Amines Chemical / Biological / Neurological Activity

Measures of Basicity The basicity of amines may be measured by: 1) K b 2)pK b 3)K a of conjugate acid 4) pK a of conjugate acid

Basicity Constant (K b ) and pK b K b is the equilibrium constant for the reaction: R3NR3NR3NR3N + HOH R3NR3NR3NR3N+H – OH + K b = [R 3 NH + ][HO – ] [R 3 N] pK b = - log K b and

K a and pK a of Conjugate Acid K a = [R 3 N][H + ] [R 3 NH + ] pK a = - log K a and R3NR3NR3NR3N R3NR3NR3NR3N+H + H+H+H+H+ K a is the equilibrium constant for the dissociation of the conjugate acid of the amine:

Relationships between acidity and basicity constants pK a + pK b = 14 K a K b =

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 & (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) m.p. 98 o C b.p. (very volatile > 90 o C) Solubility: Water: 1.67 x g/mL CHCl 3 : 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) m.p. >195 o C Solubility: Water: 2.5 g/mL CHCl 3 : 0.08 g/mL Ether: insoluble What accounts for the differences in solubilities of the base and conjugate acid?

Acid -Base Reactions

Acid Base Reactions

AmineConj. AcidpK a NH 3 NH CH 3 CH 2 NH 2 CH 3 CH 2 NH Basicity of Amines in Aqueous Solution CH 3 CH 2 NH 3 + is a weaker acid than NH 4 + ; therefore, CH 3 CH 2 NH 2 is a stronger base than NH 3.

Effect of Structure on Basicity 1. Alkylamines are slightly stronger bases than ammonia. 2. Alkylamines differ very little in basicity.

AmineConj. AcidpK a NH 3 NH CH 3 CH 2 NH 2 CH 3 CH 2 NH (CH 3 CH 2 ) 2 NH(CH 3 CH 2 ) 2 NH (CH 3 CH 2 ) 3 N(CH 3 CH 2 ) 3 NH Basicity of Amines in Aqueous Solution Notice that the difference separating a primary, 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 than ammonia.

AmineConj. AcidpK a NH 3 NH CH 3 CH 2 NH 2 CH 3 CH 2 NH (CH 3 CH 2 ) 2 NH(CH 3 CH 2 ) 2 NH (CH 3 CH 2 ) 3 N(CH 3 CH 2 ) 3 NH C 6 H 5 NH 2 C 6 H 5 NH Basicity of Amines in Aqueous Solution

+ HOH NH2NH2NH2NH2 + NH3NH3NH3NH3 +– OH Aniline (reactant) is stabilized by conjugation of nitrogen lone pair with ring  system. This stabilization is lost on protonation. Decreased basicity of arylamines

C 6 H 5 NH 2 (C 6 H 5 ) 2 NH (C 6 H 5 ) 3 N KbKbKbKb 3.8 x x ~ 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, but only slightly (less than 1 pK unit). 2. Electron withdrawing groups, especially ortho and/or para to amine group, decrease basicity and can have a large effect.

XpK b pK a H CH CF O 2 N Basicity of Arylamines X NH 2 X NH 3 +

p-Nitroaniline NH 2 O N O – + O N O – – NH 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 than p-nitroaniline. Aniline is ~1,000,000,000 times more basic than 2,4-dinitroaniline.

Heterocyclic Amines N H N piperidinepyridine is more basic than K b = 1.6 x K b = 1.4 x (an alkylamine) (resembles an arylamine in basicity)

Heterocyclic Amines N imidazolepyridine is more basic than K b = 1 x K b = 1.4 x NH N

Imidazole NH N Which nitrogen is protonated in imidazole? H+H+H+H+ H+H+H+H+ NH N H + N H N H +

Imidazole NH N Which nitrogen is protonated in imidazole? H+H+H+H+ NH N H +

Imidazole NH N Protonation in the direction shown gives a stabilized ion. H+H+H+H+ NH NH+ NH N H +

Alkaloids: Naturally Occuring Bases Nitrogen Heterocycles

Preparation and Reactions of Amines

The Gabriel Synthesis of Primary Amines

Reductive Amination

The aldehyde or ketone equilibrates with the imine faster than hydrogenation occurs. Synthesis of Amines via Reductive Amination O CRR' + NH3NH3NH3NH3 fast NHNHNHNH CRR' + H2OH2OH2OH2O In reductive amination, an aldehyde or ketone is subjected to catalytic hydrogenation in the presence of ammonia or an amine.

Synthesis of Amines via Reductive Amination H 2, Ni O CRR' + NH3NH3NH3NH3 fast NHNHNHNH CRR' + H2OH2OH2OH2O NH2NH2NH2NH2RR' C H The imine undergoes hydrogenation faster than the aldehyde or ketone. An amine is the product.

Example: Ammonia gives a primary amine. O + NH3NH3NH3NH3H NH2NH2NH2NH2 H 2, Ni ethanol (80%) via: NHNHNHNH

Example: Primary amines give secondary amines H 2, Ni ethanol (65%) CH 3 (CH 2 ) 5 CH 2 NH + H2NH2NH2NH2N CH 3 (CH 2 ) 5 CH O

Example: Primary amines give secondary amines H 2, Ni ethanol (65%) via: CH 3 (CH 2 ) 5 CH 2 NH + H2NH2NH2NH2N CH 3 (CH 2 ) 5 CH O N

Example: Secondary amines give tertiary amines H 2, Ni, ethanol (93%) + CH 3 CH 2 CH 2 CH O N H N CH 2 CH 2 CH 2 CH 3

Amine Oxides Undergo a Cope Elimination Reaction

Amines & Neurotransmitters

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

Mescaline

Tagamet: cimetidine Histidine receptor antagonist (a precursor to histamine, a vasodilator) Inhibits gastric secretions & pepsin output

Dopamine, Serotonin, Melatonin

Adrenalin

Cathecols: epinephrine & mdma Principal sympathomimetic adrenal hormone & a controlled substancesubstance