Chapter 19 Amines - PSAU · When the amino group of aniline is acetylated, the resulting amide is...

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Copyright © 2010 Pearson Education, Inc.

Organic Chemistry, 7th Edition L. G. Wade, Jr.

Amines

• Amines are formally derivatives of

ammonia, wherein one or more

hydrogen atoms have been replaced

by a substituent such as an alkyl or

aryl group (these may respectively

be called alkylamines and

arylamines; amines in which both

types of substituent are attached to

one nitrogen atom may be called

alkylarylamines).

• Classification of amines

• Primary (1): Has one alkyl group bonded to the nitrogen (RNH2).

• Secondary (2): Has two alkyl groups bonded to the nitrogen (R2NH).

• Tertiary (3): Has three alkyl groups bonded to the nitrogen (R3N).

• Quaternary (4): Has four alkyl groups bonded to the nitrogen and the nitrogen bears a positive charge(R4N

+).2

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IUPAC Names

Name is based on longest carbon chain.

-e of alkane is replaced with -amine.

Substituents on nitrogen have N- prefix.

3-bromo-1-pentanamine N,N-dimethyl-3-hexanamine

NH2CH2CH2CHCH2CH3

Br

CH3CH2CHCH2CH2CH3

N(CH3)2

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Common Names

In aromatic

amines, the amino

group is bonded to

a benzene ring.

Parent compound

is called niline.

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Heterocyclic AminesWhen naming a cyclic amine the nitrogen is

assigned position number 1.

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Amine as Substituent

On a molecule with a higher priority functional

group, the amine is named as a substituent.

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Biologically Active Amines

The alkaloids are an important group of biologically active amines, mostly synthesized by plants to protect them from being eaten by insects and other animals.

Many drugs of addiction are classified as alkaloids.

Dopamine is a neurotransmitter.

Epinephrine is a bioregulator.

Niacin, Vitamin B6, is an amine.

Alkaloids: nicotine, morphine, cocaine

Amino acids

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Structure of Amines

Nitrogen is sp3 hybridized with a lone pair of electrons.

The angle is less than 109.5º.

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Boiling Points

N—H less polar than O—H.

Weaker hydrogen bonds, so amines will have a lower

boiling point than the corresponding alcohol.

Tertiary amines cannot hydrogen-bond, so they have

lower boiling points than primary and secondary

amines.

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Solubility and Odor

Small amines (< 6 Cs) are soluble in water.

All amines accept hydrogen bonds from water

and alcohol.

Branching increases solubility.

Most amines smell like rotting fish.

1,5-pentanediamine or cadaverine

NH2CH2CH2CH2CH2CH2NH2

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Basicity of Amines

Lone pair of electrons on nitrogen can

accept a proton from an acid.

Aqueous solutions are basic to litmus.

Ammonia pKb = 4.74

Alkyl amines are usually stronger bases

than ammonia.

Increasing the number of alkyl groups

decreases solvation of ion, so 2 and 3

amines are similar to 1 amines in basicity.

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Alkyl Group Stabilization of Amines

Alkyl groups make the nitrogen a stronger

base than ammonia.

13

Reactivity of Amines

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Resonance Effects

Any delocalization of the electron pair weakens the base.

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Protonation of Pyrrole

When the pyrrole nitrogen is protonated,

pyrrole loses its aromatic stabilization.

Therefore, protonation on nitrogen is

unfavorable and pyrrole is a very weak base.

16

Hybridization Effects

Pyridine is less basic than aliphatic amines,

but it is more basic than pyrrole because it

does not lose its aromaticity on protonation.

Hückel's Rule

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The molecule is cyclic (a ring of atoms)

The molecule is planar (all atoms in the molecule lie

in the same plane)

The molecule is fully conjugated(p orbitals at every

atom in the ring)

The molecule has 4n+2π electrons (n=0 or any

positive integer)

http://chemwiki.ucdavis.edu/Organic_Chemistry/Hydrocarbons/Arenes/Properties_of_Arenes/Aromaticity/H

%C3%BCckel's_Rule

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Reaction of Amines with Carbonyl

Compounds

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Electrophilic Substitution

of Aniline

—NH2 is strong activator, ortho- and

para-directing.

Multiple alkylation is a problem.

Protonation of the amine converts the

group into a deactivator (—NH3+).

Attempt to nitrate aniline may burn or

explode.

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Protonation of Aniline in

Substitution Reactions

Strongly acidic reagents protonate the amino group, giving an ammonium salt.

The —NH3+ group is strongly deactivating (and meta-

allowing).

Therefore, strongly acidic reagents are unsuitable for substitution of anilines.

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Orientation and Reactivity Effects of Ring Substituents

Activating Substituents

ortho & para-Orientation

Deactivating Substituents

meta-Orientation

Deactivating

Substituents

ortho & para-

Orientation

–O(–)

–OH

–OR

–OC6H5

–OCOCH3

–NH2

–NR2

NHCOCH3

–R

–C6H5

–NO2

–NR3(+)

–PR3(+)

–SR2(+)

–SO3H

–SO2R

–CO2H

–CO2R

–CONH2

–CHO

–COR

–CN

–F

–Cl

–Br

–I

–CH2Cl

CH=CHN

O2

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Electrophilic Substitution

of Pyridine

Strongly deactivated by electronegative N.

Substitutes in the 3-position.

Electrons on N react with electrophile.

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Electrophilic Aromatic Substitution

of Pyridine

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Electrophilic Aromatic Substitution

of Pyridine (Continued)

Attack at the 2-position would have an

unfavorable resonance structure in which the

positive charge is localized on the nitrogen.

Substitution at the 2-position is not observed.

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The Octet Rule is violated in these three scenarios:

1. When there are an odd number of valence electrons

2. When there are too few valence electrons

3. When there are too many valence electrons

The octet rule states that elements gain or lose electrons

to attain an electron configuration of the nearest noble gas.

Noble Gases have complete outer electron shells,

which make them very stable.

Octet Rule

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Nucleophilic Substitution

of Pyridine

Deactivated toward electrophilic attack.

Activated toward nucleophilic attack.

Nucleophile will replace a good leaving group in the 2- or 4-position.

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Mechanism for

Nucleophilic Substitution

Attack at the 3-position does not have the

negative charge on the nitrogen, so

substitution at the 3-position is not observed.

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Acylation of Amines

Primary and secondary amines react with

acid halides to form amides.

This reaction is a nucleophilic acyl

substitution.

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Acylation of Aromatic Amines

When the amino group of aniline is acetylated, the resulting amide is still activating and ortho, para-directing.

Acetanilide may be treated with acidic (and mild oxidizing) reagents to further substitute the ring.

The acyl group can be removed later by acidic or basic hydrolysis.

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Show how you would accomplish the following synthetic conversion in good yield.

Problem 1

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Formation of Sulfonamides

Primary or secondary amines react with

sulfonyl chloride.

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Synthesis of Sulfanilamide

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Hofmann Elimination

A quaternary ammonium salt has a good

leaving group—a neutral amine.

Heating the hydroxide salt produces the least

substituted alkene.

After the first step, a quaternary ammonium iodide salt is created. After replacement of

iodine by an hydroxyl anion, an elimination reaction takes place to the alkene.

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Mechanism of the Hofmann Elimination

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Oxidation of Amines

Amines are easily oxidized, even in air.

Common oxidizing agents: H2O2 , MCPBA.

2 Amines oxidize to hydroxylamine (—NOH)

3 Amines oxidize to amine oxide (R3N+—O-)

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Preparation of Amine Oxides

Tertiary amines are oxidized to amine oxides,

often in good yields.

Either H2O2 or peroxyacid may be used for

this oxidation.

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Reductive Amination: 1º Amines

Primary amines result from the condensation of

hydroxylamine (zero alkyl groups) with a ketone or an

aldehyde, followed by reduction of the oxime.

LiAlH4 or NaBH3CN can be used to reduce the oxime.

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Reductive Amination: 2º Amines

Condensation of a ketone or an aldehyde with a primary amine forms an N-substituted imine (a Schiff base).

Reduction of the N-substituted imine gives a secondary amine.

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Reductive Amination: 3º Amines

Condensation of a ketone or an aldehyde with a

secondary amine gives an iminium salt.

Iminium salts are frequently unstable, so they are

rarely isolated.

A reducing agent in the solution reduces the iminium

salt to a tertiary amine.

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Synthesis of 1º Amines by

Acylation–Reduction

Acylation of the starting amine by an acid chloride gives an amide with no tendency toward overacylation.

Reduction of the amide by LiAlH4 gives the corresponding amine.

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Synthesis of 2º Amines by

Acylation–Reduction

Acylation–reduction converts a primary amine

to a secondary amine.

LiAlH4, followed by hydrolysis, can easily

reduce the intermediate amide to the amine.

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Synthesis of 3º Amines by

Acylation–Reduction

Acylation–reduction converts a secondary

amine to a tertiary amine.

Reduction of the intermediate amide is

accomplished with LiAlH4.

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Show how to synthesize N-ethylpyrrolidine from pyrrolidine using acylation–reduction.

Solved Problem 4

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Reduction of Azides

Azide ion, N3-, is a good nucleophile.

React azide with unhindered 1 or 2 halide

or tosylate (SN2).

Alkyl azides are explosive! Do not isolate.

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Reduction of Nitriles

Nitrile (CN) is a good SN2 nucleophile.

Reduction with H2 or LiAlH4 converts the

nitrile into a primary amine.

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Reduction of Nitro Compounds

The nitro group can be reduced to the amine

by catalytic hydrogenation or by an active

metal and H+.

Commonly used to synthesize anilines.

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The Hofmann Rearrangement of

Amides

In the presence of a strong base, primary amides react with chlorine or bromine to form shortened amines, with the loss of the carbonyl carbon atom.

This reaction, called the Hofmann rearrangement, is used to synthesize primary and aryl amines.

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Mechanism of the Hofmann

Rearrangement: Steps 1 and 2

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Mechanism of the Hofmann

Rearrangement: Steps 3 and 4

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