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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
CHM'224'•'Organic'Chemistry'IISpring'2013,'Des'Plaines'•'Prof.'Chad'Landrie
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
Classifica(on+of+Amines
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
Classifica(on+of+Amines
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).
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
Classifica(on+of+Amines
6
Alkaloids: Naturally occurring compounds containing N
OHN
O
Nquinine
coniine
NH
H
NH3C O
cocaine
O
Ph
OCH3O
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
Classifica(on+of+Amines
7
Alkaloids: Naturally occurring compounds containing N
H3CN
NH
(S)-3-(1-methylpyrrolidin-2-yl)pyridineor nicotine
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
CHM'224'•'Organic'Chemistry'IISpring'2013,'Des'Plaines'•'Prof.'Chad'Landrie
24.2
Structure'and'ProperHes
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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)
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
Resonance+in+Aryl+Amines
17
• no delocalization of lone-pair• N is sp3 hybridized
• delocalization of lone-pair• N is sp2 hybridized
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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)
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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.
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
Carboxylic+Acids+at+Physiological+pH
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+
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
Carboxylic+Acids+at+Physiological+pH
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+
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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+
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
CHM'224'•'Organic'Chemistry'IISpring'2013,'Des'Plaines'•'Prof.'Chad'Landrie
24.2,&,24.4
Solubility'and'ExtracHon
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
crude solid:• not pure/clean• depressed mp
• possibly discolored
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
1. recrystallize from boiling water 2. vacuum filter
CH2Cl2 is denser than water = bottom layer
Amides are not bases due to resonance delocalization of lone-pair. They are not protonated!
© 2013, Dr. Chad L. LandrieOrganic Chemistry II (CHM 224)
Slide Lecture 14: March 19
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
• possibly discolored
C
crude solid:• not pure/clean• depressed mp
• possibly discolored
purify NH2
pure solid:• white crystals
• sharp mp• narrow mp range
1. recrystallize from boiling water 2. vacuum filter
NH2
NH
HH
Cl–
OHO
OHO
OH
O
OH
OC
OH
O
NH
HH
Cl–