**1. Introduction**

*Salen* type ligands, derived from the condensation between salicylaldehyde and a primary diamine, are considered versatile ligands in coordination chemistry because the steric and electronic properties can be modulated by di fferent amine aldehydes precursors. The metal*salen* complexes have been widely studied in diverse areas of chemistry. The interest lays in its easy synthesis, versatility, and kinetic and thermodynamic stability provided by the chelating capacity of the tetradentate ligand with N2O2

donor atoms. For the aforementioned reasons, such complexes not only play an important role in coordination chemistry, but in various areas such as asymmetric catalysis [1], epoxide formation [2–4], olefin hydrogenation [5,6], or in polymerization reactions [7,8]. Moreover, they have been extensively studied in connection with metalloprotein models and, more recently, in bioinorganic chemistry. A complex of NiII, FeII, and CuII-*salen* has been synthesized as a biomimetic compound for the study of metalloenzyme active sites and their catalytic mechanism [9–12].

It is well known that the steric and electronic effect plays an important role in the reactivity of M-*salen* compounds. The incorporation of electron-donor/withdrawing groups on *salen* skeleton allows redox potential modulation [9,13] and favors certain geometries [14,15] that impact the interaction with the substrates or specific recognition sites. In recent years, attention has focused on the biological properties of Schiff bases and their metal-compounds [16], showing that ligands by themselves can inhibit a carbonic anhydrase enzyme. The efficiency of these enzymes depend on the properties of the bridge N/N [16]. Several metal-*salen* complexes have presented different biological activities, such as an antibacterial [17,18] and antiproliferative against different tumor lines [19–22]. One of the proposed mechanisms of action of these complexes with *salen*-type ligands is the specific interactions with DNA and RNA. Different types of damage can occur depending on the chemical reactivity of the metal complex. MnIII-*salen* in the presence of an oxidant induces DNA cleavages [23,24], whereas CoIII-*salen* can cleave DNA under aerobic conditions [25]. CoII-*salen* and FeIII-*salen* bind DNA at the minor groove [26], while NiII-*salen* causes damage to nucleic acids, specifically causing divisions in guanine residues in the hairpin region of a single chain [27]. On the other hand, it has been reported that square coordination compounds with conjugated systems in their coordination spheres present stacking interactions with DNA [28] and G-quadruplexes. The binding affinity and selectivity of interaction with the latter is modulated by changing the substituents on the *salen* skeleton and modifying the nature of the N/N-bridge for the Schiff base [29,30]. The correct choice of the N/N bridge plays an important role in the geometry of these compounds, as it lengthens the chain and favors octahedral geometry [31] while adding aromatic rings that favor planar-square geometry. Moreover, it increases π-π interactions [32]. These type of complexes also present a square-planar geometry [33] and multiple studies have shown how the reactivity of nickel-*salen* complexes can modulate by the design and control of the nature of the ligands by the choice of the N/N bridge or its substituents. Therefore, in this work, we study the effect the N/N bridge has on geometry and how the half-wave potential (E1/2) changes when a substitute is added. We report the structure of four Nickel complexes with tetradentate N2O2 ligands, analyzing the intermolecular interactions favored by the substituent and the N/N bridge, which modify the distance of Ni-Ni interaction found between dimers.

## **2. Materials and Methods**

The experiments were carried out in ambient conditions. Nickel acetate tetrahydrate, salicylaldehyde, 2-hydroxi-5-metoxybenzaldehyde, 2-hydroxi-5-metylbenzaldehyde, 2-hydroxi-5-nitrobenzaldehyde, 2-hydroxi-5-clorobenzaldehyde, 2-hydroxi-5-bromorobenzaldehyde, and o-phenylenediamine were acquired from Sigma-Aldrich (Saint Louis, MO, USA), whereas 1,2-diaminoethane was acquired from Merck (Darmstadt, Germany.). The solvents used were acquired from Quimica Alvi (Ciudad de México, Mexico). All reactive materials were used without further purification. Elemental analysis was carried out in the Reach and Industry Support Services Unit (USAII for its Spanish abbreviations), using an EAGER 200 elemental analyzer (EAGER 200 CHNS/method, Ciudad de México, Mexico). IR (infrared) spectra were performed on a Nicolet AVATAR 320 FT-IR (Ciudad de México, Mexico) in an interval of 4000–400 cm<sup>−</sup>1. The samples incorporated onto a KBr disk in the range of 3500–500. UV-VIS (ultraviolet-visible) spectra were obtained on a Hewlett Packard 845× UV-visible system diode array spectrophotometer in a range from 250 nm to 800 nm in dimethylsulfoxide (DMSO) solutions Sigma-Aldrich (Saint Louis, MO, USA). The 1H-NMR 13C-NMR (nuclear magnetic resonance) (Ciudad de México, Mexico), COSY (correlation spectroscopy), and HSQC (heteronuclear single quantum correlation) (Tables S7 and S8, Figures S21–S39, Supplementary Materials), were performed

with the USAII, collected by a VARIAN VNMRS 400 MHz. Chemical shifts were reported in ppm relative to the internal TMS (tetramethylsilane) standard. The solvents used were CDCl3, Acetone-d6, DMF-d7, and DMSO-d6, all of which were acquired from Sigma-Aldrich (Saint Louis, MO, USA). Mass spectrometers were acquired in the USAII (Ciudad de México, Mexico). All of the ligands and NiR*salen* were obtained using FAB<sup>+</sup> in a LECO PEGASUSIII. NMR and mass spectrometry were not obtained for NiCl*salphen* and NiBr*salphen* due to their low solubility. Cyclic voltammetry was performed using PAR27 potentiostat/galvanostat (Ciudad de México, Mexico) with a conventional three-electrode array. Tetrabutylammonium hexafluorophosphate (Sigma-Aldrich, Saint Louis, MO, USA), served as a support electrolyte and DMSO (99.995, Sigma-Aldrich, Misuri, United State). Voltammogram were referenced with an internal adjustment using ferrocene (99.9%, Sigma-Aldrich, Saint Louis, MO, USA).
