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Ozonolysis

Ozonolysis is a chemical reaction in organic synthesis wherein the carbon-carbon double bonds of alkenes (or triple bonds of alkynes) are oxidatively cleaved by ozone (O₃) to produce carbonyl compounds, such as aldehydes and ketones under reductive conditions or carboxylic acids under oxidative conditions.^[1] This reaction, typically conducted at low temperatures like -78°C in solvents such as dichloromethane, proceeds via the formation of unstable intermediates called ozonides, which are subsequently decomposed during workup.^[2] It serves as a powerful tool for both structural elucidation of unsaturated compounds and the preparation of specific carbonyl functionalities from alkenes.^[1] The history of ozonolysis traces back to the mid-19th century, when Christian Friedrich Schönbein, the discoverer of ozone in 1840, first observed its reaction with ethylene in 1845, noting the production of aldehydes and formic acid without complete mineralization to carbon dioxide.^[3] In the early 20th century, German chemist Carl Dietrich Harries (1866–1923) systematically developed ozonolysis as a method for degrading unsaturated hydrocarbons, establishing experimental protocols and demonstrating its generality for cleaving multiple double bonds, particularly in natural products like terpenes and rubber.^[4] The modern understanding of the reaction mechanism was advanced by Rudolf Criegee in the 1940s and 1950s, who proposed the involvement of a carbonyl oxide zwitterion intermediate, later summarized in his influential 1975 review.^[5] The mechanism of ozonolysis begins with a 1,3-dipolar cycloaddition between ozone and the alkene, forming an initial molozonide (a 1,2,3-trioxolane), which rapidly rearranges via cleavage into a carbonyl compound and a Criegee intermediate (a carbonyl oxide).^[6] This intermediate then undergoes another cycloaddition with the carbonyl to yield the more stable ozonide (a 1,2,4-trioxolane).^[2] Ozonides are explosive and must be handled carefully; they are not isolated but decomposed in the workup step.^[1] Workup procedures determine the final products: reductive workup with reagents like dimethyl sulfide (DMS), zinc in acetic acid, or triphenylphosphine yields aldehydes or ketones by preserving aldehydic C-H bonds, while oxidative workup with hydrogen peroxide converts aldehydes to carboxylic acids.^[2] For example, ozonolysis of cyclohexene under reductive conditions produces adipic dialdehyde (hexanedial), whereas oxidative conditions give adipic acid.^[1] The reaction's regioselectivity follows the pattern where each carbon of the original double bond becomes a carbonyl group, with terminal =CH₂ groups yielding formaldehyde and =CHR groups yielding aldehydes or acids.^[6] Ozonolysis finds broad applications in synthetic organic chemistry for constructing complex molecules by breaking down cyclic alkenes into acyclic dicarbonyls, as well as in degradative analysis to determine the position of double bonds in unknown alkenes.^[2] It has been instrumental in elucidating the structures of natural products, such as terpenes, and remains a staple in laboratory protocols despite alternatives like the Lemieux–Johnson oxidation for milder conditions.^[1] Limitations include the explosiveness of ozonides and sensitivity to over-oxidation, necessitating controlled conditions.^[2]

Fundamentals

Definition and Scope

Ozonolysis is an organic reaction in which ozone (O₃), a reactive allotrope of oxygen, reacts with the carbon-carbon double or triple bonds in unsaturated compounds such as alkenes, alkynes, or other substrates containing multiple bonds, resulting in oxidative cleavage and the formation of carbonyl compounds including aldehydes, ketones, and carboxylic acids.^[7] This process targets the π-bonds of these unsaturated functional groups, assuming familiarity with basic organic structures like alkenes (C=C) and alkynes (C≡C) as the primary reactive sites.^[8] The scope of ozonolysis is broadest for alkenes, where it serves as a key method for cleaving the double bond to generate aldehydes or ketones from the corresponding carbon fragments, depending on the reaction conditions and workup procedure.^[9] A simplified general equation for alkene cleavage illustrates this transformation:

\mathrm{R_2C=CR_2 + O_3 \rightarrow \ intermediates \rightarrow R_2C=O + O=CR_2}

where \mathrm{R} represents alkyl or hydrogen substituents, and the intermediates lead to the final carbonyl products without specifying workup details here.^[7] This reaction is widely valued in synthetic organic chemistry for its ability to predictably convert alkenes into two distinct carbonyl moieties, facilitating the construction of complex molecules from simpler unsaturated precursors.^[10] Beyond alkenes, ozonolysis extends to alkynes, where the triple bond is cleaved to yield carboxylic acids, often via intermediate anhydrides that hydrolyze in the presence of water.^[11] It can also apply to other unsaturated substrates, such as allenes, under controlled conditions to produce carbonyl derivatives, though these applications are less common and typically require specific experimental setups. Aromatic compounds react with ozone but generally resist full cleavage, forming addition products or partial oxidation species only under harsh conditions, limiting their practical scope in standard ozonolysis protocols.^[8]

Historical Development

The discovery of ozone, the key reagent in ozonolysis, is credited to Christian Friedrich Schönbein in 1840, who identified it during experiments on the electrolysis of water by noting its distinctive odor resembling chlorine in damp air.^[13] Schönbein named the gas "ozone" from the Greek word ozein, meaning "to smell," and soon explored its reactivity with organic compounds. In 1845, he reported the first ozonolysis reaction, observing that ozone reacted with ethylene to form an unstable addition product that, upon treatment with water, yielded products including formaldehyde and formic acid.^[3] Practical advancements followed with the 1857 patent by Werner von Siemens for generating ozone via silent electric discharge between two electrodes separated by a dielectric, enabling more reliable production for chemical studies.^[14] The reaction was initially termed "ozonization" to describe the addition of ozone to unsaturated compounds. Between 1893 and 1900, Adolf von Baeyer and Victor Villiger conducted systematic investigations, demonstrating that ozonolysis cleaves alkene double bonds to produce carbonyl compounds such as aldehydes and ketones, establishing its utility for structural elucidation in organic chemistry.^[15] Baeyer, recognized for his broader contributions to organic synthesis including indigo dye, received nominations for the Nobel Prize in Chemistry, which he ultimately won in 1905 for work on hydroaromatic compounds. In the 1920s and 1930s, Carl Dietrich Harries advanced the field by isolating and characterizing stable ozonides as key intermediates, using improved ozone generation and low-temperature techniques to study polyenes and terpenes.^[13] This work clarified the role of 1,2,4-trioxolanes in the process. During the 1940s, Rudolf Criegee proposed a detailed mechanism involving initial [3+2] cycloaddition to form a primary ozonide (molozonide), followed by rearrangement to the secondary ozonide, providing a unifying framework for observed products.^[16] Post-1950s developments focused on workup variations to control product selectivity; Karl Griesbaum and collaborators introduced refined reductive procedures using reagents like triphenylphosphine, which efficiently cleave ozonides to aldehydes without overoxidation, enhancing ozonolysis as a synthetic tool.^[17] These innovations, building on earlier hydrolytic and oxidative methods, solidified ozonolysis's role in modern organic synthesis.

Reaction Mechanisms

Mechanism with Alkenes

The ozonolysis of alkenes follows the Criegee mechanism, a multi-step process initiated by the 1,3-dipolar cycloaddition of ozone (O₃) to the carbon-carbon double bond of the alkene. This concerted [3+2] cycloaddition forms the primary ozonide, or molozonide, a five-membered 1,2,3-trioxolane ring that incorporates the alkene's substituents and the ozone molecule.^[16] The reaction is stereospecific in this initial step, retaining the cis or trans geometry of the alkene in the molozonide structure due to the suprafacial nature of the cycloaddition.^[18] The molozonide is highly unstable and decomposes rapidly via cleavage of the peroxide O-O bond and the original C-C σ-bond, generating an aldehyde or ketone (carbonyl compound) and a carbonyl oxide intermediate, known as the Criegee zwitterion (R₂C=OO⁻ ↔ R₂C⁺-O-O⁻).^[19] This rearrangement step may proceed through a concerted pathway or involve a short-lived diradical intermediate, depending on the substituents and conditions, with computational studies favoring a zwitterionic character for the carbonyl oxide.^[16] The overall transformation can be represented as:

\ce{R2C=CR2 + O3 -> molozonide -> R2C=O + R2C=OO}

The stereochemistry is preserved in the carbonyl oxide relative to the original alkene geometry, with cis-alkenes preferentially forming anti-carbonyl oxides and trans-alkenes forming syn-carbonyl oxides, though bulky groups can influence conformer populations.^[18] The carbonyl oxide then reacts with the carbonyl compound in a second 1,3-dipolar cycloaddition to form the secondary ozonide, a more stable 1,2,4-trioxolane ring.^[19] This step is also stereospecific, leading to cis or trans ozonides that reflect the conformer of the carbonyl oxide, though experimental ratios often favor trans ozonides due to faster reaction of anti conformers.^[18] The process is depicted as:

\ce{R2C=OO + R2C=O -> ozonide}

Factors such as solvent and temperature significantly influence the mechanism. In protic solvents like methanol, the carbonyl oxide intermediate is stabilized by nucleophilic addition, forming an α-methoxyhydroperoxide that alters the reaction pathway and prevents further decomposition. Low temperatures (typically -78°C) are essential to control the highly exothermic reaction and mitigate explosion risks from peroxides and oxygen buildup.^[20]

Variations in Workup Procedures

After the formation of the ozonide intermediate from the reaction of ozone with an alkene, the workup procedure determines the final products by decomposing the ozonide while controlling the oxidation state of the resulting carbonyl compounds.^[21] These variations allow chemists to selectively obtain aldehydes, ketones, or carboxylic acids, depending on the synthetic goals.^[21] In reductive workup, the ozonide is treated with a reducing agent such as zinc in acetic acid (Zn/AcOH), dimethyl sulfide (DMS), or triphenylphosphine (PPh₃) to yield aldehydes from non-terminal alkenes and prevent over-oxidation to carboxylic acids.^[21] This approach is particularly useful for preserving sensitive aldehyde functionalities in complex molecules, such as during total synthesis where further oxidation must be avoided.^[21] The reaction with DMS, for example, proceeds as follows:

\text{Ozonide} + \text{[DMS](/page/DMS)} \rightarrow 2 \text{ RCHO} + \text{Me}_2\text{S=O}

where the sulfide is oxidized to the sulfoxide, driving the reduction of peroxide linkages in the ozonide.^[21] Oxidative workup employs oxidizing agents like hydrogen peroxide (H₂O₂) to convert any aldehydes formed into the corresponding carboxylic acids, while ketones remain unchanged.^[21] This method is favored when carboxylic acids are the desired products, especially from terminal alkenes that would otherwise yield formaldehyde.^[21] A representative transformation is:

\text{RCHO} + \text{H}_2\text{O}_2 \rightarrow \text{RCOOH} + \text{H}_2\text{O}

This step ensures complete cleavage and oxidation under mild conditions.^[21] Neutral workup involves simple hydrolysis, typically with water or aqueous solvents, to decompose the ozonide into aldehydes and ketones without additional redox agents, avoiding further oxidation or reduction.^[21] This procedure is suitable for substrates where the carbonyl products are stable and no transformation of aldehydes to acids is needed.^[21] The choice of workup is guided by the desired product profile and substrate sensitivity: reductive conditions are selected for aldehyde preservation in sensitive syntheses, oxidative for direct access to acids from terminal positions, and neutral for straightforward carbonyl isolation.^[21] Modern variants include catalytic and supported methods, such as polymer- or silica-bound reductants, which facilitate cleaner separations and scalable processes by immobilizing reagents and minimizing byproducts.^[21]

Substrates and Products

Ozonolysis of Alkenes

Ozonolysis of alkenes involves the oxidative cleavage of the carbon-carbon double bond, resulting in the formation of carbonyl compounds such as aldehydes or ketones, depending on the substitution pattern of the alkene. For symmetrical alkenes like trans-2-butene (CH₃CH=CHCH₃), the reaction yields a single dicarbonyl product, specifically two molecules of acetaldehyde (2 CH₃CHO). In contrast, unsymmetrical alkenes, such as 2-butene derivatives with different substituents (RCH=CHR'), produce a mixture of two distinct carbonyl compounds, RCHO and R'CHO, without any selectivity in the cleavage direction.^[1] The regioselectivity of ozonolysis shows no inherent preference for cleavage at one side of the double bond over the other, as the reaction proceeds through a symmetrical intermediate that fragments equally. For terminal alkenes (RCH=CH₂), the products are typically the substituted aldehyde RCHO and formaldehyde (HCHO), though formaldehyde may require careful isolation due to its volatility.^[1] Representative examples illustrate the versatility of this transformation. Cycloalkenes, such as cyclohexene, undergo ring-opening to yield dicarbonyl compounds like adipdialdehyde (O=CH(CH₂)₄CHO), a dialdehyde that serves as a key intermediate in synthesis. The reaction preserves the configuration of stereocenters in the alkene substituents, allowing for stereospecific product formation in chiral substrates.^[1] Standard conditions for ozonolysis of alkenes involve bubbling ozone (generated from O₂) through a solution of the substrate in dichloromethane (CH₂Cl₂) at -78°C to control reactivity and prevent side reactions, followed by a reductive workup with dimethyl sulfide (Me₂S) or triphenylphosphine (PPh₃) to liberate the carbonyl products. Limitations include the potential for over-oxidation of allylic alcohols, where the hydroxyl group can react preferentially with ozone, leading to epoxide or cleavage products instead of the desired carbonyls. Additionally, alkenes bearing electron-withdrawing groups adjacent to the double bond may exhibit reduced reactivity or altered product distributions due to stabilization of the ozonide intermediate.^[6]

Ozonolysis of Alkynes

Ozonolysis of alkynes proceeds via an initial [4+2] cycloaddition of ozone to the triple bond, forming an unstable trioxolene intermediate analogous to the molozonide in alkene ozonolysis, but with distinct rearrangement pathways due to the triple bond's higher electron density and bond strength. This intermediate decomposes through Criegee-type mechanisms involving carbonyl oxides and further ozone additions, often requiring excess ozone for complete cleavage. Unlike alkenes, the reaction is slower and typically more oxidative, yielding alpha-diketones under reductive conditions or carboxylic acids under oxidative workup, reflecting the triple bond's propensity for deeper oxidation.^[22] For internal alkynes (RC≡CR'), oxidative conditions lead to cleavage into two carboxylic acids (RCOOH and R'COOH), while partial ozonolysis or reductive workup can produce alpha-diketones (e.g., RC(O)C(O)R for symmetrical cases). A simplified oxidative equation is:

\ce{RC#CR' ->[O3][H2O/H2O2] RCO2H + R'CO2H}

^[23] Terminal alkynes (RC≡CH) yield RCOOH along with CO₂ and formic acid (HCOOH) under oxidative conditions, as the terminal carbon is further oxidized.^[22]^[24] The reaction is typically conducted with excess ozone in protic solvents like methanol or water at low temperatures (-70°C to room temperature), followed by workup; cleavage often requires heating or UV irradiation to promote decomposition of intermediates. For example, ozonolysis of phenylacetylene (PhC≡CH) in methanol followed by oxidative workup affords benzoic acid (PhCOOH) and formic acid. This method is applied in alkyne degradation for synthetic transformations, such as converting internal alkynes to dicarboxylic acids in natural product synthesis.^[22]

Reactions with Other Unsaturated Substrates

Ozonolysis of allenes, which feature cumulated double bonds, has been proposed to proceed via a single-electron transfer mechanism rather than the typical Criegee pathway observed with alkenes, leading to cleavage that yields multiple carbonyl products such as ketones and aldehydes. For instance, the ozonolysis of 1,2-butadiene under standard conditions produces acetone and formaldehyde as primary cleavage products, reflecting the fragmentation across the cumulated system. These reactions often occur in polar solvents like methanol or dichloromethane at low temperatures to control the reactivity of the intermediates. Aromatic compounds exhibit limited reactivity toward ozone due to the stability of the delocalized π-system, requiring harsh conditions such as elevated temperatures, high ozone concentrations, or UV irradiation to achieve ring cleavage. Benzene, for example, undergoes ozonolysis under these forcing conditions to form glyoxal upon reductive workup or mucic acid (galactaric acid) with oxidative treatment, highlighting the need for multiple ozone additions to disrupt the aromatic ring. Yields are generally low owing to competing side reactions, including polymerization or partial oxidation products. Alpha,β-unsaturated carbonyl compounds, such as enones, react with ozone primarily at the C=C double bond, but the conjugated system can lead to alternative pathways including potential conjugate addition of ozone or solvent participation.^[25] In protic solvents like methanol, these substrates yield a mixture of carboxylic acids, aldehydes, and esters as cleavage products, with the carbonyl group influencing the regioselectivity of the attack.^[25] Sulfides or amines may serve as co-reactants to trap reactive intermediates like carbonyl oxides, mitigating side reactions and improving product isolation in these systems.^[25] Overall, ozonolysis with these substrates is conducted in polar solvents to enhance solubility and intermediate stability, though lower yields are common due to side reactions such as over-oxidation or polymerization. Applications to heterocycles are not routine, as selectivity issues arise from competing reactions at heteroatoms or multiple unsaturated sites, often resulting in complex product mixtures.

Applications

Synthetic Applications

Ozonolysis plays a pivotal role in organic synthesis by enabling the oxidative cleavage of carbon-carbon double bonds, which is essential for retrosynthetic disconnections in the construction of complex molecules such as steroids and terpenes.^[26] This reaction transforms alkenes into carbonyl compounds, often aldehydes or ketones, providing a strategic entry point for subsequent functionalizations in total synthesis routes.^[13] Its utility stems from high regioselectivity, particularly with unsymmetrical alkenes, where the cleavage occurs predictably at the double bond without affecting other functional groups.^[26] Additionally, ozonolysis is compatible with many protecting groups, allowing it to be integrated into multi-step sequences without the need for deprotection-reprotection cycles in sensitive intermediates. Notable applications include the preparation of dialdehydes as precursors in prostaglandin analog syntheses, where ozonolysis of cyclohexene derivatives followed by reductive workup yields key building blocks for compounds like PGF_2α. Ozonolysis of cyclohexene has been investigated as a laboratory route to adipic acid, with a reported yield of 75% based on ozone absorbed.^[27] Historically, ozonolysis of β-carotene was used to elucidate the structure of retinal and related vitamin A components.^[28] In the total synthesis of taxol, ozonolysis facilitates the preparation of intermediates by cleaving allyl groups to aldehydes, as seen in the Nicolaou route where protection of an allyl alcohol followed by ozonolysis and DMS workup provided the desired aldehyde in approximately 80% yield. Recent developments since 2000 have focused on integrating ozonolysis with flow chemistry to enhance safety and scalability, enabling continuous processing for pharmaceuticals like ivacaftor while minimizing explosion risks from peroxides. Efforts toward enzymatic mimics, such as heme-based catalysts, aim to improve selectivity in alkene cleavage under milder conditions, offering bio-inspired alternatives for sustainable synthesis.^[29]

Analytical Applications

Ozonolysis serves as a valuable tool for structural elucidation in organic chemistry, particularly for identifying the position of carbon-carbon double bonds in alkenes through the analysis of cleavage products. Introduced by Carl D. Harries in the early 20th century, the method involves oxidative cleavage of unsaturated bonds to yield carbonyl compounds, whose identification reveals the original alkene structure. Harries' work in 1905 demonstrated this by applying ozonolysis to natural rubber, degrading it to levulinic acid and confirming the repeating isoprene units in its polymer chain. This approach was pivotal before spectroscopic methods became widespread, allowing chemists to map double bond locations in complex hydrocarbons via product isolation and characterization. In contemporary applications, ozonolysis is integrated with advanced analytical techniques to precisely locate double bonds in intricate molecules such as polymers and natural products. For instance, reductive ozonolysis followed by gas chromatography-mass spectrometry (GC-MS) enables the determination of double bond distribution in polyolefins by quantifying fragmented carbonyl species. Similarly, coupling ozonolysis with high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) spectroscopy facilitates alkene positioning in unsaturated lipids and terpenes from natural sources, where the cleavage products are separated and structurally verified. Online ozonolysis-HPLC-mass spectrometry systems allow direct analysis of double bond positions in lipid mixtures without prior isolation, enhancing efficiency for biological samples. Quantitatively, ozonolysis quantifies the degree of unsaturation in fats and oils by measuring ozone absorption, which corresponds to the number of reactive double bonds; this value correlates closely with the traditional iodine value used in quality control. The absorbed ozone, or formed ozonides, is assessed via iodometric titration, where ozonides react with potassium iodide in acidic medium to liberate iodine, which is then titrated with sodium thiosulfate using starch as indicator. This method provides a reliable measure of unsaturation levels, as demonstrated in studies on vegetable oils where ozone uptake tracked the decline in olefinic protons monitored by NMR. Representative examples include the confirmatory degradation of natural rubber to establish its isoprene-based structure, as originally performed by Harries, and the cleavage of alkene moieties in pesticides like pyrethroids for residue identification in environmental samples via subsequent MS analysis of fragments. However, ozonolysis is inherently destructive, consuming the sample and potentially complicating analysis if products are unstable or require pure substrates free from interfering functionalities.

Natural and Environmental Aspects

Biological Occurrence

Ozonolysis-like processes occur rarely in direct form within living organisms, but endogenous ozone generation has been identified as a component of immune responses and oxidative stress mechanisms. In mammalian systems, particularly in human neutrophils, ozone is produced through the action of myeloperoxidase (MPO), an enzyme that facilitates the oxidation of hydrogen peroxide and chloride ions to form hypochlorous acid, which can lead to ozone via reactions involving singlet oxygen intermediates. This ozone reacts with unsaturated lipids in bacterial membranes during antimicrobial activity, contributing to pathogen killing without relying on high external concentrations.^[30]^[31] In plants, exposure to environmental ozone induces stress responses involving the ozonolysis of alkenes in cell membrane lipids, primarily unsaturated fatty acids such as linoleic and linolenic acids. This process triggers lipid peroxidation, yielding reactive aldehydes like malondialdehyde and hexanal, which serve as signaling molecules to activate defense pathways, including the production of antioxidants and pathogenesis-related proteins. These peroxidation products help coordinate systemic acquired resistance against further oxidative damage.^[32] Within human lungs, endogenous ozone, generated at low levels through MPO activity in inflammatory cells or via singlet oxygen pathways, reacts with unsaturated fatty acids in the epithelial lining fluid to form Criegee-like intermediates. These intermediates contribute to inflammatory signaling, exacerbating conditions like asthma by promoting cytokine release and neutrophil recruitment, though they are rapidly scavenged by antioxidants such as ascorbic acid. The discovery of endogenous ozone in biological fluids dates to the early 2000s, with typical concentrations estimated in the nanomolar range (10–100 nM), far lower than those used in synthetic chemistry. Unlike synthetic ozonolysis, biological instances operate at these minimal levels and are tightly regulated by endogenous antioxidants to prevent widespread cellular damage.^[33]

Atmospheric Chemistry

Ozonolysis is a fundamental process in tropospheric chemistry, where ozone reacts with alkenes emitted from biogenic sources, such as isoprene and monoterpenes from vegetation, and anthropogenic sources, including ethene and other alkenes from vehicle exhaust and industrial activities. These reactions initiate the formation of secondary organic aerosols (SOA), which contribute to particulate matter that affects visibility, human health, and radiative balance. Biogenic volatile organic compounds (BVOCs) like α-pinene dominate in forested areas, while anthropogenic alkenes prevail in urban settings, with ozonolysis serving as a primary oxidation pathway under nighttime or low-NOx conditions.^[34]^[35] Central to these gas-phase reactions are Criegee intermediates, short-lived biradicals of the form R₂C=OO produced during the decomposition of the primary ozonide. These intermediates drive subsequent oxidation chains by reacting with trace gases like NO₂, SO₂, and water vapor, facilitating the production of hydroxyl radicals (OH) and other oxidants that propagate smog formation in polluted atmospheres. In low-NOx environments, stabilized Criegee intermediates enhance aerosol yields by forming low-volatility dimers and oligomers, amplifying the overall oxidative capacity of the troposphere.^[36]^[37] The environmental impacts of tropospheric ozonolysis include the generation of low-volatility products such as carboxylic acids, aldehydes, and peroxides, which condense to form SOA with lifetimes of days to weeks. Atmospheric models indicate that ozonolysis contributes a major fraction to global SOA budgets, with biogenic pathways alone accounting for a significant portion (often 50–90% depending on models) of aerosol mass in continental regions, influencing cloud formation and precipitation patterns. These aerosols exert a net cooling effect by scattering incoming solar radiation, potentially offsetting some greenhouse gas warming, though their precise climate forcing remains uncertain due to variability in emission sources and meteorology.^[38] Illustrative examples highlight ozonolysis's role in diverse settings. In urban air, the reaction of ozone with ethene produces formaldehyde (HCHO) and peroxy radicals, fueling photochemical cycles that elevate ground-level ozone levels and contribute to haze. In forested environments, ozonolysis of terpenes like β-pinene and limonene generates fine particles responsible for the characteristic blue haze over regions such as the Great Smoky Mountains, where BVOC emissions interact with regional ozone to scatter blue wavelengths of light.^[39]^[40] Recent studies from the 2020s have advanced understanding through quantum chemical calculations, refining rate constants and branching ratios for alkene ozonolysis under atmospheric pressures and temperatures. For instance, computational analyses of 19 alkenes have improved predictions of Criegee yields and product distributions, revealing temperature-dependent prereactive complexes that modulate reaction kinetics. These insights underscore ozonolysis's implications for climate, as enhanced SOA formation could amplify aerosol-induced cooling, though rising temperatures may alter emission rates and oxidation efficiencies.^[41]^[42]

Safety and Practical Considerations

Hazards of Ozone and Byproducts

Ozone (O₃) is a highly reactive strong oxidant that poses significant health risks primarily through inhalation, as it readily damages lung tissues and mucous membranes upon exposure.^[43] In laboratory and industrial settings involving ozonolysis, the Occupational Safety and Health Administration (OSHA) establishes a permissible exposure limit of 0.1 parts per million (ppm) as an 8-hour time-weighted average to prevent acute irritation of the respiratory tract, which can manifest as coughing, throat dryness, and chest pain.^[44] Higher concentrations, such as 5-10 ppm, can lead to severe symptoms including pulmonary edema—a potentially life-threatening accumulation of fluid in the lungs—within hours of exposure.^[45] Additionally, ozone irritates the eyes and skin, causing redness, discomfort, and potential inflammation even at lower levels.^[46] Chronic exposure to ozone at sub-acute levels contributes to oxidative stress in the lungs, exacerbating conditions like asthma, bronchitis, and chronic obstructive pulmonary disease (COPD) by promoting inflammation and reducing lung function over time.^[47] In the context of ozonolysis, byproducts such as aldehydes—particularly formaldehyde from the cleavage of terminal alkenes—introduce further hazards, as formaldehyde is classified as a human carcinogen associated with nasopharyngeal cancer and leukemia following prolonged occupational exposure.^[48]^[1] Ozonides, the initial unstable intermediates formed during the reaction, are especially dangerous if isolated or concentrated, as they can decompose explosively due to their peroxide-like structure, leading to shock-sensitive detonations in laboratory incidents.^[49] Ozone's extreme reactivity with organic materials heightens fire and explosion risks, as it can initiate vigorous oxidation reactions with solvents, reducing agents, or unsaturated compounds, potentially resulting in spontaneous combustion or blasts.^[50] Environmentally, unintended releases of ozone from ozonolysis processes contribute to local tropospheric pollution, where it acts as a phytotoxin damaging vegetation and ecosystems by disrupting photosynthesis and plant growth, while also posing indirect health risks through elevated ground-level ozone concentrations.^[51]

Laboratory and Industrial Protocols

In laboratory settings, ozonolysis is typically conducted as a batch process using an ozone generator to produce O₃ from O₂ via electrical discharge, with the gas bubbled through the alkene substrate dissolved in a solvent such as dichloromethane or a dichloromethane-methanol mixture at low temperatures ranging from -78°C to 0°C to control the exothermic reaction and minimize side products.^[52]^[53] The reaction progress is monitored by the disappearance of the alkene (e.g., via TLC) or the appearance of a blue color from the methanol-ozone complex, ensuring complete consumption to avoid unreacted ozone hazards.^[52] Safety protocols emphasize conducting the reaction in a well-ventilated fume hood with ozone scrubbers, as O₃ is toxic (exposure limit 0.1 ppm) and can form explosive peroxides; excess ozone is purged with O₂ post-reaction.^[53]^[54] Workup procedures vary based on desired products: reductive workups using dimethyl sulfide (DMS) or triphenylphosphine (PPh₃) at room temperature yield aldehydes or ketones by decomposing the ozonide intermediate, often achieving 70-80% yields; for example, in the ozonolysis of methyl vinyl ketone derivative to 2,5-heptanedione, DMS addition followed by stirring overnight and distillation provides 73% yield.^[55]^[53] Oxidative workups with hydrogen peroxide or performic acid convert aldehydes to carboxylic acids, as seen in the cleavage of oct-1-ene to nonanal and pelargonic acid derivatives, involving zinc dust reduction in acetic acid and steam distillation for isolation.^[54] Recent innovations include integrated batch-flow systems using DIY syringe pumps for sequential ozonolysis, Pinnick oxidation (with NaClO₂), and reductive quench (with NaHSO₃), enabling safe handling of renewables like palmitoleic acid to azelaic acid in 80% yield at 5°C with a throughput of 18 g/h.^[56] Industrial protocols address scalability challenges of batch ozonolysis, such as peroxide accumulation and explosion risks, by adopting continuous flow microreactors that enhance mass transfer and limit reactive volumes to grams, allowing safe operation under pressure.^[57] For instance, the ozonolysis of β-pinene to myrtanal employs a pressurized flow system with an ozone dosing line, achieving >16 g/h productivity while mitigating hazards through inherent safety design and risk assessments.^[57] Microstructured reactors, often 3D-printed with integrated calorimetry, facilitate rapid reactions (e.g., cyclohexene to hexanedial in 1.7 s at 0°C with 94% yield) and high space-time yields up to 1.84 kg L⁻¹ h⁻¹, as demonstrated for thioanisole oxidation.^[58] Large-scale implementations, such as Lonza's ton-scale process, integrate feasibility studies and hazard evaluations to transfer lab methods to production reactors, reducing by-products and reaction times compared to traditional oxidations.^[59] These flow-based approaches prioritize sustainability, with off-gas treatment to capture unreacted ozone, ensuring compliance with environmental regulations.^[58]

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Historic ozone discharge tube of W. Siemens, 1857 (Ref. 1, nat ̈ rl ...
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The History of Ozone. Part III - Rubin - 2003 - Wiley Online Library
Apr 29, 2003 · The introduction of ozone into organic chemistry is due to the work of C. D. Harries, first in Berlin but mainly in Kiel, during the period ...
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Mechanism of Ozonolysis - Criegee - 1975 - Wiley Online Library
The formation of ozonides (1,2,4-trioxolanes) from alkenes and ozone can be described as a succession of three [2+3] cycloadditions or cycloreversions ...
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Three decades of selective product formation via Griesbaum co ...
The Griesbaum co-ozonolysis reaction was first described by Karl Griesbaum and his collaborators in the mid-1990s. Their pioneering work laid the foundation ...Missing: history Harries Criegee
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https://pubs.rsc.org/en/content/articlelanding/2025/ra/d5ra05620a
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Gas-Phase Ozonolysis of Alkenes. Recent Advances in Mechanistic ...
Insights into the Reaction Mechanism of Criegee Intermediate CH2OO with Methane and Implications for the Formation of Methanol. ... Experimental and theoretical ...Missing: seminal | Show results with:seminal
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Risk Assessment and Safety Evaluation Study for Ozonolysis of β ...
However, ozonolysis is known to be a very dangerous reaction which may cause explosions. Recently, microreactor systems have been used for kilogram-scale ...
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https://pubs.acs.org/doi/10.1021/op100065d
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https://doi.org/10.1016/j.tet.2017.03.039
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https://doi.org/10.24820/ark.5550190.p011.942
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https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_%28Organic_Chemistry%29/Alkynes/Properties_of_Alkynes/Ozonolysis_of_Alkynes
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https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Organic_Chemistry_(Morsch_et_al.)/09%3A_Alkynes_-_An_Introduction_to_Organic_Synthesis/9.06%3A_Oxidative_Cleavage_of_Alkynes
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Adipic Acid by Ozonolysis of Cyclohexene - ACS Publications
Adipic Acid by Ozonolysis of Cyclohexene. Click to copy article link ... The synthesis of carboxylic acids and esters and their derivatives. 1991, 1 ...Missing: precursors | Show results with:precursors
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75 Years of Vitamin A Production: A Historical and Scientific ...
Aug 14, 2023 · ... ozonolysis of β-carotene was the key experiment to fully understand the structure of vitamin A (retinol). The final proof of the structure ...Development of the First... · β-Ionone Synthesis · Recent Entrants into Vitamin A...
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Alkene Cleavage Catalysed by Heme and Nonheme Enzymes
Ozonolysis is the most employed chemical method for cleaving alkenes since it is considered the most efficient and cleanest. However, the ozonolysis requires ...Missing: mimics | Show results with:mimics
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Endogenous Generation of Singlet Oxygen and Ozone in Human ...
Neutrophils employ myeloperoxidase to oxidize nearly all amino acids ... ozone in biological systems. Thus, the current evidence for endogenous ozone ...
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Can systemic parenteral ozone therapy generate biological ozone ...
In this article, the proposal of a hypothesis on the production of endogenous ozone from the application of ozone therapy has been presented. This is taking ...
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The ozonation of unsaturated fatty acids: aldehydes and hydrogen ...
The ozonation of unsaturated fatty acids: aldehydes and hydrogen peroxide as products and possible mediators of ozone toxicity
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Lipid Peroxide-Derived Reactive Carbonyl Species as Mediators of ...
A novel aldose/aldehyde reductase protects transgenic plants against lipid peroxidation under chemical and drought stresses. Plant J. 24, 437–446. doi ...
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Lung macrophages: current understanding of their roles in Ozone ...
Through the Criegee reaction, ozonation of unsaturated fatty acids yields aldehydes, such as hexanal, nonanal, heptanal, and carbonyl oxide. These aldehydes ...
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Influence of ambient and endogenous H 2 O 2 on reactive oxygen ...
May 1, 2023 · We show that H 2 O 2 concentrations in the ELF may be primarily determined by the release of endogenous H 2 O 2 and the inhalation of ambient gas-phase H 2 O 2.1. Introduction · 2. Methods · 4. Conclusions
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Contrasting impacts of humidity on the ozonolysis of monoterpenes
Sep 29, 2023 · Secondary organic aerosol (SOA) formed from the ozonolysis of biogenic monoterpenes is a major source of atmospheric organic aerosol.Missing: anthropogenic | Show results with:anthropogenic
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Secondary Organic Aerosol Formation from Aromatic Alkene ...
The influence of the precursor chemical structure on secondary organic aerosol (SOA) formation was investigated through the study of the ozonolysis of two ...
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Atmospheric Chemistry of Criegee Intermediates: Unimolecular ...
Criegee intermediates are produced in the ozonolysis of unsaturated hydrocarbons in the troposphere, and understanding their fate is a prerequisite to ...
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Quantification of the role of stabilized Criegee intermediates ... - ACP
Jan 20, 2021 · This study quantitatively investigates the performance of SCIs in SOA formation at different relative humidity (RH) levels.
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Real-Time Identification of Aerosol-Phase Carboxylic Acid ...
May 8, 2024 · This study presents a method for determining the presence of carboxylic acid functional groups in real time using extractive electrospray ionization mass ...
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Aerosols and their Relation to Global Climate and Climate Sensitivity
Aerosols that mainly scatter solar radiation have a cooling effect, by enhancing the total reflected solar radiation from the Earth. Strongly absorbing aerosols ...
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Production of the radicals in the ozonolysis of ethene
The ozonolysis of ethene was investigated in a reaction chamber by in situ analysis of stable species by FTIR and of total peroxy radicals PO2 (PO2 = HO2 + RO2) ...
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Formation of nanoparticles of blue haze enhanced by anthropogenic ...
Forests emit an enormous amount of nonmethane hydrocarbons, such as monoterpenes that have a global emission rate on the order of 1014 g yr−1 (1). The α- and β- ...
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[PDF] Tropospheric alkene ozonolysis chemistry
This systematic computational chemistry analysis produces the rate constants and product branching ratios for the ozonolysis of nineteen different alkenes,.
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Atmospheric Temperature Dependence of β-Caryophyllene ...
Oct 27, 2025 · Atmospheric Temperature Dependence of β-Caryophyllene Ozonolysis Kinetics Is Governed by Stabilized Prereactive Complexes. October 2025; The ...
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Ozone Generators that are Sold as Air Cleaners | US EPA
How is Ozone Harmful? The same chemical properties that allow high concentrations of ozone to react with organic material outside the body give it the ability ...
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[PDF] Ozone - NJ.gov
OSHA: The legal airborne permissible exposure limit. (PEL) is 0.1 ppm averaged over an 8-hour workshift. NIOSH: The recommended airborne exposure limit is. 0.1 ...
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Ozone - IDLH | NIOSH - CDC
It has been reported that on the basis of animal data, exposure at 50 ppm for 60 minutes will probably be fatal to humans [King 1963]. Revised IDLH: 5 ppmBasis ...
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Ozone (O3): Evaluating Health Impacts and Safety Measures
Aug 16, 2024 · Eye and Skin Irritation: Ozone exposure can also irritate the eyes, causing redness and discomfort. While skin contact is less common, it ...
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Health effects of ozone - Review of evidence on health ... - NCBI - NIH
The results suggest that long-term exposure to ozone is associated with uncontrolled asthma in adults, defined by symptoms, exacerbations and lung function.
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Formaldehyde and Cancer Risk
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Explosion properties of highly concentrated ozone gas - ScienceDirect
Ozone at more than 10–11 vol% will lead to an explosive chain decomposition reaction leading to its complete conversion to oxygen in a vessel.
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Ozone Limits, Exposure & Material Safety Data Sheet
Toxicity is dependent on concentration and length of exposure. An exposure of less than 0.2 mg.m-3 can be tolerated indefinitely, 2 mg.m-3 (1 ppm) can be ...
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Health & Environmental Effects of Ozone
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[PDF] ozone experiment_1
Sep 21, 2023 · Experimental Guidelines for the Ozonolysis Reaction: Ozone is typically generated from molecular oxygen by electrical discharge--you may ...
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[PDF] Alkene ozonolysis in the academic lab - UNL Digital Commons
Aug 1, 2018 · Ozone reacts with most alkenes to form ... synthesis of esters and lactones that complements the Baeyer-Villiger oxidation of ketones”.
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[PDF] Experiment 6 Ozonolysis of an Alkene
The identities and yields of carbonyl products provide information on the positions of the double bonds in the alkene. Hence ozonolysis is frequently used ...
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Organic Syntheses Procedure
Dimethyl sulfide is added as a safety precaution, to reduce any highly oxidized and potentially dangerous by-products that might have formed during ozonolysis.
[58]
Laboratory Ozonolysis Using an Integrated Batch–DIY Flow System ...
Apr 25, 2022 · ... ozone─was discovered in the mid-18th century by Christian Friedrich Schönbein. Ozonolysis can provide an alternative to heavy metal ...
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Scale-Up of Ozonolysis using Inherently Safer Technology in Continuous Flow under Pressure: Case Study on β-Pinene
### Summary of Industrial Scale-Up Protocol for Ozonolysis of β-Pinene
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Process intensification of ozonolysis reactions using dedicated ...
Aug 18, 2021 · In this article, the development of ozonolysis reactions within a dedicated microreactor platform suitable for gas–liquid transformations is described.Missing: industrial protocols
[61]
Mastering ozonolysis: production from laboratory to ton scale in ...
In most cases, ozonolysis is more sustainable and costeffective for the oxidative treatment of organic unsaturatedcompounds than other oxidation technologies.