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Evaluating the role of the cation in the Suzuki-Miyaura cross-coupling mechanism
By using Hartree-Fock 6-31G* Quantum Calculations
Matthew Welmers*, Seth Clark, and Rebecca DeVasher, Ph.D.
Department of Chemistry, Rose-Hulman Institute of Technology, Terre Haute, IN 47803
Abstract: Results:
Experimental Procedure:
Acknowledgements:
Department of Chemistry, Rose-Hulman Institute of
Technology, 5500 Wabash Avenue, Terre Haute,
IN 47803 http://www.rose-hulman.edu/chem/
Special Thanks go to: Lou Johnson, Cyndi Erwin,
Dr. Rebecca DeVasher PhD, Greg Horne, and the
American Chemical Society
Additional Group Members: Kaitlin Schneider
The following characteristics of the substrate
were varied in our study:
Identity of the functional group
Identity of the cation in the alkali base
Identity of the halogen and position of halogen
Conclusions:
Suzuki Coupling Mechanism:
Phenylboronic acid (3.1 mmol), aryl halide (3 mmol), alkali base (9
mmol), palladium acetate (0.012 mmol), PEG (1 gram), and water (6
mL) was added to the microwave reaction vessel containing a stir bar.
The reaction vessel was sealed and placed into the MARS reactor. The
reactor heated the vessels in 3 minutes to 160 ⁰C and held this
temperature for 5 minutes. The reactions were then allowed to cool to
room temperature.
Each reaction was then filtered through a Celite column using a sintered
glass filter under vacuum pressure. Water was used to wash the
reaction contents through the Celite. The aqueous solution collected
was acidified using 10% HCl. When the acid was added, the solution
turned chalky and precipate immediately began to form. The solution
was then cooled in an ice bath to promote any further crystallization. In
order to ensure complete product collection, additional water was run
through the Celite column until no further precipitate was formed when
acid was added.
The mixture was suction filtered to collect the solid product. The
product was allowed to air dry for approximately 1 week, and then the
mass and melting point was recorded. Yields were calculated from the
dry mass.
Calculations were performed with Spartan ’10 molecular modeling
software to determine equilibrium geometry using Hartree-Fock 6-
31G*.For the halogenated salicylic acids the trend in free energy supports the trend in yield: the lower the energy the
greater the yield.
The halogenated benzoic acids have no apparent trend between the free energy change and the observed
yield.
Microwave technologies are being employed to increase
yields and decrease reaction times for many reactions. For
both brominated and iodinated substrates, we have observed
higher yields for microwave Suzuki-Miyaura cross-couplings
using cesium carbonate rather than sodium carbonate as the
base; however, this increase in product yield was not
observed for all substrates and it is of interest to determine if
functional group placement with respect to the halogen has
an effect on the product yield difference resulting from
changing the cation from sodium to cesium. Additionally,
we are evaluating the cesium effect using traditional heating
methods to determine whether the observed effect is due to
the microwave or an inherent factor of the reaction. Finally,
in an effort to determine the role of the alkaline base,
molecular modeling is being performed using Hartree-Fock
6-31G* quantum calculations in Spartan. The primary goal
of this research is to learn more about the role of the cation
in the Suzuki-Miyaura cross-coupling mechanism.
Substrate
Cation
Yield
(%) DGrxno
(kJ/mol)*
4
-iodosalicylic acid |
Cesium
98.131
-693002.50
4
-bromosalicylic acid
Cesium
93.458
-692986.75
4
-iodosalicylic acid
Sodium
76.324
-692519.06
4
-bromosalicylic acid
Sodium
35.826
-692504.78
Free energy changes and yields of Suzuki-Miyaura
cross coupling reactions between halogenated
salicylic acids and phenylboronic acid
Substrate
Cation
Yield
(%) DGrxno
(kJ/mol)*
2
-iodobenzoic acid
Cesium
n/a**
-693010.96
2
-bromobenzoic acid
Cesium
14.310
-692996.42
4
-iodobenzoic acid
Cesium
30.303
-692915.57
3
-iodobenzoic acid
Cesium
88.889
-692911.74
4
-bromobenzoic acid
Cesium
23.569
-692899.59
3
-bromobenzoic acid
Cesium
90.572
-692896.41
2
-iodobenzoic acid
Sodium
n/a**
-692517.36
2
-bromobenzoic acid
Sodium
17.508
-692501.88
4
-iodobenzoic acid
Sodium
90.909
-692420.52
3
-iodobenzoic acid
Sodium
92.929
-692418.06
4
-bromobenzoic acid
Sodium
53.872
-692405.97
3
-bromobenzoic acid
Sodium
90.909
-692404.14
Free energy changes and yields of Suzuki-Miyaura
cross coupling reactions between halogenated
benzoic acids and phenylboronic acid
* Free energy was calculated by using the difference in energy between
the sum of the energies of the products and the sum of the energies
of the reactants
** This reaction was performed however solid crystals could not be isolated
using traditional separation techniques.
* Free energy was calculated by using the difference in energy between
the sum of the energies of the products and the sum of the energies
of the reactants
Products Generated:
O
OH
O
OH
O
OH
O
OH
OH
2-phenylbenzoic acid
3-phenylbenzoic acid
4-phenylbenzoic acid
4-phenylsalicylic acid