Cyclization reactions isotope effects

Wawzonek et al. first investigated the mechanism of the cyclization of A-haloamines and correctly proposed the free radical chain reaction pathway that was substantiated by experimental data. "" Subsequently, Corey and Hertler examined the stereochemistry, hydrogen isotope effect, initiation, catalysis, intermediates, and selectivity of hydrogen transfer. Their results pointed conclusively to a free radical chain mechanism involving intramolecular hydrogen transfer as one of the propagation steps. Accordingly, the... 

Arnett and coworkers later examined the reaction of lithium pinacolone enoiate with substituted benzaldehydes in THE at 25 °C. The determination of the heat of reaction indicated that the Hammett p value for the process is 331. Although the aldol reaction was instantaneous in THF at 25 °C, the reaction with o- or p-methylbenzaldehyde could be followed using a rapid injection NMR method in methylcyclohexane solvent at —80 °C. Application of Eberson s criterion based on the Marcus equation, which relates the free energy of ET determined electrochemically and the free energy of activation determined by kinetics, revealed that the barriers for the ET mechanism should be unacceptably high. They concluded that the reaction proceeds via the polar mechanism . Consistent with the polar mechanism, cyclizable probe experiments were negative . The mechanistic discrepancy between the reactions of benzaldehyde and benzophenone was later solved by carbon kinetic isotope effect study vide infraf. ... 

Reaction of atomic carbon with alkenes generally involves both DBA and vinyl C—H insertion. An interesting example is the reaction of C atoms with styrene in which the major products are phenylallene (21) and indene (22). The synthesis of a number of specifically deuterated styrenes and the measurement of the deuterium isotope effects on the 21/22 ratio led to the conclusion that 21 was formed by DBA followed by ring expansion and by C—H(D) insertion into and followed by rearrangement of the resultant frawi-vinylcarbene (23). The indene was formed by C—H(D) insertion into Xb followed by cyclization of the resultant cw-vinylcarbene (24) (Eq. 18). An examination of the product ratios and their label distributions when atoms are used leads to the conclusion that the ratio of C=C addition to C—H insertion is 0.72 1 in this case. 

In the course of an examination of isotope effects in the ene reactions of this reagent, Stephenson and Orfanopoulos3 have observed a potentially useful cyclization. An example is shown in equation (1). 

Base-catalysed cyclization of proximate diacetyl aromatics [e.g. o-diaccty I benzene (36)] gives the corresponding enone (37). Relative rates, activation parameters, and isotope effects are reported for (36), and also for 1,8-diacetylnaphthalene, 4,5-diacetylphenanthrene, and 2,2/-diacetylbiphenyl, in aqueous DMSO.61 Reaction proceeds via enolate formation (rate determining for the latter three substrates), followed by intramolecular nucleophilic attack [rate determining for (36)], and finally dehydration. 

Singleton and coworkers took up the ene cyclization reaction of ene-allene (Scheme 4) and carried out combined experimental-computational investigation.43 The ene reaction had been known to show mechanistic uncertainty, in particular whether it proceeds via a concerted or stepwise route, and therefore provided a challenge for dynamics study. KIE measurement for the reaction of 22 (Ri = R.2 = TMS) in toluene at 50°C gave kcus/kcm of 1.43, which was smaller than what was normally observed in concerted ene reactions. However, the isotope effect was too large to support a stepwise ene reaction. Thus, this was in line with the idea that the mechanism is near the concerted-stepwise borderline. 

Experimental and computational studies of the pericyclic Meisenheimer rearrangement and a competitive rearrangement of A-propargyl morphol i nc N-oxide revealed a novel inverse secondary kinetic isotope effect (kn/kD 0.8) for the rate-determining cyclization step, probably occurring because of a C(sp) to C(sp2) change in hybridization at the reaction center (Scheme 3).5... 

When the hydrogen transferred as hydride to the cofactor is retransferred to the same carbon atom in the product, the movement is far more difficult to detect. The conversion of D-glucose 6-phosphate (58) into lL-mt/o-inositol 1-phosphate (61) occurs by cyclization of the carbon skeleton, with formation of a new bond between C-l and C-6. When each carbon atom in turn was specifically labeled with tritium, there was complete retention of tritium, even in the presence of added NADH, although there was an apparent, small isotope-effect with D-glucose-5-t 6-phosphate.19 The mechanism proposed for the cyclization19 was an initial oxidation at C-5 to give NADH and xylo-hexos-5-ulose 6-phosphate (59), followed by an aldol reaction causing cyclization to lL-myo-inosose-2 1-phosphate (60), which is then... 

Even though the Paal-Knorr pyrrole synthesis has been around for 120 years, its precise mechanism was the subject of debate. In 1991, V. Amarnath et al. investigated the intermediates of the reaction and determined the most likely mechanistic pathway. The formation of pyrroles was studied on various racemic and meso-3,4-diethyl-2,5-hexanediones. The authors found that the rate of cyclization was different for the racemic and meso compounds and the racemic isomers reacted considerably faster than the meso isomers. There were two crucial observations 1) the stereoisomers did not interconvert under the reaction conditions and 2) there was no primary kinetic isotope effect for the hydrogen atoms at the C3 and C4 positions. These observations led to the conclusion that the cyclization of the hemiaminal intermediate is the rate-determining (slow) step. 

The observation of an isotope effect in the case of 2 ( h/Zcd 3.0), and the effect of substituents indicates that the reaction proceeds by hydrogen transfer from the d-position of the side ehain to Cl of the cyclopropene to produce a diradical, e.g. 3, followed by a second hydrogen transfer. The second hydrogen-transfer reaction competes with cyclization (see Section I.I.6.2.2.). 

Scheme 2.32, R = H, half-life 40 s at 39 °C). Cyclization is rate determining and the reaction is not buffer catalyzed) [67]. (The lO -fold greater electrophilic reactivity of the alkyne means that the steric acceleration provided by the orthomethyl groups in 4.2 is not needed in 4.3.) The solvent deuterium isotope effect knio/ko20 on the proton transfer step (derived from the product isotope effect) is... 

In 100% H2SO4 the cyclization shown below occurs. If one of the ortho hydrogens is replaced by deuterium, the rate of cyclization drops from 1.56 X 10 to 1.38 X 10 s . Calculate the kinetic isotope effect. The product from such a reaction contains 60% of the original deuterium. Write a mechanism for this reaction that is consistent with both the magnitude of the kinetic isotope effect and the deuterium retention data. 

When geraniol reacts with phenols in the presence of acid, the common products are usually cyclized the use of 1 % oxalic acid has now been found to minimize cyclization in the reaction between orcinol and geraniol. Nerol has been labelled with deuterium in various positions [a, b, c, and d in (32)] and then converted into the chloride (33). Kinetic isotope effects on hydrolysis of (33) were measured, and 7r-participation in the cationic intermediate (34) leading to the cyclized terpinyl derivatives is discussed. Schwartz and Dunn proposed to use the complex (35), from geranyl methyl ether, as a model for a farnesol cyclization. They were not able to isolate this complex (although there was some evidence for its formation), the main complex (36%) being a dimeric a-complex (36), together with 39 % of the ketone (37), but no cyclized material. The cyclization of the acid chloride (38) to menthone and the C9 hydrocarbon (39) with tributyltin hydride, and also the optimum conditions for the cyclization of (-i-)-citronellal... 

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