PETER PAZMANY CATHOLIC UNIVERSITY Consortium members

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

ORGANIC AND BIOCHEMISTRY

Nucleophilic and electrophilic; ionic, radical;

pericyclic reactions

(Szerves és Biokémia )

(Nukleofil és elektrofil; ionos és gyökös; periciklusos reakciók)

Compiled by dr. Péter Mátyus

with contribution by dr. Gábor Krajsovszky

Table of Contents

1. Concerted reaction 4 – 4

2. Pericyclic reactions 5 – 12

3. Diels-Alder reaction 13 – 13

4. Reactions in Organic Chemistry 14 – 15

5. Radical Reactions 16 – 37

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., S_N2

Pericyclic reactions

- Cycloaddition

- Electrocyclic reactions

- Sigmatropic rearrangements - Cheletropic 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).

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

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.

antibonding interaction HOMO

HOMO LUMO LUMO

LUMO

Butadiene

Butadiene

Ethylene Ethylene

Ethylene

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.

Ethylene

Ethylene LUMO

HOMO

Ethylene

Ethylene HOMO

LUMO

π_2s + π_2a is allowed

HOMO

LUMO

antibonding

HOMO

LUMO HOMO

LUMO

π_4s + π_4s

π_8s + π_2s

π_6s + π_4s

Selection rule:

a. (4q+2)_s and (4r)_a

if the total number of the components is odd

e.g., [π

+ π

]

(4q + 2)

1 (q = 0)

(4r)

0

allowed

Diels-Alder reaction [4+2]

+

O O

O

O H O

H

+

C H₃

H

CH₃ H

CH₃ H

+

endo exo

CH₂

COOR COOR

+

Reactions in Organic Chemistry

Classification of reagents

O

H ^- H₂O RO^- ROH RS^- RSH NH₃ ^-NO₂ ^-CN Br^-

(CH₃)C^{+ +}NO₂ H⁺ Br⁺ AlCl₃ BF₃ CH₂

CH₃ Cl

Nucleophilic reagents

Electrophilic reagents

Radical reagents

A B

+

+

+

A B C A B C

+

A B C

A B C

A B C A C B

Substitution:

Addition:

Elimination:

Rearrangement:

(isomerisation)

(or a reagent which can provide C)

(or a derivative of B)

Radical Reactions

The variation of the orbital energies of Period 2 homonuclear diatomic molecules.

Energy →

2σ_u 1π_g

2σ_g 1π_u 1σ_u

1σ_g

Li₂ Be₂ B₂ C₂ N₂ O₂ F₂

C H₃ H

C

H₃ H₂C H

C H (H₃C)₂H

C H (H C)

H H

H

H H

H H

H

H H

H H H

H H

H

H

H H

H

H H

H

i.e., 1 no-bond resonance form per H_b

H H

H H

H H

H

6 no-bond resonance forms

H

H

H H H

9 no-bond resonance forms

Stabilization of radicals by alkyl substituents

VB formulation of the radical R•

DE kcal/mol

104

98

95

92

Stabilization of radicals by unsaturated substituents

DE

kcal/mol VB formulation of the radical R•

98

89

89

H

H

H

*_C=C

C=C 2p_z

2p_z

2p_z

n

*_C=C

C=C 1/2 the

delocalization energy

E

(1st interaction)

(2nd interaction) localized MOs

delocalized MOs

localized MO

(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.

CH₃CH₂CH₂

+H _CH

3CHCH₃

+H

CH₃CH₂CH₃ CH₃CHCH₃ CH₃ CH₃C CH₃

CH₃

+^H

CH₃CHCH₂ CH₃

+^H

Potential energy Potential energy

1 radical

3 radical

2 radical

1 radical

10 kJ mol^-1

ΔH = +423 kJ mol^-1

ΔH = +413 kJ mol^-1

ΔH = +400 kJ mol^-1

ΔH = +422 kJ mol^-1 22 kJ mol^-1

Translation

Vibration

Potential energy diagrams for (a) the reaction of a chlorine atom with

Potential energy

Reaction coordinate

Potential energy

Reaction coordinate Transition state

Transition state

Reactants Products Reactants Products

E_act = +16 kJ mol^-1

E_act =

+78 kJ mol^-1 ΔH = +74 kJ mol^-1

ΔH = +8 kJ mol^-1

Cl +^CH4 Br +^CH4

H CH₃ Cl

H CH₃ Br

(a) (b)

+^CH3

H Cl

+^CH3

H Br

Potential energy diagram for the dissociation of a chlorine molecule into

Potential energy

Reaction coordinate

ΔH = E_act = +243 kJ mol^-1

Cl Cl

2 Cl

Potential energy diagram for the combination of two methyl radicals to form a

Potential energy

Reaction coordinate

CH₃ 2

CH₃ CH₃

ΔH = -378 kJ mol^-1 E_act = 0

The stereochemistry of chlorination at C2 of pentane

(S)-2-Chloropentane (50 %)

(R)-2-Chloropentane (50 %)

Trigonal planar radical (achiral)

(S)-2-Chloropentane

The stereochemistry of chlorination at C3 of (S)-2-chloropentane

reaction ΔH = -BDE (products) - [ -BDE (reactants)]

Radical reactionsThermochemistry I.

Halogenation of methane

BDE (kcal/mol) F—F → 2 F^• 38

Cl —Cl → 2 Cl^• 58 Br —Br → 2 Br^• 46 I —I → 2 I^• 36

H —F → H^• + F^• 136 H —Cl → H^• + Cl^• 103 H —Br → H^• + Br^• 87

H₃C—F + X^• → H₃C^• + HX (1) chain

X—X + ^•CH₃ → X^• + CH₃—X (2) propagation

Radical reactions Thermochemistry II.

R—H 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

Radical reactions Thermochemistry III.

BDE (kcal/mol) 104 58 83

162 186

ΔH_r = - 186 - (-162) = - 24 kcal/mol

The first step of chain propagation for halogenation:

bond ΔH_r

H₃C—H -103-(-104) = +1 -87-(-104) = +17

X = Cl X = Br

103 CH₃ H

+

+

C H

+

+

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 (1) chain

X—X + ^•CH₃ → X^• + CH₃—X (2) propagation

C H

+

+

Radical reactions Thermochemistry IV.

X X + CH₃ H₃C X + X CH₄ + X CH₃ + HX

(2) (1)

Energy profile of the chain propagation steps of halogenation:

+33 +17 +1

0

I

13

Br -7 Cl

-25 F

F₂ → extremely reactive → explosion I₂ → endothermic → does not react

Cl₂ → of high reactive → is not selective Br₂ → sluggish → selective (with reactive substrate only)

Radical reactions Thermochemistry V.

CH₃ CH₂ CH₃

CH₃ CH₂ CH₂Cl

CH₃ CH CH₃ Cl

CH₃ CH₂ CH₂Br

CH₃ CH CH₃ Br

Cl₂

Br₂

45%

55%

< 1%

> 99%

CH₄ Cl₂ CH₃Cl CH₂Cl₂ CHCl₃ CCl₄ -HCl

Cl₂ -HCl

Cl₂ -HCl

Cl₂ -HCl

Láncvivő reakció CH₄

CH₃Cl Láncindító reakció Cl₂

+ HCl 2Cl

CH₃

Cl +

CH₃Cl + Cl₂

CH₃

+ Cl

Cl

+ Cl

+ Cl Cl₂

243 kJ mol^-1

Láncletörő reakció CH₃ 350 kJ mol^-1

-243 kJ mol^-1 3 kJ mol^-1 -108 kJ mol^-1 Chain starter reaction:

Chain carrier reaction:

Chain breaker reaction:

H^# _CH

3 CH CH₂ CH₃

+ HCl

CH₃ C CH₃ + HCl CH₃

CH₃ CH CH₃ + Cl CH₃

E

reakciókoordináta

H^# E

CH₃ CH CH₃ + Br

CH₃ CH₃ C CH₃ + HBr

CH₃ CH₃ CH CH₂

CH₃

+ HBr

reaction coordinate

-HBr

h Br₂

Br

+ Br + Br

C H ₃ C H C H ₂ p r o p é n

C H ₃ C H C H B r

C H ₃ C H ₂ C H ₂ B r

C H ₃ C H C H ₃ B r

C H ₃ C H ₂ C H ₂ B r

2 - b r ó m p r o p á n ~ 2 0 % 1 - b r ó m p r o p á n ~ 8 0 % B r

H B r

H B r

+ B r

+ B r H B r

R O O R 2 R O

R O + R O H + B r

propane

1-bromo-propane ~80%

2-bromo-propane ~20%

CH₂ CH CH₃ + N O

O

Br h

NH O

O CH₂ CH CH₂ Br +

propén N-brómszukcinimid allil-bromid szukcinimid

propane N-bromo-succinimide allyl-bromide succinimide

Further radical reactions by N-bromo-succinimide

O C

H₃ CH₃

+

O

Br

O C

H₃ Br

N O

+