By

MUHAMMAD SHAKAIB QURESHI

M.PHIL-CHEMISTRY

CHEM-2017-717

INSTITUTE OF CHEMISTRY

SHAH ABDUL LATIF UNIVERSITY KHAIRPUR MIRS

COUPLING REACTIONS

INSTITUTE OF CHEMISTRY SHAH ABDUL LATIF UNIVERSITY

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1.SUZUKI-MIYAURA REACTION--1979

2.SONOGASHIRA REACTION--1975

TABLE OF CONTENT • Introduction

• Suzuki Miyaura Reaction – Oxidative Addition, Transmetalation, Reductive

Elimination

– Mechanism and Example

– Why Palladium is used in Suzuki Reaction

– Advantages and Application

• Sonogashira Reaction – Mechanism

– Example

– Application

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COUPLING REACTIONS

• A coupling reaction in organic chemistry is a general term for a variety of reactions where two hydrocarbon fragments are coupled with the aid of a metal catalyst.

• It is divided into two broad classes – Homocoupling, in which two identical partners are

couple to form a new molecule i.e Wurtz coupling

– Hetro Coupling/ C-C Cross Coupling, C-C Bond formation Between Organohalide R’—X (E) and a Organometallic R’’—M (Nu) in the presence of Transition Metal Catalyst, usually Palladium (Pd), i-e Suzuki Miyaura Reaction, Sonogashira Reaction etc

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Suzuki—Miyaura Reaction

Wurtz Coupling

Take place in the presence of Palladium Catalyst,

catalyzed cross—coupling C—C Bond Forming

reaction Between Aryl-vinyl and Boronic Acid.

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Suzuki—Miyaura Reaction

Getting Start

• OXIDATION ADDITION

• oxidative Addition is the rate

determining step of the

catalytic cycle. During this

step, the palladium catalyst

is oxidized from palladium(0)

to palladium(II). The palladium

catalyst is coupled with the

alkyl halide to yield an

organopalladium complex.

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TRANSMETALATION

• Transmetalation is

an organometallic reaction

where ligands are

transferred from one

species to another.

• In the case of the Suzuki

coupling the ligands are

transferred from the

organoboron species to the

palladium(II) complex.

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REDUCTIVE ELIMINATION

• The final step is the

reductive elimination

step where the

palladium(II) complex

eliminates the product

and regenerates the

palladium(0) catalyst.

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Suzuki—Miyaura Reaction

Mechanism

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PHARMACEUTICAL PRODUCT

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Singulair (montelukast) is a

leukotriene inhibitor.

Leukotrienes are chemicals your

body releases when you breathe

in an allergen (such as pollen).

These chemicals cause swelling

in your lungs and tightening of

the muscles around your

airways, which can result in

asthma symptoms.

Sensipar (cinacalcet) decreases

levels of parathyroid hormone

(PTH), calcium, and phosphorous

in the body.

Sensipar is used to

treat hyperparathyroidism

(overactive functioning of the

parathyroid glands) in people

who are on long-term dialysis for

kidney disease.

Celebrex is used to treat pain or

inflammation caused by many

conditions such

as arthritis, ankylosing

spondylitis, and menstrual pain.

Celebrex is used to treat juvenile

rheumatoid arthritis in children

who are at least 2 years old.

WHY PALLADIUM CATALYST?

• Due to two main reasons

– Simultaneously availability of Empty and filled

Non-bonding Orbital, because of the Synergic

bonding occurs.

– Ready and reversible oxidation and reduction

under one set reaction condition.

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ADVANTAGE OF SUZUKI REACTION

• Mild Reaction Conditions

• Availability of common boronic acids

• Inorganic by-products are easily removed from reaction mixture.

• Stereoselective

• Less toxic than other competitive methods, (ie. Boronic acids are environmentally safer and less toxic than organostannanes)

• Reaction will take place in the presence of other functional groups (ie. protecting group is not always necessary)

• Relatively cheap reagents, easy to prepare, and GREEN!

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APPLICATION

• INDUSTRIAL APPLICATION

• Polyene antibiotic

• Cost-effective for use in the synthesis of intermediates for pharmaceuticals or fine chemicals.

• SYNTHETIC APPLICATION

• Isolated from the bacterium Myxococcus xanthus. • The Suzuki coupling has been used on a citronellal

derivative for the synthesis of caparratriene, a natural product that is highly activeagainst leukemia.

• The last step in the synthesis of Myxalamide A Observed to have antibiotic and antifungal activity

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SONOGASHIRA REACTION Pd-cataltzed coupling reaction of terminal Alkynes with Aryl or vinyl halides

using an amine base and CuI as Co—catalyst

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SONOGASHIRA REACTION

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SONOGASHIRA REACTION • THE PALLADIUM CYCLE

• An inactive palladium PdII catalyst is activated by a

reduction to the Pd0 compound.

• The active palladium catalyst is the 14 electron compound

Pd0L2, complex A, which reacts with

the aryl or vinyl halide in an oxidative addition to produce

a PdII intermediate, complex B. This step is believed to be

the rate-limiting step of the reaction.

• Complex B reacts in a transmetallation with the

copper acetylide, complex F, which is produced in the

copper cycle, to give complex C, expelling the copper

halide, complex G.

• Both organic ligands are trans oriented and convert to cis

in a trans-cis isomerization to produce complex D.

• In the final step, complex D undergoes reductive

elimination to produce the alkyne, with regeneration of the

palladium catalyst.

• THE COPPER CYCLE

• It is suggested that the presence of base results in the

formation of a pi-alkyne complex, complex E, which

makes the terminal proton on the alkyne more acidic,

leading to the formation of the copper acetylide,

compound F.

• Compound F continues to react with the palladium

intermediate B, with regeneration of the copper halide, G. 17

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APPLICATION OF SONOGASHIRA REACTION

• Its applications pharmaceuticals, natural products,

• organic materials, and nanomaterials.

• Sonogashira reaction use in the synthesis of tazarotene, which is a treatment for psoriasis and acne

• The preparation of SIB-1508Y, also known as Altinicline, which is a potential treatment for Parkinson’s disease, Alzheimer’s disease, Tourette syndrome, schizophrenia, and attention deficit hyperactivity disorder (ADHD).

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THANK YOU

• Think Like a Proton and Stay Positive.

Muhammad Shakaib Qureshi

M.Phil Chemistry

Email

muhammad.shakaib786@gmail.com

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