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Related Concept Videos

Acidity and Basicity of Alcohols and Phenols02:36

Acidity and Basicity of Alcohols and Phenols

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Like water, alcohols are weak acids and bases. This is attributed to the polarization of the O–H bond making the hydrogen partially positive. Moreover, the electron pairs on the oxygen atom of alcohol make it both basic and nucleophilic. Protonation of an alcohol converts hydroxide, a poor leaving group, into water—a good one. The two acid–base equilibria corresponding to ethanol are depicted below.
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Acidity and Basicity of Carboxylic Acid Derivatives01:25

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Carboxylic acids are the strongest among organic acids, as they readily lose the hydroxyl proton to form a resonance-stabilized carboxylate ion. In comparison, the acid derivatives lack acidic hydrogens directly attached to a functional group. In these compounds, the acidic nature arises from their ability to lose α hydrogens, making them weakly acidic.
The relative acidic strength of the derivatives can be explained based on the extent of resonance stabilization of the conjugate base. The...
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Titration of a Polyprotic Acid02:08

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A polyprotic acid contains more than one ionizable hydrogen and undergoes a stepwise ionization process.  If the acid dissociation constants of the ionizable protons differ sufficiently from each other, then the titration curve for such polyprotic acid generates a distinct equivalence point for each of its ionizable hydrogens. Therefore, titration of a diprotic acid results in the formation of two equivalence points, whereas the titration of a triprotic acid results in the formation of three...
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Acid and Bases: Ka, pKa, and Relative Strengths02:35

Acid and Bases: Ka, pKa, and Relative Strengths

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This lesson delves into a critical aspect of the relative strengths of acids and bases. The strength of an acid is evaluated by the acid dissociation into its conjugate base and a hydronium ion in water. The complete dissociation of a strong acid is confirmed with a very high concentration of hydronium ions. As a result, an incomplete dissociation process affirms a weak acid. Therefore, the equilibrium is in the forward direction for strong acids and backward for weak acids in these reactions.
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Titration of Polyprotic Acids with a Strong Base01:23

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Titration of a polyprotic acid, which contains multiple ionizable protons, involves distinct dissociation steps, each with its own dissociation constant (Ka). Each successive Ka is weaker than the previous one. In the titration of a polyprotic acid like sulfurous acid with a strong base such as sodium hydroxide, the base first neutralizes the initial ionizable proton, forming an intermediate species (e.g., hydrogen sulfite ions). This step's titration curve resembles that of a weak...
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Acidity of Carboxylic Acids01:21

Acidity of Carboxylic Acids

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Carboxylic acids are the strongest organic acids. However, their acidic strength is much less than mineral acids like HCl. Carboxylic acids ionize in water and readily lose the hydroxyl proton to form a resonance-stabilized carboxylate ion.
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Determination of the Gas-phase Acidities of Oligopeptides
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pK50─A Rigorous Indicator of Individual Functional Group Acidity/Basicity in Multiprotic Compounds.

Robert Fraczkiewicz1, Marvin Waldman1

  • 1Simulations Plus, Inc., 42505 10th Street West, Lancaster, California 93534, United States.

Journal of Chemical Information and Modeling
|April 27, 2023
PubMed
Summary
This summary is machine-generated.

Apparent pKa is insufficient for multiprotic compounds in drug discovery. The new pK50 measure, derived from statistical thermodynamics, accurately tracks acidity/basicity and avoids costly errors in lead optimization.

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Area of Science:

  • Chemical Thermodynamics
  • Medicinal Chemistry
  • Analytical Chemistry

Background:

  • Apparent pKa from standard titrations is often inadequate for multiprotic compounds.
  • This limitation poses challenges in pharmaceutical lead optimization.
  • Misleading acidity/basicity measures can lead to significant research and development costs.

Purpose of the Study:

  • To introduce pK50 as a superior measure of acidity/basicity for multiprotic organic functional groups.
  • To demonstrate the limitations of apparent pKa in pharmaceutical research.
  • To provide a more accurate method for evaluating compound properties during drug development.

Main Methods:

  • Statistical thermodynamics treatment of multiprotic ionization.
  • Development and application of the pK50 metric.
  • Specialized Nuclear Magnetic Resonance (NMR) titration experiments for direct pK50 measurement.

Main Results:

  • Apparent pKa is an insufficient metric for multiprotic systems.
  • pK50 provides a more accurate representation of a functional group's true acidity/basicity.
  • pK50 effectively tracks changes in acidity/basicity across congeneric series.
  • pK50 converges to the standard ionization constant for monoprotic systems.

Conclusions:

  • The proposed pK50 measure offers a more reliable assessment of acidity/basicity in multiprotic compounds.
  • Implementing pK50 can prevent costly mistakes in pharmaceutical lead optimization.
  • Specialized NMR titrations enable direct measurement of pK50, enhancing its practical utility.