Kinetic or Thermodynamic Product? Case Studies on the Formation of Regioisomers of Tetraphenyladamantanes

Abstract

Tetraaryldamantanes (TAAs) with alkoxyphenyl groups are interesting synthetic targets because they can act as crystallization chaperones for liquid compounds. Their carbon framework is set up by Friedel-Crafts alkylation, using adamantane-1,3,5,7-tetraol and anisole derivatives as starting materials. One successful chaperone is 1,3,5,7-tetrakis(2-bromo-4-methoxyphenyl)adamantane (TBro). This compound was initially considered the thermodynamic product of alkylation. We now report that exposure of TBro to strong Brønsted acid leads to its regioisomer 1,3,5,7-tetrakis(4-bromo-2-methoxyphenyl)adamantane (iTBro) as the dominant product, obtained in a yield of 68%, far surpassing the 20% yield reported earlier for TBro. We also investigated the reactions of 3-iodo-, 3-chloro-, and 3-fluoroanisole to the corresponding TAAs and obtained yields of 66%, 26% and 52% for the main regioisomer. While 3-iodoanisole gave the same regioisomer as bromoanisole, 3-chloroanisole gave complex mixtures and 3-fluoroanisole gave 1,3,5,7-tetrakis(2-fluoro-4-methoxyphenyl)-adamantane (TFM) in 52% yield as the main product. When mixtures of regioisomers were isomerized with an excess of triflic acid, the thermodynamic products were obtained in 76-91%. These results show how subtle effects govern the regioisomeric product distribution of aryladamantanes. They also help to make novel crystallization chaperones accessible in yields.

A Fluorinated Chaperone Gives X‐ray Crystal Structures of Acyclic Natural Product Derivatives up to 338 Molecular Weight

“…As for other TAA chaperones [14] solvate‐free forms do exist for TFM, and crystals of these crystal forms can appear in conglomerates containing the solvates as the other species. We have found earlier that thermal transitions of TAA solvate crystals typically lead to loss of solvent molecules [23] . Perhaps, our quick temperature jump from the not saturated, hot solution to a temperature cold enough to prevent recrystallization to such solvate‐free form favors capturing analyte molecules in the lattice of not fully desolvated chaperones.…”

“…Further, our results suggest that encapsulation of the liquid analyte in the crystal lattice of the TAA host is a kinetic phenomenon. [23] As for other TAA chaperones [14] solvate-free forms do exist for TFM, and crystals of these crystal forms can appear in conglomerates containing the solvates as the other species. We have found earlier that thermal transitions of TAA solvate crystals typically lead to loss of solvent molecules.…”

“…We have found earlier that thermal transitions of TAA solvate crystals typically lead to loss of solvent molecules. [23] Perhaps, our quick temperature jump from the not saturated, hot solution to a temperature cold enough to prevent recrystallization to such solvate-free form favors capturing analyte molecules in the lattice of not fully desolvated chaperones.…”

“…For well resolved structures, this limit appears to be 240 g/mol for analytes devoid of heavy elements. [15,19,23] The largest natural product successfully encapsulated thus far is muscone of molecular weight 238 g/mol, but it yielded a structure of insufficient resolution to determine the absolute configuration unambiguously. [15] Larger liquid analytes do not appear to form solvate crystals under the experimental conditions tested by us, which included different temperature and concentration regimes, as well as diffusion and evaporative approaches.…”

“…Among them is the size limit for the analytes to be incorporated in solvate crystals. For well resolved structures, this limit appears to be 240 g/mol for analytes devoid of heavy elements [15,19,23] . The largest natural product successfully encapsulated thus far is muscone of molecular weight 238 g/mol, but it yielded a structure of insufficient resolution to determine the absolute configuration unambiguously [15] .…”