Supramolecular template-directed synthesis of triazole oligomers

Abstract

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 via 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. CuAAC oligomerisation was carried out in the presence of a chain capping agent to prevent intermolecular reactions between the templated products, which carry reactive chain ends. The templated-directed oligomerisation resulted in selective formation of a duplex, which contains two identical chains of triazole oligomers connecting the porphyrin linkers. The effective molarity for the intramolecular CuAAC reactions on the template is 3-9 mM, and because the triazole backbone has a direction, the product duplex was obtained as a 4 : 1 mixture of the parallel and antiparallel isomers. Hydrolysis of the ester bonds connecting the oligomers to the template gave a single product, the phenol 2-mer, in excellent yield. The introduction of a supramolecular element into the template considerably broadens the scope of the covalent template-directed oligomerisation methodology that we previously developed for the replication of sequence information in synthetic oligomers.

Fig. 1. (a) Untemplated oligomerization of the monomer (red) gives a mixture of cyclic oligomers. (b) Covalent template-directed synthesis. In the attach step, monomers are covalently linked to complementary sites on the template (blue). In the ZIP step, intramolecular reactions between the monomers leads to oligomerization. In the cleave step, the new oligomer is released from the template. (c) Supramolecular template-directed synthesis. In the attach step, monomers are covalently attached to a linker (grey). In the bind step, linkers are connected via non-covalent interactions. In the ZIP step, intramolecular reactions between the monomers leads to oligomerization. In the cleave step, the new oligomer is released from the template.

Scheme 1. Synthesis of free base porphyrin 4.

Scheme 2. Synthesis of 7, and structures of 8 and 9.

Scheme 3. Synthesis of zinc porphyrins 10, 11 and 12.

Fig. 2. (a) Reaction pathways in the CuAAC reaction between 10 and 11 in the absence or presence of DABCO. HPLC chromatograms of the product mixture obtained from reaction of 10 (15 μM), 11 (15 μM) and CuTBTA (0.02 mM) in CH₂Cl₂ at room temperature for 16 h (b) in the absence of DABCO, and (c) in the presence of DABCO (15 μM). The sharp peak at 11 minutes corresponds to the point at which the eluant switched to 100% THF and washed all remaining species off the column.

Fig. 3. (a) Chemical structure of the DABCO complex of duplex 13. (b) MALDI-HRMS of 13 (calculated mass for [M]⁺ = 4017.7608). (c) Partial 500 MHz ¹H NMR spectrum of the DABCO complex of 13 in CDCl₃ at room temperature. The signals due to the amide NCH₂ groups (purple), and the upfield shifted signal due to bound DABCO (blue) are indicated.

Fig. 4. UV-visible titration experiments. (a) UV-visible absorption spectrum for titration of DABCO into 10 (0.38 μM) in chloroform at 298 K. (b) Best fit of the titration data for 10 to a 1 : 1 binding isotherm: absorption measured at 425 nm (black) and 436 nm (red). (c) UV-visible absorption spectrum for titration of DABCO into 13 (0.029 μM) in chloroform at 298 K. (d) Best fit of the titration data for 13 to a 1 : 1 binding isotherm: absorption measured at 423 nm (black) and 429 nm (red).

Fig. 5. DABCO templated synthesis of duplexes p-15 and a-15. The relative orientations of backbones are indicated with purple arrows for parallel and green arrows for antiparallel.

Fig. 6. (a) Partial 500 MHz ¹H NMR spectrum of the DABCO complex of 15 in CDCl₃ at room temperature. The signals due to the NCH₂ groups (green and purple), and the upfield shifted signal due to bound DABCO (blue) are indicated. (b) UV-visible absorption spectrum for titration of DABCO into 15 (0.027 μM) in chloroform at 298 K. (c) Best fit of the titration data to a binding isotherm that assumes there are two different duplexes a-15 and p-15, which are present in different amounts and each form a 1 : 1 complex with DABCO with different association constants: absorption measured at 422 nm (black) and 430 nm (red).

Fig. 7. Cartoon representation of reaction pathways in the CuAAC ZIP reaction of 10 and 11 in the presence of DABCO and capping agent 14, followed by ester hydrolysis to cleave the products from the porphyrin linker.

Fig. 8. (a) Cartoon representation of products obtained from the CuAAC ZIP reaction of 10 and 11 in the presence of DABCO and capping agent 14, followed by ester hydrolysis to cleave the porphyrin linker. (b) Cartoon representation of products obtained from the CuAAC ZIP reaction of 12 in the presence of DABCO and capping agent 14, followed by ester hydrolysis to cleave the porphyrin linker. (c) HPLC chromatograms showing the effect of capping agent 14 on the product distribution obtained from reaction of 10 (15 μM), 11 (15 μM), DABCO (15 μM) and CuTBTA (0.02 mM) in CH₂Cl₂ at room temperature for 16 h followed by hydrolysis with LiOH (1 M). (d) HPLC chromatograms showing the effect of capping agent 14 on the product distribution obtained from reaction of 12 (15 μM) DABCO (7.5 μM) and CuTBTA (0.02 mM) in CH₂Cl₂ at room temperature for 16 h followed by hydrolysis with LiOH (1 M).

Fig. 9. Product distribution for the templated reaction of 10 with 11 (red), and for the templated oligomerisation of 12 (black) in the presence of different concentrations of 14 ([cap]). The data are plotted as the ratio of the area of the HPLC peaks assigned to the product of the intermolecular reaction with the capping agent (A_inter for 21 and 23) compared with the area of the HPLC peaks assigned to the product of the intramolecular ZIP reaction (A_intra for 20 and 22). Reactions were carried out using 10 (15 μM) and 11 (15 μM), or 12 (15 μM), with CuTBTA (0.02 mM) in CH₂Cl₂ at room temperature for 16 h, followed by hydrolysis with LiOH (1 M). The lines represent the best fit to eqn (1).