Journal of Chemical Crystallography, Vol. 29, No. 1, 1999

Structural study of the molecular complex in crystals ofbrucine with pantolactone

K. Chandramohan(1) and K. Ravikumar(1)*

Received February 19, 1998

We have determined an X-ray crystal structure, a 5 12.482(1), b 5 14.349(1), c 5 14.342(1)A, orthorhombic, P212121, for a molecular complex of brucine with pantolactone. The crystalstructure is composed of corrugated sheets of brucine molecules containing the guest panto-lactone molecules. The conformational twist of the pyrrolidine ring in brucine may probablybe important in projecting the amine N2 to provide a strong and specific binding site for achiral complexation. The pseudo-equatorial orientation of the hydroxyl group of the pantolac-tone anchors itself for binding via hydrogen bonding. In the crystal packing, the pantolactonemolecules form helices and the brucine molecules are attached to these helices by OUH ? ? ? N hydrogen bonds.

KEY WORDS : Crystal structure; brucine; pantolactone; molecular complex; chiral resolution.

Introduction

Pantolactone (I) is a key intermediate in thesynthesis of pantothenic acid (II). Optical resolutionof pantolactone by the diastereomeric method, viathe corresponding 2,4-dihydroxy acid half-ester ofthe hydroxyl group, is successful and known.1 How-ever, the synthetic material used in the resolution,itself had to the resolved before use. Indole alka-loids, strychnine and Brucine (III), isolated fromthe seeds of Strycnnos nuxvomica and related plants,form stable 1 : 1 molecular complexes with com-pounds having acid functional groups, and havebeen widely used as resolving agents.2 In a generalobjective, aimed to find an optically active baseuseful in the resolution of pantolactone, a 1 : 1molecular complex with brucine was prepared. Fur-ther, in order to understand how the pantolactoneand brucine form crystalline complexes in which thecomponents recognize so efficiently one another’s

(1) Laboratory of Crystallography, Indian Institute of ChemicalTechnology, Hyderabad 500 007, India.

* To whom correspondence should be addressed.

121

1074-1542/99/0100-0121$16.00/0 1999 Plenum Publishing Corporation

chirality, the crystal structure of the 1 : 1 brucinecomplex of pantolactone was determined by X-raydiffraction methods.

122 Chandramohan and Ravikumar

Experimental

The molecular complex crystals of pantolac-tone : brucine were obtained as well formed needlesfrom an aqueous solution of an equimolar mixtureof brucine dihydrate and pantolactone. The crystalsused for data collection were sealed in a Lindemann-glass tube. The diffraction data were collected on aSIEMENS R3m/V four-circle diffractometer usinggraphite monochromated MoKa radiation.3 Cell con-stants were determined from least-squares fitting tothe setting angle for 25 reflections. Two check reflec-tions monitored periodically showed no significantintensity variation. Normal Lorentz-polarization cor-rections were applied, but not absorption or extinc-tion correction.

Structure solution and refinement

Relevant data concerning crystal properties,data collection and refinement are summarized inTable 1. The structure was solved by direct methods.Full-matrix least-squares refinement was carried out.All non-H-atoms were refined anisotropically and H-atoms were found in a difference Fourier map, placedin calculated positions, and refined with a ridingmodel. Atomic scattering factors used were thosein SHELXTL-Plus.4 SHELXTL-Plus was used forstructure solution, refinement, and graphical repre-sentation. Geometrical calculations and crystal pack-ing were computed using the program PARST.5

Results and discussion

Final atomic coordinates are given in Table 2with derived parameters in Table 3. The ORTEP ofthe molecule (Fig. 1) displays the atom labeling andthe main conformational features.6

The crystal structure is composed of brucinemolecules separated by guest molecules of pantolac-tone. As reported in other related brucine complexes,the present structure also manifests the characteristicfeatures of brucine, forming hydrogen bonds with theguest molecule.7,8 This hydrogen bond may play asignificant role in bringing the two components closetogether so that they may recognize each other’s chi-rality.

It is worthwhile to mention that the molecularcomplex formed between brucine and pantolactonewas not stable in the gas phase. The crushed crystal

Table 1. Crystal Data, Summary of Intensity Data Collection andStructure Refinement

Empirical formula C29H36N2O7

CCDC deposit no. CCDC-1003/5466Formula weight 524.6Crystal system OrthorhombicSpace group P212121

Cell constantsa, A 12.482(1)b, A 14.349(1)c, A 14.342(1)

Volume, A3 2568.7(6)Z 4Dcal g cm23 1.356n (calc), cm21 0.906Diffractometer/scan Siemens R3m/V

Omega-2thetaRadiation/wavelength MoK (alpha) (lambda 5 0.71073)F (000) 1120Crystal size, mm 0.23 3 0.15 3 0.14u range for data collection 1.5–258

Index rangesh 0 to 16k 0 to 17l 0 to 17

Reflections collected 3374Reflections observed [I $ 2033

3s(I)]Corrections applied LpRefinement method Full-matrix least-squares on FComputing SHELXTL-PlusWeights 1/[s 2(Fo) 1 gFo2]

g 5 0.00101GOF 1.41Final R [I $ 3s(I)] 0.056RW 0.067Residual electron density

Dr min (e/A3) 20.18Dr max (e/A3) 0.17

Largest shift/esd 0.01

was analyzed by liquid secondary ion mass spectrom-etry (LSIMS) techniques using glycerol as the matrix.No peaks corresponding to the complex/adduct couldbe seen. The only abundant ion observed in the spec-trum corresponds to protonated brucine. This proba-bly indicates that the complex may not be stable ingas phase and also that brucine is not solvated bypantolactone. Perhaps the complex formation may bedue to noncovalent interactions viz. hydrogen bond,confirmed later by crystal structure analysis.

Brucine molecule

The brucine molecule contains seven fused rings.The seven-membered ring, the most flexible part of

Molecular complex of brucine with pantolactone 123

Table 2. Atomic Coordinates and Equivalent IsotropicDisplacement Coefficients (A2 3 103) with esd’s in Parentheses

Atom x y z Ueqa

O1 1845(2) 4030(3) 3779(2) 58(1)O2 3685(3) 3438(3) 6567(2) 60(1)O3 7668(3) 3649(3) 7057(2) 58(1)O4 8771(2) 3906(2) 5558(2) 49(1)O5 6777(4) 1868(4) 288(4) 109(1)O6 6803(3) 3712(3) 719(3) 86(1)O7 8407(3) 1741(3) 450(3) 76(1)N1 4407(3) 3383(2) 5112(2) 33(1)N2 5206(3) 3763(3) 2003(2) 37(1)C1 7096(4) 3614(3) 6241(3) 41(1)C2 6002(4) 3461(3) 6204(3) 41(1)C3 5512(3) 3464(3) 5326(3) 33(1)C4 6095(3) 3590(3) 4521(3) 31(1)C5 7197(3) 3745(3) 4573(3) 33(1)C6 7694(3) 3768(3) 5431(3) 36(1)C7 9390(4) 4098(4) 4752(3) 57(1)C8 7094(5) 3502(6) 7905(3) 85(1)C9 5381(3) 3513(3) 3674(3) 30(1)C10 5494(3) 2579(3) 3154(3) 35(1)C11 4931(4) 2785(3) 2228(3) 43(1)C12 5608(3) 4217(3) 2881(3) 33(1)C13 5108(3) 5175(3) 3032(3) 38(1)C14 3908(3) 5050(3) 3139(3) 38(1)C15 3716(3) 4559(3) 4079(3) 32(1)C16 4250(3) 3601(3) 4113(3) 29(1)C17 3579(3) 3528(3) 5731(3) 40(1)C18 2525(3) 3789(3) 5283(3) 44(1)C19 2565(3) 4444(3) 4435(3) 41(1)C20 1648(4) 4592(5) 2952(4) 75(1)C21 2433(4) 4347(4) 2206(4) 57(1)C22 3452(4) 4539(3) 2292(3) 43(1)C23 4296(3) 4275(3) 1578(3) 45(1)C24 9104(5) 2254(4) 1084(4) 70(1)C25 8613(4) 3241(4) 1125(3) 53(1)C26 7461(4) 2999(4) 1027(3) 57(1)C27 7454(5) 2170(4) 382(4) 62(1)C28 8864(8) 3721(6) 1998(5) 127(1)C29 9019(5) 3783(5) 285(4) 86(1)

a Ueq 5 (1/3) SiSj Uijai*aj*aiaj.

the molecule, has a distorted chair conformation[q2 5 0.470(5) A, c2 5 240.8(6)8, q3 5 0.605 A, c3 555.2(5)8], with C19 forming the apex.9 The cyclohex-ane ring is in the usual chair conformation (DC2 53.618).10 The 2-oxopiperidine ring adopts a half-chairconformation (DC2 (C17UC18) 5 4.318). The confor-mation of the piperidine ring can best be describedas a boat, (DCS(C13) 5 6.878). The pyrrolidine ringapproximates more closely to a half-chair conforma-tion (DC2(C9UC10) 5 6.848) than to an envelope(DCS(C10) 5 10.538). This conformational twist mayprobably be important in exposing the amine N2 in

Table 3. Bond Lengths (A) and Angles (8)

O1UC19 1.431(5) O1UC20 1.454(7)O2UC17 1.213(5) O3UC1 1.371(5)O3UC8 1.427(6) O4UC6 1.371(5)O4UC7 1.418(6) O5UC27 1.165(8)O6UC26 1.384(7) O7UC24 1.458(7)O7UC27 1.342(7) N1UC3 1.418(5)N1UC16 1.479(5) N1UC17 1.379(5)N2UC11 1.481(6) N2UC12 1.504(5)N2UC23 1.484(6) C1UC2 1.384(6)C1UC6 1.399(6) C2UC3 1.400(6)C3UC4 1.377(6) C4UC5 1.396(5)C4UC9 1.511(5) C5UC6 1.379(6)C9UC10 1.541(6) C9UC12 1.546(6)C9UC16 1.552(5) C10UC11 1.531(6)C12UC13 1.526(6) C13UC14 1.517(6)C14UC15 1.539(6) C14UC22 1.529(6)C15UC16 1.528(6) C15UC19 1.533(6)C17UC18 1.511(6) C18UC19 1.538(6)C20UC21 1.493(7) C21UC22 1.308(7)C22UC23 1.516(6) C24UC25 1.545(8)C25UC26 1.486(7) C25UC28 1.463(9)C25UC29 1.521(8) C26UC27 1.507(8)

C19UO1UC20 114.3(4) C1UO3UC8 117.4(4)C6UO4UC7 117.0(3) C3UN1UC16 108.7(3)C3UN1UC17 125.3(3) C16UN1UC17 119.5(3)C11UN2UC12 107.8(3) C11UN2UC23 112.4(3)C12UN2UC23 112.7(3) O3UC1UC2 123.6(4)O3UC1UC6 115.1(4) C2UC1UC6 121.3(4)C1UC2UC3 117.8(4) N1UC3UC2 128.3(4)N1UC3UC4 110.1(3) C2UC3UC4 121.6(4)C3UC4UC5 119.8(4) C3UC4UC9 110.7(3)C5UC4UC9 129.5(3) C4UC5UC6 119.6(4)O4UC6UC1 115.8(4) O4UC6UC5 124.3(4)O6UC26UC25 115.6(4) O6UC26UC27 112.6(4)O5UC27UO7 120.9(5) O5UC27UC26 130.8(6)O7UC27UC26 108.2(5) O7UC24UC25 104.5(4)C1UC6UC5 119.9(4) C4UC9UC10 113.5(3)C4UC9UC12 115.8(3) C10UC9UC12 101.3(3)C4UC9UC16 101.8(3) C10UC9UC16 110.5(3)C12UC9UC16 114.3(3) C9UC10UC11 102.1(3)N2UC11UC10 105.4(3) N2UC12UC9 105.8(3)N2UC12UC13 111.9(3) C9UC12UC13 114.2(3)C12UC13UC14 108.1(3) C13UC14UC15 107.3(3)C13UC14UC22 110.1(3) C15UC14UC22 114.7(3)C14UC15UC16 111.8(3) C14UC15UC19 119.2(3)C16UC15UC19 107.5(3) N1UC16UC9 104.8(3)N1UC16UC15 106.2(3) C9UC16UC15 117.2(3)O2UC17UN1 122.6(4) O2UC17UC18 122.7(4)N1UC17UC18 114.6(4) C17UC18UC19 117.3(4)O1UC19UC15 114.5(3) O1UC19UC18 104.3(3)C15UC19UC18 111.1(3) O1UC20UC21 110.1(5)C20UC21UC22 121.4(5) C14UC22UC21 122.5(4)C14UC22UC23 113.5(4) C21UC22UC23 124.0(4)N2UC23UC22 112.2(4) C24UO7UC27 110.0(4)C24UC25UC26 99.5(4) C24UC25UC28 112.3(5)C26UC25UC28 113.4(5) C24UC25UC29 107.9(5)C25UC26UC27 104.4(4) C26UC25UC29 111.6(4)C28UC25UC29 111.5(5)

124 Chandramohan and Ravikumar

Fig. 1. ORTEP drawing of the complex of brucine : pantolactoneillustrating the strong OUH ? ? ? N hydrogen bond (broken line).Non-H-atoms are shown as principal ellipses at the 50% probabilitylevel. H-atoms are omitted for clarity.

brucine to the guest cavity, providing a strong andspecific binding site for a preferred chiral complex-ation. The pyrrole ring is almost in an envelope con-formation with C16 as the flap (DCS(C16) 5 5.038).As expected the phenyl ring is planar. The protrudingmethoxy groups are almost coplanar with the phenylring; C8UO3UC1UC2 5 1.2 (6)8 and C7UO4UC6UC5 5 4.4(6)8 which give the molecule awedge shape.

Pantolactone molecule

The five-membered ring of the Pantolactone hasC27, C26, C24, and O7 coplanar, while C25 is 0.562(5)A from that plane, in an envelope conformation(DCS(C25) 5 3.598). The substituents on the lactonering may be classified as pseudo-axial and pseudo-equatorial by virtue of the resemblance between the

Table 4. Hydrogen-Bonding Geometry (A, 8)a

DUH ? ? ? A DUH H ? ? ? A D ? ? ? A DUH ? ? ? A

O6UH6 ? ? ? N2 1.097(6) 1.692(6) 2.715(6) 152.80(3)C2UH2 ? ? ? O2 0.960(6) 2.403(6) 2.939(6) 114.9(4)C16UH16 ? ? ? O1 0.960(5) 2.723(5) 3.101(5) 104.2(4)C7UH7A ? ? ? O1i 0.960(6) 2.711(6) 3.369(6) 126.3(5)C23UH23A ? ? ? O7ii 0.960(7) 2.508(6) 3.438(6) 163.2(5)

a Symmetry codes: (i) x 1 1, y, z (ii) x 2 1/2, 2y 1 1/2, 2z.

Fig. 2. A perspective view of the helical arrangements (singlestrand) of brucine-pantolactone molecules viewed along the Z-axis. Hydrogen atoms are omitted for clarity. Dashed lines indi-cates the N ? ? ? HUO hydrogen bonds.

envelope form of a five-membered ring and the chairconformation of the cyclohexane.11 Hence, in thepresent structure, the hydroxyl group, O6 (H), occu-pies the pseudo-equatorial position. This orientationof the hydroxyl group provides a specific directionfor pantolactone to anchor itself for binding withbrucine via hydrogen bonding. Such an arrangementmay play an important role for the host-guest chiralrecognition in the complex. Absolute configuration ofthe lactone could not be experimentally determinedowing to the choice of wavelength (MoKa) and alsoto the lack of an anomalous scatterer in the titlecomplex.

Molecular packing

The crystal structure is composed of corrugatedsheets of brucine molecules containing the guest pan-tolactone molecules. This contrasts with the arrange-ment found in the crystal structures of brucine withaminoacids and solvate of brucine, where guests andwater molecules form distinct hydrophilic sheets sepa-rating the sheets of brucine molecules.12,13 Figure 2shows the strong hydrogen bond formation betweenthe hydroxyl group, O6(H), of pantolactone and ac-

Molecular complex of brucine with pantolactone 125

ceptor amine N2 of brucine; N2 ? ? ? O6, 2.715(6) A,O6UH ? ? ? N2, 152.80(3)8, and H ? ? ? N2, 1.692(6) A.As alluded in the previous section, this hydrogen bondplays a characteristic role in bringing the two compo-nents close together, facilitating them so efficiently soas to recognize each other’s chirality. It is interestingto note that the pantolactone molecules form helicesup the 21 axes parallel to ‘‘a’’ at x, 1/4, 0 and x, 3/4, 1/2. The brucine molecules are attached to these helicesby the above-mentioned N2 ? ? ? O6 hydrogen bond.

There are possible CUH ? ? ? O interactions inthe crystal packing environment (Table 4). Some ofthese interactions internally stabilize the conforma-tion of the molecule. All other interactions, in gen-eral, are essentially van der Waals in nature.

Acknowledgment

The authors thank Dr. M. Vairamani of the MassSpectrometry Centre for mass spectral data and in-formation.

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