Proton‐Transfer Reactions of Acridine in Water‐Containing Ionic‐Liquid‐Rich Mixtures

To assess the potential of ionic liquids (ILs) as a solubilizing media that facilitates proton‐transfer reactions, acridine prototropism is investigated using UV/Vis molecular absorbance as well as steady‐state and time‐resolved fluorescence with different ILs in the presence of a small amount of dilute acid or base. It is found that protonation and deprotonation of acridine, when dissolved in different ILs, can be triggered by the addition of a small amount of dilute aqueous HCl and NaOH, respectively, in both the ground and excited states, irrespective of the identity of the IL. However, the amount of dilute acid/base needed to protonate/deprotonate acridine dissolved in different ILs is found to vary from one IL to another. Steady‐state fluorescence measurements also imply the presence of interactions between the acidic proton(s) of IL cation and excited acridine. The interconversion of neutral and protonated acridine, as well as the presence of a weakly fluorescent complex between excited acridine and the acidic proton(s) of the IL cation, is further corroborated by the parameters recovered from the fitting of the excited‐state intensity‐decay data. It is established that ILs as solubilizing media readily support facile proton transfer in both ground and excited states.     

Pharmaceutical modulation of diffusion potentials at aqueous-aqueous boundaries under laminar flow conditions

In this work, the modulation of the diffusion potential formed at the microfluidic aqueous-aqueous boundary by a pharmaceutical substance is presented. Co-flowing aqueous streams in a microchannel were used to form the stable boundary between the streams. Measurement of the open circuit potential between two silver/silver chloride electrodes enabled the diffusion potential at the boundary to be determined, which is concentration dependent. Experimental results for protonated propranolol as well as tetrapropylammonium are presented. This concept may be useful as a strategy for the detection of drug substances.     

Remarkable sensitivity of the electrochemical reduction of benzophenone to proton availability in ionic liquids

The reduction of benzophenone was investigated in five different ionic liquids by using transient cyclic voltammetry, near steady-state voltammetry, and numerical simulation. Two reversible, well-resolved one-electron-reduction processes were observed in dry (≤20 ppm water, ca. 1 mM)) 1-butyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide ([Bmpyrd][NTf(2)]) and 1-butyl-1-methylpiperidinium bis(trifluoromethylsulfonyl)imide ([Bmpipd][NTf(2)]), which did not contain any readily available proton source. Upon addition of water, the second process became chemically irreversible and shifted to a more positive potential by approximately 600 mV; moreover, the two reduction processes merged into a single two-electron proton-coupled process when about 0.6 M H(2)O was present. This large dependence of potential on water content, which was not observed in molecular solvents (electrolyte), was explained by a reaction mechanism that incorporated protonation and hydrogen-bonding interactions of the benzophenone dianion with as many as seven water molecules. In the three imidazolium-based ionic liquids used herein, the first benzophenone-reduction process was again reversible, whilst the second reduction process became chemically irreversible owing to the availability of the C2-H imidazolium protons in these ionic liquids. The reversible potentials for benzophenone reduction were remarkably independent of the identity of the ionic liquids, thereby implying either weak interactions with the ionic liquids or relatively insignificant differences in the levels of ion-pairing. Thus, the magnitude of the separation of the potentials of the reversible first and irreversible second reduction processes mainly reflected the proton availability from either the ionic liquid itself or from adventitious water. Consequently, voltammetric reduction of benzophenone provides a sensitive tool for the determination of proton availability in ionic liquids.     

Ligand versus metal protonation of an iron hydrogenase active site mimic

The protonation behavior of the iron hydrogenase active-site mimic [Fe2(mu-adt)(CO)4(PMe3)2] (1; adt=N-benzyl-azadithiolate) has been investigated by spectroscopic, electrochemical, and computational methods. The combination of an adt bridge and electron-donating phosphine ligands allows protonation of either the adt nitrogen to give [Fe2(mu-Hadt)(CO)4(PMe3)2]+ ([1 H]+), the Fe-Fe bond to give [Fe2(mu-adt)(mu-H)(CO)4(PMe3)2]+ ([1 Hy]+), or both sites simultaneously to give [Fe2(mu-Hadt)(mu-H)(CO)4(PMe3)2]2+ ([1 HHy]2 +). Complex 1 and its protonation products have been characterized in acetonitrile solution by IR, (1)H, and (31)P NMR spectroscopy. The solution structures of all protonation states feature a basal/basal orientation of the phosphine ligands, which contrasts with the basal/apical structure of 1 in the solid state. Density functional calculations have been performed on all protonation states and a comparison between calculated and experimental spectra confirms the structural assignments. The ligand protonated complex [1 H]+ (pKa=12) is the initial, metastable protonation product while the hydride [1 Hy]+ (pKa=15) is the thermodynamically stable singly protonated form. Tautomerization of cation [1 H]+ to [1 Hy]+ does not occur spontaneously. However, it can be catalyzed by HCl (k=2.2 m(-1) s(-1)), which results in the selective formation of cation [1 Hy]+. The protonations of the two basic sites have strong mutual effects on their basicities such that the hydride (pK(a)=8) and the ammonium proton (pK(a)=5) of the doubly protonated cationic complex [1 HHy]2+ are considerably more acidic than in the singly protonated analogues. The formation of dication [1 HHy]2+ from cation [1 H]+ is exceptionally slow with perchloric or trifluoromethanesulfonic acid (k=0.15 m(-1) s(-1)), while the dication is formed substantially faster (k>10(2) m(-1) s(-1)) with hydrobromic acid. Electrochemically, 1 undergoes irreversible reduction at -2.2 V versus ferrocene, and this potential shifts to -1.6, -1.1, and -1.0 V for the cationic complexes [1 H]+, [1 Hy]+, and [1 HHy]2+, respectively, upon protonation. The doubly protonated form [1 HHy]2+ is reduced at less negative potential than all previously reported hydrogenase models, although catalytic proton reduction at this potential is characterized by slow turnover.     

Theoretical studies on the mechanism of C-P bond cleavage of a model alpha-aminophosphonate in acidic condition

Various reaction paths of the P-C bond cleavage of alpha-aminophosphonates in acidic media, resulting in the derivatives of phosphonic acid, has been investigated using density functional level of theories in the gas phase as well as in aqueous medium. Dimethyl (alpha-anilinobenzyl)phosphonate has been used as the model molecule and our investigation confirms a three steps process including protonation, P-C bond cleavage, and the transformation of the products from the final transition state (imine cation and H-phosphonate) through hydrolysis. The most favorable reaction path starts from the amino group protonation, followed by a proton transfer through N-H...O(P) hydrogen bond, and the P-C bond cleavage from the resulting protonated structure. Explicit inclusion of water molecules indicated that two waters are needed for the P-C bond cleavage, and the calculated mechanistic paths in this hydrated model are similar to those of the aqueous solvation model.     

The mechanism of proton transfer between adjacent sites exposed to water

The surface of a protein, or a membrane, is spotted with a multitude of proton-binding sites, some of which are only a few angstroms apart. When a proton is released from one site, it propagates through the water by a random walk under the bias of the local electrostatic potential determined by the distribution of the charges on the protein. Some of the released protons disperse into the bulk, but during the first few nanoseconds, the released protons can be trapped by encounter with nearby acceptor sites. This process resembles a scenario which corresponds with the time-dependent Debye-Smoluchowski equation. In the present study, we investigated the mechanism of proton transfer between sites that are only a few angstroms apart, using as a model the proton exchange between sites on a small molecule, fluorescein, having two, spectrally distinguishable, proton-binding sites. The first site is the oxyanion on the chromophore ring structure. The second site is the carboxylate moiety on the benzene ring of the molecule. Through our experiments, we were able to reconstruct the state of protonation at each site and the velocity of proton transfer between them. The fluorescein was protonated by a few nanosecond long proton pulse under specific conditions that ensured that the dye molecules would be protonated only by a single proton. The dynamics of the protonation of the chromophore were measured under varying initial conditions (temperature, ionic strength, and different solvents (H(2)O or D(2)O)), and the velocity of the proton transfer between the two sites was extracted from the overall global analysis of the signals. The dynamics of the proton transfer between the two proton-binding sites of the fluorescein indicated that the efficiency of the site-to-site proton transfer is very sensitive to the presence of the screening electrolyte and has a very high kinetic isotope effect (KIE = 55). These two parameters clearly distinguish the mechanism from proton diffusion in bulk water. The activation energy of the reaction (E(a) = 11 kcal mol(-1)) is also significantly higher than the activation energy for proton dissociation in bulk water (E(a) approximately 2.5 kcal mol(-1)). These observations are discussed with respect to the effect of the solute on the water molecules located within the solvation layer.     

Aqueous NaCl and CsCl solutions confined in crystalline slit-shaped silica nanopores of varying degree of protonation

All-atom molecular dynamics simulations were conducted to study the dynamics of aqueous electrolyte solutions confined in slit-shaped silica nanopores of various degrees of protonation. Five degrees of protonation were prepared by randomly removing surface hydrogen atoms from fully protonated crystalline silica surfaces. Aqueous electrolyte solutions containing NaCl or CsCl salt were simulated at ambient conditions. In all cases, the ionic concentration was 1 M. The results were quantified in terms of atomic density distributions within the pores, and the self-diffusion coefficient along the direction parallel to the pore surface. We found evidence for ion-specific properties that depend on ion-surface, water-ion, and only in some cases ion-ion correlations. The degree of protonation strongly affects the structure, distribution, and the dynamic behavior of confined water and electrolytes. Cl(-) ions adsorb on the surface at large degrees of protonation, and their behavior does not depend significantly on the cation type (either Na(+) or Cs(+) ions are present in the systems considered). The cations show significant ion-specific behavior. Na(+) ions occupy different positions within the pore as the degree of protonation changes, while Cs(+) ions mainly remain near the pore center at all conditions considered. For a given degree of protonation, the planar self-diffusion coefficient of Cs(+) is always greater than that of Na(+) ions. The results are useful for better understanding transport under confinement, including brine behavior in the subsurface, with important applications such as environmental remediation.     

A Non-aqueous H3PO4 Electrolyte Enables Stable Cycling of Proton Electrodes

A non-aqueous proton electrolyte is devised by dissolving H₃PO₄ into acetonitrile. The electrolyte exhibits unique vibrational signatures from stimulated Raman spectroscopy. Such an electrolyte exhibits unique characteristics compared to aqueous acidic electrolytes: 1) higher (de)protonation potential for a lower desolvation energy of protons, 2) better cycling stability by dissolution suppression, and 3) higher Coulombic efficiency owing to the lack of oxygen evolution reaction. Two non-aqueous proton full cells exhibit better cycling stability, higher Coulombic efficiency, and less self-discharge compared to the aqueous counterpart.     

Proton mobility and main fragmentation pathways of protonated lysylglycine

Theoretical model calculations were performed to validate the 'mobile proton' model for protonated lysylglycine (KG). Detailed scans carried out at various quantum chemical levels of the potential energy surface (PES) of protonated KG resulted in a large number of minima belonging to various protonation sites and conformers. Transition structures corresponding to proton transfer reactions between different protonation sites were determined, to obtain some energetic and structural insight into the atomic details of these processes. The rate coefficients of the proton transfer reactions between the isomers were calculated using the Rice-Ramsperger-Kassel-Marcus (RRKM) method in order to obtain a quantitative measure of the time-scale of these processes. Our results clearly indicate that the added proton is less mobile for protonated KG than for peptides lacking a basic amino acid residue. However, the energy needed to reach the energetically less favorable but-from the point of view of backbone fragmentation-critical amide nitrogen protonation sites is available in tandem mass spectrometers operated under low-energy collision conditions. Using the results of our scan of the PES of protonated KG, the dissociation pathways corresponding to the main fragmentation channels for protonated KG were also determined. Such pathways include loss of ammonia and formation of a protonated alpha-amino-epsilon-caprolactam. The results of our theoretical modeling, which revealed all the atomic details of these processes, are in agreement with the available experimental results.     

How Does a Membrane Protein Achieve a Vectorial Proton Transfer Via Water Molecules?

We present a detailed mechanism for the proton transfer from a protein‐bound protonated water cluster to the bulk water directed by protein side chains in the membrane protein bacteriorhodopsin. We use a combined approach of time‐resolved Fourier transform infrared spectroscopy, molecular dynamics simulations, and X‐ray structure analysis to elucidate the functional role of a hydrogen bond between Ser193 and Glu204. These two residues seal the internal protonated water cluster from the bulk water and the protein surface. During the photocycle of bacteriorhodopsin, a transient protonation of Glu204 leads to a breaking of this hydrogen bond. This breaking opens the gate to the extracellular bulk water, leading to a subsequent proton release from the protonated water cluster. We show in detail how the protein achieves vectorial proton transfer via protonated water clusters in contrast to random proton transfer in liquid water.     

Microfluidic chip for electrochemically-modulated liquid∣liquid extraction of ions

A microfluidic device with integrated electrodes for the electrochemically-modulated extraction of ions across immiscible aqueous–organic liquid–liquid interfaces is presented. Using a Y-shaped microfluidic channel with in situ electrodes and co-flowing aqueous and organic immiscible electrolyte solutions, the manipulation of the applied interfacial potential enabled the extraction of ions from the aqueous phase into the organic phase. Data for the extraction of tetraethylammonium cations from aqueous electrolyte into 1,2-dichloroethane electrolyte are presented. The device demonstrates the benefits of combination of microfluidics and liquid–liquid electrochemistry.     

The Solvent Effect on H2O2 Generation at Room Temperature Ionic Liquid|Water Interface

H₂O₂ is a versatile chemical and can be generated by the oxygen reduction reaction (ORR) in proton donor solution in molecular solvents or room temperature ionic liquids (IL). We investigated this reaction at interfaces formed by eleven hydrophobic ILs and acidic aqueous solution as a proton source with decamethylferrocene (DMFc) as an electron donor. H₂O₂ is generated in colorimetrically detectable amounts in biphasic systems formed by alkyl imidazolium hexafluorophosphate or tetraalkylammonium bis(trifluoromethylsulfonyl)imide ionic liquids. H₂O₂ fluxes were estimated close to liquid|liquid interface by scanning electrochemical microscopy (SECM). Contrary to the interfaces formed by hydrophobic electrolyte solution in a molecular solvent, H₂O₂ generation is followed by cation expulsion to the aqueous phase. Weak correlation between the H₂O₂ flux and the difference between DMFc/DMFc⁺ redox potential and 2 electron ORR standard potential indicates kinetic control of the reaction.     

Dissociative protonation and proton transfers: fragmentation of alpha, beta-unsaturated aromatic ketones in mass spectrometry

In mass spectrometry of the alpha,beta-unsaturated aromatic ketones, Ph-CO-CH=CH-Ph', losses of a benzene from the two ends and elimination of a styrene are the three major fragmentation reactions of the protonated molecules. When the ketones are substituted on the right phenyl ring, the electron-donating groups are in favor of losing a styrene to form the benzoyl cation, PhCO(+), whereas the electron-withdrawing groups strongly favor loss of benzene of the left side to form a cinnamoyl cation, Ph'CH=CHCO(+). When the ketones are substituted on the left phenyl ring, the substituent effects on the reactions are reversed. In both cases, the ratios of the two competitive product ions are well-correlated with the sigma p(+) substituent constants. Theoretical calculations indicate that the carbonyl oxygen is the most favorable site for protonation, and the olefinic carbon adjacent to the carbonyl is also favorable especially when a strong electron-releasing group is present on the right phenyl ring. The energy barrier to the interconversion between the ions formed from protonation at these two sites regulates the overall reactions. Transfer of a proton from the carbonyl oxygen to the ipso position on either phenyl ring, which is dissociative, triggers loss of benzene.     

桥链冠醚卟啉胆固醇酯的表观质子化常数

用光度法测得三种桥链冠醚卟啉和二种卟啉胆固醇酯的质子化常数，并用ＨＭＯ法进行了量子化学计算，讨论了取代基的电子效应及空间效应对常数的影响。     

Three-phase electrochemistry with a cylindrical microelectrode

A new experimental approach is proposed to examine the ion transfer across the boundary of two immiscible liquids. A cylindrical platinum or gold microelectrode is immersed into the two-liquid system in such a way that a part of it is located in one liquid and the other part resides in the second liquid. The organic liquid contained either ferrocene or decamethylferrocene and no supporting electrolyte. The aqueous phase contained various inorganic salts. Well defined and reproducible linear-scan and square-wave voltammograms of oxidation of ferrocene and decamethylferrocene were obtained. The dependence of the formal potential derived from the square-wave voltammograms of decamethylferrocene vs. the standard potentials of transfer of anions present in the aqueous phase was perfectly linear. The developed method is more precise, since the three-phase boundary is better defined compared to placing a drop of organic liquid on the surface of a graphite electrode, and should be applicable to a larger set of organic liquids.     

Gas-phase reaction: alkyl cation transfer in the dissociation of protonated pyridyl carbamates in mass spectrometry

In the mass spectrometry of pyridyl carbamates, alkyl cation transfer is one of the major fragmentation reactions of the protonated molecules. Literature results and theoretical calculations indicate that the pyridine nitrogen is the most favorable site for protonation in these structures. Substituent and comparison experiments run to elucidate the fragmentation patterns reveal that the proton is localized at the pyridine nitrogen and the reaction center is charge-remote when the alkyl cation transfer occurs. The mechanism involving configuration inversion via an ion-neutral complex is favorable in energy for the alkyl cation transfer in these structures.     

Substituent and solvent effects on the beta-heterolysis reaction of beta-hydroxy arylethyl radicals

Time-resolved conversion of a series of beta-hydroxy arylethyl radicals with electron-donating and -withdrawing aromatic substituents to their corresponding styrene radical cation via heterolytic loss of the beta-hydroxy leaving group was examined with nanosecond laser flash photolysis. In all cases, the reaction was catalyzed by added perchloric acid. Radicals 2a-d reacted via a pre-equilibrium protonation mechanism in acidic 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), and measuring rate constants for radical cation formation as a function of acid content allowed for the determination of absolute rate constants ranging from 3.6 x 10(6) to 3.8 x 10(7) s(-1) for the loss of water from the protonated beta-hydroxy arylethyl radicals 2a-d, as well as the acidity constants, pKa approximately 1.5 (in HFIP), for the protonated radicals. The 4-methoxy-substituted beta-hydroxy arylethyl radical 2e reacted by rate determining protonation in HFIP with a second-order rate constant of k(H+) = 7.8 x 10(8) M(-1) s(-1). However, in acetonitrile, 2,2,2-trifluoroethanol, and mixtures of these two solvents, 2e reacted by pre-equilibrium protonation, allowing for solvent effects on the rate constant for loss of water from the protonated radical 2e to be determined. With use of these data, substituent electronic effects on the kinetics of the beta-heterolysis reaction are discussed. Differences in the effect of solvent on the rate constant for loss of water from the protonated beta-hydroxy arylethyl radicals and other beta-substituted arylethyl radicals are also discussed.     

Mechanism of pyridine protonation in water clusters of increasing size

This work presents a theoretical mechanistic study of the protonation of pyridine in water clusters, at the B3LYP/cc-pVDZ theory level. Clusters from one to five water molecules were used. Starting from previously determined structures, the reaction paths for the protonation process were identified. For complexes of pyridine with water clusters of up to three water molecules just one transition state (TS) links the solvated and protonated forms. It is found that the activation energy decreases with the number of water molecules. For complexes of four and five water molecules two transition states are found. For four water molecules, the first TS links the starting solvated structure with a new, less stable, solvated form through a concerted proton transfer between a ring of water molecules. The second TS links the new solvated structure to the protonated form. Thus, protonation is a two-step process. For the five water molecules cluster, the new solvated structure is more stable than the starting one. This structure exhibits two double hydrogen bonds involving the pyridinic nitrogen and several water molecules. The second TS links the new structure with the protonated form. Now the process occurs in one step. In all cases considered, the proton transfers involve an interconversion between covalent and hydrogen bonds. For four and five water molecules, the second TS is structurally and energetically very close to the protonated form. As evidenced by the vibration frequencies, this is due to a flat potential energy hypersurface in the direction of the reaction coordinate. Determination of DeltaG at 298.15 K and 1 atm shows that the protonation of pyridine needs at least four water molecules to be spontaneous. The complex with five water molecules exhibits a large DeltaG. This value yields a pKa of 2.35, relatively close to the reported 5.21 for pyridine in water.     

The mobility and ion structure of protonated aminoazoles

The reduced mobility of protonated pyrazole derivatives was measured by ion mobility spectrometry (IMS) in air, nitrogen, and carbon dioxide, at temperatures between 150 and 250°C. It was found that the mobility of protonated 5-amino-1-phenylpyrazole was higher than that of its 3- and 4-isomers. This was attributed to the fact that in the 5-isomer the preferred site of protonation is on the endocyclic nitrogen, which leads to delocalization of the ionic charge, and thus to a diminished interaction with the drift gas molecules. On the other hand, protonated 5-amino-1-methylpyrazole has a slightly lower mobility than its isomers, which is indicative of a different protonation mechanism.     

Ionization of aqueous cations: photoelectron spectroscopy and ab initio calculations of protonated imidazole

Photoelectron spectroscopy and ab initio calculations employing a nonequilibrium polarizable continuum model were employed for determining the vertical ionization potential of aqueous protonated imidazole. The experimental value of 8.96 eV is in in excellent agreement with calculations, which also perform quantitatively for ionization of aqueous alkali cations as benchmark species. The present results show that protonation of imidazole increases its vertical ionization potential up in water by 0.7 eV, which is significantly larger than the resolution of the experiment or the error of the calculation. This combined experimental and computational approach may open the possibility for quantitatively analyzing the protonation state of histidine, of which imidazole is the titratable side chain group, in aqueous peptides and proteins.