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The 400 MHz 1 H NMR spectra of macrocycles and acyclic models. Two subpopulations are indicated with yellow (V-V and both isomers of I-I) and blue boxes (G-G). Arrows indicate a common change in chemical shift between the macrocycle and its corresponding acyclic model. Elements shared across the acyclic intermediates are indicated with a green asterisk. See text for additional detail.
Source publication
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 forma...
Contexts in source publication
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... bonding was also apparent in the 1 H NMR spectra of these macrocycles. Figure 2 shows the appearance of well-resolved resonances in the downfield "fingerprint" region of the NMR spectrum. Both the chemical shift and shape were indicative of hydrogen bonding interactions. ...
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... bonding was also apparent in the 1 H NMR spectra of these macrocycles. Figure 2 shows the appearance of well-resolved resonances in the downfield "fingerprint" region of the NMR spectrum. Both the chemical shift and shape were indicative of hydrogen bonding interactions. ...
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... of the use of substituted triazines, melamines, in molecular recognition led to a second explanation: the rotamer equilibrium can be influenced by noncovalent interactions. From Figure 2, it is evident that protonation was sufficient to bias the rotamer equilibrium. Computation offered insight into these energetic costs. ...
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... of the use of substituted triazines, melamines, in molecular recognition led to a second explanation: the rotamer equilibrium can be influenced by noncovalent interactions. From Figure 2, it is evident that protonation was sufficient to bias the rotamer equilibrium. Computation offered insight into these energetic costs. ...
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... of the use of substituted triazines, melamines, in molecular recognition led to a second explanation: the rotamer equilibrium can be influenced by noncovalent interactions. From Figure 2, it is evident that protonation was sufficient to bias the rotamer equilibrium. Computation offered insight into these energetic costs. ...
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... preorganization was important, we hypothesized that the rotamer equilibrium would shift to the rotamer that facilitated the formation of the hydrogen bond. The NMR spectra of the ethylamide model systems substantiated this belief (Figure 2). In all cases, the models favored one rotamer and the spectra were well resolved, a stark contrast to the spectra of the precursors (available in the supporting information). ...
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... Materials: Supporting information including spectra and synthetic details can be downloaded at https://www.mdpi.com/article/10.3390/molecules28031144/s1. Experimental Details; Chart S1: Compounds described in the supporting material; Figure S1: DFT-computed relative energies of protonated triazine models; Figure S2: Coding the computational data onto the rotamer diagrams; Figure S3: Relative energies of protonated triazine models; Figure S4: Folding energy of the neutral (unprotonated) intermediate; Figure S5: Folding energy of the monoprotonated (terminal) intermediate; Figure S6: Folding energy of the monoprotonated (interior) intermediate; Figure S7: Folding energy of the diprotonated intermediate; Figure S8: Folding energy vs. number of protons; Figure S9: The 400 MHz 1H NMR spectrum of 1 in DMSO-d6; Figure S10: The 100 MHz 13C{1H} NMR spectrum of 1 in DMSO-d6; Figure S11: The 400 MHz 1H NMR spectrum of 2 in DMSO-d6; Figure S12: The 100 MHz 13C{1H} NMR spectrum of 2 in DMSO-d6; Figure S13: The 400 MHz 1H NMR spectrum of 3 in DMSO-d6; Figure S14: The 100 MHz 13C{1H} NMR spectrum of 3 in DMSO-d6; Figure S15: The 400 MHz 1H NMR spectrum of GEA in DMSO-d6; Figure S16: The 100 MHz 13C{1H} NMR spectrum of GEA in DMSO-d6; Figure Author Contributions: Conceptualization, E.E.S.; investigation, A.J.M., N.C.H., L.C.K., A.N.E. and B.G.J.; writing-original draft preparation, E.E.S.; writing-review and editing, A.J.M., B.G.J. and E.E.S.; supervision, A.J.M.; project administration, E.E.S.; funding acquisition, B.G.J. and E.E.S. All authors have read and agreed to the published version of the manuscript. ...
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Citations
Hinge motion is observed in macrocyclic, mortise‐type molecular hinges using variable temperature NMR spectroscopy. The data is consistent with dynamic hinging from a folded‐to‐extended‐to‐folded enantiomeric state. Crystallographic and solution structures of the folded states are reported. Chemical shift predictions derived from crystallographic data corroborate fully revolute hinge motion. The rate of hinging is affected by steric congestion at the hinge axis. A macrocycle containing glycine, 1, hinges faster than one comprising aminoisobutyric acid, 2. The free energies of activation, ΔG≠, for 1 and 2 were determined to be 13.3±0.3 kcal/mol and 16.3±0.3 kcal/mol, respectively. This barrier is largely independent of solvent across those surveyed (CD3OD, CD3CN, DMSO‐d6, pyridine‐d5, D2O). Experiment and computation predict energy barriers that are consistent with disruption of an intramolecular network of hydrogen bonds. DFT calculations reveal a pathway for hinge motion.
Experiment and computation are used to develop a model to rapidly predict solution structures of macrocycles sharing the same Murcko framework. These 24-atom triazine macrocycles result from the quantitative dimerization of identical monomers presenting a hydrazine group and an acetal tethered to an amino acid linker. Monomers comprising glycine and the β-branched amino acids threonine, valine, and isoleucine yield macrocycles G-G, T-T, V-V, and I-I, respectively. Elements common to all members of the framework include the efficiency of macrocyclization (quantitative), the solution- and solid-state structures (folded), the site of protonation (opposite the auxiliary dimethylamine group), the geometry of the hydrazone (E), the C2 symmetry of the subunits (conserved), and the rotamer state adopted. In aggregate, the data reveal metrics predictive of the three-dimensional solution structure that derive from the fingerprint region of the 1D 1H spectrum and a network of rOes from a single resonance. The metrics also afford delineation of more nuanced structural features that allow subpopulations to be identified among the members of the framework. Well-tempered metadynamics provides free energy surfaces and population distributions of these macrocycles. The areas of the free energy surface decrease with increasing steric bulk (G-G > V-V ∼ T-T > I-I). In addition, the surfaces are increasingly isoenergetic with decreasing steric bulk (G-G > V-V ∼ T-T > I-I).
