8.10
Oxidation of Alkenes: Syn Dihydroxylation with Osmium Tetraoxide
Alkenes are converted to 1,2-diols or glycols through a process called dihydroxylation. It involves the addition of two hydroxyl groups across the dou…
Dihydroxylation is an oxidative addition reaction, where two hydroxyl groups are added across a carbon–carbon double bond to form 1,2-diols or glycols.
Dihydroxylation of alkenes can be carried out by two different stereochemical routes: anti dihydroxylation and syn dihydroxylation.
In syn dihydroxylation, an alkene is treated with osmium tetroxide in pyridine, forming a cyclic osmate ester, followed by reduction with aqueous sodium bisulfite to give a cis-diol along with the reduced form of osmium tetroxide.
The mechanism is a two-step process that begins with the addition of osmium tetroxide across the alkene double bond in a concerted manner to form a five-membered cyclic osmate ester.
Osmium tetroxide is a strong oxidizing agent and electrophilic in nature. It readily accepts electrons from the alkene π bond, thereby reducing the oxidation state of osmium from +8 to +6.
The two oxygen atoms add simultaneously across the same face of the alkene double bond with syn stereochemistry.
In the second step, the osmate ester is hydrolyzed in the presence of sodium bisulfite, which cleaves the osmium–oxygen bond without altering the stereochemistry of the carbon–oxygen bond to form a cis-diol.
Although the reaction is stereospecific and produces cis-diols in good yields, the use of osmium tetroxide is limited because it is very toxic and expensive.
To overcome these limitations, typical co-oxidants like N-methylmorpholine N-oxide or tert-butyl hydroperoxide are added to the reaction mixture.
The co-oxidant oxidizes osmium +6 to +8 and regenerates the osmium tetroxide for oxidation of the remaining alkenes.
Since the reaction is stereospecific, the syn dihydroxylation of (E)-hex-3-ene forms a pair of enantiomers, whereas the syn dihydroxylation of (Z)-hex-3-ene forms one product, which is a meso compound.
A friendlier enantioselective method for syn dihydroxylation of alkenes was developed by Karl Barry Sharpless, for which he was awarded the Nobel prize. The reaction is carried out in the presence of chiral amine ligands and is referred to as Sharpless asymmetric dihydroxylation.
Q1: What is syn dihydroxylation and how does it differ from anti dihydroxylation?
Syn dihydroxylation adds two hydroxyl groups across an alkene double bond with both groups attaching to the same face of the molecule, forming a cis-diol. Anti dihydroxylation adds hydroxyl groups to opposite faces, forming a trans-diol. Osmium tetroxide catalyzes syn dihydroxylation through a concerted mechanism, while anti dihydroxylation uses peroxycarboxylic acids. The stereochemical outcome depends on the reaction pathway and reagent used.
Q2: How does osmium tetroxide form a cyclic osmate ester intermediate?
Osmium tetroxide adds across the alkene double bond in a concerted, single-step process. The electrophilic osmium accepts an electron pair from the alkene π bond, forming a five-membered cyclic osmate ester intermediate. During this addition, osmium's oxidation state reduces from +8 to +6. Both oxygen atoms add simultaneously to the same face of the double bond, establishing syn stereochemistry before the intermediate is reduced.
Q3: What role does sodium bisulfite play in syn dihydroxylation?
Sodium bisulfite acts as a reducing agent in the second step of syn dihydroxylation. It cleaves the osmium-oxygen bonds in the cyclic osmate ester without altering the stereochemistry of the newly formed carbon-oxygen bonds. This hydrolysis releases the cis-diol product while preserving the syn stereochemistry established in the first step, yielding the final 1,2-diol or glycol.
Q4: Why are co-oxidants like N-methylmorpholine N-oxide used in osmium tetroxide reactions?
Osmium tetroxide is toxic and expensive, limiting its practical use. Co-oxidants such as N-methylmorpholine N-oxide or tert-butyl hydroperoxide regenerate osmium tetroxide by reoxidizing the reduced osmium +6 species back to +8. This catalytic recycling allows a small amount of osmium tetroxide to oxidize multiple alkene molecules, improving efficiency and reducing the quantity of expensive reagent required.
Q5: How does the stereochemistry of the starting alkene affect the dihydroxylation product?
Since syn dihydroxylation is stereospecific, the E and Z geometry of the starting alkene determines the product structure. Dihydroxylation of (E)-hex-3-ene produces a pair of enantiomers because the two faces of the double bond are different. Dihydroxylation of (Z)-hex-3-ene yields a single meso compound, which is achiral despite containing stereogenic centers.
Q6: What is Sharpless asymmetric dihydroxylation and why is it significant?
Sharpless asymmetric dihydroxylation is an enantioselective method developed by Karl Barry Sharpless for syn dihydroxylation of alkenes. It uses osmium tetroxide with chiral amine ligands and co-oxidants to produce optically pure diols from prochiral or racemic alkenes. This breakthrough earned Sharpless the Nobel Prize and provides a friendlier, more practical alternative to stoichiometric osmium tetroxide reactions.
Q7: What is the mechanism of the first step in syn dihydroxylation with osmium tetroxide?
The first step is a concerted addition where osmium tetroxide, an electrophilic strong oxidizing agent, accepts electrons from the alkene π bond. The two oxygen atoms add simultaneously across the same face of the double bond, reducing osmium from +8 to +6 oxidation state. This forms a five-membered cyclic osmate ester intermediate that can be isolated and characterized before proceeding to hydrolysis.