In the Laboratory
W
Synthesis and Resolution of the Atropisomeric 1,1’-Bi-2-naphthol: An Experiment in Organic Synthesis and 2-D NMR Spectroscopy
Kendrew K. W. Mak Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong, P. R. China;
[email protected] The synthesis and resolution of chiral compounds is an important area in organic synthesis as the vast majority of organic molecules of interest to organic chemists are chiral. The demands for synthetic enantiopure compounds can be exemplified by the requirement set by FDA that drugs for testing and marketing should contain just one enantiomer, after the well-known thalidomide tragedy occurred in Europe in the late 1950s (1).1 Out of the $410 billion worldwide sales of formulated pharmaceutical products in 2001, $146 billion (36%) resulted from single-enantiomeric drugs (2). Therefore, the incorporation of the synthesis and resolution of chiral compounds into undergraduate laboratory curriculum is valuable (3). We have incorporated the synthesis and resolution of 1,1´-bi-2-naphthol, 1, into the sophomore organic laboratory course for four consecutive years. 1,1´-Bi-2-naphthol is a chiral compound without a stereogenic center. The chirality of the binaphthol is the result of a hindered rotation about the C(sp2)–C(sp2) single bond that connects the two naphthol moieties (Figure 1). These types of compounds, chirality arising from the restricted bond rotation, are known as atropisomers (4). Although several articles have been published in this Journal describing experiments synthesizing chiral compounds, the synthesis and resolution of atropisomers has not been mentioned (3, 5). Compound 1 serves as a good example to illustrate the synthesis and resolution of chiral compounds. The synthesis is adopted from literature methods. Racemic 1,1´-bi-2-naphthol, rac-1, is synthesized by the oxidative coupling of the inexpensive 2-naphthol, 2, in aqueous suspension (6) or in solvent-free conditions (7). This reaction introduces the concept of green chemistry (8). The resolution of rac-1 by (−)-N-benzylcinchonidinium chloride, 3, is easy and efficient (9, 10). The optical purity of the resolved enantiomers is determined accurately by chiral HPLC. The class averages of the enantiomeric excess (ee) obtained for the resolution are about 91% while some careful students can achieve a purity that exceeds 99%. A similar experiment has been described in Reactions and Synthesis in the Organic Chemistry Laboratory (11); however, the resolution takes four synthetic steps to complete in contrast to the resolution described here that only takes one step. The title compound is a challenging exercise for NMR spectroscopy. Both 1H and 13C NMR spectra of 1 shows complicated and overlapping signals in the aromatic region. Structural characterization by 1-D NMR spectra alone is difficult and ambiguous. Nonetheless, 2-D NMR spectra such as 1H– 1 H COSY (COrrelated SpectroscopY), 1H–13C HMQC (Heteronuclear Multiple Quantum Coherence), and 1H–13C COLOC (COrrelation spectroscopy via LOng-Coupling) spectra indicate the spin–spin coupled nuclei from the cross 1636
Journal of Chemical Education
•
peaks and are useful for complete NMR signal assignments (12, 13). The synthesis can be completed in two to three 4-hour laboratory sessions and is valuable for undergraduate students of intermediate to advanced levels. Instructors may adopt the synthetic part only if they found the 2-D NMR analysis is too difficult for students. Nonetheless, the 2-D NMR analysis for 1,1´-bi-2-naphthol is a good example for illustrating the applications of 2-D NMR in structural elucidation for advanced NMR courses. In our sophomore course, instead of letting the students work out the NMR assignments on their own, the assignments are discussed in the lab tutorial classes.
restricted rotation
5 6
OH
10
4 3 2
7 8
9
1
OH
H H
H H OH
OH
(R)-(+)-1,1'-bi-2-naphthol (R)-1
(S )-(−)-1,1'-bi-2-naphthol (S)-1
Figure 1. 1,1’-Bi-2-naphthol, an atropisomer.
Figure 2. Assigning stereodescriptor for atropisomers.
Vol. 81 No. 11 November 2004
•
www.JCE.DivCHED.org
In the Laboratory
Stereodescriptor Assignment for Chiral Compounds without Stereogenic Centers
Synthesis and Resolution of 1,1´-2-Binaphthol, 1
1,1´-Bi-2-naphthol is an atropisomer that may undergo racemerization upon heating. When the molecules acquire sufficient kinetic energy to overcome the rotational barrier, interconversion between the two enantiomers becomes feasible. Nonetheless, 1,1´-binaphthol is fairly thermally stable. The optical purity is retained at 100 ⬚C in dioxane–water for 24 h (14). The assignment of stereodescriptors for compounds possessing a chiral axis (such as atropisomers, allenes, and spiranes) is described as follows. First identify the chiral axis (shown as dotted line in Figure 2) and the four atoms linking to the single bond about which rotation is restricted (shown as black dots in Figure 2). Consider the four atoms as the vertices of an elongated tetrahedron. View the structure along the axis and assign priorities a > b > c > d to the atoms. The highest priorities, a and b, are given to the nearer pair of atoms along the viewing direction and in accordance with the CIP sequence rules. Assuming the molecule is viewed from the top, the carbon atom attaching to the hydroxyl group in the upper naphthol unit is given the highest priority, a, while the bridging carbon atom is given the second highest priority, b. Priorities c and d are assigned to the two carbon atoms in the lower naphthol unit. Rotate the structure with the least preferred atom, d, pointing away and count the order of priority on the trigonal face for the atoms a, b, and c. The compound shown in Figure 2 is the R enantiomer.
The synthesis and resolution of 1 involves (i) oxidative coupling of 2-naphthol by FeCl3⭈6H20 to give rac-1 (Figure 3) (15), (ii) preparation of the resolving agent (−)-Nbenzylcinchonidinium chloride (3) (Figure 4), and (iii) resolution of rac-1 by the resolving agent (Figure 5). The oxidative coupling of 2 with FeCl3⭈6H2O can be carried out either in an aqueous suspension (6) or solid state (7) at 50 ⬚C for 1–2 hours. The isolation procedures are straightforward and the yields are good. Resolution of the racemic 1,1´-bi-2-naphthol involves reacting rac-1 with 3 in refluxing acetonitrile. Compound 3 is readily prepared in quantitative yield by heating equimolar amounts of (−)-cinchonidine and benzyl chloride in refluxing acetone for five days (9). The resolution is based on the principle that the resolving agent reacts preferentially with one enantiomer, R, of 1 and forms an insoluble inclusion complex, while the other enantiomer, S, remains unreacted and soluble in the reaction solvent. The two enantiomers can be readily separated by careful filtration. Optically pure (S )-1 is obtained from the mother liquor as the free compound by typical workup procedure. The crystalline inclusion complex of (R )-1 is heated in refluxing methanol to enhance the optical purity by recrystallization (optional),2 and (R )-1 is recovered from the inclusion compound by acid hydrolysis. The free enantiopure (R )-1 is collected from the organic solution.
H
Cl H
N
HO H
+
OH
2-naphthol 2
N dry acetone reflux, 5 days
(−)-cinchonidine FeCl3·6H2O 50 °C, 1 h
H
OH
HO H
OH
OH
Cl Ph
(−)-N-benzylcinchonidinium chloride 3
Figure 3. Synthesis of racemic 1,1'-bi-2-naphthol, rac-1.
•
N
N
1,1' -bi-2-naphthol (racemic) rac-1
www.JCE.DivCHED.org
H
OH
+
Figure 4. Synthesis of (−)-N-benzylcinchonidinium chloride, 3.
Vol. 81 No. 11 November 2004
•
Journal of Chemical Education
1637
In the Laboratory
Hazards The experiment possesses no unusual hazards if carried out in a well-ventilated fumehood and protective gloves are worn properly. 2-Naphthol and 1,1´-bi-2-naphthol are mild irritants. Benzyl chloride is a strong lachrymator and toxic. Both (−)-cinchonidine and N-benzylcinchonidinium chloride are toxic and in a very fine powdery form. Avoid exposure through inhalation and skin-contact. Acetonitrile and methanol are highly flammable and toxic; handle with care in a well-ventilated fumehood. Determination of the Enantiopurity of the Resolved Enantiomers by Chiral HPLC The enantiomeric excesses of the resolved samples are determined by HPLC with a column packed with a chiral stationary phase [Daicel ChiralPak OT(+)]. Methanol is used
OH OH
for the mobile phase. The eluted solution is monitored by UV–vis detector at 254 nm. Since the two enantiomers should have identical molar absorptivity, the enantiomeric excess can be determined directly from the ratio of the peak areas. The HPLC chromatogram for the racemic mixture of 1,1´-bi-2-naphthol is shown in Figure 6A; the chromatograms for the resolved (R )-1 and (S )-1 are shown in Figures 6B and 6C, respectively. The retention times for (R )-1 and (S )1 are 8.59 and 11.29 min respectively (methanol 0.5 mL min᎑1, 4 ⬚C). The results are compared with those obtained for standard samples purchased from Aldrich. The ee obtained exceed 99% for both enantiomers. The ee of the samples can be determined by optical activity measurement with a polarimeter if chiral HPLC is not available. The specific rotations of (R )-1 and (S )-1 in THF are +34⬚ and −34⬚, respectively. Chiral HPLC measurement, however, is superior in accuracy and is readily automated.
+ 3
1,1'-bi-2-naphthol (racemic)
CH3CN reflux, 1.5 h
OH OH
(R)-(+)-enantiomer complex (insoluble in CH3CN)
OH
+
OH
(S )-(−)-1,1'-bi-2-naphthol (dissolves in mother liquor)
1) recrystallize in refluxing methanol 2) acid hydrolysis
(R)-(+)-1,1'-bi-2-naphthol Figure 6. HPLC chromatograms for (A) racemic mixture of 1, (B) resolved sample of (R )-1, and (C) resolved sample of (S )-1
Figure 5. Resolution of 1,1’-bi-2-naphthol.
1638
Journal of Chemical Education
•
Vol. 81 No. 11 November 2004
•
www.JCE.DivCHED.org
In the Laboratory
Structural Elucidation by 1-D and 2-D NMR Spectroscopy The molecular structure of 1 possesses a C2 axis and therefore the two naphthol units are chemically and magnetically equivalent. However, the 6 protons (excluding the phenolic proton) and the 10 carbon atoms of a naphthol unit are all chemically and magnetically nonequivalent. The enlarged 1H and 13C NMR spectra obtained for rac-1 with a 300 MHz FT–NMR spectrometer are shown in Figures 7 and 8. Six overlapping spin-coupled aromatic proton signals are observed from the 1H NMR spectrum. The 13C NMR spectrum shows six tertiary and four unprotonated aromatic carbon signals. It is obvious that unambiguous signal assignment is extremely difficult with the 1-D spectra alone. The complete assignment of the proton and carbon resonances becomes practicable by analyzing the 2-D 1H–1H COSY, 1H–13C HMQC, and 1H–13C COLOC spectra (12, 13). The COSY spectrum is shown in Figure 9. The crosspeaks indicate proton resonances that are spin coupled to each other and the chemical shifts are shown on the axes. The COSY spectrum clearly shows that the two doublets at δ = 7.97 and 7.38 are spin coupled to each other and have no long-range coupling (see also Figure 7). Therefore they are assigned to the two protons on the phenol ring (H-3 and H4). H-3 is comparatively upfielded (δ = 7.38) owing to the shielding effect of the ortho hydroxyl groups and the anisotropic effects of the naphthalene [naphthalene H-1, δ = 7.81; H-2, δ = 7.46 (13)]. Other signals are assigned in a similar manner. The 13C NMR signals for the tertiary and unprotonated carbon atoms can be assigned according to the connectivity shown on the 1H–13C HMQC and COLOC spectra, respectively. The cross-peaks on the HMQC spectra show pairs of 13 C and 1 H nuclei that are directly bonded. A typical COLOC spectrum, on the other hand, shows correlations of 1H and 13C nuclei that are spin coupled and having coupling constants of 5–20 Hz (13). It covers most of the 1 H⫺C⫺13C (2-bond, 2JCH) and 1H⫺C⫺C⫺13C (3-bond, 3 JCH) couplings. The complete NMR assignments for rac-1 are summarized in Table 1. Complete 1-D and 2-D spectra and detailed discussion on signal assignments are available in the Supplementary Materials.W Since the data acquisition time for 2-D NMR experiments is long (3–6 hours) and undergraduate students are usually unfamiliar with the operation of a high-field NMR spectrometer, instructors are advised to obtain the 2-D NMR spectra beforehand and distribute the spectra to the students during the classes for discussion.
Figure 7. 1H NMR spectrum of racemic 1,1’-bi-2-naphthol.
Figure 8.
13C
NMR spectrum of racemic 1,1’-bi-2-naphthol.
1,1´-Bi-2-naphthol in Asymmetric Catalysis 1,1´-Bi-2-naphthol and its derivatives are useful chiral ligands for asymmetric catalysis (16). A keyword search for BINOL (a common abbreviation for 1,1´-bi-2-naphthol) and BINAP (a derivative of BINOL, having the two –OH groups replaced by PPh2) in SciFinder for the period of 1995 to present returned more than 1700 documents, which indicates that these compounds have gained much attention in frontier chemistry research. Our students were asked to search the chemical literature for BINOL or BINAP catalyzed enanwww.JCE.DivCHED.org
•
Figure 9. COSY spectrum of rac-1. The spectrum shows the correlation of spin–spin coupled hydrogen nuclei.
Vol. 81 No. 11 November 2004
•
Journal of Chemical Education
1639
In the Laboratory Table l. Summary of 1H and 1
a
13
C NMR Data for Rac-1
Spin Multiplicity and Coupling Constants
13
Hydrogen Nuclei
H Chemical Shift (ppm)
Phenolic - OH
5.04
s
C-10
110.9
---
---
---
C-20
152.7
H-3
7.38
d, J = 9 Hz
C-30
117.7
H-4
7.97
d, J = 9 Hz
C-40
131.3
Carbon Nuclei
a
C Chemical Shift (ppm)
H-5
7.89
d , J = 7.8 Hz
C-50
128.3
H-6
7.38
td, J = 7.8, 1.5 Hz
C-60
124.0
H-7
7.30
td, J = 8.1, 1.5 Hz
C-70
127.4
d , J = 8.1 Hz
C-80
124.2
a
H-8
7.15
---
---
---
C-90
133.4
---
---
---
C-10
129.4
Long-range coupling not resolved.
tioselective reactions and include two recent examples in their laboratory report. This serves as an exercise of searching the chemical literature and reading research publications. Through the literature search students acquire introductory knowledge on the principles of asymmetric catalysis as well as the development of modern organic synthesis.
2. The enantiomeric excesses of R enantiomer attainable without this refluxing step are generally in the range of 86–91%. Therefore, the instructors have the option of omitting this recrystallization step if the time for the laboratory sessions is tight, as long as the principle of the resolution process is already well demonstrated.
Summary The synthesis and resolution of 1,1´-bi-2-naphthol serves as a good experiment for teaching organic synthesis and NMR spectroscopy. It illustrates an important synthetic strategy to obtain enantiopure compounds from achiral starting materials. The high enantiomeric excess obtainable for the apparently difficult resolution gives the students a sense of accomplishment and strengthens their interests and confidence in practical works. The experiment also illustrates the relationships and physical properties of enantiomers and diastereoisomers, and the enantiomeric excess determination by chromatographic method based on the diastereomeric interactions. Furthermore, students can gain valuable experience on the structural characterization of organic compounds by advanced NMR spectroscopy.
Literature Cited
Supplemental Material Detailed experimental procedures for the students, suggestions for instructors, instrumentation methods, detailed NMR analysis, NMR spectra, and HPLC chromatograms are available in this issue of JCE Online. W
Acknowledgments The author would like to thank Kin Shing Chan and Yuan Tian for their valuable advice and suggestions. Notes 1. Animal tests had shown that the S enantiomer of thalidomide is teratogenic while the R enantiomer is not. However, subsequent studies show that the R and S enantiomers can racemize in vivo and in vitro, and so the drug may still be teratogenic even administrated as enantiopure form. Related literature: Mason, S. New Scientist 1984, 19, 10–14. Wnendt, S.; Zwingenberger, K. Nature 1997, 385, 303–304.
1640
Journal of Chemical Education
•
1. Bennett, N.; Cornely, K. J. Chem. Educ. 2001, 78, 759–761. Fabro, S.; Smith, R. L.; Williams, R. T. Nature 1967, 215, 296. 2. Rouhi, A. M. Chem. Eng. News 2002, 80 (June 10), 43–50. 3. Lipkowitz, K. B.; Naylor, T.; Anliker, K. S. J. Chem. Educ. 2000, 77, 305–307 and references therein. 4. Eliel, E. L.; Wilen, S. H.; Doyle M. P. Basic Organic Stereochemistry; Wiley-Interscience: New York, 2001; pp 622–632. 5. Hanson, J. J. Chem. Educ. 2001, 78, 1266–1268. 6. Ding, K.; Wang, Y.; Zhang, L.; Wu, Y. Tetrahedron 1996, 52, 1005–1010. 7. Toda, F.; Tanaka, K.; Iwata, S. J. Org. Chem. 1989, 54, 3007– 3009. 8. Kirchhoff, M. M. J. Chem. Educ. 2001, 78, 1577. Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025–1074. 9. Cai, D.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1995, 36, 7991–7994. 10. Hu, Q.-S.; Vitharana, D.; Pu, L. Tetrahedron: Asymmetry 1995, 6, 2123–2126. 11. Tietze, L. F.; Eicher, Th. Reactions and Synthesis in the Organic Chemistry Laboratory; translated by Ringe, D.; University Science Books: Mill Valley, CA, 1989; pp 410–413. 12. Williams, D. H.; Fleming, I. Spectroscopic Methods in Organic Chemistry, 5th ed.; McGraw-Hill: London, 1995; pp 63–169. 13. Silverstein, R. M.; Bassler. G. C.; Morrill, T. C. Spectrometric Identifications of Organic Compounds, 6th ed.; John Wiley & Son: New York, 1998; pp 144–279. 14. Colonna, S.; Re, A.; Wynberg, H. J. Chem. Soc., Perkin Trans. I 1981, 1, 547. 15. Whiting, D. A. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 3, Chapter 2.9. 16. Pu, L. Chem. Rev. 1998, 98, 2405–2494.
Vol. 81 No. 11 November 2004
•
www.JCE.DivCHED.org
