Jennifer Davis
Gaston Bonenfant
Scott Zellmer
Organic Chemistry Lab: 102
Special Library Project
Synthesis Paper
March 23, 2012
Proton Abstraction from 4-Picoline through a Palladium Catalyst to
Yield 4,4’-Dimethyl-2,2’-Bipyridine
Introduction/Purpose:
The function of 4,4’-Dimethyl-2,2’-Bipyridine is to act as a carrying agent able to
complex with a separate molecule in order to form functional groups through the process
of photoreactivation. 2,2’-Bipyridines are often used as ligands and as such are versatile
in organometallic and inorganic chemistry.7
Liglands are a substance that can complex with an additional bimolecule for
some biological and mechanistic purpose. Essentially, it is a signal triggering
molecule that binds to a site on a target protein. The binding of a receptor alters its
chemical conformation in turn determining the ligland functional state. 13
When a bipyridine ligand is attached to a ruthenium complex in the presence of
blue light, the ruthenium ion looses an electron to the surrounding functional groups,
making the compound unstable. This new unstable complex is an outstanding oxidizing
agent and is able to produce a desired purpose.10 For example, 4,4’-Dicarboxy-2,2’Bipyridine, an easy transition from 4,4’-Dimethyl-2,2’-Bypridine, is employed as an
essential ligand for the dye-sensitized solar system of ruthenium.8 Organic dyes can
generate electricity at oxide electrodes in electrochemical cells.9
4,4’-Dimethyl-2,2’-Bipyridine is being synthesized for the purpose of Dr.
Contakes research. It is his desire that in the future the synthesized compound is to be
complexed with a ligand and tested for a specific purpose, similar to the example above.
Chosen Procedure:
The overall chosen scheme/reaction and mechanism for the synthesis of 4,4’Dimethyl-2,2’-Bipyridine is shown bellow.
*Overall reaction
*Reaction Mechanism
10g of 4,4’-Dimethyl-2,2’-Bipyridine will be synthesized in accordance to a
previous journal entry by Sprintschnik published in 1977.1 To begin, 175mL of freshly
distilled 4-picoline ($0.71/g) and 7g of palladium on 10% charcoal is refluxed for 72
hours. The reflux is set using a boiling flask and water jacket. The mixture is under
constant boiling in conjunction with a magnetic stir bar. Using this refluxation method,
the palladium catalyst pulls electrons away from the pyridine nitrogen in effect
weakening the nearby C-H bonds. This bond weakening facilitates H abstraction.3
After having refluxed for approximately three days, 62.5mL of hot toluene is
added and the reflux is continued for an additional half hour. The mixture is then filtered
from the palladium catalyst while the solution is still hot. The filtrate is evaporated and
concentrated in vacuo to approximately 75mL. Recrystallization form ethyl acetate
finally yields 10g of colorless crystals, which is the desired 4,4’-Dimethyl-2,2’Bipyridine product.1
It is important to note that the above method borrowed form Sprintschnik was
originally designed for synthesizing 40g of 4,4’-Dimethyl-2,2’-Bipyridine. In the above
procedure the reactants are modified and scaled to yield approximately 10g of product.
Because of this, all the reactant quantities in the article were divided by a quarter.
An additional note is this is a crude experiment involving cheap reactants and a
simple mechanism. With this is mind it makes since that the synthesized percent yield is
very low. The expected value is a mere 6.06%. Theoretical yield is calculated to be 165g
with 4-picoline acting as the limiting reagent.
Sprintschnik’s journal article provided physical data for the synthesis of 4,4’Dimethyl-2,2’-Bipyridine. They are as follows: MP 175-179°C. NMR spectrum (in
CDCl3): d at 8.54, t at 8.24, dq at 7.14, and s at 2.42.1 A second article by V. Alexander
provided further spectral data for comparison. MP 174 °C. 1H NMR (400 MHz, CDCl3,
298 K): δ2.42 (s, CH3, 6H), 7.45 (d, H5,5’, 2H), 7.66 (t, H6,6’, 2H), 8.52 (d, H3,3’, 2H). 13C
NMR (100 MHz, CDCl3, 298 K): δ21.0, 121.9, 124.5, 132.9, 148.8, 155.9. Mass Spec:
m/z 183 (M+). 2 No information on IR was provided through the obtained articles.
However, using the organic laboratory technique textbook, predicted IR absorptions
include 1500-1700 cm-1, 680-860, ~3300, 3300-3500, and 2850-2950. 12
Alternative Methods:
Method #1: Transformation of 2-Amino-4-Methylpyridine to Yield 2-Bromo-4Methylpyridine, a Precursor of 4,4’-Dimethyl-2,2’-Bipyridine
One equivalent method to that above included two different procedures in order to
produce the intermediate product, 2-Bromo-4-methylpyridine. This intermediate can be
used to create the final product, 4,4’-Dimethyl-2,2’-Bipyridine. Because the intermediate,
2-Bromo-4-methylpyridine, is fairly expensive ($34.30/g), it is more cost effective to
generate the compound from cheaper materials.
The synthesis involves 17mL of bromine ($0.04/mL) added to a solution
containing 12g of 2-amino-4-methypyridine ($0.30/g) in 70mL of 47% HBr. 21g of
sodium nitrite ($0.07/g) in 115mL of water is added to the previous reaction mixture at a
temperature below 25°C. The oil that results is extracted with ether and distilled in vacuo.
15g of liquid product is obtained resulting in a 77% yield.4 The 15g of synthesized
product costs approximately $5.75 instead of purchasing a pre-prepared version at over
$450.00.
To create the final product, 4,4’-Dimethyl-2,2’-Bipyridine, zinc dust ($0.38/g) is
added to a solution of dry THF, Et4NI, & Ni(PPh3)2Cl2 ($3.86/g) under argon. The
mixture is heated to 50°C and 2-Bromo-4-methylpyridine in THF is added. The reaction
is allowed to sit for 12 hours at 50°C upon which the mixture is poured over 2M aqueous
ammonia. It is then filtered and washed with equal amounts of ether and benzene. The
organic layer can then be separated, washed with water and aqueous sodium chloride,
dried over anhydrous magnesium sulfate, and evaporated. Purification involves silica-gel
column chromatography (neutral, 100-200 mesh) using petroleum ether-ethyl acetate
(98:2, v/v) as the eluent.5
One problem with the above method is time. Compared to the selected method by
Sprintschnik, this reaction would most likely take an additional two days. In addition,
there is limited spectral data given in the article in regards to 2-Bromo-4-methylpyridine,
which is necessary to confirm the identity of the product.
Method 2: Formation of 2,2’-Bipyridyl by Ligand Coupling on the Phosphorous Atom
This method produced a high percent yield of 84% for the desired product 4,4’Dimethyl-2,2’-Bipyridine. However, it also accounted for a 17% yield of the by-product
4-methylpyridine. This clearly presents a problem because over a 100% yield is obtained.
With this in mind, the article may not be taken as seriously as others on the same subject.
The procedure presented was very simple and clear, however. 4,4’-Dimethyl-2,2’Bipyridine was produced through the coupling of 4-methyl-2-pyridiyl within the
phosphonium salt, benzyltri[2-(4-methylpyridyl)]phosphonium bromide. When this ion
undergoes nucleophilic attack with water on the phosphorous atom, a pentacoordinated
intermediate is formed that allows for ligand coupling.
The procedure includes the reaction of benzyltri[2-(4-methylpyridyl)] –
phosphonium bromide with dilute HCl at room temperature for 30 minutes. The addition
of NaOH makes the mixture slightly alkaline, and is then extracted with CH2Cl2.. The
organic layer is dried with Na2SO4 to obtain the product. No re-crystallization or
purification methods were proposed in this procedure. The product was subjected to GC
analysis to confirm its structure. An additional problem with this simple process is the
difficulty in finding the reactant benzyltri[2-(4-methylpyridyl)]phosphonium bromide.6
Method 3: Dehydrogenative Coupling of 4-Substituted Pyridines Catalyzed by
Diruthenium Complexes
The final proposed synthesis involves a ruthenium catalyst opposed to the
primarily suggested palladium catalyst. The synthesis of 4,4’-Dimethyl-2,2’-Bipyridine,
through a transition-metal-catalyzed cross-coupling reaction method. works by
dehydrogenative coupling of functionalized pyridines by way of direct C-H bond
activation in an alternative, economical, and environmental point of view. The reaction of
4-methylpyridine ($0.71/g) is catalyzed by diruthenium complexes, Cp*Ru(μ-H)4RuCp
and (Cp*Ru)2(μ-H)( μ-PMe2)( μ-C6H6). Prices for the exact diruthenium complex used
were not listed, however similar compounds were found, and can be regarded as too
expensive to purchase for this synthesis. This necessary reactant was found to be greater
than $194.80/g.
In addition to the difficulty of finding one of the necessary reactants, the synthesis
accounted only for a 50% yield within 20 hours. Very slight instructions were given in
regards to the way the experiment was carried out, and no additional properties for
product conformation were provided.
Discussion:
Although all of the procedures outlined above would synthesized the desired 4,4’Dimethyl-2,2’-Bipyridine, several problems, here addressed, lead to the selection of the
chosen method using 4-picoline refluxed with palladium on charcoal. The first alternative
procedure involves a large number of steps to yield the 4,4’-Dimethyl-2,2’-Bipyridine.
One in particular involves the synthesis of 2-bromo-4-methylpyridine that acts as a
primary starting material. (4, 5) The article provides no data analysis for 2-bromo-4methylpyridine making the possibility of error too great. Also, a large number of
reagents complicate the procedure indicating that this synthesis is not the best option.
In the second alternative procedure, the inability to obtain the phosphonium salt,
benzyltri[2-(4-methylpyridyl)]phosphonium, that acts as the starting material renders this
procedure unrealistic. Regardless of the fact that the synthesis of 4,4’-Dimethyl-2,2’Bipyridine is an extremely simple procedure requiring little time and common reagents
with a high percent yield of 84%. (11)
The third alternative method follows a similar mechanism found in our selected
synthesis, yet the cost of the diruthenium complexes, Cp*Ru(μ-H)4RuCp & (Cp*Ru)2(μH)( μ-PMe2)( μ-C6H6) that catalyze the reaction are far too expensive as it ranges around
$190/g. (7) In addition, the experiment also gives a relatively low yield of 50% while
using costly reagents with a limited procedure description. The lack of any product
analysis data, in addition to these other difficulties, places this procedure in an
unfavorable light. The exorbitant costs, inconveniently long reaction times, incomplete
instructions, or lack of product confirming data for the alternative procedures makes our
selected synthesis procedure the preferred option.
The refluxing of 4-picoline with 10% palladium on charcoal provides a cost
effective and simple procedure. Our selected procedure produces a relatively low yield
of 6.06%, however the benefits far outweigh this negative aspect. 4-picoline costs
$33.90/50-mL from Aldrich Chemicals and only 175mL is required in the chosen
procedure. The price of palladium over charcoal is not included because the Westmont
laboratory already owns some of this reusable catalyst. Therefore, the overall cost of the
selected synthesis totals $135.60. Toluene and ethyl acetate are also relatively
inexpensive and are available at the laboratory site. Sprintschnik’s article also provided a
wealth of spectral data confirming the product including melting point, H1-NMR, C13NMR, and mass spectroscopy. The synthesis of the final product, 4,4’-Dimethyl-2,2’Bipyridine, is simple in comparison to the other methods. It is a “brute-force” method
where the molecules are heated and forced to combine. (10)
Works Cited:
1
Sprintschnik, G.; Sprintschnik, H.W.; Kirsch, P.P.; Whitten, D.G.; Journal of the American
Chemical Society, 1977, 99 (15), 4947-4954, “Photochemical reactions in organized
monolayer assemblies. 6. Preparation and photochemical reactivity of surfactant
ruthenium(II) complexes in monolayer assemblies and at water-solid interfaces”
2
Alexander, V.; Rajalakshmanan, E.; Synthetic Communications. 2005, 35, 891-895.
“Synthesis of Dimethylbipyridines by the Reductive Coupling of 2-Halomethylpyridines with
Nickel Catalyst”
3
Neal L.M., Everett M.L., Hoflund G.B., Hagelin-Weaver H.E., Journal of Molecular
Catalysis A: Chemical, 2010, 335, 210-221, “Characterization of palladium oxide catalysts
supported on nanoparticle metal oxides for the oxidative coupling of 4-methylpyridine.”
Case, F.; Temple University, 1946, 68, 2574-2577, “The Synthesis of Certain Substituted
2,2’-Bipyridyls”
5
Rajalkshmanan, E.; Alexander, V.; Synth. Comm. 2005, 35, 891-895. “Synthesis of
Dimethylbipyridines by the Reductive coupling of 2-Halomehtylpyridines with Nickel
Catalyst”
4
de França, K.W.R.; Oliveira, J.L.; Florêncio, T.; Silva, A.P.; Navarro, M.’ Léonel, E.;
Nédélec, J.Y.; J. Org. Chem. 2005, 70, 10778-10781. “Mixed Effect of the Supporting
Electrolyte and the Zinc Anode in the Electrochemical Homocoupling of 2-Bromopyridines
Catalyzed by Nickel Complexes in an Undivided Cell.”
6
7
Kawashima, T.; Tako, T.; Suzuki, H.; J. AM. Chem. Soc. 2007, 129, 11006-11007.
“Dehyrogenative Coupling of 4-Substitited Pyridines Catalyzed by Diruthenium Complexes”
O’Regan. B.; Grätzel. M. Nature 1991. 353. 737-740, “A low-cost, high-efficiency solar
cell based on dye-sensitized colloidal TiO2 films”
8
9
Gerischer, H.; Michel-Beyerle, M.; Rebentrost, E.; Tributsch, H. Electrochemica Acta,
1968, 13, 1509-1515, “Sensitization of Charge-Injection into Semiconductor with Large
Band Gap”
10
Contakes, Stephen. Personal Interview. 22-03-2012.
11
Kozawa, H; Uchida, Y.; Pergamon Press. 1989, 30, 46, 6365-8. “Formation of 2,2’bipyridyl by Ligand Coupling on the Phosphorous Atom”
12
Pavia, Donald, Gary Lampman, George Kriz, and Randall Engel. Introduction to Organic
Laboratory Techniques: A Microscale Approach . 4. Belmont: Brooks Cole, 2006. 851. Print.
13
Wikipedia contributors. "Ligand (biochemistry)." Wikipedia, The Free Encyclopedia.
Wikipedia, The Free Encyclopedia, 21 Mar. 2012. Web. 23 Mar. 2012.