Transmétallation | EPFL Graph Search

La transmétallation est un type générique de réaction en chimie organométallique qui consiste en l'échange de deux ligands entre deux centres métalliques. Les centres métalliques ne sont pas nécessairement les mêmes, et les ligands R et R' peuvent être organiques ou non. La réaction de double déplacement y est conceptuellement rattachée. La transmétallation est une étape importante dans la synthèse de nombreux composés organométalliques. Les complexes carbéniques N-hétérocycles d'argent sont ainsi facilement formés et sont parfois utilisés pour transférer les ligands carbéniques à d'autres complexes métalliques à ligands labiles comme l'acétonitrile ou le 1,5-cyclooctadiène. Ainsi, par exemple : :2 L-H+ + Ag2O → L2Ag+...AgX− (X = contre-ion du ligand précurseur L-H+) :L-Ag...AgX + PdCl2MeCN2 → PdL2Cl2 Ce type de réaction apparaît aussi fréquemment dans les cycles catalytiques de nombreuses réactions organiques comme la réaction de Stille et le couplage de Negishi. Références

Synthesis and structure-activity studies of well-defined nickel complexes as catalysts for cross coupling of alkyl electrophiles

Pablo Marcelo Perez Garcia

This dissertation is devoted to the development of well-defined nickel complexes as catalysts for cross coupling processes of alkyl electrophiles. In chapter one, we summarize recent cross coupling methodologies of alkyl electrophiles using nickel based catalysts. The description of each study includes the coupling conditions, the substrate scope and the mechanistic considerations. In chapter two, we report the development of high diastereoselective alkyl-alkyl Kumada coupling method for 1,3- and 1,4-substituted cyclohexyl halides and tetrahydropyrans using an amido bis(amine) nickel complex "Nickamine" as catalyst. The stereochemical properties of the starting materials and of the coupling products were determined by NMR techniques. The mechanistic investigations of the coupling provided evidence of a reversible activation of the alkyl halide. In chapter three, we present the synthesis of new bidentate amido â amine ligands derived from 2,5-dimethylpyrrolidine or Î±-methylbenzylamine. The ligands were used to synthesize well-defined bidentate nickel complexes by transmetallation from the corresponding lithium complexes. A complex having an Î±-methylbenzylamine derived ligand and 2,4-lutidine as co-ligand was an effective catalyst for the coupling of non-activated secondary iodides with alkyl Grignard reagents. An enantiomerically pure version of this complex was synthesized and no racemization was observed during the synthesis. The chiral complex showed no asymmetric induction capacity as a cross coupling catalyst. In chapter four, the synthesis of new amido bis(amine) pincer ligands derived from Î±-methylbenzylamine or pyrrolidine are described. The metallation of a NNN ligand derived from Î±-methylbenzylamine was not possible by transmetallation from the corresponding lithium complex or by oxidative addition from the corresponding chloroamine. A well-defined pincer nickel complex was synthesized by Li â Ni transmetallation using a NNN ligand having dimethyl amino and pyrolidine donors. Crystal structure analysis shows that the pyrrolidine donor is slightly less hindered. This complex is an effective catalyst for alkyl-alkyl and alkyl-aryl Kumada coupling of non-activated primary and secondary alkyl halides. The coupling process shows good functional group tolerance. This is the first time that a well-defined nickel pincer complex shows high catalytic activity for Kumada coupling reactions of sterically hindered alkyl substrates. In chapter 5, a well-defined nickel pincer complex bearing an alkyl amine donor is synthesized. The complex is able to catalyzed direct coupling of non-activated primary halides with terminal alkynes at room temperature. The catalysis has a good substrate scope and high functional group tolerance. Kinetic data suggest that the new pincer ligand is hemilabile, and the dissociation of the alkyl amine donor is the turnover-determining step of the catalysis. An intermediate Ni-alkynyl species has been isolated and structurally characterized. The reactivity of this species gives insight into the nature of the active species for the activation of alkyl halide.

EPFL2015

Physicochemical Properties of the High-Field MRI-Relevant [Gd(DTTA-Me)(H2O)2]− Complex

Lothar Helm, Loïck Moriggi, Cora Prestinari

To study the physicochemical properties of the DTTA chelating moiety (H4DTTA = diethylenetriaminetetraacetic acid = N,N′-[iminobis(ethane-2,1-diyl)]bis[N-(carboxymethyl)glycine]), used in several compounds proposed as magnetic resonance imaging (MRI) contrast agents, the methylated derivative H4DTTA-Me (N,N′-[(methylimino)bis(ethane-2,1-diyl)]bis[N-(carboxymethyl)glycine]) was synthesized. Protonation constants of the ligand were determined in an aqueous solution by potentimetry and 1H NMR pH titration and compared to various DTTA derivatives. Stability constants were measured for the chelates formed with Gd3+ (log KGdL = 18.60 0.10) and Zn2+ (log KZnL = 17.69 0.10). A novel approach of determining the relative conditional stability constant of two paramagnetic complexes in a direct way by 1H NMR relaxometry is presented and was used for the Gd3+ complexes [Gd(DTTA-Me)(H2O)2]− (L1) and [Gd(DTPA-BMA)(H2O)] (L2) [KL1/L2*(at pH 8.3, 25 °C) = 6.4 0.3]. The transmetalation reaction of the Gd3+ complex with Zn2+ in a phosphate buffer solution (pH 7.0) was measured to be twice as fast for [Gd(DTTA-Me)(H2O)2]− in comparison to that for [Gd(DTPA-BMA)(H2O)]. This can be rationalized by the higher affinity of Zn2+ toward DTTA-Me4− if compared to DTPA-BMA3−. The formation of a ternary complex with L-lactate, which is common for DO3A-based heptadentate complexes, has not been observed for [Gd(DTTA-Me)(H2O)2]− as monitored by 1H NMR relaxometric titrations. From the results, it was concluded that the heptadentate DTTA-Me4− behaves similarly to the commercial octadentate DTPA-BMA3− with respect to stability. The use of [Gd(DTTA-Me)(H2O)2]− as an MRI contrast agent in vitro and in animal studies is conceivable, mainly at high magnetic fields, where an increase of the inner-sphere-coordination water actually seems to be the most certain way to increase the relaxivity.

2008

Highly efficient MRI contrast agents

Loïck Moriggi

Since contrasts agents are used in magnetic resonance imaging (MRI), numerous efforts have been done to increase their relaxivity (parameter allowing to quantify contrast agent efficiency). Few years ago, the Merbach group developed the chelating agent DTTA (H4DTTA = diethylenetriaminetetraacetic acid = N,N'-[iminobis(ethane-2,1-diyl)]bis[N-(carboxymethyl)glycine]), which contains when complexed with gadolinium(III) in aqueous solution two inner-sphere coordination sites for water molecules. This chelate unit complexed with gadolinium(III) presents also a relatively fast inner-sphere water exchange rate which is favorable for the relaxivity. Three types of compounds have been studied in this thesis, all of them containing the DTTA chelate unit. The first is considered to be the monomer and allows studying the stability of the chelate unit. The second is a close derivative to the metallostar compound {Fe[Gd2bpy-DTTA2(H2O)4]3}4-, when the iron(II) central ion is replaced by a ruthenium(II) ion. The third is represented by the DTTA thiol derivative coated to gold nanoparticles. The first part of this thesis, chapter II, is thus the study of the physicochemical properties of the DTTA chelating moiety. For this purpose, the methylated derivative H4DTTA-Me (N,N'-[(methylimino)bis(ethane-2,1-diyl)]bis[N-(carboxymethyl)glycine]) was synthesized. Protonation and deuteration constants of the ligand were determined in an aqueous solution by potentimetry and 1H NMR pH titration and compared to various DTTA derivatives. Stability constants were measured for the chelates formed with Gd3+ (log KGdL = 18.60 ± 0.10) and Zn2+ (log ΚZnL = 17.69 ± 0.10). A novel approach of determining in a direct way the relative conditional stability constant of two paramagnetic complexes by 1H NMR relaxometry is presented and was used for the Gd3+ complexes [Gd(DTTA-Me)(H2O)2]- (L1) and [Gd(DTPA-BMA)(H2O)] (L2) [Κ*L1/ L2 (at pH 8.3, 25°C) = 6.4 ± 0.3]. The transmetalation reaction of the Gd3+ complex with Zn2+ in phosphate buffer solution (pH 7.0) was measured to be twice as fast for [Gd(DTTA-Me)(H2O)2]- in comparison to that for [Gd(DTPA-BMA)( H2O)]. This can be rationalized by the higher affinity of Zn2+ toward DTTA-Me4- if compared to DTPA-BMA3-. The formation of a ternary complex with L-lactate, which is common for DO3A-based heptadentate complexes, has not been observed for [Gd(DTTA-Me)( H2O)2]- as monitored by 1H NMR relaxometric titrations. From the results, it was concluded that the heptadentate DTTA-Me4- behaves similarly to the commercial octadentate DTPA-BMA3- with respect to stability. Considering recent suspicions against [Gd(DTPA-BMA)( H2O)] for being involved in Nephrogenic Systemic Fibrosis (NSF) disease, DTTA-type chelates will not be admitted as contrast agents in clinical MRI. However, their use in vitro and in animal studies is absolutely conceivable, mainly at high magnetic fields, where the increase of inner-sphere-coordination water actually seams to be the only promising way to increase the relaxivity markedly. The second part of this thesis, chapter III, presents the synthesis in aqueous solution and the magnetic and optical properties of the Ru(II)-based metallostars Na4{Ru[Ln2bpy-DTTA2(H2O)4]3} (Ln = Y, Gd, and Eu). The synthesis and the purification of the new, highly stable heptametallic entities have been optimized for the diamagnetic Y3+ complex and followed by 1H NMR. The europium(III) ruthenium-based metallostar {Ru[Eu2bpy-DTTA2(H2O)4]3}4- displays sensitized 5D0→7FJ luminescence upon excitation of the tris-(2,2'-bipyridyl)ruthenium(II) unit in both the ultraviolet around 293 nm, as well as in the visible around 450 nm (1MLCT state). NMRD profiles at two temperatures (25°C and 37°C) were measured on the {Ru[Gd2bpy-DTTA2(H2O)4]3}4-. NMRD profiles of the ruthenium-based {Ru[Gd2bpy-DTTA2(H2O)4]3}4- and iron-based {Fe[Gd2bpy-DTTA2(H2O)4]3}4- metallostars were fitted with SBM theory coupled to the model-free Lipary-Szabo method for internal motion as well as with the modified Florence approach. Comparison of both fitting methods shows that the Florence approach is able to fit NMRD profiles up to 100 MHz, fails however at higher frequencies because it does not account for internal motion. Overall, the results detailed point to the heptametallic self-assembled edifices being potential relaxivity and luminescence bimodal bioprobes. The third part of this thesis, chapter IV, is devoted to nano objects. We developed small, water-dispersible, stable nanoparticles covalently linked to Ln-DTTA derivative complexes (with Ln=Gd and Y) on the surface. Characterizations of these DTTA thiol capped gold nanoparticles (Gd-DtNP) using TEM images, dynamic light scattering technique and STEM with EDX analysis indicate 1.5-15.5 nm particle diameters, coated by Ln-Dt complexes on the surface. Molecular modeling shows a rough distance in the range of 1.3 nm between the lanthanide(III) ion and gold core surface and the structure that possess Ln-DtNP offers to lanthanide(III) a tightly bonding on the surface of particles. Accurate Au, Gd and Y concentrations have been determined by ICP-MS technique. Bulk magnetic susceptibility of samples with different gadolinium concentration has been established following the Evans method and no significant magnetic contribution can be attributed to the gold core. NMRD profiles of Gd-DtNP at 25°C show very high relaxivities and present broad relaxivity humps indicating very large systems with slow rotational motion. The modified Florence approach allows fitting well the experimental NMRD profil of Gd-DtNP, and the fitted electronic relaxation parameters are in good coherence with what was expected from the Ru-based metallostar values. Our Gd-DtNP systems are very rigid nano-object.

EPFL2008