Master Organic Chemistry Reaction Guide

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.

Notes:

  • 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.

Examples:

Mechanism:

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.

Notes:

  • 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

1. First example
Kharasch, M. S.; Reinmuth, O. Grignard Reactions of Nonmetallic Substances, Prentice-Hall, Englewood Cliffs, NJ, 1954, pp. 767-845

2. a. Effet du benzene dans la reaction de Grignard sur les nitriles
Persephone Canonne, George B.Foscolos, Gilles Lema  Tetrahedron Letters 1980, 155 DOI: 10.1016/S0040-4039(00)71400-6
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.

    b. 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 DOI: 10.1021/ja00796a022
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.

    c. The Mechanism of Addition of Grignard Reagents to Nitriles
C. Gardner Swain Journal of The American Chemical Society, 1947, 69(10), 2306 DOI: 10.1021/ja01202a018
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.

3. 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 DOI: 10.1021/jo00226a033
The nucleophilic addition of Grignard reagents to nitriles, especially when using sterically demanding components, is effectively catalyzed by copper(I) salts.

4. Pearson-Long, M. S. M., Boeda, F., & Bertus, P. (2016).
Double Addition of Organometallics to Nitriles: Toward an Access to Tertiary Carbinamines. Advanced Synthesis & Catalysis, 359(2), 179–201 DOI: 10.1002/adsc.201600727
This review describes a variant of this reaction – the double addition of organometallics (e.g. Grignard reagents or organolithium reagents) to nitriles.

 

Comments

Comment section

25 thoughts on “Addition of Grignard reagents to nitriles to give ketones (after hydrolysis)

      1. no i think JARED is asking about why not the ketone formed further react with grignard reagent to give 3 degree alcohol….if it does is it a negative aspect of this reaction?? (if we wanted to get ketone)

      2. I remember that imine salt will generate after nitrile reacts with grignard reagent. Is it possible two equiv of grignard and one equiv of nitrile form the imine salt like R2C-N(MgX)2 ?? Could the negative charges on nitrogen be stabilized by magnesium cation ??

    1. You can’t. Because the that will form a -2 negative nitrogen which is highly unstable. There is another thing to mention here, your form the negative -1 nitrogen firstly then water or acid is added.

  1. On reaction with terminal alkyne Grignard reagent forms alkane but on reaction with hydrogen cyanide it does not form alkane…. Why???

  2. When adding the nitrile to the grignard, should it be dissolved in benzene and added by dripping at an appropriate rate to keep things under control?

    1. In general ethereal solvents tend to be used for Grignard reactions (e.g. THF, diethyl ether) but according to March’s Advanced Organic Chemistry 5th Ed., p. 1216, using benzene as a co-solvent increases yields. In one prep I found the Grignard is made and then the nitrile is added quickly at 0°C and then stirred for 3h. Interestingly reactions with nitriles are fairly slow (compared to near-instantaneous for ketones and aldehydes). Double addition is rare. See this prep. http://www.orgsyn.org/Result.aspx?ga=na [Org Syn Coll. 3, p. 26]

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