An introduction to alcohols, their uses and substitution reactions; conversion to go leaving groups.

1. FUNCTIONALGROUP
123.312
most nucleophiles also act as
bases
INTERCONVERSIONS functional group previously we had seen
CHAPTER3
that alcohols can rarely undergo
interconversions sn2 substitution
Nuc O Nuc H O R
CHAPTER three H R
functional group
interconversions &
alcohols
E 1 2 3
Text Solution one: so the general scheme is...
sulfonate esters...
functional O O R Nuc
O O Nuc
group O O
R S 1
R OH R S 1
O R S 1
interconversion O R
O R
readily formed &
readily substituted
©pal berge@flickr
4 5 6
sulfonates are good
leaving groups because... p-toluenesulfonate (tosyl) methanesulfonate (mesyl)
OO OO
S S
O O O O O O
S 1
R O R O not as acidic; not as
S 1 S 1 most common. good a leaving group .
O R O R O R good balance of but small size is an
O reactivity & usability O advantage
R Ts R Ms
resonance/
delocalisation stabilise
negative charge pKa = ~ –6 pKa = –2.6
7 8 9

2. trifluoromethanesulfonate superacids
(triflate) acid with an acidity greater than
100% pure sulfuric acid
OO F F
S F
F F how do we prepare
R O F incredible leaving H Sb
F
sulfonate esters ?
O
group; very unstable;
very acidic; very useful F
R Tf if you are careful F
about 2x1019
about 1000 times stronger than
pKa = –14 more acidic than H2so4
H2SO4 ©mali mish@flickr
10 11 12
standard substitution... and the mechanism... and the mechanism...
OO HCl OO HCl OO HCl
H OH O O pyridine N H OH O O pyridine N H OH O O pyridine N
H O S H O S H O S
S S S
R1 R2 Cl Tol Tol R1 R2 Cl Tol Tol R1 R2 Cl Tol Tol
R1 R2 R1 R2 R1 R2
H O O H OO N H O O remember, sulfur His OO N
H O S Cl H O S H O S Cl in the third row O S
H
Tol Tol Tol so can have 18 Tol
R1 R2 R1 R2 R1 R2 valence electrons R2
R1
13 14 15
standard substitution... Please Note: most common mistake mesylate is not formed by a
is the believe that pyridine can standard substitution...
deprotonate an alcohol...look
OO HCl at the pka, it can’t! HCl OO
H OH O O pyridine N N H H OH O O pyridine N
X
H O S H O H H O N H O S
S S
R1 R2 Cl Tol Tol R1 R2 Cl
R1 R2 R1 R2 R1 R2 R1 R2
stereochemistry of H
alcohol unaffected H O H N
(its not involved in the
reaction) R1 R2
pKa = 16.5 pKa = 5.2
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3. mesylate is not formed by a triflate is formed by a standard Not with the
standard substitution... substitution... chloride...
HCl OO OO HX
H OH O O pyridine N H OH O O pyridine N
H O S H O S
unstable
S S
R1 R2 Cl
R1 R2
H
R1 R2 X CF3
R1 R2
CF3
O O
base causes
elimination
S
O O
S
N H OH
H Cl CF3
S H O S
Cl
R1 R2 O O OO
H R1 R2
but...
19 20 21
triflate is formed by a
standard substitution...
OO
!
H OH O O O O pyridine
S S
H O S Examples
R1 R2 F3C O CF3 CF3
R1 R2
N
O
dapoxetine is a relative of
prozac...but its not for
dapoxetine treating her depression...
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O O
...rather it is the only OH
(licenced) drug that could have MsCl, S
Et3N, O
made things last a little O DMAP
longer (or so I’m told...) O Ph
N
N
H
H H OH
H N
N
H N
N
N
O
Dapoxetine can be
made by sn2 of a O
manzamine A
mesylate. Note
the inversion of
stereochemistry.
dapoxetine attractive biological profile
25 26 27

4. intramolecular a second method is the
sn2-like reaction use of alkyl halides
H
CO2Me
H OH
CO2Me R X
HN i. iPr2NEt
ii. H2, Lindlar's H H OH
method 2
N
H N
catalyst
H N
X = Cl,
O
O
S
O
Tol Br or I
28 29 30
so the general scheme is... Method 1: Acid H–X
Nuc
R OH R X R Nuc
How do we H
X
synthesize alkyl R OH H X R O R X
H X Nuc H Nuc halides ? H
R1 R2 R1 R2
cheap dirty & crude
,
substitution of halide method but effective for
normally occurs with stereochemistry of halide simple molecules
inversion formation is more complex...
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Method 1: Acid H–X Method 2: thionyl chloride S(O)Cl2 Method 2: thionyl chloride S(O)Cl2
H OH O N Cl H H OH O N Cl H
S S
R1 R2 Cl Cl R1 R2 R1 R2 Cl Cl R1 R2
H
X N
R OH H X R O R X
Cl
H SN2
H O S N
O Cl H O S
problem is it R1 R2 O
can proceed by sn1 or only get inversion R1 R2
sn2 & thus causes if we use a base the reason for this is in the
stereochemical issues like pyridine mechanism & the formation of a
inversion good leaving group
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5. Method 2: thionyl chloride S(O)Cl2
Text
X
H OH O N H Cl
S
R1 R2 Cl Cl R1 R2
SNi
new mechanism!
why does the Yay!
no pyridine & we
observe retention base make a
difference?
retention! ©the monk@flickr
37 38 39
Method 2: thionyl chloride S(O)Cl2 Method 3: Phosphorus
tribromide PBr3 Text
H OH O H Cl
S
R1 R2 Cl Cl R1 R2
SNi R OH PBr3 R Br
Cl
H O S
O
R1 R2
the mechanism is a bit
retention! inversion of a nightmare...
40 41 42
R
R OH Br P Br O P O R 3 x H–Br
Br R O
Br MeO
H H
!
R R
O P O
R O
R Br
O P O R
R O
Br
Examples N
H HO
H H
H R Br R Br
O P O H O P O H
R O H O
Br
venlafaxine is an
mechanism... antidepressant...
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6. an early step in its synthesis is... the original patent contains
the following step...
Cl
O
N
H
CF3
MeO
Na CN MeO
CF3
CN CF3
O
Br
N O
H
N
Prozac™ is the third most prescribed H
antidepressant in the usA...
46 47 48
©New line cinema
a third method is the Step 1:
Mitsunobu reaction...
Ph3P O
H OH
EtO2C N N
Nuc H Ph P Ph N CO2Et EtO2C N OEt
R1 R2 Ph (DEAD) Ph3P:
...THE REACTION IS SIMPLE N CO2Et
EtO2C N
TO PERFORM BUT...
O H Ph3P O
Nuc H
EtO2C N NEED TO ACTIVATE
Ph P Ph N CO2Et
THE PHOSPHINE
N
R1 R2 EtO2C N OEt
Ph H ...the mechanism is a
bit of a nightmare
49 50 51
Step 2: Step 3: Step 4:
Ph3P O Ph3P O
N N H O H O PPh3
EtO2C N OEt EtO2C N OEt
R1 R2 R1 R2 Nuc H O Nuc
H H Ph3P O O H O
H O H O N N N N
EtO2C N OEt EtO2C N OEt EtO2C N OEt EtO2C N OEt
R1 R2 R1 R2 H H H H
NEXT WE NEED deprotonation of NOW we activate
TO ACTIVATE THE THE ALCOHOL IS NOW
alcohol normally a A GOOD LEAVING the nucleophile
ALCOHOL
problem, here it is GROUP
essential!
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7. Step 4: Step 5:
Nuc H O Nuc H O H O PPh3 Nuc H
Nuc O PPh3
N N R1 R2
EtO2C N OEt EtO2C N OEt R1 R2
H H
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!
...Substitution!
56
©larskflem@flickr
yay! 57
the mitsunobu reaction permits thienamycin is a during the merck synthesis the
inversion of alcohol potent antibacterial stereochemistry had to be altered
stereochemistry...
iPrO2C O
stereochemistry of
OH OH N N alcohol incorrect
H H H3N H H
CO2iPr H O
O H H
O
S NH PPh3
N HCO2H
H OH HO H O
O pNBO2C NH
O pNBO2C
CO2
HCl
R1 R2 R1 R2 MeOH
OH
H H
this means it is a popular O
reaction for the correction pNB =
of stereochemical mistakes NH
O2N O pNBO2C
http://staff.science.uva.nl/~dcslob/lesbrieven/maarten/Bacterien.html
58 59 60
during the merck synthesis the
stereochemistry had to be altered
iPrO2C O
OH N N
H H
O CO2iPr H O
H H
O
NH PPh3
O pNBO2C HCO2H NH
O pNBO2C
HCl
MeOH
mitsunobu reaction allows a
two step (inversion/hydrolysis) OH
sequence to correct it H H
O
pNB =
NH
O2N O pNBO2C
61