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. The corresponding hetero-sequence AD 2-mers also form duplexes, but the observed self-association constants are strongly affected by folding equilibria in the monomeric states. When the backbone is flexible (five or more rotatable bonds separating the recognition sites), intramolecular H-bonding is favored, and the folded state is highly populated. For these systems, the stability of the AD·AD duplex is 1–2 orders of magnitude lower than that of the corresponding AA·DD duplex. However, for three architectures which have more rigid backbones (fewer than five rotatable bonds), intramolecular interactions are not observed, and folding does not compete with duplex formation. These systems are promising candidates for the development of longer, mixed-sequence synthetic information molecules that show sequence-selective duplex formation.


TABLE OF CONTENTS Page
NMR binding studies S2

Molecular modelling S7
X-ray crystallography S8 Synthesis and characterization of described compounds S10 Synthesis and characterization of C7-PO A and D 1-mers S126 References S142 S2 NMR binding studies.

C7-PO A•D and AA•DD complexes.
Binding constants were measured by 31 P NMR titrations in a Bruker 500 MHz AVIII HD Smart Probe spectrometer. The host (phosphine oxide derivatives S11 or 41) was dissolved in toluene-d 8 at a known concentration. The guest (phenol derivatives S10 or 40) was dissolved in the host solution and made to a known concentration. A known volume of host was added to an NMR tube and the spectrum was recorded. Known volumes of guest in host solution were added to the NMR tube, and the spectra were recorded after each addition. The chemical shifts of the host spectra were monitored as a function of guest concentration and analysed using a purpose written software in Microsoft Excel. Errors were calculated as two times the standard deviation from the average value (95% confidence limit).        Pure compound 47 (4 mg) was dissolved in toluene (0.5 mL), and the mixture was filtered to a vial and sealed with a plastic cap, resulting in crystallization after 10 days at room temperature. Crystals suitable for X-ray crystallography were selected using an optical microscope and examined at 180 K on a Nonius KappaCCD diffractometer using Mo Kα radiation (λ = 0.7107 Å). All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed in idealized position. R factor 0.0686 Figure S11. X-ray structure of derivative 47 in ORTEP view (ellipsoids are drawn at 50% probability level).

General experimental details
All the reagents and materials used in the synthesis of the compounds described below were bought from commercial sources, without prior purification. UV irradiations were performed using an UVP lamp model UVL-28 (2x365 nm tubes, 8 watt). Thin layer chromatography was carried out using with silica gel 60F (Merck) on aluminium. Flash chromatography was carried out on an automated system (Combiflash Companion, Combiflash Rf+ or Combiflash Rf Lumen) using prepacked cartridges of silica (25μ or 50μ PuriFlash® Columns). All NMR spectroscopy was carried out on a Bruker AVI250, AVI400, DPX400, AVIII400 spectrometer using the residual solvent as the internal standard. All chemical shifts (δ) are quoted in ppm and coupling constants given in Hz. Splitting patterns are given as follows: s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet). FT-IR spectra were measured on a PerkinElmer Spectrum 100 or One spectrometer equipped with an ATR cell. Melting points were measured in a Mettler Toledo MP50 Melting Point System. Optical activity was measured in an AA-10 or an Anton Paar (MCP 100) at 589 nm. ES+ was carried out on a Waters LCT-TOF spectrometer or a Waters Xevo G2-S bench top QTOF machine.
5-Hydroxy-2-nitrobenzaldehyde (10.0 g, 59.8 mmol), K 2 CO 3 (18.6 g, 135 mmol), methyl iodide (3.2 mL, 134.8 mmol) and DMF (100 mL) were stirred at room temperature for 16 h. The suspension was then poured into water (100 mL) and washed with EtOAc (3 x 200 mL). The combined organic extracts were subsequently washed with water (5 x 100 mL) then brine (100 mL), dried with MgSO 4 , filtered and the solvent was removed on a rotary evaporator to yield the product as a yellow solid, which required no further purification (10.1 g, 92 %). The spectroscopic data matches previously reported literature. S6 S54

Synthesis of C7-PO A and D 1-mers.
Scheme S1: Synthesis of C7-PO A and D 1-mers.