Patricia A. Marzilli

Coordination Modes of Multidentate Ligands in fac-[Re(CO)3(polyaminocarboxylate)] Analogues of 99mTc Radiopharmaceuticals. Dependence on Aqueous Solution Reaction Conditions

We study Re analogues of (99m)Tc renal agents to interpret previous results at the (99m)Tc tracer level. The relative propensities of amine donors versus carboxylate oxygen donors of four L = polyaminocarboxylate ligands to coordinate in fac-[Re(I)(CO)(3)L](n) complexes were assessed by examining the reaction of fac-[Re(I)(CO)(3)(H(2)O)(3)](+) under conditions differing in acidity and temperature. All four L [N,N-bis-(2-aminoethyl)glycine (DTGH), N,N-ethylenediaminediacetic acid, diethylenetriamine-N-malonic acid, and diethylenetriamine-N-acetic acid] can coordinate as tridentate ligands while creating a dangling chain terminated in a carboxyl group. Dangling carboxyl groups facilitate renal clearance in fac-[(99m)Tc(I)(CO)(3)L](n) agents. Under neutral conditions, the four ligands each gave two fac-[Re(I)(CO)(3)L](n) products with HPLC traces correlating well with known traces of the fac-[(99m)Tc(I)(CO)(3)L](n) mixtures. Such mixtures are common in renal agents because the needed dangling carboxyl group can compete for a coordination site. However, the HPLC separations needed to assess the biodistribution of a single tracer are impractical in a clinical setting. One goal in investigating this Re chemistry is to identify conditions for avoiding this problem of mixtures in preparations of fac-[(99m)Tc(I)(CO)(3)L](n) renal tracers. After separation and isolation of the fac-[Re(I)(CO)(3)L](n) products, NMR analysis of all products and single crystal X-ray crystallographic analysis of both DTGH products, as well as one product each from the other L, allowed us to establish coordination mode unambiguously. The product favored in acidic conditions has a dangling amine chain and more bound oxygen. The product favored in basic conditions has a dangling carboxyl chain and more bound nitrogen. At the elevated temperatures used for simulating tracer preparation, equilibration was facile (ca. 1 h or less), allowing selective formation of one product by utilizing acidic or basic conditions. The results of this fundamental study offer protocols and guidance useful for the design and preparation of fac-[(99m)Tc(I)(CO)(3)L](n) agents consisting of a single tracer.

New Porphyrins Bearing Pyridyl Peripheral Groups Linked by Secondary or Tertiary Sulfonamide Groups: Synthesis and Structural Characterization

New pyridyl meso-tetraarylporphyrins (TArP, Ar = -C(6)H(4)-) of the general formula, T(R(1)R(2)NSO(2)Ar)P (R(1) = N-py-n-CH(2) (n = 2 or 4) and R(2) = CH(3)), have been synthesized by the versatile approach of utilizing meso-tetra(4-chlorosulfonylphenyl)porphyrin. After characterization by mass spectrometry and by visible absorption and (1)H NMR spectroscopy, the porphyrins were converted to various metalloderivatives, including Cu(II) and Zn(II). Treatment of T(N-py-4-CH(2)(CH(3))NSO(2)Ar)P (5) or TpyP(4) (meso-tetra(4-pyridyl)porphyrin) with CH(3)Co(DH)(2)H(2)O (DH = monoanion of dimethylglyoxime) afforded [CH(3)Co(DH)(2)](4)T(N-py-4-CH(2)(CH(3))NSO(2)Ar)P (6) and [CH(3)Co(DH)(2)](4)TpyP(4) (7). Typically, basic pyridines shift the axial methyl (1)H NMR signal of CH(3)Co(DH)(2)L upfield but leave the equatorial methyl signal unshifted. However, both signals for [CH(3)Co(DH)(2)](4)TpyP(4) are approximately 0.2 ppm more downfield than normal, suggesting perhaps an extremely non-basic pyridyl group. However, TpyP(4) forms CH(3)Co(DH)(2)py adducts with binding ability comparable to that of other pyridine ligands with normal basicity and to that of T(N-py-4-CH(2)(CH(3))NSO(2)Ar)P. Consequently, in 7 the deshielding of the methyl signals, even the axial Co-CH(3) signal, is attributed to anisotropy of the porphyrin core. The methyl signals for [CH(3)Co(DH)(2)](4)T(N-py-4-CH(2)(CH(3))NSO(2)Ar)P (6) have normal shifts. The absence of an anisotropic effect is attributable to the large distance of the CH(3)Co(DH)(2) moieties from the porphyrin core caused by the intervening linker in 6. Indeed, the separation led to only a slightly reduced (25%) fluorescence emission of 6 compared to 5, whereas that of 7 is considerably reduced (90%) compared to TpyP(4). The X-ray structures of 5, its Cu(II) complex, and [CH(3)Co(DH)(2)](4)TpyP(4) (7) (all of which have C(i) symmetry) support the spectroscopy. For example, the Co-N(ax) bond lengths of [CH(3)Co(DH)(2)](4)TpyP(4) (2.055(4) and 2.079(4) A) are comparable to that of CH(3)Co(DH)(2)py (2.068(3) A), consistent with the normal coordinating ability of TpyP(4). In an accompanying study, the new pyridylporphyrins have been converted to DNA-binding, water-soluble cationic porphyrins.

Mixed-ligand rhenium(V) oxo monomers with triphenylphosphine oxide and lopsided and symmetrical heterocyclic ligands. Putative intermediates in rhenium(V) oxo synthetic chemistry☆

Normally, ReOCl3 (Me2S) (OPPh3) (1) serves as a useful source of ReO3+ or ReOClx(3−x)+ for the synthesis of Re complexes by ligand exchange. Complexes of the type ReOCl3(OPPh3)(L) (L = 1,5,6-trimethylbenzimidazole (Me3Bzm) (2); 3,5-lutidine (3,5-lut) (3); pyridine (py) (4)) were prepared from 1 and one equivalent of L. Formation of these mixed-ligand complexes is unsual because the normally labile OPPh3 in 1 was retained. Addition of non-coordinating triethylamine (NEt3) gave [HNEt3][ReOCl4(OPPh3] (5). The anion in 5 has been populated to be an intermediate in some synthetic schemes. ReOCl3(OPPh3)(Me3Bzm) (2) was characterized by X-ray crystallography. Crystallographic data are: C28H27Cl3N2O2PRe, P21/c, a = 18.503(3), b = 9.780(2), c = 15.735(4) A, β = 97.56(2)°, Dcalc = 1.76 g cm−3, Z = 4, R = 0.041, Rw = 0.066 for 3193 independent reflections. In 2, the pseudo-octahedral Re has the OPPh3 ligand trans to the oxo ligand, and one of the OPPh3 phenyl rings lies nearly over the five-membered ring of Me3Bzm. Reaction of ReOCl3(OPPh3)(Me3Bzm) (2) with one equivalent of 3,5-lut or py resulted in the precipitation of mixed-ligand species best formulated as Re2O3Cl4(Me3Bzm)2(3,5-lut)2 (6) and Re2O3Cl4(Me3Bzm)2(py)2 (7), respectively.

Near-IR Fourier transform Raman spectroscopy of photolabile organocobalt B12 and model compounds. Identification of the Co–C bond stretch in cobalamins

The frequency of the Raman-active Co–C bond stretch in photolabile methylcoenzyme B12 has been conclusively determined by the new technique of near-IR Fourier transform (FT) Raman spectroscopy to be 500 cm–1 for methylcobalamin and 470 Cm–1 for deuteriated methyl (CD3–) cobalamin.

New porphyrins bearing positively charged peripheral groups linked by a sulfonamide group to meso-tetraphenylporphyrin: interactions with calf thymus DNA.

New water-soluble cationic meso-tetraarylporphyrins (TArP, Ar = 4-C(6)H(4)) and some metal derivatives have been synthesized and characterized. One main goal was to assess if N-methylpyridinium (N-Mepy) groups must be directly attached to the porphyrin core for intercalative binding of porphyrins to DNA. The new porphyrins have the general formula, [T(R(2)R(1)NSO(2)Ar)P]X(4/8) (R(1) = CH(3) or H and R(2) = N-Mepy-n-CH(2) with n = 2, 3, or 4; or R(1) = R(2) = Et(3)NCH(2)CH(2)). Interactions of selected porphyrins and metalloporphyrins (Cu(II), Zn(II)) with calf thymus DNA were investigated by visible circular dichroism (CD), absorption, and fluorescence spectroscopies. The DNA-induced changes in the porphyrin Soret region (a positive induced CD feature and, at high DNA concentration, increases in the Soret band and fluorescence intensities) indicate that the new porphyrins interact with DNA in an outside, non-self-stacking binding mode. Several new metalloporphyrins did not increase DNA solution viscosity and thus do not intercalate, confirming the conclusion drawn from spectroscopic studies. Porphyrins known to intercalate typically bear two or more N-Mepy groups directly attached to the porphyrin ring, such as the prototypical meso-tetra(N-Mepy)porphyrin tetracation (TMpyP(4)). The distances between the nitrogens of the N-Mepy group are estimated to be approximately 11 A (cis) and 16 A (trans) for the relatively rigid TMpyP(4). For the new flexible porphyrin, [T(N-Mepy-4-CH(2)(CH(3))NSO(2)Ar)P]Cl(4), the distances between the nitrogens are estimated to be able to span the range from approximately 9 to approximately 25 A. Thus, the N-Mepy groups in the new porphyrins can adopt the same spacing as in known intercalators such as TMpyP(4). The absence of intercalation by the new porphyrins indicates that the propensity for the N-Mepy group to facilitate DNA intercalation of cationic porphyrins requires direct attachment of N-Mepy groups to the porphyrin core.

Complexes of lopsided N-donor heterocyclic bioligands: has the electrostatic effect of the N2CH proton been overlooked in metallobiochemistry?

The orientation and fluxional motions of planar N-donor heterocyclic coordinated ligands (Ls), historically difficult to assess in solution, need to be evaluated because these properties influence the structure and function of many metallobiochemicals. Compelling NMR evidence on the solution conformer of cis, bis imidazole-ring-ligated untethered ligands indicates that orientation is dictated by the electrostatic attraction of the N2C6+ proton for the negative cis ligands (e.g. 0x0, Cl). Apowerful strategy in which complexes similar except that one has a lopsided L and the other has a Cz-symmetrical L are examined by using exchange-NOE cross-peaks afforded insightful information on L dynamics, including the extent and direction of rotation about the metal-N bond, and even the halves of Cz-symmetrical Ls that interchange during dynamic processes. Since metal centers make this imidazole proton more positive, it is likely that this electrostatic effect has some influence on both structure and function of all biological systems with metal sites ligated by imidazole rings (namely imidazole and benzimidazole bound to Biz, Pt drug adducts to G of DNA, and numerous metalloenzymes and.metalloproteins).

Metallation of Isatin (2,3-Indolinedione). X-Ray Structure and Solution Behavior of Bis(Isatinato)Mercury(II).

The first X-ray structure of an isatin (2,3-indolinedione, isaH) metal complex, bis(isatinato)memury(II) (C16H8N2O4Hg) (1), was determined. (1) was obtained from the reaction of isaH with mercury(II) acetate in methanol. Analogously, treatment of sodium saccharinate and mercury(II) acetate in methanol yielded Hg(saccharinato)2•0.5CH3OH (3). (1) crystallizes in the monoclinic system, space group P21/ a with a = 7.299(1) Å, b = 8.192(1) Å, c = 11.601(1) Å , β = 105.82(1)°, V = 667.4 Å3, Z = 2, Dcalc = 2.452 g cm−3, MoKα radiation(λ = 0.71073 Å), μ = 115.5 cm-1, F(000) = 460, 21(1) °C. The structure was refined on the basis of 2023 observed reflections to R= 0.044. The two deprotonated, non coplanar isa ligands are trans to each other in a head to tail orientation and bound to the Hg through the nitrogen in a linear N-Hg-N arrangement. The Hg atom is at the center of symmetry of the complex and displaced by 0.62 Å from the two planes of the isa ligands (τ Hg-N1-C2-O2= -16°). The Hg-N bond length is 2.015 Å. Noπ-aryl-memury(ll)-π-aryl stacking interaction was observed either in the solid state or in the solution state. The IR, electronic, and 1H and 13CNMR spectral data of (1) and (3) suggest binding of the memury to the heterocyclic nitrogen, in agreement with the crystal structure determination of (1).

The synthesis and isolation of the stereospecific ligand, N-(2-aminoethyl)-2-[(2-aminoethyl)thio]acetamide (egeH). Comparison of the crystal structure of [Co(ege)(NO2)2] ·4H2O with related systems

A convenient synthetic scheme that utilizes readily available starting materials and leads to the isolation of the linear, stereospecific NSNN tetradentate ligand, N -(2-aminoethyl)-2-[(2-aminoethyl)thio]acetamide (egeH, 6 ), as its dihydrobromide salt is reported. Ligand 6 deprotonates and forms octahedral complexes with cobalt(III) of only one geometric isomer, for example, [Co(ege)(NO 2 ) 2 ]·4H 2 O ( 7 ). Compound 7 crystallized in the monoclinic space group I 2/ c , a = 25.83(2), b = 7.896(6), c = 15.703(8) A, β = 90.36(5)°, V = 3202(3) A 3 , Z = 8. Refinement was based on 3105 reflections and converged at R = 0.038, R w = 0.047. The structural determination reveals that the geometry of the backbone ligand is cis -β. In addition, the structures of [Co(egpy)(NO 2 ) 2 ] ( 8 ) (where egpyH = N -(2-aminoethyl)-2-[(2-pyridylmethyl)thio]acetamide) and [Co(eee)(NO 2 ) 2 ]Br ( 9 ) (where eee = 1,8-diamino-3,6-dithiaoctane), which also contain stereospecific ligands, were also determined. Compound 8 crystallized in the monoclinic space group P 2 1 / c , a = 7.628(3), b = 12.347(4), c = 16.433(8) A, β = 108.39(3)°, V = 1470(1) A 3 , Z = 4. Refinement was based on 2249 reflections and converged at R = 0.034, R w = 0.042. Compound 9 crystallized in the monoclinic space group P 2 1 / a , a = 12.719(9), b = 13.855(4), c = 8.033(6) A, β = 111.32(4)δ, V = 1319(1) A 3 , Z = 4. Refinement was based on 2300 reflections and converged at R = 0.029, R w = 0.035. The tetradentate ligand in the former adopts the cis -β conformation, while for the latter, the expected cis -α geometry is observed. The structural parameters are compared and the origins of the attendant stereospecificities are discussed in terms of the nature of the internal donor atoms of the tetradentate ligands.

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 = (186/188)Re, (99m)Tc) 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 Re(I)-N(sulfonamide) bonds are normal in length and statistically identical and that the methyl (13)C 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(I) 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.

Steric effect of the adamantyl ligand on crystal structure and dissociation rates in organocobalt B12 models

The synthesis and crystal structure analyses of two new complexes of the type [Co(Hdmg)2(ad) L], where Hdmg = monoanion of dimethylglyoxime and ad = adamantyl have been performed, with L =(NH2Ph)(1) or 4-dimethylaminopyridine (2). Complex (1) crystallizes in the triclinic space group P with a= 11.196(2), b= 15.616(4), c= 16.129(4)A, α= 70.28(2), β= 83.53(2), γ= 79.58(2)°, Z= 4, and R= 0.054 for 6 133 independent reflections. Complex (2) crystallizes in the monoclinic space group P21/c with a= 9.268(3), b= 15.178(2), c= 20.286(4)A, β= 90.31(2)°, Z= 4, and R= 0.055 for 3 595 independent reflections. Both compounds are characterized by long axial Co–N bonds 2.215(4)(1) and 2.102(3)A(2) and Co–C bonds 2.159(4)(1) and 2.160(4)A(2). The steric effect of the ad ligand is evident in the ‘butterfly’ bending of the Hdmg ligands toward L. In order to determine how such steric effects could be reflected in the rates of L dissociation and in Co–L distances, log k1 and Co–L bond lengths in series of the type [Co(Hdmg)2R(L)] with L = NH2Ph, 1,5,6-trimethylbenzimidazole, 4-cyanopyridine, or P(OMe)3 and R = Me, Et, Pri, or ad were analysed as a function of an electronic parameter for R derived from 13C n.m.r. data in a previous study. This analysis suggests that the steric effect of adamantyl on rates is mainly reflected in the transition state.