Name…………………………………….
SCHOOL OF CHEMISTRY
CH3621
Organic Chemistry
Laboratory
LABORATORY MANUAL
2023
MODULE CH3621:
JUNIOR HONOURS
ORGANIC LABORATORY COURSE
ORGANISATION .........................................................................................................2
EXPERIMENT TRACKS .............................................................................................2
EQUALITY, DIVERSITY and INCLUSION ..................................................................3
HEALTH AND SAFETY IN UNDERGRADUATE LABORATORIES ............................4
RISK ASSESSMENTS .............................................................................................. 10
LABORATORY HOUSEKEEPING ............................................................................ 10
ADVANCED TECHNIQUES ...................................................................................... 11
INERT GAS METHODS ............................................................................................ 11
THIN LAYER CHROMATOGRAPHY (t.l.c.) .............................................................. 13
FLASH CHROMATOGRAPHY .................................................................................. 16
DISTILLATION UNDER REDUCED PRESSURE USING A “VIGREUX” MODIFIED
CLAISEN FLASK....................................................................................................... 18
TRACK A EXPERIMENTS ........................................................................................ 19
TRACK B EXPERIMENTS ........................................................................................ 28
TRACK C EXPERIMENTS ........................................................................................ 39
PLANNING TASK...................................................................................................... 49
1
ORGANISATION
The course lasts for a total of 42 hours laboratory time, spread over a six-week period.
In addition, there will be options to attend the lab to perform analytical tasks (such as
preparing NMR samples, obtaining IR spectra, acquiring melting points etc) on days
you are not scheduled to be conducting synthetic work.
During the course each student should complete 2 experiments, AND an
experiment that involves experimental planning.
In order to successfully complete the course, you will need to make efficient use of the
available hours in the laboratory.
Trying to finish the course in a rush during the final two weeks will NOT work.
If you have any questions or doubts, please discuss these with a member of
academic staff.
EXPERIMENT TRACKS
You will be assigned a “track” with a set of numbered experiments to complete (see
List of Experiments). You will only be assigned one track (A, B, or C) and must only
complete the experiments allocated to that track.
The tracks are listed below. Please note, you should plan your time carefully, for
example don’t start a reaction involving a 2 hour stirring period when it is already 1100.
Track A
Track B
Track C
Report 1
A1
B1
C1
Report 2
A2
B2
C2
Interview
Planning
Task (A3)
Planning
Task (B3)
Planning
Task (C3)
Experimental deadlines and submission instructions are outlined
on the course Moodle page.
2
EQUALITY, DIVERSITY and INCLUSION
The University and School of Chemistry are committed to supporting equality
and diversity in all aspects of its activity. Everyone has the right to study and
work in a supportive, tolerant environment free from discrimination and
harassment, regardless of gender, race, religion, disability, ethnicity or sexual
identity/orientation. To support us in this, if you are subject to, or witness,
discrimination or harassment of any kind, please make this known to us. This
can be through a member of Chemistry staff (your advisor of studies, tutor or
any other member of staff); alternatively, you can raise the issue with student
services.
3
HEALTH AND SAFETY IN UNDERGRADUATE
LABORATORIES
1. General
All work in the school of chemistry is covered by the Health and Safety at Work etc.
Act 1974 (http://www.hse.gov.uk/legislation/hswa.htm). The school's safety policy and
regulations are described in detail in the school safety handbook, available for
consultation on the school of chemistry web site. Select the “Intranet” tab and then the
“Health & Safety” menu https://chemhealthandsafety.wp.st-andrews.ac.uk/
2. Evacuation Procedure
The building is equipped with an automatic alarm system activated by automatic
sensors and break-glass units. When the alarm sounds (continuous siren) immediate
evacuation of the building is called for.
When the alarm sounds
(a)
Shut off gas burners and electrical heaters (lower lab jacks if in use). Make safe
other equipment where this can be done quickly and without personal risk.
(b)
Leave the building immediately by the nearest Fire Exit, and proceed to the
grass verge at the front door of the Gateway Building
(c)
DO NOT:
• stop to collect coats, bags and other personal belongings
• use lifts
• run (except in a life-threatening situation)
• enter a smoke-filled stairwell (use alternative exit)
• re-enter the building until told to do so by the academic in charge
(d)
•
•
DO:
close doors behind you.
Stay with the academic in charge of the laboratory session at the assembly point
in the event of an evacuation.
Note: In order to test the alarm system, the fire alarm may sound for up to 10 seconds
at 12:55 each Wednesday. In this case, do not leave unless the alarm sounds for
more than 10 seconds. At all other times, leave immediately.
3. Appropriate Clothing and Personal Protection Equipment (PPE)
It is important to be aware that PPE does not completely eliminate the hazards
encountered in a laboratory environment.
3.1. Appropriate and Inappropriate Clothing
In the laboratory you should wear clothing that fully covers your arms and legs and
good stout shoes should also be worn. Sandals or open shoes (even with socks),
shorts, skirts, tights or dresses are NOT appropriate since the skin could be
exposed to corrosive and/or toxic chemicals and could be exposed to broken glass.
Long hair should be tied back to avoid contact with open flames, chemical spillages or
becoming entangled in moving parts of machinery.
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3.2. Eye Protection
The Personal Protective Equipment at Work Regulations (1992) place a statutory
requirement on the School to ensure that all persons within its precincts have their
eyes adequately protected. In the undergraduate laboratories, the wearing of eye
protection is mandatory at all times. Persons who normally wear eyeglasses must
also wear safety glasses over their glasses or have prescription safety glasses. Normal
spectacles do not provide appropriate splash and impact protection.
The wearing of contact lenses is not banned in the laboratory however it is strongly
discouraged. This is because any chemical in vapour or liquid form entering the eye
may penetrate behind the lens and be difficult to wash out. First-aid workers must be
aware of any contact lens wearers so that they can take appropriate action in an
emergency. If you intend to wear contact lenses in the laboratory at any time,
you must inform the lab management such that your name is added the list at
the beginning of the session.
3.3. Laboratory Coats
Laboratory coats provide protection for the wearer from contamination by the
chemicals encountered in the teaching laboratory. In the undergraduate
laboratories, the wearing of laboratory coats is mandatory at all times. The
wearing of laboratory coats in areas outwith the laboratory (in the computer “wedge”
area outside the laboratory for example) lecture theatres the library or and social
spaces, i.e. cafeteria or chemistry common room in the Purdie building is forbidden.
They should be taken off when leaving the laboratory and stored in a locker.
3.4. Gloves
The laboratory environment can present a variety of hazards that may necessitate the
use of gloves, examples include: handling corrosives, toxic materials, solvents that can
be absorbed rapidly through the skin, certain sharp materials and very cold/very hot
objects.
No single type of glove is suitable for all eventualities, however in many teaching
laboratory situations nitrile or vinyl gloves are sufficient. The risk assessment or
laboratory manual procedure (if appropriate) will direct the user to the appropriate
glove for a particular operation. Full details for chemical compatibilities of different
types of gloves are usually available from the manufacturer.
It SHOULD NOT be assumed that gloves provide an impervious barrier and continuous
use of a single pair of gloves can result in chemical exposure without the user being
aware (this is particularly the case with substances with long breakthrough times/slow
rates of permeation). The wearer should be aware that cross-contamination to other
objects (such as doors, laboratory manuals, computer keyboards etc.) can occur by
inappropriate use of gloves. Gloves should be removed and replaced when they
become contaminated. Gloves that have been contaminated MUST be made safe
before disposal. Misuse of gloves could harm you or other workers in the
laboratory. While they provide a degree of protection for the wearer,
careless/inappropriate use of gloves may increase the likelihood of accidental
exposure of other people in the vicinity to substances in use.
Allergies to Glove Materials – It is not uncommon to be allergic to certain glove
materials, latex being perhaps the most common. If you have a known allergy to glove
materials, you should notify a member of staff before proceeding with any laboratory
work that requires hand protection.
5
Any person that refuses to follow the PPE regime outlined will be
excluded from the laboratory and could be awarded a mark of 0 for
failing to complete the relevant experiment. The person(s) involved
will be sent to discuss the situation with the School Safety
Coordinator and/or the Head of School.
3.5. Use of Electronic Devices
This guidance applies to mobile phones and other portable electronic devices such as
tablets and laptops. The pervasive use of smart phones and other portable electronic
devices in the teaching labs may present a hazard, not only for the owner of the device,
but for others in the work area. These following guidelines must be observed.
Uses of electronic devices permitted within the School of Chemistry teaching
labs:
• Use as a calculator.
• Use as a timer.
• Used to search suitable internet sources for information e.g., NOMAD, Moodle. Use
of social media, mobile games etc. is strictly forbidden.
• Use as a camera for taking photos of reaction set ups, products etc. for use in lab
reports. You are not permitted to take photos of any person without obtaining their
permission.
• Any other safe/appropriate use agreed with the supervisor in charge of the relevant
laboratory class.
Contamination:
In all Chemistry labs the risk of contamination must be carefully considered. Phones
and devices may be taken into the lab area, but must not be:
• Handled with gloved hands, potentially contaminated hands.
• Placed within a fume cupboard.
• Placed on contaminated bench surfaces.
You must ensure the bench surface is CLEAN before you place your belongings on it.
On no account must phones or devices be handled if there is any possibility of
contamination. It is often difficult to tell whether gloves are contaminated, and hence
this should always be assumed.
Phones are often held near the mouth and eyes, which are more susceptible to
infection or damage following contamination with chemical agents. Having to take
gloves off repeatedly to use mobile devices potentially increases the likelihood of a
lapse in concentration that would allow skin to come in contact with contaminants on
the gloves.
Distraction:
Mobile phones can be a severe distraction, which is why it is illegal to use a handheld
mobile when driving. They may also distract people, which may result in an accident
during a safety critical process. Phones must be turned to silent if kept on one’s person.
Fire risk:
Portable electronic devices contain Li-ion batteries. These batteries contain no free
lithium metal but do contain lithium ions and highly flammable electrolytes. Devices
should be kept well away from sources of ignition or equipment that may risk damaging
the integrity of the battery. Devices may NOT be charged in the teaching labs unless
the charger and device itself has been PAT tested by the University.
6
Listening to music through earbuds/headphones:
Portable music devices (mp3 players, iPods etc.) are strictly forbidden from use in the
teaching labs as per the guidance in the School of Chemistry Safety Handbook as they
are a significant source of distraction. Using your mobile electronic device to listen to
music is also forbidden.
4. Chemical Hazards
The toxicological properties of many chemicals used in the School of Chemistry have
not been fully investigated. All chemicals should be treated as potentially hazardous.
As required by the Control of Substances Hazardous to Health (COSHH) Regulations
(2002), the degree of hazard associated with each substance in use in the
undergraduate laboratories has been assessed.
The result of the Hazard Assessment is expressed as a hazard rating according to the
following five-point scale:
5 = highly hazardous
3 = moderate hazard
1 = no significant hazard
4 = hazardous
2 = low hazard
The nature of the hazard(s) involved is also indicated by adding letters as follows:
A = corrosive or irritant
F = flammable
O = oxidising agent
R = radioactive
X = explosive
C = carcinogenic
M = mutagenic
P = prohibited
T = toxic
All containers of chemicals are marked with the hazard assessment code. All students
must note the hazard rating of each substance they are to use and take the appropriate
precautions.
As required by the Control of Substances Hazardous to Health Regulations (1999) and
the Management of Health and Safety at Work Regulations (1992), a written risk
assessment has been carried out for each experiment and is available for consultation
in the laboratory. Students should always consult the risk assessment before beginning
an experiment, although special precautions needed for individual experiments are
described in the Laboratory Manual. Always read the procedure carefully, and if you
are in any doubt consult a demonstrator.
It is forbidden to carry out any unauthorized experiment. It is
forbidden to remove any chemical substance, sample, or item of
equipment from the laboratories. Any student found doing this will
be subject to severe penalties up to and including exclusion from the
University.
5. Accidents
If an accident occurs in the laboratory inform the Laboratory Supervisor or a
demonstrator immediately so that the necessary action can be taken.
7
6. Waste Disposal
Due to health, safety, environmental and legal concerns it is essential that laboratory
waste is properly segregated and disposed of. School policy is laid down in the
Health & Safety booklet available on the web site. Practices applying to the smallscale work in the teaching laboratory are outlined below and specific disposal
instructions accompany many experiments and procedures but, if at any time you are
in any doubt, please consult a member of the laboratory staff for advice.
6.1. Glass and ceramics
ALL waste glass and ceramics must be decontaminated and deposited in the specially
marked waste glass bins. NOTE IN PARTICULAR that pipettes, melting point tubes,
broken glass or ceramics MUST NOT be left on the bench or in any sink or waste bin.
6.2. Sharps
A plastic container is provided in the preparation room for disposal of non-glass sharps,
such as needles and knife blades.
6.3. General waste
Decontaminated harmless general waste can go in the plastic bins provided for
ordinary refuse collection. The following materials may typically be disposed of in this
way: Aluminium foil, cotton wool, glass wool, paper, plastics, and rubber.
6.4. Chemical spillages
You MUST attend to your spillages promptly.
As well as damaging the work surfaces and expensive instrumentation (notably
balances!) unidentifiable heaps and puddles left by you are an extraordinary health
and disposal problem for other people. Only you know what you've spilled, only you
can arrange appropriate disposal.
6.5. Powders
A “controlled waste” container for DRY, DECONTAMINATED low-hazard powders is
provided in the overnight fume cupboard. This is for powders only and is not for
disposal of filter papers or cotton wool. NO chemical waste or powder (e.g. samples,
chromatography supports, filter aid, charcoal, clay) is to be disposed of in the
general waste bins.
6.6. Inorganic chemical waste
Low-hazard water-soluble waste such as acids, alkalis, and decontaminated drying
agents (CaCl2, MgSO4, K2CO3, Na2SO4) can be flushed down a sink with plenty of
water. Low to moderate-hazard insoluble inorganic waste (e.g. alumina, silica,
charcoal, Celite/Hyflo, BaSO4, soda-lime) must be deposited in the controlled waste
container. Toxic waste must be deposited in the appropriate labelled container.
6.7. Organic chemical waste
NOTE: This includes organic samples and solvents but NOT solutions of organic
compounds in water.
ORGANIC SOLVENTS MUST NEVER BE POURED DOWN THE SINK!!!
8
Separate containers are provided for halogenated and non-halogenated
ORGANIC waste. This is ultimately disposed of by combustion, when it is important
that acid forming waste (halogenated) is treated separately. A dangerous reaction may
occur if the two types are mixed or become contaminated with oxidising agents, strong
acids, strong bases, or metal compounds. If you have a mixture, neutralise, if
necessary, then recover, for disposal, the organic portion by distillation (rotary
evaporator) or extraction, disposing of the inorganic fraction separately.
ORGANIC phosphorus and sulfur compounds also form acids on combustion and are
disposed of with the halogenated ORGANIC waste. This waste bottle is kept in a fume
cupboard, as it is also used for the disposal of malodorous compounds such as
pyridines and amines.
The following must NOT be put into these waste bottles:
INORGANIC halides, e.g. bromine, calcium chloride, hydrochloric acid, iodine,
phosphorus chlorides, potassium bromide, sodium chloride, thionyl chloride.
Halogens, reactive non-metal halides and organic acid chlorides must be cautiously
hydrolysed and/or neutralised (consult a demonstrator) then flushed down the sink with
plenty of water.
Any person that refuses to follow the disposal procedures outlined
could be excluded from the laboratory and could be awarded a mark
of 0 for failing to complete the relevant experiment. The person(s)
involved will be sent to discuss the situation with the School Safety
Coordinator and/or the Head of School.
7. New and Expectant Mothers
Under the Management of Health and Safety at Work (Amendment) Regulations 1994,
relating to new and expectant mothers, a special assessment has to be carried out in
respect of the work activities of any new or expectant mother. Any student who
becomes pregnant or has had a baby in the last 6 months should inform the Laboratory
Supervisor in confidence as soon as possible so that the required assessment can be
carried out.
Dr K. Jones
Environmental Health and Safety Manager
September 2023
Prof. C. J. Baddeley
Head of School of Chemistry
September 2023
9
RISK ASSESSMENTS
For each experiment, a full risk assessment must be carried out as required under the
School of Chemistry Safety regulations and the COSHH legislation. The risk
assessment sheets have been generated using the University CHARM system and are
available on the CH3621 Moodle page. Before attempting an experiment you MUST
download and read the CHARM form and then complete the Moodle quiz by clicking “I
agree” to confirm you have read and understood the risk assessment. It is your
responsibility to ensure this is done BEFORE starting any experimental work.
In certain experiments, you will also have to complete a short safety quiz based on the
information provided by the supplier MSDS (material safety data sheet) for particular
reagents.
The school laboratory safety regulations state clearly “It is forbidden
to carry out any unauthorized experiment”. Attempting an
experiment without completing the relevant risk assessment will be
considered as an “unauthorised experiment”. In this case, 0 marks
will be awarded and persons concerned will discuss the situation
with the Head of School and Safety Coordinator.
LABORATORY HOUSEKEEPING
It is essential that the fume cupboards are kept tidy, so each student will be assigned
a numbered fume cupboard and must carry out all their work therein.
Apart from designated areas for overnight experiments, all fume cupboards must be
cleaned and cleared of equipment at the end of each laboratory session.
10
ADVANCED TECHNIQUES
• Discussion of general techniques that will also be relevant can be
found in the 2nd year techniques manual.
• Online films for all the advanced techniques discussed below are
available (see course Moodle page).
INERT GAS METHODS
Many reactions need to be conducted under an inert atmosphere, usually nitrogen or
argon are used. Even when the solid starting materials and products are air-stable it is
quite often the case that in solution they (or the intermediates in the reaction) are
oxygen and/or water sensitive, especially if the reaction is conducted at high
temperature. Also, oxygen is much more soluble in organic solvents than in water.
Nitrogen flow
Nitrogen flow is normally used for protection during the actual reaction, most often
during heating under reflux. It is best arranged by having a minibubbler (figure 1.1)
filled with paraffin oil placed at the top of the condenser in a flyover fashion. The design
of the minibubbler prevents any suckback of oil (but not air) if used correctly.
Minibubblers are kept in a cupboard beside the Drechsel bottles cupboard, below the
fume hoods at the end of the lab.
Figure 1.1 – Minibubbler for apparatus under inert atmosphere
An alternative (less preferable) is to use clamped Drechsel bottles containing a little
liquid paraffin (about 6 cm deep). One should be placed between the nitrogen supply
and the apparatus to monitor the flow of gas into the apparatus and a further similar
bottle on the outlet side of the apparatus. The outlet bubbler monitors not just the gas
going in but also the evolution of gas from the reaction, as a result of the latter the
paraffin often gets dirtier than the paraffin in the inlet bubbler. Strictly, only one bubbler
is necessary and sometimes the inlet bubbler is dispensed with. Since suck-back of oil
can occur on the outlet, it is recommended that two bubblers are used back-to-back
with an empty one closer to the apparatus (see figure 1.2). During a reflux, it is often
11
undesirable to have a flow of nitrogen from the reaction flask up the condenser, as
solvent is evaporated rapidly. Therefore a T-piece arrangement (with nitrogen flow at
the top of the condenser) is used with Drechsel bottles.
Figure 1.2 – Drechsel bottle outlet
Starting nitrogen flow
Set up your apparatus with a condenser and minibubbler. Degas (“bubble”) the solvent
in your reaction flask for 5 mins via a disposable pipette placed in a screwcap
(thermometer) adapter. The gas is vented via minibubbler. Once the apparatus and
solvent have been initially flushed out with nitrogen, stopper the side neck and
reconnect the nitrogen tubing to set a flow rate of ca. 1 bubble per second through the
minibubbler. When it is desirable to flush out a gaseous product from a reaction, set a
higher flow rate. Clamp the Drechsel bottles (if used) and do not use too great a length
of rubber tubing, i.e. try to keep the set-up reasonably tidy. To seal the glass joints use
PTFE sleeves (in your kit) throughout. If solids require to be added to a reaction running
under nitrogen, turn up the gas flow somewhat, then add the solid using powder funnel
through a spare neck of the reaction flask, quickly replace the stopper, and then reduce
the gas flow back to its previous value. Remember to increase the flow of nitrogen
when switching off heating the reaction mixture under reflux, as the condensing
vapours will result in rapid decrease of pressure and can lead to suckback of air into
the reaction.
12
THIN LAYER CHROMATOGRAPHY (t.l.c.)
Thin layer chromatography is performed using a t.l.c. plate. This "plate" is usually a
piece of plastic, or glass that is coated on one side with a highly polar solid substance
like silica gel. Silica gel is the stationary phase. The surface of silica gel contains a
large number of Si-OH groups. Consequently, silica gel is a good hydrogen bond donor
and acceptor, and hydrogen bonding compounds stick tightly to silica gel. (Ionic
compounds stick too tightly to silica gel and cannot be separated in this way.) After a
sample is applied to the silica gel, the "sample" end of the t.l.c. plate is dipped in a
solvent, the mobile phase. The solvent moves up the plate carrying the sample with it.
Non-polar compounds move the farthest, while more polar compounds (the ones that
stick more tightly to silica gel) tend to stay near the bottom. You can adjust how far a
sample moves by using solvents of different polarity. More polar solvents are used to
make polar compounds move further up the plate. For each compound an Rf value
can be measured;
Rf = distance moved by compound/distance moved by solvent
So, in simple terms, compounds are applied to the plate, the plate is dipped in solvent
and after the solvent soaks up the plate, the plate is removed from the solvent and
dried (see figure 2). The spots on the plate are then visualised, usually using UV (the
empty ovals do not represent compounds; they are included just to show the starting
points of each sample). If the compounds do not show up under UV light then
alternative methods of visualisation are possible. The plate may be dipped into, or
sprayed with, a suitable solution, that will react with the compounds of interest and
produce coloured spots. Such solutions include aqueous potassium permanganate
(which will oxidise most organic compounds) and 10% phosphomolybdic acid in
ethanol. Another method is to stand the dried plate in a closed vessel containing a few
crystals of iodine. The iodine evaporates and reveals the spots as brown stains. In this
case, however, when left in air the iodine evaporates from the plate and the spots
disappear again.
Figure 2 – Application and running a TLC sample
In order to get a suitable t.l.c. system to follow the course of reaction, or assess the
purity of a compound, you may need to try a number of solvent systems to get good
13
results. In many cases a mixture of petroleum ether and ethyl acetate can be
employed, varying the polarity of the eluant by altering the ratio of the two solvents.
The detailed procedure is as follows:
Before running a tlc, you will need to cut an aluminium backed silica plate. The
plates are cut from a large sheet of aluminium backed silica, these are stored on
one of the side benches. Using scissors, you should cut a plate 40 × 66 mm.
Don’t use more silica than you need, this is wasteful.
Step 1 – Make up sample solutions. Compounds are applied as dilute solutions
(typically 5-10%) in a volatile solvent, like ethyl acetate. Dilute solutions are used so
that the plate does not get overloaded. Instead of binding to the stationary phase, the
overloaded compound spreads out and makes a big worthless streak.
Step 2 – Apply samples to t.l.c. plate. Samples are applied using t.l.c. spotters.
These are made from narrow glass tubes called capillaries. The width of the capillary
is decreased by drawing it out using a Bunsen flame to give a finer tube of
approximately 1/3 the original bore. The idea is to make the initial sample spot as small
as possible (preferably 2-4 mm in diameter) because sample spots always grow as
they move up the plate. To apply a sample, dip the t.l.c. spotter in your sample solution,
and then gently and briefly touch the end of the capillary to the silica gel. If you need
to add more compound to the sample spot, let the spot dry completely first. Then touch
the capillary in exactly the same location. You will usually apply three or four different
samples to the same plate so that you can compare them. To facilitate this, draw a
pencil line across the plate, in pencil not ink, about 1-2 cm from (and parallel to) the
end of the plate. Place all of your sample spots just above this line. Also, label each
lane at the other end of the plate.
Step 3 – Elute the t.l.c. plate (soak the plate in solvent). Use a tall, narrow beaker or
jar Cut off the bottom from a piece of filter paper and press it up against the wall of the
beaker. Pour your chromatography solvent (or solvent mixture) into the beaker and
then cap the beaker with a watch glass. Next, carefully rest the plate inside the beaker.
The solvent will immediately begin to soak upwards through the plate, so you must set
the plate up so that exactly the same amount of solvent flows through each part of the
plate and the solvent "front" rises as a horizontal line. Here are some useful tips:
•
Limit the amount of solvent. Do not let the solvent cover or
touch the sample spots.
•
Stand the plate upright as much as you can. Do not let the
edges touch the filter paper.
•
Do not move the beaker once you insert the plate. Moving
the beaker splashes solvent up the sides of the plate.
•
Place the silica gel side towards you so that you can monitor
the solvent's progress.
It is important to stop the plate at the right time. If you stop too early, all of the
compounds will be grouped near the bottom of the plate. If you stop too late, all of the
compounds will be grouped near the top (compounds gradually collect at the top
because solvent continuously flows up through the plate and evaporates). Therefore,
the quality of your t.l.c. separation improves and then declines with time. A good rule
of thumb is to wait for the solvent to cover at least 50-70% of the distance between the
14
sample spots and the top of the plate. However, if it looks to you like the solvent "front"
has stopped or has slowed down significantly, immediately remove the plate from the
beaker.
Step 4 – Visualise the result. Once you remove your plate from the beaker,
immediately mark the location of the solvent "front" with a pencil. Then allow the solvent
to evaporate from the plate by standing in air for a few minutes (when using toluene a
hair dryer will also be required to remove all the solvent from the plate). Use the UV
lamp to detect your compounds by examining your plate under a UV light. Mark the
outlines of all significant spots with a pencil.
If the compounds do not show up under UV light then alternative methods of
visualisation are possible. The plate may be dipped into, or sprayed with, a suitable
solution, that will react with the compounds of interest and produce coloured spots.
Such solutions include aqueous potassium permanganate (which will oxidise most
organic compounds), 10% H2SO4 in ethanol and 10% phosphomolybdic acid in
ethanol. Frequently the coloured spots are not observed until the plate is “developed”
by heating with a hot air blower. Another useful method is to stand the dried plate in a
closed vessel containing a few crystals of iodine. The iodine evaporates and reveals
the spots as brown stains. In this case, however, when left in air the iodine evaporates
from the plate and the spots disappear again.
The Rf values for spots on a t.l.c plate are measured as shown below (figure 3) and
are defined as the distance moved by the compound, divided by the distance moved
by the solvent.
------------
Solvent front
Rf value = b / a
a
b
______
_
Start
Figure 3 –TLC sample Rf values
15
FLASH CHROMATOGRAPHY
Distillation, recrystallisation, and extraction are all important techniques for the
purification of organic compounds. But the technique used most commonly in modern
organic research is "flash" chromatography. In traditional column chromatography a
sample to be purified is placed on the top of a column containing some solid support,
often silica gel. The solvent is then run through the solid support under the force of
gravity. The various components to be separated travel through the column at different
rates and can then be collected separately as they emerge from the bottom of the
column. Unfortunately, the rate at which the solvent percolates through the column is
slow. In flash chromatography however air pressure is used to speed up the flow of
solvent, dramatically decreasing the time needed to purify the sample.
Table 1.
sample:
column
diameter
vol of
eluanta
(mm)
(cm3)
Rf = 0.2
Rf = 0.1
(cm3)
10
100
100
40
5
20
200
400
160
10
30
300
900
360
20
40
600
1600
600
30
50
1000
2500
1000
50
aTypical
typical loading(mg)
typical
fraction size
volume of eluant required for packing and elution.
The detailed procedure is as follows:
Step 1 - Finding a suitable eluant
First a low viscosity solvent system (e.g. ethyl acetate/40-60 °C petroleum ether) is
found which separates the mixture and moves the desired component on analytical
t.l.c. to an Rf of 0.35. If several compounds are to be separated which run very close
on t.l.c., adjust the solvent to put the midpoint between the components at Rf = 0.35. If
the compounds are widely separated, adjust the Rf of the less mobile component to
0.35. Having chosen the solvent, a column of the appropriate diameter is selected. We
will be using columns of 20 mm diameter.
Step 2 - Packing the column
Chromatography columns can be packed in two ways. They are either dry packed with
silica and then the solvent added; otherwise they are packed using a slurry of silica in
the eluant. In this case the columns will be slurry packed. Silica gel (ca. 40 g) is mixed
with a 10-fold excess of the eluant to produce a slurry. This is then poured gently into
a clean dry column. The absorbent will settle evenly and free from bubbles if the
column is gently tapped. A column depth of 15 cm is required. Next a 0.5 cm. layer of
16
sand is carefully placed on the flat top of the silica gel bed and the column is clamped
for pressure packing and elution. The solvent chosen above is then poured carefully
over the sand to fill the column completely. Air pressure is then applied using the
bellows. This will cause the pressure above the absorbent bed to climb rapidly and
compress the silica gel as solvent is rapidly forced through the column. It is important
to maintain the pressure until all the air is expelled and the lower part of the column is
cool; otherwise, the column will fragment and should be repacked unless the
separation desired is a trivial one. The pressure is then released and excess eluant is
forced out of the column.
The top of the silica gel should not be allowed to run dry.
Step 3 - Running the column
The sample is applied by pipette as a solution in the minimum amount of eluant to the
top of the adsorbent bed and then pressure used to push the entire sample into the
silica gel. The walls of the column are washed down with a few millilitres of fresh
eluant, the washings are pushed onto the column as before, and the column is carefully
filled with eluant so as not to disturb the adsorbent bed. Fractions are collected until all
the solvent has been used. It is best not to let the column run dry since further elution
is occasionally necessary. Purified components are identified by t.l.c. (figure 4) and the
appropriate fractions are combined and the solvent removed by rotary evaporation to
yield the desired material.
Figure 4 –TLC fractions from a silica column
(From: W.C. Still, M. Kahn, and A. Mitra, J. Org. Chem., 1978, 43, 2923–2925.)
17
DISTILLATION UNDER REDUCED PRESSURE USING A
“VIGREUX” MODIFIED CLAISEN FLASK
Section 3.7 (“Distillation under reduced pressure”) of the second year techniques
manual outlines the procedure to set up a simple vacuum distillation. A similar
technique is employed in the 3rd year laboratory, however a more efficient “Vigreux”
modified Claisen flask (figure 5) is used instead of a round bottom flask/still head
combination. Vigreux flasks are named after Henri N. Vigreux, he was a French
glassblower who introduced condensers and flasks equipped with specially shaped
indentations. This modification leads to a large increase in the surface area of the glass
(relative to conventional still head) that is in contact with vapour from the distillation
flask. As hot vapour rises through the flask, a portion of it condenses and returns to
the vapour phase again. Each cycle of condensation and revaporisation enriches the
vapour phase in the most volatile component of the mixture being distilled, the upper
part of the sidearm should contain vapour most enriched in the most volatile
component.
The
indentations
in
the
Vigreux
flask
allow
more
condensation/revaporisation cycles to take place and hence superior fractionation
performance than simpler distillation equipment.
Pictures of example distillation set-ups can be found on the course
Moodle page
Figure 5 – Vigreux modified claisen flask
adapted from http://www.tradeindia.com/fp545387/Claison-Type-Vigreux-Flasks.html
[accessed 28-8-2015]
For background, see the article below written by Prof A. Sella and published in the
RSC Chemistry World magazine.
http://www.rsc.org/chemistryworld/Issues/2008/April/VigreuxsColumn.asp
18
TRACK A EXPERIMENTS
19
EXPERIMENT A1
Alkene Synthesis: The Wittig Reaction
INTRODUCTION
In 1953, Georg Wittig reported that reaction of methylenetriphenylphosphorane with
benzophenone afforded 1,2-diphenylethylene and triphenylphosphine oxide. The
outcome in this case was unexpected, however it was immediately realised that this
reaction was a useful method for the formation of C=C bonds and has been in
continuous use since. The importance of the “Wittig reaction” was recognised in 1979
when Georg Wittig shared the Nobel prize in chemistry with Herbert C. Brown (see
hydroboration experiment in track A) for “development of the use of boron- and
phosphorus-containing compounds, respectively, into important reagents in organic
synthesis”.
The key intermediates in Wittig reactions are phosphorus ylides, these can exist in an
-ylide or -ylene form (see below). These species have a range of stabilities, the most
frequently encountered examples are “stabilised ylides” where the carbon atom
carrying the negative charge is adjacent to the phosphoryl (P=O) group and an
electron-withdrawing substituent. The ylide shown below is employed in this
experiment, it is a well-known example and is commercially available. This compound
can easily be prepared via the phosphonium intermediate as illustrated, however, the
bromoester starting material is a potent lachrymator so the ylide formation steps will
be omitted in this experiment.
In the first part of this experiment, an unknown aldehyde is allowed to react with the
pre-formed phosphorus ylide to afford an alkene product that can potentially exist as
the E or Z isomer. 1H NMR spectroscopy can be used to confirm which isomers are
present. In the second part of the experiment, the reaction in part 1 will be repeated
and an alternative purification process will be evaluated.
BEFORE STARTING: Read the Advanced Techniques Sections, which describe
how to perform the chromatography steps. Videos have been linked on the
course Moodle page that show how to perform tlc analysis and how to purify
materials using flash chromatography.
20
PROCEDURE
Part 1
Select an unknown aldehyde to work with for this experiment, you will use the same
one in both parts. Transfer the unknown (Unknown X 0.50 g; Unknown Y; 0.66 g;
Unknown Z 0.66 g) and dichloromethane (20 cm3) to a 100 cm3 flask equipped with
a magnetic stirring bar and immediately stopper the flask. The mixture should be
cooled in an ice bath and allowed to stir for 15 minutes.
(carbethoxymethylene)triphenylphosphorane (2.0 g, 5.7 mmol) should be added in
portions to the reaction mixture through a powder funnel and the reaction mixture
stirred for 30 minutes. When the reaction is complete, the reaction flask should be
allowed to warm to room temperature and then the solvent should be removed invacuo. Transfer 40-60 petrol (20 cm3) to the flask and stir the resulting suspension
with a glass rod to precipitate as much triphenylphosphine oxide as possible and filter
under suction retain a sample of this material. Rinse out the flask and wash the
solid with 40-60 petrol (20 cm3) and concentrate the filtrate under reduced pressure
to afford crude product. Acquire a 1H NMR spectrum of the crude product and use
this data to determine the E:Z alkene ratio.
Part 2
Repeat the procedure for part 1, however, this time you should use ethanol as the
reaction solvent instead of DCM. Acquire a 1H NMR spectrum of the crude product and
use this data to determine the E:Z alkene ratio.
Part 3
Analysis of the products from parts 1 and 2 should allow you to calculate the
approximate E:Z alkene ratio in each case. Select the product that has the greater
proportion of the E isomer and purify the crude material by flash chromatography.
Note: The primary reason for the chromatography step is to remove any residual
triphenylphosphine oxide.
You should allow a full lab session to purify a product using flash
chromatography.
You should use silica as the stationary phase and you should use 40-60 petroleum
ether and ethyl acetate mixture (9:1) as the eluting solvent. Be careful to take fractions
of a suitable size. Characterise your product (1H NMR, IR. You should also acquire a
31P NMR spectrum of the product to show that triphenylphoshine oxide has been
removed. You may also wish to acquire a 31P NMR spectrum of the sample of
triphenylphosphine oxide you retained in part 1 of the experiment to make a
comparison).
You can identify which collection tubes contain eluted material by t.l.c. analysis using
a mixture of 40-60 petroleum ether and ethyl acetate (9:1). The t.l.c. plate is best
visualised in this case by placing the developed plate under a UV light. However,
dipping in aqueous potassium permanganate solution can be considered if no spots
21
are visible under UV light. Permanganate dip should give white or yellow spots on a
purple background. (The plate may need warming with a heat gun to make the spots
show up more clearly).
Housekeeping
Clean out the chromatography column and return it to the cupboard as soon as you
have finished with it, putting the used silica into the labelled waste container. NOTE Silica gel or alumina cannot be disposed of into the solid waste bottle while damp with
hazardous organic solvents. It must be dry, i.e. a free-flowing powder, with no lumps.
To clean out the column, you should clamp it upside down, with the tap open, over a
beaker, on a short retort stand, at the back of your fume cupboard. Columns
containing damp silica can be clamped the right way up, stoppered, and left in your
bench cupboard overnight, then left open as before in a fume cupboard the following
day.
Use your experimental results to provide clear and convincing experimental
evidence to determine which set of reaction conditions allowed the best control
over the E:Z isomer ratio.
Table of potential unknowns
The unknown aldehyde you used is one of the compounds listed below, you should be
able to use your experimental results to ascertain which product you prepared and
hence which aldehyde you started with.
22
Notes and Calculations
23
EXPERIMENT A2
Alkene Hydroboration
INTRODUCTION
The hydration of alkenes is often a required step in an organic synthesis. A variety of
methods exist for effecting this conversion. Hydroboration of alkenes involves the
addition of a boron-hydrogen unit to the carbon-carbon double bond (hydroboration of
cyclohexene is shown below as an example). This reaction provides a convenient route
to the corresponding organoboranes, making them readily accessible as intermediates
in organic synthesis. Organoboranes undergo rapid and essentially quantitative
oxidation with alkaline hydrogen peroxide.
If the alkene is unsymmetrically substituted, two products are possible. The direction
of addition of the boron-hydrogen unit to the double bond is strongly influenced by
steric and electronic effects (The product distribution is also influenced by the boronderived reagent). Hydroboration of alkenes results in a cis addition of the boronhydrogen unit, the boron atom becoming preferentially attached to the less substituted
of the two alkene carbon atoms (it is also noteworthy that the oxidation occurs with
retention of configuration).
As a result, hydroboration followed by oxidation with alkaline hydrogen peroxide has
become an important synthetic method for the cis hydration of double bonds.
Hydroboration is often carried out with borane in tetrahydrofuran (BH3.C4H8O). It may
also conveniently be generated in-situ by the action of boron trifluoride or a strong acid
on a metal borohydride (NaBH4, LiBH4, KBH4) in ether solvents such as
tetrahydrofuran and diglyme. In this experiment, borane will be generated by treating
sodium borohydride with iodine.
BEFORE STARTING
1. Read the Advanced Techniques Sections, these describe the procedure
for working with air-sensitive reagents. A video has been linked on the
course Moodle page that show the correct way to add the reagents when
generating the borane-THF complex.
2. You must place the glassware required in the oven to dry in advance. It is
best to store the necessary equipment in an oven for at least 16 hours prior to
attempting the reaction.
24
3. Note that the reaction will require a full 3.5 hour lab session and careful
time management is necessary. Make sure you have read the procedure in
advance. For example, some of the solutions required in the oxidation step can
be prepared after the hydroboration reaction is in progress.
PROCEDURE
[CARE! Hydrogen gas is evolved – ensure potential ignition sources are
removed from the work area]
Equip a 250 cm3 three-necked flask with a magnetic stirring bar, a D.S. condenser
[fitted with a CaCl2 tube (centre socket)], a dropping funnel and a thermometer (use
the appropriate adapter). Transfer 1,2-dimethoxyethane (“glyme”, 10 cm3),
tetrahydrofuran (10 cm3), sodium borohydride (500 mg, 13.2 mmol) and your chosen
alkene (20 mmol of either hex-1-ene or oct-1-ene) to the flask. Immerse the reaction
flask in an ice/water bath and allow the mixture to cool while preparing the iodine
solution in the next step.
CARE! Iodine is very corrosive to skin and will damage metal components, such
as top pan balances – transfer using a powder funnel, all spillages must be
attended to immediately!], see instructions overleaf about iodine contamination.
Prepare a solution of iodine (1.2 g, 4.7 mmol) in dry THF (18 cm3) and transfer this to
the dropping funnel. Add the iodine solution to the vigorously stirred mixture at a rate
that allows any iodine colour to rapidly disappear (see below).
Important notes about iodine addition: If the reaction mixture persistently appears
dark brown, you are adding the iodine too quickly, you should slow the rate of addition
and allow the brown colour to fade. In the initial stages, the iodine should be consumed
rapidly, however, in the latter stages (once c.a 5 cm 3 of iodine solution is left) the
solution may remain yellow after each drop of solution is added. The addition will
likely take ca. 35-40 minutes.
After the addition is complete, transfer 10 cm3 of THF to the dropping funnel and use
this to quickly rinse any residual iodine into the reaction flask. On completion of addition
of the iodine solution, remove the ice bath and stir the reaction mixture for a further
50-60 minutes at room temperature.
Care! this reaction may froth. Immerse the reaction flask in a water bath (room
temperature) and carefully add 3 M aqueous sodium hydroxide (20 cm3) via the
dropping funnel.
Transfer 30% (9 M, "100 volumes") hydrogen peroxide (10 cm3) to the dropping funnel
and add the solution a few drops at a time to the vigorously stirred mixture so that the
reaction temperature is maintained between 40-45 °C. This reaction is particularly
exothermic. Your product is likely to decompose if you add the solution too
quickly and the reaction becomes too hot. On completion of the addition, remove
the water bath and stir the mixture for 30-35 minutes. During the stirring period, prepare
an aqueous solution of sodium sulfite by dissolving 2 g of the solid in 15 cm3 of water,
this will be used to destroy any residual hydrogen peroxide. Once the stirring period is
complete, Carefully! add the sodium sulfite solution to the reaction mixture – this
reaction can become very hot if the sulfite solution is added too quickly. Once the
sulfite addition is complete, the reaction can be stopped at this stage.
25
Add diethyl ether (50 cm3) to the reaction mixture, then separate and retain the organic
phase. Saturate the aqueous layer with sodium chloride and extract it with diethyl
ether (3 × 25 cm3 portions). Combine the ether extracts and wash them with saturated
aqueous sodium chloride (2 × 25 cm3). Dry the ether extracts over Na2SO4 and
evaporate the solvent under vacuum. Obtain a 1H NMR spectrum and an IR
spectrum of the crude product. Prepare a sample of the crude product for
analysis by Gas Chromatography (GC).
Preparation of a crystalline derivative
The product from the hydroboration reaction will be liquid, however it is possible to
make a derivative that can be isolated as a crystalline solid. In this case, you will
prepare a 3,5-dinitrobenzoate derivative of the alcohol you prepared via the
hydroboration/oxidation sequence.
Transfer a sample of the crude alcohol (0.5 g) to a dry 25 mL RB flask containing a
magnetic stirring bar and add 3,5-dinitrobenzoyl chloride (0.6 g). Equip the flask with
a condenser (you do not need to use water cooling) and heat the reaction mixture to
100 °C for 15 minutes. Allow the reaction mixture to cool to room temperature, then
add saturated sodium bicarbonate solution (10 cm3), the crude product should be solid
at this point. Allow the mixture to stir for 5 minutes and then filter off the crude product
under suction and wash the filter cake with distilled water (5 cm 3). Purify the crude
product by recrystallization from ethanol (aqueous ethanol can be used if necessary).
Characterise your product (melting point, 1H NMR and IR spectroscopy).
Glassware contaminated by iodine can be cleaned by immersion in dilute sodium
metabisulfite or sodium sulfite solution. In the event of a spillage, sweep up any solid
iodine then dissolve it in a dilute solution of sodium sulfite or thiosulfate. Stains or
solution spillages should also be treated with sulfite or thiosulfate. If the iodine is swept
up or neutralised promptly there will be little to no staining or damage. If left unattended
to, iodine will diffuse into the work surface and then clean-up will be harder to complete.
Iodine will damage metal surfaces, the surface of balances in particular.
26
Notes and Calculations
27
TRACK B EXPERIMENTS
28
EXPERIMENT B1
Synthesis of Heterocycles: Hantzsch Route to Pyridines
INTRODUCTION
The pyridine ring is a recurring motif in naturally occurring compounds and
pharmaceuticals.
Pyridines can be prepared by a variety of routes, one of the best known methods is
the Hantzsh synthesis, this is a two-step cyclisation/oxidation process. The first step is
a multi-component reaction between a -keto ester, an aldehyde and an amine (or
ammonia). The product from step one is a 1,4-dihydropyridine, such compounds can
be oxidised under relatively mild conditions to afford the corresponding pyridine. 1,4dihydropyridines are also found in Nature and comprise an important family of calcium
channel blocking drugs that are used to treat cardiovascular disease.
The aim of this experiment is to prepare Diludine (a 1,4-dihydropyridine) and to convert
this to the corresponding pyridine via a Hantzsch sequence.
29
BEFORE STARTING: Read the Advanced Techniques Sections, which describes
how to perform the chromatography steps for method 2. Videos have been
linked on the course Moodle page that show how to perform tlc analysis and
how to purify materials using flash chromatography.
The work-up for this experiment requires brine solution, you have a 250 mL reagent
bottle in your benchkit that can be used to prepare a stock solution, this might also
useful for other experiments too.
PROCEDURE
Part 1: Synthesis of the 1, 4-Dihydropyridine (Diludine)
Transfer ethyl acetoacetate (2.97 g), ammonium acetate (1.29 g) and formaldehyde
(38% aqueous solution, 0.85 cm3) to a 50 cm3 round bottomed flask. Add a magnetic
stirrer bar and start stirring the solution, then heat the reaction to 80 °C under reflux for
10-15 minutes. A yellow solid should accumulate at this point, allow the flask to cool
and add distilled water (10 cm3). Break up the solid with a glass rod until a fine
suspension is obtained. Filter off the crude product under suction and wash the filter
cake with distilled water (20 cm3). Recrystallise the crude product from ethanol.
Characterise your product (1H NMR, IR and melting point).
Part 2: Oxidation of Diludine
Transfer the 1,4-dihydropyridine (780 mg) from step 1 and ethyl acetate (15 cm3) to a
100 cm3 conical flask. Add a magnetic stirrer bar and start stirring the suspension, then
slowly add UHP (urea-hydrogen peroxide complex, 570 mg) and iodine (300 mg).
Allow the reaction mixture to continue stirring for 45 minutes at room temperature then
dilute the reaction mixture with water (20 cm3). Add sodium metabisulfite to the solution
in small portions with gentle swirling until the strong iodine colouration is no longer
visible in both phases (they should become completely colourless or pale yellow).
Separate off the organic layer and extract the aqueous layer with ethyl acetate (2 × 15
30
cm3). Wash the combined ethyl acetate layers with brine (20 cm3), dry the combined
organic extracts over Na2SO4 and concentrate under reduced pressure.
You should allow a full lab session to purify a product using flash
chromatography.
Purify the crude product by flash chromatography eluting with 40-60 petroleum ether
and ethyl acetate (9:1). Be careful to take fractions of a suitable size. You have the
option to purify further by recrystallisation from aqueous methanol if you think it is
necessary. Characterise your product (1H NMR, IR and melting point).
You can identify which collection tubes contain eluted material by t.l.c. analysis using
a mixture of 40-60 petroleum ether and ethyl acetate (4:1). The t.l.c. plate is best
visualised in this case by placing the developed plate under a UV light. However,
dipping in aqueous potassium permanganate solution can be considered if no spots
are visible under UV light. Permanganate dip should give white or yellow spots on a
purple background. (The plate may need warming with a heat gun to make the spots
show up more clearly).
Housekeeping
Clean out the chromatography column and return it to the cupboard as soon as you
have finished with it, putting the used silica into the labelled waste container. NOTE Silica gel or alumina cannot be disposed of into the solid waste bottle while damp with
hazardous organic solvents. It must be dry, i.e. a free-flowing powder, with no lumps.
To clean out the column, you should clamp it upside down, with the tap open, over a
beaker, on a short retort stand, at the back of your fume cupboard. Columns
containing damp silica can be clamped the right way up, stoppered, and left in your
bench cupboard overnight, then left open as before in a fume cupboard the following
day.
31
Notes and Calculations
32
EXPERIMENT B2
Generation and Reaction of a Grignard Reagent
INTRODUCTION
Reaction of alkyl and aryl halides with magnesium metal affords the corresponding
organomagnesium species, these are known as “Grignard” reagents, named in honour
of Victor Grignard who discovered them in the early 20th century. The discovery was
considered so significant, that he was awarded the 1912 Nobel prize in chemistry for
his work.
Mg0, ether
R X
d- d+
R Mg X
Grignard reagents are very important organometallic compounds in synthesis due to
their ability to serve as carbanion equivalents, some representative reactions of these
reagents are illustrated below. Although very useful, organomagnesium compounds
are water sensitive and therefore must be handled under dry conditions and with
exclusion of atmospheric oxygen.
In this experiment, triphenylmethanol will be prepared by a Grignard reaction
sequence. The Grignard reagent will be prepared in-situ from bromobenzene and then
reacted with methyl benzoate. The product will then be used to prepare an unknown
compound that will be identified using spectroscopic techniques and melting point
analysis.
33
PROCEDURE
BEFORE STARTING
1. Read the Advanced Techniques Section, which describes the procedure
for working with air-sensitive reagents. Videos have been linked on the
course Moodle page that show how to use inert gas assemblies and how
the Grignard initiation step works.
2. You should place the glassware required for the reaction in part 2 in the
oven to dry overnight before attempting the experiment.
3. Note that the reaction will likely require a full 3.5 hour lab session and
careful time management is necessary. Make sure you have read the
procedure in advance.
The work-up for this experiment requires brine solution, you have a 250 mL reagent
bottle in your benchkit that can be used to prepare a stock solution, this might also
useful for other experiments too.
Part 1 – In-situ preparation of phenylmagnesium bromide
Assemble the hot apparatus over a stirrer hotplate (see figure 6), with PTFE sleeves
inserted in the joints (ensure all joints are sealed to prevent loss of solvent vapour).
Allow to cool under N2, place dry magnesium turnings (0.85 g) in the flask and place a
solution of bromobenzene (5.30 g) in DRY diethyl ether (20 cm3) in the dropping funnel,
then immediately replace the CaCl2 guard tube. Only now run water through the
condenser, then stir the turnings for 5 minutes and add only 1-2 cm3 of the
bromobenzene solution dropwise. The reaction should start after a few minutes, when
this happens you will see the mixture become cloudy and then it should boil without
external heating.
Patience is required at this point, but don’t wait too long to seek help if the reaction
does not initiate. If the reaction does not start, see suggestions overleaf.
Once the reaction has started, add the remainder of the solution dropwise at a rate
that maintains gentle boiling. On completion of the addition and when the reaction
34
subsides, heat the mixture under reflux for 15 minutes. Cool the flask to room
temperature and proceed to part 2 immediately.
My Grignard reaction won’t initiate! What can I do?
There are several options:
1. Ensure all the apparatus was dried in the oven and that the dried ether was used.
Grignards don’t work if water is present! (Why do you think water would be a
problem?)
2. Heat the solution until it starts boiling, remove the heat source and leave to stand
for a few minutes.
3. Add a pellet of iodine to the mixture. leave it unstirred for a minute then begin stirring
again. The reaction may not start immediately so allow 5 minutes before trying
anything else. Don't add any more iodine, but try warming again.
4. Ask a demonstrator to add some pre-formed Grignard reagent or a few drops of a
bromoalkane initiator.
Figure 6 - Apparatus for Grignard reaction
Part 2 – Preparation of triphenylmethanol
Place a solution of methyl benzoate (2.2 g) in diethyl ether (10 cm3) in the dropping
funnel and add the solution slowly to the freshly prepared Grignard reagent. On
completion of the addition, heat the mixture to reflux for 15 minutes and allow to cool.
Pour the the reaction mixture onto crushed ice (ca. 50-60 g) add solid ammonium
chloride (8 g) and allow the resulting mixture to stir for 15 minutes.
NOTE: It is not uncommon for a significant quantity of solid residue to be observed in
the reaction flask at this stage, this material could contain the magnesium complex of
the product and residual magnesium metal. If any solid material is present, rinse the
flask with small portions of 1M sulfuric acid and transfer to the reaction mix/ice. Finally,
35
the reaction flask should be rinsed with ether (20 cm 3 bench ether should be used
here, not anhydrous diethyl ether) into the reaction mix/ice. Transfer the mixture to
a separating funnel and separate off the ether layer. Wash the ether layer with brine
(2 × 20 cm3). Dry the ether layer over sodium sulfate and evaporate off the solvent
under vacuum.
The crude compound should be purified by recrystallisation, you can choose to use
either propan-2-ol (“isopropyl alcohol”) or cyclohexane. Do not discard the solvent
that the product has crystallised from, this should be retained for analysis by tlc.
Biphenyl is a common by-product from this reaction, therefore the remaining solvent
from the purification step may contain a mixture of the desired product and biphenyl.
Transfer the solvent to a round bottom flask and evaporate off the solvent under
vacuum. If there is any residual solid material, you can use tlc to identify whether any
product or biphenyl is present. Use a mixture of 40-60 petroleum ether and ethyl
acetate (9:1) as the eluting solvent, a sample of biphenyl is available to you to use for
comparison purposes. The tlc plate is best visualised in this case by placing the
developed plate under a UV light. If there is no product present, you can discard the
residue. However, if there is evidence that some triphenylmethanol is present in the
residue, you may be able to isolate more product by recrystallising the solid material
from propan-2-ol or cyclohexane. Characterise all the samples you have purified (1H
NMR, IR and melting point).
Part 3 – Reaction of triphenylmethanol
Under acidic conditions, triphenylmethanol can be quite reactive, this is because it is
readily converted to the corresponding triphenylmethyl carbocation. Treatment of
triphenylmethanol with perchloric acid, fluoroboric acid or hexafluorophosphoric acid
results in isolable salts of the triphenylmethyl carbocation. The anions in each case are
weakly coordinating, the tetrafluoroborate and hexafluorophosphate salts are stable
enough to be made available from commercial suppliers.
In this part of the experiment, you will react triphenylmethanol with malonic acid and
use your experimental results to identify the product (the product is either A, B or C).
This reaction must be attempted in a fumehood! Transfer triphenylmethanol (0.4 g)
and malonic acid (1 g) to a boiling tube, then mix the dry solids together for a few
minutes with a glass rod. Obtain a heating block that can heat 4 tubes at a time, there
may be one in operation already, if not you can obtain one from a technician. Insert
36
the tube into the heating block, and heat the block to 200 °C. Once the mixture is hot
enough, the mixture will melt, turn yellow/brown and start to release bubbles of gas.
Allow the tube to heat for 20 minutes, then remove it and allow the tube to cool (the
liquid will solidify on cooling). Dissolve the solid residue in ethyl acetate (10 mL) and
transfer the mixture to a separating funnel. Rinse out the boiling tube with ethyl acetate
(10 mL) and transfer the solvent to the separating funnel. Wash the ethyl acetate layer
with saturated sodium bicarbonate solution (20 mL) and then water (20 mL). Dry the
ethyl acetate layer over MgSO4 and evaporate off the solvent under vacuum.
Recrystallise the crude product from aqueous methanol. To initiate crystallisation, it is
likely that the solution will need cooled in ice, and crystallisation induced by scratching
the glass gently with a glass rod. If scratching fails to initiate crystallisation, store the
solution in your cupboard overnight (or until the following week). This action will allow
some of the methanol to evaporate off and allow crystals to form.
Characterise the purified compound using 1H NMR spectroscopy, IR spectroscopy and
melting point analysis.
Points for discussion
1. A variety of species is present in a solution of Grignard reagent. Suggest possible
species derived from Mg and bromobenzene in ether solution.
2. Why must the Grignard reagent addition be performed using dry glassware and
solvents?
3. Consider the potential mechanism for the formation of the product in part 3.
37
Notes and Calculations
38
TRACK C EXPERIMENTS
39
EXPERIMENT C1
Preparation of Substituted Biphenyls: A Comparison
Between Friedel-Crafts and Suzuki Reactions
INTRODUCTION
Transition metal mediated reactions are becoming increasingly important in organic
synthesis, since they frequently allow very direct routes to the types of molecules found
in drugs, agrochemicals and natural products; relatively few multi-step syntheses of
complex molecules do not rely on at least one metal catalysed reaction. In addition,
the use of a small amount of catalyst to promote chemical reactions under mild
conditions generally makes for 'greener chemistry' with reduced waste products.
Palladium catalysis is by far the most widely used, as far as organic synthesis is
concerned, because it can be used to catalyse a range of C–C bond forming reactions.
One of the most important palladium catalysed reactions is the Suzuki (or SuzukiMiyaura) cross coupling reaction. This reaction represents an extremely versatile
methodology for the generation of carbon-carbon bonds. This is a reaction of an aryl-,
alkyl- or vinyl-boronic acid with an aryl- or vinyl- halide catalysed by palladium
complexes. It is widely used to synthesize poly-olefins, styrenes and in particular,
substituted biaryls. These latter motifs are found in many biologically active
compounds, and the Suzuki reaction is likely to be one of the more common reactions
carried out in drug-discovery laboratories. The reaction is also used in the commercial
production of some of today's pharmaceuticals (see examples below). The importance
of this type of reaction was acknowledged by the award of the 2010 Nobel Prize in
Chemistry to Richard F. Heck, Ei-ichi Negishi and Akira Suzuki "for palladiumcatalyzed cross couplings in organic synthesis".
Despite their versatility palladium catalysed coupling can be very expensive to conduct,
so it is important that the cost of the catalyst versus the value of the product is carefully
considered before employing this type of process to make a target compound. This is
especially true when used on a large scale where a significant financial investment is
being made in purchasing the catalyst. In this practical task, you will also use FreidelCrafts acylation to prepare the target compound. Although much older, this type of
reaction has its origins in the 19th century), these reactions can still be very useful.
40
In this experiment you will prepare 4-acetylbiphenyl using 2 different methods: FriedelCrafts acylation and palladium catalysed Suzuki coupling of phenylboronic acid with
4’-bromoacetophenone. In each case, you will use the results you obtain to evaluate
which method you think is most efficient in terms of hazard/risk, time required, ease of
purification and financial cost.
PROCEDURES
Method 1
CARE! rapid addition of the reagents in this experiment, will result in an
exothermic reaction that will release toxic and corrosive gases.
The work-up for this experiment requires brine solution, you have a 250 mL reagent
bottle in your benchkit that can be used to prepare a stock solution, this might also
useful for other experiments too.
Transfer aluminium chloride (1 g) to a dry 100 mL RB flask containing a magnetic
stirring bar and add 5 mL of DCM. Slowly add acetyl chloride (0.7 g, 0.64 mL)
dropwise to the stirred mixture. Dissolve biphenyl (1 g, 6.5 mmol) in 10 mL of DCM
and add slowly dropwise to the acetyl chloride solution. On completion of the addition,
rinse any residual biphenyl with 2 mL of DCM and add the rinse solution to the reaction
flask. Equip the flask with a condenser and heat the reaction to reflux for 20 minutes,
then allow the solution to cool. Quench the reaction by pouring the mixture onto
crushed ice (10 g) and then add 5 M HCl (15 mL). Once the ice melts, add 20 mL of
DCM to the mixture and transfer to a separating funnel. Run off the organic (DCM)
layer, extract the aqueous phase with an additional portion of DCM (20 mL) and
combine the two DCM layers. wash the combined organic fractions with 1 M NaOH (20
mL), followed by brine (20 mL). Dry the combined DCM fractions over sodium sulfate
and concentrate under vacuum. Purify the crude product by recrystallization from
ethanol or methanol.
Characterise your product (melting point, 1H NMR and IR).
Method 2
BEFORE STARTING: Read the Advanced Techniques Sections, which describes
how to use Drechsel bottles as part of an inert gas set-up. A video that shows
the use of inert gas techniques is also linked to the course Moodle page. A video
that shows how to filter samples through a celite pad is also available.
41
The work-up for this experiment requires brine solution, you have a 250 mL reagent
bottle in your benchkit that can be used to prepare a stock solution, this might also
useful for other experiments too.
Assemble the apparatus in figure 7 and, using a top-pan balance, weigh out the
phenylboronic acid (0.75 g, 6.2 mmol), potassium carbonate (2.2 g, 16 mmol) and 4’bromoacetophenone (1 g, 5 mmol). Transfer the boronic acid, potassium carbonate
and 4’-bromoacetophenone into the 3-necked flask, followed by a magnetic stirrer bar
and propan-1-ol (10 cm3). Ensure you equip both of the side-necks with appropriately
sized stoppers. Slowly open the nitrogen supply valve until a rapid flow of nitrogen
through the oil in the bubblers is observed (5 bubbles per second). Leave the
apparatus to purge with nitrogen for 15 minutes.
Figure 7 – Suzuki reaction inert gas set-up
Using a top-pan balance, weigh out urea (0.1 g, 1.7 mmol). Weigh out palladium
acetate (8.0 – 10.0 mg) into the smallest size sample vial available [use an analytical
balance - This is a precision instrument therefore 1. Chemicals must not be
transferred on the balance itself! Tare a small sample vial on the balance then, using
forceps, remove it to a tissue on the bench. Add a small quantity of material before,
again using forceps, returning the charged vial to the balance. If necessary, remove
the vial from the balance to add or remove material then reweigh. 2. Ensure the
balance is clean after use! Brush any spilled material onto a tissue].
Briefly remove the condenser and charge the reaction flask with the urea and palladium
acetate via the central neck of the flask. Immediately replace the condenser securely
and reduce the nitrogen flow to 1-2 bubbles per second.
Heat the reaction to reflux under nitrogen for 1 hour. Disconnect the nitrogen
bubbler as soon as you turn off the heat to avoid the oil sucking back into the
reaction flask. Allow the stirring reaction mixture to cool to room temperature and
42
remove the condenser. Allow the reaction to stir open to the air for 5 minutes before
adding ethyl acetate (30 cm3). Note: a large quantity of solid material will likely form
on cooling. If necessary, the reaction can be stopped at this point, although it is
better to get to the point where any undissolved sold material is removed by
filtration through celite.
The key by-product of the reaction is Pd(0), this will likely be observed as fine black or
dark grey particles entrained within insoluble inorganic material. This material is
removed by filtering through a pad of celite (also known as “Hi-Flo”). Ask a
demonstrator to show you how to prepare the celite pad (a video is also available on
Moodle). Filter the reaction mixture through the celite pad, then rinse the reaction flask
with portions of ethyl acetate (3 × 20 cm3, each time, filter the flask rinse liquid through
the celite pad).
Transfer the filtrate (this contains the reaction mixture plus additional solvent rinses) to
a separating funnel. Wash the solvent mixture with water (1 × 25 cm3), separate off the
aqueous layer and then wash the solvent mixture with brine (1 × 25 cm3). Separate off
the organic layer and dry over MgSO4. Remove the solvent under reduced pressure to
afford the crude product. Purify the crude product by recrystallization from ethanol or
methanol.
Characterise your product (melting point, 1H NMR and IR).
Disposal of Palladium wastes
Decontaminate the sample vial used to weigh out palladium acetate by dissolving any
residue in a little dichloromethane. Use a dropper to transfer the dichloromethane
solution onto the contaminated celite/potassium salts pad. After drying, the palladiumcontaminated solids must be disposed of in the palladium waste bottle, available from
a technician.
Once both steps are complete, you can use your results to evaluate which of the
two methods you think was more effective for the preparation of 4acetylbiphenyl in terms of: hazard/risk, time required, ease of purification and
financial cost.
43
Notes and Calculations
44
EXPERIMENT C2
Conversion of Carvone to Carvacrol and Carvacrol Acetate
INTRODUCTION
Most of the carbon-based chemicals we use are produced from fossil sources
(predominantly oil or coal). However, there are options to obtain some key feedstocks
from natural sources, in many cases, the source material would historically have been
regarded as waste. Fossil-derived resources will become depleted in future, so there
is an increasing focus on the use of biomass as a renewable source of carbon-based
chemicals. Discarded fruit peel from the food and drink industry is an abundant
biomass source of organic compounds, several useful feedstocks can be recovered
from this material. Limonene (both enantiomers) is recovered from discarded citrus
peel and has found to be particularly versatile. For example, Limonene is used as a
solvent in cleaning products and in organic synthesis, it is also a precursor to many
other useful organic compounds, such as carvone and p-cymene.
In this experiment, you will apply some of the key principles of green chemistry to
prepare compounds from (-)-carvone, a compound derived from a renewable biomass
source. In the first step of the synthetic sequence you will attempt, carvone will be
converted to carvacrol, this will subsequently be converted to carvacrol acetate.
Carvacrol has a distinctive smell (similar to chopped oregano), so this substance, and
45
carvacrol acetate are used in industry as flavourings and fragrances. The second step
is an esterification reaction, classical acetylation procedures usually require the alcohol
and acylating reagent to be dissolved in a solvent (usually pyridine). In this case there
is no additional solvent, acetic anhydride serves both as a solvent and a reagent.
PROCEDURES
The work-up for this experiment requires brine solution, you have a 250 mL reagent
bottle in your benchkit that can be used to prepare a stock solution, this might also
useful for other experiments too.
Part 1: Conversion of carvone to carvacrol
Transfer carvone (2 mL, 12.8 mmol) and 5 M H2SO4 (20 mL) to a dry 100 mL RB flask
containing a magnetic stirring bar. Equip the flask with a condenser, heat the reaction
to reflux for 45 minutes, then allow the solution to cool. Add 40-60 petroleum ether to
the mixture (20 mL) and transfer to a separating funnel. Run off the organic layer,
extract the aqueous phase with an additional portion of 40-60 petroleum ether (20 mL)
and combine the two organic layers. Wash the combined petroleum ether fractions
with saturated sodium bicarbonate (2 × 20 mL) and dry the organic layer over sodium
sulfate. Remove the solvent in vacuo to afford the crude product, then obtain a 1H NMR
spectrum and IR spectrum of the material obtained.
Part 2: Acetylation of carvacrol
BEFORE STARTING: Read the Advanced Techniques Sections, which describe
how to perform the chromatography steps. Videos have been linked on the
course Moodle page that show how to perform tlc analysis and how to purify
materials using flash chromatography.
Transfer crude carvacrol (0.75 g, 5 mmol), 1,4-diazabicyclo[2.2.2]octane “DABCO”
(0.56 g, 5 mmol) and a small magnetic stirring bar to a 25 mL RB flask. Acetic
anhydride (0.7 mL, 7.4 mmol) should then be added, and the reagents mixed for 40
minutes (the reaction will become warm and may become more viscous). Once the
reaction period is complete, add ethyl acetate (15 mL). Transfer the resulting mixture
to a separating funnel and wash with saturated sodium bicarbonate solution (20 mL).
Separate off the ethyl acetate fraction and extract the aqueous layer with a second
portion of ethyl acetate (15 mL). Wash the combined ethyl acetate fractions with water
(20 mL), then brine (20 mL) and dry over sodium sulfate. Remove the solvent in vacuo,
then purify the resulting crude material (this will be an oil) by flash chromatography
(see comments below).
46
You should allow a full lab session to purify a product using flash
chromatography.
You should use silica as the stationary phase, and you should use 40-60 petroleum
ether and ethyl acetate mixture (10:1) as the eluting solvent. Be careful to take fractions
of a suitable size. Characterise your product (1H NMR, IR)
You can identify which collection tubes contain eluted material by t.l.c. analysis using
a mixture of 40-60 petroleum ether and ethyl acetate (10:1). The t.l.c. plate is best
visualised in this case by placing the developed plate under a UV light. However,
dipping in aqueous potassium permanganate solution can be considered if no spots
are visible under UV light. Permanganate dip should give white or yellow spots on a
purple background. (The plate may need warming with a heat gun to make the spots
show up more clearly).
Housekeeping
Clean out the chromatography column and return it to the cupboard as soon as you
have finished with it, putting the used silica into the labelled waste container. NOTE Silica gel or alumina cannot be disposed of into the solid waste bottle while damp with
hazardous organic solvents. It must be dry, i.e. a free-flowing powder, with no lumps.
To clean out the column, you should clamp it upside down, with the tap open, over a
beaker, on a short retort stand, at the back of your fume cupboard. Columns
containing damp silica can be clamped the right way up, stoppered, and left in your
bench cupboard overnight, then left open as before in a fume cupboard the following
day.
47
Notes and Calculations
48
PLANNING TASK
49
EXPERIMENTAL PLANNING TASK: Experiment A3/B3/C3
Multistep Synthesis of a Heterocycle from Benzaldehyde
INTRODUCTION
Executing efficient multistep synthetic sequences is an essential part of academic and
commercial research work, the ability to design and conduct such procedures is
therefore a key skill that organic chemists must have. These skills are likely to be useful
in the near future as part of industrial placement, research/study abroad or in honours
research projects. In this experiment, you will complete a 3-step synthesis of a
heterocycle. The procedure for the 1st step is provided for you, a choice of procedures
for the 2nd step is available, and you will need to adapt a literature procedure to attempt
the final step.
The assessment of this experiment will be conducted in the format of an
interview. You will also need to submit a short risk assessment for approval by
staff prior to attempting the final step of the synthesis.
This system is in many respects, analogous to conducting research work, all
experiments conducted in the Purdie building research laboratories must be planned,
risk assessed and approved by senior research staff before commencing any
laboratory work. The project you complete in year 4 or year 5 will include an oral
assessment, as well as writing a thesis that summarises your findings.
The reaction sequence you will follow is illustrated below, your task is to prepare 2,3diphenylquinoxaline from benzaldehyde in 3 steps.
The quinoxaline motif is an important synthetic target since it is present in many
pharmaceuticals, some examples are shown below: Brimonidine is used to treat ocular
hypertension, Varenicline is used to treat nicotine addiction and Quinacillin is a betalactam antibiotic.
50
PROCEDURES
Step 1 – Synthesis of Benzoin
Transfer benzaldehyde (61.2 mmol), 24 mL of ethanol, 0.86 g of 3-benzyl-5-(2hydroxyethyl)-4-methylthiazolium chloride and 2.5 mL of triethylamine to a 100 mL
round-bottom flask. Equip the flask with a reflux condenser, calcium chloride drying
tube and magnetic stirrer and heat the stirred mixture to reflux for 1 hour. After cooling
to room temperature, pour the reaction mixture onto crushed ice (ca. 60 g). Once the
ice has melted, add ca.18 mL of 2 M HCl in small portions with stirring until the reaction
mixture reaches pH 1. The resulting precipitate should be collected by filtration and
washed with ice-cold water. Recrystallise the crude product from a minimal volume of
aqueous ethanol.
Characterise the product (1H NMR, IR and melting point).
Step 2 – Oxidation of Benzoin to Benzil: Overview
Videos relating to all of the oxidation procedures have been provided for you on
the course Moodle page.
Before you attempt this part of the planning task, you must first select which of the
oxidation procedures you will use. There are 3 potential options (outlined below) for
oxidising benzoin to benzil. You should read all the procedures very carefully
before selecting one of them to allow you to prepare the target compound. You
will be asked to justify your selection as part of the assessment for this
experiment. As part of the selection process, you should consider the following points:
how hazardous the procedure is, how efficient you think the isolation/purification* of
the product will be and how much time is required to prepare the target compound.
You will also be expected to consider the processes required to remediate the
waste you generate, this is a major consideration in research and industry settings,
indeed in many cases, the hazards and costs (in time and money) of proper disposal
is the deciding factor when selecting an appropriate reaction. In addition to the potential
oxidation procedures, you have also been provided with the associated methods
approved by the school safety officer for disposal of the waste from these reactions.
* There are different ways of considering the efficiency of a chemical reaction, three examples are
provided, see the Appendix below for further details.
Option 2a: Oxidation of Benzoin to Benzil
Transfer benzoin (9.4 mmol), 15 mL of glacial acetic acid, 5 mL of water and 3.75 g of
cupric acetate monohydrate to a 250 mL round-bottom flask. Equip the flask with a
reflux condenser and magnetic stirrer and heat the stirred mixture to reflux for 15
minutes. Ensure the mixture is well stirred and that the aqueous acetic acid is actually
boiling before you start timing. Using a large pre-heated funnel plugged with a small
quantity of glass wool (heat the funnel/glass wool assembly in an oven), remove the
51
resulting cuprous oxide by “hot filtering” the hot reaction mixture. After cooling to room
temperature add 50 mL of water, filter off the resulting yellow-green solid under suction
and wash the filter cake with cold water (2 × 15 mL). Recrystallise the crude product
from a minimal volume of ethanol.
Characterise the product (1H NMR, IR and melting point).
Management of waste for option 2a: Wash the copper(I) oxide off the glass wool
using about 20 mL of water. To the suspension of Cu 2O, add 40 mL of 1 M H2SO4.
(this causes a self-redox or "disproportionation" whereby half of the Cu 2O becomes
blue CuSO4 in solution while the other half becomes Cu metal in powdered form)
The next reaction can be vigorous and releases flammable/explosive hydrogen
gas - ensure there are no flames in the fume cupboard and that all electrical
apparatus is switched off. In SMALL portions, commensurate with the size of your
beaker or flask, add a total of 1 g of Mg turnings. If after all the Mg has reacted the
solution is still blue, add some more Mg turnings. When the solution is colourless, filter
off the copper powder on a small paper, rinse with acetone, dry under suction, then
deposit the copper powder in the waste copper container. The filtrate can be flushed
down the sink and the filter paper disposed of in a waste bin.
Option 2b: Oxidation of Benzoin to Benzil
Transfer benzoin (9.4 mmol), 15 mL of glacial acetic acid, 5 mL of water, 2.1 g of
ammonium nitrate and 0.24 g of cupric acetate monohydrate to a 250 mL round-bottom
flask. Equip the flask with a reflux condenser and magnetic stirrer, then heat the
mixture to reflux for 90 minutes. Ensure the mixture is well stirred and that the aqueous
acetic acid is actually boiling before you start timing. Cool to room temperature, then
add 50 mL of water. Filter off the resulting solid under suction and wash the filter cake
with 10 mL of water.* Recrystallise the crude product from a minimal volume of ethanol.
*The solution should be clear and green. In the event that a brown suspension of cuprous
oxide is obtained, this can be removed by hot filtration. This is achieved by plugging a glass
filter funnel with a small quantity of glass wool and heating the funnel in an oven. The hot
funnel should then be used to filter the hot reaction mixture.
Characterise the product (1H NMR, IR and melting point).
Management of waste for option 2b: This quantity of copper waste does not pose a
significant hazard, in this case the aqueous waste can be flushed down the sink with
plenty of water.
Option 2c: Oxidation of Benzoin to Benzil
Before starting the reaction, transfer 300 mL of water to a 600 mL beaker and add 10
drops of bromothymol blue indicator. This will serve as a “scrubber” to dissolve the
acidic gases released in the reaction (see figure 8). A video is available on the
Moodle page that shows how to connect the reaction assembly to the solution.
52
Figure 8 – Gas scrubbing apparatus
Transfer benzoin (9.4 mmol), to a 100 mL round-bottom flask, then carefully add 10
mL of concentrated nitric acid. Equip the flask with a reflux condenser and magnetic
stirrer, then heat the mixture to 100-110 °C for 60 minutes. The reaction of benzoin
with hot nitric acid proceeds with the significant release of corrosive and toxic nitrogen
oxide fumes. As the reaction progresses, the release of red/brown fumes should begin
to subside. As the reaction proceeds, you will see the colour of the scrubbing solution
will change from blue to green or yellow. Do not remove the condenser once the
reaction period ends (See waste management section below) Allow the reaction
mixture to cool (after 10 minutes of cooling in air, the reaction flask can be immersed
in a water bath). After cooling to approximately room temperature, add 30 mL of water
down the condenser while stirring the cooled reaction mixture. It is now safe to carefully
remove the condenser and place it in the fumehood. Filter off the resulting solid under
suction and wash the filter cake with water until the filtrate emerging from the funnel is
neutral to pH paper (this will likely generate a large quantity of aqueous waste). The
crude product does not always solidify quickly when water is added to the reaction
flask, so cooling in ice may be required to obtain a solid. Recrystallise the crude product
from a minimal volume of ethanol.
Characterise the product (1H NMR, IR and melting point).
Management of waste for option 2c:
As highlighted above, the reaction releases a significant quantity of gaseous nitrogen
oxides. It is essential that when the reaction is complete, the residual gases in the
reaction assembly are carefully ventilated in the fumehood. The procedure above
instructs you to pour water down the condenser into the reaction flask once the reaction
mixture has cooled. The addition of water will dissolve some of the nitrogen oxides,
however, the condenser should be removed carefully and stored in the fumehood to
allow all the gaseous substances to be vented in the hood for 10-15 minutes.
53
The scrubbing solution will likely be acidic, this should be neutralised with sodium
bicarbonate, CARE! Addition of sodium bicarbonate should be gradual, with stirring to
avoid frothing. The solution can be washed down the sink once it has been neutralised.
Similarly, the aqueous solutions used to wash the crude product will also be acidic.
The acidic aqueous filtrates must be neutralised and then washed down the sink.
Step 3 – Preparation of 2,3-Diphenylquinoxaline
The procedure for the final step should be selected from the publications listed below
(also linked on the Moodle page). You should read all the documents very carefully
before selecting one of the procedures to allow you to prepare the target
compound. You will be asked to justify your selection as part of the assessment
for this experiment. As part of the selection process, you should consider the
following points: how hazardous the procedure is, how efficient you think the
isolation/purification* of the product will be and how much time is required to prepare
the target compound.
* There are different ways of considering the efficiency of a chemical reaction, three examples are
provided, see the Appendix below for further details.
The reaction procedure you select should be adjusted so that:
1. The reaction scale is based on 3 mmol of Benzil.
2. The crude compound should be purified by recrystallisation from ethanol or
methanol.
3. The final product must be characterised by 1H NMR spectroscopy, IR
spectroscopy and melting point).
References
1.
C. Delvipo, G. Micheletti and C. Boga, Synthesis, 2013, 45, 1546-1552.
2.
R. W. Bost and E. E. Towell, J. Am. Chem. Soc., 1948, 70, 903-905.
Note – The procedure suggests treating the product with “Norite”, this is not required.**
3.
H. R. Darabi, F. Tahoori, K. Aghapoor, F. Taala, and F. Mohsenzadeh, J. Braz. Chem.
Soc., 2008, 19, 1646-1652.
**In older procedures, it was frequently recommended that compounds with coloured
impurities be treated with activated charcoal (one of the trade names being "Norit" or
“Norite”). This involved heating the compound in a polar solvent in the presence of a
small quantity of charcoal, the objective being that the coloured impurity would be
absorbed by the charcoal. The resulting solution would be hot filtered and the desired
(colourless) product allowed to crystallise.
If you decide to try the prep in reference 2 you do not have to perform the
decolourising step using charcoal (although note, that you would probably have to if
you repeated the reaction on the scale described in the paper).
54
Appendix: Reaction Efficiency
1) % Yield: This term allows the quantity of product obtained to be expressed as a %
of maximum that can be made in theory.
% 𝐘𝐢𝐞𝐥𝐝 =
𝑨𝒄𝒕𝒖𝒂𝒍 𝒚𝒊𝒆𝒍𝒅
× 𝟏𝟎𝟎
𝑻𝒉𝒆𝒐𝒆𝒕𝒊𝒄𝒂𝒍 𝒚𝒊𝒆𝒍𝒅
2) Atom Economy: This term allows efficiency to be measured in terms of the
proportion of the atoms in the starting materials that are transferred to the desired
product.
𝐀𝐭𝐨𝐦 𝐄𝐜𝐨𝐧𝐨𝐦𝐲 =
𝑭𝒐𝒓𝒎𝒖𝒍𝒂 𝒘𝒆𝒊𝒈𝒉𝒕 𝒐𝒇 𝒑𝒓𝒐𝒅𝒖𝒄𝒕
× 𝟏𝟎𝟎%
𝑭𝒐𝒓𝒎𝒖𝒍𝒂 𝒘𝒆𝒊𝒈𝒉𝒕 𝒐𝒇 𝒂𝒍𝒍 𝒓𝒆𝒂𝒄𝒕𝒂𝒏𝒕𝒔
3) E Factor: This term is closely related to atom economy, this allows the amount of
overall waste generated by a chemical reaction to be considered.
𝐄 𝐅𝐚𝐜𝐭𝐨𝐫 =
𝒎𝒂𝒔𝒔 𝒐𝒇 𝒎𝒂𝒕𝒆𝒓𝒊𝒂𝒍𝒔 𝒖𝒔𝒆𝒅 − 𝒎𝒂𝒔𝒔 𝒐𝒇 𝒑𝒓𝒐𝒅𝒖𝒄𝒕
𝒎𝒂𝒔𝒔 𝒐𝒇 𝒑𝒓𝒐𝒅𝒖𝒄𝒕
References
C-J. Li, B. M. Trost, Proc. Natl. Acad. Sci. U.S.A., 2008, 105, 13197.
R. A. Sheldon, Pure Appl. Chem., 2000, 72, 1233.
55
Notes and Calculations
56