E FUNCTIONAL GROUP INTERCONVERSIONS CHAPTER9 123.312 1 functional group interconversions CHAPTER nine c–c bond formation: enolates 2 previously we looked at the substrate & which leaving groups were good in substitution reactions R LG Nuc R Nuc looked at substrate (R-LG)... now look at c-based nucleophiles 3 we’ll concentrate on... ©alfred sim@flickr 4 enolates O 5 O H :base O O formation pK a = 19 easily prepared by deprotonation of the !- hydrogen 6 enolates O O two resonance forms. The anion residing on the oxygen contributes the most to the resonance hybrid (or is the more ‘realistic’ if you like) 7 stable as electrons spread out... O 8 it is easier to deprotonate a 1,3- diketone O O H H O H O :base pK a = 9 p pKa of acetone is 19 so this is much easier (remember it is a log scale) 9
Lecture6: 123.312
May 11, 2015
Lecture 6: C-C bond formation
The big one; the all important formation of C-C bonds. Reagents include organometallics and enolates. There will also be a slight detour into the wonderful world of pKa.
The big one; the all important formation of C-C bonds. Reagents include organometallics and enolates. There will also be a slight detour into the wonderful world of pKa.
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E
FUNCTIONAL GROUPINTERCONVERSIONS
CHAPTER 9
123.3
12
1
functional group interconversions
CHAPTER ninec–c bond formation:
enolates
2
previously we looked atthe substrate & which leaving
groups were good in substitution reactions
R LGNuc
R Nuc
looked at substrate (R-LG)...
now look at c-based nucleophiles3
we’ll concentrate on...
©alfred sim@flickr
4
enolates
O
5
O
H:base
O
O
formation
pKa = 19easily prepared by
deprotonation of the !-hydrogen
6
enolates
OO
two resonance forms. The anion residing on the oxygen contributes the most to the resonance hybrid (or is the more
‘realistic’ if you like)7
stable as electrons spread out...
O
8
it is easier to deprotonate a 1,3-diketone
O O
H H
O
H
O
:base
pKa = 9
p pKa of acetone is 19 so this is much easier (remember it is a log scale)
9
resonance stablisation (delocalisation)
O
H
O O
H
OO
H
O
O
H
O
more resonance forms more stable
spread charge over more atoms more
stable
10
©horia varlan@flickr
another question
11
the normal representation...
O
oxygen is more electronegative so
charge more associated with o
12
...but the majority of neutral electrphiles react at carbon...
O
Elec
13
©e-magic@flickr
14
MO theory can give us the answer
15
overall, there is more charge / electron density on oxygen but...
O
16
O
carbon has bigger coefficient in homo
oxygen has greater charge overall, but in the highest occupied molecular orbital
(HOMO) the carbon has greatest charge so electrophiles with
little charge & low lying LUMO react at
carbon
17
carbon has bigger coefficient in homo
soft nucleophile
hard nucleophile (big charge
small volume)
Oneutral/weakly
charged electrophileshighly charged electrophiles
18
carbon has bigger coefficient in homo
soft nucleophile
hard nucleophile (big charge
small volume)
Oin other words it is pearson’s Hard soft acid base at work...
19
if you want a good introduction to molecular orbital theory (for organic chemists not theoreticians then ian Fleming’s book is a must
20
SOft electrophiles...
O
H3C I
O
CH3
soft electrophile reacts with soft nucleophile (the
carbon) iodomethane is considered soft as iodine is big &
diffuse 21
hard electrophiles...
O
H3C OMsOMe
hard electrophile reacts with hard nucleophile (the
oxygen) hard as charge/electrons concentrated in a small
volume22
stable as electrons spread out...
Olets get back to deprotonations & forming enolates
23
stability of other enolates...
Ph
O O
pKa = 12.7
Ph
O
OEt
O
H H:base
Ph
O
OEt
O
H
Ph
O
OEt
O
H
pKa = 13
slightly less acidicas ester can donate electrons from oxygen lone pair but very
little difference
24
Ph
O
C
H H:base
Ph
O
C
H
Ph
O
C
H
pKa = 10.2
N N
N
stability of other enolates...
Ph
O O
pKa = 12.7
nitrile strong electron withdrawing group (EWG) so
proton more acidic
25
Ph
O
NO
O
H H:base
Ph
O
NO
O
H
Ph
O
NO
O
H
pKa = 7.7
stability of other enolates...
Ph
O O
pKa = 12.7
nitro group is strong EWG. Both an inductive &
resonance effect
26
good indicator of ease of deprotonation
pKaIt is a good guide but not perfect...
27
enolate formation
O
H
base
O
H base
the general formula is easy, but...
28
which base do we use?
©marcarena c.@flickr
29
base must have conjugate acid with pKa higher than carbonyl
H base >
pKa pKaO
Hin english...the base must be more basic!
30
base must have conjugate acid with pKa higher than carbonyl
H base >
pKa pKaO
Hthe base must want to hold on to the proton more than the acid does
31
is ethoxide sufficiently strong?
O
OEt
O
H H
OEt ?
32
look at pKa...
H OEt >
O
OEt
O
H HpKa = 15-16 pKa = 11
conjugate acid of ethoxide (ethanol) has a higher pKa than
carbonyl so it will take the proton
33
it is a good choice...
O
OEt
O
H H
O
H
OEt
O
H OEtOEt
34
can we use methoxide (Meo-)?
start to try & think about the chemistry & not just learn facts
35
what about...?
O
H
OEt ?
36
look at pKa...
H OEt >pKa = 15-16 pKa = 26.5
O
H
KETONE (CONJUGATE ACID OFENOLATE) IS MORE BASIC (HIGHER pKa than
ethoxide/ethanol) so we do not get deprotonation
37
O
H
OEtO
H OEt
no enolate formation...
x
38
what about...?
?O
H
BuLi
39
H Bu>
pKa = 48-51 pKa = 26.5
O
H
Li Bu
Li Bu
look at pKa...
base has high enough pKa so can cause deprotonation...
40
theoretically possible...
O
H
BuLi
OLi
H BuO
H
BuLi
41
Text
problem!©caramdir@flickr
42
competing addition
O
H
BuLi
OLi
OLi Bu
H
43
start to try & think about the chemistry & not just learn facts
44
?the solution
45
N
H
Li Bu
pKa = 48-51(conjugate
acid)
pKa = 36
lithium diisopropylamide
we can react butyllithium and an amine (just look at the pKa)
46
lithium diisopropylamide
N
H
Li Bu N
Li
H Bu
this forms a new sterically demanding
(bulky) base
47
non-nucleophilic means it rarely
attacks a functional group
lithium diisopropylamide LDA
N
Li
N
Li
non-nucleophilic48
O
H
NiPr2
Li
what about...?
?
49
look at pKa...
therefore...
>pKa = 36 pKa = 26.5
O
H
N
Li
much higher pKa so readily deprotonates
ketone50
deprotonation and no nucleophilic attack
O
H
NiPr2
LiO
Li
N
H
size of lda means it does not attack carbonyl
51
a second solution
52
Silyl enol ethers
OSiR3
this is an enolate equivalent or a compound that reacts like an enolate
53
they rely on thestrength of the si-O bond to activate the carbonyl
allow the use of weak bases
O
HR3Si Cl
O
H
SiR3
Et3N:
OSiR3
these allow the use of a weak base to form the
enolate equivalent
54
reactions
©-andor-@flickr
55
Cnuc C LG C C LGsubstitution
Cnuc CC
CCC
alkene
addition
will approach by mechanism...
©Zanthia@flickr
Cnuc C C C CC
Cnuc
O
CC
C
Ocarbonyl addition
56
General mechanism
Cnuc C LG C C LG
57
enolates as nucleophiles
OLi
R X
O
RLi X
simple sn2 reactions
58
Text
O
OH
vitamin E©darwin bell@flickr
avocados are a good source of
vitamin e
59
N
PhO2S O O
Cy(iPr)NLiHMPA / THF
N
PhO2S O O
Li
I
O
O
Xc
Enolate alkylation
in this reaction we form the enolate as normal but it is part of a chiral amide & this permits control of
stereochemistry
60
reactions of silyl enol
ethers
61
silyl enol ethers & strong electrophiles
OSiR3 Cl
AlCl3 O
OSiR3
AlCl4
OSiR3
Cl
do not need to activate the silyl enol ether if it is reacting with a strong
electrophile
62
silyl enol ethers & strong electrophiles
OSiR3 Cl
AlCl3 O
OSiR3
AlCl4
OSiR3
Cl
here, we use a Lewis acid to form a cation (a strong
electrophile)
63
silyl enol ethers & weak electrophiles
R X
O
R
OSiR3 MeLi
OSiR3
Li Me
Me SiR3
OLi
R X
if we react the silyl enolether with a weak electrophile then we must regenerate the
enolate first...
64
silyl enol ethers & weak electrophiles
R X
O
R
OSiR3 MeLi
OSiR3
Li Me
Me SiR3
OLi
R X
this is achieved by attacking the silicon with a strong organometallic reagent or
an acid
65
?what about
regioselectivity
©earl -what i saw 2.0@flickr
66
unsymmetrical ketones can give two products
O
R XLDA
O
R
and / or
O
R
67
?how can we control
regioselectivity
68
method 1: Activated starting material
O
OEt
O
OEt
H
O
OEt
O
RX
O
OEt
O
R
by adding a second carbonyl group
deprot0nation is limited to one position only
69
...then remove activating group
O
OEt
O
R
NaOH
O
O
O
R
Na
H
O
O
O
R
H
heat
O
R
CO2
note: lovely six-membered ring with 3 curly arrows. Organic chemistry does repeat the same motif so
often...
70
©Jill Greenseth@flickr
but how do we selectively add the activating group?
71
O
O
method 2: selective enolate formation
O O O
O
reaction progressenerg
y
kinetic
thermo-dynamic
one product is more stable & one product is formed more rapidly
72
O
O
method 2: selective enolate formation
O O O
O
reaction progress
energ
y
kinetic
thermo-dynamic
thus changing howwe form the enolate (reagents/temperature) we can selectively
form either
73
formation of thermodynamic enolate
OO
SiR3R3Si Cl
OSiR3
H
NEt3!+
!+OSiR3
!+
!+
H
NEt3
OSiR3
or
NEt3
this is the morestable enolate (it is the more substituted double
bond)74
formation of thermodynamic enolate
OO
SiR3R3Si Cl
OSiR3
H
NEt3!+
!+OSiR3
!+
!+
H
NEt3
OSiR3
or
NEt3
silicon activates the carbonyl so that we only have to use a weak base to deprotonate
75
formation of thermodynamic enolate
OO
SiR3R3Si Cl
OSiR3
H
NEt3!+
!+OSiR3
!+
!+
H
NEt3
OSiR3
or
NEt3
deprotonation occurs through a cationic transition state that is more stable if it is spread over a secondary position rather than a primary position
76
or...
OOH OH
minor major
R3Si Cl
OH SiR3
OSiR3 Et3N
an alternativeargument is that silyl
reagents can react with theenol & that the more substituted
enol is formed in preferenceto the terminal enol
77
then regenerate enolate
OSiR3 MeLi O
Li
finally re-generate the enolate, a process that occurs with retention
of regiochemistry
78
kinetic enolate
O
HH
O
H
more accessiblebulky base gives good selectivity
79
kinetic enolate
O
HH
O
H
more acidicstrong base at low temperature gives good selectivity
80
kinetic enolate
O
HH
O
H
statisticsmore of these protons
81
O LDA O
O
O
OH
kinetic enolateLda is bulky & strong basereaction is performed at low
temperature
82
O LDA O
O
O
OH
sn2 reactionepoxides good electrophiles
as we control alcohol stereochemistry
83
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