Free Radicals in Organic Synthesis

Convenor: Dr. Fawaz Aldabbagh

Recommended Texts

Chapter 10, by Aldabbagh, Bowman, Storey

H Cl H Cl+

0 electrons 8 electrons in outer shell

water

H2O

H3O Cl

ONLY POSSIBLE IN SOLUTION

H Cl H Cl+

1 electron 7 electrons in outer shell

Less Energy Demand

Gaseous phase

Monoatomic - Radicals

When bonds break and one atom gets both bonding electrons- Pairs of Ions – Driven by the Energy of solvation

When bonds break and the atoms get one electron each

By Thermolysis or Photolysis.

Light is a good energy source

Red Light – 167 KJmol-1

Blue Light – 293 KJmol-1

UV- Light (200nm) – 586 KJmol-1

UV will therefore decompose many organic compounds

Cl Cl 2 Cl

Br Br 2 Br

I I 2 I

G# = 243 KJmol-1

G# = 192 KJmol-1

G# = 151 KJmol-1

Explains the instability of many iodo-compounds

Photolysis allows radical reactions to be carried out at very low temperatures (e.g.

room temperature)

Useful for products that are unstable at higher temperatures

Radical Formation or Initiation

Ph

O

Ph

hvPh

O

Ph

*

Ph

OH

PhPh

O

Ph

H-abstraction

Ph

Ph

OH

H2 X

Ph

Ph

OH

Ph

PhOH

Benzpinacol

Benzhydrol

Excited Triplet or Biradical

O

CR O

OC

R

O

O

CR O

OC

R

O

C

O

O

R+

Peroxides

When R is alkyl, loss of CO2 is very fast. Therefore, alkyl peroxides generally avoided, as they tend to be explosive.

Benzoyl peroxide has a half-life of 1 hour at 90 oC, and is useful, as it selectively decomposes to benzoyl radicals below 150 oC

Photochemical Reaction

OO

O

O

OO

C

O

O

2 X O2 X+

DTBPO

Half-life 10 mins at 70oCO

acetone

CH3

+

NC N

N

NCN N

CN C

N

Azobisisobutyronitrile (AIBN)

Heat

CN

H SnBu3

CN

H SnBu3+

Weak Tin-Hydrogen Bond Strong Carbon-Hydrogen Bond

Other Peroxide Initiators

Azo InitiatorsAzo Initiators

A combination of AIBN-Bu3SnH is most popular radical initiation pathway in organic synthesis

HEATPb CH34

CH3

PbH3C CH3

CH3

+

Ph Br Mg Ph Mg Br Ph MgBr

OC

OR

OC

OR R + CO2

1 e - oxidation

Kolbe Reaction - Electrochemical oxidation

R R

OrganoMetallic INITIATORSC-M bonds have low BDE, and are easily homolyzed into radicals;

FORMATION OF GRIGNARD REAGENTS

Electron Transfer Processes

SET (Single Electron Transfer) reactionsSET (Single Electron Transfer) reactions

R X R X R + XSET

M +n M +n+1

N

N

CH3

Br

NaNa

N

N

CH3

Br

N

N

CH3

NH3

Br +

imidazoyl radical

CH3

radical anion

ArX + e-NH3 (ArX)

Initiation using a metal in ammonia

E.g.

CH3

CH3

Fentons Reaction

HO OH Fe2+ Fe3+ OH OH+ + +

hydrogen peroxide

HO OH OH OH+

analysis

also,

Fe2+ Fe3+OHt-BuO+ + +t-BuOOH

All the radical initiation pathways so far discussed give very

reactive, short-lived radicals (< 10-3s), which are useful in synthesis

Stable and Persistent Radicals

ClAg

Gomberg - 1900

triphenylmethyl radical

Original Structure - 1900

radical dimerization

1970 Real Structure Determined by NMR

AgCl+

Steric Shielding is more important than Resonance Stabilisation of the radical centres- Kinetically Stabilised Radicals (Half-life = 0.1 s)

N N

O2N

O2N

NO2

diphenylpicrylhydrazyl radical, DPPH

N O

TEMPO

N O

TMIO

(red) (orange-yellow)

– Thermodynamic Stabilisation is most importantThese radicals can be stored on the bench, and handled like other ordinary chemicals, without

any adverse reaction in air or light.

Often – very colourful compoundsNitroxides

Why so stable?

Very Stable Radicals (Half-life = years)

Nitroxides are used as radical traps of carbon-centred radicals

N O R+ N O R109 M-1s-1

Alkoxyamine

Identifying reactive radicals and studying radical reactions

No dimerization via nitroxide, NO-bond

----------- Explain

Configuration or Geometry of RadicalsNormally, configurational isomers are only obtained by breaking covalent bonds, this is not the

case with radicals

With radicals, bond rotation determines the geometry and hybridisation of molecules.

A

X

X X

A

XX

XA

XX

X

AX3

sp2

+ p-character+ p-charactersp3 sp3

PlanarPyramidal PyramidalTetrahedral Tetrahedral

Similarly,

X A X AX X

AX2

Linear Radical Non-Linear

ESR spectroscopy is usually used to determine such features

CHH

H

CH3CH3

0o 10o10o

Energy

Pyramidisation

Methyl radical can be regarded as planar

Unlike, carbocations, carbon-centred radicals can tolerate serious deviations from planarity e.g. CH3 , CH2F , CHF2 , CF3

Because of Orbital Mixing

-Donors (+M) , Attractors (-)- F, - Cl , - Br , - I

- OH- NH2

FSubstituent Effects

-Acceptors (-M) , Acceptors (-)HC C

N C

(+M)

LUMO

SOMO

Stabilization

AX3

SOMO

Planar

acceptor

HOMO donor

AX3

Pyrimidised

LUMO

Group IV Hydrides

CH3 < SiH3 < GeH3 PbH3<

Pyrimidized

HH

X

H H

X

H H

H

H

Staggered EclipsedPyrimidized rotamer

As alkyl radicals become more substituted so they become more pyramidal.Also, when X = SR , Cl , SiR3 , GeR3 or SnR3 – delocalisation of the unpaired electron

into the C-X bond increases. The eclipsed rotomer becomes the transitional structure for rotation

Alkyl Radicals

a/ Thermodynamic StabilityIs quantified in terms of the enthalpy of dissociation of R-H into R and H

R H R + H

The main factors which determine stability are Conjugation,

Hyperconjugation, Hybridisation and Captodative effects

1. Conjugation or MesomerismThis is the primary reason for the existence of stable radicals (see notes on nitroxides and DPPH)

CH2CH2 CH2

CH2

allylic radical

benzylic radical

sp2 or radical

cannot be resonance stabilised

Vinyl and Aryl Radicals

Very Reactive Radicals

2. HybridisationRadical is more stable than Radical.

As the p- character of a radical increases so does its thermodynamic

stabilisation

CH

O

CH

O

sp3 radical - almost tetrahedral

more stable

radical anion

CH

O

e-

Resonance Stabilised ketyl radical

3. Hyperconjugation

CC

H

H

H

CH3

CH3

CC

H

H

H

H

CH3

CC

H

H

H

H

H

CH

H

H

>> >

9 Hyperconjugatable H s

6 Hyperconjugatable H s

3 Hyperconjugatable H s

CC

H

H

H

H

H

CCH

H

H

H

H

thermodynamic stability

Remember, that inductive and steric effects may also contribute to the relative stability of the radical

H2C C

d

c

R RH2C C

d

c

c - Electron Withdrawing Group

d - Electron Donating Group

4. Captodative effect

CH(CHO)2

CH(NO2)2

CH(t-Bu)2

CH(OCH3)2

CHCH3(OCH3)

CH(NH2)CHO

CH(NH2)CO2H

BDE (R-H)

99

99

98

9191

73

76

The phenomenon is explained by a succession of orbital interactions; the acceptor

stabilizes the unpaired electron, which for this reason interacts more strongly with the

donor than in the absence of the acceptor.

SOMO

HOMO

LUMO

Radical Stabilised

This is generally due to steric factors.

triphenylmethyl radical

1,4 - Hydrogen abstraction

Half-lives increased from 10-3 to 0.1 s

Radicals can be detected by normal spectroscopic methods

b/ Kinetic Stability

The Polar Nature of Radicals

Radicals can have electrophilic or nucleophilic character

RR Relectrophilicnucleophilic

+ e-- e-Increasing Electron AffinityDecreasing Ionization Potential

ROCl

R S

O

O

F

N H

R CO

O

Cl3C

Bu3Sn

CH3 < CH3CH2 < (CH3)2CH < (CH3)3C

R3C

Increasing Nucleophilic Character and Increasing Cation Stability

X + H- H-X +

ClH C(CH3)3

H CCl3

H C(CH3)3

H CCl3CH3

Ea

0.2

6.5

8.1

5.8

O

OH

Cl

CH3

H-abstraction - the prefered positions of attack

However, “philicity” of a radical is a kinetic property, not thermodynamic, i.e. it depends on whether the substrate is a donor or attractor. e.g.

HO

H

O H3CH

Ph

Bu3Sn H

12700

0 30007 X 105

O H Rkrela

Electrophiles react faster with electron-rich alkenes (electron-donating substituents

adjacent to the alkene DB).

Nucleophiles react faster with electron-poor alkenes (electron-withdrawing substituents

adjacent to the alkene DB).

e.g.

Y

Y = CHO = 34 ; Y = CO2CH3 = 6.7 ; Ph = 1.0 ; OAc = 0.016

krel

LUMO

SOMO

C C

nucleophile

SOMO

HOMO

RO2C

CH

RO2C electrophile

AIBN (CH3)2CCN

(CH3)2CCN Bu3SnH+ (CH3)2CHCN Bu3Sn+

Initiation

Reduction of Alkyl Bromides

Propagation

R-Br R-H

Bu3Sn R-Br+ Bu3SnBr R+

R + Bu3SnH R-H Bu3Sn+

Termination

Bu3Sn Bu3Sn-SnBu3

R R-R

(CH3)2CCN

+ N2

R +

2 X

2 X

2 X

Bu3Sn Bu3Sn-R

C

C

CH3H3C

CN

CH3H3C

CN

CN

ButBr + ButCN

Bu3SnH , AIBN

+ Bu3SnBrslow addition

CN

But

ButCN

Bu3SnH

Bu3Sn

ButCN

CN

But

ButCN

Bu3SnH

Bu3Sn

ButCN

Bu3SnBr

ButBr

1

Problems with Bu3SnH

We can overcome the use of Tin-hydride-

By using Silanes as Bu3SnH substitutes

X R Si

R

R

R

X R

Sn

R

R

R

X RX RSn

R

R

R

R

R

Si

R

R

R

H

Sn

R

R

R

H

R H Si

R

R

R

Si

R

R

R

R H Sn

R

R

R

+ .+

.++.

Halogen-atom abstraction

Hydrogen-atom abstraction

.

.

+

+

+ .

.

+ .

kx = 106 lmol-1s-1

kx = 106 lmol-1s-1

kH = 103 lmol-1s-1

kH = 106 lmol-1s-1

Si

Si

Si

SiCH3

CH3

CH3CH3

CH3

CH3

CH3CH3

CH3

.Si

Si

Si

SiCH3

CH3

CH3CH3

CH3

CH3

CH3CH3

CH3

H R H.+ +

kH = 105 lmol-1s-1Tris(trimethylsilyl)silane

R

Prof. Chris Chatgilialoglu, Bologna

BDE’s (kcal/mol)

Et3Si-H 95.1

[(CH3)3Si]3Si-H 84

Bu3GeH 89

Bu3Sn-H 79

Polarity Reversal Catalysis

Et3Si-H can be used if a catalytic amount of alkyl thiol (RS-H) is added.

Et3Si-H = 375 KJmol-1

RS-H = 370 KJmol-1

Et3Si-X = 470 KJmol-1

Prof. Brian RobertsUCL

RS -H Et3Si-H Et3Si● RS● R●

R X

Et3Si XR H

Et3Si H

PhS H

Et3Si .PhS.

R .

PhSH

Polarity Reversal Catalysis

Radical-Anions

M M

M + A MA

SET

OX

RED

LUMO

HOMOEnergy

1 eSOMO

HOMO

M M

Na Nafast

e [NH3]nslow

NH H

HNH2

Blue Solution+H

H2

colourless

Sodium Amide, (Na+NH2-) is made by dissolving Na in liquid ammonia, and then waiting

until the solution is no longer blue

C

O

C

O

C

O

C

O

Na

Na

C

O

Drying Ether or THF

Birch Reduction

Li , NH3(l), EtOH, Et2O

Prof. Arthur Birch, ANU

OMg

O Mg2+O OMg

benzene or ether

HO OH

EtOH

OH

Other REDOX reactions

Pinocol CouplingIn aprotic solvents, ketyl

radical anions dimerise

OTiCl3 , K

OO

+

40%

50%26%

TiCl3 , 3 eq. Li

McMurry Coupling

Heterogeneous Reaction occurring on the surface of the titanium metal particle

generating TiO2 and an alkene

Prof. John McMurryCornell

Sandmeyer Reaction

NH2HCl , NaNO2

N2

HNO3

CuBr , Heat

Br

Other Nucleophiles can also displace the diazonium ion, including Chlorides,

Iodides and Cyanides

Prof. Traugott Sandmeyer, Wettingen, Switzerland

M M

R + M MA

SET

OX

RED

LUMO

HOMOEnergy

- 1 eLUMO

SOMO

M M

Radical-Cations

N N

R

R R

R+

Wurster – isolable, highly coloured radical cation

C C

X

C C

X

exo

C C

X

endoC C

X

+1

2

34

5

6

5-exo 6-endo

98% 2%5-hexenyl radical

3-, 5- and 6-membered radical cyclizations are usually faster than the analogous intermolecular addition.

Draw six-membered chair transition state for 5-exo trig cyclization

Kinetic product favoured over thermodynamic product

The exo or endo cyclization rate depends greatly on chain length.

And the reverse of radical cyclization is Ring-Opening.

CH2( )

n

n = 1 kexo = 1.8 X 104

k-exo = 2 X 108

kendo = not observed

'Radical Clock'

n = 2 kexo = 1

k-exo = 4.7 X 103

kendo = not observed

e.g.

e.g.CH2

CH2( )

n

n = 1 kexo = 1.8 X 104

k-exo = 2 X 108

kendo = not observed

'Radical Clock'

n = 2 kexo = 1

k-exo = 4.7 X 103

kendo = not observed

e.g.

e.g.CH2

The ‘Radical Clock’ is a standard fast reaction of known rate constant, which the rates of other competing radical or product radical reactions can be measured.

ko = 1.7 X 109 s-1

ko = 3 X 108 s-1

kc = 1.7 X 107 s-1

kc = 3 X 104 s-1

Thorpe-Ingold Effect

Cyclization onto triple bonds is always exo, but slower than onto DBs

Tandem or Cascade Radical Cyclizations

BrBu3SnH, AIBN

H H

H

Capnellene

Two sequential 5-exo radical cyclizations

Write a full chain mechanism