Protonated forms of the tetrazine ligand L2 (3,6-bis(morpholin-4-ylethyl)-1,2,4,5-tetrazine) interact with iodide in aqueous solution forming relatively stable complexes (ΔG° = -11.6(4) kJ mol for HL2 + I = (HL2)I and ΔG° = -13.4(2) kJ mol for HL2 + I = [(HL2)I]). When solutions of [(HL2)I] are left in contact with air, crystals of the oxidation product (HL2)(I)I·4HO are formed. Unfortunately, the low solubility of I complexes prevents the determination of their stability constants. The crystal structures of HL2I·HO (1), HL2(I)·2HO (2) and (HL2)(I)I·4HO (3) were determined by means of X-ray diffraction analyses. In all crystal structures, it was found that the interaction between I and I with HL2 is dominated by anion interactions with the π electron density of the receptor. Only in the case of 1, the iodide anions involved in close anion-π interactions with the ligand tetrazine ring form an additional H-bond with the protonated morpholine nitrogen of an adjacent ligand molecule. Conversely, in crystals of 2 and 3 there are alternate segregated planes which contain only protonated ligands hydrogen-bonded to cocrystallized water molecules or I and I forming infinite two-dimensional networks established through short interhalogen contacts, making these crystalline products good candidates to behave as solid conductors. In the solid complexes, the triiodide anion displays both end-on and side-on interaction modes with the tetrazine ring, in agreement with density functional theory calculations indicating a preference for the alignment of the I molecular axis with the molecular axis of the ligand. Further information about geometries and structures of triiodide anions in 2 and 3 was acquired by the analysis of their Raman spectra.

Ligands L1 and L2, consisting of a tetrazine ring decorated with two morpholine pendants of different lengths, show peculiar anion-binding behaviors. In several cases, even the neutral ligands, in addition to their protonated HL(+) and H2L(2+) (L = L1 and L2) forms, bind anions such as F(-), NO3(-), PF6(-), ClO4(-), and SO4(2-) to form stable complexes in water. The crystal structures of H2L1(PF6)2·2H2O, H2L1(ClO4)2·2H2O, H2L2(NO3)2, H2L2(PF6)2·H2O, and H2L2(ClO4)2·H2O show that anion-π interactions are pivotal for the formation of these complexes, although other weak forces may contribute to their stability. Complex stability constants were determined by means of potentiometric titration in aqueous solution at 298.1 K, while dissection of the free-energy change of association (ΔG°) into its enthalpic (ΔH°) and entropic (TΔS°) components was accomplished by means of isothermal titration calorimetry measurements. Stability constants are poorly regulated by anion-ligand charge-charge attraction. Thermodynamic data show that the formation of complexes with neutral ligands, which are principally stabilized by anion-π interactions, is enthalpically favorable (-ΔG°, 11.1-17.5 kJ/mol; ΔH°, -2.3 to -0.5 kJ/mol; TΔS°, 9.0-17.0 kJ/mol), while for charged ligands, enthalpy changes are mostly unfavorable. Complexation reactions are invariably promoted by large and favorable entropic contributions. The importance of desolvation phenomena manifested by such thermodynamic data was confirmed by the hydrodynamic results obtained by means of diffusion NMR spectroscopy. In the case of L2, complexation equilibria were also studied in a 80:20 (v/v) water/ethanol mixture. In this mixed solvent of lower dielectric constant than water, the stability of anion complexes decreases, relative to water. Solvation effects, mostly involving the ligand, are thought to be responsible for this peculiar behavior.

The formation of halide and hydroxide anion complexes with two ligands L1 (3,6-bis(morpholin-4-ylmethyl)-1,2,4,5-tetrazine) and L2 (3,6-bis(morpholin-4-ylethyl)-1,2,4,5-tetrazine) was studied in aqueous solution, by means of potentiometric and ITC procedures. In the solid state, HF, Cl and Br complexes of HL2 were analysed by single crystal XRD measurements. Further information on the latter was obtained with the use of density functional theory (DFT) calculations in combination with the polarizable continuum model (PCM). The presence of two halide or bifluoride HF (F-H-F) anions forming anion-π interactions, respectively above and below the ligand tetrazine ring, is the leitmotiv of the [(HL2)X] (X = HF, Cl, Br, I) complexes in the solid state, while hydrogen bonding between the anions and protonated morpholine ligand groups contributes to strengthen the anion-ligand interaction, in particular in the case of Cl and Br. In contrast to the solid state, only the anion : ligand complexes of 1 : 1 stoichiometry were found in solution. The stability of these complexes displays the peculiar trend I > F > Br > Cl which was rationalized in terms of electrostatic, hydrogen bond, anion-π interactions and solvent effects. DFT calculations performed on [(HL2)X] (X = F, Cl, Br, I) in PCM water suggested that the ligand assumes a U-shaped conformation to form one anion-π and two salt bridge interactions with the included anions and furnished structural information to interpret the solvation effects affecting complex formation. The formation of hydroxide anion complexes with neutral (not protonated) L1 and L2 molecules represents an unprecedented case in water. The stability of the [L(OH)] (L = L1, L2) complexes is comparable to or higher than the stability of halide complexes with protonated ligand molecules, their formation being promoted by largely favourable enthalpic contributions that prevail over unfavourable entropic changes.

Most of traditional and contemporary interest in s-tetrazine derivatives focuses onto their redox properties, reactivity and energy density. In recent times, however, an increasing number of reports highlighted the possible usefulness of the s-tetrazine moiety as a binding site for anionic and electron rich species, according to the high and positive quadrupolar moment of this heterocycle and the consequent strength of anion-π and lone pair-π interactions. Herein, after giving a quick perspective on s-tetrazine properties and on how they foster these types of π interactions, we present statistical and critical examination of the available structural data, doing justice to the debated topic of the existence and directionality of anion-and lone pair-π interactions. Finally, available literature material concerning the usage of s-tetrazine as supramolecular binding site in solution, i.e. paving the way to applications such as molecular recognition and sensing, is presented and discussed. Contents 1. Introduction 2. s-Tetrazine Synthesis & Properties 2.1. Synthesis of s-tetrazine derivatives 2.2. General perspective on the properties and applications s-tetrazines 2.3. Anion-π and lone pair-π: nature of the interactions and relevance of the s-tetrazine ring 3. Anion-π and lone pair-π interactions with s-tetrazines in the solid-state: CSD Survey 3.1. Methodology and rationale of the survey 3.2. Structural data analysis 4. Selected evidences of anion-π and lone pair-π interactions with s-tetrazines in the solid state 5. Anion-π and lone pair-π interactions with s-tetrazines in solution 6. Conclusions Appendix A. Supplementary data Referencesthe aromatic s-tetrazine ring enables compact molecular packings which are essential to realize substances with a high (volumetric) energy density [116,117]. This is a field that continues very active in seeking for new s-tetrazine derivatives of interest [118][119][120].Other important applications of s-tetrazines derive from their particular reactivity, that serves as the base of the usefulness that these structures are proving in molecular biology studies, as reacting partners in bioorthogonal chemistry [121] methods (a field that has boosted the research and literature devoted to stetrazines from the first 2000s) [84,122]. These applications take advantage of two properties of stetrazines: i) the propensity of the s-tetrazine nucleus to act as 2,3-diazadiene in fast inverse-electrondemand Diels-Alder (iedDA) reactions with alkenes and alkynes that affords, in a first term, a bicyclic adduct which immediately suffers a retro-Diels-Alder (rDA) reaction, evolving N 2 , to give rise to dihydropyridazines or aromatic pyridazines, respectively (Scheme 2) [123,124]; ii) the inertness of s-tetrazine derivatives towards natural substances under biological conditions. Scheme 2 to be inserted about here.But the property that focused our interest in s-tetrazines, and constitutes the main subject of this review, is their ability to establish non-covalent bonds to negatively charged species (a...

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