Alkene Reactions: Ozonolysis

Ozonolysis of Alkenes and Alkynes 

• Alkenes can undergo oxidative cleavage with ozone (O3) to give carbonyl compounds, cleaving the C=C bond
• The reaction generates an ozonide intermediate, which is then treated with a reducing agent (e.g. dimethyl sulfide or zinc) gives aldehydes or ketones depending on the structure of the starting alkene.
• Less commonly, the ozonide can be treated with an oxidizing agent such as hydrogen peroxide H2O2 (“oxidative workup”) which will convert any aldehydes to carboxylic acids
• Cyclic alkenes are converted into linear products; molecules with multiple alkenes are converted into a mixture of fragments
• More electron-rich (i.e. more substituted) alkenes tend to react faster
• Alkynes can also undergo oxidative cleavage with O3, giving carboxylic acids. Alkynes are less reactive than alkenes towards O3.

Table Of Contents

1. Ozone (O₃) Is A Powerful Oxidant For Cleaving Alkenes To Carbonyl Compounds
2. Ozonolysis With “Reductive Workup” :  All C–H Bonds Are Preserved
3. Oxidative Workup of Ozonolysis
4. Ozonolysis Of A Cyclic Alkenes Results In A Chain With Two Carbonyls
5. Ozonolysis Of A Compound With Multiple Alkenes Results In Fragments
6. Mechanism of Ozonolysis
7. Oxidative Workup Mechanism
8. Summary: Ozonolysis of Alkenes
9. Notes
10. Quiz Yourself!
11. (Advanced) References and Further Reading

1. Ozone (O₃) Is A Powerful Oxidant For Cleaving Alkenes To Carbonyl Compounds

Ozone (O₃) is a form of molecular oxygen containing three oxygen atoms, in contrast to the the more familiar dioxygen (O₂) which we all know and breathe.  [O₃ and O₂ are allotropes of oxygen, just as diamond and graphite are allotropes of carbon]. It has a distinctive sharp, almost metallic odor, detectible by the human nose in trace quantities, that will invoke memories of lightning storms and being near high-voltage power equipment.

Ozone is a much more aggressive oxidant than molecular oxygen. In organic chemistry, it is useful for oxidative cleavage of alkenes, a reaction that converts alkenes (and alkynes) to carbonyl compounds. It also has many commercial uses, such as disinfecting surfaces, rooms, and drinking water. Ozone can be conveniently generated on demand by passing a stream of O₂ through high voltage  (8000-15000 V, see this freely accessible article from Org. Syn for the original design) ; household ozone generators are available for purchase on Amazon.

Ozone forms naturally in the upper atmosphere through the interaction of O₂ with ultraviolet light, and serves to screen out damaging high-energy ultraviolet rays from hitting the earth’s surface (UV light promotes the pi-pi* transition of an electron from the highest-occupied molecular orbital (HOMO) of ozone to the lowest unoccupied molecular orbital (LUMO) – see UV spectroscopy for more background on how this works).

Less usefully, O₃ forms in the lower atmosphere through interaction of oxygen with light, heat, and nitrogen oxides (byproducts of gasoline combustion) and is a component of smog. High levels of O₃ lead to rapid degradation of rubber and plastics and also cause respiratory problems.

Ozone has two equivalent resonance forms. The resonance hybrid has an O-O bond length of 1.27 Å, intermediate between O=O (1.21 Å) and O-O (1.47 Å) , and an interior bond angle of about 117°,  pretty close to the 120° bond angle of an ideal sp² hybridization. [Note 1]

The hybridization of the terminal oxygen of ozone makes for a good quiz question:

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2. Oxidative Cleavage of Alkenes With “Reductive Workup”

When alkenes are treated with ozone, they undergo a reaction known as ozonolysis (ozone,  + lysis = breaking), a type of reaction known as oxidative cleavage.

(In organic chemistry, any reaction where a C-H or C-C bond is converted to a C-O bond is classified as an oxidation reaction – see Oxidations and Reductions in Organic Chemistry).

The C=C bond is broken and two new C=O bonds are formed. The resulting C=O groups are known as carbonyl functional groups.

Depending on the structure of the starting alkene, either aldehydes or ketones will be formed. If the alkenyl carbon has two hydrogens attached, formaldehyde (H₂C=O) will be formed.

In carrying out an ozonolysis reaction, O₃ is added to the alkene at low temperature until the alkene is completely consumed. The beautiful blue color of ozone serves as a convenient indicator – when the blue color persists, you know the reaction is done! [Note 2]

Ozonolysis of an alkene results in an intermediate known as an ozonide (more detail in the “Mechanism” section, below).

Like peroxides, ozonides are potentially explosive (the O-O bond is weak! ) and reasons of chemical safety, they should be broken down to carbonyl compounds through adding additional reagents, a procedure known as the workup. [The explosive nature of ozonides was first encountered in 1873 –  Note 3 ]

There are two different families of workups for ozonolysis reactions.

The most common type of workup (“reductive workup“) involves adding a reducing agent to the ozonide, which accepts an oxygen atom and results in the formation of two new C=O groups.  Typical reducing agents include dimethyl sulfide [also known as (CH₃)₂S or DMS), zinc with acid, or triphenylphosphine (PPh₃). These safely break the O-O bond of the ozonide and leave all C-H bonds intact.

Note the pattern of bonds formed and bonds broken in ozonolysis of alkenes with reductive workup: the C=C bond breaks and two new C=O bonds form.

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Depending on the structure of the starting alkene, either aldehydes or ketones will be formed. Reductive workup does not alter any additional bonds on the substrate.

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When terminal alkenes (i.e. alkenes that end in =CH₂ ) are treated with O₃ and subjected to reductive workup, formaldehyde will be formed.

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3. Oxidative Workup

A less common workup is known as “oxidative workup”. In this case, an oxidant such as hydrogen peroxide (H₂O₂)  is added to the ozonide. What happens is that any aldehydes that form will be oxidized to give carboxylic acids.

That is, in addition to the C=C bond breaking and two new C=O bonds forming, any C-H bonds on the alkenyl carbons will be converted into C-OH bonds.

Here is a specific example:

Note that the same transformation can be achieved by treating the alkene with hot, acidic KMnO₄.

4. Cyclic Alkenes

Ozonolysis of cyclic alkenes results in linear chains. For example, this ozonolysis of 1-methylcyclohexene gives the aldehyde-ketone below:

When dealing with these types of examples it can be very helpful to number your carbons and also to take your time with redrawing. My advice is to draw the ugly version first, [See article: Draw the ugly version first] to make sure you get the connectivity right, before trying to re-draw it neatly.

See if you can predict the product of the following ozonolysis.

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It’s also helpful to be able to think in reverse. Can you work backwards from the following product to the starting alkene?

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5. Ozonolysis of Molecules Containing Multiple Alkenes

When molecules with multiple alkenes are treated with O₃, fragments will result.  For example treatment of the triene below results in the following collection of carbonyl compounds:

In olden days of yore,  before our current powerful spectroscopic methods like nuclear magnetic resonance (NMR), a useful strategy for to determining the structure of unknown compounds was to subject them to cleavage with ozone, isolate and characterize the fragments, and then to do some detective work to put the pieces back together in the proper order. This type of structural analysis is known as degradation. (For a typical example, see Case Study: Structure Determination of Deer Tarsal Gland Pheromone)

An example of a molecule with multiple alkenes that results in fragments after ozonolysis is shown below:

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6. Mechanism

The mechanism of ozonolysis took several decades to work out and involves a series of reactions that are not commonly encountered in introductory organic chemistry. So learning the mechanism of ozonolysis is going to feel a lot like memorization without understanding. Sorry in advance.

In the first step, an alkene combines with ozone in a concerted reaction known as a cycloaddition. [The closest thing you will likely encounter to this reaction in introductory organic chemistry is the Diels-Alder reaction, which is a cousin of this process – See post – the Diels-Alder reaction ] [Note 4]

The C-C pi bond breaks, and two new C-O bonds form.  An unstable cyclic intermediate known as a “molozonide” forms, which has three consecutive oxygen atoms:

Molozonides have a very short lifetime. In the lab, they can be observed at temperatures around -100°C to -130°C [ref] but quickly break down in a reaction known as a reverse cycloaddition. The central C-C bond breaks, with simultaneous formation of two new C-O (pi) bonds.

Two fragments result. The first one is a conventional carbonyl compound (either an aldehyde or ketone depending on structure). The second one is a zwitterionic structure known as a carbonyl oxide (although don’t worry if you can’t remember the name).

What next? It turns out to be another cycloaddition [Note 5] where the two fragments recombine to give a new five-membered ring containing an ether linkage and a peroxide. This structure is commonly referred to as an ozonide. although sometimes the term “1,2,4-trioxolane” is used.

Ozonides can be,

Upon warming, ozonides will break down to give aldehydes/ketones, but because ozonides, just like organic peroxides, can be ” ‘splodey ” as some people would put it, they are best kept cold and in dilute solution, rather than isolated. Apparently they can form nice crystals though! 

For this reason ozonides are usually broken down at low temperature by adding a reducing agent, which breaks the weak O–O bond and liberates the two carbonyl compounds, and also destroys any excess ozone.

Two common reagents for reductive workup are dimethyl sulfide (DMS) and zinc.

• Reduction using dimethylsulfide has the advantage of generating benign dimethylsulfoxide (DMSO). To see a plausible mechanism, Hover here for the mechanism or click this link.
• Reduction using acidic zinc results in zinc oxide (ZnO).  To see a plausible mechanism, hover here or click this link.

In addition, triphenylphosphine (PPh₃) can also be used, but from a practical perspective this tends to be a less popular choice owing to the difficulty of separating triphenylphosphine oxide (PPh₃O) from the resulting product. 

7. Oxidative workup

Alternatively, allowing the ozonide to warm up in the presence of hydrogen peroxide (H₂O₂) will lead to the oxidation of any aldehydes to carboxylic acids. 

For a possible mechanism (generally not covered in introductory organic) hover here or click this link.

8. Alkynes

Alkynes can also undergo oxidative cleavage with O₃ to give carboxylic acids. 

Alkynes tend to be less reactive toward ozone than alkenes. There are plenty of examples of selective ozonolysis of an alkene in the presence of an alkyne. [like here]

Ozonolysis of terminal alkynes (i.e. those that have a C-H bond) results in carbon dioxide. =

Alkynes are more reactive than aromatic rings, however (if you’re in Org 1, the special stability of aromatic rings like benzene is usually covered in Org 2 – see Aromaticity).

9. Summary

The ozonolysis of alkenes and alkynes belongs to a class of reactions known as oxidative cleavage. Some other reactions in this family include the cleavage of vicinal diols by NaIO₄ or Pb(OAc)₄, as well as the cleavage of alkenes with hot, acidic potassium permanganate (KMnO₄).

• Make sure you understand the difference between reductive workup (leaves C-H bonds alone) and oxidative workup (oxidizes C-H bonds to C-OH bonds)
• Practice examples of the ozonolysis of cyclic alkenes. Don’t forget to count your carbons.
• Practice working backwards from ozonolysis products to the starting alkenes.
• In synthesis problems, be alert to the possibility of using alkenes as precursors to carbonyl compounds.

Notes

Note 1. These values are obtained from microwave spectroscopy. See Hughes, R. J. Chem. Phys. 24, 131–138 (1956). DOI: 10.1063/1.1700813

Note 2. Generally, more electron-rich alkenes (more substituted) undergo ozonolysis more quickly than electron-poor alkenes. When multiple reactive functional groups are present in a molecule, it is possible to obtain good selectivity through the use of appropriate dyes such as Sudan Red (for an example, see here)

Note 3. Apparently the first isolation of an ozonide was made in 1873 by Houzeau, who obtained white, explosive crystals from the oxidative cleavage of benzene with ozone. [Ref]

Note 4. Technically this is a “1,3-dipolar cycloaddition” reaction, a process similar to the Diels-Alder in which a 4 pi-electron component undergoes a cycloaddition with a 2 pi-electron component. One key difference in this case is that it operates with “inverse electron demand”; in contrast to the normal Diels-Alder, which is fastest with electron-rich dienes and electron-poor dienophiles, the reaction with ozone operates fastest with electron-rich alkenes.

Note 5. Another 1,3-dipolar cycloaddition, this time between a carbonyl oxide and a carbonyl. For some fairly conclusive evidence that this step is a concerted cycloaddition and not a two-step series of 1,2-addition reactions snapping shut to give a five-membered ring, see [ref]. This recombination step is stereoselective and dependent on starting alkene geometry.

Note 6. Ozonides are not generally a class of compound you would want to work with, but the naturally occurring ozonide arteminisin is a known antimalarial drug. The ozonide functional group is key to its activity.  Other derivatives of arteminisin have been developed as drug candidates.

For a short, fun article on developments on this field, see: “Ozonides as Drugs: What Will They Think of Next?” by Derek Lowe.

Quiz Yourself!

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(Advanced) References and Further Reading

A fun article on the history of the discovery of ozone written by Mordecai B. Rubin is found here, from the Bulletin of Chemical History. [PDF]

1. Ueber die Einwirkung des Ozons auf organische Verbindungen
   Harries
   Just. Lieb. Ann. Chem. 1905, 343 (2-3), 311-344
   DOI: 10.1002/jlac.19053430209
   The first paper describing the oxidative cleavage of unsaturated compounds with ozone in solution.
2. OZONE
   I. Smith, F. L. Greenwood, and O. Hudrlik
   Org. Synth. 1946 26, 63
   DOI: 10.15227/orgsyn.026.0063
   This procedure from Organic Syntheses, a source of reliable, reproducible and independently tested organic chemistry laboratory experimental procedures, provides a detailed explanation of how to build a laboratory ozonizer.
3. The Preparation of Aldehydes, Ketones, and Acids by Ozone Oxidation
   Albert L. Henne and Philip Hill
   Journal of the American Chemical Society 1943 65 (5), 752-754
   DOI: 1021/ja01245a003
   This paper shows that carboxylic acids are formed in good yields from aldehydes when the ozonolysis reaction mixture is worked up in the presence of excess hydrogen peroxide.
4. Notes- A Convenient Method for Reduction of Hydroperoxide Ozonation Products
   Knowles and Q. Thompson
   The Journal of Organic Chemistry 1960 25 (6), 1031-1033
   DOI: 10.1021/jo01076a044
   Although the current practice is to use dimethyl sulfide in a reductive ozonolysis workup, trimethyl phosphite can also be used, as this paper from Nobel Laureate W. S. Knowles demonstrates.
5. OZONOLYTIC CLEAVAGE OF CYCLOHEXENE TO TERMINALLY DIFFERENTIATED PRODUCTS: METHYL 6-OXOHEXANOATE, 6,6-DIMETHOXYHEXANAL, METHYL 6,6-DIMETHOXYHEXANOATE
   Ronald E. Claus and Stuart L. Schreiber
   Org. Synth. 1986, 64, 150
   DOI: 10.15227/orgsyn.064.0150
   This procedure in Organic Syntheses demonstrates how ozonolysis can be used to quickly generate differentiated bifunctional compounds.
6. Mechanism of Ozonolysis
   Dr. Rudolf Criegee
   Angew. Chem. Int. Ed. 1975, 14 (11), 745-752
   DOI: 10.1002/anie.197507451
   This is an account by Prof. Rudolf Criegee on work done towards determining the mechanism of ozonolysis. Criegee himself carried out extensive work in this area – the ‘Criegee intermediate’ in ozonolysis is named after him.The following papers are further mechanistic studies on ozonolysis:
7. Formation and Structure of Ozonides
   Robert L. Kuczkowski
   Accounts of Chemical Research 1983 16 (2), 42-47
   DOI: 10.1021/ar00086a002
   A good overview on evidence for the the various steps of the ozonolysis reaction.
8. New evidence in the mechanism of ozonolysis of olefins
   Klopman and C. M. Joiner
   Journal of the American Chemical Society 1975 97 (18), 5287-5288
   DOI: 10.1021/ja00851a049
9. Mechanism of ozonolysis. (a) Microwave spectra, structures, and dipole moments of propylene and trans-2-butene ozonides. (b) Orbital symmetry analysis
   Robert P. Lattimer, Robert L. Kuczkowski, and Charles W. Gillies
   Journal of the American Chemical Society 1974 96 (2), 348-358
   DOI:1021/ja00809a006
10. Stereospecificity in ozonide and cross-ozonide formation
    Nathan L. Bauld, James A. Thompson, Charles E. Hudson, and Philip S. Bailey
    Journal of the American Chemical Society 1968 90 (7), 1822-1830

    DOI: 10.1021/ja01009a026

11. Ozonolysis. X. Molozonide as an intermediate in the ozonolysis of cis- and trans-alkenes
    Lois J. Durham and Fred L. Greenwood
    The Journal of Organic Chemistry 1968 33 (4), 1629-1632
    DOI: 10.1021/jo01268a068
    Evidence for the formation of a molozonide, which decomposes at -130°C (cis) or -100°C (trans) depending on the stereochemistry of the alkene.