Date post: | 27-May-2015 |
Category: |
Education |
Upload: | gareth-rowlands |
View: | 3,135 times |
Download: | 3 times |
E
FUNCTIONAL GROUPINTERCONVERSIONS
CHAPTER 7
123.3
12
1
functional group interconversions
CHAPTER sevenreduction
2
R O
H H
S
HH
R O
H H
Cr
O
O
OH
previously we had looked atoxidations now we turn our attention to
the opposite, reduction
3
R H
R OH
R NH2
R Cl
R
R1/H
O
R
RR
Cl Cl
Cl
RR
R1O OR1
OH
O
R
OR1
O
R
NH2
O
R
NR O C O
H2N
O
NH2
ClCl
Cl Cl
oxidation
Reduction
now adding hydrogen or removing oxygen (or other
heteroatom)
4
need to be able to control chemoselectivity
R1 H
O
R1 R2
O
R1 O
O
R2vs vs
5
TextHO
HO
OHHN
OMesalmefamol
lets approach this by example & look at the synthesis of this
anti-asthma drug6
NaBH4 MeO
O OH
HON
Ph Ph
MeO
O O
HON
Ph Ph
starting material contains many reducible groups
sodium borohydride only reacts with the ketone &
not the ester
7
hydrogenolysis & reductive amination
H2, Pd / C, H+, ketone
MeO
O OH
HOHN
OMe
MeO
O OH
HON
Ph Ph
O
OMehydrogenation reductively cleaves benzyl groups (as seen
earlier) but...
8
hydrogenolysis & reductive amination
H2, Pd / C, H+, ketone
MeO
O OH
HOHN
OMe
MeO
O OH
HON
Ph Ph
O
OMeit also reduces imine formed by condensation of amine & ketone in a process called
reductive amination9
MeO
O OH
HOHN
OMe
LiAlH4OH OH
HOHN
OMe
ester reduction
finally lithium aluminium hydride reduces the ester
10
©status frustration@flickr
many different forms of reduction in organic synthesis
11
look at various reagents
©golbog@flickr
12
Reduction of Aldehydes/ketones
R1
O
R2
NaBH4
or LiAlH4
R1 R2
H OH
relatively easy reduction
13
R1
O
R2
H
BH
H
H
OHEt
Na HO
Et
R1 R2
H OHH
BH
O
H
Et
mechanism of borohydride reduction
solvent, reductant & cation are all important
14
R1
O
R2
H
BH
H
H
OHEt
Na HO
Et
R1 R2
H OHH
BH
O
H
Et
mechanism of borohydride reduction
I doubt mechanism is concerted but all these
steps must occur
15
H is not a reducing agent, it is a base (eg sodium
hydride)16
H
BH
O
H
Et
Et
BH
Et
Et
by-product is also a (less) powerful reductant
add electron donating groups & get more powerful reductant (superhydride LiBH4)
17
sodium borohydride was developed during the war but
not reported until 1953
©alifaan@flickr
18
NaBH4R1 H
O
R1 R2
O
R1 Cl
O
only reduces reactive c=o bonds
19
Reduction of esters
R1
O
O R1 OH
H HLiAlH4
R2HO
R2
lithium aluminium hydride reduces esters all the way
down to alcohols
20
LiAlH4
reduces nearly all carbonyls
R1 H
O
R1 R2
O
R1 Cl
O
R1 OR2
O
R1 NR2
O
21
mechanism of lithium aluminium hydride reduction
R1
O
OR2
H
AlH
H
H
LiO
Li
OR2
R1
H
R1
O
H
H
AlH
H
H
Li
HO
R2
OLi
HR1
H
OAlH3
HR1
H
AlH
H
H
OH
HR1
H
Hagain, note H– is not the reductant
22
R1
O
OR2
H
AlH
H
H
LiO
Li
OR2
R1
H
R1
O
H
H
AlH
H
H
Li
HO
R2
OLi
HR1
H
OAlH3
HR1
H
AlH
H
H
OH
HR1
H
H
mechanism of lithium aluminium hydride reduction
cation important; remove it &
reaction stops23
by-product is also a (less) powerful reductant...
...could be termed a more selective reagent!
OAlH3
HR1
H
24
Reduction of amides
R1
O
N
LiAlH4R2
R2
R1 NR2
R2
H H
lithium aluminium hydride can perform
this reduction25
mechanism of lithium aluminium hydride reduction of amides
R1
O
NR2
R2
H
AlH
H
H
Li
R1
O
NR22H
Li
R1
O
NR22H
AlH3
R1
NR22
H
H
AlH
H
H
R1 NR2
R2
H H
AlH3
second reduction (of the iminium cation) does not require metal cation as it
is already charged
26
amine normally a poor leaving group
R1
O
NR22H
R1 H
O
R2N
R2
Li
X
Amine anions often used as bases (think LDA) they have high pka so
are poor leaving groups
27
Textthe reduction of amides really isn’t this simple to be honest!
28
Reduction of acids
R1
O
O
LiAlH4
HR1 O
H
H H
Xlithium aluminium hydride
does not reduce acids under standard conditions
29
Reduction of acids
R1
O
O
LiAlH4
HR1
O
O Li
just get salt formation along with the evolution of hydrogen
gas (h2)
30
R1
O
O
BH3
HR1 O
H
H H
Reduction of acids
the reduction can be achieve with a different reagent, borane (or
diborane)
31
R1
O
OH
BH3
R1
O
OB
3 R1 OH
H HBH3
reactive
Reduction of acids
first step is to ‘protect’ the acid the second
equivalent of borane does the reduction
32
Text
©jnthnhys@flickr
big difference between lithium aluminium hydride & borane
33
importance: liAlH4 is nucleophilic
R1
O
OR2
H
AlH
H
H!+
attacks electron poor carbonyls
more !+ve the carbonyl the faster it
should react
34
reacts with weaker more ‘electron rich’
carbonyls
importance: BH3 is electrophilic
attacks electron rich carbonyls
R1
O
NR2
H
BH
R2
H
borane needs activation
35
Text
©j heffner@flickr
borane reverses normal
chemoselectivity
36
borane reduction of amides
R1
O
NR2
R2
H
BHH
R1
O
NR2
R2
BH
HH
O
NR1
H
R2
R2
BH2
R1
H
N
R2
R2
H B
H
HR1 N
R2
H HBH2
R2R1 N
H H
R2
R2
37
chemoselectivity (enantiospecific)
EtO2C CO2HCO2H
HO
O O
H
H H
EtO2C
H
OH
OO
H
LiBH4 BH3
H+ H+
start with a single enantiomer of starting
material
38
chemoselectivity (enantiospecific)
EtO2C CO2HCO2H
HO
O O
H
H H
EtO2C
H
OH
OO
H
LiBH4 BH3
H+ H+
select the correct reagent & we can form either enantiomer of
lactone
39
partial reduction very hard
R1 OR2
O
R1 NR22
O
R1 H
O
difficult to prevent full reduction to either alcohol or amine
40
Text theoretically it is possible...practice can be more problematic
©0olong@flickr
41
diisobutylaluminium hydride (dibal)
Al
H
dibal’s reactivity is more similar to bh3 than liaiH4
42
R1 OR2
O
R1 H
ODIBAL
–78°C
must be cold
©Rachel's flickrs@flickr
react ester at low temperature & you can isolate the aldehyde
43
mechanism
R1 OR2
OAl
iBuiBu
H
R1 OR2
OAl
H
iBu iBu
R1
O
OR2
H
AliBu2
stable at low temp
R1 H
O H3O
the crucialbit is the stability of the tetrahedral intermediate
44
summary
R1
NR2
H R1
O
H R1
O
R2 R1
O
OR2 R1
O
NR2 R1
O
OH
NaCNBH3
NaBH4
LiBH4
LiAlH4
BH3
R1
NHR2
R1
OH
R1
OH
R2 R1
OH
R1
NR2
R1
OH
reduced slow no!reaction
product
starting material
45
want to achieve the following transformation...
O
OEt
Oreduction
O
OH
46
chemoselectivity
which functional group will
react?©amortize@flickr
47
problem: no reagent suitable
O
OEt
O
OH
OH
OH
OEt
O
reduction
nabh4 only reduces ketone
LiAlh4 reduces everything
48
use a protecting group49
O
OEt
O reduction O
OH
OEt
OOO
HOOH
H
LiAlH4
OH
OO
H2O
H
solution: Acetal protecting group
50
O
OEt
O reduction O
OH
OEt
OOO
HOOH
H
LiAlH4
OH
OO
H2O
H
solution: Acetal protecting group
diol reactswith more reactive ketone to give
acetal then we can do the reduction
51
hydrogenation
52
H H
C X
H
C X
H
hydrogenation is the addition of hydrogen
hydrogen can be added across most double or triple bonds & can cleave some single bonds
53
this permits exquisite chemoselectivity
O
H
H2, Pd / C
O
H
catalytic hydrogenation can be chemoselective...
hydrogenation normally requires a catalyst
54
catalytic hydrogenatation reduces alkynes
R1 R2
R1 R2
HH
HH
H2, Pd / C
can we stop this reaction halfway & form
an alkene?55
poison the catalyst...
©furryscaly@flickr
this blocks some of the reactive sites on the
catalyst56
partial hydrogenation...
R1 R2
R1 R2
H2, Pd / CaSO4, Pb
Lindlar catalyst
H H
the reaction is stereoselective giving the cis product (we’ll find out how to
make the trans isomer later)
57
hydrogenation can cleave single bonds
H H
C X
H
C X
H
58
hydrogenolysis can also cleave alkyl halides
hydrogenolysis of benzyl ethers
R1O
H2, Pd / C
R1O
H
H
seen this before during protection/deprotection
section
59 E
FUNCTIONAL GROUPINTERCONVERSIONS
CHAPTER 8
123.3
12
60
functional group interconversions
CHAPTER eightc–c bond formation
61
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 nucleophiles62
C–C bond formation is foundation of organic synthesis
©Ricketts Fish@flickr
63
Need...
Cnuc Celec C C
virtually all C-C bond forming reactions come down to this...(not necessarily charged species but
certainly polarised
64
Need...
Cnuc Celec C C
we are now going to concentrate on carbanions C–
65
...a carbanion
Cdo not really exist
(just ask an inorganic chemist) just behave
like this
66
...a carbanion
Ctwo ways to make
carbanions
67
1. organometallics
68
R X
metal
M R MX
R Mor
1. organometallics
insert a metal into a carbon halide bond
69
behave as...
R ©jurvetson@flickr
but more complex
MgXMg
XR
Sol
Sol
R
70
grignard reagents made from halides
R Br R MgBrMg
insertion occurs via single electron transfer (SET) process and the final
structure is solvent dependent
71
organolithium reagents made from chlorides (normally)
R ClR Li2 x Li
LiCl
much more reactive than grignard reagents
structure in solution depends on r. normally oligomeric (dimer,
trimer etc)72
methyl lithium is a tetramer in the solid state (& solution)
Copyright: Ben Mills (2007)
73
many other organometallic reagents...
all with their own pros & cons
Zr
Cl
R
R Zn R
RCu
RLi
74
2. deprotonation
75
2. deprotonation
R Hbase
R H base
this can be considered is removal of a proton to give a carbanion but reality more complex & we
are invariably forming an organometallic reagent
76
?but, how easy is it to selectively remove a proton
©smeerch@flickr
77
revision ©dhammza@flickr
78
we can use pKa to assess ease of deprotonation...
H X HO
HHO
H
H
X
acidconjugatebase
remember, pKa indicates wherethe equilibrium lies or how easy it is to
remove the proton from the acid
79
we can use pKa to assess ease of deprotonation...
R H
conjugateacid
base R H base
base
with deprotonations to form carbanions
we are effectively looking at removing the proton from the
conjugate acid80
low pKa
more acidic proton
easier to form (carb)anion
81
CH4 CH3
NH3 NH2
H2C CH2 H2C CH
HH H
EtO CH3
O
EtO CH2
O
H3C CH3
O
H3C CH2
O
OH O
acidconjugate
base pKa value
49
36
36
26
23
19
19
82
OH O
O
OEt
O O
OEt
O
O OO O
OH
O
O
O
S
O
O
OH S
O
O
O
HCl Cl
acidconjugate
base pKa value
17
11
9
4.8
-0.6
-783
http://www2.lsdiv.harvard.edu/labs/evans/
best pKa table I know
84
You do not need to learn these values
©Graham Johnson, Graham Johnson Medical Media, Boulder, Colorado
85
But, you do need to understand what factors effect them...
86
electron withdrawing groups stabilise anion & make H+ more acidic
OH
H3C
pKa = 15.9
OH
F3C
pKa = 12.4
OH
F3C
CF3
pKa = 9.3
OH
F3C
F3C CF3
pKa = 5.4
this is the inductive effect, electrons being pulled through ! bonds
87
resonance
©stefan linecker@Flickr
you all love the other effect that stabilises a
carbanion...
88
delocalisation stabilises anion
H
H H
O
HH
O
H
O
H
pKa = 51
pKa = 28.3
the ability to spread the chargeover more atoms causes a large degree of anion stabilisation & hence the big differences observed
in pKa
89
remember, many groups involved in resonance...
CRN
CRN
NRO
O
NRO
O
SRPh
O O
SRPh
O O
90
we’ll concentrate on...
©alfred sim@flickr
91
enolates
O
92