Presented By:Rashmi GaurResearch ScholarC /o Prof. R.K Sharma

Prof. Akira Suzuki

Prof. Richard F. Heck Prof. Ei-ichi

Negishi

1. Importance of chemical processes inthe pharmaceutical and industries.

2. The key steps in building complexmolecules from simple precursors.

The Nobel Prize wasawarded jointly toRichard F. Heck, Ei-ichiNegishi and AkiraSuzuki for Palladium-catalyzed C-C crosscoupling reaction in2010.

The C-C bond formation between an organic electrophile(RX) and a nucleophile (Organometallic R’M or R’-C=C) inthe presence of a transition metal catalyst, usually Pd (evenCu, Ni, Fe etc. are also used).

5.

HECK (1972)

4. SONOGASHIRA (1975)

3. NEGISHI (1977)

2. STILLE (1978)

1. SUZUKI-MIYAURA (1979)

Negishi- M= Organiozincompound

Suzuki- M= Organoboran compound

Stille-M= organotin compound

General Mechanism of Pd catalysed cross coupling reactions

Heck-Mizoroki

Negishi –R1-M= Organozinc compoundStille- R1-M = Organotin compoundSuzuki- R1-M = Organoborane compound

CuI can increase the reaction rate and

ability to scavenge the free ligand.

• Variable oxidation states and coordination number

Metals are Lewis acid (electron deficient):- origin ofChemical reactivity.

There are some other type of lewis acid.

One way interaction only.

RepulsionTwo major reasons are:-1. Simultaneous availability of empty and filled non bonding orbitals ,

because of that Synergic bonding occurres. 2. Ready and reversible oxidation and reduction under one set of reaction

condition.

Charge polarization can be cancelled. Hence required very less energybarrier.

Two way interaction

Palladium is a d-block transition metal.

Pd favours the formation of tetrahedral d10 and square planar d8 complexes of low oxidation states (0 and II respectively).

This feature affords Pd good electron-donating and electron-accepting capabilities, allowing fine-tuning by altering the electronic properties of its ligands.

Pd may easily participate in concerted processes due to its closely lying HOMO and LUMO energies.

Pd complexes tend to be less sensitive to oxygen and are less toxic.

The oxidative addition of organic electrophiles (halides, sulfonates, andrelated activated compounds) to Pd(0) is the first step in cross-coupling.

• Increases both the oxidation state and coordination number of ametal centre.

• In order for the oxidative addition to succeed, the formation of a low-coordinate Pd(0)-species is required (e.g. the formation of 14-electronPd-species, L2Pd(0)).

• Oxidative additions may proceed via two major pathways that dependon the metal center and the substrates (also any added additives,metal-bound ligands and solvent).

Concerted Mechanism : Normally found in addition of non-polar reagents and aryl halides. Retention of configuration is in case of chiral A-B reagents.

SN2 Mechanism : Its an associative bimolecular process. Oftenfound in oxidative additions of polar reagents and in polarsolvents. Oxidative addition of C(sp3)-X electrophiles to Pd(0)complexes PdL4 (L =phosphine) takes place usually by thismechanism. Results in inversion of configuration

Predominant retention in noncoordinating solvents as benzene, CH2Cl2, tetrahydrofuran (THF), or acetone. On the other hand, in coordinating solvents such as MeCN or dimethylsulfoxide(DMSO), complete or near-complete inversion was observed .

Electron-withdrawing substituents on aryl electrophiles led to rate acceleration.Higher the electron density on metal , more favours the oxidative addition.Electron rich and bulky phosphine ligands, enhances reactivity of transition metal

• Transmetallation reactions involve the transfer of an organic group R from one metal M to another one M.

Transmetallation in the Suzuki Reaction:

• Due to the low nucleophilicity of the borane reagents(compared with organostannanes, for example), the Suzukireaction requires the use of base in order to take place.

• The main role of base is to generate a more reactive borate bycoordination of hydroxide to boron, which will react with theintermediate R-Pd(II)-X complex.

• It is the reverse of oxidative addition.

• Reductive elimination involves the elimination or expulsion ofa molecule from a transition metal complex. In the process ofthis elimination, the metal centre is reduced by two electrons.

• The groups being eliminated must be in a mutually cisorientation

• A carbometallation reaction is defined by the addition of a carbon-metal bond of an organometallic 1 across a carbon-carbon multiple bond 2, leading to a new organometallic 3, in which the newly formed carbon-metal bond can be used for further transformations.

• This step is subsequently followed by a syn-insertion process .(resulting in a σ-organopalladium intermediate ).

• This process is sensitive not only to steric but also electronic factors, which in turn influences the regiochemical outcome of the reaction.

β-

The beta-hydride elimination can either be a vital step in a reaction or an unproductive side reaction.

.

• β-Hydride elimination may occur if a β-hydrogen is accessible.

• C-C bond rotation of intermediate D is required, as well as a coordinationvacancy on the metal centre.

• Then cis β-hydrogen elimination takes place, generating a coordinatedpalladium hydride complex E. The hydridopalladium species is subsequentlyliberated from E, producing complex F and the free Mizoroki-Heck product G

• All the C-C cross-couplings reaction broadly follow the samecatalytic cycle, which involves number of processes.

• Heck reaction follows a slightly different pathway from otherC-C couplings.

• Rate-determining step depends on the nature of theelectrophile, nucleophile, and the ligands on palladium.

• Recently many C-C coupling reactions catalyzed by Ni(0), Pt(0),or Cu(I) also. May follow the similar reaction schemes.

• Future scope is that various transition metals are available, you can try some other organic reaction with some other metal and can lead to be a new Nobel prizes pathway.

Metal-Catalyzed Cross-Coupling Reactions, 2nd Edition. Wiley -Edited by Armin de Meijere, Franois Diederich

https://www.youtube.com/watch?v=B3Oz90EfNO0(Nobel Prize Lectures in Uppsala 2010 - Chemistry Laureate Ei-ichi Negishi)

Any Questions?