Amines Chemical / Biological / Neurological Activity

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Amines Chemical / Biological / Neurological
Activity
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Measures of Basicity

• The basicity of amines may be measured and
  compared by using any of these values
• 1) Kb
• 2) pKb
• 3) Ka of conjugate acid
• 4) pKa of conjugate acid

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Basicity Constant (Kb) and pKb

• Kb is the equilibrium constant for the reaction

R3NHHO
Kb
R3N
and
pKb
- log Kb
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Ka and pKa of Conjugate Acid

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

R3NH
Ka
R3NH
and
pKa
- log Ka
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Relationships between acidity and basicity
constants
Ka Kb 10-14
pKa pKb 14
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Basicity of Amines in Aqueous Solution

• Amine Conj. Acid pKa
• NH3 NH4 9.3
• CH3CH2NH2 CH3CH2NH3 10.8

CH3CH2NH3 is a weaker acid than NH4therefore,
CH3CH2NH2 is a stronger base than NH3.
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Effect of Structure on Basicity

• 1. Alkylamines are slightly stronger bases than
  ammonia.
• 2. Alkylamines differ very little in basicity.

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Basicity of Amines in Aqueous Solution

• Amine Conj. Acid pKa
• NH3 NH4 9.3
• CH3CH2NH2 CH3CH2NH3 10.8
• (CH3CH2)2NH (CH3CH2)2NH2 10.9
• (CH3CH2)3N (CH3CH2)3NH 11.1

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

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Basicity of Amines in Aqueous Solution

• Amine Conj. Acid pKa
• NH3 NH4 9.3
• CH3CH2NH2 CH3CH2NH3 10.8
• (CH3CH2)2NH (CH3CH2)2NH2 10.9
• (CH3CH2)3N (CH3CH2)3NH 11.1
• C6H5NH2 C6H5NH3 4.6

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Decreased basicity of arylamines

• Aniline (reactant) is stabilized by conjugation
  of nitrogen lone pair with ring p system.
• This stabilization is lost on protonation.

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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
3.8 x 10-10
6 x 10-14
10-19
Kb
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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.

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Basicity of Arylamines

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

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p-Nitroaniline

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

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Effect is Cumulative

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

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Heterocyclic Amines
is more basic than
piperidine
pyridine
Kb 1.6 x 10-3
Kb 1.4 x 10-9
(an alkylamine)
(resembles anarylamine inbasicity)
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Heterocyclic Amines
is more basic than
imidazole
pyridine
Kb 1 x 10-7
Kb 1.4 x 10-9
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Imidazole

• Which nitrogen is protonated in imidazole?

H
H

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Imidazole

• Which nitrogen is protonated in imidazole? (HINT
  Resonance is the key.)

H
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Imidazole

• Protonation in the direction shown gives a
  stabilized ion.

H


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Question

• Which of the following amines is more basic?
• A) B)
• C) D)

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Preparation of Amines by Reduction
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Preparation of Amines by Reduction

• Almost any nitrogen-containing compound canbe
  reduced to an amine, including
• azides nitriles nitro-substituted benzene
  derivatives amides

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Synthesis of Amines via Azides

• SN2 reaction, followed by reduction, gives a
  primary alkylamine.

NaN3
(74)
Azides may also bereduced by catalytichydrogenat
ion.
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Question

• What is the product of the reaction shown?
• A) B)
• C) D)

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Question

• Identify compound C formed in the synthetic
  sequence below.
• A) (R)-2-octanamine B) (S)-2-octanamine
• C) (R)-2-octanol D) octane

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Synthesis of Amines via Nitriles

• SN2 reaction, followed by reduction, gives a
  primary alkylamine.

NaCN
CH3CH2CH2CH2Br
CH3CH2CH2CH2CN
(69)
Nitriles may also bereduced by lithiumaluminum
hydride.
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Synthesis of Amines via Nitriles

• SN2 reaction, followed by reduction, gives a
  primary alkylamine.

NaCN
CH3CH2CH2CH2Br
CH3CH2CH2CH2CN
(69)
The reduction alsoworks with cyanohydrins.
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Question

• What is the major organic product of the
  synthesis shown?
• A) C6H5CH2CN
• B) C6H5CH2CHO
• C) C6H5CH2CH2NH2
• D) C6H5CH2NH2

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Synthesis of Amines via Nitroarenes
HNO3
Cl
H2SO4
Nitro groups may alsobe reduced with tin (Sn)
HCl or by catalytichydrogenation.
(88-95)
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Question

• Which one of the following is produced when
  m-nitroacetophenone is treated with Sn and HCl
  followed by NaOH?
• A) B)
• C) D)

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Question

• Starting with benzene, which of the sequences
  below will produce p-methylaniline as the major
  product of the reaction?
• A) 1. HNO3, H2SO4 2. CH3Cl, AlCl3 3. Fe, HCl
  4. NaOH
• B) 1. HNO3, H2SO4 2. Fe, HCl 3. NaOH 4.
  CH3Cl, AlCl3
• C) 1. CH3Cl, AlCl3 2. HNO3, H2SO4 3. Fe, HCl
  4. NaOH
• D) 1. CH3Cl, AlCl3 2. HNO3, H2SO4 3. H2

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Synthesis of Amines via Amides
1. SOCl2
2. (CH3)2NH
(86-89)
Only LiAlH4 is anappropriate reducingagent for
this reaction.
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Question

• Identify the product of the synthesis shown.
• A) C6H5NH2
• B) C6H5CHNH
• C) C6H5CH2NH2
• D) C6H5C(O)NH2

LiAlH4
5. H2O
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Preparation and Reactions of Amines
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The Gabriel Synthesis of Primary Amines
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Question

• What is the product of the Gabriel synthesis
  shown?
• A) diethyl ether
• B) ethanol
• C) ethyl amine
• D) CH3CH2NHNH2

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Reductive Amination
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Synthesis of Amines via Reductive Amination
In reductive amination, an aldehyde or ketoneis
subjected to catalytic hydrogenation in
thepresence of ammonia or an amine.
fast


NH3
H2O

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

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Synthesis of Amines via Reductive Amination
The imine undergoes hydrogenation fasterthan the
aldehyde or ketone. An amine is the product.
fast


NH3
H2O
H2, Ni
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Example Primary amines give secondary amines
NaBH3CN or
H2, Ni
ethanol
via
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Example Secondary amines give tertiary amines

H2, Ni, ethanol
(93)
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Question

• How would you accomplish the conversion of
  propanal into N-ethyl-N-methylpropanamine?
• A) NH3, NaBH3CN CH3I CH3CH2I
• B) CH3NH2, NaBH3CN CH3COCl, pyridine LiAlH4
  H2O
• C) CrO3, H2SO4 SOCl2, pyridine 2 equiv CH3NH2
  CH3I
• D) CH3CH2NH2, H2, Ni (CH3CO)2O, pyridine NaBH4

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Quarternary Amines Can Undergo an E2 Elimination
Reaction
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The Hofmann Elimination
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The Hofmann Elimination

• a quaternary ammonium hydroxide is the
  reactantand an alkene is the product
• is an anti elimination
• the leaving group is a trialkylamine
• the regioselectivity is opposite to the Zaitsev
  rule.

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Quaternary Ammonium Hydroxides
are prepared by treating quaternary
ammmoniumhalides with moist silver oxide
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Regioselectivity
Elimination occurs in the direction that gives
the less-substituted double bond. This is
called the Hofmann rule.
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Regioselectivity
largest group is between two H atoms
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Regioselectivity
H
CH3
H
CH3
H

largest group is between anH atom and a methyl
group
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Nitrosation of Arylamines
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Nitrosation of Primary Arylamines

• Gives aryl diazonium ions.
• Aryl diazonium ions are much more stable
  thanalkyl diazonium ions.
• Most aryl diazonium ions are stable under the
  conditions of their formation (0-10C).

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Synthetic Origin of Aryl Diazonium Salts
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Synthetic Transformationsof Aryl Diazonium Salts
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Transformations of Aryl Diazonium Salts
CuCl or CuBr heat
CuCN, heat
HBF4 / heat
KI
H3PO2
H2O, heat
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Question

• Identify the product isolated from the reaction
  of p-nitroaniline with NaNO2 in H2SO4 followed by
  the addition of potassium iodide (KI).
• A) nitrobenzene
• B) p-iodoaniline
• C) p-iodonitrobenzene
• D) p-diiodonitrobenzene

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Alkaloids
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Alkaloids Naturally Occuring Bases Nitrogen
Heterocycles
ibogaine
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Amines Neurotransmitters
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R-ethylamine dopamine mescaline
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Serotonin --------- Melatonin
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Acetylcholine Epinephrine (Adrenaline)
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Cathecols epinephrine mdma http//faculty.washi
ngton.edu/chudler/mdma.html Principal
sympathomimetic adrenal hormone a controlled
substance
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Drug Uptake Rank from slowest to fastest. a)
injection b) ingestion c) inhalation d)
snorting

• altbltcltd B) cltaltdltb
• C) bltdltaltc D) dltbltclta

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Drug Uptake Rank from slowest to fastest. a)
injection b) ingestion c) inhalation d)
snorting

• altbltcltd B) cltaltdltb
• C) bltdltaltc D) dltbltclta

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morphine
LSD
ibogaine