A|do| Condensat|on

ln some casesţ Lhe adducLs obLalned from Lhe Aldol AddlLlon can easllv be converLed (ln slLu) Lo ĐţĒŴunsaLuraLed
carbonvl compoundsţ elLher Lhermallv or under acldlc or baslc caLalvslsŦ 1he formaLlon of Lhe con[uaaLed svsLem
ls Lhe drlvlna force for Lhls sponLaneous dehvdraLlonŦ under a varleLv of proLocolsţ Lhe condensaLlon producL can
be obLalned dlrecLlv wlLhouL lsolaLlon of Lhe aldolŦ
1he aldol condensaLlon ls Lhe second sLep of Lhe 8oblnson AnnulaLlonŦ
Mechan|sm of the A|do| Condensat|on


Azo Coup||ng

Azo coupllna ls Lhe mosL wldelv used lndusLrlal reacLlon ln Lhe producLlon of dvesţ lakes and plamenLsŦ AromaLlc
dlazonlum lons acLs as elecLrophlles ln coupllna reacLlons wlLh acLlvaLed aromaLlcs such as anlllnes or phenolsŦ
1he subsLlLuLlon normallv occurs aL Lhe para poslLlonţ excepL when Lhls poslLlon ls alreadv occupledţ ln whlch
case ottbo poslLlon ls favouredŦ 1he pP of soluLlon ls qulLe lmporLanLŤ lL musL be mlldlv acldlc or neuLralţ slnce no
reacLlon Lakes place lf Lhe pP ls Loo lowŦ

Mechan|sm of Azo Coup||ng



8aeyerŴV||||ger Cx|dat|on

1he 8aeverŴvllllaer CxldaLlon ls Lhe oxldaLlve cleavaae of a carbonŴcarbon bond ad[acenL Lo a carbonvlţ whlch
converLs keLones Lo esLers and cvcllc keLones Lo lacLonesŦ 1he 8aeverŴvllllaer can be carrled ouL wlLh peracldsţ
such as MC8ÞAţ or wlLh hvdroaen peroxlde and a Lewls acldŦ
1he realospeclflclLv of Lhe reacLlon depends on Lhe relaLlve mlaraLorv ablllLv of Lhe subsLlLuenLs aLLached Lo Lhe
carbonvlŦ SubsLlLuenLs whlch are able Lo sLablllze a poslLlve charae mlaraLe more readllvţ so LhaL Lhe order of
preference lsť LerLŦ alkvl ƽ cvclohexvl ƽ secŦ alkvl ƽ phenvl ƽ prlmŦ alkvl ƽ CP
3
Ŧ ln some casesţ sLereoelecLronlc or
rlna sLraln facLors also affecL Lhe realochemlcal ouLcomeŦ
1he reacLlon of aldehvdes preferablv alves formaLesţ buL someLlmes onlv Lhe llberaLed alcohol mav be lsolaLed
due Lo Lhe solvolvLlc lnsLablllLv of Lhe producL formaLe under Lhe reacLlon condlLlonsŦ

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



8eckmann kearrangement

An acldŴlnduced rearranaemenL of oxlmes Lo alve amldesŦ
1hls reacLlon ls relaLed Lo Lhe Pofmann and SchmldL 8eacLlons and Lhe CurLlus 8earranaemenLţ ln LhaL an
elecLroposlLlve nlLroaen ls formed LhaL lnlLlaLes an alkvl mlaraLlonŦ

Mechan|sm of the 8eckmann kearrangement

Cxlmes aenerallv have a hlah barrler Lo lnverslonţ and accordlnalv Lhls reacLlon ls envlsloned Lo proceed bv
proLonaLlon of Lhe oxlme hvdroxvlţ followed bv mlaraLlon of Lhe alkvl subsLlLuenL ƍttoosƍ Lo nlLroaenŦ 1he nŴC
bond ls slmulLaneouslv cleaved wlLh Lhe expulslon of waLerţ so LhaL formaLlon of a free nlLrene ls avoldedŦ


8enz|||c Ac|d kearrangement

1ţ2ŴulkeLones underao a rearranaemenL ln Lhe presence of sLrona base Lo vleld ĐŴhvdroxvcarboxvllc acldsŦ 1he
besL vlelds are obLalned when Lhe sub[ecL dlkeLones do noL have enollzable proLonsŦ
1he reacLlon of a cvcllc dlkeLone leads Lo an lnLeresLlna rlna conLracLlonť

keLoaldehvdes do noL reacL ln Lhe same mannerţ where a hvdrlde shlfL ls preferred (see Cannlzzaro 8eacLlon)

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

8enzo|n Condensat|on

1he 8enzoln CondensaLlon ls a coupllna reacLlon beLween Lwo aldehvdes LhaL allows Lhe preparaLlon of ĐŴ
hvdroxvkeLonesŦ 1he flrsL meLhods were onlv sulLable for Lhe converslon of aromaLlc aldehvdesŦ

Mechan|sm of 8enzo|n Condensat|on
AddlLlon of Lhe cvanlde lon Lo creaLe a cvanohvdrln effecLs an umpoluna of Lhe normal carbonvl charae afflnlLvţ
and Lhe elecLrophlllc aldehvde carbon becomes nucleophlllc afLer deproLonaLlonť A Lhlazollum salL mav also be
used as Lhe caLalvsL ln Lhls reacLlon (seeSLeLLer 8eacLlon)Ŧ

A sLrona base ls now able Lo deproLonaLe aL Lhe former carbonvl CŴaLomť

A second equlvalenL of aldehvde reacLs wlLh Lhls carbanlonŤ ellmlnaLlon of Lhe caLalvsL reaeneraLes Lhe carbonvl
compound aL Lhe end of Lhe reacLlonť


8|rch keduct|on

1he 8lrch 8educLlon offers access Lo subsLlLuLed 1ţ4ŴcvclohexadlenesŦ

Mechan|sm of the 8|rch keduct|on

1he quesLlon of whv Lhe 1ţ3Ŵdlene ls noL formedţ even Lhouah lL would be more sLable Lhrouah con[uaaLlonţ can
be raLlonallzed wlLh a slmple mnemonlcŦ When vlewed ln valence bond Lermsţ elecLronŴelecLron repulslons ln Lhe
radlcal anlon wlll preferenLlallv have Lhe nonbondlna elecLrons separaLed as much as posslbleţ ln a 1ţ4Ŵ
relaLlonshlpŦ
1hls quesLlon can also be answered bv conslderlna Lhe mesomerlc sLrucLures of Lhe dlenvl carbanlonť

1he numbersţ whlch sLand for Lhe number of bondsţ can be averaaed and compared wlLh Lhe 1ţ3Ŵ and Lhe 1ţ4Ŵ
dleneŦ 1he sLrucLure on Lhe lefL ls Lhe averaae of all mesomers deplcLed above followed bv 1ţ3 and 1ţ4Ŵdleneť

1he dlfference beLween Lhe dlenvl carbanlon and 1ţ3Ŵdlene ln absoluLe numbers ls 2ţ and beLween Lhe dlenvl
carbanlon and 1ţ4Ŵdlene ls 4/3Ŧ 1he comparlson wlLh Lhe leasL chanae ln elecLron dlsLrlbuLlon wlll be preferredŦ
8eacLlons of arenes wlLh +lŴ and +MŴsubsLlLuenLs lead Lo Lhe producLs wlLh Lhe mosL hlahlv subsLlLuLed double
bondsť

1he effecL of elecLronŴwlLhdrawlna subsLlLuenLs on Lhe 8lrch 8educLlon varlesŦ lor exampleţ Lhe reacLlon of
benzolc acld leads Lo 2ţ3Ŵcvclohexadlenecarboxvllc acldţ whlch can be raLlonallzed on Lhe basls of Lhe carboxvllc
acld sLablllzlna an ad[acenL anlonť

Alkene double bonds are onlv reduced lf Lhev are con[uaaLed wlLh Lhe areneţ and occaslonallv lsolaLed Lermlnal
alkenes wlll be reducedŦ

8|anc keact|on

1hls reacLlonţ whlch ls comparable Lo a lrledelŴCrafLs AlkvlaLlonţ ls useful for Lhe preparaLlon of chloromeLhvlaLed
arenes (for exampleţ Lhe Merrlfleld resln based on polvsLvrene) from Lhe parenL arene wlLh formaldehvdeţ PClţ
and ZnCl
2
Ŧ

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 subsLlLuLlonŦ
1he lnLermedlaLe zlnc alkoxlde reacLs wlLh Lhe arene Lo form Lhe chloromeLhvlaLed producL and zlnc oxldesť


When Lhe concenLraLlon (orţ effecLlve concenLraLlon ln Lhe case of polvmer resldues) ls hlahţ Lhe formaLlon of slde
producLs due Lo a second addlLlon are observedť


1hls meLhod ls an lnexpenslve subsLlLuLe for LAP reducLlons of esLers ln lndusLrlal producLlonţ and was Lhe onlv
alLernaLlve prlor Lo Lhe developmenL of Lhe meLal hvdrlde reduclna aaenLsŦ 1hls dlssolvlna meLal reducLlon ls also
relaLed Lo Lhe 8lrch 8educLlonŦ

Mechan|sm of the 8ouveau|tŴ8|anc keduct|on
Sodlum serves as slnale elecLron reduclna aaenL and LLCP ls Lhe proLon donorŦ lf no proLon donor ls avallableţ
dlmerlzaLlon wlll Lake placeţ as Lhe Acvloln CondensaLlonŦ

Cann|zzaro keact|on

1hls redox dlsproporLlonaLlon of nonŴenollzable aldehvdes Lo carboxvllc aclds and alcohols ls conducLed ln
concenLraLed baseŦ
ĐŴkeLo aldehvdes alve Lhe producL of an lnLramolecular dlsproporLlonaLlon ln excellenL vleldsŦ


Mechan|sm of the Cann|zzaro keact|on

An lnLeresLlna varlanLţ Lhe Crossed Cannlzzaro 8eacLlonţ uses formaldehvde as reduclna aaenLť

AL Lhe presenL Llmeţ varlous oxldlzlna and reduclna aaenLs can be used Lo carrv ouL such converslons (wlLh hlaher
vlelds)ţ so LhaL Lodav Lhe Cannlzzaro 8eacLlon has llmlLed svnLheLlc uLlllLv excepL for Lhe abovemenLloned
converslon of ĐŴkeLo aldehvdesŦ
1he Cannlzzaro 8eacLlon should be kepL ln mlnd as a source of poLenLlal slde producLs when aldehvdes are
LreaLed under baslc condlLlonsŦ
Acetoacet|cŴLster Condensat|on
C|a|sen Condensat|on

1he Clalsen CondensaLlon beLween esLers conLalnlna ĐŴhvdroaensţ promoLed bv a base such as sodlum eLhoxldeţ
affords ĒŴkeLoesLersŦ 1he drlvlna force ls Lhe formaLlon of Lhe sLablllzed anlon of Lhe ĒŴkeLo esLerŦ lf Lwo dlfferenL
esLers are usedţ an essenLlallv sLaLlsLlcal mlxLure of all four producLs ls aenerallv obLalnedţ and Lhe preparaLlon
does noL have hlah svnLheLlc uLlllLvŦ
Poweverţ lf one of Lhe esLer parLners has enollzable ĐŴhvdroaens and Lhe oLher does noL (eŦaŦţ aromaLlc esLers or
carbonaLes)ţ Lhe mlxed reacLlon (or crossed Clalsen) can be svnLheLlcallv usefulŦ lf keLones or nlLrlles are used as
Lhe donor ln Lhls condensaLlon reacLlonţ a ĒŴdlkeLone or a ĒŴkeLonlLrlle ls obLalnedţ respecLlvelvŦ
1he use of sLronaer basesţ eŦaŦ sodlum amlde or sodlum hvdrlde lnsLead of sodlum eLhoxldeţ ofLen lncreases Lhe
vleldŦ
1he lnLramolecular verslon ls known as uleckmann CondensaLlonŦ

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



C|a|sen kearrangement

1he allphaLlc Clalsen 8earranaemenL ls a ż3ţ3ŽŴslamaLroplc rearranaemenL ln whlch an allvl vlnvl eLher ls
converLed Lhermallv Lo an unsaLuraLed carbonvl compoundŦ
1he aromaLlc Clalsen 8earranaemenL ls accompanled bv a rearomaLlzaLlonť

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

Mechan|sm of the C|a|sen kearrangement
1he Clalsen 8earranaemenL mav be vlewed as Lhe oxaŴvarlanL of Lhe Cope 8earranaemenLť
Mechanlsm of Lhe Cope 8earranaemenL
Mechanlsm of Lhe Clalsen 8earranaemenL
1he reacLlon proceeds preferablv o a chalr LranslLlon sLaLeŦ Chlralţ enanLlomerlcallv enrlched sLarLlna maLerlals
alve producLs of hlah opLlcal purlLvŦ

A boaL LranslLlon sLaLe ls also posslbleţ and can lead Lo slde producLsť

1he aromaLlc Clalsen 8earranaemenL ls followed bv a rearomaLlzaLlonť

When Lhe ottboŴposlLlon ls subsLlLuLedţ rearomaLlzaLlon cannoL Lake placeŦ 1he allvl aroup musL flrsL underao
a Cope 8earranaemenL Lo Lhe potoŴposlLlon before LauLomerlzaLlon ls posslbleŦ

All Clalsen 8earranaemenL reacLlons descrlbed Lo daLe requlre LemperaLures of ƽ 100 ¨C lf uncaLalvzedŦ 1he
observaLlon LhaL elecLron wlLhdrawlna aroups aL CŴ1 of Lhe vlnvl moleLv exerL a poslLlve lnfluence on Lhe reacLlon
raLe and Lhe vleld has led Lo Lhe developmenL of Lhe followlna varlaLlonsť
lrelandŴClalsen
8earranaemenL
LschenmoserŴClalsen 8earranaemenL
!ohnsonŴClalsen 8earranaemenL
C|emmensen keduct|on

1he Clemmensen 8educLlon allows Lhe deoxvaenaLlon of aldehvdes or keLonesţ Lo produce Lhe correspondlna
hvdrocarbonŦ
1he subsLraLe musL be sLable Lo sLrona acldŦ 1he Clemmensen 8educLlon ls complemenLarv Lo Lhe WolffŴklshner
8educLlonţ whlch ls run under sLronalv baslc condlLlonsŦ AcldŴlablle molecules should be reduced bv Lhe WolffŴ
klshner proLocolŦ

Mechan|sm of the C|emmensen keduct|on
1he reducLlon Lakes place aL Lhe surface of Lhe zlnc caLalvsLŦ ln Lhls reacLlonţ alcohols are noL posLulaLed as
lnLermedlaLesţ because sub[ecLlon of Lhe correspondlna alcohols Lo Lhese same reacLlon condlLlons does noL lead
Lo alkanesŦ 1he followlna proposal emplovs Lhe lnLermedlacv of zlnc carbenolds Lo raLlonallze Lhe mechanlsm of
Lhe Clemmensen 8educLlonť

Curt|us kearrangement

1he CurLlus 8earranaemenL ls Lhe Lhermal decomposlLlon of carboxvllc azldes Lo produce an lsocvanaLeŦ 1hese
lnLermedlaLes mav be lsolaLedţ or Lhelr correspondlna reacLlon or hvdrolvsls producLs mav be obLalnedŦ
1he reacLlon sequence Ŵ lncludlna subsequenL reacLlon wlLh waLer whlch leads Lo amlnes Ŵ ls named Lhe CurLlus
8eacLlonŦ 1hls reacLlon ls slmllar Lo Lhe SchmldL 8eacLlon wlLh acldsţ dlfferlna ln LhaL Lhe acvl azlde ln Lhe presenL
case ls prepared from Lhe acvl hallde and an azlde salLŦ


Mechan|sm of the Curt|us kearrangement
ÞreparaLlon of azldesť

uecomposlLlonť

8eacLlon wlLh waLer Lo Lhe unsLable carbamlc acld derlvaLlve whlch wlll underao sponLaneous decarboxvlaLlonť


lsocvanaLes are versaLlle sLarLlna maLerlalsť

lsocvanaLes are also of hlah lnLeresL as monomers for polvmerlzaLlon work and ln Lhe derlvaLlsaLlon of
blomacromoleculesŦ
Dak|n keact|on

1he uakln 8eacLlon allows Lhe preparaLlon of phenols from arvl aldehvdes or arvl keLones vla oxldaLlon wlLh
hvdroaen peroxlde ln Lhe presence of baseŦ 1he arvl formaLe or alkanoaLe formed as an lnLermedlaLe ls
subsequenLlv saponlfled Lo vleld Lhe subsLlLuLed phenol producLŦ
ttbo or poto +M subsLlLuenLs (nP
2
ţ CP) favor Lhls reacLlonŦ
Darzens keact|on
Darzens Condensat|on

1he uarzens 8eacLlon ls Lhe condensaLlon of a carbonvl compound wlLh an ĐŴhalo esLer ln Lhe presence of a base
Lo form an ĐţĒŴepoxv esLerŦ

Mechan|sm of the Darzens keact|on
AfLer deproLonaLlonţ Lhe ĐŴhalo esLer adds Lo Lhe carbonvl compound Lo alve svo and oot dlasLereomersť

ln Lhe subsequenL sLepţ an lnLramolecular S
n
2 reacLlon forms Lhe epoxldeť

D|azot|sat|on

1he nlLrosaLlon of prlmarv aromaLlc amlnes wlLh nlLrous acld (aeneraLed ln slLu from sodlum nlLrlLe and a sLrona
acldţ such as hvdrochlorlc acldţ sulfurlc acldţ or P8l
4
) leads Lo dlazonlum salLsţ whlch can be lsolaLed lf Lhe
counLerlon ls nonŴnucleophlllcŦ
ulazonlum salLs are lmporLanL lnLermedlaLes for Lhe preparaLlon of halldes (Sandmever 8eacLlonţ Schlemann
8eacLlon)ţ and azo compoundsŦ ulazonlum salLs can reacL as pseudohalldeŴLvpe elecLrophllesţ and can Lherefore
be used ln speclflc proLocols for LhePeck 8eacLlon or Suzukl CoupllnaŦ
1he lnLermedlaLes resulLlna from Lhe dlazoLlzaLlon of prlmarvţ allphaLlc amlnes are unsLableŤ Lhev are rapldlv
converLed lnLo carbocaLlons afLer loss of nlLroaenţ and vleld producLs derlved from subsLlLuLlonţ ellmlnaLlon or
rearranaemenL processesŦ

Mechan|sm of D|azot|sat|on



D|eckmann Condensat|on

1he baseŴcaLalvzed lnLramolecular condensaLlon of a dlesLerŦ 1he uleckmann CondensaLlon works well Lo produce
3Ŵ or 6Ŵmembered cvcllc ßŴkeLo esLersţ and ls usuallv effecLed wlLh sodlum alkoxlde ln alcohollc solvenLŦ
1he vlelds are aood lf Lhe producL has an enollzable proLonŤ oLherwlseţ Lhe reverse reacLlon (cleavaae wlLh rlna
sclsslon) can compeLeŦ See Lhe Clalsen CondensaLlonŦ
D|e|sŴA|der keact|on


1he ż4+2ŽŴcvcloaddlLlon of a con[uaaLed dlene and a dlenophlle (an alkene or alkvne)ţ an elecLrocvcllc reacLlon
LhaL lnvolves Lhe 4 nŴelecLrons of Lhe dlene and 2 nŴelecLrons of Lhe dlenophlleŦ 1he drlvlna force of Lhe reacLlon
ls Lhe formaLlon of new oŴbondsţ whlch are eneraeLlcallv more sLable Lhan Lhe nŴbondsŦ
ln Lhe case of an alkvnvl dlenophlleţ Lhe lnlLlal adducL can sLlll reacL as a dlenophlle lf noL Loo sLerlcallv hlnderedŦ
ln addlLlonţ elLher Lhe dlene or Lhe dlenophlle can be subsLlLuLed wlLh cumulaLed double bondsţ such as
subsLlLuLed allenesŦ
WlLh lLs broad scope and slmpllclLv of operaLlonţ Lhe ulelsŴAlder ls Lhe mosL powerful svnLheLlc meLhod for
unsaLuraLed slxŴmembered rlnasŦ
A varlanL ls Lhe heLeroŴulelsŴAlderţ ln whlch elLher Lhe dlene or Lhe dlenophlle conLalns a heLeroaLomţ mosL ofLen
nlLroaen or oxvaenŦ 1hls alLernaLlve consLlLuLes a powerful svnLhesls of slxŴmembered rlna heLerocvclesŦ

Mechan|sm of the D|e|sŴA|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|scherŴ5pe|er Lster|f|cat|on

1he Lewls or 8rønsLedL acldŴcaLalvzed esLerlflcaLlon of carboxvllc aclds wlLh alcohols Lo alve esLers ls a Lvplcal
reacLlon ln whlch Lhe producLs and reacLanLs are ln equlllbrlumŦ
1he equlllbrlum mav be lnfluenced bv elLher removlna one producL from Lhe reacLlon mlxLure (for exampleţ
removal of Lhe waLer bv azeoLroplc dlsLlllaLlon or absorpLlon bv molecular sleves) or bv emplovlna an excess of
one reacLanLŦ

Mechan|sm of the I|scher Lster|f|cat|on
AddlLlon of a proLon (eŦaŦť pŴ1sCPţ P
2
SC
4
) or a Lewls acld leads Lo a more reacLlve elecLrophlleŦ nucleophlllc
aLLack of Lhe alcohol alves a LeLrahedral lnLermedlaLe ln whlch Lhere are Lwo equlvalenL hvdroxvl aroupsŦ Cne of
Lhese hvdroxvl aroups ls ellmlnaLed afLer a proLon shlfL (LauLomerlsm) Lo alve waLer and Lhe esLerŦ

AlLernaLlve reacLlons emplov coupllna reaaenLs such as uCC (SLeallch LsLerlflcaLlon)ţ preformed esLers
(LransesLerlflcaLlon)ţ carboxvllc acld chlorldes or anhvdrldes (see overvlew)Ŧ 1hese reacLlons avold Lhe producLlon
of waLerŦ AnoLher paLhwav for Lhe producLlon of esLers ls Lhe formaLlon of a carboxvlaLe anlonţ whlch Lhen reacLs
as a nucleophlle wlLh an elecLrophlle (slmllar reacLlons can be found here)Ŧ LsLers mav also be produced bv
oxldaLlonsţ namelv bv Lhe 8aeverŴvllllaer oxldaLlon and oxldaLlve esLerlflcaLlonsŦ
Iavorsk|| keact|on

1he rearranaemenL of cvclopropanonesţ ofLen obLalned as lnLermedlaLes from Lhe baseŴcaLalvzed reacLlon of ĐŴ
halo keLonesţ leadlna Lo carboxvllc aclds and derlvaLlvesŦ

Mechan|sm of the Iavorsk|| keact|on

LsLers are obLalned lf alkoxlde bases are usedť

A dlrecL converslon from ĐŴhalo keLones ls posslbleť

8lnaŴconLracLlonť

Ir|ede|ŴCrafts Acy|at|on

1hls elecLrophlllc aromaLlc subsLlLuLlon allows Lhe svnLhesls of monoacvlaLed producLs from Lhe reacLlon beLween
arenes and acvl chlorldes or anhvdrldesŦ 1he producLs are deacLlvaLedţ and do noL underao a second subsLlLuLlonŦ
normallvţ a sLolchlomeLrlc amounL of Lhe Lewls acld caLalvsL ls requlredţ because boLh Lhe subsLraLe and Lhe
producL form complexesŦ

1he lrledelŴCrafLs AlkvlaLlon mav alve polvalkvlaLed producLsţ so Lhe lrledelŴCrafLs AcvlaLlon ls a valuable
alLernaLlveŦ 1he acvlaLed producLs mav easllv be converLed Lo Lhe correspondlna alkanes vla Clemmensen
8educLlon or WolffŴklshner 8educLlonŦ


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




Ir|ede|ŴCrafts A|ky|at|on

1hls Lewls acldŴcaLalvzed elecLrophlllc aromaLlc subsLlLuLlon allows Lhe svnLhesls of alkvlaLed producLs vla Lhe
reacLlon of arenes wlLh alkvl halldes or alkenesŦ Slnce alkvl subsLlLuenLs acLlvaLe Lhe arene subsLraLeţ
polvalkvlaLlon mav occurŦ A valuableţ LwoŴsLep alLernaLlve ls lrledelŴCrafLs AcvlaLlon followed bv a carbonvl
reducLlonŦ

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


uslna alkenes ť

Ir|es kearrangement

1he lrles 8earranaemenL enables Lhe preparaLlon of acvl phenolsŦ

Mechan|sm of the Ir|es kearrangement
1he reacLlon ls caLalvzed bv 8rønsLed or Lewls aclds such as Plţ AlCl
3
ţ 8l
3
ţ 1lCl
4
or SnCl
4
Ŧ 1he aclds are used ln
excess of Lhe sLolchlomeLrlc amounLţ especlallv Lhe Lewls acldsţ slnce Lhev form complexes wlLh boLh Lhe sLarLlna
maLerlals and producLsŦ

1he complex can dlssoclaLe Lo form an acvllum lonŦ uependlna on Lhe solvenLţ an lon palr can formţ and Lhe lonlc
specles can reacL wlLh each oLher wlLhln Lhe solvenL caaeŦ Poweverţ reacLlon wlLh a more dlsLanL molecule ls also
posslbleť

AfLer hvdrolvslsţ Lhe producL ls llberaLedŦ

1he reacLlon ls ottboţpotoŴselecLlve so LhaLţ for exampleţ Lhe slLe of acvlaLlon can be reaulaLed bv Lhe cholce of
LemperaLureŦ Cnlv sLerlcallv unhlndered arenes are sulLable subsLraLesţ slnce subsLlLuenLs wlll lnLerfere wlLh Lhls
reacLlonŦ
1he requlremenL for equlmolar quanLlLles of Lhe caLalvsLţ Lhe corroslve and Loxlc condlLlons (Pl)ţ and Lhe vlolenL
reacLlon of Lhe caLalvsL wlLh waLer have prompLed Lhe developmenL of newer proLocolsŦ ZeollLes have proven Lo
be unsulLableţ slnce Lhev are deacLlvaLedţ buL sLrona acldsţ such as sulfonlc acldsţ provlde a reasonable
alLernaLlveŦ
An addlLlonal opLlon for lnduclna a lrles 8earranaemenL ls phoLochemlcal exclLaLlonţ buL Lhls meLhod ls onlv
feaslble ln Lhe laboraLorvť

Gabr|e| 5ynthes|s

ÞoLasslum phLhallmlde ls a
Ŵ
nP
2
ŴsvnLhon whlch allows Lhe preparaLlon of prlmarv amlnes bv reacLlon wlLh alkvl
halldesŦ AfLer alkvlaLlonţ Lhe phLhallmld ls noL nucleophlle and does noL reacL anvmoreŦ ÞroducL ls cleaved bv
reacLlon wlLh base or hvdrazlneţ whlch leads Lo a sLable cvcllc producLŦ

Mechan|sm of the Gabr|e| 5ynthes|s
noLeť ÞhLhallmlde ls acldlc!


Cleavaaeť

Gr|gnard keact|on
Gr|gnard keagents

1he Crlanard 8eacLlon ls Lhe addlLlon of an oraanomaaneslum hallde (Crlanard reaaenL) Lo a keLone or aldehvdeţ
Lo form a LerLlarv or secondarv alcoholţ respecLlvelvŦ 1he reacLlon wlLh formaldehvde leads Lo a prlmarv alcoholŦ
Crlanard 8eaaenLs are also used ln Lhe followlna lmporLanL reacLlonsť 1he addlLlon of an excess of a Crlanard
reaaenL Lo an esLer or lacLone alves a LerLlarv alcohol ln whlch Lwo alkvl aroups are Lhe sameţ and Lhe addlLlon of
a Crlanard reaaenL Lo a nlLrlle produces an unsvmmeLrlcal keLone vla a meLallolmlne lnLermedlaLeŦ (Some more
reacLlons are deplcLed below)

Mechan|sm of the Gr|gnard keact|on
Whlle Lhe reacLlon ls aenerallv LhouahL Lo proceed Lhrouah a nucleophlllc addlLlon mechanlsmţ sLerlcallv hlndered
subsLraLes mav reacL accordlna Lo an SL1 (slnale elecLron Lransfer) mechanlsmť

WlLh sLerlcallv hlndered keLones Lhe followlna slde producLs are recelvedť
1he Crlanard reaaenL can acL as baseţ wlLh deproLonaLlon vleldlna an enolaLe lnLermedlaLeŦ AfLer work upţ Lhe
sLarLlna keLone ls recoveredŦ

A reducLlon can also Lake placeţ ln whlch a hvdrlde ls dellvered from Lhe ĒŴcarbon of Lhe Crlanard reaaenL Lo Lhe
carbonvl carbon vla a cvcllc slxŴmembered LranslLlon sLaLeŦ

Add|t|ona| react|ons of Gr|gnard keagentsť
WlLh carboxvllc acld chlorldesť

LsLers are less reacLlve Lhan Lhe lnLermedlaLe keLonesţ Lherefore Lhe reacLlon ls onlv sulLable for svnLhesls of
LerLlarv alcohols uslna an excess of Crlanard 8eaaenLť

WlLh nlLrllesť

WlLh CC
2
(bv addlna drv lce Lo Lhe reacLlon mlxLure)ť

WlLh oxlranesť

na|oform keact|on

1hls reacLlon has been used ln quallLaLlve analvsls Lo lndlcaLe Lhe presence of a meLhvl keLoneŦ 1he producL
lodoform ls vellow and has a characLerlsLlc odourŦ 1he reacLlon has some svnLheLlc uLlllLv ln Lhe oxldaLlve
demeLhvlaLlon of meLhvl keLones lf Lhe oLher subsLlLuenL on Lhe carbonvl aroups bears no enollzable ĐŴproLonsŦ

Mechan|sm of the na|oform keact|on
1he reacLlon readllv proceeds Lo compleLlon because of Lhe acldlfvlna effecL of Lhe haloaen subsLlLuenLsŦ

ne||ŴVo|hardŴ2e||nsky keact|on

1reaLmenL wlLh bromlne and a caLalvLlc amounL of phosphorus leads Lo Lhe selecLlve ĐŴbromlnaLlon of carboxvllc
acldsŦ

Mechan|sm of the ne||ŴVo|hardŴ2e||nsky keact|on
Þhosphorus reacLs wlLh bromlne Lo alve phosphorus Lrlbromldeţ and ln Lhe flrsL sLep Lhls converLs Lhe carboxvllc
acld lnLo an acvl bromldeŦ

An acvl bromlde can readllv exlsL ln Lhe enol formţ and Lhls LauLomer ls rapldlv bromlnaLed aL Lhe ĐŴcarbonŦ 1he
monobromlnaLed compound ls much less nucleophlllcţ so Lhe reacLlon sLops aL Lhls sLaaeŦ 1hls acvl lnLermedlaLe
compound can underao bromlde exchanae wlLh unreacLed carboxvllc acld vla Lhe anhvdrldeţ whlch allows Lhe
caLalvLlc cvcle Lo conLlnue unLll Lhe converslon ls compleLeŦ

nofmann L||m|nat|on

SomeLlmes referred Lo as Lhe Pofmann uearadaLlonŦ 1hls ellmlnaLlon reacLlon of alkvl LrlmeLhvl amlnes proceeds
wlLh ootŴsLereochemlsLrvţ and ls aenerallv sulLable for produclna alkenes wlLh one or Lwo subsLlLuenLsŦ 1he
reacLlon follows Lhe Pofmann 8uleŦ

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


nunsd|ecker keact|on

1he sllver(l) salLs of carboxvllc aclds reacL wlLh haloaens Lo alve unsLable lnLermedlaLes whlch readllv
decarboxvlaLe Lhermallv Lo vleld alkvl halldesŦ 1he reacLlon ls belleved Lo lnvolve homolvsls of Lhe CŴC bond and a
radlcal chaln mechanlsmŦ

Mechan|sm of the nunsd|ecker keact|on



8rown nydroborat|on

1he svoŴaddlLlon of hvdroboranes Lo alkenes occurs wlLh predlcLable selecLlvlLvţ whereln Lhe boron adds
preferenLlallv Lo Lhe leasL hlndered carbonŦ 1hls selecLlvlLv ls enhanced lf sLerlcallv demandlna boranes are usedŦ

Coupllna Lhe hvdroboraLlon wlLh a subsequenL oxldaLlon of Lhe new formed borane vlelds ootŴ
Markovnlkov alcoholsŦ 1he hvdroboraLlon/oxldaLlon sequence consLlLuLes a powerful meLhod for Lhe realoŴ and
sLereoselecLlve svnLhesls of alcoholsŦ
1he producL boranes mav also be used as sLarLlna maLerlals for oLher reacLlonsţ such as Suzukl Coupllnas (see
8ecenL LlLeraLure)Ŧ

Mechan|sm of the 8rown nydroborat|on
1he selecLlvlLv of Lhe flrsL addlLlon of borane can be relaLlvelv lowť


1he subsequenL addlLlons are more selecLlve as Lhe sLerlc bulk lncreasesţ and ootŴMarkovnlkov selecLlvlLv
predomlnaLes ln Lhe endť

CxldaLlon wlLh hvdroaen peroxlde leads Lo alcoholsť

SLerlcallv demandlna boranes offer enhanced selecLlvlLvŦ Cne example of a sLerlcallv demandlna borane (9Ŵ88n) ls
aeneraLed bv Lhe double addlLlon of borane Lo 1ţ3ŴcvcloocLadleneť
9Ŵ8orablcvcloż3Ŧ3Ŧ1Žnonane


1he reacLlvlLv and selecLlvlLv of Lhe borane reaaenL mav be modlfled Lhrouah Lhe use of boraneŴLewls base
complexesŦ
ko|be L|ectro|ys|s

1he elecLrochemlcal oxldaLlve decarboxvlaLlon of carboxvllc acld salLs LhaL leads Lo radlcalsţ whlch dlmerlzeŦ lL ls
besL applled Lo Lhe svnLhesls of svmmeLrlcal dlmersţ buL ln some cases can be used wlLh a mlxLure of Lwo
carboxvllc aclds Lo furnlsh unsvmmeLrlcal dlmersŦ

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

ko|beŴ5chm|tt keact|on

A baseŴpromoLed carboxvlaLlon of phenols LhaL allows Lhe svnLhesls of sallcvllc acld derlvaLlvesŦ

Mechan|sm of the ko|beŴ5chm|tt keact|on


Meerwe|nŴÞonndorfŴVer|ey keduct|on

1he alumlnlumŴcaLalvzed hvdrlde shlfL from Lhe aŴcarbon of an alcohol componenL Lo Lhe carbonvl carbon of a
second componenLţ whlch proceeds vla a slxŴmembered LranslLlon sLaLeţ ls referred Lo as Lhe MeerwelnŴ
ÞonndorfŴverlev 8educLlon (MÞv) or LheCppenauer CxldaLlonţ dependlna on whlch componenL ls Lhe deslred
producLŦ lf Lhe alcohol ls Lhe deslred producLţ Lhe reacLlon ls vlewed as Lhe MeerwelnŴÞonndorfŴverlev 8educLlonŦ
lsopropanol ls useful as a hvdrlde donor because Lhe resulLlna aceLone mav be conLlnuouslv removed from Lhe
reacLlon mlxLure bv dlsLlllaLlonŦ
Crlanard 8eaaenLs wlll someLlmes vleld Lhe resulL of an MÞv reducLlon lf Lhe carbonvl carbon ls Loo hlndered for
nucleophlllc addlLlonŦ
M|chae| Add|t|on

1he 1ţ4ŴaddlLlon (or con[uaaLe addlLlon) of resonanceŴsLablllzed carbanlonsŦ 1he Mlchael AddlLlon ls
Lhermodvnamlcallv conLrolledŤ Lhe reacLlon donors are acLlve meLhvlenes such as malonaLes and nlLroalkanesţ
and Lhe accepLors are acLlvaLed oleflns such as ĐţĒŴunsaLuraLed carbonvl compoundsŦ
Lxamplesť
donors
accepLors

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


Nef keact|on



1he converslon of nlLro compounds lnLo carbonvls ls known as Lhe nef 8eacLlonŦ varlous meLhodoloales have
been developedţ buL Lhe mosL lmporLanL ls Lhe sLandard procedureť a preformed nlLronaLe salL ls poured lnLo
sLrona aqueous acld (pP Ƽ 1)Ŧ Some oxldaLlve varlaLlons have also found wlde appllcaLlonţ and some reducLlve
meLhods have even been developedŦ

Mechan|sm of the Nef keact|on
nlLroalkanes are relaLlvelv sLrona carbon acldsţ and deproLonaLlon leads Lo Lhe nlLronaLe salLŦ 1he hvdrolvsls of
Lhls lnLermedlaLe musL Lake place ln sLrona acldţ Lo prevenL Lhe formaLlon of slde producLs such as oxlmes or
hvdroxvnlLroso compoundsť

Nuc|eoph|||c 5ubst|tut|on (5
N
1
5
N
2)

nucleophlllc subsLlLuLlon ls Lhe reacLlon of an elecLron palr donor (Lhe nucleophlleţ nu) wlLh an elecLron palr
accepLor (Lhe elecLrophlle)Ŧ An sp
3
Ŵhvbrldlzed elecLrophlle musL have a leavlna aroup (x) ln order for Lhe reacLlon
Lo Lake placeŦ

Mechan|sm of Nuc|eoph|||c 5ubst|tut|on
1he Lerm S
n
2 means LhaL Lwo molecules are lnvolved ln Lhe acLual LranslLlon sLaLeť

1he deparLure of Lhe leavlna aroup occurs slmulLaneouslv wlLh Lhe backslde aLLack bv Lhe nucleophlleŦ 1he S
n
2
reacLlon Lhus leads Lo a predlcLable conflauraLlon of Lhe sLereocenLer Ŵ lL proceeds wlLh lnverslon (reversal of Lhe
conflauraLlon)Ŧ
ln Lhe S
n
1 reacLlonţ a planar carbenlum lon ls formed flrsLţ whlch Lhen reacLs furLher wlLh Lhe nucleophlleŦ Slnce
Lhe nucleophlle ls free Lo aLLack from elLher sldeţ Lhls reacLlon ls assoclaLed wlLh racemlzaLlonŦ

ln boLh reacLlonsţ Lhe nucleophlle compeLes wlLh Lhe leavlna aroupŦ 8ecause of Lhlsţ one musL reallze whaL
properLles a leavlna aroup should haveţ and whaL consLlLuLes a aood nucleophlleŦ lor Lhls reasonţ lL ls worLhwhlle
Lo know whlch facLors wlll deLermlne wheLher a reacLlon follows an S
n
1 or S
n
2 paLhwavŦ
verv aood leavlna aroupsţ such as LrlflaLeţ LosvlaLe and mesvlaLeţ sLablllze an lnclplenL neaaLlve charaeŦ 1he
delocallzaLlon of Lhls charae ls reflecLed ln Lhe facL LhaL Lhese lons are noL consldered Lo be nucleophlllcŦ

Pvdroxlde and alkoxlde lons are noL aood leavlna aroupsŤ howeverţ Lhev can be acLlvaLed bv means of Lewls or
8rønsLed acldsŦ

Lpoxldes are an excepLlonţ slnce Lhev relleve Lhelr rlna sLraln when Lhev underao nucleophlllc subsLlLuLlonţ wlLh
acLlvaLlon bv acld belna opLlonalť

1rlflaLeţ LosvlaLe and mesvlaLe are Lhe anlons of sLrona acldsŦ 1he weak con[uaaLe bases are poor nucleophllesŦ
nucleophlllclLv lncreases ln parallel wlLh Lhe base sLrenaLhŦ 1husţ amlnesţ alcohols and alkoxldes are verv aood
nucleophllesŦ 8ase sLrenaLh ls a rouah measure of how reacLlve Lhe nonbondlna elecLron palr lsŤ Lhusţ lL ls noL
necessarv for a nucleophlle Lo be anlonlcŦ
under subsLlLuLlon condlLlonsţ amlnes proceed all Lhe wav Lo form quaLernarv salLsţ whlch makes lL dlfflculL Lo
conLrol Lhe exLenL of Lhe reacLlonŦ

Poweverţ as a nucleophlleƌs base sLrenaLh and sLerlc hlndrance lncreaseţ lLs baslclLv Lends Lo be accenLuaLedŦ lf
Lhere are absLracLable proLons aL Lhe ĒŴposlLlon of Lhe elecLrophlleţ an ellmlnaLlon paLhwav can compeLe wlLh Lhe
nucleophlllc subsLlLuLlonŦ

An addlLlonal facLor LhaL plavs a role ls Lhe characLer of Lhe solvenLŦ lncreaslna sLablllzaLlon of Lhe nucleophlle bv
Lhe solvenL resulLs ln decreaslna reacLlvlLvŦ 1husţ polar proLlc solvenLs wlll sLablllze Lhe chlorlde and bromlde lons
Lhrouah Lhe formaLlon of hvdroaen bonds Lo Lhese smaller anlonsŦ lodlde ls a comparaLlvelv beLLer nucleophlle ln
Lhese solvenLsŦ 1he reverse behavlor predomlnaLes ln aproLlc polar medlaŦ
1he solvenL also plavs an lmporLanL role ln deLermlnlna whlch paLhwav Lhe reacLlon wlll Lakeţ S
n
1 versus S
n
2Ŧ lL
mav safelv be assumed LhaL a prlmarvŴsubsLlLuLed leavlna aroup wlll follow an S
n
2 paLhwav ln anv caseţ slnce Lhe
formaLlon of Lhe correspondlna unsLable prlmarv carbenlum lon ls dlsfavoredŦ 8eacLlon bv Lhe S
n
1 paLhwav ls
hlahlv probable for compounds wlLh LerLlarv subsLlLuLlonţ slnce Lhe correspondlna LerLlarv carbenlum lon ls
sLablllzed Lhrouah hvpercon[uaaLlonť

1he beLLer Lhe solvenL sLablllzes Lhe lonsţ Lhe more probable LhaL Lhe reacLlon wlll follow an S
n
1 paLhwav (eŦaŦţ ln
polar proLlc solvenLs such as waLer/aceLone)Ŧ 1he more hlahlv subsLlLuLed ls Lhe lnclplenL carbenlum lonţ Lhe
more probable LhaL Lhe reacLlon wlll follow an S
n
1 paLhwavŦ 1he more unreacLlve Lhe nucleophlleţ Lhe more
probable lL becomes LhaL a reacLlon wlLh secondarv and LerLlarv elecLrophlles wlll follow an S
n
1 paLhwavŦ A
weaker nucleophlle ls noL as effecLlve ln Lhe backslde aLLackţ slnce Lhls locaLlon ls sLerlcallv shleldedţ especlallv ln
Lhe case of LerLlarv subsLraLesŦ Carbenlum lons are planar and Lherefore less sLerlcallv hlnderedţ and are naLurallv
more reacLlve as elecLrophlles Lhan Lhe uncharaed parenL compoundŦ
1he hvdrolvsls of tettŴbuLvl chlorlde ls a Lvplcal S
n
1 reacLlonť

Cppenauer Cx|dat|on

1he alumlnlumŴcaLalvzed hvdrlde shlfL from Lhe ĐŴcarbon of an alcohol componenL Lo Lhe carbonvl carbon of a
second componenLţ whlch proceeds over a slxŴmembered LranslLlon sLaLeţ ls named MeerwelnŴÞonndorfŴverlevŴ
8educLlon (MÞv) or Cppenauer CxldaLlon (CÞÞ) dependlna on Lhe lsolaLed producLŦ lf aldehvdes or keLones are
Lhe deslred producLsţ Lhe reacLlon ls vlewed as Lhe Cppenauer CxldaLlonŦ
nonŴenollzable keLones wlLh a relaLlvelv low reducLlon poLenLlalţ such as benzophenoneţ can serve as Lhe
carbonvl componenL used as Lhe hvdrlde accepLor ln Lhls oxldaLlonŦ
Czono|ys|s
Cr|egee Mechan|sm



Czonolvsls allows Lhe cleavaae of alkene double bonds bv reacLlon wlLh ozoneŦ uependlna on Lhe work upţ
dlfferenL producLs mav be lsolaLedť reducLlve workŴup alves elLher alcohols or carbonvl compoundsţ whlle
oxldaLlve workŴup leads Lo carboxvllc aclds or keLonesŦ

Mechan|sm of Czono|ys|s
1he mechanlsm was suaaesLed bv Crleaee (ooewŦ cbemŦ lotŦ £JŦţ 1975ţ ţ 743Ŧ uCl) and has been recenLlv
revlslLed uslna
17
CŴnM8 SpecLroscopv bv Lhe 8eraer Croup (£otŦ IŦ toŦ cbemŦţ 1998ţ 1623Ŧ uCl)Ŧ
llrsL sLep ls a 1ţ3Ŵdlpolar cvcloaddlLlon of ozone Lo Lhe alkene leadlna Lo Lhe prlmarv ozonlde (molozonldeţ 1ţ2ţ3Ŵ
Lrloxolaneţ or Crleaee lnLermedlaLe) whlch decomposes Lo alve a carbonvl oxlde and a carbonvl compoundť

1he carbonvl oxldes are slmllar Lo ozone ln belna 1ţ3Ŵdlpolar compoundsţ and underao 1ţ3Ŵdlpolar cvcloaddlLlon
Lo Lhe carbonvl compounds wlLh Lhe reverse realochemlsLrvţ leadlna Lo a mlxLure of Lhree posslble secondarv
ozonldes (1ţ2ţ4ŴLrloxolanes)ť



1hese secondarv ozonldes are more sLable Lhan prlmarv ozonldesŦ Lven lf Lhe peroxv brldae ls shlelded bv sLerlc
demandlna aroups leadlna Lo lsolable producLsţ Lhev should noL be lsolaLed from an unmodlfled ozonolvslsţ
because sLlll more exploslve slde producLs (LeLroxanes) mav have been formedť

As endoperoxldes are lnvesLlaaLed as anLlmalarlal compoundsţ more selecLlve meLhods have been developed for
Lhelr preparaLlon (for example Lhe Crlesbaum Coozonolvsls)Ŧ Some reacLlons can be found hereť vŦ uŦ8Ŧ
8onlfacloţ toŦ cbemŦ noblobts 2004ţ CcLober 23Ŧ Llnk
1he Crleaee mechanlsm ls valld for reacLlons ln hvdrocarbonsţ CP
2
Cl
2
ţ or oLher nonŴlnLeracLlve solvenLsŦ Alcohols
reacL wlLh Lhe carbonvl oxlde Lo alve hvdroperoxv hemlaceLalsť

1he svnLheLlc value lles ln Lhe wav Lhe complex mlxLures of lnLermedlaLes can be worked up Lo alve a deflned
composlLlon of producLs and a clean converslon of all peroxlde speclesŦ 1he Lhree maln posslblllLles are alven
aboveţ alona wlLh examples for Lhe reaaenLs usedŦ
Þ|naco| kearrangement

ln Lhe converslon LhaL aave lLs name Lo Lhls reacLlonţ Lhe acldŴcaLalvzed ellmlnaLlon of waLer from plnacol alves tŴ
buLvl meLhvl keLoneŦ

Mechan|sm of the Þ|naco| kearrangement
1hls reacLlon occurs wlLh a varleLv of fullv subsLlLuLed 1ţ2Ŵdlolsţ and can be undersLood Lo lnvolve Lhe formaLlon
of a carbenlum lon lnLermedlaLe LhaL subsequenLlv underaoes a rearranaemenLŦ 1he flrsL aeneraLed lnLermedlaLeţ
an ĐŴhvdroxvcarbenlum lonţ rearranaes Lhrouah a 1ţ2Ŵalkvl shlfL Lo produce Lhe carbonvl compoundŦ lf Lwo of Lhe
subsLlLuenLs form a rlnaţ Lhe Þlnacol 8earranaemenL can consLlLuLe a rlnaŴexpanslon or rlnaŴconLracLlon reacLlonŦ



Þróvost keact|on

1he ÞrevosL 8eacLlon allows Lhe svnLhesls of ootŴdlols from alkenes bv Lhe addlLlon of lodlne followed bv
nucleophlllc dlsplacemenL wlLh benzoaLe ln Lhe absence of waLerŦ Pvdrolvsls of Lhe lnLermedlaLe dlesLer alves Lhe
deslred dlolŦ
1he Woodward ModlflcaLlon of Lhe ÞrevosL 8eacLlon alves svoŴdlolsŦ

Mechan|sm of the Þrevost keact|on
1he lnlLlal addlLlon of lodlne leads Lo a cvcllc lodonlum lonţ whlch ls opened Lhrouah nucleophlllc subsLlLuLlon bv
benzoaLe anlonť

A nelahbourlnaŴaroup parLlclpaLlon mechanlsm prevenLs Lhe lmmedlaLe nucleophlllc subsLlLuLlon of lodlne bv a
second equlvalenL of benzoaLe LhaL would lead Lo a svoŴsubsLlLuLed producLŦ lnsLeadţ a cvcllc benzoxonlum lon
lnLermedlaLe ls formedť

Cpenlna of Lhls lnLermedlaLe bv a second addlLlon of benzoaLe alves Lhe ootŴsubsLlLuLed dlbenzoaLeť

Pvdrolvsls Lhen dellvers Lhe dlolŦ
Þr|ns keact|on
1he Þrlns 8eacLlon ls Lhe acldŴcaLalvzed of addlLlon aldehvdes Lo alkenesţ and alves dlfferenL producLs dependlna
on Lhe reacLlon condlLlonsŦ lL can be LhouahL of concepLuallv as Lhe addlLlon of Lhe elemenLs of Lhe aemŴdlol
carbonvl hvdraLe of Lhe aldehvde across Lhe double bondŦ

An excess of aldehvde and LemperaLures Ƽ 70 ¨C lead Lo Lhe formaLlon of aceLalsŦ When one equlvalenL of
aldehvde ls used and LemperaLures are ƽ 70 ¨C dlols or allvllc alcohols mav be lsolaLedŦ


AlLhouah Lhe mechanlsm ls dlfferenLţ a Þrlns allvllc alcohol producL ls equlvalenL Lo Lhe resulL of an Lne 8eacLlonŦ

Mechan|sm of the Þr|ns keact|on




keformatsky keact|on

1he formaLlon of esLerŴsLablllzed oraanozlnc reaaenLs and Lhelr addlLlon Lo carbonvl compounds

Mechan|sm of the keformatsky keact|on
Craanozlnc compounds are prepared from ĐŴhaloaenesLers ln Lhe same manner as Crlanard 8eaaenLsŦ 1hls
reacLlon ls posslble due Lo Lhe sLablllLv of esLers aaalnsL oraanozlncsŦ uue Lo Lhe verv low baslclLv of zlnc enolaLesţ
Lhere ls hardlv anv compeLlLlon from proLon Lransferţ and Lhe scope of carbonvl addlLlon parLners ls qulLe broadŦ
ln presence of keLones or aldehvdesţ Lhe oraanozlnc compounds reacL as Lhe nucleophlllc parLner ln an addlLlon
Lo alve ĒŴhvdroxv esLersŦ
An esLerŴsLablllzed oraanozlnc reaaenL
Compared Lo oraanollLhlums and oraanomaaneslum halldes (Crlanard reaaenLs)ţ Lhe oraanozlnc hallde reaaenLs
used ln Lhe 8eformaLskv 8eacLlon are relaLlvelv sLableţ and manv are avallable commerclallvŦ
kosenmund keduct|on

1he caLalvLlc hvdroaenaLlon of acld chlorldes allows Lhe formaLlon of aldehvdesŦ

Mechan|sm of the kosenmund keduct|on
Slde producLsť

1he Þd caLalvsL musL be polsonedţ for example wlLh 8aSC
4
ţ because Lhe unLreaLed caLalvsL ls Loo reacLlve and wlll
alve some overreducLlonŦ Some of Lhe slde producLs can be avolded lf Lhe reacLlon ls conducLed ln sLrlcLlv
anhvdrous solvenLsŦ
5andmeyer keact|on

1he subsLlLuLlon of an aromaLlc amlno aroup ls posslble vla preparaLlon of lLs dlazonlum salL and subsequenL
dlsplacemenL wlLh a nucleophlle (ClŴţ lŴţ CnŴţ 8SŴţ PCŴ)Ŧ Manv Sandmever 8eacLlons proceed under copper(l)
caLalvslsţ whlle Lhe SandmeverŴLvpe reacLlons wlLh Lhlolsţ waLer and poLasslum lodlde donƌL requlre caLalvslsŦ

1he Sandmever 8eacLlon ls a verv lmporLanL LransformaLlon ln aromaLlc chemlsLrvţ because lL can resulL ln some
subsLlLuLlon paLLerns LhaL are noL achlevable bv dlrecL subsLlLuLlonŦ
lluorlnaLlon ls posslble bv uslna Lhe relaLed Schlemann 8eacLlonŦ

Mechan|sm of the 5andmeyer keact|on

8a|zŴ5ch|emann keact|on

1he converslon of arvl amlnes Lo arvl fluorldes vla dlazoLlsaLlon and subsequenL Lhermal decomposlLlon of Lhe
derlved LeLrafluoroboraLes or hexafluorophosphaLesŦ 1he decomposlLlon mav also be lnduced phoLochemlcallvŦ

Mechan|sm of the 8a|zŴ5ch|emann keact|on
see ulazoLlsaLlonŦ
1he mechanlsm of Lhe 8alzŴSchlemann reacLlon remalns obscureŦ A posslble paLhwav ls shown belowť

5chm|dt keact|on





1he acldŴcaLalvsed reacLlon of hvdroaen azlde wlLh elecLrophllesţ such as carbonvl compoundsţ LerLlarv alcohols
or alkenesŦ AfLer a rearranaemenL and exLruslon of n
2
ţ amlnesţ nlLrllesţ amldes or lmlnes are producedŦ

Mechan|sm of the 5chm|dt keact|on
8eacLlon of carboxvllc aclds alves acvl azldesţ whlch rearranae Lo lsocvanaLesţ and Lhese mav be hvdrolvzed Lo
carbamlc acld or solvolvsed Lo carbamaLesŦ uecarboxvlaLlon leads Lo amlnesŦ

1he reacLlon wlLh a keLone alves an azldohvdrln lnLermedlaLeţ whlch rearranaes Lo form an amldeť

Alkenes are able Lo underao addlLlon of Pn
3
as wlLh anv Px reaaenLţ and Lhe resulLlna alkvl azlde can rearranae Lo
form an lmlneť

1erLlarv alcohols alve subsLlLuLlon bv azlde vla a carbenlum lonţ and Lhe resulLlna alkvl azlde can rearranae Lo
form an lmlneŦ
5chottenŴ8aumann keact|on
5chottenŴ8aumann Cond|t|ons

1he use of added base Lo drlve Lhe equlllbrlum ln Lhe formaLlon of amldes from amlnes and acld chlorldesŦ
1he acvlaLlon of amlnes wlLh carboxvllc acld chlorldes leads Lo Lhe producLlon of one equlvalenL acldţ whlch wlll
form a salL wlLh unreacLed amlne and dlmlnlsh Lhe vleldŦ 1he addlLlon of an addlLlonal equlvalenL of base Lo
neuLrallse Lhls acld ls a wav Lo opLlmlse Lhe condlLlonsŦ normallvţ aqueous base ls slowlv added Lo Lhe reacLlon
mlxLureŦ
ln aeneralţ Lhe use of blphaslc aqueous baslc condlLlons ls ofLen named ƍSchoLLenŴ8aumann condlLlonsƍŦ

Mechan|sm of the 5chottenŴ8aumann keact|on

5|mmonsŴ5m|th keact|on

1hls reacLlon affords Lhe cvclopropanaLlon of oleflnsŦ

Mechan|sm of the 5|mmonsŴ5m|th keact|on
ulLrasonlcaLlon lmproves Lhe raLe of formaLlon of Lhese oraanozlnc compoundsţ as wlLh manv oraanomeLalllc
reacLlons occurrlna aL a surfaceŦ

1he mechanlsm has noL been fullv clarlfledţ buL pure carbenes can be excludedţ and a meLal carbenold ls llkelv Lo
be lnvolvedŦ 1he followlna resulLs mav be lnLerpreLed Lo lndlcaLe a posslble complexaLlon of Lhe acLlve specles bv
hvdroxv aroups leadlna Lo reacLlon on Lhe same face as Lhls subsLlLuenLŦ 1hls would onlv be posslble lf an
oraanozlnc reaaenL ls presenLŦ

varlous research aroups have developed varlanLs of Lhe SlmmonsŴSmlLh cvclopropanaLlna reaaenL Lhrouah Lhe
replacemenL of Lhe lodlde llaand on Lhe zlnc aLom wlLh a sLronalv elecLronŴwlLhdrawlna subsLlLuenLŦ Whereas Lhe
orlalnal reaaenL ofLen requlres a dlrecLlna aroup such as Lhe hvdroxvl of an allvllc alcoholţ carbenolds such as
Cl
3
CC
2
ZnCP
2
l and (ÞhC)
2
Þ(C)CZnCP
2
l enable a rapld cvclopropanaLlon of alkenes wlLhouL Lhe need for such a
dlrecLlna aroupŦ
5wern Cx|dat|on

1he Swern CxldaLlon of alcohols avolds Lhe use of Loxlc meLals such as chromlumţ and can be carrled ouL under
verv mlld condlLlonsŦ 1hls reacLlon allows Lhe preparaLlon of aldehvdes and keLones from prlmarv and secondarv
alcoholsţ respŦ Ŧ Aldehvdes do noL reacL furLher Lo alve carboxvllc acldsŦ A drawback ls Lhe producLlon of Lhe
malodorous slde producL dlmeLhvl sulphldeŦ

Mechan|sm of the 5wern Cx|dat|on
ulmeLhvlchlorosulphonlum lon ls aeneraLed ln slLu from uMSC and oxalvl chlorldeŦ

1he reacLlon wlLh an alcohol aL Ŵ78¨C leads Lo an alkoxvsulphonlum lonť

ueproLonaLlon of Lhls lnLermedlaLe alves a sulphur vlldeţ whlch underaoes lnLramolecular deproLonaLlon vla a
flveŴmembered rlna LranslLlon sLaLe and fraamenLaLlon Lo vleld Lhe producL and uMS (odour!)ť


lf Lhe LemperaLure ls noL kepL near Ŵ78¨Cţ mlxed LhloaceLals mav resulLť

1|shchenko keact|on

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

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

1hls specles underaoes an lnLramolecular 1ţ3Ŵhvdrlde shlfL LhaL resulLs ln Lhe producLlon of Lhe alumlnlumŴ
coordlnaLed esLerŦ

A poLenLlal slde reacLlon ls Lhe lnvolvemenL of one of Lhe alkoxlde aroups from Lhe caLalvsLť


1hls can be mlnlmlsedţ lf Lhe reacLlon ls conducLed aL low LemperaLures and low caLalvsL loadlnasŦ
U||mann keact|on

1here are Lwo dlfferenL LransformaLlons referred as Lhe ullmann 8eacLlonŦ 1he ƍclasslcƍ ullmann 8eacLlon ls Lhe
svnLhesls of svmmeLrlc blarvls vla copperŴcaLalvzed coupllnaŦ 1he ƍullmannŴLvpeƍ 8eacLlons lnclude copperŴ
caLalvzed nucleophlllc AromaLlc SubsLlLuLlon beLween varlous nucleophlles (eŦaŦ subsLlLuLed phenoxldes) wlLh arvl
halldesŦ 1he mosL common of Lhese ls Lhe ullmann LLher SvnLheslsŦ


Mechan|sm of the U||mann keact|on
8larvls are avallable Lhrouah coupllna of Lhe arvl hallde wlLh an excess of copper aL elevaLed LemperaLures (200
¨C)Ŧ 1he acLlve specles ls a copper(l)Ŵcompound whlch underaoes oxldaLlve addlLlon wlLh Lhe second equlvalenL of
halldeţ followed bv reducLlve ellmlnaLlon and Lhe formaLlon of Lhe arvlŴarvl carbon bondŦ


1he oraanocopper lnLermedlaLe can be aeneraLed aL a more moderaLe 70 ¨C uslna a novel LhlophenecarboxvlaLe
reaaenLŦ 1he reacLlon oLherwlse follows Lhe same reacLlon paLh as aboveŦ

AnoLher posslblllLv ls Lhe use of Cu(l) for Lhe oxldaLlve coupllna of arvlllLhlum compounds aL low LemperaLuresŦ
1hls meLhod can also be used Lo aeneraLe asvmmeLrlc blarvlsţ afLer addlLlon of Lhe approprlaLe halldeŦ

ullmannŴLvpe reacLlons proceed Lhrouah a caLalvLlc cvcleţ and ln one mechanlsm Lhe copper ls posLulaLed Lo
underao oxldaLlon Lo Cu(lll)Ŧ As some Cu(lll) salLs have been preparedţ Lhe suaaesLlon for Lhe mechanlsm ls
lnLrlaulna (see also ChanŴLam Coupllna)ť

V||sme|erŴnaack keact|on

1he vllsmeler 8eacLlon allows Lhe formvlaLlon of elecLronŴrlch arenesŦ

Mechan|sm of the V||sme|erŴnaak keact|on
1he formvlaLlna aaenLţ also known as Lhe vllsmeverŴPaack 8eaaenLţ ls formed o sto from uMl and phosphorus
oxvchlorldť

An elecLrophlllc aromaLlc subsLlLuLlon leads Lo ĐŴchloro amlnesţ whlch are rapldlv hvdrolvzed durlna work up Lo
alve Lhe aldehvdeť

W||||amson 5ynthes|s

1hls meLhod ls sulLable for Lhe preparaLlon of a wlde varleLv of unsvmmeLrlc eLhersŦ 1he nucleophlllc subsLlLuLlon
of halldes wlLh alkoxldes leads Lo Lhe deslred producLsŦ
lf Lhe halldes are sLerlcallv demandlna and Lhere are accesslble proLons ln Lhe ĒŴposlLlonţ Lhe alkoxlde wlll acL as a
baseţ and slde producLs derlved from ellmlnaLlon are lsolaLed lnsLeadŦ

Mechan|sm of the W||||amson 5ynthes|s


W|tt|g keact|on

1he WlLLla 8eacLlon allows Lhe preparaLlon of an alkene bv Lhe reacLlon of an aldehvde or keLone wlLh Lhe vllde
aeneraLed from a phosphonlum salLŦ 1he aeomeLrv of Lhe resulLlna alkene depends on Lhe reacLlvlLv of Lhe vlldeŦ
lf 8 ls Þhţ Lhen Lhe vllde ls sLablllzed and ls noL as reacLlve as when 8 ƹ alkvlŦ SLablllzed vlldes alve (£)Ŵalkenes
whereas nonŴsLablllzed vlldes lead Lo (2)Ŵalkenes (seeWlLLlaŴPorner 8eacLlon)Ŧ

Mechan|sm of the W|tt|g keact|on
AddlLlon of Lhe vllde Lo Lhe carbonvl ls posLulaLed Lo lead flrsL Lo Lhe zwlLLerlonlc lnLermedlaLe beLalneţ whlch
would Lhen close Lo form a fourŴmembered cvcllc lnLermedlaLeţ an oxaphospheLaneŦ 1he exlsLence of Lhe beLalne
hasnƌL been fullv esLabllshedţ alLhouah lLs lnLermedlacv plavs an lmporLanL role ln Lhe Schlosser ModlflcaLlonŦ
8eLalnes mav be sLablllzed bv llLhlum salLs leadlna Lo slde producLsŤ Lhereforeţ sulLable bases ln Lhe WlLLla
8eacLlon are for exampleť naPţ naCMeţ nLL
3


1he drlvlna force ls Lhe formaLlon of a verv sLable phosphlne oxldeť

8eacLlve vlldes alve rapld reacLlon and subsequenL rapld rlna openlna Lo alve Lhe (Z)Ŵalkeneť

Wo|ffŴk|shner keduct|on

1he reducLlon of aldehvdes and keLones Lo alkanesŦ CondensaLlon of Lhe carbonvl compound wlLh hvdrazlne
forms Lhe hvdrazoneţ and LreaLmenL wlLh base lnduces Lhe reducLlon of Lhe carbon coupled wlLh oxldaLlon of Lhe
hvdrazlne Lo aaseous nlLroaenţ Lo vleld Lhe correspondlna alkaneŦ
1he Clemmensen 8educLlon can effecL a slmllar converslon under sLronalv acldlc condlLlonsţ and ls useful lf Lhe
sLarLlna maLerlal ls baseŴlablleŦ

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

Wo|ff kearrangement

1he Wolff 8earranaemenL allows Lhe aeneraLlon of keLenes from ĐŴdlazokeLonesŦ normallvţ Lhese keLenes are noL
lsolaLedţ due Lo Lhelr hlah reacLlvlLv Lo form dlkeLenesŦ
Wolff rearranaemenLs LhaL are conducLed ln Lhe presence of nucleophlles aeneraLe derlvaLlves of carboxvllc acldsţ
and ln Lhe presence of unsaLuraLed compounds can underao ż2+2Ž cvcloaddlLlons (for example SLaudlnaer
SvnLhesls)Ŧ

1he formaLlon of ĐŴdlazokeLones from carboxvllc aclds (vla Lhe acvl chlorlde or an anhvdrlde) and Lhe subsequenL
Wolff 8earranaemenL ln Lhe presence of nucleophlles resulLs ln a oneŴcarbon homoloaaLlon of carboxvllc acldsŦ
1hls reacLlon sequenceţ whlch flrsL showed Lhe svnLheLlc poLenLlal of Lhe WolffŴ8earranaemenLţ was developed
bv ArndL and LlsLerLŦ

Mechan|sm of the Wo|ff kearrangement
ĐŴulazokeLones underao Lhe Wolff 8earranaemenL Lhermallv ln Lhe ranae beLween room LemperaLure and 730 ¨C
ln aas phase pvrolvslsŦ uue Lo compeLlna reacLlons aL elevaLed LemperaLuresţ Lhe phoLochemlcal and meLalŴ
caLalvzed varlanLs LhaL feaLure a slanlflcanLlv lowered reacLlon LemperaLure are ofLen preferred (Zellerţ ooewŦ
cbemŦ lotŦ £JŦţ 1975ţ ţ 32Ŧ uCl)Ŧ
nlLroaen exLruslon and Lhe 1ţ2ŴshlfL can occur elLher ln a concerLed manner or sLepwlse vla a carbene
lnLermedlaLeť

Sllver lon caLalvsls falls wlLh sLerlcallv hlndered subsLraLesţ polnLlna Lo Lhe requlslLe formaLlon of a subsLraLe
complex wlLh Lhe lonŦ ln Lhese casesţ phoLochemlcal exclLaLlon ls Lhe meLhod of cholceŦ
1he solvenL can affecL Lhe course of Lhe reacLlonŦ lf WolffŴ8earranaemenLs are conducLed ln MeCP as solvenLţ Lhe
occurrence of slde producLs derlved from an CŴP lnserLlon polnL Lo Lhe lnLermedlacv of carbenesť

1he course of Lhe reacLlon and Lhe mlaraLorv preferences can depend on Lhe condlLlons (Lhermalţ phoLochemlcalţ
meLal lon caLalvsls) of Lhe reacLlonŦ Analvsls of Lhe producL dlsLrlbuLlon helps Lo deLermlne dlfferenL dearees of
concerLedness or Lhe mlaraLorv apLlLude of Lhe aroup LhaL rearranaesŦ lf 8 ls phenvlţ Lhe maln producL comes
from Lhe rearranaemenLţ whereas Lhe meLhvl aroup alves more of Lhe lnserLlon slde producLŦ
1he reacLlons of 2ŴdlazoŴ1ţ3Ŵdlones also help Lo deLermlne Lhe mlaraLorv apLlLudeť

ln a phoLolvslsţ meLhvl ls preferred for rearranaemenLţ whereas under Lhermolvsls condlLlons Lhe phenvl
subsLlLuenL mlaraLes preferenLlallvŦ Pvdroaen alwavs exceeds Lhe mlaraLorv apLlLude of phenvl aroupsŦ 1he alkoxv
aroup ln arvl or alkvl 2ŴdlazokeLocarboxvlaLes never mlaraLesŦ
Wurtz keact|on

1he WurLz Coupllna ls one of Lhe oldesL oraanlc reacLlonsţ and produces Lhe slmple dlmer derlved from Lwo
equlvalenLs of alkvl halldeŦ 1he lnLramolecular verslon of Lhe reacLlon has also found appllcaLlon ln Lhe
preparaLlon of sLralned rlna compoundsť

uslna Lwo dlfferenL alkvl halldes wlll lead Lo an approxlmaLelv sLaLlsLlcal mlxLure of producLsŦ A more selecLlve
unsvmmeLrlc modlflcaLlon ls posslble lf sLarLlna maLerlals have dlfferenL raLes of reacLlvlLv (see WurLzŴllLLla
8eacLlon)Ŧ

Mechan|sm of the Wurtz keact|on

Slde producLsť

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