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Chapter 20

Amines

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

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

Nomenclature for amines

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

Aryl amines

N (C H 3)2

C HO

Cl

N O2

N H2

3-chloro-4-nitroaniline p-dimethylaminobenzaldehyde

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t The important heterocyclic amines have common namest 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

Heterocyclic Amines

DNA base pairs are a purine with a pyrimidine

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)

Physical Properties and Structure of Amines

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t The unshared electron pair around nitrogen - along with the three groups results in a tetrahedral geometry

t The shape of the amine itself is trigonal pyramidal

t It is usually impossible to resolve amine enantiomers that are chiral at nitrogen because they interconvert rapidlyl Nitrogen inversion of the unshared electron pair

Structure of Amines = sp3 hybridized

t Quaternary ammonium salts can be resolved into enantiomersl Nitrogen inversion not possible with 4 substituents

Chiral: racemizes at 200o C

Organophosphorus analogs can be resolved

P CH3

..

t Amines are weak basest Relative basicitydefined by pKa of its conjugate acid

l The more basic the amine, the higher the pKa of its conjugate acid

t Primary alkyl amines are more basic than ammonial An alkyl group helps to stabilize the alkylaminium ion

Basicity of Aminest 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 methylamine

t Solvation of the ion becomes important

t The trimethylaminium ion is solvated less well than the dimethylaminiumion, which has two hydrogen atoms for hydrogen bonding

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t Arylamines are weaker bases than the corresponding nonaromatic cyclohexylamines

t The unshared electron pair on nitrogen of an arylamine is delocalized to the ortho and para positions of the ringl Lone pair is less available for protonation, i.e., it is less basic

t Less resonance stablization available to the anilinium ion

t Greater resonance stabilization of aniline than its aniliniumion means a larger ∆ Ho for protonation, as compared with ∆ Ho for protonation of an amine that is not aromatic

t Nonaromatic heterocyclic amines have comparable basicityto acyclic counterparts

t Aromatic heterocyclic amines (in aqueous solution) are much weaker bases than nonaromatic amines

Basicity of Heterocyclic Amines t Amides are much less basic than aminesè The pKa of a protonated amide is typically about zero

1. Amide is stabilized by resonance and protonated amide is not

2. The nitrogen lone pair is delocalized to the carbonyl oxygenl Amides are actually protonated at the oxygen atoml Allows resonance stabilization of the positive charge

Amines versus Amides

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t Protonation of amines with acids leads to aminium saltsl Aminium salts are formed from 1o, 2 o or 3o amines

l An aminium ion bears at least one hydrogen

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

Aminium Salts and Quaternary Ammonium Salts 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

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 water, but not organic solvents

Q+ = (Bu)4N+

Purple benzene??

Herriott and Picker, Journal of the American Chemical Society, 97, 2345 (1975)

Herriott, Journal of Chemical Education, 54, 229 (1977)

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

t Used as a chemical test to distinguish amines

t Extraction : water-insoluble amines can be separated from other water-insoluble organic compoundsl 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

Solubility of Amines in Aqueous Acid

t A chiral amines can be used to resolve a racemic mixture of carboxylic acids by formation of diastereomeric saltsl Diastereomers = different physical properties (solubility, m.p .)

l Acidification of the separated diastereomeric salts gives the resolved carboxylic acids

Amines as Resolving Agents

t Nucleophilic Substitution Reactionsl Alkylation of Ammonia with an alkyl halide

è Initial aminiumsalt is treated with base to give the primary amineè The method is limited because multiple alkylations usually occur

l Using an excess of ammonia helps to minimize multiple alkylations

Preparation of Amines

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t Alkylation of Azide Ion followed by Reduction

l A primary amine is prepared more efficiently by reaction of azide anion with an alkyl halide and subsequent reduction of the alkylazide to the amine

Amines via Nucleophilic Substitution Reactions

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

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

Amines via Nucleophilic Substitution Reactions – Gabriel Synthesis

t Preparation of Aromatic Amines by Reduction of Nitro Compounds

Useful way to introduce an amino group on a benzene ring:

1. Nitration

2. Reduction

t Aldehydes and ketones react with ammonia, primary or secondary amines to yield imines or iminium ionsl These are then be reduced to alkylated amines

Amines through Reductive Amination

[H]

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t The reduction can be accomplished using catalytic hydrogenation or a hydride reducing reagentl NaBH3 CN and LiBH3CN are especially effective in reductive

aminations (milder; added sequentially, but one pot)

t Reduction of nitriles or oximes yield primary amines

t Reduction of amides can yield primary, secondary or tertiary amines

Amines through Reduction of Nitriles, Oximes, and Amides

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 chloridel Reduction of the resulting amide

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t An unsubstituted amide can be converted with bromine in 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

Primary Amines by the Hofmann and Curtius Rearrangements The N-bromo amide losses a second proton and then a bromide ion, and rearranges to an isocyanate

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

NH2

Br2

NaOH

CO 2H CO2NH2

t The Curtius rearrangement occurs similarly through the intermediacy of an acyl azidel The acyl azide is obtained from an acid chloride with sodium azidel 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