15N and 31P NMR Insights into LactamâLactim Tautomerism Activity

Article pubs.acs.org/JPCB

15

N and 31P NMR Insights into Lactam−Lactim Tautomerism Activity Using cyclo-μ-Imidopolyphosphates

Hideshi Maki,* Daisuke Kataoka, and Minoru Mizuhata Department of Chemical Science and Engineering, Graduate School of Engineering, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan

Downloaded by UNIV OF SHEFFIELD on September 7, 2015 | http://pubs.acs.org Publication Date (Web): September 2, 2015 | doi: 10.1021/acs.jpcb.5b07083

S Supporting Information *

ABSTRACT: The effects of the molecular structure and solution pH on compounds prone to lactam−lactim tautomerism have been evaluated by 15N NMR spectroscopy. The lactam−lactim tautomerism activities of cP3O6(NH)33− and cP4O8(NH)44− showed a significant pH dependence, with the process being inactivated under alkaline conditions because of the decrease in the number of hydrogen atoms by the deprotonation of the anions. The tautomerism was activated under the acidic conditions by the increase in the number of dissociative hydrogen atoms resulting from the protonation of the anions. cP3O6(NH)33− has much more of a planar molecular structure than cP4O8(NH)44−, meaning that the hydrogen atoms in cP3O6(NH)33− would be delocalized over the entire structure to a greater extent than those in cP4O8(NH)44−. This difference in the distribution of hydrogen atoms would result in the lactam−lactim tautomerism activity of cP3O6(NH)33− being higher than that of cP4O8(NH)44−. The results have shown that the following factors are critical to the achievement of an efficient anhydrous proton conductor: (1) the regular molecular arrangement of highly planar molecules; (2) the existence of a large number of dissociative protons in a molecule; and (3) a molecular structure with a small energy barrier for the structural rearrangement required of the tautomerism process.

1. INTRODUCTION Proton conductors have received considerable attention during the last two decades from researchers in various areas because of their potential applications in diverse electrochemical devices, including hydrogen sensors,1,2 molecular switches,3−7 fuel cells,8−12 electrochromic devices (ECDs),13 and supercapacitors.14,15 Proton conductors composed of a solid oxide generally exhibit high proton conductivity at temperatures above 600 °C as this favors hopping of the protons through the solid oxide’s oxygen atoms.9 However, the proton conductivity of these materials decreases sharply at low temperature. In contrast, conventional hydrated perfluorinated sulfonic membranes such as Nafion use water molecules as charge transport carriers16−18 and require high levels of hydration. These materials are therefore limited to operating temperatures below 90 °C.19,20 On the basis of these limitations, there has been considerable interest in developing new high-performance anhydrous proton conductors that can operate in the intermediate temperature range (100−300 °C).8 Five-membered N-heterocyclic polymers (e.g., imidazole derivatives) in particular have been studied extensively as anhydrous proton conductors12,21−24 because the proton transport processes in © XXXX American Chemical Society

these systems occur between neighboring heterocyclic molecules through intermolecular hydrogen bonding interactions. Furthermore, imidazole derivatives contain two nitrogen atoms and can therefore act as a proton acceptor and donor during proton transport. Despite the interesting properties of heterocyclic systems as proton transporters, few studies exist on the impact of their pH and molecular properties on their lactam−lactim tautomerism activity. When the tautomerism activity is high, the hydrogen atoms move around in a molecule or move between molecules, and the rate of tautomerism is fast. However, when the tautomerism activity is low, the hydrogen atoms localize to a specific coordination atom, and the rate of tautomerism is slow. Further work is needed in this area not only to develop a better understanding of lactam−lactim tautomerism in heterocyclic rings but also to better understand amide−imidic acid tautomerism, which is based on intramolecular proton transfer between a nitrogen donor and an oxygen donor (e.g., in nucleobases guanine, thymine, and Received: July 22, 2015 Revised: August 19, 2015

A

DOI: 10.1021/acs.jpcb.5b07083 J. Phys. Chem. B XXXX, XXX, XXX−XXX

Article

The Journal of Physical Chemistry B

cyclo-tri-μ-imidotriphosphate tetrahydrate, 15NNa3cP3O6(NH)3·4H2O (15N-Na3cP3O6(NH)3), and 15N-labeled (98 atom %) tetrasodium cyclo-tetra-μ-imidotetraphosphate dihydrate, 1 5 N-Na 4 cP 4 O 8 (NH) 4 ·2H 2 O ( 1 5 NNa4cP4O8(NH)4), were prepared by an improvement of the previously reported method25 as illustrated in Scheme S1 (Supporting Information). Phosphorus pentachloride (PCl5, 8.7 g) was dissolved in 23 mL of chlorobenzene, C6H5Cl, in a three-necked round-bottomed flask at 126 °C. 15NH4Cl (3.55 g) which was ground in detail with a ball mill after 12 h of drying in a vacuum at 110 °C was added to the C6H5Cl solution of PCl5. This mixture solution was reacted at 126 °C for 17 h with stirring at a speed of 800 rpm. After cooling at room temperature, unreacted 15NH4Cl was filtrated out of the reaction solution, and the separation of the reaction mixture from the filtrate was carried out by distillation under reduced pressure. After cooling an oily residue including needlelike crystals at room temperature, 2.47 g of the mixture of 15Nlabeled (98 atom %) hexachlorocyclotriphosphazene (phosphonitrilic chloride trimer), 15N-(PNCl2)3, and 15N-labeled (98 atom %) octachlorocyclotetraphosphazene (phosphonitrilic chloride tetramer), 15N-(PNCl2)4, as needlelike crystals was filtered off by suction filtration and washed with acetone in order to remove unreacted PCl5. The mixture of 15N-(PNCl2)3 and 15N-(PNCl2)4 was dissolved in 24 mL of 1,4-dioxane in a three-necked round-bottomed flask at 45 °C. Sodium acetate trihydrate (30 g) was dissolved in 48 mL of water. This solution was heated to 45 °C and then added to the mixture of 15N(PNCl2)3 and 15N-(PNCl2)4 solution. This solution was reacted at 45 °C for 4 h with stirring at a speed of 90 rpm. After standing overnight in a refrigerator, a white precipitate of a mixture of 15N-Na3cP3O6(NH)3 and 15N-Na4cP4O8(NH)4 formed in the solution. Products 15N-Na3cP3O6(NH)3 and 15 N-Na4cP4O8(NH)4 have similar molecular structures as well as similar physical and chemical properties and are difficult to separate by conventional recrystallization. Furthermore, fractionation by the ion-exchange resin drastically decreases the yields of the products. Hence in this study the product mixture was separated and purified by a pH-controlled recrystallization process by applying the pH dependence of the difference in the solubility of Na3cP3O6(NH)3 and Na4cP4O8(NH)4 as illustrated in Scheme S2 (Supporting Information) as well as our previous report.37 The product mixture (1.59 g) was dissolved in 45 mL of water, adjusted to pH 2.5 with nitric acid, and 18 mL of acetone was added to this solution, and then 15NNa4cP4O8(NH)4 precipitated. The precipitate was collected by suction filtration, and then the filtrate was adjusted to pH 6.7 with sodium hydroxide. Acetone (24 mL) was added to this solution, and 15N-Na3cP3O6(NH)3 precipitated. The precipitate was collected by suction filtration. Each white precipitate was washed with 5 mL of ethanol followed by 10 mL of acetone. The overall yields were 0.47 g, 10.1% for 15N-Na4cP4O8(NH)4· 2H2O and 0.72 g, 13.7% for 15N-Na3cP3O6(NH)3·4H2O, respectively. The purity was determined by XRD, HPLC, and 31 P NMR and was found to be over 98%. The XRD patterns of s y n t h e s i z e d 1 5 N -Na 3 cP 3 O 6 ( NH ) 3 · 4H 2 O an d 1 5 NNa4cP4O8(NH)4·2H2O are shown in Figure S1 (Supporting Information). 2.2. 15N NMR Measurements. All 15N NMR spectra were recorded on a Varian INOVA400 (9.39T) superconducting Fourier transform pulse NMR spectrometer with a 5 mm tunable broad-band probe at 40.533 MHz and 22.0 ± 1.0 °C. The acquisition time was 1.02 s, and the FID were collected in

cytosine) because these processes can significantly impact these systems’ proton conductivity properties. Imidophosphate derivatives are phosphorus-, oxygen-, and nitrogen-(PON) containing compounds25 that can be used as highly water-soluble flame retardants. They can also assume many different molecular shapes (i.e., cyclic, short-chain, and long-chain polymers)25−30 and form stable complexes with various metal cations.26,27,29,31−33 Furthermore, cyclo-μ-imidophosphates Na3cP3O6(NH)3 and Na4cP4O8(NH)4 possess several interesting properties regarding their application as proton conductors, including (1) a high concentration of dissociation protons that can perform as charge transport carriers34 through a lactam−lactim tautomerism process, as shown in Scheme 1, where H+ complexes of the cyclo-μ-


Scheme 1. Structural Formulas and Lactam−Lactim Tautomerism Equilibria in cyclo-μ-Imidophosphate Anions, cP3O6(NH)33− and cP4O8(NH)44−

imidophosphate anions can contain six (for H3cP3O6(NH)3) or eight (for H4cP4O8(NH)4) dissociated protons per molecule; (2) six (for Na3cP3O6(NH)3) or eight (for Na4cP4O8(NH)4) oxygen atoms per cyclic molecular skeleton that could act as both proton acceptors and donors; and (3) lower pKa values than for imidazole (pKa1 = 7.18, pKa2 = 14.5235) for the cP3O6(NH)33− and cP4O8(NH)44− anions (3.22 and 3.7926,36), affording them better proton-donating properties. We investigated the influence of the solution pH and cyclic molecular structure on teh lactam−lactim tautomerism activity of cyclo-μimidopolyphosphates using 15N NMR. We also investigated the feasibility of developing an anhydrous proton conductor based on cyclo-μ-imidophosphates through lactam−lactim tautomerism. We expect that the results of this 15N NMR study will provide deeper insights into lactam−lactim tautomerism and its impact on the proton transfer mechanism and will guide the practical molecular design and synthesis of novel anhydrous proton conductors.

2. EXPERIMENTAL METHODS 2.1. Chemicals. 2.1.1. Chemicals Used. All chemicals used in this work were of analytical grade. 15N-labeled(98 atom %) ammonium chloride, 15NH4Cl, was purchased from Taiyo Nippon Sanso Corporation, and octachlorocyclotetraphosphazene (phosphonitrilic chloride tetramer), (PNCl2)4, was kindly offered by Otsuka Chemical Co., Ltd. All other reagents were purchased from Nacalai Tesque Inc. 2.1.2. Synthesis of 1 5 N-Labeled (98 Atom %) Na 3 cP 3 O 6 (NH) 3 ·4H 2 O and 15 N-Labeled (98 Atom %) Na4cP4O8(NH)4·2H2O. 15N-labeled(98 atom %) trisodium B


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buffer solutions. From eqs 1 and 2, the following relationship can be addressed:40

8196 data points and were used with a sweep width of 8100 Hz (199.8 ppm); that is, the digital resolution in the frequency dimension was 1.977 Hz (0.0488 ppm). The Lorentzian linebroadening factor of 1.0 Hz was applied to the total free induction decay prior to Fourier transformation. In order to avoid saturation of the resonances, the intervals between each pulse irradiation were 5.0 s or more.38 The chemical shifts were recorded against a second-order external standard of 90% formamide + 10% dimethyl sulfoxide-d6 for −267.5 ppm (nitromethane as a first-order standard is 0 ppm).39 All sample solutions contain 10% D2O for field-frequency locking. All spectra were recorded in the presence and absence of 1H decoupling. A proper quantity of ca. 0.1 mol·L−1 15NNa3cP3O6(NH)3 or 15N-Na4cP4O8(NH)4 added to an NMR tube with a 5 mm outside diameter (Wilmad-LabGlass 528-PP8). Any supporting electrolyte has not been added to the measurement solutions. Small aliquots of HClO4 or NaOH aqueous solution were added by a PTFE tubule in order to define the pH of the solutions, and the pH meter readings were recorded just before the NMR measurements by using a microcombination glass electrode (Horiba 6069-10C) connected to a pH meter (Orion 250A). The electrode was calibrated at pH 4, 7, and 9 with a phthalate buffer, a phosphate buffer, and a tetraborate buffer, respectively. 2.3. 31P NMR Measurements. All 31P NMR spectra were recorded on a Varian INOVA400 (9.39T) superconducting Fourier transform pulse NMR spectrometer with a 5 mm probe specialized for 1H, 13C, 19F, and 31P nuclei at 161.908 MHz. The acquisition time was 3.37 s, and the FID was collected in 65 536 data points and was used at a sweep width of 19 400 Hz (119.8 ppm); that is, the digital resolution in the frequency dimension was 0.592 Hz (0.0037 ppm). The Lorentzian linebroadening factor was 0.25 Hz. In order to avoid saturation of the resonances, the intervals between each pulse irradiation were 5.0 s or over.38 The chemical shifts were recorded against an external standard of 75% H3PO4 in 10% D2O. All sample solutions contain 10% D2O for field-frequency locking. All spectra were recorded in the absence of 1H decoupling. A proper quantity of ca. 0.1 mol·L−1 Na3cP3O6(NH)3 or Na4cP4O8(NH)4 was added to the 5 mm NMR tube. All other details are the same as for 15N NMR measurements. 2.4. pH of NMR Measurement Solutions. In the pH of the H2O/D2O mixture solvent, the following factors should be considered: (1) the difference in the self-dissociation constant of H2O and D2O and (2) the relation between the activities of H+ and D+ ions.40 The negative logarithms of the selfdissociation constants for pure solvents are pKWH = 13.995 and pKWD = 14.951, respectively.41 From the self-dissociation equilibria for these pure solvents with identical molar fractions of protonated and deprotonated solvent, the following relationship can be established: pD = pH ×

pH = (pH* + 0.44) ×

= 0.936 × pH* + 0.41 (3)

H⎫ ⎧ pKW ⎬ pH = 0.9 × pH* + 0.1 × ⎨(pH* + 0.44) × D pKW ⎩ ⎭

= 0.994 × pH* + 0.04

(4)

All pH values of the NMR measurement solutions in this study were compensated for by eq 4.

3. RESULTS AND DISCUSSION The direct observation of prototropic equilibria (i.e., prototropic tautomerism equilibria) can be difficult to achieve using general spectroscopic methods because of the small energy differences between the isomers and the minor perturbations in their structures, which give rise to the intramolecular bonding interactions. NMR analysis not only provides a high resolution of free energies but also displays high sensitivity to the prototropic equilibria being analyzed, as well as excellent sensitivity to 1H nuclei. NMR spectroscopy is therefore extremely useful for the elucidation of prototropic equilibria in tautomerism processes. The high resolution of free energies of NMR for dipolar 15N nuclei is similar to those of 1H and 13C NMR.44,45 Furthermore, it was envisaged that information pertaining to the inter- and intramolecular proton bonding sites of compounds, as well as the dynamic behaviors of protons, could be observed by the spin−spin coupling interactions between the 15N and 1H nuclei. However, the natural abundance of the 15N nucleus is only 0.37%, and its gyromagnetic ratio is one of the lowest of all of the NMRsensitive nuclei. For this reason, the relative sensitivity of 15N NMR is about 1/1000 of that of 1H NMR.44,45 Unfortunately, however, the hydrogen atoms that are frequently transferred through intermolecular and intramolecular processes during lactam−lactim tautomerism form weak bonds to the nitrogen atoms of imidopolyphosphates. The formation of these weak bonds could therefore undermine any of the potential improvements in the sensitivity resulting from the polarization transfer effect between 15N and 1H nuclei (i.e., INEPT and DEPT44−47). With this in mind, we synthesized a series of 15N isotopically enriched cyclo-μ-imidophosphates to develop a deeper understanding of the lactam−lactim tautomerism process by 15N NMR. It is noteworthy that an 15N isotopic enrichment of almost 100% is desirable because the coexistence of 14N and 15N nuclei in the same molecule (i.e., the coexistence of 14N-P-14N, 14N-P-15N, and 15N-P-15N bonding interactions) can complicate the spin−spin coupling interactions between 15N and 31P nuclei. The coexistence of 14N and 15 N nuclei in the same molecule can also lead to the occurrence of interfering isotopic effects, which can lead to a decrease in the NMR resolution and the misassignment of the NMR signals. Representative 1H-decoupled 15N and 31P NMR spectra of the 15N-cP3O6(NH)33− and 15N-cP4O8(NH)44− anions are shown in Figure 1. In the case of the 15N-cP4O8(NH)44− anion,

(1)

The relationship between the activities of H+ and D+ ions, according to Gross−Butler−Purlee theory,42,43 can be expressed as follows pD = pH* + 0.44

D pKW

The solvent for NMR measurement solutions in this study is 90% H2O + 10% D2O; therefore, the following approximation will be established:

D pKW H pKW

H pKW

(2)

where pH* is the measured value of the D2O-based solution with a pH meter which was calibrated with an H2O-based C


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Figure 1. Representative 15N and presence of 1H decoupling.

31

P NMR spectra of

15

N-Na3cP3O6(NH)3 (left) and

15

N-Na4cP4O8(NH)4 (right) aqueous solutions in the

Figure 2. Stack plot for the pH dependence of 1H-decoupled 15N NMR spectra of 15N-Na3cP3O6(NH)3 (left) and 15N-Na4cP4O8(NH)4 (right) aqueous solutions. D


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The Journal of Physical Chemistry B the spectra contained a single triplet signal, which indicated the presence of an equivalent spin−spin coupling state resulting from two different adjacent nuclei (i.e., 1J(15N−31P) = 1 31 J( P−15N) = 18 Hz). In contrast, the spectra of the 15NcP3O6(NH)33− anion contained six peaks belonging to a doublet of triplet signals. Notably, the shorter-distance coupling path afforded a much stronger coupling interaction than the longer-distance coupling path. For example, 1J(15N−31P) = 1 31 J( P−15N) = 14 Hz and 3J(15N−31P) = 3J(31P−15N) = 6 Hz, as shown in Figure 1 (the difference between the 1J and 3J values was based on the shorter- and the longer-distance spin− spin coupling paths shown in Scheme S3 (Supporting Information)). These 1J(N−P) values were very similar to those of the imidodiphosphate and 5′-adenylyl imidodiphosphate anions investigated by Reynolds et al.31 The spin−spin coupling constants of nJ(15N−31P) and nJ(31P−15N) (n = 1, 3) were also found to be very similar, which highlighted the validity of the assignments described above for the characterization of the multiplet patterns. It should be noted that the intensity ratio in six peaks belonging to the doublet of triplet signals differs from the usual ratio. It may be that this peculiar intensity ratio originates from the polarization transfer which originates from the nuclear Overhauser effect between 31P and 15 N nuclei. The spin−spin coupling interactions can be enhanced in molecules with a planar structure.48 Given that the cP3O6(NH)33− anion has a rigid molecular structure49,50 with a greater degree of planarity than that of the cP4O8(NH)44− anion,51,52 the spin−spin coupling of this system would occur not only between two different adjacent nuclei but also between two different nuclei over larger distances. Spin−spin coupling interactions can also be enhanced by the presence of an unsaturated bond in the coupling path, which leads to a σ−π configuration interaction.48 Given that the cP3O6(NH)33− anion contains an unsaturated bond, the imino proton could reside on the bridging nitrogen atom (lactam form) as well as the nonbridging oxygen atom (lactim form), as shown in Scheme 1. The higher activity of the lactam−lactim tautomerism in the cP3O6(NH)33− anion could therefore be explained by the detection of the long-distance spin−spin coupling interactions in this system. In contrast, the cP4O8(NH)44− anion, where the long-distance spin−spin coupling interaction was not detected, possesses weak π character in its cyclic molecular skeleton. In this case, it is much more likely that the proton resides on the bridging nitrogen atom (lactam form) rather than the nonbridging oxygen atom (lactim form), as shown in Scheme 1. The lactam−lactim tautomerism activity of the cP4O8(NH)44− anion was therefore lower than that of the cP3O6(NH)33− anion. The effect of pH on the 1H decoupled 15N NMR spectra of the 15N-cP3O6(NH)33− and 15N-cP4O8(NH)44− anions, in terms of their 15N NMR chemical shifts, δN values, and spin−spin coupling constants, 1J(15N−31P), is shown in Figures 2 and 3. It was not possible to obtain the 15N NMR spectra of the anions at pH values of less than 1.3 for the 15NcP3O6(NH)33− anion and pH values of less than 3.6 for the 15 N-cP4O8(NH)44− anion because the anions were hydrolyzed under these conditions. Furthermore, it was not possible to measure the 15N NMR spectra of the 15N-cP3O6(NH)33− and 15 N-cP4O8(NH)44− anions at pH values of >13 and >12, respectively, because of the precipitation of the corresponding sodium complexes. The protonation of the 15N-cP3O6(NH)33− and 15N-cP4O8(NH)44− anions was accompanied by an upfield

Figure 3. 15N NMR chemical shifts, δN, and spin−spin coupling constants, 1J(15N−31P), in the presence of 1H decoupling of 15NNa3cP3O6(NH)3 and 15N-Na4cP4O8(NH)4 aqueous solutions as a function of pH at 22.0 ± 1.0 °C. Open symbols, 15N NMR chemical shifts; filled symbols, spin−spin coupling constants. (●, ○), 15NcP3O9(NH)33−; (▲, △), 15N-cP4O8(NH)44−.

shift in the δN values, as well as an increase in the 1J(15N−31P) values at pH values of

15N and 31P NMR Insights into LactamâLactim Tautomerism Activity

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15N and 31P NMR Insights into LactamâLactim Tautomerism Activity