Post on 20-Jun-2015
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E
FUNCTIONAL GROUPINTERCONVERSIONS
CHAPTER 10
123.3
12
1
functional group interconversions
CHAPTER tenc–c bond formation: other nucleophiles
2
enolates as nucleophiles
OLi
R X
O
RLi X
previously, we had looked the reaction of enolates &
their equivalents...
3
other nucleophiles
that are not enolates...
4
can we deprotonate them like this?
R C C H H2N Na
what about...?
?alkynes are useful
nucleophiles due to wealth of functional group interconversions
they can undergo
5
look at pKa...
>pKa = 35 pKa = 26
R C C HH2N Na
the pKa would suggest that we can
6
R C C H H2N Na R C C
PhBr
R C C
Ph
once formed, alkynyl anion undergoes standard nucleophilic
reactions
other nucleophiles: alkynes
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Text
why can we readily deprotonate alkynes but not alkenes (or
alkanes)?
©marco belluci@flickr
think about molecular orbitals
8
other nucleophiles: nitriles
Na CN Ph Br Ph CN
nitriles are good nucleophiles the simplest is cyanide, a
long cylinder of charge
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cyanide has an obvious problem
©mouse@flickr
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other nucleophiles: nitriles
Ph
C
N
H
H
:base
Ph
C
N
H
Br
Ph
CNnitriles are Electron
withdrawing & allow resonance stabilisation so are easily
deprotonated
11
the use of nitriles...
R CNOH
RC
OH
O
R CN
Ni / H2
R NH2nitriles are useful as they readily undergo functional
group interconversion12
Now, attack on...
O
Cthis is the
important one
13
mechanism 1: carbonyl without leaving group
R1 R2
O
Cnuc
R1 R2
O Cnuc
R1 R2
HO Cnuc
there are two outcomes to attack on the carbonyl group
if the substrate has no leaving group get simple
addition
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mechanism 2: carbonyl with leaving group
R1 LG
O
Cnuc
R1 LG
O Cnuc
R1 Cnuc
O
R1 Cnuc
O CnucCnuc
R1 Cnuc
HO Cnuc
if there is a leaving group then carbonyl is reformed & double
addition is observed
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Addition of Grignard reagents
R1 R2
ORc MgBr
R1 R2
HO Rc
R1 R2
O Rc
BrMgH
addition to aldehyde/ketonefirst forms an alkoxide, which is
then protonated on work-up
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Addition of Grignard reagents
R1 OR2
ORc MgBr
R1 Rc
HO Rc
addition to an ester always results in double addition
reason: the ketone intermediate is more reactive than the starting material
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organolithium reagents
R1 R2
O
Rc Li
R1 R2
HO Rc
R1 OR2
O
Rc Li
R1 Rc
HO Rc
similar to Grignard reagents except more nucleophilic (& BAsic) this can cause
problems (see later)18
increased reactivity allows...
R1
O
OH
R1
O
O Li R1
O
O
Me
Li
Li
R1
OH
OH
MeR1 Me
O
Me Li Me Li
H2Odeprotonation gives
the normally non-electrophilic carboxylate anion
but reactivity of organolithiums allows a second attack and a route
to ketones19
examples
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©bmooneyatwork@flickr
Cl
ClOH
N
Nfenarimolantifungal
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organometallic reagent in total synthesis
Cl
ClOH
N
N
Cl
ClO
N N
Li
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N
OMe
N
OH
quinine23
deprotonate methyl group;I can’t find pKa but anywhere
from 40 to 25
C–C bond formation important...
N
OMe
N3
OTBDPS
O
LiNiPr2
N
OMe
N3HO
OTBDPS
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C–C bond formation important...
N
OMe
N3
OTBDPS
O
LiNiPr2
N
OMe
N3HO
OTBDPS
reactive species is:
N
OMe
Li
N
OMe
25
bigproblem
especially with organolithiums
26
big problem©furryscaly@flickr
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MeO
OMe
O
Li
MeO
OMe
OH
Nucleophilicity versus basicity
this is what we want...
x
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Nucleophilicity versus basicity
MeO
OMe
O
H H
Li
MeO
OMe
O
H
this is what we get...organolithium reagents are
basic & often cause deprotonation not addition
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organocerium is less basic so will perform the desired
addition
transmetallation can give a less basic derivative
Li
Cl2Ce
CeCl3
MeO
OMe
O
MeO
OMe
OH
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formation of alkenes
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the wittig reaction (or at least one of them)
R1
O PPh3
R2R1
R2
this is the basic transformation, reaction of an
aldehyde/ketone with a phosphorus ylid
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formation of ylide
Ph3P: R2 Br
R2
PPh3
Br
H
base
PPh3
R2
PPh3
R2
a ylid (or ylide) is a compound with positive &
negative charges on adjacent atoms
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formation of ylide
Ph3P: R2 Br
R2
PPh3
Br
H
base
PPh3
R2
PPh3
R2
the phosphorane or ylide (resonance forms of each other) is made prior to addition of the
electrophile
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two possible mechanisms...
OPPh3 O
PPh3
PPh3O
betaine
oxaphosphetane
this is the easier of themechanisms to understand & is good for explaining the stereochemical
outcomeit is almost
certainly wrong
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second mechanism
O PPh3
PPh3
O
Ph3P
O
H H
R
R
better mechanism but some of the stereochemical arguments are less
convincing
proceeds by a[2+2] cycloaddition
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R1
O PPh3
R2
R1 R2
Wittig normally gives Z-alkenes
if R2 is not involved inreaction (non-stabilised ylid) then
the cis alkene is favoured
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Reason: Sterics of addition
Ph3P
O
R2 H
H
R1
O PPh3
R2R1
R1
O PPh3
R2
R1 R2
the substituents tryto stay as far apart as possible during cycloaddition (or nucleophilic addition
depending on the mechanism)
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Reason: Sterics of addition
Ph3P
O
R2 H
H
R1
O PPh3
R2R1
R1
O PPh3
R2
R1 R2
this means that substituentsare same side once oxaphosphetane has
formed. this step is irreversible so must proceed to cis-alkene even though it is
less stable
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example
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Text
©cotinis@flickr
O
O
OAc
OAc
OAc
OAc
anamarine
natural product isolate from bushmint
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OEtOH
PPh3
O
O
O
OOHC
H
OEtO
O
O
O
O
HH
Wittig normally gives Z-alkenes
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R2
O
PPh3
R2
O
PPh3
Stabilised ylides
if the substituent on the ylid canstabilise anion (EWG or resonance stabilisation) then we are said to have a stabilised ylid and
the trans-alkene predominates
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R1
OPPh3
O
R2 R1
R2
Stabilised ylide normally givesE-alkenes
the mechanism hopefully explains why stabilised ylides favour the more stable
trans-alkene44
Reason: reversibility of addition
O PPh3
CO2EtR1
R1
O PPh3
CO2Et
O PPh3
CO2EtR1
R1 CO2Et
R1
CO2Et
slow
fast
the first step, cycloaddition(or nucleophilic attack) is reversible. The equilibrium
favours the more stable adduct in which the substituents are as far apart as possible
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Stabilised ylide normally givesE-alkenes
EtO
O
PPh3
OHC
O
O
O
O
EtO2C
this is from a different synthesis of anamarine
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