Functional Group Transformation Notebook

2012
Functional Group
Transformation
Notebook
M. Huffstickler, K. Syler, and H. Wayland
For Organic Chemistry I and II
Huffstickler, Syler, and Wayland

Henderson State University
8/3/2012
Table of Contents
Alkene and Alkyne Chemistry

p.5
Acid-Catalyzed Addition of an Alcohol to an Alkene
p.6
Addition of Halogen to an Alkyne
p.7
Addition of Peroxyacid to an Alkene
p.8
Addition of Halogen to an Alkene
p.9
Addition of Hydrogen Halide to an Alkyne
p.10
Addition of Hydrogen to an Alkene
p.11
Addition of Hydrogen to an Alkyne
p.12
Addition of Water to an Alkyne
p.13
Alkoxymercuration of an Alkene
p.14
Alkylation of Alkynes
p.15
Addition of Hydrogen Halide to an Alkene
p.16
Addition of Water to an Alkene
Benzene Chemistry
p.17
EAS Electrophiles
p.18
EAS
p.19
More Benzene Chemistry
Carbonyl Compounds I
p.20
Activating Carboxylic Acids
p.21
Ethers
p.22
Hydrolysis of Nitriles
p.23
Reactions of Acid Anhydrides
p.24
Reactions of Acyl halides
p.25
Reactions of Amides
p.26
Reactions of Carboxylic Acids
p.27
Reactions of Esters
Carbonyl Compounds II
p.28
Acetal or Ketal Formation
p.29
Alcohol Protecting Groups
p.30
Amino Protecting Groups
p.31
Carbonyl Compounds with Acetylide Ions
p.32
Carbonyl Compounds with Amines
p.33
Carbonyl Compounds with Hydride Ions
p.34
Carbonyl Compounds with Hydrogen Cyanide
p.35
Carbonyl Compounds with Water
p.36
Carbonyl Oxygen Protecting Groups
p.37
Wittig Reaction
Carbonyl Compounds III

p.38
Acid-Catalyzed Alpha-Carbon Halogenation
p.39
Aldol Condensation and Dehydration e1cB
p.40
Base-Catalyzed Alpha-Carbon Halogenation
p.41
Claisen Condensation
p.42
Dieckmann Condensation
p.43
Haloform Reaction
p.44
Hell-Volhard-Zelinski Reaction
p.45
Intramolecular Aldol Addition
p.46
Keto-Enol Interconversion
p.47
LDA to Form Enolates
p.48
Michael Reaction
p.49
Nucleophilic Addition to Unsaturated Ketones
Elimination Reactions
p.50
Alkyl Fluorides
p.51
Dehydration of Alcohols
p.52
E1
p.53
E2
Organometallic Chemistry
p.54
Carbonyl Compounds Grignard Reactions
p.55
Gilman Reaction
p.56
Grignardlithium
p.57
Palladium
p.58
Diels-Alder Ring Formation
Other
Oxidation
p.59
Hydroboration-Oxidation of an Alkene Part 1
p.60
p.61
Hydroboration-Oxidation of an Alkyne
p.62
Oxidation of Alcohols
p.63
Oxidation of Aldehydes and Ketones
p.64
Oxidation of Alkenes to 1,2-Diols
p.65
Oxidative Cleavage of 1,2-Diols
p.66
Oxidative Cleavage of Alkenes
p.67
Addition of Radicals to an Alkene
p.68
Formation of Explosive Peroxides
p.69
Radical Halogenation of Alkanes
p.70
Radical Substitution of Benzylic and Allylic Hydrogens
Radicals
Reduction
p.71
Catalytic Hydrogenation
p.72
Dissolving Metal Reduction
p.73
Metal Hydride Reduction
p.74
Oxymercuration-Reduction of an Alkene
Substitution Reactions
p.75
Nucleophilic Substitution of Epoxides
p.76
Sn1
p.77
Sn2
p.78
Substitution of Alcohols
Acid catalyzed Addition of Alcohol to an Alkene

f unctional group transformation:
alkene
ether
general scheme:
OH
R
H2SO4
OH
2
Mechanism:
H2SO4
OH
H
H
O
H
OH
OH
Key Points:
O
alcohol quick to deprotonate the protonated

ether
- pH of solution is greater than pka of
protonated ether
regiospecific, Markovnikov
H
O
H
Addition of Halogen to an Alkyne

alkyne
halogenated alkane
general scheme:
R
X
X
R
R
X
X
mechanism:
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Key Points:
solvent is typically CH2Cl2
anti addition
Addition of a Peroxyacid to an Alkene

alkene
epoxide + carboxylic acid
general scheme:
+1R
OOH
OH
mechanism:
epoxide
O
O
R
carboxylic acid
OO
OH
H
Key Points:
concerted reaction
syn addition
Addition of a Halogen to an Alkene

alkene
viscinal halogenated alkane
general scheme:
R
X
R
X2
"X" is any halogen

X
Mechanism:
Br
Br
Br
Br-
Br
Br
Key Points:
forms cyclic intermediate
stereospecific, anti-addition
racemic mix
Addition of Hydrogen Halide to an Alkyne

alkyne
geminal dihalide
general scheme:
R
R
R
X
mechanism:
Br
H
Br
Br
H
Br
Br
Br
Br
Br
Key Points:
anti addition
H+ adds to sp carbon bonded to the hydrogen
results in geminal (on same carbon) dihalide
The Addition of a Hydrogen to an Alkene

Alkene
Alkane
general scheme:
H2
R
Pd/C
mechanism:
H
H
R
H
R
R
H
Key Points:
don't know precise mechanism
concerted reaction
syn addition
reduction reaction
10
Addition of Hydrogen to an Alkyne

alkyne
alkane or alkene
general scheme:
R
H2
mechanism:
Lindler's catalyst
( cis)
H2
Pd/C
Na or
Li
( trans)
NH3 (liquid)
Na or
NH 2
Li
+ NH2
NH3 (liquid)
Na
+ Na
Na
H
NH 2
H
H
H
+ NH2
Na
Key Points:
Linder's catalyst causes syn addition
cis alkene
Na or Li in NH3 cause trans alkene
because is most stable radical
f ormation
11
Addition of Water to an Alkyne

alkyne
ketone
general scheme:
R
H2O
R
R
H2SO4
R
O
mechanism:
O
H2SO4
H
enol
H
O
OH
keto-enol
tautomerization
O
H
ketone
H
H
Key Points:
an enol is unstable and will tautomerize
most, if not all, of the product will be a ketone
12
Alkoxy-Mercuration Reduction of an Alkene

Alkene
Ether
general scheme:
OCH 3
R1
1.) Hg(O2CCF3)2 , CH3OH
R
R
2.) NaBH4
Mechanism:
O2 CCF3
1.) Hg(O2CCF3)2 , CH3OH
Hg
CH 3
2.) NaBH4
HO
Hg
F3 CCO2
O2 CCF3
CH 3
HO
H 3C
H 3C
O
O2 CCF3
Hg
NaBH4
H 3C
H
O2 CCF3
Hg
Key Points:
regiospecific, anti-Markovinikov
syn addition
+ Hg + CF3CO2-
13
Alkylation of Alkynes
Functional Group Transf ormation: terminal alkyne to internal alkyne
General Scheme:
R
NaNH2
CH
RX
C-
CR
Reaction Mechanism:
CH 3C
CH
NaNH2
CH 3 C
CCH3
CH 3 C
Br
Br
+ NH2
CH3
H3 CC
NH3
Notes:
-an alkylation reaction is the attachment of an alkyl group to a species by selection of an alkyl halide of
the appropriate structure
-actual alkylation is second step, f irst step is the removal of a hydrogen f rom the terminal sp2 carbon by
NaNH2
-negatively charged acetylide ion (nucleophile) is attracted to the partially positively charged carbon
(electrophile) of the alkyl halide, represented as RX in General Scheme
14
Addition of Hydrogen Halide to an Alkene

alkene
alkyl halide
general scheme:
HX
(Z)
R1
"X" is any halogen
R
1
Mechanism:
Cl
( E)
+ Cl
Cl
+ Cl
Key Points:
regiospecific, Markovnikov addition
racemic mixture
carbocation intermediate subject to 1,2 hydride/methyl shifts
15
Acid Catalyzed addition of Water to an Alkene

alkene
alcohol
general scheme:
R
H2SO4
H2O
R
OH
Mechanism:
H2SO4
O
O
H
OH
O
H
H
H
O
O
H
Key Points:
regiospecif ic, Markovnikov
carbocation intermediate subject to 1,2 hydride/methyl shifts
16
Electrophilic Aromatic Substitution
Functional Group Transf ormation:

Benzene
Substituted Benzene
General Reaction Mechanism:
E+
Notes:
Benzene does not undergo nucleophilic substitution due to its cloud of pi electrons repelling any
incoming nucleophiles
The intermediate carbocation is stabilized by resonance
The hydrogen attached to the same carbon as the incoming electrophile is eliminated to restore
aromaticity to the benzene ring
Where multiple electrophiles will be directed onto a benzene ring depends on the substituents already
on the ring
Activating substituents have electrons pairs to push into the benzene ring and stabilize the
intermediate carbocation, these substituents are ortho-para directors; alkyl chains and halogens do
not push electrons into the benzene ring, but they still ortho-para direct
Deactivating substituents draw electron density f rom the benzene ring and they direct electrophiles to
the electron dense meta positions
Benzene can only be reduced with Nickel at 225 degrees celsius and 25 atmospheres of pressure
17
Generation of EAS Electrophiles

Halogenation:
Br
FeBr3
Br
Br
Br
FeBr3
Also works with chlorine. The reagents are Br2 and FeBr3
Iodination:
I2
H2O2
H2SO4
2I
Nitration:
HO
NO2 + H
OSO3 H
HOH
NO2
NO2
Reagents are HNO3 and H2SO4

Sulfonation:
HO
SO3H
OSO3H
HOH
SO3H
SO3 H
Reagents are Sulfuric acid and heat, reversible

Friedel-Crafts Acylation:
O
AlCl3
Cl
Friedel-Crafts Reagents are the acyl chloride, or haloalkane and AlCl3

Friedel-Crafts Alkylation:
Cl
AlCl 3
Notes:
Friedel-Crafts chemistry can not be done on deactivated rings or aniline
Aniline can not be nitrated safely
18
More Benzene Chemistry

To remove the carbonyl group af ter acylation the Wolf f -Kishner or Clemmensen reductions can be
used.
H2NNH2
Wolff-Kishner Reagents:
-OH,
Clemmenson Reagents:
Heat
Zn(Hg), HCl
Heat
Conditions for the Clemmenson reduction will react with double bonds.
Arenediazonium Salts:
NH2
NaNO2
HCl, 0oC
X=Br, Cl, CN
N
CuX
Also works with KI for X=I, H3O+ for X=OH, HBF4 for X=F, and H3PO2 for X=H
Arenediazonium salts can also act as electrophiles with benzene to form azo linkages that consist of two
benzene rings conected by
N
N
Mechanism f or Nucleophilic Aromatic Substitution:

Cl
Cl
O2 N
NO 2
O 2N
NO2
O 2N
NO2
For substitution to take place the benzene ring must be highly deactivated
19
Activation of Carboxylic Acids

Functional Group Transf ormation: Carboxylic Acid to Acyl Halide or Acid Anhydride
General Scheme:
O
or
R
OH
Cl
Reactions:
O
SOCl2
OH
HCl
OH
H3PO3
Cl
P 2O 5
R
Cl
PCl3
R
SO2
OH
+
R
H 2O
Notes:
-Converting a carboxylic acid into an acyl halide or an acid anhydride is a priceless tool in the laboratory,
as carboxylic acids are the most used type of compound and changing them into something more reactive
increases the number of things that they can be used f or.
20
Nucleophilic Substitution Reactions of Ethers

Ether
Alkyl Nucleophile
General Scheme:
O
R
HX
Heat
Reaction Mechanism:
Br
+O
Br-
Heat
Br
Heat
+
OH
Notes:
Ethers can only undergo nucleophilic substitution with HBr and HI

If a secondary or tertiary carbocation would be f ormed, the reaction will proceed through the SN1
mechanism
If an unstable carbocation would be f ormed the reaction will proceed through the SN2 mechanism
(methyl, vinyl, aryl, primary)
Only substitution occurs, because any elimination product would react with HBr or HI to f orm the
substitution product
Ethers can also be activated by tosyl chlorides, SOCl 2, and PCl 3 in the same way as alcohols to f orm
an alkyl chloride
21
Hydrolysis of Nitriles
Functional Group Transf ormation: Nitrile to Carboxylic Acid
General Scheme:
O
R
H2O
+
R
NH4Cl
OH
Reaction Mechanism:
NH
H
R
B
R
NH
H2O
R
OH
NH 2
NH 2
NH
H2O
R
H
R
OH
OH
B
R
OH
Notes:
-Nitriles are harder to hydrolyze than amides, but it can be done by the above mechanism when water, acid,
and heat are used.
22
Reactions of Acid Anhdrides

Functional Group Transf ormation: Acid Anhydride to Ester and Carboxylic Acid via Alcohol
Acid Anhydride to Amide and Carboxylate Ion via Amine
General Scheme:
O
+
R
R1
OR/OH/N
Reaction Mechanism:
O
O
O
+
R
OH
OR
H
B
O
+
R
HO
OR
OR
Notes:
-Acid anhydrides do not react with sodium chloride or bromide because the incoming halide is a weaker base
than the departing carboxylate ion.
-All of the mechanisms f ollow the general mechanistic scheme of the nucleophilic addition-elimination
reaction with a neutral nucleophile.
23
Reactions of Acyl Halides

Functional Group Transformation: Acyl Halide to Anhydride via Carboxylate Ion
Acyl Halide to Ester via Alcohol
Acyl Halide to Carboxylic Acid via Water
Acyl Halide to Amide via Amine
General Scheme:
O
+
R
Cl
Cl
Reaction Mechanism:
O
O
O
R
Cl
+
R
Cl
O
R
O
OH
Cl
+
R
OH
Cl
Cl
OR
Cl
R
OR
+ B
OR
+ Cl
Notes:
-The mechanisms shown are f or the conversions of acyl chlorides to anhydride and ester, respectively.
-The reaction of an acyl chloride with an amine to f orm an amide calls f or twice as much amine as acyl
chloride because the HCl f ormed as a byproduct will protonate any amine that has not reacted yet.
-In each mechanism, the incoming nucleophile is a stronger base than the departing chloride ion, so the
reaction is a nucleophilic substitution.
24
Reactions of Amides
Functional Group Transf ormation: Amide to Carboxylic Acid
Amide to Nitrile
General Scheme:
O
NH2
OH
R2CN
R
NH2
Reaction Mechanism:
OH
OH
H2O
R
NH2
NH 2
NH2
O
H
OH
NH4
OH
OH
OH
R
NH 3
NH 2
OH
NH3
OH
OH
Notes:
-Amides cannot be hydrolyzed without catalysts.
-The mechanism is similar to that of the acid catalyzed hydrolysis of an ester.
25
Reactions of Carboxylic Acids

Functional Group Transf ormation: Carboxylic Acid to Ester via Alcohol
General Scheme:
O
+
R
OH
OH
H 2O
OR'
Reaction Mechanism:
H
O
B
OH
CH3OH
+
R
OH
OH
OCH 2
OH
OH
H
O
OH
OH
R
R
OCH 3
OCH3
H2O
O
H
OCH 3
OH
Notes:
-The mechanism is the exact reverse of the acid catalyzed ester hydrolysis.
-Carboxylic acids have approximately the same reactivity as esters, theref ore they do not react with halide
ions or carboxylate ions either.
26
Reactions of Esters
Functional Group Transf ormation: Ester to Carboxylic Acid and Alcohol via Water
Ester to New Ester and New Alcohol via Alcohol
Ester to Amide via Amine
General Scheme:
O
+
R
H
R
OR
OH
Reaction Mechanism:
Acid Catalyzed Ester Hydrolosis:
H
O
H
R
OH
OCH3
H2O
OCH3
OCH 3
OH
B
H
OH
B
OH
R
OH
OH
OCH 4
OCH 3
OH
CH3OH
OH
OH
Notes:
-Curiously enough, this mechanism is the exact reverse of the mechanism f or the acid catalyzed reaction
of a carboxylic acid and an alcohol to f orm an ester.
-The reaction of an ester with an amine is not as slow as the reaction of an ester with water or alcohol
because amine is a better nucleophile.
-Transesterif ication is also acid catalyzed.
27
Acid-Catalyzed Acetal or Ketal Formation

aldehyde
hemiacetal
acetal
ketone
hemiketal
ketal
Reaction Scheme:
O
HCl
CH3OH, HCl
+ CH3OH
R
H
O
OH
HCl
CH3OH
OH
CH3OH, HCl
Reaction Mechanism:
H
OH
CH3OH
H
R
OH
R
H
O
O
O
O
R
R
CH3OH
OHH
O
Notes:
acid catalyst is required
one equivalence of alcohol is added to the aldehyde or ketone, goes to hemiacetal
or hemiketal
two equivalence of alcohol takes aldehyde or ketone all the way to acetal or ketal
28
Alcohol Protecting Groups

OH of an alcohol
triethylsilyl ether
OH of carboxylic acid
OH of an alcohol
ester
OH of carboxylic acid
Reaction Scheme:
OH
Cl
(CH3CH2)3N
OSi(CH 2 CH 3) 3
Si
Br
alcohol
H3O
OH
Br
Br
O
excess OH
HO
OH
HCl
HO
O
carboxylic acid
HCl, H2O
heat
O
HO
OH
29
Amino Protecting Group

amino
amide
amino
Reaction Scheme:
O
NH 2
HN
Cl
1. HCl, H2O, heat

2. HO
30
Reactions of Carbonyl Compounds with Acetylide Ions

Functional Group Transf ormation: Aldehyde or Ketone to Alkoxide
General Scheme:
OH
1. acetylide ion
2. H3O+
R
R
R
Reaction Mechanism:
O
OH
H+
+
R
R
R
Notes:
-As a method of making carbon-carbon double bonds, this reaction is extremely important to chemists.
-The acetylide ion f orms a nucleophilic addition product.
31
Reactions of Carbonyl Compounds with Amines

Functional Group Transf ormation: Aldehyde or Ketone to Imine
General Scheme:
O
H+
+
R
NR"
H2NR"
H 2O
Reaction Mechanism:
O
+
R
R"NH2
OH
B
R
NH 2 R"
R
NHR"
H
H
NR"
B
R
R
H
O
NR"
OH
H
R
R'
NHR"
NHR"
Notes:
-Imine f ormation is reversible, with equilibrium f avoring the nitrogen protonated tetrahedral intermediate.
-Overall the addition of an amine to an aldehyde or ketone is nucleophilic addition-elimination.
-Other amine reactions are possible, which are not mentioned here, but which include f ormation of
derivatives such as oxime, semicarbazone, and Wolf f -Kishner reduction.
32
Reactions of Carbonyl Compounds with Hydride Ions

Functional Group Transf ormation: Aldehyde, Ketone, Acyl Chloride, or Carboxylic Acid to Alcohol
Ester to Aldehyde
Amide to Amine
General Scheme:
O
OH
1. NaBH4
2. H3O+
R
Reaction Mechanism:
+
R
OH
O
H
BH3
R
H
H3O+
R
H
Notes:
-The mechanism shown above is specif ically f or a ketone or aldehyde, but the other reactions f ollow the
same pathway.
-Sodium borohydride will reduce aldehydes, ketones, and acyl chlorides.
-Lithium aluminum hydride is required to reduce carboxylic acids, esters, and amides.
33
Reactions of Carbonyl Compounds with Hydrogen Cyanide

Functional Group Transf ormation: Aldehyde or Ketone to Cyanohydrin
General Scheme:
OH
CN
HCl
R
Reaction Mechanism:
OH
O
O
+
R
N
R
N
R
Notes:
-The hydrogen cyanide is generated in situ by adding copius amounts of HCl to a mixture of the aldehyde
or ketone in excess sodium cyanide.
-Only ketones and aldehydes react with hydrogen cyanide.
-The catalytic addition of hydrogen to the cyanohydrin will f orm a primary amine.
34
Carbonyl Compounds with Water

Functional Group Transf ormation: Aldehyde or Ketone to Hydrate
General Scheme:
OH
HCl
H 2O
OH
Reaction Mechanism:
OH
OH
O
H
OH
+
R
H
1
H 2O
O
H
H 2O
OH
R
+
OH
H 3O +
Notes:
-Water is a poor nucleophile, so addition is sped up by addition of an acid catalyst.
-The hydrate product is also known as a geminal-diol.
35
Ketone or Aldehyde Protecting Groups

Ketone or Aldehyde
5 or 6-membered ring ketal or acetal
ketone or aldehyde
Reaction Scheme:
OH
HO
O
O
, HCl
R
HO
R
OH
R
O
, HCl
R
R
HS
SH
, BF3
R
O
H3O
HgSO4
S
H3O
H3O
Notes:
aldeydes and ketones can be protected by being converted into acetals
can be brought back by use of aq acid or mercury sulfate in aq acid
thioketal can be reduced to an alkyl group through Raney Nickel
36
Wittig Reaction
aldehyde or ketone
alkene
Reaction Scheme:
O
R'
R'
(C6 H5 )3 P
(C6 H5 )3 P
Phosphonium
ylide
Reaction Mechanism:
P(C6 H 5) 3
O
P(C 6H 5) 3
P(C 6H 5) 3
H 2C
R
CH 2
CH 2
R
R
R
R
Notes:
concerted cycloaddition reaction
O
Horner-Wittig Reaction uses
but gives same product
P
R
37
Acid- Catalyzed Halogenation of Alpha Carbon

f uncitonal group transformation
aldehyde or ketone
halogenated aldehyde or ketone
Reaction Scheme:
H3O
O + HCl
Cl2
Cl
Reaction Mechanism:
H
O
H
OH
H
R
R
R
R
H
H
O
H
Br
H
Br
O
H
R
R
H
R
Br
Br
Notes:
can add to either alpha carbon
each successive halogenation is slower than the previous
-basicity of carbonyl oxygen is decreased, making protonation of O less favorable
38
Aldol Condensation and Dehydration, E1cB

Aldehydes or Ketones
Beta-hydroxyaldehydes or Beta-hydroxyketones
Reaction Scheme:
condensation:
OH
H3O
OH, H2O
R
heat
R
H
dehydration:
OH
OH
OH, H2O
heat
Reaction Mechanism: E1cB mechanism

OH
OH
B
H
OH
H
R
R
H
B
O
Notes:
heating the aldol addition product leads to dehydration which produces an enone
base catalyzed deyhdration reaction represents E1cB reaction
39
Base-Catalyzed Halogenation of an Alpha

Carbon
aldehyde or ketone
halogenated aldehyde or ketone
Reaction Scheme:
O
Br
Br
OH
Br2
Br
Br
Br
Br
Reaction Mechanism:
O
Br
Br
+ H20
H
O
O
Repeat first 2 steps
Br
R
Br
+ Br
Br
Notes:
each successive halogenation is more rapid than the previous
-acidity of remaining H's is increased
40
Claisen Condensation
Ester
Beta-keto ester
Reaction Scheme:
O
1. CH3CH2O
2. HCl
HO
O
O
Reaction Mechanism:
O
O
H
CH3O
R
O
R
O
O
R
R
O
R
O
Notes:
nucleophilic addition-elimination reaction
crossed claisen condensation reaction is between two different esters, will form a
mixture of products
41
Dieckmann Condensation
1,6- Diester
5-membered ring beta-keto ester
1,7- Diester
6-membered ring beta-keto ester
Reaction Scheme:
O
O
1.CH3O
2.HCl
O
1,6-diester
beta-keto ester
O
O
1. CH3O
O
2. HCl
O
beta-keto ester
1.7-diester
Reaction Mechanism:
O
O
O
OCH3
O
O
Notes:
intramolecular Claisen condensation
42
Halof orm Reaction

methyl ketone
carboxylate ion + halof orm
Reaction Scheme:
O
O
+ Br2
excess
R
Br
OH
Br
H
C
CH 3
Br
Reaction Mechanism:
O
R
O
HO
R
CH 3
I2 excess
CI3
HO
CI 3
H
O
O
O
I
O
H
C
I
C
I
R
OH
Notes:
only works with methyl ketone
43
Hell-Volhard-Zelinski Reaction
Carboxylic Acid
Alpha-brominated carboxylic acid
Reaction Scheme:
O
O
1. PBr3 (or P), Br2

R
OH
OH
2. H2O
Br
Reaction Mechanism:
O
PBr3
OH
R
Br
R
Br
OH
Br
Br
H2O
Br
Br
OH
Br
OH
Br
Br
Notes:
Alpha substitution occurs because acyl bromide is undergoing the substitution,
not the carboxylic acid
44
Intramolecular Aldol Addition

1,4- diketone or 1,6-diketone
f ive membered ring
1,5-diketone or 1,7-diketone
six membered ring
Reaction Scheme:
OH
O
1,4-diketone
OH, H2O
OH
O
1,5-diketone
Reaction Mechanism:
O
OH, H2O
OH
H2O, HO
O
O
Notes:
can potentially f orm a different numbered ring but most stable ring will form
45
Keto-Enol Interconversion
functional group transformation:
keto tautomer
enolate ion
enol tautomer
Mechansim: (acid -catalyzed interconversion)

O
OH
O
R
OH
R
R
H
O
H
Mechanism: (base-catalyzed interconversion)

O
O
H
O
R
R
R
R
OH
H
OH
R
R
+ OH
Key Points:
46
Using LDA to f orm an Enolate Ion
Functional Group Transformation:

carbonyl compound
enolate ion
Reaction Scheme:
O
O
LDA/THF
Notes:
LDA is a very strong base so all of carbonyl compound is converted to the enolate ion
47
The Micheal Reaction

alpha, beta-unsaturated carboxylic acid derivative
or conjugate addition product
nucleophilic addition product
Reaction Scheme:
Nu
1. Nu
2. H3O
R
Nu
OH
direct addition
an alpha, beta-unsaturated
aldehyde or ketone
conjugate addition
Reaction Mechanism:
O
O
HO
H2O
R
O
H
Notes:
if either of reactants has an ester group, the base used to remove the alpha proton
must be same as leaving group of the ester
form 1,5-dicarbonyl compounds
use enolate ions of : beta-diketones, beta-diester, beta-keto esters, beta-keto nitriles
48
Nucleophilic Addition to Alpha, BetaUnsaturated Ketones and Aldehydes
Direct Addition:
Y
Y
R
H3O
Y
OH
alpha, beta-unsaturated carbonyl compound
Conjugate Addition:
R
H3O
Y
O
alpha, beta-unsaturated carbonyl compound
keto
tautomer
OH
enol
tautomer
Usually direct addition:

R-MgX
R-Li
C
Usually Conjugate addition:

(R)2CuLi
HO-R, H
H2N-R
H-X
CN
49
Reactivity of Alkyl Fluorides

Anti-Zaitsev Elimination Product
Alkyl Fluoride
General Scheme:
F
Heat / Conc. Base

Polar Protic Solvent
Reaction Mechanism:
Conc. NaOEt
H
Heat/EtOH
Notes:
Anti-Zaitsev product is f ormed because the reaction mechanism goes through a carbanion like
transition state *
The mechanism f or this reaction is E2
Reaction conditions are E2 conditions
* The carbanion like transition state occurs because f luorine is a relatively strong base and a very poor leaving
group; the reason the product is anti-Zaitsev is because the carbanion transition state does not want to
hyperconjugate with the neighboring carbon-hydrogen bonds. It wants to avoid additional electron density due
to its partial negative charge.
50
Dehydration of Alcohols
Alcohol
Alkene
General Scheme:
OH
H 2SO4
Heat
Reaction Mechanism:
OSO3H
Heat
Heat
OH2
OH
H2O
Heat
Notes:
Secondary and Teriary alcohols react through the E1 mechanism, and Primary alcohols react
through the E2 mechanism
To prevent ref ormation of the alcohol f rom the product and H2O, the alkene is distilled f rom the
reaction mixture because it boils at a lower temperature than the alcohol
The reagents POCl3/pyridine, 0 degrees celsius also convert an alcohol to an alkene through the
E2 reaction mechanism
51
Elimination Unimolecular Reactions, E1

Alkyl Halide
Alkene
General Scheme:
Low conc. Base

Polar Protic Solv.
Heat
Reaction Mechanism:
Low conc.
NaOEt
Low conc.
NaOEt
EtOH
Heat
X
EtOH
Heat
H
Notes:
Two step mechanism, Rate=k[alkyl halide][Base]
Mechanism involves f ormation of a carbocation, rearrangement can occur
E2 can go through a syn-periplanar or anti-periplanar mechanism, the major product will have the
most stable stereochemistry (E or trans/Zaitsev product)
If a bulky enough base or substrate is used an anti-Zaitsev product will be the major product
Reactivity of Alkyl Halides: Benzyl, Allyl, Tertiary, Secondary, [Primary] (Only when a bulky
base/substrate is used)
Bases: NaOEt, NaOR, NaOH
Protic Polar Solvents: H2O, EtOH, ROH
Elimination is f avored by heat, EtOH, conjugation, and a good base
52
Elimination Bimolecular Reactions, E2

Alkene
Alkyl Halide
General Scheme:
Strong Base, conc.

X
Polar Protic/Aprotic Solvent
Reaction Mechanism:
NaOt
Br
tOH, heat
Notes:
Concerted Mechanism, Rate=k[alkyl halide][Base]
H and X must be anti-periplanar to eliminate through E2
When reacting a cycloalkyl halide the H and X must be in axial positions
When two H's are present on the beta carbon two stereoisomers will be f ormed, but the more stable
trans or E isomer will be the major product (Zaitsev Product).
If only one H is present on the beta carbon the stereochemistry will be determined by the substrate's
configuration.
Strong Base: NaOH, NaNH2, NaOR
Ethanol as a solvent, heat, and conjugation f avor Elimination
If a bulky base or substrate is used Elimination is more likely to occur (anti-Zaitsev)
Reactivity of Alkyl Halides: Benzyl, Allyl, Tertiary, Secondary, [Primary] (f avors substitution
unless a bulky base or substrate is used)
53
Reactions of Carbonyl Compounds with Grignard Reagents

Functional Group Transf ormations: Aldehyde, Ketone, Ester, or Acyl Chloride to Alcohol
Carbon Dioxide to Carboxylic Acid
General Scheme:
O
OH
1. R'MgBr
(H) R
R (H)
2. H3O+
(H) R
R(H)
R(H)
1
Reaction Mechanism:
O
MgBr +
OH
+
R
MgBr
H3O
Notes:
-Although only the mechanism f or the reaction of a ketone with a Grignard reagent is shown, they all
react by the same pathway, f orming primary, secondary, or tertiary alcohols depending on the number of
hydrogens in place of the R groups and the number of potential leaving groups the compound has.
54
Gilman Coupling Reactions

Reaction Scheme:
Organolithium Reagent
Alkyl Chain
General Scheme:
THF
Li
CuI
) 2CuLi + LiI
Sample Reaction:
) 2CuLi
THF
Br
Notes:
Couples any two alkyl, aryl, or vinylic groups
Alkyl Fluorides will not undergo this reaction
The precise mechanism f or this reaction is not known
Gilman reagents, dialkyl lithium cuprates, react with primary secondary, vinylic, or aryl,
halides
This reaction works even if the halogenated compound contains other f unctional groups
(without acidic protons)
If a vinylic halide is reacted, it will maintain its E or Z conf iguration
55
Organolithium and Organomagnesium Reactions

Haloalkane
Carbon Nucleophile
General Scheme:
Br
Li or MgBr
Li, Hexanes
or
Mg, THF
Reaction Mechanism:
Sample Reaction of Organolithiums and Grignard Reagents
O
MgBr +
THF
H+
OH
Notes:
Organolithiums and Grignard (Organomagnesium) reagents react in the same way, as a source of
carbon nucleophile
The solvent f or these reactions is important, an aqueous solvent, or any solvent with acidic
hydrogens, would destroy the reagent
56
Palladium Based Coupling Reactions: Heck, Suzuki

Couples two alkyl pieces, at least one of them with a halogen attached to an aryl or vinyl position.
General Scheme:
OR
X + Ar
PdL2
OR
Ar
Suzuki
HO-
X
PdL2
Heck
TEA
Reaction Mechanism
PdL2
R
Ar
Pd
X
OR
Pd
R'
R'
Suzuki
B
OR
Pd
R
PdL 2
Pd
X
R
Heck
Z
Z
Notes:
The organopalladium compoud can not have beta hydrogens, or an elimination reaction will occur
instead of the coupling
The suzuki boron ester must have an aryl group
Triethyl amine is a necessary reagent f or the heck reaction; it reduces the Pd2 to Pd0
57
Diels-Alder Reactions
Substituted Cylohexene, or Cyclohexadiene
Diene + Dienophile
General Scheme:
Heat
W-electron withdrawing group
Reaction Mechanism:
O
Heat
+
OH
OH
Notes:
The diene is the nucleophile and the dienophile is the electrophile
A six memebered ring is always f ormed
The reaction will not occur if the diene is locked in the s-trans configuration
[4+2] cycloaddition reaction: 4 pi electrons f rom the diene, and 2 f rom the dienophile
Concerted reaction mechanism
If a stereocenter is f ormed, the product will be a racemic mixture
Syn addition reaction, stereochemistry of substituents is conserved
58
Hydroboration-Oxidation of an Alkene
Alkene
Alcohol
general scheme:
1.) BH3 / THF
OH
2.) OH- , H2O , H2O2
partial positive
mechanism:
partial negative
H
BH
H
B
BH2
x3
R
R
R
OH- , H2O2 , H2O
R
B
HO
OH
OR
RO
OH
OR
RO
H
OH
OR
B
RO
R
B
OR
H
O
OR
OR
OH
59

continuation of mechanism:
OH
R
OH
B(OH)4
OH
R
Key Points:
no carbocation rearrangement
concerted reaction
syn addition
60
Hydroboration-Oxidation of an Alkyne
alkyne
ketone or aldehyde
general scheme:
R
R
BH3/THF
aldehyde
OH-, H20, H2O2

R
BH3/THF
OH-, H20, H2O2
ketone
O
mechanism:
BH3
THF
R
H
HO- , H2O2
H2O
OH
3
O
Key Points:
mechanism basically same as hydroboration of alkene
electrophile (BH3) adds to C with most H's
product is ketone due to keto-enol tautomerization
if terminal alkyne then aldehyde is produced
61
Oxidation of Alcohols
Functional Group Transf ormation: Primary Alcohol to Aldehyde
Secondary Alcohol to Ketone
O
OH
General Scheme:
or
R
OH
Reaction Mechanism:
SWERN Oxidation:
R(H)
R(H)
R
OH
H
S+
Cl
R
S
Notes:
-Chromic acid (H2CrO4) is used to oxidize secondary alcohols to ketones, but it will oxidize primary
alcohols all the way to carboxylic acids.
-SWERN is CH3SCH3, ClCOCOCl, and TEA at 60 degrees Celcius
62
Oxidation of Aldehydes and Ketones

Functional Group Transf ormation: Aldehyde to Carboxylic Acid
Ketone to Ester
O
General Scheme:
R
R(H)
O/R(H)
Reaction Mechanism:
Baeyer-Villager Oxidation:
O
+
R
F
O
O
O
F
O
R
F
OR
Notes:
-Tollens reagent: oxidizes an aldehyde, too mild f or anything else, it is (1) Ag2O, NH3 (2) H3O+
-Any reagent used to oxidize primary alcohols to carboxylic acids can be used to oxidize aldehydes to
carboxylic acids.
-Ketones do not react with most of the reagents used to oxidize aldehydes, but both can be oxidized by
conjugate base of a peroxyacid, i.e. a Baeyer-Villager reaction.
63
Oxidation of Alkenes to 1,2-Diols

Functional Group Transf ormation: Alkene to 1,2-Diol (vicinal diol)
General Scheme:
OH
OH
Reaction Mechanism:
H
O
OH
H
H 2O 2
Os
O
O
O
O
Os
O
OH
OsO4
Notes:
-Syn addition
-Forms cyclic intermediate
-Hydrogen peroxide reoxidizes osmium reagent
64
Oxidative Clevage of 1,2-Diols

Functional Group Transf ormation: 1,2-Diol to Ketone or Aldehyde
General Scheme:
OH
+
H
OH
Reaction Mechanism:
HIO4
OH
OH
I
O
O H
H2O
HIO3
Notes:
-Periodic acid is used to f orm a cyclic intermediate f rom the diol, and when the intermediate breaks down,
the bond between the two carbons bonded to the oxygens breaks as well.
-It is called an oxidative clevage because it cuts a reactant into two pieces.
65
Oxidative Clevage of Alkenes

Functional Group Transf ormation: Alkene to Aldehyde or Ketone
General Scheme:
O
Reaction Mechanism:
O
H
O
O
O
Zn, H2O
or (CH3) 2S
O
H 2O 2
OH
Notes:
-When an alkene is treated with ozone at low temperatures, the double bond breaks and the carbons are
doubly bonded to oxygens instead of to each other, known as ozonolysis.
-The immediate reaction results in a molozonide, which is unstable and theref ore quickly rearranges into
an ozonide.
-Ozonide treated with reducing conditions yields ketones and aldehydes.
-Ozonide treated with oxidizing conditions yields ketones and carboxylic acids.
66
Addition of Radicals to an Alkene

Functional Group Transformation: alkene to alkyl halide
General Scheme:
R
C
H
C
H
peroxide
H Br
CH2 CH 2 R
Br
Reaction Mechanism:
light
H 3 CO
H 3C
Br
OCH 3
H 2C
BrCH 2CHCH 3
Br
2 CH 3O
or
Br
H3 C
BrCH2CH 2CH3
Br
Br
Br
BrCH 2CHCH 3
Br
Br
Br
Br
BrCH 2CHCH 3
Br
BrCH 2CHCH3
CHCH 3
OH
CH 2 CHCH 3
Br
CH3CH
CHCH 3
BrCH 2CHCH 3
Br
CH 2 H 2 C
Br
Notes:
-mechanism is divided into three groups of reactions: initiation, propagation, and termination
-this is known as a radical addition reaction
-in the presence of peroxide, Br becomes the electrophile which adds to the less substituted carbon, causing anti-Markovnikov
addition of the Br
67
Formation of Explosive Peroxides

Functional Group Transf ormation: ether to peroxide
General Scheme:
R
CH R
O2
CH R
O
Reaction Mechanism:
H 3C
CH
CH 3
H 3C
CH CH 3
HY
O2
H 3C
CH
CH 3
H 3C
H 3C
CH CH 3
O
CH
H 3C
CH 3
H 3C
CH CH 3
CH CH 3
OH
Notes:
-must have chain initiating radical (i.e., Y) to remove H f rom ether
-a peroxide is simply a compound with an O-O bond, which is easily cleaved homolytically to f orm
radicals that can propogate f urther radical production
-a peroxide is a radical initiator
-ethers contain stabilizers to trap chain-imitating radicals to prevent explosive situations
68
Radical Halogenation of Alkanes

Functional Group Transf ormation: alkane to alkyl halide
General Scheme:
heat
RCHn
X2
RCHn-1X
HX
or hv
Reaction Mechanism:
heat
Cl
2 Cl
Cl
or hv
HCl
CH3
CH3Cl
Cl
Cl
CH3
Cl
Cl
Cl
Cl2
Cl
CH3
CH3Cl
CH3
CH3
CH3CH3
H CH 3
Cl
Notes:
-heat or UV light supplies energy to break dihalide bond homolytically; that is, so that each atom
retains one of the two bonding electrons, f orming radicals
-the specif ic reaction above is called the monochlorination of methane, where the chlorine radical
removes a hydrogen atom from methane, the alkane, making HCl and a methyl radical
-in any radical reaction such as this, there are three types of steps: initiation (f irst above), propogation
(second and third above), and termination (f ourth through sixth above)
-any step that continues the radical cycle started in the initiation step(s) is a propogation step, while any
step that combines two radicals to f orm a product with all paired electrons is termination
69
Radical Substitution of Benzylic and Allylic Hydrogens

Functional Group Transf ormation: alkene to halogenated alkene
General Scheme:
X
CH 2R
CHR
X2
X2
Reaction Mechanism:
Br
CH 3
CH 3
hv or
H 2O 2
CH 3
Br
CH 2
Br
CH2
HBr
Br
CH 2Br
Br 2
CH2
CH 2Br
Br
Notes:
-Bromine radical f rom NBS removes allylic H, but bromine radical f rom HBr + H2O2 adds to double
bond
70
Catalytic Hydrogenation
Alkene or Alkyne to Alkane
Aldehyde to Primary Alcohol
Ester to Secondary Alcohol
Acyl Halide to Aldehyde
General Scheme:
or
Reaction Mechanism:
Pd/C
or PtO2
Lindlar
Catalyst
O-
H
C+
R
Raney Ni
OH
H
Raney Ni
R
OH
C+
OH
OC+
Cl
Cl
Partially
Deactivated
Pd
71
Dissolving Metal Reductions

Functional Group Transf ormation: Alkyne to Trans Alkene
General Scheme:
Reaction Mechanism:
C-
Na
Na
H
H2 N
NH 2
C-
Na
H
Notes:
-Na or Li in liquid NH3 cannot reduce double bonds
-Na and Li have a strong tendency to lose single electron in outer shell s-orbital
-Radical anion is strong enough base to deprotonate NH3, as is vinylic anion
72
Metal Hydride Reduction

Functional Group Transf ormation: Carbonyl group to Alcohol
Acyl chloride to Aldehyde or Alcohol
Amide to Amine (*doesn't use H3O+)
General Scheme:
O
OH
Reaction Mechanism:
OO
NaBH4
H3
R
H
R
OH
O+
H+
R
H
Notes:
-metal hydrides: sodium borohydride (NaBH4) or lithium aluminum hydride (LiAlH4) in H3O+
-metal-hydrogen bonds in LiAlH4 are more polar than NaBH4, making LiAlH4 a stronger reducing agent
-both NaBH4 and LiAlH4 reduce aldehydes, ketones, and acyl halides, but NaBH4 is a saf er choice
-LiAlH4 used to reduce carboxylic acids, esters, and amides
-replacing some hydrogens of LiAlH4 with alkoxy groups decreases reactivity of metal hydrides; lithium
tri-tert-butoxyaluminum hydroxide reduces acyl chlorides to aldehydes
-metal hydride reduction will not reduce alkynes or alkenes
73
Oxymercuration- Reduction of an Alkene

functional group transformation:
alkene
alcohol
general scheme:
R
1.) Hg(O2CCH3)2 , H2O, THF

R
2.) NaBH4
OH
Mechanism:
O2CH 3
1.) Hg(O2CCH3)2 , H2O, THF
Hg
2.) NaBH4
O
H
Hg
H3 CO2
O2CH 3
OH
O 2CH3
H
O
O 2CH3
Hg
H
Hg
NaBH4
OH
+ Hg + CH3CO2-
Key Points:
regiospecific, anti-Markovnikov
syn addition
74
Nucleophilic Substitution of Epoxides

Epoxide
Vicinal Alcohol/Nucleophile
General Scheme:
Nu
O
R
Acidic Conditions
Or Neutral/Basic Conditions
OH
OH
Nu
or
Acidic
Neutral/Basic
Racemic Mixture of Conditional Product
Reaction Mechanism:
H+
+
OH
OCH 3
CH3OH
CH3OH
OH
Notes:
If the conditions are acidic, the nucleophile will attack the more substituted carbon; if conditions are
neutral or basic the nucleophile will attack the less substituted carbon because of reduced steric
hindrance
This reaction is an anti-addition because the epoxide blocks one face of the reactive site
Stereochemistry is a racemic mixture if a stereocenter is f ormed
Epoxides can be f ormed f rom the addition of a peroxy acid (RCO3H) to a double bond, or through the
addition of Cl2 and H2O to a double bond f ollowed by HO-
75
Substitution Nucleophilic Unimolecular Reactions, SN1
Alkyl Halide
Alkyl Nucleophile
General Scheme:
Nu
Weak Nucleophile
Enantiomer
Polar Protic Solvent
Reaction Mechanism:
Cl
EtOH
EtOH
OEt
Notes:
Two step mechanism, Rate=k[alkyl halide]
Carbocation f ormation, carbocation rearrangement is possible
Racemic mixture, due to Sp2 carbocation intermediate
Alkyl Halide Reactivity: Tertiary, Secondary, Primary and Methyl do not react
Weak Nucleophile: EtOH, MeOH, H2O
Protic Polar Solvent: H2O, Acetic Acid, EtOH
76
Substition Nucleophilic Bimolecular Reactions-SN2

Alkyl Halide
Alkyl Nucleophile
General Scheme:
Good Nucleophile
R
X
Polar Aprotic Solvent
NH 2
Reaction Mechanism:
NaOEt
+
DMSO
Br
Br -
OEt
Notes:
100% Inversion of Stereochemistry through Back Side Attack
Reactivity of Alky Halides: Methyl, Primary, Secondary, Tertiary will not react
Concerted Mechanism, Rate=k[alkyl halide][nucleophile]
Polar Aprotic Solvents: DMSO, DMF, Acetone
Strong Nucleophiles: NaOEt, NaOMe
77
Nucleophilic Substitution of Alcohols

Alcohol
Alkyl Nucleophile
General Scheme:
HX
R
OH
Heat
Reaction Mechanism:
OH
Br
Heat
OH2
Br -
HBr
Br
Heat
Notes:
This reaction can proceed through either an SN2 or SN1 mechanism, depending on the degree of
the alcohol
Primary goes through SN2, Secondary and Tertiary go through SN1
The same reaction can also proceed using PX3/Pyridine as reagents
Alcohols can also be made into good leaving groups by reacting them with pyridine/tosCl, and
then a good nucleophile (ex. NaCN, SMe)
78

Functional Group Transformation Notebook

Hochgeladen von

Dokumentinformationen

Originalbeschreibung:

Originaltitel

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

Functional Group Transformation Notebook

Hochgeladen von

Copyright:

Verfügbare Formate

2012

Huffstickler, Syler, and Wayland

Alkene and Alkyne Chemistry

Acid-Catalyzed Addition of an Alcohol to an Alkene

Addition of Halogen to an Alkyne

Addition of Peroxyacid to an Alkene

Addition of Halogen to an Alkene

Addition of Hydrogen Halide to an Alkyne

Addition of Hydrogen to an Alkene

Addition of Hydrogen to an Alkyne

Addition of Water to an Alkyne

Addition of Hydrogen Halide to an Alkene

Addition of Water to an Alkene

More Benzene Chemistry

Activating Carboxylic Acids

Reactions of Acid Anhydrides

Reactions of Acyl halides

Reactions of Carboxylic Acids

Acetal or Ketal Formation

Alcohol Protecting Groups

Amino Protecting Groups

Carbonyl Compounds with Acetylide Ions

Carbonyl Compounds with Amines

Carbonyl Compounds with Hydride Ions

Carbonyl Compounds with Hydrogen Cyanide

Carbonyl Compounds with Water

Carbonyl Oxygen Protecting Groups

Carbonyl Compounds III

Acid-Catalyzed Alpha-Carbon Halogenation

Aldol Condensation and Dehydration e1cB

Base-Catalyzed Alpha-Carbon Halogenation

Intramolecular Aldol Addition

LDA to Form Enolates

Nucleophilic Addition to Unsaturated Ketones

Carbonyl Compounds Grignard Reactions

Diels-Alder Ring Formation

Hydroboration-Oxidation of an Alkene Part 1

Hydroboration-Oxidation of an Alkene Part 2

Oxidation of Aldehydes and Ketones

Oxidation of Alkenes to 1,2-Diols

Oxidative Cleavage of 1,2-Diols

Oxidative Cleavage of Alkenes

Addition of Radicals to an Alkene

Formation of Explosive Peroxides

Radical Halogenation of Alkanes

Radical Substitution of Benzylic and Allylic Hydrogens

Dissolving Metal Reduction

Metal Hydride Reduction

Nucleophilic Substitution of Epoxides

Acid catalyzed Addition of Alcohol to an Alkene

alcohol quick to deprotonate the protonated

Addition of Halogen to an Alkyne

Addition of a Peroxyacid to an Alkene