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Molecular Models02:00

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Physical models representing molecular architectures of chemical compounds play essential roles in understanding chemistry. The use of molecular models makes it easier to visualize the structures and shapes of atoms and molecules.
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Some compounds produce hydroxide ions when dissolved by chemically reacting with water molecules. In all cases, these compounds react only partially and so are classified as weak bases. These types of compounds are also abundant in nature and important commodities in various technologies. For example, global production of the weak base ammonia is typically well over 100 metric tons annually, being widely used as an agricultural fertilizer, a raw material for chemical synthesis of other...
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This lesson defines the leveling effect in acidic and basic solutions and its role in aqueous and non-aqueous solutions. It is essential to understand the competing nature of various species in a chemical system.
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At room temperature, the chair conformer of cyclohexane undergoes rapid ring flipping between two equivalent chair conformers at a rate of approximately 105 times per second. These two chair conformers are in equilibrium. The rapid ring flipping results in the interconversion of the axial proton to an equatorial proton and an equatorial to the axial proton. Such interconversions are too rapid and cannot be detected on the NMR timescale. Hence, the NMR spectrometer cannot distinguish between the...
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The axial and equatorial protons in cyclohexane can be distinguished by performing a variable-temperature NMR experiment. In this process, except for one proton, the remaining eleven protons are replaced by deuterium. The deuterium substitution avoids the possible peak splitting caused by the spin-spin coupling between the adjacent protons. The remaining proton flips between the axial and equatorial positions.
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Strong Acid and Base Solutions03:22

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A strong acid is a compound that dissociates completely in an aqueous solution and produces a concentration of hydronium ions equal to the initial concentration of acid. For example, 0.20 M hydrobromic acid will dissociate completely in water and produces 0.20 M of hydronium ions and 0.20 M of bromide ions.
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Modeling Flexible Molecules in Solution: A pKa Case Study.

Naomi L Haworth1, Qinrui Wang1, Michelle L Coote1

  • 1ARC Centre of Excellence for Electromaterials Science, Research School of Chemistry, Australian National University , Canberra, ACT 2601, Australia.

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|July 1, 2017
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Summary

Continuum solvation models are effective for large, flexible molecules, but require careful consideration of conformational searching and vibrational frequencies. Entirely solution-phase approaches accurately predict pKa values for amines when using explicit water complexation and a proton exchange scheme.

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Area of Science:

  • Computational Chemistry
  • Physical Chemistry
  • Molecular Modeling

Background:

  • Continuum solvation models are widely used for efficient computation of chemical reactions in solution.
  • Their application to large, flexible, and ionizable molecules presents unique challenges not seen with small, rigid molecules.
  • Key issues include selecting appropriate computational approaches (thermocycle vs. solution-phase), reliably identifying molecular conformations in solution, and mitigating errors from vibrational frequency predictions.

Purpose of the Study:

  • To explore the challenges of applying continuum solvation models to large, flexible, and ionizable molecules.
  • To investigate appropriate methodologies for calculating solution-phase free energies and pKa values for such species.
  • To identify reliable methods for conformational searching and accurate vibrational frequency analysis in solvation models.

Main Methods:

  • Utilized continuum solvation models to calculate pKa values for a diverse set of amine-containing species.
  • Compared thermocycle-based and entirely solution-phase approaches for free energy calculations.
  • Investigated the impact of different energy metrics and vibrational frequency treatments (quasi-harmonic approximation) on conformational stability.
  • Employed explicit water complexation and a proton exchange scheme within the solution-phase approach.

Main Results:

  • Thermocycle approaches are suitable only for systems with minimal structural changes between gas and solution phases and are not recommended for conformational searching.
  • Gas-phase or solution-phase energies, or gas-phase free energies, can lead to inaccuracies in identifying the most stable molecular conformations.
  • Scaling low-energy vibrational modes (quasi-harmonic approximation) is beneficial, but requires careful handling of modes affected by the reaction.
  • Entirely solution-phase methods, with explicit water complexation and a suitable proton exchange scheme, accurately predicted pKa values for the studied amine set.

Conclusions:

  • Entirely solution-phase approaches are more robust for calculating pKa values of flexible, ionizable molecules like amines compared to thermocycle methods.
  • Accurate conformational identification and pKa prediction necessitate careful consideration of solvation effects, vibrational analysis, and computational methodology.
  • The study provides a validated framework for applying continuum solvation models to complex molecular systems.