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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
