Structure-Guided Selection of Natural Deep Eutectic Solvents for Phytochemical Extraction: A Critical Review

Abstract

Natural deep eutectic solvents (NADES) have recently emerged as valuable alternative extraction media to recover plant-derived phytochemicals. Their interest derives from the propensity of combinations of naturally occurring hydrogen-bond acceptors and donors to form liquids with depressed melting points, tunable polarity, high solvation capacity and very low volatility. From their first systematic description as a potential green solvent system, research has progressed from proof-of-concept solubilization to extraction of phenolic acids, flavonoids, anthocyanins, alkaloids, saponins and other bioactive constituents. This critical review examines NADES from a phytochemical-selection perspective (rather than as replacements for conventional organic solvents). The review links molecular features of target compounds (hydrogen-bonding capacity, ionisation, polarity, aromaticity, lipophilicity and chemical stability) with solvent characteristics (hydrogen-bond basicity/acidity, water content, viscosity and component ratio). Representative studies illustrate that extraction performance is highly formulation-dependent (a solvent that favours one phytochemical class may not be optimal for another). NADES can also impact stability and, in some systems, apparent solubility or bioaccessibility of extracted compounds. However, the term "green" should not be assigned automatically: component toxicity, persistence, preparation energy, water demand, downstream recovery and life-cycle impacts must also be considered. The major unresolved issue is the lack of a predictive framework for selecting a NADES before experimental screening. A phytochemical-NADES selection framework is therefore proposed, together with reporting recommendations and a research agenda focused on standardisation, solvent recovery, comparative green metrics and structure-guided solvent design. The review provides a laboratory-independent conceptual basis for selecting NADES for phytochemical extraction and for designing future experimental studies.Keywords: natural deep eutectic solvents; NADES; green extraction; phytochemicals; flavonoids; polyphenols; anthocyanins; solvent design; sustainable extraction.