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Amines

Organic nitrogen compounds

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• Alkylamines: RNH2 ; arylamines: ArNH2

• Amines are classified as primary (1°), secondary (2°), or tertiary (3°):

• N atom is sp3 hybridized and trigonal pyramidal in shape.

Amine Structure

• The sp3 hybridized

nitrogen is stereogenic,

but the two enantiomers

interconvert quickly (N-

inversion) and make most

amines become achiral.

• A quarternary ammonium

salt with 4 different groups

cannot invert. The two

enantiomers can be

resolved and separated.

Chirality of Amines

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• Find the longest continuous chain bonded to the nitrogen, and change

the –e ending of the parent alkane to the suffix –amine.

• Number the chain and name the substituents.

• A substituent –NH2 is called amino group.

Nomenclature of Amines

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• Heterocyclic amines have unique names.

• The N atom is position “1” in each of these rings.

Aromatic and Heterocyclic Amines

• Aromatic amines are named as derivatives of aniline.

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• Due to the presence of lone pair e-, amines are basic and used mostly as

organic bases.

• N–H is less polar than O-H. Primary and 2° amines can form H-bonds,

but less than alcohols. Therefore, amines have lower bp than alcohols

(with comparable MW).

• 3° amines cannot form H-bonds: lower bp than 2°.

• Small amines (<6 C) are water soluble. (can form H-bonds with water)

• Larger nonpolar alkyl or aryl groups make them insoluble.

• Most small amines are terribly stinky.

Physical properties

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Preparation of Amines

• Nucleophilic Substitution: multiple alkylations

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• Practical substitutions:

Use excess NH3 gives 1 amines.

Use excess RX gives 4 salts.

Preparation of Amines

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• The deprotonated phthalimide reacts as Nu- in SN2.

• The substituted product is then either 1) hydrolyzed with aqueous base,

or 2) react with hydrazine to give the final 1 amine.

Gabriel Synthesis of 1° Amines

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• From azides

• From nitro compounds

Reductions

R

H

R

NO2

R

NH2HNO3

H2SO4

H2, catalyst

1. Fe, HCl2. NaOH

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Reductions • From nitriles: adding one more C atom to the substrate.

• From amides: the carbonyl group is reduced to CH2

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• Nucleophilic addition of amine/NH3 on the carbonyl forms an imine.

• Reduction of the imine forms an amine. Sodium cyanoborohydride

(NaBH3CN) is the preferred reducing agent.

Reductive Amination

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• Determine what aldehyde or ketone and nitrogen compound are needed

to prepare a given amine.

Reductive Amination in Synthesis

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• Dominated by the lone pair electrons on nitrogen

• Amines are stronger bases and nucleophiles than other neutral organic

compounds.

• Amino group increases electron density in aniline and makes it more

reactive towards electrophilic substitution.

Reactions of Amines

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• The ammonium salt is water soluble, can be “extracted” from organic

mixture.

Amines as Bases

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• The relative basicity can be compared using the pKa values of their

conjugate acids.

• Basicity: 3 >2 >1 > NH3 in gas phase, because of electron donating

inductive effect of the R groups.

Basicity of Amines

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• The electron pair is delocalized on the benzene ring, which decreases

the electron density on N, and makes it less basic than alkylamines.

• Protonation on N of aniline destroys this delocalization.

• EDG on Ar- makes it more basic, EWG: makes it less basic.

Basicity of Anilines

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Non-basic Amides

• The electron pair is delocalized on the carbonyl oxygen by resonance,

and decreases the electron density on N.

• With acid, protonation occurs at the carbonyl oxygen, not the nitrogen,

because the resulting cation is resonance stabilized.

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• Nonaromatic heterocycles are as basic as normal aliphatic amines.

• For pyrrole, the N lone electron pair is part of the delocalized aromatic

system. This makes it unavailable as base. (Protonation would destroy

the aromaticity.)

• For pyridine, the N lone electron pair occupies an sp2 hybridized orbital.

With higher s-character, these electrons are held more tightly and make

them less basic.

Basicity of Heterocyclic Amines

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• Inductive effects: EDG bonded

to N increases basicity.

• Resonance effects: Delocalizing

the lone pair e- on N decreases

basicity.

• Aromaticity: Having the lone pair

electrons on N as part of the

aromatic system decreases

basicity.

• Hybridization effects: Increasing

s-character in the orbital

occupying the lone pair e-

decreases basicity.

Factors That Determine Amine Basicity

• Examples: Basicity order in gas

phase: R3N > R2NH > RNH2 >

NH3.

• Arylamines (ArNH2) are less

basic than alkylamines (RNH2).

Amides (RCONH2) are much

less basic than amines.

• Pyrrole is less basic than

pyridine.

• Pyridine is less basic than

piperidine.

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• The Hofmann elimination converts an amine into an alkene.

• Repeated methylations [1] create a good leaving group, OH- generated

from silver oxide [2] then attack -H and eliminate through E2

mechanism. [3]

E2 Eliminations: Hofmann

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E2 Eliminations: Hofmann

• The quarternary ammonium group is large and bulky.

• The base removes a proton from the less substituted, more accessible

carbon atom.

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E2 Eliminations: Hofmann

• The major alkene has the less-substituted double bond.

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Reactions with Aldehydes and Ketones

• Reactions with 1 amines form imines, with 2 amines form enamines.

• Nucleophilic addition of the amine to the carbonyl group, then lose water

to the products.

• Imines can be reduced to amines. (reductive amination)

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Reactions with Acid Derivatives

• Reactions with acid chlorides and anhydrides form amides.

• Nucleophilic attack on the carbonyl group, followed by elimination of the

leaving group, resulting in substitution.

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Amides as Protecting Groups

• Anilines cannot undergo Friedel–Crafts reaction due to direct reaction

with Lewis acid.

• Anilines can be first protected as anilides, undergo Friedel-Crafts, then

deprotected by hydrolysis to give the substitution products.

• Nitrous acid, HNO2, is formed from NaNO2 and a strong acid.

Diazotization

• Alkyl diazonium salts are unstable and decompose to carbocations,

which then form a complex mixture of many products.

• Diazotization: reaction of HNO2 and 1 amine to form diazonium salt.

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• Aryl diazonium salts are stable below 5C, and can undergo

substitutions replacing N2, a very good leaving group.

• Diazonium salts react with water at high temperature to form phenols.

• Diazonium salts react with hypophosphorus acid (H3PO2) to form

arenes. (deamination)

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Substitutions of Aryl Diazonium Salts

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• A diazonium salt reacts with copper(I) chloride/bromide to form an aryl

chloride/bromide. An alternative to direct chlorination/bromination.

• Similar reaction with copper(I) cyanide forms benzonitrile.

Sandmeyer Reactions

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• Diazonium salts react with fluoroboric acid (HBF4) to form aryl fluorides.

More Substitutions on Diazonium Salts

• Diazonium salts react with sodium/potassium iodide to form aryl iodides.

• No copper is needed for these reactions.

• Aryl fluorides and iodides cannot be produced by direct halogenation.

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• Aryl diazonium salt + aromatic compound with strong EDG (NR2 or OH),

the two rings join together to form an azo compound. (Ar-N=N-Ar’)

• The mechanism is electrophilic aromatic substitution.

• Azo compounds are highly conjugated, rendering them colored.

• Many of these compounds are synthetic dyes.

Coupling Reactions of Aryl Diazonium Salts

Methyl orange

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Substitutions of Aryl Diazonium Salts

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Synthesis of 1,3,5-Tribromobenzene

• It is not possible to synthesize 1,3,5-tribromobenzene from benzene by

direct bromination.

• The NH2 group on aniline is a very powerful o,p director, three Br atoms

are introduced in a single step on halogenation.

• Remove the NH2 group by diazotization and reaction with H3PO2.

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Synthesis of 1,3,5-Tribromobenzene

• The four-step diazo sequence:

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Synthesis of m-bromotoluene

CH3CH3 CH3

N2 +

p-Toluidine 65%(from p-Toluidine)

NH2 HN NH2

O

O2

(1) Br2

(2) OH, H2OBrheat

H2SO4, NaNO2

H2O, 0 - 5oC

H2O, 25oC

O

H3PO2

CH3

N2

Br

CH3

Br

m-Bromotoluene(85% from 2-bromo-

4-methylaniline)

• The use of N-protection:

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Analysis of Amines

• Most small amines dissolve in aqueous acid solution.

• Water-soluble amines change the color of litmus paper from red to blue.

• Hinsberg test is used to differentiate 1, 2, 3 water-insoluble amines.

• The test: amines + benzenesulfonyl chloride + KOH solution, observe

the solubility, then acidified by HCl solution

• 1 amines give clear solution in base, but precipitate in acid.

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Hinsberg test

• 2 amines give precipitate in base, which is still insoluble in acid.

• 3 amines do not react with the reagent. The compounds themselves

remain insoluble (oil/precipitate) in base, but dissolve in acid.

• Summary:

Amine

type

primary secondary tertiary

base dissolve precipitate insoluble

acid precipitate precipitate dissolve

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• 1° and 2° Amines show two and one N–H absorptions respectively, at

3300–3500 cm−1. 3° amines show none in this region.

IR Spectra of Amines

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• in 1H NMR, the N–H signal is broad and appears at 0.5 and 5.0 ppm,

depending on the degree of H-bonding and the sample concentration.

• NH absorption is not split by adjacent protons, nor does it cause splitting

of adjacent C–H.

• The protons on the -carbon bonded to the nitrogen absorb at 2.3–3.0

ppm. In 13C NMR, this carbon absorbs at 30–50 ppm.

NMR Spectra of Amines