Organic Pedagogical Electronic Network Aryl Fluorination This document summarizes aryl fluorination, an important reaction for introducing fluorine groups onto aromatic rings. It notes that two of the top 10 grossing drugs, Lipitor and Reserdal, contain aryl fluorines. The mechanism proceeds through oxidation of an aryl group to a high valent metal species, followed by transmetalation and reductive elimination to introduce the fluorine. Examples are given of stoichiometric and catalytic aryl fluorination reactions using Selectfluor and silver oxide catalysts.

1. Organic Pedagogical Electronic
Network
Aryl Fluorination
Zach Niemeyer, Justin Salvant
University of Utah
Lipitor

2. Aryl Fluorination
Wiki Page: http://en.wikipedia.org/wiki/Balz%E2%80%93Schiemann_reaction
Overview: Aryl fluorines are present in two of the top 10 grossing drugs (Lipitor and
Reserdal). The C-F bond is uniquely strong and prevents facile metabolism, giving
these compounds longer T1/2 in vivo. The generalized mechanism for electrophilic aryl
fluorination proceeds through a high valent metal species.
Mechanism:
F
R
MX
R
Transmetalation
F+ source
Reductive
Elimination
[M]
M
R
Oxidation
M
R
F
High Valent Metal
N
N
F
Cl
2 PF6
-
N
F
N
N
F
Cl
2 BF4
-
SelectfluorF-TEDA-PF6
N-fluoro-2,4,6-
trimethylpyridinium
triflate

3. Aryl Fluorination
Wiki Page: http://en.wikipedia.org/wiki/Balz%E2%80%93Schiemann_reaction
Overview: Aryl fluorines are present in two of the top 10 grossing drugs (Lipitor and
Reserdal). The C-F bond is uniquely strong and prevents facile metabolism, giving
these compounds longer T1/2 in vivo. The generalized mechanism for electrophilic aryl
fluorination proceeds through a high valent metal species.
Early Examples
NH2 N
N
F
BF4
HNO2
HBF4
D
Balz-Schiemann Reaction
-N2
First reported in 1927, the Balz-Schiemann reaction involves the fluorination of aryl
diazonium tetrafluoroborates. Some more recent methods for aryl fluorination involve
the use of cationic fluorine species.

4. Examples
REFERENCES: Tang, P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2010, 12150-12154. Lee, E.; Kamlet, A.; Powers, D.;
Neumann, C.; Boursalian, G.; Furuya, T.; Choi, D.; Hooker, J.; Ritter, T. Science 2011, 639-642
N
N
Pd
S
O
O
OMe
N
OAc
B(OH)2R FR
Stoichiometric
benzene/MeOH (1:1),
K2CO3, 10h
1.)
2.) Selectfluor
acetone, 10 min
Me
O
O
O
O
SnBu3
HO
OBz
H
OAc
AcO
OH
Me
O
O
O
O
F
HO
OBz
H
OAc
AcO
OH
5 mol% Ag2O
2 equiv. NaHCO3
1 equiv. NaOTf
1.5 equiv. F-TEDA-PF6
acetone

5. Problems
References: Tang, P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2010, 12150-12154.
Assuming the catalytic cycle
shown, predict the product
formed upon the
addition of exogenous water:
F
R
MX
R
Transmetalation
F+ source
Reductive
Elimination
[M]
M
R
Oxidation
M
R
F
High Valent Metal
What is the role of NaOTf in the reaction below? (Hint: Ag2O is only partially soluble)
Me
O
O
O
O
SnBu3
HO
OBz
H
OAc
AcO
OH
Me
O
O
O
O
F
HO
OBz
H
OAc
AcO
OH
5 mol% Ag2O
2 equiv. NaHCO3
1 equiv. NaOTf
1.5 equiv. F-TEDA-PF6
acetone

6. This work is licensed under a
Creative Commons Attribution-
ShareAlike 4.0 International
License.
Contributed by:
Zach Niemeyer, Justin Salvant (Undergraduates)
University of Utah, 2013