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Liquid Chromatography of Enantiomers Determination of Enantiomeric Purity in Spite of Extensive Peak Overlap.

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nals disappears under the signals of the aromatic protons at
- 50 "C, the last only at ca. - 100 "C. This can be interpreted
in the sense of a successive transition from (3b) to (3a). The
presence of the T '-bonded benzyl ligand in the low-temperature form (3a) can be regarded as a further indication that
the fluctuation of the q3-benzyl ligand takes place at higher
temperature via this a-form. The signals of the rigid cyclooctadiene ligand also show temperature-dependent changes.(3a) and (3c) formally contain 16 valence electrons. In the
case of complexes of the type (diene)Rh(allyl) several such
systems are k n ~ w n [ ~ . ' ~ .
A selective antarafacial rearrangement of an q3-benzyl
ligand has to our knowledge hitherto not been reported. This
rearrangement at the same time proves that an qi-bonded
benzyl moiety must be present in its transition state.
Procedure
All operations must be carried out under an inert gas. A
solution of styrene (3 ml) in ether (10 ml) is added to a solu(0.98
tion of di-p-chlorobis(l,5-cyclooctadiene)dirhodium181
g, 2 mmol) in ether (20 ml) at -78 "C and the stirred mixture
treated with a Grignard solution prepared from 0.19 g (8
mmol) Mg and 1 ml i-C3H7Br. The mixture is allowed to
warm within 3 h to 0°C and the solvent and excess ligand
are then removed in a high vacuum. After elution with 200
ml of pentane and filtration on A1203(7% H20) (frit and receiver cooled to - 78 "C), analytically pure orange-red (3)
crystallizes at - 78 "C; yield 1.498 g (3.75 mmol; 89%), m. p.
-9°C.
Received: October 8, 1979 [ Z 476 IE]
German version: Angew. Chem. 92,475 (1980)
As far as the measurement of P by chromatography is concerned, conversion of the enantiomers to diastereoisomers by
a reagent and subsequent analysis on an achiral sorbent represent an established procedure. It relies on the absence of
racemization and on a knowledge of P of the reagenti2].
Chromatography on an optically active stationary phase does
not need a standard for P and is therefore one of the few absoZute121methods. In this respect, gas chromatography has advanced considerably, i. e. baseline separations of enantiomers
have been achieved in many cases. The areas under their
peaks permit the direct calculation of P. Gas chromatography usually requires elevated temperatures, whereas liquid
chromatography (LC) can be performed at room temperature, thus reducing the rates of possible decompositions or
racemizations. However, this technique has not been widely
used for P determinations, mainly because enantiomers frequently give overlapped or even fused peak^^'".^]. Therefore,
a method applicable in spite of peak overlap or fusion (Fig.
la), would clearly extend the analytical possibilities.
In eq. (l)'"]v is the actual eluate volume, a ( v ) the angle of rotation and A ( v ) the absorbance (see e. g. Fig. 1). The factorf4]
C , = a + / A + relates the rotation angle and absorbance of the
predominant, dextrorotatory enantiomer. If this enantiomer
appears at higher u, the eluate cannot contain a relevant
amount of the less abundant enantiomer in the Av region of
Fig. 1. Therefore, in this region, a equals a+ and A equals
CAS Registry numbers:
(3), 73758-13-1; di-&-chiorobis(1.5-cyclooctadiene)dirhod1um, 12092-47-6; styrene, 100-42-5: i-C1H7Br, 75-26-3
[l]
[2]
[3]
[4]
[5]
161
[7]
[8]
R. B. King. A. Fronzaglia, J . Am. Chem. SOC.US. 709 (1966).
F. A. Corfon, T. J. Marks, J. Am. Chem. SOC.
91, 1339 (1969).
Y. Becker. J. K . Srille, J. Am. Chem. SOC.lW, 845 (1978).
F. A. Corfon, C. Wiikinson: Anorganische Chemie, 3. Aufl. Verlag Chemie,
Weinheim 1974, Kap. 23; Advanced Inorganic Chemistry. 3rd Ed. Wiley-Interscience. New York 1972, Chapt. 23.
H:O. Sriihler. J. Miiller, Chem. Ber. 112. 1359 (1979).
Cf. 8. E. Mann, A . Keasey, A . Sonoda, P. M. Marrlis, J. Chem. SOC.Dalton
Trans. 1979. 338.
J. Muller, H . - 0 . Sftihler, W. Coll. Chem. Ber. 108, 1074 (1975).
J. Char?, L. M. Venanzi, J. Chem. SOC.1957, 4735.
Liquid Chromatography of Enantiomers:
Determination of Enantiomeric Purity in Spite of
Extensive Peak Overlap'"]
By Albrecht Mannschreck, Mladen Mintas, Georg Becher,
and Georgine Stiihlerf*l
Several methods have been used for determining the enantiomeric purity P of a chiral substratef2];however, none of
them seems to be universally applicable.
1'1 Prof. Dr. A. Mannschreck, Dr. M. Mintas, Dr. G. Becher. and G . Stuhler
Institut fur Chemie der Universitat
Universitatsstrasse 31, D-8403 Regensburg (Germany)
["I
Liquid Chromatography on Triacetylcellulose, Part 3. This work was supported by the Deutsche Forschungsgemeinschaft and by the Fonds der Chemischen Industrie. The samples of (?)-(I) and (-)-(I) were provided by Professor
Dr. K. H Buchel and Dr. C. Jager, Bayer AG, Leverkusen. who have also kindly
checked the manuscript. We are grateful to Dr. M.Holik and Dipi.-Phys. R. Kiisper?, Regensburg. for helpful suggestions.-Part I: [la]. Part 2: [lb].
Angew. Chem. Int. Ed. Engl. 19 (1980) No. 6
Fig. 1. Schematic chromatograms a) A ( v ) and b) n ( v ) for a mixture of enantiomers (+prevailing) after passage through an optically active sorbent. v: Actual
volume of eluate. Av: Region of v, where the eluate does not contain a relevant
amount of Ihe less abundant enantiomer. A : Absorbance of eluate. A and A :
Absorbances of the enantiomers (A + + A = A ) . a: Rotation angle of eluate. a +
and a-:Rotation angles of the enantlomeis ( a ++ a - = a).The derivation 14) of
eq. (1) does not depend upon the particular shapes (e.g. symmetry) of the component peaks (-----) chosen for demonstration.
+
A +, i. e. a + / A + = C , can be measured from a plot of a versus A (cf. Fig. 2b) by determining its slope at high volumes.
J a dv, consisting of a positive and a negative area, and J A dv
are also accessible, e. g. by the cut-and-weigh procedure,
from the same experiment. In a preliminary test, LC (Fig. 2)
of (+)-1-phenylethanol (P=52%, calculated from the specific rotation) resulted in P= 54% via eq. (1).
@ Verlag Chemie, GmbH, 6940 Weinheim, 1980
0570-0U33/U0/0606-469 $ 02.50/0
469
As application of our method to a n enantioselective synthesis, we investigated 6 mg@I( - ) - ( 3 ) ([a]&=- 584", 1.07
mg/ml, ethanol), which were likewise obtained by LC on
triacetylcellulose. We found P= 71%, z. e. [a]:&= - 826" for
pure (-)-(R)-(3), from which the unknown optical yields of
(+ )- and ( -)-(3) samples['I obtained cathodically (in presence of alkaloids) can be calculated.
/
Fig. 2. a) Chromatograms A ( v ) and u ( u ) and b) diagram u ( A ) of (+)-I-phenylethanol (P=52?6) in ethanol/H>O (96.4) after passage (flow rate 3.1 ml/min)
through a column of triacetylcellulose. u. Actual volume of eluate; injection at
u = O . A : Absorbance at 254 nm, measured in "units" i.e. mV; a: Rotation angle
at 365 nm. The straight line in b) has a slope of C , =0.0031 "/unit. We have used
microcrystalline, swollen triacetylcellulose [ I , 3b, S] (particle sizes 0.03 to 0.06
mm. column 30 cm x 2.5 cm). Further details are: Eluent ethanol/water (96:4):
1 1 bar; flow rate 2.1 ml/min. except for Fig. 2.
temperature 22 " C pressure
The eluate was passed through one compartment (path length 2.0 mm. volume
0 0 8 ml) of the photometer double-cell, then through the polarimeter cell (path
length 100 mm. volume 1 ml), and back through the photometer, in order to simulate the simultaneity of the detections which seems to be important for the
measurement of C , (or C ). A x.y recorder was used for the diagrams a ( A ) . a
two-pen recorder for A ( c ) and a ( u ) .
-
Our procedure was checked by 25 mg
of ( -)-(I)
(Table l), the P-values of which were known (for experimental details see legend of Fig. 2; flow rate 2.1 ml/min). The
67.6% sample gave recordings very similar to Figure 2. For
all measurements, C - =0.0045 to 0.0051 "/unit in the linear
a ( A ) region. The agreement (Table 1) between the initial Pvalues and the ones obtained via eq. (1) is satisfactory. The
determination of errors must be deferred until more results
are available.
Further support for our method is derived from samples of
( + )- and ( -)-1,2-diphenylcyclopropane,separatedI51 by LC
on triacetylcellulose. Application of eq. (1) yields P= 86%
and loo%, respectively. As the overlap of the (+)- and (-)peaks is weak, the areas under the a ( ~curve
)
must represent
good approximations for the relative concentrations. As expected, the results P= 84% and 100% are close to the above
findings"'.
Table I. Enantiomeric purity P of ( - )-(I) samples.
>
"
L
R
(R)-/I)
P 1x1 [a1
p [XI Ibl
48.9
67.6
88.3
49
68
87
[a] Weighed amounts of (f) - ( l ) ,Triadimefon (Bayleton", Bayer AG), and of a
sample of ( - )-(I/ were mixed. For the latter, P= 99.8% had been measured using
calorimetry [7] by Dr. H. Doerr. Bayer AG, Leverkusen. The error of the above
initial P-values is estimated to amount to -c0.2%. [bj For these mixtures, P was
determined via eq. (1) (see text).
As a first application we have analyzed a sample of (-)(2), obtained by LC on triacetylcellulose ( [ u ] $ =
~ -29",
2.48 mg/ml, acetone; m.p. 99-10O0C), in order to obtain
the hitherto unknown specific rotation of the pure enantiomer. Similarly to Figure 2 and to the diagrams of ( - ) - ( I ) , the
A ( v ) curve showed no sign of a splitting, i. e. the peaks of
(+)- and (-)-(2) were fused. Application of eq. (l), using a
35 mg sample['', resulted in P = 29%, which means [a]
:
9
=
- 100" for pure (-)-(2). From this figure, the unknown P of
an earlier preparation[*]of (- )-(2) via crystallization of diastereoisomers has now been calculated to 14%.
470
D Verlag Chemie, GmbH, 6940 Wernheim, 1980
The present determination of P depends neither upon the
symmetry of each peak nor upon equal widths of the peaks.
It does, however, depend upon some separation by the sorbent (generating a n a (u) detection), though a separation
yielding a split A ( v ) chromatogram is not needed. Our method may be improved by avoiding manual area determination. Finally, eq. (7)["' suggests the calculation of [a],the specific rotation of a pure enantiomer, from the measurement of
C , (or C - ) by using excfusiveIy the racemate. A preliminary
trial showed that this suggestion is realistic.
Received: September 18, 1979
revised: April 3, 1980
German version: Angew. Chem. 92,490 (1980)
CAS Registry numbers:
(R)-(I), 73804-20-3; (S)-(Z). 53152-83-3 ( R ) - / 3 / ,71808-83-8
[I] a) H. Hakli, M. Mintas, A. Mannschreck, Chem. Ber. 112. 2028 (1979); b) K.
R. Lindner. A. Mannschreck. J. Chromatogr. 193, 308 (1980).
[2] Review: M. Raban, K. Mislow, Top. Stereochem. 2, 199 (1967).
[3] a) See e.g. ?I Mike% G. Bosharl, J. Chromatogr. /4Y. 455 (1978), and earlier
papers; I. S. Krull, Adv. Chromatogr. 16. 175 (1978); b) G. Hesse. R. Hagel,
Justus Liebigs Ann. Chem. 1976. 996, and earlier papers.
[4] If a mixture contains n + and n . moles of the enantiomers ( n + > n -), P i s given PI by
P=(n,
-n
)/(n,+n.)=i(c,-c_)du/J(c++c.)du
(2)
where n + and n have been replaced by J c + du and I c .du, respectively, 1. e.
the injected n , moles are distributed (actual concentration c , ) in the eluate
volume u. The absorbances A + and A (Fig. 1a) are expressed by Beer's law,
the rotation angles a + and a . (Fig 1 b) by Biot's law:
Fb(c, + c ) = A + + A _ - A
+ [a1k +
-[a]k-
=a+
=a-
[ a ] l ( c +- C . ) = a , + a
-a
A ( u ) and a ( o ) represent chromatograms (e.g. Fig. 1) of passage through an
optically active sorbent, whereby partial separation of the enantiomers, 1. e.
overlap or fusion of their peaks, has occurred. Introduction of eq. (4) and (6)
transforms eq. (2) into eq. (I); then
C , =[all6 ' b .
'
(7)
Using eq. (3) and (5) we get C , = a +/ A
[5] M. Minras, A. Mannschreck. M. P. Schnerder. J. Chem. SOC.Chem. Commun.
1979,602.
161 The diagrams obtained suggest that Iower amounts of sample (about one half
of the amounts used) would have resulted in similar accuracy.
I71 S. Wilen,A. Collet. J. Jacques. Tetrahedron 33, 2725 (1977). and earlier papers; R. Luckenbach, L. Horner, Thermochim. Acta l l , 216 (1975).
[ S ] M. Rosner, G. Kobrich. Angew. Chem. 86, 775 (1974): Angew. Chem. Int. Ed.
Engl. 13. 741 (1974).
[9] R. Huzard, S. Jaouanner, A. TaIlec, Tetrahedron Lett. 1979, 1105. and unpublished results.
OS70-0833/80/0606-470 $ 02 SO/O
Angew. Chem Inl. Ed. Engl. 19 (1980) No. 6
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