New Monodentate Amidine Superbasic Ligands with a Single Configuration infac-[Re(CO)₃(5,5′- or 6,6′-Me₂bipyridine)(amidine)]BF₄Complexes

Abstract

Treatment of two precursors, fac-[Re(CO)3(L)(CH3CN)]BF4 [L = 5,5′-dimethyl-2,2′-bipyridine (5,5′-Me2bipy) (1) and 6,6′-dimethyl-2,2′-bipyridine (6,6′-Me2bipy) (2)], with five C2-symmetrical saturated heterocyclic amines yielded ten new amidine complexes, fac-[Re(CO)3(L)(HNC(CH3)N(CH2CH2)2Y)]BF4 [Y = CH2, (CH2)2, (CH2)3, NH or O]. All ten complexes possess the novel feature of having only one isomer (amidine E configuration), as established by crystallographic and 1H NMR spectroscopic methods. We are confident that NMR signals of the other possible isomer (amidine Z configuration) would have been detected, if it were present. Isomers are readily detected in closely related amidine complexes because the double-bond character of the amidine C–N3 bond (N3 is bound to Re) leads to slow E to Z isomer interchange. The new fac-[Re(CO)3(L)(HNC(CH3)N(CH2CH2)2Y)]BF4 complexes have C–N3 bonds with essentially identical double-bond character. However, the reason that the Z isomer is so unstable as to be undetectable in the new complexes is undoubtedly because of unfavorable clashes between the equatorial ligands and the bulky N(CH2CH2)2Y ring moiety of the axial amidine ligand. The amidine formation reactions in acetonitrile (25 °C) proceeded more easily with 2 than with 1, indicating that the distortion in 6,6′-Me2bipy resulting from the proximity of the methyl substituents to the inner coordination sphere enhanced the reactivity of the coordinated CH3CN. Reaction times for 1 and 2 exhibited a similar dependence on the basicity and ring size of the heterocyclic amine reactants. Moreover, when the product of the reaction of 1 with piperidine, fac-[Re(CO)3(5,5′-Me2bipy)(HNC(CH3)N(CH2CH2)2CH2)]BF4, was challenged in acetonitrile-d3 or CDCl3 with a fivefold excess of the strong 4-dimethylaminopyridine ligand, there was no evidence for replacement of the amidine ligand after two months, thus establishing that the piperidinylamidine ligand is a robust ligand. This chemistry offers promise as a suitable means for preparing isomerically pure conjugated fac-[99mTc(CO)3L]n+/− imaging agents, including conjugates with known bioactive heterocyclic amines.

Models for B12-Conjugated Radiopharmaceuticals. Cobaloxime Binding to Newfac-[Re(CO)3(Me2Bipyridine)(amidine)]BF4Complexes Having an Exposed Pyridyl Nitrogen

“…19 Thus, amidine groups have potential as linkers for the conjugation of the fac-[M I (CO) 3 ] core (M = 99m Tc and 186/188 Re radionuclides) to bioactive targeting moieties. 4,19 The Re I amidine moiety, Re I −N3(H)−C am (CH 3 )−N4(H)R, in these reported complexes has two different substituents (H and R) on the remote nitrogen (N4) and double-bond character in the C−N bonds (C am −N3 and C am −N4). 19 These features lead to the possibility of four configurations and hence four conceivable isomers for fac-[Re(CO) 3 (Me 2 bipy)-(HNC(CH 3 )NHR)]BF 4 complexes ( Figure 1).…”

“…1−3 Rhenium and technetium complexes bearing the fac-[M I (CO) 3 ] core have received much attention owing to the many ideal properties of this core. 4−7 Some fac-[ 99m Tc I (CO) 3 L] n imaging agents have recently undergone evaluations in humans, 4,7,8 and fac-[ 186/188 Re I (CO) 3 L] n agents are emerging among the most promising radionuclides for therapeutic applications. 1−4 The concept of combining 99m Tc and 186/188 Re with bioactive molecules to produce selective targeting agents is currently receiving much attention.…”

“…19 Recently we overcame the "isomer problem" by forming the amidines by using bulky C 2 -symmetrical saturated heterocyclic secondary amines (HN(CH 2 CH 2 ) 2 Y; Y = CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , NH, or O). 4 Only two configurations (E and Z) are possible when the two N4 substituents are equal, and the bulk of two CH 2 CH 2 chains attached to N4 was expected to destabilize the Z configuration. Complexes of the type fac-[Re(CO) 3 (Me 2 bipy)(HNC(CH 3 )N(CH 2 CH 2 ) 2 Y)]BF 4 (Me 2 bipy = 5,5′-Me 2 bipy or 6,6′-Me 2 bipy) 4 were prepared and found to be robust and to exist as only one isomer having the E configuration.…”

“…4 Only two configurations (E and Z) are possible when the two N4 substituents are equal, and the bulk of two CH 2 CH 2 chains attached to N4 was expected to destabilize the Z configuration. Complexes of the type fac-[Re(CO) 3 (Me 2 bipy)(HNC(CH 3 )N(CH 2 CH 2 ) 2 Y)]BF 4 (Me 2 bipy = 5,5′-Me 2 bipy or 6,6′-Me 2 bipy) 4 were prepared and found to be robust and to exist as only one isomer having the E configuration. 4 In the present study, we prepare analogues of the fac-[Re(CO) 3 (L)(HNC(CH 3 )N(CH 2 CH 2 ) 2 Y)]BF 4 complexes, 4 but with a novel dangling and potentially metal-ligating donor group incorporated with Y.…”

“…Complexes of the type fac-[Re(CO) 3 (Me 2 bipy)(HNC(CH 3 )N(CH 2 CH 2 ) 2 Y)]BF 4 (Me 2 bipy = 5,5′-Me 2 bipy or 6,6′-Me 2 bipy) 4 were prepared and found to be robust and to exist as only one isomer having the E configuration. 4 In the present study, we prepare analogues of the fac-[Re(CO) 3 (L)(HNC(CH 3 )N(CH 2 CH 2 ) 2 Y)]BF 4 complexes, 4 but with a novel dangling and potentially metal-ligating donor group incorporated with Y. Such donors can coordinate to metal centers with targeting or therapeutic potential, thereby allowing us to use coordinate bonds in the approach to form bioconjugates.…”