A Cambridge Structural Database analysis of the C–H⋯Cl interaction: C–H⋯Cl⁻ and C–H⋯Cl–M often behave as hydrogen bonds but C–H⋯Cl–C is generally a van der Waals interaction

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Abstract

A survey of organic crystal structures in the CSD for C–H⋯Cl contacts with Cl–M, Cl⁻ and Cl–C acceptor moieties shows the inverse distance–angle correlation characteristic of a hydrogen bond for C–H⋯Cl–M and C–H⋯Cl⁻ type interactions. The d–θ scatter plot for the C–H⋯Cl–C interaction has many points in the van der Waals region. Further, the H⋯Cl bond is shorter with activated donors for Cl–M and Cl⁻ acceptors but not for Cl–C. These frequency data may be useful to classify C–H⋯Cl interactions as hydrogen bonds or van der Waals interactions in crystal structure analysis.

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Intermolecular interactions of the halogen atom, namely halogen⋯halogen and D–H⋯halogen (halogen⊕=⊕F, Cl, Br; D⊕=⊕O, N, C), continue to attract significant attention in chemical, crystallographic and crystal engineering literature. In a recent communication,¹ Orpen, Brammer and coworkers have analysed the geometry of O–H and N–H donors to Cl–M (M⊕=⊕transition metal), Cl⁻ (chloride ion) and Cl–C (organic chlorine) acceptor groups. Their crystallographic analysis shows that the anisotropy at acceptor chlorine (M–Cl⋯H⊕=⊕90–140°) and the large number of short H⋯Cl contacts (<2.5 Å) with Cl–M and Cl⁻ are significantly diminished or absent with the Cl–C moiety. The picture that emerges from recent studies^1,2 is that metal-bound chlorine and fluorine as well as halide ions are good hydrogen bond acceptors with O–H and N–H donors. On the other hand, the exact nature of C–H⋯Cl interactions is still not clearly understood. They have been observed in some structures,^3a ascribed to determine the molecular conformation^3b and also the arrangement of molecules and ions in the crystal.^3c Polymorphism and twinning in crystals of 1,2,4,5-tetrabromobenzene have been explained through Br⋯Br and Br⋯H interactions.⁴ Resolution of racemic 1,2-dibromohexafluoropropane with (–)-sparteine hydrobromide occurs through robust halogen bond helices in the co-crystal.⁵ Intermolecular interactions involving halogen atoms need not always be structure determining. Because of their weak nature, a balance of forces and interplay of halogen and hydrogen bonding drive self-assembly during crystallisation when strong hydrogen bonding groups, such as OH, are present.⁶

Statistical analysis of crystallography databases is well suited for the study of weak halogen⋯halogen and D–H⋯halogen interactions.⁷ C–H⋯Cl interactions are even weaker compared with the weak O–H⋯Cl and N–H⋯Cl hydrogen bonds because the donor atom is much less electronegative.⁸ Yet, the phrase ‘C–H⋯Cl hydrogen bond’ has appeared in the title of many recent papers,^3b,3c,9,10 of which one is in this journal.^9b While there appears to be a general consensus that the weak O–H⋯Cl and N–H⋯Cl interactions are hydrogen bonds^1,2 the nature of even weaker C–H⋯Cl interactions is still not fully understood – are they hydrogen bonds or mere van der Waals interactions? Aakeröy, Seddon and coworkers¹⁰ have argued that the traditional van der Waals cut-off be dropped for the analysis of C–H⋯Cl interactions and instead be replaced by a softer distance–angle criterion, determined empirically. We show herein through a crystallographic survey that the weak C–H⋯Cl⁻ and C–H⋯Cl–M interactions exhibit the characteristics of conventional hydrogen bonds and hence could be significant in molecular recognition and crystal engineering. On the other hand, the less polarisable C–H⋯Cl–C interaction has no specific directionality and is mostly a van der Waals contact. These trends are in agreement with an earlier study¹⁰ and are corroborated in sub-sets of data with activated donor atoms, when bifurcation is removed, and when competing donor/acceptor groups are excluded.

The Cambridge Structural Database¹¹ (CSD, version 5.19, April 2000 update, 215 403 entries) was searched for C–H⋯Cl contacts in the range 2.0⊕<⊕H⋯Cl⊕(d/Å)⊕<⊕3.3, 90⊕<⊕C–H⋯Cl⊕(θ/°)⊕<⊕180 from three different sub-databases of the Cl acceptor moiety: Cl⁻ (chloride ion, 1858 hits), Cl–M (metal-bound chlorine, M⊕=⊕transition metal, 11 861 hits) and Cl–C (organic chlorine 5304 hits). The C–H distance was neutron-normalised to 1.083 Å. Liberal distance (Σ_vdW H 1.20 Å and Cl 1.75 Å⊕+⊕10%⊕=⊕3.3 Å) and angle (bent geometry up to 90°) cut-off criteria were used. Screens 33 (error-free), 35 (no disorder), 85 (chemical/crystallographic connectivity match), 88 (R-factor⊕≤⊕0.10), and 153 (atom coordinates present) were applied. Only organic compounds were considered (screen 57) with Cl–C and Cl⁻ acceptors; screen 57 was not applied with Cl–M. Duplicate refcodes were not removed. Bifurcated hits were not removed except in one case of C–H⋯Cl–C contacts to compare distance–angle scatter plots of single and bifurcated motifs. The d–θ plot, with or without bifurcation, did not show much difference. However, by removing bifurcated motifs the number of hits dropped to a mere 10% of when bifurcation was included. Moreover, bifurcation will perturb all types of contacts uniformly and so the chemical conclusions should not be altered in a comparative study. In order that the number of fragments is about the same and also statistically significant in different distributions, the R-factor was varied such that the scatter plot or histogram contained ca. 1000 fragments. The R-factor cut-off for each search is mentioned in the figure caption. d–θ Plots of hydrogen bond distribution are displayed using VISTA, a visualisation program distributed with the CSD package. Distance and spatial distributions were normalised:¹²x⊕=⊕(R_H–Cl)³ where R_H–Cl⊕=⊕d⊕/⊕2.95 (Σ_vdW); y⊕=⊕θ_norm⊕=⊕1⊕−⊕cos (180⊕−⊕θ). The corrected (R_H–Cl)³vs.θ_norm plots are justified when θ is close to 180°. Since many C–H⋯Cl contacts deviate from linearity and the conventional d–θ plots are a more familiar representation to chemists, they are used in this paper.

Fig. 1 shows the d–θ scatter plot for C–H⋯Cl interactions from any C-atom (sp³, sp², sp) to Cl–M, Cl⁻ and Cl–C acceptors. The inverse length–angle correlation characteristic of a hydrogen bond with significant electrostatic contribution⁸ that is short-d–linear-θ and long-d–bent-θ is clear in Fig. 1(a) and 1(b). There are a few contacts in the off-diagonal region (long-d, linear-θ), but this is not surprising because soft, weak interactions have a variable geometry in crystals. In Fig. 1(c), however, the van der Waals region (upper right) is heavily populated suggesting that in the C–H⋯Cl–C interaction there is very little electrostatic component. A comparison of histograms in Fig. 2 is instructive. We define a C–H⋯Cl contact as either short, medium or long using the criteria <2.6 Å (d⊕≪⊕Σ_vdW), 2.6–3.0 Å (d⊕≤⊕Σ_vdW), and >3.0 Å (d⊕>⊕Σ_vdW), respectively. The proportion of short and medium contacts – that is, those below the van der Waals radius sum – decreases as the acceptor changes from Cl⁻ (56/1059 and 574/1059; 5.3% and 54.2%) to Cl–M (35/1424 and 745/1424; 2.5% and 52.3%) to Cl–C (1/1395 and 495/1395; <0.1% and 35.5%). This is not surprising because the strength of a hydrogen bond increases not only with donor acidity but also with acceptor basicity.¹³ For the C–H⋯Cl–C contact [Fig. 3(c)] there is only one interaction with a short geometry (refcode BOJJOZ, 2.54 Å, 160.5°).

Fig. 1 Distance–angle (d–θ) scatter plot: (a) C–H⋯Cl–M, R-factor⊕≤⊕0.02; (b) C–H⋯Cl⁻, R-factor⊕≤⊕0.03; (c) C–H⋯Cl–C, R-factor⊕≤⊕0.03. Notice that the upper-right van der Waals region is more populated in scatter plot (c) compared with (a) and (b).

Fig. 2 Distance histogram of Fig. 1: (a) C–H⋯Cl–M; (b) C–H⋯Cl⁻; (c) C–H⋯Cl–C. Contacts⊕<⊕2.6 Å are shaded black (≪Σ_vdW), 2.6–3.0 Å grey (≤Σ_vdW) and >3.0 Å white (>Σ_vdW). Notice that there are a few to more short contacts in (a) and (b) but only one in (c).

Fig. 3 d–θ Scatter plot: (a) (sp²)C–H⋯Cl–M, R-factor⊕≤⊕0.02; (b) (sp²)C–H⋯Cl⁻, R-factor⊕≤⊕0.035; (c) (sp²)C–H⋯Cl–C, R-factor⊕≤⊕0.035. Compare with Fig. 1.

Sub-sets of data with activated acidic C–H donors were considered next. Table 1 shows H⋯Cl distances with different categories of donors, namely CHCl₃, (sp)C–H, CH₂Cl₂, (CH₃)₂S[double bond, length half m-dash]O, etc. The shortness of d for more acidic donors is apparent with Cl–M and Cl⁻ acceptors (entries 1 and 2 vs. 5 and 6) compared with Cl–C where the difference is negligible (within esd). The correlation of hydrogen bond distance with C–H pK_a shows that C–H⋯Cl–M and C–H⋯Cl⁻ interactions have a significant electrostatic component whereas C–H⋯Cl–C is an isotropic interaction that is insensitive to donor acidity. The d–θ scatter plots of H⋯Cl contacts with (sp²)C–H donors are displayed in Fig. 3.

Table 1 Mean H⋯Cl distance, d (Å), with activated C–H donors to Cl⁻, Cl–M and Cl–C acceptor moieties. The number of observations is given in square brackets

Entry	Donor	Cl^−	Cl–M	Cl–C
1	CHCl3	2.38(3) [16]	2.66(3) [170]	2.98(5) [16]
2	(sp)C–H	2.56(3) [16]	2.82(13) [6]	3.07(6) [7]
3	CH2Cl2	2.64(4) [25]	2.86(1) [683]	3.06(2) [51]
4	CH3CN	2.89(8) [10]	2.95(1) [654]	3.03(4) [17]
5	(CH3)2S[double bond, length half m-dash]O	2.81(3) [15]	2.98(1) [559]	3.05(5) [8]
6	(CH3)2C[double bond, length half m-dash]O	3.04(4) [3]	3.03(2) [94]	2.87 [1]

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Lastly, the C–H⋯Cl–C interaction was analysed in the absence of interfering and competing effects – strong OH and NH groups were excluded, electronegative atoms in the vicinity of Cl were removed, and only single interactions were considered – so that even a very weak hydrogen bond type character will be manifested. These results are displayed in Fig. 4. There is no significant improvement in the d–θ distribution when interference from OH and NH groups is removed [Fig. 4(a)] or when competing electronegative O, N, Cl atoms in the vicinity of the Cl acceptor are excluded up to a radius of 4.0 Å [Fig. 4(b)]. Refcodes with a bifurcated motif were removed from the sub-database of 2854 (sp²)C–H⋯Cl–C contacts with the R-factor⊕≤⊕0.10 to provide the scatter plot of Fig. 4(c) with 299 contacts. Notwithstanding that the donor is moderately activated and that these are single interactions, there is little improvement in the quality of the d–θ plot suggesting that C–H⋯Cl–C is a van der Waals interaction. In a study of the weak C–H⋯F–C interactions, similar CSD distributions were observed and the inverse d–θ correlation without the off-diagonal ‘noise’ could be obtained only with a small sub-set of carefully selected fluorobenzene crystal structures.¹⁴

Fig. 4 d–θ Scatter plot of C–H⋯Cl–C interaction: (a) all C–H donors, no OH and NH groups present, R-factor⊕≤⊕0.03; (b) all C–H donors, N, O and Cl atoms excluded up to 4 Å distance from acceptor Cl atom, R-factor⊕≤⊕0.05; (c) (sp²)C–H donors, single contacts (hits with bifurcation removed), R-factor⊕≤⊕0.10. Notice that these distributions are qualitatively not very different from Fig. 1(c) and 3(c), although the number of points is different in each plot.

It is difficult to establish conclusively the nature of halogen⋯halogen and X–H⋯halogen interactions from this database study – are they hydrogen bonds with electrostatic and polarisation contributions or are they mere space-filling van der Waals interactions? These issues have been the subject of intense debate for about two decades now.¹⁵ Our analysis of C–H⋯Cl interactions parallels the observations with stronger OH and NH donors,¹ keeping in mind that as the interaction becomes weaker the distribution is more diffuse.¹⁰ We note that acidic C–H donors form shorter contacts with electronegative Cl–M and Cl⁻ acceptors. Thus, the structural significance ascribed to C–H⋯Cl–M hydrogen bonds in recent crystallographic studies (M⊕=⊕Au, Ti, Sb)^3,9 is confirmed by this database analysis. A statistical validation for weak hydrogen bonds is necessary because they are subject to crystal forces and exhibit a smear of distance–angle features. On the other hand, C–H⋯Cl–C interactions with organic chlorine are more a result of van der Waals close packing. There is little improvement in the scatter plot correlation coefficient in sub-sets of selected crystal structures. To summarise, the electrostatic nature of C–H⋯Cl–M and C–H⋯Cl⁻ hydrogen bonds is revealed through chemical probes whereas C–H⋯Cl–C interactions continue to exhibit isotropic behaviour even after competing and interfering effects are removed. Even so, the contribution of C–H⋯Cl interactions towards self-assembly in a crystal structure must be assessed by a combination of the following parameters: (1) the distance–angle characteristics; (2) the nature of the Cl acceptor; and (3) the presence of other donors and acceptors.

Acknowledgements

We thank the Department of Science and Technology for research funding (SP/S1/G29/98). P. K. T. thanks the CSIR for a research fellowship.

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