Chapter 19: Chapter 19: AminesAminesChapter 19: Chapter 19: AminesAmines

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� Introduction (19-1)Amines are abundant in nature. There are many natural products with the amino group in their structures that you know. Can you name these compounds (common names)?

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Physical PropertiesPhysical Properties� Amines are basic (pH ~ 9-11).� Since they can hydrogen bond with each

other, boiling point is somewhat high, but not as high as alcohols since H-bonding is not as strong.not as strong.

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Effect of HEffect of H--Bond on Boiling PointBond on Boiling Point

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Synthesis of Amines Synthesis of Amines (review)(review)• Reduction of Nitriles (19-21)

Nitriles can be produced by SN2 reaction of alkyl halides. Reduction produces the corresponding amines. corresponding amines.

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• Reduction of Amides (19-20)Amides can also be reduced to the corresponding amines using LiAlH4.

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� Reduction of Aromatic Nitro Group (19-21)Aromatic nitro (NO2) group can be reduced to the corresponding amine under two different set of conditions. Non-aromatic nitro group are not reactive.

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New Synthesis of AminesNew Synthesis of Amines

• SN2 reaction with Alkyl Halides (19-12)This is not a good method to make amines, because the resulting product is more reactive than the original nucleophile due reactive than the original nucleophile due to the inductive effect.

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• SN2 reaction of Azide ion/reduction (19-21)This is a much better way to make amines via the SN2 reaction. Reduction of the alkyl azide that is formed yields the amine.

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� Gabriel Synthesis (19-21)This second indirect method involves the SN2 reaction of an imide followed by its hydrolysis generating 1o amines. The first step is a simple SN2 reaction: deprotonation of the nitrogen, followed by nucleophilic attack. The hydrolysis can be either acid or base catalyzed.catalyzed.

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BaseBase--catalyzed hydrolysis of the alkyl catalyzed hydrolysis of the alkyl imide.imide.

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� An alternative second step is to react the alkylated phthalimide with hydrazine generating the very stable phthalimide hydrazide and a primary amine.

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Practice QuestionPractice Question

� Complete the following reactions.

N H

O1) EtO-

2) CH2=CHCH2Br

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O 3) NaOH/H2O,

N H

O

O

1) EtO-

2)

4) NaOH/H2O,

I

3) H3O+,

� Reductive Amination (19-19)We have seen in chapter 18 that amines react with ketones and aldehydes to give imines and enamines. It is possible to reduce these compounds as they are formed, hence producing substituted amines.amines.◦ The intermediate can be an imine, enamine or

oxime.◦ A reducing agent is necessary, either H2/catalyst

or a borohydride reagent, or LiAlH4 are commonly used.

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� Hofmann Rearrangement (19-21)Primary amide react with bromine under basic condition to produce amines via a rearrangement reaction. The reaction is limited to primary amide. Secondary and tertiary do not give the reaction.

NH2

O NaOH

Br2/H2ONH2 + CO2

NH

O NaOH

Br2/H2Ono reaction

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Mechanism of Hofmann RearrangementMechanism of Hofmann Rearrangement

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Practice QuestionPractice Question� Complete the following reactions.

NH2

O

NaOH

Br2 / H2O

HN NaOH

Br2 / H2O

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Br2 / H2O

Reactions of AminesReactions of Amines (Review)(Review)

� Acylation (19-13)

Amines react with acid chlorides and anhydrides to give amides.

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� Imine and Enamine Formations (19-10)Reaction with aldehydes and ketones give either imines (with 1o amines) or enamines (with 2o amines).

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New Reactions of AminesNew Reactions of Amines� Hofmann Elimination (19-15)

Reaction of quaternary ammonium salt in the presence of a base gives alkenes following the Hofmann elimination mechanism. The least substituted alkene is produced, hence the name: Hofmann product.Hofmann product.

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� The reaction is a three step process.

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� If the ammonium salt has more than one ββββ-hydrogen, the least substituted will be removed. This is due to the stability of the anion like transition state of the elimination.

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Practice QuestionPractice Question� How would you prepare the following

compounds from the identified starting material?

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� Oxidation/Cope Elimination (19-16)Amines can be oxidized with hydrogen peroxide (or a peracid) to other nitrogen containing compounds that also possess oxygen in their structure. The oxidation level of nitrogen containing compounds follow the trend below:

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� All amines can be oxidized:◦ 1o amines can be oxidized all the way to the

nitro function

◦ 2o and 3o amines give either the hydroxylamine ◦ 2o and 3o amines give either the hydroxylamine or the tertiary amine oxide

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R NHR NOH

[O]

2o amine hydroxylamine

RR N

R N+

O-[O]

3o amine amine oxide

R

R

R RR

� The Cope elimination reaction takes place when the tertiary amine oxide is heated. An alkene and hydroxylamine are produced.

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� This process is very similar to the Hofmann elimination seen before, but is internal to the molecule. Once again, the least substituted alkene is produced (the Hofmann product). The deprotonation takes place at the ββββ-carbon.

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� The entire reaction process can be summarized by the reaction:

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Practice QuestionPractice Question� What are the products of the following

reactions?

NH2O2

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H2O2

N

Reactions of Aryl AminesReactions of Aryl Amines

� Halogenation (19-11)We have seen in the first semester that the amino group is amongst the strongest activator in aromatic

NH2

strongest activator in aromatic substitution. In fact, it is so strong, that most reactions of aromatic amines do not require the activation of the electrophile.

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� Reactions of Arenediazonium Salts (19-18)A very important reaction in aromatic chemistry since this represents is a nucleophilic substitution where the aromatic system is now the electrophile. The reaction uses the aromatic amine to form a diazonium salt that will be attack by form a diazonium salt that will be attack by nucleophiles.

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� The diazonium salt can be formed from an the aromatic amine by treatment with nitrous acid (HNO2).

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Mechanism of Diazonium ion FormationMechanism of Diazonium ion Formation

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� A large variety of nucleophiles can now displace N2and give nucleophilic aromatic substitutions.

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� When a copper (I) salt is reacted with the diazonium ion, the reaction is known as the Sandmeyer reaction.

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� Iodo and fluoro benzenes can also be prepared using different nucleophiles.

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� Phenols can be formed by addition of aqueous acid.

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� Treatment with hypophosphorus acid (H3PO2) provide the benzene derivative

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Practice QuestionPractice Question

� Complete the following reactions.

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