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

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 o...

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Published in:	Molecules (Basel, Switzerland) Vol. 28; no. 3; p. 1144
Main Authors:	Menke, Alexander J, Henderson, Nicholas C, Kouretas, Lola C, Estenson, Anne N, Janesko, Benjamin G, Simanek, Eric E
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 23-01-2023 MDPI
Subjects:	Amino acids Carbonyl compounds Carbonyl groups Carbonyls Chemical bonds computation Computer applications Condensates Conformation Diffraction Dimerization Equilibrium Hydrazine Hydrazines hydrazone Hydrazones Hydrogen Hydrogen bonding Hydrogen bonds Isomers Long range order macrocycle Magnetic resonance spectroscopy NMR NMR spectroscopy Nuclear magnetic resonance Nuclear magnetic resonance spectroscopy Oligomers Polymers preorganization Protonation Single crystals Stability triazine X-ray diffraction X-rays hydrogen bonding macrocycle hydrazone preorganization triazine computation
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1420-3049 1420-3049
DOI:	10.3390/molecules28031144