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ORIGINAL PAPER

X-Ray Crystal Structure of BetulinDMSO Solvate

Stanisaw Boryczka Ewa Michalik

Maria Jastrzebska Joachim Kusz

Maciej Zubko Ewa Bebenek

Received: 7 July 2011 / Accepted: 3 December 2011 / Published online: 21 December 2011

Springer Science+Business Media, LLC 2011

Abstract Betulin is a lupane triterpenoid [lup-20(29)-ene-

3b,28-diol, C30H50O2] showing high biological activity.This activity is supposed to be strongly affected by the

molecular structure of its polymorphic forms. Different

solvate polymorphic forms of betulin have aroused

increasing interest as the possible anticancer agents of nat-

ural origin. X-ray diffraction was used to investigate crystal

structure of (1:1) betulinDMSO solvate. Title compound

crystallizes in the orthorhombic P212121 space group. Unit

cell parameters are as follows: a = 7.0006(2) A, b =

12.1623(3) A, c = 33.6991(8) A, Z = 4. Crystal packing

and selected geometric parameters are described. It has been

found that the hydrogen bonding and the dipoledipole

interaction between DMSO molecules play the major role in

the formation of the crystal structure.

Keywords X-ray crystal structure Betulin DMSO Hydrogen bonds Polymorphism

Introduction

Betulin [lup-20(29)-ene-3b,28-diol, C30H50O2] (1), alsoknown as betulinic alcohol, is a pentacyclic triterpene of

the lupane type which was one of the first natural products

identified and isolated from plants as a pure chemical

substance in 1788 by Lowitz [1]. Betulin can be obtained

from the birch bark either by sublimation or by the

extraction with organic solvents. The still growing interest

in betulin (1) and its derivatives results from their wide

spectrum of biological activities such as: anticancer, anti-

viral, antibacterial or hepatoprotective properties [13].

The structure of 1 is based on a 30-carbon skeleton com-

prising of four 6-membered rings and one 5-membered

ring. Betulin (1) has three available sites for simple

chemical modification, namely: secondary hydroxyl group

at position C-3, primary hydroxyl group at position C-28

and isopropenyl side chain at position C-20. The high

content of betulin (up to 30%) in white birch bark and the

ease of its isolation in almost any amount, make it

important starting material for synthesis of new compounds

with various interesting biological activities. In the last few

years a large number of betulin derivatives have been

reported to possess anticancer, anti-inflammatory, anti-HIV

and anti-leishmanial activity [1, 4]. Figure 1 shows the

numbering scheme for betulin (1).

It is well known that the large numbers of natural

molecules are capable of exhibiting polymorphism or

pseudopolymorphism [5]. More importantly, different

polymorphic forms of pharmaceutical compounds display

varying physicochemical properties, such as: solubility,

stability, density as well as bioavailability, particularly

when the drug substance is poorly soluble. Various solvent

used in the crystallization process and different melting

points reported may indicate the existence of several

S. Boryczka (&) E. Michalik E. BebenekDepartment of Organic Chemistry, Silesian Medical University,

4 Jagiellonska Str., 41-200 Sosnowiec, Poland

e-mail: [email protected]

M. Jastrzebska

Department of Solid State Physics, Institute of Physics,

University of Silesia, 4 Uniwersytecka Str., 40-007 Katowice,

Poland

J. Kusz M. ZubkoDepartment of Physics of Crystals, Institute of Physics,

University of Silesia, 4 Uniwersytecka Str., 40-007 Katowice,

Poland

123

J Chem Crystallogr (2012) 42:345351

DOI 10.1007/s10870-011-0251-z

crystal polymorphic forms of betulin. It is therefore

important to investigate molecular structure of different

polymorphs of betulin and describe how their properties

may differ.

Dimethyl sulfoxide (DMSO) is a commercially impor-

tant product, commonly used in chemical laboratories and

in cosmetology and pharmaceutical industry, particularly

as an excellent aprotic solvent. DMSO has been intensively

studied for its pharmacological activity, as it has many

effects; e.g. it has been found to relieve symptoms of

arthritis, secondary amyloidosis associated with rheuma-

toid arthritis, bursitis and myositis [6]. The semipolar sul-

phur-oxygen linkages in DMSO have a full or partial

positive charge on the sulphur and the negative charge on

the oxygen atom. Therefore SO bonds can interact or

associate with various reagents both through the sulphur

and oxygen atoms or form the hydrogen bonds with water,

alcohols, phenols, proteins, carbohydrates, nucleic acid and

other H-donor compounds of living systems [7]. The

molecular and crystal structure of DMSO was described in

detail by Thomas et al. [8].

Biological activity of a drug substance is usually tested in

the solvent environment. The most frequently solvents used

are water and DMSOwater mixtures. Solvent molecules can

strongly affect the energies of different conformations, the

hydrogen bonding pattern as well as the hydrophilic/hydro-

phobic group exposures to protein molecules.

Biological activity of the betulin is supposed to be

strongly affected by the ability of its polymorphs to form

hydrogen bonds. In our work it has been found, that in the

crystal structure of betulinDMSO solvate the hydrogen

bonding plays a major role.

The hydrogen bonding in the crystal structure of betulin

ethanol solvate was reported previously by Drebushchak

et al. [9]. They found three sites, where the hydrogen bonds

were formed.

In this work, we describe the crystal structure of the new

betulinDMSO (1:1) solvate in order to gain better

understanding of this important molecule.

Experimental

General Techniques

Melting points were determined in open capillary tubes on

a Boetius melting point apparatus and were uncorrected.

NMR spectra were recorded on a Bruker MSL 600 spec-

trometer in CDCl3 solvents with tetramethylsilane as

internal standard; chemical shifts are reported in ppm (d)and J values in Hz. Multiplicity is designated as singlet (s),

doublet (d), multiplet (m). IR spectra (KBr, pellet) were

recorded on a IRAffinity-1 Shimadzu spectrophotometer.

TLC was performed on silica gel 60 254F plates (Merck)

using a mixture of dichloromethane and ethanol (20:1, v/v)

as an eluent. Spots were detected by spraying a solution of

5% sulfuric acid, followed by gentle heating. Column

chromatography was performed on silica gel 60, \63 lm(Merck) using a mixture of dichloromethane and ethanol

(40:1 v/v) as an eluent. Solvents were dried and purified

according to usual procedures.

Isolation of Betulin (1)

Betulin (1) was isolated from the bark of birch (Betula

verrucosa), collected in Poland, by extraction with

dichloromethane. The crude betulin was purified by col-

umn chromatography using a mixture of dichloromethane

and ethanol (40:1, v/v) as an eluent. Recrystallization from

DMSOwater solution (9:1, v/v) afforded (1) as a white

crystals, Rf 0.35 (silica gel, dichloromethane-ethanol, 20:1,

v/v), mp 245-247 C. 1H NMR (600 MHz, CDCl3) d: 0.76(s, 3H, CH3), 0.82 (s, 3H, CH3), 0.97 (s, 3H, CH3), 0.98 (s,

3H, CH3), 1.02 (s, 3H, CH3), 1.68 (s, 3H, CH3), 1.021.94

(m, 25H, CH, CH2), 2.39 (m, 1H, H-19), 2.67 (s, 6H,

2xCH3), 3.19 (m, 1H, H-3), 3.34 (d, J = 10.8 Hz, 1H,

H-28), 3.81 (d, J = 10.8 Hz, 1H, H-28), 4.58 (s, 1H,

H-29), 4.69 (s, 1H, H-29). 13C NMR (150 Hz, CDCl3) d:14.76 (C27), 15.37 (C26), 15.93 (C24), 16.07 (C25), 18.24

(C6), 19.03 (C30), 20.77 (C11), 25.13 (C12), 26.99 (C15),

27.30 (C2), 27.94 (C23), 29.11 (C16), 29.68 (C21), 33.93

(C7), 34.16 (C22), 37.09 (C10), 37.24 (C13), 38.64 (C1),

38.81 (C4), 40.64 [(CH3)2SO], 40.85 (C8), 42.66 (C14),

47.73 (C17, C19), 48.69 (C18), 50.33 (C9), 55.22 (C5),

60.47 (C28), 78.96 (C3), 109.66 (C29), 150.45 (C20). IR

(KBr, cm-1) m: 3328, 2943, 1626, 1449, 1375, 1244, 1043,1006, 882.

12

34

5

67

8

9

10

1112

13

1415

16

1718

19

20

21

22

2324

25 26

27

28

29

30

H3C

CH3 CH3

H

CH2OH

HO

CH3H

H CH3

H

CH2

H3C

A B

C D

E

Fig. 1 Atomic numbering scheme of betulin (1)

346 J Chem Crystallogr (2012) 42:345351

123

X-Ray Diffraction Experiment

The single crystal X-ray experiment was performed at

100.0(1) K. For this measurement, a colourless single

crystal (0.15 9 0.22 9 0.60 mm3) of good quality was

preselected under a polarizing microscope. The crystal was

mounted on a quartz capillary and cooled down by a cold,

dry nitrogen gas stream (Oxford Cryosystems equipment).

The data were collected using Oxford Diffraction kappa

diffractometer with Sapphire3 CCD detector. Accurate cell

parameters were determined and refined with using pro-

gram CrysAllis CCD (Oxford Diffraction, 2008) [10]. For

the integration of the collected data the program CrysAllis

RED was used (Oxford Diffraction, 2008).

Refinement

The structure was solved using direct method with SHEL-

XS97 software and then the solution was refined using

SHELXL97 program [11]. The aromatic hydrogen atoms

were treated as riding on their parent carbon atoms with

d(CH) = 0.95 A

and assigned isotropic atomic displace-

ment parameters equal to 1.2 times the value of the equivalent

atomic displacement parameters of the parent carbon atom

(Uiso(H) = 1.2Ueq(C)). The methylene H atoms were con-

strained to an ideal geometry with d(CH) = 0.99 A

or

d(CH) = 0.95 A

(for terminal methylene group) and Uiso(H) = 1.2Ueq(C). Methyl H atoms were constrained as riding

atoms, fixed to the parent atoms with distance of 0.98 A

and

Uiso(H) = 1.5Ueq(C). The methyl group at C31 and C32 were

constrained as riding atoms and torsion angle were refined.

Hydrogen atoms involved in hydrogen bonding were refined

freely with isotropic atomic displacement parameters.

Results and Discussion

Chemistry

Betulin (1) was isolated from the bark of birch by extrac-

tion with dichloromethane. The crude betulin was purified

by column chromatography using a mixture of dichloro-

methane and ethanol. Crystals of betulin (1) for X-ray

structural analysis were grown from a DMSOwater (9:1,

v/v) solution. Full structural elucidation of the new betulin

DMSO solvate was made using 1H, 13C NMR and IR

spectroscopy, and assignments were performed based on

our analysis and related literature. The significant feature

of the 1H and 13C NMR spectra of betulinDMSO solvate

lies in the presence of characteristic signals for the protons

and carbons atoms of methyl groups at 2.67 and

40.64 ppm, respectively, attributed to the DMSO.

X-Ray Crystal Structure

BetulinDMSO solvate (1:1) crystallizes in the orthorhom-

bic, P212121 space group. Table 1 shows crystal parameters,

data collections and refinement details. The asymmetric unit

contains one betulin molecule and one DMSO molecule.

They are shown in Fig. 2 with displacement ellipsoids of

50% probability. The unit cell contains four molecules of

betulin and DMSO (Z = 4). The selected bond lengths, bond

angles and torsion angles are presented in Table 2. Bond

lengths and valency angles have typical values for this type

of compound [12].

Six-members ring have chair conformation, while the

cyclopentane ring adopts twisted conformation as shown

by the Cremer and Pople parameters [13] [ring A:

Q = 0.5480 A, h = 4.17 and u = 110.54; B: Q =0.5813 A, h = 10.47 and u = 358.76; C: Q = 0.6079 A,h = 9.95 and u = 319.02; D: Q = 0.5685 A, h =168.36 and u = 102.42; E: q2 = 0.4397 A, u2 = 3.92].The calculations were made by PLATON program [14].

All ring junctions in the betulinDMSO solvate are

trans-fused. A similar ring conformation was also observed

in 3,28-O,O-diacetylbetulin [15], 3,28-O,O-diacetyl-29-

bromobetulin [16], and betulinethanol solvate [9].

Table 1 Crystal parameters, data collection and refinement detailsfor studied compound

Chemical formula C30H50O2C2H6OSFormula mass 520.83

Crystal system Orthorhombic

Space group P212121

a (A) 7.0006(2)

b (A) 12.1623(3)

c (A) 33.6991(8)

a () 90.00b () 90.00c () 90.00Unit cell volume (A3) 2869.26(13)

No. of formula units per unit cell, Z 4

Temperature (K) 100(1)

Crystal size (mm3) 0.60 9 0.22 9 0.15

Radiation type MoKa

Absorption coefficient (l/mm-1) 0.144

No. of reflections measured 17,912

No. of independent reflections 5,093

Rint 0.0286

Final R1 values (I [ 2r(I)) 0.0786Final wR(F2) values (I [ 2r(I)) 0.2195Final R1 values (all data) 0.0858

Final wR(F2) values (all data) 0.2243

Goodness of fit on F2 1.061

Flack parameter 0.1(4)

J Chem Crystallogr (2012) 42:345351 347

123

The cyclopentane ring is characterized by envelope

conformation with the C17 atom being displaced from C18

C19C21C22 plane about 0.668 A so that the C17C18

C19C21 and C19C21C22C17 torsion angles are equal

to 28.76 and -24.26 correspondingly (for betulinethanolsolvate 0.654 A, 29.23 and -23.06, respectively [9]).

It is important to emphasize that the C29C20C19

C21 torsion angle describing the orientation of the iso-

propenyl group is equal to -96.84, while for betulinethanol solvate and the 3,28-O,O-diacetylbetulin it was

88.64 [9] and -107.18 [15], respectively. Figure 3 showsdifferent orientations of isopropenyl group in two confor-

mational polymorphic structures of betulin. The OH group

is attached to the atom C3 of the ring A in an equatorial

orientation, while the hydroxymethyl group is attached to

the atom C17 of the ring D in an axial orientation.

The hydroxyl group of betulin is involved in intermo-

lecular O1H1O2 hydrogen bonding, which links themolecules into chains running along the a axis. The crystal

Table 2 Selected geometric parameters (A, ) for the crystal struc-ture of betulinDMSO solvate

O1C3 1.426(4) C29C20C30 120.1(4)

O2C28 1.425(5) C29C20C19 118.4(4)

C17C28 1.538(6) C30C20C19 121.4(4)

C17C22 1.538(5) O2C28C17 111.6(3)

C17C18 1.549(5) O1C3C4C23 67.1(4)

C18C19 1.546(5) O1C3C4C5 -176.9(3)

C19C20 1.519(6) C18C19C20C29 146.5(4)

C19C21 1.569(6) C21C19C20C29 -96.8(5)

C20C29 1.386(7) C18C19C20C30 -36.8(6)

C20C30 1.424(7) C21C19C20C30 79.9(5)

S1O3 1.552(12) C16C17C28O2 66.3(4)

O1C3C2 107.3(3) C22C17C28O2 -62.6(4)

O1C3C4 113.0(3) C18C17C28O2 -173.3(3)

C20C19C18 116.0(3) O3S1O3iS1i -144.3(11)

C20C19C21 110.0(3)

Symmetry codes: (i) x - 1/2, -y ? 3/2, -z ? 1

a bFig. 3 Different orientations ofthe isopropenyl groups (marked

as a circle) towards the C18C19C21C22 plane: a betulinDMSO solvate (this work) and

b betulinethanol solvate(according to Drebushchak et al.

[9])

Fig. 2 Molecular structure withatomic numbering scheme of

betulinDMSO solvate with

displacement ellipsoids of 50%

probability


123

packing is further stabilized by weak intermolecular

CHO hydrogen bonds. In the chain, betulin moleculesare zigzag arranged and linked head-to-tail by the

O1H1O2 hydrogen bonds. Similar arrangement wasfound in the betulinethanol solvate crystal [9]. However,

in the ethanol solvate the O1H1O2 hydrogen bond wasfound stronger in comparison to our result for DMSO sol-

vate. According to Drebushchak et al. [9], the HA distanceand DHA angle were equal to 2.01 A and 172 whereas forbetulinDMSO solvate they are 2.16 A and 146, respec-tively. In Table 3, the main parameters of the all hydrogen

bonds found in the betulinDMSO solvate are collected.

Beside the hydrogen bonds between betulin molecules,

there exist also H-bonds between betulin and solvent

molecules. The oxygen atom of DMSO and the hydroxy-

methyl group of betulin are involved in the O2H2O3bond, which is relatively strong with short HA distance(1.85 A) and almost linear directionality (Table 3). This is

the strongest H-bond in the betulinDMSO solvate com-

plex and play an important role in determining the solid-

state.

It should be noted, that in the betulinDMSO solvate the

O1H1O3 hydrogen bond has not been detected. It canbe due to the fact that the hydroxymethyl group of betulin

acts as stronger proton donor than the secondary OH group

at C3. The strength of the H-bond depends on the relative

acidities and basicities of the donor and acceptor sites and

in the case of intramolecular bonds, on the spatial

arrangement present [17]. However, the H-bond of

O3H3O1 involving the proton from the OH group at C3,was observed by Drebushchak et al. [9] in the betulin

ethanol solvate. The hydroxyl group at C28 in betulin

molecule participates in two hydrogen bonds acting as both

donor and acceptor of protons (Fig. 4). It results in

enhancing the hydrogen bond energy over that of the sum

of individual bond energies. It can also contribute to the

fact that the O1H1O2 bond has been found weaker thanreported earlier by Drebushchak et al. [9] for the betulin

ethanol solvate (Table 3).

BetulinDMSO solvate was prepared using DMSO

water (9:1) mixture. DMSO molecules were found to pre-

dominate the formation of H-bonds in the solvate.

According to literature data, DMSO oxygen can act as a

Table 3 Hydrogen-bond parameters (A, ) for the betulinDMSOsolvate

DHA DH HA DA DHA

O1H1O2i 0.72(6) 2.16(6) 2.793(4) 146(6)O2H2O3ii 0.72(7) 1.85(7) 2.570(7) 175(8)C22H22AO2 0.99 2.53 2.944(6) 105C31H31BO2iii 0.98 2.46 3.168(11) 129C31H31CO3iv 0.98 2.51 3.070(17) 116C31H31CO1v 0.98 2.21 2.926(11) 129C32H32BO1v 0.98 2.51 3.209(12) 128

Symmetry codes: (i) -x ? 2, y ? 1/2, -z ? 1/2; (ii) x, y - 1, z;(iii) x, y ? 1, z; (iv) x - 1/2, -y ? 3/2, -z ? 1; (v) -x ? 1, y ? 1/2,-z ? 1/2

Fig. 4 View of the O1H1O2and O2H2O3 hydrogenbonds in betulinDMSO solvate


123

successful competitor in hydrogen bonding against water

[18].

Beside the H-bonding between betulin and DMSO

molecules, solvent molecules interact also between them-

selves via a electrostatic interaction. In the DMSO mole-

cule, the partial positive and negative charges on sulphur

and oxygen atoms, respectively, give rise to the large

dipole moment (4.1 D, gas phase [19]). The length of the

S=O bond for free molecule was 1.495 A [20], while in our

measurements the length is found to be longer

(1.552(12) A) due to the H-bond formation with the betulin

molecule (see Fig. 5; Table 2). Wiewior et al. [19] calcu-

lated the electrostatic potential (ESP) for the gas phase

DMSO molecule using the B3LYP/6-311??G(d,p)

geometry optimization. They determined the hemispherical

symmetric ESP about the oxygen atom. The DMSO oxy-

gen charge was about -0.56e-, that is enough to form two

or more hydrogen bonds or other weak electrostatic inter-

actions. They found also that depending on the basis of the

ESP calculation, the sulphur charge was varying from

?0.343 to ?0.725e-.

Considering the large dipole moment of the DMSO

molecules and the short distance between them

(3.2244(12) A; Table 2, Fig. 5), the interaction of DMSO

DMSO occurs most probably via dipoledipole interaction.

Such dipoledipole interaction was observed earlier by

Tukhvatullin et al. [21] in pure liquid DMSO.

Our measurements have shown, that H-bonding and

dipoledipole interaction play the crucial role in the for-

mation of the crystal structure of DMSObetulin solvate. As

it is seen in Fig. 6, H-bonds link betulin molecules into

zigzag arranged ribbons laying in the bc plane. DMSO

molecules form columns in a direction by dipoledipole

interactions. Neighbouring betulin ribbons are connected

via H-bonds to DMSO columns giving the final three

dimensional network (Fig. 6). Longitudinal structures of

DMSODMSO associations were also observed in crystal

structures of two solvents of 9,10-anthraquinonecarboxylic

acids and DMSO [22], however the dipoledipole interac-

tion was not stated.

Conclusions

BetulinDMSO (1:1) solvate crystallizes in the ortho-

rhombic P212121 space group. It was found that the

Fig. 5 View of the DMSOdipoledipole interaction in

betulinDMSO solvate

Fig. 6 Hydrogen bonds in betulinDMSO solvate crystal structure:a view down the a axis and b view down the b axis


123

hydrogen bonding is the major bond responsible for the

crystal structure of the solvate. H-bonds occur between

betulinbetulin as well as betulinDMSO molecules. The

DMSO oxygen and the hydroxymethyl group of betulin are

involved in the strongest H-bond in the solvate. The col-

umn-like structures of the DMSO molecules coupled by the

dipoledipole interactions were found in the crystal lattice.

They were H-bonded to betulin molecules giving the final

3-D crystal structure.

DMSO is one of the most frequently used solvents in the

medicinal chemistry and its interaction with the biologi-

cally active substances like betulin is of great importance.

Supplementary Material

X-ray crystallographic data reported in this paper is

deposited at the Cambridge Crystallographic Data Centre

as supplementary publication number CCDC 810332.

Acknowledgments This work was supported by the Medical Uni-versity of Silesia, Poland, Grant No KNW-1-073/P/1/0. The work of

M.Z. was partially supported by PhD scholarship within the frame-

work of the University as a Partner of the Economy Based on Sci-

ence (UPGOW) project, subsidized by the European Social Fund

(EFS) of the European Union.

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X-Ray Crystal Structure of Betulin--DMSO SolvateAbstractIntroductionExperimentalGeneral TechniquesIsolation of Betulin (1)X-Ray Diffraction ExperimentRefinement

Results and DiscussionChemistryX-Ray Crystal Structure

ConclusionsSupplementary MaterialAcknowledgmentsReferences

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