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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.

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Proposed mechanisms of through-space SEAr control.Resonance structures of the cationic Wheland intermediates for favoured mono-nitration of 1 in the 2 position, illustrating the key DMATS-inspired5 through-space-directing effects observed in our system. (a) Endo and (b) exo [NO2]+ attack.
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f6: Proposed mechanisms of through-space SEAr control.Resonance structures of the cationic Wheland intermediates for favoured mono-nitration of 1 in the 2 position, illustrating the key DMATS-inspired5 through-space-directing effects observed in our system. (a) Endo and (b) exo [NO2]+ attack.

Mentions: In general, our approach combines enzyme-inspired hydrogen bonding with electron donation from an oxygen lone pair to direct SEAr's through space. This combined tactic—designed to optimally stabilize carbocations—is best illustrated with resonance structures (Fig. 6), which also highlight the need to precisely position the key carbonyl group directly above carbons 1 and 2.


Precise through-space control of an abiotic electrophilic aromatic substitution reaction
Proposed mechanisms of through-space SEAr control.Resonance structures of the cationic Wheland intermediates for favoured mono-nitration of 1 in the 2 position, illustrating the key DMATS-inspired5 through-space-directing effects observed in our system. (a) Endo and (b) exo [NO2]+ attack.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Proposed mechanisms of through-space SEAr control.Resonance structures of the cationic Wheland intermediates for favoured mono-nitration of 1 in the 2 position, illustrating the key DMATS-inspired5 through-space-directing effects observed in our system. (a) Endo and (b) exo [NO2]+ attack.
Mentions: In general, our approach combines enzyme-inspired hydrogen bonding with electron donation from an oxygen lone pair to direct SEAr's through space. This combined tactic—designed to optimally stabilize carbocations—is best illustrated with resonance structures (Fig. 6), which also highlight the need to precisely position the key carbonyl group directly above carbons 1 and 2.

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.


Related in: MedlinePlus