Crystal Structures of Inclusion Complexes of P-Cyclodextrin with (S

J , A m . Chem. Soc. 1988, 110, 4379-4391

4379

Crystal Structures of Inclusion Complexes of P-Cyclodextrin with (S)-( )- and (I?)-( -)-Fenoprofen

+

Jean A. Hamilton* and Longyin Chen Contribution f r o m the Department of Biochemistry. Indiana Unicersity School of Medicine, Indianapolis, Indiana 46223. Receiued April 9, I987

Abstract: The crystal structures of the inclusion complexes of P-cyclodextrin (0-CD, cycloheptaamylose) with ( S ) - ( + ) - and (R)-(-)-fenoprofen [FP, 2-(3-phenoxyphenyl)propionic acid] have been determined by X-ray diffraction techniques. The complexes crystallize in space group P2, with cell dimensions as follows. (R)-(-) complex: a = 15.259 (16) A, b = 32.759 (44) A, c = 15.353 (11) A; @ = 101.53 ( 1 ) O . ( S ) - ( + )complex: a = 15.310 ( 3 ) A, b = 32.124 ( 7 ) A. c = 15.277 ( 3 ) A; LI = 100.76 (1)O. I n the crystal the 0-CD molecules exist as a head-to-head dimer by means of extensive hydrogen bonding across the secondary hydroxyl ends of two symmetry-independent p-CD molecules. One guest molecule is included in the cavity of each (3-CD monomer. Although the p-CD is isomorphous in both complexes, the two independent guest molecules of the S complex pack in a parallel, or head-to-tail, arrangement while those of the R complex pack in an antiparallel, or head-to-head, manner. One of the carboxylic acid groups of the (S)-FP, which is located in the p-CD dimer interface, forms hydrogen bonds with secondary hydroxyl oxygen atoms from 8-CD molecules, while the other one, which protrudes from the p-CD dimer, forms a hydrogen bond with a primary hydroxyl oxygen from a neighboring 0-CD dimer. In the (R)-FP complex, both carboxylic acid groups form hydrogen bonds with water alone. These water molecules are not present in the (S)-FP complex. Fenoprofen is a nonsteroidal antiinflammatory drug. Recent studies have shown that only the (S)-(+)isomer is pharmacologically active. The different interactions between p-CD with the enantiomeric isomers of FP revealed by the crystal structures help to explain the inhibition of the enzyme cyclooxygenase by (S)-FP alone, as well as the ability of cyclodextrins to act as a racemic resolution phase.

T h e cyclodextrins ( C D ) , also called cycloamyloses and Schardinger dextrins, are cyclic oligosaccharides consisting of 6-1 2 D-glucopyranosyl units, linked by CY-( 1+4)-glycosidic bonds.'** P-Cyclodextrin (p-CD), or cycloheptaamylose, containing seven glucose units with a n inner diameter of 6.5-8.0 A, is one of the most chemically useful cyclodextrins. Cyclodextrins have a "round", slightly conical form with all the secondary hydroxyl, Le., the O(2)-H and O(3)-H groups located on the wider end and all primary hydroxyl groups O(6)-H on the narrower end. The glucose units a r e in the 4Cichair conformation. T h e inner surface of the cavity is dominated by hydrogen atoms and glycosidic oxygen atoms and is thus relatively hydrophobic.* In the crystal structure, the C(6)-0(6) bonds are usually directed away from the center of the cyclodextrin ring,'s2 forming hydrogen bonds with water. They can, however, turn "inward" due to hydrogen bonding between the O(6)-H group and the guest molecule. Intramolecular hydrogen bonds 0(3)-H-0( 2) or O( 3)--H-O(2) exist between the secondary hydroxyl groups of adjacent glucose units (Figure 1). The cyclodextrins have the ability to form inclusion compounds with a variety of molecules that fit inside the CD ~ a v i t y . l - ~The guest molecule is surrounded or encapsulated by C D in the inclusion complex and, as a result, shows advantageous changes in its chemical and physical properties. In particular, drug properties such as stability, solubility, and bioavailability, as well as toxicity, can be improved, and these changes have been intensively investigated. Examples of CD-drug complexes reported include C D with prostaglandins, barbiturates, chemotherapeutics, steroids, and nonsteroid antiinflammatory drugs (NSAID). Many studies of the crystal structures of C D complexes have been reported. The first structure of a 0 - C D complex was reported by Hamilton et al. in 1976.4 Compounds containing meta-substituted phenyl rings have usually resulted in disordered crystal structures when complexed with /3-CD.S Fenoprofen, however, is a meta-substituted phenol derivative that does not show any disorder in the p - C D complexes. (1) Saenger, W. Angew. Chem., I n l . Ed. Engl. 1980, 19, 344-362.

(2) Jones, S. P.; Grant, J . W.; Hadgraft, J.; Parr, Technol. 1984, 30, 213-223. (3) Jones, S. P.; Grant, J. W.; Hadgraft, J.; Parr, Technol. 1984, 30, 263-211. (4) Hamilton, J. A.; Sabesan, M . N.; Steinrauf, L. chem. Biophys. Res. Commun. 1976, 7 3 , 659-664. (5) Hamilton, J. A.; Sabesan, M. N.; Steinrauf, L. 1981, 89, 33-53

G.D. Acta Pharm. G. D. Acta Pharm. K.; Geddes, A . BioK . Carbohydr. Res.

0002-7863/88/ 15 10-4379$01.50/0

Fenoprofen (FP), dl-2-(3-phenoxyphenyI)propionicacid (Figure 2 ) (a-methyl-3-phenoxybenzeneaceticacid), is a nonsteroidal antiinflammatory, antipyretic, analgesic drug developed a t the Lilly Research L a b o r a t ~ r i e s . ~ , 'I t belongs to the group of compounds commonly referred to as the 2-arylpropionic acids. Other members of this group that have been widely studied include ibuprofen, naproxen, ketoprofen, and flurbiprofen.8 The marketed form of fenoprofen is the calcium dihydrate (Nalfon; Eli Lilly CO.). Fenoprofen has a n asymmetric center, which allows the existence of two enantiomers, (I?)-(-) and (S)-(+). Recently, the resolved R and S isomers and the RS racemate of FP were compared in vitro as inhibitors of the fatty acid cyclooxygenase system from human platelets, which is often used to detect drugs that have antiinflammatory activity associated with inhibition of prostaglandin s y n t h e s i ~ . On ~ the basis of 50% inhibition of the system, one isomer was found to be 2 times more active than the racemate and -35 times more active than the other isomer.I0 An X-ray crystallographic study" of FP showed that the absolute configuration of the active isomer is 5'. This present X-ray crystal structure determination was undertaken in order to examine and compare the binding of the optical isomers of FP in the cavity of p-CD. Different interactions were anticipated. The results should be significant in the studies of the pharmacology of fenoprofen as well as in the application of cyclodextrin in chromatography.

Experimental Section ( R ) - and (S)-fenoprofencalcium salts (FPCa) were obtained from the Eli Lilly Co. as white powders. The solubility of the calcium salts in water is about 2.5 mg/mL (pK, 4.5). The FPCa's were each added to a two-layer water-ethyl acetate (EA) (1:3) system. The mixture was adjusted to pH 3-3.5 with HCI. After several cycles of separation and washing with EA, all EA portions were collected and combined. The

(6) Nickander, R.; Marshall, W.; Emmerson, J. L.; Todd, G. C.; McMahon, R.; Culp, H. W. Pharmacol. Biochem. Prop. Drug Subst. 1977, I , 183-21 3. (7) Brogden, R. N.; Pinder, R. M.; Speight, T. M.; Avery, G. S. Drugs 1977. 13. 241-265. (8) Hutt, A. J.; Caldwell, J. J . Pharm. Pharmacol. 1983, 35. 693-704. (9) Appleton, R. A . ; Brown, K. Prostaglandins 1979, 18, 29-33. (10) Rubin, A,; Knadler, M. P.; Ho, P. P. K.; Bechtol, L. D.; Wolen, R. L. J . Pharm. Sei. 1985, 74, 82-84. ( 1 I ) Jones, N . D.; Swartzendruber, J. K., X-ray Crystallography Laboratory Report of Eli Lilly, unpublished results. 1983.

0 1988 American Chemical Society

Hamilton and Chen

4380 J . A m . Chem. SOC.,Vol. 110, No. 13, 1988 -Cyclodextrin O(6'

m

A

J

G' ^,*

m . i

Figure 1. Numbering shceme for @-cyclodextrin. S (+)

- F e nopr

0 Ien

Cl03!

B d

R ( 4 - F e nop r o Ie n

o%o; 2

,CH3

/

C1ZSI

Figure 2. Numbering scheme for ( S ) - ( + ) and (R)-(-)-fenoprofen.

concentration of the FP in EA extracts was measured by U V at 271 nm. The EA was evaporated; the acid fenoprofens thus obtained were oils. 0-CD was dissolved in water, and the solution was mixed with each oil in a molar ratio of 1:3 (0-CD to FP). The mixtures were heated for 2 h in a water bath (50 "C), and on cooling, microprecipitates were formed. The mixtures were refrigerated for 5-7 days, and good crystals in the form of parallelogram plates were obtained for both the R and S complexes. Determination of the unit cell parameters and data collection were done on a Picker four-circle automated diffractometer at -130 to -135 OC using Cu KO radiation. A total of 6571 and 6430 reflections in the range of 5O < 20 < 93O was collected for S and R complexes respectively, corresponding to approximately 1.07-A resolution. The crystals are monoclinic with space group P2,. The asymmetric unit contains two 8-CD monomers and two FP molecules not related by symmetry, i.e., one complex dimer. The crystal parameters are listed in Table I. Structure Determination and Refinement. The structures were solved with data from an isomorphous crystal of the complex of @-CDwith p-ethylaniline, which was in turn solved by single isomorphous replacement using the @-CD-p-iodoaniline complex.12 Atomic coordinates for @-CD(omitting the primary hydroxyl groups) from the @-CD-p-ethylaniline complex were used for the initial structure factor calculations. After several cycles of structure factor calculation followed by Fourier synthesis, the electron density map showed the primary hydroxyl groups of the CD and the two FP guest molecules, as well as the water of crystallization (25 water molecules for the (S)-FP and 28 for the (R)FP). Refinement was carried out using a combination of difference Fourier synthesis and full-matrix and block-diagonal least-squares calculations. During refinement of the anisotropic temperature factors, the amount of CPU time needed, even on a large, fast computer like CDC Cyber 855, was enormous. The huge quantity of parameters and variables [215 and 218 non-hydrogen atoms for the ( S ) - and (R)-FP complexes, respectively] also exceeded the maximum core memory of the computer. The refinement was therefore carried out in a series of partial refinements: Only one P-CD or only guest or water molecules were refined in alternate cycles. The calculated hydrogen positions for the p-CD carbon atoms and guest benzene rings were added after the first cycle of anisotropic refinement. Isotropic temperature factors equal to half of the equivalent isotropic temperature factor of the bonding atom were used for the hydrogen atoms. Many hydrogen atoms were in fact observed on the later difference Fourier maps in positions expected from calculation. The parameters of the hydrogen atoms were refined during the final least-squares calculation and behaved well. During the refinement, only those reflections with F, > 3u(F,) were used. The percentage of reflections with F, > 3u is 97.1% for R and 87.2% for S . In the final (12) Tokuoka. R . ; Fujiwara, T.; Tomita. K . Acra Cryslallogr.,Secr. 8: Srrucf. Crysrallogr.Crysr. Chem. 1981, 8 3 7 , I 1 58-1 160.

Figure 3. ORTEP plot of dimer structure: (A) 0-CD-(R)-FP complex; (B) P-CD-(S)-FP complex. Atoms of guests and waters are shown with thermal motion. Table 1. Crystal Data and Refinement Results for the FP-@-CD Complexes (R)- (-) - FP-C D (S)-(+)-FP-CD complex complex

mol formula mw space group cell parameters a, 8, 6, A

(C42H70035)2' (C42H70035)2' ( C I S H I ~ O ~ ) Y ~ ~ (C,5Hi403)2'2H20 H~O 3222.89 3 186.87 p 21 p2 I

15.26 (2) 15.310 (3) 32.76 (4) 32.124 (7) 15.35 (2) 15.277 (3) c, A 101.5 ( I ) 100.76 (2) @,deg 75 19.63 7381.41 v,A3 1.424 1.441 Dmeasd, mg/mL 2 Z 2 6430 no. of measd reflcns" 6571 6378 (97.1%) 5610 (87.28) F,, 2 3 4 F J 0.08 1 0.106 R (3a) 6526 (99.3%) 6196 (96.4%) F, 2 lu(F,) 0.083 0.113 R (10) "The reflection data were collected at a wavelength of 1.5418 8, (Cu) and temperature of -135 OC. The resolutions are 1.07 A.

cycle of structure factor calculation, a cutoff of I u was used, which resulted in a reflection percentage of 99.3% for R and 96.4% for S. The final R values for reflections with F, > 1 u are 0.083 for R and 0.1 13 for S (Table I).

Results and Discussion General Description. T h e final atomic coordinates for the non-hydrogen atoms are given in Table 11. The numbering scheme uses a three-digit code as follows: The first digit represents the monomer of p-CD or FP molecule, the second represents the individual glucose residues of p-CD or the phenyl rings for FP (0 for ring side-chain atoms), and the third digit represents atoms within the glucose residue or F P molecule as shown in Figures 1 and 2. T h e structure analysis showed that in both complexes a head-to-head p - C D dimer is formed by means of extensive hydrogen bonding across the secondary hydroxyl ends of two adjacent i3-CD monomers, with one guest being included in each of the two p-CD monomer units. For ease of discussion the symmetry-independent (S)-FP molecules will be called S 1 and S2, the symmetry-independent (R)-FP molecules R1 and R2.

Fenoprofen-@- Cyclodextrin Complexes

J . Am. Chem. SOC.,Vol. 110, No. 13, 1988 4381

a

a

b

C

b

C

Figure 4. Stereoview of the space-filling model: (A) P-CD-(R)-FP complex; (B) P-CD-(S)-FP complex. Key: (a) viewed from side; (b) viewed from top; (c) viewed from bottom.

Figures 3 and 4 show ORTEP plots and space-filling plots of these dimer structures. The bond lengths and angles for the p-CD and F P molecules are within expected values. They are available as supplementary material. All D-ghCOSyl residues are in 4C1conformation. In the R complex, all primary hydroxyl groups point away from the cavity and are in the gauche-gauche orientation except one, O( 126), which points in toward the cavity and is in the gauche-trans orientation; in the S complex, there are two primary hydroxyl groups, O( 126) and 0(276), one for each p-CD monomer, which point in toward the cavity. This is to facilitate hydrogen bonding to the guest or water in the primary end of the p-CD. The P-CD Macrocycles. The formation of the p-CD dimer results in an overall more rigid complex structure than in the case of monomeric complexes. For example, motion of the glucose residues about the glucosidic bonds is restricted. Calculation of radial distances from the center of gravity of the /3-CD molecule to each of the sevenfold related atoms of any type shows remarkable uniformity in the case of a spherical guest such as adamantane derivative^.'^ One might expect some tendency toward ellipticity of the p-CD due to the planar benzene rings of the FP, but in fact, the radii show only slightly greater internal deviation than for the adamantane complexes. The average values of the 0(4),-0(4),+, distances (see Table 111) are 4.38 8, (a 0.06) and 4.37 8, (a 0.12) for the S complex and 4.37 8, (a 0.06) and 4.36 8, (a 0.14) for the R complex. These agree with a value of 4.367 f 0.065 8, averaged over several dimer c0mp1exes.l~ The average 0(4),-0(4),+,-0(4),+2 angles (Table 111) are 128.5' (a 2.5) and 128.6' (a 4.2) for the R and 128.6' (a 3.7) and 128.5' (a 5.3) for the S complex. The value is 128.6' for an ideal heptagon.

(13) Hamilton, J. A. Curbohydr. Res. 1985, 142, 21-37.

The glucosidic angles C(4)-0(4)-C( 1)' have average values of 1 18.0' (zt2.9) and 118.0' (zt2.3) for the S complex and 117.4' (zt2.6) and 117.8' (zt1.2) for the R complex. These are in agreement with a value of 117.4 zt 1 .O" averaged over eight independent p-CD structure determination^.'^ These data show that the p-CD molecule (in particular the dimer form) is very consistent as far as the central circle of 0 ( 4 ) , C ( l ) , C(4) atoms are concerned. Packing Scheme. No hydrogen positions were determined experimentally. Hydrogen bonding was analyzed in a distance range of 2.3-3.2 8, and an angle range of 90-1 30'. Tables IV and V list the hydrogen bonds for both complexes. Figure 5 illustrates the hydrogen-bond network stabilizing the complexes. Several structural features are apparent. The intermolecular hydrogen bonds that form the p-CD dimer involve only O(3) hydroxyl groups (Table VI), in contrast to previous crystalline complexes where both O(2) and O(3) hydroxyl groups have taken * ' ~ contact distances in the postulated part in dimer f o r m a t i ~ n . ~The hydrogen-bonding pair O( 123)-O(253) in both complexes are considerably longer than all others. The O(2) hydroxyl groups do form four intermolecular hydrogen bonds; however, their partners are not from the same C D dimer but from other symmetry-related units. The number of hydrogen bonds forming the C D dimer appears to vary with included guest.5J3 Within each /3-CD molecule, intramolecular hydrogen bonding always exists between O(3) and O(2) hydroxyl groups of adjacent glucose residues. The intramolecular hydrogen-bond lengths are listed in Table VII. They are more varied in length for the S complex. This is due to interaction of (S)-FP with the secondary hydroxyl groups of CD, as will be discussed later. The carbonyl oxygen and hydroxyl oxygen in the carboxylic acid group can be differentiated on the basis of bond length (Table VIII). Thus, for both (R)-and (S)-FP, O(101G) and O(201G) are carbonyl oxygen atoms, while O(102G) and O(202G) are hydroxyl oxygen

Hamilton and Chen

4382 J . Am. Chem. SOC.,Vol. 110, No. 13, 1988 Table 11. Fractional Coordinates (X104) and Isotropic Temperature Factors (X102) of the Non-Hydrogen Atoms of (5’)-(+)-FP-P-CD Complexes’ (5’)-(+)-FP-6-CD ( R )- (-) - FP-P-CD complex atom X V z U X V CD 1 1.53 -3546 (12) 5711 (3) 1702 (6) 5735 (7) -3562 (6) C(111) -4107 (12) 2.68 1145 (7) 5406 (6) -4125 (7) 5383 (3) C(112) 2.02 -4010 (13) 185 (7) 5422 (7) -4004 (7) 5408 (3) C(113) -4281 (12) 5851 (6) 5831 (4) 2.83 -183 (8) -4300 (7) C(114) 2.95 -3756 (12) 6188 (6) 422 (8) 6163 (4) -3786 (8) C(ll5) -4150 (15) 6615 (7) 204 (7) 2.41 6585 (3) -4091 (7) C(116) 2.89 -3886 (8) 5010 (4) 4997 (2) 1504 (5) -3924 (5) O(112) -4567 (8) 2.58 5107 (4) 5099 (2) -323 (5) -4552 (5) O(113) -4162 (9) 1.74 5881 (4) 5865 (2) -1058 (4) -4124 (4) O(114) -3808 (9) 6105 (2) 1338 (5) 2.47 6134 (4) -3808 (5) O(115) -5016 (9) 6641 (2) 3.17 6656 (4) 340 (5) -4967 (5) O(116) -1760 (7) -4813 (11) 2.74 6030 (6) 6019 (3) -4838 (7) C(121) 2.96 -2451 (9) -5045 (10) 5698 (4) 5679 (5) -5044 (8) C(122) -4242 (14) 2.87 5627 (6) -4240 (9) -2892 (8) 5634 (4) C( 123) 2.29 6020 (6) -3221 (7) -3909 (1 1) 6034 (3) -3918 (8) C( 124) 3.42 6344 (5) -3762 (8) -2462 (8) -3793 (1 1) 6345 (4) C(125) -2799 (9) -3618 (14) 6784 (4) 3.31 6790 (6) -3594 (9) C(126) -5295 (9) 5327 (2) 3.08 5312 (4) -5308 (5) -2091 (5) O(122) -4408 (8) 3.1 1 5326 (4) -4432 (6) -3559 (5) 5333 (2) O( 123) -3091 (8) 2.7 1 5958 (4) -3074 (5) -3471 (4) 5963 (3) O( 124) 2.60 -4587 (8) -2076 (5) 6385 (2) 6390 (4) -4570 (5) O( 125) 4.18 7066 (4) -3288 (10) -3249 (6) -2051 (6) 7039 (3) O(126) 6033 (6) -2954 (13) 2.12 6032 (3) -2996 (7) -4377 (6) C(131) 5639 (6) -2606 (1 3) 3.60 -4694 (7) -2671 (8) 5644 (4) C( 132) 5532 (6) -1724 (12) 2.80 -4167 (7) -1732 (8) 5534 (3) C( 133) 5904 (6) -1097 (13) 2.69 -1125 (8) 5892 (4) -4215 (7) C(134) -1463 (7) 6286 (3) -3911 (8) 6310 (5) -1434 (11) 2.69 C(135) -4112 (8) -904 (13) 6652 (4) 6660 (6) 4.51 -923 (10) C( 136) -4696 (5) -3245 (8) 5319 (2) 5317 (4) 3.56 -3267 (5) O( 132) 3.54 -1375 (9) -1453 (6) -4526 ( 5 ) 5170 (2) 5133 (4) O(133) -3614 (5) -241 (8) 5793 (2) 5798 (4) 2.86 -283 (5) O( 134) -2357 (9) 6363 (4) -2384 (5) -4400 (5) 6362 (2) 2.95 O(135) -873 (10) 6693 (4) -922 (7) -5038 (7) 6674 (3) 5.80 O( 136) 529 (7) 525 (11) 5871 (6) -3921 (7) 5829 (3) 2.63 C(141) 994 (9) 994 (1 1) 5445 (5) -3887 (8) 5447 (4) 3.83 C(142) -2884 (7) 1299 (13) 5329 (6) 5301 (4) 2.73 1278 (8) C(143) -2410 (8) 5656 (6) 2.47 1862 (8) 1883 (13) 5647 (3) C(144) 1359 (11) -2513 (9) 1363 (12) 6065 (6) 6044 (4) 4.93 C(145) 6434 (7) 6408 (4) 4.18 -2115 (10) 1940 (10) 2004 (17) C(146) 5172 (4) 3.21 -4362 (5) 435 (5) 466 (9) 5137 (2) O(142) 3.40 4934 (2) -2846 (5) 1783 (5) 1787 (7) 4929 (4) O(143) 5551 (2) -1480 ( 5 ) 2105 (7) 5541 (4) 2.56 O(144) 2103 (5) 6151 (2) -3420 (5) 6171 (4) 3.70 O(145) 1086 (6) 1047 (8) 2761 (10) 6437 (3) 6465 (5) 5.91 -2378 (8) O(146) 2773 (7) 1.91 -1092 (7) 3014 (13) 5540 (7) 5536 (3) 3045 (6) C(151) -687 (9) 5111 (5) 3195 (11) 5113 (3) 3236 (8) 3.72 C(152) 5046 (3) 2.28 2705 (7) 2689 (1 1) 5064 (6) C(153) 72 (7) 2950 (8) 2923 (12) 724 (7) 5401 (4) 2.67 5431 (5) C( 154) 2810 (7) 2858 (11) 5846 (6) 305 (9) 5822 (4) 3.70 C(155) 6169 (3) 3160 (7) 3220 (12) 6189 (6) 886 (8) 2.42 C( 156) -1318 (6) 3021 (5) 2963 (8) 4808 (2) 3.30 4781 (3) O( 152) 529 (6) 4684 (3) 3.26 4688 (4) O(153) 2966 (8) 2982 (5) 3.12 5405 (4) O( 154) 2363 (7) 1344 (5) 2343 (5) 5354 (2) -444 (5) 5860 (4) 3274 (8) 3260 (4) 5838 (2) 2.35 O(155) 1314 (5) 4129 (8) 6132 (4) 6106 (3) 3.17 O( 156) 4095 (5) 2724 (12) 2.87 2257 (8) C(161) 2716 (8) 5415 (7) 5367 (3) 2453 (12) 4972 (4) 2.55 2384 (7) 2674 (8) C( 162) 5007 (6) 1454 (11) 1400 (7) 2553 (7) C(163) 5020 (6) 4996 (3) 1.80 1151 (7) 5375 (3) 1135 (12) 2974 (7) C(164) 5417 (6) 1.35 1518 (15) 1523 (8) 2601 (8) C(165) 5806 (6) 5748 (4) 3.06 1368 (9) 3047 (9) 1406 (15) C(166) 6194 (7) 6148 (4) 4.14 2690 (5) 4621 (3) 3.14 O( 162) 2279 (5) 2739 (9) 4649 (4) O(163) 2999 (6) 1119 (8) 11 14 (5) 4665 (4) 4639 (2) 3.1 1 179 (5) 5428 (3) 2.97 O(164) 2790 (5) 173 (7) 5461 (4) O(165) 2694 (5) 2458 (8) 2466 (5) 5710 (2) 3.24 5767 (4) 6127 (3) 4.91 3980 (6) O( 166) 1728 (9) 1756 (6) 6180 (5) 3498 (8) -262 (8) 5452 (4) 3.11 C(171) -294 (12) 5487 (6) C(172) -968 (12) -955 (7) 5113 (4) 3.08 3406 (8) 5137 (6) -1638 (8) 2556 (7) 5165 (4) 2.59 C(173) -1625 (11) 5172 (6) -2075 (8) 5572 (3) 2.25 C(174) -2078 (12) 2560 (7) 5582 (6) -1358 (12) 2671 (7) -1382 (7) 5907 (4) 3.33 C(175) 5955 (6) C(176) -1820 (11) -1789 (8) 6358 (5) 6332 (4) 2.45 2807 (7) -498 (5) 2.76 O(172) -530 (9) 3459 (5) 4728 (4) 4722 (2)

the (I?)-(-)- and complex z

U

1632 (12) 1040 (13) 103 (11) -248 (1 1) 349 (12) 66 (13) 1482 (8) -394 (8) -1143 (8) 1236 (8) 223 (7) -1786 ( I O ) -2576 (10) -2974 (14) -3319 (13) -2585 (13) -2918 (13) -2182 (8) -3638 (9) -3549 (7) -2192 (8) -2172 (8) -4435 (13) -4777 (14) -4178 (12) -4278 (12) -3900 (1 1) -4106 (17) -4816 (8) -4427 (10) -3637 (8) -4477 (9) -5007 (10) -3988 (1 3) -3936 (12) -3006 (1 2) -2482 (15) -2556 (13) -2098 (15) -4439 (9) -2922 (8) -1571 (8) -3500 (8) -2480 (10) -1142 (15) -730 (10) 27 (13) 640 (12) 252 (13) 795 (12) -1360 (8) 507 (8) 1300 (7) -537 (8) 1197 (8) 2242 (13) 2651 (13) 2562 (13) 2937 (14) 2539 (14) 3065 (1 3) 2284 (10) 2968 (8) 2721 (7) 2667 (10) 3988 (9) 3435 (12) 3319 (14) 2470 (1 1) 2462 (12) 2577 (11) 2769 (12) 3399 (9)

2.97 2.80 3.09 1.88 2.41 4.12 2.33 2.23 3.19 3.10 3.13 1.57 0.76 3.33 2.26 2.10 3.46 3.01 2.93 1.86 2.72 3.12 3.19 3.68 2.32 2.81 1.49 4.04 2.69 3.79 2.55 4.07 4.15 2.02 1.72 2.74 3.33 3.08 5.OO 3.13 2.35 2.19 2.89 4.61 4.27 1.22 2.29 1.96 2.45 2.90 2.06 2.60 2.18 2.32 3.09 3.24 2.54 2.14 2.92 3.64 4.28 4.40 2.95 1.80 3.94 4.22 2.38 2.80 2.32 2.02 2.41 1.73 3.50

J . A m . Chem. SOC.,Vol. 110, No. 13, 1988 4383

Fenoprofen-P- Cyciodextrin Complexes Table I1 (Continued) atom O(173) O( 174) O( 175) O(176)

-2277 -2671 -706 -2224

C(211) C(212) C(213) C(214) C(215) C(216) O(212) O(213) O(214) O(215) O(216) C(221) C(222) C(223) C(224) C(225) C(226) O(222) O(223) O(224) O(225) O(226) C(231) C(232) C(233) C(234) C(235) C(236) O(232) O(233) O(234) O(235) O(236) C(241) C(242) C(243) C(244) C(245) C(246) O(242) O(243) O(244) O(245) O(246) C(251) C(252) C(253) C(254) C(255) C(256) O(252) O(253) O(254) O(255) O(256) C(261) C(262) C(263) C(264) C(265) C(266) O(262) O(263) O(264) O(265) O(266) C(271) C(272) C(273) C(274)

-199 (7) 512 (7) 915 (6) 1296 (6) 604 (7) 969 (10) 117 (4) 1624 (5) 1550 (4) 182 (4) 1736 (6) 2426 (6) 2821 (7) 2259 (8) 2280 (7) 1969 (7) 21 10 (6) 2861 (5) 2609 (5) 1650 (4) 2463 (5) 3023 (5) 1942 (7) 1925 (8) 909 (8) 421 (8) 496 (8) 55 (9) 2419 (5) 867 (5) -525 (5) 1427 (4) 390 (6) -864 (8) -1290 (9) -2037 (7) -2697 (7) -2250 (7) -2846 (8) -655 (5) -2495 (5) -3345 (5) -1485 (5) -3191 (6) -4260 (7) -4640 (7) -4522 (8) -4981 (7) -4636 (8) -5116 ( I O ) -4266 (5) -4973 (5) -4757 (4) -4704 (5) -6053 (6) -5462 (7) -5408 (7) -4520 (8) -4569 (7) -4651 (7) -4792 (7) -5489 (5) -4438 (5) -3664 (4) -5442 (4) -5546 (5) -3651 (8) -3135 (7) -2158 (7) -1801 (7)

X

(5) (5) (5) (5)

(R)-(-)-FP-P-CD Y 4834 (2) 5625 (2) 5844 (2) 6332 (2) 3159 (3) 3498 (4) 3550 (3) 3148 (3) 2825 (3) 2408 (4) 3853 (2) 3854 (2) 3220 (2) 2795 (2) 2312 (3) 3142 (3) 3530 (4) 3627 (4) 3281 (4) 2880 (3) 2513 (4) 3852 (2) 3990 (2) 3382 (2) 2813 (2) 2488 (2) 3317 (4) 3720 (3) 3855 (4) 3511 (3) 3125 (3) 2768 (4) 4017 (2) 4232 (2) 3628 (2) 3016 (2) 2716 (3) 3621 (4) 4039 (4) 4097 (4) 3754 (3) 3346 (3) 2975 (4) 4369 (2) 4479 (2) 3791 (2) 3313 (2) 3016 (3) 3806 (4) 4192 (4) 4147 (3) 3775 (3) 3398 (3) 3017 (4) 4555 (2) 4515 (2) 3726 (2) 3457 (3) 3064 (3) 3684 (3) 4000 (3) 3967 (4) 3553 (4) 3213 (4) 2801 (3) 4410 (2) 4281 (2) 3496 (2) 3295 (2) 2797 (3) 3404 (4) 3741 (3) 3729 (3) 3306 (3)

complex z

U

2499 (6) 1718 (4) 3496 (5) 3565 (5)

3.45 2.51 2.95 3.72

2916 (8) 3123 (9) 2299 (6) 2040 (6) 1898 (7) 1754 (11) 3362 (4) 2485 (5) 1185 (5) 2679 (5) 2501 (6) 1107 (7) 739 (8) -161 (9) -766 (7) -410 (8) -911 (7) 1384 (5) -474 (5) -1575 (4) 494 (5) -1055 (5) -2370 (8) -2858 (7) -3174 (8) -3716 (7) -3207 (8) -3710 (9) -2329 (5) -3689 (5) -4022 (5) -2891 (5) -4541 (6) -4961 (7) -5203 (7) -4740 (7) -4946 (7) -4766 (7) -5105 (7) -4996 ( 5 ) -4985 (5) -4374 (5) -5198 (5) -6071 (6) -4756 (7) -4388 (7) -3403 (7) -3145 (7) -3602 (7) -3433 ( I O ) -4687 (5) -3078 (5) -2232 (5) -4501 (5) -3751 (6) -1738 (8) -1068 (7) -409 (9) 35 (7) -677 (7) -285 (7) -1476 (5) 278 (5) 638 (5) -1349 (5) 148 (5) 1517 (9) 2103 (7) 2007 (7) 2249 (7)

CD 2 2.66 3.50 1.76 2.00 2.40 5.99 2.19 3.66 2.85 2.80 5.17 2.9 1 3.32 4.00 2.85 2.36 2.90 3.29 3.44 2.51 2.77 4.06 3.30 2.91 3.63 2.81 3.33 4.27 3.47 3.09 3.04 2.81 5.38 2.69 3.49 2.73 2.42 2.47 3.08 3.68 3.23 3.53 3.17 4.97 2.83 2.88 2.82 2.80 2.81 5.39 3.19 3.14 2.46 3.99 5.17 2.85 2.54 3.67 2.68 3.19 2.53 3.01 3.28 2.73 2.68 3.23 4.01 2.09 2.74 2.10

X

-2270 -2635 -750 -2248

(8) (8) (8) (8)

-215 (14) 444 (12) 884 (12) 1282 (13) 589 (15) 980 (15) 98 ( I O ) 1594 (7) 1549 (10) 138 (7) 1678 (10) 2450 (12) 2805 ( 1 3) 2310 (12) 2200 (1 1) 1962 (14) 2195 (18) 2885 (10) 2612 (8) 1650 (9) 2441 (7) 3082 (9) 1909 (17) 1911 (13) 897 (14) 402 (1 4) 449 (1 8) -36 (18) 2413 (8) 903 (8) -510 (8) 1339 (9) 248 (17) -833 (12) -1259 (13) -2058 (12) -2685 (13) -2213 (12) -2734 (1 3) -606 (9) -2527 (8) -3321 (9) -1444 (8) -3074 (1 0) -4252 (14) -4647 (1 4) -4566 (12) -4975 (13) -4512 (10) -4926 (15) -4336 (9) -5042 (9) -4749 (7) -4623 ( I O ) -5778 (13) -5495 (1 4) -5385 (14) -4604 (14) -4523 (13) -4681 (12) -4804 (1 3) -5492 (8) -4469 (8) -3677 (7) -5480 (8) -5534 (7) -3648 (1 1) -3179 (14) -2167 (14) -1833 (13)

(S)-(+)-FP-P-CD Y 4832 (4) 5646 (4) 5872 (4) 6346 (4) 3173 (6) 3512 (7) 3545 (6) 3138 (6) 2820 (7) 2366 (6) 3888 (4) 3866 (4) 3187 (4) 2776 (4) 2302 (4) 3102 (7) 3499 (6) 3646 (6) 3247 (6) 2862 (7) 2484 (7) 3807 (4) 3970 (4) 3383 (4) 2776 (4) 2489 (4) 3313 (8) 3696 (7) 3851 (6) 3500 (6) 3094 (7) 2753 (8) 4014 (4) 4224 (4) 3632 (4) 2977 (4) 2667 (6) 3635 (6) 4049 (7) 4093 (6) 3753 (8) 3325 (6) 2931 (6) 4384 (4) 4466 (4) 3786 (4) 3299 (4) 2941 (5) 3789 (7) 4144 (6) 4145 (6) 3740 (6) 3363 (5) 2945 (9) 4529 (4) 4489 (4) 3696 (4) 3401 (4) 2927 (5) 3670 (6) 3998 (6) 3995 (6) 3548 (7) 3217 (5) 2790 (7) 4410 (3) 4297 (4) 3509 (4) 3274 (4) 2776 (4) 3371 (6) 3689 (6) 3734 (6) 3282 (5)

complex z

U

2378 (9) 1639 (8) 3405 (7) 3523 (8)

3.25 3.12 2.43 2.48

2787 (13) 2999 (13) 2201 (13) 1945 (15) 1905 (17) 1833 (15) 3231 (10) 2391 (8) 11 13 (8) 2634 (8) 2531 (9) 1087 (13) 672 (15) -212 (13) -809 (12) -496 (21) 1007 (15) 1357 (9) -521 (8) -1621 (8) 424 (8) -1151 (8) -2407 (17) -2955 (14) -3251 (15) -3777 (12) -3220 (1 7) -3664 (23) -2423 (8) -3786 (8) -4085 (8) -2934 (9) -4512 (15) -4995 (14) -5301 (14) -4832 (12) -5050 (12) -4855 (12) -5140 (15) -5059 (9) -5155 (9) -4482 (8) -5233 (8) -6097 (10) -4818 (13) -4556 (15) -3487 (12) -3236 (13) -3627 (10) -3424 ( 1 4) -4822 (8) -3232 (8) -2295 (8) -4568 (9) -3815 (11) -1838 (11) -1150 (11) -522 (12) -19 (17) -796 (11) -355 (15) -1578 (9) 177 (8) 517 (8) -1448 (8) 150 (8) 1405 (13) 2019 (11) 1910 (13) 2148 (12)

2.38 2.50 2.76 3.20 3.11 3.94 3.77 2.13 3.15 1.79 3.44 2.04 3.56 2.63 2.62 4.93 3.89 4.11 2.01 2.97 1.46 2.00 5.52 2.87 3.45 2.34 4.16 6.22 3.02 1.85 1.80 2.37 10.42 3.83 3.15 2.60 3.27 2.12 3.57 2.72 2.59 2.86 2.84 3.92 3.75 3.51 1.49 2.56 0.63 3.35 3.39 2.12 1.87 4.50 7.72 2.24 2.16 1.91 4.96 1.09 2.95 2.39 1.95 1.90 2.22 1.98 2.10 2.31 2.67 1.60

Hamilton and Chen

4384 J . Am. Chem. SOC.,Vol. 1 IO, No. 13, 1988 Table I1 (Continued)

(R)-(-)-FP-P-CD complex atom C(275) C(276) O(272) O(273) O(274) O(275) O(276)

-2347 -2065 -3554 -1663 -876 -3266 -2157

O(OO1W) O(002W) O(003W) O(004W) O(005W) O(006W) O(007W) O(008W) O(009W) O(Ol0W) O(O11W) O(012W) O(013W) O(014W) O(015W) O(0 16W) O(017W) O(Ol8W) O(019W) O(020W) O(02lW) O(022W) O(023W) O(024W) O(025W) O(026W) O(027W) O(028W)

2620 (9) -4318 (10) -6070 (6) 2687 (15) 3990 (21) 851 (19) -3985 (6) 3580 (8) 4653 (7) -4092 (8) -5962 (8) -6680 (9) 1699 (12) -5412 (7) -5689 (7) -3855 (6) 3129 (10) 3157 (9) 1520 (16) 4584 (7) -6335 (1 1) -4982 (7) -7347 (IO) 3254 (6) -5249 (6) -573 (8) 1961 (7) -5286 (7)

X

(9) (10) (5) (4) (4) (5)

(7)

(S)-(+)-FP-P-CD complex

U

Y

Z

2981 (4) 2547 (5) 4111 (3) 4024 (2) 3294 (2) 3015 (2) 2541 (3)

1747 (9) 2047 (14) 1908 (5) 2598 (4) 2145 (4) 1772 (6) 3124 (6)

4.10 7.50 3.60 2.56 2.57 3.51 6.29

7201 (5) 6957 (5) 6912 (3) 6863 (7) 6800 (12) 6714 (8) 6501 (4) 6044 (4) 5941 (3) 5324 (3) 5227 (4) 5188 (6) 4721 (6) 4657 (4) 4635 (4) 4481 (3) 4342 ( 5 ) 3981 (4) 3937 (8) 3789 (4) 3149 (5) 3034 (4) 2521 (7) 2479 (3) 2446 (3) 2342 (3) 2321 (3) -1963 (3)

-235 (12) 4948 (9) -1184 (7) -3884 (13) -4694 (29) -5302 (1 5) 3516 (6) 4404 (8) 3100 (7) -6368 (7) -4983 (8) -3463 (9) -5123 (12) 1844 (8) -6278 (8) 3439 (6) -3667 (1 1) 3910 (10) 4746 (16) 2392 (9) -5725 (1 1) -6843 (8) -5767 (8) -2785 (6) 1753 (7) -5959 (9) -4326 (7) -2138 (7)

Water 11.16 9.46 5.00 14.74 28.37 11.82 6.10 7.24 5.56 6.46 6.86 8.56 14.30 7.39 5.65 5.33 1 1.06 9.62 4.76 7.35 10.53 4.81 11.35 4.80 5.68 3.70 5.35 3.56

Y

X

-2320 -2031 -3592 -1720 -881 -3224 -2496

(121 (i6j (8) (8) (8) (8) (9)

2990 2536 4103 4016 3302 2973 2282

1521 (13) 1569 (16) 1819 (9) 2534 (9) 2045 (8) 1577 (9) 876 (IO)

U 2.17 3.92 3.39 2.5 1 1.57 2.44 3.88

Z

(6) (7) (5) (4) (4) (4)

(5)

-4378 (25) -6035 (8) 2509 (18) 4081 (32) 934 (15) -3996 (8) 3612 (12) 4705 (1 1) -4136 (11) -5942 (12) -6614 (14) 1659 (13) -5398 (10) -5702 (1 1) -3923 (11) 3080 (12) 3188 (12)

7096 (12) 6936 (4) 7051 (8) 6756 (16) 6828 (6) 6627 (5) 6071 (6) 6026 ( 5 ) 5367 (5) 5250 (5) 5149 (8) 4730 (6) 4660 (7) 4650 (6) 4482 (5) 4294 (7) 3696 (5)

4914 (20) -1342 (9) -3815 (14) -4565 (27) -5240 (14) 6490 (10) 4342 (10) 2999 (9) -6466 (8) -5052 (10) -3537 (15) -5187 (12) 1725 (13) -6340 (11) 3310 (10) -3863 (15) 3837 (11)

17.44 3.44 10.08 20.89 9.87 5.28 6.04 5.82 5.03 5.16 9.04 8.05 5.65 7.10 5.82 8.88 7.59

4525 (13) -6284 (22) -4840 (10) -7533 (18) 3307 (11) -5275 (8) -630 (30) 1888 (11)

3777 (6) 3156 (9) 3052 (5) 2614 (8) 2413 (5) 2473 (4) 2335 (11) 2353 (6)

2309 (14) -5791 (18) -6800 (1 1) -5843 (16) -2836 (12) 1809 (9) -6076 (25) -4343 ( I O )

8.30 13.20 6.16 14.76 6.53 3.50 7.16 5.70

Guests* 6.04 676 (9) 1348 (6) 6636 (3) 7300 (5) 4.78 O( 101G) 861 (8) -1 (9) -442 (6) 6.77 1630 (9) 917 (6) 6963 (3) 6789 (4) 4.70 -88 (9) O(102G) 226 (9) 207 (14) 4.71 922 (13) 757 (9) 6732 (4) 3.86 6956 (8) C( 101G) 125 (20) 6894 (8) 1078 (10) 1520 (16) 6.00 -418 (9) 6583 (4) 6.14 C(103G) 4.74 513 (12) 6644 (7) 774 (11) -221 (8) 6643 (4) 8.58 185 (7) C( 102G) -184 (15) 6412 (7) 138 (14) 3.55 6261 (4) 6.81 -431 (8) -388 (7) C(111G) -83 (14) 3.56 5906 (4) 6043 (8) -122 (17) -198 (7) 5.83 C( 1 12G) 97 (7) 4.67 -778 (14) -124 (8) 5831 (7) -695 (14) 4.75 5567 (4) C(113G) -705 (9) -1047 (18) -1431 (17) -1439 (8) 4.61 5552 (4) 6025 (8) -823 (8) 3.20 C( 114G) -1354 (9) -1664 (22) 5.64 5900 (5) -817 (18) -1608 (9) 6422 (9) 3.17 C(115G) -1012 (21) 6256 (4) -202 (20) -1174 (9) -1108 (8) 6590 (8) 6.64 C(116G) 4.65 -500 (6) -451 (14) 5.51 5213 (2) O( 1OOG) 427 (5) 5460 (7) -1178 (13) 3.37 -60 (7) -186 (18) 3.39 4898 (3) C(121G) 5109 (7) -615 (15) 6.61 92 (7) 545 (8) 377 (18) 4.97 4528 (4) C( 122G) 4841 (8) -982 (14) 6.90 40 (8) 226 (8) 647 (17) 5.55 4208 (4) 446 (9) 4493 (11) C(123G) -526 (23) 6.68 4.45 4266 (4) -533 (8) 4427 (10) 427 (21) 558 (20) 834 (8) C( 124G) 8.90 -971 (8) 764 (8) -50 (20) 5.90 4627 (5) 705 (18) 4747 (10) C(125G) 6.28 303 (8) -387 (17) 4.32 4951 (4) -678 (8) 5090 (9) 234 (17) C( 126G) 6.70 2430 (6) -3267 (11) -2214 (12) 2041 (21) -2550 (21) C(201G) 5.83 7.30 4649 (8) -2818 (15) -2165 (12) -3092 (10) -1316 (14) C(203G) 5.56 7.28 2267 (4) 4609 (7) -2710 (14) -3345 (8) -1479 (9) 8.48 10.60 2471 (4) 4719 (6) -3161 (14) O(201G) -3896 (9) -1211 (11) 9.12 2185 (4) O(202G) 4651 (5) -2761 (9) -2815 (10) 6.94 -2579 (10) -1945 (14) C(202G) 4513 (10) -2638 (13) -1577 (23) 7.22 8.43 2598 (6) -1779 (14) -1904 (14) -1999 (17) -1471 (14) 4.33 10.07 2838 (8) C(211G) 4049 (7) 3254 (7) 2058 (14) -1838 (13) -1997 (15) 5.05 9.32 C(212G) 3731 (8) -2230 (13) 3499 (8) C(213G) -1211 (24) -1682 (19) -1777 (26) 5.78 13.61 -1854 (16) 3344 (7) 3331 (21) -994 (33) -613 (23) -1200 (28) -1048 (41) 3225 (13) C(2 14G) 13.33 19.19 2902 (20) -745 (25) 17.70 -842 (25) -363 ( 2 5 ) -1044 (26) 3547 (11) C(215G) 11.07 -1304 (19) -1386 (21) -581 (14) 2700 (6) -1370 (15) C( 2 16G) 4.64 9.36 3932 (6) 3924 (1 1) -1877 (11) -1026 (27) -1958 (33) O(200G) -2496 (14) 8.25 31.36 3052 (6) -1712 (19) -1929 (12) C(221G) 4188 (5) -2383 (17) 8.45 10.95 2675 (8) -2443 (23) 4567 (6) -2508 (1 1) C(222G) 2401 (9) -3164 (18) -2443 (19) -1968 (13) 7.32 8.30 C(223G) -2270 (9) -2971 (18) 4846 (4) -2515 (9) 7.38 5.43 2071 (9) -3094 (22) -3467 (12) 4809 (5) -2882 (9) 6.59 C(224G) 1986 (8) -1546 (11) -2410 (24) 9.20 C(225G) -1033 (10) -1663 (18) -3329 (19) 4477 (5) -2701 (91 7.52 6.11 2251 (10) C(226G) -2150 (10) -1208 (9) -1780 (21) -2813 (20) 4166 (4) 7.80 6.25 2650 (8) “Atom names start with atomic name followed by three digits. For atoms in CD: (i) CD molecule, (ii) glucosyl residue, (iii) atom position in each glucose. For atoms in guests: (i) FP molecule, (ii) phenyl ring unit (0 for side chain), (iii) atom position. Extension: G stands for guest, W for water. I.e., (R)-fenoprofen in the (R)-(-)-FP-P-CD complex and (S)-fenoprofen in the (S)-(+)-FP-P-CD complex.

J. Am. Chem. SOC.,Vol. 110, No. 13, 1988 4385

Fenoprofen-/3- Cyclodextrin Complexes R(

- ) - FP- CD

-

S( + ) FP - C D I365

lO2G5

3WS

6WS

1265

COMPLEX DIMER

COMPLEX DIMER 1165

3WS

2665

21WS

21w

1165

4ws

25WS

2165

ZWS

1565

24WS

2265

Figure 5. Hydrogen-bonding network scheme of ( R ) -and (5')-FP-P-CD dimers along with the crystalline water molecules. The dotted lines show the hydrogen bonding. Extension: W for water; G for guest; S for atoms from symmetrical related position. Table 111

(R)(S)(R)(S)FP-CDI FP-CDI FP-CD2 FP-CD2 (a) O(4),- -0(4)n+lDistances (A) of the p-CD Molecules 4.30 (2) 4.33 (2) 4.25 ( I ) 4.30 (2) O(14)-0( 24) 4.42 ( I ) 4.34 (2) 4.59 (3) 4.56 (3) O(24)-O( 34) 4.26 (2) O(34)-O(44) 4.39 (3) 4.46 (3) 4.26 ( I ) 4.33 (2) 4.33 (2) 4.28 (2) O(44)-O(54) 4.35 ( I ) O(54)-O(64) 4.32 (2) 4.34 (2) 4.35 (2) 4.45 (2) O(64)-O(74) 4.35 (2) 4.38 (2) 4.53 (2) 4.47 (3) O(74)-O( 14) 4.46 (2) 4.46 (3) 4.24 (2) 4.26 (2) mean 4.37 (2) 4.38 (2) 4.36 (2) 4.37 (2) 0.14 0.12 0 0.06 0.06 (b) 0(4),1-0(4),-0(4),+, Angles (deg) of' the 8-CD Molecules O(74)-O(14)-O(24) 126.9 (2) 129.2 (4) 120.8 (2) 122.6 (4) O(14)-O(24)-O(34) 123.7 (2) 124.6 (3) 132.7 (2) 132.1 (4) O(24)-O(34)-O(44) 132.8 (2) 130.2 (4) 133.6 (2) 132.6 (4) O(34)-O(44)-O(54) 130.6 (2) 131.0 (4) 121.6 (2) 123.1 (3) O(44)-O(54)-O(64) 124.7 (2) 125.7 (3) 128.3 (2) 128.5 (3) 0(54)-0(64)-O(74) 128.2 (2) 128.0 (3) 132.5 (2) 131.8 (4) O(64)-O(74)-O(14) 133.0 (2) 130.6 (4) 130.1 (2) 129.3 (4) mean 128.6 (2) 128.5 (4) 128.5 (2) 128.6 (4) U 3.7 2.5 5.3 4.2

atoms. In the R complex, both protruding carboxylic acid groups (Le., for molecules RI and R2) interact with water molecules via the hydroxyl oxygen atoms, Le., O( 102G)-0(001 W) and 0-

(202G)-0(028W), and these two water molecules do not exist in the S complex. In the S complex, the hydroxyl oxygen O( 102G) of the carboxylic acid group that protrudes (on SI) interacts with a primary hydroxy1 oxygen O(276) of the next symmetry-related C D dimer, whereas the carboxylic acid group that is enclosed in the dimer interface (on S 2 ) interacts again by means of the hydroxyl oxygen with the secondary hydroxyl group O( 133) of a p-CD. Comparison of the ORTEP packing schemes in Figure 6 shows differences in the relationship of a CD dimer with the neighboring dimers above and below. As mentioned previously, in the R complex both carboxylic acid groups interact with water molecules, while in the S complex there is no water involved and the carboxylic acid group that protrudes forms a hydrogen bond to a primary hydroxyl group on the neighboring /3-CD ring. Both situations result in the fit of adjacent symmetry-related CD dimers, which stack to form a disjointed channel throughout the crystal. This channel is stabilized by hydrogen bonds to a parallel water channel. The distance apart of the complex dimers at the primary hydroxyl junction is slightly greater for the (R)-FP structure due to the presence of extra water molecules that hydrogen bond to the carboxylic acid group of the (R)-FP. In contrast to the strong and direct hydrogen bonds across the secondary hydroxyl ends of the /3-CD monomers, the primary ends are farther apart and are mostly connected via hydrogen-bonded water molecules. The R and S complexes have 25 water molecules

Hamilton and Chen

4386 J . Am. Chem. Soc.. Vol. 110, No. 13, 1988 Table IV. Hydrogen Bonds Involving the CD and FP Oxygen Atoms (R)-(-)-FP-B-CD comdex' .,., , sym code' dist, A angle, deg 2.72 120 c i i 12j-oti i z j . . . o ( o ~ W ) 2.67 109 C( 1 13)-O( 1 13)-*0(122) 2.83 114 C(113)-0(113)**~0(263) 2.83 120 C( 1 16)-O( 116)***0(003W) 2.74 111 8 C(116)-0(116)-~0(156) 2.87 126 14 C(116)-0(116)-0(028W) 2.91 104 C( 122)-O( 122)...0( 1 13) 2.83 120 94 C(122)-0(122)...0(012W) 2.69 1I4 C( 123)-O( 123)*-0(132) 2.73 1I9 2.94 C( 123)-0(123)-0(253) 131 2.88 C(123)-0(123)~*~0(011 W) 100 2.69 IO C( 126)-O( 126)***0(216) 103 2.77 14 C( 126)-O( 126)-0(025W) 1 I9 2.73 C(132)-0(132)*-0(123) 100 2.62 C( 132)-O( 132)*-0(010W) 112 2.84 C( 133)-0(133)...0( 142) 126 2.78 C( 133)-O( 133)-*0(243) 126 6 2.85 C( 136)-O( 136)*-0(176) 1I O 2.82 C(136)-0(136)-**0(006W) 106 2.71 11 C(136)-O( 136)-0(027W) 121 2.84 C( 142)-O( 142)*-0(133) 100 C( 142)-O( 142)-0(013W) 2.80 1 I6 2.73 C( 143)-0(143)*-0(152) 117 C( 143)-O( 143)-*0(233) 2.86 I02 2 C( 143)-O( 143)...0(012W) 2.83 113 2.68 C( 146)-O( 146)..*0(004W) 2 1I O 2.76 C(146)-O( 146)*-0(003W) 121 C ( 152)-0(152)...0(143) 2.73 109 2 C( 152)-O( 152)-*0(262) 2.67 117 2.82 C( 153)-O( 1S3)*-0(162) 1 I4 2.74 C( 153)-O( 153)...0(223) 121 2 ~ ( 1 5 3 ) - O 153)...0(014w) ( 2.85 103 2 2.87 C( 1 S6)-0( 156)-0( 1 16) 124 2.76 C( 1S6)-0( 156)-*0(009W) 118 C(162)-0(162)-0(153) 2.82 117 2 C( 162)-O( 162)--0(014W) 3.10 114 2.70 C( 163)-O( 163)*-0(172) 118 2.84 C( 163)-O( 163)***0(2 13) 4 1I O C( 163)-O( 163)*-0(013W) 2.85 1 I6 2.74 C( 166)-O( 166)*-0(008W) 103 4 C(166)-O( 166)-0(006W) 2.73 122 2.70 C( 172)-O( 172)-0( 163) 4 107 C( 172)-O( 172).**0(242) 2.69 115 C(173)-0(173)~**0(112) 2.72 119 C( 173)-O( 173)*-0(273) 2.81 4 104 C( 176)-O( 176)-0( 136) 2.85 126 C( 176)-0(176).-0(007W) 2.73 119 C(2 12)-0(2 12)--0(273) 2.79 89 2.71 C(2 12)-O(2 12)...0(019W) 1 I6 C(2 13)-0(213)*-0( 163) 2.84 1 I7 C(213)-0(213)*-0(222) 2.77 135 C(213)-0(213)-~*0(018W) 2.89 12 117 C(216)-0(216)**-0(126) 2.69 C(222)-0(222)...0(213) 119 2.77 103 c(222)-0(222)...0(020w) 2.78 123 C(223)-0(223)*-0( 153) 2.74 113 C(223)-0(223)-*0(232) 2.8 1 2.75 122 2 C(226)-0(226)-*0(266) 117 2.75 C(226)-O( 226)*-0(024W) 120 C(232)-0(232)*-0(223) 2.81 9s C(232)-0(232)*-0(0 17W) 2.72 118 C(233)-0(233)*-0( 143) 2.86 118 C(233)-0(233)--0(242) 2.79 2.94 6 100 C(233)-0(233)...0(0l9W) 122 C(236)-0(236)*-0(026W) 2.67 1 I4 C(236)-0(236).-0(027W) 2.69 118 C(242)-0(242)-0(233) 2.79 6 108 C(242)-0(242)*-0( 1 72) 2.69 C(243)-0(243)-*0(133) 115 2.78 C(243)-0(243)-*0(252) 117 2.84 C(243)-0(243)*-0(0 I6W) 6 117 2.86 6 107 C(246)-0( 246)-0(276) 2.68 C(252)-0(252).**0(243) 2.84 115 C(252)-0(252)***0(015W) 94 2.94

C( 112)-0(1121*..0( 173) C(112)-0(112)-0(014W) C( 1 13)-O( 1 13)-0( 122) C(113)-0(113)*-0(263) C(116)-0(116)-*0(156) C(116)-0(116)-~0(003W) C(122)-0(122)*-*0(113) C( 122)-O( 122)...0(012W) C( 123)-O( 123)-0( 132) C( 123)-0(123)*-0(253) C( 123)-0( 123)...0(011 W) C(126)-0(126)*-0(216) C( 126)-O( 126)-0(025W) C( 132)-O( 132)...0( 123) C(132)-0(132)~**0(010W) C(I33)-0(133)*-0( 142) C(133)-0(133)*-0(243) C(133)-0(133)-0(2026) C( 136)-O( 136)-0( 176) C( 136)-O( 136)-0(006W) C( 136)-O( 136)*-0(027W) C( 142)-0(142)*-0( 133) C( 142)-O( 142)...0(013w) C( 143)-0(143)...0( 152) C( l43)-0( 143)-O(233) C( 143)-O( 143).-0(012W) C( 146)-O( 146)--0(004W) C( l46)-0( 146)-*0(003W) C(152)-0( 152)-*0(143) C(152)-0(152)-*0(262) C(153)-0( 153)-*0(162) C(153)-0(153)*-0(223) C( 153)-0(153)*-0(014W) C(156)-0(156)-*-0(116) C( 1S6)-0( 156)-*0(009W) C(162)-0(162)-*0(153) C( l62)-0( 162)-*0(015W) C( 163)-0(163)***0(172) C( l63)-O( 163)--0(213) C( l63)-0( 163)*-0(013W) C( 166)-0(166)-*0(008W) C( 166)-O( 166)--0(006W) C( 172)-O( l72)*-0( 163) C( 172)-0(172)*-0(242) C( 173)-0( 173)...0( 1 12) C( 173)-0(173)*-0(273) C( 176)-O( 176)-*0(136) C(176)-0(176)-.0(007W) C(212)-O( 212).-0(273) C(213)-0(213)*-0( 163) C(213)-0(213)-*0(222) C(213)-0(213)*-0(018W) C( 21 1)-0(215).-0(026W) C(216)-0(216)*-0( 126) C(222)-0(222)...0(213) c(222)-0(222)...0(020w) C(223)-0(223)-*0( 153) C(223)-0(223)-*0(232) C(226)-O( 226)--0(266) C( 226)-0(226)-*0(024W) C (232)-O( 232)-0( 223) C(232)-0(232)...0(017W) C(233)-0(233)-*0(143) C(233)-0(233)-*0(242) C(236)-0(236)-0(026W) C(236)-O( 236)*-0(027W) C(242)-0(242)*-0(233) C(242)-0(242)*-0( 172) C(243)-0(243)--0( 133) C(243)-0(243)***0(252) C(243)-0(243)-*0(016W) C( 246)-0(246)*-0(022W) C(246)-0(246)-0(004W) C(252)-0(252)*-0(243) C(252)-0(252)--0(015W)

(SM comDlexb . . .CLFP-B-CD , sym codeC dist, A angle, deg 2.66 123 2.66 108 2.83 115 2.74 I20 8 2.74 127 2.75 106 2.83 121 2.66 93 2.76 115 2.96 120 2.89 128 10 2.73 I02 14 2.70 106 2.76 1 I9 2.67 103 2.82 I12 2.86 122 2.88 103 5 2.99 124 2.89 110 11 2.71 107 2.82 122 2.72 102 2.75 118 2.83 118 2 2.87 102 2.75 110 2 2.74 107 2.75 120 2 2.72 107 117 2.80 2.79 114 2 2.83 120 2 2.74 102 2.75 123 2.80 117 1 2.87 89 2.73 118 2.85 118 4 2.79 108 2.85 110 4 2.78 107 2.73 118 4 111 2.62 2.66 116 2.75 121 4 2.99 103 2.82 124 2.82 115 2.85 118 2.76 115 2.99 133 4 2.85 96 12 2.73 1 I9 2.76 120 2.66 109 2.79 121 2.87 116 2 2.78 121 I17 2.67 2.87 119 2.14 91 2.83 117 2.77 117 2.73 132 2.67 114 2.77 119 6 2.62 103 2.86 105 2.91 115 6 2.86 123 2.74 123 13 3.00 88 2.91 112 2.84 97

Fenoprofen- P- Cyclodextrin Complexes

J . A m . Chem. SOC..Vol. 110, No. 13, 1988 4387

Table IV (Continued) (S)-(+)-FP-P-CD complexb sym code' dist, A angle, deg 2.96 1 I6 C(253)-0(253)-*0(123) C(253)-0(253)*-0( 123) 2.75 1 I4 C(253)-0(253)--0(262) C(253)-0(253)*.*0(262) 8 2.92 105 C(253)-0(253)-*0(017W) C(253)-0(253)-*0(017W) 3.06 119 C(256)-0(256)*-0(021 W) C(256)-0(256)-*0(02 1W) 8 2.78 109 C(256)-0(256)*-0(024W) C(256)-0(256)-*0(024 W) C(256)-0(256)***0(002W) 16 3.19 96 C(262)-0(262)*-0(253) C(262)-0(262).-0(253) 2.75 118 C(262)-0(262)-**0(152) 8 2.72 111 C(262)-0(262)-*0(152) C(263)-0(263)**.0(113) C(263)-0(263)--0(272) C(263)-0(263)-0(113) 2.74 1 I4 2.69 121 C(263)-0(263)-*0(272) C( 266)-0(266)*-0(226) C(266)-0(266)*-0(226) 8 2.78 101 C(272)-0(272)-0(263) C(266)-0(266)*-0(025W) 2.67 121 C(272)-0(272)-.0(016W) C(272)-0(272).*-0(263) 2.69 121 C(273)-0(273)-0( 173) C(272)-0(272)*-0(016W) 2.71 112 C(273)-0(273)-*0(212) 2.75 1 I7 C(273)-0(273)*-0(173) C(276)-0(276)-*0(246) C(273)-0(273)-*0(212) 2.82 119 C(276)-0(276)*-0(026 W) C(276)-0(276)-*0( 102G) 12 2.51 119 C(276)-0(276)**.0(004W) C(lOlG)-O(lO2C)~-O(OOlW) C(276)-0(276)-*0(003W) 16 2.72 111 c(201G)-0(202G)...0(028w) C( lOlG)-O(l02G)-O(276) 10 2.51 116 2.88 108 C(20 1G)-0(202G)--O( 133) 'Standard deviation range: for distance, 0.01-0.03 A;for angle, 0.2-1.2'. bStandard deviation range: for distance, 0.01-0.04 p\; for angle, 0.3-1.3O. CSymmetrycodes and corresponding operations: 1, 65601;~ 1, y , z + 1; 2, 65501, x + 1, y , z ; 3, 65401, x + 1, y , z - I ; 4, 55601, x, y , z + 1; 5, 55501, X, y , z; 6, 55401, X , y , z - 1; 7, 45601, x - 1, y . z + 1; 8, 45501, x - 1, y , Z ; 9, 45401, x - I , y, Z- I ; IO, 55502, -x, JJ+ ' / 2 , -2; 11, 55402, -x, y + ' / 2 , -2 - 1; 12, 54502, -x, y - '/2, -z; 13, 54402, -x, y - ' / 2 , -Z - 1; 14, 45502, -X - 1, y + '/I, -2; 15, 45402, -X - I , y + '/2, -2-1; 1 6 , 4 4 5 0 2 , - ~ - 1 , ~ - ' / 2 , - 1~ 7; , 4 4 4 0 2 , - ~ - 1 , ~ - ' / 2 , - ~ - 1 . (R)-(-)-FP-@-CD complex" dist, A angle, deg 2.94 118 2.75 115 8 2.91 103 2.99 107 8 2.76 102 119 2.75 114 8 2.67 2.83 116 2.65 119 107 8 2.75 121 2.65 1I O 2.76 2.8 1 118 2.79 118 4 2.68 128 106 4 2.62 121 12 2.71 2.67 113 2.60 117

sym codeC

+

P

\ '

I-\+\

I

,

i_

--

,

. b

m

Figure 6. ORTEP packing schemes of (S)-FP-8-CD (left) and (R)-FPj3-CD (right) complexes.

in c m - " . The R complex has three d d i t i o n a l unique water molecules, two of which are hydrogen b m d e d to the guest carboxylic acid groups (one to R1 and one to R2). Guest and Packing* The most interesting Of the crystal structure determinations is the different mode of inclusion of the two enantiomers within the C D dimer cavity (Figures and 4). I n the complex, R1 and R2 are in an antiparallel or head-to-head " i e m e n t ; that is, both guests are oriented in the p-CD cavities with their phenoxy groups pointing toward the secondary hydroxyl end of the CD and the Propionic acid group protruding into the water matrix. In contrast, in the "plexy s1 and s2 are in a parallel Or head-to-tailarrangement? where one guest (S2) is oriented with its phenoxy group within the C D dimer interface and the other (SI) with its polar UrbxYlic acid group in the C D dimer interface oPPsint3 the Phenoxy group of the first. The phenoxy group of s 1 Protrudes from the C D cavity. The arrangement of the S dimer is unexpected. The C D cavity is relatively hydrophobic, and the expected packing of the F P would have been head-to-head, with the more hydrophobic parts of the molecules in the hydrophobic cavity of the C D dimer.

s

Recent studies on a complex of (i)-flurbiprofen with p-CD'4t'5 showed no difference in orientation of the R and S guests in the p-CD cavity. Crystallization of the racemic flurbiprofen with 6-CD resulted in the R isomer in one half of the p-CD dimer and S in the other. The structures of the separate R and S complexes showed the same orientation for the guests as was found in the racemate complex. All have the expected head-to-head arrangement of the F P in the b-CD dimer. T h e difference in packing of the F P molecules in the p-CD cavity is presumably d u e to the influence of the R versus S configuration of the m-propionic acid group. For ease of discussion, the phenyl ring containing the propionic acid substituent in each F P molecule will be called ring 1 and the other phenyl ring, ring 2. The atom numbering for the F P molecules is shown in Figures 1 and 2. The FP molecules have possible freedom of rotation about the 0(00G)-C(13G) and 0(00G)-C(21G) bonds for the phenyl rings and about the C ( l lG)-C(02G), C(02G)C(OlG), and C(O2G)-C(03G) bonds for the propionic acid group. The possible interplanar angles for the phenyl rings are restricted to a small range of values in the region of 60-90'. There can of course be a twofold rotation of the phenyl rings, which has no effect as far as ring 2 is concerned but will change the position of the propionic acid group by 180" in ring 1. The possible conformations for the propionic acid group are limited to those where the hydrogen atom on chiral carbon C(02G) is near the plane of the phenyl ring 1 and the methyl and carboxylic acid groups are staggered with respect to this plane. The approach of the methyl group to the plane is sterically hindered, as is the close approach of the carboxylic acid group, ~h~ closer than the methyl c a r b x y l i c acid group can certainly group if the oxygen atoms of the carboxylic acid group rotate out of the plane of the phenyl ring. Keeping these steric restrictions in mind, the observed conformations for the propionic acid group (diagrammed in Figure 7 relative to ring 1) can be discussed. The propionic acid groups o f S 1 , R1,and R2 show the expected stable conformation, with the methyl groups and carboxylic acid groups staggered with respect to the plane of ring 1 and the hydrogen lying in the plane. Interchanging the methyl and carboxylic acid groups, which changes R to S,as in R1 to S1 in the figure, changes the direction in which the carboxylic acid group points and ne(14) Uekama, K.; Hirayama, F.; Imai, T.; Otagiri, M.; Harata, K. Chem. Pharm, Bull. 1983, 31, 3363-3365, (15) Uekama, K . ; Imai, T.; Hirayama, F.; Otagiri, M.; Harata, K. Chem. Pharm. Bull. 1984, 32, 1662-1664.

Hamilton and Chen

4388 J . A m . Chem. SOC.,Vol. 110, No. 13, 1988 Table V. HvdroPen Bonds Involving . - Water Molecules I

-

angleC 0(003W)(2)*-0(001W)*-O(102G) 0(005w)(7)...0(002w)...0(007w) 0(023W)( 14)*-0(002W)***0(007W) O( 146)(8)~~~0(003W)~~~O(l16) 0(025W)( 14)~*~0(003W)~-0(001 W) (8) 0(005W)**~O(O04W)***O( 146) 0(276)( 10)~**0(004W)~-0(006W) O(OO8 W)(6)**.0(005W)***O(004W) 0(008W)(6)~*~0(005W)*-0(002W) (3) 0(004W)~-0(006W)-0( 136) O( 166)(6)*-0(006W)***O(I 36) 0(028W)( 14)-*0(007W).**O(176) 0(009w)(8)...0(007w)...0(002w) O(O11W)(l)..*O(OO8W)-.O(166) o(005 W) (4)...0(008w)...0(009w) O(007W)(2)***0(009W)--O( 156) O(0l o w ) ( 1)**.0(009W).**O(008 W) O(016W) (6)*-0(010W)-*O( 132) 132) O(009W) (9)*-0(01OW)***O(

O(Ol5W)-~O(Ol1W)~~~O(213) O(OOSW)(9)~~*0(011 W)*-0(012W) O(O1lw)...o(o12w)...o(122) O( 143)(8)***0(012W).**0(122) 0(017W)(8).**0(012W).-O(122) O( 163)(6)*-0(013W)*-O(142) O( 153)(8)~~*0(014W)**-0(112) O( 162)(8)-*0(014W)-.O(O16W)

length$ A 2.86 2.79 3.19 2.76 2.93 2.56 2.71 2.85 2.85 3.22 2.73 2.66 2.75 2.88 2.85 2.75 2.79 2.81 2.79 2.87 2.88 2.77 2.86 2.80 2.85 2.85 NO

angle, deg ( R )- (-)- FP-P-CD 127 2.67 2.79 112 2.79 111 2.74 126 2.86 123 118 2.68 97 3.22 101 2.56 2.79 101 130 2.82 127 2.82 2.73 113 107 2.79 2.74 110 2.85 110 100 2.76 110 2.85 2.62 93 2.62 1 I7 114 2.88 2.77 102 2.69 106 111 2.69 2.69 108 111 2.80 2.67 120 3.10 115

length, t%

angleC

angle, deg

Complex" 0(018W~(9~**-0(015Wb-0(252~

2.83

2.94

O(OlOW)(4)~-0(016W)-~0(272) O(015 W)(4)*-0(016W)*-0(243) (4)

2.81 2.96 2.91 2.80 2.83 2.86 3.03 2.94 2.76 2.86 2.56 2.76 2.86 2.72 3.19 2.81 2.76 2.86 2.93 2.62 2.81 2.71 2.82 2.91

2.76 2.86 2.72 2.72 2.89 3.03 2.71 2.71 2.78 2.99 2.56 2.75 2.96 2.56 2.56 2.75 2.82 2.67 2.77 2.67 2.69 2.72 2.60 2.66

103 119 125 115

2.96 o ~ o ~ ~ w j ~ ~ j . . . o ~ o ~i ~w w ) j...o ~ o i2.88 0(253)(2)-*0(017W)*-0(232) 0(012W)(2).-0(017W)*-O(232) 0(015W)( 1 )*-O(OI8 W)*-0(213) O(021 W)( I)...O(Ol8 W)...0(019W) O(018W)*-0(019W)***0(2 12) 0(233)(4)*-0(019W)*-0(212) 0(022W)( 1)...0(020w)...0(222) O(0 18W) (9)-*0(02 1W)-O( 256) 0(022w)...0(021 w)...0(023w) 0(02OW)(9)~*~0(022W)-~O( 246) O(025W) (6)*-0(022W)**.0(021W) 0(027w)(8)...0(023w)...0(021 W) 0(002W)( 16)*-0(023W)*-0(021W) 0(027W).**0(024W)***0(226) 0(256)(2).-0(024W).**O(O28W) (2) 0(22W)(4)***0(25W)-.0(266) 0(003W)(l6)+-0(025W)*-0(126) (16) O(276)(6)-*0(026W)-0(236) 0(024W)-.0(027W)***0(236) 0(136)(13)*-0(027W)~-0(023W) (2) 0(024W)(8)*-0(028 W)-*0(202G) O( 1 16)( I4)-*0(028W)*-O(007W) (14)

11 1

111 117 95 105 109 115 105 112 110 121 120 92 128 104 112

114 128 118 101

110 120

(S)-(+)-FP-P-CD Complexb 2.83 2.66 108 0(153)(8)--0(014W)*-0(112) 2.81 2.84 3.19 128 0(018W)(9)-*0(015W)*-0(252) 2.72 106 O(O18W) (9).-0(0 15W)*-O(O16W) (6) 2.81 2.92 2.83 2.87 2.84 127 0(011W)~~~O(015W)-*O(162) (9) 2.86 2.71 2.99 105 0(243)(4)*.*0(016W)-0(272) 2.89 2.71 3.01 104 O(O1OW)(4)*-0(016W)-*O(272) 3.00 113 O(Ol5W)(4)*-O(Ol6W)-*O(272) 2.92 2.71 2.92 2.74 2.78 110 0(253)(2)-*0(017W)***0(232) 2.81 2.74 2.78 106 0(012w)(2)...0(0l7w)...0(232) 2.81 2.99 2.78 116 0(015W)( 1)-~0(018W)*-0(213) 2.76 2.99 3.02 127 O(021W)( 1)...0(018W)...0(213) 2.78 2.66 2.90 120 0(022W)( 1)...0(020w)...0(222) 2.94 3.06 2.77 114 0(022W)--0(021W)-*0(256) 2.76 2.58 2.83 110 0(018w)(9)...0(021 w)...0(023w) 2.78 2.74 2.78 110 0(020W)(9)-*0(022W)-*0(246) o(oo5w)(4)...o(oosw)...o(oo9w) 2.81 2.94 2.77 105 0(025W)(6)-0(022W)-~O(O21 W) O(007 W)(2)*-0(009W)*-O(156) 2.74 2.58 105 0(027w)(8)...0(023w)...0(021 W) O(OlOW)( 1)*~*0(009W)~~~O(OOSW) 2.79 2.86 2.67 2.89 90 O(027 W)-.0(024W)*+.0(226) 0(016W)(6)~**0(010W)*-0( 132) 2.78 2.67 2.79 121 0(256)(2)*-0(024W)*-0(226) O(OO~W)(9)~~~O(OlOW)*-O( 132) 2.67 2.67 2.83 113 0(022W)(4)*~~0(025W)*-0(266) 0(015W)-~O(011W)*~~0(123) 2.83 106 0(003W)(l6)~*~0(025W)~~~0(126) (16) 2.84 2.70 O(OO8W)(9)-*0(011W).-O(O12W) 2.85 2.73 2.72 107 0(215)(6)-*0(026W)*-0(236) 0(011w)*..0(012w)...0(122) 2.99 2.73 2.87 111 0(004W)( 13)*-0(026W).**0(236) O( 143)(8)-.0(012W)*.*O(122) 2.86 2.67 2.81 114 0(024W)*-O(027W)***0(236) o(ol7w)(8)~~~o(ol2w)...o( 122) O( 163)(6)*-*0(013W)*.*0(142) 2.79 112 0(023W)(2).**0(027W)--0(136) (13) 2.74 2.71 *Standard deviation range: for distance, 0.02-0.06 a Standard deviation range: for distance, 0.01-0.04 A; for angle, 0.4-1.6". 0.5-1.7'. 'The number in parentheses after the atom name is the symmetry code (see Table IV). 0(007w)...0(002w)...0(005w) (7) 0(256)( I4)*~*0(002W)*.*O(005W) (7) 0(276)( 14)**.0(003W)**-O( 116) 0(025W)(l4)*~~0(003W)~*~0(146) (8) 0(026W)( 11)***0(004W).**0(146) O(005W)***O(OO4W)-.O(006W) W) O(246) ( 1 1)~*~0(004W)~-0(006 O(OOSW)(6)***0(005 W)-*0(004W) 0(008W)(6)~~*0(005W)...o(oo2w) (3) 0(166)(6)-0(006W)*-O( 136) 0(004W)-**O(O06W)-*.O( 136) O(002W)-.0(007 W)*-O( 176) O(009W) (8)-*0(007W)*-O( 176) O(0l lW)(l)***O(OOSW)**-O(166)

2.80

2.84 2.84 2.75 2.74 2.75 3.02 3.02 3.01 2.84 2.89 2.89 2.82 2.82 2.85 2.88 2.75 2.88 2.64 2.64 2.89 2.72 2.66 2.66 2.66 2.73

Table VI. Intermolecular Hydrogen Bonding (A) between Secondary Hydroxyl Groups bond (R) - FP-CD (S)- FP-CD bond O( 1 13)-O(263) 2.83 (1) 2.74 (2) O( 152)-O(262) (65501) O( 123)-O(253) 2.94 (1) 2.96 (2) O( 133)-O(243) 2.78 ( I ) 2.86 (2) O( 172)-O(242) (5560 I ) O( 143)-O(233) 2.86 ( I ) 2.83 (2) O( 153)-O(223) 2.74 (1) 2.79 (2) O(262)-O(152) (45501) O( 163)-O(213) 2.84 (1) 2.85 (2) O( 173)-O(273) 2.81 ( 1 ) 2.75 (2) O(242)-O( 172) (55401) mean 2.83 ( I ) 2.83 (2) U 0.06 0.08 cessitates movement of the methyl and carboxylic acid groups to more favorable positions, mainly in order to point the carboxylic acid group to a suitable environment for hydrogen bonding. This results in a change in the direction in which the hydrogen atom

126 100 118 108 117

126 124 107 105 116 102 120 114 116 122 I12 122 125 129 117

113 102 119 128 101 A;for angle,

( R ) -FP-CD 2.67 ( I )

(S)-FP-CD 2.72 (2)

2.69 (1)

2.62 (2)

2.67 41)

2.72 (2)

2.69 (1) 2.68 (1)

2.62 (2) 2.67 (2) 0.06

0.01

points and to changes in orientation of the phenyl rings, all of these having to maintain compatibility with the restrictions imposed by the CD cavity. Co-incidence of the carboxylic acid group in the ( R ) - and (S)-FP cannot be achieved by sterically possible