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Synthesis 2024; 56(11): 1775-1786
DOI: 10.1055/s-0042-1751534
short review

Recent Advances in Photoinduced Oxidative Cleavage of Alkenes

Waseem A. Hussain
,
Marvin Parasram  ∗

Funding was provided through the generous start-up funds from New York University, the American Chemical Society Petroleum Research Fund (665501-DNI1), and the National Institute of General Medical Sciences of the National Institutes of Health (1R35GM150777-01).
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Abstract

Oxidative cleavage of alkenes leading to valuable carbonyl derivatives is a fundamental transformation in synthetic chemistry. In particular, ozonolysis is the mainstream method for the oxidative cleavage of alkenes that has been widely implemented in the synthesis of natural products and pharmaceutically relevant compounds. However, due to the toxicity and explosive nature of ozone, alternative approaches employing transition metals and enzymes in the presence of oxygen and/or strong oxidants have been developed. These protocols are often conducted under harsh reaction conditions that limit the substrate scope. Photochemical approaches can provide milder and more practical alternatives for this synthetically useful transformation. In this review, we outline recent visible-light-promoted oxidative cleavage reactions that involve photocatalytic activation of oxygen via electron transfer and energy transfer. Also, an emerging field featuring visible-light-promoted oxidative cleavage under anaerobic conditions is discussed. The methods highlighted in this review represent a transformative step toward more sustainable and efficient strategies for the oxidative cleavage of alkenes.

1 Introduction

2 Photochemical Methods for Oxidative Cleavage of Alkenes under Aerobic Conditions

2.1 Transition-Metal-Catalyzed Oxidative Cleavage of Alkenes under Visible Light

2.2 Photopromoted Organocatalyzed Oxidative Cleavage of Alkenes

2.3 Oxidative Cleavage of Alkenes with Molecular Iodine under Visible Light

2.4 Polymer-Catalyzed Oxidative Cleavage under Visible Light Irradiation

2.5 Oxidative Cleavage via Direct Visible Light Excitation with Molecular Oxygen

3 Anaerobic Oxidative Cleavage of Alkenes under Visible Light

4 Conclusion


#

Key words

oxidative cleavage - alkenes - ozonolysis - nitroarenes - photochemistry - anaerobic - visible light - aerobic
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Waseem Hussain(left) earned an M.Sc. in chemistry at BZU Multan, Pakistan followed by a Ph.D. in chemistry at Southern Illinois University Carbondale (USA) as a Fulbright fellow, where he specialized in organic materials under the supervision of Prof. Kyle N. Plunkett. He then transitioned to New York University (USA) for his postdoctoral research under the mentorship of Prof. Marvin Parasram, focusing on the advancement of synthetic methodology and photochemical transformations. Marvin Parasram (right) earned his B.Sc. in chemistry from Stony Brook University (USA) before completing his doctoral studies at the University of Illinois at Chicago (USA) supervised by Prof. Vladimir Gevorgyan where he focused on the development of Pd-catalyzed synthetic methods. He then joined the group of Prof. Abigail Doyle at Princeton University (USA) as a National Institutes of Health Ruth L. Kirschstein NRSA Postdoctoral Scholar where he developed dual Ni/photoredox-catalyzed methods. In 2020, he began his independent career at New York University (USA) where his group is developing sustainable photochemical methods for organic synthesis.
1

Introduction

Carbonyl derivatives are ubiquitous functionalities in active pharmaceutical ingredients, natural products, and in organic materials.[1] Ozonolysis continues to be the predominant method for accessing carbonyl compounds through the oxidative cleavage of alkenes. The oxidative cleavage of alkenes traces back to the discovery of ozone in 1840 by Schönbein, through the electrolysis of water.[2] In 1846, Schönbein reported the first ozonolysis reaction, by oxidatively cleaving ethylene to yield formaldehyde.[3] [4] Expanding on this progress, Harries, in the early 1900s, demonstrated the synthetic utility of ozonolysis by showcasing the oxidative cleavage of various hydrocarbon derivatives.[5,6] The mechanism of ozonolysis occurs via a [3+2] cycloaddition of ozone with an alkene to form the primary ozonide (POZ) intermediate 1, which fragments to generate intermediate 2 and a carbonyl group (Scheme [1]). Studies by Criegee in the mid-1900s supported the mechanism featuring carbonyl oxide 2, known as the Criegee intermediate.[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] Subsequent cycloaddition generates ozonide intermediate 3. The ozonide 3 can undergo reductive or oxidative workup to generate the carbonyl products or carboxylic acids, respectively. A detailed review of the mechanism of ozonolysis was recently published by Bräse and co-workers.[16]

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Scheme 1 (A) Mechanism of ozonolysis and (B) ozonolysis in the synthesis of complex bioactive molecules

The ozonolysis of alkenes is a widely employed transformation to convert feedstock hydrocarbon substrates into valuable oxidized products.[17a] For example, Avery and co-workers reported a total synthesis of (+)-artemisinin (4), a potent antimalarial (Scheme [1]B), that featured ozonolysis as a key step to construct the polycyclic core.[18a] Another example from Shen, Danishefsky, and co-workers is the synthesis of antitumor agent camptothecin, where ozonolysis was employed to generate the key molecular fragment 5.[18b] On an industrial scale, ozonolysis is a key step in the synthesis of high-value antibiotics like ceftibuten and cefaclor from intermediate 6,[17a] and several other compounds with various applications.[17b] A review highlighting the synthetic applications of ozonolysis in the synthesis of important therapeutics was published by Pariza and co-workers.[17a]

Despite the broad applications of ozonolysis, significant limitations still exist. The reaction requires the use of an ozonizer to generate ozone, which can be expensive to obtain for academic institutions. Moreover, ozone is a toxic gas and poses serious health risks for practitioners of ozonolysis. In terms of synthetic limitations, superstoichiometric ratios of ozone are often employed, which can result in poor regiocontrol and the generation of overoxidation products.[19] [20] For industrial-scale processes, precise control over ozone addition is imperative to mitigate the inherent risks of explosion owing to the high reactivity of ozone.[17b] While stringent safety measures are required to safeguard against such hazardous scenarios, there have been numerous reports of explosions while conducting ozonolysis reactions in both industrial and academic settings. In 2011, reports of utilizing ozonolysis in homogenous flow provided a safer and user-friendly protocol; however, excess ozone is still required.[21] [22]

One of the alternatives to ozonolysis is the Lemieux–Johnson reaction mediated by OsO4 in the presence of strong oxidants such as NaIO4 and KMnO4 [23] [24] In recent years, transition-metal-catalyzed approaches for the oxidative cleavage of alkenes involving noble metal and porphyrin/heme-based complexes have been reported.[25] [26] [27] [28] While promising, the highly oxidizing conditions often lead to undesired reactivity, such as overoxidation, low yield, and limited scope.[28] Metal-free approaches have been developed using heterogeneous polymeric carbon nitrides, oxygen, and sunlight.[29] Enzyme-catalyzed oxidative cleavage protocols can address the issues of overoxidation but suffer from challenges of enzyme specificity, sluggish reactions, and the high cost of the radical precursors.[28] [30]

Considering the drawbacks of both ozonolysis and its alternative methods, there is a pressing need for safer, more efficient, and sustainable protocols for the oxidative cleavage of alkenes. In the past decade, strategies for visible-light-promoted oxidative cleavage have emerged as promising alternatives to ozonolysis. In this review, we highlight two distinct photochemical approaches featuring the aerobic and anaerobic cleavage of alkenes. The aerobic protocols discussed herein feature the activation of oxygen as a sustainable oxidant via photocatalyzed sensitization or single electron transfer (SET) to promote the oxidative cleavage event under mild conditions. Seminal work by Leonori, Simonetti, and co-workers[58] and Parasram and co-workers[53] has illustrated a new avenue for the anaerobic oxidative cleavage of alkenes promoted by photoinduced nitroarenes that do not require the use of exogenous oxidants, thus, leading to an expansion of substrate scope compared to prior oxidative cleavage protocols. The aim of this review is to inform the synthetic community of the recent advances in the photochemical cleavage of alkenes and to illustrate that this modality can provide complementary alternatives to existing oxidation protocols.


# 2

Photochemical Methods for Oxidative Cleavage of Alkenes under Aerobic Conditions

2.1

Transition-Metal-Catalyzed Oxidative Cleavage of Alkenes under Visible Light

In 2021, Xiao and co-workers reported a visible-light-driven, Mn-catalyzed oxidative cleavage of alkenes under an oxygen atmosphere (Scheme [2]).[31] The oxidative cleavage of unactivated aliphatic alkenes to carbonyl derivatives was accomplished by employing Mn catalyst 7 under blue light. The authors proposed the following mechanism. Photoexcitation of Mn(II) complex 7 with blue light generates 8, which engages in SET event with O2 to yield Mn(III)-superoxo complex 9. It should be noted that the authors ruled out the participation of singlet oxygen (1O2) by conducting trapping experiments using diphenylanthracene (DPA), where no endoperoxide product was observed. Hydrogen atom transfer (HAT) of methanol with complex 9 furnishes methanol addition intermediate 10. Fragmentation of the latter generates Mn(IV)-oxo 11, formaldehyde, and water. Complex 11 can undergo reversible dimerization to form catalytically inactive bis-μ-O2-Mn2 14, which was identified by UV-vis studies and X-ray diffraction. Photoirradiation of 14 leads to catalytically active complex 11, which engages in radical addition with an alkene to generate intermediate 12. Radical recombination of the latter with the ground state of oxygen leads to metal peroxo species 13. Decomposition of 13 yields the desired carbonyl products and turns over the catalytic cycle. Notably, mono-, di, tri-, and tetrasubstituted alkenes possessing a range of functional groups including amides, esters, and amino acids underwent successful cleavage under the reaction conditions. Dipeptide, urea, and glucose-containing alkenes were selectively oxidized, illustrating the synthetic utility of this protocol. Sensitive functional groups like pinacolatoboronate (Bpin) in 15 were also tolerated by this protocol. However, accessing aldehydes remained a challenge. For example, oxidative cleavage of simple styrene generated the overoxidation product, methyl benzoate (16). Also, cleavage of terminal alkenes led to acetal products 17 and 18.

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Scheme 2 Mn-catalyzed, visible-light-driven alkene cleavage protocol (Xiao)

In 2021, Xie and co-workers reported the oxidative cleavage of styrene derivatives utilizing tetrabutylammonium decatungstate (TBADT) as a photocatalyst under sustainable reaction conditions featuring water, air, and sunlight or blue LEDs (Scheme [3]).[32] The authors performed various mechanistic studies to determine the operative mechanism of the transformation. The radical nature of the protocol was confirmed by the reaction inhibition in the presence of common radical traps TEMPO and BHT. While the reaction yields were unaffected by the addition of hydroxyl radical traps, trace yields were obtained when superoxide and singlet oxygen quenchers were added to the reaction conditions. These studies support the involvement of either superoxide and/or singlet oxygen, thus suggesting that electron transfer (ET) and/or energy transfer (EnT) pathways are plausible. For the ET pathway, TBADT 19 undergoes photoexcitation to generate complex 20 that undergoes reductive quenching with styrene leading to styrene radical cation 22 and the intermediate complex 21. Oxidation of the latter with molecular oxygen closes the photocatalytic cycle and generates superoxide radical anion. Finally, the reaction between 22 and the superoxide radical anion results in the formation of dioxetane intermediate 23, which subsequently fragments to generate formaldehyde and the desired carbonyl product 24. The EnT route was proposed to occur through the excitation of photocatalyst 19 and subsequent sensitization of molecular oxygen to yield singlet oxygen, which engages in a [2+2] cycloaddition event with styrene to produce dioxetane 23. Photodecomposition of 23 yields the corresponding carbonyl product. The authors stated the need for further investigation to determine the major operative mechanism. A possible solution could involve the use of transient absorption spectroscopy (TAS), which has proven to be a reliable tool for identifying the triplet-triplet energy transfer processes[33] that could scrutinize the proposed ET or EnT pathways

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Scheme 3 Visible-light-promoted, transition-metal-catalyzed oxidative cleavage of styrenes under ambient atmosphere (Xie)

A series of styrenes and α-methylstyrenes underwent oxidative cleavage leading to corresponding carbonyls 25–27 in 42–54% yield. 1-Heteroarylalkenes and 1,1-diaryl- and 1-aryl-1-heteroarylalkenes were also amenable to this protocol giving product such as 28–30. However, modest yields were obtained with the o-substituted styrenes, e.g. the formation of 31, presumably due to unfavorable steric interactions. While this protocol offers sustainability benefits, there are notable concerns. For instance, this approach relies upon an expensive transition metal catalyst and necessitates the use of 18-crown-6 to handle the biphasic nature of the reaction. With the tendency of terminal styrenes to undergo polymerization instead of oxidative cleavage under the reaction conditions, the substrate scope remained limited to activated molecules, specifically, styrenes, α-methylstyrenes, and 1,1-di(hetero)arylalkenes.

A complimentary protocol to Xie’s method was reported by Ryu and co-workers in 2023 employing TBADT catalyst with acetonitrile and water mixture, promoted by black/UV 365 nm light.[34] The authors showcased a slight expansion of scope toward aliphatic substrates. Using a continuous photoflow setup, the standard reaction time of 12–20 h in batch was significantly reduced to 6 minutes.

The employment of quantum dots for photocatalytic transformations represents an emerging area of synthetic chemistry.[35] [36] [37] Based upon the ability of quantum dots to promote the redox reactions, a protocol for the oxidative cleavage of alkenes was reported by Meng and co-workers in 2021 (Scheme [4]).[38] Mercaptopropionic acid capped cadmium selenide quantum dots (CdSe-QDS), blue light, water, and oxygen were employed for the oxidative cleavage of styrenes. Notably, turnover numbers as high as 37,000 were achieved using this protocol.

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Scheme 4 Cadmium selenide quantum dots assisted photooxidative cleavage of alkenes under air (Meng)

The authors proposed two potential mechanisms featuring ET (path a) or EnT pathways (path b). When exposed to blue light, electrons are excited from the valence band (VB) of the quantum dots QDS to the conduction band (CB), creating an active redox system (Scheme [4]). For the ET mechanism, the hole in the VB facilitates the oxidation of styrene 32 through a single electron transfer (SET) event, resulting in the formation of styrene radical cation 33. The CB reduces oxygen to a reactive superoxide radical anion that subsequently undergoes cycloaddition with 33 to form dioxetane 34, which eventually decomposes to produce the desired carbonyl product. Alternatively, the EnT pathway, [2+2] cycloaddition event of styrene 32 with singlet oxygen, formed via sensitization with the photoexcited quantum dots occurs leading to dioxetane 34 that fragments to the carbonyl products. The focus of the substrate scope continues to be on styrenes and their substituted derivatives. A decreased conversion was observed for electron-poor styrenes (35 and 36). Polyaromatic systems were poor performing substrates, resulting in low conversion into, for example, 37 and 38. Overall, this solvent-free, practical methodology leverages the high catalytic activity of CdSe-QDS for the oxidative cleavage of styrenes.

This work was preceded by a similar report by Hosseini-Sarvari and Firoozi in 2020 where they utilized photoexcited CdS nanoparticles for photooxidative cleavage and photo-difunctionalization of alkenes.[39] The oxidative cleavage is reported to go through an ET pathway as described above. Similarly, Le and co-workers presented a facile visible-light-driven photocatalytic protocol using CsPbBr3 nanocrystals to cleave alkenes, yielding carbonyls.[40] A range of terminal and internal alkenes were amenable under this protocol. The CsPbBr3 catalytic system occurs via an ET route to generate the dioxetane intermediate which fragments to give the final carbonyl products.


# 2.2

Photopromoted Organocatalyzed Oxidative Cleavage of Alkenes

Since the 1990s, reports of organocatalyzed methods have grown substantially. Compared to transition-metal-catalyzed methods, organocatalyzed reactions typically occur under mild conditions using inexpensive catalysts that are often recyclable. Organophotocatalysis using dyes and conjugated π-systems has enabled novel bond-forming events to occur under sustainable and cost-effective conditions. Very recently, organophotocatalyzed methods for the cleavage of alkenes leading to important carbonyl derivatives have been reported which will be discussed in this section.

In 2009, You and co-workers designed a singlet oxygen-mediated photooxidation of alkenes by employing a porphyrin-based dye as a photocatalyst under atmospheric conditions to selectively access the aldehyde products.[41] Low-intensity light of 200 mW/cm2 in the range of 400–800 nm and short reaction times (15 min) were applied to make this methodology applicable for biological applications. The substrate scope was centered around heteroatom-activated alkenes including dioxy-substituted alkenes, which could be used as linkers for site-specific prodrug release. This study shows the potential of photopromoted oxidative cleavage chemistry for biological applications; however, the low yields of the transformation warrant further optimization.

Advancing toward sustainable photocatalytic systems, Wang and co-workers in 2016, demonstrated that aromatic disulfides can photooxidatively cleave unsaturated systems under aerobic conditions (Scheme [5]).[42] The authors reported that direct photoexcitation of disulfide-alkene complex 39 triggers a homolysis event of the disulfide catalyst to generate a thiyl radical and a carbon-centered radical 40. Support for the disulfide-alkene complex was obtained by simulated UV-vis studies and NMR titration experiments. Carbon-centered radical intermediate 40 reacts with ground-state oxygen to generate intermediate 41. However, the authors reported that a competitive pathway leading to alkene 45 via α-abstraction and radical recombination of 40 was observed in some cases. Intermediate 41 underwent an abstraction and substitution event with the thiyl radical to furnish dioxetane 42 and regenerate the catalyst. Spontaneous photolysis of the former leads to the formation of carbonyl products. Evidence for the intermediacy of 42 was supported by trapping studies with methionine and water leading to 43, which decomposes to generate diol 44.

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Scheme 5 Diaryl disulfide catalyzed photooxidative alkene cleavage via a disulfide olefin complex formation (Wang)

In terms of reaction scope, several ortho-, meta-, and para-substituted styrenes were tested under the reaction conditions and led to efficient yields of the corresponding carbonyl products 46–49. In 2022, Gorve and colleagues reported a similar strategy where they utilized catalytic amounts of 2,2′-dipyridyl disulfide (aldrithiol) under photochemical conditions to transform arylbutadienes to cinnamaldehydes.[43]

In 2021, Zhang and co-workers reported a photocatalyzed oxidative cleavage of styrene under blue light irradiation (Scheme [6]).[44]. Their protocol employed the commercially available dye Rose Bengal as the photocatalyst, H2O as a sustainable solvent, and O2 as a green oxidant. The mechanism of the transformation is as follows. Blue light irradiation of Rose Bengal leads to the photoexcited state that is capable of oxidizing styrenes 50 to generate styrene radical cation 51 and the reduced form of Rose Bengal. The latter undergoes single electron oxidation with molecular oxygen to turnover the photocatalytic cycle and generate superoxide. The formed superoxide undergoes a [2+2] cycloaddition with 51 to generate dioxetane 52, which was detected through HRMS. Finally, fragmentation of 52 leads to the cleavage products.

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Scheme 6 Rose Bengal catalyzed photooxidative alkene cleavage (Zhang)
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Scheme 7 Visible-light-promoted aerobic oxidative alkene cleavage via charge transfer complex formation (Yang)

The substrate scope of this method is limited to styrenes, with the yield significantly decreasing for ortho-substitution substrates (54) due to steric factors. Interestingly, trans-stilbene derivatives led to diketone formation 55 instead of the cleavage product owing to the reduced reactivity of the highly conjugated starting material. The authors nicely illustrated that their protocol is amenable to late-stage functionalization of medicinally relevant molecules (56, 57).

In 2022, a visible-light-promoted, sodium benzenesulfinate catalyzed aerobic cleavage of alkenes was reported by Xiang, Chen, Yang, and co-workers (Scheme [7]).[45] This work involves the formation of a charge transfer complex (CTC) 59 between sodium benzenesulfinate (58) and molecular oxygen, which undergoes a photoinduced ET event leading to radical anion 60 and superoxide. Radical addition of 60 with styrene and subsequent trapping with the formed superoxide leads to intermediate 61. Intramolecular substitution of 61 expels the active catalyst and generates oxetane 62. Fragmentation of 62 furnishes the carbonyl products. A variety of olefinic substrates, including simple, α-, and β-substituted styrenes, were successfully transformed to produce carbonyl compounds. Vinyl-substituted polyaromatic hydrocarbons and sterically encumbered alkenes were competent substrates under the reaction conditions, e.g. the formation of 63 and 64. Late-stage functionalization for medicinal compounds was also featured including a probenecid derivative that gave 65.

Singh and Shee reported a related strategy to the method of Xiang, Chen, Yang, and co-workers also in 2022.[46] Their work involves a photocatalytic activation of sodium azide which serves as an HAT catalyst under blue light and aerobic conditions. The proposed mechanism shows similarities to that in Scheme [7].


# 2.3

Oxidative Cleavage of Alkenes with Molecular Iodine under Visible Light

In 2014, Itoh and co-workers reported an aerobic, visible-light-mediated cleavage of symmetrical stilbene derivatives to access aldehydes using catalytic amounts of iodine with substoichiometric trifluoroacetic acid (TFA) in MeOH/EtOAc solvent mixture (Scheme [8]).[47] This solved an inherent limitation of their prior 2009 report where the cleavage of symmetrical stilbene derivatives led to low yields of aldehydes due to overoxidation to carboxylic acids in the presence of carbon tetrabromide.[48] By redirecting the reaction pathway to feature an iodomethoxylation event 66 in acidic media, this suppressed the formation of the overoxidation product. After the formation of 66, photoinduced homolysis of the C–I bond generates benzylic radical 67, which leads to the formation of hydroperoxide species 69 via radical addition with molecular oxygen and HAT of 68 with HI. Acid-promoted C–C bond cleavage yields either aldehyde or acetal 72, which eventually releases aldehyde upon acidic workup.

The scope of this methodology comprises of a few examples of ortho-, and para-substituted stilbenes, where the cleavage products, such as 73–75, were formed in moderate to good yields. However, stilbenes possessing strongly electron-donating or electron-withdrawing groups were poor-performing substrates giving products, such as 76 and 77, in low or 0% yield. Also, monosubstituted styrenes and unactivated alkenes did not generate the desired aldehyde products. Though selective oxidation to aldehydes was accomplished, the dependency upon symmetrical stilbenes and the use of acid workup limits the substrate scope.

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Scheme 8 Iodine-catalyzed photooxidative alkene cleavage (Itoh)

# 2.4

Polymer-Catalyzed Oxidative Cleavage under Visible Light Irradiation

In 2018, Zhang and co-workers presented a novel approach employing conjugated microporous polymers (CMPs), as a type of metal-free and recyclable heterogenous photocatalyst to facilitate alkene cleavage reactions under visible light (Scheme [9]).[49] The electronic tuning of CMPs was accomplished by coupling either thiophenes (Th) as electron-rich monomers, benzothiodiazole (BT) as electron-poor monomers, or triethynylbenzene (B) featuring both properties affording BTh 78, BBT 79, or BThBT 80 polymers, respectively. The optoelectronic properties of these CMPs reveal that BBT 79 (electron-poor polymer) is best suited for redox catalysis owing to its higher reduction potential (–0.92 V vs. SCE) compared to O2/O2 – (–0.57 V vs. SCE). The authors postulated the involvement of both ET and EnT pathways for the mechanism of the transformation based on prior literature evidence and their control experiments. The ET pathway was supported by nucleophilic trapping studies, which led to diminished yields suggesting the involvement of a radical cation intermediate. Active participation of both singlet oxygen and superoxide was confirmed through electron spin resonance EPR studies. However, the authors were unable to assign the major contributing route. The authors proposed that visible light excitation of CMP enables an electron-hole pair separation, capable of severing as both the oxidant and reductant. The photogenerated hole oxidizes styrene to a radical cationic species 81 that undergoes cycloaddition with superoxide 82 to form the transient dioxetane species 83. The superoxide was formed via reduction of O2 from the LUMO of excited CMP. Hydrolysis of 83 leads to diol 85, which subsequently undergoes oxidative cleavage to generate the aldehyde products. Alternatively, EnT of the triplet excited state of the CMP with molecular oxygen can lead to singlet oxygen 84, which can engage in a [2+2] cycloaddition event to generate key intermediate 83, which eventually furnishes the cleavage products.

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Scheme 9 CMP-assisted photooxidative cleavage of alkenes (Zhang)

In terms of substrate scope, styrene derivatives reacted well under this transformation, e.g. formation of 86 and 87; however, electron-poor and -rich styrenes resulted in moderate yields of the corresponding aldehydes. However, cyclic systems did not undergo cleavage, instead, the allylic oxidation products, such as 88, were obtained. The catalyst can be recycled up to five times before experiencing a 50% decline in selectivity for aldehyde products.

In 2020, Das and co-workers reported a sustainable protocol for the aerobic cleavage of styrene derivatives by harnessing solar energy or blue light in the presence of polymeric carbon nitrides (PCN) as metal-free heterogeneous photocatalysts and N-hydroxysuccinimide (NHS) as a co-catalyst (Scheme [10]).[29] The PCN catalyst has a low energy band gap of 2.7 eV, making it ideal for capturing solar energy. The high conduction band (CB) value of PCN (–1.10 V) can efficiently generate reactive oxygen radical anions, while its elevated valence band can readily oxidize aryl-substituted alkenes.

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Scheme 10 Solar energy promoted PCN catalyzed oxidative cleavage protocol (Das)

Mechanistic studies suggest photoexcited PCN triggers a redox reaction event via oxidation of styrene 89 to produce radical cation 90 and reduction of molecular oxygen to generate superoxide. The latter engages in a HAT event with the NHS co-catalyst to produce superoxide radical anion 91 and aminoxyl radical 92. Radical recombination of 92 with 90 forms intermediate 93 that undergoes nucleophilic trapping with 91 to produce peroxide 94. Release of NHS from 94 delivers dioxetane 96 via an intramolecular SN2 reaction. Finally, fragmentation of 96 furnishes the carbonyl products. Alternatively, 90 can also engage in a direct [2+2] cycloaddition with superoxide to yield the carbonyl products via intermediate 96. A diverse set of styrenes, including fused heterocycles (97), and electron-rich systems (98), were obtained in high to moderate yields. Notably, cleavage of challenging systems such as tri-O-acetylresveratol and trans-chlorprothixene worked well under this transformation, resulting in 57% yield of 99 and 62% yield of 100.


# 2.5

Oxidative Cleavage via Direct Visible Light Excitation with Molecular Oxygen

Despite significant advances made in photochemical oxidative cleavage chemistry, most methodologies are dependent upon a photocatalyst and additives to facilitate the activation of molecular oxygen, which increases both costs and waste. Hence, oxidative cleavage reactions that are promoted independent of external catalysts and aided by the singlet oxygen species are desirable from a sustainability standpoint. Recently, advances have been made in the direct sensitization of molecular oxygen promoted by either electron-donor acceptor complexation with substrates/solvents or direct irradiation.

In 2021, Fu and co-workers reported an oxidative cleavage approach for (Z)-2-(1,2-diphenylvinyl)pyridines leading to important pyridyl ketones under ambient air with purple light (Scheme [11]A).[50] The requirement for an external photomediator was eliminated by employing photoactive (Z)-2-(1,2-diphenylvinyl)pyridines that are capable of sensitizing molecular oxygen. The proposed mechanism is as follows. First 1n–π photoexcitation of 101 generates singlet excited state S1, which undergoes intersystem crossing (ISC) to the longer-lived T1 3π–π* state 102. The latter undergoes an energy transfer (ET) event with the 3O2 molecule to yield a highly reactive 1O2 singlet oxygen species. The singlet oxygen molecule can produce a dioxetane intermediate 104 through a [2+2] cycloaddition with (Z)-S1 101 (path a). Alternatively, a single electron transfer SET can occur between the 3O2 and photoexcited (Z)-S1* 102 leading to the formation of superoxide radical anion and complex 103. Radical combination of 103 with superoxide radical anion can also furnish dioxetane 104 (path b). Cleavage of dioxetane 104 affords the aldehyde and ketone 105. Mechanistic studies support that both pathways are viable. This protocol features good substrate tolerance as sensitive heterocyclic and strained ring systems on the pyridyl system (106–108). While the given methodology was able to circumvent an exogenous photomediator, the scope remains limited to (Z)-2-(1,2-diphenylvinyl)pyridines.

In the same year, Zhang and co-workers reported a mild and practical approach for the photoinduced oxidative cleavage of styrenes with O2 in the presence of substoichiometric amounts of THF and water as solvent (Scheme [11]B).[51] The authors proposed that the transformation is initiated via autooxidation of THF with O2 under blue light irradiation leading to the formation of hydroperoxide 109. Homolysis of the latter generates the alkoxy radical 110 which undergoes radical addition to styrene 111 to form carbon-centered radical 112. Trapping of 112 by O2 leads to the formation of peroxy radical 113 which converts into the dioxetane intermediate 114. Finally, the photochemical decomposition of 114 yields carbonyl products 115. For cases where aldehydes are formed, concomitant formation of carboxylic acids 116 via overoxidation was observed. Interestingly, under higher energy UV light, the overoxidation products 117 and 118 can be obtained selectively. Overall, this study showcases a mild protocol that tolerates heterocyclic systems and halogen functionalities (119 and 120). However, only activated styrenes were oxidized to their respective carbonyls, which also had issues of overoxidation even at higher wavelengths.

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Scheme 11 (A) Ambient air oxidative cleavage protocol via photoactive pyridyl-containing substrates (Fu) and (B) Protocol for autooxidation promoted cleavage of alkenes (Zhang)

#
# 3

Anaerobic Oxidative Cleavage of Alkenes under Visible Light

The photochemical oxidative cleavage methods described above signify the advancements in comparison to classical protocols. Consequently, ozone utilization no longer remains a necessity, thereby mitigating the safety hazards associated with ozonolysis. Nonetheless, the use of molecular oxygen remains prevalent to facilitate the oxidative cleavage of alkenes. Reliance on external oxidants, however, can pose drawbacks due to their nonselective nature and tendency to promote undesired overoxidations, thus limiting the substrate scope. Considering these constraints, the utilization of anaerobic photooxidative cleavage methods holds promise for the synthetic community. This approach operates independently of exogenous oxidants, thereby providing milder oxidation conditions that can overcome the issues of limited substrate scope.

Such a strategy necessitates the use of an oxygen atom source that is not inherently oxidizing, which is scarce. Recently, there have been reports on the use of photoexcited nitroarenes to initiate the oxidative cleavage of alkenes, yielding valuable carbonyl products.

Seminal work by Büchi and Ayer has demonstrated the potential of photoexcited nitrobenzene in the oxidative cleavage of alkenes to produce carbonyl compounds, albeit with a yield of only 12%.[52] Inspired by this, Parasram and co-workers developed a mild, safer, sustainable, and atom-economical protocol for the anaerobic oxidative cleavage of alkenes (Scheme [12]).[53] This protocol illustrates a departure from the requirement of exogenous oxidants and utilizes photoexcited nitroarenes as oxygen atom transfer reagents.

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Scheme 12 Protocol for anaerobic oxidative cleavage of alkenes via photoinduced nitroarenes (Parasram)

Mechanistic studies performed by the authors shed light on the processes involved in the transformation. UV-vis studies supported that electron-deficient nitroarenes are the sole photoabsorbing species under purple light irradiation leading to a putative triplet diradical intermediate. Evidence for the triplet diradical intermediate was obtained through HAT studies and triplet quenching experiments. In the presence of an alkene, the nitroarene diradical undergoes a stepwise radical cycloaddition leading to dioxazolidine intermediate 122. The latter undergoes a polar fragmentation route via two distinct possibilities, each leading to the formation of a carbonyl and carbonyl imine 123 or 125. Formation of aryl nitrene via fragmentation of 122 intermediates was ruled out based on nitrene trapping experiments. Intermediates 123 and 125 subsequently partake in a 1,3-dipolar cycloaddition, yielding transient 1,4,2-dioxazolidines 124 and 126, respectively, that subsequently decompose to yield the desired carbonyl products. Evidence for these two distinct polar fragmentation pathways A and B was supported through 1H and 19F photo NMR studies.

For substrate scope, styrenes underwent anaerobic oxidative cleavage resulting in high yields of the carbonyl products (Scheme [12]). Notably, no overoxidation products were observed. While unactivated alkenes worked, low yields of the corresponding cleavage products were obtained. Heterocyclic styrenes and halogen functionalities were successfully transformed. The synthetic utility of this method was tested via late-stage functionalization of cytotoxic quinoline and therapeutic betulin derivatives to give 127 and 128, respectively, in good yields. These yields were comparable to those obtained via traditional ozonolysis,[54] [55] illustrating that this approach can serve as a viable alternative to ozonolysis without the need for a complex reaction setup and safety concerns. Molecules containing oxidatively sensitive functional groups such as alkyne 129 and Bpin 130 which are not amenable to ozonolysis, were tolerated well under this protocol. The ability of photoexcited nitroarenes to yield oxygen atom transfer reactions was further investigated to furnish a variety of oxidized products in later studies.[56,57]

A contemporaneous study by Leonori, Simonetti, and co-workers was also reported (Scheme [13]).[58] The methodology is similar to Parasram’s protocol in featuring the cleavage of alkenes promoted by electron-deficient nitroarenes. This method provided highly efficient yields for the oxidative cleavage of aliphatic alkenes. This was due to the utilization of 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), 2,6-lutidine, and nonafluoro-tert-butyl alcohol to suppress the overoxidation and hydridic α-N/O/S(sp3)–H abstraction. Also, conducting the reaction at –30 °C enabled the accumulation of transient dioxazolidine intermediate whose subsequent thermal decomposition at 80 °C in either CH3CN/H2O or THF/H2O solvent mixtures furnished quantitative release of the carbonyl products.

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Scheme 13 (A) Protocol for anaerobic oxidative cleavage of alkenes via photoinduced nitroarenes and (B) regioselectivity for competing C=C bonds (Leonori)

Control studies illustrated the pivotal roles of water and formaldehyde in the second stage of the reaction. D2O studies supported a hydrolysis-assisted decomposition of dioxazolidine and hydrolysis of the formed carbonyl imine, leading to the carbonyl products and the aryl hydroxylamine byproduct. The use of formaldehyde is responsible for trapping the latter byproduct.

Mechanistic findings are similar to Parasram’s protocol highlighting the formation of dioxazolidine intermediate 133 via [3+2] cycloaddition of photoexcited nitroarene diradical 131 with alkene (Scheme [13]A). The dioxazolidine was isolated and possible decomposition pathways were investigated. Again, trapping studies ruled out the intermediacy of nitrene formation via fragmentation of the dioxazolidine 133. Hence, dioxazolidine 133 was supported to undergo polar decomposition pathways, resulting in the formation of a carbonyl and carbonyl imine 134. The intermediacy of carbonyl imine was supported via 1,3-dipolar cycloaddition with acetonitrile. Hydrolysis of 134 yields N-hydroxylamine 135 and the desired carbonyl product. The authors conducted regioselectivity studies for systems possessing multiple alkenes that could undergo competitive cleavage. With diene 136 and highly electron-poor 3,5-bis(trifluoromethyl)nitrobenzene, both the mono- and dicleavage products were obtained (Scheme [13]B). However, when nitrobenzene was employed, the monocleavage product was obtained selectively, illustrating an electronic dependence for controlling regioselectivity. Leonori’s protocol exhibits broad substrate scope. A vast array of styrenes and unactivated alkenes resulted in high yields of the cleavage products 137–139.

Overall, the anaerobic oxidative cleavage protocols presented by Parasram and Leonori offer a viable alternative to conventional ozonolysis. These methods demonstrate independence from exogenous oxidants by employing commercial nitroarenes, effectively addressing the challenges of overoxidation and limited substrate scope often encountered in traditional approaches using molecular oxygen. Since the publication of these findings, numerous studies have emerged emphasizing the practicality of photoinduced nitroarenes in synthetic applications.[34] [59] [60] [61] [62]


# 4

Conclusion

In summary, this review provides a concise perspective on the advancements within the field of oxidative cleavage reactions. While classical ozonolysis continues to be the mainstream protocol for this, economical and practical alternatives featuring visible-light-promoted aerobic and anaerobic cleavage have been developed. Most aerobic methods rely on electron transfer and/or sensitization of abundant molecular oxygen promoted by a photocatalyst to trigger the oxidative cleavage of alkenes. Compared to classical ozonolysis and its alternatives, these protocols feature improved reaction efficiency and cost economy. However, challenges still remain such as the competitive formation of overoxidation products and limitations in reaction scope to styrene derivatives. Recently, the emergence of anaerobic cleavage reactions empowered by photoexcited nitroarenes presents a safer, sustainable, and practical alternative to traditional ozonolysis. Markedly, this new avenue does not result in overoxidation products due to the anaerobic nature of the transformation; thus, leading to a significant expansion in substrate scope compared to prior art. However, the requirement for stoichiometric amounts of nitroarene is a limitation; hence, the need for a catalytic anaerobic approach is warranted. Nevertheless, the methods discussed herein provide important foundational advancement for the future design of sustainable oxidative cleavage reactions.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

Dr. Dan Wise, Dr. Ajay H. Bansode, and Mr. Ryan M. O’Connor are gratefully acknowledged for their proof-reading of this manuscript.


Corresponding Author

Marvin Parasram
Department of Chemistry, New York University
29 Washington Pl, New York, New York 10003
USA   

Publication History

Received: 30 October 2023

Accepted after revision: 14 November 2023

Article published online:
11 December 2023

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Zoom Image
Waseem Hussain(left) earned an M.Sc. in chemistry at BZU Multan, Pakistan followed by a Ph.D. in chemistry at Southern Illinois University Carbondale (USA) as a Fulbright fellow, where he specialized in organic materials under the supervision of Prof. Kyle N. Plunkett. He then transitioned to New York University (USA) for his postdoctoral research under the mentorship of Prof. Marvin Parasram, focusing on the advancement of synthetic methodology and photochemical transformations. Marvin Parasram (right) earned his B.Sc. in chemistry from Stony Brook University (USA) before completing his doctoral studies at the University of Illinois at Chicago (USA) supervised by Prof. Vladimir Gevorgyan where he focused on the development of Pd-catalyzed synthetic methods. He then joined the group of Prof. Abigail Doyle at Princeton University (USA) as a National Institutes of Health Ruth L. Kirschstein NRSA Postdoctoral Scholar where he developed dual Ni/photoredox-catalyzed methods. In 2020, he began his independent career at New York University (USA) where his group is developing sustainable photochemical methods for organic synthesis.
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Scheme 1 (A) Mechanism of ozonolysis and (B) ozonolysis in the synthesis of complex bioactive molecules
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Scheme 2 Mn-catalyzed, visible-light-driven alkene cleavage protocol (Xiao)
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Scheme 3 Visible-light-promoted, transition-metal-catalyzed oxidative cleavage of styrenes under ambient atmosphere (Xie)
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Scheme 4 Cadmium selenide quantum dots assisted photooxidative cleavage of alkenes under air (Meng)
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Scheme 5 Diaryl disulfide catalyzed photooxidative alkene cleavage via a disulfide olefin complex formation (Wang)
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Scheme 6 Rose Bengal catalyzed photooxidative alkene cleavage (Zhang)
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Scheme 7 Visible-light-promoted aerobic oxidative alkene cleavage via charge transfer complex formation (Yang)
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Scheme 8 Iodine-catalyzed photooxidative alkene cleavage (Itoh)
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Scheme 9 CMP-assisted photooxidative cleavage of alkenes (Zhang)
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Scheme 10 Solar energy promoted PCN catalyzed oxidative cleavage protocol (Das)
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Scheme 11 (A) Ambient air oxidative cleavage protocol via photoactive pyridyl-containing substrates (Fu) and (B) Protocol for autooxidation promoted cleavage of alkenes (Zhang)
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Scheme 12 Protocol for anaerobic oxidative cleavage of alkenes via photoinduced nitroarenes (Parasram)
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Scheme 13 (A) Protocol for anaerobic oxidative cleavage of alkenes via photoinduced nitroarenes and (B) regioselectivity for competing C=C bonds (Leonori)