Alkyl Halides

• The alkyl halides are a group of chemical compounds derived from alkanes containing one or more halogens.

• They are used as flame retardants, fire extinguishants, refrigerants, propellants, solvents, and pharmaceuticals.

• Alkyl halides can also be classified according to the connectivity of the carbon atom to which the halogen is attached-In primary,

secondary and trtiary alkyl halides.

Aryl halides

• Aryl halides are compounds like chlorobenzene - in which a halogen atom is attached directly to a benzene ring.

Grignard Reactions

• The Grignard reaction is an organometallic chemical reaction in which alkyl- or aryl-magnesium halides (Grignard reagents) act as nucleophiles and attack electrophilic carbon atoms that are present within polar bonds to yield a carbon-carbon bond, thus altering hybridization about the reaction center.

• The Grignard reaction is an important tool in the formation of carbon-carbon bonds and for the formation of carbon-phosphorus, carbon-tin, carbon-silicon, carbon-boron and other carbon-heteroatom bonds.

Grignard Reactions

Reaction Mechanism• Grignard reactions and reagents were discovered by and are

named after the French chemist François Auguste Victor Grignard (University of Nancy, France) who was awarded the 1912 Nobel Prize in Chemistry for this work.

• The addition of the Grignard reagent to the carbonyl typically

proceeds through a six-membered ring transition state.

Grignard Reaction conditions

• In a reaction involving Grignard reagents, it is important to ensure that no water is present, which would otherwise cause the reagent to rapidly decompose.

• Thus, most Grignard reactions occur in solvents such as anhydrous diethyl ether or tetrahydrofuran, because the oxygen of these solvents stabilizes the magnesium reagent.

• The reagent may also react with oxygen present in the atmosphere, inserting an oxygen atom between the carbon base and the magnesium halide group.

• Usually, this side-reaction may be limited by the volatile solvent vapors displacing air above the reaction mixture. However, it may be preferable for such reactions to be carried out in nitrogen or argon atmospheres, especially for smaller scales.

Synthesis of Grignard reagents • Grignard reagents are formed via the action of

an alkyl or aryl halide on magnesium metal.• The reaction is conducted by adding the organic

halide to a suspension of magnesium in an ether, which provides ligands required to stabilize the organomagnesium compound.

• Typical solvents are diethyl ether and tetrahydrofuran.

• Oxygen and protic solvents such as water or alcohols are not compatible with Grignard reagents. The reaction proceeds through single electron transfer.

Synthesis of Grignard reagents

– R−X + Mg → R−X•− + Mg•+– R−X•− → R• + X−– X− + Mg•+ → XMg•– R• + XMg• → RMgX

• Grignard reactions often start slowly. As is common for reactions involving solids and solution, initiation follows an induction period during which reactive magnesium becomes exposed to the organic reagents. After this induction period, the reactions can be highly exothermic. Alkyl and aryl bromides and iodides are common substrates. Chlorides are also used, but fluorides are generally unreactive, except with specially

activated magnesium, such as Rieke magnesium • Many Grignard reagents, e.g. methylmagnesium chloride,

phenylmagnesium bromide, and allylmagnesium bromide are available commercially in tetrahydrofuran or diethyl ether solutions.

Initiation• Many methods have been developed to initiate sluggish Grignard

reactions.• Mechanical methods include crushing of the Mg pieces in situ, rapid

stirring, and sonication of the suspension. Iodine, methyl iodide, and 1,2-dibromoethane are commonly employed activating agents.

• The use of 1,2-dibromoethane is particularly advantageous as its action can be monitored by the observation of bubbles of ethylene. Furthermore, the side-products are innocuous:

• Mg + BrC2H4Br → C2H4 + MgBr2

• The amount of Mg consumed by these activating agents is usually insignificant.

• The addition of a small amount of mercuric chloride will amalgamate the surface of the metal, allowing it to react.

• These methods weaken the passivating layer of MgO, thereby exposing highly reactive magnesium to the organic halide.

Reactions of Grignard Reagents with carbonyl groups

Reactions with other electrophiles

Formation of bonds to B, Si, P, Sn • Also the Grignard reagent is very useful for forming carbon-

heteroatom bonds.

Carbon-carbon coupling reactions • A Grignard reagent can also be involved in coupling reactions. For

example, nonylmagnesium bromide reacts with an aryl chloride to a nonyl benzoic acid, in the presence of . Ordinarily, the Grignard reagent will attack the ester over the aryl halide.

• For the coupling of aryl halides with aryl Grignards, nickel chloride in THF is also a good catalyst. Additionally, an effective catalyst for the couplings of alkyl halides is (Li2CuCl4), prepared by mixing lithium chloride (LiCl) and copper(II) chloride (CuCl2) in THF. The Kumada-Corriu coupling gives access to styrenes.

Oxidation• The oxidation of a Grignard reagent with oxygen takes

place through a radical intermediate to a magnesium hydroperoxide. Hydrolysis of this complex yields hydroperoxides and reduction with an additional equivalent

of Grignard reagent gives an alcohol.

Oxidation• The synthetic utility of Grignard oxidations can be increased by a

reaction of Grignards with oxygen in presence of an alkene to an ethylene extended alcohol.

• This modification requires aryl or vinyl Grignards. • Adding just the Grignard and the alkene does not result in a reaction

demonstrating that the presence of oxygen is essential. • Only drawback is the requirement of at least two equivalents of

Grignard although this can partly be circumvented by the use of a dual Grignard system with a cheap reducing Grignard such as n-butylmagnesium bromide

Nucleophilic aliphatic substitution • Grignard reagents are nucleophiles in

nucleophilic aliphatic substitutions for instance with alkyl halides in a key step in industrial Naproxen production:

Industrial Use• An example of the Grignard reaction is a key

step in the industrial production of Tamoxifen (currently used for the treatment of estrogen receptor positive breast cancer in women) :