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Observation of the Keto Tautomer of D-Fructose in D2O Using 1H NMR Spectroscopy ⇑ Thomas Barclay A, , Milena Ginic-Markovic A, Martin R

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Observation of the Keto Tautomer of D-Fructose in D2O Using 1H NMR Spectroscopy ⇑ Thomas Barclay A, , Milena Ginic-Markovic A, Martin R Carbohydrate Research 347 (2012) 136–141 Contents lists available at SciVerse ScienceDirect Carbohydrate Research journal homepage: www.elsevier.com/locate/carres Observation of the keto tautomer of D-fructose in D2O using 1H NMR spectroscopy ⇑ Thomas Barclay a, , Milena Ginic-Markovic a, Martin R. Johnston a, Peter Cooper b,c, Nikolai Petrovsky c,d a School of Chemical and Physical Sciences, Flinders University, Adelaide 5042, Australia b Cancer Research Laboratory, ANU Medical School at The Canberra Hospital, Australian National University, Canberra 2605, Australia c Vaxine Pty. Ltd, Flinders Medical Centre, Adelaide 5042, Australia d Department of Endocrinology, Flinders Medical Centre, Adelaide 5042, Australia article info abstract 1 Article history: D-Fructose was analysed by NMR spectroscopy and previously unidentified H NMR resonances were Received 2 August 2011 assigned to the keto and a-pyranose tautomers. The full assignment of shifts for the various fructose tau- Received in revised form 1 November 2011 tomers enabled the use of 1H NMR spectroscopy in studies of the mutarotation (5–25 °C) and tautomeric Accepted 3 November 2011 composition at equilibrium (5–50 °C). The mutarotation of b-pyranose to furanose tautomers in D Oata Available online 12 November 2011 2 concentration of 0.18 M was found to have an activation energy of 62.6 kJ molÀ1. At tautomeric equilibrium (20 °CinD2O) the distribution of the b-pyranose, b-furanose, a-furanose, a-pyranose and Keywords: the keto tautomers was found to be 68.23%, 22.35%, 6.24%, 2.67% and 0.50%, respectively. This tautomeric D-Fructose composition was not significantly affected by varying concentrations between 0.089 and 0.36 M or acid- Carbohydrate structural analysis Mutarotation ification to pH 3. Upon equilibrating at 6 temperatures between 5 and 50 °C there was a linear relation- Tautomeric equilibrium ship between the change in concentration and temperature for all forms. Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. 1. Introduction β-D-Fructofuranose α-D-Fructofuranose HO OH HO OH The exact molecular structure that carbohydrates adopt in solu- O O tion is an area of research that has received considerable investiga- HO HO 1–3 tion because of their relevance to biological systems. Nuclear OH OH magnetic resonance (NMR) spectroscopy is a valuable tool for this HO HO analysis, being used extensively in the conformational analysis of both polysaccharides and simple sugars.1,3–5 In the latter case there is considerable complexity created by the existence of multiple keto D-Fructose tautomeric forms of these sugars in solution.1,5–7 These tautomers OH O possess small ranges of shifts, leading to congested and strongly OH HO coupled spectra, which are particularly problematic in 1H NMR spectroscopy.8,9 Additionally, the combination of congested spec- OH OH tra with the low concentrations of some of the tautomeric forms means that for several biologically important carbohydrates the β-D-Fructopyranose α-D-Fructopyranose 1 resolution of H NMR spectroscopy was insufficient to detect the OH OH minor forms in previous investigations.10,11 Fructose as either a free sugar or in polysaccharide forms, such O OH O OH as inulin, is a highly valuable commercial product. As the free su- OH OH HO HO gar, fructose is an example of a simple reducing sugar that has a HO HO complex 1H NMR spectrum as a result of it existing in at least five 4,12–14 4 tautomers in solution (Fig. 1). At equilibrium in water Figure 1. Tautomeric forms of D-fructose in solution. b-D-fructopyranose (b-pyr) is the preponderant tautomer, followed ⇑ Corresponding author. Tel.: +61 0 8 82013823. by b-D-fructofuranose (b-fur), and then a-D-fructofuranose (a-fur). E-mail addresses: thomas.barclay@flinders.edu.au (T. Barclay), milena. These tautomers have previously been determined to account for ginic-markovic@flinders.edu.au (M. Ginic-Markovic), martin.johnston@ flinders.e- du.au (M.R. Johnston), [email protected] (P. Cooper), nikolai.petrovsky@- 69.6%, 21.1% and 5.7% of the solubilised sugar at room temperature, 14 flinders.edu.au (N. Petrovsky). respectively. The minor tautomers of fructose are a-D-fructopyr- 0008-6215/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.carres.2011.11.003 T. Barclay et al. / Carbohydrate Research 347 (2012) 136–141 137 anose (a-pyr) and the linear keto form of fructose.12–16 The keto Table 1 1 form of fructose has not been previously identified using 1H NMR H NMR shifts for D-fructose equilibrated in D2O 11,15,17–19 a spectroscopy in D2O. The a-pyranose tautomer has also Tautomer Chemical shift (ppm) 1 been difficult to identify using H NMR spectroscopy in aqueous H-1 H-10 H-3 H-4 H-5 H-6 H-60 solution, only being observed in experiments measuring the ano- b-Pyranose 3.71 3.56 3.80 3.90 4.00 4.03 3.71 meric hydroxyl group conducted on samples equilibrated in water, a-Pyranose 3.69 3.65 4.03 3.95 3.88 3.87 3.70 flash frozen, and then melted into DMSO-d6. This relies on the slow b-Furanose 3.59 3.55 4.12 4.12 3.85 3.81 3.68 tautomeric equilibration in DMSO-d6 to provide data for the tauto- a-Furanose 3.67 3.64 4.11 4.00 4.06 3.82 3.70 meric composition in water.18 keto 4.65 4.54 4.64 3.94 3.78 3.85 3.67 a Both of the minor tautomers of fructose have been detected For D-fructose equilibrated in D2O (0.18 M) at 20 °C (fructose shifts calibrated to using 13C NMR spectroscopy.14,15,17,20 However, because of the TPS using internal AcOH). low isotopic ratio of 13C as compared to 12C, these experiments are time consuming. This is particularly the case when trying to re- 13 solve components in low concentrations, and so C NMR spectros- b-furanose and a-furanose have previously been assigned in the copy is not practical for determining changing aqueous tautomeric literature8,11,25 and our 2D NMR analyses confirm those assign- 13,21 ratios, for example in the study of the mutarotation reaction. ments (see Supplementary data). Other smaller resonances were 13 The speed of such C NMR experiments can be increased through first observed by us in the 1H NMR spectra created while monitor- 9,22–24 isotope labelling, but this increases the cost and inconve- ing the hydrolysis of inulin (a polysaccharide comprised of linear 13 nience of the method. Fortunately, NMR technology and methods fructose chains having b-(2?1) glycosidic linkages and capped at have progressed and herein we report the straightforward identifi- the reducing end with glucose26). These small peaks were not ex- 1 cation and quantitation of the keto form of fructose using H NMR plained by the literature for the polymeric starting material or 1D and 2D techniques and subsequently investigate the mutarota- the fructose and glucose hydrolysis products and as such, an inves- tion of fructose and the effect of temperature and pH on its tauto- tigation was made to explain these resonances. A preliminary iden- meric composition in solution. tification of the most obvious of these small resonances, occurring between 4.50 and 4.70 ppm, was made by comparison to 1HNMR 2. Results and discussion shifts reported for erythrulose, a linear tetrose that is analogous to the keto form of fructose at C1–C3.27,28 This enabled assignment of 2.1. NMR spectroscopic analysis H1a, H1b and H3 of the linear keto form. The presence of this iso- mer in the equilibrated mixture was supported by Fourier-trans- 1 A H NMR spectrum for fructose dissolved in D2O and equili- form infrared (FTIR) spectroscopy (see Supplementary data). The brated at 20 °C is shown in Figure 2, and shifts for all tautomers FTIR results showed that fructose equilibrated in D2O(1M)at are listed in Table 1. The largest resonances for b-pyranose, room temperature was found to have a diagnostic peak for the keto 1 Figure 2. H NMR spectrum (600 MHz) for D-fructose equilibrated in D2O (0.18 M) at 20 °C. 138 T. Barclay et al. / Carbohydrate Research 347 (2012) 136–141 tautomer at 1728 cmÀ1,13,21 while freshly dissolved samples did not. Confirmation of the 1H NMR peak assignments for H1a, H1b and H3 was provided by heteronuclear 2D NMR techniques (HMBC and HMQC) for which correlations between the 1H NMR shifts and 13C NMR shifts agreed with the literature 13C NMR assignments for the keto tautomer.15,24 This analysis, combined with further 2D NMR experiments (including homonuclear DQF-COSY and NOESY spec- tra), allowed the full assignment of all resonances for the keto tau- tomer. Similarly, other previously unidentified 1H NMR peaks were assigned to the a-pyranose form on the basis of 2D correlations with the literature values for the 13C NMR spectrum for this tauto- mer.15,17,20 The identification of the keto and a-pyranose tautomers 1 in D2O using H NMR spectroscopy meant that an investigation of the mutarotation reaction and the influences on the tautomeric composition of fructose could be investigated with relative ease. 2.2. Mutarotation The mutarotation of fructose from the exclusively b-pyranose conformation of the crystalline solid4 to the equilibrium composi- Figure 3. Arrhenius plot for the mutarotation of D-fructose in D2O (0.18 M). tion of tautomeric forms in solution is a complex process due to the differing rates of transformations between tautomers.
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