The Synthesis of 1,4,7,10-Tetraazacyclododecanes with Acetylsalicylic Side Arm as Potential Cobalt(II) Fluorophores

New derivatives of 1,4,7,10-tetraazacyclododecanes have been synthesized. The coordination properties toward Co²⁺ of these ligands have been studied by means of spectroscopic methods. The stability constants of cobalt complexes with ligand L-1 and L-2were determined. Unusual complexes with a 2:1 (L:Co²⁺) stoichiometry have been found.     

Chelators for radioimmunotherapy: I. NMR and ab initio calculation studies on 1,4,7,10-tetra(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO4Pr) and 1,4,7-tris(carboxymethyl)-10-(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO3A1Pr)

This work describes the modification of the chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N' ',N' "-tetraacetic acid (DOTA) to improve the rate of metal loading for radioimmunotherapy applications. Previous ab initio calculations predicted that the compounds 1,4,7,10-tetra(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO4Pr) and 1,4,7-tris(carboxymethyl)-10-(carboxyethyl)-1,4,7,10-tetraazacyclododecane (DO3A1Pr) have a ca. 2000-fold improvement in yttrium metal loading rates compared to those of DOTA (Jang, Y. H.; Blanco, M.; Dasgupta, S.; Keire, D. A.; Shively, J. E.; Goddard, W. A., III. J. Am. Chem. Soc. 1999, 121, 6142-6151). In this study, we report the synthesis, purification, (1)H-NMR chemical shift assignments, pK(a) values, metal loading rate measurements, and additional ab initio calculations of these two compounds. The yttrium loading rates of DO3A1Pr are approximately twice those of DOTA, at pH 4.6 and 37 degrees C. The NMR data indicates that the DO4Pr analogue forms a stable type I complex but does not form a type II complex. The new ab initio calculations performed on DO4Pr and DO3A1Pr indicate that the rate-determining step is the deprotonation of the first macrocycle amine proton, not the second proton as assumed in the previous calculations. The new calculations predict an improvement in the rate of metal loading that more closely matches the experimentally observed change in the rate.     

1,4,7,10-Tetraazacyclododecane incorporating salicylic acid moieties synthesis and properties

The synthesis of salicylic acid derivatives of 1,4,7,10-tetraazacyclododecane has been described. The complexing properties of these compounds towards metal cations were investigated by absorption and emission spectroscopy, and ¹H NMR. The X-ray structure of L-2 nitrate is reported.     

Complexing mechanism of the lanthanide cations Eu3+, Gd3+, and Tb3+ with 1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane (dota)-characterization of three successive complexing phases: study of the thermodynamic and structural properties of the complexes by potentiometry, luminescence spectroscopy, and EXAFS

Complexation of the lanthanides Eu3+, Gd3+, and Tb3+ with 1,4,7,10-tetrakis(carboxymethyl)-1,4,7,10-tetraazacyclododecane (dota) has been studied in solution by using potentiometry, luminescence spectrometry, and EXAFS. Three series of successive complexes were characterized by at least two of these methods: the immediate [LnHn(dota)](n-1)+** and intermediate [LnHn(dota)](n-1)+* complexes with 0 相似文献   

SYNTHESIS OF 1,4,7,10-TETRA-N-ALKYL-1,4,7,10-TETRAAZA-CYCLODODECANES

ABSTRACT

We report a concise method for the preparation of 1,4,7,10-tetra-N-alkyl-1,4,7,10-tetraaza-cyclododecanes via deprotonation to the fourfold lithium amide followed by alkylation with alkyl bromides. The procedure circumvents the problem of ammonium salt formation and provides direct access to hydrophobic 1,4,7,10-tetraaza-cyclododecanes in moderate yield. The so obtained hydrophobic macrocycles were converted into the corresponding zinc(II), copper(II), nickel(II) and cobalt(II) complexes, that may be used as water stable Lewis-acids in catalysis and anion extraction.     

Synthesis and acid-base and complex-forming properties of 1,4,7,10-tetrakis(dihydroxyphosphorylmethyl)-1,4,7,10-tetraazacyclododecane

Conclusions A new complexone, 1,4,7,10-tetrakis(dihydroxyphosphorylmethyl)-1,4,7,10-tetraazacyclododecane, has been synthesized and its acid-base and complex-forming properties have been studied. It shows a very high complexing capability and marked selectivity for cations of large ionic radius (Cd²⁺, Hg²⁺, Pb²⁺, La³⁺).Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 844–849, April, 1984.     

1，4，7，10－四氮杂环十二烷及其衍生物的合成

1，4，7，10－四氮杂环十二烷（cyclen）及其衍生物具有优良的配位性能， 在化学及生物医学等领域有广泛的应用潜力，合成高纯度的cyclen非常困难，制备 符合不同要求的cyclen衍生物也有相当的难度，本文着重介绍cyclen及其N－取代 衍生物的各种合成方法，并对不同方法的优缺点进行比较，以供研究者选择。另外 ，还简要介绍了部分重要的cyclen衍生物在不同领域的应用情况。     

Short and straightforward synthesis of 1,7-dimethyl-1,4,7,10-tetraazacyclododecane

A novel, cost-effective, and efficient process for the synthesis of 1,7-dimethyl-1,4,7,10-tetraazacyclododecane 1 has been developed. The two-step process involved the selective conversion of commercially available cyclen to N1,N7-diethylcarbamate cyclen 3 that afforded the title compound in high yield after the reduction step.     

Über Reaktionen Oxygenierter Kobalt (II)-Komplexe. X. 1,4,7,10-Tetraazadecan-kobalt (II) und 4, 7-dimethyl-1,4,7,10-tetraazadecan-kobalt (II) als sauerstoffträger

Reactions of oxygenated cobalt (II) complexes. X. 1,4,7,10-tetraazadecanecobalt (II) and 4,7-dimethyl-1,4,7,10-tetraazadecanecobalt (II) as dioxygen carriers

1 IX: siehe [1].

Oxygenation of cobalt (II) chelates with fourdentate amines such as 1,4,7,10-tetraazadecane (= tad) in aqueous solution yields μ-peroxo-μ-hydroxo-dicobalt (III) complexes. Due to facultative ligand disposition of the amine, 8 different diastereoisomers are possible. Introducing methyl groups in positions 4 and 7 of tad destabilizes the isomers with β-configuration. A crystallized perchlorate, obtained by oxygenation of 4, 7-dimethyl-1,4,7,10-tetraazadecanecobalt (II) (= dmtad) in alcaline solution, proved to be of the expected μ-peroxo-μ-hydroxo type. The ligand configuration is and lattice constants a (ΔΔ/ΛΛ). The X-ray structure was solved by Patterson's method and refined to R = 0.093. The crystals are orthorhombic with space group Pna2₁ and lattice constants a = 14.632 (4), b = 17.525 (5), c = 12.888 (5) Å. In its UV./VIS. absorption spectrum and its solution reactivity the binuclear cation is closely related to oxygenation products obtained with the chelate of unsubstituted tad. The kinetic parameters of the decomposition reaction of the μ-peroxo complexes in acidic solution are compared. The binuclear cations with 4, 7-dimethyl-1,4,7,10-tetraazadecane as ligand are generally more reactive. In slightly alcaline solution isomerization of the μ-peroxo-μ-hydroxo complexes has been observed.     

On the sensitivity of f electrons to their chemical environment

Density functional calculations have been carried out on three families of lanthanide complexes of D3 or C4 symmetry, namely [Ln(H2O)9]3+, [Ln(DPA)3]3-, and [Ln(DOTAM)]3+ (Ln = Y, La, Lu; DPA = pyridine-2,6-dicarboxylate; DOTAM = 1,4,7,10-tetracarbamoylmethyl-1,4,7,10-tetraazacyclododecane), to get some insights concerning the sensitivity of 4f electrons to the surrounding ligands. We show that the electron density accumulations found within 0.7 A of the metal center, that precisely give the opposite image of the coordination sphere as they are located trans with respect to the Ln-ligand bonds, are almost exclusively due the f electrons. This polarization of the 4f electrons in lanthanides complexes has therefore to be considered as a general feature that plays a crucial role in some experimentally observed phenomenons such as the dependency of quadratic hyperpolarizability to the number of f electrons in [Ln(DPA)3]3- complexes that we have evidenced.     

Investigation of the two-step spin crossover complex Fe[5-NO2-sal-(1,4,7,10)] using density functional theory

A quantum chemical study of the Fe[5-NO2-sal-(1,4,7,10)] ((1,10-bis(5-nitrosalicylaldehyde)-1,4,7,10-tetra-ezdecane-O,O',N,N',N' ',N' ')iron(II)) molecule was performed using density functional theory (DFT). Starting from the different X-ray crystallographic structures, geometry optimizations have been performed. These calculations confirmed the conformational isomerism of this complex in each spin states of the molecule ((1)A(1g) and (5)T(2g)). Each employed DFT method (B3LYP, B3LYP*, BP86, HCTH407) reproduced correctly the structural differences between the two calculated conformers when compared to the experimental structures. Furthermore, electronic polarizabilities have been calculated in each spin state and for each conformer. These calculations revealed a higher polarizability in the singlet state in agreement with the measured higher dielectric constant in this state.     

1,4,7,10-四氮杂环十二烷配体的夹心型双核Mn配合物[Mn_2(cyclen)_2(μ-O)_2](ClO_4)_3·4H_2O的量子化学研究

[Mn2(cyclen)2(μ-O)2](ClO4)3.4 H2O(cyclen=1,4,7,10-四氮杂环十二烷)是一种新型的Mn(Ⅲ/Ⅳ)混合价双核配合物.为了了解其详细的结构信息,在其晶体结构基础上进行了量子化学研究;同时在相同水平上计算了优化结构的前沿分子轨道及自然电荷分布.结果表明,采用B3LYP/6-31G(d)方法对其结构进行优化,优化结果与实验结果吻合良好.     

Metal Complexes with Macrocyclic Ligands,VI. The role of substituents on the complexation rate of transition metal ions with several 1,4,7,10-tetraazacyclotridecanes

12,12-Dimethyl-1,4,7,10-tetraazacyclotridecane (I), 11,13-dimethyl-1,4,7,10-tetraazacyclotridecane (II), 11,11,13-trimethyl-1,4,7,10-tetraazacyclotridecane (III) and 1,4,7,10,12,12-hexamethyl-1,4,7,10-tetraazacyclotridecane (IV) have been synthesized and their properties are described. While the Ni²⁺ and Cu²⁺ complexes of I–III have square planar geometries, those of IV are pentacoordinate according to their absorption spectra. Similarly, while the Co²⁺ complex of I is octahedral and readily oxygenated, the analogous complex with IV is pentacoordinate and not sensitive to oxygen. The rate of complexation of these ligands with Cu²⁺ and Ni²⁺ decreases in the order I > II > III ? IV, indicating that the number as well as the position of the methyl groups are important. Finally for Cu²⁺ the formation of the thermodynamic stable end product is slown down by methyl substitution in α-position to the coordinating nitrogen atoms (ligand II and III) so that an intermediate can be observed, whereas with I Cu²⁺ directly forms the end product.     

Improved Synthesis of 10-(2-Alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic Acid Derivatives Bearing Acid-Sensitive Linkers

Alkylation of the hydrobromide salts of 1,4,7-tris(methoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane and 1,4,7-tris(ethoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane with appropriate α-bromoacetamides, followed by hydrolysis, provides convenient access to 10-(2-alkylamino-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid derivatives that contain acid-sensitive functional groups. The utility of the method is demonstrated by improved syntheses of two known 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamides bearing acid-sensitive ω-tritylthio alkyl chains in much greater yields based on cyclen as the starting material.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

On the Synthesis of 1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane

1,4,7-Tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is widely used as an intermediate in the preparation of medically important DO3A and DOTA metal chelators. Despite its commercial availability and importance, the literature describing the preparation and properties of the free base is limited and sometimes unclear. We present herein an efficient synthesis of the hydrobromide salt of 1,4,7-tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane, characterize this compound spectroscopically and by X-ray crystallographic analysis, describe its simple conversion to the corresponding free base, characterize this compound spectroscopically and by X-ray crystallographic analysis, and make observations on the reactivity of this interesting and useful compound.     

Formation kinetics and stability studies on the lanthanide complexes of 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid by capillary electrophoresis

In this study, the kinetic behaviors of four lanthanide ions, Sm(3+), Dy(3+), Yb(3+) and Lu(3+), when mixed with a polyazamacrocyclic chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), were investigated by capillary electrophoresis (CE) in the pH range of 2.0-6.0. At pH 2.0, the formation rate of DOTA-metal complex is extremely low as very little complex was detected after 5 days reaction, whereas almost no free DOTA was found in the mixture of metal ion and DOTA after 4 min at pH 6.0. The second-order kinetic association rate constants of the four lanthanide ions chelates at pH 4.2 were calculated as 1.44 x 10(-2) mM(-1)min(-1), 5.20 x 10(-2) mM(-1)min(-1), 4.56 x 10(-2) mM(-1)min(-1) and 4.54 x 10(-2) mM(-1)min(-1) at 25 degrees C with CE, respectively. In addition, the stability constants of the four lanthanide ions with DOTA were determined by CE at pH 3.0 where approximately 80-90% of the metal ions were associated with DOTA at 25 degrees C. The measured stability constants (log K(f)) of the four DOTA-metal complexes were 23.36, 23.93, 23.39 and 23.06, respectively, and correlated well with published data obtained by different methods. The percentage of metal ion bound with DOTA was evaluated as a function of reactant concentration in pH 6.0 buffer. After adding excess strong acid (0.1 M HCl) to each solution of DOTA-metal was formed at pH 6.0, no released DOTA was detected after 24 h; thus, dissociation of these lanthanide complexes did not occur under strongly acidic conditions. The Ln(DOTA)(-) species for the four DOTA-metal complexes were characterized by electrospray ionization-mass spectroscopy (ESI-MS), and the results correlated with proposed structures.     

Synthesis of novel 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA) derivatives for chemoselective attachment to unprotected polyfunctionalized compounds

A convenient synthesis of novel bifunctional poly(amino carboxylate) chelating agents allowing chemoselective attachment to highly functionalized biomolecules is described. Based on the well known chelator 1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA), we synthesized novel bifunctional chelating agents bearing additional functional groups by alkylating 1,4,7,10-tetraazacyclododecane (cyclen) with one equivalent of para-functionalized alkyl 2-bromophenyl-acetate and three equivalents of tert-butyl 2-bromoacetate. The resulting compounds, which contain an additional carbonyl or alkyne functionality, allow site specific labeling of appropriately functionalized unprotected biomolecules in a rapid manner via click reactions. This was demonstrated by the attachment of our new DOTA derivatives to the somatostatin analogue Tyr3-octreotate by chemoselective oxime ligation and CuI-catalyzed azide-alkyne cycloaddition. Initial biodistribution studies in mice with the radiometalated compound demonstrated the applicability of the described DOTA conjugation.     

Synthesis and Crystal Structure of 1,4,7,10-Tetrakis-（2-（2,3-difluorophenyl）-ethyl）-1,4,7,10-tetraazacyclododecane

The new compound 1,4,7,10-tetrakis-(2-(2,3-difluorophenyl) ethyl) -1,4,7,10-tetra-zacyclododecane 2 has been synthesized and structurally characterized by single-crystal X-ray diffraction. The molecule turned into diamond crystals grown from CH3CN by slow diffusion at room temperature. It crystallizes in the triclinic system,space group P1 with a = 9.543(2) ,b = 10.507(3) ,c = 10.734(3) ,α = 60.979(3) ,β = 81.870(4) ,γ = 84.279(4) o,V = 931.1(4) 3,Z = 1,Dc = 1.307 g/cm3,C40H44F8N4,Mr = 732.79,F(000) = 384,μ = 0.105 mm-1,T = 296(2) K,MoKa radiation(λ = 0.71073) ,R = 0.0494 and wR = 0.0989 for 1589 observed reflections with I > 2σ(I) . Hydrogen bonds and C-H···π stacking interactions in 2 contribute to a supramolecular structure. Moreover,compound 2 has been determined by 1H NMR,13C NMR,MS,IR spectra and elemental analysis.     

17O NMR and density functional theory study of the dynamics of the carboxylate groups in DOTA complexes of lanthanides in aqueous solution

The rotation of the carboxylate groups in DOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) complexes of several lanthanide ions and Sc(3+) was investigated with density functional theory (DFT) calculations and with variable temperature (17)O NMR studies at 4.7-18.8 T. The data obtained show that the rotation is much slower than the other dynamic processes taking place in these complexes. The exchange between the bound and unbound carboxylate oxygen atoms for the largest Ln(3+) ions (La(3+)→Sm(3+)) follows a pathway via a transition state in which both oxygens of the carboxylate group are bound to the Ln(3+) ion, whereas for the smaller metal ions (Tm(3+), Lu(3+), Sc(3+)) the transition state has a fully decoordinated carboxylate group. The activation free energies show a steady increase from about 75 to 125-135 kJ·mol(-1) going from La(3+) to Lu(3+). This computed trend is consistent with the results of the (17)O NMR measurements. Fast exchange between bound and unbound carboxylate oxygen atoms was observed for the diamagnetic La-DOTA, whereas for Pr-, Sm-, Lu-, and Sc-DOTA the exchange was slow on the NMR time scale. The trends in the linewidths for the various metal ions as a function of the temperature agree with trends in the rates as predicted by the DFT calculations.     

Selective monoprotection of 1,4,7,10-tetraazacyclododecane via direct reaction with 4-nitrophenyl active esters

A simple, one-pot preparation of monoprotected 1,4,7,10-tetraazacyclododecanes via an efficient acylation reaction with 4-nitrophenyl active esters has been developed.