John Goodwin
Abstract
Since Victor Grignard discovered his Grignard reagent 110 years ago, these organomagnesium compounds have been highly utilized in synthetic organic chemistry.
These reagents have proven to be a highly effective method for forming a carbon-carbon bond. The reaction, its history, and its application will be explored in this paper.3
Introduction
The Grignard Reaction is a carbon-carbon bond forming reaction involving an
organomagnesium reagent capable of acting as a nucleophile. In the reaction the
organomagnesium compound attacks an electrophilic carbon in another molecule resulting in the
formation of a carbon-carbon bond.1
The R’MgBr reagent (shown above) is known as a Grignard reagent; this reagent is
synthesized by adding the desired halogenoalkane to small pieces of magnesium turnings in a
flask containing ethoxyethane and equipped with a reflux condenser. This mixture is then
warmed in a water bath for 20-30 minutes. This reaction must be carried out under dry conditions
because the Grignard reagent will react with water.1,2
Formation of Grignard Reagent
After the Grignard Reagent is prepared it is usually added slowly to a 0 degree Celsius solution
of the desired electrophile. Dry solvents must be used to dissolve the electrophile typically
tetrahydrofuran, diethylether, and dimethylsolfoxide are used. After addition of the nucleophilic
Grignard reagent the solution is warmed back up to room temperature.
The mechanism most likely proceeds through a cyclic transition state, although in some cases it
is believed that the mechanism involves the transfer of a single electron.3
Cyclic transition state of Grignard Reaction
Structure of the Grignard Reagent
In order to elucidate the structure of the Grignard reagent various structural studies have
been conducted on Grignard reagents, including Nuclear Magnetic Resonance (NMR), x-ray crystallography and x-ray absorption fine structure (XAFS). When NMR is used the structure is highly dependent on temperature, solvent, and concentration. In solution they usually will be ligated by two molecules of the solvent (providing they are able to do so) and the magnesium will assume a near tetrahedral geometry.7 Several crystal structures have shown, like the NMR,
that the metal is ligated by solvent molecules. But, crystal structures also suggest that sometimes
the reagents will form a dimer.7 XAFS data has shown that there is likely an equilibrium between
several structures depending on the R' group and the solvent the Grignard reagent was made in.5
History of the Reaction and Inventor François Auguste Victor Grignard, the man for whom the Grignard reaction is named, was born in Cherbourg, France on May 6, 1871. Grignard originally studied mathematics, but failed his licentiate exam and was unable to receive his degree. After failing his exam he took time to fulfill his military service, shortly after service he returned to the University of Lyons and earned his degree in mathematics. In the same year as receiving his degree he accepted a junior post under Philippe Barbier at Lyon. It was here that Grignard, directed by Barbier, began his work with organomagnesium compounds, which would later serve as the basis for his doctorial thesis. In 1909 he became the head of the department of organic chemistry at Nancy. His work at
Nancy was cut short when he was mobilized for WWI, where he was commissioned to work on chemical warfare agents. After the war he returned to Nancy and succeeded his mentor, Barbier, as Professor of General Chemistry at Lyons.
At the time of Grignard's death he had authored 170 academic papers and was in the process of publishing his “Treatise on Organic Chemistry”. Later his students published a textbook based on Grignard's organic chemistry lecture course.9
Prizes and Awards
Cahours Prize 1901 and 1902
Berthelot Medal 1902
Prix Jecker 1905
Lavoisier Medal 1912
Nobel Prize in Chemistry 1912
Applications
Grignard himself immediately began employing his reagents to make a series of complex alcohols, ketones, keto-esters, nitriles, and was able to devise a synthetic route to making fulvenes (compounds with the same molecular formula as benzene).8 The use of Grignard reagents was so popular, that at the time of his death in 1935 there were over 6,000 references to them in scientific works.9 The impact of his work was also noticed by the Nobel committee who
in 1912 awarded Victor Grignard the Nobel Prize in Chemistry for his work with
organomagnesium compounds.
The reaction is still utilized today in chemistry labs all over the world and is still a powerful tool
in synthetic chemistry. The reaction has found utilization in many industrial processes, including
the pharmaceutical industry, the agricultural, and in the perfume industry.3 Some examples of a
Grignard reaction's use in industrial processes is in the synthesis of dimethisterone( a
progesterone), chlorphenoxamine (an anti-parkinsoinian), and cyclofenil(selective estrogen receptor modulator ).6 An example of a Grignard reaction employed in the synthesis of
clortermine hydrochloride an anti-obesity drug is shown below.
First step in the synthesis of clortermine hydrochloride
Grignard Reactions forming C-X bond
Grignard reagents have also found utilization in forming carbon-heteroatom bonds. Grignard
reagents have been used to from bonds with carbon and several other heteroatoms including;
nitrogen, oxygen, phosphorus, sulfur and boron. The reaction procedure is very similar to that of
the carbon-carbon bond forming reaction.8
Stereoselective Grignard reactions
While the exact reasoning of what makes some Grignard reactions stereoselective and others not
is still not fully understood, there are several Grignard reactions in the literature that have been
found to proceed with stereoselectivity.3
An example of a Grignard reaction that proceeds with high stereoselectivity is the reaction of cyclopropenyl carboxylates with Grignard reagent. These compounds have two functional groups capable of reacting with the Grignard reagent. However the reaction was only found to open the three membered ring to form a stereodefined multi-substituted alkene.4
Many other examples of stereoselective Grignard reagents appear in the literature. Most of these
can be explained by steric hindrance of substituents blocking the reactive functional group.
Finding ways to control the stereoselectivity of Grignard reagents is currently an active area of
research in organic chemistry.4
Conclusion
In summary the versatility and utility of Grignard reagents make them a very powerful
tool in synthetic organic chemistry. While some challenges still remain in the field of
stereoselectivity these reactions are still employed in several applications 110 years after their
initial discovery. References
1. Grignard, V; Compt Redn 1900, v130, P1322 2. Grignard. V; Bulletin de la Societe Chimique de France 1926, V39,P1285-1321 3. Rakita, Philip E.; Silverman, Gary, ed.,Handbook of Grignard reagents, New York, N.Y 1996 4. Liu and Ma Chem. Sci., 2011,V 2,P 811 5. Ertel and Bertagnolli,Polyhedron Vol. 12, No. 18. pp. 2175-2184, 1993 6. Sittig, Marshall. Pharmaceutical Manufacturing Encyclopedia, Volume 1, Noyes Publishing New Jersey, 2004. 7. Guggenberger, L.J. and Rundle R.E. Journal of American Chemical Society 90:20, 1968 8. Victor Grignard - Nobel Lecture.Nobelprize.org.13 Apr 2011;http://nobelprize.org/nobel_prizes/ 1912 9. Victor Grignard - Biography. Nobelprize.org. 13 Apr 2011;http://nobelprize.org//1912/grignard-bio.html