CHIRALITY 651C512 (1994)

Enantiomerization of 2,2'-Diisopropylbiphenyl During Chiral Inclusion Gas Chromatography: Determination of

the Rotational Energy Barrier by Computer Simulation of Dynamic Chromatographic Elution Profiles

MARTIN JUNG, MARKUS FLUCK, AND VOLKER SCHURIG Institute of Organic Chemistly, University of Tubingen, Tubingen, Germany

ABSTRACT By computer simulation of experimental dynamic gas chromatographic elution profiles, the rotational energy barrier AG= of racemic 2,2'-diisopropylbiphenyl has been determined as 114.6-115.0 kJ/mol(75-100°C). These data are in good agreement with a value that was determined previously by measuring the racemization kinetics of an enriched sample. This indicates that there is no measurable catalytic or inhibitory effect of the stationary phase. o 1994 Wiey-Liss, Inc.

KEY WORDS: 2,2'-diisopropylbiphenyl, racemization and enantiomerization, rotational en- ergy barrier, computer simulation, dynamic chiral gas chromatography, cy- clodextrin stationary phase

In recent years enantiomerization as well as epimerization and isomerization phenomena have attracted increasing atten- tion, e.g., with respect to the configurational stability of drugs.

As previously, ' , 3 we define enantiomerization as the re- versible interconversion of the enantiomers, i.e., (+) = (-) (K), while racemization is often considered the irreversible transformation of one of the enantiomers in an optically en- riched mixture into the racemic modifications, i.e., (+) -. (2) (K'),4 where K' = 2k,5 since the interconversion of one molecule reduces the enantiomeric excess (ee) by two molecules.

Dynamic chromatography represents a versatile tool for the investigation of enantiomerization equilibria. 2,3 If enantio- merization proceeds at a suitable rate on the chromatographic time scale, the interconversion of configurationally (or confor- mationally) labile enantiomers during the separation process yields a typical plateau between the peaks of the enantiomers separated on a chiral stationary phase. More than 10 years ago we were the first group to report on such an elution profile, which was observed for a chiral aziridine and a spiroketal, respectively, in complexation gas chromatogra- phy.' Subsequently we reported on the determination of the corresponding rate constants and free energy barrier by com- puter simuiation of the experimental elution p r ~ f i l e . ~ Later, similar approaches, although on the basis of a Merent mathe- matical model, were followed by other authors who described several examples of enantiomerization profiles observed in HPLC.6*7 Recently we advanced a new general computer program for the simulation of dynamic chromatographic elu- tion profiles' and used it for the investigation of enantiomer- ization barriers by dynamic gas chromatography: two diaziri- 0 1934 Wiley-Liss, Inc.

dines on a cyclodextrin stationary phaseg and homofuran on Chirasil-Metal. lo

Thus, it has been proved that computer simulation of dy- namic chromatographic elution profiles is a simple and straightforward method for the determination of enantiomer- ization barriers. The method is suitable for barriers in the range of -70-130 kJ/mol, where dynamic NMR techniques cannot be applied. Whereas other methods, such as polarime- try, involve tedious preparative enantiomer enrichment for the subsequent kinetic investigation, the described procedure requires only trace amounts of the racemic sample. It can also be applied to related dynamic phenomena, e.g., epimeriza- tion, diastereomerization, or intramolecular chemical reac- tions. In this work we demonstrate another example for the applicability of our method.

METHODS The experimental chromatographic elution profiles of 2,2'-

diisopropylbiphenyl were recorded by Konig et al. l1 on an 8.5 m x 0.25 mm (i.d.) capillary column coated with a 1:l (w/w) mixture of octakis(2,3-di-O-n-pentyl-6-O-methyl)-y-cyclo- dextrin and OV-1701. Using the retention times and theoreti- cal plate numbers measured from these chromatograms, the simulation was performed as previously described in much detail.g However, in the present case the free energy barriers

Received for publication March 14, 1994; accepted April 18, 1994. Address reprint requests to Dr. Voker Schurig, Institute of Organic Chemis- try, University of Tubingen, Auf der Morgenstelle 18, D-72076 Tubingen, Germany.

ENANTIOMERUATION OF 2,2'-DIISOPROPYLBIPHENn. 511

ExDeriment a1

40 50 80 90 50 60 32 36

Simulated min

.

80 90 50 60 32 36 28 30 32 - min

75 OC 80 OC 85 O C 90 OC 95 OC 100 OC Fig. 1. Experimental and simulated gas chromatograms of 2,2'-diisopropylbiphenyl on a 1:l (w/w) mixture of octakis(2,3-

di-o-n-pentyl-6O-meth~)-y-cyclodexttin and OV-1701 as stationary phase at different temperatures (for details see Meth- ods: experhnental chromatograms reprinted with permission from Ref. [lll).

to rotation (enantiomerization) were assumed as equal in the mobile and the stationary phase. As a consequence, the dead time does not have any influence on the resulting simulated elution profiles. The following data were used as a basis for the simulation (retention times for the enantiomer peaks in min, theoretical plate number): 75"C, 41.90, 47.91, 16000; 80°C: 78.40, 87.80, 27000; 85°C: 50.80, 55.40, 27000; 90°C: 32.90, 35.34, 27000; 95°C: 28.48, 30.25, 27000; 100°C: 21.08, 22.16, 27000; dead time: 0.3 min (all temperatures).

RESULTS AND DISCUSSION The gas chromatographic enantiomer separation of a series

of atropisomeric 2,2'-dialkylbiphenyls was recently reported by Konig et al. l1 On the one hand, they achieved a complete enantiomer separation, indicating slow enantiomerization, for 2-tert-butyl-2'-isopropylbiphenyl and 2,2'-di-tert-butyIbiphe- nyl. On the other hand, one single peak, indicating fast enan- tiomerization, was obtained for 2,2'-diethylbiphenyl. Only for 2,2'-diisopropylbiphenyl and 2,2'-bis(trifluoromethy1) biphenyl were the typical plateaus observed between the peaks of the enantiomers.

As previously de~cribed,~ the computer simulation of these experimental elution profiles yields the forward and backward overall rate constants of enantiomerization (rotation), kl and k1, from which the corresponding energy barriers AG= can be calculated. The results are shown in Figure 1 and listed in Table 1. In this case, with a dead time of only a few seconds and retention times of 20 to 90 min, the overall rate constants are almost exclusively governed by the rate constants kS1 and k"-l in the stationary phase.

By measuring the thermal racemization kinetics of an enan- tiomeridy enriched sample, the rotational energy barrier was previously determined as 115 kJ/mol." This value is in good agreement with our data, which indicates that there is no measurable catalytic or inhibitory effect of the stationary phase.

Figure 2 shows the simulation experiment for T = 95"C, performed for a series of different rate constants of enanti- omerization, in order to give a practical idea of the described method's accuracy. The chromatogram in the center is the one which is in agreement with the experimental elution pro- file.

512 JUNG ET AL.

TABLE 1. Overalla rate constants of enantiomenzation* k (min-’) and the corresponding enantiomerization barriers” AG= (kJ/mol) for 2,2’-diisopropyIbiphenyl on a 1: 1 (w/w) mixture of o c t a k i s ( 2 , 3 - d i ~ - ~ - ~ n t y l - ~ O - m e t h y l ) - ~ - ~ c l ~ e ~ ~ n

and OV-1701 as stationary phase

28 30 32 28 30 32

75 80 85 90 95 100

28 I 30 3

k, (min-’) 0.0032 0.0057 0.0093 0.0164 0.024 0.039

AG= (k0.5) (kJ/mol) 114.6 114.6 114.7 114.6 115.0 115.0 kk, (min-’) 0.0024 0.0041 0.0071 0.0133 0.020 0.034

“For the entire chromatographic system consisting of mobile and stationary phase. *Obtained by simulation and comparison to the experimental elution profiles (see Fig. 1, cf. Methods). %aI&ted from the corresponding rate constants (average of k, and k-& according to the Eyring equation (one step reaction with no intermediate product) as previously described.g

0.01 8 11 5.6 I I(! . . . . . . .

28 30 2

.020 15.3

. . . . . . I; 28 30

0.022 0.024 115.0 114.0 -- I ! I t ! I

,026 [mi 14.5 [W!

-]I

Time [min]

Fig. 2. Series of chromatograms for T = 95°C. simulated with different rate constants (d. text).

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