Unlocking the Potential of Polar Organometallic Reagents in Sustainable Solvents

Abstract

Polar organometallic reagents of the s- and d-block elements are key tools for C–C and C–heteroatom bond formation. Recent advances show that these highly reactive species can operate efficiently in sustainable solvents like water and deep eutectic solvents, under air and at room temperature. Acting as living solvents, these media enable sustainable organometallic transformations and redefine classical reactivity paradigms through the principle of green chemistry.

Key words

organolithium reagents - Grignard reagents - organozinc reagents - organosodium reagents - water - deep eutectic solvents - sustainable solvents

Biosketches

Joaquín García Álvarez is at the University of Oviedo (Spain), where he co-leads the Sustainable Synthetic Chemistry (QuimSinSos) group. He obtained his Ph.D. (2005) under the supervision of Profs. José Gimeno and Victorio Cadierno, and subsequently carried out postdoctoral research with Prof. Robert E. Mulvey at the University of Strathclyde (Glasgow, UK). He later held prestigious Juan de la Cierva and Ramón y Cajal fellowships before his appointment as a faculty member at the University Oviedo. His research focuses on organometallic catalysis in sustainable media [particularly deep eutectic solvents (DESs) and water], aiming at greener and more efficient synthetic organic methodologies. He has authored over 100 scientific publications and received: (i) the Leonardo Grant for Researchers­ and Cultural Creators (BBVA Foundation, 2017); (ii) the PhosAgro/ UNESCO/IUPAC ‘Green Chemistry for Life’ Grant (2018); and (iii) the GEQO Young Researcher Award [Real­ Sociedad Española de Química (RSEQ), 2016]. He has been also recognized among the Top 2% most influential chemists in Spain, according to the Stanford University ranking (2023–2025).

Vito Capriati is Full Professor of Organic Chemistry at the University of Bari (Italy), where he earned his M.Sc. in Chemistry and Pharmaceutical Technology, summa cum laude, in 1990. In 1991, he served as a forensic chemistry officer at the Carabinieri’s Scientific Investigation Department (RIS) in Rome. From 1992 to 1993, he held a CNR fellowship at the ‘MISO’ (Innovative Methodologies in Organic Synthesis) Centre, later merged into ICCOM (Institute of Chemistry of Organometallic Compounds) in Bari. He was a visiting scientist at The Ohio State University (USA, 2001) in the group of Prof. Gideon Fraenkel and a visiting professor at the University of Gothenburg (Sweden, 2003). Since 2016, he has been Director of the Interuniversity Consortium CINMPIS. His research focuses on the chemistry of polar organometallic compounds of s- and d-block elements, heterocyclic chemistry, asymmetric catalysis, and the development of sustainable processes in unconventional media such as water and deep eutectic solvents. He received the CINMPIS Prize for Innovation in Organic Synthesis (2009) and the Italian Chemical Society Award (Organic Division) for Mechanistic and Theoretical Aspects of Organic Chemistry (2014). He is the author of over 180 publications, seven book chapters and two international patents, and co-edited ‘Lithium Compounds in Organic Synthesis: From Fundamentals to Applications’ (2014). He has been a Fellow of the Royal Society of Chemistry since 2019.

Polar organometallic compounds of the s- and d-block elements, such as organolithium, Grignard­, organosodium, and organozinc reagents, are true workhorses of modern organic synthesis, being widely employed for the construction of C–C and C–heteroatom bonds, owing to their versatility, availability, and low cost. However, their highly polarized C–M bonds (M = Li, Mg, Na, Zn) demand strictly anhydrous, aprotic, fossil-derived volatile organic compounds (VOCs), inert atmospheres and often cryogenic temperatures. This conventional approach—still thought in most textbooks—raises major sustainability concerns as it relies on non-renewable resources and toxic, persistent solvents that generate vast amounts of waste. Indeed, over 90% of chemicals are still produced from oil and gas through inefficient, waste-intensive processes, leading to the release of more than 100 million tons of solvents into the environment each year. Since solvents crucially influence chemical equilibria, reaction kinetics, and selectivity, the quest for renewable, biodegradable, and non-toxic media has become a major frontier in synthetic chemistry. But can such sustainable solvents, especially protic ones, be compatible with highly reactive organometallics?

Over the past decade, a paradigm shift has taken place. Starting in 2014, the groups of Capriati, García-Álvarez and Hevia independently demonstrated that organolithium, Grignard and organozinc reagents, as well as lithium amides and phosphides, can operate efficiently in water and deep eutectic solvents (DESs), often under air, at room temperature and within seconds, without undergoing rapid quenching. Direct ortho- and side-chain lithiations, nucleophilic additions to carbonyl compounds, imines, nitriles, alkenes, and cyclic carbonates, nucleophilic substitutions at amides, esters, and epoxides, as well as cross-coupling and tandem oxidation–addition sequences, can all proceed smoothly in these unconventional media, both in batch and under continuous-flow conditions. Even organosodium reagents–long regarded as being too reactive–have now been successfully tamed and employed in water or DESs for addition and substitution reactions, as well as for the multigram-scale synthesis of active pharmaceutical ingredients (APIs). These studies revealed that water and DESs are not merely benign solvents but dynamic, cooperative reaction environments capable of modulating reactivity and even exhibiting catalytic behavior.

The remarkable stability and reactivity of these reagents in the above protic media have prompted mechanistic investigations suggesting that the reactions likely proceed at solvent–organic interfaces, with water acting primarily as a coordinating ligand to the metal cation rather than as a Brønsted acid. Water and DESs are therefore far more than passive reaction media: they are living solvents, capable of mediating reactivity, stabilizing reactive intermediates, and enabling sustainable pathways in organometallic chemistry.

This graphical review highlights foundational studies and recent advances in the use of polar organometallic reagents in sustainable solvents (or under neat conditions), illustrating how long-standing reactivity paradigms can be reshaped through the lens of green chemistry.

Figure 1 Foundational studies on polar organometallic chemistry in the presence of water[1`] [b] [c] [d] [e] [f] [g] [h] [i] [j] [k] [l] [m] [n] [o] [p] [q] [r] [s]

Figure 2 Nucleophilic addition and substitution reactions of Grignard and organolithium reagents to various electrophiles in water and DES mixtures, part I[1k] ^, [2`] [b] [c] [d]

Figure 3 Nucleophilic addition and substitution reactions of Grignard and organolithium reagents to various electrophiles in water and DES mixtures, part II[3`] [b] [c] [d]

Figure 4 Nucleophilic addition and substitution reactions of Grignard and organolithium reagents to various electrophiles in water and DES mixtures, part III[4`] [b] [c] [d] [e] [f] [g] [h] [i] [j]

Figure 5 Sustainable cross-coupling reactions of polar organometallic compounds[5`] [b] [c] [d] [e] [f] [g] [h] [i] [j] [k] [l] [m] [n] [o] [p] [q] [r] [s] [t] [u] [v] [w] [x]

Figure 6 Preparation and trapping of organosodium and organolithium compounds: batch and flow polar organometallic transformations ‘on water’ or in DESs[5v] ^, [6`] [b] [c] [d] [e] [f]

Figure 7 Continuous nucleophilic addition of organolithium reagents to imines and computational insights into Grignard and organolithium additions to carbonyl compounds in DESs and ‘on-water’ conditions[3a] ^, [7`] [b] [c] [d] [e] [f] [g] [h]

Figure 8 Nucleophilic addition and substitution reactions of Grignard and organolithium reagents with various electrophiles under neat conditions or in greener ethereal solvents, part I[8`] [b] [c]

Figure 9 Nucleophilic addition and substitution reactions of Grignard and organolithium reagents with various electrophiles under neat conditions or in greener ethereal solvents, part II[9`] [b] [c] [d] [e]

Figure 10 Nucleophilic addition reactions of in situ generated lithium amides (LiNHR) and phosphides (LiPR₂) to various organic electrophiles under neat conditions or in DESs[10a] [b]

Figure 11 Nucleophilic addition reactions of Grignard and organolithium reagents to α,β-unsaturated carbonyl compounds in DESs under bench-type conditions[11]

Figure 12 Directed ortho-metalation (DoM) and anionic Fries rearrangement of O-arylcarbamates promoted by organolithium reagents (RLi) or lithium amides under aerobic conditions in greener ethereal solvents[12a] [b]

Figure 13 Nucleophilic addition reactions of RLi/RMgCl reagents to N-tert-butanesulfinyl imines in DESs, or to in situ generated ketones and aldehydes obtained through catalytic oxidation of alcohols in water or DESs[13`] [b] [c]

Figure 14 Design of one-pot hybrid transformations involving RLi reagents and biocatalytic or acidic DES-promoted organic reactions[14`] [b] [c] [d] [e]

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The University of Bari, the University of Oviedo, the Instituto Universitario de Química Organometálica ‘Enrique Moles’ (IUQOEM), and the CINMPIS Consortium are gratefully acknowledged for their support of this work.

• References

• 1a Taylor R. Tetrahedron Lett. 1975; 7: 435
• 1b Wipf P, Lim S. Angew. Chem. Int. Ed. 1993; 32: 1068
• 1c Barr D, Raithby PR, von Ragué Schleyer P, Snaith R, Wright DS. J. Chem. Soc., Chem. Commun. 1990; 643
• 1d Lambert C, von Ragué Schleyer P, Pieper U, Stalke D. Angew. Chem., Int. Ed. Engl. 1992; 31: 77
• 1e Gimbert Y, Lesage D, Fressigné C, Maddaluno J. J. Org. Chem. 2017; 82: 8141
• 1f Koehne I, Bachmann S, Herbst-Irmer R, Stalke D. Angew. Chem. Int. Ed. 2017; 56: 15141
• 1g Pocker Y, Exner JH. J. Am. Chem. Soc. 1968; 90: 6764
• 1h Levine R, Karten MJ, Kadunce WM. J. Org. Chem. 1975; 40: 1770
• 1i Laube T, Dunitz JD, Seebach D. Helv. Chim. Acta 1985; 68: 1373
• 1j Kuo S.-C, Chen F, Hou D, Kim-Meade A, Bernard C, Liu J, Levy S, Wu GG. J. Org. Chem. 2003; 68: 4894
• 1k Chung LW, Chan TH, Wu Y.-D. Organometallics 2005; 24: 1598
• 1l Juste-Navarro V, Delso I, Tejero T, Merino P. Chem. Eur. J. 2016; 22: 11527
• 1m García-Álvarez J. Eur. J. Inorg. Chem. 2015; 5147
• 1n García-Álvarez J, Hevia E, Capriati V. Eur. J. Org. Chem. 2015; 6779
• 1o García-Álvarez J, Hevia E, Capriati V. Chem. Eur. J. 2018; 24: 14854
• 1p Hevia E. Chimia 2020; 74: 681
• 1q Perna FM, Vitale P, Capriati V. Curr. Opin. Green Sustain. Chem. 2021; 30: 100487
• 1r García-Garrido SE, Presa Soto A, Hevia E, García-Álvarez J. Eur. J. Inorg. Chem. 2021; 3116
• 1s Rodríguez-Álvarez MJ, Ríos-Lombardía N, García-Garrido SE, Concellón C, del Amo V, Capriati V, García-Álvarez J. Molecules 2024; 29: 1422
• 2a Osztrovszky G, Holm T, Madsen R. Org. Biomol. Chem. 2010; 8: 3402
• 2b Mallardo V, Rizzi R, Sassone FC, Mansueto R, Perna FM, Salomone A, Capriati V. Chem. Commun. 2014; 50: 8655
• 2c Sassone F, Perna FM, Salomone A, Florio S, Capriati V. Chem. Commun. 2015; 51: 9459
• 2d Vidal C, García-Álvarez J, Hernán-Gómez A, Kennedy AR, Hevia E. Angew. Chem. Int. Ed. 2014; 53: 5969
• 3a Cicco L, Sblendorio S, Mansueto R, Perna FM, Salomone A, Florio S, Capriati V. Chem. Sci. 2016; 7: 1192
• 3b Dilauro G, Dell’Aera M, Vitale P, Capriati V, Perna FM. Angew. Chem. Int. Ed. 2017; 56: 10200
• 3c Vidal C, García-Álvarez J, Hernán-Gómez A, Kennedy AR, Hevia E. Angew. Chem. Int. Ed. 2016; 55: 16145
• 3d Yamamoto Y, Uchida H, Tadano R, Hayashi Y, Yasui T. J. Org. Chem. 2025; 90: 16517
• 4a Cicco L, Rodríguez-Álvarez MJ, Perna FM, García-Álvarez J, Capriati V. Green Chem. 2017; 19: 3069
• 4b Rodríguez-Álvarez MJ, García-Álvarez J, Uzelac M, Fairley M, O’Hara CT, Hevia E. Chem. Eur. J. 2018; 24: 1720
• 4c Sánchez-Condado A, Carriedo GA, Presa Soto A, Rodríguez-Álvarez MJ, García-Álvarez J, Hevia E. ChemSusChem 2019; 12: 3134
• 4d Quivelli AF, D’Addato G, Vitale P, García-Álvarez J, Perna FM, Capriati V. Tetrahedron 2021; 81: 131898
• 4e Hammond OS, Bowron DT, Edler KJ. Green Chem. 2016; 18: 2736
• 4f Hammond OS, Bowron DT, Edler KJ. Angew. Chem. Int. Ed. 2017; 56: 9782
• 4g Perna FM, Vitale P, Capriati V. Curr. Opin. Green Sustain. Chem. 2020; 21: 27
• 4h Cicco L, Dilauro G, Perna FM, Vitale P, Capriati V. Org. Biomol. Chem. 2021; 19: 2558
• 4i Antenucci A, Bonomo M, Ghinato S, Blangetti M, Dughera S. Molecules 2022; 27: 8566
• 4j Shah PA, Chavda V, Hirpara D, Sharma VS, Shrivastav PS, Kumar S. J. Mol. Liq. 2023; 390: 123171
• 5a Pinxterhuis EB, Giannerini M, Hornillos V, Feringa BL. Nat. Commun. 2016; 7: 11698
• 5b Dilauro G, Quivelli AF, Vitale P, Capriati V, Perna FM. Angew. Chem. Int. Ed. 2019; 58: 1799
• 5c Dilauro G, Azzollini CS, Vitale P, Salomone A, Perna FM, Capriati V. Angew. Chem. Int. Ed. 2021; 60: 10632
• 5d Keh CC. K, Wei C, Li C.-J. J. Am. Chem. Soc. 2003; 125: 4062
• 5e Zhou F, Li C.-J. Nat. Chem. 2014; 5: 4254
• 5f Yang Y.-S, Shen Z.-L, Loh T.-P. Org. Lett. 2009; 11: 1209
• 5g Lipshutz BH, Huang S, Leong WW. Y, Zhong G, Isley NA. J. Am. Chem. Soc. 2012; 134: 19985
• 5h Krasovskiy A, Duplais C, Lipshutz BH. J. Am. Chem. Soc. 2009; 131: 15592
• 5i Krasovskiy A, Duplais C, Lipshutz BH. Org. Lett. 2010; 12: 4742
• 5j Duplais C, Krasovskiy A, Wattenberg A, Lipshutz BH. Chem. Commun. 2010; 46: 562
• 5k Krasovskaya V, Krasovskiy A, Bhattacharjya A, Lipshutz BH. Chem. Commun. 2011; 47: 5717
• 5l Krasovskaya V, Krasovskiy A, Lipshutz BH. Chem. Asian J. 2011; 6: 1974
• 5m Duplais C, Krasovskiy A, Lipshutz BH. Organometallics 2011; 30: 6090
• 5n Cao Q, Howard JL, Wheatley E, Browne DL. Angew. Chem. Int. Ed. 2018; 57: 11339
• 5o Betzemeier B, Knochel P. Angew. Chem. Int. Ed. 1997; 36: 2623
• 5p Sirieix J, Oßberger M, Betzemeier B, Knochel P. Synlett 2000; 1613
• 5q Furuyama T, Yonehara M, Arimoto S, Kobayashi M, Matsumoto Y, Uchiyama M. Chem. Eur. J. 2008; 14: 10348
• 5r Dell’Aera M, Perna FM, Vitale P, Altomare A, Palmieri A, Maddock LC. H, Bole LJ, Kennedy AR, Hevia E, Capriati V. Chem. Eur. J. 2020; 26: 8742
• 5s Dell’Aera M, Perna FM, Vitale P, Salomone A, Altomare A, Capriati V. ARKIVOC 2023; (iii): 50
• 5t Kalvet I, Magnin G, Schoenebeck F. Angew. Chem. Int. Ed. 2017; 56: 1581
• 5u Antenucci A, Dughera S. ChemistrySelect 2023; 8: 202303046
• 5v Asako S, Nakajima H, Takai K. Nat. Catal. 2019; 2: 297
• 5w Takahashi I, Tortajada A, Anderson DE, Ilies L, Hevia E, Asako S. Nat. Synth. 2025; 4: 816
• 5x Knyszek D, Löffler J, Anderson DE, Hevia E, Gessner VH. J. Am. Chem. Soc. 2025; 147: 5417
• 6a Dilauro G, Luccarelli C, Quivelli AF, Vitale P, Perna FM, Capriati V. Angew. Chem. Int. Ed. 2023; 62: e202304720
• 6b Harenberg JH, Weidmann N, Wiegand AJ, Hoefer CA, Annapureddy RR, Knochel P. Angew. Chem. Int. Ed. 2021; 60: 14296
• 6c Harenberg JH, Annapureddy RR, Karaghiosoff K, Knochel P. Angew. Chem. Int. Ed. 2022; 61: e202203807
• 6d Anderson DE, Tortajada A, Hevia E. Angew. Chem. Int. Ed. 2024; 63: e202313556
• 6e Mulks FF, Pinho B, Plattern AW. J, Andalibi MR, Expósito AJ, Edler KJ, Hevia E, Torrente-Murciano L. Chem 2022; 8: 3382
• 6f Platten AW, Pinho B, Torrente-Murciano L, Hevia E. ACS Sustain. Chem. Eng. 2025; 13: 19351
• 7a Brucoli J, Puglisi A, Rossi S, Gariboldi D, Brenna D, Maule I, Benaglia M. Cell Rep. Phys. Sci. 2024; 5: 101838
• 7b Yoshida J.-i, Nahaki A, Yamada T. Chem. Eur. J. 2008; 14: 7450
• 7c Power M, Alcock E, McGlacken GP. Org. Process Res. Dev. 2020; 24: 1814
• 7d Colella M, Nagaki A, Luisi R. Chem. Eur. J. 2020; 26: 19
• 7e Capriati V. Chem 2022; 8: 3159
• 7f Brucoli J, Gariboldi D, Puglisi A, Rossi S, Capriati V, Benaglia M. Eur. J. Org. Chem. 2024; e202301289
• 7g Manasi I, Bortoli M, Bowron DT, Campana M, Hammond OS, Headen TF, Hooton J, Hevia E, Cascella M, Eisenstein O, Edler KJ. Angew. Chem. Int. Ed. 2025; 64: e202513649
• 7h Mador SD, Milet A. J. Comput. Chem. 2025; 46: e70200
• 8a Elorriaga D, de la Cruz-Martínez F, Rodríguez-Álvarez MJ, Lara-Sánchez A, Castro-Osma JA, García-Álvarez J. ChemSusChem 2021; 14: 2084
• 8b Elorriaga D, Carrillo-Hermosilla F, Parra-Cadenas B, Antiñolo A, García-Álvarez J. ChemSusChem 2022; 15: e202201348
• 8c Ghinato S, Territo D, Maranzana A, Capriati V, Blangetti M, Prandi C. Chem. Eur. J. 2021; 27: 2868
• 9a Erker G, Riedel M, Koch S, Jödicke T, Würthwein E.-U. J. Org. Chem. 1995; 60: 5284
• 9b Grassberger MA, Horvath A, Schulz G. Tetrahedron Lett. 1991; 32: 7393
• 9c Parra-Cadenas B, Fernández I, Carrillo-Hermosilla F, García-Álvarez J, Elorriaga D. Chem. Sci. 2024; 15: 5925
• 9d Fairley M, Bole LJ, Mulks FF, Main L, Kennedy AR, O’Hara CT, García-Alvarez J, Hevia E. Chem. Sci. 2020; 11: 6500
• 9e Mulks FF, Bole LJ, Davin L, Hernán-Gómez A, Kennedy A, García-Álvarez J, Hevia E. Angew. Chem. Int. Ed. 2020; 59: 19021
• 10a Elorriaga D, Parra-Cadenas B, Antiñolo A, Carrillo-Hermosilla F, García-Álvarez J. Green Chem. 2022; 24: 800
• 10b Cicco L, Fombona-Pascual A, Sánchez-Condado A, Carriedo G, Perna FM, Capriati V, Presa Soto A, García-Álvarez J. ChemSusChem 2020; 13: 4967
• 11 Platten AW. J, Manasi I, Campana M, Edler KJ, Hevia E. ChemSusChem 2025; 18: e202402083
• 12a Ghinato S, De Nardi F, Bolzoni P, Antenucci A, Blangetti M, Prandi C. Chem. Eur. J. 2022; 28: e202201154
• 12b Marra F, Morelli F, De Nardi F, Priola E, Coldham I, Blangetti M. Org. Biomol. Chem. 2025; 23: 8029
• 13a Cicco L, Salomone A, Vitale P, Ríos-Lombardía N, González-Sabín J, García-Álvarez J, Perna FM, Capriati V. ChemSusChem 2020; 13: 3583
• 13b Elorriaga D, Rodríguez-Álvarez MJ, Ríos-Lombardía N, Morís F, Presa Soto A, González-Sabín J, Hevia E, García-Álvarez J. Chem. Commun. 2020; 56: 8932
• 13c Cicco L, Roggio M, López-Aguilar M, Ramos-Martín M, Perna FM, García-Álvarez J, Vitale P, Capriati V. ChemistryOpen 2022; 11: e202200160
• 14a Ramos-Martín M, Lecuna R, Cicco L, Vitale P, Capriati V, Ríos-Lombardía N, González-Sabín J, Presa-Soto A, García-Álvarez J. Chem. Commun. 2021; 57: 13534
• 14b Arnodo D, Ramos-Martín M, Cicco L, Capriati V, Ríos-Lombardía N, González-Sabín J, Presa Soto A, García-Álvarez J. Org. Biomol. Chem. 2023; 21: 4414
• 14c Ríos-Lombardía N, Morís-Menéndez G, Lavandera I, Gotor-Fernández V, García-Álvarez J. Adv. Synth. Catal. 2024; 366: 3144
• 14d Arnodo D, De Nardo E, Ghinato S, Baldino S, Blangetti M, Prandi C. ChemSusChem 2023; 16: e202202066
• 14e Arnodo D, Meazzo C, Baldino S, Blangetti M, Prandi C. Chem. Eur. J. 2023; 29: e202300820

Publication History

Received: 24 October 2025

Accepted after revision: 03 December 2025

Accepted Manuscript online:
05 December 2025

Article published online:
20 January 2026