Amines Chemical / Biological / Neurological Activity 3

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 6

Basicity Constant (Kb) and pKb Kb is the equilibrium constant for the reaction: R3N + H H OH •• – • • OH •• R3N • • + + [R3NH+][HO–] Kb = [R3N] and pKb = - log Kb 2

Ka and pKa of Conjugate Acid Ka is the equilibrium constant for the dissociation of the conjugate acid of the amine: R3N • • + H H+ [R3N][H+] Ka = [R3NH+] and pKa = - log Ka 3

Relationships between acidity and basicity constants Ka Kb = 10-14 pKa + pKb = 14 3

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) 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) m.p. >195 oC Solubility: Water: 2.5 g/mL CHCl3: 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

Basicity of Amines in Aqueous Solution Amine Conj. Acid pKa NH3 NH4+ 9.3 CH3CH2NH2 CH3CH2NH3+ 10.8 CH3CH2NH3+ is a weaker acid than NH4+; therefore, CH3CH2NH2 is a stronger base than NH3. 6

Effect of Structure on Basicity 1. Alkylamines are slightly stronger bases than ammonia. 2. Alkylamines differ very little in basicity. 5

Basicity of Amines in Aqueous Solution Amine Conj. Acid pKa NH3 NH4+ 9.3 CH3CH2NH2 CH3CH2NH3+ 10.8 (CH3CH2)2NH (CH3CH2)2NH2+ 11.1 (CH3CH2)3N (CH3CH2)3NH+ 10.8 Notice that the difference separating a primary, secondary, and tertiary amine is only 0.3 pK units. 6

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. 5

Basicity of Amines in Aqueous Solution 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 6

Decreased basicity of arylamines NH2 •• H OH •• + Aniline (reactant) is stabilized by conjugation of nitrogen lone pair with ring p system. This stabilization is lost on protonation. NH3 + – • • OH •• + 2

Decreased basicity of arylamines Increasing delocalization makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine. C6H5NH2 (C6H5)2NH (C6H5)3N Kb 3.8 x 10-10 6 x 10-14 ~10-19 2

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. 5

Basicity of Arylamines X NH2 X NH3+ X pKb pKa H 9.4 4.6 CH3 8.7 5.3 CF3 11.5 2.5 O2N 13.0 1.0 7

p-Nitroaniline NH2 O N – + O N – NH2 + + •• • • + O N – •• • • NH2 + + Lone pair on amine nitrogen is conjugated with p-nitro group—more delocalized than in aniline itself. Delocalization lost on protonation. 2

Aniline is 3800 times more basic than p-nitroaniline. 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. 2

(resembles an arylamine in basicity) Heterocyclic Amines N •• N H •• is more basic than piperidine pyridine Kb = 1.6 x 10-3 Kb = 1.4 x 10-9 (an alkylamine) (resembles an arylamine in basicity) 9

Heterocyclic Amines N N H is more basic than imidazole pyridine •• N H • • is more basic than imidazole pyridine Kb = 1 x 10-7 Kb = 1.4 x 10-9 9

Imidazole Which nitrogen is protonated in imidazole? N H H+ H+ N H N H • • H+ H+ N H • • N H • • + + 11

Imidazole Which nitrogen is protonated in imidazole? N H H+ N H + • • 11

Imidazole Protonation in the direction shown gives a stabilized ion. N • • H+ N H • • + + N H • • 11

Alkaloids: Naturally Occuring Bases Nitrogen Heterocycles

Preparation and Reactions of Amines 3

The Gabriel Synthesis of Primary Amines

Reductive Amination 3

Synthesis of Amines via Reductive Amination In reductive amination, an aldehyde or ketone is subjected to catalytic hydrogenation in the presence of ammonia or an amine. O C R R' fast NH C R R' + NH3 + H2O The aldehyde or ketone equilibrates with the imine faster than hydrogenation occurs. 12

Synthesis of Amines via Reductive Amination The imine undergoes hydrogenation faster than the aldehyde or ketone. An amine is the product. O C R R' fast NH C R R' + NH3 + H2O NH2 R R' C H H2, Ni 12

Example: Ammonia gives a primary amine. H2, Ni O H NH2 + NH3 ethanol (80%) NH via: 18

Example: Primary amines give secondary amines CH3(CH2)5CH O + H2N H2, Ni ethanol CH3(CH2)5CH2NH (65%) 18

Example: Primary amines give secondary amines CH3(CH2)5CH O + H2N H2, Ni ethanol CH3(CH2)5CH2NH (65%) N CH3(CH2)5CH via: 18

Example: Secondary amines give tertiary amines H CH3CH2CH2CH O + H2, Ni, ethanol N CH2CH2CH2CH3 (93%) 18

Cope Elimination Reaction 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

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

Dopamine, Serotonin, Melatonin

Adrenalin

Cathecols: epinephrine & mdma http://faculty.washington.edu/chudler/mdma.html Principal sympathomimetic adrenal hormone & a controlled substance