Amines Chemical / Biological / Neurological Activity

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Arnold O’Brien’
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1 Amines hemical / Biological / eurological 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 onstant (K b ) and pk b K b is the equilibrium constant for the reaction: 3 K b = 3 [ 3 ][ ] [ 3 ] and pk b = - log K b K a and pk a of onjugate Acid K a is the equilibrium constant for the dissociation of the conjugate acid of the amine: 3 3 K a = [ 3 ][ ] [ 3 ] elationships between acidity and basicity constants K a K b = pk a pk b = 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. owever, both its base and conjugate acid are currently controlled substances under U.S. Federal egulations: Title 21 secs & (1987). an you name the beverage and the base? and pk a = - log K a

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.: aution: May be habit forming.

2 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.: aution: May be habit forming... 3 Acid -Base hemistry (Physical Properties) "rack" ocaine What structural feature makes cocaine a base? What simple compound can you relate it to? m.p. 98 o b.p. (very volatile > 90 o ) Solubility: Water: 1.67 x 10-3 g/ml l 3 : 1.43 g/ml Ether: 0.29 g/ml egular ocaine onjugate Acid of ocaine (Physical Properties) 3 l - m.p. >195 o 2 3 Solubility: Water: 2.5 g/ml 2 l 3 : 0.08 g/ml ocaine ydrochloride Ether: insoluble What accounts for the differences in solubilities of the base and conjugate acid? Acid -Base eactions Acid Base eactions Basicity of Amines in Aqueous Solution l l 2 2 ocaine ydrochloride 3 l "rack" ocaine Amine onj. Acid pk a is a weaker acid than 4 ; therefore, is a stronger base than 3.

3 Effect of Structure on Basicity Basicity of Amines in Aqueous Solution Effect of Structure on Basicity 1. Alkylamines are slightly stronger bases than ammonia. 2. Alkylamines differ very little in basicity. Amine onj. Acid pk a ( 3 2 ) 2 ( 3 2 ) ( 3 2 ) 3 ( 3 2 ) otice that the difference separating a primary, secondary, and tertiary amine is only 0.3 pk units. 1. Alkylamines are slightly stronger bases than ammonia. 2. Alkylamines differ very little in basicity. 3. Arylamines are much weaker bases than ammonia. Basicity of Amines in Aqueous Solution Decreased basicity of arylamines Decreased basicity of arylamines Amine onj. Acid pk a ( 3 2 ) 2 ( 3 2 ) ( 3 2 ) 3 ( 3 2 ) Aniline (reactant) is stabilized by conjugation of nitrogen lone pair with ring π system. This stabilization is lost on protonation. Increasing delocalization makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine ( 6 5 ) 2 ( 6 5 ) 3 K b 3.8 x x ~10-19

Effect of Substituents on Basicity of Arylamines Basicity of Arylamines p-itroaniline 1. Alkyl groups on the ring increase basicity, but only slightly (less than 1 pk unit). 2.

4 Effect of Substituents on Basicity of Arylamines Basicity of Arylamines p-itroaniline 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. X 2 X 3 X pk b pk a F Lone pair on amine nitrogen is conjugated with p-nitro group more delocalized than in aniline itself. Delocalization lost on protonation. 2 Effect is umulative eterocyclic Amines Aniline is 3800 times more basic than p-nitroaniline. Aniline is ~1,000,000,000 times more basic than 2,4-dinitroaniline. piperidine is more basic than pyridine K b = 1.6 x 10-3 K b = 1.4 x 10-9 (an alkylamine) (resembles an arylamine in basicity)

5 eterocyclic Amines Imidazole is more basic than Which nitrogen is protonated in imidazole? imidazole pyridine K b = 1 x 10-7 K b = 1.4 x 10-9 Imidazole Which nitrogen is protonated in imidazole? Imidazole Protonation in the direction shown gives a stabilized ion.

6 The Gabriel Synthesis of Primary Amines Alkaloids: aturally ccuring Bases itrogen eterocycles Preparation and eactions of Amines eductive Amination Synthesis of Amines via eductive Amination In reductive amination,, an aldehyde or ketone is subjected to catalytic hydrogenation in the presence of ammonia or an amine. ' 3 fast 2 The aldehyde or ketone equilibrates with the imine faster than hydrogenation occurs. ' Synthesis of Amines via eductive Amination The imine undergoes hydrogenation faster than the aldehyde or ketone.. An amine is the product. ' ' 3 2 fast ' 2 2, i

7 Example: Ammonia gives a primary amine. Example: Primary amines give secondary amines Example: Primary amines give secondary amines 3 2, i ethanol 2 3 ( 2 ) 5 2 2, i ethanol 3 ( 2 ) 5 2 2, i ethanol (80%) 3 ( 2 ) 5 2 (65%) 3 ( 2 ) 5 2 (65%) via: via: 3 ( 2 ) 5 Example: Secondary amines give tertiary amines Amine xides Undergo a ope Elimination eaction , i, ethanol (93%)

8 Amines & eurotransmitters Barbiturates ' ' an you draw the enolized form? Is it aromatic? ould it possibly be aromatic? Mescaline S Adrenalin Tagamet: cimetidine istidine receptor antagonist (a precursor to histamine, a vasodilator) Inhibits gastric secretions & pepsin output Dopamine, Serotonin, Melatonin

9 athecols: epinephrine & mdma Principal sympathomimetic adrenal hormone & a controlled substance

Models of Acids and Bases. Acid-Base Equilibrium Conjugate Acid/Base Pairs. Weak Acids QUESTION: 1. Acids & Bases/ Organic Chemistry

Models of Acids and Bases. Acid-Base Equilibrium Conjugate Acid/Base Pairs. Weak Acids QUESTION: 1. Acids & Bases/ Organic Chemistry Chapter 1 Structure and Bonding Acids and Bases Acids & Bases/ rganic Chemistry Dr. Ron Rusay Fall 2009 Models of Acids and Bases Arrhenius: Acids produce + & bases produce ion in aqueous solutions. Brønsted-Lowry: