1. Chapter 7 Organohalides: Nucleophilic Substitutions and Eliminations
Suggested Problems: 20,22-26,28-38,44-45,47,57

2. What Is an Organohalide?
An organic compound containing at least one carbon-halogen bond (C-X)
X (F, Cl, Br, I) replaces H
Can contain many C-X bonds
Properties and some uses
Fire-resistant solvents
Refrigerants
Pharmaceuticals and precursors

3. 7.1 Naming Alkyl Halides Find longest chain, name it as parent chain
(Contains double or triple bond if present)
Number from end nearest any substituent (alkyl or halogen)

4. Naming if Two Halides or Alkyl Are Equally Distant from Ends of Chain
Begin at the end nearer the substituent having its name first in the alphabet
Name halide as a substituent

5. 10.2 Preparing Alkyl Halides from Alkenes
Two best ways:
Alkyl halide from addition of HCl, HBr, HI to alkenes to give Markovnikov product
Alkyl dihalide from anti addition of bromine or chlorine

6. 10.2 Preparing Alkyl Halides Via Radical Halogenation

7. Preparing Alkyl Halides Via Radical Halogenation
Alkane + Cl2 or Br2, heat or light replaces C-H with C-X but gives mixtures
Hard to control
Occurs via free radical mechanism
It is usually not a good idea to plan a synthesis that uses this method

8. Radical Halogenation of Alkanes
If there is more than one type of hydrogen in an alkane, reactions favor replacing the hydrogen at the most highly substituted carbons (not absolute)

9. Relative Reactivity
Based on quantitative analysis of reaction products, relative reactivity is estimated
Order parallels stability of radicals
Reaction selectivity is greater with bromine than chlorine
i.e. 3o > 2o > 1o

10. 7.2 Preparing Alkyl Halides
Addition reactions of X2 and HX with alkenes (Chapter 4)
Reaction of an alkane with Cl2 (Chapter 2)

11. Preparing Alkyl Halides from Alcohols
Reaction of tertiary C-OH with HX is fast and effective
Add HCl or HBr gas into ether solution of tertiary alcohol (ether is solvent)

12. Preparing Alkyl Halides from Alcohols
Primary and secondary alcohols react very slowly and often rearrange under acidic conditions (with HX), so alternative methods are used usually thionyl chloride (SOCl2) or phosphorus tribromide (PBr3)

13. 7.3 Reactions of Alkyl Halides: Grignard Reagents
Reaction of RX with Mg in ether or THF
Product is RMgX – an organometallic compound (alkyl-metal bond)
R is alkyl 1° ,alkyl 2° , alkyl 3°, aryl, alkenyl
X = Cl, Br, I

14. 7.3 Reactions of Alkyl Halides: Grignard Reagents
Grignard reagent – magnesium salt of a carbon-based acid
Carbon atom is a carbon anion, or carbanion
This carbon atom is both nucleophilic and basic
Water or protic solvents (eg. ROH) must be excluded

15. 7.4 Nucleophilic Substitution Reactions
Aklyl halides (RX) when they react with nucleophiles/bases can undergo
Substitution of the X group by the nucleophile
Elimination of HX to yield an alkene by the base

16. The Discovery of Nucleophilic Substitution Reactions
In 1896, 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 inversion of chirality
Reaction of (-)-malic acid with PCl5 gives (+)-chlorosuccinic acid
Further reaction with wet silver oxide gives (+)-malic acid
The reaction series starting with (+) malic acid gives (-) acid

17. Reactions of the Walden Inversion
retention
retention
inversion

18. Significance of the Walden Inversion
The PCl5 reactions invert the stereochemistry at the chirality center
The reactions involve substitution at that center
Therefore, nucleophilic substitution can invert the configuration at a chirality center
The Ag2O reactions occur with retention (without inverting the stereochemistry at the chirality center)

19. Nucleophilic Substitution Reactions
Regardless of mechanism, the overall changes during a nucleophilic substitution reaction are the same
Nucleophile (Nu: or Nu:– ) reacts with a substrate R— X
Substitutes for the leaving group X:–
To yield a new product R— Nu

20. Nucleophiles

21. 7.5 Substitutions: The SN2 Reaction
Reaction occurs with inversion at reacting center
Takes place in a single step
Without intermediates
Entering nucleophile is 180˚ from the leaving group
Reaction is bimolecular
The rate of the reaction depends on the concentration of both the nucleophile and the substrate

22. SN2 Process
The reaction involves a transition state in which both reactants are together

23. SN2 Transition State
The transition state of an SN2 reaction has a roughly planar arrangement of the carbon atom and the remaining three groups
Rate = k [Nu][RX] (bimolecular)
Alkyl Halide: 1°> 2°>> 3°
Backside attack
One step

24. Steric Effects on SN2 Reactions
The carbon atom in (a) bromomethane is readily accessible
resulting in a fast SN2 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 SN2 reactions.

25. Order of Reactivity in SN2
The more alkyl groups connected to the reacting carbon, the slower the reaction

26. The Leaving Group
A good leaving group reduces the energy barrier to a reaction
Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge
Best leaving groups

27. 7.6 The SN1 Reaction
Tertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to addition of the nucleophile
Called an SN1 reaction – occurs in two distinct steps while SN2 occurs with both events in same step
If nucleophile is present in reasonable concentration (or it is the solvent), then ionization is the slowest step

28. Rates of SN1 Reactions
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 this step
SN1 reactions are unimolecular
The rate depends on the concentration of the substrate (Rate = k[RX])
The substrate must undergo a reaction without involvement of the nucleophile

29. Rates of SN1 Reactions

30. Stereochemistry of SN1 Reaction
The planar intermediate leads to loss of chirality
A free carbocation is achiral
Product is racemic or has some inversion

31. The Leaving Group in SN1 Reactions
Critically dependent on leaving group
The best leaving groups are those that give the most stable anions

32. 7.7 Eliminations: The E2 Reaction
Elimination is an alternative pathway to substitution
Opposite of addition
Generates an alkene
Can compete with substitution and decrease yield, especially for SN1 processes

33. Zaitsev’s Rule for Elimination Reactions
In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates

34. Mechanisms of Elimination Reactions
Eliminations can take place by several different mechanisms differing in the time of C—H and C—X bond breaking

35. Mechanisms of Elimination Reactions

36. Mechanisms of Elimination Reactions

37. E2 Mechanism: Elimination, Bimolecular

38. 7.8 Eliminations: The E1 and E1cB Reactions
E1 Reaction: elimination, unimolecular
Involves a carbocation intermediate

39. 7.8 Eliminations: The E1 and E1cB Reactions
E1cB Reaction: elimination, unimolecular
Involves a carbanion intermediate

40. 7.9 A Summary of Reactivity: SN1, SN2, E1, E1cB, and E2

41. 7.10 Substitions and Eliminations in Living Organisms
Both substitution reactions occur in biological pathways
Among the most common is methylation

42. 7.10 Substitions and Eliminations in Living Organisms
All three elimination reactions occur in biological pathways
E1cB very common
Typical example occurs during biosynthesis of fats when 3-hydroxybutyryl thioester is dehydrated to corresponding thioester