The different conformations and crystal structures of dihydroergocristine

Article abstract of DOI:10.1016/j.molstruc.2015.10.008

The identification of different forms of dihydroergocristine (DHEC) was carried out by crystallization from different organic solvents. DHEC was identified as potential template for molecularly imprinted polymers (MIPs) for the epimeric specific analysis of ergot alkaloids (EAs) in food. DHEC was crystallized from different solvents in order to mimic the typical MIP synthesis conditions. Four new solvatomorphs of DHEC were obtained. All solvatomorphs contain a water molecule in the crystal structure, whereas three compounds contain an additional solvent molecule. Based on the conformation of DHEC a comparison with typical EA molecules was possible. The analysis showed that DHEC is a suitable template for MIPs for EAs.

Full text of DOI:10.1016/j.molstruc.2015.10.008

Journal of Molecular Structure 1105 (2016) 389e395
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
The different conformations and crystal structures of
dihydroergocristine
*
€
€
B. Monch, W. Kraus, R. Koppen, F. Emmerling
€
Federal Institute for Materials Research and Testing (BAM), Richard-Willstatter-Str. 11, D-12489 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The identification of different forms of dihydroergocristine (DHEC) was carried out by crystallization
from different organic solvents. DHEC was identified as potential template for molecularly imprinted
polymers (MIPs) for the epimeric specific analysis of ergot alkaloids (EAs) in food. DHEC was crystallized
from different solvents in order to mimic the typical MIP synthesis conditions. Four new solvatomorphs
of DHEC were obtained. All solvatomorphs contain a water molecule in the crystal structure, whereas
three compounds contain an additional solvent molecule. Based on the conformation of DHEC a com-
parison with typical EA molecules was possible. The analysis showed that DHEC is a suitable template for
MIPs for EAs.
Received 12 May 2015
Received in revised form
11 August 2015
Accepted 13 October 2015
Available online 21 October 2015
Keywords:
Molecularly imprinted polymer
Ergot alkaloids
© 2015 Elsevier B.V. All rights reserved.
Solvatomorphs
Hirshfeld surface
1. Introduction
In recent years EAs and their epimer-specific determination
have gained increasing importance in preventing poisoning of
Fungi of the genus Claviceps are specialized parasites of grasses,
rushes and sedges, including forage grasses, corn, wheat, barley,
oats, rice, and rye [1]. The most prominent member of the genus
Claviceps is C. purpurea. Infection with these species leads to the
formation of dark purplish-black mycelia mass called sclerotium.
The sclerotium itself contains inter alia a number of highly toxic
secondary fungal metabolites, the so-called ergot alkaloids (EAs),
which can cause severe diseases in humans and animals (e. g.
gangrene, paresis / ergotism) after consumption of contaminated
food and feed.
livestock and consumers and economic losses.
For analysing EAs often methods based on the use of high-
performance liquid chromatography in combination with fluores-
cence detection were used. This requires an efficient clean-up to
remove matrix components from the raw extracts. Otherwise the
quantification is exacerbated by spectral interferences especially
when analysing processed cereal samples. In the literature some of
the clean-up methods based on the removal of matrix components
by binding the EAs on an adsorbent material [4e8], are described.
Another approach is the binding of EAs to a resin, and subsequently
eluting the EAs after removing matrix components by washing
with a suitable solvent. Therefore, Chromabond® C18 ec SPE car-
tridges [9], EXtrelut® NT3 columns [10e13] or strong cation ex-
change (SCX) columns [14,15] were applied. A very selective sample
clean-up procedure based on the use of molecularly imprinted
polymers (MIPs) as solid-phase extraction materials for analysing
EAs was described so far only once [16].
MIPs are synthetic polymers featuring receptor or catalytically
active sites. Synthesis of MIPs is commonly based on the formation
of reticulated polymers in the presence of templates, which could
be the analyte itself or a structurally related substance. Because the
EAs vary in their substituents at the C8-position it is reasonable to
use a structurally related substance as template instead of using
one of the priority EAs. Furthermore, using an EA analogue as
template molecule for polymer synthesis leads to the avoidance of
The main ergot alkaloids produced by C. purpurea are ergome-
trine, ergotamine, ergosine, ergocristine,
a-ergocryptine, and
ergocornine, along with their corresponding isomeric forms
(-inine-forms) [2]. All these EAs are based on a tetracyclic ergoline
ring which is methylated on the N-6 nitrogen atom, substituted on
C-8 and possesses a double bond in C9eC10 position. They can be
divided into simple lysergamides (ergometrine/-inine) and ergo-
tpeptines (ergosine/inine, ergotamine/-inine, ergocornine/-inine,
a
-ergocryptine/inine and ergocristine/-inine). While the C8-(R)-
isomers (suffix “-ine”) show a high toxicity, the C8-(S)-isomers
(“-inine”) are considered as biologically less or not active [1,3].
* Corresponding author.
E-mail address: franziska.emmerling@bam.de (F. Emmerling).
http://dx.doi.org/10.1016/j.molstruc.2015.10.008
0022-2860/© 2015 Elsevier B.V. All rights reserved.

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B. Monch et al. / Journal of Molecular Structure 1105 (2016) 389e395
390
inaccuracies in measurements caused by residual template
bleeding.
C
35H41N5O5 ꢁ H2O (%): C, 66.75; H, 6.88; N, 11.12; found: C, 66.22;
H, 6.85; N, 10.91. HR-MS: calc. for C35H42N5Oþ5 612.3181; found
A feasibly and reasonably priced template for the synthesis of
MIPs for EAs is Dihydroergocristine (DHEC), which can be obtained
from commercial available Dihydroergocristine mesylate (DHEC
mesylate, Fig. 1). To form suitable receptor or catalytically active
sites for EAs during the imprinting process it is essential that DHEC
possess the same configuration of the asymmetric centres as the
EAs. Since it is not known in detail whether the configurations of
the asymmetric centres are influenced during the synthesis steps, it
is necessary to identify the absolute configuration of DHEC, based
on single crystal X-ray data. Furthermore, only if the conformation
of the DHEC reveals a high degree of shape similarity with those of
the EAs a selective interaction between the MIP and the EAs can be
ensured. Otherwise during imprinting of the polymer an arrange-
ment of potential binding sites would be generated which is not
suitable for the EAs. Therefore it is necessary to verify the shape
similarity under the influence of different solvents used for the
synthesis. A reliable possibility to prove this requirement approx-
imately is based on the single crystal X-ray analysis. For answering
these two questions the crystal structures of DHEC crystallized
from different solvents were determined. Here we present
the crystal structure of four different solvatomorphs of DHEC, the
conformational relation among these structures, and prove the
suitability of DHEC as a template for EAs for MIPs.
612.3180 [M þ Hþ]. 1H NMR (600 MHz, CD3OD, ppm)
d: 7.37e7.34
(m, 2H, H-180/220), 7.22e7.18 (m, 2H, H-190/210), 7.15 (dt, J ¼ 8.2,
0.7 Hz, 1H, H-14), 7.14e7.10 (m, 1H, H-200), 7.09 (dd, J ¼ 8.1, 7.1 Hz,
1H, H-13), 6.91 (d, J ¼ 1.5 Hz, 1H, H-2), 6.86 (ddd, J ¼ 7.3, 1.4, 0.6 Hz,
1H, H-12), 4.68 (t, J ¼ 5.8 Hz, 1H, H-50), 3.83 (dd, J ¼ 9.2, 6.8 Hz, 1H,
H-110), 3.59e3.52 (m, 1H, H-80A), 3.52e3.47 (m, 1HH-80B), 3.44 (dd,
J ¼ 14.6, 4.3 Hz, 1H, H-4A), 3.33 (dd, J ¼ 14.1, 6.1 Hz, 1H, H-160A), 3.21
(dd, J ¼ 14.0, 5.5 Hz, 1H, H-160B), 3.04 (ddd, J ¼ 11.5, 3.8, 2.0 Hz, 1H,
H-7A), 2.97e2.90 (m, 1H, H-10), 2.93e2.87 (m, 1H, H-8), 2.84e2.76
(m, 1H, H-9A), 2.64 (ddd, J ¼ 14.6, 11.1, 1.8 Hz, 1H, H-4B), 2.49 (s, 3H,
H-17), 2.46 (t, J ¼ 11.6 Hz, 1H, H-7B), 2.20 (ddd, J ¼ 11.2, 9.9,4.3 Hz,
1H, H-5) 2.16e2.12 (m, 1H, H-130), 2.13 (dd, J ¼ 13.6, 6.8 Hz, 1H, H-
100A), 2.12e2.08 (m, 1H, H-100B), 2.07e1.99 (m, 1H, H-90A), 1.92e1.80
(m, 1H, H-90B), 1.61 (q, J ¼ 12.5 Hz, 1H, H-9B), 1.12 (d, J ¼ 6.7 Hz, 3H,
H-140/150), 0.96 (d, J ¼ 6.8 Hz, 3H, H-140/150). 13C NMR (151 MHz,
CD3OD, ppm) d
: 178.2 (C-18), 167.9 (C-30), 167.2 (C-60), 139.9 (C-170),
135.1 (C-15), 132.8 (C-11), 131.0 (C-180/C-220), 129.0 (C-190/C-210),
127.3 (C-200), 127.3 (C-16), 123.5 (C-13), 119.4 (C-2), 113.5 (C-12),
111.2 (C-3), 109.9 (C-14), 105.1 (C-120), 92.2 (C-20), 68.4 (C-5), 65.3
(C-110), 59.8 (C-7), 58.2 (C-50), 47.4 (C-80), 43.3 (C-8), 43.2 (C-17),
40.9 (C-10), 40.3 (C-160), 35.1 (C130), 32.4 (C-9), 27.7 (C-4), 27.3 (C-
100), 23.1 (C-90), 17.2 (C-140/150), 16.1 (C-140/C-150). IR (microscope,
cmꢂ1): 3620, 3425, 3339, 2945, 2806, 1710, 1668, 1643, 1632, 1533,
1443, 1225, 1209, 1036, 1015.
2. Experimental
2.2. Crystallization of dihydroergocristine
2.1. Synthesis of dihydroergocristine
Dihydroergocristine was crystallized from various solvents
(methanol, chloroform, dichloromethane, acetonitrile), for details
see Table 1. Colourless crystals suitable for X-ray analysis were
formed after several weeks on slow evaporation of the solvent at
ambient temperature in the absence of light.
20.3 g (28.7 mmol) Dihydroergocristine mesylate (Teva Czech
ꢀ
Industries s.r.o., Opava, Komarov, Czech Republic) were suspended
in 200 mL of a 25% ammonia solution (p. A., Merck KGaA, Darm-
stadt, Germany). Then 1000 mL chloroform (p. A., neoLab Migge
Laborbedarf-Vertriebs GmbH, Heidelberg, Germany) were added
and the suspension was stirred at ambient temperature until the
solid was dissolved. After phase separation the aqueous layer was
extracted twice with chloroform (1000 mL each). The combined
organic layers were washed with 1000 mL brine, subsequently
dried over Na2SO4 (p. A., Merck KGaA), filtered and evaporated to
dryness. The resulting white product was further dried 4 days at
50 ꢀC in vacuo. Codestillation with acetone (CHEMSOLUTE®, Th.
Geyer GmbH & Co. KG, Renningen, Germany) and water (Seralpure)
was performed to remove small amounts of remaining solvent.
Subsequently, the powder was dried again in vacuo for 2 days at
70 ꢀC to give 15.1 g (24.7 mmol, 85.8%) dihydroergocristine.
M.p.: 180.7e181.6 ꢀC. Elemental composition: calc. for
2.3. Instrumental
The melting point was determined by the capillary tube method
using an automatic melting point meter (KSP I N, A. Krüss Optronic,
Hamburg, Germany). Elemental analysis was conducted using a
vario MACRO elemental analyzer (Elementar Analysensysteme
GmbH, Hanau, Germany). The NMR spectra were recorded on a
Bruker Avance 600 MHz (Bruker Corporation, Billerica, USA) with
the CD3OD peak as internal standard. Carbons were assigned based
on two dimensional NMR analysis (H,H-COSY, HSQC, HMQC). High-
resolution mass spectra were obtained with an Exactive Benchtop
Orbitrap™ mass spectrometer (Thermo Scientific™, Bremen, Ger-
many, USA). Infrared spectra were recorded on a Bruker Equinox 55
FT-IR spectrometer (Bruker Corporation, Billerica, USA) in the range
of 4.000e800 cmꢂ1. The single crystal X-ray data were collected at
room temperature using a Bruker AXS SMART diffractometer with
9´
8´
21´
18´
G
7´
6´
an APEX CCD area detector (Mo K
chronator,
were carried out using the Bruker AXS SAINT and SADABS packages.
The structures were solved by direct methods and refined against
F2 by full-matrix least squares calculation using SHELX97 [17].
a radiation, graphite mono-
¼ 0.71073 Å). Data reduction and adsorption correction
10´
N
F
O
l
20´
19´
22´
17´
11´
12´
H
13
H O
5´
N
12
14
15
1´
16´
O
4´
O
E
2´
3´
B
H
H
9
H
19
11
18
N
H
O
10
16
8
7
Table 1
13´
1 H N
A
C
D
6
Overview of solvents and masses of Dihydroergocristine used for crystallisation.
5
15´
14´
3
N
2
Solvent
mDHEC [mg]
VSolvent [mL]
4
Methanol
4.1
5.6
2.6
4.0
200
500
1000
200
17
Chloroform
Dichloromethane
Acetonitrile
Fig. 1. Chemical structure of DHEC with the numbering system used for
characterization.

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B. Monch et al. / Journal of Molecular Structure 1105 (2016) 389e395
391
Anisotropic thermal parameters were employed for non-hydrogen
atoms. The hydrogen atoms were treated isotropically with
Uiso ¼ 1.2 times the Ueq value of the parent atom. The Hydrogen
atoms were placed in calculated positions, allowing them to ride on
their parent C atoms with Uiso(H) ¼ 1.2 Ueq(C). Crystal data and
structure refinement details are summarized in Table 1. The crys-
tallographic data of the structures have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publi-
cations. CCDC 1020057e1020060 contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or
from the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: þ44 1223 336033). The CCDC
numbers [23] are listed in Table 2.
determined as: C5(R), C10(R), C8(R), C20(R), C120(S), C110(S), C50(S).
The obtained chirality is in agreement with that found in related
structures [19,20].
As an example for the obtained structures of compound 1e4 the
molecular configuration of compound 3 is shown in Fig. 2 (for
structures of compound 1, 2 and 4 see supplementary information).
The ergoline rings, forming the indole moiety (ring A and B), are
nearly planar, such as ring E and G (see Fig. 2). The plane displace-
ment (rms) vary from 0.0047 to 0.0098 Å. The non-aromatic ring C of
the ergoline skeleton (C3eC4eC5eC10eC11eC16) and the pipera-
zine part of the tripeptide moiety (ring F, C50eC60eN70
eC110eC120eN40) adopt an envelope E6 conformation. Ring D
(C5eN6eC7eC8eC9eC10) has a regular chair conformation. A
hydrogen bond between the hydroxyl group (O4) and the amide
carbonyl oxygen (O1) could be determined as an intramolecular
interaction for all the four structures with distances in the range of
2.759e2.796 Å for dO4eO1 and 1.997e2.054 Å for dO4HeO1 and the
corresponding angle from 150.36 to 154.50ꢀ (for details see Table 3).
The solvatomorphs 1e4 crystallize in the non-centrosymmetric
orthorhombic space group P212121 with four formula units in the
unit cell and a cell volume ranging from 3312.6 to 3775.2 Å3 (see
Table 2). In contrast, the already known dioxan solvatomorph of
DHEC QABBUQ [19]; crystallizes in the monoclinic space group P21
with two molecules in the unit cell and a cell volume of 2091.1 Å3.
When comparing the crystal structure known from literature
with the crystal structure of compound 1e4 three types of packing
arrangement can be distinguished. The conformation of the DHEC
molecule differs regarding to the position of the phenyl ring, the
part with the highest degree of freedom within the molecule. In
Fig. 3 the three different conformations are depicted in an overlay
representation. The solvents incorporated in the crystal structure
influence the packing motif. Three types of crystal packing
regarding the interactions between the molecules and the dimen-
sionality the formed network can be identified (Type IeIII). Com-
Powder diffraction measurements were performed on a D8
Discover diffractometer (Bruker AXS, Karlsruhe, Germany) equip-
ped with a Lynxeye detector and operated in transmission geom-
etry (Cu Ka1 radiation.
l
¼ 0.154056 nm). The samples were sealed
in a glass capillary of 0.5 mm diameter (WJM-Glas, Müller GmbH,
Berlin, Germany) and the powder diffraction measurements were
conducted over a 2q
range of 5e50ꢀ with a step size of 0.009ꢀ and
0.5 s per step at room temperature. The obtained powder patterns
display a very good correlation with the calculated pattern from the
determined structures (see Fig. S1).
3. Results
Colourless crystals of compound 1e4 were obtained after slow
evaporation of the solvent methanol (compound 1), chloroform
(compound 2), dichloromethane (compound 3), and acetonitrile
(compound 4) at ambient temperature. Compound 1 contains an
additional water molecule in the asymmetric unit. The other three
analysed compounds 2e4 contain a water molecule and an addi-
tional solvent molecule in the crystal structure.
The molecular configuration of DHEC crystallized from different
solvents is comparable in all crystal structures. The compounds 1e4
crystallize in the same configuration with chiral centres at C5, C10,
C8, C20, C120, C110 and C50. For compound 2 and 3 the absolute
configuration could be determined since these structures contain a
solvent molecule with a heavy atom [18]. The final value of the
Flack parameter was 0.00(4) for compound 2 respectively 0.00(11)
for compound 3. The absolute chirality at the chiral centres was
mon for all structures is the absence of pep interactions. This
might be a reason for an unconstrained packing and different
conformations (see Supporting information, Figs. S1eS4).
Type I: The crystal structure of QABBUQ [19] contains two
molecules of 1,4-Dioxane per DHEC molecule. One molecule of 1,4-
Dioxane interacts with a DHEC molecule via hydrogen bonds be-
tween the N1 atom of the indole moiety to the oxygen of the
dioxane with a distance of dN1eO 2.988 Å (for detailed information
Table 2
Selected crystallographic data and structure refinement parameters of compounds 1e4.
Compound reference
1
2
3
4
Chemical formula
Formula mass
Crystal system
a/Å
C35H41N5O5$H2O
629.74
C35H41N5O5$CHCl3$H2O
749.11
C35H41N5O5$CH2Cl2$H2O
714.67
C35H41N5O5$C2H3N$H2O
669.79
Orthorhombic
8.9068(9)
17.3351(17)
21.455(2)
3312.6(6)
296(2)
Orthorhombic
10.0319(11)
14.3662(16)
26.195(3)
3775.2(7)
296(2)
Orthorhombic
9.6940(17)
14.084(3)
26.075(5)
3560.1(12)
296(2)
Orthorhombic
9.6837(7)
14.0741(10)
26.3065(17)
3585.3(4)
296(2)
b/Å
c/Å
Unit cell volume/Å3
Temperature/K
Space group
P212121
P212121
P212121
P212121
No. of formula units per unit cell, Z
Radiation type
4
4
4
4
Mo K
0.087
a
Mo K
0.293
a
Mo K
0.235
a
Mo Ka
0.085
Absorption coefficient,
m
/mmꢂ1
No. of reflections measured
No. of independent reflections
Rint
29,052
8319
32,599
9186
30,084
8912
32,482
8739
0.0658
0.0572
0.1404
0.0740
0.1540
1.052
0.0674
0.0835
0.2202
0.1495
0.2494
0.901
0.0902
0.0625
0.1506
0.1128
0.1703
0.898
0.1172
0.0739
0.1746
0.1162
0.2006
1.005
Final R1 values (I > 2s(I))
Final wR(F2) values (I > 2
Final R1 values (all data)
s(I))
Final wR(F2) values (all data)
Goodness of fit on F2
Flack parameter
ꢂ0.5(6)
0.00(4)
1020057
0.00(11)
1020058
ꢂ0.4(9)
CCDC number
1020060
1020059

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392
Fig. 2. Ortep representation and numbering scheme of the DHEC molecule in compound 3 [21]. The displacement ellipsoids are shown with 30% probability. The labelling of
asymmetric carbon atoms depicted in green. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Table 3
Distances and angles of the intramolecular hydrogen bonds.
Compound
dO4eO1 [Å]
dO4HeO1 [Å]
A [ꢀ]
1
2
3
4
2.796
2.780
2.769
2.759
2.054
2.028
2.014
1.997
150.36
152.32
152.92
154.50
see Table S1, supporting information). No interactions between the
DHEC molecules and the second 1,4-Dioxane or between two DHEC
molecules could be detected (Table 4).
Type II: As mentioned above compound 1 crystallizes with a
water molecule in the lattice. The study of the interactions in the
crystal lattice indicates the formation of a three dimensional
network. The water molecule is involved in the hydrogen bonded
network with two intermolecular hydrogen bonds. Three different
intermolecular hydrogen bonds connect the DHEC molecules
directly and by a water molecule. The first hydrogen bond is formed
between the nitrogen atom (N1) of the indole moiety to the oxygen
atom (O2) attached to the oxazolidine part with dN1eO2 ¼ 2.864 Å
and dN1HeO2 ¼ 2.037 Å. A further hydrogen bond is formed between
the oxygen atom (O5) bound to the piperazine moiety to the water
molecule (O6) (see Fig. 4A) with dO5eO6
¼
2.808 Å and
dO6HeO5 ¼ 1.953 Å. The third hydrogen bond is formed between the
nitrogen atom (N19) to the water molecule (O6) with
dN3eO6 ¼ 2.999 Å and dN3HeO6 ¼ 2.147 Å (for detailed information
see Table 5). The resulting structure is shown in Fig. 4A. The com-
pounds 2e4 belong to type III. Within this type the DHEC molecules
are connected via hydrogen bonds including the bridging crystal
water (see Fig. 4AeC). No direct interaction between the DHEC
molecules is formed. Three different types of hydrogen bonds can
be identified. One hydrogen bond is formed between the oxygen
atom of the water molecule and oxygen atom bound to the piper-
azine moiety with dO6eO5 within a range of 2.794e2.840 Å and
Fig. 3. Stereographic representation showing the overlay of the three DHEC sol-
vatomorphs containing additional solvent molecules in the crystal structure: (A)
methanol (purple), chloroform (orange), and 1,4 dioxane (blue; QABBUQ); (B) chlo-
roform (orange), dichloromethane (grey), and acetonitrile (green). (For interpretation
of the references to colour in this figure legend, the reader is referred to the web
version of this article.)
d
O6HeO5 1.905e2.137 Å. Another hydrogen bond is formed between
water and the piperidine moiety in the range of dO6eN6
2.827e2.859 Å and dO6HeN6 1.924e1.995 Å. The third hydrogen
bond is formed between water and the indole moiety. The corre-
sponding distances are in a range of dO6eN1 2.777e2.855 Å and
The resulting structures consist of layers stacked parallel to the
aec-plane. Between these layers cavities for the solvent molecules
can be found. The solvent molecules are not involved in the
d
O6eHN1 1.928e2.014 Å (for detailed information see Table 5). The
corresponding structure motifs involving the connection to the
water molecules are shown in Fig. 4

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393
Table 4
Different dimensionality of the packing of the crystal structures.
Structure type
I
II
III
Compound
Included Solvent
Intramolecular hydrogen bond
Interactions between
QABBUQ [19]
2ꢁ Dioxane molecules
þ
1
H2O
þ
2e4
H2O þ other
þ
1 Dioxane e DHEC
DHECeDHEC
2ꢁ H2O-DHEC
3D network
3ꢁ H2O-DHEC
Network/Packing
Dimers
2 D Layer structure
Fig. 4. Obtained structures showing the influence of the water molecules on the packing arrangement (A compound 1, B compound 2, C compound 3, D compound 4).
Table 5
Intermolecular hydrogen bonds of compound 2, 3 and 4.
Compound
O
WatereO5 (piperazine)
O
WatereN6 (piperidine)
OWatereN1 (indole)
dO6eO5 [Å]
dO6HeO5 [Å]
dO6eN6 [Å]
dO6HeN6 [Å]
dO6eN1 [Å]
dO6eHN1 [Å]
1
2
3
4
2.808
2.840
2.825
2.794
1.953
2.137
1.936
1.905
2.999
2.859
2.835
2.827
2.147
1.995
1.961
1.924
2.864
2.855
2.806
2.777
2.037
2.014
1.954
1.928
interaction between the different layers. In Fig. 5 the possible vol-
ume (voids) without the corresponding solvent (water, chloroform)
of compound 2 are depicted exemplarily [25]. The potential solvent
area in this case would be 671.7 Å3 per unit cell volume of 3775.2 Å3
(17.8%).
Despite these similarities the conformation of the DHEC mole-
cule is slightly different due to the solvent involved in the crystal
lattice (see Fig. 4). Depending on the existing solvent in the layer
cavities different lattice constants are realized (see Table 1).
Fig. 6 presents the different crystal packing mentioned above
and the corresponding powder patterns for compound 2e4. The
small changes of the lattice constants lead to a significant shifting of
the peaks in the powder pattern.
To estimate the suitability of DHEC as template for EA in the MIP
synthesis, a Hirshfeld surface analysis was performed [22e24]. One
hastokeepinmind thatatemplateshould mimicthesizerespectively
the volume and the potential binding sites capable of the EAs. The
Hirshfeld surface analysis depicted in Fig. 7 covers the relevant

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B. Monch et al. / Journal of Molecular Structure 1105 (2016) 389e395
394
Fig. 5. Voids of compound 2 by excluded solvents.
Fig. 7. Hirshfeld surface of compound 2 (A) and ergotamine (B) [25] mapped with dnorm
over the range of ꢂ0.572 and 1.854 The normalized contact distance dnorm is defined in
terms of de, di and the vdW radii of the atoms, where de is the distance from a point on the
surface to the nearest nucleus outside the surface and di is the distance from a point on
the surface to the nearest nucleus inside the surface. Red colour indicates distances
shorter than the sum of vdW radii through white to blue which distances longer than
sum of vdW radii (For details see Ref. [24]). (For interpretation of the references to colour
in this figure legend, the reader is referred to the web version of this article.)
Fig. 8. Electrostatic potential mapped on Hirshfeld surface for compound 2 (A) and
ergotamine (B). The potential are mapped over the range of 0.002 a.u. and were
calculated using Gaussian09 and the HF/Midi! e wavefunction [26].
formed during polymerization. The functionalized monomers used
should arrange around the template DHEC in a way that the
resulting binding sites could interact selective with the corre-
sponding part of EAs.
4. Conclusion
Dihydroergocristine seems to be
a suitable template for
molecularly imprinted polymers for the epimeric specific analysis
of ergot alkaloids. DHEC was crystallized from different solvents
and the obtained crystals were characterized by single crystal X-ray
analysis. The structural analysis showed that depending on the
solvent different solvatomorphs are formed containing DHEC, wa-
ter molecules and additional solvent molecules in the assymetric
unit. These solvatomorphs can be divided into three types of crystal
structures in consequence of the different affinity towards forming
hydrogen bonds. The obtained structures indicate that the absolute
configuration remains unchanged and is in accordance with the
expected values. The analysis of the overall geometry, the surface
and volume of the DHEC molecule in the different crystal structures
confirm that DHEC is a suitable template for mimicking ergot al-
kaloids for molecularly imprinted polymers.
Fig. 6. A) View of the unit cells of compound 2 (orange), 3 (grey) and 4 (green) and B)
the corresponding powder patterns (calculated). (For interpretation of the references
to colour in this figure legend, the reader is referred to the web version of this article.)
parameters for compound 2 in comparisonwith ergotamine, a typical
EA. It could be seen that the parameters for DHEC are in a very good
agreement with the ones for ergotamine. Therefore, DHEC is able to
form suitable cavities for EAs during the MIP synthesis process.
The comparison of the calculated electrostatic potentials (Fig. 8)
for both substances suggests a good accordance of the binding sites
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.2015.10.008.

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395
1395e1399.
References
€
€
[15] R. Koppen, T. Rasenko, S. Merkel, B. Monch, M. Koch, J. Agric. Food Chem. 61
(2013) 10699e10707.
[16] P. Lenain, J.D. Mavungu, P. Dubruel, J. Robbens, S. De Saeger, Anal. Chem. 84
(2012) 10411e10418.
[1] European Food Safety Authority (EFSA), Panel on Contaminants in the Food
Chain (CONTAM). Scientific opinion on ergot alkaloids in food and feed, EFSA J.
10 (2012) 2798e2955.
[2] E.L. Komarova, O.N. Tolkachev, The chemistry of peptide ergot alkaloids, part
1. Classification and chemistry of ergot peptides, Pharm. Chem. J. 35 (2001)
304e513.
[3] L. Pierri, I.H. Pitman, I.D. Rae, D.A. Winkler, P.R. Andrews, Conformational
analysis of the ergot alkaloids ergotamine and ergotaminine, J. Med. Chem. 25
(1982) 937e942.
[4] C. Müller, S. Kemmlein, H. Klaffke, W. Krauthause, A. Preiss-Weigert,
R. Wittkowski, Mol. Nutr. Food Res. 53 (2009) 500e507.
[5] C. Müller, H.S. Klaffke, W. Krauthause, R. Wittkowski, Mycotoxin Res. 22
(2006) 197e200.
[17] G.M. Sheldrick, Acta Crystallogr. Sect. A 64 (2008) 112e122.
[18] H.D. Flack, Acta Crystallogr. Sect. A 39 (1983) 876e881.
ꢁ
[19] J. Cejka, B. Kratochvil, A. Jegorov, L. Cvak, Z. Krist. New Cryst. Struct. 212
(1997) 111e112.
ꢁ
ꢀꢁ
ꢁꢀ
[20] J. Cejka, J. Ondracek, M. Husak, B. Kratochvíl, A. Jegorov, J. Stuchlík, Collect.
Czechoslov. Chem. Commun. 60 (1995) 1333e1342.
[21] L.J. Farrugia, J. Appl. Crystallogr. 30 (1997) 565.
[22] F.L. Hirshfeld, Theor. Chim. Acta 44 (1977) 129e138.
[23] M.A. Spackman, P.G. Byrom, Chem. Phys. Lett. 267 (1997) 215e220.
[24] M.A. Spackman, D. Jayatilaka, Cryst. Eng. Comm. 11 (2009) 19e32.
[25] S. Pakhomova, J. Ondracek, M. Husak, B. Kratochvil, A. Jegorov, J. Stuchlík, Acta
Crystallogr. Sect. C 51 (1995) 308.
[6] R. Krska, G. Stubbings, R. Macarthur, C. Crews, Anal. Bioanal. Chem. 391 (2008)
563e576.
[26] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheese-
man, G. Scalmani, V. Barone, B. Mennucci, G.A. Petersson, H. Nakatsuji, M.
Caricato, X. Li, H.P. Hratchian, A.F. Izmaylov, J. Bloino, G. Zheng, J.L. Sonnen-
berg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery, Jr., J.E.
Peralta, F. Ogliaro, M. Bearpark, J.J. Heyd, E. Brothers, K.N. Kudin, V.N. Star-
overov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C. Burant, S.S.
Iyengar, J. Tomasi, M. Cossi, N. Rega, J.M. Millam, M. Klene, J.E. Knox, J.B. Cross,
V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J.
Austin, R. Cammi, C. Pomelli, J.W. Ochterski, R.L. Martin, K. Morokuma, V.G.
Zakrzewski, G.A. Voth, P. Salvador, J.J. Dannenberg, S. Dapprich, A.D. Daniels,
[7] C. Crews, W.A.C. Anderson, G. Rees, R. Krska, Food Addit. Contam. Part B
Surveill. 2 (2009) 79e85.
[8] M.K. Kokkonen, M.N. Jestoi, Food Anal. Methods 2 (2009) 128e140.
[9] R. Mohamed, E. Gremaud, J. Richoz-Payot, J.C. Tabet, P.A. Guy, J. Chromatogr. A
1114 (2006) 62e72.
[10] C. Klug, W. Baltes, W. Kronert, R. Weber, Z. Leb. Unters. Forsch. 186 (1988)
108e113.
[11] C. Klug, W. Baltes, W. Kronert, R. Weber, Z. Leb. Unters. Forsch. 179 (1984)
245e246.
€
[12] J. Wolff, C. Neudecker, C. Klug, R. Weber, Z. Ernahrungswiss. 27 (1988) 1e22.
[13] U. Lauber, R. Schnaufer, M. Gredziak, Y. Kiesswetter, Mycotoxin Res. 21 (2005)
258e262.
[14] G.M. Ware, G. Price, L. Carter, R.R. Eitenmiller, J. AOAC Int. 83 (2000)
€
O. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox, Gaussian, Inc.,
Wallingford CT, (2009).