Named Organic Reactions

Named Organic Reactions

In the field of organic chemistry, significantly important reactions are often named by or after their founders. Such reactions are collectively referred to as named organic reactions. It includes a very long list of reactions of different types of mechanisms such as the Birch reaction, the Swern oxidation, the McMurry reaction, etc.

Prelude

This article is going to briefly touch on one of such named organic reactions, the Mitsunobu reaction. The Mitsunobu reaction was discovered by Professor Oyo Mitsunobu (1934-2003) in 1967. Since the publication of his findings on the use of triphenyl phosphine (TPP) and diethyl azodicarboxylate (DEAD) to convert an alcohol into other functional groups, using a suitable substrate, while undergoing a stereochemical inversion; the Mitsunobu reaction has become an integral part of numerous natural product syntheses. The equation below is a simplified example of an esterification of an alcohol with a carboxylic acid showing the inversion of stereochemistry in the resulting ester.

The Mitsunobu Reaction

Discovered in 1967¹, the Mitsunobu reaction essentially converts a hydroxyl group of an alcohol into a strong leaving group which can be displaced by a large variety of nucleophiles¹. This reaction is able to proceed under mild conditions, producing good yields with stereochemical inversions at the carbon bearing the hydroxyl group of secondary alcohols².

In general, reagents such as triphenyl phosphine (TPP) and diethyl azodicarboxylate (DEAD) are used to mediate the Mitsunobu reaction³. It has been noted that tributyl phosphine (TBP) can be used instead of TPP² and di-isopropylazodicarboxylate (DIAD) works equally well as compared to DEAD⁴. Although the efficiency of the reaction is mainly dependent on the alcohol and nucleophile used⁴, results have shown that the use of TBP instead of TPP gives better yield in some Mitsunobu reactions⁵. However, TBP is reported to be inferior to TPP in other cases⁶. Over the past 4 decades since the discovery of the Mitsunobu reaction, many other alternatives for these two mediating reagents had been found⁷.

Although the original findings for the Mitsunobu reaction¹ used carboxylic acids as the nucleophile to form an ester, other acidic nucleophiles such as imides, thiols, etc can be used instead to incorporate the desired functional groups such as sulfonamides, azides, nitriles, etc⁸. However, it is important to note that besides the product which contains the newly formed C-O, C-N, C-S, C-X or C-C bond, phosphane oxide and hydrazinedicarboxylate or hydrazinedicarboxamide are also produced as side products⁷ as shown below.

With such a wide area of usage, this reaction is therefore recognised as one of the most invaluable and robust synthetic transformation and hence named after its discoverer Professor Oyo Mitsunobu⁹.

The Mechanism of the Mitsunobu Reaction

Despite twenty years after Mitsunobu first reported this useful reaction, there were no thorough study on its mechanism until 1987¹⁰. Prior to this, the mechanism was generally assumed to proceed through phosphonium salts⁹. Subsequent studies carried out demonstrated that the true mechanism of the Mitsunobu reaction was more complex than earlier studies suggest¹¹. The mechanism of this reaction is still being debated upon mainly due to the number of intermediates and the roles they play¹ as well as the formation of products with retained stereochemistry when trying to invert hindered secondary alcohols¹². Three decades after the discovery of the Mitsunobu reaction, the standard mechanism proposed for this reaction is still considered to be incomplete¹².

Today, it is widely accepted⁸ that the Mitsunobu reaction involves the formation of a betaine intermediate from nucleophilic attack on DEAD by TPP. This is followed by the deprotonation of the nucleophilic carboxylic acid by the betaine. The carboxylate anion which is generated deprotonates the alcohol, forming an alkoxide. The alkoxide attacks the betaine at phosphorus forming oxyphosphonium ion. The attack of the carboxylate anion on the oxyphosphonium ion forms the desired product and triphenylphosphine oxide as shown below.

It is important to note that during the deprotonation of the alcohol by the carboxylate anion forming the alkoxide, the alkoxide attacks the betaine at phosphorous forming the key oxphosphonium ion as well as many other intermediates.

As can be seen from the above range of various intermediates formed, only the key oxyphosphonium ion intermediate is capable of forming the desired product. The ratio between these intermediates with one another is largely dependent on the pKa of the acid and solvent polarity^{11, 13}.

Popularity & Advances

Conducting a simple search on Chemical Abstracts or SciFinder reveals that the Mitsunobu reaction had gained increasing popularity and attention over the recent years. Many review articles were written on the numerous applications of the Mitsunobu reaction in the field of chemistry^{4, 14}. This popularity can be due to the reaction’s mild conditions, stereoselectivity and wide range functional group compatibilities⁷.

However, the generation of by-products often makes the isolation of the desired product difficult. In addition, the pka of the acid component has to be lower than 10 in order to achieve desired alkylation¹⁵. As mentioned briefly before, it was not long before studies were made to try to improve on this technique either by improving the removal of by-products¹⁴, using alternative reagents¹⁴ or by coupling with other techniques. For example, by combining the use of high reaction concentrations and sonification techniques, the Mitsunobu reaction of sterically hindered alcohols can be greatly increased¹⁶. A review article by Roman Dembinski provided a detailed outline of the recent advances in the Mitsunobu reaction, from modifications of classical reagents to using fluorous approach as well as other advances⁷.

Applications using novel approaches

I. Maleimide compounds are a class of substrates crucial for both biological and chemical applications. In biological applications, such compounds can react spontaneously with cysteine residues and hence are used as linkers for the conjugation of molecules to proteins and chemical probes of protein structures. These derivatives will have several uses such as serving as immuno-conjugates for cancer therapy. In chemical applications, the maleimide, with its Micheal-accepting ability and dienophilic nature, can be used as a platform in total synthesis. Despite its numerous uses, there are very few literature for its synthesis¹⁷. Most methods are either limited by the starting materials or limited by the complexity of the maleimide desired to be formed. A method of synthesizing high yields of N-alkyl maleimides using a novel modification of the Mitsunobu reaction was found¹⁷. By using the Mitsunobu reaction, complex N-alkyl maleimides can be synthesized using a variety of substrates.

The modification of the Mitsunobu procedure by using of a nonreacting alcohol-additive also increased the yields by more than ninety percent for a variety of substrates¹⁷.

II. The mitsunobu reaction was also used as the key step in peptide nucleic acid (PNA) monomers synthesis¹⁸. PNA are relatively novel DNA analogues. They are able to mimic oligonucleotides forming Watson & Crick heteroduplexes with DNA or RNA which are complementary. They have the potential to act as gene-targeted compounds with antigene and antisense properties. Instead of relying on unstable Boc-aminoacetaldehyde as the key component in the synthesis of the peptidic part of PNA monomer, the Mitsunobu reaction was employed instead as the key first step as shown below¹⁸.

III. EDOT (3,4-ethylenedioxythiophene) are widely used as antistatic coatings in photographic films, as electrode materials for solid electrolyte capacitors as well as many other applications. This is because of its unique combination of high environmental stability, high conductivity and transparency in the oxidised state¹⁹. In 2002, the synthesis of EDOT derivatives not accessible by the conventional Williamson ether synthesis as well as the first ever synthesis of chiral EDOTs was achieved by using the Mitsunobu reaction as the key step¹⁹. Furthermore, for derivatives which can be synthesized by the Williamson ether method, yields obtained by using the Mitsunobu reaction were higher¹⁹. The step involving the Mitsunobu reaction is between 3,4-dihydroxy-2,5-thiophenedicarboxylic acid diethyl ester and 1,n-alkanediols with dialkylazodicarboxylates and trialkylphosphines as mediating reagents.

Following that, from 2003 to 2006, there were many new applications found for the Mitsunobu reaction. Methods such as the synthesis of 2’-O-Benzyladenosine using the Mitsunobu reaction²⁰, the synthesis of hydroxyindoline-derived tricyclic derivatives in solid phase library using the Mitsunobu Approach²¹ as well as a one-pot, coupling of various aliphatic/aromatic amines and various alcohols with a range of primary, secondary and tertiary alcohols using a Mitsunobu zwitterion and carbon dioxide²² were developed.

In this year alone, 2007, there were numerous publications of new found applications for the Mitsunobu reaction as well. Below are three of such applications.

IV. Old methods for the esterification of carboxylic acids required heating the carboxylic acid in an alcoholic solvent under acidic catalysis. Other procedures involve converting the carboxylic acid into its corresponding acid chloride or mixed anhydride before the addition of an alcohol nucleophile. Using these methods to convert benzoic acid to phenyl ester proved to be problematic⁸. Till then, there was no literature available with regards to using the Mitsunobu reaction for coupling benzoic acids with phenolic nucleophiles. The study later showed that Mitsunobu reaction was a convenient and effective method for the esterification of various benzoic acids with differentially functionalised phenols, yielding the corresponding phenyl esters, as shown in the example below, in excellent quantities⁸.

V. In generating biological molecules, triazolopyridines and fused triazoles are often used as scaffoldings. The conventional procedure for the synthesis of triazolopyridines involves the dehydration of a 2-hydrazidopyridine using concentrated hydrochloric acid, refluxing phosphorus oxychloride or refluxing acetic acid. Such harsh reaction conditions are often not suitable with many acid or base labile functional and protecting groups like esters or carbamates²³. Therefore, the types of precursors which can be used for the synthesis of fused triazoles were limited. Although mild conditions for the synthesis of triazoles had been found in literature, the choice of substrates is often limited by the significant variations in yields and reaction times. In an effort to develop a general, efficient and mild procedure for the synthesis of triazolopyridines and other fused triazoles, in which amino acid substrates and other polar functional groups can be used; a modified Mitsunobu reaction using TMS-N₃ as an additive was devised and employed. The addition of TMS-N₃ and TPP to the reaction mixture of acylated hydrazinopyridines followed by DEAD enhanced the yield of the desired products by more than 75 percent in less than ten minutes of reaction time at room temperature²³.

VI. In the attempt of synthesizing orthogonally protected alpha, beta-diaminopropionic acids for solid-phase peptide synthesis, Kelleher and coworkers²⁴ had devised a method which produced good yields under the Mitsunobu reaction conditions through the reaction of N-trityl L-serine esters with N-substituted sulfonamides. By using N-Boc p-toluenesulfonamide as the nitrogen nucleophilic precursor in the Mitsunobu reaction, the best yields were obtained. It was later found that by replacing the N-trityl group with the more stable allyloxycarbonyl group increases the efficiency of the reaction²⁴.

As this is a new area of study, the chemistry of the reactions such as the clean removal of the individual protecting groups, the incorporation of such groups into peptide structures using solid-phase peptide synthesis are still being examined²⁴.

Conclusion

As can be seen from above, the increasing new applications of the Mitsunobu reaction even after nearly 4 decades since its discovery has proven itself to be one of the best methods for C-O, C-N, C-C and C-X bond formation as well as its vast potential in organic synthesis both in biological and chemical applications. In many cases, its mild reaction conditions and excellent stereoselectivity makes it the optimum choice as the key step of certain product synthesis. Studies will continue to be done on how to improve and modify this reaction for different purposes. Therefore, it is apparent that the Mitsunobu reaction will continue to be an important named organic reaction as well as an irreplaceable tool for organic chemistry.

References

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