Isotope effects Claisen rearrangement

Final remarks. The 14C-KIE and 2H-SKIE data presented in this Section (VLB) clearly indicate the usefulness of isotope effect methodology in studies of mechanistic details of thermally induced Claisen rearrangement, which provides a synthetic route to y,5-unsaturatcd carbonyl compounds. The primary and secondary 14C KIE supplement strongly the deuterium SKIE. Especially easy for interpretation are 14C and 2H isotope... 

Verification of different theoretical methods used in calculations of transition states was thoroughly discussed by Singleton et al.60 on the basis of their own and published by others studies of Claisen rearrangement. The rearrangements of allyl vinyl ether (Equation (31)) and allyl phenyl ether (Equation (32)) were chosen for by the combined 2H, 13C and l70 isotope effects and calculation studies. 

The experimental KIEs were determined for the aliphatic Claisen rearrangement in p-cymene at 120°C and for the aromatic Claisen rearrangement either neat at 170°C or in diphenyl ether at 220°C. Changes in 2H, 13C or 170 composition were determined for unreacted substrates. For carbon analysis of allyl vinyl ether the C5 carbon was used as an internal standard. The C4 atom and rneta aryl protons were used as references in analysis of allyl phenyl ether. The 170 analysis was based on a new methodology. The results are summarized in Table 1, along with predicted isotope effects calculated for experimental temperatures by means of different computational methods. The absolute values of predicted isotope effects for C4 and C5 atoms varied with theoretical level and all isotope effects were rescaled to get reference effects equal to 1.000. 

Taking into consideration the agreement between experimental and predicted isotope effects, in the case of the aliphatic Claisen the best transition state is represented by the MP4/6-31G structure. For both aliphatic and aromatic rearrangements the transition states are intermediate between the B3LYP/6-31G and the MP2/6-31G structures. This publication is a valuable guide in application of KIEs in mechanistic studies. 

Another series of publications from Ken s group compared kinetic isotope effects, computed for different possible transition structures for a variety of reactions, with the experimental values, either obtained from the literature or measured by Singleton s group at Texas A M. These comparisons established the most important features of the transition states for several classic organic reactions — Diels-Alder cycloadditions, Cope and Claisen rearrangements, peracid epoxidations, carbene and triazolinedione cycloadditions and, most recently, osmium tetroxide bis-hydroxylations. Due to Ken s research, the three-dimensional structures of many transition states have become nearly as well-understood as the structures of stable molecules. 

Wiest, O. Black, K. A. Houk, K. N. Density functional theory isotope effects and activation energies for the Cope and Claisen rearrangements, J. Am. Chem. Soc. 1994, 116, 10336-10337. 

Al-Sader, B.H. and Al-Fekri, D.M., On the mechanism of flash vacuum pyrolysis of phenyl propargyl ether. Intramolecular deuterium kinetic isotope effect on Claisen rearrangement, J. Org. Chem., 43, 3626, 1978. 

Experimental Heavy atom, I60/I80, 12c/14c, (H/D2) kinetic isotope effects for the Claisen Rearrangement ... 

Supportive of the suggestion that ionization is not a major pathway in the Claisen rearrangement of the parent compound is the fact that the SDKIEs in aqueous solution are comparable to those in the gas phase and in m-xylene. Furthermore, attempts to solvolyze 1,1-dideuterioaUyl mesylate in aqueous methanol resulted in no ionization to an allyl cation instead, the direct displacement product was formed exclusively. Finally, determinations of a solvent kinetic isotope effect in deuterium oxide resulted in values around unity 10%. ° In the solvolysis reaction of tert-butyl chloride the value is 40% at room temperature. " It is possible to cause allylvinyl ethers to ionize by providing cation stabilizing substituents and Lewis acids or Lewis acidic solvents. ... 

In contrast to the thermal Claisen rearrangement, studies of isotopic labeling in the photochemical Claisen rearrangement support a dissociative mechanism. Figure 6.10 shows the results obtained from irradiation of 3- C-allyl 2,6-dimethylphenyl ether (37) to produce 2,6-dimethylphenol (38) and 4-allyl-2,6-dimethylphenol (39). In 39, the label was distributed nearly equally between the a and y positions, suggesting that it was formed by the recombination of 2,6-dimethylphenoxy and allyl intermediates and that rotation of the allyl fragment allows the label to become effectively scrambled between the two end carbon atoms of the allyl group by the time... 

The kinetic isotope effect and theoretical calculation of transition state model of the aromatic Claisen rearrangement were also reported. For example, Singleton et al. investigated the nature of the transition state of the Claisen rearrangement by a combined experimental and theoretical study [7]. It was shown that the experimental isotope effects coincide well with the predicted kinetic isotope effects. Detail of the theoretical studies is discussed in Chapter 11. 

Kupczyk-Subotkowska et al. studied heavy-atom kinetic isotope effects (KIE) of the thermal Claisen rearrangement of the parent [2- C]-, [4- C]-, [6- Cj- and [ 0]-allyl vinyl ether [38]. From the experimental KIEs they concluded, It is concerted a two-step process in which one bond is made (or broken) before the other is broken (or formed) is ruled out. From isotope effect calculations (BEBOVIB program) it was deduced that, "... the C4-O bond is 50-70% broken and the Cj-Cg bond 10-30% formed in the transition structure. ... 

Geometries, charge separation and kinetic isotope effects for the transition structure of the Claisen rearrangement of the parent aUyl vinyl ether were predicted on different levels of theory (RHF/6-31G, MCSCF/6-31G, CASSCF/6-31G ) by Yoo and Houk in 1994 [41]. The isotope effects calculated on the CASSCF/6-31G level were closest to the experimental values. The optimized MP2/6-31G structure of the transition structure was 1,4-diyl-like whereas the CASSCF/6-31G calculation predicted more oxallyl-allyl radical-pair character. 

The comparison of experimental and theoretically predicted kinetic isotope effects (KIEs) can be used to probe the accuracy of the computationally predicted transition structure provided that the experimental KIEs have been determined accurately. A comparison of predicted and experimental KIEs by Meyer et al. [55] led to the conclusion that, There is a firm disagreement in about half the cases between predicted and literature experimental heavy atom KIEs for both the aliphatic and aromatic Claisen rearrangements . Therefore, they reinvestigated the experimental KIEs for the Claisen rearrangement of aUyl phenyl and allyl vinyl ether and compared the determined values (solution) with the calculated data (gas phase). Eor the Claisen rearrangement of allyl vinyl ether, the transition structure was calculated on the MP4(SDQ)/6-31G level of theory and the predicted KIEs were in excellent agreement with the new experimental KIEs. The authors collected and compared previously reported data for the calculated distance between C- l/C-6 and O/C-4 and added their own predicted data (Scheme 11.40). 

This then does a Claisen rearrangement to produce pre-phenate, which is taken on to both Phe and Tyr. The Claisen rearrangement is catalyzed by the enzyme chorismate mutase. The enzyme catalyzes the reaction by as much as a factor of 10 . Extensive mechanistic studies have established that the enzyme-mediated reaction has all the hallmarks of a Claisen rearrangement, including appropriate isotope effects. A major role of the enzyme is to pre-organize chorismate into the proper conformation for rearrangement. However, the enzyme also uses substantial electrostatic interactions to stabilize partial charges in what is a fairly polar pericyclic transition state. 

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