In the Laboratory
A Simple Method for Determining the Absolute Configuration of ␣-Amino Acids
W
María Dolores Díaz-de-Villegas Departamento de Química Orgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain Esteban P. Urriolabeitia* Departamento de Química Inorgánica, Instituto de Ciencia de Materiales de Aragón, Universidad de Zaragoza-CSIC, 50009 Zaragoza, Spain
The increasing interest in enantioselective synthesis (1) has led to a high demand for accurate and convenient methods of measuring both the enantiomeric purity of the resulting mixtures and the absolute configuration of each compound in the mixture. The development of NMR spectroscopy has provided a variety of valuable methods for determining enantiomeric purity (2). More recently, techniques such as gas chromatography (3) and high-performance liquid chromatography (4) have also been used. The determination of absolute configuration in enantiomerically pure compounds has, in the past, been achieved through chemical methods (5). However, the scope of these methods is limited because they rely on suppositions about the inversion or retention of configuration at stereocenters during the course of the synthetic procedure to or from a substrate of known configuration. NMR spectroscopy has also been extensively applied to the determination of the relative stereochemistry (6, 7 ) using nuclear Overhauser effect (NOE) measurements. Such measurements can be used to determine the pattern of relative interatomic interactions in molecules with a fixed geometry, although some degree of internal molecular motion can be tolerated (6 ). However, these measurements require the existence of protons (or other nuclei) that are very close to one another, because NOE interactions depend on the inverse sixth power of the internuclear distance. Chiroptical methods such as polarimetry, optical rotatory dispersion (ORD), and circular dichroism (CD) overcome this particular problem. Circular dichroism is especially attractive for the determination of absolute configuration, since the shape of the CD curve can provide information about the orientation of the groups around the stereogenic center (8). In accord with this, we propose here a simple experiment comprising two well-defined sections. The first is a preparative section, in which the students will synthesize a dinuclear C,N-cyclometallated compound [Pd(C6H4CH2NMe2-2)(µ-Cl)]2 (1) (or [Pd(dmba)(µ-Cl)]2) via carbon–hydrogen activation of N,N-dimethylbenzylamine (dmbaH, C6H5CH2NMe2) by the complex Li2[PdCl4] (Scheme I).
W Supplementary materials for this article are available on JCE Online at http://jchemed.chem.wisc.edu/Journal/issues/1999/ Jan/abs77.html.
*Email:
[email protected].
+
2
Li 2 [PdCl4]
NMe2
MeOH - [PhCH2N(H)Me2]Cl - 2 LiCl
Cl
1/2
Pd N Me2
2
Complex 1
Scheme I
Treatment of 1 with Tl(acac) (acac = acetylacetonate) yields the starting compound [Pd(dmba)(acac)] (2) (Scheme II).
Cl
+
Pd N Me2
2 Tl(acac)
CH2Cl2 - 2 TlCl
O Pd
2
N Me2
2
Scheme II
O
Complex 2
Further reactivity of 2 with selected enantiomerically pure (R- or S-) α-amino acids results in the formation of the [Pd(dmba)(Aa)] complexes (Scheme III) (Aa = S-alaninate [3], S-2-amino butyrate [4], R-2-amino butyrate [5], (2S,3S)isoleucinate [6], (2S,3R)-threoninate [7], S-asparaginate [8]), which will be studied spectroscopically.
O
R1 R2
HO
O
+
Pd N Me2
H 2N
O
H2 N
MeOH -Hacac
Pd N Me2
O
R1 R2 O
R1 = Me, R2 = H (3 ); R1 = Et, R2 = H (4 ) R1 = H, R2 = Et (5 ); R1 = S-C(H)MeEt, R2 = H (6 ) R1 = R-C(H)Me(OH), R2 = H (7 ); R1 = CH2C(O)NH2, R2 = H (8 )
Scheme III
The second section is devoted to the spectroscopic characterization of these complexes, using three methods: infrared, nuclear magnetic resonance, and circular dichroism. The students will themselves measure the IR spectra, comparing them with those provided by the instructor, in order to check the purity of the compounds obtained. The 1H NMR spectra will be provided by the instructor, leaving the task of their interpretation for the students. Some additional information can also be provided (see online Lab DocumentationW) to complete the structural characterization. Thus, the preparative section
JChemEd.chem.wisc.edu • Vol. 76 No. 1 January 1999 • Journal of Chemical Education
77
In the Laboratory
introduces the student to some common concepts and skills in organometallic chemistry (C–H activation, substitution of ligands by different methods), while the IR and NMR section could be seen as a classical exercise in interpretation of spectra. However, the main subject of this experiment is the introduction to the student of a nonroutine spectroscopic method, such as is circular dichroism. Complexes 3–8 have been prepared deliberately in the enantiomerically pure form of the α -amino acidate ligand (R or S) in order to establish a clear correlation between the shape of the CD spectrum and the absolute configuration of the Cα at the amino acidate ligand. This is the main goal of this experiment, and this correlation is clearly found by comparing the CD spectra of complexes 3–8 (see Fig. 1). All complexes with the same absolute configuration at the Cα show the same shape of the CD spectrum (same sign of Cotton effect at a given wavelength), whereas those with the opposite absolute configuration show mirror-image spectra. We think that in this context, this experiment could complement a classroom course in organometallic chemistry and thus be valuable for undergraduate students. The synthesis section has the advantage that all compounds prepared are air stable, both in the solid sate and in solution, and they can be prepared under mild conditions. The synthesis of 1 requires the availability of PdCl2, LiCl, and C6H 5CH2NMe 2. The synthesis of 2 requires the use of Tl(acac), which is toxic and should be provided by the instructor (when used, gloves and protective glasses are highly recommended; see Safety Notes in the Lab Documentation). Synthesis of the amino acidato complexes 3–8 requires the use of the α -amino acids S-alanine, R- and S-2-amino butyric acid, (2S,3S)-isoleucine, (2S,3R)-threonine, and S-asparagine, all of which are commercially available. The solvents do not require a high degree of purity, except for use in the measurement of the CD spectra (HPLC grade). Students can complete the first section (synthesis of the starting complexes 1 and 2) individually. For the subsequent syntheses of complexes 3–8, the work can be performed by students working in groups; we recommend groups of six, and each student synthesizes only one complex. The instructor must explain the measurement of the CD spectra, and then
each student can measure the spectrum of his or her own complex. Each group can then discuss the structural data provided by the IR, NMR, and CD spectra. The complete experiment can be performed easily in four consecutive 3-hour periods: (i) synthesis of 1 and explanation of carbon–hydrogen activation; (ii) isolation of 1, synthesis of 2, and explanation of ligand substitution reactions; (iii) synthesis of 3–8 and characterization by IR; (iv) CD spectra and structural discussion). In our experience with undergraduate students, this method has given the best results. Literature Cited 1. Stinson, S. C. Chem. Eng. News 1992, 70(39), 46; Stinson, S. C. Chem. Eng. News 1993, 71(39), 38. 2. Parker, D. Chem. Rev. 1991, 91, 1441; Hulst, R.; Kellog, R. M.; Feringa, B. L. Recl. Trav. Chim. Pays-Bas, 1995, 114, 115. 3. See for example Schurig, V.; Nowotny, A. P. Angew. Chem. Int. Ed. Engl. 1990, 29, 939. Okamoto, Y.; Hatada, K. J. Chromatogr. 1987, 389, 95. Ramachandran, P. V.; Rangaishenvi, M. V.; Singaram, B.; Goralski, C. T.; Brown, H. C. J. Org. Chem. 1996, 61, 341. 4. Allenmark, S. G. Chromatographic Enantioseparation: Methods and Applications, 2nd ed.; Prentice Hall: New York, 1991. Pirkle, W.; Brice, L. J.; Widlanski, T. S.; Roestamadji, J. Tetrahedron: Asymmetry 1996, 7, 2173. 5. Nasipuri, D. Stereochemistry of Organic Compounds: Principles and Applications; Wiley: New Delhi, 1991; pp 168–174. 6. Bookham, J. L.; McFarlane, W. J. Chem. Soc., Chem. Commun. 1993, 1352. Jiang, Q.; Rüegger, H.; Venanzi, L. M. J. Organomet. Chem. 1995, 488, 233. Aw, B.-H.; Selvaratnam, S.; Leung, P.-H.; Rees, N. H.; McFarlane, W. Tetrahedron: Asymmetry 1996, 7, 1753. 7. Trost, B. M.; Seoane, P.; Mignani, S.; Acemoglu, M. J. Am. Chem. Soc. 1989, 111, 7487. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. 8. Lo, L.-C.; Berova, N.; Nakanishi, K.; Schlingmann, G.; Carter, G. T.; Borders, D. B. J. Am. Chem. Soc. 1992, 114, 7371.
Figure 1. CD spectra of complexes 3–8.
78
Journal of Chemical Education • Vol. 76 No. 1 January 1999 • JChemEd.chem.wisc.edu
