High Proton Affinity Research Articles

Anisole, a new dopant for atmospheric pressure photoionization mass spectrometry of low proton affinity, low ionization energy compounds.

Atmospheric pressure photoionization (APPI) is a novel method of ionization in liquid chromatography/mass spectrometry (LC/MS). It was originally developed in order to broaden the range of LC/MS ionizable compounds towards less polar compounds that cannot be analyzed by electrospray (ESI) and atmospheric pressure chemical ionization (APCI). Studies done thus far have shown that non-polar compounds that earlier were not ionizable in LC/MS can indeed be ionized by the use of APPI. However, the best ionization efficiency for low polarity samples has been achieved with low proton affinity (PA) solvents that are not suitable in reversed-phase LC (RP-LC). Here it is demonstrated that the signals for analytes with low proton affinities in acetonitrile can be increased 100-fold by using anisole as the dopant for APPI, which takes the sensitivity to the same level achieved in the analysis of high PA analytes.

Bohr-effect and buffering capacity of hemocyanin from the tarantula E. californicum

A previous report showed that binding of oxygen to the 24-meric hemocyanin from E. californicum does not correlate linearly with the release of protons as known from hemoglobin. However, this unusual complex phenomenological observation could not be explained at that time. Here, I present a full analysis of the thermodynamic coupling between protons and oxygen for the 24-meric tarantula hemocyanin in Ringer-solution based on the Nested-MWC-model. A strategy is presented which allows to reduce the number of free parameters when fitting the model to the data by including explicitly the equilibrium constants for binding of protons to the different conformations. The results show that the Nested-MWC-model presents a good description of the cooperative and allosteric properties of spider hemocyanin also under physiological conditions and additional constraints imposed by proton-binding data. The analysis allowed to estimate the average number of allosteric proton-binding sites per subunit and the corresponding p K for each conformation. Furthermore, an estimate of the number and affinity of proton buffering binding sites could be given. Approximately 80% of all proton-binding sites are non-allosteric buffering binding sites. The results obtained in this study allow to predict the relative contribution of the four different conformations under conditions found in vivo . The conformational distribution indicates that the conformation with the highest proton affinity ( tR) might be important for the proton transport in the hemolymph.

Favorable effects of weak acids on negative-ion electrospray ionization mass spectrometry.

Despite widespread use in pharmacokinetic, drug metabolism, and pesticide residue studies, little is known about the factors governing response during reversed-phase liquid chromatography coupled with negative-ion electrospray ionization (ESI(-)) mass spectrometry. We examined the effects of various mobile-phase modifiers on the ESI(-) response of four selective androgen receptor modulators using a postcolumn infusion system. Acetic, propionic, and butyric acid improved the ESI(-) responses of analytes to varying extents at low concentrations. Formic acid suppressed ionization, as did neutral salts (ammonium formate, ammonium acetate) and bases (ammonium hydroxide, triethylamine) under most conditions. Two modifiers (2,2,2-trifluoroethanol, formaldehyde) that produce anions with high gas-phase proton affinity increased ESI(-) responses. However, the concentrations of these modifiers required to enhance ESI(-) response were higher than that of acidic modifiers, which is a phenomenon likely related to their low pK(a) values. 2,2,2-Trifluoroethanol increased response of more hydrophobic compounds but decreased response of a more hydrophilic compound. Formaldehyde improved response of all the compounds, especially the hydrophilic compound with lower surface activity. In summary, these results suggest that an ideal ESI(-) modifier should provide cations that can be easily electrochemically reduced and produce anions with small molecular volume and high gas-phase proton affinity.

The Proton/Amino Acid Cotransporter PAT2 Is Expressed in Neurons with a Different Subcellular Localization than Its Paralog PAT1

The new member of the mammalian amino acid/auxin permease family, PAT2, has been cloned recently and represents an electrogenic proton/amino acid symporter. PAT2 and its paralog, PAT1/LYAAT-1, are transporters for small amino acids such as glycine, alanine, and proline. Our immunodetection studies revealed that the PAT2 protein is expressed in spinal cord and brain. It is found in neuronal cell bodies in the anterior horn in spinal cord and in brain stem, cerebellum, hippocampus, hypothalamus, rhinencephalon, cerebral cortex, and olfactory bulb in the brain. PAT2 is expressed in neurons positive for the N-methyl-d-aspartate subtype glutamate receptor subunit NR1. PAT2 is not found in lysosomes, unlike its paralog PAT1, but is present in the endoplasmic reticulum and recycling endosomes in neurons. PAT2 has a high external proton affinity causing half-maximal transport activation already at a pH of 8.3, suggesting that its activity is most likely not altered by physiological pH changes. Transport of amino acids by PAT2 activity is dependent on membrane potential and can occur bidirectionally; membrane depolarization causes net glycine outward currents. Our data suggest that PAT2 contributes to neuronal transport and sequestration of amino acids such as glycine, alanine, and/or proline, whereby the transport direction is dependent on the sum of the driving forces such as substrate concentration, pH gradient, and membrane potential.

Polymorph of 1,4-diketo-3,6-dipyridyl–pyrrolo-[3,4-c]pyrrole

Diketopyrrolopyrroles (DPP) are well-known organic pigments. The title compound (DPPP) is one of DPP derivatives that shows a high proton affinity because of the N atoms of the pyridyl ring. Protonation at the N-site brings about a variety of changes in color as well as in electrical and photoelectrical conductivities. Two crystal modifications have been found to exist: DPPP I (grown from vapor phase) and DPPP II (grown from solution). Structure analysis revealed that there is a striking difference in intermolecular hydrogen bonds between two modifications: DPPP I is characterized only by NH…O hydrogen bonds whereas DPPP II include two of the H-bond based on NH…N and NH…O.

Substituent effect on ion–molecule reaction of disubstituted benzenes with acetone plasma

We investigated the ion–molecule reactions of disubstituted benzenes with acetone or acetone-d 6 as reagent gases under chemical ionization conditions, and the fragmentation reactions of the adduct ions (mostly acetyl ion and protonated acetone adducts) using collision-induced dissociation (CID) technique. The CID results of [M+A dD] + ions of phenylamine derivatives suggest that the phenylamine derivatives have higher proton affinities than acetone. Our experiments also suggest: (1) electron-releasing substituents favor the adduct reactions, while electron-withdrawing groups do not; (2) the position and properties of substituting groups have an effect on the relative abundances of the adduct ions; (3) the fragmentation reaction of the acetyl adduct ion formed by the reaction of ortho-phenylenediamine with acetyl ion is similar to the reductive alkylation reaction in the liquid phase.

Binding energies of water to sodiated valine and structural isomers in the gas phase: the effect of proton affinity on zwitterion stability.

The structures of valine (Val) and methylaminoisobutyric acid (Maiba) bound to a sodium ion, both with and without a water molecule, are investigated using both theory and experiment. Calculations indicate that, without water, sodiated Val forms a charge-solvated structure in which the sodium ion coordinates to the nitrogen and the carbonyl oxygen (NO-coordination), whereas Maiba forms a salt-bridge structure in which the sodium ion coordinates to both carboxylate oxygens (OO-coordination). The addition of a single water molecule does not significantly affect the relative energies or structures of the charge-solvated and salt-bridge forms of either cluster, although in Maiba the mode of sodium ion binding is changed slightly by the water molecule. The preference of Maiba to adopt a zwitterionic form in these complexes is consistent with its higher proton affinity. Experimentally, the rates of water evaporation from clusters of Val.Na(+)(H(2)O) and Maiba.Na(+)(H(2)O) are measured using blackbody infrared radiative dissociation (BIRD). The dissociation rates from the Val and Maiba complexes are compared to water evaporation rates from model complexes of known structure over a wide range of temperatures. Master equation modeling of the BIRD kinetic data yields a threshold dissociation energy for the loss of water from sodiated valine of 15.9 +/- 0.2 kcal/mol and an energy of 15.1 +/- 0.3 kcal/mol for the loss of water from sodiated Maiba. The threshold dissociation energy of water for Val.Na(+)(H(2)O) is the same as that for the charge-solvated model isomers, while the salt-bridge model complex has the same water threshold dissociation energy as Maiba.Na(+)(H(2)O). These results indicate that the threshold dissociation energy for loss of a water molecule from these salt-bridge complexes is approximately 1 kcal/mol less than that for loss of water from the charge-solvated complexes.

Cluster chemical ionization for improved confidence level in sample identification by gas chromatography/mass spectrometry.

Upon the supersonic expansion of helium mixed with vapor from an organic solvent (e.g. methanol), various clusters of the solvent with the sample molecules can be formed. As a result of 70 eV electron ionization of these clusters, cluster chemical ionization (cluster CI) mass spectra are obtained. These spectra are characterized by the combination of EI mass spectra of vibrationally cold molecules in the supersonic molecular beam (cold EI) with CI-like appearance of abundant protonated molecules, together with satellite peaks corresponding to protonated or non-protonated clusters of sample compounds with 1-3 solvent molecules. Like CI, cluster CI preferably occurs for polar compounds with high proton affinity. However, in contrast to conventional CI, for non-polar compounds or those with reduced proton affinity the cluster CI mass spectrum converges to that of cold EI. The appearance of a protonated molecule and its solvent cluster peaks, plus the lack of protonation and cluster satellites for prominent EI fragments, enable the unambiguous identification of the molecular ion. In turn, the insertion of the proper molecular ion into the NIST library search of the cold EI mass spectra eliminates those candidates with incorrect molecular mass and thus significantly increases the confidence level in sample identification. Furthermore, molecular mass identification is of prime importance for the analysis of unknown compounds that are absent in the library. Examples are given with emphasis on the cluster CI analysis of carbamate pesticides, high explosives and unknown samples, to demonstrate the usefulness of Supersonic GC/MS (GC/MS with supersonic molecular beam) in the analysis of these thermally labile compounds. Cluster CI is shown to be a practical ionization method, due to its ease-of-use and fast instrumental conversion between EI and cluster CI, which involves the opening of only one valve located at the make-up gas path. The ease-of-use of cluster CI is analogous to that of liquid CI in ion traps with internal ionization, and is in marked contrast to that of CI with most other standard GC/MS systems that require a change of the ion source.

Feasibility of atmospheric pressure desorption/ionization on silicon mass spectrometry in analysis of drugs.

The feasibility of atmospheric pressure desorption/ionization on silicon mass spectrometry (AP-DIOS-MS) for drug analysis was investigated. It was observed that only compounds with relative high proton affinity are efficiently ionized under AP-DIOS conditions. The limits of detection (LODs) achieved in MS mode with midazolam, propranolol, and angiotensin II were 80 fmol, 20 pmol, and 1 pmol, respectively. In MS/MS mode the LODs for midazolam and propranolol were 10 fmol and 5 pmol, respectively. The good linearity (r(2) > 0.991), linear dynamic range of 3 orders of magnitude, and reasonable repeatability showed that the method is suitable for quantitative analysis.

Ionization and protonation of NaC 3: a theoretical study

A theoretical study of the NaC 3 + and NaC 3H + systems has been carried out. Predictions have been made for some of the molecular properties, which could help in their possible experimental detection. The predicted global minimum for NaC 3 + is the linear isomer 1s ( 1Σ). The lowest-lying triplet state is a three-membered ring 3t ( 3B 2), lying about 27.1 kcal/mol higher in energy than the predicted global minimum at the G2(P) level. In the case of NaC 3H +, there are two isomers that lie close in energy: a linear species, 1d ( 2Π), and a three-membered ring, 4d ( 2A′). The most reliable levels of theory employed predict that 1d ( 2Π) is the global minimum, whereas 4d ( 2A′) is predicted to lie 5.3 kcal/mol higher in energy at the G2(P) level. In any case it seems that both structures could be accessible to experimental detection. Low ionization potential and high proton affinities are obtained for the most stable NaC 3 isomers. Therefore, if present in the interstellar medium, NaC 3 should be easily ionized and would react quite easily to give the protonated species.

Ab initio calculations and mass spectrometric determination of the gas-phase proton affinities of 4,4'-disubstituted 2,2'-bipyridines.

The gas-phase proton affinities of 4,4'-di(R)-2,2'-bipyridines (R: H, Br, Cl, NO(2), Me) were determined by mass spectrometric measurements and by ab initio calculations at the HF/6-31G and MP2/6-31G levels of theory. The energy barriers for rotation about the central C-C bond were also studied computationally. Two minima were found for both unprotonated and protonated species, the global minima being at the trans planar and cis planar conformations, respectively. Local minima for the unprotonated compounds were at the cis nonplanar conformation and for the protonated compounds at the trans nonplanar. Two different proton affinity values were calculated for each compound by employing different conformations for the protonated species. The computational values were in good agreement with the experimental proton affinities. Substituents affect the proton affinity according to their ability to withdraw or to donate electrons, halogen and nitro-substituted bipyridines having a lower proton affinity and methyl-substituted bipyridine having a higher proton affinity than 2,2'-bipyridine itself.

The intramolecular hydrogen bond and intrinsic proton affinity of neutral organic molecules: N,N ′,N ″‐tris (3‐aminopropyl)guanidine and some related systems

AbstractMultiple aminopropyl substitutions of the initial N,N′,N″‐trimethylguanidine lead to high intrinsic absolute proton affinities (APA) and basicities culminating in APA = 268.4 kcal mol−1 (1 kcal = 4.184 kJ) in N,N′,N″‐tris(3‐aminopropyl)guanidine (9). The reason behind a high proton affinity is identified as a strong cationic resonance in the central guanidine moiety and the strength of the intramolecular hydrogen bonding (IMHB), which is enhanced upon protonation. A cooperative IMHB effect in 9 and 9H + realized by three N(sp3)H···N(sp3) H‐bridges is estimated to be as high as 14.7 and 33.0 kcal mol−1, respectively. It follows that the IMHB effect contributes 18.3 kcal mol−1 to the absolute proton affinity of 9, which is a respectable amount. The basicity of 9 in acetonitrile is estimated to be very high, as evidenced by the corresponding pKa = 28.8. A derivative of 9, N,N′,N″‐tris(3‐dimethylaminopropyl)guani‐dine (10), assumes an even higher superbasic proton affinity of 275 kcal mol−1 due to an additional relaxation effect caused by the methyl groups. The corresponding pKa(MeCN) = 29.4. Copyright © 2002 John Wiley & Sons, Ltd.

Predicted high proton affinity of poly‐2,5‐ dihydropyrrolimines—the aromatic domino effect

AbstractThe basicity of a family of 2,5‐dihydropyrrolimines is examined by the Hartree‐Fock model. It is found that these systems exhibit high proton affinity, which increases with the number of the five‐membered rings present. The origin of the pronounced basicity is identified as the tandem or domino aromatic effect occurring in the conjugate acids. The aromatization is triggered by protonation and spread over whole systems via mobile π‐electrons. Proton affinities as high as 300 kcal/mol or more can be achieved in the gas phase, if the aromatization is combined with the favourable substituent effects and with the intramolecular hydrogen bond corona effect. Copyright © 2002 John Wiley & Sons, Ltd.

Isomer separation of hyperbranched polyesteramides with gas-phase H/D exchange and a novel MS(n) approach: DoDIP.

Two approaches are introduced that provide information about the isomeric composition of hyperbranched polyesteramides. The first approach is based on a novel tandem mass spectrometric (MS(n)) approach that allows the study of different types of isomeric structures by a separation based on their difference in appearance energy. The method is called DoDIP: dissociation of depleted ion populations. A first MS/MS step is used to fragment isomers with relatively low appearance energy. The isomers with higher appearance energy are fragmented in a second MS/MS step of higher energy. The second approach is based on gas-phase H/D exchange experiments that result in a bimodal isotopic distribution for oligomers X(n)D(n+1) of which one distribution corresponds to a type of isomeric structure that exhibits H/D exchange behaviour and the other to an isomeric structure that does not exhibit H/D exchange behaviour. X is a difunctional anhydride of phthalic acid (P), 1,2-cyclohexanedicarboxylic acid (C), succinic acid (S) or glutaric acid (G). D in X(n)D(n+1) is a trifunctional diisopropanolamine and n the degree of polymerization. The type of isomeric structure that does not exhibit H/D exchange behaviour has a non-alternating monomer sequence that contains an amine bond with a relatively high proton affinity. The other isomeric structure that does exhibit H/D exchange behaviour has an alternating monomer sequence containing only amide and ester bonds with relatively low proton affinity. Oligomer structures were confirmed with additional MS(2) experiments after H/D exchange. H/D exchange experiments on the fragments obtained after MS(2) of the parent ion show that next to previously postulated mechanisms for the cleavage of the ester and amide bond another reaction pathway must be operational. A new mechanism is introduced to explain the H/D exchange behaviour of the fragments that requires a cleavage of the amide bonds only. Two types of fragments are formed by this mechanism. One type is protonated due to the cleavage of the amide bond whereas the other type has an oxazolonium ion structure due to the loss of an additional H(2)O.

Protonation of fluorophenols and fluoroanisoles in the gas phase: experiment and theory

The proton affinities (PA) of the 2-, 3- and 4-fluorophenols and related anisoles have been determined with the use of Fourier transform ion cyclotron resonance (FT–ICR) mass spectrometry. Based on proton equilibria with suitable reference bases the following proton affinities have been obtained: 788 kJ mol−1 (2-fluorophenol), 802 kJ mol−1 (3-fluorophenol), 775 kJ mol−1 (4-fluorophenol), 808 kJ mol−1 (2-fluoroanisole), 825 kJ mol−1 (3-fluoroanisole) and 795 kJ mol−1 (4-fluoroanisole). The experimental proton affinities have been evaluated on the basis of ab initio calculations performed with the G3, G3(MP2) and MP2(fc)/6–11G(2d,p)//HF/6–31G(d,p) procedures. The main aspects of the calculations are: (i) the G3(MP2) proton affinity for the most basic site in each molecule is in good agreement with the experimental value, (ii) the values calculated at the MP2 level are systematically lower than the experimental values and (iii) the relative order of the proton affinities is essentially the same at the different levels of theory. The calculations indicate that the 4-position of the aromatic ring is the most basic site in 2- and 3-fluorophenol, whereas the 2-positon of 4-fluorophenol is associated with the higher proton affinity. For the fluoroanisoles, only MP2-calculations were performed and exclusively for the ring position expected to be associated with the higher PA value.

Ship-in-a-Bottle Synthesis of Methylphenols in HSAPO-34 Cages from Methanol and Air

The conversion of methanol to olefins on the silico-aluminophosphate solid acid catalyst HSAPO-34 usually requires methylbenzenes that function as scaffolds (reaction centers) for carbon−carbon bond making and breaking steps. Here, we report the first high-yield synthesis of heteroatom-substituted methylbenzenes in HSAPO-34 cages. When we metered 20% air into the He carrier gas during methanol conversion at 350 °C the methylbenzenes initially formed were partially oxidized in the HSAPO-34 cages to methylphenols with very high selectivity. 100% N2O was less effective than 20% air. Methylphenols proved to be substantially less active than methylbenzenes as reaction centers for methanol to olefin (MTO) catalysis on HSAPO-34. Even pentamethylphenol resisted the loss of methyl groups as olefin products, and phenols showed little carbon label scrambling into the ring during methanol conversion. Whereas 1:10 (mol:mol) toluene in methanol was very reactive on zeolite HZSM-5, 1:10 (mol:mol) p-cresol in methanol was no more reactive than pure methanol. We speculate that the MTO deactivating effect of oxygen substitution on methylbenzene rings is a consequence of the high gas-phase proton affinities of phenolic groups.

The unusually high proton affinity of aza-18-crown-6 ether: implications for the molecular recognition of lysine in peptides by lariat crown ethers

Recent studies have shown that 18-crown-6 ether (18C6) will selectively form adducts in the gas phase with small, lysine containing peptides. The present study extends this work by investigating the ability of aza-18-crown-6 ether (A18C6) and L1 (a simple lariat crown ether derivative of A18C6) to form similar noncovalent adducts with the side chain of lysine in model peptides in the gas phase. The substitution of nitrogen for oxygen greatly increases the proton affinity of A18C6 relative to 18C6 and inhibits the formation of noncovalent adducts with small lysine containing peptides. The proton affinity of A18C6 is determined by the kinetic method to be 250 ± 1 kcal/mol. This value is much higher than that for diethanolamine (228 kcal/mol) or for 18C6 (231 kcal/mol). This unusually high basicity is rationalized by semi-empirical calculations that suggest a highly symmetrical structure for protonated A18C6 in which the three most distant oxygens are able to fold back and hydrogen bond with the protonated nitrogen. In the case of L1, the lariat side chain is attached by an amide bond, lowering the proton affinity of L1 relative to that of A18C6. This allows L1 to form noncovalent adducts with lysine despite the fact that steric repulsion within the cavity of the crown is increased to some extent. The relative ammonium ion affinities of these various crown ethers are shown to serve as qualitative predictors for the molecular recognition of lysine. The order of the relative ammonium ion affinities is 18C6≫L1>A18C6 as determined by the kinetic method. These results suggest that the substitution of nitrogen for oxygen in the crown ether is not beneficial for the molecular recognition of lysine.

The proton affinity of the superbase 1,8-bis(tetramethylguanidino)naphthalene (TMGN) and some related compounds: a theoretical study.

The spatial and electronic structure of the very strong neutral organic bases bis(tetramethylguanidino)naphthalene (TMGN), 4,5-bis(tetramethylguanidino)fluorene (TMGF) and some related compounds are explored by ab initio computational methods. Their affinity towards the proton is scrutinized both in the gas phase and in solution in acetonitrile. The protonation at the most basic center (the imine nitrogen) yields asymmetric and relatively strong intramolecular hydrogen bonds (IHB). It is found that the angular strain effect and steric repulsion practically vanish in TMGN which implies that its high absolute proton affinity (APA) has its origin in the inherent basicity of the guanidine fragment and a relatively strong IHB in [TMGN]H(+). The nonbonded repulsions in TMGF are higher than in TMGN, which in conjunction with a slightly stronger IHB in the corresponding conjugate acid makes it more basic: APA(TMGF)>APA(TMGN). An interesting new phenomenon is observed in both TMGN and TMGF: the proton triggers the resonance stabilization not only in the directly bonded guanidine moiety, but also in the other guanidine fragment which is more distant from the proton, albeit in a less pronounced manner. The latter feature is termed a partial protonation. This supports the hydrogen bonding and contributes to the IHB stabilization. Convincing evidence is presented that the solvent effect in acetonitrile is determined by two antagonistic factors: 1) the intrinsic (gas phase) proton affinity and 2) the size effect which is given by the ratio between the positive charge in molecular cation (conjugate acid) and the magnitude of the molecular surface. The resulting pK(a) values are given by an interplay of these factors.

Carboxylic Acids and Their Anions. Acid and Ligand Properties

Calculated deprotonation energies of acids RCOOH (R = H, Me, CMe3, CH2Cl, CHCl2, CCl3, CH2F, CHF2, and CF3) correlate satisfactorily with experimental pKa values. The enhancing acid strength over this series is associated with the enhancing stabilization of the anionic forms, under the action of solvent inclusive. Carboxylate anions are characterized by a high proton affinity, excess electron density on the oxygen atoms, and low ionization energies of the highest occupied molecular orbitals. The anions of halogenated acids are slightly weaker donors than the anions of nonhalogenated acids. However, the fluorine derivatives have very low unoccupied π* molecular orbitals favorable for π-dative interaction with metal ions, which can provide additional stabilization of fluorocarboxylate coordination compounds.

Ionization and protonation of MgC3: A theoretical study

AbstractA theoretical study of the MgC3+ and MgC3H+ species has been carried out. Predictions for their geometries and vibrational frequencies have been made at both second‐order Møller–Plesset (MP2) and B3LYP levels, whereas electronic energies have been computed at G2 and coupled cluster single and double excitation model augmented with a noniterative triple excitation conection (CCSD(T)) levels. The predicted global minimum for MgC3+ is a rhombic structure (2A1 electronic state), whereas a T‐shaped structure and an open‐chain isomer lie about 10 and 12 kcal/mol, respectively, higher in energy. In the case of MgC3H+ the predicted global minimum is also a four‐membered ring obtained upon protonation of the most stable neutral isomer. Low ionization potentials and high proton affinities are generally obtained, especially for the most stable MgC3+ isomer. The estimated values at the CCSD(T) level for the predicted global minimum are 7.20 eV [ionization potential (IP)] and 256.5 kcal/mol [proton affinities (PA)]. Therefore, if present in the interstellar medium, MgC3 should be easily ionized and would react quite easily to give the protonated species. © 2002 John Wiley & Sons, Inc. Int J Quantum Chem, 2001