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CH 19 Problem Answers (All)
CH 19 Problem Answers (All)
Amines 1
Reactions of Amines
O OH NZ
ZNH 2, H + H+ , -H2O
R' R R' NHZ R' R
+ R
aldehyde H2O, H , -ZNH2 H2O, H+
tetrahedral imine
or ketone
"aminol"
Notes:
Z can be a carbon, nitrogen, oxygen, or hydrogen atom/group.
The aminol cant be isolated, its only present at equilibrium.
Equilibrium factors apply. Water drives to the carbonyl side; removal of water
drives to the imine side.
Mechanism: Learned for last test (not tested this time)
Must have at least 2 Hs on nitrogen 2, 3 amines cant do this
Chem 360 Jasperse Ch. 19 Notes + Answers. Amines 2
H H
R Br
R N R N X
H R
H
ammonium salt
3 CH3-Br CH3
Ph NH2 Ph N Br
NaHCO3 H3C CH3
2 CH3CH2-Br
NH N Br
NaHCO3
PhCH2-Br
Et3N Et3N CH2Ph Br
3b. Monosubstitution is possible when excess ammonia (or other cheap amines) is
used.
Mechanism for monosubstitution required. This involves simple SN2,
followed by deprotonation by the excess amine.
excess NH3
Br NH2
O
O
R1 H HO R R1
N N R
R2 heat R2
5. Substitution for Aromatic Amines via the Diazonium Salts (The Sandmeyer Reaction)
(Section 19-17, 18)
ArCN
CuCN
CuBr ArBr
ArOH
H3PO2
ArH
Synthesis of Amines
6. From Aldehydes or Ketones: Reductive Amination (Section 19-19)
O R2 NaBH3CN R2 R3 R2 R3
+ N N
N via
R R1 H R3 cat. H+ R R1 R R1
Ketone or H
aldehyde
Access: 1, 2, or 3 Amines
Mechanism: Not required. (Basic workup)
The carbonyl reactant can be an aldehyde or a ketone
The amine reactant must have at least one hydrogen, as shown above; but R2
and/or R3 can be either a carbon or a hydrogen. Thus:
o NH3 1 RNH2
o 1 RNH2 2 R2NH
o 2 R2NH 3 R3N
o 3 R3N dont react
O H NaBH3CN H H H H
+ N N
N via
R R1 H H cat. H+ R R R R1
Ketone or ammonia H 1
aldehyde 1 amine
O R2 NaBH3CN R2 H R2 H
+ N N
N via
R R1 H H cat. H+ R R1 R R1
Ketone or 1 amine H
aldehyde 2 amine
O R2 NaBH3CN R2 R3 R2 R3
+ N N
N via
R R1 H R3 cat. H+ R R R R1
Ketone or 2 amine H 1
aldehyde 3 amine
O
O H R1 acylation
+ N R1 LiAlH4 R1
R N R N
R OH R2 heat
R2 R2
Access: 1, 2, or 3 Amines
Acylation mechanism required (see reaction 4) but reduction mechanism not
required.
NO2 NH2
Fe, HCl
10. From 1 Alkyl Halides: Alkylation of Ammonia (Section 19-12, 19-21A) (See reaction 3).
excess NH3
R Br R NH2
Access: 1 amines
Mechanism not required.
1 #6 Aldehydes R2NH, H+ 1, 2, or 3
or Ketones NaBH3CN, Amines
Mechanisms
1. Protonation
H Cl
NH2 NH3 Cl
1.-Reverse. Deprotonation
H OH
N NH2
H
H
3. Polyalkylation
Ex:
3 Br
Ph NH2 Et
Ph N Br
NaOH Et Et
Mech:
Br H OH
Ph NH2 Ph N
H Ph NHEt
Et Deprotonate
SN2
SN2
Br
Br OH H
Et Ph N
Ph N Ph NEt2
Et SN2 Deprotonate Et Et
Et
3b. Monoalkylation
NH3
OH
Br NH3 NH2
SN2 Deprotonate
Chem 360 Jasperse Ch. 19 Mechanisms 8
4. Acylation
Ex:
O
O
Cl
NH2 N
NaOH H
O
O O O
Cl Elim Deprotonate
NH2 N N N
Add H Cl H H
H H OH
Chem 360 Jasperse Ch. 19 Notes + Answers. Amines 9
Pyrrole sp2 p
NH
Pyridine
N
H
Purine N
RNA, DNA,
N ATP, and ADP
N N are made from
H derivatives of
Pyrimidine Purine and
N Pyrimidine
N
Amino Acids
H O H R2 H O H O H R2 H O
Loss of Water
N H OH N N N etc
H OH N H OH etc N N
Makes Amide
R1 H H O R3 H Bonds, Polymers R1 H H O R3 H H
amide polymer
"protein"
-The major natural amino acids all have "S" configuration "polypeptide"
-20 major natural amino acids
-Under neutral conditions, the amine actually
deprotonates the acid to give not an "amino acid" H O
H O H O
but actually an "ammonium carboxylate"
H N H N N
-The side groups "R" can be acid, basic, hydrophilic, H O
or hydrophobic. H OH H O
R1 H R1 H R1 H
-The sequence or R groups on thepolymer
essentially spells out the biological activity of the protein. acidic pH neutral pH basic pH
Chem 360 Jasperse Ch. 19 Notes + Answers. Amines 10
Nomenclature. Draw the structure or provide the name for the following.
CH3
HN
1. N-methyl-3-phenyl-2-octanamine
NH2
2. Z-3-penten-1-amine
3. 3-hexanamine NH2
4. pyridine
NH2
H CH3
5. 2-methyl-1-butanamine
NH2 O
sp3 sp2
N sp2
N CH3 N
NH p
p N N sp2
H
8. Boiling Points. Rank the following in terms of boiling point, 1 being highest, 4 being lowest.
OH NH2 OH
N
2 3 4 1
Alcohols H-bond themselves no H-bonding H-bonding
better than amines (because amine + molecular weight
H is less positive
9. Water Solubility. Rank the following in terms of water solubility, 1 being most water
soluble, 5 being least water soluble.
OH NH2 OH CH3
O
2 1 3 4 5
Carboxylic O 10-5 O
Acid
R OH R O
Phenol OH 10-10
O
1,3-Dicarbonyl O O 10-12 O O
!
OMe OMe
When comparing/ranking any two acids or bases, go through the above checklist to see
which factors apply and might differentiate the two.
When a neutral acids are involved, its often best to draw the conjugate anionic bases,
and to think from the anion stability side.
Chem 360 Jasperse Ch. 19 Notes + Answers. Amines 12
Acidity/Basicity Table 19.2: With both Neutral and Cationic Acids and both
Neutral and Anionic Bases
Acid Base
Class Structure Ka Strength Base Strength
2. Electronegativity:
Acidity: H-X (halogen) > H-O > H-N > H-C
3. Resonance/Conjugation:
Oxygen Series:
Acidity: sulfurice acid > carboxylic acid > phenol > alcohol
O O
Anion Basicity: < < <
HO S O
O O O
O
O O
> >
Anion Stability: HO S O >
O O O
O
Carbon Series:
o Acidity: 1,3-dicarbonyl > ketone (monocarbonyl) > alkane
O O O
< <
Anion Basicity:
o OMe
O O O
> >
Anion Stability:
o OMe
Nitrogen Series:
o Acidity: amide > amine
O
Anion Basicity: <
o NH NH
O
>
Anion Stability:
o NH NH
4. Hybridization:
For lone-pair basicity, (all else being equal), sp3 > sp2 > sp > p
O
Neutral > >
NH2 > N H3C C N
Nitrogen NH2
sp3 sp2 sp p
Series
O
Carbanion CH2 > > H 3C C C >
Series C
sp CH2
sp3 sp2 p
O
Oxygen
Anion O > O
Series sp3 p
This means that for acidity, alkynes > alkenes > alkanes
4 N sp2 10-5
NH
c. Amides are much less basic than amines, or even other nitrogens with p-lone pairs (less than
amines reflects hybridization and conjugation; amides are less basic than other p-hybrid
conjugated lone pairs because or the electron-withdrawing group factor).
d. Conjugated nitrogens are in general less basic than isolated nitrogens (both hybridization and
conjugation factors)
Note: The acidity of conjugate ammonium cations (conjugate acids relative to the
amines) is directly and inversely related to the basicity of the neutral amines.
Key: remember patterns (a) and (b) above. That should help you solve relative basicity
problems. If given ammoniums, draw the related conjugate neutral amines, rank them as
bases, and realize that the strongest amine base relates to the weakest ammonium acid.
You should be able to handle any ranking problems involving either amines as bases or their
conjugate ammoniums as acids. This should include relative to non-nitrogen acids and bases.
Chem 360 Jasperse Ch. 19 Notes + Answers. Amines 16
H H H A A H
N N N N
H H H H B C B C
Anything that stabilizes the cation increases the basicity of the nitrogen
Anything that destabilizes the cation decreases the basicity of the nitrogen
Anything that stabilizes the amine decreases the basicity of the nitrogen (especially if that
stabilizing factor is sacrificed upon protonation)
Anything that destabilizes the amine increases its basicity
When lone pair is p, that always reflects stabilizing conjugation and reduced basicity. This is
the origin of both the p-hybridization factor and the resonance/conjugation factor.
Choose the More Acidic for Each of the Following Pairs: Single Variable Problems
NH3 NH4
10. The ammonium. Charge factor.
OH OH
13. The acid. Resonance factor.
O
NH2 NH2
14. The amide. Resonance factor.
O O O
NO2 OMe
15. Ph Ph Ph
1-2-3. Electron donor/withdrawer factor. Nitro withdrawer stabilizes anion;
methoxy donor destabilizes anion.
1-2-4.
Choose the More Basic for Each of the Following Pairs (Single Variable)
O O O
NO2 OMe
Ph Ph Ph
20.
3-2-1. Donor/withdrawer factor. Nitro withdrawer stabilizes, methoxy donor destabilizes.
NH2 NH3 O2N NH2
21.
1 - 2 - 3 Donor/withdrawer. Alkyl is donor, nitro is withdrawer.
Choose the More Basic for Each of the Following (Multiple Variables, apples and oranges)
22. NH3 O Alkoxide. Charge trumps electronegativity.
O
O
23. Ph Enolate. Resonance isnt
enough to outweight electronegativity.
O O
O
24. Ph Alkoxide. Resonance
is so good that even a C anion beats the O anion.
Chem 360 Jasperse Ch. 19 Notes + Answers. Amines 18
29. NH3 O
Alkoxide. Charge factor.
30. NH3 O
Ammonia. The anion is so stabilized by resonance that the neutral amine is more basic.
O
Cl or HO S O
31. NH3 O
Ammonia. Both of these strong acid anions are so stable that they dont function as bases.
34. For the following sets of bases, rank them, 1 being the most basic.
So we see both the charge factor and the electronegativity factors at play.
b. O O CH3NH2 OH
1 3 2 4
Anion, no res Anion, with res Neutral, Nit Neutral, Ox
Alkoxide with charge is stronger than neutral nitrogen. But carboxylate with resonance is
weaker than neutral nitrogen. Neutral oxygen is weakest (loses all charge and electroneg wars)
Chem 360 Jasperse Ch. 19 Notes + Answers. Amines 19
35. Amine Basicity. For the following pairs or sets of bases, rank them, 1 being the most basic.
N N
a. H H
Second thing is stronger. Hybridization factor. Sp3 nitrogen versus p nitrogen.
O
b. NH2 NH2
First thing is stronger. Hybridization factor. Sp3 nitrogen versus p nitrogen.
F F F
h. triethylamine NaOH
2 1. Charge factor.
36. Rank the acidity of the following compounds, 1 being most acidic.
a. H3O+ NH4+Cl- water acetic acid (CH3CO2H) NH3
1 3 4 2 5
Charge factor, electronegativity factor, and resonance factor all impact.
Of the three neutrals, acetic acid is most due to resonance, ammonia least due to electroneg.
Of the two cations, hydronium is stronger than ammonium (electronegativity).
Ammonium ion is weaker than carboxylic acid (due to carboxylate resonance trumping charge
factor)
b. H3O+ acetic acid (CH3CO2H) Me3NH+Cl- ethanol
1 2 3 4
Charge, electroneg, and resonance.
Acetic acid is stronger than ammonium due to resonance on resulting carboxylate.
c. NH4+Cl- Me3NH+Cl- PhNH3+Cl-
2 3 1
Hybridization and donor effect. #1 wins because it produces aniline, which has p hybridization
and is stabilized by conjugation. #2 and #3 both produce sp3 lone pairs. #3 is least acidic
because of the alkyl donors, which stabilize the cation.
37. Suppose all of the molecules A-D are dissolved in diethyl ether.
O
OH
OH OH NHMe
A B C D
a. Which one or ones will extract (dissolve) into aqueous sodium hydroxide? (And why?)
Answer: B and C.
Key: An organic will move into the organic phase if it is ionized.
Why: B and C give resonance stabilized anions that are more stable than hydroxide. Hydroxide
is unable to deprotonate A and D, since that would result in anions less stable than hydroxide.
Since they stay neutral, they stay in the organic layer.
b. Which, if any, will extract into aqueous hydrochloric acid? (And why?)
Answer: D.
Key: An organic will move into the organic phase if it is ionized.
Why: Amine D is protonated in acid to give a water soluble ammonium ion. The oxygen
compounds are not protonated and ionized by acidic water; since they stay neutral, they stay in
the ether layer.
c. Which, if any, will extract into neutral water? (Why or why not?)
Answer: None.
Key: an organic will move into the organic phase if it is ionized.
Why: Neutral water neither protonates nor deprotonates the compounds. They all stay neutral,
so they all stay in the organic layer.
d. Explain how you could use an extraction scheme to separate D from A.
Dissolve in ether.
Treat with aqueous acid, which protonates/ionizes D but not A.
Separate layers.
Concentrate the organic phase; get pure A.
Add base to the aqueous layer, to convert DH+ back to neutral D. In its neutral form,
amine D will no longer be soluble in water, and will either crystallize out or can be
extracted out with an organic solvent.
Chem 360 Jasperse Ch. 19 Notes + Answers. Amines 21
NPh Ph
4-phenyl-2-hexanone, H+
38. PhNH2
NNH2
Cyclohexanone + H2NNH2
39.
CH3
Me3N + PhCH2I H3C N CH2Ph I
40. CH3
Excess NH3
PhCH2Br Ph NH2
42.
Br Intramolecular
NaOH HN
H2N SN2
43.
O
O
Cl
PhNH2
44. PhHN
O O
+ N-methylbutanamine
Ph Cl Ph N
45.
O O
heat
NH2 + Ph OH Ph N
46. H
Chem 360 Jasperse Ch. 19 Notes + Answers. Amines 22
1. HNO3, H2SO4 Cl
2. Br2, Fe
3. Fe, HCl Br
4. NaNO2, HCl
5. CuCl
47.
3. NaNO2, HCl
4. CuCN
5. KMnO4 CN
48.
2. H3PO2
49. Br Br
Design Synthesis
CN
1. HNO3, H2SO4 (installs nitro group, meta director)
O -HCl O
N H + Cl S R N S R Sulfonamide
O O
Keys:
Sulfonamides are Nonbasic
Sulfonamides in which the nitrogen has a hydrogen are acidic
O excess excess
Basic Conditions: Acidic Conditions:
N H + Cl S R Soluble or Insoluble?
NaOH HCl Soluble or Insoluble?
O
Starting Derived
Amine Sulfonamide Basic Conditions Acidic Conditions
O O O
1 Amine R N S R R N S R R N S R
H O O H O
Soluble Insoluble
O O O
2 Amine R N S R R N S R R N S R
R O R O R O
Insoluble Insoluble
H
R N R
3 Amine None Can Form R N R
R
R
Insoluble
Soluble
Chem 360 Jasperse Ch. 19 Notes + Answers. Amines 24
+
O + MeNH NaBH3CN, H NHMe
2
53.
O NaBH3CN, H+ NH2
+ NH3
54.
O NaBH3CN, H+ NHMe
+ MeNH2
55. Ph Ph
1. PCC
2. PhMgBr; H3O+ Ph
OH
3. H2CrO4 NHPh
56. 4. PhNH2, NaBH3CN, H+
O LiAlH4
NH NH
57.
O
1. Cl H
NH2 N
2. LiAlH4
58.
O
1. MeNH2
Ph Cl Ph NHMe
2. LiAlH4
59.
Ph 1. NaCN
Br Ph NH2
2. LiAlH4
60.
Chem 360 Jasperse Ch. 19 Notes + Answers. Amines 25
61. Come up with various pathways (4 good ones) to the following 1 amine:
NH3
NaBH3CN, H+
excess LiAlH4
Br NH2 NH2
NH3 1 amine O
1. NaCN NH3
2. LiAlH4
Cl
Br
O
Cl
H2N
H 2N
+ NaBH3CN, H
H+ LiAlH4
N
O
H O
or N or
O 2 amine H
NaBH3CN, N
LiAlH4
+ H+
NH2 O
NH2
Cl
O
Chem 360 Jasperse Ch. 19 Notes + Answers. Amines 26
O NH2
N
H
63. NaBH3CN, H+
1. PCC
OH NMe2
64. 2. Me2NH, NaBH3CN, H+
O 1. NH3
Ph Ph
Cl NH2
2. LiAlH4
65.
O O
1. HNO3, H2SO4
Cl
AlCl3 2. Zn(Hg), HCl
3. Fe, HCl
(either order, steps 2 and 3) NH2
66.
excess NH3
Ph Br Ph NH2
67.
NaCN LiAlH4
Ph Br Ph CN NH2
68. Ph