lecture1: 123.312

E

FUNCTIONAL GROUPINTERCONVERSIONS

GARETH J ROWLANDS123.

312

functional group interconversions

CHapter one - introduction

CHapter two - Alcohols

CHapter three - functional group group ... .........interconversions & alcohols

CHapter four - protecting groups

CHapter five - carboxylic acids & their their ...... .....derivatives

CHapter six - oxidation & reduction

CHapter seven - reduction

CHapter eleven - aldol rct & conjugate conjugate .......additions

CHapter eight - C–C bond formation introduction

CHapter nine - c–c bond formation: enolates

CHapter ten - C-C bond formation: other other ...... ...nucleophiles

functional group interconversions

CHAPTER oneintroduction

recommended book...

other useful books...

in the beginning...

in the beginning, man used natural products to treat illness.

willow bark has been used in the treatment of pain and fever for

centuries

in the beginning, man used natural products to treat illness.

OH

OH

Othe active component is salicin and its metabolite

salicylic acid

©Gustty@Flickr

OH

OH

O

unfortunately, salicylic acid is too corrosive to the walls of the stomach

for prolonged use

O

OH

O

O

Aspirin treats inflammation & is not corrosive (but is more dangerous than you think)

©Chaval Brasil from Flickr

how is aspirin related to salicylic acid?

chemical synthesisor an increase in complexity

some quick revision should make things easier to understand...

Bn H

OBn

H Br

SiMe3

Fu (jacs 2008, 130, 12645) needed one of his students to perform the following transformation:

©David Reeves from Flickr

how would/could they do it?

the first step is nucleophilic attack

Bn H

OBn

H Br

SiMe3

H SiMe3n-BuLi

Bn

H OH

SiMe3

here we are adding a group or building the

molecule

Bn H

OBn

H Br

SiMe3

H SiMe3n-BuLi

Bn

H OH

SiMe3

imidazolePh3PBr

step two substitutes a bromide for an alcohol

we are not building the molecule, just

altering it...

Bn H

OBn

H Br

SiMe3

H SiMe3n-BuLi

Bn

H OH

SiMe3

imidazolePh3PBr

step two substitutes a bromide for an alcohol

this is a functional group interconversion

a potent insect antifeedant & potential natural insecticide

OHOH

HO

AcOMeO2C

O

OO OH

CO2Me

O

O

O

azadirachtin

an alcohol

what is a functional group?

a group of atoms that (chemically) behaves the same in every molecule

OH

both alcohols share very similar chemical

properties

what isfunctional group interconversion

(FGI)?

Text

©dmcneil@flickr

OHOH

O

altering group but not increasing molecular

complexity

how could we achieve this reaction?

OH

R1 HH

OH

R1 R2R2

we cannot add two R2 groups directly to

alcohol

OH

R1 HH

OH

R1 R2R2

PCCoxidation

O

R1 OH

CH3OHH+ O

R1 OCH3

First we have to perform two functional group interconversions to prepare for addition...

we haven’t increased complexity or built

molecule...

OH

R1 HH

OH

R1 R2R2

PCCoxidation

O

R1 OH

CH3OHH+ O

R1 OCH3

R2–MgBr

...Now we can add the two R2 groups

8 lectures look at FGI and reactions that

increase complexity...

...then, when we have the tools, we will look

at retrosynthesis

before we go any further...

the next few slides are only in the notes...I will not be going through it in

the lectures.

a quick look at the basics...

key to organic chemistry is...

...the “curly arrow”...

...you do not have to remember all this...

...if...

...you know how to use...

the “curly arrow”...

...you know how to use...

the “curly arrow”...

you’ve been putting off learning this for three years! but now is the moment of

truth...

a bond (line) is two electrons.

C C

the electrons are not evenly distributed...

Clelectrons are attracted to electronegative elements or groups

the most electronegative elements attract electrons

...top right...

some examples...

Cl O

SiMe3 MgBr

R

RR

I hope you rememberthat the arrow points in the direction the electrons are

attracted (or the cross is the +ve end!)

polarisation occurs in conjugated systems...

Oδ+ δ–

δ+ δ–

this is due to resonance...

O O O O

Oδ+ δ–

δ+ δ–

O ≡

a reaction is the movement of electrons...

electron rich

electron poor

new bond

Nuc Elec Nuc Elec

common nucleophiles include...

NHH

H

H3C MgBr

LONE PAIRS

HIGH ENERGY BONDS (HIGH HOMO)

common electrophiles include...

empty atomic orbital

H F BFF

empty molecular

orbital

polarised bonds

(low LUMO)

CO

HO

H

FB

F FO B

H

H F

FF

so a reaction goes a little something like this...

electron rich

electron poor

new bond

8 is themagic number for valence electrons

remember the octet rule

Cl

so, if i see the following...I’m allowed to deduct marks?

RN

HRR

NucRN

RR

NucH

X

10electrons not allowed

RN

HRR

Nuc NRR

R

H Nuc

...is the correct reaction.

another common mistake...

RN

HRR

Nuc

...”curly arrow” always starts from most electrons

X

electrons do not like other electrons. So...

...is very rare and...

Nuc R

...never happens!

Nuc R X

if you are unsure of any of this material...revise!

E

FUNCTIONAL GROUPINTERCONVERSIONSCHAPTER 2

123.

312

functional group interconversions

CHAPTER twoalcohols

alcohols are found in many natural products...

OHOH

HO

AcOMeO2C

O

OO OH

CO2Me

O

O

O

azadirachtin

Text

O OH O NH2O

OH

HO

OH O

discodermolide

alcohols increasesolubility & hydrogen

bonding allows interactions with enzymes & proteins

Alcohols are very useful starting materials...

R OH

R O

H

R O

OH

O R2

OR Cl

R

R OR2

R2

O O

R O R2

R R

R

Alcohols are also the product of many reactions...

R OH

R O

H

R O

OH

O R2

OR Cl

R

R OR2

R2

O O

R O R2

R R

R

need to knowabout the reactivity

of alcohols

Alcohols are one of the cornerstones of synthesis

C OH C XC OH C C

©cornerstones of ny@flickr

B C BAA C

the basis of alcohols utility comes from...

substitution

Text

©Aidan o’sullivan@flickr

some revision!

Two important substitution mechanisms (but there are more)

R LG R R NucSN1

R LG R NucSN2

R LGNuc

R Nuc

R LGstep 1

R LG

the SN1 reaction...

...2 step process

step 2R Nuc R Nuc

R LGNuc

R Nuc

R LGstep 1

R LG

the SN1 reaction...

...2 step process

step 2R Nuc R Nuc

rate only depends on1st step. Thus substrate

strucutre important

the rate of Sn1 reaction depends on the stability of the cation...

R R

R

R R R> >

...and...

remember resonance can stabilise cation

as well

LGleaving group (LG) ability.

the more stable the anion the better.

the Nucleophile is not important (to the rate of reaction)

NucX

R1 R2

H LG Nuc

R1 R2

H Nuc

a consequence of the mechanism of Sn1 reactions

racemisationthe reason for this should be obvious...

trigonal planar carbocation

HR1R2

nucleophilecan attack from either face (top or bottom)

all moleculesinvolved in mechanism so all control rate

R LGNuc

R Nuc

R LGNuc

R Nuc

the SN2 reaction...

...1 step process

controlled by the substrate...

R LGsterics etc will affect reaction

LGleaving group (LG) ability.

the more stable the anion the better.

the Nucleophile is important

Nuc

R1 R2

H LG Nuc

R1 R2

H Nuc

A consequence of the mechanism of the Sn2 reaction is...

inversion

Text

©e-magic@flickr

why are these mechanisms important?

hypothetical example...©hurleygurley@flickr

You have been asked to perform the following transformation...

OHN3

conditions

N3

You have been asked to perform the following transformation...

OHN3

conditions

N3

you need to control stereochemistry

OHHN3

N3

lets say we could achieve this by an SN1 reaction...

?

Sn1H

R1R2

racemisation

fail

Sn2

inversion

H

R2 R1LGNuc

δ– δ–

Textsuccess

Textsuccess

but...

N3

OH N3

can this happen...

?

question 1is HO– a good leaving group?

question 2what about

chemoselectivity?

©oberazzi@flickr

Text

question 1is all about leaving group

ability...©mag3737@flickr

H2O H X H3O XKa

base acid

you will remember that...

the more stable X- the more X- we have...

...and...

Ka = [H3O ][X ][H–X]

pKa = –logKa

...therefore...

Xsmall pKa

high concentration

of...

Xsmall pKa

good leaving group

H–X has large pKa H–X has small pKa

H–X is weak acid

X– is strong base

H–X is strong acid

X– is weak base

Xis a poor

leaving group

Xis a Good

leaving group

pKa is a very useful guide to reactivity... a table of values can

be found at:

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

h2o pKa 15.7

HO- is a poor leaving group

Text

©alexanderdrachmann@flickr

question 2chemoselectivity is also an issue!

Nuc HO

R Nuc H O R

most nucleophiles also act as bases

and thesolution?

Text

©pal berge@flickr

functional group

interconversion