Hydroboration Oxidation

Core Concepts

This article explores hydroboration oxidation, a useful reaction in synthetic organic chemistry to add a single alcohol to an alkene.

Topics Covered in Other Articles

Reactants for Hydroboration Oxidation

Diborane

Diborane is a boron hydride that dimerizes at STP to form a molecule with the formula B₂H₆. This unconventional bonding combined with boron’s unusual metalloid behavior creates a potent electrophile, which is especially important for hydroboration.

Hydrogen Peroxide

Hydrogen peroxide is a strong oxidizer in aqueous solution, and eventually produces the hydroperoxide anion in this reaction, which is the active oxidizing species. Additionally, hydrogen peroxide is a good source of hydroxide anions, which are also useful to this reaction.

Base

Not always used in hydroboration oxidation, the addition of an Arrhenius base improves the yield for regiospecific hydroboration oxidation by exploiting Le Chatelier’s principle. Arrhenius bases contain a positive alkali cation (i.e. Na⁺, K⁺, Mg²⁺, etc.) and the negative hydroxide anion (OH^–).

Solvent

Tetrahydrofuran (THF) is the most common solvent for this reaction. THF is a Lewis base, and thus is used to stabilize the diborane in solution and prevents it from splitting into the borane monomers. Also used for this purpose is diglyme, also a Lewis acid. THF does not react during the main mechanism, and is effective at solvating both hydrocarbons and hydrocarbon-alcohols.

Mechanism of Hydroboration Oxidation

Hydroboration

1. Diborane disassociates into two BH₃, later, the pi electron pair from the alkene attacks the boron atom.

2. An intermediate forms where the boron bonds to the more accessible carbon. Electrons flow from the B-H bond to a H atom in borane, conferring a negative charge which then donates the pair to the carbocation. Note that the carbocation cannot migrate due to the filled octet of the adjacent carbon. This differs from traditional electrophilic substitution, and hence explains why the major product does NOT obey Markovnikov’s rule.

3. The alkene is successfully underwent hydroboration so that a boron and hydrogen atoms added to different carbons with syn stereochemistry.

Alkene reacts with borane during the first step of hydroboration oxidation.
A BH2 group is added to the less substituted carbon and a hydrogen is added to the other side. — The Alkene reacts with borane in a hydroboration reaction to add a BH₂ and an H across the double bond.

4. This reaction repeats similarly two more times with the remaining two hydrogen atoms on the borane, to yield the tri-substituted product.

Tri-substituted borane with 3 equivalents of the reactant — This tri-substituted borane is produced from 3 equivalents of the reactant under ideal conditions

Oxidation

5. Hydrogen peroxide intermittently disassociates into the hydroperoxide anion, which then attacks the substituted boron center.

6. An electron pair from the boron-carbon bond travels to the proximal oxygen atom, and the peroxide electron pair travels to the further oxygen, and eventually to one of the hydrocarbon groups, creating an ether-like intermediate:

After the hydroboration, oxidation from hydrogen peroxide introduces an oxygen atom between the boron and the carbon-based reactant group — The oxidation reaction of the borane intermediate to form an oxyborate intermediate.

7. (Not Shown) A hydroxide anion is also a product, making a basic solution. This is an important consideration if other parts of your reactant are base-sensitive.

8/9. This oxidation step continues two more times, inserting oxygen atoms between the boron and they hydroborated reactant.

10. Water hydrolyzes this structure at all three oxygen atoms to create boric acid, and the alcohol.

After complete oxidation of the borane, it is hydrolyzed at the three sites to yield boric acid and 3 equivalents of the alcohol.

Stereochemistry of Hydroboration Oxidation Reactions

Hydroboration creates the anti-Markovnikov product. This means that the alcohol will end up on the less substituted carbon, while the hydrogen adds to the more substituted carbon.

Hydroboration oxidation produces the anti-markovnikov product, not the Markovnikov product. — Both the Anti Markovnikov (center) and Markovnikov (right) products are shown from hydroborating/oxidizing the starting material (left).

Hydroboration/oxidation proceeds with syn stereochemistry, where the alcohol and hydrogen add to the same face of the double bond.

Hydroboration oxidation proceeds with syn stereochemistry. The H and the OH are added to the same face of the double bond. — Both the Syn and the Anti products of hydroborating/oxidizing the starting material are shown. Only the syn product is created.

With no outstanding steric or electrical factors, the product will be racemic if the most substituted carbon on the alkene in the reactant is secondary.

Other Hydroboration Oxidation Reactions

Hydroboration oxidation can also proceed with other borane derivatives. By replacing some of the hydrogens on borane with engineered carbon groups, hydroboration of certain alkenes (regioselectivity) and in a certain direction (stereoselectivity) is certainly possible. This property makes synthesis of alcohols a very exact process, which is indeed very useful in the synthesis of medicinal molecules.