1. Chapter 9 The Chemistry of Alkyl Halides
Organic Chemistry, 6th ed.
Marc Loudon and Jim Parise
Chapter 9 The Chemistry of Alkyl Halides
Finally some more chemistry ! !

2. Chapter 9 Overview
9.1 – Overview of Nucleophilic Substitution and b- Elimination Reactions 9.2 – Equilibria in Nucleophilic Substitution Reactions end Quiz 4 coverage – Reaction Rates 9.4 – The SN2 Reaction 9.5 – The E2 Reaction 9.6 – The SN1 and E1 Reactions 9.7 – Summary of Substitution and Elimination Reactions of Alkyl Halides 9.8 – 9.9 Organometallic Compounds. Grignard Reagents and Organolithium Reagents / Carbenes and Carbenoids 9.10 – Industrial Preparation and Use of Alkyl Halides

3. Nucleophilic Substitution Reactions
In the simplest type of nucleophilic substitution reaction, a nucleophile donates an electron pair to an electrophilic site to displace a leaving group.
in-coming group electrophilic site (not E) -- a nucleophilic displacement
9.1 Overview of Nucleophilic Substitution and b-Elimination Reactions

4. Nucleophilic Substitution Reactions
Intramolecular substitution reaction – where the nucleophile and electrophilic site (and the leaving group) are in the same molecule – are also possible.
9.1 Overview of Nucleophilic Substitution and b-Elimination Reactions

5. Nucleophilic Substitution Reactions
9.1 Overview of Nucleophilic Substitution and b-Elimination Reactions

6. b-Elimination Reactions
In an elimination reaction two or more groups are lost from within the same molecule.
An elimination that involves the loss of two groups from adjacent carbons to form a double bond is called a b-elimination.
9.1 Overview of Nucleophilic Substitution and b-Elimination Reactions

7. b-Elimination Reactions
Strong bases promote the b-elimination reactions of alkyl halides.
Strong bases you will see frequently; they work :
Sodium Ethoxide (NaOEt); hydroxide not as good
Potassium tert-Butoxide (KOtBu) – stronger base
less good nucleophile
9.1 Overview of Nucleophilic Substitution and b-Elimination Reactions

8. b-Elimination Reactions
If the reacting alkyl halide has more than one type of b-hydrogen atom, then more than one b- elimination product is possible.
9.1 Overview of Nucleophilic Substitution and b-Elimination Reactions

9. Substitution vs Elimination
Nucleophilic substitution and b-elimination reactions often compete with one another.
A typical secondary alkyl halide under ethoxide conditions undergoes both reactions.
9.1 Overview of Nucleophilic Substitution and b-Elimination Reactions

10. Equilibria in Substitution Reactions
How do we know whether the equilibrium for a given substitution reaction is favorable?
Very Favorable:
Reversible:
Very Unfavorable:
9.2 Equilibria in Nucleophilic Substitution Reactions

11. Equilibria in Substitution Reactions
Recognize that each nucleophilic substitution reaction is similar to a BrØnsted-Lowry acid-base reaction.
The equilibrium in a nucleophilic substitution reaction also favors the release of the weaker base. The acid/base analogy.
9.2 Equilibria in Nucleophilic Substitution Reactions

12. Equilibria in Substitution Reactions
Some unfavorable equilibria can be driven to completion by applying Le Chȃteleir’s principle.
Typically iodide, the weaker base, can not replace chloride.
In the solvent acetone, alkyl chlorides and KI are soluble, but KCl is not.
The equilibrium compensates for the los of KCl by forming more of it.
9.2 Equilibria in Nucleophilic Substitution Reactions

13. Definition of Reaction Rates
Knowledge of the equilibrium constant for a reaction says nothing about how fast it will take place, or if it will occur at all.
The quantities that change with time in a chemical reaction are reactant and product concentrations, [reactants] & [products].
9.3 Reaction Rates

14. The Rate Law
The rate law expresses how the reaction rate depends on the concentrations of reactants and a rate constant (k). The constant (k) depends on the specific reaction and conditions (temperature, solvent, etc.)
A rate law is determined experimentally.
For example,
As illustrated, the overall kinetic order is second order.
First order in [A], first order in [B].
9.3 Reaction Rates

15. Rate Constant and DG°‡
The energy barrier determines the rate of a reaction; and is directly, inversely, related to the rate constant.
The rate constant is related to DG‡. Under standard conditions, it’s the standard free energy of activation, DG°‡
9.3 Reaction Rates

16. Rate Constant and DG°‡ not to be testedXX X
9.3 Reaction Rates

17. Rate Constant and DG°‡
Each increment of 2.3RT (1.4 kcal/ or 5.7 kJ/mol at 298K) in the DG°‡ difference for two reactions corresponds to a one log unit (10 fold) factor in their relative rate constants.
9.3 Reaction Rates

18. The SN2 Reaction
The rate law for this reaction was experimentally determined to be:
Specifically, the concentration terms indicate which atoms are present in the transition state of the rate-limiting step
9.4 The SN2 Reaction

19. The SN2 Reaction
The simplest possible mechanism consistent with the rate law is then:
This one-step, concerted mechanism is classified as an SN2 reaction:
9.4 The SN2 Reaction

20. The SN2 Reaction
The rate law tells us nothing about how the atoms are arranged.
The following two mechanism for the SN2 reaction of ethoxide ion with methyl iodide are equally consistent with the rate law.
Inversion
9.4 The SN2 Reaction

21. SN2 vs BrØnsted-Lowry Reaction Rates
Most ordinary acid-base reactions occur instantaneously.
Most nucleophilic substitution reactions are much slower.
If there is competition, the acid-base reaction always wins.
9.4 The SN2 Reaction

22. Stereochemistry of the SN2 Reaction
Experimental results have shown that SN2 reactions proceed via inversion!
Inversion of stereochemical configuration at the a carbon stereocenter is a general observation for all SN2 reactions.
9.4 The SN2 Reaction

23. Stereochemistry of the SN2 Reaction

24. MO Analysis of the SN2 Reaction NO
The MO of the nucleophile that contains the donated e- pair interacts with the unoccupied alkyl halide MO of lowest energy (LUMO, lowest unoccupied molecular orbital).
9.4 The SN2 Reaction

25. Effect of Alkyl Halide Structure
The reaction rate varies with the structure of the alkyl halide.
If an alkyl halide is very reactive, the SN2 occurs under mild conditions.
If an alkyl halide is relatively unreactive, the severity of the rxn conditions must be increased.
Harsh conditions are more likely to have competing side reactions.
The reaction rate is also strongly influenced by alkyl halide structure (a steric effect).
9.4 The SN2 Reaction

26. Effect of Alkyl Halide Structure
R – X Nuc – R R = Et, rate = 1 NO
NO, different
mechanism
SN2 reactions impossible for tertiary halides
9.4 The SN2 Reaction

27. Nucleophilicity in the SN2 Reaction
A wide variety of nucleophiles may be used for the SN2 reaction.
This adds great versatility to the SN2 reaction.
There is a correlation between nucleophilicity and basicity (both are aspects of Lewis basicity).
The relative reactivity of a nucleophile – how rapidly it reacts with a reference R-X under a defined set of conditions – is called nucleophilicity.
9.4 The SN2 Reaction

28. Nucleophilicity in the SN2 Reaction
Nucleophilicity reflects:
The Bronsted basicity of the nucleophile
But is further influenced by
The solvent in which the reaction is carried out
The polarizability (size) of the nucleophile
9.4 The SN2 Reaction

29. Nucleophile Basicity and SN2 Rates
The following apply to nucleophilic anions in polar, protic solvents (e.g., water, alcohols):
For nucleophiles in the same period, more basic nucleophiles are more nucleophilic.
For nucleophiles in the same group (column), less basic (bigger) nucleophiles are more nucleophilic
The solvent employed has a great influence on these relationships.
9.4 The SN2 Reaction

30. Nucleophile Basicity and SN2 Rates
Notice the incomplete correlation of basicity and the rate of SN2 reaction.
9.4 The SN2 Reaction

31. Nucleophile Basicity and SN2 Rates
Notice the reversal of the basicity vs nucleophilicity trend for these cases.
9.4 The SN2 Reaction

32. NHA ranking
Summary of relative nucleophilicities in protic media: (R = H or alkyl)
Excellent nucleophiles - PhS- ≥ RS- >
Good (useful) nucleophiles - X > X°
Acceptable (slow with all but best primary halides) nucleophiles - X > X
Probably unacceptable -

33. Solvent Effects on Nucleophilicity
In protic solvents, H-bonding can occur with the nucleophilic (Lewis basic) anions. Desolvation required for nucleophilic attack.
9.4 The SN2 Reaction

34. Solvent Effects on Nucleophilicity
Changing to a polar, aprotic solvent greatly enhances nucleophilicity.
9.4 The SN2 Reaction

35. Nucleophilicity: Polarizability Effects
In a polar aprotic solvent – the most basic anions are the most nucleophilic.
Consider, however, Cl- is 10,000x more basic than I-, yet Cl- is only 6x as nucleophilic.
I- more nucleophilic than its basicity suggests due to its polarizability.
Nucleophiles derives from higher number rows on the periodic table are more polarizable.
Weak bases can be good nucleophiles if the nucleophilic atom is highly polarizable.
9.4 The SN2 Reaction

36. Leaving-Group Effects in the SN2 Reaction
The best leaving groups are the ones that give the weakest bases.
Leaving groups are not limited to halogens.
A variety of alcohol derivatives will soon be introduced.
9.4 The SN2 Reaction

37. The E2 Reaction Base promoted b-elimination of alkyl halides.
Dominant reaction of tertiary alkyl halides.
Competes with SN2 in secondary halides – favored with a strong base.
Less common with primary alkyl halides except with K t-butoxide as the base.
9.5 The E2 Reaction

38. Rate Law and Mechanism of E2
9.5 The E2 Reaction

39. A Concerted Mechanism
Removal of the b-H and loss of the leaving group occurs simultaneously.
Shown by three curved arrows. The first is proton abstraction.
Blue arrows – p-bond formation, book says “shows the b-carbon acting as the leaving group and as a nucleophile that reacts with the a-carbon”.
9.5 The E2 Reaction

40. It’s Concerted Mechanism
But a fictional two step mechanism can be drawn:
The concerted mechanism avoids the formation of the very unstable carbanion (carbon anion).
9.5 The E2 Reaction

41. Leaving Group Effects
The trend observed for the SN2 reaction is seen again for the E2 reaction.
Relative rates of E2 reactions:
R-I > R-Br > R-Cl
9.5 The E2 Reaction

42. Stereochemistry of the E2 Reaction
The E2 reaction could take place in two stereochemically distinct ways: 
rotamers 
9.5 The E2 Reaction

43. Stereochemistry of the E2 Reaction
The stereochemical changes that take place during an E2 elimination:
9.5 The E2 Reaction

44. E2 Reactions: why Anti-elimination preferred.
In a syn-elimination, the dihedral angle between the C-H and C-X bonds is 0°.
In an anti-elimination, the dihedral angle between the C-H and C-X bonds is 180°.
Newman and sawhorse projection for anti- elimination:
9.5 The E2 Reaction

45. E2 Reaction -- why Anti-elimination preferred.
Most E2 eliminations are stereoselectively anti- eliminations.
anti:
syn:
9.5 The E2 Reaction

46. E2 Reaction -- why Anti-elimination preferred.
Because eclipsed conformations are unstable, the transition state for syn-elimination is less stable than for anti-elimination.
Some conformationally restricted cases may proceed via syn-elimination
9.5 The E2 Reaction

47. Regioselectivity of the E2 Reaction
When more than one type of b-H is available, more than one alkene product can be formed.
With simple alkoxide bases, the most stable alkene isomer usually dominates.
9.5 The E2 Reaction

48. Regioselectivity of the E2 Reaction
The predominance of the more stable alkene isomer does not result from equilibration.
The alkenes products are stable under the reaction conditions.
Hence, the product distribution reflects the relative rates of product formation.
Product selectivity explanation lies in transition state theory.
9.5 The E2 Reaction

49. Regioselectivity and Transition States
Transition state is stabilized by the same factors that stabilize the alkene products.
9.5 The E2 Reaction

50. Competition Between SN2 and E2
SN2 vs E2 is dependent on the structure of the alkyl halide and the nature of the base.
The reaction pathway that occurs more rapidly is the one that dominates.
9.5 The E2 Reaction

51. Competition Between SN2 and E2
Two variables determine which pathway will predominate:
The structure of the alkyl halide
The strength and steric hindrance of the base
9.5 The E2 Reaction

52. Competition Between SN2 and E2
The number of alkyl substituents at both the a and b carbons of the alkyl halide impacts the amount of substitution versus elimination.
Tertiary halides do not undergo SN2 reactions
9.5 The E2 Reaction

53. Competition Between SN2 and E2
Secondary alkyl halides:
9.5 The E2 Reaction

54. Competition Between SN2 and E2
Primary alkyl halides:
9.5 The E2 Reaction

55. Competition Between SN2 and E2
Structure of the Base:
9.5 The E2 Reaction

56. Competition Between SN2 and E2
Weaker bases that are good nucleophiles give a greater fraction of substitution.
For example, iodide is an excellent nucleophile, but a weak base and thus gives mostly substitution product.
Cyanide, as stronger base, would give some elimination.
9.5 The E2 Reaction

57. Rate Law and Mechanism of SN1 and E1
The reaction of an alkyl halide with a solvent (and no other base or nucleophile) is called a solvolysis reaction.
9.6 The SN1 and E1 Reactions

58. Rate Law and Mechanism of SN1 and E1
The rate-determining first step is common to both reactions:
For elimination:
9.6 The SN1 and E1 Reactions

59. Rate Law and Mechanism of SN1 and E1
For substitution:
9.6 The SN1 and E1 Reactions

60. Rate-Limiting and Product-Determining Steps
The rates of the product-forming steps have nothing to do with the rate at which the alkyl halide dissociates into ions.
9.6 The SN1 and E1 Reactions

61. Rate-Limiting and Product-Determining Steps
SN1 and E1 competition is different than SN2 and E2 competition.
Unlike SN1 and E1, SN2 and E2 do not share a common intermediate.
9.6 The SN1 and E1 Reactions

62. Rate-Limiting and Product-Determining Steps
SN1 and E1 reactions share not only common starting materials, but also a common rate limiting step and hence a common intermediate.
9.6 The SN1 and E1 Reactions

63. Rate-Limiting and Product-Determining Steps
SN1 - E1 Solvolysis
9.6 The SN1 and E1 Reactions

64. Reactivity and Product Distribution
SN1 and E1 are most rapid with tertiary alkyl halides, slower with secondary, and never observed with primary alkyl halides.
tertiary >> secondary >> primary
Solvent also has an effect on reactivity.
Example tert-butylbromide vs isopropylbromide.
In H2O
In CH3CH2OH
(CH3)3C-Br
105x more reactive
1150x more reactive
(CH3)2CH-Br 1
9.6 The SN1 and E1 Reactions

65. Reactivity and Product Distribution
SN1 and E1 are fastest in polar, protic, donor solvents.
The critical role of solvent shows that SN1 and E1 reactions cannot truly be the unimolecular process suggested by their nicknames.
Solvent molecules actively stabilize transition states and solvate the developing ions.
9.6 The SN1 and E1 Reactions

66. Reactivity and Product Distribution
The ratio of E1 products to SN1 is greater when the alkene formed contains more than two alkyl substituents.
9.6 The SN1 and E1 Reactions

67. Reactivity and Product Distribution
When an alkyl halide contains more than one type of b-hydrogen, more than one E1 product can be formed.
9.6 The SN1 and E1 Reactions

68. Rearrangements
Rearrangements are a telltale sign of carbocation intermediates.
9.6 The SN1 and E1 Reactions

69. Stereochemistry of the SN1 Reaction
Racemization is expected.
9.6 The SN1 and E1 Reactions

70. Stereochemistry of the SN1 Reaction
…but, experimentally:
Partial racemization is observed; some ‘net’ inversion is also observed.
9.6 The SN1 and E1 Reactions

71. Stereochemistry of the SN1 Reaction
An ion-pair mechanism can explain the observed stereochemical outcome of the SN1 reaction.
9.6 The SN1 and E1 Reactions

72. Summary of Substitution and Elimination
Key questions for evaluation:
Is the alkyl halide primary, secondary, tertiary? If primary or secondary, is there significant b- substitution?
Is a Lewis base present? Is it a good nucleophile, strong BrØnsted base, or both?
What is the solvent? Polar protic or polar aprotic?
9.7 Summary of Substitution and Elimination Reactions of Alkyl Halides

73. Summary of Substitution and Elimination
9.7 Summary of Substitution and Elimination Reactions of Alkyl Halides

74. Free-Radical Halogenation of Alkanes
When an alkane is treated with Cl2 or Br2 in the presence of heat or light, a mixture of alkyl halides is formed by successive halogenation.
9.10 Industrial Preparation and Use of Alkyl Halides

75. Free-Radical Halogenation of Alkanes
The halogenation products are formed in a series of substitution reactions.
Initiation:
9.10 Industrial Preparation and Use of Alkyl Halides

76. Free-Radical Halogenation of Alkanes
Propagation:
This is an example of a free-radical substitution.
9.10 Industrial Preparation and Use of Alkyl Halides

77. Regioselectivity of Free-Radical Halogenation
If the alkane has more than one type of hydrogen, more than one product can be obtained.
9.10 Industrial Preparation and Use of Alkyl Halides

78. Regioselectivity of Free-Radical Halogenation
The reactivity difference is a consequence of the stabilities of the free-radical intermediates.
9.10 Industrial Preparation and Use of Alkyl Halides

79. Regioselectivity of Free-Radical Halogenation
Chlorination is much less selective than bromination.
9.10 Industrial Preparation and Use of Alkyl Halides

80. Chlorination vs Bromination Selectivity
9.10 Industrial Preparation and Use of Alkyl Halides

81. Likely ending point
This has been a very busy chapter full of important reactions and mechanisms.