AUTHORS
Jonas Spang, Francesco Mascia, Wolfgang Kroutil
When chemists today want to produce a carboxylic acid, the process often seems straightforward: take the relevant alcohol, oxidise it, and the acid is ready. In practice, however, it is precisely this seemingly simple oxidation of primary alcohols to carboxylic acids that is one of the most problematic steps in organic synthesis, particularly on a large scale.
Why carboxylic acids are so important
Carboxylic acids are found in hundreds of medicines, such as painkillers, cholesterol-lowering drugs and antibiotics. Nevertheless, in industry they are often not obtained directly from alcohols, but via indirect routes such as the hydrolysis of esters or nitriles, because traditional oxidation methods are often hazardous, lack selectivity or generate a great deal of waste.
In the JACS-Au article ‘Evolution of Methods for the Oxidation of Primary Alcohols to Carboxylic Acids: From Metal Oxides to Biocatalysis’, acib researchers Jonas Spang, Francesco Mascia and Wolfgang Kroutil from the University of Graz systematically summarise how this key reaction has evolved over recent decades, moving away from toxic metal oxide reagents towards modern catalytic and biocatalytic processes.
They classify the methods according to the oxidising agent used – from chromium oxides to molecular oxygen – and demonstrate how this can improve selectivity, sustainability and practicality.
In the past: lots of chromium, lots of manganese, lots of waste
Conventional oxidation reactions use large quantities of heavy-metal oxides such as potassium permanganate or toxic chromium oxides, for example in the famous Jones oxidation. These reagents are highly oxidising and often perform robustly in the lab, but they generate large quantities of toxic metal sludge – a ‘no-go’ from a green chemistry perspective, with poor E-factors and high disposal costs.
More sustainable approaches
In response to these problems, catalytic systems have been developed that utilise sustainable oxidising agents, such as molecular oxygen or hydrogen peroxide.
Another step towards sustainability is electrochemical methods, in which the current itself serves as the oxidising equivalent. Electrochemical systems oxidise alcohols in aqueous solution and produce only hydrogen gas as a by-product – although scaling is often limited by electrochemical cell geometry and mass transfer.
‘Acceptorless dehydrogenation’ methods are also promising; in these, catalysts release hydrogen from the alcohol and form carboxylates without an external oxidising agent – technically attractive, but usually still associated with high temperatures and expensive precious metals.
And that is where enzymes come into play
The second major section of the article is devoted to biocatalytic strategies: enzymes such as alcohol and aldehyde dehydrogenases, FAD oxidases, haem enzymes and copper radical oxidases catalyse the same reaction under mild conditions in water.
Enzymes are particularly attractive for selective oxidations, as they control the oxidation of the substrate at the active site in such a way as to prevent side reactions. Furthermore, enzymes are ‘naturally trained’ to utilise simple oxidising agents such as molecular oxygen or hydrogen peroxide, often producing only water as a ‘waste product’.
What makes biocatalysis special in this context
Enzymes offer a number of clear advantages over conventional chemistry:
- They are highly selective and minimise by-products.
- They are produced biotechnologically from renewable raw materials and are biodegradable.
- They generate less waste.
- They operate under mild conditions.
At the same time, they have typical weaknesses – lower substrate loading, limited stability, and sometimes narrow substrate specificity – but these can be addressed through enzyme and process engineering.
The aim of the acib researchers is to replace conventional, often multi-step and waste-intensive synthetic pathways with shorter, more robust and ‘greener’ enzyme cascades that can be integrated into industrial processes.
What does this mean in concrete terms for industrial processes?
For companies, the ‘evolution’ of oxidation chemistry described here offers several options:
- In the short term: replacing existing chemical oxidation processes with more efficient catalytic methods (e.g. TEMPO/O2 systems or flow catalysis), thereby reducing waste and energy consumption.
- In the medium term: testing biocatalysis in sub-processes, such as ADH/ALDH cascades for selected alcohols or laccase/TEMPO systems for bio-based platform chemicals such as 2,5-furandicarboxylic acid.
- In the long term: redesign entire synthetic routes so that biocatalysis takes centre stage and alcohols are used as strategic starting materials.
acib as a partner on the path to the ‘enzyme factory’
It is precisely for these steps that acib offers companies collaborative projects – ranging from enzyme discovery and development, through process optimisation, to integration into continuous reactor concepts.
The development of metal oxides into biocatalysts, as outlined in the JACS-Au article, is therefore not merely an academic success story, but precisely describes the path that acib is taking, together with industry partners, towards sustainable chemistry.
Picture by acib