OsO4 (Osmium Tetroxide) for Dihydroxylation of Alkenes | Chemistry Optional Notes for UPSC PDF Download

Osmium tetroxide, OsO₄

• Osmium tetroxide (OsO₄) is a useful reagent for the dihydroxylation of alkenes
• The products of these reactions are 1,2-diols (“vicinal” diols), where the two C-O bonds are formed on the same face of the alkene via a concerted mechanism.
• Dihydroxylation of alkenes with OsO₄ is functionally equivalent to dihydroxylation with cold, basic KMnO₄.
• OsO₄ does not dihydroxylate alkynes!
• The vicinal diols can subsequently be cleaved with NaIO₄ providing products that are eqivalent to those obtained through ozonolysis.

Osmium Tetroxide, OsO₄ And The Dihydroxylation of Alkenes

• Osmium tetroxide (OsO₄) is a very useful reagent for the dihydroxylation of alkenes. In this reaction,
  • A C-C (pi) bond is broken
  • Two C-O bonds form on adjacent carbons
  • The two new C-O bonds are delivered syn, which is to say, on the same face of the alkene.
• For example, the reaction of cyclohexene with OsO₄ gives exclusively cis-cyclohexan-1,2-diol, with none of the trans diol formed.
  
• Since we are breaking a C-C bond and forming two C-O bonds, this is an example of an oxidation reaction.
• Two alkenes that differ only in their configuration (e.g. the stereoisomers cis– and trans– pent-2-ene) will result in products that are themselves stereoisomers.
• This fits the definition of a stereospecific reaction, as per IUPAC.
  
• Chiral molecules with exactly opposite (R, S) designations are enantiomers. Chiral molecules that share the configuration at at least one chiral center and differ at the configuration of another chiral center will be diastereomers.
• Note that in each case the two new C-OH bonds form on the same face of the alkene.

The Mechanism for Dihydroxylation of Alkenes With OsO₄

• The mechanism of alkene dihydroxylation is a concerted cycloaddition reaction where the C-C pi bond combines with two Os=O bonds to give a five-membered ring structure known as an osmate ester. (Note that in the osmate ester the Os is in the +6 oxidation state as opposed to the +8 oxidation state found in OsO₄)
• This concerted mechanism nicely accounts for the cis stereochemistry observed in the dihydroxlyation of cyclohexene.
  
• Osmate esters are fairly stable products and can be isolated. However, since we are generally much more interested in the diol, a reagent such as potassium bisulfite (KHSO₃) or sodium bisulfite (NaHSO₃) is commonly used to break the Os-O bonds and liberate the diol.
  Just a heads-up – in introductory courses, this second reagent may or may not be included. It purpose is just to get rid of the osmium.
• (It is much more common nowadays to use catalytic OsO₄ and a stoichiometric amount of an oxidant such as N-methylmorpholine N-oxide (NMO) or H2O2 to regenerate OsO₄ from the Os(VI) species. In these cases, KHSO₃ is not needed.
• As a fairly electron-poor reagent, reactions with OsO₄ increase in rate as the alkene becomes more electron-rich.
• For practical purposes, this means that
  • reaction rates generally increase with increasing substitution on the alkene ( tetrasubstituted (fastest) > trisubstituted > disubstituted > monosubstituted (slowest)
  • reaction rates generally decrease if the alkene is attached to electron-withdrawing groups such as carbonyls
• It’s possible to selectively dihydroxylate an electron-rich alkene in the presence of other alkenes. 

Predicting The Stereochemistry Of Dihydroxylation Products

cis– and trans- alkenes can be each be prepared from alkynes, depending on the reagent(s) used for reduction.

• Alkynes treated with sodium (Na) in ammonia (NH₃) gives trans-alkenes.
• Alkynes treated with Lindlar’s catalyst (palladium made less active through the addition of lead and quinoline) in the presence of hydrogen gives cis-alkenes.

OsO₄ versus KMnO₄ As A Reagent for Dihydroxylation

• A reagent similar to OsO₄ that is also capable of performing dihydroxylation is potassium permanganate, KMnO₄.
• Treatment of alkenes with cold, alkaline KMnO₄ will also result in vicinal diols.
  
• Like the reaction with OsO₄, this also proceeds through a cyclic, concerted transition state that results in a cyclic metal species (this time called a “manganate ester”).
• The key difference here is that unless  the manganate ester will react further to give the products of oxidative cleavage unless hydroxide ion HO(-) is present to hydrolyze the Mn-O bonds and liberate the vicinal diol. This is not generally a problem with OsO₄.
• This is also why the temperature is kept low for KMnO₄ oxidations.
• Yields with KMnO₄ tend to be lower and KMnO₄ is also much less tolerant of sensitive functional groups like alcohols and aldehydes.
• Dihydroxylations with KMnO₄ are often used with a phase transfer catalyst. 

Catalytic OsO₄ Using Stoichiometric Oxidant

• It’s one thing to write a reaction down on a sheet of paper that uses a stoichiometric amount of osmium tetroxide.
• It’s another thing entirely to carry it out in the lab.
• For one thing, OsO₄ is expensive – $332/g last time I checked, slightly cheaper if you buy in bulk. The other thing is that it is a highly toxic liquid with a low vapor pressure that should be treated with extreme care.
• Particularly noteworthy is its potential to cause blindness – all that retinol in your cornea is full of juicy double bonds that OsO₄ would love to hydroxylate. 
• The report on the first synthesis of cortisol from 1952 has a reaction that used 68.48 g of OsO₄. That clocks in at, let’s see…  $22,768 worth of OsO₄ at today’s prices. Surely there must be a better way? Thankfully, yes.
  
• The Upjohn process uses a catalytic amount of OsO₄ (usually about 1-2 mol% ) in the presence of a stoichiometric amount of oxidant that converts the Os(VI) product back to OsO₄. The oxidant of choice is generally N-methylmorpholine N-oxide (NMO) although various other oxidants can be used.
• [The original paper is here  – Org Synth. 1978, 58, 43 – and has helpful tables that compare oxidants and also its performance to KMnO₄]
• Yields are generally high and the reaction is mild. Furthermore there’s no need to add KHSO₃ since the osmate ester is cleaved under these conditions.
• It’s even possible to perform a hydroxylation on an alkene without affecting an alkyne, as OsO₄ does not react with alkynes.
  
• An enantioselective version of dihydroxylation known as the Sharpless asymmetric dihydroxylation has been developed. It also uses catalytic osmium (potassium osmate)  in the presence of a stoichiometric amount of oxidant.

Reactions of Vicinal Diols – Cleavage with NaIO₄

• Vicinal diols can undergo oxidative cleavage with various reagents to break a C-C bond and form two new C-O (pi) bonds.
• The most commonly used reagents for these purposes are sodium periodate (NaIO₄) and lead tetraacetate Pb(OAc)₄, although earlier we also touched on the fact that this is a prominent side reaction when performing dihydroxylations with KMnO₄.
• Sequentially treating a double bond with OsO₄ to give a diol followed by oxidative cleavage with NaIO₄ or Pb(OAc)₄ gives the functional equivalent of ozonolysis (reductive workup).
  

Summary

Let’s summarize the key points we’ve covered about OsO₄.

• OsO₄ will convert alkenes into vicinal diols (1,2-diols) via a concerted syn addition
• A reducing agent such as KHSO₃ is often added to liberate the diol from the osmate ester.
• The diols can undergo oxidative cleavage using a reagent such as NaIO₄ or Pb(OAc)₄ to give aldehydes/ketones.
• Using the oxidant N-methylmorpholine N-oxide (NMO) allows for the catalytic use of osmium.
• In the presence of multiple alkenes, OsO₄ will react with the most electron-rich alkene.
• A related reagent is cold, basic KMnO₄ that will also make vicinal syn diols. With KMnO₄, however, there is an increased risk of the resulting diol undergoing oxidative cleavage.