Heck Reaction
I
+
O
Pd(OAc) 2
O
OEt
OEt
Bu 4NBr
Bu 4NOAc
Δ
Background:
The Heck reaction is named after Professor Emeritus Richard Heck of the University of
Delaware. It is sometimes referred to as the Mizoroki-Heck reaction, to recognize the
early contributions of the late Tsutomu Mizoroki , a professor at the Tokyo Institute of
Technology . In recognition of Prof. Heck’s contribution to the field of organopalladium
chemistry, he was awarded the Nobel prize in Chemistry in 2010, along with Akira
Suzuki (Hokkaido University) and Ei-ichi Negishi (Purdue University) for their
eponymous palladium-catalyzed cross coupling reactions.
The Heck reaction couples a vinyl or aryl halide with an alkene. The net effect is as if
the two coupling partners are “stapled together” with net loss of HX:
X
+
R
Pd 0
R
R
and/or
+ HX
If the alkene is asymmetric (i.e. the two vinylic carbons are not identical), two products
are theoretically possible, as shown in the reaction above. The issue of regiocontrol is
complex and beyond the scope of this course. In practice, the correct choice of alkene
and of reaction conditions often provides one product with high selectivity.
Although palladium is costly ($800/oz at the time of writing), these reactions use only a
catalytic amount, and the mass of palladium required to effect one of these
transformations can be vanishingly small. In some cases, the palladium catalyst can be
recovered, which increases the economy further. The catalytic cycle for the Heck
reaction is shown in Fig. 1. (Note: “Ln” represents some number (n) of ligand(s) L that
are left unspecified, and will vary depending on the exact conditions chosen)
Pd(OAc) 2
B•HI
Δ
I
LnPd 0
B
oxidative
addition
reductive
elimination
H
PdL n
LnPd
X
I
Ph
CO 2Et
CO 2Et
product
β-elimination
(mixture of
E- and Z-)
LnIPd
H
I
R
LnPd
migratory
insertion
Me
Ph
CO 2Et
Ph
π-complex
Figure 1: The catalytic cycle for the Heck Reaction
This cycle illustrates several common reactions that transition metals participate in.
Oxidative Addition: insertion of a metal M into a bond:
Mn
+
X Y
X Mn+2 Y
The addition is described as “oxidative” because the metal’s formal oxidation number is
raised by two.
Reductive Elimination: the opposite of oxidative addition. This is seen in the final step:
LnPd
H
X
LnPd 0
+
H X
Formation of a π-complex: the alkene donates its π-electrons towards the transition
metal. This is analogous to the first step of oxymercuration:
LnPd
X
+
X
R
Ar
Hg 2+
R
LnPd
Ar
+
R
R
or
Hg 2+
R
Hg 2+
Migratory Insertion: one of the ligands of the π-complex migrates to one of the vinylic
carbons of the π-ligand, leaving the metal bonded to the other.
M R
M
R
β-hydride elimination: an organometallic compound may lose a hydride from the βcarbon to yield an alkene and a metal hydride:
M
H
M H
The reaction you will be performing uses “Jeffery conditions”: an ionic liquid as the
reaction medium, and a weak base. An ionic liquid is an ionic compound or mixture of
compounds that melts at a relatively low temperature (typically < 100 °C). In this
experiment, the mixture of tetrabutylammonium bromide and tetrabutylammonium
acetate melts when heated, and acts as solvent. The acetate anions serve as the base
in this medium.
Procedure:
Hazards: The quaternary ammonium salts and palladium acetate are toxic if ingested,
are toxic to aquatic life, and can cause skin irritation and serious eye damage. Ethyl
crotonate is highly flammable, and can cause skin burns and eye damage. Iodobenzene
is combustible, harmful if swallowed or inhaled, causes eye irritation, and is toxic to
aquatic life. Ethyl acetate and hexanes are flammable solvents. Wear eye protection
and gloves, and keep liquids and the reaction mixture in the fume hood.
Note: the ammonium salts used are hygroscopic. If the container is left open, they
absorb water from the air and dissolve in it. Weigh these reagents quickly, and
immediately close the containers after use!
Set up a sand bath by filling a 100-mL beaker with a layer of sand 1-2 cm deep. Heat
the sand bath on a stirrer/hotplate, gradually increasing the temperature until a
temperature of 100-120 °C is maintained. While your sand bath comes to temperature,
assemble the reaction mixture as follows. To a 10-mL vial containing a magnetic stir bar
add: 1.0 g tetrabutylammonium bromide; 0.45 g tetrabutylammonium acetate; 2 mg
palladium acetate; 0.22 mL ethyl crotonate; and 0.11 mL iodobenzene. Heat in a sand
bath at 100-120 °C for 30 minutes.
Cool the reaction mixture to room temperature, dilute with 20 mL of 5% aqueous sodium
bisulfite, and extract with ethyl acetate (3 x 20 mL). Dry the combined organics with
sodium sulfate, then filter into a tared 250-mL round-bottom flask. Analyze the organic
solution by TLC (3% EtOAc in hexanes), cospotting with both iodobenzene and ethyl
crotonate. Concentrate the solution in vacuo as your TLC plate develops. You should
see a major and a minor spot, corresponding to the E- and Z- product isomers
respectively.
Purify the crude organic product by flash column chromatography, using a Pasteur
pipette as a micro-column and 5% EtOAc in hexanes. Collect about 3 fractions per
column volume of solvent. Pool the fractions that are pure in each component by TLC,
concentrate them in vacuo, and obtain their masses. Your TA will collect a
representative sample of each to analyze by NMR.