Regioselective Dimerization of Methylcyclopentadiene inside Cucurbit[7]uril

Abstract

The molecular confinement within rigid macrocyclic receptors can trigger catalytic activity and steer the selectivity of organic reactions. In this work, the dimerization of methylcyclopentadiene (MCPD) isomers in the presence of cucurbit[7]uril (CB7) was found to display, besides a large rate acceleration, a striking regioselectivity in aqueous solution at pH 3, different from the products predominating in the absence of the supramolecular catalyst. Among the different possible regioisomers and diastereomers, the endo-3,7-dimethyl-3a,4,7,7a-tetrahydro-1H-4,7-methanoindene adduct was selectively formed, which is otherwise found only as a minor product in the dimerization of neat MCPD or in commercial dimeric mixtures. This product originates from the reaction of the heteroternary complex of 1-MCPD and 2-MCPD within CB7, in which the methyl groups are positioned in an "anti-diaxial" arrangement and point towards the open portals of the macrocycle, resulting in a preferred packing of the reacting cyclopentadiene rings. The selectivity of the dimerization of MCPD in the absence and presence of CB7 is supported by quantum-chemical calculations.

Keywords: Host-Guest Complexes; Macrocycles; Rate Acceleration; Regioisomers; Supramolecular Chemistry.

Figure 1

Chemical structures of a. cucurbit[7]uril (CB7) and β‐cyclodextrin (β‐CD), b. cyclopentadiene (CPD), the methylcyclopentadiene isomers (MCPD), and their corresponding dimerization product(s); major products for MCPD (1‐8) are shown.

Figure 2

a.‐d. GC‐FID chromatograms for a. commercial MCPD dimer and the dimerization products (the chemical structures of the 8 main dimers are given in Figure 1b) of b. in the neat liquid and inside the macrocyclic cavity of c. CB7 and d. β‐CD (3 mM of host and 6 mM MCPD, pH 2.8; products were extracted with organic solvent). Note the entirely new product peak of unidentified origin in the presence of CB7 (marked with *). e. Dimerization of MCPD (40 mM) in the presence of CB7 (3 mM), monitored by ¹H NMR in D₂O, pD ~3; see Figure 1b for peak assignment.

Figure 3

Raw ITC data for sequential twenty‐seven injections of a 3.8 mM MCPD solution injected into a CB7 solution (0.1 mM, top) and apparent reaction heats obtained from the integration of the calorimetric traces (bottom) at pH 7. ΔH _1:1 and ΔH _1:2 were −2.6±0.5 and −3.9±0.5 kcal/mol. The error in K _a values, extracted from a fitting according to a sequential binding site model, is 10 %.

Figure 4

GC‐FID chromatograms for the dimerization of MCPD (6 mM) inside CB7 (3 mM) after 24 h at different pH values.

Figure 5

a. Schematic arrangement of the two MCPD reactants resembling the transition states for the dimerization leading to the 8 experimentally observed dimers 1–8. The dashed lines indicate the upper and lower cavity boundaries of CB7, that is, all groups positioned in between the boundaries will increase the packing coefficient of the already tightly packed complexes. DFT‐calculated activation enthalpies of dimerization (ΔH ^≠) and relative stabilities (ΔE _rel) of the corresponding dimers are given below the structures (B3LYP−D3(BJ)/6‐31+G* level of theory). b. Space‐filling representations of the optimized structure (B3LYP−D3(BJ)/6‐31+G* level of theory) of the host‐guest inclusion complex of dimer 8 with CB7. Note the ideal packing of the diametrally opposed methyl groups protruding into the portal regions, which is reminiscent of the ultrahigh affinity complexes of disubstituted ferrocene and diamantane guests inside the same macrocycle.