Measures of Basicity

Amines Chemical / Biological / Neurological Activity

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

Basicity Constant (Kb) and pKb • Kb is the equilibrium constant for the reaction: R3N •• + H

+ R3N

••

OH ••

Kb =

H +

– •• •• OH ••

[R3NH+][HO–] [R3N]

and pK b = - log K b

Ka and pKa of Conjugate Acid •

K a is the equilibrium constant for the dissociation of the conjugate acid of the amine: + R3N

R3N •• + H+

H

Ka =

[R3N][H+] [R3NH+]

and pK a = - log K a

Relationships between acidity and basicity constants Ka K b = 10-14 pK a + pK pK b = 14

Basicity of Amines in Aqueous Solution

•Amine

Conj. Acid +

•NH3

NH4

•CH3CH2NH2

CH3CH2NH3+

pKa 9.3 10.8

CH3CH2NH3+ is a weaker acid than NH4+; therefore, CH3CH2NH2 is a stronger base than NH3.

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

Conj. Acid

pKa

Effect of Structure on Basicity

9.3

•1. Alkylamines are slightly stronger bases than ammonia.

CH3CH2NH3+

10.8

•2. Alkylamines differ very little in basicity.

•(CH3CH2) 2NH

(CH3CH2)2NH2+

10.9

•(CH3CH2) 3N

(CH3CH2)3NH+

11.1

•3. Arylamines are much weaker bases than ammonia.

•NH3

NH4

•CH3CH2NH2

+

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

Basicity of Amines in Aqueous Solution

•Amine

Conj. Acid

pKa

•NH3

NH4 +

9.3

•CH3CH2NH2

CH3CH2NH3+

Decreased basicity of arylamines

••

NH 2 + H

10.8 +

•(CH3CH2) 2NH

(CH3CH2)2NH2

•(CH3CH2) 3N

(CH3CH2)3NH+

11.1

•C6H5NH2

C6H5NH3+

4.6

••

10.9 + NH 3 +

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

Decreased basicity of arylamines •Increasing delocalization makes diphenylamine a weaker base than aniline, and triphenylamine a weaker base than diphenylamine.

Kb

C6H5NH2

(C6H5) 2NH

(C6H5) 3N

3.8 x 10-10

6 x 10-14

~10-19

Basicity of Arylamines

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.

X

NH2

•X •H •CH3 •CF3 •O2 N

NH3+

X

pKb 9.4 8.7 11.5 13.0

••

N

is more basic than

••

O ••

+ N

pKa 4.6 5.3 2.5 1.0

•O• –• •• •

••

NH2

– •• •• O ••

+ N

•O • – • •• •

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

Heterocyclic Amines

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.

p-Nitroaniline

N ••

H piperidine Kb = 1.6 x 10-3

pyridine Kb = 1.4 x 10-9

(an alkylamine)

(resembles an arylamine in basicity)

+ NH2

Heterocyclic Amines

•• N

•• N

Imidazole • Which nitrogen is protonated in imidazole?

is more basic than

N

H

••

imidazole Kb = 1 x 10-7

•• N

pyridine Kb = 1.4 x 10-9

Imidazole

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

•• N

•

•• N

H+

H

+ N

•• N

H

H

+ N

•• N

H

•• N

•• N

H

+ N H H

Which of the following amines is more basic?

•

A)

B)

•

C)

D)

H

H+

•• N

+ N

H+

Question

Protonation in the direction shown gives a stabilized ion.

H

H

H+

H

Imidazole

•• N

H

N ••

+ N H

Preparation of Amines by Reduction

Preparation of Amines by Reduction

Synthesis of Amines via Azides

•Almost any nitrogen-containing compound can be reduced to an amine, including:

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

• azides nitriles nitro-substituted benzene derivatives amides

CH2CH2Br

NaN NaN 3

CH2CH2N3 (74%) 1. LiAlH4 2. H2O

Azides may also be reduced by catalytic hydrogenation.

CH2CH2NH2 (89%)

Question • What is the product of the reaction shown?

Question • Identify compound C formed in the synthetic sequence below.

Synthesis of Amines via Nitriles •SN2 reaction, followed by reduction, gives a primary alkylamine. CH3CH2CH2CH2Br

•

A)

B)

•

C)

D)

• A) (R)-2-octanamine • C) (R)-2-octanol

B) (S)-2-octanamine D) octane

Nitriles may also be reduced by lithium aluminum hydride.

NaC NaC N

CH3CH2CH2CH2CN (69%) H2 (100 atm), Ni

CH3CH2CH2CH2CH 2NH2 (56%)

Synthesis of Amines via Nitriles •SN2 reaction, followed by reduction, gives a primary alkylamine. CH3CH2CH2CH2Br

NaC NaC N

The reduction also works with cyanohydrins.

Synthesis of Amines via Nitroarenes

Question • What is the major organic product of the synthesis shown?

CH3CH2CH2CH2CN • • • •

(69%) H2 (100 atm), Ni

CH3CH2CH2CH2CH 2NH2

A) B) C) D)

C 6H5CH2CN C 6H5CH2CHO C 6H5CH2CH2NH2 C 6H5CH2NH2

HN O 3

Cl

Nitro groups may also be reduced with tin (Sn) + HCl or by catalytic hydrogenation.

B)

• C)

D)

1. Fe, HCl 2. NaOH NH 2 (95%)

Question

Question

• A)

(88-95%)

Cl

(56%)

• Which one of the following is produced when mnitroacetophenone is treated with Sn and HCl followed by NaOH?

NO 2

Cl

H2SO4

• Starting with benzene, which of the sequences below will produce p-methylaniline as the major product of the reaction?

•

A)

•

B)

•

C)

•

D)

1. HNO3, H2 SO4 ; 2. CH3 Cl, AlCl3 ; 3. Fe, HCl; 4. NaOH 1. HNO3, H2 SO4 ; 2. Fe, HCl; 3. NaOH; 4. CH3Cl, AlCl3 1. CH3 Cl, AlCl3 ; 2. HNO3, H2 SO4 ; 3. Fe, HCl; 4. NaOH 1. CH3 Cl, AlCl3 ; 2. HNO3, H2 SO4 ; 3. H2

Synthesis of Amines via Amides O COH

O 1. SOCl2

CN (CH3)2

2. (CH3) 2NH

(86-89%)

Only LiAlH4 is an appropriate reducing agent for this reaction.

1. LiAlH4 2. H2O

CH2N(CH3) 2 (88%)

The Gabriel Synthesis of Primary Amines

Question • Identify the product of the synthesis shown.

Preparation and Reactions of Amines LiAlH4 5. H2 O

• • • •

A) B) C) D)

C 6H5NH2 C 6H5CH=NH C 6H5CH2NH2 C 6H5C(=O)NH2

Question

Synthesis of Amines via Reductive Amination

• What is the product of the Gabriel synthesis shown?

Reductive Amination • • • •

A) B) C) D)

diethyl ether ethanol ethyl amine CH3CH2NHNH2

In reductive amination, an aldehyde or ketone is subjected to catalytic hydrogenation in the presence of ammonia or an amine. R

fast C

R'

R

O + NH 3

C

NH +

H2O

R'

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

Synthesis of Amines via Reductive Amination

O

The imine undergoes hydrogenation faster than the aldehyde or ketone. An amine is the product. R C

O + NH 3

R'

C

NaBH3CN or H2, Ni C

NH +

Example: Secondary amines give tertiary amines O CH3CH2CH2CH

+

ethanol

N H

H2, Ni, ethanol

H2O

CH3(CH2) 5CH2NH

R'

R R'

CH3(CH2) 5CH + H2N

R

fast

Example: Primary amines give secondary amines

H2, Ni NH 2

H

Question • How would you accomplish the conversion of propanal into N-ethyl-N-methylpropanamine? •

• A) NH3 , NaBH3 CN; CH3 I; CH3CH2I • B) CH3 NH2 , NaBH3 CN; CH3 COCl, pyridine; LiAlH4; H2 O • C) CrO3 , H2 SO4 ; SOCl2 , pyridine; 2 equiv CH3 NH2 ; CH3 I • D) CH3 CH2 NH2 , H2 , Ni; (CH3 CO)2 O, pyridine; NaBH4

via:

CH3(CH2) 5CH

N

N CH2CH2CH2CH3

Quarternary Amines Can Undergo an E2 Elimination Reaction

The Hofmann Elimination

(93%)

Quaternary Ammonium Hydroxides

The Hofmann Elimination •a quaternary ammonium hydroxide is the reactant and an alkene is the product

Regioselectivity

are prepared by treating quaternary ammmonium halides with moist silver oxide

•is an anti elimination

CH2N(CH3) 3 I

–

Ag2O

+ N(CH3)3

H2O, CH3OH

– HO

+ – CH2N(CH3) 3 HO

Regioselectivity

H2C

CH3CHCH2CH3

•the leaving group is a trialkylamine •the regioselectivity is opposite to the Zaitsev rule.

Elimination occurs in the direction that gives the less-substituted double bond. This is called the Hofmann rule. CHCH2CH3 (95%)

heat

+ CH3CH

CHCH3 (5%)

Regioselectivity

H

H

CH3CH2

H

H

H

H

CH3CH2

+ N(CH3)3 largest group is between two H atoms

C C

H

H

major product

H CH3

CH3 H + N(CH3)3

largest group is between an H atom and a methyl group

CH3

H

C C

H

CH3

minor product

Nitrosation of Arylamines

Synthetic Origin of Aryl Diazonium Salts

Nitrosation of Primary Arylamines

Ar

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

N

+ ArN ArN

N

fast

+ R

+ N2

slow

+ Ar

+ N2

Ar

CN

CuCN, heat

Cl

CuCl CuCl or CuBr CuBr heat

+ N

Ar

N

H3PO2

Ar

H

Br

Ar

H2O, heat

Ar

OH

Ar

F

HBF4 / heat KI

Ar

Ar

Synthetic Transformations of Aryl Diazonium Salts

NO 2 Ar

NH 2

Ar

Transformations of Aryl Diazonium Salts Ar

H

I

+ N

N

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

Alkaloids

Alkaloids: Naturally Occuring Bases

Amines & Neurotransmitters

Nitrogen Heterocycles

ibogaine

R-CH2CH2 NH2

CH2CH2NH2 HO

CH2CH2 NH2

CH3O

CH2CH2NH2

CH3 O H3 CO

N H

CH3O

HO

HO CH2CH2NH2

CH3 HOCH2CH2N CH3 CH3 O CH2CH2NHCCH3

CH3O N H

OH CHCH2NHCH3

N H

H3CO

R-ethylamine dopamine mescaline

HO HO

O CH3 CH3COCH2CH2N CH3 CH3

Serotonin --------- Melatonin

Acetylcholine Epinephrine (Adrenaline)

Cathecols: epinephrine & mdma http://faculty.washington.edu/chudler/mdma.html

Drug Uptake:

Drug Uptake:

Rank from slowest to fastest.

Rank from slowest to fastest.

a) injection; b) ingestion; c) inhalation; d) snorting

a) injection; b) ingestion; c) inhalation; d) snorting

A) a