Kiliani-Fischer Synthesis

by James

Description: The Kiliani-Fischer synthesis is a way of extending sugars by one carbon. It leads to a mixture of stereoisomers.

1-header

Notes: This reaction essentially applies two reactions we cover in other sections – cyanohydrin formation and nitrile hydrolysis – toward the extension of sugars by a single carbon. Here, step 1 leads to formation of a cyanohydrin. There is no control of stereochemistry in this reaction, so a mixture of stereoisomers will form. Note how the aldehyde oxygen (blue) becomes the hydroxide oxygen in the second step. Step 2 involves hydrolysis of the nitrile to the carboxylic acid.

Examples:

2-examplesNotes: Step 1 is formation of the cyanohydrin, which can be done with any source of cyanide ion, such as NaCN, KCN, and so on. Step 2 is hydrolysis of the nitrile, which is performed with aqueous acid. H2SO4/H2O, H3O+, and so forth all perform exactly the same purpose.

Mechanism: The reaction begins with attack of the aldehyde by nitrile anion (Step 1, arrows A and B). Protonation of the anionic oxygen then leads to the cyanohydrin (Step 2, arrows C and D). Any stereoisomer formed in this process will be a mixture of stereoisomers. For example in the situation below one would obtain a 1:1 mixture of enantiomers.

3a-mech

Hydrolysis of the nitrile then leads to a racemic mixture of alpha-hydroxy acids.

3b-mech

If a stereoisomer is already present, then a mixture of diastereomers will form. This is the case with sugars, for example.

3a-mech-diastThe mechanism for acidic hydrolysis of a nitrile is exactly as depicted in the nitrile section:

Protonation of nitrogen by acid (Step 1, arrows A and B) makes the attached carbon more electrophilic. It is then attacked by water (Step 2, arrows C and D)
to give the protonated tautomer of an amide. Transfer of a proton from oxygen to nitrogen (Step 3, arrows E and F) leads to a species best depicted [by drawing a resonance form, arrows G and H] of an amide protonated on oxygen. Addition of water to the carbonyl carbon (Step 4, arrows I and J) is followed by a second proton transfer, which forms NH3+ (Step 5, arrows K and L). Elimination of ammonia (NH3) (Step 6, arrows M and N) lead to the protonated carboxylic acid, which is deprotonated by a weak base (Step 7, arrows O and P) to give the neutral carboxylic acid.

3c-nitrile hydr

Notes: This reaction is more of historical interest than anything else, seeing very little modern usage.

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