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Volume 68 
Part 8 
Pages o323-o326  
August 2012  

Received 22 June 2012
Accepted 9 July 2012
Online 19 July 2012

(1S)-1-Phenyl­ethanaminium 4-{[(1S,2S)-1-hy­droxy-2,3-dihydro-1H,1'H-[2,2'-biinden]-2-yl]methyl}benzoate

aPharmorphix Solid State Services, A Sigma-Aldrich Company, 250 Cambridge Science Park, Milton Road, Cambridge CB4 0WE, England,bTrino Therapeutics Ltd, The Tower, Trinity Technology and Enterprise Campus, Pearse Street, Dublin 2, Ireland, and cDrug Discovery Group, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland
Correspondence e-mail: chris.frampton@sial.com

The title mol­ecular salt, C8H12N+·C26H21O3-, contains a dimeric indane pharmacophore that demonstrates potent anti-inflammatory activity. The indane group of the anion exhibits some disorder about the [alpha]-C atom, which appears common to many structures containing this group. A model to account for the slight disorder was attempted, but this was deemed unsuccessful because applying bond-length con­straints to all the bonds about the [alpha]-C atom led to instability in the refinement. The absolute configuration was determined crystallographically as S,S,S by anomalous dispersion methods with reference to both the Flack parameter and Bayesian statistics on Bijvoet differences. The configuration was also determined by an a priori knowledge of the absolute configuration of the (1S)-1-phenyl­ethanaminium counter-ion. The mol­ecules pack in the crystal structure to form an infinite two-dimensional hydrogen-bond network in the (100) plane of the unit cell.

1. Comment

The indane pharmacophore occurs in many different bioactive mol­ecules, including the nonsteroidal anti-inflammatory indane sulindac (Clinoril, Merck) (Scheper et al., 2007[Scheper, M. A., Nikitakis, N. G., Chaisuparat, R., Montaner, S. & Sauk, J. J. (2007). Neoplasia, 9, 192-199.]; Shiff et al., 1995[Shiff, S. J., Qiao, L., Tsai, L. L. & Rigas, B. (1995). J. Clin. Invest. 96, 491-503.]) and the protease inhibitor indinavir (Crixivan, Merck), used as a component of highly active anti­retroviral therapy (HAART) (Vacca et al., 1994[Vacca, J. P., Dorsey, B. D., Schleif, W. A., Levin, R. B., McDaniel, S. L., Darke, P. L., Zugay, J., Quintero, J. C., Blahy, O. M. & Roth, E. (1994). Proc. Natl Acad. Sci. USA, 91, 4096-4100.]; Lin, 1999[Lin, J. H. (1999). Adv. Drug. Deliver. Rev. 39, 33-49.]). As part of our drug-discovery programme, we have identified a number of indanes that demonstrate smooth-muscle relaxation and inhibit mediator release (Sheridan et al., 1990[Sheridan, H., Lemon, S., Frankish, N., McArdle, P., Higgins, T., James, J. P. & Bhandari, P. (1990). Eur. J. Med. Chem. 25, 603-608.], 1999a[Sheridan, H., Frankish, N. & Farrell, R. (1999a). Planta Med. 65, 271-272.],b[Sheridan, H., Frankish, N. & Farrell, R. (1999b). Eur. J. Med. Chem. 34, 953-966.]). More recently, we have synthesized and characterized a series of dimeric indanes that demonstrate potent anti-inflammatory activity (Frankish et al., 2004[Frankish, N., Farrell, R. & Sheridan, H. (2004). J. Pharm. Pharmacol. 56, 1423-1427.]; Sheridan, Walsh, Cogan et al., 2009[Sheridan, H., Walsh, J. J., Cogan, C., Jordan, M., McCabe, T., Passante, E. & Frankish, N. H. (2009). Bioorg. Med. Chem. Lett. 19, 5927-5930.]; Sheridan, Walsh, Jordan et al., 2009[Sheridan, H., Walsh, J. J., Jordan, M., Cogan, C. & Frankish, N. (2009). Eur. J. Med. Chem. 44, 5018-5022.]). The title compound, (I)[link], a single enantio­mer, is the 1-phenyl­ethan­aminium salt of 4-{[(1S,2S)-1-hy­droxy-2,3-dihydro-1H,1'H-[2,2'-biinden]-2-yl]methyl}benzoic acid (PH46) and represents a first-in-class anti-inflammatory indane scaffold with potential therapeutic use in the treatment of inflammatory bowel disease (Frankish & Sheridan, 2012[Frankish, N. & Sheridan, H. J. (2012). J. Med. Chem. 55, 5497-5505.]). The crystal structure and absolute stereochemistry determination of (I)[link] are described here.

[Scheme 1]

The structure of (I)[link] is shown in Fig. 1[link]. The inden-2-yl group, defined by atoms C18-C26, demonstrates disorder in the position of the C-C and C=C bonds in the five-membered ring. The disorder manifests itself in the appearance of three potential H-atom positions in a difference Fourier synthesis about each of atoms C19 and C26, both [alpha] to atom C18. The potential disorder in this group was also revealed through a Hirshfeld rigid-bond test (Hirshfeld, 1976[Hirshfeld, F. L. (1976). Acta Cryst. A32, 239-244.]), where the differences in the components of the anisotropic displacement parameters along the C18-C19 and C18-C26 bonds exceed 6 s.u.

A simple Conquest (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]) search of the Cambridge Structural Database (CSD, Version 5.33; Allen, 2002[Allen, F. H. (2002). Acta Cryst. B58, 380-388.]) for inden-2-yl fragments as shown in (II)[link] (see Scheme[link]), where R1 is defined as any substituent other than hydrogen, returned a total of 33 entries. The disorder present in the inden-2-yl fragment was documented in a number of structures and the use of a two-part disorder model to separate the two components was attempted [see, for example, CSD refcodes APOVUX (Nikitin et al., 2010[Nikitin, K., Fleming, C., Muller-Bunz, H., Ortin, Y. & McGlinchey, M. J. (2010). Eur. J. Org. Chem. pp. 5203-5216.]), CORBOB (Nikitin et al., 2009[Nikitin, K., Muller-Bunz, H., Ortin, Y. & McGlinchey, M. J. (2009). Chem. Eur. J. 15, 1836-1843.]), OGEKAN (Nikulin et al., 2008[Nikulin, M. V., Voskoboynikov, A. Z. & Suponitsky, K. Y. (2008). Acta Cryst. E64, o2317.]) and TENBAP (Li et al., 1996[Li, S., Lundquist, K. & Stomberg, R. (1996). J. Chem. Crystallogr. 26, 287-291.])], although in the case of APOVUX it was specifically noted that the disorder model failed. A scatterplot of C-C distances versus C=C distances is shown in Fig. 2[link]. The correlation between these two parameters is clear, such that for structures where there is no disorder present, or where the disorder model has been successfully implemented, the values of the C=C and C-C bond lengths are clearly different, ca 1.35 and 1.50 Å, respectively (e.g. OGEKAN), whereas for structures that demonstrate the disorder phenomenon these two bond lengths appear to be correlated and ultimately equilibrate to a value of ca 1.42 Å. The outlier point circled in Fig. 2[link] (QUGWUK; Basavaiah et al., 2001[Basavaiah, D., Bakthadoss, M. & Reddy, G. J. (2001). Synthesis, pp. 919-923.]) is due to the incorrect assignment of the C-atom type when geometrically placing the H atoms; the 1.378 and 1.463 Å bond lengths should be assigned as C=C and C-C bonds, respectively, and not vice versa. The complete list of structures contained within this data set is available in the Supplementary materials.

In keeping with the findings above, the C=C and C-C bond lengths (C18=C19 and C18-C26, respectively) in (I)[link] refined to values of 1.420 (3) and 1.443 (2) Å, respectively (shown as a square in Fig. 2[link], indicated with an arrow). A disorder model incorporating the two different components, with the sum of the occupancies constrained to unity, was attempted. However, in order for the refinement to converge successfully, the displacement parameters for the [alpha]-C atom C18 and its disordered component C18A had to be constrained as isotropic. The model converged, yielding occupancies of the two inden-2-yl components of 0.57 (2) and 0.43 (2). The resulting C=C and C-C bond lengths about C18/C18A were 1.29 (2)/1.52 (2) Å for component 1 and 1.35 (2)/1.60 (3) Å for component 2 (lower and upper triangles in Fig. 2[link], respectively). Further refinement cycles in which additional bond-length constraints were applied to all bonds about the [alpha]-C atom led to instability in the refinement. From this analysis it was concluded that the disorder model was insufficient and so the data presented here is based on the ordered model.

For the inden-2-yl moiety, the five-membered C18-C20/C25/C26 ring is planar, with C18-C19-C20-C25 and C20-C25-C26-C18 torsion angles of 1.36 (16) and -0.69 (16)°, respectively, whereas the five-membered C9-C11/C16/C17 ring of the indan-2-yl moiety adopts an envelope conformation or E form, with atom C9 displaced by 0.478 (2) Å from the mean plane defined by the other four atoms.

The absolute configuration of (I)[link], viz. S, S and S at the chiral centres C9, C10 and C33, respectively, was determined by reference to the a priori knowledge of the chirality of the (S)-(-)-methyl­benzyl­amine used in the salt-formation step and by anomalous dispersion methods (Flack, 1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]). The determination of the absolute configuration of (I)[link] by anomalous dispersion methods was likely to be challenging, given that the mol­ecular formula and asymmetric unit contain only a single N and three O atoms. To maximize the likelihood of success, a full sphere of data was collected using Cu K[alpha] radiation to a maximum resolution of 0.80 Å. A total of 25 532 reflections were collected, yielding a Flack parameter x and standard uncertainty u for this structure of 0.00 (15) based on 2343 Friedel pairs. The value of u is slightly beyond the limit of enantio­pure-sufficient distinguishing power (Flack & Bernardinelli, 1999[Flack, H. D. & Bernardinelli, G. (1999). Acta Cryst. A55, 908-915.], 2000[Flack, H. D. & Bernardinelli, G. (2000). J. Appl. Cryst. 33, 1143-1148.]), and for further confirmation of the absolute configuration a determination using Bayesian statistics on Bijvoet differences (Hooft et al., 2008[Hooft, R. W. W., Straver, L. H. & Spek, A. L. (2008). J. Appl. Cryst. 41, 96-103.]), as implemented in the program PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]), was performed. This gave probability values p3(ok), p3(twin) and p3(wrong) of 1.000, 0.000 and 0.000, respectively. The calculation was based on 2343 Bijvoet pairs. The absolute structure parameter and standard uncertainty calculated using this method was 0.11 (4). An improvement in the absolute structure parameter can be made using a Student t distribution rather than a Gaussian distribution (Hooft et al., 2010[Hooft, R. W. W., Straver, L. H. & Spek, A. L. (2010). J. Appl. Cryst. 43, 665-668.]), giving -0.03 (13) for a [nu] parameter of 9.79. The overall p3 probability values calculated using this method remain unchanged at 1.000, 0.000 and 0.000.

The packing arrangement for (I)[link] is best descibed as an infinite two-dimensional hydrogen-bond network in the (100) plane of the unit cell. The primary building block of this network is the formation of an infinite chain of PH46 anions through a translational symmetry operation along the c axis of the unit cell. This inter­action is formed by a single hydrogen bond from the hy­droxy group of the substituted indenyl group, acting as donor, to a carbonyl O atom of the benzoate group, acting as acceptor [O3-H3A...O2i = 2.7113 (14) Å; see Table 1[link] for hydrogen-bond geometry and symmetry codes]. The hydrogen-bond network is extended by the formation of three further inter­actions linking the PH46 anion to the (1S)-1-phenyl­ethanaminium cation. These three inter­actions are formed by the -NH3+ ammonium group acting as donor to O atoms of three different PH46 anions acting as acceptors. Two of these inter­actions bridge the infinite chain along the c axis to form an R33(8) ring (Bernstein et al., 1995[Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.]); N1-H1...O1 = 2.6697 (16) Å and N1-H1C...O3ii = 2.8799 (18) Å. The -NH3+ ammonium group of the cation makes a further donor inter­action with the carbonyl O atom of a PH46 anion to form a larger overall two-dimensional network in the (100) plane; N1-H1D...O2iii = 2.7991 (17) Å. Fig. 3[link] shows the four hydrogen-bond inter­actions described above. An overall view of the crystal packing down the a axis of the unit cell is shown in Fig. 4[link]. All potential hydrogen-bond donors are utilized in the hydrogen-bonding arrangement, thus concurring with Etter's first rule of hydrogen bonding for organic compounds, which states that all good H-atom donors and acceptors are used in hydrogen bonding (Etter, 1990[Etter, M. C. (1990). Acc. Chem. Res. 23, 120-126.]).

[Figure 1]
Figure 1
The mol­ecular structure of (I)[link], showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level for non-H atoms. The dashed line indicates a hydrogen bond.
[Figure 2]
Figure 2
A scatterplot of C=C versus C-C bond lengths for inden-2-yl fragments in the CSD. See the Comment for an explanation of the symbols.
[Figure 3]
Figure 3
A view of part of the crystal packing of (I)[link]. The figure shows the four hydrogen-bond inter­actions (thin lines) and the formation of the R33(8) ring. [In the electronic version of the paper, mol­ecules generated by the symmetry codes (i), (ii) and (iii) are represented by the colours green, red and blue, respectively, with hydrogen bonds shown as thin turquoise lines and incomplete hydrogen bonds as thin red lines.] For clarity, only H atoms attached to heteroatoms are shown. (The symmetry codes are as given in Table 1[link].)
[Figure 4]
Figure 4
The packing of (I)[link], viewed down the a axis, with hydrogen bonds shown as thin lines. (In the electronic version of the paper, hydrogen bonds are shown as thin turquoise lines and incomplete hydrogen bonds as thin red lines.) For clarity, only H atoms attached to heteroatoms are shown.

2. Experimental

To an ethanol (7.5 ml) suspension of 4-{[(1S,2S)-1-hy­droxy-2,3-dihydro-1H,1'H-[2,2'-biinden]-2-yl]methyl}benzoic acid (PH46; 0.5 g, 1.31 mmol) was added (S)-(-)-[alpha]-methyl­benzyl­amine (0.2 ml, 1.5 mmol, 1.1 equivalents) portionwise. This reaction mixture was stirred for 2 h at 323 K and then left overnight at room temperature. Since no solid material was obtained, the solution was then concentrated under reduced pressure and diethyl ether (2 ml) was added to the flask. A white solid was immediately observed, which was further washed with diethyl ether (3 × 4 ml). The organic solvent was removed using a Pasteur pipette and the remaining white solid was dried in a vacuum oven at 313 K (yield 0.56 g, 85%). Crystals of the salt, (I)[link], were obtained by dissolving the crude material (ca 100 mg) in MeOH (3 ml) in a flat-bottomed sample tube, followed by the addition of diethyl ether (6 ml), which was added until the sample solution became slightly cloudy. The solution was filtered and placed in a dry-box at room temperature. A small amount of tetra­hydro­furan (ca 0.5 ml) was added to the diethyl ether-methanol solution. After 5 d, colourless crystals of (I)[link] were obtained (m.p. 467.2-467.9 K). 1H NMR (100 MHz, d6-DMSO): [delta] 1.33 (d, 3H, J = 6.7 Hz), 2.68 (d, 1H, J = 13.5 Hz), 2.94, (d, 1H, J = 15.5 Hz), 2.99 (d, 1H, J = 15.5 Hz), 3.17 (d, 1H, J = 13.6 Hz), 3.44 (d, 1H, J = 23.0 Hz), 3.58 (d, 1H, J = 23.0 Hz), 4.12 (q, 1H, J = 6.7 Hz), 5.05 (s, 1H), 5.85 (br s, 1H), 6.41 (s, 1H), 6.86 (d, 2H, J = 8.2 Hz), 7.08 (td, 1H, J = 7.3, 1.3 Hz), 7.14-7.44 (m, aromatic 12H), 7.65 (d, 2H, J = 8.2 Hz).

2.1.1. Crystal data
  • C8H12N+·C26H21O3-

  • Mr = 503.61

  • Monoclinic, P 21

  • a = 11.0350 (3) Å

  • b = 10.1713 (3) Å

  • c = 11.8533 (3) Å

  • [beta] = 93.678 (2)°

  • V = 1327.68 (6) Å3

  • Z = 2

  • Cu K[alpha] radiation

  • [mu] = 0.63 mm-1

  • T = 100 K

  • 0.50 × 0.47 × 0.42 mm

2.1.2. Data collection
  • Agilent SuperNova Dual diffractometer, with Cu at zero and an Atlas detector

  • Absorption correction: multi-scan (CrysAlis PRO; Agilent, 2011[Agilent (2011). CrysAlis PRO. Agilent Technologies, Yarnton, Oxfordshire, England.]) Tmin = 0.749, Tmax = 1.000

  • 25532 measured reflections

  • 5221 independent reflections

  • 5157 reflections with I > 2[sigma](I)

  • Rint = 0.026

2.1.3. Refinement
  • R[F2 > 2[sigma](F2)] = 0.035

  • wR(F2) = 0.098

  • S = 1.01

  • 5221 reflections

  • 362 parameters

  • 1 restraint

  • H atoms treated by a mixture of independent and constrained refinement

  • [Delta][rho]max = 0.21 e Å-3

  • [Delta][rho]min = -0.21 e Å-3

  • Absolute structure: Flack (1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]), with 2343 Friedel pairs

  • Flack parameter: 0.00 (15)

Table 1
Hydrogen-bond geometry (Å, °)

D-H...A D-H H...A D...A D-H...A
O3-H3A...O2i 0.85 (2) 1.86 (2) 2.7113 (14) 177 (2)
N1-H1B...O3ii 0.91 (2) 2.05 (2) 2.8799 (18) 151 (2)
N1-H1C...O2iii 0.92 (2) 1.88 (2) 2.7991 (17) 178 (2)
N1-H1D...O1 0.91 (2) 1.77 (2) 2.6697 (16) 174 (2)
Symmetry codes: (i) x, y, z-1; (ii) x, y, z+1; (iii) [-x+2, y+{\script{1\over 2}}, -z+2].

H atoms bonded to heteroatoms were located in a difference map and refined. Other H atoms were positioned geometrically and refined using a riding model (including free rotation about the methyl C-C bond), with C-H = 0.95-0.99 Å and Uiso(H) = 1.5Ueq(C) for methyl groups or 1.2Ueq(C) otherwise.

Data collection: CrysAlis PRO (Agilent, 2011[Agilent (2011). CrysAlis PRO. Agilent Technologies, Yarnton, Oxfordshire, England.]); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL and Mercury (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]); software used to prepare material for publication: SHELXTL and Mercury.


Supplementary data for this paper are available from the IUCr electronic archives (Reference: SK3440 ). Services for accessing these data are described at the back of the journal.


Acknowledgements

The authors are grateful to Andrew Carr of Phamorphix for his assistance with the 1H NMR assignment and to Professor A. L. Spek for helpful comments regarding the probability analysis.

References

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Acta Cryst (2012). C68, o323-o326   [ doi:10.1107/S0108270112031265 ]