Chapter 10.
Halohydrocarbons
Based on
McGraw Hill’s Organic Chemistry, 5th edition, Chapters
4, 8,14 and 23
What Is a Halohydrocarbon?
„ An organic compound
Functional
group
containing at least one
carbon-halogen bond (C-X)
„
H
X (F, Cl, Br, I) replaces H
H C Br
H
H
H C H
H
„ Can contain many C-X bonds
F
Cl
„ Properties and some uses
„
„
„
C F
Cl
Fire-resistant solvents
Refrigerants
Pharmaceuticals and precursors
2
10.1 Class of Halohydrocarbons
„ Kinds of halogen atom (or functional group)
Fluoride
Bromide
Chloride
Iodide
„ Numbers of halogen atom
Monohalide
Multiple Halide
3
Class of Halohydrocarbons
„ the carbon that bears the functional group
a primary halide
a secondary halide
a tertiary halide
4
Class of Halohydrocarbons
„ Kinds of hydrocarbyl
X
X
R C X
alkyl halide
aryl halide
vinyl halide
The main topic of this chapter
5
10.2 Naming Halohydrocarbons
„ Name is based on the longest carbon chain
„
„
(Contains double or triple bond if present)
Number from end nearest any substituent (alkyl or halogen)
Treat halogen as halo-
2-Bromopentane
Halo
Alkyl group
R-F:
Flouro-
R-Cl:
Chloro-
R-Br:
Bromo-
R-I:
Iodo-
6
Naming with Multiple Halides
„ If more than one of the
same kind of halogen is
present, use prefix di,
tri, tetra
„ If there are several different
halogens, number them and
list them in alphabetical order
Cl Cl
CH3CHCHCH2CH3
2,3-dichloropentane
Br
Cl
1-bromo-4-chlorobenzene
7
Naming with Multiple Substituents
CH2=CHCH2Br
3-bromoproprne
8
Naming if Two Halides or Alkyl Are
Equally Distant from Ends of Chain
„ Begin at the end nearer the substituent whose name
comes first in the alphabet
9
Many Halohydrocarbons That Are
Widely Used Have Common Names
„ Chloroform
„ Carbon tetrachloride
„ Methylene chloride
„ Methyl iodide
„ Trichloroethylene
10
Examples: Common Names
F
F
Cl
C
C H
F
Br
Halothane(氟烷)
(a anesthetic)(麻醉剂)
H
Br C H
H
Bromomethane
(a fumigant) (薰剂)
11
10.3 Structure of Alkyl Halides
„ Electronegativity (EN): intrinsic ability of an atom to attract
the shared electrons in a covalent bond
EN (电负性）: F > Cl > Br > I > C
F
4.0
Cl
3.2
Br
3.0
I
2.7
12
C-X Bond in Alkyl Halides
„ C-X bond is longer as you go down periodic table
„ C-X bond is weaker as you go down periodic table
„ C-X bond is polarized with slight positive on carbon
and slight negative on halogen
CH3-H:
CH3-F:
109 pm
CH3 H
140 pm
methane
(µ= 0 D)
nonpolarizable
CH3-Cl: 179 pm
CH3-Br: 197 pm
CH3-I:
216 pm
polarizable
chloromethane
(µ=1.9 D)
C-X bond is more reactive than C-H
13
10.4 IR Spectra of Alkyl Halides
σ=
1
k
2πc
µ
m1m2
µ=
m1 + m2
„
C—F： 1400～1000 cm-1
„
C—Cl：800～600 cm-1
„
C—Br：600～500 cm-1
„
C—I： ~500 cm-1
14
10.5 1H NMR Spectra of Alkyl Halides
Chemical shift: (δ, ppm)
HC—F: 4～4.5
HC—Cl: 3～4
HC—Br: 2.5～4
HC—I: 2～4
F
4.0
Cl
3.2
Br
3.0
I
2.7
15
1H
NMR Spectra of Cl2CHCH3
Cl2CHCH3
16
10.6 Alkyl Halides: Preparation
from Alkanes
„ Alkane + Cl2 or Br2, heat or light replaces C-H with C-
X but Gives mixtures
„ Hard to control
„ Via free radical mechanism
„ It is usually not a good idea to plan a synthesis that
uses this method
17
Alkyl Halides: Preparation from
Allylic Compounds
„ N-bromosuccinimide (NBS) selectively brominates
allylic positions
„ Requires light for activation
„ A source of dilute bromine atoms
18
Alkyl Halides: Preparation from
Alkenes
„ Alkyl halide is from addition of HCl, HBr, HI to
alkenes to give Markovnikov product (see Alkenes
chapter)
„ Alkyl dihalide from anti addition of bromine or chlorine
19
Alkyl Halides: Preparation by
Halide Exchange
„ Preparation by Halide Exchange
RX + Na I
acetone
RI + Na X
X = Br or Cl
™ NOTE: Na+ is used as counter cation and acetone as solvent;
reaction good for preparation of R-X with X = Br or Cl
™ In principle the reaction could be reversible;
NaCl and NaBr are less soluble in acetone and precipitate out
to drive reaction to right
20
Alkyl Halides: Preparation From
Alcohols
RX + H2O
ROH + HX
PBr3
R
R OH
X
(X = Cl, Br, I)
(X = Br, Cl)
or SOCl2
CH3CH2OH
CH3CH2I
P + I2
IN GENERAL:
change OH to a good leaving group before substitution reaction
21
10.7 Alkyl Halides: Reactions
The sites of reactions of alkyl halides :
A polar covalent bond
readily broken
Nucleophilic
substitution
δ+
C
H
Elimination
C
δ-
X
Nu:
H
:B
B
22
Alkyl Halides: Main Reactivities
Nucleophilic
reagent
Mg
C C MgX
organometallic
compound
H
C C
X
Z
C C
Z + X
substitution
H
H
+ baseH + X
elimination
base
23
10.8 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
a mixture
dry ether
R
X + Mg
R MgX
or THF
ether: CH3CH2OCH2CH3
the 1912 Nobel Prize in chemistry
THF:
O
24
Grignard Reagents (1)
„ RMgX behaves as Celectrophilic
δ+
nucleophilic
δ−
R
R X
Nu
nucleophile
MgX
E
electrophile
„ Role of ether: stabilization
R
C2H5
O
C2H5
Mg
X
C2H5
O
C2H5
25
Grignard Reagents (2)
„ Reactivity:
R-I > R-Br > R-Cl
CH2X
CH2=CHCH2X
,
Decreasing
R3C-X
R2CH-X
RCH2-X
CH2=CHX,
X
26
Grignard Reagents (3)
„ Preparation from alkyl halides with high reactivity
CH2=CHCH2Cl + Mg
-200C, Et2O
dilute solution
violently stir
CH2=CHCH2MgCl
> 90%
CH2=CHCH2Cl + Mg
Et2O
CH2=CHCH2CH2CH=CH2
65％
RCH=CHCH2X,
PhCH2X
27
Grignard Reagents (4)
„ Preparation from vinyl halides with low reactivity
„ Reaction with reagents with active hydrogen
HOH RH + Mg X
OH
X
ROH
RH + Mg
RMgX
HX RH + MgXOR
2
X
R'C CH
RH + Mg
C CR'
28
Grignard Reagents (5)
N2
Conditions:
No water,
no acid,
No base.
29
Grignard Reagents (6)
„ Many useful reactions
RMgX + CO2
RMgX +
O
CH3MgI + HC
RCOOMgX
H+
H2O
RCH2CH2OMgX
C-R
O
RC-OH
H+
H2O
RCH2CH2OH
R-C CMgI + CH4
Determine active hydrogen
30
10.9 Organometallic Coupling
Reactions
„ Wurtz reaction——produces larger molecules with
even carbon atoms
R Na + R X → R—R + NaX
„ Alkyllithium (RLi) forms from RBr and Li metal
C4H9X + 2Li
ether
C4H9Li + LiX
„ RLi reacts with copper iodide to give lithium dialkylcopper
(Gilman reagents)
R Li + CuI → R2CuLi + LiI
R2CuLi + R’X → R－R’
31
Utility of Organometallic Coupling
in Synthesis
CH3CH2CH CH2CH2CH2CH2CH3
CH3
R
R'
CH3CH2CHBr
Li
CuI
(CH3CH2CH)2CuLi
CH3
CH3
(CH3CH2CH)2CuLi
CH3
CH3CH2CH2CH2CH2Br
CH3CH2CHCH2CH2CH2CH2CH3
CH3
32
10.10 Oxidation in Organic Chemistry
„ In organic chemistry, we say that oxidation occurs
when a carbon or hydrogen that is connected to a
carbon atom in a structure is replaced by oxygen,
nitrogen, or halogen
„
Not defined as loss of electrons by an atom as in inorganic
chemistry
„ Oxidation is a reaction that results in loss of electron
density at carbon (as more electronegative atoms
replace hydrogen or carbon)
Oxidation: break C-H (or C-C) and form C-O, C-N, C-X
33
10.11 Reduction in Organic Chemistry
„ Organic reduction is the opposite of oxidation
„
Results in gain of electron density at carbon (replacement of
electronegative atoms by hydrogen or carbon)
Reduction: form C-H (or C-C) and break C-O, C-N, C-X
34
10.12 Reduction of Alkyl/aryl Halides
C-X
⇒ C-H
LiAlH4
NaBH4
CH
CH3
C
H
CH3
D
Cl
LiAlD4
LiAlH4:
H
C
H
CH3
Suitable for R-X, R is alkyl 1°, 2°.
NaBH4： Suitable for R-X, R is alkyl 2°, 3°.
35
10.13 Alkyl Halides: Nucleophilic
Substitution
R:L + :Nu → R:Nu + :L
HO- + RX → X- + ROH
R’O- + RX → X- + R’OR
HS- + RX → X- + RSH
R’S- + RX → X- + R’SR
CN- + RX → X- + RCN
R’COO- + RX → X- + R’COOR
NH3 + RX → X- + R+NH3
36
Reactivity of Alkyl Halides
C-F
C-Cl
C-Br
C-I
C-H
544 KJ/mol
293 KJ/mol
251 KJ/mol
209 KJ/mol
414 KJ/mol
37
10.14 The SN2 Mechanism of
Nucleophilic Substitution
Rate = k[CH3Br][HO-]
Mechanism:
38
How SN2 Reaction Occur?
39
Characteristics of SN2 Mechanism
„ SN2 mechanism : bimolecular nucleophilic substitution
C
Nu
δ−
X
tetrahedral
Nu
δ−
C
X
planar T.S.
Nu
C
+ X
tetrahedral
100
T.S.
r.d.s.
∆G‡
R–Nu + X–
R–X + Nu–
0
0.5
40
Stereochemistry of SN2
inversion of stereochemistry at stereogenic carbon centre
41
SN2: Inversion of Configuration
—— Walden Inversion
Et
Et
OH
C Br
H
Me
(S)-2-bromobutane
HO
C
H Me
Et
Br
HO C
+ Br
H
Me
(R)-2-butanol
42
Steric Effects in SN2 Rractions
„ In general, SN2 reactions exhibit the following
dependence of rate on substrate structure
43
10.15 The SN1 Mechanism of
Nucleophilic Substitution
„ the hydrolysis of tert-butyl bromide, which occurs
readily, is characterized by a first-order rate law
Rate = k [(CH3)3CBr]
44
Characteristics of SN1
Mechanism
„ SN1 mechanism : unimolecular nucleophilic substitution,
step-wise.
+
Nu
solvent
δ+
C
100
X
T.S.
r.d.s.
C
δ-
T.S.
∆G1‡
Nu
+
X
∆G1‡ >> ∆G2‡
∆G2‡
R+ + X− + Nu:
R–X
0
05
R–Nu
45
SN1: Mechanism
Step 1
Step 2
Step 3
46
How SN1 Reaction Occur?
47
Stereochemistry of SN1
The Product
is racemic
and optically
inactive?
48
Stereochemistry of SN1
„ In fact, the product is somewhat optical.
Because: the carbocation not being completely “free”
49
10.16 Carbocation Rearrangements
in SN1 Reactions
Reason: carboncation rearrangements
50
10.17 Nucleophilic Substitutions:
Reaction Characteristics
„ Important Factors
1. Structure of substrate (R⎯ X)
2. Attacking nucleophile (Nu)
3. Nature of Leaving Group (X)
4. Nature of solvent used in reaction
51
10.17.1 Nucleophilic Substitutions:
Alkyl Group
„ SN1 reactivity:
methyl < primary < secondary < tertiary
„ SN2 reactivity:
tertiary < secondary < primary < methyl
52
SN2 : Steric Effects
R Cl + Br
R Br + Cl
H
H
Me
Me
C Br >> Me
C Br > Me
C CH2Br > Me
C Br
H
H
Me
Me
Me
Methyl
1°
2°
neopentyl (1°)
3°
2,000,000
40,000
500
1
<1
H
H C Br >>> Me
relative reactivity order
53
SN1 : Stability of C+
RBr + H2O → ROH + HBr
RBr
Relative
Reactivity
Me3CBr (3°)
1,200,000
12
1
1
less stable T.S.
90
energy
Me2CHBr (2°) MeCH2Br (1°) MeBr
90
less stable C+
more stable C+
more stable T.S.
00
1.51.5
2
2.5
3
3.5
4
4.5
reaction progress →
54
A Special Example
„ The nucleophilic substitutions of bridged carbons
30% KOH / C2H5OH
Cl
reflux, 21h
HO
very little
SN2: incoming nucleophilie from the back is almost impossible——steric
SN1: carbocation is different to form——planar
55
10.17.2 Nucleophilic Substitutions:
Attacking Nucleophile
SN1:
CH3
CH3
C X
CH3
CH3
slow
CH3
C+ + X−
CH3
CH3
fast
H2 O
CH3
C
CH3
+
CH3
H fast
O
CH3
H
C
OH
CH3
Rate = k [(CH3)3CBr]
Dose not affect rate of reaction
56
SN2: Attacking Nucleophile
CH3Br + Nu:– → CH3Nu + Br–
Nucleophilicity increases
down a column in periodic
table (reverse order to
basicity correlation) due to
polarizability and/or solvent
effect, and other factors
Nu = HS–
12.5 x
104
nucleophilicity
≈ basicity
(Nu with same
attacking atom)
Negatively charged Nu–
is usually more reactive
than neutral Nu.
CN–
I–
CH3O–
HO–
Cl–
NH3
CH3CO2–
H2 O
12.5 x
104
10 x
104
2.5 x
104
1.6 x
104
1000
700
500
1
Relative reactivity (in protic solvents)
57
SN2: Attacking Nucleophile ——
Nucleophilicity
Basicity:
affinity for a proton
Nucleophilicity: affinity for an “electron poor” carbon
™ Charged vs Neutral Nu : HO– > H2O; NH2– > NH3; HS– > H2S, etc
100
100
Stronger
nucleophile
Weaker
nucleophile
00
0.5
0.5
58
SN2 : Attacking Nucleophile——
Polarizability
™ Polarizability of Nu (opposite to basicity order):
e.g. H2S > H2O and HS– > HO– 100
100
Less
polarizable
nucleophile
3p orbital;
more polarized
_
HS
δ+
C
δ−
X
2p orbital;
less polarized
_
HO
0
δ+
C
δ−
X
0.5
More polarizable
nucleophile
0
0.5
59
10.17.3 Nucleophilic Substitutions:
Leaving Group
SN1:
CH3
CH3 C
slow
X
r.d.s.
CH3
CH3
δ+
CH3 C
CH3
δ−
X
CH3
CH3 C+
+ X−
CH3
Reactivity order：
TsO– > I– > Br– > Cl– > OH–
O−
O
Me
S O−
Me
S O
O
O
O
Me
S O
O−
60
SN2: Leaving Group
SN2 :
Nu
C
X:
TsO–
Relative
Reactivity:
60,000
100
X
Nu
I–
30,000
C
Br–
Cl–
10,000
200
X
Nu
F–
HO–
C
H2N–
+ X
OR–
1
100
poor leaving group
good leaving gorup
0
0
61
10.17.4 Nucleophilic Substitutions:
Solvent Effects
SN1:
Me3C⎯ Cl + ROH
Solvent: H2O
Relative
Rate
100,000
Solvent
———→
20% aq. EtOH
Me3C⎯ OR + HCl
40% aq. EtOH
14,000
100
EtOH
1
SN1 reactions:
much faster in polar solvents (high dielectric constants) due to
solvation (stabilization) of C+
H
H O
H O
H
H
O
H
C+
H
O
H
O H
O H
H
H
62
SN2 : Solvent Effects
CH3CH2CH2CH2Br + N3−
solvent
O
N
N P NH
H
N
Polar
Solvent:
Reaction
Rate:
CH3CH2CH2CH2N3 + BrO
N
S
HMPA
CH3CN
DMF
DMSO
H 2O
200,000
5,000
2,800
1,300
7
aprotic solvents
CH3OH
1
protic solvents
63
SN2 : Solvent Effects
„ polar protic solvents—— they all have OH
groups that allow them to form hydrogen bonds to
anionic nucleophiles
„ protic solvents—— lack OH groups and do not
solvate anions very strongly
Hydrogen
bonding
FIGURE ：Hydrogen bonding of the
solvent to the nucleophile stabilizes
the nucleophileand makes it less
reactive
64
SN2 : Solvent Effects
CH3CH2CH2CH2Br + Na+ N3−
Solvent:
Reaction Rate:
CH3-O-H
CH3-O-H
DMSO
1,300
solvent
CH3CH2CH2CH2N3 + Br-
CH3OH
1 100100
Solvated anions
→ lower
nucleophilicity →
H-O-CH3 decrease
reaction rate
H-O-CH3
N3
CH3-O-H
N3– in DMSO
S
S
O
O
N3– in CH3OH
Na
O
S
O S
00
0.50.5
Aprotic solvent → solvate cations but not
nucleophilic anions → “naked anions” higher in E
→ decrease ∆G‡ → increase reaction rate
65
SN2 : Solvent Effects
CH3Br + X
SN2
CH3X + Br
In gaseous phase → reactivity order: X = F– > Cl– > Br– > I–
relatively “naked” nucleophiles
In protic solvent → reactivity order: X = I– > Br– > Cl– > F–
solvate nucleophile
66
10.18 A Summary of Substitution
Halide type
SN1
SN2
RCH2X (1O)
Does not occur
Highly favored
R2CHX (2O)
Can occur with benzylic
and allylic halides
Occurs in
competition with
E2
R3CX (3O)
Favored in protic
solvents
Does not occur
67
A Summary of Substitution
SN1
SN2
Structure of
R–X
Favors R–X that forms
more stable C+
Favors sterically less hindered
R–X
Nucleophile
or Base
Not an important factor
Favors strong nucleophile (high
basicity or polarizability)
Solvent
Effect
Favors polar, protic
solvents
Favors polar, aprotic solvents
Leaving
Group
In all cases favor a good leaving group (one that could
accommodate the negative charge or has a high
tendency to leave as a weak conjugate base)
68