Isotope scrambling

Using Isotopic Scrambling to Distinguish Exocyclic vs. Endocyclic Cleavage Pathways for a Pyranoside 

The hydrolysis of pyranosides is postulated to largely proceed via exocyclic cleavage to give a cyclic oxocarbe-nium ion (Path A). Yet, it has long been recognized that an alternative pathway is also possible—namely, endocyclic cleavage to give an acyclic oxocarbenium ion (Path B). 

In fact, molecular dynamics calculations have suggested that the endocyclic pathway may be operative in enzyme-catalyzed processes. In order to delineate the extent to which this alternative pathway occurs in solution, an isotopic scrambling experiment was performed. 

and Anslyn, E. V. The Ratio between Endocyclic and Exocyclic Cleavage of Pyranoside Acetals is Dependent upon the Anomer, the Temperature, the Agy Icon Group, and the Solvent. /. Am. 

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Selectivities to various isomers are more difficult to predict when metal oxides are used as catalysts. ZnO preferentially produced 79% 1-butene and several percent of i7j -2-butene [624-64-6] (75). CdO catalyst produced 55% 1-butene and 45% i7j -2-butene. It was also reported that while interconversion between 1-butene and i7j -2-butene was quite facile on CdO, cis—trans isomeri2ation was slow. This was attributed to the presence of a TT-aHyl anion intermediate (76). High i7j -2-butene selectivities were obtained with molybdenum carbonyl encapsulated in 2eohtes (77). On the other hand, deuteration using H1O2 catalyst produced predominantly the 1,4-addition product, trans-2-huX.en.e-d2 with no isotope scrambling (78). 

At low temperatures unstable adsorption products or reaction intermediates could be trapped. Thus, carbonite CO, ions arise on CO interaction with basic oxygen ions which account for catalytic reaction of isotopic scrambling of CO or thiophene on activated CaO. 

Racemization, however, does not alwiys accompany isotopic scrambling. In the case of 5ec-butyl 4-bromobenzenesulfonate, isotopic scrambling occurs in trifluoroethanol solution witiiout any racemization. Two mechanisms are possible. Scrambling may involve an intimate ion pair in which the sulfonate can rotate with respect to the caibocation without allowing migration to die other face of the caibocation. The alternative is a concerted mechanism, which avoids a caibocation intermediate but violates the prohibition of front-side displacement. ... 

A detailed study of the solvolysis of L has suggested the following mechanism, with the reactivity of the intermediate M being comparable to that of L. Evidence for the existence of steps ki and k 2 was obtained fiom isotopic scrambling in the sulfonate M when it was separately solvolyzed and by detailed kinetic analysis. Derive a rate expression which correctly describes the non-first-order kinetics for the solvolysis of L. 

Two techniques, electrochemical reduction (section IIl-C) and Clem-mensen reduction (section ITI-D), have previously been recommended for the direct reduction of isolated ketones to hydrocarbons. Since the applicability of these methods is limited to compounds which can withstand strongly acidic reaction conditions or to cases where isotope scrambling is not a problem, it is desirable to provide milder alternative procedures. Two of the methods discussed in this section, desulfurization of mercaptal derivatives with deuterated Raney nickel (section IV-A) and metal deuteride reduction of tosylhydrazone derivatives (section IV-B), permit the replacement of a carbonyl oxygen by deuterium under neutral or alkaline conditions. 

The successful preparation of Il,ll-d2-5l5-androstan-3o -oh and 11,11-d2-(25R)-5a-spirostane in 83% and 91% isotopic purity by Raney nickel treatment of the 11,1 l-d2-12-ethylene thioketal derivatives further confirms the low degree of isotope scrambling with C-12 keto steroids. 

Some advantages of this reaction are high yield if the tosylate is in a sterically accessible position excellent isotopic purity of the product (usually higher than-95%) and perhaps most important, access to stereospecifically labeled methylene derivatives. For example, deuteride displacement of 3j -tosylates (183) yields the corresponding Sa-d derivative (185) in 96-98% isotopic purity. Application of this method to the labeled sulfonate (184), obtained. by lithium aluminum deuteride reduction of a 3-ketone precursor (see section HI-A) followed by tosylation, provides an excellent synthesis of 3,3-d2 labeled steroids (186) without isotopic scrambling at the adjacent positions. The only other method which provides products of comparable isotopic purity at this position is the reduction of the tosyl-hydrazone derivative of 3-keto steroids (section IV-B). 

The unreacted ethanol and the diethylether product retained >98% of from the starting 0-ethanol, indicating that no isotope scrambling occurred. Data in Table 4 demonstrate that was retained in the mixed ether and ethanol attack of the acid-activated 2-pentanol via an axial S 2 rear-attack was the predominant synthesis pathway. Evidently, the shape selectivity induced by the 2 M-5 zeolite channel structure (Figure 2) plays an important role in achieving the remarkably higher configuration inversion... 

Silene-transition metal complexes were proposed by Pannell121 for some iron and tungsten systems, and such species were observed spectroscopically by Wrighton.122,123 Thus intermediates such as 33 have been proposed in the preparation of carbosilane polymers from hydrosilanes,124 both as intermediates in the isotope scrambling observed to occur in similar ruthenium hydride systems125 126 and in the 5N2 addition of alkyllithium species to chlorovinylsilanes.47... 

Thus, upon photolyzing a mixture of two nitrites, one of which contains an isotopically labeled nitrogen, the products should show the original isotopic distribution if mechanism (a) is operative, the original isotopic distribution in unreacted nitrite but scrambling in the nitroso product if (c) is operative, and complete isotopic scrambling if (b) is operative. 

Energetic Materials. 2. Deuterium Isotope Effects and Isotopic Scrambling in Condensed-Phase Decomposition of Octahydro-l,3,5,7-tetranitro-l,3,5,7-tetrazocine. 

Powell, M.F. and Bruice, T.C. (1983). Effect of isotope scrambling and tunneling on the kinetic and product isotope effects for reduced nicotinamide adenine dinucleotide model hydride transfer reactions. J. Am. Chem. Soc. 105, 7139-7149... 

The thermodynamic stabilities of phenonium ions relative to the parent have been determined in the gas phase by measuring the position of the equilibrium between (46) and (47)7 The results followed a Yukawa-Tsuno relationship with a p value of -12.6 and an r+ value of 0.62, the general behaviour being more like benzenium ions than benzyl cations, with tt-delocalization less effective than in benzyl cations. A theoretical study of the elimination of molecular H2 from the benzenium ion C6H7+ shows that the barrier to this process appears to be very small.The gas-phase Friedel-Crafts alkylation reaction of CF3C6L6+ (L = H or D) with C2L4 is accompanied by isotopic scrambling, which has been used to elucidate the mechanism of this process. A theoretical calculation shows that the lifetime of triplet phenyl cation must be very short. ... 

The importance of isotopic scrambling by reaction (13) is diminished because the partial pressure of O2 is reduced. 

The initially observed perturbation (or equilibrium isotope effect) will disappear as isotopic scrambling (or mixing) subsequently occurs. This is illustrated above for the malic enzyme note the initial displacement of the equilibrium toward malate, followed by readjustment of the system to its flnal equilibrium position. The magnitude of the initial perturbation provides information on the occurrence of kinetic isotope effects and the nature of the rate-limiting step in an enzymatic process. See also Kinetic Isotope Effect Solvent Isotope Effect... 

ISOTOPE RATIO MASS SPECTROMETER ISOTOPE SCRAMBLING... 

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