(toluene-4-sulponyl-oxy)-phenyl]-propionic acid: Variations in L-tyrosine Backbone Conformation, Intramolecular Aromatic �– � Stacking and Short C–H�O Interactions

The syntheses and crystal structures of benzenesulfonylamino-3-(4-benzenesulfonyloxy-phenyl)-propionic acid (1) and 2-(toluene-4-sulfonylamino)-3-[4-(toluene-4-sulponyloxy)-phenyl]-propionic acid (2) are described. The L-tyrosine cores of the molecules show significant conformational differences. In 1, both organic molecules show intramolecular aromatic π–π stacking and in 2 a very short intermolecular Cα–H···O interaction is seen. The structures of 1 and 2 are compared with those of related materials. Crystal data: 12·H2O·MeOH [2(C21H19NO7S2)·H2O·CH4O], Mr = 973.04, monoclinic, P21 (No. 4), a = 8.0078 (4) A, b = 34.0704 (16) A, c = 8.5506 (3) A, β = 94.239 (3)°, V = 2326.47 (18) A3, Z = 2, T = 296 K, R(F) = 0.062, wR(F2) = 0.157, 2·H2O (C23H25NO7S2·H2O), Mr = 507.56, monoclinic, P21 (No. 4), a = 5.7171 (7) A, b = 24.359 (3) A, c = 9.1043 (10) A, β = 104.563 (6)°, V = 1227.2 (2) A3, Z = 2, T = 296 K, R(F) = 0.055, wR(F2) = 0.092.


Introduction
Tyrosine (C 9 H 11 NO 3 ) is one of the non-essential amino acids, which has been found as a constituent of naturally occurring proteins [1,2].The crystal structures of chiral L-tyrosine and racemic DLtyrosine were reported nearly 40 years ago, with both found to crystallize in their zwitterionic forms.The chiral form (space group P2 1 2 1 2 1 ) [3] features intermolecular N-HO c and N-HO h (c = carboxyl, h = hydroxyl) hydrogen bonds as well as O-HO h links, which generate a threedimensional network in the crystal.Although it was not identified at the time, a very short intermolecular C-HO c link (HO = 2.36 Å, compared to the van der Waals' contact distance of about 2.72 Å) arising from the stereogenic (chiral)  carbon atom also occurs [3].This is now recognized as an important general interaction in amino acids, peptides and even proteins [4,5].There is no possibility of aromatic - stacking in L-tyrosine, as the minimum separation of aromatic ring centroids is greater than 4.51 Å.In the racemic DL-tyrosine crystal structure [6] (space group Pna2 1 ), the zwitterions are linked by the same types of hydrogen bond, although the N-HO h bond is notably longer (HO = 2.31 Å).Again, a three-dimensional array of molecules is generated by the hydrogen bonds and an intermolecular C-HO c link also occurs: the equivalent  C atom is again involved, although the HO separation of 2.54 Å is significantly longer than that in the chiral form.

Structure of 1
The asymmetric unit of 1 2 •H 2 O•MeOH consists of two organic molecules (1A containing N1 and 1B containing N2), accompanied by one molecule of water and one molecule of methanol, which is consistent with the mixed solvent used for recrystallization (see Experimental section).1 has arisen from the reaction of L-tyrosine with two molecules of benzene sulfonyl chloride to form new S-N and S-O bonds in the product [10].It is notable that there are no other compounds containing L-tyrosine with an equivalent S-N bond in the Cambridge Structural Database (version 5.32 of November 2010 with two updates) [11].The transferrable hydrogen atoms (acidic protons) are clearly located on atoms O4 and O12, i.e. the molecules of 1 are not zwitterions.The absolute structure of 1 2 •H 2 O•MeOH is well established based on the refined value of -0.03 (8) of the Flack absolute structure parameter [12] and the S configurations of the stereogenic atoms in 1 (C6 in molecule A and C27 in molecule B) are consistent with that of the equivalent carbon atom in L-tyrosine itself [3].In order to simplify the comparison of 1 with related structures, we will designate atom-sets C13, C6, C5 and C4 (molecule A) and C34, C27, C26 and C25 (molecule B) as Ca, C, C and C, respectively.1A are similar to those in 2 (vide infra) but quite different to those in related N-acylated L-tyrosine derivatives (Table 1) and in L-tyrosine and DL-tyrosine.
The dihedral angles between the mean planes of the central C1/C2/C3/C4/C14/C15 aromatic ring and the terminal C7-C12 and C16-C21 rings in 1A are 7.9 (2) and 60.1 (2), respectively.The dihedral angle between the terminal rings is 66.9 (2).Equivalent values for 1B for the C22/C23/C24/C25/C35/C36, C28-C33 and C37-C42 rings are 6.1 (2), 53.5 (2) and 58.33 (19), respectively.The molecular conformation of 1A (Figure 2) leads to a striking intramolecular aromatic - stacking interaction between the C1/C2/C3/C4/C14/C15 and C7-C12 rings, with a centroidcentroid separation of 3.807 (3) Å.In 1B, which has a broadly similar overall shape (Figure 3), the separation between the equivalent rings is significantly longer at 4.067 (3) Å, which must indicate a much weaker interaction.A similar situation has been seen in a series of isostructural 5-phenyl-2-(benzalhydrazonyl)-1,3,4-thiadiazoles [13], in which some compounds show much shorter centroidcentroid separations than others.In the crystal of 1, the components are linked by N-HO and O-HO hydrogen bonds (Table 2).One of the N-HO links is to a C=O (carboxylic acid) acceptor oxygen atom and the other is to a sulfonyl O atom.Both -OH groups of the carboxylic acids form hydrogen bonds to the solvent molecules (one to a water O atom and one to a methanol O atom).In terms of the C6-H6 and C27-H27 groupings (i.e., the  carbon atoms), the first of these has a distant HO contact to a sulfonyl O atom (2.63 Å) whereas the second does not have any possible acceptor atoms within 3.5 Å.
Finally, the solvent molecules form further O-HO links and overall a two-dimensional network lying parallel to (010) arises.With this diversity of hydrogen-bond types observed in the structure, it is hard to draw conclusions as to the preferred hydrogen bonding modes of the organic molecule in 1, although the very short C α -HO link noted in the introduction is not present.Any intermolecular aromatic - stacking must be very weak, with a minimum centroid-centroid separation of greater than 4.06 Å.  7) 172 ( 7) The four values refer to the D-H, HA, DA separations (Å) and the D-HA angle (), respectively (also in Table 3).Symmetry codes: (i) x, y, z-1; (ii) x, y, z+1; (iii) x+1, y, z.

Structure of 2
The crystal structure of 2•H 2 O (Figure 4) shows that L-tyrosine has reacted with two equivalents of 4-toluenesulfonyl chloride to form the S1-N1 and S2-O7 bonds in the product and that a water molecule of crystallization is present.The S-configuration of the C7 stereogenic center [refined value of the Flack absolute structure parameter = -0.01(7)] is consistent with that of the L-tyrosine starting material and the bond lengths and angles in 2 may be regarded as normal.The molecule of 2 is nonzwitterionic, i.e. the proton is clearly attached to O4 and not to N1, as also seen for related molecules [5][6][7].In order to simplify the comparison with related structures, atoms C8, C7 C9 and C10 in 2 are referred to as Ca, C, C and C, respectively.
The conformation of the S1-N1-C-C bond in 2 is close to gauche [torsion angle = 129.7 (3)] as is N1-C-C-C [-61.1 ( 5)] whereas that of Ca-C-C-C is close to anti [174.4 (4)].The N1-C-Ca-O4 torsion angle of 165.3 (3) indicates that the -OH group of the carboxylic acid is close to anti with respect to the NH group.These torsion angles are broadly similar to the situation in molecule 1A but different to those of other L-tyrosine derivatives (Table 1).
The dihedral angles between the mean planes of the central C10-C15 aromatic ring and the terminal C1-C6 and C16-C21 rings are 44.8 (2) and 56.1 (2), respectively.The dihedral angle between the terminal rings is 81.4 (2).Their relative orientations, which are completely different to the conformations of molecules 1A and 1B in 1 indicate that no intramolecular aromatic - stacking interactions can occur in 2. In the crystal, the molecules are linked by N-HO and O-HO hydrogen bonds.The N-HO (see Table 3 for atom labels and symmetry codes) hydrogen bond links the organic molecules into C(5) chains propagating in the [100] direction.The carboxylic acid forms an O-HO bond to the water molecule and the water molecule forms two further O-HO links; one of the acceptors is the C=O bond of the carboxylic acid, the other is part of a sulfonyl group.Together, these bonds generate a three-dimensional network.An extremely short intermolecular C-HO bond (2.34 Å) from the -carbon atom occurs in 2, as does a longer C-HO interaction from C9 (the  carbon atom).There are no aromatic - stacking interactions in the crystal of 2, the shortest centroid-centroid separation being longer than 4.5 Å.

Syntheses
All reagents were purchased from commercial sources and used without further purification and compound 1 was synthesized following the "green" literature method [10].L-Tyrosine (0.50 g, 5.52 mmol) was dissolved in 15 mL of 1 M Na 2 CO 3 solution.Benzene sulfonyl chloride (1.41 mL, 11.04 mmol) was suspended in the solution with stirring at room temperature.The pH was maintained at 8-9 until a clear solution resulted.Then, the pH was adjusted to 1-2, using 1 M HCl solution.The white precipitate obtained was filtered, washed with distilled water, dried and recrystallized from methanol and water (98:2 v/v) to yield colorless blocks.Calc.(obs.)analysis (%) for 1 (C 21 H 19 NO 7 S 2 ): C 54.65 (54.65),H 4.15 (4.15), N 3.04 (3.03), S 13.90 (13.90).

Data collections and refinements
Intensity data for the solvated crystals of 1 and 2 were collected at 296 K using a Bruker Kappa APEXII CCD diffractometer.The unit-cell refinements and data reductions were carried out with SAINT [14].The structures were solved by direct methods with SHELXS-97 and the atomic models refined against F 2 with SHELXL-97 [15].The "observed data" criterion for calculating the R(F) residuals was set as I > 2σ(I).The carbon-bound H atoms were geometrically placed and refined as riding atoms with U iso (H) = 1.2-1.5Ueq (C).The methyl groups were allowed to rotate, but not to tip, to best fit the electron density.The O-and N-bond H atoms were located in difference maps and refined as riding atoms in their as-found relative positions with U iso (H) = 1.2U eq (carrier).Because of the poor

Figure 2 .
Figure 2. The molecular structure of molecule 1A showing 40% displacement ellipsoids.The intramolecular - stacking interaction is indicated by a double-dashed line.

Figure 3 .
Figure 3.The molecular structure of molecule 1B showing 50% displacement ellipsoids.The intramolecular - stacking interaction is indicated by a double-dashed line.

Figure 4 .
Figure 4.The molecular structure of 2•H 2 O showing 40% displacement ellipsoids.The O-HO hydrogen bond is indicated by a double-dashed line.