N OH quinine -...

CHM'224'•'Organic'Chemistry'IISpring'2013,'Des'Plaines'•'Prof.'Chad'Landrie

•Classifica)on,&,Nomenclature,of,Amines,(24.1)•Structure,,Proper)es,,Basicity,,(24.2B24.5)•Synthesis,of,Amines,(24.6)

Lecture'14:'March'19,'2013

OHN

O

Nquinine


24.1

ClassificaHon,'Nomenclature'&'Examples'of'Amines

© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)

Slide Lecture 14: March 19

Classifica(on+of+Amines

3

Alkyl Amine: N attached to an alkyl group

Aryl Amine: N attached to an aryl (aromatic) group

N

triethylamine cyclohexylamine

NH2

dimethylamine

H3CHN

CH3

NH2

aniline

HN

diphenylamine




4

Heterocyclic Amine: N in a ring; often aromatic

N NH

pyrrolepyridine

N

quinoline

NHN

imidazole

HN

indole

N

N

pyrimidine

NH

pyrrolidine

NH

piperidine

heterocycle is any ring containing two or more atom types




5

Alkaloids: Naturally occurring compounds containing N

Order: coleoptera

Family: coccinellidae

Order: Tetraodontoformes

NHN

H2N

OHOHHO

OO

OHO

(-)-tetrodotoxin

N

C6H13NCS

fasicularin

3

6 7

3'

A

BC

NH

O

(-)-adalinine

C5H11

O

Wardrop, D. J., Landrie, C. L. & Ortiz, J. A. Total synthesis of the coccinellid alkaloid (+/-)-adalinine utilizing a nitrenium ion cyclization. Synlett 1352-1354 (2003).

Wardrop, D. J., Zhang, W. M. & Landrie, C. L. Stereoselective nitrenium ion cyclizations: asymmetric synthesis of the (+)-Kishi lactam and an intermediate for the preparation of fasicularin. Tetrahedron Lett. 45, 4229-4231 (2004).




6


OHN

O

Nquinine

coniine

NH

H

NH3C O

cocaine

O

Ph

OCH3O




7


H3CN

NH

(S)-3-(1-methylpyrrolidin-2-yl)pyridineor nicotine



Classifica(on+of+Amines:+Subs(tu(on

8

H3C CH3

NH2

H3C CH3

OH

2º alcohol 1º amine

HN

CH3

2º amine

N

3º amine

N

F–

quaternary ammonium salt(tetrabutyl ammonium fluoride, TBAF)

Unlike alcohols, amine substitution is determined by the number of Cs directly attached to N.



Nomenclature

9

1. Primary Amines

functional class name:• add -amine to alkyl group• name alkyl group as a substituent (-yl)• commonly used when amino group is

at locant 1 with no branching

NH2H3CNH2

NH2

ethylamine butyl-2-amine 3-methylbutylamine

substitutive name:• add -amine to alkane parent (drop -e)• name alkyl group as a substituent (-yl)• common for complex alkyl groups

ethanamine 2-butanamine 3-methylbutanamine



Nomenclature

10

2. 1º Amines with more than one functional group

OH

O

NH2

2-aminobutanoic acid

OHNH2

NH2

2,4-diaminophenol

ONH

4-(methylamino)pentan-2-one

NH2 OH

4-aminopentan-2-ol

OHNH2

2,3-diaminopropan-1-ol

H2N

• name -NR2 group as -amino substituent• amines have lower priority than alochols



Nomenclature

11

3. Symmetrical 2º and 3º amines

• use use functional class name (-ylamine)• add replicating prefix di- or tri-

HN

diphenylamine

N

triethylamine

NH

diisopropylamine



Nomenclature

12

4. Unsymmetrical 2º and 3º amines

• name as N-substituted primary amines• alkyl group with longest chain is parent

N

N,N-diethylpropan-1-amineor N,N-diethylpropylamine

N

N-ethyl-N-methylcyclohexanamineor N-ethyl-N-methylcylohexylamine


24.2

Structure'and'ProperHes



Hybridiza(on

14

• N and C are sp3-hybridized in methyl amine

• electron lone-pair on N is in a sp3 orbital

• site of protonation

• electron density concentrated at location of electron lone-pair

• Hs on N, relatively acidic (less than alcohols though)



Chirality+Centers+Other+Than+Carbon

15

Since nitrogen undergoes rapid pyramidal inversion, it is not considered a chirality center. The energy barrier to inversion is large enough for phosphines and sulfoxides, that they are considered chirality centers.

Ea (amines)~ 24 kcal/mol

Ea (sulfoxide)~ 45 kcal/mol

Ea (phospine)~ 132 kcal/mol



Hybridiza(on

16

• increased resonance with adjacent π-systems increases sp2-character of N• as sp2-character increases, bisector angle increases from 125º to 180º (flat)

NHH

H

HH

methylamine

N HH

aniline

H N

OH

H

H N

OH

Hformamide



Resonance+in+Aryl+Amines

17

• no delocalization of lone-pair• N is sp3 hybridized

• delocalization of lone-pair• N is sp2 hybridized



Resonance+in+Aryl+Amines

18

• actual picture is somewhen in between• the resonance structures of aniline show nucleophilic sites of benzene ring in

nucleophilic aromatic substitution (ortho-para director)



Boiling+Point

19

• N less electronegative than oxygen• smaller N-H dipole than O-H dipole = weaker H-bonding in amines• less polar, lower boiling point than alcohols



Boiling+Point

20

• among similar MW amines (similar LDFs); 1º have highest bp• more N-H bonds = more H-bonding = higher bp• tertiary no H-bonding = lowest bp


24.3B24.5

Basicity



Basicity

22

Amines, while relatively weak bases, are the strongest bases among neutral organic compounds

HO CH3

O

H3C NH2 +O CH3

O

H3C NH3 +

methylamine acetic acid methylammonium acetate

pKa = 4.7 pKa = 10.7

Keq = 106

HOHH3C NH2 + O

HH3C NH3 +

methylamine water methylammonium hydroxide

pKa = 15.7 pKa = 10.7

Keq = 10–5



Basicity

23

Aryl Amines are Significantly Less Basic

the stronger the conjugate acid, the weaker the conjugate basethe weaker the conjugate acid, the stronger the conjugate base

strongest acid weakest basestrongest base weakest acid

• N electron lone-pair conjugated with aromatic ring (resonance) in aniline and thus more delocalized and less available for bond formation

• N electron lone-pair is more localized in cyclohexylamine and thus more available to form bonds to H atoms

NH

HH N

H

H

+N

H

H

NH

H

+

H

anilinium ion cyclohexylamine aniline cyclhexylammonium ion

pKa = 4.6 pKa = 10.6

Keq = 106



Basicity

24

Aryl Amines are Significantly Less Basic

more and more conjugated aryl amine = less and less basic

NH2HN N

aniline diphenylamine triphenylamine

pKa of conjugate acid 4.6 0.8 –5



Y

NH2

Y

NH2

Y

NH2

Y

NH2

Amine Y pKa of conjugate acid

H 4.6

CH3 5.3

CF3 3.5

NO2 1.0

Basicity+of+Subs(tuted+Arylamines

25

Basicity of Aryl Amines Influenced by Substituents

EDGs increase electron density on N inductively or through resonance

EWGs decrease electron density on N inductively or through resonance



Basicity

26

Pyridine is Less Basic than Piperidine

the stronger the conjugate acid, the weaker the conjugate basethe weaker the conjugate acid, the stronger the conjugate base

strongest acid weakest basestrongest base weakest acid

• N electron lone-pair in a sp2 orbital in pyridine and sp3 in piperidine• more s-character in pyridine = more electronegative = holds on to

electron lone-pair tighter = not as available for bonding• OR, pyridinium less stable than pyridine because higher s-character =

more electronegative atom, which is less stable with positive charge

N N+

pyridinium ion piperidine

pKa = 5.2 pKa = 11.2

HN N

+

pyridine piperidinium ion

H H

HKeq = 106



Amidine+Bases

27

NR

NR2amidine

functional group

• amidines are common non-nucleophilic bases (don’t participate in SN)• conjugate acid is stabilized by resonance (more stable acid, stronger base)

More acidic compared to:

N N H N N H N N HH H

Imidazole (Im) Imidazolium ionpKa = 7

1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)pKa = 12

N N N NH

N NH

N

pyridinium ion

pKa = 5.2

H

EtN

Et

EtH

triethylammonium

pKa = 10.6



Amine pKa of ammonium ion

12

11.3

10.8

7.0

5.3

4.6

0.4

Summary

28

Basicity of Amines is compared by considering the pKa of their conjugate acids

weaker base: smaller pKa for ammonium ion (stronger acid)

stronger base: larger pKa for ammonium ion (weaker acid)

NH

pyrrolidine

N N

DBU

EtN

Et

Et

triethylamine (Et3N)

N N HImidazole (Im)

N

pyridine (Py)

NH2

aniline

NH

pyrrole

Why is pyrrole such a weak base? (Why is it’s conjugate acid so strong)?

Incr

easi

ng B

asic

ity



Carboxylic+Acids+at+Physiological+pH

29

What is the percent dissociation in a 0.15 M aqueous solution of acetic acid buffered at pH = 7.0? The pKa of acetic acid is 4.30.

H3C

O

OH H3C

O

O+ H+

If pH remains constant (i.e. a buffered solution), use the Henderson-Hasselbach equation.

If pH is allowed to change, use an ICE table.




30

What is the percent dissociation in a 0.15 M aqueous solution of acetic acid buffered at pH = 7.0? The pKa of acetic acid is 4.30.Henderson-Hasselbalch equation

Note: When pH=pKa, the acid is 50% ionized.

H3C

O

OH H3C

O

O+ H+




31

What is the percent dissociation in a 0.15 M aqueous solution of acetic acid buffered at pH = 7.0? The pKa of acetic acid is 4.30.

Note: When pH=pKa, the acid is 50% ionized.

At physiological pH (7.3), carboxylic acids exist almost entirely as their conjugate bases!

H3C

O

O

H3C

O

OH H3C

O

O+ H+



Amines+at+Physiological+pH

32

What is the percent of ammonium ion in a 0.15 M aqueous solution of methyl amine buffered at pH = 7.3? The pKa of methyl ammonium is 10.64.Henderson-Hasselbalch equation

H3C NH3H3C NH2

+ H+



Amines+at+Physiological+pH

33

What is the percent of ammonium ion in a 0.15 M aqueous solution of methyl amine buffered at pH = 7.3? The pKa of methyl ammonium is 10.64.

H3C NH3H3C NH2

+ H+

At physiological pH (7.3), amines exist almost entirely as their conjugate acids! They are fully

protonated.

H3C NH3



Amino+Acids+Are+ZwiFerions+at+Physiological+pH

34

O

OH3N

PhH

amino group fully protonated at pH = 7.3

acid group fully deprotonated at pH = 7.3

amino acids contain both an amino group and a carboxylic acid group. They are the building blocks for proteins.

zwitterions are neutral molecules containing both a positively charged atom and a negatively charged atom


24.2,&,24.4

Solubility'and'ExtracHon



Solubility

36

Amines with ≤ 6 carbon atoms are generally soluble in water. The N atom is a H-bond acceptor to water.

Water insoluble amines can be made soluble by making the solution acidic to obtain the ammonium ion.

NH2

aniline

+ H3O+

NH

HH

anilinium ion

not water soluble water soluble



Three+Ionizable+Func(onal+Groups+in+Water

37

R

O

O HR

O

OOH+ + H2O

carboxylic acid(conjugate acid)

carboxylate anion(conjugate base)

OOH H2O

phenol(conjugate acid)

phenoxide anion(conjugate base)

O+ +

H2O

amine(conjugate base)

ammonium cation(conjugate acid)

+ +R NH2

H

H OH2

deprotonation

deprotonation

protonationR NH3

R R

pKa ~ 4 pKa = 15.7

pKa ~ 4 pKa = 15.7

pKa ~ –1.7 pKa ~ 9.0



General+Scheme+for:Base+Extrac(on+of+1:1+Benzoic+Acid/Acetanilide

38

OH

O

HN

O

CH2Cl2CH2Cl2

HN

O

O

O

Na

OHAdd 3 MNaOH (aq)

H2O

separatelayers

HN

O

CH2Cl2

H2O

O

O

Na

1. Neutralize/ Protonate with 3 M HCl 2. Vacuum filter precipitated benzoic acid

evaporateCH2Cl2

OH

O

crude solid:• not pure/clean• depressed mp

• possibly discolored

HN



CH3

O

1. recrystallize from boiling water 2. vacuum filter

OH

O

pure solid:• white crystals

• sharp mp• narrow mp range

HN CH3

Opure solid:

• white crystals• sharp mp

• narrow mp range


CH2Cl2 is denser than water = bottom layer

Amides are not bases due to resonance delocalization of lone-pair. They are not protonated!



Acid+Extrac(on+of+an+Amine

39

Often, the amine was used as a base in a reaction and is discarded with the aqueous layer.

CH2Cl2CH2Cl2

Add 3 MHCl (aq)

H2O

separatelayers

CH2Cl2

H2O

1. Neutralize/ Protonate with 3 M HCl 2. Separate aniline and water layers or discard if unwanted

evaporateCH2Cl2

NH2

crude liquid:• not pure/clean• depressed mp


C



purify NH2

pure solid:• white crystals

• sharp mp• narrow mp range


NH2

NH

HH

Cl–

OHO

OHO

OH

O

OH

OC

OH

O

NH

HH

Cl–


Finish,Ch.,24

Next'Lecture.'.'.

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