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Ozonolysis
Ozonolysis
Ozonolysis
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Ozonolysis
Reaction type Organic redox reaction
Identifiers
Organic Chemistry Portal ozonolysis-criegee-mechanism

In organic chemistry, ozonolysis is an organic reaction where the unsaturated bonds are cleaved with ozone (O3). Multiple carbon–carbon bond are replaced by carbonyl (C=O) groups, such as aldehydes, ketones, and carboxylic acids. The reaction is predominantly applied to alkenes, but alkynes and azo compounds are also susceptible to cleavage. The outcome of the reaction depends on the type of multiple bond being oxidized and the work-up conditions.[1]

Detailed procedures have been reported.[2][3][4]

Ozonolysis of alkenes

[edit]
Alkene Ozonolysis
Reaction type Organic redox reaction
Reaction
Alkene
+
O3
+
Typically reducing agents
↓
Cleavage products
Identifiers
Organic Chemistry Portal ozonolysis-criegee-mechanism
RSC ontology ID RXNO:0000344

Alkenes can be oxidized with ozone to form alcohols, aldehydes or ketones, or carboxylic acids. In a typical procedure, ozone is bubbled through a solution of the alkene in methanol at −78 °C (−108 °F; 195 K) until the solution takes on a characteristic blue color, which is due to unreacted ozone. Industry however recommends temperatures near −20 °C (−4 °F; 253 K).[5] This color change indicates complete consumption of the alkene. Alternatively, various other reagents can be used as indicators of this endpoint by detecting the presence of ozone. If ozonolysis is performed by introducing a stream of ozone-enriched oxygen through the reaction mixture, the effluent gas can be directed through a potassium iodide solution. When the solution has stopped absorbing ozone, the excess ozone oxidizes the iodide to iodine, which can easily be observed by its violet color.[6] For closer control of the reaction itself, an indicator such as Sudan Red III can be added to the reaction mixture. Ozone reacts with this indicator more slowly than with the intended ozonolysis target. The ozonolysis of the indicator, which causes a noticeable color change, only occurs once the desired target has been consumed. If the substrate has two alkenes that react with ozone at different rates, one can choose an indicator whose own oxidation rate is intermediate between them, and therefore stop the reaction when only the most susceptible alkene in the substrate has reacted.[7] Otherwise, the presence of unreacted ozone in solution (seeing its blue color) or in the bubbles (via iodide detection) only indicates when all alkenes have reacted.

After completing the addition, a reagent is then added to convert the intermediate ozonide to a carbonyl derivative. Reductive work-up conditions are far more commonly used than oxidative conditions.

The use of triphenylphosphine, thiourea, zinc dust, or dimethyl sulfide produces aldehydes or ketones. While the use of sodium borohydride produces alcohols. (R group can also be hydrogens)

The use of hydrogen peroxide can produce carboxylic acids.

Amine N-oxides produce aldehydes directly.[8] Other functional groups, such as benzyl ethers, can also be oxidized by ozone. It has been proposed that small amounts of acid may be generated during the reaction from oxidation of the solvent, so pyridine is sometimes used to buffer the reaction. Dichloromethane is often used as a 1:1 cosolvent to facilitate timely cleavage of the ozonide. Azelaic acid and pelargonic acids are produced from ozonolysis of oleic acid on an industrial scale.

An example is the ozonolysis of eugenol converting the terminal alkene to an aldehyde:[9]

Eugenol ozonolysis

By controlling the reaction/workup conditions, unsymmetrical products can be generated from symmetrical alkenes:[10]

Reaction mechanism

[edit]
Carbonyl oxide (Criegee zwitterion)

In the generally accepted mechanism proposed by Rudolf Criegee in 1953,[11][12][13] the alkene and ozone form an intermediate molozonide in a 1,3-dipolar cycloaddition. Next, the molozonide reverts to its corresponding carbonyl oxide (also called the Criegee intermediate or Criegee zwitterion) and aldehyde or ketone (3) in a retro-1,3-dipolar cycloaddition. The oxide and aldehyde or ketone react again in a 1,3-dipolar cycloaddition, producing a relatively stable ozonide intermediate, known as a trioxolane (4).

The reaction mechanism of ozonolysis.
The reaction mechanism of ozonolysis.

Evidence for this mechanism is found in isotopic labeling. When 17O-labelled benzaldehyde reacts with carbonyl oxides, the label ends up exclusively in the ether linkage of the ozonide.[14] There is still dispute over whether the molozonide collapses via a concerted or radical process; this may also exhibit a substrate dependence.

History

[edit]

Christian Friedrich Schönbein, who discovered ozone in 1840, also did the first ozonolysis: in 1845, he reported that ethylene reacts with ozone – after the reaction, neither the smell of ozone nor the smell of ethylene was perceivable.[15] The ozonolysis of alkenes is sometimes referred to as "Harries ozonolysis", because some attribute this reaction to Carl Dietrich Harries.[16] Before the advent of modern spectroscopic techniques, the ozonolysis was an important method for determining the structure of organic molecules. Chemists would ozonize an unknown alkene to yield smaller and more readily identifiable fragments.

Ozonolysis of alkynes

[edit]

Ozonolysis of alkynes generally gives an acid anhydride or diketone product,[17] not complete fragmentation as for alkenes. A reducing agent is not needed for these reactions. The mechanism is unknown.[18] If the reaction is performed in the presence of water, the anhydride hydrolyzes to give two carboxylic acids.

Other substrates

[edit]

Although rarely examined, azo compounds (N=N) are susceptible to ozonolysis. Nitrosamines (N−N=O) are produced.[19]

Applications

[edit]

The main use of ozonolysis is for the conversion of unsaturated fatty acids to value-added derivatives. Ozonolysis of oleic acid is an important route to azelaic acid. The coproduct is nonanoic acid:[20]

CH3(CH2)7CH=CH(CH2)7CO2H} + 4 O3 → HO2C(CH2)7CO2H} + CH3(CH2)7CO2H

Erucic acid is a precursor to brassylic acid, a C13-dicarboxylic acid that is used to make specialty polyamides and polyesters. The conversion entails ozonolysis, which selectively cleaves the C=C bond in erucic acid:[21]

CH3(CH2)7CH=CH(CH2)11CO2H + O3 + 0.5 O2 → CH3(CH2)7CO2H + HO2C(CH2)11CO2H

A number of drugs and their intermediates have been produced by ozonolysis.[22] The use of ozone in the pharmaceutical industry is difficult to discern owing to confidentiality considerations.[5]

Ozonolysis as an analytical method

[edit]
Ozone cracking in natural rubber tubing

Ozonolysis has been used to characterize the structure of some polyolefins. Early experiments showed that the repeat unit in natural rubber was shown to be isoprene.

Occurrence

[edit]

Ozonolysis can be a serious problem, known as ozone cracking where traces of the gas in an atmosphere degrade elastomers, such as natural rubber, polybutadiene, styrene-butadiene, and nitrile rubber. Ozonolysis produces surface ketone groups that can cause further gradual degradation via Norrish reactions if the polymer is exposed to light. To minimize this problem, many polyolefin-based products are treated with antiozonants.

Ozone cracking is a form of stress corrosion cracking where active chemical species attack products of a susceptible material. The rubber product must be under tension for crack growth to occur. Ozone cracking was once commonly seen in the sidewalls of tires, where it could expand to cause a dangerous blowout, but is now rare owing to the use of modern antiozonants. Other means of prevention include replacing susceptible rubbers with resistant elastomers such as polychloroprene, EPDM or Viton.

Safety

[edit]

The use of ozone in the pharmaceutical industry is limited by safety considerations.[5]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Ozonolysis

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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. 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. It serves as a powerful tool for both structural elucidation of unsaturated compounds and the preparation of specific carbonyl functionalities from alkenes. The history of ozonolysis traces back to the mid-19th century, when Christian Friedrich Schönbein, the discoverer of in 1840, first observed its reaction with in 1845, noting the production of aldehydes and without complete mineralization to . In the early , German 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 and rubber. The modern understanding of the was advanced by Rudolf Criegee in the 1940s and 1950s, who proposed the involvement of a carbonyl zwitterion intermediate, later summarized in his influential 1975 review. The mechanism of ozonolysis begins with a 1,3-dipolar between and the , forming an initial molozonide (a 1,2,3-trioxolane), which rapidly rearranges via cleavage into a carbonyl compound and a Criegee intermediate (a carbonyl ). This intermediate then undergoes another with the carbonyl to yield the more stable ozonide (a 1,2,4-trioxolane). Ozonides are explosive and must be handled carefully; they are not isolated but decomposed in the step. Workup procedures determine the final products: reductive workup with reagents like (DMS), zinc in acetic , or yields aldehydes or ketones by preserving aldehydic C-H bonds, while oxidative workup with converts aldehydes to carboxylic acids. For example, ozonolysis of under reductive conditions produces adipic dialdehyde (hexanedial), whereas oxidative conditions give . The reaction's follows the pattern where each carbon of the original becomes a , with terminal =CH₂ groups yielding and =CHR groups yielding aldehydes or acids. Ozonolysis finds broad applications in synthetic for constructing complex molecules by breaking down cyclic alkenes into acyclic dicarbonyls, as well as in degradative to determine the position of double bonds in unknown alkenes. It has been instrumental in elucidating the structures of natural products, such as , and remains a staple in protocols despite alternatives like the Lemieux–Johnson oxidation for milder conditions. Limitations include the explosiveness of ozonides and sensitivity to over-oxidation, necessitating controlled conditions.

Fundamentals

Definition and Scope

Ozonolysis is an in which (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. 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. The scope of ozonolysis is broadest for alkenes, where it serves as a key method for cleaving the to generate aldehydes or ketones from the corresponding carbon fragments, depending on the reaction conditions and procedure. A simplified general equation for cleavage illustrates this transformation: R2C=CR2+O3→ intermediates→R2C=O+O=CR2\mathrm{R_2C=CR_2 + O_3 \rightarrow \ intermediates \rightarrow R_2C=O + O=CR_2} where R\mathrm{R} represents alkyl or substituents, and the intermediates lead to the final carbonyl products without specifying details here. This reaction is widely valued in synthetic for its ability to predictably convert alkenes into two distinct carbonyl moieties, facilitating the construction of complex molecules from simpler unsaturated precursors. Beyond alkenes, ozonolysis extends to alkynes, where the is cleaved to yield carboxylic acids, often via intermediate anhydrides that hydrolyze in the presence of . It can also apply to other unsaturated substrates, such as , under controlled conditions to produce carbonyl derivatives, though these applications are less common and typically require specific experimental setups. Aromatic compounds react with but generally resist full cleavage, forming addition products or only under harsh conditions, limiting their practical scope in standard ozonolysis protocols.

Historical Development

The discovery of , the key reagent in ozonolysis, is credited to Christian Friedrich Schönbein in 1840, who identified it during experiments on the by noting its distinctive odor resembling in damp air. Schönbein named the gas "" 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 reacted with to form an unstable addition product that, upon treatment with water, yielded products including and . Practical advancements followed with the 1857 patent by for generating via silent electric discharge between two electrodes separated by a , enabling more reliable production for chemical studies. The reaction was initially termed "ozonization" to describe the addition of to unsaturated compounds. Between 1893 and 1900, and Victor Villiger conducted systematic investigations, demonstrating that ozonolysis cleaves double bonds to produce carbonyl compounds such as aldehydes and ketones, establishing its utility for structural elucidation in . Baeyer, recognized for his broader contributions to including , received nominations for the , 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 generation and low-temperature techniques to study polyenes and . This work clarified the role of 1,2,4-trioxolanes in the process. During the , Rudolf Criegee proposed a detailed mechanism involving initial [3+2] to form a primary ozonide (molozonide), followed by rearrangement to the secondary ozonide, providing a unifying framework for observed products. Post-1950s developments focused on workup variations to control product selectivity; Karl Griesbaum and collaborators introduced refined reductive procedures using reagents like , which efficiently cleave ozonides to aldehydes without overoxidation, enhancing ozonolysis as a synthetic tool. These innovations, building on earlier hydrolytic and oxidative methods, solidified ozonolysis's role in modern .

Reaction Mechanisms

Mechanism with Alkenes

The ozonolysis of alkenes follows the Criegee mechanism, a multi-step process initiated by the 1,3-dipolar of (O₃) to the carbon-carbon of the . 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 molecule. The reaction is stereospecific in this initial step, retaining the cis or trans geometry of the in the molozonide structure due to the suprafacial nature of the . 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 or (carbonyl compound) and a carbonyl intermediate, known as the Criegee (R₂C=OO⁻ ↔ R₂C⁺-O-O⁻). This rearrangement step may proceed through a concerted pathway or involve a short-lived intermediate, depending on the substituents and conditions, with computational studies favoring a zwitterionic character for the carbonyl . The overall transformation can be represented as: \ceR2C=CR2+O3−>molozonide−>R2C=O+R2C=OO\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. 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. 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. The process is depicted as: \ceR2C=OO+R2C=O−>ozonide\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.

Variations in Workup Procedures

After the formation of the ozonide intermediate from the reaction of with an , the procedure determines the final products by decomposing the ozonide while controlling the of the resulting carbonyl compounds. These variations allow chemists to selectively obtain , , or carboxylic acids, depending on the synthetic goals. In reductive , the ozonide is treated with a such as in acetic acid (Zn/AcOH), (DMS), or (PPh₃) to yield from non-terminal alkenes and prevent over-oxidation to carboxylic acids. This approach is particularly useful for preserving sensitive aldehyde functionalities in complex molecules, such as during where further oxidation must be avoided. The reaction with DMS, for example, proceeds as follows: Ozonide+DMS→2 RCHO+Me2S=O\text{Ozonide} + \text{DMS} \rightarrow 2 \text{ RCHO} + \text{Me}_2\text{S=O} where the sulfide is oxidized to the , driving the reduction of peroxide linkages in the ozonide. Oxidative workup employs oxidizing agents like (H₂O₂) to convert any aldehydes formed into the corresponding carboxylic acids, while ketones remain unchanged. This method is favored when carboxylic acids are the desired products, especially from terminal alkenes that would otherwise yield . A representative transformation is: RCHO+H2O2→RCOOH+H2O\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. Neutral workup involves simple , typically with water or aqueous solvents, to decompose the ozonide into aldehydes and ketones without additional agents, avoiding further oxidation or reduction. This procedure is suitable for substrates where the carbonyl products are stable and no transformation of aldehydes to acids is needed. 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. 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.

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. The of ozonolysis shows no inherent preference for cleavage at one side of the 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 RCHO and (HCHO), though may require careful isolation due to its volatility. Representative examples illustrate the versatility of this transformation. Cycloalkenes, such as , 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. Standard conditions for ozonolysis of alkenes involve bubbling (generated from O₂) through a solution of the substrate in (CH₂Cl₂) at -78°C to control reactivity and prevent side reactions, followed by a reductive with (Me₂S) or (PPh₃) to liberate the carbonyl products. Limitations include the potential for over-oxidation of allylic alcohols, where the hydroxyl group can react preferentially with , leading to or cleavage products instead of the desired carbonyls. Additionally, alkenes bearing electron-withdrawing groups adjacent to the may exhibit reduced reactivity or altered product distributions due to stabilization of the ozonide intermediate.

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. 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 is: \ce{RC#CR' ->[O3][H2O/H2O2] RCO2H + R'CO2H} Terminal alkynes (RC≡CH) yield RCOOH along with CO₂ and (HCOOH) under oxidative conditions, as the terminal carbon is further oxidized. The reaction is typically conducted with excess in protic solvents like or at low temperatures (-70°C to ), followed by ; cleavage often requires heating or UV irradiation to promote decomposition of intermediates. For example, ozonolysis of (PhC≡CH) in followed by oxidative affords (PhCOOH) and . This method is applied in alkyne degradation for synthetic transformations, such as converting internal s to dicarboxylic acids in synthesis.

Reactions with Other Unsaturated Substrates

Ozonolysis of , 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 as primary cleavage products, reflecting the fragmentation across the cumulated system. These reactions often occur in polar solvents like or at low temperatures to control the reactivity of the intermediates. Aromatic compounds exhibit limited reactivity toward due to the stability of the delocalized π-system, requiring harsh conditions such as elevated temperatures, high concentrations, or UV irradiation to achieve ring cleavage. , for example, undergoes ozonolysis under these forcing conditions to form upon reductive workup or (galactaric acid) with oxidative treatment, highlighting the need for multiple additions to disrupt the aromatic ring. Yields are generally low owing to competing side reactions, including or products. Alpha,β-unsaturated carbonyl compounds, such as enones, react with primarily at the C=C double bond, but the can lead to alternative pathways including potential conjugate addition of or participation. In protic s like , these substrates yield a of carboxylic acids, aldehydes, and esters as cleavage products, with the influencing the of the attack. 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. Overall, ozonolysis with these substrates is conducted in polar solvents to enhance and intermediate stability, though lower yields are common due to side reactions such as over-oxidation or . 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. This reaction transforms alkenes into carbonyl compounds, often aldehydes or ketones, providing a strategic entry point for subsequent functionalizations in total synthesis routes. Its utility stems from high regioselectivity, particularly with unsymmetrical alkenes, where the cleavage occurs predictably at the double bond without affecting other functional groups. 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 analog syntheses, where ozonolysis of derivatives followed by reductive workup yields key building blocks for compounds like PGF2α. Ozonolysis of has been investigated as a laboratory route to , with a reported yield of 75% based on absorbed. Historically, ozonolysis of was used to elucidate the structure of and related components. In the of taxol, ozonolysis facilitates the preparation of intermediates by cleaving allyl groups to s, as seen in the Nicolaou route where protection of an followed by ozonolysis and DMS workup provided the desired 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 while minimizing explosion risks from peroxides. Efforts toward enzymatic mimics, such as heme-based catalysts, aim to improve selectivity in cleavage under milder conditions, offering bio-inspired alternatives for sustainable synthesis.

Analytical Applications

Ozonolysis serves as a valuable tool for structural elucidation in , particularly for identifying the position of carbon-carbon s in s through the of cleavage products. Introduced by Carl D. Harries in the early , the method involves oxidative cleavage of unsaturated bonds to yield carbonyl compounds, whose identification reveals the original structure. Harries' work in 1905 demonstrated this by applying ozonolysis to , degrading it to and confirming the repeating units in its polymer chain. This approach was pivotal before spectroscopic methods became widespread, allowing chemists to map locations in complex hydrocarbons via product isolation and . 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 in fats and oils by measuring absorption, which corresponds to the number of reactive double bonds; this value correlates closely with the traditional used in . The absorbed , or formed ozonides, is assessed via , where ozonides react with in acidic medium to liberate iodine, which is then titrated with using as indicator. This method provides a reliable measure of unsaturation levels, as demonstrated in studies on vegetable oils where uptake tracked the decline in olefinic protons monitored by NMR. Representative examples include the confirmatory degradation of to establish its isoprene-based structure, as originally performed by Harries, and the cleavage of 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 generation has been identified as a component of immune responses and mechanisms. In mammalian systems, particularly in human neutrophils, is produced through the action of (MPO), an enzyme that facilitates the oxidation of and chloride ions to form , which can lead to via reactions involving intermediates. This reacts with unsaturated in bacterial membranes during activity, contributing to killing without relying on high external concentrations. In , exposure to environmental induces stress responses involving the ozonolysis of alkenes in lipids, primarily unsaturated fatty acids such as linoleic and linolenic acids. This process triggers , yielding reactive aldehydes like 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 against further oxidative damage. Within human lungs, endogenous , generated at low levels through MPO activity in inflammatory cells or via 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 by promoting release and recruitment, though they are rapidly scavenged by antioxidants such as ascorbic acid. The discovery of endogenous ozone in biological fluids dates to the early , 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.

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. 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 , facilitating the production of hydroxyl radicals (OH) and other oxidants that propagate formation in polluted atmospheres. In low-NOx environments, stabilized Criegee intermediates enhance yields by forming low-volatility dimers and oligomers, amplifying the overall oxidative capacity of the . 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 fraction to global SOA budgets, with biogenic pathways alone accounting for a significant portion (often 50–90% depending on models) of mass in continental regions, influencing formation and patterns. These aerosols exert a net cooling effect by incoming solar radiation, potentially offsetting some warming, though their precise climate forcing remains uncertain due to variability in emission sources and . Illustrative examples highlight ozonolysis's role in diverse settings. In urban air, the reaction of with ethene produces (HCHO) and peroxy radicals, fueling photochemical cycles that elevate levels and contribute to . In forested environments, ozonolysis of like β-pinene and generates fine particles responsible for the characteristic blue haze over regions such as the , where BVOC emissions interact with regional to scatter blue wavelengths of light. Recent studies from the have advanced understanding through quantum chemical calculations, refining rate constants and branching ratios for 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 , as enhanced SOA formation could amplify aerosol-induced cooling, though rising temperatures may alter emission rates and oxidation efficiencies.

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. 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. 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. Additionally, ozone irritates the eyes and skin, causing redness, discomfort, and potential inflammation even at lower levels. Chronic exposure to at sub-acute levels contributes to in the , exacerbating conditions like , , and (COPD) by promoting and reducing function over time. In the context of ozonolysis, byproducts such as aldehydes—particularly from the cleavage of terminal alkenes—introduce further hazards, as is classified as a associated with nasopharyngeal cancer and following prolonged occupational exposure. 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 incidents. Ozone's extreme reactivity with organic materials heightens and risks, as it can initiate vigorous oxidation reactions with solvents, reducing agents, or unsaturated compounds, potentially resulting in or blasts. Environmentally, unintended releases of from ozonolysis processes contribute to local tropospheric pollution, where it acts as a damaging vegetation and ecosystems by disrupting and plant growth, while also posing indirect health risks through elevated concentrations.

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 substrate dissolved in a such as or a -methanol at low temperatures ranging from -78°C to 0°C to control the and minimize side products. The reaction progress is monitored by the disappearance of the (e.g., via TLC) or the appearance of a color from the methanol- complex, ensuring complete consumption to avoid unreacted hazards. Safety protocols emphasize conducting the reaction in a well-ventilated with , as O₃ is toxic (exposure limit 0.1 ppm) and can form explosive peroxides; excess is purged with O₂ post-reaction. Workup procedures vary based on desired products: reductive workups using (DMS) or (PPh₃) at yield aldehydes or ketones by decomposing the ozonide intermediate, often achieving 70-80% yields; for example, in the ozonolysis of derivative to 2,5-heptanedione, DMS addition followed by stirring overnight and provides 73% yield. Oxidative workups with or convert aldehydes to carboxylic acids, as seen in the cleavage of oct-1-ene to and derivatives, involving dust reduction in acetic acid and for isolation. Recent innovations include integrated batch-flow systems using DIY syringe pumps for sequential ozonolysis, (with NaClO₂), and reductive quench (with NaHSO₃), enabling safe handling of renewables like to in 80% yield at 5°C with a throughput of 18 g/h. Industrial protocols address scalability challenges of batch ozonolysis, such as peroxide accumulation and risks, by adopting continuous flow microreactors that enhance and limit reactive volumes to grams, allowing safe operation under pressure. For instance, the ozonolysis of to myrtanal employs a pressurized flow system with an ozone dosing line, achieving >16 g/h productivity while mitigating through design and risk assessments. 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. Large-scale implementations, such as Lonza's ton-scale process, integrate feasibility studies and evaluations to transfer lab methods to production reactors, reducing by-products and reaction times compared to traditional oxidations. These flow-based approaches prioritize , with off-gas treatment to capture unreacted , ensuring compliance with environmental regulations.

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