A brief look at alcohol protecting groups and then an introduction to carboxylic acid derivatives. Start of the reactions of carboxylic acids.

1. FUNCTIONALGROUP
123.312
Alcohols are very useful
starting materials...
INTERCONVERSIONS functional group H OH O O
CHAPTER4
interconversions R O R O previously, we2
R R R
introduced the alcohol
(hydroxy) group ...
R O R2 R OH R
CHAPTER four
protecting groups
R O
R Cl R2
R O
E 1 2
O R2
3
so the general scheme is...
we had found the
protecting
Text
fully
protected AcO
OAc
substitution was hard unless
we derivatised the alcohol
groups intermediate
during the OTBS
HO
first. synthesis of O
vancomycin O Cl
R Nuc O O
O O Nuc
R OH O O
R S 1 TBSO
O
Cl O OTBS
O R O Cbz
S 1 H
N
H H
O R N N N
N N
O H H
O H O
NH
O NH2
we looked at sulfonates, MeO2C
halides & reactions such as OTBS
the mitsunobu OTBS
©gianni d.@flickr
TBSO
4 5 6
protecting protecting
groups... groups...
why do we need
add at least two
steps to synthesis
(bad)
protecting groups
?
but allows chemistry that
might not have been possible
©showtime
...a necessary evil. ©showtime
...a necessary evil.
(good)
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2. so we must protect
reaction occurs at the alcohol prior to
the alcohol first reaction
O HO Nuc O O
O
R1
R2 Nuc
X R1
R2
R1
R2 Nuc R1
R2
R2
OH OH O O R1
H
O
why does this reaction we have removed PG
fail? acidic hydrogen
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many reactions are many reactions are by blocking certain reactivity we
not chemoselective not chemoselective control chemoselectivity
OH OH
Br Nuc
OH OH
Nuc Nuc
OH OH +PG
Nuc Nuc –PG
Br Br
the use of protecting
groups permits selective PG PG
O O
synthesis of the desired O O
Nuc
this reaction gives a mixture product
Br Nuc
of products due to the
reactivity of the alcohol
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be attached
in high yield
+PG O
R OH R PG
OH
how would you selectively a protecting
make the other product?
Nuc group should have
OH
Br
Nuc the following
properties:
O
©leo reynolds@flickr
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3. survive reaction be removed in
conditions high yield
+PG O +PG O
R OH R PG R OH R PG
examples of
protecting
reaction reaction
groups:
O –PG O
R* PG R* OH R* PG
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Silyl protecting groups Synthesis Synthesis: mechanism
Me Me O Me Me Me O Me
R OH N NH R Si R OH N NH R Si
Si Me Si Me
O R1 Cl t-Bu t-Bu Cl t-Bu t-Bu
R Si HN N
R1
based on strength of the R1
oxygen-silicon bond (think about
Me Me
R OH
H
Si O Me
glass or the most common form N t-Bu R Si
of sand) note: we do not often use HN Me
very easy to prepare Me3Si (trimethylsilyl/TMS) as t-Bu
stable to nucleophiles & Carbon or it is relatively unstable
Nitrogen bases
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Synthesis: mechanism Synthesis: mechanism Synthesis: mechanism
Me Me O Me Me Me O Me Me Me O Me
R OH N NH R Si R OH N NH R Si R OH N NH R Si
Si Me Si Me Si Me
Cl t-Bu t-Bu Cl t-Bu t-Bu Cl t-Bu t-Bu
note: initially, imidazole does
not act as a base (it is too HN N HN N HN N
weak a base to deprotonate
an alcohol
Me Me H Me Me H Me Me H
R OH R OH R OH
Si O Me Si O Me Si O Me
N t-Bu R Si N t-Bu R Si N t-Bu R Si
HN Me HN imidazole activates the silyl Me HN note: the reactions of siliconMe
t-Bu reagent (this kind of behaviour is t-Bu groups are not actually snt-Bu
2 but
important to the reactivity of the we will let than one slip for the
amino acid histidine time being
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4. deprotection: fluoride deprotection: Acid tetrahydropyranyl (THP) group
H
O Me H3O
O Me F R Si O Me R OH
R Si Me R Si
R OH
Me
t-Bu (Bu4N+F–)
t-Bu
H2O:
Me
t-Bu R
the silicon fluorine
O O
bond is one of the can also use acid note: an excellent review
strongest known bonds, so to remove some on the selective removal
this reaction is pretty silyl ethers of silyl ethers is:
effective synthesis 1996, 1031 stable to strong bases
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synthesis do you know the acetal formation / hydrolysis
mechanism? H
R OH
R
O O O
H Text
R OH
R
O O O
H
H R OH
Yes, look at O O
it...it’s an acetal!
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deprotection do you know the acetal formation / hydrolysis
H3O mechanism? H3O
R OH R OH
R R
O O HO O O O HO O
H
H2O
R R OH
Yes, look at it...it
O O
O
is an acetal! H
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5. problem: we have added benzyl (bn) ether Synthesis
Text
a stereocentre so could
have diastereoisomers
R
O Br
R
NaH O
R R OH
O O good on nitrogen
as well as oxygen
simplest synthesis
involves sn2
vrey robust protecting group; displacement of a halide
©camil tulcan@flickr
stable to just about everything
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deprotection Aromatic ring is its achilles’s heel deprotection
R
O
R R HBr or
O O H2, Pd / C
R OH R OH
cleaving an ether can be aromatic ring increases the
hard (hence it’s a robust but the benzyl activity of this particular ether,
protecting group) group as a weak permitting selective
spot... deprotections
©Warner Bros / DC Comics
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Acid-mediated removal hydrogenation hydrogenation
R H2, R H2,
R O Pd/C H O Pd/C H
O HBr Br R OH R OH
R OH
Br
H mechanism not fully understood
hydrogenation with (it is a surface reaction &
R palladium on charcoal consequently hard to study)
O H H H H
(pd/c) allows selective &
H H H (relatively) mild H H
deprotection the first step is for
acid permits Pd metal Pd metal
but the acid must surface surface adsorption of the hydrogen
removal by sn2 on the palladium (interaction of
be very strong
(which limits its use) the H2 with the surface
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6. hydrogenation hydrogenation hydrogenation
R H2, R H2, R H2,
O Pd/C H O Pd/C H O Pd/C H
R OH R OH R OH
interaction of the aromatic
group & the Pd/C facilitates
substrate adsorption...
H H H H H H O
R
H H H H H H H H ...this places the benzylic
Pd metal once on the surface Pd metal
the activated hydrogen Pd metal ether in close proximity to
surface the hydrogen is surface is now ready to react surface the activated hydrogen
activated... with the benzyl ether
so...
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hydrogenation hydrogenation
R H2, R H2,
O Pd/C H O Pd/C H
R OH R OH
an example of
the use of
H H
protecting
H H O O H H O O groups:
R R R R
H H H H H H H H H H
H
Pd metal hydrogen adds Pd metal
surface across the reactive surface & somehow it all
benzylic C-O bond comes to an end...
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during the synthesis of milbemycin synthesis
Text b3, the following conversion was
required
MeO2C O
OH MeO2C
H O H O O
O Me
Me
MeO2C
OH BnO LiAlH4
O O
Me Me
add THP protecting group
Ph Br
prior to reduction (reactivity &
this is a Ph O O primarily differentiation of the two
O HO O O
natural product that is readily available alcohols NaH will be formed)
that
used to control pests starting material Me Me
OH
on pets mibemycin !3 (Roche ester)
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7. synthesis synthesis synthesis
protect second alcohol as robust
MeO2C benzylOgroup so that original MeO2C O
OH H3O Ph O OH OH
alcohol can be MeO2C
selectively reacted MeO2C
H O O Ph O O O H O O
Me Me Me
Me Me Me
LiAlH4 LiAlH4
PBr3
why not just use the initial alcohol?
Li
Ph Br BnO Ph O Br Ph Br
Ph O O O NaH HO O O THpMe
removed before simple Me Ph O O O NaH HO O O
Me Me
functional group interconversion Me Me
©mag3737@flickr
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synthesis synthesis
synthesis of this fragment is
MeO2C O
finished by the addition of the
OH MeO2C H3O
alkyne (C-C Ph formation)
bond O OH
H O O Ph O O O
Me Me
Me Me
LiAlH4
PBr3
why couldn’t we use
Ph Br
Li this molecule?
BnO Ph O Br
Ph
or this alcohol? O
O O
Why add so HO O O Me Me
Me
many steps? NaH
Me
HO OH
©sarawestermark@flickr ©ocreactive@flickr
Me
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FUNCTIONALGROUP
it is a meso
123.312
compound
INTERCONVERSIONS functional group
CHAPTER5
interconversions
HO OH
CHAPTER five
Me carboxylic acids &
which means we their derivatives
would have to resolve the
E
compound at some point
achiral
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8. Alcohols are very useful fully carboxylic acids & their derivatives
starting materials... protected AcO
OAc
H OH O O
intermediate
during the
synthesis of HO
O
OTBS
O
R O R O R R2 R vancomycin
previously, we O Cl
introduced the alcohol O O
(hydroxy) group ...
R O R2 R OH R
TBSO
H
N
O
Cl
H
N
N
O
H
N
OTBS
O Cbz
N
R X
X = OH, OR2,
...& looked at some of O H N
H
H
their simple reactions O O
NH
R O O NH2
then
we looked at
NR2, Cl etc.
R2 MeO2C protecting groups. now we turn
R Cl R O OTBS
O R2 OTBS
our attention to carboxylic acids
TBSO & their derivatives
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O
Text causes diarrhetic Text
shellfish used in research;
H poisoning... NZD$975 per 1 mg
H O
formic acid
O OH O OH
H H H H
O O O O
HO HO
O O O O O O
OH H OH H
found in nature OH O O OH O O
©Richard Bartz ©Michelle Selvans
okadaic acid OH ©adamjtaylor@flickr
okadaic acid OH
67 68 69
esters proteins carboxylic acids are useful FG...
amides are obviously O O O
O found in proteins
R S R1 R H R O R1
O O O O
R Cl R OH R R1
esters are often
responsible for sweet
smells (like bananas)
R1 O R3 O O O O
H H
N N R OH
N N R O R1 R N R1
H H H
©Telrúnya@german wikipedia
O R2 O R4 © Thomas Splettstoesser
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9. carboxylic acids are useful FG...
R
carbonyl group is
the foundation of
O
much organic
Ssynthesis
R1 R
O
H R
O
O R1
Text
O infrared spectroscopy
good at identifying
different acid derivatives
O O O
properties
R Cl R OH R R1
R
O
O
O
R1
R OH
R
O
N
H
R1
R
©wonderferret@flickr
X
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Bond strength and IR stretch Bond strength and IR stretch Bond strength and IR stretch
O O O
O
>
R X R X
R
C=O
X R
C=O
X
C O
frequency inductive effect frequency
(electronegativity) shortens
reduced & strengthens c=O bond increased
stronger c=o results in a
conjugation lengthens & higher wavenumber stretch
weakens c=O bond in Ir spectra
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Bond strength and IR stretch carboxylic acid
derivatives Text
!+ !– O
>
O O
R
O
>
OR R
O
NH2 R
O
O
C O
R O R
R Cl
inductive inductive inductive conjugation conjugation
effect effect effect ~1650 cm–1 ~1630,
1815 cm–1 ~1810, (just) 1360 cm–1
stronger c=o often has 1790 cm–1 1745 cm –1
more positive carbon...
...more positive carbon most reactive least reactive reactivity
is the more reactive ©stuck in customs@flickr
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10. reactivity of carboxylic acid derivatives the mechanism of substitution is carboxylic acids
acid (acyl)
O addition / elimination...
O
chlorides
R Cl H2O
shows relationship
R2CO2 between various acid
O O H2 O
derivatives addition
anhydrides O O Nuc O
R O R2 Nuc LG
R2OH R LG R LG R Nuc
esters
R2OH
R
O
OR2
H2O
R2OH R
O
carboxylic
OH
acid
elimination
H
R O
NH3 one underlying mechanism
for most of the chemistry ...specific reactions
NH3 O H2O
we will be talking about normally differ by how
amides the leaving group (LG)
R NH2 is formed ©pawpaw67@flickr
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Reaction of carboxylic acids: mechanism mechanism
acid chloride formation
O
O O SO2
S O O HCl
SOCl2 Cl Cl S S
O or PCl5 O O Cl O Cl S S O
O Cl O Cl O Cl
H Cl
H H
R O R O H
Cl H R Cl
R O R Cl R O R O O
R
many reagents can need to
achieve this reaction dehydrate acid thus activate
hydroxyl group
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2nd mechanism Reaction of carboxylic acids:
similar mechanism. This one
Cl
relies on strength of P=O
bond O O Ester synthesis
O O
PCl4 H O
PCl4
R O R O
R O
PCl4
Cl N O O
H H
Cl HO R1
H
R1
O R OH R O
O PCl3 O
H
Cl Cl H
O
O catalytic
Cl this reaction can be
Cl P PCl4 my favourite
R Cl O Cl uses (COCl)2 & achieved directly as stated above, but
R Cl R O
catalytic DMF there are many better, milder conditions
can you work out that can be employed
the mechanism?
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11. why can’t you use mechanism of acid catalysed mechanism of acid catalysed
base catalysis? ester formation ester formation
H H
O H O HO OH H
H O OH
R1
R OH R O R1
R OH R O
note: all steps are
hopefully this is reversible. so how do we get
just revision... R1 OH
the product we want
HO OH H
HO OH O O
R1
this is a first year R1 R O R1
question so you better R O R O R1
know the answer! H R O
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Reaction of carboxylic acids: mechanism of ester formation
Text Ester synthesis
H2C N N
O O
O O H H3C N N
H2C N2 R O R O
CH3
R OH R O H2C N N N2
need to disrupt equilibrium; O
remove water or at more alcohol diazomethane offers a mild,
will force the reaction in the CH3
almost neutral route to R O
direction we want methyl esters
©fortinbras@flickr
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Reaction of carboxylic acids:
diazomethane is explosive,
sharp edges like scratches on glass or Amide synthesis
ground-glass joints are enough to
detonate it
most safer routes
to esters involve
functional group O reagents O
interconversion H2N R1 R1
first R OH R N
H
there are many ways to
convert acids into amides (due
to researchers wanting to make
proteins etc)
©Roy lichtenstein
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