Hydrolysis of imines to give ketones (or aldehydes)
Description: Treatment of imines with water leads to their hydrolysis back to aldehydes (or ketones) and an amine.
Notes: The reaction is assisted through the use of an acid catalyst.
Notes: Note that the third example is intramolecular.
Mechanism: Protonation of the imine nitrogen (Step 1, arrows A and B) results in the formation of the iminium ion, which undergoes 1,2-addition by water (Step 2, arrows C and D). Transfer of a proton (Step 3, arrows E and F) followed by 1,2 elimination of ammonia (Step 4, arrows G and H) lead to an oxonium ion, which is then deprotonated to give the neutral ketone.
- Acid is helpful but not an absolute requirement for this reaction. Reasonable mechanisms can be drawn without acid.
- The “Cl” here in H3O+ Cl- is completely unimportant, just meant to show a balance of charge for H3O+. Other counter ions such as Br-, HSO3-, etc. would work just as well.
- Note that this is an equilibrium reaction and goes in this direction because of the large excess of water. It is the exact reverse of imine formation.
- There are certainly other reasonable ways to draw proton transfer (Step 3) and other species besides H2O that could conceivably act as bases in the last step.
(Advanced) References and Further Reading
Imines are also known as “Schiff bases” in the classical organic chemistry literature, hence the name in the titles of some of these papers.
- On the Mechanism of Schiff Base Formation and Hydrolysis
E. H. Cordes and W. P. Jencks
Journal of the American Chemical Society 1962, 84 (5), 832-837
In this classic paper, the authors present evidence that at neutral pH, loss of H2O is rate determining, but at acidic pH, attack of the amine is rate-determining. The maximum rate occurs near pH 4.
- The Mechanism of Hydrolysis of Schiff Bases Derived from Aliphatic Amines
E. H. Cordes and W. P. Jencks
Journal of the American Chemical Society 1963, 85 (18), 2843-2848
Under acidic conditions, the reaction proceeds through attack of water on the conjugate acid of the imine. In neutral and basic conditions, the rate-determining step is attack of water; under acidic conditions, the rate-determining step is decomposition of the tetrahedral addition intermediate.
- Kinetics and mechanism of the hydrolysis of N-isobutylidenemethylamine in aqueous solution
Jack Hine, John C. Craig Jr., John G. Underwood II, and Francis A. Via
Journal of the American Chemical Society 1970, 92 (17), 5194-5199
These papers provide experimental evidence for the varying mechanisms of the hydrolysis of imines in both acidic and basic media.
- The Chemistry of Imines.
Robert W. Layer
Chemical Reviews 1963, 63 (5), 489-510
Section IV.A. in this review (“Addition of Water”) has a short discussion on the hydrolysis of imines, which is a good place to get started.
- Hydrolysis of imines: kinetics and mechanism of spontaneous acid-, base-, and metal ion-induced hydrolysis of N-salicylidene-2-aminothiazole
Anadi C. Dash, Bhaskar Dash, and Somnath Praharaj
Chem. Soc., Dalton Trans., 1981, 2063-2069
Lewis-acid (e.g. metal ion) catalyzed hydrolysis of imines is also possible, as this paper describes.
- Kinetic Study of the Hydrolysis of Schiff Bases Derived from 2-Aminothiophenol
Hassib, H.B., Abdel-Kader, N.S. & Issa, Y.M.
J. Solution Chem 41, 2036–2046 (2012)
A very nice thorough investigation of the mechanism of hydrolysis of a specific imine, and includes the deriving of the specific rate equations for acid-catalyzed and base-catalyzed hydrolysis.
- Deprotonation of the Schiff base of rhodopsin is obligate in the activation of the G protein
C. Longstaff, R. D. Calhoon, and R. R. Rando
PNAS June 1, 1986 83 (12) 4209-4213
The chemistry of imines is of tremendous significance in biochemistry. Vision is based on the isomerization of retinal, which is bound to a protein called rhodopsin via a imine linkage through the amine side chain of a lysine