Warwick University
Department of Chemistry
Year 3 Organic Chemistry
Laboratory Courses –
Organic 2 (O2) – experiment
and write up.
2012-2013
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Year 3 Organic Chemistry course O2.
Introduction
It is of vital importance that you read thoroughly the information obtained in this course
manual and attend the pre-lab talk. You should also read the accompanying ‘Experimental
techniques and methods booklet‘ before starting this course.
Year 3 organic laboratory experiment O2: Pd-catalysed coupling reactions
between sp2 centres.
The use of palladium reagents for the catalysis of C-C, C-N and C-O bond formation
provides a powerful synthetic method in organic chemistry, largely because it
provides an efficient method for the formation of bonds that would otherwise be very
difficult to create, for example between two sp2-carbon atoms. A large number of
highly active catalysts, active across a diverse range of substrates, have been reported,
and the importance of the area was reflected by the award of a Nobel prize in 2010 to
three pioneers of the field; Akira Suzuki, Richard Heck and Ei-Ichi Negisihi. Several
new ligand/metal combinations have been developed for these reactions.
The mechanism of the reaction will not doubt have been discussed in some of your
lecture courses. However, briefly, the coupling process usually involves the insertion
of a Pd species (usually Pd(0)) into an appropriate C-X bond where X might typically
be a halide, triflate, etc. The halide or triflate is then exchanged for a second aryl or
vinylic group on the metal then reductive elimination generates the organic product
and inorganic side products (Scheme XX).
In this experiment, you will gain experience in the planning and undertaking of a Pdcatalysed coupling reaction between an alkene and an aromatic halide. You will first
prepare a vinyltrifluoroborate salt, which will then be coupled to an aromatic halide in
the second step. Some references to this process are given at the end of the
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experimental details. An example of the coupling reaction is summarised below, using
4-bromoacetophenone. You will be assigned a target molecule, the structure of which
will determine the halide that you use:
This protocol has recently been adopted as a valuable and versatile synthetic method
for the formation of C-C bonds. Both the vinylic and the aromatic group can be
substituted with a number of functional groups. The intermediate potassium salt is
relatively air stable and is fully water stable, however all synthetic steps should be
carried out under an inert atmosphere using dry apparatus. A variety of palladium
sources can be employed as the catalyst, and the solvent is normally an alcohol, most
commonly methanol or isopropanol.
In this experiment you will first attempt the standard reaction above to prepare the
vinyltrifluoroborate intermediate. In the second step you will be given a synthetic
target (in the same way as was done in laboratory O1), the structure of which will
indicate what starting materials you need to use. You will then have to design and
execute a synthetic sequence to this target molecule, which will include the
completion of risk assessments where required.
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Preparation of the intermediate salt:
This reaction involves the use of a highly water-sensitive Grignard reagent, and
therefore must be carried out under an inert nitrogen atmosphere with careful transfer
of the Grignard reagent to the flask. Dry reagents and solvents should be used, and a
full risk analysis should be completed before the reaction is undertaken. A typical
procedure is as follows:
Set up an appropriately-sized (ca. 100mL), (at least) two-necked flask with a gas to
gas nitrogen inlet and a suba seal. Flush nitrogen through at a suitable rate for five
minutes. Add dry THF (4.5 mL) to the flask using the syringe-which will be kept in
the seal of the THF bottle). Only do this under the direct supervision of a
demonstrator. Add trimethoxyborate (0.696g, 0.0067 mol, 1.2 eq.) to the solution by
injecting the neat liquid carefully through the suba in one portion. Leave the syringe,
after use, in the seal of the trimethoxyborate bottle (ready for the next user). The
mixture then needs to be cooled to -78oC using a cooling bath containing solid carbon
dioxide in acetone - caution. The temperature of the solution does not have to be
measured, but the solution should be allowed to cool for a full 15 minutes to ensure
that it has fully cooled. Be aware that dry ice and this cold bath may cause burns in
contact with your skin!!
Carefully, by syringe, a solution of vinylmagnesium bromide (5.4 mL of a 1.0M
solution in THF, 5.4 mmol, 1.0 eq.) should be added to this cold solution. This
addition should be completed dropwise over a total time of about 10 minutes. At the
end of the addition the syringe should be replaced in the seal of the Grignard reagent
bottle, ready for the next user. The solution should then be stirred at -78 oC for 20 min
and then allowed to warm to room temperature by removal of the cooling bath (but
keeping the reaction under the nitrogen atmosphere). After the reaction has been at
room temperature for at least 15 minutes, solid KHF2 (2.11g, 26.8 mmol, 4.0eq.)
should be added in a single portion. This should be done by briefly removing the suba
seal and adding the solid rapidly against the flow of nitrogen as a single portion, then
replacing the suba seal immediately. This should be followed by the slow addition of
water (3.6 mL) to the reaction mixture, again by removing the seal (which does not
have to be replaced after this point) and adding the water dropwise over ca 10
minutes. The resulting mixture should be stirred for 30 minutes. An inert atmosphere
is no longer required,
The reaction should then be concentrated under reduced pressure on a Buchi (rotary
evaporator, warm bath at around 50 oC). It is important to remove all of the water so
that a white solid is formed. This will require elevated temperature (about 50-60 oC)
on a rotary evaporator and also further drying by the direct use of a vacuum pump for
the removal of the final traces of water. Once the water has been removed, acetone
(about 10 mL) should be added to the solid, and warmed. When warm, the acetone
should be decanted from the remaining solid (use a pipette) and filtered through a
simple filter paper/funnel combination into a conical flask. This sequence should be
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repeated a further three times with fresh acetone and in each case the hot acetone
should be filtered into the same conical flask so that the acetone extracts gradually
accumulate in the flask.
At this point, there should be a white solid remaining in the original reaction flask.
This is not the product but you should retain it until you have completed the isolation
of the required compound, since this may still contain some product.
The combined acetone extracts contain the product that you require. The solvent
should be carefully removed under reduced pressure using a rotary evaporator, to
leave a white solid. If any water is still left in the product from the earlier step, then
the product will be a waxy solid. If this is the case with your product then you need to
place it under high vacuum (i.e. vacuum pump) for an extended period until it
becomes a solid. This is the vinyltrifluoroborate product salt required for the next
step. The salt can be recrystallised from acetone or precipitated using diethylether if
required. Record your final yield of dried white solid product carefully.
A sample of this white product should be submitted for NMR analysis in d6-acetone
(it will not dissolve in CDCl3). You do not need to get any other data.
Palladium-catalysed coupling reaction.
Note that this example is for coupling with 4-bromoacetophenone. If your product
requires an alternative halide, you will need to calculate how much of the reagent to
use (based on 0.50 mmol as per the procedure below).
A two necked, 100 mL flask, fitted with a reflux condenser attached to a nitrogen
inlet, magnetic stirrer bar and a subaseal, should be set up under a nitrogen
atmosphere. At room temperature, the vinyltrifluoroborate salt from the previous step
(80 mg, 0.6 mmol, 1.3 eq.), PdCl2(dppf).dcm (8.5 mg, 0.01 mmol, 0.02 eq), 4bromoacetophenone (100 mg, 0.50 mmol, 1.0 eq.) and triethylamine (48 mg, 0.50,
1/.0 eq. mmol) are dissolved in MeOH (6 mL). The recommended order of addition is
that any solid reagents should be added to the dry empty flask first after removing the
condenser. The reflux condenser (attached to a nitrogen inlet) should then be
reattached to the flask and flushed for minutes with nitrogen. Through the sidearm,
the solvent should be added next, followed by any other reagents that are liquids, and
finally the triethylamine. The solids and any low-volatility liquids should be weighed,
whilst the volume of the triethylamine should be accurately measured using a Gilson
syringe. Following addition of all the reagents, the subaseal should be replaced. The
stirred mixture is then heated at reflux (ca. 80 oC) for three hours. At the end of this
time the reaction should be allowed to cool (15 mins to cool is OK) and a sample
should be taken for TLC analysis against the ketone starting material. A suitable
solvent will have to be found for this, as well as a suitable visualisation technique. If
significant amounts of starting material still remained, the reaction can be heated for a
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further 1h at reflux. At the end of this time the reaction is allowed to cool. From this
point an inert atmosphere is no longer required.
The coupling product is entirely organic and should be soluble in organic solvents but
not aqueous ones. A typical work up would involve addition of water and CH2Cl2
(about 10 mL of each) to the reaction, transfer of the reaction mixture to a separating
funnel, shaking and then separation of the lower, CH2Cl2, layer (which contains the
product). If the two layers do not separately cleanly then further quantities of each
solvent may be added, but no more than 20 mL of each. The remaining aqueous layer
should be extracted further twice with a similar volume of CH2Cl2 to that which was
used in the initial separation (but no more than 20 mL). The three different CH2Cl2
extracts should be combined and together washed with water (twice, about 20 mL
each time) using a separating funnel again to assist separation of the layers. As
always, the two layers in the separating funnel should be given sufficient time to
separate in order to minimise the amount of water which gets into the
dichloromethane layer. The CH2Cl2 solution should be dried using MgSO4 and then,
after filtration, the solvent should be removed to yield crude product.
The crude reaction should be investigated by TLC and this information used to purify
the product using column chromatography on SiO2. Be careful when removing the
solvent from the final product, since it might be volatile. 1H-NMR spectrum of the
product (in CDCl3) should be obtained, as well as an IR spectrum of the product.
Relevant references/background reading:
Formation of alkenyltrifluoroborates and coupling with aryl halides: G. A. Molander
and M. R. Rivero, Org. Lett. 2002, 4, 107-109. This paper contains an account of the
preparation of the potassium vinyltrifluoroborate, and its coupling to a series of aryl
halides using PdCl2(dppf).DCM in eiher i) nPrOH/Et3N or ii) THF/H2O and Cs2CO3.
The full experimental details are given in the supporting information for this paper.
Coupling of aryltrifluoroporates with aryl halides. G. A.Molander and B. Biolatto, J.
Org. Chem. 2003,68, 6302-6314. Aryltrifluoroborates were prepared by the reaction
of boronic acids with an aqueous solution of KHF2. The couplings were typically
carried out using Pd(OAc) 2 and K2CO3 in methanol or water at reflux. In some cases,
triphenylphosphine was added. PdCl2(dppf).DCM was also used as the catalyst, with
Et3N at reflux in ethanol.
Preparation of potassium vinyltrifluoroborate and coupling with an aromatic bromide:
G. D. Williams, C. E. Wade and M. Wills, Chem. Commun. 2005, 4735-4737.
Experimental details are in the supporting information for this paper. In this case the
salt was prepared as described above and precipitated from acetone using ether. The
coupling was carried out using Pd(PPh3)4 and K2CO3 in toluene/ethanol.
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An earlier preparation of the potassium vinyltrifluoroborane: S. Darses, G. Michaud
and J.-P. Genet, Tetrahedron Lett. 1998, 39, 5045-5048. This paper contains an
account of the synthesis of the salt and its purification (in reference 9).
Another preparation of potassium vinyltrifluoroborate: R. Grisorio, P. Mastrorilli, C.
F. Nobile, G. Romanazzi, G. P. Suranna, G. Gigli, C. Piliego, G. Ciccarella, P.
Cosma, D. Acierno, and E. Amendola Macromolecules 2007, 40, 4865-4873. A
slightly modified, but not dramatically different, procedure, using a Soxhlet extraction
to obtain the product.
A later reference describing an extension of the methodology: G. A. Molander, S. L.
J. Price, S. M. Kennedy, S. D. Dreher and M. T. Tudge, J. Am. Chem. Soc. 2012, 134,
11667-11673.
The preparation of the salts has been investigated in some detail: A. J. J. Lennox and
G.C. Lloyd-Jones, Angew. Chem. Int. Ed. 2012, 51, 9385-9388.
Writing up your work
You should write up your experiments in an A4 bound-booklet (i.e. the same as in
years 1 and 2) as you go along using the format described earlier in the ‘Experimental
techniques and methods booklet’. The experimentals should contain all the important
information such as quantities of material used, yield, procedure in detail etc.
At the end of the laboratory course, when all the experiments have been completed,
you should write up the results of your work, together with an analysis of your data, in
the proforma (see below). The completed write-up proforma, your spectra and your
labook should then be handed in to the undergraduate office by the deadline given at
the end of the course.
The write-up should be a maximum of 4 sides of A4 in length, written on the
proforma required (see Appendix 1) and taped or stuck into your laboratory
book after the individual records of each experiment. This will include the
following sections (note there is no need to write out the entire procedure from the
laboratory manual). The pieces of data underlined below must be obtained and added
as an appendix after the write-up. i.e. you need to hand in your laboratory book with
the write-up proforma and spectra stuck in it.
Section 1: A summary of your experimental results (consisting of the following
components):
Step 1: Vinyltrifluoroborate salt:
Any modifications to the general procedure. Details of purification and yield as (mass,
moles, %), Retain a small sample (<50mg) and hand it in.
Step 2: Palladium-catalysed coupling product:
A listing of names and quantities of reagents used. Full details of how it was purified.
Details of the reaction which you carried out with yields as (mass, moles, %).
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TLC details of the reaction as it was followed and illustrations of plates – NOT the
original plates, as they contain hazardous materials. Melting point if applicable.
Hand in your product (fully labelled) at the end of the laboratory course.
Section 2: A full interpretation of the spectroscopic data for each of the
compounds which have been prepared and purified above.
Spectra for vinyltrifluoroborate: 1H-NMR, for final product: 1H-NMR and IR.
This section should be structured in a logical way that allows you to prove or confirm
the structure of the compound(s) which you have prepared. The analysis should
include the following details (see the proforma):
IR: just 2 major peaks, indicating the key functional groups in the molecule.
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H-NMR: Each peak from 0-10 ppm should be characterised as: position (in ppm),
no. of protons (from integral), multiplicity (i.e. doublet, triplet etc.), J values (coupling
constants in Hz) and assignment (i.e. which H it is in the molecule). Do not quote
solvents or peaks which are not part of the structure.
Section 3: Questions:
Suggest a synthesis of your target molecule which does not involve a coupling
reaction. Discuss any difficulties you might encounter and how the Pd-catalysed
reaction circumvents these.
_____________________________________________________________________
Notes
 Your general competence will be assessed throughout the course by the
demonstrators. They will note your attention to safety matters and your
experimental technique. They will note your ability to answer questions about the
experiment you are doing and the quality of the planning of each experiment you
undertake. They will also take particular note of the general cleanliness and
tidiness of your work. If you work in an unclean and messy way (e.g. if you do not
immediately attend to solid or liquid spills), you will have marks deducted.

You have been given explicit guidance in the manual on how to keep a proper
record of your experiments. The importance of keeping an accurate laboratory
notebook cannot be overemphasised. If in doubt as to whether or not something
should be recorded, remember the basic criterion that your experiments should be
recorded in sufficient detail that another worker could repeat them exactly. (When
you have written up an experiment, imagine that you are another chemist and ask
yourself if you could repeat the experiment as described exactly.) Remember that
work not recorded accurately = work not done.

Sample quality is of paramount importance. The two things that are essential are
that (i) the compounds you make are adequately characterised and that (ii) they are
pure and that you have evidence of their purity. Remember that you must retain a
reference sample of each compound you make, properly labelled with its structure,
your name and the page number of you laboratory notebook in which its
preparation is described. It is normally sufficient to retain ca. 50-100 mg of a
compound as a reference standard. If for whatever reason your data are incomplete
when you come to write up your report, with a reference sample in hand, you will,
always be able to obtain the missing data. Your reference samples will be used by
the demonstrators to allocate a mark for “quality of samples” (see above).
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APPENDIX 1: Write-up proforma for O2 (to be downloaded as word document from):
http://www2.warwick.ac.uk/fac/sci/chemistry/research/willsgroup/teaching_materials.
SUBMISSION DEADLINE: 12.00 noon one week after the last day of the course
Year 3 Organic Chemistry O2 Laboratory Report. 2012-2013 academic year
Please read these instructions carefully:
Any text in red can be deleted.
Type your write up into this pro-forma or print it out and write on in (leaving suitable spaces where
required).
You can change the spacing between each heading and prompt, but you should not change the font
size or type. However, the finished report should not exceed four pages in total (not counting the
appended spectra).
Paste this report into your laboratory book, with the three IR and three NMR spectra (see below), and
hand it in to the undergraduate office.
Student name: ______________________________
Section 1: Summary of experimental results.
Part One: Preparation of vinyltrifluoroborate salt:
i) Describe any changes to the laboratory procedure (do not write out the full procedure):
ii) Give the yield of product you obtained (mass in g, no. moles, % obtained, solvent from
which it was recrystalised if applicable), and melting point if it was a solid:
iii) Confirm that you have handed in a labelled (with your name and a diagram of the
compound) sample by ticking this box: □
Part Two: Pd- catalysed coupling reaction:
i) List reagents used (name, mass in g, no. moles):
ii) Describe the full procedure which you followed, including pictures of the TLC plate with
solvents used:
iii) Give the yield of product you obtained (mass in g, no. moles, % obtained, solvent from
which it was recrystalised if applicable), and melting point if it was a solid:
iv) Confirm that you have handed in a labelled (with your name and a diagram of the
compound) sample by ticking this box: □
Section 2: Spectroscopic data (attach ONE NMR spectrum for step 1 and ONE NMR spectrum
and ONE IR spectrum for step 2 at the end of the report). If you have more than one spectra
of product, append only the one you have selected for the tables below. Draw a diagram of
the molecule on the 1H-NMR spectrum, and label each proton or group of protons with
(a,b,c…etc.) so that you can refer to them in the table*). You do not have to draw a diagram
on the IR spectra.
Step 1 product:
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NMR spectrum: Complete the table, add more rows if required. DO NOT include solvents or
peaks unrelated to the product.
Use a diagram to assign peaks a,b,c etc…:
Position of peak
Integral
Multiplicity (s, d, J value if not Proton(s)
(relative no. of t, q, quin)**
a S or m)
responsible for
selected/ppm(),
Hs)
the peak
highest first.
(a,b,c..etc.*).
** s=singlet, d=doublet, t-triplet, q=quartet, quin=quintet, m=multiplet, dd=double doublet, etc.
Please give ppm (d) values to two decimal places and couplings (J) values to 1 decimal place only.
Step 2 product:
IR spectrum: Complete the table, do not include more than 2 key absorptions, i.e. select only
the most significant ones.
Position of peak
Strong (S), Medium
Functional group
Bond stretch or
/cm-1, highest first.
(m) or weak (w)?
creating the peak
bend?
NMR spectrum: Complete the table, you may add more rows if required. DO NOT include
solvents or peaks unrelated to the product.
Use a diagram to assign peaks a,b,c etc…:
Position
selected/ppm(),
highest first.
Integral
(relative no. of
Hs)
Multiplicity (s,
d, t, q, quin)**
J value(s) if
not m or s)
Proton(s)
responsible for
the peak
(a,b,c..etc.*).
** s=singlet, d=doublet, t-triplet, q=quartet, quin=quintet, m=multiplet, dd=double doublet, etc.
Please give ppm (d) values to two decimal places and coulings (J) values to 1 decimal place only.
Section 3: questions: Suggest a synthesis of your target molecule which does not
involve a coupling reaction. Briefly discuss any difficulties you might encounter and
how the Pd-catalysed reaction circumvents these (free hand or computer-drawn).
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APPENDIX 2: marking scheme:
Year 3 Organic Laboratory ‘O2’ marking scheme.
The marks are distributed as follows:
Safe working 10%
Lab notes and experimental design (calculations etc) 20%
Quality of samples as assessed by sample and spectra, 30%
Quality of spectroscopic interpretation 30%
Synthetic question on proforma 10%
Loss of marks; Students should be advised that marks will be reduced; i) if an experiment is
not accompanied by a signed (by an academic) safety assessment, ii) if the final report is over
4 pages in length (with margins, but not counting spectra, which may be added as an
appendix). Marks will also be reduced if the report is handed in late without permission or
good reason.
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