TECHNIQUES AND
`EXPERIMENTS FOR —
`
`ORGANIC CHEMISTRY Page 1 of 18
`
`EISAI EXHIBIT 1058
`Eisai v. Crystal Pharm.
`PGR2021-00047
`
`Page 1 of 18
`
`EISAI EXHIBIT 1058
`Eisai v. Crystal Pharm.
`PGR2021-00047
`
`

`

`‘Techniques and
`~ Experiments for
`Organic Chemistry
`
`FOURTH EDITION
`
`
`
`i=
`
`Addison Ault
`Cornell College-~
`
`Bhaky a
`BRi ite
`DIVISION
`LEN!”
`13.«¢ (983
`
`83/36507
`
`
`
`ALLYN AND BACON, INC.
`
`Boston London Sydney Toronto
`
`~ Page 2 of 18
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`Page 2 of 18
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`

`

`
`
`Copyright © 1983, 1979, 1976, 1973 by Allyn and Bacon,Inc., 7 Wells Avenue,
`Newton, Massachusetts 02159. All rights reserved. No part of the material
`protected bythis copyright notice may be reproduced or utilized in any form or
`by any means,electronic or mechanical, including photocopying, recording, or
`by any information storage and retrieval system, without written permission
`from the copyright owner.
`
`Library of Congress Cataloging in Publication Data
`Ault, Addison.
`Techniques and experiments for organic chemistry.
`Includes bibliographical references and index.
`1. Chemistry, Organic—Laboratory manuals.
`QD261.A94
`1983
`547'.0078
`82-22781
`ISBN 0-205-07920-2
`
`I. Title.
`
`Printed in the United States of America
`
`
`
`
`
`
`
`
`
`
`
`1 98765 43 2 «1+=88 87 86 85 84 83
`
`
`
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`
`
`Page3 of 18
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`Page 3 of 18
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`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Page 4 of 18
`
`

`

`4106
`
`SEPARATION OF SUBSTANCES
`
`A andBcan beeffected if one of the substances, say A, is much more
`soluble in water than in ether, and the otheris much moresoluble in
`ether than in water.If, at equilibrium, most of the A molecules are in
`the water phase and mostof the B molecules are in the ether phase, a
`physical separation of the layers by means ofa separatory funnel (Fig-
`ure 13.1) will result in a separation of the two kinds of molecules. The
`material in each layer can be recovered, typically, by distillation or
`evaporation of the solvent.
`Table 13.1 indicatesin a general waytherelative solubility of differ-
`ent types of compoundsin water and organic solvents.
`
`—
`7
`4
`
`Table 13.1. Estimated relative solubility of different types of compoundsin
`organic solvents and water
`Solubility in all solvents decreases with increasing molecular weight.
`Estimated Ratio of Solubility ‘
`in Organic Solvent to
`Solubility in Water
`
`
`
`Type of Compound
`Covalent substances containing only carbon,
`hydrogen, and halogen
`Covalent substances containing oxygen and/or
`nitrogen in addition to carbon, hydrogen,
`and halogen
`a. 5 carbon atoms per functional group
`b. 2 carbon atomsper functional group
`c.
`1 carbon atom per functional group
`Salt of an organic acid
`Salt of an organic base; aminesalt
`Inorganic salts
`
`Very much greater than 1
`
`10:1
`bil
`1:10
`Very muchless than |
`Very muchless than |
`Very muchless than 1
`
`4
`
`13.2. EXTRACTION OF ACIDS AND BASES
`The extraction of an acidic or basic substance,either the productof the
`reaction or an undesired side product, from an organic solvent into
`water can be effected by mixing (shaking) thesolution in the separatory
`funnel with an aqueoussolution of base or acid, respectively.
`ay
`In the extraction of an acidic material with aqueousbase, the acid
`in the organic solution dissolves in the water and is immediately con-
`verted to its salt. The salt is very much more soluble in water than in
`the organic solvent. Thus, the concentration of free acid in the aqueous |
`phase will remain very low as long as the aqueous phase remains suffi-
`ciently basic to convert the acid to its salt. After equilibrium has been |
`established, the ratio of free acid dissolved in the organicsolvent to free
`acid dissolved in water may be muchgreater than 1 (because of greater
`
`
`
`
`
`
`Extraction of acids by
`bases
`
`Page 5 of 18
`
`Page 5 of 18
`
`

`

`SECTION 13
`
`107
`
`
`
`
`
`‘solubility in the organic solvent than in water). Still, the fact that the
`yast majority of acid molecules are in the form of their corresponding
`salt dissolved in water meansthat only a very small amount ofthe acid
`originally present in the organic solventis still there. From this analy-
`sis,"you can see that the degree of completeness with which an acid can
`ye extracted from an organic solvent depends uponthebasicity of the
`extracting aqueoussolution: the solution mustbe basic enough to con-
`ert
`the acid “completely”toits salt. A useful approximation is that the
`IH of the extracting solution should be atleast 4 pH units on the basic
`ide of the pK, of the acid to be extracted. Thus, aqueous sodium
`arbonate solution (pH ~ 11) should “completely” extract acids
`tronger than pK, ~ 7 (see Table 13.2).
`
`
`
`Table 13.2. pH required for extraction of different acids and
`bases
`
`Approximate pH of Aqueous Solution Needed to Extract an Acid
`
`from Organic Solvent
`
`
`Compound
`pK,
`pH as Basic or More Basic Than:
`
`Mineral acids
`
`Ar—b—on
`
`>|
`
`~4
`
`~4
`
`~8
`
`~9
`~S
`r—t_on
`
`Phenols
`~10
`~14
`
`Approximate pH of Aqueous Solution Needed to Extract a Base
`from an Organic Solvent
`
`
`
`Compound
`pK,
`PH as Acidic or More Acidic Than:
`
`:
`
`_ Anilines
`~5
`~1
`_ Pyridines
`~6
`~2
`Aliphatic amines
`~iil
`~7
`Approximate pH ofAqueous Solutions, _ 10% by Weight
`
` Compound Approximate pH
`
`HCl; H,SO,
`Acetic acid
`NaHCo,
`Na,CO,; K,CO,
`NaOH; KOH
`
`0
`3
`8
`i
`14
`
`Page6 of 18
`
`Page 6 of 18
`
`

`

`108
`
`SEPARATION OF SUBSTANCES
`
`ment of the equilibrium vapor pressure of the solvent will cause the —
`
`Similarly, you could expect to “completely” extract an amine from
`an organic solvent by means of an aqueousacid solution whose PHis at
`least 4 pH units on theacidic side of the pK,, of the conjugate acid of
`the amine (see the data of Table 13.2).
`It should also be apparent that if a basic aqueous solution of an
`organic acid is acidified with a mineral acid (pH ~ 1; [OH™] ~ 10°"),
`the acid should be extractable from water into an organic solventif the
`free acidis less soluble in water than in the organic solvent. Of course,
`if the acid is not very soluble in water, it will separate or precipitate
`from the acidified solution before the organic solvent is added.
`In a similar way, it is possible to extract an organic base from an
`acidic aqueous solution by making the solution basic and then extract-
`ing the mixture with an organic solvent.
`
`;
`
`13.3 TECHNIQUE OF EXTRACTION
`The objective of a simple extraction is to partition one or more sub-
`stances between two immiscible solvents. Thisis usually accomplished
`—
`with the use of a separatory funnel (Figure 13.1). If the separatory
`funnel has a glass stopcock, prepare the funnel for use by making sure
`that the stopcock is lightly greased and will turn without difficulty;
`—
`Teflon stopcocks need not be greased. With the separatory funnel sup-
`ported in a ring (Figure 13.1), check to make sure that the stopcock is
`closed and pourin the solution to be extracted. Then add the extracting —
`solvent (the funnel should notbe filled to more than about three-fourths
`of its height), replace the stopperafter wettingit with water (to keep the
`organic solvent from creeping out around the stopper), and swirl or
`4
`shake the contents to mix them. With vigorous shaking, a total mixing
`period of ten to thirty seconds is usually considered adequate to estab-
`—
`lish equilibrium. After allowing the mixture to stand in the separatory —
`funnel until the two immiscible layers have separated cleanly, remove a
`the stopper at the top and draw off part of the lower layer through the ~
`stopcock at the bottom. Wait a litle while for the remainder of the
`lowerlayer to drain down (gentle swirling of the separatory funnel can d
`speed this up), and draw this off also. Then pour the upperlayer out the —
`top.
`3
`If a glass stopcock plug is used,it should be removed from the —
`separatory funnel, cleaned, and stored out of the funnel. If this is not —
`done, you mayfind it impossible to turn the stopcock next time you use —
`the funnel. (Teflon stopcock plugs are much better suited for separatory —
`funnels than are glass plugs since they will not freeze in place, do not —
`need to be greased, and do not need to be removed for storage.)
`3
`When a volatile solvent is involved in an extraction, the establish- —
`
`Extraction of bases by acid
`
`Close the stopcock
`
`Mix thoroughly
`
`Let the air in
`
`Remove stopcock for
`storage
`
`Page 7 of 18
`
`Page 7 of 18
`
`

`

`SECTION 13.
`
`109
`
`less dense
`
`
`
`
`
`@ 13.1. A separatory funnel.
`
`
`
`
`Page 8 of 18
`
`Page 8 of 18
`
`

`

`410
`
`SEPARATION OF SUBSTANCES
`
`pressure to rise inside the stoppered separatory funnel. The pressure is
`best released by turning the funnel upside down (with the stopper held
`in place with the palm of the hand) and cautiously opening the stop-
`cock. When a very volatile solvent such as ether is being used,thefirst
`mixing should consist only of a slow inversion of the separatory funnel
`followed by release of the pressure. After alternate cautious sloshing of
`the contents of the separatory funnel and then release of pressure, the
`soundof the escaping vaporswill indicate that the pressure is not being
`built up so fast and the periods of mixing can be longer and more
`vigorous. If you neglect to release the pressure inside the funnel, the
`stopper may be forced out. If the contents of the funnelare forced out
`as well, the escape of a volatile and flammable solvent can result in a
`dangerousfire.
`It should be obvious thatit is dangerous to attempt to extract a
`solution if its temperature is near or above the boiling point of the
`extracting solvent. This meansthatif an extraction is to be carried out
`with pentane, ether, or dichloromethane, it may be necessary to cool
`the solution to below room temperature. When these solvents are used,
`it is also a good idea to hold the separatory funnel by the ends so that
`the contents will not be warmed by your hands.
`If a strong acid is to be extracted with carbonate or bicarbonate
`solution, the carbon dioxide produced can cause a large buildup in _
`pressure unless mixing is done very cautiously with frequent release of
`j
`pressure. In cases where much carbon dioxide production is antici-
`pated,it is best to do the mixing in a flask or beaker and then to transfer
`the mixture to the separatory funnel for separation.
`
`4
`
`Choice of Solvent
`
`If an organic product is to be purified by dissolution in an organic —
`solventfollowed by extraction of the solution with two or more portions —
`of aqueoussolution, the whole process will be much faster and easier,
`andwill involvelessloss,if the organic solutionis less dense than water.
`—
`In this case, the waterlayer can be drawn off through the stopcock, and 3
`the organic solution is retained in the funnel ready for the next extrac- —
`tion. If the organic phase is heavier than water, it will have to be drawn
`off through the stopcock, the aqueouslayer poured out, and the organic 4
`layer returned to the separatory funnel for the next extraction. Each |
`such transfer will take time and may involve a loss of material. Con- —
`versely, if it is necessary to extract an aqueous solution with several —
`portions of solvent
`in order to achieve the maximum recovery of a ©
`substance, it will be more convenient to extract with a solvent heavier —
`than water so that the solvent can simply be drawn off each time —
`through the stopcock without removal of the water layer first. The —
`densities of a numberof solvents are listed in Table 8.1.
`
`Relief of pressure
`
`Warning: beware ofboiling
`solvent
`
`Warning: beware of CO,
`evolution
`
`Page 9 of 18
`
`Page 9 of 18
`
`

`

`SECTION 13°
`
`191
`
`tion in Batches
`
`
`
`
`fitis necessary to extract a larger volume of material than will fit into
`available separatory funnel, the extraction may, of course, be done
`hes. Small amounts of water-insoluble material may be efficiently
`
`noved from large amounts of water by addinga little ether (or other
`
`nt less dense than water)to the flask containing the water/product
`
`» Swirling the mixture well, and then addingit in portions to the
`
`atory funnel, drawing off most of the water layer after each addi-
`
`Theconverse of this procedure can be used to wash a large amount
`an organic solution withalittle water, if the organic solution is
`eavier
`than water.
`
`Suggestions
`
`
`
`
`
`Distinguishing the layers
`
`Smell won't tell
`
`Insoluble material
`
`iiten it is possible to tell which layer in the separatory funnel is organic
`ad which is aqueous from knowledgeof the relative volumes used or
`elative densities of the two solvents. Sometimes, however, the transfer
`terial from one layer to the other or the presence of several sub-
`
`of different densities can make the identification of the layers
`
`ain. It is not possible, of course, to tell by smell which layer is
`
`» Since the vaporpressure of each componentin each phase will
`@ same. But sometimes you can determine which is which by
`
`ding a little water and seeing with which layer the added water
`mbines. Or you can withdrawalittle of the lower layer andsee if it is
`
`ible with water. If doubtstill remains, each layer should be carried
`the procedure as if it were the desired one until it becomes
`
`s that one of the two cannotbe theright one. It is very common
`card the product layer through error or ignorance; it is always
`
`ble to save everything until the product has beensafely isolated.
`
`In most extractions, at least a trace of insoluble material collects at
`terface between the two immiscible layers. It is often impossible
`
`‘Separate the layers without taking along someofthis insoluble mate-
`I. This is not a crucial matter, since whateveris picked up can always
`
`noved byfiltration at the end of the extraction or at somelater
`ge
`in the purification. For example, in the very common case in
`ii eh the organic productofa reactionis isolated by dissolvingit in an
`
`anic solvent, extracting (“washing”) the solution with one or more
`Ueous solutions in order to removecertain undesired materials, dry-
`
`it (Section 15.2), and removing the drying agent by gravity filtra-
`H, any insoluble impurity that may have been carried along in the
`
`layer will be removed along with the drying agentin the gravity
`On.
`
`the distribution coefficient for a substance to be extracted from
`
`is muchless than |—thatis, if the ratio at equilibrium of the
`
`
`Don't throw away the
`wronglayer
`
`Page 10 of 18
`
`Page 10 of 18
`
`

`

`
`
`SEPARATION OF SUBSTANCES
`472
`concentration in the organic solvent to the concentration in water is —
`muchless than 1—a simple extraction process will not give a satisfac-
`tory recovery. The distribution coefficient can sometimes be increased —
`by adding sodium chloride or sodium sulfate to the aqueous solution,
`—
`since the solubility of most organic compoundsisless in salt solutions —
`than in water. (The interpretation for this phenomenon, known as 3
`salting out,
`is given in Section 22.1.) Alternatively, the distribution —
`coefficient can be increased by using an organic solvent thatis @ better
`solvent for the type of compound being extracted. For substances with 3
`oxygen-containing functional groups, ethyl acetate and n-butyl alcohol —
`are probably better solvents than non-oxygen-containing solvents. 3
`Chloroform is an especially good solvent for amines. (The factors that
`4
`determine solubility are also discussed in Section 22.1.)
`Sometimes the mixture in the separatory funnel does not separate
`into two phases, but forms a single, homogeneoussolution. This can —
`happen when large amounts of methanol, ethanol, or tetrahydrofuran
`
`are present, as these liquids are good solvents for both waterand organic
`
`materials. Sometimes separation into two liquid phases can be brought —
`
`aboutby the addition of more water and more of the organic solvent, or —
`
`by the addition of saturated, aqueous, sodium chloride solution. It is —
`
`best, however, to avoid this problem by removing most of the metha-
`
`nol, ethanol, or tetrahydrofuran, possibly by distillation, before doing —
`
`the extraction.
`2
`
`Occasionally, when the organic substance being purified is a solid,
`
`it will begin to crystallize during the extraction. This happens when the-
`amountoforganic solventis reduced below that required to dissolveall
`
`of the solid, the loss of the organic solvent occurring because of its”
`
`slight solubility in the aqueous liquids that are used to washthe organic
`
`solution. Or this can happen because another substance, perhaps an-
`
`alcohol, that helped to dissolve the solid productin the organic layer”
`hasitself been removed by extraction. No matter what the cause, addi-|
`tion of more of the same solvent or of a better solvent should bringth e
`solid material back into solution.
`
`
`
`Emulsions
`
`A commonproblem in extraction is failure of the immiscible solution
`
`to separate completely and cleanly into twolayers; a certain volume of
`
`the mixture at the interface sometimes consists of droplets of one solu-
`
`tion suspended in the other (an emulsion). In somecases, the separa’ tion
`
`becomes clean and complete if the separatory funnel and its contents
`the
`are allowed to stand undisturbed for a few minutes. At other times,
`
`emulsion maypersist for hours or days. If the volume of the emulsionis-
`
`relatively small, it can sometimes be temporarily ignored and the ex-
`traction procedure continued in the hope that the emulsion will disap-
`
`
`
`Salting out
`
`0.
`C7\ /
`tetrahydrofuran
`THF
`
`
`
`Page 11 of 18
`
`Page 11 of 18
`
`

`

`SECTION 13.
`
`113
`
`
`in later extractions. But if most of the mixture is emulsified, it
`ear
`must either be allowed to stand(if the timeis available) or be broken in
`some other way.
`
`___
`If the emulsion is caused by too small a difference in density be-
`
`ween the twolayers, the addition of solvent to one or both layers may
`sroduce a larger density difference. Pentane will mostefficiently de-
`srease the density of an organic solution, while carbontetrachloridewill
`
`ost efficiently increase the density. The addition of water may either
`
`prease or decrease the density of the aqueous phase, depending upon
`
`its composition. If the aqueous phase contains appreciable amounts of
`nic solvents (such as alcohols), it may have a density of less than
`
`ne
`gram per milliliter; if, on the other hand, it is a solution of inor-
`
`anic materials, its density will be greater than one gram permilliliter.
`he
`addition of salt or saturated sodium chloride solution can also
`ase the density of the aqueous phase.
`
`_
`Emulsions are most commonly encountered in extractions involv-
`ng basic solutions. Presumablythis is because traces of higher-molecu-
`
`lar-weight organic acids are converted to their salts, and the resulting
`
`Soap causes emulsification. The tendency of an extraction with a “neu-
`tral” aqueoussolution to emulsify can sometimes be overcome by add-
`ing a few drops of acetic acid, thus suppressing soap formation.
`
`Stubborn emulsions can sometimes be broken by centrifugation or
`
`ion filtration of the emulsified material. Suction filtration of an
`sion is a very messy operation and should be done only in despera-
`
`
`
`
`With emulsions, preventionis far better than cure. If the mixtureis
`hed or shaken gently atfirst and then allowed to stand, the tendency
`toward emulsion formation can be estimated. When it appears that
`emulsion formation may be a problem,it is wise to mix the layers more
`ently for a longer time. In extreme cases, it may be desirable to carry
`the mixing in a round-bottomflask by slowstirring with a magnetic
`er. Since in this case the area of the interface will be much less than
`[the mixture were broken up into a suspension of tiny bubbles by
`orous shakingorstirring, it may take 30-60 minutes to approach
`equilibrium.
`
`
`
`
`Problems
`
`Estimate whether or not each of the following acids could be “completely
`A.
`_ &xtracted”’ with one portion of an excess of (a) aqueous sodium bicarbonate
`E solution, (b) aqueous sodium carbonate solution, and (c) aqueous sodium
`hydroxide solution:
`
`Page 12 of 18
`
`Breaking emulsions
`
`GU
`
`Page 12 of 18
`
`

`

`414
`
`SEPARATION OF SUBSTANCES
`
`oO
`
`ac-t-0n
`trichloroacetic acid
`K,=2~ 10"
`pk, = 0.70
`
`OH
`A
`Sa
`
`(
`
`oO
`
`CH,CH,CH.—¢—OH
`butyric acid
`K, = 1.5 * 10°
`pK, = 4.52
`
`OH
`
`NO,
`
`NO,
`
`NO,
`
`picric acid
`phenol
`K, = 1.6 x 10°
`K, = 13 x 10°"
`pK, = 0.80
`pK, = 9.89
`2. Using extraction procedures only, how would you separate a mixture of
`a. p-Dichlorobenzene, p-chlorobenzoic acid, and p-chloroaniline?
`b. p-Dichlorobenzene, p-chlorobenzoic acid, and p-chlorophenol?
`°
`Lon
`
`NH,
`
`oO
`
`OH
`
`¢
`
`cl
`cl
`a
`p-Chloroaniline
`p-Chlorophenol
`p-Chlorobenzoic acid
`3. Whyis carbon dioxide produced whena strong acid, such as sulfuric acid or
`hydrochloric acid, is neutralized with sodium bicarbonate or with sodium —
`carbonate? Illustrate your answer with balanced equations.
`4. The solubility of adipic acid in wateris 1.5 g per 100 mL at 15°C, and 0.6g
`per 100 mLin ether at the same temperature.
`3
`a. What fraction of a sample of adipic acid could not be extracted from
`water into ether with one extraction with a volume of ether equal to that
`—
`of the aqueous solution?
`y
`b. Whatfraction of a sampleof adipic acid could not be extracted from ether
`into water with one extraction with a volumeof water equalto thatof the 3
`ethereal solution?
`q
`c. Repeat a, but use three portions of ether, each equal to one-third of the —
`volume of the aqueous solution.
`3
`d. Repeat b, but use three portions of water, each equal to one-third of the ~
`volume of the ethereal solution.
`3
`e. Calculate the limiting fraction, which could not be extracted with an —
`equal volume ofether.
`a
`f. Calculate the limiting fraction, which could not be extracted with an ©
`equal volume of water.
`§
`g. Repeat a, c, and e, but use a total volumeof ether equalto five times the a
`volume of the aqueous solution.
`
`3
`
`a
`
`Oo
`
`cl
`p-Dichlorobenzene
`
`Page 13 of 18
`
`Page 13 of 18
`
`

`

`
`
`SECTION 13°
`
`115
`
`Exercises
`
`1. Extraction ofcaffeine from tea or NoDoz (Section 42).
`2. Extraction of eugenol from oil of cloves (Section 44).
`3, Separation of a mixture of an acid A—H, a base B:, and a neutral substance
`N.
`
`Procedure. Dissolve about 5 grams of the mixture in 50 mL of diethyl
`ether and transfer the solution to a 125-mL separatory funnel. Add to the
`_ funnel 30 mL of | M HCI solution. Shake the mixture well
`in order to
`extract the basic substance as its hydrochloric acid salt into the water layer:
`
`
`
`
`
`
`
`B: +H,O+ Cl ——> B-H+Cl- +H,0
`
`__ Drawoff the lower, aqueous, layer and saveit.
`Addto the ethersolution in the separatory funnel about 30 mL of 1 M
`_ NaOHsolution. Shake the mixture well in order to extract the acidic sub-
`Stance as its sodium salt into the water layer:
`
`A—H + HO-
`
`+ Na* ——~> A:
`
`+ Na* + H,O
`
`Drawoff the lower, aqueous, layer and save it, The ether layer should now
`___
`contain only the neutral substance N.
`:
`Isolation of the neutral substance, N. Wash the ether layer by adding to
`__
`the separatory funnel about 25 mL of water, shaking the mixture, allowing
`___
`the layers to separate, and then drawing off and discarding the lower, aque-
`ous, layer. Transfer the ethereal solution of the neutral compound to a small
`_ Erlenmeyerflask, dry the solution over 1-2 grams of anhydrous sodium
`sulfate for a few minutes (Section 15.2), remove the drying agent by gravity
`filtration (Section 7.1), and remove theether by evaporation ordistillation on
`the steam bath (Section 36). The infrared spectrum of the residue may be
`_ determined (Section 23); or, if the residueis a solid, it may be recrystallized
`_ (Section 8) and its melting point determined (Section 17).
`Isolation of the basic substance, B:, Transter the aqueoussolution of the
`hydrochloric acid salt of the basic substance to a clean 125-mL separatory
`funnel. Make the solution strongly basic by adding about 2 mL of 50%
`_ aqueous sodium hydroxide. Make sure the solution is well mixed. The basic
`substance will now be presentas the free base:
`
`B—H + Cl- + Nat +HO- ——> B: + Na’ +Cl- + H,O
`
`_ Add 25 mLofetherto the separatory funnel. Shake the mixture well so as to
`_ extract the free base into the ether layer. Draw off the lower, aqueous, layer
`_ (which may now be discarded) and transfer the ethereal solution of the basic
`substance to a small Erlenmeyer flask. Dry the solution over 1-2 grams of
`a anhydrous potassium carbonate for a few minutes, remove the drying agent
`_ by gravity filtration, and removethe ether by evaporation or distillation on
`__ the steam bath. The infrared spectrum ofthe residue may be determined; or,
`4 if the residue is a solid, it may be recrystallized and its melting point deter-
`mined.
`
`
`
`
`a
`Page 14 of 18
`
`Page 14 of 18
`
`

`

`416
`
`SEPARATION OF SUBSTANCES
`
`ether solution of
`N, AH, and B:
`
`extract with acid
`
`
`
`ether solution
`of Nand AH
`
`aqueous, acidic
`solution of B-H
`make basic
`extract with ether
`
`ether solution
`aqueouslayer;
`of B
`discard
`
`anhydrous sodium sulfate for a few minutes, remove the drying agent by
`
`Add 25 mLofetherto the separatory funnel. Shake the mixture well so as to
`extract the free acid into the ether layer. Draw off the lower, aqueous, layer
`(which may now be discarded) and transfer the ethereal solutionof the acidic
`substance to a small Erlenmeyerflask. Dry the solution over 1-2 grams of
`
`| isolate B
`
`
`B:
`
`.
`
`aqueous, basic
`solution of A:
`
`make acid:
`
`extract with base
`
`ether solution
`of N
`isolate N
`
`N
`
`extract with ether
`
`aqueouslayer;
`discard
`
`ether solution
`of ATH
`isolate A-H
`
`AH
`
`Flow chart for the separation of a mixture of an acid
`Figure 13.2.
`A—H. a base B:, and a neutral substance N.
`Isolation of the acidic substance, A—H. Transfer the aqueous solution of
`the sodium salt of the acidic substance to a clean 125-mL separatory funnel.
`Makethesolution strongly acidic by adding about 3 mL of conc. HCl. Make
`sure the solution is well mixed. The acidic substance will now be present as
`the free acid:
`
`A: + Na‘ + H,O* + Cl ——> A—H + Na* + Cl + H,O
`
`Page 15 of 18
`
`Page 15 of 18
`
`

`

`filtration, and remove the ether by evaporationordistillation on the
`bath. The infrared spectrum of the residue may be determined;or,if
`residue is a solid, it may be recrystallized and its melting point deter-
`ined
`
`
`
`
`Separation of the components of a commercial mixture of aspirin, phen-
`
`acetin, and caffeine.
`___ Some brands of headacheor cold tablets, the so-called APC tablets,
`
`contain a mixture ofacetylsalicylic acid (aspirin), phenacetin, and caffeine. It
`
`possible to take advantageofthe acid-base properties of these compounds
`
`© as to separate them by an extraction procedure. Caffeine, whose conjugate
`
`‘acid has a pK, of —0.16, can just be extracted as the conjugate acid from
`
`oform into 4 M HCl. After the acidic extract has been neutralized,
`feine can be reextracted from the water with additional chloroform and
`
`solated by evaporation of the chloroform. Aspirin, having a pXK,, of 3.49, can
`be extracted from chloroform by 0.5 M aqueous sodium bicarbonate solu-
`
`n. After the aqueous extractis neutralized by addition of HCI,the precipi-
`
`ed aspirin can be isolated by reextraction with more chloroform and recov-
`d by evaporation of the chloroform. Phenacetin, a substance that is
`
`her acidic nor basic, remains in the original chloroform solution and is
`covered by evaporation of the chloroform after the other two substances
`been removed.
`
`Procedure
`
`Isolation of caffeine. Crush 3 APC tablets (Note 1) and add them to a
`Separatory funnel that contains 25 mL of chloroform. Then add to the fun-
`‘Rel 20 mL. of 4 M HCI (80 milliequivalents of acid), Shake the funnelin
`fder
`to thoroughly mix the contents (Note 2). Allow the funnel to stand so
`
`at the layers will separate. Draw off and save the lower, chloroform, layer
`
`contains the unextracted aspirin and phenacetin (Note 3).
`
`Recovery of caffeine. Neutralize the aqueousacidic extract of caffeine in
`
`the
`separatory funnel by adding 7.0 gramsof solid sodium bicarbonate (83
`
`meq. of base). Since a lot of carbon dioxide will be produced, you should add
`i€ sodium bicarbonate in portions. Swirl the contents of the funnel after
`
`ach
`portion has appeared to react. After all the base has been added and the
`Feaction appears to be complete, add 10 mL of chloroform, stopper the
`
`unnel, invert it, and release the pressure by opening the stopcock, Cau-
`y mix the contentsof the funnel and frequently release the pressure by
`
`ig
`the stopcock of the inverted separatory funnel. Finally, when the
`sure does not build up any more, shake the funnel to thoroughly mix the
`
`mmtents of the funnel (Note 2), allow the layers to separate (Note 4) and
`raw off the lower, chloroform, layer into a small Erlenmeyer flask labeled
`
`Heine.” Reextract the neutralized acid solution with a second 5-mL por-
`of chloroform and add this further chloroform extract to the flask la-
`
`led
`“‘caffeine.”’ Dry the combined extracts with a small portion of anhy-
`
`tus Magnesium sulfate (Section 15.2) and filter the mixture by gravity
`
`Section 7.1) into a small, weighed Erlenmeyer flask containing a boiling
`ne
`(Note 5), Remove the chloroform by distillation on the steam bath
`ote 6) and determine the weight of the residual solid by reweighing the
`ask. The recovered caffeine (Note 7) can be recrystallized from 10 mL of
`
`
`NyeJ LN.
`ateO77
`
`~N
`
`~nN~
`H,
`caffeine
`
`|C
`
`H
`
`Page 16 of 18
`
`SECTION 13.
`
`117
`
`¢
`
`The accompanying flow chart (Figure 13.2) summarizes these proce-
`
`Page 16 of 18
`
`

`

`118
`
`SEPARATION OF SUBSTANCES
`
`aspirin, phenacetin, and
`caffeine in 25 mL of CHCl,
`extract with 20 mL
`of4M HCI
`
`
`
`CHOI, solution of
`aspirin and phenacetin
`
`aqueousacidic solution
`of caffeine
`
`extract with 25 mL of
`0.5 M NaHCO,
`
`neutralize with NaHCO,
`extract caffeine with CHCI,
`
`aqueous phase of caffeine
`
`CHC), solution
`of phenacetin
`
`aqueous basic solution
`of aspirin
`
`CHICL, solution
`
`(discard)
`
`acidify with 4M HCt
`extract aspirin with CHCI,
`
`
`
`aqueous phase
`CHCT, solution
`(discard)
`of aspirin
`
`
`Flow chart for the separation of a mixture of aspirin,
`Figure 13.3.
`phenacetin, and caffeine.
`
`
`carbontetrachloride,if desired. The melting pointof caffeine is reported to j
`
`be 238°C, with sublimation starting at 170°C, and its infrared and NMR~
`
`spectra are shown in Figures 42.1 and 42.2.
`3
`Isolation ofaspirin. Place the original chloroform solution that was saved —
`6
`?
`from the first extraction in a clean separatory funnel. Then add 25 mL of0,5
`
`C—OH i
`M sodium bicarbonate solution (12.5 meq. of base) and thoroughly mix the
`
`LL o-C—cH,
`contents of the funnel (Note 2) so as to extract the aspirin into the basic
`
`cf Ss
`waterlayer. Since carbondioxide will be formed, the funnel must be vented —
`
`2
`lL
`occasionally in order to prevent too great an increase in pressure. After
`
`Sn mixing,allow the funnel to stand undisturbed so that the layers can separate._
`
`acetylsalicylic acid
`Draw off the lower, chloroform, layer into a small Erlenmeyer flask labeled —
`
`“phenacetin” and add to this a small amount of anhydrous magnesium
`(aspirin)
`
`sulfate.
`
`Recovery of aspirin. Add to the basic aqueous solution of aspirin in the
`—
`
`separatory funnel 5 mL of 4M HCl (20 meq.of acid). Mix the contents of
`
`the funnel by swirling it gently. Carbon dioxide will be evolved and the
`
`aspirin will separate as a solid. Recover the aspirin by extracting first with a
`
`
`
`Page 17 of 18
`
`Page 17 of 18
`
`

`

`?
`H—N—C—CcH,
`
`
`
`O—CH,—CH,
`p-ethoxyacetanilide
`(phenacetin)
`
`SECTION 13.
`
`119
`
`
`mL. portion of chloroform and then with a S-mL portion. Combine these
`extracts in a small Erlenmeyerflask labeled “aspirin.” Dry the aspirin
`'s with a small portion of anhydrous magnesium sulfate and then filter
`mixture by gravity into a small, weighed Erlenmeyerflask containing a
`
`ing stone (Note 5). Remove the chloroform by distillation on the steam
`ith (Note 6) and determine the weightof the residue. The recovered aspirin
`
`8) can be recrystallized by adding 5 mL of water, heating the mixture
`the steam bath,and adding slightly more than the minimum amountof
`
`ethanol required to dissolve the solid; about 1.5 mL should be added.
`in is reported to melt at 135°C with rapid heating. Its IR and NMR
`
`tra
`are shown in Figures 58.6 and 58.7.
`
`Recovery ofphenacetin. Remove the magnesium sulfate from the chloro-
`rm solution of phenacetin by gravity filtration, collecting the filtrate in a
`
`» weighed Erlenmeyer flask containing a boiling stone (Note 5). Re-
`the chloroform by distillation on the steam bath (Note 6) and deter-
`
`¢ the weightofthe residual solid. The recovered phenacetin (Note 9) can
`recrystallized from a very small amount of 95% ethanol. The melting
`
`t of phenacetin is reported to be 134-135°C, and its IR and NMR
`ira are shown in Figures 62.2 and 62.3.
`
`The flow chart (Figure 13.3) summarizes these procedures.
`
`hree APC tablets typically weigh 1.5 grams and contain 10.5 grains aspirin
`(680 mg), 7.5 grains phenacetin (486 mg), and 1.5 grains caffeine (97 mg).
`»
`One
`full minute of continuous shaking is sufficient.
`
`you