Substituent Effects in the Crystal Packing of Derivatives of 4 ′-Phenyl-2 , 2 ′ : 6 ′ , 2 ′ ′-Terpyridine

We report the preparation of a series of new 4′-substituted 2,2′:6′,2′′-terpyridines: 4′-(3,5-dimethylphenyl)-2,2′:6′,2′′-terpyridine (2), 4′-(3-fluoro-5-methylphenyl)-2,2′:6′,2′′-terpyridine (3), 4′-(3,5-difluorophenyl)-2,2′:6′,2′′-terpyridine (4), and 4′-(3,5bis(trifluoromethyl)phenyl)2,2′:6′,2′′-terpyridine (5). The compounds have been characterized by mass spectrometry, solid-state IR spectroscopy and solution NMR and absorption spectroscopies. The single-crystal X-ray diffraction structures of 3, 5 and 6·EtOH (6 = 4′-(3,5-bis(tert-butyl)phenyl)-2,2′:6′,2′′-terpyridine) have been elucidated. The molecular structures of the compounds are unexceptional. Since 3 and 5 crystallize without lattice solvent, we are able to understand the influence of introducing substituents in the 4′-phenyl ring and compare the packing in the structures with that of the previously reported 4′-phenyl-2,2′:6′,2′′-terpyridine (1). On going from 1 to 3, face-to-face π-stacking of pairs of 3-fluoro-5-methylphenyl rings contributes to a change in packing from a herringbone assembly in 1 with no ring π-stacking to a layer-like packing. The latter arises through a combination of π-stacking of aromatic rings and N . . . H–C hydrogen bonding. On going from 3 to 5, N . . . H–C and F . . . H–C hydrogen-bonding is dominant, supplemented by π-stacking interactions between pairs of pyridine rings. A comparison of the packing of molecules of 6 with that in 1, 3 and 5 is difficult because of the incorporation of solvent in 6·EtOH.


Introduction
The relevance of energetically small intermolecular interactions in determining the arrangement of molecules and molecular ions in crystal lattices is well documented [1,2].In particular, the role of hydrogen-bonding in crystal packing has been widely investigated, and specific attention has been paid to the varying types of hydrogen bonds, ranging from the strongest interaction in [HF 2 ] − [3] to non-classical (weak) hydrogen bonds [2,4,5].One of the weakest hydrogen bonds is the CH . . .π contact [2], but despite its weakness, it plays a substantial role in crystal packing [6,7].Although the interpretation of crystal packing in terms of donor . . .acceptor interactions is commonly discussed in the literature, the combination of electron donors (e.g., N, O, F, π-systems) and acceptors (e.g., O-H, N-H, C-H units) within a molecule does not necessarily result in a predetermined organization of molecules in the solid state.Statistical analysis of structures in the Cambridge Structural Database demonstrates that many more H . . .acceptor interactions, especially weak C-H . . .X contacts occur in crystals than would be expected, based on a model of random contacts [8].However, Lo Presti has pointed out that, from a crystal-engineering point of view, weak C-H . . .X interactions, on their own, are unlikely to be a significant thermodynamic driving force toward a specific crystal form [9,10].
problem of predicting the outcome of assemblies in crystalline materials, and crystal structure prediction is now a mature, but complex, field (see for example, References [11][12][13][14][15]).
We present here a series of new tpy compounds, 2-5 (Scheme 1) and the single crystal structures of 3 and 5.The packing is compared with that in 1, and we discuss the effects of introducing F or CF3 in place of H in the 3-and 5-positions of the 4'-phenyl substituent.We also describe the single crystal structure of 6 .EtOH.

General
Scheme 1. Structures of the tpy ligands 1-6, with atom numbering in 2-6 for NMR spectroscopic assignments.
We present here a series of new tpy compounds, 2-5 (Scheme 1) and the single crystal structures of 3 and 5.The packing is compared with that in 1, and we discuss the effects of introducing F or CF 3 in place of H in the 3-and 5-positions of the 4 -phenyl substituent.We also describe the single crystal structure of 6•EtOH.
Compounds 1 and 6 were prepared by the one-pot method of Wang and Hanan [33], and the NMR spectroscopic data matched those previously reported [34].

Synthesis and Solution Characterization of Complexes
Compounds 2-6 were prepared by the one-pot method of Wang and Hanan [33].For 6, the spectroscopic data were in accord with those previously reported [34].The syntheses of 2-5 are summarized in Scheme 2, and the compounds were isolated as white solids in between 40.6% and 45.3% yields.Electrospray mass spectra showed peak envelopes at m/z 338.1 for 2, 342.1 for 3, 346.1 for 4, and 446.1 for 5 assigned to the [M+H] + ion.The assignments were further confirmed with high-resolution mass spectra (Figures S1-S4, in the Supplementary Materials) in which peaks for [M+H] + were observed for all compounds, as well as [M+Na] + for 3, 4 and 5.
Crystals 2019, 9, x FOR PEER REVIEW 5 of 15 Compounds 2-6 were prepared by the one-pot method of Wang and Hanan [33].For 6, the spectroscopic data were in accord with those previously reported [34].The syntheses of 2-5 are summarized in Scheme 2, and the compounds were isolated as white solids in between 40.6% and 45.3% yields.Electrospray mass spectra showed peak envelopes at m/z 338.1 for 2, 342.1 for 3, 346.1 for 4, and 446.1 for 5 assigned to the [M+H] + ion.The assignments were further confirmed with high-resolution mass spectra (Figures S1-S4, in the Supplementary Materials) in which peaks for [M+H] + were observed for all compounds, as well as [M+Na] + for 3, 4 and 5. Scheme 2. One-pot synthetic approach to compounds 2-5.The solution 1 H and 13 C NMR spectra of 2-5 were assigned using 2D methods (COSY, NOESY, HMQC and HMBC) and representative 1D and 2D spectra are shown in Figures S5-S17.The aromatic regions of the 1 H NMR spectra are shown in Figure 1.As expected, the signals for the tpy domains (rings A and B, see Scheme 1) do not change significantly upon the introduction of different substituents in the phenyl ring (ring C).A change from a 3,5-dimethylphenyl group in 2 to 3,5-bis(trifluoromethyl)phenyl in 5 shifts the signals for protons H C2 and H C4 to higher frequency.The 1 H NMR spectrum of 3 (Figure 1) is consistent with the lower symmetry of the 3-fluoro-5-methylphenyl substituent compared to the substituents in 2, 4 or 5, and the signals in the spectrum of 3 for H C4 and H C2 (both of which show coupling to 19 F) were distinguished by a NOESY cross-peak between the signals for H B3 and H C2 (Figure 2).The loss of the resonance for H C6 on going from 3 to 4 (Figure 1) is consistent with the change in symmetry on going from a 3-fluoro-5-methylphenyl to 3,5-difluorophenyl substituent.The 13 C{ 1 H} NMR spectra of 4 and 5 are shown in Figure 3 and Figure S15, respectively.In 4, nucleus C C3 is characterized by a doublet of doublets at δ 163.6 ppm with values of 1 J FC = 248.9Hz and 4 J FC = 12.8 Hz (Figure 3c), while signals for C C4 and C C2 appear as a triplet at δ 104.4 ppm ( 2 J FC = 25.3Hz) and a doublet of doublets at δ 110.5 ppm ( 2 J FC = 26.1 Hz and 4 J FC = 13.6 Hz), respectively (Figure 3b).In 5, the signal for C C3 is a quartet ( 2 J FC = 33.6Hz), and the quartet for the CF 3 group has 1 J FC = 273 Hz (Figure S15).The 1 H NMR spectrum of 3 (Figure 1) is consistent with the lower symmetry of the 3-fluoro-5-methylphenyl substituent compared to the substituents in 2, 4 or 5, and the signals in the spectrum of 3 for H C4 and H C2 (both of which show coupling to 19 F) were distinguished by a NOESY cross-peak between the signals for H B3 and H C2 (Figure 2).The loss of the resonance for H C6 on going

Single Crystal Structures of 3, 5 and 6
Compounds 2-6 were recrystallized from a hot mixture of chloroform and ethanol.Upon cooling the solutions, X-ray quality single crystals of 3, 5 and 6 .EtOH were obtained.Compounds 3 and 6 .EtOH crystallize in the triclinic space group P-1, while 5 crystallizes in the monoclinic space group C2/c.The molecular structures of 3, 5 and 6 are shown in Figures 5-7 and selected bond distances and angles are given in the figure captions.Each CF3 group in 5 is rotationally disordered, and each fluorine atom has been modeled over two sites of partial occupancies 0.532(8) and 0.468 (8) for the F atoms bonded to C23, and 0.598(10) and 0.402 (10) for the F atoms bonded to C22.Only the major occupancy sites are used in the discussion below.As expected, the tpy unit in each of 3, 5 and       In 6 .EtOH, a molecule of EtOH is held within a pocket between a pyridine ring and tert-butyl group (Figure 8a) with hydrogen-bonded contacts of N3…H1-O100 = 2.08 Å and O100...H21 i -C2 i = 2.46 Å (N3…O100 = 2.919(1) Å, O100...C2 i = 3.257(1) Å).As Figure 8b shows, the interaction is extended by symmetry to give centrosymmetric pairs of molecules with two rings of each tpy unit stacked over one another.However, as can be judged from the similar values of the distance between the centroid of the ring with N2 to the plane of the ring with N1 i (3.61 Å) and the inter-centroid separation (3.62 Å), the rings are not offset as is required for an optimal face-to-face π-stacking interaction [21].The angle between the planes of the rings containing N2 and N1 i is 3.5°.In 6•EtOH, a molecule of EtOH is held within a pocket between a pyridine ring and tert-butyl group (Figure 8a) with hydrogen-bonded contacts of N3 . . .H1-O100 = 2.08 Å and O100...H21 i -C2 i = 2.46 Å (N3 . . .O100 = 2.919(1) Å, O100...C2 i = 3.257(1) Å).As Figure 8b shows, the interaction is extended by symmetry to give centrosymmetric pairs of molecules with two rings of each tpy unit stacked over one another.However, as can be judged from the similar values of the distance between the centroid of the ring with N2 to the plane of the ring with N1 i (3.61 Å) and the inter-centroid separation (3.62 Å), the rings are not offset as is required for an optimal face-to-face π-stacking interaction [21].The angle between the planes of the rings containing N2 and N1 i is 3.5 • .In 6 .EtOH, a molecule of EtOH is held within a pocket between a pyridine ring and tert-butyl group (Figure 8a) with hydrogen-bonded contacts of N3…H1-O100 = 2.08 Å and O100...H21 i -C2 i = 2.46 Å (N3…O100 = 2.919(1) Å, O100...C2 i = 3.257(1) Å).As Figure 8b shows, the interaction is extended by symmetry to give centrosymmetric pairs of molecules with two rings of each tpy unit stacked over one another.However, as can be judged from the similar values of the distance between the centroid of the ring with N2 to the plane of the ring with N1 i (3.61 Å) and the inter-centroid separation (3.62 Å), the rings are not offset as is required for an optimal face-to-face π-stacking interaction [21].The angle between the planes of the rings containing N2 and N1 i is 3.5°.

Comparison of Packing Interactions in 1, 3, 5 and 6
Crystal packing in 4 -phenyl-2,2 :6 ,2 -terpyridine, 1, has not previously been discussed, although two entries of the single crystal structure (refcodes SIXLAM [24] and SIXLAM01 [25]) appear in the Cambridge Structural Database (CSD, v. 5.40, November 2018 [41]).In order to assess the role of the 4 -(3,5-substituted) phenyl group, it is instructive to first examine the crystal packing in 1 using data from SIXLAM [24].Figure 9a shows that the almost planar molecules are arranged in ribbon-like assemblies that slice obliquely through the unit cell.The ribbons form herringbone assemblies, which nest next to one another.The arrangement of molecules in adjacent ribbons is displayed in Figure 9b,c.Although the planes of the pyridine rings containing N1 and N1 i are 3.56 Å apart, the slippage of the rings leads to non-optimal face-to-face π-stacking [21].The same is true of any possible π-interaction between the rings containing N2 and N1 i .The phenyl ring is not involved in face-to-face π-stacking.
Both 1 and 3 crystallize without lattice solvent, and we can therefore directly assess the effects of introducing the 3-fluoro-5-methylphenyl group in place of a phenyl ring.The herringbone assembly in 1 is replaced by a layer-like packing (Figure S18), which arises through a combination of face-to-face π-stacking of aromatic rings and N . . .H-C hydrogen bonding.Centrosymmetric pairs of molecules of 3 associate through hydrogen bonding or π-stacking of the 3-fluoro-5-methylphenyl substituents (Figure 10a).Hydrogen bonding involves one of the outer pyridine rings (N16 . . .H171 i = 2.61 Å, N16 . . .H171 i -C17 i = 146 • , symmetry code i = −x, −1−y, 1−z).Face-to-face π-stacking contacts between phenyl rings containing C7 and C7 ii (symmetry code i = 1−x, −y, 2−z) are characterized by a separation of the ring planes of 3.47 Å and a ring centroid separation of 4.08 Å. Together, these interactions lead to the assembly of chains of molecules running through the lattice.The chains associate through π-stacking tpy domains.Centrosymmetric pairs of bipyridine units containing N12/N16 iii and N16/N12 iii (symmetry code iii = −x, −y, 1−z) stack as shown in Figure 10b with a centroid . . .plane separation of 3.44 Å and centroid . . .centroid distance of 3.79 Å.
ribbon-like assemblies that slice obliquely through the unit cell.The ribbons form herringbone assemblies, which nest next to one another.The arrangement of molecules in adjacent ribbons is displayed in Figure 9b,c.Although the planes of the pyridine rings containing N1 and N1 i are 3.56 Å apart, the slippage of the rings leads to non-optimal face-to-face π-stacking [21].The same is true of any possible π-interaction between the rings containing N2 and N1 i .The phenyl ring is not involved in face-to-face π-stacking.Both 1 and 3 crystallize without lattice solvent, and we can therefore directly assess the effects of introducing the 3-fluoro-5-methylphenyl group in place of a phenyl ring.The herringbone assembly in 1 is replaced by a layer-like packing (Figure S18), which arises through a combination of face-to-face π-stacking of aromatic rings and N…H-C hydrogen bonding.Centrosymmetric pairs of molecules of 3 associate through hydrogen bonding or π-stacking of the 3-fluoro-5-methylphenyl substituents (Figure 10a).Hydrogen bonding involves one of the outer pyridine rings (N16…H171 i = 2.61 Å, N16…H171 i -C17 i = 146°, symmetry code i = -x, -1-y, 1-z).Face-to-face π-stacking contacts between phenyl rings containing C7 and C7 ii (symmetry code i = 1-x, -y, 2-z) are characterized by a separation of the ring planes of 3.47 Å and a ring centroid separation of 4.08 Å. Together, these interactions lead to the assembly of chains of molecules running through the lattice.The chains associate through π-stacking tpy domains.Centrosymmetric pairs of bipyridine units containing N12/N16 iii and N16/N12 iii (symmetry code iii = -x, -y, 1-z) stack as shown in Figure 10b with a centroid…plane separation of 3.44 Å and centroid…centroid distance of 3.79 Å.Like 1 and 3, compound 5 crystallizes without solvent.On going from 3 to 5, the N…H-C hydrogen bonds between tpy units increase in number, involving both outer pyridine rings (Figure 11a).Comparison of Figures 10 and 11 show that the basic centrosymmetric hydrogen-bonded motif is replaced with a motif with C2 symmetry, while retaining the N…H-C hydrogen bonds.In 5, the N1…H1 i and N2…H12 ii distances are 2.68 and 2.64 Å, and the N1…H1 i -C1 i and N2…H12 ii -C12 ii angles are 128 and 127 o , respectively.The hydrogen-bonded chain that results from these interactions is further supported by F…HC hydrogen bonds (Figure 11a) with F2…H2 i and F11…H11 ii separations of 2.46 and 2.41 Å, and F2…H2 i -C2 i and F11…H11 ii -C11 ii angles of 166° and 160°, respectively.The zigzag profile of the hydrogen-bonded assembly (which runs along the crystallographic c axis) is shown in Figure 11b.The chains pack with pairs of tpy domains of adjacent chains lying in a head-to-tail arrangement with optimal π-stacking of the central pyridine rings (Figure 12).The separation of the planes of the rings containing N3 and N3 iii is 3.37 Å, and the inter-centroid distance is 3.69 Å (symmetry code iii = -x, 1-y, -z).In 5, a combination of hydrogen-bonding and the π-stacking of tpy units leads to highly efficient crystal packing with close approach of CF3 groups as shown in Figure S19.The closest F…F contact is 2.54(1) Å, which is less than the sum of the van der Waals radii (2.94 Å [32], 2.70 Å [42]).Like 1 and 3, compound 5 crystallizes without solvent.On going from 3 to 5, the N . . .H-C hydrogen bonds between tpy units increase in number, involving both outer pyridine rings (Figure 11a).Comparison of Figures 10 and 11 show that the basic centrosymmetric hydrogen-bonded motif is replaced with a motif with C2 symmetry, while retaining the N . . .H-C hydrogen bonds.In 5, the N1 . . .H1 i and N2 . . .H12 ii distances are 2.68 and 2.64 Å, and the N1 . . .H1 i -C1 i and N2 . . .H12 ii -C12 ii angles are 128 and 127 • , respectively.The hydrogen-bonded chain that results from these interactions is further supported by F . . .HC hydrogen bonds (Figure 11a) with F2 . . .H2 i and F11 . . .H11 ii separations of 2.46 and 2.41 Å, and F2 . . .H2 i -C2 i and F11 . . .H11 ii -C11 ii angles of 166 • and 160 • , respectively.The zigzag profile of the hydrogen-bonded assembly (which runs along the crystallographic c axis) is shown in Figure 11b.The chains pack with pairs of tpy domains of adjacent chains lying in a head-to-tail arrangement with optimal π-stacking of the central pyridine rings (Figure 12).The separation of the planes of the rings containing N3 and N3 iii is 3.37 Å, and the inter-centroid distance is 3.69 Å (symmetry code iii = −x, 1−y, −z).In 5, a combination of hydrogen-bonding and the π-stacking of tpy units leads to highly efficient crystal packing with close approach of CF 3 groups as shown in Figure S19.The closest F . . .F contact is 2.54(1) Å, which is less than the sum of the van der Waals radii (2.94 Å [32], 2.70 Å [42]).
angles are 128 and 127 , respectively.The hydrogen-bonded chain that results from these interactions is further supported by F…HC hydrogen bonds (Figure 11a) with F2…H2 i and F11…H11 ii separations of 2.46 and 2.41 Å, and F2…H2 i -C2 i and F11…H11 ii -C11 ii angles of 166° and 160°, respectively.The zigzag profile of the hydrogen-bonded assembly (which runs along the crystallographic c axis) is shown in Figure 11b.The chains pack with pairs of tpy domains of adjacent chains lying in a head-to-tail arrangement with optimal π-stacking of the central pyridine rings (Figure 12).The separation of the planes of the rings containing N3 and N3 iii is 3.37 Å, and the inter-centroid distance is 3.69 Å (symmetry code iii = -x, 1-y, -z).In 5, a combination of hydrogen-bonding and the π-stacking of tpy units leads to highly efficient crystal packing with close approach of CF3 groups as shown in Figure S19.The closest F…F contact is 2.54(1) Å, which is less than the sum of the van der Waals radii (2.94 Å [32], 2.70 Å [42]).The effect of going from a 3,5-bis(trifluoromethyl)phenyl substituent in 5 to a 3,5-bis(tert-butyl)phenyl group in 6 is difficult to assess because 6 crystallizes as the solvate 6 .EtOH.As discussed earlier, the EtOH molecule is hosted within a cavity between a pyridine ring and tert-butyl group, and is associated with the formation of π-stacked pairs of tpy units (Figure 8).This is, in fact, the dominant packing motif in 6 .EtOH.The centrosymmetric dimeric units (Figure 8b) pack with close association of a tert-butyl of one dimer with a pyridine ring of the next.Figure 13 illustrates this packing, and the closest Htert-butyl…centroidpyridine distance is 3.14 Å.The effect of going from a 3,5-bis(trifluoromethyl)phenyl substituent in 5 to a 3,5-bis(tert-butyl)phenyl group in 6 is difficult to assess because 6 crystallizes as the solvate 6•EtOH.As discussed earlier, the EtOH molecule is hosted within a cavity between a pyridine ring and tert-butyl group, and is associated with the formation of π-stacked pairs of tpy units (Figure 8).This is, in fact, the dominant packing motif in 6•EtOH.The centrosymmetric dimeric units (Figure 8b) pack with close association of a tert-butyl of one dimer with a pyridine ring of the next.Figure 13 illustrates this packing, and the closest H tert-butyl . . .centroid pyridine distance is 3.14 Å.

Figure 2 .
Figure 2. Part of the NOESY spectrum of compound 3, showing the cross-peak between the signals for H B3 and H C2 .

Figure 2 .
Figure 2. Part of the NOESY spectrum of compound 3, showing the cross-peak between the signals for H B3 and H C2 .

Figure 2 .
Figure 2. Part of the NOESY spectrum of compound 3, showing the cross-peak between the signals for H B3 and H C2 .

Figure 4
Figure 4 displays the solution absorption spectra of compounds 2-5.The absorptions are assigned to spin-allowed π*←π transitions in 2, and to π*←π and π*←n transitions in 3, 4 and 5. On going from 2 to 3 to 4, the change from 3,5-dimethylphenyl to 3-fluoro-5-methylphenyl to 3,5-difluorophenyl substituent leads to a dominance of the highest energy absorption around 253 nm and a decrease in intensity of the absorption around 280 nm.This trend is particularly noticeable upon introducing the trifluoromethyl groups in compound 5. Crystals 2019, 9, x FOR PEER REVIEW 7 of 15

Figure 9 .
Figure 9. Packing of molecules in the crystal lattice of 1 (refcode SIXLAM [24,41]).(a) Molecules assemble into ribbons, which then stack in a herringbone manner.(b) Arrangement of molecules in adjacent ribbons; molecules colored red are in one ribbon, and the third molecule is in an adjacent ribbon.Symmetry code i = -x, -y, 1-z.(c) Side view and space-filling representation of the three molecules are shown in (b).

Figure 9 .
Figure 9. Packing of molecules in the crystal lattice of 1 (refcode SIXLAM [24,41]).(a) Molecules assemble into ribbons, which then stack in a herringbone manner.(b) Arrangement of molecules in adjacent ribbons; molecules colored red are in one ribbon, and the third molecule is in an adjacent ribbon.Symmetry code i = −x, −y, 1−z.(c) Side view and space-filling representation of the three molecules are shown in (b).

Figure 11 .
Figure 11.Assembly of part of a hydrogen-bonded chain in 5, showing (a) the N…H-C and F…H-C interactions (symmetry codes i = -x, y, -1 /2-z; ii = -x, y, 1 /2-z) and (b) the zigzag profile of the chain.The chain follows the crystallographic c-axis.

Figure 13 .
Figure 13.Adjacent centrosymmetric dimers {6.EtOH}2 colored blue and red (EtOH molecules omitted for clarity) associate through CHtert-butyl…centroidpyridine contacts; methyl groups (of the tert-butyl) and pyridine rings are shown in space-filling representation.The central red and blue pyridine rings are not π-stacked.