Download Sample 3 - University of Puget Sound

Summary
The overall goal of the proposed research is to develop new iron-based catalysts for the
hydrogenation of carbonyl groups and alkenes. Since hydrogenation reactions are so prevalent
within drug syntheses, efficient catalysis for these reactions will contribute significantly to
decreasing the waste produced by the pharmaceutical industry and thereby promoting green
chemistry. Current catalysts for such reactions are highly efficient but also toxic and expensive.
Developing efficient catalysts based on iron, a relatively nontoxic and inexpensive metal, will be
an excellent solution to the problems that plague current catalysts. The catalysts that will be
synthesized will be composed of an organic ligand attached to an iron complex. Two versions of
one ligand were successfully synthesized during the summer of 2013 and work will resume on a
second ligand. With these ligands in hand, the next step is to attach them to iron complexes to
form potential catalysts. Experiments performed last summer aimed at forming these iron
complexes were not completely successful, so the next step toward catalyst formation will be to
synthesize more reactive iron precursors to attach to the ligands. Once effective iron precursors
are synthesized and attached to ligands, the resulting potential catalysts will be tested for
catalytic efficiency. This research will involve synthesis including specialized air-free
techniques, and characterization of products will be carried out using NMR and IR spectroscopy
and GC-MS.
Proposed direct cost budget
→ This budget was prepared by Prof. Luc Boisvert.
All chemicals involved in this research are either already in the Chemistry Department's
chemical inventory, or will be bought using departmental funds or using Prof. Boisvert's
own funds. The equipment necessary to conduct the research is already present in the
department and normal operating costs will be paid by the Department or by Prof. Boisvert's own
funds. Solvents and basic supplies have not been included in the table below.
Some of the necessary chemicals are more expensive than more common chemicals and solvents.
These more expensive chemicals (the first four chemicals in the table below) have been included
in the McCormick budget proposal.
Direct budget costs:*
Chemical
2-bromo-6-methoxypyridine
2-hydroxy-6-methylpyridine
lithium 1,2,3,4,5pentamethylcyclopentadienide
potassium diphenylphosphide
N,N,N′,N′-tetramethylethylenediamine
sodium borohydride
lithium aluminum hydride
iodomethane
cyclopentadienyllithium
butyl lithium
Quantity
50 g
25 g
2g
Price
264
181
99
100 mL
96.40
100 mL
31.10
25 g
41.30
25 g
49.60
100 g
49.30
5g
43
100 mL
43
Total:
897.70
*Prices in the table below were taken from the Sigma-Aldrich website in March of 2014.
2-bromo-6-methoxypyridine
lithium 1,2,3,4,5-pentamethylcyclopentadienide
264
99
1
Synthesis of Iron-Based Hydrogenation Catalysts
Shelby Willis
Background
Energy consumption in chemistry. As of 2013, fossil fuels contributed annually to 80% of
global energy consumption. Such an imbalance is unsustainable without inevitable conflict
between stable ecosystems and global welfare.1 Since chemical processes rely on fossil fuels as a
source of energy and primary feedstock, reducing this fuel dependence poses a serious challenge
for the chemical industry.1 The need to reduce energy consumption is driving many chemistry
related fields to develop sustainable methods of synthesizing chemical compounds. For example,
the pharmaceutical industry has a particularly significant energy footprint due to the excessive
production of waste during the synthesis of drugs. This waste problem can be illustrated in terms
of E Factor, which is a metric that expresses a ratio of kilograms of chemical waste per kilogram
of target product. The pharmaceutical industry’s E Factor of 25-100 is the largest in the chemical
industry; by comparison, large scale industry has an E Factor of <1-5.2 Recognition of these
fundamental sustainability issues in the chemical sector has created a movement towards green
chemistry which seeks to counteract the environmental and financial burden of the excessive
waste and energy consumption in chemistry.3
Green chemistry and catalysis. Green chemistry encourages the use of catalysts in chemical
reactions to reduce energy consumption. A catalyst is a substance that can be added to a
chemical reaction to speed it up without itself being consumed in the reaction. Catalysts can
significantly lower the energy input, quantity of chemicals necessary and waste production in
chemical reactions.4 The manufacture of propylene oxide illustrates the efficacy of catalysts in
reducing reaction waste (Scheme 1).5 The traditional method of synthesis of propylene oxide (2)
proceeds through two non-catalytic steps and produces 1.9 kilograms of CaCl2 waste for every
kilogram of propylene oxide (2). By comparison, in the new catalytic method developed in 2008,
no intermediate step is required, fewer chemicals are necessary and every kilogram of propylene
oxide product (2) is only accompanied by 0.3 kilograms of water—a much more desirable and
green ‘waste’ co-product.5
2
Scheme 1
Many cornerstone reactions in the synthesis of pharmaceuticals are now performed
exclusively through catalysis because of the economic and environmental benefits. One such
foundational reaction is hydrogenation in which hydrogen atoms are added to a compound. Since
this reaction is a key step in many drug syntheses, its efficient catalysis has a huge impact on
sustainability in the pharmaceutical industry. As shown in Scheme 2, hydrogenation involves the
addition of hydrogens to a double bond 3, in this case a double bond to oxygen. The double bond
is replaced by a single bond to a hydrogen and the formation of an alcohol 4.
Scheme 2
Limitations of hydrogenation catalysts. Currently, there are numerous very efficient catalysts
for hydrogenation reactions, but they have some serious limitations.2 The most significant issue
is that they are based on rhodium, iridium, or ruthenium which are very expensive metals, with
prices hovering around 236, 3500, and 1500 US$/mol, respectively.6 Since pharmaceutical
syntheses often involve large scale hydrogenation reactions, the expense of these metals is a
serious deterrent. Additionally these metals are toxic and environmentally detrimental.
Iron is an ideal replacement for current hydrogenation metals, as it is naturally occurring,
nontoxic, and costs around 0.10 US$/mol.7 Some iron-based hydrogenation catalysts have been
reported in recent years, but research in the field is still only starting.7 The main objective of this
project is to contribute to the development of this promising new area of research. Last summer
my research centered on synthesizing the organic ligand compounds that I would then attach to
an iron center to create the catalysts. I also started testing strategies to attach the ligands to the
iron center. My results in this research will be presented in March at the 2014 American
Chemical Society annual meeting. Since we successfully synthesized the ligand, we are in a great
3
position to move on to the next stage of synthesizing iron precursors on which the ligands can be
attached. In this stage, the main objective is to synthesize three different iron precursors that can
be attached to the ligands and tested for catalytic activity.
Proposed Research
Homogeneous hydrogenation. Hydrogenation reactions usually proceed by one of two general
mechanisms. In the first mechanism, oxidative addition of H2 to a metal 5 creates a metal
dihydride complex 8 (Scheme 3 top). The second mechanism involves a heterolytic cleavage that
is made possible by the dramatic increase in acidity of the bound hydrogens in the metaldihydrogen complex 7, which allows even a mild base to deprotonate it (Scheme 3 bottom).8
This deprotonation results in a protonated base 10 and a metal hydride complex 9.
Scheme 3
In the proposed research, the heterolytic cleavage is carried out by a base that is part of a
ligand attached to the iron center (Scheme 4). This type of heterolytic cleavage, called ligandassisted heterolytic cleavage, is well documented for rhodium and ruthenium.9,10 Studies by
Casey and Morris indicate that iron can also efficiently participate in this type of H2
cleavage.11,12 This mechanism begins with the iron catalyst 11 forming a metal dihydrogen
complex 12 in the presence of H2. Ligand-assisted heterolytic cleavage by the pyridone ligand
produces complex 13 that can then catalyze a hydrogenation reaction. The pyridone unit shown
here is part of the ligands that I previously synthesized for this project. This type of pyridone
ligand has been shown to have high reactivity in hydrogenation reactions with iridium
complexes.13--16
Ligand Assisted
Heterolytic Cleavage
Scheme 4
H2
N
O
N
O
N
OH
H
Fe
Fe
11
Empty Orbital
Fe
H
12
13
H
4
Once all pyridone-based ligands are synthesized, both their methoxy (15, 18) and alcohol
(14, 17) forms will be reacted with a commercially available iron complex to form the desired
hydrogenation catalyst 16 and 19 (Scheme 5). In attaching the ligand to the iron center, both the
alcohol and methoxy forms of the ligands will be used. Once added to the iron complex, the
methoxy derivatives will be deprotected and converted to the alcohol form.
Scheme 5
Synthesis of ligands. Last summer I synthesized ligands that contain diphenylphosphine (15)
and dimethylamino groups (18) (Schemes 6 and 7).
The dimethylamino derivative was
successfully synthesized using the series of reactions shown in Scheme 6.
Scheme 6
Last summer, good progress was made on the synthesis of the diphenylphosphine
derivative 15 (Scheme 7). The initially proposed synthesis demonstrated in Scheme 7 involved
the transformation of lithiated derivative 23 into ligand 15. This method will be attempted again
with starting material of higher purity this summer.17 Alternatively, we began exploring the
potential use of alkyl chloride intermediate 24 (Scheme 7). Both routes to the ligand will be
revisited this summer, and deprotection of the methoxy group will afford the alcohol derivative
of the ligand needed for catalysis.
Scheme 7
5
Iron complex formation. With one ligand synthesized and another well on its way, the next step
will involve attaching them to an iron center. Last summer I studied the reactivity of CpFe(CO)2I
(25) with triphenylphosphine as a model for the ligands being synthesized. In a successful test,
triphenylphosphine would displace both CO groups on the iron complex to form complex 26,
though we have not yet confirmed that complex 26 has been obtained (Scheme 8a). Last summer
we didn’t have a proper photochemical reactor to conduct this reaction. Since the lab is now
equipped with a photochemical reactor, we will attempt this reaction again.
Scheme 8
a)
b)
The photochemical reactor may not make the reaction successful, and even if it does it is
possible that this iron complex will not react favorably with other ligands. In light of this, I plan
to synthesize new more reactive iron precursors through two new strategies.
In the first new strategy, triphenylphosphite will be reacted with the same iron complex
25 in a photochemical reactor (Scheme 8b). Triphenylphosphite has been documented to displace
the CO groups readily and the triphenylphosphite derivative 27 is known to react quickly with
the types of ligands we are using.18
In a third strategy, complex 29 will be synthesized (Scheme 9).19 The TMEDA group
attached to iron precursor 29 can be easily displaced making this a promising step toward ligand
attachment and catalyst synthesis.19
Scheme 9
Catalytic Testing. Once a potential catalyst is formed, we will test it for catalytic activity. Our
standard substrates for catalytic testing will be acetophenone and styrene. The progress of the
reactions will be monitored by IR, 1H and
13
C NMR spectroscopies and GC-MS. This project,
though focused on hydrogenation, will contribute to a broader objective of transforming
chemistry into a more sustainable industry that can contribute to the global community without
detracting so significantly from global energy resources.
6
Bibliography
1
Jess, A.; Wasserscheid, P. Chemical Technology: An Integral Textbook. “Raw materials,
products, environmental aspects, and costs of chemical technology” Wiley, Hoboken. 2013, 408524.
2
Ager, J.; de Vries, H. M.; de Vries, G. “Asymmetric homogeneous hydrogenations at scale”
Chem. Soc. Rev. 2012, 41, 3340–3380.
3
Poliakoff, M.; Licence, P. “Green Chemistry” Nature 2007, 450, 810-812.
4
Arpe, H.-J. Industrial Organic Chemistry, 4th ed.; Wiley: Germany, 2003.
5
Parker, D. “Propylene oxide gets a green makeover” Chem. Sci. 2008, 5, C73.
6
Prices for Ru, Rh and Ir verified online at www.platinum.matthey.com on March 2014. Prices
for Fe (scrap metal-iron) verified online at www.metalprices.com on March 2014.
7
Iron Catalysis in Organic Chemistry: Reactions and Applications; Plietker, B., ed.; WileyVCH: Weinheim, 2008.
8
Hartwig, J. Organotransition Metal Chemistry: From Bonding to Catalysis, 1st ed.; Edwards
Brothers: USA, 2012.
9
Conley, B. L.; Pennington-Boggio, M. K.; Boz, E.; Williams, T. J. "Discovery, applications,
and catalytic mechanisms of Shvo’s catalyst" Chem. Rev. 2010, 110, 2294-2312.
10
Noyori, R.; Kitamura, M.; Ohkuma, T. "Toward efficient asymmetric hydrogenation:
architectural and functional engineering of chiral molecular catalysts" Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5356-5362.
11
Casey, C. P.; Guan, H. "An efficient and chemoselective iron catalyst for the hydrogenation of
ketones" J. Am. Chem. Soc. 2007, 129, 5816-5817.
12
Morris, R. H. "Dihydrogen, dihydride and in between: NMR and structural properties of iron
group complexes" Coord. Chem. Rev. 2008, 252, 2381-2394.
13
Yamaguchi, R.; Ikeda, C.; Takahashi, Y.; Fujita, K.-i. "Homogeneous catalytic system for
reversible dehydrogenationhydrogenation reactions of nitrogen heterocycles with reversible
interconversion of catalytic species" J. Am. Chem. Soc. 2009, 131, 8410-8412.
14
Kawahara, R.; Fujita, K.; Yamaguchi, R. “Dehydrogenative oxidation of alcohols in aqueous
media using water-soluble and reusable Cp*Ir catalysts bearing a functional bipyridine ligand” J.
Am. Chem. Soc. 2012, 134, 3643−3646.
15
Fujita, K.-i.; Tanino, N.; Yamaguchi, R. "Ligand-promoted dehydrogenation of alcohols
catalyzed by Cp*Ir complexes. A new catalytic system for oxidant-free oxidation of alcohols"
Org. Lett. 2007, 9, 109-111.
16
Royer, A. M.; Rauchfuss, T. B.; Wilson, S. R. "Coordination chemistry of a model for the GP
cofactor in the Hmd" Inorg. Chem. 2008, 47, 395-397.
17
Brodney, M.; Padwa, A. “Electrophilic Aromatic Substitution on Pyridine Rings.
Intramolecular Cyclization Using N-Acyliminium Ions” Tetrahedron Lett. 1997, 38, 6153-6156.
18
Levison, J.J.; Robinson, S. D. “Hydrido(triarylphosphite) complexes of cobalt, rhodium, and
iridium” Chem. Commun. 1968, 22, 1405-1406.
19
Strohmeier, W.; Steigerwald, H.; Weigelt, L. “Einfluss des quantenflusses φ auf die
photoaktivierung des homogenen hydrierungskatalysators IrClCO(PPh3)2” J. Organomet. Chem.
1977, 129, 243-248.
Approximate timeline
→ This approximate timeline was prepared by Prof. Luc Boisvert.
The proposed research involves the multistep synthesis of organic and organometallic complexes by
using techniques and strategies that are well known. However, the target compounds have not been
previously synthesized using these strategies. As such, each individual step of the proposed syntheses
will need to be attempted and optimized. As a normal process for this kind of research, the synthetic
plan may have to be significantly modified if some of the proposed steps cannot be successfully
accomplished. Due to the nature of this research, it is entirely possible that the approximate timeline
detailed below will be respected, or that not even the first step involving the synthesis of the organic
ligands will have been accomplished successfully by the end of the ten weeks of research.
Week
1-2
3 - 10
9 - 10
Description of work
- Synthesis, purification and characterization of ligands 14, 15, 17 and 18 according to
Scheme 6 and 7 of the proposal
- Test of reactivity of iron complex 25 according to Scheme 8 of the proposal
- Synthesis, purification and characterization of ligands 14, 15, 17 and 18 according to
Scheme 6 and 7 of the proposal
- Synthesis, purification and characterization of iron complexes 28 and 29 according to
Scheme 9
- Test of reactivity of complexes 28 and 29
- Testing iron complexes for catalytic activity in hydrogenation reactions, and
optimization of reaction conditions
- Wrapping up synthesis studies
- Analysis, preparation and planning for final report and poster