research communications Acta Cryst. (2019). E75, 277–283 https://doi.org/10.1107/S2056989019001464 277 Received 31 December 2018 Accepted 25 January 2019 Edited by J. Ellena, Universidade de Sa ˆo Paulo, Brazil Keywords: crystal structure; tetraphosphonate cavitands; inclusion compounds; mephedrone; illicit drugs. CCDC reference: 1893628 Supporting information: this article has supporting information at journals.iucr.org/e Crystal structure of a host–guest complex between mephedrone hydrochloride and a tetraphosphonate cavitand Elisa Biavardi and Chiara Massera* Dipartimento di Scienze Chimiche, della Vita e della Sostenibilita ` Ambientale, Universita ` di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy. *Correspondence e-mail: [email protected]A new supramolecular complex (I) between the tetraphosphonate cavitand Tiiii[C 3 H 7 ,CH 3 ,C 6 H 5 ] [systematic name: 2,8,14,20-tetrapropyl-5,11,17,23-tetra- methyl-6,10:12,16:18,22:24,4-tetrakis(phenylphosphonato-O, O 0 )resorcin[4]- arene] and mephedrone hydrochoride {C 11 H 16 NO + Cl ; systematic name: methyl[1-(4-methylphenyl)-1-oxopropan-2-yl]azanium chloride} has been obtained and characterized both in solution and in the solid state. The complex of general formula (C 11 H 16 NO)@Tiiii[C 3 H 7 ,CH 3 ,C 6 H 5 ]ClCH 3 OH or C 11 H 16 NO + Cl C 68 H 68 O 12 P 4 CH 3 OH, crystallizes in the monoclinic space group P2 1 /c with one lattice methanol molecule per cavitand, disordered over two positions with occupancy factors of 0.665 (6) and 0.335 (6). The mephedrone guest interacts with the P O groups at the upper rim of the cavitand through two charge-assisted N—HO hydrogen bonds, while the methyl group directly bound to the amino moiety is stabilized inside the basic cavity via cationinteractions. The chloride counter-anion is located between the alkyl legs of the cavitand, forming C—HCl interactions with the aromatic and methylenic H atoms of the lower rim. The chloride anion is also responsible for the formation of a supramolecular chain along the b-axis direction through C—HCl interactions involving the phenyl substituent of one phosphonate group. C— HO and C—Hinteractions between the guest and adjacent cavitands contribute to the formation of the crystal structure. 1. Chemical context Mephedrone (2-methylamino-1-p-tolylpropan-1-one), often abbreviated as 4-MMC, the acronym of 4-methyl methcathi- none, is a synthetic drug belonging to the family of metham- phetamines known for its stimulant effects (Winstock et al., 2010; Morris, 2010; Wood et al., 2010). It can be considered a ‘designer drug’, that is, a compound resulting from the chemical modification of an existing drug, which in this case is cathinone, a natural alkaloid found in the plant Catha edulis. As a result of the major impact these substances have on human health and social security, it is extremely important to have sensitive, selective and fast methods to identify them as a class, independently from all the synthetic modifications that can be devised to market them and to bypass the legal restrictions to which the parent compounds are subjected. Among the existing analytical methods used to detect 4-MMC in human biological samples or in different media (water, mixtures of powders, etc), solid-phase extraction (SPE) and liquid chromatography combined with mass spectrometry (LC/MS) are the most common, as can be seen from the ISSN 2056-9890
25
Embed
Crystal structure of a host–guest complex between ......‘designer drug’, that is, a compound resulting from the chemical modification of an existing drug, which in this case
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
arene] and mephedrone hydrochoride {C11H16NO+�Cl�; systematic name:
methyl[1-(4-methylphenyl)-1-oxopropan-2-yl]azanium chloride} has been
obtained and characterized both in solution and in the solid state. The complex
of general formula (C11H16NO)@Tiiii[C3H7,CH3,C6H5]Cl�CH3OH or
C11H16NO+�Cl��C68H68O12P4�CH3OH, crystallizes in the monoclinic space
group P21/c with one lattice methanol molecule per cavitand, disordered over
two positions with occupancy factors of 0.665 (6) and 0.335 (6). The mephedrone
guest interacts with the P O groups at the upper rim of the cavitand through
two charge-assisted N—H� � �O hydrogen bonds, while the methyl group directly
bound to the amino moiety is stabilized inside the � basic cavity via cation� � ��interactions. The chloride counter-anion is located between the alkyl legs of the
cavitand, forming C—H� � �Cl interactions with the aromatic and methylenic H
atoms of the lower rim. The chloride anion is also responsible for the formation
of a supramolecular chain along the b-axis direction through C—H� � �Cl
interactions involving the phenyl substituent of one phosphonate group. C—
H� � �O and C—H� � �� interactions between the guest and adjacent cavitands
contribute to the formation of the crystal structure.
1. Chemical context
Mephedrone (2-methylamino-1-p-tolylpropan-1-one), often
abbreviated as 4-MMC, the acronym of 4-methyl methcathi-
none, is a synthetic drug belonging to the family of metham-
phetamines known for its stimulant effects (Winstock et al.,
2010; Morris, 2010; Wood et al., 2010). It can be considered a
‘designer drug’, that is, a compound resulting from the
chemical modification of an existing drug, which in this case is
cathinone, a natural alkaloid found in the plant Catha edulis.
As a result of the major impact these substances have on
human health and social security, it is extremely important to
have sensitive, selective and fast methods to identify them as a
class, independently from all the synthetic modifications that
can be devised to market them and to bypass the legal
restrictions to which the parent compounds are subjected.
Among the existing analytical methods used to detect 4-MMC
in human biological samples or in different media (water,
mixtures of powders, etc), solid-phase extraction (SPE) and
liquid chromatography combined with mass spectrometry
(LC/MS) are the most common, as can be seen from the
Figure 1ORTEP view of (C11H16NO)@Tiiii[C3H7,CH3,C6H5]Cl (I) with partialatom-labelling scheme and anisotropic displacement parameters drawn atthe 20% probability level. The solvent molecules and the H atoms of thecavitand are omitted for clarity; only one orientation of the disorderedalkyl chain is shown.
The chloride anion is located between the alkyl legs of the
cavitand, with a Cl1� � �N1 distance of 7.097 (5) A, forming
numerous C–H� � �Cl interactions with the aromatic and
methylenic hydrogen atoms of the lower rim (see Table 1), as
well as a hydrogen bond with the O2S—H2S group of the
methanol molecule of occupancy factor 0.665 (6) [O2S—
H2S� � �Cl1, 3.105 (5) A and 168.5 �]. Moreover, the O1S atom
from the other methanol fraction accepts a hydrogen bond
from the methyl group C3 of the mephedrone guest [C3—
H3B� � �O1S, 3.51 (2) A and 164.3 �].
3. Supramolecular features
Besides the supramolecular interactions that yield the 1:1
host–guest complex, mephedrone hydrochloride also influ-
ences the overall packing of the crystal structure, as can be
seen from Figs. 4 and 5. The chloride anion is responsible for
the formation of a supramolecular chain along the b-axis
direction through C14B—H14B� � �Cl�(�x, 12 + y, 3
2 � z)
contacts involving the phenyl substituents of one of the four
phosphonate groups (Fig. 4). On the other side, the cationic
part of the guest is involved in C—H� � �O and C—H� � ��interactions with the phenyl ring bound to the P1D O3D
group and the aromatic ring C1D–C6D belonging to the wall
of an adjacent cavitand (Fig. 5 and Table 2). More precisely,
the oxygen atom O1 of the guest acts as a hydrogen-bond
acceptor towards the C17Di—H17Di group [3.204 (6) A and
125.0�; symmetry code (i):�x + 1, y + 12,�z + 3
2], while C9—H9
and C10—H10 act as donors towards the centroid Cg2i
[3.594 (5) A and 158.7�] and the oxygen atom O1Di
[3.555 (4) A and 151.8�], respectively. These sets of inter-
actions can be summarized visually by calculating the two-
dimensional fingerprint plots derived from the Hirshfeld
surface analysis (Spackman & McKinnon, 2002; McKinnon et
al., 2004), using the program Crystal Explorer 17 (Turner et al.,
2017). The overall fingerprint plot for (I) is shown in Fig. 6a
and those delineated in H� � �H (67.8%), C� � �H/H� � �C
Figure 2Left: view of the main host–guest supramolecular interactions shown asblue and green dotted lines. Only relevant H atoms are shown, while thealkyl chains, the chloride anion and the methanol lattice molecules havebeen omitted for clarity. Right: side view of the host–guest complex.
Figure 3Supramolecular interactions (blue dotted lines) involving the chlorideanion (represented as a green sphere) and the disordered methanollattice molecules.
4. Studies in solution
In solution, complexation was observed both via phosphorous
and proton NMR spectroscopy following the shift of the 31P
signals of the Tiiii[C3H7, CH3, Ph] host and the shift of the+N—CH3 protons of the mephedrone hydrochloride guest.
The titration was performed in deuterated methanol at 253 K,
in order to be under slow chemical exchange in the NMR time
scale and better observe the complexation event. The NMR
tube was filled with 0.4 mL of a deuterated methanol solution
containing the cavitand (7.5 mM concentration). The meph-
edrone hydrochloride titrant solution was prepared by
dissolving the guest in 0.1 mL of deuterated methanol
(31 mM). Two portions (0.5 eq., 48.5 mL) of the titrant were
added by syringe to the NMR tube. During the titration, the
phosphorous singlet of the cavitand shifted downfield, from
8.70 (free host) to 11.14 ppm upon addition of one equivalent
of the guest (Fig. 7a and 7c), indicating the presence of cation–
Figure 4View of the packing of (I) along the b-axis direction, mediated by C14B—H14B� � �Cl� interactions (blue lines). The C and H atoms highlighted in purpleare in general positions, while the chloride anion is at the symmetry position �x, 1
2 + y, 32 � z.
Figure 5View of the packing of (I) mediated by C—H� � �O and C—H� � �� interactions between the guests and adjacent cavitands. Symmetry code: (i) 1� x, 1
2 + y,32 � z.
dipole interactions between the +N–CH3 and the phosphonate
groups at the upper rim. The addition of 0.5 eq. of guest
caused the appearance of two phosphorous signals at 8.74 and
11.14 ppm related to the free host and to the complex,
respectively (Fig. 7b).
In the proton NMR, after the addition of 0.5 equivalent of
mephedrone hydrochloride the diagnostic upfield shift of the
guest +N–CH3 signals was observed, as expected for the
shielding effect caused by its inclusion in the aromatic cavity
of the host (Fig. 8b). After the addition of one equivalent of
guest, the +N—CH3 singlet appeared still shifted upfield but
broadened (Fig. 8c).
5. Database survey
As already discussed in Section 1, tetraphosphonate cavitands
of general formula Tiiii[R, R1, R2] (where R, R1 and R2 are
the substituents at the lower rim, on the four benzene rings of
the cavity, and on the phosphonate groups, respectively;
Pinalli et al., 2004), are excellent receptors for molecular
recognition of neutral and charged guests because of the
presence of P O groups that act as hydrogen-bond acceptors,
and of the aromatic cavity that allows the formation of C—
H� � �� interactions. The substituent R at the lower rim can be
modified to tune the solubility of the host, to enhance the
crystallization process, or to graft the cavity on different
surfaces, but does not play any significant role in the recog-
nition process, if not that of interacting with the anionic
counterpart of a positively charged guest. A search in the
Cambridge Structural Database (Version 5.38, update August
2018; Groom et al., 2016) for a tetraphosphonate scaffold
without limitations on R, R1 and R2 yielded 82 hits, with the
most populated class (44 hits) being the one of general
formula Tiiii[H, CH3, CH3]. The substitution of the alkyl
chains with hydrogen atoms favours the formation of crystals,
albeit lowering the solubility of the macrocycle, and the
methyl group on the phosphonate moiety generates less steric
hindrance than a phenyl one. Besides these general consid-
erations, the most interesting structural comparisons with the
title compound are to be made with supramolecular
complexes in which the guests are: (i) the zwitterionic species
Figure 6The full two-dimensional fingerprint plot (a) and those delineated intoH� � �H (b), C� � �H/H� � �C (c), O� � �H/H� � �O (d) and Cl� � �H/H� � �Cl (e)contacts for (I).
Figure 731P NMR (162 MHz, MeOD, 253 K) spectra of (a) free host Tiiii[C3H7,CH3, Ph]; (b) addition of 0.5 equivalent of mephedrone HCl to the hostsolution; (c) addition of 1 equivalent of mephedrone HCl to the hostsolution.
Figure 81H NMR (400 MHz, MeOD, 253 K) spectra of (a) free host Tiiii[C3H7,CH3, Ph]; (b) addition of 0.5 equivalent of mephedrone HCl to the hostsolution; (c) addition of 1 equivalent of mephedrone HCl to the hostsolution. The arrows indicate the up-shift of +N—CH3 protons.
RefinementR[F 2 > 2�(F 2)], wR(F 2), S 0.077, 0.275, 1.02No. of reflections 15077No. of parameters 929No. of restraints 2H-atom treatment H-atom parameters constrained�max, �min (e A�3) 1.78, �0.52
Computer programs: APEX2 and SAINT (Bruker, 2008), SIR97 (Altomare et al., 1999),SHELXL2014/7 (Sheldrick, 2015), Mercury (Macrae et al., 2006), WinGX (Farrugia,2012), PARST (Nardelli, 1995) and publCIF (Westrip, 2010).
atoms were refined isotropically. Four reflections showing
poor agreement (031, 231, 020 and 231) were omitted from the
final refinement.
Acknowledgements
The Centro Interfacolta di Misure ‘G. Casnati’ and the
‘Laboratorio di Strutturistica Mario Nardelli’ of the Univer-
sity of Parma are kindly acknowledged for the use of NMR
and Maldi-MS facilities and of the diffractometer. Permission
to use small quantities of illicit drugs has been granted in the
framework of the FP7 Dirac project by the Italian Ministero
della Salute.
Funding information
Funding for this research was provided by: European Union
through the DIRAC project (award No. FP7-SEC-2009-
242309); Regione Lombardia-INSTM, SNAF project .
References
Altomare, A., Burla, M. C., Camalli, M., Cascarano, G. L.,Giacovazzo, C., Guagliardi, A., Moliterni, A. G. G., Polidori, G.& Spagna, R. (1999). J. Appl. Cryst. 32, 115–119.
Biavardi, E., Battistini, G., Montalti, M., Yebeutchou, R. M., Prodi, L.& Dalcanale, E. (2008). Chem. Commun. pp. 1638.
Biavardi, E., Federici, S., Tudisco, C., Menozzi, D., Massera, C.,Sottini, A., Condorelli, G. G., Bergese, P. & Dalcanale, E. (2014).Angew. Chem. Int. Ed. 53, 9183–9188.
Biavardi, E., Ugozzoli, F. & Massera, C. (2015). Chem. Commun. 51,3426–3429.
Bruker (2008). APEX2, SAINT and SADABS. Bruker AXS Inc.,Madison, Wisconsin, USA.
Castro, A. de, Lendoiro, E., Fernandez-Vega, H., Steinmeyer, S.,Lopez-Rivadulla, M. & Cruz, A. (2014). J. Chromatogr. A, 1374,93–101.
Clement, P., Korom, S., Struzzi, C., Parra, E. J., Bittencourt, C.,Ballester, P. & Llobet, E. (2015). Adv. Funct. Mater. 25, 4011–4020.
Concheiro, M., Anizan, S., Ellefsen, K. & Huestis, M. A. (2013). Anal.Bioanal. Chem. 405, 9437–9448.
Cram, D. J. (1983). Science, 219, 1177–1183.Cram, D. J. & Cram, J. M. (1994). Container Molecules and their
Guests, Monographs in Supramolecular Chemistry, vol. 4, edited byJ. F. Stoddart. Royal Society of Chemistry, Cambridge.
Dougherty, D. A. (2013). Acc. Chem. Res. 46, 885–893.Dutasta, J.-P. (2004). Top. Curr. Chem. 232, 55–91.Farrugia, L. J. (2012). J. Appl. Cryst. 45, 849–854.Fontanals, N., Marce, R. M. & Borrull, F. (2017). J. Chromatogr. A,
1524, 66–73.Frison, G., Gregio, M., Zamengo, L., Zancanaro, F., Frasson, S. &
Sciarrone, R. (2011). Rapid Commun. Mass Spectrom. 25, 387–390.Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta
Cryst. B72, 171–179.Kanu, A. B., Brandt, S. D., Williams, M. D., Zhang, N. & Hill, H. H.
(2013). Anal. Chem. 85, 8535–8542.Kolmonen, M., Leinonen, A., Kuuranne, T., Pelander, A. & Ojanpera,
I. (2009). Drug Test. Anal. 1, 250–266.Lendoiro, E., Jimenez-Morigosa, C., Cruz, A., Paramo, M., Lopez-
Rivadulla, M. & de Castro, A. (2017). Drug Test. Anal. 9, 96–105.Lua, I. A., Lin, S.-L., Lin, H. R. & Lua, A. C. (2012). J. Anal. Toxicol.
36, 575–581.Macrae, C. F., Edgington, P. R., McCabe, P., Pidcock, E., Shields, G. P.,
Taylor, R., Towler, M. & van de Streek, J. (2006). J. Appl. Cryst. 39,453–457.
Mayer, M., Benko, A., Huszar, A., Sipos, K., Lajtai, A., Lakatos, A. &Porpaczy, Z. (2013). J. Chromatogr. Sci. 51, 851–856.
McKinnon, J. J., Spackman, M. A. & Mitchell, A. S. (2004). ActaCryst. B60, 627–668.
Melegari, M., Massera, C., Pinalli, R., Yebeutchou, R. M. &Dalcanale, E. (2013). Sens. Actuators B, 179, 74–80.
Mercieca, G., Odoardi, S., Cassar, M. & Strano Rossi, S. (2018). J.Pharm. Biomed. Anal. 149, 494–501.
Mercolini, L., Protti, M., Catapano, M. C., Rudge, J. & Sberna, A. E.(2016). J. Pharm. Biomed. Anal. 123, 186–194.
Morris, K. (2010). Lancet, 375, 1333–1334.Mwenesongole, E. M., Gautam, L., Hall, S. W., Waterhouse, J. W. &
Cole, M. D. (2013). Anal. Methods 5, 3248–3254.Nardelli, M. (1995). J. Appl. Cryst. 28, 659.Pedersen, A. J., Dalsgaard, P. W., Rode, A. J., Rasmussen, B. S.,
Muller, I. B., Johansen, S. S. & Linnet, K. (2013). J. Sep. Sci. 36,2081–2089.
Perera, R. W. H., Abraham, I., Gupta, S., Kowalska, P., Lightsey, D.,Marathaki, C., Singh, N. S. & Lough, W. J. (2012). J. Chromatogr. A,1269, 189–197.
Pinalli, R., Dalcanale, E., Ugozzoli, F. & Massera, C. (2016).CrystEngComm, 18, 5788–5802.
Pinalli, R., Pedrini, A. & Dalcanale, E. (2018). Chem. Eur. J. 24, 1010–1019.
Pinalli, R., Suman, M. & Dalcanale, E. (2004). Eur. J. Org. Chem. pp.451–462.
Power, J. D., McDermott, S. D., Talbot, B., O’Brien, J. E. & Kavanagh,P. (2012). Rapid Commun. Mass Spectrom. 26, 2601–2611.
Robin, T., Barnes, A., Dulaurent, S., Loftus, N., Baumgarten, S.,Moreau, S., Marquet, P., El Balkhi, S. & Saint-Marcoux, F. (2018).Anal. Bioanal. Chem. 410, 5071–5083.
Salomone, A., Gazzilli, G., Di Corcia, D., Gerace, E. & Vincenti, M.(2016). Anal. Bioanal. Chem. 408, 2035–2042.
Santali, E. Y., Cadogan, A.-K., Daeid, N. N., Savage, K. A. & Sutcliffe,O. B. (2011). J. Pharm. Biomed. Anal. 56, 246–255.
Sheldrick, G. M. (2015). Acta Cryst. C71, 3–8.Singh, N., Day, P., Katta, V. R., Mohammed, G. P. & Lough, W. J.
(2010). J. Pharm. Pharmacol. 62, 1209–1210.Spackman, M. A. & McKinnon, J. J. (2002). CrystEngComm, 4, 378–
392.Strano-Rossi, S., Anzillotti, L., Castrignano, E., Romolo, F. S. &
Chiarotti, M. (2012). J. Chromatogr. A, 1258, 37–42.Strano-Rossi, S., Odoardi, S., Fisichella, M., Anzillotti, L., Gottardo,
R. & Tagliaro, F. (2014). J. Chromatogr. A, 1372, 145–156.Trzcinski, J. W., Pinalli, R., Riboni, N., Pedrini, A., Bianchi, F.,
Zampolli, S., Elmi, I., Massera, C., Ugozzoli, F. & Dalcanale, E.(2017). ACS Sens. 2, 590–598.
Tudisco, C., Fragala, M. E., Giuffrida, A. E., Bertani, F., Pinalli, R.,Dalcanale, E., Compagnini, G. & Condorelli, G. G. (2016). J. Phys.Chem. C, 120, 12611–12617.
Turner, M. J., Mckinnon, J. J., Wolff, S. K., Grimwood, D. J.,Spackman, P. R., Jayatilaka, D. & Spackman, M. A. (2017). CrystalExplorer 17. The University of Western Australia.
Vachon, J., Harthong, S., Jeanneau, E., Aronica, C., Vanthuyne, N.,Roussel, C. & Dutasta, J.-P. (2011). Org. Biomol. Chem. 9, 5086–5091.
Vircks, K. E. & Mulligan, C. C. (2012). Rapid Commun. MassSpectrom. 26, 2665–2672.
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925.Winstock, A. R., Marsden, J. & Mitcheson, L. (2010). BMJ, 340,
c1605.Wood, D. M., Davies, S., Puchnarewicz, M., Button, J., Archer, R.,
Ovaska, H., Ramsey, J., Lee, T., Holt, D. W. & Dargan, P. I. (2010).J. Med. Toxicol. 6, 327–330.
Wu, Y. L., Tancini, F., Schweizer, B. W., Paunescu, D., Boudon, C.,Gisselbrecht, J.-P., Jarowski, P. D., Dalcanale, E. & Diederich, F.(2012). Chem. Asian J. 7, 1185–1190.
Hydrogen site location: inferred from neighbouring sites
H-atom parameters constrainedw = 1/[σ2(Fo
2) + (0.1708P)2 + 6.7275P] where P = (Fo
2 + 2Fc2)/3
(Δ/σ)max = 0.001Δρmax = 1.78 e Å−3
Δρmin = −0.52 e Å−3
supporting information
sup-2Acta Cryst. (2019). E75, 277-283
Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)