What is Delepine Reaction?
Delepine reaction is the synthesis of primary amines, in which halogenated hydrocarbons react with hexamethylenetetramine (urotropine) to produce salts, which in ethanol are hydrolysed into primary amines using hydrochloric acid. The most commonly used halogenated hydrocarbons are active halogenated hydrocarbons, including allylic, benzyl and α-haloketones.
The advantages of the reaction are easy availability of substrates, few side reactions, simple reaction steps, and mild conditions. Hexamethylenetetramine is already a tertiary amine, and the first step can only introduce an alkyl group on nitrogen, so relatively pure primary amines are generated after hydrolysis.
- Reagents: Hexamethylenetetramine (HMTA), alkyl halide, acid (e.g., HCl)
- Reactants: Alkyl halide (primary or secondary), HMTA.
- Products: Primary amines.
- Reaction type: Formation of C-N bonds.
- Related reactions: Gabriel synthesis (another method for synthesizing primary amines).
Fig 1. Delepine reaction and its mechanism. [1]
Mechanism of Delepine Reaction
The hexamethylenetetraammonium salt is obtained by SN2 reaction. In chloroform, the starting materials are soluble and the product can be crystallized after the reaction, usually without further purification.
In neutral aqueous solution, hexamethylenetetraammonium salt remains stable even at high temperatures. Hexamethylenetetraammonium salt decomposes in dilute aqueous acid, and the derived ammonium salt also decomposes to form amine hydrochloride and formaldehyde (and formaldehyde diethyl acetal).
During acidic or ethanolic hydrolysis, hemiacetals are first formed; these further decompose to form formaldehyde or diethyl acetal, ammonium salt and amine hydrochloride.
Application Examples of Delepine Reaction
The delepine reaction is widely used in organic synthesis, especially in the pharmaceutical industry. Some notable examples include:
- Example 1: Isoindoline-1-imine derivatives have been successfully used in drug discovery in medicinal chemistry, such as inhibitors, intermediates, DNA intercalators and pesticides. Igor V. Levkov et al. reported an unconventional procedure for the Delépine reaction of o-bromomethylbenzonitrile, leading to the synthesis of 2-(methoxymethyl)isoindolin-1-imine derivatives. [2]
- Example 2: Ahmed A. Al-Amiery et al. synthesized 4-iminocoumarin from 4-chlorocoumarin instead of 4-aminocoumarin using the Delepine reaction. [3]
Fig 2. Synthetic examples via Delepine reaction.
Related Products
| CAS No. | Structure | Product | Inquiry |
| 106089-20-7 |  | (2S)-3-Bromo-2-hydroxy-2-methylpropanoic acid | Inquiry |
| 1113-59-3 |  | Bromopyruvic acid | Inquiry |
| 261904-39-6 |  | (2R)-3-Bromo-2-hydroxy-2-methylpropanoic acid | Inquiry |
| 526-78-3 |  | 2,3-Dibromosuccinic acid | Inquiry |
| 56970-78-6 |  | 3-Bromoisobutyric acid | Inquiry |
| 600-05-5 |  | 2,3-Dibromopropionic acid | Inquiry |
| 608-36-6 |  | 2,3-Dibromo butanedioic acid | Inquiry |
| 923-06-8 |  | Bromosuccinic acid | Inquiry |
| 72707-66-5 |  | 2-(Bromomethyl)acrylic Acid | Inquiry |
References
- Delepine, M. Bull. Soc. Chim. Fr. 1895, 13, S352.
- Levkov, Igor V., et al. Tetrahedron Letters, 2021, 67, 152866.
- Al-Amiery, Ahmed A., et al. Research on Chemical Intermediates, 2013, 39, 1385-1391.
