Reactions of trimethinecyanines of the 1,3-dioxenium series with nucleophiles. The structures of the parent carbocation and of a product of its reaction with methanol

The chemistry and the regioselectivity of alcoholysis, aminolysis, and hydrolysis of symmetrical trimethinecyanine carbenium ions in 4-[3-(2,2-diorganyl-6-phenyl-4H-1,3-dioxen-4-ylidene) prop-1-enyl]-2,2-diorganyl-6-phenyl-1,3-dioxenium perchlorates (4a,b) were investigated. The structures of trimethinecyanine 4,5:4′,5′-bisannelated at the methine chain (3) and of a product of the reaction of nonannelated trimethinecyanine with the methoxide anion were established by X-ray diffraction analysis,¹H NMR spectroscopy, and quantum-chemical calculations (PM3). The nucleophile attacks the mesomeric π-conjugated system of the trimethinecyanine cation selectivily at the C(6) atom of one of the dioxenium fragrments, the second dioxenium ring being deactivated. Alcoholysis affords products of addition of the methoxy group to trimethinecyamines. In the course of aminolysis and hydrolysis, the dioxenium ring that is subjected to the attack eliminates acetone to form 1,3-dioxenylidenepropenylic derivatives of 1,3-enaminoketones and 1,3-ketoenols, respectively. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 521–529, March. 1999.     

Intramolecular catalysis of aminolysis of phosphorus heterocycles incorporating an α‐aminoamide moiety. III. Synthesis of 2‐oxo or 2‐thioxo 1,3‐disulfonyl‐1,3,2‐diazaphospholidines and reactions with amines and alcohols

A series of 2‐oxo or 2‐thioxo 1,3‐disulfonyl‐1,3,2‐diazaphospholidines 4 was prepared by condensation of phosphonyl dichlorides 2 with bis‐N,N'‐sulfonylethylenediamines 1 in pyridine. Complete aminolysis or alcoholysis of heterocycles 4 took place with regeneration of sulfonyldiamines 1 . These reactions are very sensitive to steric hindrance, and hydrolysis is generally favoured over aminolysis. The results are discussed in terms of mechanisms of phosphorylation.     

An uncharged amine in the transition state of the ribosomal peptidyl transfer reaction

The ribosome has an active site comprised of RNA that catalyzes peptide bond formation. To understand how RNA promotes this reaction requires a detailed understanding of the chemical transition state. Here, we report the Br?nsted coefficient of the alpha-amino nucleophile with a series of puromycin derivatives. Both 50S subunit- and 70S ribosome-catalyzed reactions displayed linear free-energy relationships with slopes close to zero under conditions where chemistry is rate limiting. These results indicate that, at the transition state, the nucleophile is neutral in the ribosome-catalyzed reaction, in contrast to the substantial positive charge reported for typical uncatalyzed aminolysis reactions. This suggests that the ribosomal transition state involves deprotonation to a degree commensurate with nitrogen-carbon bond formation. Such a transition state is significantly different from that of uncatalyzed aminolysis reactions in solution.     

Nucleophilic substitution reactions of diethyl 4‐nitrophenyl phosphate triester: Kinetics and mechanism

The reactions of diethyl 4‐nitrophenyl phosphate ( 1 ) with a series of nucleophiles: phenoxides, secondary alicyclic (SA) amines, and pyridines are subjected to a kinetic study. Under excess of nucleophile, all the reactions obey pseudo‐first‐order kinetics and are first order in the nucleophile. The nucleophilic rate constants (k_N) obtained are pH independent for all the reactions studied. The Brønsted‐type plot (log k_N vs. pK_a nucleophile) obtained for the phenolysis is linear with slope β=0.21; no break was found at pK_a 7.5, consistent with a concerted mechanism. The Brønsted‐type plots for the SA aminolysis and pyridinolysis are linear with slopes β=0.39 and 0.43, respectively, also suggesting concerted processes. The concerted mechanisms for the latter reactions are proposed on the basis of the lack of break in the Brønsted‐type plots and the instability of the hypothetical pentacoordinate intermediates formed in these reactions. © 2011 Wiley Periodicals, Inc. Int J Chem Kinet 43: 708–714, 2011     

Phenolysis and aminolysis of 4‐nitrophenyl and 2,4‐dinitrophenyl S‐methyl thiocarbonates in aqueous ethanol

The reactions of S‐methyl O‐(4‐nitrophenyl) thiocarbonate ( 1 ) and S‐methyl O‐(2,4‐dinitrophenyl) thiocarbonate ( 2 ) with a series of secondary alicyclic (SA) amines and phenols are subjected to a kinetic investigation. Under nucleophile excess, pseudo‐first‐order rate coefficients (k_obs) are obtained. Plots of k_obs against the free nucleophile concentration at constant pH are linear with slopes k_N. The Brønsted plots (log k_N vs. nucleophile pK_a) for the reactions are linear with slope (β) values in the 0.5–0.7 range, in accordance with concerted mechanisms. Comparison of the SA aminolysis of 1 with the same one carried out in water shows that the change of solvent from water to aqueous ethanol destabilizes the zwitterionic tetrahedral intermediate, changing the mechanism from stepwise to concerted. This destabilization is greater than that due to the change from SA amines to quinuclidines. For the phenolysis reactions, the k_N values in aqueous ethanol are smaller than those for the same reactions in water. Considering that the nucleophile is an anion, this result is unexpected because the anion should be more stabilized in the more polar solvent. This result is explained by the facts that the phenoxide reactant has a negative charge that is delocalized in the aromatic ring and the transition state is highly polar. © 2011 Wiley Peiodicals, Inc. Int J Chem Kinet 43: 353–358, 2011     

Lipase-Catalyzed Synthesis of Carboxylic Amides: Nitrogen Nucleophiles as Acyl Acceptor

 The lipase-catalyzed aminolysis of carboxylic esters is a fairly general reaction that has been performed with a wide range of esters and amines, generally in anhydrous organic media to avoid undesirable hydrolysis of the ester. Alternatively, carboxylic amides can be synthesized by lipase mediated condensation of carboxylic acids and amines if an excess of either reactant is avoided. Chiral carboxylic esters have been resolved by lipase-catalyzed aminolysis. In the majority of these resolutions, Candida antarctica lipase B has been employed as the catalyst. A range of chiral amines has been resolved by lipase mediated acylation, using mainly the lipases from C. antarctica (B type) and Pseudomonas species. The enantiorecognition was frequently found to depend critically on the acylating agent and the reaction medium.     

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.     

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.     

synthesis and some transformations of 4-oxo-2-(β-ethoxyvinyl)-4H-1,3-benzoxazinium salts

A method was developed for the synthesis of 4-oxo-(-ethoxyvinyl)-4H-1,3-benzoxazinium salts by condensation of oxo-2-alkylbenzoxazinium salts by condensation of oxo-2-alkylbenzoxazinium salts with ethyl orthoformate. During hydrolysis and aminolysis, attack of the nucleophile is directed to the -carbon atom of the benzoxazinium salts. The previously unknown 2-formylmethylene-4-oxo-3,4-dihydro-2H-1,3-benzoxazines and their nitrogen derivatives were obtained.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 322–327, March, 1977.     

Lipase-Catalyzed Synthesis of Carboxylic Amides: Nitrogen Nucleophiles as Acyl Acceptor

Summary.  The lipase-catalyzed aminolysis of carboxylic esters is a fairly general reaction that has been performed with a wide range of esters and amines, generally in anhydrous organic media to avoid undesirable hydrolysis of the ester. Alternatively, carboxylic amides can be synthesized by lipase mediated condensation of carboxylic acids and amines if an excess of either reactant is avoided. Chiral carboxylic esters have been resolved by lipase-catalyzed aminolysis. In the majority of these resolutions, Candida antarctica lipase B has been employed as the catalyst. A range of chiral amines has been resolved by lipase mediated acylation, using mainly the lipases from C. antarctica (B type) and Pseudomonas species. The enantiorecognition was frequently found to depend critically on the acylating agent and the reaction medium. Received December 20, 1999. Accepted January 1, 2000     

Computational study of the aminolysis of esters. The reaction of methylformate with ammonia

The aminolysis of esters is a basic organic reaction considered as a model for the interaction of carbonyl group with nucleophiles. In the present computational study the different possible mechanistic pathways of the reaction are reinvestigated by applying higher level electronic structure theory, examining the general base catalysis by the nucleophile, and a more comprehensive study the solvent effect. Both the ab initio QCISD/6-31(d,p) method and density functional theory at the B3LYP/6-31G(d) level were employed to calculate the reaction pathways for the simplest model aminolysis reaction between methylformate and ammonia. Solvent effects were assessed by the PCM method. The results show that in the case of noncatalyzed aminolysis the addition/elimination stepwise mechanism involving two transition states and the concerted mechanism have very similar activation energies. However, in the case of catalyzed aminolysis by a second ammonia molecule the stepwise mechanism has a distinctly lower activation energy. All transition states in the catalyzed aminolysis are 10-17 kcal/mol lower than those for the uncatalyzed process.     

Effects of mixed CH3CN(SINGLEBOND)H2O solvents on rate of intramolecular general base-catalyzed cleavage of ionized phenyl salicylate in the presence of 3-aminopropan-1-ol, 1,2-diaminoethane,and glycine

The effects of mixed CH₃CN(SINGLEBOND)H₂O solvents on rates of aminolysis of ionized phenyl salicylate, PS⁻, reveal a nonlinear decrease in the nucleophilic second-order rate constants, k_n^ms, (for aminolysis) with increase in the content of CH₃CN until it becomes ∼50%, v/v. The values of k_n^ms remain almost unchanged with change in the CH₃CN content within 50 to 70 or 80%, v/v. The effects of mixed CH₃CN(SINGLEBOND)H₂O solvents on pK_a of leaving group, phenol, and protonated amine nucleophile have been concluded to be the major source for the observed mixed solvent effects on k_n^ms. © 1998 John Wiley & Sons, Inc. Int J Chem Kinet: 30: 301–307, 1998.     

Reactions of polymers having β-alkoxyenoate moieties in the main chain

The hydrolysis and the substitution reaction of the main chain of the polymer having β-alkoxyenoate moieties in the main chain are described. The hydrolysis of the polymer prepared from 2,2-dimetylpropylene-1,3-bis(propiolate) and p-xylene glycol under acidic conditions proceeded smoothly to obtain diols in quantitative yield by the cleavage of both ester and vinyl ether moieties. On the other hand, carboxylic acids were obtained by the hydrolysis of the polymer under alkaline conditions. The aminolysis with pyrrolidine gave the β-aminoenoate by the selective fission of vinyl ether moieties in quantitative yield. Furthermore, a polymer having β-aminoenoate moieties in the main chain was obtained by the reaction with piperazine via the displacement of the main chain. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 787–793, 1997     

The aminolysis of N-aroyl beta-lactams occurs by a concerted mechanism

N-aroyl beta-lactams are imides with exo- and endocyclic acyl centres which react with amines in aqueous solution to give the ring opened beta-lactam aminolysis product. Unlike the strongly base catalysed aminolysis of beta-lactam antiobiotics, such as penicillins and cephaloridines, the rate law for the aminolysis of N-aroyl beta-lactams is dominated by a term with a first-order dependence on amine concentration in its free base form, indicative of an uncatalysed aminolysis reaction. The second-order rate constants for this uncatalysed aminolysis of N-p-methoxybenzoyl beta-lactam with a series of substituted amines generates a Br?nsted betanuc value of +0.90. This is indicative of a large development of positive effective charge on the amine nucleophile in the transition state. Similarly, the rate constants for the reaction of 2-cyanoethylamine with substituted N-aroyl beta-lactams gives a Br?nsted betalg value of -1.03 for different amide leaving groups and is indicative of considerable change in effective charge on the leaving group in the transition state. These observations are compatible with either a late transition state for the formation of the tetrahedral intermediate of a stepwise mechanism or a concerted mechanism with simultaneous bond formation and fission in which the amide leaving group is expelled as an anion. Amide anion expulsion is also indicated by an insignificant solvent kinetic isotope effect, kH2ORNH2/kD2ORNH2, of 1.01 for the aminolysis of N-benzoyl beta-lactam with 2-methoxyethylamine. The Br?nsted betalg value decreases from -1.03 to -0.71 as the amine nucleophile is changed from 2-cyanoethylamine to propylamine. The Br?nsted betanuc value is more invariant although it changes from +0.90 to +0.85 on changing the amide leaving group from p-methoxy to p-chloro substituted. The sensitivity of the Br?nsted betanuc and betalg values to the nucleofugality of the amide leaving group and the nucleophilicity of the amine nucleophiles, respectively, indicate coupled bond formation and bond fission processes.     

Desymmetrization of dimethyl 3-substituted glutarates through enzymatic ammonolysis and aminolysis reactions

The desymmetrization of differently 3-substituted glutarates through enzymatic aminolysis and ammonolysis has been studied. The effect of the diester and nucleophile structures, the enzymatic preparation as well as the reaction conditions have been compared in terms of both the chemical yield and enantiomeric excess of the corresponding monoamide products.     

Hydrazine as a Nucleophile and Antioxidant for Fast Aminolysis of RAFT Polymers in Air

The bifunctional role of hydrazine as a potent nucleophile and antioxidant was investigated for the rapid aminolysis of RAFT polymers within minutes in air with effective suppression of the formation of disulfides. Using both dithioesters and trithiocarbonates as model compounds, we showed that hydrazine exhibited a significantly improved aminolysis rate when compared with a commonly used primary alkyl amine. On the basis of the exellent results with CTAs, we further studied the aminolysis of RAFT polymers prepared with either dithioesters or trithiocarbonates. In accord with the aminolysis results on CTAs, hydrazine aminolyzed RAFT polymers in an impressively short time and, more importantly, it significantly suppressed the formation of disulfides as comfirmed with GPC.

     

Kinetics and mechanisms of hydrolysis and aminolysis of thioxocephalosporins

The effect of replacing the beta-lactam carbonyl oxygen in cephalosporins by sulfur on their reactivity has been investigated. The second-order rate constant for alkaline hydrolysis of the sulfur analogue is 2-fold less than that for the natural cephalosporin. The thioxo derivative of cephalexin, with an amino group in the C7 side chain, undergoes beta-lactam ring opening with intramolecular aminolysis by a reaction similar to that for cephalexin itself. However, the rate of intramolecular aminolysis for the S-analogue is 3 orders of magnitude greater than that for cephalexin. Furthermore, unlike cephalexin, intramolecular aminolysis in the S-analogue occurs up to pH 14 with no competitive hydrolysis. The rate of intermolecular aminolysis of natural cephalosporins is dominated by a second-order dependence on amine concentration, whereas that for thioxocephalosporins shows only a first-order term in amine. The Bronsted beta(nuc) for the aminolysis of thioxo-cephalosporin is +0.39, indicative of rate-limiting formation of the tetrahedral intermediate with an early transition state with relatively little C-N bond formation.     

Regioselective Functionalization of 3‐Hydroxy‐pyridine Carboxylates by Neighboring Group Assistance

Regioselective hydrolysis, transesterification, and aminolysis of unactivated, highly substituted pyridine esters were realized under mild conditions by employing neighboring group assisted catalysis. Excellent yields were achieved without active removal of the alcohol byproduct. Regioselective aminolysis had a considerable substrate scope ([hetero]aryl, alkyl and amino acid). A mechanism involving assistance by the deprotonated phenolic OH‐group is suggested for hydrolysis and transesterification.     

Redesigning the mechanism of the lipase-catalysed aminolysis of esters

In a previous work, several 2-phenylcycloalkanamines were subjected to aminolysis catalysed by the lipase B from Candida antarctica (CAL-B). In these processes, the size of the cycle and the stereochemistry of the stereogenic centres of the amines had a strong influence on both the enantiomeric ratio and the reaction rate. Herein, molecular modelling approaches have been used to revise the lipase-catalysed aminolysis mechanism. Thus, complexes of CAL-B with the phosphonamidate analogues related to substrates in the kinetic resolution of several 2-phenylcycloalkanamines by this enzyme were built and minimised. This computational study suggests the formation of zwitterionic species (named TI-Z), resulting from the direct His-unassisted attack of the amine onto the carbonyl group of the acyl-enzyme, as the most plausible intermediate for the CAL-B-catalysed aminolysis. This proposal differs slightly from the commonly accepted serine-mediated mechanism, where removal of the proton from the amine occurs simultaneously to the nucleophile attack to the acyl-enzyme complex (TI-2). Subsequently, His-assisted deprotonation of the resulting ammonium group takes place, and a molecule of water could be necessary in some cases to facilitate the transfer of the proton to the catalytic histidine.     

N-甲基b-磺内酰胺氨解反应机理的理论研究

The aminolysis and the effect of water on the aminolysis processes of n-methyl β-sultam have been studied using density functional theory （DFF） method at the B3LYP/6-31G＊ level. The stationary structures and energies have been investigated for both reactions to find two different reaction channels. Specific and general solvent effects have been evaluated and the most favored pathway was found. The presence of solvent disfavors the reaction, whereas the participation of water in the aminolysis reaction plays a positive role and reduces the activation energy greatly. All transition states in the assisted aminolysis are 35-70 kJ/mol lower than those for the non-assisted reaction.