the physical and chemical properties, and reactions of amines

The Physical and Chemical

Properties, and Reactions of

Amines

Chem-261

IntroductionOOrganic derivatives of ammoniaOMany are biologically active.

04/20/23Dr Seemal Jelani 2 =>

Classes of Amines

OPrimary (1): one C-N bond, 2 N-H bonds.

OSecondary (2): two C-N bonds, 1 N-H bond.

OTertiary (3): three C-N bonds, no N-H bond.

OQuaternary (4): four C-N bonds, nitrogen has a + formal charge. 04/20/23Dr Seemal Jelani 3

Classify:

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N

H

CH3 C

CH3

CH3

NH2

NCH3

CH3

CH3CH2 N

CH3

CH2CH3+

Br_

=>

Common NamesName the alkyl or aryl groups bonded to

nitrogen, then add suffix -amine.


(CH3CH2)2NCH3

NHCH3

NH

diethylmethylamine

cyclopentylmethylamine

Diphenylamine =>

Amine as SubstituentOOn a molecule with a higher priority

functional group the amine is named as a substituent.


NH2CH2CH2CH2COOH

NHCH3

OH

-aminobutyric acid or4-aminobutanoic acid

2-methylaminophenol =>

IUPAC NamesO Name is based on longest carbon chain.O -e of alkane is replaced with -amine.O Substituents on nitrogen have N- prefix.


NH2CH2CH2CHCH2CH3

BrCH3CH2CHCH2CH2CH3

N(CH3)2

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

=>

Aromatic AminesAmino group is bonded to a benzene ring. Parent compound is called aniline.


NH2

aniline

NCH3

CH3

N,N-dimethylaniline

=>

NH2

H3C

4-methylanilineor p-toluidine

Heterocyclic AminesThe nitrogen is assigned the

number 1.


N

H

N

H

N

HN N CH3

aziridinePyrrole

PyrrolidinePyridine

2-methylpyridine

Structure of AminesNitrogen is sp3 hybridized with a lone pair of

electrons in an sp3 orbital.


Chirality of AminesNitrogen may have 3 different groups and a lone pair, but enantiomers cannot be isolated due to inversion around N.


=>

Boiling PointsO N-H less polar than O-H.O Weaker hydrogen bonding.O Tertiary amines cannot hydrogen bond.


=>

Solubility and Odor

OSmall amines (<6 C) soluble in water.OAll amines accept hydrogen bonds from

water and alcohol.OBranching increases solubility.OMost amines smell like rotting fish.


NH2CH2CH2CH2CH2CH2NH2

1,5-pentanediamine or cadaverine=>

Basicity of AminesOLone pair of electrons on nitrogen can

accept a proton from an acidOAqueous solutions are basic to litmus.OAmmonia pKb = 4.74

OAlkyl amines are usually stronger bases than ammonia

O Increasing the number of alkyl groups decreases solvation of ion, so 2 and 3 amines are similar to 1 amines in basicity. 04/20/23Dr Seemal Jelani 14


OAlkyl Amine is more basic than ammonia because of the +I effect of the Alkyl group present

O It donates its electron cloud to the nitrogen group therefore nitrogen has a greater tendency to donate it lone pair of electrons

O This makes it more basic than ammonia where such a positive inductive effect is absent.

Why is alkyl amine more basic than ammonia?

Energy Diagram

Alkyl groups are electron-donating and stabilize the cation.


=>

Resonance EffectsAny delocalization of the electron pair weakens

the base.


=>

Amine Salts

OIonic solids with high melting points OSoluble in water ONo fishy odor

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Reactions of AminesChem-261


Reaction of AminesO Amines are BASES!

O React with acids and accept a proton (H+) to Form alkyl ammonium salts

methylamine

NH2H3C + HCl

methylammonium chlorideNH3

+ Cl-H3C

diethylamine

NH CH2 CH3CH2CH3 + HCl

diethylammonium chloride

NH2CH2 CH3CH2CH3+

Cl-

N,N-dimethylaniline

N CH3CH3

+ HCl

NH CH3CH3

N,N-dimethylanilinium chloride

+Cl-

Amines are BASES!React with acids and accept a proton (H+) to Form Alkyl Ammonium salts

Reaction of AminesO Amines are BASES!

?

Electrophilic Substitution of Aniline

O-NH2 is strong activator, o-,p-directing.

OMay trisubstituted with excess reagent.OH+ changes -NH2 to -NH3

+, a meta-directing deactivator.

OAttempt to nitrate aniline may explode.

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Aniline Substitution

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Electrophilic Substitution of Pyridine

OStrongly deactivated by electronegative N.OSubstitutes in the 3-position.OElectrons on N react with electrophile.


N

fuming H2SO4

HgSO4, 230oC

N

SO3H

=>

Chemistry of pyridine

Electrophilic substitution in pyridine

N CH3H3C

H N O 3

H 2 S O 4 N CH3H3C

NO2

81%

Pyridine is less active, than benzene towards electrophilic agents, because nitrogen is more electronegative, than carbon and acts like an electron withdrawing substituent,including the meta-directing effect.

Example:

Nucleophilic Substitutionof Pyridine

ODeactivated toward electrophilic attack.OActivated toward nucleophilic attack.ONucleophile will replace a good leaving

group in the 2- or 4-position.


N Cl

OCH3

_

N OCH3

+ Cl_

=>

Alkylation of AminesO Amines react with 1 alkyl halides via the SN2

mechanism.O Mixtures of the mono-, di-, and tri-alkylated

products are obtained.

04/20/23Dr Seemal Jelani 27 =>

Useful AlkylationsO Exhaustive alkylation to form the

tetraalkylammonium salt.


CH3CH2CHCH2CH2CH3

N(CH3)3

CH3CH2CHCH2CH2CH3

NH23 CH3I

NaHCO3

+ _I

• Reaction with large excess of NH3 to form the primary amine.

CH3CH2CH2BrNH3 (xs)

CH3CH2CH2NH2 + NH4Br

=>

Acylation of Aminesby Acid Chlorides

OAmine attacks C=O, chloride ion leaves.OProduct is amide, neutral, not basic.OUseful for decreasing activity of aniline

toward electrophilic aromatic substitution.


NH2

CH3 C

O

Cl

NH

C

O

CH3

N

to remove HCl=>

Formation of Sulfonamides

OPrimary or secondary amines react with sulfonyl chloride.


R NH2 S

O

O

R' Cl S

O

O

R' NH R

H

+Cl

_base S

O

O

R' NH R

• Sulfa drugs are sulfonamides that are antibacterial agents.

NH2

S OO

NH2=>

Oxidation of AminesOAmines are easily oxidized, even in air.OCommon oxidizing agents: H2O2 , MCPBA.OMeta chloroperoxybenzoic acidO2 Amines oxidize to hydroxylamine (-NOH)O3 Amines oxidize to amine oxide (-N+-O-)


=>


ONitrous acid is produced in situ by mixing sodium nitrite with HCl.

OThe nitrous acid is protonated, loses water to form the nitrosonium ion.

H O N OH

+

H O N O

H

+H2O + N O

+N O

+

=>

Nitrous Acid Reagent


O 1 Amines form diazonium salts, R-N+N.O Alkyldiazonium salts are unstable, but arenediazonium salts are widely used for synthesis.

O 2 Amines form N-nitrosoamines, R2N-N=O, found to cause cancer in laboratory animals.

=>

Reaction with Nitrous Acid

Arenediazonium SaltsO Stable in solution at 0°–10°C.O The -+NN group is easily replaced by many

different groups.O Nitrogen gas, N2, is a by-product.


HBF4 (KI)

H3O+

CuCl (Br)

CuCN

H3PO2

H Ar'

Ar N N+

Ar OH

Ar Cl

Ar C N

Ar F

Ar H

Ar N N Ar'

(Br)

(I)

phenolsaryl halides

benzonitriles

aryl halides

benzene

azo dyes =>

Synthesis by Reductive Amination

O To produce a 1 amine, react an aldehyde or ketone with hydroxylamine, then reduce the oxime.

O To produce a 2 amine, react an aldehyde or ketone with a 1 amine, then reduce the imine.

O To produce a 3 amine, react an aldehyde or ketone with a 2 amine, then reduce the imine salt. =>


Examples


primary amine

CH3CH2CH2 CH

NH2

CH3NiH2CH3CH2CH2 C

N

CH3

OH

H+

NH2 OHCH3CH2CH2 C

O

CH3

secondary amine

CH3 CH

NHCH3

CH32)

1)

H2O

LiAlH4CH3 C

NCH3

CH3H+

CH3NH2CH3 C

O

CH3

tertiary amine =>

C

N

H

CH3H3C

HNa(CH3COO)3BHC

N

H

CH3H3C+

H+

HN(CH3)2C

O

HCH3COOH

Acylation-ReductionO An acid chloride reacts with ammonia or a 1

amine or a 2 amine to form an amide.O The C=O of the amide is reduced to CH2 with

lithium aluminum hydride.O Ammonia yields a 1 amine.O A 1 amine yields a 2 amine.O A 2 amine yields a 3 amine.

=>


Examples


CH3 C

O

ClNH3

CH3 C

O

NH2

LiAlH4

H2O

1)

2)CH3 CH2 NH2

primary amine

LiAlH4

H2O

1)

2)C

O

ClHN(CH3)2

C

O

N(CH3)2CH2 N(CH3)2

tertiary amine =>

Direct Alkylation (1)O Use a large excess (10:1) of ammonia with a

primary alkyl halide or tosylate.O Reaction mechanism is SN2.


CH3CH2CH2 BrNH3

+CH3CH2CH2 NH2 NH4Br

=>

Gabriel Synthesis (1)O Use the phthalimide anion as a form of

ammonia that can only alkylate once.O React the anion with a good SN2 substrate,

then heat with hydrazine.


+N

O

O_

R XN

O

O

R H2N NH2heat

NH

NH

O

O

R NH2

=>

Azide Reduction (1)O Azide ion, N3

-, is a good nucleophile.

O React azide with unhindered 1 or 2 halide or tosylate (SN2).

O Alkyl azides are explosive! Do not isolate.


Br

NaN3

N3LiAlH4

H2O

1)

2)

NH2

=>

Nitrile Reduction (1)O Nitrile, -CN, is a good SN2 nucleophile.

O Reduction with H2 or LiAlH4 adds -CH2NH2.


Br

NaCN

CNLiAlH4

H2O

1)

2)

CH2NH2

=>

Reduction of Nitro Compounds (1)

O -NO2 is reduced to -NH2 by catalytic hydrogenation, or active metal with acid.

O Commonly used to synthesize anilines.


CH3

NO2

Zn, HCl

CH3CH2OH

CH3

NH2

=>

Hofmann Rearrangement of

Amides (1)In the presence of a strong base, primary amides react with chlorine or bromine to form amines with one less C.


C

O

NH2H2O

Br2, OH_

NH2

=>

the physical and chemical properties, and reactions of amines

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