1. Synthesis of Benzofuran through a Palladium-Catalyzed Alkyne Coupling
Reaction
Lewis Steen, Edward Poku, & Margaret Kerr, Ph. D.
Department of Chemistry, Worcester State University, MA 01602
Palladium (II) acetate
Triphenylphosphine
CuI
N-methlylmorpholine
Acetone
Figure 2a. NMR spectrum for 5-Iodovanillin Figure 2c. NMR spectrum for the reaction that produced
the high yield
Results and Discussion
4 mm
2 mm
15 mm
44 mm
Figure 2b. Computer Stimulated NMR spectrum of the benzofuran
product
Introduction
Catalysis is the acceleration of a chemical reaction by a catalyst and catalysts are extremely important and effective in
numerous chemical transformations1. The transition metal palladium has garnered attention, as it is a very effective
catalyst that allows for the formation of a benzofuran through a catalytic coupling reaction. Currently, it is purported that
for products with high added value, the use of palladium can be cost effective since it is much cheaper than platinum or
rhodium and high recoveries of palladium can be achieved.
While the redox behavior of palladium plays an important role in its relevance to organic synthesis, other
characteristics allow for it to enrich organic synthesis such as the ability of palladium’s conversion between +2 and 0. An
important feature of palladium-catalyzed reactions is ring closure, which normally results in high selectivity to the larger
size ring whereas other cyclisation procedures favor the formation of the most stable ring. This feature allows palladium
to be used in constructing odd numbered rings of larger sizes. Due to this palladium is mostly used in synthesizing
pharmacologically active compounds that are used in treatment of different disease conditions3.
Following established procedures a new carbon-carbon bond was constructed by coupling 5-iodovanillin in this
experiment. A carbanion (“acetylide”) was formed from the deprotonation of the terminal alkyne. 3-methyl-3-butyne-2-ol
was then catalyzed by a palladium complex through the Sonogashira coupling reaction mechanism. Triphynelphosphine
was used as an efficient electron donor to activate palladium. 5-iodovanillin then reacted with the palladium complex
through oxidative addition to form a palladium(II) intermediate. Deprotonation of the terminal alkyne occurred leading to
the exchange of ligands, essentially transmetallation. The ligands were then rearranged through isomerization forming
the coupling product and the original palladium complex was regenerated.
Figure 1a. Sonogashira Coupling Reaction for the Formation of the Benzofuran2
Palladium played a significant role in this experiment through its ability of lending electrons to the 5-
iodovanillin to form the intermediate, which then allows for transmetallation and isomerization. Without palladium
the reaction would not be able to form the intermediate or share electrons that initiates the Sonogashira coupling
reaction. Once the coupling product is formed the triple bond spontaneously breaks and atoms are joined forming a
new ring. The main functional group that adds to the spontaneity of this process is the alcohol group connected to
the benzene ring. It will encourage the removal of the hydrogen on it and the breaking of the triple bond1. Instead of
using trisodium tri(3-sulfonatophenyl)phosphine [3,3’,3”-phosphinidyne-tris(benzenesulfonic acid) trisodium salt,
(TPPTS) as an electron donor, triphenylphosphine was used to ascertain if the reaction will proceed which could
allow this experiment’s potential incorporation into senior level laboratory protocol. Additionally, TPPTS was not
favored due to its lack of availability and expensive price tag. Triphenylphosphine is much more favorable since it is
less expensive and readily available.
Abstract
Benzofuran is a natural compound taken from coal tar that is a key ingredient in the synthesis of resins. Natural
resins are excreted from plants and are used as raw materials in the synthesis of other products. A green way to
synthesize a benzofuran is through deprotonation of a terminal alkyne for the use of forming a new carbon-carbon bond
through nucleophilic addition to an electrophile or through a Sonogashira coupling reaction. In this experiment 2-
methyl-3-butyne-2-ol was coupled with 5-iodovanillin in a reaction catalyzed by a palladium complex. A palladium
catalyst was used to accelerate the reaction due to its high surface area-to-volume ratio and efficiency of palladium
itself. This reaction demonstrated principles of green chemistry that made it a green reaction in various ways such as
using a catalyst to effect chemical transformations, use of renewable chemical feedstocks, and use of a less hazardous
solvent. The study of the palladium catalyst in organic synthesis as senior level lab protocol will then be applied at
Worcester State University.
Experimental
The amount of reagent and catalysts were altered to study the behavior of the palladium catalyst. This
was also done to ascertain if this reaction can be completed in small volumetric amounts.
Triphenylphosphine was used in proportionate ratios to ascertain which amount was optimal. Table 1
corresponds to the amounts of reagents, catalyst, and solvent used in each reaction, which yielded a certain
amount of product. The overall reaction for the synthesis this particular benzofuran is shown in figure 1b.
Table 1. Amounts of catalysts, reagents, solvent, and product yielded for each reaction
The full 1HNMR spectrum of the synthesis of the product is shown in Figure 2c. Figure 2a shows
the 1HNMR of the starting material 5-idovanillin and Figure 2b shows the computer simulated
1HNMR of product. Based on the 1HNMR of experimental product of benzofuran, signals at 10 ppm
appeared and integrated one proton. These signals that appeared in this region of the spectrum were
assigned to the aldehyde attached to the aromatic ring. This matched the same signal on the computer
simulated 1HNMR as well as that of the 1HNMR of 5-idovanillin since the aldehyde functional
group was still present in these compounds. Signals appeared at about 7.79 ppm and integrated for 2
protons in the NMR of the product. Although these peaks failed to match the expected singlet peaks
shown by the computer simulated 1HNMR spectrum and the doublet on the 5-iodovanillin 1HNMR ,
it can be noted that these peaks arose from the protons on the aromatic ring as their values were
consistent with aromatic ring proton values.
Again from the spectrum of the product, a signal appeared at around 6.5 ppm and this
corresponded to a similar peak noted in the computer simulated NMR spectrum, which corresponds
to the proton on the fused ring. Another signal at 4.5 ppm appeared as a singlet and this suggests that
it is the methoxy group protons attached to the aromatic ring and this value was consistent with
methoxy around an aromatic ring. A similar corresponding peak was noted as a singlet in the
computer simulated NMR but this did not correspond exactly to the peak observed in the product.
Finally multiple peaks of intense activity were noted at around 2 ppm. Although the computer
simulated spectrum showed a singlet at this point the product collected after synthesis produced
different peaks. The appearance of this peak suggests that some amount of desired product was
formed although it was impure. The lack of purity could have been due to the formation side
reactions, which is usually encouraged by the copper co catalyst.
Melting point range of 102-105 °C was noted for the experiment with the highest yield. Literature
melting point is between 105-110 °C and based on this the conclusion can be made that there was
some amount of product formed nonetheless it was impure. This reaction synthesis presented an
impressive atom economy however, from Table 1, it was noted that different yields were obtained, as
well as some yield were lost. Percent yield for the most product collected was 7.45% which was
relatively low. It was discovered that centrifugation allowed for the collection of most product
compared to vacuum filtration as most product got stuck to the filter paper. Also, more products are
being synthesized at this time awaiting crystallization.
Conclusion
Overall, using palladium as a catalyst to synthesize benzofuran proves to be an impressive and
efficient means as it has spectacular atom economy and the catalysis in a acetone solvent system is
simple although must be carried out methodologically. Further research is however needed to
ascertain how to overcome the side reactions that is encouraged by the copper co catalyst as well as
how to directly recover the palladium catalyst without going through extensive extraction procedure.
This ongoing research on palladium catalysts will eventually be incorporated into senior level organic
chemistry protocol if improved.
Acknowledgements
Grant Awarded for Carbon Bond Formation Research by the WSU Foundation
Faculty Mini-grants, Worcester State University
Department of Chemistry, Worcester State University
References
1) Doxsee, K.M., Hutchison, J.E. Experiment 13: Palladium-Catalyzed Alkyne
Coupling/Intramolecular Alkyne Addition:Natural Product Synthesis. In Green Orgnaic Chemistry
Strategies, Tools, and Laboratory Experiments,, Brooks/Cole, Pacific Grove, Ca. 2004, 189-196.
2) Organic Chemistry Portal. Sonogashira Coupling. http://www.organic-
chemistry.org/namedreactions/sonogashira-coupling.shtm (Accessed April 22, 2013).
3) Russell M. J. H. An Advantageous Use of Palladium Compounds in Organic Synthesis the
formation of carbon-carbon bond Johnson Matthey, Materials Technology Division, Royston
Platinum Metals Rev., 1989, 33, (4), 186-193
4) Succaw, G. L.; Doxsee, K. M. "Palladium-Catalyzed Synthesis of a Benzofuran: A Case Study
in the Development of a Green Chemistry Laboratory Experiment", Educacion Quimica. 2009,
433-44.
5-iodovanillin
(mmol)
5-Iodovanillin:
Palladium (II)
Acetate:
Triphenylphosphine
ratio
Palladium
(II) acetate
(mmol)
Triphenylphosphine
(mmol)
2-methyl-
3-butyne-
2-ol
(mmol)
N-methylmorpholine
(mmol)
Cuprous
Iodide
(mmol)
Acetone
(ml)
Product
Yield
(grams)
%
yield
Melting
Point (°C)
1.453 46:1:6.61 0.031 0.205 3.095 4.092 0.075 10 0.00719 2.10 __
2.972 48:1:6.56 0.062 0.407 6.191 8.185 0.151 30 0.02811 4.03 120-148
3.505 49:1:6.66 0.071 0.473 7.223 9.550 0.189 35 0 __ 200
2.516 49:1:2 0.051 0.106 5.159 6.821 0.131 25 0.00362 0.61 __
4.010 45.5:1:1.87 0.088 0.165 8.254 10.91 0.212 35 0 __ __
3.057 49:1:1.93 0.062 0.120 6.191 8.185 0.171 30 0 ___ __
3.086 46:1:1.76 0.067 0.118 6.191 8.185 0.172 30 0 ___ __
3.024 50:1:2.56 0.060 0.154 6.191 8.185 0.154 30 0.0530 7.45 102-105
3.044 50:1:1.93 0.061 0.118 6.191 8.185 0.158 30 0.00600 0.838 125
3.005 23.5:1:1.24 0.127 0.158 6.191 8.185 0.162 30 0.02017 2.85 110-116
3.004 23.5:1:1.25 0.127 0.160 6.191 8.185 0.165 30 0.04725 6.69 99-101
3.033 24:1:1.48 0.125 0.185 6.191 8.185 0.162 30 0.03713 5.20 102-107
1HNMR spectroscopy was carried out on the highest yielded reaction and the spectrum is compared with the
spectrum of 5-iodovanillin and computer simulated spectrum of the expected benzofuran.
Figure 1b. Overall reaction of the synthesized benzofuran
O
O
CH3
CH3
OH
H
O H
15 mm
2 mm
4 mm
I
OH
H
O
O
H3C
3.72
1.0
+ H
CH3
CH3
OH
Results and Discussion