E

FUNCTIONAL GROUPINTERCONVERSIONS

CHAPTER 10

123.3

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1

functional group interconversions

CHAPTER tenc–c bond formation: other nucleophiles

2

enolates as nucleophiles

OLi

R X

O

RLi X

previously, we had looked the reaction of enolates &

their equivalents...

3

other nucleophiles

that are not enolates...

4

can we deprotonate them like this?

R C C H H2N Na

what about...?

?alkynes are useful

nucleophiles due to wealth of functional group interconversions

they can undergo

5

look at pKa...

>pKa = 35 pKa = 26

R C C HH2N Na

the pKa would suggest that we can

6

R C C H H2N Na R C C

PhBr

R C C

Ph

once formed, alkynyl anion undergoes standard nucleophilic

reactions

other nucleophiles: alkynes

7

Text

why can we readily deprotonate alkynes but not alkenes (or

alkanes)?

©marco belluci@flickr

think about molecular orbitals

8

other nucleophiles: nitriles

Na CN Ph Br Ph CN

nitriles are good nucleophiles the simplest is cyanide, a

long cylinder of charge

9

cyanide has an obvious problem

©mouse@flickr

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other nucleophiles: nitriles

Ph

C

N

H

H

:base

Ph

C

N

H

Br

Ph

CNnitriles are Electron

withdrawing & allow resonance stabilisation so are easily

deprotonated

11

the use of nitriles...

R CNOH

RC

OH

O

R CN

Ni / H2

R NH2nitriles are useful as they readily undergo functional

group interconversion12

Now, attack on...

O

Cthis is the

important one

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mechanism 1: carbonyl without leaving group

R1 R2

O

Cnuc

R1 R2

O Cnuc

R1 R2

HO Cnuc

there are two outcomes to attack on the carbonyl group

if the substrate has no leaving group get simple

addition

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mechanism 2: carbonyl with leaving group

R1 LG

O

Cnuc

R1 LG

O Cnuc

R1 Cnuc

O

R1 Cnuc

O CnucCnuc

R1 Cnuc

HO Cnuc

if there is a leaving group then carbonyl is reformed & double

addition is observed

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Addition of Grignard reagents

R1 R2

ORc MgBr

R1 R2

HO Rc

R1 R2

O Rc

BrMgH

addition to aldehyde/ketonefirst forms an alkoxide, which is

then protonated on work-up

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Addition of Grignard reagents

R1 OR2

ORc MgBr

R1 Rc

HO Rc

addition to an ester always results in double addition

reason: the ketone intermediate is more reactive than the starting material

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organolithium reagents

R1 R2

O

Rc Li

R1 R2

HO Rc

R1 OR2

O

Rc Li

R1 Rc

HO Rc

similar to Grignard reagents except more nucleophilic (& BAsic) this can cause

problems (see later)18

increased reactivity allows...

R1

O

OH

R1

O

O Li R1

O

O

Me

Li

Li

R1

OH

OH

MeR1 Me

O

Me Li Me Li

H2Odeprotonation gives

the normally non-electrophilic carboxylate anion

but reactivity of organolithiums allows a second attack and a route

to ketones19

examples

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©bmooneyatwork@flickr

Cl

ClOH

N

Nfenarimolantifungal

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organometallic reagent in total synthesis

Cl

ClOH

N

N

Cl

ClO

N N

Li

22

N

OMe

N

OH

quinine23

deprotonate methyl group;I can’t find pKa but anywhere

from 40 to 25

C–C bond formation important...

N

OMe

N3

OTBDPS

O

LiNiPr2

N

OMe

N3HO

OTBDPS

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C–C bond formation important...

N

OMe

N3

OTBDPS

O

LiNiPr2

N

OMe

N3HO

OTBDPS

reactive species is:

N

OMe

Li

N

OMe

25

bigproblem

especially with organolithiums

26

big problem©furryscaly@flickr

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MeO

OMe

O

Li

MeO

OMe

OH

Nucleophilicity versus basicity

this is what we want...

x

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Nucleophilicity versus basicity

MeO

OMe

O

H H

Li

MeO

OMe

O

H

this is what we get...organolithium reagents are

basic & often cause deprotonation not addition

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organocerium is less basic so will perform the desired

addition

transmetallation can give a less basic derivative

Li

Cl2Ce

CeCl3

MeO

OMe

O

MeO

OMe

OH

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formation of alkenes

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the wittig reaction (or at least one of them)

R1

O PPh3

R2R1

R2

this is the basic transformation, reaction of an

aldehyde/ketone with a phosphorus ylid

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formation of ylide

Ph3P: R2 Br

R2

PPh3

Br

H

base

PPh3

R2

PPh3

R2

a ylid (or ylide) is a compound with positive &

negative charges on adjacent atoms

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formation of ylide

Ph3P: R2 Br

R2

PPh3

Br

H

base

PPh3

R2

PPh3

R2

the phosphorane or ylide (resonance forms of each other) is made prior to addition of the

electrophile

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two possible mechanisms...

OPPh3 O

PPh3

PPh3O

betaine

oxaphosphetane

this is the easier of themechanisms to understand & is good for explaining the stereochemical

outcomeit is almost

certainly wrong

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second mechanism

O PPh3

PPh3

O

Ph3P

O

H H

R

R

better mechanism but some of the stereochemical arguments are less

convincing

proceeds by a[2+2] cycloaddition

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R1

O PPh3

R2

R1 R2

Wittig normally gives Z-alkenes

if R2 is not involved inreaction (non-stabilised ylid) then

the cis alkene is favoured

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Reason: Sterics of addition

Ph3P

O

R2 H

H

R1

O PPh3

R2R1

R1

O PPh3

R2

R1 R2

the substituents tryto stay as far apart as possible during cycloaddition (or nucleophilic addition

depending on the mechanism)

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Reason: Sterics of addition

Ph3P

O

R2 H

H

R1

O PPh3

R2R1

R1

O PPh3

R2

R1 R2

this means that substituentsare same side once oxaphosphetane has

formed. this step is irreversible so must proceed to cis-alkene even though it is

less stable

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example

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Text

©cotinis@flickr

O

O

OAc

OAc

OAc

OAc

anamarine

natural product isolate from bushmint

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OEtOH

PPh3

O

O

O

OOHC

H

OEtO

O

O

O

O

HH

Wittig normally gives Z-alkenes

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R2

O

PPh3

R2

O

PPh3

Stabilised ylides

if the substituent on the ylid canstabilise anion (EWG or resonance stabilisation) then we are said to have a stabilised ylid and

the trans-alkene predominates

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R1

OPPh3

O

R2 R1

R2

Stabilised ylide normally givesE-alkenes

the mechanism hopefully explains why stabilised ylides favour the more stable

trans-alkene44

Reason: reversibility of addition

O PPh3

CO2EtR1

R1

O PPh3

CO2Et

O PPh3

CO2EtR1

R1 CO2Et

R1

CO2Et

slow

fast

the first step, cycloaddition(or nucleophilic attack) is reversible. The equilibrium

favours the more stable adduct in which the substituents are as far apart as possible

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Stabilised ylide normally givesE-alkenes

EtO

O

PPh3

OHC

O

O

O

O

EtO2C

this is from a different synthesis of anamarine

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