Rather than use two steps to convert the OH group first to a sulfonate ester, and then displace it, it is possible to use a method that allows us to put an alcohol straight into a reaction mix ture and get an SN2 product in one operation. This is the Mitsunobu reaction. In this reaction, the alcohol becomes the electrophile, the nucleophile is usually relatively weak (the conjugate base of a carboxylic acid, for example), and there are two other reagents.

One of these reagents, Ph3P, triphenylphosphine, is the simple phosphine you met in Chapter 11. Phosphines are nucleophilic, but not basic like amines. The other reagent deserves more comment. Its full name is diethyl azodicarboxylate, or DEAD. So how does the Mitsunobu reaction work? It’s a long mechanism, but don’t be discouraged: there is a logic to each step and we will guide you through it gently. The first stage involves neither the alcohol nor the added nucleophile. The phosphine adds to the weak N=N π bond to give an anion stabilized by one of the ester groups.

You will note that the nucleophile has been added as its conjugate acid ‘HNu’—often this might be a carboxylic acid, for example benzoic acid. The anion produced by this first stage is basic enough to remove a proton from this acid, generating Nu− ready for reaction.

Oxygen and phosphorus have a strong affinity, and the positively charged phosphorus is now attacked by the alcohol, displacing a second nitrogen anion in an SN2 reaction at phosphorus. The nitrogen anion generated in this step is stabilized by conjugation with the ester, but rapidly removes the proton from the alcohol to give an electrophilic R–O–PPh₃⁺ species and a by-product, the reduced form of DEAD.

Finally, the anion of the nucleophile can now attack this phosphorus derivative of the alcohol in a normal SN2 reaction at carbon with the phosphine oxide as the leaving group. We have arrived at the products.

The whole process takes place in one operation. The four reagents are all added to one flask and the products are the phosphine oxide, the reduced azo diester with two NH bonds replacing the N=N double bond, and the product of an SN2 reaction on the alcohol. Another way to look at this reaction is that a molecule of water must formally be lost: OH, must be removed from the alcohol and H from the nucleophile. These atoms end up in very stable molecules— the P=O and N–H bonds are strong where the N=N bond was weak, compensating for the sacrifice of the strong C–O bond in the starting alcohol. If this is all correct, then the vital SN2 step should lead to inversion as it always does in SN2 reactions. This turns out to be one of the great strengths of the Mitsunobu reaction—it is a reliable way to replace OH by a nucleophile with inversion of configuration. The most dramatic example is probably the formation of esters from secondary alcohols with inversion. Normal ester formation leads to retention as the C–O bond of the alcohol is not broken: com pare these two reactions and note the destination of the coloured oxygen (and hydrogen) atoms.

مواضيع ذات صلة

A very bad nucleophile in a good SN1 reaction: the Ritter reaction

The nucleophile in SN1 reactions

Epoxides as electrophiles

Ethers as electrophiles

Nucleophilic substitutions on alcohols: how to get an OH group to leave

A closer look at electronic effects

The effect of solvent

A closer look at steric effects

Adjacent C=C or C=O π systems increase the rate of SN2 reactions

An adjacent C=C π system stabilizes a carbocation: allylic and benzylic carbocations

Alkyl substituents stabilize a carbocation

Shape and stability of carbocations