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Amines

Nitrogen-Based Functional Groups

Amines as Pharmaceutical Agents

22.1Amine Nomenclature

The Naming of Parts

Alkylamines

Nitrogen atom isattached to alkyl group:

Arylamines

Nitrogen atom isattached to aryl group:

Nomenclature of Primary Alkylamines (RNH2)

Two IUPAC styles

1) analogous to alcohols: replace -e ending by -anamine

2) name alkyl group and attach -amine as a suffix

Nomenclature of Primary Alkylamines

n-propylamineor

propanamine

cyclopropylamineor

cyclopetanamine

2-bromo-3-chlorobutylamine

Nomenclature of Arylamines (ArNH2)

aniline

2,4-dibromoaniline

4-bromo-2-ethylaniline

These compounds are named as derivatives of aniline

Amino Groups have Lower Priority than Alcohols

aminoethanol

p-aminobenzoic acid

With regards to nomenclature, amines rank lower than alcohols and are named as substituents:

Secondary and Tertiary Amines

N,N-diisopropylethylamine(a.k.a. Hünig’s base)

4-bromo-N,N-dimethyl-2-methylaniline

Name as N-substituted derivatives of parent primary amine. The longest chain takes the root name.

Ammonium Salts (R4-nHnN+ X-)

Nitrogen atoms are positively charged when bonded to four substituents. The root name in this case is the ammonium ion (NH4

+). Remember to name as a salt - two words.

methylammonium acetate

N-ethyl-N-methylbenzylammonium chloride

Quaternary Ammonium Salts (R4N+ X-)

Nitrogen atoms are positively charged when bonded to four

substituents: when all of these substituents are carbon, the

molecule is referred to as a quaternary ammonium ion.

tetrabutylammonium fluoride(TBAF)

benzyltrimethylammonium hydroxide

Quaternary ammonium salts are relatively soluble in organic solvents and consequently are used as phase transfer catalysts

22.2Structure and Bonding

of Amines

147 pm147 pm

106°106°112°112°

Structure of Alkylamines

Note the high electron density on the nitrogen atom. The

chemistry of amines is dominated by reactivity of the lone

pair on this atom. Amines behave as nucleophiles and

Bronsted bases.

Alkylamines - Distribution of Electron Density

The hybridization adopted by nitrogen depends upon the nature of the N-substituents.Compare methylamine and formamide:

Alkylamines - Hydridization at Nitrogen

the hybridization adopted by nitrogen depends upon the nature of the N-substituents - compare methylamine and formamide.

Amines & Amides - Geometry at Nitrogen

Angle that the C—N bond makes with bisector ofH—N—H angle is a measure of the pyramidalization at nitrogen.

spsp33 spsp22

~125°~125°180°180°

142.5°142.5°

Amines - Geometry at Nitrogen

Angle that the C—N bond makes with bisector ofH—N—H angle is a measure of the pyramidalization at nitrogen.

142.5°142.5°

Amines - Geometry at Nitrogen

Geometry at the nitrogen atom in aniline is pyramidal; closer tomethylamine than to formamide.

142.5°142.5°

The hybridization of the nitrogen atom in aniline lies between sp2 and sp3

1) Delocalization of the nitrogen lone pair into the aromatic ring is most effective if the nitrogen atom is sp2-hybridized and planar.

2) A planar nitrogen atom increases repulsion between filled lone pair orbital and -system of aromatic ring - sp3 hybridization reduces this “bad” interaction.

Geometry of Aniline

Aniline - Distribution of Electron Density

Enforce a non-planar geometry (sp3-like) at the nitrogen center

- highest negative potential is on nitrogen.

Enforce a planar geometry (sp2-like) at the nitrogen center

- negative potential is shared by both nitrogen and ring.

22.3Physical Properties of

Amines

Amines - Physical Properties

Amines are more polar and have higher boiling points than alkanes; but are less polar andhave lower boiling points than alcohols.

CH3CH2CH3 CH3CH2NH2 CH3CH2OH

dipolemoment ():

boiling point:

0 D 1.2 D 1.7 D

-42°C 17°C 78°C

Amines - Physical Properties

Boiling points of isomeric amines decrease ingoing from primary to secondary to tertiary amines.

Primary amines have two hydrogens on nitrogen capable of being involved in intermolecular hydrogen bonding. Secondary amines have one. Tertiary amines cannot be involved in intermolecular hydrogen bonds.

CH3CH2NHCH3CH3CH2CH2NH2 (CH3)3N

boilingpoint:

50°C 34°C 3°C

22.4Basicity of Amines

Amines are Brønstead Bases and Nucleophiles

Brønstead Basicity of Amines

Basicity of Amines in Aqueous Solution

The Relationship between pKa and Basicity

The Relationship Between Basicity and Structure

Arylamines are Relatively Weak Brønstead Bases

Anilinium Ion

Arylamines are Relatively Weak Brønstead Bases

Increasing delocalization makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine.

Arylamines - Effect of Substituents on Basicity

1. Alkyl groups on the ring increase basicity by only one 1 pK unit.

2. Electron withdrawing groups, especially orthoand/or para to amine group, decrease basicityand can have a large effect.

Arylamines - Effect of Substituents on Basicity

Basicity of Arylamines - p-Nitroaniline

Lone pair on amine nitrogen is conjugated with p-nitro group—more delocalized than in aniline itself. This delocalization is lost upon protonation.

Electron Withdrawing Effects are Cumulative

piperidine pyridinepyridinepKa of conjugate acid:

11.2

pKa of conjugate acid:

5.2

(an alkylamine)(an alkylamine)(resembles an(resembles anarylamine inarylamine in

basicity)basicity)

Heterocyclic Amines

imidazole pyridinepKa of conjugate acid:

7.0

pKa of conjugate acid:

5.2

Heterocyclic Amines

q. Which nitrogen is protonated in imidazole?

Protonation of Imidazole

Protonation in the direction shown gives a stabilized ion.

Protonation of Imidazole - Resonance Picture

The Term ‘Alkaloid’

Amines as Natural Products - Alkaloids

Conium maculatum Hemlock contains the alkaloid

coniine, among other compounds

The Toxic Alkaloids of Conium maculatum

Reduction of Nitroarenes - Example

Aromatic nitro compounds are easy to prepare and are readily Aromatic nitro compounds are easy to prepare and are readily reduced to the corresponding anilines under a wide range of reduced to the corresponding anilines under a wide range of conditions.conditions.

Reduction of Nitroarenes - Example

18.918.9

The Aldol CondensationThe Aldol Condensation

Aldol CondensationAldol Condensation

Aldol Condensation of ButanalAldol Condensation of Butanal

dehydration of dehydration of -hydroxy aldehyde can be-hydroxy aldehyde can be

catalyzed by either acids or basescatalyzed by either acids or bases

Dehydration of Aldol Addition ProductDehydration of Aldol Addition Product

CC OO

CC

CCOHOH

HHCC OO

CC

CC

in base, the enolate is formed in base, the enolate is formed


OHOH

HHCC OO

CC

CC

NaOHNaOH

OHOH

CC OO

CC

CC

••••––

the enolate loses hydroxide to form the the enolate loses hydroxide to form the

,,-unsaturated aldehyde-unsaturated aldehyde


OHOH

HHCC OO

CC

CC

NaOHNaOH

OHOH

CC OO

CC

CC

••••––

Aldol reactions of ketonesAldol reactions of ketones

the equilibrium constant for aldol addition the equilibrium constant for aldol addition reactions of ketones is usually unfavorablereactions of ketones is usually unfavorable

Termite Self-Defense!

Diethyl Zinc and Deacidification of Brittle BooksDiethyl Zinc and Deacidification of Brittle Books

14.1314.13Carbenes and Carbenes and

CarbenoidsCarbenoids

CarbeneCarbene

name to give to species that contains aname to give to species that contains adivalent carbon (carbon with two bondsdivalent carbon (carbon with two bondsand six electrons)and six electrons)

CC••••

BrBr BrBr

dibromocarbenedibromocarbene

Carbenes are very reactive; normally cannot be Carbenes are very reactive; normally cannot be isolated and stored.isolated and stored.Are intermediates in certain reactions.Are intermediates in certain reactions.

Generation of DibromocarbeneGeneration of Dibromocarbene

CC

BrBr

BrBr

BrBr

HH ++ OC(CHOC(CH33))33

––

••••

••••••••

HH++ OC(CHOC(CH33))33••••

••••CC

BrBr

BrBr

BrBr

––••••

Generation of DibromocarbeneGeneration of Dibromocarbene

++

CC

BrBr

BrBr

BrBr

––••••

CC••••

BrBr BrBr BrBr––

Carbenes react with alkenesCarbenes react with alkenesto give cyclopropanesto give cyclopropanes

+ CH+ CHBrBr33

BrBr

BrBr

(75%)(75%)CBrCBr22 is a highly reactive is a highly reactive (shortlived) intermediate(shortlived) intermediate

KOC(CHKOC(CH33))33

(CH(CH33))33COHCOH

Why the synthesis ofWhy the synthesis ofcyclopropanes is important?cyclopropanes is important?

Chrysanthemum cinerariaefolium

Why the synthesis ofWhy the synthesis ofcyclopropanes is important?cyclopropanes is important?

20.720.7Sources of EstersSources of Esters

3-methylbutyl acetate

also called "isopentyl acetate" and "isoamyl also called "isopentyl acetate" and "isoamyl acetate"acetate"

contributes to characteristic odor of bananascontributes to characteristic odor of bananas

Esters are Commonly Found in Natural Products

R, R', and R" can be the same or differentR, R', and R" can be the same or different

called "triacylglycerols," "glyceryl triesters," or called "triacylglycerols," "glyceryl triesters," or "triglycerides""triglycerides"

fats and oils are mixtures of glyceryl triestersfats and oils are mixtures of glyceryl triesters

Esters of Glycerol

Tristearin: found in manyanimal and vegetable fats

Fat & Oil are Mixtures of Glyceryl Triesters

(Z)-5-Tetradecen-4-olide(Z)-5-Tetradecen-4-olide(sex pheromone of female Japanese beetle)(sex pheromone of female Japanese beetle)

OOOO

HH

HH

CHCH22(CH(CH22))66CHCH33

Lactones are Cyclic Esters

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