New Robust Bleomycin Analogues: Synthesis, Spectroscopy, and Crystal Structures of the Copper(II) Complexes

Two new bleomycin analogues, 2-[((2-(4-imidazolyl)ethyl)amino)carbonyl]-6-[((2-amino-2-methylpropyl)amino)methyl]pyridine = L3 and 2-[((2-(4-imidazolyl)ethyl)amino)carbonyl]-6-[((2-amino-1,1,2-trimethylpropyl)amino)methyl]pyridine = L4, were synthesized in order to create air-stable ligands of their CuI (and FeII) complexes.
The protonation constants (log Kn) of the ligands at 25 °C and I = 0.1 M NaNO3 were 9.9, 6.9, and 5.2 for L3
and 10.0, 6.7, and 3.9 for L4. The complexation of the triprotonated L3 and L4 with CuII started at pH < 5 to
yield 4-coordinate [CuII(H-1L)·H+]2+ complexes, 4 and 6, respectively, followed by formation of square-pyramidal
[CuII(H-1L)]+ complexes, 5 and 7, with pKa values of 5.6 for 5 and 5.9 for 7. The complexation constants, log
KCuIIH−1L, were 8.9 for [CuII(H-1L3)]+, 5, and 8.6 for [CuII(H-1L4)]+, 7, respectively. The structures of
[CuII(H-1L3)]ClO4 (5·ClO4) and [CuII(H-1L4)]BF4 (7·BF4) were determined by X-ray crystallography. Crystal
data for 5·ClO4:  monoclinic, space group P21/n (No. 14), a = 13.978(6) Å, b = 8.103(3) Å, c = 18.037(5) Å,
β = 98.61(3)°, V = 2019(1) Å3, Z = 4, R = 0.053, and Rw = 0.044 for 2996 [I > 3σ(I)] reflections. Crystal data
for 7·BF4:  monoclinic, space group P21/n (No. 14), a = 16.092 (4) Å, b = 7.974(4) Å, c = 16.819(2) Å, β =
99.64(1)°, V = 2127(1) Å3, Z = 4, R = 0.040, and Rw = 0.025 for 1633 [I > 4σ(I)] reflections. The coordination
geometry around the copper was a distorted square-pyramid in 5, while that of 7 was the intermediate between
a trigonal-bipyramid and a square-pyramid. The distortion is influenced strongly by the number of the methyl
group. The EPR spectral data for both copper(II) complexes were consistent with the retention of the solid-state
structure in frozen DMF/MeOH (1:1) solution at 77 K. The visible absorption spectra of 10% DMF/aqueous
solutions (pH 9.5) of 5 and 7 at I = 0.1 M NaNO3 showed absorption maxima at 646 nm with a shoulder at ca.
900 nm for 5 and at 658 and 888 nm for 7. The red-shift of 7 by ca. 12 nm relative to 5 reflects the distortion
toward the trigonal-bipyramidal geometry of 7 in solution. Both complexes displayed irreversible redox behavior
in DMF at I = 0.1 M tetra(n-butyl)ammonium tetrafluoroborate. The anodic and cathodic peak potentials obtained
by cyclic voltammetry for 5 and 7 were −0.14 and −0.76 V for 5 and −0.17 and −0.80 for 7 vs Ag/AgCl. The
cathodic potentials of copper(II) complexes were shifted toward the anodic direction by ca. 20−60 mV compared
to the nonsubstituted 5-coordinate, [CuII(H-1L1)]+ complex, 16 (−0.82 V vs Ag/AgCl). The CuI complexes (9
and 10) are air-oxidized to the corresponding CuII complexes, 5 and 7, respectively.