Modeling the reaction mechanisms of the imide formation in an N-(o-carboxybenzoyl)-L-amino acid

Reaction mechanisms of the imide formation in an N-(o-carboxybenzoyl)-l-amino acid have been studied using density functional theory. Our results suggest that the reaction route initiated by protonation at the oxygen of the carboxyl group of the amino acid is favored, while those initiated by deprotonation at the oxygen of the carboxyl group of phthalic acid and at the amidic nitrogen are minor pathways. During the dehydration process, water functions as a catalyst. These conclusions are in good agreement with the experimental facts that at highly acidic conditions (hydrogen ion concentration H(0) < -1), imide formation is the most favorable pathway, whereas in the pH range 0-5, cyclization to the imide is not the dominant reaction. Our calculations also show that the carboxyl group of the amino acid is involved in the catalytic reaction in both the favored and minor pathways and that solvent effects have little influence on the reaction barriers.     

Synthesis and complex formation of 2-ammoethylthioacet(N-2-pyridylmethyl)amide

Summary A new ligand, 2-aminoethylthioacet(N-2-pyridylmethyl)amide was synthesized. The complex formation of the ligand with Cu^II, Co^II and Co^III ions and that of the carbobenzoxy derivative of the ligand with Cu^II ions has been investigated. Structures are proposed for all complexes isolated and the factors influencing metal-sulphur bond formation in the complexes discussed.     

Mechanistic studies on the hydrolysis of a dimeric alkylzinc bis(2-pyridylmethyl)amide

Bis(2-pyridylmethyl)amine 7 reacts with selected dialkylzinc compounds to give dimeric alkylzinc bis(2-pyridylmethyl)amides 8. Regardless of the steric bulk of the alkyl substituent, dimers with central Zn₂N₂ rings are formed. Compounds 8 undergo spontaneous hydrolysis reactions upon exposure to air/moisture which can be partially controlled if the alkyl substituent R is bulky enough [R = CH(SiMe₃)₂]. A dimeric compound 9 containing both zinc-alkyl substituents and a μ-OH functionality results. In the course of this reaction, an amide instead of the expected RH is eliminated. Extensive DFT calculations show that the facile formation of a three-centered Zn[μ-(HO?H?NHR)]Zn functionality is a crucial step. Further evidence for the importance of Zn[μ-(X?H?Y)]Zn intermediates (X, Y = O and now N) in the general mechanism of hydrolysis catalyzed by binuclear zinc compounds is thus provided.     

Elucidation of hydrolysis mechanisms for fatty acid amide hydrolase and its Lys142Ala variant via QM/MM simulations

Fatty acid amide hydrolase (FAAH) is a serine hydrolase that degrades anandamide, an endocannabinoid, and oleamide, a sleep-inducing lipid, and has potential applications as a therapeutic target for neurological disorders. Remarkably, FAAH hydrolyzes amides and esters with similar rates; however, the normal preference for esters reemerges when Lys142 is mutated to alanine. To elucidate the hydrolysis mechanisms and the causes behind this variation of selectivity, mixed quantum and molecular mechanics (QM/MM) calculations were carried out to obtain free-energy profiles for alternative mechanisms for the enzymatic hydrolyses. The methodology features free-energy perturbation calculations in Monte Carlo simulations with PDDG/PM3 as the QM method. For wild-type FAAH, the results support a mechanism, which features proton transfer from Ser217 to Lys142, simultaneous proton transfer from Ser241 to Ser217, and attack of Ser241 on the substrate's carbonyl carbon to yield a tetrahedral intermediate, which subsequently undergoes elimination with simultaneous protonation of the leaving group by a Lys142-Ser217 proton shuttle. For the Lys142Ala mutant, a striking multistep sequence is proposed with simultaneous proton transfer from Ser241 to Ser217, attack of Ser241 on the carbonyl carbon of the substrate, and elimination of the leaving group and its protonation by Ser217. Support comes from the free-energy results, which well reproduce the observation that the Lys142Ala mutation in FAAH decreases the rate of hydrolysis for oleamide significantly more than for methyl oleate.     

4,5-Dihydroxyimidazolidin-2-ones in the α-ureidoalkylation reaction of N-(carboxyalkyl)-, N-(hydroxyalkyl)-, and N-(aminoalkyl)ureas 1. α-Ureidoalkylation of N-(carboxyalkyl)ureas

Russian Chemical Bulletin - The α-ureidoalkylation of N-(carboxyalkyl)ureas (ureido acids) with 1,3-H2 s-, 1,3-Me 2 s-, and 1,3-Et2 s-4,5-dihydroxyimidazolidin-2-ones was systematically...     

Copper(II) complexes of acid amide derivatives of 2-aminopyridineand an exogenous ligand

The bidentate ligands, 2-[(N-acetyl)aminopyridine] (AAPH, A) and 2-[(N-benzoyl)aminopyridine] (BAPH, B) have been used to synthesize copper(II) complexes including an exogenous ligand X (X = AcO^–, HCO₂ ^–, N₃ ^– and benzimidazole). The complexes were characterized by elemental analysis, electronic and vibrational spectroscopy, magnetic and e.s.r. studies. E.s.r. parameters and visible spectra indicated that all the complexes are monomers and exist in distorted octahedral geometry except for benzimidazole. With benzimidazole as an exogenous ligand, a five coordinate complex is formed.     

Synthesis of N-(3-arylpropyl)amino acid derivatives by Sonogashira types of reaction in aqueous media

[reaction: see text]. N-propargylamino acids and peptides including them can be efficiently derivatized in aqueous media with a wide variety of (hetero)aryl halides by cross-coupling reactions catalyzed by palladium on carbon (10% Pd/C).     

Kinetics and mechanism of an unique hydrolysis reaction of (hexafluoroacetylacetonato)bis(ethylenediamine)cobalt(III) in aqueous solution

Summary Addition of base to the title complex results in the rapid reversible formation of the hydrolysed species Co(en)₂-(hfac · OH)⁺ in which the coordinated hexafluoroacetylacetonato ligand contains a hydroxyl group on the carbonyl carbon atom. The kinetics of both the forward hydrolysis and reverse acidolysis reactions were followed spectrophotometrically using stopped-flow and T-jump techniques. The corresponding rate constants areca. 3×106 and 1×10⁸ M^–1s^–1, respectively, for various buffer systems at 25 °C and ionic strength 1.0 M. A combination of the kinetic and equilibrium data enables the estimation of the uncatalyzed (spontaneous) forward and reverse reaction components. The results are discussed with reference to similar data reported for the hydrolysis and reverse acidolysis reactions of the uncoordinated acetylacetonato ligand.     

Unusual course of the reaction of N-(tosylmethyl)thiourea and N-(azidomethyl)thiourea with sodium enolate of dimedone

The end product of the reaction of N-(tosylmethyl)thiourea or N-(azidomethyl)thiourea with sodium enolate of dimedone is bis(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)methane (methylenebisdimedone) instead of the expected 8a-hydroxy-7,7-dimethyl-2-thioxoperhydroquinazolin-5-one.M. V. Lomonosov State Academy of Fine Chemical Technology, Moscow 117571, Russia; Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 70–72, January, 2000.     

QM/MM modelling of oleamide hydrolysis in fatty acid amide hydrolase (FAAH) reveals a new mechanism of nucleophile activation

Fatty acid amide hydrolase (FAAH), a promising target for the treatment of several central and peripheral nervous system disorders, such as anxiety, pain and hypertension, has an unusual catalytic site, and its mechanism has been uncertain; hybrid quantum mechanics/molecular mechanics (QM/MM) calculations reveal a new mechanism of nucleophile activation (involving a Lys-Ser-Ser catalytic triad), with potentially crucial insights for the design of potent and selective inhibitors.