes. A total volume of 105 mL of organic
phase was collected, providing a theoretical yield of 14.7 g of
methyl 5-nitro-2-furoate. Purification was accomplished via
filtration through a plug of silica with EtOAc. A total of 11.0 g
of pure methyl 5-nitro-2-furoate (75% yield) was obtained.
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ASSOCIATED CONTENT
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Supporting Information. (1) General procedures for oxi-
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b
VCH: Weinheim, 2000. (b) Hessel, V., Hardt, S., L €o we, H., Eds. Chemical
Micro Process Engineering; Wiley-VCH: Weinheim, 2004. (c) Wirth, T.,
Ed. Microreactors in Organic Synthesis; Wiley-VCH: Weinheim, 2008.
dation reactions; (2) experimental details, analytical data and spectra
for synthesized compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(
d) Yoshida, J., Ed. Flash Chemistry: FastOrganic Synthesis in Microsystems;
Wiley-Blackwell: Oxford, 2008; (e) Hessel, V., Renken, A., Schouten,
J. C., Yoshida, J., Eds. Micro Process Engineering; Wiley-Blackwell: Oxford,
’
AUTHOR INFORMATION
2
2
009. (f) J €a hnisch, K.; Hessel, V.; L €o we, H.; Baerns, M. Angew. Chem.
004, 116, 410. Angew. Chem., Int. Ed. 2004, 43, 406. (g) Doku, G. N.;
Corresponding Author
tfj@mit.edu
Verboom, W.; Reinhoudt, D. N.; van den Berg, A. Tetrahedron 2005,
1, 2733. (h) Geyer, K.; Cod ꢀe e, D. C.; Seeberger, P. H. Chem.—Eur.
6
J. 2006, 12, 8434. (i) Mason, P. B.; Price, K. E.; Steinbacher, J. L.; Bogdan,
A. R.; McQuade, D. T. Chem. Rev. 2007, 107, 2300. (j) Watts, P.; Wiles, C.
Org. Biomol. Chem. 2007, 5, 727. (k) Ahmed-Omer, B.; Brandt, J. C.;
Wirth, T. Org. Biomol. Chem. 2007, 5, 733. (l) Wiles, C.; Watts, P. Eur.
J. Org. Chem. 2008, 1655. (m) Fukuyama, T.; Rahman, M. T.; Sato, M.;
Ryu, I. Synlett. 2008, 151. (n) Yoshida, J.; Nagaki, A.; Yamada, T. Chem.—
Eur. J. 2008, 14, 7450. (o) Hartman, R. L.; Jensen, K. F. Lab Chip 2009,
’
ACKNOWLEDGMENT
This work was supported by the Novartis-MIT Center for
Continuous Manufacturing. We thank the members of this team,
particularly Gerhard Penn, Berthold Schenkel, Oljan Repic,
Thierry Schlama, Mike Girgis, Lukas Padeste, and Felix Kollmer
for advice and stimulating discussions. We also thank Professor
Klavs F. Jensen, Professor Stephen L. Buchwald, and their co-workers
for further insightful discussions. A.B.L. thanks the Natural Sciences
and Engineering Research Council of Canada for a Postdoctoral
Fellowship.
9, 2495. (p) Webb, D.; Jamison, T. F. Chem. Sci. 2010, 1, 675.
(11) Palde, P. B.; Jamison, T. F. Angew. Chem. 2011, 123, 3587.
Angew. Chem., Int. Ed. 2011, 50, 3525.
(12) Gutmann, B.; Roduit, J.-P.; Roberge, D.; Kappe, C. O. Angew.
Chem. 2010, 122, 7255. Angew. Chem., Int. Ed. 2010, 49, 7101.
(13) (a) Sedelmeier, J.; Ley, S. V.; Baxendale, I. R.; Baumann, M.
Org. Lett. 2010, 12, 2618. (b) O’Brien, M.; Baxendale, I. R.; Ley, S. V.
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Organic Process Research & Development
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