Gas-phase behaviour of Ru(II) cyclopentadienyl-derived complexes with N-coordinated ligands by electrospray ionization mass spectrometry: fragmentation pathways and energetics Paulo J. Amorim Madeira 1 * ,† , Tânia S. Morais 2† , Tiago J. L. Silva 2,3 , Pedro Florindo 2 and M. Helena Garcia 2 1 Centro de Química e Bioquímica, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal 2 Centro de Ciências Moleculares e Materiais, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal 3 Centro de Química de Évora, Departamento de Química da Escola de Ciências e Tecnologia da Universidade de Évora, Rua Romão Ramalho 59, 7002-554 Évora, Portugal RATIONALE: The gas-phase behaviour of six Ru(II) cyclopentadienyl-derived complexes with N-coordinated ligands, compounds with antitumor activities against several cancer lines, was studied. This was performed with the intent of establishing fragmentation pathways and to determine the Ru–L N and Ru–L P ligand bond dissociation energies. Such knowledge can be an important tool for the postulation of the mechanisms of action of these anticancer drugs. METHODS: Two types of instruments equipped with electrospray ionisation were used (ion trap and a Fourier transform ion cyclotron resonance (FTICR) mass spectrometer). The dissociation energies were determined using energy-variable collision-induced dissociation measurements in the ion trap. The FTICR instrument was used to perform MS n experi- ments on one of the compounds and to obtain accurate mass measurements. Theoretical calculations were performed at the density functional theory (DFT) level using two different functionals (B3LYP and M06L) to estimate the dissocia- tion energies of the complexes under study. RESULTS: The influence of the L N on the bond dissociation energy (D) of RuCp compounds with different nitrogen ligands was studied. The lability order of L N was: imidazole < 1-butylimidazole < 5-phenyl-1H-tetrazole < 1-benzylimidazole. Both the functionals used gave the following ligand lability order: imidazole < 1-benzylimidazole < 5-phenyl-1H-tetrazole 1-butylimidazole. It is clear that there is an inversion between 1-benzylimidazole and 1-butylimidazole for the experimental and theoretical lability orders. The M06L functional afforded values of D closer to the experimental values. The type of phosphane (L P ) influenced the dissociation energies, with values of D being higher for Ru–L N with 1-butylimidazole when the phosphane was 1,2-bis(diphenylphosphino)ethane. The Ru–L P bond dissociation energy for triphenylphosphane was independent of the type of complex. CONCLUSIONS: The D values of Ru–L N and Ru–L P were determined for all six compounds and compared with the values calculated by the DFT method. For the imidazole-derived ligands the energy trend was rationalized in terms of the increasing extension of the s-donation/p-backdonation effect. The bond dissociation energy of Ru–PPh 3 was independent of the fragmentations. Copyright © 2012 John Wiley & Sons, Ltd. Ruthenium compounds have attracted a great deal of attention largely because of their ability to inhibit the growth of cancer cells. Biological studies carried out in vitro and in vivo revealed that ruthenium-containing compounds were interesting potential candidates for anticancer drugs. [1–6] An important topic of research is the interaction of these compounds with DNA and serum proteins in order to understand the possible mechanisms of action. A fundamental issue for these studies is the ligand exchange chemistry inherent to the Ru-coordination compounds, knowledge of which will certainly help in the overall understanding of the process. Thus, studies of the metal– ligand bond strength together with preferred pathways for fragmentation of the potential drug candidates can be an important tool for determining their mechanisms of action. Electrospray ionization (ESI) is a useful technique for the study of organometallic compounds in the gas phase. This technique [7,8] has gained recognition as a versatile way of transferring intact organometallic complexes from * Correspondence to: P. J. A. Madeira, Centro de Química e Bioquímica, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal. E-mail: pmadeira@fc.ul.pt † These authors contributed equally to this work. Copyright © 2012 John Wiley & Sons, Ltd. Rapid Commun. Mass Spectrom. 2012, 26, 1675–1686 Research Article Received: 15 March 2012 Revised: 10 May 2012 Accepted: 11 May 2012 Published online in Wiley Online Library Rapid Commun. Mass Spectrom. 2012, 26, 1675–1686 (wileyonlinelibrary.com) DOI: 10.1002/rcm.6276 1675