1. Substitution Reactions of Alkyl Halides: Chapter 8

2. Contents of Chapter 8 Reactivity Considerations The SN2 Reaction
Reversibility of the SN2 Reaction
The SN1 Reaction
Stereochemistry of SN2 and SN1 Reactions
Benzylic, Allylic, Vinylic & Aryl Halides
Competition between SN2 and SN1 Reactions
Role of the Solvent
No Biological Methylating Reagents
Chapter 8

3. Substitution and Elimination
A compound with an sp3 hybridized carbon bonded to a halogen can undergo two types of reactions
Two different mechanisms for substitution are SN1 and SN2 mechanisms
These result in diff prods under diff conditions
Chapter 8

4. SN2 Mechanism
SN2 mechanism: C–X bond weakens as nucleophile approaches all in one step
Chapter 8

5. SN1 Mechanism
SN1 mechanism: C–X bond breaks first without any help from nucleophile
slow step
fast step
This is a two-step process
Chapter 8

6. Substitution Reactions
Both mechanisms are called nucleophilic substitutions
Which one takes place depends on
the structure of the alkyl halide
the reactivity and structure of the nucleophile
the concentration of the nucleophile, and
the solvent in which reaction is carried out
Chapter 8

7. The SN2 Reaction Bimolecular nucleophilic substitution
rate = k [alkyl halide][nucleophile]
Chapter 8

8. The SN2 Reaction
The inversion of configuration resembles the way an umbrella turns inside out in the wind
If a single chiral enantiomer reacts a single chiral product (inverted) results.
Chapter 8

9. Steric Accessibility in the SN2 Reaction
Chapter 8

10. The SN2 Reaction: Leaving Group Stability
Chapter 8

11. The SN2 Reaction: Nucleophile Basicity
stronger base weaker base better nucleophile poorer nucleophile
HO– > H2O
CH3O– > CH3OH
–NH2 > NH3
CH3CH2NH– > CH3CH2NH2
Chapter 8

12. The SN2 Reaction: Nucleophile Basicity
Comparing nucleophiles with attacking atoms of approximately the same size, the stronger base is also the stronger nucleophile
Chapter 8

13. The SN2 Reaction: Nucleophile Size
In nonpolar solvents nucleophilicity order same as basicity order- size doesn’t matter
Chapter 8

14. The SN2 Reaction: Nucleophile Size
Size is related to polarizability
Chapter 8

15. The SN2 Reaction: Nucleophile Size and Type
Nucleophilicity ~ both size and basicity
Chapter 8

16. The SN2 Reaction: Nucleophile Bulkiness
Nucleophilicity is affected by steric effects
A bulky nucleophile has difficulty getting near the back side of a sp3 carbon
ethoxide ion tert-butoxide ion
better nucleophile stronger base
Chapter 8

17. The SN1 Reaction
The more stable the C+ the lower the DG‡, and the faster the rxn
Chapter 8

18. The SN1 Reaction
Chapter 8

19. The SN1 Reaction The SN1 reaction leads to a mixture of stereoisomers
Chapter 8

20. The SN1 Reaction: Factors Affecting the Rate
Two factors affect the rate of formation of the carbocation
ease with which the leaving group leaves
RI > RBr > RCl > RF
increasing reactivity
stability of the carbocation
3º alkyl halide > 2º alkyl halide > 1º alkyl halide
increasing reactivity
Chapter 8

21. The SN1 Reaction: Carbocation Rearrangements
Chapter 8

22. Stereochemistry of SN2 and SN1 Reactions
inversion
both enantiomers
Chapter 8

23. Competition Between SN2 and SN1 Reactions
Chapter 8

24. Competition Between SN2 and SN1 Reactions
TABLE Summary of the Reactivity of Alkyl Halides in Nucleophilic Substitution Reactions
methyl & 1o alkyl halides SN2 only
2o alkyl halides SN2 & SN1
3o alkyl halides SN1 only
vinylic & aryl halides neither SN2 nor SN1
benzylic & allylic halides SN2 & SN1
3o benzylic & allylic halides SN1 only
Chapter 8

25. Competition Between SN2 and SN1 Reactions
What are the factors that determine which mechanism operates?
concentration of the nucleophile
reactivity of the nucleophile
solvent in which the reaction is carried out
For SN2 rate = k2 [alkyl halide][nucleophile]
For SN1 rate = k1 [alkyl halide]
Chapter 8

26. Competition Between SN2 and SN1 Reactions
An increase in the concentration of the nucleophile increases the rate of the SN2 reaction but has no effect on rate of SN1 reaction
An increase in the reactivity of nucleophile also speeds up an SN2 rxn but not an SN1 rxn
Chapter 8

27. Role of the Solvent
The solvent in which a nucleophilic substitution reaction is carried out has an influence on whether the reaction proceeds via an SN2 or an SN1 mechanism
Two important solvent aspects include
solvent polarity
whether it is protic or aprotic
Chapter 8

28. Solvent Polarity
The dielectric constant is a measure of how well the solvent can insulate opposite charges from each other
Chapter 8

29. Role of the Solvent Polar solvents have a high dielectric constant
Water
Alcohols
Dimethylsulfoxide (DMSO)
Solvents having O–H or N–H bonds are called protic solvents
Polar solvents without O-H or N-H bonds called polar aprotic solvents
Chapter 8

30. Role of the Solvent
If charge on reactants(s) in slow step is greater than the charge on the transition state, a polar solvent will slow down rxn (by stabilizing reactants)
If all reactant(s) involved in slow step are neutral polar solvent will speed up rxn
If reactant(s) involved in slow step are charged polar solvent slows down rxn
Chapter 8

31. SN1 Reaction: Effect of Solvent
Most SN1 reactions involve a neutral alkyl halide which needs to produce a C+
Consequently a polar solvent stabilizes the transition state more than the reactant
Increasing the polarity of the solvent speeds up such an SN1 reaction
Protic solvents stabilize the leaving group by H-bonding and thus stabilize the transition state
Chapter 8

32. SN2 Reaction: Effect of Solvent
Most SN2 reactions involve a neutral alkyl halide and a charged nucleophile
Consequently a polar solvent stabilizes the nucleophile more than the transition state and slows rxn
The nucleophiles used in SN2 reactions however are generally insoluble in nonpolar solvents - some solvent polarity is needed, but it’s best to use an aprotic solvent to avoid overstabilizing nucleophile reactant
Chapter 8

33. Competition Between SN2 and SN1 Reactions
When a halide can undergo both an SN2 and SN1 reaction:
SN2 will be favored by a high concentration of a good (negatively charged) nucleophile
SN2 will be favored in a polar aprotic solvent
SN1 will be favored by a poor (neutral) nucleophile in a polar protic solvent
Chapter 8

34. Problem-solving Info Nucleophile strength Protic solvent
Size most important
Look at basicity if same row of periodic table
Aprotic solvent- look at basicity only
Strength in aprotic solvent > protic solvent
First two points not strictly true but will work in this course
Chapter 8

35. Problem-solving Info Electrophile strength SN2 reactions SN1 reactions
Steric accessibility
Electron withdrawing group (EWG) attached to C reaction site
Good leaving group
SN1 reactions
Carbocation stability
EWG not attached to reaction site
Chapter 8

36. Problem-solving Info Solvent polarity
Reduces rate with charged reactants
Charge on both nucleophile and electrophile important in SN2
Only electrophile important in SN1
Increases rate with uncharged reactants
Reduces nucleophilicity
Stabilizes leaving group for SN1
Chapter 8

37. Problem-solving Info Reaction speed comparisons
Increasing speed in SN1 reaction
Polar solv/uncharged electrophile, vice-versa
Relief of steric strain making C+
More stable carbocation formed
Anything which destabilizes electrophile
Increased leaving group stability (less basic)
Increasing speed in SN2 reaction
Charge on electrophile & nuc vs. solv polarity
Chapter 8

38. Problem-solving Info Stereochemistry Increased leaving group stability
Less steric hindrance (both nuc & electrophile)
Switch from protic to aprotic solvent
Higher concentration of nucleophile
More basic nucleophile
Larger size of nucleophile’s attacking atom
Anything which destabilizes nuc or electrophile
Stereochemistry
SN1 reactions give both isomers at chiral C
SN2 reactions give only inversion at chiral C
Chapter 8

39. Problem-solving Info Carbocation rearrangements SN1 vs SN2 chemistry
Will occur if posible with SN1
Will not occur with SN2
SN1 vs SN2 chemistry
Conditions which give SN1
Tertiary C reaction center
C+ stability  2 & weak nuc (H-nuc pKa <7)
Carboxylates and sulfonates
Neutral O nucleophiles
Halides
Neutral large-atom (row >2) nucleophiles
Chapter 8

40. Problem-solving Info Conditions which give SN2
C+ stability index = 1 and unhindered rxn site
C+ stability  2, not 3°, strong nucleophile
Any nuc with conj acid pKa  7 (Table 10.3 pg 373)
Alkoxides and hydroxide
Ammonia and amines
Carbanions
Sulfides
Hydride
Nitrogen anions
In this text “high conc” of nuc is code for SN2
Other conditions give SN1/SN2 mixture
Chapter 8