Computational and Experimental Evidence for Templated Macrocyclization: The Role of a Hydrogen Bond Network in the Quantitative Dimerization of 24-Atom Macrocycles

Abstract

In the absence of preorganization, macrocyclization reactions are often plagued by oligomeric and polymeric side products. Here, a network of hydrogen bonds was identified as the basis for quantitative yields of macrocycles derived from the dimerization of monomers. Oligomers and polymers were not observed. Macrocyclization, the result of the formation of two hydrazones, was hypothesized to proceed in two steps. After condensation to yield the monohydrazone, a network of hydrogen bonds formed to preorganize the terminal acetal and hydrazine groups for cyclization. Experimental evidence for preorganization derived from macrocycles and acyclic models. Solution NMR spectroscopy and single-crystal X-ray diffraction revealed that the macrocycles isolated from the cyclization reaction were protonated twice. These protons contributed to an intramolecular network of hydrogen bonds that engaged distant carbonyl groups to realize a long-range order. DFT calculations showed that this network of hydrogen bonds contributed 8.7 kcal/mol to stability. Acyclic models recapitulated this network in solution. Condensation of an acetal and a triazinyl hydrazine, which adopted a number of conformational isomers, yielded a hydrazone that adopted a favored rotamer conformation in solution. The critical hydrogen-bonded proton was also evident. DFT calculations of acyclic models showed that the rotamers were isoenergetic when deprotonated. Upon protonation, however, energies diverged with one low-energy rotamer adopting the conformation observed in the macrocycle. This conformation anchored the network of hydrogen bonds of the intermediate. Computation revealed that the hydrogen-bonded network in the acyclic intermediate contributed up to 14 kcal/mol of stability and preorganized the acetal and hydrazine for cyclization.

Controlling Swing Rates in Macrocyclic Molecular Mortise Hinges

“…On average, ΔG ≠ is 13.3±0.3 kcal/mmol for 1 , and 16.3±0.3 kcal/mol for 2 . These values are in line with the cost of breaking the hydrogen bond network, calculated to be 14 kcal/mol [37] . Models show that the geometries of these interactions are affected and the network may disappear transiently in the flat, extended intermediate.…”

“…These values are in line with the cost of breaking the hydrogen bond network, calculated to be 14 kcal/mol. [37] Models show that the geometries of these interactions are affected and the network may disappear transiently in the flat, extended intermediate. At the current level of theory and model systems, the qualitative picture that emerges is one in which these modestly flexible.…”

A Model for the Rapid Assessment of Solution Structures for 24-Atom Macrocycles: The Impact of β-Branched Amino Acids on Conformation

“…Here, the quantitative formation of macrocyclesindependent of steric bulkis surprising. We infer that these macrocycles represent thermodynamic minima and hypothesize that the acidic environment might template dimerization . Macrocyclization appears to be independent of the concentration across the range explored to datefrom 3 to 100 mM (corresponding to 5 to 165 mg/mL).…”

“…We infer that these macrocycles represent thermodynamic minima and hypothesize that the acidic environment might template dimerization. 41 Macrocyclization appears to be independent of the concentration across the range explored to date�from 3 to 100 mM (corresponding to 5 to 165 mg/mL). The rate of evaporation is critical to success.…”

“…They survive conventional silica gel chromatography. Ongoing efforts address the mechanistic basis for the quantitative cyclization (a result that we hypothesize to be due to templating through the formation of a network of hydrogen bonds), the chiral sorting that appears to be occurring and the reaction conditions required to minimize racemization …”