Proton Transfer Agent Research Articles

The Unusual Stability of Homoleptic Di- and Tetravalent Chromium Alkyls

Reaction of CrCl3(THF)3 with 3 equiv of R−M [R = Me3CCH2 (a), Me3SiCH2 (b)] afforded either the previously reported tetravalent homoleptic R4Cr (1a, b) [M = MgCl] or the unprecedented divalent and tetranuclear homoleptic [R2Cr]4 (2b) [M = Li]. Both types of compounds display a remarkable chemical inertness toward proton transfer agents but readily react with ethylene.

A Mechanistic Study of the Influence of Proton Transfer Processes on the Behavior of Thiol/Disulfide Redox Couples

The mechanism of the oxidation of 2-mercapto-5-methyl-1,3,4-thiadiazole (McMT) to its disulfide dimer and its subsequent reduction has been examined with a combined approach employing experimental data and digital simulation. In order to elucidate the influence of proton transfers on these redox processes, special attention has been paid to the influence of various bases, including triethylamine, pyridine, 3-chloropyridine, lutidine and 2,6-di-tert-butylpyridine, and proton donors, including methanesulfonic acid and trifluoromethanesulfonic acid, on both the oxidation and reduction reactions. On the basis of detailed comparisons of the experimental data with simulations of several mechanistic models, it is found that proton transfer pathways have a pronounced influence on both the oxidative and reductive pathways. In particular, McMT oxidation is facilitated by a rapid bimolecular proton transfer from McMT to weak bases such as Py that produces McMT-, the thiolate form, which is then oxidized. There is no such facilitation in the presence of the sterically hindered base 2,6-di-tert-butylpyridine, suggesting that the facilitation occurs through the formation of a discrete hydrogen-bonded complex. The overall kinetic scheme by which these redox processes proceed both in the presence and absence of proton transfer agents is discussed, especially with regard to the potential use of a related dithiolate compound as a cathode material in Li secondary batteries.

Amines That Transport Protons across Bilayer Membranes: Synthesis, Lysosomal Neutralization, and Two-Phase pK(a) Values by NMR.

It is desirable to be able to control the pH of lysosomes. A collection of lipophilic, nitrogenous bases, designed to act as membrane-active, catalytic proton transfer agents, were prepared and their effective pK(a)s measured in a vigorously stirred, two-phase system. One phase was a phosphate buffer whose pH was varied over the range ca. 1-11. The other was an immiscible, deuterated organic solvent in which the compounds preferentially resided even when protonated. When chemical shift changes versus the pH of the buffer were plotted, clear pK(a) curves were generated that are relevant to transmembrane proton transfer behavior. The two-phase pK(a)s increased with increasing counterion lipophilicity and with increasing organic solvent polarity. The compounds were also tested for their ability to neutralize the acidity of lysosomes, a model for other acidic vesicles involved in drug sorting. The most successful of these, imidazole 6a, has >100 times the neutralizing power of ammonia, a standard lysosomotropic amine, causing a 1.7 unit rise in lysosomal pH of RAW cells at 0.1 mM, compared to a 0.2 and 1.4 unit rise for ammonium chloride at 0.1 and 10 mM, respectively.

Novel, CO 2-promoted synthesis of anhydrous alkylammonium tetraphenylborates: a study on their reactivity as intra- and inter-molecular proton-transfer agents

Anhydrous alkylammonium tetraphenylborates (RR′R″NH)BPh 4 [ R′ = R″= H, R = allyl ( 1), cyclohexyl ( 2), or benzyl ( 3) ; R″ = H, R = R′ = ethyl ( 4); R″ = H, RR′ = −CH 2 CH 2 OCH 2 CH 2− ( 5); R = R′ = R″ = Bu ( 6)] have been prepared with high yield in mild conditions from the corresponding amines and NaBPh 4 in the presence of carbon dioxide. The synthesis of trialkylammonium salts, (R 3NH)BPh 4, also requires a suitable reagent that can act as a proton source. The method has been extended to the direct synthesis of [RNH 3 · (18-crown-6)]BPh 4 salts [ R = allyl ( 1a), cyclohexyl ( 2a), or benzyl ( 3a) ]. The behaviour of 1–6 in several solvents has been investigated. In CH 2Cl 2 or THF, 1–6 salts can undergo intramolecular protolytic cleavage of a BC bond to form benzene and RR′R″NBPh 3 adducts. In acetone, both mono- and di-alkylammonium tetraphenylborates easily convert in high yield into the corresponding iminium-BPh 4 salts, (RR′N = CMe 2)BPh 4 (R = alkyl; R′ = H, or alkyl) through intermolecular transfer of a proton to a solvent molecule. The reactivity of alkylammonium tetraphenylborates can be modified markedly by a complexing agent that firmly coordinates the cation and acts as a proton-transfer inhibitor.

Dimaprit, [S-[3-(N,N-dimethylamino)propyl]isothiourea]. A highly specific histamine H2-receptor agonist. Part 2. Structure-activity considerations

Dimaprit, S-[3-(N,N-dimethylamino)propyl]isothiourea, appears to be a highly specific histamine H2-receptor agonist. Further indications of specificity are obtained from chemical considerations. Dimaprit has two basic centres (pKa values respectively 8.23 and 9.23, at 40°.) and at pH 7.4 about 5% of the molecules will be present as the monocation analogous to histamine monocation. Chemical comparison suggests that the −N+HMe2 group corresponds to the −N+H3 of histamine, and that the isothiourea group of dimaprit (which can undergo 1,3-prototropic tautomerism) may simulate the imidazole ring of histamine and function as a proton transfer agent at H2 receptors.

Reversal of doxorubicin resistance and catalytic neutralization of lysosomes by a lipophilic imidazole

A number of lipophilic nitrogenous bases, designed to act as membrane-active, catalytic proton transfer agents, were tested for their ability to neutralize the acidity of lysosomes, a model for other acidic intracellular vesicles involved in drug sorting. The most successful of these, an imidazole 1, caused a 1.7 unit rise in lysosomal pH of RAW cells at 100 μM, compared to a 0.2 and 1.4 unit rise for ammonium chloride at 100 μM and 10 mM, respectively. Compound I also exhibited potent reversal of doxorubicin (DOX) resistance in the HCT116-VM46 cell line by a factor of 14 over the sensitive strain, and superior to that of widely used verapamil (VRP) by a factor of 1.75 at 20 μM. It also has antiviral properties, and potential applications in other lysosome-related areas such as immunotoxin potentiation and the control of bacterial toxins, immune response, prion replication, malaria and intralysosomal microorganisms.

Kinetics of cerium(IV) oxidation of propionic acid in perchloric acid: Role of solvent

The oxidation rate of propionic acid (PROA) by cerium(IV) in aqueous perchloric acid (1.0–6.0 mol/dm3) is proportional to the PROA concentration, the total order of the reaction being two. It was found that the rate is related to the values of Hammett's acidity function (H0) in agreement with both Zucker-Hammett's hypothesis and Bunnett-Olsen's criterion, the water acting as a proton transfer agent. A mechanism consistent with the findings is proposed.

Role of solvent acidity in the cerium(IV) oxidation of butanoic acid

The oxidation of butanoic acid by cerium(IV) has been studied kinetically in aqueous perchloric acid (1.0–6.0 mol/dm3). It has been found that the reaction is first order with respect to both oxidant and the reductant. Analysis of the influence of the solvent acidity permits to clarify the role of water which acts as a proton transfer agent. A reaction mechanism is proposed.

Mechanistic studies in strong acids. VIII. Hydrolysis mechanisms for some thiobenzoic acids and esters in aqueous sulfuric acid, determined using the excess acidity method

The excess acidity method has been applied to hydrolysis rate data, obtained as a function of medium composition, for four thiobenzoic acids, thioacetic acid, eight ethyl thiolbenzoates, and eight ethyl thionbenzoates in aqueous sulfuric acid. The mechanistic behaviour thus revealed has both similarities to and differences from that of a typical ester like ethyl benzoate, which gives benzoic acid by an A-2 reaction involving two water molecules in weak acid, and by A-1 acylium ion formation in strong acid. The thioacids follow this behaviour, except that the A-2 process involves three water molecules, and that the mechanistic changeover occurs in 60% rather than 80% acid. The A-2 process for the ethyl thiolbenzoates is slow; the major hydrolysis mechanism is acylium ion formation, not in an A-1 reaction but by a concerted A-SE2 process involving both proton transfer to sulfur and carbon–sulfur bond breaking. The major proton transfer agent is the undissociated sulfuric acid molecule. The thionbenzoate esters, in contrast, undergo very fast A-2 hydrolysis; so fast, in fact, that the initial protonation of sulfur is the rate-determining step in acids more dilute than about 62% w/w. It appears that proton transfer to sulfur is a comparatively slow process.

Identification of the active-site residue of gamma-cystathionase labeled by the suicide inactivator beta, beta, beta-trifluoroalanine.

Inactivation of gamma-cystathionase by beta, beta, beta-trifluoroalanine, a suicide inactivator of the enzyme, results in covalent labeling of an amino group of the protein [Silverman, R. B., & Abeles, R. H. (1977) Biochemistry 16, 5515-5520]. We have established that this modified amino function is the epsilon-NH2 group of a lysine residue. A heptapeptide which includes this modified lysine residue was isolated, and its sequence was found to be Cys-Ser-Ala-Thr-Lys-Tyr-Met. The amino acid sequence was the same as that determined for peptides containing the active-site lysine residue which forms a Schiff base with pyridoxal phosphate. Therefore the epsilon-NH2 group of the active-site lysine which binds pyridoxal phosphate is capable of interacting with the beta carbon of trifluoroalanine, and presumably the beta carbon of normal substrates. We therefore propose that this lysine residue may function as a proton-transfer agent in the reactions catalyzed by gamma-cystathionase.

Deuterium isotope effects and the bunnett w factor in elimination reactions of 4-alkoxyimino-5,6-dihydro-6-alkoxyaminopyrimidin-2(1H-)one in strong acid media

Rate coefficients for the elimination of hydroxylamines from 4-alkoxyimino-5,6-dihydro-6-alkoxyaminopyrimidin-2(1H)-ones (1a) show maxima at Ho values of –1.8 (for O-benzylhydroxylamine) and –0.8 (for hydroxylamine) in a variety of mineral acids. The hitherto unknown values of Ho for trifluoromethanesulphonic acid are reported and this acid also gives a rate maximum at –1.8 for the elimination of O-benzylhydroxylamine from (1a; R2= Bz). Bunnett w values for these eliminations fall in the range 6.0–16.0 (dependent upon the acid) implying that water is involved as a proton transfer agent. In contrast, eliminations in formic acid show low and variable w values and formate ion is involved as the proton transfer agent which explains the lack of a rate maximum in this acid. Deuterium isotope effects reveal a highly stereoselective elimination and support the proposal of an E1cB (irreversible) mechanism. The inhibition of elimination by the 5-fluoro-substituent [as in (1b)] is probably due to destabilisation of the intermediate carbanion by the lone pair electrons on fluorine.

Isotopically decoupled vibrational spectra and proton exchange rates for crystalline NH3 and ammonia hydrate

Codeposits of NH3 with ND3 or D2O have been prepared at liquid nitrogen temperatures in the absence of proton exchange. Vibrational data for the anhydrous cubic crystalline ammonia, containing isolated NH3 or ND3, confirm that, relative to water ice, intermolecular coupling in ammonia ice exerts a relatively minor influence on the infrared and Raman spectra. Nevertheless, sizeable decoupling shifts, particularly for ν1, have been observed and attributed to a combination of factors including correlation field and Fermi resonance effects. The Raman polarization data has also affirmed long standing assignments of ν1 and ν3 for ammonia ice. Warming of the ammonia thin films resulted in limited isotopic scrambling at 130 K, apparently possible only through the agency of trace concentrations of water. The vibrational coupling pattern for the resultant NHD2 and NH2D molecules suggest that proton (deuteron) migration away from the exchange centers is impossible at temperatures up to 150 K. By contrast, isotopic scrambling was rapid and complete at 140 K for amorphous ammonia hydrate films (∼35% NH3, ∼65% D2O) which were also prepared without exchange at ∼90 K. The proton (deuteron) exchange rate is much greater for the amorphous ammonia hydrate at 140 K than for pure water ice. Such exchange requires both ion-pair defect formation and proton mobility. Since the NH3 suppresses the H3O+ concentration via formation of NH+4, a suppression the likes of which has been shown to stop proton exchange in water ice, the evidence strongly suggests that NH4+ in ammonia, like H3O+ in water, is an effective proton transfer agent, probably acting through a tunneling mechanism (i.e., H3N+–H⋅⋅⋅NH3→H3N⋅⋅⋅H–N+H3 etc.) to render the proton mobile in the ammonia hydrate. This mobility combined with the greater NH4+ concentration, relative to the H3O+ concentration in H2O ice Ic, results in isotopic scrambling at the reduced temperature.

The aquation of trans-bis(ethylenediamine)difluorochromium(III) and related lons in aqueous solutions of strong acids

The hydrolysis of a series of fluoro-complexes in aqueous solutions of strong acids has been studied over a wide range of acid concentrations. The kinetic results have been analysed by the treatments of Hammett and Zucker, Bunnett, and Bunnett and Olsen. Analysis of the results indicates that hydroxonium ion acts as a proton-transfer agent in the rate-determining step. The mechanism involves attack by hydroxonium ion adjacent to the leaving protonated fluoro-ligand and should lead to retention of configuration. The hydrolysis of trans-[Cr(en)2F2]+(en = ethylenediamine) ion in perchloric acid is catalysed by added sodium fluoride, maximum catalysis being effected by only a five-fold excess of fluoride ion over complex-ion concentration. Addition of other salts has no effect on the rate constants, demonstrating that general acid–base catalysis is not involved.

Dimaprit, (S-[3-(N,N-dimethylamino)propyl]isothiourea). A highly specific histamine H2-receptor agonist. Part 2. Structure-activity considerations.

Dimaprit, S-[3-(N,N-dimethylamino)propyl]isothiourea, appears to be a highly specific histamine H2-receptor agonist. Further indications of specificity are obtained from chemical considerations. Dimaprit has two basic centres (pKa values respectively 8.23 and 9.23, at 40 degrees) and at pH 7.4 about 5% of the molecules will be present as the monocation analogous to histamine monocation. Chemical comparison suggests that the --N+HMe2 group corresponds to the --N+H3 of histamine, and that the isothiourea group of dimaprit (which can undergo 1,3-prototropic tautomerism) may simulate the imidazole ring of histamine and function as a proton transfer agent at H2 receptors. Simple structural analogues of dimaprit are only weakly active, indicating a high degree of chemical specificity for H2-receptor stimulation; such compounds (e.g. the lower homologue, SK & F 91487) may serve as useful chemical controls when studying the actions of dimaprit.

Hydrolysis of phenylureas. Part II. Hydrolysis in acid and aqueous solutions

The rate constants of hydrolysis of 4-methyl-, 4-methoxy-, 4-ethoxy, 4-isopropyl-, 4-n-butyl-, 4-chloro-, 4-bromo-, 4-nitro-, and 3-nitro-phenylurea have been measured in aqueous H2SO4(0.5–98% w/w) at 101.0°. The rate profiles exhibit a bell shape up to intermediate acidities, followed by a localised minimum, and then an increase in rate. In acidities up to the minimum application of the standard criteria of mechanism for hydrolysis of the Oprotonated conjugate acid have proved unsatisfactory. The rate constants of hydrolysis of 4-chloro- and 4-methyl-phenylurea have also been measured in 2.5–37%(w/w) HCl and 5–60%(w/w) HClO4 and in mixtures of LiCl–HCl at 101.0°. Results show that there is a strong dependence on water activity but that the counter anion has little effect. Rate constants of hydrolysis of 4-fluoro- and 3-methyl-phenylurea, the phenylureas listed above, and also phenylurea have been measured in water (pH 6.48), and these differ little from the ‘acid-catalysed’ rate constants. A new mechanism of hydrolysis is postulated, for which water acts as a proton transfer agent to either the unprotonated species or the minor N-protonated conjugate acid. Solvent deuterium isotope effects and Hammett ρ constants support the new mechanism. Electron donating substituents cause sulphonation in >70%(w/w) H2SO4 and a mechanism of hydrolysis at these higher acidities is postulated as A-1 decomposition of the O-protonated conjugate acids.

Catalyse par les sels en solvant acide acetique : Importance de la nature des agregats moleculaires sur la relation lineaire acidite-vitesse

Salt catalysis of the rate of addition of acetic acid to p-methoxystyrene in acetic acid solvent has been studied. Acidity and addition rate are increased by salt addition. A linear correlation exists between log k exp and H 0 (log k exp = −α H 0 + β), α depending on the salt species, α is characteristic of the proton transfer agent for a particular olefine, confirmed by the study of solvent isotope effect.

Acid-catalysed hydrolysis of S(IV)N bond in N-sulphonyl sulphilimines—I

Abstract The acid-catalysed hydrolysis of sulphilimines of XC 6 H 4 (Me)SNTs and MePhSNSO 2 C 6 H 4 Y type has been studied by a kinetic method in moderately concentrated (1–6 M) aqueous H 2 SO 4 and HClO 4 solutions. The rate law: rate = k ψ [sulphilimine] is valid for hydrolysis leading to sulphoxides and sulphonamides. The dependence of k ψ on acidity, temperature and substituents X and Y has been measured and interpreted, ϱ X , ϱ Y and ΔS ‡ data (+ 1·19, + 1·00 and −18·7- - 22·6 e.u., resp) show that the nucleophilic attack of water on the positively polarized S(IV) atom of protonated sulphilimines can be regarded as the rate-determining step of the hydrolysis. From φ parameters (0·94−1·5) calculated for the hydrolysis of MePhSNTs it follows that water participates in the reaction as a nucleophile and proton-transfer agent.

Hydrogen exchange as a probe of the dynamic structure of DNA: I. General acid-base catalysis

In this paper it is shown that positively-charged proton transfer agents can catalyze the exchange-out from native DNA of the hydrogens involved in internucleotide hydrogen-bonding. The negatively-charged catalysts tested did not increase the rate of exchange. The effectiveness of hydronium ion catalysis is decreased by increasing concentrations of sodium ion, while that of hydroxide ion is increased. The measured rates of proton transfer in the presence of various catalysts can be quantitatively accounted for in terms of a Bronsted-type relationship involving the p K′ A values of both the catalyst and the titratible sites of DNA, plus a superimposed electrostatic effect of the DNA phosphates which decreases the effectiveness of negatively-charged catalysts and facilitates catalysis by positively-charged species. The two types of chemically distinct DNA proton exchange sites (amino and imino groups), do not participate independently in exchange, since the addition of catalysts affects all kinetic classes of hydrogens equally. These results support the hypothesis (Printz & von Hippel, 1968) that exchange of the interchain hydrogens of DNA proceeds via a local, transiently-open (non-hydrogen bonded) conformational state which is maintained (“propped” open) by the presence of two (at acid pH) or no (at alkaline pH) hydrogens at the locus of the NH … N internucleotide hydrogen bond. The over-all rate of the exchange process appears to depend on the product of the equilibrium constant for the formation of open (propped) sites, and the rate constant for the initial transfer of protons to and from the open DNA sites exposed in this process.

Methods of preparation of sulfanes

Sulfane crude oils obtained by acidification of aqueous sodium polysulfide solutions vary little in composition with varying sulfur content of the solution. Evidence presented suggests that the distribution of the sulfanes in such crude oils reflects the equilibrated distribution of the various polysulfide anions in the aqueous solution before acidification. The sulfane distribution in mixtures obtained by reaction of liquid H2S with Br2, SCl2, and S2Cl2 respectively varies over a wide range, depending on the molar ratio of the reactants. Liquid H2S reacts with Br2 or SCl2 to yield essentially the same products. These reactions, however, differ in the nature of their intermediates. By using a large excess of liquid H2S, H2S3 was directly synthesized in over 90% purity. Liquid H2S reacts with S2Cl2 to yield H2S4 in over 90% purity. Gaseous HCl catalyzes the reaction of H2S with the chlorosulfanes and a mechanism is suggested involving HCl as a proton transfer agent in the formation of the reactive intermediates.