Complexes Possessing Rare “Tertiary” Sulfonamide Nitrogen-to-Metal Bonds of Normal Length: fac -[Re(CO) 3 ( N (SO 2 R)dien)]PF 6 Complexes with Hydrophilic Sulfonamide Ligands

Tertiary sulfonamide nitrogen-to-metal bonds of normal length are very rare. We recently discovered such a bond in one class of fac-[Re(CO)(3)(N(SO2R)(CH(2)Z)(2))](n) complexes (Z = 2-pyridyl) with N(SO2R)dpa ligands derived from di-(2-picolyl)amine (N(H)dpa). fac-[M(CO)(3)(N(SO2R)(CH(2)Z)(2))](n) agents (M = Re-186/188, Tc-99m) could find use as radiopharmaceutical bioconjugates when R is a targeting moiety. However, the planar, electron-withdrawing 2-pyridyl groups of N(SO2R)dpa destabilize the ligand to base and create relatively rigid chelate rings, raising the possibility that the rare M-N(sulfonamide)bond is an artifact of a restricted geometry. Also, the hydrophobic 2-pyridyl groups could cause undesirable accumulation in the liver, limiting future use in radiopharmaceuticals. Our goal is to identify a robust, hydrophilic, and flexible N(CH(2)Z)(2) chelate framework. New C-2-symmetric ligands, N(SO2R)(CH(2)Z)(2) with (Z = CH2NH2; R = Me, dmb, or tol), were prepared by treating N(H)dien(Boc)(2), a protected diethylenetriamine (N(H)dien) derivative, with methanesulfonyl chloride (MeSO2Cl), 3,5-dimethylbenzenesulfonyl chloride (dmbSO(2)Cl), and 4-methylbenzenesulfonyl chloride (tolSO(2)Cl). Treatment of fac-[Re(CO)(3)(H2O)(3)](+) with these ligands, designated as N(SO2R)dien, afforded new fac-[Re(CO)(3)(N(SO2R)dien)]PF6 complexes. Comparing the fac-[Re(CO)(3)(N(SO2Me)dien)]PF6 and fac-[Re(CO)(3)(N(SO2Me)dpa)]PF6 complexes, we find that the Re-1-N(sulfonamide) bonds are normal in length and statistically identical and that the methyl C-13 NMR signal has an unusually upfield shift compared to that in the free ligand. We attribute this unusual upfield shift to the fact that the sulfonamide N undergoes an sp(2)-to-sp(3) rehybridization upon coordination to Re-1 in both complexes. Thus, the sulfonamide N of N(SO2R)dien ligands is a good donor, even though the chelate rings are conformationally flexible. Addition of the strongly basic and potentially monodentate ligand, 4-dimethylaminopyridine, did not affect the fac-[Re(CO)(3)(N(SO(2)tol)dien)]PF6 complex, even after several weeks. This complex is also stable to heat in aqueous solution. These results indicate that N(SO2R)dien ligands form fac-[Re(CO)(3)(N(SO2R)dien)]PF6 complexes sufficiently robust to be utilized for radiopharmaceutical development.