AminesAmines Chemical / Biological / Neurological Chemical / Biological / Neurological

ActivityActivity

Measures of Basicity

• The basicity of amines may be measured by:• 1) Kb

• 2) pKb

• 3) Ka of conjugate acid

• 4) pKa of conjugate acid

Basicity Constant (Kb) and pKb

• Kb is the equilibrium constant for the reaction:

RR33NN •••• ++ HH OHOH••••

••••RR33NN

++HH

––•••• OHOH••••

••••++

KKbb = =[R[R33NHNH++][HO][HO––]]

[R[R33N]N]

ppKKbb = = - log - log KKbbandand

Ka and pKa of Conjugate Acid

KKaa = =[R[R33N][HN][H++]]

[R[R33NHNH++]]

ppKKaa = = - log - log KKaaandand

RR33NN ••••RR33NN++

HH ++ HH++

• Ka is the equilibrium constant for the dissociation of the conjugate acid of the amine:

Relationships between acidity and basicity constants

ppKKaa + p + pKKbb = 14 = 14

KKa a KKbb = 10 = 10-14-14

A natural base from Erythroxylon spp.

• It is very valuable. The leaves are chewed by indigenous tribes in the Andes to boost their energy.

• It has been used as a psycho-therapeutic, an opthalmic anesthetic and was purportedly used in a popular beverage that is at the heart of a $20 billion corporation.

• However, both its base and conjugate acid are currently controlled substances under U.S. Federal Regulations: Title 21 secs. 329.1 & 1308.12 (1987).

• Can you name the beverage and the base?

The beverage reportedly produced using the extract of leaves of Erythroxylon coca:

The compound: cocaine, it is an organic base: Merck Index, #2450, 11th ed.: Caution: May be habit

forming….

Acid -Base Chemistry(Physical Properties)

NCO2CH3

O2C

CH3..

"Crack" Cocaine

• m.p. 98 oC• b.p. (very volatile

> 90 oC)Solubility: • Water: 1.67 x 10-3

g/mL • CHCl3: 1.43 g/mL • Ether: 0.29 g/mL

What structural feature makes cocaine a base? What simple compound can you relate it to?

“Regular” Cocaine Conjugate Acid of Cocaine

(Physical Properties)

CH3 NCO2CH3

O2C

H Cl -

Cocaine Hydrochloride

+ • m.p. >195 oC

Solubility:• Water: 2.5 g/mL • CHCl3: 0.08

g/mL • Ether:

insolubleWhat accounts for the differences in solubilities of the base and conjugate acid?

Acid -Base Reactions

NCO2CH3

O2C

CH3

+ H Cl

..

CH3N

CO2CH3

O2C

H Cl -

Cocaine Hydrochloride

+

Acid Base Reactions

CH3 NCO2CH3

O2C

H Cl -+

+ OH -

..

"Crack" Cocaine

CH3N

CO2CH3

O2C

•Amine Conj. Acid pKa

•NH3 NH4+ 9.3

•CH3CH2NH2 CH3CH2NH3+ 10.8

Basicity of Amines in Aqueous Solution

CHCH33CHCH22NHNH33++ is a weaker acid than NH is a weaker acid than NH44

++;;therefore, CHtherefore, CH33CHCH22NHNH22 is a stronger base is a stronger base than NHthan NH33..

Effect of Structure on Basicity

•1. Alkylamines are slightly stronger bases than ammonia.

•2. Alkylamines differ very little in basicity.

•Amine Conj. Acid pKa

•NH3 NH4+ 9.3

•CH3CH2NH2 CH3CH2NH3+ 10.8

•(CH3CH2)2NH (CH3CH2)2NH2+ 11.1

•(CH3CH2)3N (CH3CH2)3NH+ 10.8

Basicity of Amines in Aqueous Solution

Notice that the difference separating a primary,Notice that the difference separating a primary,secondary, and tertiary amine is only 0.3 pK units.secondary, and tertiary amine is only 0.3 pK units.

Effect of Structure on Basicity

•1. Alkylamines are slightly stronger bases than

ammonia.

•2. Alkylamines differ very little in basicity.

•3. Arylamines are much weaker bases thanammonia.

•Amine Conj. Acid pKa

•NH3 NH4+ 9.3

•CH3CH2NH2 CH3CH2NH3+ 10.8

•(CH3CH2)2NH (CH3CH2)2NH2+ 11.1

•(CH3CH2)3N (CH3CH2)3NH+ 10.8

•C6H5NH2 C6H5NH3+ 4.6

Basicity of Amines in Aqueous Solution

++ HH OHOH••••

••••

NNHH22••••

++

NNHH33

++ ––•••• OHOH••••

••••

• Aniline (reactant) is stabilized by conjugation of nitrogen lone pair with ring system.

• This stabilization is lost on protonation.

Decreased basicity of arylamines

Decreased basicity of arylamines

CC66HH55NHNH22 (C(C66HH55))22NHNH (C(C66HH55))33NN

KKbb 3.8 x 103.8 x 10-10-10 6 x 106 x 10-14-14 ~10~10-19-19

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

Effect of Substituents on Basicity of Arylamines

•1. Alkyl groups on the ring increase basicity, butonly slightly (less than 1 pK unit).

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

•X pKb pKa

•H 9.4 4.6•CH3 8.7 5.3•CF3 11.5 2.5•O2N 13.0 1.0

Basicity of Arylamines

XX NHNH22

XX NHNH33++

p-Nitroaniline

NHNH22

OO

NN

OO

–– ••••••••••••

••••

++••••

••••

OO

NN

OO

–– ••••••••••••

•••• ••••••••––

NHNH22

++

++

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

Effect is Cumulative

•Aniline is 3800 times more basic thanp-nitroaniline.•Aniline is ~1,000,000,000 times more basic than 2,4-dinitroaniline.

Heterocyclic Amines

NN

HH

••••

NN••••

piperidinepiperidine pyridinepyridine

is more basic thanis more basic than

KKbb = 1.6 x 10 = 1.6 x 10-3-3 KKbb = 1.4 x 10 = 1.4 x 10-9-9

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

basicity)basicity)

Heterocyclic Amines

NN••••

imidazoleimidazole pyridinepyridine

is more basic thanis more basic than

KKbb = 1 x 10 = 1 x 10-7-7 KKbb = 1.4 x 10 = 1.4 x 10-9-9

NN HHNN•••• ••••

Imidazole

NN HHNN•••• ••••

• Which nitrogen is protonated in imidazole?

HH++ HH++

NN HHNN ••••HH++

NN HHNN••••HH

++

Imidazole

NN HHNN•••• ••••

• Which nitrogen is protonated in imidazole?

HH++

NN HHNN ••••HH++

Imidazole

NN HHNN•••• ••••

• Protonation in the direction shown gives a stabilized ion.

HH++

NN HHNNHH++ ••••

NN HHNNHH••••

++

Alkaloids: Naturally Occuring BasesNitrogen Heterocycles

Preparation and Reactions of Amines

The Gabriel Synthesis of Primary Amines

Reductive Amination

•The aldehyde or ketone equilibrates with theimine faster than hydrogenation occurs.

Synthesis of Amines via Reductive Amination

OOCC

RR

R'R'

++ NNHH33

fastfast

NNHHCC

RR

R'R'

++ HH22OO

In reductive amination, an aldehyde or ketoneIn reductive amination, an aldehyde or ketoneis subjected to catalytic hydrogenation in theis subjected to catalytic hydrogenation in thepresence of ammonia or an amine.presence of ammonia or an amine.

Synthesis of Amines via Reductive Amination

HH22, Ni, Ni

OOCC

RR

R'R'

++ NNHH33

fastfast

NNHHCC

RR

R'R'

++ HH22OO

NNHH22

RR

R'R' CC

HH

The imine undergoes hydrogenation fasterThe imine undergoes hydrogenation fasterthan the aldehyde or ketone. An amine is than the aldehyde or ketone. An amine is the product.the product.

Example: Ammonia gives a primary amine.

OO ++ NNHH33

HH

NNHH22

HH22, Ni, Ni

ethanolethanol

(80%)(80%)

via:via:

NNHH

Example: Primary amines give secondary amines

HH22, Ni, Ni ethanolethanol

(65%)(65%)

CHCH33(CH(CH22))55CHCH22NNHH

++ HH22NN

CHCH33(CH(CH22))55CHCH

OO

Example: Primary amines give secondary amines

HH22, Ni, Ni ethanolethanol

(65%)(65%)

via:via:

CHCH33(CH(CH22))55CHCH22NNHH

++ HH22NN

CHCH33(CH(CH22))55CHCH

OO

NN

CHCH33(CH(CH22))55CHCH

Example: Secondary amines give tertiary amines

HH22, Ni, ethanol, Ni, ethanol

(93%)(93%)

++CHCH33CHCH22CHCH22CHCH

OO

NN

HH

NN

CHCH22CHCH22CHCH22CHCH33

Amine Oxides Undergo a Cope Elimination Reaction

Amines & Neurotransmitters

NH2CNH2

OCH3CH2OC C COCH2CH3

O OR'

R

N

N

H

HO

R'RO

O

+

Barbiturates

•Can you draw the enolized form?•Is it aromatic? •Could it possibly be aromatic?

RCH2CH2NH2

CH2CH2NH2

CH2CH2NH2

CH3O

CH3O

CH3O

Mescaline

RCH2CH2NH2

CH2CH2NH2

N NH

N

N

CH3H

CH3NHCNHCH2CH2SCH2

O

Tagamet: cimetidineHistidine receptor antagonist (a precursor to histamine, a

vasodilator)Inhibits gastric secretions & pepsin output

CH2CH2NH2

NH

CH3O

CH3O

NH

HOCH2CH2NH2

NH

CH3OCH2CH2NHCCH3

O

Dopamine, Serotonin, Melatonin

HOCH2CH2N CH3CH3

CH3CH3COCH2CH2N CH3

CH3

CH3O

CHCH2NHCH3

HO

HOOH

Adrenalin

Cathecols: epinephrine & mdmahttp://faculty.washington.edu/chudler/mdma.html

Principal sympathomimetic adrenal hormone & a controlled substance

http://web.indstate.edu/thcme/mwking/nerves.html#tablehttp://www.sfn.org/briefings/addiction.htmlhttp://faculty.washington.edu/chudler/amp.html

http://www%2Drci.rutgers.edu/%7Elwh/drugs/