Nomenclature for amines

t Common names are widely used, named as alkylamines t Systematic (IUPAC) nomenclature replaces the - e of the

Chapter 20 Amines

corresponding parent alkane with - amine

t Simple secondary and tertiary amines are named by designating

the organic groups separately in front of the word amine

t In systematic nomenclature, the smaller groups on the amine

nitrogen are designated as substituents and given the locant N

Aryl amines

t In IUPAC nomenclature the substitutent -NH2 is called the amino group

N H2

C HO

Cl N O2

N (C H 3)2

3-chloro-4-nitroaniline

p-dimethylaminobenzaldehyde

Heterocyclic Amines
t The important heterocyclic amines have common names t In IUPAC nomenclature the prefixes aza-, diaza- and triaza-

are used to indicate that nitrogen has replaced carbon in the corresponding hydrocarbon
H The nitrogen is assigned position 1 and the ring is numbered to give the lowest overall set of locants to the heteroatoms

DNA base pairs are a purine with a pyrimidine

Physical Properties and Structure of Amines

l Primary and secondary amines can form hydrogen bonds to

each other and water

l Tertiary amines cannot hydrogen bond to each other but can

form hydrogen bonds to hydrogen bond donors such as water

l Tertiary amines have lower boiling points than primary or

secondary amines of comparable molecular weights

l Low molecular weight amines tend to be water soluble whether

they are primary, secondary or tertiary

l Amines smell fishy (or worse)

Structure of Amines = sp3 hybridized

t The unshared electron pair around nitrogen - along with the

Organophosphorus analogs can be resolved

..
P CH3

three groups results in a tetrahedral geometry t The shape of the amine itself is trigonal pyramidal

Chiral: racemizes at 200o C

t Quaternary ammonium salts can be resolved into enantiomers l Nitrogen inversion not possible with 4 substituents t It is usually impossible to resolve amine enantiomers that are

chiral at nitrogen because they interconvert rapidly l Nitrogen inversion of the unshared electron pair

Basicity of Amines
t Amines are weak bases t Relative basicitydefined by pK a of its conjugate acid l The more basic the amine, the higher the pKa of its conjugate acid t In the gas phase, basicityin the family of methylamines increases with increasing methyl substitution l More alkyl substitution = more stabilization of the alkylaminium ion

t In aqueous solution, trimethylamine is less basic than dimethyl- or t Primary alkyl amines are more basic than ammonia l An alkyl group helps to stabilize the alkylaminium ion

methylamine

t Solvation of the ion becomes important t The trimethylaminium ion is solvated less well than the dimethylaminium ion, which has two hydrogen atoms for hydrogen bonding

t Arylamines are weaker bases than the corresponding

t Greater resonance stabilization of aniline than its anilinium

nonaromatic cyclohexylamines

ion means a larger Ho for protonation, as compared with Ho for protonation of an amine that is not aromatic

t The unshared electron pair on nitrogen of an arylamine is

delocalized to the ortho and para positions of the ring

l Lone pair is less available for protonation, i.e., it is less basic

t Less resonance stablization available to the anilinium ion

Amines versus Amides Basicity of Heterocyclic Amines

t Nonaromatic heterocyclic amines have comparable basicity t 1.

Amides are much less basic than amines

The pKa of a protonated amide is typically about zero

to acyclic counterparts

Amide is stabilized by resonance and protonated amide is not

t Aromatic heterocyclic amines (in aqueous solution) are

2.

The nitrogen lone pair is delocalized to the carbonyl oxygen

l l Amides are actually protonated at the oxygen atom Allows resonance stabilization of the positive charge

much weaker bases than nonaromatic amines

Aminium Salts and Quaternary Ammonium Salts

t Protonation of amines with acids leads to aminium salts l Aminium salts are formed from 1o, 2 o or 3o amines l An aminium ion bears at least one hydrogen

t Quaternary ammonium halides are not basic because they

do not have an unshared electron pair on nitrogen and are not acidic because they have no H to donate
t Quaternary ammonium hydroxides are very basic because

they contain the very strong base hydroxide

t Quaternary ammonium salts have four groups on the nitrogen l The nitrogen atom is positively charged but has no hydrogen atom

These ions can be soluble in water because they are charged They can also be soluble in organic solvents if alkyl groups are larger

Phase Transfer Catalysis (Solomons , p.504)

t General problem: anionic nucleophiles tend to be soluble in

Purple benzene??

water, but not organic solvents

Herriott and Picker, Journal of the American Chemical Society, 97, 2345 (1975) Herriott, Journal of Chemical Education, 54, 229 (1977)

Q+

= (Bu)4

N+

Solubility of Amines in Aqueous Acid

t Most aminium salts are water soluble
l Amines in soluble in water usually dissolve in dilute aqueous acid

Amines as Resolving Agents

t A chiral amines can be used to resolve a racemic mixture of

carboxylic acids by formation of diastereomeric salts

l Diastereomers = different physical properties (solubility, m.p .) l Acidification of the separated diastereomeric salts gives the resolved carboxylic acids

t Used as a chemical test to distinguish amines t Extraction : water-insoluble amines can be separated from other

water-insoluble organic compounds

l The amine is extracted into aqueous acid l The amine is recovered by making the solution basic and extracting the amine into an organic solvent t Amides are not basic and are not soluble in aqueous acids

Preparation of Amines
t Nucleophilic Substitution Reactions l Alkylation of Ammonia with an alkyl halide Initial aminium salt is treated with base to give the primary amine The method is limited because multiple alkylations usually occur

l Using an excess of ammonia helps to minimize multiple alkylations

Amines via Nucleophilic Substitution Reactions

Amines via Nucleophilic Substitution Reactions Gabriel Synthesis

t Primary amines can also be made cleanly by the Gabriel Synthesis

t Alkylation of Azide Ion followed by Reduction

l A primary amine is prepared more efficiently by reaction of azide anion with

t First step in the Gabriel synthesis is alkylation of potassium phthalimide t Reaction of the N-alkylphthalimide with hydrazine in boiling ethanol gives the primary amine

an alkyl halide and subsequent reduction of the alkylazide to the amine

t Preparation of Aromatic Amines by Reduction of Nitro Compounds

t

Amines through Reductive Amination

Aldehydes and ketones react with ammonia, primary or secondary amines to yield imines or iminium ions
l

These are then be reduced to alkylated amines

Useful way to introduce an amino group on a benzene ring: 1. 2. Nitration Reduction

[H ]

t The reduction can be accomplished using catalytic hydrogenation

Amines through Reduction of Nitriles, Oximes, and Amides

t Reduction of nitriles or oximes yield primary amines

or a hydride reducing reagent

l NaBH3 CN and LiBH 3 CN are especially effective in reductive aminations (milder; added sequentially, but one pot)

t Reduction of amides can yield primary, secondary or tertiary

amines

t Reduction can be accomplished by dissolving metal reduction, catalytic hydrogenation, or LiAlH4

t Reductive amination can be used for monoalkylation of an amine

l Acylation the amine with an acid chloride l Reduction of the resulting amide

Primary Amines by the Hofmann and Curtius Rearrangements

t An unsubstituted amide can be converted with bromine in

The N-bromo amide losses a second proton and then a bromide ion, and rearranges to an isocyanate

base to a primary amine by formal loss of the amide carbonyl

t The initial steps of the mechanism result in N -bromination of

the amide

Isocyanates readily hydrolyzed to a carbamate and lose CO2 to yield the primary amine

Converts a carboxylic acid to an amine with one fewer carbons

t The Curtius rearrangement occurs similarly through the

intermediacy of an acyl azide

l The acyl azide is obtained from an acid chloride with sodium azide l Rearrangement of the acyl azide occurs with loss of N2 , a very stable leaving group l In the last step, the isocyanate is hydrolyzed by adding water

CO 2H

CO2NH2

NH 2

Br 2 NaOH