The secondCu - cycle is still poorly understood.

The base employed to abstract the acetylenic proton of the terminal alkyne leading to
copper acetylide in the presence of copper(1) salt is usually not basic enough.
In order to deprotonate the alkyne to generate the anionic nucleophile that should form
the copper acetylide in the presence of copper(l)salt involvement of a T-alkyne-Cu
complex is therefore suggested that should render the alkyne proton mo acidic and
thus easier for abstraction.

The in situ formation of copper acetylides have never been proved except somerecent
indirect evidence.

The reaction medium must be basic for neutralizing the hydrogen halide produced durina
the reaction.
The bases like triethylamine or diethylamine used for this purpose can also be used as
solvents. However, dimethylformamide or ether are also used as solvents.,
Other bases such as potassium carbonate or cesiunm carbonate are also occasionally
used.

The reaction has to be carried out under inert condition (nitrogen or argon) since Pd(O)
are unstable in air and oxygen and also promotes the formation of homocoupled
acetylenes.
 Phosphine-palladium complexes such as tetrakis(triphenylphosphyine)palladium(0),
Pd(PPh)a are used but in many cases palladium(ll) complexes, such as
bis(triphenylphosphine) palladium(l1) Pd(PPh),CI, have proved to be the catalyst of choice,
where oxidation of triphenyl phosphine to triphenylphosphine oxide leads to the formation
of Pd(0) in situ.

Copper(|) halides react with the terminal alkyne to afford copper(l) acetylide in situwhich
acts as an activated species in the coupling reactions and there is no need to prepare the
copper compound separately.

The addition of copper salts as cocatalysts in the typical Sonogashira protocol has its
drawbacks:

The unwanted side reaction is problematic when the terminalalkyne is difficult to obtain
or expensive.

This difficulty has prompted chemists todevelop so called copper free Sonogshira
Reaction.
 RLX
P°Lg
R1-*-R2

L
R1. Pd-X
R1-Pd
L

RgNH*X
R- Pd-X H R2

RJNtL H

Proposed mechanism for copper-free Sonogashira reaction

 However, some commercially available common palladium salts such as palladium(ll)
dichloride or palladium(!l) diacetate, which are starting materials for the preparation of
many palladium complexes, contain small amounts of copper.

This would raise doubt about howcopper-free are some "copper-free" Sonogashira
reactions.

The mechanism of "copper-free" Sonogashira reaction is not well-known.

The proposed mechanism encounters a similar problem when atempting to deprotonate the
acetylide.

The idea of weakening the terminal alkyne hydrogen bond through complexation is the
same.

The "copper - free" mechanism is most hindered by complexation of the amine (when used
as base) with the Pd(ll) species formed after oxidative addition.
The amines cansubstitute for one of the triphenylphosphane ligands reversibly, creatina
competition between the alkyne and amine for the ligand substitution.
 An interestinggeneralized strategy has been developed by [Link] and co - workers for
palladium catalyzed heteroannulation leading to molecules consistingof a heterocyclic
moiety annulated to a benzene ring e.g. benzofurans, phthalides, quinolines benzo- or
naphtha dioxins.

The starting material used to be an aryl halide which contained a reactive nucleophilic
group in the ortho- position.
The strategy relied on
(i) C-C bond formation with terminal alkynes under palladium - copper catalysis

(i)subsequent nucleophilic attack on the triple bond

Atypical example is the synthesis of 2-substituted benzofurans from ortho-iodo
phenol
through palladium catalysed condensation of various acetylinic substrates
Pd(Ph,P),Cl,(2 to3.5 mol%)
+ HCSCR
Cul(3-5 mol%)
DMF, Et3N R
OH
The wide range of substituents in the 2-position of the synthesized benzofuran
the important scope of the reaction.
 (Ph,P),Pd®
OH
+
Et,NH
EC-R
C-R Et,N

OH Pd

OH

-R CuCSCR

Cul
2-substituted benzofuran
-cc-R

OH

Cul
C C E c -R+ EtyNHI
H-C=EC-R
(PhP)2Pd - (CS CR),+ CuCi RCE G-CECR+ (PhP)Pd
Cu-c=SC-R + Pd(PhP)Clz
Oxidative addition of ortho-iodophenol to a Pd(0) complex gives a G-arylpalladium()
complex (A).

Subsequent transmetallation of the latter with cuprous acetylide generates the

arylalkynylpalladium(ll) species (B). This on reductive elimination then affords the acvclic
products e.g. 2-alkynylphenols (C)with regeneration of the catalyst Pd (0).

In the presence of triethylamine, intramolecular nucleophilic attack by the phenoxide anion

on the triple bond results in the formation of benzofuran.
 The Negishi coupling is a widely employed transition metal catalyzed cross-coupling
reaction.

The action couples organic halides or triflates with organozinc compounds, forming
carbon-carbon bonds (C-C) in the process.
Apalladium (0) species is generally utilized as the metal catalyst, though nickel is
sometimes used.
The leaving group Xis usually chloride,bromide, or iodide,but triflate and acetyloxy groups
usually leads to slow reactions.
are feasible as well. X = Cl
The organic residue R= alkenyl, aryl, allyl, alkynyl or propargyl.
The halide X' in the organozinc compound can be chlorine, bromine or iodine and the
organic residue R' is alkenyl, aryl,allyl, alkyl, benzyl, homoallyl, and homopropargyi.
The metal Min the catalyst is nickel or palladium.
The ligand L in the catalyst can be
triphenylphosphine, dppe (1,2
Bis(diphenylphosphino)ethane),
binaphthy) or chirapos (chiral phosphine).
BINAP
(2,2-bis(diphenylphosphino)-1,1
The reaction mechanism is thought to proceed via a standard Pd catalyzed
cross-coupling pathway,starting with aPd(0)species, which is oxidized to Pd(ll) in an
oxidative addition step involvingthe organohalide species.
This step proceeds with aryl, vinyl, alkynyl, and acyl halides, acetates, or triflates, with
substrates following standard oxidative addition relative rates (| > OTf > Br >> CI).
 L
R-X
R-R1 Pd(0)

Reductive R=aryl, acyl, alkenyl, propargyl

Elimination Oxidative
addition R,= aryl, allyl, alkenyl,benzyl,
homopropargyl,
X=I,
homoallyl
Br, CL. OT, OAc
L X'=CL, Br, I
L= ligand
L -Pd(ID-R RPd (I) X
R

Transmetalation

X-Zn-X R,Zn-X'
The actualmechanism of oxidative addition is unresolved, though there are two likely
pathways. One pathway is thought to proceed via aSN2 like mechanism resulting in
inverted stereochemistry. The other pathway proceeds via concerted addition and retains
stereochemistry. Concerted
R
PdL,
R

PdLn PdLn X

PdL---R----x
Sy2 like

Though the additions are cis- the Pd(ll) complex rapidly isomerizes to the trans- complex.
R
L, R
cis/trans
Pd
Pd,
isomerization
X X
 The transmetalation step occurs where the organozinc reagent exchanges its organic
substituent
and a zinc
with the halide in the Pd(ll) complex, generating the trans- Pd(ll) complex
halide salt.

The organozinc substrate can be aryl, vinyt, aly!l, benzyl, homoallyl, or homopropargyl.
Transmetalation is usually rate determining and a complete mechanistic understanding of
this step has not yet been reached though several studies have shed light on this process.
The alkylzinc species go on to forma higher-order zincate species prior to transmetal ation
whereas arylzinc species do not.
ZnXR and ZnR, can both be used as reactive reagents, and Zn is known to prefer four
coordinate complexes, which means solvent coordinated Zn complexes, suchas
ZnXR(solvent), cannot be ruled out aapriori. Studies indicate competing equilibriums
exist between cis- and trans- bis alkyl organopalladium complexes, but that the ony
productive intermediate is the cis complex.
L R
R
CIs/trans
Pd
Pd
1Somenzation

R1 R1

RR4
 The last step in the catalytic pathway of the Negishicoupling is reductive elimination,
which is thought to proceed via a three coordinate transition state, yielding the coupled
regenerating the Pd(0) catalyst. For this step to occur, the
organic product and
aforementioned cis- alkyl organopalladium complex must be formed.

PdLn' PdLr-. R4
R-R,

Bothorganozinc halides and diorganozinc compounds can be used as starting materials.

In one model system it was found that in the transmetalation step the former give the
cis-adduct R-Pd-R' resulting in fast reductivo olimination to product while the latter aives
-adduct which has to go through a slow trans-cis isomerization first
A
common sido roaction is homocoupling.
The homocoupling was found to be the result of a scond transmetalation roaction between
the diaryimetal intermediate and arylmetal halide.
Ar-Pd-Ar' + Ar-Zn-X Ar-Pd-Ar + Ar-Zn-X
Ar'-Pd-Ar Ar-Ar' + Pd(0) (homocoupling)
Ar-Zn-X + H,0 Ar-H + HO-Zn-X (reaction accompanied by dehalogenation)
 The Suzuki reaction (Suzuki-Miyaura reaction) is a coupling reaction, where the
organohalide catalyzed by
coupling partners are a boronic acid and an
a palladium(0) complex.
Acarbon-carbon single bond is formed by coupling an organoboron species (R,
BY,) with a orgaic halide (R,-X) using a palladium catalyst and a base.
R-R R,-X
9 2
P0
Reductive 1 Oxidative
Elimination Addition

Ra-Pal-R, R2-Pd-X
Na Y 8 3 Nao'Bu
'Buo -o'Bu
7 Transmetalation R2-Pd-o'Bu
4

Na NaX
R1 NaO'Bu
R,-0'Bu
YBy
5 6
The mechanism of the Suzuki reaction is best viewed from the perspective of the
palladium catalyst 1.
The first step is the oxidative addition of palladium to the halide 2 to form the
organopalladium species 3.

Reaction with base gives intermediate 4, which via transmetalation with the
boron-ate complex 6 (produced by reaction of the boronic acid 5 with base) forms
the organopalladium species 8.
Reductive elimination of the desired product 9 restores the original palladium
catalyst 1which completes the catalytic cycle.
The Suzuki coupling takes place in the presence of a base and for a long time the
role of the base was not fully understood.
Duc and coworkers studied the role of the base in the reaction
mechanism for the Suzuki coupling and they found that the base has
three roles:
i) Formation of the palladium complex [ArPd(OR)Ll,
ii) formation of the anionic trialkyl borate
iii) acceleration of the reductive elimination step by reaction of the
alkoxide with Pd complex. Promotion of reductive elimination from
stable trans-bis(aryl)palladium complexes, presumably through the
addition of OH- as a fifth ligand (path A in Scheme) and
circumvention of the thermodynamically uphill formation of
a cis complex.

L Path A
reductive
Ar-Pd-OH elimination Ar-Ar
L Ar -

L transmetallation OH
Ar-Pd-Ar Via Ar-Pd
L fast (Pd°L,]
trans
ArB(OH)2
reductve
slow elimination
Ar fast
Ar-Pd-L
Cis L

Path B