Professional Documents
Culture Documents
Created by
Professor William Tam & Dr. Phillis
Chang
Copyright 2014 by John Wiley & Sons, Inc. All rights reserved.
Table of Contents
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
to
Alkenes
This is an addition reaction: ENu
added across the double bond
E
+E
Nu
C
Nu
-bond
-bond
Bonds broken
2 -bonds
Bonds formed
electron
clouds
Electrophilic
electron seeking
C=C and CC bonds are particularly
susceptible to electrophilic reagents
(electrophiles)
Common electrophiles
H+, X+ (X = Cl, Br, I), Hg2+, etc.
Nu
Nu E
C
2. Electrophilic Addition:
Markovnikovs Rule
Mechanism
Markovnikovs Rule
For symmetrical substrates, no
problem for regiochemistry
H
C
Nu
E
H
same
H as H
E
C
Nu
Nu
same
H as H
Nu E
C
Markovnikovs Rule
But for unsymmetrical
substrates, two regioisomers
are possible E
E
H3C
C
H
Nu
CH3
or
CH3
H
Nu
Nu
CH3
Nu
different
H from CH3
Nu E
C
Markovnikovs Rule
In the electrophilic addition of an electrophile
across an unsymmetrical alkene, the more
highly substituted and more stabilized
carbocation is formed as the intermediate in
preference to the less highly substituted and
less stable one
H
C
C
H
H X
step 1
(slow
r.d.s.)
H
CH3
H
H or CH3
H H
2o carbocation
H H
1o carbocation
(more stable)
(more stable)
Br
(minor)
Br
Br
slow
(r.d.s.)
Br
Step 1
2014 by John Wiley & Sons, Inc. All rights reserved.
Step 2
Br
(major)
(1)
Examples
H
Cl
Cl
H
+
H
(95
(2)
5)
Br
Br
+
Br
(98
2014 by John Wiley & Sons, Inc. All rights reserved.
Cl
H
:
2)
Examples
OH
OH
Cl
(1)
Cl OH
more stable
3o cation
Cl
(major)
Examples
Cl
I
more stable
3o cation
I
Cl
(major)
Cl
+
(major)
Cl
(minor)
regioisomers
Regioselectivity:
95
H
C
Bu
C
H
H
Bu
CH2 H
H C CH3
Bu
(S)-2-Halohexane
(50%)
achiral
trigonal planar
carbocation
Bu C
X
attack from
racemate
CH3
X
bottom (R)-2-Halohexane
(50%)
Acid-Catalyzed Hydration
H
H
H2O
slow
fast
(step 2)
(step 1)
more stable
3o cation
Follows Markovnikovs
rule
OH
H2O
+
dilute H3O
(e.g. dilute H
2SO4, H3PO4)
fast
(step 3)
H2O
H
O
H
H
+
OH
4B. Rearrangements
H2SO4
1,2-alkyl shift
NOT
OH
H2O
OxymercurationDemercuration:
Markovnikov Addition
Step 1: Oxymercuration
C
Hg(OAc)2
THF-H2O
Follows Markovnikovs
rule
Step 2: Demercuration
C
HO
C
HgOAc
2. Oxymercuration
Demercuration
H2O
H2SO4
1,2-alkyl shift
H
H
H
H2O
H2O
OH
e.g.
H2O
H2SO4
OH
H
no rearrangement
via
OH
Hg(OAc)
2014 by John Wiley & Sons, Inc. All rights reserved.
5C. Mechanism of
Does
not undergo a free carbocation
Oxymercuration
HgOAc
AcO +
H2O
HgOAc
HO
2014 by John Wiley & Sons, Inc. All rights reserved.
H2O
Stereochemistry
Usually anti-addition
OH
CH3
Hg(OAc)
H2O
Solvomercuration-Demercuration
3. HydroborationOxidation:
Anti-Markovnikov Syn Hydration
C
"BH3"
BH2
H
H
H
O
H
(BH3-THF)
Me
S
Me
(BH3-DMS)
syn addition
Anti-Markovnikov addition
of H & OH
2014 by John Wiley & Sons, Inc. All rights reserved.
CH3
Hg(OAc)
Hg(OAc)2
H3C
THF-H2O
anti addition
Markovnikov addition
of H & OH
2014 by John Wiley & Sons, Inc. All rights reserved.
NaBH4
OH
CH3
anti-Markovnikov
syn addition
Example
BH3-THF
H3C
BH2
CH3
Markovnikov
Anti-Markovnikov
Regiochemistr
y
Occurrence of
Stereochemistr Rearrangemen
y
ts
Acid-catalyzed
hydration
Markovnikov
addition
Not controlled
Frequent
Oxymercuratio
ndemercuration
Markovnikov
addition
Not controlled
Seldom
Stereospecific:
syn addition of
H and OH
Seldom
Hydroboration- Antioxidation
Markovnikov
addition
3. Electrophilic Addition of
Bromine & Chlorine to Alkenes
Br2
CCl4
Br
C
C
Br
(vicinal
dibromide)
2014 by John Wiley & Sons, Inc. All rights reserved.
Examples
(1)
Br
Br2
Br
+
5 C
Br
Br
(racemate)
Cl
(2) Ph
Cl2
Ph
10oC
Ph
Ph
Cl
Ph
Ph
Cl
Cl
same as
(rotation of C1-C2 bond)
2014 by John Wiley & Sons, Inc. All rights reserved.
Br
Br
BrBr bond
becomes polarized
when close to
alkene
Br
Br
Br
+ Br
Br
Br
(vicinal
dibromid
(bromoniu
e) 2014 by John Wiley & Sons, Inc. Allm)
rights reserved.
Stereochemistry
Anti addition
Br
Br
Br
CCl4
Br
H
Br
Br
enantiomer +
(anti)
2014 by John Wiley & Sons, Inc. All rights reserved.
SN2 reaction
(a)
H
H3C
H
CH3
Br
Br
H3C
Br (b)
H
C
H
C
CH3
H
Br
H3C
(2R,3R)-2,3-Dibromobutane
(chiral)
CH3
Br
bromonium
ion
(b)
(achiral)
H
H3C
Br
C
H
Br
CH3
(2S,3S)-2,3-Dibromobutane
(chiral)
H
H3C
CH3
H
Br
Br
H3C
Br (b)
CH3
C H
H C C
Br
H3C
(R,S)-2,3-Dibromobutane
(meso)
Br
bromonium
ion
(b)
(achiral)
H
H3C
Br
C
CH3
Br
H
(R,S)-2,3-Dibromobutane
(meso)
4. Halohydrin Formation
X2
C
H2O
OH
C
C
X
Follows
Markovnikovs rule
Mechanism
Br
H3C
H2O
Br
H2O
H3C
Br
OH
CH3
Br
Other variation
If H2O is replaced by ROH, ROH
will be the nucleophile
e.g.
Br2
MeOH
OMe
Br
CH2
Diazomethane
heat
CH2
or light
Methylene Nitrogen
(a carbene)
H
Cl
C
Cl
OtBu
Cl
CCl2 + tBuOH + Cl
BuOK
Cl
CHCl3
H
Stereospecific reactions
Cl
(a cyclopropane)
CCl2
CCl2
2014 by John Wiley & Sons, Inc. All rights reserved.
Cl
Cl
Cl
Cl
5. The Simmons-Smith
CH2I 2
Zn(Cu)
(Zinc-copper
couple)
ZnI
C
H2
(a carbenoid)
6. Oxidation of Alkenes:
Syn 1,2-Dihydroxylation
C
OH OH
2. H
OH
+ O
OH
Other examples
R"
R'
1. O3
2. Zn, AcOH
or Me2S
R"
O + O
R'
H
O
(1)
1. O3
2. Zn, AcOH
O
(2)
1. O3
2. Me2S
+
O
Mechanism
O
O
C
O
initial ozonide
O
C
O
C
O
C
O
ozonide
C
O
H3C
X (excess)
(X = Cl, Br, I)
Regioselectivity
Follows Markovnikovs rule
C
HBr
Br
H
C
CH3
C
H
HBr
Br H
CH3
Br H
gem-dibromide
Mechanism
CH3
Br
H
CH3
Br
C
H
Br
H
C
CH3
Br H
CH3
Br H
Br
Br
C
CH3
C
H
Br
C
H
Anti-Markovnikov addition of
hydrogen bromide to alkynes
occurs when peroxides are
present in the reaction mixture
H
Br
peroxides
Br
H
(E) and (Z)
(74%)
How to synthesize
?
OH
Retrosynthetic analysis
OH
(target molecule)
2014 by John Wiley & Sons, Inc. All rights reserved.
(precursor)
Synthesis
Markovnikov addition
of H2O
How to synthesize
OH
Retrosynthetic analysis
OH
(target molecule)
(precursor)
Synthesis
anti-Markovnikov addition of
H 2O
2014 by John Wiley & Sons, Inc. All rights reserved.
Example
How?
Ph
Br
Br
CH3
Ph
Retrosynthetic analysis
(i)
Br
Ph
Br
CH3
Ph
CH3
Retrosynthetic analysis
synthons
(ii)
Ph
CH3
Ph
+ CH3
disconnection
H3C
+ Ph
Na
synthetic equivalent
2014 by John Wiley & Sons, Inc. All rights reserved.