Assembly of Macrocycles by Zirconocene-Mediated, Reversible Carbon−Carbon Bond Formation

Abstract

Macrocyclic compounds have attracted considerable attention in numerous applications, including host-guest chemistry, chemical sensing, catalysis, and materials science. A major obstacle, however, is the limited number of convenient, versatile, and high-yielding synthetic routes to functionalized macrocycles. Macrocyclic compounds have been typically synthesized by ring-closing or condensation reactions, but many of these procedures produce mixtures of oligomers and cyclic compounds. As a result, macrocycle syntheses are often associated with difficult separations and low yields. Some successful approaches that circumvent these problems are based on "self-assembly" processes utilizing reversible bond-forming reactions, but for many applications, it is essential that the resulting macrocycle be built with a strong covalent bond network. In this Account, we describe how zirconocene-mediated reductive couplings of alkynes can provide reversible carbon-carbon bond-forming reactions well-suited for this purpose. Zirconocene coupling of alkenes and alkynes has been used extensively as a source of novel, versatile pathways to functionalized organic compounds. Here, we describe the development of zirconocene-mediated reductive couplings as a highly efficient method for the preparation of macrocycles and cages with diverse compositions, sizes, and shapes. This methodology is based on the reversible, regioselective coupling of alkynes with bulky substituents. In particular, silyl substituents provide regioselective, reversible couplings that place them into the α-positions of the resulting zirconacyclopentadiene rings. According to density functional theory (DFT) calculations and kinetic studies, the mechanism of this coupling involves a stepwise process, whereby an insertion of the second alkyne influences regiochemistry through both steric and electronic factors. Zirconocene coupling of diynes that incorporate silyl substituents generates predictable macrocyclic products in very high yields. In the absence of significant steric repulsion, the macrocyclization appears to be entropically driven, thereby providing the smallest strain-free macrocyclic structure. The scope of the reaction has been explored by variation of the spacer group between the alkynyl substituents and by incorporation of functional and chiral groups into the macrocycle. The size and shape of the resulting macrocycles are largely determined by the length and geometry of the dialkyne spacer, especially in the case of terminal trimethylsilyl-substituted diynes. For example, linear, rigid diynes with four or fewer phenylene rings lead to trimeric macrocycles, whereas bent or flexible diynes produce dimers. Depending on the reaction conditions, functional groups (such as N-heterocycles and imines) are tolerated in zirconocene coupling reactions, and in selected cases, they can be used to influence the shape of the final macrocyclic product. More recently, Cp(2)Zr(pyr)(Me(3)SiC≡CSiMe(3)) has been employed as a more general zirconocene synthon; it affords hig...

Site-selective [2 + 2 +n] cycloadditions for rapid, scalable access to alkynylated polycyclic aromatic hydrocarbons

“…Given their high carbon content and synthetic versatility, alkynyl substituents are attractive for the elaboration of PAHs into more complex functional materials. 12 Such substituents are especially useful for macrocyclization reactions to give arylene ethynylene macrocycles (AEMs), 13 cycloarylenes, 14 and other exotic macrocycles. 15 These and related macrocyclic nanocarbons 5c,7,16 represent a broad structural class of tremendous interest for their internal cavities and unique spatial arrangements of carbon-rich building blocks.…”

Self‐Assembly Reactions To Form Multinuclear Zirconium(III) and Titanium(III) Complexes with Imidazole Derivatives as Bridging Ligands

“…Multinuclear, especially trinuclear titanium or zirconium complexes are known, [22][23][24][25][26] but these complexes are not formed by self-assembly and the metal atoms do not occupy the vertices of the molecular architectures. Here, the increased steric demand hinders the formation of rectangles or squares.…”

Zirconacyclopentadiene‐Annulated Polycyclic Aromatic Hydrocarbons

“…We have previously reported the synthesis of π‐conjugated oligomers, polymers, and macrocycles through the reductive coupling of alkynes with a low‐valent zirconocene reagent. Given its ability to form new rings in high yield, this reaction should be well‐suited for PAH syntheses.…”