Dealkylation Reactions Research Articles

Novel reactions of cyclocarbaphosphazenes and cyclocarbathiazenes

The hybrid inorganic-organic heterocycles, pentachlorocyclocarba phosphazene, (ClCN)2(Cl2PN) and triachlorocyclocarbathiazene, (ClCN)2(ClSN) were synthesized and their reaction chemistry explored with emphasis on dealkylation reactions of the heterocycles with tertiary amines. Reactions of (ClCN)2(Cl2PN) were carried out with bicyclic, unsymmetric and sterically hindered tertiary amines as well as aminomethyl ferrocenes. In all cases, the C-Cl bonds of the carbaphosphazene were found to react with the tertiary amines resulting in the cleavage of an alkyl group and regiospecific substitution of the dialkylamino group on the ring carbon atoms of the heterocycle. While bicyclic amines were found to undergo ring opening, the preference of the cleaved group in the case of unsymmetrical amines were found to depend on the stability of the carbocations formed. Similar dealkylation was observed in the reactions of the carbathiazene (ClCN)2(ClCN) with tertiary amines.

Crystal structures of aged phosphonylated acetylcholinesterase: nerve agent reaction products at the atomic level.

Organophosphorus acid anhydride (OP) nerve agents are potent inhibitors which rapidly phosphonylate acetylcholinesterase (AChE) and then may undergo an internal dealkylation reaction (called "aging") to produce an OP-enzyme conjugate that cannot be reactivated. To understand the basis for irreversible inhibition, we solved the structures of aged conjugates obtained by reaction of Torpedo californica AChE (TcAChE) with diisopropylphosphorofluoridate (DFP), O-isopropylmethylphosponofluoridate (sarin), or O-pinacolylmethylphosphonofluoridate (soman) by X-ray crystallography to 2.3, 2.6, or 2.2 A resolution, respectively. The highest positive difference density peak corresponded to the OP phosphorus and was located within covalent bonding distance of the active-site serine (S200) in each structure. The OP-oxygen atoms were within hydrogen-bonding distance of four potential donors from catalytic subsites of the enzyme, suggesting that electrostatic forces significantly stabilize the aged enzyme. The active sites of aged sarin- and soman-TcAChE were essentially identical and provided structural models for the negatively charged, tetrahedral intermediate that occurs during deacylation with the natural substrate, acetylcholine. Phosphorylation with DFP caused an unexpected movement in the main chain of a loop that includes residues F288 and F290 of the TcAChE acyl pocket. This is the first major conformational change reported in the active site of any AChE-ligand complex, and it offers a structural explanation for the substrate selectivity of AChE.

Dealkylation reactions of dialkylaminomethylferrocenes with cyclic chlorocarbaphosphazene, (ClCN) 2(Cl 2PN)

Dialkylaminomethylferrocenes, FcCH 2NRR′ (NRR′=NMe 2 ( 1), NEt 2 ( 2), N(CH 2CH=CH 2) 2 ( 3), N(CH 2CH 2) 2O ( 4), N(Me)(CH 2Ph) ( 5) and N(Me)( c-C 6H 11) ( 6) (Fc=Ferrocenyl) were synthesized by the reaction of ferrocene with the corresponding diamines, RR′NCH 2NRR′. The identity of 3 was further confirmed by X-ray structural analysis of its hydrochloride, FcCH 2NH(CH 2CHCH 2) 2 +Cl − ( 7). Reactions of compounds 1– 6 were carried out with tetrachlorodicarbaphosphatriazene, (ClCN) 2(Cl 2PN) in diethylether medium at room temperature or in refluxing toluene. The amines 1, 2, 4, 5 and 6 were found to undergo a facile C–N bond cleavage at the bridging methylene group irrespective of the nature of substituents on the nitrogen. The cleaved dialkylamino groups were found to substitute regiospecifically at the ring carbon atoms of the carbaphosphazene, yielding the dialkylamino substituted carbaphosphazenes [(RR′N)CN] 2(Cl 2PN) 8– 12. The X-ray crystal structure of the substituted carbaphosphazene (Me 2NCN) 2(Cl 2PN) 8 has also been determined.

Structural and hydration changes in the active site gorge of phosporhylated butyrylcholinesterase accompanying the aging process

Wild-type (wt) butyrylcholinesterase (BuChE) and the E197D and D70G mutants were inhibited by diisopropylfluorophosphate (DFP) or soman under standard conditions of pH, temperature and pressure. The effect of hydrostatic and osmotic pressures on the aging process of DFP-phosphorylated enzymes (diisopropylphosphoryl-BuChE (DIP-BuChE)) was investigated. Hydrostatic pressure strongly increased the rate of aging of wt enzyme. The activation volumes (ΔV≠) for the dealkylation reaction was −150 ml/mol for DIP-wtBuChE. On the other hand, pressure had little effect on the aging of the DIP-E197D mutant and no effect on the DIP-D70G mutant, indicating that the transition state of the aging reaction (dealkylation of an isoproxy chain) was associated with an extended conformation/hydration change in wtBuChE but not in mutants. The rate of aging decreased with osmotic pressure, supporting the idea that water is important for stabilizing the transition state. Molecular dynamics simulations were performed on the wtDIP adduct to relate the kinetic data to hydration changes in the enzyme active site gorge. The pH dependence of the melting temperature (Tm) of native and soman-wtBuChE, as determined by differential scanning calorimetry (DSC), indicated that the stabilization energy of aged BuChE is mainly due to the salt bridge between protonated H438 and PO−, with pKH438=8.3. Electrophoresis under high pressure up to 2.5 kbar showed that aged wtBuChE did not undergo pressure-induced molten globule transition unlike the native enzyme. This transition was not seen for the mutant enzymes, indicating that mutants are resistant to the penetration of water into their structure. Our results support the conclusion that D70 and E197 are major residues for the water/H-bond network dynamics in the active site gorge of BuChE, both residues acting like valves. In mutant enzymes, mutated residues function like check valves: forced penetration of water in the gorge is difficult, release of water is facilitated.

C–H activation

Although the biocatalytic activation of carbon–hydrogen bonds by oxidation to alcohols was one of the first biotransformations to be exploited by the chemical industry, this remarkable process continues to be the subject of intense research activity. Recent developments in this area have centred on the use of new biocatalysts and substrates for C–H activation, in particular on the use of recombinant strains of yeast and bacteria expressing useful hydroxylase enzymes, on mechanistic work using hydroxylase enzymes that relies on the tools of molecular biology to address outstanding questions, particularly those of substrate selection and product predictability, and on the application of these systems for hydroxylation and heteroatom dealkylation reactions.

Rearrangement of alkyl phenyl ethers over dealuminated HY zeolites under liquid-phase conditions

The rearrangement reaction of alkyl phenyl analogue ethers of anisole, such as ethoxybenzene, n-propoxybenzene and n-butoxybenzene, over a dealuminated HY zeolite (Si/Al=10) has been investigated. Phenol, alkoxyalkylbenzenes and alkylphenols are obtained as main products. From the systematic study of the rearrangement reaction of ethoxybenzene, chosen as a model substrate, a general scheme has been advanced for the dealkylation reaction. Such a scheme, which involves both intramolecular and intermolecular rearrangements, has been confirmed by the use of kinetic modelling software. The influence of the temperature on the rate constants of each step of the reactional process and on the product distribution has been studied, together with the isomer distribution in ethoxyethylbenzene and ethylphenol formation.

Reactions of Ruthenium Acetylide Complexes with Isothiocyanate

Treatment of Cp(PPh3)[P(OMe)3]RuC⋮CPh (2; Cp = η5-C5H5) with PhNCS at room temperature affords the [2 + 2] cycloaddition (3a), containing a four-membered ring, and the neutral vinylidene phosphonate complex Cp(PPh3)[P(O)(OMe)2]RuCC(Ph)C(SH)NPh (4a) in a 9:1 ratio. Formation of 4a results from an Arbuzov-like dealkylation reaction possibly after addition of PhNCS. The same reaction at 40 °C affords a higher yield of 4a (5a; R = Ph) which results from addition of a second isothiocyanate to the four-membered ring of 3a. The reaction of 2 with PhCH2NCS at room temperature directly affords the six-membered-ring product 5b (R = CH2Ph). Trimerization of phenyl isothiocyanate is catalyzed by Cp(dppe)RuC⋮CPh (1‘; dppe = Ph2PCH2CH2PPh2) in refluxing CH2Cl2. This catalytic reaction proceeds through a pathway in which the first two steps are the same as those observed in the reaction of 2a. An attempt to purify the precursor of the trimerization product gave the cocrystallization of 1‘ and (PhNCS)3 (8). The structure...

Aging of di-isopropyl-phosphorylated human butyrylcholinesterase

Organophosphate-inhibited cholinesterases can be reactivated by nucleophilic compounds. Sometimes phosphylated (phosphorylated or phosphonylated) cholinesterases become progressively refractory to reactivation; this can result from different reactions. The most frequent process, termed 'aging', involves the dealkylation of an alkoxy group on the phosphyl moiety through a carbocation mechanism. In attempting to determine the amino acid residues involved in the aging of butyrylcholinesterase (BuChE), the human BuChE gene was mutated at several positions corresponding to residues located at the rim of the active site gorge and in the vicinity of the active site. Mutant enzymes were expressed in Chinese hamster ovary cells. Wild-type BuChE and mutants were inhibited by di-isopropylfluorophosphate at pH 8.0 and 25 degrees C. Di-isopropyl-phosphorylated enzymes were incubated with the nucleophilic oxime 2-pyridine aldoxime methiodide and their reactivatability was determined. Reactivatability was expressed by the first-order rate constant of aging and/or the half-life of aging (t12). The t12 was found to be of the order of 60 min for wild-type BuChE. Mutations on Glu-197 increased t12 60-fold. Mutation W82A increased t12 13-fold. Mutation D70G increased t12 8-fold. Mutations in the vicinity of the active site serine residue had either moderate or no effect on aging; t12 was doubled for F329C and F329A, increased only 4-fold for the double mutant A328G+F329S, and no change was observed for the A328G mutant, indicating that the isopropoxy chain to be dealkylated does not directly interact with Ala-328 and Phe-329. These results were interpreted by molecular modelling of di-isopropylphosphorylated wild-type and mutant enzymes. Molecular dynamics simulations indicated that the isopropyl chain that is lost interacted with Trp-82, suggesting that Trp-82 has a role in stabilizing the carbonium ion that is released in the dealkylation step. This study emphasized the important role of the Glu-197 carboxylate in stabilizing the developing carbocation, and the allosteric control of the dealkylation reaction by Asp-70. Indeed, although Asp-70 does not interact with the phosphoryl moiety, mutation D70G affects the rate of aging. This indirect control was interpreted in terms of change in the conformational state of Trp-82 owing to internal motions of the Omega loop (Cys-65-Cys-92) in the mutant enzyme.

Identification and Characterization of a Permethrin Resistance Mechanism in Populations of the Fungus GnatLycoriella Mali(Fitch) (Diptera: Sciaridae)

The commercial mushroom pestLycoriella mali(Fitch) (Diptera: Sciaridae) has evolved resistance to the adulticide permethrin. Preliminary investigations have indicated that oxidative metabolism was the most likely resistance mechanism. Monooxygenase activity (dealkylation reactions) against model substrates was used to examine specific metabolic activity associated with resistance. Differences in monooxygenase activity reflected resistance ranking of the field populations. The most resistant population was determined, by carbon monoxide difference spectrophotometry, to have a 1.7-fold greater level of cytochrome P-450 compared to the next most resistant population. This finding suggested that the quantity of enzyme was not solely responsible for variation in resistance. Enzyme kinetics were used to compare variation in metabolism of two model substrates, tetramethylbenzidine andpara-phenylenediamine, between populations. The enzyme preparation from the most resistant population had a higher affinity for both model substrates. This suggested that this population possessed a different monooxygenase and that this enzyme was more active in metabolizing the model substrates.

Unique push-pull mechanism of dealkylation in soman-inhibited cholinesterases.

The pH-dependence and solvent isotope effects of dealkylation in diastereomeric adducts of Electric eel (Ee) and fetal bovine serum (FBS) acetylcholinesterase (AChE) inactivated with P(-)C(+) and P(-)C(-) 2-(3,3-dimethylbutyl) methylphosphonofluoridate (soman) were studied at 4.0 +/- 0.2 degrees C. The rate constant versus pH profiles were fit to a bell-shaped curve for all adducts. Best fit parameters are pK1 4.4-4.6 and pK2 6.3-6.5 for Ee AChE and pK1 4.8-5. 0 and pK2 5.8 for FBS AChE. The pKs are consistent with catalytic participation of the Glu199 anion and HisH+440. Maximal rate constants (kmax) are 13-16 x 10(-3) s-1 for Ee AChE and 8 x 10(-3) s-1 for FBS AChE. The solvent isotope effects at the pH maxima are 1.1-1.3, indicating unlikely proton transfer at the enzymic transition states for the dealkylation reaction. Slopes of log rate constant versus pH plots are near 1 at 25.0 +/- 0.2 degrees C between pH 7.0 and 10.0. In stark contrast, the corresponding adducts of trypsin are very stable even at 37.0 +/- 0.2 degrees C. The rate constants for diastereomers of soman-inhibited trypsin at 37.0 +/- 0.2 degrees C are pH independent and approximately 10(4) times smaller than kmax for analogous adducts with AChE. Dealkylation in soman-inhibited AChEs is estimated to occur at >10(10) times faster than a plausible nonenzymic reaction. Up to 40% of the catalytic acceleration can be attributed to an electrostatic push, and an electrostatic pull provides much of the balance. The results of this work together with results of a product analysis by Michel et al. (1969) can be explained by an initial and rate-determining methyl migration from Cbeta to Calpha. This is driven by the high electron density of residues (Glu199 and Trp84) at a crowded active site and may be concerted with C-O bond breaking. The positive charge at the rate-determining transition state is distributed between Cbeta and His440. A tertiary carbocation may have a fleeting existence before it is trapped by water or neighboring electrons which is likely to be promoted by Glu199 as the proton acceptor.

Reactions of Cationic Piano Stool Iron Complexes Containing Phosphorus Ligands with Phosphorus Ylide

Reactions of PF6- salts of cationic piano stool iron complexes with a phosphorus ylide, CH2PPh3, were examined. In the reaction of the dicarbonyl complex [Cp(CO)2FeL]+ (L = P(OMe)3, P(OEt)3, PPh2(OMe)), Cp(CO)LFe{C(O)CHPPh3} is formed by the nucleophilic attack of the carbene carbon of CH2PPh3 on the carbonyl carbon of the complex. In contrast, the reaction of the monocarbonyl complex [Cp(CO)LFe{P(OR)3}]+ (L = P(OMe)3, R = Me; L = PMe3, R = Me; L = P(OEt)3, R = Et) yields Cp(CO)LFe{P(O)(OR)2} by the Arbuzov-like dealkylation reaction. [Cp(PMe3)2Fe{P(OMe)3}]+, having no CO ligand, also exhibits the Arbuzov-like dealkylation reaction under forced conditions. These results indicate that increasing the back donation ability from a central transition metal to a ligand induces a change in the reaction site from a carbonyl carbon in a CO ligand to an α-carbon in a phosphite ligand. In the reaction of [Cp(CO)2Fe{PPh2H}]+, proton abstraction from the PPh2H ligand takes place to give a phosphide complex Cp(CO)2FePPh2.

Molecular Activation of Organic Bis Chalcogen Compounds via Through-Space and Through-Bond Interactions between Chalcogen Atoms.

Various types of bis-chalcogenides and their monooxides which have the two chalcogen atoms in close proximity can be activated photochemically or chemically to generate a reactive species such as o-quinodimethane or to promote dealkylation reactions. These molecular activations proceed via intramolecular through-space interaction between the two chalcogen atoms or the formation of σ-bonded dichalcogenadication. Intermolecular through-space and intramolecular through-bond interactions as new modes are also described.

Isomerization of dimethylnaphthalenes over zeolites

A dimethylnaphthalene (DMN) isomer mixture from a reforming unit was reacted at 350°C and atmospheric pressure over H-mordenites (Si/Al ranging from 5 to 100), a partially decationated NaY (Si/Al=2.4) and a slightly dealuminated HY (Si/Al=5), with the aim of increasing the 2,6- and 2,7-DMN content by isomerization. The best results were obtained on H-mordenite with Si/Al=10, where shape selective effects made possible to double the amount of the valuable isomers while limiting to a negligible extent the side reactions of disproportionation and dealkylation.

Photosensitized degradation of terbuthylazine in water

We investigated the photodegradation of terbuthylazine, an s-triazine herbicide, in the presence of hydrogen peroxide (H 2O 2), titanium dioxide (TiO 2), acetone or humic substances. In the presence of H 2O 2 and UV light, the degradation of terbuthylazine quickly leads to the formation of ammeline. The degradation pathway consists of dealkylation reactions giving 2-chloro-4,6-diamino-1,3,5-triazine, and then ammeline through hydroxylation. Irradiation of terbuthylazine with simulated solar light in the presence of titanium dioxide gives also dealkylation products in the first stage of degradation. Acetone at ∗1 % (v/v) produces a 7-fold enhancement of the degradation rate. In the presence of humic substances, different results were obtained, depending on the origin of the substances tested. The humic acids isolated from a soil accelerate the degradation speed, whereas the fulvic acids from a small stream reduce it.

Study of the porphyrins released from the Messel oil shale kerogen by hydrous pyrolysis experiments

Eight samples of pre-extracted Messel oil shale have been submitted to hydrous pyrolysis at different temperatures between 225°C and 350°C. The porphyrins released were evaluated, fourteen isolated, and seven of them characterized (from the sample heated at 250°C) by comparison with geological and/or synthetic standards (UV-visible, HPLC, MS and NMR). We followed the thermal release of porphyrins by HPLC and MS to examine changes in the distributions and, to get a better idea of the porphyrins bound to the macromolecular kerogen network of the Messel shale. The structures of the released porphyrins indicate that dealkylation reactions occur during the thermal stress. The presence of acid porphyrins, in the case of the lowest temperature experiments (225°C and 250°C), suggests that at least part of the released alkyl porphyrins are formed by the decarboxylation of acid porphyrins present in the kerogen. Etioporphyrins are more abundant and they are released later (at higher temperature) than DPEP's. This observation may indicate that ETIO's are more strongly attached to the macromolecular network than DPEP's. The results obtained seem to indicate that, during these maturation experiments, the DPEP's are destroyed by the thermal stress rather than being transformed into ETIO's.

Deactivation Kinetics of Toluene Alkylation with Methanol over Magnesium-Modified ZSM-5

The deactivation kinetics of toluene alkylation with methanol over a Mg-modified ZSM-5 catalyst has been studied. A kinetic model taking into account both the deactivation of the main and the secondary reactions and the influence of the intracrystalline diffusion has been developed. The best fit of the experimental data has been obtained assuming that gaseous hydrocarbons, formed mainly by ethylene, are the coke precursors. The secondary reactions of p-xylene dealkylation, toluene disproportionation, and external p-xylene isomerization deactivate faster than the main reaction, probably due to differences in the strength of the acid sites over which they take place. The paraselectivity corresponding to the primary product decreases with the time on stream as a consequence of the pore blockage by coke, which attenuates the diffusional control of the internal xylene isomerization. Methanol dehydration is the reaction least affected by coke.

CpAlN(2,6-i-Pr(2)C(6)H(3))](2): A Dimeric Iminoalane Obtained by Alkane Elimination.

The dimeric iminoalane, [CpAlN(2,6-i-Pr2C6H3)]2 (2), has been prepared from a double dealkylation reaction between Cp3Al and 2,6-diisopropylaniline. The single-crystal X-ray structure of 2 reveals a nearly square planar Al2N2 core, with each cyclopentadienyl ring coordinated to its aluminum atom in a pentahapto fashion. This structure represents the first solid-state characterization of an η5-coordination geometry between a simple C5H5 ring and aluminum.

Catalytic pyrolysis—gas chromatography

A new technique which allows the rapid catalytic testing of a small amount of solid (3–10 mg) has been developed and tested on standard ethylbenzene dealkylation and disproportion reactions in mid-pore zeolites. It consists of an adaptation of a commercial pyrolyser, to function as a fixed bed catalytic reactor, connected on line to a gas chromatograph. Test results with H +-ZSM-5 zeolite, as the fixed bed, obtained under different experimental conditions of flow rate and amount of catalyst, show that data can be evaluated and compared with standard methods, provided they are referred to the same space velocity. All other standard catalytic characterisation parameters (temperature, conversion, selectivity, including estimates of the difference between the activation energies of different catalysts) can also be extracted directly. The exception is TOS (time on stream) which can be measured indirectly after injecting an excess of volatile organic reactant (here, ethylbenzene). Since a small concentration of ethylbenzene with respect to the zeolite is required for each test, coking phenomena (which reduce the catalyst activity) cannot be observed.

Experimental simulation of gas generation from coals and a marine kerogen

The purpose of this work is to determine both the gas and oil potential of Type II and Type III organic matter in open and closed systems. As it is not possible to measure directly the gas generated at various depths from source rocks, due to sampling problems, we have carried out experimental simulations of coal and kerogen degradation in open and closed pyrolysis systems. In the two systems, the total effluents were quantified. For the gas mixture, non-hydrocarbon species such as CO, CO 2, H 2S and H 2O were analyzed together with the C 1–C 5 hydrocarbons. In a closed system, coals generate mainly gases with a maximum yield around 70–100 mg CH 4/g orgC. This methane derives mainly from dealkylation reactions of coal and is produced at high temperatures. The corresponding vitrinite reflectance ranges from 1.3 to 2.7% R o. Marine Type II kerogen can also produce a significant amount of methane (300 mg/g orgC), which originates mainly from the secondary cracking of oil. In an open system, methane yields are much lower compared to the closed system. This means that, as far as gas generation is concerned, the cracking mechanisms are not the same for the two kinds of experiments and, consequently, estimation of gas potential strongly depends on the choice of the experimental pyrolysis system for simulating artificial maturation of organic matter.

Modeling of the Kinetics of Alkali Metal Fusion

Alkali fusion is applied to substitute a sulfonic acid group with a hydroxyl group in a substituted aromatic ring. Beside the main reaction, also side reactions appear, because the substituents in the aromatic ring are eliminated and the aromatic rings are polymerized. A kinetic model for the main and the side reactions in alkali fusion of a substituted aminobenzenesulfonic acid was developed. The substitution reaction of sulfonic acid with a hydroxyl group, the elimination of sulfonic acid and amino groups, the dealkylation reactions, and the polymerization reactions were included in the kinetic model. The system consisted of the main reaction and of 27 side reactions. The number of adjustable constants in the kinetic model was reduced by assuming that the reactivity of any functional group in the aromatic ring is not affected by the other substituents. The reactions could then be described with eight kinetic parameters only. The kinetic data were obtained from isothermal experiments carried out in a batchwise operating laboratory reactor at the temperature range of 220-270 °C. The kinetic parameters were estimated from the experimental data using nonlinear regression analysis. The model agreed well with the experimental data, which implies that the proposed reaction scheme is suitable for the description of alkali fusion and that the assumption concerning the reactivities of the functional groups is reasonable