Pranay Vemulamada

Lab 4: Kumada Coupling: Nickel-Catalyzed Cross-Coupling of iPrMgCl with Chlorobenzene

Due: 12/10/2018
TA: Qiuran Wang

Introduction

This experiment was designed to catalyze a Kumada coupling between

chlorobenzene and isopropylmagnesium chloride, a Grignard reagent, using three Ni(II)
complex catalysts synthesized in a prior experiment. Grignard reagents are commonly used
to form carbon-carbon bonds because of their versatility. This reaction was performed in
an inert nitrogen atmosphere, as Grignard reagents are very reactive and easily ignite upon
exposure to air. The product was then analyzed by gas chromatography to find the product
distribution in order to qualitatively judge the success of the coupling.
Procedure
A 100-mL Schlenk flask was charged with a stir bar and 0.34 mmol of a chosen
nickel catalyst: one of Ni(dppe)Cl2 (0.1795 g), Ni(dppp)Cl2 (0.1843 g), or Ni(PPh3)2Cl2
(0.2224 g). A condenser was attached to the top of the Schlenk flask, while both the other
opening of the flask and top of the condenser were sealed with rubber septums. The
apparatus was purged for 10 minutes with a steady stream of N2 to create an inert
atmosphere inside the flask. The reflux condenser was then turned on, and 5 mL of dry,
degassed diethyl ether was added anaerobically using a syringe. Following the complete
addition of the diethyl ether, 2.03 mL of chlorobenzene was added anaerobically using a
new, clean syringe. The mixture was stirred until the catalyst dissolved and was cooled in
an ice bath, still stirring.
In a new syringe, 10 mL of 2.0 M iPrMgCl was anaerobically added slowly dropwise
to the cooled solution, still stirring, through the septum. The syringe was then cleaned with
hexanes and water to remove any traces of the very reactive Grignard reagent. The reaction
was stirred and removed from the ice bath, dried and placed on a metal reaction block. The
flask was then heated to a gentle reflux and allowed to reflux for two hours.
After two hours, the reaction was removed from the hot metal reaction block and
cooled in an ice bath. 20 mL of water was added slowly via syringe in order to quench
unreacted iPrMgCl. After the iPrMgCl was quenched, the septum was removed from the top
of the flask and 25 mL of diethyl ether was added to the flask. The mixture was then
Pranay Vemulamada
Lab 4: Kumada Coupling: Nickel-Catalyzed Cross-Coupling of iPrMgCl with Chlorobenzene
Due: 12/10/2018
TA: Qiuran Wang

separated in a separatory funnel; the aqueous layer was washed with 25 mL of fresh
diethyl ether. The two fractions of diethyl ether were combined and washed twice with 25
mL of saturated aqueous sodium thiosulfate and twice with 25 mL of distilled water. The
organic layer was then dried over sodium sulfate and analyzed via gas chromatography.
Discussion
The products were isolated in the form of a clear, slightly yellow oil. The yield was
not measured, as the experiment was more concerned with the product distribution in
order to judge the success of each catalyst.
Gas chromatography was used to find said product distribution in each product
mixture. All three chromatograms had two peaks that represent the two products that
show up through gas chromatography: the isopropylbenzene and n-propylbenzene. The
left-most peak was the isopropylbezene; we know this because it has a lower boiling point
(~152°C) than n-propylbenzene (159°C), and therefore evaporates first into the gas
chromatogram. This makes the right-most peak n-propylbenzene; benzene, the third
product, doesn’t appear on the chromatogram because its boiling point (80.1°C) is too low
to register on the column, which has an internal temperature of 105°C.
The larger peak on each chromatogram is the favored product for that catalyst. If
isopropylbenzene is the favored product, the Kumada coupling was more successful than
the β-hydride elimination; if n-propylbenzene is the favored product, the β-hydride
elimination was favored over the reductive elimination of the Kumada coupling.
Ni(dppp)Cl2 had a product distribution with the first peak having 62.5% of the area
and the second peak having 37.5%. This means the isopropylbenzene was the favored
product, and the Kumada coupling was rather successful.
Ni(dppe)Cl2 had a product distribution with the first peak having 36.5% of the area
and the second having 63.5%. N-propylbenzene was the major product, and
isopropylbenzene the minor; this means the β-hydride elimination was favored over the
reductive elimination step. This is likely due to the rigidity and inflexibility of the dppe
ligand, compared to the dppp (which has an extra carbon and therefore is less sterically
locked).
Ni(PPh3)Cl2 had a product distribution with the first peak having 17.6% of the area
and the second having 82.4%. N-propylbenzene was extremely favored over
isopropylbenzene, which means the β-hydride elimination was favored almost completely
over the reductive elimination of the Kumada coupling. This is likely due to the bulkiness of
the PPh3 ligand, preventing an effective reductive elimination.
Questions
Pranay Vemulamada
Lab 4: Kumada Coupling: Nickel-Catalyzed Cross-Coupling of iPrMgCl with Chlorobenzene
Due: 12/10/2018
TA: Qiuran Wang

1. From the integration on the GC, estimate the relative extent of overall coupling
and the ratio of products for the three catalysts.

Catalyst: Ni(dppp)Cl2
The gas chromatography reveals the first peak is around twice the size of the
second one (67.5% to 32.5%); this means that isopropylbenzene was more than
twice as prevalent as n-propylbenzene. This means the Kumada coupling was
more effective than the β-hydride elimination for Ni(dppp)Cl2.

Catalyst: Ni(dppe)Cl2
The second peak of the dppe chromatogram was the larger one, with a ratio
of 63.5%:36.5%. This means the n-propylbenzene was the more favored
product, signifying that the β-hydride elimination was favored over the
reductive elimination step in the coupling cycle.

Catalyst: Ni(PPh3)2Cl2
The second peak of the PPh3 chromatogram was much larger than the first
peak at a ratio of 82.4%:17.6%. This means the β-hydride elimination was much
more effective than the reductive coupling (this makes sense because PPh3 is a
bulky functional group.)

2. The active catalyst for this coupling is a Ni(0) species. Draw a mechanism for
reduction of L2NiCl2 to the active Ni(0) catalyst.

3. Suggest a plausible catalytic cycle for the cross-coupling reaction, explaining, by

way of a suitable scheme, the nature of each step.
Pranay Vemulamada
Lab 4: Kumada Coupling: Nickel-Catalyzed Cross-Coupling of iPrMgCl with Chlorobenzene
Due: 12/10/2018
TA: Qiuran Wang

4. Suggest why the three catalysts differ in their activity, particularly with respect
to the regioselectivity of the coupling reaction. Provide a mechanistic
explanation for the observed rearrangement.
The ligands differ in activity because of the bulkiness of the functional groups
and the way they lock the nickel catalyzed into an enantioselective position.
The bulkiest ligand is PPh3, which has the most difficulty completing the
desired Kumada coupling and therefore undergoes the β-hydride elimination
that produces the n-propylbenzene.

The dppp is more successful at coupling than the dppe because the extra
carbon on dppp makes the locked ring that forms on the nickel more flexible
(adds more possibility for rotation).
Pranay Vemulamada
Lab 4: Kumada Coupling: Nickel-Catalyzed Cross-Coupling of iPrMgCl with Chlorobenzene
Due: 12/10/2018
TA: Qiuran Wang

5. The Kumada coupling can also be catalyzed using palladium in lieu of nickel.
Indeed, there is a whole family of related cross-coupling reactions that utilize
palladium with various transmetallating reagents. In addition, many of these
reactions have a name or names of the scientists that discovered and/or did
much work to develop these transformations. Provide the associated
name/names for the cross-coupling reactions using 1) boron, 2) silicon, 3) tin,
and 4) zinc as the respective transmetallating reagents.
1) Boron: Suzuki-Miyaura coupling
2) Silicon: Hiyama coupling
3) Tin: Stille reaction
4) Zinc: Negishi coupling
References
“Nickel Catalyzed Cross-Coupling of Alkylmagnesium with Haloarene:” Young, G.B.
In Inorganic Experiments. Woolins, J.D. Ed. VCH: Weinheim, 1994, 76-79.
Tamao, K.; Sumitaini, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 4374-4376.
Tamao, K.; Sumitaini, K.; Kiso, Y.; Kumada, M. J. Am. Chem. Soc. 1972, 94, 9268-9269.
Spectra
dppp chromatogram:

dppe chromatogram:
Pranay Vemulamada
Lab 4: Kumada Coupling: Nickel-Catalyzed Cross-Coupling of iPrMgCl with Chlorobenzene
Due: 12/10/2018
TA: Qiuran Wang

PPh3 chromatogram: