Abstract
The physicochemical properties and reactivity of macrocycles are critically shaped by their conformations. In this work, we have identified seven conformations of the macrocyclic ketone cyclododecanone using chirped-pulse Fourier transform microwave spectroscopy in combination with ab initio and density functional theory calculations. Cyclododecanone is strongly biased towards adopting a square configuration of the heavy atom framework featuring three C–C bonds per side. The substitution and effective structures of this conformation have been determined through the observation of its 13C isotopologues. The minimisation of transannular interactions and, to a lesser extent, HCCH eclipsed configurations drive conformational preferences. Our results contribute to a better understanding of the intrinsic forces mediating structural choices in macrocycles.
Highlights
IntroductionMacrocycles are molecules containing twelve-membered or larger rings, used in drug discovery [1], catalysis and materials [2]
Torsional and angle strain are basically removed in sixmembered cyclohexane (n = 6), which adopts a chair conformation wherein bond and torsional angles are close to their optimal values for tetrahedral carbons, and all C–H bonds are staggered, avoiding eclipsed interactions [9]
The lower-energy conformations of cyclododecanone were predicted by mapping its potential energy surface using the semiempirical method AM1 within the program HyperChem [45] and the conformer sampling program CREST [46]
Summary
Macrocycles are molecules containing twelve-membered or larger rings, used in drug discovery [1], catalysis and materials [2]. Their stability, reactivity and physicochemical characteristics are intimately related to their structural properties, to the conformations they adopt and their intramolecular forces. Studies of cycloalkanes Cn H2n have mainly focused on small rings (up to 7 atoms) and, to a smaller degree, on medium rings (8 to 11 atoms) [3–8]. Torsional and angle strain determine the conformations of small cycloalkanes with n = 3–5. In cycloheptane (n = 7), there is torsional strain due to eclipsing interactions between H atoms, like in smaller rings, and steric strain caused by transannular repulsive interactions, which are characteristic of medium-sized rings [10]. Cycloheptane is not strain-free and experiences pseudorotation [10–12]
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