Ozonolysis

Dussault and coworkers have shown that in the ozonolysis of alkenes in the presence of the weak boron Lewis acid triphenoxy borate, a directed addition of the phenoxy group from boron onto the coordinated carbonyl oxide takes place to furnish hydroperoxyacetals (161) under aprotic conditions (Equation 96) [98]. 

Several procedures that intercept the intermediates have been developed. When ozonolysis is done in alcoholic solvents, the carbonyl oxide fragmentation product can be trapped as an a-hydroperoxy ether.202 Recombination to the ozonide is then prevented, and the carbonyl compound formed in the fragmentation step can also be 

Bailey, Ozonization in Organic Chemistry, Vol. 1, Academic Press, New York, 1978. 

Oxidative Cleavage of Carbon-Carbon Double Bonds 

Ozonolysis in the presence of NaOH or NaOCH3 in methanol with CH2C12 as a cosolvent leads to formation of esters. This transformation proceeds by trapping both 

203j J. J. Pappas, W. P. Keaveney, E. Gancher, and M. Berger, Tetrahedron Lett., 4273 (1966). 

Alkenes react with peroxy acids to form epoxides and carboxylic acids as products. Ozonolysis 

Alkenes react with O3 (Ozone) to form ozonides, which on hydrolysis with water form aldehydes or ketones or both, depending on the type of the reacting alkene. This is illustrated by the sample reactions. 

The reaction of alkenes with ozone constitutes an important method of cleaving carbon-carbon double bonds.138 Application of low-temperature spectroscopic techniques has provided information about the rather unstable species that are intermediates in the ozonolysis process. These studies, along with isotope labeling results, have provided an understanding of the reaction mechanism.139 The two key intermediates in ozonolysis are the 1,2,3-trioxolane, or initial ozonide, and the 1,2,4-trioxolane, or ozonide. The first step of the reaction is a cycloaddition to give the 1,2,3-trioxolane. This is followed by a fragmentation and recombination to give the isomeric 1,2,4-trioxolane. The first step is a 

3-dipolar cycloaddition reaction. Ozone is expected to be a very electrophilic 1,3-dipole because of the accumulation of electronegative oxygen atoms in the ozone molecule. The cycloaddition, fragmentation, and recombination are all predicted to be exothermic on the basis of thermochemical considerations.140 

SECTION 12.3. CLEAVAGE OF CARBON-CARBON DOUBLE BONDS 

Especially reactive carbonyl compounds such as methyl pyruvate can be used to trap the carbonyl ylide component. For example, ozonolysis of cyclooctene in the presence of methyl pyruvate leads to G, which, when treated with triethylamine, is converted to H, in which the two carbons of the original double bond have been converted to different functionalities.148 

In both epoxidation and dihydroxylation reactions, oxidation occurs at the carbon atoms of the original double bond, but the hydrocarbon skeleton remains intact. Now we consider a reaction in which the products are more highly oxidized. In this reaction, called ozonolysis, the carbon-carbon double bond is cleaved to produce carbonyl compounds. 

Alkenes react rapidly with ozone (O even at —78°C. Ozone is produced in the laboratory by a device called an ozonator, which forms ozone by passing oxygen gas through an arc discharge. As the ozone forms, oxygen gas containing a few percent ozone is passed through an inert solvent, such as dichloromethane, that contains the alkene. After the reaction is complete, the solution is worked up under reductive conditions such as zinc in acetic acid. 

Ozonolysis occurs in several steps. First, an unstable intermediate, called a molozonide, forms by a cyclic concerted addition of the terminal oxygen atoms of ozone to the 7i bond of the alkene. This step requires a total of three electron pair shifts, as shown below. 

In subsequent steps, the molozonide rapidly rearranges when the n bond of the alkene and an O—O peroxide bond break. The fragments then recombine to give an ozonide. The individual fragments are reoriented to illustrate the addition reaction in the second step, which is shown below. 

The molozonide has two weak peroxide bonds, but the ozonide has only one. This difference accounts for the direction of the reaction. The rearrangement of the molozonide is exothermic. However, ozonides are explosively unstable compounds. For that reason, the reaction mixture is maintained at low temperatures and immediately reduced or oxidized after the reaction is complete. 

When appreciable concentrations of carbonyl compounds are present before complete formation of ozonide, crossed ozonides are formed. This occurs when the added carbonyl compound traps the zwitterion formed in the cleavage step. When c -stilbene is subjected to ozonolysis in the presence of 0-labeled benzal-dehyde, the label is incorporated into the ether rather than the peroxide portion of the ozonide  

This result is consistent with formation of the crossed ozonide via the cleavage-recombination mechanism  

Reactive solvent molecules can modify the course of ozonolysis reactions. We have already mentioned that when ozonolysis is carried out using certain carbonyl compounds as solvents, the reaction is diverted from its normal course. Under these 

Show syntheses of these compounds from (Z)-2-butene  

CHAPTER I I ADDITIONS TO CARBON-CARBON DOUBLE AND TRIPLE BONDS 

Ozonolysis is not used often in synthesis because it is a degradative reaction—it breaks larger molecules into smaller ones. In synthetic schemes we are usually attempting to build larger molecules from smaller ones. However, the ozonolysis reaction can provide a useful way to prepare an aldehyde or ketone if the appropriate alkene is readily available. One such example is provided by the cleavage of cyclohexene to produce the dialdehyde shown in the previous equation. 

A historically important use of the ozonolysis reaction was in the area of structure determination. In the days before the advent of spectroscopic techniques (Chapters 13-15), the structure of an unknown organic compound was determined by submitting it to a host of reactions. Often, a complex molecule was broken into several fragments to simplify the structural problem. After the individual fragments were identified, the original molecule could be mentally reconstructed from them. Alkenes were often cleaved to aldehydes and ketones by reaction with ozone. 

The next step is to react the unknown alkene with ozone, followed by treatment with dimethyl sulfide. The products of this reaction are isolated and identified (by other 

Multivariate calibrations are powerful tools, but the number and type of calibration samples required often is prohibitive. To overcome this problem, Pelletier employed a powerful but relatively uncommon tool, spectral stripping. This technique takes advantage of existing system knowledge to use spectra of fewer, more easily generated samples. More applications of this approach can be expected. 

Cleavage of a carbon-carbon double bond by reaction with ozone R3 

Named Organic Reactions, Second Edition T. Laue and A. Plagens 2005 John Wiley Sons, Ltd ISBNs 0-470-01040-1 (HB) 0-470-01041-X (PB) 

The reaction of ozone with an aromatic compound is considerably slower than the reaction with an alkene. Complete ozonolysis of one mole of benzene with workup under non-oxidative conditions will yield three moles of glyoxal. The selective ozonolysis of particular bonds in appropriate aromatic compounds is used in organic synthesis, for example in the synthesis of a substituted biphenyl 8 from phenanthrene 7  

In general however, ozonolysis is of limited synthetic importance. For quite some time ozonolysis has been an important tool for structure elucidation in organic chemistry, but has lost its importance when spectroscopic methods were fully developed for that purpose. The identification of the aldehydes and/or ketones obtained by ozonolysis of unsaturated compounds allowed for conclusions about the structure of the starting material, but has practically lost its importance since then. 

Ozone has received increased attention for its occurrence and function in the Earth s atmosphere.For example the decreasing ozone concentration in the stratospheric ozone layer, becoming most obvious with the Antarctic ozone hole. 

is an allotrope of oxygen that adds rapidly to carbon-carbon double bonds, which is followed by reductive or oxidative cleavage. 

From the analysis of products obtained in an ozonolysis experiment, it is possible to deduce structural formulas for the starting alkenes. 

the structure of the starting alkene in the above reaction is as follows  

Caution Ozone is toxic, and ozonides potentially explosive. 

Ozone is generated using a commercial ozonator (or ozonizer) which can produce a concentration of up to 8% in oxygen, and which will be available in most organic research establishments. The operation of these is very simple providing that the instructions for the particular device are followed carefully. Make sure that these are consulted before attempting the reaction. 

The compound to be ozonized is dissolved in the appropriate solvent, and cooled to the desired temperature. Ozone is then passed through the solution until no more starting material remains. For most purposes an excess of ozone can be used. It can be difficult to avoid this, but an indicator which can be added to the solution to show you when there is free ozone in the solution can sometimes be most valuable in avoiding over-oxidation.  

The work up depends upon the desired product, but will include a reagent which reacts with the ozonide. This reagent is almost always added in excess, and before any product isolation is attempted. Make sure that you allow plenty of time for the ozonide to react, as isolation of ozonides is to be avoided due to their potential for violent explosive decomposition. Once the ozonide is fully reacted the reaction can be processed in the usual manner. 

Poly(styrene) samples were exposed to a constant flow of ozone (ozone generator BMT 802N operated at 100% power) at room temperature for 15 min. Thereafter, the samples were annealed for 24h at 60 °C in air. 

Note that in the oxidative work-up case, we obtain a negative value for HI as expected for an oxidation taking place at the oleflnic carbon atoms. However, the reductive work-up case yields an apparent isohypsic situation because the newly formed sulfur-oxygen bond in dimethyl sulfoxide is not counted in the HI calculation, as it is not one of the target bonds found in the intended target pixxiucts. 

The reaction of alkenes with ozone constitutes an important method of cleaving carbon-carbon double bonds. Application of lo V-temperature spectroscopic techniques has provided information about the rather unstable species that are intermediates in the ozonization process. These studies, along with isotope labeling results, have provided an understanding of the reaction mechanism.  

The fragmentation-recombination may take place more rapidly than diffusion, or it may be represented as a concerted process. 

The reaction of alkenes with ozone is used to cleave the double bond to two carbonyl compounds. This combined with spectroscopic analysis of the products (mainly mass spectrometry) allows a double bond to be located in a long chain of carbon atoms. As you will remember from Chapter 4, we write ozone in a dipolar form, with a positive charge on the central carbon atom, one oxygen-oxygen double bond, and one negatively charged oxygen. There are two identical resonance forms (11.37). 

The key feature of the careless reaction with HBr is that if air (oxygen is a diradical and can initiate radical reactions) is present, a radical pathway, leading to anti-Markovnikov products, will predominate. However, this will not be stereospecific, so both cis- and traHs-isomers will be formed  

In order to understand what is happening in the elimination reaction, we need to draw proper chair forms for each of the bromides. Taking the c/s-isomer first, elimination can only occur when the bromine is axial, and two products can be obtained, depending on which of the two available axial protons is removed. As we saw in the previous chapter, the more stable, more substituted alkene usually predominates, in this case 1-methylcyclohexene, 11.38. In the transisomer, only one elimination reaction is possible, as there is only one available hydrogen that is trans anti to the departing bromine. 

What can we conclude here 11.40 gave the single product 11.41 gave two products, mainly 11.38. Thus, 11.40 is the trans-isomer, and 11.41 is the ds-isomer. Finally, 11.42, 3-methylcyclohexene, is ozonized to the dialdehyde 11.43  

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VI,14. OXIDATION OF UNSATURATED COMPOUNDS WITH OZONISED OXYGEN (OZONOLYSIS)... 

Nickel(O) forms a n-complex with three butadiene molecules at low temperature. This complex rearranges spontaneously at 0 °C to afford a bisallylic system, from which a large number of interesting olefins can be obtained. The scheme given below and the example of the synthesis of the odorous compound muscone (R. Baker, 1972, 1974 A.P. Kozikowski, 1976) indicate the variability of such rearrangements (P. Heimbach, 1970). Nowadays many rather complicated cycloolefins are synthesized on a large scale by such reactions and should be kept in mind as possible starting materials, e.g. after ozonolysis. 

Versatile [3 + 2]-cydoaddition pathways to five-membered carbocydes involve the trimethylenemethane (= 2-methylene-propanediyl) synthon (B.M. Trost, 1986). Palladium(0)-induced 1,3-elimination at suitable reagents generates a reactive n -2-methylene-l,3-propa-nediyl complex which reacts highly diastereoselectively with electron-deficient olefins. The resulting methylenecyclopentanes are easily modified, e. g., by ozonolysis, hydroboration etc., and thus a large variety of interesting cyclopcntane derivatives is accessible. 

Conventional synthetic schemes to produce 1,6-disubstituted products, e.g. reaction of a - with d -synthons, are largely unsuccessful. An exception is the following reaction, which provides a useful alternative when Michael type additions fail, e. g., at angular or other tertiary carbon atoms. In such cases the addition of allylsilanes catalyzed by titanium tetrachloride, the Sakurai reaction, is most appropriate (A. Hosomi, 1977). Isomerization of the double bond with bis(benzonitrile-N)dichloropalladium gives the y-double bond in excellent yield. Subsequent ozonolysis provides a pathway to 1,4-dicarbonyl compounds. Thus 1,6-, 1,5- and 1,4-difunctional compounds are accessible by this reaction. 

The early Escherunoser-Stork results indicated, that stereoselective cyclizations may be achieved, if monocyclic olefins with 1,5-polyene side chains are used as substrates in acid treatment. This assumption has now been justified by many syntheses of polycyclic systems. A typical example synthesis is given with the last reaction. The cyclization of a trideca-3,7-dien-11-ynyl cyclopentenol leads in 70% yield to a 17-acetyl A-norsteroid with correct stereochemistry at all ring junctions. Ozonolysis of ring A and aldol condensation gave dl-progesterone (M.B. Gravestock, 1978 see p. 279f.). 

The final step can involve introduction of the amino group or of the carbonyl group. o-Nitrobenzyl aldehydes and ketones are useful intermediates which undergo cyclization and aromatization upon reduction. The carbonyl group can also be introduced by oxidation of alcohols or alkenes or by ozonolysis. There are also examples of preparing indoles from o-aminophcnyl-acetonitriles by partial reduction of the cyano group. 

The oxidative generation of o-aminophenylacetaldehydes can be done by ozonolysis (retrosynthetic path d in Scheme 2.2) but this requires an elec-... 

The only example involving the 4-5 double bond in a 1-3 dipolar addition is given by the ozonolysis of the optically active 2-aminothiazOle (176) reported by Lardicci et al. (Scheme 112) (17). 

Ozonolysis of 2-styryl-4-methylthiazole followed by oxidation of the intermediate carbonyl compound with peracetic acid yields 4-methyl-2-thiazolecarboxylic acid (30). 

As mentioned previously, aldehydes can be prepared by Stephen s method of reduction of nitriles by stannous chloride (37, 91). Polaro-graphic reduction of thiazolecarboxylic acids and their derivatives gives lower yields of aldehydes (58). Ozonolysis of styrylthiazoles, for example, 2-styryl-4-methylthiazole, followed by catalytic reduction gives aldehyde with 47% yield of crude product (30). 

The two stage reaction sequence is called ozonolysis and is represented by the gen eral equation... 

Ozonolysis has both synthetic and analytical applications m organic chemistry In synthesis ozonolysis of alkenes provides a method for the preparation of aldehydes and ketones... 

When the objective is analytical the products of ozonolysis are isolated and identi lied thereby allowing the structure of the alkene to be deduced In one such example an alkene having the molecular formula C Hig was obtained from a chemical reaction and was then subjected to ozonolysis giving acetone and 2 2 dimethylpropanal as the products... 

The same reaction that gave 2 4 4 trimethyl 2 pentene also yielded an isomeric alkene This second alkene produced formaldehyde and 4 4 dimethyl 2 pentanone on ozonolysis Identify this alkene... 

Cleavage occurs here on ozonolysis each doubly bonded carbon becomes the carbon of a C=0 unit... 

FIGURE6 15 Ozonolysis of 2 4 4 trimethyl 2 pentene On cleavage each of the doubly bonded carbons becomes the carbon of a carbonyl (C=0) group... 

The structures of these two CsHie alkenes were deter mined by ozonolysis as de scribed in Section 6 19... 

Alkenes are cleaved to carbonyl compounds by ozonolysis This reaction IS useful both for synthesis (preparation of aldehydes ketones or car boxyhc acids) and analysis When applied to analysis the carbonyl com pounds are isolated and identified allowing the substituents attached to the double bond to be deduced... 

Dehydration of 2 2 3 4 4 pentamethyl 3 pentanol gave two alkenes A and B Ozonolysis of the lower boiling alkene A gave formaldehyde (H2C=0) and 2 2 4 4 tetramethyl 3 pentanone Ozonolysis of B gave formaldehyde and 3 3 4 4 tetramethyl 2 pentanone Identify A and B and suggest an explanation for the formation of B in the dehydration reaction... 

Compound A (C7Hi3Br) is a tertiary bromide On treatment with sodium ethoxide in ethanol A IS converted into B (C7H12) Ozonolysis of B gives C as the only product Deduce the struc tures of A and B What is the symbol for the reaction mechanism by which A is converted to B under the reaction conditions ... 

Sabinene and carene are isomeric natural products with the molecular formula CjoHig (a) Ozonolysis of sabinene followed by hydrolysis in the presence of zinc gives compound A What IS the structure of sabinene" What other compound is formed on ozonolysis" (b) Ozonoly SIS of A carene followed by hydrolysis in the presence of zinc gives compound B What is the structure of A carene" ... 

The sex attractant by which the female housefly attracts the male has the molecular formula C23H46 Catalytic hydrogenation yields an alkane of molecular formula C23H4g Ozonolysis yields... 

A certain compound of molecular formula Ci9H3g was isolated from fish oil and from plank ton On hydrogenation it gave 2 6 10 14 tetramethylpentadecane Ozonolysis gave (CH3)2C=0 and a 16 carbon aldehyde What is the structure of the natural product" What is the structure of the aldehyde" ... 

CH3(CH2)ioCH CH3(CH2)4CH and HCCH2CH on ozonolysis What is the constitution of this matenal" ... 

Consider the ozonolysis of tram 4 5 dimethylcyclohexene having the configuration shown... 

Carboxylic acids are produced when alkynes are subjected to ozonolysis... 

Ozonolysis is sometimes used as a tool m structure determination By identifying the carboxylic acids produced we can deduce the structure of the alkyne As with many... 

A certain hydrocarbon had the molecular formula C16H26 and contained two triple bonds Ozonolysis gave CH3(CH2)4C02H and HO2CCH2CH2CO2H as the only products Suggest a reasonable structure for this hydrocarbon ... 

Carbon-carbon triple bonds can be cleaved by ozonolysis The cleavage products are carboxylic acids... 

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