Classes of reactions under Curtin—Hammett control[ edit ] Three main classes of reactions can be explained by the Curtin—Hammett principle: either the more or less stable conformer may react more quickly, or they may both react at the same rate. Case I: More stable conformer reacts more quickly[ edit ] One category of reactions under Curtin—Hammett control includes transformations in which the more stable conformer reacts more quickly. This occurs when the transition state from the major intermediate to its respective product is lower in energy than the transition state from the minor intermediate to the other possible product. The major product is then derived from the major conformer, and the product distribution does not mirror the equilibrium conformer distribution. Example: piperidine oxidation[ edit ] An example of a Curtin—Hammett scenario in which the more stable conformational isomer reacts more quickly is observed during the oxidation of piperidines. In the case of N-methyl piperidine, inversion at nitrogen between diastereomeric conformers is much faster than the rate of amine oxidation.
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Classes of reactions under Curtin—Hammett control[ edit ] Three main classes of reactions can be explained by the Curtin—Hammett principle: either the more or less stable conformer may react more quickly, or they may both react at the same rate.
Case I: More stable conformer reacts more quickly[ edit ] One category of reactions under Curtin—Hammett control includes transformations in which the more stable conformer reacts more quickly. This occurs when the transition state from the major intermediate to its respective product is lower in energy than the transition state from the minor intermediate to the other possible product.
The major product is then derived from the major conformer, and the product distribution does not mirror the equilibrium conformer distribution. Example: piperidine oxidation[ edit ] An example of a Curtin—Hammett scenario in which the more stable conformational isomer reacts more quickly is observed during the oxidation of piperidines.
In the case of N-methyl piperidine, inversion at nitrogen between diastereomeric conformers is much faster than the rate of amine oxidation. In this case, despite an energetic preference for the less reactive species, the major product is derived from the higher-energy species.
An important implication is that the product of a reaction can be derived from a conformer that is at sufficiently low concentration as to be unobservable in the ground state. In this case, product selectivity would depend only on the distribution of ground-state conformers. In this case, both conformers would react at the same rate.
Example: SN2 reaction of cyclohexyl iodide[ edit ] Ernest L. Eliel has proposed that the hypothetical reaction of cyclohexyl iodide with radiolabeled iodide would result in a completely symmetric transition state.
However, equilibration of the products precludes observation of this phenomenon. For instance, high selectivity for one ground state conformer is observed in the following radical methylation reaction. However, transition state energies depend both on the presence of A 1,3 strain and on steric hindrance associated with the incoming methyl radical.
In this case, these two factors are in opposition, and the difference in transition state energies is small compared to the difference in ground state energies. As a result, poor overall selectivity is observed in the reaction. Application to stereoselective and regioselective reactions[ edit ] The Curtin—Hammett principle is used to explain the selectivity ratios for some stereoselective reactions.
Application to dynamic kinetic resolution[ edit ] The Curtin—Hammett principle can explain the observed dynamics in transformations employing dynamic kinetic resolution , such as the Noyori asymmetric hydrogenation  and enantioselective lithiation.
The use of a chiral catalyst results in a higher-energy and a lower-energy transition state for hydrogenation of the two enantiomers. The transformation occurs via the lower-energy transition state to form the product as a single enantiomer. The relative free energy profile of one example of the Noyori asymmetric hydrogenation is shown below: Enantioselective lithiation[ edit ] Dynamic kinetic resolution under Curtin—Hammett conditions has also been applied to enantioselective lithiation reactions.
In the reaction below, it was observed that product enantioselectivities were independent of the chirality of the starting material. Were the two reactant complexes not rapidly interconverting, enantioselectivity would erode over time as the faster-reacting conformer was depleted. Application to regioselective acylation[ edit ] The Curtin—Hammett principle has been invoked to explain regioselectivity in the acylation of 1,2-diols.
Ordinarily, the less-hindered site of an asymmetric 1,2-diol would experience more rapid esterification due to reduced steric hindrance between the diol and the acylating reagent. Developing a selective esterification of the most substituted hydroxyl group is a useful transformation in synthetic organic chemistry, particularly in the synthesis of carbohydrates and other polyhdyroxylated compounds.
This compound is then treated with one equivalent of acyl chloride to produce the stannyl monoester. Two isomers of the stannyl ester are accessible, and can undergo rapid interconversion through a tetrahedral intermediate. Initially, the less stable isomer predominates, as it is formed more quickly from the stannyl acetal. However, allowing the two isomers to equilibrate results in an excess of the more stable primary alkoxystannane in solution. The reaction is then quenched irreversibly, with the less hindered primary alkoxystannane reacting more rapidly.
This results in selective production of the more-substituted monoester. This is a Curtin—Hammett scenario in which the more stable isomer also reacts more rapidly.
Application to asymmetric epoxidation[ edit ] The epoxidation of asymmetric alkenes has also been studied as an example of Curtin—Hammett kinetics. In a computational study of the diastereoselective epoxidation of chiral allylic alcohols by titanium peroxy complexes, the computed difference in transition state energies between the two conformers was 1. This product ratio is consistent with the computed difference in transition state energies. This is an example in which the conformer favored in the ground state, which experiences reduced A 1,3 strain, reacts through a lower-energy transition state to form the major product.
Synthetic applications[ edit ] Synthesis of ATA1[ edit ] The Curtin—Hammett principle has been invoked to explain selectivity in a variety of synthetic pathways. One example is observed en route to the antitumor antibiotic ATA1, in which a Mannich-type cyclization proceeds with excellent regioselectivity.
Studies demonstrate that the cyclization step is irreversible in the solvent used to run the reaction, suggesting that Curtin—Hammett kinetics can explain the product selectivity. The structure of each of the two compounds contains a twisted membered macrocycle. However, because the amide-bond-forming step was irreversible and the barrier to isomerization was low, the major product was derived from the faster-reacting intermediate.
This is an example of a Curtin—Hammett scenario in which the less-stable intermediate is significantly more reactive than the more stable intermediate that predominates in solution. Because substrate isomerization is fast, throughout the course of the reaction excess substrate of the more stable form can be converted into the less stable form, which then undergoes rapid and irreversible amide bond formation to produce the desired macrocycle.
See Talk pages. A key step in the synthesis is the rhodium-catalyzed formation of an oxonium ylide, which then undergoes a [2,3] sigmatropic rearrangement en route to the desired product. Obtaining high selectivity for the desired product was possible, however, due to differences in the activation barriers for the step following ylide formation. If the ortho-methoxy group undergoes oxonium ylide formation, a 1,4-methyl shift can then generate an undesired product.
The oxonium ylide formed from the other ortho-alkoxy group is primed to undergo a [2,3] sigmatropic rearrangement to yield the desired compound. Pirrung and coworkers reported complete selectivity for the desired product over the product resulting from a 1,4-methyl shift.
This result suggests that oxonium ylide formation is reversible, but that the subsequent step is irreversible. The symmetry-allowed [2,3] sigmatropic rearrangement must follow a pathway that is lower in activation energy than the 1,4-methyl shift, explaining the exclusive formation of the desired product.
The reaction could result in the formation of two possible double bond isomers. The reaction provided good selectivity for the desired isomer, with results consistent with a Curtin-Hammett scenario. Initial oxidative cycloruthenation and beta-hydride elimination produce a vinyl-ruthenium hydride. Hydride insertion allows for facile alkene isomerization.
It is unlikely that the reaction outcome mirrors the stability of the intermediates, as the large CpRu group experiences unfavorable steric interactions with the nearby isopropyl group. Instead, a Curtin—Hammett situation applies, in which the isomer favored in equilibrium does not lead to the major product. Reductive elimination is favored from the more reactive, less stable intermediate, as strain relief is maximized in the transition state.
This produces the desired double bond isomer.