Chapter 10 Alkyl Halide

S N 2 Mechanism

S N 2 Process 5

6 S N 2 Transition State The transition state of an S N 2 reaction has a planar arrangement of the carbon atom and the remaining three groups Hybridization is sp 2

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Characteristics of the S N 2 Reaction Sensitive to steric effects Methyl halides are most reactive Primary are next most reactive Unhindered secondary halides react under some conditions Tertiary are unreactive by this path No reaction at C=C (vinyl or aryl halides)

10 Reactant and Transition-state Energy Levels Affect Rate Higher reactant energy level (red curve) = faster reaction (smaller  G ‡ ). Higher transition- state energy level (red curve) = slower reaction (larger  G ‡ ).

11 Steric Effects on S N 2 Reactions The carbon atom in (a) bromomethane is readily accessible resulting in a fast S N 2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower S N 2 reactions.

12 Steric Hindrance Raises Transition State Energy Steric effects destabilize transition states Severe steric effects can also destabilize ground state Very hindered

13 Order of Reactivity in S N 2 The more alkyl groups connected to the reacting carbon, the slower the reaction

14 Kinetics of Nucleophilic Substitution Rate = d[CH 3 Br]/dt = k[CH 3 Br][OH -1 ] This reaction is second order: two concentrations appear in the rate law S N 2: Substitution Nucleophilic 2 nd order

15 The Leaving Group

16 Poor Leaving Groups If a group is very basic or very small, it does not undergo nucleophilic substitution.

17 The Solvent Protic solvents (which can donate hydrogen bonds; -OH or –NH) slow S N 2 reactions by associating with reactants (anions). Energy is required to break interactions between reactant and solvent Polar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reaction

S N 1 Mechanism

19 Some Polar Aprotic Solvents 极性的非质子溶剂

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22 Summary of S N 2 Characteristics: Substrate: CH 3 ->1 o >2 o >>3 o (Steric effect) Nucleophile: Strong, basic nucleophiles favor the reaction Leaving Groups: Good leaving groups (weak bases) favor the reaction Solvent: Aprotic solvents favor the reaction; protic reactions slow it down by solvating the nucleophile Stereochemistry: 100% inversion

S N 1 Reactivity: 23

S N 1 Energy Diagram 24

25 Rate-Limiting Step The overall rate of a reaction is controlled by the rate of the slowest step The rate depends on the concentration of the species and the rate constant of the step The step with the largest energy of activation is the rate-limiting or rate-determining step. See Figure 11.9 – the same step is rate- determining in both directions)

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27 Stereochemistry of S N 1 Reaction The planar carbocation intermediate leads to loss of chirality Product is racemic or has some inversion

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29 Effects of Ion Pair Formation

30 Relative Reactivity of Halides:

31 Effect of Solvent

32 Effects of Solvent on Energies Polar solvent stabilizes transition state and intermediate more than reactant and product

Alkyl Halides: Elimination Elimination is an alternative pathway to substitution Elimination is formally the opposite of addition, and generates an alkene It can compete with substitution and decrease yield, especially for S N 1 processes 亲核取代反应 消除反应

Nucleophiles that are Brønsted bases produce elimination Alkyl halides are polarized at the carbon- halide bond, making the carbon electrophilic Nucleophiles will replace the halide

Alkyl halides which have a proton attached to a neighboring β-carbon atom can undergo an elimination reaction to produce an alkene plus a hydrogen halide.

36 Zaitsev’s Rule ( 扎依采夫规则） for EliminationReactions （消除 反应 ） (1875) In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates

37 Mechanisms of Elimination Reactions 消除反应机理 Ingold nomenclature: E – “elimination” E1 (1 st order): X - leaves first to generate a carbocation – a base abstracts a proton from the carbocation E2 (2 nd order): Concerted transfer of a proton to a base and departure of leaving group

E1 mechanism: starts out like S N 1 38

E1 SN1SN1

E1 Mechanism

E2 mechanism: concerted 41

E2 Mechanism

43 Reactivity Summary: S N 1, S N 2, E 1, E 2 1o1o 2o2o 3o3o

reaction conditions the nature of the nucleophile the nature of the alkyl halide. RX E SNSN E1 E2 SN1SN1SN2SN2

45 The Nature of Substitution Substitution requires that a "leaving group", which is also a Lewis base, departs from the reacting molecule. A nucleophile is a reactant that can be expected to participate as a Lewis base in a substitution reaction.

RX 1o1o nucleophiles (e.g. RS, I, CN, NH 3, or Br) in polar aprotic solvents hexamethylphosphoramide (HMPA; [(CH 3 ) 2 N] 3 PO). strong bases HO - or EtO -. bulky base tert-butoxide [(CH 3 ) 3 C–O]. E2 SN2SN2 Increasing the temperature S N 2 higher activation energy due to more bonds being broken. E2 sodium tert-butoxide

RX 2o2o S N 2 and E2 reactions to give a mixture of products. a polar aprotic solvent S N 2 a strong base E2 Increasing the temperature E2 If weakly basic or nonbasic nucleophiles are used in protic solvents, elimination and substitution may occur by the SN1 and E1 mechanisms to give mixtures.

RX 3o3o S N 1( 极性溶剂） and E1 （强碱） reactions