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AminesAmines Chemical / Biological / Neurological Chemical / Biological / Neurological

ActivityActivity

Measures of Basicity

• The basicity of amines may be measuredand compared by using any of these values:

• 1) Kb• 2) pKb• 3) Ka of conjugate acid• 4) pKa of conjugate acid

Basicity Constant (Kb) and pKb

• Kb is the equilibrium constant for thereaction:

RR33NN •••• ++ HH OHOH••••

••••RR33NN

++HH

––•••• OHOH••••

••••++

KKbb = =[R[R33NHNH++][HO][HO––]]

[R[R33N]N]

ppKKbb = = - log - log KKbbandand

Ka and pKa of Conjugate Acid

KKaa = =[R[R33N][HN][H++]]

[R[R33NHNH++]]

ppKKaa = = - log - log KKaaandand

RR33NN ••••RR33NN++

HH ++ HH++

• Ka is the equilibrium constant for thedissociation of the conjugate acid of the amine:

Relationships between acidity and basicity constants

ppKKaa + p + pKKbb = 14 = 14

KKa a KKbb = 10 = 10-14-14 •Amine Conj. Acid pKa

•NH3 NH4+ 9.3

•CH3CH2NH2 CH3CH2NH3+ 10.8

Basicity of Amines in Aqueous Solution

CHCH33CHCH22NHNH33++ is a weaker acid than NH is a weaker acid than NH44

++;;therefore, CHtherefore, CH33CHCH22NHNH22 is a stronger base is a stronger base than NHthan NH33..

Effect of Structure on Basicity

•1. Alkylamines are slightly stronger bases than ammonia.

•2. Alkylamines differ very little in basicity.

•Amine Conj. Acid pKa

•NH3 NH4+ 9.3


•(CH3CH2)2NH (CH3CH2)2NH2+ 10.9

•(CH3CH2)3N (CH3CH2)3NH+ 11.1


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

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 thanammonia.

•Amine Conj. Acid pKa

•NH3 NH4+ 9.3


•(CH3CH2)2NH (CH3CH2)2NH2+ 10.9

•(CH3CH2)3N (CH3CH2)3NH+ 11.1

•C6H5NH2 C6H5NH3+ 4.6


++ HH OHOH••••

••••

NNHH22••••

++

NNHH33

++ ––•••• OHOH••••

••••

• Aniline (reactant) isstabilized byconjugation ofnitrogen lone pairwith ring π system.

• This stabilization islost on protonation.

Decreased basicity of arylamines Decreased basicity of arylamines

CC66HH55NHNH22 (C(C66HH55))22NHNH (C(C66HH55))33NN

KKbb 3.8 x 103.8 x 10-10-10 6 x 106 x 10-14-14 ~10~10-19-19

•Increasing delocalization makes diphenylamine aweaker base than aniline, and triphenylamine aweaker base than diphenylamine.

Effect of Substituents on Basicity of Arylamines

•1. Alkyl groups on the ring increase basicity, butonly slightly (less than 1 pK unit).

•2. Electron withdrawing groups, especially orthoand/or para to amine group, decrease basicityand can have a large effect.

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

Basicity of Arylamines

XX NHNH22

XX NHNH33++

p-Nitroaniline

NHNH22

OO

NN

OO

–– ••••••••••••

••••

++••••

••••

OO

NN

OO

–– ••••••••••••

•••• ••••••••––

NHNH22

++

++

•Lone pair on amine nitrogen is conjugated withp-nitro group—more delocalized than in anilineitself. Delocalization lost on protonation.

Effect is Cumulative

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

Heterocyclic Amines

NN

HH

••••

NN••••

piperidinepiperidine pyridinepyridine

is more basic thanis more basic than

KKbb = 1.6 x 10 = 1.6 x 10-3-3 KKbb = 1.4 x 10 = 1.4 x 10-9-9

(an alkylamine)(an alkylamine) (resembles an(resembles anarylamine inarylamine in

basicity)basicity)

Heterocyclic Amines

NN••••

imidazoleimidazole pyridinepyridine

is more basic thanis more basic than

KKbb = 1 x 10 = 1 x 10-7-7 KKbb = 1.4 x 10 = 1.4 x 10-9-9

NN HHNN•••• ••••

Imidazole

NN HHNN•••• ••••

• Which nitrogen is protonated in imidazole?

HH++ HH++

NN HHNN ••••HH++

NN HHNN••••HH

++

Imidazole

NN HHNN•••• ••••

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

HH++

NN HHNN ••••HH++

Imidazole

NN HHNN•••• ••••

• Protonation in the direction shown gives astabilized ion.

HH++

NN HHNNHH++ ••••

NN HHNNHH ••••++

QuestionWhich of the following amines is more basic?

• A) B)

• C) D)

Preparation of Amines by Reduction

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

• azidesnitrilesnitro-substituted benzene derivativesamides

Preparation of Amines by Reduction

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

Synthesis of Amines via Azides

CHCH22CHCH22BrBr

CHCH22CHCH22NN33

NaNaNN33

(74%)(74%)

CHCH22CHCH22NNHH22

(89%)(89%)

1. LiAlH1. LiAlH44

2. H2. H22OO

Azides may also bereduced by catalytichydrogenation.

Question

• What is the product of the reaction shown?

• A) B)

• C) D)

• Identify compound C formed in the syntheticsequence below.

• A) (R)-2-octanamine B) (S)-2-octanamine• C) (R)-2-octanol D) octane

Question


Synthesis of Amines via Nitriles

CHCH33CHCH22CHCH22CHCH22BrBrNaNaCCNN

(69%)(69%)

CHCH33CHCH22CHCH22CHCH22CCNN

CHCH33CHCH22CHCH22CHCH22CCHH22NNHH22

(56%)(56%)

HH22 (100 atm), Ni (100 atm), Ni

Nitriles may also bereduced by lithiumaluminum hydride.


Synthesis of Amines via Nitriles

CHCH33CHCH22CHCH22CHCH22BrBrNaNaCCNN

(69%)(69%)

CHCH33CHCH22CHCH22CHCH22CCNN

CHCH33CHCH22CHCH22CHCH22CCHH22NNHH22

(56%)(56%)

HH22 (100 atm), Ni (100 atm), Ni

The reduction alsoThe reduction alsoworks with cyanohydrins.works with cyanohydrins.

Question

• What is the major organic product of thesynthesis shown?

• A) C6H5CH2CN• B) C6H5CH2CHO• C) C6H5CH2CH2NH2

• D) C6H5CH2NH2

Synthesis of Amines via Nitroarenes

HHNNOO33

(88-95%)(88-95%)

ClCl

ClCl NNOO22HH22SOSO44

(95%)(95%)

1. Fe, HCl1. Fe, HCl2. NaOH2. NaOH

ClCl NNHH22

Nitro groups may alsobe reduced with tin (Sn)+ HCl or by catalytichydrogenation.

Question• Which one of the following is produced when m-

nitroacetophenone is treated with Sn and HClfollowed by NaOH?

• A) B)

• C) D)

Question• Starting with benzene, which of the sequences below will

produce p-methylaniline as the major product of thereaction?

• 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

Synthesis of Amines via Amides

(86-89%)(86-89%)

COHCOH

OO1. SOCl1. SOCl222. (CH2. (CH33))22NNHH

CCNN(CH(CH33))22

OO

(88%)(88%)

1. LiAlH1. LiAlH44

2. H2. H22OO

CHCH22NN(CH(CH33))22

Only LiAlH4 is anappropriate reducingagent for this reaction.

Question• Identify the product of the synthesis shown.

• A) C6H5NH2• B) C6H5CH=NH• C) C6H5CH2NH2• D) C6H5C(=O)NH2

LiAlH45. H2O

Preparation and Reactions of Amines

The Gabriel Synthesis of Primary Amines

Question

• What is the product of the Gabrielsynthesis shown?

• A) diethyl ether• B) ethanol• C) ethyl amine• D) CH3CH2NHNH2

Reductive Amination

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

Synthesis of Amines via Reductive Amination

OOCC

RR

R'R'

++ NNHH33

fastfast

NNHHCC

RR

R'R'

++ HH22OO

In reductive amination, an aldehyde or ketoneIn reductive amination, an aldehyde or ketoneis subjected to catalytic hydrogenation in theis subjected to catalytic hydrogenation in thepresence of ammonia or an amine.presence of ammonia or an amine.

Synthesis of Amines via Reductive Amination

HH22, Ni, Ni

OOCC

RR

R'R'

++ NNHH33

fastfast

NNHHCC

RR

R'R'

++ HH22OO

NNHH22

RR

R'R' CC

HH

The imine undergoes hydrogenation fasterThe imine undergoes hydrogenation fasterthan the aldehyde or ketone. An amine is than the aldehyde or ketone. An amine is the product.the product.

Example: Primary amines give secondary amines

HH22, Ni, Ni ethanolethanol

CHCH33(CH(CH22))55CHCH22NNHH

++ HH22NN

CHCH33(CH(CH22))55CHCH

OO

NaBHNaBH33CN CN oror

via:via: NN

CHCH33(CH(CH22))55CHCH

Example: Secondary amines give tertiary amines

HH22, Ni, ethanol, Ni, ethanol

(93%)(93%)

++CHCH33CHCH22CHCH22CHCH

OO

NN

HH

NN

CHCH22CHCH22CHCH22CHCH33

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

Quarternary Amines Can Undergo anE2 Elimination Reaction

The Hofmann Elimination

The Hofmann EliminationThe 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.

Quaternary Ammonium Hydroxides

AgAg22OO HH22O, CHO, CH33OHOH


++HOHO––

are prepared by treating quaternary ammmoniumare prepared by treating quaternary ammmoniumhalides with moist silver oxidehalides with moist silver oxide


II ––

Regioselectivity

heatheat

Elimination occurs in the direction that gives Elimination occurs in the direction that gives the less-substituted double bond. This is called the less-substituted double bond. This is called the the Hofmann rule.Hofmann rule.

NN(CH(CH33))33++

HOHO––

CHCH33CHCHCHCH22CHCH33 HH22CC CHCHCHCH22CHCH33

CHCH33CHCH CHCHCHCH33

++

(95%)(95%)

(5%)(5%)

Regioselectivity

NN(CH(CH33))33++

HH

HH

HH HH

CHCH33CHCH22

largest group is between two H atomslargest group is between two H atoms

CC

HHCC

HHHH

CHCH33CHCH22

major productmajor product

Regioselectivity

NN(CH(CH33))33++

HH

HH

HH

CHCH33

largest group is between anlargest group is between anH atom and a methyl groupH atom and a methyl group

CC

HHCC

CHCH33 HH

CHCH33

minor productminor product

CHCH33Nitrosation of Arylamines

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 theconditions of their formation (0-10°C).

ArArNN NN++

RRNN NN++ fastfast

slowslow

RR++ ++ NN22

ArAr++ ++ NN22

Synthetic Origin of Aryl Diazonium Salts

ArAr HH

ArAr NNOO22

ArAr NNHH22

ArAr NN NN++

Synthetic Transformationsof Aryl Diazonium Salts

Transformations of Aryl Diazonium Salts

ArAr NN NN++

ArAr HH

ArAr OOHH

ArAr II

ArAr FF

ArAr BrBrArAr ClCl

ArAr CNCN

HH22OO, heat, heatKKII

HBFHBF4 4 / heat/ heat

CuCuCl Cl oror CuCuBrBr heat heatCuCN,CuCN,

heatheat

HH33POPO22

Question

• Identify the product isolated from thereaction of p-nitroaniline with NaNO2 inH2SO4 followed by the addition ofpotassium iodide (KI).

• A) nitrobenzene• B) p-iodoaniline• C) p-iodonitrobenzene• D) p-diiodonitrobenzene

Alkaloids

Alkaloids: Naturally Occuring BasesNitrogen Heterocycles

ibogaine

Amines & Neurotransmitters

R-ethylaminedopaminemescaline

R

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C

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C

H

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N

H

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C

H

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H

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2

C

H

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N

H

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CH3O

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Serotonin --------- Melatonin

HOCH2CH

2N CH

3

CH3

CH3

CH3COCH

2CH

2N CH

3

CH3

CH3

O

CHCH2NHCH

3

HO

HO

OH

AcetylcholineEpinephrine (Adrenaline)

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

Principal sympathomimetic adrenal hormone& a controlled substance

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

A) a<b<c<d B) c<a<d<b

C) b<d<a<c D) d<b<c<a

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

A) a<b<c<d B) c<a<d<b

C) b<d<a<c D) d<b<c<a

http://web.indstate.edu/thcme/mwking/nerves.html#table

http://www.sfn.org/briefings/addiction.html

http://faculty.washington.edu/chudler/amp.html

http://www%2Drci.rutgers.edu/%7Elwh/drugs/

morphine LSD

ibogaine

amines - welcome to chemconnections

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