The Meerwein–Ponndorf–Verley (MPV) reduction in

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 materials, i.e., matter in its various forms that contain carbon atoms.Clay ...

is the reduction of

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bon ...

s and

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 group ...

s to their corresponding

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 utilizing aluminium alkoxide catalysis in the presence of a sacrificial alcohol. The advantages of the MPV reduction lie in its high chemoselectivity, and its use of a cheap environmentally friendly metal catalyst. The MPV reduction was independently discovered Albert Verley and the team of

Hans Meerwein Hans Meerwein (May 20, 1879 in Hamburg, Germany – October 24, 1965 in Marburg, Germany) was a German chemist. Several reactions and reagents bear his name, most notably the Meerwein–Ponndorf–Verley reduction, the Wagner–Meerwein rearr ...

and Rudolf Schmidt in 1925. They found that a mixture of

aluminium ethoxide Aluminium triethoxide (also aluminium ethoxide) is an metallo-organic compound with the empirical formula . It is a moisture-sensitve white powder. Properties left, Structure of aluminium isopropoxide indicates the tendency of aluminium alkoxi ...

and ethanol could reduce aldehydes to their alcohols. Ponndorf applied the reaction to ketones and upgraded the catalyst to aluminium isopropoxide in

isopropanol Isopropyl alcohol (IUPAC name propan-2-ol and also called isopropanol or 2-propanol) is a colorless, flammable organic compound with a pungent alcoholic odor. As an isopropyl group linked to a hydroxyl group (chemical formula ) it is the simp ...

Mechanism

The MPV reduction is believed to go through a catalytic cycle involving a six-member ring transition state as shown in Figure 2. Starting with the aluminium alkoxide 1, a carbonyl oxygen is coordinated to achieve the tetra coordinated aluminium intermediate 2. Between intermediates 2 and 3 the hydride is transferred to the carbonyl from the alkoxy ligand via a pericyclic mechanism. At this point the new carbonyl dissociates and gives the tricoordinated aluminium species 4. Finally, an alcohol from solution displaces the newly reduced carbonyl to regenerate the catalyst 1. Each step in the cycle is reversible and the reaction is driven by the thermodynamic properties of the intermediates and the products. This means that given time the more thermodynamically stable product will be favored. Several other mechanisms have been proposed for this reaction, including a

radical Radical may refer to: Politics and ideology Politics * Radical politics, the political intent of fundamental societal change *Radicalism (historical), the Radical Movement that began in late 18th century Britain and spread to continental Europe an ...

mechanism as well as a mechanism involving an

aluminium hydride Aluminium hydride (also known as alane and alumane) is an inorganic compound with the formula Al H3. Alane and its derivatives are common reducing (hydride addition) reagents in organic synthesis that are used in solution at both laboratory an ...

species. The direct

hydride In chemistry, a hydride is formally the anion of hydrogen( H−). The term is applied loosely. At one extreme, all compounds containing covalently bound H atoms are called hydrides: water (H2O) is a hydride of oxygen, ammonia is a hydride of ...

transfer is the commonly accepted mechanism recently supported by experimental and theoretical data.

Chemoselectivity

One of the great draws of the Meerwein–Ponndorf–Verley reduction is its

chemoselectivity Chemoselectivity is the preferential outcome of a chemical reaction over a set of possible alternative reactions. In another definition, chemoselectivity refers to the selective reactivity of one functional group in the presence of others; often ...

. Aldehydes are reduced before ketones allowing for a measure of control over the reaction. If it is necessary to reduce one carbonyl in the presence of another, the common carbonyl protecting groups may be employed. Groups, such as alkenes and alkynes, that normally pose a problem for reduction by other means have no reactivity under these conditions.

Stereoselectivity

The aluminium based Meerwein–Ponndorf–Verley reduction can be performed on prochiral ketones leading to

chiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from i ...

alcohols. The three main ways to achieve the asymmetric reduction is by use of a chiral alcohol hydride source, use of an intramolecular MPV reduction, or use of a chiral ligand on the aluminium alkoxide. One method of achieving the asymmetric MPV reduction is with the use of chiral hydride donating alcohols. The use of chiral alcohol (R)-(+)-''sec''-''o''-bromophen-ethyl alcohol gave 82%ee (percent

enantiomeric excess In stereochemistry, enantiomeric excess (ee) is a measurement of purity used for chiral substances. It reflects the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has an ee of 0%, while a s ...

) in the reduction of 2-chloroacetophenone. This enantioselection is due to the sterics of the two phenol groups in the six membered transition state as shown in Figure 3. In Figure 3, 1 is favored over 2 due to the large

steric Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...

effect in 2 from the two

phenyl In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydroge ...

groups. The use of an intramolecular MPV reduction can give good enantiopurity. By tethering the ketone to the hydride source only one transition state is possible (Figure 4) leading to the asymmetric reduction. This method, however, has the ability to undergo the reverse Oppenauer oxidation due to the proximity of the two reagents. Thus the reaction runs under thermodynamic equilibrium with the ratio of the products related to their relative stabilities. After the reaction is run the hydride-source portion of the molecule can be removed. Chiral

ligand 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 ele ...

s on the aluminium alkoxide can affect the stereochemical outcome of the MPV reduction. This method lead to the reduction of substituted

acetophenone Acetophenone is the organic compound with the formula C6H5C(O)CH3. It is the simplest aromatic ketone. This colorless, viscous liquid is a precursor to useful resins and fragrances. Production Acetophenone is formed as a byproduct of the cumene ...

s in up to 83%ee (Figure 5). The appeal of this method is that it uses a chiral ligand as opposed to a

stoichiometric Stoichiometry refers to the relationship between the quantities of reactants and products before, during, and following chemical reactions. Stoichiometry is founded on the law of conservation of mass where the total mass of the reactants equ ...

source of chirality. It has been recently shown that the low selectivity of this method is due to the shape of the transition state. It has been shown that the transition state is a planar six member transition state. This is different than the believed Zimmerman-Traxler model like transition state.

Scope

Several problems restrict the use of the Meerwein–Ponndorf–Verley reduction compared to the use of other reducing agents. The stereochemical control is seriously limited. Often a large amount of aluminium alkoxide is needed when using commercial reagent, and there are several known side reactions. While commercial aluminium isopropoxide is available, the use of it often requires catalyst loadings of up to 100-200 mol%. This hinders the use of the MPV reduction on scale. Recent work has shown that aluminium alkoxides made in situ from trimethyl aluminium reagents have far better activity requiring as little as 10% loading. The activity difference is believed to be due to the large aggregation state of the commercially available product. Several side reactions are known to occur. In the case of ketones and especially aldehydes

aldol condensation An aldol condensation is a condensation reaction in organic chemistry in which two carbonyl moieties (of aldehydes or ketones) react to form a β-hydroxyaldehyde or β-hydroxyketone (an aldol reaction), and this is then followed by dehydration ...

s have been observed. Aldehydes with no α-hydrogens can undergo the Tishchenko reaction. Finally, in some cases the alcohol generated by the reduction can be dehydrated giving an

alkyl In organic chemistry, an alkyl group is an alkane missing one hydrogen. The term ''alkyl'' is intentionally unspecific to include many possible substitutions. An acyclic alkyl has the general formula of . A cycloalkyl is derived from a cycloal ...

carbon.

Variations

The Meerwein–Ponndorf–Verley reduction has been recently used in the synthesis of chiral

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 substituent su ...

s from ketimines using a chiral alkoxide. The addition of a phosphinoyl group to the nitrogen of the ketimine allowed for high enantioselectivity up to 98%ee. Work has been done in the use of

lanthanide The lanthanide () or lanthanoid () series of chemical elements comprises the 15 metallic chemical elements with atomic numbers 57–71, from lanthanum through lutetium. These elements, along with the chemically similar elements scandium and y ...

s and

transition metal In chemistry, a transition metal (or transition element) is a chemical element in the d-block of the periodic table (groups 3 to 12), though the elements of group 12 (and less often group 3) are sometimes excluded. They are the elements that c ...

s for the Meerwein–Ponndorf–Verley reduction. Both

ruthenium Ruthenium is a chemical element with the symbol Ru and atomic number 44. It is a rare transition metal belonging to the platinum group of the periodic table. Like the other metals of the platinum group, ruthenium is inert to most other chemic ...

and

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 has the oxidation state +3. Compounds of samar ...

have shown high yields and high stereoselectivity in the reduction of carbonyls to alcohols. The ruthenium catalyst has been shown, however, to go through a ruthenium hydride intermediate. The Meerwein–Ponndorf–Verley reduction has also been effected with synthetically useful yield by plutonium (III) isopropoxide. The standard MPV reduction is a homogeneous reaction several heterogeneous reactions have been developed.

References