An Environmentally Responsive Reciprocal Replicating Network

A reciprocal replication system is constructed from four building blocks, A, B, C, and D, which react in a pairwise manner through either a 1,3-dipolar cycloaddition or the condensation reaction between an amine and an aldehyde to create two templates, trans-T^AB and T^CD. These templates are equipped with complementary recognition sites - two carboxylic acids (trans-T^AB) or two 4,6-dimethylamidopyridines (T^CD) - that enable each template to direct the formation of its complementary partner through two mutually reinforcing cross-catalytic pathways, in which the templates trans-T^AB or T^CD preorganize the appropriate building blocks within two catalytically active ternary complexes: [C•D•trans-T^AB] and [A•B•T^CD]. The template-directed processes within these complexes generate a heteroduplex [trans-T^AB•T^CD], which is shown to possess significant stability through kinetic simulations and fitting. As a consequence, the individual cross-catalytic pathways perform more efficiently in template-directed experiments when the concentration of the template being formed is below that of the template added as instruction. Comprehensive analysis of the system in which A, B, C, and D are mixed together directly, using a series of ¹H NMR spectroscopic kinetic experiments, demonstrates that the behavior of the reciprocal system is more than the simple sum of its parts - as part of the interconnected network, the product of each reaction clearly directs the fabrication of its reciprocal partner, facilitating both higher rates of formation for both templates and improved diastereoselectivity for trans-T^AB. A simple change in experimental conditions (from dry to "wet" CDCl₃) demonstrates the sensitivity of the replication pathways within the network to the reaction environment, which leads to a >10-fold increase in the contribution of a new minimal self-replicator, trans-T^AB, to the replication network.