Told you that this was the important one. This weeks reagents include more enolates and then reactions with the C=O group including the such classics as the Wittig reaction.

1. FUNCTIONALGROUP
123.312
enolates as nucleophiles
previously, we had looked
INTERCONVERSIONS
the reaction of enolates &
functional group their equivalents...
CHAPTER 10
interconversions
Li O
O
R X Li X
R
CHAPTER ten
c–c bond formation:
other nucleophiles
E 1 2 3
what about...? look at pKa...
other
nucleophiles
R C C H H2N Na
? H2N
pKa = 35
Na
>
R C C H
pKa = 26
alkynes are useful
nucleophiles due to wealth of
that are not functional group interconversions
enolates... they can undergo can we deprotonate the pKa would
them like this? suggest that we can
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©marco belluci@flickr
other nucleophiles: alkynes other nucleophiles: nitriles
Text
R C C H H2N Na R C C
Br Ph Na CN Ph Br Ph CN
R C C
Ph
nitriles are good
once formed alkynyl anion
, why can we readily deprotonate nucleophiles
undergoes standard nucleophilic the simplest is cyanide, a
alkynes but not alkenes (or long cylinder of charge
reactions
?
alkanes) think about molecular orbitals
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2. other nucleophiles: nitriles the use of nitriles...
N N O
C :base
C OH
R CN C
H
Ph
H Ph H R OH
cyanide has an
obvious problem Br Ni / H2
nitriles are Electron
withdrawing & allow resonance CN
R CN R NH2
stabilisation so are easily nitriles are useful as they
deprotonated readily undergo functional
Ph group interconversion
©mouse@flickr
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mechanism 1: carbonyl without mechanism 2: carbonyl with
leaving group leaving group
Now, attack
on... O O Cnuc O O Cnuc
Cnuc Cnuc
R1 R2 R1 LG R1 LG
O R1 R2
there are two
outcomes to attack on
if there is a leaving group then
carbonyl is reformed & double
addition is observed
the carbonyl group O
HO Cnuc O Cnuc Cnuc
this is the if the substrate has no
C important one leaving group get simple
addition
HO Cnuc
R1 R2
R1 Cnuc R1 Cnuc R1 Cnuc
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Addition of Grignard reagents Addition of Grignard reagents organolithium reagents
O HO Rc O HO Rc
Rc MgBr Rc Li
R1 R2 R1 R2 O HO Rc R1 R2 R1 R2
Rc MgBr
R1 OR2 R1 Rc O HO Rc
O Rc
BrMg
H Rc Li
R1 R2
addition to an ester always R1 OR2 R1 Rc
results in double addition
addition to aldehyde/ketone reason: the ketone similar to Grignard
first forms an alkoxide, which is intermediate is more reactive reagents except more
than the starting material nucleophilic (& BAsic) this can cause
then protonated on work-up problems (see later)
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3. increased reactivity allows...
O Me Li O Me Li O Li
H O Li
R1 O R1 O Li R1
Me
deprotonation gives
the normally non-electrophilic H2O examples Cl
carboxylate anion
O OH
R1 OH OH Cl
R1 Me Me N
but reactivity of organolithiums
N
allows a second attack and a route fenarimol
to ketones antifungal ©bmooneyatwork@flickr
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organometallic reagent in total C–C bond formation important...
synthesis
deprotonate methyl group;
OMe I can’t find pKa but anywhere
from 40 to 25
Li
Cl OMe
Cl
LiNiPr2 HO N3
N N N
OH Cl OTBDPS OTBDPS
OMe
O Cl N
N N N
N3
OH
O
N
quinine
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C–C bond formation important...
big
OMe
OMe
N
LiNiPr2 HO N3 problem
OTBDPS OTBDPS
N reactive species is:
OMe OMe
N3
Li
O especially with
N N organolithiums
©furryscaly@flickr
big problem
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4. Nucleophilicity versus basicity Nucleophilicity versus basicity transmetallation
Li can give a less
basic derivative
CeCl3
organocerium is less basic so
Li Li will perform the desired
MeO MeO MeO H H MeO H addition
OH Cl2Ce
O O O
x
MeO MeO
OH
O
OMe OMe OMe OMe
this is what we get...
this is what we want... organolithium reagents are OMe OMe
basic & often cause deprotonation
not addition
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the wittig reaction (or at least one of them) formation of ylide
PPh3
Ph3P: R2 Br Br
O PPh3 R2 H
formation of R2 a ylid (or ylide) is a
compound with positive &
alkenes R1 negative charges on adjacent
base
R1 R2 atoms
PPh3 PPh3
this is the basic
transformation, reaction of an
aldehyde/ketone with a R2 R2
phosphorus ylid
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formation of ylide two possible mechanisms... second mechanism
PPh3 O PPh3 Ph3P R
O
PPh3 O
PPh3 O
Ph3P: R2 Br Br R
this is the easier of the
R2 H mechanisms to understand & is good H H
for explaining the stereochemical betaine
the phosphorane or ylide better mechanism but some of the
(resonance forms of each other) base outcome stereochemical arguments are less
is made prior to addition of the it is almost convincing
electrophile certainly wrong
PPh3 proceeds by a PPh3
PPh3 PPh3 [2+2] cycloaddition
O O
R2 R2
oxaphosphetane
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5. Wittig normally gives Z-alkenes Reason: Sterics Reason: Sterics of addition
of addition
O PPh3
O PPh3 R1 R2
R1 R2 this means that substituents
areR1 side once R2
same oxaphosphetane has
R1 R2 formed. this step is irreversible so must
O PPh3 proceed to cis-alkene even though it is
R1 R2 the substituents try
to stay as far apart as possible during less stable
cycloaddition (or nucleophilic addition
R1 R2 Ph3P
depending on the mechanism) Ph3P H
H O PPh3
O PPh3 O
O
if R2 is not involved in R1 R1 R2
R1 R1 R2
reaction (non-stabilised ylid) then R2 H
the cis alkene is favoured R2 H
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Wittig normally gives Z-alkenes
Text product
natural
isolate from bushmint
O
O
PPh3 O
EtO O OHC
H H O
example
OAc OAc O
O
O
O OAc OAc EtO O H
H O
©cotinis@flickr O anamarine
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Stabilised ylides Stabilised ylide normally gives Reason: reversibility of addition
E-alkenes
O PPh3
slow
R1 CO2Et
R1 CO2Et
O PPh3 O PPh3
O O
PPh3 R2 R1 R1 CO2Et
R2 PPh3 R2
R2 R1 O PPh3
fast
R1
O CO2Et
R1 CO2Et
if the substituent on the ylid can
stabilise anion (EWG or resonance stabilisation) the first step cycloaddition
,
then we are said to have a stabilised ylid and the mechanism hopefully explains why (or nucleophilic attack) is reversible. The equilibrium
the trans-alkene predominates stabilised ylides favour the more stable favours the more stable adduct in which the substituents
trans-alkene are as far apart as possible
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6. Stabilised ylide normally gives
E-alkenes
O
PPh3
EtO EtO2C
O
OHC O
O
O
this is from a different
synthesis of anamarine
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