The Role of Organic Fluorine in the Supramolecular Assembly of

The Role of Organic Fluorine in the Supramolecular Assembly of Halogenated β-Hydroxysulphoxides Diastereomers Gregorio Asensio, Mercedes Medio-Simon, Pedro Alemań, and Carmen Ramı´rez de Arellano*

CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 12 2769-2778

Departamento de Quı´mica Orga´ nica, Facultad de Farmacia, UniVersidad de Valencia, 46100 Valencia, Spain ReceiVed July 18, 2006; ReVised Manuscript ReceiVed September 16, 2006

ABSTRACT: A series of optically pure γ-halogenated β-hydroxysulphoxides containing two stereogenic centers have been prepared, and the X-ray crystal structures have been determined. The conformational behavior in the solid state and the crystal packing of the different β-hydroxysulphoxide diastereoisomers have been determined. The intermolecular and intramolecular interactions present have been studied in both halogenated and nonhalogenated β-hydroxysulphoxides to establish the influence of the halogen atom in the supramolecular structure. The main intermolecular hydrogen bond OH‚‚‚OdS is always present and produces molecular chains. Self-assembly of these chains includes weak CH‚‚‚F, C-F‚‚‚F-C, and C-F‚‚‚π interactions. While the C-F‚‚‚F-C and C-F‚‚‚π interactions present do not appear to drive the crystal packing, partially fluorinated methyl groups induce C-H‚‚‚F-C hydrogen bridges within CF-H‚‚‚F-C crystal homosynthons that clearly change the packing mode. Introduction The role of organic fluorine (C-F bond) in intermolecular interactions has been shown to be of great interest in different biological, pharmacological, organic chemistry and crystal chemistry fields.1 Fluorine has been used in organic mimetic molecules, such as in peptides substitution, or pharmacologically active modifications of compounds.2 Interactions involving the C-F bond may affect the binding affinity of molecules, which is determinant in enzyme-substrate complex formation, activation and deactivation of biological mechanisms or hydrophobic/ lipophilic properties of molecules.3 The increasing interest of the unusual biological activity of fluorinated compounds requires a deeper understanding of the role that organic fluorine plays in intermolecular interactions. Crystals have provided a field in which weak directing interactions are identified and recognized as being involved in the design and manipulation of molecular systems that depend on noncovalent binding.4 The influence of organic fluorine in crystal packing has been a subject of controversy. Its low participation, if any at all, in halogen contacts, and the tendency of the C-F bond to segregate and pack separately due to less attractive C-F‚‚‚F-C interactions have been reported.5 Despite the polarity of the C-F bond, the low polarizability of fluorine seems to be responsible for this limited ability to participate in interactions.6 However, C-F bonds may produce C-F‚‚‚F-C nonbonded contacts that direct crystal packing.7 The poor hydrogen bond acceptor ability of the C-F bond has been reported. In fact, the most common X-H‚‚‚F-C interactions seem to occur between fluorine and C-H rather than the O-H or N-H hydrogen donor given the competing ability of the C-O or C-N groups to act as hydrogen acceptors.8 The C-F bond, unlike the heavier organic halogens, prefers to form C-H‚‚‚F interactions rather than F‚‚‚F contacts, which mainly appear in fluorine-rich structures.9 The C-H‚‚‚F-C interaction has been considered as a hydrogen bridge that features a very weak interaction (less than 5 kcal mol-1).10 Furthermore, spectroscopic and crystallographic evidence for the existence of C-H‚‚‚F-C interactions has been reported.11 * To whom correspondence should be addressed. E-mail: [email protected].

A different type of interaction involving fluorine, the C-F‚‚‚π interaction, is especially active for fluorinated aromatic systems. The C-F‚‚‚π interaction has been mainly described as destabilizing, except for perfluorinated phenyl rings acting as π acceptors.12 Moreover, a study on structures reported in the Cambridge Crystallographic Database has shown that organic fluorine is more likely to form C-F‚‚‚π interactions than other halogens.13 On the other hand, the indirect role of fluorine increasing the acidity of neighboring C-H groups has been suggested.14, 15 Normally, intermolecular interactions involving organic fluorine appear in crystals when these are compatible within a packing scheme that is predominantly determined by other stronger interactions. To understand the steering ability of the C-F group in crystal packing, we have prepared crystals of a series of optically pure (RS,S)- and (RS,R)-β-hydroxysulphoxides diastereomers, containing CCl3, CF2Cl, CF3, CHF2, CH2F, or iPr groups. The isopropyl group has been selected due to its similar steric properties when compared to the CF3 group.16,17 β-Hydroxysulphoxides have a remarkable hydrogen bond donor and acceptor ability that allows the existence of O-H‚‚‚OdS intermolecular interactions to generate a packing motif. The main motif assembly in the crystal is then governed by interactions between C-H, C-F, C-Cl bonds and/or π systems. Optically pure (RS,S)- and (RS,R)-β-hydroxysulphoxides have been used to minimize crystal packing possibilities by excluding all operations other than rotations or screw axes. To the best of our knowledge, this is the first systematic study on the crucial role of the alkyl C-F group in crystal packing to use a series of designed organic molecules. Results and Discussion The descriptions of the following crystal structures are based upon a consideration of such interactions that lie within the sum of van der Waals radii for the pair of interacting atoms (F‚‚‚F 2.94 Å, Cl‚‚‚Cl 3.52, F‚‚‚Cl 3.23 Å).18 A cut off of 2.8 Å for the pair of interacting atoms H‚‚‚F, 2.9 Å for H‚‚‚O and 3.2 Å for H‚‚‚Cl, and an angular cut off of >120°, have been adopted. All reported hydrogen bond geometries are based upon H-atom positions that have been adjusted along their bond vector to

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2770 Crystal Growth & Design, Vol. 6, No. 12, 2006

Asensio et al.

Table 1. Summary of Crystal Data, Data Collection, and Refinement Parameters for 1r-6β 1r

2r

3r

4r

5r

6r

formula crystal habit a (Å) b (Å) c (Å) R (°) β (°) γ (°) V (A3) Z T (K) space group crystal size (mm) µ (mm-1) 2θmax reflns measured unique reflns Rint S (F2) wR2 (all reflns) R1 [I > 2σ(I)] max ∆F (e Å3)

C10H13FO2S colorless lath 5.5610(1) 8.6113(2) 21.9162(5) 90.00 90.00 90.00 1049.51(4) 4 100(2) P212121 0.32 × 0.30 × 0.10 0.294 52.74 7279 2140 0.0794 1.005 0.0917 0.0474 0.16

C10H12F2O2S colorless lath 5.6291(7) 8.8502(11) 21.790(3) 90.00 90.00 90.00 1085.6(2) 4 291(2) P212121 0.60 × 0.34 × 0.16 0.303 55.00 4037 2034 0.0224 1.008 0.0802 0.0322 0.19

C10H11F3O2S colorless prism 5.0858(5) 9.5412(10) 11.5677(14) 90.00 93.875(4) 90.00 560.04(11) 2 173(2) P21 0.44 × 0.20 × 0.14 0.312 54.88 4436 2423 0.0600 1.031 0.1243 0.0533 0.30

C10H11ClF2O2S colorless prism 9.1588(17) 5.7511(13) 12.097(2) 90.00 103.858(15) 90.00 618.7(2) 2 291(2) P21 0.60 × 0.52 × 0.48 0.485 55.00 5668 2838 0.0267 1.062 0.2112 0.0623 0.45

C10H11Cl3O2S colorless prism 12.215(2) 6.1978(12) 17.611(4) 90.00 106.52(3) 90.00 1278.3(4) 4 173(2) P21 0.42 × 0.22 × 0.18 0.861 60.04 14074 7332 0.0327 1.027 0.0713 0.0319 0.31

C12H18O2S colorless needle 9.3954(19) 5.3324(11) 12.688(3) 90.00 105.36(3) 90.00 613.0(2) 2 173(2) P21 0.38 × 0.06 × 0.06 0.243 56.54 5780 2993 0.0880 1.002 0.1177 0.0597 0.26

1β

2β

3βI

3βII

6β

formula crystal habit a (Å) b (Å) c (Å) R (°) β (°) γ (°) V (A3) Z T (K) space group crystal size (mm) µ (mm-1) 2θmax reflns measured unique reflns Rint S (F2) wR2 (all reflns) R1 [I >2σ(I)] max ∆F (e Å3)

C10H13FO2S colorless lath 5.6382(11) 8.4542(17) 21.822(4) 90.00 90.00 90.00 1040.2(3) 4 173(2) P212121 0.40 × 0.18 × 0.08 0.297 56.54 7846 2579 0.0843 1.008 0.0743 0.0463 0.16



C10H11F3O2S colorless needle 17.200(3) 5.9594(12) 13.889(3) 90.00 126.25(3) 90.00 1148.0(6) 4 173(2) C2 0.56 × 0.08 × 0.08 0.304 59.82 4706 2749 0.0564 0.845 0.0806 0.0445 0.22

C12H18O2S colorless prism 23.226(5) 6.0154(12) 9.885(2) 90.00 114.92(3) 90.00 1252.5(5) 4 173(2) C2 0.55 × 0.40 × 0.30 0.238 60.00 6149 3537 0.0387 1.040 0.1461 0.0527 0.48

positions consistent with their expected nuclear positions (C-H 1.083 Å and O-H 0.983 Å).19 Conformational Analysis. The X-ray crystal structure of a series of β-hydroxysulphoxides containing two stereogenic centers have been determined (Table 1, Figure 1). The (S,Rs) and (R,Rs) diastereomers of the β-hydroxysulphoxides with R ) CH2F (1), CHF2(2), CF3 (3), CF2Cl (4), CCl3 (5), and iPr (6) are shown in Figure 1. The R or β configuration has been assigned to the (S,Rs) and (R,Rs) diastereomers respectively (Figure 2). The conformational behavior of compounds 1-6 has been analyzed and is summarized in Table 2. Previous studies on the conformation in the solution of diastereomeric β-Hydroxysulphoxides have been reported.20 For both the R and β configurations, the sulfur atom lone pair is always eclipsed with the hydroxyl group oxygen atom, in relation to the S‚‚‚C2 line. As a consequence, the C2-O2 bond is gauche to both the S-O1 and S-C11 bonds in relation to the S‚‚‚C2 axis. This conformation presents the minimum 1,3-repulsion possible. The O1 atom is eclipsed with the H-atom or the R group in the described conformation in relation to the S‚‚‚C2 axis, for the R or β diastereomers, respectively. For all the R species studied, the C2 atom is anti to the p-tolyl group in relation to the S-C1

bond, which is co-incident with the studies that have been performed in solution. However, two different conformations with regard to the S-C1 bond have been found for the β diastereomers. As expected, the C2 atom is anti to the O1 atom for compounds 3β and 6β, thus avoiding 1,3-O1 repulsions. However, the C2 atom is anti to the p-tolyl group in compounds 1β and 2β. This difference can be explained in terms of an existing intramolecular R‚‚‚O1 interaction for compounds 1β and 2β, i.e., CF-H‚‚‚OdS (CF ) -CF2 or -CHF) hydrogen bond (Table 3). This interaction is not possible for compounds 3β and 6β, and thus the less repulsive and sterically hindered conformation is given. General Features for the Crystal Packing of β-Hydroxysulfoxides. All the reported compounds form infinite O-H‚‚‚OdS hydrogen bonded chains in which the stronger hydrogen bond donor and acceptor atoms are involved. Recent reported calculations have measured the strength of an optimum Csp3F‚‚‚H bond (1.9 Å) to be 2.38 kcal mol-1, which is weaker than O‚‚‚H hydrogen bonds (conservatively estimated to be ca. 5 kcal mol-1).2b The sulfoxides bearing the CF3 group (3r, 3βI and 3βII) produce linear chains in which the molecules are translationally related, while the other compounds form zigzag chains along a screw axis (Figure 3, Table 3). For the R or β

Halogenated β-Hydroxysulphoxides Diastereomers

Crystal Growth & Design, Vol. 6, No. 12, 2006 2771

Figure 1. Ellipsoid plot of the X-ray structures of β-hydroxysulphoxides 1r-6β. The labeling scheme is shown for compound 1r. Yellow sulfur, red oxygen, and green fluorine or chlorine atoms.

Figure 2. Conformation of the R and β diastereomers (RS,S)-1r, 2r, 3r, 6r, and (RS,R)-4r, 5r, 1β, 2β, 3β, 6β.

conformers of compounds with the CF2Cl (4), CCl3 (5), and iPr (6) groups, the formation of linear chains through an O-H‚‚‚OdS hydrogen bond could possibly not occur due to

the slightly larger space requirement with respect to the CF3 groups (3). On the other hand, the space requirement would be adequate for both the R or β conformers of compounds 1 and


Asensio et al.

Table 2. Torsion Angles (°) for 1r-6β comp

O1-S1‚‚‚C2-O2

C11-S1‚‚‚C2-O2

O1-S1-C1-C2

C11-S1-C1-C2

S1-C1-C2-O2

S1-C1-C2-C3

1r 2r 3r 4r 5rA 5rB 6r 1β 2β 3βI 3βII 6β

110.08(18) 104.49 119.35 116.2(4) 125.05(13) 98.66(11) 111.21(18) 103.64(15) 110.32(12) 127.37(15) 119.67(17) 120.51(16)

-136.32(17) -143.08 -124.36 -130.0(3) -120.64(13) -155.55(11) -135.09(18) -143.76(16) -136.34(12) -120.33(12) -129.94(16) -128.07(14)

66.2(2) 62.27 72.53 68.4(4) 71.49(16) 52.35(14) 68.6(3) 67.4(2) 67.66(17) 178.32(14) 179.27(19) 179.38(17)

176.0(2) 172.42 -177.08 178.0(3) -179.43(14) 160.87(13) 177.4(2) 176.7(2) 177.48(15) -72.18(15) -72.5(2) -71.25(19)

51.3(3) 49.06 58.86 56.5(5) 63.65(17) 54.00(17) 50.3(3) 43.8(3) 49.79(19) -54.24(19) -65.2(2) -65.7(2)

174.2(2) 171.03 -177.58 179.0(3) -175.25(14) -178.76(12) 172.7(2) -78.1(3) -71.8(2) -172.85(14) 174.91(19) 169.0(2)

Table 3. Intramolecular and Intermolecular Hydrogen Bond (X-H‚‚‚Y) and Contact (X‚‚‚Y) Lengths (Å) and Angles (°) Involved in the Infinite Chains Formation for Compounds 1r-6β H-bond/contact 1r

2r

3r 4r 5r

6r

1β

2β 3βI 3βII 6β

zigzag chain zigzag chain zigzag chain side chain zigzag chain zigzag chain zigzag chain zigzag chain side chain linear chain linear chain zigzag chain zigzag chain A zigzag chain B zigzag chain B zigzag chain B zigzag chain B zigzag chain B zigzag chain zigzag chain side chain side chain intramolecular zigzag chain zigzag chain zigzag chain intramolecular zigzag chain linear chain linear chain linear chain zigzag chain zigzag chain side chain side chain side chain

X-H/X O2-H2 C3-H3A C2-H2A C1-H1B O2-H2 C3-H3A C2-H2A C12-H12 C1-H1B O2-H2 C1-H1A O2-H2 O2-H2 O2-H2A O2-H2A C1A-H1C C12A-H12A C12A-H12A O2-H2 C4-H4A C1-H1B C3-H3 C3-H3B O2-H2 C1-H1A C16-H16 C3-H3 O2-H2 O2-H2 C12-H12 O2-H2 O2-H2 C1-H1A C1-1B C5-5B C12-H12

Y O1i a O1ii O2ii O2iii O1i O1ii O2ii F1ii O2iii O1i O1i O1i O1i O1Aii S1Aii O2Aii Cl2Aii O2Aii O1i O1i O2ii O2ii O1 O1i O2i F1i O1 O1i O1i O1i O1i O1i O1i O2ii O2ii O2ii

XY

HY/ CX‚‚‚Y

XHY/ X‚‚‚YC

2.737(3) 3.470(4) 3.726(3) 3.734(4) 2.705(2) 3.260(3) 3.835(2) 3.509(3) 3.840(3) 2.762(3) 3.184(4) 2.641(6) 2.676(2) 2.635(2) 3.763(2) 3.306(2) 3.842(2) 3.460(2) 2.735(3) 3.458(4) 3.665(4) 3.738(4) 3.104(3) 2.728(3) 3.871(3) 3.564(3) 3.020(3) 2.713(2) 2.638(2) 3.643(3) 2.663(3) 2.758(3) 3.256(3) 3.732(3) 3.777(6) 3.391(3)

1.757 2.584 2.734 2.718 1.734 2.556 2.886 2.447 2.859 1.789 2.456 1.786 1.714 1.773 2.784 2.596 2.990 2.591 1.753 2.702 2.694 2.780 2.460 1.751 2.790 2.538 2.317 1.754 1.660 2.691 1.727 1.784 2.432 2.691 2.716 2.334

173.6 138.5 152.1 156.0 169.1 121.9 146.4 166.4 150.7 169.7 123.4 143.4 165.0 144.3 173.6 122.5 135.9 136.8 177.1 126.5 149.1 147.4 116.9 171.6 176.7 157.8 120.9 164.2 172.4 146.5 157.9 170.4 131.8 161.1 166.2 164.8

a Symmetry operators: 1r (i: x - 1/2, -y + 3/2, -z; ii: x + 1/2, -y + 3/2, -z; iii: x + 1, y, z), 2r (i: x + 1/2, -y + 1/2, -z + 1; ii: x - 1/2, -y + 1/2, -z + 1, -z; iii: x - 1, y, z), 3r (i: x - 1, y, z), 4r (i: -x + 2, y - 1/2, -z), 5r (i: -x + 1, y + 1/2, -z + 1; ii: -x + 1, y + 1/2), 6r (i: -x + 2, y - 1/2, -z + 1; ii: x, y + 1, z), 1β (i: -x + 2, y - 1/2, -z + 1/2), 2β (i: -x + 2, y + 1/2, -z + 1), 3βI (i: x + 1, y, z), 3βII (i: x, y + 1, z), 6β (i: -x + 2, y - 1/2, -z + 1; ii: x, y + 1, z).

2, although they show interactions involving the CH2F or CHF2 groups that take place in the zigzag arrangement. Once the chains are formed, both the stronger donor and acceptor atoms are occupied, and only weak interactions can be observed in interchain assembly. For most of the described compounds, chain assembly occurs by pairing the phenyl rings of a chain with the aliphatic part of a neighboring chain (Figure 4, Table 4). Exceptions have been found for the R conformers containing partially fluorinated Me groups (CHF2 1r and CF2H 2r), in which chain assembly occurs by pairing the aliphatic part of neighboring chains (Figure 4, Table 4). This different chain assembly allows the existence of CF-H‚‚‚F-C interactions within a newly described catemer type (CF-H‚‚‚F-C)n crystal homosynthon (Figure 5). Supramolecular synthons have been described as recognizable groups of intermolecular interac-

tions.21 In all the described compounds, chain assembly produces molecular layers with a ring-R-ring-R profile that pack in an alternated fashion, as expected (Figure 4, Table 4). Layer packing involves weak C-H‚‚‚π interactions. The infinite linear or zigzag chains that involve the main O-H‚‚‚OdS hydrogen bond are parallel to the shortest cell axis except for the 1β and 2β compounds. In the last two compounds, the shortest axis occurs in the chain assembly direction through CFH‚‚‚OH intermolecular bonds. The CH2F and CHF2 groups in compounds 1 and 2 show no F/H disorder that might otherwise be expected if the C-H‚‚‚F interactions were not significant. Discussion of Specific Structures. Crystal Packing for Compounds 1r, 2r. Both compounds are isomorphs and isostructural (Table 1). A moderate-to-strong catemer type O-H‚‚‚OdS hydrogen bond leads to one-dimensional (1-D)



Figure 3. Crystal packing views showing the chain formed through the O-H‚‚‚OdS hydrogen bond (O2-H2‚‚‚O1i) of β-hydroxysulphoxides 1r-6β. Other interactions within the chains have been omitted for clarity. Brown sulfur, red oxygen, and green fluorine or chlorine atoms.

head-to-tail zigzag chains along the shortest axis. Weak intermolecular CF-H‚‚‚OdS (1r, 2r), C-H‚‚‚OH (1r, 2r) and C-H‚‚‚F (2r) hydrogen bonds are also present in the chains (Figure 3, Table 3). The zigzag chains present a tubular section of a 10-membered ring and parallel off-center p-tolyl rings (Figure 4). Chains are connected by pairing the aliphatic moieties through weak catemer-type CF-H‚‚‚F-C hydrogen bonds. This CF-H‚‚‚F-C catemer-type interaction can be considered as a crystal homosynthon, (CF-H‚‚‚F-C)n (Figure 5). The head-to-tail chain connection yields molecular layers with holes or cavities formed by parallel off-center p-tolyl rings (Figure 4). The three-dimensional (3-D) crystal is formed by interpenetration of molecular layers through herring bone ring

packing and weak C-H‚‚‚F (1r, 2r) and C-H‚‚‚OH (2r) hydrogen bonds (Table 4). Crystal Packing for Compounds 4r, 6r, 6β. Both the isomorphs compounds 4r and 6r and compound 6β pack in a similar way. As in compounds 1r and 2r, the crystals show 1-D head-to-tail zigzag chains along the shortest axis through O-H‚‚‚OdS hydrogen bonds with a tubular section and parallel off-center p-tolyl rings (Figures 3 and 4). The octagonal-shaped chain section is similar for compounds 1r, 2r, 4r, and 6r and slightly different for compound 6β. Weak intermolecular C-H‚‚‚OH (6r and 6β) and C-H‚‚‚OdS (6r and 6β) hydrogen bonds are also present in the chains (Table 3). For these compounds, however, chain assembly occurs under a quite


Asensio et al.

Figure 4. Crystal packing views along the chain formed through O-H‚‚‚OdS hydrogen bond, showing the chain cross-section and the molecular layer by the chain assembly of β-hydroxysulphoxides 1r-6β. Yellow sulfur, red oxygen, and green fluorine or chlorine atoms.

different pattern, since the phenyl rings of a chain pair with the neighboring chain aliphatic part. Additional C-H‚‚‚Cl weak interactions are present in the chains for 4r crystals (Table 4). As expected, the presence of CX3 (X ) halogen) or iPr groups avoids the above-mentioned chain assembly through the (CFH‚‚‚F-C)n crystal synthon. Once again, the molecular layers show parallel p-tolyl rings alternating with holes of the CX3 or iPr groups at the surface. The layer interpenetration packing conveys C-H‚‚‚Cl (4r) and C-H‚‚‚O (4r, 6r and 6β) weak interactions together with a herringbone type of ring packing. The CF2Cl group in compounds 4r shows F/Cl disorder, which could be related to the weakness of the C-H‚‚‚Cl interactions. Crystal Packing for Compound 5r. Two independent molecules have been found in the asymmetric unit of this compound. Each independent molecule, produces an independent strong catemer-type O-H‚‚‚OdS hydrogen bond. Therefore, two different 1-D head-to-tail zigzag chains along the shortest axis are observed in the crystal (A and B, Figure 3, Table 3). The shape for the zigzag chain A (S1-C7) is similar to that observed in compounds 1r, 2r, 4r and 6r. However, additional interactions are not observed. The zigzag chain B is slightly different, showing a twisted octagonal tubular profile. This is a consequence of the O-H vector being perpendicular

to the octagonal ring and interacting with both the oxygen and the sulfur atoms of the neighboring molecule SdO bond. Weak intermolecular C-H‚‚‚OH and C-H‚‚‚Cl hydrogen bonds are also present in the B chains (Table 3). Chains are connected by pairing the aliphatic and aromatic parts in an alternating fashion, as observed for 4r, 6r, 6β (Figure 4). The chain connection of 5r involves weak catemer-type C-H‚‚‚Cl-C hydrogen bonds. The head-to-tail connection of the chains leads to the formation of molecular layers with prominent parallel off-center p-tolyl rings alternating with cavities of C-Cl bonds as observed in compound 4r. The 3-D crystal is formed by interpenetration of molecular layers through herring bone rings packing and weak C-H‚‚‚Cl and C-H‚‚‚OdS hydrogen bonds (Table 4). Crystal Packing for Compounds 1β and 2β. For both compounds an intramolecular CF-H‚‚‚OdS hydrogen bond has been found (Table 3). Compound 1β is isomorphic but not isostructural to compounds 1r and 2r. In this case, 1-D headto-tail zigzag chains along a screw axis through O-H‚‚‚OdS hydrogen bonds similar to those in compounds 1r and 2r are observed (Figure 3, Table 3). The helicoidal chains show parallel off-center p-tolyl rings, although the cross-section observed for the chains is not the same. The helicoidal chains present a sixmembered ring cross-section for 1β, while the cross-section is



Table 4. Intermolecular Hydrogen Bond (X-H‚‚‚Y) and Contact (X‚‚‚Y) Lengths (Å) and Angles (°) Involved in the Chain and Layer Assembly for Compounds 1r-6β

1r 2r

H-bond/contact

X-H/X

Y

XY

HY/ CX‚‚‚Y

XHY/ X‚‚‚Y

chain assembly layer assembly chain assembly layer assembly

C3-H3A C7-H7C C3-H3A C7-H7C C7-H7A C16-H16 C15-H15 C1-H1B C12-H12 C13-H13 C12-H12 C7-H7C C7-H7C C1-H1B C7-H7A C1-H1A C16-H16 C16A-H16A C7-H7C C7A-H7F C7-H7C C3-H3A C15-H15 C7-H7B C3-H3 C1-H1B C2-H2A C3-H3 C12-H12 C15-H15 C12-H12 C7-H7A C7-H7C C1-H1A C1-H1A C2-H2A F3 C7-H7C F3 F3 F3 F3 F3 F3 C7-H7A C15-H15

F1iva F1v F2iv O2v F1vi O2ii F3ii O1ii F2iii F3iv Cl1ii O1iii Cl1'iv Cl1A Cl2A Cl1Aiii Cl1Aiii Cl1iv Cl3v O1Avi O1iii O2ii F1iii F1iii O2ii O1iii O2iii F1iv F2v F2vi F1ii F2iii F1iv O2ii F2ii F3iii F3iii O1iv C11iv C12iv C13iv C14iv C15iv C16iv O1v O1iii

3.364(4) 3.600(4) 3.352(3) 3.489(3) 3.473(3) 3.345(4) 3.708(5) 3.672(5) 3.487(4) 3.666(4) 4.129(6) 3.676(6) 3.851(7) 3.705(2) 4.077(3) 3.747(2) 4.097(2) 3.756(2) 3.928(3) 3.969(3) 3.737(4) 3.703(4) 3.512(3) 3.411(4) 3.836(3) 3.863(3) 3.546(2) 3.587(3) 3.170(2) 3.576(2) 3.627(3) 3.688(3) 3.481(4) 3.486(4) 3.494(3) 3.340(3) 2.819(4) 3.727(4) 3.292(2) 3.241(2) 3.255(2) 3.342(2) 3.392(2) 3.378(2) 3.727(4) 3.578(3)

2.597 2.628 2.672 2.462 2.715 2.528 2.647 2.671 2.469 2.706 3.089 2.816 3.066 2.862 3.155 2.945 3.135 2.784 2.999 2.900 2.720 2.637 2.579 2.478 2.900 2.820 2.854 2.814 2.396 2.701 2.790 2.623 2.713 2.420 2.744 2.649 165.90(2) 2.733

127.1 149.1 120.3 157.7 126.7 131.4 166.3 153.3 156.1 147.5 161.3 136.4 129.8 134.7 143.5 131.1 148.4 149.4 144.1 169.1 156.2 168.2 143.8 143.6 144.8 161.8 121.8 128.3 127.2 137.6 134.1 167.6 127.6 167.6 126.1 121.1 109.55(17) 140.9

3r

chain assembly

4r

layer assembly chain assembly layer assembly

5r

chain assembly

layer assembly 6r 1β

layer assembly chain assembly layer assembly

2β

chain assembly

3βI

layer assembly chain assembly

3βII

layer assembly chain assembly ladder assembly

6β

layer assembly layer assembly

2.718 2.573

154.9 153.9

a Symmetry operators: 1r (iv: x + 1/2, -y + 5/2, -z; v: -x + 1, y - 1/2, -z + 1/2), 2r (iv: x - 1/2, -y - 1/2, -z + 1; v: -x + 2, y + 1/2, -z + 3/2; vi: -x + 3/2, -y, z + 1/2), 3r (ii: -x + 1, y + 1/2, -z; iii: -x, y - 1/2, -z; iv: x, y, z + 1), 4r (iii: x, y + 1, z; iv: x, y, z + 1), 5r (iii: x, y + 1, z; iv: x, y - 1, z; v: x, y - 1, z; vi: -x + 2, y + 1/2, -z + 2), 6r (iii: -x + 2, y + 1/2, -z + 2), 1β (ii: x - 1, y, z; iii: -x + 3/2, -y + 1, z + 1/2), 2β (ii: -x + 2, y - 1/2, -z + 1; iii: x - 1, y, z; iv: x + 1, y, z; v: -x + 1, y - 1/2, -z + 1; vi: x - 1, y, z - 1), 3βI (ii: -x + 2, y - 1/2, -z + 2; iii: -x + 2, y + 1/2, -z + 2; iv: x, y, z - 1), 3βII (ii: -x + 3/2, y - 1/2, -z + 2; iii: -x + 1, y, -z + 1; iv: x - 1/2, y + 1/2, z; v: -x + 1/2, y + 1/2, -z), 6β (iii: -x + 2, y + 1/2, -z + 2).

Figure 5. Catemer type (CF-H‚‚‚F-C)n crystal homosynthon (left) and packing view for compound 1r showing the catemer type C-H‚‚‚F interaction (right).

not ring shaped for 2β. The chains of 1β also show weak intermolecular C-H‚‚‚F and C-H‚‚‚OH hydrogen bonds (Table 3). However, the zigzag chain screw axis is not parallel to the cell shortest axis (5-6 Å) as observed in the other compounds.

Catemer type CF-H‚‚‚O (1β) or CF-H‚‚‚O (2β) hydrogen bonds along the shortest axis are involved in the chains assembly (Table 4). The chains connection, also occurs pairing aliphatic and aromatic ends as in conformers 4r, 5r, 6r, 6β, forming molecular layers (Figure 4). The molecular layers contain again parallel p-tolyl rings alternated with cavities of C-F bonds at the surface. The layer interpenetration packing conveys C(Me)H‚‚‚F and C(Ar)-H‚‚‚F weak interactions together with edgeto-face π stacking interactions. Crystal Packing for Compound 3r and 3β. Two different polymorphs, I and II, have been found for compound 3β. In all 3r, 3βI, and 3βII crystals, the stronger catemer-type O-H‚‚‚Od S hydrogen bond leads to 1-D head-to-tail linear chains along the shortest axis, rather than the zigzag chains observed in the other sulfoxides. Weak intermolecular C-H‚‚‚OdS (3r, 3βI) hydrogen bonds are also present within the chains (Table 3, Figure 3). Two chain assembly types are observed. In 3r


Asensio et al.

Figure 6. Scatter plot form the CSD (CCDC) of the F‚‚‚X (X: phenyl ring center) distance (DIST, Å) versus the ring mean plane vector and the F‚‚‚X vector angle (ANG, °).

and 3βI crystals, the chains connection occurs by pairing aliphatic and aromatic ends, as observed in 4r, 5r, 6r, 1β, 2β, and 6β. Weak C-H‚‚‚F, C-H‚‚‚OdS (3r), and C-H‚‚‚OH (3r) hydrogen bonds are observed in the chains connection that forms one-molecule-thick molecular layers. The layer profile shows parallel p-tolyl rings alternated with CF3 fragments (Figure 4). The layer interpenetration packing conveys C-H‚‚‚F (3r, 3βI) weak interactions, while no ring interaction is observed. For the compound 3βII however, every two-chain assembly occurs through catemer-type strong C-H‚‚‚OH [H‚‚‚Oii 2.420 Å, C-H‚‚‚Oii 167.6°] and weak CH‚‚‚F interactions and the pairing of aliphatic parts with the formation of a ladder. Ladders are then connected by pairing aliphatic and aromatic ends and by forming molecular layers. This type of assembly, which has been observed for all the described halogenated and nonhalogenated crystals except for the above-mentioned 1r and 2r, could possibly be the preferred form for steric and space filling reasons. Weak C-H‚‚‚F, C-H‚‚‚O hydrogen bonds and F‚‚‚F and F‚‚‚π contacts are involved. The F‚‚‚F contact of 2.819(4) Å is within the range of polarization-induced halogen‚‚‚halogen nonbonded interactions.5b This F‚‚‚F contact, with C-F‚‚‚F angles of 14.09(2) and 109.45(16)°, could be considered to present type II geometry (C-F‚‚‚F angles of 180° and 90°).6a The layer profile, which is substantially different from any of the analyzed compounds, shows how the aromatic rings are almost parallel (28°) to the layer surface. The layer contacts involve weak C(Me)-H‚‚‚OdS and C-H‚‚‚π interactions. OdS‚‚‚O-H Torsion Angle. The compounds forming infinite linear chains (3r and 3β) show an OdS‚‚‚O-H torsion angle of ca. 180°, while the compounds forming infinite chains along a screw axis show an OdS‚‚‚O-H torsion angle in the 20-178° range. Therefore, there is not an obvious relation between the hydroxyl hydrogen position and the configuration, conformation, or crystal packing. F‚‚‚π Contacts. We have undertaken a search in the Cambridge Crystallographic Data Base to confirm the possibility of F‚‚‚π contacts in crystal lattices.22 We have searched for phenyl rings at ca. 4 Å from any fluorine atom, and plotted the F‚‚‚ring center distance over the angle between the F‚‚‚ring center vector and the ring plane vector (Figure 6). The fluorine atom lies in the same plane as the ring at 90°, and therefore only C-H‚‚‚F interactions are possible (Figure 6, I). As the fluorine atom goes out of the aromatic ring plane (the angle

decreases) F‚‚‚π contacts are possible. We can observe from the scatter plot a shortening in the van der Waals minimum distance when the angle decreases. It is interesting to notice the tendency observed in the 0 to 30° area, where the fluorine atom is almost at the center of the ring, for distances in the 2.8-4 region (Figure 6, II). That is, when the fluorine atom is near a ring center, the contact length tends to be shorter. This fact could be explained in terms of the existence of a positive F‚‚‚π interaction. This type of interaction does not play a directing role in the crystal packing of the β-hydroxysulphoxides under study, probably due to its low energy. However, once the C-F group is near to the phenyl ring due to other packing effects the position of the fluorine atoms seems to be driven to the center of the ring and a shortening of the F‚‚‚ring distance occurs. CF-H‚‚‚F-C Synthons. We have shown that the presence of partially fluorinated alkyl groups produces both acidic C-H that could act as hydrogen bond donors and electronegative F-C groups that act as hydrogen bond acceptors. The formation of the so-described (-CF-H‚‚‚F-C-)n crystal homosynthon is likely under such conditions and clearly affects the final crystal packing (Figure 5). A search in the CSD has been carried out to check the frequency of this synthon in crystal structures of organic compounds containing partially fluorinated methyl groups. The search in the CSD has afforded 156 structures, 63 of which present the (-CF-H‚‚‚F-C-)n synthon with H‚‚‚F distances ranging from 2.5-2.9 Å and C-H‚‚‚F angles in the 110-170° range. The dimeric crystal synthon (-CF-H‚‚‚F-C-)2 is present in 19 out of the 63 structures containing the (-CF-H‚‚‚F-C-)n crystal homosynthon. Conclusions For all the described compounds, except those bearing partially fluorinated groups, chain assembly occurs by pairing the phenyl rings of a chain with the neighboring chain aliphatic part. The presence of halogen atoms and the corresponding C-F‚‚‚F-C, C-F‚‚‚H-C, or C-F‚‚‚π interactions does not seem a determinant for this type of geometry, which is also found for the isopropyl substituted sulfoxides. Therefore, chain assembly geometry could be a consequence of steric and effective space filling reasons and not any directing effect of C-F bonds. Clear exceptions have been found for the pairs of diastereomers containing partially fluorinated Me groups (1r, 2r, 1β, 2β).


The indirect role of fluorine increasing the acidity of the CF-H group and generating a relatively strong hydrogen bond donor is observed for compounds 1β and 2β. Intramolecular and conformation determinant CFH‚‚‚OdS interactions are present in the 1β and 2β conformers. Furthermore, the unit cell shortest axis is parallel to the chain assembly for the 1β and 2β conformers that occurs through CFH‚‚‚OH intermolecular interactions. The shortest cell axis, however, is along the chain direction in the rest of the compounds, which involves the main O-H‚‚‚OdS hydrogen bond. The double role of the CF-H group acting both as hydrogen bond donor and acceptor is observed for compounds 1r and 2r. The chain assembly in these conformers occurs through CF-H‚‚‚F interactions, and the pairing of the phenyl rings of a chain with the neighboring chain aliphatic part observed for the rest of compounds is no longer observed. A supramolecular homosynthon (CF-H‚‚‚F)n strong enough to overcome the sterical and space filling based packing geometry is observed, thus suggesting the importance of the double role that the CF-H group plays in crystal packing, since it is able to act as either an O-H or an N-H connector. The above-described crystal synthon could open new perspectives for the design of crystals involving partially fluorinated alkyl groups. The substitution of perfluorinated or non-fluorinated alkyl groups by partially fluorinated alkyl groups conveys important changes in the intramolecular and intermolecular β-hydroxysulphoxides interactions under study. The use of partially fluorinated alkyl groups could be of importance for the design of new connectors in crystal engineering as well as for the design of organic mimetic molecules of biological interest. Experimental Section Preparation of Crystals. Compounds 1r-6β were prepared following procedures in the literature.23 Crystals were grown by slow diffusion of diethylether/n-hexane (5r), diethylether/n-pentane solutions (1r) or dichloromethane/n-hexane (6r, 3βII, 6β) solutions or by slow evaporation of dichloromethane/diethylether/n-pentane (1β), dichloromethane/n-hexane (2r, 4r), diethylether/n-pentane (3r), diethylether/ n-hexane (2β, 3βI) solutions. Crystal Data for Compounds 1r-6β. Crystals suitable for X-ray diffraction were measured at r.t. (2r and 4r), -50 °C (1r) or -100 °C (3r, 5r, 6r, 1β, 2β, 3βI, 3βII, 6β) on a Nonius Kappa CCD or Siemens P4 (2r, 4r) diffractometers using graphite-monochromated Mo-KR radiation (λ ) 0.71073 Å) and a ω scan mode (Table 1). Structures were solved by direct methods, and all non-hydrogen atoms were refined anisotropically on F2 (program SHELXL-97).24 The hydrogen atoms of the OH and methyl groups were refined as rigid. Other hydrogen atoms were included using a riding model. For compound 1r, the CF2Cl group is disordered over three positions that were refined with a common carbon position. The absolute structure was determined with Flack parameters 0.06(11) (1r), 0.12(8) (2r), 0.12(11) (3r), 0.01(19) (4r), 0.04(4) (5r), 0.19(11) (6r), 0.05(11) (1β), 0.04(6) (2β), 0.01(7) (3βI), 0.16(8) (3βII) and 0.15(10) (6β).25 1r crystals were sensitive to temperatures lower than -50 °C. The programs use neutral atom scattering factors, ∆f′ and ∆f′′ and absorption coefficients from International Tables for Crystallography.26

Acknowledgment. Financial support from the Ministerio de Educacioń y Ciencia (BQU2003-00315 and Programa Ramoń y Cajal) and Generalitat Valenciana (GV-027/2005) is gratefully acknowledged. We thank Prof. Peter G. Jones from the Institut fu¨r Anorganische und Analytische Chemie, Technische Universita¨t Braunschweig, Postfach, Braunschweig, Germany, for helpful discussions. Supporting Information Available: Crystallographic information files (CIF) for compounds 1r-6β contain the supplementary crystal-

Crystal Growth & Design, Vol. 6, No. 12, 2006 2777 lographic data for this paper. This material is available free of charge via the Internet at http://pubs.acs.org.

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(18) (19) (20) (21) (22)

Gil, J.; Domingo, L. R.; Medio-Simon, M. J. Org. Chem. 1998, 63,9342. (c) Asensio, G.; Gavinã, P.; Cuenca, A.; Ramı´rez, de Arellano, M. C.; Domingo, L. R.; Medio-Simon, M. Tetrahedron: Asymmetry 2000, 11, 3481. (d) Asensio, G.; Cuenca, A.; Rodriguez, N.; Medio-Simon, M. Tetrahedron: Asymmetry 2003, 14, 3851. (e) Gil, J.; Medio-Simon, M.; Mancha, G.; Asensio, G. Eur. J. Org. Chem. 2005, 1561. Bondi, A. J. Phys. Chem. 1964, 68, 441. Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R. J. Chem. Soc., Perkin Trans. 1987, 2, S1. Alva´rez-Ibarra, C.; Cuervo, Rodrı´guez, R.; Fernańdez-Monreal, M. C.; Ruiz, M. P. J. Org. Chem. 1994, 59, 7284. (a) Desiraju, G. R. Angew. Chem. Int. Ed. 1995, 34, 2311. (b) Desiraju, G. R. Chem. Comm. 1997, 1475. (c) Desiraju, G. R. Nat. Mat. 2002, 1, 77. Cambridge Structural Database, version 5.26; 325709 entries.

Asensio et al. (23) For the synthesis of halogenated hydroxysulphoxides see (a) Bravo, P.; Frigerio, M.; Resnati, G. Synthesis 1988, 955 and references cited therein. (b) Asensio, G.; Aleman, P. A;, Gil, J.; Domingo, L. R.; Medio-Simon, M. J. Org. Chem. 1998, 63, 9342. (c) Cavicchio, G.; Marchetti, V.; Arnone, A.; Bravo, O. Gazz. Chim. Ital. 1990, 120, 741; for the synthesis of nonhalogenated hydroxysulphoxides see (d) Carrenõ, M. C. et al. J. Org. Chem. 1990, 55, 2120 and references cited therein. (24) Sheldrick, G. M. SHELXL-97; University of Go¨ttingen, Germany, 1997. (25) Flack, H. D. Acta Crystallogr. 1983, A39, 876. (26) International Tables for Crystallography, Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992; Vol. C, Tables 6.1.1.4 (pp 500-502), 4.2.6.8 (pp 219-222), and 4.2.4.2 (pp 193-199).

CG060465M

The Role of Organic Fluorine in the Supramolecular Assembly of

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