Complexes Possessing Rare “Tertiary” Sulfonamide Nitrogen-to-Metal Bonds of Normal Length: fac-[Re(CO)3(N(SO2R)dien)]PF6 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)­(CH2Z)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)­(CH2Z)2)]n agents (M = 186/188Re, 99mTc) 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(CH2Z)2 chelate framework. New C2-symmetric ligands, N­(SO2R)­(CH2Z)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 (dmbSO2Cl), and 4-methylbenzenesulfonyl chloride (tolSO2Cl). 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 ReI–N­(sulfonamide) bonds are normal in length and statistically identical and that the methyl 13C 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 sp2-to-sp3 rehybridization upon coordination to ReI 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(SO2tol)­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.