{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T11:03:48Z","timestamp":1790247828643,"version":"4.1.0"},"reference-count":42,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MICIU-AEI-FEDER","award":["PID2024-159264OB-C21\/C22"],"award-info":[{"award-number":["PID2024-159264OB-C21\/C22"]}]},{"name":"MICIU-AEI-FEDER","award":["CPP2023-010883"],"award-info":[{"award-number":["CPP2023-010883"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Diethyl succinate (DEtS) synthesis by lipase-catalyzed direct esterification was successfully carried out in succinic acid (SA):trioctylphosphine oxide (TOPO) mixtures acting as reactive deep eutectic solvents (rDES). By this strategy, the succinic acid concentration in this non-aqueous eutectic mixture reaches up to 1.92 M at room temperature, enabling a suitable reaction system for the biocatalytic double esterification of SA with ethanol (EtOH) to yield DEtS. The best results were obtained when using an SA:TOPO equimolar ratio and a stepwise addition of EtOHinto the reaction system, leading to 92% SA conversion and 60% selectivity for the DEtS product synthesis after 20 h at 60 \u00b0C. For the subsequent pure product separation, the direct addition of dimethyl sulfoxide into the reaction system provokes TOPO crystallization, which is easily removed by filter centrifugation at room temperature. This novel approach, TOPO-based rDES, has been demonstrated as a green and low-waste strategy for biocatalytic diester synthesis under mild conditions, validated by green metrics.<\/jats:p>","DOI":"10.3390\/molecules31193402","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:16:28Z","timestamp":1790244988000},"page":"3402","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biocatalytic Synthesis of Diethyl Succinate in Hydrophobic Trioctylphosphine Oxide (TOPO)-Based Reactive DES"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3026-7876","authenticated-orcid":false,"given":"Susana","family":"Nieto","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular \u201cB\u201d e Inmunolog\u00eda, Facultad de Qu\u00edmica, Universidad de Murcia, 30100 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5211-5975","authenticated-orcid":false,"given":"Francisco J.","family":"Ruiz","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular \u201cB\u201d e Inmunolog\u00eda, Facultad de Qu\u00edmica, Universidad de Murcia, 30100 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Juan","family":"Martinez-Garcia","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular \u201cB\u201d e Inmunolog\u00eda, Facultad de Qu\u00edmica, Universidad de Murcia, 30100 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4391-0875","authenticated-orcid":false,"given":"Rocio","family":"Villa","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular \u201cB\u201d e Inmunolog\u00eda, Facultad de Qu\u00edmica, Universidad de Murcia, 30100 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Jairton","family":"Dupont","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular \u201cB\u201d e Inmunolog\u00eda, Facultad de Qu\u00edmica, Universidad de Murcia, 30100 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6043-3893","authenticated-orcid":false,"given":"Pedro","family":"Lozano","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular \u201cB\u201d e Inmunolog\u00eda, Facultad de Qu\u00edmica, Universidad de Murcia, 30100 Murcia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"ref_1","unstructured":"Anastas, P.T., and Warner, J.C. (1998). Green Chemistry: Theory and Practice, Oxford University Press."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/s41557-019-0226-9","article-title":"Circular chemistry to enable a circular economy","volume":"11","author":"Keijer","year":"2019","journal-title":"Nat. Chem."},{"key":"ref_3","unstructured":"(2026, May 12). Diethyl Succinate Green Solvent Market. Available online: https:\/\/dataintelo.com\/report\/diethyl-succinate-green-solvent-market."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Escanciano, I.A., Wojtusik, M., Esteban, J., Ladero, M., and Santos, V.E. (2022). Modeling the succinic acid bioprocess: A review. Fermentation, 8.","DOI":"10.3390\/fermentation8080368"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Chen, X., Wu, H., Chen, Y., Liao, J., Zhang, W., and Jiang, M. (2023). Recent advancements and strategies of improving CO2 utilization efficiency in bio-succinic acid production. Fermentation, 9.","DOI":"10.3390\/fermentation9110967"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.eurpolymj.2017.10.028","article-title":"Lipase-catalyzed synthesis of biobased and biodegradable aliphatic copolyesters from short building blocks: Effect of the monomer length","volume":"97","author":"Debuissy","year":"2017","journal-title":"Eur. Polym. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"111926","DOI":"10.1016\/j.eurpolymj.2023.111926","article-title":"Lipase-catalyzed solution polycondensation of 1,4-butanediol and diethyl succinate: Effect of diphenyl ether concentration on enzyme stability, reuse and PBS molar mass distribution","volume":"187","author":"Guckert","year":"2023","journal-title":"Eur. Polym. J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.seppur.2011.11.033","article-title":"Diethyl succinate synthesis by reactive distillation","volume":"88","author":"Orjuela","year":"2012","journal-title":"Sep. Purif. Technol."},{"key":"ref_9","unstructured":"Orjuela, A., Yanez, A., Lira, C.T., and Miller, D.J. (2011). Carboxylic Acid Recovery and Methods Related Thereto. (No. US2011275851A1 (B2)), U.S. Patent."},{"key":"ref_10","first-page":"637","article-title":"Direct downstream catalysis: From succinate to its diethyl ester without intermediate acidification","volume":"200\u2013202","author":"Ottens","year":"2012","journal-title":"Chem. Eng. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"111573","DOI":"10.1016\/j.eurpolymj.2022.111573","article-title":"Synthesis of polybutylene succinate via lipase-catalyzed transesterification: Enzyme stability, reuse and PBS properties in bulk polycondensations","volume":"179","author":"Guckert","year":"2022","journal-title":"Eur. Polym. J."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nghiem, N.P., Kleff, S., and Schwegmann, S. (2017). Succinic acid: Technology development and commercialization. Fermentation, 3.","DOI":"10.3390\/fermentation3020026"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.seppur.2015.07.039","article-title":"Extraction of succinic acid by aqueous two-phase system using alcohols\/salts and ionic liquids\/salts","volume":"155","author":"Pratiwi","year":"2015","journal-title":"Sep. Purif. Technol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2669","DOI":"10.1021\/je900205h","article-title":"Extraction of pyridine-3-carboxylic acid using 1-dioctylphosphoryloctane (TOPO) with different diluents: Equilibrium studies","volume":"54","author":"Kumar","year":"2009","journal-title":"J. Chem. Eng. Data."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.seppur.2011.10.002","article-title":"Extraction of L-lactic, L-malic, and succinic acids using phosphonium-based ionic liquids","volume":"85","author":"Oliveira","year":"2012","journal-title":"Sep. Purif. Technol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"113471","DOI":"10.1016\/j.fluid.2022.113471","article-title":"Succinic acid recovery from a glycerol-based solution using phosphonium ionic liquids supported by COSMO-RS","volume":"559","author":"Zurob","year":"2022","journal-title":"Fluid Phase Equilib."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"129199","DOI":"10.1016\/j.seppur.2024.129199","article-title":"Development of an asymmetric cellulose acetate-ionic liquid P6,6,6,14[PHOS] gel membrane for the perstraction of succinic acid from a model fermentation solution of Yarrowia lipolytica","volume":"354","author":"Zurob","year":"2025","journal-title":"Sep. Purif. Technol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1039\/b210714g","article-title":"Novel solvent properties of choline chloride\/urea mixtures","volume":"1","author":"Abbott","year":"2003","journal-title":"Chem. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"16083","DOI":"10.1039\/D6CC03854A","article-title":"Room temperature ionic liquids and deep eutectic solvents: Distinct classes or a continuum of liquid matter?","volume":"62","author":"Dupont","year":"2026","journal-title":"Chem. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1021\/acs.chemrev.0c00385","article-title":"Deep Eutectic Solvents: A Review of Fundamentals and Applications","volume":"121","author":"Hansen","year":"2021","journal-title":"Chem. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1039\/C9GC01076A","article-title":"Biocatalytic synthesis of panthenyl monoacyl esters in ionic liquids and deep eutectic solvents","volume":"21","author":"Lozano","year":"2019","journal-title":"Green Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5737","DOI":"10.1021\/acssuschemeng.3c00266","article-title":"Sustainable setups for the biocatalytic production and scale-up of panthenyl monoacyl esters under solvent-free conditions","volume":"11","author":"Nieto","year":"2023","journal-title":"ACS Sustain. Chem. Eng."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"114500","DOI":"10.1016\/j.cattod.2023.114500","article-title":"New sustainable biocatalytic approach for producing lipophilic (hydroxy)cinnamic esters based on deep eutectic mixtures","volume":"431","author":"Nieto","year":"2024","journal-title":"Catal. Today"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1007\/s10967-021-07994-4","article-title":"New hydrophobic DES based on tri-n-octylphosphine oxide and dicarboxylic acids: Synthesis, spectroscopy and liquid\u2013liquid extraction of actinides","volume":"330","author":"Kshirsagar","year":"2021","journal-title":"J. Radioanal. Nucl. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"116692","DOI":"10.1016\/j.seppur.2020.116692","article-title":"Extraction of adipic, levulinic and succinic acids from water using TOPO-based deep eutectic solvents","volume":"241","author":"Riveiro","year":"2020","journal-title":"Sep. Purif. Technol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1021\/acs.iecr.0c04551","article-title":"Development of new hydrophobic deep eutectic solvents based on trioctylphosphine oxide for reactive extraction of carboxylic acids","volume":"60","author":"Lalikoglu","year":"2021","journal-title":"Ind. Eng. Chem. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Xu, Y., Sheng, S., Liu, X., Wang, C., Xiao, W., Wang, J., and Wu, F.-A. (2017). Cooperative reinforcement of ionic liquid and reactive solvent on enzymatic synthesis of caffeic acid phenethyl ester as an in vitro inhibitor of plant pathogenic bacteria. Molecules, 22.","DOI":"10.3390\/molecules22010072"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"101682","DOI":"10.1016\/j.jics.2025.101682","article-title":"Evaluation of the efficiency of reactive extraction of malic acid using TPA or TOPO in imidazolium-based ionic liquid or conventional solvents","volume":"102","author":"Gunaydin","year":"2025","journal-title":"J. Indian Chem. Soc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e70846","DOI":"10.1002\/cctc.70846","article-title":"Deciphering pH behavior in deep eutectic solvents: Synergizing experimental data and computational modeling","volume":"18","author":"Puglisi","year":"2026","journal-title":"ChemCatChem"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"123728","DOI":"10.1016\/j.molliq.2023.123728","article-title":"Acidity and pH of DES-like mixtures and the possibilities of their determination","volume":"394","author":"Majova","year":"2024","journal-title":"J. Mol. Liq."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.molcatb.2012.03.010","article-title":"Esterification of bio-based succinic acid in biphasic systems: Comparison of chemical and biological catalysts","volume":"80","author":"Delhomme","year":"2012","journal-title":"J. Mol. Catal. B Enzym."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.molcatb.2009.03.004","article-title":"Role of apparent pKa of carboxylic acids in lipase-catalyzed esterifications in biphasic systems","volume":"59","author":"Bargeman","year":"2009","journal-title":"J. Mol. Catal. B Enzym."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1080\/10242420500285561","article-title":"pH-optima in lipase-catalysed esterification","volume":"23","author":"Buthe","year":"2005","journal-title":"Biocatal. Biotransform."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e202102674","DOI":"10.1002\/cssc.202102674","article-title":"Integrating biocatalysis with viscous deep eutectic solvents in lab-on-a-chip microreactors","volume":"15","author":"Guajardo","year":"2022","journal-title":"ChemSusChem"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.memsci.2014.02.006","article-title":"Nanofiltration coupled with vapor permeation-assisted esterification as an effective purification step for fermentation-derived succinic acid","volume":"459","author":"Lubsungneon","year":"2014","journal-title":"J. Membr. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.scp.2016.08.002","article-title":"Eco-friendly one pot synthesis of caffeic acid phenethyl ester (CAPE) via an in-situ formed deep eutectic solvent","volume":"4","author":"Fischer","year":"2016","journal-title":"Sustain. Chem. Pharm."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s10295-010-0817-3","article-title":"Modeling and optimization of lipase-catalyzed production of succinic acid ester using central composite design analysis","volume":"38","author":"Jarmi","year":"2011","journal-title":"J. Ind. Microbiol. Biotechnol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40508-016-0051-z","article-title":"Tools and techniques for solvent selection: Green solvent selection guides","volume":"4","author":"Byrne","year":"2016","journal-title":"Sustain. Chem. Process."},{"key":"ref_39","unstructured":"Andraos, J. (2012). The Algebra of Organic Synthesis: Green Metrics, Design Strategy, Route Selection, and Optimization, CRC Press. [1st ed.]."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"730","DOI":"10.2533\/chimia.2019.730","article-title":"Environmental Metrics to Drive a Cultural Change: Our Green Eco-Label","volume":"73","author":"Onken","year":"2019","journal-title":"Chimia"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1039\/b007871i","article-title":"So you think your process is green, how do you know?-Using principles of sustainability to determine what is green-a corporate perspective","volume":"3","author":"Curzons","year":"2001","journal-title":"Green Chem."},{"key":"ref_42","unstructured":"(2026, August 03). Process Mass Intensity Calculation Tool. Available online: https:\/\/www.acs.org\/green-chemistry-sustainability\/green-chemistry-nexus\/articles\/process-mass-intensity-calculation-tool.html."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/19\/3402\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T10:17:02Z","timestamp":1790245022000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/19\/3402"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,24]]},"references-count":42,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["molecules31193402"],"URL":"https:\/\/doi.org\/10.3390\/molecules31193402","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,24]]}}}