Corso di Laurea in Scienze Chimiche
Complementi di Chimica Organica (a.a. 2013/2014) !
Maurizio Taddei E-mail [email protected] Tel. 0577234275
http://www3.unisi.it/ricerca/dip/dfct/english/pagine_personali/taddei/didattica.htm
La reattività in Chimica Organica
.
..
Principî generali: attrazione di cariche, sovrapposizione orbitalica, flusso elettronico.
Sostituzione nucleofila al C saturo. Carbocationi: struttura e reattività. SN1 e SN2 e fattori che controllano i due processi.
Cationi coniugati. Ingombro sterico. Effetto del substrato, del gruppo uscente e del nucleofilo. Stereochimica della reazione.
Interconversione gruppi funzionali.
.. Eliminazione. Eliminazione o sostituzione ? Influenza del substrato, del nucleofilo e del mezzo. E1 ed E2 e fattori che
controllano i due processi. Esempi. Influenza della coniugazione.
.. Addizione a doppi legami C=C. Regola di Markovnikov. Addizione elettrofila ed altri meccanismi. Stereochimica
dell’addizione. Esempi. Idrogenazione, epossidazione, alogenazione. Addizione a tripli legami.
.. Intermediati reattivi: Carbanioni. Reattivi organometallici: Grignard, reagenti di organolitio. Reattivi organometallici per
deprotonazione. Stabilità dei carbanioni. Scambio metallo/alogeno.
.. Intermedi reattivi: radicali. Come generare un radicale. Stabilità dei radicali. Esempi di reazioni radicaliche. Polimerizzazione
radicalica.
. Chimica del gruppo carbonilico. Tabella delle trasformazioni red-ox che coinvolgono il gruppo carbonilico. Addizione
nucleofila al C=O. Addizione in ambiente basico ed in ambiente acido. Nucleofili all' O, S, N e C. Amminazione riducente.
Metodi di sintesi di ammine per via indiretta. Chimica degli enolati. Enolato cinetico e termodinamico. Condensazione aldolica
semplice ed incrociata. Reazione di Mannich e Cannizzaro. Reazione di Wittig e di Woodworth-Horner-Emmons. Reattività dei
sistemi coniugati addizione 1,2 o 1,4. Reazione di Michael. Anellazione di Robinson. Principî di base di "protezionedeprotezione".
.. Sostituzione nucleofila al C sp2. Reattività dei derivati degli acidi carbossilici. Condensazione di Claisen, reazione di
Dieckmann. Chimica dei Composti beta-dicarbonilici. Reazione di Masamune. Reazione di Knoevanagel. Trasposizione di
Curtius e Hoffmann. Reazione di Michael di derivati degli Acidi Carbossilici.
.. Reattività del sistema aromatico. Sostituzione elettrofila. Nitrazione, solfonazione, alchilazione ed acilazione di Friedel e Crafts.
Influenza dei sostituenti. Esempi: Reazione di Kolbe, Gatterman-Koch, Vilsmeir-Haak. Solfonammidi, sali di diazonio.
Reazione di copulazione, reazione di Sandmayer. Sostituzione nucleofila aromatica. Meccanismo di addizione eliminazione.
Reazioni red-ox sugli aromatici: reazione di Heck.
… Chimica dei composti eterociclici. reattività generale di furano, tifone pirrolo, indoli e piridina
Corso di Laurea in Scienze Chimiche
Complementi di Chimica Organica (a.a. 2013/2014) Maurizio Taddei E-mail [email protected]
Tel. 0577234275
Chimica Organica: perchè ?
Reattività in Chimica Organica
Una molecola termodinamicamente stabile può essere mantenuta per anni senza decomporsi.
Però, in presenza di un'altra molecola con particolari caratteristiche, la prima molecola cambia la sua
natura ed assume una natura nuova. !
!
!
I due fattori principali che controllano questo processo sono i parametri termodinamici ed i parametri
cinetici.
!
Termodinamica di una reazione: influenza dell'energia associata alle specie coinvolte in una reazione
(reagenti prodotti ecc).
ΔG = ΔH -­‐ T ΔS ΔH: contenuto entalpico legato all'energia dei legami e degli altri contributi elettronici correlati al legame
chimico (risonanza, delocalizzazione, tensione di anello ecc).
ΔS: contributo entropico legato al "disordine" del sistema, maggiore è il "disordine" maggiore è l'entropia.
!
Cinetica di una reazione:
velocità con cui un prodotto si trasforma in un reagente. Dipende dalla concentrazione delle specie
coinvolte nel processo. Dobbiamo sempre ricordare che non abbiamo mai a che fare con una sola molecola
(come scriviamo sul foglio) ma con una popolazione di molecole che non necessariamente si trovano tutte
nella stessa situazione.
Dalla diversità di popolazione si introduce il fattore tempo da cui la velocità.
Una reazione è una trasformazione, quindi una evoluzione che necessita di tempo.
Reattività in Chimica Organica
Reattività in Chimica Organica
It is possible to relate these functions with the rate
he
Per definire
un meccanismo
definire
cammino
di reazione
descritto in un grafico che
k, byunusing
a model
known
constant
for thedobbiamo
reaction,
materials
riporta in
transition state theory. We will not go into any
energy),ordinataas
l'energia
libera associata alle varie specie
•
‡
details
here,
but the net result is that
S , and the
•ascissa la cosiddetta coordinata di reazione, cioè un parametro grafico che rappresenta l'evoluzione
ntropy and
di una reazione.
k BT ‡
k
=
K
materials
!
h
directly Una trasformazione della materia (reazione chimica) prevede la modifica del reagente fino ad arrivare
where
kB and
h are(stato
universal
constants
known
asl'energia decresce per tornare
ad un punto
di massima
energia
di transizione).
Raggiunto
questo,
he
al punto di
partenza o per evolvere
verso
il prodotto
di reazione.
Botlzmann’s
constant
and
Planck’s
constant,
e between
Stato di transizione:
Struttura che rappresenta il massimo di energia raggiunto durante unaA + B
respectively
er than trasformazione.
Non è una specie realmente identificabile –Δ
o isolabile
in quanto ha legami
rotti materials
e
G
starting
‡
KT
legami incipienti.
Essendo al massimo
di energia, qualsiasi
By substituting
in the equation
K = e intervento
the esterno fatto per identificarla, lo
porta verso una specie ad energia minore.
‡ = –RT lnK ‡) we arrive at an
rearranged
form
of
Δ
G
an
Teoria dello stato di transizione: esiste un "quasi equilibrio" tra i reagenti e lo stato di transizione che
equation, known as the Eyring equation, which
ts and the
poi si trasforma nei reagenti permettendo il calcolo della velocità (cinetica) del processo. Inoltre la
relates
fast a reaction
(k) to the
"forma" dello
stato how
di transizione
rassomigliagoes
più ai prodotti
che activation
ai reagenti, in quanto si considera
‡
l'ultimo passaggio
energy possibile
(ΔG ) prima della finalizzazione al prodotto.
Δ
‡
!
Eq di Eyring
k=
k BT
e
−
ΔG ‡
RT
kB= costante di Boltzmann; h: costante di Plank
!
h
s apply
Un processo può anche passare attraverso dei minimi relativi di energia che sono detti intermedi, cioè
This can be rearranged and the numerical values of
so that we
specie reali, spesso isolabili o sperimentalmente identificabili, spesso caratterizzate da presenza di
constants
inserted to give an alternative form
cariche o the
elettroni
liberi.
ΔS‡.
AB‡
ΔG‡ (in J mol–1) = 8.314 × T × [23.76 + ln(T/k)]
Δ
Reattività in Chimica Organica
Reazione:
Definizione termodinamica: Due molecole stabili per reagire tra loro devono collidere tra loro e l'energia della
collisione deve essere sufficiente a far avvenire la reazione (somma delle energie cinetiche > energia di
attivazione)
Definizione cinetica: Due molecole stabili per reagire tra loro devono avvicinarsi sufficientemente per
permettere la riorganizzazione elettronica a carico dei legami chimici (nuvole elettroniche) con la modifica degli
orbitali coinvolti
Poiché le molecole espongono la nuvola elettronica, il principale fenomeno sarà la repulsione.
Affinché una reazione avvenga è necessario che le molecole abbiano delle caratteristiche strutturali che
permettano loro l'avvicinamento (attrazione)
Forze attrattive:
•cariche reali di segno opposto: di rado si hanno specie organiche cariche.
•cariche formali - dipoli: la presenza di atomi con differente elettronegatività porta alla deformazione della
nuvola elettronica di legame verso l'atomo più elettronegativo. Questo determina un'aumento della densità
elettronica su un atomo (parziale carica negativa) e la scopertura del nucleo dell'altro atomo (parziale carica
positiva) con generazione di un dipolo. La presenza di doppietti elettronici non condivisi su di un atomo porta
ad un aumento della densità elettronica (parziale carica negativa) mentre alcuni nuclei presentano orbitali vuoti
e quindi una diminuita densità elettronica (parziale carica positiva).
•polarità indotta: La presenza di legami π o di doppietti elettronici non condivisi
porta ad una facile
deformazione della nuvola elettronica per avvicinamento con scopertura del nucleo e quindi generazione di
dipoli indotti.
•sovrapposizione orbitalica: due molecole apolari possono essere attratte dall'interazione tra un orbitale pieno
ad alta energia (ad esempio il π di un doppio legame C=C) ed un orbitale vuoto a bassa energia di una molecola
con un orbitale molecolare complesso (es il σ* di una molecola di Br2).
Reattività in Chimica Organica
La chiave della reattività in molte reazioni organiche è il flusso di elettroni che si muove da una
molecola che ha orbitali pieni esterni (quelli a più alta energia tra gli orbitali molecolari di legame,
HOMO Highest Occupied Molecular Orbitals) ad una molecola che ha orbitali vuoti disponibili (gli
orbitali di antilegame (o di non legame) vuoti a più bassa energia, LUMO Lowest Unoccupied
Molecular Orbital).
Il reagente che dona gli elettroni è detto Nucleofilo (formalmente amico del nucleo)
Il reagente che accetta elettroni è detto Elettrofilo (formalmente amico degli elettroni)
Anche se per convenzione diamo questa rappresentazione, bisogna ricordare che gli elettroni non
interagiscono mai con il nucleo che è ad energia troppo elevata) ma con con orbitali vuoti ad energia
disponibile. Il coinvolgimento della carica nucleare è solo nel processo attrattivo che permette agli
orbitali di interagire e di sovrapporsi.
!
!
In una reazione organica di norma si formano (o si rompono) dei legami e perché ciò avvenga è
necessario che vi sia una corretta sovrapposizione degli orbitali. Gli orbitali sono sempre orbitali
direzionali e quindi è necessario che durante il processo di avvicinamento gli orbitali coinvolti siano
correttamente allineati. Gli urti che non consentono un corretto allineamento degli orbitali non
portano alla formazione di un legame.
Inoltre è necessario che l'energia degli orbitali in gioco sia corretta. In genere gli orbitali pieni sono ad
energia minore mentre gli orbitali vuoti sono ad energia maggiore. L'ideale sarebbe che l'orbitale
pieno del nucleofilo fosse alla stessa energia (o ad una energia di poco inferiore) all'orbitale
dell'elettrofilo. In tal modo il guadagno energetico è maggiore. In ogni caso, se la reazione avviene, c'è
un guadagno energetico. L'energia di attivazione che si spende è quella necessaria ad "orientare"
correttamente gli orbitali e vincere le forze di repulsione.
Sostituzione nucleofila al C saturo
Gruppo Uscente (leaving group)
C saturo
Elettrofilo
Nucleofilo
Il nucleofilo è OH-, una specie reattiva con un atomo di ossigeno che ha tre doppietti di
non legame. La carica negativa gli conferisce un contributo energetico elevato. Inoltre
può essere attratto da specie positive.!
Nell' alogenuro alchilico il C che subisce l'attacco è sp3. Però è legato ad un atomo più
elettronegativo (il Cl) e quindi gli elettroni del legame σ sono maggiormente localizzati
sul Cl- In questo modo si genera una "scopertura" sul nucleo che permette l'attrazione
dell'OH-!
Affinché si abbia la formazione del nuovo legame è necessario che si rompa il legame
C-Cl. Con la rottura del legame C-Cl (e movimento degli elettroni del legame σ verso il
Cl) si genera un orbitale vuoto sul carbonio che può accettare il doppietto presente nell'
orbitale pieno di OH-
Sostituzione nucleofila al C saturo
Sono possibili due meccanismi: !
prima si rompe il legame C-Cl (sotto la spinta dell' OH- che si avvicina) e poi si forma il nuovo
legame C-OH) Meccanismo a due stadi. La velocitá di reazione dipende solo dalla
concentrazione dell'alogeno derivato!
via via che l' OH- si avvicina il legame C-Cl si indebolisce e si allunga fino ad un punto in cui l'OH
è così vicino da poter sovrapporre i suoi orbitali con l'orbitale deformato di C sp3. Si forma quindi
il nuovo legame C-OH con contemporanea rottura del legame C-Cl. Meccanismo concertato.
La velocitá di reazione dipende dalla concentrazione di entrambe i reagenti.!
!
Il primo meccanismo genera una specie al C che ha solo tre legami detta carbocatione.
Come si calcola la carica di un atomo presente in una molecola ?!
!
Si scrive la formula otteziale. Si assegna formalmente all'atomo in
questione un elettrone per legame ed i due elettroni di un doppietto. Si
sommano gli elettroni esterni. Se sono uguali al gruppo nel quale si trova
l'atomo, l'atomo è neutro, altrimenti se ha un elettrone in meno è positivo,
se ha un elettrone in più è negativo.
Carbocationi
17 .
414
I carbocationi sono specie molto reattive in quanto il carbonio non è in situazione
otteziale e quindi ha un contenuto energetico elevato. Per potersi formare necessita di una
stabilizzazione aggiuntiva da parte della struttura nella quale si viene a formare.
σ orbital
Fattori che stabilizzano il carbocatione:
•struttura planare
empty p orbital
•retrodonazione di elettroni σ da parte di atomi vicini (diversi dall' H).
CH3
possibilità
di
delocalizzazione
su
strutture
diverse.
•
H
CH3
!
In generale quindi un carbocatione su un C legato ad altri 3 carboni
(o atomi che possono dare una retrodonazione) è più stabile di
un carbocatione legato a 2 atomi che è a sua volta più stabile di
un carbocatione legato ad un solo atomo.
Stabilità (probabilità di formarsi)
C+terziario > C+ secondario > C+ primario
CH3+ non esiste (in condizioni normali)
H
CH2
extra stabilization
from σ donation
into empty p orbital
of planar carbocation
H
CH2
CH2
H
doesn
parall
orbita
Th
bond
orbita
some
there
hydro
and n
cation
If a
which
Catione benzilico e allilico
Sistema delocalizzato (o coniugato).
I due elettroni del sistema sono distribuiti su tutti e tre i C, con la massima densità sul C centrale
I tre legami sono uguali. I due carboni alle estremità sono equivalenti (da un punto di vista elettronico) ed
entrambi possono funzionare da nucleofili (il LUMO dei due C è uguale).
Per descrivere correttamente il sistema allilico abbiamo avuto bisogno di scrivere due formule di risonanza.
on reaction pathway
progressNucleofile
of reaction al C sp3 ?
Qualistarting
fattori influenzano le Sostituzioni
materials:
nucleophile
A transition state +is MeX
not an intermediate. It can never be isolated
because any change in its strucproducts:
X
Struttura
del substrato
ture leads
to a lower-energy state. In an SN2 reaction any moleculeMe-Nu
at the+transition
state cannot stay
Le reazioni
di tipo
SN1
avvengono
in presenza
substratiorche
stabilizzano
il carbocatione.
there—it
must
roll
down thesolo
slope
towards di
products
back
to starting
materials. So what does it
lookterziari
like and
why are
we interested
indelocalizzare
it? The transition
state
incarbocatione
an SN2 reaction
is about halfway
Es centri
oppure
strutture
in grado di
con
facilità
(catione
progress
of il
reaction
alilico,
cationethe
benzilico
o catione
adiacente
un eteroatomo
con doppietti
non condivisi).
between
starting
materials
and theadproducts.
The bond
to the nucleophile
is partly formed and
the bond
the
partly
broken.
It It
looks
Substrati
primari
nonleaving
sonostate
in group
grado
dian
stabilizzare
il carbocatione
ethis.
quindi
passano
attraverso
A to
transition
is notis
intermediate.
can like
never
be isolated
because
any change in its strucun meccanismo SN2
ture H
leads to a lower-energy state. HIn an SN2 ‡
reaction any molecule
H at the transition state cannot stay
(–)
(–)
Per come there—it
sono stati must
definiti
i meccanismi
della SN2
si puòproducts
pensare che
le restrizioni
strutturali
roll
down the
slope
towards
orNuback
to starting
So what does it
X
+
X materials.
Nu
X
sianoNu
più stringenti
che
nella
SN1.
Pertanto
un
aumento
delle
dimensioni
dei
gruppi
attorno
al
H like and why are we interested in it? The transition state inHan SN2 reaction is about halfway
look
centro reattivo (non
al centro reattivo) H
può determinare una
H necessariamente legatiHdirettamente
H
between
the
starting
materials
and
the
products.
The
bond
to
the nucleophile is partly formed and
diminuzione della reattività. Ingombro sterico
starting
materials
products
the bond
to the leaving grouptransition
is partlystate
broken. It looks like this.
‡ bond is partly formed
The dashedHbonds indicate partial bondsH(the C—-Nu
and the C—-X bond
H
(–)
(–)
partly broken) and X
the charges in brackets
indicate
substantial partial
charges+ (about
half a minus
X
Nu
X
Nu
Nueach in
H this case as they must add up to one!). Transition states are often
H shown in square brackcharge
H
H H
H
ets and marked with the symbol ‡. Another way to look at this situation is to consider the orbitals. The
starting materials
transition state
nucleophile
must have lone-pair electrons,
which will interact with theproducts
σ* orbital of the C–X bond.
The dashed
bonds indicate partial bondsH(the C—-Nu ‡
bond is partly formed
and the C—-X bond
H
H
(–) brackets indicate(–)substantial partial charges (about half a minus
partly broken) and the charges in
Nu
X
Nu
Nu
X
charge each
in
this
case
as
they
must
add
up
to
one!).
Transition
states
are oftenHshown in square brackH
H
H
H consider the orbitals. The
H with the symbol ‡. Another way to look at this situation is to
ets and marked
must
have lone-pair
which will
the
σ* orbital of the C–X bond.
filled nucleophile
orbital
empty
σ* orbital
new σelectrons,
bond p orbital
old σinteract
bond with
new
σ bond
of nucleophile
of C–X bond
H
being formed on C atom being broken
(–)
H
(–)
‡
H
Quali fattori influenzano le Sostituzioni Nucleofile al C sp3 ?
Struttura del gruppo uscente (leaving group)
Nel caso di una reazione SN1 la rottura del legame C-X è lo stadio lento del processo.
Anche per una SN2 possiamo pensare che la velocità della reazione dipenda dalla facilità
con la quale si rompe il legame C-X.
!
Come stabilire se un gruppo X è un buon gruppo uscente.
Una regola empirica ci aiuta suggerendoci che data una generica SN, il gruppo X viene
sostituito più facilmente tanto più è acido il suo acido coniugato HX
Scala di reattività al C sp3
Scala crescente
Quali fattori influenzano le Sostituzioni Nucleofile al C sp3 ?
Natura del nucleofilo (nucleophile)
I nucleofili sono molecole che possiedono almeno un doppietto elettronico non condiviso localizato in
un orbitale ad alta energia.
Possiamo suddividere i nucleofili in due grandi famiglie: nucleofili carichi (negativamente) e nucleofili
neutri. (es OH-/ H2O; RO- / ROH; Cl- / HCl ecc)
Principi che governano la reattività dei nucleofili
•Un nucleofilo carico è sempre più forte del suo acido coniugato
•Confrontando nucleofili dello stesso periodo, la nucleofilia aumenta con l'aumentare della basicità,
sebbene la basicità sia una proprietà termodinamica mentre la nucleofilia sia una proprietà cinetica.
!
!
!
!
!
!
Scala crescente
•Scendendo nel gruppo la nucleofilia aumenta mentre la basicità diminuisce:
I- > Br- >Cl- >>F-; i
nucleofili allo S sono più forti dei corrispondenti nucleofili all'O e lo stesso succede confrontando P e
N. Possiamo associare questo effetto all'influenza dell’elettronegatività dell’atomo sulla disponibilità
del doppietto non condiviso (effetto schermante degli elettroni intermedi).
•La nucleofilia viene depressa dalla presenza di un ampio guscio di solvatazione.
è la "libertà" della specie nell'ambiente di reazione, maggiore è la nucleofilia.
Pertanto, maggiore
Quali fattori influenzano le Sostituzioni Nucleofile al C sp3 ?
Se la reazione prevede l'uso di un nucleofilo carico o neutro possiamo avere un diverso
meccanismo (pur rimando all'interno delle classi SN1 o SN2)
In presenza di un nucleofilo neutro è necessaria
la presenza di una base che strappi il protone
alla specie intermedia per dare il prodotto
finale. La base deve essere meno nucleofila del
nucleofilo stesso.
Se il nucleofilo non ha H da estrarre, la specie
che si forma resta carica positivamente e può
subire attacco da parte del gruppo uscente
(uscito) per riformare il prodotto di partenza.
make
thing clear. In spite of
the proton from
theone
alcohol.
SN2 displacement of hydroxide Ion is not a known reaction
what
you alcohols
may suppose,
alcohols substitution
But we want
to use
in
nucleophilic
reactions because they are easily made.
Sostituzione
nucleofila con alcoli
Nu
do not
react
with
nucleophiles.
joined to the carbon atomThe
by asimplest
C–O bond?
There
are
many
of
these
Nu
answer is to protonate the OH group with strong
acid. This will work only if the nucleWhy not?
Hydroxide
ion
is very
+
OH
itself, the carboxylic esters,
andisthe
sulfonate
esters.
Firstacid,
we
must
X
ophile
compatible
with
strong
but many are. The preparation
simply
R
OH of t-BuCl from t-BuOH
R
basic, very reactive, and a bad
of
by ofshaking
it Ion
with
concentrated
HCl is a good example. This is obviously an SN1 reaction with the
SN2 displacement
hydroxide
is not
a knownIfreaction
leaving
group.
the nucleophile
if the nucleophile reacts, it attacks the proton instead
ls
t-butyl cationwere
as intermediate.
strong Nu
enough to produce
s.
Nu
The leaving
group
The leaving group 429
H
Me
hydroxide ion, it would
beOH
more MeR
y
+
O
Nu
+ HNu
R
O
X
conc. HCl
R
OH
than
strong
enough
to
remove
R
OH
Cl
d
Me
Me
the
proton
from
the
alcohol.
shake
20 in
minutes
substituting
acid
bstituting
a secondary
initacid
substituting
a primary alcohol in acid
substituting
a secondary
alcohol
acida primary alcohol in
e
if the
nucleophilealcohol
reacts,
attacks the
proton instead
Me
Me
at
toom
temperature
But we want to use alcohols in nucleophilic substitution reactions because they are easily made.
e
(48%) HBr
conc. (48%) HBr
OH conc. (48%) HBr
tthe
-BuCl
t-BuOH OH The
conc.
(48%)answer
HBr is to protonate
Br
Brconc.
simplest
OH group with strong
acid. This91%
willyield
work only if the nucle-91% yield
H
90% yield
t-butanol
e
Br
Br
Br
HO O
OH acid, HO
R
O
OHpreparation of t-BuClBr
Nu
+ HNu
R compatible
ophile is
with
strong
but many are. The
from t-BuOH simply
H2SO4
SO
H
e
2
4
rate-determining
on alcohols
by Hshaking Me
it with concentrated HCl is a good
an SN1 reaction with the
Me
Meexample. This is obviously
fast
step
H
SO
H2SO
same
same
2
4
OH t-butyl cation as intermediate.
OHyield
Cl
Cl 4
74% yield
2
74%
again
in nucleophilic substitution
reactions
because
they
are
easily
made.
again
Me
Me
Me
Me
Me
Me
Me
Me
Me if the conc.
Meacid. This will work only
Me
nate the OH group with strong
nucleThe leaving group
429
HCl
t
-butyl
cation
OH
Cl
Br
Br
acid, but many are. The preparation of Me
t-BuCl from t-BuOH simply
Me
shake 20 minutes S 2
SN2
N
Me can
Me
HCl is a good substituting
example. aThis
is obviously
reaction
with
the
Similar
methods
usedattotoom
make
secondary
bromides
alkyl
temperature
HO with HBr alone
Br and primary
substituting
a primaryalkyl
alcohol
in acid
secondary
alcohol
in an
acidSN1be
HO
Br
HO
OH
HO
OH
2
2
t
-BuCl
t
-BuOH
bromides using a mixture of HBr and H2SO4. The second is certainly an SN2 reaction and we show
conc.
(48%)
90%
yield HBr
-butanol
OH conc. (48%) tHBr
Br
just
one
in is
ainto
two-step
process
that
is very
efficient.
91% yield
Another way isMe
to convert
the
OHstage
group
a better
leaving
group
Another
way
to convert
the
OH
group
into
a
better
leaving
groupBrPBr
Br
PBr3
HO
OH
3
rate-determining
Me
Me
Me
Me
OH
Br
OH
H2SO
91% yield
combination with anClelement
that forms
bonds
to
by combination
withvery
an strong
element
that forms
very strong
bonds
to
4
H
fast
step
OH
OH
Cl
Cl same
Mepopular choices
ygen. The most
andchoices
sulfur.are
Making
oxygen.are
Thephosphorus
most popular
phosphorus
H22SO4and sulfur. Makingreflux
tes
reflux
Me
Me
Me
74%
yield
Me
Me
Me
again
ature
Me works well.
Me well.
Me
imary alkyl bromides with
PBr3 usually
works
primary
alkyl bromides
with PBr3 usually
t-BuCl
t-butyl cation
first attacked
the OH
(an SN2and
reaction at phosphorus) and
The phosphorus
reagent is The
firstphosphorus
attacked by reagent
the OHisgroup
(an SNBr2 by
reaction
atgroup
phosphorus)
90% yield
methods
can
be
used
make secondary
bromides
withbecause
HBr alone
andanion
primary alkyl
the displacement
of an oxyanion
bonded
to to
phosphorus
is now
good
reaction
of the
e displacement of an oxyanion
bonded toSimilar
phosphorus
is now
a good
reaction
because
ofathe
anion
SN2 alkyl
rate-determining
HO
Br
Me
Me
bromides
using a mixture
H2SO4. The second is certainly an SN2 reaction and we show
HO of HBr andOH
by
phosphorus.
bilization by
phosphorus.stabilizationfast
step
OH2
Br
Br
just one stage inCl
a two-step process that is very efficient.
Br
way
OH group into a better leaving group
BrAnother
Me
Me
Me–isHto convert the
PBr3
PBr2
PBr2– H
Me
OH
by
combination
with
an
element
that
forms
very
strong
bonds
to
OH
P
Br
O
Br
OH
O
Br
tP-butylBr
cation
oxygen. The most popular choices are phosphorus and sulfur. Making
reflux
Br
Br
primary
bromides
with
PBr
usually
works
well.
to make secondary
alkylalkyl
bromides
with
HBr
alone
and
primary
alkyl
3
The
phosphorus
reagent
is
first
attackedand
by the
OH group (an SN2 reaction at phosphorus) and
Br and H2SO4. The second is certainly an SN2 reaction
we show
The
reaction
ausing
modern
SN2a good
reaction
using
phosphorus
he
is Mitsunobu
aofmodern
SN
2 reaction
phosphorus
chemistry
thereaction
displacement
an oxyanion
bonded
to is
phosphorus
is now
reaction
because
of the anion chemistry
ess Mitsunobu
that is very efficient.
Cl
Br
91% yield
OR
Ethers as electrophiles
OR THF
Ethers are stable molecules, which do not react with nucleophiles: they must be stable because
Casistica
per
gli
eteri
and Et2O are used as solvents. But we can make them react by using an acid with a nucleophilic
asand
electrophiles
counterion (HBr or HI, for Ethers
example)
then nucleophilic attack will occur preferentially at the
more susceptible carbon atom.
Aryl
ethers
cleave which
only on
shall explain
Ethers
arealkyl
stable
molecules,
dothe
notalkyl
reactside.
with We
nucleophiles:
theyinmust be stable because THF
Et2does
O arenot
used
as solvents.
But we
can make them react by using an acid with a nucleophilic
Chapter 23 why nucleophilicand
attack
occur
on a benzene
ring.
H
counterion (HBr
or HI, for example) and then nucleophilic attack will occur preferentially at the
more susceptible
carbon atom. Aryl alkyl ethers cleave only on the alkyl side. We shall explain in
O
OH
Chapter 23 whyMe
nucleophilic
attack does not occur on a benzene ring.
I
O
HI
H
SN2 attack at sp3
Me
O
aliphatic carbon atom
O
anisole
phenyl methyl ether
methoxybenzene
HI
HI
Me
OH
I
+ MeI
SN2 attack at sp3
MeH
O
I
+ MeI
aliphatic carbon
I atom
X
Me
+ MeOH
H
impossible anisole
no SN2 attack at sp2
phenyl methyl ether
line of
HI
methoxybenzenearomatic carbon atom
I
approach
O
I
X
Me
+ MeOH
impossible
2
no SN2
attack
at spwell
So far we have used only protic acids to help oxygen
atoms to leave. Lewis
acids
work
too, and
line of
atom
the cleavage of aryl alkyl ethers with BBr3 is a good approach
example. Trivalentaromatic
boroncarbon
compounds
have an
lkyl
empty p orbital so they are very electrophilic and prefer to attack oxygen. The resulting oxonium ion
far we have used only protic acids to help oxygen atoms to leave. Lewis acids work well too, and
can be attacked by Br– in an SN2Soreaction.
the cleavage of aryl alkyl ethers with BBr3 is a good example. Trivalent boron compounds have an
Br
R electrophilic and prefer to attack oxygen. The resulting oxonium ion
empty p orbital so they are very
Br
Br
Br
Br
Br
Br
–
can be attacked
B
B by Br in an SN2 reaction. B
BBr3
O
R
Br
O
aryl alkyl
R
BBr3
ether
O
Br
O
Br
R
B
R
Br
Br
O Br R
Br
Br
B
O
Br
H2O
work-up Br
O
R
R
OH
Br
B
O
Br
H2O
work-up
Br
OH
Casistica per gli epossidi (ossirani)
SN2
SN1
Stereochimica e Sostituzioni Nucleofile al C sp3
SN1 : racemizzazione
SN2 : inversione di configurazione
H
slow
fast
OH2 Eliminazioni
OH
Br
Br
t-butyl bromide
t-butanol
Bromide, the nucleophile, is not involved in the rate-determining step, so we know that the rate of
the reaction will be independent of the concentration of Br–. But what happens if we use an acid
E2
whose counterion is such a weak nucleophile that it doesn’t even attack the carbon
of the carbocation? Here is an example—t-butanol in sulfuric acid doesn’t undergo substitution, but undergoes
elimination instead.
E1 elimination of t-BuOH in H2SO4
O
H2SO4
H
+
H
HO
slow
OH
OH2
t-butanol
O
S
E1
O
H
fast
isobutene
(2-methylpropene)
–
–
Now, the
involved l'eliminazione.
in the rate-determining
step—HSO
basic forte
and only
4 is notfavorisce
4 is not at all base
L'aumento di basicità
del HSO
nucleofilo
Quindi per
avere eliminazione
behaves
as a basenelle
(thatdimensioni
is, it removes
a proton)
because
it is even
more feeble as a nucleophile. The
poco nucleofila.
L'aumento
del
nucleofilo
favorisce
l'eliminazione.
rate equation will not involve the concentration of HSO –4, and the rate-determining step is the same
L'aumento di temperatura favorisce l'eliminazione in quanto questa ha un bilancio entropico favorevole (da
as that in the SN1 reaction—unimolecular loss of water from the protonated t-BuOH. This eliminadue molecole si ottengono tre
molecole, aumento di disordine).
tion mechanism is therefore called E1.
ΔG = ΔH - T ΔS
Quindi se in questa reazione il ΔS è positivo, un aumento di temperatura porterà ad una diminuzione
dell'energia libera del prodotto finale e quindi avrà un effetto favorevole. :
Se vuoi eliminazione: base forte poco nucleofila, base di grosse dimensioni, riscaldamento
Se vuoi sostituzione: nucleofilo poco basico e non troppo ingombrato, riscaldamento limitato
only one alkene possible
OH
Ph
Ph
Eliminazione
E1: sterochimica e regiochimica
OH
H
H
two regioisomeric alkenes possible
OH
H
regioisomers
trisubstituted
alkene
disubstituted
alkene
Ph
Ph
two stereoisomeric alkenes possible
OH
Ph
definition. Fo
alkenes, E co
and Z corres
assign E or Z
tetrasubstitu
groups at eit
are given an
according to
those outline
Chapter 16.
priority group
is Z; if they a
E. Of course,
know these r
sometimes (
example her
less stable th
H
E-alkene
stereoisomers
(geometrical isomers)
Z-alkene
For steric reasons, E-alkenes (and transition states leading to E-alkenes) are usually lower in
energy than Z-alkenes (and the transition states leading to them) because the substituents can get
Si forma preferenzialmente l'olefina (alchene) più sostituito o/e quello meno ingombrato (ingombro
sterico).!
Con il meccanismo E1 prevale la stabilità del prodotto finale (termodinamica)!
MeO
syn-coplanar(gauche)
(gauche)- syn-coplanar
more
hindered
more hindered
anti-periplanar––less
less
anti-periplanar
hindered
hindered
Eliminazione:
influenza della
coniugazione
e stereochimica
There is
is aa choice
choice of
of protons
protons
to be
be eliminated—the
eliminated—the
stereochemistry
theproduct
product
resultsfrom
from
There
to
stereochemistry
ofofthe
results
which proton
proton isis anti-periplanar
anti-periplanarto
tothe
theleaving
leavinggroup
groupwhen
whenthe
thereaction
reactiontakes
takesplace,
place,and
andthe
thereaction
reaction
which
is stereoselective
stereoselective as
as aa result.
result.
is
E2 eliminations
eliminations can
canbe
bestereospecific
stereospecific
Reazione stereoselettiva.
In the next
next example,
example, there
there isis only
onlyone
oneproton
protonthat
thatcan
cantake
takepart
partininthe
theelimination.
elimination.Now
Nowthere
thereisisnono
anti-periplanar transition
transition states.
states.Whether
Whetherthe
theproduct
productisisEEororZ,Z,the
theE2
E2reaction
reactionhas
hasonly
only
choice of anti-periplanar
one course
course to
to follow.
follow. And
Andthe
theoutcome
outcomedepends
dependson
onwhich
whichdiastereoisomer
diastereoisomerofofthe
thestarting
startingmaterial
materialisis
When the
the first
first diastereoisomer
diastereoisomer isis drawn
drawn with
with the
theproton
protonand
andbromine
bromineanti-periplanar,
anti-periplanar,asas
used. When
required, and
and in
in the
the plane
planeof
ofthe
thepage,
page,the
thetwo
twophenyl
phenylgroups
groupshave
havetotolie
lieone
oneininfront
frontand
andone
onebehind
behind
–
of the
the paper.
paper. As
Asthe
thehydroxide
hydroxideattacks
attacksthe
theC–H
C–Hbond
bondand
andeliminates
eliminatesBrBr–, this
, thisarrangement
arrangement
the plane of
preserved and
and the
the two
two phenyl
phenylgroups
groupsend
endup
uptrans
trans(the
(thealkene
alkeneisisE).
E).This
Thisisisperhaps
perhapseasier
easiertotosee
seeinin
is preserved
Newman projection
projectionof
ofthe
thesame
sameconformation.
conformation.
the Newman
Le
reazioni
E2
procedono
con
meccanismo
"anti-periplanare".!
Reazione
stereospecifica.
diastereoisomer
eliminatesto
togive
givethis
thisalkene
alkene(E(E) )
this diastereoisomer
eliminates
thisdiastereoisomer
diastereoisomer
eliminates
give
this
alkene
this
eliminates
toto
give
this
alkene
(Z)(Z)
Me
Me
Me
Me
Ph
Ph
NaOH
NaOH
Ph
Ph
Ph
Me
Me
Ph
Ph
Me
Me
Br
Br
Ph
Ph
NaOH
NaOH
Ph
Ph
PhPh
BrBr
redraw
redraw
redraw
redraw
Me
Me
Ph
Ph
Br
Br
Ph
Ph
Ph
Ph
HH
HH
Me
Me
Ph
Ph
HO
HO
only
only this
this proton
proton can
can
–
be
attacked
by
HO
be attacked by HO–
Br
Br
HH
Me
Me
Ph
Ph
HH
HHand
andBr
Brmust
mustbe
be
anti-periplanar
anti-periplanar
BrBr
PhPh
slower
reaction
because
of of
slower
reaction
because
gauche
interactions
in
gauche interactions in
reactive
conformation
reactive
conformation
PhPh
HH
HH
PhPh
PhPh
HO
HO
only
onlythis
thisproton
protoncan
can
–
bebeattacked
by
HO
attacked by HO–
BrBr
HH
Me
Me
HH
HH
and
BrBr
must
bebe
and
must
anti-periplanar
anti-periplanar
have
no alkenes
nearby
group
toand
accept
they typically act as nucleophiles and attack
onjugated
are nucleophilic
react
with electrophiles.
mine
to attack.
The carbonyl
only
way the
π HOMO
canelectrons—and
interact
in a bondelectrophiles.
e the
ai legami C=C
if
Br2 approaches end-on—andalkene
this is=how
theAddizione
product forms.
nucleophile
Br2 = electrophile
with
Br
filled
π
2, the alkene’s
ring
product
is
called
a
bromonium
ion.
lassic tests for alkenes is that they turn a brown
aqueous
H
H
O)
will
interact
with
the
Simple,
unconjugated
alkenes
are
and react with electrophiles.
on
ethylene
hilic
attack
by
Br
colourize bromine
water: alkenes react with bromine.nucleophilic
The
2
* orbital
to
give abelow
product.
Br Br
ne,
and the
reaction
bonding
interaction shows what happens with the
alkene = nucleophile
product
Look with
at theBr , the alkene’s
H
HBr π
Br2 = electrophile
Whenbe?
it reacts
filled
•
Br22
LUMO = empty σ* orbital
HOMO = filled π orbital
and
H
H
H the H(the HOMO) will interact with the
orbital
=
ron density
apter,
you in the π orbital is right in theBrmiddle, between the two carbon atoms,
Br
Br
Br
bromine’s
empty Br
σ* orbital
to give a product.
Br Br
ethylene
xpect
the bromine
to
attack.
The
only
way
the
π
HOMO
can
interact
in
a
bondwe
started
(ethene)
1,2-dibromoethylene
But
what
will that product be?
Look at the
H
H
H
H
philes
and
σ* LUMO is ifLUMO
the Br
approaches
end-on—and
this ision
how the product forms.
bromonium
= 2empty σ* orbital
LUMO = empty σ* orbital
HOMO = filled π orbital
orbitals
involved.
action,
you should
immediately
‘Which
ee-membered
ring
product isthink
calledtoayourself,
bromonium
ion.
we
draw curly
arrows
for the
formation
of is
theright
bromoniThe
highest
electron
density
in the
π orbital
in the middle, between the two carbon atoms,
tow
is shall
the
electrophile?’
Evidently,
neither
the
alkene
nor
electrophilic
attack
by Br
2 on ethylene
on?
have
a choice.
The
to
show
middle
of
nergy
empty
orbital
(theexpect
Br–Brsimplest
σ*),
andis isjust
therefore
antheThe
soWe
this
is where
we
the
bromine
to
attack.
only
way the
π HOMOofcan
interactto
in aform
bondOxidation
alkenes
epoxides
bonding interaction
rbon,
π
bond
attacking
Br–Br,
mirroring
what
we
know
happens
with
onally
weak,
and
bromine
reacts
with
nucleophiles
like
ing manner with the σ* LUMO is if the Br approaches end-on—and this is how the product forms.
2
rbitals.
The symmetrical
ring product is called a bromonium ion.
H three-membered
H
HOMO
=
Of
course,
the
final
product of the reaction isn’t the bromonium ion. The second step of
repe–Br,
electrophilic
attack by Br2 on ethylene Br
Br
Br
Br
filled π
Br
Br bromonium
Br
follows on at once: the
ion is an electrophile, and it reacts with the
ir +of Br orbital theBrreaction
bonding interaction
bromide
lost from
theσ*bromine
addition step.
Hat carbon,
Hion LUMO
es
of SN2 reactions
two
ion We can now draw the correct mechanism
= empty
orbital in the bromonium
on
is also
a nucleophilic
forC–Br
the whole
is Yet
termed
electrophilic addition to the double bond, because bromine
then
represent
the
bondsreaction,
as partialwhich
bonds.
the bromoniH
H
How
shall
we
draw
curly
arrows
for
the
formation
of the bromonif the bromine)
at Br.
Just
and
and bacteria,
usually
for
the bathroom)
while
others
is
an
electrophile.
Overall,
the
molecule
of
bromine
adds across the double bond of the alkene.
HOMO
=
two
proper
C–Br
bonds
(read
the
box
in
the
margin
on
p.
000
for
Br
nt
contain
ammonia
dissolve
fatty deposits,
usually
for the is just to show
um
ion?
We(to
have
a choice.
The
simplest
the
eophile,
and
Br–Br
with
Me–Br,
Br Br middle of
Br
Br
filled π
way
kitchen).
Ammonia
is
nucleophilic,
chlorine
electrophilic,
electrophilic
addition
of
bromine
to
ethylene
.
the
πproducts
bondofattacking
Br–Br,
mirroring
what we know happens with
orbital
ome
and
the
their
reaction
are
the
highly
toxic
and
ve
a explosive chloramines
H BrLUMO =Brempty σ* orbital
Br
Br Br
bromonium ion
oulds
NH2Cl, NHCl2, and NCl3H
.
the orbitals.
blem with this
H repHow shall we
draw curly
arrows for the formation
of the bromonifurtherorbital
reactions interaction
nts
more
involved,
and
we
NH2ClaccuratelyBrthe key
Br
Br
Br
Br
Br
Br
e only one pair
N of
Me
Br
um ion? We have a choice. The simplest is just to show the middle of
H too.
chloramine
swe
acceptable
can’t form
two
H
the π bond attacking Br–Br,
what we know happens with
BrYetmirroring
its HOMO
is the
C=C
π bond.the
ThisC–Br
is a very
important
ed should
really
then
represent
bonds
as partial bonds.
the bromoniBr
bital
bromonium
ion
the orbitals.
nes you met,
in two
Chapter
10, the
conjugated
alkenethe
wasbox
an in the margin on p. 000 for
rmediate
with
proper
C–Br
bonds (read
But
there
is a Attack
problem
repoxygen's
lone
pairisstabilizes
alkenes
first,
because
their chemistry
isthis
very
similar
to the
of with
Br– on
a bromonium
ion
a normal SN2 substitution—the key orbitals involved are
an alternative
way
!
Co
nu
17
regioselectivity.
The
alcohol attacks the more hindered end of the bromonium ion—the end where
partial
positive
charge
tertiarypositive
end than
at theinprimary
end,Sbecause
the substituents stabilize the build-up of positive
(+) partial
Brthe
there can be greatest stabilization of
charge
the ‘loose
N2’ transition state. This
charge. The bromonium
ionBromonio
can be more accurately represented as shown in the margin, with one
Reattività dello
ione
the way
a
mechanism
can
lie
in between SN1 and than
SN2.the
Weother.
see
Br reaction really does illustrate
longer, weaker
bondin which
C–Br bond longer than the other, and more polarized
a configurational
inversion,
indicative of anThe
SNnucleophile
2 reaction,now
happening
at a does
tertiary
centre
whereaccessible,
you
same
product whichever
end
has a choice:
it attack
the more
primary end of the bromois attacked
would usually expect SN1.
nium ion, or does it attack the more charged end with the weaker C–Br bond? Here, the latter is
Br
ilic sololecules
ion. As
an broso high
s 55M),
is what
mine in
only at
clearly the faster reaction. The transition state has considerable positive charge on carbon, and is
known as a loose SN2 transition state.
Br
HO
Me
MeOH
OMe
Br2, MeOH
NBS
Br
Br
HO
MeOH
methanol attacks at the more
substituted end of the
bromonium ion
Me
–H
(+)
(+) H
MeO
(+)
Me
‡
H
OMe
OMe
Unsymmetrical bronomium ions open regioselecti
O
Br (+)
Br (+)
(±)
Br
Br
loose SN2 transition
The products of bromination
in waterstate
are called bromohydrins. They can be treated with b
which deprotonates the alcohol. A rapid intramolecular SN2 reaction follows: bromide is expelle
a leaving group and an epoxide is formed. This can be a useful alternative synthesis of epox
avoiding peroxy-acids.
Iodolactonization
and bromolactonization
bromohydrin make new rings
Br
To finish our discussion of bromonium ions, you need to know about
Brone more important class
Br of reacBr2, H2O
NaOH
it is most hindered,
so
there
must
be
some
effect
tions, those in which the nucleophile is located within the same molecule as the bromonium ion. Here is
ay of looking atan
this
is to reconsider
our assumpexample:
the nucleophile
is a carboxylate, and the productOis a lactone (a cyclic ester).
O This type of reacs. Here, it hardly
looks
S
2.
We
have
a
tertiary
N
tion—the cyclization
of an unsaturated acid—is known as a bromolactonization. Intermolecular attack
H
ow. But we have already said that cations like this
OH
on the bromonium ion by bromide ion does not compete with the intramolecular
cyclization step.
ed bromonium ion and, if we let this happen, we
Br
k to where we started: an SN2 mechanism!
Rates of bromination of alkenes
bromolactonization
Br
O
relative rates of reaction of alkenes with bromine in methanol solve
The pattern you saw for epoxidation withBr
peroxyBr
O
acids (more substituted
alkenes react faster) is
followed by bromination reactions too. The
OMe
O R1
O R1
R3
R3
S N1
Br2 O
O
NaHCO3
bromonium
ion
is
a
reactive
intermediate,
so
the
O
O
rate-determining step of the brominations is the
MeO
Br
cyclic ester (lactone)
–H
MeOH
bromination
reaction
itself.
The
chart
shows
the
Br
Br
Br addition of a halogen to an alkene that we have shown
Every example of electrophilic
R4
R2 youR4so far
R2
!
effect on the rate of reaction with bromine in
been with bromine. This is quite methanol
representative:
bromine
is of
the
most widely used halogenn-Bu
for
carbocation has
t-Bu
of increasing
the number
alkyl
MeOH
It should
be mentionedMe
at this po
substituents
from
none
(ethylene)
to
four.
Each
H
C
CH
electrophilic addition, since its reactivity is second only to iodine, yet the products2 are more
stable.
2
that five-membered ring formation
additional alkene substituent produces an
iodolactonizations—
However,
in by
these
lactonization
iodine is the more commonly used reagent, 1and the prod- 100is the norm in 27
2700
n reactions don’t
always go
pure
SN1 or purereactions,
enormous increase in rate. The degree of branching
you will need to wait until Chapter
ucts ofPerhaps
iodolactonizations
important
(you
mewhere in between.
the leaving are
group
(Meintermediates
versus n-Bu versus
t-Bu) will
withinmeet
the them again in Chapter 33). In
Me
42 to
hear the full details
Me why—bM
Me
Me
substituents
has
a
much
smaller,
negative
carbon which is
by thethe
nucleophile.
theintercepted
next example,
iodolactonization product is treated with sodiumeffect
methoxide,
which appears
here this preference is reinforced
(probably of steric origin) as does the geometry (E
OH
Br2
Addizione ai legami C=C
"Regola di Markovnikov" In una addizione elettrofila al legame C=C il H si lega al C
che porta più protoni o meglio si forma il prodotto che deriva dal carbocatione più
stabile.
Vladimir Markovnikov!
1837-1904
Markovnikov’s rule
Addizione elettrofila ai legami C=C
There is a traditional mnemonic called ‘Markovnikov’s
rule’ for electrophilic additions of H–X to alkenes, which
can be stated as ‘The hydrogen ends up attached to the
carbon of the double bond that had more hydrogens to
start with.’ We don’t suggest you learn this rule, though
you may hear it referred to. As with all ‘rules’ it is much
more important to understand the reason behind it. For
example, you can now predict the product of the reaction
below. Markovnikov couldn’t.
Br
Prevale la coniugazione
conPhil
HBr
Ph
Br
sistema aromatico
Br
The protonation of alkenes to give carbocations is quite general. The carbocations may trap a
nucleophile, as you have just seen, or they may simply lose a proton to give back an alkene. This is
just the same as saying the protonation is reversible, but it needn’t be the same proton that is lost. A
more stable alkene may be formed by losing a different proton, which means that acid can catalyse
the isomerization of alkenes—both between Z and E geometrical isomers and between regioisomers
isomerization of an alkene in acid
loss of green proton gives back
starting material
H
H
protonation leads to stable,
tertiary carbocation
E1 and isomerization
H
loss of orange proton leads to
more stable trisubstituted
double bond
OH
nometallic
soft electrophiles such as transition metal cations. Here, for example, is the complex formed between
Addizione di acqua
an alkene and mercury(II) cation. Don’t
be too concerned about the weird bond growing from the
middle of the alkene: this is a shorthand way of expressing the rather complex bonding interaction
between the alkene and mercury. An alternative, and more useful, representation is the three-membered ring on the right.
Hg2
Hg2
R
R
Hg2
or alternatively
R
The complex should remind you of a bromonium ion, and rightly so, because its reactions are
really rather similar. Even relatively feeble nucleophiles such as water and alcohols, when used as the
solvent, open the ‘mercurinium’ ion and give alcohols and ethers. In the next scheme, the
mercury(II) is supplied as mercury(II) acetate, Hg(OAc)2, which we shall represent with two covalent Hg–O bonds (simply because it helps with the arrows and with electron-accounting to do so).
Unsurprisingly, water attacks at the more substituted end of the mercuronium ion.
oxymercuration
OH
OH
Hg(OAc)2, H2O
R
HgOAc
R
–H
OAc
AcO
R
mercurinium ion
OAc
Hg
OH2
Hg
R
H2O
R
HgOAc
NaBH4
R
B oxidation occurs by nucleophilic attack
alkene
under way, a hydrogen
atom
from
the boron
The
ofgets
the hydroperoxide
ion on the
empty
orbital
of theadds
H
H
H
H
It is, of course, impossible to tell in this case whether the addition
is which
syn or anti
and in any case
the
atom,
is becoming
positively
charged.
two by
steps s
boron atom followed byAddizione
a migration
of
the
alkyl
chain
from
boron
to
oxygen.
Do
not be The
alarmed
Boron
acqua "anti-Markovnikov
alkyl borane products are rather unstable. Althoughdi
organoboranes
can be stored, and some are
tion
of
the aleaving
C–B
bond
goes
ofweak
formation
of theO–O
C–H bon
ion
asbe
leaving
group.
It is,
of
course,
a into
bad
group
but
a very
bond—the
It is,hydroxide
of course,
impossible
to tell
in
this
whether
the
addition
isahead
syn
available commercially,
air must
rigorously
excluded
as case
they burst
spectacular
green
flameor anti and in any case the
lyboron
charged
in
the
four-centred
σcontrolled
bond—is
being broken.
Finally,
hydroxide
attacks
the
now
neutral
boron
to stored,
cleavestate.
the
B–O–alkyl
!
in air.
A moreborane
is required
to
remove
theAlthough
and organoboranes
reveal
the
useful organic
alkyl
products
are
rather
unstable.
cantransition
be
and
some are
Hydroboration
isoxidation
regioselective
More
modern
alternative
bond
and
release
the
alcohol.
fragment. The simplest is alkaline hydrogen peroxide, which replaces the carbon–boron bond with a
available
commercially,
air
must
be rigorously
excluded
as they
burst
into
a spectacular
flame
Hgreen
reagents,
which
are stable,
You
will
notice
that
the
boron
atom
always
adds
to
the
end
of
the
alkene.
This
is
just
as
well;
otherH
(–)
R
carbon–oxygen bond to give an alcohol.
R
oxidation
inexpensive,
safe
easy to
! and
OH
R rise
R ofthe
BHThe
Buseful
in three
air.RAsequential
more controlled
oxidation
is to
required
to mixture
remove
boron
reveal
the
organic
2and
wise,
additions would
give
a complex
products.
boron
always
(+)
H
handle but achieve the same
BH
O
H
2
2 oxidation B
The hydrogen mus
hydroboration
R double
H BH
becomes
attached
to
the
carbon
of
the
bond
that
is
less
substituted.
This
is
what
we
should
R
fragment.
The
simplest
is
alkaline
hydrogen
peroxide,
which
replaces
the
carbon–boron
bond
with
a
transformation
underBH
mild
H
H
R
R
H
+
2
B
H2O2, NaOH
carbon
of
the
alke
OH
B π orbital of the alkene adds to the empty
O in higher
O
conditions
often
expect
if the filled
sta- andfewer
OH the more
carbon–oxygen
to
give
an
alcohol.
H2Oorbital
, NaOHof the borane to give
hydrogens a
2
H
H bond
O OH
OH
yield,
arecase
sodium
perboratethe a
H
It is, of course, impossible to tell in
this
whether
ble cationic intermediate.
a formal vio
(NaBO3·4H2O)This
andis
sodium
H
oxidation
The oxidation occurs by nucleophilic
attack
of
the
hydroperoxide
ion
on
the
empty
orbital
of
the
Markovnikoff’s
rul
hydroboration
are rather unstable.
Although
organ
Ralkyl
HH
percarbonate
(Na2CO3·1.5H
R borane products
2O2)
R
R
H
H
R
In
this
sequence
boron
goes
backwards
and
forwards
between
planar
neutral
structures
and
warning:
this
is
+ a migration of the alkyl
in Chapter 20
boron
to oxygen.
by be rigorouslymet
B B Do not be alarmed
R atom followed by
B chain from boron
OH
available
commercially,
aircomplete
must
excluded
as th
NOT the
B
warning
to
unders
structures.
This
is
typical
of
the
organic
chemistry
of
boron.
The
planar
structure
H leaving
hydroxide ion anionic
as leavingtetrahedral
group.
It
is,
of
course,
a
bad
group
but
a
very
weak
bond—the
O–O
B
H2mechanism
O2, oxidation
NaOH
H
H
H controlled
in
air.
A
more
is required
to remove
t
H
H
mechanisms
H
H
σ bond—is being
broken.but
Finally,
hydroxide
attacks
the nowelectrons.
neutral boron
cleave the B–O–alkyl
is neutral
boron
has only
six valency
Theto
tetrahedral
structure gives boron eight
valen- of th
rather than follow
fragment. The simplest is alkaline hydrogen peroxide, which
bond and release
the
alcohol.occurs
electrons
but it isby
negatively
charged.
Boron
flitshydroperoxide
restlessly between
twoempty
types of
structure,
Thecyoxidation
nucleophilic
attack
of the
ionthese
on the
orbital
of the
less
electronegati
We know that this is not the whole story because ofcarbon–oxygen
the stereochemistry.
Hydroboration
is a syn
bond
to
give
an
alcohol.
hydrogen
andby
so t
oxidation
becoming
content
when it of
has
three
oxygen
atoms
around
it.toReturning
to
oxidation
but
boronacross
atom
followed
a migration
ofthe
the
alkyl
chain
from
boron
oxygen.
not
be
alarmed
R addition
OH endDo
R by
R
the
alkene.
Asonly
the
addition
empty
pBH
orbital
to the
less substituted
of the
the
2
R
regioselectivity is
BH2 concentrating on the boron
BH2 product, we find
O that B(OH) is the
H
stable
product
as
it
is
neutral
and
3
hydroboration
alkene
gets under
way,
a
hydrogen
atom
from
the
boron
adds,
with
its
pair
of
electrons,
to
the
carbon
hydroxide
ion
as
leaving
group.
It
is,
of
course,
a
bad
leaving
group
but
a
very
weak
bond—the
O–OH
R moreOH
R
BH2
electronegat
H2O2, NaOH
R
+
O
B
alcohol
hasisthree
oxygen
atomsOdonating
electrons
into shown
the
p orbital
onboron
boron.
OH empty
atom,
which
becoming
positively
charged.
The two steps
above
are
but
becoming
attache
σ bond—is
toformacleave the
B–O–alkyl
B concerted,
O OH being broken. Finally,
OH hydroxide attacks the now neutral
substituted centre
H
H carbon are partialtion
of theand
C–Brelease
bond goes
ahead
of formation of the C–H bond so that boron
and
H
OH
bond
the
alcohol.
OH and
OH
ly this
charged
in theboron
four-centred
transition
state.
In
sequence
goes backwards
and
forwards between planar
neutral
structures
H
O
2
2
oxidation HO
occurs by nucleophilic
attack of the hydrop
R
R
BH
2
+
oxidation
HO The
BH
HO B
R tetrahedral structures.
OH
BH
anionic
This
is typicalRof the organic
chemistry
of2R
boron. The planarB
structure
2
OH
O
H
R
H
H BH2
boron
atom
followed
by
a
migration
of
the
alkyl
chain
from
NaOH
(–)
R
BH2
O eightOH
alcohol
OH
is neutral
but boron has only six valency electrons.
The
tetrahedral
structure
gives
boron
valenR
B
B
(+)Boron flits restlessly
H
2
hydroxide
ion
astypes
leaving
group.
is, ofR
course, a bad BH
leaving
stableItboric
acid
H2Ocharged.
cy electrons butB it is negatively
between
these
two
of
structure,
2, NaOH
O
O
Idroborazione
ossidativa!
OH
H
H
Honly when it has three oxygen
H atoms around
σ bond—is
being
broken.
Finally,
becoming content
it. Returning
to the
oxidation
but hydroxide attacks the now
O OH
OH
concentrating
the boron
product,
we
find
thatcase
B(OH)
stable
asthe
it isanti
neutral
andany case the
bond
andproduct
release
alcohol.
3 is the
It is, of on
course,
impossible
to
tell
in
this
whether
the
addition
is
syn
or
and
in
Herbert C (HC Brown)!
has three oxygen atoms donating electrons
into the empty p orbital on boron.
1912-2004!
alkyl borane
products
are
rather
unstable.
Although Rorganoboranes
be
stored,
and
some are
In this sequence boron
goes
backwards
and forwardscan
between
planar
oxidation
R neutral structures
R and
Nobel
Laureate
Chemistry!
OH
available
commercially,
must be1969!
rigorously
excluded
as
they
burst
a spectacular
green The
flame
BH2 into
BH
2
anionic
tetrahedralair
structures.
This isHtypical
of
the
organic
chemistry
of
boron.
planar
structure
OH
OH
O
!
2
2
R
is required
to remove
boron and
the useful organic
R in air. A more
BH2 controlled oxidation
H2reveal
OB2, NaOH
+ HO
BH2
HO B the
HO
is neutral
but boron hasOHonly
six
valency
electrons.
The
tetrahedral
structure
gives boron
eightmodern
valenO
O
More
alte
fragment. The simplestalcohol
is alkaline hydrogen peroxide,
whichOH
replaces
the
carbon–boron
bond
with
a
NaOH
OH
O OH
OH
reagents, which ar
Addizione ad un diene coniugato
Electrophilic
addition to dienes
Electrophilic
additio
ion. This is what happens when 2-methylbuta-1,3-diene (isoprene) is treated
on gives a stable
delocalized
allylic cation.
by acid
to give a cation.
This is what happens when 2-methylbuta-1,3-diene (isoprene) is treated
by acid to give a cation. This is what happens when 2-methylbuta-1,3-diene (isopr
with acid. Protonation gives a stable delocalized allylic cation.
with acid. Protonation gives a stable delocalized allylic cation.
H
H
isoprene
his double bond
positive charge not delocalized on
isoprene
Why
protonate
this
double
bond
to this carbon, so Me cannot positive charge not delocalized on
one? The cation
so Me cannot
contribute
and not the
other
one? Thethis
cation
Why
protonate
double
bond to stability of cation to this carbon,positive
ng the other doucontribute to stability ofcharge
cation not de
to this carbon, so M
you get by protonating the other douic, but it cannot and not Hthe other one? The cation
contribute to stabilit
ble bond
is also
allylic,
but it cannot
H
you
get
by
protonating
the
other
douditional stabilizabenefit from
the additional
stabilizable
bond
is
also
allylic,
but it cannot
H
yl group because
tion from
the methyl
group
because stabilizabenefit
from
the
additional
s not delocalized
the positive charge is not delocalized
tion from the methyl group because
ying the methyl.
on to the carbon carrying the methyl.
the positive charge is not delocalized
Br
Br
on to the
carbon
carrying
the methyl.
HBr
X
isoprene
HBr
X
X
Br
prenyl bromide
–
Br
Br
prenyl bromide
– on nucleophilic
If the attack
acid
is by
HBr,
attack byThe
Br cation
on theiscation
follows.
at
then nucleophilic
Brthen
the cation follows.
attacked
at The cation is attacked
isoprene
prenyl bro
less hindered
end to give
the important
compound
This is very much the sort of
to give thethe
important
compound
prenyl
bromide. This
is veryprenyl
muchbromide.
the sort of
– on
reaction
you
met acid
in half
Chapter
is
the second half
of an
SBr
substitution
reaction
onThe
an allylic
Ifsecond
the
is HBr,
then
attack
byon
the cation
follows.
cation
N1an
Chapter 17—it
is the
of an17—it
SN1 nucleophilic
substitution
reaction
allylic
compound.
the less hindered end to give the important compound prenyl bromide. This is very m
The most commonly
used peroxy-acid
is known to
as m-CPBA,
20 . Electrophilic
addition
alkenesor meta-ChloroPeroxyBenzoic
Epossidazione
Acid. m-CPBA is a safely crystalline solid. Here it is, reacting with cyclohexene, to give the epoxide in
95% yield.
H
O
O
H
O
+
OH
Nu
O
O
Cl O
R
O
R
O Nu
O
504
H
H
electrophilic
oxygen
(= m-CPBA)
20 . Electrophilic addition to alkenes
O
+
HO
Cl carboxylate: good
leaving group
95% yield
AsOyou will expect, the alkene attacks theO peroxy-acid from the centre of the HOMO, its π orbital.
Making
peroxy-acids
First, here is the orbital
involved.
+
OH
Nu
H
Nu
O
O
R attack by aPeroxy-acids
O
R the corresponding acid
from
electrophilic
peroxy-acid onare
anprepared
alkene
group): one of the most powerfully oxidizing per
anhydride and high-strength
peroxide. In
is peroxy-trifluoroacetic acid. Hydrogen peroxide
carboxylate: hydrogen
good
bonding interaction
electrophilic
leaving
group
general, the stronger
the parent acid, the more
powerful
concentrations
(> 80%),
is explosive and di
O
Oxidation
ofhigh
alkenes
to form
epoxides
oxygen
the oxidant (because the carboxylate
is
a
better
leaving
transport.
R
H
H
R
H
Ar
H O
HOMO =
O
O
O
O O
O
filled π
ArO
Epoxidation
is
stereospecific
Making peroxy-acids
orbital
H2O2
O
OH
R
H
R
H
LUMO = empty σ* orbital
Because
new C–O
formed
onCF
the
same
face
of
the
alkene’s
π
bond,
the+geometry
of OH
Peroxy-acids are prepared
from theboth
corresponding
acid bonds
group):
ofO
the most
powerfully
oxidizing
peroxy-acids
F
F3Careone
C
O
F3C
3
3
O
H
O
epoxide
anhydride and high-strength hydrogen peroxide. In
is peroxy-trifluoroacetic acid.
Hydrogen peroxide, at very
the
alkene
is
reflected
in
the
stereochemistry
of
epoxide.
The to
reaction
is therefore
general, the stronger the parent acid, the more powerful
high
concentrations
(> 80%),the
is explosive
and difficult
trifluoroacetic
anhydride
peroxy-trifluoroacetic
acidstereospecific.
trifluoroacetic acid
And
now
the
curly
arrow
mechanism.
The
essence
of
the
mechanism
is
electrophilic
attack
the oxidant (because Here
the carboxylate
is
a
better
leaving
transport.
are two examples demonstrating this: cis-alkene gives cis-epoxide and trans-alkene gives trans-
by theepoxide.
weak,O polarized O–O bond onOthe π orbital of the
alkene, which we can represent most
O
O
Ar
most commonly
used
peroxy-acid
is known
or meta-ChloroPero
simply as shown in The
theH2Omargin.
But, in the
real reaction,
a proton
(shownasin m-CPBA,
brown in this
2
OH
+
F3C
O
CF3transferred
C aepoxide
O
OH
mechanism)
has
fromF3the
oxygenF3Cto the
carboxylic
by-product.
can
O
Acid. m-CPBA
is
safely
crystalline
solid.
Here it acid
is, reacting
withYou
cyclohexene,
to give the
O
mdraw
-CPBA the arrows
m -CPBA
trifluoroacetic
anhydride
peroxy-trifluoroacetic
acid
trifluoroacetic
represent
this
all in
oneyield.
step if you
carefully.acid
Start with the nucleophilic π bond:
95%
send the electrons on to oxygen, breaking O–O and forming a new carbonyl bond. Use those
O m-CPBA,
The mostelectrons
commonlytoused
is H
known
meta-ChloroPeroxyBenzoic
pickperoxy-acid
up the proton,
and asuse
the old orO–H
bond’s electrons to make the second new
Acid. m-CPBA
is
a
safely
crystalline
solid.
Here
it
is,
reacting
with
cyclohexene,
to give the epoxide in
C–O bond. Dont’ be put off byOthe spaghetti effect—each
Cl arrow is quite logical when you think the
95% yield. mechanism through.
trans -stilbene
trans -stilbene
-stilbene
cis
O state for the reaction
The transition
makes oxide
the bond-forming andOcis
-breaking
‡
H processes
O
clearer.
R
H
More substituted alkenes epoxidize faster
Di-idrossilazione
!
RCO2R
RX
Ph
R
X = O, NH
hardest to hydrogenate
RCN
R
RCH2OH
RXH + PhCH3
R
Idrogenazione
RCH NH
R
2
2
Like hydrogenolysis, the mechanism
RCH2OH of the hydrogenation of C=C double bonds starts with coordination of the double bond to the catalyst surface.
Like hydrogenolysis, the
of C=C double bonds starts with coorMe
R mechanism of the hydrogenation
R
dination of the double bond to the catalyst surface.
Me
Me
hardest to hydrogenateRCO2R
Me
hardest to hydrogenate
Me
Me
Me
Me
Me
Like hydrogenolysis, the mechanism of the hydrogenation of C=C double
bonds
starts with coorMe
H
H
H
H
hydrogen adsorbed
H
H
dination
the catalyst surface.
Me on to catalyst
Me
Me
surface of the double bond toMe
Me
H
hydrogen adsorbed
H
on to catalyst surface
Me
Me
hydrogen adsorbed
on to catalyst surface
H
metal catalyst
alkene coordinates to catalyst H
H
H
Me
both hydrogens delivered
Me
from
H same face
Me
H
Me
H
H
metal catalyst
Me they
Me
Me
both hydrogens
delivered
H
Two
hydrogen atoms
are transferred
to the alkene,
and
are often
both added to the same face
alkene Pd,
coordinates
catalyst
metal
catalyst
Metallo:
Pt, Ag,toRh,
Ru, Ni,!
H
metal catalyst
from
same
face
H
of
met other reactions
of
H alkenes: some, like bromination, were antiH 20 you
H
H theH alkene. In Chapter
selective, but
others
like epoxidation
syn-selective
likeoften
hydrogenation.
Two hydrogen
atoms
are
transferred
to thewere
alkene,
and theydelivered
are
both added to the same face
both
hydrogens
alkene coordinates to catalyst
metal catalyst
metal catalyst
from same face
of the alkene. In Chapter 20 you met other reactions of alkenes: some, like bromination,
were antiTwo hydrogen
atoms
transferred
to
the syn-selective
alkene, and they
arehydrogenation.
often both added to the same face
H2, PtO2, were
AcOH
selective,
but others
likeare
epoxidation
like
of the alkene. In Chapter 20 you met other reactions of alkenes: some,
+ like bromination, were antihis cannot be relied upon
ough! The same reaction with selective, but others like epoxidation were syn-selective like hydrogenation.
H2, PtO2, AcOH
d as catalyst gives mainly the
82%
18% trans
+ cis
be relied upon
ans isomer, because of the
H2, PtO2, AcOH
e same reaction with
+
versibility
of theupon
hydrogenation
cannot be relied
yst
gives
mainly
the with
gh!
The
same
reaction
ocess. This intermediate can
82% cis
18% trans
er,
because
of mainly
the
H
s catalyst
gives
asily
escape
from thethe
catalyst as
Me
82% cis
18% trans
Me
of
the hydrogenation
isomer,
because
of which
the
ns isomeric
alkene,
can be
H
rsibility
of the hydrogenation
H
his
intermediate
can
Me H
Me
-hydrogenated
from can
the other
Me
Me
H
ess.
Thisthe
intermediate
pe
from
catalyst
as
Me
ce.
Isomerizations
of this sort
H
Me
ly
escape
from the catalyst
Me
alkene,
which
can be as
H
H
Me
H
ometimes
accompany
someric alkene, which can be
H
H
H
Me
Me
nated
from
the
other
Me
Me
H
Me
Me
ydrogenated from the other
ydrogenations.
metal catalyst
metal catalyst
Me
Me
H
erizations
of this
. Isomerizations
of sort
this sort
Paul Sabatier!
HH
H
H
accompany
etimes
accompany
1854-1941!
ogenations.
metal
catalyst
metal catalyst
ions.
metal
catalyst
metal catalyst
Nobel Laureate Chemistry!
1912!
Addizione agli alchini
L' addizione agli alchini segue le regole di regiochimica delle addizioni agli alcheni
Chimica Organica e Red-ox
Il numero di ossidazione ( o meglio livello di ossidazione) di un C in una struttura organica si calcola
assegnando gli elettroni di legame all'atomo più elettronegativo ( C = 2.5 ; H = 2.1 nella scala di Pauling) ed un
solo elettrone se gli atomi legati sono uguali (C-C). Si confronta con il numero di elettroni dell'ultimo strato e si
definisce il livello di ossidazione
Carbanioni / composti organometallici
12
Composto di Grignard. Reazione Red-ox, il C si riduce ed il Mg si ossida. !
Il sistema è omogeneo in un solvente organico che stabilizza il composto con un effetto
donatore!
E' una specie molto reattiva, molto basica e nucleofila. !
A causa della basicità reagisce rapidamente ( e violentemente) con specie che presentano
legami OH, SH o NH.
9 . Using organometallic reagents to make C–C bonds
Victor Grignard!
1871-1935!
Nobel Laureate Chemistry!
The reaction takes place not in solution but on the surface of the metal, and how easy
it is to make
1912!
O
R
O
Mg
X
complex between
Lewis-acidic metal atom
and lone pairs of THF
R can be alkyl
or aryl
X can be I, Br
or Cl
a Grignard reagent can depend on the state of the surface—how finely divided the metal is, for example. Magnesium is usually covered by a thin coating of magnesium oxide, and Grignard formation
generally requires ‘initiation’ to allow the metal to come into contact with the alkyl halide. Initiation
can be accomplished by adding a small amount of iodine or 1,2-diiodoethane, or by using ultrasound to dislodge the oxide layer. The ether solvent is essential for Grignard formation because (1)
ethers (unlike, say, alcohols or dichloromethane) will not react with Grignards and, more importantly, (2) only in ethers are Grignard reagents soluble. In Chapter 5 you saw how triethylamine
forms a complex with the Lewis acid BF3, and much the same happens when an ether meets a metal
ion such as magnesium or lithium: the metals are Lewis-acidic because they have empty orbitals (2p
in the case of Li and 3p in the case of Mg) that can accept the lone pair of the ether.
How to make organolithium reagents
Carbanioni / composti organometallici
Gli alchil o aril-litio derivati sono specie basiche (e nucleofile) molto forti che sono in grado di strappare
protoni anche da specie relativamente poco acide
Stabilità carbanioni: C p° > C s° >> C t°
I carbanioni possono essere stabilizzati per risonanza,
attraverso un processo di aggregazione o per interazione
metallo/solvente
Carbanioni: reattività
Carbanioni: reattività
OMT
!
R-MgX or R-Li
!
!
!
Elettrofilo
CO2
Prodotto
acido carbossilico
formaldeide
alcol primario
aldeide
alcol secondario (chetone)
chetone
alcol terziario
epossido
alcol secondario o terziario
alogenuro allilico o benzilico
idrocarburo allilico o benzilico
alogenuro alchilico
eliminazione (prevale la basicità)
Organolithiums can be converted to other types of organometallic reagents by transmetallation—
reattività
simply treating with the salt of a lessCarbanioni:
electropositive
metal. The more electropositive lithium goes
into solution as an ionic salt, while the less electropositive metal (magnesium and cerium in these
examples) takes over the alkyl group.
R
MgBr + LiBr
Grignard
MgBr2
dry Et2O or THF
R
CeCl3
Li
alkyllithium
dry Et2O or THF
R
!
You will see se
transmetallati
the next chapt
CeCl2 + LiCl
organocerium
Transmetallazione: il metallo meno elettronegativo va in soluzione mentre quello più elettronegativo si
But why bother? Well, the high reactivity—and in particular the basicity—of organolithiums, !
lega al residuo organico. In questo modo si modifica la reattività del sistema che diviene sempre meno You met the id
which we
have
just been
causes
unwanted
side-reactions.
You non
saw in
Chapter 8 and aromatic r
"ione" e sempre
più
"neutro".
In extolling,
tal modosometimes
diminuisce
la basicità
mentre
la nucleofilia
cambia
that
protons
next to
carbonyl
moderately
acidic
(pKa about
20), and
because
of this protons in Cha
tantissimo.
Usando
metalli
diversi
con groups
valenzeare
diverse
si hanno
aggregati
di diversa
natura
in soluzione,
organolithiums
occasionally
act as bases towards carbonyl compounds instead of as nucleophiles.
con influenza
di nuovo sulla
reattività.
Organoceriums,
example,
are rather
lesslebasic,
and may give higher
of the
nucleophilic
Hard &soft:
la natura delfor
metallo
influenza
anche
caratteristiche"hard
and yields
soft" del
nucleofilo.
addition
products
than
organolithiums
or Grignard
reagents.
Una specie
si definisce
hard
quando
il centro reattivo
è piccolo
ed "elettronegativo".
Una specie si definisce soft quando il centro reattivo è grande (con elettroni di non legame nel mezzo) e
Grignard
R M
meno elettronegativo.
An instance where transmetallation is needed to produce another
Un centro hard
reagisce preferenzialmente
per
elettrostatica,
unacentro
soft reagisce
organometallic,
which does act
asvia
a base
but not as
nucleophile!
preferenzialmente
sovrapposizione
Dialkylzincsper
are stable,
distillable liquidsorbitalica.
that can be
alkanes. They are used to preserve old books from
!
Nucleofili
!
made by transmetallating Grignard reagents with zinc
bromide.
They are much elettrofili
less reactive hard,
than organolithium
hard
preferiscono
nucleofili
or organomagnesium compounds, but they are still rather
basic and react with water to give zinc hydroxides and
gradual decomposition due to acid in the paper. The
volatile
dialkylzinc penetrates
the pages
soft
preferiscono
elettrofili
soft. thoroughly,
where contact with water produces basic hydoxides that
neutralize the acid, stopping the deterioration.
dialkylzinc
Nei carbanioni il carattere soft del metallo si ripercuote in un carattere più soft anche del centro reattivo
!
Elettrofili hard: H+, C+, O+ . Elettrofili soft: C-Br, Br2, cationi delocalizzati
!
Acidic protons were a major problem in several syntheses of the anticancer compounds,
daunorubicin and adriamycin, which start with a nucleophilic addition to a ketone with a pair of
particularly acidic protons. Organolithium and organomagnesium compounds remove these pro-
R
Z
H2O
Zn(O
basic zinc
ary cation
were
made
of gaseous
HCl at
icals
contain
unpaired
electrons
HCl
H
Cl
+
thanism
a single
molecule
would
be of the H–Br takes place, Radicali
is quite
different.
Homolysis
+
8 electrons
in
outer
shell
ay
remember
that
at
the
beginning
of
Chapter
8
we
said
that
the
cleavage
of
H–Cl
into
H
+
–
=C
double
bond
at
its
less
hindered
end
are
formed.
Mostly
d
into
H
and
Cl
ions.
–
is possible in solution only because the ions that are formed are solvated: in the gas phase,
mperatures above about 200 °C, however, HCl
does begin to dissociate, but not into
!
ction is endothermic with !G = +1347 kJ mol–1, a value so vast that even if the whole
ead
of the
chlorine atom taking both bonding electrons with it, leaving a naked proton,
The single, unpaired electron
Br
e were
made of gaseous HCl at
possessed by each atom is
on
forming
thewould
H–Clbebond
HCl is shared out between
H the two
Cl !G for this
+ atoms.
not pair
aBrsingle
molecule
–1 and, at high temperatures8(above
represented by a dot. The Cl
electronsabout
in outer200
shell°C,
+
–
sated
a much
more
reasonable
+431
kJ
mol
Br
into H and Cl ions.
atom, of course, has another
>200
°C
HCl
gas
can
be
dissociated
emperatures above about 200 °C, however, HCl does begin to dissociate, but not into
! three pairs of electrons that a
HCl
H
Cl
+
6%
yield
91%
yield
d Clisoatoms.
nstead
of the
chlorine tert
atom
it, leaving
a nakedinproton,
shown.
Radicals
contain
unpair
Thenot
single,
unpaired
electron
contain
unpaired
electron
one with
electron
-butyl
bromide
-butyltaking
bromideboth bonding electrons
7 electrons
outer shell Radicals
possessed by each atom is
ctron pair forming the H–Cl bond is shared out between the two atoms. !G for this
Radicals
contain
unpaired
electrons
1021
–1 and, at high There
by a dot. to
The
Cl
are
a number
of compounds
whose
homolysis
is
particularly
important
chemists,
an
There
are a(above
number
of compounds
whose represented
homolysis
is particularly
important
to
n does
is a much
more
reasonable
+431
kJ
mol
temperatures
about
200
°C,
eterolysis
and
homolysis
its
atom,
of
course,
has
another
the
most
important
ones
are
discussed
in
turn
below.
They
all
have
weak
#
bonds,
and
generate
rad
!There
G forareX–Y
Bond X–Y
G°Cforhomolysis
X–Y
the most important ones are discussed in turn below. They all have weak # bonds, an
>200!whose
),peroxide
HCl gas Bond
can X–Y
be dissociated
a •number of compounds
is particularly important to chemists, and
• + Y
• + Y•icals
three
pairs
electrons
that
areThes
that
can weak
be put
to
chemical
The!
halogens
quite
readily
homolysed
light.
"
X
,
"
X
,
can
besome
put
togenerate
some
chemical
use.
Theare
halogens
areofquite
readilyby
homolysed
Hicals
Cl use.
+
the most importantHCl
ones are discussed in turn below. They all
havethat
# bonds,
and
rad‡ is the activation energy for
!
G
When
bonds
break
and
one
atom
gets
both
bonding
electrons,
the
process
is
–1
–1
and
Cl
atoms.
notweshown.
process
are important
in
halogenation
reactions
shallthat
discuss
later.discuss later.
–O bond
kJthat
molcan be put to some chemical use.
kJ mol
process
are homolysed
important
radical
halogenation
reactions
we shall
one
icals
The halogens
areelectron
quite
readily
byin
light.
7 radical
electrons
inThese
outer
shell that
the reaction.
light (hlater.
!)
process
in radical
halogenation
alled
initiatesheterolysis
a H–OH
498 are importantCH
293 reactions that we shall discuss
light (h!)
3–Br
Cl
Cl
"G = 243 kJ mol
2 x Cl
light (h!)
Cl
Cl
"G = 243 kJ mol
2 x Cl
Heterolysis
and
homolysis
–Cl
in
the
Cl
Cl
"
G
=
243
kJ
mol
2 x Cl234
H3C–H
435
he products
of heterolysis
are,CH
of3–Icourse,
ions.
light (h!)
light (h!)
erence to
Br Br
2 x Br
"G = 192 kJ mol
light (h!)
Br
Br
H3C–OH
383
Cl–Cl get
243bonding
2 x Br
"G = 192 kJ mol
Br
Br
2
x
Br
"
G
=
192
kJ
mol
When
bonds
break
and
the
atoms
one
electron
each,
the
process
bonds
break
and
one
atom
gets
both
bonding
electrons,
the
process
is
•venWhen
more
light (h!)
I
I
"G = 151 kJ mol
light (hBr–Br
!)
light (h!) 2 x I
H3C–CH3
368
192
called
e called
this forheterolysis
homolysis
I
I
2xI
"G = 151 kJ Imol I
2xI
"G = 151 kJ mol
Dibenzoyl
peroxide
is
an
important
compound
because
it
can act as another initiator of radica
d The
dissociH–Cl
431
I–I
151
products
heterolysis
are,
of
ions.may
Dibenzoyl are
peroxide
is ancourse,
important
compound
because
it atoms
can act as another
initiator of radicaland
he products
ofofhomolysis
radicals,
which
be
or
molecules,
Dibenzoyl
is an important
compound
reactions; we’ll
see whyperoxide
later. It undergoes
homolysis
simply onbecause
heating. it can act as another init
reactions; we’ll see why later. It undergoes homolysis simply on heating.
H–Br breakelectron.
366
HO–OHget one
213bonding electron
reactions;
we’ll see why later. It undergoes homolysis simply on heating.
Whenisan
bonds
and the
atoms
unpaired
•ontain
O each, the process
O
O
Ph
O
oxide
O
O
Ph
‡
‡
–1
‡
–1
‡
–1
‡
‡
–1
–1
–1
‡
‡
–1
–1
‡
–1
60–80 °C
dibenzoyl
is called
H–I
298
MeO–OMe
151
OO
Ph
O
O
dibenzoyl
O
Ph
eak
O–O homolysis
peroxide
60–80 °C
peroxide Ph
Ph
O
O
Ph
O
O
Phdibenzoyl
O
O O among
‡ = 139
–1
in
fact,
a reaction
of a 349
closely related
molecule,
hydrogen
was
the
first
Ph
kJ mol
"G
G‡ = 139
kJ may
mol–1
"which
ticThe
cleavCH3–Clof homolysis
products
are radicals,
bebromide,
atomsPh
orthat
molecules,
and
peroxide
O
OO
Ph
O
O
"G‡ = 139 kJ mol–1
emists
to the
possibility
that
radicals
can
be
formed
in
chemical
reactions
even
at
ambient
le
heat or
contain
an unpaired
electron.
Another compound that is often used in synthetic reactions
forcompound
the same reason
reacts
O it
Another
that (though
is often
used
in synthetic reactions for the same reason (though it reac
•
in reaction’, which results
the formation
of theis AIBN
Br radicals,
with in
a different
set of compounds)
(azoisobutyronitrile).
with a different set of compounds) is AIBN (azoisobutyronitrile).
Another compound that is often used in synthetic reactions for the same reason (
CNamong the first
66–72
°C
eas,bond.
Wea shall
return
radicalrelated
chain
reactions
and
their
in fact,
reaction
of atoclosely
molecule,
hydrogen
bromide,
thatset
was
CN
66–72 °Cis AIBN (azoisobutyronitrile).
with a different
of compounds)
N
CN
N N
AIBN
N
CN
N
N
NC thatNradicals can be
AIBN
er.
chemists to the possibility
formed
CN
NC
Nreactions even at ambient
"G‡ = 131
kJ mol–1 in chemical
60–80 °C
°C
–1
"G‡ = 131 kJ mol66–72
N
CN
Some organometallic compounds, for example organomercuries
have very
NCor organocobalts,
N
AIBN
CN
N
N
C
Br
I
Br
2xI
2 x Br
= 151 kJ mol
• •, R"G =O192I kJ Imol
+ "GBr
product
and regenerate
ROH
H Br
(radical
substitution)
to give BrBr
Dibenzoyl peroxide is an important compound because it can act as another initiator of radical
light (hcan
!)
which
react with another ‡
Radicali
I
2
x
I
"
G
=
151
kJ
mol–1we’ll see why later. It undergoes homolysis simply on heating.
reactions;
Br
alkene to give a
3 Br•molecule
adds to ofisobutene
O
Dibenzoyl
peroxide is an radical
important compoundBrbecause it can act as another initiator of radical
O
O
Ph
carbon-centred
60–80 °C
The whole process
can conveniently be represented cyclically.
‡
–1
dibenzoyl
reactions; we’ll see why later. It undergoes homolysis simply
on heating.
peroxide
O chain reaction: addition of HBr to isobutene
a radical
60–80 °C
Ph
O
‡
O
O
–1
Ph
O
O
‡
–1
Ph "G = 139 kJHmol Br
Ph
O
O
Br
radical ab- Br
Another compound that is often used in synthetic reactions for the same reason (though it reacts
Ph
O
O
+
Br
stracts a hydrogen atom
H set
Brof compounds) is AIBN (azoisobutyronitrile).
139 kJ mol–1
"G‡ =from
with a different
O
H–Br
CN
66–72 °C
h ! to form the final addition
N reason
CN(though it reacts
N N
•
Br
AIBN
Another
compound
that
is
often
used
in
synthetic
reactions
for
the
same
product and regenerate Br ,
NC
N
CN
"G‡ = 131 kJ mol–1
with a different
set
of
compounds)
is
AIBN
(azoisobutyronitrile).
H
Br
2 which
x RO can Hreact
Br with another
Br
CN
66–72 °C
molecule of alkene
Some organometallic compounds,
for example organomercuries or organocobalts, have very
dibenzoyl
O
Ph
4 The carbon-centred
peroxide Ph
ROOR O
AIBN
N
CN
N N
weak carbon–metal bonds, and are easily homolysed to give carbon-centred radicals. Alkyl mercury
NCThe whole
N
process can"Gconveniently
be
represented
cyclically.
‡
CN
= 131 kJ mol–1
hydrides
are formed by reducing alkyl mercury halides, but they are unstable at room temperature
because the Hg–H bond is very weak. Bonds to hydrogen never break to give radicals spontaneously
Br
H Br
a radical
chain reaction:
addition of for
HBr example
to isobutene
Some
organometallic
compounds,
organomercuries
or unstable
organocobalts,
have
very
because H• is too
to exist, but
interaction
with almost any radical removes the H atom and
weak carbon–metal bonds, and are easily homolysed to give
carbon-centred
radicals.
mercury
breaks
the Hg–H bond.
This is Alkyl
the process
of hydrogen abstraction, which forms the next section of
ROOR
the chapter.
hydrides
are formed by reducing alkyl mercury halides, but
they are unstable at room temperature
because the Hg–H bond is very weak. Bonds to hydrogen never
break
+
+ R
R Hg
R to give radicals
R spontaneously
Hg R
Hg
each
step intothe
cycle
radical is consumed
and
a
new
radical
is
formed.
This
type
of
reaction
is
because H•hIn
is! too
unstable
exist,
butainteraction
with almost
any
radical
removes
the
H
atom
and
weak C–metal bonds
Br
therefore
known
asisathe
radical
chain
reaction,
and the two
steps
that
form the cyclic process
20 °Cthat keeps
breaks the
Hg–H bond.
This
process
of hydrogen
abstraction,
which
forms
the
NaBH
4 next section of
+ R
R
Hg
Cl
R
Hg
H
Hg + H R
H
Br
2 xtheRO
chain running
one molecule of peroxide RinitiaH Br are known
the chapter.
Bras the chain propagation steps. Only
weak C–metal and metal–H bonds
tor Ris
R Hg
necessary for
of product
to be formed and, indeed, the peroxide
+ R
R a+ large
Hg number
R
Hg molecules
weak C–metal
bonds
needs
to be added in only catalytic quantitiesRadicals
(about 10
mol%) for this reaction to proceed in good
in cars
20 °C
yield.
NaBH4
Radicals
generated
organometallic
vapour in internal combustion engines, and prevent the
+ from
R Hg Cl
R Hg H + R
R Hg
H another
R Pb, were
Br
compound,
tetraethyllead
Et4problem
the reason
for the chain
phenomenon
known as
Any less than
10
mol%,
however,
and
the
yield
drops.
The
is
that
reaction
is‘knocking’. Nowadays simple
weak C–metal and metal–H bonds
adding this compound to petrol. These radicals react with
organic compounds such as MeOBut are used instead in
not 100% efficient. Because the concentrationother
of radical
radicals
ininvolved
the reaction
mixture
radical–radspecies
in the pre-ignition
of petrolis low,
‘green’
petrol.
ical in
reactions
Radicals
cars are rare, but nonetheless they happen often enough that more peroxide keeps being
Radicals
abstraction
needed
start
again is consumed
In eachto
step
in the
the chain
cycle aoff
radical
and aform
new by
radical
is formed. This type of reaction is
Radicals generated from another organometallic
vapour in internal combustion engines, and prevent the
Notice
that
we
didn’tthat
putNowadays
HBr
on the
list
of molecules
that
formkeeps
radicals by homolysis: relative to the
therefore
known
radical
chain
and
the
two
form
the
cyclic
process
that
compound,
tetraethyllead
Et4as
Pb,awere
the reason
for reaction,
phenomenon
known
as steps
‘knocking’.
simple
possible
radical–radical
chain
termination
steps
bondssuch
we have
beent talking
adding this compound to petrol. These radicals react with
organic weak
compounds
as MeOBu
are usedabout,
insteadthe
in H–Br bond is quite strong (just about as strong as a C–C
the chain running are known as the chain
propagation
Only one molecule
of peroxide
initiaBrinvolved
Brthe addition
Br Yet westeps.
other radical species involved in the pre-ignition of petrol
‘green’ bond).
petrol.
said that Br• radicals were
in
reaction we talked about on p. 000.
tor is necessary for a large number of product
molecules
to
be formed
and,of indeed,
the
peroxide
These
radicals
are
formed
by
the
action
the
alkoxy
radicals
(generated
by homolysis of the peroxBr
Br
Br2
Br
on HBr—a
process
as radicalto proceed in good
needsform
to beby
added
in only catalytic quantities ide)
(about
10 mol%)
forknown
this reaction
+
ROH
Br
R O
H Br
Radicals
abstraction
abstraction.
Here
is
the
mechanism.
yield.
Notice thatReactions
we didn’t put
HBr
onare
theknown
list of molecules
that form
radicals
byare
homolysis:
relative
to thethe HBr
The
peroxy
radical
RO• ‘abstracts’
H• from
toofgive
ROH,
leaving behind a new radical Br•.
like
this
as
termination
steps
and
actually
an
important
part
any
chain
Anyweless
than
mol%,
however,
and
theisWe
yield
drops.
The
problem
is that
thewith
chain
reaction is
have
described
this
process
usingasarrows
‘half-heads’ (also known as ‘fish-hook arrows’).
weak bonds
have
been10
talking
about,
thesteps
H–Br
bond
quite
strong
(just
about
as strong
a C–C
reaction;
without
termination
the
reaction
would
be uncontrollable.
greater value greater
meansvalue
higher
energy
(more
unstable)
radicals radicals
means
higher
energy
(more unstable)
ch indicate the movement of electron pairs.
greater value means higher energy (more unstable) radicals
d
Dissociation Dissociation
Bond
Dissociation
of
movement
of ais particularly
This
true if wetrue
compare
the strengths
of bonds
between
the same
atoms,
for exThis
isifparticularly
ifstrengths
we compare
the strengths
of
bonds
between
theexsame
atoms,
for exenergy, X energy,
This
particularly
true
we
compare
the
of
bonds
between
the
same
atoms,
for
rons X
singleiselectron
energy,
Radicali
–1
–1
and hydrogen,
in different
molecules;
tablethis.
does this.
ample,
andcarbon
hydrogen,
in different
molecules;
the this.
tablethe
does
kJ mol
kJ–1mol
ample,
carboncarbon
andample,
hydrogen,
in different
molecules;
the table
does
kJ mol
A are
few
simple
are apparent.
example,
C–H
bonds
decrease
inwhen
strength
in R–H
439
few simple
trends
are trends
apparent.
For example,
C–H
bonds
inR–H
strength
inR R–H
whenwhen
R
A few A
simple
trends
apparent.
For example,
C–HFor
bonds
decrease
indecrease
strength
in
R
goes
fromtoprimary
to secondary
to alkyl
tertiary.
Tertiary
alkyl radicals
are therefore
the most
stable;
from primary
secondary
to Tertiary
tertiary.
Tertiary
alkylareradicals
arethetherefore
the most
stable;
MeCH
423 goes primary
2–H
423
torepresented
secondary
to tertiary.
radicals
therefore
most
stable;
2–Hthan one423
nH
correct
way
of drawing agoes from
example, we could have
the abstraction
Hmore
methyl
radicals
the least
stable.
anism using half-headed
arrows. For
reaction
shown
above
in either
of
thesestable.
alternative
ways.
radicals
the
least
Me CH–H
410 methyl
methyl
radicals
the
least
stable.
CH–H
H
410 2410
CH –H
–H
adical mechanisms
439 3439
CH3
CH3
H
CH
3
H
His more
is3more CH3
is more
O is more
H Br CH
is
more stable
is morestable
isRmore
is
more
is more
stable
CH3
stable stable
stable
HC!C–H
544
stable than
stable than
than
. stable
shows
odd electron
CH
H
CH3
CH
CH3 1024
39
Radical
reactions
C–Hthat the544
544 on RO• pairsCH
CH3
H
CH3
H3
3
than
than
than
than
than
than
CH
CH3ROH CH
CH3
HCH3
CH
3 CH
3
he electrons in the
bond while the other
H
H
+ H 3Br
R 3
O
H 3
Br
HH–Br
431
2C=CH–H
tertiary
secondary
primary
methyl
–Hbromine atom.
431
the
=CH–H
431
tertiary tertiary
secondarysecondary
primary
methyl
primary
methyl
Ph–H
464
397+ CH
Br3
Me C–H
H 397
Br 3397
R O
C–H
ROH
!
ical reactions always involve the
464
H
on of electron pairs, we464
can choose whether to
each pair. In most examples in this book, we will draw
arrows only in one direction.
!
bonds next
to conjugating
groups
suchare
asMost
allyl
or radicals
benzyl
are particularly
so allyl
and
extremely
reactive
...
C–H bonds
next toC–H
conjugating
groups
such
as allyl
or as
benzyl
particularly
weak,
soare
allylweak,
and weak,
C–H bonds
next
to
conjugating
groups
such
allyl
or
benzyl
are
particularly
so
allyl
and
benzyl radicals areC–H
more
stable.
C–H
bonds tooralkynyl,
alkenyl,
or aryl groups are strong.
célibataire
is the
French
benzyl
bonds
toBut
alkynyl,
aryl groups
are strong.
372 radicals are more stable. ButElectron
electrons
are desperate
to be paired up again. This means th
benzyl radicals are more stable.
But
C–H
bonds
toalkenyl,
alkynyl,Unpaired
alkenyl,
or aryl
groups
are strong.
H both
C=CH
2CH
2–H of364
appens
to either364
or 2
of the
members
2CH2–H
=CH
CH –H
364
2
2 PhCH –H
2
Hty of radicals372
term forwhich
these bachelor electrons
to propagate
by abstraction is a key feature of radical chain reactions,
H2–H
372
RCO–H
364
short lifetime; they don’t survive long before undergoing a chemical re
searching
earnestly for a partner.
me to later. There
as a way
364 is an important difference between homolysis and abstraction
–H
364
Chemists are more interested in radicals that are reactive, because
EtOCHMe–H
radicals:
homolysis
is a reaction of385
a spin-paired molecule that produces two radicals;
e–H
385
is a reaction ofNa radical
with a spin-paired
molecule that produces one new radical and a
interesting and useful things. However, before we look at their reaction
CHMe–H
385
CCH2–H
360
!
allyl
benzyl
vinyl
alkynyl
phenyl
Haired
360
2–H molecule.
Radical abstractions allyl
like this are therefore
examples
of
your
first
radical
benzyl
vinyl
alkynyl icals that are
phenyl
unreactive
so
that
we can analyse the factors that contribu
CCH
–H
360
MeCOCH
385 reactions
2
2–H
they
are
in
fact
substitution
at
H
and
can
be
compared
with
proton
allyl
benzyl
vinyl
alkynyl
phenyl
more
stable
than
alkyl
radicals
less
stable
than
alkyl
radicals
Hchanism:
–H
385
Adjacent
functional
groups
appear
to
weaken
C–H
bonds:
radicals
next to carbonyl, nitrile, or
2
more stable than alkyl radicals
less stable than alkyl radicals
even
an
S
2
reaction.
OCHwith
–H
385
N
2
. . . but
fewradicals
radicals
unreactive
more stable
than
alkyl radicalsgroups, or centred onless
stable
thana
alkyl
ether
functional
a carbonyl
carbon
atom,are
arevery
more
stable than even tertiary
Radical stability
H
ROH
Br
+
Br
hydrogen abstraction
Whilst simple alkyl radicals are extremely short-lived, some other ra
nitely. Such radicals are known as persistent radicals. We mentioned t
+
proton removal
ROH
Br
H Br
O
p. 000: this yellow substance
exists in solution in equilibrium with
O
triphenylmethyl radical –
enough to account for 2–10% of the equilibrium mixture.
stable in solution
ROCH3 + Br
SN2 reaction
CH3 Br
in equilibrium with its dimer
OEt
Persistent
radicals with the single electron carried by an oxygen
N
known: these three radicals can all be handled as stable compounds. Th
ubstitutions differ considerably from SN1 or SN2 reactions: importantly, radical substituradicals stabilized by functional groups
never occur at carbon atoms. We shall come back to radical substitutions, or abstractions
commercial product and can even be sublimed.
alkyl radicals.
on whether you take the point of view of the H atom or the Br atom), later in the chapter.
Whether the functional group is electron-withdrawing or electron-donating Ois clearly irrelevant
here: both types seem to stabilize radicals. We can explain all of this if we look at how the different
groups next to the radical centre interact electronically with the radical.
ical detected
radical to
the
hyl radical,
1900 by
of Cl• from
metal.
s relatively
hall see why
reacts with
Ag
Cl
N
+ AgCl
Radicals are stabilized
by conjugating, electron-withdrawing,
and electronO
donating groups
O
TEMPO
relatively
stable triphenylmethyl
radical
Let’s
consider
first what
happens when a radical
centre
finds
itself next to an
electron-withdrawing
TEtraMethylPiperidine
N-Oxide
dark blue solid
m.p. 36–38°C
97°C
group. Groups like C=O and C$N are electron-withdrawing because they havem.p.
a low-lying
empty %*
orbital. By overlapping with the (usually p) orbital
containing
the some
radical
(theareSOMO),
two than
newot
There are
two reasons why
radicals
more persistent
O
R
yl radical anion
C=O $*
Titanium promotes
the pinacol
coupling
and then
convenient.
You met
an example
O
O promotes the pinacol
O
Titanium
coupling
and reduction
then
e–
EtOH
of the Bouveault–Blanc
deoxygenates
the products:
the
McMurry
reaction
Radicali
deoxygenates
the products:
the McMurry reaction
R
in Chapter 33 (conformational
O
OH
H
R
Rthe
R reaction and, provided
RTitanium
R can be used as the
R metalRsource of electrons in Rthe pinacol
R
R
Titanium can be used as the metal source
of electrons in the pinacol reaction
and, provided the
H from
H
analysis–reduction
reaction is kept cold and not left
for too long, diols can of
be isolated
the reaction (see theHexample
reaction is kept cold and not left for too long, diols can be isolated from the reaction (see the example
at the end aprotic
of the previous
section).
However,
unlike
aluminium, titanium
reacts
cyclohexanones).
solvents,
suchunlike
as benzene
ormagnesium
no orprotons
at the end of theInprevious
section).
However,
magnesium
orether,
aluminium,
titanium are
reactsavailable so the concentration of
further
with
these
diol to
products
tooverall:
give
inknown
a reaction
as the
McMurry
reaction, after
further with
these
diol
products
giveup
alkenes
in aalkenes
reactionand
theknown
McMurry
reaction,
after
ketyl
radical
builds
significantly
theasketyl
radical
anions
start
to dimerize. As well as being a
1. Na,
OH
its inventor.
O
its inventor.
radical–radical process, this dimerization
EtOH process is an anion–anion reaction, so why doesn’t electrothem from
approaching one another? The key to success
Ostatic repulsion between the anions prevent R
O
R
R
R 2. H+
H
is to use a metal such as magnesium or aluminium
that
HO forms strong, covalent metal–oxygen bonds
HO
TiCl3, LiAlH
TiCl
4 3, LiAlH4
+
+
and that can coordinate
to more
one
ketyl
at once. Once two ketyls are coordinated to the same
Notice
that than
this
is
a reaction
OH
OH
LiAlH4 produces
LiAlH4 produces
metal
atom,
they react
rapidly.
using
sodium metal in ethanol,
C=O $
Ti(0)
from the
Ti(III)
Ti(0)
from the Ti(III)
86%
observed
only ifobserved
the reaction
andyield
sodium
ethoxide,
which
86%
yield
pinacol dimerization of acetone (ketyl radical reaction
innot
hydrocarbon
solvent)
diol product known as "pinacol"
onlyisifis
the reaction is
carried out at low temperature
carried out at low temperature
the basic Mg
product that forms once Mg
Notice that the titanium(0),
which
is
the
source
of
electrons in the reaction, is O
producedOduring
OH
O
O the titanium(0),
which
ishas
the dissolved
source
of electrons
in the reaction,
is produced
during HO
Mg2+ sodium
Mg Notice that
in
ethanol.
O
O
H
reaction
by reacting a Ti(III) salt, usually TiCl3, with a reducing agent such as LiAlH4 or Zn/Cu.
hat they are in.the
In
protic
the
reactionsolvents
by reacting a Ti(III)
usually TiCl
reducing agent
as LiAlH or Zn/Cu.
3, with
It issalt,
important
that
theaMcMurry
sodium
is such
The reaction does not work with, say, powdered
titanium metal.
The
reaction
is believed 4
The reaction
does
not work
with,
say, powdered
titanium
metal.
The McMurry
is believed
accepts a second
from
the
to benzene
beelectron
a two-stage
process
involving
firstly
a pinacol
radical–radical
coupling.
Evidence
for this isreaction
that
dissolving
as the reaction
takes
to be a two-stage process involving
firstly
pinacolunder
radical–radical
coupling.
Evidence
the 80
pinacol
from
theareaction
certain conditions
(you’ve
just for this is that 43–50% yield
°C products (diols) can be isolated
place,
since
only
then
are
the
free
results, which, on
ofproducts
acid
(diols)
can be
seenaddition
howthe
thispinacol
was done
duringat
the
synthesis
of isolated
Taxol). from the reaction under certain conditions (you’ve just
electrons
available.
The
example
shows
dimerization
seen
how
this
was done during
thethe
synthesis
of Taxol). of acetone to give a diol (2,3-dimethylbutane-2,3-diol)
first step of
the McMurry
reaction
Ti
of thetrivial
McMurryname,
reaction
O first step
Ti this type of reaction using any ketone. Sometimes
O
whose
pinacol,
O
Tiis used as a name for
O
O
O Ti(0)
Ti
O new chiral
O
pinacol
reactions
create
centres:
in
this
example,
ould be better off using one of the
O the two diastereoisomeric diols are
O
Ti(0)
ds described in Chapter 34 on
formed in a 60:40 mixture. If you want to make a single diastereoisomer of a diol, a pinacol reaction
reoselectivity.
is not a good choice!
McMurryofreaction
of cyclohexanone
McMurry reaction
cyclohexanone
The Ti(0) then proceeds to deoxygenate the diol by a mechanism not fully understood, but
thought to involve bindingOof the diol to the surface of the Ti(0) particles produced in the reduction
The Ti(0) then proceeds to deoxygenate the diol by a mechanism not fully understood, but
of TiCl3.
HO
HO
Al, Hg
thought to involve binding of the diol to the surface of the Ti(0) particles produced in the reduction
titanium metal
titanium metal
+
second step
the .
of ofTiCl
3
McMurry reaction:
deoxygenation on the
step of the
surface ofsecond
a Ti(0) particle
O
McMurry reaction:
deoxygenation on the
surface of a Ti(0) particle
O
benzene
50 °C
titanium metal
45% yield
O
O
O
OH titanium metal
O
anti-diastereoisomer O
60% of mixture
O
OH
syn-diastereoisomer
40% of mixture
styrene
radical initiators like AIBN or peroxides radicals.
(Chapter 39), polystyrene
high pressures and temperatures are still
O
O
needed. At 75 °C andRadicali
1700
atmospheres
polymerization,
initiated
bywere
dibenzoyl
Polythene
is-polimerizzazione
difficult topressure
make andethylene
was discovered
only when chemists
at ICI
attempting
reactreaction.
ethylene with
compounds
pressure.
Eventowith
correct
O under
Phhigh
O reagents,
Ph
peroxide, is a radical to
chain
The other
peroxide
is first
cleaved
homolytically
givethetwo
benzoate
heat
+
Phor peroxides
O
Ph and O
radical
initiators
like
AIBN
(Chapter
39),
high
pressures
temperatures
are
still
radicals.
52 . Polymerization
460
needed. At 75 °C and 1700 atmospheres pressure
ethylene polymerization, initiated by dibenzoyl
O
O
O
peroxide, is a radical chain reaction. The peroxide is first cleaved homolytically to give two benzoate
TheseOoxyradicals
add to the alkene to give an unstable primary carbon r
Phradicals.heat
Ph
can lead
to branched
polymers
hydrogen
atom
another
of alkene, and so
on.
Ph
O + molecule
O
Oby intramolecular
O
O
RadicalPhpolymerization
O
transfer, a process sometimes
called backbiting.
Removal
of O
H through
a Ph
six-membered
transO
Ph
O
O
heat O
O
Ph
O
Ph
O +
ition state moves the growing radical atom five atoms back down the chain, and leads to butyl
These oxyradicals add to the Oalkene to give an unstable primary
carbon radical that adds to
O then
side-chains. A more stable secondary radical
is produced
and
Ph
O chain growth
PhoccursOfrom that
another molecule of alkene,
and
so on. add to the alkene to give an unstable primary carbon radical that adds to
These
oxyradicals
point.
another moleculeOof alkene, and so
O on.
O
5
ROO
RO
Ph 1
5
O
Ph
O
Ph
O
O H-abstraction
O
H
Ph
Ph
RO
O
Ph
O
O
Me
Eventually, the chain is terminated by combination
with another radical (unl
O
O
O
gen abstraction from another polymer molecule. This approach to polythene syn
ene liquefied Ph
by pressure
and small amounts (<0.005% by weight) of peroxide,
Ph
O
O
change conformation
Ph
O
Ph
O
polymerization
RO
Me
RO
n
low molecular weight polymer as a white solid.
Eventually, the chain is terminated by combination with another radical (unlikely) or by hydroEventually, the chain
is
terminated
by
combination
with another radical (unlikely) or
hydroO
O by using
gen abstraction from another polymer
molecule. This approach to polythene synthesis,
ethylchain now gen
growsabstraction from another polymer molecule. This approach to polythene synthesis, using ethylene liquefied by pressure and small amounts (<0.005% by weight) of peroxide, produces relatively
from new radical
low molecular
weight
polymer
as a white
ene liquefied by pressure
and small
amounts
by weight) of Hperoxide,
produces
relatively
Ph (<0.005%
O solid.
X
Ph
O
Me
n
n
Radicallow
polymerization
of vinyl
styrene
Ochloride
O than that of ethylene because
molecular weight
polymer
as aand
white
solid.is much easier
the intermediate
stable. You saw in Chapter
39 that any substituent stabilizes a radO radicals are more
O
Ph
O
H X
Ph
O
Me
ical, but Cl and Ph are particularly good because
of conjugation of
the unpaired
n
nelectron with a lone
Polietilene
pair on chlorine
orOthe π bonds in the benzene
Ph
H X ring.Ph
O
Me
O
n
benzylic radical stabilized
by conjugation
Ph
Ph
X
X
Cl
Cl
Cl
Cl
atactic PVC— poly(vinyl chloride)
Cl
Cl
Cl
Cl
n
benzylic radical stabilized
by conjugation
Ph
Ph
X
Ph
polymerization
Ph
Ph
Ph
X
n
Neither PVC nor polystyrene is very crystalline and polystyrene often has poor mechanical
Polistirene
strength. Both of these may be results of the stereorandom nature of the polymerization process. The
substituents (Cl or Ph) are randomly to one side or other of the polymer chain and so the polymer is
a mixture of many diastereoisomers as well as having a range of chain lengths. Such polymers are
called atactic. In some polymerizations, it is possible to control stereochemistry, giving (instead of
atactic polymers) isotactic (where all substituents are on the same side of the zig-zag chain) or syn-
isotactic PVCX
n
polymer
formed
by the radical
polymerization
ofa tetrafluoroethylene
ical, but Cl and A
Phunique
are particularly
goodis
because
of conjugation
of the unpaired
electron with
lone
and is called
or Ph)
are
randomly
toπ one
side
or is
other
of the polymer
chain and often
so thehas
polymer
is
Cl substituents
Cl
Cl (ClCl
Neither
PVC
nor
polystyrene
veryring.
and consists
polystyrene
poor mechanical
on chlorine
or the
bonds
inThe
the benzene
PTFE
or
Teflon.
outside
ofcrystalline
the polymer
of a layer of
fluorine
atoms which repel all other
Cl
Cl
Cl pairCl
poly(vinyl chloride)
Radicali
-polimerizzazione
a mixture of many diastereoisomers
as well
as
having
athe
range
of
chain
lengths.
Such
polymers process.
are The
benzylic
radical
stabilized
benzylic
stabilized
strength. Both
ofradical
these
be
results
stereorandom
nature
of the
polymerization
molecules.
Itmay
is used
as theofcoating
by conjugation
by conjugation
F
or Ph)
one
side orstereochemistry,
other of the polymergiving
chain and
soF theFpolymer
called atactic. In somesubstituents
polymerizations,
itareisrandomly
possible
control
(instead
of F F isF F
Cl
Cl
Cl
Ph
Ph pans Ph
in (Cl
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n
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actic PVC
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aradical
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otactic PVC
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A unique
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made
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acrylate
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acrylate
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e
ate
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as acrylatesIndeed,
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easilyto store
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methyl
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compounds
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often difficult
to store
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thatvery
we easily
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several
times already,
acrylic acid
methyl acrylate
(even oxygen)
arewith
present.
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polymerization
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because
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car- and each rad
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Alkenes
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such
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(derivatives
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(even
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or
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has
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stabilization
from
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bon
radical
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bymechanisms.
conjugation
with the
carbonyl
polymerized
a variety
of
Indeed,
these
compounds
are often
difficult to store
methyl acrylate
(even
Radical
polymerization
occurs
very
easily
because
the
intermediate
carOH oxygen) are
OMe
N present.
because they polymerize spontaneously when
traces of weak nucleophiles (even water) or radicals
O
O
O
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acrylicbon
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methyl
acrylate
is stabilized
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conjugation
with
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carbonyl Ogroup.
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stablevery
delocalized
radical the intermediate car-
O
O
N
methyl methacrylate
OMe
acrylonitrile
methyl methacrylate
X
acrylonitrile
O N
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bon radical is stabilized
OMe O
X
OMe
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stable delocalized radical X
acrylonitrile
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stable delocalized radical
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OMe
X
X
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Me CO2Me CO2Me CO2Me
CO
2OMe
OMe
With two stabilizing groups on the carbon radical, polymerization becomes even easier. A famo
example is ‘SuperGlue’, which is methyl 2-cyanoacrylate. The monomer in the tube polymerizes
to any surface (wood, metal, plastic, fingers, eyelids, lips, ...) catalysed by traces of moisture or
and the bonds, once formed, are very difficult to break. The intermediate radical in this polymeri