New ways to make pharmaceuticals

Electrochemistry

Electrochemistry as a tool for synthetic chemistry is often considered as an inherently green approach. The sustainability of electrosynthesis arises from the use of electrons as traceless redox reagents. By eliminating the need for conventional oxidising and reducing agents, electrochemistry significantly reduces the environmental footprint of chemical synthesis. Moreover, the generation of reactive intermediates in-situ enhances the safety profile of the process (compared to stockpiling larger quantities). Electrochemical reactions commonly proceed under mild conditions: often room temperature and atmospheric pressure. The ability to precisely control the reaction's driving force by adjusting the potential (Boettcher et al., 2021) not only enhances productivity but also optimises energy consumption. 

As a result, organic electrosynthesis aligns with several key principles of Green Chemistry (Schäfer, 2011). However, the choice of solvents, electrode materials and supporting electrolytes also influences the sustainability of the process (Cembellín and Batanero, 2021). 

Fundamentals of electrolysis

In an electrochemical reaction, a heterogeneous electron transfer happens on the surface of the electrode, where electrons are either removed (oxidation) or added (reduction) to the molecule, followed by a chemical transformation. To ensure charge balance, the number of electrons consumed at the anode needs to be equal to the number of electrons released at the cathode. To avoid the influence of the counter reaction on the reaction of choice, a divided cell can be used where the anodic and the cathodic compartments are separated by a semipermeable membrane or frit. In an undivided cell, both electrodes are placed in the same compartment. Regardless of the type of the cell used, both electrodes need to be connected to a power source and in contact with a conducting solution. Usually, a supporting electrolyte is added to the reaction mixture to ensure sufficient conductivity of the solution. 

Electrolysis can be performed under constant current or constant potential conditions. In constant current electrolysis, the current is kept constant while the potential is allowed to drift, gradually increasing to sustain the current flowing. Constant current electrolysis is operationally simpler and faster method. In constant potential electrolysis, the potential is kept constant while the current drops, allowing for greater selectivity of the process (Leech and Lam, 2022). The efficiency of an electrosynthetic process is described by chemical yield and Faradaic efficiency (Cembellín and Batanero, 2021). A unique feature of electrochemistry is the inversion of substrate reactivity by electron transfer, also called umpolung (from the German for 'polarity reversal'). In this process, a nucleophile is converted into an electrophile or vice versa.  

There are several types of electrosynthetic reactions with distinct features:

Direct electrolysis

In direct electrolysis, the electrode replaces the redox reagent and the substrate is directly oxidised or reduced on the electrode. Direct electrolysis is the simplest and most commonly used method, especially in industry.

A common approach in direct electrolysis is to use solvent reactivity as a way to introduce functional groups. Methoxylations in methanol and acetoxylations in acetic acid are two common examples.  

Indirect electrolysis

In indirect electrolysis, the redox process is facilitated by an electrocatalyst or redox mediator, which is activated on the electrode and then reacts with the substrate in the bulk solution. Then, the electrocatalyst or redox mediator is regenerated at the electrode and therefore can be used in lower quantities than the reagent. This use of a chemical mediator can decrease the potential needed for the reaction, increase the reaction rate and improve selectivity, resulting in lower energy consumption and more sustainable processes.   

Paired electrolysis

Normally, only one of the half-reactions is the reaction of interest, taking place on the working electrode while the counter electrode reaction is disregarded, which significantly reduces the energy efficiency. In paired electrolysis, products of value are generated on both electrodes, increasing the theoretical electrochemical yield up to 200%. Cathodic and anodic reactions can be coupled or independent (Cembellín and Batanero, 2021).  

A notable example of paired electrolysis used in industry is the BASF process where t-butyltoluene is methoxylated at the anode while dimethyl phthalate is hydrogenated at the cathode (Frontana-Uribe et al., 2010). 

Flow electrolysis

Flow conditions are used to scale-up electrosynthetic reactions. Flow cells consist of two planar electrodes, forming a narrow gap where the electrolysis solution flows. In an electrochemical flow reactor, the distance between the electrodes is usually very small which results in a lower ohmic drop of the system, enabling the use of low or no amount of supporting electrolyte (Maljuric et al., 2020).