Supramolecular Method for the Determination of Absolute

Jul 20, 2007 - Tadashi Ema , Daisuke Tanida , Kazuki Hamada and Takashi Sakai ... Onoda , Ryohei Kano , Kyosuke Tsuda , Yuko Hinohara , Yoshito Tobe...
5 downloads 0 Views 189KB Size
Download PDF
Anal. Chem. 2007, 79, 6295-6302

Supramolecular Method for the Determination of Absolute Configuration of Chiral Compounds: Theoretical Derivatization and a Demonstration for a Phenolic Crown Ether-2-Amino-1-ethanol System Keiji Hirose,* Yoko Goshima, Takanori Wakebe, Yoshito Tobe, and Koichiro Naemura

Division of Frontier Materials Science, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531, Japan

A combination of anisotropic shielding effect and temperature dependence of NMR chemical shifts makes it possible to develop a supramolecular method for determination of absolute configuration of chiral compounds. The concept, theoretical derivatization, and first demonstration of this daedal noncovalent method using a hostguest system is described. This noncovalent method requires only three substrate solutions and can in principle be applied to any host-guest systems that follow the van’t Hoff relation and have a clear anisotropic shielding effect based on a well-defined complex structure regardless of the extent of enantiomer selectivity. Determination of absolute configuration of organic molecules has been of great importance, since many chiral compounds are known to possess potent biological activities that are specific for each enantiomer. Several instrumental methods have been developed for determination of absolute configuration. The wellknown nonempirical methods include X-ray crystallography and circular dichroism (CD) methods1 including infrared vibrational circular dichroism (IRVCD) and supramolecular chirogenesis methods. However, the equipment is specific and requires special training to handle. In the case of X-ray diffraction, a single crystal of high quality is required. Various NMR methods have been widely developed because NMR spectrometers are now common instruments and these can be applied to a solution of the sample * To whom correspondence should be addressed. E-mail: [email protected]. Fax:+81-6-6850-6229. (1) For CD methods, see: (a) Harada N.; Nakanishi K. Circular Dichroism Exciton Coupling in Organic Stereochemistry; University Science Books: Mill Valley, CA, 1983. (b) Nakanishi, K.; Berova, N.; Woody, R. W. Circular Dichroism: Principles and Applications; VCH Publishers: New York, 1994. For IRVCD, see: (c) Wang, F.; Wang, Y.; Polavarapu, P. L.; Li, T.; Drabowicz, J.; Pietrusiewicz, K. M.; Zygo, K. J. Org. Chem. 2002, 67, 6539. For supramolecular chirogenesis, see: (d) Kikuchi, Y.; Kobayashi, K.; Aoyama, Y. J. Am. Chem. Soc. 1992, 114, 1351. (e) Yashima, E.; Matsushima, T.; Okamoto, Y. J. Am. Chem. Soc. 1997, 119, 6345. (f) Huang, X.; Rickman, B. H.; Borhan, B.; Berova, N.; Nakanishi, K. J. Am. Chem. Soc. 1998, 120, 6185. (g) Borovkov, V. V.; Lintuluoto, J. M.; Inoue, Y. Org. Lett. 2000, 2, 1565. (h) Borovkov, V. V.; Yamamoto, N.; Lintuluoto, J. M.; Tanaka, T.; Inoue, Y. Chirality 2001, 13, 329. (i) Borovkov, V. V.; Lintuluoto, J. M.; Inoue, Y. J. Am. Chem. Soc. 2001, 123, 2979. (j) Lintuluoto, J. M.; Borovkov, V. V.; Inoue, Y. J. Am. Chem. Soc. 2002, 124, 13676. (k) Proni, G.; Pescitelli, G.; Huang, X.; Nakanishi, K.; Berova, N. J. Am. Chem. Soc. 2003, 125, 12914. (l) Kubo, Y.; Ishii, Y.; Yoshizawa, T.; Tokita, S. Chem. Commun. 2004, 1394. (m) Lintuluoto, J. M.; Nakayama, K.; Setsune, J.-i. Chem. Commun. 2006, 3492. 10.1021/ac070217c CCC: $37.00 Published on Web 07/20/2007

© 2007 American Chemical Society

compounds. Based on the formation of covalently bound diastereomers of sample compounds, several NMR methods have been reported and there are continuing efforts to improve them.2 Among all, various NMR methods using chiral derivatizing agents have been developed.3 Of these methods, the modified Mosher’s method and its improved methods have frequently been employed to determine the absolute configuration of secondary alcohols and amines from natural sources.4 In contrast, noncovalent methods have been believed to be difficult to develop, because of the weak binding interactions and the dissociation phenomena between a chiral auxiliary and a substrate.5 On the other hand, since noncovalent methods do not involve chemical reactions or purification processes, only a small amount of a substrate compound is required. Moreover, the substrate can in principle be recovered. (2) (a) Dickins, R. S.; Badari, A. Dalton Trans. 2006, 25, 3088. (b) Diaz, G. E.; Jios, J.; Della Vedova, C. O.; March, H. D.; Di Loreto, H. E.; Toth, G.; Simon, A.; Albert, D.; Moeller, S.; Wartchow, R.; Duddeck, H. Tetrahedron: Asymmetry 2005, 16, 2285. (c) Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17. (d) Van Klink, J. W.; Baek, S.-H.; Barlow, A. J.; Ishii, H.; Nakanishi, K.; Berova, N.; Perry, N. B.; Weavers, R. T.; Dunedin, N. Z. Chirality 2004, 16, 549. (e) Schroeder, F. C.; Weibel, D. B.; Meinwald, J. Org. Lett. 2004, 6, 3019. (f) Daligault, F.; Arbore, A.; Nugier-Chauvin, C.; Patin, H. Tetrahedron: Asymmetry 2004, 15, 917. (g) Wenzel, T. J.; Wilcox, J. D. Chirality 2003, 15, 256. (h) Serebryakov, E. P.; Shcherbakov, M. A.; Gamalevich, G. D.; Struchkova, M. I. Russ. Chem. Bull. 2003, 52, 734. (i) Kosaka, M.; Sugito, T.; Kasai, Y.; Kuwahara, S.; Watanabe, M.; Harada, N.; Job, G. E.; Shvet, A.; Pirkle, W. H. Chirality 2003, 15, 324. (j) Omata, K.; Fujiwara, T.; Kabuto, K. Tetrahedron: Asymmetry 2002, 13, 1655. (3) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370. (c) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092. (d) Takahashi, T.; Fukushima, A.; Tanaka, Y.; Takeuchi, Y.; Kabuto, K.; Kabuto, C. Chem. Commun. 2000, 788. (e) Harada, N.; Watanabe, M.; Kuwahara, S.; Sugio, A.; Kasai, Y.; Ichikawa, A. Tetrahedron : Asymmetry 2000, 11, 1249. (f) Latypov, S. K.; Galiullina, N. F.; Aganov, A. V.; Kataeva, V. E.; Riguera, R. Tetrahedron 2001, 57, 2231. (g) Vavra, J.; Vodicka, P.; Streinz, L.; Budesinsky, M.; Koutek, B.; Ondracek, J.; Cisarova, I. Chirality 2004, 16, 652. (h) Sureshan, K. M.; Miyasou, T.; Miyamori, S.; Watanabe, Y. Tetrahedron: Asymmetry 2004, 15, 3357. (4) (a) Murata, M.; Matsuoka, S.; Matsumori, N.; Paul, G. K.; Tachibana, K. J. Am. Chem. Soc. 1999, 121, 870. (b) Morohashi, A.; Satake, M.; Nagai, H.; Oshima, Y.; Yasumoto, T. Tetrahedron 2000, 56, 8995. (c) Chang, L. C.; Chavez, D.; Song, L. L.; Farnsworth, N. R.; Pezzutto, J. M.; Kinghorn, D. Org. Lett. 2000, 2, 515. (d) Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3, 1363. (e) Adams, C. M.; Ghosh, I.; Kishi, Y. Org. Lett. 2004, 6, 4723.

Analytical Chemistry, Vol. 79, No. 16, August 15, 2007 6295

This paper reports the development of a supramolecular method including (1) background and comparison of covalent and supramolecular methods for the determination of absolute configuration, (2) a method on how to obtain the correct sign for ∆S-Rδcomp in a supramolecular system, (3) outline of the present method based on the theoretical derivatization from fundamental equations, and (4) practical method and the first demonstration in host-guest complexation of a chiral phenolic crown ether and an amino alcohol. EXPERIMENTAL SECTION Apparatus. 1H NMR spectra were recorded at 270 MHz on a JEOL JNM-MH-270 spectrometer for solutions in CDCl3 with SiMe4 as an internal standard, and J values are given in hertz. Materials. Solvents and reagents used were of reagent-grade purity. Enantiomers of amino alcohols and amino compounds were purchased from Aldrich Chemicals, Japan (Tokyo, Japan), Nacalai Tesque (Kyoto, Japan), Tokyo Kasei Kogyo (Tokyo, Japan), and Wako Pure Chemicals (Tokyo, Japan). General Procedures for Determination of Binding Constants. The titration experiment for the complexation of host (S,R,R,S)-1 with chiral amine (R)-2-amino-1-propanol is described as an example for the determination of binding constants by 1H NMR spectroscopy. A solution of (S,R,R,S)-1 (14.4 mM) and a solution of (R)-2amino-1-propanol (128 mM) each in CDCl3 were prepared. An initial 1H NMR spectrum of (S,R,R,S)-1 was recorded. Samples were made by adding the guest solutions to 600 µL of the host solution. Namely, 10, 20, 35, 40, 50, 60, 80, 100, 120, 160, and 200 µL portions of the guest solution were added. Then, spectra of these samples were recorded. The association constant was calculated by the nonliner least-squares method6 following the chemical shifts of one of the aromatic protons of (S,R,R,S)-1 shown in Figure 2 as Ha. The titration curves, δcomp, and K are shown in Supporting Information (Figure S1 and Table S1). The chemical shift change of the guest CH3 protons is shown in Figure 3. The titration experiment for the complexation of host (S,R,R,S)-1 with (S)-2-amino-1-propanol was carried out with procedures similar to those described above using a solution of (S)-2-amino1-propanol (138 mM). The titration curves, δcomp, and K are shown in Supporting Information (Figure S2 and Table S2). The chemical shift change of the guest CH3 protons is shown in Figure 3. General Procedures To Elucidate Temperature Dependence of Chemical Shifts of Complexes. The complexation of host (S,R,R,S)-1 with valinol is described as an example for the (5) Chiral shift reagents are used as a standard method to differentiate enantiomers through the formation of diastereomeric complexes. However, these cannot be used to determine absolute configuration in general. In some special cases, the use of chiral shift reagents was reported. For the pioneering works on a determination of absolute configuration with chiral solvating agents, see: (a) Pirkle, W. H.; Beare, S. D. J. Am. Chem. Soc. 1969, 91, 5150. (b) Pirkle, W. H.; Pavlin, M. S. J. Chem. Soc., Chem. Commun. 1974, 274. (c) Pirkle, W. H.; Hoekstra, M. S. J. Am. Chem. Soc. 1976, 98, 1832. (d) Pirkle, W. H.; Rinaldi, P. L. J. Org. Chem. 1977, 42, 3217. (e) Pirkle, W. H.; Sikkenga, D. L. J. Org. Chem. 1975, 40, 3430. (f) Pirkle, W. H.; Adams, P. E. J. Org. Chem. 1980, 45, 4111. (g) Pirkle, W. H.; Hoover, D. J. Top. Stereochem. 1982, 13, 263. For recent works, see: (h) Latypov, S.; Franck, X.; Jullian, J.-C.; Hocquemiller, R.; Figadere, B. Chem. Eur. J. 2002, 8, 5662. (i) Ghosh, I.; Zeng, H.; Kishi, Y. Org. Lett. 2004, 6, 4715. (6) Hirose, K. J. Inclusion Phenom. Macrocyclic Chem. 2001, 39, 193.

6296

Analytical Chemistry, Vol. 79, No. 16, August 15, 2007

elucidation of temperature dependence of chemical shifts of complexes. A solution of (S,R,R,S)-1 (5.11 mM) and a solution of (R)valinol (146 mM) each in CDCl3 were prepared. An initial 1H NMR spectrum of (S,R,R,S)-1 was recorded. Two sample solutions containing (S,R,R,S)-1 and the guest amine with a 1:1 and a 1:4 molar ratio were made by adding 16.3 or 65.0 µL of the guest solution to 650 µL of the host solution, respectively. Then, the spectra of these samples were recorded at eight different temperatures, 244.05, 253.35, 263.05, 272.05, 280.65, 290.25, 301.25, and 311.05 K. The temperature was calibrated using chemical shifts of deuterated methanol according to the literature.7 According to the calculation method described in the following text, the binding constants, enthalpy, and entropy terms were obtained based on the temperature dependence of chemical shifts of one of the aromatic protons of (S,R,R,S)-1 shown in Figure 2 as Ha.8 The enthalpy and entropy terms were used to calculate the desired δcomp of a “guest” proton based on the temperature dependences of the chemical shifts of the guest proton in a pure guest solution and the observed chemical shifts of the sample solution with a 1:4 molar ratio. The calculated chemical shifts (calcd δcomp) of CH3 protons in valinol at the eight temperatures were 0.8103, 0.8089, 0.8160, 0.8219, 0.8297, 0.8350, 0.8244, and 0.8234 ppm, respectively. According to the same procedures, the calculated chemical shifts (calcd δcomp) of the complex between (S,R,R,S)-1 (5.11 mM) and (S)-valinol at the same eight temperatures (0.7425, 0.7406, 0.7432, 0.7479, 0.7556, 0.7584, 0.7874, and 0.7951 ppm, respectively), were obtained. The temperature dependences of the calcd δcomp of the guest proton are summarized in Tables 1 and 2. Titration of (S,R,R,S)-1 with Valinol (Control Experiment). Titration experiments of (S,R,R,S)-1 with valinol at 244.05, 253.35, 263.05, 272.05, 280.65, 290.25, 301.25, and 311.05 K were carried out according to the procedure described above. The titration curves, δcomp, and K are shown in Supporting Information (Figures S3-S18 and Tables S3-S18). RESULTS AND DISCUSSION Background and Comparison between Covalent Methods and Supramolecular Methods for the Determination of Absolute Configuration. In Figure 1 are shown comparison of a supramolecular method (a) and the Mosher covalent method (b), and a graphical expression of the relation (c) between chemical shifts of complexes (δcomp), free guest (δfree), and observed chemical shifts (δobs) assuming that the exchange rate between complex formation and dissociation is faster than the NMR time scale. The Mosher method involves preparation of the corresponding R-methoxy-R-trifluoromethyl-R-phenylacetic (MTPA) amides from the two enantiomers of MTPA acid and an amine of unknown configuration. After purification, the NMR spectra of the two isolated derivatives are then recorded and the differences in the chemical shifts (∆S-Rδ ) δ(S) - δ(R)) are calculated. Mosher proposed that the most-relevant conformer would be the one in which the CF3, carbonyl, NH, and CH groups are placed in the (7) Van Geet, L. A. Anal. Chem. 1970, 42, 679. (8) Spreadsheets for the calculation of the present method were programmed by the authors. These are useful not only for the automation of practical calculations but also for a clear comprehension of the theory and the calculation procedures. These spreadsheets are filed in Supporting Information.

Figure 1. Comparison of a supramolecular method (a) and Mosher’s covalent method (b) for the determination of absolute configuration of a guest molecule using 1H NMR spectroscopy. Parameters to be considered for each method are shown in parentheses. The curved dotted arrows show dominant anisotropic shielding in each diastereomer. (c) A graphical expression regarding ∆δ, ∆δobs, ∆δcomp, and complexation ratio (x) in a noncovalent method. Case 1: a nonenantiomer selective complexation (the signs of ∆δ and ∆δobs are same). Case 2: typical example where the signs of ∆δ and ∆δobs are opposite.

Figure 2. Anisotropic shielding in a complex of (S,R,R,S)-1 with a chiral ethanolamine.

same plane, and the CF3 and carbonyl units are in a syn-periplanar position as shown in Figure 1b. In accordance with this model, the substituent R′ in the (S)-MTPA amide would be more shielded

than that in the (R)-MTPA amide, whereas the substituent R in the (R)-MTPA amide would be more shielded than in its diastereomer. Hence, for the amine with the configuration shown in Figure 1b, the substituent R′ would have a negative ∆S-Rδ value and the substituent R would exhibit a positive value.9 The corresponding supramolecular method is shown in Figure 1a. The (S)- and (R)-MTPA acids in covalent method correspond to the (S)-, (R)-hosts in the supramolecular method, respectively. The covalent bond formation in Mosher’s method corresponds to the noncovalent complex formation with a 1:1 stoichiometry. Therefore, R′ in the (S)-complex would suffer from more shielding than that in the (R)-complex and vice versa. The important parameter of the Mosher method, the sign of the chemical shift Analytical Chemistry, Vol. 79, No. 16, August 15, 2007

6297

the noncovalent method, there exist a free host, a free guest, and a complex in a certain equilibrium ratio. The chemical shift of the guest is the weight averaged between those of the free guest (δfree) and the complexed guest (δcomp), as shown in eq 1. The graphs shown in Figure 1c represent the linear relation between δobs and complexation ratio (x) following eq 1 with (S)- and (R)guests assuming δcomp(S) > δcomp (R).

δobs ) (1 - x)δfree + xδcomp

Figure 3. Chemical shift changes of the guest CH3 protons upon complexation of (R)- and (S)-2-amino-1-propanol with host (S,R,R,S)-1 in CDCl3 at 298 K. Table 1. Estimated Chemical Shifts of the Complex (δcomp) and ∆H and ∆S in Complexation of (S,R,R,S)-1 with (R)-Valinol in CDCl3 temperature (K) 311.05 301.25 290.25 280.65 272.05 263.05 253.35 244.05 ∆H (kJ‚mol-1) ∆S (J‚mol-1‚K-1)

δcomp (ppm)a 8.5760 8.5890 8.6160 8.6290 8.6410 8.6550 8.6690 8.6820 -48.8 -134

δcomp (ppm)b 8.5830 8.5980 8.6070 8.6250 8.6400 8.6520 8.6680 8.6820

∆δcomp (ppm) -0.007 -0.009 0.009 0.004 0.001 0.003 0.001 0.000

-44.6 -119

a Obtained from the present method. b Obtained from the titration experiment and the van’t Hoff relation.

Table 2. Estimated Chemical Shifts of the Complex (δcomp) and ∆H and ∆S in Complexation of (S,R,R,S)-1 with (S)-Valinol in CDCl3 temperature (K) 311.05 301.25 290.25 280.65 272.05 263.05 253.35 244.05 ∆H (kJ‚mol-1) ∆S (J‚mol-1‚K-1)

δcomp (ppm)a 8.6170 8.6190 8.6310 8.6380 8.6480 8.6590 8.6730 8.6860 -41.9 -105

δcomp (ppm)b 8.6010 8.6160 8.6270 8.6400 8.6510 8.6620 8.6740 8.6870

∆δcomp (ppm) 0.016 0.003 0.004 -0.002 -0.003 -0.003 -0.001 -0.001

-45.2 -116

a Obtained from the present method. b Obtained from the titration experiment and the van’t Hoff relation.

difference ∆S-Rδ ()δ(S) - δ(R)) between the diastereomers, corresponds to that of the chemical shift difference of a guest proton ∆S-Rδcomp ()δcomp(S) - δcomp(R)) between diastereomeric complexes. In order to correlate the NMR chemical shift and absolute configuration, the sign of the differences in the chemical shifts (∆S-Rδcomp ) δcomp(S) - δcomp (R)) should be calculated. However, δcomp(S) and δcomp (R) cannot be directly measured, because host-guest complexation is an equilibrium process. In 6298

Analytical Chemistry, Vol. 79, No. 16, August 15, 2007

(1)

If the difference between the ratios of formation of diastereomeric complexes is negligible, one can use the sign of ∆S-Rδobs instead of ∆S-Rδcomp. Thus, a nonselective complexation is an ideal case for the noncovalent method, because the sign of ∆S-Rδcomp is identical to that of ∆S-Rδobs (Figure 1c, case 1). Nonenantiomerselective complexation is a special case where the complexation ratios (x) of the diastereomeric complexes are same because the equilibrium constants KS and KR are same. However, in most cases, the equilibrium constants are not identical. When KR is smaller than KS as shown in Figure 1c as case 2, the sign of ∆S-Rδobs can be opposite to the sign of ∆S-Rδcomp. This is an inherent problem in the supramolecular method that should be overcome. On the basis of the above analysis, we propose in this article a supramolecular method for the determination of absolute configuration. The purpose of this article is as follows: (1) to proffer our solution for the inherent problem in the noncovalent method mentioned above, and (2) to demonstrate examples of application of the present method using a convenient practical procedure devised for the present purpose. Method To Obtain the Correct Sign of ∆S-Rδcomp in a Supramolecular System. According to the modified GibbsHelmholz eq 2, ∆S-R∆G is linearly correlated to temperature (T). Consequently, it is possible to realize a situation in which complexation is nonselective when the temperature is equal to an isoenantioselective temperature (Tiso) at which KS/KR is 1,

∆S-R∆G ) ∆S-R∆H - T∆S-R∆S

(2)

∆S-R∆G ) ∆GS - ∆GR ∆S-R∆H ) ∆HS - ∆HR ∆S-R∆S ) ∆SS - ∆SR where ∆GS, ∆GR refer to Gibbs free energy change; ∆HS, ∆HR and ∆SS, ∆SR refer to enthalpy and entropy change in complexations with (S)- and (R)-enantiomer guests, respectively. In principle, Tiso can be derived from ∆H and ∆S of the complexation for each enantiomer, since Tiso ) ∆S-R∆H/∆S-R∆S. Then, case 1 shown in Figure 1c is realized and one can easily obtain the sign of ∆S-Rδobs which is same as the sign of ∆S-Rδcomp. (9) In an effort to establish the scope and limitations of this method, theoretical calculations (MM, semiempirical AM1) and NMR studies (aromatic anisotropy increments, dynamic NMR) have recently been conducted.10 In the conformational equilibrium, each conformer plays a different role (shielding or deshielding) and the overall result is the weighted average of the conformer populations and their shielding/deshielding effects. The overall result is that the R′ substituent is more shielded in the (S)-MTPA than that in the (R)-MTPA amide.11 Conversely, substituent R is more shielded in the (R)-MTPA than in the (S)-MTPA amide. When the differences in the chemical shifts are calculated for an amine with the configuration shown in Figure 1b, ∆δ has a negative value for substituent R′ and a positive value for substituent R.

These thermodynamic parameters are usually calculated from the association constants, determined by titration experiments at several different temperatures using the van’t Hoff eq 3. However, titration methods require a substantial amount of substrates.12 In addition to the amount of substrate required, there is a problem because in many case Tiso is outside the practically possible range of measurement at which δobs should be observed.

ln K ) -

∆H 1 ∆S + R T R

()

(3)

In order to solve the above two problems, we devised an alternative method that requires only two sample solutions of substrate,13 using the temperature dependence of the complexation ratio determined by 1H NMR measurements. This method is widely applicable to host-guest systems with different KS and KR. Outline of the Present Method Based on the Theoretical Derivatization from Fundamental Equations. Our method is based on the following eq 4 and its modified form (5), where [H]t and [G]t refer to total concentration of a host and a guest molecules at the initial stage, respectively.

δcomp )

[{

∆S ( (∆H RT R )}

δfree + 2[H]t(δobs - δfree) [H]t + [G]t + exp

∆S - 4[H] [G] ] x{[H] + [G] + exp(∆H RT R )}

-1

2

t

t

t

(4)

t

The eqs 4 and 5 are derived from the law of mass action (eq

δobs ) δfree +

(δcomp - δfree) 2[H]t

[{

∆S ( (∆H RT R )}

[H]t + [G]t + exp

∆S - 4[H] [G] ] (5) x{[H] + [G] + exp(∆H RT R )} 2

t

t

t

t

6), the relation between NMR chemical shifts for fast exchange equilibrium (eq 7), and the van’t Hoff relation (eq 3).14 [C] refers to concentration of a complex. (10) (a) Latypov, S. K.; Galiullina, N. F.; Aganov, A. V.; Kataev, V. E.; Riguera, R. Tetrahedron 2001, 57, 2231. (b) Sasaki, M.; Omata, K.; Kabuto, K.; Sasaki, Y. Kidorui 2003, 42, 198. (c) Sureshan, K. M.; Miyasou, T.; Hayashi, M.; Watanabe, Y. Tetrahedron: Asymmetry 2004, 15, 3. (d) Iwamoto, H.; Kobayashi, Y.; Kawatani, T.; Suzuki, M.; Fukazawa, Y. Tetrahedron Lett. 2006, 47, 1519. (11) Seco, J. M.; Latypov, Sh. K.; Quinoa, E.; Riguera, R. J. Org. Chem. 1997, 62, 7569. (12) For a typical titration method, 12 sample preparations and 96 measurements at 8 different temperatures were carried out in this work. (13) For this temperature change method, 3 sample preparations and 24 measurements at 8 different temperatures were carried out. (14) The validity of this relationship has been confirmed for the complexation of phenolic 18-crown-6 derivatives.15 When using a host that has low enantiomer selectivity at ambient temperature, Tiso would be found near ambient temperature or the enantiomer selectivity would remain low for a wide range of temperatures. This means that there is a high probability of finding Tiso within the practical temperature range of NMR measurements.

K)

[C] ([H]t - [C])([G]t - [C])

(6)

(

(7)

δobs ) 1 -

)

[C] [C] δ + δ [H]t free [H]t free

Practically, NMR chemical shift data of three sample solutions of a guest substrate with different host-guest stoichiometries (e.g., guest only, host:guest ) 1:1, and host:guest ) 1:4) at eight different temperatures are required. By fitting the curve of the temperature dependence of δobs based on eq 5 using δfree at each temperature, we determined ∆H and ∆S (and δcomp). At this stage, there are two options depending on the calculated Tiso; (option 1) when Tiso is within the practical temperature range, one can determine experimentally the sign of ∆S-Rδcomp using ∆S-Rδobs by adjusting the temperature of the NMR measurement to Tiso, or (option 2) when Tiso is beyond the practical temperature range, one can calculate ∆S-Rδcomp for a “guest” proton. Practical Method and the First Demonstration: HostGuest Complexation of a Chiral Phenolic Crown Ether and Amino Alcohol. (a) Selection of a Host Molecule. Here we demonstrate an application of the present method for the two cases regarding Tiso using a crown ether-amine system. We have been investigating the synthesis of the chiral crown ethers having C2 symmetric pseudo-18-crown-6 as a basic structure, which consists of two chiral barriers and a phenol moiety and their enantiomerselective salt complex (saltex16) formation with primary amines.15 The enantiomer selectivity is drastically influenced by the structure of chiral moieties with regard to not only the magnitude but also the temperature dependence. Among the crown ethers investigated, we selected (S,R,R,S)-117 as a possible chiral anisotoropic reagent to demonstrate the noncovalent method to determine the absolute configuration of chiral amines, especially chiral ethanolamines, because (S,R,R,S)-1 has been shown to exhibit no enantiomer selectivity at room temperature in complexations with 2-amino-1-propanol (an example for option 1) and in general low enantiomer selectivity in complexations with other ethanolamine derivatives (examples for option 2). In Figure 2, a structure of a complex between (S,R,R,S)-1 and a chiral ethanolamine is shown. It is expected that (S,R,R,S)-1 would function as a chiral auxiliary like MTPA. This is expected because, for a β-amino alcohol guest, the ammonium and the hydroxy groups are tightly bound to the oxygen atoms of the crown ring and the phenoxide oxygen atom18 by ion-dipole interactions and hydrogen bonding, respectively. Accordingly, one of the groups of the guest (R1) would suffer from the anisotoropic shielding effect of the aromatic ring of (S,R,R,S)-1 thanks to its planar and rigid tetralin structure. (15) (a) Kaneda, T.; Hirose, K.; Misumi, S. J. Am. Chem. Soc. 1989, 111, 742. (b) Hirose, K.; Fuji, J.; Kamada, K.; Tobe, Y.; Naemura, K. J. Chem. Soc., Perkin Trans. 1997, 2, 1649. (c) Naemura, K.; Matsunaga, K.; Fuji, J.; Ogasahara, K.; Nishikawa, Y.; Hirose, K.; Tobe, Y. Anal. Sci. 1998, 14, 175. (d) Hirose, K.; Ogasahara, K.; Nishioka, K.; Tobe, Y.; Naemura, K. J. Chem. Soc., Perkin Trans 2000, 2, 1984. (e) Hirose, K.; Aksharanandana, P.; Suzuki, M.; Wada, K.; Naemura, K.; Tobe, Y. Heterocycles 2005, 66, 405. (16) Kaneda, T.; Ishizaki, Y.; Misumi, S.; Kai, Y.; Hirao, G.; Kasai, N. J. Am. Chem. Soc. 1988, 110, 2970. (17) Naemura, K.; Wakebe, T.; Hirose, K.; Tobe, Y. Tetrahedron: Asymmetry 1997, 8, 2585. (18) Naemura, K.; Tobe, Y.; Kaneda, T. Coord. Chem. Rev. 1996, 148, 199.

Analytical Chemistry, Vol. 79, No. 16, August 15, 2007

6299

(b) Option 1 (Tiso within Practical Temperature Range). The binding constants of complexes of the host (S,R,R,S)-1 with (S)- and (R)-2-amino-1-propanol were known to be identical at 298 K.17 Then, the chemical shifts of the guest CH3 protons of (S)and (R)-2-amino-1-propanol in the presence of an equimolar amount of (S,R,R,S)-1 were measured at this temperature. As a result, ∆S-Rδobs of the guest CH3 protons was 0.057 ppm when the host/guest ratio was 1 (13.0 mM). This result is consistent with the prediction based on the shielding effect shown in Figure 2. To check the independence of the sign of ∆δobs with respect to the guest/host ratio ([G]t/[H]t), the chemical shifts of the guest CH3 protons were measured at the different [G]t/[H]t ratios of 0.1 to 3.0. In Figure 3, chemical shift changes of the guest CH3 protons upon complexation of (R)- and (S)-2-amino-1-propanol with host 1 in CDCl3 at 298 K are shown. At all concentrations, the chemical shifts of the methyl protons of (S)-2-amino-1-propanol always appear at higher magnetic fields than those of the (R)-enantiomer. As a result, it was confirmed that the signs of ∆S-Rδobs and ∆S-Rδcomp are identical at all host-guest ratios. (c) Option 2 (Tiso beyond Practical Temperature Range). It is not always possible to apply the simplest version (option 1) of the noncovalent method, since Tiso does not always occur within the practical temperature range. To overcome such an obstacle, we devised a useful method (option 2) to determine δcomp, from which the sign of ∆S-Rδcomp can be calculated, using the NMR chemical shifts of the three sample solutions with different host/ guest stoichiometry (guest only, host:guest ) 1:1, and host:guest ) 1:4) at eight different temperatures according to eq 5. As a typical example, the complexation of (S,R,R,S)-1 with valinol is shown here. In this case, low enantiomer selectivity was observed for a wide range of temperatures, and no Tiso was observed within the temperature range examined.17 To precisely elucidate δcomp, the temperature dependence of the complexation ratio (x) between (S,R,R,S)-1 and the guest substrate should be accurately determined. Therefore, NMR chemical shifts of a host solution are employed to obtain the ∆H and ∆S values. First, three solutions in CDCl3 were prepared as follows; host (S,R,R,S)-1 (5.12 mM), ∼1:1 mixture of (S,R,R,S)-1 (4.97 mM) and (R)-valinol (4.29 mM), and ∼1:4 mixture of (S,R,R,S)-1 (4.51 mM) and the guest (17.5 mM). The NMR spectra were measured at eight different temperatures ranging from 244 to 311 K. The temperature dependence of the chemical shifts, δfree, δobs(1:1), and δobs(1:4), of the “host” aromatic proton Ha (see Figure 2)19 in each solution were recorded. Then, curve fitting was carried out using the least-squares method as follows: (1) Setting initial values of ∆H and ∆S by assuming that the values should not have large differences from true ∆H and ∆S, respectively. (2) δcomp was calculated from eq 4 using δfree, [H]t, [G]t, the observed chemical shift for the 1:4 solution (δobs(1:4)), and the above assumed ∆H and ∆S values. (3) The chemical shift of Ha for the 1:1 solution (δcalcd(1:1)) was calculated from eq 5 using calculated δcomp, δfree, [H]t, [G]t, and the assumed ∆H and ∆S. (4) The sum of the square deviations were minimized for the data at eight temperatures by changing (19) In order to obtain reliable data of ∆H and ∆S, the chemical shift of the Ha proton of (S,R,R,S)-1 was chosen for the curve fitting, because it resonated at low magnetic field well separated from other signals due to the guest amines. However, it is not perturbed by the complexed guest.

6300 Analytical Chemistry, Vol. 79, No. 16, August 15, 2007

Figure 4. Observed temperature dependency of the chemical shifts of Ha of host (S,R,R,S)-1 in complexation with (R)-valinol in CDCl3 and calculated δcalcd(1:1) and δcomp obtained by the curve fitting.

Figure 5. Observed temperature dependency of the chemical shifts of Ha of host (S,R,R,S)-1 in complexation with (S)-valinol in CDCl3 with calculated δcalcd(1:1) and δcomp obtained by the curve fitting.

the assumed ∆H and ∆S, yielding ∆H ) -48.8 kJ‚mol-1 and ∆S) -133 J‚K-1‚mol-1. The deviation was defined as the difference of the calculated δcalcd(1:1) from those observed for the 1:1 solution (δobs(1:1)). The observed chemical shifts (δfree, δobs(1:1), δobs(1:4)) and the calculated ones (δcalcd(1:1) and δcomp) are shown in Figure 4. ∆H (-41.9 kJ‚mol-1), ∆S (-105 J‚K-1‚mol-1), and δobs(1:1), and δcomp for (S)-valinol were similarly obtained (Figure 5) using the following three solutions of host (S,R,R,S)-1 and (S)-valinol in CDCl3, host (S,R,R,S)-1 (5.11 mM), 1:1 mixture of (S,R,R,S)-1 (4.96 mM) and (S)-valinol (4.35 mM), and 1:4 solution of (S,R,R,S)-1 (4.49 mM) and the guest (17.7 mM). In order to assess the reliability of ∆H, ∆S, and δcomp obtained from the present method, normal titration experiments at eight different temperatures were carried out. Following the data treatment using a nonlinear least-squares method, we obtained association constants K and δcomp at each temperature, which are listed in Tables 1 and 2 together with the ∆H and ∆S values obtained from the slope and intercept of the van’t Hoff plots. The difference between the chemical shifts (∆δcomp) determined by these two methods were small (