Recognition in Organized Aggregates Formed by a Chiral Amidic

Drug Research Institute, a.s. Horna 36 Sk-90001, Modra, Slovakia. Received March 9, 1999. In Final Form: July 20, 1999. Chiral discrimination of racem...
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Recognition in Organized Aggregates Formed by a Chiral Amidic Surfactant Juray Bella,† Stefano Borocci,‡ and Giovanna Mancini*,‡ Centro CNR di Studio sui Meccanismi di Reazione, Dipartimento di Chimica, Universita` “La Sapienza”, P.le A.Moro 5, 00185 Roma, Italy, and NMR lab., Drug Research Institute, a.s. Horna 36 Sk-90001, Modra, Slovakia Received March 9, 1999. In Final Form: July 20, 1999 Chiral discrimination of racemic 2-carboxy-2′-dodecyloxy-6-nitrobiphenyl by aqueous micelles of sodium N-dodecanoyl-L-prolinate was observed by 1H NMR. 2D ROESY experiments show that the biphenylic system interacts preferentially with one of the two domains respectively formed by the E and Z isomers of sodium N-dodecanoyl-L-prolinate and that the biphenylic solute induces larger and more rigid aggregates. An estimate of the rotational barrier of the biphenylic system both in aggregating and in nonaggregating conditions has been carried out by dynamic NMR, and results are in good agreement with reported data obtained by racemization rates.

Introduction Chiral recognition in selfassemblies has been largely investigated over the past 30 years with various approaches. Stereoselective hydrolysis of enantiomeric esters in chiral aggregates has been investigated in the context of micellar catalysis as the model of enzimic catalysis1 and as a probe for investigating the mechanism of the reaction and the morphology of the aggregates.2 Chiral micelles have been used as chiral environment for enantioselective preparations starting from prochiral substrates.3 Moreover, chiral recognition may have consequences on the morphology of the aggregates,4 as it was † ‡

reported that assemblies formed by racemic mixtures may have a different morphology4a from those formed by homochiral surfactants; analogously homochiral vesicles have been found to be more stable than racemic ones under some conditions.4b Finally, the formation of enantiomorphous monolayer crystals from enantiomers and the spontaneous resolution of the corresponding racemic mixture in enantiomorphic domains were reported.4c We have recently reported5 on the NMR observation of enantiomeric discrimination by chiral micelles formed by sodium N-dodecanoyl-L-prolinate, 1. The observation of

Drug Research Institute. Universita` “La Sapienza”.

(1) (a) Bunton, C. A.; Robinson, L.; Stam, M. F. Tetrahedron Lett. 1971, 121-124. (b) Brown, J. M.; Bunton, C. A. J. Chem. Soc., Chem. Commun. 1974, 969-971. (c) Moss, R. A.; Sunshine, W. L. J. Org. Chem. 1974, 39, 1083-1089. (d) Moss, R. A.; Nahas, R. C.; Lukas, T. J. Tetrahedron Lett. 1978, 507-510. (e) Yamada, K.; Shosenji, H.; Ihara, H.; Otsubo, Y. Tetrahedron Lett. 1979, 2529-2532. (f) Ihara, H.; Ono, S.; Shosenji, H.; Yamada, K. J. Org. Chem. 1980, 45, 1623-1625. (g) Moss, R. A.; Lee, Y.-S.; Alwis, K. W. J. Am. Chem. Soc. 1980, 102, 6646-6648. (h) Yamada, K.; Shosenji, H.; Otsubo, Y.; Ono, S. Tetrahedron Lett. 1980, 21, 2649-2652. (i) Ihara, H.; Kunikiyo, N.; Kunimasa, T.; Nango, M.; Kuroki, N. Chem. Lett. 1981, 667-670. (j) Ono, S.; Shosenji, H.; Yamada, K. Tetrahedron Lett. 1981, 22, 2391-2394. (k) Ueoka, R.; Matsumoto, Y.; Yoshino, T.; Watanabe, N.; Omura, K.; Murakami, Y. Chem. Lett. 1986, 1743-1746. (l) Brown, J. M.; Elliott, R. L.; Griggs, C. G.; Helmchen, G.; Nill, G. Angew. Chem., Int. Ed. Engl., 1981, 20, 890-892. (2) (a) Moss, R. A.; Taguchi, T.; Bizzigotti, G. O. Tetrahedron Lett. 1982, 23, 1985-1988. (b) Ueoka, R.; Moss, R. A.; Swarup, S.; Matsumoto, Y.; Strauss, G.; Murakami, Y. J. Am. Chem. Soc., 1985, 107, 21852186. (c) Ihara, Y.; Okamoto, M.; Kawamura, Y.; Nakanishi, E.; Nango, M.; Koga J. J. Chem. Soc., Perkin Trans. 2 1987, 607-611. (d) Moss, R. A.; Hendrickson, T. F.; Ueoka, R.; Kim, K. Y.; Weiner, P. K. J. Am. Chem. Soc. 1987, 109, 4363-4372. (e) Ueoka, R.; Matsumoto, Y.; Moss, R. A.; Swarup, S.; Sugii, A.; Harada, K.; Kikuchi, J.-I.; Murakami, Y. J. Am. Chem. Soc. 1988, 110, 1588-1595. (f) Ihara, Y.; Igata, K.; Okubo, Y.; Nango, M. J. Chem. Soc., Chem. Commun. 1989, 1900-1902. (g) Ihara, Y.; Asakawa, S.; Igata, K.; Matsumoto, Y.; Ueoka, R. J. Chem. Soc., Perkin Trans. 2 1991, 543-548. (h) Scrimin, P.; Tecilla, P.; Tonellato, U. J. Org. Chem. 1994, 59, 4194-4201. (i) Cleij, M. C.; Scrimin, P.; Tecilla, P.; Tonellato, U. Langmuir 1996, 12, 2956-2960. (3) (a) Zhan, Y.; Wu, W. Tetrahedron: Asymmetry 1997, 8, 35753578. (b) Diego-Castro, M. J.; Hailes, H. C. Chem. Commun. 1998, 15491550. (4) (a) Furhop, J.-H.; Schnieder, P.; Rosenberg, J.; Boekema, E. J. Am. Chem. Soc. 1987, 109, 3387-3390. (b) Morigaki, K.; Dallavalle, S.; Walde, P.; Colonna, S.; Luisi, P. L. J. Am. Chem. Soc. 1997, 119, 292301. (c) Stevens, F.; Dyer, D. J.; Walba, D. M. Angew. Chem., Int. Ed. Engl. 1996, 35, 900-901.

two diastereomeric signals was attributed to the high affinity of the chiral solute for the aggregate. We report here the 1H NMR observation of another interesting example of chiral discrimination by micelles formed by sodium N-dodecanoyl-L-prolinate, 1. The 1H NMR spectrum of an aqueous solution of 2-carboxy-2′-dodecyloxy6-nitrobiphenyl, 2, in the presence of sodium N-dodecanoylL-prolinate, 1, shows splitting of five among the seven signals relative to the aromatic protons of the biphenylic derivative. Analogously to other amidic surfactants6 sodium N-dodecanoyl-L-prolinate7 aggregates in separate domains on the basis of the E/Z stereochemical code. 2D ROESY experiments indicated that the biphenylic system shows a higher affinity for the Z than for the E domains. Moreover, a higher extent of spin diffusion in the presence of a higher concentration of the biphenylic compound shows the solute to influence the organization of the amidic surfactant in larger and more rigid aggregates. (5) Belogi, G.; Croce, M.; Mancini, G. Langmuir 1997, 13, 29032904. (6) Cerichelli, G.; Luchetti, L.; Mancini, G. Langmuir 1997, 13, 47674769. (7) Borocci, S.; Cerichelli, G.; Luchetti, L.; Mancini, G. Langmuir 1999, 15, 2627-2630.

10.1021/la990277g CCC: $18.00 © 1999 American Chemical Society Published on Web 09/14/1999

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Figure 1. Signal relative to the protons of the first methylene of the aliphatic chain of the biphenylic compound in the 1H NMR spectrum (run at 300.13 MHz) of a CDCl3 solution 0.050 M in 2: (a) under standard conditions; (b) under irradiation (low power) of the second methylene of the chain.

Experimental Section 1H NMR spectra were run on a Bruker AC 300 P spectrometer

and on a Bruker AMX 600 operating respectively at 300.13 and 600.13 MHz. Dynamic NMR Experiments.8 These experiments were performed on a Bruker AC 300 P spectrometer. 1H NMR spectra were performed at various temperatures between 298 and 343 K on an aqueous solution of 0.10 M 1 and 0.020 M 2. A plot of the ∆ν between the diastereomeric aromatic signals versus temperature allowed us to extrapolate the ∆ν value in the absence of interconversion to be used in eq 18

kc )

x2 π∆ν 2

(1)

where kc is the rate of interconversion between the two enantiomers at the coalescence temperature. 1H NMR spectra were performed on a CDCl solution of 0.050 3 M 2 at various temperatures between 294 and 323 K. The multiplet relative to the protons of the second methylene of the biphenylic aliphatic chain was irradiated (low power) in order to reduce the multiplet relative to the first methylene of the chain to an AB system (Figure 1). The extrapolated ∆ν value of the AB system in the absence of interconversion was used in eq 2 (which is used for an AB system8) for calculating the rate of interconversion at the coalescence temperature.

kc )

x2 π ∆ν2 + 6JAB2 2 x

(2)

2D 1H ROESY Experiments.9 These experiments were performed on a Bruker AMX 600 in the phase-sensitive mode (TPPI)10 method of quadrature detection in F2. An 80 ms mixing time of on-resonance CW (continuous wave) spinlock at γH2 ) 5000 Hz was used.The sweep width was 5435 Hz in both dimensions. Data were collected as 512 (F1) by 1024 (F2) complex points and processed using the Bruker XWINNMR software. Two-dimensional spectra were apodized with a 90° phase-shifted square-sine bell before zero-filling to 1024 × 1024 real data points. 2-Bromo-3-nitromethylbenzoate. The compound was prepared as previously described;11 mp 77-78 °C. 1H NMR, δ(CDCl3): 3.961 (s, 3H, CH3), 7.507 (t, 1H, Jo ) 8.0 Hz), 7.746 (8) Friebolin, H. Basic One and Two-Dimensional NMR Spectroscopy, 3rd ed.; VCH: Weinheim, 1998; pp 301-311. (9) Bax, A.; Davis, D. G. J. Magn. Reson. 1985, 63, 207-213. (10) Marion, D.; Wu¨thrich, K. Biochem. Biophys. Res. Commun. 1983, 113, 967-974. (11) Stoughton, R. W.; Adams, R. J. Am. Chem. Soc. 1932, 54, 44264434.

(d, 1H, Jm ) 1.6 Hz, Jo ) 8.0 Hz), 7.838 (d, 1H, Jm ) 1.6 Hz, Jo ) 8.0 Hz). 13C NMR, δ(CDCl3): 53.07, 112.72, 126.64, 128.19, 135.71, 151.93, 165.49. 2-Nitrophenyl Dodecyl Ether. An amount of 90 g of potassium carbonate was added to a solution of 26 g of bromododecane (0.10 mol) and of 30 g of 2-nitrophenol (0.26 mol) in 200 mL of acetonitrile. After 18 h under reflux, the reaction mixture was filtered and the solvent partially removed by rotary evaporation. The residue was diluted with Et2O and washed with water up to neutrality, washed with brine, and then dried over Na2SO4. Removal of ether by rotary evaporation yielded 27 g (94%) of a dark-yellow oil. 1H NMR, δ(CDCl3): 0.866 (t, 3H, CH3, 3J ) 6.4 Hz), 1.250 (s, 16H), 1.462 (m, 2H), 1.817 (m, 2H), 4.077 (t, 2H, 3J ) 6.30 Hz), 6.983 (t, 1H, Jm ) 0.80 Hz, Jo ) 7.5 Hz), 7.051 (d, 1H, Jo ) 8.2 Hz), 7.489 (t, 1H, Jm ) 1.7 Hz, Jo ) 8.2 Hz), 7.799 (d, 1H, Jm ) 1.6 Hz, Jo ) 7.5 Hz). 13C NMR, δ(CDCl3): 14.14, 22.70, 25.84, 28.95, 29.29, 29.36, 29.53, 29.59, 29.64, 29.67, 31.93, 69.62, 114.37, 119.96, 125.53, 133.97, 139.95, 152.50. 2-Aminophenyl Dodecyl Ether. 2-Nitrophenyl dodecyl ether was reduced under mild conditions with ammonium formiate in MeOH in the presence of 10% Pd/C.12 1H NMR, δ(CDCl3): 0.872 (t, 3H, 3J ) 6.6 Hz), 1.253 (s, 16H), 1.453 (m, 2H), 1.802 (m, 2H), 3.976 (t, 2H, 3J ) 6.5 Hz), 6.740-6.830 (m, 4H). 13C NMR, δ(CDCl3): 14.15, 22.72, 26.16, 29.39, 29.45, 29.63, 29.66, 29.69, 31.94, 68.25, 111.44, 115.21, 118.68, 120.89, 135.93, 146.89. 2-Iodophenyl Dodecyl Ether. 2-Aminophenyl dodecyl ether was diazotized by standard procedure.13 1H NMR, δ(CDCl3): 0.857 (t, 3H, 3J ) 6.6 Hz), 1.242 (m, 16H), 1.488 (m, 2H), 1.793 (m, 2H), 3.974 (t, 2H, 3J ) 6.6 Hz), 6.636 (t, 1H, Jm ) 1.4 Hz, Jo ) 7.6 Hz), 6.739 (d, 1H, Jm ) 1.4 Hz, Jo ) 7.5 Hz), 7.222 (t, 1H, Jm ) 1.7 Hz, Jo ) 7.5 Hz), 7.719 (d, 1H, Jm ) 1.7 Hz, Jo ) 7.6 Hz). 13C NMR, δ(CDCl3): 14.15, 22.71, 26.10, 29.10, 29.32, 29.38, 29.58, 29.60, 29.68, 31.94, 69.10, 111.96, 122.20, 129.32, 139.34, 157.58. 2-Carboxymethyl-2′-dodecyloxy-6-nitrobiphenyl. An amount of 6.0 g of 2-iodophenyl dodecyl ether (15 mmol) and 1.0 g of 2-bromo-3-nitromethylbenzoate (3.8 mmol) were added to 35 mL of dry DMF. To the reaction mixture, heated to 100 °C in an inert atmosphere, 1.5 g of finely powdered Cu (Fluka) was added under stirring. After 15 min the reaction mixture was allowed to cool and was then filtered. The filtrate was diluted with 40 mL of Et2O, washed with water, aqueous ammonia solution (30%), and brine, and then dried over Na2SO4. Purification on silica gel using hexane/Et2O as eluent yielded 0.25 g (15%) of a yellow oil. 1H NMR, δ(CDCl3): 0.877 (t, 3H, 3J ) 6.4 Hz), 1.216 (m, 18H), 1.577 (m, 2H), 3.577 (s, 3H), 3.869 (t, 2H, 3J ) 6.8 Hz), 6.900 (d, 3′, 1H, J ) 0.9 Hz, J ) 8.3 Hz), 6.966 m o (t, 5′, 1H, Jm ) 0.9 Hz, Jo ) 7.4 Hz), 7.071 (d, 6′, 1H, Jm ) 1.7 Hz, Jo ) 7.4 Hz), 7.333 (t, 4′, 1H, Jm ) 1.7 Hz, Jo ) 8.3 Hz), 7.525 (t, 4, 1H, Jo ) 8.1 Hz), 7.958 (d, 5, 1H, Jm ) 1.4 Hz, Jo ) 8.1 Hz), 8.012 (d, 3, 1H, Jm ) 1.4 Hz, Jo ) 8.1 Hz). 13C NMR, δ(CDCl3): 14.13; 22.69, 25.70, 28.77, 29.20, 29.36, 29.51, 29.65, 31.92, 52.28, 68.37, 111.47, 120.46, 124.53, 126.22, 127.88, 128.98, 129.90, 132.97, 134.49, 150.76, 155.56, 166.99. 2-Carboxy-2′-dodecyloxy-6-nitrobiphenyl, 2. An amount of 0.20 g of 2-carboxymethyl-6-nitro-2′-dodecyloxybiphenyl was added to 5 mL of an aqueous solution of 10% NaOH. The mixture was kept under reflux up to disappearance of the organic layer, then it was acidified with 6 M HCl. The mixture was extracted with Et2O; the ether fraction was washed with brine and dried over Na2SO4. Removal of Et2O by rotary evaporation yielded 0.19 g of a pale-yellow compound; mp 73-75 °C. 1H NMR, δ(CDCl3): 0.881 (t, 3H, 3J ) 6.4 Hz), 1,210 (m, 18H), 1.415 (m, 2H), 3.852 (m, 2H), 6.874 (d, 3′, 1H, Jm ) 0.9 Hz, Jo ) 8.3 Hz), 6.948 (t, 5′, 1H, Jm ) 0.9 Hz, Jo ) 7.4 Hz), 7.066 (d, 6′, 1H, Jm ) 1.7 Hz, Jo ) 7.4 Hz), 7.328 (t, 4′, 1H, Jm ) 1.7 Hz, Jo ) 8.3 Hz), 7.540 (t, 4, 1H, Jo ) 8.1 Hz), 7.965 (d, 5, 1H, Jm ) 1.4 Hz, Jo ) 8.1 Hz), 8.898 (d, 3, 1H, Jm ) 1.4 Hz, Jo ) 8.1 Hz). 13C NMR, δ(CDCl3): 14.15, 22.71, 25.75, 28.79, 29.23, 29.37, 29.52, 29.54, 29.67, 29.68, 31.94, 68.42, 111.61, 120.57, 123.92, 127.01, 127.96, 129.01, 130.09, 133.01, 133.46, 133.50, 151.08, 155.60, 171.42. Resonances were assigned on the basis of H,H-COSY and C,HCOSY experiments. (12) Ram, S.; Ehrenkaufer, R. E. Tetrahedron Lett. 1984, 25, 34153418. (13) Li, C. C.; Adams, R. J. Am. Chem. Soc. 1935, 57, 1565-1569.

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Figure 2. Aromatic region of the 1H NMR spectrum of (a) a CDCl3 solution 0.050 M in 2 (run at 300.13 MHz) and (b) a D2O solution 0.10 M in 1 and 0.010 M in 2 (run at 600.13 MHz). Determination of the cmc of Compound 2 in 0.10 M Aqueous NaOH. Surface tension measurements were carried out at 298 K on a Kru¨ss K10T digital tensiometer.

Results Preparation of Compound 2. The biphenylic derivative was synthesized according to a described pattern.13 A good improvement in the yield of 2 with respect to the reported pattern was obtained by reducing the nitro group of 2-nitrophenyl dodecyl ether with ammonium formiate 12 in the presence of Pd/C instead of with Zn under acidic conditions. Moreover, the use of mild conditions14 in the Ulmann type coupling of 2-bromo-3-nitromethylbenzoate and 2-iodophenyl dodecyl ether gave a 15% yield, the reported yield under fusion conditions13 for analogous compound bearing an alkoxy chain of three to five carbons, being between 7 and 11%. The main problem in the coupling reaction was represented by the occurrence of reductive dehalogenation products. These are reported15 as difficult to avoid also in a rigorously inert atmosphere when no obvious hydrogen source is present. Compound 2 is insoluble in neutral water; on the other hand, it is soluble in alkaline water, since it forms micellar aggregates with a cmc of 2.8 × 10-5 M measured in 0.10 M NaOH. 1 H NMR Experiments. 1H NMR experiments were performed on aqueous solutions of 0.10 M sodium Ndodecanoyl-L-prolinate, 1, and 0.010 or 0.020 M 2-carboxy2′-dodecyloxy-6-nitrobiphenyl, 2 (this being the solubility limit of 2 in the aggregates formed by the chiral surfactant (14) Fanta, P. E. Chem. Rev. 1964, 64, 613-632. (15) Carlin, R. B.; Swakon, E. A. J. Am. Chem. Soc. 1955, 77, 966973.

1). Under both conditions a splitting of the signals relative to the aromatic protons in positions 3, 4, 4′, 5′, 6′ showed the diastereomeric interactions of compound 2 with the chiral aggregates16 (Figure 2). Moreover, 1H NMR spectra show that the presence of the aromatic solute causes an upfield shift of the signals relative to the Z isomer of the chiral surfactant (Figure 3) so that the signals in the region between 3.3 and 3.7 ppm (δ protons17 of the proline ring) are more resolved (Figure 3b,c) in the presence of the biphenylic structure with respect to the spectrum of the surfactant performed in the absence of the solute (Figure 3a). Analogously the signal relative to the RE (4.3 ppm) proton is more visible at higher concentration of the biphenilic compound because of the upfield shift of the RZ proton signal. 2D 1H ROESYexperiments performed on the abovementioned samples show a different extent of spin diffusion (i.e., magnetization transfer18 between nuclei of 1 and 2 inside the aggregates). In fact spin diffusion is higher in the sample containing a larger amount of biphenylic compound as evidenced in Figure 4, which shows the magnetic state of nuclei after an elapsed time of 80 ms. Signals relative to aromatic protons show cross-peaks (Figure 5) with the signals relative to the protons of the (16) Both the experiments at 300.13 and 600.13 MHz show split of signals. (17) It may be worthwhile to point out that δ protons of the proline ring, as well as the β and γ protons, are diastereotopic; this explains why they give rise to four signals (two diastereotopic protons for the E isomer and two for the Z isomer). (18) Ernst, R. R.; Bodenhausen, G.; Wokaun, A. Principles of NMR in One and Two Dimensions; Oxford University Press: Oxford, 1985; pp 534-538.

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Figure 3. Region relative to the R and δ proton signals of the proline ring in the 1H NMR spectra (run at 600.13 MHz) of (a) a D2O solution 0.10 M in 1, (b) a D2O solution 0.10 M in 1 and 0.010 M in 2, (c) a D2O solution 0.10 M in 1 and 0.020 M in 2.

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intensities with the signals relative to the protons in the R and δ positions of the proline ring (Figure 6). Dynamic 1H NMR experiments were performed between 298 and 343 K on an aqueous solution of 0.10 M 1 and 0.020 M 2 and between 294 and 323 K on a CDCl3 solution19 of 0.050 M 2. As far as the micellar solution was concerned, coalescence of the two diastereomeric signals was observed at 338 K. This value and the value of the rate of interconversion between the two enantiomers at the coalescence temperature kc ) 11.10 s-1 obtained by eq 1 were used in the Eyring equation8 and yielded a ∆G#338 ) 18 kcal/mol for the rotational barrier. In the experiments carried out on the CDCl3 solution, we reduced the multiplet relative to the first methylene of the aliphatic chain to an AB system (Figure 1) and observed coalescence at 312 K. The coalescence temperature and the rate of interconversion, kc ) 50.6 s-1, obtained by eq 2 allow us to calculate a ∆G#312 ) 16 kcal/mol for the rotational barrier. If we consider the approximations of this method, both values, under aggregating and nonaggregating conditions, can be considered in good agreement with ∆G#298 ) 20 kcal/ mol reported in the litterature.13,20 On the basis of the chemical shift difference between the 4′ and 6′ positions, we were able to evaluate the dihedral angle between the two aromatic rings of compound 2. In fact it is reported21 that, as illustrated in Table 1, ∆δ values between the 4′ and 6′ positions correspond to particular values of the dihedral angle. 1H NMR spectra of compound 2 run in aqueous (in the presence of surfactant 1) and in CDCl3 solutions at 25 °C show a chemical shift difference of, respectively, ∆δ ) 0.075 ppm and ∆δ ) 0.25 ppm between signals relative to protons in the 4′ and 6′ positions (see Table 1). These values show that under aggregating conditions the dihedral angle is closer to orthogonality with respect to nonaggregating conditions. Discussion

Figure 4. (a) Portion of the 1H NMR spectrum of a D2O solution 0.10 M in 1 and 0.020 M in 2 and spin diffusion evidenced by the same portion of the traces in the F1 dimension of 2D ROESY spectra, chosen with maximum intensity (fixed as 20 000) of the signal relative to the terminal methyl (∼0.8 ppm) of the aliphatic chain, in experiments run respectively on (b) a D2O solution 0.10 M in 1 and 0.010 M in 2 and (c) a D2O solution 0.10 M in 1 and 0.020 M in 2.

Z isomer of the chiral amidic surfactant (3.4, 3.7 ppm for δ position protons; 4.27 ppm for R position proton), while no cross-peaks are present with the proton signals belonging to the E isomer (3.45, 3.55 ppm for δ position protons; 4.32 ppm for R position proton). The diasteromeric signals relative to the aromatic protons in positions 6′ and 4′ show cross-peaks of different

Before stressing the outcome of recognition results we observed in our experiments, it is worthwhile to spend a few words on the chiral anionic surfactant we used as chiral auxiliary. Besides chiral discrimination of another axially chiral structure,5 sodium N-dodecanoyl-L-prolinate is responsible for another recognition event. In fact it contains an amidic bond, and analogous to other amidic surfactants,6 under aggregating conditions it organizes in domains on the basis of the E/Z stereochemical code.7 In fact the 1H and 13C NMR spectra7 of aqueous solutions of 1 at concentrations above the cmc show two different signals for 12-CH3; moreover, in the 13C NMR spectra every resolved carbon nucleus causes two signals. These findings indicated that the chains of the Z and E isomers experience a different environment, owing to the presence of separate Z and E domains. The diastereomeric signals of aromatic protons of compound 2 revealed by the 1H NMR spectra (Figure 2b) performed in the presence of the chiral surfactant 1 are in a ratio 1:1; this demonstrates that the chiral aggregates do not interact preferentially with one of the enantiomers; in such a case in fact, the low rotational barrier of the biphenylic compound would have allowed a deracemiza(19) A CD3OD solution would have been a better choice as a reference because of its polarity and dielectric constant, but we chose a CDCl3 solution because in CD3OD the diastereotopic nature of the two protons is not revealed and the first methylene of the chain gives a triplet. (20) Hall, D. M.; Harris, M. H. J. Chem. Soc. 1960, 490-494. (21) Vo¨gtle, F.; Bronbach, D. Chem. Ber. 1975, 108, 1682-1693.

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Figure 5. Cross-peaks (dashed line) between the aromatic proton signals and R and δ proton signals of the proline ring in 2D ROESY spectra (run at 600.13 MHz) of (a) a D2O solution 0.10 M in 1 and 0.010 M in 2 and (b) a D2O solution 0.10 M in 1 and 0.020 M in 2.

tion, as we recently observed22 in an analogous investigation with a chiral cationic surfactant. We did not measure the binding constant of compound 2 with the chiral aggregates, but considering that under these conditions of ionic strength and pH (the spontaneous pH of the aqueous solution of chiral surfactant is 9), the cmc should not vary from 2.8 × 10-5 M measured in 0.10 M aqueous NaOH; the maximum amount of free monomer we may expect is ∼0.3% of the total. We believe that the association is due to a combination of Coulombic, hydrophobic, and (22) Borocci, S.; Erba, M.; Mancini, G.; Scipioni, A. Langmuir 1998, 14, 1960-1962.

specific interactions. Comparison23 of the two spectra reported in Figure 2 indicates a large chemical shift variation that may depend on the different state of charge of 2, on a different dihedral angle between the two aromatic rings under aggregating and nonaggregating conditions, and of course on specific interactions with the headgroups of the chiral surfactant. In the 1H NMR spectrum of the chiral amidic surfactant (23) The reasonable use of D2O in both solutions was not possible becaue of the insolubility of 2 in neutral water and of the formation of aggregates under higher pH conditions; in this second case the vicinity of aromatic headgroups causes an upfield shift of all signals and overlapping of some of them.

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Figure 6. Details of the 2D ROESY spectrum (run at 600.13 MHz) of a D2O solution 0.10 M in 1 and 0.020 M in 2 showing cross-peaks (dashed line) between the signal relative to protons in the 4′ and 6′ positions of the biphenylic compound and the R and δ proton signals of the proline ring. Table 1. Evaluation of the Dihedral Angle O, Defined by the Planes of the Two Aromatic Rings, on the Basis of the Chemical Shift Difference between the 4′ and 6′ Positions ∆δ(H4-H6) (ppm)

φ (deg)

0 0.09-0.33 0.5-0.8

90 45-60 0

in the presence of the biphenylic derivative we observed an upfield shift of the signals relative to the Z isomer protons (RZ and δZ proton signals) with respect to the spectrum of the surfactant performed in the absence of the solute (Figure 3a); this finding indicated a shielding of the Z isomer protons due to a selective interaction with the aromatic solute. Analogous to the 2D ROESY spectra, signals relative to the aromatic protons show cross-peaks only with the signals of the Z isomer protons, indicating the vicinity of the aromatic solute with this isomer of the surfactant; this means that the biphenylic system recognizes the stereochemical information of the amidic surfactant and binds selectively to the Z isomer. The different packing of the two geometrical isomers seems to influence deeply the binding of the biphenylic solute. Other evidence of the 2D ROESY experiments concerns the different intensities of the cross-peaks between the diastereomeric aromatic signals and RZ and δZ proton signals. In Figure 5 it is evident that the signals corresponding to the diastereomeric aromatic protons in the 6′ and 4′ positions have cross-peaks of different intensities with the RΖ and δΖ proton signals of the proline ring. The difference in intensity corresponds to a different position of the two enantiomeric biphenylic molecules relative to the R and δ protons of the proline ring. The different intensities of the cross-peaks show, for example, that the R proton has a stronger interaction with the 6′ position of one of the enantiomers (7.215 ppm) and that the δ protons have a stronger interaction with the other one (7.225 ppm). Similar evidence is observed as far as the

protons relative to the 4′ position of the enantiomeric compounds are concerned. Because of the correlation time of our systems, we were forced to use ROESY rather than NOESY experiments24 in order to increase the intensity of cross-peaks; this choice allowed us an easy identification24 of the cross-peaks due to spin diffusion. The increasing extent of spin diffusion corresponding to the presence of a higher concentration of biphenylic compound is evidence in favor of the formation of larger and more organized aggregates. In fact it is known25 that in micelles and other polymolecular aggregates spin diffusion may raise and that it is higher for slower correlation times. Conclusions The micelles formed by the chiral amidic surfactant sodium N-dodecanoyl-L-prolinate 1 show an organization on the basis of the E/Z stereochemical information into separate domains.7 The additional findings of this investigation, namely, chiral discrimination of the racemic mixture of 2-carboxy-2′dodecyloxy-6-nitrobiphenyl, 2, and selective binding of compound 2 to one of the isomeric domains of the amidic surfactant, are a demonstration of a high degree of organization in the molecular aggregates. It is clear that specific interactions are responsible for the selective binding to the Z isomer domains and for the different locations of the biphenylic enantiomers inside the chiral aggregate. The presence of the biphenylic solute increases the high extent of organization of the aggregates formed by the chiral amidic surfactant; in fact, according (24) (a) Frenkiel, T. A. In NMR of Macromolecules: A Practical Approach; Roberts, G. C. K., Ed.; Oxford University Press: Oxford, 1993; Chapter 3, pp 57-70. (b) Brown, L. R.; Farmer, B. T., II. In Methods in Enzymology, Nuclear Magnetic Resonance; Part A; Oppenheimer, N. J.; James, T. L., Eds.; Academic Press: San Diego, 1989; Vol. 176, pp 199-216. (25) (a) Neuhaus, D.; Williamson, M. P. The Nuclear Overhauser Effect in Structural and Conformational Analysis; VCH: New York, 1989; Chapter 3. (b) Bonaccio, S.; Capitani, D.; Segre, A. L.; Walde, P.; Luisi, P. L. Langmuir 1997, 13, 1952-1956.

Recognition in Organized Aggregates

to the spin diffusion data, the selective binding to one of the geometrical domains induces more organized aggregates. The evaluation of the rotational barrier by dynamic NMR, taking into account the limitations due to the many approximations characteristic of this methodology,8 yielded a value in good agreement with that reported,13,20 which was calculated on the basis of the racemization rate. According to our results, the binding to an organized environment does not yield a substantial variation in the rotational barrier. We believe that the evaluation of a possible difference in the dihedral angle under aggregating and nonaggregating conditions can be judged in the sense of a preferential geometrical and stereochemical packing. We believe that these results are the starting point for formulating a model of the supramolecular organization involved in the overall packing with the support of further NMR experiments and molecular dynamics calculations.

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The fundamental result of our work is indeed the finding of a high extent of organization in molecular aggregates, micelles, which are generally considered as disordered entities and which are supposed to be among the less organized systems of molecular assemblies.26 Acknowledgment. We are grateful to Dr. Anna Laura Segre for helpful discussions, and we are indebted to Servizio NMR of the Istituto di Strutturistica Chimica, G. Giacomello, CNR, Area della Ricerca di Roma for the NMR experiments run at 600.13 MHz. LA990277G (26) Menger, F. M.; Ding, J. Angew. Chem., Int. Ed. Engl. 1996, 35, 2137-2139.