60th Annual Report on Research 2015

            Workduring the reporting period focussed on the synthesis of a new ditopic hostmolecule and the preliminary investigation of its binding properties with mono-and di-guest molecules in aqueous solution.

            Wesuccessfully executed the synthesis of a fully sulfonated dicalixarene specieswhich has two basket units oriented in opposite directions. Treatment of adicalixarene (1) with concentrated sulfuric acid at 80°C for four hours led to octasulfonated dicalixarene 2 in 74% yield (Figure 1). This reaction is reproducible andsucceeds at a multi-gram scale, providing sufficient material for furtherstudies.

Figure 1. Synthesis of a directly linkeddicalixarene di-host.

            Thescope of initial studies was constrained to using 2 as the di-host, and selected mono- and di-guests (Figure2). The behavior with mono-guests methylpyridinium (3) and 1,1′-dimethyl-4,4′-bipyridinium (4, methyl viologen) is described first, then the behaviorwith di-guest 5, which is two alkylated bipyridiniumunits joined by a –CH₂CH₂– spacer.

Figure 2. Mono- and di-guest species studied.

            Thebinding behavior of di-host 2 with the methylpyridinium cation (3) was investigated by Job plot analysis and ¹HNMR titration experiments. The anticipated behavior, that 2 would bind two  equivalents of the cationic species 3 was verified with a Job plot (Figure 3). The plot has amaximum at a guest (3) fraction of 0.70, close to the 0.67fraction that would indicate one molecule of 2binds two molecules of 3.

Figure 3. Job plot for the host species 2 and guest 3.

            Furtheranalysis with titration experiments showed large shifts in the ¹HNMR spectral signals for guest 3, indicating interaction with the hostmolecule. The shifts were largest for protons 1 and 2 (Figure 4), suggesting,but not proving, that the guest enters the host with the nitrogen groupfarthest from the basket interior, as depicted in Figure 4(a). Further study,such as with single crystal x-ray diffraction will shed light on this behavior,at least in the solid state.

Figure 4. ¹H NMR spectral titrationdata for the association of dicalixarene 2 with guest 3.

            Thetitration data as plotted in Figure 4(b) corroborate the expected stoichiometryof reaction, showing a break in each curve at a mole ratio for 2:3 of 0.5, indicating a guest molecule foreach basket present (two per dicalixarene). Data like shown in Figure 4(b) canbe analyzed with a non-linear curve-fitting program, such as WinEQNMR2. In thiscase however the association constant is too high for the program to refine toa meaningful value. Future work to obtain the association constant will be doneeither by competition studies, by isothermal titration calorimetry, or both. Wewill seek information about the step-wise binding of guests (positive ornegative cooperativity) in these future studies.

Studies of theinteraction between di-host 2 and methyl viologen (4) generated similar data in terms of stoichiometry (Jobplot, Figure 5) and titration data (Figure 6). Once again, the binding of hostand guest was too strong to allow extraction of an association constant fromthe NMR spectral titration method. All that can be said at this point forcertain is that the association constants for both mono-guests (3 and 4) are greater than 10⁺⁵.

Figure 5. Job plot for the host species 2 and guest 4.

Figure6. ¹H NMRspectral titration data for the association of dicalixarene 2 with guest 4.

            Preliminarystudies indicate that dicalixarene 2 and the di-guest 5 interact in aqueous solution as judged by the appearance ofnew distinct signals in the ¹H NMR spectrum of the mixture. Aproduct of undetermined stoichiometry and degree of association precipitates atconcentrations of 2 and 5 above ca. 0.7 mM.

            Furtherwork will focus on the synthesis of other dicalixarene units with specificlinks between the baskets and on the synthesis of (known) di-guest species withlonger linkers and linkers with different solubility tendencies, such aspoly(ether) groups rather than hydrocarbon groups.