Dataset Information

Structural Distortion of Cycloalkynes Influences Cycloaddition Rates both by Strain and Interaction Energies.

ABSTRACT: The reactivities of 2-butyne, cycloheptyne, cyclooctyne, and cyclononyne in the 1,3-dipolar cycloaddition reaction with methyl azide were evaluated through DFT calculations at the M06-2X/6-311++G(d)//M06-2X/6-31+G(d) level of theory. Computed activation free energies for the cycloadditions of cycloalkynes are 16.5-22.0 kcal mol^-1 lower in energy than that of the acyclic 2-butyne. The strained or predistorted nature of cycloalkynes is often solely used to rationalize this significant rate enhancement. Our distortion/interaction-activation strain analysis has been revealed that the degree of geometrical predistortion of the cycloalkyne ground-state geometries acts to enhance reactivity compared with that of acyclic alkynes through three distinct mechanisms, not only due to (i) a reduced strain or distortion energy, but also to (ii) a smaller HOMO-LUMO gap, and (iii) an enhanced orbital overlap, which both contribute to more stabilizing orbital interactions.

SUBMITTER: Hamlin TA

PROVIDER: S-EPMC6519225 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Structural Distortion of Cycloalkynes Influences Cycloaddition Rates both by Strain and Interaction Energies.

Hamlin Trevor A TA Levandowski Brian J BJ Narsaria Ayush K AK Houk Kendall N KN Bickelhaupt F Matthias FM

Chemistry (Weinheim an der Bergstrasse, Germany) 20190327 25

The reactivities of 2-butyne, cycloheptyne, cyclooctyne, and cyclononyne in the 1,3-dipolar cycloaddition reaction with methyl azide were evaluated through DFT calculations at the M06-2X/6-311++G(d)//M06-2X/6-31+G(d) level of theory. Computed activation free energies for the cycloadditions of cycloalkynes are 16.5-22.0 kcal mol<sup>-1</sup> lower in energy than that of the acyclic 2-butyne. The strained or predistorted nature of cycloalkynes is often solely used to rationalize this significant r ...[more]

PMID: 30779472

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Project description:Kinetic and thermodynamic models of biological systems are commonly used to connect microscopic features to system function in a bottom-up multiscale approach. The parameters of such models-free energy differences for equilibrium properties and in general rates for equilibrium and out-of-equilibrium observables-have to be measured by different experiments or calculated from multiple computer simulations. All such parameters necessarily come with uncertainties so that when they are naively combined in a full model of the process of interest, they will generally violate fundamental statistical mechanical equalities, namely detailed balance and an equality of forward/backward rate products in cycles due to T. Hill. If left uncorrected, such models can produce arbitrary outputs that are physically inconsistent. Here we develop a maximum likelihood approach (named multibind ) based on the so-called potential graph to combine kinetic or thermodynamic measurements to yield state resolved models that are thermodynamically consistent while being most consistent with the provided data and their uncertainties. We demonstrate the approach with two theoretical models, a generic two-proton binding site and a simplified model of a sodium/proton antiporter. We also describe an algorithm to use the multibind approach to solve the inverse problem of determining microscopic quantities from macroscopic measurements and as an example we predict the microscopic p K a s and protonation states of a small organic molecule from 1D NMR data. The multibind approach is applicable to any thermodynamic or kinetic model that describes a system as transitions between well-defined states with associated free energy differences or rates between these states. A Python package multibind , which implements the approach described here, is made publicly available under the MIT Open Source license.Why it mattersThe increase in computational efficiency and rapid advances in methodology for quantitative free energy and rate calculations has allowed for the construction of increasingly complex thermodynamic or kinetic "bottom-up" models of chemical and biological processes. These multi-scale models serve as a framework for analyzing aspects of cellular function in terms of microscopic, molecular properties and provide an opportunity to connect molecular mechanisms to cellular function. The underlying model parameters-free energy differences or rates-are constrained by thermodynamic identities over cycles of states but these identities are not necessarily obeyed during model construction, thus potentially leading to inconsistent models. We address these inconsistencies through the use of a maximum likelihood approach for free energies and rates to adjust the model parameters in such a way that they are maximally consistent with the input parameters and exactly fulfill the thermodynamic cycle constraints. This approach enables formulation of thermodynamically consistent multi-scale models from simulated or experimental measurements.

Dataset Information

Structural Distortion of Cycloalkynes Influences Cycloaddition Rates both by Strain and Interaction Energies.

Publications

Structural Distortion of Cycloalkynes Influences Cycloaddition Rates both by Strain and Interaction Energies.

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