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Gelbrich et al. Chemistry Central Journal (2016) 10:8 DOI 10.1186/s13065-016-0152-5 RESEARCH ARTICLE Open Access Specific energy contributions from competing hydrogen‑bonded structures in six polymorphs of phenobarbital Thomas Gelbrich* , Doris E. Braun and Ulrich J. Griesser Abstract Background: In solid state structures of organic molecules, identical sets of H-bond donor and acceptor functions can result in a range of distinct H-bond connectivity modes. Specifically, competing H-bond structures (HBSs) may differ in the quantitative proportion between one-point and multiple-point H-bond connections. For an assessment of such HBSs, the effects of their internal as well as external (packing) interactions need to be taken into consideration. The semi-classical density sums (SCDS-PIXEL) method, which enables the calculation of interaction energies for molecule–molecule pairs, was used to investigate six polymorphs of phenobarbital (Pbtl) with different quantitative proportions of one-point and two-point H-bond connections. Results: The structures of polymorphs V and VI of Pbtl were determined from single crystal data. Two-point H-bond connections are inherently inflexible in their geometry and lie within a small PIXEL energy range (−45.7 to −49.7 kJ mol−1). One-point H-bond connections are geometrically less restricted and subsequently show large variations in their dispersion terms and total energies (−23.1 to −40.5 kJ mol−1). The comparison of sums of interaction energies in small clusters containing only the strongest intermolecular interactions showed an advantage for compact HBSs with multiple-point connections, whereas alternative HBSs based on one-point connections may enable more favourable overall packing interactions (i.e. V vs. III). Energy penalties associated with experimental intramolecular geometries relative to the global conformational energy minimum were calculated and used to correct total PIXEL energies. The estimated order of stabilities (based on PIXEL energies) is III > I > II > VI > X > V, with a difference of just 1.7 kJ mol−1 between the three most stable forms. Conclusions: For an analysis of competing HBSs, one has to consider the contributions from internal H-bond and non-H-bond interactions, from the packing of multiple HBS instances and intramolecular energy penalties. A compact HBS based on multiple-point H-bond connections should typically lead to more packing alternatives and ultimately to a larger number of viable low-energy structures than a competing one-point HBS (i.e. dimer vs. catemer). Coulombic interaction energies associated with typical short intermolecular C–H···O contact geometries are small in comparison with dispersion effects associated with the packing complementary molecular shapes. Background The competition between alternative H-bonded structures (HBSs) is an important aspect of crystal polymorphism. The polymorphic forms of an organic compound may contain different HBSs which are based on the same set of (conventional [1]) H-bond donor (D-H) and *Correspondence: thomas.gelbrich@uibk.ac.at Institute of Pharmacy, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria acceptor (A) functions. Similarly, chemically distinct molecules with identical H-bond functions may form different HBSs, leading to the question of how molecular structure and H-bond preferences are correlated with one another. The dimer versus catemer competition (Fig. 1) in small carboxylic acids [2, 3] is an example for two HBSs which are based on identical D-H and A sites but differ in the multiplicity of their H-bond connections (two-point vs. one-point). The stabilisation contribution from a molecule–molecule © 2016 Gelbrich et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gelbrich et al. Chemistry Central Journal (2016) 10:8 Fig. 1 Competing H-bonded dimer (t-connection) and catemer (o-connection) structures composed of molecules with one H-bond donor (D-H) and one acceptor group (A) interaction involving two H-bonds exceeds that from each of two alternative one-point interactions significantly. Polymorphs differing in the multiplicity of their H-bond connections therefore also differ substantially in the relative distribution of energy contributions from individual molecule–molecule interactions, whereas the lattice energy differences for polymorph pairs of small organic molecules are typically very small [4–6] (<2 kJ mol−1 for 50 % of pairs and >7.2 kJ mol−1 for only 5 % of pairs [7]). This means that compensation effects arising from the packing of multiple HBS instances may be critical for the competition between one-point and multiple-point HBSs. In order to gain a better understanding of the nature of this competition, the molecule–molecule interactions in the corresponding crystals need to be examined in their entirety. Aside from small carboxylic acids [2, 3, 8] and aromatic urea dicarboxylic acids [9], competing one-point/multiple-point H-bond motifs occur for example in uracils [10], carbamazepine and its analogues [11–14], compound DB7 [15], aripiprazole [16–18], sulfonamides [19–21] and in barbiturates [22–24]. The 5,5-disubstituted derivatives of barbituric acid display a rigid 2,4,6-pyrimidinetrione skeleton whose two N–H and three carbonyl groups can serve as donor and acceptor sites, respectively, of N–H···O=C bonds. The rigid geometry of the 2,4,6-pyrimidinetrione fragment predetermines the geometries of intermolecular N–H···O=C bonds (Fig. 2) within the ensuing 1-, 2or 3-periodic HBSs (chains, layers and frameworks). As a result of these restrictions, only a limited number of experimental HBSs are found in this set of barbiturates [23] (see Table 1), and these HBSs are based on different combinations of one-point and two-point N–H···O=Cbond connections (o- and t-connections). A prototypical barbiturate is phenobarbital [Pbtl, 5-ethyl-5-phenyl-2,4,6(1H, 3H, 5H)-pyrimidinetrione, Scheme 1] which is a sedative and anticonvulsant agent, applied as an anaesthetic and in the treatment of epilepsy and neonatal seizures. The polymorphism of Pbtl has been studied extensively [25–27] and eleven Page 2 of 21 polymorphic forms, denoted by I–XI, are known [28– 31]. Forms I–VI are relatively stable at ambient conditions. Their experimental order of stability at 20 °C is I > II > III > IV > V/VI [26], and they can be produced by sublimation (I–VI) or crystallisation from solution (I–III; IV only as an intermediate [32]) or from the melt (IV– VI). Each of the modifications VII–XI can be obtained only in a melt film preparation and only in the presence of a specific second barbiturate as a structural template (“isomorphic seeding”) [25]. Crystal structure reports exist for I–III (Table 2) [26, 33, 34], several solvates [35] and a monohydrate [36] of Pbtl. Herein we report single crystal structure determinations for forms IV and V. A structure model for polymorph X was derived from an isostructural cocrystal. The polymorphs I–V and X contain five distinct N–H···O=C-bond motifs (or combinations of such motifs) with different quantitative proportions of o- and t-connections. Interaction energies associated with these HBSs were systematically compared using specific energy contributions of molecule–molecule interactions obtained from semi-classical density sums (SCDS-PIXEL) calculations [37–40]. An optimisation of molecular geometry was carried out and the intramolecular energy penalties of the experimental molecular geometries were determined. Using the XPac method [41], the new crystal data for V, VI and X were compared to theoretical Pbtl structures from a previous study [42]. Results Hydrogen‑bonded structures The Cambridge Structural Database (version 5.35) [43] and recent literature contain the 53 unique crystal structures of barbituric acid and its 5-substituted derivatives listed in Table 1. These crystals have in common that each of the two N–H groups per molecule is engaged in a single intermolecular N–H···O=C interaction. The availability of three carbonyl groups per molecule enables various H-bond connectivity modes, whereas the inflexible arrangement of the D and A functionalities within the 2,4,6(1H,3H)-pyrimidinetrione unit predetermines the geometry of the resulting H-bonded structures. Altogether, 13 distinct H-bonded chain, layer or framework structures have been identified so far (Table 2), with onedimensional structures, specifically the loop chains C-1 and C-2, dominating this set of barbiturates (Table 1). For the purpose of classification, one has to distinguish between the carbonyl group at C2 on the one hand and the two topologically equivalent carbonyl groups at C4 and C6 on the other (Fig. 2).1 The observed HBSs contain 1 The carbonyl group at C2 will be referred to as “C2 carbonyl group” and any one of the two topologically equivalent carbonyl groups at C4 or C6 will be referred to as “C4/C6 carbonyl group”. Gelbrich et al. Chemistry Central Journal (2016) 10:8 Page 3 of 21 Fig. 2 Schematic representation according to Ref. [23] of selected N–H···O=C bonded chain and layer HBSs found in derivatives of barbituric acid different quantitative proportions of o- and t-connections, but as each NH donor function is employed exactly once, the condition No + 2Nt = 4 (1) applies throughout, where No and Nt is the number of o- and t-connections, respectively. Each [No, Nt] combination of [0, 2], [4, 0] and [2, 1] is permitted for uninodal nets. The structures C-5 (form VI) and L-3 (forms I and II) are both binodal, i.e. they feature two sets of topologically distinct molecules, whereas the layer L-6 [23] contains three molecule types with distinct H-bond connectivity modes. In these cases, condition (1) applies for No and Nt parameters averaged over the HBS (Table 2). Molecules forming the loop chains C-1 and C-2 (Fig. 2) are linked by two antiparallel t-connections so that [No, Nt] = [0, 2]. The underlying topology of each of C-1 and C-2 is that of a simple chain. In an alternative graphset description according to Etter [44, 45], their “loops” represent R22 (8) rings. The C-1 type (form X) contains two topologically distinct R22 (8) rings in which either two O2 or two O4/6 sites are employed, whereas in a C-2 chain (forms I, II and III) only O4/6 acceptor sites Gelbrich et al. Chemistry Central Journal (2016) 10:8 Page 4 of 21 Table 1 N–H···O=C bonded chain (C-1 to C-5), layer (L-1 to L-6) and framework (F-1, F-2) structures found in solid forms of barbituric acid and its 5-substituted derivatives R5 R5′ Methyl Methyl Ethyl Common name(s) Form Motif CSD refcode References Isopropyl Ipral I C-1 NUXTAC [63] C-1 FUFTAC Ethyl Butyl Soneryl, butobarbital [25] RT-Form C-1 ETBBAR Ethyl Butyl Soneryl, butobarbital [64] LT-Form C-1 ETBBAR01 Ethyl Butyl [65] Soneryl, butobarbital C-1 ETBBAR02 Allyl [66] Isobutyl Sandoptal C-1 FUFTIK [25] Ethyl Pentan-2-yl Pentobarbital, nembutal I C-1 FUFTEG01 [48] Ethyl Pentan-2-yl Pentobarbital, nembutal II C-1 FUFTEG04 [48] Ethyl Pentan-2-yl or phenyl a co-crystal C-1 LATMEA [48] Ethyl n-pentyl C-1 ENPBAR [67] Ethyl Isopentyl Amobarbital IIb C-1 AMYTAL10 [68] Ethyl Isopentyl Amobarbital Ib C-1 AMYTAL11 [68] Ethyl But-2-enyl C-1 BEBWUA [69] Ethyl 3-Methylbut-2-enyl C-1 BECLIE [70] Ethyl 1,3-Dimethylbut-1-enyl C-1 BEBWOU [71] Ethyl 1,3-Dimethylbut-2-enyl C-1 JIFRIZ [72] Ethyl 1,3-Dimethylbutyl α-Methylamobarbital C-1 MAOBAR [73] Ethyl Phenyl Phenobarbital CH3CN solvate C-1 – [35] Ethyl Phenyl Phenobarbital CH3NO2 solvate C-1 – [35] Ethyl 1-Cyclohexen-1-yl Phanodorm C-1 ETCYBA01 [25] Ethyl Cyclohexyl C-1 YOZJUU01 [49] Allyl Allyl Dial C-1 DALLBA [74] Allyl Isopropyl Aprobarbital C-1 AIPBAR [75] F Phenyl C-2 HEKTOG [47] Ethyl Ethyl Barbital II C-2 DETBAA02 [76] Ethyl Pentan-2-yl Pentobarbital, nembutal III C-2 FUFTEG02 [48] Ethyl Phenyl Phenobarbital III C-2 PHBARB09 [26] Ethyl Phenyl Phenobarbital CH2Cl2 solvate C-2 – [35] Ethyl 6-Oxocyclohexenyl 6-Oxocyclobarbital C-2 OXCBAR [77] Cl Cl C-3 UXIYOQ02 [78] Ethyl 3,3-Dimethyl-n-butyl γ-Methylamobarbital C-3 EMBBAR20 [79] Ethyl Phenyl Phenobarbital C-3 – This work Allyl Phenyl Alphenal C-3 FUFSOP [25] Propenyl 1-Methylbutyl Quinal barbitone C-3 TICFER [80] H H Barbituric acid I C-4 BARBAC01 [46] H Ethyl I C-4 ETBARB [81] Methyl Phenyl Rutonal, heptobarbital I C-4 MPBRBL01 [25] Methyl Phenyl Rutonal, heptobarbital II C-4 MPBRBL [82] Ethyl Ethyl Barbital I C-4 DETBAA01 [76] Allyl Cyclopent-2-en-1-yl Cyclopal I C-4 FUFSUV [25] Ethyl Butyl Soneryl, butobarbital ETBBAR03 [83] Ethyl Phenyl Phenobarbital VI C-4 + C-3 C-5 – This work Ethyl Ethyl Barbital IV L-1 DETBAA03 [84] Ethyl Pentan-2-yl Pentobarbital, nembutal IV L-1 FUFTEG03 [48] Ethyl 1-Methylbutenyl Vinbarbital L-1 VINBAR [85] Ethyl 1-Cyclohepten-1-yl Medomin L-1 CHEBAR01 [25] H H Barbituric acid II L-2 BARBAC02 [46] Ethyl Phenyl Phenobarbital I L-3 + C-2 PHBARB07 [26] II I III V Gelbrich et al. Chemistry Central Journal (2016) 10:8 Page 5 of 21 Table 1 continued R5 R5′ Common name(s) Form Motif CSD refcode References Ethyl Phenyl Phenobarbital II [26] Cyclohexyl L-3 + C-2 PHBARB08 Ethyl L-4 YOZJUU [49] Isopropyl 2-Bromoallyl II L-4 UXIYIK [23] Cl Cl I L-5 UXIYOQ [23] Cl Cl II L-6 UXIYOQ01 [23] Br Br I L-6 UXIZAD [23] F F F-1 HEKTIA [47] Br Br F-2 UXIZAD01 [23] I Noctal II 5 5′ See Fig. 2 and Ref. [23] for graphical representations. R and R are the substituents at ring position 5 a Co-crystal of phenobarbital and pentobarbital b Nomenclature according to Ref. [25] Scheme 1 Structural formula of Pbtl Table 2 Descriptors for HBS types found in barbiturates: short HBS symbol [19] and number of o- and t-connections [No, Nt] Type Short HBS symbol [No, Nt] [No, Nt]A [No, Nt]B … Pbtl form(s) C-1 C42[0] [0, 2] X C-2 C42[0] [0, 2] I, II, III C-3 3 2 C44[3 .4 .5] [4, 0] V C-4 C43[42.6] [2, 1] C-5 C54.32[(53.62.7)(5)] [2, 1] L-1 L43[63-hcb] [2, 1] L-2 L44[44.62-sql] [4, 0] L-3 L64.22[(64.8.10)(6)] [2, 1] L-4 L43[63-hcb] [2, 1] L-5 L43[63-hcb] [2, 1] L-6 L32.54.43[(10) (63.103)(63)] [2, 1] F-1 F44[66-dia] [4, 0] F-2 F43[103-ths] [2, 1] [3, 1][1, 1] VI [2, 2][2, 0] I, II [1, 1][3, 1][2, 1] For graphical representations, see Fig. 2 and Ref. [23] are employed, and all its R22 (8) rings are topologically equivalent. The molecules in a C-3 tape (form V) possess four o-connections so that [No, Nt] = [4, 0] (Fig. 2). Via C4/6 carbonyl groups, they form two parallel N–H···O=C bonded strands which are offset against one another by one half of a period along the translation vector. N–H···O=C bonding between the strands via C2 carbonyl groups results in fused R33 (12) rings. Four o-connections per molecule are also present in the layer structure L-2 [46] which has the topology of the (4,4) net and in the dia framework F-1 [47]. In an L-3 layer (forms I and II), molecules of type A are linked into C-2 chains and B-type molecules serve as N–H···O=C bonded bridges between these chains (Fig. 2). In molecule A, the H-bond acceptor functions of the carbonyl groups at C4 and C6 are each employed twice, whereas none of the carbonyl groups of molecule B is involved in hydrogen bonding. Each molecule A forms two t-connections to A molecules and o-connections to two B molecules. There are no H-bonds between B molecules. The [No, Nt] parameters for molecules A and B are [2, 2] and [2, 0], respectively, and the overall [No, Nt] parameter combination for the L-3 layer is [2, 1]. The binodal tape C-5 (Fig. 2) is a novel structure found exclusively in the Pbtl polymorph VI. Molecules of type A are linked, by o-connections via C4 carbonyl groups, into two parallel strands. Additionally, the C4 and C2 carbonyl groups of molecules A and B, respectively, are employed in an asymmetrical and antiparallel t-connection. Molecule A forms also an o-connection to a second B molecule via its C2 carbonyl group. There are no H-bonds between B molecules, which serve as H-bridges between two strands. The molecule types A and B have Gelbrich et al. Chemistry Central Journal (2016) 10:8 the parameters [No, Nt]A = [3, 1] and [No, Nt]B = [1, 1] and the overall [No, Nt] combination for the C-5 tape is [2, 1]. Five uninodal HBSs with [No, Nt] = [2, 1] are known, namely the C-4 ladder, three distinct layer structures (L-1, L-4, L-5), each having the topology of the (6,3) net, and the ths framework F-2 [23]. The connectivity and topology characteristics of the barbiturate HBSs are listed in Table 2 and an illustration of the variations in No and Nt is given in Fig. 3. SCDS‑PIXEL calculations Total PIXEL energies of individual molecule–molecule interactions (ET) can be divided into contributions from Coulombic (EC), polarisation (EP), dispersion (ED) and repulsion (ER) terms. The polarisation energy is not pairwise additive (many-body effect) so that the total PIXEL energy for the crystal, ET,Cry, differs slightly from the sum of all individual PIXEL interaction energies ET,Σ. For the Pbtl polymorphs, this difference is 2–3 kJ mol−1 (<2.5 % of ET,Cry; see Table 3). Various aspects of the PIXEL calculation for each poly­ morph will be visualised in a special kind of diagram whose data points represent molecule–molecule interactions energies accounting for at least 95 % of ET,Cry, with internal HBS interactions separated from contacts between different instances of the HBS (labelled @1, @2,…). Moreover, sums of PIXEL energies will be compared in order to assess relative contributions from Fig. 3 The parameters [No, Nt] for the HBS types formed by barbiturates and for two combinations of HBS types (L-3 + C-2 and C-3 + C-4). Roman numerals indicate the relevant data points for Pbtl polymorphs Page 6 of 21 certain groups of interactions. The molecule–molecule interactions in each crystal structure will be ranked in descending order of their stability contributions (#1, #2, #3…), with symmetry equivalence indicated by a prime (e.g. #1/1′). Polymorphs containing exclusively or predominantly t-connections, i.e. X (C-1), III (C-2), I and II (C-2 + L-3), will be discussed first, followed by forms V (C-3) and VI (C-5). PIXEL energies do not account for differences in molecular conformation, and this topic will be discussed in a separate section. Detailed results of SCDS-PIXEL calculations are given in Additional file 1: Fig. S7 and Tables S1–S12. HBS type C‑1: polymorph X The structure of polymorph X has not been determined from single crystal data. Melt film experiments [25] indicated it to be isostructural with the co-crystal of Pbtl with 5-ethyl-5-(pentan-2-yl)barbituric acid (pentobarbital). The asymmetric unit of this co-crystal (space group C2/c) consists of a single barbiturate molecule whose R5′ substituent is disordered between the pentan-2-yl and phenyl groups of the two chemical components [48]. An approximate structure model for polymorph X was derived by removing the pentan-2-yl disorder fragment from the co-crystal structure (Additional file 1: Section 8). The C-1 structure (Fig. 2) is defined by two independent t-connections with very similar interaction energies (#1: −47.5 kJ mol−1; A: O4) and (#2: −47.2 kJ mol−1; A: O2), with a crystallographic two-fold axis passing through the centre of the respective R22 (8) ring. As expected, these interactions are dominated by the EC term and the C-1 tape contains no significant non-Hbonded interactions (Fig. 4a). Each Pbtl molecule interacts with eight other molecules belonging to four different C-1 chains, i.e. @1 (#3, #4, #9), @2 (#6/6′, #8), @3 (#5) and @4 (#9). Each of the eight interactions (PIXEL energies −19.7 to −12.1 kJ mol−1) is dominated by the ED term (Additional file 1: Table S12). The chain–chain contact @1 involves the mutual interdigitation of phenyl groups (#3, #4) and contact @2 the interdigitation of ethyl groups (#6/6′) (Figs. 4b, 5). Internal C-1 interactions contribute 39 % to the ET,Cry value of −121.1 kJ mol−1, whilst @1 and @2 account for 21 and 18 %, respectively, of ET,Cry. A number of 2D and 3D packing relationships between barbiturates are based on the packing motif of the centrosymmetric chain pair @2 [25, 49]. Each of the molecule–molecule interactions #3, #5 and #8 involves a pair of symmetry-related C–H···O contacts (H···O = 2.51–2.68 Å and CHO = 140°–170° and a significant EC contribution (−9.1 to −9.8 kJ mol−1), which Gelbrich et al. Chemistry Central Journal (2016) 10:8 Page 7 of 21 Table 3 Crystal data and PIXEL energies of polymorphs of Pbtl Form I II III Va VI Xb References [26] [26] [26] This work This work [25, 48] CCDC refcode PHBARB07 PHBARB08 PHBARB09 – – LATMEA Space group P21/n P1 P21/c P21/n P21/n C2/c Z′ 3 3 1 2 2 1 a (Å) 10.70 10.74 9.55 12.76 14.67 12.67 b (Å) 47.26 23.40 11.85 6.76 6.90 20.69 c (Å) 6.80 6.72 10.81 26.85 23.03 10.25 α (°) 90 91.0 90 90 90 90 β (°) 94.2 94.5 111.6 98.8 94.1 118.5 γ (°) 90 88.4 90 90 90 90 Texp (K) 298 173 298 173 173 173 D (g cm−3) 1.349 1.376 1.357 1.348 1.327 d C-2 + L-3 HBS [No, Nt] [4/3, 4/3] C-2 + L-3 [4/3, 4/3] C-2 C-3 C-5 C-1 [0, 2] [4, 0] [2, 1] [0, 2] m.p. (°C) [26] 176 174 168 160 156 126 ET,Cry/ΔEintra (kJ mol−1) c c ET,Σ (kJ mol−1) −123.3 −122.4 −118.3/3.9 −120.5 −122.4/13.1 −124.1 −114.9/3.7 −117.9 −118.3/8.0 −103.8/6.9 −104.0/8.2 – −127.4/17.6 −107.5/7.1 ET,Σ(A)/ΔEintra (kJ mol−1) ET,Σ(B)/ΔEintra (kJ mol−1) ET,Σ(C)/ΔEintra (kJ mol−1) Density order /7.3 −143.1/8.9 f Stability order (calc.) −141.4/8.7 – −120.9/8.5 −128.3/0.3 −121.1 – – −122.9/6.0 −121.9/5.5 – – – – 1st 2nd 4th 5th d 1st 2nd 3rd 4/5th 4/5th e 2nd 3rd 1st 6th 4th 5th 3rd Stability order (RT) [26] /7.5 a The matrix (100001101) transforms the room temperature data reported by Williams [36] (a = 12.66, b = 6.75, c = 27.69 Å; β = 106.9°; P21/c) into a unit cell (a′ = 12.66, b′ = 6.75, c′ = 26.89 Å; β’ = 99.9°; P21/n) which matches our data b The structure model for form X (Additional file 1: Section 8) was derived from the isostructural co-crystal of Pbtl with pentobarbital (the quoted CCDC refcode, unit cell data and Texp all refer to the co-crystal) c ET,Cry not determined because of Z′ > 2 d Not applicable e Exists only in a melt-film preparation and in the presence of a structurally analogous second barbiturate f Based on the results of SCDS-PIXEL calculations, corrected for ΔEintra is however still considerably lower than the respective ED contribution (−15.1 to −21.4 kJ mol−1). These C–H···O contacts are formed between the phenyl group (#3) or the CH2 group (#5) and the C4/6 carbonyl group not involved in classical H-bonds or between the methyl and the C2 carbonyl group (#8; for details, see Additional file 1: Table S12). HBS type C‑2: polymorph III The structure of III (space group P21/c) contains one independent molecule. Its C-2 chain (Fig. 2) possesses 21 symmetry. The interaction energy of its t-connections (#1/1′) of −45.4 kJ mol−1 is similar to the corresponding values in X. The energies of the next four strongest interactions (#3, #4, #5/5′) lie between −22.1 and −19.7 kJ mol−1 and each of them is dominated by the ED term (Additional file 1: Table S7). They result mainly from the pairwise antiparallel alignment of ethyl-C5-phenyl fragments in the case of #3 and from the pairwise stacking of ethyl groups with phenyl groups in the case of #5/5′. The relatively large EC term (−13.2 kJ mol−1) for interaction #4 coincides with the presence of two symmetry-related (phenyl)C–H···O=C contacts (H···O = 2.53 Å, CHO = 139°) involving the C2 carbonyl group, which is not engaged in classical hydrogen bonding. However, the stabilisation contribution from ED (−17.3 kJ mol−1) is still higher than EC for interaction #4. A similar (phenyl)C–H···O=C contact geometry (H···O 2.61 Å, CHO = 151°), also involving the C2 carbonyl group, is associated with interaction #10/10′, but here the EC contribution is just −5.5 kJ mol−1. The two internal C-2 interactions account for approximately 38 % of ET,Cry of −118.3 kJ mol−1, and the interactions with molecules belonging to four neighbouring chains @1 (2 pairwise interactions), @2 (2), @3 (2) and @4 (3) account for 17, 13, 12 and 11 %, respectively, of Gelbrich et al. Chemistry Central Journal (2016) 10:8 Page 8 of 21 glide symmetry, whereas the latter contain inversion centres (Additional file 1: Fig. S5). The energy associated with the centrosymmetric t-interaction between A molecules is −49.2 kJ mol−1 (#2/2′) and energies of −40.5 and −34.0 kJ mol−1 (5/5′ and 7/7′) are calculated for the o-interactions between A and B molecules (Fig. 8). Within an L-3 layer, the strongest non-H-bonded AA interactions of −17.2 kJ mol−1 (#10/10′), between neighbouring C-2 subunits (related by a [001] translation), and the strongest BB interactions of −15.5 kJ mol−1 (#14/14′) each involve relatively large ED contributions. There are another eight intra-L-3 contacts with energies between −11.1 and −8.4 kJ mol−1. The energies for the t-connections of the C-2 chain of molecule C, −49.7 and −48.1 kJ mol−1, are very similar to the corresponding values for the C-2 chains formed by A molecules and in polymorph III. Internal H-bond and non-H-bond interactions of the L-3 layer account for 54 % and internal C-2 chain interactions of C molecules account for 13 % of ET,Σ. Contacts between L-3 layers (molecules A + B) and C-2 stacks (molecule C) contribute 19 % to ET,Σ (@1), and the contacts @2 and @3 between neighbouring C-2 chains contribute 5 and 4 %, respectively (Figs. 8, 9). Due to their fundamentally different environments and different Fig. 4 Results of SCDS-PIXEL calculations for polymorph X. a Interaction energies, represented by balls, are separated into internal C-1 interactions (blue) and chain–chain contacts (highlighted @1, red; @2, orange; @3, green). The horizontal bars indicate cumulative PIXEL energies (summation from left to right) relative to ET,Cry (scale on the right-hand side). b The eight most important pairwise interactions involving a central molecule (orange). The mean plane of the pyrimidine ring of the central molecule is drawn, H atoms are omitted for clarity and H-bonds are indicated by blue lines ET,Cry (Figs. 6, 7). This situation differs somewhat from the packing of C-1 chains in X which is dominated by just two chain–chain interactions (@1, @2) which contribute 40 % of ET,Cry. HBS types L‑3 + C‑2: polymorph I The crystal structure of form I (space group P21/c) contains three independent molecules, labelled A–C. A and B molecules are linked into an L-3 layer (Fig. 2). This layer consists of C-2 chains, formed exclusively by A molecules, and bridging B molecules. The L-3 structures lie parallel to (010) and alternate with stacks of C-2 chains composed of C molecules (Additional file 1: Fig. S4). The two distinct C-2 chains formed by A and C molecules differ in that the former (as part of a L-3 layer) possess Fig. 5 Packing diagram of polymorph X, showing interactions of a selected Pbtl molecule (drawn in ball-and-sticks-style) within the same C-1 chain (blue) and with molecules belonging to three neighbouring chains (@1–@3; see Fig. 4). Together, hydrogen bonding and the …@1 @2 @1 @2… stacking of chain pairs account for 78 % of ET,Cry Gelbrich et al. Chemistry Central Journal (2016) 10:8 involvement in N–H···O=C bonds, the three independent molecules also differ substantially in their PIXEL energy sums: 143.1 kJ mol−1 (A), −103.8 kJ mol−1 (B) and −122.9 kJ mol−1 (C). HBS types L‑3 + C‑2: polymorph II Polymorph II (space group P 1) is a Z′ = 3 structure whose molecules A and B are linked into an L-3 layer, whilst C-type molecules form a C-2 chain, and it exhibits a very close 2D packing similarity with polymorph I [26]. In fact, the only fundamental difference between these two modifications is the symmetry of the C-2 chain formed by the respective A-type molecules (I: glide symmetry, II: inversion; see Additional file 1: Fig. S4). Fig. 6 Results of SCDS-PIXEL calculations for polymorph III. a Interaction energies, represented by balls, are separated into internal C-2 interactions (blue) and chain–chain interactions (highlighted @1, red; @2, orange; @3, green). The horizontal bars indicate cumulative PIXEL energies (summation from left to right) relative to the ET,Cry (scale on the right-hand side). b The six most important pairwise interactions involving a central molecule (orange). The mean plane of the pyrimidine ring of the central molecule is drawn, H atoms are omitted for clarity and H-bonds are indicated by blue lines Page 9 of 21 The comparison of interaction energy diagrams (Additional file 1: Fig. S7; see also Tables S1–S6) shows that this packing similarity results in a striking similarity of corresponding pairwise interaction energies. Therefore, the general assessment of relative energy contributions attributable to L-3 and C-2 units and to their packing in polymorph I (previous section) is also valid for polymorph II. HBS type C‑3: polymorph V Williams [36] reported space group and unit cell data for polymorph V which indicated a crystal structure with two independent molecules, and these data are consistent, after unit cell transformation, with those of the full crystal structure analysis carried out by us (see footnote a of Table 3). Form V has the space group symmetry P21/c and contains two independent molecules, labelled A and B. It contains N–H···O=C bonded C-3 tapes (Fig. 10) which are arranged parallel to [010]. Each molecule forms o-connections to four neighbouring molecules. A and B molecules are linked into separate H-bonded strands with translation symmetry, which are offset against one another by one half of a translation period. The linkage between the two parallel strands via N–H···O=C bonds results in fused R33 (12) rings. Although A and B molecules are crystallographically distinct, they are topologically equivalent in the context of the (uninodal) C-3 structure. Fig. 7 Packing diagram of polymorph III, showing interactions of a selected Pbtl molecule (drawn in ball-and-sticks-style) within the same C-2 chain (blue) and with molecules belonging to four neighbouring chains (@1–@4; see Fig. 6). Together, these interactions account for 91 % of ET,Cry Gelbrich et al. Chemistry Central Journal (2016) 10:8 Page 10 of 21 Fig. 8 Results of SCDS-PIXEL calculations for polymorph I. a Interaction energies, represented by balls, are separated into internal L-3 (blue) interactions, internal C-2 (red) interactions, interactions between a L-3 layer and a stack of C-2 chains (@1, orange) and interactions between neighbouring C-2 (@2, green; @3, beige). The horizontal bars indicate cumulative PIXEL energies (summation from left to right) relative to the ET,Cry (scale on the right-hand side). b–d A central molecule A, B or C (coloured orange) and neighbouring molecules involved in six (b, c) or seven (d) pairwise interactions (see Additional file 1: Tables S1–S3). The mean plane of the pyrimidine ring of the central molecule is drawn, H atoms are omitted for clarity and H-bonds are indicated by blue lines Interaction energies of −32.9 kJ mol−1 were obtained both for the o-interactions between A-type molecules (#1/1′) and the analogous interactions between B-molecules (#2/2′). Considerably lower stabilisation effects of −23.8 and −23.2 kJ mol−1 result from the o-interactions (#5/5′ and #10/10′) between A and B