A technique full of potential

When synthetic reactions are discovered, organic chemists typically report a set of conditions that works for a large range of substrates. We understand that this is in fact a compromise, as the optimal conditions for any individual substrate may vary significantly.

The multitude of reasons for this difference of reactivity between substrates are often lumped together as ‘stereoelectronic effects’. However, the inductive effect on reactivity – electron-withdrawing or donating through sigma bonds of nearby functional groups – reported by Louis Plack Hammett in 1937 is perhaps the most fundamental and also conceptually intuitive process underlying our understanding of chemical reactivity. In its simplest form: opposites attract.

This idiom is not only the key to organic chemists remembering multitudes of apparently unrelated reaction mechanisms, but is the principle we most often use to modulate reactivity: increasing or decreasing the electron density at a reaction centre by changing the chemical structure will respectively increase nucleophilicity or electrophilicity.

The application of this principle has now been revisited by the group of Mu-Hyun Baik at the Korea Advanced Institute of Science and Technology, Republic of Korea.¹ This beautifully simple study does not modulate the reactivity of a molecule by changing its chemical structure, but rather by applying a voltage.

The team began by studying the base-catalysed hydrolysis of a tert-butyl 4-mercaptobenzoate (figure 1) bound to the surface of a gold electrode and demonstrated that the Stark effect – the modulation of electronic structure on a surface by the application of a voltage – can be used to modulate chemical reactivity. The reaction progress was qualitatively monitored using surface-enhanced Ramen spectroscopy (Sers) and an internal standard, and hydrolysis of the ester with 3M potassium hydroxide solution in the absence of any voltage established a baseline of reactivity.

The proof of concept was then demonstrated as the team showed the rate of reaction could both be increased by the application of a positive voltage, effectively withdrawing electrons from the ester and increasing its electrophilicity, as well as by reducing the rate of reaction through the application of a negative current, thus donating electron density to the ester and reducing its electrophilicity. The team was also able to show that the reactivity of arylbromides tethered to the electrode surface could be modulated in a palladium-catalysed Suzuki reaction.

Finally, in the piece de resistance, the team inverted the voltage in a ‘two-part’ amide bond-forming reaction, enhancing the rate of sequential elementary steps with opposing electronic requirements (figure 2). 4-Mercaptobenzoic acid was first immobilised on the gold electrode surface and in the presence of the coupling reagent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) was reacted with 4-(aminomethyl)benzonitrile to form the corresponding amide. Again using Sers to monitor the reaction, the team initially observed that no reaction occurs on mixing the reagents in the absence of a voltage, or with the application of a positive charge that effectively reduces the nucleophilicity of the benzoic acid. In contrast, applying a voltage of -0.7 V – approximately equivalent in inductive terms to introducing a para-dimethylamino group – effectively switched on reactivity. The now more nucleophilic benzoic acid reacted with the coupling reagent to form the activated ester intermediate.

Although product formation could then be observed to some degree in the absence of a voltage as the amine reacted with the activated ester, excitingly the team could subsequently invert the applied voltage to withdraw electron density from the activated intermediate. By increasing the electrophilicity of the intermediate, this increased the rate of reaction with the amine nucleophile. Whereas a functional group used to modulate reactivity has a discreet inductive effect that is either electron-donating or withdrawing, this experiment introduces the concept of using voltage as a continuously modifiable functional group that can fine-tune reactivity as desired.

This work is clearly conceptual, but as a proof of principle that appears both so elegantly simple and somehow obvious, it is incredibly exciting. On a fundamental level, chemical reactivity really is as simple as ‘opposites attract’, and being able to continuously modulate the electronic properties of a molecule, or even reaction intermediates, without changing the chemical structure is a synthetic strategy with great potential.

Editor’s note: This is Karl’s final column, ending an era that began when he wrote the very first Organic Matter article in January 2014. Thank you Karl for the many entertaining insights you’ve provided over the years. We wish you all the best for the future.