Accelerated Oxidation of Organic Sulfides by Microdroplet Chemistry

Article abstract of DOI:10.1021/acs.joc.0c02942

We report the rapid oxidation of organic sulfides to sulfoxides by means of microdroplet chemistry at room temperature using a spray solution containing an organic sulfide dissolved in water/methanol, dilute (11%-14%) sodium hypochlorite (NaClO), and 5% chloroauric acid (HAuCl4). Ultrasonic nebulization, easy ambient sonic-spray ionization, or electrosonic spray ionization serves as the microdroplet source. High-resolution mass spectrometry was used as an online detector, and nuclear magnetic resonance was used as an offline detector. We found that the sulfoxide yields vary between 66 and 95%, the highest rate of product formation is 195 mg/min for benzyl phenyl sulfoxide, and the time required is a few minutes, which is much less than that required for the conventional means of achieving this chemical transformation. We also applied this microdroplet method to protein fingerprinting. We found that protein sequences containing methionine can be quickly oxidized, providing useful information for protein structure determinations.

Full text of DOI:10.1021/acs.joc.0c02942

pubs.acs.org/joc
Article
Accelerated Oxidation of Organic Sulfides by Microdroplet
Chemistry
Jia Li,⊥ Chengyuan Liu,⊥ Hao Chen, and Richard N. Zare*
Cite This: J. Org. Chem. 2021, 86, 5011−5015
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We report the rapid oxidation of organic sulfides to sulfoxides by
means of microdroplet chemistry at room temperature using a spray solution
containing an organic sulfide dissolved in water/methanol, dilute (11%−14%)
sodium hypochlorite (NaClO), and 5% chloroauric acid (HAuCl4). Ultrasonic
nebulization, easy ambient sonic-spray ionization, or electrosonic spray ionization
serves as the microdroplet source. High-resolution mass spectrometry was used as an online detector, and nuclear magnetic
resonance was used as an offline detector. We found that the sulfoxide yields vary between 66 and 95%, the highest rate of product
formation is 195 mg/min for benzyl phenyl sulfoxide, and the time required is a few minutes, which is much less than that required
for the conventional means of achieving this chemical transformation. We also applied this microdroplet method to protein
fingerprinting. We found that protein sequences containing methionine can be quickly oxidized, providing useful information for
protein structure determinations.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
We initially investigated how to optimize the oxidation of
thioanisole, which was synthesized with an isolated yield of
90%.27 The best conditions are using a spray solution of
methanol/water (1:1 v:v) containing thioanisole (10 mM) and
a commercial 11%−14% NaClO liquid (10 mM) with or
without a chloroauric acid catalyst via the EASI offline setup
(Figure S1a). The collection time was 2 min for each entry
given in Table 1. In the absence of a catalyst, the thioanisole
was completely converted to the corresponding sulfoxide and
sulfone but with poor chemoselectivity (57:43) (Table 1, entry
3). When 1% HAuCl4·3H2O was added to the reaction system
while all other quantities were kept the same, the selectivity
increased slightly so that the sulfoxide to sulfone ratio became
66:34 (Table 1, entry 2). In the case of 5% HAuCl4·3H2O, the
chemoselectivity was found to be 91:9 (Table 1, entry 1), and
the performance remained stable with increasing dosages of
the catalyst. However, when the same equivalent of Au(PPh3)
Cl was used in place of HAuCl4·3H2O, the selectivity declined
to some degree (Table 1, entry 4). We also tested the effect of
temperature on this offline reaction progress. We found that it
was easier to form sulfone at a higher temperature (Table 1,
entry 5). By contrast, under bulk solution-phase conditions the
reactant could not be fully consumed and the selectivity was
not good (Table 1, entry 6).
Sulfoxides are important intermediates for the synthesis of
many natural compounds1−3 and can be prepared by oxidizing
organic sulfides under various conditions.4−10 In past work, the
oxidation has generally been achieved using hydrogen peroxide
(H2O2), molecular oxygen (O2), photocatalysis, and catalytic
metallic nanoparticles. This procedure is in contrast to special
conditions such as promoter ionic liquids or inorganic
salts.11−22 Bulk reactions require a long reaction time, and
oxidation does not necessarily stop at the first step of
converting the sulfides to sulfoxides.23 Thus, there is a need
to produce sulfoxides more selectively. Sodium hypochlorite is
a cheap and convenient oxidizing reagent and can react with a
variety of functional groups. Commercial sodium hypochlorite
(11%−14%) in water is a strong oxidant, which oxidizes sulfide
compounds. When using sodium hypochlorite to oxidize
sulfides or disulfides in a bulk solution, a mixture of sulfones
and sulfoxides appears at the same time. We describe an
alternative approach for transforming sulfides into sulfoxides
using easy ambient sonic-spray ionization (EASI) of a solution
containing a sulfide, sodium hypochlorite, and chloroauric
acid.24 As previously reported,25,26 owing to the limit flow rate
of EASI, ultrasonic nebulization (UN) was developed as a new
method to scale up the synthesis of accelerated microdroplet
reactions. The reactant solution in the ultrasonic nebulization
cell can be immediately atomized to large amount of
microdroplets with an average diameter of 6.9 μm to form a
so-called “ultrasonic fountain”. Therefore, we scaled up the
accelerated synthesis of sulfoxides from sulfides in micro-
droplets using ultrasonic nebulization.
Received: December 14, 2020
Published: March 3, 2021
https://dx.doi.org/10.1021/acs.joc.0c02942
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 5011−5015
5011

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
Table 1. Optimization of Thioanisole Oxidation Using
Table 2. Scope of Sulfide Oxidation Reactions
Offline Collection
a
yield (%)
entry
catalyst
2
3
1
2
3
4
5% HAuCl4·3H2O
1% HAuCl4·3H2O
91
66
57
76
85
35
9
34
43
24
15
10
5% Au(PPh3)Cl
5% HAuCl4·3H2O
5% HAuCl4·3H2O
b
5
c
6
a
Yield (%) was determined by NMR (−CH3) from the crude reaction
b
c
mixture. Heated at 85 °C. The bulk reaction was carried out for 2
min at room temperature.
Additionally, we took advantage of online mass spectrometry
analysis to assess these reaction conditions using 1 mM 4-
methoxyphenyl sulfoxide, which had a similar ionization
efficiency as that of the internal standard we used. First, the
capillary temperature was varied from 50 to 250 °C, the travel
distance was fixed at 2 cm, and the solution sample was diluted
ten times to 1 mM. The droplets were generated using the
ESSI setup under 120 psi N2 and high voltage (+3.0 kV). The
reaction occurred during the travel distance, and the yield was
calculated from Ip/Is, where Ip was the intensity of product and
Is was the intensity of the internal standard. The yield
decreased as the temperature increased, indicating that a lower
temperature was favorable for this reaction. Consequently,
offline collections were finished at room temperature. Second,
we found that the pH of the diluted NaClO had a marked
effect on this reaction. When the pH was 7 or lower, the
reaction performed poorly. The highest peak appeared near pH
12 in which the yield of product was 79%. When the distance
from the sprayer to the collection surface was varied from 0.2
to 5 cm under the conditions of 50 °C and pH 12 of the
diluent NaClO, we found that the best distance was 3.5 cm.
The variations with temperature, flight distance, and the
NaClO pH value are presented in Figures S2−S4, respectively.
For this setting, the yield was 87%. Because a velocity of 84 m/
s was reported for charged droplets under 120 psi, the time
scale was so short that a highly accelerated reaction in the
microdroplets must have been involved.28−30 To verify this
idea, we investigated the first-order reaction kinetics of online
experiments and the reaction in the bulk solution and plotted
the ln Ct/Co function of the reaction time (Figure S5). For the
microdroplets, the reaction time was the distance divided by 84
m/s. For the bulk, the reaction time was controlled within
0.5−10 min. The rate acceleration factor was 106 for the two-
slopes ratio. Thus, we conclude that the reaction rate for
product formation is much faster in the microdroplets than in
the bulk.
a
Yield (%) in blue was determined by 1H NMR on the liquid by EASI
within 2 min and yield (%) in black was the isolated yield of UN
reactions. 2h−2j was 2.0 equiv NaClO and 5% HAuCl4·3H2O over 2
min. 2k−2m was 1.0 equiv NaClO and 5% HAuCl4·3H2O over 10
min by UN reactions.
donating groups that make sulfides more readily oxidized. The
highest rate of product formation was 48 mg/min (2e).
However, in the case of electron-withdrawing groups (2h−2j),
the oxidation process was reduced, and the amount of
oxidizing reagent had to be doubled for the same reaction
time to obtain a higher yield. The yields reached moderate
levels with single sulfoxides products. We also investigated the
condition where sulfur connects to more than one aromatic
group. Instead of doubling the oxidant, we prolonged the
reaction time to 10 min under the same conditions to obtain
the appropriate yields (2k−2m). Finally, we tested the sulfur-
containing amino acid methionine (Met), which could prevent
oxygen radical damage in living organisms. We found that Met
could be converted to sulfoxide by 1 equiv of NaClO and 5%
HAuCl4·3H2O within 2 min, which provided a relative yield of
73%. All the products in Table 2 were characterized by NMR
spectroscopy and MS. We also tested this reaction on a
millimolar scale with a substrate of benzyl phenyl sulfide. The
parallel device of the ultrasonic nebulization system made up
of four similar reaction cells and used in this step under the
same concentration of reactant, obtaining the final sulfoxide
Encouraged by this outcome, we continued to examine this
method using a variety of substituted thioanisoles (Table 2).
Based on the results obtained from the EASI experiments, we
applied the ultrasonic nebulizing setup to scale up the reaction
(Figure S1b). When using reactants with 1.0 equiv of NaClO
and a catalytic amount of HAuCl4·3H2O (5%), the reactions
were conducted over 2 min with good isolated yields (2a−2g).
We attribute this performance to the effect of the electron-
5012
https://dx.doi.org/10.1021/acs.joc.0c02942
J. Org. Chem. 2021, 86, 5011−5015

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(2e) at a rate of 195 mg/min. To further evaluate the oxidation
method, we designed a protein fingerprinting experiment to
achieve a specific modification of the adrenocorticotropic
hormone (ACTH, human 1−24). There are many strategies to
modify protein structure, such as post-translational modifica-
tion and interactions, and chemical modification. The fast
photochemical oxidation of proteins was developed by Chance
and co-worker using synchrotron radiolysis to produce
hydroxyl radicals that could label a protein on the millisecond
or shorter time scale.31−36 The use of MS for proteomics and
metabolomics is in full swing, and electrosonic spray ionization
(ESSI) technology provides more efficient desolvation and
makes droplets more abundantly charged, both of which
enhance the MS sensitivity and increase the resolution.37,38
Recently, our group had developed a technology for the
ultrafast enzymatic digestion of proteins using trypsin, and we
have applied this to digest ACTH within 0.24 ms and obtain
nearly 100% sequence coverage.39
In this step, we sprayed a room-temperature sample solution
that consisted of 10 μM human ACTH and a 10 μM NaClO
dilution with or without adding trypsin. Microdroplets were
generated using our homemade ESSI sprayer setup under a
+3.0 kV voltage, a flow rate of 20 μL/min, and a N2 pressure of
120 psi. Initially when fixing the distance to inlet at 20 mm and
keeping the stream spraying for 1 min, we observed that the
oxidized fragment peak at m/z 738.7 (z = 4) increased as the
flight distance of the microdroplets increased, corresponding to
longer reaction times. When comparing the MS/MS fragments
with the control experiment, we observed peaks at m/z 675.6
(z = 4), m/z 871.5 (z = 3), and m/z 900.5 (z = 3) (Figure 1a),
which corresponded to adding one O atom to the peaks at m/z
671.6 (z = 4), m/z 866.2 (z = 3), and m/z 895.2 (z = 3) found
in the control experiment (Figure 1b).
after online digestion. The masses of the fragments had an
added value 16 Da compared to the corresponding fragments
before oxidation (Table S1).
CONCLUSIONS
■
In summary, we have used microdroplets containing sodium
hypochlorite and chloroauric acid to synthesize sulfoxides from
sulfides within 2 min, which is a very short time compared to
traditional bulk reactions. A series of substrates was
investigated by this method, and the yields were found to be
good. In addition, we demonstrated that this reaction can be
scaled up using an ultrasonic nebulizing system. We applied
this approach to protein fingerprinting to determine specific
methionine sites. This enables us to extend the ability to
perform protein sequencing by combining it with the
previously introduced method for the ultrafast enzymatic
digestion of proteins using microdroplet mass spectrometry.
The initial results appear to offer a new method for the
preparation of sulfoxides from sulfides and allow the oxidative
fingerprinting of proteins.
EXPERIMENTAL SECTION
■
General Information. All mass spectrometry (MS) experiments
were performed using an LTQ Orbitrap Velos mass spectrometer
(Thermo Fisher Scientific, San Jose, CA). The temperature of the MS
inlet capillary varied between 50 and 275 °C, the S-lens voltage was
set at 55 V, and a high voltage (+3.0 kV) supplied from an external
high-voltage power source. A collision energy of 20−30 eV was
selected for tandem mass spectrometry (MS/MS). The easy ambient
sonic-spray ionization (EASI) and electrosonic spray ionization
(ESSI) instruments were constructed of an inner fused silica capillary
(o.d. 148 μm and i.d. 74 μm) and an outer capillary (o.d. 360 μm and
i.d. 250 μm). Dry N2 with a pressure of either 60 or 120 psi was used
as nebulization gas. An ultrasonic nebulizer (Model 402AI, Yuwell
Medical Equipment & Supply Corp., Suzhou, China) was used. The
sodium hypochlorite (NaClO, 11−14%) solution was purchased from
Energy Alfa Aesar Co., Inc., and other reagents and solvents were
purchased from Adamas Reagent Co., Ltd. (Shanghai, China) and
1
used as received without further purification. H NMR spectra and
13C NMR spectra were recorded on a Bruker 400 MHz spectrometer
in CDCl3; δ values were given in ppm, and coupling constants (J)
were given in hertz (Hz). The high-resolution mass spectra (HRMS)
were recorded on a LTQ Orbitrap Elite mass spectrometer with a
FTMS.
General Procedure: Microdroplet Reactions by EASI. First,
100 μL of 100 mM methyl phenyl sulfide (also called thioanisole) in
methanol, 50 μL of 200 mM commercial 11−14% NaClO in water,
and 5 μL of 100 mM chloroauric acid in water were mixed, and an
extra 400 μL of methanol and 445 μL of water were added to the
system. The sprayed droplets were collected by a vial containing 100
μL of a saturated solution of Na2S2O3 for 2 min under 60 psi N2. The
flow rate was 100 μL/min, and the reaction distance was 3.5 cm. After
collection, the mixture was extracted by 1 mL of ethyl acetate,
transferred into a new vial, dried for NMR analysis. The bulk reaction
was performed by mixing the same concentration of liquids at room
temperature for 2 min, followed by adding 100 μL of a saturated
solution of Na2S2O3. After extraction and drying, the collected sample
was prepared for NMR analysis. The relative yield was calculated by
the integration of the product of interest. Other sulfides were reacted
following the same steps as those for thioanisole.
Figure 1. MS/MS spectra of ACTH for m/z 738.559 (z = 4) and
734.6568 (z = 4) showing (a) the oxidized fragmentation pattern and
(b) the unmodified fragmentation pattern.
Scaling-Up Reactions Using the UN System. First, 0.5 mmol
sulfides in 5 mL of methanol, 0.5 mmol commercial 11−14%NaClO
in 2.5 mL of water, and 250 μL of 100 mM chloroauric acid in water
were added into the UN cell. To the cell were added 7.5 mL methanol
and 9.75 mL water to make a total volume of 25 mL. Nebulization
was maintained for 2 or 10 min, then 1 mL of a saturated solution of
Na2S2O3 was added to quench the reaction. After extraction and
To determine where the location of the oxidation point is on
the peptide, 5 mM ammonium bicarbonate containing 5 μg/
mL trypsin was added to the prepared mixture. We found the
m/z 1072 peak increased markedly after adding one oxygen
compared to the fragment at m/z 1056. Moreover, we used the
energy of CID (23−30 eV) to confirm the MS MS fragments
5013
https://dx.doi.org/10.1021/acs.joc.0c02942
J. Org. Chem. 2021, 86, 5011−5015

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
drying with Na2SO4, the mixture was concentrated under vacuum,
and the residue was purified by flash column chromatography with
petroleum and ethyl acetate as the eluent to give the desired sulfoxide
products. All products were characterized by NMR spectroscopy and
high-resolution MS.
To further test this method, we tested four parallel devices using
the same reactant concentration of benzyl phenyl sulfide (Figure S5).
After nebulizing for 2 min, the mixture was combined, and 4 mL of a
saturated solution of Na2S2O3 was added to quench the reaction. After
extraction and drying by Na2SO4, the mixture was concentrated under
vacuum before the residue was purified by flash column
chromatography. The isolated yield was 90% with 389 mg of product,
which was similar to the one batch with a yield of 89%.
Oxidation of Adrenocorticotropic Hormone (ACTH). At room
temperature, 10 μM human ACTH (1−24) and 10 μM dilute NaClO
solution were mixed and sprayed for 1 min under +3.0 kV and 120 psi
N2. The flow rate was 20 μL/min. For online digestion, a 5 μg/mL
trypsin solution was added to the spray solution. The control
experiments were done without a NaClO oxidant, which allowed us to
confirm the sequences either with or without the addition of an
oxygen (16 Da) atom in the tandem MS with CID 23−30 eV. Using
the same procedure, we scaled up the reactions to obtain products
2a−2m using the UN system.
Methyl Phenyl Sulfoxide (2a). Colorless oil, 90% yield (63 mg).
1H NMR (400 MHz, CDCl3): δ 7.69−7.66 (m, 2H), 7.60−7.51 (m,
3H), 2.76 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 145.7,
131.1, 1 29.4, 123.5, 44.0. HRMS (ESI): m/z [M + Na]+ calcd for
C7H8NaOS+ 163.0188, found 163.0189.
7.77 (m, 2H), 2.79 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
153.3, 149.5, 124.7 (2C), 124.5 (2C), 43.9. HRMS (ESI): m/z [M +
H]+ calcd for C7H8NO3S+ 186.0219, found 186.0221.
1-Bromo-2-(methylsulfinyl)benzene (2j). Yellow oil, 67% yield
1
(73 mg). H NMR (400 MHz, CDCl3): δ 7.97 (dd, J = 7.8, 1.6 Hz,
1H), 7.68−7.55 (m, 2H), 7.39 (td, J = 7.8, 1.6 Hz, 1H), 2.84 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 145.4, 132.9, 132.3, 128.8,
125.7, 118.4, 41.9. HRMS (ESI): m/z [M + H]+ calcd for C7H8BrOS+
218.9474, found 218.9476.
Sulfinyldibenzene (2k). Yellow oil, 79% yield (80 mg). 1H NMR
(400 MHz, CDCl3): δ 7.70−7.65 (m, 4H), 7.52−7.43 (m, 6H).
13C{1H} NMR (101 MHz, CDCl3): δ 145.6 (2C), 131.1 (2C), 129.3
(4C), 124.8 (4C). HRMS (ESI): m/z [M + H]+ calcd for C12H11OS+
203.0525, found 203.0527.
1
(Vinylsulfinyl)benzene (2l). Yellow oil, 87% yield (66 mg). H
NMR (400 MHz, CDCl3): δ 7.69−7.61 (m, 2H), 7.61−7.49 (m, 3H),
6.62 (dd, J = 16.5, 9.6 Hz, 1H), 6.23 (d, J = 16.5 Hz, 1H), 5.92 (d, J =
9.6 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ 143.3, 143.0,
131.3, 129.5, 124.7, 120.7. HRMS (ESI): m/z [M + H]+ calcd for
C8H9OS+ 153.0369, found 153.0370.
Dibenzo[b,d]thiophene 5-Oxide (2m). White solid, 70% yield
1
(70 mg). H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 7.6 Hz, 2H),
7.85 (d, J = 7.6 Hz, 2H), 7.63 (td, J = 7.6, 1.0 Hz, 2H), 7.53 (td, J =
7.6, 1.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3): δ 145.2, 137.1,
132,6, 129.6, 127.6, 121.9. HRMS (ESI): m/z [M + H]+ calcd for
C12H9OS+ 201.0369, found 201.0371.
ASSOCIATED CONTENT
■
2-(Methylsulfinyl)pyridine (2b). Colorless oil, 90% yield (63
1
sı
* Supporting Information
mg). H NMR (400 MHz, CDCl3): δ 8.64−8.59 (d, J = 4.6, 1H),
8.04−7.99 (d, J = 7.7, 1H), 7.94 (td, J = 7.7, 1.6 Hz, 1H), 7.41−7.35
(m, 1H), 2.84 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 165.9,
149.6, 138.2, 124.6, 119.3, 41.3. HRMS (ESI): m/z [M + H]+ calcd
for C6H8NOS+ 142.0321, found 142.0322.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02942.
Descriptions of the microdroplet generation setups and
NMR spectra (PDF)
4-Methoxypheny Methyl Sulfoxide (2c). Colorless oil, 92%
1
yield (78 mg). H NMR (400 MHz, CDCl3): δ 7.61 (d, J = 8.7 Hz,
2H), 7.05 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H), 2.72 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3): δ 162.0, 136.6, 125.5, 114.9, 55.5, 44.0.
HRMS (ESI): m/z [M + H]+ calcd for C8H11O2S+ 171.0474, found
171.0475.
AUTHOR INFORMATION
■
Corresponding Author
Richard N. Zare − Department of Chemistry, Fudan
University, Shanghai 200438, China; Department of
Chemistry, Stanford University, Stanford, California 94305,
United States; orcid.org/0000-0001-5266-4253;
Email: rnz@fudan.edu.cn, rnz@stanford.edu
2-(Methylsulfinyl)naphthalene (2d). White solid, 92% yield (88
1
mg). H NMR (400 MHz, CDCl3): δ 8.11 (s, 1H), 7.84 (m, 3H),
7.59−7.41 (m, 3H), 2.70 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ142.7, 134.5, 133.0, 129.6, 128.5, 128.1, 127.9, 127.4, 124.1,
119.5, 43.8. HRMS (ESI): m/z [M + H]+ calcd for C11H11OS+
191.0525, found 191.0526.
Authors
Benzyl Phenyl Sulfoxide (2e). White solid, 89% yield (96 mg).
1H NMR (400 MHz, CDCl3): δ 7.47−7.33 (m, 1H), 7.28−7.18 (m,
1H), 6.99−6.90 (m, 1H), 4.08 (d, J = 12.6 Hz, 1H), 3.97 (d, J = 12.6
Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3): δ142.8, 131.2, 130.4
(2C), 129.2, 128.9 (2C), 128.5 (2C), 128.3, 124.5 (2C), 63.60 (s).
HRMS (ESI): m/z [M + H]+ calcd for C13H13OS+ 217.0682, found
217.0683.
Jia Li − Department of Chemistry, Fudan University, Shanghai
200438, China
Chengyuan Liu − National Synchrotron Radiation
Laboratory, University of Science and Technology of China,
Hefei 230029, China
Hao Chen − Department of Chemistry & Environmental
Science, New Jersey Institute of Technology, Newark, New
Jersey 07102, United States; orcid.org/0000-0001-8090-
8593
Thiane-1-oxide (2f). Yellow liquid, 95% yield (56 mg). 1H NMR
(400 MHz, CDCl3): δ 3.01−2.68 (m, 4H), 2.26 (m, 2H), 1.78−1.55
(m, 4H). 13C{1H} NMR (101 MHz, CDCl3): δ 48.9 (2C), 24.6
(2C), 19.1. HRMS (ESI): m/z [M + K]+ calcd for C5H10KOS+
157.0084, found 157.0098.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02942
1-(Butylsulfinyl)butane (2g). Yellow liquid, 91% yield (74 mg).
1H NMR (400 MHz, CDCl3): δ 2.67 (m, 4H), 1.77−1.73 (m, 4H),
1.51−1.46 (m, 4H), 1.02−0.97 (t, J = 4.0 Hz, 6H). 13C{1H} NMR
(101 MHz, CDCl3): δ 52.1, 24.6, 22.1, 13.7. HRMS (ESI): m/z [M +
H]+ calcd for C8H19OS+ 163.1151, found 163.1153.
1-Bromo-4-(methylsulfinyl)benzene (2h). Yellow oil, 66%
yield (72 mg). 1H NMR (400 MHz, CDCl3): δ 7.77−7.62 (m,
2H), 7.62−7.49 (m, 2H), 2.74 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 144.8, 132.6, 125.5, 125.1, 43.9. HRMS (ESI): m/z [M +
H]+ calcd for C7H8BrOS+ 218.9474, found 218.9476.
Author Contributions
⊥J.L. and C.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Scientific Research Startup
Foundation of Fudan University (Grant IDH1615113) and the
1-(Methylsulfinyl)-4-nitrobenzene (2i). White solid, 68% yield
(63 mg). 1H NMR (400 MHz, CDCl3): δ 8.47−8.32 (m, 2H), 7.92−
5014
https://dx.doi.org/10.1021/acs.joc.0c02942
J. Org. Chem. 2021, 86, 5011−5015

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(19) Noguchi, T.; Hirai, Y.; Kirihara, M. Highly selective 30%
hydrogen peroxide oxidation of sulfides to sulfoxides using micro-
mixing. Chem. Commun. (Cambridge, U. K.) 2008, 3040.
National Natural Science Foundation of China (Grant
21974027).
(20) Panda, M. K.; Shaikh, M. M.; Ghosh, P. Controlled oxidation of
organic sulfides to sulfoxides under ambient conditions by a series of
titanium isopropoxide complexes using environmentally benign H2O2
as an oxidant. Dalton Trans. 2010, 39, 2428.
REFERENCES
■
(1) Maezaki, N.; Yagi, S.; Yoshigami, R.; Maeda, J.; Suzuki, T.;
Ohsawa, S.; Tsukamoto, K.; Tanaka, T. Pd-Catalyzed Sulfinylzinca-
tion of Activated Alkynes with 1-Alkynyl Sulfoxides as a Sulfinyl
Source. J. Org. Chem. 2003, 68, 5550.
(2) Rademacher, P. M.; Woods, C. M.; Huang, Q.; Szklarz, G. D.;
Nelson, S. D. Differential Oxidation of Two Thiophene-Containing
Regioisomers to Reactive Metabolites by Cytochrome P450 2C9.
Chem. Res. Toxicol. 2012, 25, 895.
(3) Kim, D. G.; Vershinina, E. A. e.; Sharutin, V. V. Synthesis,
transformations and halocyclization of 8-(Prop-2-ynylsulfanyl)-
quinoline and 8-(2-Bromoprop-2-enylsulfanyl)quinoline. J. Sulfur
Chem. 2020, 41, 71.
(4) Shukla, V. G.; Salgaonkar, P. D.; Akamanchi, K. G. A Mild,
Chemoselective Oxidation of Sulfides to Sulfoxides Using o-
Iodoxybenzoic Acid and Tetraethylammonium Bromide as Catalyst.
J. Org. Chem. 2003, 68, 5422.
(5) Wang, S. H.; Mandimutsira, B. S.; Todd, R.; Ramdhanie, B.; Fox,
J. P.; Goldberg, D. P. Catalytic Sulfoxidation and Epoxidation with a
Mn(III) Triazacorrole: Evidence for A “Third Oxidant” in High-
Valent Porphyrinoid Oxidations. J. Am. Chem. Soc. 2004, 126, 18.
(6) Matteucci, M.; Bhalay, G.; Bradley, M. Mild and Highly
Chemoselective Oxidation of Thioethers Mediated by Sc(OTf)3. Org.
Lett. 2003, 5, 235.
(7) Baig, N.; Madduluri, V. K.; Sah, A. K. Selective oxidation of
organic sulfides to sulfoxides using sugar derived cis-dioxo
molybdenum(vi) complexes: kinetic and mechanistic studies. RSC
Adv. 2016, 6, 28015.
(8) Cao, J.-P.; Xue, Y.-S.; Li, N.-F.; Gong, J.-J.; Kang, R.-K.; Xu, Y.
Lewis Acid Dominant Windmill-Shaped V8 Clusters: A Bifunctional
Heterogeneous Catalyst for CO2 Cycloaddition and Oxidation of
Sulfides. J. Am. Chem. Soc. 2019, 141, 19487.
(9) Pye, S. J.; Dalgarno, S. J.; Chalker, J. M.; Raston, C. L. Organic
oxidations promoted in vortex driven thin films under continuous
flow. Green Chem. 2018, 20, 118.
(10) Velusamy, S.; Kumar, A. V.; Saini, R.; Punniyamurthy, T.
Copper catalyzed oxidation of sulfides to sulfoxides with aqueous
hydrogen peroxide. Tetrahedron Lett. 2005, 46, 3819.
(11) Gu, X.; Li, X.; Chai, Y.; Yang, Q.; Li, P.; Yao, Y. A simple metal-
free catalytic sulfoxidation under visible light and air. Green Chem.
2013, 15, 357.
(12) Imada, Y.; Iida, H.; Ono, S.; Murahashi, S.-I. Flavin Catalyzed
Oxidations of Sulfides and Amines with Molecular Oxygen. J. Am.
Chem. Soc. 2003, 125, 2868.
(13) Sato, K.; Hyodo, M.; Aoki, M.; Zheng, X.-Q.; Noyori, R.
Oxidation of sulfides to sulfoxides and sulfones with 30% hydrogen
peroxide under organic solvent- and halogen-free conditions.
Tetrahedron 2001, 57, 2469.
(14) Firouzabadi, H.; Iranpoor, N.; Jafari, A. A.; Riazymontazer, E.
Metal-Free Chemoselective Oxidation of Sulfides to Sulfoxides by
Hydrogen Peroxide Catalyzed byin situ Generated Dodecyl Hydrogen
Sulfate in the Absence of Organic Co-Solvents. Adv. Synth. Catal.
2006, 348, 434.
(15) Fukuda, N.; Ikemoto, T. Imide-catalyzed oxidation system:
sulfides to sulfoxides and sulfones. J. Org. Chem. 2010, 75, 4629.
(16) Kermanshahi, M. G.; Bahrami, K. Fe3O4@BNPs@SiO2−SO3H
as a highly chemoselective heterogeneous magnetic nanocatalyst for
the oxidation of sulfides to sulfoxides or sulfones. RSC Adv. 2019, 9,
36103.
(17) Liu, J.; Liu, G.; Liu, C.; Li, W.; Wang, F. Nano-sized
mesoporous sodium iron hydroxyphosphate supported gold: an
effective catalyst for the oxidation of sulfides. Catal. Sci. Technol. 2016,
6, 2055.
́
́
(21) Wang, S.; Wang, L.; Đakovic, M.; Popovic, Z.; Wu, H.; Liu, Y.
Bifunctional Ionic Liquid Catalyst Containing Sulfoacid Group and
Hexafluorotitanate for Room Temperature Sulfoxidation of Sulfides
to Sulfoxides Using Hydrogen Peroxide. ACS Catal. 2012, 2, 230.
(22) Zolfagharinia, S.; Kolvari, E.; Koukabi, N. A practical
heteropolyacid nanocatalyst supported on nano-sized ceramic for
the chemoselective oxidation of sulfides to sulfoxides through an
experimental design approach. Chemical Papers 2017, 71, 2505.
(23) Khurana, J. M.; Panda, A. K.; Ray, A.; Gogia, A. Rapid
Oxidation of Sulfides and Sulfoxides with Sodium Hypochlorite. Org.
Prep. Proced. Int. 1996, 28, 234.
(24) Teunissen, S. F.; Fernandes, A. M. A. P.; Eberlin, M. N.;
Alberici, R. M. Celebrating 10 years of easy ambient sonic-spray
ionization. TrAC, Trends Anal. Chem. 2017, 90, 135.
(25) Liu, C.; Li, J.; Chen, H.; Zare, R. N. Scale-up of microdroplet
reactions by heated ultrasonic nebulization. Chem. Sci. 2019, 10, 9367.
(26) Luo, K.; Li, J.; Cao, Y.; Liu, C.; Ge, J.; Chen, H.; Zare, R. N.
Reaction of chloroauric acid with histidine in microdroplets yields a
catalytic Au−(His)2 complex. Chem. Sci. 2020, 11, 2558.
(27) Yuan, Y.; Bian, Y. Gold(III) catalyzed oxidation of sulfides to
sulfoxides with hydrogen peroxide. Tetrahedron Lett. 2007, 48, 8518.
(28) Lee, J. K.; Kim, S.; Nam, H. G.; Zare, R. N. Microdroplet fusion
mass spectrometry for fast reaction kinetics. Proc. Natl. Acad. Sci. U. S.
A. 2015, 112, 3898.
(29) Muller, T.; Badu-Tawiah, A.; Cooks, R. G. Accelerated carbon-
carbon bond-forming reactions in preparative electrospray. Angew.
Chem., Int. Ed. 2012, 51, 11832.
(30) Crawford, E. A.; Esen, C.; Volmer, D. A. Real Time Monitoring
of Containerless Microreactions in Acoustically Levitated Droplets via
Ambient Ionization Mass Spectrometry. Anal. Chem. 2016, 88, 8396.
(31) Maleknia, S. D.; Brenowitz, M.; Chance, M. R. Millisecond
Radiolytic Modification of Peptides by Synchrotron X-rays Identified
by Mass Spectrometry. Anal. Chem. 1999, 71, 3965.
(32) Shi, L.; Gross, M. L. Fast Photochemical Oxidation of Proteins
Coupled with Mass Spectrometry. Protein Pept. Lett. 2019, 26, 27.
(33) Li, K. S.; Shi, L.; Gross, M. L. Mass Spectrometry-Based Fast
Photochemical Oxidation of Proteins (FPOP) for Higher Order
Structure Characterization. Acc. Chem. Res. 2018, 51, 736.
(34) Hambly, D. M.; Gross, M. L. Laser flash photolysis of hydrogen
peroxide to oxidize protein solvent-accessible residues on the
microsecond timescale. J. Am. Soc. Mass Spectrom. 2005, 16, 2057.
(35) Cheng, M.; Zhang, B.; Cui, W.; Gross, M. L. Laser-Initiated
Radical Trifluoromethylation of Peptides and Proteins: Application to
Mass-Spectrometry-Based Protein Footprinting. Angew. Chem., Int.
Ed. 2017, 56, 14007.
(36) Chen, J.; Cui, W.; Giblin, D.; Gross, M. L. New protein
footprinting: fast photochemical iodination combined with top-down
and bottom-up mass spectrometry. J. Am. Soc. Mass Spectrom. 2012,
23, 1306.
(37) Orita, A.; Uehara, G.; Miwa, K.; Otera, J. Rate acceleration of
organic reaction by immediate solvent evaporation. Chem. Commun.
(Cambridge, U. K.) 2006, No. 45, 4729.
(38) Banerjee, S.; Mazumdar, S. Electrospray ionization mass
spectrometry: a technique to access the information beyond the
molecular weight of the analyte. Int. J. Anal. Chem. 2012, 282574.
(39) Zhong, X.; Chen, H.; Zare, R. N. Ultrafast enzymatic digestion
of proteins by microdroplet mass spectrometry. Nat. Commun. 2020,
11, 1049.
(18) Liu, K.-J.; Deng, J.-H.; Yang, J.; Gong, S.-F.; Lin, Y.-W.; He, J.-
Y.; Cao, Z.; He, W.-M. Selective oxidation of (hetero)sulfides with
molecular oxygen under clean conditions. Green Chem. 2020, 22, 433.
5015
https://dx.doi.org/10.1021/acs.joc.0c02942
J. Org. Chem. 2021, 86, 5011−5015