Article

Photoexcited nitroarenes for the oxidative

cleavage of alkenes

https://doi.org/10.1038/s41586-022-05211-0 Alessandro Ruffoni1,3, Charlotte Hampton2,3, Marco Simonetti2 ✉ & Daniele Leonori1 ✉

Received: 24 April 2022

Accepted: 9 August 2022 The oxidative cleavage of alkenes is an integral process that converts feedstock
Published online: xx xx xxxx materials into high-value synthetic intermediates1–3. The most viable method to
achieve this in one chemical step is with ozone4–7; however, this poses technical
Check for updates
and safety challenges owing to the explosive nature of ozonolysis products8,9. Here
we report an alternative approach to achieve oxidative cleavage of alkenes using
nitroarenes and purple-light irradiation. We demonstrate that photoexcited
nitroarenes are effective ozone surrogates that undergo facile radical [3+2]
cycloaddition with alkenes. The resulting ‘N-doped’ ozonides are safe to handle and
lead to the corresponding carbonyl products under mild hydrolytic conditions.
These features enable the controlled cleavage of all types of alkenes in the presence of
a broad array of commonly used organic functionalities. Furthermore, by harnessing
electronic, steric and mediated polar effects, the structural and functional diversity of
nitroarenes has provided a modular platform to obtain site selectivity in substrates
containing more than one alkene.

Alkenes are feedstock materials that are obtained on the ton scale
from petroleum and vegetable biomass and are exploited by the bulk
chemical industry to access oxygen-enriched synthetic intermedi-
ates1–3. Ozonolysis is a widely adopted method to achieve this and
requires specialized apparatus for the conversion of molecular oxy-
gen (O2) into highly reactive ozone (O3)6,7. This species undergoes a
[1,3]-dipolar cycloaddition with the alkene, converting a stable chemical
into a high-energy 1,2,3-ozonide A from which cycloreversion is
immediate. The consequent C–C σ-bond cleavage event generates
carbonyl oxide B and carbonyl compound C, which recombine to give
1,2,4-ozonide D. Depending on the reaction solvent and the work-up
procedure, B or D can lead to aldehydes or ketones, as well as carboxylic
acids or alcohols4,5 (Fig. 1a).
Despite its attractive synthetic versatility, ozone toxicity (lethal at
5 ppm), explosivity and extreme oxidizing power (standard reduc-
tion potential E0 = 2.07 V) raise critical safety, technical and chemical
concerns8,9. As a result, ozonolytic strategies are often challenging to
translate into the fine chemical industry10–12, particularly in the dis-
covery sector, which heavily relies on parallel and high-throughput
screening platforms13. Consequently, alternative strategies for
alkene oxidation based on high-valent heavy-metal oxides (MO4, where
M is a metal) have been devised14–16. However, these approaches can
yield mixtures of products of various oxidation degrees, and cause
trace-metal contaminations that are problematic with the stringent
pharmaceutical sector regulations17. Oxidative cleavages using O2 and
a suitable (photo)catalyst have also been developed, but they are
limited to activated alkenes18,19.
Overall, there is no other type of reactivity able to mirror the unique
ability of ozone to cleave alkenes. Here we introduce nitroarenes, a class
of abundant feedstocks, as photoexcitable and easy-to-dose ozone
surrogates. Upon simple purple-light absorption, these species react
with alkenes enabling access to ‘N-doped’ ozonides, which can be accu-
mulated until a devised controlled C–C bond cleavage step takes place.
This reactivity engages a large class of alkenes, is tolerant of the most
used organic functionalities and allows the targeting of specific double
bonds in molecules with multiple C–Cπ sites.
In approaching the design of an alternative method to oxidatively
cleave alkenes, we considered the possibility of using nitroarenes N as
ozone surrogates to access 1,3,2-dioxazolidines E (Fig. 1b). Despite the
nitro group being isoelectronic with ozone, nitroarenes do not engage
in thermal [1,3]-dipolar cycloadditions with alkenes owing to high
kinetic barriers20,21. The pioneering works of refs. 22,23 demonstrated an
opportunity to by-pass these challenging pericyclic processes through
direct nitroarene photoexcitation. As such, intersystem crossing from
the singlet excited nitroarene delivers the long-lived triplet state (T1) *N.
In analogy to T1 carbonyls, *N have a (n,π*) configuration, which trans-
lates into O-radical-type reactivity. *N can intercept alkenes in radical
[3+2]-like fashion and, via the formation of biradical F, deliver N-doped
ozonides E. However, this chemistry necessitated high-energy irradia-
tion, utilized the alkene as the solvent, and the mechanism by which
E evolves into the C–C cleavage products and defines their subsequent
fate was unsolved22–25. These rather unpractical reactivity requirements
and limited understanding have resulted in no synthetic application.
We envisaged that by tailoring the nature of the nitroarene, we would
have been able to translate this reactivity over the broad spectrum
of alkenes, including challenging terminal substrates, and run it in
a stoichiometric manner, which is crucial for synthetic purposes.
Furthermore, understanding and thereby controlling the decompo-
sition of E would be pivotal to channel its reactivity towards alkene
cleavage.
We started our investigation evaluating the initial rates of disappear-
ance of 1 (kobs) in photocycloaddition reactions (purple light-emitting

1
Institute of Organic Chemistry, RWTH Aachen University, Aachen, Germany. 2Department of Chemistry, University of Manchester, Manchester, UK. 3These authors contributed equally:
Alessandro Ruffoni, Charlotte Hampton. ✉e-mail: marco.simonetti@manchester.ac.uk; daniele.leonori@rwth-aachen.de

Nature | www.nature.com | 1
Article
a
bulk material
O2 – O
O2 O O Explosive
Ozone
Ozonizer
[1,3]-Dipolar
O O
cycloaddition
1,2,3-Ozonide
Highly unstable
b (T 1) * N
(n,S*) excited state
Ar Ar
N N
– O O •O O•
:
hQ
Thermal [3+2] is Stepwise radical
kinetically [3+2] is facile
challenging
Fig. 1 | Excited nitroarenes as ozone surrogates. a, Ozonolysis for the oxidative cleavage of alkenes. b, Mechanism for the formation of E. Ar, aryl; ISC, intersystem
crossing.
diode irradiation, wavelength λ = 390 nm (refs. 26,27)) with a variety of
electronically diverse meta- and/or para-(di)substituted nitroarenes
N to give stable bisadamantene-containing24 E (Fig. 2a). The result-
ing Hammett plot28 showed a strong linear free-energy relationship
between the electronic character of the nitroarene and kobs (sensitivity
constant ρ = 0.82). This means that the reactivity profile of nitroarenes
as photo-responsive oxidants can be easily tuned by correct placement
of electron-withdrawing groups on their aromatic core to amplify the
electrophilic character of their excited states. Ortho-substituted N were
less effective, which suggests that steric hindrance can also influence
their reactivity (Supplementary Information).
We then evaluated the reaction of unactivated 2, which is a challeng-
ing type of alkene in this chemistry. Irradiation of 2 with commercial N1
resulted in the high-yielding formation of E1 (Fig. 2b). In contrast to the
explosive nature of A, N-doped ozonides can be accumulated in solution
at –30 °C and are stable in the solid state (Supplementary Information).
Subsequently, we set out to understand how to convert E into the corre-
sponding carbonyl compounds C and C′ (Fig. 2c). We speculated that two
pathways might be operating: an ozonolysis-type cycloreversion would
deliver C and carbonyl imine G (path a) or a different cycloreversion-mode
could directly lead to C/C′ and nitrene I (path b). To shed light on
this, we prepared E2 which features an ortho-3,5-dimethylpyrazole
group as a probe for nitrene formation29,30. Simple exposure of E2 to
CH3CN–H2O led to the almost quantitative formation of ketone 3 and
N-arylhydroxylamine H1. Conversely, in acetonitrile (CH3CN), E2 yielded
3 in 98% yield and 4 in 97% yield, whose structure was confirmed by X-ray
analysis. As 4 is indicative of a [1,3]-dipolar cycloaddition between G1
and CH3CN, these experiments rule out the intermediacy of nitrenes
and demonstrate that E undergoes an ozonolysis-type cycloreversion
generating C and G, which, with water (H2O), is hydrolysed to C′ and H.
Although the generation of G was postulated by Huisgen22, its existence
has not been demonstrated before. Related dipoles have been engaged
in 1,3-dipolar cycloadditions only twice since Huisgen’s initial predic-
tion31,32, but never with nitrile dipolarophiles.
2 | Nature | www.nature.com
Integral synthetic intermediates
Chemical
oxidation O O OH O
Alkene H OH
Aldehydes Ketones Alcohols Acids
Ad hoc work-up
–
O Retro [1,3]
O O O O
cycloaddition O Recombination
O
A B C D
Carbonyl
oxide
Ar Ar
ISC then Controlled
N O•
cyclization N cleavage O O
O O O
•
C C′
F E
Triplet ‘N-doped’ ozonide
biradical Stable
Next, we studied the decomposition of E1 in CH3CN–H218O (Fig. 2d),
which gave 5 in 93% yield and 92% 18O-incorporation, along with H2
(20%), azoxy derivative K1 (3%) and nitrone J1 (condensation of H2
with formalin 6, 61%). K1 stems from disproportionation of H2 (Supple-
mentary Information). This experiment demonstrates that the cyclor-
eversion of E1 generates 6 and the more stabilized dipole G, which is
then hydrolysed. However, when decomposition of E3 was evaluated
in CH3CN–H2O, 7 was obtained in a decreased 71% yield, probably via
the in situ formation of nitrone J. Indeed, when decomposition of E3
was run with external formalin, 7 was obtained in 95% yield (Supple-
mentary Information). Despite the decomposition step being very
effective, the equilibrium in the condensation between H and C/C′, and
subsequent side reactions33, rendered the purification of the aldehydes
products challenging. Thus, we developed two simple one-pot work-up
procedures to remove H by addition of either dipotassium phosphate
(K2HPO4) and urea (conversion of H into K) or N-phenylmaleimide
(conversion of nitrones such as J1 into L), which eased the purification
of the aldehydes (Fig. 4e and Supplementary Information).
Having devised conditions to accumulate and decompose N-doped
ozonides, we decided to benchmark the synthetic utility of the process.
Although N1 was able to engage all substrates present in Fig. 3, other
nitroarenes (N2–N7) were evaluated to improve the yield depending on
the alkene. We believe that this is a powerful aspect of this reactivity as
functionalized nitroarenes are readily available and dosable reagents
that can be evaluated in screening platforms. Exploration began with
linear terminal alkenes 2 and 8–32 equipped with a distal functionality
R. Several commonly encountered organic functional groups, such
as nitrile (8), aldehyde (9), ketone (10), carboxylic acid (11), halogens
(12–15), free (16) and protected (17–20) amines, azide (21), nitro
group (22), free (23 also on 5-mmol scale, 27) and protected (24 and
25) alcohols, epoxide (26), thiocyanate (28), thioethers (29 and 30),
phosphonate (31) and boronic ester (32), proved compatible, giving the
corresponding aldehydes in high yields. In some cases, we found that the
use of dichloromethane (CH2Cl2) solvent with hexafluoroisopropanol
 a 1.2
NO2
3-F, 4-SO2CF 3

NO2 3,4-(CN) 2
1.0
O O 3 5
+ R N 0.8 4 3-NO2, 5-CF 3
CH2Cl2, –10 ºC 3,5-(CF 3) 2
1 N Purple light- U = 0.82 3-F, 4-SO2Me
R 0.6

log[kX/kH]
(1.0 equiv.) (3.0 equiv.) emitting diodes 3-CN
4-SO2Me
3-CF 3
E 0.4 3,5-(F) 2
3-F
Reactivity of excited state nitroarenes (*N) 0.2
y = 0.82x – 0.03
H R² = 0.98
3-F, 4-Me
•O Electronic effects:
0
N Electron-withdrawing groups –0.2 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
accelerate the cycloaddition 3-Me 4-F
•O –0.2 ΣV
R

b CF3
NO2
O
+ N
Me EtOAc (0.5 M), –30 ºC, 24 h Me O
2 O2N CF3 Purple light-emitting diodes NO2
(1.0 equiv.) N1 E1, 71%
(5-mmol scale)
Unactivated olefin (2.0 equiv.)
Stable solid

c Ar Ar
Ar
Ar O O N N O O
H2O N O O O O Ar
O – versus
NH Path a Path b N
HO

:
C′ C Ozonolysis-type Nitrene-forming C C′ I
H E E
G cycloreversion cycloreversion Singlet
Carbonyl
nitrene
imine

Me Me Me
Ar – O
N G1
O N N O N
Me N Me Me
OH N O CH3CN N O
CH3CN–H 2O
+ + N
O2N NH O2N N O2N N Me N
80 °C, 1 h O 80 °C, 1 h
3, 197% 3, 98% Me [1,3]-Dipolar cycloaddition
E2 of carbonyl imine
CF3 CF3 CF3
H1, 94% 4, 97%, X-ray

d CF3 CF3 CF3

( )9 O HO O Ar O –
Me CH3CN–H 218O 16/18
( )9 H2 +
N O + HN + N + N N
Me H H
O 80 °C, 1 h – O Ar
5, 93% 6
E1 NO2 H2, 20% NO2 J1, 61% NO2
18O = 92% K1, 3%

NO2 e O –
6, urea
O O 6 (equiv.) Yield (%) N Ar
6
Ar N
N 0 71 K2HPO 4
O CH3CN–H 2O K
O 5 95 H
E3 CF3 80 °C, 15 min 7 N
Ar OH
O O O
H N H
Ph O
O
– O Ar Ph N N Ar
H N Product
N + 6
Ar OH decomposition
O H
H
C J L

Fig. 2 | Mechanistic experiments. a, Hammett plot analysis. k X refers to kobs c, Mechanism for the decomposition of E and the role of H2O. d, 18O-labelling
with 3-, 4-, 3,5- or 3,4-(di)substituted nitroarenes, kH refers to the parent experiments and the role of 6. e, Methods for the removal of H.
unsubstituted nitrobenzene and σ is the Hammett constant. b, Preparation of E1.

(HFIP) as the additive to be crucial to ensure good reactivity. As *N can of different size (40 and 41). Furthermore, both gem-disubstituted
abstract hydridic α-N/O/S C(sp3)–H bonds34,35, the inclusion of HFIP (–)-dihydrocarveol 42 and trisubstituted 43 were compatible, as well
suppressed this unwanted process by hydrogen bonding to the as diene 44. Electron-rich and -poor styrenes (45–47), (E and Z)-β-Me
heteroatom36 (Supplementary Information). In the case of amines, and α-Me-styrenes (48, 49 and 50), as well as (E and Z)-stilbenes
simple protonation was required to insulate the substrate from reacted smoothly (51 and 52). Next, we explored the cleavage of
detrimental side oxidations. Disubstituted substrates reacted well, structurally complex and densely functionalized derivatives (53–63).
as demonstrated by the cleavage of several industrially relevant oleic Unactivated terminal alkenes of isophytol (53), sclareol (54) and
acid derivatives 33–38 (Z-), as well as ether E-39 and cyclic systems alibendol (55), which also features an electron-rich aromatic core,

Nature | www.nature.com | 3
Article
R R1 R2

R N1: NO2 H CF 3 Condition A or B

R R3
N2: CF 3 H CF 3 –30 ºC,12–24 h Conditions:
Purple light-emitting diodes R R3 A = EtOAc (0.08–0.33 M)
R1 NO2 N3: CN CN H
R1 R2 + O + O
N4: F H H B = CH2Cl2 (0.05–0.33 M)
2 and 8–63 then cleavage R1 R2
R2 N5: F CF 3 H (see footnotes for B = HFIP (1–8 equiv.)
(1.0 equiv.)
(2.0 equiv.) work-up procedures)
N6: F SO 2Me H
N7: F SO 2CF 3 H

R1
R
6 ( )6
()
Ph O Me R2
Me C(O)R
R R3
39
02, R = C4H9 82%A,N1 22, R = NO 2 76%A,N1 33, R = OH 71%B,N2,f 71%B,N3 R R1 R2 R3
08, R = CN 82%A,N1 23, R = OH 88%B,N1 34, R = OMe 82%A,N2 45, H H H H 94%A,N1,g
09, R = CHO 76%B,N1,a,b 71%B,N1,e 35, R = SHex 77%B,N2 46, OMe H H H 89%A,N3,g
10, R = Ac 88% A,N1 24, R = OTBS 83%B,N1 36, R = NH2 63%B,N1 47, CF 3 H H H 98%A,N1,g
11, R = CO 2H 70%A,N1,c 25, R = OAc 78%A,N1 37, R = NHMe 67%B,N2 48, H H Me H 83%A,N3,g
12, R = F 80% A,N1 38, R = N(CH 2) 5 80%B,N2 40 41 49, H H H Me 87%A,N3,g
O
13, R = Cl 84%A,N1 26, R = 78%A,N1 89%A,N2 67%A,N2 50, H Me H H 94%A,N1,g
14, R = Br 78%A,N1 51, H H Ph H 74%A,N1,g
OH Me
15, R = I 57%A,N1,c 27, R = 82%B,N1 Me 52, H H H Ph 73%A,N1,g
16, R = NH2•HBF4 62%A,N1,d Ph
NPhth
17, R = NHAc 72%B,N1 28, R = SCN 79%A,N1
Me Me Me Me Me OH
B,N1,b
18, R = NHBoc 62%B,N1 29, R = SAc 67% Me
B,N1,b
HO
19, R = NHTs 59% B,N1 30, R = SMe 57% Me 44 Me ( )3 ( )3 ( )3
Me
20, R = NPhth 82%A,N1 31, R = PO 3Et2 85%A,N1 43 50% + 61%A,N2,g 53, isophytol
42, (–)-dihydrocarveol
21, R = N3 86%A,N1 32, R = B(pin) 70%A,N1 89%A,N6 (r.s.m. 60%) 67%A,N7
70%B,N1 Cl

H CO2Me
Me Me
Me OH O N H Me
H H OH HO
N S Me Me Me Me Me OH
Me Me
AcO
Me ( )3 ( )3 ( )3
Me H O Me

OH 58, phytol
MeO
54, sclareol 56, caryophyllene oxide 70%B,N3
55, alibendol acetate
57, montelukast Me-ester
65%A,N7,h (r.s.m. 60%) 62% B,N7 87% A,N1
59% + 61%B,N3,b,i
Me HO
HCl NBu2 HCl
Me Me2N Me
Me Cl
Cl
HCl Cl
NMe2
Me Me N
S HCl
59, (–)- α-cedrene N Cl
63, tamoxifen•HCl
65%A,N5,h (r.s.m. 41%) 61, chlorprothixene•HCl
60, triprolidine•HCl 62, lumefantrine•HCl 66%B,N4,l
72%B,N1,j
68%B,N6,j,k 76% + 91%B,N1 (r.s.m. 84%; Z:E 1.2:1)

Fig. 3 | Scope of the process. ‘A’ and ‘B’ refer to the reaction conditions and N1–N7
refer to the nitroarenes. If the yield of two cleaved fragments deriving from the
same alkene differs, the first yield refers to the carbonyl compound with the
higher molecular weight. Cleavage: CH2O (0–6 equiv.) in CH3CN/THF:H2O
(3.1:1); work-up: K 2HPO 4 and urea or N-phenylmaleimide. See Supplementary
Information for details. aAlkene with a 10C linear chain. bPerfluoro-tert-butanol
(PFTB) used in place of HFIP. cAlkene with a 6C linear chain. d60 h. e5.0-mmol
scale; N1 (1.5 equiv.); 48 h. f2,6-Lutidine in place of HFIP. gNMR yield. hAlkene
(2 equiv.). iAnother product of S oxidation to sulfoxide, 6% yield.
j
Aminoaldehyde derivative not detected. k40 h. lAlkene (5 equiv.). r.s.m.,
remaining starting material.

could all be oxidized. The disubstituted alkenes of caryophyllene
oxide (56) and montelukast (57), the trisubstituted alkenes of phy-
tol (58), (–)-α-cedrene (59), triprolidine (60), chlorprothixene (61)
and lumefantrine (62), as well as the tetrasubstituted (Z)-tamoxifen
63, were successfully engaged. Another feature of *N is their aptitude
to act as triplet sensitizers37, which can isomerize the alkenes dur-
ing photocycloaddition. Indeed, unreacted 63 was recovered as Z/E
mixture.
An often-encountered challenge in oxidative cleavage chemistry is
achieving regiocontrol in substrates containing more than one C–Cπ
site. We speculated that the inherent modularity of our approach would
enable chemoselective differentiation through the interplay of electronic
effects. To test this hypothesis, we prepared substrates 64–69 that con-
tain two different alkenes linked by an identical alkyl spacer and evalu-
ated them in stoichiometric reactions with N1, N2, N4 and N8 providing
the heat map shown in Fig. 4a. These results show that site selectivity
depends on the electronic nature of the nitroarene and that of the two
alkenes. Specifically, the selectivity increases when using less electro-
philic nitroarenes, and when the two alkenes have substituents that make
one C–Cπ bond increasingly more electron-rich than the other. This
means that the reactivity of *N (ref. 23) parallels that of ozone and Huisgen
type-III dipolar cycloadditions in general38. Consequently, modulation
of the nitroarene electronics can be used to amplify narrow reactivity
differences when substrate control is difficult to implement. Indeed,

4 | Nature | www.nature.com
 a R1 R1
R R R1 EtOAc, –30 ºC O O
Purple light-
( )7 R2 N1: NO2 CF 3 ( )7 ( )7 R2 ( )7
64–69 NO2 emitting diodes
O + N2: CF 3 CF 3 O + O + O
(1.0 equiv.) then cleavage
( )7 R3 N4: F H ( )7 R3 ( )7 ( )7
R1 O O
(1.0 equiv.) N8: H H
R4 Major R4 Minor Bis
Electrophilic character of *Ar–NO 2

N8 N4 N2 N1
100
Me H
100 99 89 88 64 versus 83%N8 Alkene
100%
Me H versus
90 H H alkyne
100 99 90 89 65 versus 80%N4
99%
Ph H
5(
Olefin site-selectivity (%)

H H )
80 versus O
95 90 74 66 66 68%N4,a
97% 5( )
C8H17 H
Me C8H17
versus 79%N8,a
70 83 77 67 65 67 87%
Me H
70
H C8H17
82%N1,b
versus 86%N8,a
79 74 67 66 68 85%
60 Ph H
Ph Ph 100%
versus
64 60 58 55 69 85%N8,a
Ph H 69%
50

b Me
Me O Me Ac
Me CO2H OAc OAc
O H Me
HO Me H Me H
Me
Me Me OAc Me H
H H H
Me
H H Me O O H H
HO Me
71, (–)-carvone 72, fusidic acid 73, exemestane 74, megestrol acetate 75, lynestrenol
Me
95%N1,a,b 42%N1,a,d 64%N3,a,b 35%N7,a,b 47%N4,e,f
100%
100% 1100%
00% 100%
100% 100%
100% 0%
100%
(r.s.m. 43%c) (r.s.m. 68%c) (r.s.m. 63%c) (r.s.m. 63%c)

Me OAc
Me Me
Me H OAc
Me Me OH H Me Me Me OAc Me
H H
Me
Me H
76, allylestrenol acetate 77, linalool 78, (–)- trans-caryophyllene 79, geranyl acetate 80, (–)-perillyl acetate
60%N4,b,e 71%N10,d,e 89%N9,e,f,g 66%N4,a,f,h 73%N2,a,b
100%
100% 1100%
00% 884%
4% 991%
1% 77%
(r.s.m. 38%c) (r.s.m. 49%c) (r.s.m. 55%c; E:Z 19:1) (r.s.m. 56%c)

R R1 R2
AcO Me Me NO2 H CF 3
Me N1:
R
N2: CF 3 H CF 3
Me Me
HCl N3: CN CN H
R1 NO2
NMe2 Me Me N4: F H H
81, cyclobenzaprine•HCl 82, (–)-bisabolol acetate 83, (+)-valencene N7: F SO 2CF 3 H
R2
99%N1,b,i 78%N2,b,e,j 46%N2,a,k N9: CN Me H
95%
95% 72%
72% 93%
93%
(r.s.m. 42%c) (r.s.m. 55%c) (r.s.m. 91%c) N10: CN H H

Fig. 4 | Achieving alkene selectivity. a, Competition experiments. N1, N2, N4 b, Complex examples. N1–N4, N7, N9 and N10 refer to the nitroarenes used.
a
and N8 refer to the nitroarenes used. Cleavage: CH2O (0–6 equiv.) in CH3CN/ CH2Cl2 with HFIP (0.5–6 equiv.). bAlkene (2 equiv.). cNMR yield. dN (2 equiv.).
e
THF:H2O (3.1:1). Selectivity determined considering bis gas chromatography- EtOAc. fAlkene (3 equiv.). gBis-cleaved product 3% yield. hBis-cleaved product
flame ionization detection (GC-FID) yield. See Supplementary Information 2% yield. iCH2Cl2 without HFIP. jBis-cleaved product 6% yield. k Alkene (5 equiv.).
for details. aAlkene (2.5 equiv.). bN1 (2 equiv.); CH2Cl2 with HFIP (1 equiv.).

the use of N8 and N4 enabled the fully selective cleavage of trisubsti- 85%), as well as the two highly activated alkenes of 69 (69%). Moreover, a
tuted alkene (64) and styrene (65) in the presence of monosubstituted complete selectivity for the terminal alkene of 70 was obtained even with
alkenes. Furthermore, striking discrimination was achieved between N1, yielding the corresponding alkyne-containing product in 82% yield.
internal and terminal double bonds (66, 97%), tri-alkyl versus di-alkyl To demonstrate reactivity control through electronic, steric and
substituted C–Cπ sites (67, 87%), styrene versus an internal alkene (68, mediated polar effects, we evaluated several complex and bio-active

Nature | www.nature.com | 5
Article
molecules containing multiple C–Cπ sites (Fig. 4b and Supplemen-
tary Information). (–)-Carvone 71 and fusidic acid 72 showed regi-
ocontrol based on electronics as alkene conjugation with carbonyl
functionalities directed the reactivity towards the other alkenes.
In the case of polyunsaturated steroids exemestane 73 and megestrol
acetate 74, oxidative cleavage occurred at the distal, hence less deac-
tivated, C–Cπ sites. Lynestrol 75 showcased alkene oxidation in the
presence of alkynes, whereas allylestrenol acetate 76, linalool 77 and
trans-caryophyllene 78 showed the selective cleavage of trisubstituted
alkenes over terminal and gem-disubstituted ones. Geranyl acetate 79
and perillyl acetate 80 contain trisubstituted alkenes with an allylic OAc
group that provides weak inductive deactivation. Although this enables
the preferential cleavage of the other C–Cπ sites, higher selectivity was
obtained adding HFIP (hydrogen bonding with the OAc group). Analo-
gously, the presence of the electron-withdrawing ammonium group in
cyclobenzaprine 81 allowed the disubstituted stilbene-type alkene to
react over the trisubstituted one. We propose that steric control might
be the main factor determining the selectivity in the oxidative cleav-
age of bisabolol acetate 82 and valencene 83 where the least hindered
acyclic alkenes were oxidized despite their degree of substitution.
Owing to the striking functional group compatibility and levels of site
selectivity achievable, our findings demonstrate that nitroarenes are
tunable and easy-to-dose photo-responsive ozone surrogates, which
have the premise to become a powerful and reliable tool to oxidatively
cleave alkenes.
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availability are available at https://doi.org/10.1038/s41586-022-05211-0.
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Data availability
The data that support the findings of this study are available from the
corresponding author (D.L.) upon reasonable request.
Acknowledgements D.L. thanks EPSRC for a Fellowship (EP/P004997/1) and a grant (EP/
V046799/1), the European Research Council for a research grant (758427), the Leverhulme Trust
for additional support (Philip Leverhulme Prize to D.L.). We acknowledge I. J. Vitorica-Yrezabal
(University of Manchester) for solving the X-ray crystal structure of 4, and N. S. Sheikh for
discussions.
Author contributions M.S. and D.L. designed the project; M.S. directed the work; M.S., A.R. and
C.H. performed all synthetic and mechanistic experiments. M.S. and D.L. wrote the manuscript.
Competing interests The authors declare no competing interests.
Additional information
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