The Mitsunobu reaction
is an organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. In organic synthesis,...
that converts an alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
into a variety of functional groups, such as an ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
, using triphenylphosphine
Triphenylphosphine is a common organophosphorus compound with the formula P3 - often abbreviated to PPh3 or Ph3P. It is widely used in the synthesis of organic and organometallic compounds. PPh3 exists as relatively air stable, colorless crystals at room temperature...
and an azodicarboxylate such as diethyl azodicarboxylate
Diethyl azodicarboxylate, conventionally abbreviated as DEAD and sometimes as DEADCAT, is an organic compound with the structural formula CH3CH2O2CN=NCO2CH2CH3. Its molecular structure consists of a central azo functional group, RN=NR, flanked by two ethyl ester groups. This orange-red liquid is a...
(DEAD) or diisopropyl azodicarboxylate
Diisopropyl azodicarboxylate is the diisopropyl ester of azodicarboxylic acid. It is used as a reagent in the production of many organic compounds. It is often used in the Mitsunobu reaction where it serves as an oxidizer of triphenylphosphine to triphenylphosphine oxide. It has also be used to...
(DIAD). The alcohol undergoes an inversion
Walden inversion is the inversion of a chiral center in a molecule in a chemical reaction. Since a molecule can form two enantiomers around a chiral center, the Walden inversion converts the configuration of the molecule from one enantiomeric form to the other. For example, in a SN2 reaction,...
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
. It was discovered by Oyo Mitsunobu (1934–2003).
Several reviews have been published.
The reaction mechanism
In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical change occurs.Although only the net chemical change is directly observable for most chemical reactions, experiments can often be designed that suggest the possible sequence of steps in...
of the Mitsunobu reaction is fairly complex. The identity of intermediates and the roles they play has been the subject of debate.
Initially, the triphenyl phosphine (2
) makes a nucleophilic attack upon diethyl azodicarboxylate (1
) producing a betaine intermediate 3
, which deprotonates the carboxylic acid (4
) to form the ion pair 5
. DEAD itself deprotonates the alcohol (6
) forming an alkoxide that can form the key oxyphosphonium ion 8
. The ratio and interconversion of intermediates 8
depend on the carboxylic acid pKa and the solvent polarity. Although several phosphorus intermediates are present, the attack of the carboxylate anion upon intermediate 8
is the only productive pathway forming the desired product 12
and triphenylphosphine oxide
Triphenylphosphine oxide is the chemical compound with the formula OP3. Often chemists abbreviate the formula by writing Ph3PO or PPh3O . This white crystalline compound is a common side product in reactions involving triphenylphosphine...
Hughes et al.
have found that the formation of the ion pair 5
is very fast. The formation of the oxyphosphonium intermediate 8
is slow and facilitated by the alkoxide. Therefore, the overall rate of reaction is controlled by carboxylate basicity and solvation.
Order of addition of reagents
The order of addition of the reagents of the Mitsunobu reaction can be important. Typically, one dissolves the alcohol, the carboxylic acid, and triphenylphosphine in tetrahydrofuran
Tetrahydrofuran is a colorless, water-miscible organic liquid with low viscosity at standard temperature and pressure. This heterocyclic compound has the chemical formula 4O. As one of the most polar ethers with a wide liquid range, it is a useful solvent. Its main use, however, is as a precursor...
or other suitable solvent (e.g. diethyl ether
Diethyl ether, also known as ethyl ether, simply ether, or ethoxyethane, is an organic compound in the ether class with the formula . It is a colorless, highly volatile flammable liquid with a characteristic odor...
), cool to 0 °C using an ice-bath, slowly add the DEAD dissolved in THF, then stir at room temperature for several hours. If this is unsuccessful, then preforming the betaine may give better results. To preform the betaine, add DEAD to triphenylphosphine in tetrahydrofuran at 0 °C, followed by the addition of the alcohol and finally the acid.
Other nucleophilic functional groups
Many other functional groups can serve as nucleophile
A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...
s besides carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
s. For the reaction to be successful, the nucleophile must have a pKa
PKA, pKa, or other similar variations may stand for:* pKa, the symbol for the acid dissociation constant at logarithmic scale* Protein kinase A, a class of cAMP-dependent enzymes* Pi Kappa Alpha, the North-American social fraternity...
less than 15.
Several modifications to the original reagent combination have been developed in order to simplify the separation of the product and avoid production of so much chemical waste. One variation of the Mitsunobu Reaction uses resin-bound triphenylphoshine and uses di-tert
-butylazodicarboxylate instead of DEAD. The oxidized triphenylphosphine resin can be removed by filtration, and the di-tert
-butylazodicarboxylate byproduct is removed by treatment with trifluoroacetic acid. Bruce H. Lipshutz
Bruce H. Lipshutz is an American chemist. He is a professor at the University of California, Santa Barbara.-Biography:Bruce Lipshutz received his undergraduate degree in chemistry from SUNY Binghamton in 1973. He did his graduate work under the supervision of Professor Harry H. Wasserman at Yale...
has developed an alternative to DEAD, Di-(4-chlorobenzyl)azodicarboxylate (DCAD) where the hydrazine by-product can be easily removed by filtration and recycled back to DCAD.
A modification has also been reported in which DEAD can be used in catalytic versus stoichiometric quantites, however this procedure requires the use of stoichiometric (diacetoxyiodo)benzene to oxidise the hydrazine by-product back to DEAD.
Tsunoda et al.
have shown that one can combine the triphenylphosphine and the diethyl azodicarboxylate into one reagent: a phosphorane
A phosphorane is a functional group in organophosphorus chemistry with pentavalent phosphorus. It has the general formula PR5. The parent hydride compound is the unstable molecule PH5...
An ylide or ylid is a neutral dipolar molecule containing a formally negatively charged atom directly attached to a hetero atom with a formal positive charge , and in which both atoms have full octets of electrons. Ylides are thus 1,2-dipolar compounds...
. Both (cyanomethylene)trimethylphosphorane (CMMP, R = Me) and (cyanomethylene)tributylphosphorane (CMBP, R = Bu) have proven particularly effective.
The ylide acts as both the reducing agent and the base. The byproducts are acetonitrile
Acetonitrile is the chemical compound with formula . This colourless liquid is the simplest organic nitrile. It is produced mainly as a byproduct of acrylonitrile manufacture...
) and the trialkylphosphine oxide (8
The Mitsunobu reaction has been applied in the synthesis of aryl ethers:
With these particular reactants the conversion with DEAD fails because the phenol is only weakly acidic. Instead the related 1,1'-(azodicarbonyl)dipiperidine
(ADDP) is used of which the betaine intermediate is a stronger base. The phosphine is a polymer-supported triphenylphosphine (PS-PPh3