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The Selectivity of Maltol and Allomaltol Oxidopyrylium [5+2] Cycloaddition Reactions
One topic that fascinates Ryan Murelli, Ph.D.'s research group is the oxidopyrylium [5+2] cycloaddition reaction, which is the reaction between an oxidopyrylium ylide and a dipolarophile. This reaction leads to the formation of seven-membered carbocycles and has extensive use in synthesis. The molecules of interest are maltol and its isomer, allomaltol, in their ylide and cycloadduct forms.
Figure 1. Oxidopyrylium [5+2] cycloaddition.
A previous lab member studied this cycloaddition reaction using maltol and allomaltol ylides and various dipolarophiles. During his experiments, he observed the formation of 2:1 ylide/alkyne adducts, referred to as “sandwich complexes”. These sandwich complexes, which emerge from two subsequent [5+2] cycloadditions, formed with surprisingly high regio- and stereoselectivities. Thus, it was worthwhile to gain a more detailed mechanistic insight leading to selective product formation.
The cycloaddition reactions can theoretically lead to up to eight different regio- and stereoisomers, depending on the approach between the dipolarophile and the ylide. We first wanted to explain the selective product formation using computational methods. To do this, the reactions were modeled using the Maestro Schrodinger software with M06-2X/6-311G** as the theory and basis set. According to the results, the selective products that were experimentally observed had the smallest transition state energies, leading us to believe that the product formation is kinetically driven.
My current research is focused on building onto this discovery by exploring new cycloaddition reactions. More specifically, the sandwich complexes formed by crossing over the allomaltol ylide with the maltol-derived dipolarophile and the maltol ylide with the allomaltol-derived dipolarophile. The molecules will be characterized using techniques such as nuclear magnetic resonance (NMR) and infrared (IR) spectroscopies. After the characterization, it will be possible to conclude if the favored products of the “cross over” sandwich complexes are also kinetically driven. I aim to determine which products are favored and why, and to see if this knowledge can be applied to different cycloaddition reactions.
Computational Method:
To better understand the selectivity of the sandwich complexes, the two [5+2] cycloaddition reactions were modeled using Maestro Schrodinger (M06-2X as the theory and 6-311G** as the basis set). The approach of the cycloadducts toward the ylides could theoretically result in eight different stereochemical products for each reaction: concave-endo-E, concave-endo-Z, concave-exo-E, concave-exo-Z, convex-endo-E, convex-endo-Z, convex-exo-E, and convex-exo-Z. Previous research in our lab has shown that the concave approaches require substantially larger Gibbs free energy values in the transition state than the convex approaches. Therefore, I minimized my focus only on the products formed by the convex approaches, assuming that the concave pathways don’t lead to product formation (Figure 2).
Figure 2A. The possible isomers of the allomaltol ylide/maltol cycloadduct sandwich complex.
B. The possible isomers of the maltol ylide/allomaltol cycloadduct sandwich complex.
The reagents and the products were optimized and submitted for a transition state search. The search gave me access to the energy profiles of each cycloaddition reaction. The convex-endo-Z product had the smallest transition state Gibbs free energy value out of the four possible products for the allomaltol ylide/maltol cycloadduct complex. Based on the working theory that the product formation is kinetically driven, the reaction is expected to occur through this approach. Additionally, the convex-exo-Z product has the smallest ∆G for the maltol ylide/allomaltol cycloadduct complex, which suggests that the product observed in the laboratory should contain this regio- and stereochemistry.
Table 1. Gibbs free energy values of transition states and products of the sandwich complexes.
Experimental Method:
The preliminary experimental step was to synthesize all of the necessary reagents: maltol and allomaltol-derived ylides and ylide/methyl propiolate cycloadducts as the dipolarophiles.
Figure 3A. Allomaltol ylide 10 is formed using allomaltol 9. The ylide then reacts with methyl propiolate to form the allomaltol cycloadduct 11.
B. Maltol ylide 13 is formed using maltol 12. The ylide then reacts with methyl propiolate to form the maltol cycloadduct 14.
The sandwich complexes were formed using a 1:1 ratio of the ylide to the cycloadduct. The [5+2] cycloadditions were run under microwave conditions, and the major products were isolated using column chromatography (ethyl acetate/hexanes as the solvents). The product that emerged from the allomaltol-derived ylide and the maltol-derived cycloadduct was crystallized, while the other product appears to be an oil at room temperature.
Figure 4A. Allomaltol ylide and maltol cycloadduct are expected to undergo a [5+2] cycloaddition to form the convex-endo-Z sandwich complex 1.
B. Maltol ylide and allomaltol cycloadduct are expected to undergo a [5+2] cycloaddition to form the convex-exo-Z sandwich complex 7.
NMR, IR, and mass spectroscopies were used to characterize the sandwich complexes. Proton and carbon NMR helped assess the progress of the procedures and to verify the formation of the products. Nuclear Overhauser Effect Spectroscopy (NOESY) also helped assign the regio- and stereoselectivity of the complexes by showing the interactions between the hydrogens. The NOESY spectra of the two complexes suggest that the products that form are 1 and 7. For further confirmation, the allomaltol ylide/maltol cycloadduct crystal was sent to obtain a crystal structure. It confirmed that 1 does form selectively.
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