Class 22: Relative Rates in Substitution Reactions Part I Flashcards
Analyze relative rate data and propose reasoning for how the steric of the alkyl halide influence substitution mechanisms.
- Compare rates for SN1 vs SN2 with different alkyl halides
- Methyl halides undergo SN2 much faster than SN1
- Primary alkyl substrates favor SN2 mechanism
- Little steric hindrance for backside nucleophilic attack
- Tertiary alkyl halides undergo SN1 much faster than SN2
- High steric strain disfavors backside SN2 attack
- Ionization to planar carbocation is less hindered
- Secondary alkyl halides have rates in between
- Can undergo mixture of SN1 and SN2 pathways
- Steric factors impact:
- Nucleophile’s ability to achieve backside trajectory
- Degree of orbital overlap for SN2
- Stability of formed carbocation intermediate
- Bulky groups destabilize SN2 transition states
- But can stabilize SN1 carbocation intermediates
- Generally: SN2 is favored for unstrained substrates
SN1 is favored for sterically congested substrates
So analyzing rate trends for different alkyl substrates provides insight into the preferred SN1 or SN2 pathway based on steric effects.
Propose how, in borderline cases where two mechanisms are possible, reactant concentrations influence which is dominant.
- For some substrates, both SN1 and SN2 pathways are accessible
- E.g. Neopentyl substrates, benzylic systems
- Mechanism depends on reactant concentrations and solvent
- SN1: Unimolecular rate = k[Substrate]
- SN2: Bimolecular rate = k[Substrate][Nucleophile]
- At high substrate concentration, SN1 favored
- Rate depends more strongly on [Substrate]
- At low substrate concentration, SN2 favored
- Rate depends on both [Substrate] and [Nucleophile]
- Higher [Nucleophile] drives bimolecular pathway
- In polar protic solvents, SN1 is favored
- Solvents can stabilize carbocation intermediates
- In polar aprotic solvents, SN2 is favored
- Solvents facilitate nucleophiles, but not carbocations
- Temperature effects also differentiate mechanisms
- SN1 has higher Ea, so favored at higher temperatures
So concentrations, along with solvent and temperature, can be used to bias the reaction conditions toward either SN1 or SN2 mechanisms for borderline substrates.
Analyze relative rate data and propose how the pKa of the conjugate acid of the leaving group affects the rate of a substitution reaction.
- Lower pKa values mean better leaving groups
- More stable conjugate base
- More favorable leaving group departure
- For SN1 reactions:
- Rate depends on ionization to carbocation
- Lower pKa facilitates this rate-limiting ionization
- So reactions with good leaving groups (low pKa) are faster
- For SN2 reactions:
- Lower pKa leaving groups give faster rates
- Bond to leaving group is weaker and breaks more easily
- Backside attack by nucleophile is facilitated
- Relative rate data shows:
- Cl > Br > I (pKa of conjugate acids decrease)
- Tosylate > Halides (Tosylate more stable anion)
- Alcohols < Halides (Alcohols are poor leaving groups)
- Exceptions when steric factors dominate
- E.g. Tertiary substrates, where SN2 is very slow
- Curve-crossing behavior possible between good/poor leaving groups
So in general, a lower pKa for the leaving group conjugate acid correlates with a faster substitution rate, especially for SN2 reactions.
Analyze relative rate data and propose how nucleophilic strength affects the rate and outcome of a substitution reaction.
- Stronger nucleophiles have higher reaction rates
- Nucleophilicity controlled by basicity, polarizability, sterics
- For SN2 reactions:
- Rate ∝ [Nucleophile]
- Stronger Nu: causes faster backside attack
- E.g. I- > Br- > Cl- > F- > H2O
- For SN1 reactions:
- Nucleophile only involved in second step
- So Nu strength has less effect on rate
- Stronger Nu favors SN2 over SN1
- Bimolecular pathway outcompetes unimolecular
- Exceptions with steric hindrance
- Weak Nu may be required for backside approach
- Nucleophilicity competition experiments
- Determine relative Nu strengths
- Products show which Nu is more reactive
- Stronger Nu can lead to different product
- By reacting at different site than weaker Nu
So in summary, stronger nucleophiles increase SN2 rates dramatically but have less effect on SN1. They can also alter product outcomes based on their higher reactivity.
Analyze relative rate data and propose how the solvent affects the rate and mechanism of substitution reactions.
- Protic solvents favor SN1 mechanism
- Can stabilize carbocation intermediates via solvation
- E.g. Rates are higher in alcoholic solvents
- Aprotic polar solvents favor SN2 mechanism
- Better solvation and nucleophilicity of entering group
- But do not stabilize carbocations well
- E.g. Rates higher in solvents like DMSO, acetone
- Ionic strength effects
- High salt concentrations disfavor SN2 due to ion pair formation
- Separate ion pair reactants needed for SN2
- Solvent hydrogen bonding
- Protic solvents H-bond to Nu, decreasing its reactivity
- Aprotic solvents allow “naked” high energy nucleophiles
- Relative rate data:
- SN2 is faster in polar aprotic than protic solvents
- SN1 is faster in protic, polar solvents
- Steric and substrate effects can override solvent influences
So in essence, protic solvents facilitate SN1 while aprotic solvents facilitate the SN2 pathway based on solvation abilities, leading to dramatic rate differences.
Draw transition state structures and reaction coordinate diagrams to support your proposals.
SN2 Transition State:
* Backside nucleophilic attack
* Partial bonds to both nucleophile and leaving group
* Trigonal bipyramidal geometry
* Steric hindrance disfavors this geometry
SN1 Transition State:
* Ionization to carbocation
* Partial C-LG bond break
* Flattened/planar geometry
SN2 Reaction Coordinate:
* Reactants
* SN2 Transition State (‡)
* Products
* Steep barrier for primary substrates
* Higher barrier for tertiary substrates
SN1 Reaction Coordinate:
* Reactants
* Ionization TS (‡)
* Carbocation Intermediate
* Second TS for Nu addition (‡)
* Products
Solvent Effects:
* Protic solvents stabilize carbocation (lower energy)
* Aprotic solvents destabilize carbocation (higher energy)
* SN2 barrier lowered in aprotic solvents
Nucleophile Strength:
* Stronger Nu has lower SN2 barrier
* Weaker Nu has higher barrier
Leaving Group Ability:
* Good LG (low pKa) has lower SN1/SN2 barriers
* Poor LG has higher barriers
The structures and diagrams illustrate the effects of sterics, solvents, nucleophiles, and leaving groups on the transition state energies and overall energy profiles.
Make predictions for the outcome of substitution reactions if given an alkyl halide, nucleophile and solvent.
- Identify substrate (1°, 2°, 3° alkyl halide)
- Consider sterics around substitution site
- Analyze leaving group ability (halide, tosylate, etc.)
- Evaluate nucleophile strength (hard/soft, charge, polarizability)
- Consider solvent effects (protic, aprotic, polar, non-polar)
Then predict:
* SN1 or SN2 mechanism based on:
- Substrate (3° favors SN1, 1° favors SN2)
- Solvent (protic favors SN1, aprotic favors SN2)
* If SN1:
- Racemate or racemic mixture likely
- Carbocation rearrangements possible
* If SN2:
- Inversion of configuration
- Stronger Nu may lead to different regiochemistry
- Predict major and minor products
- Including regioisomers and stereoisomers
- Identify potential side reactions
- E.g. E2 elimination, rearrangements
- Note any expected stereochemistry
- Retention or inversion
- Racemic vs optically active
So in summary, analyze all reactant properties to predict if SN1 or SN2 is favored, then use that to predict the likely product(s) and stereochemistry.
Analyze relative rate data and propose reasoning for how the sterics and hyperconjugation of the alkyl halide influence substitution mechanisms.
Steric Bulk/hindrance: if it is to big with lots of carbon groups attached to the carbocation, it is hard for the nucleophile to attack
Hyperconjugation: AKA weak resonance due to the partial overlap between the empty P on the C+ and the sigma bond on the neighboring carbon
Propose how, in borderline cases where two mechanisms are possible, reactant concentrations influence which is dominant.
With a higher concentration of the strong nucleophile, it will go through SN2 more than SN1 but with a weak electrophile then it will be more SN1
Analyze relative rate data and propose how the pKa of the conjugate acid of the leaving group affects the rate of a substitution reaction.
Weakest base is the best leaving group because it is happen with a negative charge
Size makes it a better leaving group because it is more able to handle the negative charge
Analyze relative rate data and propose how nucleophilic strength affects the rate and outcome of a substitution reaction.
The nucleophile matters the most for SN2 reactions: it must be a strong nucleophile like OH
Want small molecules to easily fit in
Want larger atoms to bind – ex. S better nucleophile vs O because of better overlap
ONLY IN SAME ROW COMPARISON
