lecture2: 123.312
DESCRIPTION
An introduction to alcohols, their uses and substitution reactions; conversion to go leaving groups.TRANSCRIPT
E
FUNCTIONAL GROUPINTERCONVERSIONS
CHAPTER 3
123.3
12
1
functional group interconversions
CHAPTER threefunctional group
interconversions & alcohols
2
NucHO
RNuc H O R
most nucleophiles also act as bases
previously we had seenthat alcohols can rarely undergo
sn2 substitution
3
Text
©pal berge@flickr
functional group
interconversion
4
OSR1
R
O O
Solution one:sulfonate esters...
5
R OH
OSR1
R
O O Nuc
R Nuc
OSR1
O O
so the general scheme is...
readily formed & readily substituted
6
OSR1
O O
OSR1
O O
OSR1
O O
sulfonates are good leaving groups because...
resonance/delocalisation stabilise
negative charge
7
RO
Ts
S
OR
OO
p-toluenesulfonate (tosyl)
pKa = ~ –6
most common.good balance of
reactivity & usability
8
ROMs
S
OR
OO
methanesulfonate (mesyl)
pKa = –2.6
not as acidic; not as good a leaving group.but small size is an
advantage
9
RO
Tf
S
OR
OO
F
F
F
trifluoromethanesulfonate (triflate)
pKa = –14
incredible leaving group; very unstable;
very acidic; very useful if you are careful
about 1000 times more acidic than
H2SO410
superacidsacid with an acidity greater than 100% pure sulfuric acid
©mali mish@flickr
SbF
F F
F
F
F
H
about 2x1019 stronger than
H2so4
11
?how do we prepare sulfonate esters
12
standard substitution...
R1 R2
H OH
ClS
Tol
O O pyridine
R1 R2
H O S
Tol
OO HClN
13
R1 R2
H OH
ClS
Tol
O O pyridine
R1 R2
H O S
Tol
H
R1 R2
H O S
Tol
OO HClN
O OCl
R1 R2
H O S
Tol
OOH N
and the mechanism...
14
R1 R2
H OH
ClS
Tol
O O pyridine
R1 R2
H O S
Tol
H
R1 R2
H O S
Tol
OO HClN
O OCl
R1 R2
H O S
Tol
OOH N
and the mechanism...
remember, sulfur is in the third row so can have 18
valence electrons
15
standard substitution...
R1 R2
H OH
ClS
Tol
O O pyridine
R1 R2
H O S
Tol
OO HClN
stereochemistry of alcohol unaffected
(its not involved in the reaction)
16
Please Note:
R1 R2
H ON
H
R1 R2
H OHN
X
pKa = 16.5
R1 R2
H O HHN
pKa = 5.2
most common mistakeis the believe that pyridine can deprotonate an alcohol...look
at the pka, it can’t!
17
mesylate is not formed by a standard substitution...
R1 R2
H OH
ClS
O O pyridine
R1 R2
H O S
OOHClN
18
R1 R2
H OH
ClS
O O pyridine
R1 R2
H O S
OOHClN
ClS
O O
H
N
R1 R2
H OH
OSO
R1 R2
H O
H
S
OO
H
mesylate is not formed by a standard substitution...
base causes elimination
19
R1 R2
H OH
XSCF3
O O pyridine
R1 R2
H O S
CF3
OO HXN
triflate is formed by a standard substitution...
but...20
unstable
Not with the chloride...
ClSCF3
O O
21
triflate is formed by a standard substitution...
R1 R2
H OH
SCF3
O O pyridine
R1 R2
H O S
CF3
OO
OS
F3C
OO
22
!Examples
23
O
N
dapoxetine
dapoxetine is a relative of prozac...but its not for treating her depression...
24
O
N
dapoxetine
...rather it is the only (licenced) drug that could have
made things last a little longer (or so I’m told...)
25
O
OH MsCl,
Et3N,
DMAPO Ph
OS
O O
HN
O
NDapoxetine can be made by sn2 of a mesylate. Note the inversion of stereochemistry.
26
attractive biological profile
N
N
NNH
OHH
H
H
manzamine A
27
N
HN
CO2Me
OHH
H
H
O
S TolO
O
N
N
CO2Me
OHH
H
Hi. iPr2NEt
ii. H2, Lindlar's catalyst
intramolecular sn2-like reaction
28
method 2
29
R X
X = Cl, Br or I
a second method is the use of alkyl halides
30
R1 R2
XH
R1 R2
NucHNuc
R XR OH R NucNuc
so the general scheme is...
substitution of halide normally occurs with
inversionstereochemistry of halide formation is more complex...
31
?How do we
synthesize alkyl halides
32
R OH H X R O
H
H
R XX
Method 1: Acid H–X
cheap, dirty & crude method but effective for
simple molecules
33
R OH H X R O
H
H
R XX
Method 1: Acid H–X
problem is itcan proceed by sn1 or sn2 & thus causes
stereochemical issues
34
R1 R2
OHH
ClS
O
Cl
N
R1 R2
HCl
only get inversion if we use a base
like pyridine
Method 2: thionyl chloride S(O)Cl2
inversion35
the reason for this is in the mechanism & the formation of a
good leaving group
Method 2: thionyl chloride S(O)Cl2
R1 R2
OHH
ClS
O
Cl
N
R1 R2
HCl
R1 R2
OH S
O
Cl
R1 R2
OH S
O
N
N
Cl
SN2
36
no pyridine & we observe retention
R1 R2
OHH
ClS
O
Cl
N
R1 R2
ClH
Method 2: thionyl chloride S(O)Cl2
retention!
X
37
Text
why does the base make a difference?
©the monk@flickr
38
SNinew mechanism!
Yay!
39
R1 R2
OHH
ClS
O
Cl R1 R2
ClH
R1 R2
OH S
O
Cl
SNi
Method 2: thionyl chloride S(O)Cl2
retention!40
R OH PBr3 R Br
Method 3: Phosphorus tribromide PBr3
inversion41
Text
the mechanism is a bit of a nightmare...
42
R OH PBr
Br
Br
PO
O
O
R
R
R 3 x H–Br
PO
O
O
R
R
R
H
BrPO
O
O
R
R
H
Br
R Br
H
PO
O
OR
H
H R BrH
Br
PO
O
OH
H
H R Br
mechanism...43
!Examples
44
venlafaxine is an antidepressant...
MeO
NHO
45
MeO
Br
Na CNMeO
CN
an early step in its synthesis is...
46
Prozac™ is the third most prescribed antidepressant in the usA...
NH
O
CF3
47
the original patent contains the following step...
NH
ClO
CF3
NH
O
CF3
48
R1 R2
OHHNuc H P
PhPh
Ph
NN
CO2EtEtO2C
R1 R2
HNucO
PPhPh
Ph
NN
CO2EtEtO2C
H
H
(DEAD)
a third method is the Mitsunobu reaction...
...THE REACTION IS SIMPLE TO PERFORM BUT...
49
©New line cinema
...the mechanism is a bit of a nightmare
50
Step 1:
NCO2EtN
EtO2C
Ph3P:
NN
EtO2C
Ph3P
OEt
O
NN
EtO2C
Ph3P
OEt
O
NEED TO ACTIVATE THE PHOSPHINE
51
R1 R2
OH
H
NN
EtO2C
Ph3P
OEt
O
R1 R2
OH
NN
EtO2C
Ph3P
OEt
O
H
Step 2:
deprotonation of alcohol normally a problem, here it is essential!
NEXT WE NEED TO ACTIVATE THE
ALCOHOL
52
R1 R2
OH
NN
EtO2C
Ph3P
OEt
O
H
R1 R2
OH PPh3
NN
EtO2C OEt
O
H
Step 3:
THE ALCOHOL IS NOW A GOOD LEAVING
GROUP
53
NN
EtO2C OEt
O
H
HNuc
NN
EtO2C OEt
O
H
Nuc H
Step 4:
NOW we activate the nucleophile
54
NN
EtO2C OEt
O
H
HNuc
NN
EtO2C OEt
O
H
Nuc H
Step 4:
note: the nucleophile must be acidic enough to allow activation or the reaction will fail & this limits the nucleophiles that
can be employed
55
finally!
Nuc
R1 R2
OH PPh3
R1 R2
HNuc
O PPh3
Step 5:
...Substitution!56
yay!©larskflem@flickr
57
R1 R2
OHH
R1 R2
HHO
the mitsunobu reaction permits inversion of alcohol stereochemistry...
this means it is a popular reaction for the correction of stereochemical mistakes
58
http://staff.science.uva.nl/~dcslob/lesbrieven/maarten/Bacterien.html
thienamycin is a potent antibacterial
N
HHOH
OCO2
S
H3N
59
NH
H HOH
O
pNBO2CO
N N
CO2iPr
iPrO2C
PPh3HCO2H NH
H HO
O
pNBO2CO
O
H
HClMeOH
NH
H HOH
O
pNBO2CO
during the merck synthesis the stereochemistry had to be altered
pNB =
O2N
stereochemistry of alcohol incorrect
60
NH
H HOH
O
pNBO2CO
N N
CO2iPr
iPrO2C
PPh3HCO2H NH
H HO
O
pNBO2CO
O
H
HClMeOH
NH
H HOH
O
pNBO2CO
during the merck synthesis the stereochemistry had to be altered
pNB =
O2N
mitsunobu reaction allows a two step (inversion/hydrolysis)
sequence to correct it
61