Synthesis of Ligands for the Functionalization of Magnetic Nanoparticles to be used as
Organic Catalysts
By: Joseph McKillip, Advisor - Dr. Raja Annamalai
University of Wisconsin-Platteville, Department of Chemistry
Abstract
The purpose of this project is to develop iron nanoparticle compounds to be used as
renewable organic catalysts.
Organic synthesis is vital to the development of new
pharmaceutical and petroleum based chemicals. However, it is often expensive and time
consuming, which is not favorable for industrial processes. The solution to this problem is the
use of iron nanoparticle reusable catalysts, which can decrease reaction time and be reused
through multiple cycles of reactions. The magnetic property of iron allows for easy collection of
the catalyst after each cycle. This project is specifically interested in the Mukaiyama-Aldol
reaction, which produces β-hydroxyl carbonyl compounds common in pharmaceuticals and
natural products. The current focus is the synthesis of a class of ligands that catalyze this
reaction, when attached to iron nanoparticles. The reaction has two steps. The first step has
successfully been completed, as monitored by 1H proton NMR. Step 2 requires more work to
solve problems with the synthesis. Clearly, this research is important to improving organic
synthesis, in order to continue providing new and important chemical compounds.
Introduction
Organic synthesis is extremely important in industry, but it can be difficult to do
efficiently.
Synthesis is vital for the development of pharmaceutical and petroleum based
chemicals (Figure 1). These are materials used in everyday life. However, the processes
required to make these
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Figure 1: Pictured here are some examples of materials made possible by organic synthesis. a)
Polymerization of nylon. b) Common, everyday plastics. c) Kevlar.1,2
products can be time consuming and costly. For instance, on average, it takes 10-15 years and
$800 million to develop a drug.3 In addition, the use of organic solvents and their disposal can
be expensive. These problems require attention in research, in order to improve the production
of the important products made by organic synthesis.
One of the main solutions to the time efficiency issue is the use of organic catalysts, but
this solution comes with its own problems. The use of catalysts decreases the time required for
reactions. However, catalysts can be toxic and tough to recover from reaction solutions. These
difficulties can make the use of catalysts costly, which is why there is minimal use of them in
industry right now.3 A main focus in organic synthesis research has been placed on improving
the use of organic catalysts in industrial processes, since catalysts can be beneficial in improving
time efficiency.
A major area of research now focuses on solving the problems of catalysts, through the
development of reusable magnetic nanoparticle catalysts.
These catalysts are created by
attaching a catalytic ligand to a nanoparticle made with a paramagnetic compound, typically
iron. These are heterogeneous particles, meaning they do not dissolve in reaction solutions. This
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makes it easy to separate the catalyst from the reaction solution, simply by using a magnet
(Figure 2). Since
Figure 2: General example of using a magnet to separate the catalyst from the reaction solution.4
catalysts are not altered in reactions, these easily recovered magnetic catalysts can be used in
multiple cycles of the reaction. This makes these compounds less wasteful and increases the cost
efficiency of using catalysts.
For the purposes of this research project, we are interested in developing reusable
magnetic catalysts for the Mukaiyama-Aldol reaction (Figure 3). This reaction is important
because it
OTMS
R1
R3
Silyl enol ether
Si(CH3)3
R4
OH
Lewis acid
+
R2
TMS =
O
O
H
Carbonyl
compound
R3
R1 R 2
R4
b-Hydroxy carbonyl compound
Figure 3: General reaction scheme for the Mukaiyama-Aldol reaction.5
produces the chiral β-hydroxyl carbonyl motif, which is common in pharmaceuticals and natural
products (Figure 4). This motif is formed by creating a new carbon-carbon bond from the
reaction of a silyl enol ether with an aldehyde. The Lewis acid catalyst must be chiral because
stereoselectivity is important for products made using this reaction. While there are other ways
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to make the chiral β-hydroxyl carbonyl motif, the Mukaiyama-Aldol reaction is favored because
it is a simple, one step reaction.
O
O
Me 2N
OH
HO
OH
O
O
O
O
O
HO
MeO
OH
O
O
Erythromycin A: Antibiotic
OH
NH O
HO
O
O
O
H
O
OH O
Ph
O
O
O
Taxol: Anticancer drug
Figure 4: Two examples of important products containing the chiral β-hydroxyl carbonyl
structure, the antibiotic Erythromycin A and the anticancer drug Taxol.5
There are many parts to the overall research project. Other students are working on
synthesizing the iron nanoparticles. The focus of my PURF project is on synthesizing the
catalytic ligand. The next stages will be attaching the ligand to the nanoparticle and using the
functionalized catalyst in reactions. (Figure 5)
Figure 5: General reaction scheme for the synthesis of iron nanoparticles (left), and a general
structure of the ligand to be attached (right).6
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Experimental
Ligand provided by Dr. Matthew Allen and purchased magnetic nanoparticles were used
to try a specific Mukaiyama-Aldol reaction previously reported (Figure 6).7 These tests were
run to gain firsthand experience in the effectiveness of the reusable catalysts. To do this, three
reactions were run, one without any ligand, one with just the ligand provided by Dr. Allen, and
one with the ligand attached to the nanoparticle.
Figure 6: Specific reaction scheme and ligand used in test Mukaiyama-Aldol reaction.7
The synthesis of (2R,2R’)-Dimethyl 2,2’-(1,7-dioxa-4,10-diazacyclododecane-4,10diyl)dipropanoate chiral ligand was the main focus of my research and was previously reported
(Figure 7).8 The synthesis is two steps. The R groups make the ligand customizable. To keep
things simple for this project, methanol was used in step 1, making the R group a methyl group.
Figure 7: Synthesis of (2R,2R’)-Dimethyl 2,2’-(1,7-dioxa-4,10-diazacyclododecane-4,10diyl)dipropanoate chiral ligand.8
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Results and Discussion
The initial tests of the Mukaiyama-Aldol reaction provide valuable insight into the use of
reusable catalysts. All three reactions are analyzed by 1H NMR. The NMR of the reaction with
no ligand shows no product being made. This supports the necessity of the ligand in catalyzing
the reaction. The NMRs of both reactions with ligand and ligand attached to nanoparticle shows
successful product being made. This shows that the ligand itself catalyzes the reaction. Still,
only when attached to the nanoparticle is it possible to recover the ligand. Clearly, the use of
ligands attached to iron nanoparticles is the best choice for catalyzing the Mukaiyama-Aldol
reaction.
The synthesis of the ligand portion of the project has faced many problems. For instance,
in step 1, the heating required is evaporating the small reaction solution, and NMR analysis has
been showing impure product. These problems have been overcome. To solve the evaporation
problem, a larger reaction solution volume is used, and the solution is heated for less time. A
highly pure product is successfully synthesized by fixing problems with the washes used after the
reaction is complete. The purity of the product is confirmed via NMR analysis (Figure 8). The
only peaks in the spectrum can all be assigned to protons on the product. Therefore, step 1 has
been successfully completed.
Step 2 in the synthesis of the ligand is more difficult. Initially, attempts are made to
make the final product using the initial reactant from step 1 directly. If the reaction could be
done in one step instead of two, it would increase the cost efficiency of synthesizing the ligand.
However, NMR analysis shows no product being made. This makes it clear that the reaction
must be done in two steps. In addition, it is possible that Cs2CO3, a reagent in the second step, is
forming a salt with the product of step 1, due to the presence of water in the reaction vial. This is
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suggested because NMR analysis shows no final product being made, but also none of the peaks
from the product of step 1. Attempts are still in progress to solve this problem. Likely solutions
are to run the reaction under inert atmosphere, which is not ideal because it increases costs, and
simply decrease the time the reaction vial is open to the air.
Figure 8: NMR of step 1 product.
Conclusion
Step 2 of the ligand synthesis shown in Figure 7 needs to be completed. We will then
proceed to large scale synthesis of the ligand. Another student (David Henkel) will begin testing
new methods of adding the ligand to the nanoparticles. We want to be able to add ligands to
metal nanoparticles in one step. He will be running reactions with more simple materials to
simulate the addition of the ligand on to the nanoparticles (Figure 9). This research is taking
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valuable steps toward improving the use of catalysts in organic synthesis, which is vital to the
industrial processes used in making necessary and important products.
Figure 9: Test reactions to be run that will simulate adding ligand to metal nanoparticles.
References
1
http://en.wikipedia.org/wiki/Plastic
2
http://en.wikipedia.org/wiki/Kevlar
3
Congress of the United States Congressional Budget Office, Research and Development in the
Pharmaceutical Industry 2006.
4
http://www.gignano.com/products/magnetic-nanoparticles/polymer-coatedmagnetic-nanoparticles/pei-coated-magnetic-nanoparticles/
5
Xuan, R. et. al. Journal of Organic Chemistry 2008, 73 (4), 1456-1461.
6
McCarthy, S. A. et. al. Nat Protoc. 2012, 7 (9), 1677—1693.
7
Mlynarski, J. et al. Chemical Society Reviews 2014, 43 (2), 577-587.
8
Mei, Y. et. al. JACS. 2010, 132, 12871-12873.