A Systematic Experimental and Theoretical Study of the Crystalline

Part of the Special Issue: Facets of Polymorphism in Crystals

A Systematic Experimental and Theoretical Study of the Crystalline State of Six Chloronitrobenzenes

CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 1 24–36

Sarah A. Barnett,† Andrea Johnston,‡ Alastair J. Florence,‡ Sarah L. Price,† and Derek A. Tocher*,† Department of Chemistry, UniVersity College London, 20 Gordon Street, London WC1H 0AJ U.K., and Solid State Research Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, The John Arbuthnott Building, UniVersity of Strathclyde, 27 Taylor Street, Glasgow, G4 0NR, U.K. ReceiVed February 5, 2007; ReVised Manuscript ReceiVed September 17, 2007

ABSTRACT: Experimental and computational searches for the crystal structures of the five commercially available isomers of dichloronitrobenzene and 3,4-dinitrochlorobenzene were performed to assess the relationship between functional group interactions and steric requirements in determining the solid forms. Experimentally, this resulted in the first crystal structure determination of 2,4-dichloronitrobenzene, two solvates of 3,4-dichloronitrobenzene and one of 3,4-dinitrochlorobenzene. Additionally, low temperature redeterminations of the crystal structures were obtained for 2,5-dichloronitrobenzene, 3,4-dichloronitrobenzene, and both the β- and γ-forms of 3,4-dinitrochlorobenzene. The searches for energetically feasible structures of each of these compounds showed a wide variety of distributions leading to varying degrees of clarity of prediction of the solid state behavior. These range from 2,3-dichloronitrobenzene, which only adopts the crystal structure that was clearly the most thermodynamically stable of all five isomers, through complex systems, which show a range of low energy minima indicating possible polymorphism and solvate formation, to 2,4-dichloronitrobenzene, which can conformationally distort and adopts a complicated Z′ ) 2 crystal structure.

1. Introduction Contrasting the thermodynamically feasible with the experimentally observed crystal structures is the first step toward understanding the factors that control crystallization1 and can result in polymorphism.2 Computational methods of searching for minima in the lattice energy can generate a set of crystal structures that lie within a plausible energy range for polymorphism (allowing for approximations within the computational model) of the global minimum. This range of possible crystal structures is often far greater than the actual number of known, or likely, polymorphs.3 There are cases in which the computed structures have later been found as new experimental polymorphs, even for widely studied molecules such as aspirin4 and piracetam.5 For other systems, the known crystal structure [as reported in the Cambridge Structural Database (CSD)6] is that of the first crystal examined, and so could be a kinetically favored metastable polymorph. Therefore, polymorph screening is required to enable the comparison of experimentally observed structures with those produced by the computational search and develop an understanding of why a compound either adopts a single structure or would be expected to be polymorphic. This paper focuses on an isomeric set of compounds to contrast the first searches for hypothetical crystal structures with the first systematic investigation of their polymorphism since Groth reported crystal morphologies for three of them in 1917.7 The system chosen was a series of five of the dichloronitrobenzenes (DCNB) which are important compounds used as synthetic intermediates in the production of pigments, pesticides, and * Author to whom correspondence should be addressed. Tel: +44 (0)20 7679 4709. Fax: +44 (0)20 7679 7463. E-mail: [email protected]. † University College London. ‡ University of Strathclyde.

pharmaceuticals. Since 2,6-DCNB is not available commercially, but was the only DCNB noted by Groth to be polymorphic, the related polymorphic compound 3,4-dinitrochlorobenzene (DNCB) was also studied (Scheme 1). These six chloronitrobenzenes have the potential to show the competition between a variety of well-studied intermolecular interactions, that is, Cl · · · O(N), C-H · · · Cl, C-H · · · O, and Cl · · · Cl interactions.8–11 Also, since the rotation of the nitro group is the only potential form of molecular flexibility, the experimentally determined structures can be readily contrasted with those found in the computational search, which are calculated using a rigid, ab initio optimized molecular structure. This combined analysis of predicted and experimental structures should yield insights into how to develop crystal structure prediction for these systems. Crystal structures for 2,3-DCNB12 and 3,5-DCNB13 suitable for use in the computational studies were available from the CSD (refcodes DOXWIW and HIBWEU, respectively). The crystal structures of 2,5-DCNB (ZZZEKW0114) and 3,4-DCNB (CAGPUV15) were redetermined to obtain low temperature versions of these structures. Since the crystal structure of 2,4DCNB had not been previously deposited with the CSD, crystals suitable for single crystal X-ray diffraction were grown for comparison with the computational search results as an internal blind test. Although crystal structures for two of the three previously reported polymorphs of 3,4-DNCB7,16 were available from the CSD, β-3,4-DNCB (DEFDUN) and γ-3,4-DNCB (DEFDUN01), low temperature redeterminations were also obtained for both forms. All of these compounds were subjected to manual experimental crystallization screens to try and find new polymorphs. A combination of the manual screening and the computational results led to 3,4-DCNB being selected for an extensive semiautomated crystallization screen. The resulting crystal forms

10.1021/cg070131c CCC: $40.75  2008 American Chemical Society Published on Web 01/02/2008

Crystalline State of Six Chloronitrobenzenes

Crystal Growth & Design, Vol. 8, No. 1, 2008 25

Table 1. Outline of Conditions Included in the Automated Parallel Crystallization Search on 3,4-Dichloronitrobenzenea crystallization conditionb

crystallization method

agitation (rpm)

number

1. Tsat (max) 2. Tsat (min) 3. Tsat (min)

coolingc to 5 °C coolingc to 20 °C coolingc to 5 °C

900 900 850

64 128 32

a Condition 2 used the complete library of 64 solvents in replicate. Conditions 1 and 3 used a subset of the solvent library. Full details of each crystallization carried out are provided in the Supporting Information. b Solutions were prepared by adding excess solid to between 2 and 4 mL of solvent (see Supporting Information) to ensure that solutions were saturated at the appropriate temperature, prior to being filtered automatically into a clean crystallization vessel. The solvent library was ranked according to solvent boiling point and divided into four groups of ca. 16 solvents each. Within each group, the temperature at which solutions were prepared (Tsat) is equivalent to Tsat(max) ) minimum boiling point within group - 10 °C; Tsat(min) ) 35 °C. c The cooling rate used in each experiment was approximately 3.5 °C min-1.

were compared with the low energy hypothetical structures obtained using the ab initio optimized (gas phase) molecular structure.

2. Experimental Procedures 2,4-DCNB, 2,5-DCNB, 3,4-DCNB, 3,5-DCNB, and 3,4-DNCB were purchased from Aldrich Chemicals, while 2,3-DCNB was purchased from Lancaster Chemicals; all were used without further purification. The six compounds were recrystallized from a range of 30–40 solvents as part of a manual experimental polymorph screen, and it was found that all of the compounds were highly soluble in all of the solvents used except water. The majority of the crystallizations were performed by slow evaporation at either room temperature or at ∼5 °C, although some supplementary techniques were also used including sublimation and cooling of the melts. (Further details and results can be found in the Supporting Information.) 2.1. Automated Parallel Crystallization. Following the computational predictions and the manual screen, 3,4-DCNB was also recrystallized from solution under a range of conditions using an automated parallel crystallization approach.17 The search for physical forms utilized an initial library of 64 solvents covering a wide range of physicochemical properties.18 A total of 224 individual crystallizations were implemented using the range of conditions outlined in Table 1 and described in detail in the Supporting Information. Crystallization was induced in the filtered solutions by controlled cooling (Table 1). Upon recrystallization, suspended samples were reclaimed by filtration and transferred to a multiposition sample holder for identification using multisample foil transmission XRPD.19 Samples of 3,4-DCNB were identified by a combination of standard procedures, including pattern matching (in the program Eva;20) unit

cell indexing (DICVOL-91;21 Topas v3.122) and Pawley refinement (DASH v3;23 reference patterns for all forms are provided in the Supporting Information). 2.2. Single Crystal X-Ray Diffraction. Single crystal X-ray experiments were performed on a Bruker AXS SMART APEX CCD detector diffractometer equipped with a Bruker AXS Kryoflex open flow cryostat (graphite monochromated Mo KR radiation (λ ) 0.71073 Å); ω scans). For the β-form of 3,4-DNCB, all crystals within the sample appeared to be twinned. However, data were collected for the best crystal examined of this more difficult to obtain polymorph. GEMINI24 was used to index the data and gave two components (approx 2:1), which were integrated simultaneously using SAINT+.25 The data set had 941 data from component 1 only, 868 data from component 2 only, and 4261 data belonging to both, while I/σ for overlapping reflections was 17.0. The data set was corrected for absorption using TWINABS,26 which was also used to produce two files, one with nonoverlapping reflections for component 1 only, used for structure solution and initial refinement, and a second file containing all data derived from one domain for final refinement of the structure. The twin components were found to be related by the twin law (1 0 0, 0 1j 0, 0.34 0 1) and with the ratio 88:22. For all other structures, absorption corrections were applied by a semiempirical approach using SADABS.27 Other details of crystal data, data collection, and processing are given in Table 2. In all cases, the single crystal structures were solved by direct methods using SHELXS97,28 and all nonhydrogen atoms were located using subsequent difference-Fourier methods in SHELXL-97.29 Hydrogen atoms were placed in calculated positions and treated as riding. Crystal structure diagrams were produced using SHELXTL30 and Mercury,31 and interactions were defined as being contacts shorter than the sum of the van der Waals radii (except 3,5-DCNB and 2,4-DCNB where contacts shorter than the sum of the van der Waals radii + 0.1 Å were identified). 2.3. Crystal Structure Prediction. A gas phase ab initio model for each molecule was obtained by optimization of the MP2/6-31G** energy using the program GAUSSIAN98.32 The corresponding wave function was also calculated for the X-ray determined molecular structures, with the C-H bond length elongated to the standard neutron value of 1.081 Å.33 A distributed multipole analysis (DMA)34 of the ab initio charge density of the molecule was performed to provide an accurate description of the electrostatic contribution to the lattice energy in the rigid molecule crystal structure modeling. This atomic multipole electrostatic model automatically represents the electrostatic effects of lone pair and π-electron density.35 All other intermolecular contributions to the lattice energy were represented by an empirical repulsiondispersion model of the form: U)

∑

(AιιAκκ)1⁄2exp(-(Bιι + Bκκ)Rik/2) -

i∈1,k∈2

(CιιCκκ)1⁄2 Rik6

where atom i in molecule 1 is of type ι and atom k in molecule 2 of type κ. The parameters used were a combination of those derived by Rice and Sorescu36 and Price and Day37 following extensive testing

Table 2. Crystallographic Data Summary for Compounds 2,5-DCNB, 2,4-DCNB, 3,4-DCNB, β-3,4-DNCB, and γ-3,4-DNCB

empirical formula M crystal system space group a/Å b/Å c/Å R/° β/° γ/° U/Å3 Z T/K µ/mm-1 reflections collected unique reflections (Rint) final R1 [F > 4σ(F)] wR2 (all data)

2,5-DCNB

2,4-DCNB

3,4-DCNB

3,4-DNCB (β-form)

3,4-DNCB (γ-form)

C6H3Cl2NO2 191.99 triclinic P1j 7.1403(8) 7.2638(8) 8.2418(9) 72.781(2) 70.300(2) 66.349(2) 362.18(7) 2 150(2) 0.835 3169 1654 (0.0136) 0.0240 0.0700

C6H3Cl2NO2 191.99 monoclinic P21/n 20.682(3) 3.7484(5) 20.961(3) 90 118.235(2) 90 1431.6(3) 8 150(2) 0.845 12576 3870 (0.0392) 0.0317 0.0836

C6H3Cl2NO2 191.99 tetragonal I41/a 27.9342(19) 27.9342(19) 3.7655(5) 90 90 90 2938.3(5) 16 150(2) 0.823 12690 1999 (0.0385) 0.0428 0.0892

C6H3ClN2O4 202.55 monoclinic P21/n 7.554(3) 7.821(3) 13.453(5) 90 96.307(7) 90 790.0(5) 4 150(2) 0.465 6070 2730 (0.0526) 0.0606 0.1473

C6H3ClN2O4 202.55 orthorhombic P212121 5.5245(11) 11.778(2) 11.939(2) 90 90 90 776.8(3) 4 150(2) 0.473 6680 1122 (0.0241) 0.0236 0.0625

26

Crystal Growth & Design, Vol. 8, No. 1, 2008

Barnett et al.

Figure 1. Plots of lattice energy against cell volume per molecule for the unique structures within 5 kJ mol-1 of the global minimum denoted by the space group for (a) 2,3-DCNB, (b) 3,5-DCNB, (c) 2,5-DCNB, (d) 2,4-DCNB, (e) 3,4-DCNB, and (f) 3,4-DNCB. The structures corresponding to the known forms using the optimized molecular model are represented by an open square, or with an open circle or diamond for the polymorphs of 3,4-DNCB. The lattice energy minima corresponding to the optimized molecular models with the same torsion angles as found in the experimental structure are shown by an open triangle when this energy is significantly different to the fully optimized model. of alternative combinations of parameters for the different functional groups (see Supporting Information).

3. Results

The hypothetical crystal structures for all chloronitrobenzenes were generated by MOLPAK,38 which performs a systematic grid search on orientations of the rigid central molecule in 39 common co-ordination geometries of organic molecules, belonging to the space groups Cc, j P2/c, P21, P21/c, P21212, P212121, Pba2, Pc, Pca21, C2, C2/c, P1, P1, Pna21, Pbcn, Pbca, Pma2, Pmn21, and Pnn2 with one molecule in the asymmetric unit. Approximately 50 of the densest packings in each coordination type were then used as starting points for lattice energy minimization by DMAREL39 using the atom-atom based model potential described above. Thus, the search only produces structures with one entire molecule in the asymmetric unit of the space groups considered. The distinct low energy minima within 20 kJ mol-1 of the global minimum were established by considering the reduced cell parameters40 using PLATON.41 The second derivative properties of each unique lattice energy minimum were examined,42 and those that were mechanically unstable were eliminated.

The computational search for crystal structures of 2,3-DCNB, 3,5-DCNB, 2,5-DCNB, 2,4-DCNB, 3,4-DCNB, and 3,4-DNCB all produced more than 150 distinct, mechanically stable structures within 10 kJ mol-1 of the global minimum. The unique structures within 5 kJ mol-1 of the global minimum are plotted for each molecule in Figure 1 and tabulated in the Supporting Information. The six plots in Figure 1 show very different distributions of the hypothetical crystal structure minima and also reveal that the lattice energies of the global minima for the five isomers of DCNB vary by over 6 kJ mol-1 (between -97.3 and -91.0 kJ mol-1). Visualization of the low energy structures shows them to be dominated by Cl · · · O interactions and C-H · · · O and C-H · · · Cl hydrogen bonds with combinations of these interactions giving rise to very different extended motifs, ranging from


Figure 2. (a) The sheet structure of 2,3-DCNB and (b) overlay of part of the structure comparing the single crystal X-ray structure (red) with the structure found in the computational search (blue) for 2,3-DCNB.

one-dimensional (1-D) ribbons, through two-dimensional (2D) sheets, to others with extended three-dimensional (3-D) networks. 3.1. 2,3-Dichloronitrobenzene. The search for low energy crystal structures of 2,3-DCNB produced one structure that was significantly (1.75 kJ mol-1) more stable than any of the other structures for either this, or the other, isomers (Figure 1a). This structure was virtually superimposable with the experimentally known form of 2,3-DCNB, DOXWIW12 (Figure 2). The qualitative agreement for the unit cell and close contacts between the two structures is given in Table 3. The structure of 2,3-DCNB comprises a sheet formed by a pair of short Cl · · · O contacts and another, further, Cl · · · O contact utilizing the second oxygen of the nitro group. The rotation of the nitro group out of the plane contributes to the undulating nature of the sheet, which is well reproduced by the computational prediction, as the nitro group torsion angle is virtually the same in the crystal structure (54.09°) as in the ab initio optimized structure (50.44°). There is a 1.75 kJ mol-1 energy gap between the global minimum and the band of next lowest energy structures, which includes one that is much less densely packed than the global minimum and is based on a ribbon motif. The other three are based on a similar sheet pattern to the global minimum, but with less favorable intrasheet interactions. Given this similarity, a significant energy barrier for the transformation of these structures to the global minimum structure is unlikely and, although these alternative structures are well within the energy limits of polymorphism, it is doubtful that they correspond to long-lived, metastable polymorphs. Thus, since the known form



is found as a distinct global minimum and as the densest structure, in conjunction with the manual crystallization screen failing to produce any new forms, it follows that other polymorphs of this compound are improbable. 3.2. 3,5-Dichloronitrobenzene. The search for possible crystal structures of 3,5-DCNB (HIBWEU)13 using the ab initio optimized structure revealed that the global minimum corresponded to the known form (Figure 1b, Table 3) and that the nitro group torsion angles are essentially identical (1.09° in the crystal structure and 0.05° for the ab initio optimized structure). The structure comprises undulating sheets of planar molecules linked by Cl · · · O interactions and C-H · · · Cl and C-H · · · O hydrogen bonds (Figure 3). In this case, the energy gap between the global minimum and the next lowest energy structure is only 0.30 kJ mol-1. There are three hypothetical low energy structures worth considering as they are within 0.41 kJ mol-1 of the experimental structure and well separated from the other theoretical structures (Figure 1b). The less dense structure is a variation on the packing of the known form with flat, rather than undulating, sheets. The two denser structures, however, are essentially identical to each other and based on an alternative 2-D sheet arrangement. These sheets are composed of rows built up by C-H · · · Cl and Cl · · · O contacts similar to those found in the known form, but, instead of these being linked by bifurcated C-H · · · O hydrogen bonds, the second row is shifted parallel to the first such that only one C-H · · · O hydrogen bond can be formed and an additional Cl · · · O interaction is invoked. The small energy gap, the greater density, and the similarity in structure to the known form mean that these could be possible candidates for polymorphism. However, the manual crystallization screen on 3,5-DCNB failed to yield any new forms. This could be because the structures

3.94 156.8

152.1

3.58

149.6

3.25

P21/ m 3.943 13.749 6.762 90 96.19 90 364.42

comp.

170.6

3.47

176.9

3.00

expt. j P1 7.1403(8) 7.2638(8) 8.2418(9) 72.781(2) 70.300(2) 66.349(2) 362.18(7)

165.5

3.55

175.4

3.12

comp. P1j 7.186 7.314 8.317 72.19 70.67 66.94 371.64

2,5-DCNB

3.13 3.3 3.32 156.5 161.3 145.1 3.22 3.26 121.2 116.6

P21/ n 20.682(3) 3.7484(5) 20.961(3) 90 118.235(2) 90 1431.6(3)

expt.

3.17 3.33 3.38 155.6 160.4 139.2 3.28 3.31 115.6 113.1

P21/ n 20.768 3.717 20.962 90 117.47 90 1435.77

comp.b

2,4-DCNB

3.22 3.39 129.6 128.2

164.3

3.06

I41/ a 27.9342(19) 27.9342(19) 3.7655(5) 90 90 90 2938.3(5)

expt.

3.27 3.71 132.5 132.4

164.5

3.13

I41/ a 28.194 28.194 3.793 90 90 90 3015.43

comp.

3,4-DCNB

3.28 3.49 129.1 130.6

162.8

3.16

I41/ a 28.097 28.097 3.8 90 90 90 2999.9

comp.b

3.52 3.24 159.7 133.9

165.7

3.00

P21/ c 7.554(3) 7.821(3) 14.687(5) 90 114.437(7) 90 790.0(5)

expt.

beta

3.57 3.5 161.6 140.4

167.9

3.64

P21/ c 7.748 8.145 14.578 90 121.83 90 781.65

comp.

gamma

161.4

3.44

163.9

3.03

P212121 5.5245(11) 11.778(2) 11.939(2) 90 90 90 776.8(3)

expt.

3,4-DNCB

162.4

3.54

168.2

3.1

P212121 5.683 11.663 11.806 90 90 90 782.46

comp.

a This is the closest to the experimental crystal structure that could be found in the search. b Values corresponding to the ab initio optimized molecule with the nitro group torsion angle constrained to be the same as the experimental value. S.G. ) space group.

4 156.2

C-H · · · Cl/Å C-H · · · Cl/°

148.7

152.4

144.8 171.3

3.28

C-H · · · O/°

158.8 172.2

C-Cl · · · O/°

3.1 3.24

P21/ m 3.873(2) 13.687(2) 7.013(3) 90 92.94(6) 90 371.27

P21/ c 3.664 13.779 14.152 90 95.98 90 710.72

3.6

3.15 3.11

Cl · · · O/Å

expt.

comp.

3,5-DCNB HIBWEU

C-H · · · O/Å

P21/ c 3.810(1) 13.765(3) 14.302(3) 90 97.764(5) 90 743.19

S.G. a/Å b/Å c/Å R/° β/° γ/° V/Å3

expt.

2,3-DCNB DOXWIW

Table 3. Comparison of the Unit Cell Dimensions and Pertinent Interactions Found for the Experimental Crystal Structures (expt.) of the Five Isomers of DCNB and the Two Polymorphs of 3,4-DCNB with Those Corresponding To the Structure Calculated Using the Ab Initio Optimized Molecule (comp.)a

28 Crystal Growth & Design, Vol. 8, No. 1, 2008 Barnett et al.



Figure 5. The asymmetric unit of 2,4-DCNB showing the labelling scheme used. Displacement ellipsoids are drawn at the 50% probability level.


are sufficiently similar that even if alternative packing arrangements were adopted, they would readily transform to the most stable known form. 3.3. 2,5-Dichloronitrobenzene. The computational search on 2,5-DCNB successfully found a structure with unit cell dimensions that corresponded to the known form (Figure 1c, Table 3) as shown by the overlay of the crystal structures (Figure 4) and the comparison of close contact information (Table 3). The ab initio gas phase optimization gave a good approximation of the molecular conformation in the crystal structure with nitro group torsion angles of 45.32° and 43.41(15)°. It is, perhaps, notable that the ortho chlorine does not form a short contact, although this is also true for the meta chlorine in 3,4-DCNB. Although the known structure was found in the search, it was 2.32 kJ mol-1 above the global minimum and only the 12th most stable. The global minimum was found to have a very different structure to that of the known form with a complicated 3-D packing arrangement. This energy gap indicates that there is a strong possibility of alternative structures and that 2,5DCNB should be a good candidate for an experimental polymorph screen. Unfortunately, the manual experimental crystallization screen failed to yield any new forms, although crystals suitable for single crystal X-ray diffraction were grown for a redetermination of the structure (see Table 2 for the crystallographic data summary, Table 3 for close contact information and Supporting Information for other crystallographic information). Since the experimental structure appears more crystallographically reasonable than the lower energy structures, and the crystal grew particularly well, it could be that this structure is kinetically favored. However, crystallographic insight is fallible,43 and the thermodynamic modeling is limited so this study certainly does not eliminate the possibility of further polymorphs being found. 3.4. 2,4-Dichloronitrobenzene. Although no previous structures for 2,4-DCNB had been deposited with the CSD, the computational search (Figure 1d) performed using the ab initio

Figure 6. (a) Packing diagram showing the chains of 2,4-DCNB molecules built up by C-H · · · O and C-Cl · · · O interactions and the extended network formed by further, longer C-Cl · · · O interactions and (b) schematic of a 4 · 82 network.

optimized molecular structure (with a nitro group torsion angle of 43.80°) gave three, dense, low energy structures (see Supporting Information) that seemed good candidates for the crystal structure. Indeed, had 2,4-DCNB been one of the blind tests of crystal structure prediction set by the CCDC,44–46 the permitted three guesses would have been made with some confidence. All three structures produce sheets with similar molecular arrangements, but slight changes in the molecule orientation give rise to different degrees of sheet undulation and variations in the short contacts (see Supporting Information). The manual polymorph screen on 2,4-DCNB from various solutions mainly produced supersaturated oils which would only form a solid once triturated. However, the slow evaporation (2 weeks) of a concentrated hexane solution gave crystals suitable for the first single crystal X-ray determination. 2,4-DCNB

30


Barnett et al.

Figure 8. (a) overlay figure comparing the torsion angles exhibited by molecule 1 (red) and molecule 2 (blue) in the single crystal X-ray structure with the gas phase ab initio optimized structure (green) and (b) schematic showing the molecular orientation of the overlay.

Figure 7. Packing diagram showing three interpenetrating 4 · 82 nets of 2,4-DCNB molecules illustrating an eight-membered ring of the blue net being interpenetrated by two rings each of the red and green nets in (a) the actual structure and (b) in schematic form; (c) illustrates the undulating nature of the three interpenetrating nets.

crystallizes in the space group P21/n with two independent molecules in the asymmetric unit (Figure 5). These two molecules exhibit very different conformations with molecule 1 having a nitro group torsion angle (O1-N1-C1-C2) of 23.3(2)°, while in molecule 2 the corresponding angle (O11N11-C11-C12) is 50.3(2)°. The crystal structure of 2,4-DCNB consists of 1-D chains formed by C-H · · · O hydrogen bonds and Cl · · · O interactions

that are then linked by further Cl · · · O interactions into an undulating 2-D sheet with a 4 · 82 topology (Table 3, Figure 6). Since the sheets are corrugated, three of these 4 · 82 nets are able to interpenetrate in a parallel fashion through the large eight-membered rings with each ring catenated by two other rings from each of the other nets (Figure 7). This type of network has been observed previously for co-ordination networks, although the exact modes of interpenetration differ.47,48 The complexity of this structure means that it is outside the scope of the computational predictions. This is due to having two crystallographically independent molecules with different torsion angles between the aryl ring and the nitro group, neither of which correspond to the gas phase ab initio optimized structure (Figure 8). The lattice energy is calculated to be -98.16 kJ mol-1 using the experimental molecular structure but is -94.37 kJ mol-1 using the ab initio optimized molecular structure. If the nitro groups are constrained to have the experimentally observed torsion angles, but are otherwise optimized, the calculated lattice energy is -96.42 kJ mol-1. Since the global minimum found in the search is -94.94 kJ mol-1, it is clear that the independent variation of the torsion angles for the two molecules in the asymmetric unit produces a significantly better intermolecular lattice energy. The intramolecular energy penalty for the conformational change is estimated as 2.67 kJ mol-1 for MP2 6-31G** wave functions or 3.20 kJ mol-1 if the larger double-ζ (aug-cc-pVDZ) basis set is used, thus illustrating the uncertainty in the intramolecular energy penalty paid for this molecular distortion even with computationally expensive ab initio methods.49 Hence, it seems probable that the large variation of the nitro group torsion angles is primarily responsible for the formation of a more stable crystal structure. 3.5. 3,4-Dichloronitrobenzene. The computational search for possible crystal structures of 3,4-DCNB showed that there are many more stable and dense structures than the known form which crystallizes in the high symmetry space group I41/a. As a consequence, an alternative search method50 was used for this space group. The most stable I41/a structure, corresponding to the experimentally known form, was the only one within 5 kJ mol-1 of the global minimum (Figure 1e, Figure 9b). Since the experimental structure was found to be 3.77 kJ mol-1 above the global minimum and considerably less dense, the effect of the nitro group torsion angle on the lattice energy was investigated. By using the experimental nitro torsion angle of 10.8(3)° (cf. 0.02° for the full ab initio optimization), but otherwise optimizing the molecular structure, the lattice energy was lowered by 2.24 kJ mol-1 even though the conformational energy penalty is 0.28 kJ mol-1. This confirmed that the tilted nitro group gives a denser, more favorable, packing arrangement. The known form of 3,4-DCNB comprises squares of molecules formed by Cl · · · O interactions. These squares are then linked by two C-H · · · O hydrogen bonds from each 3,4-DCNB into a complex 3-D network (Figure 9, Table 3). Channels



Figure 10. (a) The sheet structure of the β-form of 3,4-DNCB and (b) overlay of part of the structure comparing the single crystal X-ray structure (red) with the structure found in the search (blue) for the β-form of 3,4-DNCB.

Figure 9. Packing of 3,4-DCNB (a) viewed down the c-axis illustrating the Cl · · · O and C-H · · · O interactions, (b) overlay of part of the structure comparing the single crystal X-ray structure (red) with the structure found in the search (blue), (c) view down the b-axis showing the 3-D network and channels, and (d) the two interpenetrating networks.

running parallel to the a- and b-axes (Figure 9c) are large enough to allow interpenetration of a second, identical network (Figure 9d). Given that the computational search suggested that polymorphism was likely, an automated parallel crystallization screen was carried out in addition to the manual screen. Of the 224 recrystallizations carried out, all but two yielded sufficient sample for XRPD analysis. Of these, 220 were identified as the known form and two were identified as novel crystalline solvates: 3,4-DCNB · 1,4-dioxane (4/1)51 and 3,4-DCNB · aniline (2/1).52 Both solvates are based on sheets in which the solvent molecules play a major role forming obvious, stabilizing, interactions. Consequently, there is no similarity in motif to either the known structure (i.e., a solvate has not been found with the solvent molecules occupying the channels shown in Figure 9), or to the low energy hypothetical structures, many of which were based on a sheet structure that could, conceivably, have formed a layer solvate. This is in marked contrast to 5-fluorocytosine53 and hydrochlorothiazide54 where multiple solvates were discovered to have structural motifs in common with those found in the corresponding computational searches. Thus, 3,4-DCNB molecules do not have a clear preference for a particular packing motif, and there is a range of plausible structures that have somewhat lower static lattice energies. The high symmetry of the observed structure suggests that it may be stabilized by thermal motion, with there being the possibility of a low temperature transition to a lower symmetry structure, although no experimental evidence for this has been observed.

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Barnett et al.

redetermination of this structure (see Table 3 for close contact information and Supporting Information for other crystallographic information). Although crystals of the β-form were also successfully prepared, there was no indication of the previously reported7 R-form during the screen. This is in accord with the previous study in 198516 that had determined both the γ- and β-structures, but had also been unable to obtain the R-form. However, during the course of the investigation, crystals of a novel 1:1 solvate structure were produced by evaporation at room temperature from 1,4-dioxane.55 Although several of the low energy structures have a similar sheet motif to that of the β-form, only one other structure has an identical sheet motif, but it has an alternative stacking arrangement and is 1.95 kJ mol-1 lower in energy. The dense, second lowest energy structure is also related to the β-form, but with undulating, as opposed to flat, sheets. The motifs of the γ-form do not occur in any of the other low energy structures. The variety of low energy structures observed is consistent with this compound being polymorphic, and this study cannot rule out short-lived metastable polymorphism being generated by alternative crystallization methods.

4. Discussion

Figure 11. (a) Part of a sheet of the γ-form of 3,4-DNCB and (b) overlay of part of the 3-D structure comparing the single crystal X-ray structure (red) with the structure found in the search (blue) for the γ-form of 3,4-DNCB.

3.6. 3,4-Dinitrochlorobenzene. The search for possible crystal structures of 3,4-DNCB using the ab initio optimized conformer gave the γ polymorph as the global minimum structure, although there was one structure that was considerably more dense (0.05 g cm-3) and at a very slightly higher energy (0.2 kJ mol-1). The β-form is also found in the search, but it is only the 22nd lowest energy structure and 5.05 kJ mol-1 above the global minimum. The computational model rather poorly reproduces the β-form (Figure 10, Table 3) but models the γ-form well (Figure 11, Table 3). The torsion angles experimentally observed for the nitro groups are different for the two polymorphs: 41.4(5)° and 45.9(4)° for the β-form but 35.00(17)° and 46.91(16)° for the γ-form. The gas phase ab initio optimized structure reproduces the torsion angle for the meta nitro group well (43.51°), but the computed value for the para nitro group (37.72°) lies between those of the two forms. However, calculations with the nitro group torsions constrained to the experimental values suggest that the nitro group conformation is not the main factor behind the poor reproduction of the β-form. The manual crystallization polymorph screen on 3,4-DNCB predominantly gave samples of the γ-form, and crystals suitable for single crystal X-ray diffraction were grown to obtain a good

This extensive crystallization screen and theoretical study has revealed a considerable diversity in the range of solid forms found and the ease with which they can be computationally predicted, as summarized in Table 4. The only common feature observed for the crystal structures of these six chloronitrobenzenes is the presence of C-Cl · · · O(N) interactions. Additionally, all but 2,3-DCNB also show C-H · · · O hydrogen bonds. In contrast to iodonitrobenzenes which tend to form bifurcated C-I · · · O2(N) interactions,8,56 these chloronitrobenzenes only form monocoordinate C-Cl · · · O(N) interactions with the C-Cl · · · O angle approaching linearity (145–172°) in accordance with a general trend.8 Such C-Cl · · · O short contacts are clearly formed in preference to Cl · · · Cl interactions which have been widely observed and analyzed11 in the chlorobenzenes37,57 and coordination compounds.58 The experimental preference is reinforced by examination of the low energy calculated structures which also only give structures based on C-Cl · · · O interactions and C-H · · · O and C-H · · · Cl hydrogen bonds. The five DCNB isomers differ in their distribution of low energy structures as revealed by their superposition, shown in Figure 12. 2,3-DCNB is notable as it exhibits the lowest energy computed and experimental structures (DOXWIW) and is well below both its alternative and the real and hypothetical structures of the other isomers. The lowest energy structures for 3,4-DCNB and 3,5-DCNB (corresponding to HIBWEU) are approximately 6 kJmol-1 higher in energy than DOXWIW. The structure of 2,3-DCNB is readily predicted by the computational model as the one, uniquely stable, structure produced, possibly due to the greater opportunity to form strong intermolecular interactions than is possible for the other isomers. Searches for two of the other chloronitrobenzenes found the known structure as the global minimum in the lattice energy, but by much smaller margins. This is consistent with the alternative low energy structures for 3,5-DCNB being sufficiently closely related as to be unlikely to form isolable polymorphs and 3,4-DNCB having at least one metastable polymorph. The experimental study has clearly shown that improvements in the computational model are necessary to determine the most thermodynamically favorable structures even for this simple type of molecule. The implicit modeling of the nitro group flexibility is clearly necessary: the phenyl-nitro dihedral angle can be



Table 4. Summary of the Results of Both the Computational and Experimental Polymorph Screens for Each of the Chloronitrobenzenes Studied

† Molecular overlay is the RMS value as calculated by Mercury for all non-hydrogen atoms between the experimental and ab initio optimized molecules (or ab initio optimized with constrained nitro group torsion angles where appropriate, ConOpt). ‡ Packing overlay is the RMS value calculated for a 15 molecule co-ordination sphere using COMPACK64 between the experimental and computed crystal structure with the ab initio optimized molecular structure (or ab initio optimized with constrained nitro group torsion angles where appropriate, ConOpt). The tolerance level in the atom-atom distances for finding the overlay was the 20% default, unless a higher level was required, as shown: $ ) 50%. * ∆E negative values give the energy between the known form and the global minimum structure and positive values give the energy between the known form at the global minimum and the next lowest energy hypothetical structure.

34


Figure 12. Plot of lattice energy against cell volume per molecule for each of the dichloronitrobenzene isomers with the fully optimized known forms denoted by open symbols except for 2,4-DCNB where the optimized structure with constrained nitro torsion angle is shown.

Scheme 1. Five of the Isomers of Dichloronitrobenzene and 3,4-Dinitrochlorobenzene Showing the Numbering Scheme and Abbreviations Used for the Naming of the Compounds in This Paper

Barnett et al.

entropy, but this would probably require an advance in current methods to allow for the molecular flexibility as rigid-body entropies have been shown to give little variation for the crystal structures of six nitrotoluene derivatives.59 However, these improvements in modeling are unlikely to make the observed structure of 2,5-DCNB more stable than all the hypothetical structures, so this remains the compound for which it is most probable that new, long-lived polymorphs could be discovered. The model potential used is less well theoretically based than the nonempirical model used for the chlorobenzenes,37 particularly in the assumption of an isotropic empirical atom-atom potential for everything apart from the electrostatic interactions (see Supporting Information). Hence, all the relative energies of the crystal structures are likely to change with improvements in the model intermolecular potential and modeling of molecular structure and flexibility. Notwithstanding the need for more accurate modeling of the relative stabilities, this study clearly shows that there are many theoretical dichloronitrobenzene structures that could be thermodynamically feasible polymorphs. Solvates for 3,4-DCNB and 3,4-DNCB have been discovered whose range of low energy structures demonstrates that there are many, equally poor, compromise packings of the molecule and that interactions with solvent molecules are clearly competitive. However, only 3,4DNCB has been shown experimentally to be polymorphic. The manual crystallization screens covered a wide range of solvents, but since the compounds were highly soluble in most of them, any nuclei of metastable structures formed could readily redissolve. Most of the crystallizations were performed just below the melting points of the compounds implying there is considerable scope for the rearrangement of any metastable polymorphs. The weaker intermolecular interactions of the chloronitrobenzenes also suggests that the barriers to rearrangement may be lower than for compounds capable of conventional hydrogen-bonding. Hence, the failure to isolate any new polymorphs can be rationalized, despite there being energetically feasible alternative structures, while not ruling out the potential for further polymorphs to be discovered, for example, at high pressure.

5. Conclusions

readily deformed by packing forces, varying by around as much as 30° for the same adjacent substituents59 (further exemplified by 2,4 DCNB), and a significant proportion of aromatic nitro groups in short Cl · · · O contacts have torsion angles in the range of 70–90°,8 well above the range shown in Table 4. Taking account of the nitro group rotation in crystal structure prediction has been deemed “a very problematic task”59 as it appears to have a significant influence on the packing mode of nitrobenzene derivatives, both in CSD surveys60 and in the observed and hypothetical structures. Computational methods taking into account the packing forces on the conformation are being developed,61 but they are very sensitive to the accurate balance of inter and intramolecular energies which proved, for 2,4DCNB, to require very computationally demanding ab initio methods. If this could have been combined with newly developed extensive search methods50,62,63 which also consider Z′ ) 2 structures and higher symmetry space-groups, then the observed structures of 2,4-DCNB and 3,4-DCNB may well be predicted to be the thermodynamically most stable. Evaluating the relative stability at normal temperatures would include

This combined experimental and theoretical search for the crystal structures of five isomers of dichloronitrobenzene and of 3,4-dinitrochlorobenzene clearly shows that the only feature in common is the formation of near linear C-Cl · · · O(N) interactions rather than Cl · · · Cl close contacts. While none of the isomers adopt a highly diverse range of experimental polymorphs or solvates, the observed crystal structures and propensity to form solvates and polymorphs differs considerably between these relatively simple molecular compounds, and this observation can be related to the computed structures and their energy differences. 2,3-DCNB has one crystal structure in its lowest energy molecular conformation that is more stable than any other. Encouragingly, this structure, and the lack of any other forms, is readily predicted by the relatively straightforward rigid-body lattice energy minimization approach to crystal structure prediction. Other chloronitrobenzenes have a variety of possible crystal packings that are close together in energy, representing different compromises between the various intermolecular interactions. To overcome the poor packing options available to the molecule in its fully optimized form, 2,4-DCNB and 3,4-DCNB adopt distorted molecular conformations and form unusually complex crystal structures. In these cases, considerable qualitative improvements to the computational


model are necessary to predict the most thermodynamically stable structure. The existence of a variety of packings that are close in energy indicates the thermodynamic possibility of polymorphs or solvates, and it is, perhaps, surprising that a greater number of solvates, in particular, are not observed across all isomers. The moderate range of crystallization conditions that gave a relatively low number of additional forms suggests that the crystallization of these chloronitrobenzenes rarely involves the kinetic stabilization of metastable forms. Overall, this study clearly shows that it is not currently possible to correlate the crystallization outcome with the functional groups present in any general way. Similarly, it is not readily possible to foresee whether the crystal structure of a compound is straightforward or demanding to predict until the energy differences between the potential structures have been calculated using a reasonable model. Nevertheless, the computational predictions for a specific molecule can help rationalize its solid-state behavior and so provide a valuable complement3 to solid form screening. Most significantly, this type of extensive experimental screening provides the data necessary to test and develop sufficient understanding of the factors that determine crystallization behavior essential65–69 toward the advancement of more reliable methods of polymorph prediction. Acknowledgment. The authors would like to acknowledge the Research Councils UK Basic Technology Programme for supporting “Control and Prediction of the Organic Solid State” (http://www.cposs.org.uk). Mr. M. Vickers is thanked for performing powder X-ray diffraction experiments at UCL, Dr. P. Karamertzanis for conducting the high symmetry search, and Juliette Pradon for initial investigations of 3,4-DNCB. Supporting Information Available: Potential parameter testing. Results of the searches for possible crystal structures. Full experimental details comprising physicochemical solvent properties, principal component analysis results, individual crystallization conditions and results, thermal analysis data, and powder diffraction figures for 3,4-DCNB. Manual crystallization screen details of all compounds. Thermal ellipsoid plots for crystal structure redeterminations. CIFs for 2,5DCNB, 2,4-DCNB, 3,4-DCNB, β-3,4-DNCB, and γ-3,4-DNCB. This material is available free of charge Via the Internet at http://pubs.acs.org. The hypothetical crystal structures are stored on CCLRC e-Science Centre dataportal and are available from the authors on request.

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