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CHAPTER 25: AMINES

GENERAL INFO

EXAMPLES OF AMINES

Fish smell Trimethylamine from decay of

trimethylamine oxide (osmolyte) Decay compound

Serotonin Neurotransmitter, feeling of

happiness

Psilocin Hallucinogenic mushrooms

5-MeO-DMT Psychedelic found in the skin

of Bufo alvarius toad

Mescaline Hallucinogenic in peyote

cactus

Nightshade berries

“Nightlock berries” from the Hunger Games

Deadly Nightshade Contains atropine (+2

related compounds) which cause delirium and

hallucinations

Hemlock plant

Hemlock Contains poison coniine, Used to execute Socrates

(philosopher).

MeNMe

MeO Me

NMe

Medecay H2N

NH2OH

O

H2N

NH2

Lysine (amino acid)

decay

Cadaverine

H2N

NH2

Putrescine

MeN

O

O

Ph

OH

NH

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NOMENCLATURE 1. Common system for simple amines: order alkyl groups alphabetically. “Alkyl alkyl amine”

2. IUPAC: Ending is –amine.

3. Use “N-alkyl” and consider it a substituent for 2˚ and 3˚ amines.

Common: IUPAC:

CHIRALITY1

1 Nitrogen LP inversion: Jones, M., Fleming, S.A., Organic Chemistry, 4th ed., Norton, 2010, pp. 254. Phosphorous chirality: Carey, F.A., Sundberg, R.J., Advanced Organic Chemistry, 4th ed., Kluwer Academic/Plenum Publishing, 2000, pp. 103.

PCH3H P

H3CH

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TRENDS IN BASICITY

WHY ARE AMINES BASIC? Amines are the only mainstream functional group that produce a noticeably basic aqueous solution, which can be verified by litmus paper.

NH3 + H2O

CH3OH + H2O

BASICITY TRENDS

ALKYL VS. ANILINE

CH3CH2NH2

pKb

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HYBRIDIZATION DIFFERENCES

piperidine

pyridine

acetonitrile

pKb

AVAILABILITY CONSIDERATIONS

pyridine

pyrrole

acetamide

pKb

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SUMMARY

Problem: which compound is more basic in each set?

Set A Set B

Set C Set D

APPLICATION: UREA CYCLE

O

OH3N

R

generic amino acid

metabolismO

OH3N

glutamate

NAD+O

OO

OO OO

H2O+ NH3

urea cycle

α-ketoglutarate

H2N NH2

O

urea

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SYNTHESIS OF AMINES

CHALLENGES OF SN2

THROUGH A NITRILE

GABRIEL SYNTHESIS

Concept of “Atom Economy”

One of the tenets of Green Chemistry is the consideration of how many atoms are incorporated into the desired product (in comparison to how many atoms are “wasted”). This idea was proposed by Dr. Barry Trost (American chemist at Stanford). The Gabriel Synthesis is a poor reaction in terms of its atom economy.

I NH3

Siegmund Gabriel (German chemist)

Rxn published in 1887

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REDUCTIVE AMINATION

REACTION + MECHANISM

EXAMPLES

HNO

H

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BREAKING BAD

Pseudoephedrine Methamphetamine (Sudafed, decongestant) (psychostimulant)

“P2P Synthesis”

APPLICATION: BIOSYNTHESIS OF GLUTAMIC ACID

α-ketoglutaric acid

SUMMARY OF SYNTHESES

Synthesize this amine using three different methods:

1. Using a Nitrile

2. Using the Gabriel Synthesis

3. Using a Reductive Amination

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AMINE REACTIONS

ACID-BASE REACTIONS

APPLICATION: LEMON AND FISH

fish smell citric acid (in lemon)

APPLICATION: HYDROCHLORIDE SALTS

Diphenylhydramine-hydrochloride

Antihistamine used for allergies

Cetirizine-dihydrochloride Antihistamine used for allergies

Loperamide Anti-diarrheal

NHHCl HBr

N

+

O

HO

OH O

OHO

OH

NMeMe

Me

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APPLICATION: COCAINE

Free basing; smoking

“Crack” cocaine

→

⟵

Cocaine

Snorting; Injecting

HOFMANN ELIMINATION

Product distribution2

MECHANISM OF Ag2O STEP

EXAMPLES

2 Jones, M., Fleming, S.A., Organic Chemistry, 4th ed., Norton, 2010, pp. 324.

NH2 a. excess CH3I

b. Ag2O, H2O

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HOFMANN ELIMINATION CYCLES What is formed when this amine is treated to 3 “cycles” of Hofmann elimination?

DIAZONIUM SALTS

REACTION + MECHANISM

Nitrosamines (carcinogens) may be formed in the stomach from reaction of nitrites:

N

H

CH3

NaNO2

HClN

CH3

NO

a nitrosamine

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SYNTHESIS PROBLEMS

APPLICATION: DIAZO DYES

Para Red The first azo dye (1880);

used to dye cotton

Methyl Orange pH indicator

Sunset Yellow Food coloring. Chemically similar to a possible carcinogen, so limited usage.

NN OH

NN

OH

H

Cl

NN

OH