No abstract

Metal ligation by N-donor ligands in biological systems involves heterocyclic ligands almost exclusively.1 The two most common classes of such ligands are macrocycles (e.g., porphyrins) and lopsided bases (B, e.g., imidazoles). Ligation by two or more of the same type of B is widespread. For two cis B's, the corresponding atoms of each ligand can be on the same side or opposite sides of the N-M-N plane, giving the head-to-head (HH) and the head-to-tail (HT) orientations, respectively. The most lopsided B's are five-six bicyclic ligands, Bs_6 (purines, benzimidazoles). The vast majority of cij-bis(B5_6) complexes are HT.2-* The very few reported HH c/í-bisfBs-é) complexes are square-planar.2,5-8 These HH cii-bis(Gua)Pt(II) complexes

In examining NMR methods to assess orientation and fluxional motions of planar N-donor heterocyclic coordinated ligands (L's) in solution, we introduce the use of exchange-NOE NMR data as a powerful method for defining (i) the extent of L rotation about the metal-N bond, (ii) the direction of L rotation, and (iii) even the halves of C 2 -symmetrical L's that interchange during dynamic processes. The full value of the approach depends on a strategy in which the complexes studied are chiral and similar except that one has a lopsided L (Me 3 Bzm ) 1,5,6trimethylbenzimidazole in [Re 2 O 3 Cl 4 (Me 3 Bzm) 4 ] ( 1)) and the other has a C 2 -symmetrical L (3,5-lut ) 3,5-lutidine in [Re 2 O 3 Cl 4 (3,5-lut) 4 ] (2)). Each Re is part of a nearly linear OdRe-O-RedO grouping and has a "terminal" L (L t ) and a stacked L (L s ). The fluxional inversion of the two chiral dimers involves rotations of ∼180°about the Re-O-Re bonds and of ∼90°about all four Re-L bonds. The exchange-NOE data for 2 show that the half of L t away from the dimer center interchanges with the half of L s close to the center, with the L plane rotating past the OdRe-O bonds, not the N-Re-Cl bonds. Thus, the exchange-NOE data help to establish the direction of L rotation. In 1, Me 3 Bzm t has the rare head-to-head (HH) orientation with respect to the partner. This partner Me 3 -Bzm s stacks with the Me 3 Bzm s from the other Re in the common head-to-tail (HT) orientation. Compelling evidence that the predominant solution conformer of 1 has the HH,HT,HH structure includes unusual chemical shift dispersions and a strong interligand NOE cross-peak. This is the only case in which cis,bis imidazole-ring-ligated untethered ligands have been found to be predominantly HH in solution. This predominance can be attributed to the electrostatic attraction of the δ + N 2 C proton for the negative core of the molecule (bridging O, cis Cl on same Re, and two cis Cl's on the other Re).

Efficient radiopharmaceutical design demands an understanding of factors that lead to one isomeric species in one ionization state at physiological pH. Thus, all pK a values must be outside the range of 6−9 for the typical M(V)O(N2S2) (M = 99mTc, 186/188Re) agents. The pendant carboxyl group needed for rapid clearance of renal agents in particular must be either only syn or only anti to the oxo ligand with respect to the N2S2 ligand plane. Monoamide-monoamine-dithiol (monoamide-monoamine = MAMA) ligands useful in preparing radiopharmaceuticals typically form M(V)O(N2S2) complexes with one core ligand pK a of ∼6−7 (secondary amine) and with both syn and anti isomers. We designed a new MAMA ligand, mercaptoacetamide-ethylene-cysteine (MAECH5), with the electron-withdrawing carboxyl group separated by only two bonds from the NH group. Only syn-ReO(MAECH2) was isolated. The structure of the monoanion syn-[ReO(MAECH)]- in the crystal of a [AsPh4]+ salt reveals lattice H-bonding between the CO2H of a tautomer (t2 ) with a CO2H and an amine N- and the CO of a neighboring t2 anion; this interaction results in preferential crystallization of t2 . However, in aqueous solutions of syn-[ReO(MAECH)]-, the predominant monoanionic tautomer (t1 ) has a CO2 - and an amine NH, as indicated by 1H NMR and resonance Raman spectra. The endo-NH configuration favored in M(V)O(N2S2) complexes places the NH and CO2 - groups in t1 spatially close. The NH is less acidic due to the cancellation of the electron-withdrawing and electrostatic effects of the negative CO2 -; as a result, syn-[ReO(MAECH)]- has a pK a value (6.0 ± 0.1) similar to that of the regioisomer syn-[ReO(CACAH)]- in which the carboxyl group and the NH are not close (CACAH5 = cysteine-acetyl-cysteamine). Our results suggest that the carboxyl group position also influences the syn/anti equilibrium. Attachment of the carboxyl group to a puckered ring in syn-[ReO(MAECH)]- appears both to favor the syn isomer and to increase the rate of syn/anti isomerization. ReO(CACAH2), with a carboxyl group attached to a less puckered chelate ring anchored by the amido donor, formed as a noninterconverting roughly equal mixture of syn/anti isomers. Thus, for a MAMA ligand to form a syn isomer with a pK a < 6, it must be designed with a nonionizable electron-withdrawing group near the NH group and a pendant carboxyl on a puckered ring.