A series of molecular rotors was designed to study and measure the rate accelerating effects of an intramolecular hydrogen bond. The rotors form a weak neutral O–H/O]C hydrogen bond in the planar transition state (TS) of the bond rotation process. The rotational barrier of the hydrogen bonding rotors was dramatically lower (9.9 kcal mol1) than control rotors which could not form hydrogen bonds. The magnitude of the stabilization was significantly larger than predicted based on the independently measured strength of a similar OH/OC hydrogen bond (1.5 kcal mol-1). The origins of the large transition state stabilization were studied via experimental substituent effect and computational perturbation analyses. Energy decomposition analysis of the hydrogen bonding interaction revealed a significant reduction in the repulsive component of the hydrogen bonding interaction. The rigid framework of the molecular rotors positions and preorganizes the interacting groups in the transition state. This study demonstrates that with proper design a single hydrogen bond can lead to a TS stabilization that is greater than the intrinsic interaction energy, which has applications in catalyst design and in the study of enzyme mechanisms.
more »
« less
Large transition state stabilization from a weak hydrogen bond
A series of molecular rotors was designed to study and measure the rate accelerating effects of an intramolecular hydrogen bond. The rotors form a weak neutral O–H⋯OC hydrogen bond in the planar transition state (TS) of the bond rotation process. The rotational barrier of the hydrogen bonding rotors was dramatically lower (9.9 kcal mol −1 ) than control rotors which could not form hydrogen bonds. The magnitude of the stabilization was significantly larger than predicted based on the independently measured strength of a similar O–H⋯OC hydrogen bond (1.5 kcal mol −1 ). The origins of the large transition state stabilization were studied via experimental substituent effect and computational perturbation analyses. Energy decomposition analysis of the hydrogen bonding interaction revealed a significant reduction in the repulsive component of the hydrogen bonding interaction. The rigid framework of the molecular rotors positions and preorganizes the interacting groups in the transition state. This study demonstrates that with proper design a single hydrogen bond can lead to a TS stabilization that is greater than the intrinsic interaction energy, which has applications in catalyst design and in the study of enzyme mechanisms.
more »
« less
- Award ID(s):
- 1709086
- NSF-PAR ID:
- 10174654
- Date Published:
- Journal Name:
- Chemical Science
- Volume:
- 11
- Issue:
- 28
- ISSN:
- 2041-6520
- Page Range / eLocation ID:
- 7487 to 7494
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
null (Ed.)The torsional barriers along the C aryl –C aryl axis of a pair of isosteric disubstituted biphenyls were determined by variable temperature 1 H NMR spectroscopy in three solvents with contrasted hydrogen bond accepting abilities (1,1,2,2-tetrachloroethane-d 2 , nitrobenzene-d 5 and dimethyl sulfoxide-d 6 ). One of the biphenyl scaffolds was substituted at its ortho and ortho ′ positions with N ′-acylcarbohydrazide groups that could engage in a pair of intramolecular N–H⋯O=C hydrogen bonding interactions at the ground state, but not at the transition state of the torsional isomerization pathway. The torsional barrier of this biphenyl was exceedingly low despite the presence of the hydrogen bonds (16.1, 15.6 and 13.4 kcal mol −1 in the three aforementioned solvents), compared to the barrier of the reference biphenyl (15.3 ± 0.1 kcal mol −1 on average). Density functional theory and the solvation model developed by Hunter were used to decipher the various forces at play. They highlighted the strong stabilization of hydrogen bond donating solutes not only by hydrogen bond accepting solvents, but also by weakly polar, yet polarizable solvents. As fast exchanges on the NMR time scale were observed above the melting point of dimethyl sulfoxide-d 6 , a simple but accurate model was also proposed to extrapolate low free activation energies in a pure solvent (dimethyl sulfoxide-d 6 ) from higher ones determined in mixtures of solvents (dimethyl sulfoxide-d 6 in nitrobenzene-d 5 ).more » « less
-
more » « less
Abstract Arginine methylation is an important mechanism of epigenetic regulation. Some Fe(II) and 2‐oxoglutarate dependent Jumonji‐C (JmjC) Nϵ‐methyl lysine histone demethylases also have N‐methyl arginine demethylase activity. We report combined molecular dynamic (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) studies on the mechanism of N‐methyl arginine demethylation by human KDM4E and compare the results with those reported for N‐methyl lysine demethylation by KDM4A. At the KDM4E active site, Glu191, Asn291, and Ser197 form a conserved scaffold that restricts substrate dynamics; substrate binding is also mediated by an out of active site hydrogen‐bond between the substrate Ser1 and Tyr178. The calculations imply that in either C−H or N−H potential bond cleaving pathways for hydrogen atom transfer (HAT) during N‐methyl arginine demethylation, electron transfer occurs via a σ‐channel; the transition state for the N−H pathway is ∼10 kcal/mol higher than for the C−H pathway due to the higher bond dissociation energy of the N−H bond. The results of applying external electric fields (EEFs) reveal EEFs with positive field strengths parallel to the Fe=O bond have a significant barrier‐lowering effect on the C−H pathway, by contrast, such EEFs inhibit the N−H activation rate. The overall results imply that KDM4 catalyzed N‐methyl arginine demethylation and N‐methyl lysine demethylation occur via similar C−H abstraction and rebound mechanisms leading to methyl group hydroxylation, though there are differences in the interactions leading to productive binding of intermediates.
-
more » « less
A new class of rod‐shaped strongly dipolar molecular rotors for insertion into channels of hexagonal tris(
o ‐phenylenedioxy)cyclotriphosphazene (TPP) has been examined. Seven different 3,6‐disubstituted pyridazines and one singly 3‐substituted system have been prepared and studied by solid‐state nuclear magnetic resonance (NMR), X‐ray powder diffraction, and dielectric spectroscopy. NMR and X‐ray diffraction both show that all but one of these molecular rotors form hexagonal bulk inclusion compounds with TPP. In‐plane lattice parameters for the hexagonal phases increase with the size of the end group, which also controls the energy barriers for rotation of the pyridazine dipole. The barriers range from ≈4 kcal mol−1for small or flexible end groups to less than 0.7 kcal mol−1for 3‐methylbicyclo[1.1.1]pent‐1‐yl end groups after annealing to 235 °C, and an interpretation of these differences is offered. Computer modeling of the relaxed TPP channels followed by density functional calculation of the environment for one of the rotors provides quantitative agreement with the observed barrier. The systems with the lowest rotational barriers show signs of collective behavior, discussed in terms of antiferroelectric intrachannel and ferroelectric interchannel dipole–dipole interactions. A Curie temperature of 22 K is deduced for 3,6‐diadamant‐1′‐ylpyridazine, but no ordered dielectric phases are found. Conclusions have been drawn for improved rotor design. -
more » « less
Abstract The structures of zinc carbene ZnCH2and zinc carbyne HZnCH, and the conversion transition states between them are optimized at B3LYP/aug‐cc‐pVTZ, MP2/aug‐cc‐pVTZ, and CCSD/aug‐cc‐pVTZ levels of theory. The thermodynamic energies with CCSD(T) method are further extrapolated to basis set limit through a series of basis sets of aug‐cc‐pVXZ (X=D, T, Q, 5). The Zn−C bonding characteristics are interpreted by molecular plots, Laplacian of density plots, the integrated delocalization indices, net atomic charges, and derived atomic hardness. On the one hand, the studies demonstrated the efficiency of DFT method in structure optimizations and the accuracy of CBS method in obtaining thermodynamic energies; On the other hand, the density analysis of CCSD/aug‐cc‐pVDZ density demonstrates that both the sharing interaction and ionic interaction are important in ZnCH2ad HZnCH. The3B1state of ZnCH2is the global minimum and formed in visible light, but its small bond dissociation energy (47.0 kcal/mol) cannot keep the complex intact under UV light (79.4–102.1 kcal/mol). However, the3Σ−state of HZnCH can survive the UV light due to the greater Zn−C dissociation energy (100.7 kcal/mol). The delocalization indices of Zn…C in both3B1of ZnCH2(0.777) and the3Σ−state of HZnCH (0.785) are close to the delocalization index of the single C−C bond of ethane (0.841), i. e. the nomenclature of Zinc carbene and Zinc carbyne is incorrect. The stronger Zn−C bond in the3Σ−state of HZnCH than in the3B1state of ZnCH2can be attributed to the larger charge separation in the former. It was found that the Zn−C bonds in related Zinc organic compounds were also single bonds no matter whether the organic groups are CR, CR2, or CR3. The ionic interactions were discussed in terms of the atomic hardness that were in turn related to ionization energy and electron affinity. The unique combination of covalent and ionic characteristics in the Zn−C bonds of organic Zinc compounds could be the origin of many interesting applications of organic Zinc reagents.
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/D0SC02806A
