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The ANRORC mechanism in 
The exclusion of a second intermediate in this reaction, the Meisenheimer complex B in favor of the ring-opened ANRORC intermediate is based on several pieces of evidence. With other amines such as 
More evidence is gained by isotope labeling with 
The final piece of evidence is provided by an isotope scrambling experiment with both nitrogen atoms in the pyrimidine core replaced by the 14N 
In the final product 4 (reversed to the reactant, after acid hydrolysis and bromination of 2) roughly half the isotope content is lost, clearly demonstrating that one internal nitrogen atom has been displaced to an external nitrogen atom.
The
organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...
describes a special type of substitution reaction
A substitution reaction (also known as single displacement reaction or single substitution reaction) is a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. Substitution reactions ar ...
. ANRORC stands for Addition of the Nucleophile, Ring Opening, and Ring Closure in nucleophilic attack on ring systems and it helps to explain product formation and distribution in some nucleophilic substitution
In chemistry, a nucleophilic substitution (SN) is a class of chemical reactions in which an electron-rich chemical species (known as a nucleophile) replaces a functional group within another electron-deficient molecule (known as the electrophile) ...
s especially in heterocyclic compound
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 organic chemistry is the branch of organic chemistry dealing with the synthesis, proper ...
s. It is widely used in medicinal chemistry
Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with drug design, designing and developing pharmaceutical medication, drugs. Medicinal chemistry involves the identification, ...
.
This reaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical reaction occurs.
A chemical mechanism is a theoretical conjecture that tries to describe in detail what takes place at each stage ...
has been extensively studied in reactions of metal amide nucleophiles (such as sodium amide
Sodium amide, commonly called sodamide (systematic name sodium azanide), is the inorganic compound with the formula . It is a salt composed of the sodium cation and the azanide anion. This solid, which is dangerously reactive toward water, is whit ...
) and substituted pyrimidine
Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The oth ...
s (for instance 4-phenyl-6-bromopyrimidine 1) in ammonia
Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...
at low temperatures. The main reaction product is 4-phenyl-6-aminopyrimidine 2 with the bromine
Bromine is a chemical element; it has chemical symbol, symbol Br and atomic number 35. It is a volatile red-brown liquid at room temperature that evaporates readily to form a similarly coloured vapour. Its properties are intermediate between th ...
substituent
In organic chemistry, a substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule.
The suffix ''-yl'' is used when naming organic compounds that contain a single bond r ...
replaced by an 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 ...
. This rules out the formation of an aryne intermediate A which would also give the 5-substituted isomer.
The exclusion of a second intermediate in this reaction, the Meisenheimer complex B in favor of the ring-opened ANRORC intermediate is based on several pieces of evidence. With other amines such as piperidine
Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor de ...
the ring-opened compound after loss of hydrogen bromide
Hydrogen bromide is the inorganic compound with the formula . It is a hydrogen halide consisting of hydrogen and bromine. A colorless gas, it dissolves in water, forming hydrobromic acid, which is saturated at 68.85% HBr by weight at room temper ...
to the nitrile
In organic chemistry, a nitrile is any organic compound that has a functional group. The name of the compound is composed of a base, which includes the carbon of the , suffixed with "nitrile", so for example is called " propionitrile" (or pr ...
is also the isolated reaction product:
More evidence is gained by isotope labeling with deuterium
Deuterium (hydrogen-2, symbol H or D, also known as heavy hydrogen) is one of two stable isotopes of hydrogen; the other is protium, or hydrogen-1, H. The deuterium nucleus (deuteron) contains one proton and one neutron, whereas the far more c ...
at C5:
The deuterium atom is no longer present in the reaction product and this is again explained by the ANRORC mechanism where the ring-opened intermediate 4 is a tautomer
In chemistry, tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert.
The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the reloca ...
ic pair enabling fast H-D exchange:
The final piece of evidence is provided by an isotope scrambling experiment with both nitrogen atoms in the pyrimidine core replaced by the 14N isotope
Isotopes are distinct nuclear species (or ''nuclides'') of the same chemical element. They have the same atomic number (number of protons in their Atomic nucleus, nuclei) and position in the periodic table (and hence belong to the same chemica ...
to a degree of 3% each:
In the final product 4 (reversed to the reactant, after acid hydrolysis and bromination of 2) roughly half the isotope content is lost, clearly demonstrating that one internal nitrogen atom has been displaced to an external nitrogen atom.
The Zincke reaction
The Zincke reaction is an organic reaction, named after Theodor Zincke, in which a pyridine is transformed into a pyridinium salt by reaction with 2,4-dinitro-chlorobenzene and a primary amine.
The Zincke reaction should not be confused with t ...
is a named reaction involving an ANRORC mechanism.
References
{{Reflist Reaction mechanisms