Lecture3: 123.312
13
E FUNCTIONAL GROUP INTERCONVERSIONS CHAPTER 4 123.312 1 functional group interconversions CHAPTER four protecting groups 2 Alcohols are very useful starting materials... R OH R O H R O OH O R 2 O R Cl R R O R 2 R 2 O O R O R 2 R R R previously, we introduced the alcohol (hydroxy) group ... 3 R OH O S R 1 R O O Nuc R Nuc O S R 1 O O so the general scheme is... we had found the substitution was hard unless we derivatised the alcohol first. we looked at sulfonates, halides & reactions such as the mitsunobu 4 Text ©gianni d.@flickr protecting groups 5 fully protected intermediate during the synthesis of vancomycin N H H N O O O O O O OAc AcO HO OTBS OTBS H N O H NH 2 O N H O N Cbz H N O OTBS OTBS TBSO NH MeO 2 C O TBSO Cl Cl 6 protecting groups... ...a necessary evil. ©showtime 7 protecting groups... ...a necessary evil. ©showtime add at least two steps to synthesis (bad) but allows chemistry that might not have been possible (good) 8 ? why do we need protecting groups 9
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A brief look at alcohol protecting groups and then an introduction to carboxylic acid derivatives. Start of the reactions of carboxylic acids.
Transcript of Lecture3: 123.312
E
FUNCTIONAL GROUPINTERCONVERSIONS
CHAPTER 4
123.3
12
1
functional group interconversions
CHAPTER fourprotecting groups
2
Alcohols are very useful starting materials...
R OH
R O
H
R O
OH
O R2
O
R Cl
R
R OR2
R2
O O
R O R2
R R
R
previously, we introduced the alcohol
(hydroxy) group...
3
R OH
OSR1
R
O O Nuc
R Nuc
OSR1
O O
so the general scheme is...we had found the
substitution was hard unless we derivatised the alcohol
first.
we looked at sulfonates, halides & reactions such as
the mitsunobu4
Text
©gianni d.@flickr
protecting groups
5
fully protected intermediate during the synthesis of vancomycin
NH
HN
O
O
O
OO
O
OAcAcO
HO OTBS
OTBS
HN
OH
NH2O
NH
O
N
CbzHN
O
OTBS
OTBS
TBSO
NH
MeO2C
O
TBSO
Cl
Cl
6
protecting groups...
...a necessary evil.©showtime
7
protecting groups...
...a necessary evil.©showtime
add at least two steps to synthesis
(bad)
but allows chemistry that might not have been possible
(good)8
?why do we need
protecting groups
9
R1R2
OH
O
Nuc R1R2
OH
HO Nuc
X
why does this reaction fail?
10
R1R2
O
O
Nuc R1R2
O
H
O
reaction occurs at the alcohol first
11
R1R2
O
O
PG
so we must protect the alcohol prior to reaction
we have removed acidic hydrogen
12
many reactions are not chemoselective
OH
BrNuc
OH
Nuc
O
this reaction gives a mixture of products due to the reactivity of the alcohol
13
many reactions are not chemoselective
OH
BrNuc
OH
Nuc
O
the use of protecting groups permits selective synthesis of the desired
product
14
OH
Br
+PG
O
Br
PG
NucO
Nuc
PG
OH
Nuc
–PG
by blocking certain reactivity we control chemoselectivity
15
OH
BrNuc
OH
Nuc
O
how would you selectively make the other product?
©leo reynolds@flickr
16
a protecting group should have
the following properties:
17
R OH+PG
RO
PG
be attached in high yield
18
R OH+PG
RO
PG
reaction
R*O
PG
survive reaction conditions
19
be removed in high yield
R OH+PG
RO
PG
reaction
R*O
PG
–PGR* OH
20
examples of protecting groups:
21
based on strength of the oxygen-silicon bond (think about glass or the most common form
of sand)
ROSi
R1
R1R1
Silyl protecting groups
stable to nucleophiles & Carbon or Nitrogen bases
22
R OH
ClSi
t-Bu
Me MeN NH R
OSi
Me
t-BuMe
Synthesis
very easy to preparenote: we do not often use Me3Si (trimethylsilyl/TMS) as it is relatively unstable
23
R OH
ClSi
t-Bu
Me MeN NH R
OSi
Me
t-BuMe
NSi
t-Bu
Me Me
HNROSi
Me
t-BuMe
H
NHN
R OH
Synthesis: mechanism
24
R OH
ClSi
t-Bu
Me MeN NH R
OSi
Me
t-BuMe
NSi
t-Bu
Me Me
HNROSi
Me
t-BuMe
H
NHN
R OH
Synthesis: mechanism
note: initially, imidazole does not act as a base (it is too weak a base to deprotonate
an alcohol
25
R OH
ClSi
t-Bu
Me MeN NH R
OSi
Me
t-BuMe
NSi
t-Bu
Me Me
HNROSi
Me
t-BuMe
H
NHN
R OH
Synthesis: mechanism
imidazole activates the silyl reagent (this kind of behaviour is important to the reactivity of the
amino acid histidine26
R OH
ClSi
t-Bu
Me MeN NH R
OSi
Me
t-BuMe
NSi
t-Bu
Me Me
HNROSi
Me
t-BuMe
H
NHN
R OH
Synthesis: mechanism
note: the reactions of silicon groups are not actually sn2 but we will let than one slip for the
time being27
ROSi
Me
t-BuMe
F
(Bu4N+F–)
R OH
deprotection: fluoride
the silicon fluorinebond is one of the
strongest known bonds, so this reaction is pretty
effective28
ROSi
Me
t-BuMe
H3O
ROSi
Me
t-BuMe
H
R OH
H2O:
deprotection: Acid
can also use acid to remove some silyl ethers
note: an excellent review on the selective removal
of silyl ethers is:synthesis 1996, 1031
29
OOR
tetrahydropyranyl (THP) group
stable to strong bases30
R OH
O
H
OOR
synthesis
31
Text
do you know the mechanism?
Yes, look at it...it’s an acetal!
32
R OH
O
H
OOR
O
H
O
HR OH
acetal formation / hydrolysis
33
deprotection
OOR
H3OR OH
OHO
34
do you know the mechanism?
Yes, look at it...it is an acetal!
35
OOR
H3OR OH
OHO
OOR
H
O
R OH
H2OH
acetal formation / hydrolysis
36
Text
OOR
©camil tulcan@flickr
problem: we have added a stereocentre so couldhave diastereoisomers
37
OR
benzyl (bn) ether
vrey robust protecting group; stable to just about everything
good on nitrogen as well as oxygen
38
R OHBr NaH O
R
Synthesis
simplest synthesis involves sn2
displacement of a halide
39
OR
R OH
deprotection
cleaving an ether can be hard (hence it’s a robust
protecting group)but the benzyl group as a weak
spot...
40
Aromatic ring is its achilles’s heel
OR
©Warner Bros / DC Comics
41
OR HBr or
H2, Pd / CR OH
deprotection
aromatic ring increases the activity of this particular ether,
permitting selective deprotections
42
Acid-mediated removal
OR
R OHBrHBr
H
OR
H
Br
acid permits removal by sn2 but the acid must
be very strong (which limits its use)
43
OR
R OHH
H2, Pd/C
hydrogenation
Pd metal
surface
H H
H H
hydrogenation with palladium on charcoal
(pd/c) allows selective & (relatively) mild deprotection
44
OR
R OHH
H2, Pd/C
hydrogenation
Pd metal
surface
H H
H H
mechanism not fully understood (it is a surface reaction &
consequently hard to study)
the first step is for adsorption of the hydrogen
on the palladium (interaction of the H2 with the surface
45
OR
R OHH
H2, Pd/C
hydrogenation
Pd metal
surface
H H
H H
once on the surface the hydrogen is activated...
46
OR
R OHH
H2, Pd/C
hydrogenation
Pd metal
surface
H H
H H
the activated hydrogen is now ready to react with the benzyl ether
so...
47
OR
R OHH
H2, Pd/C
OR
H H
hydrogenation
Pd metal
surface
H H
H H
interaction of the aromatic group & the Pd/C facilitates
substrate adsorption...
...this places the benzylic ether in close proximity to the activated hydrogen
48
OR
H
H
OR
H H
OR
R OHH
H2, Pd/C
hydrogenation
Pd metal
surface
H H
H H
hydrogen adds across the reactive benzylic C-O bond
49
H
OR
H
H
OR
H H
OR
R OHH
H2, Pd/C
hydrogenation
Pd metal
surface
H H
H H
& somehow it all comes to an end...
50
an example of the use of protecting groups:
51
Text
O
O O
OH
H O
mibemycin !3
this is anatural product that is used to control pests
on pets
52
during the synthesis of milbemycin b3, the following conversion was required
MeO2COH
Me Me
BnO
readily available starting material (Roche ester)
53
MeO2COH
Me
O
H
MeO2CO
Me
O
O
Me
OHO
Ph Br
NaHO
Me
OOPh
LiAlH4
synthesis
add THP protecting groupprior to reduction (reactivity &
primarily differentiation of the two alcohols that will be formed)
54
MeO2COH
Me
O
H
MeO2CO
Me
O
O
Me
OHO
Ph Br
NaHO
Me
OOPh
LiAlH4
synthesis
protect second alcohol as robust benzyl group so that original
alcohol can be selectively reacted
55
OH
Me
OPh
O
Me
OOPh
H3O
PBr3
Br
Me
OPhLi
Me
BnO
synthesis
THp removed before simple functional group interconversion
56
MeO2COH
Me
O
H
MeO2CO
Me
O
O
Me
OHO
Ph Br
NaHO
Me
OOPh
LiAlH4
synthesis
why not just use the initial alcohol?
©mag3737@flickr
57
MeO2COH
Me
O
H
MeO2CO
Me
O
O
Me
OHO
Ph Br
NaHO
Me
OOPh
LiAlH4
synthesis
or this alcohol? Why add so many steps?
©sarawestermark@flickr
58
OH
Me
OPh
O
Me
OOPh
H3O
PBr3
Br
Me
OPhLi
Me
BnO
synthesis
synthesis of this fragment is finished by the addition of the alkyne (C-C bond formation)
59
why couldn’t we use this molecule?
OH
Me
HO
©ocreactive@flickr
60
it is a meso compound
achiral
OH
Me
HO
which means wewould have to resolve the compound at some point
61 E
FUNCTIONAL GROUPINTERCONVERSIONS
CHAPTER 5
123.3
12
62
functional group interconversions
CHAPTER fivecarboxylic acids & their derivatives
63
Alcohols are very useful starting materials...
R OH
R O
H
R O
OH
O R2
O
R Cl
R
R OR2
R2
O O
R O R2
R R
R
previously, we introduced the alcohol
(hydroxy) group...
...& looked at some of their simple reactions
64
fully protected intermediate during the synthesis of vancomycin
NH
HN
O
O
O
OO
O
OAcAcO
HO OTBS
OTBS
HN
OH
NH2O
NH
O
N
CbzHN
O
OTBS
OTBS
TBSO
NH
MeO2C
O
TBSO
Cl
Cl
then we looked atprotecting groups. now we turn our attention to carboxylic acids
& their derivatives65
carboxylic acids & their derivatives
R X
O
X = OH, OR2, NR2, Cl etc.
66
Text
H O
O
H
formic acid
©Richard Bartz
found in nature
67
O
O
OH
O
O
O
OHH
HO
OH
OH
HO
O
OH
okadaic acid©Michelle Selvans
causes diarrhetic shellfish poisoning...
68
Text
O
O
OH
O
O
O
OHH
HO
OH
OH
HO
O
OH
okadaic acid©adamjtaylor@flickr
used in research;NZD$975 per 1 mg
69
esters
©Telrúnya@german wikipedia
O
O
esters are often responsible for sweet smells (like bananas)
70
proteins
© Thomas Splettstoesser
NH
O R3
HN
O R4
O
R2
HN
O
NH
R1
amides are obviously found in proteins
71
R
O
O R1
R
O
NH
R1
R
O
H
R
O
R1
R OH
R
O
Cl
R
O
S R1
R
O
O R1
O
R
O
OH
carboxylic acids are useful FG...
72
R
O
O R1
R
O
NH
R1
R
O
H
R
O
R1
R OH
R
O
Cl
R
O
S R1
R
O
O R1
O
R
O
OH
carboxylic acids are useful FG...
carbonyl group is the foundation of much organic synthesis
73
properties
74
Text
©wonderferret@flickr
R X
Oinfrared spectroscopy good at identifying
different acid derivatives
75
Bond strength and IR stretch
R X
O
R X
O
C=O frequency reduced
conjugation lengthens & weakens c=O bond
76
R X
O
R X
O
C=O frequency increased
>
Bond strength and IR stretch
inductive effect (electronegativity) shortens & strengthens c=O bond
77
C O
Bond strength and IR stretch
stronger c=o results in a higher wavenumber stretch
in Ir spectra
78
...more positive carbon is the more reactive
C O!+ !–
stronger c=o often has more positive carbon...
Bond strength and IR stretch
79
R Cl
O
>
inductive
effect
1815 cm–1
R O
O
R
O
inductive
effect
~1810,
1790 cm–1
R OR
O
>
inductive
effect
(just)
1745 cm–1
R NH2
O
conjugation
~1650 cm–1
R O
O
conjugation
~1630,
1360 cm–1
carboxylic acid derivatives
least reactivemost reactive
80
Text
reactivity©stuck in customs@flickr
81
R O
O
R Cl
O
R OR2
O
R NH2
O
R OH
O
acid (acyl) chlorides
anhydrides
esters
amides
R2CO2
H2O
H2O
H2O
H2O
R2OH
R2OH
NH3
NH3
carboxylic acid
R2OH
R2
O
reactivity of carboxylic acid derivatives
shows relationship between various acid
derivatives
82
...specific reactions normally differ by how the leaving group (LG)
is formed
R LG
O
Nuc
R LG
O Nuc
R Nuc
O
LG
addition
elimination
the mechanism of substitution is addition / elimination...
one underlying mechanism for most of the chemistry we will be talking about
83
carboxylic acids
R
O
OH
©pawpaw67@flickr
84
R
O
OH
SOCl2
or PCl5
R
O
Cl
Reaction of carboxylic acids:acid chloride formation
many reagents can achieve this reaction
85
thus activate hydroxyl group
R
O
OH
O
SClCl
R
O
OH
SCl
O
Cl
R
O
O
SCl
O
mechanism
need to dehydrate acid
86
R
O
OH
SCl
O
Cl O
OH
SCl
O
R
ClR
O
Cl
SO2HCl
mechanism
87
similar mechanism. This one relies on strength of P=O
bond
R O
O
H
R O
O
H
PCl4
Cl
PCl4
R O
O
PCl4
R O
O
PCl4
HO
H
OP
ClCl
ClCl
Cl
RR
O
Cl
O
PCl3 Cl
H
2nd mechanism
88
can you work out the mechanism?
my favourite uses (COCl)2 & catalytic DMF
Cl
O
Cl
O
N
O
catalytic
89
Reaction of carboxylic acids:Ester synthesis
R
O
OH
HO R1
R
O
OR1
H
this reaction can beachieved directly as stated above, but
there are many better, milder conditions that can be employed
90
why can’t you use base catalysis?
this is a first year question so you better
know the answer!91
R
O
OH
H
R
O
OH
H
OHR1
R O
HO OH
R1
HR O
HO OH
R1
mechanism of acid catalysed ester formation
hopefully this is just revision...
92
R O
HO OH
R1
H
R O
O OH
R1
H
H
R
O
O
H
R1R
O
OR1
mechanism of acid catalysed ester formation
note: all steps are reversible. so how do we get
the product we want
93
Text
©fortinbras@flickr
need to disrupt equilibrium;remove water or at more alcohol will force the reaction in the
direction we want
94
R
O
OH
H2C N2
R
O
OCH3
Reaction of carboxylic acids:Ester synthesis
diazomethane offers a mild, almost neutral route to
methyl esters95
R
O
O
H2C N N
H2C N N
HR
O
O
H3C N N
N2
R
O
OCH3
mechanism of ester formation
96
©Roy lichtenstein
diazomethane is explosive,sharp edges like scratches on glass or
ground-glass joints are enough to detonate it
97
most safer routes to esters involve
functional group interconversion
first
98
R
O
OHH2N R1
R
O
NH
R1
reagents
Reaction of carboxylic acids:Amide synthesis
there are many ways to convert acids into amides (due to researchers wanting to make
proteins etc)99
R
O
OH
H2N R1
R
O
NH
R1X
Reaction of carboxylic acids:Amide synthesis
but direct addition is not one of them!
100
why can’t you use base catalysis?
why can’t you do the direct reaction?
this is a first year question so you better
know the answer!©wavetraced@flickr
101
Reaction of carboxylic acids:Amide synthesis
R
O
O
H2N R1
R
O
HO
H3N R1
salt formation
102
100sof
reagents
Reaction of carboxylic acids:Amide synthesis
due to protein/peptide synthesis there are...
103
R
O
OHH2N R1
R
O
NH
R1
DCC, HOBt
N C N
DCC
N
N
N
OH
HOBt
Reaction of carboxylic acids:Amide synthesis
104
Text
its a complex mechanism to say the
least...
105
mechanism
R
O
OH
N C N
Cy
Cy R
O
O
N C N
Cy
CyH
R
O
O NH
N
Cy
Cy
R
O
ON
N
N
O
NH
NH
Cy Cy
N
N
N
OH
H
106
mechanism
R
O
OH
N C N
Cy
Cy R
O
O
N C N
Cy
CyH
R
O
O NH
N
Cy
Cy
R
O
ON
N
N
O
NH
NH
Cy Cy
N
N
N
OH
H
DCC acts as adehydrating agent. the intermediate ester is highly activated due to the
stability of the urealeaving group
107
mechanism
R
O
OH
N C N
Cy
Cy R
O
O
N C N
Cy
CyH
R
O
O NH
N
Cy
Cy
R
O
ON
N
N
O
NH
NH
Cy Cy
N
N
N
OH
H
HOBt is not essential for amide formation. it is primarily used in peptide synthesis to make a highly activated intermediate that minimises the racemisation of an alpha-stereocentre
108
R
O
ON
N
N
H2N R1
R
O
NH
R1
mechanism
the hobt ester is highly reactive so reacts with an amine faster than
racemisation can occur
109
Acid (acyl) Chlorides
R Cl
O
normally very reactive
110
R
O
OH
SOCl2
or PCl5
R
O
Cl
Reaction of carboxylic acids:acid chloride formation
already seen how we can form acyl chlorides
111
R
O
Cl R
O
OHH
OH
Reaction of acid chlorides: hydrolysis
acyl chlorides are readily converted back into acids
112
R
O
Cl
HO R1
R
O
OR1
Reaction of acid chlorides: ester formation
similarly, they can easily be converted into esters
113
R
O
Cl
H2N R1
R
O
NH
R1
Reaction of acid chlorides: amide formation
surprise! Amides can be formed in the same manner
114
viagratm
OEt
SN
N
N
HNN
N
O
Pr
O
O
115
N
NHO
O
O2N
Pr
SOCl2
N
NCl
O
O2N
Pr
NH4OH
N
NH2N
O
O2N
Pr
Acid chlorides in synthesis
first convert an acid into an acid chloride then prepare an amide
116
N
NH2N
O
H2NPr
OEt
Cl
O
pyr N
NH2N
O
NH Pr
O
EtO
OEt
SN
N
N
HNN
N
O
Pr
OO
the synthesis of viagra™
©velo city@flickr
a second acid chloride is used in the synthesis
of a second amide
117
