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University of Malaya
Organic Chemistry
Laboratory Manual
Level 3
Organic Chemistry
CONTENTS
Page
Introduction
3. Lactone Synthesis
10
12
5. Appendices
15
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SCES/P3120
INTRODUCTION
Laboratory Notebook:
One laboratory notebook or jotter (e.g. inexpensive exercise book ) is required for recording
all primary experimental data. All reaction products must be submitted.
Course Content
The Course is designed so that on completion you should know of the following:
(a) How to separate and identify organic compounds by classical and spectrophotometric
techniques and chromatographic techniques including LC and TLC
(b) How to do routine operations e.g. crystallization, distillation, sublimation, vacuum
distillation, and extractions.
(c) How to synthesize compounds and study reaction mechanisms
The following is an approximate guide as to how you should spend your time in the lab.
1. Two organic synthesis experiments
50% Credit
50% Credit
This is a final Year Organic chemistry course and you are expected to do most of the
laboratory operations on your own. As a matter of routine you may have to perform
recrystallizations, distillations, extractions, steam distillation, vacuum distillation and other
things learnt during the earlier years. You have no excuse if you do not know them. If you are
unsure or have forgotten refer back to your manuals or texts. You are also reminded not to
neglect safety precautions (e.g. in anticipation of fire hazards, in handling corrosive
chemicals,
recovery/disposal
of
solvents,
in
handling
toxic/carcinogenic/explosive
chemicals). As a matter of good personal habits expected of a potential UM graduate you are
to be tidy, save on chemicals and handle equipment or glassware with intelligence and care.
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Experiment 1
CONVERSION OF CHOLESTEROL TO CHOLESTENONE
Preparation of 5-cholesten-3-one and 4-cholesten-3-one from cholesterol use of a
protecting group in organic synthesis
In an attempt to oxidize cholesterol (I) to the corresponding ketone 5-cholesten-3one (II), it was found (L. F. Fieser, J. Am. Chem. Soc., 1953, 75, 4377, 4386) that it was not
possible to obtain pure 5-cholesten-3-one. Due to the presence of a double bond , - to the
alcohol group, an array of products were obtained:
HO
O
(I)
HO
(II)
HOOC
HOOC
HO
O
O
To avoid this difficulty it is necessary to temporarily remove the double bond and to
regenerate it after oxidation. This is carried out by adding bromine across the double bond,
and later debrominating using zinc (Note: modern reagents for carrying out the oxidation
directly without affecting the double bond include PCC, TPAP/NMO, and (COCl)2/DMSO;
Et3N or the Swern oxidation).
Br2
HO
Na2Cr2O7
HO
Br
O
Br
(III)
Zn
Br
Br
(IV)
(CO2H)2
O
O
(II)
(V)
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Procedure
suction filtration and wash with a small amount of glacial acetic acid.
CrO3.2(C5H5N))
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Question:
1.
Calculate the max for the compounds I V. Compare the IR and NMR
spectra for both ketones (II) and (V).
2.
Write mechanisms for the transformations that you have carried out.
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Experiment 2
WITTIG REACTION
THE SYNTHESIS OF 3-PHENYLPROPENOIC ACID
Background
The Wittig reaction is used to convert the carbonyl group of aldehydes and ketones
into an alkene group. This reaction is named after Georg Wittig who won the Nobel
Prize for the reaction in 1979. In a typical Wittig reaction, triphenylphosphine (1)
reacts with an alkyl halide (2) to first form a phosphonium halide (3). Subsequently,
addition of a strong base eliminates the hydrogen halide to form an ylide,
alkylidenephosphorane (4) (Scheme 1).
Scheme 1
Base
Ph3P:
(1)
R'H2C
(2)
Ph3P
X
CH2R'
Ph3P
CHR'
Ph3P
CHR'
(3)
(4)
The carbon of the ylide acts as a nucleophile and adds to the carbonyl group (5) to
form a betaine intermediate which undergo an in situ 1,2-elimination to give the
triphenylphosphine oxide (6) and an alkene (7) as the product (Scheme 2).
Scheme 2
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CHR'
Ph 3 P
R'HC
O
R''
(4)
R''
(5)
R
CHR'
Ph 3 P
R''
(7)
(8)
This experiment illustrates the general procedure with the preparation of (E)-3phenylprop-2-enoate (10) from the reaction of the ylide, methyltriphenylphosphoranylethanoate (9) and benzaldehyde. The ester which is formed (10) is then
hydrolyzed with base and 3-phenylpropenoic acid (11) is then isolated as crystalline
solids (Scheme 3).
Scheme 3
Br
Br
CO2Me
Ph3P
CO2Me
Ph3P
CO2Me
(9)
(8)
Ph3P
(9)
Ph
CO2Me
Ph
(10)
CO2Me
CO2H
Ph
(11)
Procedure
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(II)
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Method 2:
Add dichloromethane (10 mL) to benzaldehyde (1g, 0.0094 mol) in a roundbottomed flask. Loosely stopper the flask, place it in an ice bath, and stir for at
least ten minutes. After this time, slowly stir the crude product (4) (3 g, 0.0089
mol) and continue to stir in the ice bath for an additional ten minutes. Then
allow the solution to warm up to room temperature while continuing to stir.
Retrieve the stir bar from the flask and remove the solvent from the reaction
mixture using a rotary evaporator. Add hexane (20 mL) to the residue in the
flask and gently stir with a glass rod. The product ester is soluble in hexane
but the triphenylphosphine oxide is not. Vacuum filter the solution using
another 20 mL hexane to rinse the flask. Transfer the filtrate to another dry
and clean round-bottomed flask. Remove hexane using a rotary evaporator.
Weigh and record the melting point of the product. Characterize the product
using UV and IR.
Notes:
1. Methyl bromoethanoate is a lachrymator. Please use the fume-cupboard to weigh.
2. More precipitate could be obtained if the filtrate is kept overnight.
3. Distilling of about 50 mL solution is sufficient to remove any volatile compound
from the reaction mixture.
QUESTIONS
1. What is the structure of the triphenylphosphoranyl ethanoate (4)?
2. Write a mechanism for formation of (E)-3-phenylpropenoic acid.
3. What is the limiting reagent in the above Wittig reaction above?
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Me3CCOCH3
OH
Zn/C6H6
BrCH2CO2Me
Reformatsky
Me3C C CH2CO2Me
CH3
O
50% H2SO4
O
Me3C
Procedure
Preparation of Methyl-3-hydroxy-3,4,4-trimethylpentanoate
Weigh 8g of granulated zinc into a 250 mL 3-necked flask with two necks closed by
stoppers. Add 25 mL of bench dilute sulphuric acid to the zinc, and allow the steady reaction
to proceed for 5 min by which time the metal surface should appear bright. Then, decant off
the acid and wash the metal successively with water (2 x 10 mL) followed by a good grade of
acetone (1 x 10 mL). After decanting off as much solvent as possible, add 30 mL of benzene,
fit the flask for downward distillation and distil to a final volume of approximately 5 mL.
While the flask remains warm, fit it with a mechanical stirrer, a reflux condenser and
dropping funnel (Note 1), and place in the dropping funnel a mixture of pinacolone (10g),
methyl bromoacetate (15.4g) in dry (Note 2) benzene (50 mL). Run in 10 mL of this solution,
and observe carefully for the reaction to begin (Note 3). After the reaction has started, the
remainder of the solution should be added at a rate to maintain gentle reflux ( cf. Grignard
Reaction, Level II Practical ). When addition is complete, reflux the reaction until almost all
the zinc has disappeared (2 3 hr). Then, cool the flask in an ice bath, and with stirring, add
enough 10% H2SO4 to dissolve the Zn(OH)2.
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Notes
1. All apparatus used in this step must be thoroughly oven dried before use, and
assembled while warm. Wet apparatus will result in poor yields.
2. Dried with molecular sieves or sodium
3. Gentle warming may be required. Do not add any further reagent until the reaction
has begun.
Questions
1. Based on the spectra obtained, assign a reasonable structure to the product, and
propose a mechanism for its formation ( Hint : acid catalysed rearrangement ).
2. What is the purpose of distilling benzene from the zinc before starting the
Reformatsky reaction ?
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Solubility Differences
This involves extraction and is probably the easiest way but it is unlikely that one
encounters such a simple mixture. One component can be extracted into a solvent, the
other component being insoluble. This component can then be isolated by distillation
or evaporation of solvent. Normally solvent with wide differences in polarity are tried
first, e.g. water and petroleum ether. Some examples where this method will work are
sucrose/naphthalene, acetamide/ diphenyl and glycine hydrochloride/benzophenone,
where contrasting differences in polarity of the components exist.
(b)
Chemical Differences
A derivative is made and this is separated from the other components by precipitation
or extraction.* The usual type of derivative is formation of a salt, e.g. if given an
acidic/neutral mixture insoluble in water, the acidic component can be extracted into
aqueous basic solution. Similary, a phenol/neutral mixture can be treated in the same
way as most phenols are sufficiently acidic to be extracted into aqueous sodium
hydroxide. For a basic/neutral mixture, extraction into aqueous acid will effect a
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* Caution:
( d)
Recrystallization
Often one component can easily be obtained from a mixture by a suitable choice of
solvents for recrystallization
(e)
Chromatography Methods.
Generally TLC, LC, GLC and other chromatographic methods are extremely effective
separation methods but they can be long and tedious and furthermore are limited to
small scale work involving less than 1g. unless appropriate facilities are available.
The above methods should only serve as a guide as there can be no hard and fast
rules. Usually, methods (b) and (c) would be suitable. Note also that many problems
could arise in the process of recovering the separated components (refer text). In
principle, all the given amounts should be recoverable unless they are accidently
thrown away or are extremely volatile. It may be wise to try a small scale separation
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References:
1. Shriner, Hermann, Morrill, Curtin, and Fuson, The Systematic Identification of
Organic Compounds (Wiley).
2. Furniss, Hannaford, Smith, and Tatchell, Vogels Textbook of Practical Organic
Chemsitry (Longman).
3. Williams and Fleming, Spectroscopic Methods in Organic Chemistry (McGraw-Hill).
4. Silverstein and Webster, Spectrometric Identification of Organic Compounds (Wiley).
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Appendix 1
CHROMATOGRAPHY
The various types of chromatography is summarized in the Diagram below.
Chromatography
Liquid
Chromatography
Gas
chromatography
Gas Liquid
Chromatography
GLC
Gas Solid
chromatography
Ion
exchange
Exclusion
Gel permeation
Gel filtration
Liquid/ solid
Liquid/ liquid
chromatography chromatography
LSC
LLC
Thin layer
TLC
Paper PC
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Abbreviation
LSC
Predominant Mechanism
Adsorption of Surface
Liquid liquid
LLC
Bonded Phase
BPC
Reverse Phase
RPC
Ion Exchange
None
Steric
Exclusion
None
Partition and / or
adsorption
Paritition and / or
adsorption
Adsorption on Fixed Ionic
Site
Diffusion into Pores
Common Names
Adsortion chromatography, liquid solid
chromatography,
linear elution
adsorption
chromatography
Partition chromato
graphy, Sorption
chromatography
Gel chromatography
Sorption
chromatography
Cation or Anion
Exchange
Gel permeation (GPC)
,molecular exclusion,
gel filtration ( GFC )
Chemical
Structure
( SiO2 )x
( Al2 O3 )x
Estimated
Usage %
70
20
1
Magnesia
Silica
Coprecipitate
Slightly acidic
Silightly basic *
Graphitized
nonpolar , Oxidized
Polar (silightly basic)
Strongly acidic
Polyamides
Basic
Others ( clay,
Kieselguhr,
diatomaceous
earth, Celite )
Relatively nonpolar
Silica
Alumina
Charcoal
Florisil
Surface Properties
Application
General purpose
General purpose
Sample cleanup
General purpose
adsorbent
Phenols and
aromatic nitro
compounds
Very polar
compounds
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Caution:
Read & understand the instrument first. Consult lecturer & lab. Assistant in charge.
Handle microsyringe with loving care.
The mixture to be separated is introduced onto the adsorbent at the top of the column
in solution form. The two components will be adsorbed to different extents depending
upon the polarity of the molecules. The eluant is introduced and allowed to flow
down the column. The components of the mixture will undergo many adsorption
desorption processes as they pass down, the least polar molecule moving more
quickly.
Compound Elution Sequences*
Hydrocarbons
Olefins
Ethers
Halogen Compounds
Aromatics
Ketones
Aldehydes
EstersAlcohol, amines, mercaptans
Acid and strong bases.
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Eluotropic Series*
Petroleum ether
Cyclohexane
Carbon tetrachloride
Benzene
Methylene chloride
Chloroform (alcohol free)
Diethyl ether
Ethyl acetate
Pyridine
Methanol
Acetone
n- Propanol
Ethanol
Acetic Acid
Increasing Polarity
The type of adsorbent chosen also effects the speed at which the compounds are
eluted. The more active the adsorbent the more slowly the compounds will move
down the column.
Silica-gel and alumina are the most common adsorbents. For T.L.C. those are
usually combined with Plaster of Paris which acts as a binding agent.
If the components are colourless they can be detected by various means, eg using
U.V. light, iodine vapour or charring with sulphuric acid.
The great advantage of T.L.C. is its short development time, usually of the order
of 30 mins.
After separation the components & carrier gas pass through a detector which
indicates when a compound is being eluted by drawing a curve on chart paper. The
area under the curve can be considered to be proportional to the number of moles
eluted.
The compounds can be characterized by their Retention Times i.e. the time taken
from being injected to being eluted under set conditions.
The solution is filtered through a fluted filter paper under gravity. While filtering
this crystals may be deposited. This can be avoided by (a) Warning the funnel and
receiving conical flask. (b) Having prepared a hot saturated solution, adding more
solvent, filtering and evaporating until the original volume is obtained.
From Mixed Solvents The two solvents must be miscible and are chosen such that
the compound is soluble in solvent I and insoluble or appreciably less soluble in
solvent II. A hot solution is prepared in solvent I. After filtering solvent II is added
dropwise until the solution just turns cloudy. On cooling crystals are formed.
Choosing a solvent A suitable solvent is found by trial and error, and this should be
conducted on a small scale. The aim is to find a solvent or combination of solvents in
which the solute is soluble at high temperatures and much less soluble at room
temperature.
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See Renfrow Hawkins, Organic Chemistry Laboratory Operations p 13, 147 Louis
F. Fieser, Organic Experiment p.30
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See: Renfow Hawkins, Organic Chemistry Laboratory Operation, m.s. 13, 147
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The pressure at which the liquid boils is measured by a manometer. The most
common type is a closed-end monometer.
The pressure in the closed arm is zero. This manometer is kept closed off from the
system as solvent vapour can dissolve in the mercury. Then the pressure in the closed
arm will no longer be zero, resulting in an uncorrect reading. This type of manometer
is accurate up to a few millimeters of mercury.
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Appendix 6
I.R
IR samples All samples must be DRY. Test first to ensure that your sample is NOT
water or in an aqueous solution. Water will dissolve away the NaCl cells which are
rather expensive (RM 600) . Solids can be dried in a vacuum dessicator.
Liquids can be used neat between NaCl plates. Solids can be micro-pelleted with
KBR.
Liquids and solids if soluble in CCl4 or CS2 can be used in solution cells. Spectral
grade CHCl3 may be used for less soluble compounds. Note the bands cut off when
solvents are used.
Solids can be mulled in Nujol but note the bands cut off by Nujol ( hydrocarbon
oil )
If you get poor spectra go to the instrument room and instruct the lab. assistant as
to your requirements.
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