Synthesis, potentiometric, kinetic, and NMR studies of 1,4,7,10-tetraazacyclododecane-1,7-bis(acetic acid)-4,10-bis(methylenephosphonic acid) (DO2A2P) and its complexes with Ca(II), Cu(II), Zn(II) and lanthanide(III) ions
Synthesis, potentiometric, kinetic, and NMR studies of 1,4,7,10-tetraazacyclododecane-1,7-bis(acetic acid)-4,10-bis(methylenephosphonic acid) (DO2A2P) and its complexes with Ca(II), Cu(II), Zn(II) and lanthanide(III) ions
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DOI：
10.1021/ic7024704
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发表时间：
2008-05-05
影响因子：
4.6
通讯作者：
Kovacs, Zoltan
中科院分区：
文献类型：
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作者：
Kalman, Ferenc K.;Baranyai, Zsolt;Kovacs, Zoltan
合成了一种含反式乙酸酯和反式亚甲基膦酸酯侧基的环戊二烯配体H（6）DO 2A 2 P，并通过pH电位法和核磁共振氢谱法测定了其质子化常数（12.6，11.43，5.95，6.15，2.88和2.77）。前两个质子化被证明发生在两个大环N-CH 2-PO 32-氮，而第三和第四质子化发生在两个膦酸酯基团。与两个-PO 32-基团的质子化平行，来自NH+-CH 2-PO 32-的质子被转移到N-CH 2-COO-氮。通过直接pH-电位法测定了Ca 2+、Cu 2+和Zn 2+（ML、MHL、MH 2L和M2 L）络合物的稳定常数。镧系离子（Ln（3+））形成类似的物种，但络合物的形成是缓慢的;因此，“细胞外”pH-电位法（La 3+，Eu 3+，Gd 3+，Y 3+）和与Cu（II）离子（Lu 3+）的竞争分光光度法用于确定稳定常数。通过比较相应DOTA（H（4）DOTA = 1，4，7，10-四氮杂环十二烷-1，4，7，10-四乙酸）和DOTP的log K-ML值，（H8 DOTP = 1，4，7，10-四氮杂环十二烷-1，4，7，10-四亚甲基膦酸）络合物，对于这里检测的所有金属离子络合物，发现顺序为DOTA <DO 2A 2 P < DOTP，但Ca 2+络合物除外，其顺序相反。Gd（DO 2A 2 P）的弛豫率在pH 2和7之间减小，但在pH 7 < pH < 12的范围内保持恒定（r（1）= 3.6mM（-1）s（-1））。水的O-17 NMR信号在Gd（DO 2A 2 P）的存在和不存在下（在pH = 3.45和8.5）在274和350 K之间的线几乎是相同的，q = 0的复合物的特征。Ce ~（3+）和Gd ~（3+）与DO_2A_2P配合物的详细动力学研究表明，配合物的形成是缓慢的，并涉及高稳定性的双质子化中间体Ln（H（2）DO_2A_2P）~*。双质子化的中间体重排为最终络合物是OH辅助的过程，但与Ln（DOTA）络合物的形成不同，Ln（H（2）DO 2A 2 P）* 的重排也自发地发生，可能是由于质子之一从环氮转移到膦酸酯基团。配合物的OH-辅助形成速率顺序为DOTA > DO 2A 2 P> DOTP，而Gd ~（3+）配合物的质子辅助解离速率顺序则相反，DOTP > DO 2A 2 P> DOTA。采用二维相关谱（2D COSY）、异质多重量子相干（HMQC）、异质化学位移相关（HETCOR）和交换谱（EXSY）等方法对Eu（DO 2A 2 P）和Lu（DO 2A 2 P）的H-1和C-13 NMR谱进行了归属。Eu（DO_2A_2P）的H-1 NMR谱中出现了两组特征峰，分别为93%和7%的扭曲正方形反棱柱（TSAP）和正方形反棱柱（SAP）。对Lu（DO_2A_2P）配合物的H-1 NMR谱的线形分析表明，Ln（DO_2A_2P）配合物与La（DOTP）配合物的配位异构体间的相互转化活化参数较低，这可能是由于Ln（DO_2A_2P）配合物中羧酸根和膦酸根的尺寸和空间要求不同所致。
A cyclen-based ligand containing trans-acetate and trans-methylenephosphonate pendant groups, H(6)DO2A2P, was synthesized and its protonation constants (12.6, 11.43, 5.95, 6.15, 2.88, and 2.77) were determined by pH-potentiometry and H-1 NMR spectroscopy. The first two protonations were shown to occur at the two macrocyclic ring N-CH2-PO32- nitrogens while the third and fourth protonations occur at the two phosphonate groups. In parallel with protonation of the two -PO32- groups, the protons from the NH+-CH2-PO32- are transferred to the N-CH2-COO- nitrogens. The stability constants of the Ca2+, Cu2+, and Zn2+ (ML, MHL, MH2L, and M2L) complexes were determined by direct pH-potentiometry. Lanthanide(III) ions (Ln(3+)) form similar species, but the formation of complexes is slow; so, "out-of-cell" pH-potentiometry (La3+, Eu3+, Gd3+, Y3+) and competitive spectrophotometry with Cu(II) ion (Lu3+) were used to determine the stability constants. By comparing the log K-ML values with those of the corresponding DOTA (H(4)DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and DOTP (H8DOTP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylenephosphonic acid) complexes, the order DOTA < DO2A2P < DOTP was found for all the metal ion complexes examined here with the exception of the Ca2+ complexes, for which the order is reversed. The relaxivity of Gd(DO2A2P) decreases between pH 2 and 7 but remains constant in the pH range of 7 < pH < 12 (r(1) = 3.6 mM(-1) s(-1)). The linewiths of the O-17 NMR signals of water in the absence and presence of Gd(DO2A2P) (at pH = 3.45 and 8.5) between 274 and 350 K are practically the same, characteristic of a q = 0 complex. Detailed kinetic studies of the Ce3+ and Gd3+ complexes with DO2A2P showed that complex formation is slow and involves a high stability diprotonated intermediate Ln(H(2)DO2A2P)*. Rearrangement of the diprotonated intermediate into the final complex is an OH- assisted process but, unlike formation of Ln(DOTA) complexes, rearrangement of Ln(H(2)DO2A2P)* also takes place spontaneously likely as a result of transfer of one of the protons from a ring nitrogen to a phosphonate group. The order of the OH- assisted formation rates of complexes is DOTA > DO2A2P > DOTP while the order of the proton assisted dissociation rates of the Gd3+ complexes is reversed, DOTP > DO2A2P > DOTA. H-1 and C-13 NMR spectra of Eu(DO2A2P) and Lu(DO2A2P) were assigned using two-dimensional correlation spectroscopy (2D COSY), heteronuclear multiple quantum coherence (HMQC), heteronuclear chemical shift correlation (HETCOR), and exchange spectroscopy (EXSY) NMR methods. Two sets of H-1 NMR signals were observed for Eu(DO2A2P) characteristic of the presence of two coordination isomers in solution, a twisted square antiprism (TSAP) and a square antiprism (SAP), in the ratio of 93% and 7%, respectively. Line shape analysis of the H-1 NMR spectra of Lu(DO2A2P) gave lower activation parameters compared to La(DOTP) for interconversion between coordination isomers.This indicates that the Ln(DO2A2P) complexes are less rigid probably due to the different size and spatial requireents of the carboxylate and phosphonate groups.