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Precise through-space control of an abiotic electrophilic aromatic substitution reaction

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ABSTRACT

Nature has evolved selective enzymes for the efficient biosynthesis of complex products. This exceptional ability stems from adapted enzymatic pockets, which geometrically constrain reactants and stabilize specific reactive intermediates by placing electron-donating/accepting residues nearby. Here we perform an abiotic electrophilic aromatic substitution reaction, which is directed precisely through space. Ester arms—positioned above the planes of aromatic rings—enable it to distinguish between nearly identical, neighbouring reactive positions. Quantum mechanical calculations show that, in two competing reaction pathways, both [C–H···O]–hydrogen bonding and electrophile preorganization by coordination to a carbonyl group likely play a role in controlling the reaction. These through-space-directed mechanisms are inspired by dimethylallyl tryptophan synthases, which direct biological electrophilic aromatic substitutions by preorganizing dimethylallyl cations and by stabilizing reactive intermediates with [C–H···N]–hydrogen bonding. Our results demonstrate how the third dimension above and underneath aromatic rings can be exploited to precisely control electrophilic aromatic substitutions.

No MeSH data available.


Molecular orbital analysis.Isosurface plot of the lowest unoccupied molecular orbital (LUMO) belonging to the favoured cationic intermediate [endo-2a-H]+. Delocalization of the LUMO into the carbonyl group of the ester arm, which likely plays a crucial role in directing the electrophilic aromatic substitution reaction to the C2 position, is circled in red.
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f4: Molecular orbital analysis.Isosurface plot of the lowest unoccupied molecular orbital (LUMO) belonging to the favoured cationic intermediate [endo-2a-H]+. Delocalization of the LUMO into the carbonyl group of the ester arm, which likely plays a crucial role in directing the electrophilic aromatic substitution reaction to the C2 position, is circled in red.

Mentions: Yet, the DFT-optimized structures (Table 1) of the lowest Gibbs free energy tetrahedral intermediates [endo-2a-H]+ and [endo-2b-H]+ for nitration in the C2 and C3 positions, respectively, also offer an intuitive explanation for the observed selectivity. Close contacts between the cationic C1 and a carbonyl oxygen of the ester arm positioned directly above C1 are observed in [endo-2a-H]+. Furthermore, the lowest energy unoccupied molecular orbital of [endo-2a-H]+ (Fig. 4) clearly shows delocalization into one of the carbonyl oxygen's lone pairs. Both of these observations indicate through-space electron donation from an oxygen lone pair to stabilize the delocalized carbocation underneath.


Precise through-space control of an abiotic electrophilic aromatic substitution reaction
Molecular orbital analysis.Isosurface plot of the lowest unoccupied molecular orbital (LUMO) belonging to the favoured cationic intermediate [endo-2a-H]+. Delocalization of the LUMO into the carbonyl group of the ester arm, which likely plays a crucial role in directing the electrophilic aromatic substitution reaction to the C2 position, is circled in red.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382318&req=5

f4: Molecular orbital analysis.Isosurface plot of the lowest unoccupied molecular orbital (LUMO) belonging to the favoured cationic intermediate [endo-2a-H]+. Delocalization of the LUMO into the carbonyl group of the ester arm, which likely plays a crucial role in directing the electrophilic aromatic substitution reaction to the C2 position, is circled in red.
Mentions: Yet, the DFT-optimized structures (Table 1) of the lowest Gibbs free energy tetrahedral intermediates [endo-2a-H]+ and [endo-2b-H]+ for nitration in the C2 and C3 positions, respectively, also offer an intuitive explanation for the observed selectivity. Close contacts between the cationic C1 and a carbonyl oxygen of the ester arm positioned directly above C1 are observed in [endo-2a-H]+. Furthermore, the lowest energy unoccupied molecular orbital of [endo-2a-H]+ (Fig. 4) clearly shows delocalization into one of the carbonyl oxygen's lone pairs. Both of these observations indicate through-space electron donation from an oxygen lone pair to stabilize the delocalized carbocation underneath.

View Article: PubMed Central - PubMed

ABSTRACT

Nature has evolved selective enzymes for the efficient biosynthesis of complex products. This exceptional ability stems from adapted enzymatic pockets, which geometrically constrain reactants and stabilize specific reactive intermediates by placing electron-donating/accepting residues nearby. Here we perform an abiotic electrophilic aromatic substitution reaction, which is directed precisely through space. Ester arms—positioned above the planes of aromatic rings—enable it to distinguish between nearly identical, neighbouring reactive positions. Quantum mechanical calculations show that, in two competing reaction pathways, both [C–H···O]–hydrogen bonding and electrophile preorganization by coordination to a carbonyl group likely play a role in controlling the reaction. These through-space-directed mechanisms are inspired by dimethylallyl tryptophan synthases, which direct biological electrophilic aromatic substitutions by preorganizing dimethylallyl cations and by stabilizing reactive intermediates with [C–H···N]–hydrogen bonding. Our results demonstrate how the third dimension above and underneath aromatic rings can be exploited to precisely control electrophilic aromatic substitutions.

No MeSH data available.