Solvent-induced hydrogen tunnelling in ascorbate proton-coupled electron transfers Ana Karkovic ´ , Cvijeta Jakobušic ´ Brala, Viktor Pilepic ´ , Stanko Uršic ´ ⇑ Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovac ˇic ´a 1, 10000 Zagreb, Croatia article info Article history: Received 16 December 2010 Revised 18 January 2011 Accepted 28 January 2011 Available online 4 February 2011 Keywords: Proton-coupled electron transfer Kinetic isotope effect Hydrogen tunnelling Dynamics Solvent Ascorbate abstract The over-the-barrier proton-coupled electron transfer interaction of an ascorbate monoanion with a hexacyanoferrate(III) ion in water entered into a tunnelling regime in water–1,4-dioxane, water–ethanol and water–acetonitrile mixed solvents. Ó 2011 Elsevier Ltd. All rights reserved. Quantum-mechanical hydrogen tunnelling is of remarkable sig- nificance for chemistry and biochemistry. 1–19 The role of hydrogen tunnelling in such fundamental chemical reactions as hydrogen transfers is well documented 3,4,17–19 and enzymatic C–H activation has been shown to take place via tunnelling. 2–10,13,14,16 Many non- enzymatic H-transfer reactions, including those where there is N–H, S–H and O–H activation 17,18 also involve hydrogen tunnelling. The tunnelling in a condensed phase has sometimes revealed somewhat ‘exotic’ features. Some examples are the appearance of ‘colossal’ kinetic isotope effects (KIEs) ranging up to k H /k D = 455 at room temperature 18a (in the case of N–H–O transfer) in water– acetonitrile solution, and the rearrangement of matrix-isolated hydroxymethylene at 11 K into formaldehyde 19 which involves H-transfer from oxygen to carbon by pure tunnelling through a large energy barrier. Proton-coupled electron transfer (PCET) reactions play a key role in a wide range of biological, biochemical and chemical systems, 20–34 including those related to artificial photosynthesis and solar fuels, 23–27 and nanostructures and interfaces. 33,34 Many processes in biology would not be possible without the coupling of proton and electron motion. 22,24 From a theoretical viewpoint, both sequential electron transfer followed by proton transfer (ET/ PT) or vice versa (PT/ET), and the concerted transfer of these parti- cles could be viewed within a unified theoretical framework 35 of PCET reactions. Hydrogen atom transfer (HAT) reactions, in which the electron and proton transfer simultaneously between the same donor and acceptor 21,22,35 are also included in the framework. However, the concerted transfer of a proton and an electron where there is a single chemical reaction step, direct coupling of the elec- tron and proton in the transfer is the elementary characteristic of an authentic PCET reaction. We report here the observation of solvent-induced tunnelling in the oxidation of an ascorbate monoanion with hexacyanoferrate(III) ions 36–38 (Scheme 1). This PCET reaction 37 in ‘pure’ water does not exhibit hydrogen tunnelling. 37 Very unexpectedly, on the addition of only 1 M of an organic co-solvent, the reaction exhibited hydro- gen tunnelling as demonstrated by the markedly changed isotopic ratios of the Arrhenius pre-factors that are well beyond the semi- classical limits of 0.5–1.4 for the A H /A D ratio in a hydrogen transfer process, 1,3,4,39–41 as well as the isotopic differences in the enthalpies of activation (DD r H à ) between D 2 O and H 2 O, which are greater than the semiclassical value of 5.1 kJ/mol for the difference between zero-point energies E o D  E o H for the dissociation of an O–H bond and are indicative of hydrogen tunnelling in the reaction. 1,3,4,38–40 (Table 1). To the best of our knowledge, the observation of solvent- induced tunnelling is unprecedented. Our findings are as follows: (i) The oxidation of ascorbate monoanions with hexacyanofer- rate(III) ions (Scheme 1) in various water–organic co-solvent mixtures involves a PCET process. This is true for the water– acetonitrile, water–1,4-dioxane, water–ethanol and water–acetone solvents used in this Letter (see Table 1 and Supplementary data (SI)). Thermochemical analysis of the corresponding consecutive (PT/ET or ET/PT) reactions (see also the Supplementary data) 21,38 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.01.142 ⇑ Corresponding author. Tel.: +385 1 4818 306; fax: +385 1 4856 201. E-mail address: stu@pharma.hr (S. Uršic ´). Tetrahedron Letters 52 (2011) 1757–1761 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet