Kinetic isotope effects cyclization

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. ... 

The oxidation of a-hydroxy acids by benzyltrimethylammonium tribromide (BTMAB) to the corresponding carbonyl compounds shows a substantial solvent isotope effect, A (H20)/A (D20) = 3.57, but no KIE for a-deuteromandelic acid.133 The oxidation of glucose by hypobromous acid is first order in glucose and the acid.134 [l,l-2H2]Ethanol shows a substantial kinetic isotope effect when oxidized by hexamethylenetetramine-bromine (HABR) in acetic acid to aldehyde.135 Kinetics of the oxidation of aliphatic aldehydes by hexamethylenetetramine-bromine have been studied by the same group.136 Dioxoane dibromide oxidizes y-tocopherol to 5-bromomethyl-y-tocopherylquinone, which spontaneously cyclizes to 5-formyl-y-tocopherol.137... 

Kensy et al. [1993] showed that the zwitterion formation and subsequent cyclization due to hydrogen transfer take place in the lowest triplet excited state of diphenylamine and its methyl substituents. The crossover temperature is about 100 K, and the values of C(H) are 10 2-10 4 s 1 for various substituents. The H/D kinetic isotope effect at T [Pg.177]

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... 

A study of kinetic isotope effects, theoretical calculations, and dynamic trajectories of the C(2)-C(6) (Schmittel)/ene cyclization of enyne-allenes has been reported.178 For (74), the isotope effect l=h/ l=d = 1-43 is consistent with a highly asynchronous... 

Kinetic isotope effects have been reported that suggest that the thermal cyclization of enyne-allenes proceeds through a stepwise diradical mechanism (Scheme 121). This is even true if steric bulk at the alkyne terminus is large, contrary to theoretical predictions.182... 

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. 

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... 

It has been found that this oxidative cyclization does not exhibit kinetic isotope effect ( h/ d = 10), thus indicating that the cleavage of the p-C-H bond in the amidine adduct is not involved into the rate-determining step. Although the exact mechanistic details are not clear yet, it is assumed that the I species are initially coordinated with the amidine nitrogen atom, followed by ring closure and elimination of iodobenzene and acetic acid from the azoline intermediate 66 (Scheme 42). It is worth mentioning that the reaction proceeds under mild conditions and is free from acid or metal catalyst. 

The isotope effect was also studied in the palladium-catalyzed cyclization of substrates 15 to form oxindoles 16 via C—H bond functionalization (Scheme 11.5) [34]. Whereas, no kinetic isotope effect was observed in the competitive reaction of 15a and 15a-d5, an intramolecular primary isotope effect of 4 was found in the cyclization of the ortho-monodeuterated substrate 15a-di. The absence of any inter-molecular isotope effects suggests that the first step, the oxidative addition, is both slow and rate-determining overall. Although different mechanistic scenarios were considered, the significant intramolecular isotope effect shows that the palladation... 

In contrast with arylations of other heterocycles, the palladium-catalyzed arylation of benzoxazoles at C-2 proceeds readily at ambient temperature (Scheme 11.21) [67]. Although, as in other cases no kinetic isotope effect was found for 59a, a Hammett plot revealed a correlation with ct with a positive p, which indicates that a phenolate intermediate is formed in this reaction. Therefore, this reaction has been shown to proceed by a totally different mechanism. According to experimental results and DFT calculations, the reactions proceed by the deprotonation of benzoxazoles 59 to form 61, which is in equilibrium with o-phenoxyisocyanide 62. Coordination of the oxidative addition product PdI(Ph)L2 to the isocyanide then forms 63 which cyclizes to form palladate 64, from which the 2-phenylbenzoxazoles 60 are formed by reductive ehmination. 

The Ni(COD)2/PCy3-catalysed and Et3SiH-mediated reductive cyclization of ynals in THF is first order in catalyst and ynal and zero order in silane, which was used only in the presence of alkyne and aldehyde. The kinetic isotope effect, = 1 ... 

Reactions with aikynes may aiso result in the formation of cyclized products. Thus a ruthenium-catalysed reaction with aromatic amides has been used to give isoquinoline derivatives. On the basis of values of the kinetic isotope effect, A h/ d> proposed that the rate-determining step is a concerted acetate-assisted metalation-deprotonation process to yield the intermediate (30), followed by aikyne insertion and ring closure. The reaction of arylketones with alkynes may yield indenols when catalysed by rhodium cyclopentadienyl in the presence of silver and copper salts. The reaction proceeds regioselectively, so that reaction of acetophenone with 1-phenyl-1-propene... 

The expected rate-enhancing effects of gem-dimethyl substituents were not seen in the base-catalysed cyclizations of ethyl A-(4-nitrophenyl)hydantoate (106 R, = Me, R = 4-O2NC6H4) and of ethyl A-phenylhydantoate (106 R R = Me, R° = Ph). Solvent kinetic isotope effects and other data led to the conclusion that the loss of the gem-dimethyl effects was due to steric hindrance to proton transfer of... 

Triphenyltris-(tetrahydrofuran)chromium(m) (4) reacts with but-2-yne to give 1,2,3,4-tetramethylnaphthalene (5). From deuterium labelling and kinetic isotope effects, and from the isolation of intermediates, it proved possible to propose the mechanism shown in Scheme 1. The sequence is insertion, then cyclization of the styrylchromium intermediate to a benz-chromole, followed by reaction with a second molecule of but-2-yne. ... 

Intramolecular Cyclizations.—Base-induced 1,3-bonding occurs in the conversion of (24) into (25) even though the reaction is a 1,7-elimination. A spiro-product is also obtained in the dehydration of (26) with dicyclohexyl-carbodi-imide (DCQ. The mechanism of the 1,3-elimination from 3-phenyl-propyltrimethylammonium iodide with potassium amide in liquid ammonia has been investigated. The reaction is concurrent with 1,2-elimmation and shows a nitrogen kinetic isotope effect = 1.022 + 0.001). This and deuterium-... 

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