Mechanism of hydrolysis and aminolysis of homocysteine thiolactone

Homocysteine thiolactone (tHcy) is deemed a risk factor for cardiovascular diseases and strokes, presumably because it acylates the side chain of protein lysine residues (“N‐homocysteinylation”), thereby causing protein damage and autoimmune responses. We analysed the kinetics of hydrolysis and aminolysis of tHcy and two related thiolactones (γ‐thiobutyrolactone and N‐trimethyl‐tHcy), and we have thereby described the first detailed mechanism of thiolactone aminolysis. As opposed to the previously studied (thio and oxo)esters and (oxo)lactones, aminolysis of thiolactones was found to be first order with respect to amine concentration. Anchimeric assistance by the α‐amino group of tHcy (through general acid/base catalysis) could not be detected, and the Brønsted plot (nucleophilicity versus pK_a) for aminolysis yielded a slope (β^nuc) value of 0.66. These data support a mechanism of aminolysis where the rate‐determining step is the formation of a zwitterionic tetrahedral intermediate. The β^nuc value and steric factors dictate a regime whereby, at physiological pH values (pH 7.4), maximal reactivity of tHcy is exhibited with primary amine groups with a pK_a value of 7.7; this allows the reactivity of various protein amino groups towards N‐homocysteinylation to be predicted.     

Kinetics of the aminolysis and hydrolysis of alkyl nitrites: Evidence for an orbital controlled mechanism

Summary The kinetics of the nitrosation of piperidine by propyl,iso-propyl, butyl,iso-butyl,sec-butyl, andtert-butyl nitrites in 0.1M NaOH and of the hydrolysis of the nitrite esters were studied spectrophotometrically by monitoring the absorbance of the nitrites at 381 nm. The observed correlation between logk ₂ and * (*=4.5) shows the reaction to proceedvia electrophilic attack by the nitrites; the existence of an isokinetic relationship suggests a single mechanism for the whole series. Comparison of the relative reactivities of the alkyl nitrites (primary>secondary>tertiary) with characteristic parameters of theirR groups (vertical ionization potentials and heats of formation ofR ⁺) suggests that these reactions are orbital controlled. All hydrolysis reactions were slower than the corresponding aminolysis reactions. This is attributed to a retardation of the former reaction by unfavourable interactions between the lone pairs of the nucleophile and the nitroso nitrogen atom.

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Kinetik der Aminoloyse und Hydrolyse von Alkylnitriten: Hinweise auf einen orbitalkontrollierten Mechanismus

Zusammenfassung Die Kinetik der Nitrosierung von Piperidin durch Propyl-,iso-Propyl-, Butyl-,iso-Butyl-,sec-Butyl- undtert-Butylnitrit sowie die Hydrolyse der entsprechenden Nitritester wurde in alkalischem Medium (NaOH, 0.1M) spektrophotometrisch (=381 nm) untersucht. Die beobachtete Relation zwischen logk ₂ und * (*=4.5) zeigt, daß die Reaktion durch nucleophile Attacke des Amines erfolgt. Die Existenz einer isokinetischen Relation läßt einen einheitlichen Mechanismus für die gesamte untersuchte Serie vermuten. Aus dem Vergleich der gefundenen Reaktivitätssequenzen für die Alkylnitrite (primär>sekundär>tertiär) mit den strukturellen Parametern ihrer ResteR (Ionisationspotentiale, Bildungswärme vonR ⁺) schließen wir, daß die untersuchten Reaktionen orbitalkontrolliert verlaufen. In allen Fällen wurde bei gleichen Bedingungen eine im Vergleich zur Aminolyse entsprechend langsamere Hydrolyse beobachtet. Der Unterschied ist einer ungünstigen Wechselwirkung zwischen den einsamen Elektronenpaaren der Nucleophile und des Stickstoffatoms der NO-Gruppe während der Reaktion mit der OH^–-Gruppe zuzuschreiben.

     

Regioselective aminolysis and hydrolysis of chiral 1,4-ferrocenyl diacetate

The treatment of (1R,4R)-1,2-bis(phenylmethyl)ferrocenyl diacetate 2a with aqueous ammonium in THF/MeOH at room temperature for 18 h gave the single diastereomer of the (1R,4R,Sp)-1,2-acetoamido alcohol 4a with retention of the configuration. This result showed that the aminolysis occurred regioselectively at one side of the two acetates. Similarly, hydrolysis of the diacetate 2a at room temperature for 18 h occurred regio- and stereoselectively to give the optically active half-ester 10 in a good yield. The ease of the substitution may depend on the geometry of the two stereogenic centers. Only one of the acetoxy groups is suitably aligned for ionization (exo to the ferrocenyl group) to proceed efficiently; the aminolysis takes place smoothly by iron-assisted ionization, i.e., neighboring group participation. The leaving group on the second acetoxy group is not suitably aligned (endo to the ferrocenyl group) and also cannot undergo a conformational change for it to adopt the appropriate orientation for ionization to occur. This reaction is the first case of substitution in a chiral molecule in which a conformational difference between two leaving groups happened to affect the rate of aminolysis and hydrolysis at two stereogenic centers.     

Kinetics and mechanism of the aminolysis of O-aryl S-methyl thiocarbonates

[reaction: see text] The reactions of secondary alicyclic (SA) amines and quinuclidines (QUI) with 4-nitrophenyl and 2,4-dinitrophenyl S-methyl thiocarbonates (1 and 2, respectively) and those of SA amines with 2,3,4,5,6-pentafluorophenyl S-methyl thiocarbonate (3) are subjected to a kinetic study in aqueous solution, at 25.0 degrees C, and an ionic strength of 0.2 M (KCl). The reactions of thiocarbonates 1, 2, and 3 were followed spectrophotometrically at 400, 360, and 220 nm, respectively. Under amine excess, pseudo-first-order rate coefficients (k(obsd)) are found. Plots of k(obsd) vs amine concentration at constant pH are linear, with the slope (kN) independent of pH. The Br?nsted-type plots (log kN vs pKa of aminium ions) are linear for all the reactions, with slopes beta = 0.9 for those of 1 with SA amines and QUI, beta = 0.36 and 0.57 for the reactions of 2 with SA amines and QUI, respectively, and beta = 0.39 for the reactions of SA amines with 3. The magnitude of the slopes indicates that both aminolyses of 1 are governed by stepwise mechanisms, through a zwitterionic tetrahedral intermediate (T+/-), where expulsion of the nucleofuge from T+/- is the rate-determining step. The values of the Br?nsted slopes found for the aminolyses of thiocarbonates 2 and 3 suggest that these reactions are concerted. By comparison of the reactions under investigation between them and with similar aminolyses, the following conclusions arise: (i) Thiocarbonate 2 is more reactive than 1 toward the two amine series. (ii) The change of the nonleaving group from MeO in 4-nitrophenyl methyl carbonate to MeS in thiocarbonate 1 results in lower kN values. (iii) The greater reactivity of this carbonate than thiocarbonate 1 is attributed to steric hindrance of the MeS group, compared to MeO toward amine attack. (iv) The change of a pyridine to an isobasic SA amine or QUI destabilizes the T+/- intermediate formed in the aminolyses of 2. (v) The change of 4-nitrophenoxy to 2,3,4,5,6-pentafluorphenoxy or 2,4-dinitrophenoxy as the leaving group destabilizes the tetrahedral intermediate formed in the reactions with SA amines, changing the mechanism from a stepwise process to a concerted reaction.     

Kinetics and mechanism of the aminolysis of thiophenyl methylacetates in acetonitrile

The aminolysis of Z‐thiophenyl methylacetates (C₂H₅C(O)SC₆H₄Z) with X‐benzylamines in acetonitrile has been investigated at 45°C. The reaction is found to proceed by a stepwise mechanism in which the rate‐determining step is the breakdown of the zwitterionic tetrahedral intermediate, T^±, with possibly a hydrogen‐bonded four‐center‐type transition state. These mechanistic conclusions are drawn based on (i) the large magnitude of β_X (= 1.2 ∼ 2.5) and β_z (= −0.9 ∼ −1.5), (ii) the normal kinetic isotope effects (k_H/k_D ≅ 1.2) involving deuterated benzylamines (XC₆H₄CH₂ND₂), (iii) a large positive ρ_xz (= 2.4) and (iv) adherence to the reactivity‐selectivity principle in all cases. The extremely large β_X (β_nuc) values can be accounted for by the loss of a strong localized cationic charge on the N atom of benzylamines in the expulsion from the T^±. The pK_a^o (≥ 10.0) is high due to a large ratio of the expulsion rates of the amine (k_−a) to thiophenolate (k_b) (k_−a/k_b) from the T^±. © 2000 John Wiley & Sons, Inc. Int J Chem Kinet 32: 485–490, 2000     

Kinetics and mechanism of the aminolysis of O-ethyl S-aryl dithiocarbonates in acetonitrile

The aminolysis reactions of O-ethyl S-(Z-phenyl) dithiocarbonates (Z=p-CH₃, H, p-Cl, and p-NO₂) with anilines (AN) and N,N-dimethylanilines (DMA) in acetonitrile at 30.0°C are investigated. Relatively small values of β_X (β_nuc,0.4 ca. 0.7) and β_Z (β_lg −0.1 ca. −0.4) for both ANs and DMAs, significantly large k_H/k_D values (1.1 ca. 1.9) involving deuterated anilines, and large negative ρ_XZ values for ANs (−0.56) are interpreted to indicate a concerted mechanism for both ANs and DMAs but with a hydrogen bonded four-center type transition state (TS) for ANs. The relative leaving ability, k(Z=p-NO₂)/k(Z=p-CH₃), is smaller for ANs than for DMAs, especially for a weaker nucleophile (1.9 and 4.7 for AN and DMA, respectively, with X=p-Cl). This suggests that the rate enhancement by the hydrogen-bond formation in the four-center type TS for AN is greater for a weaker nucleofuge (Z=p-CH₃), especially when the nucleophile (X=p-Cl) is weaker. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 419–423,1998     

Kinetics and mechanism of the aminolysis of aryl N-ethyl thiocarbamates in acetonitrile

The aminolysis of aryl N-ethyl thiocarbamates (EtNHC(=O)SC(6)H(4)Z) with benzylamines (XC(6)H(4)CN(2)NH(2)) in acetonitrile at 30.0 degrees C is investigated. The rates are faster than the corresponding values for aryl N-phenyl thiocarbamates (PhNHC(=O)SC(6)H(4)Z), reflecting a stronger push to expel the leaving group by EtNH than the PhNH nonleaving group in a concerted process. The negative rho(XZ) (-0.86) and failure of the reactivity-selectivity principle found are consistent with the concerted mechanism. The kinetic isotope effects involving deuterated nucleophiles (k(H)/k(D) = 1.5-1.7) and low Delta H(++) with large negative Delta S(++) values suggest a hydrogen bond cyclic transition state.     

Kinetics and mechanism of the aminolysis of aryl phenyl chlorothiophosphates with anilines

Kinetic studies of the reactions of aryl phenyl chlorothiophosphates (1) and aryl 4-chlorophenyl chlorothiophosphates (2) with substituted anilines in acetonitrile at 55.0 degrees C are reported. The negative values of the cross-interaction constant rhoXY (rhoXY = -0.22 and -0.50 for 1 and 2, respectively) between substituents in the nucleophile (X) and substrate (Y) indicate that the reactions proceed by concerted SN2 mechanism. The primary kinetic isotope effects (kH/kD = 1.11-1.13 and 1.10-1.46 for 1 and 2, respectively) involving deuterated aniline nucleophiles are obtained. Front- and back-side nucleophilic attack on the substrates is proposed mainly on the basis of the primary kinetic isotope effects. A hydrogen-bonded, four-center-type transition state is suggested for a front-side attack, while the trigonal bipyramidal pentacoordinate transition state is suggested for a back-side attack. The MO theoretical calculations of the model reactions of dimethyl chlorothiophosphate (1') and dimethyl chlorophosphate (3') with ammonia are carried out. Considering the specific solvation effect, the front-side nucleophilic attack can occur competitively with the back-side attack in the reaction of 1'.     

Kinetics and mechanism of the aminolysis of O-ethyl S-phenyl dithiocarbonate in aqueous ethanol

The reactions of secondary alicyclic amines with the title substrate (PDTC) are subjected to a kinetic study in 44 wt.% aqueous ethanol, 25.0°C, ionic strength 0.2 M (KCl). Pseudo-first-order rate coefficients (k_obs) are found under amine excess. Linear plots of [N]/k_obs against 1/[N], where N is the free amine, are obtained for the reactions with piperidine, piperazine, 1-(2-hydroxyethyl)piperazine, and morpholine. The reaction with 1-formylpiperazine exhibits a linear plot of k_obs against [N]². These results are interpreted through a mechanism consisting of two tetrahedral intermediates: a zwitterionic ( T ^±) and an anionic ( T ^?), where the amine catalyzed proton transfer from T ^± to T ^? is partially rate determining for the four former reactions and is fully rate determining for the reaction of 1-formylpiperazine. The rate microcoefficients involved in the reaction scheme are either determined experimentally or estimated. Comparison with the corresponding microcoefficients reported for the same reactions in water reveals that the rate coefficient for formation of T ^± from reactants (k₁) is smaller and that for the reversal of this (k_?1) is larger in aqueous ethanol compared to water, in agreement with the expected structure of the corresponding transition state. Bronsted-type plots are obtained for k₁, k_?1, and K₁ (=k₁/k_?1) with slopes ca. 0.4, ?0.6, and 1.0, respectively. Comparison of the present stepwise reactions with the concerted ones found in the same aminolysis of O-ethyl 2,4,6,-(trinitrophenyl) dithiocarbonate indicates that T ^± is so destabilized by the change of PhS by the 2,4,6-trinitrobenzenethio group that T ^± no longer exists and becomes a transition state. © 1995 John Wiley & Sons, Inc.     

Catalysis of hydrolysis and aminolysis of non-classical beta-lactam antibiotics by metal ions and metal chelates.

The Zn(2+)-tris (hydroxymethyl)aminomethane (Tris) system has a great catalytic effect on the hydrolysis and aminolysis of some beta-lactam antibiotics. In order to ascertain the mechanism of this catalysis we have analysed the effects of the beta-lactam antibiotic structure. First we studied the kinetics of the decomposition of imipenem, SCH 29482, aztreonam and nocardicin A in aqueous solution of Tris at 35.0 degrees C, 0.5 mol.dm-3 ionic strength and in the presence of metal ions (Zn2+, Cd2+, Co2+, Cu2+, Ni2+ and Mn2+). From these studies, we conclude that Tris and metal ions (in separate solutions) exert a great catalytic effect on the hydrolysis of imipenem and SCH 29482. We suggest that in metal ion solutions a 1:1 complex is formed between the metal ion and beta-lactam antibiotic, which is attacked by hydroxide ions. Studies of the degradation of the antibiotics studied in solutions of Tris and metal ions together indicate that the systems Cd(2+)-Tris and Zn(2+)-Tris have a great catalytic effect on the hydrolysis and aminolysis of imipenem and SCH 29482. We suggest that this catalysis takes place via a ternary complex in which the metal ion plays a double role by (a) placing the antibiotic and the Tris in the right position for the reaction and (b) lowering the pKa of the hydroxide group of Tris, which is coordinated with the metal ion, generating a strong nucleophile.     

Kinetics and mechanism of the aminolysis of aryl ethyl chloro and chlorothio phosphates with anilines

The reactions of ethyl Y-phenyl chloro (1) and chlorothio (2) phosphates with X-anilines in acetonitrile at 55.0 degrees C are studied kinetically and theoretically. Kinetic results yield the primary kinetic isotope effects (k(H)/k(D) = 1.07-1.80 and 1.06-1.27 for 1 and 2, respectively) with deuterated aniline (XC(6)H(4)ND(2)) nucleophiles, and the cross-interaction constants rho(XY) = -0.60 and -0.28 for and , respectively. A concerted mechanism involving a partial frontside attack through a hydrogen-bonded, four-center-type transition state is proposed. The large rho(X) (rho(nuc) = -3.1 to -3.4) and beta(X) (beta(nuc) = 1.1-1.2) values seem to be characteristic of the anilinolysis of phosphates and thiophosphates with the Cl leaving group. Because of the relatively large size of the aniline nucleophile, the degree of steric hindrance could be the decisive factor that determines the direction of the nucleophilic attack to the phosphate and thiophosphate substrates with the relatively small-sized Cl leaving group.     

Interaction of molybdocene dichloride with cysteine-containing peptides: coordination, regioselective hydrolysis, and intramolecular aminolysis

Reactions of the organometallic compound molybdocene dichloride (Cp2MoCl2, Cp = eta5-cyclopentadienyl) with the cysteine-containing peptides L-cysteinylglycine (Cys-Gly), N-acetyl-L-cysteine (AcCys), glycyl-L-cysteine (Gly-Cys), glycyl-L-cysteinylglycine (Gly-Cys-Gly), and gamma-L-glutamyl-L-cysteinylglycine (glutathione, GSH) have been studied in aqueous solution in the pH range 2-9. The dipeptides Cys-Gly and Gly-Cys and the acetylated amino acid AcCys form 1:1 and 2:1 complexes of composition [Cp2Mo(peptide-S)(OH(2))]n+/- and [Cp2Mo(peptide-S)2]n+/- as well as the chelates [Cp2Mo(AcCys-S,O)], [Cp2Mo(Gly-Cys-S,O)]+, and [Cp2Mo(Cys-Gly-S,N)] with the Cp2Mo2+ unit binding to the deprotonated thiolate group and the free amino or carboxylate group of the cysteine residue. Upon treatment of Gly-Cys-Gly and the naturally occurring tripeptide GSH with Cp2MoCl2 at elevated temperature, release of free glycine was observed. The Cp2Mo2+ entity coordinates to the thiolate group of GSH and mediates regioselective hydrolysis of the Cys-Gly peptide bond by intramolecular metal hydroxide activation. Cp2Mo2+-promoted hydrolysis of GSH was followed at pD 7.4 and 5.2 and 40 and 60 degrees C. By contrast, the Cys-Gly bond in [Cp2Mo(Gly-Cys-Gly-S,N)] is cleaved by intramolecular aminolysis at pD > or = 7.4 and 60 degrees C leading to glycine and the Cp2Mo2+ complex of the 2,5-diketopiperazine derivative cyclo-(Gly-Cys). Chelating coordination of the Cp2Mo2+ moiety to the thiolate group and to the deprotonated amide nitrogen of the tripeptide changes the configuration of the peptide bond from (preferred) trans to cis, thus enabling nucleophilic attack of the primary amino group at the Cys-Gly bond. The reaction product [Cp2Mo{cyclo-(Gly-Cys)}] x 2H2O has been characterized by X-ray crystallography.     

Kinetics and mechanisms of hydrolysis of tetraphenylporphyrins tethered to silicate glass via a primary or tertiary alcohol linker

Tetraphenylporphyrins carrying primary or tertiary alcohols in a phenyl group were bonded to silicate glass by heat treatment. The rate of base catalyzed hydrolysis of tertiary ester was 20 times slower than that of primary ester, while the rate of acid catalyzed hydrolysis of tertiary ester was only 2.5 times slower than that of primary ester. Hydrolysis of tertiary alcohol bonded silica in HCl/H₂¹⁸O${{\text{H}}_2}^{18}\text{O}$ displayed that there is a covalent bond between alcohol oxygen and silicon, and the C–O bond is cleaved under acidic conditions, while the Si–O bond is cleaved under basic conditions.     

Kinetics and mechanism of acid hydrolysis of peroxyketals

The kinetics of hydrolysis of aliphatic ketone di-tert-butylperoxyketals R¹R²C=O, R¹, R²=CH₃, CH₃; CH₃, C₂H₅; CH₃, n-C₃H₇; CH₃, n-C₆H₁₃; CH₃, i-C₅H₁₀; CH₃, i-C₄H₉; C₂H₅, i-C₃H₇; n-C₄H₉, n-C₄H₉; CH₃, C₆H₅-CH₂, in dioxane in the presence of H₂SO₄ were investigated by IR spectroscopy. It was found that the reaction is reversible and takes place according to the equation R¹R²C· (OOC(CH₃)₃)₂ + H₂O;_H+ R¹R²C=O + 2HOOC(CH₃)₃. The proposed mechanism of hydrolysis includes the fast, quasiequilibrium formation of protonated peroxyketal and subsequent formation of the alkylperoxycarbenium ion. A three-parameter correlation equation is proposed for describing the initial rates of hydrolysis of R¹R²C(oo-t-Bu)₂ peroxyketals.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2501–2506, November, 1990.     

Kinetics and mechanism of the aminolysis of aryl thiocarbamates: effects of the non-leaving group

The kinetics of the aminolysis of aryl thiocarbamates [ATC: H2NC(=O)SC6H4Z] with benzylamines (XC6H4CH2NH2) in acetonitrile at 10.0 degrees C have been studied. The rate order with variation of the non-leaving amino group, RNH, in RNHC(=O)SC6H4Z is NH2 < PhNH < EtNH indicating that the polar (sigma*) and steric (E(s)) effects of the RNH group are insignificant, and the strength of push to expel the leaving group in the tetrahedral transition state is the sole, important effect. The strong push provided by the NH2 group, the negative rhoXZ(-0.38) value, the size of betaZ(-0.54), and failure of the reactivity-selectivity principle are all consistent with the concerted mechanism. The kinetic isotope effects involving deuterated amine nucleophiles (XC6H4CH2ND2) are normal (k(H)/k(D)approximately 1.40-1.73) suggesting a hydrogen-bonded cyclic transition state.