A fast and user-friendly computational for predicting the regioselectivity of electrophilic aromatic substitution reactions of heteroaromatic systems is presented.

The validity of calculated NMR shifts to predict the outcome of electrophilic aromatic substitution reactions on different heterocyclic compounds has been examined. Based on an analysis of >130 literature examples, it was found that the lowest predicted (13)C and/or (1)H chemical shift of a heterocycle correlates qualitatively with the regiochemical outcome of halogenation reactions in >80% of the investigated cases. In the remaining cases, the site of electrophilic aromatic substitution can be explained by the calculated HOMO orbitals obtained using density functional theory. Using a combination of these two methods, the accuracy increases to >95%.

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Solid-phase synthesis is of tremendous importance for small-molecule and biopolymer synthesis. Linkers (handles) that release amide-containing products after completion of solid-phase synthesis are widely used. Here we present a new class of highly acid-labile backbone amide linkers (BAL handles) based on 3,4-ethylenedioxythiophene (EDOT), which we have termed T-BAL. These thiophene linkers are synthesized in three convenient steps from commercially available EDOT. In the linker design, the spacer was introduced to the EDOT core either via a carbon-carbon bond or via a thioether linkage. Introduction of the spacer via a C-C bond was performed by a chemoselective Negishi coupling without transient protection of the aldehyde group to provide the T-BAL1 handle. Introduction via a thioether linkage was performed by a facile nucleophilic aromatic substitution between the brominated EDOT aldehyde and unprotected mercapto acids to provide T-BAL2 and T-BAL3 handles. The minimal use of protecting groups gave the corresponding linker molecules in few synthetic steps and in good yields. After anchoring of the linker to a polymeric support, introduction of the first amino acid was achieved by reductive amination, giving a secondary amine. A following acylation of the secondary amine with a symmetrical amino acid anhydride resulted in a backbone amide linkage between the handle and the growing substrate (e.g., peptide chain). After solid-phase synthesis, the substrates could be released from the resin by either low acid conditions using 1% TFA in CH2Cl2 or high acid conditions such as 50% TFA in CH2Cl2. Peptide thioesters could be released from the T-BAL1 handle under very mild conditions using aqueous acetic acid. Tert-butyl based protecting groups, tert-butyl esters, tert-butyl ethers, and Boc groups, as well as dimethyl acetals were relatively stable to these mild conditions for release of the peptides.