trans-[Ru(NO)(NH 3 )P(O  )(OEt) 2 ] 2+ : A new and robust NO/HNO-donor in aqueous media Daniela R. Truzzi, Douglas W. Franco ⇑ Departamento de Química e Física Molecular, Instituto de Química de São Carlos, Universidade de São Paulo, Av. Trabalhador São-carlense, 400, Centro, São Carlos, São Paulo, Brazil article info Article history: Received 14 February 2014 Received in revised form 21 April 2014 Accepted 9 May 2014 Available online 27 May 2014 Keywords: Ruthenium complex Nitric oxide Nitroxyl Phosphite abstract This study describes the synthesis and reactivity in aqueous media of a new potential NO/HNO-donor: trans-[Ru(NO)(NH 3 ) 4 P(O  )(OEt) 2 ](PF 6 ) 2 . This compound exhibits a remarkable robustness over a wide range of pH relative to other similar ruthenium phosphorus nitrosyl complexes. At pH 3.0 and 25 °C, trans-[Ru(NO)(NH 3 ) 4 P(O  )(OEt) 2 ](PF 6 ) 2 decays, yielding free diethyl phosphite with a half-life of 9 days (k = 8.9  10 7 s 1 ). At pH 7.5 and 25 °C, this complex is competitively consumed by diethyl phosphite dissociation (k = 5.15  10 5 s 1 ) and nucleophilic attack at the nitrosyl group (k = 7.25  10 5 s 1 ). Nevertheless, the trans-[Ru(NO)(NH 3 ) 4 P(O  )(OEt) 2 ](PF 6 ) 2 exhibits a half-life of 1.5 h (pH 7.5 and 25 °C) for delivering NO/HNO by electrochemical activation at potentials of 0.50 and 0.80 V versus SCE. The NO liberation from trans-[Ru(NO)(NH 3 ) 4 P(O  )(OEt) 2 ] + ion occurs with k –NO = 0.24 ± 0.01 s 1 , and electrochemical data indicate that k –HNO  k –NO . Ó 2014 Elsevier B.V. All rights reserved. 1. Introduction Ruthenium nitrosyl complexes of the type trans-[Ru(NO)(NH 3 ) 4 L] 3+ are a promising nitric oxide donor (NO-donor) platform [1,2]. In vitro and in vivo tests have successfully established their activity in the hippocampus [3], aorta rings [4–6] and against Chagas dis- ease [7–9], Leishmania major [10] and cancer cells [11]. Among the tested compounds are those in which L = 4-pic, py, pz, imN, imC, nic, ina and P(OEt) 3 [2,6,7,9–12]. Their biological activity is attributed to their NO-donor ability upon reduction, which can be modulated through the judicious choice of L. Phosphorus(III) ligands, such as phosphites (P(OR) 3 ) and phosphines (P(R) 3 ) are interesting due to their high trans effect and trans influence [12–15] properties, which can tune the reduction potential (E NO þ =NO ) and the specific rate constant for NO liberation (k –NO ) of the NO + fragment in these nitrosyl complexes [4,5,14]. Further- more, due to the possibility of varying the nature of R, additional tuning of the phosphorus atom r and p donor/acceptor abilities and the complex solubility can be achieved. For example, trans-[Ru(NO)(NH 3 ) 4 P(OEt) 3 ](PF 6 ) 3 exhibits E NO þ =NO ¼0:24 V versus SCE and k –NO = 0.97 s 1 [14], characteris- tics that are relevant for situations in which fast nitric oxide liber- ation is required. In addition, after NO-donation, the resulting complex ion trans-[Ru(H 2 O)(NH 3 ) 4 P(OEt) 3 ] 2+ is able to react with nitrite (NO 2  ) and, through an acid–base equilibrium, convert NO 2  into NO + ligand [16], renewing the NO source. This system would be very interesting in hypoxic conditions, where oxygen- dependent NO synthases may be inhibited, by providing an alter- native pathway for the production of nitric oxide through nitrite conversion [17]. It is interesting to recall that nitrite is present in plasma at an average concentration of 114 ± 11 nmol L 1 [18], and the reduction potential of the [RuNO] 3+ fragment is accessible to biological reductors [9,10,14]. Despite the interesting characteristics of trans-[Ru(NO)(NH 3 ) 4 P(OEt) 3 ](PF 6 ) 3 as a NO-donor, it is not stable for practical applica- tion in biological media (pH P 5) due to nucleophilic attack at the triethyl phosphite ligand and at the nitrosonium group [19], decreasing the NO-donation efficiency of this compound. Recently, phosphorous acid (the simplest phosphite) was cho- sen as a probe in which nucleophilic attack on the phosphite mol- ecule is avoided by the absence of carbon chains [20]. In this case, the trans-[Ru(NO)(NH 3 ) 4 P(O  )(OH) 2 ] 2+ undergoes isomerisation promoted by the nitrosyl group, yielding trans-[Ru(NO)(NH 3 ) 4 (O)P(OH) 2 ] 2+ and trans-[Ru(NO)(NH 3 ) 4 (O)P(H)(OH) 2 ] 3+ ions in aqueous media. This isomerisation reaction also would reduce the compound NO-donor efficiency [20]. Therefore, this work presents a synthesis and reactivity study in aqueous media of the new trans-[Ru(NO)(NH 3 ) 4 P(O  )(OEt) 2 ](PF 6 ) 2 complex. Diethyl phosphite is an interesting alternative to the phosphorus(III) ligand because, unlike triethyl phosphite and phos- phorous acid, it maintains both the dissociable proton (hydroxyl group) and the ethyl groups (electron donors). http://dx.doi.org/10.1016/j.ica.2014.05.010 0020-1693/Ó 2014 Elsevier B.V. All rights reserved. ⇑ Corresponding author. Tel./fax: +55 16 33739976. E-mail address: douglas@iqsc.usp.br (D.W. Franco). Inorganica Chimica Acta 421 (2014) 74–79 Contents lists available at ScienceDirect Inorganica Chimica Acta journal homepage: www.elsevier.com/locate/ica