Reactions of synthertic importance organic chem

Reactions of synthertic importance organic chem
Metal hydride reduction (NaBH4 and LiAlH4), Clemmensen reduction, Birch
reduction, Wolff Kishner reduction.
 Oppenauer-oxidation and Dakin reaction.
 Beckmanns rearrangement and Schmidt rearrangement.
 Claisen-Schmidt condensation

1. Reactions of Synthetic

Importance

2. > METAL HYDRIDE REDUCTION:

o Metal hydride reductions are probably the most
widely used, followed by catalytic hydrogenation.

BORON REAGENTS
Boron Based Reagents
- Sodium Borohydride - NaBH,
+ Sodium Cyanoborohydride - NaCNBH,
- Sodium Triacetoxyborohydride - Na(OAc)¿BH
- Lithium Borohydride - LiBH,
- Potassium Borohydride - KBH,
- Tetramethylammonium Borohydride

3. > SODIUM BOROHYDRIDE - NABH,

> Sodium borohydride was first prepared by reaction of sodium hydride
(NaH) with trimethylborate, B(OMe),.

> NaBH, is less reactive than LiAIH,

> Itis only powerful enough to reduce aldehydes, ketones and acid
chlorides to alcohols.

> Esters, amides, acids and nitriles are largely untouched.
> An aldehyde is reduced to 1° & ketone to a 2° alcohol respectively.
> Selective (chemoselectivity) reagent

1. NaBH _
CH¿CH¿CH» m. mo” CHsCH>CH;CH

an aldehyde a primary alcohol

i B. (
1. NaBH
CH¿CH2CH2CCH> — 9° =, 40° CH3CH,CH¿CHCH;
a ketone . a secondary alcohol

4. NABH, - MECHANISM

H 4 H

= +R -
A DUT RE D. —> + HO + R-0
A In R HO] *H I Sy

OSelectivity:

o NeBHy OH
Am A

o OH

ER a ie
—

5
d 0°C, EtOH

2

5. + SODIUM BOROHYDRIDE - NABH,
o Aqueous and alcohol solvents are preferred due to the excellent
solubility of NaBH,.

NaBH, reacts with water to form hydroxyborohydride intermediates, but

these are also mild reducing agents.

Itis relatively insoluble in ether solvents , so these are rarely used for

borohydride reductions.

o In most cases aqueous ammonium chloride, aqueous acetic acid, or
dilute mineral acids are used for hydrolysis .

o An important use of NaBH, is reduction of enamines, imines or iminium

salts, which is particularly useful in alkaloid and amino acid syntheses.

o

o

6. + ALUMINUM-BASED REAGENTS

o Lithium aluminum hydride (LiAIH4)
o Lithium tri-tert-butoxyaluminumhydride [Li(OtBu)3AIH]

o Diisobutylaluminum hydride ([(CH;),>CHCH,],AIH, Dibal
or Dibal-H)

7. > LITHIUM ALUMINUM HYDRIDE (LIALH4)

Very powerful reducing reagent

Available as either powder or pallet

Used as a suspension in ether or THF

Reacts violently with water, alcohol

Reduces carbonyl, carboxylic acid & ester

Reduces nitrile, amide & aryl nitro group to amine

Reduces acetylene to olefin

Reduces C-X bond, opens epoxide

LiAIH, is a stronger reducing agent than NaBH, due to weaker Al-H bond
LiAIH, is used to reduce compounds that are nonreactive toward NaBH,

0000000006060

Mechanism:

+ a o
a À Li

o DE A Re pr
5 GE RO 3 Li Arpo-c-H| —— RER
R

H

8. > LIALH4 |

LAI, reduction ot esters

©

© ul o

ul u LOA Alls iin, HO a
quench
4 cm gq a mid
H

R H H H

H H H
© ica
Hon tetrahedral intermediate
collapses to give an aldehyde

LiAIH, reduction of amides

A AA LE

©
sical WATER ci Hal DOES NOT HAPPEN
tetrahedral intermediate collapses NO
to give an iminium ion Nes not eliminated in this step

1. LiAIH a
comen don momo CM3CH,CH,CH¿0H + HO @
a carboxylic acid N a primary alcohol

9. > DIISOBUTYLALUMINUM HYDRIDE
(CH ),CHCH J,ALH. DIBAL OR DIBAL-H)

in the solvent heptane. H
o Highly pyrophoric : peut !
o Dibal-H is a strong reducing reagent, m Me :
reducing most functional . H

o Selective reagent (alkyne to alkene, ser! DIBAL

or ketone to aldehyde). | „DHsoButylALuminiurnnychice |

© Specialist reductant of nitrile to aldehyde

CHO

96% yield p

1. DIBAL, -70 °C

A >

2. H,0, HO

10. > DIBAL-H

o Under carefully controlled conditions, will partially reduce an
ester to an aldehyde.

If complex
is Unstable Fast
—— R=CHO ——3> RCH¿0H

If complex
is Stable

— R-CHO

o Direct conversion of acids to aldehydes:

A TMSCI o DIBAL-H À
—_ —>
RT SCH gun ONE nou zee © 4

o Acid chloride to aldehyde using Weinreb’s amide:

u
= uno o pent Hg à unes
A > ey ®
CI

y-ÓMe

E
a ©
Weinreb's gg, la i

amide

11. ALDEHYDES

BASIC REACTION :

NaBH,
Aldehydes primary alcohol
methanol

12. Examples

H.C
HC No + [H] = u”

Ethanal Ethanol

OH

o
TT
+ [HI —

benzylalcohol

13. « A balanced equation for the reaction can be
written using [H] to represent hydrogen from
reducing agent:

14. Ketones

— ::

O H NaBH,
27. MA

T
C-C-C-H >
|
H

H methanol

propanone

H OHH

I | |
H_C C-—C—H

EL LL À

H H H

propan-2-ol

15. Carboxylic acids

BASIC REACTION :

(i) LiAIH, in ethoxyethane
Carboxylic acids primary alcohol
(ii) H*/H,0

Ethanoic acid

Ethanol

16. « This can also be written as a balanced
equation using [H] to represent hydrogen
from the reducing agent:

* CH¿COOH +4[H] > CH,CH,OH + H,O

If you need to make an aldehyde from a carboxylic
acids, the carboxylic acids must be reduced to a

primary alcohol using LiAIH, and then the primary
alcohol must be oxidised back to an aldehyde .
(partial oxidation with distillation)

17. CLEMMENSEN REDUCTION

18. GENERAL REACTION

Ri=Alkyl, Aryl
R2= H, Alkyl, Aryl

19. MECHANISM

BR — 5

Zn,HCI

I X =

20. APPLICATIONS

= This reaction has widely used to convert a carbonyl group into a
methylene group.

= Also important application in the preparation of polycyclic
aromatics and aromatics containing unbranched side hydrocarbon
chains.

® To reduce aliphatic and mixed aliphatic-aromatic carbonyl
compounds

Zn/Hg
CH (CH2)sCHO aci > CHs-(CH2)s CH;
HEPTANAL HEPTANE
Zn-Hg

CeHsCOC3Hs Ha CeHsCH2C2H3
BENZOYL CYCLO ALLYLBENZENE

PROPANE

21. WOLFF-KISHNER REACTION

22. > GENERAL REACTION

23. MODIFICATION

æ The reaction has been extensively modified.

= One of the modification uses the Huang Minlon modification using
distillation to remove excess water and also used 85% hydrazine and
solvent used is ethylene glycol.

® In addition, the Wolff- kishner reduction has been carried out in
DMSO instead of hydroxylic solvent by addition of hydrazones into
anhydrous DMSO containing freshly sublimed potassium tert-
butoxide at 25°C.

æ Moreover.it has been reported that the Wolff-Kishner reduction can
occur in a very short period of time in a microwave irradiation,
affording product with high purity.

25. INTRODUCTION

= Named after Rupert Viktor Oppenauer.

= It is a gentle method for selectively oxidizing
secondary alcohols to ketones.

= The reaction is the opposite of Meerwein— Ponndorf —Verley
reduction.

® The alcohol is oxidized with aluminium isopropoxide in
excess acetone.

æ This shifts the equilibrium toward the product side.

26. GENERAL REACTION

Al(i-PrO3)/ heat
OH

OH o Oppenauer Oxidation o 4
N 7 A MPV Reduction

R Ry MC CHa
Ri Ra H¿C Ch; | E

27. APPLICATIONS

= The Oppenauer oxidation is used to prepare analgesics in
the pharmaceutical industry such as morphine and codeine. For
instance, codeinone is prepared by the Oppenauer oxidation
of codeine.

ALO i-Pr);
>65%

Ho

codeine codeinone

28. =» The Oppenauer oxidation is also used to synthesize hormones.

æ Progesterone is prepared by the Oppenauer oxidation
of pregnenolone.

(AlOPr)3

Me,CO

pregnenolone Progesterone

29. Birch reduction :-

Principle:-

Reduction of aromatic rings by means of
alkali metals (Li or Na ) in liquid ammonia or
amines with ethanol as proton donar,to give

mainaly unconjugated dihydroderivatives is
known as birch reduction.

General reaction:-

30. Mechanism:-

. ONHy . .

Li > U + efi,
solvated
electron

radical | I
anion

31. The Birch Reduction: Reduction of Benzene To 1,4 Cyclohexadiene

Bonds Bonds

H Formed Broken
O Na (or Li) "O c-H C-C (x)
NH; a c-H o-H
CH3CH20H H
Benzene 1,4-Cyclohexadiene on

+ NH; is the solvent
* The alcohol is the source of H
+ Conducted at temperatures from -80°C to -33°C

[-78° C is the temperature of the easily prepared acetone/dry-ice bath,
and -33°C is the boiling point of NH3]

32. Birch ER

R,
em orK
her.

Alkylbenzene 2-Alkyl-1,4- 3-Alkyl-1,4-
cyclohexadiene cyclohexadiene
(if R, isanelectron (if R, is an electron
donating group) withdrawing group)

33. Beckmann rearrangement

The acid-catalysed conversion of ketoximes to amides is
known as the Beckmann rearrangement

The Beckmann rearrangement, named after the German
chemist Ernst Otto Beckmann (1853-1923)

This rearrangement is occurs in both cyclic and acyclic
compounds .

Aldoximes are less reactive.
Cyclic oximes yield lactams and acyclic oximes yield amides

34. Beckmann rearrangement
Reagents:-
Conc.H,SO,, HCI, PCI, PCI,, SOCI,, ZnO, SiO,, PPA
(Poly phosphoric acid) etc., are commonly employed in
Beckmann rearrangement.

o NH¿OH yon Acid NH
A ed Ga” dés

Oxime Amide

35. Reaction mechanism

The first step in the process is formation of an oxime from the

aldehyde or ketone,

Formation of oxime
(similar to formation of imine)

Step 1: Addition Step 2: Proton Transfer

H
2 9 gio aa
H

a

Ketone

‚Step 3: Elimination a Step 4: Deprotonation
(of HO) e

2 20H
Ho, ou

FO

36. Migratory aptitude

The relative migratory aptitudes of different groups in Beckmann
rearrangement is illustrated below.

yon
H,SO, NCH,
cr m T faster
9 Anti isomer

OS NH,0H
HO,
pes Le Cr" slower

Syn isomer

37. Applications in drug synthesis:-

+ An alternative industrial synthesis method for Paracetamol.

It is involves direct acylation of phenol with acetic anhydride
catalyzed by HF, conversion of the ketone to a ketoxime

with hydroxylamine, followed by the acid-catalyzed Beckmann
rearrangement to give the amide

AGO 0 —NHLOH „OH
HF
HO.
SN

CF,COOH / SOCI, /

Y

°
Paracetamol

38. Applications in polymer synthesis:

* The Beckmann rearrangement is also used in
the synthesis of Nylon 6

OH
O N“ e)
NH,OH H,SO, yA
—> —

cyclohexanone cyclohexanoxime caprolactam

39. SCHMIDT REARRANGEMENT =

+ Carboxylic acids react with hydrazoic acid in presence of concentrated
sulphuric acid to give amine directly, the reaction is known as Schmidt
reaction.

* RCOOH+N3H H2S04 R-NH2 +CO2+ Na?
A ——Á

= Schmidt reaction also occurs between ketones or
aldehydes and hydrazoic acid.
RCHO + HN, = ES RCN + RNHCHO

ALDEHYDE CYANIDE N-formyl derivative of
amine

H,SO,
RCOR + Ne RCONHIRY N:
ketones amides

Ketones ——___ Substituted amides

Aldehydes 2 Niriles & N-formyl derivatives

40. * es @

Mechanism
Mechanism involves following steps:

1.elimination of nitrogen.

2.formation of intermediate.

3.intermediate undergo rearrangement to form isocyanate.
4-hydrolysis of isocyanate to form amine & co.

Transformation occurs more rapidly with out heating
with sterically hindered acids(mesitoic acid)

41. —H,0

A C 2 i
IL ou sie =n; =
Er Br
ISOCYANATE „ze
e
mo
——— HE + co

RATIO PRIMARY AMINE

42. he reaction with acids i.e.benzoic acid,which require heating for the removal
of nitrogen from acid azide proceed as below

43. NH

H’

-N2

AE

= 4

44. Y
q j

aldehyde
- HO
p 2 EE N; =>
| —_—_ IF R MOVES NN
NR

HR
" FORMYL DERIVATIVE OF PRIMARY AMINE 36

45. Claisen Rearrangement

of A on
EEE €
Pr =

à à

The aliphatic Claisen Rearrangement is a [3,3]-
sigmatropic rearrangement in which an allyl vinyl ether
is converted thermally to an unsaturated carbonyl
compound,

46. it
CH ae
H
| | ES
IF

Ul
O)

47. Examples of Claisen Condensation Reaction

A. General Claisen Condensation Reaction

1 1 of
2 CH—C—OCH, => CH—C—CH—C—OCH, + C,H,OH
Ethyl acetate B-keto ester Ethanol

B. Mixed Claisen Condensation Reaction | I

1 o O—C—CH—C—CH

| ; E
o—C—CH,+ CH c— och, 2, + En on
. B-keto ester Methanol

Phenyl acetate Methyl acetate

48. =0

49. | D CH;
UA
Acetophenone

Benzaldehyde

NaOH/KOH
|

A

SS

E

Chalcone

50. Mechanism:

= NS Be ‘5
R

a

- &|-9

—

D

O ©
|

Mechanism of the Cope Rearrangamant

>
|

$

Machanism of tha Claisen Rearrangement

51. Conditions:

OGenerally diphenyl ether is used as the

catalyst.

All Claisen Rearrangement reactions described to date
require temperatures of

>100if uncatalyzed.

52. Aromatic Claisen Rearrangement
Reaction

HCH

CH-ICH,
| © diphenyl ether
Allyl phenyl ether ally! phenol

> This reaction leads to the rearrangement of
allyl aryl ethers to allyl phenols.

53. Mechanism of Aromatic Claisen
Rearrangement

The aromatic Claisen Rearrangement is followed by a
rearomatization by enolisation.

54. Note:

When the ortho-position is — substituted,
rearomatization cannot take place. The allyl group
must first undergo a Cope Rearrangement to the
para-position before tautomerization is possible.

Pei

55. Example:

I

OH
A or
—,—,

Here the vinylic deuterium gets attached to benzylic
carbon in the product.