Aqueous microdroplets containing only ketones or aldehydes undergo Dakin and Baeyer-Villiger reactions

Article abstract of DOI:10.1039/c9sc05112k

The Dakin and Baeyer-Villiger (BV) oxidation reactions require addition of peroxides as oxidants and an acid or a base as a catalyst. Reaction times range from hours to days to obtain target products. Previously, we reported that hydrogen peroxide (H₂O₂) is spontaneously generated in water microdroplets without any added chemicals or applied electrical potential. Here, we report that the Dakin and BV reactions occur in modest yields within milliseconds in aqueous microdroplets at room-temperature without the addition of external peroxides and catalysts. H₂O₂ generation is the result of the special environment of the microdroplet surface, which promotes water autoionization. We find that increasing the content of water and decreasing the droplet size improve the product yield of the Dakin and BV reactions, supporting the contention that the amount of H₂O₂ generated in aqueous microdroplets could induce the two reactions and the reactions occur at or near the air-water interface of the microdroplet surface.

Full text of DOI:10.1039/c9sc05112k

Volume 10 Number 48 28 December 2019 Pages 10965–11148
Chemical
Science
rsc.li/chemical-science
ISSN 2041-6539
EDGE ARTICLE
Richard N. Zare et al.
Aqueous microdroplets containing only
ketones or aldehydes undergo Dakin and
Baeyer–Villiger reactions

Chemical
Science
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Aqueous microdroplets containing only ketones or
aldehydes undergo Dakin and Baeyer–Villiger
reactions†
Cite this: Chem. Sci., 2019, 10, 10974
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
ab
Feng Jin,‡ Jae Kyoo Lee‡ and Richard N. Zare *a
ac
a
Dan Gao,
‡
The Dakin and Baeyer–Villiger (BV) oxidation reactions require addition of peroxides as oxidants and an acid
or a base as a catalyst. Reaction times range from hours to days to obtain target products. Previously, we
2 2
reported that hydrogen peroxide (H O ) is spontaneously generated in water microdroplets without any
added chemicals or applied electrical potential. Here, we report that the Dakin and BV reactions occur in
modest yields within milliseconds in aqueous microdroplets at room-temperature without the addition
2 2
of external peroxides and catalysts. H O generation is the result of the special environment of the
Received 9th October 2019
Accepted 12th November 2019
microdroplet surface, which promotes water autoionization. We find that increasing the content of water
and decreasing the droplet size improve the product yield of the Dakin and BV reactions, supporting the
DOI: 10.1039/c9sc05112k
2 2
contention that the amount of H O generated in aqueous microdroplets could induce the two
rsc.li/chemical-science
reactions and the reactions occur at or near the air–water interface of the microdroplet surface.
water microdroplets can be used to carry out the Dakin and
Baeyer–Villiger (BV) reactions, which are classic synthetic
Introduction
Many studies have shown that the rates of chemical reactions in approaches for the oxidation of carbonyl groups.
microdroplets sprayed in air under ambient conditions can be
Dakin oxidation is one of the most common chemical reac-
markedly accelerated compared to the same reactions in bulk tions for the synthesis of phenols from hydroxybenzaldehydes,
1
6
solution. It is also possible for the reaction products in and BV oxidation is oen used to prepare esters from ketones.
microdroplets to differ substantially compared to those from Both reactions need aldehydes or ketones and peroxides (typically
2
the same reaction conditions in bulk solution. Recent work has hydrogen peroxide (H
2
O
2
) or peroxyacid) as reactants with the
7
demonstrated that aqueous microdroplets can cause sponta- addition of acid or base (such as NaOH) catalysts. Most modern
neous reduction. Two examples are the formation of gold synthetic strategies for these oxidation reactions require
nanoparticles and nanowires from aqueous microdroplets hazardous peroxides, a high concentration of acid or base or an
3
containing only chloroauric acid, and the reduction of expensive organometallic compound as the catalyst. Moreover,
a number of different organic compounds dissolved in aqueous the Dakin and BV reactions typically need hours to days to obtain
4
8
microdroplets, such as the conversion of pyruvate to lactate. In target products. Therefore, many efforts have been made to
9
all these cases, no external potential is applied to the spraying develop oxidation systems with aqueous H
source for microdroplet generation and the room-temperature biocatalytic reagents such as BV monooxygenases.
aqueous microdroplets do not contain other compounds, such
Due to the unique characteristics of aqueous microdroplets,
as catalysts. Perhaps, the most striking example is the recent like production of H and hydrated excess hydronium and
discovery that aqueous microdroplets under ambient condi- hydroxide ions on the microdroplet surface, we present a proof
tions (room temperature and 1 atmosphere pressure of air) of principle here that the Dakin and BV reactions can be ach-
2 2
O as the oxidant or
10
2 2
O
11
contain a small concentration (ꢀ30 mM) of hydrogen peroxide ieved using aqueous microdroplets containing only the
5
(
H
2
O
2
). In this study, we demonstrate that the H
2
O
2
formed in carbonyl compound that is desired to be transformed (see
Fig. 1a). Much more work needs to be done to show how such
reactions can be scaled up and how yields can be improved to
a
Department of Chemistry, Stanford University, Stanford, CA 94305, USA. E-mail: make this method practical for preparative synthesis. It is
zare@stanford.edu
hoped that this work is a rst step in realizing this goal.
b
State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International
Graduate School, Tsinghua University, Shenzhen, 518055, China
c
Shenzhen Deepdrug Information Technology Co. Ltd., Shenzhen, 518052, China
Results and discussion
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c9sc05112k
1
Fig. 1b shows our experimental setup. A 1 : 1 solution of water
and acetonitrile (to aid solubility) containing aldehyde or
‡
These authors contributed equally.
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reaction includes the following steps. 4-hydroxybenzaldehye 1 is
protonated followed by the attack of hydrogen peroxide on the
carbonyl carbon to form a tetrahedral intermediate 2. This step
is followed by aryl migration and water elimination to yield
a phenyl ester 3. Then hydrolysis of 3 via intermediate 4 yields
the nal product 5, 1,2-dihydroxybenzene. We dissolved ortho-
or para-hydroxybenzaldehyde in water/acetonitrile (1 : 1, v/v)
and sprayed this solution using our experimental setup into the
inlet of a mass spectrometer for real-time analysis of reaction
products. As shown in Fig. 2b and c, we observed a small
amount of ortho- or para-hydroxyphenol 5 in microdroplets
containing reactant 1, hydroxybenzaldehye. We also observed
the expected intermediate 3 in the two Dakin reactions. The
chemical structures of intermediate 3 and product 5 were
conrmed by comparing observed fragment ions from the
microdroplet reactions and the corresponding standard
samples with tandem mass spectrometry using collision
induced dissociation (CID) (see Fig. S1 and S2†). The observa-
tion of intermediate 3 supports the above-indicated reaction
mechanism. In the bulk phase, the Dakin reaction is carried out
Fig. 1 (a) Dakin oxidation in microdroplets of hydroxybenzaldehydes
1
2
to phenols and BV oxidation of ketones to esters (R and R denote the
migrating groups). (b) Schematic of the experimental setup used to run
and monitor the Dakin and BV reactions in aqueous microdroplets
sprayed in air.
ketone was sprayed with a high-pressure nebulizing gas (N , 120
2
psi) to produce microdroplets encapsulating the reactants with
12
2 2
with excess H O and high concentrations of acid or base at
sizes ranging from 1 to 50 mm in diameter.
13
elevated temperatures. This means that the reaction cannot
The Dakin reaction is an oxidation reaction in which
hydroxybenzaldehyde is converted to a phenol on treatment
occur when only the reactant is present in bulk water–organic
solvents at room temperature. However, our results indicated
2 2
with H O (Fig. 2a). The classical mechanism of the Dakin
5
that the amount of H
2
O
2
generated (as well as the hydrated
Fig. 2 The Dakin reaction of ortho- or para-hydroxybenzaldehyde in microdroplets: (a) reaction scheme; (b) and (c) mass spectra using ortho-
and para-hydroxybenzaldehyde; and (d) kinetics of intermediate 3 and product 5 ranged from microsecond to millisecond timescale by adjusting
the distance between the spray emitter to the MS inlet.
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excess hydronium and hydroxide ions on the surface of the
11
microdroplets could meet the requirement of oxidants as
reactants and drive acid/base-catalyzed Dakin reactions. It
might seem paradoxical that both the oxidation reaction
studied in this work and the reduction reaction reported by our
previous work can occur in an aqueous microdroplets. The
observations are not inconsistent, however, because the auto-
ionization of water is enhanced at the air–water interface,
À
+
producing both more OH and more H than in bulk water.
Thus, both oxidation and reduction reactions are promoted in
water microdroplets.
The travel distance of the microdroplets between the spray
source and the MS inlet greatly inuences the degree of product
conversion, which has been widely reported in many other
reactions. This phenomenon seems sensible because of two
factors, namely, the increase of reaction time and solvent
12,14
evaporation, which increased the concentration of reagents.
In the Dakin reaction of ortho-hydroxybenzaldehyde, we varied
the distance between the spray emitter and the MS inlet from 1
cm to 11 cm, corresponding to approximate ight times of 100
ms to 13 ms. Because different compounds have different ioni-
zation efficiencies, we have corrected the conversion ratios by
incorporating the ionization efficiency of each ion. The relative
ionization efficiency of intermediate 3 to reactant 1 was 0.19,
and that of product 5 to reactant 1 was 0.011. The detailed
calculation is shown in the ESI.† As shown in Fig. 2d, as the
reaction time increased, the ratio of product 5 to the sum of
reagent 1, intermediate 3, and product 5 increased gradually
from 3.5% to 6.9%, whereas the ratio of intermediate 3 to the
same sum decreased from 7.1% to 2.7%. The corresponding
mass spectra at the distances of 1 cm and 11 cm are shown in
Fig. S3.† Given the microsecond-timescale kinetics, we
conclude that the Dakin reaction rate in microdroplets is
markedly accelerated compared to the bulk reaction, which Fig. 3 BV reactions in microdroplets of (a) 4-hydroxyacetophenone 6
1
5
and (b) 2-hydroxybenzophenone microdroplets without using an acid,
base or peroxide and their corresponding mass spectra. For clarity,
product 7 is enlarged 5 times.
typically takes minutes to hours.
The BV reaction is another type of oxidation requiring an
acid or a base as a catalyst and peroxide as an oxidant. We began
our investigation by examining two BV reactions with 4-
hydroxyacetophenone 6 and 2-hydroxybenzophenone 8 as the
reactants in microdroplets without addition of any catalyst and
oxidant. Microdroplets containing 6 and 8 at 100 mM concen-
tration in 1 : 1 water–acetonitrile solution were sprayed sepa-
rately using nebulizing gas into the MS inlet. Mass spectra were
recorded in the negative ion mode. As shown in Fig. 3, the
oxidation product, 4-hydroxyphenyl acetate 7 generated from
reactant 6, and product 9 generated from reactant 8 in aqueous
microdroplets were detected by the ion signals at m/z 151.0403
and m/z 213.0559, respectively. The results indicated the
spectrometry using CID (Fig. S4 and S5†). Please note that these
BV reactions do not spontaneously occur in bulk water con-
taining a small amount of organic solvent without catalysts and
oxidants.
To ensure the critical role of the H O generated in micro-
2
2
droplets that can induce the BV reaction, 1 eq. and 3 eq. of H O2
2
were added to microdroplets containing reactant 6 to detect by
mass spectrometry how the yield of the reaction product
changes. When the reaction is carried out in aqueous micro-
droplets without adding any H
about 2.7%. However, with the addition of 1 eq. and 3 eq. H
the yield of product 7 increased to 6.5% and 18.6%, respectively
Table S1†). These ndings show that the microdroplets can
induce the BV reaction without adding any H O . We also
2 2
O , the yield of product 7 was
2 2
generation of H O and accumulation of hydrated excess
2 2
O ,
hydronium and hydroxide ions for BV reactions in micro-
droplets. We also corrected the conversion ratio of the corre-
sponding products in these two BV reactions by measuring the
relative ionization efficiencies of the corresponding product to
reactant. The calculated values for BV reactions of 6 and 8 were
.23 and 3.90, see the ESI.† Their corresponding conversion
ratios of products 7 and 9 were 2.7% and 3.5%, respectively.
Their structures were further conrmed by tandem mass
(
2
2
examined the relationship between the concentration of reac-
tant 6 and the conversion yield of product 7 from 6 in micro-
droplets. The conversion yield increased as the reactant
concentration decreased (Fig. S6†), which is consistent with the
0
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4
observation reported in a previous study. When we decreased
the concentration of reactant 6 to 10 nM, this conversion ratio
reached 24.6%.
Under bulk conditions, BV reactions are affected by several
factors, such as the type of oxidizing agent and reaction
16
conditions, oen producing a mixture of phenol and ester. In
an interesting example, Roy et al. found that in the BV reaction
2 2
with sulphuric acid as a catalyst and H O as an oxidation
17
reagent, only para-benzenediol was obtained. However, we
observe exclusively the ester product, but no para-benzenediol,
when the BV reaction is carried out in aqueous microdroplets
without any oxidant and catalyst. These markedly different
behaviors between bulk and microdroplet reactions might be
caused by the fact that the bulk reactions need longer reaction
times (several hours) that allow ester hydrolysis to phenol.
Encouraged by these results, we examined several other BV
reactions including ketones in a chain or ring. In all tested
reactions, the desired BV oxidation products of individual
reactants (cyclohexanone and 3-pentanone) in microdroplets
were obtained without adding external catalyst and oxidant
(Fig. S7 and S10†).
As it was suggested by our previous report that H
formed by hydroxyl radical recombination, we investigated the
2
O
2
was
5
effects of water and organic solvent ratio in microdroplets on
the formation of hydroxyl radicals and thus the amount of H O
2 2
generated, which will nally inuence the product yield of the
Dakin and BV reactions. The BV reaction of reactant 8 to form
product 9 was tested as an example. Because reactant 8 is not
water soluble, we varied the volume ratio of water to ACN (0, 0.2,
0
.4, 0.6, and 0.8; v/v) in the microdroplets. The concentration of
reactant 8 was kept at 100 mM. As shown in Fig. 4a, the
conversion ratio of product 9 increased from 0.03% to 12.5% Fig. 4 Conversion ratio of product 9 from the BV reaction of reactant
8
in microdroplets with respect to the (a) volume ratio of water to
with increasing concentration of water in the solvent. This
result indicates that BV reactions preferentially occur in
microdroplets with a high water content. We also noticed that
when no water is present in the solvent, there was still a small
amount of product 9 generated in microdroplets. The reason
might be a trace moisture in the air which led to introduction of
water into the microdroplets.
acetonitrile, (b) sheath gas pressure, and (c) voltage applied to the ESI
spray source.
microdroplets have higher surface-to-volume ratios so that for
the same volume of solution, smaller microdroplets provide
18
more surface sites for chemical reaction. It is also true that
diffusion is more effective in mixing the contents of a micro-
droplet when it is smaller for a given short reaction time.
Next, we explore the effect of applied voltage on the conver-
sion yield from reactant 8 to product 9 by applying different
negative voltages to the spray source (Fig. 4c). When increasing
the voltage from À5 to 0 kV, the conversion ratio of product 9
has only a small uctuation at around 12.0%. These data
suggest that the voltage has little or no contribution to this
reaction. Possible reasons for the different reaction efficiencies
might be related to the varied ionization efficiencies of the
reactant and product under different voltages.
The sharply different behaviors of the Dakin and BV reac-
tions in the bulk from those in aqueous microdroplets
emphasize the importance of the droplet size (surface area-to-
volume ratio) in driving these two reactions. We further inves-
tigated the effect of surface area-to-volume ratio on the product
yield in microdroplets for the BV reaction of reactant 8 to form
product 9 in aqueous microdroplets. Water/ACN (0.8) was used
to dissolve reactant 8 (100 mM) because of the optimal conver-
sion ratio of product 9 under this solvent condition. The reac-
tant solution was then sprayed from the experimental setup
with the sheath gas pressure changed in steps of 20 psi from 40
psi to 120 psi to control the droplet size from larger to smaller.
À1
The ow rate of the reactant solution was kept at 5 mL min . As
shown in Fig. 4b, we observed that the conversion ratio of
product 9 increased gradually from 3.1% to 13.2% with
Conclusions
decreasing size of the microdroplets. The improvement of the Many previous research studies have reported that the Dakin
reaction efficiency in smaller microdroplets suggests the and BV reactions can be induced by employing H as a more
important role played by the surface environment. Smaller environmentally friendly oxidant with only water as an
2 2
O
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1
9
ecologically benign byproduct. In this work, we have demon-
strated that the Dakin and BV reactions can be carried out in
microdroplets by employing water as one of the reactants.
Compared to the previously reported synthetic methods, water
as the reactant and reaction medium has many signicant
advantages, such as low cost, nonammability, and environ-
mental compatibility. However, switching from organic solvents
to water as a reaction medium is a non-traditional approach,
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although on-water reactions have received much attention. As
shown in this study, the Dakin and BV reactions can take place
in water microdroplets containing a small amount of organic
solvent to aid dissolution of the carbonyl compound, but the
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microdroplets. Our results do demonstrate that microdroplets
have a unique microenvironment for inducing chemical reac-
tions, suggesting their potential to be used as powerful micro-
reactors for oxidation and reduction in organic reactions. We
also demonstrated that the unique characteristics of aqueous
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Acknowledgements
We thank Gaoweiang Dong for assistance in some of the
experiments. Feng Jin thanks Shenzhen Neptunus Pharmaceu-
tical Science and Technology Institution Co. Ltd. for the
opportunity to spend a sabbatical leave at Stanford University.
This work was supported by the Air Force Office of Scientic
Research through a Basic Research Initiative grant (AFOSR
FA9550-16-1-0113) and the National Natural Science Founda-
tion of China (No. 21675096).
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