SEMMELWEIS
PETER PAZMANY
UNIVERSITY
CATHOLIC UNIVERSITY
Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework**
Consortium leader
PETER PAZMANY CATHOLIC UNIVERSITY
Consortium members
SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER
The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund ***
**Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben
***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg.
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semmelweis-egyetem.hu
ORGANIC AND BIOCHEMISTRY
(Szerves és Biokémia )
Nucleophilic and electrophilic; ionic, radical;
pericyclic reactions
(Nukleofil és elektrofil; ionos és gyökös; periciklusos
reakciók)
Compiled by dr. Péter Mátyus
with contribution by dr. Gábor Krajsovszky
Formatted by dr. Balázs Balogh
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Organic and Biochemistry: Pericyclic and radical reactions
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Table of Contents
1. Concerted reaction
4 –
2. Pericyclic reactions
5 – 12
3. Diels-Alder reaction
13 – 13
4. Reactions in Organic Chemistry
14 – 15
5. Radical Reactions
16 – 37
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Organic and Biochemistry: Pericyclic and radical reactions
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Concerted reaction
Definition
This reaction takes place in one step (without formation of any
intermediates), by changing two or more bonds.
Changings happen either by synchronous or asynchronous ways.
Types:
- through a cyclic transition state: pericyclic reactions
- not through a cyclic transition state e.g., SN2
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Organic and Biochemistry: Pericyclic and radical reactions
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Pericyclic reactions
A pericyclic reaction is a chemical reaction in which concerted reorganization of
bonding takes place throughout a cyclic array of continuously bonded atoms. It
may be viewed as a reaction proceeding through a fully conjugated cyclic
transition state. The number of atoms in the cyclic array is usually six (other
numbers are also possible).
- Cycloaddition
- Electrocyclic reactions
- Sigmatropic rearrangements
- Cheletropic reactions
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Organic and Biochemistry: Pericyclic and radical reactions
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Fukui - Woodward - Hoffmann
Principle of conservation of orbital symmetry
Woodward - Hoffmann's rules
- Are valid for concerted reactions only
- There are allowed and forbidden reactions
• the allowed reaction might take place otherwise: a theory is
not the proof for itself
• however, a forbidden reaction can not take place according
to this mechanism
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Organic and Biochemistry: Pericyclic and radical reactions
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Application to cycloadditions:
There are three possible ways
- FMO
- Hückel-Möbius
- Correlation diagram
The fragment molecular orbital method (FMO) is a computational method
that can compute very large molecular systems with thousands of atoms
using ab initio quantum-chemical wave functions.
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Organic and Biochemistry: Pericyclic and radical reactions
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HOMO
Butadiene
LUMO
Ethylene
LUMO
Butadiene
HOMO
Ethylene
LUMO
Ethylene
antibonding interaction
HOMO
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Ethylene
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Organic and Biochemistry: Pericyclic and radical reactions
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Suprafacial reaction: the new bond is formed on the same side
of the π bond (or conjugated system) present in the substrate.
Antarafacial: the new bond is formed across the opposite sides
of the π bond (or conjugated system) present in the substrate.
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Organic and Biochemistry: Pericyclic and radical reactions
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π2s + π2a is allowed
LUMO
Ethylene
HOMO
Ethylene
HOMO
Ethylene
LUMO
Ethylene
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Organic and Biochemistry: Pericyclic and radical reactions
π4s + π4s
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HOMO
antibonding
π6s + π4s
LUMO
HOMO
π8s + π2s
LUMO
HOMO
LUMO
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Organic and Biochemistry: Pericyclic and radical reactions
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Selection rule:
a. (4q+2)s and (4r)a
if the total number of the components is odd
e.g., [π14a + π2s]
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(4q + 2)s
1
(4r)a
0
(q = 0)
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allowed
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Organic and Biochemistry: Pericyclic and radical reactions
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[4+2]
Diels-Alder reaction
O
+
H
O
O
O
H
O
H3C
CH3
+
H
O
+
H
endo
CH2
COOR
COOR
H
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exo
H
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+
H
CH3
H
COOR
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Organic and Biochemistry: Pericyclic and radical reactions
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Reactions in Organic Chemistry
Classification of reagents
-
Nucleophilic reagents
HO
Electrophilic reagents
(CH3)C
Radical reagents
11/27/2011.
H2O
+
CH3
+
RO
NO 2
-
-
ROH
+
H
Br
RS
+
RSH
AlCl 3
NH3
BF3
-
NO 2
-
CN
-
Br
CH2
Cl
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Organic and Biochemistry: Pericyclic and radical reactions
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Substitution:
A
B
+
C
(or a reagent which
can provide C)
Addition:
A
+
Elimination:
A
B
Rearrangement: A
(isomerisation)
B
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B
C
A
C
B
(or a derivative
of B)
A
B
C
A
+
C
A
C
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+
C
B
C
B
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Organic and Biochemistry: Pericyclic and radical reactions
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Radical Reactions
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Organic and Biochemistry: Pericyclic and radical reactions
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Li2
Be2
B2
C2
N2
O2
F2
2σu
Energy →
1πg
2σg
1πu
1σu
1σg
The variation of the orbital energies of Period 2 homonuclear diatomic molecules.
Only the valence shell orbitals are shown.
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Organic and Biochemistry: Pericyclic and radical reactions
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Stabilization of radicals by alkyl substituents
DE
kcal/mol
VB formulation of the radical R•
H
H3C
H
104
H
H
H
H3C
H2C
H
98
H
H
H
H
H
H
H
H
H
H
9 no-bond resonance forms
H
H
H
H
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H
6 no-bond resonance forms
H
92
H
H
H
H
H
i.e., 1 no-bond
resonance form
per Hb
H
H
(H3C)3C
H
H
H
95
H
H
H
H
H
H
H
(H3C)2HC
H
H
H
H
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Organic and Biochemistry: Pericyclic and radical reactions
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Stabilization of radicals by unsaturated substituents
DE
kcal/mol
H
98
H
89
H
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VB formulation of the radical R•
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Organic and Biochemistry: Pericyclic and radical reactions
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*C=C
E
2pz
*C=C
(1st interaction)
C=C
n 2pz
2pz
1/2 the
delocalization
energy
C=C
(2nd interaction)
localized
MOs
delocalized
MOs
Stabilization by overlap of a singly occupied 2pz AO with adjacent parallel
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localized
MO
-
C=C
or *C=C- MOs.
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Organic and Biochemistry: Pericyclic and radical reactions
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+H
3 radical
2 radical
1 radical
CH3 CH2 CH2
+
CH3
CH3 C CH3
ΔH = +423 kJ mol-1
ΔH = +413 kJ mol-1
Potential energy
10 kJ mol-1
CH3
CH3 CHCH2
H
CH3 CHCH3
+H
Potential energy
1 radical
+H
22 kJ mol-1
ΔH = +400 kJ mol-1
ΔH = +422 kJ mol-1
CH3
CH3 CH2 CH3
(a)
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CH3 CHCH3
(a) Comparison of the potential
energies of the propyl
radical (+H•) and the
isopropyl radical (+H•)
relative to propane. The
isopropyl radical (a 2
radical) is more stable than
the 1 radical by 10kJ mol-1.
(b) Comparison of the potential
energies of the tert-butyl
radical (+H•) and the
isobutyl
radical
(+H•)
relative to isobutane. The 3
radical is more stable than
the 1 radical by 22 kJ mol-1.
(b)
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Organic and Biochemistry: Pericyclic and radical reactions
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Vibration
Translation
Translational, rotational and vibrational degrees of freedom for a simple diatomic molecule.
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Organic and Biochemistry: Pericyclic and radical reactions
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Transition state
Br
H
CH 3
Potential energy
Transition state
Cl
H
CH 3
Eact = +16 kJ
H
Cl
+ CH4
Reactants
Cl
mol-1
+ CH3
ΔH = +8 kJ mol-1
Products
Potential energy
H
Eact =
+78 kJ mol-1
Br
+ CH3
ΔH =
+74 kJ mol-1
+ CH4
Reactants
Reaction coordinate
(a)
Br
Products
Reaction coordinate
(b)
Potential energy diagrams for (a) the reaction of a chlorine atom with
methane and (b) the reaction of a bromine atom with methane.
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Organic and Biochemistry: Pericyclic and radical reactions
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Potential energy
2 Cl
ΔH = Eact = +243 kJ mol-1
Cl
Cl
Reaction coordinate
Potential energy diagram for the dissociation of a chlorine molecule into
chlorine atoms.
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Organic and Biochemistry: Pericyclic and radical reactions
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Potential energy
2 CH3
ΔH = -378 kJ mol-1
Eact = 0
CH3 CH3
Reaction coordinate
Potential energy diagram for the combination of two methyl radicals to form a
molecule of ethane.
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Organic and Biochemistry: Pericyclic and radical reactions
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The stereochemistry of chlorination at C2 of pentane
(S)-2-Chloropentane
(50 %)
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Trigonal planar
radical
(achiral)
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(R)-2-Chloropentane
(50 %)
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Organic and Biochemistry: Pericyclic and radical reactions
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The stereochemistry of chlorination at C3 of (S)-2-chloropentane
(S)-2-Chloropentane
(2S,3S)-2,3-Dichloropentane
(chiral)
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Trigonal planar radical
(achiral)
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(2S,3R)-2,3-Dichloropentane
(chiral)
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Organic and Biochemistry: Pericyclic and radical reactions
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Radical reactionsThermochemistry I.
reaction ΔH = -BDE (products) - [ -BDE (reactants)]
Halogenation of methane
H3C—F + X• → H3C• + HX
X—X + •CH3 → X• + CH3—X
F—F
Cl —Cl
Br —Br
I —I
H —F
H —Cl
H —Br
H —I
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→
→
→
→
→
→
→
→
(1)
(2)
chain
propagation
BDE (kcal/mol)
2 F•
38
2 Cl•
58
2 Br•
46
2 I•
36
H • + F•
136
H• + Cl•
103
H• + Br•
87
H • + I•
71
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Organic and Biochemistry: Pericyclic and radical reactions
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Radical reactions Thermochemistry II.
R—H
2011.11.27..
BDE (kcal/mol)
H3C—H
104
1° C —H
98
2° C —H
94
3° C —H
91
H3C —F
108
H3C —Cl
83
H3C —Br
70
H3C —I
56
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Organic and Biochemistry: Pericyclic and radical reactions
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Radical reactions Thermochemistry III.
CH3
BDE (kcal/mol)
H
+
Cl
104
CH3
Cl
58
+
H
83
HCl
103
186
162
ΔHr = - 186 - (-162) = - 24 kcal/mol
The first step of chain propagation for halogenation:
C
bond
H3C—H
3° C—H
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H
+
C
X
X = Cl
-103-(-104) = +1
-103-(-91) = -12
ΔHr
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+
H
X
X = Br
-87-(-104) = +17
-87-(-91) = +4
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Organic and Biochemistry: Pericyclic and radical reactions
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Conclusion:
The first step of chain propagation is endothermic process, but steps
(1) and (2) together make exothermic reaction.
Br is a much more selective radical, than Cl, considering especially the
tertiary substrates (not for primary substrates).
H3C—F + X• → H3C• + HX
X—X + •CH3 → X• + CH3—X
C
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H
+
X
(1)
(2)
C
+
chain
propagation
H
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X
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Organic and Biochemistry: Pericyclic and radical reactions
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Radical reactions Thermochemistry IV.
X X + CH3
CH4 + X
H3C X + X
CH3 + HX
(2)
(1)
Energy profile of the chain propagation steps of halogenation:
+33
I
+17
+1
0
13
Br
-7
Cl
F2 → extremely reactive → explosion
I2 → endothermic → does not react
Cl2 → of high reactive → is not selective
Br2 → sluggish → selective (with reactive
substrate only)
-25
F
-100
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-102
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Organic and Biochemistry: Pericyclic and radical reactions
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Radical reactions Thermochemistry V.
Cl 2
CH3
CH2
CH3
CH
CH2 Cl
CH3
45%
55%
Cl
CH3
CH2
CH3
Br2
CH3
CH2
CH3
CH
CH2 Br
CH3
< 1%
> 99%
Br
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Organic and Biochemistry: Pericyclic and radical reactions
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CH4
Cl2
-HCl
CH3Cl
Chain
starterreakció
reaction:
Láncindító
Cl2
-HCl
CH2Cl2
Cl2
Láncvivő
reakció
Chain
carrier
reaction: CH4 + Cl
CH3 + Cl2
Chain
breakerreakció
reaction: CH3 + Cl
Láncletörő
Cl + Cl
CH3 + CH3
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Cl2
-HCl
CHCl3
CCl4
243 kJ mol-1
2Cl
CH3
Cl2
-HCl
+
CH3Cl +
HCl
Cl
3 kJ mol-1
-108 kJ mol-1
CH3Cl
350 kJ mol-1
Cl2
-243 kJ mol-1
CH3 CH3
-369 kJ mol-1
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Organic and Biochemistry: Pericyclic and radical reactions
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E
CH3
CH3
CH
CH3 + Cl
CH3
H#
CH3
CH
CH2 + HCl
CH3
CH3
C
CH3 + HCl
reakciókoordináta
reaction
coordinate
E
CH3
CH3
CH
CH2 + HBr
CH3
CH3
CH3
CH
H#
CH3
C
CH3 + HBr
CH3 + Br
reaction coordinate
reakciókoordináta
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Organic and Biochemistry: Pericyclic and radical reactions
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bromine
brómgyökradical
képződproduction:
és :
R O O R
2 RO
RO
ROH +
+ HBr
Br
Br
CH3 CH CH
HB r
Br
CH3 CH CH2
1-bromo-propane
1-brómpropán ~80~80%
%
Br
propane
propén
Br
CH3 CH2 CH2
H Br
Br
+ Br
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CH3 CH CH3
allyl-type
radical
allil-típusú
gyök
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+ Br
2-bromo-propane
2-brómpropán ~2~20%
0%
Br2
h
-HBr
cyclohexane
ciklohexén
CH3 CH2 CH2 + Br
+ Br
Br
3-bromo-cyclohexane
3-brómciklohexén
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Organic and Biochemistry: Pericyclic and radical reactions
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Further radical reactions by N-bromo-succinimide
O
O
CH2
CH CH3 +
N Br
h
CH2 CH CH2 Br +
O
O
propén
propane
N-brómszukcinimid
N-bromo-succinimide
allil-bromid
allyl-bromide
szukcinimid
succinimide
O
O
H3C
CH3
+
H3C
N
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Br
+
Br
O
acetone
NH
N
H
O
O
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O
37