Hydrolysis addition-elimination pathway

Thus, N-nitrosamides also undergo deamination (hydrolysis) by an addition-elimination pathway involving nucleophilic rather than... 

Ester hydrolysis, alcoholysis, and aminolysis may be regarded as substitution reactions (via addition-elimination pathways). The activation of (methylthio)methyl esters by S-methylation [51] is an example demonstrating the usefulness of polarity alternation accentuation. 

DFT studies of the hydrolysis of acetyl and chloroacetyl chloride and of variously substituted benzoyl chlorides supported an S 2 mechanism. An extended Grunwald-Winstein equation correlation for the specific rates of solvolysis of 3,4,5-trimethoxybenzoyl chloride gave sensitivities towards changes in solvent nucleophilic-ity (/-value) of 0.29 and solvent ionizing power (m-value) of 0.54. The low m-value allowed specific rates to be determined in highly ionizing fiuoroalcohol/H20 mixtures. A parallel correlation of the specific rates of solvolysis of 2,4,6-trichlorobenzoyl chloride revealed that solvolyses in 100% and 90% ethanol or methanol did not appreciably follow the ionization pathway indicated for solvolyses in the other solvents and it was proposed that, despite the two or//to-substituents, the addition-elimination pathway had become dominant. ... 

In the acid-catalyzed process, initial protonation on nitrogen facilitates nucleophilic attack by water. Loss of a proton from oxygen furnishes a neutral intermediate, which is a tautomer of an amide. A second protonation on the nitrogen occurs, followed again by deprotonation of oxygen and formation of the amide. Hydrolysis of the amide proceeds by the usual addition-elimination pathway. 

Hydrolysis. Esters are cleaved (hydroly2ed) into an acid and an alcohol through the action of water. This hydrolysis is cataly2ed by acids or bases. The mechanistic aspects of ester hydrolysis have received considerable attention and have been reviewed (16). For most esters only two reaction pathways are important. Both mechanisms involve a tetrahedral intermediate and addition-elimination reactions i7i7... 

It should be mentioned, however, that the phosphoramidothioate 202 can undergo hydrolysis by another mechanism which becomes operative above all in polar solvents (e.g. aqueous KOH, and less so in methanol or acetone). P—O bond cleavage occurs, presumably via an addition/elimination mechanism, while the metaphosphorimidate pathway is characterized by P—S bond cleavage. 

Figure I. Oxyphosphorane intermediates corresponding to possible primary reaction pathways (I)-(4) in hydrolysis of[y-M0] A TP in lN and 0.1 N HCl by the addition-elimination mechanism. Key 1 denotes attack by water on Pg 2 and 3, on Pp 4, on Pa denotes the heavy isotope, sO.

Treatment of adenosine 5 -[ 3-morpholino]diphosphate with P 04]ortho-phosphate affords [y- 04]ATP, which has been used to study non-enzymatic hydrolytic pathways of ATP. Upon hydrolysis, the orthophosphate released was isolated, converted to trimethyl phosphate, and the isotope content analysed by mass spectrometry. In 1m and 0.1m HCl, the data suggest addition-elimination as the hydrolysis mechanism, with attack occurring predominantly at Py to... 

Although an addition/elimination sequence involving the formation of a tetrahedral carbonyl addition intermediate is the most common mechanism for the hydrolysis of esters, alternative pathways are followed in special cases. One such case occurs with methyl esters in basic conditions. Recall that... 

The acid-catalyzed hydrolysis of methyl 2,4,6-trimethylbenzoate proceeds via a less common mechanism, neither the addition-elimination nor the Sn2 pathway. Predict what this mechanism is, rationalize why this new mechanism is viable, and propose one or two experiments to demonstrate that this new mechanism is operative. 

Acid-catalyzed ester hydrolysis can occur by more than one mechanism, depending on the structure of the ester. The usual pathway, however, is just the reverse of a Fischer esterification reaction (Section 21.3). The ester is first activated toward nucleophilic attack by protonation of the carboxyl oxygen atom, and nucleophilic addition of water then occurs. Transfer of a proton and elimination of alcohol yields the carboxylic acid (Figure 21.8). Because this hydrolysis reaction is the reverse of a Fischer esterification reaction, Figure 21.8 is the reverse of Figure 21.4. 

Alkanesulfonyl halides are not the only alkanesulfonyl derivatives that can undergo substitution by an elimination-addition mechanism. A number of aryl esters of phenylmethanesulfonic acid, PhCH2SOzOAr, undergo alkaline hydrolysis and aminolysis by such a pathway, and study of these reactions has been particularly valuable in providing insight into the detailed mechanism for sulfene formation (Williams et al., 1974 King and Beatson, 1975 Davy et al., 1977). 

Fig. 9.1. Simplified reaction mechanisms in the hydrolytic decomposition of organic nitrates. Pathway a Solvolytic reaction (Reaction a) with formation of a carbonium ion, which subsequently undergoes SN1 addition of a nucleophile (e.g., HO ) (Reaction b) or proton E1 elimination to form an olefin (Reaction c). Pathway b HO -catalyzed hydrolysis (,SN2). Pathway c The bimolecular carbonyl-elimination reaction, as catalyzed by a strong base (e.g., HO or RO ), which forms a carbonyl derivative and nitrite.

Ah initio calculations to map out the gas-phase activation free energy profiles of the reactions of trimethyl phosphate (TMP) (246) with three nucleophiles, HO, MeO and F have been carried out. The calculations revealed, inter alia, a novel activation free-energy pathway for HO attack on TMP in the gas phase in which initial addition at phosphorus is followed by pseudorotation and subsequent elimination with simultaneous intramolecular proton transfer. Ah initio calculations and continuum dielectric methods have been employed to map out the lowest activation free-energy profiles for the alkaline hydrolysis of a five-membered cyclic phosphate, methyl ethylene phosphate (247), its acyclic analogue, trimethyl phosphate (246), and its six-membered ring counterpart, methyl propylene phosphate (248). The rate-limiting step for the three reactions was found to be hydroxyl ion attack at the phosphorus atom of the triester. ... 

A dissociative elimination-addition pathway has also been proposed to account for the kinetics of alkaline hydrolysis of 2,4-dinitrophenyl 4 -hydroxyphenylpropionitrile in 40% (v/v) dioxane-water, although participation of the associative Bac2 mechanism cannot be ruled out since it may be facilitated by the electronic effect of the triple bond. Formation of intermediate (15), having a conjugated and cumulated double-bond system, should favour the ElcB mechanism and thereby account for the contrasting entropies of activation found for hydrolysis of (14) and the corresponding 4 -methoxyphenylpropionate. 

The extremely short duration of action of succinylcholine (5-10 minutes) is due to its rapid hydrolysis by butyrylcholinesterase and pseudocholinesterase in the liver and plasma, respectively. Plasma cholinesterase metabolism is the predominant pathway for succinylcholine elimination. Since succinylcholine is more rapidly metabolized than mivacurium, its duration of action is shorter than that of mivacurium (Table 27-1). The primary metabolite of succinylcholine, succinylmonocholine, is rapidly broken down to succinic acid and choline. Because plasma cholinesterase has an enormous capacity to hydrolyze succinylcholine, only a small percentage of the original intravenous dose ever reaches the neuromuscular junction. In addition, as there is little if any plasma cholinesterase at the motor end plate, a succinylcholine-induced blockade is terminated by its diffusion away from the end plate into extracellular fluid. Therefore, the circulating levels of plasma cholinesterase influence the duration of action of succinylcholine by determining the amount of the drug that reaches the motor end plate. 

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