Nucleophilic Substitution and Reaction Mechanisms

Nucleophilic Substitution

SN1 and SN2 Reactions

• Two major types of nucleophilic substitution reactions:
  • SN1 Reaction (Unimolecular Nucleophilic Substitution):
  • Involves two steps: Formation of a carbocation intermediate followed by nucleophilic attack.
  • Single rate-determining step (the slowest step is carbocation formation).
  • Reaction rate depends solely on the concentration of the substrate.
  • General formula: ext{Rate} = k[ ext{RX}]
  • SN2 Reaction (Bimolecular Nucleophilic Substitution):
  • Involves a simultaneous nucleophilic attack and leaving group departure in one transition state.
  • Reaction rate depends on the concentrations of both the substrate and the nucleophile.
  • General formula: ext{Rate} = k[ ext{R-X}] [ ext{Nu}]

Key Terms

• Nucleophile (Nu): A species that donates an electron pair to form a chemical bond.
• Leaving Group: An atom or group that departs from the substrate, facilitating the substitution.
• Transition State: A temporary state during the reaction where old bonds are partially broken and new bonds are partially formed.

Transition State Description

• In SN1, the formation of a carbocation is characterized by a transition state where the leaving group is partially detached.
• In SN2, the transition state has a pentacoordinate carbon where both the nucleophile and leaving group are temporarily attached.

Reactivity of Alkyl Halides

• Objective: To relate substrate structure to its reactivity.
• Series of experiments planned will test different alkyl halides using two reagents:
  • Sodium iodide in acetone (an SN2 reaction).
  • Silver nitrate in ethanol (an SN1 reaction).

Experiment Overview (Experiment 19, Pavia)

• Reactivity testing will involve a panel of ten different alkyl halide substrates.
• Predictions regarding the reactive structure of the alkyl halides will be made based on their classification (primary, secondary, tertiary).
  • Start reactions at room temperature and apply heat if there is no immediate precipitate.

List of Alkyl Halides for Testing

1. 1-chlorobutane
2. 1-bromobutane
3. 2-chlorobutane
4. 2-bromobutane
5. 2-chloro-2-methylpropane
6. Crotyl chloride
7. Benzyl chloride
8. Bromobenzene
9. Bromocyclohexane
10. Bromocyclopentane

Sodium Iodide in Acetone (SN2 Reaction)

• Reaction Mechanics:
  • Example: R-Cl + NaI
    ightarrow R-I + NaCl
  • 1° alkyl bromides lead to the formation of precipitate (sodium bromide) in approximately 3 minutes at RT.
  • 1° and 2° alkyl chlorides require heating to 50°C for complete reaction.
  • SN2 Mechanism is characterized by:
  • Reactivity order: primary > secondary > tertiary.

Silver Nitrate in Ethanol (SN1 Reaction)

• Reaction Formulation:
  • Example: R-X + EtOH + Ag^+
    ightarrow AgX + ROEt + H^+
• Predominantly favorable for tertiary or secondary halides.

Preparation of Alkyl Halides from Alcohols

• Overview of Modified Experiment 20A/20B:
  • 20A: SN2 reaction of 1-butanol
  • 20B: SN1 reaction of 2-methyl-2-butanol
• Methodology:
  • Modified to microscale with only one nucleophile to simplify the experiments.

SN2 Reaction of 1-Butanol

• Experiment Parts:
  1. Preparation of reagents (solvent-nucleophile).
  2. Reflux.
  3. Purification or "Work Up".
  4. Drying.
  5. Analysis.

Reflux Process

• Overview and Protocol:
  • The process of heating a reaction mixture wherein vapor is condensed back into the liquid phase to prevent loss of volatile components.
  • Example: Video demonstrates the stark difference between boiling water in an open container vs. using a closed reflux apparatus.

SN2 Reaction Mechanism for 1-Butanol with Ammonium Bromide and Strong Acid

• Detailed Steps:
  1. Combine primary alcohol with a stock nucleophile-solvent medium (NH4Br/H2SO4).
  2. Reflux for 75 minutes, cool.
  3. Perform microscale extraction and dry with sodium sulfate.
  4. Record IR spectrum of both starting material and product.

Analysis of IR Spectra

• Starting Material (1-butanol): Identify O-H stretching: 3300-3500 ext{ cm}^{-1}
• Product (1-bromobutane): Observe disappearance of O-H peak and presence of C-Br peak at 670 ext{ cm}^{-1} .

SN1 Reaction of 2-methyl-2-butanol

• Experiment Steps:
  1. Prepare reagents and nucleophile medium.
  2. Establish a reaction at RT with 3 ml of the nucleophile medium and 0.5 ml of 2-methyl-2-butanol.
  3. Purification involves removing the aqueous layer and drying the product.

SN1 Mechanism

• The reaction proceeds as follows:
  1. Formation of carbocation after loss of the leaving group (OH) from the alcohol.
  2. Nucleophilic attack by Br occurs to form the product.

Experimental Setup for SN1

• Mix reaction components and shake to allow dissolution and reaction. Heat if solid present. Separate layers post reaction.

Key Mechanics in SN2 Reactions

• Steric Accessibility: SN2 reactions favor less hindered (less substituted) alkyl halides due to steric effects.
• Kinetics: Characterized as bimolecular; dependent on both nucleophile and substrate.

Stereochemistry in SN2 Reactions

• Reactants form products with inversion of configuration due to backside attack.

Nucleophilic Strength and Leaving Groups

• Guidelines:
  • Stronger bases generally serve as better nucleophiles.
  • Weak leaving groups hinder nucleophilic substitutions.
  • Good leaving groups exhibit stability after departure (e.g., ext{I}^- ext{, } ext{Br}^- ext{, } ext{Cl}^- ).

Solvent Effects on SN2 and SN1

• Protic solvents hinder SN2 due to interactions with nucleophiles, costly in energy to break these interactions.
• Polar aprotic solvents are favorable for SN2 reactions as they do not stabilize nucleophiles or substrates hinderingly.

Summary of Reaction Types & Mechanisms

Conclusion

• Understanding the structural implications of substrates in nucleophilic substitution reactions is central to predicting the course of these chemical processes. The exchange of functional groups via nucleophiles and careful choice of solvents dictate the pathway taken significantly in synthesis.