Class 18: Reactions Driven By Entropy or Stability Flashcards
Apply your knowledge of pKa’s to illustrate how a reaction can go ‘uphill.’
- pKa and Equilibrium Position:
- pKa measures acid strength (proton donating ability)
- Weaker acid (higher pKa) is favored product at equilibrium
- “Uphill” Proton Transfer:
- If pKa(acid) < pKa(conjugate acid)
- Then proton transfer from stronger acid to weaker base is uphill
- Products have higher free energy than reactants
- Example:
- pKa(HCl) = -7, pKa(H2O) = 15.7
- Reaction: HCl + H2O ⇌ Cl- + H3O+
- Products (Cl-, H3O+) higher energy than reactants
- Driving Force:
- Concentration effects can drive uphill proton transfer
- If products rapidly removed, can shift equilibrium
- Relevance:
- Many biochemical proton transfers are thermodynamically uphill
- Enzymes/solvents provide driving forces to overcome barriers
So in essence, by comparing pKa values, you can identify thermodynamically unfavorable but kinetically possible proton transfers that go “uphill” against the equilibrium position.
Understand the concept of kinetic v. thermodynamic products and the conditions that lead to each.
- Kinetic Products:
- Formed faster, under kinetic control
- Result of reaction pathway with lowest activation energy
- May be unstable and undergo further reaction
- Thermodynamic Products:
- Most stable products at equilibrium
- Determined by thermodynamics (free energy minimization)
- Represent global energy minimum
- Determining Product:
- Kinetic product favored under conditions minimizing rearrangement
- Low temperatures, high reaction rates
- Thermodynamic product favored under equilibrium conditions
- High temperatures, longer reaction times
- Kinetic product favored under conditions minimizing rearrangement
- Factors Favoring Kinetic Products:
- Steric effects favoring less hindered transition state
- Reaction solvent stabilizing charge development
- Acid/base catalysts reducing activation barriers
- Factors Favoring Thermodynamic Products:
- Highly exergonic reactions with stable products
- Heating to overcome activation barriers
- Equilibration over long reaction times
So in summary, reaction conditions like temperature, time, catalysts determine if the kinetically or thermodynamically favored product predominates.
Apply your knowledge of nucleophilicity and electrophilicity to new nucleophiles and electrophiles.
- Nucleophilicity Factors:
- Nu: availability (high for anions, free neutral species)
- Polarizability (increases in order: C < N < O)
- Basicity/ability to stabilize positive charge
- Steric factors (more nucleophilic when less hindered)
- Electrophilicity Factors:
- Electropositivity (favors δ+ inductive effects)
- Polarizability (increases in order: F < O < N < C)
- Ability to stabilize developing negative charge
- Steric accessibility of electrophilic site
- Analyzing New Nucleophiles:
- Consider nucleophile HSAB classification (hard/soft)
- Evaluate charge, polarizability, orbital availability
- Hard nucleophiles favor hard electrophiles
- Analyzing New Electrophiles:
- Identify electrophilic site (cation, δ+ atoms)
- Assess polarizability, electropositivity of electrophile
- Predict reactivity trends based on these factors
- Case Studies:
- Phosphines/phosphites as nucleophiles (polarizable, basic)
- Oxocarbenium ions as electrophiles (electron-deficient O)
So in essence, by evaluating factors like charge, polarizability, orbital availability and hard/soft character, you can gauge and compare nucleophilicity and electrophilicity of new species.
Explain the difference between an acid-catalyzed reaction and an acid-promoted reaction.
- Acid-Catalyzed Reaction:
- Acid participates directly in the rate-determining step
- Acid is regenerated in each catalytic cycle
- Rate depends on acid concentration
- Example: Esterification of carboxylic acids
- Acid-Promoted Reaction:
- Acid does not directly participate in rate-determining step
- Acid generates a more reactive species that undergoes reaction
- Rate may be independent of acid concentration after generation of reactive species
- Example: Formation of carbocations from alkyl halides
- Key Distinctions:
- In acid-catalyzed, acid is involved throughout the mechanism
- In acid-promoted, acid activates a precursor then is not directly involved
- Acid-catalyzed has a first-order dependence on acid
- Acid-promoted may have zero-order dependence after precursor formation
- Mechanistic Basis:
- Acid-catalyzed follows classic catalytic cycle with regeneration
- Acid-promoted involves precursor activation then separate rate-limiting step
So in summary, an acid-catalyzed reaction has the acid participating repeatedly in the rate-determining transition state, while an acid-promoted reaction uses the acid to initially generate a more reactive species.
Draw the mechanism for and predict the product of a base-promoted reaction that results in a carboxylate anion.
Mechanism:
Step 1: The base (typically a strong base like hydroxide ion, alkoxide ion, or an amine) deprotonates a carbonyl compound (such as an ester, acid chloride, or anhydride) by abstracting an acidic proton, forming a tetrahedral intermediate.
Step 2: The tetrahedral intermediate collapses, expelling the leaving group (such as an alkoxide ion or a halide ion), resulting in the formation of an acyl carboxylate anion.
Step 3: The acyl carboxylate anion can undergo further reactions, such as proton transfer or nucleophilic addition, depending on the reaction conditions and the specific substrate.
Predicted Product:
The predicted product of this base-promoted reaction will be a carboxylate anion. The specific structure of the carboxylate anion will depend on the starting carbonyl compound.
For example, if the starting compound is an ester (R-CO-OR’), the product will be a carboxylate anion with the general formula R-CO2⁻.
If the starting compound is an acid chloride (R-CO-Cl), the product will be a carboxylate anion with the general formula R-CO2⁻ and a chloride ion (Cl⁻) as the leaving group.
If the starting compound is an anhydride (R-CO-O-CO-R’), the product will be a carboxylate anion with the general formula R-CO2⁻ and a carboxylate anion (⁻O2C-R’) derived from the other carbonyl group.
Draw the mechanism for and predict the product of a reaction between a carboxylic acid and SOCl2.
Mechanism:
Step 1: The carboxylic acid (R-COOH) reacts with thionyl chloride (SOCl₂), forming an electrophilic acylating species (R-CO-Cl) and sulfurous acid (H₂SO₃) as a byproduct.
R-COOH + SOCl₂ → R-CO-Cl + SO₂ + HCl
Step 2: The sulfurous acid (H₂SO₃) is unstable and decomposes into sulfur dioxide (SO₂) and water (H₂O).
H₂SO₃ → SO₂ + H₂O
Step 3: The hydrochloric acid (HCl) formed in the first step acts as a catalyst, protonating the carboxylic acid and making it a better leaving group.
R-COOH + HCl → R-COO⁻ + H₃O⁺
Step 4: The protonated carboxylic acid expels water, forming the acyl chloride (R-CO-Cl) as the final product.
R-COO⁻ + H₃O⁺ → R-CO-Cl + H₂O
Predicted Product:
The predicted product of the reaction between a carboxylic acid (R-COOH) and thionyl chloride (SOCl₂) is an acyl chloride (R-CO-Cl).
The acyl chloride is a highly reactive compound and can undergo further reactions, such as nucleophilic acyl substitution reactions, to form various products like esters, amides, or ketones, depending on the nucleophile used.
Explain why the reaction between a carboxylic acid and SOCl2 is considered “entropy-driven”
- Increase in number of particles:
- The reactants (carboxylic acid and SOCl₂) consist of two molecules.
- The products (acyl chloride, sulfur dioxide, and hydrogen chloride) consist of three molecules.
- Entropy and molecular complexity:
- Entropy is a measure of disorder or randomness in a system.
- An increase in the number of particles or molecular complexity generally leads to an increase in entropy.
- Favorable entropy change:
- The formation of three product molecules from two reactant molecules results in a favorable increase in entropy (ΔS > 0).
- This positive entropy change contributes to a more negative Gibbs free energy change (ΔG = ΔH - TΔS), making the reaction more spontaneous.
- Gaseous products:
- Two of the products (sulfur dioxide and hydrogen chloride) are gaseous molecules.
- The formation of gaseous products further increases the entropy of the system due to their greater molecular disorder and higher translational entropy compared to liquids or solids.
- Entropy-driven reactions:
- Reactions that have a positive entropy change (ΔS > 0) and a negative Gibbs free energy change (ΔG < 0) are said to be “entropy-driven.”
- In this case, the favorable entropy change contributes significantly to the spontaneity of the reaction, even if the enthalpy change (ΔH) is slightly positive or endothermic.
Therefore, the reaction between a carboxylic acid and SOCl₂ is considered “entropy-driven” because the increase in the number of particles and the formation of gaseous products lead to a favorable increase in entropy, which drives the overall reaction forward despite any potential endothermic contributions.
Apply your knowledge of pKa’s to illustrate how a reaction can go ‘uphill.’
If the leaving group is a stronger base than the nucleophile, then the reaction will be uphill
It is more unstable, less resonance, more “uphill” in energy
Understand the concept of kinetic v. thermodynamic products and the conditions that lead to each.
A simple definition is that the kinetic product is the product that is formed faster, and the thermodynamic product is the product that is more stable
Explain the difference between an acid-catalyzed reaction and an acid-promoted reaction.
Acid catalyzed: no acid used up
Acid promoted: acid used in reaction
Explain why the reaction between a carboxylic acid and SOCl2 is considered “entropy-driven”
Entropy driven because the products are far more disordered than the reactants
Extra
Note: to determine reactivity of carbonyls
Induction increases the reactivity of carbonyl
Resonance decreases positive charge so decreases reactivity
Types of reactions:
Acyl Substitutions: nucleophilic addition, elimination
Acid-catalyzed nucleophilic Acyl substitutions: protonate carbonyl, nucleophilic addition, deprotonate nucleophile, protonate leaving group, elimination, deprotonate carbonyl (Esters and Carboxylic acid)
