The Betti reaction is a

chemical A chemical substance is a form of matter having constant chemical composition and characteristic properties. Some references add that chemical substance cannot be separated into its constituent elements by physical separation methods, i.e., wi ...

addition Addition (usually signified by the Plus and minus signs#Plus sign, plus symbol ) is one of the four basic Operation (mathematics), operations of arithmetic, the other three being subtraction, multiplication and Division (mathematics), division. ...

reaction of

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

s, primary

aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...

s and

phenol Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it req ...

s producing α-aminobenzylphenols. The Betti reaction is a special case of the

Mannich reaction In organic chemistry, the Mannich reaction is a three-component organic reaction that involves the amino alkylation of an acidic proton next to a carbonyl () functional group by formaldehyde () and a primary or secondary amine () or ammonia (). ...

History

The reaction is named after the Italian chemist Mario Betti (1857-1942). Betti worked at many universities in Italy, including

Florence Florence ( ; it, Firenze ) is a city in Central Italy and the capital city of the Tuscany region. It is the most populated city in Tuscany, with 383,083 inhabitants in 2016, and over 1,520,000 in its metropolitan area.Bilancio demografico an ...

Cagliari Cagliari (, also , , ; sc, Casteddu ; lat, Caralis) is an Italian municipality and the capital of the island of Sardinia, an autonomous region of Italy. Cagliari's Sardinian name ''Casteddu'' means ''castle''. It has about 155,000 inhabitant ...

Siena Siena ( , ; lat, Sena Iulia) is a city in Tuscany, Italy. It is the capital of the province of Siena. The city is historically linked to commercial and banking activities, having been a major banking center until the 13th and 14th centuri ...

Genoa Genoa ( ; it, Genova ; lij, Zêna ). is the capital of the Italian region of Liguria and the List of cities in Italy, sixth-largest city in Italy. In 2015, 594,733 people lived within the city's administrative limits. As of the 2011 Italian ce ...

and

Bologna Bologna (, , ; egl, label= Emilian, Bulåggna ; lat, Bononia) is the capital and largest city of the Emilia-Romagna region in Northern Italy. It is the seventh most populous city in Italy with about 400,000 inhabitants and 150 different nat ...

, where he was the successor of Giacomo Ciamician. Betti's main research was focused on

stereochemistry Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...

, and the resolution of

racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

compounds, the relationship between molecular constitution and

optical rotation Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circul ...

, as well

asymmetric synthesis Enantioselective synthesis, also called asymmetric synthesis, is a form of chemical synthesis. It is defined by IUPAC as "a chemical reaction (or reaction sequence) in which one or more new elements of chirality are formed in a substrate molecul ...

using chiral auxiliaries or in the presence of

polarized light Polarization (also polarisation) is a property applying to transverse waves that specifies the geometrical orientation of the oscillations. In a transverse wave, the direction of the oscillation is perpendicular to the direction of motion of the ...

. In 1939 Mario Betti was appointed the

Senator of the Kingdom of Italy The Senate of the Kingdom of Italy () was the upper house of the bicameral parliament of the Kingdom of Italy, officially created on 4 March 1848, acting as an evolution of the original Subalpine Senate. It was replaced on 1 January 1948 by the ...

. In 1900 Betti hypothesized that 2-naphthol would be a good carbon

nucleophile In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

to the

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 bo ...

produced from the reaction of

benzaldehyde Benzaldehyde (C6H5CHO) is an organic compound consisting of a benzene ring with a formyl substituent. It is the simplest aromatic aldehyde and one of the most industrially useful. It is a colorless liquid with a characteristic almond-like odor. ...

and

aniline Aniline is an organic compound with the formula C6 H5 NH2. Consisting of a phenyl group attached to an amino group, aniline is the simplest aromatic amine In organic chemistry, an aromatic amine is an organic compound consisting of an aroma ...

. This led to the Betti reaction.Cardellicchio, C.; Capozzi, M.A.M.; Naso, F. '' Tetrahedron: Asymmetry''. 2010, ''21'', 507-517.() OriginalBetti

Today, the name has grown to refer to any reaction of aldehydes, primary aromatic amines and phenols producing α-aminobenzylphenols.

Mechanism

The

reaction mechanism In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs. A chemical mechanism is a theoretical conjecture that tries to describe in detail what takes place at each stage of ...

begins with an imine condensation of a primary aromatic amine and

formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...

Once the imine is produced, it reacts with

in the presence of water to yield an α-aminobenzylphenol. BettiMechanism

First, the lone-pair on the nitrogen of the imine deprotonates the phenol, pushing the

bond Bond or bonds may refer to: Common meanings * Bond (finance), a type of debt security * Bail bond, a commercial third-party guarantor of surety bonds in the United States * Chemical bond, the attraction of atoms, ions or molecules to form chemica ...

ing

electrons 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 ...

onto the oxygen. The

carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...

is then reformed and a

double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...

in the

benzene ring Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen atoms, ...

attacks the carbon atom in the pronated imine cation. Water then acts as a base and deprotonates the

α-carbon In the nomenclature of organic chemistry, a locant is a term to indicate the position of a functional group or substituent within a molecule. Numeric locants The International Union of Pure and Applied Chemistry (IUPAC) recommends the use of ...

, reforming the aromatic ring and pushing electrons onto oxygen. The oxygen, which now has a negative

formal charge In chemistry, a formal charge (F.C. or q), in the covalent view of chemical bonding, is the charge assigned to an atom in a molecule, assuming that electrons in all chemical bonds are shared equally between atoms, regardless of relative electroneg ...

, then attacks a hydrogen on the

hydronium In chemistry, hydronium (hydroxonium in traditional British English) is the common name for the aqueous cation , the type of oxonium ion produced by protonation of water. It is often viewed as the positive ion present when an Arrhenius acid is d ...

, resulting in an α-aminobenzylphenol, with water as the only byproduct.

Betti Base

The product of the Betti reaction is called the Betti base. The stereochemistry of the base was resolved into two isomers by using

tartaric acid Tartaric acid is a white, crystalline organic acid that occurs naturally in many fruits, most notably in grapes, but also in bananas, tamarinds, and citrus. Its salt, potassium bitartrate, commonly known as cream of tartar, develops naturally i ...

. Uses for the Betti base and its derivatives include:Cardellicchio, C.; Ciccarella, C.; Naso, F.; Schingaro,E.; Scordari, F. '' Tetrahedron: Asymmetry''. 1998, ''9'', 3667-3675. () *

Enantioselective In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...

addition of

diethylzinc Diethylzinc (C2H5)2Zn, or DEZ, is a highly pyrophoric and reactive organozinc compound consisting of a zinc center bound to two ethyl groups. This colourless liquid is an important reagent in organic chemistry. It is available commercially as a s ...

aryl In organic chemistry, an aryl is any functional group or substituent derived from an aromatic ring, usually an aromatic hydrocarbon, such as phenyl and naphthyl. "Aryl" is used for the sake of abbreviation or generalization, and "Ar" is used as ...

aldehydes. *Enantioselective alkenylation of aldehydes. *Preparation of stable boronate complexes, which can be

alkylated 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 ...

to yield

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

precursors. *Separation of

enantiomers In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical anti ...

History

Mechanism

Betti Base

References

Further reading