Comparative Structural Studies of Four Homologous Thioamidic

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Comparative structural studies of four homologous thioamidic unclosed crytpands: self-encapsulation of lariat arm, odd-even effects, anomalously short S···S chalcogen bonding, and more Kajetan D#browa, Magdalena Ceborska, Marcin Pawlak, and Janusz Jurczak Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01551 • Publication Date (Web): 29 Dec 2016 Downloaded from http://pubs.acs.org on January 5, 2017

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Crystal Growth & Design

Comparative structural studies of four homologous thioamidic unclosed crytpands (UCs): self-encapsulation of lariat arm, odd-even effects, anomalously short S···S chalcogen bonding, and more Kajetan Dąbrowa,† Magdalena Ceborska,‡ Marcin Pawlak,† and Janusz Jurczak*,† † Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland. ‡ Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland. Keywords: Chalcogen bond, noncovalent interactions, macrocycles, hydrogen bonds, odd-even effects, homologues

Unclosed cryptands (UCs) 4a-d containing flexible (CH2)n spacers (n = 2–5) and a fixed pnitrophenyl thioamide substituent (lariat arm) were synthetized and characterized by a single crystal X-ray analysis. Comparative analysis of their crystal structures provided an opportunity to recognize that conformation of 4a-d and occurrence of lattice solvent strictly depend on the length and parity of aliphatic linkers. Namely, the degree of self-inclusion of the lariat arm within the macrocyclic cavity was found to increase with greater elongation of the CH2 spacer. Odd-membered UCs (4b and 4d) showed a tendency to crystallize without lattice solvent while

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even-membered UCs (4a and 4c) crystallized as various solvates. For two solvates of UC 4c an anomalously short and highly directional C=S···S=C chalcogen interactions (dS···S=3.21-3.35 Å) were observed between adjacent UC molecules, forming a dimeric cube-like supramolecular assembly. Packing of dimers as well as length of homo-chalcogen interaction were affected by lattice solvent. Evaluation of data on C=S···S=C contacts retrieved from Cambridge Structural Database (CSD) suggests that a precisely positioned external H-bond donor (NH or water) is important for stabilization of this type of noncovalent interaction.

Introduction Unclosed cryptands (UCs) belong to a new class of macrocyclic host molecules, introduced recently as putative anion receptors.1-3 Their macrocyclic skeleton is based on a 1,2,3trisubstituted benzene core decorated with multiple amide groups interconnected with alkyl or alkyl-aryl linkers of varying lengths. An inherent property of UCs is the presence of a suitably functionalized substituent (lariat arm) installed at the intraannular position of the macroring. Such a tether feature provides additional anchoring points for enhanced and selective guest binding, as in the case of structurally related cryptands. Contrary to the latter, however, the iterative strategy for the synthesis of UCs via an efficient macrocyclization step1,2,4 and siteselective post-functionalization of the lariat arm4 enables easy access to a series of macrocyclic derivatives with fine-tuned binding properties. In addition, UCs readily crystallize to form highpurity monocrystals, in which the host molecules are generally predictably and more efficiently packed than other organic molecules.1,5 Together, these unique properties of UCs make them potentially useful macrocyclic platforms for the investigation of various types of weak noncovalent interactions via solid-state analytical techniques, such as X-ray crystallography and


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FT-IR.1,4-5 For example, the 26-membered pentaamide 1 has been found to trap a discrete octameric water cluster, forming a closely packed 1ˑ4H2O assembly (CPk = 0.80)6 that does not decompose even at 293K.1

This supramolecular stabilization was mainly attributed to the dense network of hydrogen bonds provided by the five amide groups of the UC, among which the lariat amide group was particularly important, being engaged in an intramolecular hydrogen bond that forces the macrocycle to adopt a more preorganized conformation. We envisioned that weakening of this crucial interaction would therefore affect solid-state formation of water clusters. To evaluate this hypothesis we decided to replace the lariat amide C=O bond with a C=S bond, since in supramolecular systems such substitution is known to greatly decrease the number of possible intramolecular H-bonds.2,7 In this contribution, we present the synthesis and crystal structure analysis of homologous UCs 4a-d, varying in macroring size and bearing a fixed 4-nitrophenyl-thioamide lariat arm. Unexpectedly, we found that all these new thioamide analogs of UC 1 were unable to stabilize water clusters. Instead, for the 26-membered 4c, a close analog of UC 1, an unprecedentedly short chalcogen-chalcogen S···S interaction between monovalent C=S moieties was observed. In addition, comparative analysis of the crystal structures provided an opportunity to recognize that the conformation of 4a-d and the occurrence of lattice solvent strictly depend on the length and parity of aliphatic linkers.


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Results

Scheme 1. Synthesis and structures of the examined unclosed cryptands 4a-d. The macrocyclic probes 4a-d were readily synthetized from simple precursors as depicted in Scheme 1. The macrocyclization between corresponding α,ω-diamine hydrochlorides 2a-d2,4 and α,ω-dimethyl ester 3,2 under optimized conditions (c ~ 0.03 M, excess of sodium methoxide in methanol) provided target compounds 4a-d in moderate to very good yields. Notably, the highest yields were obtained for 24 and 26-membered macrocycles (78% for 4b and 74% for 4c), which is presumably a result of chloride-templated stabilization of the folded conformation of the linear intermediate. This process is known to be dependent on the geometrical match between the macrocyclic cavity of the host and the size of the templating guest.4,8-11 Crystals suitable for Xray analysis were obtained for all of the macrocycles 4a-d (Figures 1-4). Data describing the relative contributions of various close intermolecular interactions to the Hirshfeld surface (HS) area and also comparison between these crystals is presented in Figures 5 and 6, respectively. Macrocycle 4a, bearing the smallest 22-membered ring, crystallizes as a monohydrate in monoclinic space group I2/a (Figure 1). The close packing of macrocyclic entities (CPk = 0.76) is


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supported by a number of close intramolecular interactions, particularly by the highly directional hydrogen bonds, which are clearly visible in Figure 1b as large red spots on the Hirsfeld surface (HS). The thioamide sulfur atom is weakly H-bonded with one amidic group of the pyridine substituent (dS1-N2 = 3.47 Å, ∠ = 170°), and the water molecule that resides in the macrocyclic cavity is located at the side opposite to the lariat arm and takes part in hydrogen bonding with the host and two other symmetrically related 4a molecules (see Figure 1a). Carbonyl oxygen interacts with the adjacent 4a molecule (dN2-O5* = 2.78 Å, ∠ = 154°) and symmetrically related water molecule H-bonds to carbonyl oxygen O4. a)

b)

Figure 1. Crystal structure of 4a·H2O (a) and front- and side-view of the Hirshfeld surface plotted against dnorm (b). Dashed lines represent hydrogen bonds; non-acidic protons and disorder were omitted for clarity. Asterisks within atom labels denote symmetry-equivalent atoms. The HS fingerprint breakdown analysis (see Figure 6) shows that weak and non-directional van der Waals interactions account for nearly 53% of the total surface area, from which H···H


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dominates over C-H···Cπ contacts (39% vs 14%). Careful inspection of the molecular environment of 4a reveals that H···H and C-H···Cπ contacts arise mainly from interaction of either CH2 or C-H aromatic protons with CH2 protons and carbon atoms of the aromatic rings, respectively. In addition, strong and directional C=O···H-N/O, and to a lesser extent C=O···H-C interactions, account for less than 34% of the total surface area. Other types of interactions, e.g. Cπ···Cπ, N···H, and S···H/C/N/O, contribute marginally to HS (1%, 2%, and 1.4%, respectively). Macrocycle 4b crystallizes as a racemate in C2/c space group (Figure 2).2 a)

b)

Figure 2. Crystal structure of 4b (a) and front- and side-view of the Hirshfeld surface plotted against dnorm (b). Dashed lines represent hydrogen bonds. Non-acidic protons were omitted for clarity. Asterisks within atom labels denote symmetry-equivalent atoms.


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The elemental cell contains eight molecules without any solvent present. All of the macroring amide protons are directed inwards, as is the thiocarbonyl sulfur atom, which, like 4a, forms a weak hydrogen bond with one of the amide protons (dS1-N3 = 3.41 Å, ∠ = 158°). Interestingly, the exceptionally acidic lariat amide proton does not participate in any hydrogen bonding, which is presumably responsible for a slight contraction of the C=S bond length in comparison to UC 4a (dC=S = 1.675 Å for 4a vs dC=S = 1.664 Å for 4b). Likewise, only one of the four available carbonyl oxygen atoms (O4) takes part in bifurcated hydrogen bonding with amidic protons of the pyridine substituent (dS1···N3 = 2.98, 3.11 Å, ∠ = 152,150°). The crystal structure is additionally stabilized by complementary π···π and C-H···π interactions, accordingly, between local dipoles of carbonyl group, p-nitrophenyl substituent, and 2,6-pyridinedicarboxamide moiety (Figure S3). These local interactions12-14 likely contribute to the high CPk of this assembly (CPk = 0.77). Interestingly, despite the absence of lattice water and relatively limited number of close intermolecular contacts, in particular hydrogen bonds, the crystals of both macrocyclic 4a and 4b have comparable packing efficiency and a closely similar contribution of intermolecular interactions to the HS area. Both solvates of 26-membered macrocycle 4c, i.e. 4c·0.75H2O·2DCE and 4c·2MeCN, crystallize in the monoclinic C2/c space group sharing the same structural motif of 4c dimer. They show far-reaching similarities, therefore only structure of water/DCE solvate (shown in Figure 3) will be discussed in detail with only some key differences between the two being explained later in the text. Structure analysis once again demonstrates that the NH amide protons belonging to the macroring and lariat arm are directed inwards and outwards, respectively. As in the case of the smaller 4a, the macrocyclic entity of 4c is engaged in a number of close intramolecular interactions (notice the plethora of red spots in Figure 3b), in particular the


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thioamide NH proton is strongly H-bonded with a carbonyl oxygen from the adjacent macrocycle (dN2···O8’ = 2.82 Å, ∠ = 177°). The thioamide sulfur atom, however, in contrast to both 4a and 4b, is here engaged in a weak intermolecular H-bonding with an amidic group of the pyridine moiety of an adjacent macrocycle (dS1-N4* = 3.45 Å, ∠ = 142°). A careful analysis of intermolecular contacts demonstrates pronounced contribution of solvent molecules in the stabilization of crystal lattice. a)

b)

Figure 3. Crystal structure of 4c·0.75H2O·2DCE (a) and front- and side-view of the Hirshfeld surface plotted against dnorm (b). Dashed lines represent hydrogen (green), halogen (violet), and chalcogen (yellow) bonds. Non-acidic protons and disorder were omitted for clarity. Asterisks within atom labels denote symmetry-equivalent atoms.


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For example, water molecule (O1W) takes part in three hydrogen bonds, two of them couple adjacent molecules 4c (dO8···O1W = 2.87 Å, ∠ = 158°, dN3···O1W = 2.93 Å, ∠ = 140°) and the third binds to one of the DCE molecules (dCl1···O1W = 3.46 Å, ∠ = 168°). The second DCE molecule is disordered, but the positions of chloride and carbon atoms nevertheless indicate that it is engaged in halogen bonding with the resorcine ring as well as in weak H-bonds with alkyl chain of the macrocycle and the first DCE molecule. Notice that the relatively high contribution of this Cl···H interaction to the HS surface (14%) is presumably realized at the expense of the O···H interaction, which is considerably smaller than in 4a and 4b (24% vs 32%), whereas share of H···H and C···H is similar. The crystal lattice is additionally stabilized by complementary π···π and C-H···π local interactions,12-14 accordingly, between nitro group, 2,6-disubstituted pyridine, and resorcine ring (Figure S3). Further analysis indicates the occurrence of a highly directional and an anomalously short interaction between sulfur atoms (dS···S’ = 3.210 Å, ∠C=S···S = 153°). This bond is shorter by 0.57 Å than the sum of the van der Waals radii (3.78 Å), which makes it one of the shortest reported interactions between organic divalent sulfur atoms in the solid state. A comprehensive analysis of this noncovalent interaction along with a discussion of potential factors influencing its occurrence is provided later in the text. 28-Membered UC 4d, the largest of the whole series, crystallizes in P21/c space group and without any solvent (Figure 4).


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b)

a)

Figure 4. Crystal structure of 4d (a) and front- and side-view of the Hirshfeld surface plotted against dnorm (b). Only one structure of two independent molecules is shown. Dashed lines represent hydrogen bonds. Non-acidic protons and disorder were omitted for clarity. Asterisks within atom labels denote symmetry-equivalent atoms. The thioamide sulfur atom is engaged in very weak intramolecular hydrogen bond (dS1-N3 = 3.79 Å, ∠ = 158°), but there is no direct interaction between sulfur atoms. Interestingly, the lariat arm is self-encapsulated within the macrocyclic cavity, as is clearly visible in Figure 4b. As in the case of 4b, for 4d the crystal lattice is stabilized by rather weak intramolecular hydrogen bonds between amide groups of four neighboring receptor molecules (dN4/N6-O7’’ = 2.93-2.96 Å, ∠ = 155-158°, dN2/N7-O5’ = 2.85-3.03 Å, ∠ = 150-154°), two of which are symmetrically equivalent (notice the small number of red spots in Figure 4b). Nevertheless, the macrocyclic molecules form a well-packed assembly (CPk = 0.80) which originates from a large number of cumulative non-covalent interactions. Among the obvious close H···H contacts, which account for 43% of


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the total surface area (see Figure 5), the π···π stacking between perpendicularly arranged pyridine rings (dmin = 3.43 Å) and CH···π contacts, accordingly, between alkyl chain and lariat arm, and carbonyl oxygen and -OCH2 moiety (dmin = 3.11 Å), likely make the largest contribution. Collectively, these interactions render some distortion in the arrangement of the pyridine substituent and a flexible pentamethylene linker of the neighboring macrocycle, and hence two symmetry independent conformations of UC 4d are presented in the unit cell. Comparative analysis of the crystals Comparison of the crystal structures of 4a-d helped us to decipher similarities and relevant differences in packing behavior and molecular environment of these homologous macrocyclic compounds, which differ only in terms of aliphatic linker length. We found that for all crystal structures studied, C=S bond and macrocyclic NH protons are directed inward towards the macrocyclic cavity, whereas the lariat NH proton is directed outwards. Such a well-defined structural preorganization of amide groups was already observed in crystal structures of various di5, tri-15-17 and pentamide1,2,4 UCs, and hence it is a rather common feature for these kinds of macrocyclic compounds. Analysis of the Hirshfeld fingerprint plots reveals some additional common features (Figure 5). The plots are dominated by weak and non-directional H···H and C···H close contacts, which account for roughly 50-55% of the total surface area.


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Figure 5. Hirshfeld fingerprint plots for 4a·H2O, 4b, 4c·0.75H2O·DCE, 4c·2MeCN, 4d, and 1·4H2O (from top-left to bottom-right) with resolved H···H and C···H contacts (blue dots); di is distance from surface to the nearest atom interior to surface and de is the distance from surface to the nearest atom exterior to surface. The short and highly directional H-bonds (mainly between oxygen carbonyl atoms and NH amide protons) account for 21-32% of the total surface area, and are clearly visible as two sharp features pointing to the lower left of the plot. In addition, the features near di and de 1.2 Å indicate bifurcated H-bond. The fingerplots for 4b and 4d vs 4a and 4d visibly differ in terms of a more dotted nature for the former in regions where di and de are greater than 2.8 Å. As can be deduced from the HS fingerprint plots, the densest packing among this series is observed for 26membered 4c and 1 (values of both di and de do not exceed 2.6 Å), whereas 4b provides the least dense packing (values of di and de exceed 2.8 Å). In addition, the fingerplot for 1 differs from


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others in terms of the presence of characteristic sharp features near 2.2 Å. The above-mentioned similarity of HS fingerplots is also reflected in HS fingerprint breakdown analysis, albeit with some notable differences for solvates of 4c (Figure 6).

H···H O···H

C···H S···S/C/H/O

50 Contributions to the HS area (%)

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3 4 Number of CH2 units

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Figure 6. Percentage contributions to the Hirshfeld surface area for the various close intermolecular contacts for crystals of UCs 4a-d and 1; inset - percentage contributions versus the number n of methylene groups in the linkers. Namely, it is clearly evident that pronounced share of X···H and N···H contacts in solvates with DCE/water and MeCN molecules, respectively, occur at the expense of O···H contacts. A final observation to be made from Figure 6 concerns the relative shares of H···H, O···H, and S···all (with S, C, H, N, or O atom): interactions increase non-linearly with the size of the macrocycles, whereas the share of C···H interactions remains at the similar level (see inset in Figure 6). Interestingly, the number of methylene groups in the flexible aliphatic spacer was found to affect the eventual presence of lattice solvent, and hence the solvation of macrocycles in the solid state. Specifically, UCs containing diamines with an odd number of methylene units (4b and 4d), regardless of the crystallization method, resulted a single crystal of the corresponding


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macrocycle without any solvent molecule, even though UCs with an even number of CH2 units (4a and 4c) always provided solvates. Bearing in mind that entrapping of a solvent guest, in particular water, is routinely observed for various macrocyclic structures containing amide groups, the clearly seen inability of the odd membered 4b and 4d to form such inclusion complexes is quite puzzling. Since the only structural difference among 4a-d is the length of an aliphatic linker, this observation might be rationalized in terms of the so-called “odd-even” effect.18 This solid-state effect is a phenomenon quite often observed across many disciplines in chemistry,19-21 materials science,22-25 and biology,26 involving an alternation in the structure and/or properties of an chemical entity depending upon whether there are odd or even numbers of a basic unit, such as methylene groups in α,ω-di-functionalized alkanes.27-29 This phenomenon stems from the differing crystal-packing requirements of odd and even members, of which the latter are, in a majority of cases, characterized by a denser packing.29 To evaluate if this effect indeed occurs in the studied compounds, we took a closer look at the geometrical descriptors of the macrocyclic cavity, which for these UCs can be described as a trapezoid-like space delimited by five nitrogen atoms and the distance between the N2 and N5 atoms (Figure 7). 50

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dN2···N5 (Å)

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7 6 5

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3 4 5 Number of CH2 units

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3 4 5 Number of CH2 units

Figure 7. Geometrical descriptors of macrocyclic cavity: calculated surface area Pcalc delimited by nitrogen atoms N2-N4 and N5-N7, and distance h between N2···N5 atoms (a), plots of Pcalc (b) and h (c) versus the number n of methylene groups in the linkers.


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These parameters exhibit noticeable alteration as the length and parity of aliphatic linkers is varied. Thus, for even-membered UCs (n=2 for 4a and n=4 for 4c) the height and surface of macrocyclic cavity are considerably smaller than for odd-membered ones (n=3 for 4b and n=5 for 4d). In other words, the even-membered UCs are better packed, which gives rise to increased intermolecular interactions, in particular with solvent molecules. This is also supported by the less dense packing around the ends of the molecules in Hirschfeld fingerplots for odd-membered UCs. The exact origin of this phenomenon is, however, currently under investigation and will be published in the future. Comparison of crystal structures of 4a-d uncovers another interesting structural behavior of these homologous macrocyclic compounds (Figure 8). First, analysis of the molecular electrostatic potential surface (EPS) for UCs 4a-d confirms their highly polar nature (Figure 8a). In particular, regions of negative potential surround the oxygen atoms of the nitro, ether, and carbonyl groups, and regions of positive potential are mainly located at NH protons and the aromatic lariat and pyridine rings. a)

b)


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Figure 8. Exemplification of the burying of the lariat-arm as a result of expansion of the macrocyclic skeleton (left-to-right: 4a, 4b, 4c, and 4d; the corresponding CPk are 0.76, 0.77, 0.79, and 0.80, respectively): electrostatic potential surfaces EPS (a, calculated at DFT/M062X/6-31G(d,p) level of theory, mapped at 0.001 au, inset ─ values are in kJ/mol) and side-view of the macrocyclic entity (b). Secondly, Figure 8b shows that a progressive elongation of the methylene linker, which is accompanied by an expansion of the macrocyclic cavity (see Figure 7c), forces the macrocycle to adopt a more planar conformation. For a sufficiently large macrocycles, such as the 28membered 4d, this step-by-step process leads to a complete “burying” (or self-encapsulation) of the lariat arm within the macrocyclic cavity. Surely, this process maximizes the noncovalent interactions between the lariat arm and residues belonging to the macroring, and hence facilitates a more compact crystal packing (values of CPk parameter describing crystal packing efficiency progressively increase from 0.76 for 4a to 0.80 for 4d). Notably, both free macrocycles as well as their solvates follow this trend, which demonstrates that geometrical constrains produced by the cyclic scaffold and the progressive burying of the lariat arm are the main factors governing packing of UCs 4 in the crystal lattice. Inspection of crystal structures of 4c and its fully amidated analog 1 further confirms this assumption (Figure 9).


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Figure 9. Superposition of the 4c.0.75H2O·2DCE (blue) and 1.4H2O (green). Note that, despite the presence of octameric water clusters in the crystal lattice of 1, conformation of macrocyclic entity of thioamide 4c closely resembles that of 1. Collectively, these results indicate that conformation of a given UC could potentially be predicted by analyzing the reported crystal structures of analogous compounds, and to some extent theoretically.1,5 Nevertheless, it is known from the solution studies that pentamidic UCs are capable of selective recognition of anions within their macrocyclic cavities, and this process is accompanied by a rotation of lariat arm in such a way that NH amide proton is directed toward macrocyclic cavity.2 Since this process strictly depends on the size and geometry of the anionic guest, one can assume that a similar process of rotation of lariat arm could be also realized during crystallization in the presence of a suitable guest. This, in turn opens the possibility to utilize cavities of these macrocyclic structures for the selective recognition and enclathration of diverse set of small guest compounds by a number of close and highly directional intramolecular interactions. This approach may be potentially attractive for the problem of separation of isomers which have similar physicochemical properties, hence are difficult to separate using conventional


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techniques such as distillation and fractional crystallization.30-33 Efforts toward this goal are currently underway in our laboratory. Analysis of the chalcogen bond in 4c The anomalously short and highly directional C=S···S=C interaction observed in the structure of crystal 4c is an example of a chalcogen bond.34,35 Interactions of this type involving heavier elements of group 14 (S, Se, Te) are much less explored than hydrogen and halogen36,37 bonds, both in supramolecular chemistry and in crystal engineering. Nevertheless, chalcogen bonds involving a sulfur atom play a prominent role in biological systems, e.g. in stabilizing the conformation of peptides containing methionine and cysteine residues.38,39 The vast majority of the S···S interactions reported so far utilize divalent sulfur,40-48 whereas interactions involving monovalent sulfur are currently mainly a subject of theoretical investigation,35,45 hence studies geared towards experimental proof are of great interest for scientific community. According to the σ-hole concept,46-48 a chalcogen bond may be defined as an attractive noncovalent interaction between covalently linked electron-deficient chalcogen atom that has a directional and positive area (i.e. σ-hole) on its electrostatic potential surface (EPS), with an electron-rich area (i.e. anion, lone electron pair or π-system) on the second chemical entity. In the macrocycles we studied, the thiocarbonyl group is attached to the electron-withdrawing (pnitrophenyl) and -donating (2,6-dimethylenoaniline) residues. Such an attachment likely renders a pronounced charge anisotropy in the EPS of the C=S bond. To unravel the origin of this interaction and identify a plausible location of the anticipated σ-hole, we decided to take a closer look at the geometry of this assembly and carry out quantum mechanical calculations for all studied structures (Figures 10 and S8).


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a)

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c)

d)

Figure 10. Structure of dimeric capsule of 4c in ORTEP (a) and CPk representation (b), computed electrostatic potential mapped on the 0.001 au molecular surfaces of 4c calculated at DFT/B3LYP/6-311G(d,p) (c) and DFT/M06-2X/6-31G(d,p) (d) level of theory utilizing CrystalExplorer 3.149 and Spartan'14 computer programs, respectively. Thermal ellipsoids are drawn at the 50% probability level. Non-acidic protons, solvent molecules, and disorder are omitted for clarity. Blue and red colors on EPS represent electropositive and electronegative regions, respectively. It is evident from Figure 10a-b that the formation of the chalcogen bond is facilitated by a favorable head-to-head conformation of the 4c···4c dimer, which enables formation of additional and rather short dispersive interactions of types π···π and CH···π (dmin = 3.28 Å) as well as hydrogen bonds (dN4···S1 = 3.45 Å, ∠ = 142°). Therefore, despite marginal contribution of S···S interaction (0.6% and 0.7% for DCE/H2o and MeCN solvates, respectively) to the total surface


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area and the presence of many strong intermolecular interactions, in particular hydrogen bonds, this homo chalcogen interaction has a directing role in the formation of the dimeric assembly of 4c in the crystal lattice. The presence of characteristic strongly directional region of depleted charge on the extension of C=S bond, i.e. σ-hole, could be recognized only for UCs in which C=S group is directed outside the macroring, i.e. UCs 4c (Figure 10c-d) and 4d (Figure S5). Analysis of the geometry of C=S···S=C interaction indicates that σ-holes interact with the area of negative potential on the adjacent sulfur atom (notice belt of negative potential around σ-hole). The obtained results are consistent with theoretical data obtained for complexes interacting by σ holes.46,48 The structure of 4c solvated with MeCN crystallizes in the same space group as DCE/H2O solvate (C2/c) and also exhibits the occurrence of the analogous 4c···4c dimer, which is involved in chalcogen bonding, suggesting that the solvent does not determine the formation of such supramolecular assembly (Figures 10a-b and 11).

Figure 11. Superposition of the 0.75H2O·2DCE (blue) and 2MeCN (red) solvates of the 4c.


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Presumably, solvent molecules can only modulate the strength of S···S interactions (S···S interaction is 0.14 Å longer in acetonitrile solvate than in DCE/H2O). Acetonitrile molecule is able to form only one H-bond, which affects the orientation of the 4c···4c dimer in the crystal lattice (the hydrogen bond is elongated by 0.1 Å as compared to DCE/H2O solvate). The thioamide sulfur atom, in contrast to DCE/H2O solvate, is here engaged in two, albeit weaker, intermolecular H-bonding with amidic groups of the pyridine moiety of an adjacent macrocycle (dS1-N4* = 3.62 Å, ∠ = 120° and dS1-N6* = 3.59 Å, ∠ = 124°). Interestingly, acetonitrile molecule positions itself in the exact manner as water molecule in the DCE/H2O solvate, as is confirmed by the identical parameters for both hydrogen bonds (d = 2.93 Å, ∠ = 140°). The possibility of replacing water molecule, without significantly changing the host structure, has been previously described in literature. In-depth analysis of the solvate structures reveals that strength of the S···S interaction (described by distance between S atoms) is higher when the corresponding Hbonds originating from the NH amide groups are shorter. Amide group H-bonded to the sulfur atom (d=3.45 Å, 2σ(F2)) = 0.038, R (all) = 0.091, CCDC 1498218. Selected crystallographic data for 4d·2MeCN: monoclinic, C2/c,


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a = 24.8857(9) Å, b = 13.6551(4) Å, c = 21.9683(6) Å, β = 97.178(3) °, V = 7406.7(4) Å3, Z = 6, R (F2 > 2σ(F2)) = 0.038, R (all) = 0.060, CCDC 1498214. Macrocycle 4d. Following procedure A, using diester 2 (256 mg, 0.59 mmol) and hydrochloride of diamine 2d (240 mg, 0.59 mmol), after 7 days of stirring, macrocycle 4d (230 mg, 55 %) was obtained in the form of intensive yellow crystals (mp 266 oC). 1H NMR (400 MHz, DMSO): 11.71 (1H), 9.27 (t, 2H, J 6.0), 8.33 (jjab, 4H), 8.16 (m, 3H), 7.36 (t, 2H), 7.27 (t, 1H, J 8.5), 6.70 (d, 2H, J 8.5), 4.59 (s, 4H), 3.27 (m, 4H), 3.08 (m, 4H), 1.45 (m, 4H), 1.29 (m, 2H), 1.16 (m, 2H). 13C NMR (100 MHz, DMSO): δ = 167.2, 167.2, 163.0, 153.2, 148.8, 148.6, 139.4, 129.0, 124.0, 123.4, 106.2, 67.2, 38.6, 38.0, 29.0, 28.6, 25.6. HRMS (ESI, MeOH): m/z [M+Na]+

calc.

for

C34H39N7O8SNa

728.2473,

found:

728.24614.

Anal.

calc.

for

C34H39N7O8S⋅CH3OH⋅H2O: C 55.62, H 6.00 N 12.97, S 4.24, found: C 55.64, H 5.89, N 13.05, S 4.45. Single crystals of compound 4d suitable for X-ray crystallographic analysis were obtained by slow evaporation of DMSO solution. Selected crystallographic data for 4d: monoclinic, P21/c, a = 17.239(1) Å, b = 16.479(1) Å, c = 27.904(2) Å, β = 121.216(4) °, V = 6779.8(8) Å3, Z = 8, R (F2 > 2σ(F2)) = 0.033, R (all) = 0.102, CCDC 1498215. ASSOCIATED CONTENT Supporting Information. X-ray data for compounds 4a, 4c, and 4d (CIF files), Hirshfeld fingerprint plots, details of the CSD survey concerning C=S···S=C interaction, copies of 1H and

13

C NMR spectra for all new

compounds, and Cartesian coordinates of calculated structures. This material is available free of charge via the Internet at http://pubs.acs.org.


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AUTHOR INFORMATION Corresponding Author * [email protected] ACKNOWLEDGMENT We would like to acknowledge financial support from Poland’s National Science Centre (project 2011/02/A/ST5/00439). The X-ray structures were determined in the Advanced Crystal Engineering Laboratory (aceLAB) at the Chemistry Department of the University of Warsaw by Dr. Łukasz Dobrzycki. REFERENCES (1) Dąbrowa, K.; Ceborska, M.; Jurczak, J. Cryst. Growth Des. 2014, 14, 4906−4910. (2) Dąbrowa, K.; Pawlak, M.; Duszewski, P.; Jurczak, J. Org. Lett. 2012, 14, 6298−6301. (3) Piatek, P.; Jurczak, J. Chem. Commun. 2002, 2450−2451. (4) Dabrowa, K.; Niedbala, P.; Majdecki, M.; Duszewski, P.; Jurczak, J. Org. Lett. 2015, 17, 4774−4777. (5) Ziach, K; Dabrowa, K.; Niedbala, P.; Kalisiak, J.; Jurczak, J. Tetrahedron 2016, 72, 8373−8381. (6) In crystallography, crystal packing coefficient (CPk) and atomic packing factor (APF) parameters are interchangeably used to describe an efficiency of packing of the molecules in a crystal lattice; for the definition, see ref. 1 and Suryanarayana, C.; Norton, M. G., X-Ray Diffraction: A Practical Approach. Springer US: 2013, respectively.


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For Table of Contents Use Only Comparative structural studies of four homologous thioamidic unclosed crytpands (UCs): selfencapsulation of lariat arm, odd-even effects, anomalously short S···S chalcogen bonding, and more Kajetan Dąbrowa,† Magdalena Ceborska,‡ Marcin Pawlak,† and Janusz Jurczak*,†

SYNOPSIS Comparative analysis of crystal structures of a series of homologous unclosed cryptands 4a-d showed that their conformation and the occurrence of lattice solvent strictly depend on the length and parity of the aliphatic linkers. Additionally, for a 26-membered UC 4c an anomalously short and highly directional C=S···S=C chalcogen interaction was observed between adjacent UC molecules, forming a dimeric assembly. Analysis of Cambridge Structural Database (CSD) suggests that O/N-H···S hydrogen bonds are crucial for stabilization of this type of noncovalent interaction.

TOC GRAPHIC


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Comparative Structural Studies of Four Homologous Thioamidic

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