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Alcohols and Alkyl Halides
Overview of Chapter
This chapter introduces chemical reactions and
their mechanisms by focusing on two reactions
that yield alkyl halides.
(1) alcohol + hydrogen halide
ROH + HX
RX + H2O
(2) alkane + halogen
RH + X2
RX + HX
Both are substitution reactions
4.1
IUPAC Nomenclature
of Alkyl Halides
IUPAC Nomenclature
There are several kinds of IUPAC nomenclature.
The two that are most widely used are:
functional class nomenclature
substitutive nomenclature
Both types can be applied to alcohols and
alkyl halides.
Functional Class Nomenclature of Alkyl Halides
Name the alkyl group and the halogen as
separate words (alkyl + halide)
CH3F
CH3CH2CHCH2CH2CH3
Br
CH3CH2CH2CH2CH2Cl
H
I
Functional Class Nomenclature of Alkyl Halides
Name the alkyl group and the halogen as
separate words (alkyl + halide)
CH3F
CH3CH2CH2CH2CH2Cl
Methyl fluoride
Pentyl chloride
CH3CH2CHCH2CH2CH3
Br
1-Ethylhexyl bromide
H
I
Cyclohexyl iodide
Substitutive Nomenclature of Alkyl Halides
Name as halo-substituted alkanes.
Number the longest chain containing the
halogen in the direction that gives the lowest
number to the substituted carbon.
CH3CH2CH2CH2CH2F
CH3CHCH2CH2CH3
Br
CH3CH2CHCH2CH3
I
Substitutive Nomenclature of Alkyl Halides
Name as halo-substituted alkanes.
Number the longest chain containing the
halogen in the direction that gives the lowest
number to the substituted carbon.
CH3CH2CH2CH2CH2F
1-Fluoropentane
CH3CH2CHCH2CH3
I
3-Iodopentane
CH3CHCH2CH2CH3
Br
2-Bromopentane
Substitutive Nomenclature of Alkyl Halides
Cl
CH3
CH3
Cl
Halogen and alkyl groups
are of equal rank when
it comes to numbering
the chain.
Number the chain in the
direction that gives the
lowest number to the
group (halogen or alkyl)
that appears first.
Substitutive Nomenclature of Alkyl Halides
Cl
5-Chloro-2-methylheptane
CH3
CH3
2-Chloro-5-methylheptane
Cl
4.2
IUPAC Nomenclature
of Alcohols
Functional Class Nomenclature of Alcohols
Name the alkyl group and add "alcohol" as a
separate word.
CH3CH2OH
CH3
CH3CCH2CH2CH3
CH3CHCH2CH2CH2CH3
OH
OH
Functional Class Nomenclature of Alcohols
Name the alkyl group and add "alcohol" as a
separate word.
CH3CH2OH
Ethyl alcohol
CH3CHCH2CH2CH2CH3
OH
1-Methylpentyl alcohol
CH3
CH3CCH2CH2CH3
OH
1,1-Dimethylbutyl
alcohol
Substitutive Nomenclature of Alcohols
Name as "alkanols." Replace -e ending of alkane
name by -ol.
Number chain in direction that gives lowest number
to the carbon that bears the —OH group.
CH3CH2OH
CH3
CH3CCH2CH2CH3
CH3CHCH2CH2CH2CH3
OH
OH
Substitutive Nomenclature of Alcohols
Name as "alkanols." Replace -e ending of alkane
name by -ol.
Number chain in direction that gives lowest number
to the carbon that bears the —OH group.
CH3CH2OH
Ethanol
CH3CHCH2CH2CH2CH3
OH
2-Hexanol
CH3
CH3CCH2CH2CH3
OH
2-Methyl-2-pentanol
Substitutive Nomenclature of Alcohols
OH
CH3
CH3
OH
Hydroxyl groups outrank
alkyl groups when
it comes to numbering
the chain.
Number the chain in the
direction that gives the
lowest number to the
carbon that bears the
OH group
Substitutive Nomenclature of Alcohols
OH
6-Methyl-3-heptanol
CH3
CH3
5-Methyl-2-heptanol
OH
4.3
Classes of Alcohols
and Alkyl Halides
Classification
Alcohols and alkyl halides are classified as
primary
secondary
tertiary
according to their "degree of substitution."
Degree of substitution is determined by counting
the number of carbon atoms directly attached to
the carbon that bears the halogen or hydroxyl group.
Classification
H
CH3CH2CH2CH2CH2F
OH
primary alkyl halide
secondary alcohol
CH3
CH3CHCH2CH2CH3
Br
secondary alkyl halide
CH3CCH2CH2CH3
OH
tertiary alcohol
Bonding in Alcohols
and Alkyl Halides
Dipole Moments
alcohols and alkyl halides are polar
H
H
H
d+
C
d+
H
H
d+
O d–
H
C
Cl
H
m = 1.7 D
m = 1.9 D
d–
Dipole Moments
alcohols and alkyl halides are polar
m = 1.7 D
m = 1.9 D
Dipole-Dipole Attractive Forces
d+
d–
d+
d–
d–
d+
d+
d–
d+
d–
Dipole-Dipole Attractive Forces
d+
d–
d+
d–
d–
d+
d+
d–
d+
d–
Physical Properties of
Alcohols and Alkyl Halides:
Intermolecular Forces
Boiling point
Solubility in water
Density
Effect of Structure on Boiling
Point
CH3CH2CH3
CH3CH2F
CH3CH2OH
Molecular
weight
44
48
46
Boiling
point, °C
-42
-32
+78
0
1.9
1.7
Dipole
moment, D
CH3CH2CH3
Molecular
weight
44
Intermolecular forces
are weak.
Boiling
point, °C
-42
Only intermolecular
forces are induced
dipole-induced dipole
attractions.
Dipole
moment, D
0
CH3CH2F
Molecular
weight
48
Boiling
point, °C
-32
Dipole
moment, D
1.9
A polar molecule;
therefore dipole-dipole
and dipole-induced
dipole forces contribute
to intermolecular
attractions.
CH3CH2OH
Molecular
weight
46
Boiling
point, °C
+78
Dipole
moment, D
1.7
Highest boiling point;
strongest intermolecular
attractive forces.
Hydrogen bonding is
stronger than other
dipole-dipole attractions.
Hydrogen bonding in ethanol
d–
d–
d+
d+
Hydrogen bonding in ethanol
Boiling point increases with increasing
number of halogens
Compound
CH3Cl
CH2Cl2
CHCl3
CCl4
Boiling Point
-24°C
40°C
61°C
77°C
Even though CCl4 is the only compound in this list without
a dipole moment, it has the highest boiling point.
Induced dipole-induced dipole forces are greatest in CCl4
because it has the greatest number of Cl atoms. Cl is more
polarizable than H.
But trend is not followed when halogen
is fluorine
Compound
CH3CH2F
CH3CHF2
CH3CF3
CF3CF3
Boiling Point
-32°C
-25°C
-47°C
-78°C
Fluorine is not very polarizable and induced dipoleinduced dipole forces decrease with increasing
fluorine substitution.
Solubility in water
Alkyl halides are insoluble in water.
Methanol, ethanol, isopropyl alcohol are
completely miscible with water.
The solubility of an alcohol in water
decreases with increasing number of
carbons (compound becomes
more hydrocarbon-like).
Hydrogen Bonding Between
Ethanol and Water
d+
d–
d+
d+
d–
d–
Density
Alkyl fluorides and alkyl chlorides are
less dense than water.
Alkyl bromides and alkyl iodides are
more dense than water.
All liquid alcohols have densities of
about 0.8 g/mL.
4.6
Acids and Bases: General Principles
Acids and Bases: General Principles
Brønsted-Lowry definition
an acid is a proton donor
a base is a proton acceptor
Proton Transfer from HBr to Water
hydronium ion
H
.. O ..
H
.. .
.
H Br
.
.
base
acid
H
.. O+
H
H
.. . –
.. Br
.
.
.
conjugate conjugate
acid
base
Acid Strength
A strong acid is one that is completely
ionized in water.
A weak acid is one that ionizes in water
to the extent of less than 100%.
Acid strength is measured by Ka or pKa
Equilibrium constant for proton transfer
H
.. . –
.
.. O+
.
H + . Br
.
.
H
H
.. .
.. O .. + H Br .
.
.
H
K=
[H3O+][Br–]
[HBr]
[H+][Br–]
Ka =
[HBr]
pK a = – log Ka
Table 4.2 Strength of Some Brønsted Acids
Acid
Ka
pKa
Conj. Base
10
–10
I
9
–9
Br
7
–7
Cl
–4.8
HSO4
–1.7
H 2O
HI
~10
HBr
~10
HCl
~10
H2SO4
1.6 x 10
+
H 3O
55.5
5
–
–
–
–
strong acids are stronger than hydronium ion
Table 4.2 Strength of Some Brønsted Acids
Acid
H 3O
+
HF
CH3CO2H
+
NH4
H2O
Ka
pKa
Conj. Base
55.5
–1.7
H 2O
3.5 x 10
1.8 x 10
5.6 x 10
1.8 x 10
–4
–5
–10
–16
–
3.5
F
4.6
–
CH3CO2
9.2
NH3
15.7
–
HO
weak acids are weaker than hydronium ion
Table 4.2 Strength of Some Brønsted Acids
Acid
Ka
H 2O
1.8 x 10
CH3OH
~10
CH3CH2OH
~10
(CH3)2CHOH
~10
(CH3)3COH
~10
pKa
-16
Conj. Base
–
15.7
HO
-16
~16
CH3O
-16
~16
CH3CH2O
-17
~17
(CH3)2CHO
-18
~18
(CH3)3CO
–
–
–
–
alcohols resemble water in acidity; their conjugate
bases are comparable to hydroxide ion in basicity
Table 4.2 Strength of Some Brønsted Acids
Acid
NH3
(CH3)2NH
Ka
-36
~10
-36
~10
pKa
~36
~36
Conj. Base
NH2
–
(CH3)2N
–
ammonia and amines are very weak acids;
their conjugate bases are very strong bases
Proton Transfer to Alcohols
alkyloxonium ion
R
.. O ..
H
.. .
.
H Br
.
.
base
acid
R
.. O+
H
H
.. . –
.. Br
.
.
.
conjugate conjugate
acid
base
4.7
Acid-Base Reactions:
A Mechanism for Proton Transfer
Proton Transfer from HBr to Water
H
.. O ..
H
.. .
.
H Br
.
.
base
acid
H
.. O+
H
H
.. . –
.. Br
. .
.
conjugate conjugate
acid
base
Mechanism:
single step
transition
state
Potential
energy
activation energy
reactants
products
Reaction coordinate
Mechanism:
single step
d+
H2O
Potential
energy
H2O + H—Br
Reaction coordinate
d-
H
Br
bimolecular:
both H2O and
HBr involved at
transition state
+
H2O—H + Br –
Halogenation of Alkanes
RH + X2
RX + HX
Energetics
RH + X2
RX + HX
explosive for F2
exothermic for Cl2 and Br2
endothermic for I2
Chlorination of Methane
carried out at high temperature (400 °C)
CH4 + Cl2
CH3Cl + HCl
CH3Cl + Cl2
CH2Cl2 + HCl
CH2Cl2 + Cl2
CHCl3 + HCl
CHCl3 + Cl2
CCl4 + HCl
Mechanism of Chlorination of Methane
Free-radical chain mechanism.
Initiation step:
..
.. ..
..
. + . Cl:
: Cl: Cl
:
:
Cl
..
.. ..
..
The initiation step "gets the reaction going"
by producing free radicals—chlorine atoms
from chlorine molecules in this case.
Initiation step is followed by propagation
steps. Each propagation step consumes one
free radical but generates another one.
Mechanism of Chlorination of
Methane
First propagation step:
H3C : H
+
..
. Cl:
..
H3C .
+
..
H : Cl:
..
First propagation step:
H3C : H
+
..
. Cl:
..
Second propagation step:
.. ..
:
H3C . + : Cl: Cl
..
..
H3C .
+
..
H : Cl:
..
..
..
H3C: C : + . Cl:
..
..
l
First propagation step:
H3C : H
+
..
. Cl:
..
Second propagation step:
.. ..
:
H3C . + : Cl: Cl
..
..
.. ..
: Cl
:
H3C : H + : Cl
..
..
H3C .
+
..
H : Cl:
..
..
..
H3C: C : + . Cl:
..
..
l
..
..
H3C: C : + H : Cl:
..
..
l
Almost all of the product is formed by repetitive
cycles of the two propagation steps.
First propagation step:
H3C : H
+
..
. Cl:
..
Second propagation step:
.. ..
:
H3C . + : Cl: Cl
..
..
.. ..
: Cl
:
H3C : H + : Cl
..
..
H3C .
+
..
H : Cl:
..
..
..
H3C: C : + . Cl:
..
..
l
..
..
H3C: C : + H : Cl:
..
..
l
Termination Steps
stop chain reaction by consuming free radicals
..
H3C: C :
..
l
hardly any product is formed by termination step
because concentration of free radicals at any
instant is extremely low
..
H3C . + . Cl:
..
Chlorination of Alkanes
can be used to prepare alkyl chlorides
from alkanes in which all of the hydrogens
are equivalent to one another
CH3CH3 + Cl2
420°C
CH3CH2Cl + HCl
(78%)
+ Cl2
hn
Cl + HCl
(73%)
Chlorination of Alkanes
Major limitation:
Chlorination gives every possible
monochloride derived from original carbon
skeleton.
Not much difference in reactivity of
different hydrogens in molecule.
Example
Chlorination of butane gives a mixture of
1-chlorobutane and 2-chlorobutane.
(28%)
CH3CH2CH2CH2Cl
CH3CH2CH2CH3
Cl2
hn
CH3CHCH2CH3
(72%)
Cl
Percentage of product that results from
substitution of indicated hydrogen if
every collision with chlorine atoms is
productive
10%
10%
10%
10%
10%
10%
10%
10%
10%
10%
Percentage of product that actually results
from replacement of indicated hydrogen
18%
18%
4.6%
4.6%
4.6%
4.6%
4.6%
4.6%
18%
18%
Relative rates of hydrogen atom
abstraction
divide by 4.6
18%
4.6%
4.6
=1
4.6
18
4.6
= 3.9
A secondary hydrogen is abstracted 3.9 times
faster than a primary hydrogen by a chlorine
atom.
Similarly, chlorination of 2-methylbutane
gives a mixture of isobutyl chloride and
tert-butyl chloride
(63%)
CH3
CH3CCH2Cl
CH3
CH3CCH3
H
H
Cl2
hn
CH3
CH3CCH3
(37%)
Cl
Percentage of product that results from
replacement of indicated hydrogen
7.0%
37%
Relative rates of hydrogen atom abstraction
divide by 7
7.0
7
=1
37
7
= 5.3
A tertiary hydrogen is abstracted 5.3 times faster
than a primary hydrogen by a chlorine atom.
Selectivity of free-radical halogenation
R3CH
> R2CH2 >
RCH3
chlorination:
5
4
1
bromination:
1640
82
1
Chlorination of an alkane gives a mixture of
every possible isomer having the same skeleton
as the starting alkane. Useful for synthesis only
when all hydrogens in a molecule are equivalent.
Bromination is highly regioselective for
substitution of tertiary hydrogens. Major synthetic
application is in synthesis of tertiary alkyl
bromides.
Preparation of Alkyl Halides from
Alcohols and Hydrogen Halides
ROH + HX  RX + H2O
Reaction of Alcohols with Hydrogen Halides
ROH +
HX  RX + HOH
Hydrogen halide reactivity
HI
most reactive
HBr
HCl
HF
least reactive
Reaction of Alcohols with Hydrogen Halides
ROH +
HX  RX + HOH
Alcohol reactivity
R3COH
Tertiary
R2CHOH
Secondary
most reactive
RCH2OH CH3OH
Primary Methanol
least reactive
Preparation of Alkyl Halides
25°C
(CH3)3COH + HCl
(CH3)3CCl + H2O
78-88%
OH + HBr
80-100°C
Br + H2O
73%
CH3(CH2)5CH2OH + HBr
120°C
CH3(CH2)5CH2Br + H2O
87-90%
Preparation of Alkyl Halides
A mixture of sodium bromide and sulfuric
acid may be used in place of HBr.
CH3CH2CH2CH2OH
NaBr
H2SO4
heat
CH3CH2CH2CH2Br
70-83%
Mechanism of the Reaction of
Alcohols with Hydrogen
Halides
Mechanism
Step 1:
Proton transfer from HCl to tert-butyl alcohol
(CH3)3C
..
O: + H
..
:
Cl
..
H
fast, bimolecular
H
+
(CH3)3C O :
+
H
tert-Butyloxonium ion
.. –
: Cl:
..
Mechanism
Step 2:
Dissociation of tert-butyloxonium ion
H
+
(CH3)3C O :
H
slow, unimolecular
H
+
(CH3)3C
+
:O:
tert-Butyl cation
H
Mechanism
Step 3:
Capture of tert-butyl cation by chloride ion.
(CH3)3C
+
+
.. –
: Cl:
..
fast, bimolecular
(CH3)3C
..
Cl
.. :
tert-Butyl chloride
Carbocations
+ +
(CH3)3C
.. –
: Cl:
..
(CH3)3C
..
Cl
.. :
The last step in the mechanism of the reaction of
tert-butyl alcohol with hydrogen chloride is the
reaction between an electrophile and a nucleophile.
tert-Butyl cation is the electrophile. Chloride ion
is the nucleophile.
Fig. 4.11 Combination of tert-butyl cation and
chloride ion to give tert-butyl chloride
nucleophile
(Lewis base)
+
electrophile
(Lewis acid)
–
Potential Energy Diagrams for
Multistep Reactions:
The SN1 Mechanism
Extension
The potential energy diagram for a
multistep mechanism is simply a collection of the
potential energy diagrams for the individual
steps.
Consider the mechanism for the reaction of
tert-butyl alcohol with HCl.
(CH3)3COH + HCl
25°C
(CH3)3CCl + H2O
Mechanism
Step 1:
Proton transfer from HCl to tert-butyl alcohol
(CH3)3C
..
O: + H
..
:
Cl
..
H
fast, bimolecular
H
+
(CH3)3C O :
+
H
tert-butyloxonium ion
.. –
: Cl:
..
Mechanism
Step 2:
Dissociation of tert-butyloxonium ion
H
+
(CH3)3C O :
H
slow, unimolecular
H
+
(CH3)3C
+
tert-Butyl cation
:O:
H
Mechanism
Step 3:
Capture of tert-butyl cation by chloride ion.
(CH3)3C
+
+
.. –
: Cl:
..
fast, bimolecular
(CH3)3C
..
Cl
.. :
tert-Butyl chloride
carbocation
formation
carbocation
capture
R+
proton
transfer
ROH
+
ROH2
RX
carbocation
formation
d–
d+
(CH3)3C
O
carbocation
capture
H
Cl
R+
H
ROH
+
ROH2
RX
H
d+
(CH3)3C
O
d+
carbocation
capture
H
R+
proton
transfer
ROH
+
ROH2
RX
d+
carbocation
formation
(CH3)3C
R+
proton
transfer
ROH
+
ROH2
RX
d–
Cl
Mechanistic notation
The mechanism just described is an
example of an SN1 process.
SN1 stands for substitution-nucleophilicunimolecular.
The molecularity of the rate-determining
step defines the molecularity of the
overall reaction.
Mechanistic notation
The molecularity of the rate-determining
step defines the molecularity of the
overall reaction.
H
d+
(CH3)3C
O
d+
H
Rate-determining step is unimolecular
dissociation of alkyloxonium ion.
4.12
Effect of Alcohol Structure
on Reaction Rate
slow step is:
ROH2+  R+ + H2O
The more stable the carbocation, the faster
it is formed.
Tertiary carbocations are more stable than
secondary, which are more stable than primary,
which are more stable than methyl.
Tertiary alcohols react faster than secondary,
which react faster than primary, which react faster
than methanol.
Hammond's Postulate
If two succeeding states (such as a
transition state and an unstable intermediate)
are similar in energy, they are similar in structure.
Hammond's postulate permits us to infer the
structure of something we can't study (transition
state) from something we can study
(reactive intermediate).
carbocation
formation
carbocation
capture
R+
proton
transfer
ROH
+
ROH2
RX
carbocation
formation
R+
proton
transfer
ROH
+
ROH2
Rate is
carbocation
governed by
capture
energy of this
transition state.
Infer structure of
this transition
state from
structure of
state of closest
energy; in this
case the
nearest state is
the
RXcarbocation.
Reaction of Primary Alcohols with
Hydrogen Halides.
The SN2 Mechanism
Preparation of Alkyl Halides
25°C
(CH3)3COH + HCl
(CH3)3CCl + H2O
78-88%
OH + HBr
80-100°C
Br + H2O
73%
CH3(CH2)5CH2OH + HBr
120°C
CH3(CH2)5CH2Br + H2O
87-90%
Preparation of Alkyl Halides
Primary carbocations are too high in energy to
allow SN1 mechanism. Yet, primary alcohols
are converted to alkyl halides.
Primary alcohols react by a mechanism called
SN2 (substitution-nucleophilic-bimolecular).
CH3(CH2)5CH2OH + HBr
120°C
CH3(CH2)5CH2Br + H2O
87-90%
The SN2 Mechanism
Two-step mechanism for conversion
of alcohols to alkyl halides:
(1) proton transfer to alcohol to form
alkyloxonium ion
(2) bimolecular displacement of water
from alkyloxonium ion by halide
Example
CH3(CH2)5CH2OH + HBr
120°C
CH3(CH2)5CH2Br + H2O
Mechanism
Step 1:
Proton transfer from HBr to 1-heptanol
CH3(CH2)5CH2
..
O: + H
..
:
Br
..
H
fast, bimolecular
H
+
CH3(CH2)5CH2 O :
H
Heptyloxonium ion
+
.. –
: Br:
..
Mechanism
Step 2:
Reaction of alkyloxonium ion with bromide
ion.
H
.. –
+
: Br: + CH3(CH2)5CH2 O :
..
H
slow, bimolecular
H
CH3(CH2)5CH2
..
Br
.. :
1-Bromoheptane
+
:O:
H
d+
d–
Br
CH2
OH2
CH3(CH2)4 CH2
proton
transfer
ROH
+
ROH2
RX
Sostituzione nucleofila bimolecolare
H3C
+
Br
OH
bromuro di metile
H3C
+ Br
metanolo
CH3
H3C
Br
C2H5
OH
+ OCH3
H
2R 2-bromobutano
H3CO
+
H
C2H5
2S metossibutano
Br
Meccanismo della sostituzione nucleofila
alifatica bimolecolare SN2
cinetica
stereochimica
struttura del substrato
nucleofili
gruppi uscenti
solventi
H3C
Br
+ OH
bromuro di metile
v = k [CH3Br][-OH]
H3C
OH
metanolo
+ Br
CH3
H3C
Br
C2H5
H
+ OCH3
H3CO
+
H
Br
C2H5
2S
2R
Inversione di Configurazione
Reazione stereospecifica in quanto lo stereoisomero
di partenza è trasformato in uno specifico
stereoisomero del prodotto
110
Reattività relativa dei bromuri alchilici
k rel
CH 3 Br
150
CH 3 CH 2 Br
1
CH 3 CH Br
0 .0 0 8
CH 3
CH 3
CH 3 C
CH 3
Br
unreac t iv e!
Nucleofilo KI
R
Cl
+
-
OH
R
OH +
-
Cl
R
Cl
+
-
R
OH
OH +
-
Cl
R METILE ETILE ISOPROPILE T-BUTILE NEOPENTILE
v
30
1
0,3
0
10-6
Gli stati di transizione delle reazioni spiegano la reattività
differente in quanto un aumento dell’ingombro sterico al
carbonio diminuisce la stabilità dello stato di transizione
(maggiore energia) facendo aumentare l’Eatt e quindi
diminuire la velocità.
Nu
L
+
nucleofilo
prodotto
OH
alcoli
H2O
RO-
alcoli
ROH
eteri
-
HS
CN
RC C
NH3
I
eteri
tioli
nitrili
alchini
ammine
ioduri
RCOO esteri
RCOOH esteri
d
Nu
d
L
+L
Nu
solventi
costante dielettrica
O
diossano
2
O
2
C6H14 esano
C6H6 benzene
3
C2H5OC2H5etere etilico 4
CH3COOH a. acetico
NH3 ammoniaca
6
17
CH3CH2OH alcol etilico 24
CH3COCH3 acetone 25
HCOOH acido formico 59
H2O
acqua
80
solventi polari aprotici
H3C O
dimetilsolfossido
S O
N C H
H3C
H
C
38
3
H3C
dimetilformammide
45
IDROSSIDO DI SODIO ACQUOSO
CIANURO DI POTASSIO
ORDINE DI NUCLEOFILICITA'
elettroni 
elettroni non legame
elettroni 
gli anioni sono più nucleofili degli acidi coniugati
RO-
ROH
a parità di centro nucleofilo l'ordine di nucleofilicità
corrisponde a quello di basicità
ROHOper gli elementi di uno stesso gruppo la nucleofilicità
aumenta con il peso atomico (in solventi protici)
I-
Br-
Cl-
F-
H2Se > H2S > H2O, and PH3 > NH3
L’effetto è dovuto alla
maggiore polarizzabilità
degli atomi più grandi. Le
nubi elettroniche più
grandi permettono una
maggiore sovrapposizione
nello stato di transizione
SN2.
La nucleofilicità decresce andando da sinistra a
destra nella tavola periodica
H2N- > HO- > FI nucleofili stericamente ingombrati reagiscono più lentamente.
I migliori gruppi uscenti sono le basi molto deboli
Ioduro > bromuro > cloruro
Lo ione idrossido è un pessimo gruppo uscente
gruppo uscente NH2-, RO-, OH-, F-, Cl-, H2O, Br-, I-,
CH3C6H4SO3-, CH3SO3O
R
O
S
CH3
R
OTs
O
para-Toluenesulfonate
Tosylate
O
R
O
S
Br
R
OBs
O
para-Bromobenzenesulfonate
Brosylate
Quando un soluto viene sciolto in un solvente le molecole o gli
ioni possono essere circondate da molecole del solvente ed
essere pertanto solvatate.
I solventi si distinguono in:
solventi polari protici (formano legami idrogeno) acqua,
alcoli
solventi aprotici (non formano legami idrogeno) benzene, esano
solventi polari aprotici (non formano legami idrogeno) ma
hanno alta costante dielettrica ed alta polarità DMSO, DMF
In generale la solvatazione formando una sfera di
solvente intorno al nucleofilo indebolisce la sua forza
attaccante un elettrofilo. Gli ioni più piccoli sono solvatati
meglio dei più grandi. Così F- è maggiormente solvatato
rispetto ad I-.
Because aprotic solvents do not form hydrogen bonds, they
solvate anionic nucleophiles relatively weakly.
This results in an increase in the nucleophiles reactivity.
Bromomethane reacts with KI 500 times faster in propanone than
in methanol.
Consider the reaction of iodomethane with chloride:
The rate of the reaction is more than 106 times greater in the
aprotic solvent DMF than in methanol.
Scegliedo solventi aprotici la reattività aumenta ed ovviamente
l’effetto è più marcato nel caso di piccoli anioni.
Il bromometano reagisce con KI 500 volte più velocemente
in acetone che in metanolo.
Nella reazione dello iodometano con Cl- la velocità della
Reazione passando dal metanolo alla DMF aumenta di
106 volte.
Solvolisi del bromuro di t-butile
La velocità delle reazioni SN2 diminuisce drasticamente
quando il centro di reazione passa da primario a secondario e
terziario.
Questo è vero solo per le sostituzioni bimolecolari.
Gli alogenuri secondari e terziari possono essere sostituiti con
un meccanismo differente.
Consideriamo la reazione del bromuro di t-butile ed acqua.
(CH3)3CBr + H2O

(CH3)3COH + HBr
Quando un substrato subisce sostituzione ad opera del
solvente la reazione prende il nome di solvolisi. L’acqua è il
nucleofilo anche se il suo carattere nuclefilico è basso.
La reazione non avviene con il bromuro di isopropile, il
bromuro di etile e quello di metile.
The rate law for the solvolysis of 2-bromo-2-methylpropane by
water in formic acid (polar, low nucleophilicity) has been
determined by varying the concentrations of the two reactants
and measuring the rate of solvolysis.
The rate law consistent with the kinetic data depends only on the
halide concentration, not the water concentration:
Rate = k[(CH3)3CBr] mol L-1 s-1
Two account for this kind of behavior it is necessary to postulate a
mechanism consisting of 2 or more steps having an initial ratedetermining step, or slowest step which does not involve a water
molecule.
The sum of all of the steps in the proposed mechanism must add
up to the observed overall reaction as shown in the stoichiometric
equation.
Sostituzione nucleofila monomolecolare
CH3
CH3
CH3 C
CH3
+
acetone
H2O
CH3 C
CH3
+
H
Br
OH
Br
+ other products
v = k [alogenuro]
(CH3)3CBr + H2O

(CH3)3COH + HBr
CH3Br CH3CH2Br (CH3)2CHBr (CH3)3CBr
0,001
0,01
(CH3)3COH + HBr
0,012
1200
(CH3)3CBr + H2O
CH3OH < CH3CH2OH < (CH3)2CHOH < (CH3)3COH
Br
H
C2H5
CH3
H3C
H3C
OCH3 H3CO
+ CH3OH
H
C2H5
H
C2H5
1)
CH3
CH3 C
CH3
CH3
slow
CH3 C
+
.. _
: Br :
..
+
CH3
: Br :
..
2)
CH3
CH3 C
+
H
CH3
+ :O:
CH3
fast
CH3 C
H
:O
CH3
+
H
H
3)
CH3
CH3
fast
CH3 C
:O
H
CH3
+
H
CH3 C
:O
..
CH3
+
H
+
H
1935: Hughes & Ingold
1)
CH3
CH3 C
2)
CH3
slow
CH CH3
CH3 Br
CH3
CH3
CH3
CH3 C
CH3 C
+
CH CH3
+
+ Br
CH CH3
CH3
CH3
CH3 C
+
CH CH3
+
CH3
CH3
3)
CH3 C
_
CH CH3
CH3
+
ROH
CH3 C
CH CH3
OR CH3
+
+
H
C2H5
C2H5
C2H5
Cl + H2O
OH HO
H
C
CH3
H3C
3
C6H5
C6H5
C6H5
2-idrossi-2-fenilbutano
(2R) 2-cloro-2-fenilbutano
R
40%
Nu
Nu
L
S 60%
Nu
L
L
Nu
Nu
Nu
Other Methods for Converting
Alcohols to Alkyl Halides
Reagents for ROH to RX
Thionyl chloride
SOCl2 + ROH  RCl + HCl + SO2
Phosphorus tribromide
PBr3 + 3ROH  3RBr + H3PO3
Examples
CH3CH(CH2)5CH3
SOCl2
K2CO3
CH3CH(CH2)5CH3
Cl
OH
(81%)
(pyridine often used instead of K2CO3)
(CH3)2CHCH2OH
PBr3
(CH3)2CHCH2Br
(55-60%)
Preparation of Alkenes:
Elimination Reactions
b-Elimination Reactions Overview
dehydrogenation of alkanes:
X=Y=H
dehydration of alcohols:
X = H; Y = OH
dehydrohalogenation of alkyl halides:
X = H; Y = Br, etc.
X
b
C
C
a
Y
C
C
+
X
Y
Dehydrogenation
limited to industrial syntheses of ethylene,
propene, 1,3-butadiene, and styrene
important economically, but rarely used in
laboratory-scale syntheses
CH3CH3
CH3CH2CH3
750°C
750°C
H2C
CH2 + H2
H2C
CHCH3 + H2
Dehydration of Alcohols
Dehydration of Alcohols
CH3CH2OH
OH
H2SO4
160°C
H2C
CH2 +
H2O
+
H2O
H2SO4
140°C
(79-87%)
CH3
H3C
C
CH3
OH
H2SO4
H3C
C
heat
H3C
CH2
(82%)
+
H2O
R'
Relative
Reactivity
R
C
OH
tertiary:
most reactive
R"
R'
R
C
OH
H
H
R
C
H
OH
primary:
least reactive
Regioselectivity in Alcohol Dehydration:
The Zaitsev Rule
Regioselectivity
H2SO4
HO
+
80°C
10 %
90 %
A reaction that can proceed in more than
one direction, but in which one direction
predominates, is said to be regioselective.
Regioselectivity
CH3
CH3
CH3
H3PO4
+
OH
heat
16 %
84 %
A reaction that can proceed in more than
one direction, but in which one direction
predominates, is said to be regioselective.
The Zaitsev Rule
When elimination can occur in more than one
direction, the principal alkene is the one formed
by loss of H from the b carbon having the
fewest hydrogens.
R
R
OH
C
C
H
CH3
CH2R
three protons on this b carbon
The Zaitsev Rule
When elimination can occur in more than one
direction, the principal alkene is the one formed
by loss of H from the b carbon having the
fewest hydrogens.
R
R
OH
C
C
H
CH3
CH2R
two protons on this b carbon
The Zaitsev Rule
When elimination can occur in more than one
direction, the principal alkene is the one formed
by loss of H from the b carbon having the
fewest hydrogens.
R
R
OH
C
C
H
CH3
CH2R
only one proton on this b carbon
The Zaitsev Rule
When elimination can occur in more than one
direction, the principal alkene is the one formed
by loss of H from the b carbon having the
fewest hydrogens.
R
R
OH
C
C
H
CH3
R
CH2R
C
CH2R
R
only one proton on this b carbon
C
CH3
Stereoselectivity in Alcohol
Dehydration
Stereoselectivity
H2SO4
+
heat
OH
(25%)
(75%)
A stereoselective reaction is one in which
a single starting material can yield two or more
stereoisomeric products, but gives one of them
in greater amounts than any other.
The Mechanism of Acid-Catalyzed
Dehydration of Alcohols
A connecting point...
The dehydration of alcohols and the reaction
of alcohols with hydrogen halides share the
following common features:
1) Both reactions are promoted by acids
2) The relative reactivity decreases in the
order tertiary > secondary > primary
These similarities suggest that carbocations are
intermediates in the acid-catalyzed dehydration of
alcohols, just as they are in the reaction of alcohols
with hydrogen halides.
Dehydration of tert-Butyl Alcohol
CH3
H3C
C
CH3
H3C
OH
H2SO4
C
heat
CH2
+
H3C
first two steps of mechanism are identical to
those for the reaction of tert-butyl alcohol with
hydrogen halides
H2O
Mechanism
Step 1:
Proton transfer to tert-butyl alcohol
H
(CH3)3C ..
O: + H O +
..
H
H
fast, bimolecular
H
+
(CH3)3C O :
H
+
H
tert-Butyloxonium ion
:O:
H
Mechanism
Step 2:
Dissociation of tert-butyloxonium ion
to carbocation
H
+
(CH3)3C O :
H
slow, unimolecular
H
+
+
:O:
tert-Butyl cation
H
(CH3)3C
Mechanism
Step 3:
Deprotonation of tert-butyl cation.
H
H3C
+C
H
+
:O:
H
CH2
H3C
fast, bimolecular
H
H3C
C
H3C
CH2
+
H
+
O:
H
Carbocations
are intermediates in the acid-catalyzed dehydration
of tertiary and secondary alcohols
carbocations can:
react with nucleophiles
lose a b-proton to form an alkene
Dehydration of Primary Alcohols
H2SO4
CH3CH2OH
160°C
H2C
CH2
+
H2O
avoids carbocation because primary carbocations
are too unstable
oxonium ion loses water and a proton in a
bimolecular step
Mechanism
Step 1:
Proton transfer from acid to ethanol
H
..
CH3CH2 O : + H O
..
H
H
fast, bimolecular
H
+
CH3CH2 O :
H
Ethyloxonium ion
H
+
:O:
H
Mechanism
Step 2:
Oxonium ion loses both a proton and
a water molecule in the same step.
H
H
+
: O : + H CH2 CH2 O :
H
H
slow, bimolecular
H
+
:O
H
H
H
+
H2C
CH2
+
:O:
H
Rearrangements in Alcohol Dehydration
Sometimes the alkene product does not have
the same carbon skeleton as the starting alcohol.
Example
OH
H3PO4, heat
+
3%
+
64%
33%
Rearrangement involves alkyl group migration
CH3
CH3 C
CHCH3
+
carbocation can
lose a proton as
shown
CH3
3%
or it can undergo
a methyl migration
CH3 group
migrates with its
pair of electrons to
Rearrangement involves alkyl group
migration
CH3
CH3
CH3 C
CHCH3
+
97%
CH3
+
C
CHCH3
CH3
CH3
3%
tertiary
carbocation;
more stable
Rearrangement involves alkyl group
migration
CH3
CH3
CH3 C
CHCH3
+
97%
CH3
+
C
CH3
CH3
3%
CHCH3
Another rearrangement
CH3CH2CH2CH2OH
H3PO4, heat
CH3CH2CH
12%
CH2
+
CH3CH
CHCH3
mixture of cis (32%)
and trans-2-butene (56%)
Rearrangement involves hydride shift
CH3CH2CH2CH2
CH3CH2CH
H
+
O:
CH2
oxonium ion can
lose
H water and a proton
(from C-2) to give
1-butene
doesn't give a
carbocation directly
because primary
carbocations are
too
Rearrangement involves hydride shift
CH3CH2CH2CH2
H
+
O:
CH3CH2CHCH3
+
H
CH3CH2CH
CH2
hydrogen
migrates with its
pair of electrons
from C-2 to C-1 as
water is lost
carbocation formed
by hydride shift is
Rearrangement involves hydride shift
CH3CH2CH2CH2
H
+
O:
CH3CH2CHCH3
+
H
CH3CH2CH
CH2
CH3CH
CHCH3
mixture of cis
and trans-2-butene
Hydride Shift
H
CH3CH2CHCH2
+
O:
H
H
+
CH3CH2CHCH2 +
H
H
: O:
H
Carbocations can...
•react with nucleophiles
•lose a proton from the b-carbon to form an alkene
•rearrange (less stable to more stable)
Dehydrohalogenation of
Alkyl Halides
b-Elimination Reactions Overview
dehydrogenation of alkanes:
X=Y=H
dehydration of alcohols:
X = H; Y = OH
dehydrohalogenation of alkyl halides:
X = H; Y = Br, etc.
X
b
C
C
a
Y
C
C
+
X
Y
b-Elimination Reactions Overview
dehydrogenation of alkanes:
industrial process; not regioselective
dehydration of alcohols:
acid-catalyzed
dehydrohalogenation of alkyl halides:
consumes base
X
b
C
C
a
Y
C
C
+
X
Y
Dehydrohalogenation
is a useful method for the preparation of alkenes
NaOCH2CH3
Cl
ethanol, 55°C
(100 %)
likewise, NaOCH3 in methanol, or KOH in ethanol
Dehydrohalogenation
When the alkyl halide is primary, potassium
tert-butoxide in dimethyl sulfoxide is the
base/solvent system that is normally used.
CH3(CH2)15CH2CH2Cl
KOC(CH3)3
dimethyl sulfoxide
CH3(CH2)15CH
(86%)
CH2
Regioselectivity
KOCH2CH3
Br
+
ethanol, 70°C
29 %
71 %
follows Zaitsev's rule
more highly substituted double bond predominates
Stereoselectivity
KOCH2CH3
ethanol
Br
+
(23%)
(77%)
more stable configuration
of double bond predominates
Mechanism of the
Dehydrohalogenation of Alkyl Halides:
The E2 Mechanism
Facts
(1) Dehydrohalogenation of alkyl halides
exhibits second-order kinetics
first order in alkyl halide
first order in base
rate = k[alkyl halide][base]
implies that rate-determining step
involves both base and alkyl halide;
i.e., it is bimolecular
Facts
(2)
Rate of elimination depends on halogen
weaker C—X bond; faster rate
rate: RI > RBr > RCl > RF
implies that carbon-halogen bond breaks in
the rate-determining step
The E2 Mechanism
concerted (one-step) bimolecular process
single transition state
–C—H bond breaks
 component of double bond forms
–C—X bond breaks
The E2 Mechanism
R
.. –
O
.. :
H
C
C
: X:
..
Reactants
The E2 Mechanism
R
.. –
O
.. :
H
C
C
: X:
..
Reactants
The E2 Mechanism
R
d–
..
O
..
H
Transition state
C
C
d–
: X:
..
The E2 Mechanism
R
..
O
..
H
C
C
.. –
: X:
..
Products
Anti Elimination in E2
Reactions
Stereoelectronic Effects
Stereoelectronic effect
Br
KOC(CH3)3
(CH3)3COH
(CH3)3C
cis-1-Bromo-4-tertbutylcyclohexane
(CH3)3C
Stereoelectronic effect
(CH3)3C
trans-1-Bromo-4-tertbutylcyclohexane
Br
(CH3)3C
KOC(CH3)3
(CH3)3COH
Stereoelectronic effect
cis
Br
KOC(CH3)3
(CH3)3COH
(CH3)3C
Rate constant for
dehydrohalogenation of cis
is 500 times
greater than that of trans
(CH3)3C
Br
(CH3)3C
trans
KOC(CH3)3
(CH3)3COH
Stereoelectronic effect
cis
Br
KOC(CH3)3
(CH3)3COH
(CH3)3C
H H
(CH3)3C
H that is removed by base must be
anti periplanar to Br
Two anti periplanar H atoms in cis
stereoisomer
Stereoelectronic effect
trans
H
Br
H
(CH3)3C
KOC(CH3)3
(CH3)3COH
H H
(CH3)3C
H that is removed by base must be
anti periplanar to Br
No anti periplanar H atoms in trans
stereoisomer; all vicinal H atoms are
gauche to Br
cis
more reactive
trans
less reactive
Stereoelectronic effect
An effect on reactivity that has
its origin in the spatial arrangement of
orbitals or bonds is called a
stereoelectronic effect.
The preference for an anti
periplanar arrangement of H and Br in
the transition state for E2
dehydrohalogenation is an example of a
stereoelectronic effect.
A Different Mechanism for
Alkyl Halide Elimination:
The E1 Mechanism
Example
CH3
CH3
CH2CH3
C
Br
Ethanol, heat
H3C
CH3
H2C
+
C
CH2CH3
(25%)
H
C
C
CH3
H3C
(75%)
The E1 Mechanism
1. Alkyl halides can undergo elimination in
absence of base.
2. Carbocation is intermediate
3. Rate-determining step is unimolecular
ionization of alkyl halide.
CH3
Step 1
CH3
CH2CH3
C
: Br:
..
slow, unimolecular
CH3
C
CH3 + CH2CH3
.. –
: Br :
..
CH3
Step 2
CH3
C
+
CH2CH3
– H+
CH3
CH2
+
C
CH3
CH2CH3
C
CH3
CHCH3