No abstract

The concept of net electrophilicity (electroaccepting power relative to electrodonating power) is introduced. It provides expected trends in most cases. A net electrophilicity scale is presented. Various reactivity descriptors for 32 molecules are calculated at the B3LYP/6-311+G(d) level of theory. Profiles of net electrophilicity along the reaction paths of thermoneutral, exothermic, endothermic, and cycloaddition reactions are analyzed. Net electrophilicity often attains its minimum value for a stable state or a favorable reaction.

Methylene-bridged glycoluril dimers are the fundamental building blocks of cucurbituril (CB[6]), its homologues (CB[n]), and its derivatives. This paper describes three complementary methods for the synthesis of C- and S-shaped methylene-bridged glycoluril dimers (29-34 and 37-44). For this purpose, we prepared glycoluril derivatives (1a-d) bearing diverse functionalities on their convex face. These glycoluril derivatives were alkylated under basic conditions (DMSO, t-BuOK) with 1,2-bis(halomethyl)aromatics 6-15 to yield 4a-d and 16-24, which contain a single aromatic o-xylylene ring and potentially nucleophilic ureidyl NH groups. Glycoluril derivatives bearing potentially electrophilic cyclic ether groups (5a-f) and 25-28 were prepared by various methods including condensation reactions in refluxing TFA containing paraformaldehyde. The condensation reactions of 4a-d and 16-24 with paraformaldehyde under anhydrous acidic conditions (PTSA, ClCH(2)CH(2)Cl, reflux) give, in most cases, the C-shaped and S-shaped methylene-bridged glycoluril in good to excellent yields. In many cases, the C-shaped compound is formed preferentially with high diastereoselectivity. Cyclic ethers 5a,d-f and 25-26 undergo highly diastereoselective dimerization reactions to yield methylene-bridged glycoluril dimers with the formal extrusion of formaldehyde. Last, it is possible to perform selective heterodimerization reactions using both cyclic ethers and glycoluril derivatives bearing ureidyl NH groups. These reactions deliver the desired C- and S-shaped heterodimers with low to moderate diastereoselectivities. This heterodimerization route is the method of choice in cases where the homodimerization reactions fail. The formation of side products (+/-)-35b and (+/-)-35d helps clarify the electronic requirements for a successful CB[n] synthesis. The X-ray structures of 30C, 38C, and 38S allow for a discussion of the structural features of this class of compounds.

Cucurbit[6]uril (CB[6]) is a macrocyclic compound, prepared in one pot from glycoluril and formaldehyde, whose molecular recognition properties have made it the object of intense study. Studies of the mechanism of CB[n] formation, which might provide insights that allow the tailor-made synthesis of CB[n] homologues and derivatives, have been hampered by the complex structure of CB[n]. By reducing the complexity of the reaction to the formation of S-shaped (12S-18S) and C-shaped (12C-18C) methylene bridged glycoluril dimers, we have been able to probe the fundamental steps of the mechanism of CB[n] synthesis to a level that has not been possible previously. For example, we present strong evidence that the mechanism of CB[n] synthesis proceeds via the intermediacy of both S-shaped and C-shaped dimers. The first experimental determination of the relative free energies of the S-shaped and C-shaped dimers indicates a thermodynamic preference (1.55-3.25 kcal mol(-)(1)) for the C-shaped diastereomer. This thermodynamic preference is not because of self-association, solvation, or template effects. Furthermore, labeling experiments have allowed us to elucidate the mechanism of this acid-catalyzed equilibrium between the S-shaped and C-shaped diastereomers. The equilibration is an intramolecular process that proceeds with high diastereoselectivity and retention of configuration. On the basis of the broad implications of these results for CB[n] synthesis, we suggest new synthetic strategies that may allow for the improved preparation of CB[n] (n > 8) and CB[n] derivatives from functionalized glycolurils.