Transition structures Cope rearrangement

Step through the sequence of stmctures depicting Cope rearrangement of 1,5-hexadiene. Plot energy (vertical axis) vs. the length of either the carbon-carbon bond being formed or that being broken (horizontal axis). Locate the transition state. Measure all CC bond distances at the transition state, and draw a structural formula for it... 

This chapter has attempted to demonstrate how secondary deuterium and tritium KIEs can be used to elucidate the mechanisms of reactions and determine the structure of their transition states. In particular, the advantages of using both theoretical calculations and experimental data to solve these problems has been emphasized. Unfortunately, several important topics where the combination of theoretical calculations and experimental work has been very useful in extending our understanding of KIEs could not be discussed. In particular, the extensive studies on the Diels-Alder and the Cope rearrangement by Houk and co-workers (Beno et al., 1996 Houk et al., 1992 Storer et al., 1994) are noteworthy. 

The mechanism and stereochemistry of the ortho ester Claisen rearrangement are analogous to those of the Cope rearrangement. The reaction is stereospecific with respect to the double bond present in the initial allylic alcohol. In acyclic molecules, the stereochemistry of the product can usually be predicted on the basis of a chairlike transition state.158 When steric effects or ring geometry preclude a chairlike structure, the reaction can proceed through a boatlike transition state.159... 

The X-ray crystal structure for AZ-28 has a variety of structural features that are consistent with the proposed mechanism operative for the oxy-Cope rearrangement. The antibody binds the transition stage analog in a chair-like conformation, consistent with the preferred chair transition state for this pericyclic reaction (Doering and Roth, 1962). The positions of the C-2 and C-5 atoms are fixed in the antibody-bound hapten molecule in a similar fashion, the C-2 and C-5 positions in the hexadiene substrate should be held in a fixed position by conserved van der Waals interactions locking in the two phenyl substituents in the antibody combining site. This bound conformation of the acyclic (47T + 2er) system of the hexadiene substrate should enforce a molecular conformation close to the transition state for the rearrangement reaction, consistent with the catalysis observed for AZ-28. 

Table 8. Transition structure geometries, activation energies, and reaction energies for transition structures of Cope rearrangement of 1,5-hexadiene...

A number of theoretical studies have been conducted to understand the mechanism of the Cope rearrangement.16 According to calculations by Houk and co-workers, the chairlike transition state is more stable than the boatlike transition state by 7.8 kcal/mol (Scheme l.XII). When Schleyer and colleagues performed calculations to compute the magnetic properties of the transition-state structures, transition states A and B had a magnetic susceptibility of—55.0 and—56.6, respectively. These values are comparable to that of benezene (—62.9), confirming the existence of an aromatic transition state in the Cope rearrangement. 

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. 

Two minor processes sometimes operate competitively with that illustrated in the scheme. One of these involves 1,4-addition of the second vinyl anion to give a reactive intermediate that differs structurally from 1, but is capable of setting into motion a closely related sequence of chemical events leading to an isomeric diquinane.4 This is the route followed to produce the minor product characterized here. The other option consists of cis-t, 2-addition, an event that is followed by a dianionic oxy-Cope rearrangement via a boat-like transition state.4 When sufficient substitution is present to allow the installation of multiple stereogenic centers, the adoption of this pathway is easily distinguished from the electrocyclic alternative since a cis relationship between relevant substituents is in place, instead of the trans arrangement required by the electrocyclization cascade. 

The same is true for Cope rearrangements in general. Most substituents at C-1 and C-3 accelerate the reaction, and with more than one of them, their effects are cooperative. Substituents at C-2, however, shift the balance of the transition structure towards a biradical-like intermediate in which the new a bond is formed ahead of the old one breaking. Substituent effects at this site are not cooperative with substituent effects at C-l and C-3, because they change the nature of the transition structure rather than contribute to it in the same way. 

Density functional theory has also been applied to the Cope rearrangement. Nonlocal methods, such as BLYP and B3LYP, find a single transition state with approximately 2 A. The barrier height is in excellent agreement with experiment. These first DFT results were extremely encouraging because DFT computations are considerably less resonrce-intensive than MRPT. Moreover, analytical first and second derivatives are available for DFT, allowing for efficient optimization of stmc-tures (particularly transition states) and the computation of vibrational frequencies needed to characterize the nature of the stationary points. Analytical derivatives are not available for MRPT calculations, which means that there is a more difficult optimization procedure and the inability to fully characterize structures. 

Gajewski, J. J. Conrad, N. D. Variable transition-state structure in the Cope rearrangement as deduced from secondary deuterium kinetic isotope effects, J. Am. Chem. Soc. 1978,100, 6269-6270. 

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