Initiation reversibility

Tetraene 4 (Scheme 1.3), when treated with 40 mol % of triflic acid in methylene chloride at -23 °C for 1 h, gives the adducts 5 and 6 in a 1 1 ratio as the main reaction products. The formation of these adducts has been justified [21] by a stepwise mechanism that requires an initial reversible protonation of 4 to produce the allyl cation 7, which then cyclizes to 8 and 9 in a non-reversible process. Deprotonation of 8 and 9 gives 5 and 6, respectively. 

In view of these results a new mechanism is suggested with initial reversible formation of a quinquecovalent intermediate (9), followed by... 

To address this problem, the authors devised two modifications. [30] The first one, two-stage glycosylation (Scheme 5.7), employed an initial, reversible trans-orthoes-terification step (12 —> 14, Scheme 5.7) in which the departing alcohol was removed either azeotropically or by molecular sieves [31]. The new orthoester 14 was then processed to give the glycoside (6) under the conditions developed in their previous work. The second variation consisted of the use of orthoacetates of hindered alcohols (isopropyl and tert-butyl) that minimize the return of the alcohol that is split off. 

In the earlier scheme, I represents a product formed by metabolism of the inhibitor by the enzyme. This product may be released into bulk solvent, or may interact (often covalently) with a suitably reactive component of the enzyme within the active site. This irreversibly inactivated enzyme complex is shown as El". There are two kinetic constants that can be obtained from relatively straightforward experiments with a suicide inhibitor. The Ki value is an equilibrium constant for the initial reversible step, and all the rate constants from the above scheme contribute to its value. The rate of irreversible inactivation of enzyme at a saturating concentration of the suicide inhibitor is given by fcinact. to which only k2> h, and k contribute (Silverman, 1995). At infinitely high concentrations of the inhibitor, the half-Ufe for inactivation is equal to ln2/ l inact ... 

Ethanol-related high levels of NADH+H and acetyl-CoA in the liver lead to increased synthesis of neutral fats and cholesterol. However, since the export of these in the form of VLDLs (see p. 278) is reduced due to alcohol, storage of lipids occurs (fatty liver). This increase in the fat content of the liver (from less than 5% to more than 50% of the dry weight) is initially reversible. However, in chronic alcoholism the hepatocytes are increasingly replaced by connective tissue. When liver cirrhosis occurs, the damage to the liver finally reaches an irreversible stage, characterized by progressive loss of liver functions. 

Postoperative narcotic depression - Follow the recommendations and cautions under adult administration guidelines. For initial reversal of respiratory depression, inject in increments of 0.005 to 0.01 mg IV at 2- to 3-minute intervals to desired degree of reversal. 

The third hypothesis to explain the observed conductivity effect is that of Morrison (31) who used a modification of the adsorption theory presented in Section III. As has been pointed out, the adsorption theory in its basic form is adequate to explain the high-temperature conductivity and the low-temperature conductivity in zinc oxide. However, it must be expanded slightly to present an adequate explanation of the conductivity effects in the intermediate temperature range. The adsorption theory predicts the slow irreversible fall in the conductance shown in Fig. 3, but does not predict the initial reversible rise, observed in experiments such as illustrated in Fig. 3 for temperatures above 80°C, and which is shown isolated in Fig. 6. 

This process is an early morphological change in cells often seen in isolated cells in vitro but also known to occur in vivo. The blebs, which appear before membrane permeability alters, are initially reversible. However, if the toxic insult is sufficiently severe and the cellular changes become irreversible, the blebs may rupture. If this occurs, vital cellular components may be lost and cell death follows. The occurrence of blebs may be due to damage to the cytoskeleton, which is attached to the plasma membrane as described above. The cause may be an increase in cytosolic Ca2+, interaction with cytoskeletal proteins, or modification of thiol groups (see below). 

After absorption, lead enters the blood, and 97% is taken up by red blood cells. Here, lead has a half-life of two to three weeks during which there is some redistribution to the liver and kidney, then excretion into bile or deposition in bone. After an initial, reversible, uptake into bone, lead in bone becomes incorporated into the hydroxyapatite crystalline structure. Because of this, past exposure to lead is possible to quantitate using X-ray analysis. It is also possible to detect lead exposure and possible poisoning from urine and blood analysis, and the amount in blood represents current exposure. However, as lead is taken up into the red blood cell, both the free blood lead level and that in the erythrocytes needs to be known. 

Additional Preparative-Scale HPLC Separations. After mutagenesis assessment of the HPLC fractions from the initial preparative-scale separation just discussed, those fractions containing mutagenic constituents are further separated on HPLC by employing the following strategy For example, if the mutagenic constituents were found to be in Fraction D from an initial reverse-phase HPLC preparative-scale separation, that is, a mobile-phase composition of 25 water 75 acetonitrile, a... 

Dimethyl-3,4-dinitrothiophene undergoes a different type of reaction with cyclic secondary amines. The product from the reaction with morpholine, obtained in nearly quantitative yield, has been identified as 2,5-dimethyl-rrans-2,3-dimorpholino-4-nitro-2,3-dihydrothiophene. Most notable in this reaction is the high stereospecificity. The reaction probably proceeds through initial reversible addition of a molecule of morpholine to the 2,3-double bond (Scheme 139) <80JCS(P2)1764). 

Agrawal and Wei (1984) isolated the metallochlorin and confirmed that the apparent fractional order kinetics resulted from a sequential mechanism much like HDS and HDN reactions. The hydrodemetallation of both nickel- and vanadyl-etioporphyrins on oxide CoMo/A1203 proceeded through two mechanistically different steps, an initial reversible hydrogenation followed by a terminal hydrogenolysis step... 

All the three reactions show small positive Hammett p-values at 23 °C. According to Scheme 17, the reaction constants for complexation of alcohols to silene should be positive, consistent with the mechanism involving initial, reversible nucleophilic attack... 

It should be recalled here that the alcoholic hydroxyl of serine does not possess a dissociation constant within the pH range, accessible to enzymic reactions. Therefore, this amino acid cannot influence the pH-activity curve. On the other hand, it is well known that DFP inhibition is initially reversible and becomes only slowly irreversible. This has been demonstrated for true ChE from electric eel by Nachmansohn and associates (46) and for plasma ChE by Mackworth and Webb (47). Similarly, a stepwise reaction with inhibitors, containing the diethyl phosphoryl moiety, has been made probable by Hobbiger (34)- Therefore, it appears possible that phosphates are first attacked by the imidazol moiety of the esteratic site, in conformity with the catalytic influence of free imidazol on phosphate hydrolysis (48). This step is followed by transfer to serine. The final product is a trialkyl phosphate XV, which is not split by imidazol (scheme F). 

With increasing sulfide concentrations, Reaction 3.40 would initially reverse and precipitate AS2S3. However, if sulfide concentrations in hydrothermal fluids approach about 0.001 mol kg-1, orpiment could begin to dissolve and produce thioarsenic complexes. Traditionally, thioarsenic complexes in sulfide-rich and anoxic waters were identified as thioarsenites. For example, Webster and Nordstrom (2003, 111) suggested that H2As3S6 would form from the dissolution of orpiment ... 

A was supported by a 3D X-ray structure of the inhibitor at the closely related porcine elastase (Navia, 1987) (Figure 13.12). After initially reversible inhibition (Figure 13.12, top two rows), time-dependent irreversible inhibition through covalent bonding of the dihydrothiazine ring of the inhibitor to the His-57 residue of the active site of the enzyme increasingly takes over (Figure 13.12, bottom row). Peptidyl chloromethyl ketones, known unspecific inhibitors, act in similar fashion. 

There are two limiting forms of Equation 4.9. If B reverts to A in the mechanism of Equation 4.7 much faster than it proceeds to give the product C, i.e. k x k2, the initial reversible step becomes a pre-equilibrium with k /k i = Kx. The predicted rate equation of Equation... 

When R—X is enantiomerically enriched exo-2-norbornyl 4-bromobenzenesulfonate (brosylate), 1 in Fig. 4.5, and SOH is aqueous ethanol, for example, solvolysis is accompanied by racemisation. However, the rate of racemisation is faster than the rate of product formation, and starting material isolated before completion of the solvolysis is partially racemised [14]. The most economical interpretation of these results (and much other evidence, see Chapter 7) is that R+ X- includes the achiral nonclassical carbenium ion (3 in Fig. 4.5), and the ion pair undergoes internal return faster than nucleophilic capture. In other words, k- > k2 in Scheme 4.4, the precise value of the ratio k- lk2 depending upon the particular solvent, and the greater this ratio, the closer the initial reversible process approaches a pre-equilibrium. 

The build-up of appreciable concentrations of the intermediate B depends on the initial reversible step being favourable the rate of decay of the intermediate must be commensurate with its rate of formation, and the decay must also be slow enough to permit observation... 

Although free radical reactions are found less often in solution than in the gas phase, they do occur, and are generally handled by steady state methods. There are also organic and inorganic reactions that involve non-radical intermediates in steady state concentrations. These intermediates are often produced by an initial reversible reaction, or a set of reversible reactions. This can be compared with the pre-equilibria discussed in Section 8.4, where the intermediates are in equilibrium concentrations. The steady state treatment is also used extensively in acid-base catalysis and in enzyme kinetics. 

Hydroxylation of [Cu2(R—XYL—H)]2+ (10) by 02. As described in Section II.C.l, the complete kinetic analysis reveals an initial reversible binding of 02 by 10 to give [Cu2(H—XYL—H)(02)]2+ (11), followed by an irreversible hydroxylation reaction described by k2. The kinetics preclude that a Fenton-type mechanism (production of hydroxyl radical) is involved in the reaction (i.e., that an intermediate peroxo species is further attacked by LCu(I)). We note that [Cu2(H—XYL—H)]4+ (34) cleanly reacts with H202 to give product [Cu2(H—XYL—O—)(OH)]2+ (12), whereas reaction of [Cu2(H—XYL—H)]2+ (10) with hydrogen peroxide does not (unpublished observation). Addition of radical traps to solutions of 10 and 02 also does not affect the hydroxylation (unpublished observation), and all the evidence points to intramolecular hydroxylation by the peroxo-dicopper species 11. 

Scheme 1 is the simplest one that is consistent with the inactivation of an enzyme while a drug is metabolized (25). As with conventional enzyme kinetics, there is an initial, reversible step that combines the inhibitor and free enzyme to form an enzyme-inhibitor complex. 

The aqueous electrochemical reduction of 02 at inert electrodes occurs via an initial reversible electron-transfer process [analogous to the homogeneous process of pulse radiolysis, Eq. (9.19)]... 

Let step 12 represent the initial reversible adiabatic expansion, and step 23 the final constant-volume heating. 

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