6. Functional Group Interconversion, Study notes of Organic Chemistry

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2014-2015 Autumn Term

6. Functional Group Interconversion

Sky and Water I

Maurits Cornelis Escher, 1 938

Dr. Pere Romea

Department of Organic Chemistry

Organic Synthesis

Carbon Backbone & Functional Groups

The synthesis of an organic compound must pay attention to ...

Functional groups

Functional Group Interconversion (FGI)

I. Nucleophilic Substitutions

Electrophilic Additions to C=C

Addition-Eliminations on Carboxylic Acids and Derivatives

II. Reductions

III. Oxidations Mechanism!!!

Carbon backbone

(Chapters 2–4 )

Nucleophilic Substitutions

Two model mechanisms, called S

N

1 i S

N

2 ,

are used to explain the nucleophilic substitutions

Unimolecular (S

N

1) or bimolecular (S

N

nucleophilic substitution?

X

+ Nu

Nu

+ X

A slightly different model, called S

N

2’,

may be useful in substitutions on allylic substrates

+ Nu +^ X

X Nu

Nucleophilic Substitutions and FGI

5

There are three main sources to carry out FGI

through nucleophilic substitutions: sulfonates, alcohols, and alkyl halides

Nu

R–OSO

R’ R–Nu

Sulfonates

R–OH R–Nu

Nu

Alcohols

R–X R–Nu

Nu Alkyl halides

X: I, Br, Cl

Nucleophilic Substitutions and FGI

R–OSO

R’ R–Nu

Nu

Sulfonates

R–OH R–Nu

Nu

Alcohols

R–X R–Nu

Nu Alkyl halides

X: I, Br, Cl

7

How easy is to interconvert sulfonates, alcohols, and alkyl halides?

Alcohols and Sulfonic Esters

Conversion of alcohols into sulfonic esters

• Primary and secondary ROH OK, but the reaction is sensitive to steric hindrance
• The reaction does not affect the C–O bond: the configuration of the carbon remains the same
• Mesylates and tosylates are largely employed.Triflates are the most reactive sulfonates
• Rearrangements of the carbon backbone are not frequent

OH

Me

Me

H

TsCl, pyr

Me

Me

Mesyl chloride

Tosyl chloride

Triflic Anhidride

Ms Cl

Ts Cl

Tf 2

O

MeSO 2 Cl

p-MePhSO 2 Cl

(CF

3

SO

2

2

O

Mesylate

Tosylate

Triflate

OH

+ RSO

2

Cl or (RSO

2

2

O

OSO

2

R

pyridine

CH

2

Cl 2

or Et 2

O

0 °C – rt

Alcohols and Alkyl Halides

Conversion of alcohols into alkyl halides

R–OH

R–OSO

R’

R–X

X

Sulfonates

Alcohols

Alkyl halides

X: I, Br, Cl

?

R’SO

Cl

Alcohols and Alkyl Halides

Conversion of alcohols into alkyl halides

OH X

X: Cl, Br, I

11

HCl conc

HCl/ZnCl

2

(Lucas reagent)

PCl

3

SOCl

2

,1,4-dioxane

SOCl

2

, non nucleophilic solvent

Tert

Prim & Sec

Prim & Sec

Prim & Sec

Prim & Sec

S

N

1 (racemization)

S

N

2 (inversion)

S

N

2 (inversion)

S

N

2 + S

N

2 (retention)

S

N

2 (inversion)

HBr conc

HBr conc, ∆

PBr

3

Tert

Prim

Prim & Sec

S

N

1 (racemization)

S

N

S

N

2 (inversion)

P/I

2

Prim & Sec

S

N

2 (inversion)

Reagents & Conditions Alcohols Mechanism

Alcohols and Alkyl Halides

More selective transformations are required …

The most used options are based on the conversion of alcohols into alkoxyphosphonium salts,

highly reactive in S

N

2 substitutions

Ph 3

P + E–Nu Ph 3

P

Nu

E

Ph 3

P E + Nu

Ph 3

P E + Ph 3

P (^) + HE

Alkoxyphosphonium salt

H

HO

H

O

Ph 3

P

H

O (^) + Nu Ph

3

P=O +

H

Nu

Alkoxyphosphonium salt

Alcohols and Alkyl Halides

Ph

P / X

: Ph

P / I

, Ph

P / Br

, Ph

P / Cl

Ph 3

P + Br–Br Ph 3

P

Br

Br

Ph 3

P Br

+ Br

- Br

H

Ph HO 3

P Br Ph 3

P

- HBr

H

+ O

Br

- Ph 3

P=O

H

Br

S

N

Br OH

PBr Br 3

Br

Ph 3

P/Br 2

Br

This transformation is very useful for secondary alcohols and those systems that easily produce transpositions, as neopentylic alcohols

The control on the configuration is very good.

O

O

R

OH

Ph 3

P, Br 2

O

O

R

Br

OH

OMe

OBn

Ph 3

P, I

2

Imidazole

Et 2

O, rt

I

OMe

96% OBn

14

Nucleophilic Substitutions and FGI

R–OH R–Nu

R–OSO

R’ R–Nu

R–X R–Nu

Nu

Nu

Nu

Sulfonates

Alcohols

Alkyl halides

X: I, Br, Cl

Carbon Nucleophiles

R CN R C CH

R X R OH

+ C + 2 C

R NH

2

R OH R H R Me

O O O

Amine 1 Carboxylic Acid Aldehyde Methyl ketone

Red

LiAlH

4

Red

DIBALH

Hydrolisis

H 3 O

Hydration

cat Hg

2+

, H 2 O

Attention!

Alkyl halides are very useful for

the construction of C–C bonds

Nitrogen Nucleophiles: Primary Amines

Potassium phthalimide, PhthNK

N

O

O

K

Br

Ph

N

O

O

Ph NaOH

H

2

N

Ph

Potassium phthalimide, pKa 8.

S

N

Gabriel synthesis of amines

The azide anion is an excellent nucleophile that participates in a large number of S

N

2 processes

The reduction of the azide group affords a primary amine

Azide, N

Bu

I

NaN 3

DMSO, Δ

Bu

N

3

Bu

NH

2

OTBDPS

OH

O O

1 ) MsCl, Et 3

N

2 ) NaN 3 ,

DMF

OTBDPS

O O

N

3

19

Nitrogen Nucleophiles: Primary Amines

Mitsunobu conditions: Ph

P / DEAD / HN

or DPPA [(PhO)

PON

]

H

OH

H

N

3

Ph 3

P, N N CO

2

EtO Et 2

C

HN

3

o (PhO) 2

PON

3 ,

H

O PPh 3

N

3

H

N

3

+ O=PPh 3

N N

CO

2

Et

EtO 2

C

Ph 3

P

N N

CO

2

Et

EtO 2

C

Ph 3

P

H

OH

N N

CO

2

Et

EtO 2

C

Ph 3

P

N

EtO 2

C

N

H

CO

2

Et

H

O PPh 3

N

EtO 2

C

N

H

CO

2

Et

HN 3

(PhO) 2

P

N

3

O

N

(PhO) 2

PO

EtO 2

C

N

H

CO

2

Et

N

H

EtO 2

C

N

H

CO

2

Et

+ N

3

N

3

DPPA