title: Ligand Exchange Reaction of Au(I) R-N-Heterocyclic Carbene Complexes with Cysteine.
abstract: The chemotherapy with gold complexes has been attempted since the 90s after the clinical success of auranofin, a gold(I) coordination complex. Currently, the organometallics compounds have shown promise in cancer therapy, mainly in those complexes containing N-heterocylic carbenes (NHC) as a ligand. The present study shows a kinetic analysis of the reaction of six alkyl-substituted NHC with cysteine (Cys), which is taken as an important bionucleophile representative. The first and second ligand exchange processes were analyzed with the complete description of the mechanism and energy profiles. For the first reaction step, which is the rate-limiting step of the whole substitution reaction, the activation enthalpy follows the order 1/Me2 < 2/Me,Et < 4/n-Bu2 < 3/i-Pr2 < 6/Cy2 < 5/t-Bu2, which is fully explained by steric and electronic features. From a steric point of view, the previous reactivity order is correlated with the r(Au-S) calculated for the transition state structures where S is the sulfur ligand from the Cys entering group. This means that longer r(Au-S) leads to higher activation enthalpy and is consistent with the effectiveness of gold shielding from nucleophile attack by bulkier alkyl-substituted NHC ligand. When electronic effect was addressed we found that higher activation barrier was predicted for strongly electron-donating NHC ligand, represented by the eigenvalue of σ-HOMO orbital of the free ligands. The molecular interpretation of the electronic effects is that strong donating NHC forms strong metal-ligand bond. For the second reaction step, similar structure-reactivity relationships were obtained, however the activation energies are less sensitive to the structure.
authors.affiliation: Department of Chemistry, NEQC: Núcleo de Estudos em Química Computacional, Federal University of Juiz de Fora , Campus Universitário Martelos, 36.036-900, Juiz de Fora, Brazil.
authors.forename: H F
authors.initials: HF
authors.lastname: Dos Santos
authors.affiliation: Department of Chemistry, NEQC: Núcleo de Estudos em Química Computacional, Federal University of Juiz de Fora , Campus Universitário Martelos, 36.036-900, Juiz de Fora, Brazil.
authors.forename: M A
authors.initials: MA
authors.lastname: Vieira
authors.affiliation: Department of Chemistry, NEQC: Núcleo de Estudos em Química Computacional, Federal University of Juiz de Fora , Campus Universitário Martelos, 36.036-900, Juiz de Fora, Brazil.
authors.forename: G Y
authors.initials: GY
authors.lastname: Sánchez Delgado
authors.affiliation: Department of Chemistry, NEQC: Núcleo de Estudos em Química Computacional, Federal University of Juiz de Fora , Campus Universitário Martelos, 36.036-900, Juiz de Fora, Brazil.|Federal University of Rio de Janeiro , Campus Macaé, 27.930-560, Macaé, Brazil.
authors.forename: D
authors.initials: D
authors.lastname: Paschoal
mesh_terms: D003545:Cysteine / Q000737:chemistry*; D006046:Gold / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000737:chemistry*; D008024:Ligands; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D015394:Molecular Structure; D050607:Organogold Compounds / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D006571:Heterocyclic Compounds; D008024:Ligands; D050607:Organogold Compounds; C030011:carbene; D006046:Gold; D003545:Cysteine; D008697:Methane