Alkyl Spacer Length and Protonation Induced Changes in Crystalline

Subscriber access provided by CORNELL UNIVERSITY LIBRARY

Article

Alkyl spacer length and protonation induced changes in crystalline psychoactive arylpiperazine derivatives: singlecrystal X-ray, solid-state NMR, and computational studies Edyta Pindelska, Izabela D. Madura, #ukasz Szeleszczuk, Anna #eszko, Jolanta Ja#kowska, Paulina H. Marek, and Waclaw Kolodziejski Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00993 • Publication Date (Web): 15 Sep 2016 Downloaded from http://pubs.acs.org on September 19, 2016

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Crystal Growth & Design is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Alkyl spacer length and protonation induced changes in crystalline psychoactive arylpiperazine derivatives: single-crystal X-ray, solid-state NMR, and computational studies Edyta Pindelska,* a Izabela D. Madura,b Łukasz Szeleszczuk,c Anna Żeszko,a Jolanta Jaśkowska,d Paulina H. Marek, b Waclaw Kolodziejski a a

Faculty of Pharmacy, Medical University of Warsaw, Department of Inorganic and Analytical Chemistry, Banacha 1, 02-093 Warsaw, Poland; b Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland; c Faculty of Pharmacy, Medical University of Warsaw, Department of Physical Chemistry, Banacha 1, 02-093 Warsaw, Poland; d Cracow University of Technology, Institute of Organic Chemistry and Technology, 24 Warszawska Street, 31-155 Cracow, Poland.

A series of new long-chain arylpiperazine (LCAP) derivatives with a flexible alkyl spacer were synthesized. A controversy concerning a role of the spacer, whether it participates actively in binding to 5-HT1A and D2 receptors or it acts as a distance arm, encouraged us to check how the molecular and crystal structure changes with the increased length of the alkyl linker (from four CH2 units to six). In this study both the basic active compounds as well as their hydrochlorides were studied. Single crystal X-ray (scX-ray) structure analysis with combination of

13

C,

15

N solid state NMR (ssNMR) spectroscopy supported by gauge-including projector-

augmented wave (GIPAW) calculations of chemical shielding were used. These studies were aimed to examine, elucidate and compare molecular conformations and to point out the most important intermolecular interactions leading to large supramolecular synthons formed in crystals of both bases and hydrochlorides.

Edyta Pindelska Faculty of Pharmacy Medical University of Warsaw Banacha 1, 02-093 Warsaw, Poland

phone: 48 225720757 fax: 48 225720784 e-mail: [email protected]

ACS Paragon Plus Environment

1


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 46

Alkyl spacer length and protonation induced changes in crystalline psychoactive arylpiperazine derivatives: single-crystal X-ray, solid-state NMR, and computational studies Edyta Pindelska,* a Izabela D. Madura,b Łukasz Szeleszczuk,c Anna Żeszko,a Jolanta Jaśkowska,d Paulina H. Marek, b Waclaw Kolodziejski a a

Faculty of Pharmacy, Medical University of Warsaw, Department of Inorganic and Analytical

Chemistry, Banacha 1, 02-093 Warsaw, Poland. b

Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw,

Poland. c

Faculty of Pharmacy, Medical University of Warsaw, Department of Physical Chemistry,

Banacha 1, 02-093 Warsaw, Poland d

Cracow University of Technology, Institute of Organic Chemistry and Technology, 24

Warszawska Street, 31-155 Cracow, Poland. [email protected]


1

Page 3 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ABSTRACT: A series of new long-chain arylpiperazine (LCAP) derivatives with a flexible alkyl spacer were synthesized. A controversy concerning a role of the spacer, whether it participates actively in binding to 5-HT1A and D2 receptors or it acts as a distance arm, encouraged us to check how the molecular and crystal structure changes with the increased length of the alkyl linker (from four CH2 units to six). In this study both the basic active compounds as well as their hydrochlorides were studied. Single crystal X-ray (scX-ray) structure analysis with combination of

13

C,

15

N solid state NMR (ssNMR) spectroscopy supported by

gauge-including projector-augmented wave (GIPAW) calculations of chemical shielding were used. These studies were aimed to examine, elucidate and compare molecular conformations and to point out the most important intermolecular interactions leading to large supramolecular synthons formed in crystals of both bases and hydrochlorides. INTRODUCTION A knowledge about a conformation of compounds with potential biological activity is essential for studies of receptor-ligand interactions in silico.1-5 An ability to computationally simulate and predict the most important conformations and their relative changes is of great interest not only because of a possibility for a design of new generic selective ligands, but also because these conformations may represent recognizable functionally selective states.6,7 Usually, as a starting point for such studies the results of experimentally characterized crystal structures of ligands are used. It is important to note that a ligand rarely binds to a receptor with strong covalent bonds, rather weak reversible noncovalent interactions are engaged.8 Therefore, a knowledge about possible interactions which may be formed by the ligand seem to be valuable. Numerous experimental techniques which allow investigations of intermolecular interactions are known.9 Among them single crystal X-ray diffraction studies are the most widely used because


2


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 46

they provide accurate and reliable three-dimensional structural data which can be used for the detailed analysis of spatial relationships. Solid-state NMR (ss-NMR) spectroscopy combined with quantum mechanical computations of NMR shielding is complementary technique to X-ray crystallography for characterizing crystal structures, since the electronic environment of the observed nucleus is affected by the local molecular neighborhood.10-14 It has been shown that employment of all these techniques enable to analyze even subtle intra- and intermolecular structural effects.15 Our paper deals with arylpiperazine derivatives (Scheme 1), known psychoactive agents and an interesting target in a search for antidepressant drugs.16,17 It is thought that a beneficial effect of these derivatives is due to their impact on serotonin and dopamine receptors activity. 5Hydroxytyryptamine (5-HT, serotonin) is one of the major neurotransmitters in a control of the nervous system.18 Serotonin system has been linked to various psychiatric diseases, including depression, alcoholism, anxiety, epilepsy, pain and many others.19,20 The most promising group of 5-HT1A receptor ligands are Long-Chain Aryl-Piperazines (LCAPs) with several successfully developed drugs: buspirone, tandospirone, aripiprazole and pharmacological tools (NAN-190, flexinoxan, WAY 1000135, WAY 100063).21,22 Whereas dopamine is a neurotransmitter synthesized in dopaminergic neurons and released to simulate G proteincoupled receptors, affecting movement, cognition and emotion. The dopamine receptors are divided into: D1-like receptors and D2-like receptors, on the basics of signaling properties and sequence similarity. Dysfunction with the dopamine system can lead to a variety of pathological conditions, including Parkinson’s disease, schizophrenia, ADHD and drug addiction.23,24 Arylpiperazines are also a group of compounds for which accumulated knowledge and published structure-activity relationship (SAR) studies provide comprehensive data to design


3

Page 5 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


active ligands with a relatively high degree of accuracy.25 The general method for prediction of the receptor-ligand supermolecular assemblies is to use non-covalent interactions, such as hydrogen bonds, to guide the organization of small molecules into larger clusters. Therefore, from a structural viewpoint, it would be especially attractive to compare the crystal and molecular structures of the same arylpiperazine in a form of a free base with a corresponding salt, the most convenient a hydrochloride.26 Also, in the case of derivatives containing arylpiperazine fragment the SAR studies focus on the three main structural parts: an aryl group at nitrogen atom of the piperazine ring, an aliphatic chain at second N atom of the piperazine and a terminal fragment, which has an amide or imide moiety.25 In molecules under discussion in the aryl position substituted 2,3-dichlorophenyl is located (similarly to aripiprazole) while the heterocyclic head is isoindoline-1,3-dione (like in NAN-190). The arylpiperazine, a tail of the molecule, and a heterocyclic head are separated with the spacer, a chain of 4-6 methylene groups –(CH2)n–. There has been a controversy concerning the role of the spacer, whether it participates actively in binding to a receptor or it acts simply as a distance arm.27 Therefore, we decided to check how and if the linker is engaged in intermolecular interactions. For this purpose we investigated a formation of large supramolecular synthons28 and long-range synthon Aufbau modules (LSAM).29 The latter are said to be intermediates between small synthons (e.g. hydrogen bonded dimers) and 3D crystal.30 Hence, they might reflect possible binding sites of LCAPs with a receptor. Moreover, we examine an odd-even effect31,32 if it can be applied here to depict the role of the spacer on the molecular conformation and packing. Further, due to the presence of the basic nitrogen in the piperazine ring the studied compounds may bind to receptors as free bases or in protonated forms. Therefore


4


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 46

in this study both basic active forms (L4, L5 and L6) as well as their hydrochlorides (L4HCl, L5HCl, and L6HCl) are considered. EXPERIMENTAL SECTION Sample preparation. L4-L6 and L4HCl-L6HCl were synthesized according to known methods described previously.33 The structure of the compounds was confirmed by 13C and 1H NMR spectroscopy (for more details see the Supporting Information). The high quality single crystals of studies compounds were obtained by slow evaporation from a methanol solution. Solid-State NMR Spectroscopy. 13C and 15N spectra were recorded at room temperature with a Bruker Avance 400 WB spectrometer (B0 = 9.4 T) using 100.61 and 40.50 MHz resonance frequencies, respectively. The NMR experiments were done using cross-polarization (CP), high power decoupling and magic-angle spinning (MAS)34-36 using a Bruker 4.0 mm HX CP/MAS probe with zirconia rotors driven by dry air. The MAS rates were 8 kHz and 3.5-5.0 kHz for 13C and

15

N, respectively. The Hartmann-Hahn conditions for

13

C and

15

N were matched using

adamantane and glycine 15-N, respectively. Typical

13

C acquisition parameters were as follows: a proton initial π/2 pulse of 2.4 µs, a

proton lock-field of 69.4 kHz, a carbon lock-field of 61.4 kHz (CP matched on the first Hartmann-Hahn sideband), a proton decoupling field of 104.2 kHz, an acquisition time of 29 ms, SW = 261 ppm, TD = 1518, zero-filling to SI = 4 k, an optimized contact time of 4 ms and optimized recycle delays in the 70 – 250 s range. Chemical shifts were referenced to TMS using glycine as an external secondary standard (δ = 176.5 ppm from TMS for the high-frequency peak). The differences in the recycle delays reflect differences in the proton spin-lattice relaxation of the studied samples. We checked that they cannot be simply explained by proton density in those solids. Therefore, both proton-proton dipolar couplings and molecular mobility


5

Page 7 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


must be responsible for the differences in the proton relaxation. A solution of this problem is beyond the scope of this work. The

15

N CP/MAS spectra were acquired under the following conditions: a proton initial π/2

pulse of 4.1 µs, a proton lock-field of 61.0 kHz, a nitrogen lock-field from 56.0 to 57.5 kHz (CP matched on the first Hartmann-Hahn sideband), a proton decoupling field of 104.2 kHz, an acquisition time of 42 ms, SW = 600 ppm, TD = 2 k complex points, zero-filling to SI = 4 k, an optimized contact time of 5 ms and optimized recycle delays the same as for 13C CP/MAS NMR. The 15N chemical shifts were referenced to liquid nitromethane by setting the −345 ppm value to the peak of crystalline glycine-15N. The NMR spectra were processed and peaks were deconvoluted with the ACD/SpecMenager NMR program.37 Crystal structure determination. Single crystals of L4-L6 and L4HCl-L6HCl suitable for X-ray diffraction studies were selected under a polarizing microscope. Diffraction data were measured at room temperature on a Rigaku Oxford Diffraction Gemini A Ultra diffractometer using mirror monochromated CuKα radiation (λ = 1.54184 Å). Cell refinement and data collection as well as data reduction were performed with CrysAlisPro software.38 The empirical absorption corrections using spherical harmonics, implemented in multi-scan algorithm, were performed. The structures were solved by direct methods using SHELXT program39 and refined by full-matrix least-squares method against F2 using the SHELXL program40 implemented in the OLEX2 suite.41 All non-hydrogen atoms were refined with anisotropic displacement parameters. Carbon-bounded hydrogen atoms were added to the structure model at geometrically idealized coordinates and refined using a riding model approximation with Uiso(H) = 1.2×Ueq(CH and CH2). At the final stage of the refinement of L6 and L5HCl a disorder in a region of the linker was detected and modeled. The refined partial occupancies for a major component amounted to


6


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 8 of 46

0.673(5) and 0.612(13), respectively. In the case of L4 some residual electron density has been noted near the linker site but no reasonable disorder model could be achieved. Molecular diagrams were generated using: ORTEP-3 for Windows

42

(Fig. 2), Diamond43 (Figs 6 and 8)

and Mercury 2.044 (Fig. 3) programs. The crystal data and structure refinement parameters are given in Table 1. Table 1. Crystallographic Parameters for the Crystal Structures of L4-L6 and L4HCl-L6HCl. Compound

L4

L5

L6

L4HCl

L5HCl

L6HCl

Formula

C22H23Cl2N3O2

C23H25Cl2N3O2

C24H27Cl2N3O2

C22H24Cl3N3O2

C23H26Cl3N3O2

C24H28Cl3N3O2

m.wt.

432.33

446.36

460.38

468.79

482.82

496.84

monoclinic

monoclinic

monoclinic

monoclinic

orthorhombic

monoclinic

T (K)

293

293

293

293

293

293

Space group

P21/c

P21/c

P21/c

P21/n

Pna21

P21/n

a/Å

14.1231(3)

20.2776(5)

23.2382(2)

8.5129(2)

40.276(2)

14.4749(1)

b (Å)

8.8446(1)

4.7720(1)

12.11614(9)

6.9549(1)

8.4426(2)

7.5906(1)

c(Å)

17.1068(3)

23.6385(5)

8.42195(7)

37.8682(7)

6.9742(2)

22.2297(2)

α (°)

90

90

90

90

90

90

β (°)

94.591(2)

107.851(2)

97.0198(8)

91.843(2)

101.094(4)

90.9772(8)

γ (°)

90

90

90

90

90

90

V (Å3)

2130.02(7)

2177.25(9)

2353.48(3)

2240.89(7)

2371.5(1)

2442.09(4)

Z

4

4

4

4

4

4

Dcalc

1.348

1.362

1.299

1.390

1.352

1.351

Crystal system


7

Page 9 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(g/cm3) R1 (I > 2σ (I))

0.0523

0.0350

0.0372

0.0429

0.0416

0.0360

wR2 (all data)

0.1576

0.0980

0.1026

0.1212

0.1082

0.0992

Hirshfeld surface analysis. The molecular Hirshfeld surfaces (HS)45,46 and their associated 2D-fingerprint plots47 were calculated from crystal structure coordinates using CrystalExplorer program.48 The surfaces are constructed based on the electron distribution calculated as a sum of spherical atom electron densities. The normalized contact distance (dnorm) based on both de (the distances from the surface to the closest atom outside the surface) and di, (the distances from the surface to the closest atom inside the surface) and the vdW radii (r) of atoms is given by the equation: dnorm = [(di − ri)/ ri]+[(de− re)/ re].46 In Figure 4 the HS are mapped with dnorm over the range of −0.5 to 1.5 with the red-white-blue coloring scheme. The 2D-fingerprint plots47 were derived from the HS by plotting the fraction of points on the surface as a function of the pair (di, de). The range of fractions spanning 0.05% of surface areas was used. The decomposed fingerprint plots46 presenting particular contacts with the outline of the full fingerprint in gray are shown in Figure 5 and 7. GIPAW DFT calculations. The quantum-chemical calculations of geometry, energy and NMR shielding constants were carried out with the CASTEP program

49

implemented in the

Materials Studio 6.1 software.50,51 Geometry optimizations and calculations of NMR chemical shielding were performed using the plane wave pseudopotential formalism and the PerdewBurke-Ernzerhof (PBE) exchange-correlation functional, defined within the generalized gradient approximation (GGA) and the dispersion-interaction contributions were considered using the Tkatchenko-Scheffler (TS) method

52

for density functional theory dispersion correction (DFT-


8


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 10 of 46

D). All the calculations were done with ultrasoft pseudopotentials calculated on the fly, the quality of calculations was set to fine as implemented in the CASTEP standards. CASTEP default values for the geometry convergence criteria were used. The kinetic energy cutoff for the plane waves was set to 550 eV. Brillouin zone integration was performed using a discrete 2×2×1 for Monkhorst-Pack k-point sampling for a primitive cell. The computation of shielding tensors was performed using the gauge-including projector-augmented wave (GIPAW) method of Pickard et al.53 In the calculations the experimental X-ray structures were used but the positions of all atoms were optimized, while the cell parameters were fixed. To compare the theoretical and experimental data, the calculated chemical shielding constants (σiso) were converted to chemical shifts (δiso), using the following equation: δiso = (σGly + δGly) – σiso, where σGly and δGly stand for the shielding constant and the experimental chemical shift, respectively, of the glycine carbonyl carbon atom (176.5 ppm). Cohesion energy DMol3 calculations. DFT calculations of cohesion energy were performed using the DMol3 program package, implemented in the Materials Studio 6.1. software. In the DMol3,

54 -56

physical wavefunctions are expanded in terms of accurate numerical basis sets. A

double-numerical quality basis set with polarization functions (DNP) was used. It should be noted that the DNP basis set included a double zeta quality basis set that added a p-type and dtype polarization function to a hydrogen and heavier atoms, respectively. This is comparable to the 6-31G** Gaussian basis set,57 but DNP is more accurate than a Gaussian basis set of the same size.58

- 60

The Perdew-Burke-Ernzerhof (PBE) exchange-correlation functional, defined

within the generalized gradient approximation (GGA) and the dispersion-interaction contributions were considered using the Tkatchenko-Scheffler (TS) method52 for density functional theory dispersion correction (DFT-D). To improve computational performance, a


9

Page 11 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Fermi smearing of 0.005 hartrees and a global orbital cutoff of 4.5 Å were employed. The tolerances of the energy, gradient, and displacement convergences were 2×10−5 hartrees, 4×10−3 hartrees Å−1, and 5×10−3 Å, respectively. The electronic self-consistent field was converged to 1×10−5 eV. The cohesion energy (Ecoh) was calculated following the procedure described in the literature:61 Ecoh = Z-1×Ebulk - Emol where Ebulk is the total energy of a system (calculated per unit cell) and Emol is the energy of an isolated molecule extracted from the bulk (with the same geometry as in the crystal phase). Z stands for the number of molecules in the unit cell. In these calculations the experimental X-ray structures were used with the optimized positions of all atoms and the cell parameters fixed to their experimental values. RESULTS AND DISCUSION The presented analysis addresses conformational differences in the molecular structure of three designed ligands that may have an impact on serotonin and dopamine receptors’ activity. The idea of synthesizing 2-[4-(4-(2,3-dichlorophenyl)piperazyn-1-yl)butyl]izoindolo-1,3-dione (L4), 2-[4-(4-(2,3-dichlorophenyl)piperazyn-1-yl)pentyl]izoindolo-1,3-dione (L5), 2-[4-(4-(2,3dichlorophenyl)piperazyn-1-yl)heksyl]izoindolo-1,3-dione (L6) was based on the known activity of arypiprazole and NAN-190 drugs from the group of the Long-Chain Aryl-Piperazines (LCAPs).27 In our case the head from arypiprazole and the tail form NAN-190 are associated by the aliphatic chain (a long chain spacer) of a different length (4-6 CH2 groups). First of all we wanted to check how the elongation of the spacer affects the shape of the molecules in question and further the crystal packing, and if an odd-even effect31 may help to explain the observed differences. In parallel, the comparison between the basic form of the potent drug and its ionic


10


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 46

analogue (the hydrochloride) is presented. The results of biological activity of these new ligands will be presented elsewhere. The studied arylpiperazines molecules are presented in Scheme 1. The Figure 1 shows

13

C

CP/MAS NMR spectra of the studied crystalline forms of L4-L6 and L5HCl-L6HCl, whereas Table S2 presents

13

C NMR chemical shifts of these compounds. The

13

C CP/MAS NMR

experimental shifts are in good agreement with the CASTEP calculated isotropic shielding, as for all studied compounds the root mean square deviation (RMSD) between experimental and calculated δ values falls within a typical variation range of 1–4 ppm.62,63

Scheme 1.Numbering system used in ssNMR and scX-ray analyses


11

Page 13 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 1. The

13

C CP/MAS NMR spectra of L4-L6 and L4HCl-L6HCl acquired with 4 ms

contact time The free bases (L4-L6) crystallize in P21/c space group symmetry of the monoclinic system (Table 1). The hydrochlorides L4HCl and L6HCl also crystallize in the monoclinic system however, P21/n settings have been chosen. In the case of L5HCl the molecules crystallize in polar Pna21 symmetry space group. In all cases one molecule only is present in an asymmetric part of a unit cell. This is consistent with the

13

C NMR spectra wherein no signal splitting has

been observed (Fig. 1). What is more, the number of signals in the spectra is lower than the number of carbon atoms in all L4-L6 and L5HCl-L6HCl molecules. This indicates that some signals are overlapped due to similarity of chemical shifts values. First, the comparison of the


12


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 46

molecular shape will be discussed followed by the analysis of the major interactions between molecules.

Figure 2. ORTEP42 drawings of L4-L6 and L4HCl-L6HCl molecules. The ellipsoids are shown at 50% probability Molecular conformations. The comparison of the geometrical parameters for all studied compounds indicated some essential differences connected either with the protonation of the base or the length of the linker (Table S4). A slight elongation of bonds to the protonated N2 atom in the hydrochlorides series when comparing to the bases is observed. It is consistent with the

15

N NMR spectra. After the protonation, a signal of N2 atom is shifted in the direction of

higher

15

N chemical shift values and it is at -326.3 ppm for L4HCl (change by 6.6 ppm

comparing to L4), at -325.7 ppm for L5HCl (change by 4.7 ppm) and at -324.2 ppm for L6HCl


13

Page 15 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(change by 6.9 ppm). The protonation also affects the nearest C20 atom of the linker. The signal of C20 is also shifted and appears at 56.0 ppm for L4HCl (change by 2.0 ppm), at 56.5 ppm for L5HCl (change by 3.8 ppm) and at 57.6 ppm for L6HCl (change by 1.5 ppm). No substantial difference in chemical shifts has been observed for C8 and C10 atoms of the piperazine unit. It is noteworthy that in all compounds studied the piperazine ring shows a chair conformation with an amplitude parameter Q~0.59 Å.64 A magnitude of distortions from an ideal cyclohexane C-form is 2º for the bases and somewhat bigger (4-6º) for the protonated forms (see Table S3 in the Supporting Information). No further differences in bond lengths and bond angles are meaningful while the inspection of torsion angles values showed the substantial changes in molecular conformations generated by the length of the linker and the protonation.

Figure 3. Overlay of molecules showing the spacer effect (a) and protonation effect (b). The piperazine fragments were kept as a reference. Hydrogen atoms are omitted for clarity. Dots represent position of carbon atoms in disordered fragments The influence of the linker is observed in the relevant orientations of the head and the tail towards the piperazine moiety (Fig. 3 and 4). The expected odd-even effect should be present in the orientation of the end of the head, i.e. the fused ring system.32 However, in the studied series


14


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 16 of 46

it is only true when comparing the conformation of L4 and L5 molecules whereas L6 is rotated on N2−C20 bond, thus the orientation of the very end is not similar to buthyl linker (Fig.2 and 3a). The torsion angle C8–N2−C20−C22 (τ) describing these conformational differences is 58.1(4)º and -170.69(12)º for L4 and L6, respectively (-71.66(18)º for L5). In the series of hydrochlorides (Fig. 2 and 3a) the pentyl derivative is twisted on N2−C20 bond with the τ angle equals to -169.7(3)º while for L4HCl and L6HCl τ is -68.8(2) and -71.6(2)º, respectively. Noteworthy, in both molecules showing the τ angle close to 180º the substantial disorder of the linker is observed. Instead, the odd-even effect is observed when comparing the orientation of the head fragment towards the piperaziene ring (Fig.2 and 3). The values for C1−C6−N1−C9 torsion angles for derivatives with an even linker are ~70º while for pentyl ones they are equal to 150º (Table S3 in the Supporting Information). Interestingly, the dihedral angle between the dichlorophenyl ring and a least-square plane of the piperazine in the case of odd-linker derivatives being ~55º is very close to the angle observed for L4HCl (53.5º) molecules. Such orientation might cause a slight elongating of N1−C9 bond in these three compounds what is consistent with 15N CP/MAS NMR spectra. This orientation results in similar chemical shifts for the N1 nitrogen atom in the case of L4HCl and L5HCl (-322.6 and -321.7 ppm, respectively). The 15N chemical shifts value for N1 in the case of L6HCl is much higher and is -315.2 ppm. Summing up, the protonation only slightly affects the geometrical parameters such as bond lengths and bond angles. This may lead to conclusion that in form of hydrochlorides, a popular method for improving bioavailability of weakly soluble drugs, the structure of the discussed compounds is maintained. On the other hand the conformation changes both upon protonation and the length of the linker. The only regular variation introduced by the length of the linker can be seen in the change of the dihedral angle between planes defined by the head and by the tail. In


15

Page 17 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the case of acids it is gradually increasing with the elongation of the linker from almost parallel alignment in L4HCl (twist angle ~5º) to almost 45º in L6HCl. Whereas, in the bases this angle is almost unchanged and exceeds 60º (Table S3). Crystal packing. The above discussed conformational similarities and differences have further consequences in the molecular packing. In the hydrochlorides charge assisted N2−H2...Cl3 hydrogen bonds are formed (Table 3). Nevertheless, this H-bonding leads only to a finite 0D motif, so weak interactions only are responsible for the 3D structure formation, akin to a situation in free bases. Hence, the analysis of Hirshfeld surfaces (HSs) has been used to elucidated the most important intermolecular interactions wherein for hydrochlorides the HSs have been calculated for neutral adducts. Also, the resolved fingerprint plots have been generated to point out the directional interactions and/or substantial stacking. In all cases the red spots on Hirshfeld surfaces (Fig. 4) indicating short contacts are present mostly at regions of a tail (aromatic ring and Cl atoms) and a head (aromatic rings and carbonyl groups) as well as at the piperazine hydrogen atoms. Noteworthy is a minor role of the spacer in the most important interactions.

Figure 4. The HSs mapped with dnorm for L4-L6 and L4HCl-L6HCl


16


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 18 of 46

Table 2. Geometry of intra- and intermolecular interactions for compounds L4-L6 (Å, °) H…A

D…A

D–H…A

Symmetry code

L4 Intramolecular

C9–H9B…Cl1

2.64

3.243(3)

120

Motif a

C19–H19B…Cl1

2.80

3.718(4)

157

x, –y+3/2, z–1/2

Motif b

C8–H8B…Cg1_head*

2.73

3.699(3)

174

x, 3/2–y, 1/2+z

Other interactions

Cg1_head…Cg2_head

3.636(2)

1–x, 2–y, –x

C10–H10B...O1

2.70

3.411(2)

128

x, 5/2–y, 1/2+z

Intramolecular

C9–H9A…Cl1

2.78

3.331(2)

116

Motif a

C18–H18…O2

2.52

3.351(3)

148

–x, 2–y, 1–z

Other interactions

C21–H21B…Cl2

2.909

3.761(2)

147

–x+1, –y+2, –z+1

C1–Cl1…Cg_tail

3.664(1)

89.23(5)

x, –1+y, z

C12–O2…Cg2_head

3.685(2)

74.3(1)

x, –1+y, z

Cg1_head…Cg2_head

3.804(1)

L5

x, –1+y, z

L6 Intramolecular

C9–H9B…Cl1

2.60

3.216(2)

122

Motif a

C3–H3…O2

2.53

3.360(7)

149

1–x, 1–y, 1–z

Motif b

C23–H23B…Cg_tail

2.88

3.690(4)

142

1–x, 1–y, 1–z

Motif c

C11–O1…C12–O2

3.084(8)

152.9(5)

x, 1/2–y, 1/2+z

Motif d

C5–H5…C1

3.605(4)

150

x, 1/2–y, -1/2+z

2.77

*Cg1_head, Cg2_head and Cg_tail denote centers of gravity of 5-member izoindolo–1,3-dione, 6-member ring of fused system and 2,3-dichlorophenyl rings, respectively.

In the case of free bases odd analogues the HSs indicated the main role of a head-to-tail arrangement of the molecules while the even one, L5, exhibits a head-to-head connection. In L4 the C19−H19...Cl1 H-bonds (Table 2, Fig. 6) are responsible of the formation of a chain structure along the [001] direction by adjoining the molecules related by a glide plane. This motif is described by C(12) graph set65,66 and shows the rod group symmetry pc.67 It is clearly visible


17

Page 19 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


at the HS as well as causes the big change in chemical shift for C1 carbon atom in 13C CP/MAS NMR for L4 comparing to L5 and L6 (124.7 ppm, 131.9 ppm and 131.9 ppm respectively). The H…Cl/Cl…H resolved fingerprint plot revealed high directionality of these interactions (Fig. 5). Additionally, the chain is enhanced by relatively short C8−H8b…π (head) contacts of H…Cg distance of 2.73 Å, also discernible on the HS surface (Fig. 4). Interestingly, in this case the shift of C8 is reversed. The analysis of packing of these supramolecular entities showed that they are nearly hexagonally packed (Fig. 6). This points out that a large supramolecular synthon28 is in this case in a form of the infinite chain and can be treated as a long-range synthon Aufbau module (LSAM).29 The stacking and C−H…O interactions further joins the chains into a 3D structure (Table 2).

Figure 5. Resolved 2D-fingerprint plots for L4-L6


18


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 20 of 46

Figure 6. The large supramolecular synthons and packing of LSAMs (in a form of nodes showing the shape of molecules: a red end represents a head, a blue fragment the piperazine and the spacer while the green stands for a tail; for rings, their centers of gravity have been chosen and the connections goes through all three nitrogen atoms) for L4-L6 compounds


19

Page 21 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


As already mentioned, in the case of L6 the head-to-tail connection is also realized but in this case a R22(36) centrosymmetric dimer is formed via C3−H3…O2 H-bonds (Table 2). The dimer is enhanced by C23−H23B…π contacts between a donor from the linker and the head fragment. The basic ring extends along the [100] direction and it is further joined by carbonyl-carbonyl interactions occurring between head fragments (Table 2). This short contacts as well as C5−H5…π(tail) interactions are detectable on the HS surface (Fig. 4). These three motives constitute a layer on (100) plane which is actually composed of hexagonally packed dimers (Fig. 6). Surpassingly, none of these contacts is clearly detected in

13

C CP/MAS NMR spectra. This

may be due to the observed disorder in the linker and the head fragment. In L5 derivative the centrosymmetric dimer is also formed but the linking is in a head-to-head manner via C18−H18…O2 H-bonds (Table 2). This interaction is visible in the

13

C CP/MAS

NMR spectrum. Interestingly, the relatively long contact between C21−H21a…Cl2 (d C…Cl = 3.761 Å), hardly visible on the HS surface, corresponds well with solid state NMR spectrum. In the compound L5 chemical shift value for C21 carbon atom increased by 4.2 ppm and 2.8 ppm relative to L4 and L6, respectively. These interactions join dimers into a chain along the [100] direction. However, the analysis of fingerprint plots, particularly in comparison with L4, indicated that this C−H…Cl interactions are rather of secondary importance together with numerous short contacts between aromatic rings and carbonyl oxygen or chlorine atoms (Table 2). Therefore, the observed 0D dimer can be regarded as the large synthon while the 2D layer on plane (001) showing p21/b layer group symmetry might be treated as the LSAM (Fig. 6). Summing up, in the case of bases the following large synthons have been detected: 1D chains for L4, and 0D dimers for L5 and L6. The 2D layers composed of hexagonally packed long 0D dimers are observed in L6.


20


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 46

Table 3. Geometry of intra- and intermolecular interactions for L4HCl-L6HCl (Å, °) H…A

D…A

D–H…A

Symmetry code

L4HCl Intramolecular

C9–H9B…Cl1

2.77

3.282(2)

113

0D

N2–H2…Cl3

2.19(3)

3.029(2)

169(2)

Motif a

C7–H7A…O2

2.46

3.417(2)

171

1–x, 2–y, 1–z

Motif b

C9–H9B…O2

2.49

3.166(2)

127

–x, 2–y, 1–z

other interactions

C8–H8A…Cl3

2.81

3.656(2)

146

1–x, 1–y, 1–z

C20–H20A…Cl3

2.76

3.715(2)

169

–x, 1–y, 1–z

C10–H10A…Cl3

2.75

3.642(2)

153

x, 1+y, z

Cg1_head…Cg_tail

3.614(1)

1–x, 2–y, 1–z

C9–H9B…C12

2,73

3.615(3)

153

–x, 2–y, 1–z

Intramolecular

C7–H7A…C11

2.81

3.325(4)

114

0D

N2–H2…Cl3

2.07(4)

3.041(3)

169(3)

Motif a

C7–H7A…O1

2.50

3.164(4)

125

1/2–x, 1/2+y, 1/2+z

other interactions

C20–H20A…Cl3

2.75

3.633(4)

152

x, y, 1+z

C8–H8B…Cl3

2.87

3.739(4)

149

x, y, 1+z

C10–H10B…Cl3

2.93

3.774(4)

146

1/2–x, -1/2+y, 1/2+z

L5HCl

Cg1_head…Cg_tail

3.685(2)

1/2–x, 1/2+y, –1/2+z

C7–H7A...C11

2.68

3.561(5)

151

1/2–x, 1/2+y, 1/2+z

C4–H4…O2

2.66

3.564(4)

164

1/2–x, -1/2+y, –1/2+z

C9–H9B…O1

2.63

3.552(4)

159

1/2–x, –1/2+y, 1/2+z

C17–H(17)…O2

2.66

3.378(4)

134

1–x, 1–y, –1/2+z

Intra

C9–H9B…Cl(1)

2.55

3.177(2)

123

Intra

C19–H19B…O1

2.53

2.910(2)

103

0D

N2–H2…Cl3

2.20(2)

3.064(2)

176(1)

L6HCl


21

Page 23 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Motif a

C21–H21A…Cl1

2.79

3.375(2)

119

1–x, 2–y, 1–z

Motif b

C12–O2…Cg_tail

3.3023(16)

41.32

1–x, 1–y, 1–z

other interactions

C3–H3…Cl3

2.82

3.5956(18)

141

–x, 1–y, 1–z

C15–H15…Cl3

2.80

3.550(2)

139

3/2–x, 1/2+y, 1/2–z

C19–H19A…O1

2.54

3.414(3)

150

3/2–x, -1/2+y, 1/2–z

*Cg1_head, Cg2_head and Cg_tail denote centers of gravity of 5-member izoindolo–1,3-dione, 6-member ring of fused system and 2,3-dichlorophenyl rings, respectively

In L4HCl a ribbon synthon formed of alternating molecules linked in head-to-tail manner is observed (Fig. 8). It is constructed by two C−H…O motives, both R22(22), clearly discernible on the HS (Fig. 4, Table 3). In both of them O2 atom acts as an acceptor while the donors are piperazine protons occupying equatorial position in proximity of the N1 atom. Additionally, close C9−H9B…π contacts which appears on the C…H/H…C resolved finger print plot as quite sharp whiskers instead of broad “wings”46 are enhancing this supramolecular entity (Fig. 7). The ribbons arrange along the [100] direction and exhibits p-1 rod group symmetry.67 They are further joined by three charge assisted C−H…Cl3 interactions leading to a layer structure on plane (001). The pale red spots on the HS correspond to these contacts. The 3D structure is achieved by weak C−H…Cl, C−H…O and C−H…π occurring between layers related by 21 screw axis, however these interactions are not visible on the HS. Surpassingly there are no significant differences in

13

C CP/MAS NMR spectra for L4HCl and L5HCl. This observation

can be substantiate by the comparison of their crystal packing, particularly the form of LSAMs.


22


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 46

Figure 7. Resolved 2D-fingerprint plots for L4HCl-L6HCl


23

Page 25 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 8. The large supramolecular synthons and packing of LSAMs (in a form of nodes showing the shape of the molecules: a red end represents a head, a blue fragment the piperazine and the spacer while the green stands for a tail; for rings, their centers of gravity have been chosen and the connections goes through all three nitrogen atoms) for L4HCl-L6HCl compounds. The chlorine ions are shown as green spheres of arbitrary chosen radius. In the case of L5HCl the polar crystals have been detected (Table 1). The primary motif is also the ribbon extending along the [011] direction and composed of molecules related by the n glide plane. Similarly to L4HCl, the most intense red spots on the HS correspond to C7−H7A…O1 interactions. They form a serpentine-like motif described by C(12) graph set65,66


24


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 46

in which the molecules are joined in the head-to-tail manner. The adjacent linear sections are additionally joined by weaker C−H…O, π−π and C−H…Cl interactions (Table 3). The ribbons are further linked by stacking interactions between the head and the tail with the separation distance of 3.685(2) Å. In the layer there are also C20−H20A…Cl3 hydrogen bonds. The layers show pnn1 layer group symmetry67 and similarly to L4HCl a 3D structure is achieved by adjoining the sheets related by 21 screw axis through weaker contacts, not appearing on the HS. Hence, in both compared hydrochloride derivatives the LSAMs are akin, and what is more they are piled along the longest unit cell vector, being 37.8682(7) and 40.276(2) Å for L4HCl and L5HCl, respectively (Table 1). In the case of the hydrochloride derivative with the longest linker, L6HCl, the analyses of 13C CP/MAS NMR spectrum revealed some significant differences in comparison to derivatives with shorter linkers. The

13

C chemical shifts for C1 and C21 correspond to C21−H21A…Cl1

interactions joining the molecules into a R22(26) dimer. Together with the C=O…π short contacts they constitute the ribbon of molecules arranged in the head-to-tail manner along the [010] direction. Such ribbons are roughly hexagonally packed albeit numerous interactions occurring between them can be also discernible in the HS. Some of these short contacts influence the value of chemical shift for appropriate carbon atoms in 13C CP/MAS NMR spectra. The chemical shift value of C3 increased from 122.9 ppm and 124.6 ppm (L4HCl and L5HCl, respectively) to 126.3 ppm due to C3−H3…Cl3 interaction observed in L6HCl. The interaction C15−H153…Cl3 also observed in L6HCl contributed to the increase in the value of C15 chemical shift. While the presence of C21−H1…O1 contact causes the increase in C21 chemical shifts value, from 25.3 ppm for L4HCl and 28.6 ppm for L5HCl to 30.9 ppm for L6HCl.


25

Page 27 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 4. Cohesion Energy Values (Ecoh, kJ × mol-1) of the studied compound L4-L6 and L4HClL6HCl Structure L4 L4HCl L5 L5HCl L6 L6HCl

Ecoh -261.5 -848.0 -276.3 -846.6 -277.8 -862.8

It is important to note that in hydrochlorides only the head-to-tail arrangement is observed. It is in line with the calculated dipole moments for the head and the protonated piperazine and the tail fragments (see Supporting Information). The vectors are oppositely oriented and they magnitude amount to 2.29 and 9.23 D, respectively. In the case of bases the dipole moments of both parts are of comparable value and they are equal for the head and the tail fragment 2.29 and 2.60 D, respectively. In acids, the largest dipole-dipole effect seems to be observed for the longest spacer where the calculated cohesion energy is by 20 kJ/mol bigger than for remaining structures in the series of hydrochlorides (Table 4). In the case of L4HCl and L5HCl the comparable value of cohesion energy may result from similar LSAM structure. Generally, the energetic results (Table 4) clearly indicate a significant increase in crystal cohesion energy per ASU when compound exists in the hydrochloride form. This is due to the strong electrostatic interaction between the chloride and protonated bases. In the free bases series when more methylene groups are introduced the cohesion energy becomes more beneficial.


26


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 46

CONCLUSION The conducted studies allowed us to show how the molecular and the crystal structure changes with the increased length of the spacer and upon the protonation. The only regular variation introduced by the length of the linker can be seen in the change of the dihedral angle between planes defined by the head and by the tail. We also noted that in molecules showing the substantial disorder in the region of the flexible linker the τ angle changes from ~60 to ~180º. Whereas the protonation of N2 nitrogen atom in all cases affects only slightly the geometrical parameters such as bond lengths and bond angles. This may lead to conclusion that in the form of hydrochlorides, a popular method for improving bioavailability of weakly soluble drugs, the molecular structure of the discussed compounds is maintained. The geometrical parameters and Hirshfeld surface analyses, as well as differences in carbon atoms chemical shifts in 13C CP/MAS NMR spectra enabled us to elucidated the most important interactions present in crystals of the discussed compounds. Their dominant role over other contacts has been proven by indicating the large synthons and packing of long-range synthon Aufbau modules. It has been found that similar LSAM structure in the case of L4HCl and L5HCl results in the comparable value of calculated cohesion energy. In general, the lack of ionic interaction causes the cohesion energy to be almost twice lower. Concerning the role of the spacer, no significant intermolecular interactions with methylene groups of the linkers have been found. ASSOCIATED CONTENT Supporting Information. 1H and 13C NMR chemical shifts in CDCl3 solutions (Table S1), 13

C and 15N CP/MAS NMR chemical shifts (Table S2), 15N CP/MAS NMR spectra (Figure S1),


27

Page 29 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


selected geometrical parameters (Table S3) for all characterized compounds in this paper. The fragments of studied molecules used to calculate the dipole moments (Figure S2). Values of the 13

C and

15

N isotropic (δiso) and calculated chemical shifts anisotropy (CSA) for L4-L6 and

L4HCl-L6HCl (Table S4).

Accession Codes. X-ray crystallographic information data (CIFs) are included at the end of the SI file which is available free of charge via the Internet at http://pubs.acs.org. Moreover the CCDC 1487030-1487035 records contain the 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: +44 1223 336033). AUTOR INFORMATION Corresponding Author. *E-mail address: [email protected] Faculty of Pharmacy, Medical University of Warsaw, Department of Inorganic and Analytical Chemistry, Banacha 1, 02-093 Warsaw, Poland. Notes. The authors declare no competing financial interest. ACKNOWLEDGMENT E. P. and A. Ż. are grateful to the Medical University of Warsaw for the ‘Young Researcher’ grant no. FW23/NM3/14. I. D. M and P. H. M. kindly acknowledge Warsaw University of Technology for the financial support.


28


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 46

REFERENCES

(1)

Thompson, H. P. G; Day, G. M. Chem Sci. 2014, 5, 3173-3182.

(2)

Christopher, J. A.; Brown, J.; Dore,́ A. S.; Errey, J. C. M. Koglin, Marshall, F. H.; Myszka, D. G.; Rich, R.; Tate, L.C. G.; Tehan, B.; Warne, T.; Congreve, M. J. Med. Chem. 2013, 56, 3446-3455.

(3)

Butini, S.; Gemma, S.; Campiani, G. J. Med. Chem. 2012, 55, 6687-6688.

(4)

Shim, J.; Mackerell A.D. Jr. Med. Chem. Comm. 2011, 2, 356-370.

(5)

Datta, S.; Grant, D. J. W. Nat Rev Drug Discov. 2004, 3, 42-57.

(6)

Lewgowd, W.; Bojarski, A. J.; Szczesio, M.; Olczak, A.; Główka, M. L.; Mordalski S.; Stanczak, A. Eur. J. Med. Chem. 2011, 46, 3348-3361.

(7)

Handzlik, J.; Szymańska, E.; Nędza, K.; Kubacka, M.; Siwek, A.; Mogilski, S.; Handzlik J.; Filipek, B.; Kieć-Kononowicz, K. Bioorg. Med. Chem. 2011, 19, 1349–1360.

(8)

Bielenica, A.; Kozioł, A. E.; Struga, M. Mini. Rev. Med. Chem. 2013, 13, 1516-1539.

(9)

Schermann, J. P. In Spectroscopy and Modeling of Biomolecular Building Blocks; Elsevier Science: Amsterdam, 2007, 1-480.

(10)

Trzeciak-Karlikowska, K.; Bujacz, A.; Jeziorna, A.; Ciesielski, W.; Bujacz, G. D.; Gajda, J.; Pentak, D.; Potrzebowski M. J. Cryst. Growth Des. 2009, 9, 4051-4059.

(11)

Hildebrand, M.; Hamaed, H.; Namespetra, A. M.; Donohue, J. M.; Fu, R.; Hung, I.; Gan, Z.; Schurko, R. W. CrystEngComm. 2014, 16, 7334-7356.


29

Page 31 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(12)

Macholl, S.; Tietze, D.; Buntkowsky, G. CrysEngComm 2013, 15, 8627-8638.

(13)

Mazur, L.; Jarzembska, K. N.; Kamiński, R.; Woźniak, K.; Pindelska, E.; ZielińskaPisklak, M. Cryst. Growth Des., 2014, 14, 2263-2281.

(14)

Mazur, L.; Jarzembska, K. N.; Kamiński, R.; Hoser, A. A.; Madsen, A. Ø.; Pindelska, E.; Zielińska-Pisklak, M. Cryst. Growth Des., 2016, 16, 3101–3112.

(15)

Slabicki, M. M.; Potrzebowski, M. J.; Bujacz, G.; Olejniczak, S.; Olczak, J. J. Phys. Chem. B 2004, 108, 4535–4545.

(16)

Oh, S. J.; Ha, H. J.; Chi, D. Y. Lee, H. K. Curr. Med. Chem. 2001, 8, 999-1034.

(17)

Lopez-Rodriquez, M. L.; Ayala, D.; Benhamu, B.; Morcillo, M. J.; Viso, A. Curr. Med. Chem. 2002, 9, 443-469.

(18)

Barnes, N.; Sharp, M. T. Neuropharmacology 1999, 38, 1083-1152.

(19)

Romero, A. G.; McCall, R. B. in: Advances in Medicinal Chemistry, J.A. Bristol (Ed.) Vol. 27, Academic Press, New York, 1991.

(20)

Filip, M.; Bader, M. Pharmacology Rep. 2009, 61, 761-777.

(21)

Glennon, R. A.; Naiman, N. A.; Lyon, R. A.; Titeler, M. J. Med. Chem. 1998, 31, 19681971.

(22)

Caliendo, G.; Santagada, V.; Perissutti E.; Fiorino, F. Curr. Med. Chem. 2005, 12, 17211753.


30


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(23)

Page 32 of 46

Missale, C; Nash, S.R.; Robinson, S. W.; Jaber, M.; Caron, M. G. Physopl. Rev. 1998, 78, 189-225.

(24)

Iversen S. D.; Iversen L. L. Trends Neurosci. 2007, 30, 188-193.

(25)

Lopez-Rodriquz, M. L.; Atala, D.; Benhamu, B., Morcillo, M. J.; Viso, A. Curr. Med. Chem. 2002, 9, 443-469.

(26)

Karolak-Wojciechowska, J.; Mrozek, A.; Fruziński, A.; Szczesio, M.; Kowalski, P.; Kowalska, T. J. Mol. Struc. 2010, 979, 144-151.

(27)

Foye, W. O.; Lemke, T. L.; Williams, D. A. Foye's Principles of Medicinal Chemistry; Philadelphia: Lippincott Williams & Wilkins Eds.; 2008.

(28)

Desiraju, G. R. J. Am. Chem. Soc. 2013, 135, 9952-9967.

(29)

Ganguly, P.; Desiraju G. R. CrystEngComm 2010, 12, 817–833.

(30)

Mukherjee, A.; Dixit, K.; Sarma, S. P.; Desiraju, G. R. IUCrJ 2014, 1, 228-239.

(31)

Mishra, M. K.; Varughese, S.; Ramamurty, U.; Desiraju, G. R. J. Am. Chem. Soc. 2013, 135, 8121-8124.

(32)

Saeki, M.; Dai, K.; Ichimura, S.; Tamaki, Y.; Tomono, K.; Miyamura; K. Dalton Trans. 2014, 43, 17067- 17074.

(33)

Kowalski, P.; Mitka, K.; Jaśkowska, J.; Duszyńska, B.; Bojarski, A. J. Archiv der Pharmazie 2013, 346, 339-348.

(34)

Pines, A.; Gibby, M. G.; Waugh, J. S. J. Chem. Phys. 1973, 59, 569-590.


31

Page 33 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(35)

Mehring, M. High-Resolution NMR Spectroscopy in Solids, Springer-Verlag, New York, 1983.

(36)

Stejskal, E. O.; Memory, J. D. High-Resolution NMR in the Solid State. Fundamentals of CP/MAS, Oxford University Press, Oxford, 1994.

(37)

ACD/SpecMenager, version 10.08, Advanced Chemistry Development, Inc., 2007.

(38)

CrysAlisPro 1.171.38.41 Rigaku Oxford Diffraction, 2015.

(39)

Sheldrick, G. M. Acta Cryst. 2015, A71, 3.

(40)

Sheldrick, G. M. Acta Cryst. 2015, C71, 3.

(41)

Dolomanov, O.V; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K; Puschmann, H. J. Appl. Cryst. 2009, 42, 339-341.

(42)

Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837-838.

(43)

Brandenburg, K. Diamond - Crystal and Molecular Structure Visualization, Version 3.2i; Crystal Impact GbR: Bonn, Germany.

(44)

Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek J.; Wood, P. A. J. Appl. Cryst. 2008, 41, 466-470.

(45)

Spackman, M. A.; Jayatilaka, D. CrystEngComm 2009, 11, 19-32.

(46)

McKinnon, J. J.; Jayatilaka, D.; Spackman, M. A. Chem. Commun. 2007, 3814-3816.


32


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 34 of 46

(47)

Spackman, M. A; McKinnon, J. J. CrystEngComm 2002, 4, 378-392.

(48)

Wolff, S. K.; Grimwood, D. J.; McKinnon, J. J.; Turner, M. J.; Jayatilaka, D.; Spackman, M. A. CrystalExplorer, Version 3.1; University of Western Australia, 2012.

(49)

Segall, M. D.; Lindan, P. J. D.; Probert, M. J.; Pickard, C. J.; Hasnip, P. J.; Clark, S. J.; Payne’ M. C. J. Phys. Condens. Matter. 2002, 14, 2717-2744.

(50)

Yates, J. R.; Pickard, C. J.; Mauri, F. Phys. Rev. B: Condens. Matter. Mater. Phys. 2007, 76, art. no. 024401.

(51)

Materials Studio v 6.1 Copyright Accelrys Software Inc. 2013.

(52)

Tkatchenko, A.; Scheffler, M. Phys. Rev. Lett. 2009, 102, art. no. 073005.

(53)

Pickard, C. J.; Mauri, F. Phys. Rev. B: Condens. Matter. Mater. Phys. 2001, 63, 24510112451013.

(54)

Delley, B. J. Chem. Phys. 1990, 92, 508-517.

(55)

Delley, B. J. Phys. Chem. 1996, 100, 6107-6110.

(56)

Delley, B. J. Chem. Phys. 2000, 113, 7756-7764.

(57)

Kim, E.; Weck, P.F.; Berber, S.; Tomanek, D. Phys. Rev. B 2008, 78, 113404-113408.

(58)

Benedek, N. A.; Snook, I. K.; Latham, K.; Yarovsky, I. J. Chem. Phys. 2005, 122, 144102-144109.

(59)

Inada, Y.; Orita, H. J. Comput. Chem. 2008, 29, 225-232.


33

Page 35 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(60)

Chermahini, A. N.; Hosseinzadeh, B.; Beni, A. S.; Teimouri, A.; Moradi, M. J. Mol. Model 2014, 20, 2086.

(61)

Civalleri, B.; Zicovich-Wilson, C. M.; Valenzano, L.; Ugliengo, P. CrystEngComm 2008, 10, 405-410.

(62)

Harris, R. K.; Hodgkinson, P.; Pickard, C. J.; Yates, J. R.; Zorin, V. Magn. Reson. Chem. 2007, 45, 174-186.

(63)

Wu, A.; Zhang, Y.; Xu, X.; Yan, Y. J. Comput. Chem. 2007, 28, 2431-2442.

(64)

Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 1354-1358.

(65)

Etter, M. C. Acc. Chem. Res. 1990, 23, 120-126.

(66)

Etter, M. C.; MacDonald, J. C.; Bernstein, J. Acta Crystallogr., Sect. B 1990, 46, 256262.

(67)

Kopsky, V.; Litvin, D. B., Eds. International Tables for Crystallography: Subperiodic Groups; Kluwer Academic Publishers: Dordrecht, The Netherlands, 2002; Vol. E.


34


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 36 of 46

FOR TABLE OF CONTENTS USE ONLY

Alkyl spacer length and protonation induced changes in crystalline psychoactive arylpiperazine derivatives: single-crystal X-ray, solid-state NMR, and computational studies Edyta Pindelska, Izabela D. Madura, Łukasz Szeleszczuk, Anna Żeszko, Jolanta Jaśkowska, Paulina H. Marek, Waclaw Kolodziejski

TOC graphic

Synopsis: The molecular and crystal structures of three new basic active forms of Long-Chain ArylPiperazine derivatives and their hydrochlorides salts were studied using scX-ray, ssNMR and DFT calculations. It has been shown that employment of all these techniques enable to analyze subtle intra- and intermolecular structural effects.


2

Page 37 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Supporting Information. 1H and 13C NMR chemical shifts in CDCl3 solutions (Table S1), 13

C and 15N CP/MAS NMR chemical shifts (Table S2), 15N CP/MAS NMR spectra (Figure S1),

selected geometrical parameters (Table S3) for all characterized compounds in this paper. The fragments of studied molecules used to calculate the dipole moments (Figure S2). Values of the 13

C and

15

N isotropic (δiso) and calculated chemical shifts anisotropy (CSA) for L4-L6 and

L4HCl-L6HCl (Table S4).


3


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Numbering system used in ssNMR and scX-ray analyses 66x51mm (300 x 300 DPI)


Page 38 of 46

Page 39 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The

13

C CP/MAS NMR spectra of L4-L6 and L4HCl-L6HCl acquired with 4 ms contact time 158x104mm (300 x 300 DPI)



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ORTEP drawings of L4-L6 and L4HCl-L6HCl molecules. The ellipsoids are shown at 50% probability 177x109mm (300 x 300 DPI)


Page 40 of 46

Page 41 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Overlay of molecules showing the spacer effect (a) and protonation effect (b). The piperazine fragments were kept as a reference. Hydrogen atoms are omitted for clarity. Dots represent position of carbon atoms in disordered fragments 83x57mm (300 x 300 DPI)



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The HSs mapped with dnorm for L4-L6 and L4HCl-L6HCl


Page 42 of 46

Page 43 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Resolved 2D-fingerprint plots for L4-L6



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The large supramolecular synthons and packing of LSAMs (in a form of nodes showing the shape of molecules: a red end represents a head, a blue fragment the piperazine and the spacer while the green stands for a tail; for rings, their centers of gravity have been chosen and the connections goes through all three nitrogen atoms) for L4-L6 compounds 184x198mm (300 x 300 DPI)


Page 44 of 46

Page 45 of 46

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Resolved 2D-fingerprint plots for L4HCl-L6HCl



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The large supramolecular synthons and packing of LSAMs (in a form of nodes showing the shape of the molecules: a red end represents a head, a blue fragment the piperazine and the spacer while the green stands for a tail; for rings, their centers of gravity have been chosen and the connections goes through all three nitrogen atoms) for L4HCl-L6HCl compounds. The chlorine ions are shown as green spheres of arbitrary chosen radius 136x104mm (300 x 300 DPI)


Page 46 of 46

Alkyl Spacer Length and Protonation Induced Changes in Crystalline

Recommend Documents