Chapter 7 Alkyl Halides and 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

Name these compounds.

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 S N reaction

An RX S N 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 S N

Which is a better leaving group H 2 O or OH - ?

Conjugate Bases of Strong Acids Are Good LGs HCl ______ H 3 O+ ________ HF ______ HCN ______ HBr ________ H 2 O ______

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? = K a 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 used in organic chemistry. Protic - solvents that are polar but also possess a hydrogen bond Aprotic - solvents that are polar but have no hygrogen bond

These are examples of protic solvents (Fig 7.6) H 2 O, CH 3 OH, CH 3 CH 2 OH, (CH 3 ) 3 COH, and CH 3 COOH

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 always make it less nucleophilic…....however large R groups do not affect the basicity.

The S N 2 Mechanism

Energy Diagram for the S N 2 Rxn

Key Characteristics of the S N 2 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 S N 2 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 S N 2 Mechanism

Inversion of configuration is known as the Walden inversion.

Draw the product of each rxn to include the correct stereochemistry.

S N 2 : Effect of Steric Hindrance

Larger R groups will decrease the rate constant of S N 2 rxns

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

The S N 2 Mechanism: Summary

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

Let’s look at two possibilities

The S N 1 Mechanism

Key Characteristics of the S N 1 Mechanism 1.A two step 1  order rxn 2.Nu attacks from the top and bottom sides of the C+ intermediate. 3. Reactant undergoes racemization

Key Characteristics of the S N 1 Mechanism (continued) 4.Mechanism favored by stable carbocations 5. Mechanism is best in polar protic solvents

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

To answer this kind of a question we return to the mechanism of a rxn and its energy diagram.

This is an Energy Diagram for an S N 1 Rxn

Stereochemistry of S N 1

The stereochemistry of S N 1 is determined by the structure of the C+ intermediate.

Stereochemistry of S N 1

Examples of racemization in S N 1

Effect of Carbocation Stability on the Reactivity of S N 1 Reactions

Which RX in each pair reacts faster in an S N 1 reaction?

Reactivity of RX in S N 1 Rxns Note: Methyl and primary RX do not undergo S N 1 rxns

What is the explanation for this trend in S N 1 reactivity among RX?

To answer this question we again return to the mechanism and the energy diagram, 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 reactant or product on either side of the T.S.

The T.S. should resemble the side which best approximates 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 S N 1 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 E a, 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 E a 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 E a is similar for both products.

Alkyl Halides and Nucleophilic Substitution S N 1 Reactions, Nitrosamines and Cancer S N 1 reactions are thought to play a role in how nitrosamines, compounds having the general structure R 2 NN=O, act as toxins and carcinogens.

Alkyl Halides and Nucleophilic Substitution Predicting the Likely Mechanism of a Substitution Reaction. Four factors are relevant in predicting whether a given reaction is likely to proceed by an S N 1 or an S N 2 reaction—The most important is the identity of the alkyl halide.

Alkyl Halides and Nucleophilic Substitution Predicting 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 S N 2 reactions. Weak nucleophiles, such as H 2 O and ROH favor S N 1 reactions by decreasing the rate of any competing S N 2 reaction. Let us compare the substitution products formed when the 2 0 alkyl halide A is treated with either a strong nucleophile HO ¯ or the weak nucleophile H 2 O. Because a 2 0 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 S N 2 reaction. The weak nucleophile favors an S N 1 reaction.

Alkyl Halides and Nucleophilic Substitution Predicting the Likely Mechanism of a Substitution Reaction. A better leaving group increases the rate of both S N 1 and S N 2 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 H 2 O and ROH favor S N 1 reactions because the ionic intermediates (both cations and anions) are stabilized by solvation. Polar aprotic solvents favor S N 2 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 S N 1 or S N 2 reactions, because heterolysis of the C—X bond would form a highly unstable vinyl or aryl cation.

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 1 0 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 S N 2 reaction is a key step in the laboratory synthesis of many important drugs.

Alkyl Halides and Nucleophilic Substitution Mechanisms of Nucleophilic Substitution Nucleophilic substitution reactions are important in biological systems as well. This reaction is called methylation because a CH 3 group is transferred from one compound (SAM) to another (:Nu ¯ ).