Pincer complexes featuring readily tunable tridentate ligand frameworks comprise one of the most actively studied classes of organometallic and metalorganic compounds and find extensive use in catalysis, organic synthesis, materials science, and other fields of chemistry and allied disciplines. Currently growing attention is devoted to non-classical ligand scaffolds, such as functionalized carboxamides, which offer multiple options for directed structural modifications. In this study, the reactions of (methylsulfanyl)acetyl and propanoyl chlorides with 2-(aminomethyl)pyridine, 2-(2-aminoethyl)pyridine, 8aminoquinoline and 2-(diphenylthiophosphoryl)aniline afford a series of new pincer-type ligands based on functionalized carboxamides. The ligands obtained readily undergo direct cyclopalladation under the action of PdCl 2 (NCPh) 2 in dichloromethane at room temperature, resulting in Pd(II) pincer complexes with N,N,S-and S,N,S-donor sets. Importantly, some of the cyclopalladated derivatives can also be produced efficiently under solvent-free conditions according to the approach recently developed by our group. The complexes obtained have been tested for cytotoxicity against several human cancer cell lines and catalytic activity in the model Suzuki reaction. The results have been compared to those for the related Pd(II) pincer complexes to define the main structure-activity relationships and to outline the most promising structures for further investigations. Yield: 87 mg (95%). M.p. > 225°C (dec.). 1 H NMR (400.13 MHz, CDCl 3 , δ, ppm): 2.73 (ddd, 1H, CH 2 , 2 J HH = 1.9 Hz, 3 J HH = 16.8 Hz, 3 J HH = 7.3 Hz), 3.15 (ddd, 1H, CH 2 S(O), 2 J HH = 2.2 Hz, 3 J HH = 16.8 Hz, 3 J HH = 11.4 Hz), 3.36 (ddd, 1H, CH 2 , 2 J HH = 1.9 Hz, 3 J HH = 13.0 Hz, 3 J HH = 11.4 Hz), 3.47 (ddd, 1H, CH 2 S(O), 2 J HH = 2.2 Hz, 3 J HH = 13.0 Hz, 3 J HH = 7.3 Hz), 3.51 (s, 3H, Me), 5.03 and 5.22 (ABq, 2H, CH 2 Py, J AB = 20.3 Hz), 7.35-7.39 (m, 1H, H(C4)), 7.48 (d, 1H, H(C2), 3 J HH = 7.9 Hz), 7.91 (dt, 1H, H(C3), 3 J HH = 7.9 Hz, 4 J HH = 1.6 Hz), 9.05 (d, 1H, H(C5), 3 J HH = 5.4 Hz).13

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The reaction of anhydrous [12]crown-4 with a 1:1 ethanol adduct of the three-mercury anticrown (o-C 6 F 4 Hg) 3 (1) under Ar results in the formation of a double-decker sandwich complex {[(o-C 6 F 4 Hg) 3 ] 2 ([12]crown-4)} ( 4). The molecule of the crown ether in 4 is located between the mutually parallel planes of two mercury macrocycles and is coordinated to each of them through Hg-O secondary interactions. In the crown ether ligand, all four oxygen atoms are involved in the bonding to the molecules of 1, while in each anticrown species only two Hg centers take part in the coordination. If aqueous [12]crown-4 is used in the reaction with 1, the other double-decker sandwich, {[(o-C 6 F 4 Hg) 3 ] 2 ([12]crown-4)(H 2 O) 2 } (5), containing one crown ether molecule and two molecules of H 2 O in the space between the planes of the anticrown units, is produced. Every water molecule in this supramolecular aggregate is cooperatively bound through the oxygen atom by three Lewis acidic Hg sites of the neighboring anticrown, whereas one of the water protons forms the hydrogen bond with the oxygen atom of the crown ether. An additional contribution in the bonding is made by the interaction of one of the Hg centers of each anticrown unit with the nearest oxygen atom of [12]crown-4. The complex of analogous composition and close structure is formed in the reaction of 1 with aqueous [18]crown-6. However in this sandwich, {[(o-C 6 F 4 Hg) 3 ] 2 ([18]crown-6)(H 2 O) 2 } (6), both protons of each water species are involved in the formation of the H-bonds with the crown ether, while the bonding of each mercuramacrocycle to the crown ether is accomplished due to the coordination of two of its Hg atoms with two oxygen atoms of the crown compound. From the interaction of 1 3 EtOH with 1,3,5-trioxane, a 1:1 complex, {[(o-C 6 F 4 Hg) 3 ](CH 2 O) 3 } (7), having a cage structure, has been isolated. The synthesized adducts are the first complexes of crown ethers with an anticrown.

The reactions of picolinyl and 4-chloropicolinyl chlorides with methyl esters of S-methyl-l-cysteine, l- and d-methionine, and l-histidine afforded a series of functionalized carboxamides, which readily formed pincer-type complexes upon interaction with PdCl(NCPh) in solution under mild conditions. The direct cyclopalladation of the ligands derived was also accomplished in the solid phase, in particular, mechanochemically, although it was complicated by the partial deactivation of the starting amides. The resulting complexes with 5,5- and 5,6-membered fused metallocycles were fully characterized by IR and NMR spectroscopy, including variable-temperature and 2D-NMR studies. In the case of some cysteine- and methionine-based derivatives, the realization of κ-N,N,S-coordination was supported by X-ray diffraction. The cytotoxic effects of these complexes were examined on HCT116, MCF7, and PC3 human cancer cell lines as well as HEK293 as a representative of normal cells. The comparative studies allowed us to determine that the presence of the sulfide ancillary donor group is crucial for cytotoxic activity of this type of Pd(II) complexes. The main structure-activity relationships and the most promising palladocycles were outlined. The additional studies by gel electrophoresis revealed that 4-chloropicolinyl derivatives, despite the nature of an amino acid, can bind with DNA and inhibit topoisomerase I activity.

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