The Ritter reaction is a

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 ...

that transforms a

nitrile In organic chemistry, a nitrile is any organic compound that has a functional group. The prefix ''cyano-'' is used interchangeably with the term ''nitrile'' in industrial literature. Nitriles are found in many useful compounds, including met ...

into an ''N''-alkyl

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 is ...

using various

electrophilic In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carri ...

alkylating Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...

reagents. The original reaction formed the

alkylating agent Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting al ...

using an

alkene In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond. Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...

in the presence of a strong acid. Ritter-Reaktion_1d

Mechanism and scope

The Ritter reaction proceeds by the

addition of either a

carbenium ion A carbenium ion is a positive ion with the structure RR′R″C+, that is, a chemical species with a trivalent carbon that bears a +1 formal charge. In older literature the name carbonium ion was used for this class, but now it refers exclusivel ...

or covalent species to the

. The resulting

nitrilium ion A nitrilium ion is a nitrile that has been protonated, CNHsup>+, or alkylated, CNR′sup>+. Synthesis Nitriles are only weakly basic and are poor nucleophiles, but they will attack very reactive electrophiles such as carbocations. Nitrilium sa ...

hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...

water Water (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as a ...

to the desired amide. Ritter reaction mechanism, step by step

Primary, secondary, tertiary, and benzylic

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

s, as well as ''tert''-butyl acetate, also successfully react with nitriles in the presence of strong acids to form amides via the Ritter reaction. A wide range of nitriles can be used. In particular, formonitrile (hydrogen cyanide) can be used to prepare formamides, which are useful precursors to isocyanides.

Applications

The large scale application of the Ritter reaction is in the synthesis of tert-octylamine. An estimated 10,000 tons/y (year: 2000) of this and related lipophilic amines are prepared in this way. Otherwise, the Ritter reaction is most useful in the formation of amines and amides of pharmaceutical interest. Real world applications include

Merck Merck refers primarily to the German Merck family and three companies founded by the family, including: * the Merck Group, a German chemical, pharmaceutical and life sciences company founded in 1668 ** Merck Serono (known as EMD Serono in the Unite ...

's industrial-scale synthesis of anti-

HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...

drug

Crixivan Indinavir (IDV; trade name Crixivan, made by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. Th ...

(indinavir); the production of the falcipain-2 inhibitor PK-11195; the synthesis of the

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...

aristotelone;Kurti, L.; Czako, B. (2005). Strategic Applications of Named in Organic Synthesis. Burlington, MA Elsevier Academic Press. and synthesis of

Amantadine Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended due to wid ...

, an antiviral and antiparkinsonian drug. Other applications of the Ritter reaction include synthesis of dopamine receptor

ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...

and licit and illicit production of racemic

amphetamine Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...

from

allylbenzene Phenylpropene is the organic compound with the formula C6H5CH2CH=CH2. It is a colorless liquid. The compound consists of a phenyl group attached to allyl. Phenylpropene isomerizes to trans-propenylbenzene. In plant biochemistry, the phenylpro ...

and

methyl cyanide Acetonitrile, often abbreviated MeCN (methyl cyanide), is the chemical compound with the formula and structure . This colourless liquid is the simplest organic nitrile ( hydrogen cyanide is a simpler nitrile, but the cyanide anion is not cla ...

. The Ritter reaction is inferior to most

amination Amination is the process by which an amine group is introduced into an organic molecule. This type of reaction is important because organonitrogen compounds are pervasive. Reactions ;Aminase enzymes Enzymes that catalyse this reaction are termed a ...

methods because it cogenerates substantial amounts of salts. Illustrative is the conversion of isobutylene to

tert-butylamine ''tert''-Butylamine is an organic chemical compound with the formula (CH3)3CNH2. It is a colorless liquid with a typical amine-like odor. ''tert''-Butylamine is one of the four isomeric amines of butane, the others being ''n''-butylamine, ''s ...

using HCN and sulfuric acid followed by base neutralization. The weight of the salt byproduct is greater than the weight of the amine. In the laboratory, the Ritter reaction suffers from the necessity of an extremely strong acid

catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

. Other methods have been proposed in order to promote

carbocation A carbocation is an ion with a positively charged carbon atom. Among the simplest examples are the methenium , methanium and vinyl cations. Occasionally, carbocations that bear more than one positively charged carbon atom are also encountere ...

formation, including photocatalytic electron transfer or direct

photolysis Photodissociation, photolysis, photodecomposition, or photofragmentation is a chemical reaction in which molecules of a chemical compound are broken down by photons. It is defined as the interaction of one or more photons with one target molecule. ...

History

The reaction is named after John J. Ritter, who supervised the Ph.D. thesis work of P. Paul Minieri. * * *

References

{{DEFAULTSORT:Ritter Reaction Addition reactions Name reactions Amide synthesis reactions Articles containing video clips