Lecture5: 123.312

E

FUNCTIONAL GROUPINTERCONVERSIONS

CHAPTER 7

123.3

12

1

functional group interconversions

CHAPTER sevenreduction

2

R O

H H

S

HH

R O

H H

Cr

O

O

OH

previously we had looked atoxidations now we turn our attention to

the opposite, reduction

3

R H

R OH

R NH2

R Cl

R

R1/H

O

R

RR

Cl Cl

Cl

RR

R1O OR1

OH

O

R

OR1

O

R

NH2

O

R

NR O C O

H2N

O

NH2

ClCl

Cl Cl

oxidation

Reduction

now adding hydrogen or removing oxygen (or other

heteroatom)

4

need to be able to control chemoselectivity

R1 H

O

R1 R2

O

R1 O

O

R2vs vs

5

TextHO

HO

OHHN

OMesalmefamol

lets approach this by example & look at the synthesis of this

anti-asthma drug6

NaBH4 MeO

O OH

HON

Ph Ph

MeO

O O

HON

Ph Ph

starting material contains many reducible groups

sodium borohydride only reacts with the ketone &

not the ester

7

hydrogenolysis & reductive amination

H2, Pd / C, H+, ketone

MeO

O OH

HOHN

OMe

MeO

O OH

HON

Ph Ph

O

OMehydrogenation reductively cleaves benzyl groups (as seen

earlier) but...

8

hydrogenolysis & reductive amination

H2, Pd / C, H+, ketone

MeO

O OH

HOHN

OMe

MeO

O OH

HON

Ph Ph

O

OMeit also reduces imine formed by condensation of amine & ketone in a process called

reductive amination9

MeO

O OH

HOHN

OMe

LiAlH4OH OH

HOHN

OMe

ester reduction

finally lithium aluminium hydride reduces the ester

10

©status frustration@flickr

many different forms of reduction in organic synthesis

11

look at various reagents

©golbog@flickr

12

Reduction of Aldehydes/ketones

R1

O

R2

NaBH4

or LiAlH4

R1 R2

H OH

relatively easy reduction

13

R1

O

R2

H

BH

H

H

OHEt

Na HO

Et

R1 R2

H OHH

BH

O

H

Et

mechanism of borohydride reduction

solvent, reductant & cation are all important

14

R1

O

R2

H

BH

H

H

OHEt

Na HO

Et

R1 R2

H OHH

BH

O

H

Et

mechanism of borohydride reduction

I doubt mechanism is concerted but all these

steps must occur

15

H is not a reducing agent, it is a base (eg sodium

hydride)16

H

BH

O

H

Et

Et

BH

Et

Et

by-product is also a (less) powerful reductant

add electron donating groups & get more powerful reductant (superhydride LiBH4)

17

sodium borohydride was developed during the war but

not reported until 1953

©alifaan@flickr

18

NaBH4R1 H

O

R1 R2

O

R1 Cl

O

only reduces reactive c=o bonds

19

Reduction of esters

R1

O

O R1 OH

H HLiAlH4

R2HO

R2

lithium aluminium hydride reduces esters all the way

down to alcohols

20

LiAlH4

reduces nearly all carbonyls

R1 H

O

R1 R2

O

R1 Cl

O

R1 OR2

O

R1 NR2

O

21

mechanism of lithium aluminium hydride reduction

R1

O

OR2

H

AlH

H

H

LiO

Li

OR2

R1

H

R1

O

H

H

AlH

H

H

Li

HO

R2

OLi

HR1

H

OAlH3

HR1

H

AlH

H

H

OH

HR1

H

Hagain, note H– is not the reductant

22

R1

O

OR2

H

AlH

H

H

LiO

Li

OR2

R1

H

R1

O

H

H

AlH

H

H

Li

HO

R2

OLi

HR1

H

OAlH3

HR1

H

AlH

H

H

OH

HR1

H

H

mechanism of lithium aluminium hydride reduction

cation important; remove it &

reaction stops23

by-product is also a (less) powerful reductant...

...could be termed a more selective reagent!

OAlH3

HR1

H

24

Reduction of amides

R1

O

N

LiAlH4R2

R2

R1 NR2

R2

H H

lithium aluminium hydride can perform

this reduction25

mechanism of lithium aluminium hydride reduction of amides

R1

O

NR2

R2

H

AlH

H

H

Li

R1

O

NR22H

Li

R1

O

NR22H

AlH3

R1

NR22

H

H

AlH

H

H

R1 NR2

R2

H H

AlH3

second reduction (of the iminium cation) does not require metal cation as it

is already charged

26

amine normally a poor leaving group

R1

O

NR22H

R1 H

O

R2N

R2

Li

X

Amine anions often used as bases (think LDA) they have high pka so

are poor leaving groups

27

Textthe reduction of amides really isn’t this simple to be honest!

28

Reduction of acids

R1

O

O

LiAlH4

HR1 O

H

H H

Xlithium aluminium hydride

does not reduce acids under standard conditions

29

Reduction of acids

R1

O

O

LiAlH4

HR1

O

O Li

just get salt formation along with the evolution of hydrogen

gas (h2)

30

R1

O

O

BH3

HR1 O

H

H H

Reduction of acids

the reduction can be achieve with a different reagent, borane (or

diborane)

31

R1

O

OH

BH3

R1

O

OB

3 R1 OH

H HBH3

reactive

Reduction of acids

first step is to ‘protect’ the acid the second

equivalent of borane does the reduction

32

Text

©jnthnhys@flickr

big difference between lithium aluminium hydride & borane

33

importance: liAlH4 is nucleophilic

R1

O

OR2

H

AlH

H

H!+

attacks electron poor carbonyls

more !+ve the carbonyl the faster it

should react

34

reacts with weaker more ‘electron rich’

carbonyls

importance: BH3 is electrophilic

attacks electron rich carbonyls

R1

O

NR2

H

BH

R2

H

borane needs activation

35

Text

©j heffner@flickr

borane reverses normal

chemoselectivity

36

borane reduction of amides

R1

O

NR2

R2

H

BHH

R1

O

NR2

R2

BH

HH

O

NR1

H

R2

R2

BH2

R1

H

N

R2

R2

H B

H

HR1 N

R2

H HBH2

R2R1 N

H H

R2

R2

37

chemoselectivity (enantiospecific)

EtO2C CO2HCO2H

HO

O O

H

H H

EtO2C

H

OH

OO

H

LiBH4 BH3

H+ H+

start with a single enantiomer of starting

material

38

chemoselectivity (enantiospecific)

EtO2C CO2HCO2H

HO

O O

H

H H

EtO2C

H

OH

OO

H

LiBH4 BH3

H+ H+

select the correct reagent & we can form either enantiomer of

lactone

39

partial reduction very hard

R1 OR2

O

R1 NR22

O

R1 H

O

difficult to prevent full reduction to either alcohol or amine

40

Text theoretically it is possible...practice can be more problematic

©0olong@flickr

41

diisobutylaluminium hydride (dibal)

Al

H

dibal’s reactivity is more similar to bh3 than liaiH4

42

R1 OR2

O

R1 H

ODIBAL

–78°C

must be cold

©Rachel's flickrs@flickr

react ester at low temperature & you can isolate the aldehyde

43

mechanism

R1 OR2

OAl

iBuiBu

H

R1 OR2

OAl

H

iBu iBu

R1

O

OR2

H

AliBu2

stable at low temp

R1 H

O H3O

the crucialbit is the stability of the tetrahedral intermediate

44

summary

R1

NR2

H R1

O

H R1

O

R2 R1

O

OR2 R1

O

NR2 R1

O

OH

NaCNBH3

NaBH4

LiBH4

LiAlH4

BH3

R1

NHR2

R1

OH

R1

OH

R2 R1

OH

R1

NR2

R1

OH

reduced slow no!reaction

product

starting material

45

want to achieve the following transformation...

O

OEt

Oreduction

O

OH

46

chemoselectivity

which functional group will

react?©amortize@flickr

47

problem: no reagent suitable

O

OEt

O

OH

OH

OH

OEt

O

reduction

nabh4 only reduces ketone

LiAlh4 reduces everything

48

use a protecting group49

O

OEt

O reduction O

OH

OEt

OOO

HOOH

H

LiAlH4

OH

OO

H2O

H

solution: Acetal protecting group

50

O

OEt

O reduction O

OH

OEt

OOO

HOOH

H

LiAlH4

OH

OO

H2O

H

solution: Acetal protecting group

diol reactswith more reactive ketone to give

acetal then we can do the reduction

51

hydrogenation

52

H H

C X

H

C X

H

hydrogenation is the addition of hydrogen

hydrogen can be added across most double or triple bonds & can cleave some single bonds

53

this permits exquisite chemoselectivity

O

H

H2, Pd / C

O

H

catalytic hydrogenation can be chemoselective...

hydrogenation normally requires a catalyst

54

catalytic hydrogenatation reduces alkynes

R1 R2

R1 R2

HH

HH

H2, Pd / C

can we stop this reaction halfway & form

an alkene?55

poison the catalyst...

©furryscaly@flickr

this blocks some of the reactive sites on the

catalyst56

partial hydrogenation...

R1 R2

R1 R2

H2, Pd / CaSO4, Pb

Lindlar catalyst

H H

the reaction is stereoselective giving the cis product (we’ll find out how to

make the trans isomer later)

57

hydrogenation can cleave single bonds

H H

C X

H

C X

H

58

hydrogenolysis can also cleave alkyl halides

hydrogenolysis of benzyl ethers

R1O

H2, Pd / C

R1O

H

H

seen this before during protection/deprotection

section

59 E

FUNCTIONAL GROUPINTERCONVERSIONS

CHAPTER 8

123.3

12

60

functional group interconversions

CHAPTER eightc–c bond formation

61

previously we looked atthe substrate & which leaving

groups were good in substitution reactions

R LGNuc

R Nuc

looked at substrate (R-LG)...

now look at c-based nucleophiles62

C–C bond formation is foundation of organic synthesis

©Ricketts Fish@flickr

63

Need...

Cnuc Celec C C

virtually all C-C bond forming reactions come down to this...(not necessarily charged species but

certainly polarised

64

Need...

Cnuc Celec C C

we are now going to concentrate on carbanions C–

65

...a carbanion

Cdo not really exist

(just ask an inorganic chemist) just behave

like this

66

...a carbanion

Ctwo ways to make

carbanions

67

1. organometallics

68

R X

metal

M R MX

R Mor

1. organometallics

insert a metal into a carbon halide bond

69

behave as...

R ©jurvetson@flickr

but more complex

MgXMg

XR

Sol

Sol

R

70

grignard reagents made from halides

R Br R MgBrMg

insertion occurs via single electron transfer (SET) process and the final

structure is solvent dependent

71

organolithium reagents made from chlorides (normally)

R ClR Li2 x Li

LiCl

much more reactive than grignard reagents

structure in solution depends on r. normally oligomeric (dimer,

trimer etc)72

methyl lithium is a tetramer in the solid state (& solution)

Copyright: Ben Mills (2007)

73

many other organometallic reagents...

all with their own pros & cons

Zr

Cl

R

R Zn R

RCu

RLi

74

2. deprotonation

75

2. deprotonation

R Hbase

R H base

this can be considered is removal of a proton to give a carbanion but reality more complex & we

are invariably forming an organometallic reagent

76

?but, how easy is it to selectively remove a proton

©smeerch@flickr

77

revision ©dhammza@flickr

78

we can use pKa to assess ease of deprotonation...

H X HO

HHO

H

H

X

acidconjugatebase

remember, pKa indicates wherethe equilibrium lies or how easy it is to

remove the proton from the acid

79

we can use pKa to assess ease of deprotonation...

R H

conjugateacid

base R H base

base

with deprotonations to form carbanions

we are effectively looking at removing the proton from the

conjugate acid80

low pKa

more acidic proton

easier to form (carb)anion

81

CH4 CH3

NH3 NH2

H2C CH2 H2C CH

HH H

EtO CH3

O

EtO CH2

O

H3C CH3

O

H3C CH2

O

OH O

acidconjugate

base pKa value

49

36

36

26

23

19

19

82

OH O

O

OEt

O O

OEt

O

O OO O

OH

O

O

O

S

O

O

OH S

O

O

O

HCl Cl

acidconjugate

base pKa value

17

11

9

4.8

-0.6

-783

http://www2.lsdiv.harvard.edu/labs/evans/

best pKa table I know

84

You do not need to learn these values

©Graham Johnson, Graham Johnson Medical Media, Boulder, Colorado

85

But, you do need to understand what factors effect them...

86

electron withdrawing groups stabilise anion & make H+ more acidic

OH

H3C

pKa = 15.9

OH

F3C

pKa = 12.4

OH

F3C

CF3

pKa = 9.3

OH

F3C

F3C CF3

pKa = 5.4

this is the inductive effect, electrons being pulled through ! bonds

87

resonance

©stefan linecker@Flickr

you all love the other effect that stabilises a

carbanion...

88

delocalisation stabilises anion

H

H H

O

HH

O

H

O

H

pKa = 51

pKa = 28.3

the ability to spread the chargeover more atoms causes a large degree of anion stabilisation & hence the big differences observed

in pKa

89

remember, many groups involved in resonance...

CRN

CRN

NRO

O

NRO

O

SRPh

O O

SRPh

O O

90

Lecture5: 123.312

Education

Transcript of Lecture5: 123.312