Preparative microdroplet synthesis of carboxylic acids from aerobic oxidation of aldehydes

Article abstract of DOI:10.1039/c8sc01580e

Single liquid-phase and liquid-liquid phase reactions in microdroplets have shown much faster kinetics than that in the bulk phase. This work extends the scope of microdroplet reactions to gas-liquid reactions and achieves preparative synthesis. We report highly efficient aerobic oxidation of aldehydes to carboxylic acids in microdroplets. Molecular oxygen plays two roles: (1) as the sheath gas to shear the aldehyde solution into microdroplets, and (2) as the sole oxidant. The dramatic increase of the surface-area-to-volume ratio of microdroplets compared to bulk solution, and the efficient mixing of gas and liquid phases using spray nozzles allow effective mass transfer between aldehydes and molecular oxygen. The addition of catalytic nickel(ii) acetate is shown to accelerate further microdroplet reactions of this kind. We show that aliphatic, aromatic, and heterocyclic aldehydes can be oxidized to the corresponding carboxylic acids in a mixture of water and ethanol using the nickel(ii) acetate catalyst, in moderate to excellent yields (62-91%). The microdroplet synthesis is scaled up to make it preparative. For example, aerobic oxidation of 4-tert-butylbenzaldehyde to 4-tert-butylbenzoic acid was achieved at a rate of 10.5 mg min^-1 with an isolated product yield of 66%.

Full text of DOI:10.1039/c8sc01580e

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DOI: 10.1039/C8SC01580E
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Preparative microdroplet synthesis of carboxylic acids from
aerobic oxidation of aldehydes
Xin Yana, Yin-Hung Laia, and Richard N. Zare*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Single liquid-phase and liquid-liquid phase reactions in microdroplets have shown much faster kinetics than that in bulk
phase. This work extends the scope of microdroplet reactions to gas-liquid reactions and achieves preparative synthesis.
We report highly efficient aerobic oxidation of aldehydes to carboxylic acids in microdroplets. Molecular oxygen plays two
roles: (1) as the sheath gas to shear the aldehyde solution into microdroplets, and (2) as the sole oxidant. The dramatic
increase of the surface-area-to-volume ratio of microdroplets compared to bulk solution, and the efficient mixing of gas
and liquid phases using spray nozzles allow effective mass transfer between aldehydes and molecular oxygen. The addition
of catalytic nickel(II) acetate is shown to accelerate further microdroplet reactions of this kind. We show that aliphatic,
aromatic, and heterocyclic aldehydes can be oxidized to the corresponding carboxylic acids in a mixture of water and
ethanol using the nickel(II) acetate catalyst, in moderate to excellent yields (62–91%). The microdroplet synthesis is scaled
to make it preparative. For example, aerobic oxidation of 4-tert-butylbenzaldehyde to 4-tert-butylbenzoic acid was
achieved at a rate of 10.5 mg/min for the isolated product at a yield of 66%.
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Gas-liquid reactions are of great chemical, biological,
13
physiological, and ecological importance.12,
An important
Introduction
question is whether gas-liquid reactions can be accelerated in
microdroplets generated by spray-based ionization methods.
Such methods of forming microdroplets often apply sheath gas
(commonly nitrogen gas) to pneumatically assist the formation
of the sprayed droplets. An extra advantage of replacing
sheath gas with reagent gas will be gained by its dual role as an
assistant in droplet formation as well as reagent.
The oxidation of aldehydes to carboxylic acids has been of
long-standing interest in synthetic organic chemistry,14 and is
an industrially important process.15 Compared to the
Recent findings indicate that reactions in microdroplets
created by spray-based ionization/aerosol are extremely
attractive, as the microdroplet reactions can be many orders
of magnitude faster than their conventional bulk-phase
counterparts.1, 2 This phenomenon stimulates the growth of a
strong interest in using microdroplets as a chemical synthetic
tool. Remarkable acceleration has been observed in single
liquid-phase reactions and liquid-liquid phase reactions. For
example, an accelerated Pomeranz–Fritsch synthesis of
isoquinoline in methanolic solution was detected by on-line
mass spectrometry (MS) in charged droplets generated by
electrospray.3 The rate of this droplet reaction was reported to
be 106 times faster than in the bulk. Liquid-liquid bulk-phase
Stevens oxidation of alcohols to the corresponding
aldehydes/ketones is inhibited if not using a phase-transfer-
catalyst, because of the inability of reagents to come together.
In sharp contrast, non-catalytic oxidation can be achieved in
microdroplets formed by dual sonic sprays within milliseconds
in moderate to good yields.4 Other reactions involving C–C,5-7
C–N,6, 8-10 and C–O11 bond formation have been reported to be
accelerated by factors of 10–106 in single liquid-phase
solutions.
conventional methods using different oxidizing reagents such
17
as Cr(IV)-based Jones oxidation,16,
Ag(I)-based Tollen’s
reaction,18 and Cu(II)-based Fehling’s reaction,19 molecular
oxygen is considered as an ideal oxidant because it is
inexpensive, environmentally friendly,20 and exhibits highly
atom-efficient oxidation per weight (100% atom efficiency).21
Methods to achieve direct and efficient oxidation of aldehydes
to carboxylic acids using molecular oxygen as the oxidant
under mild conditions are relatively scarce and highly
needed,22 although recent progress has been made on the
development of less expensive transition-metal catalysts for
oxidation of aldehydes to carboxylic acids in the bulk.22-24 In
this work, we report a highly efficient aerobic oxidation of
aldehydes to carboxylic acids in microdroplets generated by
sonic spray ionization (Fig. 1a). Molecular oxygen has dual
roles of being the oxidant as well as the sheath gas to generate
microdroplets. Mixing of two phases occurs during
microdroplet formation. The effect of the surface-area-to-
a.Department of Chemistry, Stanford University, Stanford, CA 94305-5080 (USA)
Electronic Supplementary Information (ESI) is available. Correspondence should
be addressed to R. N. Zare. See DOI: 10.1039/x0xx00000x
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Journal Name
turbulent nebulizing gas operated at 120 psi as well as the sole
volume ratio (SA/V ratio) of microdroplets is also studied on
the yield of the reactions.
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DOI: 10.1039/C8SC01580E
oxidant. The oxidation of
between
interface. The resulting products
1 was initiated by the interactions
1
in microdroplets with molecular oxygen at the
were collected for 30 min
Another question well worth attention is the scale of
microdroplet reactions, as it determines the practicality for
chemical synthesis. Previous studies on “preparative
electrospray” employed four or eight spray sources at the
same time, and products were generated at rates on ca. 1.2-
1.6 milligram per minute for Claisen-Schmidt condensations,
2
using a microdroplet trapping system (Fig. S1). The reaction
mixture was extracted with dichloromethane and analysed by
1H NMR. The yield of
2 from oxidation of 1 was found to be
48% (Fig. 2a). A control experiment was performed in bulk
solution (O2 was supplied in a balloon). The reaction was
vigorously stirring at room temperature, and less than 1% of
product was detected after 30 min (Fig. 2b). An acceleration
factor of 50 was achieved for the reactions in microdroplets
compared to the bulk reaction calculated based on the yields
obtained after 30 min. Reaction is expected to continue on the
surface of the collected film, but the film surface area is so
small compared to the surface area of the microdroplets that
this contribution to the calculation of the acceleration factor
has been neglected.
5
benzoin condensations, and Stevens oxidations.4, Further
scale up of microdroplet reactions by paralleling more spray
sources might not be practical and economical owing to
complicated arrangements of splitting gas and liquid, as well as
the large demand for duplicated spray sources. Here, we
developed a device applying high flux of liquid droplets
colliding with gas molecules while maintaining the suitable
microdroplet sizes for fast and large-scale microdroplet
synthesis (Fig. 1b).
Next, we screened for possible catalysts without adding any
ligand or additive which would promote this reaction in
microdroplets, with an emphasis on widely available and
inexpensive metal catalysts. Nickel(II) acetate (5 mol%)
showed best efficiency among all the screened catalysts (Fig.
S2); a yield of 91% was achieved. In contrast, the addition of
nickel(II) acetate improved the yield of bulk reaction to 4% in
30 min (Fig. 2d, supporting information section 6). We
rationalized the observation as follows: the liquid-phase
oxidation of organic compounds with O2 can be affected by a
complex set of factors which include intrinsic parameters
(aldehyde reactivity, solvent, etc.) and extrinsic parameters
(catalyst, initiators/inhibitors, etc.), as well as physical
phenomenon such as gas to liquid mass transfer.25 When
oxygen transfer becomes the rate limiting step, the rate of the
overall process is no longer controlled by chemical
mechanisms but rather by physical transport.25
Fig. 1
Two-phase aerobic oxidation of aldehyde into carboxylic acid
performed in microdroplets: a) small scale in which the microdroplets are
generated by the atomization of bulk solution with turbulent nebulizing
oxygen gas at 90-120 psi (The insert shows the sprayer with external mixing
of liquid and gas); and b) preparative synthesis using a modified commercial
spray nozzle (The insert shows the nozzle with internal mixing of liquid and
gas, and mounted mesh that controls the droplet size).
Scheme 1
oxygen and 5 mol% Ni(OAc)2 in water-ethanol (v:v = 1:1.2) to form 4-
tert-butylbenzoic acid
Oxidation of 4-tert-butylbenzaldehyde 1 with molecular
2
.
Results and discussion
We began our investigation by examining (Scheme 1) the
oxidation of 4-tert-butylbenzaldehyde
solvent (v:v = 1:1.2) with molecular oxygen (O2) and without
any metal catalyst to form 4-tert-butylbenzoic acid at room
temperature. A water-ethanol solution of (0.1 M) introduced
1 in a water-ethanol
2
1
through a fused silica capillary (i.d. 50 μm) at the rate of 15
µL/min was atomized into microdroplets (average size ca. 3.1
μm; see supplementary information for method of droplet
measurement) with coaxial flow of oxygen being as the
2 | J. Name., 2012, 00, 1-3
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Fig. 3 Dependence of product yield on SA/V ratio in microdroplet aerobic
oxidation of 4-tert-butylbenzaldehyde to 4-tert-butyl benzoic acid: a) using
O2 as oxidant; and b) using air as oxidant.
Fig. 2
Oxidation of 4-tert-butylbenzaldehyde 1 with molecular
oxygen in water-ethanol (v:v = 1:1.2): a) in microdroplets without
adding Ni(OAc)2; b) in bulk without adding Ni(OAc)2; c) in
microdroplets with 5 mol% Ni(OAc)2; and d) in bulk with 5 mol%
Ni(OAc)2. The collection time for droplet reaction is 30 min and the
bulk-phase reaction time is the same. Error bars represent one
standard deviation (3 measurements).
The solvent system was investigated, because it serves not
only as the reaction medium but it also affects the formation
of microdroplets.10 We found water-ethanol (v:v = 1:1.2) gave
the best yields for the droplet reaction among various organic
solvents as well as miscible aqueous organic solvents for the
microdroplet oxidation of 4-tert-butylbenzaldehyde (Fig. S4).
Encouraged by these results, various aldehydes including
aromatic, heterocyclic and aliphatic aldehydes (Table 1) were
tested under their optimized conditions. The corresponding
Mass transfer across the interface is the rate-controlling
step in most of the two-phase reactions.26 Surface effect has
also been observed in atmospheric halogen chemistry,27
reactions with Criegee intermediates at the air-aqueous
interface,28 and catalytic oxidation of p-xylene to produce
high-purity terephthalic acid,29 as well as biphasic reactions in carboxylic acids were obtained in moderate to good yields (62-
30-33
flow systems.24,
These considerations prompted us to
91%).
investigate the effect of SA/V ratio on the product yield. We
controlled droplet size by varying the pressure of sheath gas
and using capillaries with different inner and outer diameters.
SA/V ratio of microdroplets was calculated based on the
droplet size measured by micro-particle image velocimetry
(µPIV, see supporting information for details). The experiment
started with dripping droplets with the SA/V ratio of 0.002
through the capillary (i.d. 250 µm, o.d. 365 µm) with no sheath
gas supply but in an oxygen environment protected by an O2
balloon. The flow rate was kept at 15 µL/min, and less than 6%
product was formed in 30 min. We increased the SA/V ratio of
droplets up to 500 times by increasing the O2 sheath gas
pressure from 30 to 120 psi through the capillary (i.d. 50 µm,
o.d. 365 µm). The product 4-tert-butylbenzoic acid was largely
enhanced with an increase of SA/V ratio of droplets from
0.033 to 1 (Fig. 3a), and reached the maximum yield when
droplet size decreased to about 3 µm. Similar phenomena
were also observed using compressed air as the oxidant with
less product formation (Fig. 3b). The closely related effect of
SA/V ratio to yield was found for reactions with different
aldehydes (Fig. S3).
Table 1 Aerobic oxidation of various aldehydes in microdroplets
Reagent
Product
Yield (%)
91
62
80
88
75
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