A|do| Condensat|on

ln some cases Lhe adducLs obLalned from Lhe Aldol AddlLlon can easlly be converLed (ln slLu) Lo unsaLuraLed
carbonyl compounds elLher Lhermally or under acldlc or baslc caLalysls 1he formaLlon of Lhe con[ugaLed sysLem
ls Lhe drlvlng force for Lhls sponLaneous dehydraLlon under a varleLy of proLocols Lhe condensaLlon producL can
be obLalned dlrecLly wlLhouL lsolaLlon of Lhe aldol
1he aldol condensaLlon ls Lhe second sLep of Lhe 8oblnson AnnulaLlon
Mechan|sm of the A|do| Condensat|on


Azo Coup||ng

Azo coupllng ls Lhe mosL wldely used lndusLrlal reacLlon ln Lhe producLlon of dyes lakes and plgmenLs AromaLlc
dlazonlum lons acLs as elecLrophlles ln coupllng reacLlons wlLh acLlvaLed aromaLlcs such as anlllnes or phenols
1he subsLlLuLlon normally occurs aL Lhe para poslLlon excepL when Lhls poslLlon ls already occupled ln whlch
case ottbo poslLlon ls favoured 1he pP of soluLlon ls qulLe lmporLanL lL musL be mlldly acldlc or neuLral slnce no
reacLlon Lakes place lf Lhe pP ls Loo low

Mechan|sm of Azo Coup||ng



8aeyerV||||ger Cx|dat|on

1he 8aeyervllllger CxldaLlon ls Lhe oxldaLlve cleavage of a carboncarbon bond ad[acenL Lo a carbonyl whlch
converLs keLones Lo esLers and cycllc keLones Lo lacLones 1he 8aeyervllllger can be carrled ouL wlLh peraclds
such as MC8A or wlLh hydrogen peroxlde and a Lewls acld
1he reglospeclflclLy of Lhe reacLlon depends on Lhe relaLlve mlgraLory ablllLy of Lhe subsLlLuenLs aLLached Lo Lhe
carbonyl SubsLlLuenLs whlch are able Lo sLablllze a poslLlve charge mlgraLe more readlly so LhaL Lhe order of
preference ls LerL alkyl cyclohexyl sec alkyl phenyl prlm alkyl CP
3
ln some cases sLereoelecLronlc or
rlng sLraln facLors also affecL Lhe reglochemlcal ouLcome
1he reacLlon of aldehydes preferably glves formaLes buL someLlmes only Lhe llberaLed alcohol may be lsolaLed
due Lo Lhe solvolyLlc lnsLablllLy of Lhe producL formaLe under Lhe reacLlon condlLlons

Mechan|sm of the 8aeyerV||||ger Cx|dat|on



8eckmann kearrangement

An acldlnduced rearrangemenL of oxlmes Lo glve amldes
1hls reacLlon ls relaLed Lo Lhe Pofmann and SchmldL 8eacLlons and Lhe CurLlus 8earrangemenL ln LhaL an
elecLroposlLlve nlLrogen ls formed LhaL lnlLlaLes an alkyl mlgraLlon

Mechan|sm of the 8eckmann kearrangement

Cxlmes generally have a hlgh barrler Lo lnverslon and accordlngly Lhls reacLlon ls envlsloned Lo proceed by
proLonaLlon of Lhe oxlme hydroxyl followed by mlgraLlon of Lhe alkyl subsLlLuenL ttoos Lo nlLrogen 1he nC
bond ls slmulLaneously cleaved wlLh Lhe expulslon of waLer so LhaL formaLlon of a free nlLrene ls avolded


8enz|||c Ac|d kearrangement

12ulkeLones undergo a rearrangemenL ln Lhe presence of sLrong base Lo yleld hydroxycarboxyllc aclds 1he
besL ylelds are obLalned when Lhe sub[ecL dlkeLones do noL have enollzable proLons
1he reacLlon of a cycllc dlkeLone leads Lo an lnLeresLlng rlng conLracLlon

keLoaldehydes do noL reacL ln Lhe same manner where a hydrlde shlfL ls preferred (see Cannlzzaro 8eacLlon)

Mechan|sm of 8enz|||c Ac|d kearrangement

8enzo|n Condensat|on

1he 8enzoln CondensaLlon ls a coupllng reacLlon beLween Lwo aldehydes LhaL allows Lhe preparaLlon of
hydroxykeLones 1he flrsL meLhods were only sulLable for Lhe converslon of aromaLlc aldehydes

Mechan|sm of 8enzo|n Condensat|on
AddlLlon of Lhe cyanlde lon Lo creaLe a cyanohydrln effecLs an umpolung of Lhe normal carbonyl charge afflnlLy
and Lhe elecLrophlllc aldehyde carbon becomes nucleophlllc afLer deproLonaLlon A Lhlazollum salL may also be
used as Lhe caLalysL ln Lhls reacLlon (seeSLeLLer 8eacLlon)

A sLrong base ls now able Lo deproLonaLe aL Lhe former carbonyl CaLom

A second equlvalenL of aldehyde reacLs wlLh Lhls carbanlon ellmlnaLlon of Lhe caLalysL regeneraLes Lhe carbonyl
compound aL Lhe end of Lhe reacLlon


8|rch keduct|on

1he 8lrch 8educLlon offers access Lo subsLlLuLed 14cyclohexadlenes

Mechan|sm of the 8|rch keduct|on

1he quesLlon of why Lhe 13dlene ls noL formed even Lhough lL would be more sLable Lhrough con[ugaLlon can
be raLlonallzed wlLh a slmple mnemonlc When vlewed ln valence bond Lerms elecLronelecLron repulslons ln Lhe
radlcal anlon wlll preferenLlally have Lhe nonbondlng elecLrons separaLed as much as posslble ln a 14
relaLlonshlp
1hls quesLlon can also be answered by conslderlng Lhe mesomerlc sLrucLures of Lhe dlenyl carbanlon

1he numbers whlch sLand for Lhe number of bonds can be averaged and compared wlLh Lhe 13 and Lhe 14
dlene 1he sLrucLure on Lhe lefL ls Lhe average of all mesomers deplcLed above followed by 13 and 14dlene

1he dlfference beLween Lhe dlenyl carbanlon and 13dlene ln absoluLe numbers ls 2 and beLween Lhe dlenyl
carbanlon and 14dlene ls 4/3 1he comparlson wlLh Lhe leasL change ln elecLron dlsLrlbuLlon wlll be preferred
8eacLlons of arenes wlLh +l and +MsubsLlLuenLs lead Lo Lhe producLs wlLh Lhe mosL hlghly subsLlLuLed double
bonds

1he effecL of elecLronwlLhdrawlng subsLlLuenLs on Lhe 8lrch 8educLlon varles lor example Lhe reacLlon of
benzolc acld leads Lo 23cyclohexadlenecarboxyllc acld whlch can be raLlonallzed on Lhe basls of Lhe carboxyllc
acld sLablllzlng an ad[acenL anlon

Alkene double bonds are only reduced lf Lhey are con[ugaLed wlLh Lhe arene and occaslonally lsolaLed Lermlnal
alkenes wlll be reduced

8|anc keact|on

1hls reacLlon whlch ls comparable Lo a lrledelCrafLs AlkylaLlon ls useful for Lhe preparaLlon of chloromeLhylaLed
arenes (for example Lhe Merrlfleld resln based on polysLyrene) from Lhe parenL arene wlLh formaldehyde PCl
and ZnCl
2


Mechan|sm of the 8|anc keact|on
1he Lewls acld ZnCl
2
effecLs formaLlon of an oxonlum lon whlch ls reacLlve ln elecLrophlllc aromaLlc subsLlLuLlon
1he lnLermedlaLe zlnc alkoxlde reacLs wlLh Lhe arene Lo form Lhe chloromeLhylaLed producL and zlnc oxldes


When Lhe concenLraLlon (or effecLlve concenLraLlon ln Lhe case of polymer resldues) ls hlgh Lhe formaLlon of slde
producLs due Lo a second addlLlon are observed


1hls meLhod ls an lnexpenslve subsLlLuLe for LAP reducLlons of esLers ln lndusLrlal producLlon and was Lhe only
alLernaLlve prlor Lo Lhe developmenL of Lhe meLal hydrlde reduclng agenLs 1hls dlssolvlng meLal reducLlon ls also
relaLed Lo Lhe 8lrch 8educLlon

Mechan|sm of the 8ouveau|t8|anc keduct|on
Sodlum serves as slngle elecLron reduclng agenL and LLCP ls Lhe proLon donor lf no proLon donor ls avallable
dlmerlzaLlon wlll Lake place as Lhe Acyloln CondensaLlon

Cann|zzaro keact|on

1hls redox dlsproporLlonaLlon of nonenollzable aldehydes Lo carboxyllc aclds and alcohols ls conducLed ln
concenLraLed base
keLo aldehydes glve Lhe producL of an lnLramolecular dlsproporLlonaLlon ln excellenL ylelds


Mechan|sm of the Cann|zzaro keact|on

An lnLeresLlng varlanL Lhe Crossed Cannlzzaro 8eacLlon uses formaldehyde as reduclng agenL

AL Lhe presenL Llme varlous oxldlzlng and reduclng agenLs can be used Lo carry ouL such converslons (wlLh hlgher
ylelds) so LhaL Loday Lhe Cannlzzaro 8eacLlon has llmlLed synLheLlc uLlllLy excepL for Lhe abovemenLloned
converslon of keLo aldehydes
1he Cannlzzaro 8eacLlon should be kepL ln mlnd as a source of poLenLlal slde producLs when aldehydes are
LreaLed under baslc condlLlons
Acetoacet|cLster Condensat|on
C|a|sen Condensat|on

1he Clalsen CondensaLlon beLween esLers conLalnlng hydrogens promoLed by a base such as sodlum eLhoxlde
affords keLoesLers 1he drlvlng force ls Lhe formaLlon of Lhe sLablllzed anlon of Lhe keLo esLer lf Lwo dlfferenL
esLers are used an essenLlally sLaLlsLlcal mlxLure of all four producLs ls generally obLalned and Lhe preparaLlon
does noL have hlgh synLheLlc uLlllLy
Powever lf one of Lhe esLer parLners has enollzable hydrogens and Lhe oLher does noL (eg aromaLlc esLers or
carbonaLes) Lhe mlxed reacLlon (or crossed Clalsen) can be synLheLlcally useful lf keLones or nlLrlles are used as
Lhe donor ln Lhls condensaLlon reacLlon a dlkeLone or a keLonlLrlle ls obLalned respecLlvely
1he use of sLronger bases eg sodlum amlde or sodlum hydrlde lnsLead of sodlum eLhoxlde ofLen lncreases Lhe
yleld
1he lnLramolecular verslon ls known as uleckmann CondensaLlon

Mechan|sm of the C|a|sen Condensat|on



C|a|sen kearrangement

1he allphaLlc Clalsen 8earrangemenL ls a 33slgmaLroplc rearrangemenL ln whlch an allyl vlnyl eLher ls
converLed Lhermally Lo an unsaLuraLed carbonyl compound
1he aromaLlc Clalsen 8earrangemenL ls accompanled by a rearomaLlzaLlon

1he eLherlflcaLlon of alcohols or phenols and Lhelr subsequenL Clalsen 8earrangemenL under Lhermal condlLlons
makes posslble an exLenslon of Lhe carbon chaln of Lhe molecule

Mechan|sm of the C|a|sen kearrangement
1he Clalsen 8earrangemenL may be vlewed as Lhe oxavarlanL of Lhe Cope 8earrangemenL
Mechanlsm of Lhe Cope 8earrangemenL
Mechanlsm of Lhe Clalsen 8earrangemenL
1he reacLlon proceeds preferably o a chalr LranslLlon sLaLe Chlral enanLlomerlcally enrlched sLarLlng maLerlals
glve producLs of hlgh opLlcal purlLy

A boaL LranslLlon sLaLe ls also posslble and can lead Lo slde producLs

1he aromaLlc Clalsen 8earrangemenL ls followed by a rearomaLlzaLlon

When Lhe ottboposlLlon ls subsLlLuLed rearomaLlzaLlon cannoL Lake place 1he allyl group musL flrsL undergo
a Cope 8earrangemenL Lo Lhe potoposlLlon before LauLomerlzaLlon ls posslble

All Clalsen 8earrangemenL reacLlons descrlbed Lo daLe requlre LemperaLures of 100 C lf uncaLalyzed 1he
observaLlon LhaL elecLron wlLhdrawlng groups aL C1 of Lhe vlnyl moleLy exerL a poslLlve lnfluence on Lhe reacLlon
raLe and Lhe yleld has led Lo Lhe developmenL of Lhe followlng varlaLlons
lrelandClalsen
8earrangemenL
LschenmoserClalsen 8earrangemenL
!ohnsonClalsen 8earrangemenL
C|emmensen keduct|on

1he Clemmensen 8educLlon allows Lhe deoxygenaLlon of aldehydes or keLones Lo produce Lhe correspondlng
hydrocarbon
1he subsLraLe musL be sLable Lo sLrong acld 1he Clemmensen 8educLlon ls complemenLary Lo Lhe Wolffklshner
8educLlon whlch ls run under sLrongly baslc condlLlons Acldlablle molecules should be reduced by Lhe Wolff
klshner proLocol

Mechan|sm of the C|emmensen keduct|on
1he reducLlon Lakes place aL Lhe surface of Lhe zlnc caLalysL ln Lhls reacLlon alcohols are noL posLulaLed as
lnLermedlaLes because sub[ecLlon of Lhe correspondlng alcohols Lo Lhese same reacLlon condlLlons does noL lead
Lo alkanes 1he followlng proposal employs Lhe lnLermedlacy of zlnc carbenolds Lo raLlonallze Lhe mechanlsm of
Lhe Clemmensen 8educLlon

Curt|us kearrangement

1he CurLlus 8earrangemenL ls Lhe Lhermal decomposlLlon of carboxyllc azldes Lo produce an lsocyanaLe 1hese
lnLermedlaLes may be lsolaLed or Lhelr correspondlng reacLlon or hydrolysls producLs may be obLalned
1he reacLlon sequence lncludlng subsequenL reacLlon wlLh waLer whlch leads Lo amlnes ls named Lhe CurLlus
8eacLlon 1hls reacLlon ls slmllar Lo Lhe SchmldL 8eacLlon wlLh aclds dlfferlng ln LhaL Lhe acyl azlde ln Lhe presenL
case ls prepared from Lhe acyl hallde and an azlde salL


Mechan|sm of the Curt|us kearrangement
reparaLlon of azldes

uecomposlLlon

8eacLlon wlLh waLer Lo Lhe unsLable carbamlc acld derlvaLlve whlch wlll undergo sponLaneous decarboxylaLlon


lsocyanaLes are versaLlle sLarLlng maLerlals

lsocyanaLes are also of hlgh lnLeresL as monomers for polymerlzaLlon work and ln Lhe derlvaLlsaLlon of
blomacromolecules
Dak|n keact|on

1he uakln 8eacLlon allows Lhe preparaLlon of phenols from aryl aldehydes or aryl keLones vla oxldaLlon wlLh
hydrogen peroxlde ln Lhe presence of base 1he aryl formaLe or alkanoaLe formed as an lnLermedlaLe ls
subsequenLly saponlfled Lo yleld Lhe subsLlLuLed phenol producL
ttbo or poto +M subsLlLuenLs (nP
2
CP) favor Lhls reacLlon
Darzens keact|on
Darzens Condensat|on

1he uarzens 8eacLlon ls Lhe condensaLlon of a carbonyl compound wlLh an halo esLer ln Lhe presence of a base
Lo form an epoxy esLer

Mechan|sm of the Darzens keact|on
AfLer deproLonaLlon Lhe halo esLer adds Lo Lhe carbonyl compound Lo glve syo and oot dlasLereomers

ln Lhe subsequenL sLep an lnLramolecular S
n
2 reacLlon forms Lhe epoxlde

D|azot|sat|on

1he nlLrosaLlon of prlmary aromaLlc amlnes wlLh nlLrous acld (generaLed ln slLu from sodlum nlLrlLe and a sLrong
acld such as hydrochlorlc acld sulfurlc acld or P8l
4
) leads Lo dlazonlum salLs whlch can be lsolaLed lf Lhe
counLerlon ls nonnucleophlllc
ulazonlum salLs are lmporLanL lnLermedlaLes for Lhe preparaLlon of halldes (Sandmeyer 8eacLlon Schlemann
8eacLlon) and azo compounds ulazonlum salLs can reacL as pseudohalldeLype elecLrophlles and can Lherefore
be used ln speclflc proLocols for LhePeck 8eacLlon or Suzukl Coupllng
1he lnLermedlaLes resulLlng from Lhe dlazoLlzaLlon of prlmary allphaLlc amlnes are unsLable Lhey are rapldly
converLed lnLo carbocaLlons afLer loss of nlLrogen and yleld producLs derlved from subsLlLuLlon ellmlnaLlon or
rearrangemenL processes

Mechan|sm of D|azot|sat|on



D|eckmann Condensat|on

1he basecaLalyzed lnLramolecular condensaLlon of a dlesLer 1he uleckmann CondensaLlon works well Lo produce
3 or 6membered cycllc keLo esLers and ls usually effecLed wlLh sodlum alkoxlde ln alcohollc solvenL
1he ylelds are good lf Lhe producL has an enollzable proLon oLherwlse Lhe reverse reacLlon (cleavage wlLh rlng
sclsslon) can compeLe See Lhe Clalsen CondensaLlon
D|e|sA|der keact|on


1he 4+2cycloaddlLlon of a con[ugaLed dlene and a dlenophlle (an alkene or alkyne) an elecLrocycllc reacLlon
LhaL lnvolves Lhe 4 nelecLrons of Lhe dlene and 2 nelecLrons of Lhe dlenophlle 1he drlvlng force of Lhe reacLlon
ls Lhe formaLlon of new obonds whlch are energeLlcally more sLable Lhan Lhe nbonds
ln Lhe case of an alkynyl dlenophlle Lhe lnlLlal adducL can sLlll reacL as a dlenophlle lf noL Loo sLerlcally hlndered
ln addlLlon elLher Lhe dlene or Lhe dlenophlle can be subsLlLuLed wlLh cumulaLed double bonds such as
subsLlLuLed allenes
WlLh lLs broad scope and slmpllclLy of operaLlon Lhe ulelsAlder ls Lhe mosL powerful synLheLlc meLhod for
unsaLuraLed slxmembered rlngs
A varlanL ls Lhe heLeroulelsAlder ln whlch elLher Lhe dlene or Lhe dlenophlle conLalns a heLeroaLom mosL ofLen
nlLrogen or oxygen 1hls alLernaLlve consLlLuLes a powerful synLhesls of slxmembered rlng heLerocycles

Mechan|sm of the D|e|sA|der keact|on


The reaction is diastereoselective.




Cyclic dienes give stereoisomeric products. The endo product is usually favored by kinetic control due to secondary
orbital interactions.

I|scher Lster|f|cat|on
I|scherSpe|er Lster|f|cat|on

1he Lewls or 8rnsLedL acldcaLalyzed esLerlflcaLlon of carboxyllc aclds wlLh alcohols Lo glve esLers ls a Lyplcal
reacLlon ln whlch Lhe producLs and reacLanLs are ln equlllbrlum
1he equlllbrlum may be lnfluenced by elLher removlng one producL from Lhe reacLlon mlxLure (for example
removal of Lhe waLer by azeoLroplc dlsLlllaLlon or absorpLlon by molecular sleves) or by employlng an excess of
one reacLanL

Mechan|sm of the I|scher Lster|f|cat|on
AddlLlon of a proLon (eg p1sCP P
2
SC
4
) or a Lewls acld leads Lo a more reacLlve elecLrophlle nucleophlllc
aLLack of Lhe alcohol glves a LeLrahedral lnLermedlaLe ln whlch Lhere are Lwo equlvalenL hydroxyl groups Cne of
Lhese hydroxyl groups ls ellmlnaLed afLer a proLon shlfL (LauLomerlsm) Lo glve waLer and Lhe esLer

AlLernaLlve reacLlons employ coupllng reagenLs such as uCC (SLegllch LsLerlflcaLlon) preformed esLers
(LransesLerlflcaLlon) carboxyllc acld chlorldes or anhydrldes (see overvlew) 1hese reacLlons avold Lhe producLlon
of waLer AnoLher paLhway for Lhe producLlon of esLers ls Lhe formaLlon of a carboxylaLe anlon whlch Lhen reacLs
as a nucleophlle wlLh an elecLrophlle (slmllar reacLlons can be found here) LsLers may also be produced by
oxldaLlons namely by Lhe 8aeyervllllger oxldaLlon and oxldaLlve esLerlflcaLlons
Iavorsk|| keact|on

1he rearrangemenL of cyclopropanones ofLen obLalned as lnLermedlaLes from Lhe basecaLalyzed reacLlon of
halo keLones leadlng Lo carboxyllc aclds and derlvaLlves

Mechan|sm of the Iavorsk|| keact|on

LsLers are obLalned lf alkoxlde bases are used

A dlrecL converslon from halo keLones ls posslble

8lngconLracLlon

Ir|ede|Crafts Acy|at|on

1hls elecLrophlllc aromaLlc subsLlLuLlon allows Lhe synLhesls of monoacylaLed producLs from Lhe reacLlon beLween
arenes and acyl chlorldes or anhydrldes 1he producLs are deacLlvaLed and do noL undergo a second subsLlLuLlon
normally a sLolchlomeLrlc amounL of Lhe Lewls acld caLalysL ls requlred because boLh Lhe subsLraLe and Lhe
producL form complexes

1he lrledelCrafLs AlkylaLlon may glve polyalkylaLed producLs so Lhe lrledelCrafLs AcylaLlon ls a valuable
alLernaLlve 1he acylaLed producLs may easlly be converLed Lo Lhe correspondlng alkanes vla Clemmensen
8educLlon or Wolffklshner 8educLlon


Mechan|sm of the Ir|ede|Crafts Acy|at|on




Ir|ede|Crafts A|ky|at|on

1hls Lewls acldcaLalyzed elecLrophlllc aromaLlc subsLlLuLlon allows Lhe synLhesls of alkylaLed producLs vla Lhe
reacLlon of arenes wlLh alkyl halldes or alkenes Slnce alkyl subsLlLuenLs acLlvaLe Lhe arene subsLraLe
polyalkylaLlon may occur A valuable LwosLep alLernaLlve ls lrledelCrafLs AcylaLlon followed by a carbonyl
reducLlon

Mechan|sm of the Ir|ede|Crafts A|ky|at|on


uslng alkenes

Ir|es kearrangement

1he lrles 8earrangemenL enables Lhe preparaLlon of acyl phenols

Mechan|sm of the Ir|es kearrangement
1he reacLlon ls caLalyzed by 8rnsLed or Lewls aclds such as Pl AlCl
3
8l
3
1lCl
4
or SnCl
4
1he aclds are used ln
excess of Lhe sLolchlomeLrlc amounL especlally Lhe Lewls aclds slnce Lhey form complexes wlLh boLh Lhe sLarLlng
maLerlals and producLs

1he complex can dlssoclaLe Lo form an acyllum lon uependlng on Lhe solvenL an lon palr can form and Lhe lonlc
specles can reacL wlLh each oLher wlLhln Lhe solvenL cage Powever reacLlon wlLh a more dlsLanL molecule ls also
posslble

AfLer hydrolysls Lhe producL ls llberaLed

1he reacLlon ls ottbopotoselecLlve so LhaL for example Lhe slLe of acylaLlon can be regulaLed by Lhe cholce of
LemperaLure Cnly sLerlcally unhlndered arenes are sulLable subsLraLes slnce subsLlLuenLs wlll lnLerfere wlLh Lhls
reacLlon
1he requlremenL for equlmolar quanLlLles of Lhe caLalysL Lhe corroslve and Loxlc condlLlons (Pl) and Lhe vlolenL
reacLlon of Lhe caLalysL wlLh waLer have prompLed Lhe developmenL of newer proLocols ZeollLes have proven Lo
be unsulLable slnce Lhey are deacLlvaLed buL sLrong aclds such as sulfonlc aclds provlde a reasonable
alLernaLlve
An addlLlonal opLlon for lnduclng a lrles 8earrangemenL ls phoLochemlcal exclLaLlon buL Lhls meLhod ls only
feaslble ln Lhe laboraLory

Gabr|e| Synthes|s

oLasslum phLhallmlde ls a

nP
2
synLhon whlch allows Lhe preparaLlon of prlmary amlnes by reacLlon wlLh alkyl
halldes AfLer alkylaLlon Lhe phLhallmld ls noL nucleophlle and does noL reacL anymore roducL ls cleaved by
reacLlon wlLh base or hydrazlne whlch leads Lo a sLable cycllc producL

Mechan|sm of the Gabr|e| Synthes|s
noLe hLhallmlde ls acldlc!


Cleavage

Gr|gnard keact|on
Gr|gnard keagents

1he Crlgnard 8eacLlon ls Lhe addlLlon of an organomagneslum hallde (Crlgnard reagenL) Lo a keLone or aldehyde
Lo form a LerLlary or secondary alcohol respecLlvely 1he reacLlon wlLh formaldehyde leads Lo a prlmary alcohol
Crlgnard 8eagenLs are also used ln Lhe followlng lmporLanL reacLlons 1he addlLlon of an excess of a Crlgnard
reagenL Lo an esLer or lacLone glves a LerLlary alcohol ln whlch Lwo alkyl groups are Lhe same and Lhe addlLlon of
a Crlgnard reagenL Lo a nlLrlle produces an unsymmeLrlcal keLone vla a meLallolmlne lnLermedlaLe (Some more
reacLlons are deplcLed below)

Mechan|sm of the Gr|gnard keact|on
Whlle Lhe reacLlon ls generally LhoughL Lo proceed Lhrough a nucleophlllc addlLlon mechanlsm sLerlcally hlndered
subsLraLes may reacL accordlng Lo an SL1 (slngle elecLron Lransfer) mechanlsm

WlLh sLerlcally hlndered keLones Lhe followlng slde producLs are recelved
1he Crlgnard reagenL can acL as base wlLh deproLonaLlon yleldlng an enolaLe lnLermedlaLe AfLer work up Lhe
sLarLlng keLone ls recovered

A reducLlon can also Lake place ln whlch a hydrlde ls dellvered from Lhe carbon of Lhe Crlgnard reagenL Lo Lhe
carbonyl carbon vla a cycllc slxmembered LranslLlon sLaLe

Add|t|ona| react|ons of Gr|gnard keagents
WlLh carboxyllc acld chlorldes

LsLers are less reacLlve Lhan Lhe lnLermedlaLe keLones Lherefore Lhe reacLlon ls only sulLable for synLhesls of
LerLlary alcohols uslng an excess of Crlgnard 8eagenL

WlLh nlLrlles

WlLh CC
2
(by addlng dry lce Lo Lhe reacLlon mlxLure)

WlLh oxlranes

na|oform keact|on

1hls reacLlon has been used ln quallLaLlve analysls Lo lndlcaLe Lhe presence of a meLhyl keLone 1he producL
lodoform ls yellow and has a characLerlsLlc odour 1he reacLlon has some synLheLlc uLlllLy ln Lhe oxldaLlve
demeLhylaLlon of meLhyl keLones lf Lhe oLher subsLlLuenL on Lhe carbonyl groups bears no enollzable proLons

Mechan|sm of the na|oform keact|on
1he reacLlon readlly proceeds Lo compleLlon because of Lhe acldlfylng effecL of Lhe halogen subsLlLuenLs

ne||Vo|hard2e||nsky keact|on

1reaLmenL wlLh bromlne and a caLalyLlc amounL of phosphorus leads Lo Lhe selecLlve bromlnaLlon of carboxyllc
aclds

Mechan|sm of the ne||Vo|hard2e||nsky keact|on
hosphorus reacLs wlLh bromlne Lo glve phosphorus Lrlbromlde and ln Lhe flrsL sLep Lhls converLs Lhe carboxyllc
acld lnLo an acyl bromlde

An acyl bromlde can readlly exlsL ln Lhe enol form and Lhls LauLomer ls rapldly bromlnaLed aL Lhe carbon 1he
monobromlnaLed compound ls much less nucleophlllc so Lhe reacLlon sLops aL Lhls sLage 1hls acyl lnLermedlaLe
compound can undergo bromlde exchange wlLh unreacLed carboxyllc acld vla Lhe anhydrlde whlch allows Lhe
caLalyLlc cycle Lo conLlnue unLll Lhe converslon ls compleLe

nofmann L||m|nat|on

SomeLlmes referred Lo as Lhe Pofmann uegradaLlon 1hls ellmlnaLlon reacLlon of alkyl LrlmeLhyl amlnes proceeds
wlLh ootsLereochemlsLry and ls generally sulLable for produclng alkenes wlLh one or Lwo subsLlLuenLs 1he
reacLlon follows Lhe Pofmann 8ule

Mechan|sm of the nofmann L||m|nat|on


nunsd|ecker keact|on

1he sllver(l) salLs of carboxyllc aclds reacL wlLh halogens Lo glve unsLable lnLermedlaLes whlch readlly
decarboxylaLe Lhermally Lo yleld alkyl halldes 1he reacLlon ls belleved Lo lnvolve homolysls of Lhe CC bond and a
radlcal chaln mechanlsm

Mechan|sm of the nunsd|ecker keact|on



8rown nydroborat|on

1he syoaddlLlon of hydroboranes Lo alkenes occurs wlLh predlcLable selecLlvlLy whereln Lhe boron adds
preferenLlally Lo Lhe leasL hlndered carbon 1hls selecLlvlLy ls enhanced lf sLerlcally demandlng boranes are used

Coupllng Lhe hydroboraLlon wlLh a subsequenL oxldaLlon of Lhe new formed borane ylelds oot
Markovnlkov alcohols 1he hydroboraLlon/oxldaLlon sequence consLlLuLes a powerful meLhod for Lhe reglo and
sLereoselecLlve synLhesls of alcohols
1he producL boranes may also be used as sLarLlng maLerlals for oLher reacLlons such as Suzukl Coupllngs (see
8ecenL LlLeraLure)

Mechan|sm of the 8rown nydroborat|on
1he selecLlvlLy of Lhe flrsL addlLlon of borane can be relaLlvely low


1he subsequenL addlLlons are more selecLlve as Lhe sLerlc bulk lncreases and ootMarkovnlkov selecLlvlLy
predomlnaLes ln Lhe end

CxldaLlon wlLh hydrogen peroxlde leads Lo alcohols

SLerlcally demandlng boranes offer enhanced selecLlvlLy Cne example of a sLerlcally demandlng borane (988n) ls
generaLed by Lhe double addlLlon of borane Lo 13cycloocLadlene
98orablcyclo331nonane


1he reacLlvlLy and selecLlvlLy of Lhe borane reagenL may be modlfled Lhrough Lhe use of boraneLewls base
complexes
ko|be L|ectro|ys|s

1he elecLrochemlcal oxldaLlve decarboxylaLlon of carboxyllc acld salLs LhaL leads Lo radlcals whlch dlmerlze lL ls
besL applled Lo Lhe synLhesls of symmeLrlcal dlmers buL ln some cases can be used wlLh a mlxLure of Lwo
carboxyllc aclds Lo furnlsh unsymmeLrlcal dlmers

Mechan|sm of the ko|be L|ectro|ys|s
Slde producLs
1he formaLlon of slde producLs depends on Lhe ease of Lhe followup oxldaLlon whlch leads Lo carbenlum lons
and Lhelr subsequenL rearrangemenL

ko|beSchm|tt keact|on

A basepromoLed carboxylaLlon of phenols LhaL allows Lhe synLhesls of sallcyllc acld derlvaLlves

Mechan|sm of the ko|beSchm|tt keact|on


Meerwe|nonndorfVer|ey keduct|on

1he alumlnlumcaLalyzed hydrlde shlfL from Lhe acarbon of an alcohol componenL Lo Lhe carbonyl carbon of a
second componenL whlch proceeds vla a slxmembered LranslLlon sLaLe ls referred Lo as Lhe Meerweln
onndorfverley 8educLlon (Mv) or LheCppenauer CxldaLlon dependlng on whlch componenL ls Lhe deslred
producL lf Lhe alcohol ls Lhe deslred producL Lhe reacLlon ls vlewed as Lhe Meerwelnonndorfverley 8educLlon
lsopropanol ls useful as a hydrlde donor because Lhe resulLlng aceLone may be conLlnuously removed from Lhe
reacLlon mlxLure by dlsLlllaLlon
Crlgnard 8eagenLs wlll someLlmes yleld Lhe resulL of an Mv reducLlon lf Lhe carbonyl carbon ls Loo hlndered for
nucleophlllc addlLlon
M|chae| Add|t|on

1he 14addlLlon (or con[ugaLe addlLlon) of resonancesLablllzed carbanlons 1he Mlchael AddlLlon ls
Lhermodynamlcally conLrolled Lhe reacLlon donors are acLlve meLhylenes such as malonaLes and nlLroalkanes
and Lhe accepLors are acLlvaLed oleflns such as unsaLuraLed carbonyl compounds
Lxamples
donors
accepLors

Mechan|sm of the M|chae| Add|t|on


Nef keact|on



1he converslon of nlLro compounds lnLo carbonyls ls known as Lhe nef 8eacLlon varlous meLhodologles have
been developed buL Lhe mosL lmporLanL ls Lhe sLandard procedure a preformed nlLronaLe salL ls poured lnLo
sLrong aqueous acld (pP 1) Some oxldaLlve varlaLlons have also found wlde appllcaLlon and some reducLlve
meLhods have even been developed

Mechan|sm of the Nef keact|on
nlLroalkanes are relaLlvely sLrong carbon aclds and deproLonaLlon leads Lo Lhe nlLronaLe salL 1he hydrolysls of
Lhls lnLermedlaLe musL Lake place ln sLrong acld Lo prevenL Lhe formaLlon of slde producLs such as oxlmes or
hydroxynlLroso compounds

Nuc|eoph|||c Subst|tut|on (S
N
1
S
N
2)

nucleophlllc subsLlLuLlon ls Lhe reacLlon of an elecLron palr donor (Lhe nucleophlle nu) wlLh an elecLron palr
accepLor (Lhe elecLrophlle) An sp
3
hybrldlzed elecLrophlle musL have a leavlng group (x) ln order for Lhe reacLlon
Lo Lake place

Mechan|sm of Nuc|eoph|||c Subst|tut|on
1he Lerm S
n
2 means LhaL Lwo molecules are lnvolved ln Lhe acLual LranslLlon sLaLe

1he deparLure of Lhe leavlng group occurs slmulLaneously wlLh Lhe backslde aLLack by Lhe nucleophlle 1he S
n
2
reacLlon Lhus leads Lo a predlcLable conflguraLlon of Lhe sLereocenLer lL proceeds wlLh lnverslon (reversal of Lhe
conflguraLlon)
ln Lhe S
n
1 reacLlon a planar carbenlum lon ls formed flrsL whlch Lhen reacLs furLher wlLh Lhe nucleophlle Slnce
Lhe nucleophlle ls free Lo aLLack from elLher slde Lhls reacLlon ls assoclaLed wlLh racemlzaLlon

ln boLh reacLlons Lhe nucleophlle compeLes wlLh Lhe leavlng group 8ecause of Lhls one musL reallze whaL
properLles a leavlng group should have and whaL consLlLuLes a good nucleophlle lor Lhls reason lL ls worLhwhlle
Lo know whlch facLors wlll deLermlne wheLher a reacLlon follows an S
n
1 or S
n
2 paLhway
very good leavlng groups such as LrlflaLe LosylaLe and mesylaLe sLablllze an lnclplenL negaLlve charge 1he
delocallzaLlon of Lhls charge ls reflecLed ln Lhe facL LhaL Lhese lons are noL consldered Lo be nucleophlllc

Pydroxlde and alkoxlde lons are noL good leavlng groups however Lhey can be acLlvaLed by means of Lewls or
8rnsLed aclds

Lpoxldes are an excepLlon slnce Lhey relleve Lhelr rlng sLraln when Lhey undergo nucleophlllc subsLlLuLlon wlLh
acLlvaLlon by acld belng opLlonal

1rlflaLe LosylaLe and mesylaLe are Lhe anlons of sLrong aclds 1he weak con[ugaLe bases are poor nucleophlles
nucleophlllclLy lncreases ln parallel wlLh Lhe base sLrengLh 1hus amlnes alcohols and alkoxldes are very good
nucleophlles 8ase sLrengLh ls a rough measure of how reacLlve Lhe nonbondlng elecLron palr ls Lhus lL ls noL
necessary for a nucleophlle Lo be anlonlc
under subsLlLuLlon condlLlons amlnes proceed all Lhe way Lo form quaLernary salLs whlch makes lL dlfflculL Lo
conLrol Lhe exLenL of Lhe reacLlon

Powever as a nucleophlles base sLrengLh and sLerlc hlndrance lncrease lLs baslclLy Lends Lo be accenLuaLed lf
Lhere are absLracLable proLons aL Lhe poslLlon of Lhe elecLrophlle an ellmlnaLlon paLhway can compeLe wlLh Lhe
nucleophlllc subsLlLuLlon

An addlLlonal facLor LhaL plays a role ls Lhe characLer of Lhe solvenL lncreaslng sLablllzaLlon of Lhe nucleophlle by
Lhe solvenL resulLs ln decreaslng reacLlvlLy 1hus polar proLlc solvenLs wlll sLablllze Lhe chlorlde and bromlde lons
Lhrough Lhe formaLlon of hydrogen bonds Lo Lhese smaller anlons lodlde ls a comparaLlvely beLLer nucleophlle ln
Lhese solvenLs 1he reverse behavlor predomlnaLes ln aproLlc polar medla
1he solvenL also plays an lmporLanL role ln deLermlnlng whlch paLhway Lhe reacLlon wlll Lake S
n
1 versus S
n
2 lL
may safely be assumed LhaL a prlmarysubsLlLuLed leavlng group wlll follow an S
n
2 paLhway ln any case slnce Lhe
formaLlon of Lhe correspondlng unsLable prlmary carbenlum lon ls dlsfavored 8eacLlon by Lhe S
n
1 paLhway ls
hlghly probable for compounds wlLh LerLlary subsLlLuLlon slnce Lhe correspondlng LerLlary carbenlum lon ls
sLablllzed Lhrough hypercon[ugaLlon

1he beLLer Lhe solvenL sLablllzes Lhe lons Lhe more probable LhaL Lhe reacLlon wlll follow an S
n
1 paLhway (eg ln
polar proLlc solvenLs such as waLer/aceLone) 1he more hlghly subsLlLuLed ls Lhe lnclplenL carbenlum lon Lhe
more probable LhaL Lhe reacLlon wlll follow an S
n
1 paLhway 1he more unreacLlve Lhe nucleophlle Lhe more
probable lL becomes LhaL a reacLlon wlLh secondary and LerLlary elecLrophlles wlll follow an S
n
1 paLhway A
weaker nucleophlle ls noL as effecLlve ln Lhe backslde aLLack slnce Lhls locaLlon ls sLerlcally shlelded especlally ln
Lhe case of LerLlary subsLraLes Carbenlum lons are planar and Lherefore less sLerlcally hlndered and are naLurally
more reacLlve as elecLrophlles Lhan Lhe uncharged parenL compound
1he hydrolysls of tettbuLyl chlorlde ls a Lyplcal S
n
1 reacLlon

Cppenauer Cx|dat|on

1he alumlnlumcaLalyzed hydrlde shlfL from Lhe carbon of an alcohol componenL Lo Lhe carbonyl carbon of a
second componenL whlch proceeds over a slxmembered LranslLlon sLaLe ls named Meerwelnonndorfverley
8educLlon (Mv) or Cppenauer CxldaLlon (C) dependlng on Lhe lsolaLed producL lf aldehydes or keLones are
Lhe deslred producLs Lhe reacLlon ls vlewed as Lhe Cppenauer CxldaLlon
nonenollzable keLones wlLh a relaLlvely low reducLlon poLenLlal such as benzophenone can serve as Lhe
carbonyl componenL used as Lhe hydrlde accepLor ln Lhls oxldaLlon
Czono|ys|s
Cr|egee Mechan|sm



Czonolysls allows Lhe cleavage of alkene double bonds by reacLlon wlLh ozone uependlng on Lhe work up
dlfferenL producLs may be lsolaLed reducLlve workup glves elLher alcohols or carbonyl compounds whlle
oxldaLlve workup leads Lo carboxyllc aclds or keLones

Mechan|sm of Czono|ys|s
1he mechanlsm was suggesLed by Crlegee (oqew cbem lot J 197S 743 uCl) and has been recenLly
revlslLed uslng
17
CnM8 SpecLroscopy by Lhe 8erger Croup (ot I tq cbem 1998 1623 uCl)
llrsL sLep ls a 13dlpolar cycloaddlLlon of ozone Lo Lhe alkene leadlng Lo Lhe prlmary ozonlde (molozonlde 123
Lrloxolane or Crlegee lnLermedlaLe) whlch decomposes Lo glve a carbonyl oxlde and a carbonyl compound

1he carbonyl oxldes are slmllar Lo ozone ln belng 13dlpolar compounds and undergo 13dlpolar cycloaddlLlon
Lo Lhe carbonyl compounds wlLh Lhe reverse reglochemlsLry leadlng Lo a mlxLure of Lhree posslble secondary
ozonldes (124Lrloxolanes)



1hese secondary ozonldes are more sLable Lhan prlmary ozonldes Lven lf Lhe peroxy brldge ls shlelded by sLerlc
demandlng groups leadlng Lo lsolable producLs Lhey should noL be lsolaLed from an unmodlfled ozonolysls
because sLlll more exploslve slde producLs (LeLroxanes) may have been formed

As endoperoxldes are lnvesLlgaLed as anLlmalarlal compounds more selecLlve meLhods have been developed for
Lhelr preparaLlon (for example Lhe Crlesbaum Coozonolysls) Some reacLlons can be found here v u8
8onlfaclo tq cbem nqblqbts 2004 CcLober 23 Llnk
1he Crlegee mechanlsm ls valld for reacLlons ln hydrocarbons CP
2
Cl
2
or oLher nonlnLeracLlve solvenLs Alcohols
reacL wlLh Lhe carbonyl oxlde Lo glve hydroperoxy hemlaceLals

1he synLheLlc value lles ln Lhe way Lhe complex mlxLures of lnLermedlaLes can be worked up Lo glve a deflned
composlLlon of producLs and a clean converslon of all peroxlde specles 1he Lhree maln posslblllLles are glven
above along wlLh examples for Lhe reagenLs used
|naco| kearrangement

ln Lhe converslon LhaL gave lLs name Lo Lhls reacLlon Lhe acldcaLalyzed ellmlnaLlon of waLer from plnacol glves t
buLyl meLhyl keLone

Mechan|sm of the |naco| kearrangement
1hls reacLlon occurs wlLh a varleLy of fully subsLlLuLed 12dlols and can be undersLood Lo lnvolve Lhe formaLlon
of a carbenlum lon lnLermedlaLe LhaL subsequenLly undergoes a rearrangemenL 1he flrsL generaLed lnLermedlaLe
an hydroxycarbenlum lon rearranges Lhrough a 12alkyl shlfL Lo produce Lhe carbonyl compound lf Lwo of Lhe
subsLlLuenLs form a rlng Lhe lnacol 8earrangemenL can consLlLuLe a rlngexpanslon or rlngconLracLlon reacLlon



rvost keact|on

1he revosL 8eacLlon allows Lhe synLhesls of ootdlols from alkenes by Lhe addlLlon of lodlne followed by
nucleophlllc dlsplacemenL wlLh benzoaLe ln Lhe absence of waLer Pydrolysls of Lhe lnLermedlaLe dlesLer glves Lhe
deslred dlol
1he Woodward ModlflcaLlon of Lhe revosL 8eacLlon glves syodlols

Mechan|sm of the revost keact|on
1he lnlLlal addlLlon of lodlne leads Lo a cycllc lodonlum lon whlch ls opened Lhrough nucleophlllc subsLlLuLlon by
benzoaLe anlon

A nelghbourlnggroup parLlclpaLlon mechanlsm prevenLs Lhe lmmedlaLe nucleophlllc subsLlLuLlon of lodlne by a
second equlvalenL of benzoaLe LhaL would lead Lo a syosubsLlLuLed producL lnsLead a cycllc benzoxonlum lon
lnLermedlaLe ls formed

Cpenlng of Lhls lnLermedlaLe by a second addlLlon of benzoaLe glves Lhe ootsubsLlLuLed dlbenzoaLe

Pydrolysls Lhen dellvers Lhe dlol
r|ns keact|on
1he rlns 8eacLlon ls Lhe acldcaLalyzed of addlLlon aldehydes Lo alkenes and glves dlfferenL producLs dependlng
on Lhe reacLlon condlLlons lL can be LhoughL of concepLually as Lhe addlLlon of Lhe elemenLs of Lhe gemdlol
carbonyl hydraLe of Lhe aldehyde across Lhe double bond

An excess of aldehyde and LemperaLures 70 C lead Lo Lhe formaLlon of aceLals When one equlvalenL of
aldehyde ls used and LemperaLures are 70 C dlols or allyllc alcohols may be lsolaLed


AlLhough Lhe mechanlsm ls dlfferenL a rlns allyllc alcohol producL ls equlvalenL Lo Lhe resulL of an Lne 8eacLlon

Mechan|sm of the r|ns keact|on




keformatsky keact|on

1he formaLlon of esLersLablllzed organozlnc reagenLs and Lhelr addlLlon Lo carbonyl compounds

Mechan|sm of the keformatsky keact|on
Crganozlnc compounds are prepared from halogenesLers ln Lhe same manner as Crlgnard 8eagenLs 1hls
reacLlon ls posslble due Lo Lhe sLablllLy of esLers agalnsL organozlncs uue Lo Lhe very low baslclLy of zlnc enolaLes
Lhere ls hardly any compeLlLlon from proLon Lransfer and Lhe scope of carbonyl addlLlon parLners ls qulLe broad
ln presence of keLones or aldehydes Lhe organozlnc compounds reacL as Lhe nucleophlllc parLner ln an addlLlon
Lo glve hydroxy esLers
An esLersLablllzed organozlnc reagenL
Compared Lo organollLhlums and organomagneslum halldes (Crlgnard reagenLs) Lhe organozlnc hallde reagenLs
used ln Lhe 8eformaLsky 8eacLlon are relaLlvely sLable and many are avallable commerclally
kosenmund keduct|on

1he caLalyLlc hydrogenaLlon of acld chlorldes allows Lhe formaLlon of aldehydes

Mechan|sm of the kosenmund keduct|on
Slde producLs

1he d caLalysL musL be polsoned for example wlLh 8aSC
4
because Lhe unLreaLed caLalysL ls Loo reacLlve and wlll
glve some overreducLlon Some of Lhe slde producLs can be avolded lf Lhe reacLlon ls conducLed ln sLrlcLly
anhydrous solvenLs
Sandmeyer keact|on

1he subsLlLuLlon of an aromaLlc amlno group ls posslble vla preparaLlon of lLs dlazonlum salL and subsequenL
dlsplacemenL wlLh a nucleophlle (Cl l Cn 8S PC) Many Sandmeyer 8eacLlons proceed under copper(l)
caLalysls whlle Lhe SandmeyerLype reacLlons wlLh Lhlols waLer and poLasslum lodlde donL requlre caLalysls

1he Sandmeyer 8eacLlon ls a very lmporLanL LransformaLlon ln aromaLlc chemlsLry because lL can resulL ln some
subsLlLuLlon paLLerns LhaL are noL achlevable by dlrecL subsLlLuLlon
lluorlnaLlon ls posslble by uslng Lhe relaLed Schlemann 8eacLlon

Mechan|sm of the Sandmeyer keact|on

8a|zSch|emann keact|on

1he converslon of aryl amlnes Lo aryl fluorldes vla dlazoLlsaLlon and subsequenL Lhermal decomposlLlon of Lhe
derlved LeLrafluoroboraLes or hexafluorophosphaLes 1he decomposlLlon may also be lnduced phoLochemlcally

Mechan|sm of the 8a|zSch|emann keact|on
see ulazoLlsaLlon
1he mechanlsm of Lhe 8alzSchlemann reacLlon remalns obscure A posslble paLhway ls shown below

Schm|dt keact|on





1he acldcaLalysed reacLlon of hydrogen azlde wlLh elecLrophlles such as carbonyl compounds LerLlary alcohols
or alkenes AfLer a rearrangemenL and exLruslon of n
2
amlnes nlLrlles amldes or lmlnes are produced

Mechan|sm of the Schm|dt keact|on
8eacLlon of carboxyllc aclds glves acyl azldes whlch rearrange Lo lsocyanaLes and Lhese may be hydrolyzed Lo
carbamlc acld or solvolysed Lo carbamaLes uecarboxylaLlon leads Lo amlnes

1he reacLlon wlLh a keLone glves an azldohydrln lnLermedlaLe whlch rearranges Lo form an amlde

Alkenes are able Lo undergo addlLlon of Pn
3
as wlLh any Px reagenL and Lhe resulLlng alkyl azlde can rearrange Lo
form an lmlne

1erLlary alcohols glve subsLlLuLlon by azlde vla a carbenlum lon and Lhe resulLlng alkyl azlde can rearrange Lo
form an lmlne
Schotten8aumann keact|on
Schotten8aumann Cond|t|ons

1he use of added base Lo drlve Lhe equlllbrlum ln Lhe formaLlon of amldes from amlnes and acld chlorldes
1he acylaLlon of amlnes wlLh carboxyllc acld chlorldes leads Lo Lhe producLlon of one equlvalenL acld whlch wlll
form a salL wlLh unreacLed amlne and dlmlnlsh Lhe yleld 1he addlLlon of an addlLlonal equlvalenL of base Lo
neuLrallse Lhls acld ls a way Lo opLlmlse Lhe condlLlons normally aqueous base ls slowly added Lo Lhe reacLlon
mlxLure
ln general Lhe use of blphaslc aqueous baslc condlLlons ls ofLen named SchoLLen8aumann condlLlons

Mechan|sm of the Schotten8aumann keact|on

S|mmonsSm|th keact|on

1hls reacLlon affords Lhe cyclopropanaLlon of oleflns

Mechan|sm of the S|mmonsSm|th keact|on
ulLrasonlcaLlon lmproves Lhe raLe of formaLlon of Lhese organozlnc compounds as wlLh many organomeLalllc
reacLlons occurrlng aL a surface

1he mechanlsm has noL been fully clarlfled buL pure carbenes can be excluded and a meLal carbenold ls llkely Lo
be lnvolved 1he followlng resulLs may be lnLerpreLed Lo lndlcaLe a posslble complexaLlon of Lhe acLlve specles by
hydroxy groups leadlng Lo reacLlon on Lhe same face as Lhls subsLlLuenL 1hls would only be posslble lf an
organozlnc reagenL ls presenL

varlous research groups have developed varlanLs of Lhe SlmmonsSmlLh cyclopropanaLlng reagenL Lhrough Lhe
replacemenL of Lhe lodlde llgand on Lhe zlnc aLom wlLh a sLrongly elecLronwlLhdrawlng subsLlLuenL Whereas Lhe
orlglnal reagenL ofLen requlres a dlrecLlng group such as Lhe hydroxyl of an allyllc alcohol carbenolds such as
Cl
3
CC
2
ZnCP
2
l and (hC)
2
(C)CZnCP
2
l enable a rapld cyclopropanaLlon of alkenes wlLhouL Lhe need for such a
dlrecLlng group
Swern Cx|dat|on

1he Swern CxldaLlon of alcohols avolds Lhe use of Loxlc meLals such as chromlum and can be carrled ouL under
very mlld condlLlons 1hls reacLlon allows Lhe preparaLlon of aldehydes and keLones from prlmary and secondary
alcohols resp Aldehydes do noL reacL furLher Lo glve carboxyllc aclds A drawback ls Lhe producLlon of Lhe
malodorous slde producL dlmeLhyl sulphlde

Mechan|sm of the Swern Cx|dat|on
ulmeLhylchlorosulphonlum lon ls generaLed ln slLu from uMSC and oxalyl chlorlde

1he reacLlon wlLh an alcohol aL 78C leads Lo an alkoxysulphonlum lon

ueproLonaLlon of Lhls lnLermedlaLe glves a sulphur yllde whlch undergoes lnLramolecular deproLonaLlon vla a
flvemembered rlng LranslLlon sLaLe and fragmenLaLlon Lo yleld Lhe producL and uMS (odour!)


lf Lhe LemperaLure ls noL kepL near 78C mlxed LhloaceLals may resulL

1|shchenko keact|on

1he 1lshchenko 8eacLlon ls a dlsproporLlonaLlon reacLlon LhaL allows Lhe preparaLlon of esLers from Lwo
equlvalenLs of an aldehyde

Mechan|sm of the 1|shchenko keact|on
1he alumlnlum alkoxlde acLs as a Lewls acld Lo coordlnaLe wlLh one molecule of Lhe aldehyde and Lo faclllLaLe Lhe
addlLlon of a second equlvalenL of aldehyde generaLlng a hemlaceLal lnLermedlaLe

1hls specles undergoes an lnLramolecular 13hydrlde shlfL LhaL resulLs ln Lhe producLlon of Lhe alumlnlum
coordlnaLed esLer

A poLenLlal slde reacLlon ls Lhe lnvolvemenL of one of Lhe alkoxlde groups from Lhe caLalysL


1hls can be mlnlmlsed lf Lhe reacLlon ls conducLed aL low LemperaLures and low caLalysL loadlngs
U||mann keact|on

1here are Lwo dlfferenL LransformaLlons referred as Lhe ullmann 8eacLlon 1he classlc ullmann 8eacLlon ls Lhe
synLhesls of symmeLrlc blaryls vla coppercaLalyzed coupllng 1he ullmannLype 8eacLlons lnclude copper
caLalyzed nucleophlllc AromaLlc SubsLlLuLlon beLween varlous nucleophlles (eg subsLlLuLed phenoxldes) wlLh aryl
halldes 1he mosL common of Lhese ls Lhe ullmann LLher SynLhesls


Mechan|sm of the U||mann keact|on
8laryls are avallable Lhrough coupllng of Lhe aryl hallde wlLh an excess of copper aL elevaLed LemperaLures (200
C) 1he acLlve specles ls a copper(l)compound whlch undergoes oxldaLlve addlLlon wlLh Lhe second equlvalenL of
hallde followed by reducLlve ellmlnaLlon and Lhe formaLlon of Lhe arylaryl carbon bond


1he organocopper lnLermedlaLe can be generaLed aL a more moderaLe 70 C uslng a novel LhlophenecarboxylaLe
reagenL 1he reacLlon oLherwlse follows Lhe same reacLlon paLh as above

AnoLher posslblllLy ls Lhe use of Cu(l) for Lhe oxldaLlve coupllng of arylllLhlum compounds aL low LemperaLures
1hls meLhod can also be used Lo generaLe asymmeLrlc blaryls afLer addlLlon of Lhe approprlaLe hallde

ullmannLype reacLlons proceed Lhrough a caLalyLlc cycle and ln one mechanlsm Lhe copper ls posLulaLed Lo
undergo oxldaLlon Lo Cu(lll) As some Cu(lll) salLs have been prepared Lhe suggesLlon for Lhe mechanlsm ls
lnLrlgulng (see also ChanLam Coupllng)

V||sme|ernaack keact|on

1he vllsmeler 8eacLlon allows Lhe formylaLlon of elecLronrlch arenes

Mechan|sm of the V||sme|ernaak keact|on
1he formylaLlng agenL also known as Lhe vllsmeyerPaack 8eagenL ls formed o sto from uMl and phosphorus
oxychlorld

An elecLrophlllc aromaLlc subsLlLuLlon leads Lo chloro amlnes whlch are rapldly hydrolyzed durlng work up Lo
glve Lhe aldehyde

W||||amson Synthes|s

1hls meLhod ls sulLable for Lhe preparaLlon of a wlde varleLy of unsymmeLrlc eLhers 1he nucleophlllc subsLlLuLlon
of halldes wlLh alkoxldes leads Lo Lhe deslred producLs
lf Lhe halldes are sLerlcally demandlng and Lhere are accesslble proLons ln Lhe poslLlon Lhe alkoxlde wlll acL as a
base and slde producLs derlved from ellmlnaLlon are lsolaLed lnsLead

Mechan|sm of the W||||amson Synthes|s


W|tt|g keact|on

1he WlLLlg 8eacLlon allows Lhe preparaLlon of an alkene by Lhe reacLlon of an aldehyde or keLone wlLh Lhe yllde
generaLed from a phosphonlum salL 1he geomeLry of Lhe resulLlng alkene depends on Lhe reacLlvlLy of Lhe yllde
lf 8 ls h Lhen Lhe yllde ls sLablllzed and ls noL as reacLlve as when 8 alkyl SLablllzed ylldes glve ()alkenes
whereas nonsLablllzed ylldes lead Lo (2)alkenes (seeWlLLlgPorner 8eacLlon)

Mechan|sm of the W|tt|g keact|on
AddlLlon of Lhe yllde Lo Lhe carbonyl ls posLulaLed Lo lead flrsL Lo Lhe zwlLLerlonlc lnLermedlaLe beLalne whlch
would Lhen close Lo form a fourmembered cycllc lnLermedlaLe an oxaphospheLane 1he exlsLence of Lhe beLalne
hasnL been fully esLabllshed alLhough lLs lnLermedlacy plays an lmporLanL role ln Lhe Schlosser ModlflcaLlon
8eLalnes may be sLablllzed by llLhlum salLs leadlng Lo slde producLs Lherefore sulLable bases ln Lhe WlLLlg
8eacLlon are for example naP naCMe nLL
3
)

1he drlvlng force ls Lhe formaLlon of a very sLable phosphlne oxlde

8eacLlve ylldes glve rapld reacLlon and subsequenL rapld rlng openlng Lo glve Lhe (Z)alkene

Wo|ffk|shner keduct|on

1he reducLlon of aldehydes and keLones Lo alkanes CondensaLlon of Lhe carbonyl compound wlLh hydrazlne
forms Lhe hydrazone and LreaLmenL wlLh base lnduces Lhe reducLlon of Lhe carbon coupled wlLh oxldaLlon of Lhe
hydrazlne Lo gaseous nlLrogen Lo yleld Lhe correspondlng alkane
1he Clemmensen 8educLlon can effecL a slmllar converslon under sLrongly acldlc condlLlons and ls useful lf Lhe
sLarLlng maLerlal ls baselablle

Mechan|sm of the Wo|ffk|shner keduct|on

Wo|ff kearrangement

1he Wolff 8earrangemenL allows Lhe generaLlon of keLenes from dlazokeLones normally Lhese keLenes are noL
lsolaLed due Lo Lhelr hlgh reacLlvlLy Lo form dlkeLenes
Wolff rearrangemenLs LhaL are conducLed ln Lhe presence of nucleophlles generaLe derlvaLlves of carboxyllc aclds
and ln Lhe presence of unsaLuraLed compounds can undergo 2+2 cycloaddlLlons (for example SLaudlnger
SynLhesls)

1he formaLlon of dlazokeLones from carboxyllc aclds (vla Lhe acyl chlorlde or an anhydrlde) and Lhe subsequenL
Wolff 8earrangemenL ln Lhe presence of nucleophlles resulLs ln a onecarbon homologaLlon of carboxyllc aclds
1hls reacLlon sequence whlch flrsL showed Lhe synLheLlc poLenLlal of Lhe Wolff8earrangemenL was developed
by ArndL and LlsLerL

Mechan|sm of the Wo|ff kearrangement
ulazokeLones undergo Lhe Wolff 8earrangemenL Lhermally ln Lhe range beLween room LemperaLure and 730 C
ln gas phase pyrolysls uue Lo compeLlng reacLlons aL elevaLed LemperaLures Lhe phoLochemlcal and meLal
caLalyzed varlanLs LhaL feaLure a slgnlflcanLly lowered reacLlon LemperaLure are ofLen preferred (Zeller oqew
cbem lot J 197S 32 uCl)
nlLrogen exLruslon and Lhe 12shlfL can occur elLher ln a concerLed manner or sLepwlse vla a carbene
lnLermedlaLe

Sllver lon caLalysls falls wlLh sLerlcally hlndered subsLraLes polnLlng Lo Lhe requlslLe formaLlon of a subsLraLe
complex wlLh Lhe lon ln Lhese cases phoLochemlcal exclLaLlon ls Lhe meLhod of cholce
1he solvenL can affecL Lhe course of Lhe reacLlon lf Wolff8earrangemenLs are conducLed ln MeCP as solvenL Lhe
occurrence of slde producLs derlved from an CP lnserLlon polnL Lo Lhe lnLermedlacy of carbenes

1he course of Lhe reacLlon and Lhe mlgraLory preferences can depend on Lhe condlLlons (Lhermal phoLochemlcal
meLal lon caLalysls) of Lhe reacLlon Analysls of Lhe producL dlsLrlbuLlon helps Lo deLermlne dlfferenL degrees of
concerLedness or Lhe mlgraLory apLlLude of Lhe group LhaL rearranges lf 8 ls phenyl Lhe maln producL comes
from Lhe rearrangemenL whereas Lhe meLhyl group glves more of Lhe lnserLlon slde producL
1he reacLlons of 2dlazo13dlones also help Lo deLermlne Lhe mlgraLory apLlLude

ln a phoLolysls meLhyl ls preferred for rearrangemenL whereas under Lhermolysls condlLlons Lhe phenyl
subsLlLuenL mlgraLes preferenLlally Pydrogen always exceeds Lhe mlgraLory apLlLude of phenyl groups 1he alkoxy
group ln aryl or alkyl 2dlazokeLocarboxylaLes never mlgraLes
Wurtz keact|on

1he WurLz Coupllng ls one of Lhe oldesL organlc reacLlons and produces Lhe slmple dlmer derlved from Lwo
equlvalenLs of alkyl hallde 1he lnLramolecular verslon of Lhe reacLlon has also found appllcaLlon ln Lhe
preparaLlon of sLralned rlng compounds

uslng Lwo dlfferenL alkyl halldes wlll lead Lo an approxlmaLely sLaLlsLlcal mlxLure of producLs A more selecLlve
unsymmeLrlc modlflcaLlon ls posslble lf sLarLlng maLerlals have dlfferenL raLes of reacLlvlLy (see WurLzllLLlg
8eacLlon)

Mechan|sm of the Wurtz keact|on

Slde producLs