The Michaelis–Arbuzov reaction (also called the Arbuzov reaction) is the

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 ...

of a

trivalent In chemistry, the valence (US spelling) or valency (British spelling) of an element is the measure of its combining capacity with other atoms when it forms chemical compounds or molecules. Description The combining capacity, or affinity of an ...

phosphorus ester with an

alkyl halide The haloalkanes (also known as halogenoalkanes or alkyl halides) are alkanes containing one or more halogen substituents. They are a subset of the general class of halocarbons, although the distinction is not often made. Haloalkanes are widely ...

to form a

pentavalent In chemistry, the valence (US spelling) or valency (British spelling) of an element is the measure of its combining capacity with other atoms when it forms chemical compounds or molecules. Description The combining capacity, or affinity of a ...

phosphorus species and another alkyl halide. The picture below shows the most common types of substrates undergoing the Arbuzov reaction;

phosphite ester The general structure of a phosphite ester showing the lone pairs on the P In organic chemistry, a phosphite ester or organophosphite usually refers to an organophosphorous compound with the formula P(OR)3. They can be considered as esters of a ...

s (1) react to form

phosphonate In organic chemistry, phosphonates or phosphonic acids are organophosphorus compounds containing groups (where R = alkyl, aryl, or just hydrogen). Phosphonic acids, typically handled as salts, are generally nonvolatile solids that are poorly ...

s (2),

phosphonite In organic chemistry, phosphonites are organophosphorus compounds with the formula P(OR)2R. They are found in some pesticides and are used as ligands. Preparation Although they are derivatives of phosphonous acid (RP(OH)2), they are not prepar ...

s (3) react to form

phosphinate Phosphinates or hypophosphites are a class of phosphorus compounds conceptually based on the structure of hypophosphorous acid. IUPAC prefers the term phosphinate in all cases, however in practice hypophosphite is usually used to describe inorganic ...

s (4) and

phosphinite In organic chemistry, phosphinites are organophosphorus compounds with the formula . They are used as ligands in homogeneous catalysis and coordination chemistry. Preparation Phosphinites are prepared by alcoholysis of organophosphinous chlori ...

s (5) react to form

phosphine oxide Phosphine oxides are phosphorus compounds with the formula OPX3. When X = alkyl or aryl, these are organophosphine oxides. Triphenylphosphine oxide is an example. An inorganic phosphine oxide is phosphoryl chloride (POCl3). Structure and bonding ...

s (6).

The reaction was discovered by

August Michaelis August Michaelis (26 December 1847 – 31 January 1916) was a German chemist and discovered the Michaelis–Arbuzov reaction. Michaelis studied at the University of Göttingen and University of Jena and became professor for chemistry at Universit ...

in 1898, and greatly explored by

Aleksandr Arbuzov Aleksandr Erminingeldovich Arbuzov (russian: Алекса́ндр Ермининге́льдович Арбу́зов; 12 October 1877 – 22 January 1968) was a Russian and Soviet chemist who discovered the Michaelis–Arbuzov reaction. A n ...

soon thereafter. This reaction is widely used for the synthesis of various phosphonates,

s, and

s. Several reviews have been published. The reaction also occurs for coordinated phosphite ligands, as illustrated by the demethylation of ²⁺ to give ⁻, which is called the Klaui ligand.

Reaction mechanism

center, 600px, The mechanism of the Michaelis–Arbuzov reaction The Michaelis–Arbuzov reaction is initiated with the S_N2 attack of the

nucleophilic 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 ...

phosphorus species (1 - A phosphite) with the

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 ...

alkyl halide (2) to give a

phosphonium salt In polyatomic cations with the chemical formula (where R is a hydrogen or an alkyl, aryl, or halide group). These cations have tetrahedral structures. The salts are generally colorless or take the color of the anions. Types of phosphonium c ...

as an intermediate (3). These intermediates are occasionally stable enough to be isolated, such as for triaryl phosphites which do not react to form the phosphonate without thermal cleavage of the intermediate (200 °C), or cleavage by alcohols or bases. The displaced

halide In chemistry, a halide (rarely halogenide) is a binary chemical compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative (or more electropositive) than the halogen, to make a fluor ...

anion then usually reacts via another S_N2 reaction on one of the R₁ carbons, displacing the oxygen atom to give the desired phosphonate (4) and another alkyl halide (5). This has been supported by the observation that chiral R₁ groups experience inversion of configuration at the carbon center attacked by the halide anion. This is what is expected of an S_N2 reaction. Evidence also exists for a

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 ...

based mechanism of dealkylation similar to an S_N1 reaction, where the R₁ group initially dissociates from the phosphonium salt followed by attack of the anion. Phosphite esters with tertiary alkyl halide groups can undergo the reaction, which would be unexpected if only an S_N2 mechanism was operating. Further support for this S_N1 type mechanism comes from the use of the Arbuzov reaction in the synthesis of

neopentyl Pentyl is a five-carbon alkyl group or substituent with chemical formula -C5H11. It is the substituent form of the alkane pentane. In older literature, the common non-systematic name amyl was often used for the pentyl group. Conversely, the name ...

halides, a class of compounds that are notoriously unreactive towards S_N2 reactions. Based on the principle of

microscopic reversibility The principle of microscopic reversibility in physics and chemistry is twofold: * First, it states that the microscopic detailed dynamics of particles and fields is time-reversible because the microscopic equations of motion are symmetric with respe ...

, the inert nature of the neopentyl halides towards the S_N2 reaction indicates that an S_N2 reaction is unlikely to be the mechanism for the synthesis of the neopentyl halides in this reaction. Substrates that cannot react through an S_N2 pathway or an S_N1 pathway generally do not react, which include

vinyl Vinyl may refer to: Chemistry * Polyvinyl chloride (PVC), a particular vinyl polymer * Vinyl cation, a type of carbocation * Vinyl group, a broad class of organic molecules in chemistry * Vinyl polymer, a group of polymers derived from vinyl m ...

and

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 ...

groups. For example, the triaryl phosphites mentioned above generally do not react because they form stable phosphonium salts. Since aryl groups do not undergo S_N1 and S_N2 type mechanisms, triaryl phosphites lack a low energy pathway for decomposition of the phosphonium salt. An

allylic rearrangement An allylic rearrangement or allylic shift is an organic reaction in which the double bond in an allyl chemical compound shifts to the next carbon atom. It is encountered in nucleophilic substitution. In reaction conditions that favor a SN1 reactio ...

mechanism (S_N2') has also been implicated in

allyl In organic chemistry, an allyl group is a substituent with the structural formula , where R is the rest of the molecule. It consists of a methylene bridge () attached to a vinyl group (). The name is derived from the scientific name for garlic, ...

and

propargyl In organic chemistry, the propargyl group is a functional group of 2-propynyl with the structure . It is an alkyl group derived from propyne (). The term propargylic refers to a saturated position ( ''sp''3-hybridized) on a molecular framework n ...

halides. Stereochemical experiments on cyclic phosphites have revealed the presence of both pentavalent

phosphorane A phosphorane (IUPAC name: λ5-phosphane) is a functional group in organophosphorus chemistry with pentavalent phosphorus. It has the general formula PR5. The parent hydride compound is the hypothetical molecule PH5. The derivative pentaphenylphosp ...

s and tetravalent phosphonium intermediates in

chemical equilibrium In a chemical reaction, chemical equilibrium is the state in which both the reactants and products are present in concentrations which have no further tendency to change with time, so that there is no observable change in the properties of the sy ...

being involved in the dealkylation step of the reaction using ³¹P NMR. The decomposition of these intermediates is driven primarily by the

nucleophilicity 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 ...

of the anion. There exists many instances of the intermediate phosphonium salts being sufficiently stable that they can be isolated when the anion is weakly nucleophilic, such as with

tetrafluoroborate Tetrafluoroborate is the anion . This tetrahedral species is isoelectronic with tetrafluoroberyllate (), tetrafluoromethane (CF4), and tetrafluoroammonium () and is valence isoelectronic with many stable and important species including the perchl ...

triflate In organic chemistry, triflate (systematic name: trifluoromethanesulfonate), is a functional group with the formula and structure . The triflate group is often represented by , as opposed to −Tf, which is the triflyl group, . For example, ' ...

anions.

Scope

Alkyl halide

As a general guideline, the reactivity of the organic halide component can be listed as follows: (from most reactive to least reactive) :RCOX > RCH2X > RR'CHX \gg RR'R''CX and :RI > RBr > RCl In general, tertiary alkyl halides, aryl halides and vinyl halides do not react. There are notable exceptions to this trend, including

1,2-dichloroethene 1,2-Dichloroethene, commonly called 1,2-dichloroethylene or 1,2-DCE, is the name for a pair of organochlorine compounds with the molecular formula CHCl. They are both colorless liquids with a sweet odor. It can exist as either of two geometric ...

and trityl halides. Some activated aryl halides, often involving Heterocyclic compound, heterocycles have been known to undergo the reaction. Iodobenzene and substituted derivatives have been known to undergo the reaction under photolytic conditions. Secondary alkyl halides often do not react well, producing alkenes as side-products. Allyl and propargyl halides are also reactive, but can proceed through an S_N2 or an S_N2` mechanism. Reaction with primary alkyl halides and acyl halides generally proceed smoothly. Carbon tetrachloride interestingly enough, only undergoes the reaction a single time with chloroform being inert to the reaction conditions. When a halide atom is found in the ester chain off of the phosphorus atom, isomerization to the corresponding Arbuzov product has been known without addition of an alkyl halide. The Perkow reaction is a competing reaction pathway for α-bromo- and α-chloroketones. Under the reaction conditions a mixture of the Perkow product and the normal Arbuzov product occur, usually favoring the Perkow product by a significant amount. Using higher temperatures during the reaction can lead to favoring of the Arbuzov product. The reaction of α-iodoketones give only the Arbuzov product. Other methods of producing β-ketophosphonates have been developed. The reaction of trivalent phosphorus compounds with alkyl fluorides is abnormal. One example of this reactivity is shown below. Arbuzov_Scope_Fluorine_Reactivity

Phosphorus reactant

The general form of the trivalent phosphorus reagent can be considered as follows: ABP-OR with A and B generally being alkyl, alkoxy or aryloxy groups. Electron-withdrawing groups are known to slow down the rate of the reaction, with electron donating groups increasing the rate of the reaction. This is consistent with initial attack of the phosphorus reagent on the alkyl halide as the rate-determining step of the reaction. The reaction proceeds smoothly when the R group is aliphatic. When all of A, B and R are aryl groups, a stable phosphonium salt is formed and the reaction proceeds no further under normal conditions. Heating to higher temperatures in the presence of alcohols has been known to give the isomerization product. Cyclic phosphites generally react to eject the non-cyclic OR group, though for some 5-member rings additional heating is required to afford the final cyclic product. Arbuzov_Scope_Cyclic_Phosphite

Phosphite salts (Ex: R = Na) can also undergo the reaction with precipitation of the corresponding Na-halide salt. Amidophosphites and silyloxyphosphites have been used before to yield amidophosphonates and phosphinic acids. Arbuzov_Scope_Silylmethoxy

An Arbuzov type rearrangement can also occur where the O from an OR group acts as the leaving group in the initial S_N2 attack of the phosphorus. This is only known to occur when A and B are Cl. Arbuzov_scope_PCl3_rearrangement

Phosphite esters are the least reactive class of reagents used in this reaction. They react to produce phosphonates. They require the most heating for the reaction to occur (120 °C - 160 °C is common). This high temperature allows for fractional distillation to be employed in the removal of the alkyl halide produced, though excess of the starting alkyl halide can also be used. Solvents are often not used for this reaction, though there is precedent for the improvement of selectivity with its usage. Phosphonites are generally more reactive than phosphite esters. They react to produce phosphinates. Heating is also required for the reaction, but pyrolysis of the ester to an acid is a common side reaction. The poor availability of substituted phosphonites limits the usage of this class of reagent in the Arbuzov reaction. Hydroxy group, Hydroxy, thiol, carboxylic acid, primary and secondary amine functional groups cannot be used with phosphonites in the reaction as they all react with the phosphonite. Phosphinites are the most reactive class of reagents used in this reaction. They react to produce phosphine oxides. They often require very little heating (45 °C) for the reaction to occur and have been known to self-isomerize without the presence of alkyl halides.

References

External links