Are thermodynamic cycles necessary for continuum solvent calculation of pKas and reduction potentials?

2015 ◽  
Vol 17 (4) ◽  
pp. 2859-2868 ◽  
Author(s):  
Junming Ho
Keyword(s):  
Free Energy ◽  
Gas Phase ◽  
Thermodynamic Cycle ◽  
Free Energies ◽  
Thermodynamic Cycles ◽  
Reduction Potentials ◽  
Reaction Free Energy

Continuum solvent calculations of pKas and reduction potentials usually entail the use of a thermodynamic cycle to express the reaction free energy in terms of gas phase energies and free energies of solvation.

Prediction of Alkanolamine pKa Values by Combined Molecular Dynamics Free Energy Simulations and ab initio Calculations

2019 ◽  
Author(s):  
Javad Noroozi ◽  
William Smith
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ab Initio Calculations ◽  
Gas Phase ◽  
Quantum Chemical ◽  
Phase Reaction ◽  
Pka Values ◽  
Gas Phase Reaction ◽  
Reaction Free Energy ◽  
Energy Simulations

We use molecular dynamics free energy simulations in conjunction with quantum chemical calculations of gas phase reaction free energy to predict alkanolamines pka values. <br>

Studies on the iodide–triiodide equilibrium

1977 ◽  
Vol 55 (5) ◽  
pp. 792-797 ◽  
Author(s):  
Robert L. Benoit ◽  
Michael F. Wilson ◽  
Sing-Yeung Lam
Keyword(s):  
Free Energy ◽  
Solvent Effect ◽  
Gas Phase ◽  
Formation Enthalpy ◽  
Aprotic Solvents ◽  
Free Energies ◽  
Potentiometric Measurements ◽  
Cast Doubt ◽  
Transfer Parameters ◽  
The Enthalpy Of Formation

The solvent effect on the iodide–triiodide equilibrium has been investigated by means of calorimetric and potentiometric measurements. The aprotic solvents studied were nitromethane, nitrobenzene, sulfolane, acetonitrile, propylene carbonate, acetophenone, dimethylformamide, dimethylsulfoxide, and o-dichlorobenzene. The resulting enthalpy and free energy changes imply that the variations of the enthalpies and free energies of transfer of the iodide and triiodide ions probably are small and that there is an important non-coulombic contribution to these transfer parameters. Values were obtained for the enthalpy of formation of two solid triiodides, which together with values for other triiodides, cast doubt on reported calculated lattice enthalpies of triiodides and formation enthalpy of I3− ion in the gas phase. This latter formation enthalpy is found to be, from our solution data, more negative than −22 kcal mol−1.

Prediction of Alkanolamine pKa Values by Combined Molecular Dynamics Free Energy Simulations and ab initio Calculations

2019 ◽  
Author(s):  
Javad Noroozi ◽  
William Smith
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Ab Initio Calculations ◽  
Gas Phase ◽  
Quantum Chemical ◽  
Phase Reaction ◽  
Pka Values ◽  
Gas Phase Reaction ◽  
Reaction Free Energy ◽  
Energy Simulations

We use molecular dynamics free energy simulations in conjunction with quantum chemical calculations of gas phase reaction free energy to predict alkanolamines pka values. <br>

Carbonate radical anion — Thermochemistry

2006 ◽  
Vol 84 (12) ◽  
pp. 1614-1619 ◽  
Author(s):  
D A Armstrong ◽  
W L Waltz ◽  
A Rauk
Keyword(s):  
Gas Phase ◽  
Radical Anion ◽  
Strong Acid ◽  
Free Energies ◽  
Isodesmic Reactions ◽  
Carbonate Radical ◽  
Reduction Potentials ◽  
High Level ◽  
Carbonate Radical Anion ◽  
Nitrate Species

High level ab initio calculations along with isodesmic reactions have been used to derive a set of self-consistent free energies of formation for carbonate and nitrate species in the gas phase and in aqueous solution. The results show that HCO3· is a strong acid, pKa = –4.1, and that E°(CO3·–/CO32) = 1.23 ± 0.15 V.Key words: carbonate radical anion, theoretical, thermochemistry, acidity, reduction potentials.

scholarly journals Beyond the classical thermodynamic contributions to hydrogen atom abstraction reactivity

2018 ◽  
Vol 115 (44) ◽  
pp. E10287-E10294 ◽  
Author(s):  
Daniel Bím ◽  
Mauricio Maldonado-Domínguez ◽  
Lubomír Rulíšek ◽  
Martin Srnec
Keyword(s):  
Hydrogen Atom ◽  
Hydrogen Transfer ◽  
Reorganization Energy ◽  
Catalytic Efficiency ◽  
Hydrogen Atom Abstraction ◽  
Free Energies ◽  
Classical Thermodynamic ◽  
Thermodynamic Cycles ◽  
Rational Development ◽  
Reaction Free Energy

Hydrogen atom abstraction (HAA) reactions are cornerstones of chemistry. Various (metallo)enzymes performing the HAA catalysis evolved in nature and inspired the rational development of multiple synthetic catalysts. Still, the factors determining their catalytic efficiency are not fully understood. Herein, we define the simple thermodynamic factor η by employing two thermodynamic cycles: one for an oxidant (catalyst), along with its reduced, protonated, and hydrogenated form; and one for the substrate, along with its oxidized, deprotonated, and dehydrogenated form. It is demonstrated that η reflects the propensity of the substrate and catalyst for (a)synchronicity in concerted H+/e− transfers. As such, it significantly contributes to the activation energies of the HAA reactions, in addition to a classical thermodynamic (Bell–Evans–Polanyi) effect. In an attempt to understand the physicochemical interpretation of η, we discovered an elegant link between η and reorganization energy λ from Marcus theory. We discovered computationally that for a homologous set of HAA reactions, λ reaches its maximum for the lowest |η|, which then corresponds to the most synchronous HAA mechanism. This immediately implies that among HAA processes with the same reaction free energy, ΔG0, the highest barrier (≡ΔG≠) is expected for the most synchronous proton-coupled electron (i.e., hydrogen) transfer. As proof of concept, redox and acidobasic properties of nonheme FeIVO complexes are correlated with activation free energies for HAA from C−H and O−H bonds. We believe that the reported findings may represent a powerful concept in designing new HAA catalysts.

scholarly journals Uncovering Differences in Hydration Free Energies for Model Compound Mimics of Charged Sidechains of Amino Acids

2021 ◽  
Author(s):  
Martin J. Fossat ◽  
Xiangze Zeng ◽  
Rohit V. Pappu
Keyword(s):  
Free Energy ◽  
Phase Equilibria ◽  
Thermodynamic Cycle ◽  
Heat Capacities ◽  
Free Energy Calculations ◽  
Disordered Proteins ◽  
Free Energies ◽  
Model Compounds ◽  
Intrinsically Disordered ◽  
Direct Measurements

ABSTRACTFree energies of hydration are fundamental quantities that are relevant for modeling and understanding sequence-specific conformational and phase equilibria of intrinsically disordered proteins (IDPs). Of particular importance are accurate values for the free energies of hydration of model compounds that mimic the charged sidechains of Arg, Lys, Asp, and Glu. Direct measurements of these quantities are challenging, and accordingly the values used to date rely on decompositions of measurements of whole salts. This has created considerable uncertainty regarding the desired quantities. Here, we adapt and deploy a Thermodynamic Cycle based Proton Dissociation in conjunction with published data from direct measurements along the relevant thermodynamic cycle to obtain new values for the free energies of hydration for model compounds that mimic the sidechains of Arg, Lys, Asp, and Glu. We obtain independent assessments for these inferred values using direct free energy calculations based on the polarizable AMOEBA forcefield and water model. The TCPD and AMOEBA derived values agree with one another. The new numbers suggest that Arg has the least favorable free energy of solvation, followed by Lys. On average, the sidechains of Asp and Glu have free energies of hydration that are ~1.8 times more favorable than Arg and ~1.5 times more favorable than Lys. Calculations used to extract the temperature dependence of free energies of hydration reveal positive heat capacities of hydration for Arg and Lys and negative heat capacities of hydration for Asp and Glu. We analyze the hydration structures around the different solutes to uncover a structural explanation for the observed differences in free energies of hydration. Although the sidechains of Arg and Lys are both amphiphilic, we find that the Arg sidechain has more of a hydrophobic character. In contrast, both Asp and Glu are hydrophilic both in terms of their solvation thermodynamics and hydration structure. Our results provide a physico-chemical explanation for recent accounts documenting the differences of Arg and Lys with respect to one another and with respect to Asp / Glu as determinants of conformational and phase equilibria of IDPs.

Semi-empirical calculation of rates of SN2 Finkelstein reactions in solution by a quasi-thermodynamic cycle

1978 ◽  
Vol 31 (9) ◽  
pp. 1897 ◽  
Author(s):  
DJ McLennan
Keyword(s):  
Transition State ◽  
Gas Phase ◽  
Thermodynamic Cycle ◽  
Bond Orders ◽  
Free Energies ◽  
Methyl Radical ◽  
Maximum Value ◽  
Leaving Group ◽  
Radical Transfer ◽  
Semi Empirical

Free energies of activation for the reactions: ������������� Nu-+MeX → MeNu+X- (Nu = nucleophile, X = halogen) are calculated by a quasi-thermodynamic cycle. The six steps involved are: (i) desolvation and escape into the gas phase of MeX; (ii) desolvation and escape of Nu- ; (iii) loss of an electron from Nu-; (iv) combination of Nu.(g) with MeX(g) to form a methyl radical transfer 'transition state'; (v) placement of an electron on the 'transition state'; (vi) transfer of the anionic transition state from the gas phase to the solvent. The BEBO method is used to calculate the energetics of step (iv), and the BEBO exponents for various Nu and X are calculated from the measured or estimated rates of the symmetrical halide exchanges X-+MeX and Nu-+ MeNu. The energy of the system is plotted as a function of the fractional bond orders of the Nu...C and C...X partial bonds, and ΔG‡ is identified with the maximum value of this energy. An excellent correlation of calculated against experimental results is found for reactions in water and methanol, whilst interactions between polarizable HCONMe2 and polarizable SN2 transition states lead to small but regular discrepancies in HCONMe2. Observed nucleophilic and leaving group orders of reactivity are reproduced, as is the lack of a correlation between reactivity and selectivity. The computed transition state bond orders do not concur with predictions based on the Hammond postulate.

scholarly journals The Good, the Bad, and the Ugly: “HiPen”, a New Dataset for Validating (S)QM/MM Free Energy Simulations

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 681 ◽  
Author(s):  
Fiona Kearns ◽  
Luke Warrensford ◽  
Stefan Boresch ◽  
H. Woodcock
Keyword(s):  
Free Energy ◽  
Gas Phase ◽  
Convergence Criteria ◽  
Free Energies ◽  
Acceptance Ratio ◽  
Current State ◽  
Energy Perturbation ◽  
Energy Simulations ◽  
Molecular Description ◽  
Bennett’S Acceptance Ratio

Indirect (S)QM/MM free energy simulations (FES) are vital to efficiently incorporating sufficient sampling and accurate (QM) energetic evaluations when estimating free energies of practical/experimental interest. Connecting between levels of theory, i.e., calculating Δ A l o w → h i g h , remains to be the most challenging step within an indirect FES protocol. To improve calculations of Δ A l o w → h i g h , we must: (1) compare the performance of all FES methods currently available; and (2) compile and maintain datasets of Δ A l o w → h i g h calculated for a wide-variety of molecules so that future practitioners may replicate or improve upon the current state-of-the-art. Towards these two aims, we introduce a new dataset, “HiPen”, which tabulates Δ A g a s M M → 3 o b (the free energy associated with switching from an M M to an S C C − D F T B molecular description using the 3ob parameter set in gas phase), calculated for 22 drug-like small molecules. We compare the calculation of this value using free energy perturbation, Bennett’s acceptance ratio, Jarzynski’s equation, and Crooks’ equation. We also predict the reliability of each calculated Δ A g a s M M → 3 o b by evaluating several convergence criteria including sample size hysteresis, overlap statistics, and bias metric ( Π ). Within the total dataset, three distinct categories of molecules emerge: the “good” molecules, for which we can obtain converged Δ A g a s M M → 3 o b using Jarzynski’s equation; “bad” molecules which require Crooks’ equation to obtain a converged Δ A g a s M M → 3 o b ; and “ugly” molecules for which we cannot obtain reliably converged Δ A g a s M M → 3 o b with either Jarzynski’s or Crooks’ equations. We discuss, in depth, results from several example molecules in each of these categories and describe how dihedral discrepancies between levels of theory cause convergence failures even for these gas phase free energy simulations.

Glutathione radical: Intramolecular H abstraction by the thiyl radical

2001 ◽  
Vol 79 (4) ◽  
pp. 405-417 ◽  
Author(s):  
A Rauk ◽  
D A Armstrong ◽  
J Berges
Keyword(s):  
Free Energy ◽  
Gas Phase ◽  
Hydrogen Transfer ◽  
Single Point ◽  
Continuum Models ◽  
Thiyl Radical ◽  
Free Energies ◽  
Model Compounds ◽  
Activation Free Energy ◽  
Transition Structures

Ab initio computations (B3LYP/6-31G(D)) were used to predict transition structures and energies of activation for intramolecular H atom transfer to a thiyl radical (RS.) from the α-C—H bonds of glutathione (1) and from the model compounds, N-formylcysteinylglycine (2) and N-(2-thioethanyl)-γ-glutamine (3). For each compound, transition structures were located by in vacuo calculations on the neutral non-zwitterionic system. Thermodynamic functions derived at the same level and single point calculations at the B3LYP/6-311+G(3df,2p) level, were used to derive free energies of activation (ΔG[Formula: see text]) and reaction (ΔG°). For abstraction of the α-C—H (Gly) by the thiyl radical in the gas phase, ΔG[Formula: see text] = 134 kJ mol–1 if the amide link to Gly is in the more stable (Z)-configuration, and ΔG[Formula: see text] = 52 kJ mol–1 if it is in the less stable (E)-configuration. The isomerization of the amide group requires about 95 kJ mol–1. Previous studies had indicated that for intramolecular reaction of the thiyl radical at α-C—H (Cys), ΔG[Formula: see text] = 110 kJ mol–1. The lowest energy pathway for intramolecular H-transfer to the thiyl radical is from α-C—H (Gln), ΔG[Formula: see text] = 37–42 kJ mol–1, and corresponds rather well with experimental results in solution (ΔG[Formula: see text] = 43 kJ mol–1). The calculated free energy change for the equilibrium between thiyl and α-C forms of the glutathione radical is ΔG° = –54 kJ mol–1. The value estimated from experimental data is ΔG° = –37 kJ mol–1. The agreement between the energies from theory in the gas phase and experiment in solution suggests that the free energies of solvation of reactant thiyl radical, transition structures for H abstraction, and the product α-C-centred radical, are very similar. The effects of solution were estimated by two continuum models (SCIPCM and COSMO). The SCIPCM model yields results very similar to the gas phase, predicting a modest lowering of the activation free energy. The results from the COSMO method were inconclusive as to whether a rate enhancement or decrease could be expected.Key words: glutathione, thiyl radical, α-C-radical, hydrogen transfer.

SAMPL6 Octanol-Water Partition Coefficients from Alchemical Free Energy Calculations with MBIS Atomic Charges

2019 ◽  
Author(s):  
Maximiliano Riquelme ◽  
Esteban Vöhringer-Martinez
Keyword(s):  
Free Energy ◽  
Electron Density ◽  
Free Energy Calculations ◽  
Basis Set ◽  
Energetic Cost ◽  
Atomic Charges ◽  
Free Energies ◽  
Energy Calculations ◽  
Alchemical Free Energy ◽  
Alchemical Free Energy Calculations

In molecular modeling the description of the interactions between molecules forms the basis for a correct prediction of macroscopic observables. Here, we derive atomic charges from the implicitly polarized electron density of eleven molecules in the SAMPL6 challenge using the Hirshfeld-I and Minimal Basis Set Iterative Stockholder(MBIS) partitioning method. These atomic charges combined with other parameters in the GAFF force field and different water/octanol models were then used in alchemical free energy calculations to obtain hydration and solvation free energies, which after correction for the polarization cost, result in the blind prediction of the partition coefficient. From the tested partitioning methods and water models the S-MBIS atomic charges with the TIP3P water model presented the smallest deviation from the experiment. Conformational dependence of the free energies and the energetic cost associated with the polarization of the electron density are discussed.

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