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.

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.

Nucleophiles and Electrophiles

Which species are nucleophiles?

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.

Nucleophilic Substitution

leaving group

Elimination

B:- is a species acting as a base.

FYI: Some species can act as both bases and nucleophiles.

leaving group

Kinetics of Substitution Reactions: SN1 and SN2

There are two different mechanisms by which nucleophilic substitution can happen. SN1: substitution, nucleophilic,

unimolecularrate = k[substrate]

SN2: substitution, nucleophilic,

bimolecular rate = k[substrate][nucleophile]

SN2 Reaction Mechanism

transition state

product leaving group

δ- δ-

nucleophile

substrate (electrophile)

δ-δ+

SN2 Reaction Profile

rate = k[CH3I][OH-]

k = Ae-EA/RT

EA

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.)

SN2 Reaction Products from Alkyl Halides - A Partial List

R-I alkyl iodideR-OH alcoholR-OR’ etherR-SH thiolR-NH2 amineR-C≡C-R’ alkyneR-CN nitrileR’-COO-R ester

What would the starting alkyl halide be?

What would the starting nucleophile be?

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.

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.

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-

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.

Strength of some nucleophiles in water or alcohol solvents

Strong(CH3CH2)3P:HS-

I-

(CH3CH2)2NHCN-

(CH3CH2)3N:HO-

CH3O-

ModerateBr-

NH3

CH3SCH3

Cl-

WeakCH3COO-

F-

HOHCH3OH

incre

asin

g s

tren

gth

..

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?

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.

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.

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.

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.

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!

Good Leaving Groups - Ions that are weak bases

Cl- Br- I-

sulfonates sulfates

phosphates

Good Leaving Groups - Molecules that are weak bases

alcohols amines

phosphines

Rotten Leaving Groups - strong bases

alkoxides amidehydroxide

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).

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.

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°

Factors Affecting SN2 Reactions - Structure of the Substrate

Relative rates for SN2: CH3X >1°>2°

3° halides do not react by SN2.

Methyl halides give fastest SN2 rates.

2° halides give much slower SN2 rates due to steric hindrance of the nucleophile.

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

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.