Addition of Grignard reagents to nitriles to give ketones (after hydrolysis)
Description: Grignard reagents will add once to nitriles to form imines. The imines can be treated with aqueous acid to give ketones.
- The purpose of the second step is to convert the intermediate imine into a ketone.
- Water (H2O) is generally sufficient although aqueous acid (H3O+) is more effective.
- X here can be Cl, Br or I, depending on how the Grignard reagent is made.
The Grignard reagent adds to the carbon of the nitrile, forming a new carbon-carbon bond (Step 1, arrows A and B). This is stable until water and acid is added (Step 2, arrows C an D) which forms the imine. Protonation of the imine nitrogen (Step 3, arrows E and F) results in the formation of the iminium ion, which undergoes 1,2-addition by water (Step 4,
arrows G and H). This species then undergoes proton transfer (Step 5, arrows I and J) to allow for the loss of ammonia (NH3) in a subsequent 1,2-elimination (Step 6, arrows K and L). Deprotonation of the carbonyl oxygen with base (Step 7, arrows M and N) then results in the ketone.
- Step 2 occurs only after the addition of aqueous acid. Note that a full equivalent of acid is necessary here to protonate the imine.
- Other acids can be used: the use of Cl(-) as a counter-ion for H3O(+) here is arbitrary here and of no consequence in the reaction except to balance the charge from H3O(+).
- Steps 3-7 are identical to those for the hydrolysis of imines.
- Other reasonable mechanisms can be drawn for proton transfer.
- Other bases could reasonably be used instead of water.
- A protonated imine is called an “iminium”.
(Advanced) References And Further Reading
- First example
Kharasch, M. S.; Reinmuth, O. Grignard Reactions of Nonmetallic Substances, Prentice-Hall, Englewood Cliffs, NJ, 1954, pp. 767-845
- Effet du benzene dans la reaction de Grignard sur les nitriles
Persephone Canonne, George B.Foscolos, Gilles Lema
Tetrahedron Letters 1980, 155
Use of benzene containing one equivalent of ether as solvent in Grignard reactions of nitriles at room temperature leads to increased yields of the corresponding ketones compared to results obtained for the same reactions in ether.
- Organometallic reaction mechanisms. XII. Mechanism of methylmagnesium bromide addition to benzonitrile
E. C. Ashby, Li-Chung. Chao, and H. M. Neumann
Journal of the American Chemical Society 1973 95 (15), 4896-4904
The kinetic data of the title reaction show a second-order reaction, first order in Grignard reagent and first order in nitrile. The results of rate studies in the presence of added MgBr2 show that the reaction of the Grignard reagent with benzonitrile occurs through both the (CH3)2Mg and CH3MgBr species.
- The Mechanism of Addition of Grignard Reagents to Nitriles
C. Gardner Swain
Journal of The American Chemical Society, 1947, 69(10), 2306
This paper is an early literature reference to this reaction and describes a kinetic study of the reaction between n-butylmagnesium bromide and benzonitrile, which was found to be 2nd order.
- Copper(I)-activated addition of Grignard reagents to nitriles. Synthesis of ketimines, ketones, and amines
Franz J. Weiberth and Stan S. Hall
The Journal of Organic Chemistry 1987 52 (17), 3901-390
The nucleophilic addition of Grignard reagents to nitriles, especially when using sterically demanding components, is effectively catalyzed by copper(I) salts.
- Double Addition of Organometallics to Nitriles: Toward an Access to Tertiary Carbinamines.
Advanced Synthesis & Catalysis, 359(2), 179–201
Pearson-Long, M. S. M., Boeda, F., & Bertus, P. (2016).
This review describes a variant of this reaction – the double addition of organometallics (e.g. Grignard reagents or organolithium reagents) to nitriles.