General schemes have been devised for examining unknown mixtures such as those one learns as an undergraduate chemist for a laboratory examination; such schemes as those in the classic text by Shriner, [Fuson and Curtin, [The Systematic Identification of Organic Compounds: A Laboratory Manual. Fifth Edition John Wiley & Son 1964]. The more complex of these schemes to the best of my knowledge, no matter what their wisdom, have never been adopted by real chemists to work up real reaction mixtures. The reason is simple. These schemes are designed to handle complete unknowns. The bench chemist always knows something about his mixture, even if it is no more than the fervent hope that a particular product will be present; therefore, the working chemist or chemical engineer is in a more knowledgeable position and so the protocol for a completely unknown mixture is going to be inefficient.
At least the functional groups and molecular weight of the desired product will be known and some educated guesses can be made about the likely physical properties, and so a theoretical proposal can be made for a rational separation. For example, if the hoped-for product is a neutral lipophilic aldehyde, a mild aq. acid extraction and a mild aq. base extraction can be applied to an ether solution. Then some aldehyde-specific reagents such as bisulfite or Girard’s P or T can be contemplated.
These classical schemes would also be set aside because they apply simple solubility tests in carbon
tetrachloride and benzene, which today are unacceptably toxic solvents.
What would be more interesting and have
more likelihood of application would be a scheme that can be adapted to estimated properties of a particular reaction mixture and which have consistency with the most helpful procedures for separations at
scale.
To explore this, let us assume first that
the reactor contents, at the end of the reaction period, is homogeneous and the
TLC or other in-process check is encouraging.
Let us also assume that the trial reaction has been conducted on a scale
of at least several grams. I make this assumption first because improving the
throughput in a series of reactions in a process scheme should focus on the
early steps and these are the ones using the less expensive materials.
If the reaction flask contents are not homogeneous, the
phases should be separated and treated separately. This practice is based on the wise rule that
the chemist should never refuse a phase separation offered by nature in the
course of working out a complete separation. Specifically, if there is a solid in a
liquid, filter the solid, and retain the filtrate. If there are two liquids, cut
the phases and examine each. Such natural separations are not likely to be
quantitative recoveries of any component, but the constitution of the phases
may provide a guide to a modification that delivers a quantitative separation.
Supposing then that the phase is a single
one, or that we are examining multiply phases separately, the chemist has a
very good idea that the main constituent of this phase is solvent and the
solvent is known. The object will be to
remove that solvent completely without exposing the other constituents to
conditions so severe that they may degrade. The chemist is the best judge of how to
achieve this.
Let us suppose now that the solvent has
been removed under mild conditions and the residue, either as an oil, a mixture
of solid and liquid, or a glass is ready to be examined.
It is not possible to efficiently separate viscous
oil from a solid. In this situation, oil and solid probably must be examined
together although again this is a situation where the chemist’s powers of
observation and judgment are more useful than any rule that can be offered by
me out of the blue.
The mixture will be examined with respect
to its solubility properties much as in the classic approach in Shriner Fuson and
Curtin but here the solvents are chosen based on a different principle. The solvents, which will be examined, are
hexane, acetonitrile, methanol, and ethyl ether.
The first three solvents are chosen because
methanol and hexane in the presence of a few percents of water give two
immiscible phases as does the combination of acetonitrile and hexane. As a consequence, differential solubility
information can not only direct us to a trituration step but possibly to a
partitioning between two immiscible solvents.
The tests in diethyl ether are more
standard. Although diethyl ether is not a solvent acceptable in a general-purpose chemical plant, its remarkable
ability not to form emulsions makes it irreplaceable for initial exploratory acid and basic aqueous
extraction tests.
So, in practice, one gram of the mixture is
placed in a small r.b. flask and treated with 7 ml of methanol and
swirled. If any solid remains
undissolved the slurry can be cooled in ice to maximize the quantity of solid, filtered cold, and washed with a little cold methanol. That solid is
examined.
If there is no solid in the solution we
could add 7 ml/gm of hexane(s) and mix the phases together. Again we look for any solid, which might
separate and treat it appropriately. If two immiscible liquid layers are not
present a drop or two of water is added to cause a methanol layer to separate. The two phases are separated
and each is evaporated to dryness, pumped under vacuum, and weighed. Each phase should be examined, if it is
convenient, by the analytic method that was used for the reaction’s in-process check.
The combination of the weights obtained and the analyses of the separate layers
are useful properties of the mixture.
They may provide the first hints of the most efficient methods of
isolation. If one phase or the other contains essentially all the contents of
the mixture all one can say is that the mixture is substantially polar or
apolar, depending on which solvent it has migrated to.
If the mixture is substantially apolar take
a new sample of the mixture in a small r.b. flask and tread it with 7 ml of
acetonitrile and swirl, repeating the procedure that was used with
methanol. In the case of acetonitrile,
water will very rarely be needed to get two liquid phases with added hexane.
In fact, try to avoid using water here. The two phases are separated and each is
evaporated to dryness, pumped under vacuum, and weighed. Again each phase should be examined, if it is
convenient, by the analysis that was used for the reaction’s in-process check.
The combination of the weights obtained and the analyses of the separate layers
again are useful properties of the mixture. again, they may provide the first hints at the most efficient methods of
isolation. If one phase or the other contains essentially all the contents of
the mixture all one can say once more is that the mixture is substantially polar or
apolar.
Neat water is not used in these aforementioned tests.
Nevertheless, there is a good likelihood that if an inorganic salt is present it
will be insoluble in one of methanol or acetonitrile and will have been
filtered off.
A frequent result of this work will be that
the substantial majority of the reaction mixture will remain in the hexane
layer. This is to be expected. The vast majority of organic compounds are
substantially lipophilic and non - crystalline when present as mixtures;
nevertheless, a separation made in one of these stages may be
particularly valuable.
Take a new portion of the mixture and try
to dissolve it in 7 ml/g of diethyl ether. Again, if there is a solid, separate
it. Now, in the classical way, extract the
diethyl ether with an equal volume of 1N aq. HCl and separate the phases.
Adjust the pH of the aqueous phase back to neutrality observing any cloudiness
or solid separation and then back extract the neutralized water, if this ether is murky, dry with sodium sulfate to remove the water, evaporate to dryness, and weigh.
In the same classical fashion extract the
ether, which has been acid extracted with aq. base at pH about 9.0 and recovery any acidic substances that have been taken up.
Recover the neutral constituents from the
residual ether.
Each phase should be examined if it is
convenient by the analysis, which was used for the reaction’s in-process check.
The combination of the weights obtained and the analyses of the separate layers
are useful properties of the mixture.
Quite often very little more will have been
accomplished than would have been achieved following the tried and true rules
of thumb, but a useful number of times something really exciting and
simplifying will have been drawn to your attention.
If the material, which you are seeking is
either in the acidic or the basic fractions, even if it is still a serious
mixture, your problems are well on their way to resolution because the means
for rugged separations of such mixtures on-scale are plentiful and these ways I
explore in other blog articles. See for example KiloMentor’s blog on extractive
crystallization.
If the substance you are seeking still
seems only to be found in the hexane or neutral diethyl ether phases more
sophisticate means need to be applied.
If 30% or more of a target substance has ended up in the methanol or
acetonitrile phases there is reason to hope that more intensive extractions may
give you what you need.
If TLC of the methanol, acetonitrile or
hexane solutions showed a substantial amount of material remaining at the
origin, the presence of high molecular weight or even polymeric materials is
likely. If the mixture is strongly
colored and the product sought is not expected to show color, polymer and tars
are likely and the mixture should be cleaned up before looking for the desired
species. Filtering through a plug of
adsorbant, which retains the origin material is usually successful. Charcoaling a portion in an alcohol solvent
often works. Sometimes steam
distillation, regular distillation, or co-distillation with a high boiling
hydrocarbon can be useful. In co-distillation with kerosene be mindful that you
will need to get the mixture back from the high boiling solvent!
Because cyclohexane combined with
nitromethane or nitroethane or any mixture of the two, also forms two immiscible
phases; the methods illustrated above can be applied in this system. The same goes for combinations of
nitromethane /nitroethane with cyclohexane and apparently cyclohexane and
mixtures of dimethylformamide/dimethylacetamide. With these combinations, the
temperature needs to be kept close to ambient to preserve the two-phase
behavior.
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