The interaction of the pyrazole-containing macrocyclic receptors 3,6,9,12,13,16,19,22,25,26-decaazatricyclo-[22.2.1.1(11,14)]-octacosa-1(27),11,14(28),24-tetraene 1[L1], 13,26-dibenzyl-3,6,9,12,13,16,19,22,25,26-decaazatricyclo-[22.2.1.1(1)(1,14)]-octacosa-1(27),11,14(28),24-tetraene 2[L2], 3,9,12,13,16,22,25,26-octaazatricyclo-[22.2.1.1(11,14)]-octacosa-1(27),11,14(28),24-tetraene 3[L3], 6,19-dibenzyl-3,6,9,12,13,16,19,22,25,26-decaazatricyclo-[22.2.1.1(11,)(14)]-octacosa-1(27),11,14(28),24-tetraene 4[L4], 6,19-diphenethyl-3,6,9,12,13,16,19,22,25,26-decaazatricyclo-[22.2.1.1(11,14)]-octacosa-1(27),11,14(28),24-tetraene 5[L5], and 6,19-dioctyl-3,6,9,12,13,16,19,22,25,26-decaazatricyclo-[22.2.1.1(11,14)]-octacosa-1(27),11,14(28),24-tetraene 6[L6] with l-glutamate in aqueous solution has been studied by potentiometric techniques. The synthesis of receptors 3-6[L3-L6] is described for the first time. The potentiometric results show that 4[L4] containing benzyl groups in the central nitrogens of the polyamine side chains is the receptor displaying the larger interaction at pH 7.4 (Keff = 2.04 x 10(4)). The presence of phenethyl 5[L5] or octyl groups 6[L6] instead of benzyl groups 4[L4] in the central nitrogens of the chains produces a drastic decrease in the stability [Keff = 3.51 x 10(2) (5), Keff = 3.64 x 10(2) (6)]. The studies show the relevance of the central polyaminic nitrogen in the interaction with glutamate. 1[L1] and 2[L2] with secondary nitrogens in this position present significantly larger interactions than 3[L3], which lacks an amino group in the center of the chains. The NMR and modeling studies suggest the important contribution of hydrogen bonding and pi-cation interaction to adduct formation.

Supramolecular chemistry has developed through the preparation of sophisticated molecular receptors which are able to discriminate and induce characteristic properties in given substrates. 1 Tridimensional cryptand-like receptors with appropriate arrangements of binding sites have yielded interesting patterns in many aspects of molecular recognition like metal ion or anion coordination chemistry. 1,2 We have previously reported the synthesis, basicity and complexing properties of polyamine coronands of 1H-pyrazole able to form Zn 2+ and Cu 2+ pyrazolate salts. 3,4 Herein we report on a polyamine cryptand of related structure. 5 We advance the results of a study on its interaction with Cu 2+ and on the formation of mixed complexes with the biologically relevant neurotransmitter dopamine. 6 Ligand L was prepared as reported in ref. 5 by reacting 3,5-pyrazoledicarbaldehyde and tris(2-aminoethyl)amine in 3+2 molar ratio in MeOH, followed by reaction in situ with NaBH 4 .

The interaction with Cu2+ and dopamine of three polyazacyclophanes containing pyrazole fragments as spacers is described. Formation of mixed complexes Cu2+−macrocycle−dopamine has been studied by potentiometric methods in aqueous solution. The crystal structures of the complexes [Cu2(L 1)(H2O)2](ClO4)4·2H2O (4) (L 1 = 13,26-dibenzyl-3,6,9,12,13,16,19,22,25,26-decaazatricyclo[22.2.1.111,14]octacosa-1(27),11,14(28),24-tetraene) and [Cu2(H- 1 L 3)](HClO4)(ClO4)2·2H2O (6) (L 3 = 1,4,7,8,11,14,17,20,21,24,29,32,33,36-tetradecaazapentacyclo[12.12.12.16,9.119,22.131,34]hentetraconta-6,9(41),19(40),21,31,34(39)-hexaene) are presented. In the first one (4), each Cu2+ coordination site is made up by the three nitrogens of the polyamine bridge, a sp2 pyrazole nitrogen and one water molecule that occupies the axial position of a square pyramid. The distance between the copper ions is 6.788(2) Å. In the crystal structure of 6, the coordination geometry around each Cu2+ is square pyramidal with its base being formed by two secondary nitrogens of the bridge and two nitrogen atoms of two different pyrazolate units which act as exobidentate ligands. The axial positions are occupied by the bridgehead nitrogen atoms; the elongation is more pronounced in one of the two sites [Cu(1)−N(1), 2.29(2) Å; Cu(2)−N(6), 2.40(1) Å]. The Cu−N distances involving the deprotonated pyrazole moieties are significantly shorter than those of the secondary nitrogens. The Cu(1)···Cu(2) distance is 3.960(3) Å. The pyrazole in the noncoordinating bridge does not deprotonate and lies to one side of the macrocyclic cavity. One of the aliphatic nitrogens of this bridge is protonated and hydrogen bonded to a water molecule, which is further connected to the sp2 nitrogen of the pyrazole moiety through a hydrogen bond. The solution studies reveal a ready deprotonation of the pyrazole units induced by coordination to Cu2+. In the case of L 2 (L 2 = 3,6,9,12,13,16,19,22,25,26-decaazatricyclo[22.2.1.111,14]octacosa-1(27),11,14(28),24-tetraene), deprotonation of both pyrazole subunits is already observed at pH ca. 4 for 2:1 Cu2+:L 2 molar ratios. All three free receptors interact with dopamine in aqueous solution. L 3 is a receptor particularly interesting with respect to the values of the interaction constants over five logarithmic units at neutral pH, which might suggest an encapsulation of dopamine in the macrocyclic cage. All three receptors form mixed complexes Cu2+−L−dopamine. The affinity for the formation of ternary dopamine complexes is particularly high in the case of the binuclear Cu2+ complexes of the 1-benzyl derivative L 1.

Keywords:Pyrazole macrocycles / Copper and zinc coordination / Acid-base and metal formation equilibria / Polyamine ligands / Paramagnetic NMRThe synthesis of a new macrocyclic receptor (L 4 ) containing two 3,5-dimethylpyrazole units connected by dipropylenetriamine bridges is reported for the first time; pH-metric titrations indicate that L 4 shows six protonation steps in the pH range 2−11. In the absence of metal ions, the pyrazole moieties are not involved in acid-base processes in this pH range.

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The build-up of compounds defining closed cavities plays a crucial role in supramolecular chemistry. 1 Classical approaches for the preparation of cage-type receptors very often involve long and multistep synthetic routes; the preparation of the first cryptands being a paradigm of this point. More recently several other approaches for the obtention of this kind of receptors have been put forward. Of particular relevance are those strategies in which the coordination of a specific substrate either of organic or inorganic nature induce the recognition site of a receptor in a determined shape. Within this approach, the work of Fujita's group on the Pd 2+ induced-fit of pyridine based molecular host of different architectures and that of the groups of Mingos and Ramón-Vilar on the formation of nickel cages with thiourea type ligands under anion control are of particular relevance to this communication. 2,3 Herewith we communicate on a novel way of organising a cage-like compound taking advantage of the particular characteristics of pyrazole as a ligand and the geometrical coordination preferences of Cu 2+ .Recently we have reported on the Cu 2+ complex formation of the 1H-pyrazole polyamine coronand L 1 and of the cage ligand L 2 . [4][5][6] The first of these receptors L 1 takes up, both in solution and in the solid state, two Cu 2+ metal ions. Its X-ray structure revealed a strongly distorted square pyramidal coordination geometry around each copper centre. The base of the pyramid is comprised of two nitrogen atoms of the two deprotonated pyrazolate moieties and by the two secondary nitrogen atoms closest to them in the chain (see Scheme 1). A central secondary nitrogen atom of the chain occupies the apical position. The binuclear Cu 2+ complex of the cryptand type ligand L 2 displayed similar coordination features. 5 Therefore, with the initial purpose of facilitating the coordinative interactions with axial ligands we proceeded to substitute the diethylenetriamine bridges in L 1 by 1,5-diaminopentane bridges to obtain receptor L. 7 Interestingly, addition of Cu 2+ to an aqueous solution of L in molar ratio Cu 2+ +L of 2+1 originated a red coloured solution. Room-temperature evaporation of this solution yielded red crystals suitable for X-ray analysis. The crystal structure reveals the Cu 2+ -induced formation of the centrosymmetric cageIn contrast with L 1 which formed discrete binuclear [Cu 2 (H 22 L 1 )] 2+ species, the molecular features of L favour an arrangement in which two molecules of L are connected together by four Cu 2+ metal ions. Each one of the four metal centres is bound by two secondary nitrogen and two pyrazole nitrogen atoms belonging to different macrocyclic subunits (Scheme 1) forming the base of a strongly distorted square pyramid. All the pyrazole fragments are deprotonated and behave as exobidentate ligands. The Cu-N distances involving