Announcements
•   Midterm 2 is Tues, Nov 17. Everything through alkyne synthesis.
•   Presentations on Sat, Dec 5. Paper choices were due last week!
•   Special Seminar/Workshop on Prep HPLC:
Laura Mulderig (Waters), Fri, 11/13, 12:15pm, 219 BRL

Radical Reductions
Barton McCombie Deoxygenation
R OH
S Bu
3
SnH
R O R'
(thioxoester)
AIBN
R H
AIBN =
NC
Me
Me
N N
CN
Me
Me
Azobisisobutyronitrile
Barton: Nobel 1969
Typical Conditions:
R OH
NaH, CS
2
, MeI
R O
S
SMe
S
Cl OPh
R OH
R O
S
OPh
Barton Perkin Trans I , 1975 , 1574

Barton Decarboxylation
S
R
O
OH
N
OH
Std coupling reagent
R
O
O
N
S
Bu
3
SnH
AIBN
R H
Mech:
R
O
O
N
S
Bu3Sn
R
O
O
N
S
SnBu
3
R +
O
C
O
+ N
S
SnBu
3
Barton Chem Commun . 1983 , 939

General Comments About Radical Reactions
Radical (Chain) Reactions Generally Proceed Via Three Distinct Steps:
1)   Initiation – make a radical
2)   Propagation – radical does something, usually make another radical
3)   Termination – radical does something non-productive that ends chain
RADICAL REACTIONS DENOTED WITH SINGLE HEADED ARROWS!
NOT

AIBN:
NC
Me
Me
N N
CN
Me
Me
CN
N N
Me
Me
CN
+
Me Me
Often coupled with Sn-H reagents:
CN
2
Me Me
+ N
2
Bu
3
Sn H + Me
2
CCN Bu
3
Sn + Me
2
CHCN

Homolytic Bond Cleavage:
R-I R I 2R I
2
Not normally useful. Why?
Δ G ‡ very high.
Bond Dissociations Energy (BDE) Me–I = 56 kcal/mol
Δ G ‡ must be at least this high.

Radical Initiation
Peroxide Cleavage:
O
R O
O
O
R
O
R O
-2CO
2
2R
•   R = Ph " Benzoyl peroxide "
•   BDE = 37 Kcal/mol
•   Still high for activation!

Radical Initiation
Cobalt Alkyl dimethylglyoximes:
Me
Me
R
N
O
Co
H
N
O
N N
O O
H
Py
Me
Me
BDE ~ 30 kcal/mol
Δ
-Co II
R

Radical Initiation
Trialkylboranes with oxygen:
2 Et
3
B 2 O
2
Et
Mechanism:
Et
3
B O
2
Et O
2
Et-O-O Et
3
B
Et
2
B-O-O
Et-O-O
Et-O-O-BEt
2
Et
Et

Radical Termination
Dimerization:
R R R R diffusion control rxn: k ~ 10 9 /ms
Keep [R · ] low !

Radical Termination
Disproportionation:
R
R
R
H
R
R
H
R
R
R

Radical Termination
Atom Abstraction:
R
R
H Solv
(Solvent)
Cl CCl
3
R-H solv
R Cl CCl
3
Note: depends on radical stability!
Radical reactions often run in H
2
O or C
6
H
6
and not in THF!

Radical Stability
Obvious Factors:
1) Steric Bulk slows dimerization rxns: slow
R R R R
2) No β− hydrides = No Disproportionation

Radical Stability
Inherent Stability of Radicals: Not all Radicals Are Equally Stable!
Consider:
R 1 -H + R 2 R 1 R 2 -H
R
R
1
2
H
H
R 1 H
R 2 H
H is the same for both.
Δ G
1
°
Δ G
2
°
BDE !
ΔΔ G° = difference in radical stability! = Δ BDE

Inherent Radical Stability
Radical Substitution:
R–H
Me–H
Et–H i Pr–H t Bu–H
BDE (kcal/mol)
105
101
98
96 less stable radical more stable radical
H
H
H
σ
C-H
H
H n
C
Neutral radicals are inherently electron deficient due to incomplete octet
See C&S A 11.2

Electronegativity:
Inherent Radical Stability
X–H
R
3
C–H
R
2
N–H
RO–H
BDE (kcal/mol)
96
107
119 more stable radical less stable radical
Neutral radicals are inherently electron deficient due to incomplete octet, therefore more electronegative atoms make for less stable radicals.
·OR and ·NR
2
are generally very unstable.
See C&S A 11.2

Inherent Radical Stability
Atomic Size:
X–H
Me
3
C–H
Me
3
Si–H
Me
3
Sn–H
BDE (kcal/mol)
96
93
78 less stable radical more stable radical
Heavier atoms give more stable radicals.
See C&S A 11.2

Inherent Radical Stability
Unsaturation:
Me
X–H
H
H
BDE (kcal/mol)
100
89
85
H
ψ 3
ψ 2 π *
π n
C
ψ 1 less stable radical more stable radical
See C&S A 11.2

Inherent Radical Stability
Hybridization:
X–H
Me H
H
H
BDE (kcal/mol)
100
111
125 less stable radical more stable radical
Why?
See C&S A 11.2

Inherent Radical Stability
Adjacent Electron Withdrawing Groups:
Me
X–H
H
O
H
Me
BDE (kcal/mol)
98
96 less stable radical more stable radical
Why?
See C&S A 11.2

Inherent Radical Stability
Adjacent Electron Donor Groups ( α hetroatoms):
X–H
Me CH
2
H
HO CH
2
H
BDE (kcal/mol)
101
96 less stable radical more stable radical
ψ 2 n
O
ψ 1
Net 1 e – stabilized n
C
See C&S A 11.2

Inherent Radical Stability
Captodative Radical (Push-Pull):
X
O
R
Very Stable
See C&S A 11.2

Other Important BDE’s
X–H
MeS–H
Et–I
Et–Br
Et–Cl
Et–F
BDE (kcal/mol)
101
56
70
84
113
See C&S A 11.2

Radical Geometry and Configurationally Stability
CH
3
Planar
Me
C
Me
Me
G ≤ 2 kcal/mol
( ≈ 10 12 /sec) rt
Me
Me Me
C bent
R
H
G ≤ 2 kcal/mol
R
H

Radical Propagation Steps
Reactions with oxygen:
R
R-O-O
O-O
R-H
R-O-O
R-O-O-H + R
Hydroperoxide
Important in lab:
O
Me O Me
O
2 time
O
2 time
O
OOH
OOH
Me O Me
Explode !

BHT and Other Radical Inhibitors
Me
Me
Me
OH
Me
Me
Me R
Me
BHT
Me
Me
Me
O
Me
Me
Me
Me
Stable
Radical terminator, prevents radical chains.
BHT is a preservative in both foods and solvents.

Reactions with Alkenes
Br
+
CO
2
Me
Bu
3
SnH
AIBN
O
O
Me

Mechanism
Initiation: Bu
3
Sn
Propogation:
Br
+ SnBu
3
+
O
O
Me
O
O
Me
Bu
3
SnH
+ Bu
3
SnBr
O
O
Me
Regio Chem: Most Stable Radical
O
O
Me
+ Bu
3
Sn

Reactions with Alkenes
Br
+
CO
2
Me
Bu
3
SnH
AIBN
Thermochemistry (approximation):
Breaking
Bond
C=C ( π )
Making C–C ( σ )
O
O
Me
Calculate Value of C=C ( π ):
Bond
C=C ( π + σ )
C–C ( σ )
C=C ( π )
BDE
145
85
60
Δ G° = + 60 – 85 ~ -25 kcal/mol
Swapping C–C for C=C is very favorable.

Intramolecular Cyclization
CH
2
5-exo
G ≈ 6 kcal/mol
Compare to R
H
H
H
G ≈ 3 kcal/mol
5 & 6 exo generally preferred. - FMO control

Reactions With Alkynes
R + R' R"
R
R'
R"
Thermochemistry (approximation):
Breaking
Making
Bond
C ≡ C (2 nd π )
C–C ( σ )
Calculate Value of C ≡ C (2 nd π ):
Bond
C ≡ C (2 π + σ )
C=C ( π + σ )
C ≡ C (2 nd π )
BDE
198
145
53
Δ G° = + 53 – 85 ~ -32 kcal/mol

Reactions with C=N π -Bonds
C=N π systems also generally okay
O
N
S
CN
N
1.Bu
3
SnH
AIBN
2. H
3
O +
O
N
CN
O
Bu
3
Sn-H
NH
H
3
O +
Note: “Deoxygenation” reaction is intercepted by Intramolecular cyclization.

R +
R
1
O
R
2
Reactions with Carbonyls
O
R R
R
1
2
O
R R
2
O
R R
1
Bond
C=O ( π + σ )
C–O ( σ )
C=O ( π )
BDE
175
80
95
C=O( π ) ~ 95 kcal/mol vs.
C-C( σ ) ~ 80 kcal/mol

Radical Fragmentations
R
X
R
X
R + X
R
+ X
X· = Bu
3
Sn· or PhS· or other stable radical

Fragmentations As Radical Clock
(Cyclopropyl Carbonyl Radicals)
A + B A-B
•   Fast rxns controlled by diffusion
•   Bimolecular rxn max k ≈ 10 8 M -1 s -1
Ph
Ph
R k ≈ 5x10 11 s -1 Ph
Ph
R
•   approaches " Vibrational Control " faster than Bimol rxn!
•   Used a kinetic tool & as test for radicals !

Example:
H-Atom Abstraction
R
R
H
R
R
6-member TS
R
R
H
R
R
HO
Br
H
Bu
3
SnH
AIBN
HO
Me H
H
Very fast
Bu
3
SnH
H
HO
H
H
HO
H
Most Stable Radical
H
2
C
HO
H
H

Reductive Radical Coupling of Carbonyls
Pinacol Coupling
O
Me Me
Al/Hg then H +
Me
HO
Me
OH
Me
Me e -
O
Me Me
1/2
Me
Me
O O
Me
Me

McMurry Coupling
O
R R
1
+
R
2
O
R
3
TiCl
3 or
TiCl
4
+ M°
R
M°= Li, Na, Zn, Mg etc..
R
1
R
2
R
3
Pinacol coupling
Ti
O O Ti
R
R
1
R
2
R
3 -Ti=O product

Acyloin Condensation
O
R OR
1
Na, PhMe O
R OR
1
O
R
OH
R
H +
O O
1/2
R
OR
1
R
OR
1
O
R
O
R
TMSCl
2e -
O
R
-2 OR
O
R
TMSO
R
OTMS
R

Acyloin Condensation
Example:
Me
CO
2
Et
CO
2
Et
Me
Na
TMSCl
Toluene
Me
OTMS
OTMS
Me