Class 23: Relative Rates in Substitution Reactions Part II

Question 1

Analyze relative rate data and propose reasoning for how the steric of the alkyl halide influence substitution mechanisms.

Answer 1

• Relative rate data compares the rates of different reactions under the same conditions
• It provides insights into the reaction mechanism and factors influencing it
• Steric effects refer to the spatial arrangement and bulkiness of substituents
• Bulky alkyl groups hinder approach of nucleophile in SN2 reactions
• This disfavors the SN2 mechanism for sterically hindered alkyl halides
• Less hindered primary alkyl halides favor SN2 mechanism
• More hindered secondary alkyl halides lean towards SN1 mechanism
• Tertiary alkyl halides strongly prefer SN1 mechanism due to steric crowding
• Steric effects influence the stability of transition states and reaction intermediates
• This impacts the preferred substitution pathway (SN1 vs SN2)

Question 2

Propose how, in borderline cases where two mechanisms are possible, reactant concentrations influence which is dominant.

Answer 2

• In some cases, both SN1 and SN2 mechanisms are kinetically accessible
• The dominant mechanism depends on the relative rates of the two pathways
• Higher nucleophile concentration favors the SN2 pathway
• More nucleophile available to react via one-step SN2
• Higher alkyl halide concentration favors the SN1 pathway
• Increased formation of carbocation intermediates for SN1
• Lower nucleophile concentration disfavors SN2
• Limited nucleophile availability hinders bimolecular SN2
• Lower alkyl halide concentration disfavors SN1
• Reduces formation of carbocation intermediates for unimolecular SN1
• For a given substrate, adjusting nucleophile vs. alkyl halide ratio shifts equilibrium
• Excess nucleophile pushes equilibrium towards SN2
• Excess alkyl halide pushes equilibrium towards SN1

Question 3

Analyze relative rate data and propose how the pKa of the conjugate acid of the leaving group affects the rate of a substitution reaction.

Answer 3

• Relative rate data compares rates of reactions with different leaving groups
• It provides insight into how leaving group ability affects the rate
• Leaving group ability is related to its pKa
• Lower pKa means a weaker conjugate acid and better leaving group
• For SN1 reactions:
• A good leaving group (low pKa) facilitates carbocation formation
• This increases the rate of the slow, rate-determining step
• For SN2 reactions:
• A good leaving group (low pKa) stabilizes the transition state
• By dispersing the buildup of negative charge
• This lowers the activation energy and increases the rate
• Poorer leaving groups (higher pKa) have the opposite effects
• Hindering carbocation formation in SN1
• Destabilizing the SN2 transition state
• Relative rate data shows a trend of faster rates with better (lower pKa) leaving groups
• For both SN1 and SN2 pathways

Question 4

Analyze relative rate data and propose how nucleophilic strength affects the rate and outcome of a substitution reaction.

Answer 4

• Stronger nucleophiles have higher nucleophilicity
• Greater tendency to donate electrons and form new bonds
• For SN2 reactions:
• Stronger nucleophiles react faster
• Their higher reactivity lowers the activation energy barrier
• Rate of SN2 is directly proportional to nucleophilic strength
• For SN1 reactions:
• Nucleophilic strength has little effect on the slow first step
• But stronger nucleophiles increase the rate of the second step
• Weaker nucleophiles react slower in SN2 reactions
• May favor an SN1 pathway instead if possible
• Stronger nucleophiles sometimes give different product ratios
• By altering the relative rates of competing pathways (SN1 vs SN2)
• Extremely strong nucleophiles can lead to elimination instead
• Especially with strained or tertiary alkyl substrates
• Relative rate data shows a clear trend of faster rates with stronger nucleophiles
• For SN2 reactions and the second step of SN1

Question 5

Analyze relative rate data and propose how the solvent affects the rate and mechanism of substitution reactions.

Answer 5

• Protic solvents (like water, alcohols) favor SN2 mechanism
• Can solvate nucleophile and leaving group simultaneously
• Stabilizing the SN2 transition state and increasing rate
• Aprotic polar solvents (like acetone, DMSO) favor SN1 mechanism
• Cannot efficiently solvate nucleophile and leaving group together
• But can solvate and stabilize carbocation intermediates
• Non-polar solvents disfavor both SN1 and SN2
• Cannot solvate charged species like nucleophiles or carbocations
• Rates are very slow in non-polar media
• Relative rate data shows:
• Fastest SN2 rates in protic solvents
• Fastest SN1 rates in polar aprotic solvents
• Very slow rates in non-polar solvents
• Solvent effects are most pronounced for ionic/charged nucleophiles
• Which require greater solvation
• Neutral nucleophiles are less affected by solvent polarity
• Solvent may alter the product ratios by changing the dominant mechanism

Question 6

Draw transition state structures and reaction coordinate diagrams to support your proposals.

Answer 6

For the transition state structures:

SN2 Transition State:
- Describes a coplanar arrangement of the nucleophile, electrophilic carbon, and leaving group
- Partial bonding between the nucleophile and carbon, along with partial C-LG bond breaking
- Significant charge buildup and thus stabilization by polar protic solvents is favorable

SN1 Transition State:
- Describes the C-LG bond breaking to form a planar carbocation intermediate
- Stabilized by solvation of the carbocation in polar aprotic solvents
- No significant charge buildup on the nucleophile

Reaction coordinate diagrams would illustrate the relative energy levels and transition states:

SN2 Diagram:
- A single transition state barrier between reactants and products
- Height of the barrier depends on nucleophilic strength, leaving group ability, and solvent effects

SN1 Diagram:
- Two distinct transition states, one for each step
- First barrier is carbocation formation, influenced by leaving group and solvent
- Second barrier is nucleophilic attack, influenced by nucleophile and solvent

The diagrams would visually represent how factors like sterics, nucleophilicity, leaving groups, and solvents impact the relative barrier heights and preferred mechanism.

Question 7

Make predictions for the outcome of substitution reactions if given an alkyl halide, nucleophile and solvent.

Answer 7

• Analyze the steric hindrance around the electrophilic carbon
• Primary alkyl halides prefer SN2
• Secondary alkyl halides can go SN2 or SN1
• Tertiary alkyl halides strongly favor SN1
• Consider the nucleophilic strength
• Strong nucleophiles favor SN2 if accessible
• Weak nucleophiles may only proceed via SN1
• Evaluate the leaving group ability (pKa of conjugate acid)
• Good leaving groups (low pKa) facilitate both SN1 and SN2
• Poor leaving groups disfavor both mechanisms
• Identify the solvent properties
• Protic solvents facilitate SN2
• Polar aprotic solvents facilitate SN1
• Non-polar solvents severely disfavor both
• Predict the dominant mechanism based on these factors
• SN2 if unhindered, strong nucleophile, good LG, protic solvent
• SN1 if hindered, weak nucleophile, good LG, polar aprotic
• For SN2 reactions, expect inversion of configuration
• For SN1 reactions, expect racemization if chiral center present
• Cross-over or intermolecular processes are possible for SN1
• Very hindered substrates may undergo elimination instead

Question 8

Explain the substitution reactions observed in biological systems.

Answer 8

• Many biochemical processes involve SN2 reactions
• Due to prevalence of strong biological nucleophiles like enzymes
• Example: Serine proteases cleave peptide bonds via SN2
• Active site Ser acts as nucleophile, attacking planar carbonyl
• Generates tetrahedral intermediate before expelling amine leaving group
• DNA methylation is an SN2 reaction
• Methyl group from S-adenosylmethionine transfers to nucleophilic N7 of guanine
• Some glycosylation reactions proceed via SN2
• With enzyme-activated nucleophilic sugars substituting alcohols
• Certain metabolic pathways use SN2 at carbocations
• Example: HMG-CoA reductase adds hydride to a carbocation intermediate
• SN1 reactions are rare but possible in some biosynthetic pathways
• Requires highly stabilized carbocations (e.g. non-classical cations)
• Enzyme active sites create microenvironments to facilitate mechanisms
• Binding substrates in reactive conformations
• Positioning catalytic residues as nucleophiles/bases
• Excluding water and controlling local solvent environment