Structural and conformational study of substituted triazines by15N NMR and x-ray analysis

Amm, Michel; Platzer, N.; Guilhem, Jean; Bouchet, Jean‐Paul; Volland, Jean‐Paul

doi:10.1002/(sici)1097-458x(199808)36:8<587::aid-omr347>3.0.co;2-b

Cited by 36 publications

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“…Rotamers were observed in the NMR spectra of intermediates but not in the macrocycle. Substituted triazines existed in an equilibrium of rotational isomers, the so-called rotamers, due to a hindered rotation about the triazine- N bond [ 23 , 24 , 25 ]. Experimental and computational models placed the barrier of rotation at 15–16 kcal/mol [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2023

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“…Hindered rotation about the triazine- N bonds leads to conformational isomers that are apparent in the acyclic intermediates. − The barrier to rotation for this bond in acyclic systems has been determined to be ∼15 kcal/mol . The macrocycles adopt a single rotamer state that can be assigned by rOesy experiments.…”

Section: Results and Discussionmentioning

confidence: 99%

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

et al. 2023

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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).

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“…Following ref , which used REMD from 300 to 800 K to obtain free energy landscapes of peptoids, as a reference, the REMD simulations were run with 16 replicas that uniformly spanned from 300 to 800 K for each system. The highest temperature of 800 K is used to enable and observe cis to trans and vice versa isomerizations (a single isomerization is experimentally measured to have an energy barrier of Δ G ⧧ = 15 kcal/mol), ,, as done in ref . The system was stable at the highest temperature, since numerical integration of the MD simulation was stable throughout the entire simulation.…”

Section: Methodsmentioning

confidence: 99%

Foldamer Architectures of Triazine-Based Sequence-Defined Polymers Investigated with Molecular Dynamics Simulations and Enhanced Sampling Methods

Ahn

Grate

2019

J. Phys. Chem. B

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Triazine-based sequence-defined polymers have recently been developed that are biomimetic and robust. In molecular dynamics (MD) simulations, the triazine polymers were shown to form linear nanorod foldamers through hydrogen bonding and π–π interactions. The nanorod foldamers have motifs resembling those of DNA, α-helices, and β-sheets and have potential to be useful building blocks for new macromolecules and materials. To understand the formation of nanorod foldamers, we investigate how linker structures in the middle of the triazine polymers lead to folding using MD simulations. We found that a variety of linkers can participate in folding but that specific linker structures are more favorable than others, depending on the polymer length. Folding of hexamers into well-defined nanorod foldamers was most favorable with pentanediamine and ortho-xylenediamine linkers in the center of the polymers. Foldamers with ortho-xylenediamine linkers in the center were investigated for longer polymers, i.e., octamers and decamers, using two different enhanced sampling methods, since regular MD simulations had failed to show any folding for these longer polymers. In particular, the recently developed concurrent adaptive sampling (CAS) algorithm and replica exchange molecular dynamics (REMD) were used. We found that the two enhanced sampling methods did lead to the observation of foldamers and that REMD revealed new foldamer architectures where cis–trans isomerizations had occurred. Foldamer formation, diversity, and the strengths and limitations of simulation techniques are discussed. These findings provide new insights into the diversity of foldamer architectures for a new type of biomimetic synthetic polymer.

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Structural and conformational study of substituted triazines by15N NMR and x-ray analysis

Cited by 36 publications

References 0 publications

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

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

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

Foldamer Architectures of Triazine-Based Sequence-Defined Polymers Investigated with Molecular Dynamics Simulations and Enhanced Sampling Methods

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