Chain-Cleavage and hydrolysis of activated polyethylene glycol derivatives: Evidence for competitive processes

Studies have been carried out with the tosylate of the monomethyl ether of polyethylene glycol (MeO–PEG–OTs) and with low molecular weight models to assess whether the neighboring oxygen at position 3 or 6 provides the driving force for hydrolytic cleavage of these activated derivatives. Our results reveal that MeO–PEG–OTs undergoes hydrolysis by competitive pathways. Water directly displaces the tosylate group to give the original PEG alcohol and the oxygen at position 6 nucleophilically displaces the tosylate group to give a cyclic oxonium ion as an intermediate. This intermediate can react by three pathways. First, it can lead to the production of the original PEG alcohol by attack of water on a ring carbon; second, dioxane and a lower molecular weight PEG alcohol is produced by water attack at the nonring carbon next to the charged oxygen; and third dioxane can be displaced by the oxygen atom at position 6 in the chain.     

Addition of tethered nonaromatic carbon nucleophiles to chemoselectively activated amides

[reaction: see text] In an effort to develop new ways of synthesizing polycyclic alkaloids, we successfully added silyl enol ethers, allylsilanes, and enamines to iminium ions generated from amides. Because of their higher oxidation state, such iminiums show a yet unexploited advantage of potential double cyclizations over standard Mannich monocyclizations. We report herein the first example of tethered nonaromatic carbon nucleophiles adding to activated amides for the generation of enaminals of various ring sizes, with endo- or exo-cyclic nitrogen.     

Efficient racemization of 1-phenylethylamine and its derivatives

We report on simple and efficient procedure for the racemization of 1-phenylethylamine and its derivatives. In the presence of trichloroisocyanuric acid, N-chloroimine derivative is formed as the intermediates, with subsequent hydrogenation catalyzed by Pd-C leading to the racemic product.     

Effect of dimerization and racemization processes on the electron density and the optical rotatory power of hydrogen peroxide derivatives

The variation of the electron density properties and optical rotatory power of the monomers and dimers of seven monosubstituted hydrogen peroxide derivatives, HOOX (X = CCH, CH(3), CF(3), t-Bu, CN, F, Cl), upon racemization has been studied using DFT (B3LYP/6-31+G) and MP2 (MP2/6-311+G) methods. The geometrical results have been rationalized on the basis of natural bond orbital (NBO) analysis. The atomic partition of the electron density properties within the atoms in molecules (AIM) methodology has allowed investigating the energy and charge redistribution in the different structures considered. The calculated optical rotatory power (ORP) of the dimers are, in general, twice of the values obtained for the monomers.     

Stereoregularity of poly(isopropyl acrylate) and its racemization during hydrolysis

The diad tacticity of poly(isopropyl acrylate) was measured from the β-proton absorptions of poly(isopropyl acrylate-α,β-d₂) obtained with a 100 MHz NMR spectrometer, and temperature dependence of the tacticity of the polymers obtained by radical polymerization was determined. Enthalpy and entropy differences between isotactic and syndiotactic addition for poly(isopropyl acrylate) were calculated to give the following values: Δ(ΔS) = 0.7 eu; Δ(ΔH) = 0.51 kcal/mole. In the hydrolysis of poly(isopropyl acrylate-α,β-d₂), it was found that the rate of hydrolysis of poly(isopropyl acrylate) was dependent on the molecular weight rather than on the tacticity. As for the rate of racemization during hydrolysis, the rate for syndiotactic polymer was much faster than that for the isotactic polymer. The exchange reaction of deuterium at α-position with hydrogen occurred in all the polymers during hydrolysis reaction.     

Regioselectivity in the palladium-catalyzed addition of carbon nucleophiles to carbocyclic derivatives.

The regioselectivity of Pd-catalyzed malonate additions and arylations to cycloalkenyl esters can be predicted by completing a stereochemical analysis of the Pd-pi-allyl complex. The Pd-catalyzed malonate additions which have the greatest degree of regioselectivity are in which substituents have a steric influence in blocking the incoming nucleophile. Cyclopentenyl substrates displayed lower regioselectivity than the cyclohexyl counterparts presumably due to increased planarity of the system. Arylations using tin and hypervalent silicon reagents were compared.     

Reaction of sulfolenes and their derivatives with some sulfur-containing nucleophiles

Reaction of 2-sulfolene, 4-hydroxy-2-sulfolene, 4-bromo- and 3-chloro-2-sulfolenes, 3-chloro-4-hydroxysulfolane, and 3,4-dibromo(dichloro)sulfolanes with sodium methane-, hexane-, allene-, benzene-, and p-toluenesulfinates and magnesium gave 3-methyl-, 3-hexyl-, 3-allyl-, 3-phenyl-, and 3-(p-tolylsulfonyl)sulfolanes, 3-methyl-, 3-phenyl-, and 3-(p-tolylsulfonyl)-4-hydroxysulfolanes, and 3-phenyl- and 4-phenylsulfonyl-2-sulfolenes.     

Aminothiazoles and aminothiadiazoles as nucleophiles in aminocarbonylation of iodobenzene derivatives

Various 2-, 3- and 4-substituted iodobenzenes were aminocarbonylated using aminothiazole and aminothiadiazole derivatives in palladium-catalysed reaction. The reaction is chemospecific toward the corresponding carboxamides. Consequently, the application of the above N-nucleophiles provided the N-1,3-thiazol-2-yl- and N-1,3,4-thiadiazol-2-ylcarboxamides in moderate to high yields. Due to the facile work-up of the reaction mixture isolated yields of 90% or higher were obtained in most cases.     

Palladium-catalyzed carbocyclization of allene-diene derivatives. Exploring different nucleophiles

The palladium-catalyzed carbocyclization of allene-diene derivatives leading to the stereospecific formation of various 4-substituted [4.3.0] and [5.3.0] bicyclic systems is presented. Different functionalities were introduced at the C-4 position of the bicyclic systems by using a range of external nucleophiles such as carboxylic acids, alcohols, phenols, and thiophenols. In the previous protocol acetic acid was used as solvent and also served as nucleophile. In this new methodology, reactions were run in nonnucleophlic solvents such as CH(2)Cl(2) or acetone in the presence of the appropriate nucleophile, making this new protocol a more versatile tool in organic synthesis. It is noteworthy that the Pd(II)-catalyzed cyclization of cycloheptadiene-derivative 1b gave exclusively the trans-annulated bicycle 4. Depending on the nature of the nucleophile, the regioselectivity of the reaction could be tuned to afford exclusively 4b or 4c' (Scheme 1). The mechanistic pathway is discussed.     

New method to analyze simulations of activated processes

We present a new method to analyze molecular and Brownian dynamics simulations of activated processes based on the concept of mean first-passage times. The new method provides a simple and efficient strategy to evaluate reaction rates and it facilitates the localization of the transition state directly from the kinetics of the system without the need of thermodynamical considerations. It also provides a more rigorous value of the steady-state transition rate and gives valuable information about many important characteristics of the process. We illustrate the power of this new technique by its application to the study of nucleation in rare gases.     

DABCO catalyzed reaction of various nucleophiles with activated alkynes leading to the formation of alkenoic acid esters, 1,4-dioxane, morpholine, and piperazinone derivatives

The reaction of acids, alcohols, acylamides, 1,2-diols, 1,2-diamines or amino alcohols with activated alkynes catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO) was systematically investigated. A series of unsaturated alkenoic acid esters or heterocycles were formed in the reaction of monobasic or dibasic nucleophiles in excellent yields, respectively.     

Reactivity of aziridinomitosene derivatives related to FK317 in the presence of protic nucleophiles

The syntheses and reactivity of N-TBDPS and N-trityl protected derivatives of an aziridinomitosene corresponding to FK317 are described. New reactivity patterns were observed for these highly sensitive and functionally dense heterocycles under mild nucleophilic conditions approaching the threshold for degradation. Thus, the silyl or trityl protected aziridinomitosene reacted with Cs(2)CO(3)/CD(3)OD to give isomeric products where substitution occurred at C(10) and C(9a) (mitomycin numbering) providing a CD(3) ether and a CD(3) hemiaminal, respectively. These findings show that heterolysis at C(10) is faster than at aziridine C(1), in contrast to the behavior of typical aziridinomitosenes in the mitomycin series. The labile N-TBDPS hemiaminal and the more stable N-trityl hemiaminal resemble the mitomycin K substitution pattern. A reagent consisting of CsF in CF(3)CH(2)OH/CH(3)CN desilylated a simple N-TBDPS aziridine but caused nucleophilic cleavage at C(1) as well as C(10) without cleavage of the N-TBPDS group in the fully functionalized penultimate aziridinomitosene. The high reactivity of the C(10) carbamate with nucleophiles precludes the use of deprotection methodology that requires N-protonation for fully functionalized aziridinomitosenes in the FK317 series.     

A quantum chemical study of racemization pathways in substituted chrysene derivatives

The potential-energy surfaces of 5,11-disubstituted 6,12-dimethoxychrysene and chrysene-6,12-dione derivatives were investigated by means of density functional calculations. We report relative energies of all conformers and an identification of the racemisation pathways of the chiral equilibrium structures. By analysis of homodesmotic reactions we were able to obtain an estimate for the strain energy of the substituted compounds. This strain energy can be used as a means of measuring the steric effects exerted by the substituents.     

Relationship between structure,fluxionality and racemization activity in organometallic derivatives of polyoxometalates

The catalytic activity of several organometallic derivatives of polyoxometalates, especially those of general formula [M₄O₁₆{M′(η⁶-arene)}₄] (M = Mo, W; M′ = Ru, Os), was evaluated in the racemization of secondary alcohols. A link between composition, fluxionality and catalytic activity was established.     

Theory of activated rate processes: Coupled modes

The thermally activated escape rate of a classical particle out of a potential well is studied in a simple model which includes coupling between the escape (reactive) coordinate and another coordinate. The main effect of the non-reactive coordinate is to open a new (non-markovian) channel between the reactive coordinate and the thermal bath.     

Photoreactions of aromatic compounds — XXVIII : Photo-induced reactions of 1-nitroazulene and derivatives with nucleophiles

The photosubstitutions of azulene, 1-nitroazulene and 3-substituted 1-nitroazulenes with nucleophiles have been investigated. In these azulenes the atom at position 1 proved to be the most reactive in accord with the calculated excited state charge densities. The photomethoxylation of 1-nitroazulene probably proceeds through a triplet state. The quantum efficiency of this reaction proved to be wavelength-dependent indicating that intersystem crossing from higher excited singlet states may occur.     

Syntheses and photochromic studies of dithienylethene-containing imidazolium derivatives and their reactivity towards nucleophiles

A series of dithienylethene-containing imidazolium salts with various substituents on the 2-position of the imidazolium ring has been synthesized. The photochromic properties of these compounds have been studied, and the closed forms are found to be solvatochromic due to the donor-acceptor interaction with the solvent molecules. The closed form of the imidazolium salt shows a much higher affinity towards nucleophiles over the open form of the salt. A reaction pathway has been proposed to account for this reactivity difference based on the structure-property relationship, and the possible structure of the reaction product is discussed.     

Accelerated hydrolysis of α-halo and α-cyano pyridinium relative to uracil derivatives: a model for ODCase-catalyzed hydrolysis of 6-cyanoUMP

α-Halo and α-cyano pyridiniums were found to undergo facile hydrolysis, in contrast to the sluggish reactions of corresponding uracils. The greatly enhanced rates found with pyridinium compounds have indicated a possible source of the rate acceleration seen in the hydrolysis of 6-cyanouridine 5′-monophosphate catalyzed by orotidine 5′-monophosphate decarboxylase.     

Polyhydroxylated sapphyrins: multisite non-metallic catalysts for activated phosphodiester hydrolysis

Enhanced hydrolysis rates for the cleavage of bis(4-nitrophenyl)phosphate (BNPP), a model phosphodiester, may be achieved by using appropriately designed ditopic receptors containing the known phosphate-binding nucleus, sapphyrin, attached covalently to suitably oriented polyhydroxyl subunits. Evidence for the interaction between sapphyrin and BNPP comes from solid-state X-ray diffraction analysis of a diprotonated dihydroxylated sapphyrin-BNPP complex and from solution-phase (31)P NMR spectroscopic binding studies. The sapphyrins described in this paper may have a role to play as oligonucleotide cleavage agents.     

Inverted reactivity of aryllithium derivatives—IV: The reaction of thienyl-aryliodonium chlorides with nucleophiles

The product distribution in the reaction of aryl-thienyliodonium chlorides with some nucleophiles has been studied. CIDNP effects were observed in the reaction with alkoxides. The mechanism of the reaction is discussed.