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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.


Long-distance chirality transfer in aromatic nitration reactions.Results for (a) mono- as well as (b) dinitration of 1 are shown. Both reactions are directed through space with remote chiral ester groups (illustrated in blue).
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f2: Long-distance chirality transfer in aromatic nitration reactions.Results for (a) mono- as well as (b) dinitration of 1 are shown. Both reactions are directed through space with remote chiral ester groups (illustrated in blue).

Mentions: A readily available16 starting material for SEAr reactions fulfilling these criteria presented itself in the form of the chiral tetraester 1 (Fig. 2). In this structure, two partially flexible ester arms (illustrated in blue) are located directly above positions 1 and 2 as well as 5 and 6. While the presence of stereogenic centres in these ester arms reduces their conformational freedom, a non-trivial number of low-energy conformations are still readily available to both ester arms. A MacroModel17 (OPLS-2005 force field) conformational search of 1 (with the ethyl ester groups replaced by methyl) showed (Supplementary Fig. 1) that each lactate methyl ester arm contains ca. eight low energy (Erel<1.4 kcal mol–1) conformations, with the key ester-carbonyl groups pointing in distinct directions in all of them. First and foremost, however, the carbonyl-directing groups of the lactate esters are placed approximately in between the atom pairs 1–2 and 5–6. This geometry is well suited to stabilize the intermediates of SEAr reactions in positions 2 and 6 selectively with both [C–H···O] hydrogen bonding as well as direct electron donation from the carbonyl oxygens to the carbocation intermediates underneath.


Precise through-space control of an abiotic electrophilic aromatic substitution reaction
Long-distance chirality transfer in aromatic nitration reactions.Results for (a) mono- as well as (b) dinitration of 1 are shown. Both reactions are directed through space with remote chiral ester groups (illustrated in blue).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Long-distance chirality transfer in aromatic nitration reactions.Results for (a) mono- as well as (b) dinitration of 1 are shown. Both reactions are directed through space with remote chiral ester groups (illustrated in blue).
Mentions: A readily available16 starting material for SEAr reactions fulfilling these criteria presented itself in the form of the chiral tetraester 1 (Fig. 2). In this structure, two partially flexible ester arms (illustrated in blue) are located directly above positions 1 and 2 as well as 5 and 6. While the presence of stereogenic centres in these ester arms reduces their conformational freedom, a non-trivial number of low-energy conformations are still readily available to both ester arms. A MacroModel17 (OPLS-2005 force field) conformational search of 1 (with the ethyl ester groups replaced by methyl) showed (Supplementary Fig. 1) that each lactate methyl ester arm contains ca. eight low energy (Erel<1.4 kcal mol–1) conformations, with the key ester-carbonyl groups pointing in distinct directions in all of them. First and foremost, however, the carbonyl-directing groups of the lactate esters are placed approximately in between the atom pairs 1–2 and 5–6. This geometry is well suited to stabilize the intermediates of SEAr reactions in positions 2 and 6 selectively with both [C–H···O] hydrogen bonding as well as direct electron donation from the carbonyl oxygens to the carbocation intermediates 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&mdash;positioned above the planes of aromatic rings&mdash;enable it to distinguish between nearly identical, neighbouring reactive positions. Quantum mechanical calculations show that, in two competing reaction pathways, both [C&ndash;H&middot;&middot;&middot;O]&ndash;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&ndash;H&middot;&middot;&middot;N]&ndash;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.