Several novel N-donor tridentate ligands formed in chemical studies of new fac-Re(CO)3 complexes relevant to fac-99mTc(CO)3 radiopharmaceuticals: attack of a terminal amine on coordinated acetonitrile

Abstract

To evaluate syntheses of fac-[Re(CO)(3)L](+) complexes in organic solvents, we treated fac-[Re(CO)(3)(CH(3)CN)(3)]PF(6)/BF(4) in acetonitrile with triamine ligands (L). When L had two primary or two tertiary terminal amine groups, the expected fac-[Re(CO)(3)L](+) complexes formed. In contrast, N,N-dimethyldiethylenetriamine (N,N-Me(2)dien) formed an unusual compound, fac-[Re(CO)(3)(DAE)]BF(4) {DAE = (Z)-N'-(2-(2-(dimethylamino)ethylamino)ethyl)acetimidamide = (Me(2)NCH(2)CH(2))NH(CH(2)CH(2)N=C(NH(2))Me)}. DAE is formed by addition of acetonitrile to the N,N-Me(2)dien terminal primary amine, converting this sp(3) nitrogen to an sp(2) nitrogen with a double bond to the original acetonitrile sp carbon. The three Ns bound to Re derive from N,N-Me(2)dien. The pathway to fac-[Re(CO)(3)(DAE)]BF(4) is suggested by a second unusual compound, fac-[Re(CO)(3)(MAE)]PF(6) {MAE = N-methyl-N-(2-(methyl-(2-(methylamino)ethyl)amino)ethyl)acetimidamide = MeN(H)-CH(2)CH(2)-N(Me)-CH(2)CH(2)-N(Me)-C(Me)=NH}, isolated after treating fac-[Re(CO)(3)(CH(3)CN)(3)]PF(6) with N,N',N''-trimethyldiethylenetriamine (N,N',N''-Me(3)dien). MAE chelates via a terminal and a central sp(3) N from N,N',N''-Me(3)dien and via one sp(2) NH in a C(Me)=NH group. This group is derived from acetonitrile by addition of the other N,N',N''-Me(3)dien terminal amine to the nitrile carbon. This addition creates an endocyclic NMe group within a seven-membered chelate ring. The structure and other properties of fac-[Re(CO)(3)(MAE)]PF(6) allow us to propose a reaction scheme for the formation of the unprecedented DAE ligand. The new compounds advance our understanding of the spectral and structural properties of Re analogues of (99m)Tc radiopharmaceuticals.

Figure 1

ORTEP plot of the cation in [Re(CO)₃(DAE)]BF₄. Thermal ellipsoids are drawn with 50% probability.

Figure 2

ORTEP plots of the cations in (a) [Re(CO)₃(MAE)]PF₆, (b) [Re(CO)₃(MAEH)F]PF₆, and (c) [Re(CO)₃(EAE)]BF₄. Thermal ellipsoids are drawn with 50% probability.

Figure 3

Designation of the exo-NH proton (pointing away from the carbonyl groups and toward the hydrophobic pocket of the ligand) of [Re(CO)₃(MAE)]PF₆ and [Re(CO)₃(EAE)]BF₄. N4H is not classified as either endo or exo.

Figure 4

¹H NMR spectrum showing NH signals of [Re(CO)₃(DAE)]BF₄ in DMSO-d₆ at 25 °C (top), in acetonitrile-d₃ at 25 °C (middle), and in acetonitrile-d₃ at −5 °C (bottom).

Figure 5

Designation of the N4Ha and N4Hb protons of [Re(CO)₃(DAE)]BF₄, indicating the proximity of N4Hb to the methyl group and the rotation of the NH₂ group.

Figure 6

Change in chemical shift (Δδ, ppm) of the NH signals of [Re(CO)₃(MAE)]PF₆ (5 mM) caused by added Cl⁻ in DMSO-d₆ at 25 °C.

Figure 7

Change in chemical shift (Δδ, ppm) of the NH signals of [Re(CO)₃(MAE)]PF₆ (5 mM) caused by added Cl⁻ in acetonitrile-d₃ at 25 °C.

Figure 8

Change in chemical shift (Δδ, ppm) of the NH signals of [Re(CO)₃(DAE)]BF₄ (5 mM) caused by added Cl⁻ in acetonitrile-d₃ at 25 °C.

Figure 9

¹H NMR spectra of [Re(CO)₃(MAE)]PF₆ (5 mM) in DMSO-d₆ at 25 °C before (top) and 20 min after (bottom) addition of OH⁻ (1.7 mM). The multiplet at ~4.2 ppm arises from one of the C7H₂ protons.

Scheme 1

Products obtained in the syntheses using acetonitrile as a solvent. The compound numbers correspond to the structures in Figure 1 and Figure 2. Adventitious HF from the decomposition of PF₆⁻ transformed some of 2a to 2b.

Scheme 2

The likely pathway for DAE ligand formation from N,N-Me₂dien and acetonitrile (green). Stars indicate the location of the lone pair on the nitrogens known to be used or likely to be used in Re coordination at each stage of the process. The fac-{Re(CO)₃}⁺ fragment is not shown.

Scheme 3

The likely pathway for MAE ligand formation from N,N′,N″-Me₃dien and acetonitrile (green). Stars indicate the location of the lone pair on the nitrogens known to be used or likely to be used in Re coordination at each stage of the process. The fac-{Re(CO)₃}⁺ fragment is not shown. Only one proton can be transferred (in the second step). The hypothetical step which would be needed to form the DAE analogue does not occur because the methyl group can not transfer.