Chapter 7-2. Reactions of Alkyl Halides: Nucleophilic Substitutions Based on McMurry’s Organic Chemistry, 6 th edition

2 Polarity and Reactivity Halogens are more electronegative than C. Carbon-halogen bond is polar, so carbon has partial positive charge. Carbon can be attacked by a nucleophile. Halogen can leave with the electron pair.

3 Alkyl Halides React with Nucleophiles and Bases Alkyl halides are polarized at the carbon- halide bond, making the carbon electrophilic Nucleophiles will replace the halide in C-X bonds of many alkyl halides (reaction as Lewis base)

4 Alkyl Halides React with Nucleophiles and Bases Nucleophiles that are Brønsted bases produce elimination

5 Substitution vs. Elimination

6 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.

7 S N 2 Mechanism One step: bond forming and bond breaking at same time. “concerted” process Bimolecular nucleophilic substitution. Rate = k [HO - ] [CH 3 Br], first order in each reactant second order overall Inversion of configuration.

8 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

9 S N 1 Mechanism(1) Formation of carbocation (slow) =>

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11 S N 1 Mechanism (2) Nucleophilic attack Loss of H + (if needed)

12 S N 1 Energy Diagram Forming the carbocation is endothermic Carbocation intermediate is in an energy well.

13 S N 1 Mechanism Unimolecular nucleophilic substitution. Two step reaction with carbocation intermediate. Rate = k [RX] first order in the alkyl halide zero order in the nucleophile. Racemization occurs.

14 Factors affecting the rates of S N Reactions Concentration Nature of the alkyl group Nature of the nucleophile Nature of the leaving group Nature of the solvent

15 Structure of Substrate Relative rates for S N 2: CH 3 X > 1° > 2° >> 3° Tertiary halides do not react via the S N 2 mechanism, due to steric hindrance.

16 S N 2: Reactivity of Substrate Carbon must be partially positive. Must have a good leaving group Carbon must not be sterically hindered.

17 The Nucleophile Neutral or negatively charged Lewis base Reaction increases coordination (adds a new bond) at the nucleophile Neutral nucleophile acquires positive charge Anionic nucleophile becomes neutral

18 For example:

19 Relative Reactivity of Nucleophiles Depends on reaction and conditions More basic nucleophiles react faster Better nucleophiles are lower in a column of the periodic table Anions are usually more reactive than neutrals

20 Nucleophilic Strength Stronger nucleophiles react faster in S N 2. Strong bases are strong nucleophiles, but not all strong nucleophiles are basic.

21 Bulky Nucleophiles Sterically hindered for attack on carbon, so weaker nucleophiles.

22 Trends in Nuc. Strength Decreases left to right on Periodic Table. More electronegative atoms less likely to form new bond: OH - > F - NH 3 > H 2 O Increases down Periodic Table, as size and polarizability increase: I - > Br - > Cl - Of a conjugate acid-base pair, the base is stronger: OH - > H 2 O, NH 2 - > NH 3

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25 Polarizability Effect

26 The Leaving Group A good leaving group reduces the energy of activation of a reaction Stable anions that are weak bases (conjugate bases of strong acids) are usually excellent leaving groups Stronger bases (conjugate bases of weaker acids) are usually poorer leaving groups

27 Leaving Group Ability Electron-withdrawing Stable once it has left (not a strong base) Polarizable to stabilize the transition state.

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

30 Solvent Effects (1) Polar protic solvents (O-H or N-H) reduce the strength of the nucleophile. Hydrogen bonds must be broken before nucleophile can attack the carbon.

31 Solvent Effects (2) Polar aprotic solvents (no O-H or N-H) do not form hydrogen bonds with nucleophile Examples:

32 Rates of S N 1 Reactions 3° > 2° > 1° >> CH 3 X Order follows stability of carbocations (opposite to S N 2) More stable ion requires less energy to form Better leaving group, faster reaction (like S N 2) Polar protic solvent best: It solvates ions strongly with hydrogen bonding.

33 The Discovery of the Walden Inversion In 1896, Paul Walden showed that (-)-malic acid could be converted to (+)-malic acid by a series of chemical steps with achiral reagents This established that optical rotation was directly related to chirality and that it changes with chemical alteration Reaction of (-)-malic acid with PCl 5 gives (+)- chlorosuccinic acid Further reaction with wet silver oxide gives (+)-malic acid The reaction series starting with (+) malic acid gives (-) acid

34 Stereochemistry of S N 2 Walden inversion SN2: Substitution Nucleophilic 2nd order

35 S N 2 Energy Diagram One-step reaction. Transition state is highest in energy.

36 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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38 Stereochemistry of S N 1 Racemization: inversion and retention =>

39 Two Stereochemical Modes of Substitution Substitution with inversion: Substitution with retention:

40 The Walden Inversion (1896)

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42 Significance of the Walden Inversion The reactions involve substitution at the chiral center Therefore, nucleophilic substitution can invert the configuration at a chirality center

43 Stereochemistry of Nucleophilic Substitution A more rigorous Walden cycle using 1-phenyl-2- propanol (Kenyon and Phillips, 1929) Only the second and fifth steps are reactions at carbon Inversion must occur in the substitution step

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45 Hughes’ Proof of Inversion React (S)-2-iodo-octane with radioactive iodide Observe that racemization (loss of optical activity) of mixture is twice as fast as incorporation of label Racemization in one reaction step would occur at same rate as incorporation

46 Hughes’ Proof of Inversion

47 Rearrangements Carbocations can rearrange to form a more stable carbocation. Hydride shift: H - on adjacent carbon bonds with C +. Methyl shift: CH 3 - moves from adjacent carbon if no H’s are available.

48 Hydride Shift

49 Methyl Shift

50 S N 2 or S N 1? Primary or methyl Strong nucleophile Polar aprotic solvent Rate = k[halide][Nuc] Inversion at chiral carbon No rearrangements Tertiary Weak nucleophile (may also be solvent) Polar protic solvent, silver salts Rate = k[halide] Racemization of optically active compound Rearranged products

51 Substitution Mechanisms S N 1 Two steps with carbocation intermediate Occurs in 3°, allyl, benzyl S N 2 Two steps combine - without intermediate Occurs in primary, secondary

52 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)

53 Steric Effects on S N 2 Reactions

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

55 Vinyl and Aryl Halides:

56 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

57 Prob.: Arrange in order of S N 2 reactivity

58 The S N 1 Reaction Tertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to the addition of the nucleophile. Reaction occurs in two distinct steps, while S N 2 occurs in one step (concerted). Rate-determining step is formation of carbocation:

59 S N 1 Reactivity:

60 S N 1 Energy Diagram

61 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.

62 S N 1 Energy Diagram

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64 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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66 Characteristics of the S N 1 Reaction Tertiary alkyl halide is most reactive by this mechanism Controlled by stability of carbocation

67 Relative Reactivity of Halides:

68 Allylic and Benzylic Halides Allylic and benzylic intermediates stabilized by delocalization of charge Primary allylic and benzylic are also more reactive in the S N 1 mechanism

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70 Effect of Leaving Group on S N 1 Critically dependent on leaving group Reactivity: the larger halides ions are better leaving groups In acid, OH of an alcohol is protonated and leaving group is H 2 O, which is still less reactive than halide p-Toluensulfonate (TosO - ) is an excellent leaving group

71 Summary of S N 1 Characteristics: Substrate: Benzylic~allylic > 3 o > 2 o Nucleophile: Does not affect reaction (although strong bases promote elimination) Leaving Groups: Good leaving groups (weak bases) favor the reaction Solvent: Polar solvents favor the reaction by stabilizing the carbocation. Stereochemistry: racemization (with some inversion)

72 Prob.: Arrange in order of S N 1 reactivity

73 Practice Problem: S N 1 or S N 2?

74 Problem: S N 1 or S N 2?

75 Chapter 7-2, Questions 27, 29, 31, 32, 34, 39, 46, 47