181
Ind. Eng. Chem. Fundam. 1982, 21, 181-183 Cronln. J. A.; Greenberg, D. F.; Telegdl. V. L. “University of Chicago Graduate Problems In Physics with Solutions”; Addlson-Wesley: Reading, MA, 1987. Deihaye, J. M. Eleventh Nat. ASMElAIChE lit. Transfer Conference, Minneapoiis, Aug 1969, p 58. Gregoty, 0. A.; Mattar, L. J . Can. Pet. Techno/.Aprii-June, 1973, 48. Hewkt, 0. F.; King, 1.; Lovegrove, P. C. Br. Chem. Eng. 1963, 8 , 311. Hsu. Y. Y.; Simon, F. F.; Graham, R. W. Mulfiphase Flow Symp. ASME, 1963, 26. Isbin. H. S.;Rodriguez, H. A.; Larson, H. C.; Pattie, B. D. AIChE J . 1959, 5 ,
427.
Merllo, M.; Dechene, R. L.; Clchowlas, W. M. J . Heat Transfer 1977, 99, 330. Schrock, V. E. Eleventh National ASMlAIChE lit. Transfer Conference, Minneapolis, Aug 1969, p 24. Sachs, P.; Long, R. A. K. Int. J . Heat Transfer 1961, 2 , 220.
Receiued for reuiew July 17, 1981 Accepted January 26, 1982
COMMUNICATIONS Preferential Crystallization of Ionizable Racemic Mixtures I n the separation of mixtures of optical Isomers by fractional crystallization it is essential to control the degree of supersaturation of the isomer remaining in solution. This can be accomplished for racemic mixtures of amino acids by adding acid or base to the solution. With such additions a purer crystalline product of one isomer can be obtained. An explanation of this effect is given based on ionic equilibrium in the solution.
Introduction Of the several methods of resolution or separation of mixtures of optical isomers, only conversion to diastereoisomers and resolution by enzymatic methods have been regarded as generally useful. However, in resolving racemic amino acids, mechanical resolution of the isomers has been successfully used in industry. In this method, a supersaturated solution of a racemic mixture is inoculated with a pure crystal of one of the isomers, the crystal grows, and thus one active form is separated from the racemic mixture. The other isomer remains supersaturated in the solution. This system is unstable, however, and the optical antipode which remains supersaturated in the solution tends to precipitate, resulting in poor resolution of the racemic mixture. Several devices for stabilizing the solution supersaturated with the antipode have been developed. In the case of resolution of ionizable racemic mixtures, addition of acid or base to the solution has been found to stabilize the system and the yield of the desired crystal form becomes higher than that obtained without adding acid or base (Akashi, 1962; Mizoguchi, 1967a,b). The reason for this has remained obscure. Here we describe the theoretical basis for the stabilizing effect of acid or base on solutions supersaturated with amino acids, using thermodynamical considerations. When one acid isomer of an optical pair to be crystallized selectively by seeding coexists with the corresponding salt forms, the salts are more soluble than the acids and do not change the essential separability. The acid form that is not seeded will transfer part of its acidity to the acid form that is seeded, increasing the yield of desired product and decreasing the supersaturations of the unseeded acid form. Stabilizing Effect of NaOH on Supersaturation of Racemic Glutamic Acid L-Glutamic acid imparts meat flavor to foods and resolution of racemic glutamic acid has been of practical importance in industry. We will consider in the following the resolution of racemic glutamic acid in the presence of NaOH. 0196-4313/82/1021-0181$01.25/0
In the aqueous solution containing DL-glUtamiC acid and NaOH, the following reaction occurs
L-A + D-S e L-S+ D-A
(1)
where LA, L-S,D-A, and DS are the free form of Lglutamic acid, sodium salt of L-glutamic acid, free form of Dglutamic acid, and sodium salt of Dglutamic acid, respectively. This reaction is an exchange of sodium ion between L-A and D-A. D-A differs from L-A only in optical rotatory power, but they are almost identical in any other properties such as activity coefficients. Therefore, for reaction I
where CLA,,,C CDA,and C m are the molar concentration of L-A,that of LS,that of DA and that of DS, respectively. I t is evident, therefore, that the direction of reaction I depends only on changes in entropy. By determining the solubilities of L-A (or D-A) in the solutions that contain various amounts of DA (or L-A) and that have been added a given amount of DL-S(racemic sodium glutamate), the mutual solubilities curves of L-A vs. D-A can be plotted and are shown in Figure 1. This figure demonstrates that, although the solubility of DL-A (free form of racemic glutamic acid) is almost independent of the concentration of DL-S(CDLS), the larger CD, is, the larger the solubility of D-A (or L-A) in the absence of its antipode becomes (Mizoguchi, 1967a). This result suggests that the transfer of the acidity of one isomer to the other occurs according to reaction I and the apparent solubility of D-A (or L-A) increases. On the other hand, the properties of these solutions are considered to be determined when three parameters, CLA, CD-A, and the concentration of NaOH (CNaoH),are given a t constant temperature. Therefore the mutual solubilities of L-AS (L-A plus L-S) vs. BAS (DA plus DS) are plotted and are shown in Figure 2. This figure can be considered to show the mutual solubilities of L-A vs. D-A in the NaOH-containing solutions. The sum of CD.s and CL-S equals CNaOH in the solutions. 0 1982 American Chemical Society
182
Ind. Eng. Chem. Fundam., Vol. 21, No. 2, 1982
1
C,..,(rnoles
/
lOOg
k
water)
30817
C
.,E 0
0 02'2
O 0
'
0 C ,D.
L
0;
G2
( m o l e s / 1009 w a t e r )
Figure 1. Experimentally determined mutual solubilities of D-A vs. L-A in the presence of various concentrations of DL-Sat 20 O C . ' , - A S
-
Figure 3. A theoretical mutual solubility diagram for D-ASvs. L-AS.
the supersaturation originally present in the system is distributed between two separate components, D-A and D-S;thereby the system as a whole becomes more stable than the original one. From eq 1, we obtain
00817
+ C-AC - CA + Ac Cs + AC Cs - AC
06
CA
(2)
or
04 0
(3) 02
3 3
0-
92 C,.,,
'moes
06
'00s
08
'0
water)
Figure 2. Experimentally determined mutual solubilities of D-AS vs. L-AS in the presence of various concentrations of NaOH at 20 "C. Dotted lines shows the composition of D-S and L-S.
Let us suppose that in a solution which contains the saturated amount of DL-A,2cA (moles per 100 g of water), and 2Cs (moles per 100 g of water) of DL-S,and which is designated the base solution, 2C (moles) of DL-A is dissolved by heating. Then, the solution is cooled to the original temperature and seeded with a small amount of L-A. In order to make the problem simple, let us suppose that C (moles) of L-A crystallized out and C (moles) of D-A remains supersaturated in the solution. Reaction I progresses from right to left. Let us suppose that AC (moles) of D-A is converted into AC (moles) of D-S,AC (moles) of L-A being simultaneously formed from AC (moles) of L-S. As a result, the degree of supersaturation of the antipode, D-A,originally C, decreases to (C - AC). Thereby the system is stabilized because of the AC decrement, provided that the solution is still unsaturated with D-S. If we had prepared the base solution which was saturated with D-S,this process would bring about supersaturation of D-Sby AC. In this case,
Thus, AC approaches C/2 as Cs increases. As a result, the higher Cs or CNaoHis, the easier and more stable selective crystallization becomes. However, there is a certain Cs value over which the increase of AC can be no longer expected. There is also a limit of Cs under which the supersaturation of the antipode is apt to be broken and the antipode tends to crystallize out of the solution to lower the optical purity of the precipitated crystal. Cs that is suitable for resolution should be determined by repeated measurements of the optical purity and yield of the precipitate. Let us suppose in a theoretical mutual solubility diagram (Figure 3), that resolution has progressed from point N [(Cs + CA + C), (Cs + CA + C)], which shows the composition of the solution that is prepared by dissolving 2C (moles) of DL-A in the base solution by heating. The heated solution is cooled to the original temperature and seeded with a small amount of L-A. When the preferential crystallization of L-A progresses and C' (moles) of L-A has crystallized, the composition of the solution reaches an arbitrary point P [Cs + CA + C), (Cs + CA + C - C?] on The mutual solubilities of D-AS line NQ. C' equals vs. L-AS are shown by curves GM and MH. The composition of point M is [(Cs + CA), (Cs + CA)]. The line EF along which the composition of L-Sand D-Smoves during the progression of resolution of L-A (or D-A) intersects at right angles with the line J N at point K [Cs, Cs]. The line EF intersects the line JP at point K'. When the composition of the solution reaches point P and AC' (moles) of D-A is converted into AC' (moles) of D-S, AC' (moles) of
s.
Ind. Eng. Chem. Fundam., Vol. 21, No. 2, 1982
183
L-A is simultaneously formed from AC’ (moles) of L-S. The decrement of the degree of supersaturation of the antipode, ACf, can be simply demonstrated as K D K ’ D or K L K f L in Figure 3. Therefore, CD-A, which is (CA + C - AC?, equals K ’ D N D . CL-A, which is CA + C - C’+ AC), equals K ’ L P L . Therefore, we obtain -CD-A - - CA + C -ACf (4) cD-S Cs + AC’
/
and
CL.A - - CA + C -C’ CL-s
+ AC
Cs - AC’
(5)
From eq 1,4,and 5
and ” ”,
K,
(7)
A C f increases moderately at the beginning and then with acceleration as crystal growth proceeds. This means that as the resolution progresses, the system is stabilized more and more.
Maximum Amount of an Isomer Precipitated in a Single Operation When resolution has progressed and point P started from point N has reached point Q [(Cs + CA + C),(Cs + CA)] in Figure 3, the supersaturation of L-A originally present in the system disappears. However, AC (moles) each of D-A and L-Shas been converted to D-Sand L-A, respectively. This leads to the additional supersaturation of L-A, AC at point Q; therefore, it is possible for additional resolution to proceed beyond point Q. Since the amount for saturation of L-A is CA (moles), the amount of L-A in the solution decreases to CA(moles) after completion of resolution. At this stage, the decrement of the degree of supersaturation of the antipode is specified as ACf! Then, the maximum amount of L-A to be obtained is (C + AC’? (moles). The final composition of the solution is indicated by point R in Figure 4,thus showing that the solubility of L-AS is (Cs + CA- ACf? (moles) in the presence of (Cs + CA + C) (moles) of D-AS in 100_g_of_water containing 2Cs (moles) of NaOH. AC” equals K D K l ’ D , K L K f ’ L , or From eq 2
a.
CA
+ c - A c f f --
Cs + AC”
CA
CS - AC”
(8)
Therefore AC” = ‘/[CS
+ 2 c A + C - ((CS - C)2 + 4cA(cS + CS* c + cA))1’2] (9)
AC If increases monotonously and gradually more moderately with an increase of C. By determining A C f fas a
KiM,
Co-ns
-
ND
Figure 4. A theoretical mutual solubility diagram for D-ASvs. L-AS. Bold, dotted line shows the metastable mutual solubility curve.
+ +
function of C, solubilities of L-AS against (Cs CA C) (moles) of D-AS in 100 g of water containing 2Cs (moles) of NaOH can be shown. This affords a curve which is termed the metastable mutual solubility curve MR. The metastable mutual solubility curve MR in Figure 4 is considered to be an extension of the normal mutual solubility curve GM through point R. Obviously these considerations are generally applicable to other racemic compounds having ionizable functional groups, provided that the mutual solubility curve can be obtained in the presence of base or acid. For example, (f)3,4-dihydroxy-@-phenylalanine, aspartic acid, threonine, and homocysteine have been successfully resolved by utilizing these methods. Experimental details in this type of resolution will be described elsewhere.
Literature Cited Akashl, T. Nippon Kagaku Kaishi 1962, 8 3 , 421. Mizoguchi, N. Nippon Nogeikagaku Kaishi I967a, 4 7 , 607. Mizoguchi, N. Nippon Nogeikagaku Kaishi I967b, 4 7 , 616.
Central Research Laboratories Ajinomoto Co. Ltd. Kawasaki-shi Kanagawa 210, J a p a n Department of Applied Biochemistry Hiroshima University Fukuyama-shi Hiroshima 720, J a p a n
Soichiro Asai*
Susumu Ikegami
Received for review August 13, 1980 Revised manuscript received August 3, 1981 Accepted December 7, 1981
