[Chemistry Class Notes] Mitsunobu Reaction Pdf for Exam

Mitsunobu 

The organic reaction which is responsible for transforming primary and secondary alcohols into ethers by treating them with diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) and triphenylphosphine is known as Mitsunobu reaction. The reaction requires a diazo carboxylate which is a compound having two carboxylate groups attached to nitrogen forming an azo bond(-N=N-). This reaction is named after Oyo Mitsunobu in the year 1967, who was a professor in Japan.

Every reaction has a driving force and the driving force of this reaction is the formation of the P=O bond. The affinity of phosphorus towards oxygen is very high and that is why the driving force of this reaction is the formation of the molecule Ph3P=O. 

Mitsunobu Reaction Procedure

Mitsunobu reaction follows Nucleophilic substitution reaction but the substitution reaction mechanism is not direct because alcohol(-OH) is not a good leaving group. Due to its bad leaving group characteristic, alcohol-containing hydrocarbon usually shows retention in the configuration of the final product as it has to go through SNi mechanism than the usual SN2 mechanism. 

SN2 mechanism shows inversion in the configuration of the final product and the rate of the reaction depends on both the substrate and the nucleophile i.e. the order is 2. 

Rate=k[substrate]1[Nucleophile]1

Order=1+1=2, therefore SN2 mechanism. 

Mechanism of Mitsunobu Reaction 

Step 1: 

In the first step, the triphenylphosphine donates its electron to the nitrogen in the azodicarboxylate forming an anion. 

The anion then attacks the acidic proton of the acid substrate forming a nitrogen-hydrogen bond in the dicarboxylate reagent and a zwitterion as an intermediate. 

Step 2: 

In the second step, the nitrogen then donates its lone pair to the acidic proton of alcohol which leads to the formation of an oxonium ion which then attacks the triphenylphosphine because of the affinity of oxygen towards phosphorus. 

Step 3: 

The product formed in the second step is attacked by the oxonium ion from behind which was formed due to the abstraction of an acidic proton from the acid substrate which leads to simultaneous removal of the molecule Ph3P=O and thus forming an ether, as the final product. 

Mitsunobu Reaction Conditions

The pKa value of the nucleophile is 12 or less than 12 for the reaction to take place successfully. The reason for the basic medium is to avoid the alkylation of azodicarboxylate. The overall reaction takes place in a neutral condition where the conditions aren’t too acidic or basic and the temperature can also be easily maintained as the reaction can be successfully carried out at 0°C to room temperature. The reaction uses standard non-polar solvents like THF and dichloromethane. It also uses polar solvents sometimes like DMF. 

Intramolecular Mitsunobu Reaction

As the name suggests, this reaction does not take place between two substrates rather formed from the reaction in the substrate alone. The final product achieved from this reaction is cyclic. When the phenolic oximes are activated by the triphenylphosphine and DEAD (Diethyl azodicarboxylate) at a mild neutral condition at 0°C temperature, then we get the final cyclic product, a cyclic heteroatom consisting of both oxygen and nitrogen i.e. oxazoles.

Advantages of Using DEAD

The advantages of using reagent DEAD or DIAD are-

(i) Their physical state is solid which helps in studying the reaction better.

(ii) Also, the polarity of the byproduct formed is completely different. 

Driving Force of the Mitsunobu Reaction

As we know that alcohol functional group is a bad leaving group and instead of giving an inverted final product it retains the configuration of the substrate. Therefore, for the removal of –OH groups and to obtain an inverted product, a strong driving force is needed and that is achieved in the Mitsunobu reaction by the formation of the P=O bond because of its very strong affinity.