1. Reactions of Alkyl Halides
Unit 4 - 2
4/16/2017
Reactions of Alkyl Halides
“Ninety-five percent of the reactions that we see in organic chemistry occur between a nucleophile and an electrophile.”
Klein, D.R., Organic Chemistry as a Second Language, 2004, John Wiley & Sons, Inc.
The alkyl halides undergo a variety of reactions that will help us begin the study of reactions between nucleophiles and electrophiles.

2. Nucleophiles and Electrophiles
Nucleophiles are chemical species with a negative charge or an unbonded pair of electrons.
Nucleophile = Lewis base
Electrophiles are chemical species that can accept an electron pair.
Electrophile = Lewis acid
Being able to draw Lewis structures is vital to understanding the material in this and following units.

3. Nucleophiles and Electrophiles
Which species are nucleophiles?

4. Reactions of Alkyl Halides
Alkyl halides undergo a variety of reactions because Cl-, Br-, and I- are good leaving groups.
This makes possible two types of reactions.
Substitution, where a nucleophile replaces the leaving group.
Elimination, where H+ leaves as well and an alkene is formed.

5. Nucleophilic Substitution
leaving group

6. Elimination B:- is a species acting as a base.
leaving group
B:- is a species acting as a base.
FYI: Some species can act as both bases and nucleophiles.

7. Kinetics of Substitution Reactions: SN1 and SN2
There are two different mechanisms by which nucleophilic substitution can happen.
SN1: substitution, nucleophilic, unimolecular rate = k[substrate]
SN2: substitution, nucleophilic, bimolecular rate = k[substrate][nucleophile]

8. SN2 Reaction Mechanism   nucleophile substrate (electrophile)δ- δ- δ- δ+ 
nucleophile
substrate (electrophile)
transition state 
leaving group
product

9. SN2 Reaction Profile
rate = k[CH3I][OH-]
-EA/RT
k = Ae EA

10. SN2 Reactions SN2 reactions are exothermic.
SN2 reactions are concerted: they occur in a single step as the result of a collision between the nucleophile and the substrate.
The Arrhenius equation shows that the rate constant k is a function of the activation energy EA and the temperature. (True for all reactions.)

11. SN2 Reaction Products from Alkyl Halides - A Partial List
R-I alkyl iodide
R-OH alcohol
R-OR’ ether
R-SH thiol
R-NH2 amine
R-C≡C-R’ alkyne
R-CN nitrile
R’-COO-R ester
What would the starting alkyl halide be?
What would the starting nucleophile be?

12. Factors Affecting SN2 Reactions
Strength of the nucleophile
Stronger nucleophiles give faster reactions.
The solvent in which the reaction is run.
Nature of the leaving group
Structure of the substrate
Can the nucleophile easily reach the electropositive C atom?
FYI: You will use this template to study many other types of organic reactions.

13. Factors Affecting SN2 Reactions - Strength of the Nucleophile
Look at the nucleophile in terms of the transition state.
Nucleophiles that decrease the energy of the transition state increase the rate of reaction.
A species with a negative charge is a stronger nucleophile than a similar species that is neutral.
OH- is a better nucleophile than H2O.
A base is a better nucleophile than its conjugate acid.

14. Factors Affecting SN2 Reactions - Strength of the Nucleophile
Good nucleophiles must be polarizable.
This facilitates the formation of the partial bond in the transition state and makes EA lower.
Polarizability increases down a group, due to the increase in size and decrease in electronegativity.
I- > Br- > Cl- > F-

15. Factors Affecting SN2 Reactions - Strength of the Nucleophile
Good nucleophiles must be electronegative (we say electron withdrawing), but not too electronegative.
The nucleophile must be able to hold nonbonding electrons, but it must be able to let the electrons go as it forms the bond to the substrate.
F- is a weak nucleophile.
I- is an excellent nucleophile.

16. Strength of some nucleophiles in water or alcohol solvents
Strong
(CH3CH2)3P:
HS- I-
(CH3CH2)2NH
CN-
(CH3CH2)3N:
HO-
CH3O-
Moderate
Br-
NH3
CH3SCH3
Cl- ..
increasing strength
Weak
CH3COO- F-
HOH
CH3OH

17. Nucleophilicity vs. Basicity
These terms describe functions.
The nucleophilicity of a species is a kinetic term referring to how fast the species will attack an electrophilic C atom.
The basicity of a species is how well it abstracts a proton H+. This refers to the position of the equilibrium and is a thermodynamic term.
CH3O- or I- : Which is the better base?
Which is the better nucleophile?

18. Factors Affecting SN2 Reactions - Steric Effects on Nucleophilicity
Good nucleophiles must be able to get close enough to form a bond to the electrophilic C atom.
Bulky groups on the nucleophile can hinder this approach.
 stronger base
stronger nucleophile 
Bulky groups don’t affect basicity much.

19. Factors Affecting SN2 Reactions - Solvent Effects
In SN2 reactions, the main effect of the solvent is on nucleophilicity.
Protic solvents such as water and alcohols can solvate nucleophiles through H-bonding.
This solvation impedes the formation of the partial bond in the transition state.
These must leave for the reaction to proceed.

20. Factors Affecting SN2 Reactions - Solvent Effects
Polar aprotic solvents such as acetone, THF, and acetonitrile solvate the cation but not the nucleophile.
Polar aprotic solvents enhance nucleophilicity.

21. Factors Affecting SN2 Reactions - the Leaving Group
The leaving group (LG) serves two purposes in an SN2 reaction.
It polarizes the bond that makes the C atom electrophilic.
It carries away a pair of electrons from the electrophilic C atom.

22. Factors Affecting SN2 Reactions - the Leaving Group
A good LG must be:
electron withdrawing, to polarize the bond and make the C atom electrophilic,
polarizable, to stabilize the transition state, and
stable in the solvent (so it cannot be a strong base). Best LGs are neutral species or anions with a stabilized charge.
The first two are the same as for a strong nucleophile, but the last one is not!

23. Good Leaving Groups - Ions that are weak bases
Cl- Br- I-
sulfonates
sulfates
phosphates

24. Good Leaving Groups - Molecules that are weak bases
alcohols
amines
phosphines

25. Rotten Leaving Groups - strong bases
hydroxide
alkoxides
amide

26. How to Make a Rotten LG Better
Protonate the LG by acidifying the solution.
Example: Use HBr instead of NaBr to make methyl bromide from methanol.
This turns a poor leaving group (OH-) into a good one (H2O).

27. Factors Affecting SN2 Reactions - Structure of the Substrate
To be a good substrate for SN2 attack, a molecule must have an electrophilic C atom with a good leaving group and which is not too sterically hindered for the nucleophile to attack.
Alkyl halides are not the only substrates for SN2 reactions.

28. Factors Affecting SN2 Reactions - Structure of the Substrate
The substrate is the species undergoing nucleophilic attack.
The substrate contains the electrophilic C and the LG.
Bulky groups on the electrophilic C atom can hinder nucleophilic attack.
Relative rates for SN2: CH3X>1°>2°

29. Factors Affecting SN2 Reactions - Structure of the Substrate
Relative rates for SN2:
CH3X >1°>2°
3° halides do not react by SN2.
2° halides give much slower SN2 rates due to steric hindrance of the nucleophile.
Methyl halides give fastest SN2 rates.

30. Stereochemistry of the SN2 Reaction
Because of the attack from the side opposite the LG, the configuration of the product is inverted around the electrophilic C atom. 
(S)-2-bromobutane
(R)-2-butanol

31. SN2 Reactions - Summary
The structure of the substrate around the electrophilic C affects the rate:
Relative rates for SN2: CH3X>1°>2°.
The nucleophile should be moderate to strong and not solvated by the solvent.
The LG should be more stable in the solvent than the nucleophile.
The solvent should dissolve the nucleophile but not solvate it…polar aprotic solvents are best.
There will be an inversion of configuration around the electrophilic C.