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

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?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...

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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

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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)

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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!

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mesylate is not formed by a standard substitution...

R1 R2

H OH

ClS

O O pyridine

R1 R2

H O S

OOHClN

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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

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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

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!Examples

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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.

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attractive biological profile

N

N

NNH

OHH

H

H

manzamine A

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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

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method 2

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R X

X = Cl, Br or I

a second method is the use of alkyl halides

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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...

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?How do we

synthesize alkyl halides

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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

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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

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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

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SNinew mechanism!

Yay!

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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

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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

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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...

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©New line cinema

...the mechanism is a bit of a nightmare

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Step 1:

NCO2EtN

EtO2C

Ph3P:

NN

EtO2C

Ph3P

OEt

O

NN

EtO2C

Ph3P

OEt

O

NEED TO ACTIVATE THE PHOSPHINE

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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

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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

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NN

EtO2C OEt

O

H

HNuc

NN

EtO2C OEt

O

H

Nuc H

Step 4:

NOW we activate the nucleophile

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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

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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

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http://staff.science.uva.nl/~dcslob/lesbrieven/maarten/Bacterien.html

thienamycin is a potent antibacterial

N

HHOH

OCO2

S

H3N

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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

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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

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