The Einhorn–Brunner reaction is the designation for the

chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...

of imides with

alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl is derived from a cycloa ...

hydrazines Hydrazines (R2N−NR2) are a class of chemical compounds with two nitrogen atoms linked via a covalent bond and which carry from one up to four alkyl or aryl substituents. Hydrazines can be considered as derivatives of the inorganic hydrazine ( ...

to form an

isomeric In chemistry, isomers are molecules or polyatomic ions with identical molecular formulae – that is, same number of atoms of each element – but distinct arrangements of atoms in space. Isomerism is existence or possibility of isomers. Is ...

mixture of 1,2,4-triazoles. It was initially described by the German chemist

Alfred Einhorn Alfred Einhorn (27 February 1856 – 21 March 1917) was a German chemist most notable for first synthesizing procaine in 1905 which he patented under the name Novocain. Until that time the primary anesthetic in use was cocaine, however its undesi ...

in a paper, published in 1905, describing N-methylol compounds of

amide In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...

s. In 1914 chemist Karl Brunner published a paper expanding on Einhorn's research of the reaction pictured below, thus resulting in the naming as the Einhorn-Brunner. Substituted 1,2,4-triazole have been prepared from diverse imides and hydrazines.*

Regioselectivity

In the case that the R groups of the imide are different, the reaction has

regioselectivity In chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong base ...

. In their research on the synthesis of 1,2,4-triazoles, Potts determined that the strongest acidic group attached to the side of the imide will be favored for the 3 position on the triazole ring. In the diagram below, if one considers the blue R group to be more acidic in respect to the green, the favored product would be the isomer on the right.

Mechanism

For clarity in depicting the

electron The electron ( or ) is a subatomic particle with a negative one elementary electric charge. Electrons belong to the first generation of the lepton particle family, and are generally thought to be elementary particles because they have no ...

flow of the mechanism, the image below only consists of one of the isomers generated in an Einhorn–Brunner reaction: The first step of the mechanism involves the protonating of the substituted nitrogen of the hydrazine 1, generating the cation 2. Protonated hydrazine 2 protonates the oxygen of one of the carbonyl groups of the imide. This allows for an attack on the electrophilic carbon of the protonated carbonyl group by the primary amino group of the hydrazine, producing 3. The loss of water and subsequent generation of a double bond between the recently formed nitrogen-carbon sigma bond results in the formation of iminiumion 4. 4 undergoes a 1,5-proton shift from the nitrogen to the carbonyl oxygen, seen in 5. Intramolecular attack of the electrophilic carbonyl carbon by the nitrogen, resulting in a 5-membered ring closure of the positively charged 6. Elimination of a water group, and then a proton results in the intermediates of 7 and 8 respectively, and finally results in the formation of 9, one 1,2,4-triazole isomer.

Applications

Triazole A triazole is a heterocyclic compound featuring a five-membered ring of two carbon atoms and three nitrogen atoms with molecular formula C2H3N3. Triazoles exhibit substantial isomerism, depending on the positioning of the nitrogen atoms within t ...

s have been found to have a number of real world applications as

antibacterial An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention ...

agents. The Einhorn–Brunner reaction maintains scientific importance and relevance in the production of 1,2,4-triazoles, which can be further substituted for their medicinal value. Research done by Pattan ''et al.'', specifically on 1,2,4-triazoles, found antibacterial, antifungal, antitubercular, and

anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...

activity of variously substituted compounds. Klimešová and colleagues also report antimycobacterial activity of 1,2,4-triazoles against tuberculosis, but also risk a low level of

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...

Related reactions

* Pellizzari reaction

References

{{DEFAULTSORT:Einhorn-Brunner reaction Heterocycle forming reactions Name reactions