amines the organic bases. categorizing amines amines are categorized by the number of alkyl groups...

Amines

The organic bases

Categorizing Amines

Amines are categorized by the number of alkyl groups attached to nitrogen:

1º (primary amine) RNH2

2º (secondary amine) R2NH

3º (tertiary amine) R3N

4º (quaternary amine salt) R4N+

Naming simple amines

Simple 1º amines are named as “alkylamine” Examples:

methylamine CH3NH2

ethylamine CH3CH2NH2

butylamine CH3CH2CH2CH2NH2

Symmetrical 2º or 3º amines are named as “dialkylamine” or “trialkyamine” Examples:

diethylamine (CH3CH2)2NH; trimethylamine (CH3)3N

Naming more complex amines Amines with more than one type of alkyl group may

be named as N-substituted primary amines. The longer alkyl chain determines the base name. Examples

N-methylpropylamine CH3NHCH2CH2CH3

N,N-dimethylethylamine (CH3)2NCH2CH3

Naming more complex amines Amines that have more than one functional group

may be named using “amino” as a substituent on the parent molecule. Examples:

2-aminoethanol H2NCH2CH2OH

4-aminobutanoic acid H2NCH2CH2CH2CO2H

Heterocyclic amines

Some amines have a nitrogen as part of a ring. These generally have common (non-systematic) names, which should be memorized:

NH2

N N

N

N

H

N

N

H

N

H

N

N

HN

aniline pyridine pyrimidine pyrrole

quinoline indole imidazole benzimidazole

Structure of amines

Amines have an sp3 hybridized nitrogen In principle, tertiary amines with three different R

groups should be chiral (i.e., have a stereocenter). However, rapid pyramidal inversion of the amine

nitrogen prevents isolation of the enantiomers except where the nitrogen is part of a ring or has other geometrical constraint.

N

YZ

X

N

YZ

Xfast

Properties of amines

Amines are moderately polar and are capable of hydrogen bonding.

Low MW amines (up to about C5) are soluble in water; higher MW amines will dissolve in acidic solution (as their conjugate acid).

Many amines have foul odors. Amines are weak bases.

Example of biologically active amines

H2NCH2CH2CH2CH2NH2 putrescine H2NCH2CH2CH2CH2CH2NH2 cadaverine

H2NCH2CH2CH2CH2NCH2CH2CH2CH2NH2 s permidineH

H2N(CH2)N(CH2)4N(CH2)3NH2 s permineH H

NHCH3

OHH

HO

HO

epinephrine(adrenaline)

NH2

OHH

HO

HO

norepinephrine(noradrenaline)

NH2HO

HO

dopamine

More biologically active amines…

NH2

CH3H

amphetamine(benzadrine)

N

CH2CH2NH2

HO

H

NHCH3

CH3H

methamphetamine (speed)

serotonin

mescaline

NH2CH3O

CH3O

OCH3

N

CO2H

nicotinic acid(niacin)

NN

CH2CH2NH2

H

histamine


H2N C OCH2CH3

O

benzocaine(a topical anesthetic)

Cl

N

N

H

O

O

diazepam (Valium)

N

N

O

NN

CH3

CH2CH2CH3

H

SOO

N

NCH3

CH3CH2O

Sildenafil (Viagra)


R'O

O

RO

NCH3

codeine (R = CH3, R' = H)morphine (R and R' = H)heroin (R and R' = COCH3)

mepiridine(Demerol)

N

N

N

N

O

O

CH3

H3CCH3

caffeine

N

N

CH3

H

nicotine

NH3C

C

O

HO

C

O

H

OCH3

cocaine

NCH3C

O

CH3CH2O

Methadone

C6H5 NCH3C

O

CH3CH2

CH3

CH3


N

HO

H N

H

H

quinineN

O

N

O

H

H

strychnine

N

NH

C

O

(CH3CH2)2NCH3

lysergic acid diethylamide (LSD)

N

H

CH2CH2CH3

H

coniin (the poison from hemlock used to kill Socrates)

Basicity of amines

Amines are slightly basic. This because they have a lone pair of electrons to donate to a proton. This same feature makes them nucleophiles.

Typical amines have Kb values = 10-3 to 10-4

RNH2 + H OH RNH3 + O H

Kb = [RNH3 ] [OH ]

[RNH2]

Basicity of amines…

However, instead of measuring an amine’s basicity using the above equilibrium, chemists usually refer to the acidity of the conjugate acid of the amine. The weaker the conjugate acid, the stronger the base strength of the amine.

Typical amines have Ka values (of their conjugate acids) of 10-10 to 10-11 (pKa values of 10 to 11.)

RNH3 RNH2 + H Ka = [RNH3 ]

[RNH2] [H ]

pKa values of conjugate acids of amines

CH3NH2 10.7

CH3CH2NH2 10.8

(CH3)2NH 10.7

(CH3CH2)2NH 10.5

(CH3)3N 9.8

(CH3CH2)3N 11.0

All are about the same value.

The same substituent effects that stabilize carbocations that are more highly substituted by alkyl groups are offset by diminished stabilization by solvent due to crowding.

Some amines that are weaker bases

(conj. acid)

Aniline is a weaker base because the lp of electrons is delocalized by resonance into the aromatic ring.

Pyridine is weaker because it is an imine (C=N). Pyrrole is much weaker because the lp of electrons is

delocalized with the other electrons to make 6 e-. Therefore, the lp is unavailable to act as a base.

aniline pyridine pyrrole pKa = 4.6 5.2 0.4

NH2

NN

H

Substituent Effects on Basicity of Aniline

Resonance stabilizes free base, destabilizes its protonated form (see next slide)

2 explanations of weaker basicity of nitroaniline:

NH2 NH2

OCH3

NH2

NO2pKa of conj. acid: 5.3 1.04.6

(much weaker base)

NH2

NO2

NH2

NOO

NH2

NOO

NH2

NOO

NH3

NO2

Substituent Effects on Basicity of Anilines

NH3

NH3CH3O

NH3O2N

Reaction progress (protonation)

Energy

An amine that is a stronger base There is one type of amine

that is a stronger base:

Guanidine is a strong base because its conjugate acid is stabilized by resonance:

guanidine pKa = 13.6(conj. acid)

A guanidine group is part of the structure of the amino acid arginine.

NH

CH2N NH2

NH2

CH2N NH2

NH2

CH2N NH2

NH2

CH2N NH2

NH2

CH2N NH2

Amines are Protonated at Physiological pH

Recall the Henderson-Hasselbalch equation:

Consider the neurotransmitter dopamine, a typical amine (having a pKa of its conjugate acid = 10.6) in a living cell (buffered at pH = 7.3):

That is, the concentration of the protonated amine is 2000x that of the neutral amine! Typical amines are >99.9% protonated at physiological pH.

pH = pKa + log [RNH2]

[RNH3+]

7.3 = 10.6 + log [RNH2]

[RNH3+]

log [RNH2]

[RNH3+]

-3.3 =

[RNH2]

[RNH3+]

2 x 103 =

;

;[RNH2]

[RNH3+]

5 x 10- 4 =

amines the organic bases. categorizing amines amines are categorized by the number of alkyl groups...

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