A biphasic oxidation of alcohols to aldehydes and ketones using a simplified packed-bed microreactor

Article abstract of DOI:10.3762/bjoc.5.17

We demonstrate the preparation and characterization of a simplified packed-bed microreactor using an immobilized TEMPO catalyst shown to oxidize primary and secondary alcohols via the biphasic Anelli-Montanari protocol. Oxidations occurred in high yields with great stability over time. We observed that plugs of aqueous oxidant and organic alcohol entered the reactor as plugs but merged into an emulsion on the packed-bed. The emulsion coalesced into larger plugs upon exiting the reactor, leaving the organic product separate from the aqueous by-products. Furthermore, the microreactor oxidized a wide range of alcohols and remained active in excess of 100 trials without showing any loss of catalytic activity.

Full text of DOI:10.3762/bjoc.5.17

A biphasic oxidation of alcohols to aldehydes and
ketones using a simplified packed-bed microreactor
Andrew Bogdan1 and D. Tyler McQuade*,2
Full Research Paper
Open Access
Address:
Department of Chemistry and Chemical Biology, Cornell University,
Beilstein Journal of Organic Chemistry 2009, 5, No. 17.
1
doi:10.3762/bjoc.5.17
Ithaca, NY, 14853 USA and 2Department of Chemistry and
Biochemistry, Florida State University, Tallahassee, FL 32306, USA.
Fax (850) 644-8281
Received: 23 December 2008
Accepted: 24 March 2009
Published: 29 April 2009
Email:
D. Tyler McQuade* - mcquade@chem.fsu.edu
Guest Editor: A. Kirschning
*
Corresponding author
© 2009 Bogdan and McQuade; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
alcohol oxidation; flow chemistry; heterogeneous catalysis;
microreactors; TEMPO
Abstract
We demonstrate the preparation and characterization of a simplified packed-bed microreactor using an immobilized TEMPO cata-
lyst shown to oxidize primary and secondary alcohols via the biphasic Anelli-Montanari protocol. Oxidations occurred in high
yields with great stability over time. We observed that plugs of aqueous oxidant and organic alcohol entered the reactor as plugs but
merged into an emulsion on the packed-bed. The emulsion coalesced into larger plugs upon exiting the reactor, leaving the organic
product separate from the aqueous by-products. Furthermore, the microreactor oxidized a wide range of alcohols and remained
active in excess of 100 trials without showing any loss of catalytic activity.
Introduction
Microreactors have gained attention because they can help run developed a catalytic packed-bed microreactor that could be
chemical transformations more efficiently, more selectively, used for the continuous flow oxidation of alcohols to aldehydes
and with a higher degree of safety [1-12]. Alcohol oxidations or ketones.
are well suited for microreactors due to high by-product forma-
tion, catalyst contamination and safety concerns often associ- Oxidations that do not require transition metal catalysts are
ated with scale-up in batch reactors [13]. Recent developments particularly appealing since there is neither leaching nor the
in microreactor technology and solid-supported catalysis have need for catalyst regeneration [22]. Nitroxyl radicals, such as
aimed to solve these issues. Numerous flow oxidations have 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), immobilized on
been presented in the literature [13-16], however many rely on silicates [23-32], fluorous supports [33], soluble and insoluble
stoichiometric reagents [17,18], suffer from catalyst deactiva- polymers [22,34-36], magnetic nanoparticles [37], and ionic
tion [19,20], or rely on soluble catalysts [21], all of which limit liquids [38] have been extensively studied and are useful
their potential as continuous flow processes. Realizing this, we because the oxidation conditions are mild, selective, and the
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Beilstein Journal of Organic Chemistry 2009, 5, No. 17.
microreactor is made of cheap, disposable fluoroelastomeric
tubing, wall oxidation that is commonplace with metal
microchannels is not observed [21]. The narrow dimensions of
the microreactor also allow excellent heat transfer, increasing
the safety of large-scale oxidations. Furthermore, it was determ-
ined that the use of a packed-bed microreactor facilitates effi-
cient mixing of a biphasic system without destroying the solid
support, a common problem with stirred systems [4].
Scheme 1: Preparation of azide-modified AO resin 2.
catalysts do not require regeneration. TEMPO, however, is
expensive and difficult to remove from reaction mixtures. For Results and Discussion
these reasons, TEMPO immobilization is an important goal Previously we reported that catalysts functionalized with an
because it enables facile removal and recycling.
acetylene moiety can be tethered to AO using a Huisgen
cycloaddition [39]. Azide-functionalized AO resin (AO-N3, 2)
We recently reported the development of an effective solid was prepared by treating AO with sodium azide (Scheme 1)
support for use in packed-bed microreactors [39], [41]. The coupling of 4-hydroxy-TEMPO 3 with propargyl
AMBERZYME® Oxirane (AO, 1), a commercially available bromide (4) using sodium hydride yielded the acetylene-modi-
resin with pendant epoxide functionalities designed for enzyme fied TEMPO species 5 [33,34,37]. TEMPO derivative 5 was
immobilization. AO is readily functionalized with a range of then covalently bound to AO-N3 using copper(I) iodide [42-45],
catalysts and works well as packing material for flow chemistry yielding the TEMPO-functionalized resin (AO-TEMPO, 6,
[
39]. In this report, we demonstrate the immobilization of Scheme 2, 0.46 mmol TEMPO/g resin).
TEMPO and its use in a flow system using the Anelli-
Montanari protocol for the oxidation of primary and secondary Using a simplified procedure developed by ourselves and others
alcohols [30,40]. Our simplified reactor is advantageous [39,46-49], flow reactions were performed by packing
because the reactions not only run continuously, but since the fluoroelastomeric tubing (60 cm, 1.6 mm i.d.) with the
Figure 1: The simplified microreactor setup. Empty tubing (A) is packed with functionalized AO resin and attached to caps (B). The packed bed is
woven between metal bars (C) and connected to syringe pumps (D).
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Beilstein Journal of Organic Chemistry 2009, 5, No. 17.
Scheme 2: Preparation of AO-TEMPO 6.
AO-TEMPO resin. The tubing was subsequently woven
between metal bars, to improve mixing and to enable facile
microreactor cooling (Figure 1). A Y-junction placed at the inlet
of the microreactor allowed the immiscible bleach (adjusted to
pH 9.1 using NaHCO3) and organic alcohol solutions to form
plugs before reaching the packed bed (Figure 2A). When
passing through the AO-TEMPO catalyst bed, the plugs emulsi-
fied, as indicated by visual inspection and by the plug coales-
cence at the microchannel outlet (Figure 2B). The effective
mixing was later supported by the high yields and conversions
that were achieved for this biphasic reaction.
Figure 2: The organic (colored solution) and aqueous phases (color-
less solution) forming plugs at the Y-junction (A). The phases mix upon
reaching the packed bed, leading to a coalescence of drops at the
outlet of the microchannel (B).
Preliminary reactions were performed using benzyl alcohol as
the test substrate in order to establish the optimal flow condi-
tions (Scheme 3). A solution of benzyl alcohol in CH2Cl2
(
0.2 M), an aqueous NaOCl solution (0.25 M, adjusted to column at this flow rate. Faster flow rates (200 or 400 μL
pH 9.1 using NaHCO3), and an aqueous KBr solution (0.5 M) min−1) could also be used to obtain higher outputs of benzalde-
were prepared. The organic phase was loaded into one syringe hyde, however these reaction conditions did not provide
and a mixture of NaOCl and KBr (30 μL KBr solution per mL complete conversion of starting material.
NaOCl solution) was added to another. The syringes were
placed on separate syringe pumps and the flow rates were regu- Using these optimized flow conditions for the benzyl alcohol
lated such that 1.0 equiv alcohol min−1, 1.5 equiv NaOCl oxidation, a number of different substrates were examined to
min−1, and 0.10 equiv KBr min−1 were delivered to the packed test the generality of the AO-TEMPO packed-bed microreactor.
bed. Various flow rates were examined to determine the optimal High conversions were achieved when using both aromatic and
flow conditions for the oxidation. For data relating flow rate to aliphatic alcohols (Table 1, Entries 1–6). Secondary alcohols,
residence time, see Supporting Information File 1. During our which are known to be oxidized at a slower rate than primary
optimization studies, it was shown that a total flow rate of alcohols, could effectively be oxidized to ketones by increasing
1
00 µL min−1 (aqueous flow rate 56 µL min−1 and organic flow the equivalents of NaOCl with respect to the alcohol concentra-
rate 44 µL min−1, approximately 4.8 min residence time) tion (Table 1, Entries 7–9). Primary alcohols were shown to be
afforded quantitative conversion of benzyl alcohol to benzalde- oxidized selectively over secondary alcohols (Table 1, Entry
hyde, indicating that efficient mixing was occurring in the 10). Interestingly, it was also demonstrated that ethyl acetate
was almost as effective a solvent as methylene chloride,
opening the possibility of making this process “green” (Table 1,
Entry 11). While reactions range from modest to high yields,
systems that do not perform as efficiently could readily be
optimized to afford higher conversions and yields. For the
purposes of this paper however, we were solely testing the
Scheme 3: The AO-TEMPO-catalyzed oxidation of benzyl alcohol.
generality of the method and, therefore, did not optimize every
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Beilstein Journal of Organic Chemistry 2009, 5, No. 17.
Table 1: Oxidation of alcohols using AO-TEMPO packed-bed microreactor.
Entry
1
Alcohol
Method
Aa
Solvent
CH2Cl2
Product
Conversiond
>99%
Yieldd
95%
9
3%
2
A
CH2Cl2
>99%
(86%)e
3
4
A
A
CH2Cl2
CH2Cl2
88%
89%
85%
86%
5
6
A
A
CH2Cl2
CH2Cl2
88%
80%
71%
74%
7
8
Bb
B
CH2Cl2
CH2Cl2
>99%
95%
95%
84%
9
B
CH2Cl2
89%
85%
1
0
1
Cc
A
CH2Cl2
EtOAc
79%/16%
84%
71%/11%
81%
1
aMethod A: Organic Phase – Alcohol (0.2 M) in CH2Cl2 or EtOAc set to 44 μL min−1 (8.8 μmol alcohol min−1, 1.0 equiv min−1). Aqueous Phase –
Aqueous NaOCl (0.25 M), adjusted to pH 9.1 with NaHCO3, mixed with aqueous KBr (0.5 M, 30 µL per mL NaOCl) set to 56 µL min−1 (1.5 equiv NaOCl
min−1, 0.10 equiv KBr min−1). The phases combined at a Y-junction and passed through a 60 cm channel packed with AO-TEMPO (300 mg,
0
1
.138 mmol TEMPO) submerged in an ice bath. bMethod B: Organic Phase – Alcohol (0.1 M) in CH2Cl2 set to 44 μL min−1 (4.4 μmol alcohol min−1,
.0 equiv min−1). Aqueous Phase – Aqueous NaOCl (0.25 M), adjusted to pH 9.1 with NaHCO3, mixed with aqueous KBr (0.5 M, 30 µL per mL NaOCl)
set to 56 µL min−1 (3.0 equiv NaOCl min−1, 0.20 equiv KBr min−1). The phases combined at a Y-junction and passed through a 60 cm channel packed
with AO-TEMPO (300 mg, 0.138 mmol TEMPO) submerged in an ice bath. cMethod C: Organic Phase – Benzyl alcohol (0.2 M) and 1-phenylethanol
(0.2 M) in CH2Cl2 set to 44 μL min−1 (8.8 μmol alcohol min−1, 1.0 equiv min−1). Aqueous Phase – Aqueous NaOCl (0.20 M), adjusted to pH 9.1 with
NaHCO3, mixed with aqueous KBr (0.5 M, 30 µL per mL NaOCl) set to 56 µL min−1 (1.25 equiv NaOCl min−1, 0.10 equiv KBr min−1). The phases
combined at a Y-junction and passed through a 60 cm channel packed with AO-TEMPO (300 mg, 0.138 mmol TEMPO) submerged in an ice bath.
dConversions and yields determined by GC using cyclooctane as an internal standard. eNumber in parentheses corresponds to isolated yield.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 17.
substrate. Similar to our previous packed-bed systems, these
AO-TEMPO microchannels showed a high degree of recyclab-
ility, in some cases being used in excess of 100 trials without
any apparent loss of catalytic activity. Channels also main-
tained a high activity after three months of not being used.
To test the long-term activity of the AO-TEMPO packed beds,
the oxidation of 4-chlorobenzyl alcohol to 4-chlorobenzalde-
hyde was run continuously and sampled periodically to monitor
its activity. As seen in Figure 3, the activity of the catalyst bed
remained high even after hours of use. Furthermore, the work-
up of this simplified oxidation scale-up comprised only of phase
separation followed by concentration, yielding a white crystal-
line solid with greater than 95% purity by 1H NMR.
Conclusion
Figure 3: The long-term activity of AO-TEMPO packed beds in the
oxidation of 4-chlorobenzyl alcohol. A solution of 4-chlorobenzyl
alcohol (0.2 M in CH2Cl2) set to 44 μL min−1 (8.8 μmol min−1,
We have demonstrated that using supported TEMPO is an effi-
cient method to oxidize alcohols using a simplified packed-bed
microreactor. A biphasic mixture was thoroughly mixed by
passing the immiscible liquids through the catalytic packed-bed,
leading to no disruptions or degradation of the packing material.
Thus, the AO-TEMPO resins are recyclable, showing no loss of
catalytic activity and a substrate scope that encompasses many
1.0 equiv min−1) and an aqueous solution consisting of NaOCl (0.25
M), adjusted to pH 9.1 with NaHCO3, and KBr (0.5 M, 30 µL per mL
NaOCl) set to 56 µL min−1 (1.5 equiv NaOCl min−1, 0.10 equiv KBr
min−1) were passed through the AO-TEMPO packed bed for 9 h. Frac-
tions were collected and analyzed by GC using an internal standard.
primary and secondary alcohols. The devices presented are yield. Gas chromatography-mass spectrometry (GC/MS)
predicted to be readily scaled-up to achieve the desired output analyses were performed using a Hewlett Packard HP 6890
of a reaction and is of higher throughput than other reported Series Gas Chromatograph, a Hewlett Packard HP 5973 Mass
packed-bed microreactors.
Spectrometer Detector (MSD), and a J&W Scientific DB*-5
Column (length = 30 m, inner diameter = 0.325 mm, film thick-
ness = 1.0 µm, catalog number 123-5033). The temperature
program for the analyses held the temperature constant at 50 °C
Experimental
General
Solvents were purified by standard procedures. All other for 3 min, heated samples from 50 to 80 °C at 30 °C/min,
reagents were used as received, unless otherwise noted. Sodium holding at 80 °C for 2 min, then heating samples from 80 to
hypochlorite solution (reagent grade, available chlorine 200 °C at 17 °C/min, and holding at 200 °C for 1.94 min. The
1
0–15%) was purchased from Aldrich and titrated before use. MSD temperature was held at 300 °C for 15 min.
H NMR and 13C NMR spectra were recorded in CDCl3 on
Varian Mercury 300 MHz operating at 300.070 MHz and
5.452 MHz, respectively, using the residual solvent peak as
1
Azide modified AMBERZYME® Oxirane
7
(AO-N3, 2)
reference. ATR-IR was performed on a Nicolet Avatar DTGS Sodium azide (5.26 g, 81 mmol, 8.1 equiv) and ammonium
70 infrared spectrometer with Avatar OMNI sampler and chloride (2.27 g, 42.4 mmol, 4.2 equiv) were dissolved in
3
OMNIC software. Elemental analysis was performed by 500 mL 90:10 v/v water in methanol. AMBERZYME® Oxirane
Robertson Microlit Laboratories, Inc., in Madison, New Jersey. (10.0 g, 1.0 mmol epoxide/g resin, 10.0 mmol, 1.0 equiv) was
Gas chromatographic (GC) analyses were performed using an suspended in the azide solution and the reaction mixture
Agilent 7890A GC equipped with an Agilent 7683B auto- refluxed overnight with gentle stirring. The resin was filtered
sampler, a flame ionization detector (FID), and a J&W using a Buchner funnel, washed with deionized H2O (2 ×
Scientific 19091J-413 column (length = 30 m, inner diameter = 50 mL), MeOH (2 × 50 mL), Et2O (1 × 25 mL), and dried under
3
20 μm, and film thickness = 250 μm). The temperature vacuum. Elemental analysis afforded a loading of 1.0 mmol
program for GC analysis held the temperature constant at 80 °C N3/g resin.
for 1 min, heated samples from 80 to 200 °C at 20 °C/min and
held at 200 °C for 1 min. Inlet and detector temperatures were Propargyl ether TEMPO 5
set constant at 220 and 250 °C, respectively. Cyclooctane was Sodium hydride (150 mg, 6.3 mmol, 1.1 equiv) was added to
used as an internal standard to calculate reaction conversion and DMF (10 mL) and stirred at RT. 4-hydroxy-TEMPO (1.02 g,
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Beilstein Journal of Organic Chemistry 2009, 5, No. 17.
5
.
.
Jas, G.; Kirschning, A. Chem.–Eur. J. 2003, 9, 5708–5723.
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.9 mmol, 1.0 equiv) in DMF (10 mL) was added drop wise to
the sodium hydride suspension at 0 °C and stirred until gas
evolution ceased. Propargyl bromide (80% in toluene, 800 μL,
6
Kirschning, A.; Monenschein, H.; Wittenberg, R.
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-C
7
.4 mmol, 1.3 equiv) in DMF (10 mL) was added at 0 °C and
the reaction was allowed to warm up to RT and stirred
overnight. The reaction was quenched with water and the
aqueous phase was extracted with ethyl acetate (3 × 50 mL) and
the combined organic extracts dried over MgSO4, concentrated
and dried under vacuum. The product was purified using
column chromatography (silica gel, 1:1 → 1:2 hexanes/ethyl
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1
1
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reduce the product to the corresponding hydroxylamine.
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AO-TEMPO 6
doi:10.1002/anie.200462466
5
(450 mg, 2.14 mmol, 1.3 equiv) and CuI (40 mg, 0.2 mmol,
1
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.13 equiv) were dissolved in anhydrous THF (20 mL). 2
(
1.64 g, 1.0 mmol N3/g resin, 1.64 mmol, 1.0 equiv) was added
1
to the solution and placed under a N2 atmosphere. The suspen-
sion was shaken for 3 d. The resin was washed with THF (2 ×
16.Kirschning, A.; Altwicker, C.; Dräger, G.; Harders, J.; Hoffmann, N.;
Hoffman, U.; Schönfeld, H.; Solodenko, W.; Kunz, U.
1
0 mL), MeOH (1 × 10 mL), 1 M HCl (2 × 10 mL), deionized
H2O (1 × 10 mL), sat. NaHCO3 (2 × 10 mL), deionized H2O (1
10 mL), MeOH (1 × 10 mL) and CH2Cl2 (1 × 10 mL), and
dried under vacuum to yield the white AO-TEMPO resin
1.81 g, 0.46 mmol TEMPO/g resin). The loading was calcu-
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doi:10.1002/1521-3773(20011105)40:21<3995::AID-ANIE3995>3.0.CO
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Experimental methods and spectral data
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