Efficient intramolecular general acid catalysis of nucleophilic attack on a phosphodiester

The hydrolysis of methyl 8-dimethylamino-1-naphthyl phosphate 4 and its reactions with a representative range of nucleophiles are catalyzed by the dimethylammonium group at acidic pH with rate accelerations of the order of 106. The reaction persists up to pH 7 because the strong intramolecular hydrogen bond, which is the key to efficient general acid catalysis, is present also in the reactant. The sensitivity to the basicity of the nucleophile (Br?nsted beta(nuc) = 0.29) lies between values measured previously for mono- and triesters. The comparisons suggest that general acid catalyzed reactions of phosphate mono- or diesters with strongly basic oxyanion nucleophiles (like those derived from a serine oxygen or a bound water molecule in an enzyme active site) will be fastest when their negative charges are neutralized by protonation. Reactions with NH2OH and its N-methylated derivatives show an apparent alpha-effect, but NH2OMe reacts no faster than a primary amine of similar basicity. It is suggested that the reaction involving NH2OH as an oxygen nucleophile proceeds through the pre-equilibrium formation of the tautomer H3N+-O- as the active nucleophile: ab initio calculations support this idea.     

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.     

Nucleophilic attack by oxyanions on a phosphate monoester dianion: the positive effect of a cationic general Acid

The two negative charges on a phosphate monoester RO-PO32- at neutral pH provide a considerable electrostatic barrier toward reactions with nucleophilic reagents with a negative charge on the attacking atom. Electrostatic repulsion disappears when the hydrolysis of an aryl phosphate monoester is catalyzed by a neighboring cationic general acid. The hydrolysis of 8-dimethylammonium-1-phosphate (1) is catalyzed by oxyanions, fluoride anion, and hydroxylamines at similar rates.     

Intramolecular general acid catalysis in the aminolysis of beta-lactam antibiotics

The rate of aminolysis of benzylpenicillin and cephaloridine by hydroxylamine, unlike other amines, shows only a first order dependence on amine concentration. The rate enhancement compared with that predicted from a Bronsted plot for other primary amines with benzylpenicillin is greater than 10(6). This is much more than an alpha-effect and is compatible with rate-limiting formation of the tetrahedral intermediate due to a rapid intramolecular general acid catalysed breakdown of the intermediate. For cephaloridine, the rate enhancement is greater than 10(4) which demonstrates that beta-lactam C-N bond fission and expulsion of the leaving group at C3' are not concerted.     

Intramolecular aromatic nucleophilic substitution of the benzimidazole-activated nitro group

A wide range of 2-(2-nitrophenyl)-1H-benzimidazoles undergo high-yielding intramolecular S(N)Ar of nitrite with N-pendant alkoxides under mild conditions (DMF, rt). When this operationally simple process is carried out at elevated temperatures in the presence of excess NaH, the initially formed S(N)Ar products are converted to the corresponding N-vinyl-substituted 2-(2-hydroxyphenyl)-1H-benzimidazoles via base-catalyzed isomerization. [reaction: see text]     

Intramolecular nucleophilic carbonyl trapping of alpha-ketenyl radicals by an amino group

Free-radical carbonylation of omega-alkynylamines with tributyltin hydride gives a mixture of alpha-methylene lactams and alpha-stannylmethylene lactams. Nucleophilic addition of an internal amino group to the carbonyl group of alpha-ketenyl radicals is proposed as the cyclization step. The subsequent unusual 1,4-H shift from the resulting 1-hydroxyallyl radical, followed by elimination of the beta-tributyltin radical leads to the formation of alpha-methylene lactams.     

Intramolecular charge transfer effects on 3-aminobenzoic acid

Effect of solvents, buffer solutions of different pH and β-cyclodextrin on the absorption and fluorescence spectra of 3-aminobenzoic acid (3ABA) have been investigated. The solid inclusion complex of 3ABA with β-CD is discussed by UV–Vis, fluorimetry, semiempirical quantum calculations (AM1), FT-IR, ¹H NMR and Scanning Electron Microscope (SEM). The thermodynamic parameters (ΔH, ΔG and ΔS) of the inclusion process are also determined. The experimental results indicated that the inclusion processes is an exothermic and spontaneous. The large Stokes shift emission in solvents with 3ABA are correlated with different solvent polarity scales suggest that, 3ABA molecule is more polar in the S₁ state. Solvent, β-CD studies and excited state dipole moment values confirms that the presence of intramolecular charge transfer (ICT) in 3ABA. Acidity constants for different prototropic equilibria of 3ABA in the S₀ and S₁ states are calculated. β-Cyclodextrin studies shows that 3ABA forms a 1:1 inclusion complex with β-CD. β-CD studies suggest COOH group present in non-polar part and amino group present in hydrophilic part of the β-CD cavity. A mechanism is proposed to explain the inclusion process.     

Intramolecular Diels-Alder reaction of 2-diphenylphosphinyl-5-(propargyloxymethyl)furans followed by nucleophilic 1,2-rearrangement of the phosphinyl group

The base-catalyzed intramolecular Diels-Alder reactions of 2-diphenylphosphinyl-5-(propargyloxymethyl)furans 2a-e gave the tetrahydrofuran ring annulated o-diphenylphosphinophenols 3a-e in 70-80% yields, a novel reaction involving an intramolecular Diels-Alder reaction of furan diene with allenyl ether dienophile followed by a nucleophilic 1,2-rearrangement of the diphenylphosphinyl group.     

分子内反应与分子内催化I:分子内苯并咪唑基一般碱催化2-(2'-苯并咪唑基)乙酸乙酯及3-(2'-苯并咪唑基)丙酸乙酯水解机理的探讨

本工作测定了2-(2'-苯并咪唑基)乙酸乙酯及3-(2'-苯并咪唑基)丙酸乙酯在不同pH值下的表观水解速率常数在碱性较强的溶液中, 酯的水解反应主要是由氢氧根离子进行分子间特殊碱催化来完成;而在接近中性pH值范围的溶液中, 苯并咪唑基以一般碱催化方式参与了分子内催化酯的水解反应。实验结果与所提出的理论模型较好地吻合。     

The synthesis of 2-(alkylthio)- and 2-(arylthio)-3-cyanothiophenes. The nucleophilic displacement of the alkylsulfinyl group by thiols.

The nucleophilic substitution of activated 2-(alkylsulfinyl)thiophenes with alkyl- or arylmercaptans gives the corresponding 2-(alkylthio)- or 2-(arylthio)- substituted thiophenes. When thiolate anion is used instead of thiol, sulfoxide reduction is the main reaction.     

Intramolecular nucleophilic cyclization of 3-substituted pyridylalkylamines onto the 2-position of the pyridine ring

The intramolecular nucleophilic cyclization of 4-(3-pyridyl)butylamine ( 4a ) to yield 6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine ( 5 ) was investigated. Of eleven different alkali metal reagents sodium, sodium hydride, sodium amide, and potassium hydride gave good yields of 5 . The sodium conditions when applied to 3-(3-pyridyl)propylamine ( 4b ) afforded 1,2,3,4-tetrahydro-1,8-naphthyridine ( 6 ) in good yield.