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W i s e b r i d g e L ear ning Syst ems
Organic Chemistry
Rea ct i o n M e c h a n i s m s Po c ke t -Book
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© 2006 J S We tzel
LEARNING STRATEGIES
●
The key to building intuition is to develop the habit
of asking how each particular mechanism reflects
general principles. Look for the concepts behind
the chemistry to make organic chemistry more coherent and rewarding.
●
Exothermic reactions tend to follow pathways
where like charges can separate or where unlike charges can come together. When reading
organic chemistry mechanisms, keep the electronegativities of the elements and their valence
electron configurations always in your mind. Try
to nterpret electron movement in terms of energy
to make the reactions easier to understand and
remember.
●
For MCAT preparation, pay special attention to
reactions where the product hinges on regioand stereo-selectivity and reactions involving
resonant intermediates, which are special favorites of the test-writers.
ALYL HALIDES
SN2 Mechanism with Alkyl Halides . . . . . . . . . . . . . . 21
SN1 Mechanism with Alkyl Halides . . . . . . . . . . . . . . 22
E2 Mechanism with Alkyl Halides . . . . . . . . . . . . . . . 23
E1 Mechanism with Alkyl Halides . . . . . . . . . . . . . . . 24
ALLYLIC AND CONJUGATED STRUCTURES
SN1 Mechanism with Allylic Cation Intermediate. . . 25
1,2 and 1,4 Addition to Conjugated Diene . . . . . . . . . 27
Diels-Alder Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . 29
AROMATIC COMPOUNDS
Electrophilic Aromatic Substitution with Halogen . . 31
Electrophilic Aromatic Substitution - Nitration. . . . . 33
Electrophilic Aromatic Substitution - Sulfonation . . 35
Friedel-Crafts Alkylation . . . . . . . . . . . . . . . . . . . . . . 37
Friedel-Crafts Acylation . . . . . . . . . . . . . . . . . . . . . . . 39
Alkylbenzene Oxidation . . . . . . . . . . . . . . . . . . . . . . . 43
Alkylbenzene Halogenation . . . . . . . . . . . . . . . . . . . . 44
Nucleophilic Aromatic Substitution . . . . . . . . . . . . . . 41
ALCOHOLS AND ETHERS
Dehydration of Alcohols . . . . . . . . . . . . . . . . . . . . . . . 45
Reaction of Alcohols with HX – Dehydrohalogenation. . 47
Reaction of Alcohols with Thionyl Chloride . . . . . . . 48
Reaction of Alcohols with Phosphorus Tribromide . . . 49
Oxidation of Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . 50
Alkoxide Ion Formation from Alcohols . . . . . . . . . . . 50
Reaction of Alcohols to form Ethers. . . . . . . . . . . . . . 51
Williamson Ether Synthesis . . . . . . . . . . . . . . . . . . . . 52
Acid Cleavage of Ethers . . . . . . . . . . . . . . . . . . . . . . . 53
Epoxidation of Halohydrins . . . . . . . . . . . . . . . . . . . . 54
Acid Epoxide Ring Opening . . . . . . . . . . . . . . . . . . . . 55
CONTENTS
ALKANES
Thermal Cracking - Pyrolysis . . . . . . . . . . . . . . . . . . . . 1
Combustion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Free Radical Halogenation. . . . . . . . . . . . . . . . . . . . . . 2
ALKENES
Electrophilic Addition of HX to Alkenes . . . . . . . . . . . 3
Acid Catalyzed Hydration of Alkenes . . . . . . . . . . . . . . 4
Electrophilic Addition of Halogens to Alkenes . . . . . . 5
Halohydrin Formation . . . . . . . . . . . . . . . . . . . . . . . . . 6
Free Radical Addition of HX to Alkenes . . . . . . . . . . . 7
Catalytic Hydrogenation of Alkenes . . . . . . . . . . . . . . . 8
Oxidation of Alkenes to Vicinal Diols. . . . . . . . . . . . . . 9
Oxidative Cleavage of Alkenes . . . . . . . . . . . . . . . . . . 10
Ozonolysis of Alkenes . . . . . . . . . . . . . . . . . . . . . . . . . 10
Allylic Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Oxymercuration-Demercuration . . . . . . . . . . . . . . . . 13
Hydroboration of Alkenes . . . . . . . . . . . . . . . . . . . . . . 14
ALKYNES
Electrophilic Addition of HX to Alkynes . . . . . . . . . . 15
Hydration of Alkynes. . . . . . . . . . . . . . . . . . . . . . . . . . 15
Free Radical Addition of HX to Alkynes . . . . . . . . . . 16
Electrophilic Halogenation of Alkynes. . . . . . . . . . . . 16
Hydroboration of Alkynes . . . . . . . . . . . . . . . . . . . . . . 17
Catalytic Hydrogenation of Alkynes . . . . . . . . . . . . . . 17
Reduction of Alkynes with Alkali Metal/Ammonia . . 18
Formation and Use of Acetylide Anion Nucleophiles . 19
Coupling of Alkyl Halides with Gilman Reagents . . . 20
ALDEHYDES AND KETONES
Reduction of Ketones and Aldehydes . . . . . . . . . . . . . 57
Reduction of Aryl Alkyl Ketones . . . . . . . . . . . . . . . . 58
Oxidation of Aldehydes and Ketones . . . . . . . . . . . . . 59
Reaction with Grignard Reagents. . . . . . . . . . . . . . . . 60
The Wittig Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Acetal Formation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
The Wolff-Kishner Reaction . . . . . . . . . . . . . . . . . . . . 65
Reductive Amination . . . . . . . . . . . . . . . . . . . . . . . . . . 67
The Cannizzaro Reaction . . . . . . . . . . . . . . . . . . . . . . 69
Acid or Base Catalyzed Enolization . . . . . . . . . . . . . . 71
Alpha Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Haloform Reaction of Methyl Ketones . . . . . . . . . . . . 75
Aldol Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Claisen Condensation . . . . . . . . . . . . . . . . . . . . . . . . . 79
Conjugate Nucleophilic Addition . . . . . . . . . . . . . . . . 81
Conjugate Addition of Gilman Reagents . . . . . . . . . . 83
CARBOXYLIC ACIDS AND DERIVATIVES
Acid Halide Formation . . . . . . . . . . . . . . . . . . . . . . . . 85
Fischer Esterification . . . . . . . . . . . . . . . . . . . . . . . . . 86
Use of Carboxylate Anion Nucleophile to form Esters . 87
Hydrolysis of Acid Halides . . . . . . . . . . . . . . . . . . . . . 88
Reaction of Acyl Halide with Ammonia or Amine . . . 89
Esterification of Acid Halides . . . . . . . . . . . . . . . . . . . 90
Esterification of Acid Anhydrides . . . . . . . . . . . . . . . . 91
Saponification of Esters . . . . . . . . . . . . . . . . . . . . . . . 92
Nitrile Hydrolysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Nitrile Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Hofmann Rearrangement . . . . . . . . . . . . . . . . . . . . . . 95
Thermal Cracking - Pyrolysis
Alkanes
heat
CH3(CH2)xCH3
CH3CH3
+
CH4
+
H 2C
CH2
+
etc
Lower carbon number
cleavage product mixture
High carbon number
petroleum distillate
A process carried out on petroleum distillates at high temperature and pressure, thermal cracking yields lower carbon
number product, probably by means of a radical (homeolytic) mechanism. The thermodynamics are dominated by the
entropy change rather than the enthalpy change, especially if the volume is kept constant.
Combustion
Alkanes
CnH2n + 2
+
(3n + 1)/2 O2
nCO2
Oxygen
Carbon dioxide
Hydrocarbon
+
(n + 1) H2O
Water
Many organic molecules can undergo combustion, forming carbon dioxide and water in an exothermic reaction. The heat
released in the combustion reaction (the enthalpy change) can be used as an indicator of the relative stability of isomers.
Combustion is more exothermic for unbranched alkanes, for example, than for their branched isomers, and we can infer that
the branched isomer is the more stable. Such comparisons are often used in organic chemistry. For example, ketones are
pointed out as more stable than their aldehyde isomers. The more stable the isomer, the lower the heat of combustion.
1
Free Radical Halogenation
Alkanes
RCH3
+
Alkane
Initiation
X2
hv
X2
X.
2 X.
Halide radical
+
Halide radical
X2
+
Halogen
Termination
X.
HX
Hydrogen
halide
Alkyl halide
Halogen
Propagation
+
RCH2X
Halogen
RCH2.
RCH3
Alkane
RCH2.
RCH2X
Alkyl radical
+
X. +
Alkyl halide
RCH2.
X.
RCH2. +
+
HX
Alkyl radical
+
X.
Halide radical
RCH2X
X2
RCH2.
RCH2CH2R
Because of the relative stability of alkyl radical intermediates, selectivity in free radical halogenation favors tertiary over
secondary over primary carbon radicals. Bromination, though, is more selective than chlorination, because the proton
extraction step is more endothermic in bromination than chlorination. This follows from Hammond’s postulate, which
governs the correlation between proximity in energy and proximity in structure among transition states and intermediates.
Halogenation is the classic illustration of Hammond’s postulate. Because the activated complex prior to formation of
the alkyl radical intermediate must have more radical character for bromination compared to chlorination, the effect of
substitution in stabilizing radicals plays a greater roll with bromination leading to a higher degree of regioselectivity.
2
Electrophilic Addition of HX to Alkenes
Alkenes
X
R
H
C
C
Alkene
H
H
R
+ HX
Hydrogen
halide
C
C
C
H
H
Alkene
+
R
H C
δ+
R
H
C
C
Br
H
Carbocation
Intermediate
δ-
H
H
Br
H
H
R
Br-
+
H
H
Alkyl halide
+ HBr
Hydrogen
halide
C
C
H
H
R
H
H
C
H
C
H
H
Alkyl halide
H
Because tertiary and secondary carbocations are more stable than primary carbocations, Markovnikov addition is observed
in the electrophilic addition of HX to alkenes, so the product formed is the one with the halogen substituent upon the more
highly substituted carbon. Also, rearrangement (hydride or methyl shift to form a more stable carbocation) might occur,
typical of reactions that have a carbocation intermediate. Remember that electrophilic addition will not be observed in the
presence of peroxides. Peroxides initiate anti-Markovnikov addition via free-radical addition. An interesting fact about
electrophilic addition of HX to alkenes, is that the more acidic the hydrogen halide, the more electrophilic it will be. HF,
for example, only a weak acid, does not react.
3
Acid Catalyzed Hydration of Alkenes
Alkenes
H
R
H
C
H20, H+
H
H
C
Alkene
R
Aqueous
Sulfuric acid
C
H
H
R
H
C
C
H2
H
H
R
H
δ+
C
C
Alcohol
O
H
0, H+
H
O
H
H
δ+
H
H
+
R
C
H C
H
Carbocation H
intermediate
H
H
C
Alkene
H
R
H
O+
C
H
C
H
H
H
Oxonium ion
H
R
H
O
H
H
O
C
+
C
H
H
Alcohol
H
+
H+
Markovnikov’s rule is followed in hydration of alkenes. Therefore, in the alcohol product, the hydroxyl group is located
upon the more highly substituted carbon. Watch for rearrangement of the carbocation intermediate, if methyl or hydride
shift is probable. Note that this reaction is the reverse of acid catalyzed dehydration of alcohols.
4
Electrophilic Addition of Halogens to Alkenes
R
H
C
H
H
C
Alkene
Halogen
molecule
C
H
H
C
+ Br2
R
H
δ+
C
H
X
R
+ X2
C
C
H
H
X
Vicinal dihalide
Br
R
H
Alkenes
Br
δ-
Br
+
R
C
H C
H
H
C
H
Br-
+
H
Alkene
+
Br
C
δ+
C
H
H
H
Cyclic halonium
ion intermediate
R
Br-
+
R
Br
C
R
C
H
H
H
Br
H
Br
C
C
Br
H
H
Vicinal dihalide
δ-
In analysis of the addition of halogen to an alkene, the anti stereospecificity of the dihalide product serves as evidence that
the mechanism occurs via a cyclic halonium ion intermediate. For problem solving, this anti stereospecificity is especially
pertinent in the cases of addition to cyclic alkenes or where the product carbons are chiral.
5
Halohydrin Formation
R
H
Alkenes
C
H
H
C
Alkene
R
X2
H2O
C
H
H
C
+ Br2
R
H
Halogen
δ+
C
C
C
H
OH
Halogen in
aqueous conditions
H
+
HX
Halohydrin
Br
R
H
X
H
Br
δ-
Br
+
R
C
H C
H
H
C
H
Br-
+
H
Alkene
+
Br
C
+
H
H
H
Cyclic halonium
ion intermediate
R
R
R
H
C
C
H
H
Br-
H
R
H
O
H
C
Br-
Br
C
Br
H
+O
H
Br-
+
C
H
C
OH
R
H
Br
H
C
C
+O
H
H
H
H
H
Br-
Br
C
H
H
+
HBr
Halohydrin
In aqueous solution, electrophilic addition of halogen results in the formation of halohydrin. Water performs the ring opening
instead of halide ion, which opens the ring in non aqueous halogenation. Water addition is preferential for the more highly
substituted carbon, which receives a bit more of the distributed positive charge in the halonium ion than the other carbon.
6
Free Radical Addition of HX to Alkenes
H
H
C
Alkene
R
O
Alkyl
radical
peroxide
aqueous conditions are
sufficient to supply peroxide
hv
2R
H
H
+
Br
H Alkyl halide
Halide
radical
O
ROH
H Br
Hydrogen
halide
H
H
C
C
C
Alkoxy radical
C
C
Alkene
Br
R
H
R
H
+
H
Br
Hydrogen halide
H
+
Br
Halide
radical
H
C
C
H
H
C
R
H
Br
hv
HBr
R
+
+
Br
Br
+
O O
Peroxide
initiator
Alkoxy R
radical
Halide
radical
Hydrogen halide
R
H
C
Alkenes
Br
R
H Alkyl
radical
R
H
C
C
H
H
Alkyl halide
H
+
Br Halide
radical
In the presence of a peroxide initiator, hydrogen halide adds to alkene via an anti-Markovnikov, free-radical mechanism.
The carbanion radical product of the first propagation step will be more stable if the carbon with the lone electron, the
radical carbon, is highly substituted. For this reason, the halogen atom binds to the less substituted carbon, in other words,
anti-Markovnikov addition.
7
Catalytic Hydrogenation of Alkenes
RCH
CH2
+
H
Alkenes
H
R
H
C
H
C
H
catalyst
H
H
catalyst
H
Hydrogen
Alkene
H
R
C
C H
RCH2CH3
Alkane
H
H
catalyst
catalyst
+
R
H
C
H
H
C
H
H
Hydrogenation of alkenes occurs in the presence of a metal catalyst, a syn addition process. The two hydrogen atoms add to
the same face of the double bond. Furthermore, if one side is more hindered than the other, addition is stereoselective for the
less hindered side. Hydrogenation is exothermic, and relative heats of hydrogenation can be used to infer the relative stability
of double bonds in different contexts. The more stable the double bond, the lower the heat of hydrogenation will be.
8
Oxidation of Alkenes to Vicinal Diols
Alkenes
O
O
Mn
Potassium permanganate
in basic solution
KMnO4
O
R
C
C
C
H
C
C
OH
H
H
H
Vicinal diol
H
Cyclic manganate
or osmate intermediate
H
H
C
OH
R
H 2O
O
H
R
H
-
Alkene
O
OsO4
Osmium tetroxide
O
Os
O
R
O
C
C
H
OH
R
NaHSO3
H 2O
C
OH
H
H
H
Vicinal diol
H
H
C
Both of the above oxidation mechanisms proceed by syn addition. To accomplish anti hydroxylation of alkenes, the
method to employ is hydrolysis of epoxides. As shown above, in basic conditions, oxidation of alkene with potassium
permanganate results in formation of vicinal diol, but with acidic or neutral conditions, complete cleavage occurs to produce
carboxylic acids or ketones (or carbon dioxide).
9
Oxidative Cleavage of Alkenes
R
H
C
Alkenes
Alkene
O
KMnO4
H
H
C
R C OH
H 2O
Potassium
permanganate
in acid or neutral
solution
+
CO2
Carboxylic acids
(CO2 from terminal alkene carbon)
In basic conditions, treatment of alkene with potassium permanganate forms a vicinal diol. Oxidative cleavage by
permanganate in neutral or acidic conditions, however, leads to cleavage to form carbonyl compounds by means of the
same cyclic manganate ester intermediate. Where ozonolysis, another method of oxidative cleavage of alkenes, produces
an aldehyde or formaldehyde, cleavage with permanganate produces a carboxylic acid or carbon dioxide respectively.
Ozonolysis of Alkenes
R
H
C
Alkenes
O
C
O
O3
H
H
CH2Cl2
Alkene
Ozone
R
H
O O
C
C
O
Ozonide
H
H
R
O
C
H
C
H
H
Zn
CH3COOH
Reducing
agent
Molozonide
O
O
RCH
+
HCH
Aldehyde mixture
If aldehyde product is desired over carboxylic acid, ozonolysis is preferred in cleavage of alkenes over potassium
permanganate cleavage. Also, with terminal alkenes, the end carbon leads to formaldehyde molecule. Cleavage of such
alkenes by potassium permanganate forms carbon dioxide.
10
Allylic Halogenation
H 3C
H
C
H
C
C
Alkene
C
H
C
C
H
H3C
HC C
C
H
H
CC
C
C
H
C
H3C
H
C
H 3C
H
hv
H3C
H
C
H
H
C
H
C
Br
H3C
CH
or
H3C
H
H
C
C
H
H3C
H
C
H3C
H
H
H H
C
H
Br
Br
C
C
H
H
C
H
H
H
H
C
Br
Resonance stabilized allylic
radical
H
H
H
H
C
C CCC
H
H
H
Br
Br
or
H
C
H3C
H
H
H
C
H
H
C
Br
H
C
C
H
H 3C
H
C
C
H
continued
Br
H
C
C
C
C
H
Allyl halide mixture
C
C
C
H
Br
H3C
H
or
H
H
Br
Br
H
C
Br
Br
+
H3C
H
H
H
C
Br
Br2
H
H
C
C
H3C
H
H
H
H H
C
H H
C
Br
H 3C
H
Halide radical
2 Br
C
C
Br
Br
H
C
H
H
C
Halogen
H
hv
C
Halide radical
C
H3C
H
H3C
H
hv
H
+
HBr
Br2
H 3C
H
H
H
H3C
H
C
Br2
2 Br
Alkene
H 3C
H
H
H
hv
Br2
Halogen
H3C
H
Alkenes
11
+
Br
+
Br
H
C
H
H
C
H
H
Br
C
C
H
Br
or
H
H3C
H
C
C
H
C
H
H
Allyl halide mixture
At high temperatures chlorine and bromine react with alkenes larger than ethylene by free-radical substitution. (At low
temperatures, electrophilic addition to produce vicinal dihalides occurs). Halogenation is selective for two particular
carbons due to the resonance stabilization that can occur with an allylic radical intermediate.
12
Oxymercuration-Demercuration
Alkenes
OH
R
H
C
H
H
C
R
1. Hg(OAc)2 in THF, H2O
C
2. NaBH4, OH-
C
H
H
H
Alcohol
+
Hg(O2CCH3)2
H
O
C
O
O
-OC CH
+
H
H +
R C
3
H
R
H
O +
C
O
C
H
H
O
R
H
C
H
3
C
H
H
H
C
O
C
H
HgOCCH3
C
H
HgOCCH3
H
-
H3CC O
H
O
HgOCCH3
Mercuric acetate H
carbocation Intermediate
H
R
Mercuric
acetate
Alkene
+
H
R C
C
H
H
C
O
C
O
H
R
H
g
O
C
C
H
3
O
Alkene
H
R
H
O+
O
HgOCCH3
C
C
H
H
H
Oxonium Intermediate
H
O
H
HgOCCH3
O
+
C
H
NaBH4, OH-
HOCCH3
H
R
H
O
C
C
H
H
H
Alcohol
Hydroxyalkyl mercuric acetate
Oxymercuration-demercuration is usually preferred over acidic hydration to form Markovnikov alcohols from alkenes.
The reaction begins with electrophilic approach onto the alkene by mercuric acetate to form a mercuric acetate carbocation
derivative, which can rearrange. Hydration then occurs followed by a demercuration step with sodium borohydride.
13
Hydroboration of Alkenes
H
R
C
C
Alkene
Alkenes
-OH
H2O2
BH3
THF
H
H
H
H
H
R
C
C
BH3
THF
H
H
Alkene
H
R
C
δ+
B
C
δ-
H
OH
H
C
R
C
Alcohol
H
H
H
H
H
H
H
H
B
H
C
R
C
H
H
-OH
H2O2
Alkylborane
-OH
H2O2
H
H
C
OH
C
H
H
R
Alcohol
Hydroboration-oxidation of an alkene forms an alcohol by means of a mechanism leading to anti-Markovnikov regioselectivity. Furthermore, the geometry of the activated complex produces a syn addition product. Note as a point of general
interest that borane derives its electrophilicity from a vacant p orbital.
14
Electrophilic Addition of HX to Alkynes
R
C
CH
Alkyne
HX
no peroxides
Alkynes
R
X
H
C
CH
Vinyl
halide
Hydrogen
halide
HX
no peroxides
R
Hydrogen
halide
X
H
C
CH
X
H
Geminal
dihalide
Electrophilic addition to alkynes is very similar to the analogous reactions upon alkenes, although two additions occur.
Markovnikov addition is observed. Due to the greater instability of vinylic carbocations, however, alkynes are somewhat
less reactive than alkenes.
Hydration of Alkynes
C
R
Alkynes
CH
Alkyne
H2O, H2SO4
HgSO4
OH H
C
R
O
CH
Enol
Aqueous sulfuric acid
with mercuric sulfate
catalyst
C
R
Ketone
H
CH
H
The vinylic alcohol, or enol, intermediate forms when an alkyne is hydrated which immediately rearranges to form a ketone.
This process of rearrangement is called keto-enol tautomerism. Due to decreased reactivity of alkynes for electrophilic
addition compared to alkenes, acid catalyzed hydration of alkynes requires a mercuric sulfate catalyst.
15
Free Radical Addition of HX to Alkynes
R
C
HX
CH
Alkyne
peroxides
Alkynes
R
H
X
C
CH
Vinyl
halide
Hydrogen halide
with peroxides
HX
peroxides
R
Hydrogen halide
with peroxides
H
X
C
CH
H
X
Geminal
dihalide
As with alkenes, free radical addition occurs when hydrogen halide reacts with alkynes in the presence of peroxides. Two
anti-Markovnikov additions occur leading to a geminal dihalide product.
Electrophilic Halogenation of Alkynes
R
C
C
Alkyne
R'
X2
CCl4
Halogen
molecule
Alkynes
R
X
C
C
Vicinal vinylic
dihalide
X
R'
X2
CCl4
X
X
C
R
R'
C
X
X
Tetrahaloalkane
Bromine and chlorine add with trans stereochemistry to an alkyne. The process may be concluded at the trans vinylic
dihalide, or if excess halogen is employed, addition can be made to occur a second time.
16
Hydroboration of Alkynes
R
C
Alkynes
-OH
BH3
THF
CH
Alkyne
R
H 2O 2
H
OH
C
CH
R
Alkyne
Borane in tetrahydrofuran solution
followed by aqueous hydrogen
peroxide in basic solution
H
O
C
CH
H
Aldehyde
Due to its anti-Markovnikov selectivity, hydroboration-oxidation of a terminal alkyne leads to an enol which rearranges to
form a terminal aldehyde. The alternative method, hydration (either acidic hydration or oxymercuration-demercuration)
applied to such an alkyne would result in a ketone.
Catalytic Hydrogenation of Alkynes
RC
H
+
CR'
Alkyne
Alkynes
catalyst
H
C
H
R'
C
C
C H
R
H
C
R'
H
C
Cis alkene
R'
R
R
H
Hydrogen
H
+ R
H
catalyst
catalyst
catalyst
C
C
R'
H
Catalytic hydrogenation occurs by syn addition resulting in the formation of a cis alkene. Metal-ammonia reduction, an
alternative hydrogenation method, yields trans alkenes.
17
Reduction of Alkynes with Alkali Metal/Ammonia
R
C
1. Na, NH3
2. H2O
R'
C
Alkyne
R
C
C
Alkyne
C
R'
C
Alkenyl radical
R
-
C
Alkenyl anion
C
R
H
Sodium or Lithium
in Ammonia
R
C
C
R'
Alkenyl anion
radical
R
Alkynes
H
R'
H
R'
+
+
Na
Sodium
R
Na
Sodium
H NH2
Ammonia
H
R'
C
Trans alkene
-
+
C
C
R'
Alkenyl anion
radical
+
Na
Sodium ion
H
C
C
R'
Alkenyl radical
R
H NH2
Ammonia
+
C
R
-
C
C
Alkenyl anion
R
H
C
H
R'
C
Trans alkene
H
R'
+
-
NH2
Amide ion
+
+
Na
Sodium ion
+
-
NH2
Amide ion
Of two alternative means of carrying out the hydrogenation of an alkyne, catalytic hydrogenation yields a cis alkene, while
metal-ammonium reduction yields a trans alkene. The latter occurs due to the trans stereochemistry of the alkenyl anion
radical intermediate in metal/ammonia reduction..
18
Formation and Use of Acetylide Anion Nucleophiles
H
H
R
C
C
CH3CH2
+
H
Alkyne
Alkynes
C
NH2Na
Br
R
Sodium amide
C
C
CH2CH3
C
Alkylated alkyne
H
H
Primary alkyl halide
R
C
C
+
NH2Na
+
H
Alkyne
Na
R
C
-
C
C Na
+
+
Acetylide anion
Sodium amide
+
C
R
H
H
-
CH3CH2
Acetylide anion
NH3
Ammonia
C
R
Br
C
C
C
H
H
Primary alkyl halide
CH2CH3
+
NaBr
Alkylated alkyne
An acetylide anion is formed by reaction of a terminal alkyne with sodium amide, which is a very strong base. The acetylide
anion can then perform nucleophilic substitution upon methyl and primary alkyl halides. (Being a strong base, acetylide
anion would react by elimination with secondary and tertiary alkyl halides, rather than by nucleophilic substitution).
19
Coupling of Alkyl Halides with Gilman Reagents
H
CH3CH2
CH3
C
R
C
+
Br
CH3
H3C
R
Alkyl halide
R
2 Li
+
X
R
R
2 R
Li
H
-
+
Cu Li
CH3CH2
Li
+
LiBr
+
CH3
C
C
R
CH3
H3C
Gilman reagent
(Lithium dialkylcuprate)
- +
Cu Li
CuI
+
Alkyl Halides
Alkyl substituted
product
Formation of
Gilman reagent
(Lithium dialkylcuprate)
LiI
R
R
CH3CH2
C
H3C
H
CH3
R
C
+
Br
CH3
R
Alkyl halide
H
CH3CH2
C
H3C
-
+
Cu Li
Gilman reagent
CH3
CH3CH2
C
H3C
CH3
Cu
-
R
Br Li
CH3
C
+
H
Mechanism isn’t
fully understood
C
R
CH3
Alkyl substituted product
Lithium dialkylcuprates react with alkyl halides via a substitution mechanism which is not well understood. It appears that
nucleophilic attack by the negatively charged copper atom leads to an intermediate which fragments to produce the alkane
product. Reactions such as this which form new carbon-carbon bonds are extremely useful in organic synthesis.
20
SN2 Mechanism with Alkyl Halides
Alkyl Halides
H
H3C
C
H
-
Nu
Br
Nu
H
H
Alkyl halide
H3C
H
C
C
Substitution product
-
H3C
Nu
Br
CH3
-
Nu
H
H
H
C
Br
Nu
H
C
H
CH3
Nucleophilic bimolecular substitution (SN2) occurs mainly with primary and sometimes secondary alkyl halides. Because of the geometry of the bimolecular mechanism, the reaction always takes place with inversion of configuration. A
polar aprotic solvent like DMSO is used, because a protic solvent like water will over-stabilize the nucleophile through
solvation and promote E1 elimination instead, or the SN1 mechanism. Both E2 and SN2 prefer polar aprotic solvents.
With primary alkyl halides, however, regardless of solvent, the SN2 mechanism almost always predominates. This occurs
even if the nucleophile is a strong Bronsted base. With primary alkyl halides, only strong, bulky (hindered) base like
tert-butoxide can cause elimination (E2) to occur rather than SN2 substitution. The SN2 mechanism is more difficult to
achieve with secondary alkyl halides than with primary. Instead of substitution, strong bases react by elimination (E2)
with secondary alkyl halides. SN2 substitution is possible with secondary alkyl halides if the solvent is polar and aprotic
and the nucleophile is a weak base, like cyanide ion or alcohol. SN2 substitution does not occur with tertiary alkyl halides,
which are too hindered for nucleophilic attack, and it does not occur with vinylic or aryl halides.
21
SN1 Mechanism with Alkyl Halides
H 3C
H 3C
C
H 3C
H3C
H3C
C
H3C
Alkyl Halides
H 3C
H 3C
C
-
Nu
Br
H 3C
Alkyl halide
H3C
H3C
C
-
Nu
Br
Nu
H3C
+
C
CH3
CH3
attack from either side
Attack from either side
+
C
CH3
CH3
Carbocation
intermediate
H3C
Br
H3C
Alkyl halide
-
Nu
Substitution product
H3C
H3C
C
Nu
H3C
Substitution product
With secondary and tertiary alkyl halides, SN1 and E1 occur in protic solvents with weakly basic nucleophiles. The reactions
occur more easily with tertiary alkyl halides, if the nucleophile is not a strong base. The SN1 mechanism is always in competition with E1 because both occur under the same reaction conditions. These conditions are as follows: the alkyl halide is
secondary and tertiary (especially); the solvent is protic, to stabilize the intermediate stage (consisting of the carbocation and
departed leaving group); and the nucleophile is a weak base. With a strong base, remember that E2, bimolecular elimination
is favored, not SN1 or E1 (with both secondary and tertiary alkyl halides). The SN1 mechanism, because it proceeds through
a trigonal planar carbocation intermediate, will not lead to a product that is composed of pure enantiomer, as would happen if
only SN2 occurred. Although the nucleophile prefers the side of the carbocation opposite the leaving group, attack can occur
onto either face of the carbocation, and also rearrangement can occur in the carbocation intermediate.
22
E2 Mechanism with Alkyl Halides
H
H3C
H3CH2C
H
C
Alkyl Halides
-
CH3
C
H3C
H3CH2C
Base
Br
C
C
Alkene
H
CH3
Alkyl halide
-
H
H3C
H3CH2C
H
C
C
Base
Base
CH3
H
H3C
H3CH2C
Br
H
C
C
CH3
H3C
H3CH2C
C
C
H
CH3
Br
anti periplanar transition state
Strong bases react with secondary and tertiary alkyl halides by the E2 (bimolecular elimination) mechanism. As with SN2,
the best solvent for E2 is polar and aprotic. While SN2 predominates with primary alkyl halides even if the nucleophile
is a strong base, E2 will always predominate with a strong base on secondary and tertiary alkyl halides (if weak base is
used with such alkyl halides, in protic solvent, E1 and SN1 will be favored.) Bimolecular elimination obeys Zaitsev’s rule,
i.e. forming as highly substituted an alkene as possible. Also, in the activated complex of the E2 mechanism, the proton
abstracted by the base is anti-periplanar to the leaving group. Such stereochemistry, in some instances, will determine
whether product will be cis or trans, and with ring alkyl halides, the anti-periplanar geometry of the transition state will
determine the conformation of alkene ring product. On rings, both the proton and leaving group must be axial to be also
anti-periplanar.
23
E1 Mechanism with Alkyl Halides
H3C
H3C
C
Alkyl halide
H3C
H3C
C
Alkyl halide
H3C
Alkyl Halides
-
H
C
H
Base
Br
H3C
H3C
H3C
C
-
Base
Br
C
Alkene
H3C
Br
CH3
CH3
+
C
CH3
CH3
Carbocation
H 3C
-
Base
H
H
C
H
+
C
CH3
CH3
CH
H
C C CH3
H
3
Alkene
With secondary and tertiary alkyl halides, the E1 and SN1 mechanisms occur in protic solvents with weakly basic nucleophiles.
The reactions occur more easily with tertiary alkyl halides if the nucleophile is not a strong base. The E1 mechanism is always in
competition with SN1 because both occur under the same reaction conditions. These conditions are as follows: the alkyl halide
is secondary and tertiary (especially); the solvent is protic, to stabilize the intermediate stage (consisting of the carbocation and
departed leaving group); and the nucleophile is a weak base. With a strong base, remember that E2, bimolecular elimination,
not E1 or SN1, is favored with both secondary and tertiary alkyl halides. E1 product is most often obtained in mixture with SN1,
and with a very weak base. With a moderately vigorous nucleophile (like ethanol), SN1 will predominate.
24
SN1 Mechanism with Allylic Cation Intermediate
H 3C
H
C
C
Alkene with allylic
leaving group
H3C
H
C
H
C
C
H 3C
H
C
C
H
H3C
H
H3C
H
C
C
C
H 3C
H
HBr
H3C
H
C
H3C
H
H3C
H
C
C
OH
H
H
C
OH
H 3C
H
C
H
C
C
C
H
C
H
H
+C H
H
H
Br
C
H3C H
H
H C
C
C
+
H
HH3C
HH
H
C
+
OC
H Br H
H
C
H
H
H
H
C
+
H3COHC
HH
C
C
H
H Br
H
H
C
Allylic carbocation
intermediate
continued
25
-
H
+
O+
H
H
H3C
H
H
H
C C
+
C
Br H
H H
C Br C C H
+ H
C
C
OH
Br
H
H
H
Alkene mixture
+
H3C C
H H C
H
C H
+ H
C
H
Br
C
H 3C
H
C C
Br H
+
H
H
+
HBr
O+
H
H
H
C
H
C
C
H
H3C
H
HBr
H
H
C
H
H3C OH
C
C
H
HH
+C H
C
C
Br
H
HHC
H3C
H
C
OH
H
H
C Oxonium
C ion
C
H3C
H
HBr
H
Alkene with allylic
leaving group
H3C
H
H
H
C
Allylic and Conjugated Structures
H3C
H
C
C
H
C
H
H
C
H
+
HH3C C
H H C
H3C
H
+
C
C
H
C
H
H
C
H
H
H
O+
H
-
Br
H3C
H
C
C
H
C
H
Br
+
H
H3C
H
C C
Br H
C
H
H
Alkene mixture
The departure of an allylic leaving group is eased by resonance stabilization within the allylic carbocation intermediate.
Allyl halides, for example, are candidates for SN1 substitution, even if the carbon is primary.
26
1,2 and 1,4 Addition to Conjugated Diene
Allylic and Conjugated Structures
H 2C
H 2C
CH
Br2
CH2
CH
Conjugated diene
CH
Br
Br
CH
CH2
+
Br
H 2C
CH
Br
CH
CH2
CH
+
Conjugated diene
H2C
Br2
H 2C
H 2C
CH
CH2
CH
H2C
CH
+
CH
CH2
Br CH Br
CH
Br
Br
CH2
H 2C
Br
CH
Halogen
Br2
1,4 product
CH2
CH
Br
H2C
1,2 product
CH2
CH
+
+
H2C
BrBr
CH
CH
Allylic carbocation
intermediate
CH
CH
CH
CH2 2
+
Br
-
continued
Br
H2C
H2C
CH
CH
CH2
CH
+
CH
+
Br2
Br
Br
H2C
CH
CH
CH2
H2C
CH
+
CH
CH2
H2C
CH
CH
+
CH
Br
Br
CH
CH2
1,2 product
CH2
Br
or
H2C
+
CH
H2C
+
H2C
CH2
CH
CH
H2C
+
CH
H2C
CH2
CH
CH2
Br
CH
CH
CH2
+
Br
-
Br
CH
CH2
Br
Br
+
Br
Br
Br
or
CHBr
2
CH
CH
+
H2C
Br
27
Br
Br
Br
Br
H2C
Br
CH
CH
CH2
1,4 product
Instead of forming the triangular halonium ion typical of electrophilic addition of halogen to alkene, halogen adds to a
conjugated diene to form a resonance stabilized allylic carbocation intermediate. The two resonance forms of the resonancestabilized allylic carbocation lead respectively to two different possible products, the 1,2 and 1,4 products of addition. A
very interesting and significant discussion arises from the fact that while the pathway to the 1,4 product occurs with greatest
free energy decrease, the pathway to the 1,2 product is achieved with less activation energy. This means that formation of
1,4 product is favored thermodynamically, but 1,2 product is favored kinetically. Higher temperatures, ‘thermodynamic
conditions’, promote the formation of 1,4 product, because if a larger fraction of the molecules possess activation energy
for either pathway, as would occur at higher temperature, a large portion of diene concentration continuously moves down
the 1,4 pathway and forms the more stable 1,4 product. Lower temperatures, however, are ‘kinetic conditions’. At lower
temperatures, fewer reagent diene particles have enough energy to get over the activated complex energy hump to form
the 1,4 product, so 1,2 addition predominates.
28
Diels-Alder Reaction
H
H
Allylic and Conjugated Structures
C
C
H
CH2
+
CH2
H3C
Conjugated diene
C
C
C
H
N
H
H3C
Dienophile
C
N
H
Diels-Alder adduct
H
H
C
C
H
CH2
+
CH2
H3C
H
H3C
C
C
C
C
H
N
H
H3C
C
N
H
N
H
29
A conjugated diene, such as 1,4 butadiene, combines with an alkene in the Diels-Alder reaction. Especially favored are
those alkenes which are dienophiles (having electron withdrawing substituents). The Diels-Alder reaction is a pericyclic
process. In other words, it occurs by means of a particular type of transition state in which electrons simultaneously redistribute in a cyclic manner. The process starts with the bonding overlap of the terminal π lobes of the conjugated diene
with those of the alkene. The stereochemistry of the Diels-Alder reaction is informed by concerns particular to pericyclic
reactions. The overlap occurs between the HOMO of one of the species (Highest Occupied Molecular Orbital) and the
LUMO of the other (lowest unoccupied molecular orbital). Cycloaddition reactions can be antarafacial or, suprafacial,
which means that the reagents must rotate for orbital overlap or not, respectively. Diels-Alder is of the suprafacial type, so
it takes place more easily, i.e. at lower temperatures. Note that if the alkene reagent is trans, the derived ring substituents
will also be trans.
30
Electrophilic Aromatic Substitution with Halogen
Aromatic Compounds
Br
+
FeBr3
Br2
Ferric bromide
catalyst
Halogen
Aromatic ring
Halogenated
aromatic ring
Br
+
Aromatic ring
Br
Br2
Halogen
Br
FeBr3
Ferric
bromide
catalyst
Br
H
H
+
Br
H
Br
+
Resonance stabilized
carbocation intermediate
-
+
Br
H
Br
-
Br
+
+
HBr
Halogenated
aromatic ring
31
Electrophilic aromatic substitution of bromine is assisted by a ferric bromide catalyst, ferric chloride for chlorination.
Unlike electrophilic addition to alkenes, a catalyst is necessary to enhance the electrophilicity of the halogen to react with
an aromatic ring because aromatic π electrons are more stable than vinylic π electrons, Electrophilic aromatic substitution
begins with the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate
is formed, a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions
and one para relative to the halide substituent. After this addition, a proton departs, completing the overall substitution
with aromaticity restored.
Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an
original halogen substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents,
the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or
destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent
already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will
occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents
destabilize a carbocation, so the new substitution will most likely be meta. Being electronegative, halide substituents
are ring deactivating by induction. However, nonbonded pairs of electrons are present on the halide substituent which
can donate by resonance. Because of these combined effects, a halide substituent, already present on the ring, is a ring
deactivating, ortho-para director for further electrophilic aromatic substitution.
32
Electrophilic Aromatic Substitution - Nitration
Aromatic Compounds
NO2
HNO3
H2SO4
Aromatic ring
Nitric acid/
sulfuric
acid mixture
Nitrated ring
+
+
NO2
Nitronium
ion
+
HNO3
H2SO4
Sulfuric acid
Nitric acid
-
HSO4
+
H2O
+
NO2
+
+
NO2
Nitronium ion
Aromatic ring
NO2
H
NO2
H
+
NO2
H
+
Resonance stabilized
carbocation intermediate
+
H
NO2
H
O
NO2
H
+
+
+
H3O
Nitrated ring
33
2+
The electrophile for the nitration reaction, the nitronium cation (NO ), is generated by reaction of nitric acid (HNO3) with
sulfuric acid (H2SO4). Electrophilic aromatic substitution begins with the addition of the electrophile into the aromatic π
system of the ring. A conjugated, carbocation intermediate is formed, a resonance combination of three forms, concentrating
positive charge at three locations, the two ortho positions and one para. After this addition, a proton departs, completing
the overall substitution with aromaticity restored.
Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an
original nitro substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents,
the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or
destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent
already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will
occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents
destabilize a carbocation, so the new substitution will most likely be meta. Nitro is such a substituent. Containing only
electronegative atoms, nitro is electron-withdrawing by induction. Furthermore, the nitrogen atom in nitro also has no
electron pairs capable of donating into the ring by resonance. A nitro group, already present on the ring, is a ring deactivating, meta director for further electrophilic aromatic substitution.
(Some substituents, such as halogen or hydroxide, even though being electronegative (electron withdrawing inductively),
will donate electron pairs to the ring by resonance and are still ortho para directing, though deactivating by induction.)
34
Electrophilic Aromatic Substitution - Sulfonation
Aromatic Compounds
SO3H
SO3
H2SO4
Aromatic ring
Fuming sulfuric
acid
Sulfonated ring
O
S
H2SO4
SO3
Sulfur trioxide
+
OH
+
O
Aromatic ring
SO3H
H
+
SO3H
H
Resonance stabilized
carbocation intermediate
+
SO3H
H
+
H
SO3H
H
O
H
SO3H
+
+
+
H3O
Sulfonated ring
35
Sulfur trioxide, the electrophile in sulfonation of benzene, is present in small amounts in normal sulfuric acid and sulfonation
of benzene will occur with sulfuric acid. Frequently, though, a solution of sulfur trioxide and sulfuric acid is used (called
oleum or fuming sulfuric acid). Electrophilic aromatic substitution begins with the addition of the electrophile into the
aromatic π system of the ring. A conjugated, carbocation intermediate is formed, a resonance combination of three forms,
concentrating positive charge at three locations, the two ortho positions and one para. After this addition, a proton departs,
completing the overall substitution with aromaticity restored.
Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an original
sulfonate substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents, the
location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution
occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or
destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent
already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will
occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents
destabilize a carbocation, so the new substitution will most likely be meta. Sulfonate is such an electron withdrawing
substituent. Containing only electronegative atoms, sulfonate is electron-withdrawing by induction. Furthermore, the
sulfur atom has no lone electron pairs to donate into the ring in resonance. A sulfonate group, already present on the ring,
is a ring deactivating, meta director for further electrophilic aromatic substitution.
36
Friedel-Crafts Alkylation
Aromatic Compounds
+
Cl
H3C
Alkyl halide
AlCl3
Cl
Aluminum
trichloride
H 3C
Aromatic ring
H3C
H
C
CH(CH3)2
H 3C
H
C
Alkylated ring
Alkyl halide
AlCl3
H
Aluminum
trichloride
C
+
CH3
CH3
-
AlCl4
Carbocation
H
+
Aromatic ring
H
C
+
C
+
CH3
CH3
CH3
CH3
Carbocation
CH(CH3)2
H
+
Resonance stabilized
carbocation intermediate
CH(CH3)2
H
+
CH(CH3)2
H
+
CH(CH3)2
H
Cl
CH(CH3)2
+
+
HCl
Alkylated ring
37
The aluminum chloride catalyst in Friedel-Crafts alkylation facilitates carbocation formation from an alkyl halide, preparing
the species as an alkyl electrophile for electrophilic aromatic substitution. Electrophilic aromatic substitution begins with
the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate is formed,
a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions and one
para. After this addition, a proton departs, completing the overall substitution with aromaticity restored.
Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an original
alkyl substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents, the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs
ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or destabilizes
a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent already present
is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will occur ortho or
para to such electron donating substituents already present on the ring. Electron withdrawing substituents destabilize a
carbocation, so the new substitution will most likely be meta. Alkyl groups are electron-donating by induction. Because
carbon is only moderately electronegative, alkyl groups have negative charge to share with the positive carbon in the orthopara resonance form. An alkyl group, already present in the ring, is ring activating and ortho-para directing.
38
Friedel-Crafts Acylation
Aromatic Compounds
R
O
+
R
C
AlCl3
Cl
Aluminum
trichloride
Acyl halide
Aromatic ring
O
C
Acylated ring
O
R C
Cl
Acylated ring
AlCl3
+
C
R
Aluminum
trichloride
R
O
Carbocation
+
O
C
+
-
AlCl4
Acyl cation
R
+
O
C
+
R C O
Acyl cation
+
Aromatic ring
R
O
C
R
H
+
+
Resonance stabilized
carbocation intermediate
R
R
+
H
O
C
H
+
O
C
O
C
H
-
R
O
C
Cl
+
HCl
Acylated ring
39
The same aluminum chloride catalyst used in Friedel-Crafts alkylation is also used for Friedel-Crafts acylation. In this
context, aluminum chloride assists in the formation of an acyl cation from acid halide to serve as an electrophile for aromatic
substitution. Unlike alkyl cation, acyl cation has the advantage of not rearranging. Electrophilic aromatic substitution
begins with the addition of the electrophile into the aromatic π system of the ring. A conjugated, carbocation intermediate
is formed, a resonance combination of three forms, concentrating positive charge at three locations, the two ortho positions
and one para. Finally, the proton departs and substitution at the carbon is complete with aromaticity restored. Acylation is
frequently followed by Clemmensen reduction in synthesis, which will transform the acylbenzene into an alkylbenzene.
Consider the case where electrophilic aromatic substitution is attempted on an aromatic ring that already contains an
original acyl substituent. If electrophilic aromatic substitution is attempted upon rings that already contain substituents,
the location of the next substitution depends on the characteristics of the original substituent. Whether the new substitution occurs ortho, para or meta to the original substituent depends on whether the original substituent either stabilizes or
destabilizes a concentration of positive charge upon its carbon at the carbocation intermediate stage. If the substituent
already present is electron donating, it will stabilize the carbocation by donating negative charge. New substitutions will
occur ortho or para to such electron donating substituents already present on the ring. Electron withdrawing substituents
destabilize a carbocation, so the new substitution will most likely be meta. Acyl group is electron withdrawing due to
the electronegativity of the oxygen atom, which draws electron density toward itself and leaves the carbon electron poor.
Acyl is a ring deactivating, meta director for further electrophilic aromatic substitution.
40
Nucleophilic Aromatic Substitution
Aromatic Compounds
Br
Br
or
Aryl halide with electron
withdrawing substituent
ortho or para
Ortho
or
Product with
nucleophile
substituted for halogen
NO2
Aryl halide with ortho
electron-withdrawing substituent
-
Br Nu
NO2
Resonance stabilized
carbanion intermediate
-
Nu
Br Nu O
N+
Br
NO2
- Nu
or
NO2
Ortho
Product with nucleophile
substituted for halogen
Para
Ortho
O
NO2
Br
Br
- Nu
- Nu
- Nu
- Nu
41
-
Br Nu
Br Nu O
N+
NO2
O
Br Nu
NO2
Br Nu
-
-
-O
N
+ O
Br
Br
NO2
-
NO2
-
NO2
- Nu
- Nu
Br
- Nu
NO2
Br Nu
NO2
Br Nu
Br Nu
Br Nu
-
Resonance stabilized
carbanion intermediate
Br Nu
NO2
NO2
Meta
continued
NO2
NO2
NO2
Nu
Para
Nu
NO2
NO2
Br
Br Nu
Br Nu
Aryl halide with para
electron-withdrawing substituent
or
Br
NO2
Nu
Br Nu
Nu
-
NO2 Para
NO2
--
NO2
- Nu
Br
- Nu
NO2
Ortho
NO2
NO2 Para
Br
Br
Nu
Nu
- Nu
NO2
NO2
NO2
-O
N
+ O
NO2
-
Nu
Product with nucleophile
substituted for halogen
NO2
Br
Meta
Aryl halide with meta
electron-withdrawing substituent
- Nu
NO2
Nucleophilic aromatic substitution (also called addition-elimination), requires an electron withdrawing substituent to be
present on the ring ortho or para to the halide being substituted. The reaction is difficult to achieve with aryl halides for
which halogen is the lone ring substituent. If a strongly electron-withdrawing substituent is present, however, ortho or para
to the halogen, the carbanion intermediate will be more stable. A substituent such as nitro, while deactivating electrophilic
aromatic substitution (which forms a carbocation intermediate), activates ortho and para positions, if they contain halogen,
for nucleophilic aromatic substitution. Basicity of the nucleophile also facilitates the reaction.
42
Alkylbenzene Oxidation
Aromatic Compounds
H
C
H
O
KMnO4
COH
CH3
Benzoic acid
Aromatic ring with
alkyl substituent
Potassium permanganate or chromic acid oxidize an alkyl side chain on an aromatic ring to form a carboxyl group. If the
alkyl group has more than one carbon, cleavage occurs at the benzylic position.
43
Alkylbenzene Halogenation
Aromatic Compounds
H
C
H
CH3
Br2
C
H
Halogen
Aromatic ring with
alkyl substituent
hv
Halogen
Br
Br2
hv
+
CH3
Br
Halide radical
Haloalkylbenzene
(Halogen at the
alkyl position)
2 Br
Halide radical
H
C
CH3
H
Aromatic ring with
alkyl substituent
H
+
C
Br
Halide radical
H
Br
C CH3
H
Br
CH3
Br
C CH3
H
Benzyl radical
Br
C
Haloalkylbenzene
H
CH3
+
Br
Halide radical
Free-radical halogenation of alkylbenzene is selective for benzylic carbons because the benzylic radical is stabilized by resonance (like the allylic). Otherwise, the mechanism is completely analogous to the free-radical halogenation of alkanes.
44
Dehydration of Alcohols
H3C
CH3CH2
C
Alcohols and Ethers
OH
C
CH3CH
Acid catalysis
H3C
CH2
CH3
+
H
major product
C
CH3
CH3
Alcohol
Alkene mixture
H3C
CH3CH2
C
H3C
CH3CH2
+
OH
+
+
O
H
H3C
CH3CH2
C
H
H
Alcohol
H3C
H3C
H
CH3CH2
CH3CH
C2 COH+O
H3C
+
H
H3C
H
C
CH
CH3CH
+
2 3CH
C O
H
H3C
OH +
H
+
O
H
H
H3C
H
H3C
CH3
+
CH3
CH2
H3C
CH3
CH CH+
CH 3 C 2
2
Carbocation
C
H3C
CH3
Alkyloxonium ion
H2O
H3C
CH3CH2
C
H
H H C H
CH C C +
H
OH
continued
CH3
C
H3C
CH3
CH3CH2
C
OH +
45
CH3CH
3
H C H +
+
H H O
H
H
H2O
H
H
H3C
H3C
H
H H C H
H3C
H
CH C C ++
CH3CH32
C O
H H C H
H3C H H
H
+
O
H3C
H
CH3CH2
CH3CH2
+
C O
H3C
CH2
C
CH3CH2
CH3
H3C
+
C
H3C
H
H2O
H
H H C H
CH C C +
CH3
CH3CH
3
H
C
CH3
H C H
H
Alkene mixture
H
H H C H
C+
CH3C
H
H C H
H
CH2
H2O
CH3CH2
C
CH3
Protonation in acidic conditions of the hydroxyl group of secondary and tertiary alcohols converts the hydroxyl group into
a leaving group, which departs as water. The carbocation intermediate, which can rearrange, will then be deprotonated in
an E1 elimination mechanism. This reaction is the reverse of acid-catalyzed hydration of alkenes.
46
Reaction of Alcohols with HX – Dehydrohalogenation
H3C
CH3CH2
C
+
OH
H3C
CH3CH2
C
HX
Hydrogen
halide
H3C
Alcohol
H3C
CH3CH2
C
HX
Hydrogen
halide
H3C
OH +
H
CH3CH2
H3C
H3C
CH3CH2
C
Cl
H3C
+
C
+
O
H
H
H3C
Alkyloxonium ion
+
H2O + Cl-
CH3CH2
Halide anion
H3C
Carbocation
H
H3C
CH3CH2
C
H
H3C
+
O
H3C
H2O
Alkyl halide
OH +
H3C
CH3CH2
C
+
X
H3C
Alcohol
H3C
CH3CH2
C
Alcohols and Ethers
H3C
+
C
Cl
-
H3C
Cl
Alkyl halide
Dehydrohalogenation only takes place with secondary and tertiary alcohols. The reaction begins with protonation in
acidic conditions of a hydroxyl group. The hydroxyl group is converted into a leaving group and it departs as water. The
carbocation intermediate formed attracts a nucleophile, in this case a halide ion, completing the SN1 substitution. This
reaction competes with acid-catalyzed dehydration (E1 elimination).
47
Reaction of Alcohols with Thionyl Chloride
Alcohols and Ethers
H
SOCl2
RCH2OH
Cl
Thionyl
chloride
Alcohol
C
R
H
Alkyl halide
O
RCH2OH
Alcohol
SOCl2
RCH2 O S Cl
Alkylsulfonyl
chloride
Thionyl
chloride
H
Cl
C
R
+
SO2
+
+
HCl
Hydrochloric acid
-
Cl
R
O
H
C
O
S
Cl
H
HCl
H
Alkyl halide
Reaction of alcohols with thionyl chloride followed by hydrochloric acid results in the replacement of the hydroxyl
group of the alcohol with a chloride substituent, forming an alkyl chloride product. This mechanism does not, like
dehydrohalogenation, pass through a carbocation intermediate. Therefore, rearrangement cannot occur in reaction with
thionyl chloride. Note that thionyl chloride can also convert a carboxylic acid into an acid chloride.
48
Reaction of Alcohols with Phosphorus Tribromide
RCH2OH
Alcohol
RCH2OH
Alcohol
PBr3
C
R
Br
Phosphorus
tribromide
O PBr2
Phosphobromide
ether
H
Br
H
PBr3
RCH2
Phosphorus
tribromide
+
Alcohols and Ethers
C
H
+
R
Alkyl bromide
R
-
HBr
Br
Hydrogen
bromide
H
C
O
PBr2
H
HOPBr2
H
Alkyl bromide
Analogous to their reaction with thionyl chloride, reaction of alcohols with phosphorus tribromide followed by hydrobromic
acid results in the replacement of the hydroxyl group of the alcohol with bromine, forming the alkyl bromide product.
This mechanism does not, like dehydrohalogenation, pass through a carbocation intermediate. Therefore, rearrangement
cannot occur in this reaction. A carboxylic acids can be converted to an acyl bromide with this reaction.
49
Oxidation of Alcohols
Alcohols and Ethers
O
R
CH2
O
H
R
C
OH
Carboxylic acid
Primary alcohol
O
R
CH2
O
H
R
H
R
Secondary alcohol
H
H
O
O
C R'
C
Aldehyde
Primary alcohol
R
C
R'
Ketone
Oxidation of a primary alcohol yields an aldehyde or, under the most strong, vigorous oxidizing conditions, a carboxylic
acid. The stronger oxidizing agents KMnO4 and K2Cr2O7 both mainly transform primary alcohols into carboxylic acids,
while Collin’s reagent, PCC and PDC form aldehydes. Oxidation of a secondary alcohol yields a ketone. Extreme conditions are necessary to oxidize a tertiary alcohol, producing cleavage mixtures.
Alkoxide Ion Formation from Alcohols
ROH
Alcohol
+
NaH
Sodium hydride
Alcohols and Ethers
RO- Na+
+
H2
Alkoxide salt
Alkoxide ions can be formed by a very strong base such as sodium hydride. (The alkoxide ion may be later used to serve
as an SN2 nucleophile upon a primary alcohol to produce an ether.)
50
Reaction of Alcohols to form Ethers
Alcohols and Ethers
H2SO4
2 CH3CH2OH
H2SO4
CH3CH2
Acid
catalyst
O
H2 O
Ether
+
H
2 CH3CH2OH
2 Alcohol
+
CH3CH2OCH2CH3
Acid catalyst
2 Alcohol
H
O+
H
Oxonium ion
+
CH3CH2
H
CH3CH2OH
Alcohol
CH3CH2OH
+
OH2
H
H
C
C
H
H
H
H
H
C
H
C
CH3CH2OCH2CH3
Ether
H
HOCH2CH3
+
Ether oxonium ion
CH3CH2OH
H
With primary alcohols, acidic conditions prepare hydroxyl to leave in an SN2 reaction in which another alcohol serves
as the nucleophile. In this condensation reaction, the product formed is an ether. Two alcohols have combined releasing
water. (Note that the conversion of hydroxyl group into a leaving group with secondary and tertiary alcohols leads to
E1 and SN1).
51
Williamson Ether Synthesis
Alcohols and Ethers
RO- Na+
- +
O Na
Alkoxide ion
R'I
+
Alkoxide ion
ROR'
Alkyl halide
Ether
H
+
CH3I
Alkyl halide
OCH3
+
O
-
H
C
I
H
NaI
Ether
In the Williamson ether synthesis, alkoxide ion acts as an SN2 nucleophile upon a primary alkyl halide forming an ether.
Williamson ether synthesis can be used to form asymmetrical ethers. The mechanism will not work upon secondary or
tertiary alkyl halides because of competition from the E2 mechanism, which would form an alkene.
52
Acid Cleavage of Ethers
Alcohols and Ethers
Hydrogen
halide
Ether
Alkyl halide
Alcohol
Hydrogen
halide
Ether
Dialkyl
oxonium ion
Halide ion
Alcohol
Alkyl halide
Ethers are generally unreactive to most species. With strong acid, however, ethers undergo a cleavage through a process
begun by protonation of the ether oxygen. HI and HBr are often used. The products separate in either an SN1 or SN2
style process, determined by the shape of the ether, the halide anion serving as nucleophile. Some of E1’s alkene product,
as always, will be mixed in if SN1 occurs.
53
Epoxidation of Halohydrins
Alcohols and Ethers
OH
C
C
H3C
H3C
CH3
CH3
Br
O
NaOH
H2O
C
H3C
H3C
Base
Halohydrin
C
CH3
CH3
Epoxide
H
OH
C
C
CH3
CH3
H3C
Br
H3C
Halohydrin
NaOH
H2O
Base
-
O
C
H3C
H3C
OH
O
C
CH3
CH3
Br
C
H3C
H3C
C
CH3
CH3
Br
-
CH3
O
CH3
C
C
H3C
Br
H3C
Halohydrin anion
O
C
C
H3C
CH3
CH3
H 3C
Epoxide
Basic conditions activate a halohydrin to complete an intramolecular process to form an epoxide. The oxygen of the
hydroxyl substituent displaces the halide through nucleophilic attack. This mechanism is essentially an intramolecular
Williamson ether synthesis. The product formed is a triangular epoxide molecule. Epoxides are useful substances because
of their own high reactivity toward nucleophiles in epoxide ring opening reactions.
54
Acid Epoxide Ring Opening
Alcohols and Ethers
O
H
C
H+
C
H
H
H
-
Nu
C
H
H
H
O
acid-induced with
normal nucleophile
H
C
C
H
H
Alcohol with nucleophile
as new substituent
O
H
OH
R
Nu
Epoxide
C
H
C
C
H
H
-
R
Nu
H
C
C
Nu
H
H +
O
H+
Nu
H
OH
R
C
H
C
-
H
H
H
H
R
C
Nu
Nu
OH
C
H
H
Alcohol with nucleophile
as new substituent
O
basic nucleophile
H
C
H
O
C
H
H
-
Nu
R
C
H
C
H
R
H
Nu -
OH
C
H
H
C
Nu
H
55
In epoxide ring opening reactions, the SN2 approach of a nucleophile on an epoxide results in cleavage of the epoxide.
Nucleophilic attack occurs at the more highly substituted carbon in acidic conditions. In basic conditions, steric hindrance
is the determining factor with nucleophilic attack occurring at the less substituted carbon.
56
Reduction of Ketones and Aldehydes
Aldehydes and Ketones
O
R
OH
C
R
H
Aldehyde
Reducing agent
C
H
OH
O
R
C
Primary alcohol
H
R
R'
Reducing agent
Ketone
C
H
Secondary alcohol
R'
NaBH4 and LiAlH4 are reducing agents commonly used for transforming an aldehyde or a ketone, respectively, into a
primary or a secondary alcohol. Note that Wolff-Kishner and Clemmensen reduction reduce aldehydes and ketones further than NaBH4 and LiAlH4, all the way to alkanes. (Note the special case where catalytic hydrogenation may be used
to reduce a benzylic carbonyl group to an alkane.) Remember of the sequence in oxidation states of carbon, from more
reduced to more highly oxidized: alkyl, alcohol, aldehyde, ketone, carboxylic acid.
57
Reduction of Aryl Alkyl Ketones
Aldehydes and Ketones
O
C
CH2CH3
H2
catalyst
CH2CH2CH3
Alkyl aromatic
Aryl alkyl ketone
O
O
CH2 C
CH3
H2
catalystC
OH
CH2
CH2CH
3
H
23
CH
catalyst
C
O
CH2 C
CH3
H2
catalyst
CH2CH2CH3
OH
CH2 C
CH3
Reduction with hydrogen in the presence of a catalyst reduces a
non-benzylic carbonyl group only to a hydroxyl group.
A carbonyl carbon located at the benzylic position may be reduced to become an alkyl carbon. It is not necessary to
employ Wolff-Kishner reduction or Clemmensen reduction, which reduce even nonbenzylic carbons to this point. For
benzylic carbonyl groups, the process can be carried out by catalytic hydrogenation. (The reducing agents NaBH4 and
LiAlH4 reduce aldehydes or ketones only to alcohols, even if the carbonyl is benzylic.)
58
Oxidation of Aldehydes and Ketones
O
R
C
O
-
1. KMNO4, OH
H
R
2. H3O
Aldehyde
Aldehydes and Ketones
C
OH
Carboxylic acid
O
O
-
1. KMNO4, OH
CH3 C CH2CH3
Ketone
2. H3O
CH3
+
O
C
OH
+
C
CH3CH2
+
OH
CO2
Carboxylic acid cleavage mixture
(CO2 if methyl ketone)
Potassium permanganate
(extreme conditions)
Many of the stronger oxidizing agents such as KMnO4 will transform aldehydes into carboxylic acids. Tollens’ reagent
(Ag2O) is frequently used. A shiny mirror of metallic silver is deposited through oxidation of aldehydes by Tollens’ reagent, so it is frequently used as a test for aldehydes. Aldehydes are themselves oxidation products of alcohols. A strong
oxidizing agent like KMnO4 will oxidize a primary alcohol past the aldehyde all the way to the carboxylic acid oxidation
state, while other, weaker oxidizing agents, like PCC, can be used to form aldehydes from alcohols, not oxidizing the
aldehyde further. In general, normal ketones are not oxidized except under extreme conditions, with benzylic carbonyl
group being an exception, which KMnO4 oxidizes easily.
59
Reaction of Grignard Reagents with Aldehydes and Ketones
O
C
R'
+
R
R''
+
Mg
Magnesium
O
C
R''
R'
Aldehyde or ketone
+
H3O
+
R'
+
2. H3O
Grignard reagent
Aldehyde or ketone
R Br
Alkyl halide
R'
MgBr
Aldehydes and Ketones
R''
C
R
OH
Alcohol
Acid only for clean-up
after the initial reaction.
R MgBr
Grignard reagent
R MgBr
Grignard reagent
R''
C
R'
R
O
MgBr
R'
R''
C
R
OMgBr
+
H3O
Alkoxymagnesium
halide
R''
C
OH
R Alcohol
Grignard reagents, which are obtained by reaction of alkyl, aryl, acetylenic halides, are very important instruments of
synthesis. A Grignard reagent provides a nucleophilic carbon which can be used for bonding to another carbon. (The
carbon bonded to magnesium in the Grignard reagent is nucleophilic, being the more electronegative end of the bond with
magnesium.) For example, Grignard reagent carbon reacts with electropositive carbonyl carbons. Grignard reagents also
react to form new carbon-carbon bonds with esters, nitriles, epoxides, and carbon dioxide carbons. (Grignard reagents can’t
be used in the presence of acidic protons. The acid in the mechanism above is only applied in the reaction’s last stage.)
60
The Wittig Reaction
Aldehydes and Ketones
H
R
O
+
Br
C
(C6H5)3P
C
R''
Triphenylphosphine
R'
H
R (C6H5)3P
Triphenylphosphine
C Br
+
(CR6' HAlkyl
5)3P halide
+
H
+
(C6H5)3P
C
R'
O
C
R
R'''
R''
+
(C6H5)3P
Aldehyde or ketone
+
(C6H5)3P
C
R'
R
R' +
- (C6H5)R3P''
O C R'''
+
(C6H5)3P
-
O
R'''
C
C
-
R
Br
R
(C6H5)3P
H
C
R'
-
R
Br
NaH
BuLi
- R
+
(C6H5)3P C
R'
or
O
C
O
C
R
R'
R''
R'''
R
R' C
C
R''
R'''
- R
+
(C6H5)3P C
R'
H
R''
R
O C R'''
C Br
C
C
continued
R'
R
R' C
-
Br
Triphenylphosphonium
ylide
+
R
(C6H5)3P C
R' +
NaH
- (C6H5R)3''P C R'
R
or BuLi O
C R'''
+
(C6H5)3P
(C6H5)3P
C
R'
R'''
R
- R
+
(C6H5)3P C
R'
+
(C6H5)3P C
R'
R''
O C R'''
R
R'
R''
R'''
H
C
R''
- R
+
(C6H5)3P C
R'
Br
Triphenylphosphonium (C H ) P
6 5 3
ylide
+H
C
O
O
Br
C
R''
R'''
C
Alkene
H
R
+
R'
C
R''
R
R' C
R'''
Aldehyde or ketone
Alkyl halide
Unstable betaine
intermediate
+
C
O
C
R
R'
R''
R'''
- R
+
(C6H5)3P C
R'
''
R
+ R'' (C6H5)3P
C R'''
O C R'''
R
R'
R''
R'''
R
R' C
(C6H5)3P
C
R''
R'''
(C6H5)3P
C
O
C
+
(C6H5)3P
61
O
R
R'
R''
R'''
O
Alkene
Phosphorus ylides are used in the Wittig reaction to convert aldehydes and ketones to alkenes. In the process a new
carbon-carbon bond is formed. To prepare the triphenylphosphonium ylide reagent, an SN2 reaction is utilized between
triphenylphosphine and an alkyl halide (followed by deprotonation). The ylide (an ylide is a dipolar substance with adjacent
opposite charges) is then made to undergo a reaction with an aldehyde or ketone that is somewhat analogous to the reaction
of aldehydes or ketones with Grignard reagents. The ylide carbanion electrons lead to bond formation with the positive
carbon pole of the carbonyl group. A betaine is formed, which is unstable (a betaine is a dipolar substance with nonadjacent
opposite charges.) Electron pair movement continues as oxygen departs its bond with carbon to bond with phosphorus.
The two carbons of interest now possess a double bond between them. (Carbon-carbon bond forming reactions are of
particular importance for organic synthesis. Other important reactions that form carbon-carbon bonds include the use of
acetylide anion as an SN2 nucleophile, Grignard reagents, Gilman reagents, and the aldol & Claisen condensations.)
62
Acetal Formation
Aldehydes and Ketones
O
R'
+
R''
C
2 equiv.
Alcohol
Aldehyde or
Ketone
R'
HCl
2ROH
Acid
+
R' C O R''
Aldehyde or
' C
RKetone
ROH
Alcohol
+
R''
+
O
R'
O
R
R'
O
R'
C
R'
Acid
HCl
R'
C
R'
OH
R'
R''
C
R''
O
R + H
H
O
C R'' H
RO O
R' C
R''
HCl
+
OH
H2
R' +
O
C R''
R'ROC
''
C + RH
O
RO
R'
C
+
O
R'
R
63
C OHR''
R'
C R''
O O
R R +H H
O
R + H
R'
O
R'' H
O' OH O
R
R + H
C R''
C
Cl
H
H
RO
H
H
OR
R'
C + R''
OH2
RO
R'
R''
C
+
O
R
+
O
R''
O
RO
+
OH2
R'
RO
continued
R''
R
RO
C
R'
R
+
O
OH
'
'' ''
R' R C C RR
R''
RR O H
O
'
R
''
C
OH R
R' O
R + C H R''
Cl
H
H
+
OH2
Cl
OH
R'
RO Hemiacetal
+
ROH
R''
R'
R''
C
R''
C
O
R
R
H
R
R
O
R'
C
R''
C
R''
RO
OH
C
OR
H
H
R''
R'
+
O
O
R + H
OH
C
Cl
R''
C
R'
R''
C
Acetal
O
HCl
2ROH
H
R''
C
RO
H
O
OR
R''
O
R + H
R'
O
C
R'
R''
O
R + H
O
H
H
OR
C
RO
R''
Acetal
An aldehyde or a ketone reacts with alcohol in the presence of an acid catalyst to form a geminal diether product called an
acetal. Acetal formation begins with protonation of the ketone or aldehyde carbonyl oxygen by an acid catalyst, increasing
the attractiveness of the carbonyl group to the approaching alcohol nucleophile. A tetrahedral intermediate forms, which
is typical of nucleophilic reactions with carbonyl compounds. After a subsequent protonation, the hydroxyl group leaves
as water, forming a cation intermediate. This intermediate is approached by another alcohol nucleophile.
One interesting use of acetal formation is to protect carbonyl groups from hostile reaction conditions. Ethylene glycol is
often used in this way to form a cyclic acetal, which can be converted back into the aldehyde or ketone at a later stage.
64
The Wolff-Kishner Reaction
-
O
R
Aldehydes and Ketones
C
H
N
H
+
R'
Hydrazine
H
OH
H
H
N
R
C
Aldehyde or Ketone
H
N
H
+
O
C
R'
R
C
Aldehyde or Ketone
R'
N
H
+ Hydrazine
N
H
R
-C
H
H
N
R'
N
C
R
N
H
O
H
+ HH N
H
C H N
R'
N+
H
H
N
-
+
OHR
OH
- OH
R
N C R'
N
N
H
C
'
N RH
R
H
HC R'
N
H +
H N HN
H
N C
R H R'
-
+ OH
R
C CH
R'
R '
R
OH
-
OH H
O
HH
N
- H N
R C H
R' R C R'
-
+ OH
H
R
N
C
O
NH
N
H
N
R
H
R' N H
H
-
-
O
N
N
+
H
-
C
H
N
OH
H
C
R'
R'
R
Hydrazone anion
+ H2O
R
C
-
R
R'
-
+ OH
N
N
N
R'
H
H
-
R
continued
65
C
H
N
H
N
+ N N+ + HH
2O
2O
C
R' R
R'
OH
-
+ OH
N
C R'
+ H2O
N
H
-
C
H
R
-
O
R
C R'
+
+H H2O
C
N H
R'
R
H
Hydrazone
H
N
H
N
R
OH H
H N
H
N
H
N
N +
R C H
C
R'
R
R'
- OH
+
N H
H
-
H
H
H HN N
H
H N
N ++
R'
C
C OH'
H
R
N RH
H
H
N +
H
N
N
H
H
C
R'
R
-
O
O
N
H
N H
H
R'
-
H
R'
R'
O
C
C
C R'
+
N HN + H O
+H N
2
N H Tetrahedral
H intermediate
H
N H
H
R
HR
H
OH
R
C R'
+
N H
H
R
OH
H
N
H
-
O
R
H
-
O
R
H
H
+ H2O
N
N
Alkane
O
O
R
+
H
R'
C
O
H
H
N
N
-
R'
H
N
N
R
+
C
OH H
-
R
H
R
H
H
-
C
R'
R
C
H
R'
R'
O
N
N
OH
H
R
H
C
H
R'
Alkane
+
-
C
H
+
+ H2O
R'
Carbanion
-
OH
A ketone or an aldehyde is reacted with hydrazine in Wolff-Kishner reduction. The reaction begins with nucleophilic attack
of hydrazine upon the carbonyl carbon. This is one of the more challenging mechanisms. Conceptual framing is helpful
to learning. Wolff-Kishner belongs to the group of reactions that are possible between ketones/aldehydes and amines and
amine derivatives. In these reactions, if the nucleophile is a primary amine, having two hydrogens to lose, reaction with a
ketone or an aldehyde will produce an imine form, in which the carbon originally double bonded to oxygen will be double
bonded to nitrogen. If the amine is secondary, the product is an enamine, in which the carbon-nitrogen bond is single, but
the carbon is double bonded. In Wolff-Kishner, the tetrahedral intermediate formed by the nucleophilic attack, resolves
itself by losing the original carbonyl oxygen as hydroxide, forming eventually a hydrazone, the structure of which is of
the imine type (not enamine). Deprotonating with a strong base puts electrons on the move within the hydrazone in a
manner similar to an elimination mechanism, except that here we have electrons moving into nitrogen-nitrogen bonds, not
carbon-carbon, with resonance stability also. Two deprotonations occur moving two electron pairs between the nitrogens,
displacing electrons onto the original carbonyl carbon, eventually turning the alkyl portion of the molecule into an E2 style
leaving group, which, after departing, is protonated to form the alkane product.
66
Reductive Amination
Aldehydes and Ketones
O
R
R'
C
Aldehyde
or ketone
H
R
1. NH3
2. H2
R'
C
N
Ammonia
then
Hydrogen
H
H
Amine
O
O
R
+
R'
C
Aldehyde
or ketone
R
NH3
Ammonia
R
-C
C
R'
N+
H
H
R'
1. NH3
2. H2
R
R'
C
Tetrahedra
intermediate
R'
H
H
H
O
R
R'
C
N
H
H
H
H
C
N
OH
N
H
H
R
R'
C
N+
H
NH3
O
RO
C
-
O
R
R'
H
H
Carbinolamine
H
N +
+ NH+
3
C
R'
R C
R'
O
R
H
R
H2
H
-
OH
-
O
H
H
C NR' +
R
R C
NH3
OH
R'
O
R
-
continued
NH
+
C R'
R C
R'
N+
H
H
H
-
H2O
H2
67
H
C OR'
R
'
N C R
H
HH N +
H
H
R
OH
R
R'
C
N
C
N
H
H
O
H
R'
H
H
H
N +
R C
R'
Conjugate acid
of imine
H2
R
+
-
H
OH
R
OH
H
N +
C
NH
R'
R
C
R'
Imine
+
H2O
H2
H
C
N
H
R'
H
Amine
Reductive amination is a means of converting an aldehyde or a ketone into an amine. The reaction begins with nucleophilic
addition of ammonia or an amine to the carbonyl group of an aldehyde or a ketone. The imine or enamine derivative
formed is subsequently reduced by hydrogen to form the amine product. If the nucleophile is ammonia, a primary amine
will be formed in reductive amination. If the nucleophile is a primary amine, the product will be a secondary amine.
With a secondary amine nucleophile, a tertiary amine product will be obtained. Recall that the nucleophilic addition of
ammonia or primary amine results in imine formation and addition of a secondary amine to an aldehyde or ketone results
in enamine formation. Both are ultimately reduced to form amines in reductive amination.
68
The Cannizzaro Reaction
O
H3C
C
H3C C
2
2
O
H3C
C OH
C
H3C
H3C
H C Aldehyde
3
H3C
C
C
OH
O
O
H3C
C
H3C
H3C CC C HH
H3C
H3C
H3C
-
1. OH
H
2. H3O +
-
--H
O
H3C
C
H3C C
H3C
H
+
H
H3C
H3C
OH
H3C
+
+
-
O
OH
HH3C
HOH
3C Tetrahedral
C
C
intermediate H
H3C
H
C
-
H
Hydride ion
continued
-
H
-H
O
H3C
C
OH
C
H3C
O
H-3C
H3C H3C OC
C
H3C
H
C
C
H3C H H
H3C
OH
+
+
H3O
69
-
H
H3C
H3C
Aldehyde
H3C
H3C
C
-
O
H3C
C
H3C C
-
OH
H3C
Carboxylic acid
H3C
H3C C
OH
+
H3C
H3C
C
H3C
O
O
H3C
C
C
HC3C H
H
H
Alcohol
O
H3C
C
OH
H3C C
H
OH
C
H3C
O
H
H3C
C
OH
H-3C C
O
H3C - OH
H
H33C
C C OC
H3C
H
C
C
H3C
HH
H3C
OH
+
H3O
H3C
C
H3C
+
H3O
+
H3C
O
H3C
C
C
H3C
-
H3C
H3C
C
H3C
2. H3O +
OH
H3C
H3C
C
Carboxylic acid
H3C
2
O
H3C
C
OH
H3C C
-
1. OH
H
H3C
Two equivalents
aldehyde
2
Aldehydes and Ketones
H
-H
H3C
H3C
C
-
O
C
H
+
H3O
H3C
H
New tetrahedral
intermediate
OH
C
H
H
The Cannizzaro reaction resembles the acyl exchange reactions among carboxylic acid derivatives, although it occurs
with aldehyde. With aldehyes (or ketones) tetrahedral intermediate formation is not typically followed by the departure
of an acyl type leaving group. Reactions of nucleophiles with aldehydes and ketones differ in this respect from reactions
of carboxylic acids. Although sometimes the original carbonyl oxygen will depart (as in acetal or imine/enamine formation) the reaction of a nucleophile with an aldehydes most commonly results in a tetrahedral product) In the Cannizzaro
reaction, a strong base reacts with an aldehyde having no α-hydrogens. The hydroxyl adds to the aldehyde to produce a
typical tetrahedral intermediate, except that this intermediate resolves itself with hydride (hydride!) departing as an ‘acyl
type’ leaving group, forming a carboxylic acid. The freshly departed hydride then acts as a nucleophile upon another
aldehyde, producing a new tetrahedral intermediate, which, after protonation, becomes an alcohol. One equivalent of
aldehyde becomes carboxylic acid and the other leads to the alcohol form.
70
Acid or Base Catalyzed Enolization
H 3C
O
H
+
H 3O
CH3
C
C
Aldehydes and Ketones
or
C
H 3C
H
1. OH
CH3
CH3
H
H
O
2. H2O
Aldehyde or Ketone
C
H
H
+
H3O
CH3
C
C
C
H
CH3
-
H3C
O
CH3
+
CH3 +
C H O
C C
3
CH
3
C HC
CH
3
CH3
CH3
H2O
HO
3C
H
C
H
H3C
C
O
H
H
+
O
CH3
CH3
OH
C
C C
C
C
CH3
CH3 CH3
H
CH3
H H CO
3
H
H
C
H H3O
H
H3C
C C
H
O - CH3
O
CH3
H3C
+
C
C C
H3C C C
C CH3
HH
CH3CH3
CH3
H2O
H
3C
HH
2O
C
H
O
-O
CH
OH3
C
H3C C C CHC
3
H
CH3
O
C
-
CH3
Base
CH3
-
CH3
CH3 CH3
Enol
CH3
CH3
C
H
H
H3C
H
C
H
HO
O
CH3
O
CH CC
3
CH
H CHC 3C
H2O
H3C
H
C
C
C
CH3
CH3
H
CH3
C
CH3
CH3
3
-
O
C
CH3
C
CH3
CH3
O
CH3
71
O
CH3
O
CH3
C C
C
CH3
C
C
CH
CH33
CH3
H
H
-O
continued
3
H3C C
H
CH3
CH3
Resonant Enolate anion
intermediate
C
C
C
-
H3CH3C H
H C
C
Aldehyde or Ketone
H3C
H
CH3
C CHC3
O
H
CH3
CH3
CH3
CH3
HH OO
CH
3
+
3C
HH
3C
C C C C C C CH
CH3 3
CH3
HH
CH
H
H
C
H
HO
H
Base
Catalyzed
CH3
CH3
O
H
CH3
+ H3C
C
C C
H 3O
CH3
CH3
Acid
HH O
CH
CH
H
CH3
3 3
O
Aldehyde or
or
H 3C H C C
C
C
C Ketone
H3
CH
H
1. OH
+
O
H
CH3
H
HCHO
CH3
3
H3C
+
H3C
2. H2O
C
C C
C
C C
CH3
CH3
H
CH3
H
CH3
Resonant cation intermediate
H
H +O
H
H
H
H3C
H 3C
O
H
C
Enol
Either Acidic
or Basic conditions
H +O
Acid
Catalyzed
CH3
C
O
H3C
H
C
C
Enol
CH3
C
CH3
CH3
Keto-enol tautomerism is one of the most important aspects of the reactivity of aldehydes or ketones. The movement from
an aldehyde or ketone to its enol isomer involves proton exchange between an α-carbon and the carbonyl oxygen of an
aldehyde or ketone. Although continuous interchange between the carbonyl compound and its enol does exist normally
in neutral conditions, keto-enol tautomerism can be catalyzed by the addition of either acid or base. The particular events
differ between the cases, but the same net intramolecular process occurs with either acid or base catalyzed enol formation,
the transfer of a proton from the α-carbon to the carbonyl oxygen, accompanied by the shifting of electron pairs up toward
oxygen, forming the vinylic alcohol known as an enol. α halogenation, the haloform reaction, and aldol condensation,
among other reactions, involve the reactivity of the enol form, which, in these processes, is approached by an electrophile
at the α-carbon. In another instance, the presence of enolate anion intermediate contributes to the special reactivity of α-β
unsaturated carbonyl compounds to nucleophiles at the β carbon.
72
Alpha Halogenation
Aldehydes and Ketones
O
H
H3C
CH3
C
C
Br2, HBr
C
CH3
C
C
CH3
CH3
H
O
H
H3C
C
CH3
CH3
Br
Aldehyde or Ketone
H
H3C
O
H
CH3
C
C
H
C
+
O
H
H 3C
C H3CC C
C
C
CH3
CH3
H
Br32,
CH
O
C
CH
3
H 3
CH
H
CH3
C
C
H
CH3+
H
O
H
H3C
CH3
H
CH3
Aldehyde or Ketone
Br
HBr
H
H CH
H3C3
C
CC
C
CH3 Resonant cation
H
CH3
intermediate
H
O
+
O
C
C
CH3 CH3
CH3 CH3
Br
H3C
O
H
C C
HCH3
H
O
Br
Br
+
CH3CC
CH3 +
O
H
CH3
+
CHH
3
H3C
-
H3C
CH3
C
CH3
CH3
-
C
Br
Br
C
C
+
O
continued
CH3
CH3
H
H
O
H
CH3
CH3 H
H3C
+
O
H
CH3
C
C , C
C
C C
Br
H3C
2
CH3
CH+3
C
C
Br
CH3
CH3C
Br
CH3
H
CH3
H
OH
H
H3C
H3C
H
C
O
C C
Br
3
C
CH3
CH3
C
CH3
C
CH
CH33
CH3
+
73
HBr
Br
H
O
C
C
CH3
C
C
CH
CH3 CH 3
3
H
Br
H
+H
O
H
CH
O
H
CH3 3
H3C
H3C
+
C C C C C C CH
CH3 3
H Br
CHCH3
H3C
H
H3C C
H
O
H
C
H
3
CCHC
CH3
H
O
Br
H
CH3
CH3
H
C
CH3
C - Br
C
C
H3C
H
H
O
H
Br2,
C
H
H3C
CH3
CH3
CH3
H3C
C
CH3
CH3
H
C
Br
C
Br
H3C
H
+
O
C
H
C
H
H
CH3
H3C
C
CH3
CH3 Resonant cation
H
C
O
C
Br
+
CH3
C
CH3
CH3
intermediate
Br
CH3
C
+
O
CH3
CH3
H3C
H
C
Br
O
C
CH3
C
CH3
CH3
+
HBr
α-halo derivative
The process of acid catalyzed keto-enol tautomerism allows aldehydes and ketones with α-hydrogens to react with
electrophiles. α-halogenation is a typical reaction of this type. In this reaction, the π electrons between the vinylic
carbons of an enol form of the aldehyde or ketone are subject to electrophilic attack, leading to a new bond between the
α−carbon and halogen.
74
Haloform Reaction of Methyl Ketones
H
O
H
H
CH3
C
C
Aldehydes and Ketones
O
Br2
C
CH3
CH3
OH
-
Halogen
with base
Methyl ketone
CH3
C
HO
C
CH3
CH3
Carboxylic acid
H
H
H
H
C
H
O
C
CH3
OH
C
O
CH
CH
3 3
CH3
C
MethylC
ketoneC
H
H
-
-
Br2
H
H C
OH
CH3
C
C
CH3
CH3
H
O
CH3
H
C C
C HC
CH3
Br CH
Br 3
-
-
-
C OH
CH3
CH3
Br2
OH
-
Br2
OH
-
Br2
OH
O
-
CH
3
-Above mechanism
Br
C
C twice
repeated
CH3
CH3
O
Br
CH3
-
C
O
C
CH3CH3
CH3
H Br
C
C
C
H
CH3
O
H CH
3
Br Br
C
Br
Br
O
C
C
H
H
Br
Br
C
Br
O
O
C
H
-
O
CH3
CH3
-
CH3
C
CH3
CH3
+
-
Br
continued
O
CH3
O
CH3
Br
C
C C
Br2
H
CH3
C
C
H C
CH3 CH3
Br
CH3
Br
Br
HC
H
Br
C
O
O
C
C
O
-Br
O
O
Br
C
C
CH3
CH
C 3
C CH3
CHCH
3 3
H
CH3
O CH3CH3
+
C
CH3CH3
CH3CH3
CC
Br
Br
Br
C
Br
-O
O
-
Carboxylate anion
-
75
+
-
Br
-
HCBr
OH 3
CH3
C
C
O
H
O
C
OH
-
Br
H
H
Br2
C
-Br
CH3
CH3
C
CH3
CH3 CH3
O H CHO
CH3
3
H
+
C
C
C
C C
CH3
CH3
CH3
BrCH3
CH3
C
Br
-
C
CH3
C
-
O
-
Br
CH3
O
C
Above C
mechanism
C
CH3
repeated twice
Br
O
CH3
H
Br
C
H
CH3
O
H
H C
CH3
O
CH3
H
H C
Enolate anion
HO
OH
CH3
C
- HO
HO
Br2 H
H
C
C
C
+
H
Base
CH3
CH3
O
O
H
H
CH3
CH3
Tetrahedral
intermediate
CH3
C
CH3
CH3
+
HCBr3
Haloform
The haloform reaction is a variation of α-halogenation. Under basic conditions for enolate formation of a methyl ketone,
halogenation of the α-carbon continues until its supply of hydrogens is exhausted. The resulting trihalo-derivative is
unstable, undergoing an acyl type substitution resulting in formation of carboxylate and haloform. The iodoform version
of this reaction is used as a qualitative test for methyl ketones. Yellow iodoform precipitate convincingly indicates upon
reaction with iodine the presence of a methyl ketone.
76
Aldol Condensation
Aldehydes and Ketones
O
H
2 H 3C C
-
CH3
C
CH3
CH3
H
C
2. H2O
Aldehyde or Ketone
O
H
OH
C
O
CH3
CH3
H
2 H 3C
C
C C
Aldehyde or Ketone
H
O
H3C
H
H3C
CH3
-
H 3C
C
C
-H
HO
2. H2O
C
CH3
CH3
O
-
H3C
H
C
OH
CH3
C
CH3
H 3C C H
CH3
O C
H3CH
C3
C
Aldol addition
product
C
C
CH3
CH3
H
-
CH3
C
CH3
H
CH
3
O
H
1. OH
CH3
CH3
C
C
-
CH3
C
H 3C
CH3
2 H3C C C
H
CH3
C
C
H H C C
CH
3
H CH 3
3
O C
1. OH
C
OH
H
H 3C
C
C
CH3
CH3
CH3
CH3
Enolate anion
H3C
2
H3C
H
C
O
H
C
C
O
CH
H 3
C
C
3
H3CCHC
CH
H3
H
CH3
H3C
C
CH3
CH3OOH CH3
C
H3C
H
C
O
C
H
C
CH3
CH3
HO
-
-
OH O
H
CH3
CH3
H3C H C
C
C
C3
C
H C C
CH3
H2O
H H C C
CH
CH
+
3
H CH 3 3
3
O C
H3C
C
H
3C
CH
3
CH3 O
H
C
C
H
H3C
H
H3C
H2O
H
-
C
OH
CH3
CH3
CH3
O
CH3
O
C
77
H2O
CH3
C
CH3
CH3
H
O
-
CH3
C
C
C
H H C C
CH
3
H CH 3
3
O C
C
CH3
CH3
CH3
C
C
CH3
C
H H C C
CH
3
H CH 3
C
3
CH3 O C
CH3
C CH3
H3C
CH3
H3C
C
C
-
C
continued
-
H3C
C
CH3
H2O
CH3
Anion form of
product
OH
CH3
C
C
C
H H C C
CH
3
H CH 3
3
O C
H3C
-
H3C
H
O
H
C
CH3
+
-
OH
CH3
Aldol addition
product
Many of the reactions involving aldehydes or ketones fall into one of two categories. One set of reactions take place
by means of nucleophilic attack upon the electropositive carbonyl carbon. The other set occurs by means of keto-enol
tautomerism, a process that exposes an aldehyde or ketone to electrophilic attack at its α-carbon (as in α-halogenation).
Aldol condensation, however, belongs to both categories. Aldol condensation occurs with bond formation between the
carbonyl carbon of one equivalent of aldehyde or ketone and the α-carbon of another equivalent. Keto-enol tautomerism
generates the enolate form from one molecule of the aldehyde or ketone, and the α-carbon of the enolate acts as a nucleophile,
forming a bond with the carbonyl carbon of another aldehyde or ketone molecule.
78
Claisen Condensation
H
2
Aldehydes and Ketones
-
O
H
C
C
H
O
Ester
2
O
H
H
C
C
2
O
CH3
C
C
O
O
CH3 C
CH2 C
O
-
H
H
H
H C
C
O
+
CH3
CH3OH
Alcohol
O
H
C
C
O
CH3
H
Base
HO
O -
1. OH
- +
O 2. H3O
CH3
O
Claisen condensation product
-
O
H
OH
Ester
H
H
1. OH
+
2. H3O
CH3
CH3 C
O
+
CH3
CH3OH
O
-
H
H C
CH3
O
CH2 C
C
O
CH3
Enolate ester
2
H
O
C
C
CH3
O
C HO -CH3
C
H C
C
H
H
H
O
H
O
H
H
OH
O
-
H
CH3
H
C
C
O
H C H
O OCHC
3
C
H
C
H
HO
79
CH3
O
CH3
-
-
-O
C O C
H
O CH
C CH CO CH3 3
H H
H
O C
H
H
O
continued
-
O
H
O
-
+H C
H3OH
O
O
C
CH3
CH3 C
O
CH2 C
O
+
CH3
CH3OH
O
H
CH3
O
H
C
C
O
-
O
H
CH3
H
H
O
C
C
CH3
-
C
C
H
H
O
H
O CH3
H C H
O C
Tetrahedral
O intermediate
CH3
H
O
H
C
H
C
-
O
H C H
O C
O
CH3
+
H3O
O
O
CH3 C CH2 C O CH3
Claisen condensation product
+
CH3OH
Alcohol
CH3
Claisen condensation of esters is very similar to aldol condensation (which is why we have included this methanism in
this section, even though esters are carboxylic acid derivatives). In Claisen condensation, the enolate form of one ester
molecule carries out nucleophilic attack on the carbonyl carbon of another ester molecule. How Claisen condensation
differs from aldol condensation illustrates a general difference in the reactivity of esters vs. aldehydes and ketones. In
Claisen condensation, the enolate form of one ester molecule approaches another, similarly to aldol condensation, but,
in this case, the tetrahedral intermediate resolves itself along an acyl substitution pathway. Both the aldol and Claisen
condensations begin with an α-substitution, but in aldol condensation the overall pathway corresponds to nucleophilic
addition, while Claisen condensation resolves itself in the manner of an acyl substitution reaction with sp2-hybridization
returning with the departure of the leaving group.
80
Conjugate Nucleophilic Addition
Aldehydes and Ketones
O
O
CH3CH2
C
-
+
CH2
CH
CH3CH2
Nu
α,β – unsaturated
aldehyde or ketone
CH3CH2
C
C
Nu
H
H
Nucleophile
Product with nucleophile
having added at β position
O
O
C
H
H
C
CH
-
+
CH2
α,β – unsaturated
aldehyde or ketone
O
CH3CH2
CH3CH2
Nu
C
CH
O
H
-
C
Nu
C
CH3CH2
H
C
H
H
-
H
+
H
C
C
Nu
H
Resonance stabilized
enolate ion
O
C
C
Nu
-
H
H
CH3CH2
C
Nucleophile
H
H
C
H
C
Nu
H
Product with nucleophile
added at β position
81
With α,β unsaturated carbonyl compounds (also called conjugated enones), some nucleophiles will approach and bond to
the β-carbon, such as amines, cyanide, and Gilman reagents. Normally with aldehydes and ketones, a nucleophile will
only approach and bond to the carbonyl carbon. Being in a polar bond with oxygen, carbonyl carbons are electropositive.
However, with an α,β unsaturated carbonyl compound, the positive charge arising due to the polarity of the carbonyl group
is shared between the carbonyl carbon and the β-carbon by means of allylic resonance. This is why the β-carbon of α,β
unsaturated carbonyl compounds is attractive to nucleophiles.
82
Conjugate Addition of Gilman Reagents
Aldehydes and Ketones
O
CH3CH2
O
R
C
CH
+
CH2
Cu Li
α,β-unsaturated
aldehyde or ketone
R
2 Li
+
X
R
R
CH3CH2
+
Li
2 R
Li
CH3CH2
C
+
CuI
CH
CH2
- R+
Cu Li
+
R
R
CH3CH2
CH CH2
α,β-unsaturated
aldehyde or ketone
O
R
+
X
2 R
Li
CH3CH2
2 Li
-
C
CuI
CH3CH2
C
Li
R
- +
Cu Li
+
LiBr
+
CH3CH2
CH3CH2
C
C
-
C
R
C
H
H
R
- +
Cu Li
continued
H
C
R
C
83
H
H
O
CH3CH2
RH
- +
H
C+
CCu RLi
CR H
H
O
H
CH3CH2
C
LiI
O
CH CH2
CH3CH2
H
H
C
C
H
H
R
-
C
R
O
CH
O
H
R
+
H
CH3CH2
O
R
C
Product with alkyl group
added at β position
O
LiI
-
H
+
+
Cu Li
H
C
H
Formation of
Gilman reagent
+
+
Cu Li
Gilman
reagent
R
C
H
LiBr
R
O
R
C
C
Gilman reagent
(lithium dialkylcuprate)
O
R
H
H
C
O
R
C
H
H
C
Resonance stabilized
enolate ion
CH3CH2
C
CH
C
H
H
R
- +
Cu Li
R
-
H
C
C
R
H
H
+
H
O
CH3CH2
C
H
H
C
R
C
H
H Product with alkyl group
added at β position
Gilman reagents (lithium dialkylcuprates) can be used to carry out nucleophilic addition upon α,β unsaturated carbonyl
compounds, adding an alkyl group to the β-carbon. This is a useful reaction for organic synthesis.
84
Acid Halide Formation
Carboxylic Acids and Derivatives
O
CH3CH2
O
C
+
OH
SOCl2
Carboxylic acid
CH3CH2
Thionyl chloride
O
CH3CH2
C
O
OH
Carboxylic acid
+
SOCl2
Thionyl chloride
O
CH3CH2
O
CH3CH2
-
Cl
CH3CH2
O
C
O
Cl
O
C
O S
Chlorosulfite
+
Cl
-
O
S
-
Cl
O
CH3CH2
O
C
C
Acid halide
HCl
O
C
O
Cl
Tetrahedral intermediate
S
Cl
O
S
Cl
CH3CH2 C
Cl
Acid halide
Cl
+
SO2
+
-
Cl
Thionyl chloride can be used to convert a carboxylic acid into an acid chloride. (Phosphorus tribromide will accomplish
an analogous reaction, converting carboxylic acids to acid bromides.) The mechanism is composed of two successive
nucleophilic acyl substitutions, the first substitution converting the carboxylic acid into the reactive chlorosulfite form,
which is then attacked by chlorine anion, resulting in the formation of the acid chloride product.
85
Fischer Esterification
Carboxylic Acids and Derivatives
O
R
C
OH
H
O
+
R C
OH
Carboxylic
acid
R
R'OH
Alcohol
C
C
+
O
C
R
OH
R
OH
+
O
H
+
O
R
C
OH
OH
C
R
O
R' + H
H
+
O
OR'
Cl
OH
R'
OH
O
R' + H
Tetrahedral
intermediate
R
R
OR'
C
Ester
O
HCl
Acid
R
Acid
Alcohol
Carboxylic acid
O
HCl
R'OH
+
R
C
H
OH
C
H
O+
R'O
O
R
O
OH
H
OH
H
O+
H
H
H
O
OR'
C
C
R'O
H
H
R
C
OR'
Ester
+
+
H3O
Fischer esterification involves the formation of an ester from a carboxylic acid and an alcohol. The mechanism is an acid
promoted acyl substitution, which results in the substitution of an alkoxy group for the hydroxyl portion of the carboxyl
group. (An alternate method of ester formation involves the use of the carboxylate anion as an SN2 nucleophile upon a
primary alkyl halide.)
86
Use of Carboxylate Anion Nucleophile to form Esters
O
O
CH3CH2
Carboxylic Acids and Derivatives
C
1. NaOH
OH
CH3CH2
2. CH3Br
Carboxylic acid
C
O
O
+
CH3CH2 C
OH
Carboxylic acid
-
+
CH3CH2 C
O Na
Carboxylate anion
NaOH
Base
O
O
- +
O Na
Carboxylate anion
CH3CH2
OCH3
Ester
Base then
Alkyl halide
+
C
CH3Br
Alkyl halide
CH3CH2
C
O
+
-
H
H2O
H
C
Br
H
O
CH3CH2
C
+
OCH3
NaBr
Ester
Titrating carboxylic acid with a strong base forms a carboxylate salt. The carboxylate anion can then serve as a nucleophile
in an SN2 reaction upon a primary or secondary alkyl halide to form an ester. (Fischer esterification is often the choice
over this SN2 process to form esters from carboxylic acids, especially if the alkoxy portion is tertiary.)
87
Hydrolysis of Acid Halides
Carboxylic Acids and Derivatives
O
R
O
H2O
C
Water
Cl
R
C
OH
Carboxylic acid
Acid halide
O
O
R
C
R
C
R
Cl
O
Cl
H
Acid halide
R
H
O
O
C
H
Cl
OH2
+
R
C
OH2
+
+
-
Cl
O
C
O+
H
Cl
Tetrahedral
intermediate
-
O
R
C
+
H
O
Cl
H
O
R
C
OH
Carboxylic acid
A typical acyl substitution reaction is the hydrolysis of acyl halides to form carboxylic acids. The progression among acyl
derivatives from highest to lowest enthalpy (toward greatest stability) is as follows: acid chloride, acid anhydride, ester,
amide, and finally carboxylic acid. Therefore, thermodynamics favors the hydrolysis of an acid halide.
88
Reaction of Acyl Halide with Ammonia or Amine
O
R
Carboxylic Acids and Derivatives
O
+
C
2 NH3
Cl
Amide
Acid halide
NH2
Ammonium salt
O
O
R
C
+
R
NH3
Cl
C
Amine
R
Cl
H H H
R
O
O
C
Cl
R
C
NH3
+
O
R
+
C
NH2
Amide
HCl
Acid
O
Cl
C
Tetrahedral
N+
H H H intermediate
N
Acid halide
+ NH4 Cl
+
C
R
2 equiv. amine
NH3
+
-
O
-
+
Cl
Cl
C
R
N
+
H
H
H
O
NH3
R
Ammonia
C
NH2
Amide
+ NH4 Cl Ammonium
salt
+
Among acyl derivatives, amides are next in stability to carboxylic acids, and both are more stable than acid halides. Just
as water will easily hydrolyze an acid halide to form a carboxylic acid, ammonia will aminolyze an acid halide to form
an amide. These types of reactions are characterized by the pattern of the electropositive acyl carbon accepting a pair
of electrons from the nucleophile while shifting a bond pair over to oxygen, forming the tetrahedral intermediate. The
amide product is formed after departure of the halide leaving group. The conjugate acid of the amide has formed, which
is a stronger acid than hydrogen halide, so proton transfer occurs onto the halide ion. The amide product will therefore
be accompanied by hydrogen halide. Thus two equivalents of ammonia are consumed in the reaction, one consumed in
neutralizing the acidic hydrogen halide.
89
Esterification of Acid Halides
Carboxylic Acids and Derivatives
O
R
O
C
R'OH
+
Cl
R
Alcohol
Acid halide
C
Ester
OR'
O
O
R'OH
Alcohol
+
R C
Cl
Acid halide
R
R
O
C
O
-
C
O
R' + H
Cl
Tetrahedral
intermediate
O
C
O
R
Cl
O
H
R'
Cl
R
O
R' + H
R
C
R'
O
+ H
R'
O
+ H
C
-
+
Cl
C
OR'
Ester
+
O
Cl
R
HCl
Because of their relative thermodynamic instability, acyl halides are good starting points for the formation of the whole
array of carboxylic acid derivatives (carboxylic acids, amides, esters, or acid anhydrides). An alcohol, like water or ammonia, begins the reaction by donating an electron pair to the acyl carbon. An ester is formed when an alcohol performs
as the nucleophile in an acyl substitution reaction.
90
Esterification of Acid Anhydrides
O
O
O
R
Carboxylic Acids and Derivatives
C
R'OH
+
R
C
O
R
Alcohol
Acid anhydride
O
O
O
R
C
O
C
Acid anhydride
R
R
R'OH
+
C
O
C
R
O
O
C
C
O
+
OR'
C
C
R
Tetrahedral
intermediate
+
O R'
C
R
H
H
O
R' + H
O
O
O
R' + H
+
O R'
C
R
R
-
C
O
O
O
O
R
O
H
R'
R
R
O
Alcohol
-
OR'
C
Ester
Cl
-
HCl
Ester
Acid anhydrides are somewhat unstable carboxylic acid derivatives. Like acyl halides, which are also unstable, acid
anhydrides may be hydrolyzed, aminolyzed, or esterified through acyl substitution.
91
Saponification of Esters
Carboxylic Acids and Derivatives
-
O
R
O
OH
C
OR'
Base
C
R
O
-
+
Carboxylate anion
Ester
O
-
O
R
C
Ester
R
OH
-
Base
OR'
R
C
R
OR'
R'OH
Alcohol
OH
O
C
OH
OR'
Tetrahedral
intermediate
O
O
O
OR'
C
R
OH
C
OH
Carboxylic
acid
+
-
OR'
Alkoxide
anion
R
C
O
OR'
H
H
O
R
C
O
-
Carboxylate anion
+
R'OH
Alcohol
Refer to the order of stability among carboxylic acid derivatives to predict the ease of carrying out a given acyl transfer
reaction. Among common derivatives, the acyl chloride form is the most unstable, followed in order by acid anhydride,
ester, amide, and lastly carboxylate (or carboxylic acid), the most stable (lowest free energy). Reaction equilibrium favors
the more stable form. For this reason it is a simple process to carry out the saponification of an ester by a strong base and
transform the relatively unstable ester molecule into a carboxylate anion. The most common use of this reaction is the
saponification of triglyceride to make soap.
92
Nitrile Hydrolysis
Carboxylic Acids and Derivatives
-
O
1. OH
R
N
C
Nitrile
+
2. H3O
R
R
H2O
Base
C
O
N
C
R
O
N
C
N
-
O
H
C
R
-
H
R
H
-
OH
OH
C N
Nitrile
OH
Carboxylic acid
Base then
Acid
R
C
O
1. OH
+
H
2. H3O
C
O
R
H
R
C
C
R OH- NH2
Amide
H2O
N
R
O
N
R
C
C
-
-
O
+
+
H3O
NH3
O
C
R
R
N
R
Carboxylate anion
+
+
H3O
Acid
Ammonia
Tetrahedral
intermediate
-
O
NH2
R
O
HC
C
R
H
C
-
OH
R
-
OH
R
Carboxylic
acid
NH3
NH2
C
-
N
NH2
continued
93
H
O
H
O
NH2
C
OH
O
-
N
O
OH
-
NH2
C
NH2
C
O
C
H
N
O
OH
O
O
-
C
R
O
H +
OH
O
R
OH
C
C
R
NH2
-
NH2
OH
N
R
C
R
R
NH2
O
H
H
OH
O
RO
R
OH
-
H
C
C
R
H
N
O
O
H
C
C
R
-
O
OH
O
O
-
H
C
R
N
+
-
O
-
NH2
R
Amine
ion
C
NH2
O
H
O
C
OH
R
Carboxylic acid
The electropositive nitrile carbon is similar to a carbonyl carbon in that it can accept the approach of a nucleophile for
addition, although the overall process is significantly different with nitriles. Nitrile hydrolysis begins with the nucleophilic
addition of hydroxide anion to the nitrile. The first intermediate formed then takes a proton from water and subsequently
undergoes an intramolecular rearrangement to form an amide. This amide is temporary, however, in a strong base environment, becoming transformed through the acyl substitution hydrolysis to form the carboxylate anion.
Nitrile Reduction
Carboxylic Acids and Derivatives
R
C
Nitrile
N
LiAlH4
Reducing
agent
R
CH2 NH2
Amine
Nitrile is a highly oxidized form, and it will mine the reducing agent, LiAlH4, for its hydrides (H–). The reduction of a
nitrile produces an amine.
94
Hofmann Rearrangement
Carboxylic Acids and Derivatives
O
C
R
Amide
O
C
R
N
-N
C
OH, Br2
-
+
Br
N
-
-
OH
OH, Br2
R
H2O
O
R
C
-N
C
R
H2O
N
H
Br
- R
N
C - C Br+ H+
N
O
O
H
O
R
C N
H
N
H
O
H
H
-
N
O
R
C
-
+ H
O
H
C
N
H
Br
O
R
-
N
Br
R
C
-
N R +
H O+ CH2O
N-Alkyl isocyanate
N
Br
R
+
O
H2O
O
C R - Br
C
R N HN
H O
N
C + H
O
H
Betaine
intermediate
O
R
N
H O
H
N-Alkylcarbamic acid
C RN
N
H
continued
-
C
O
R
95
+
-
Br
R
N
+ H
O
H
O
O
C
O
O
C
H O
R
-
CO2
-
Br
R
OH
N
O
- C + H
CO
O
H
R
NH
Br
O R
N
H
-R CC N+ H
O Br
O
H
R
H
N
H
Amine
C
R
OH
O
R
-
OH
O
O
H
H
N R
H
O
H
H2O
CO2
+
H
R
N
Br
N-Bromo amide
Br
O
C
H
H
N
+
C
H
R
N
Conjugate base
of amide
C
Conjugate base
of N-Bromo amide
O
Carbon
dioxide
O
-
O
H
N
H C
R
CO2
+
O
H
H
N
H
Br
R
C
-
H
H
ON
R
Amine
O
R
Halogen in
OAqueous Base
C
H
H
N
Halogen in Aqueous
Base
OH, Br2
C
R
R
H2O
-
H
H
Amide
O
-
OH, Br2
H
H
N
H O
C
N
R
H
CO2
+
Carbon dioxide
Hofmann rearrangement converts an amide, with the loss of one carbon, into an amine. Beginning with the amide, strong
base, and halogen, the strong base ionizes the amide to form an amide anion. Amide anions have certain characteristics
in common with the enolate anions, and halogenation occurs in manner similar to the α-halogenation of aldehydes and
ketones. Halogenation enhances the acidity of the remaining hydrogen, which the base removes easily. To assist the task
of retaining in memory the formidable Hofmann rearrangement mechanism, imagine the point of view of nitrogen atom
at this point. In the bromoamide anion, nitrogen has one bond to a carbonyl carbon, which has the strong electronegative
pull of oxygen working across it, and another bond to bromine, which also pulls tenaciously on electrons. From the point
of view of nitrogen, these are two greedy neighbors. Intramolecular electron pair migrations occur to stabilize the entire
system as an alkyl shift occurs from the carbonyl carbon onto nitrogen and the departure of halide ion. Isocyanate results,
which contains a very electropositive carbon that draws the approach of a nucleophilic water molecule. This leads to
N-alkylcarbamic acid, which is still unstable. Decarboxylization occurs as the last major step, releasing carbon dioxide
to leave the final amine, with a new carbon-nitrogen bond.
96