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The Minisci reaction () is a 
named reaction A name reaction is a chemical reaction named after its discoverers or developers. Among the tens of thousands of organic reactions that are known, hundreds of such reactions are well-known enough to be named after people. Well-known examples include ...
in organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, ...
. It is a nucleophilic radical substitution
In organic chemistry, a radical-substitution reaction is a substitution reaction involving free radicals as a reactive intermediate.March Jerry; (1985). Advanced organic chemistry reactions, mechanisms and structure (3rd ed.). New York: John Wile ...
to an electron deficient aromatic compound
Aromatic compounds, also known as "mono- and polycyclic aromatic hydrocarbons", are organic compounds containing one or more aromatic rings. The parent member of aromatic compounds is benzene. The word "aromatic" originates from the past grouping ...
, most commonly the introduction of an 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 ...
group to a nitrogen containing heterocycle
A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...
. The reaction was published in 1971 by F. Minisci. In the case of N-Heterocycles, the conditions must be acidic to ensure protonation of said heterocycle. A typical reaction is that between pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a ...
and pivalic acid
Pivalic acid is a carboxylic acid with a molecular formula of (CH3)3CCO2H. This colourless, odiferous organic compound is solid at room temperature. A common abbreviation for the pivalyl or pivaloyl group (''t''-BuC(O)) is Piv and for pivalic acid ...
with silver nitrate
Silver nitrate is an inorganic compound with chemical formula . It is a versatile precursor to many other silver compounds, such as those used in photography. It is far less sensitive to light than the halides. It was once called ''lunar causti ...
, sulfuric acid and ammonium persulfate
Ammonium persulfate (APS) is the inorganic compound with the formula (NH4)2S2O8. It is a colourless (white) salt that is highly soluble in water, much more so than the related potassium salt. It is a strong oxidizing agent that is used as a catalys ...
to form 2-tert-butylpyridine. The reaction resembles Friedel-Crafts alkylation but with opposite reactivity and selectivity.
The Minisci reaction often produces a mixture of regioisomers that can complicate product purification, but modern reaction conditions are incredibly mild, allowing a wide range of alkyl groups to be introduced. Depending on the radical source used, one side-reaction is acylation
In chemistry, acylation (or alkanoylation) is the chemical reaction in which an acyl group () is added to a compound. The compound providing the acyl group is called the acylating agent.
Because they form a strong electrophile when treated with ...
, with the ratio between alkylation and acylation depending on the substrate and the reaction conditions. Due to the inexpensive raw materials and simple reaction conditions, the Minisci reaction has found many applications in heterocyclic chemistry.
Utility of the Minisci Reaction
The reaction allows for alkylation of electron deficient heterocyclic species which is not possible with Friedel-Crafts chemistry. A method for alkylating electron deficient arenes,nucleophilic aromatic substitution
A nucleophilic aromatic substitution is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring. Aromatic rings are usually nucleophilic, but some aromatic compou ...
, is also unavailable to electron deficient heterocycles as the ionic nucleophilic species used will deprotonate the heterocycle over acting as a nucleophile. Again, in contrast to nucleophilic aromatic substitution, the Minisci reaction does not require functionalisation of the arene, allowing for direct C-H functionalisation.
Further to this, the generated alkyl radical species will not rearrange during the reaction in the way that alkyl fragments appended by Friedel-Crafts alkylation often will; meaning groups such as n-pentyl and cyclopropyl groups can be added unchanged. The alkyl radical is also a 'soft' nucleophile and so is very unlikely to interact with any 'hard' electrophiles (carbonyl species for example) already present on the heterocycle. Which increases the functional group
In organic chemistry, a functional group is a substituent or moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions regardless of the re ...
tolerance of the reaction.
The reaction has been the subject of much research in recent years, with a focus placed on improved reactivity towards a greater variety of heterocycles, increasing the number of alkylating reagents that can be used, and employing milder oxidants and acids.
Mechanism
Afree radical
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is formed from the carboxylic acid in an oxidative decarboxylation
Oxidative decarboxylation is a decarboxylation reaction caused by oxidation. Most are accompanied by α- Ketoglutarate α- Decarboxylation caused by dehydrogenation of hydroxyl carboxylic acids such as carbonyl carboxylic acid, malic acid, isocitr ...
with silver
Silver is a chemical element with the symbol Ag (from the Latin ', derived from the Proto-Indo-European ''h₂erǵ'': "shiny" or "white") and atomic number 47. A soft, white, lustrous transition metal, it exhibits the highest electrical ...
salts and an oxidizing agent. The oxidizing agent (ammonium persulfate) oxidizes the Ag(+) to Ag(2+) under the acidic reaction conditions. This induces a hydrogen atom abstraction
In chemistry, a hydrogen atom abstraction or hydrogen atom transfer (HAT) is any chemical reaction in which a hydrogen free radical (neutral hydrogen atom) is abstracted from a substrate according to the general equation:
:X^\bullet + H-Y -> X-H ...
by the silver, followed by radical decarboxylation. The carbon-centered radical then reacts with the pyridinium
Pyridinium refers to the cation . It is the conjugate acid of pyridine. Many related cations are known involving substituted pyridines, e.g. picolines, lutidines, collidines. They are prepared by treating pyridine with acids.
As pyridine is ...
aromatic compound. The ultimate product is formed by rearomatization. The acylated product is formed from the acyl radical.
References
{{Reflist Organic reactions Name reactions Carbon-carbon bond forming reactions