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JOURNAL O F Pharmaceutical

Sciences
MUY 1968 volume 57, number 5

Review Article-
The Mannich Reaction
Mechanistic and Technological Considerations
By B. BLACKBURN THOMPSON

T HE EARLIEST EXAMPLES of the Mannich reac-


tion were published in succession by Tollens
and co-workers (1, 2), Petrenko-Kritschenko and
aminomethylation of phenols.’ In this case the
replaceable hydrogens are not all equivalent as
indicated in Scheme III. These examples
co-workers (3-6), and by Mannich and Krosche illustrate the complications which may result
(7). Mannich was the first to recognize the re- from the presence of multiple replaceable hydro-
action as a general one, and a detailed investiga- gen atoms in the molecule.
tion was begun in 1917. The Mannich reaction
was reviewed by Blicke (8), Karbe (9), Nobles
(10, 1 l ) , Reichert (12), and others (13, 14) and it
was the subject of recent books by Reichert (15)
@!-CH3
0
+ 2CH20 + 2HNb -
arid by IHellmann and Optiz (16). 0
The Mannich reaction consists of the condensa- p-CH(CH2-NR,), + 2H,O
tion of ammonia or a primary or secondary
aminc usually as the hydrochloride salt, an al- Scheme I
dehyde, and a compound capable of supplying one
or more active hydrogen atoms. As a result of
the reaction an aminomethyl group generally re- & C H 3 + CH20 + HNR, -+
places the active hydrogen atom. Products of
the condensation are known as “Mannich bases.”
A typical condensation, with acetophenone as the
active hydrogen compound, may be illustrated as
in Scheme I.
As cited in the excellent review by Blicke (8),
multiple product formation is possible. For ex- The amine used also promotes formation of
ample, multiple aminomethylations may occur at mixed products. With secondary amines, only
the a-position of compounds such as acetophe- a single product is possible, however, with pri-
none of the previous example, oiz., Scheme 11. mary amines and ammonia, reacting ratios of
Similarly, mono- and disubslituted products in- active hydrogen compounds, formaldehyde, and
cluding position isomers, result from multiple amine may be 2 : 2 : 1 and 3:3: 1, respectively. In
Received from the School of Pharmacy, University of
the reaction of antipyrine salicylate, formalde-
Georgia, Athens, GA 30601
The author acknowledges financial support from The Office I The observation that ortho-mono-substitution pre-
of General Research, The University of Georgia, Athens, G A dominates has been the subject of the mechanistic studies
30601. (17, 36).

715

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