Solvent-controlled formation of alkali and alkali-earth-secured cucurbituril/guest trimers

Cucurbit[7]uril (CB[7]) encapsulates adamantyl and trimethylsilyl substituents of positively charged guests in dimethyl sulfoxide (DMSO). Unlike in water or deuterium oxide, addition of a selection of alkali and alkali-earth cations with van der Waals radii between 1.0 and 1.4 Å (Na+, K+, Ca2+, Sr2+, Ba2+ and Eu3+) to the CB[7]/guest complexes triggers their cation-mediated trimerization, a process that is very slow on the nuclear magnetic resonance (NMR) time scale. Smaller (Li+, Mg2+) or larger cations (Rb+, Cs+ or NH4+) are inert. The trimers display extensive CH–O interactions between the equatorial and pseudo-equatorial hydrogens of CB[7] and the carbonyl rim of the neighboring CB[7] unit in the trimer, and a deeply nested cation between the three interacting carbonylated CB[7] rims; a counteranion is likely perched in the shallow cavity formed by the three outer walls of CB[7] in the trimer. Remarkably, a guest must occupy the cavity of CB[7] for trimerization to take place. Using a combination of semi-empirical and density functional theory techniques in conjunction with continuum solvation models, we showed that trimerization is favored in DMSO, and not in water, because the penalty for the partial desolvation of three of the six CB[7] portals upon aggregation into a trimer is less unfavorable in DMSO compared to water.


General Information
Standard Schlenk and vacuum line techniques were employed for all manipulations of air-or moisture-sensitive compounds. Yields refer to isolated and spectroscopically homogeneous materials.
Starting material used for synthesis of guests and titration experiments was purchased from following sources: abcr (Karlsruhe, Germany), Combi-Blocks (San Diego, CA), Sigma-Aldrich (St. Louis, MO; Prague, Czech Republic), TCI America (Portland, OR), Fisher Scientific (Fair Lawn, NJ), Oakwood Chemical (Estill, SC), Strem Chemicals (Newburyport, MA) and used without further purification. Anhydrous dimethyl sulfoxide (DMSO) was used as solvent in UV-Vis titrations. Solvents used in preparation of samples for NMR measurements were purchased from Cambridge Isotope Laboratories (Andover, MA) and Eurisotop. Deuterated dimethyl sulfoxide (DMSO-d6) was distilled over calcium hydride as needed. Cucurbit [7]uril (CB [7]) was prepared using known procedures. 1 The apparent molar mass of CB [7] was determined by recording its 1 H NMR spectrum with p-toluidine hydrochloride as an internal standard. Sodium dodecamethylcarba-closo-dodecaborate (NaCB11Me12) and sodium 2, 3,4,5,6,7,8,9,10,11,12undecamethylcarba-closo-dodecaborate (NaHCB11Me11) were prepared by cation exchange from cesium salts of the same anions, 2 which were synthesized according to the literature procedures. 2,3 Solvents were of analytical grade and either used as purchased or dried according to previously described procedures. 4 1-Adamantylamine and 2-adamantylamine were isolated from hydrochloride salt following the published procedure. 5 Characterization of prepared guests by Nuclear Magnetic Resonance spectroscopy (NMR) was carried out using a Bruker Avance III TM HD 400MHz Prodigy spectrometer at the Institute of Organic Chemistry and Biochemistry, Prague. 1 H NMR titration experiments, varying temperature experiments, DOSY and NOESY experiments were carried out using a Bruker Avance II TM 500MHz and JEOL JNM-EZCR 500 MHz spectrometers at the Institute of Organic Chemistry and Biochemistry, Prague, and Bruker Ascend 500 MHz at the department of Chemistry and Biochemistry, Ohio University. 1 H and 13 C NMR chemical shifts are reported in parts per million (ppm) and are referenced to the residual signal of solvent. Coupling constants (J) are reported in hertz (Hz). Standard abbreviations were used to indicate multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets.

Preparation of CB[7]·1 and [(CB[7]·1)3·Na]Cl
Guest 1 (6.3 mg, 0.02 mmol) was dissolved in deionized water (5 mL) in a round bottom flask. A solution of cucurbit [7]uril (1 mmol) in deionized water (28 mL) was prepared in a separate flask. One equivalent of CB [7]solution was added portion-wise to the solution of guest, while stirring with magnetic stir bar at room temperature. Water was removed under reduced pressure and the resulting solid was dried on a Kugelrohr distillation apparatus (60 °C, 750 mTorr) yielding CB[7]·1 as a white crystalline solid (30 mg, 0.2 mmol).

Titrations of guests with CB[7]
1 H NMR titrations of guests with CB [7] were performed by step-wise addition of 1 equivalent of saturated CB [7] solution (c = 0.70 mmol L -1 in DMSO-d6,) to guest solution in NMR tube by either micropipette or a Hamilton syringe at 25 °C.

Addition of D2O to a mixture of CB[7]·1 and [(CB[7]·1)3·Na]Cl
Deuterium oxide was added portion-wise to the solution containing a mixture of CB [7]

X-ray Crystallographic Data
Crystallographic data for 1, 2, 3 and 7 were collected on Bruker D8 VENTURE Kappa Duo PHOTONIII by IμS micro-focus sealed tube either MoKα (λ= 0.71073 Å) (2 and 3) or CuKα ( λ = 1.54178 Å) (1 and 7) at low temperature. The structures were solved by direct methods (XT) 1 and refined by full matrix least squares based on F 2 (SHELXL2018). 2 The hydrogen atoms on carbon were fixed into idealized positions (riding model) and assigned temperature factors either Hiso(H) = 1.2 Ueq(pivot atom) or Hiso(H) = 1.5 Ueq (pivot atom) for methyl moiety. The results of structure determination of 1, 2 and 3 exhibit standard level of precision, however the results of 7 were hampered by the poor quality of the single crystal farther complicated by non-merohedral twinning. The orientation of displacement ellipsoids with their longest axis parallel to c -lattice vector are also suggesting a presence of stacking fault in a row of molecules.