Barbier reaction

The Barbier reaction is an organometallic reaction between an alkyl halide (chloride, bromide, iodide), a carbonyl group and a metal. The reaction can be performed using magnesium, aluminium, zinc, indium, tin, samarium, barium or their salts. The reaction product is a primary, secondary or tertiary alcohol. The reaction is similar to the Grignard reaction but the crucial difference is that the organometallic species in the Barbier reaction is generated in situ, whereas a Grignard reagent is prepared separately before addition of the carbonyl compound.[1] Unlike many Grignard reagents, the organometallic species generated in a Barbier reaction are unstable, necessitating their immediate usage. Barbier reactions are nucleophilic addition reactions that involve relatively inexpensive, water insensitive metals or metal compounds. For this reason it is possible in many cases to run the reaction in water, making the procedure part of green chemistry. In contrast, Grignard reagents and organolithium reagents are highly moisture sensitive and must be used under an inert atmosphere without the presence of water. The Barbier reaction is named after Victor Grignard's teacher Philippe Barbier.

Barbier reaction
Named after Philippe Barbier
Reaction type Coupling reaction
Identifiers
RSC ontology ID RXNO:0000084
Samariumiodide
Barbier reaction with samarium(II) iodide

Scope

Examples of Barbier reactions are the reaction of propargylic bromide with butanal with zinc metal (the reaction is carried out in THF, the saturated aqueous ammonium chloride solution added later to quench the reaction):[2]

Barbier reaction

the intramolecular Barbier reaction with samarium(II) iodide:[3]

Barbier reaction

the reaction of an allyl bromide with formaldehyde in THF with indium powder:[4]

Barbier reaction

or another allyl bromide in a reaction with benzaldehyde and zinc powder in water:[5]

Barbier reaction

Asymmetric Variants

The synthesis of (+)-aspicillin, starts first with a hydroboration, then transmetallation to zinc which can then do an addition into the aldehyde substituent.[6]

The total synthesis of (+)-aspicillin involves a Barbier reaction

See also

External links

  • Barbier reaction @ University of Connecticut Website

References

  1. ^ Barbier, P. (1899). "Synthèse du diéthylhepténol". Compt. Rend. 128: 110.
  2. ^ Artur Jõgi & Uno Mäeorg (2001). "Zn Mediated Regioselective Barbier Reaction of Propargylic Bromides in THF/aq. NH4Cl Solution" (PDF). Molecules. 6 (12): 964–968. doi:10.3390/61200964. ISSN 1420-3049.
  3. ^ Tore Skjæret & Tore Benneche (2001). "Preparation of oxo-substituted α-chloro ethers and their reaction with samarium diiodide". Arkivoc: KU–242A.
  4. ^ George D. Bennett and Leo A. Paquette. "Methyl 3-(hydroxymethyl)-4-methyl-2-methylenepentanoate". Organic Syntheses.; Collective Volume, 10, p. 77
  5. ^ Gary W. Breton; John H. Shugart; Christine A. Hughey; Brian P. Conrad; Suzanne M. Perala (2001). "Use of Cyclic Allylic Bromides in the Zinc–Mediated Aqueous Barbier–Grignard Reaction" (PDF). Molecules. 6 (8): 655–662. doi:10.3390/60800655.
  6. ^ De Brabander,J;et al. Tetrahedron Letters, 1995, Vol. 36, No. 15, pp. 2607-2610
Allyl group

An allyl group is a substituent with the structural formula H2C=CH−CH2R, where R is the rest of the molecule. It consists of a methylene bridge (−CH2−) attached to a vinyl group (−CH=CH2). The name is derived from the Latin word for garlic, Allium sativum. In 1844, Theodor Wertheim isolated an allyl derivative from garlic oil and named it "Schwefelallyl". The term allyl applies to many compounds related to H2C=CH−CH2, some of which are of practical or of everyday importance, for example, allyl chloride.

Asymmetric addition of dialkylzinc compounds to aldehydes

In asymmetric addition of dialkylzinc compounds to aldehydes dialkyl zinc compounds can be used to perform asymmetric additions to aldehydes, generating substituted alcohols as products (See Barbier reaction). Chiral alcohols are prevalent in many natural products, drugs, and other important organic molecules. Dimethyl zinc is often used with an asymmetric amino alcohol, amino thiol, or other ligand to affect enantioselective additions to aldehydes and ketones. One of the first examples of this process, reported by Noyori and colleagues, features the use of the amino alcohol ligand (−)-3-exo-dimethylaminoisobornenol along with dimethylzinc to add a methyl group asymmetrically to benzaldehyde (see figure). Many ligands have been developed for binding zinc during addition reactions. TADDOLs (tetraaryl-1,3-dioxolane-4,5-dimethanols), which are derived from chiral tartaric acid, are a class of diol ligands often used to bind titanium, but have been adopted for zinc addition chemistry. These ligands require relatively low catalyst loadings, and can achieve up to 99% ee in dialkylzinc additions to aromatic and aliphatic aldehydes. Martens and colleagues have used azetidine alcohols as ligands for asymmetric zinc additions. The researchers found that when paired with catalytic n-butyllithium, diethylzinc can add to aromatic aldehydes with ee in the range of 94-100%.

Many studies have shown that in zinc addition reactions, the enantioselectivity is not linearly correlated with catalyst enantiomeric purity. Researchers propose that this is because the kinetics of the reaction are controlled by the relative concentrations of hetero and homodimeric catalytic complexes; that is, the system displays autocatalysis because the product alcohol itself acts as an asymmetric ligand on zinc.

Barbier

Barbier may refer to:

Barbier (surname)

Barbier (crater), a feature on the Moon

Barbier reaction, a reaction in organic chemistry

Barbier's theorem in mathematics

Boord olefin synthesis

The Boord olefin synthesis is an organic reaction forming alkenes from ethers carrying a halogen atom 2 carbons removed from the oxygen atom (β-halo-ethers) using a metal such as magnesium or zinc. The reaction, discovered by Cecil E. Boord in 1930 is a classic named reaction with high yields and broad scope.

The reaction type is an elimination reaction with magnesium forming an intermediate Grignard reagent. The alkoxy group is a poor leaving group and therefore an E1cB elimination reaction mechanism is proposed. The original publication describes the organic synthesis of the compound isoheptene in several steps.

In a 1931 publication the scope is extended to 1,4-dienes with magnesium replaced by zinc (see also: Barbier reaction). In the first part of the reaction the allyl Grignard acts as a nucleophile in nucleophilic aliphatic substitution.

Grignard reaction

The Grignard reaction (pronounced /ɡriɲar/) is an organometallic chemical reaction in which alkyl, vinyl, or aryl-magnesium halides (Grignard reagent) add to a carbonyl group in an aldehyde or ketone. This reaction is important for the formation of carbon–carbon bonds. The reaction of an organic halide with magnesium is not a Grignard reaction, but provides a Grignard reagent.

Grignard reactions and reagents were discovered by and are named after the French chemist François Auguste Victor Grignard (University of Nancy, France), who published it in 1900 and was awarded the 1912 Nobel Prize in Chemistry for this work.

Indium-mediated allylation

Indium-Mediated Allylations (IMAs) are important chemical reactions for the formation of carbon–carbon bonds. This reaction has two steps: first, indium inserts itself between the carbon–halogen bond of an allyl halide, becoming the organoindium intermediate; second, this allyl indide intermediate reacts with an electrophile to synthesize one of a wide range of compounds, such as carbohydrates and antihelminthic drugs. This reaction is depicted in the scheme below:

Although this reaction occurs in two steps, it is commonly done as a Barbier reaction where the indium, allyl halide, and electrophile are all mixed together in a one-pot process.

Indium reacts more readily than other metals, such as Mg, Pb, Bi, or Zn and does not require a promoter or flammable organic solvent to drive the reaction. IMAs have advantages over other carbon bond forming reactions because of their ability to be carried out in water, which is cheap and environmentally friendly. Therefore, these reactions represent Green chemistry, providing a safer alternative to the very common Grignard reaction, performed with Mg. Reactions yield high stereo- and regio-selectivity with few by-products making it easy to purify the desired product.

List of inorganic reactions

Well-known types of reactions that involve organic compounds include:

Acetylation

Alkylation

Alkyne trimerisation

Alkyne metathesis

Aminolysis

Amination

Arylation

Aufbau reaction

Barbier reaction

Beta-hydride elimination

Birch reduction

Bönnemann cyclization

Bromination

Buchwald–Hartwig coupling

Cadiot–Chodkiewicz coupling

Calcination

Carbometalation

Carbothermal reduction

Carbonation

Carbonylation

Cassar reaction

Castro–Stephens coupling

Clemmensen reduction

Chain walking

Chan–Lam coupling

Chlorination

Clusterification

Comproportionation

C–C coupling

C–H activation

Cyanation

Cyclometalation

Decarbonylation

Decarboxylation

Dehydration

Dehalogenation

Dehydrogenation

Dehydrohalogenation

Deprotonation

Desilylation

Diastereomerisation

Dimerisation

Disproportionation

Dötz reaction

Eder reaction

Electromerism

Electron transfer (inner sphere and outer sphere)

Étard reaction

Fenton oxidation

Fischer–Tropsch process

Fisher–Hafner synthesis

Fisher–Muller reaction

Fluorination

Formylation

Fowler process

Fukuyama coupling

Gilman reagent coupling

Glaser coupling

Gomberg–Bachmann reaction

Haber–Weiss reaction

Halcon process

Halogenation

Hapticity change

Hay coupling

Heck reaction

Heck–Matsuda reaction

Hiyama coupling

Hofmann-Sand reaction

Homolysis

Huisgen cycloaddition

Hydride reduction

Hydroamination

Hydration

Hydroboration

Hydrocarboxylation

Hydrocyanation

Hydrodesulfurization

Hydroformylation

Hydrogenation

Hydrohalogenation

Hydrolysis

Hydrometalation

Hydrosilylation

Iodination

Isomerisation

Jones oxidation

Kulinkovich reaction

Kumada coupling

Lemieux–Johnson oxidation

Ley oxidation

Ligand association

Ligand dissociation

Ligand substitution

Linkage isomerization

Luche reduction

McMurry reaction

Meerwein–Ponndorf–Verley reduction

Mercuration

Methylation

Migratory insertion

Negishi coupling

Nicholas reaction

Nitrosylation

Noyori asymmetric hydrogenation

Olefin isomerization

Olefin metathesis

Olefin oxidation

Olefin polymerization

Oppenauer oxidation

Oxidation

Oxidative addition

Oxidative decarbonylation

Oxygenation

Oxymercuration reaction

Pauson–Khand reaction

Photodissociation

Pseudorotation

Protonation

Protonolysis

Proton-coupled electron transfer

Racemization

Redox reactions (see list of oxidants and reductants)

Reduction

Reductive elimination

Reppe synthesis

Riley oxidation

Ring whizzing

Salt metathesis

Sarett oxidation

Sharpless epoxidation

Shell higher olefin process

Silylation

Simmons–Smith reaction

Sonogashira coupling

Staudinger reaction

Stille reaction

Sulfidation

Suzuki reaction

Transmetalation

Ullmann reaction

Upjohn dihydroxylation

Vollhardt cyclization

Wacker process

Water gas shift reaction

Water oxidation

Wurtz coupling

Ziegler-Natta polymerization

Mercury(II) chloride

Mercury(II) chloride or mercuric chloride (historically "corrosive sublimate") is the chemical compound of mercury and chlorine with the formula HgCl2. It is white crystalline solid and is a laboratory reagent and a molecular compound that is very toxic to humans. Once used as a treatment for syphilis, it is no longer used for medicinal purposes because of mercury toxicity and the availability of superior treatments.

Noncovalent solid-phase organic synthesis

Noncovalent solid-phase organic synthesis or NC-SPOS is a form of Solid-phase synthesis whereby the organic substrate is bonded to the solid phase not by a covalent bond but by other chemical interactions. This bond may consist of an induced dipole interaction between a hydrophobic matrix and a hydrophobic anchor. As long as the reaction medium is hydrophilic (polar) in nature the anchor will remain on the solid phase. Switching to a nonpolar solvent releases the organic substrate containing the anchor.

In one experimental setup the hydrophobic matrix is RP silica gel (C18) and the anchor is acridone. Acridone is N-alkylated and the terminal alkene group is converted into an aldehyde by ozonolysis. This compound is bonded to RP silica gel and this system is subjected to a tandem sequence of organic reactions. The first reaction is a Barbier reaction with propargylic bromide in water (green chemistry) and the second reaction is a Sonogashira coupling. Substrates may vary in these sequences and in this way a chemical library of new compounds can be realized.

The phosphorus ligand in the Sonogashira coupling with phenyliodine is the water-soluble TPPTS ligand

Nozaki–Hiyama–Kishi reaction

The Nozaki–Hiyama–Kishi reaction is a nickel/chromium coupling reaction forming an alcohol from the reaction of an aldehyde with an allyl or vinyl halide. In their original 1977 publication, Tamejiro Hiyama and Hitoshi Nozaki reported on a chromium(II) salt solution prepared by reduction of chromic chloride by lithium aluminium hydride to which was added benzaldehyde and allyl chloride:

Compared to Grignard reactions, this reaction is very selective towards aldehydes with large tolerance towards a range of functional groups such as ketones, esters, amides and nitriles. Enals give exclusively 1,2-addition. Solvents of choice are DMF and DMSO, one solvent requirement is solubility of the chromium salts. Nozaki-Hiyama-Kishi reaction is a useful method for preparing medium-size rings.In 1983 the scope was extended by the same authors to include vinyl halides or triflates and aryl halides. It was observed that the success of the reaction depended on the source of chromium(II) chloride and in 1986 it was found that this is due to nickel impurities. Since then nickel(II) chloride is used as a co-catalyst.

In the same year Yoshito Kishi et al. independently discovered the beneficial effects of nickel in his quest for palytoxin:

Palladium acetate was also found to be an effective cocatalyst.

Nucleophile

Nucleophile is a chemical species that donates an electron pair to form a chemical bond in relation to a reaction. All molecules or ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.

Nucleophilic describes the affinity of a nucleophile to the nuclei. Nucleophilicity, sometimes referred to as nucleophile strength, refers to a substance's nucleophilic character and is often used to compare the affinity of atoms. Neutral nucleophilic reactions with solvents such as alcohols and water are named solvolysis. Nucleophiles may take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge.

Nucleophilic addition

In organic chemistry, a nucleophilic addition reaction is an addition reaction where a chemical compound with an electron-deficient or electrophilic double or triple bond, a π bond, reacts with electron-rich reactant, termed a nucleophile, with disappearance of the double bond and creation of two new single, or σ, bonds. The reactions are involved in the biological synthesis of compounds in the metabolism of every living organism, and are used by chemists in academia and industries such as pharmaceuticals to prepare most new complex organic chemicals, and so are central to organic chemistry. Addition reactions require the presence of groups with multiple bonds in the electrophile(due to the fact that double bonds and even triple bonds can both lack electron rich sources): carbon–heteroatom multiple bonds as in carbonyls, imines, and nitriles, or carbon–carbon double or triple bonds. The lack of electron rich sources is due to the fact that these bonds are partially empty, even though they remain connected, since the region occupying the orbital is essentially dead. This electrophilic behavior is defined as empty space since everything inside is basically without any source of electricity except from outside the bond, since bonds tend to want to attract more to themselves(whether this be electric or non-electric can differ in most situations). The addition of the nucleophile means the continuous addition of a negative charge throughout the reaction, unless an electrophile also makes itself present to form a complete structure with no charge at all. The negative charge being continuous throughout the reaction until the formation of an intermediate, bearing the charge, thus is the addition reaction we have before us. Once this meets an electrophile, then the intermediate formed with the negative charge can thus be neutralized to form a complete structure via a type of bond.

Organomanganese chemistry

Organomanganese chemistry is the chemistry of organometallic compounds containing a carbon to manganese chemical bond. In a recent review Cahiez et al. argue that as manganese is cheap and benign (only iron performs better in these aspects), organomanganese compounds have potential as chemical reagents, although currently they are not widely used as such despite extensive research.The first organomanganese compounds were synthesised in 1937 by Gilman and Bailee who reacted phenyllithium with manganese(II) iodide to form phenylmanganese iodide (PhMnI) and diphenylmanganese (Ph2Mn).

The reactivity of organomanganese compounds can be compared to that of organomagnesium compounds and organozinc compounds. The electronegativity of Mn (1.55) is comparable to that of Mg (1.31) and Zn (1.65) making the carbon atom (EN = 2,55) nucleophilic. The reduction potential of Mn is also intermediate between Mg and Zn. Key disadvantage of organomanganese compounds is that they can be obtained directly from the metal only with difficulty.

Organozinc compound

Organozinc compounds in organic chemistry contain carbon to zinc chemical bonds. Organozinc chemistry is the science of organozinc compounds describing their physical properties, synthesis and reactions.Organozinc compounds were among the first organometallic compounds made. They are less reactive than many other analogous organometallic reagents, such as Grignard and organolithium reagents. In 1848 Edward Frankland prepared the first organozinc compound, diethylzinc, by heating ethyl iodide in the presence of zinc metal. This reaction produced a volatile colorless liquid that spontaneous combusted upon contact with air. Due to their pyrophoric nature, organozinc compounds are generally prepared using air-free techniques. They are unstable toward protic solvents. For many purposes they are prepared in situ, not isolated, but many have been isolated as pure substances and thoroughly characterized.Organozinc can be categorized according to the number of carbon substituents that are bound to the metal.

Diorganozinc (R2Zn): A class of organozinc compounds in which two alkyl ligands. These may be further divided into subclasses depending on the other ligands attached

Heteroleptic (RZnX): Compounds which an electronegative or monoanionic ligand (X), such as a halide, is attached to the zinc center with another alkyl or aryl substituent (R).

Ionic organozinc compounds: This class is divided into organozincates (RnZn−) and organozinc cations (RZnLn+).

Philippe Barbier

Philippe Antoine Francoise Barbier (2 March 1848 – 18 September 1922) was a French organic chemist. He is considered the father of organometallic chemistry having synthesized the first organomagnesium compound in 1899. He is most famous for the Barbier reaction.

Barbier was Victor Grignard's supervisor during his PhD. A method to prepare reactive Grignard reagents such as allylic magnesium halides is known as the Barbier method, where the Grignard reagent is made in situ with the other reagent.

Propargyl bromide

Propargyl bromide, also known as 3-bromo-1-propyne, is an organic compound with the chemical formula CHCCH2Br. It is a halogenated organic compound consisting of propyne with a bromine substituent on the methyl group. It has a lachrymatory effect, like related compounds. The compound is a useful reagent in organic synthesis.

RXNO Ontology

The RXNO Ontology is a formal ontology of chemical named reactions.

It was originally developed at the Royal Society of Chemistry (RSC) and is associated with the Open Biomedical Ontologies Foundry. The RXNO ontology unifies several previous attempts to systematize chemical reactions including the Merck Index and the hierarchy of Carey, Laffan, Thomson and Williams.

Samarium

Samarium is a chemical element with symbol Sm and atomic number 62. It is a moderately hard silvery metal that slowly oxidizes in air. Being a typical member of the lanthanide series, samarium usually assumes the oxidation state +3. Compounds of samarium(II) are also known, most notably the monoxide SmO, monochalcogenides SmS, SmSe and SmTe, as well as samarium(II) iodide. The last compound is a common reducing agent in chemical synthesis. Samarium has no significant biological role but is only slightly toxic.

Samarium was discovered in 1879 by the French chemist Paul-Émile Lecoq de Boisbaudran and named after the mineral samarskite from which it was isolated. The mineral itself was earlier named after a Russian mine official, Colonel Vassili Samarsky-Bykhovets, who thereby became the first person to have a chemical element named after him, albeit indirectly. Although classified as a rare-earth element, samarium is the 40th most abundant element in the Earth's crust and is more common than metals such as tin. Samarium occurs with concentration up to 2.8% in several minerals including cerite, gadolinite, samarskite, monazite and bastnäsite, the last two being the most common commercial sources of the element. These minerals are mostly found in China, the United States, Brazil, India, Sri Lanka and Australia; China is by far the world leader in samarium mining and production.

The major commercial application of samarium is in samarium–cobalt magnets, which have permanent magnetization second only to neodymium magnets; however, samarium compounds can withstand significantly higher temperatures, above 700 °C (1,292 °F), without losing their magnetic properties, due to the alloy's higher Curie point. The radioactive isotope samarium-153 is the active component of the drug samarium (153Sm) lexidronam (Quadramet), which kills cancer cells in the treatment of lung cancer, prostate cancer, breast cancer and osteosarcoma. Another isotope, samarium-149, is a strong neutron absorber and is therefore added to the control rods of nuclear reactors. It is also formed as a decay product during the reactor operation and is one of the important factors considered in the reactor design and operation. Other applications of samarium include catalysis of chemical reactions, radioactive dating and X-ray lasers.

Samarium(II) iodide

Samarium(II) iodide is an inorganic compound with the formula SmI2. When employed as a solution for organic synthesis, it is known as "Kagan's reagent". SmI2 is a green solid and its solutions are green as well. It is a strong one-electron reducing agent that is used in organic synthesis.

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