Concept 04 / 06Haloalkanes and Haloarenes
Nucleophilic Substitution I: The SN2 Mechanism
Nucleophilic substitution in haloalkanes, the bimolecular SN2 mechanism with second-order kinetics, backside attack and transition state, Walden inversion of configuration, effect of the structure of the alkyl group (steric hindrance), leaving group ability and nucleophile strength, and ambident nucleophiles (KCN versus AgCN, KNO2 versus AgNO2).
The polar C-X bond makes the carbon electrophilic, so haloalkanes react with nucleophiles, which replace the halide (the leaving group): . Examples: aqueous KOH gives alcohols; NaOR gives ethers (Williamson); gives amines; KCN gives nitriles; gives alkanes; gives esters.
SN2 (substitution, nucleophilic, bimolecular). Example: , with rate (second order).
Mechanism (see figure): a single concerted step. The nucleophile attacks the carbon from the side opposite the leaving group (backside attack), because the halogen's electron cloud blocks the front. In the transition state, carbon is partially bonded to both the incoming and the outgoing groups, and its other three groups lie in a plane. As the leaving group departs, the three groups flip over like an umbrella in a strong wind.
Stereochemistry: complete inversion of configuration (Walden inversion). An (R)- or (S)-chiral haloalkane gives the product with inverted configuration; for example (–)-2-bromooctane with hydroxide gives (+)-octan-2-ol.
Structure of alkyl group: bulky groups around the reacting carbon hinder the approach of the nucleophile (steric hindrance). Reactivity: . Tertiary halides hardly react by SN2.
Leaving group: weaker bases leave more easily: , matching C-X bond strengths.
Nucleophile and solvent: strong, negatively charged nucleophiles and polar aprotic solvents (acetone, DMSO, DMF) favour SN2.
Ambident nucleophiles. Nucleophiles with two possible attacking atoms give different products depending on conditions:
KCN (ionic; the more nucleophilic carbon attacks) gives alkyl cyanides (nitriles), R-CN; AgCN (largely covalent Ag-C bond; nitrogen lone pair attacks) gives alkyl isocyanides, R-NC.
(O attacks) gives alkyl nitrites, R-O-N=O; (N attacks) gives nitroalkanes, .
Key Takeaways:
- SN2: one step, second order, backside attack, inversion.
- Reactivity: (steric).
- Leaving ability: .
- KCN gives nitriles; AgCN gives isocyanides. gives nitrites; gives nitroalkanes.
- Pitfall: inversion in SN2 means the spatial arrangement flips; the R/S label may or may not change depending on priorities.
Brain-Teaser 1: Arrange in order of SN2 reactivity: 1-bromopentane, 2-bromopentane, 2-bromo-2-methylbutane.
Solution: 1-bromopentane () > 2-bromopentane () > 2-bromo-2-methylbutane (). Crowding around the carbon increases from primary to tertiary, hindering backside attack.
Brain-Teaser 2: Bromoethane gives mainly ethyl cyanide with alcoholic KCN but ethyl isocyanide with AgCN. Explain.
Solution: KCN is ionic, so the free attacks through the carbon atom (more nucleophilic, forms the stronger C-C bond): . In AgCN, carbon is tied up in a covalent Ag-C bond, so the nitrogen lone pair attacks: .
Brain-Teaser 3: If the concentration of both and is doubled, how does the rate of the SN2 reaction change? And if only is doubled for an SN1 reaction of ?
Solution: SN2: rate , so it becomes times faster. SN1: rate only, so doubling has no effect.