Disruption of nucleobase stacking to restore reactivity.

Strong intermolecular interaction can prevent an organic molecule from dissolving in a reaction solution, thereby jeopardizing its reactivity and usefulness. Nucleobases and nucleosides (especially many purines and their derivatives) are notoriously difficult to dissolve in most organic solvents, generally attributed to their strong intermolecular interactions caused by the aromaticity, polarity and hydrogen-bonding. Guided by our computational study and prediction, to address this challenge, we have found that by doping the reaction solution with toluene (an inert aromatic compound), the added solvent molecules are capable of generating the stacking interaction with the solute molecules (e.g., purine derivatives) and disrupting the intermolecular stacking of the solute molecules. Thus, this inert doping can successfully address the insoluble challenge, dissolve the poorly soluble reactants (such as purine phosphoramidites), and restore the amidite reactivity for oligonucleotide synthesis. Our research has offered a simple strategy to efficiently synthesize labile oligonucleotides, via disrupting stacking interaction with inert aromatic molecules.