Elimination reactions deuterium isotope effects

A very large deuterium isotope effect has been observed240 by ESR at 77 K on hydrogen-deuterium elimination reaction from 2,3-dimethylbutane (H-DMB)-SFg and 2,3-dimethylbutane-2,3-D2 (D-DMB)-SFg (0.6 mol% mixtures), /-irradiated at 70 K and then stored at 77 K. The significant isotope effect, h2 Ad2 = 1-69 x 104 at 77 K, has been explained by tunnelling elimination of hydrogen (H2) molecules from a DMB+ ion240. 

The ratio of products (36) and (37) from VNS of hydrogen (Pe) and substimtion of halogen (Px), respectively (Scheme 4), will depend on the strength and concentration of base, provided that the elimination is a kinetically important step in the VNS reaction, namely Pr/Px = kikE[B]/k-ikx. The influence of base will decrease until a constant value Ph/Px = k /kx is reached as kslB] k i. This has been demonstrated for 4-chloronitrobenzene, which undergoes exclusive substimtion of chlorine unless strong base is present to favour the VNS process. The deuterium isotope effect for VNS hydroxylation by Bu OOH, determined as me ratio of H versus D substitution of l-deutero-2,4-dinitrobenzene, varied from 7.0 0.3 to 0.98 0.01 as the base in NH3 was changed from NaOH to Bu OK me former value is consistent with a rate determining E2 process. 

Ab initio calculations at the MP2/6-31+ G level have been performed for gas-phase El elimination reactions of CH3CH2X (X = NH3"1", Br, Cl, F, SH) promoted by NH . OH-, F-, PH2. SH-, and Cl- in order to determine how changes in transition-state geometry, from reactant-like to product-like, influence kinetic isotope effects.9 Secondary isotope effects (a-H) on leaving group departure are correlated with the hybridization at C7 in the transition state, whereas there is no such correlation between secondary (/5-H) isotope effects and the transition state hybridization at C/ . The primary deuterium isotope effect is influenced markedly by the nucleophilic atom concerned but approach to a broad maximum for a symmetric transition structure can be discerned when due allowance is made for the element effect. 

Elimination reactions of ( )- and (Z)-benzaldehyde Opivaloyloximes (19a) and (19b) with DBU in MeCN have been found to occur by a nitrile-forming E2 mechanism which is ca 2000-fold faster for the latter isomer in each case.15 The corresponding Hammett substituent constants, activation parameters, and primary deuterium isotope effects, suggest that the anti elimination from (19b) (for which p = 2.4 0.1, H/ D = 2.7 0.3, A/H = 12.5 0.2 kcal mol-1, and A= —31.0 0.6eu) proceeds to (20) via a more symmetrical transition state with a smaller degree of proton transfer, less charge development at the jS-carbon and greater extent of triple bond formation than for syn elimination from (19a) (for which p = 1.4 0.1, kn/kn = 7.8 0.3, AH = 8.8 0.1 kcal mol 1 and A= -23.6 0.4 eu). 

Solvolysis of (29-X, X = I, Br, OBs) in 25vol.% acetonitrile in water gives elimination product (32) and substitution products (33a) and (33b).17 The rate of elimination increases with increasing acidity of the substrate (Bronsted a > 0) as evidenced by results for ring-substituted substrates (30-X) and (31-X). However, for elimination reactions of the brosylates (29-OBs) and (31-OBs), the small kinetic deuterium isotope effect (kH/kD = 2.0 0.1 and 2.8 0.1, respectively) is believed to be a consequence of competing El reaction via a primary ion pair. 

Molecular orbital calculations of the w-electron distribution in pyridine predict that more 4- than 2-aminopyridine should be formed in the Tschitschibabin reaction.4 The fact that no 4-aminopyridine can be detected when the two positions are allowed to compete for a deficiency of sodamide (see, e.g., Abramovitch et al 268) has led to the suggestion that the observed orientation in this reaction depends on the relative ease of elimination of a hydride ion from C-2 and C-4 and not upon the initial mode of addition (which, by implication, must take place predominantly at C-4 as predicted by the molecular orbital calculations).4 This hypothesis necessitates that the addition step be rapidly reversible and that the second stage, the elimination of hydride ion, be the rate-determining one (Scheme VII). Although it seems reasonable to assume that the hydride ion eliminations are the slow steps in this reaction, the fact that no deuterium isotope effect was observed in the reaction of 3-picoline-2d and of pyridine-2d with sodamide implies that the first stage must be virtually irreversible,268 as was found also in the case of the addition of phenyllithium to pyridine.229 The addition stage must, therefore, be the product-... 

The propene ion is one system in which determination of isotope effects is hampered by hydrogen randomisation. Nevertheless, deuterium isotope effects upon ion abundances following El have been obtained by making allowances for the extent of hydrogen randomisation [see Sect. 7.5.1(f)]. For hydrogen atom elimination, the isotope effect/H//D has been put at 1.7—2.0 for source reactions [372] and 2.3—3.0 and 3.6 (first and second field-free regions, respectively) for metastable ions [510]. For hydrogen atom elimination from propenoic acid ions, the isotope effect /H//D has been put at 4.3 for metastable ions [587]. 

Ion abundances for methane loss from metastable (CH3CD2CHD2)t ions have been found to be in the ratios 87 1 12 (CH4 CH3D CH2D2) after correction for the numbers of equivalent pathways [250]. The reaction is a 1, 2 elimination, so these results indicate both a large primary and a large secondary deuterium isotope effect (see Sect. 7.5.4). On the basis of these intramolecular isotope effects, a mechanism involving a non-classical transition state with a CCH three-centre bond has been proposed for this methane elimination [250]. 

The deuterium isotope effect can add to the information from Hammett plots in building up a picture of a transition state. Three separate Hammett p values can be measured for this elimination reaction and this information is very valuable. But it would be sadly incomplete without the information that a large deuterium isotope effect fo/fo = 7.1 is observed for the hydrogen atom under attack. 

With proton transfer (k ) rate determining, the primary deuterium isotope effect is satisfied as well as the sensitivity of the reaction rates to (C-O) bond rupture. The latter is reflected in the (kjk2) ratio. It was noted that rearrangement in the carbonium ion of the ion pair (e.g., loss of optical activity at the a-carbon center in the reactant ester, Atj > fcj) would substantiate the ion pair mechanism. Results of this kind of experiment in the stereospecific m-elimination that is observed in ester pyrolyses is not compatible with the ion-pair mechanism. For example, the acetate of the erythro-isomsT of 2-deutero-l,2-dipenylethanol gave /runs-stilbene with predominant retention of deuterium (95.6 1.7%). In contrast, the threo-isomer gave Iranj-stilbene with predominant loss of deuterium (26.4+0.6% deuterium) . 

Elimination Reactions and Cyclohexane Conformation The Deuterium Isotope Effect 420 The El Reaction 421... 

Anti-cancer drugs such as cyclophosphamide (15), aniline mustard, and nitrosoureas are transformed to reactive metabolites which are the toxic species required for their anti-cancer activity. Experiments with selectively deuterated analogs of these drugs has distinguished which pathway, among several alternative pathways of metabolism, is responsible for antitumor activity. For example, a deuterium isotope effect was observed for the formation of 4-ketocyclophosphamide (16), formed by the oxidation of the carbon alpha to the phosphoramide nitrogen, but there was no Isotope effect on the anti-tumor activity. However, there was a marked effect on the subsequent -elimination reaction and consequent decrease in anti-tumor activity by deuterium substitution at C-5. Thus, the formation of acrolein and phosphoramide mustard is rate determining for the anti-tumor activity of cyclophosphamide. 

Primary and secondary kinetic isotope effects are of general importance in the study of neighboring group participation. Isotopic substitution a to the incipient carbo-cation produces a secondary isotope effect whereas 0 and y substituents may give rise to both primary and secondary effects. For example, if the rate determining step of a solvolytic reaction involves a hydrogen shift or elimination, primary deuterium isotope effects are clearly implicated. 

In the elimination reaction of the (2-phenylethyl)trimethyl- 1 ammonium ion D with the ethoxide ion, there is a l4N/l5N nitrogen isotope effect uN/fcijN of 1.0133 0.0002 and a deuterium isotope effect at the position shown ( ) kn/ko of 3.2. Which of the following mechanisms does this evidence support ... 

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