Esters are a highly relevant class of compounds in the industrial context, and biocatalysis applied to ester syntheses is already a reality for some chemical companies.

Biocatalysis—specifically the use of immobilized lipases—has been proposed as a greener alternative for ester production. Several critical challenges, such as the high cost of biocatalysts, are delaying the industrial implementation of biocatalysis. Moreover, for short-chain ester synthesis, the strong inhibition/inactivation potential of short-chain acids and alcohols on lipases leads to long reaction cycles and/or the need to use organic solvents to overcome the limitations of solvent-free systems and, consequently, the decrease in product concentrations. This review presents an overview of the scientific developments in enzymatic short-chain ester synthesis, compiling the constraints on their syntheses from a process perspective, including insights about key performance indicators (KPI) and economic parameters.

The adoption of biocatalysis in solvent-free systems is an alternative to establish a greener esters production. An interesting correlation between the acid:alcohol molar ratio and biocatalyst (immobilized lipase) loading in the optimization of ester syntheses in solvent-free systems had been observed and explored. A simple mathematical tool named Substrate-Enzyme Relation (SER) has been developed, indicating a range of reaction conditions that resulted in high conversions. Here, SER utility has been validated using data from the literature and experimental assays, totalizing 39 different examples of solvent-free enzymatic esterifications. We found a good correlation between the SER trends and reaction conditions that promoted high conversions on the syntheses of short, mid, or long-chain esters. Moreover, the predictions obtained with SER are coherent with thermodynamic and kinetics aspects of enzymatic esterification in solvent-free systems. SER is an easy-to-handle tool to predict the reaction behavior, allowing obtaining optimum reaction conditions with a reduced number of experiments, including the adoption of reduced biocatalysts loadings.

Although the current literature describes significant advances in biocatalytic ester syntheses, few industrial plants worldwide are currently producing esters using biocatalysts. Green and sustainable esters can be obtained via a biocatalytic route, including some operational advantages over conventional syntheses. An analysis of the literature revealed that most articles neglect or describe the economic issues generically, without quantitative information. Scaling-up studies are also scarce in this field. The main disadvantage of biocatalysis using immobilized lipases—their cost—has not been studied at the same level of depth as other technical aspects. This gap in the literature is less intense in enzymatic biodiesel production studies and, despite the lack of a strict correlation, enzymatic biodiesel commercial plants are relatively more common. Preliminary techno-economic assessments are crucial to identify and circumvent the economic drawbacks of biocatalytic ester syntheses, opening the way to broader application of this technology in a large-scale context.

This study evaluated coupled effects of molar ratio of substrates and enzyme loading in a solvent-free system using a simple mathematical approach to obtain high conversions on octyl caprylate synthesis with Novozym 435. When molar ratios of caprylic acid to n-octanol (1:1 and 1:3) were evaluated with enzyme loadings of 1% to 4% (wt/wt acid), an interdependence between the masses of reagents and the enzymes was observed, that was expressed as a mathematical relation. The study of this relation, named as SER, indicated a specific range of reaction conditions that resulted in conversions above 90%. The most suitable condition corresponded to an acid:alcohol molar ratio of 1:1.3 and an enzyme loading of 1.5%, resulting in 94.5% of conversion at 65 °C in 3 hours of reaction. A different reaction system (bottle reactor) was used to evaluate the influence of reagents mixture and heat distribution. The use of a bottle reactor allowed yield improvement that reached 99.3%. At this condition, Novozym 435 was reused, without washing steps, in three subsequent batches keeping high conversion. A possible balance between the shift of chemical equilibrium by stoichiometric excess of reagents and enzymatic inhibition effects by substrates can be expressed mathematically in a convenient way, helping to predict the behaviour of synthesis in different conditions. The mathematical relation proposed, SER, allowed the achievement of 99% of conversion on enzymatic synthesis of octyl caprylate.