Organic Chemistry 2 Notes

Chapter 15
Introduction to Organometallic Compounds

William H. Brown Beloit College
William H. Brown
Christopher S. Foote
Brent L. Iverson
Eric Anslyn
www.cengage.com/chemistry/brown
15-1
Organometallic Compounds
Organometallic compound: A compound that contains a carbon-
metal bond.
In this chapter, we focus on organometallic compounds of Mg, Li,
and Cu.
These classes illustrate the usefulness of organometallics in
modern synthetic organic chemistry.
They illustrate how the use of organometallics can bring about
transformations that cannot be accomplished in any other way.
3
Other Reactions of Alkyl Halides:
Grignard Reagents
Reaction of RX with Mg in ether or THF
Product is RMgX an organometallic compound (alkyl-metal bond)
R is alkyl 1, 2, 3, aryl, alkenyl
X = Cl, Br, I
RLi
Organolithium reagents
Prepared by reaction of an alkyl, aryl, or alkenyl
halide with lithium metal.
Cl
+
+
1-Chlorobutane Butyllithium
pentane
2 Li Li Cl
Li
RMgX and RLi
RMgX and RLi are valuable in synthesis as nucleophiles.
The carbon bearing the halogen is transformed from an electrophile
to a nucleophile.
Their most valuable use is addition to the electrophilic carbon of the
C=O group of aldehydes, ketones, carboxylic esters, and acid
chlorides to form a new carbon-carbon bonds.
Br
-
C Br
CH
3
CH
2
CH
2
H
H
C
-
CH
3
CH
2
CH
2
H
H
Mg
2 +
+ -
carbon is an
electrophile
carbon is a
nucleophile
RMgX and RLi
Reaction with proton acids
RMgX and RLi are strong bases. RLi are extremely strong bases.
They remove these types of acidic protons readily.
CH
3
CH
2
-MgBr H-OH
CH
3
CH
2
-H
Mg
2 +
OH
-
Br
-
Weaker
base
Stronger
base
Weaker
acid
Stronger
acid
pK
a
51 pK
a
15.7
+
+
+ -
pK
e q
= -35
-
+
+ +
R
2
NH ArOH RSH RCOOH ROH HOH
RC CH
1 and 2
Amines
Alcohols
Water Phenols Thiols Carboxylic
acids
pK
a
4-5 pK
a
8-9 pK
a
9-10 pK
a
15.7 pK
a
16-18 pK
a
38-40
Terminal
alkynes
pK
a
25
RMgX and RLi
Reaction with oxiranes (epoxides)
Reaction of RMgX or RLi with an oxirane followed by
protonation gives a primary alcohol with a carbon chain two
carbons longer than the original chain.
H
3
O
+
OH
Mg Br
O
O Mg Br
+
+
Butylmagnesium
bromide
Ethylene
oxide
A magnesium
alkoxide
1-Hexanol
RMgX and RLi
Reaction with oxiranes (epoxides)
The major product corresponds to S
N
2 attack of RMgX or RLi
on the less hindered carbon of the epoxide.
Mg Br
H
2
O
HCl
Methyloxirane
(Propylene oxide)
(racemic)
A magnesium
alkoxide
1-Phenyl-2-propanol
(racemic)
+
Phenyl-
magnesium
bromide
OH
O
-
MgBr
+
O
9
Organometallic Coupling Reactions
RLi reacts with copper iodide to give lithium dialkylcopper (Gilman
reagents)
Lithium dialkylcopper reagents react with alkyl halides to give alkanes
10
Utility of Organometallic Coupling in Synthesis
Coupling of two organometallic molecules produces larger molecules of defined structure
Aryl and vinyl organometallics also effective
Coupling of lithium dialkylcopper molecules proceeds through trialkylcopper intermediate
11
20. Conjugated Dienes and
Ultraviolet Spectroscopy
12
Conjugated and Nonconjugated Dienes
Compounds can have more than one double or triple bond
If they are separated by only one single bond they are conjugated
and their orbitals interact
The conjugated diene 1,3-butadiene has properties that are very
different from those of the nonconjugated diene, 1,5-pentadiene
13
Measuring Stability
From heats of hydrogenation, we can compare relative stabilities of conjugated
and unconjugated dienes.
14
Molecular Orbital Description of 1,3-Butadiene
The single bond between the conujgated double
bonds is shorter and stronger than sp
3-
sp
3
C-C. It is
strengthened by overlap of p orbitals
The bonding -orbitals are made from 4 p orbitals that
provide greater delocalization and lower energy than
in isolated C=C
15
Electrophilic Additions to Conjugated Dienes:
Allylic Carbocations
Review: Markovnikov regiochemistry via more stable carbocation
16
Carbocations from Conjugated Dienes
Addition of H
+
leads to delocalized secondary allylic carbocation
17
Kinetic and Thermodynamic Control
Kinetic
control:
The
distribution
of products
is
determined
by their
relative
rates of
formation.
Thermodynamic
control:
The
distribution of
products is
determined by
their relative
stabilities.
18
The Diels-Alder Cycloaddition Reaction
Conjugate dienes can combine with alkenes to form six-membered cyclic compounds
The formation of the ring involves no intermediate (concerted formation of two bonds)
Discovered by Otto Paul Hermann Diels and Kurt Alder in Germany in the 1930s
19
Generalized View of the Diels-Alder Reaction
In 1965, Woodward and Hoffman showed this shown to be an example of the
general class of pericyclic reactions
Involves orbital overlap, change of hydbridization and electron delocalization in
transition state
The reaction is called a cycloaddition
The alkene component is called a dienophile
Alkynes can also be dienophiles
20
Stereochemistry of the Diels-Alder Reaction
21
Summary
Conjugate systems are more stable than non-conjugate system
Experimental evidence: (a) measurement of heat of formation (H)
(b) bond length
Theoretical rationale: Energy calculation based on MO theory
Chemical properties:
1. Kinetic control vs. thermodynamic control 2. [4+2] reaction
22
UV-Visible Spectroscopy
Region of
Spectrum
Wavelength
(nm)

kcal/mol
near ultraviolet
visible
200-400
400-700
71.5 - 143
40.9 - 71.5
Energy

kJ/mol
299-598
171-299
724 (173)
552 (132)
448 (107)
385 (92)
290
268
217
165
max
Structural Formula Name
(3E,5E)-1,3,5,7-Octatetraene
(3E)-1,3,5-Hexatriene
1,3-Butadiene
Ethylene
(nm)
Energy
[kJ (kcal)/mol]
max
: wavelength where UV
absorbance for a compound is
greatest
max
increases as conjugation
increases (lower energy)
23
Quantitative Use of UV Spectra
Beer-Lambert law: The relationship between absorbance, concentration,
and length of the sample cell (cuvette):
A = absorbance (unitless): A measure of the extent to which a
compound absorbs radiation of a particular wavelength.
= molar absorptivity (M
-1
cm
-1
): A characteristic property of a
compound; values range from zero to 10
6
M
-1
cm
-1
.
I = length of the sample tube (cm)
Beer-Lambert Law: A = c l
I
I
o
Absorbance (A) = log
Absorbance for a particular compound in a specific solvent at a specified wavelength
is directly proportional to its concentration
You can follow changes in concentration with time by recording absorbance at the
wavelength
24
21. Benzene and Aromaticity
25
Benzene
Aromatic was used to described some fragrant compounds in early 19
th
century
Current: distinguished from aliphatic compounds by electronic configuration
In 1872, August Kekul proposed the following structure for benzene. This
structure, however, did not account for the unusual chemical reactivity of
benzene.
C
H
C
H
C
H
C
H C
H
C
H
C
C
C
C
C
C
H
H
H
H
H
H
We often represent benzene as a hybrid of two equivalent Kekul structures.
Each makes an equal contribution to the hybrid and thus the C-C bonds are
neither double nor single, but something in between.
Benzene as a hybrid of two equivalent
contributing structures
26
Benzene
The concepts of hybridization of atomic orbitals and the theory of resonance,
developed in the 1930s, provided the first adequate description of benzenes
structure.
The carbon skeleton is a planar regular hexagon. All its C-C bonds are
the same length: 139 pm between single (154 pm) and double (134
pm) bonds.
All C-C-C and H-C-C bond angles 120.
Electron density in all six C-C bonds is identical.
sp
2
-sp
2

sp
2
-1s
109 pm
120
120
120
139 pm
C
C
C
C
C C
H
H
H
H
H
H
27
Benzene
The carbon framework with the six 2p orbitals. Each C is sp
2
and
has a p orbital perpendicular to the plane of the six-membered
ring
Overlap of the parallel 2p orbitals forms one torus above the plane
of the ring and another below it. This orbital represents the lowest-
lying pi-bonding molecular orbital.
28
Drawing Benzene
The two benzene resonance forms can be represented by a single structure
with a circle in the center to indicate the equivalence of the carboncarbon
bonds
This does not indicate the number of electrons in the ring but reminds us
of the delocalized structure
We shall use one of the resonance structures to represent benzene for ease
in keeping track of bonding changes in reactions
29
Structure and Stability of Benzene
Benzene reacts slowly with Br
2
to give bromobenzene (where Br replaces H)
This is substitution rather than the rapid addition reaction common to compounds
with C=C, suggesting that in benzene there is a higher barrier
30
Heats of Hydrogenation as Indicators of Stability
Resonance energy: The
difference in energy between a
resonance hybrid and the
most stable of its hypothetical
contributing structures in
which electrons are localized
on particular atoms and in
particular bonds.
One way to estimate the
resonance energy of
benzene is to compare the
heats of hydrogenation of
benzene and
cyclohexene.
Benzene has about 150 kJ more
stability than an isolated set of
three double bonds
31
Concept of Aromaticity
The underlying criteria for aromaticity were recognized in the early 1930s
by Erich Hckel, based on molecular orbital (MO) calculations.
To be aromatic, a compound must
Be cyclic.
Have one p orbital on each atom of the ring.
Be planar or nearly planar so that there is continuous or nearly
continuous overlap of all p orbitals of the ring.
Have a closed loop of (4n + 2) pi electrons in the cyclic arrangement of
p orbitals. (n is 0,1,2,3,4). For n=1: 4n+2 = 6; benzene is stable and
the electrons are delocalized
32
Molecular Orbital Description of Benzene
The 6 p-orbitals combine to give
Three bonding orbitals with 6 electrons,
Three antibonding orbitals with 0 electrons
Orbitals with the same energy are degenerate
33
Molecular Orbital Description of Benzene
Frost circle: A graphic method for determining the relative order of pi MOs in
planar, fully conjugated monocyclic compounds.
Inscribe in a circle a polygon of the same number of sides as the ring to be
examined such that one of the vertices of the polygon is at the bottom of the circle.
The relative energies of the MOs in the ring are given by where the vertices of the
polygon touch the circle.
Those MOs
Below the horizontal line through the center of the ring are bonding MOs,
on the horizontal line are nonbonding MOs,
above the horizontal line are antibonding MOs.
34
Concept of Anti-aromaticity
Antiaromatic hydrocarbon: A monocyclic, planar, fully conjugated
hydrocarbon with 4n pi electrons (4, 8, 12, 16, 20...).
An antiaromatic hydrocarbon is especially unstable relative to an open-
chain fully conjugated hydrocarbon of the same number of carbon
atoms.
Cyclobutadiene is antiaromatic.
35
Compounds With 4n Electrons Are Not
Aromatic (May be Antiaromatic)
4- and 8-electron compounds are not delocalized
(single and double bonds)
Cyclobutadiene is so unstable that it dimerizes by a
self-Diels-Alder reaction at low termperature
Cyclooctatetraene:
with 8 pi electrons is not aromatic; it shows
reactions typical of alkenes.
X-ray studies show that the most stable
conformation is a nonplanar tub conformation.
Although overlap of 2p orbitals occurs to form pi
bonds, there is only minimal overlap between sets
of 2p orbitals because they are not parallel.
has four double bonds, reacting with Br
2
, KMnO
4
,
and HCl as if it were four alkenes.
cyclobutadiene
cyclooctatetraene
36
If it is conjugated planar comformation
37
Aromatic Ions
Any neutral, monocyclic, unsaturated hydrocarbon with an odd number of
carbons must have at least one CH
2
group and, therefore, cannot be
aromatic.
Cyclopropene, for example, has the correct number of pi electrons to be
aromatic, 4(0) + 2 = 2, but does not have a closed loop of 2p orbitals.
Cyclopropene Cyclopentadiene Cycloheptatriene
CH
2
CH
2
CH
2
38
Aromatic Ions
If, however, the CH
2
group of cyclopropene is transformed into a CH
+
group in which carbon is sp
2
hybridized and has a vacant 2p orbital, the
overlap of orbitals is continuous and the cation is aromatic.
Cyclopropenyl cation represented as a hybrid
of three equivalent contributing structures
+
H
H
H
H
H
H
H
H
H
+
+
39
Aromatic Ions
The 4n + 2 rule applies to ions as well as neutral species
Both the cyclopentadienyl anion and the cycloheptatrienyl cation are
aromatic
The key feature of both is that they contain 6 electrons in a ring of
continuous p orbitals
40
Aromaticity of the Cyclopentadienyl Anion
1,3-Cyclopentadiene contains conjugated double bonds joined by a CH
2
that
blocks delocalization
Removal of H
+
at the CH
2
produces a cyclic 6-electron system, which is stable
Removal of H
-
or H generate nonaromatic 4 and 5 electron systems
Relatively acidic (pKa = 16) because the anion is stable
41
Aromatic Hydrocarbons
[14]Annulene
(aromatic)
HH
HH
H
H
H
H
H H
H
H
H H
[18]Annulene
(aromatic)
H
H
H
H
H
H
H
H
H H
H
H
H
H
H
H
H
H
[10]Annulene
Nonplanar: not aromatic
42
Naphthalene Orbitals
Three resonance forms and delocalized electrons
43
Naming Aromatic Compounds
Many common names are retained.
Toluene Cumene Ethylbenzene Styrene
Phenol Aniline Benzoic acid Anisole
COOH NH
2
OCH
3
OH
Benzaldehyde
CHO
44
Naming Aromatic Compounds
Monosubstituted benzenes systematic names as hydrocarbons with
benzene
C
6
H
5
Br = bromobenzene
C
6
H
5
NO
2
= nitrobenzene, and C
6
H
5
CH
2
CH
2
CH
3
is propylbenzene
45
The Phenyl Group
When a benzene ring is a substituent, the term phenyl is used (for
C
6
H
5
)
You may also see Ph or in place of C
6
H
5
Benzyl refers to C
6
H
5
CH
2
46
Disubstituted Benzenes
Relative positions on a benzene ring
ortho- (o) on adjacent carbons (1,2)
meta- (m) separated by one carbon (1,3)
para- (p) separated by two carbons (1,4)
Describes reaction patterns (occurs at the para position)
47
Naming Benzenes With More Than Two Substituents
Choose numbers to get lowest possible values
List substituents alphabetically with hyphenated numbers
Common names, such as toluene can serve as root name (as in TNT)
48
Aromatic Heterocycles: Pyridine and Pyrrole
Heterocyclic compounds contain elements other than carbon in a ring, such
as N,S,O,P
Aromatic compounds can have elements other than carbon in the ring
There are many heterocyclic aromatic compounds and many are very
common
Cyclic compounds that contain only carbon are called carbocycles (not
homocycles)
Nomenclature is specialized
49
Pyridine
A six-membered heterocycle with a nitrogen atom in its ring
electron structure resembles benzene (6 electrons)
The nitrogen lone pair electrons are not part of the aromatic system
(perpendicular orbital)
Pyridine is a relatively weak base compared to normal amines but
protonation does not affect aromaticity
50
Pyrrole
A five-membered heterocycle with one nitrogen
electron system similar to that of cyclopentadienyl anion
Four sp2-hybridized carbons with 4 p orbitals perpendicular to the ring and
4 p electrons
Nitrogen atom is sp
2
-hybridized, and lone pair of electrons occupies a p
orbital (6 electrons)
Since lone pair electrons are in the aromatic ring, protonation destroys
aromaticity, making pyrrole a very weak base
51
Spectroscopy of Aromatic Compounds
IR: Aromatic ring CH
stretching at 3030 cm
1
and peaks 1450 to
1600 cm
1
UV: Peak near 205 nm
and a less intense
peak in 255-275 nm
range
52
Spectroscopy of Aromatic Compounds
1
H NMR: Aromatic Hs strongly deshielded by ring and absorb between 6.5
and 8.0
Peak pattern is characteristic positions of substituents
Aromatic ring oriented perpendicular to a
strong magnetic field, delocalized
electrons producing a small local magnetic
field
Opposes applied field in middle of ring
reinforces applied field outside of ring
Results in outside Hs resonance at
lower field
53
13
C NMR of Aromatic Compounds
Carbons in aromatic ring absorb
at 110 to 140
Shift is distinct from alkane
carbons but in same range as
alkene carbons
54
22. Chemistry of Benzene:
ElectrophilicAromatic Substitution
55
Reactions at aromatic skeleton:
Mechanism #1: Electrophilic substitution
Mechanism # 2: Nucleophilic substitution
Mechanism #3: Benzyne intermediated substitution
Evidence of benzyne mechanism
Structure of benzyne
Overview
Reactions at the Benzylic position:
Oxidation
Halogenation
Hydrogenolysis
56
Comparison of Reactivity in Reduction
Aromatic rings are inert to catalytic hydrogenation under conditions that reduce
alkene double bonds
Can selectively reduce an alkene double bond in the presence of an aromatic ring
Reduction of an aromatic ring requires more powerful reducing conditions
Substitution Reactions of Benzene and Its Derivatives
Reactions of benzene lead to the retention of the aromatic core
Electrophilic aromatic substitution replaces a proton on benzene with
another electrophile
General question: What is the electrophile and how is it generated?
1: Electrophilic substitution
Chlorination
Step 1: Formation of a chloronium ion.
Step 2: Attack of the chloronium ion on the ring.
Cl Cl Cl
Cl
Cl
Fe
Cl
Cl
Cl Fe Cl Cl
Cl
FeCl
4
+
A molecular complex
with a positive charge
on chlorine
Ferric chloride
(a Lewis
acid)
Chlorine
(a Lewis
base)
+
+
An ion pair
containing a
chloronium ion
+
+
+
Resonance-stabilized cation intermediate; the positive
charge is delocalized onto three atoms of the ring
+
slow, rate
determining
Cl
H H
Cl
H
Cl
Cl
Step 3: Proton transfer regenerates the aromatic character of the ring.
Cl
H
Cl-FeCl
3
Cl
HCl
FeCl
3
Chlorobenzene
f ast
Cation
intermediate
+ +
+
-
+
Wheland
Intermediate
59
Bromination of Aromatic Rings
Substitution Reactions of Benzene and Its Derivatives
+
Benzenesulfonic acid
Sulfonation:
H SO
3
H SO
3
H
2
SO
4
+ +
An alkylbenzene
Alkylation:
R RX
Al X
3
HX
+
+
Acylation:
An acylbenzene
H
RCX
Al X
3
HX
O
CR
O
H
61
Aromatic Nitration
The combination of nitric acid and sulfuric acid produces NO
2
+
(nitronium ion)
The reaction with benzene produces nitrobenzene
COOH
NO
2
3 H
2
Ni
COOH
NH
2
2H
2
O
4-Aminobenzoic acid
4-Nitrobenzoic acid
+
(3 atm)
+
Application:
62
Aromatic Sulfonation
Substitution of H by SO
3
(sulfonation)
Reaction with a mixture of sulfuric acid and SO
3
Reactive species is sulfur trioxide or its conjugate acid
Reaction occurs via Wheland intermediate and is reversible
63
Alkylation of Aromatic Rings: The FriedelCrafts Reaction
Step 1: Formation of an alkyl cation as an ion pair.
Step 2: Attack of the alkyl cation on the aromatic ring.
Step 3: Proton transfer regenerates the aromatic ring.
R Cl Cl Al
Cl
Cl
R Cl
Cl
Cl
Al Cl R
+
AlCl
4
-
An ion pair containing
a carbocation
+
-
+
A molecular
complex
+
R
+
R
H
R
H
R
H
A resonance-stabilized cation
+
+
+
H
R
Cl AlCl
3
R
AlCl
3
HCl
+ + +
64
Limitations of the Friedel-Crafts Alkylation
Only alkyl halides can be used (F, Cl, I, Br)
Aryl and vinylic halides do not react (their carbocations are too hard to form)
Will not work with rings containing an amino group substituent or a strongly
electron-withdrawing group
65
Synthetic Application
Aromatic ring activates neighboring carbonyl group toward reduction
Ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd
catalyst
Oxidation
Halogenation
Hydrogenolysis
Review
Cl Cl Cl
Cl
Cl
Fe
Cl
Cl
Cl Fe Cl Cl Cl FeCl
4
+
A molecular complex
with a positive charge
on chlorine
Ferric chloride
(a Lewis
acid)
Chlorine
(a Lewis
base)
+
+
An ion pair
containing a
chloronium ion
R Cl Cl Al
Cl
Cl
R Cl
Cl
Cl
Al Cl R
+
AlCl
4
-
An ion pair containing
a carbocation
+
-
+
A molecular
complex
E
+
= X
+
E
+
= N
+
E
+
= S
+
E
+
= C
+
67
O
C
O
O
O
C
H
O
O OH
C
O
O
A cyclohexadienone
intermediate
+
Sodium
phenoxide
Salicylate anion
keto-enol
tautomerism
(1) (2)
OH
NaOH
H
2
O
O
-
Na
+
CO
2
H
2
O
OH
CO
-
Na
+
O
HCl
H
2
O
OH
O
COH
Phenol Sodium
phenoxide
Sodium salicylate Salicylic acid
Kolbe Carboxylation
Aspirin
68
Substituent Effects in Aromatic Rings
-OCH
3
is ortho-para directing.
-COOH is meta directing.
OCH
3
HNO
3
CH
3
COOH
OCH
3
NO
2
OCH
3
NO
2
H
2
O
p-Nitroanisole
(55%)
o-Nitroanisole
(44%)
Anisole
+ +
+
COOH
HNO
3
H
2
SO
4
NO
2
COOH COOH
NO
2
NO
2
COOH
100C
m-Nitro-
benzoic
acid
(80%)
Benzoic
acid
+ + +
o-Nitro-
benzoic
acid
(18%)
p-Nitro-
benzoic
acid
(2%)
69
An Explanation of Substituent Effects
Weakly
activating
O
r
t
h
o
-
p
a
r
a

D
i
r
e
c
t
i
n
g
Weakly
deactivating
Moderately
activating
Strongly
activating
NH
2
NHR NR
2
OH
NHCR NHCAr
OR
OCAr OCR
R
F Cl Br I
:::::
: :
:::
:
:
:
:
:
:
:
:
:
:
:
: : : :
Strongly
deactivating
Moderately
deactivating
CH
O O
CR COH
SO
3
H
COR
O
CNH
2
NO
2
NH
3
+
CF
3
CCl
3
M
e
t
a

D
i
r
e
c
t
i
n
g
C N
O O O O
O O
Alkyl, phenyl, and all other substituents in which the atom
bonded to the ring has an unshared pair of electrons are
ortho-para directing. All other substituents are meta
directing.
All ortho-para directing groups except the halogens are
activating toward further substitution. The halogens are
weakly deactivating.
70
Ortho- and Para-Directing Activators: OH and NH
2
Alkoxyl, and amino groups have a strong, electron-donating resonance
effect
Most pronounced at the ortho and para positions
71
Meta-Directing Deactivators
Inductive and resonance effects reinforce each other
Ortho and para intermediates destabilized by deactivation from carbocation
intermediate
Resonance cannot produce stabilization
72
Origins of Substituent Effects
An interplay of inductive effects and resonance effects
Inductive effect - withdrawal or donation of electrons through a bond
Resonance effect - withdrawal or donation of electrons through a bond
due to the overlap of a p orbital on the substituent with a p orbital on the
aromatic ring
73
Resonance Effects Electron Donation
Halogen, OH, alkoxyl (OR), and amino substituents donate electrons
electrons flow from the substituents to the ring
Effect is greatest at ortho and para
74
Ortho- and Para-Directing Deactivators: Halogens
Electron-withdrawing inductive effect outweighs weaker electron-donating
resonance effect
Resonance effect is only at the ortho and para positions, stabilizing
carbocation intermediate
75
Summary Table: Effect of Substituents in
Aromatic Substitution
76
Important Application
CH
3
K
2
Cr
2
O
7
H
2
SO
4
HNO
3
H
2
SO
4
CH
3
NO
2
COOH
H
2
SO
4
HNO
3
K
2
Cr
2
O
7
H
2
SO
4
COOH
NO
2
COOH
NO
2
m-Nitrobenzoic
acid
p-Nitrobenzoic
acid
77
Trisubstituted Benzenes: Additivity of Effects
If the directing effects of the two groups are the same, the result is additive
78
Substituents with Opposite Effects
If the directing effects of two groups oppose each other, the more
powerful activating group decides the principal outcome
Usually gives mixtures of products
79
Meta-Disubstituted Compounds Are Unreactive
The reaction site is too hindered
To make aromatic rings with three adjacent substituents, it is best to start with
an ortho-disubstituted compound
80
Nucleophilic Aromatic Substitution
Aryl halides with electron-withdrawing substituents
ortho and para react with nucleophiles
Form addition intermediate (Meisenheimer
complex) that is stabilized by electron-withdrawal
Halide ion is lost to give aromatic ring
Aryl halides do not undergo
nucleophilic substitution by
either S
N
1 or S
N
2
pathways.
They do undergo
nucleophilic substitutions,
but by mechanisms quite
different from those of
nucleophilic aliphatic
substitution.
Nucleophilic aromatic
substitutions are far less
common than electrophilic
aromatic substitutions.
2: Nucleophilic substitution
81
Application: Alkali Fusion of Aromatic Sulfonic Acids
Sulfonic acids are useful as intermediates
Heating with NaOH at 300 C followed by neutralization with acid
replaces the SO
3
H group with an OH
Example is the synthesis of p-cresol
2: Nucleophilic substitution
82
Benzyne
Phenol is prepared on an industrial scale by treatment of chlorobenzene
with dilute aqueous NaOH at 340C under high pressure
The reaction involves an elimination reaction that gives a triple bond
The intermediate is called benzyne
3: Benzyne intermediated substitution
83
Evidence of Benzyne Intermediate
3-Methylphenol
(m-Cresol)
2-Methylphenol
(o-Cresol)
+
CH
3
Cl
OH
CH
3
CH
3
OH
1. NaOH, heat, pressure
2. HCl, H
2
O
84
Structure of Benzyne
Benzyne is a highly distorted alkyne
The triple bond uses sp
2
-hybridized carbons, not the usual sp
The triple bond has one bond formed by pp overlap and by weak sp
2
sp
2
overlap
85
Reactions at aromatic skeleton:
Mechanism #1: Electrophilic substitution
Mechanism # 2: Nucleophilic substitution
Mechanism #3: Benzyne intermediated substitution
Review
Oxidation
Halogenation
Hydrogenolysis
E
+
= X
+
N
+
S
+
C
+
Mechanism #1:
Mechanism #2: S
N
Ar
Mechanism #3:
86
Benzylic Oxidation
Benzene is unaffected by strong oxidizing agents such as H
2
CrO
4
and KMnO
4
An alkyl group with at least one hydrogen on its benzylic carbon is oxidized to
a carboxyl group.
1,4-Dimethylbenzene
(p-xylene)
1,4-Benzenedicarboxylic acid
(terephthalic acid)
CH
3
H
2
SO
4
K
2
Cr
2
O
7
H
3
C
COH
O
HOC
O
Oxidation
Halogenation
Hydrogenolysis
87
BenzylicHalogenation
Reaction of an alkylbenzene with N-bromo-succinimide (NBS) and
benzoyl peroxide (radical initiator) introduces Br into the side chain
CH
3
Cl
2
+
CH
2
Cl
HCl
+
Toluene
heat
or light
Benzyl chloride
Oxidation
Halogenation
Hydrogenolysis
88
Mechanism of NBS (Radical) Reaction
Abstraction of a benzylic hydrogen atom generates an intermediate
benzylic radical
Reacts with Br
2
to yield product
Br radical cycles back into reaction to carry chain
Br
2
produced from reaction of HBr with NBS
Oxidation
Halogenation
Hydrogenolysis
89
Benzylic Hydrogenolysis
Hydrogenolysis: Cleavage of a single bond by H
2
Among ethers, benzylic ethers are unique in that they are cleaved under
conditions of catalytic hydrogenation.
O
H
2
Pd/ C
OH
Me
+
Benzyl butyl ether Toluene 1-Butanol
+
this bond
is cleaved
Oxidation
Halogenation
Hydrogenolysis
90
Chapter 10
Alcohols and Phenols
91
Alcohols and Phenols
Alcohols contain an OH group connected to a a saturated C (sp
3
)
They are important solvents and synthetic intermediates
Phenols contain an OH group connected to a carbon in a benzene ring
Methanol, CH
3
OH, called methyl alcohol, is a common solvent, a fuel additive,
produced in large quantities
Ethanol, CH
3
CH
2
OH, called ethyl alcohol, is a solvent, fuel, beverage
Phenol, C
6
H
5
OH (phenyl alcohol) has diverse uses - it gives its name to the
general class of compounds
General classifications of alcohols based on substitution on C to which OH is
attached
Methyl (C has 3 Hs), Primary (1) (C has two Hs, one R), secondary (2) (C
has one H, two Rs), tertiary (3) (C has no H, 3 Rs),
92
Nomenclature of Alcohols
IUPAC names
The parent chain is the longest chain that contains the OH group.
Number the parent chain to give the OH group the lowest possible
number.
Change the suffix -e to -ol.
Common names
Name the alkyl group bonded to oxygen followed by the word alcohol.
1-Propanol
(Propyl alcohol)
2-Propanol
(Isopropyl alcohol)
1-Butanol
(Butyl alcohol)
OH
OH
OH
2-Butanol
(sec-Butyl alcohol)
2-Methyl-1-propanol
(Isobutyl alcohol)
2-Methyl-2-propanol
(tert -Butyl alcohol)
OH
OH
OH
93
More Names
cis-3-Methylcyclohexanol
OH
OH
Bicyclo[4.4.0]decan-3-ol
1
4
5
8
10
9
1
2
2
3
3
4
5
6
7
6
Numbering of the
bicyclic ring takes
precedence over
the location of -OH
1
2 3
4 5
6
(E)-2-Hexene-1-ol
(t rans-2-Hexen-1-ol)
HO
94
Properties of Alcohols and Phenols: Hydrogen Bonding
The structure around O of the alcohol or
phenol is similar to that in water, sp
3
hybridized
Alcohols and phenols have much higher
boiling points than similar alkanes and alkyl
halides. WHY?
bp -24C
Ethanol
bp 78C
Dimethyl ether
CH
3
CH
2
OH CH
3
OCH
3
Alcohols Form Hydrogen Bonds
A positively polarized OH hydrogen atom from one molecule
is attracted to a lone pair of electrons on a negatively polarized
oxygen atom of another molecule
This produces a force that holds the two molecules together
These intermolecular attractions are present in solution but not
in the gas phase, thus elevating the boiling point of the solution
Alcohols Form Hydrogen Bonds
Hydrogen bonding:
When the positive end of one dipole is an H bonded to F, O, or N
(atoms of high electronegativity) and the other end is F, O, or N.
Alcohols Form Hydrogen Bonds with water
Alcohols are more soluble in water.
The presence of additional -OH groups in a
molecule further increases solubility in water.
sugar
98
Spectroscopy of Alcohols and Phenols
Characteristic OH stretching absorption at 3300 to 3600 cm
1
in the
infrared
Sharp absorption near 3600 cm
-1
except, if H-bonded: then broad
absorption 3300 to 3400 cm
1
range
Strong CO stretching absorption near 1050 cm
1
Phenol OH absorbs near 3500 cm
-1
13
C NMR: C bonded to OH absorbs at a lower field, 50 to 80
1
H NMR: electron-withdrawing effect of the nearby oxygen, absorbs at
3.5 to 4
Usually no spin-spin coupling between OH proton and neighboring
protons on C due to exchange reactions with moisture or acids
Spinspin splitting is observed between protons on the oxygen-
bearing carbon and other neighbors
Phenol OH protons absorb at 3 to 8
99
Basicity of alcohols
Weakly basic and weakly acidic
Alcohols are weak Brnsted bases
Protonated by strong acids to yield oxonium ions, ROH
2
+
100
Acidity of Alcohols
In dilute aqueous solution, alcohols are weakly acidic.
CH
3
O H
:
H O
H
[ CH
3
OH]
[ CH
3
O
-
] [ H
3
O
+
]
CH
3
O:
O
H
H H
+
+
= 10
- 15.5
pK
a
= 1 5.5
K
a
=
+
( CH
3
)
3
COH
( CH
3
)
2
CHOH
CH
3
CH
2
OH
H
2
O
CH
3
OH
CH
3
COOH
HCl
Hydrogen chloride
Acetic acid
Methanol
Water
Ethanol
2-Propanol
2-Methyl-2-propanol
Structural
Formula
Stronger
acid
Weaker
acid
Also given for comparison are p K
a
values for
water, acetic acid, and hydrogen chloride.
Compound
pK
a
-7
15.5
15.7
15.9
17
18
4.8
Simple alcohols are about as
acidic as water
Alkyl groups make an alcohol a
weaker acid
The more easily the alkoxide
ion is solvated by water the
more its formation is
energetically favored
Steric effects are important
Alkoxides are bases
used as reagents in
organic chemistry
101
Inductive Effects
Electron-withdrawing groups make an alcohol a stronger acid by stabilizing
the conjugate base (alkoxide)
102
Phenol Acidity
Phenols (pK
a
~10) are much more acidic than alcohols (pK
a
~ 16) due to
resonance stabilization of the phenoxide ion
Phenols react with NaOH solutions, forming soluble salts that are soluble in
dilute aqueous
A phenolic component can be separated from an organic solution by
extraction into basic aqueous solution and is isolated after acid is added to
the solution
103
Phenol Acidity
These 2 Kekul
structures are
equivalent
H
H
O
O
O
O
H
O
These three contributing structures
delocalize the negative charge
onto carbon atoms of the ring
H
O
O
O
O
H
O
The greater acidity of phenols compared with alcohols is due to the
greater stability of the phenoxide ion relative to an alkoxide ion.
104
Substituted Phenols
Can be more or less acidic than phenol itself
An electron-withdrawing substituent makes a phenol more acidic by
delocalizing the negative charge
Phenols with an electron-donating substituent are less acidic because these
substituents concentrate the charge
105
pK
a
Values for Typical OH Compounds
106
Phenols. Reactions
no reaction
+ X
RO
-
Na
+
OH CH
2
=CHCH
2
Cl
NaOH, H
2
O, CH
2
Cl
2
OCH
2
CH=CH
2
Phenyl 2-propenyl ether
(Allyl phenyl ether)
+
Phenol 3-Chloropropene
(Allyl chloride)
107
Phenols. Oxidation/Reduction
H
2
Cr O
4
Phenol
1,4-Benzoquinone
(p-Quinone)
O
O
OH
OH
OH
K
2
Cr
2
O
7
OH
OH
H
2
SO
4
K
2
Cr
2
O
7
H
2
SO
4
O
O
O
O
1,4-Benzoquinone
(p-Quinone)
1,2-Benzenediol
(Catechol)
1,2-Benzoquinone
(o-Quinone)
1,4-Benzenediol
(Hydroquinone)
1,4-Benzoquinone
(p-Quinone)
(reduction)
1,4-Benzenediol
(Hydroquinone)
O
O
OH
OH
Na
2
S
2
O
4
, H
2
O
Sodium dithionite
Chromic acid
Potassium dichromate
108
Preparation of Alcohols: an overview and review
109
Reactions of Alcohols
Two general classes of reaction
At the carbon of the CO bond
At the proton of the OH bond
110
Alcohols to alkoxides
Alcohols react with Li, Na, K, and other active metals to liberate hydrogen
gas and form metal alkoxides.
Alcohols are also converted to metal alkoxides by reaction with bases
stronger than the alkoxide ion.
One such base is sodium hydride.
Sodium methoxide
(MeO

Na
+
)
+
2 CH
3
O

Na
+
H
2
2 CH
3
OH
+
2 Na
Ethanol
Sodium ethoxide
CH
3
CH
2
OH CH
3
CH
2
O

Na
+
+
+
H
2
Na
+
H
Sodium
hydride
111
Alcohols to alkyl halides
3 alcohols react very rapidly with HCl, HBr, and HI.
Low-molecular-weight 1 and 2 alcohols are unreactive under these
conditions.
1 and 2 alcohols require concentrated HBr and HI to form alkyl
bromides and iodides.
OH + H
2
O + HCl
25C
Cl
2-Methyl-2-
propanol
2-Chloro-2-
methylpropane
reflux
1-Bromobutane
1-Butanol
+ +
HBr H
2
O
H
2
O
OH
Br
simple 1 alcohols react with HX by an S
N
2 mechanism.
112
2-Bromopentane 3-Bromopentane
(major product)
3-Pentanol
heat
+
+
HBr
+
H
2
O
OH
Br
Br
a product of
rearrangement

2-Bromo-2-methylbutane
(a product of rearrangement)
2,2-Dimethyl-1-
propanol
+ +
HBr
H
2
O OH
Br
reaction of 2 and 3 alcohols with HX occurs by an S
N
1 mechanism, and
involves a carbocation intermediate.
These alcohols react by a concerted loss of HOH and migration of an alkyl group.
113
An alternative method for the synthesis of 1 and 2 bromoalkanes is
reaction of an alcohol with phosphorus tribromide.
This method gives less rearrangement than with HBr.
PBr
3
H
3
PO
3
0
Phosphorous
acid
+
+
2-Methyl-1-propanol
(Isobutyl alcohol)
Phosphorus
tribromide
1-Bromo-2-methylpropane
(Isobutyl bromide)
OH
Br
Br O PBr
2
R-CH
2
H
P Br Br
Br
R-CH
2
-O-H
+ +
a good leaving group
+

Br
-
O PBr
2
R-CH
2
H
R-CH
2
-Br HO-PBr
2
+
+
+
S
N
2
Step 1:
Step 2:
114
Step 1:
Step 2:
Thionyl chloride is the most widely used reagent for the conversion of 1 and 2
alcohols to alkyl chlorides.
A base, most commonly pyridine or triethylamine, is added to catalyze the
reaction and to neutralize the HCl.
OH
SOCl
2
Cl
SO
2
HCl
+
3 amine
+
+
(S)-2-Octanol Thionyl
chloride
(R)-2-Chlorooctane
C
R
1
H
R
2
O H Cl-S-Cl
O
C
R
1
H
R
2
O S
O
Cl
H-Cl
+ +
An al kyl
chl orosul fi te
C
R
1
H
R
2
O
S
O
Cl
Cl
+
C
R
1
H
R
2
Cl
+ Cl
+
O
S
O S
N
2
115
Alcohols to sulfonates
116
Alcohols to alkenes
Tertiary alcohols are readily dehydrated with acid
Secondary alcohols require severe conditions (75% H
2
SO
4
, 100C) -
sensitive molecules don't survive
Primary alcohols require very harsh conditions impractical
Reactivity is the result of the nature of the carbocation intermediate
An alkene
An alcohol
C C
C C
H OH
+ H
2
O
acid
catalyst
Acid-catalyzed alcohol dehydration and alkene hydration are competing processes.
117
Alcohols to alkenes
180C
CH
3
CH
2
OH
H
2
SO
4
CH
2
=CH
2
+ H
2
O
140C
Cyclohexanol Cyclohexene
OH
+ H
2
O
H
2
SO
4
CH
3
COH
CH
3
CH
3
H
2
SO
4
CH
3
C=CH
2
CH
3
+
H
2
O
50C
2-Methyl-2-propanol
(tert- Butyl alcohol)
2-Methylpropene
(Isobutylene)
118
Alcohols to alkenes
Where isomeric alkenes are possible, the alkene having the greater
number of substituents on the double bond (the more stable alkene)
usually predominates (Zaitsev rule).
1-Butene
(20%)
2-Butene
(80%)
2-Butanol
+
heat
8 5 % H
3
PO
4
CH
3
CH=CHCH
3
CH
3
CH
2
CHCH
3
CH
3
CH
2
CH=CH
2
+
H
2
O
OH
119
Alcohols to alkenes. Mechanism
Step 1: Proton transfer to the -OH group gives an oxonium ion.
Step 2: Loss of H
2
O gives a carbocation intermediate.
O
H O
H
H
O
O
H
H
H
H
H
+
+
rapid and
reversible
+
+
A 2 carbocation
intermediate
O
H H
+
slow, rate
determining
H
2
O
+
Step 3: Proton transfer from a carbon adjacent to the positively charged carbon to water. The
sigma electrons of the C-H bond become the pi electrons of the carbon-carbon double
bond.
rapid and
reversible
O
H
H
H H
+
+
O
H
+
+
H
H
120
Pinacol Rearrangement
OH HO
H
2
SO
4
O
H
2
O
2,3-Dimethyl-2,3-butanediol
(Pinacol)
3,3-Dimethyl-2-butanone
(Pinacolone)
+
OH HO
+
H
H
H
O
+
rapid and
reversible
O HO
+ H
H
O
H
H
An oxonium ion
O
HO
H
H
HO
+ H
2
O
A 3
o
carbocation
intermediate
A resonance-stabilized cation intermediate
O
H
O
H
O
H
+
+
+
O
H
H
2
O
+
O
+
H
3
O
+
1 2
3
4
121
Oxidation of Alcohols
Can be accomplished by inorganic reagents, such as KMnO
4
, CrO
3
,
and Na
2
Cr
2
O
7
or by more selective, expensive reagents
122
Oxidation of Primary Alcohols
To aldehyde: pyridinium chlorochromate (PCC,
C
5
H
6
NCrO
3
Cl) in dichloromethane
Other reagents produce carboxylic acids
123
Oxidation of Secondary Alcohols
Effective with inexpensive reagents such as Na
2
Cr
2
O
7
(sodium
dichromate) in acetic acid
PCC is used for sensitive alcohols at lower temperatures
124
Mechanism of Chromic Acid Oxidation
Alcohol forms a chromate ester followed by elimination with electron transfer
to give ketone
The mechanism was determined by observing the effects of isotopes on rates
125
Mechanism of Chromic Acid Oxidation
O
R-C-H
H
2
O
H
2
CrO
4
R-C-OH
O-CrO
3
H
H
H
2
O
R-C-OH
OH
H
R-C-OH
O
HCrO
3
-
+
An aldehyde An aldehyde
hydrate
fast and
reversible
A carboxylic
acid
+
H
3
O
+
+
Chromic acid oxidizes a 1 alcohol first to an aldehyde and then to a
carboxylic acid.
In the second step, it is not the aldehyde per se that is oxidized but
rather the aldehyde hydrate.
126
Oxidation of diol
OH
OH
+ HIO
4
CHO
CHO
+ HIO
3
cis- 1,2-Cyclo-
hexanediol
Hexanedial Periodic
acid
Iodic
acid
A cyclic periodate
+
C
C
OH
OH
I O
O
O C
C
O
O
O
O
I OH OH
+ H
2
O
O C
C O
I
O
OH
O
C O
C O
O
O
I OH
+
O C
C O
I
O
OH
O
C O
C O
O
O
I OH
+
Step 1
Step 2
127
Protection of Alcohols
Hydroxyl groups can easily transfer their proton to a basic reagent
This can prevent desired reactions
Converting the hydroxyl to a (removable) functional group without an
acidic proton protects the alcohol
Si Cl
Me
Me
Me
Si Cl
Me
Me
Si Cl Si Cl
Et
Et
Et
Trimethylsilyl
chloride
(TMSCl)
t -Butyldimethylsilyl
chloride
(TBDMSCl)
Triisopropylsilyl
chloride
(TIPSCl)
Triethylsilyl
chloride
(TESCl)
128
Methods to Protect Alcohols
Reaction with chlorotrimethylsilane in the presence of base yields an unreactive
trimethylsilyl (TMS) ether
The ether can be cleaved with acid or with fluoride ion to regenerate the alcohol
129
Protection-Deprotection
An example of TMS-alcohol protection in a synthesis
130
Protection-Deprotection
Another example of TMS-alcohol protection in a synthesis
OH
H
O
H
2. Na
+
NH
2
-
3.
Br
4-Heptyn-1-ol
4-Pentyn-1-ol
Si
O Si CH
3
OH
+
1 . ( CH
3
)
3
SiCl
CH
3
CH
3
CH
3
CH
3
CH
3
4. Bu
4
N
+
F
-
F Si
CH
3
CH
3
CH
3
131
11. Ethers and Epoxides;
Thiolsand Sulfides
132
Ethers and Their Relatives
An ether has two organic groups (alkyl, aryl, or vinyl) bonded to the same
oxygen atom, ROR
Diethyl ether is used industrially as a solvent
Tetrahydrofuran (THF) is a solvent that is a cyclic ether
Thiols (RSH) and sulfides (RSR) are sulfur (for oxygen) analogs of
alcohols and ethers
133
Naming Ethers
Simple ethers are named by identifying the two organic substituents
and adding the word ether
If other functional groups are present, the ether part is considered an
alkoxy substituent
134
Physical properties
Boiling points of ethers are
lower than alcohols of comparable MW.
close to those of hydrocarbons of comparable MW.
Ethers are hydrogen bond acceptors.
They are more soluble in H
2
O than are hydrocarbons.
135
Preparation: The Williamson Ether Synthesis
Reaction of metal alkoxides and primary alkyl halides and tosylates
Best method for the preparation of ethers
Alkoxides prepared by reaction of an alcohol with a strong base such as
sodium hydride, NaH
136
Preparation: Acid-catalyzed dehydration of alcohols
2CH
3
CH
2
OH
H
2
SO
4
140C
CH
3
CH
2
OCH
2
CH
3
H
2
O +
Ethanol
Diethyl ether
CH
3
CH
2
-O-H
O
O
H-O-S-O-H CH
3
CH
2
-O-H
H
O
O
-
O-S-O-H
+
+
An oxonium ion
+
fast and
reversible
CH
3
CH
2
-O-H CH
3
CH
2
-O-H
H
S
N
2
H
CH
3
CH
2
-O-CH
2
CH
3
H
O-H
A new oxonium ion
+
+
+
+
1
2
137
Preparation:
Acid-catalyzed addition of alcohols to alkenes
1
2
+
acid
catalyst
2-Methoxy-2-methyl
propane
CH
3
CH
3
CH
3
CH
3
C=CH
2
CH
3
OH
CH
3
COCH
3
CH
3
CH
3
C=CH
2
H O
H
CH
3
CH
3
CH
3
CCH
3
O
H
CH
3
+
+
+
+
CH
3
CCH
3
CH
3
HOCH
3
O
CH
3
CCH
3
H
CH
3
CH
3
+
+
+
138
Preparation: Alkoxymercuration of Alkenes
React alkene with an alcohol and mercuric acetate or trifluoroacetate
Demercuration with NaBH
4
yields an ether
Overall Markovnikov addition of alcohol to alkene
139
Reactions of Ethers: Acidic Cleavage
Ethers are generally unreactive
Strong acid will cleave an ether at elevated temperature
HI, HBr produce an alkyl halide from less hindered component by S
N
2
(tertiary ethers undergo S
N
1)
140
Reactions of Ethers: Claisen rearrangement
141
Claisen Rearrangement Mechanism
Concerted pericyclic 6-electron, 6-membered ring transition state
Mechanism consistent with
14
C labelling
142
Cyclic Ethers: Epoxides
Cyclic ethers behave like acyclic ethers, except if ring is 3-membered
Oxirane
(Ethylene oxide)
Oxolane
(Tetrahydrofuran)
Oxane
(Tetrahydropyran)
1,4-Dioxane
O
O
1
2 3
O
O
O
O
Oxetane
Although cyclic ethers have IUPAC names, their common names are more
widely used.
IUPAC: prefix ox- shows oxygen in the ring.
The suffixes -irane, -etane, -olane, and -ane show three, four, five, and
six atoms in a saturated ring.
143
Epoxides (Oxiranes)
Three membered ring ether is called an oxirane (root ir from tri for 3-
membered; prefix ox for oxygen; ane for saturated)
Also called epoxides
Ethylene oxide (oxirane; 1,2-epoxyethane) is industrially important as an
intermediate
Prepared by reaction of ethylene with oxygen at 300 C and silver oxide
catalyst
Na
+
CN
-
CH
3
NH
2
C C
-
Na
+
CH
3
OH
O
N
OH
CH
3
H
N C
OH
N O CH
3
O
H
2
SO
4
H
2
/ M
N
OH
CH
3
OH
N N-H CH
3
OH
H
2
N
SOCl
2
NH
3
N
Cl
CH
3
Cl
(1)
(2)
(3)
(4) (6)
(8)
(5) (7)
144
Preparation of Epoxides Using a Peroxyacid
Treat an alkene with a peroxyacid: Stereospecific
145
Epoxides from Halohydrins
Addition of HO-X to an alkene gives a halohydrin
Treatment of a halohydrin with base gives an epoxide
Intramolecular Williamson ether synthesis
146
Ring-Opening Reactions of Epoxides
Water adds to epoxides with dilute acid at room temperature
Product is a 1,2-diol (on adjacent Cs: vicinal)
Mechanism: acid protonates oxygen and water adds to opposite side
(trans addition)
147
Regiochemistry of Acid-Catalyzed Opening of Epoxides
Nucleophile preferably adds to less hindered site if primary and secondary Cs
Also at tertiary because of carbocation character
148
Nucleophilic Epoxide Opening
Strain of the three-membered ring is relieved on ring-opening
Hydroxide cleaves epoxides at elevated temperatures to give trans 1,2-diols
Adds CH
2
CH
2
OH to the Grignard reagents hydrocarbon chain
Acyclic and other larger ring ethers do not react
149
Nucleophilic Epoxide Opening
Treatment of an epoxide with lithium aluminum hydride, LiAlH
4
, reduces the
epoxide to an alcohol.
The nucleophile attacking the epoxide ring is hydride ion, H:
-
Phenyloxirane
(Styrene oxide)
1-Phenylethanol
CH
2
O
CH
OH
1 . LiAl H
4
2 . H
2
O
CH- CH
3
150
Crown Ethers
Complexes between crown ethers and ionic salts are soluble in nonpolar
organic solvents
Creates reagents that are free of water that have useful properties
Inorganic salts dissolve in organic solvents leaving the anion
unassociated, enhancing reactivity
151
Thiols and Sulfides
Thiols (RSH), are sulfur analogs of alcohols
Named with the suffix -thiol
SH group is called mercapto group (capturer of mercury)
152
Sulfides
Sulfides (RSR), are sulfur analogs of ethers
Named by rules used for ethers, with sulfide in
place of ether for simple compounds and alkylthio
in place of alkoxy
Thiolates (RS
) are formed by the reaction of a thiol with a base

Thiolates react with primary or secondary alkyl halide to give sulfides (RSR)
Thiolates are excellent nucleophiles and react with many electrophiles
153
Thiols: Formation and Unique Reactions
154
Spectroscopy of Ethers
Infrared: CO single-bond stretching 1050 to 1150
cm
1
overlaps many other absorptions.
Proton NMR: H on a C next to ether O are shifted
downfield to 3.4 to 4.5
The
1
H NMR spectrum of dipropyl ether shows the
these signals at 3.4
In epoxides, these Hs absorb at 2.5 to 3.5 d in
their
1
H NMR spectra
Carbon NMR: Cs in ethers exhibit a downfield shift
to 50 to 80
155
16.Aldehydes and Ketones
Aldehydes and ketones are characterized by the the carbonyl functional group
(C=O)
The compounds occur widely in nature as intermediates in metabolism and
biosynthesis
They are also common as chemicals, as solvents, monomers, adhesives,
agrichemicals and pharmaceuticals
The carbonyl group consists of
one sigma bond formed by the
overlap of sp
2
hybrid orbitals
and one pi bond formed by the
overlap of parallel 2p orbitals
Naming Aldehydes
Aldehydes are named by replacing the terminal -e of the corresponding alkane
name with al
The parent chain must contain the CHO group
The CHO carbon is numbered as C1
H
O
3-Methylbutanal 2-Propenal
(Acrolein)
(2E)-3,7-Dimethyl-2,6-octadienal
(Geranial)
1
2
3
4
5
6
7
8
H
O
H
O
CHO
C
6
H
5
CHO
t rans-3-Phenyl-2-propenal
(Cinnamaldehyde)
Benzaldehyde
The IUPAC naming retains the
common names benzaldehyde and
cinnamaldehyde, as well
formaldehyde and acetaldehyde.
157
Naming Ketones
Replace the terminal -e of the alkane name with one
Parent chain is the longest one that contains the ketone group
Numbering begins at the end nearer the carbonyl carbon
Propanone
(Acetone)
Benzophenone 1-Phenyl-1-pentanone Acetophenone
O O O
O
The IUPAC retains the common names acetone, acetophenone, and benzophenone.
158
Ketones and Aldehydes as Substituents
The RC=O as a substituent is an acyl group is used with the suffix -yl from
the root of the carboxylic acid
CH
3
CO: acetyl; CHO: formyl; C
6
H
5
CO: benzoyl
The prefix oxo- is used if other functional groups are present and the doubly
bonded oxygen is labeled as a substituent on a parent chain
159
Order of Precedence
For compounds that contain more than one functional group indicated by a suffix.
H
COOH
O
COOH
O
COOH HO
OH
HS
COOH
NH
2
Functional
Group
Carboxyl -oic acid
Aldehyde -al oxo-
Ketone -one oxo-
Alcohol -ol hydroxy-
Amino -amine amino-
3-Oxopropanoic
acid
3-Oxobutanoic a
cid
4-Hydroxybutanoic
acid
3-Aminobutanoic
acid
Example when the
functional group has
a lower priority
Sulfhydryl -thiol mercapto 2-Mercaptoethanol
Suffix if
higher
priority
Prefix if
lower
priority
Increasing precedence
160
Physical Properties
Oxygen is more electronegative than carbon (3.5 vs 2.5) and, therefore, a
C=O group is polar.
C O C O
-
+
+
More important
contributing
structure
C O
C O C O
Polarity of
a carbonyl
group
+
C O
Aldehydes and ketones are polar
compounds and interact in the pure
state by dipole-dipole interaction.
They have higher boiling points and
are more soluble in water than
nonpolar compounds of comparable
molecular weight.
161
Spectroscopy of Aldehydes and Ketones
Infrared Spectroscopy
Aldehydes and ketones show a strong C=O peak 1660 to 1770 cm
1
aldehydes show two characteristic CH absorptions in the 2720 to 2820
cm1 range.
162
NMR Spectra of Aldehydes
Aldehyde proton signals are at 10 in
1
H NMR - distinctive spinspin
coupling with protons on the neighboring carbon, J 3 Hz
Slightly deshielded and normally absorb near 2.0 to 2.3
Methyl ketones always show a sharp three-proton singlet near 2.1
163
13
C NMR of C=O
C=O signal is at 190 to 215
No other kinds of carbons absorb in this range
164
Mass Spectrometry
Aliphatic aldehydes and ketones that have hydrogens on their gamma ()
carbon atoms rearrange as shown
Cleavage of the bond between the carbonyl group and the carbon
Yields a neutral radical and an oxygen-containing cation
165
Preparing Ketones/Aldehydes
pyridinium chlorochromate
(PCC, C
5
H
6
NCrO
3
Cl)
166
Oxidation of Aldehydes
Silver oxide, Ag
2
O, in aqueous ammonia (Tollens reagent) oxidizes
aldehydes (no acid)
167
Oxidation of Aldehydes
Benzoic acid Benzaldehyde
+ CH
O O
COH 2 O
2
2
Aldehydes are oxidized by O
2
in a radical chain reaction.
Liquid aldehydes are so sensitive to air that they must be stored under N
2
.
168
Undergo slow cleavage with hot, alkaline KMnO
4
CC bond next to C=O is broken to give carboxylic acids
Reaction is practical for cleaving symmetrical ketones
Oxidation of Ketones
169
Reduction: WolffKishner Reaction
Treatment of an aldehyde or ketone with hydrazine, H
2
NNH
2
and KOH
converts the compound to an alkane
Originally carried out at high temperatures but with dimethyl sulfoxide as
solvent takes place near room temperature
170
Reduction: Clemmensen Reaction
Refluxing an aldehyde or ketone with amalgamated zinc in concentrated
HCl converts the carbonyl group to a methylene group.
Zn( Hg) , HCl
OH O OH
171
Cannizzaro Reaction
The adduct of an aldehyde and OH
can transfer hydride ion to another

aldehyde C=O resulting in a simultaneous oxidation and reduction
(disproportionation)
172
Reduction with Hydrogen
+
25
o
C, 2 atm
Pt
Cyclohexanone
Cyclohexanol
O
OH
H
2
By careful choice of experimental conditions, it is often possible to
selectively reduce a carbon-carbon double in the presence of an
aldehyde or ketone.
O OH
RCH=CHCR' RCH=CHCHR'
1. NaBH
4
2. H
2
O
O
RCH=CHCR' H
2
Rh
RCH
2
CH
2
CR'
O
+
1-Butanol trans- 2-Butenal
(Crotonaldehyde)
2 H
2
Ni
H
O
OH
173
Reduction with Hydride
Convert C=O to CH-OH
LiAlH
4
and NaBH
4
react as donors of hydride ion
Protonation after addition yields the alcohol
Hydride ion Lithium aluminum
hydride (LAH)
Sodium
borohydride
H
H
H
H
H- B- H
H- Al- H Li
+
Na
+
H:
174
Summary
Preparing Ketones/Aldehydes
from alcohols, alkenes, alkynes, and aromatics/RCOCl
Reactions of Ketones/Aldehydes:
[O]: common for aldehydes (CrO
3
, or Tollens reagent, air, but uncommon for
ketones unless KMnO
4
/OH
-
)
[H]: (a) completely remove O: Wolff-Kishner, Clemmensen
(b) interesting self-oxidation: Cannizzaro
(c) increase # of H by using H
2
(w/ help of transition metal catalyst) or H
-
Addition reactions (some also belong to [H])
Relative Reactivity of Aldehydes and Ketones
Tetrahedral carbonyl
addition compound
+ C
R
R
O C Nu
O
-
R
R
Nu
-
175
Reaction Themes
One of the most common reaction themes of a carbonyl group is addition of a
nucleophile to form a tetrahedral carbonyl addition compound.
Tetrahedral carbonyl
addition compound
+ C
R
R
O C Nu
O
-
R
R
Nu
-
Often the tetrahedral product of addition to a carbonyl group is a new chiral center.
If none of the starting materials is chiral and the reaction takes place in an achiral
environment, then enantiomers will be formed as a racemic mixture.
Nu
-
C O
R
R'
Nu
O
R'
R
Nu
O
R
R'
+
H
3
O
+
Nu
OH
R
R'
Nu
OH
R'
R
+
A racemic mixture A new chiral
center is created
Approach from
the bottom face
Approach from
the top face
176
Aldehydes are generally more reactive than ketones in nucleophilic addition reactions
The transition state for addition is less crowded and lower in energy for an aldehyde (a)
than for a ketone (b)
Aldehydes have one large substituent bonded to the C=O: ketones have two
177
Aldehyde C=O is more polarized than ketone C=O
As in carbocations, more alkyl groups stabilize + character
Ketone has more alkyl groups, stabilizing the C=O carbon inductively
178
Reactivity of Aromatic Aldehydes
Less reactive in nucleophilic addition reactions than aliphatic aldehydes
Electron-donating resonance effect of aromatic ring makes C=O less reactive
electrophilic than the carbonyl group of an aliphatic aldehyde
179
Addition of C Nucleophiles
Addition of carbon nucleophiles is one of the most important types of
nucleophilic additions to a C=O group.
A new carbon-carbon bond is formed in the process.
We study addition of these four types of carbon nucleophiles.
RMgX
RLi
-
C RC C
-
N
A Grignard
reagent
An organolithium
reagent
An alkyne
anion
Cyanide ion
Carbanion: An anion in which carbon has an unshared pair of
electrons and bears a negative charge.
A carbanion is a good nucleophile and adds readily to the
carbonyl group of aldehydes and ketones.
180
Nucleophilic Addition of Grignard Reagents and
Hydride Reagents: Alcohol Formation
Treatment of aldehydes or ketones with Grignard reagents yields an
alcohol
Given the difference in electronegativity between carbon and magnesium (2.5 -
1.3), the C-Mg bond is strongly polarized, so a Grignard reagent reacts for all
practical purposes as R :

MgX
+
.
In its reactions, a Grignard reagent behaves as a carbanion.
181
Grignard Reaction: examples
CH
3
CH
2
-MgBr
O
H- C-H
O
-
[ MgBr]
+
CH
3
CH
2
-CH
2
HCl
H
2
O
OH
CH
3
CH
2
-CH
2
Mg
2+
ether
1-Propanol
(a 1 alcohol)
Formaldehyde
+
+
A magnesium
alkoxide
Ph- MgBr
O
Ph
O
-
[ MgBr]
+
HCl
H
2
O
Ph
OH
Mg
2+
+
Acetone
(a ketone)
ether
+
A magnesium
alkoxide
2-Phenyl-2-propanol
(a 3 alcohol)
Phenyl-
magnesium
bromide
182
Addition with other reagents
Li
O
O
-
Li
+
HCl
H
2
O
OH
3,3-Dimethyl-2-
butanone
3,3-Dimethyl-2-phenyl-
2-butanol
(racemic)
+
Phenyl-
lithium
A lithium alkoxide
(racemic)
C:
-
Na
+
HC
O
C
O
-
Na
+
HC
HCl
H
2
O
C OH HC
1-Ethynyl-
cyclohexanol
A sodium
alkoxide
+
Cyclohexanone
Sodium
acetylide
Review: Hydration of
Terminal Alkynes
2-Hydroxypropanenitrile
(Acetaldehyde cyanohydrin)
+
HC N CH
3
C-C N CH
3
CH
OH
H
O
183
Wittig Reaction
The Wittig reaction is a very versatile
synthetic method for the synthesis of
alkenes from aldehydes and ketones.
Triphenyl-
phosphine oxide
Methylene-
cyclohexane
A phosphonium
ylide
+ +
- +
CH
2
Ph
3
P=O Ph
3
P-CH
2
Cyclohexanone
O
Phosphonium ylides are formed in two steps:
Step 1: Nucleophilic displacement of iodine by triphenylphosphine.
Step 2: Treatment of the phosphonium salt with a very strong base, most
commonly BuLi, NaH, or NaNH
2
.
184
Wittig Reaction
Triphenyl-
phosphine oxide
Methylene-
cyclohexane
A phosphonium
ylide
+ +
- +
CH
2
Ph
3
P=O Ph
3
P-CH
2
Cyclohexanone
O
Phosphonium ylides react with the C=O group of aldehydes and ketones to give
alkenes.
Step 1: Nucleophilic addition of the ylide to the electrophilic carbonyl carbon.
Step 2: Decomposition of the oxaphosphatane
CR
2
O
CH
2
Ph
3
P
CH
2
-
:O CR
2
Ph
3
P
O CR
2
Ph
3
P CH
2
-
+
An oxaphosphetane
+
A betaine
CH
2
O CR
2
Ph
3
P
Ph
3
P=O
R
2
C=CH
2
An alkene
+
Triphenylphosphine
oxide
185
Wittig Reaction and modification
H
Ph
O
Ph
3
P Ph Ph
Ph
3
P=O
Phenyl-
acetaldehyde
+ +
(Z)-1-Phenyl-2-
butene
(87%)
(E)-1-Phenyl-2-
butene
(13%)
+
H
Ph
O
+
OEt
Ph
3
P
O
Ph
OEt
O
Ph
3
P=O
Ethyl (E)-4-phenyl-2-butenoate
(only the E isomer is formed)
+
Phenyl-
acetaldehyde
Horner-Emmons-Wadsworth modification
( MeO)
2
P-CH
2
-C-OEt
O O
O
H
OEt
O
MeO-P-O
-
O
OMe
1. strong
base
2.
Only the E isomer
is formed
+
Dimethylphosphate
anion
186
Reaction Themes
Nu
-
C O
R
R'
Nu
O
R'
R
Nu
O
R
R'
+
H
3
O
+
Nu
OH
R
R'
Nu
OH
R'
R
+
A racemic mixture A new chiral
center is created
Approach from
the bottom face
Approach from
the top face
RMgX
RLi
-
C RC C
-
N
A Grignard
reagent
An organolithium
reagent
An alkyne
anion
Cyanide ion
Triphenyl-
phosphine oxide
Methylene-
cyclohexane
A phosphonium
ylide
+ +
- +
CH
2
Ph
3
P=O Ph
3
P-CH
2
Cyclohexanone
O
O
H-OEt
OH
OEt
+
acid or
base
A hemiacetal
OH
OEt
H-OEt
H
+
OEt
OEt
H
2
O
A diethyl acetal
+
A hemiacetal
+
187
Nucleophilic Addition of H
2
O
Aldehydes and ketones react with water to yield 1,1-diols (geminal (gem)
diols)
Hyrdation is reversible: a gem diol can eliminate water
Equilibrium generally favors the carbonyl compound over hydrate for steric
reasons
Acetone in water is 99.9% ketone form
Exception: simple aldehydes
In water, formaldehyde consists is 99.9% hydrate
188
Role of Acid or Base
The base-catalyzed
hydration nucleophile is the
hydroxide ion, which is a
much stronger nucleophile
than water
Protonation of C=O makes it
more electrophilic
189
Addition of Alcohol to C=O:
Hemiacetal and Acetal
Hemiacetal: A molecule containing an -OH and an -OR or -OAr bonded to the
same carbon.
O
H-OEt
OH
OEt
+
acid or
base
A hemiacetal
OH
OH
OH
HO
H
O OH
O
OH
HO
HO
CH
2
OH
OH
HO
CH
2
OH
O
OH
HO OH
1
2
3
6
6
1
2
anomeric
carbon
Anomer of D-glucose
cyclic hemiacetal
(predominates
at equilibrium)
Anomer of
D-glucose cyclic
hemiacetal
+
4
5
D-Glucose
(open chain form)
1
2
3
4
5
3
4
5
6
Hemiacetals are only minor components of an equilibrium mixture, except
where a five- or six-membered ring can form.
190
Fischer Projection and Mutarotation
In solution, -D-glucose is in equilibrium with -D-glucose.
Mutarotation involves the conversion of the cyclic anomers into the open chain.
At any time, there is only a small amount of open chain.
-D-glucose D-glucose (open) -D-glucose
(36%) (trace) (64%)
191
Fischer Projection and Mutarotation
A Fischer
projection:
Is a 2-dimensional
representation of a 3-
dimensional
molecule.
Places the most
oxidized group at the
top.
Uses vertical lines in
place of dashes for
bonds that go back.
Uses horizontal lines
in place of wedges
for bonds that come
forward.
192
Addition of alcohol to C=O:
hemiacetal and acetal
Hemiacetals react with alcohols to form acetals.
Acetal: A molecule containing two -OR or -OAr groups bonded to the same
carbon.
OH
OEt
H-OEt
H
+
OEt
OEt
H
2
O
A diethyl acetal
+
A hemiacetal
+
HO
R-C-OCH
3
H
H A
H
H
O
H
R-C-OCH
3
A:
-
+
An oxonium ion
+
+
R-C OCH
3
H
O
H
H
H
R-C OCH
3
R-C
H
OCH
3
H
2
O
+
A resonance-stabilized cation
+
+
+
Step 1: Proton transfer from HA gives an oxonium ion.
Step 2: Loss of water gives a resonance-stabilized cation.
CH
3
-OH
H
R-C OCH
3
R-C OCH
3
H
O
CH
3
H
A protonated acetal
+
+
+
A:
-
R-C OCH
3
H
O
CH
3
H
OCH
3
H
R-C-OCH
3
H-A
+
(4)
An acetal
+
+
Step 3: Reaction of the cation (an electrophile) with
methanol (a nucleophile) gives the conjugate acid of the
acetal.
Step 4: Proton transfer to A
-
gives the acetal and
generates a replacement acid catalyst.
193
Uses of Acetals As Protecting Groups
Acetals can serve as protecting groups for aldehydes and ketones
It is convenient to use a diol, to form a cyclic acetal (the reaction goes
even more readily)
194
Uses of Acetals As Protecting Groups
RCH
2
OH
+
O O RCH
2
O
Dihydropyran
A tetrahydropyranyl
ether
H
+
THP group
Tetrahydropyranyl (THP) protecting group.
The THP group is an acetal and, therefore, stable to neutral and basic
solutions, and to most oxidizing and reducing agents.
It is removed by acid-catalyzed hydrolysis.
195
Nucleophilic Addition of Amines:
Imine and Enamine Formation
RNH
2
adds to C=O to form imines, R
2
C=NR (after loss of HOH)
R
2
NH yields enamines, R
2
NCR=CR
2
(after loss of HOH)
(ene + amine = unsaturated amine)
196
Nucleophilic Addition of Amines:
Imine and Enamine Formation
Formation of an imine occurs in two steps:
Step 1: Carbonyl addition followed by proton transfer.
Step 2: Loss of H
2
O and proton transfer to solvent.
C
O
H
2
N-R
H
H
C
O:
-
N-R
O
H
N-R
H
C
+
+
O H
H
H
H
C
O
H
N-R
N-R
H
C
O
H H
O
H
H
C
N-R
O H
H
H
An imine
+
+
+
+
+
+
H
2
O
197
Conjugate Nucleophilic Addition to ,-
Unsaturated Aldehydes and Ketones
A nucleophile
can add to the
C=C double
bond of an
,-
unsaturated
aldehyde or
ketone
(conjugate
addition, or 1,4
addition)
The initial
product is a
resonance-
stabilized
enolate ion,
which is then
protonated
198
Conjugate Addition of Amines
Primary and secondary amines add to , -unsaturated aldehydes and
ketones to yield -amino aldehydes and ketones
199
Conjugate Addition of Alkyl Groups:
Organocopper Reactions
Reaction of an , -unsaturated ketone with a lithium diorganocopper
reagent
Diorganocopper (Gilman) reagents from by reaction of 1 equivalent of
cuprous iodide and 2 equivalents of organolithium
1, 2, 3 alkyl, aryl and alkenyl groups react but not alkynyl groups
200
The carbon next to the carbonyl group is designated as being in the position
Electrophilic substitution occurs at this position through either an enol or
enolate ion
Tautomers Are Not Resonance Forms
Reaction Theme 2: The Position
201
Enols
The enol tautomer is usually present to a very small extent and cannot be isolated
However, it can serve as a reaction intermediate
202
Acid OR Base Catalysis of Enolization
O
Ph
OH
Ph
O
Ph
An achiral
enol
(R)-3-Phenyl-2-
butanone
(S)-3-Phenyl-2-
butanone
203
The Mechanism of Alpha-Substitution Reactions
Enols behave as nucleophiles and
react with electrophiles because the
double bonds are electron-rich
compared to alkenes
204
Acidity of Alpha Hydrogen Atoms:
Enolate Ion Formation
Carbonyl compounds can
act as weak acids (pK
a
of
acetone = 19.3; pK
a
of
ethane = 60)
The conjugate base of a
ketone or aldehyde is an
enolate ion - the negative
charge is delocalized onto
oxygen
205
Reagents for Enolate Formation
Ketones are weaker acids than the OH of alcohols so a a more powerful
base than an alkoxide is needed to form the enolate
Sodium hydride (NaH) or lithium diisopropylamide [LiN(i-C
3
H
7
)
2
] are strong
enough to form the enolate
LDA is from butyllithium (BuLi) and diisopropylamine (pK
a
40)
Not nucleophilic
206
Reactivity of Enolate Ions
The carbon atom of an enolate ion is electron-rich and highly reactive
toward electrophiles (enols are not as reactive)
Reaction on oxygen yields an enol derivative
Reaction on carbon yields an -substituted carbonyl compound
207
Halogenation of Enolate Ions: The
Haloform Reaction
Base-promoted reaction occurs through an enolate ion intermediate
Application:
208
Elimination Reactions of -Bromoketones
-Bromo ketones can be dehydrobrominated by base treatment to yield
,-unsaturated ketones
209
Alkylation of Enolate Ions
Alkylation occurs when the nucleophilic enolate ion reacts with the electrophilic
alkyl halide or tosylate and displaces the leaving group
S
N
2 reaction:, the leaving group X can be chloride, bromide, iodide, or
tosylate
R should be primary or methyl and preferably should be allylic or benzylic
Secondary halides react poorly, and tertiary halides don't react at all
because of competing elimination
210
-Dicarbonyls Are More Acidic
When a hydrogen atom is flanked by two carbonyl groups, its acidity is
enhanced
Negative charge of enolate delocalizes over both carbonyl groups
211
Condensation Reactions
Carbonyl compounds are both the electrophile and nucleophile in
carbonyl condensation reactions
212
Condensations of Aldehydes and Ketones:
The Aldol Reaction
Acetaldehyde reacts in basic solution (NaOEt, NaOH) with another molecule
of acetaldhyde
The -hydroxy aldehyde product is aldol (aldehyde + alcohol)
This is a general reaction of aldehydes and ketones
The aldol reaction is reversible, favoring the condensation product only
for aldehydes with no substituent
Steric factors are increased in the aldol product
213
Aldehydes and the Aldol Equilibrium
214
Ketones and the Aldol Equilibrium
215
Conditions for Condensations
A small amount of base is used to generate a small amount of enolate in the
presence of unreacted carbonyl compound
After the condensation, the basic catalyst is regenerated
216
Dehydration of Aldol Products:
Synthesis of Enones
The -hydroxy carbonyl products dehydrate to yield conjugated enones
The term condensation refers to the net loss of water and combination
of 2 molecules
217
Driving the Equilbrium
Removal of water from the aldol reaction mixture can be used to drive the
reaction toward products
Even if the initial aldol favors reactants, the subsequent dehydration step
pushes the reaction to completion
218
Mixed Aldol Reactions: No Use
A mixed aldol reaction between two similar aldehyde or ketone partners
leads to a mixture of four possible products
This is not useful
219
1. If one of the carbonyl partners contains no hydrogens and the carbonyl
is unhindered (such as benzaldehyde and formaldehyde) it is a good
electrophile and can react with enolates hen a mixed aldol reaction is
likely to be successful
Mixed Aldol Reactions: Useful
2. Ethyl acetoacetate is completely converted into its enolate ion under
less basic conditions than monocarbonyl partners
220
Intramolecular Aldol Reactions
3. Treatment of certain dicarbonyl compounds with base produces cyclic
products by intramolecular reaction
221
The Michael Reaction
Enolates can add as nucleophiles to ,-unsaturated aldehydes and ketones to
give the conjugate addition product
222
The Michael Reaction
O
O
+
O
+
Organolithium and Grignard reagents, on the other hand, are strong bases,
add rapidly to carbonyl groups, and given primarily 1,2-addition
PhLi
O O
-
Li
+
Ph
H
2
O
HCl
OH Ph
4-Methyl-2-phenyl-
3-penten-2-ol
4-Methyl-3-
penten-2-one
+
Phenyl-
lithium
O
1. ( CH
3
)
2
CuLi, ether, -78C
2. H
2
O, HCl
O
3-Methyl-2-
cyclohexenone
3,3-Dimethyl-
cyclohexanone
CH
3 CH
3
CH
3
Gilman reagents undergo conjugate addition to ,-unsaturated aldehydes
and ketones in a reaction closely related to the Michael reaction.
223
Conjugate Addition of Amines
Primary and secondary amines add to , -unsaturated aldehydes and
ketones to yield -amino aldehydes and ketones
224
The Stork Enamine Reaction
Enamines are equivalent to enolates in their reactions and can be used to
accomplish the transformations under milder conditions
Enamines are prepared from a ketone and a secondary amine
225
Why Enamines Are Nucleophilic
Overlap of the nitrogen lone-pair orbital with the double-bond orbitals
increases electron density on the carbon atom
226
Enamine Addition and Hydrolysis
Enamine adds to an ,-unsaturated carbonyl acceptor
The product is hydrolyzed to a 1,5-dicarbonyl compound
227
Carbonyl Condensation Reactions in Synthesis:
The Robinson Annulation Reaction
A two-step process: combines a Michael reaction with an intramolecular
aldol reaction
The product is a substituted 2-cyclohexenone
228
Carboxylic Acids and Derivatives
229
The Importance of Carboxylic Acids (RCO
2
H)
Starting materials for acyl derivatives (esters, amides, and acid chlorides)
Abundant in nature from oxidation of aldehydes and alcohols in
metabolism
Acetic acid, CH
3
CO
2
H, - vinegar
Butanoic acid, CH
3
CH
2
CH
2
CO
2
H (rancid butter)
Long-chain aliphatic acids from the breakdown of fats
230
Naming Carboxylic Acids
Carboxylic Acids, RCO
2
H
If derived from open-chain alkanes, replace the terminal -e of the alkane
name with -oic acid
The carboxyl carbon atom is C1
The carboxyl group takes precedence over most other functional groups.
Compounds with CO
2
H bonded to a ring are named using the suffix -
carboxylic acid
The CO
2
H carbon is not itself numbered in this system
231
COOH COOH
OH COOH
COOH
COOH
COOH
Benzoic
acid
2-Hydroxybenzoic
acid
(Salicylic acid)
1,2-Benzenedicarboxylic
acid
(Phthalic acid)
1,4-Benzenedicarboxylic
acid
(Terephthalic acid)
L-alanine]
[(S)--Aminopropionic acid;
(-Aminobutyric acid, GABA)
(S)-2-Aminopropanoic acid 4-Aminobutanoic acid
4
3
2
5
H
2
N
OH
O
OH
O
NH
2
OH
O
1
When common names are used, the letters , , , , etc. are often used to
locate substituents.
232
HO OH
O
Propanedioic acid
(Malonic acid)
Ethanedioic acid
(Oxalic acid)
O
HO
OH
O
O
Hexanedioic acid
(Adipic acid)
Pentanedioic acid
(Glutaric acid)
Butanedioic acid
(Succinic acid)
O
OH
O
HO
OH
O
HO
O
HO
OH
O
O
Dicarboxylic acids: add the suffix -dioic acid to the name of the parent
alkane containing both carboxyl groups.
233
Structure and Physical Properties of Carboxylic Acids
Carboxyl carbon sp
2
hybridized: carboxylic acid groups are planar with C
C=O and O=CO bond angles of approximately 120
Carboxylic acids form hydrogen bonds, existing as cyclic dimers held
together by two hydrogen bonds
Strong hydrogen bonding causes much higher boiling points than the
corresponding alcohols
234
Carboxylic acids are more
soluble in water than alcohols,
ethers, aldehydes, and ketones
of comparable molecular weight.
Water solubility decreases as
the relative size of the
hydrophobic portion of the
molecule increases.
235
Saturated fats and cholesterol are associated with diseases such as diabetes, cancers ( breast, pancreas, and colon), and
artherosclerosis ( a condition in which deposits of lipid materials accumulate in the Coronary blood vessels. These plaques restrict
the flow of blood to the tissue, causing death of the tissue. In the heart, This could result in heart attack)
236
Acidity Constant and pK
a
Carboxylic acids transfer a proton to water to give H
3
O
+
and carboxylate
anions, RCO
2
, but H
3
O
+
is a much stronger acid
The acidity constant, K
a,
, is about 10
-5
for a typical carboxylic acid (pK
a
~ 5)
Carboxylic acids are proton donors toward weak and strong bases,
producing metal carboxylate salts, RCO
2
+
M
Carboxylic acids with more than six carbons are only slightly soluble in
water, but their conjugate base salts are water-soluble
237
Acidity Compared to Alcohols
Carboxylic acids are better proton donors than are alcohols (The pK
a
of
ethanol is ~16, compared to ~5 for acetic acid)
In an alkoxide ion, the negative charge is localized on oxygen while in a
carboxylate ion the negative charge is delocalized over two equivalent
oxygen atoms, giving resonance stabilization
238
Substituent Effects on Acidity
239
Examples of Inductive Effects on Acidity
Fluoroacetic, chloroacetic, bromoacetic, and iodoacetic acids are stronger
acids than acetic acid
Multiple electronegative substituents have synergistic effects on acidity
240
Substituent Effects in Substituted Benzoic Acids
241
Preparation of Carboxylic Acids
Oxidation of a substituted alkylbenzene with KMnO
4
or Na
2
Cr
2
O
7
gives a
substituted benzoic acid. 1 and 2 alkyl groups can be oxidized, but tertiary
groups are not
Oxidative cleavage of an alkene with KMnO
4
gives a carboxylic acid if
the alkene has at least one vinylic hydrogen
Oxidative cleavage of an alkyne
242
Preparation of Carboxylic Acids
Oxidation of a primary alcohol or an aldehyde with CrO
3
in aqueous acid
243
Carboxylation of Grignard Reagents
Grignard reagents react with dry CO
2
to yield a metal carboxylate
Limited to alkyl halides that can form Grignard reagents
Mechanism
244
Hydrolysis of Nitriles
Hot acid or base yields carboxylic acids
Conversion of an alkyl halide to a nitrile (with cyanide ion) followed by
hydrolysis produces a carboxylic acid with one more carbon (RBr RCN
RCO
2
H)
About Nitrile:
Closely related to carboxylic acids named by adding -nitrile as a suffix to
the alkane name, with the nitrile carbon numbered C1
Complex nitriles are named as derivatives of carboxylic acids.
Replace -ic acid or -oic acid ending with -onitrile
245
Reactions of Carboxylic Acids: An Overview
Carboxylic acids transfer a proton to a base to give anions, which are good
nucleophiles in S
N
2 reactions
Like ketones, carboxylic acids undergo addition of nucleophiles to the carbonyl
group
In addition, carboxylic acids undergo other reactions characteristic of neither
alcohols nor ketones
246
Reactions of Carboxylic Acids:
Reduction
The carboxyl group is very resistant to reduction.
It is not affected by catalytic hydrogenation under conditions that easily
reduce aldehydes and ketones to alcohols, and reduce alkenes and
alkynes to alkanes. Nor is it reduced by NaBH
4
.
OH
O O
H
2
Pt
OH
O OH
5-Hydroxyhexanoic acid
(racemic)
5-Oxohexanoic acid
25C, 2 atm
+
C
6
H
5
OH
O O
1 . NaBH
4
2 . H
2
O
C
6
H
5
OH
O OH
5-Oxo-5-phenylpentanoic acid 5-Hydroxy-5-phenylpentanoic acid
(racemic)
247
Reduction
Reduced by LiAlH
4
to yield primary alcohols
The reaction is difficult and often requires heating in tetrahydrofuran
solvent to go to completion
Borane in tetrahydrofuran (BH
3
/THF) converts carboxylic acids to
primary alcohols selectively
Preferable to LiAlH
4
because of its relative ease, safety, and specificity
Borane reacts faster with COOH than it does with NO
2
248
Acid Chloride
The functional group of an acid halide is a carbonyl group bonded to a halogen
atom.
OH
O
SOCl
2
Cl
O
SO
2
HCl
+
+
+
Butanoic acid Thionyl chloride Butanoyl chloride
Step 1: Reaction with SOCl
2
transforms OH, a poor leaving group, into a
chlorosulfite group, a good leaving group.
Step 2: Attack of
chloride ion gives a
tetrahedral
carbonyl addition
intermediate, which
collapses to give
the acid chloride.
249
Decarboxylation
Decarboxylation: The loss of CO
2
from a carboxyl group.
Most carboxylic acids, if heated to a very high temperature, undergo
thermal decarboxylation.
Most carboxylic acids, however, are quite resistant to moderate heat and
melt or even boil without decarboxylation.
Exceptions are carboxylic acids that have a carbonyl group beta to the
carboxyl group. This type of carboxylic acid undergoes decarboxylation
on mild heating.
R-C-OH
O
R-H CO
2
decarboxylation
+
heat
OH
O O
O
CO
2
Acetone 3-Oxobutanoic acid
(Acetoacetic acid)
+
warm

250
Decarboxylation
OH
O O
O
CO
2
Acetone 3-Oxobutanoic acid
(Acetoacetic acid)
+
warm

O O
H
O
O
H
C
O
O
O
CO
2
(A cyclic six-membered
transition state)
(1) (2)
+
Enol of
a ketone
A ketone
+
O
OH
O
HO O
O
HO
O
OH
O
O
HO
CO
2
only this carboxyl
has a C=O beta to it.
+
Oxalosuccinic acid
-Ketoglutaric acid
251
Application of decarboxylation
COOEt
O
Et O
-
Na
+
O
COOEt
Na
+
Et OH
Sodium salt
of ethyl
acetoacetate
Sodium
ethoxide
Ethanol
pK
a
15.9
(weaker acid)
+ +
Ethyl acetoacetate
pK
a
10.7
(stronger acid)
O
COOEt
Na
+
Br
COOEt
O
NaBr
+
3-Bromopropene
(Allyl bromide)
S
N
2
+
(racemic)
O
COOEt
3 . NaOH, H
2
O
4 . HCl , H
2
O
COOH
O
Et OH +
(racemic) (racemic)
COOH
O O
CO
2
+
5-Hexen-2-one
(a monosubstituted acetone)
heat
(racemic)
252
Decarboxylation
253
Spectroscopy of Carboxylic Acids
OH bond of the carboxyl group gives a very broad absorption 2500 to 3300
cm
1
C=O bond absorbs sharply between 1710 and 1760 cm
1
Free carboxyl groups absorb at 1760 cm
1
Commonly encountered dimeric carboxyl groups absorb in a broad
band centered around 1710 cm
1
Carboxyl
13
COOH signals are at 165 to 185
Aromatic and ,-unsaturated acids are near 165 and saturated
aliphatic acids are near 185
254
Proton NMR
The acidic CO
2
H proton is a singlet near 12
When D
2
O is added to the sample the CO
2
H proton is replaced by D causing
the absorption to disappear from the NMR spectrum
Note that the carboxyl proton absorption occurs at 12.0
255
Carboxylic Compounds
Acyl group bonded to Y, an electronegative atom or leaving group
Includes: Y = halide (acid halides), acyloxy (anhydrides), alkoxy (esters),
and amine (amides)
H-NH
2
H-Cl H-OR' RC-OH
O
H-OCR'
O
RC=N
HO H
RC-OH
O
RC-OH
O
RC-OH
O
-H
2
O
-H
2
O -H
2
O -H
2
O
-H
2
O
RC N RCNH
2
O
RCCl
O
RCOR'
O
RCOCR'
O O
The enol of
an amide
An acid
chloride
An ester
An acid
anhydride
An amide A nitrile
256
General Reaction Pattern
Carboxylic acid derivatives have an acyl
carbon bonded to a group Y that can
leave
A tetrahedral intermediate is formed and
the leaving group is expelled to generate a
new carbonyl compound, leading to
substitution
257
Substitution in Synthesis
We can readily convert a more reactive acid derivative into a less reactive one
Reactions in the opposite sense are possible but require more complex
approaches
Halide ion is the weakest
base and the best leaving
group; acid halides are the
most reactive toward
nucleophilic acyl substitution.
Amide ion is the strongest
base and the poorest leaving
group; amides are the least
reactive toward nucleophilic
acyl substitution.
258
Naming Carboxylic Acid Derivatives
Acid Halides, RCOX
Derived from the carboxylic acid name by replacing the -ic acid ending
with -yl or the -carboxylic acid ending with carbonyl and specifying
the halide
259
Reactions of Acid Halides
Nucleophilic acyl substitution
Halogen replaced by OH, by OR, or by NH
2
Reduction yields a primary alcohol
Grignard reagent yields a tertiary alcohol
260
261
262
Reaction of Acid Chlorides with
Organometallic Reagents
Grignard reagents react with acid chlorides to yield tertiary alcohols in
which two of the substituents are the same
Reaction of an acid chloride with a lithium diorganocopper (Gilman) reagent,
Li
+
R
2
Cu
Addition produces an acyl diorganocopper intermediate, followed by loss of

RCu and formation of the ketone
263
Naming Acid Anhydride
Naming Acid Anhydrides, RCO
2
COR'
If symnmetrical replace acid with anhydride based on the related
carboxylic acid (for symmetrical anhydrides)
From substituted monocarboxylic acids: use bis- ahead of the acid name
Unsymmetrical anhydridescite the two acids alphabetically
264
Conversion of Carboxylic Acids into Acid Anhydrides
Heat cyclic dicarboxylic acids that can form five- or six-membered rings
Acyclic anhydrides are not generally formed this way - they are usually
made from acid chlorides and carboxylic acids
Prepared by nucleophilic of a carboxylate with an acid chloride
265
Reactions of Acid Anhydrides
Similar to acid chlorides in reactivity
266
Acetylation
Acetic anhydride forms acetate esters from alcohols and N-substituted
acetamides from amines
267
Naming Esters, RCO
2
R
Name R and then, after a space, the carboxylic acid (RCOOH), with
the -ic acid ending replaced by -ate
Lactone: A cyclic ester.
name the parent carboxylic acid, drop the suffix -ic acid and add -olactone.
4-Butanolactone
(-Butyrolactone)
3-Butanolactone
(-Butyrolactone)

O
O
O
O
H
3
C
2
3
1
2
1
3 4
6-Hexanolactone
(-Caprolactone)

O
O
2
1 3
4
5 6
268
Preparation of Esters
Esters are usually prepared from carboxylic acids
269
Conversion of Carboxylic Acids into Esters
Methods include reaction of a carboxylate anion with a primary alkyl halide
270
Fischer Esterification: Mechanism
1
2
3
4
271
Esterification
Treating a carboxylic acid with diazomethane gives a methyl ester.
+
+
ether
Diazomethane A methyl ester
O O
CH
2
N
2
RCOH RCOCH
3
N
2
+
+
H
H
C N N:
H
N N: C H
::
+
+
+
+
A carboxylate
anion
R C O H
O
N N CH
2
O
CH
3
N C O:
R N
Methyldiazonium
cation
O
C O:
R CH
3
+
N N
+
S
N
2
R O CH
3
C
O
N N +
Step 1:
Step 2:
Method 3:
272
Reactions of Esters
Less reactive toward nucleophiles than are acid chlorides or anhydrides
Cyclic esters are called lactones and react similarly to acyclic esters
273
Reactions of Esters
Esters react with alcohols in the presence of an acid catalyst in an
equilibrium reaction called transesterification.
Butyl propenoate
(Butyl acrylate)
(bp 147C)
1-Butanol
(bp 117C)
Methyl propenoate
(Methyl acrylate)
(bp 81C)
+
+
HCl
CH
3
OH
Methanol
(bp 65C)
OCH
3
O
HO
O
O
274
Hydrolysis:
Conversion of Esters into Carboxylic Acids
An ester is
hydrolyzed by
aqueous base or
aqueous acid to
yield a carboxylic
acid plus an alcohol
1
2
3
4
275
Reduction
Reaction with LiAlH
4
yields primary alcohols
Mechanism
276
Partial Reduction to Aldehydes
Use one equivalent of diisobutylaluminum hydride (DIBAH =
((CH
3
)
2
CHCH
2
)
2
AlH)) instead of LiAlH
4
Low temperature to avoid further reduction to the alcohol
277
Reaction with Grignard Reagents
React with 2 equivalents of a Grignard reagent to yield a tertiary alcohol
278
The Claisen Condensation Reaction
Mixed Claisen Condensations
C C C C OR
O
O
A -ket oest er

279
Mechanism
Et O
-
CH
2
-COEt H
O
Et OH CH
2
-COEt
O
O
-
CH
2
=COEt
pK
a
= 22
(weaker acid)
pK
a
15.9
(stronger
acid)
Resonance-stabilized enolate anion
-
+
+
CH
3
-C-OEt
O O
CH
2
-COEt
O
-
O
OEt
CH
3
-C-CH
2
-C-OEt +
A tetrahedral carbonyl
addition intermediate
Step 1: Formation of an enolate anion.
Step 2: Attack of the enolate anion on a carbonyl carbon gives a TCAI.
Step 3: Collapse of the TCAI gives a -ketoester and an alkoxide ion.
Et O CH
3
-C-CH
2
-C-OEt
O O O
CH
3
-C-CH
2
-C-OEt
O
OEt
+
Step 4: An acid-base reaction drives the reaction to completion.
Et O
H
CH
3
-C-CH-C-OEt
O O
CH
3
-C-CH-C-OEt
O O
Et OH
pK
a
15.9
(weaker acid)
pK
a
10.7
(stronger acid)
+ +
280
Dieckman Condensation
An intramolecular Claisen condensation
+
Diethyl hexanedioate
(Diethyl adipate)
Ethyl 2-oxocyclo-
pentanecarboxylate
1 . Et O
-
Na
+
2 . H
2
O, HCl
Et OH
OEt
O
Et O
O
OEt
O
O
281
Naming Amides, RCONH
2
Lactams: A cyclic amides are called lactams.
Name the parent carboxylic acid, drop the suffix -ic acid and add -
lactam.

6-Hexanolactam
(-Caprolactam)
H
3
C
O
NH
O
NH
1
2
1
2
3
4
5
6
3
3-Butanolactam
(-Butyrolactam)
282
Chemistry of Amides
Prepared by reaction of an acid chloride with ammonia,
monosubstituted amines, or disubstituted amines
283
Reactions of Amides
Heating in either aqueous acid or aqueous base produces a carboxylic
acid and amine
Acidic hydrolysis by nucleophilic addition of water to the protonated
amide, followed by loss of ammonia
284
Basic Hydrolysis of Amides
Addition of hydroxide and loss of amide ion
285
Reduction: Conversion of Amides into Amines
Reduced by LiAlH
4
to an amine rather than an alcohol
Converts C=O CH
2
286
Polyamides (Nylons)& Polyesters
Heating a diamine
with a diacid
produces a
polyamide called
Nylon
Nylon 66
is from
adipic acid and
hexamethylene-
diamine at 280C
The polyester
from dimethyl
terephthalate
and ethylene
glycol is called
Dacron
and
Mylar
to make
fibers
287
Spectroscopy of Carboxylic Acid Derivatives
Infrared Spectroscopy
Acid chlorides absorb near 1800 cm
1
Acid anhydrides absorb at 1820 cm
1
and also at 1760 cm
1
Esters absorb at 1735 cm
1, higher than aldehydes or ketones

Amides absorb near the low end of the carbonyl region
288
Nuclear Magnetic Resonance
Spectroscopy
Hydrogens on the carbon next to a C=O are near 2 in the
1
H NMR
spectrum.
All acid derivatives absorb in the same range so NMR does not distinguish
them from each other
13
C NMR is useful for determining the presence or absence of a carbonyl
group in a molecule of unknown structure
Carbonyl carbon atoms of the various acid derivatives absorb from 160
to 180
289
Nitriles
Nitriles and carboxylic acids both have a carbon atom with three bonds to
an electronegative atom, and both contain a bond
Both are electrophiles
The functional group of a nitrile is a cyano group
IUPAC names: name as an alkanenitrile.
common names: drop the -ic acid and add -onitrile.
CH
3
C N C N
CH
2
C N
Ethanenitrile
(Acetonitrile)
Benzonitrile Phenylethanenitrile
(Phenylacetonitrile)
290
Preparation of Nitrilesby Dehydration
Reaction of primary amides RCONH
2
with SOCl
2
or POCl
3
(or other
dehydrating agents)
Not limited by steric hindrance or side reactions (as is the reaction of alkyl
halides with NaCN)
291
Chemistry of Nitriles
Nucleophilic addition of
hydroxide to CN bond
Protonation gives a hydroxy
imine, which tautomerizes to
an amide
A second hydroxide adds to
the amide carbonyl group and
loss of a proton gives a
dianion
Expulsion of NH
2
gives the
carboxylate
292
Reduction of a nitrile with LiAlH
4
gives a primary amine
293
294
Applications of Nitriles
CH
3
( CH
2
)
8
CH
2
Cl
KCN
H
2
SO
4
, H
2
O
CH
3
( CH
2
)
9
COH
heat
ethanol,
water
O
CH
3
( CH
2
)
9
C N
1-Chlorodecane
Undecanenitrile
Undecanoic acid
CHO
HCN, KCN
CN
OH
H
2
SO
4
, H
2
O
COOH
OH
heat
Benzaldehyde Benzaldehyde cyanohydrin
(Mandelonitrile)
(racemic)
2-Hydroxyphenylacetic acid
(Mandelic acid)
(racemic)
ethanol,
water
Example 1
Example 2
295
Amines: Organic Nitrogen Compounds
296
Amines:Organic Nitrogen Compounds
Organic derivatives of ammonia, NH
3
,
N atom with a lone pair of electrons, making amines both basic and nucleophilic
Occur in plants and animals
297
NamingAmines
For simple amines, the suffix -amine is added to the name of the alkyl substituent
Symmetrical secondary and tertiary amines are named by adding the prefix
di- or tri- to the alkyl group
Classified: 1 (RNH
2
),
methyl (CH
3
NH
2
), 2
(R
2
NH), 3 (R
3
N)
298
Multiple, Different Alkyl Groups
Named as N-substituted primary amines
Largest alkyl group is the parent name, and other alkyl groups are
considered N-substituents
299
Naming Amines
Consider the NH
2
as an amino substituent on the parent molecule
The suffix -amine can be used in place of the final -e in the name of the
parent compound
300
Common Names
Alkylamines do not have common names unless they are biological molecules
Simple arylamines have common names
301
Chirality Is Possible (But Not Observed)
An amine with three different substituents on nitrogen is chiral (in principle
but not in practice): the lone pair of electrons is the fourth substituent
Most amines that have 3 different substituents on N are not resolved
because the molecules interconvert by pyramidal inversion
302
Chirality Is Possible (But Not Observed)
N
Me
Et
N
Me
Et
Cl
-
Cl
-
S Enantiomer R Enantiomer
Pyramidal
inversion is not
possible with
quaternary
ammonium ions,
and their salts can
be resolved.
303
Properties of Amines
Amines are polar compounds, and both 1 and 2 amines form
intermolecular hydrogen bonds.
N-H- - -N hydrogen bonds are weaker than O-H- - -O hydrogen bonds
because the difference in electronegativity between N and H (3.0 - 2.1
=0.9) is less than that between O and H (3.5 - 2.1 = 1.4).
Amines with fewer than five carbons are water-soluble
Primary and secondary amines form hydrogen bonds, increasing their
boiling points
bp (C) -6.3 65.0 -88.6
32.0
31.1
30.1
MW (g/mol)
CH
3
CH
3
CH
3
NH
2
CH
3
OH
304
Basicity of Amines
The lone pair of electrons on nitrogen makes amines basic and nucleophilic
They react with acids to form acidbase salts and they react with
electrophiles
Amines are stronger bases than alcohols, ethers, or water
Amines establish an equilibrium with water in which the amine
becomes protonated and hydroxide is produced
The most convenient way to measure the basicity of an amine (RNH2)
is to look at the acidity of the corresponding ammonium ion (RNH
3
+
)
High pKa weaker acid and stronger conjugate base
Most simple alkylammmonium ions have pK
a
's of 10 to 11
305
Basicity of Amines
CH
3
NH
2
CH
3
COOH CH
3
NH
3
+
CH
3
COO
-
K
e q
= 7.6 x 10
5
+
+
pK
a
10.64 pK
a
4.76
(stronger
acid)
(weaker
acid)
pK
eq
= -5.88
Tertiary Amines
diethylamine
dimethylamine
cyclohexylamine
ethylamine
methylamine
Secondary Amines
Primary Amines
Ammonia
pK
a
Structure Amine
trimethylamine
triethylamine
9.26
10.64
10.81
10.66
10.73
10.98
9.81
10.75
pK
b
4.74
3.36
3.34
3.19
3.27
3.02
4.19
3.25
CH
3
NH
2
NH
3
CH
3
CH
2
NH
2
C
6
H
1 1
NH
2
( CH
3
)
2
NH
( CH
3
CH
2
)
2
NH
( CH
3
)
3
N
( CH
3
CH
2
)
3
N
note that
pK
a
+ pK
b
= 14
306
Basicity of Substituted Arylamines
Arylamines and heterocyclic aromatic amines are considerably less
basic than alkylamines (conjugate acid pK
a
5 or less).
The N lone-pair electrons in arylamines are delocalized by interaction
with the aromatic ring electron system and are less able to accept H
+
than are alkylamines
Can be more basic or less basic than aniline
Electron-donating substituents (such as CH
3
, NH
2
, OCH
3
)
increase the basicity of the corresponding arylamine
Electron-withdrawing substituents (such as Cl, NO
2
, CN)
decrease arylamine basicity
307
Basicity of Substituted Arylamines
NH
2
CH
3
NH
2
Cl
NH
2
O
2
N
NH
2
N
N
N
H
Heterocyclic Aromatic Amines
Aromatic Amines
Structure
Amine
Aniline
4-Chloroaniline
4-Nitroaniline
4-Methylaniline
Pyridine
Imidazole
4.63
5.08
4.15
1.0
5.25
6.95
pK
a
of Conjugate Acid
308
Amines as Acids
Loss of the NH proton requires a very strong base
309
Synthesis of Amines
Reduction of nitriles and amides (review)
Reduction Aryl Nitro Compounds
310
SN2 Reactions with Alkyl Halides
Ammonia and other amines are good nucleophiles
Primary, secondary, and tertiary amines all have similar reactivity, the initially
formed monoalkylated substance undergoes further reaction to yield a
mixture of products
311
Selective Preparation of Primary Amines:
1. The Azide Synthesis
Azide ion, N
3
displaces a halide ion from a primary or secondary alkyl

halide to give an alkyl azide, RN
3
Alkyl azides are not nucleophilic (but they are explosive)
Reduction gives the primary amine
312
2. Gabriel Synthesis of Primary Amines
A phthalimide alkylation for preparing a primary amine from an alkyl halide
The N-H in imides (CONHCO) can be removed by KOH followed by
alkylation and hydrolysis
313
3. Reductive Amination of Aldehydes and Ketones
Treatment of an aldehyde or ketone with ammonia or an amine in the
presence of a reducing agent
314
Reductive Amination Is Versatile
315
Reactions of Amines
Alkylation and acylation have already been presented
316
Hofmann and Curtius Rearrangements
Carboxylic acid derivatives can be converted into primary amines with loss of
one carbon atom by both the Hofmann rearrangement and the Curtius
rearrangement
317
Hofmann Rearrangement
RCONH
2
reacts with Br
2
and base
Gives high yields of arylamines and alkylamines
318
Curtius Rearrangement
Heating an acyl azide prepared from substitution an
acid chloride
Migration of R from C=O to the neighboring
nitrogen with simultaneous loss of a leaving group
319
Review: Synthesis of Amines
1. Reduction of nitriles and amides
2. Reduction Aryl Nitro Compounds
3. The Azide Synthesis
4. Gabriel Synthesis of Primary Amines
5. Reductive Amination of Aldehydes and Ketones
6. Hofmann and Curtius Rearrangements
320
Hofmann Elimination
Converts amines into alkenes
NH
2
is a very poor leaving group so it converted to an alkylammonium

ion, which is a good leaving group
321
Orientation in Hofmann Elimination
We would expect that the more highly substituted alkene product
predominates in the E2 reaction of an alkyl halide (Zaitsev's rule)
However, the less highly substituted alkene predominates in the Hofmann
elimination due to the large size of the trialkylamine leaving group
The base must abstract a hydrogen from the most sterically accessible,
least hindered position
322
Reactions of Arylamines
Amino substituents are strongly activating, ortho- and para-directing
groups in electrophilic aromatic substitution reactions
Reactions are controlled by conversion to amide
323
Arylamines Are Not Useful for
Friedel-Crafts Reactions
The amino group forms a Lewis acidbase complex with the AlCl
3
catalyst,
preventing further reaction
Therefore we use the corresponding amide
324
Diazonium Salts: The Sandmeyer Reaction
Primary arylamines react with HNO
2
, yielding stable arenediazonium salts
Ar-NH
2
HNO
2
Ar-N
2
+
(-N
2
)
HCl, CuCl
H
2
O
HBF
4
HBr, CuBr
KCN, CuCN
KI
H
3
PO
2
Ar-I
Ar-F
Ar-H
Ar-Cl
Ar-Br
Ar-CN
Ar-OH
Schiemann
reaction
Sandmeyer
reaction
0-5C
325
Diverse Reactions of Arene diazonium Salts
326
Aryl Nitriles and Carboxylic Acids
An arenediazonium salt and CuCN yield the nitrile, ArCN, which can be
hydrolyzed to ArCOOH
327
Reduction to a Hydrocarbon
By treatment of a diazonium salt with hypophosphorous acid, H
3
PO
2
328
Mechanism of Diazonium Replacement
Through radical (rather than polar or ionic) pathways

Organic Chemistry 2 Notes

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Organic Chemistry 2 Notes

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Chapter 15

Introduction to Organometallic Compounds

) are formed by the reaction of a thiol with a base

can transfer hydride ion to another

Addition produces an acyl diorganocopper intermediate, followed by loss of

1, higher than aldehydes or ketones

displaces a halide ion from a primary or secondary alkyl

is a very poor leaving group so it converted to an alkylammonium

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