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Free Radical Reactions in Organic Synthesis Mechanism, Lecture notes of Chemistry

Radical Chain Mechanism, Vinyl Radicals ,intermolecular addition reaction

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Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis
1
FREE RADICAL REACTIONS IN ORGANIC SYNTHESIS
MECHANISM
• Before we look at free radical chemistry a quick revision of mechanisms (again)
• You should all be happy with
CO2Et
RRCO2Et
polar reaction –
nucleophile attacks
electrophile
curly arrow
represents the
movement of 2 e–
• Radicals are one electron species so we cannot use curly arrows
• Instead use fish-hooks – these show the movement of one electron
CO2Et
RRCO2Et
2e–
1e–
need 2 e– to
form new bond
• Diagrams can get quite confusing so they are normally simplified to show electrons only
moving in one direction – BUT remember the above is "more accurate"
CO2Et
RRCO2Et
simplification
• Note - we are nolonger looking at proton removal but hydrogen abstraction (it still has its 1 e–)
R O H Br R OH Br R O H Br R OH Br
deprotonation hydrogen
abstraction
INTRODUCTION
• The last 10–15 years have seen the development of free radical chemistry in organic synthesis
• Major obstacle is the ability of radicals to react with themselves
• Overcome by only having a very low concentration of radicals present in a reaction
• Now there are many ways to use these highly reactive species in selective (& synthetically
useful) organic reactions
• Good example is the radical chain process for allylic halogenation
R R R R R R
N Br
O
O
Br
Br
hν or heat /
(BzO)2
activated C-H
problem of
isomerisation
pf3
pf4
pf5
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Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis

FREE RADICAL REACTIONS IN ORGANIC SYNTHESIS

MECHANISM

  • Before we look at free radical chemistry a quick revision of mechanisms (again)
  • You should all be happy with

R (^) CO 2 Et

R

CO 2 Et

polar reaction – nucleophile attacks electrophile

curly arrow represents the movement of 2 e–

  • Radicals are one electron species so we cannot use curly arrows
  • Instead use fish-hooks – these show the movement of one electron

R (^) CO 2 Et

R

CO 2 Et

2e–

need 2 e– to 1e– form new bond

  • Diagrams can get quite confusing so they are normally simplified to show electrons only

moving in one direction – BUT remember the above is "more accurate"

R (^) CO 2 Et

R

CO 2 Et

simplification

  • Note - we are nolonger looking at proton removal but hydrogen abstraction (it still has its 1 e–)

R O H Br R OH Br R O H Br R OH Br

deprotonation

hydrogen

abstraction

INTRODUCTION

  • The last 10–15 years have seen the development of free radical chemistry in organic synthesis
  • Major obstacle is the ability of radicals to react with themselves
    • Overcome by only having a very low concentration of radicals present in a reaction
    • Now there are many ways to use these highly reactive species in selective (& synthetically

useful) organic reactions

  • Good example is the radical chain process for allylic halogenation

R R

R R R R

N Br

O

O

Br Br

hν or heat /

(BzO) 2

activated C-H

problem of isomerisation

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis

Radical Chain Mechainsm

N Br

O

O

hν or heat /

(BzO) 2

N

O

O

Br

Br H R Br H (^) R

R Br^ Br^ R^ Br^ Br

Initiation

Propagation

chain reaction as chain carrier regenerated

  • The use of NBS rather than Br 2 allows controlled formation of Br 2 and provides a mechainsm

to remove HBr

N Br

O

O

H Br N H

O

O

Br Br

Ionic

Selectivity in Free Radical Reactions: Tributyltin Hydride Methodology

  • C-H bonds very strong so need to be activated
  • Strength of bond often prevents chain reaction
  • Major problem is often the selective activation of a specific C-H bond
  • The following reduction reveals a route to overcome this problem

R Br R H

Bu 3 SnH, AIBN (0.1),

PhH, reflux

Mechanism: Another radical chain reaction

N N

NC CN NC

N N

Bu 3 Sn H

CN CN

H Bu^3 Sn

Bu 3 Sn (^) Br R Bu 3 Sn Br (^) R

Bu 3 Sn H (^) R Bu 3 Sn (^) H R

Initiation

Propagation

AIBN is an initiator

regeneration of chain carrier

  • Chain termination by variety of processes
  • Relative rates of each process allow selective formation of carbon centred radical
  • Tributyltin (TBT) propagates chain

C-Br bond weak

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis

E

E

Br

TBTH, AIBN,

Heat

E

E

E

E

Note: geometry of vinyl halide unimportant as radical can invert

Aryl Radicals

OCH 3

I

O

TBTH, AIBN

O

OCH 3

  • Aryl radicals are very reactive

Other Precursors: Sulfides and Selenides

  • Just as useful as halides (and frequently give better yields)

N

R

SPh

O

TBTH, AIBN,

Heat

N

O

R

SePh

O O

TBTH, AIBN,

Heat

Other Precursors: Alcohol Derivatives

  • Deoxygenation of alcohols a good method for preparing carbon-centred radicals
  • Good for primary and secondary alcohols but not for tertiary ( y

radicals less stable)

O

S

SR

TBTH, AIBN,

Heat O

S

SR

SnBu 3

SnBu 3 Bu 3 Sn S

O SR

H SnBu 3

H H

xanthate

oxalate

  • Works with tertiary alcohols

N

S

O

O

O

O

H SPh

N

S

SR SR

2 x CO 2

behaves like halide

forms acyl radical

driving force is strrength of C=O bond

Gareth Rowlands (g.rowlands@sussex.ac.uk) Ar402, http://www.sussex.ac.uk/Users/kafj6. Strategy in Synthesis

Other Precursors: Multiple Bonds

  • Utilise the addition of a radical to a multiple bond as the propagating step (also incorporates

further functionality into the molecule)

TBTH, AIBN

SnBu 3

PhSH, AIBN SPh

EFFICIENCY IN RADICAL REACTIONS

  • Normally chain propagation step is the abstraction of H from TBTH
  • Waste of a radical as reduced C-X to C-H
  • So chain transfer reactions developed

Group or Atom Transfer: Halogen

I E

(Bu 3 Sn) 2 , hν

E

I

Note: all atoms in SM are in product

Mechanism

Bu 3 Sn SnBu 3 Bu 3 Sn

Bu 3 Sn (^) I

E

E

E

I

E

I

Initiation

Propagation

iodine transfered in propagation step

catalytic initiator

vinyl halide useful product