Table Of ContentPreface
By combining and updating my previous laboratory manuals (1971, 1981 and
1988),thisbookdocumentsthemostimportantsyntheticmethodsinthefields
of acetylenes, allenes and cumulenes, as well as isolation techniques for
compounds with low stability or high volatility, illustrating experimental
proceduresonapreparativescalethatwereeithercarriedoutbytheauthoror
underhisclosesupervision.Mostprocedureshavebeenupdated,withsomeof
the original procedures that seemed unsafe or time-consuming being replaced
by easier alternatives.
Some useful practical tips are provided in the first chapter and in a number
of procedures explanation is given about the reaction conditions applied. In
mostcases,however,theseimplicitlyreflecttheknowledgeaboutreactivityand
reaction mechanisms in the field, acquired from the literature and during
extensive bench experience.
During the last 10 to 15 years the safety rules for experimentation have
become much more severe. A number of reagents and solvents are no longer
commercially available or have become extremely expensive. In practical
courses syntheses are now carried out on a much smaller scale for reasons of
safety and economy. The changed situation is taken into account in this new
work by the inclusion of procedures and results for smaller scale reactions. In
some procedures DMSO is used as a solvent instead of HMPT, which is
considered to be a carcinogen. Some procedures present the use of organic
solvents(e.g.DMSO–THF)asanalternativetoperformingreactionsinliquid
ammonia, which often has to be freed from water by a time-consuming,
evaporation-condensation operation. A number of procedures from more
recent research in the author’s group as well as several selected unchecked
methods from the literature are included, mostly in tabular form.
IamverygratefulforthepleasantandfruitfulcooperationofMrHermann
D.VerkruijssethatIhaveenjoyedoverfourdecades.IamalsoindebtedtoDr
Nina A. Nedolya for the painstaking correction of the manuscript and for
useful suggestions.
I dedicate this book to my wife Liesbeth who continuously supported me
during my career in chemistry.
L. Brandsma
June, 2003
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List of Tables
Table 3.1 Generation of metallated acetylenes and cumulenes
by 1,2- and 1,4-elimination reactions 29
Table 3.2 Elimination reactions from literature 30
Table 3.3 Metallation of allenes and acetylenes with a
non-terminal triple bond 32
Table 3.4 Base-promoted ‘contrathermodynamic’ isomerisations 37
Table 3.5 Lithium acetylides, RC(cid:2)CLi, from organyl-di- or
trihalogenoalkenes and alkyllithium 37
Table 3.6 Solubilities of metallated acetylenic compounds 40
Table 6.1 Reactions of metallated acetylenic and allenic
compounds, RM, with heterocumulenes 136
Table 6.2 Acylation of metallated acetylenes, R1C(cid:2)CM,
and allenes, R1R2C¼C¼CHLi 140
Table 12.1 1,3-Substitutions with acetylenic, allenic and
cumulenic derivatives 238
Table 14.1 Cadiot–Chodkiewicz cross-couplings 278
Table 15.1 Copper(I) chloride-catalysed oxidative coupling
of acetylenic compounds 284
Table 16.1a Pd/Cu-Catalysed cross-couplings of
ethynyl(trimethyl)silane with sp2-halides 295
Table 16.1b Pd/Cu-Catalysed cross-couplings of acetylenic
alcohols with sp2-halides 296
Table 16.1c Other Pd/Cu-catalysed cross-couplings 297
Table 17.1 Base-catalysed isomerisations of acetylenic compounds 321
xi
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1
Procedures and Equipment
1.1 GENERAL
For most of the procedures described in this book a round-bottomed, three-
necked flask equipped with a combination of a dropping funnel and an inlet
for inert gas, a mechanical stirrer and a combination of a thermometer and
an outlet is recommended (Figure 1.1). If during the performance of the pro-
cedure no gases are evolved from the reaction mixture, the inlet for inert gas
may be omitted and the outlet connected to a balloon or relatively big flask
filledwithinertgas.Dependingupontherequiredefficiencyofstirringasimple
glassrodwithaflattenedend,achromium-platedpaddle(Figure1.2)orother
types may be used. A flask having both of the outer necks in a non-vertical
positionisimpractical since itisdifficulttoplace thethermometerorgasinlet
tubesuchthatcontactwiththestirrerisavoided.Insteadoftheusualmercury,
alcohol or pentane thermometer an electronic thermometer may be used.
If relatively small volumes of reagents have to be added over a short period,
the combination of a syringe and a rubber septum may be more convenient
than the dropping funnel.
Magneticstirringmaybecarriedoutifthevolumeofthereactionmixtureis
limited,notmuchsuspended materialispresentandcontinuouscontrolofthe
temperature by using a cooling bath is not very essential.
1.2 REACTIONS IN LIQUID AMMONIA
Anhydrous liquid ammonia is an excellent solvent for many reactions involving
acetylenic compounds. The conversions can be carried out under atmospheric
pressure at the boiling point ((cid:1)33(cid:2)C) or if necessary, at lower temperatures.
Depending upon the conditions of the procedure, the standard set-up
(Figure 1.1) or a variant may be used. Liquid ammonia of good quality
(water content less than 0.1%, absence of rust particles) can be drawn from
cylinders with or without a dip tube (cf. A. I. Vogel’s Textbook of Practical
1
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2 1. PROCEDURES AND EQUIPMENT
Organic Chemistry, 4th edn., Longmans, p. 98) and transferred through a
plastic tube into the reaction flask. Plugs of cotton wool are temporarily
placed on the necks, after which the flask is equipped as desired.
However,inmanylaboratoriesnoammoniaofgoodqualityisavailableand
purification by distillation may be necessary. Small pieces of sodium are added
with manual swirling to (cid:3)0.6litre of ammonia in a 1-litre round-bottomed
flask. After the blue colour has persisted, an additional amount ((cid:3)2g) of
sodium is introduced and connection is made with the flask as shown in
Figure 1.9. The flask containing the solution of sodium is occasionally
placed in a bath at (cid:3)35(cid:2)C, while condensation of the vapour is achieved by
(occasionally) cooling the flask (Figure 1.9) in liquid nitrogen. The distillation
can be completed in 1 to 1.5h. Disposal of the sodium residue by addition of
ethanolshouldbecarriedoutimmediatelyafterterminationofthedistillation.
Many reactions in liquid ammonia can be carried out at its boiling point.
Evaporation can be limited by insulating the flask in cotton wool.
If a volatile compound is to be prepared or a volatile or ammonia-sensitive
reagent(e.g.methyliodide)isadded,itisdesirabletokeepthereactionmixture
below the boiling point ofammonia ((cid:1)33(cid:2)C).This can be done by occasional
cooling with liquid nitrogen or a mixture of dry ice and acetone in a Dewar
vessel (Figure 1.6).
Strong evaporation of ammonia during exothermic reactions can be avoided
by cooling the reaction mixture below the boiling point of ammonia.
Forslowreactions,whichrequireseveralhoursandwhichcanbecarriedout
withoutstirring,aflaskwithanevacuatedspacebetweenthewalls(Figure1.4)
is recommended. If the flask is covered with aluminium foil, the rate of eva-
poration of ammonia is very low. An example is the reaction between lithium
acetylide and oxirane (Chapter 4, exp. 4.5.16).
Ifareactioninammoniaisveryfastandwork-uphastobecarriedoutimme-
diately,itmaybemoreconvenienttouseawide-neckedround-bottomedflask
with the stirrer placed centrally (Figure 1.5). An example is described in
Chapter 3, exp. 3.9.28.
Note
The complicated equipment prescribed for performing reactions in liquid
ammonia,* even in some Organic Synthesis procedures (use of a reflux
*Someexamples:A.L.HenneandK.W.Greenlee,J.Am.Chem.Soc.67,484(1945);
Inorg.Synth.2,128(1946);K.E.SchulteandK.P.Reiss,Chem.Ber.86,777(1953);87,
964(1954);R.F.ParcellandC.B.Pollard,J.Am.Chem.Soc.72,2385(1950);R.W.
Bradshaw, A .C. Day, E. R. H. Jones, C. B. Page, V. Thaller and R. A. V. Hodge,
J.Chem.Soc. [C], 1156(1971).
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1.3 SOME PRACTICAL HINTS 3
condenser,cooledwithdryice,placedonthereactionflask)maybeanimpor-
tant reason to prefer organic solvents. It should be emphasised, however, that
it is possible to carry out most reactions in ammonia without using a
reflux condenser. If strong evaporation is expected, for example during
dehydrohalogenations, the reaction flask may be insulated in cotton wool or
be placed in a bath with a dry ice–acetone mixture or liquid nitrogen as
described above.
1.3 SOME PRACTICAL HINTS
During some conversions in liquid ammonia, frothing may occur, especially
in the case of very thick suspensions. This can result in the loss of part of
the reaction mixture. The reaction flask therefore should never be more
than half-filled. Frothing may effectively be suppressed by adding small
amounts of diethyl ether (if the product to be isolated is not volatile), by
lifting the stirring motor so that the paddle rotates just below the surface
of the reaction mixture or by shortly cooling the flask in a bath with
liquid nitrogen.
Iftheproductofareactioninliquidammoniaisnotveryvolatile(bp>110(cid:2)C
at atmospheric pressure), the ammonia may be allowed to evaporate
overnight or during the weekend. After removal of the usual equipment, the
flask is connected with a tube filled with cotton wool placed on the level of
the bottom of the flask so that a protecting atmosphere of ammonia remains
in the flask (Figure 1.7). Alternatively, the ammonia may be quickly removed
by placing the flask in a bath at 34–40(cid:2)C.
In the case of volatile products (bp<110(cid:2)C), removal of the ammonia
by evaporation gives rise to considerable losses. These can be considerably
minimised by adding a high-boiling solvent (e.g. a petroleum ether
fraction with bp>170(cid:2)C) to the reaction mixture after the reaction
has finished. Subsequently the mixture is poured on to a relatively
large amount of finely crushed ice in a large wide-necked round-bottomed
flask (Figure 1.8) or in a large beaker. The reaction is carried out at tempera-
tures below the boiling point of ammonia (cooling in dry ice–acetone or
liquid nitrogen).
In some elimination reactions in liquid ammonia an alkali acetylide
is formed. In some cases, for example in the preparation of methoxy-
and ethoxyacetylene, it is for reasons of safety essential to hydrolyse the
alkynylide before all ammonia has evaporated. This can be done by
successively adding the extraction solvent and a large amount of crushed
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4 1. PROCEDURES AND EQUIPMENT
ice over a very short period (cf. Chapter 3, exp. 3.9.28). For this reason
the reaction is carried out in a large one-necked round-bottomed flask
(Figure 1.5).
Fortheisolationofvolatileorunstableproductsfromthesolutioninahigh-
boilingsolventtheset-upofFigure1.10isused.Afterevacuation(between<1
and 25 Torr) the solution is warmed until a small amount of the extraction
solvent has passed over. The volatile product is collected in a strongly
cooled (bath with dry ice–acetone, (cid:1)78(cid:2)C) receiver. If a water aspirator
is used, and entrance of moisture is undesired (for example in Chapter 3,
exp. 3.9.48), a tube filled with a drying agent should be placed between the
receiver and the aspirator.
Distillation can be accompanied by foaming especially in the case of com-
pounds with a long carbon chain. Foaming can be suppressed by completely
immersing the distillation flask in the liquid of the heating bath or by
adding a few drops of some anti-foaming liquid prior to carrying out the
distillation. Although special columns can be used for preventing the
foam passing over, it is, in general, advisable to use a relatively big distilla-
tion flask in such cases. Recovery by distillation of acetylenes or allenes that
have been stored for a long period may involve the risk of an explosive
decomposition of the residue. This danger can be minimised by adding a
certain amount ((cid:3)20ml for the distillation of 50ml of product) of paraffin
oil prior to the distillation. The residue will not remain as a compact mass
but as an emulsion or dispersion in the oil after termination of the
distillation.
Concentrations of reactants in the procedures described in this book
generally are between 0.5 and 1mol/litre of solvent. A good estimate of the
timenecessaryfor(cid:3)100%conversionrequiresmuchexperienceandknowledge.
For the lithiation of a 1-alkyne with butyllithium, for example, one has to
know that the deprotonation of acetylenes with such very strongly basic
reagents is an extremely fast reaction. This means that the heat of this depro-
tonation is liberated over a very short period. Metallation of allenes, com-
pounds which are much less strongly acidic than 1-alkynes, proceeds less
fast. Nevertheless, one can make a rather good estimate of the time necessary
for (almost) complete lithiation of, for example methoxyallene,
H C¼C¼CHOMe, by performing the following experiment. A solution of
2
0.05mol of n-BuLi in 33ml of hexane (the usual 1.6mol/litre concentration
of the commercially available reragent) and 40ml of tetrahydrofuran is
cooleddownto(cid:1)70(cid:2)C,thenthecoolingbathisremovedandtheflaskisinsu-
latedincottonwool.Theincreaseofthetemperatureoftheslowlystirredsolu-
tion is observed during a few minutes (an electronic thermometer is more
convenient than the usual one). Usually, rising of the temperature will
amount by a few degrees only. The temperature of the solution is adjusted
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1.3 SOME PRACTICAL HINTS 5
again at (cid:1)70(cid:2)C by dipping the reaction flask for a few seconds in the cooling
bath.Methoxyallene(0.05mol)isthenaddedinoneportion.Thiswillresultin
arisingofthetemperaturebyseveral(atleast20)degreesoverlessthan1min.
Evenifsmalleramountsoftheallenicetherareaddedinoneportion,theeffect
is clearly visible. One may carry out a blank experiment by adding at (cid:1)70(cid:2)C
the same volume of THF. In this case the temperature rises by a few (<5)
degrees only. Of course, for completion of the lithiation the reaction
mixture has to be stirred for a (limited) additional period at a temperature
higher than (cid:1)70(cid:2)C. Reactions between strongly basic anionic species and
aldehydes or ketones usually proceed almost instantly, even at temperatures
farbelow0(cid:2)Cinsolventsoflowpolarity.Silylations(withR SiCl)andsulphe-
3
nylations (with disulphides, RSSR or thiocyanates, RSC(cid:4)N) of organoalkali
compounds are other examples of very fast reactions, which are easy to
follow by temperature observation. Reactions in boiling liquid ammonia
(bp (cid:1)33(cid:2)C) may be followed by keeping the end of a small slip of paper 1 cm
from the outlet. When there is no or a very slow reaction (e.g. when the reac-
tion has subsided) the flow of escaping ammonia is relatively weak and the
position of the slip remains vertical. In the case of very fast reactions much
ammonia may evaporate in a short time and the vigorous flow from the
outlet causes the slip to move off from the outlet. Dehydrohalogenations as
mentioned in Chapter 3, Section 3.3 are extremely fast and exothermic so
that addition of small portions of the halogen compound causes a vigorous
outward flow of ammonia. For reactions carried out at temperatures below
the boiling point of ammonia the method described above for methoxyallene
may be used.
It should be pointed out that heating effects can also be made visible by
performing the reaction on a very small (1mmolar) scale in a reagent tube
(wrapped in cotton wool) using an electronic thermometer.
Some reactions, if carried out on a preparative scale and with ‘preparative’
concentrations of the reactants, can be followed by observing the temperature
in the solution boiling under constant intensity of the reflux stirred at a
constant rate. A good example is the Pd/Cu-catalysed cross-coupling
between ethynyl(trimethyl)silane (bp (cid:3)53(cid:2)C) and 1-bromo-1-cyclooctene in
piperidine (bp 106(cid:2)C) described in Chapter 16, exp. 16.7.15. The temperature
of the reaction mixture, in the beginning (cid:3)90(cid:2)C, reaches a maximum
((cid:3)110(cid:2)C, somewhat higher than the boiling point of piperidine, due to the
presence of dissolved HBr salt) when most of the volatile acetylene
has reacted with bromocyclooctene. The isomerisation of methyl
propargyl ether (bp 61(cid:2)C) to methoxyallene (bp 51(cid:2)C) in the presence of
potassium t-butoxide in a small amount of DMSO (Chapter 17, exp. 17.2.8)
can be followed by looking at the thermometer in the refluxing solution.
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6 1. PROCEDURES AND EQUIPMENT
The temperature drops as a result of the formation of a more volatile
compound.
In other procedures, carried out with high concentrations of starting com-
pounds, the refractive index of the solution can be measured, for example
in the isomerisation of HC(cid:4)CCH(Br)C H to BrCH¼C¼CHC H under
6 13 6 13
the catalytic influence of lithium dibromocuprate, CuBr(cid:5)LiBr (Chapter 12,
exp.12.4.14),andinthebrominationof1,3-diynes,RC(cid:4)CC(cid:4)CH,withpotas-
sium hypobromite (Chapter 9, exp. 9.2.3).
In a single case the only necessary instruments are the eyes. The conversion
ofpropargylbromideintothecorrespondingiodide,usingahot((cid:3)70(cid:2)C)solu-
tion of sodium iodide in absolute ethanol (Chapter 20, exp. 20.1.11) isaccom-
panied by precipitation of sodium bromide. The reaction is finished when salt
crystals are no longer being formed in the supernatant layer (stirring is not
necessary).
Particularly in the cases of hydroxyacetylenes, the question ‘How many
extractionswithdiethyletherstillhavetobecarriedout?’mayarise.Thefollow-
ing practical tip may be useful. Take a small (0.5ml) sample from the extract
with a Pasteur pipette and allow the solution to flow along a ground-glass
stopper. Further extraction is no longer necessary when after evaporation of
the ether no residue is visible on the ground glass.
A quick and extremely simple method to investigate whether volatile
polymerisable liquids such as oxirane, ethyl vinyl ether and vinyl bromide
contain polymers is to put (cid:3)1 ml on a watch glass and to blow air over
the liquid. If not any oil-like residue is visible on the glass, purification is
not necessary.
The following generally valid advice with respect to the work-up of reac-
tion mixtures resulting from syntheses with Grignard reagents should be
given. If water or aqueous ammonium chloride is added at too fast a
rate to the reaction mixture, much heat will be evolved and as a result
part of the reaction mixture will be lost, especially if diethyl ether is
used as a solvent. Therefore, the reaction mixture always should be (cau-
tiously) poured into water or into aqueous ammonium chloride. If the pro-
duct is not acid-sensitive, dilute mineral acid can be used. Alternatively,
water or the aqueous solution of ammonium chloride or acid may be
added slowly to the efficiently stirred reaction mixture, preferably under
cooling.
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1.3 SOME PRACTICAL HINTS 7
Figure1.1 Figure1.2 Figure1.3
Figure1.4 Figure1.5
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8 1. PROCEDURES AND EQUIPMENT
Figure 1.6 Figure 1.7
Figure1.8 Figure1.9
