Conformations, Protonation Sites, and Metal Complexation of Benzohydroxamic Acid. A Theoretical and Experimental Study Begon ˜ a Garcı ´a,* ,² Saturnino Ibeas, ² Jose ´ M. Leal, ² Fernando Secco,* ,‡ Marcella Venturini, ‡ Maria L. Senent, § Alfonso Nin ˜ o, | and Camelia Mun ˜ oz | Departamento de Quı ´mica, UniVersidad de Burgos, 09001 Burgos, Spain, Dipartimento di Chimica e Chimica Industriale, UniVersita ` di Pisa, 56126 Pisa, Italy, Departamento de Astrofı ´sica Molecular e Infrarroja, Instituto de Estructura de la Materia, Consejo Superior de InVestigaciones Cientı ´ficas, 28006 Madrid, Spain, and Escuela Superior de Informa ´ tica, UniVersidad de Castilla la Mancha, 13071 Ciudad Real, Spain Received April 30, 2004 A theoretical and experimental study on the structure and deprotonation of benzohydroxamic acid (BHA) has been performed. Calculations at the RHF/cc-pVDZ level, refined by the B3LYP/AUG-cc-pVDZ method, indicate that, in the gas phase, Z amide is the most stable structure of both neutral and deprotonated BHA. 1 H- 1 H nuclear Overhauser enhancement spectroscopy and 1 H- 1 H correlation spectroscopy spectra in acetone, interpreted with ab initio interatomic distances, reveal that BHA is split into the Z and E forms, the [E]/[Z] ratio being 75:25 at -80 °C. The formation of E-E, Z-Z, and E-Z dimers has been detected; in the presence of water, the dimers dissociate to the corresponding monomers. The rates of proton exchange within the Z and E forms and between E and Z were measured by dynamic 1 H NMR in the -60 to 40 °C temperature range; an increase in water content lowers the rate of exchange of the E isomer. The effect of D 2 O on the NMR signals indicates a fast hydrogen exchange between D 2 O and the E and Z amide forms. The sequence of the acid strength at low temperatures is (N)H E ≈ (O)H E < (O)H Z ≈ (N)H Z . The kinetics of complex formation between BHA and Ni 2+ , investigated by the stopped-flow method, show that both neutral BHA and its anion can bind Ni 2+ . Whereas the anion reacts at a “normal” speed, the rate of water replacement from Ni(H 2 O) 6 2+ by neutral BHA is about 1 order of magnitude less than expected. This behavior was interpreted assuming that, in aqueous solution, BHA mainly adopts a closed (hydrogen-bonded) Z configuration, which should open (with an energy penalty) for the metal binding process to occur. Introduction Hydroxamic acids are useful reagents for biological, medical, and industrial applications; 1 particularly interesting is their ability to form stable chelates with metal ions. Despite the effort devoted to elucidate their behavior, hydroxamic acids remain poorly characterized; in fact, a reliable assign- ment of the correct structure is challenging because the several possible conformations strongly depend on concen- tration, temperature, and the nature of the solvent. 2 Earlier theoretical and NMR studies showed that certain hydroxamic acids may adopt either the Z (cis) or E (trans) conformation, separated by a high energy barrier; 3,4 moreover, amide/imide tautomerism has been postulated for the Z and E isomers; 3,5 hence, a general hydroxamic acid RCONHOH is prone to four different forms (Scheme 1). On the basis of theoretical calculations and by analogy with amides, 6 some authors concluded that the Z form becomes stabilized by either * Authors to whom correspondence should be addressed. Tel: +34 947 258819. Fax: +34 947 258831. E-mail: begar@ubu.es (B.G.). Tel.: +39 050 2219259. Fax: +39 050 2219260. E-mail: ferdi@dcci.unipi.it (F.S.). ² Universidad de Burgos. ‡ Universita ` di Pisa. § Consejo Superior de Investigaciones Cientı ´ficas. | Universidad de Castilla la Mancha. (1) Bauer, L.; Exner, O. Angew. Chem., Int. Ed. Engl. 1974, 13, 376- 384. (2) Garcı ´a, B.; Ibeas, S.; Mun ˜oz, A.; Leal, J. M.; Ghinami, C.; Secco, F.; Venturini, M. Inorg. Chem. 2003, 42, 5434-5441. (3) Senent, M. L.; Nin ˜o, A.; Mun ˜oz-Caro, A.; Ibeas, S.; Garcı ´a, B.; Leal, J. M.; Secco, F.; Venturini, M. J. Org. Chem. 2003, 68, 6535-6542. (4) (a) Brown, D. A.; Glass, W. K.; Mageswaran, R.; Girmany, B. Magn. Reson. Chem. 1988, 26, 970-973. (b) Caudle, M. T.; Crumbliss, A. L. Inorg. Chem. 1994, 33, 4077-4085. Inorg. Chem. 2005, 44, 2908-2919 2908 Inorganic Chemistry, Vol. 44, No. 8, 2005 10.1021/ic049438g CCC: $30.25 © 2005 American Chemical Society Published on Web 03/17/2005