Intramolecular General Acid Catalysis Research Articles

Revisiting the Mechanism of Hydrolysis of Betanin.

Betanin (betanidin 5-O-β-D-glucoside) is a water-soluble plant pigment used as a color additive in food, drugs and cosmetic products. Despite its sensitivity to light and heat, betanin maintains appreciable tinctorial strength in low acidic and neutral conditions, where the color of other plant pigments, such as anthocyanins, quickly fades. However, betanin is an iminium natural product that experiences acid- and base-catalyzed hydrolysis to form the fairly stable betalamic acid and cyclo-DOPA-5-O-β-D-glucoside. Here, we show that the decomposition of betanin in aqueous phosphate solution pH 2-11 is subject to general base catalysis by hydrogen phosphate ion and intramolecular general acid and base catalysis, providing new insights on the mechanism of betanin hydrolysis. UV/Vis absorption spectrophotometry, 1 H NMR spectroscopy and mass spectrometry were used to investigate product formation. Furthermore, theoretical calculations support the hypothesis that the nitrogen atom of the tetrahydropyridine ring of betanin is doubly protonated, as observed for structurally simpler amino dicarboxylic acids. Our results contribute to the study of betanin and other pigments belonging to the class of betalains and to deepen the knowledge on the chemical properties of imino acids as well as on iminium-catalyzed modifications of carbonyl compounds in water.

Phase‐Transfer‐Catalysed Synthesis of Pyrroloindolines and Pyridoindolines by a Hydrogen‐Bond‐Assisted Isocyanide Cyclization Cascade

A cascade reaction that generates pyrrolo- and pyridoindoline motifs from isocyanide precursors under phase-transfer conditions is described. This transformation proceeds at room temperature in the presence of a quaternary ammonium catalyst and base to generate functionalized products containing an all-carbon quaternary stereocentre. Quantum chemical calculations demonstrated that intramolecular general acid catalysis plays a key accelerating role through stabilization of developing charge in the transition state, and that the reaction is best described as a 5-endo dig cyclization, rather than an anionic 6π electrocyclization. Investigations employing chiral phase-transfer catalysts have given promising selectivities to date.

Intramolecular reaction and intramolecular catalysisd̊ II. Mechanism of intramolecular catalysis in hydrolysis of 2-(2'-benzimidazolyl)phenyl acetate by benzimidazolyl group

As a model for acetyl-α-chymotrypsin, 2-(2'-benzimidazolyl)phenyl acetate was synthesized in a good yield and its hydrolytic kinetics has been studied in buffer solutions at 45'C within a wide pH range (0.65–8.80). The measured pseudo-first-order rate constants (kobs) at different pH values conform well with the data derived from the proposed theoretical model. It is shown that in an acidic solution of medium strength (pH = 2.0–3.0), the ester is hydrolyzed via intramolecular general acid catalysis by benzimidazolium cation; while at pH values near neutrality (pH = 5.5–7.0), this ester is hydrolyzed via intramolecular general base catalysis by neutral benzimidazole. These findings are discussed and the activation parameters of the hydrolysis reaction were also determined.

ChemInform Abstract: Intramolecular General Acid Catalysis in the Acid Decomposition of Ethylene Bis(dithiocarbamate) and Glycinedithiocarboxylate

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Intramolecular Catalysis of Phosphodiester Hydrolysis by Two Imidazoles

Two imidazole groups act together to catalyze the hydrolysis of the phosphodiester bis(2-(1-methyl-1H-imidazolyl)phenyl) phosphate (BMIPP). A full investigation involving searching computational and electrospray ionization (ESI-MS-/MS) and ultra mass spectrometry (LTQ-FT) experiments made possible a choice between two kinetically equivalent mechanisms. The preferred pathway, involving intramolecular nucleophilic catalysis by imidazole, assisted by intramolecular general acid catalysis by the imidazolium group, offers the first simple model for the mechanism used by the extensive phospholipase D superfamily.

The efficiency of proton transfer in Kirby’s enzyme model, a computational approach

Abstract DFT and ab initio calculation results for proton transfer reactions in Kirby’s acetals reveal that the mechanism proceeds via efficient intramolecular general acid catalysis (IGAC) and not through a ‘classical’ general acid catalysis mechanism (GAC). Further, they show that the driving force for the proton transfer efficiency is the proximity of the two reactive centers (r) and the attack angle (α), and the rate of the reaction is linearly correlated with r2 and sin (180° − α). Acetals with short r values and with α values close to 180° (forming a linear H-bond) are more reactive due to the development of strong hydrogen bonds in their global minimum, transition state, and product structures.

Efficient Intramolecular General-Acid Catalysis of the Reactions of α-Effect Nucleophiles and Ammonia Oxide with a Phosphate Triester

The S(N)2(P) reactions with alpha-effect nucleophiles of the cationic form 1.H(+) of phosphate triester diethyl 8-(N,N-dimethylamino)-1-naphthyl phosphate are catalyzed by the neighboring dimethylammonium group, with accelerations as high as 10(6). Hydroxylamine and its N-methyl and N,N-dimethyl derivatives, which react through oxygen, we presume by way of the zwitterionic ammonia oxide tautomers, are of special interest. The alpha-effect and the efficient general-acid catalysis in this system are mutually reinforcing. The alpha-effect is greater for the reactions of the triester than for the corresponding mono- and diesters and qualitatively different for hydroxylamines RR'NOH, where the likely role of the ammonia oxide tautomer NH(3)(+)-O(-) is evaluated by ab initio calculations. The initial phosphorus-containing product NH(2)OPO(OEt)(2) reacts further with hydroxylamine to generate diethyl phosphate and diimide, identified by its disproportionation to hydrazine and N(2) and its reducing potential.

Intramolecular General Acid Catalysis of the Hydrolysis of 2-(2‘-Imidazolium)phenyl Phosphate, and Bond Length−Reactivity Correlations for Reactions of Phosphate Monoester Monoanions

Rate constants for the hydrolysis of 2-(2'-imidazolium)phenyl hydrogen phosphate (IMPP) in water at pH<6 indicate that activation by the imidazolium moiety disappears with the deprotonation of the phosphate group, and the reaction involves the hydrogen-bonding of the imidazolium NH with the aryl oxygen leaving group. The reaction should involve a near-planar conformation of the imidazolium and the phenyl groups in the activated complex, which favors proton-transfer. The crystal structure of IMPP was solved, and a bond length-reactivity correlation for reactions of phosphate monoester monoanions is described.

Intramolecular carboxylic group‐assisted cleavage of N‐(2‐hydroxyphenyl)phthalamic acid (7) and N‐(2‐methoxyphenyl)phthalamic acid (8): Absence of intramolecular general acid catalysis due to 2‐OH in 7

AbstractThe values of pseudo first‐order rate constants (kobs) for the cleavage of N‐(2‐hydroxyphenyl)phthalamic acid (7), obtained at 4.9 × 10−2 M HCl, 35°C, and within CH3CN content range 2–80% (v/v) in mixed aqueous solvent are smaller than kobs for the cleavage of N‐(2‐methoxyphenyl)phthalamic acid (8), obtained under almost similar experimental conditions, by nearly 1.5‐ to 2‐fold. These observations show the absence of expected intramolecular general acid catalysis due to 2‐OH group in 7. The values of kobs for the cleavage of 7 and 8 decrease by more than 20‐fold with the increase in the content of CH3CN from 2 to 80–82% (v/v) in mixed aqueous solvent. The kinetic data reveal that in acidic aqueous cleavage of 7, N‐cyclization (leading to the formation of imide) and O‐cyclization (leading to the formation of phthalic anhydride) vary from ∼10 to 15% and ∼90 to 85%, respectively, with the increase in CH3CN content from 2 to 80% (v/v). Similar increase in CH3CN content causes increase in N‐cyclization from ∼0 to 5% and decrease in O‐cyclization from ∼100 to 95% in the acidic aqueous cleavage of 8. Some speculative, yet conceivable, reasons for nearly 10 and 0% N‐cyclization in the cleavage of respective 7 and 8 at low content of CH3CN have been described. © 2006 Wiley Periodicals, Inc. Int J Chem Kinet 38: 746–758, 2006

Free energy relationships and intramolecular general acid catalysis

AbstractVariations in reactivity of substituted salicylic acid derivatives are appraised in the light of the work of Jencks on transition‐state structures, variations in transition‐state structure and variations in reaction mechanism. The transition states for the intramolecular general acid‐catalysed hydrolyses of a variety of compounds derived from salicylic acid are shown to be closely related to those for the corresponding spontaneous hydrolysis reactions of compounds derived from substituted phenols. Free energy relationships are used to estimate the potential benefits of improving intramolecular hydrogen bond geometry in an aqueous environment. Copyright © 2004 John Wiley &amp; Sons, Ltd.

Nonenzymatic breakdown of the tetrahedral (alpha-carboxyketal phosphate) intermediates of MurA and AroA, two carboxyvinyl transferases. Protonation of different functional groups controls the rate and fate of breakdown.

The mechanisms of nonenzymatic breakdown of the tetrahedral intermediates (THIs) of the carboxyvinyl transferases MurA and AroA were examined in order to illuminate the interplay between the inherent reactivities of the THIs and the enzymatic strategies used to promote catalysis. THI degradation was through phosphate departure, with C-O bond cleavage. It was acid catalyzed and dependent on the protonation state of the carboxyl of the alpha-carboxyketal phosphate functionality, with ionizations at pK(a) = 3.2 +/- 0.1 and 4.3 +/- 0.1 for MurA and AroA THIs, respectively. The solvent deuterium kinetic isotope effect for MurA THI at pL 2.0 was 1.3 +/- 0.4, consistent with general acid catalysis. The pK(a)'s suggested intramolecular general acid catalysis through protonation of the bridging oxygen of the phosphate, though H(3)O(+) catalysis was also possible. The product distribution varied with pH. The dominant breakdown products were pyruvate + phosphate + R-OH (R-OH = UDP-GlcNAc or shikimate 3-phosphate) at all pH's, particularly low pH. At higher pH's, increasing proportions of ketal, arising from intramolecular substitution of phosphate by the adjacent hydroxyl and the enolpyruvyl products of phosphate elimination were observed. With MurA THI, the product distribution fitted to pK(a)'s 1.6 and 6.2, corresponding to the expected pK(a)'s of a phosphate monoester. C-O bond cleavage was demonstrated by the lack of monomethyl [(33)P]phosphate formed upon degrading MurA [(33)P]THI in 50% methanol. General acid catalysis through the bridging oxygen is consistent with the location of the previously proposed general acid catalyst for THI breakdown in AroA, Lys22.

ZstatFlu-II test: a chemiluminescent neuraminidase assay for influenza viral diagnostics.

The ZstatFlu-II test is a highly sensitive, specific, rapid, point-of-care chemiluminescent diagnostic test for influenza infection. Influenza viral neuraminidase-specific substrate, spiroadamantyl-1,2-dioxetane-4,7-dimethoxy-N-acetyl-neuraminic acid, is at the core of the ZstatFlu-II Test. The enzymatic reaction was carried out at 25 degrees C and neutral pH, representing the optimum assay conditions for influenza types A and B viral neuraminidases. The results were outputted on a Polaroid trade mark High Speed Detector Film. Positive results appeared as a '+'-shaped white film image; negative results produced no image. The 'glow' kinetics, facilitated by a unique combination of light enhancers, also 'tuned' the wavelength of emission to match the spectral properties of the film. The substrate hydrolysed non-enzymatically at acid pH or at temperatures above 25 degrees C. In order to minimize false positives, the ZstatFlu-II Test was formatted with 0.3-0.4 K(m) substrate and freezing the test kit until use. The pH optimization of the ZstatFlu-II test is discussed with reference to model compounds of sialyl-glycosides. A nucleophilic attack or an electrostatic stabilization of a developing carbonium ion under the influence of the adjacent carboxyl group was probably responsible for non-enzymatic hydrolysis of the substrate. Intramolecular general acid catalysis is proposed as a mechanism for the lability of the O-glycosidic linkage of the substrate.

Saccharide-accelerated hydrolysis of boronic acid imines

Twenty substituted N-benzylidineaniline derivatives have been synthesised and their kinetic behaviour investigated. The rate of hydrolysis of the boronic acid imines was found to be accelerated by added saccharide. Catalytic activity was only observed below the pKa of the boronic acid. Altering the concentration or type of saccharide revealed a Brønsted-like linear free energy relationship, indicating that intramolecular general acid catalysis was operating. Structure–activity relationship studies demonstrated that the system's electronic demands were independent of the boronic acid moiety.

Catalysis of acyl group transfer by a double-displacement mechanism: the cleavage of aryl esters catalyzed by calixcrown-Ba2+ complexes

The scope of the barium salt of p-tert-butylcalix[4]arene-crown-5 as a transacylation catalyst has been defined by evaluating its efficiency in the methanolysis of a series of aryl acetates at 25.0 degrees C in MeCN/MeOH 9:1 (v/v) under slightly basic conditions. In this system a phenolic hydroxyl is the acyl-receiving and -releasing unit in a double-displacement mechanism. The complexed barium ion acts both as a nucleophile carrier and a built-in Lewis acid in providing electrophilic assistance to the ester carbonyl both in the acylation and deacylation step (nucleophilic-electrophilic catalysis). Turnover capability is ensured by the acylated intermediate reacting with the solvent more rapidly than the original ester, but a serious drawback derives from the incursion of back-acylation of the liberated phenol. A gradual shift from rate-determining deacylation (p-nitrophenyl acetate) to rate-determining acylation (phenyl acetate) is observed along the investigated series. It is shown that the scope of the catalyst is restricted to acetate esters whose reactivity lies in the range approximately defined by the phenyl acetate-p-nitrophenyl acetate pair, with a maximum efficiency for p-chlorophenyl acetate. Moreover, the catalyst effectively promotes ester interchange between phenols, showing that its activity is not limited to solvolysis reactions. The very high sensitivity of the rate of acylation of the catalyst to leaving group basicity has been interpreted as due to rate-determining decomposition of the tetrahedral intermediate, which is believed to arise from the presumably low basicity of the metal ion stabilized nucleophile. The turnover frequency was in the range of 3.8 x 10(-4) min(-1) for phenyl acetate to 7.4 x 10(-3) min(-1) for p-nitrophenyl acetate ([ArOAc]0=4.0 mM]). A first attempt to enhance the rate of acylation of the catalyst through intramolecular general acid catalysis is also described.

A mechanism for efficient proton-transfer catalysis. Intramolecular general acid catalysis of the hydrolysis of 1-arylethyl ethers of salicylic acid

The tert-butyl (1) and 1-arylethyl ethers (2) of salicylic acid are hydrolyzed with efficient general acid catalysis by the ortho-COOH group. The half-life of the neutral COOH form of the tert-butyl ether is 15.2 min at 39°, and the estimated acceleration by the COOH group of 2, X = Me, Y = H is 2.13 × 105. The salicylate leaving group from 2 (X = Me, Y = H) has an effective pKa of 2.9, compared with a nominal pKa of 8.52. Analysis of substituent effects in both arylethyl and leaving groups provides the most detailed available mechanistic insight into a reaction involving efficient intramolecular proton-transfer catalysis. The mechanism is very different from classical general acid-base catalysis. Proton transfer takes place very rapidly within a developing strong hydrogen bond, and though an integral part of the C—O cleavage process is practically uncoupled from it. "Strategic delay" of the proton-transfer step, relative to C—O cleavage, makes a significant contribution to efficiency by setting up the conditions for the formation of the strong, intramolecular hydrogen bond.Key words: catalysis, carboxyl, hydrogen bond, proton transfer, enzyme mechanism.

Mechanisms of Acid Decomposition of Dithiocarbamates. 2. Efficiency of the Intramolecular General Acid Catalysis.

The acid decomposition of ethylenebis(dithiocarbamate) (EbisDTC) and glycinedithiocarboxylate (glyDTC) was studied in water at 25 degrees C in the range of H(o) -5 to pH 5. The acid dissociation constants of all species involved were calculated from LFER and from the pH-rate profiles. According to the pK(a) of the parent amine of the reactive species, both compounds decompose through the dithiocarbamate anion and a zwitterion intermediate. The intermolecular N-protonation rate constant of the carboxylic conjugate acid of glyDTC anion is 12.6 M(-)(1) s(-)(1), slower than the C-N breakdown. This species also cleaves through an intramolecular general acid-catalyzed mechanism where the rate constant for the N-protonation is (7.1 +/- 4.2) x 10(3) s(-)(1) and the efficiency of the proton-transfer step as measured by the effective molarity is (5.6 +/- 3.3) x 10(2) M. The acid decomposition of the dithiocarbamic conjugate acid of EbisDTC anion proceeds through a fast N-protonation and a slower C-N breakdown. The intramolecular general acid catalysis rate constant is (8.2 +/- 2.8) x 10(6) s(-)(1), but the efficiency of this fast proton transfer is only (14.3 +/- 4.9) M. The intramolecular general acid catalysis of the free acid forms of the carboxylic and dithiocarbamic groups is unfavorable for about 4 kcal mol(-)(1) with respect to the protonation of the external hydron, and consequently, no external buffer catalysis is expected to be observed for dithiocarbamates that decompose through a zwitterion intermediate. The difference between the pK(b) of the proton acceptor and the pK(a) of the donor follows the order of the proton efficiency. Estimation of the strength of the hydrogen bonding in the reagent and product supports the assumption that a thermodynamically favorable change of hydrogen bonding from reagent to product increases the efficiency of proton transfer.

A mechanism for efficient proton-transfer catalysis. Intramolecular general acid catalysis of the hydrolysis of 1-arylethyl ethers of salicylic acid

A mechanism for efficient proton-transfer catalysis. Intramolecular general acid catalysis of the hydrolysis of 1-arylethyl ethers of salicylic acid

The mechanism of catalysis and the inhibition of β-lactamases

Formation of a tetrahedral intermediate by nucleophilic attack on the β-lactam carbonyl carbon of penicillins generates a lone pair on the β-lactam nitrogen which is syn to the incoming nucleophile, in contrast to the normal anti arrangement found in peptides. Ring opening of the β-lactam requires protonation of the β-lactam nitrogen by a general acid catalyst. The general acid/base catalyst in β-lactamases is probably a glutamate and a tyrosine residue in class A and C enzymes, respectively. Phosphonamidates inactivate class C β-lactamases by phosphonylation of the active site serine, the rate of which is enhanced by a factor of at least 106. The enzyme’s catalytic machinery used for hydrolysis is also used for phosphonylation. The rate enhancement may be greater than 109 if the mechanism occurs by an inhibitor assisted reaction involving intramolecular general acid catalysis. Class B metallo-β-lactamases are inhibited by thiol derivatives with Ki as low as 10 µM. The mechanism of hydrolysis of the metallo-β-lactamase involves a dianionic tetrahedral intermediate stabilised by zinc(II).

Intramolecular assistance of cis/trans isomerization of the histidine-proline moiety.

Peptidyl-prolyl cis/trans isomerization is a slow conformational interconversion in the polypeptide backbone that is frequently rate-limiting in refolding of proteins and is thought to play a role in cellular restructuring of proteins. In order to probe the influence of positively charged amino acids located in sequence segments adjacent to proline, the rotational barriers of Arg-Pro- and His-Pro-containing peptides were determined by isomer-specific proteolysis and dynamic NMR spectroscopy for Suc-Ala-His-Pro-Phe-NH-Np, Ac-Ala-Arg-Pro-Ala-Lys-NH2, Ac-Ala-His-Pro-Ala-Lys-NH2, angiotensin III, thyrotropin-releasing hormone (TRH), and [His(3-Me)2]TRH in aqueous solution. In contrast to the guanidinium group of arginine, the protonated side chain of histidine preceding proline led to an acceleration of the prolyl isomerization up to 10-fold relative to the unprotonated state. Both arginine and histidine residues succeeding proline in an amino acid sequence proved to be ineffective. Under basic and acidic conditions the kinetic solvent deuterium isotope effects Kc-->tH20/Kc-->tD20 for angiotensin III were 1.0 +/- 0.1 and 2.0 +/- 0.1, respectively. The results are interpreted in terms of intramolecular general acid catalysis of prolyl bond rotation by the imidazolium group that is without precedent in intermolecular catalysis.

Efficiency of proton transfer catalysis. Intramolecular general acid catalysis of the hydrolysis of dialkyl acetals of benzaldehyde

Intramolecular general acid catalysis is demonstrated for the first time for the hydrolysis of dialkyl acetals of benzaldehyde. Effective molarities (EM) ranging from 810 to over 104 mol dm-3 are observed for the hydrolysis of the carboxylic acid 4 and for the three dimethylammonium systems 5·H+–7·H+, which show pH–rate profile plateaux extending as far as pH 7–9. Reactivity is shown to depend significantly on the strength of the general acid involved. Efficient catalysis depends on the development of a strong hydrogen bond in the transition state for the reaction, but efficiency is reduced when significant intramolecular hydrogen bonding is present in the ground state. The most reactive acetal, the carboxylic acid 4, is hydrolysed with a halflife of 1.15 s at 20 °C, fast enough to become complicated kinetically by the build up of the hemiacetal intermediate (Scheme 2). It does not, however, show the highest EM.