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Nucleophilic substitution: A powerful strategy for creating diverse chemical structures

Aug. 7, 2018

Nucleophilic substitution reactions are amongst the most widely-used transformations in organic chemistry. They facilitate the interconversion of functional groups, typically at a saturated aliphatic carbon, allowing chemists to swap specific features on one molecule for more desirable ones on another. When it comes to synthetic manipulation, there really isn’t a substitute for nucleophilic substitution!

In this blog, we consider why these reactions are so useful and take a brief look at the history of some of the most important examples.

What is nucleophilic substitution?

Nucleophilic substitution reactions involve the interaction of an electron rich nucleophile (Nuc) with the positive or partially positive charge of one or more atoms on a substrate (R-LG). The neutral or negatively charged nucleophile forms a new bond with the substrate, replacing the neutral or positively charged leaving group (LG). The most general form of the reaction is as follows:

Nuc + R-LG → R-Nuc + LG

Some of the simplest nucleophilic substitutions involve the reaction of alcohols (R-OH) with alkyl halides (R-X). Alkyl halides often make superb substrates for nucleophilic substitution due to the electron-withdrawing nature of the halide group. Alcohols, on the other hand, make nifty nucleophiles due to the lone pair of electrons on the oxygen atom. Together, the alcohol group can displace the halide on the substrate, resulting in two new products.

Thanks to the discovery and refinement of innovative reagents and catalysts, more sophisticated nucleophilic substitution strategies have been developed that allow chemists to manipulate the functionality of a broad range of compounds. Over the years, these reactions have given organic chemists the freedom to create innovative structures and explore new areas of chemical space.

Nucleophilic substitution involves a versatile family of reactions and reagents

The wide variety of transformations that are possible mean nucleophilic substitution reactions can be used to generate many different products. From the production of pesticides to the manufacture of medicines, many of these reactions have a significant impact on our lives. Three of the most important named nucleophilic substitution reactions are highlighted below.

1. Gabriel synthesis

One of the earliest named nucleophilic substitution reactions is the Gabriel synthesis, an approach to generating primary amines from primary alkyl halides, traditionally achieved using potassium phthalimide. While the alkylation of phthalimide with alkyl halides was first reported in 1884, German chemist Siegmund Gabriel realized that the process could be applied to other transformations. He developed a mild two-step procedure for the synthesis of primary amines from their corresponding alkyl halides based on alkylation followed by hydrolysis. In subsequent years, new Gabriel reagents have been developed that replace phthalimide with other nitrogen sources, such as the sodium salt of saccharin, and di-tert-butyl-iminodicarboxylate.

The Gabriel synthesis has been used in a wide variety of important syntheses, including the total synthesis of peramine, an alkaloid produced by a fungus that protects grasses against grazing by mammals and insects (which has a range of commercial applications).

2. Baeyer-Villiger oxidation

Another important nucleophilic substitution reaction is the Baeyer-Villiger oxidation. Discovered in 1899 by Adolf von Baeyer and Victor Villiger, the reaction uses oxidants such as peroxyacids and peroxides to transform ketones into lactones and cyclic ketones into hydroxyl acids. As the product generated retains the existing stereochemistry at the migrating center, this reaction is highly prized by synthetic chemists. What’s more, it permits a wide range of oxidants to be used and tolerates the presence of a wide range of functional groups (in other words, it’s a gentle giant).

Efforts to make the Baeyer-Villiger catalytic (while also retaining its excellent regioselectivity and stereoselectivity) have resulted in the use of monooxygenases, as well as catalysts such as substituted selenic acids.

The Baeyer-Villiger reaction has been employed in a broad range of transformations, including the total synthesis applications of important natural products. For example, Shing and colleagues employed a Baeyer-Villiger transformation in their 21-step synthesis of the functionalized CD-ring of Taxol, an important anti-cancer drug.

3. Swern oxidation

In 1976, American chemist Daniel Swern and colleagues discovered that when dimethyl sulfoxide (DMSO) was treated with trifluoroacetic anhydride (TFAA) below -50 °C, the resulting trifluoroacetoxydimethylsulfonium trifluoroacetate would react rapidly with primary and secondary amines. When the alkoxydimethylsulfonium trifluoroacetates that were formed were treated with trimethylamine, the corresponding aldehydes and ketones were produced in high yields. Oxalyl chloride was subsequently found to be more efficient at activating DMSO than TFAA, and this version of the reaction has come to be known as the Swern oxidation.

The Swern oxidation played a key role in the first total synthesis of the marine dolabellane diterpene (+)-deoxyneodolabelline. In the final step of the synthesis, the oxidation of a secondary alcohol was required. While Dess-Martin and Ley oxidations were attempted, the substrate suffered carbon-carbon bond cleavage. The Swern oxidation, on the other hand, generated the product in good yield.

Speaking of oxidation (or more accurately, oxygenation), if you need to take a deep breath and read that section again, we won’t blame you—it’s very rare that we get to write about a molecule that’s 49 characters long – try saying trifluoroacetoxydimethylsulfonium trifluoroacetate at the end of a long day in the lab!

Other named substitution reactions

Of course, these named reactions aren’t the only types of nucleophilic substitution. There’s the Mitsunobu reaction, Dess-Martin oxidation, Tishchenko reaction, Sharpless asymmetric aminohydroxylation and dihydroxylation, and Wacker oxidation, to name just a few. All are important transformations in the synthetic chemist’s toolbox. To learn more, visit our nucleophilic substitution “named reaction” pages.


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