All at once arrangement of both oxygen atoms of dioxygen into aliphatic C(sp3)-C(sp3) bonds for hydroxyketone difunctionalization

Article abstract of DOI:10.1007/s11426-020-9949-7

Both β- and γ- hydroxyketone structures are important units in biologically active molecules, synthetic drugs and fine chemicals. Although there are some routes available for their manufacture from pre-functionalized groups on one or two matrix molecule(s), the approaches to simply and simultaneously deposit two oxygen atoms from dioxygen into two specific C(sp³) positions of pure saturated hydrocarbons have rarely succeeded because they are involved in the targeted activation of three inert C-H σ bonds all at once. Here, we show that a TiO₂-CH₃CN photocatalytic suspension system enables the insertion of dioxygen into one C(sp³)-C(sp³) bond of strained cycloparaffin derivatives, by which difunctionalized hydroxyketone products are obtained in a one-pot reaction. With the cleavage event to release strain as the directional driving force, as-designed photocatalytic reaction systems show 21 examples of β-hydroxyketone products with 31%–76% isolated yields for three-membered ring derivatives and 5 examples of γ-hydroxyketone products with 30%–63% isolated yields for four-membered ring substrates. ¹⁸O isotopic labeling experiments using ¹⁸O₂, Ti¹⁸O₂ and intentionally added H₂¹⁸O, respectively, indicated that both oxygen atoms of hydroxyketone products were exclusively from dioxygen, suggesting a previously unknown H⁺/TiO₂-e^? catalyzed arrangement pathway of the hydroperoxide intermediate to convert dioxygen into hydroxyketone units. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11426-020-9949-7

SCIENCE CHINA
Chemistry
•ARTICLES•
May 2021 Vol.64 No.5: 770–777
https://doi.org/10.1007/s11426-020-9949-7
All-at-once arrangement of both oxygen atoms of dioxygen into
aliphatic C(sp3)–C(sp3) bonds for hydroxyketone
difunctionalization
Xiaofeng Qiao1,2, Yuhan Lin1,2, Jiazhen Li1,2, Wanhong Ma1,2* & Jincai Zhao1,2
1Key Laboratory of Photochemistry, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese
Academy of Sciences, Beijing 100190, China;
2University of Chinese Academy of Sciences, Beijing 100049, China
Received November 26, 2020; accepted January 29, 2021; published online April 2, 2021
Both β- and γ- hydroxyketone structures are important units in biologically active molecules, synthetic drugs and fine chemicals.
Although there are some routes available for their manufacture from pre-functionalized groups on one or two matrix molecule(s),
the approaches to simply and simultaneously deposit two oxygen atoms from dioxygen into two specific C(sp3) positions of pure
saturated hydrocarbons have rarely succeeded because they are involved in the targeted activation of three inert C–H σ bonds all
at once. Here, we show that a TiO2-CH3CN photocatalytic suspension system enables the insertion of dioxygen into one C(sp3)–
C(sp3) bond of strained cycloparaffin derivatives, by which difunctionalized hydroxyketone products are obtained in a one-pot
reaction. With the cleavage event to release strain as the directional driving force, as-designed photocatalytic reaction systems
show 21 examples of β-hydroxyketone products with 31%–76% isolated yields for three-membered ring derivatives and 5
examples of γ-hydroxyketone products with 30%–63% isolated yields for four-membered ring substrates. 18O isotopic labeling
experiments using 18O2, Ti18O2 and intentionally added H218O, respectively, indicated that both oxygen atoms of hydroxyketone
products were exclusively from dioxygen, suggesting a previously unknown H+/TiO2-e− catalyzed arrangement pathway of the
hydroperoxide intermediate to convert dioxygen into hydroxyketone units.
TiO2 photocatalysis, β- or γ-hydroxyketones, strained cycloalkanes, dioxygen activation
Citation:
Qiao X, Lin Y, Li J, Ma W, Zhao J. All-at-once arrangement of both oxygen atoms of dioxygen into aliphatic C(sp3)–C(sp3) bonds for hydroxyketone
difunctionalization. Sci China Chem, 2021, 64: 770–777, https://doi.org/10.1007/s11426-020-9949-7
1 Introduction
or auxiliaries into the H2O by-product, leading to easy
cleavage of the O–O bond (based on the model of mono-
oxygenase) [3]. Incorporation of both oxygen atoms of di-
oxygen all at once to form two oxygen-containing functional
groups within a hydrocarbon molecule for oxygenation di-
functionalization is the shortest process with the best atom
economy without the loss of both hydrogen and C atoms (as
dioxygenase reactions), such as hydroxyketone preparation
from simple C(sp3)–H compounds by dioxygenase enzyme
catalysis [4]. However, it is very challenging to catalytically
reduce the two oxygen atoms of dioxygen into one alcoholic
hydroxyl and one carbonyl in one substrate molecule due to
There has been considerable interest in the direct oxidation
of inert but readily available hydrocarbons to form alcohols,
aldehydes and ketones for oxygenation functionalization [1].
Dioxygen, as a green, safe and low-cost oxidant, has been
widely applied for various hydrocarbon oxygenation func-
tionalizations [1e,1h,2]. Generally, oxygenation conversions
with dioxygen use one of its two oxygen atoms, while the
other oxygen atom abstracts hydrogen atoms from substrates
*Corresponding author (email: whma@iccas.ac.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2021
chem.scichina.com link.springer.com

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Qiao et al. Sci China Chem May (2021) Vol.64 No.5
fairly restrict incorporation followed by the fracture mode of
the O–O bond with simple C(sp3)–H σ-bonds. The most
successful use of both oxygen atoms of dioxygen for the
difunctionalization of hydrocarbons is cumene oxidation for
the production of the important industrial materials, phenol
and acetone, albeit the two oxygen atoms are not assigned to
one product molecule (Scheme 1, top). In this way, two
oxygen atoms of dioxygen insert into the C(sp3)–H bond
through a ternary C–OOH hydroperoxide arrangement cat-
alyzed by proton acids at 150–200 °C [5]. Contrary to this
very successful achievement in the industrial practice, the
catalytic placement of both oxygen atoms of dioxygen within
one hydrocarbon molecule for preparations of difunctiona-
lized oxygenation fine chemicals is very rare. Until 2010,
Jiao and co-workers [6] reported that both oxygen atoms of
dioxygen could be transformed into a α-ketoamide unit via a
Cu-catalyzed oxidative amidation-diketonization reaction of
terminal alkynes (Scheme 1), although the substrates require
certain functional groups (–NH2, –≡, and C=O) and the
process results in partial hydrogen or oxygen atom loss from
the substrates. However, few strategies on inserting both
oxygen atoms of dioxygen into two genuine σ-C(sp3) posi-
tions within one organic molecule in a one-pot reaction have
been reported so far.
cyclopentane at 7.4 kcal/mol) confer diverse possibilities
exactly to construct delicate functional structures by means
of ring-opening operations [7g,8]. Especially, it is very easy
to structure difunctionalized groups at the broken ends of the
strained ring. Nevertheless, difunctionalized oxygenations of
strained cycloparaffins with dioxygen in traditional catalysis
never came to be realized unless using some special oxidants
such as hypervalent iodine reagents [8c]. We envision that
the most plausible way to introduce dioxygen into both a
hydroxyl and carbonyl group within a genuine C(sp3) hy-
drocarbon chain would be to rearrange one C–C bond of a
cycloalkane ring unit contained in a hydrocarbon substrate
(Scheme 1, bottom), a feat that pushes two oxygen atoms of
dioxygen into C–H and C–C bonds without losing any atoms
from the reactants. For this purpose, photosensitization and
photocatalysis should be employed since both are common
and effective ways to activate dioxygen at room temperature
[1c,1d,9]. These mild reaction conditions may prevent
overoxidation once the strained ring is opened under high
oxidation pressure. For instance, König and co-workers [9b]
reported that β-chloro-ketones could be realized from
opening ring of aryl cyclopropanes through sodium anthra-
quinone-2-sulfonate sensitized activation of dioxygen in the
presence of HCl and HNO3 under visible-light irradiation. In
contrast, 9,10-dicyanoanthracene-sensitized photooxygena-
tion of 1,2-diarylcyclopropanes with dioxygen only resulted
in endoperoxide formation (3,5-diaryl-1,2-dioxolane) in the
presence of Mg(ClO4)2 [9c]. We herein report that the pre-
paration of β- or γ-hydroxyketone units can be achieved all at
once from strained cycloparaffin derivatives through aerobic
TiO2-CH3CN photocatalysis in a concerted free radical and
hydroperoxide rearrangement route. This strategy will pro-
vide, in principle, a new method to incorporate dioxygen into
the σ-C(sp3)–C(sp3) chain of alkanes in a one-pot reaction
without the loss of any hydrogen or carbon atoms of the
substrate or an O atom of activated dioxygen.
Strained ring cycloparaffin units, such as three- or four-
membered rings, are versatile building blocks in modern
organic synthesis [7] because their unique bonding and in-
herently high ring strain (the strain energy of cyclopropane is
~29.0 kcal/mol and cyclobutene is ~26.3 kcal/mol relative to
2 Experimental
2.1 Materials and instruments
TiO2 (Degussa P25) was provided by Acros Company
(Belgium) and used as received. D2O and H218O were pur-
chased from Aladdin Company (China). 18O2 was purchased
from Cambridge Isotope Laboratories, Inc. (USA). The
isotopic enrichment was greater than 97%. Diethyl zinc,
diiodomethane, and trifluoroacetic acid were purchased from
TCI Company (Japan). Acetonitrile (99.9%, extra dry with
molecular sieves, water ≤50 ppm) was purchased from In-
oChem Company (China). Tetrahydrofuran (THF) was dis-
tilled with Na, and dichloromethane (DCM) was distilled
with CaH2.
Scheme 1 Arranging both oxygen atoms of O2 for difunctionalized
oxygenation (color online).
An light-emitting diode (LED) lamp (395±10 nm, 30 W)

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Qiao et al. Sci China Chem May (2021) Vol.64 No.5
from a domestic manufacturer was used as the light source.
The light intensity irradiated on the reaction vial was mea-
sured using a light intensity meter (model CEL-NP2000-10;
Au light, China), and the value was found to be approxi-
mately 60 mW cm−2. Quantitative measurements of the
conversions of the substrates and yields of the products were
made on a gas chromatograph (Agilent 7890A) equipped
with a flame ionization detector (FID) and an Agilent
Technology 19091J-413 (USA) capillary column (30 m×
0.32 mm×0.25 µm) using high purity N2 as the carrier gas.
The standard analysis conditions were as follows: injector
temperature 250 °C, detector temperature 300 °C, and a
column temperature program of 50 °C (hold for 1.5 min)
after which increased to 300 °C (hold for 5 min) at a rate of
20 °C min−1. 1H nuclear magnetic resonance (1H NMR) and
13C NMR spectra in CDCl3 at 20 °C were obtained using a
Bruker 300/400/500 MHz Fourier transform NMR spectro-
meter (Germany). The diastereomeric ratios (d.r.) for all
compounds were determined by 1H NMR analysis based on
the peak areas of the isomers. Gas chromatography-mass
spectrometry (GC-MS) measurements were conducted using
a Shimadzu QP2010 SE system (Japan) equipped with an
HP-5 capillary column (30 m×0.32 mm×0.5 μm). High-re-
solution electrospray ionization mass spectrometry (HR-
ESI-MS) measurements were performed on an Agilent
quadrupole time-of-flight (Q-TOF) 6510 instrument (USA).
breakable valve. After both reactants had mixed completely,
the cooling bath was removed, and the reaction product was
kept at room temperature overnight. The HCl formed as a
byproduct was collected in a side ampoule cooled with liquid
nitrogen. Subsequently, the solid product was heated to
200 °C overnight in the still-closed vacuum apparatus, while
the HCl trap remained permanently cooled in the liquid ni-
trogen bath. Finally, the apparatus was opened in a glove box
under Ar, and the solid white powder was collected.
2.4 Synthesis of the substrates
(1R,2S)-1,2-diphenylcyclopropane. The cyclopropane sub-
strates were prepared according to procedures described by
Murphy et al. [11]. Commercially unavailable styrenes were
synthesized using the Wittig Olefination protocol. A solution
of trifluoroacetic acid (2.46 mL, 32 mmol, 4.6 eq.) in 20 mL
of dry dichloromethane was very slowly added at 0 °C to a
solution of diethyl zinc (32 mL, 32 mmol, 4.6 eq.) in 35 mL
of dry DCM, and the mixture stirred at 0 °C for 30 min to
form a solid on the side of the flask. A solution of diiodo-
methane (2.57 mL, 32 mmol, 4.6 eq.) in 15 mL of dry DCM
was added to the previous mixture at 0 °C. The resulting
mixture stirred for 45 min at 0 °C. A solution of (Z)-1,2-
diphenylethene (1.91 g, 10.7 mmol, 1.5 eq.) in 7 mL of dry
DCM was then added to the mixture at 0 °C. The final
mixture stirred overnight at room temperature. The reaction
was quenched with sat. NH4Cl (50 mL) and the aqueous
layer was extracted with DCM (3×100 mL). The organic
phases were combined, washed with NaHCO3 (3×60 mL),
water (80 mL) and brine (3×60 mL), and dried over Na2SO4.
Column chromatography was used to obtain the desired pure
product (1.5 g, 70%).
6-(4-Chlorophenyl)-7-(4-methoxyphenyl)-3-oxabicyclo
[3.2.0]heptane. The cyclobutene was prepared according to
procedures described by Yoon et al. [12]. A 50 mL Schlenk
flask containing MgSO4 (300 mg) was flame-dried under
vacuum and cooled under dry N2. Bis(styrene) (280 mg,
0.89 mmol), MV(PF6)2 (61 mg, 0.131 mmol), and Ru(bpy)3-
(PF6)2 (61 mg, 0.131 mmol) were then added to the cooled
flask. The flask was charged with 8 mL of MeNO2, and the
solution reacted for approximately 3.5 h. Column chroma-
tography was used to obtain the desired pure product
(220 mg, 80%).
2.2 General procedure for photocatalytic reactions
In a 15 mL Pyrex reaction vial, 0.15 mmol of substrate and
25 mg of TiO2 were dispersed in 3.0 mL of acetonitrile. The
vial was sealed with a butyl stopper and purged with O2; an
oxygen balloon was used for the continuous supply of O2
during the reaction. Afterwards, the vial was cooled in an ice
bath, magnetically stirred and irradiated from the side. After
certain intervals, an aliquot of the solution was withdrawn
with a syringe and analyzed by thin-layer chromatography
(TLC) and/or GC-MS. After completion of the reaction, the
mixture was filtered through celite to remove the TiO2 and
concentrated to produce a residue that was purified by col-
umn chromatography for further analysis (e.g., GC-MS and
NMR). The weight calculation to determine the isolate yield
was measured using an analytical balance.
2.3 Preparation of Ti18O2
Ti18O2 was prepared according to procedures described by
Kavan et al. [10]. The synthesis of Ti18O2 was carried out in a
closed all-glass vacuum apparatus. TiCl4 (99.98%, Acros,
Belgium) was distilled twice under vacuum before use. One
gram of H218O (97 atom% 18O, Aladdin) was frozen under
high vacuum by cooling in a liquid nitrogen bath, and the ice
came in contact with 2.8 mL of TiCl4 vapor through a glass-
3 Results and discussion
A typical photocatalytic reaction was performed in a 15 mL
Pyrex reaction vial. 0.15 mmol of substrate (1R,2S)-1,2-di-
phenylcyclopropane (1) and 25 mg (0.31 mmol) of com-
mercially available TiO2 (Degussa P25) were dispersed in
3.0 mL of a solvent such as acetonitrile. The vial was sealed

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Qiao et al. Sci China Chem May (2021) Vol.64 No.5
Table 1 Scope of the photocatalytic oxygenation of cyclopropane deri-
vatives
with a butyl stopper and purged with 1 atm of O2; an oxygen
balloon was used for the continuous supply of O2 during the
reaction. Afterwards, the vial was cooled in a bath to control
the reaction temperature, magnetically stirred and irradiated
from the side with a 30 W ultraviolet (UV) LED lamp. To
inhibit the overoxidation, the reaction conditions were fur-
ther optimized (Table S1, Supporting Informaiton online)
according to the yield of 1a by varying the solvent polarity,
reaction temperature and irradiation wavelength. Under the
optimized conditions (acetonitrile as the solvent, reaction
temperature of 0 °C, and 395 nm UV irradiation), 1 showed a
nearly exponential decay against irradiation times, which is
typical of a pseudo-first-order photocatalytic reaction (Fig-
ure 1, and Figure S1, Supporting Informaiton online), while
the yield of the desired product 1a increased as the photo-
catalytic reaction proceeded, and the isolated yield of 1a
reached 71%. From the inset in Figure 1, the other by-pro-
ducts, benzaldehyde and acetophenone, accounted for nearly
all of the rest of the transformation of 1. The yield of 1a
displayed some decline after complete transformation of the
substrate with extended irradiation. Control experiments
confirmed that the oxidation reaction was not possible in the
absence of light or the TiO2 photocatalyst. As expected, TiO2
photocatalyst showed as remarkable stability and recycl-
ability as ever. TiO2 photocatalyst is readily recycled by
simply filtration and shows only a slight decrease in β-hy-
droxyketone yield after five trials (<5%) and little changes in
X-ray diffraction (XRD) patterns and adsorption spectra
(Figure S2). There was no 1a formation in the absence of
dioxygen, suggesting that dioxygen is the obligatory oxygen
source in this transformation (Table S1).
a),b),c)
To test the viability of this method, we expanded the scope
of the cyclopropane substrates. As presented in Table 1, 1,2-
a) Isolated yields if not specified. The regioselectivity was determined by
1H NMR. b) Optimized conditions: P25 (25 mg, 0.25 mmol), 0 °C, 10 h,
395 nm LED, and 0.15 mmol of substrate in 3.0 mL of CH3CN. c) The
isolated yield of the major isomer is listed.
diaryl cyclopropanes possessing electron-donating groups at
the para-position of the phenyl ring, such as alkyl (1b),
methoxy (1c), and 4-Ph (1d), reacted smoothly and provided
the corresponding β-hydroxyketone in good yields (69%–
76%), while electron-withdrawing substituents gave mod-
erate yields (1e–1g). In the case of unsymmetrical 1,2-diaryl
cyclopropanes (1h–1m), the regioisomeric ratio (r.r.) was
approximately 5–6:1, the major isomer derived from defi-
nitive hydroperoxidating of the cyclopropane that pre-
ferentially takes place at the carbon site of the cyclopropane
bearing the less substituted aryl group. Thiophene and furan
derivatives (1n, 1o) could also be converted with fair yields,
and this might be useful for the synthesis of functionalized
hydroxyketone frameworks. Up to now, all transformations
have been limited to diaryl cyclopropane derivatives, which
seems to be obligatory for dioxygen insertion into the C–C
Figure 1 Plot of the kinetic profile of the photocatalytic reaction of di-
phenylcyclopropane (1). Conditions: 0.15 mmol of 1, 25 mg of TiO2,
3.0 mL of acetonitrile, and 1.0 atm O2 at 0 °C. Inset: GC spectra for the
determination of the transformation of 1 and 1a formation with different
irradiation times (color online).

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Qiao et al. Sci China Chem May (2021) Vol.64 No.5
a), b)
Table 2 Scope of the photocatalytic oxygenation of cyclobutanes
beneficial to the oxidation of cyclobutanes into γ-hydro-
xyketones. The other is to accelerate the possible proton shift
involved in placing hydroxyl or carbonyl oxygen at C(sp3)–H
or C(sp3)–C(sp3) positions during opening-ring process of
cyclobutene. Thus, we first selected substrates containing
oxabicyclo[3.2.0] units to repeat the photocatalytic trans-
formation. The yield of γ-hydroxyketone was indeed in-
creased relative to 2a case; however, it was still lower (appr.
20%) when the reaction conditions were the same as the
selective oxidation of cyclopropane (Table S1). Then, we
added 0.1% (v/v) triethylamine as proton transfer reagent to
the reaction system, and the yield was dramatically improved
and a maximum isolated yield reached up to 63% (2b–2f,
Table 2). In this way, we obtained the main products 2b-2f in
30%–63% isolated yields. We did not carry out more trans-
formations of four-membered ring derivatives due to sub-
strate limitations. However, successful examples 2b–2f
displayed the primary potential for the preparation of the
designated C(sp3)-site hydroxyketones of hydrocarbon
compounds via oxygenation with dioxygen in a one-pot
photocatalytic reaction. In addition, the oxidative cyclobu-
tane reaction presents with excellent stereoselectivity. Using
a) Reaction conditions: P25 (25 mg, 0.25 mmol), 0 °C, 10 h, 395 nm
LED, 3 µL of triethylamine (TEA) and 0.15 mmol of substrate in 3.0 mL of
CH3CN and 1,2-dichloroethane (DCE) (1:1). b) Isolated yields.
bond of the three-membered ring unit of the substrate. Un-
expectedly, a substrate with a single aryl substituent could
also be transformed into a β-hydroxyketone (1p). In addition,
a variety of single aryl-containing cyclopropanes bearing
gem-dimethyl substituents were also examined, affording the
desired products in moderate yields (1q–1u).
To extend this method to the preparation of γ-hydro-
xyketones, we set out to enable substrates containing cy-
clobutane units, which should be theoretically feasible (Table
2). We then used 1,2-bis(4-methoxyphenyl) cyclobutane as
the substrate to execute the photocatalytic oxygenation re-
action under identical conditions to the case of 1,2-diaryl-
propane. However, this reaction gave the 4-phenyltetralone
derivative (Table 2, 2a) as the major oxidation product, while
γ-hydroxyketone was present in only a tiny minority (<5%)
(Eq. (1)).
a
6-(4-bromophenyl)-7-(4-methoxyphenyl)-3-oxabicyclo
[3.2.0] heptane substrate, the 1H NMR data showed that the
value of d.r. was greater than 10:1 (see the spectrum in the
Supporting Information online). Such a one-pot catalytic
oxidation of the C(sp3)–C(sp3) bond generates both β- and γ-
hydroxyketone products, which, to the best of our knowl-
edge, had scarcely been reported before.
Furthermore, we attempted to extend this photocatalyzed
dioxygen insertion reaction to five- or six- membered ring
substrates that have little strain, and we did not achieve the
expected δ- or ε-hydroxyketone ring-opening products,
whereas the corresponding cyclopentanones or cyclohex-
anones were produced in less than 5% yield. Approximately
95% of the substrate was cracked into fewer carbon number
deep-oxidation products. This was highly consistent with all
TiO2-photocatalyzed pure aliphatic hydrocarbon reactions
with dioxygen as the sole oxidant [1c,13,14]. That is, si-
multaneous difunctionalized oxygenations of saturated car-
bon chains with dioxygen mediated by TiO2 photocatalysts
occur for these substrates that only contain strained ring
units. Nonetheless, dioxygen insertion into one C(sp3)–
C(sp3) bond of the strained ring should be a novel reaction
pathway that is significantly different from the previously
well-known routes of catalytic activation of dioxygen. To
confirm that the important properties are exclusively related
to opening strained rings by TiO2 photocatalysis, we will in
detail investigate how both oxygen atoms of dioxygen insert
into the strained ring unit of aliphatic compounds all at once
without the necessary assistance of the leaving of both hy-
drogen and carbon atoms.
This result is highly consistent with the findings reported
previously in which the secondary C–C bond of the four-
membered ring unit is cracked followed by cyclization with
parent benzene [13]. This suggested that intramolecular at-
tack and cyclization were more likely than the intermolecular
dioxygen insertion reaction after breaking the C–C bond of
the four-membered ring. We argue that two measures are
likely to significantly promote the aimed γ-hydroxyketone
yield. One is to screen the suitable substrates with substantial
steric hindrance installed in the cyclobutane unit that could
prevent intramolecular cyclization events, which may be
To elaborate the dominant mechanism and determine if the

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Qiao et al. Sci China Chem May (2021) Vol.64 No.5
oxygen atoms in 1a exclusively originate from O2 rather than
from the oxygen atom on the TiO2 surface or residual or
possibly formed intermediate H2O, several 18-oxygen iso-
topic labeling experiments were performed, as summarized
in Table 3. When the vial was purged with 18O2, the [M+4]
product approached 99% yield, indicating that all oxygen
atoms of the β-hydroxyketone were from dioxygen (entry 2),
which is significantly different from the >99% normal mo-
lecule weight [M] product from 16O2 (Table 3, entry 1). The
surface oxygen of TiO2 is not incorporated or exchanged into
the products, as we specially prepared the Ti18O2 photo-
catalyst (entry 3). This is apparently not in accordance with
the Mars-Van Krevelen mechanism, in which the lattice
oxygen is always incorporated into the carbonyl and the
consumed oxygen is restored from molecular oxygen in the
gas phase [15]. We argue that the O–O was divided into two
independent C–OH and C=O units should be through a H2O
intermediate leaving and rebounding (Scheme 2). Thus, we
intentionally added a small amount of H2O to this transfor-
mation to observe whether the oxygen atom of H2O parti-
cipates in hydroxyketone formation. In the 16O2
photocatalytic reaction system, the addition of 5 eq. of H218O
led to an [M]:[M+2] close to 1:1 (entry 4), indicating that
although H2O was incorporated into the product molecule, at
least half of the product ([M]) was formed from the initial
dioxygen, which maintained to the end of the reaction. In
other words, the formation of half of the [M+2] product and
no [M+4] product indicated that H2O participation only oc-
curred in a step parallel to that of dioxygen after the substrate
had primarily incorporated dioxygen (i.e., after hydroper-
oxide intermediate formation in Eq. (9), Scheme 2). This
speculation was further confirmed by the use of 18O2 with 5
eq. of H216O to repeat this transformation (entry 5). No [M]
product appearance and half of the [M+4] product generation
indicated that 18O2 dominated the oxygenation reaction
throughout. Furthermore, when 5 eq. of deuterated water was
added, it was found that the molecular weight of the product
had not changed (entry 6); namely, both hydrogen atoms of
the ternary C–H of the cyclopropane ring were maintained
until the end of the reaction and were not replaced by addi-
tional D2O. It should be mentioned that we isolated the hy-
droxyketone product from the photocatalytic system and
Table 3 Abundance of 18O in 1aa) b) c)
Percentage of 16O and 18O in 1a (%)
Entry
Cat.
O2
Additive
M
>99
0
M+2
0
M+4
1
2
3
4
5
6
TiO2
TiO2
Ti18O2
TiO2
TiO2
TiO2
16O2
18O2
16O2
16O2
18O2
16O2
None
None
0
>99
0
0
None
>99
47.7
0
0
5 eq. H218O
5 eq. H216O
5 eq. D2O
52.3
48.9
0
0
0
>99
0
a) Under the same conditions as Table 1; b) abundance of 18O in 1a was determined by HR-ESI-MS; c) see Figure S4 and discussion for HR-ESI-MS
spectra and data analyses.
Scheme 2 A plausible photocatalytic reaction mechanism (color online).

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Qiao et al. Sci China Chem May (2021) Vol.64 No.5
then added 5 eq. of D2O or 5 eq. of H218O and stirred the
mixtures overnight in the dark, and found that the molecular
weight of the product did not change. This control experi-
ment showed that there was no exchange of isotope either the
hydroxyl functional group or the ketone functional group in
the products after treatment with H218O or D2O (Figure S3).
To summarize briefly, the above several lines of evidence
imply that: (1) the two oxygen atoms from dioxygen have
priority insertion into the C–C bond of the strained ring re-
gardless of adding an excess of H2O; (2) the hydroxyketone
formation reaction has experienced two distinct stages to-
gether (the early stage of only O2 participation Eqs. (5)–(9)
and later stage of O2/H2O participation, namely, the ar-
rangement of intermediate II); (3) additional H2O does not
destroy the transformation selectivity and simply takes part
in the latter half-reaction after initiating by dioxygen (this is
why there was no product with both oxygen atoms from
H2O). With the above isotopic experimental evidence and
discussion, a mechanism for TiO2 photocatalysis was pro-
posed (Scheme 2). In this oxygenation process, the strained
three- and four-membered ring transformations into β- and γ-
hydroxyketones are divided into two stages: the first is the
one-electron oxidation for hydroperoxide II formation and
this is not consistent with the oxygeneation of bis(styrene), in
which the oxidation reaction proceeds through the 1,4-dis-
tonic radical cation intermediate [13]. The other is the re-
arrangement of the hydroperoxide intermediate to form the
Figure 2 HR-ESI-MS spectra of the ternary carbon free radical inter-
mediate captured by TEMPO after treatment with 16O2 (a) and 18O2 (b)
(color online).
Finally, the chain termination consists of the reaction of
•−
final product. In the former, the reaction is initiated by one-
and tertiary carbon free radical I (Scheme 2, Eqs. (7)–
O2
+
)
electron oxidation of 1 by the valence band holes (hvb
(9)), resulting in the formation of hydroperoxide inter-
mediate II. For the catalytic rearrangement stage, although
the rearrangement reaction catalyzed by Lewis and proton
acids has been applied for preparations of different oxyge-
nated compounds, such as phenol and acetone from cumine
hydroperoxide, there are few examples of the rearrangement
of these hydroperoxides established on strained rings be-
cause of the difficult cleavage of very strong C–C bonds of
three- or four-membered rings (their bond dissociation en-
ergy (BDE) is generally greater than 100 kcal/mol) [17]. We
argue that the photoinduced H+/TiO2-e− catalyzes the re-
arrangement of hydroperoxide II (Scheme 2 bottom). The
photoinduced renascent protons (Eq. (4)) on the TiO2 surface
possess strong Brønsted acid properties owing to the coex-
isting weak conjugate base. That is, the delocalized con-
duction-band electron (ecb−) functions greater than that of the
[13,16], which has been readily confirmed with the addition
of 10 eq. of CH3OH to completely quench the conversion of
1 (Table S1). Meanwhile, the electron transfer from the
conduction-band electron (ecb−) to O2 plays an indispensable
role in the formation of key intermediate hydroperoxide II
(Eqs. (5)–(9)). This could be indirectly confirmed with the
addition of typical electron acceptor decamethylferrocenium
(Cp2Fe+) to our O2/diaryl cyclopropane derivative reaction
−
system to react with ecb prior to O2, which resulted in ben-
zaldehyde (~89% yield) rather than target β-hydroxyketone
product (Eq. (4) and Scheme S1, Supporting Informait on
online). In the sequential radical chain propagation reaction
period (Eqs. (5) and (6)), the depletion and regeneration of
ternary carbon free radical intermediate I is crucial to acti-
vate dioxygen into both hydroperoxide intermediate II and
the final product. Firstly, we captured this free radical with
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and de-
termined by ESI-MS (Figure 2, Eq. (2)) as the vial was
purged with 1 atm of 18O2 or 16O2.
common conjugated Brønsted base, which enables H
+/TiO -
2
e− to protonate polybrominated benzene rings, as evidenced
by our previous work [18]. Apparently, during this re-
arrangement process, there are no hydrogen, oxygen or
carbon atoms that are forced away as leaving groups from the
stoichiometric formula of the final product, but the dis-
sociation of protons and H2O from the available inter-
mediates as well as their recombination is most likely to
occur. This proton shift is rather crucial for γ-hydroxyketone

777
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4 Conclusions
Our experimental results showed the precise arrangement of
two oxygen atoms from dioxygen within an organic mole-
cule without C=C, C≡C or C–X pre-functionalized groups
for the green manufacture of β- and γ-hydroxyketone units.
With an increasing number of synthetic methods available
for strained ring units, TiO2-based photocatalytic strategies
to prepare difunctionalized oxygenated products using di-
oxygen as the sole oxidant would definitely result in special
attractiveness because of its powerful activation of C–H and
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Acknowledgements This work was supported by the Strategic Priority
Research Program of the Chinese Academy of Sciences (XDB36000000),
the National Natural Science Foundation of China (21590811, 21777167,
21827809), and the National Key R&D Program of China
(2018YFA0209302).
Conflict of interest The authors declare no conflict of interest.
Supporting information The supporting information is available online at
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
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