Suzuki Coupling

 Defination:
palladium catalysed cross coupling of organic
halides with organoboron dvt. In the presence of a base
leading to the formation of carbon-carbon bond is
known as Suzuki cross coupling reaction.
 In Suzuki mechanism, boronicacid must be
activated, for example with base. This activation of the
boron atom enhances the polarization of the organic
ligand, and facilitates transmetallation
Reaction:
 The Suzuki reaction is the coupling of an aryl or
vinyl boronicacid with an aryl or vinyl halide or
triflate using a palladium catalyst. It is a powerful
cross coupling method that allows for the
synthesis of conjugated olefins, styrenes, and
biphenyls.
Mechanism :-
Oxidative addition :-

 Relative reactivity of leaving groups:

I – > Br – >> Cl –.
 Oxidative addition is known to proceed with retention of
stereochemistry with vinyl halides and with inversion with allylic
and benzylic halides.
 Oxidative addition intially gives a cis complex that rapidly
isomerizes to its trans isomer.
Transmetallation:-

 Organoboron compounds are highly covalent in character,

and do not undergo transmetallation readily in the absence
of base.
 The role of the base during transmetalation is unresolved.
Boron "ate" complexes, formed via quaternization of the
boron with a negatively charged base,is frequently invoked.
Reductive elimination:

 Isomerization to the cis complex is required before reductive

elimination can occur.
 Relative rates of reductive elimination from palladium(II)
complexes:
Aryl–aryl > alkyl–aryl > n-propyl–n-propyl > ethyl–ethyl
> methyl–methyl
 Application:

o synthesis of caparratriene from citronellal

derivative , a natural product that is highly active
against leukemia.
o Synthesis of a suitable arylboron compound:
Aryl halide is converted to an aryllithium or aryl
Grignard derivative, and then reacted with a
trialkoxyborane to yield an arylboronic ester,
 e.g. the phenylboronic acid diisopropylester from
bromobenzene
o Synthesis of polyphenylene compound:
o Synthesis of retinol (vitamin A)
Sonogashira coupaling
 Sonogashira coupling is a coupling reaction of
terminal alkynes with aryl or vinyl halides in the
presence of palladium and copper catalyst.
 E.g
Mechanism
Mechanism revolves around a palladium cycle and a
copper cycle.
The palladium cycle:
 Pd(0)L2 which reacts with the aryl halide or triflate in an oxidative
addition to Pd(II) complex B
 This complex reacts in a rate limiting transmetallation with the
copper acetylide produced in the copper cycle to complex C
expelling the copper halide CuX (G).
 Both organic ligands are trans oriented and convert to cis in a
trans-cis isomerization to complex D
 In the final step the product is released in a reductive elimination
with regeneration of Pd(0)
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The copper cycle:
 The copper halide compound reacts with the alkyne to
form copper acetylide .triethylamine help to
deprotonation of intermediate.
 The organocopper compound F forms after reaction with
the base and continues to react with palladium
intermediate B with regeneration of copper halide G.
 A side reaction is a Glaser coupling of two acetylene
units.
 Features:-
 A thorough deoxygenation is essential to maintain
the activity of the Pd catalyst.
 Reaction medium is basic.
 The reactivity of organohalides is of the order of
I>Br>>Cl.
 The difference between the reaction rates of iodides
& bromides allows selectively coupling with the
iodide in the presence of bromides.
Limitation :-
 At high temperature alkynes undergo side reaction.

 Aryl halides & bulky substrates require very high temp.

 Deaerated conditions are formally needed for Sonogashira

coupling reactions because the palladium (0) complexes

are unstable in the air, and oxygen promotes the formation
of homocoupled acetylenes.
 The main limitation of this mechanism is its inability to

account for deprotonation of the terminal alkyne.

 Side reaction is a Glaser coupling of two acetylene units.
Stereochemistry :-
 The coupling is stereospecific & stereochemical

information of the substrate is preserved in the

product.
 E.g.
Vilsmeier – haack reaction
 The Vilsmeier-Haack reaction is the chemical
reaction of a substituted amide (1) with phosphorus
oxychloride and an electron-rich arene (3) to
produce an aryl aldehyde or ketone (5).
Mechanism:
 The reaction of a substituted amide with
phosphorus oxychloride gives a substituted
chloroiminium ion (2), also called the Vilsmeier
reagent.
 The subsequent electrophilic aromatic substitution
produces an iminium ion intermediate, which is
hydrolyzed to give the desired aryl ketone or aryl
aldehyde.
Iminium
intermediate
Features :-
 DMF can be used instead of N-Ph-N-Me

formamide.
 Oxalyl chloride can be used instead of POCl &
3
COCl2.
 Reagent is weak electrophile so works better with
electron rich heterocycles.
 Reactivity of 5 membered heterocycles is
pyrrole > furan > thiophene
Application:
 Anthracene can be formylated exclusively at the 9-
position.

 IndoleIndole-3-aldehyde
 1,6-dimethylnaphthalene  1,6-dimethyl-4-
naphthaldehyde

 Furan, pyrrole, thiophene are formylated at 2nd

position. X=O,N,S
Swern oxidation:
 A primary or secondary alcohol is oxidized to an
aldehyde or ketone respectively using oxalyl
chloride, dimethyl sulfoxide (DMSO) and an
organic base, such as triethylamine.
Mechanism:
 Dimethyl sulfoxide 3 on treatment with oxalyl
chloride 4, hence leading to sulfonium ions 5 or 6.
 Ionic species 5, as well as 6 called ‘activated’
dimethyl sulfoxide.
 An alcohol 1 reacts with species 5, as well as 6,
leads to the formation of a sulfonium salt 7.
  Upon addition of a base—triethylamine is abstract
proton from sulfonium salt 7 to give a sulfonium
ylide 8. The latter decomposes into the carbonyl
compound 2 and dimethyl sulfide 9 through ˇ-
elimination via a cyclic transition state.

Sulfonium salt sulfonium ylide

Limitation:
 When using oxalyl chloride as the dehydration agent,

the reaction must be kept colder than −60 °C to avoid

side reactions. With trifluoroacetic anhydride instead
of oxalyl chloride, the reaction can be warmed to
−30 °C without side reactions.
 Activation of DMSO required for the reaction.

 In some cases, the use of triethylamine as the base can

lead to epimerisation at the carbon alpha to the newly

formed carbonyl.
 The activated DMSO species are stable only at low
temperature, which might in some cases be a
drawback of this method.
 Dimethyl sulfide, a byproduct of the Swern
oxidation, is one of the most foul odors known in
organic chemistry.