Chapter 7 Alkyl Halidesand Nu Substitution

Characteristics of RX

RX are classified as shown below

Practice ( see lecture notes)

RX with X near a pi bond

Naming RX

Use the nomenclature rules for naming alkanes

F

Br

Name these compounds.

I

Cl

Common Names

Practice (see lecture notes)

Occurrence of Selected RX

Chloromethane: is produced by giant kelp and algae and also found in emissions of volcanoes such as Hawaii’s Kilauea.

Dichloromethane (or methylene chloride) is an important solvent, once used to decaffeinate coffee.

Halothane is a safe general anesthetic

Physical Properties of RX

The C-X bond is polar.

RX and Nu Substitution

Recall RX undergo a Nu substitution rxn due to the + charge on the C of the C-X bond.

An example of a one step SN reaction

An RX SN rxn with a neutral Nu.

RX and the Leaving Group

Recall the leaving group is the negatively charge ion that separates from the carbon atom during SN

Which is a better leaving group H2O or OH- ?

Conjugate Bases of Strong Acids

Are Good LGsHCl ______ H3O+ ________

HF ______

HCN ______

HBr ________

H2O ______

Conjugate Bases of Strong Acids Are Good LGs

Conjugate Bases of Weak Acids

Are Poor LGs

RX and the Nucleophile

Nucleophilicity and basicity are related but are fundamentally different.

Basicity = How much? = Ka or pKa = thermodynamic property.

Nucleophilicity .. How fast? = rate constant, k, = a kinetic property.

Alkyl Halides and Nucleophilic Substitution

The Nucleophile

The Nucleophile and Solvent Effects

Two principal types of solvents usedin organic chemistry.

Protic - solvents that are polar but alsopossess a hydrogen bond

Aprotic - solvents that are polar but have no hygrogen bond

These are examples of protic solvents(Fig 7.6)

H2O, CH3OH, CH3CH2OH, (CH3)3COH, and CH3COOH

These are examples of aprotic solvents(Fig 7.7)

Effect of Protic Solvents on Nucleophilicity

Effect of Aprotic Solvents on Nucleophilicity

The Nucleophile and Steric Effects

Large R groups on a Nu will alwaysmake it less nucleophilic…..

..however large R groups do not affect the basicity.

The SN2 Mechanism

SN2

The two here indicates the order of the reaction.

Nucleophilic

Substitution

This is an example of an SN2 mechanism.

Energy Diagram for the SN2 Rxn

Key Characteristics of the SN2 Mechanism

1. A one step 2 order rxn

2. Nu attacks from the opposite side of the LG

3. Reactant undergoes inversion of configuration

Key Characteristics of the SN2 Mechanism (continued)

4. Mechanism affected by steric hindrance(i.e. bulky or large R groups)

5. Mechanism is best in polar aprotic solvents

Stereochemistry in the SN2 Mechanism

Inversion of configuration is known as the Walden inversion.

C BrCH3CH2

H

D

+ OCH2CH3

Draw the product of each rxn to includethe correct stereochemistry.

I

+ CN

SN2 : Effect of Steric Hindrance

Larger R groups will decrease the rate constant of SN2 rxns

Decreasing Rate Constant of SN2 Reaction

Decreasing Rate Constant of SN2 Reaction

Compare the T.S. for a methyl RX and a 2 RX.

The SN2 Mechanism: Summary

CH3

CH3

CH3

Br CH3

CH3

CH3

OH

reaction conditions ?

How would you prepare tert-butanol from tert-butyl bromide?

CH3

CH3

CH3

Br

OH-

O (solvent)

No substitution productOnly elimination product

SN2 conditions

H2O

CH3

CH3

CH3

OH

Let’s look at two possibilities

The SN1 Mechanism

SN1

The one here indicates the order of the reaction.

Nucleophilic

Substitution

This is an example of an SN1 mechanism.

Key Characteristics of the SN1 Mechanism

1. A two step 1 order rxn

2. Nu attacks from the top and bottom sidesof the C+ intermediate.

3. Reactant undergoes racemization

Key Characteristics of the SN1 Mechanism (continued)

4. Mechanism favored by stable carbocations

5. Mechanism is best in polar protic solvents

Why does the reaction below occur witha weaker nucleophile and a protic solvent?

CH3

CH3

CH3

Br

H2O

CH3

CH3

CH3

OH

To answer this kind of a question we returnto the mechanism of a rxn and its energydiagram.

This is an Energy Diagram for an SN1 Rxn

Stereochemistry of SN1

The stereochemistry of SN1 is determined by the structure of the C+ intermediate.

Stereochemistry of SN1

Examples of racemization in SN1

Effect of Carbocation Stability on the Reactivity of SN1 Reactions

CH3

Br

or

Br

Br Bror

Which RX in each pair reacts faster in an SN1 reaction?

Reactivity of RX in SN1 Rxns

Note: Methyl and primary RX do not undergo SN1 rxns

What is the explanation for this trend in SN1 reactivity among RX?

To answer this question we again returnto the mechanism and the energydiagram, in particular the T.S. of the r.d.s.

Carbocation stability affects the T.S. of the r.d.s.

Two questions:

(1) Why does the stability of C+ increase with more R groups?

(2) Why does the C+ affect the T.S.?

Carbocation stability is determined by:

(1) inductive effects and (2) hyperconjugation.

Let’s look at the inductive effect argument first

More positive charge at C+ = a more unstable C+

Carbocation Stability and Hyperconjugation

Delocalization of the positive charge on

C+ = increased carbocation stability

Now let’s look at the second question.s:

(2) Why does the C+ affect the T.S.?

(1) Why does the stability of C+ increase with more R groups?

The Hammond Postulate

We can’t see or measure the T.S. directly.

However, we can see or measure the reactantor product on either side of the T.S.

The T.S. should resemble the side which bestapproximates its energy.

The Hammond postulate states that the T.S. resembles the product in an endothermic rxn while the opposite is true in an exothermic rxn.

.

Now let’s look at the second question.s:

(2) Why does the C+ affect the T.S.?

(1) Why does the stability of C+ increase with more R groups?

Summary of SN1 Mechanism

Alkyl Halides and Nucleophilic Substitution

The Hammond Postulate

• The Hammond postulate relates reaction rate to stability. It provides a quantitative estimate of the energy of a transition state.

• The Hammond postulate states that the transition state of a reaction resembles the structure of the species (reactant or product) to which it is closer in energy.

Alkyl Halides and Nucleophilic Substitution

The Hammond Postulate

• In an endothermic reaction, the transition state resembles the products more than the reactants, so anything that stabilizes the product stabilizes the transition state also. Thus, lowering the energy of the transition state decreases Ea, which increases the reaction rate.

• If there are two possible products in an endothermic reaction, but one is more stable than the other, the transition state to form the more stable product is lower in energy, so this reaction should occur faster.

Alkyl Halides and Nucleophilic Substitution

The Hammond Postulate

• In the case of an exothermic reaction, the transition state resembles the reactants more than the products. Thus, lowering the energy of the products has little or not effect on the energy of the transition state.

• Since Ea is unaffected, the reaction rate is unaffected.

• The conclusion is that in an exothermic reaction, the more stable product may or may not form faster because Ea is similar for both products.

Alkyl Halides and Nucleophilic Substitution

SN1 Reactions, Nitrosamines and Cancer

• SN1 reactions are thought to play a role in how nitrosamines, compounds having the general structure R2NN=O, act as toxins and carcinogens.

Alkyl Halides and Nucleophilic SubstitutionPredicting the Likely Mechanism of a Substitution Reaction.• Four factors are relevant in predicting whether a given reaction

is likely to proceed by an SN1 or an SN2 reaction—The most important is the identity of the alkyl halide.

Alkyl Halides and Nucleophilic SubstitutionPredicting the Likely Mechanism of a Substitution Reaction.• The nature of the nucleophile is another factor. • Strong nucleophiles (which usually bear a negative charge)

present in high concentrations favor SN2 reactions.

• Weak nucleophiles, such as H2O and ROH favor SN1 reactions by decreasing the rate of any competing SN2 reaction.

• Let us compare the substitution products formed when the 20 alkyl halide A is treated with either a strong nucleophile HO¯ or the weak nucleophile H2O. Because a 20 alkyl halide can react by either mechanism, the strength of the nucleophile determines which mechanism takes place.

Alkyl Halides and Nucleophilic Substitution

Predicting the Likely Mechanism of a Substitution Reaction.• The strong nucleophile favors an SN2 reaction.

• The weak nucleophile favors an SN1 reaction.

Alkyl Halides and Nucleophilic SubstitutionPredicting the Likely Mechanism of a Substitution Reaction.• A better leaving group increases the rate of both SN1 and SN2

reactions.

Alkyl Halides and Nucleophilic Substitution

Predicting the Likely Mechanism of a Substitution Reaction.

• The nature of the solvent is a fourth factor.

• Polar protic solvents like H2O and ROH favor SN1 reactions because the ionic intermediates (both cations and anions) are stabilized by solvation.

• Polar aprotic solvents favor SN2 reactions because nucleophiles are not well solvated, and therefore, are more nucleophilic.

Alkyl Halides and Nucleophilic Substitution

Predicting the Likely Mechanism of a Substitution Reaction.

Alkyl Halides and Nucleophilic Substitution

Vinyl Halides and Aryl Halides.

• Vinyl and aryl halides do not undergo SN1 or SN2 reactions, because heterolysis of the C—X bond would form a highly unstable vinyl or aryl cation.

Alkyl Halides and Nucleophilic Substitution

Alkyl Halides and Nucleophilic Substitution

Nucleophilic Substitution and Organic Synthesis.

• To carry out the synthesis of a particular compound, we must think backwards, and ask ourselves: What starting material and reagents are needed to make it?

• If we are using nucleophilic substitution, we must determine what alkyl halide and what nucleophile can be used to form a specific product.

Alkyl Halides and Nucleophilic Substitution

Nucleophilic Substitution and Organic Synthesis.

• To determine the two components needed for synthesis, remember that the carbon atoms come from the organic starting material, in this case, a 10 alkyl halide. The functional group comes from the nucleophile, HO¯ in this case. With these two components, we can “fill in the boxes” to complete the synthesis.

Alkyl Halides and Nucleophilic Substitution

Mechanisms of Nucleophilic Substitution

The SN2 reaction is a key step in the laboratory synthesis of many important drugs.

Alkyl Halides and Nucleophilic Substitution

Mechanisms of Nucleophilic SubstitutionNucleophilic substitution reactions are important in biological systems as well.

This reaction is called methylation because a CH3 group is transferred from one compound (SAM) to another (:Nu¯).

CH3

Br

or

Br

Br Bror