Stereochemistry of Oxime formation: Steps I

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Stereochemistry of Oxime formation Steps I II
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Aim

• Condensation Reaction.
• Synthesize of an Oxime.
• Beckman Rearrangement.
• 1. React the oxime with polyphosphoric acid.
• 2. Hydrolysis of the compound from the reaction
  of oxime and polyphosphoric acid.

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Oximes Introduction

• OXIMES, in organic chemistry, compounds
  containing the grouping C N-OH, derived from
  aldehydes and ketones by condensing them with
  hydroxylamine.

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Types of Oximes

• Two types of oximes are known
• Aldoxime combination of aldehydes with
  hydroxylamine.
• Ketoxime Combination of ketones with
  hydroxylamine.

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Physical Properties

• They were first prepared by V. Meyer in 1882.
• They are either colorless liquids, which boil
  without decomposition, or crystalline solids.
• BASIC (due to NITROGEN) and ACIDIC (due to
  HYDROXYL GROUP) in character.

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Chemical Properties

• On reduction by sodium amalgam in glacial acetic
  acid solution they yield PRIMARY AMINES.
• They are hydrolyzed by dilute mineral acids
  yielding hydroxylamine and the parent ALDEHYDES
  or KETONES.

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Chemical Properties

• The aldoximes are converted by the action of
  dehydrating agents into NITRILES.
• The ketoximes by the action of polyphosphoric
  acid undergo a peculiar intramolecular
  re-arrangement known as the BECKMAN REARRANGEMENT
  yielding as final products an acid-amide or
  anilide.

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Isomers

• If you use aldehydes or asymmetrical ketones,
  there is the possibility of getting TWO
  STEREOISOMERS of the oxime.

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Part I Procedure

• Make a solution of 1.8 g of hydroxyl amine
  hydrochloride and 1.8 g of sodium acetate in 8 mL
  of water.
• Take 3 gram of p bromoacetophenone in a 50 mL
  RB flask and add 10 mL of ethanol (95 ).
• Mix both solution and set up a refluxion
  apparatus.
• Reflux the mixture for 20 minutes.

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Part I Procedure

• Filter the hot solution using filter paper and
  funnel (do not use Buchner funnel).
• Once the mixture cooled to room temperature keep
  it on a ice bath for 10 minutes.

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Part I Procedure

• You will see a nice solid or crystals.
• Filter them using Buchner funnel.
• Wash the solid with little (may be 5 -10 mL) of
  50 ethanol.
• Find the melting point of the dry oxime.

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Possible Isomers

• p Acetophenone is an asymmetric ketone.
• Two possible products are

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Characterization

• Characterization of the Oxime by
• Melting Point.
• IR.

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Beckman Rearrangement

• It is an acid-catalyzed rearrangement of an oxime
  to an amide.
• Named after the German chemist Ernst Beckmann.

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Beckman Rearrangement

• Open Chain oxime gives an open chain amide.
• Cyclic oxime gives yields lactam.

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Beckman Rearrangement

• The Beckmann solution consists of acetic acid,
  hydrochloric acid and acetic anhydride, and was
  widely used to catalyze the rearrangement.
• Other acids, such as polyphosphoric acid,
  sulfuric acid or phosphorous pentachloride, can
  also be used.

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Beckman Rearrangement

• The Beckman rearrangement is known to be
  catalyzed by Cyanuric chloride and Zinc Chloride.

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Beckman Rearrangement

• The reaction mechanism of the Beckmann
  rearrangement is generally believed to consist
• 1. An alkyl migration (trans to OH) with
  expulsion of the hydroxyl group to form a
  nitrilium ion.
• 2. Followed by hydrolysis.

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Beckman Rearrangement
Anti group always migrates. No question of
migratory aptitude!
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Beckman Rearrangement
The OH is converted into a good leaving group by
reaction with PCl5. Phenyl migration expels the
leaving group, and hydrolysis generates the amide
product.
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Part II Procedure

• Take 20 mL of polyphosphoric acid in a 125 mL
  Erlenmeyer flask.
• Heat it for 10 minutes using steam bath.
• Add 2 gram of the oxime which you made once the
  acid is hot.
• Continue the heating for 20 more minutes using
  the steam bath.

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Part II Procedure

• Add the hot solution into a beaker contain 80 mL
  of ice water (take 40 mL of water and 40 gram of
  ice).
• Stir the mixture till all ice melts.
• Filter the solid using Buchner Funnel.
• Wash the solid using cold water until the
  filtrate is neutral (no longer acidic).
• Dry the solid using suction pump.

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Possible Product
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Characterization

• Melting Point.
• IR

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Substituents Effects in 1H NMR
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1H NMR

• Effects of Substituents
• 1. Proton NMR signal always shifts to upfield
  if the substituents are electron releasing.
• 2. Proton NMR signal always shifts to
  downfield if the substituents are electron
  withdrawing.

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1H NMR

• Effect of Substituents on benzene ring
• Ortho hydrogen's have low chemical shift value
  (upfield shift) if the substituents are Electron
  Releasing.
• Ortho hydrogen's have high chemical shift value
  (downfield shift) if the substituents are
  Electron Withdrawing.

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1H NMR

• Electron Releasing Group.
• 1. CH3
• 2. NH2 NMe2 (due to lone pair of electrons)

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1H NMR

• Electron Withdrawing Group.
• 1. COOH
• 2. NO2
• 3. CHO CO

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1H NMR

• P Toluidine
• Both CH3 and -NH2 groups are electron
  releasing!.
• NH2 is stronger electron releasing group than
  -CH3.
• So Ar-H, ortho to -NH2 will be having low
  chemical shift value.

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1H NMR

• P Acetotoluidide
• Both methyl group is an electron releasing!
• NH-CO-CH3 is an little electron withdrawing group
  compare to CH3 group due to CO attached to -NH.
• So Ar-H, ortho to CH3 will be having low chemical
  shift value.

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1H NMR

• P Acetoamidobenzoic acid
• -COOH group is an electron withdrawing group!
• NH-CO-CH3 is less electron withdrawing group than
  -COOH.
• So Ar-H, ortho to NH-CO-CH3 will be having low
  chemical shift value.

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1H NMR

• P Aminobenzoic acid
• NH2 group is an electron releasing group!
• -COOH is a strong electron withdrawing group!.
• So Ar-H, ortho to -NH2 will be having low
  chemical shift value and ortho to -COOH will be
  having high chemical shift value.

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Stereochemistry of Oxime formation Step III
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Aim

• To do an acid hydrolysis of an amide.
• Check the solubility of the final product.
• Find out what kind of Beckmann Rearrangement
  taken place in the last lab.

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Preparation of Amides

• Amides are prepared from amines by acylation
  with
• 1. Acyl chlorides R-CO-Cl.
• 2. Anhydrides (R-CO)2O See the 2 lab.
• 3. Esters R-CO-O-R.

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Preparation of Amides

• Amides can also be prepared from the Beckmann
  Rearrangement reaction.
• Its an acid catalyzed rearrangement of an oxime
  to an amide

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Preparation of Amides
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Hydrolysis of Amides

• Hydrolysis of amide means cleavage of amide bond
  i.e. NH CO bond.
• Two Types
• 1. Acid Hydrolysis
• 2. Basic Hydrolysis

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Acid Hydrolysis of Amides

• Hydrolysis of amides is irreversible. In acid
  solution the amine product is protonated to give
  an ammonium salt.

R'NH3


H2O
H


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Acid Hydrolysis of Amides
H2O

H2SO4heat
(88-90)
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Basic Hydrolysis of Amides

• In basic solution the carboxylic acid product is
  deprotonated to give a carboxylate ion.

R'NH2
HO

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Basic Hydrolysis of Amides
KOH

H2Oheat
(95)
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Acid Hydrolysis of Amides

• Acid-catalyzed amide hydrolysis proceeds via the
  customary two stages
• 1. Formation of tetrahedral intermediate.
• 2. Dissociation of tetrahedral intermediate

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Acid Hydrolysis of Amides Stage I

• 1. Since we only have a weak nucleophile and a
  poor electrophile we need to activate the amide.
  Protonation of the amide carbonyl makes it more
  electrophilic.
• 2. water adds to the carbonyl group of the amide
  and forms a active tetrahedral intermediate

H
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Acid Hydrolysis of Amides Stage II

Collapse of the tetrahedral intermediate into the
acid
H
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Step 1
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Step 1

• Carbonyl oxygen is protonated because cation
  produced is stabilized by electron delocalization
  (by resonance)

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Step 2
The water O functions as the nucleophile
attacking the electrophilic C in the CO, with
the electrons moving towards the Oxonium ion,
creating the tetrahedral intermediate
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Step 3
Deprotonate the oxygen that came from the water
molecule to neutralize the charge.
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Step 4
Need to make the -NH2 leave, but need to convert
it into a good leaving group first by
protonation.
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Step 5
Use the electrons of an adjacent oxygen to help
push out the leaving group, a neutral ammonia
molecule.
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Step 6

NH4

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Step 6
Resonance structure
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Step 6

Deprotonation of the oxonium ion reveals the
carbonyl in the carboxylic acid product and
regenerates the acid catalyst.
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Acid Hydrolysis of Amides

• We made these amides in the last lab.
• We need to characterize by 1H NMR.

From Phenyl migration
From Methyl migration
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Acid Hydrolysis of Amides

• The phenyl migrated amide gives following
  products after acid hydrolysis
• 1. P bromoaniline
• 2. Acetic Acid

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Acid Hydrolysis of Amides

• The Methyl migrated amide gives following
  products after acid hydrolysis
• 1. P bromobenzoic acid
• 2. Methylamine

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Characterization

• Solubility test will tell you what kind of
  hydrolyzed product you have obtained.
• Organic acids are soluble in aqueous basic
  solutions.
• e.g. Benzoic acid is soluble in aqueous NaOH
• Organic bases are soluble in aqueous acid
  solutions.
• e.g. Aniline is soluble in aqueous HCl

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Characterization

• If your final product (after the hydrolysis) is
  soluble in aqueous HCl then you have obtained
  phenyl migrated amide in the Beckmann
  Rearrangement reaction.
• If your final product is soluble in aqueous NaOH
  then you have obtained methyl migrated amide in
  the Beckmann Rearrangement reaction.

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Procedure

• Take 1 gram of the product from the Beckmann
  Rearrangement Reaction in a 50 mL RB flask.
• Add 6 mL of concentrated hydrochloric acid.
• Set up a refluxion apparatus with HCl trapper.
• Do the refluxion for 30 minutes.

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Procedure

• Add 5 mL distilled water and cool them using ice
  bath.
• Keep the solution in the hood and carefully pour
  this solution into an ice cold ammonia hydroxide
  solution (10 mL) in a 125 mL Erlenmeyer Flask.
• Swirl the flask when you do mixing.

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Procedure

• After sometime you will see nice crystals or
  solid.
• Filter them using Buchner Funnel.
• Wash the solid with cold water (may be with 10 mL
  of water).
• Dry the product as much as you can using suction
  filtration.
• Then do the solubility test.

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Caution!

• Concentrated hydrochloric acids and Concentrated
  ammonium hydroxides fumes are dangerous to
  health. Please do not inhale them.
• Always wear safety glass.