The Grignard Reaction

Definition:

"The Grignard reaction is an organometallic chemical reaction in which alkyl- or aryl- magnesium halides (Grignard reagents) add to a carbonyl group in an aldehyde or ketone. This reaction is an important tool for the formation of carbon-carbon bonds. The reaction of an organic halide with magnesium is not a Grignard reaction, but provides a Grignard reagent."

https://en.wikipedia.org/wiki/Grignard_reaction

Who discovered it?

During the early 1900s, a French chemist by the name of François Auguste Victor Grignard was conducting research into this reaction and its reagents at the University of Nancy in France. He went on to become the recipient of the Nobel Prize in Chemistry in 1912.

What is organometallic chemistry?

Organometallic chemistry is, as the name suggests, the study of compounds containing carbon-metal bonds with largely covalent character. Naturally this incorporates a combination of aspects from both inorganic and organic chemistry.

Forming Grignard reagents

The simple answer is through the reaction between an alkyl/aryl halide with magnesium (solid) which takes place in an etherial solvent to produce ligands. A ligand is a functional group that binds to a central metal atom to form a coordination complex - typically through the donation of the ligand's electron pairs. In this case, the halide ion is the ligand. The reaction initially begins as a single electron transfer (or one-electron reduction) until the Grignard formation reaction, where a second electron transfer occurs, turning free radicals into carbanions.

R−X + Mg → R−X^•− + Mg^•+

R−X^•− → R^• + X⁻

R^• + Mg^•+ → RMg⁺

RMg⁺ + X^- → RMgX

Grignard reagents do not react readily with alkyl halides through an S_N2 mechanism due to a problem in the initiation stage. However, they do readily undergo transmetalation reactions: RMgX + ArX → ArR + MgX₂ 

Most Grignard reagents (e.g. methylmagnesium bromide/chloride, phenylmagnesium bromide etc.) are commercially available as tetrahydrofuran (THF) or diethyl ether solutions. 

Grignard reaction mechanism

Grignard reaction mechanism

The Grignard reagent behaves as a nucleophile, attracted to the electrophilic carbon atom that exists between the polar bond of a carbonyl group. The addition of the Grignard reagent to the carbonyl usually happens through an intermediate of a six-membered ring state.

Industrial application

In the process described above, the Grignard reagents formed are used in the production of organometallic compounds and primary materials/intermediates for agrochemicals and pharmaceuticals.

Organometallic compounds:

1. Organotin compounds - Grignard reagents and tin tetrachloride. Its two main uses are: to stabilise vinyl chloride resins and to catalyse the hardening of urethane/silicon resin.
2. Organosilicon compounds - Grignard reagents and appropriate raw silicon compounds produces different types of symmetric/asymmetric di-, tri- and tetra- organosilicon compounds. They are used as intermediates in pharmaceutical synthesis and as protective groups in organic synthesis.
3. Organophosphorus compounds - an example being the phosphine compound (Grignard reagents + halide phosphates) which are used for vitamin synthesis, the additives for various synthetic resins and other industrial applications.

Combatting Parkinson's

The synthesis of biperiden (an antiparkinsonian agent) involves the nucleophilic addition of acetylnorbornene with a suitable Grignard reagent - plus water to form the final product.

Potential New Medicines: A Brief Introduction

With the recent advances in technology, it's only reasonable to presume that an increase in the number of cures and medicines must come in tandem. Therefore, medical researchers are always on the lookout for new sources of drugs and medicines. In this search, two considerations must be taken into account: the usage of accessible, commonplace (hence cheap) plants and the need to maintain biodiversity. Here are two examples:

The 20 naturally-occurring "essential" amino acids

For the first time, as recently as 2011, scientists have developed a means of introducing man-made/unnatural amino acids (i.e. not from the 20 naturally occurring amino acids) to proteins in multiple locations using bacteria they had created. This finding is particularly useful for engineering bacteria that produce new types of synthetic chemicals, through protein synthesis. Crucially, it introduces the possibility of making medicines/drugs that last longer in the blood stream.

Catharanthus pusillus (Tiny Periwinkle)

Recently, the discovery of natural drugs has concentrated on tropical "rainforest" plants due to their great diversity. Around 120 prescription drugs sold worldwide today come from rainforest plants directly. Furthermore, it was claimed that two-thirds of all medicines which were found to have cancer-preventing properties came from the rainforest by the U.S. National Cancer Institute. An example is the now-extinct periwinkle plant from Madagascar, which increased the chances of survival of kids with leukaemia from 20% to 80%.

The last steps of medicine production are: clinical trials and bringing them to market, which together take several years, if not decades. A majority of this time is taken up by testing. In fact, each drug on the shelf costs £60 billion to produce, taking all research and preceding failed drugs into account.

Immunity Without Exposure

When a new bacterium or virus invades the body, the immune system mounts a "counter"-attack by sending in white blood cells called T-cells that are tailored to the molecular structure of that invader. Defeating the infection can take several weeks. However, once victorious, some T-cells stick around, turning into memory cells that remember the invader, reducing the time taken to kill it the next time it turns up.

Conventional thinking has it that memory cells for a particular microbe only form in response to an infection. "The dogma is that you need to be exposed," says Mark Davis of Stanford University in California, but now he and his colleagues have shown that this is not always the case. The team took 26 samples from the Stanford Blood Center. All 26 people had been screened for diseases and had never been infected with HIV, herpes simplex virus or cytomegalovirus. Despite this, Davis' team found that all the samples contained T-cells tailored to these viruses, and an average of 50 per cent of these cells were memory cells.

The idea that T-cells don't need to be exposed to the pathogen "is paradigm shifting," says Philip Ashton-Rickardt of Imperial College London, who was not involved in the study. "Not only do they have capacity to remember, they seem to have seen a virus when they haven't."

Electron microscope image of the H1N1 influenza virus,
which are 80-120 nanometres in diameter.

So how are these false memories created? To a T-cell, each virus is "just a collection of peptides", says Davis. And so different microbes could have structures that are similar enough to confuse the T-cells. To test this idea, the researchers vaccinated two people with an H1N1 strain of influenza and found that this also stimulated the T-cells to react to two bacteria with a similar peptide structure. Exposing the samples from the blood bank to peptide sequences from certain gut and soil bacteria and a species of ocean algae resulted in an immune response to HIV.  The finding could explain why vaccinating children against measles seems to improve mortality rates from other diseases. It also raises the possibility of creating a database of cross-reactive microbes to find new vaccination strategies. "We need to start exploring case by case," says Davis.

"You could find innocuous pathogens that are good at vaccinating against nasty ones," says Ashton-Rickardt. The idea of cross-reactivity is as old as immunology, he says. But he is excited about the potential for finding unexpected correlations. "Who could have predicted that HIV was related to an ocean algae?" he says. "No one's going to make that up!"