The Eschweiler–Clarke reaction (also called the Eschweiler–Clarke methylation) is a
chemical reaction
A chemical reaction is a process that leads to the chemistry, chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an Gibbs free energy, ...
whereby a primary (or secondary)
amine
In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...
is
methylated
Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These term ...
using excess
formic acid
Formic acid (), systematically named methanoic acid, is the simplest carboxylic acid. It has the chemical formula HCOOH and structure . This acid is an important intermediate in chemical synthesis and occurs naturally, most notably in some an ...
and
formaldehyde
Formaldehyde ( , ) (systematic name methanal) is an organic compound with the chemical formula and structure , more precisely . The compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde. It is stored as ...
.
Reductive amination
Reductive amination (also known as reductive alkylation) is a form of amination that converts a carbonyl group to an amine via an intermediate imine. The carbonyl group is most commonly a ketone or an aldehyde. It is a common method to make amine ...
reactions such as this one will not produce quaternary ammonium salts, but instead will stop at the tertiary amine stage. It is named for the German chemist
Wilhelm Eschweiler (1860–1936) and the British chemist
Hans Thacher Clarke
Hans Thacher Clarke (27 December 1887 – 21 October 1972) was a prominent biochemist during the first half of the twentieth century. He was born in England where he received his university training, but also studied in Germany and Ireland. He sp ...
(1887–1972).
Mechanism
The reaction is generally performed in an aqueous solution at close to boiling. The first methylation of the amine begins with
imine
In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...
formation with formaldehyde. The formic acid acts as a source of
hydride
In chemistry, a hydride is formally the anion of hydrogen (H−), a hydrogen ion with two electrons. In modern usage, this is typically only used for ionic bonds, but it is sometimes (and has been more frequently in the past) applied to all che ...
and
reduces the imine to a secondary amine. Loss of
carbon dioxide
Carbon dioxide is a chemical compound with the chemical formula . It is made up of molecules that each have one carbon atom covalent bond, covalently double bonded to two oxygen atoms. It is found in a gas state at room temperature and at norma ...
gas renders the reaction irreversible. Despite being more hindered, the formation of the tertiary amine is more favorable, as the intermediate in iminium ion is formed without needing to protonate. Hence the treatment of a primary amine with less than 2 equivalents of formaldehyde will give more tertiary than secondary amine, along with unreacted starting material.
From this mechanism it is clear that a quaternary ammonium salt will never form, because it is impossible for a tertiary amine to form another imine or iminium ion.
Chiral amines typically do not racemize under these conditions.
[)]
Altered versions of this reaction replace formic acid with
sodium cyanoborohydride
Sodium cyanoborohydride is a chemical compound with the formula . It is a colourless salt used in organic synthesis for chemical reduction including that of imines and carbonyls. Sodium cyanoborohydride is a milder reductant than other convention ...
.
See also
*
Leuckart–Wallach reaction
The Leuckart reaction is the chemical reaction that converts aldehydes or ketones to amines. The reaction is an example of reductive amination. The reaction, named after Rudolf Leuckart (chemist), Rudolf Leuckart, uses either ammonium formate or ...
*
Pictet–Spengler reaction
The Pictet–Spengler reaction is a chemical reaction in which a β-arylethylamine undergoes Condensation reaction, condensation with an aldehyde or ketone followed by ring closure. The reaction was first discovered in 1911 by Amé Pictet and The ...
References
{{DEFAULTSORT:Eschweiler-Clarke Reaction
Organic redox reactions
Methylation
Name reactions
Formaldehyde