Mitsunobu reaction | |
---|---|
Named after | Oyo Mitsunobu |
Reaction type | Coupling reaction |
Identifiers | |
Organic Chemistry Portal | mitsunobu-reaction |
RSC ontology ID | RXNO:0000034 |
The Mitsunobu reaction is an organic reaction that converts an alcohol into a variety of functional groups, such as an ester, using triphenylphosphine and an azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD). [1] Although DEAD and DIAD are most commonly used, there are a variety of other azodicarboxylates available which facilitate an easier workup and/or purification and in some cases, facilitate the use of more basic nucleophiles. It was discovered by Oyo Mitsunobu (1934–2003). In a typical protocol, one dissolves the alcohol, the carboxylic acid, and triphenylphosphine in tetrahydrofuran or other suitable solvent (e.g. diethyl ether), cool to 0 °C using an ice-bath, slowly add the DEAD dissolved in THF, then stir at room temperature for several hours. [2] The alcohol reacts with the phosphine to create a good leaving group then undergoes an inversion of stereochemistry in classic SN2 fashion as the nucleophile displaces it. A common side-product is produced when the azodicarboxylate displaces the leaving group instead of the desired nucleophile. This happens if the nucleophile is not acidic enough (pKa larger than 13) or is not nucleophilic enough due to steric or electronic constraints. A variation of this reaction utilizing a nitrogen nucleophile is known as a Fukuyama–Mitsunobu.
The reaction mechanism 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. The formation of the ion pair 5 is very fast.
The second phase of the mechanism is proposed to be phosphorus-centered, the DEAD having been converted to the hydrazine. The ratio and interconversion of intermediates 8–11 depend on the carboxylic acid pKa and the solvent polarity. [8] [9] [10] 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 (13).
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. [11]
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 or other suitable solvent (e.g. diethyl ether), 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. [12]
Many other functional groups can serve as nucleophiles besides carboxylic acids. For the reaction to be successful, the nucleophile must have a pKa less than 15.
Nucleophile | Product |
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hydrazoic acid | alkyl azide |
imide | substituted imide [13] |
phenol | alkyl aryl ether (discovered independently [14] [15] ) |
sulfonamide | substituted sulfonamide [16] |
arylsulfonylhydrazine | alkyldiazene (subject to pericyclic or free radical dediazotization to give allene (Myers allene synthesis) or alkane (Myers deoxygenation), respectively) [17] |
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 triphenylphosphine 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. [18] Bruce H. Lipshutz 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. [19]
A modification has also been reported in which DEAD can be used in catalytic versus stoichiometric quantities, however this procedure requires the use of stoichiometric (diacetoxyiodo)benzene to oxidise the hydrazine by-product back to DEAD. [20]
Denton and co-workers have reported a redox-neutral variant of the Mitsunobu reaction which employs a phosphorus(III) catalyst to activate the substrate, ensuring inversion in the nucleophilic attack, and uses a Dean-Stark trap to remove the water by-product. [21]
Tsunoda et al. have shown that one can combine the triphenylphosphine and the diethyl azodicarboxylate into one reagent: a phosphorane ylide. Both (cyanomethylene)trimethylphosphorane (CMMP, R = Me) and (cyanomethylene)tributylphosphorane (CMBP, R = Bu) have proven particularly effective. [22]
The ylide acts as both the reducing agent and the base. The byproducts are acetonitrile (6) and the trialkylphosphine oxide (8).
The Mitsunobu reaction has been applied in the synthesis of aryl ethers: [23]
With these particular reactants the conversion with DEAD fails because the hydroxyl group 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).
The reaction has been used to synthesize quinine, colchicine, sarain, morphine, stigmatellin, eudistomin, oseltamivir, strychnine, and nupharamine. [24]
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two organyl groups. They have the general formula R−O−R′, where R and R′ represent organyl groups. Ethers can again be classified into two varieties: if the organyl groups are the same on both sides of the oxygen atom, then it is a simple or symmetrical ether, whereas if they are different, the ethers are called mixed or unsymmetrical ethers. A typical example of the first group is the solvent and anaesthetic diethyl ether, commonly referred to simply as "ether". Ethers are common in organic chemistry and even more prevalent in biochemistry, as they are common linkages in carbohydrates and lignin.
In chemistry, an ester is a compound derived from an acid in which the hydrogen atom (H) of at least one acidic hydroxyl group of that acid is replaced by an organyl group. Analogues derived from oxygen replaced by other chalcogens belong to the ester category as well. According to some authors, organyl derivatives of acidic hydrogen of other acids are esters as well, but not according to the IUPAC.
The haloalkanes 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 used commercially. They are used as flame retardants, fire extinguishants, refrigerants, propellants, solvents, and pharmaceuticals. Subsequent to the widespread use in commerce, many halocarbons have also been shown to be serious pollutants and toxins. For example, the chlorofluorocarbons have been shown to lead to ozone depletion. Methyl bromide is a controversial fumigant. Only haloalkanes that contain chlorine, bromine, and iodine are a threat to the ozone layer, but fluorinated volatile haloalkanes in theory may have activity as greenhouse gases. Methyl iodide, a naturally occurring substance, however, does not have ozone-depleting properties and the United States Environmental Protection Agency has designated the compound a non-ozone layer depleter. For more information, see Halomethane. Haloalkane or alkyl halides are the compounds which have the general formula "RX" where R is an alkyl or substituted alkyl group and X is a halogen.
Fischer esterification or Fischer–Speier esterification is a special type of esterification by refluxing a carboxylic acid and an alcohol in the presence of an acid catalyst. The reaction was first described by Emil Fischer and Arthur Speier in 1895. Most carboxylic acids are suitable for the reaction, but the alcohol should generally be primary or secondary. Tertiary alcohols are prone to elimination. Contrary to common misconception found in organic chemistry textbooks, phenols can also be esterified to give good to near quantitative yield of products. Commonly used catalysts for a Fischer esterification include sulfuric acid, p-toluenesulfonic acid, and Lewis acids such as scandium(III) triflate. For more valuable or sensitive substrates other, milder procedures such as Steglich esterification are used. The reaction is often carried out without a solvent or in a non-polar solvent to facilitate the Dean-Stark method. Typical reaction times vary from 1–10 hours at temperatures of 60-110 °C.
In organic chemistry, an acyl chloride is an organic compound with the functional group −C(=O)Cl. Their formula is usually written R−COCl, where R is a side chain. They are reactive derivatives of carboxylic acids. A specific example of an acyl chloride is acetyl chloride, CH3COCl. Acyl chlorides are the most important subset of acyl halides.
The Appel reaction is an organic reaction that converts an alcohol into an alkyl chloride using triphenylphosphine and carbon tetrachloride. The use of carbon tetrabromide or bromine as a halide source will yield alkyl bromides, whereas using carbon tetraiodide, methyl iodide or iodine gives alkyl iodides. The reaction is credited to and named after Rolf Appel, it had however been described earlier. The use of this reaction is becoming less common, due to carbon tetrachloride being restricted under the Montreal protocol.
Phosphorus trichloride is an inorganic compound with the chemical formula PCl3. A colorless liquid when pure, it is an important industrial chemical, being used for the manufacture of phosphites and other organophosphorus compounds. It is toxic and reacts readily with water to release hydrogen chloride.
Triphenylphosphine (IUPAC name: triphenylphosphane) is a common organophosphorus compound with the formula P(C6H5)3 and often abbreviated to PPh3 or Ph3P. It is versatile compound that is widely used as a reagent in organic synthesis and as a ligand for transition metal complexes, including ones that serve as catalysts in organometallic chemistry. PPh3 exists as relatively air stable, colorless crystals at room temperature. It dissolves in non-polar organic solvents such as benzene and diethyl ether.
Diethyl azodicarboxylate, conventionally abbreviated as DEAD and sometimes as DEADCAT, is an organic compound with the structural formula CH3CH2−O−C(=O)−N=N−C(=O)−O−CH2CH3. Its molecular structure consists of a central azo functional group, RN=NR, flanked by two ethyl ester groups. This orange-red liquid is a valuable reagent but also quite dangerous and explodes upon heating. Therefore, commercial shipment of pure diethyl azodicarboxylate is prohibited in the United States and is carried out either in solution or on polystyrene particles.
N,N′-Dicyclohexylcarbodiimide (DCC or DCCD) is an organic compound with the chemical formula (C6H11N)2C. It is a waxy white solid with a sweet odor. Its primary use is to couple amino acids during artificial peptide synthesis. The low melting point of this material allows it to be melted for easy handling. It is highly soluble in dichloromethane, tetrahydrofuran, acetonitrile and dimethylformamide, but insoluble in water.
Diisopropyl azodicarboxylate (DIAD) 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 been used to generate aza-Baylis-Hillman adducts with acrylates. It can also serve as a selective deprotectant of N-benzyl groups in the presence of other protecting groups.
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Phenylmagnesium bromide, with the simplified formula C
6H
5MgBr, is a magnesium-containing organometallic compound. It is commercially available as a solution in diethyl ether or tetrahydrofuran (THF). Phenylmagnesium bromide is a Grignard reagent. It is often used as a synthetic equivalent for the phenyl "Ph−" synthon.
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In organic chemistry, the Myers deoxygenation reaction is an organic redox reaction that reduces an alcohol into an alkyl position by way of an arenesulfonylhydrazine as a key intermediate. This name reaction is one of four discovered by Andrew Myers that are named after him; this reaction and the Myers allene synthesis reaction involve the same type of intermediate. The other reactions are Myers' asymmetric alkylation and Myers-Saito Cycloaromatization.
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