An unusual macrocyclization reagent for highly selective one-pot synthesis of strained macrocyclic aromatic hexamers

Abstract

One-pot, multi-molecular macrocyclization allows the highly selective preparation of strained macrocyclic aromatic hexamers structurally stabilized by an inward-pointing continuous hydrogen-bonding network.

Formation and trapping of the thermodynamically unfavoured inverted-hemicucurbit[6]uril

“…The first inverted HC 1 can be obtained in up to 33% isolated yield ( Table 1). This contrasts the synthesis of analogous inverted double bridged CBs, the i-CB [6] and i-CB [7], which were isolated in 2.0% and 0.4% yield, respectively. 51 Formation of diastereomeric macrocycles from achiral (R,S)monomers proceeds through desymmetrisation of the monomer, resulting in either R,S,S,R-or R,S,R,S-ordered oligomers 4 and 5 (Scheme 1).…”

“…To date, no reports on the formation of stereoisomeric HCs from the same monomer units have been presented. Herein, we report for the first time the amplification of formation of a thermodynamically unfavoured inverted-ciscyclohexanohemicucurbit [6]uril 1 (Figure 1) through dynamic covalent chemistry. Such a single monomer modification and formation of diastereomeric macrocycles lead to the enrichment of the pool of hosts, which is important for the development of highly selective host-guests interactions.…”

“…Efforts to develop such reactions can, however, be rewarded by leading to complex target compounds in a single step. Many examples of single-step synthesis of oligomeric macrocycles have been described, yet achieving product selectivity often remains an obstacle [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] . Templates can offer control over product formation through preorganization of a corresponding linear precursor, or through altered thermodynamic equilibrium of the reaction.…”

“…To our surprise, heating cis-N,N-cyclohexa-1,2-diylurea 3 and paraformaldehyde in 4 M HCl gave a new six-membered cycHC 1 (Figure 1) along with the expected 2 in nearly equal quantities ( Figure 2, Scheme 1). Thorough NMR and single-crystal XRD analysis revealed that the new cycHC [6] had one monomer in an inverted configuration (see SI, S10-S20). Consequently, the new macrocycle was named inverted-ciscyclohexanohemicucurbit[6]uril 1.…”

“…The remaining two components are generated by symmetry. Inversion of the monomer does not affect the direction of hydrogen bonding between] 1 and the solvent (SI, Figure S9B, S20), nor does it significantly change the shape of the molecule, which results in the extensive disorder observed in the crystal structure and apparent isostructurality to cis-cycHC [6] 2. The first inverted HC 1 can be obtained in up to 33% isolated yield ( Table 1).…”