Anal. Chem. 1993, 65, 1350-1354
1350
Separation of from Ionizable Crown Ethers
by Solvent Extraction with
Donald J. Wood, S. Elshani, H. S. Du, N. R. Natale, and C. M. Wai' Department of Chemistry, University of Idaho, Moscow, Idaho 83843
sym-Dibenzo-16-crown-5-oxyacetic acid and its analogues are selective for the extraction of Y3+ over Sr2+from aqueous solutions into chloroform. The selectivity and the pH range of extraction are influenced by the structure of the ligand. The size of the macrocyclic cavity, the tether length of the lariat, the attachment of alkyl functional groups to the lariat, and the identity of the ionizable group can affect selectivity and extraction efficiency. When the carboxylic acid at the terminal end of the lariat is replaced by a hydroxamic acid, the selectivity for Y3+ over Sr2+is significantly increased. Using these ionizable crown ethers as extractants, 90Yfractions of greater than 99.9% purity can be obtained in a single solvent extraction step from solutions of 90Sr.
(el Ionizable Macrocyclic Polyethers
R
Radioisotopes of the rare earth elements (REE)have found many new applications in nuclear medicine. For example, the isotope has been recognized as having a half-life and decay properties which are suitable for use in the production of labeled monoclonal antibodies (MAb's) for tumor therapy studies.' In any nuclear medical application, the purity of a radioisotope and the medium in which it is taken for use are of vital importance. can be produced from its parent 90Sr according to the following decay process: "Sr
-
-
J = 0 5 MeV
3 = 2 27 MeV
t , :=289years
!, ? = 6 4 O h
"Zr (stable)
In theory, carrier-free can be repeatedly removed from its parent 90Srafter reestablishment of the secular equilibrium. However, in order to obtain pure 9OY from this generator system, a highly selective and rapid separation method is required. In addition to the requirements of nuclear medicine, an efficient chemical separation of 90Y from 90Sr is needed for the rapid analysis of radiostrontium in environmental samples.2 The presence of 90Srin the environment is of particular concern because it is a bone-seeking radi~nuclide.~ Analysis of 90Sr and 9OY in environmental samples is complicated by the fact that both of the isotopes are pure fl emitters. Their quantitation, therefore, must be preceded by chemical separation. It has been reported that ionizable crown ethers such as sym-dibenzo- 16-crown-5-oxyacetic acid and its analogues can be made highly selective for the extraction of trivalent lanthanide i0ns.43~The extraction does not require specific (1) Srivistava, S. C. Radiolabeled Monoclonal Antibodies forlmaging and Therapy; Plenum Press: New York, 1988. (2) Wilken, R. F.; Joshi, S. R. Radioact. Radiochem. 1991, 2, 14-27. (3) Engstrom, A. Bone and Radiostrontium; Wiley: New York, 1958; p 22. (4) Tang, J.; Wai, C. M. Anal. Chem. 1986, 58, 3233.
0
COOH
HOOC
1
2 3 4 5 6 7
a
INTRODUCTION
Ibl lonizeble Acyclic Polyethers
9
O 0 0 0 0 0 3 O 0
OH OH
1 1
Ceii5-- OH
H
1
C,.H,, H
C,,H,, C,H,
H H H
NHOH NHOH NHOH OH
10
1
11
7.
1 1
1 1
OH 2 NHOH 2
Figure 1. Structures of ionizable cyclic and acyclic polyethers.
counteranions and is reversible with respect to pH. Spectroscopic studies indicate that both the macrocyclic cavity and the carboxylate group are involved in the complexation.4 The mechanism of complexation is envisioned to involve first the capture of the cation followed by its insertion into the cavity. The cation to ligand ratio of the complex has been estimated to be 1:2, suggesting a possible sandwich f ~ r m a t i o n . ~ This type of ionizable crown ether has been found to behave like a bifunctional ligand which discriminates cations according to their size as well as their chemical nature.F The influence of molecular structure upon the extraction of the alkali metals with ionizable crown ethers has been investigated previously.' However, the parameters controlling the stability of the lanthanide complexes with this type of ionizable crown ether are largely unknown. It is intuitive to consider the functional group on the terminal end of the lariat, the tether length, and the cavity of the macrocycles to be important parameters for the formation of a stable configuration for the lanthanide-macrocycle complex. This paper examines the influence of these molecular parameters on the separation of Y3+ and Sr2+by solvent extraction. These molecular parameters should provide guidelines for the development of selective ionizable crown ethers for specific applications in the separation of from 90Sras well as other rare earth separations.
EXPERIMENTAL SECTION Preparation of Macrocyclic Compounds. Compounds 1 and 8 were prepared according to an established procedure (5) Tang, J.; Wai, C. M. Analyst 1989, 114, 451. (6) McDowell, W. J. S e p . Sci. Technol. 1988, 23, 1251-1268. (7) Walkowiak, W.; Charewicq, W. A.; Kang, S. I.; Yang, I. W.; Pugia M. J.; Bartsch, R. A. Anal. Chem. 1990, 62. 2018-2021.
1993 American Chemical Society 0003-2700/93/0365-1350$04.00/0@2
ANALYTICAL CHEMISTRY, VOL. 65,
reported in the literature.* The dibenzo-16-crown-5-oxyacetic acid derivatives, 2,3, and 7, were prepared from corresponding sym-hydroxydibenzo-16-crown-5 by reaction with 2-bromostearic acid, a-bromophenylacetic acid, and 4-bromobutyric acid, respectively,in THF in the presence of sodium hydride. The crown ethers were obtained in total yields of 6040%. Compounds 4-6 and 9 were prepared in three step reactions with correspondingcrown ether carboxylic acids. The carboxylic acids were converted to their acid chlorides, using oxalyl chloride followed by reaction with o-benzylhydroxylaminehydrochloride to yield crown hydroxamates. A final hydrogenation step yielded the crown ether hydroxamic acids. The acyclic polyether dicarboxylic acids, 10 and 11, were prepared by the reaction of 2-bromohexadecanic acid with corresponding biphenols. The compounds were obtained in 5383% overall yields. A detailed description of the synthetic procedures, including spectral data, for each of the macrocycles will be given elsewhere. Other Reagents. The radioisotopes and NSr were purchased from Isotope Products Laboratories, Burbank, CA. Other radioisotopes were produced in a 1-MW TRIGA nuclear was obtained reactor located near our campus. Ultrex "03 from the J. T. Baker Co. Distilled, ultrafiltered water for dissociation constant determinations was obtained from VWR Scientific. All other chemicals used were Baker Analyzed Reagents. Deionized water was prepared by passing distilled water through an ion-exchange column (Barnstead ultrapure water purification cartridge) and a 0.2-pm filter assembly (Pall, Ultipor DFA). All containers used in the experiments were acidwashed, rinsed with deionized water, and dried in a class 100 clean hood. Extraction Procedure. The extraction solutions were prepared by dissolving weighed amounts of the pure compounds in chloroform in a beaker with magnetic stirring. Aqueous sodium acetate buffer solutions containing the radioisotopes in trace quantities were mixed with equal volumes of the extraction solution for the experiments. The pH of the aqueous phase was adjusted using an Orion 91 semimicroelectrode. The mixture was shaken vigorously on a mechanical wrist-action shaker (Burrell Model 75) for a fixed time at room temperature. After shaking, the mixture was allowed to stand for several minutes for phase separation. A fixed amount of the aqueous phase and the organic phase was then removed from the system for radioactivity measurements. The extraction procedure involves chloroform and radionuclides. The use of these materials will result in a mixed hazardous waste. The disposal problems of such waste must be considered when this procedure is performed. We recommend consulting a safety expert concerningwaste disposalprior to the experiments. Radioactivity Measurements. The relative extraction efficiencies of SrZ+and Y3+ were determined by competition experiments using 87mSr( t l / z = 2.80 h) and W Y (tip = 106.6 days) as tracers. The y energies emitted from these two radioisotopes (388.4 keV for 87mSrand 898.0 keV for MY) are sufficiently different so that they can be measured simultaneously by y spectrometry. An Ortec Ge(Li) detector was used to measure y radiation from the radioisotopes used in the experiments. The detector had a resolution of 2.3 keV at 1336-keVradiation from 6OCo and an efficiency of 15% relative to a 3 X 3 NaI crystal. The activities of the 0 emitters, WSr and NY,were measured with a conventional Geiger-Miiller counter. The procedures of y spectrometry as well as neutron irradiations are given elsewhere.9 Dissociation Constants and Solubilities. The acid dissociation constant of each compound was determined by measuring the pH of solutions of known concentration with an Orion 91 semimicroelectrode. The solubilities were determined by the addition of an excess amount of the pure, crystalline compound to a polyethylene vial containing distilled, ultrafiltered water obtained from VWR Scientific. The solution was shaken at 25 "C for at least 24 h. The solution was then filtered through a No. 32, low-ash Whatman filter to remove any undissolved material. (8)Heo, G.S.;Bartsch, R. A.; Schlobohm, L. L.;Lee, J. G.J . Org.
Chem. 1981,46, 3574. (9) Mok, W.M.; Wai,
C.M. Anal. Chem. 1987,59,233.
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Flgure 2. pH dependence on the extraction of Y3+ and Sr2+ from aqueous solutions bufferedwith 0.05 M sodium acetate into chloroform Y3+ and (+) Sr2+ containing 0.01 M (a) 1, (b) 2, and (c) 9. (0) concentrations, 1 X lo4 M each.
The concentration of the compound was then determined by UV-visible spectroscopy.
RESULTS AND DISCUSSION Extraction w i t h Crown Ether Carboxylic Acids. The extraction of Y3+by 1 depends strongly on pH as shown in Figure 2. The extraction of Y3+into the organic phase becomes appreciable at pH greater than 4 and rises rapidly with further increase in pH, reaching a maximum at approximately pH 6.5. Above pH 6.5, the extraction of Sr2+ into the organic phase is observable and continues to rise with further increase in pH. A good separation of Y3+and Sr2+ can be achieved in the pH range 6-6.5, where the former is nearly quantitatively extracted and the latter is virtually not extractible. The ratio of the D value (distribution coefficient) for Y3+/ Sr2+at pH 6.5 is about 100:0.01,providing a separation factor of -104. Y3+which has been extracted into the organic phase can be stripped with a dilute nitric acid solution (0.01 M) by shaking the extraction container for 15min. This procedure regenerates the ligand for repeated use. The use of 1in solvent extraction is limited because of the solubility of the compound in the aqueous phase (1.08 X lo"' MI. Loss of the extractant from the organic phase prevents the recyclability of the compound. Attachment of alkyl functional groups to the
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ANALYTICAL CHEMISTRY, VOL. 65, NO. 10, MAY 15, 1993
Table I. Solubilities of ComDounds 1-11 in Watera
100
comDd
solub ( X l O j ) . mol/L
comDd
solub ( X l O j ) . mobL
1 2
10.8 1.34 8.91
7 8 9 10 11
23.0 54.1 1Tj.8 4.42 1.84
3
4 5 6
15.8 0.69 14.0
,
1
Measurements were performed at 25 " C .
compound should enhance the lipophilicity of the ligand, thus reducing its loss to the aqueous phase during solvent extraction. Table I shows that the placement of alkyl groups on the lariat arm decreases the solubility of the extractants in water as expected. The solubility of 2 is decreased by 1 order of magnitude while the solubility of 3 is decreased only slightly. Attachment of alkyl groups to the pendant lariat carboxylic acid on the macrocyle also alters the extraction profile. The effects of a C16 alkyl group (2) and a phenyl (3) substitution on 1 are shown in Figure 2b,c, respectively. The extraction curves of 2 for both Y3+ and Sr2+are shifted toward higher pH by -0.5 pH unit. For crown ether carboxylic acid 3, the extraction curves for both Y3+and Sr2+are extended to lower pHby -1.5units. ExtractionofY3+reachesaplateau(>90%) near pH 4.5, and detectable amounts of Sr2+are extracted above pH 5. The D values for Y3+ and Sr2+at pH 4.5 are 9 and 0.1, respectively. Although Y3+can be extracted almost free of Sr2+ under this condition, the extraction is not quantitative. The pK, value of 1 (4.7 f 0.2) is very close to that of acetic acid. Addition of an alkyl group to the a position of the pendant carboxylic acid increases the pK, value of 2 to 7.1 f 0.2. The large increase in pK, is attributed to the intramolecular hydrogen bonding with the cavity oxygen due to bending of the carboxylic group toward the ring. A previous report of crown ether carboxylic acids containing alkyl groups placed at the same attachment site as that of 2 also indicated a corresponding increase in pK,.'" The attachment of a phenyl group to acetic acid results in a lowering of the pK,. However, the pK, value of 3 actually increases over that of 1 to 5.2 f 0.2, indicating that the intramolecular hydrogen bonding with cavity oxygens exceeds the electron-withdrawing effect of the phenyl on the carboxylic acid. The extraction curves of 1-3 also indicate that complexation of Yj+ is not directly related to the pK, of the crown ether carboxylic acid extractant. Experiments with 7 resulted in poor extraction of Y7+,as shown in Figure 3a. Addition of three methylene groups to the tether reduces the extraction efficiency of the crown ether carboxylic acid by 1 order of magnitude. Longer tether length probably disfavors a stable configuration for the complexation with Y3+. The extraction profile usingsym-dibenzo-19-crown6-oxyacetic acid (8) is shown in Figure 3b. The extraction curve is similar to that of 1, except that the efficiency is slightly lower in general. Extraction with Crown Ether Hydroxamic Acids. The extraction curve of sym-dibenzo-16-crown-5-oxyhydroxamic acid (4) shown in Figure 4a is shifted to a slightly higher pH relative to 1,but the extraction efficiency remains high at pH values above 7.0. Extraction of Sr*+is negligible up to pH 9.0. Changing the ionizable functionality from carboxylic acid to hydroxamic acid suppresses the extraction of SrL+ significantly. Quantitative separation of Y3+ from SrL+can be achieved over a wide pH range from about 7 to 9. The
2
3
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PH
-
(10) Bartsch,R.A.;Heo,G.S.;Iiang.S.I.:Liu,Y.;Srzelbicki,J.J.Or~ Chem. 1982. 4 7 , 457-460.
2
3
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5
PH 100
1
80
- c
60
-
40
-
2
i 3
4
5
6
7
8
PH
Flgure 3. pH dependence on the extraction of Y3+ and Sr2+from aqueous solutions buffered with 0.05 M sodium acetate into chloroform containing 0.01 M (a) 7, (b) 8, and (c) 9. (0)Y3+ and (+) Sr2+ concentrations, 1 X M each.
distribution coefficient ratio of Y3+/Sr2+ is lo4or greater within this pH range. The solubility of 4 in water at room temperature is -50% higher than that of 1. Addition of a C16H32 alkyl group to the cy position of the hydroxamic acid lowers the solubility of 4 by a factor of 23. The alkylsubstituted crown ether hydroxamic acid 5 extracts Y3+ effectively in a narrow pH range (around 6.5),as shown in Figure 4b. The extraction efficiency drops at pH above 7, corresponding to the formation of an interfacial phase between the aqueous phase and chloroform. The phenyl-substituted hydroxamic acid 6 extracts Y?+ in nearly the same pH range as the unsubstituted compound 4, as shown in Figure 4c. The extraction efficiency of Y3+ by sym-dibenzo-19-crown-6oxyhydroxamic acid (9) is decreased when compared to the 16-crown-5 derivative 4, as shown in Figure 3c. This effect is similar to the effect observed in the structurally similar carboxylic acids 1 and 8. It appears that the larger cavity diameter tends to be less favorable for the formation of the yttrium complex. Extraction with Lipophilic Acyclic Polyether Dicarboxylic Acids. Panels a and b of Figure 5 show the results of our extraction experiments with the acyclic polyether carboxylic acids 10 and 11. Each of these extractants contains two carboxylate groups that may participate in cation complexation. In the case of compound 10, Y3+ may be quantitatively extracted within the narrow pH range of 6.5-
ANALYTICAL CHEMISTRY, VOL. 05, NO. 10, MAY 15, 1993
1359
100
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60 40 20
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PH 100
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1
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PH
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PH
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PH Figure 5. pH dependence on the extractlon of Y3+ and Sr2+from aqueous solutions buffered with 0.05 M sodium acetate into chloroform containing 0.01 M (a) 10 and (b) 11. (0)Y3+ and (4) Sr2+ concentrations, 1 X M each.
I
3
4
.:
5
7
6
0:
7
'
8
PH
Figure 4. pH dependence on the extraction of Y3+ and Sr2+from aqueous solutions buffered with 0.05 M sodium acetate Into chloroform containing 0.01 M (a) 4, (b) 5, and (c) 8. (0)Y3+ and (4) Sr2+ concentrations, 1 X M each.
6.9. However, Sr2+begins to be extracted in the same pH range, which precludes quantitative separation of Y3+ from Sr*+.Compound 11extracts Sr2+at pH values as low as 6.5, which is -0.5 unit lower than the macrocyclic extractants studies. Y3+is also extracted at a pH lower than that of 10. Quantitative separation of Y3+ and Sr2+cannot be achieved with this extractant under the given experimental conditions. A major difference between the acyclic polyether dicarboxylic acids 10 and 11 and the crown ether carboxylic acids studied is the shift of the extraction curves of Y3+ and Sr2+, especially the latter, to lower pH. The resulting curves show no pH range in which Y3+ can be quantitatively extracted while still achieving complete separation from strontium. The macrocyclicpolyether cavity appears to be an essential factor for selective complexation with Y3+ over Sr2+in slightly acidic and neutral solutions. Separationof Carrier-FreewY and 90Sr. The separation factor of two elements in solvent extraction is determined by their relative distribution coefficients (D)between the organic phases and the aqueous phase. The D values were found to depend on the concentration of the crown ether carboxylic acids in the organic phase, the nature of the solvent, the pH of the aqueous solution, and the buffer used in the experiments. For the purpose of comparison, the relative D values were measured with fixed ligand concentration (5 X lO-SM), solvent (chloroform), and buffered (acetate) aqueous phase
Table 11. D Values of Selected Lanthanides and Other Metal Ions during Solvent Extraction with sym-Dibenzo-16-crown-5-oxyacetic Acid' cation ionic radius, A D value Na+ 1.02 0.01 Sr2+ 1.26 0.01 Ba2+ 1.42 0.01 Y3+ 1.02 19.0 Zr4+ 0.84 0.01 La3+ 1.16 6.8 Lu3+ 0.98 25.2
Metal ion concentration, 1 X 10-4 M;ligand concentration, 5 X M, pH, 6.0. Ionic radii from ref 11. Coordination number: VI for Na+, VI11 for all others. at pH 6.0. The D values for Y3+ and Sr2+using 1 as an extractant are given in Table 11. Because of the uncertainties involved in measuring very small D values for 97mSr, we can only estimate its D value to be less than 0.01. The D value of Y3+ at pH 6.0 is -19, which falls between the D values of La3+ and Lu3+. The D values of other relevant cations including Na+, Ba2+, La3+, Lu3+, and Zr4+ obtained a t an aqueous pH of 6.0 are given in Table 11. Except for the trivalent rare earth elements, other cations listed in Table I are virtually not extractable by the crown ether carboxylic acids. The ionic radii of Na+ (1.02 A) and Sr2+(1.26 A) are not very different from those of Y3+ (1.02 A) and La3+ (1.16 A)." The mechanism of complexation for the lanthanide crown ether carboxylate complexes is thought to involve an initial attachment of a cation to the side-arm carboxylate group followed by its insertion into the cavity. Alkali metal and alkaline earth metal cations which do not attach strongly to the carboxylate at near-neutral pH cannot lead to a stable complex configuration involving both the cavity and the side(11) Shannon, R. D. Acta Crystallogr., Sect. A 1976, A32, 751.
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ANALYTICAL CHEMISTRY, VOL. 65, NO. 10, MAY 15, 1993
arm carboxylate. The large difference in relative D values between Ba2+ and La?+suggests that the macrocycles can also be used to separate 14”Lafrom I4(’Ba. The quantitative separation of l”-+ from Sr2+depends on the relative ratio of the ligand t o the metal ions used in the experiment. We performed experiments with 1 to determine the minimum value of this ratio which would provide quantitative extraction of Y With Y:’* and Sr2+held at constant concentrations of 1 x 10 we varied the concentration of the ligand in the chloroform. It was determined that quantitative extraction of Y,?+requires that the ligand concentration present in the organic phase must be at least 50 times that of the metal concentration in the aqueous phase. As the ratio of the concentrations of the ligand to the metal decreases below 50, the extraction of Y3+ under our experimental conditions decreases rapidly. When the ratio reaches a value of 10, the metal is extracted in the amount of 15‘’; To establish the viability of this method for the separation of carrier-free “9’from solutions of 3‘1Sr,we performed experiments using compound 1 as a chelating agent in the solvent extraction of an aqueous solution at pH 6.5. The experiments were performed with a ligand concentration of 5 x lo--?, M in chloroform. The resulting organic solution was dried, and the i3 act,ivity was measured with a Geiger-Muller counter. The activity of the extracted 9oYfraction was found to decay with a half-life of 64.1 st 0.1 h, which is consistent with the value reported in the literature. There was no observable deviation from this half-life value even after 30 days 10 half-lives) of counting. The radioisotropic purity of the obtained by this separation method is estimated to be greater than 99.95. The selection of an appropriate extractant in solvent extraction must be determined by its intended use. Nuclear medicine and environmental chemistry have high requirements for isotope purity. Additionally, the quantitation o€ YiiY and Sr:’’)requires quantitative recovery of the trace analytes. Because compounds 10 and 11 lack the desired cation selectivity and compounds 7-9 fail to meet the requirements of quantitative extraction, these extractants are probably not useful for the purpose of the E’;Sr separation. The carboxylic acid extractants 1-3 may achieve quantitative separation of Y,’* from Sr2i as well as quantitative recovery of yttrium under specific pH conditions. However. the pH must be carefully controlled with these extractants to prevent any extraction of strontium. The 16-crown4 hydroxamic acids 4-6 show the greatest selectivity for Y over Sr2+over a wide pH range. In the practical application of this solvent extraction technique, the ability to reuse the < *
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extractant must also be considered for the selection of the appropriate macrocycle. A high solubility in water results in the loss of the extractant from the organic phase. Compound 5 has a solubility in water which is much less than that of 4 and 6, as shown in Table I. This compound may be reused for multiple extractions without significant loss of the extractant. The pH range of quantitative separation and quantitative recovery of YZi+using 5 is 6.5-7.0. This range may even extend beyond pH 7.0, but the probability of hydroxide precipitation of Y3+ is great above this value. For these reasons 5 appears to provide the best separation for practical applications.
CONCLUSIONS The complexation of Yi+ by ionizable crown ethers is dependent upon the molecular structure of the complexing ligand. The studies discussed in this paper suggest that the identity of the ionizable functionality on the lariat affects the selectivity and solvent extraction efficiency of the macrocycle. In particular, hydroxamicacids, when attached to a 16-crown-5 host, offer larger selectivities for YJ+ over Sr*+ than the analogous carboxylic acid derivatives. High-purity and carrier-free SOY can be separated from by solvent extraction with ionizable crown ethers. Experiments with sym-dibenzo-16-crown-5-oxyacetic acid (1) resulted in an isotope purity of 99.9%. The extractions are rapid and reversible with respect to pH, thus providing an efficient method of obtaining pure g o y in a desirable matrix for biochemical labeling applications. This separation technique is also significant for analytical purposes. The determination of low levels of in environmental samples requires chemical separation from 90Sr prior to radioactive measurement. This new extraction method would be very suitable for such a separation procedure. This technique may also have other important applications in rare earth separations for trace determinations.
ACKNOWLEDGMENT We are grateful to Westinghouse Idaho Nuclear Co., Inc. (WINCO) for their financial support of this project. In addition, we thank Steve Fernandez and Steve Hartenstein, both of WINCO, for their contributions through scientific discussion.
RECEIVEDfor review September 16, 1992. February 3, 1993.
Accepted
