The document discusses alkyl halides, aryl halides, and Grignard reactions. Grignard reactions involve organometallic compounds called Grignard reagents that contain a carbon-metal bond between an alkyl or aryl group and magnesium. These reagents act as nucleophiles in important reactions to form carbon-carbon and carbon-heteroatom bonds. Precise control of water and oxygen is needed as Grignard reagents are pyrophoric and react violently with protic substances.

1. 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.

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

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. Reactions of Grignard Reagents with carbonyl groups

10. Reactions with other electrophiles

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

12. 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.

13. 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.

14. 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

15. Nucleophilic aliphatic substitution
• Grignard reagents are nucleophiles in
nucleophilic aliphatic substitutions for
instance with alkyl halides in a key step in
industrial Naproxen production:

16. 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) :