Compounds based on imidazole or imidazolium moieties are excellent building blocks for the preparation of a plethora of ligand precursors. The introduction of chirality in these compounds is relatively easy through the Debus-Radziszewski reaction, in which the chiral pools are natural or non-natural amino acids. Using this synthetic route, enantiopure imidazole-carboxylate, imidazolium-carboxylate, and imidazolium-dicarboxylate ligand precursors can be prepared, from which N-heterocyclic carbenes (NHC) with one or two carboxylate groups can also be obtained. This review is a personal account that summarizes our recent results regarding the use of all these compounds as chiral ligands coordinated to several transition metals (Cu, Zn, Ag and Mo). The structural features of the new synthesized coordination polymers with novel bonding modes will be described, and the bonding capabilities of these ligands rationalized on the basis of theoretical calculations. The efficiency of homochiral imidazolium-dicarboxylate compounds as chiral inductors in asymmetric catalysis will also be discussed. Finally, the antimicrobial and antitumoral activities of imidazolium- and NHC-carboxylate silver complexes and the found chirality-activity and structure–activity relationships will be highlighted., Financial support from the Spanish Ministerio de Ciencia e Innovación (PGC2018-093443-B-I00) and from the Universidad de Sevilla (VII Plan Propio, proyectos de investigación precompetitivos. V.1c) is gratefully acknowledged. C. J. C. thanks a research contract from PAIDI 2020, supported by the European Social Fund and the Junta de Andalucía. The authors thank to Centro de Investigaciones, Tecnología e Innovación (CITIUS) of the University of Sevilla for providing several research services and to Centro de Servicios de Informática y Redes de Comunicaciones (CSIRC), Universidad de Granada, for providing the computing time., Peer reviewed

Hydrazones and their metal derivatives are very important compounds in medicinal chemistry due to their reported variety of biological activities, such as antibacterial, antifungal and anticancer action. Five hydrazone-pyrazolone ligands HL (n = 1-5) were prepared and fully characterized and their tautomerism was investigated in the solid state and solution. Five zinc(ii) complexes 1-5 of composition [Zn(HL)] (n = 1 and 2), [Zn(HL)(HO)] (n = 3 and 5) and [Zn(HL)] were synthesized and characterized by elemental analysis, IR, H, F, C, and N NMR spectroscopy, and ESI mass spectrometry. In addition, the structures of two ligands and three complexes were determined by single-crystal X-ray diffraction. The ligands HL and HL exist both in the NH,NH tautomeric form. Complexes 1 and 2 are mononuclear compounds, while complex 4 is a one-dimensional coordination compound. Density functional theory (DFT) calculations were carried out on proligands, their anions and all zinc complexes, confirming the experimental results, supporting IR and NMR assignments and giving proofs of the mononuclear diaqua structure of complexes 3 and 5. The antibacterial activity of the free ligands and the Zn(ii) complexes was established against Escherichia coli and Staphylococcus aureus, and a strong efficiency has been found for Zn(ii) complexes, particularly for the polynuclear 4 and the mononuclear diaqua complex 5, the latter containing a ligand with aliphatic and fluorinated substituents able to compromise the permeability of and disrupt the bacterial cell membrane., Thanks are due to the University of Camerino (Italy) for financial support. The research grant of Dr Laura Olivieri was funded under the frame of the project Nano4-Fresh – Nanomaterials for an environmentally friendly and sustainable handling of perishable products (PRIMA19_00246), which is part of the Partnership on Research and Innovation in the Mediterranean Area (PRIMA) Programme supported by the European Union and funded by the national funding bodies of Participating States (MUR in Italy is gratefully acknowledged). We thank the Marche Region for supporting this research by funding the two-year research grant of Dr Sonila Xhafa as part of the POR Marche FSE 2014–2020 P.I. 8.1 R.A. 8.5. Financial support from the Spanish Ministerio de Ciencia e Innovación (PGC2018-093443-B-I00) is gratefully acknowledged.

Chemicals and CAS Registry Numbers
carbene 2465-56-7
silver 7440-22-4
sodium hydroxide 1310-73-2, The antimicrobial properties of a series of anionic bis(carbene) silver complexes Na3[Ag(NHCR)2] were investigated (2a–2g and 2c′ , where NHCR is a 2,2′ -(imidazol-2-ylidene) dicarboxylate-type N-heterocyclic carbene). The complexes were synthesized by the interaction of imidazolium dicarboxylate compounds with silver oxide in the presence of aqueous sodium hydroxide. Complexes 2f,g were characterized analytically and spectroscopically, and the ligand precursor 1f and complexes 2c and 2g were structurally identified by X-ray diffraction methods. The anions of 2c and 2g, [Ag(NHCR)2]3−, showed a typical linear disposition of Ccarbene-Ag- Ccarbene atoms and an uncommonly eclipsed conformation of carbene ligands. The antimicrobial properties of complexes 2a–g, which contains chiral (2b–2e and 2c′ ) and non-chiral derivatives (2a,f,g), were evaluated against Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa, and a Gram-positive bacterium, Staphylococcus aureus. From the observed values of the minimal inhibitory concentration and minimal bactericidal concentration, complexes 2a and 2b showed the best antimicrobial activity against all strains. An interesting chirality–antimicrobial relationship was found, and eutomer 2c′ showed better activity than its enantiomer 2c against the three bacteria. Furthermore, these complexes were investigated experimentally and theoretically by 109Ag nuclear magnetic resonance, and the electronic and steric characteristics of the dianionic carbene ligands were also examined, This research was funded by Ministerio de Ciencia e Innovación, PGC2018-093443-B-I00, University of Sevilla, grant number VIPPIT-2021-I.5 (VI Plan Propio de Investigación y Transferencia), and Bruker, Bruker-University of Sevilla award, Peer reviewed

Coordination polymers containing zinc and imidazolium-based dicarboxylate ligands, [L^R]⁻, were synthesized by reacting zinc acetate with HL^R compounds, <b>1</b>. The resulting complexes were characterized and structurally identified using single-crystal X-ray diffraction, revealing polymeric structures for the complexes [Zn(L^R)₂]_n (R = Gly, <b>2a</b>; βAla, <b>2b</b>) and [Zn(L^Leu)₂(H₂O)₂]_n (<b>2c</b>). In these structures, the [L^R]⁻ ligands adopt a bridging monodentate μ-κ¹-O¹,κ¹-O³ coordination mode, resulting in distorted tetrahedral (<b>2a</b>, <b>2b</b>) or octahedral (<b>2c</b>) geometries around the zinc center. When the synthesis was carried out in the presence of amino acids, mixed ligand complexes [Zn(L^R)(aa)(H₂O)]_n (R = aa = Val, <b>2d</b>, and R = aa = Ile, <b>2e</b>) were formed. Complexes <b>2d</b>–<b>2e</b> were also structurally characterized using single-crystal X-ray crystallography, revealing that the ligand [L^R]⁻ maintained the same coordination mode, while the zinc center adopted a five-coordinated geometry. The cytotoxic activity of complexes <b>2a</b>–<b>2e</b> was evaluated against three cancer cell lines and one non-cancerous cell line. Remarkably, these complexes exhibited higher toxicity against cancer cells than against the non-cancerous cell line, and they showed greater selectivity than carboplatin, a commonly used chemotherapy drug. Although, in general, these complexes did not surpass the selectivity of gemcitabine, complex <b>2c</b> stood out for exhibiting a selectivity index value similar to that of gemcitabine against melanoma cells. Among the series, compounds <b>2a</b>–<b>2c</b> demonstrated the highest activity, with <b>2a</b> being the only complex with some selective activity against lung cancer. Complex <b>2b</b> was the most active, though with low selectivity, while complex <b>2c</b> exhibited the highest selectivity for melanoma and bladder cancer (selectivity index of 3.0)., This research was funded by Ministerio de Ciencia e Innovación, PGC2018-093443-B-I00, and by the University of Sevilla through the “VII Plan Propio de Investigación y Transferencia”., Peer reviewed

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29194608/s1, Figure S1. IR spectra of compounds 1f,g and complexes 2f,g. Figure S2. 1H NMR and 13C{1H] NMR spectra of compounds 1f–g. Figure S3. Optimized structures of compounds 1f–g and ligands NHCβ−Me and NHCGlyGly. Figure S4. Optimized structures of complexes: (a) [Ag(NHCβ−Me)2]3−; (b) [Ag(NHCGlyGly)2]3−; and (c) Na3[Ag(NHCβ−Me)2], 2g. Two views of each complex are shown. Figure S5. Comparison of the calculated and experimental 1H and 13C NMR spectra for 2f. Figure S6. Comparison of the calculated and experimental 1H and 13C NMR spectra for 2g. Table S1. Comparison of experimental selected structural parameters of complexes 2c and 2g with the calculated parameters for the anions [Ag(NHCR)2]3− of these complexes. Table S2. Selected structural data of 1f, 2c and 2g. Bond distances (Å) and angles (°). Table S3. Specific rotations [α]D for complexes 2. Figure S7. Crystal packing views of complex 1f. Figure S8. Crystal packing views of complex 2c. Figure S9. Crystal packing views of complex 2g viewed along b axis. Table S4. Optimized structures of complexes [Ni(CO)3(NHCR)]2− and their calculated properties. Figure S10. Correlation between calculated TEP values (νCO) of the NHCR carbenes and the MO energy of the σ lone pair orbitals. Table S5. Percent buried volume, %Vbur, of NHCR ligands. Figure S11. Selected steric maps from optimized [Ag(NHCR)2]3− complexes viewed along the Ag-Ccarbene vector. Figure S12. 1H DOSY NMR spectra of 2b–c. Figure S13. Band selective constant time 1H-13C HMBC NMR spectra (resolution enhanced by NUS) of 2c. Figure S14. Correlation between calculated σ(109Ag) and experimental δ(109Ag) chemical shifts for selected NHC silver complexes. Table S6. Calculated σ(109Ag) and experimental δ(109Ag) data for selected NHC silver complexes. Table S7. Antimicrobial activities of complexes 2 evaluated by MIC and MBC (μg/mL). Figure S15. Qualitative hemolysis test of complex 2a and several control chemicals (AgNO3, H2O2, sodium dodecyl sulfate, SDS and NaOH) for comparison. Table S8. Crystal data and structure refinement for 1f. Table S9. Crystal data and structure refinement for 2c. Table S10. Crystal data and structure refinement for 2g. Table S11. Coordinates and optimized structures of NHC-silver complexes used for the correlation between calculated and experimental 109Ag NMR chemical shifts. Table S12. Coordinates of complexes [Ni(CO)3(NHCR)]2− used for the determination of the Tolman Electronic Parameter (TEP). Table S13. Coordinates of the optimized structures., The antimicrobial properties of a series of anionic bis(carbene) silver complexes Na-3[Ag(NHC (R))(2)] were investigated (2a-2g and 2c ', where NHC (R) is a 2,2 '-(imidazol-2-ylidene)dicarboxylate-type N-heterocyclic carbene). The complexes were synthesized by the interaction of imidazolium dicarboxylate compounds with silver oxide in the presence of aqueous sodium hydroxide. Complexes 2f,g were characterized analytically and spectroscopically, and the ligand precursor 1f and complexes 2c and 2g were structurally identified by X-ray diffraction methods. The anions of 2c and 2g, [Ag(NHC (R))(2)](3-), showed a typical linear disposition of C-carbene-Ag-C-carbene atoms and an uncommonly eclipsed conformation of carbene ligands. The antimicrobial properties of complexes 2a-g, which contains chiral (2b-2e and 2c ') and non-chiral derivatives (2a,f,g), were evaluated against Gram-negative bacteria, Escherichia coli and Pseudomonas aeruginosa, and a Gram-positive bacterium, Staphylococcus aureus. From the observed values of the minimal inhibitory concentration and minimal bactericidal concentration, complexes 2a and 2b showed the best antimicrobial activity against all strains. An interesting chirality-antimicrobial relationship was found, and eutomer 2c ' showed better activity than its enantiomer 2c against the three bacteria. Furthermore, these complexes were investigated experimentally and theoretically by Ag-109 nuclear magnetic resonance, and the electronic and steric characteristics of the dianionic carbene ligands were also examined., C.J.C. thanks a research contract from PAIDI 2020, supported by the European Social Fund and the Junta de Andalucía. The authors thank Centro de Investigaciones, Tecnología e Innovación (CITIUS) of the University of Sevilla for providing several research services and to Centro de Servicios de Informática y Redes de Comunicaciones (CSIRC), Universidad de Granada, for providing the computing time., This research was funded by Ministerio de Ciencia e Innovación, PGC2018-093443-B-I00, University of Sevilla, grant number VIPPIT-2021-I.5 (VI Plan Propio de Investigación y Transferencia), and Bruker, Bruker-University of Sevilla award., Peer reviewed

The selective synthesis of regioisomers from ambident N-heterocycles remains a challenge in organic chemistry. We report a general and modular method for the regioselective syntheses of bis-(indazolyl)-methane isomers, in which the outcome is controlled by the nature of the base. Specifically, we employed structurally diverse amines as noninnocent bases, whose steric and electronic propertiesparticularly their pK aH and ability to act as methylene carriers or activatorsplay a decisive role in directing product distribution. By fine-tuning the amine structure, we achieved selective access to symmetrical and unsymmetrical isomers under mild, one-step conditions, without intermediate isolation. The use of amines over conventional inorganic bases was essential to enable both chemo- and regioselective control, while minimizing overactivation or competing pathways. Experimental findings were supported by DFT calculations that rationalize the observed selectivity through differential activation energies and intermediate stabilities. The methodology accommodates both classical methylenating agents (e.g., CH2Br2) and in situ generated ammonium-based donors. All compounds were fully characterized, and key products were confirmed by single-crystal X-ray diffraction (SCXRD). This strategy highlights the utility of noninnocent amines as tunable reagents for regioselective transformations of ambident nucleophiles, with broad potential applications in ligand design, supramolecular chemistry, and heterocyclic synthesis., This research was supported by the Ministry of Economy and Competitiveness, Spain (grant MP09-FQM-4826), and the Ministry of Science, Innovation and Universities, Spain (grant PGC2018-093443.B-100). The authors gratefully acknowledge the Supercomputing Centre of Galicia (CESGA) for providing access to its computational facilities., Peer reviewed

7 p., Complexes [Pd{(S)-NHCMes,R}(2)] (R = Me, 2a; Pr-i, 2b; Bu-i, 2c) and [Pd{(R)-NHCMes,Me}(2)] (2a&apos;) were prepared by reaction of the corresponding imidazolium precursor [Im(Mes,R)] (namely (S)-2-alkyl(3-mesityl-1H-imidazol-3-ium-1-yl)acetate, 1a-c, and (R)-2-methyl(3-mesityl-1H-imidazol-3-ium-1-yl)acetate, 1a&apos;), with Ag2O and sub-sequent interaction with Pd(OAc)(2), under appropriate conditions. Alternatively, complexes 2 were also obtained by treating compounds [Im(Mes,R)], 1, with an in-situ prepared lithium diisopropylamide solution and then reaction with [Pd(OAc)(2)]. On the other hand, the nickel complex [Ni{(S)-NHCMes,iPr}(2)], 3b, was synthesized by the interaction of the complex [NiCp2] (Cp = eta(5)-C5H5) with [Im(Mes,iPr)], 1b, in THF. If this reaction was carried out in acetonitrile, a mixture of complex 3b and the cyclopentadienyl monocarbene complex [NiCp{(S)-NHCMes,iPr}], 4b, was obtained. Similarly to 2b, compound 3b was also prepared by the in-situ formation of the carbene [(S)- NHCMes,iPr](-) and then reaction with [NiBr2(dme)] (dme = 1,2-dimethoxyethane). Complexes 2, 3 and 4 were obtained with good yields and fully characterized by analytical (HR-ESI and microanalysis), spectroscopic (IR, H-1 and C-13 NMR and polarimetry) and X-ray methods (2c). In the solid state, 2c is a square planar complex con-taining two [(S)-NHCMes,iBu](-) ligands coordinated in a kappa(2)-C,O fashion, where the carbene and carboxylate donors have the expected trans configuration. The existence of two possible conformers of complexes 2 and 3 was analyzed using DFT methods., Ministerio de Ciencia e Innovación, Universidad de Alcalá, Comunidad de Madrid, Junta de Andalucía, European Social Fund