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Chamras Chemistry 106 Lecture Notes
Examination 3 Materials
Chapter 18: Aldehydes & Ketones General Discussion: Aldehydes & ketones are examples of carbonyl compounds: Carbon of the carbonyl group is considered a good electrophile. General Formulas: Which one of these two functional groups is more reactive towards nucleophiles? Why?
C
O
Carbonyl group
C
O
R
C
H
O
R
C
R'
O
Aldehyde Ketone
2
Nomenclature: IUPAC Method
a) Aldehydes:
b) Ketones:
Common naming method for aldehydes: Common names for structural fragments:
O O
OH
O
O
O
O O
H
O
CH3
O
C2H5
O
C3H7
O
formic acetic propionic butyric
3
Examples:
Common naming method for ketones: “Alkylalkyl ketone”
Examples:
Physical Properties of Aldehydes & Ketones: H-Bond Donors: Water Solubility: Spectroscopic Remarks:
a) Aldehydes:
IR: C=O Stretch: Around 1710. cm–1
C(carbonyl)–H Stretch: Around 2750 cm–1 1H–NMR: Aldehyde H around 9.5 ppm 13C–NMR: Carbonyl C around 200 ppm
H H
O
H CH3
O
H C2H5
O
H C3H7
O
OO O
4
b) Ketones: IR:
C=O Stretch: Around 1710. cm–1 C(carbonyl)–H Stretch: Around 2750 cm–1 ***Some structural points on the C=O stretches of Aldehydes & Ketones: 1H–NMR: 13C–NMR: Carbonyl C around 200 ppm
O
O
O
O
1685 cm–11690 cm–1 1745 cm–1
1815 cm–1
5
Syntheses of Aldehydes & Ketones:
1. Oxidation of Alcohols: (Covered in Chp. 11)
Common Oxidizing Agents: Mild: PCC Strong: Na2Cr2O7, H2SO4
2. Ozonolysis of Alkenes: (Covered in Chp. 8)
R'R
OH
[O]
R'R
O
A secondary Alcohol Ketone
R OH
[O]
R O
A primary Alcohol Aldehyde
[O]
R O
OH
Carboxylic Acid
Overoxidation
R"
R'" R
R'
1. O3
2. (CH3)2S
R"
R'" R
R'
OO +
6
3. F.C. Acylation: (Covered in Chp. 17) ***A great method for the synthesis of diaryl ketones or alkyl aryl ketones. Disadvantage: Does not work with strongly deactivated aromatic systems.
4. Hydration of Alkynes: (Covered in Chp. 9)
5. Hydroboration–Oxidation of Alkynes: (Covered in Chp. 9)
R
O
Cl
Y
+Y
O
R
+
Y
O
R
1. AlCl3
2. H2O
R H
Hg2+, H2SO4
H2OH
HR
HO
enol
H+
H
HR
O
R H
1. Sia2BH
2. H2O2, OH–
OH
HR
H
enol
O
HR
H
7
6. Substitution Reactions of 1,3-Dithianes: General Equation: Example:
7. From Carboxylic Acids: (Only ketones could be synthesized) General Equation:
S S
1. Strong Base
2. Alkylating Agent
3. HgCl2, H3O+R R'
O
S S
NaH+
Br
HgCl2, H3O+
H
O
1. NaH
2.Br
HgCl2, H3O+
R OH
O1. LiOH
2. R'–Li
3. H3O+ R R'
O1. 2 R'–Li
2. H3O+OR
8
Example: Mechanism:
O
OH
Li
2
H3O+
9
8. From the Reaction of Nitriles with Grignard Reagents: Example:
N
MgBr
+
9. From Acid Chlorides:
A) Aldehydes:
Reactivity of Carboxylic Acids: Synthetically speaking… If Carb. Acids are simply reduced:
R C N R' MgBr+
R'R
N
BrMg
H3O+
R'R
N
H
R'R
O
OH
O
LiAlH4
(Reduction)H
O
SLOW
LiAlH4
(Reduction)
FAST
O
10
Synthetic Alternative from Carb. Acids: Carb. Acids to Acid Chlorides, then into Aldehydes Example:
OH
O
Cl
O
Cl
S
Cl
O
+ + HClSO2
Li+AlH(O-t-Bu)3
H
O
11
B) Ketones: Synthetic Alternative from Carb. Acids:
Carb. Acids to Acid Chlorides, then into Ketones
Example: Gilman Reagent:
OH
O
Cl
OCl
S
Cl
O
+ + HClSO2
O
MgBr
MgBr
O
FAST
FAST
OH
O
Cl
O
Cl
S
Cl
O
+ + HClSO2
O
CuLi2
12
Reactions of Aldehydes & Ketones: Real Structure: Nucleophilic Additions: Previously Covered examples:
a) Grignard Addition to Aldehydes & Ketones:
O
O
!+
!–
13
b) Hydride (NaBH4) Reductions: Sometimes, to make the carbonyl carbon more activated (more positive) towards nucleophiles, acidic condition is suggested. The existing acid activates the carbonyl carbon in the following way: This is usually a general measure for activating the less active ketones.
The Wittig Reaction Triphenylphosphonium Ylide Triphenylphosphene Oxide *Ylide: Neutral molecules with two oppositely charged adjacent atoms. *Intermediate: Oxaphosphetane *Alkene Isomerism: Cis-product preferred.
R R'
O
C
B(C6H5)3HP
A
+
–
R R'
A B
O(C6H5)3HP+ –
++
14
Example: Mechanism: Ideal Triphenylphosphonium ylide:
O
+ Ph3P CH2
15
Hydration General Equation: Example: Reaction Conditions: a) Acidic OR b) Basic Mechanism: a) Hydration Under Acidic Conditions:
R R'
O
+ H2O
R R'
HO OH
O
OH
H
H
+
16
b) Hydration Under Basic Conditions:
Cyanohydrin Formation Cyanohydrin (General Formula): Example: Mechanism: Ideal Aldehyde or Ketone:
O
+ OH–
R R
NC OH
O
HCN, NaCN
17
The Fate of A Cyanohydrin Under Acidic Conditions:
Imine Formation Imine (General Formula): *With Primary Amines. *Intermediate: Carbinolamine *Product: An Imine Mechanism:
H3O+
N
R
O
N
H
H
+
H3O+
18
Condensation with Hydroxylamine Hydroxylamine (Formula): Example: Mechanism: Same as “Imine Formation” mechanism. Product: An Oxime
Condensation with Hydrazines Hydrazines (General Formula): Example: Mechanism: Same as “Imine Formation” mechanism. Product: A Hydrazone For a more detailed account on different functional group possibilities, see summary table on p. 844 of Wade.
N
OHH
H
N
OHH
HO
+H3O
+
N N
R
RR
R
O
+H3O
+
N N
H
HH
H
19
Acetal & Ketal Formation (Protection Group Chemistry)
General Equation: Example: Mechanism: (Shown for Acetal Formation): *Unhindered Aldehydes & Ketones are ideal for this reaction. **For more sterically hindered ones, use excess alcohol, to assure the progress of the equilibrium towards the acetal side.
R H
O
R R
O
+
+
H+
H+
R'OH
R'OH
Hemiacetal
Hemiketal
R H
HO OR'
R R
HO OR'
H+
H+
Acetal
Ketal
R H
R'O OR'
R R
R'O OR'
H
O
O
H
+
H3O+
2
20
Use of a diol instead of 2 equivalents of alcohol: Example: Reversibility of Acetal & Ketal Formation: Measures to reverse: Protecting Group Chemistry Example: Synthetic Goal: Problem:
H
O
+
H3O+
HO
HO
O
O Selective
Reduction
OH
O
21
Alternative (Protecting Group Chemistry) Approach:
Oxidation of Aldehydes General Equation: Oxidizing Agents:
a) NaCr2O7, H3O+
b) Ag2O, THF/H2O Ketones???
R H
O
[O]
R OH
O
22
Reduction of Aldehydes & Ketones
Agents for the process “A”:
1. NaBH4, ROH 2. NaBH4, H2O 3. a) LiAlH4 , b) H2O 4. Ni-H2 (AKA: Raney nickel) *Also reduces C=C to C–C
Agents for the process “B”:
1. Wolff-Kishner (basic hydrazine, water) 2. Clemmensen (mercurial zinc, hydrochloric acid)
*** Please Read on 2,4-DNP and Tollens tests. These characterization tests will be covered in detail in the laboratory in the context of the Qualitative Analysis project. Suggested Problems: 39, 41, 43, 46, 49 (part 2), 50, 51, 53, 58, 61, 66, 70, 75.
R R
O
R H
OH
R
A B
R H
H
R
23
Chapter 19: Amines Functional Group: R, R’, R”= hydrogen, alkyl, or aryl Types: Nomenclature:
a) Common Method: Is based on the “alkylalkylamine” template. Example:
R''
N
R'
R
R''
N
R'
R
1. Ammonia: 2. Primary:
3. Secondary: 4. Tertiary:
*Quaternary Ammonium Salts (or Ions):
H
N
R'
R
H
N
H
R
H
N
H
R
R'' N
R'
R
R"'
N
H
N
24
b) IUPAC method: Based on the “alkanamine” template.
Example:
*Common Names for Some Cyclic Amines: (The nitrogen is assigned the position #1) Structure & Physical Properties: Polarity: Primary & Secondary amines are polar and H-bond donors & acceptors. Tertiary amines are only H-bond donors
N
H
N
N
H
N
H
N
H
N
H
N
25
Chirality: The following amines are chiral:
a) Amines possessing chiral carbons:
Example:
b) Quaternary Ammonium salts with asymmetric nitrogen atoms:
Example:
c) Small cyclic amines with an asymmetric nitrogen as a member of the ring:
Example:
What about other amines with asymmetric nitrogens? Nitrogen Inversion in Amines: (AKA: Umbrella Motion)
N
N H
N
N
N N
26
Solubility in Water:
Basicity:
Ammonia Primary Secondary Tertiary Amines Amines Amines
Remember: Acidity / Basicity is about the extent of acidic /basic dissociation equilibrium:
N
C
H
H
H
N
HH
H
H
O
H+ pKb =
N
CH3H
H
H
O
H+ pKb =
27
Amine pKa pKb ammonia 9.3 methylamine 10.64 dimethylamine 10.72 trimethylamine 9.7 aniline 4.6 p-nitroaniline 1.0 p-chloroaniline 4.0 pyridine 5.25 *pyrrole –1.0 piperidine 11.12
The Effect of Resonance on Basicity: Aniline Vs. Protonated aniline Pyrrole Vs. Protonated pyrrole
28
The Effect of Hybridization on Basicity: Aniline Vs. Piperidine Phase Transfer Catalysts: Spectroscopic Remarks:
1. IR: N–H Stretch: 3200-3500 cm–1 1 peak for 2o and 2 peaks for 1o amines.
2. 1H–NMR: N–H proton: Usually singlets @2-3 ppm.
3. 13C–NMR: Carbon alpha to N @ 30-50 ppm.
29
Synthesis of Amines:
1. Reductive Amination:
a) For Primary Amines:
b) For Secondary Amines:
c) For Tertiary Amines:
H
N
H
OH
+
R'
O
R
H+
R'
N
R
OH
[R]
R'
N
R
HH
Reducing Agent:H2–Ni, LiAlH4, or Zn– HCl
H
N
R"
H
+
R'
O
R
H+
R'
N
R
R"
[R]
R'
N
R
R"H
A Schiff Base
H
N
R"
R"'
+
R'
O
R
H+
R'
N
R
R"
[R]
R'
N
R
R"R'"
Iminium Salt
R'"
R = sodium triacetoxyborohydride, acetic acid
30
2. Acylation–Reduction: General Scheme: Example:
3. Syntheses of 1o Amines:
a) Direct Alkylation: General Scheme: Example: Why Excess NH3?
Amine(Ammonia, 1o, or 2o)
+ Acid ChlorideOH–, pyridine
Amide
ReductionAcylation
1. LiAlH42. H2O
Higher Amine
N
H
Cl O
OH–, pyridine
N O
1. LiAlH42. H2O
N
+
Ammonia (Large excess)
Alkyl Halide or Alkyl Tosylate+ 1o Amine
SN2
N
HH
H
+
Cl
N
H
H
31
b) Gabriel Synthesis: This method uses a similar approach to protecting-group chemistry:
General Scheme: RX= tosylate or halide (1o) Example: Mechanism:
N
RH
H
N
O
O
H
1. OH–(aq)
2. RX
3. NH2NH2, HeatN
N
O
O
H
H
+
Phthalimide Phthalimide Hydrazide Primary Amine
N
H
H
N
O
O
H
1. OH–(aq)
2. CH3CH2Br
3. NH2NH2, HeatN
N
O
O
H
H
+
32
c) Reduction of Alkyl Azides: Similar to Gabriel synthesis, but using azide ion as the nucleophile (an SN
2 mechanism for alkyl Azide formation). General Scheme: RX= tosylate or halide Example:
d) Reduction of Alkyl Nitriles: Similar to Gabriel synthesis, but using cyanide ion as the nucleophile (an SN
2 mechanism for alkyl cyanide formation). General Scheme: ***Note: The alkyl group on the amine product is subjected to chain lengthening due to the carbon of the cyanide ion. Example:
N
RH
H
1. RX
2. a) LiAlH4, b) H2O or H2, Pd
N N N +
1. LiAlH4,
2. H2ON N N +
Br
N
N
N
N
H
H
N
H
H
1. RX
2. a) LiAlH4, b) H2O or H2, Pd
N C+
R
1. LiAlH4,
2. H2O+
BrC
N C
N
N
H H
33
e) Reduction of Nitro Compounds: Example:
f) Hofmann Rearrangement of Amides:
NO2 NH2 H2, catalyst
or
Active Metal, H+
Choice of Catalyst: Ni, Pd, or PtChoice of Active Metal: Fe, Zn, or Sn
R NH2
O
X2, 4NaOH+ 2NaX + Na2CO3 + 2H2O
R
N
H
H
Primary Amide
Primary Amine
X = Cl or Br
34
Mechanism:
R N
O
Primary Amide
H
HOH
Br Br
Deprotonated Amide
N-bromo amide
OH
Deprotonateed N-bromo amide
IsocyanateR
N C O
OH
H
O
H
Carbamic Acid
OH
Deprotonated Carbamic AcidDeprotonated Amine
R
N
H
H
O
H
35
Reactions of Amines:
a) Reactions with Aldehydes & Ketones (Review from Chp. 18): General Scheme:
b) Acylation: General Scheme: Amine Acid Chloride Amide Usually, pyridine is used as an acid scavenger. Mechanism:
R R'
O
Y
N
H
H
+
H+
R R'
N
Y
If Y = H or alkyl Imine (Schiff Base)
If Y = OH Oxime
If Y = NHR Hydrazone
R' Cl
O
+
R
N
H
H
R' N
O
H
R
36
c) Alkylation:
d) Formation of Sulfonamides: General Scheme: 1o or 2o Amine Sulfonyl Chloride Sulfonamide
e) Hofmann Elimination (Amine as a Leaving Group): General Scheme: Example: Mechanism:
+
R
N
H
H
S ClR'
O
O
NaOH
Quaternary Ammonium Salt Alkene + AmineHeat
(E2)
N
H
H
Heat, OH–
C C
H
HH
H
H
O
H N++
37
***Product Multiplicity (Hofmann Vs. Saytzeff Products): Why is there a preference for Hofmann product? ***When performed with a cyclic ammonium salt, an acyclic alkenamine results.
N
38
f) Oxidation of Amines: General Scheme:
R
N
H
H
R
N
H
R
R
N
R
R
[O]
[O]
[O]
R
N
OH
H
[O]R
N
O[O]
R
N
O
O1oAmine
2oAmine
3oAmine
Hydroxylamine Nitroso Nitro
R
N
OH
R
Hydroxylamine
N O
R
R
R
3oAmine Oxide Commonly Used Oxidizing Agents: H2O2 or ArCO3H
g) Cope Elimination: (Hofmann product preference)
General Scheme: Example: Mechanism:
3o Amine Oxide Alkene + 2oAmine Oxide
N
O
N
HO
+
H H
HH
39
h) Reaction with Nitrosonium Ion (Nitrous Acid): General Scheme: Generation of Nitrosonium Ion: Mechanism:
N
H
R
H
N
R
R
H
1o Amine
2o Amine
NO+
NO+
R N N
Alkyldiazonium Ion
R
N
R
N
O
2o N-Nitrosoamine
R
N
R
N
O
1o N-Nitrosoamine
NaNO2 + HCl HNO2 + NaCl
HNO2 + H+ H2NO2+
H2O + NO+
40
i) Reactions of Arenediazonium Salts:
NN
OHH3O+
CuCl or CuBrCl Bror
CuCNC N
HBF4 or KIF Ior
H3PO2
Ar'H
N
N
Diazo Coupling
Deamination
Sandmeyer Reaction
Hydrolysis