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3-23-2007
Nontraditional Synthesis of Organometallic compounds and Allylic Alcohols
Andrew J. Hesse Butler University
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Applicant Andrew Hesse (Name as it is to appear on diploma)
Thesis title Nontraditional Synthesis of Organometallic
Compounds and Allylic Alcohols
Intended date of commencement May 12'h 2007 -----'------
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Departmental Chemistry with High&~,HQud¥s,;) '_ ...... -' "'j
Nontraditional Synthesis of Organometallic compounds ·.:..l' 1 and Allylic Alcohols H I (:;
A Thesis
Presented to the Department of Chemistry
College of Liberal Arts and Sciences
and
The Honors Program
of
Butler University
In Partial Fulfillment
of the Reguirements for Graduation Honors
Andrew J. Hesse
March 23'd 2007 Table of Contents 1. Abstract. . 3 II. Background . 4 a. Organometallics . 4 b. Microwave Irradiation . 5 c. Ferrocene .. 7 d. Iron Diene Tricarbonyls . 9 e. Mechanochemistry . 11
f. Baylis-Hillman reaction . 12 III. Experimental Methods . 13 a. General Methods . 13 b. Ferrocene .. 14 c. Iron Diene Tricarbonyls . 16 d. Synthesis of Allylic Alcohols . 17 IV. Results and Discussion .. 17 a. Ferrocene .. 17 b. Iron Diene Tricarbonyls .. 20 c. Allylic Alcohols . 21 V. Conclusion .. 25 VI. References .. 26 VII. Supplemental Materials . 28
2 Abstract
One of the central dogmas of chemistry is the use of convection heating to increase rate and yields of reactions. However, other methods for the impartation of energy do exist. Microwave irradiation uses high power waves to directly excite molecule into higher energy states. This speeds up the kinetics of the reaction and thermodynamically favorable products are formed at a higher rate. This project successfully uses microwave irradiation to perform organometallic syntheses of iron based compounds such as ferrocene and iron diene tricarbonyls. Another alternative method involves using mechanical energy as a substitute for thermal energy. By rapidly colliding reactants together in the solid state, energy barriers can be overcome without increasing the temperature of the reaction. This project uses a technique known as high speed ball milling increase the formation of allylic alcohols through the Baylis-Hillman reaction.
3 I. Background a. Organometallics
Organometallic chemistry is the study of compounds that contain a carbon metal bond. The hallmark compound that was the catalyst for the formation of this
1 branch of chemistry was ferrocene ,2. Its discovery in 1951 and the subsequent debate over its structure were important for a variety of reasons. Since ferrocene was the first compound of this class to be isolated, no one was completely sure of the
structure. Based on all the information available, it was known that at least one carbon atom was directly bound to the metal, but the exact nature of the bond was unknown. Largely due to the single peak in both proton and carbon-l 3 NMR spectra,
it was determined that all 5 members of the cyclopentadiene ring were equally bound
to the iron atom on both faces (fig. 1). This basic structure resulted in this class of
molecules being dubbed "sandwich" compounds.
When ferrocene was discovered, the overall utility of organometallic
compounds was unknown. Now they are used as catalysts for a wide variety of
3 s organic reactions - . Yet the science is still relatively new and therefore many
potentially groundbreaking compounds in this class have yet to be discovered. The
American Chemical Society recognized the importance of this burgeoning science
and founded a specific journal devoted to this area, Organometallics, in 1982. If
quicker and easier ways of synthesizing specific new organometallic compounds
could be found, then the potential for continued discovery in this field is nearly
limitless.
4 9> Fe 6 Figure 1 - Ferrocene
Iron based complexes have become the main staple of classical organometallic
6 synthesis . This is due to their relative ease offormation, the commercial availability of iron based precursors and their relative inexpensive cost. Also, iron compounds are typically very stable, and have minimal toxicities. These factors make iron based compounds ideal to explore in undergraduate research. While goal of this project was not to synthesize new and novel compounds, the hope is that the methods developed here could be applied to other systems. For instance, in 2005 the Nobel Prize was awarded in part to Robert Grubbs for his development of a ruthenium based catalyst
7 for olefin metathesis and ring-openings ,8. The potential for synthesizing new active organometallic compounds is immense if alternative synthetic pathways can successfully be used in these transformations. b. Microwave Irradiation
While the formation of a metal carbon bond is exothermic, the overall process for forming an organometallic compound is not chemically trivial. To overcome this energy barrier, reactions are traditionally heated to high temperatures and allowed to react for relatively long periods of time. This makes organometallic compounds, and particularly iron-based compounds, good candidates for using alternative forms of energy. Microwave radiation has been used in food preparation since the early
5 1970's. Only recently has the technique come into large scale favor in the chemistry community9-12. Yet, while microwave irradiation has been increasing in popularity
13 17 for organic syntheses, it has been relatively underused on organometallic systems - •
Common knowledge dictates that metal species should not be placed under microwave irradiation. However, this is only true if the metal is a conductor. Since metals with ligands attached are generally not conductive, exposing them to microwave irradiation should have no negative effects on the compound or the microwave. A conductive metal contains free electron. When ligands are attached, they tie up the electrons and don't allow the metal species to conduct. While microwave radiation will never fully replace traditional heating, under the correct circumstances it can drastically reduce the amount of time and energy required for a reaction to occur.
The concept behind microwave heating is relatively simple. Traditionally, slow reactions were heated by simple convection to increase the rate of reaction. In this process, heat must be transferred from the heat source to the reaction vessel, then to the solvent and finally to the reactants. This net result is a process that is not terribly efficient. Microwave radiation allows for the direct impartation of energy to the reactants. Instead of using convection, high power waves are radiated at the reaction vessel. These waves can be directly absorbed by the molecule in the reaction and energy is transferred directly rather than through a secondary medium. The microwaves are directly absorbed by the molecules in the reaction and this causes an excitation in vibrational motion. This additional energy can they be used in the reaction. The net result is a far more efficient heating process that can speed up the
6 rate of reaction. Also, microwave reactions are typically done in a sealed vial. This allows reactions to be performed at temperatures higher than the boiling point of the solvent. Therefore the solvent can be chosen based on its microwave heating properties and relative solubility of the reactant rather than on the boiling point. Also, since the energy is imparted directly, this often allows for the reaction to be run in the absence of solvent, making work-up easier and potentially more environmentally
friendly. c. Ferrocene
The traditional synthesis of ferrocene is conducted in three step, two pot
process. The first step is the generation of cyclopentadiene monomer (Cp-H) from dicyc10pentadiene (DiCp). At room temperature, cyclopentadiene readily undergoes
a Diels-Alder reaction to form dicyclopentadiene (figure 2). This reaction is in
equilibrium at room temperature such that both the monomeric and dimeric forms are
present. To isolate the monomeric form, dicyclopentadiene is heated and the newly
formed monomer is distilled away. This process is known as "cracking". To ensure
that the cracked Cp-H does not undergo the Die1s-Alder reaction and revert back to
DiCp, the product is stored at a cold temperature where the monomer is favored.
• • 20
Figure 2 - Retrocyc1oaddition of CYc10pentadiene
The second step in the formation of ferrocene is the deprotonation of
cyclopentadiene to form the aromatic anion (figure 3). This is done by adding a
7 strong base into the solution. This base abstracts hydrogen from the sp3 hybridized
carbon to form the anionic cyclopentadiene ligand (Cp} By virtue ofresonance
through the double bonds, the negative charge is delocalized to all of the carbons in the Cpo ring.
HH 6 + Base --6 Figure 3 - Deprotonation of Cyclopentadiene
The anion is then reacted with the iron source, in this case iron(II) chloride
tetrahydrate (figure 4). Cpo acts as a ligand, adding into the sites on the metal vacated
by the other species. Typically organometallic species are most stable when they are
surrounded by 18 valence electrons. Atomic iron has 8 valence electrons and each Cp
ligand contributes 5 electrons to iron. Also, because of the geometry of the iron's
orbitals, it has 6 binding sites available. Each cyclopentadiene fills three ofthe
potential binding site on the iron. The net result is that ferrocene is an incredibly
6 thermodynamically stable moiecule ,I8,
~ , o +FeCl,' 4H,O _.~
Figure 4 - Formation of Ferrocene
While this method has been reported to make ferrocene in greater than 95%
yields, it is time intensive. The cracking process takes 2 or more hours to ensure the
monomeric form is isolated from the dimer while the anion reaction with the iron
compound typically takes 2 to 4 hours to complete. This only includes the reaction
time and doesn't include preparation or work-up. By using microwave radiation, the
8 overall rate of reaction could be drastically increased and comparable yields should be obtained in far less time. d. Iron-Diene Tricarbonyls
A second class of iron based organometallic compounds known as iron-diene tricarbonyls were also examined. These compounds consisted of a central iron atom bound to a cyclic diene system and three carbonyl ligands (figure 5). The traditional syntheses of this class of compounds calls for long reflux times (hours to days) at
I9 22 high temperatures, making them potential targets for alternative reactions • . Three different dienes were explored in this study; 1,3 cyclooctadiene, 1,5 cyclooctadiene, and tropone.
Two different iron sources have been used to synthesize these compounds in
23 the past . Fe2(CO)9 has been predominantly used because it is far more reactive than
Fe(CO)5. This leads to significantly lower reaction times when using the diiron species. However, there are drawbacks to using the diiron carbonyl. It is significantly more expensive to purchase than Fe(CO) 5. Also, it is highly air sensitive so it can easily decompose if exposed to the environment. In addition, it is pyrophoric. Therefore, for the purposes of an undergraduate research project, it made more sense to use the monoiron species. This has the dual purpose of allowing more room for improvement over traditional pathways as well as helping to limit the cost of starting materials while avoiding the difficulties of dealing with air sensitive and pyrophoric compounds.
9 a Q Q Q Fe~ co Fe~ co Fe~ co coca \coco \coco
Figure 5 - Iron-dienyl-tricarbonyl compounds
Another proposed method for synthesizing iron-diene tricarbonyl compounds is by using N-methyl morpholine (NMO) (figure 6)24. As a strong oxidant, NMO can convert one ofthe CO ligands on the iron to CO2. Since CO2 is a very poor sigma donor compared to CO, CO2 's ability to function as a ligand is rather weak, making it far more labile than a non-oxidized CO ligand. As a result, the binding sites to which the diene adds are more readily available, making it a much more kinetically favorable process. This reduces the need for energy to be added to the reaction in the form of heat or microwave irradiation. o / Figure 6 - N-methyl morpholine
e. High Speed Ball Milling
While using microwave radiation is certainly not a traditional method for heating reactions, the net result is still thermal energy being used to lower the kinetic energy barrier. However heating a reaction is not the only way to impart energy.
10 Mechanical energy can also be harnessed by chemical systems. While there are multiple ways to do this, the one on which the other portion of this project is focused is High Speed Ball Milling (HSBM). The reactants, typically in the solid phase, are placed in a small metal screw top vial. A small metal ball is also placed in the container. Then the metal canister is placed in a mill which shakes the reaction at a high frequency for the desired about of time (figure 7). While the collisions with the walls might cause some friction (and therefore small amounts of heat), the main source of energy is the direct collision of the ball with the reactants. These collisions serve two purposes. First is the breakdown of higher order solid structure. Since the molecules are not in solution, the surface area of the solid plays a major role in the rate of reaction. With each successive hit, the size of the crystal becomes smaller and smaller until a maximum surface area is reached. The second purpose is in the actual reaction of the molecules. If a collision occurs between the ball and the reactants at the correct orientation, the mechanical energy of the ball can be harnessed by the molecules to overcome the kinetic barrier of reaction.
Figure 7 - Mill used in Synthesis
There are many advantages to imparting energy to a reaction in this way.
First, since the reaction can occur in the solid phase, no volatile organic solvents are
11 required. This inunediately makes the process more environmentally friendly. There
is a major push in modern organic synthesis to make processes as green as possible
and the limitation of solvent is a significant goal in this pursuit. Solid state chemistry
is also very useful if one of the reacting compounds is unstable at higher temperature.
This method allows energy to be imparted to the reaction without significant risk of thennal decomposition.
f. Baylis-Hillman Reaction
The reaction that was chosen to be studied using HSBM was the Baylis
5 27 Hillman reaction (figure 8i - . In this reaction, an aldehyde is reacted with a
deactivated alkene (often an a-f3 unsaturated carbonyl), to fonn an allylic alcohol in
the presence of a tertiary amine catalyst (figure 8). One commonly used catalyst is
I,4-diazabicyclo[2.2.2]octane (DABCO). This reaction is very useful because the
resulting compound has mUltiple functional groups. It can be used quite effectively in
the synthesis of complex molecules, including as potential pharmaceutical targets.
While it certainly is possible to vary the nature of the aldehyde in this reaction, for the
purpose of this project, p-nitrobenzaldehyde was exclusively used. Also, DABCO
remained constant as the catalyst and the nature of the milling process remained the
same. Other researchers have looked at the effect of ball size and ball material, but in
28 this set of experiments a 1/16" chrome steel ball was exclusively used . The factors
that were varied from experiment to experiment were the nature of the electron
withdrawing group (EWG) and the nature of the beta-substituent on the alkene.
12 o EW3 OH R)lH + I DABCO ... EWG yr R y
Figure 8 - Baylis Hillman Reaction Scheme
II. Experimental Methods a. General Methods
All reagents were purchased from Aldrich Chemical Company and used without further purification. Solvents were purified through an MBraun solvent purification system, except for DMSO which was purchased in a Sure Seal bottle from Aldrich
Chemical Company. Infrared spectra used for general identification were taken with a Nicolet/Thermo Electron Avatar 370 FTIR spectrometer. Nuclear magnetic resonance spectroscopy was performed on a Bruker Avance 250 MHz NMR spectrometer for organometallic species and on an AC 250 general purpose spectrometer for allylic alcohols in deuterated chloroform. Microwave reactions were performed using a CEM Discover LabMate™ single-mode microwave instrument purchased from CEM Corporation. Reactions were performed in 10mL Pyrex tubes equipped with a stir bar and sealed with a Teflon/silicon septum. b. Ferrocene
The method for the synthesi s of ferrocene was derived from the literature preparation
29 and modified to work under microwave conditions . Each ofthe two steps in the synthesis of ferrocene was independently conducted in the microwave.
13 3o Dicyc10pentadiene was cracked under conventional conditions . The isolated monomer was stored in the freezer until used. i. Pre-cracked Cp-H
To a ]OmL microwave vial, 0.17 g (0. 85mmoIes) ofiron(II) chloride and 2mL of
THF (solvent) were added. Potassium hydroxide (0.753 g, 13.5 mmol) was then added and the vial was capped and degassed by purging with nitrogen. Cracked cyc10pentadiene monomer (0.14mL, 1.7mmol) was then injected through the septum.
The mixture was then subjected to microwave conditions (300 W, 90°C, 5 minutes).
The resulting solution was qualitatively tested for ferrocene by comparing thin layer chromatography against purified ferrocene. The general method was repeated using toluene, acetonitrile, water, DMSO, and nitrobenzene as the solvent. The method was also repeated using potassium t-butoxide (1.5] g, ]3.5mmol) in place of potassium hydroxide. ii. Microwave Cracking of Cp-H
Uncracked dicycIopentadiene (~5mL) was place in a microwave vial. The vial was then subjected to microwave conditions (300W, 90°C, 5 minutes). The resulting compound was then tested by proton NMR to determine the relative abundances of the monomer versus the dimer with up to 15% monomer being generated in situ. Also, uncracked cyc10pentadiene (~2mL) was added to 3 mL of
DMSO to test the effect of solvent on the cracking process. The solution was tested by NMR and monomer was not detected in significant amounts.
14 iii. Ferrocene synthesis (single pot)
To a 10mL reaction vial equipped with a magnetic stirrer was added FeCh'4
H20 (0.21 g, 1.1 mmo1) and finely ground KOH (0.78 g, 14 mmol, 13 eq.). The vial was sealed with a septum cap and allowed to purge under nitrogen for 10 minutes.
DMSO (5mL) and dicyc10pentadiene (0.50mL, 3.7 mmol, 7 eq. ofCp-H) were added to the reaction vial and the vessel was subjected to microwave conditions.
Microwave temperature and time were varied around the ideal cracking conditions
until optimum conditions were found (175°C, 45 minutes, 300 watts). Upon
completion, the reaction was allowed to cool to room temperature and poured over ice
(approximately 10 g). The solution was then neutralized with 10% HCl. It was then
placed in a separatory funnel and extracted with 3 X 10mL hexanes. The hexanes
solutions were combined, dried over MgS04, filtered, and concentrated in vacuo to
give purified ferrocene. Production offerrocene was confirmed by NMR comparison
to commercially available ferrocene. An average yield of 70% conversion to
ferrocene was achieved.
b. Diene-iron-tricarbonyls
i. Microwave with Fe(CO)s
THF (3mL) was added to a degassed microwave vial via syringe. Iron
pentacarbonyl (0.20mL, 1.5mmol) and 1,5 cyclooctadiene (0.37mL, 3.0 mmol) were
added to the vial via syringe and the reaction was placed under microwave conditions
(lOOoe, 1 hour, 300 W). The resulting reaction mixture was analyzed by IR
(additional materials). Using the same reagents, the time of reaction was increased to
15 4 hours to increase the degree of conversion. Exact yields are not reported because the product was unable to be isolated. ii. Microwave with Fe2(COh
Fe2(CO)9 (0.27 g, 0.75mmol) was added to a degassed microwave vial containing 3mL of THF. 1,5 cyclooctadiene (0.37mL, 3.Ommol) was added to the mixture via syringe and the reaction was placed under microwave conditions (lOO°C,
1 hour, 300 W). Results were monitored by 1R (additional materials). No yield is reported because the product was not able to be isolated. iii. NMO without Microwave
N-methyl morpholine (1.2 g, 12 mmoles) was added to approximately 10mL
THF and the mixture was degassed with nitrogen in a 1OOmL round bottom flask.
Tropone (0.58 mL, 6.0 mmol) and iron pentacarbonyl (0.40mL, 3.Ommol) were
syringed in through the septum. The mixture was allowed to stir at room temperature overnight. The contents of the reaction were monitored by 1R. Product was not able to be isolated so percent yield could not be determined.
c. Synthesis of Allylic Alcohols
DABCO (0.34 g, 3.Ommole) was added to a specially constructed metal screw
top vial already containing 1/16" metal ball. 4-Nitrobenzaldehyde (0.45 g,
3.Ommoles) was then added to the vial and an equimolar amount of the alkene to be
tested was also added. The reaction vial was then sealed with a screw-on lid with a
rubber o-ring to prevent leakage. The vial was placed in the mill, tightly clamped
into place and allowed to react for 16 hours. Upon completion, the solid was
extracted from the vial using dichloromethane (3X 5mL). The resulting solution was
16 run through a silica gel column with an attached UV detector and the remaining starting material was separated from the product. Solvent was then removed via rotary evaporation and each UV active peak from the column was then tested by
NMR. Results for specific alkenes are reported in tables 1 and 2.
Results and Discussion a. Ferrocene
The first task in the synthesis of ferrocene was to determine whether each of the steps in the synthesis of ferrocene could actually occur in the microwave and, if so, under what conditions the process would be optimized. Solubility of the reactants was a limiting factor when looking at the reaction of cyclopentadiene monomer with iron(II) chloride. The traditional method called for the iron compound to be dissolved in DMSO while the base was suspended in THF. Initial attempts to utilize THF as a solvent proved unsuccessful due to the lack of solubility of the iron compound.
Eventually DMSO was determined to be the ideal solvent for the reaction due to the solubility all compounds as well as its favorable microwave properties. Initially nitrobenzene was also thought to be a good solvent for the reaction. However, nitrobenzene proved to be explosive when used in the microwave with the iron complex. Also, the difference between using KOH and KOtBu was found to be negligible. Therefore KOH was preferred as it is significantly less expensive.
The cracking process in the microwave did not occur to the degree to which it was hoped. The appearance of the monomer was signaled by the appearance of peaks at 6.4 and 6.5 ppm (Supplemental 1). Cyc10pentadiene also results in a peak around
2.8 ppm, but that peak was not examined because it is masked by dicyclopentadiene
17 signals. The diagnostic peaks used to monitor the disappearance of the dimer were at
5.9 and 5.5 ppm (Supplemental 2). The conversion from dimer to monomer is not thermodynamically favorable and equilibrium conditions favor the dimer. In the traditional sequence, the reaction is driven toward the monomer side by continuously removing the monomer by distillation. Therefore, the equilibrium continues to shift in that direction by Le Chatelier's principle. Since there is no way to remove the monomer from the sealed vial while under microwave conditions, the equilibrium remains in favor of the dimeric form. Despite this pitfall, it was shown by NMR that the monomer is formed in solution to some extent in the microwave, with up to 15% conversion to monomer (supplemental 3). Attempts to increase the production of monomer by using solvent proved unsuccessful and significantly diminished production of monomer.
In the single pot ferrocene synthesis, the strong base should be able to take advantage of Le Chatelier's principle to move the reaction towards the product. As soon cyclopentadiene monomer is formed, it should be deprotonated by base in solution, thus creating a driving force to overcome the thermodynamically unfavorablity of the cracking. Another method to overcome this potential pitfall is to
use an excess amount of dicyclopentadiene compared to the amound of iron(II)
chloride. Since the relative cost of dicyclopentadiene is low compared to the iron
containing compounds, using excess DiCp to increase the yield of ferrocene is
certainly feasible.
Once both parts of the ferrocene reaction had been verified to take place in the
microwave, the next step was combining the steps into a one pot process. Since the
18 cracking process required more energy, the ideal cracking conditions were used as the starting point for finding the best conditions for the reaction as a whole. Maximizing the yield required using a significant excess of dicyclopentadiene (7 equivalents) to make up for the unfavorable equilibrium. H-NMR showed a peak at 4.2 ppm, which was identical to comercially available ferrocene (supplemental 4). The ideal temperature for maximizing the yield of the reaction was 175°C. Equivalent reactions run at 150°C saw a significant decrease in the amount of product formed.
At 175°C, 70% was the average yield, while at 150°C no more the 30% yield was achieved. When analogous reactions were run at 200°C did not show any increase in product (65% yields). In addition, 45 minutes seemed to be the time at which maximum product was obtained. There was a significant increase in product going from 30 to 45 minutes (45% to 70% yield). However with any reaction, an increase in time can cause unwanted side reactions to occur. Forty-five minutes seemed to be the right balance to maximize product formation while still not allowing unwanted side products to form. Using this optimized method an average yield of 70% was obtained in 45 minutes of reaction time. While the yield is not quite as high as traditional preparations, the time required for the reaction to occur was reduced from
4-6 hours down to 45 minutes. However, this reaction often proved inconsistent.
More recently, a more efficient and consistent 2-step reaction for the synthesis of
3l ferrocene has been discovered . The first step is the cracking and deprotonation of the cyc10pentadiene in the microwave for only 5 minutes. Then the anion is added to the iron(JI) chloride and no further irradiation is needed. After an additional 5 minutes at room temperature the reaction is complete and gives an 89% yield.
19 b. Diene-Iron Carbonyl
The reaction of 1,5 cyclooctadiene with iron pentacarbonyl was shown to occur to a significant degree in the microwave. Iron pentacarbonyl shows a strong IR
l stretch 1995 cm· . Diene-iron carbonyl product's marker peak appears in the IR
l around 2025 cm· . When the reaction was run at 100°C for four hours with a 2: 1 diene to iron ratio, the product and starting material indicator peaks were approximatly equal in strength (supplemental 5). When that ratio was increased to
4: 1, the iron-diene tricarbonyI peak significantly increased in intensity relative to the starting material peak (supplemental 6). A similar reaction was performed using 1,3 cycIooctadiene. The indicator peak for the I ,3-diene iron complex appears at 2044
l cm· . This reaction was also shown to occur under similar conditions (supplemental
7). Relative yields for the 1,3 species potentially could be increased by employing the same methods as were used on the 1,5 species, namely increasing the diene to iron ratio and increasing the time of the reaction.
Substituting the theoretically more reactive Fe2(CO)9 for Fe(CO)5 did not significantly increase the extent to which the reaction occurred (supplimental 8). The product peak was still observed at 2044 em') but the intensity of the stretch was not large than in the monoiron case. Since the reaction is taking place over a shorter period of time in more intense energetic conditions, the difference in the reactivities of the monoiron and diiron species is negligible. Therefore the cheaper and safer monoiron compound can used without losing reactivity under these circumstaces.
20 The nonmicrowave reaction of the iron pentacarbonyl with tropone using
NMO was shown to give product. Tropone iron tricarbonyl appears in the IR at 2019
I I I cm- and 2004 cm- while iron pentacarbonyl starting material shows up at 1995 cm- .
When the reaction was allowed to run over night, product was formed to some extent
(supplimentaI9). Efforts to fully quantify the product have been unsucessful thus far.
By IR, some level of conversion is estimated to have occurred under these conditions, but the extent of the conversion could not be determined. By increasing reaction times or increasing the number of equivalents ofNMO, reactivity could potentially be increased and more product formed. c. Allylic Alcohols
For the Baylis-Hillman reaction, reactivities were largely dependent on the nature of the electron withdrawing group attached to the alkene (Table 1). The allylic nitrile (A) and sulfone (B) proved to be the most reactive due to their strong electron withdrawing nature. While 12% and 6% are poor yields for the ester (A) and amide
(B) respectively, they are improvements over previously reported solid state synthesis attempts for these compounds25 (Supplemental 10).
21 Table 1 - Electron Withdrawing Group Variation
Reaction Alkene Product Yield
OH ° A I~ OCH 12% (OCHJ 3 .-::/ °2 N ° B NH NH 6% ( 2 ff! 2 °2 N (CN CN C I~ 37% .-::/f °2 N
II~o ° ° 11",,0 D m 48% (s, I "'" (S,OH I OH .-::/ °2 N ° E OH lOH N.R. r °2 NdY
When the reaction was run with a carboxylic acid as the EWG, none of the desired product was formed. It was determined that before the Baylis-Hillman reaction could take place an acid base equilibrium was established with the DABCO catalyst, effectively preventing the desired reaction (figure 8).
22 H o I .. C~) 2 (OH+ C?) 2(0 I H
Figure 8- Acid Base side reaction of carboxylic acid
A second series of experiments was conducted to determine the effect of adding a beta-substituent to the alkene (Table 2). Since the first step of the proposed mechanism is the catalyst attacking the beta-position, a significant decrease in rate would be expected when adding steric bulk. For both the ester (F-H) and the nitrile
(l-K) , yields were drastically reduced when steric hindrance was placed on the beta position. For the ester, no discernable difference was seen between the methyl (G) and the phenyl (H) case but both were drastically reduced from the hydrogen case (F).
This is because the reactivity was so greatly reduced that on the time scale of the reaction, there was less than 1% difference in their rates. However, if the reactions were allow to react for longer, a greater yield should be achieved in the methyl case because it is a less effective steric blocker than a bulky phenyl group. This is supported by the relative yields in the nitrile reactions. The methyl group (1) caused a significant reduction in the yield of the reaction due to its steric bulk. Adding the phenyl group (K) slowed the reaction down even further. The main conclusion that can be drawn from this is that adding any steric bulk to the beta-position results in a large scale reduction of reactivity, even when the steric blocker is a relatively small methyl group.
23 Table 2 - Steric Effect on Allylic Alcohol Formation
Reaction I Alkene I Product I Yield ° OH ° F I ~OCH31 12% CH3 rO °2 N ° ° G I 1('" l OCH 2% 3 lOCH3 I °2 N ~ °l 3 -OCH 3 I H OCH I )J 2% ~ ~ I 1 °2 N
24 Conclusions
Through this series of experiments, it has been shown that simple convection heating is not the only way to impart energy to a chemical system. Microwave radiation had the potential to be an immensely powerful tool for future synthesis. In
some cases the reaction times can be'reduced 10 fold opening extensive new doors for
future synthetic pathways. Reactions that seemed unattainable due to kinetic barriers can now be potentially conducted on realistic time scale. As this project showed, the
utility is not limited to strictly organic compounds. Metal containing species are
certainly potential targets that can be obtained in the microwave, Also, this project
showed that mechanical energy can also be used chemically. While the scope of
usefulness is somewhat limited in the HSVM case, potential uses do still exist.
Overall this project helped to show that there are nontraditional ways of conducting
experiment that can be extremely powerful under the right circumstances.
25 References
1. Kealy, T. J; Pauson, P. 1. Nature 1951,168,1039.
2. Miller, S. A.; Tebboth, 1. A.; Tremaine, 1. F. J Chern. Soc. 1952,632.
3. Wu, 1. and 1. F. Hartwig, Mild Palladium-Catalyzed Selective Monoarylation ofNitrites. 1. Am. Chern. Soc., 2005.127(45): p. 15824-15832.
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5. Developments in Catalytic Aromatic C-H Transfonnations: Promising Tools for Organic Synthesis" Goj, 1., Gunnoe, T. B. * Curro Org. Chern. 2005, 9, 671-685.
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27 Supplimental Materials
1. H-NMR of Cyclopentadiene
2. H-NMR of Dicyclopentadiene
3. H-NMR ofCp-H DiCp mixture from microwave cracking
4. Ferrocene H-NMR
5. 1,5 cyclooctadiene with Fe(CO)5 2:1 ratio lR spectrum
6. 1,5 cyclooctadiene with Fe(CO)s 4: 1 ratio IR spectrum
7. 1,3 cyclooctadiene with Fe(CO)5 IR spectrum
8. 1,3 cyc100ctadiene with Fe2(CO)9 IR spectrum
9. Tropone with Fe(CO)5 using NMO IR spectrum
10. Nitrile Baylis-Hillman Product H-NMR
28 (") '0 t-> N
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