Recognition-Encoded Synthetic Information Molecules.

ConspectusNucleic acids represent a unique class of highly programmable molecules, where the sequence of monomer units incorporated into the polymer chain can be read through duplex formation with a complementary oligomer. It should be possible to encode information in synthetic oligomers as a sequence of different monomer units in the same way that the four different bases program information into DNA and RNA. In this Account, we describe our efforts to develop synthetic duplex-forming oligomers composed of sequences of two complementary recognition units that can base-pair in organic solvents through formation of a single H-bond, and we outline some general guidelines for the design of new sequence-selective recognition systems.

Supramolecular template-directed synthesis of triazole oligomers.

Sandwich complexes formed by two zinc porphyrins and a diamine ligand (DABCO) have been used as a supramolecular template to direct the synthesis of triazole oligomers. Monomer units equipped with two polymerizable functional groups, an alkyne and an azide, were attached to the template ester bonds between a phenol unit on the monomer and benzoic acid units on the porphyrin. Self-assembly of the zinc porphyrins by addition of DABCO led to a supramolecular complex containing four of the monomer units, two on each porphyrin.

Folding and duplex formation in mixed sequence recognition-encoded -phenylene ethynylene polymers.

Oligomers equipped with complementary recognition units have the potential to encode and express chemical information in the same way as nucleic acids. The supramolecular assembly properties of -phenylene ethynylene polymers equipped with H-bond donor ( = phenol) and H-bond acceptor ( = phosphine oxide) side chains have been investigated in chloroform solution. Polymerisation of a bifunctional monomer in the presence of a monofunctional chain stopper was used for the one pot synthesis of families of -phenylene ethynylene polymers with sequences or ( = 1-5), which were separated by chromatography.

Sequence information transfer using covalent template-directed synthesis.

Template-directed synthesis is the biological method for the assembly of oligomers of defined sequence, providing the molecular basis for replication and the process of evolution. To apply analogous processes to synthetic oligomeric molecules, methods are required for the transfer of sequence information from a template to a daughter strand. We show that covalent template-directed synthesis is a promising approach for the molecular replication of sequence information in synthetic oligomers.

H-Bonded Duplexes based on a Phenylacetylene Backbone.

Complementary phenylacetylene oligomers equipped with phenol and phosphine oxide recognition sites form stable multiply H-bonded duplexes in toluene solution. Oligomers were prepared by Sonogashira coupling of diiodobenzene and bis-acetylene building blocks in the presence of monoacetylene chain terminators. The product mixtures were separated by reverse phase preparative high-pressure liquid chromatography to give a series of pure oligomers up to seven recognition units in length.

Backbone conformation affects duplex initiation and duplex propagation in hybridisation of synthetic H-bonding oligomers.

Synthetic oligomers equipped with complementary H-bond donor and acceptor side chains form multiply H-bonded duplexes in organic solvents. Comparison of the duplex forming properties of four families of oligomers with different backbones shows that formation of an extended duplex with three or four inter-strand H-bonds is more challenging than formation of complexes that make only two H-bonds. The stabilities of 1 : 1 complexes formed between length complementary homo-oligomers equipped with either phosphine oxide or phenol recognition modules were measured in toluene.

Sequence-Selective Formation of Synthetic H-Bonded Duplexes.

Oligomers equipped with a sequence of phenol and pyridine N-oxide groups form duplexes via H-bonding interactions between these recognition units. Reductive amination chemistry was used to synthesize all possible 3-mer sequences: AAA, AAD, ADA, DAA, ADD, DAD, DDA, and DDD. Pairwise interactions between the oligomers were investigated using NMR titration and dilution experiments in toluene.

H-Bond Self-Assembly: Folding versus Duplex Formation.

Linear oligomers equipped with complementary H-bond donor (D) and acceptor (A) sites can interact via intermolecular H-bonds to form duplexes or fold via intramolecular H-bonds. These competing equilibria have been quantified using NMR titration and dilution experiments for seven systems featuring different recognition sites and backbones. For all seven architectures, duplex formation is observed for homo-sequence 2-mers (AA·DD) where there are no competing folding equilibria.

Mix and match recognition modules for the formation of H-bonded duplexes.

Oligomeric molecules equipped with complementary H-bond recognition sites form stable duplexes in non-polar solvents. The use of a single H-bond between a good H-bond donor and a good H-bond acceptor as the recognition motif appended to a non-polar backbone leads to an architecture with interchangeable recognition alphabets. The interactions of three different families of H-bond acceptor oligomers (pyridine, pyridine N-oxide or phosphine oxide recognition module) with a family of H-bond donor oligomers (phenol recognition module) are compared.

Mix and match backbones for the formation of H-bonded duplexes.

The formation of well-defined supramolecular assemblies involves competition between intermolecular and intramolecular interactions, which is quantified by effective molarity. Formation of a duplex between two oligomers equipped with recognition sites displayed along a non-interacting backbone requires that once one intermolecular interaction has been formed, all subsequent interactions take place in an intramolecular sense. The efficiency of this process is governed by the geometric complementarity and conformational flexibility of the backbone linking the recognition sites.

Cooperative duplex formation by synthetic H-bonding oligomers.

A series of flexible oligomers equipped with phenol H-bond donors and phosphine oxide H-bond acceptors have been synthesised using reductive amination chemistry. H-bonding interactions between complementary oligomers leads to the formation of double-stranded complexes which were characterised using NMR titrations and thermal denaturation experiments. The stability of the duplex increases by one order of magnitude for every H-bonding group added to the chain.