Download citation
Download citation
link to html
Notwithstanding its simple structure, the chemistry of nitric oxide (NO) is com­plex. As a radical, NO is highly reactive. NO also has profound effects on the cardiovascular system. In order to regulate NO levels, direct therapeutic inter­ventions include the development of numerous NO donors. Most of these donors release NO in a single high-concentration burst, which is deleterious. N-Nitro­sated secondary amines release NO in a slow, sustained, and rate-tunable manner. Two new precursors to sustained NO-releasing materials have been characterized. N-[2-(3,4-Di­meth­oxy­phen­yl)eth­yl]-2,4-di­nitro­aniline, C16H17N3O6, (I), crystallizes with one independent mol­ecule in the asymmetric unit. The adjacent amine and nitro groups form an intra­molecular N-H...O hydrogen bond. The anti conformation about the phenyl­ethyl-to-aniline C-N bond leads to the planes of the arene and aniline rings being approximately perpendicular. Mol­ecules are linked into dimers by weak inter­molecular N-H...O hydrogen bonds such that each amine H atom participates in a three-center inter­action with two nitro O atoms. The dimers pack so that the arene rings of adjacent mol­ecules are not parallel and [pi]-[pi] inter­actions do not appear to be favored. N-(4-Methyl­sulfonyl-2-nitro­phen­yl)-L-phenyl­alanine, C16H16N2O6S, (II), with an optically active center, also crystallizes with one unique mol­ecule in the asymmetric unit. The L enanti­omer was established via the configuration of the starting material and was confirmed by refinement of the Flack parameter. As in (I), there is an intra­molecular N-H...O hydrogen bond between adjacent amine and nitro groups. The conformation of the mol­ecule is such that the arene rings display a dihedral angle of ca 60°. Unlike (I), mol­ecules are not linked via inter­molecular N-H...O hydrogen bonds. Rather, the carb­oxy­lic acid H atom forms a classic, approximately linear, O-H...O hydrogen bond with a sulfone O atom. Pairs of mol­ecules related by twofold rotation axes are linked into dimers by two such inter­actions. The packing pattern features a zigzag arrangement of the arene rings without apparent [pi]-[pi] inter­actions. These structures are compared with reported analogues, revealing significant differences in mol­ecular conformation, inter­molecular inter­actions, and packing that result from modest changes in functional groups. The structures are discussed in terms of potential NO-release capability.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229616005763/qs3054sup1.cif
Contains datablocks global, C16H17N3O6, C16H16N2O6S

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229616005763/qs3054C16H17N3O6sup2.hkl
Contains datablock C16H17N3O6

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S2053229616005763/qs3054C16H16N2O6Ssup3.hkl
Contains datablock C16H16N2O6S

CCDC references: 1472725; 1472724

Introduction top

Nitro­gen monoxide, commonly known as nitric oxide (NO), is produced in vivo from L-arginine (Miller & Megson, 2007). The conversion of L-arginine to NO and citrulline is catalyzed by nitric oxide synthases along with a series of cofactors. Notwithstanding its simple structure, the chemistry of NO is complex. As a radical, NO is highly reactive and it is consumed quickly within a radius of 100 µm. Therefore NO, which has profound effects on the cardiovascular system, must be produced slowly in small fluxes at the inner walls of blood vessels by endothelial cells (Zhou et al., 2006).

Since the discovery of the vaso-relaxing effects of NO (Cauwels, 2007), its physiological impact on the cardiovascular system has been the most studied. Endothelial cells, which line the lumen of the blood vessels, produce NO from L-arginine. The conversion is catalyzed by endothelial nitric oxide synthase (eNOS). The lypophilicity, small size, and chemical lability of NO allows for easy passage through cell membranes without the use of channels or receptors to neighboring cells (Miller et al., 2004). NO's effects on the underlying vascular smooth muscle cells (VSMC) include vasodilation and inhibition of VSMC proliferation as well as its migration to the endothelial layer (Jeremy et al., 1999).

The salutary roles of NO in the functioning of the cardiovascular, nervous, respiratory, and immune systems in addition to its protecting functions of the heart, brain, and kidneys have been well documented (Jobgen et al., 2006). On the other hand, high NO concentrations cause apoptosis and other complications including septic and hemorrhagic shock, multiple sclerosis, neurodegenerative diseases, rheumatoid arthritis, ulcerative colitis, and cancer (Jeremy et al., 1999; Lundberg et al., 2015). A wide variety of diseases and disorders have been ascribed to NO malfunctions. These maladies include endothelial dysfunction, hypertension, cardiovascular disease, asthma, pulmonary hypertension, erectile dysfunction, preeclampsia, and insulin resistance (Giles, 2006). The overall effects in the cardiovascular system can lead to further endothelial injury and atherosclerosis (Stasch et al., 2011).

In order to better regulate NO levels, several recommendations have been made, which include a polyphenol-rich diet (Anter et al., 2004), moderate alcohol consumption (Lucas et al., 2005), and regular exercise (Hambrecht et al., 2003). Direct therapeutic inter­ventions include the development of numerous NO donors. Most of these donors release NO in a single high concentration burst, which is deleterious (Cai et al., 2005). We have reported a series of N-nitro­sated secondary amines that release NO in a slow, sustained, and rate-tunable manner (Wang et al., 2009; Yu et al., 2011; Curtis et al., 2013, 2014; Lagoda et al., 2014). Furthermore, the released NO has been shown to inhibit the proliferation of human aortic smooth muscle cells, a contributing factor to the progression of atherosclerosis (Yu et al., 2011; Curtis et al., 2013).

We report herein the syntheses and X-ray crystal structures of two secondary amines, the precursors to NO donors. These secondary amines, namely N-[2-(3,4-di­meth­oxy­phenyl)­ethyl]-2,4-di­nitro­aniline, (I), and N-(4-methyl­sulfonyl-2-nitro­phenyl)-L-phenyl­alanine, (II) differ in their hydro­philic and lipophilic balances (HLBs). We hypothesize that the HLB of a NO donor will play a crucial role in the overall NO release rates of these compounds in an aqueous medium (phosphate-buffered saline solution). Compound (I) was prepared by the reaction of 3,4-di­meth­oxy­phenethyl­amine and an activated aromatic monofluoride, i.e. 2,4-di­nitro­fluoro­benzene. The synthesis of (II) was accomplished by the reaction of L-phenyl­alanine with 4-methyl­sulfonyl-2-nitro­fluoro­benzene.

Experimental top

Synthesis and crystallization top

For the synthesis of (I), sodium bicarbonate (0.373 g, 4.44 mmol), 3,4-di­meth­oxy­phenethyl­amine (97%) (0.539 g, 2.88 mmol), and 2,4-di­nitro­fluoro­benzene (0.536 g, 2.88 mmol) were all weighed separately in glass vials and transferred to a 50 ml round-bottomed flask equipped with a magnetic stir bar. The vials were rinsed with N,N-di­methyl­acetamide (DMAC, 10 ml) and the rinses transferred to the reaction vessel. The reaction mixture was allowed to stir at room temperature for 1 h, after which the mixture was poured onto a saturated sodium chloride solution (100 ml) to precipitate the crude product. The crude product was extracted with di­chloro­methane (75 ml) and washed twice with deionized water (100 ml). The organic layer was dried over anhydrous magnesium sulfate followed by gravity filtration. The solvent was evaporated at reduced pressure using a rotary evaporator. The crude product, an orange solid, was recrystallized from a di­chloro­methane–di­ethyl ether solution (1:1 v/v) to form crystals suitable for X-ray diffraction (yield 55%; m.p. 379–380 K). 1H NMR (300 MHz, CDCl3): δ 9.10 (d, 1H), 8.57 (s, 1H), 8.24 (m, 1H), 6.84 (m, 4H), 3.89 (s, 3H), 3.86 (s, 3H), 3.64 (q, 2H), 3.02 (t, 2H); 13C NMR (300 MHz, CDCl3): δ 149.29, 148.13, 148.12, 136.01, 130.29, 129.66, 124.54, 120.71, 113.85, 111.68, 111.57, 55.88, 45.10, 34.50; IR (NaCl, ν, cm-1): 3357, 3107, 2934, 1621, 1590, 1517, 1465, 1423, 1335, 1305, 1263, 1238, 1196, 1144, 1084, 1027; MS (m/z) (% base peak): 347 (8), 281 (5), 207 (18), 166 (22), 151 (100), 137 (8), 107 (11), 77 (16).

Compound (II) was prepared by dissolving 4-methyl­sulfonyl-2-nitro­fluoro­benzene (0.565 g, 2.58 mmol) in tetra­hydro­furan (THF, 15 ml) in a 100 ml round-bottomed flask equipped with a magnetic stir bar in the presence of sodium bicarbonate (2.185 g, 24.6 mmol). The reaction mixture turned yellow upon the addition of sodium bicarbonate. L-Phenyl­alanine (0.406 g, 2.46 mmol) was dissolved in deionized water (25 ml) in a 50 ml beaker and the solution was subsequently transferred into the reaction vessel using a funnel. Water (5 ml) was used to wash the funnel. The reaction vessel was fitted with an air condenser and the mixture was allowed to stir at room temperature for 12 h, after which the THF was removed at reduced pressure using a rotatory evaporator. The resulting aqueous solution was washed with di­ethyl ether (50 ml) to remove excess starting material. The crude product was precipitated via acidification of the aqueous solution (pH ca 2) using 12 M hydro­chloric acid. The precipitated crude product was extracted using ethyl acetate (50 ml), which was collected and washed with deionized water (50 ml) three times. The organic layer containing the crude product was dried over anhydrous magnesium sulfate followed by gravity filtration. The solvent was removed using a rotary evaporator to yield a bright yellow solid. Crystals suitable for X-ray diffraction were obtained by recrystallization from a di­chloro­methane–hexane solution (4:1 v/v) (yield 58%; m.p. 443–445 K). 1H NMR (300 MHz, DMSO-d6): δ 8.58 (d, 1H), 8.50 (d, 1H), 7.92 (dd, 1H), 7.27–7.15 (overlapping peaks, 6H), 4.94 (q, 1H), 3.24 (d, 2H), 3.20 (s, 3H); 13C NMR (300 MHz, DMSO-d6): δ 172.25, 146.61, 136.40, 134.13, 130.82, 129.84, 128.83, 127.75, 127.40, 127.35, 116.67, 56.33, 44.09, 37.04; IR (solid, ν, cm-1): 3379, 3176, 3090, 1733, 1611, 1518, 1367, 1299, 1145; ESI–MS (m/z) calculated for C16H16N2O6S [M - H]- 363.38, found 363.03.

Refinement top

Crystal data, data collection and structure refinement details are summarized in Table 1. H atoms on C atoms were included in calculated positions as riding atoms, with C—H bond lengths of 0.95 (aryl), 0.98 (methyl), 0.99 (methyl­ene) and 1.00 Å (methine). H atoms on N and O atoms were located from difference Fourier syntheses and were refined isotropically without any restraints (see the distances in Tables 1 and 2). For (II), the Flack x = 0.01 (4) was determined using 1620 quotients [(I+)-(I-)]/[(I+)+(I-)], and the probability P2 = 1.000, G = 0.97 (8), and Hooft y = 0.02 (3) from an analysis of the Bijvoet differences (Hooft et al., 2008). We acknowledge that the crystal of (II) was longer than optimal, but the needles were difficult to cut cleanly and the refinement results do not appear to have been adversely affected.

Results and discussion top

N-[2-(3,4-Di­meth­oxy­phenyl)­ethyl]-2,4-di­nitro­aniline, (I), crystallizes in the monoclinic space group P21/c with one independent molecule in the asymmetric unit (Fig. 1). The adjacent amine and nitro groups form an intra­molecular N—H···O hydrogen bond (Table 2) consistent with previous observations in molecules of this type (Wade et al., 2013; Payne et al., 2010; Gangopadhyay & Radhakrishnan, 2000; Clegg et al., 1994; Panunto et al., 1987). Aniline (I) is chemically very similar to 2,4-di­nitro-N-(2-phenyl­ethyl)­aniline, whose structure we reported recently (Wade et al., 2013), with (I) differing only in the presence of the meth­oxy groups in the 3- and 4-positions on the phenyl ring of the phenyl­ethyl group. In spite of the similarity of the two molecules, there are some notable differences in the conformation between them. Most importantly, the dihedral angle between the planes of the two six-membered arene rings in (I) is ca 106°, while the rings in 2,4-di­nitro-N-(2-phenyl­ethyl)­aniline are nearly parallel (dihedral angle ca 2°). This difference is attributable primarily to the C1—N1—C7—C8 torsion angle, which is 177.32 (12)° in (I) and -85.5 (2)° in the unsubstituted analog. Other less drastic differences include rotations about the N1—C1 [C7—N1—C1—C6 torsion angle = -10.9 (2)° in (I) versus -0.9 (2)°] and C4—N3 [torsion angle O3—N3—C4—C3 = -12.6 (2)° in (I) versus -1.2 (2)°] bonds.

As was the case in 2,4-di­nitro-N-(2-phenyl­ethyl)­aniline, neighboring molecules of (I) are related across centers of inversion so as to permit an inter­molecular N—H···O hydrogen bond between the amine group on one molecule and the nitro group on the other molecule (Fig. 2a). The amine H1 atom thus participates in a three-center hydrogen bond with two nitro O1 atoms and each O1 atom serves as an acceptor for both intra- and inter­molecular hydrogen bonds (Table 2). The inter­molecular H1···O1i distance of 2.822 (18) Å [symmetry code: (i) -x+1, -y+1, -z+1] is significantly longer than the distance of 2.381 (19) Å observed in 2,4-di­nitro-N-(2-phenyl­ethyl)­aniline. It is also beyond the typical range for this type of amine–nitro N—H···O inter­action (Panunto et al., 1987), making it a weak hydrogen bond at best. The nonparallel intra­molecular arrangement of the arene rings and the overall bent shape of the molecules of (I), among other factors, lead to a packing pattern (Fig. 2b) in which ππ stacking inter­actions appear to be precluded.

The enanti­omeric N-(4-methyl­sulfonyl-2-nitro­phenyl)-L-phenyl­alanine, (II), crystallizes in the noncentrosymmetric monoclinic space group C2 with one molecule in the asymmetric unit (Fig. 3). The absolute configuration was assigned based on the known configuration of the L-phenyl­alanine starting material and established through refinement of the Flack parameter (Parsons et al., 2013). As in (I), the amine H atom forms an intra­molecular N—H···O hydrogen bond with the adjacent nitro group (Table 3). The C—O bond lengths of the carb­oxy­lic acid group are consistent with the placement of the acidic H atom on atom O6 [C9—O6 = 1.324 (3) Å] and with atom O5 being part of a free carbonyl group [C9—O5 = 1.191 (3) Å]. L-Phenyl­alanine(II) differs from 4-methyl­sulfonyl-2-nitro-N-(2-phenyl­ethyl)­aniline (Wade et al., 2013) only in the presence of the carb­oxy­lic acid group on the phenyl­ethyl group.

As was the case with (I), the presence of this one additional group substanti­ally changes the conformation of the molecule. The dihedral angle between the two arene rings is ca 62° in (II), but ca 107° in 4-methyl­sulfonyl-2-nitro-N-(2-phenyl­ethyl)­aniline. The difference is attributable primarily to the torsion angles C1—N1—C8—C10 [149.3 (2)° in (II) versus -175.70 (7)° in the parent] and N1—C8—C10—C11 [-178.12 (18)° in (II) versus -61.20 (8)°]. In addition, there are smaller but noticeable differences in the positioning of the nitro [O1—N2—C2—C1 torsion angle -20.2 (3)° in (II) versus -4.4 (1)°] and methyl­sulfonyl [C7—S1—C4—C5 torsion angle 81.4 (2)° in (II) versus 110.98 (6)°] groups.

Unlike (I), the molecules of (II) are not joined through inter­molecular amine–nitro N—H···O hydrogen bonds. The molecules of (II) are positioned with the amine and nitro groups of adjacent molecules directed towards each other (Fig. 4a), but the closest inter­molecular distance H1···O2(-x+3/2, y+1/2, -z+1) of ca 3.1 Å is too great even for a three-center hydrogen bond. Instead, molecules related by twofold rotation along the b axis are linked into dimers by two inter­molecular O—H···O hydrogen bonds between the carb­oxy­lic acid and sulfone groups (Table 3). Similar O—H···O inter­molecular inter­actions between hy­droxy and sulfone groups have been observed in 4,4'-sulfonyl­diphenol (Glidewell & Ferguson, 1996). These inter­actions and the chirality of the structure of (II) preclude the familiar inversion-related hydrogen bonding between carb­oxy­lic acid groups seen in many classic structures. The overall packing is such that the arene rings form a zigzag pattern (Fig. 4b) that is devoid of ππ inter­actions between nearby parallel rings.

Recent unpublished work in our laboratory has indicated that molecules with more hydro­philic character have lower NO-release rates in aqueous solution than similar molecules with greater lipophilic character. We believe that molecules with higher HLB (more hydro­philic) form more organized micelles that restrict NO release, while molecules with lower HLB (more lipophilic) form less organized micelles that are less restrictive of NO release (Israelachvili, 2011). The presence of the carb­oxy­lic acid group on (II) would give it a greater hydro­philic balance than the previously reported 4-methyl­sulfonyl-2-nitro-N-(2-phenyl­ethyl)­aniline (Wade et al., 2013). On this basis, we would expect (II) to show a lower NO-release rate. By contrast, the addition of the two meth­oxy groups on (I) might be expected to lower the HLB relative to 2,4-di­nitro-N-(2-phenyl­ethyl)­aniline (Wade et al., 2013) (the melting point of (I) is 379 K, while that of the parent without the meth­oxy groups is 425 K suggesting weaker inter­molecular attractions in (I), leading to a higher NO-release rate. Ongoing experiments are underway to test these hypotheses and develop a better understanding of the relationship between structure and NO-release behavior.

Structure description top

Nitro­gen monoxide, commonly known as nitric oxide (NO), is produced in vivo from L-arginine (Miller & Megson, 2007). The conversion of L-arginine to NO and citrulline is catalyzed by nitric oxide synthases along with a series of cofactors. Notwithstanding its simple structure, the chemistry of NO is complex. As a radical, NO is highly reactive and it is consumed quickly within a radius of 100 µm. Therefore NO, which has profound effects on the cardiovascular system, must be produced slowly in small fluxes at the inner walls of blood vessels by endothelial cells (Zhou et al., 2006).

Since the discovery of the vaso-relaxing effects of NO (Cauwels, 2007), its physiological impact on the cardiovascular system has been the most studied. Endothelial cells, which line the lumen of the blood vessels, produce NO from L-arginine. The conversion is catalyzed by endothelial nitric oxide synthase (eNOS). The lypophilicity, small size, and chemical lability of NO allows for easy passage through cell membranes without the use of channels or receptors to neighboring cells (Miller et al., 2004). NO's effects on the underlying vascular smooth muscle cells (VSMC) include vasodilation and inhibition of VSMC proliferation as well as its migration to the endothelial layer (Jeremy et al., 1999).

The salutary roles of NO in the functioning of the cardiovascular, nervous, respiratory, and immune systems in addition to its protecting functions of the heart, brain, and kidneys have been well documented (Jobgen et al., 2006). On the other hand, high NO concentrations cause apoptosis and other complications including septic and hemorrhagic shock, multiple sclerosis, neurodegenerative diseases, rheumatoid arthritis, ulcerative colitis, and cancer (Jeremy et al., 1999; Lundberg et al., 2015). A wide variety of diseases and disorders have been ascribed to NO malfunctions. These maladies include endothelial dysfunction, hypertension, cardiovascular disease, asthma, pulmonary hypertension, erectile dysfunction, preeclampsia, and insulin resistance (Giles, 2006). The overall effects in the cardiovascular system can lead to further endothelial injury and atherosclerosis (Stasch et al., 2011).

In order to better regulate NO levels, several recommendations have been made, which include a polyphenol-rich diet (Anter et al., 2004), moderate alcohol consumption (Lucas et al., 2005), and regular exercise (Hambrecht et al., 2003). Direct therapeutic inter­ventions include the development of numerous NO donors. Most of these donors release NO in a single high concentration burst, which is deleterious (Cai et al., 2005). We have reported a series of N-nitro­sated secondary amines that release NO in a slow, sustained, and rate-tunable manner (Wang et al., 2009; Yu et al., 2011; Curtis et al., 2013, 2014; Lagoda et al., 2014). Furthermore, the released NO has been shown to inhibit the proliferation of human aortic smooth muscle cells, a contributing factor to the progression of atherosclerosis (Yu et al., 2011; Curtis et al., 2013).

We report herein the syntheses and X-ray crystal structures of two secondary amines, the precursors to NO donors. These secondary amines, namely N-[2-(3,4-di­meth­oxy­phenyl)­ethyl]-2,4-di­nitro­aniline, (I), and N-(4-methyl­sulfonyl-2-nitro­phenyl)-L-phenyl­alanine, (II) differ in their hydro­philic and lipophilic balances (HLBs). We hypothesize that the HLB of a NO donor will play a crucial role in the overall NO release rates of these compounds in an aqueous medium (phosphate-buffered saline solution). Compound (I) was prepared by the reaction of 3,4-di­meth­oxy­phenethyl­amine and an activated aromatic monofluoride, i.e. 2,4-di­nitro­fluoro­benzene. The synthesis of (II) was accomplished by the reaction of L-phenyl­alanine with 4-methyl­sulfonyl-2-nitro­fluoro­benzene.

N-[2-(3,4-Di­meth­oxy­phenyl)­ethyl]-2,4-di­nitro­aniline, (I), crystallizes in the monoclinic space group P21/c with one independent molecule in the asymmetric unit (Fig. 1). The adjacent amine and nitro groups form an intra­molecular N—H···O hydrogen bond (Table 2) consistent with previous observations in molecules of this type (Wade et al., 2013; Payne et al., 2010; Gangopadhyay & Radhakrishnan, 2000; Clegg et al., 1994; Panunto et al., 1987). Aniline (I) is chemically very similar to 2,4-di­nitro-N-(2-phenyl­ethyl)­aniline, whose structure we reported recently (Wade et al., 2013), with (I) differing only in the presence of the meth­oxy groups in the 3- and 4-positions on the phenyl ring of the phenyl­ethyl group. In spite of the similarity of the two molecules, there are some notable differences in the conformation between them. Most importantly, the dihedral angle between the planes of the two six-membered arene rings in (I) is ca 106°, while the rings in 2,4-di­nitro-N-(2-phenyl­ethyl)­aniline are nearly parallel (dihedral angle ca 2°). This difference is attributable primarily to the C1—N1—C7—C8 torsion angle, which is 177.32 (12)° in (I) and -85.5 (2)° in the unsubstituted analog. Other less drastic differences include rotations about the N1—C1 [C7—N1—C1—C6 torsion angle = -10.9 (2)° in (I) versus -0.9 (2)°] and C4—N3 [torsion angle O3—N3—C4—C3 = -12.6 (2)° in (I) versus -1.2 (2)°] bonds.

As was the case in 2,4-di­nitro-N-(2-phenyl­ethyl)­aniline, neighboring molecules of (I) are related across centers of inversion so as to permit an inter­molecular N—H···O hydrogen bond between the amine group on one molecule and the nitro group on the other molecule (Fig. 2a). The amine H1 atom thus participates in a three-center hydrogen bond with two nitro O1 atoms and each O1 atom serves as an acceptor for both intra- and inter­molecular hydrogen bonds (Table 2). The inter­molecular H1···O1i distance of 2.822 (18) Å [symmetry code: (i) -x+1, -y+1, -z+1] is significantly longer than the distance of 2.381 (19) Å observed in 2,4-di­nitro-N-(2-phenyl­ethyl)­aniline. It is also beyond the typical range for this type of amine–nitro N—H···O inter­action (Panunto et al., 1987), making it a weak hydrogen bond at best. The nonparallel intra­molecular arrangement of the arene rings and the overall bent shape of the molecules of (I), among other factors, lead to a packing pattern (Fig. 2b) in which ππ stacking inter­actions appear to be precluded.

The enanti­omeric N-(4-methyl­sulfonyl-2-nitro­phenyl)-L-phenyl­alanine, (II), crystallizes in the noncentrosymmetric monoclinic space group C2 with one molecule in the asymmetric unit (Fig. 3). The absolute configuration was assigned based on the known configuration of the L-phenyl­alanine starting material and established through refinement of the Flack parameter (Parsons et al., 2013). As in (I), the amine H atom forms an intra­molecular N—H···O hydrogen bond with the adjacent nitro group (Table 3). The C—O bond lengths of the carb­oxy­lic acid group are consistent with the placement of the acidic H atom on atom O6 [C9—O6 = 1.324 (3) Å] and with atom O5 being part of a free carbonyl group [C9—O5 = 1.191 (3) Å]. L-Phenyl­alanine(II) differs from 4-methyl­sulfonyl-2-nitro-N-(2-phenyl­ethyl)­aniline (Wade et al., 2013) only in the presence of the carb­oxy­lic acid group on the phenyl­ethyl group.

As was the case with (I), the presence of this one additional group substanti­ally changes the conformation of the molecule. The dihedral angle between the two arene rings is ca 62° in (II), but ca 107° in 4-methyl­sulfonyl-2-nitro-N-(2-phenyl­ethyl)­aniline. The difference is attributable primarily to the torsion angles C1—N1—C8—C10 [149.3 (2)° in (II) versus -175.70 (7)° in the parent] and N1—C8—C10—C11 [-178.12 (18)° in (II) versus -61.20 (8)°]. In addition, there are smaller but noticeable differences in the positioning of the nitro [O1—N2—C2—C1 torsion angle -20.2 (3)° in (II) versus -4.4 (1)°] and methyl­sulfonyl [C7—S1—C4—C5 torsion angle 81.4 (2)° in (II) versus 110.98 (6)°] groups.

Unlike (I), the molecules of (II) are not joined through inter­molecular amine–nitro N—H···O hydrogen bonds. The molecules of (II) are positioned with the amine and nitro groups of adjacent molecules directed towards each other (Fig. 4a), but the closest inter­molecular distance H1···O2(-x+3/2, y+1/2, -z+1) of ca 3.1 Å is too great even for a three-center hydrogen bond. Instead, molecules related by twofold rotation along the b axis are linked into dimers by two inter­molecular O—H···O hydrogen bonds between the carb­oxy­lic acid and sulfone groups (Table 3). Similar O—H···O inter­molecular inter­actions between hy­droxy and sulfone groups have been observed in 4,4'-sulfonyl­diphenol (Glidewell & Ferguson, 1996). These inter­actions and the chirality of the structure of (II) preclude the familiar inversion-related hydrogen bonding between carb­oxy­lic acid groups seen in many classic structures. The overall packing is such that the arene rings form a zigzag pattern (Fig. 4b) that is devoid of ππ inter­actions between nearby parallel rings.

Recent unpublished work in our laboratory has indicated that molecules with more hydro­philic character have lower NO-release rates in aqueous solution than similar molecules with greater lipophilic character. We believe that molecules with higher HLB (more hydro­philic) form more organized micelles that restrict NO release, while molecules with lower HLB (more lipophilic) form less organized micelles that are less restrictive of NO release (Israelachvili, 2011). The presence of the carb­oxy­lic acid group on (II) would give it a greater hydro­philic balance than the previously reported 4-methyl­sulfonyl-2-nitro-N-(2-phenyl­ethyl)­aniline (Wade et al., 2013). On this basis, we would expect (II) to show a lower NO-release rate. By contrast, the addition of the two meth­oxy groups on (I) might be expected to lower the HLB relative to 2,4-di­nitro-N-(2-phenyl­ethyl)­aniline (Wade et al., 2013) (the melting point of (I) is 379 K, while that of the parent without the meth­oxy groups is 425 K suggesting weaker inter­molecular attractions in (I), leading to a higher NO-release rate. Ongoing experiments are underway to test these hypotheses and develop a better understanding of the relationship between structure and NO-release behavior.

Synthesis and crystallization top

For the synthesis of (I), sodium bicarbonate (0.373 g, 4.44 mmol), 3,4-di­meth­oxy­phenethyl­amine (97%) (0.539 g, 2.88 mmol), and 2,4-di­nitro­fluoro­benzene (0.536 g, 2.88 mmol) were all weighed separately in glass vials and transferred to a 50 ml round-bottomed flask equipped with a magnetic stir bar. The vials were rinsed with N,N-di­methyl­acetamide (DMAC, 10 ml) and the rinses transferred to the reaction vessel. The reaction mixture was allowed to stir at room temperature for 1 h, after which the mixture was poured onto a saturated sodium chloride solution (100 ml) to precipitate the crude product. The crude product was extracted with di­chloro­methane (75 ml) and washed twice with deionized water (100 ml). The organic layer was dried over anhydrous magnesium sulfate followed by gravity filtration. The solvent was evaporated at reduced pressure using a rotary evaporator. The crude product, an orange solid, was recrystallized from a di­chloro­methane–di­ethyl ether solution (1:1 v/v) to form crystals suitable for X-ray diffraction (yield 55%; m.p. 379–380 K). 1H NMR (300 MHz, CDCl3): δ 9.10 (d, 1H), 8.57 (s, 1H), 8.24 (m, 1H), 6.84 (m, 4H), 3.89 (s, 3H), 3.86 (s, 3H), 3.64 (q, 2H), 3.02 (t, 2H); 13C NMR (300 MHz, CDCl3): δ 149.29, 148.13, 148.12, 136.01, 130.29, 129.66, 124.54, 120.71, 113.85, 111.68, 111.57, 55.88, 45.10, 34.50; IR (NaCl, ν, cm-1): 3357, 3107, 2934, 1621, 1590, 1517, 1465, 1423, 1335, 1305, 1263, 1238, 1196, 1144, 1084, 1027; MS (m/z) (% base peak): 347 (8), 281 (5), 207 (18), 166 (22), 151 (100), 137 (8), 107 (11), 77 (16).

Compound (II) was prepared by dissolving 4-methyl­sulfonyl-2-nitro­fluoro­benzene (0.565 g, 2.58 mmol) in tetra­hydro­furan (THF, 15 ml) in a 100 ml round-bottomed flask equipped with a magnetic stir bar in the presence of sodium bicarbonate (2.185 g, 24.6 mmol). The reaction mixture turned yellow upon the addition of sodium bicarbonate. L-Phenyl­alanine (0.406 g, 2.46 mmol) was dissolved in deionized water (25 ml) in a 50 ml beaker and the solution was subsequently transferred into the reaction vessel using a funnel. Water (5 ml) was used to wash the funnel. The reaction vessel was fitted with an air condenser and the mixture was allowed to stir at room temperature for 12 h, after which the THF was removed at reduced pressure using a rotatory evaporator. The resulting aqueous solution was washed with di­ethyl ether (50 ml) to remove excess starting material. The crude product was precipitated via acidification of the aqueous solution (pH ca 2) using 12 M hydro­chloric acid. The precipitated crude product was extracted using ethyl acetate (50 ml), which was collected and washed with deionized water (50 ml) three times. The organic layer containing the crude product was dried over anhydrous magnesium sulfate followed by gravity filtration. The solvent was removed using a rotary evaporator to yield a bright yellow solid. Crystals suitable for X-ray diffraction were obtained by recrystallization from a di­chloro­methane–hexane solution (4:1 v/v) (yield 58%; m.p. 443–445 K). 1H NMR (300 MHz, DMSO-d6): δ 8.58 (d, 1H), 8.50 (d, 1H), 7.92 (dd, 1H), 7.27–7.15 (overlapping peaks, 6H), 4.94 (q, 1H), 3.24 (d, 2H), 3.20 (s, 3H); 13C NMR (300 MHz, DMSO-d6): δ 172.25, 146.61, 136.40, 134.13, 130.82, 129.84, 128.83, 127.75, 127.40, 127.35, 116.67, 56.33, 44.09, 37.04; IR (solid, ν, cm-1): 3379, 3176, 3090, 1733, 1611, 1518, 1367, 1299, 1145; ESI–MS (m/z) calculated for C16H16N2O6S [M - H]- 363.38, found 363.03.

Refinement details top

Crystal data, data collection and structure refinement details are summarized in Table 1. H atoms on C atoms were included in calculated positions as riding atoms, with C—H bond lengths of 0.95 (aryl), 0.98 (methyl), 0.99 (methyl­ene) and 1.00 Å (methine). H atoms on N and O atoms were located from difference Fourier syntheses and were refined isotropically without any restraints (see the distances in Tables 1 and 2). For (II), the Flack x = 0.01 (4) was determined using 1620 quotients [(I+)-(I-)]/[(I+)+(I-)], and the probability P2 = 1.000, G = 0.97 (8), and Hooft y = 0.02 (3) from an analysis of the Bijvoet differences (Hooft et al., 2008). We acknowledge that the crystal of (II) was longer than optimal, but the needles were difficult to cut cleanly and the refinement results do not appear to have been adversely affected.

Computing details top

For both compounds, data collection: CrystalClear-SM Expert (Rigaku, 2011); cell refinement: CrystalClear-SM Expert (Rigaku, 2011); data reduction: CrystalClear-SM Expert (Rigaku, 2011); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: CrystalMaker (Palmer, 2013); software used to prepare material for publication: CrystalStructure (Rigaku, 2010).

Figures top
[Figure 1] Fig. 1. The molecular structure of (I), showing the atom-labeling scheme and 70% probability displacement ellipsoids for the non-H atoms. The intramolecular hydrogen bond is shown as a dashed line.
[Figure 2] Fig. 2. (a) Molecules of (I) are linked into dimers across centers of inversion by weak amine–nitro N—H···O hydrogen bonds (dashed). The view is onto the (010) plane. [Symmetry code: (#) -x + 1, -y + 1, -z + 1.] (b) An alternative view of the same set of molecules as in part (a) showing the nonparallel arrangement of the arene rings.
[Figure 3] Fig. 3. The molecular structure of (II), showing the atom-labeling scheme and 70% probability displacement ellipsoids for the non-H atoms. The intramolecular hydrogen bond is shown as a dashed line.
[Figure 4] Fig. 4. (a) Molecules of (II) are linked into dimers across twofold axes of rotation by carboxy–sulfone O—H···O hydrogen bonds (dashed). The view is onto the (010) plane. [Symmetry code: (#) -x + 2, y + 1, -z + 1.] (b) An alternative view of the packing showing the zigzag arrangement of the arene rings.
(C16H17N3O6) N-[2-(3,4-Dimethoxyphenyl)ethyl]-2,4-dinitroaniline top
Crystal data top
C16H17N3O6F(000) = 728.00
Mr = 347.33Dx = 1.475 Mg m3
Monoclinic, P21/cMelting point: 379 K
Hall symbol: -P 2ybcMo Kα radiation, λ = 0.71075 Å
a = 13.0087 (12) ÅCell parameters from 13648 reflections
b = 7.2092 (6) Åθ = 3.1–27.6°
c = 17.0024 (16) ŵ = 0.12 mm1
β = 101.297 (7)°T = 173 K
V = 1563.6 (3) Å3Prism, yellow
Z = 40.30 × 0.23 × 0.11 mm
Data collection top
Rigaku XtaLAB mini
diffractometer
2913 reflections with F2 > 2.0σ(F2)
Detector resolution: 6.827 pixels mm-1Rint = 0.030
ω scansθmax = 27.5°
Absorption correction: multi-scan
(REQAB; Rigaku, 1998)
h = 016
Tmin = 0.828, Tmax = 0.987k = 09
16236 measured reflectionsl = 2221
3578 independent reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.039Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.102H atoms treated by a mixture of independent and constrained refinement
S = 1.03 w = 1/[σ2(Fo2) + (0.0463P)2 + 0.5551P]
where P = (Fo2 + 2Fc2)/3
3578 reflections(Δ/σ)max < 0.001
232 parametersΔρmax = 0.25 e Å3
0 restraintsΔρmin = 0.21 e Å3
Primary atom site location: structure-invariant direct methods
Crystal data top
C16H17N3O6V = 1563.6 (3) Å3
Mr = 347.33Z = 4
Monoclinic, P21/cMo Kα radiation
a = 13.0087 (12) ŵ = 0.12 mm1
b = 7.2092 (6) ÅT = 173 K
c = 17.0024 (16) Å0.30 × 0.23 × 0.11 mm
β = 101.297 (7)°
Data collection top
Rigaku XtaLAB mini
diffractometer
3578 independent reflections
Absorption correction: multi-scan
(REQAB; Rigaku, 1998)
2913 reflections with F2 > 2.0σ(F2)
Tmin = 0.828, Tmax = 0.987Rint = 0.030
16236 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0390 restraints
wR(F2) = 0.102H atoms treated by a mixture of independent and constrained refinement
S = 1.03Δρmax = 0.25 e Å3
3578 reflectionsΔρmin = 0.21 e Å3
232 parameters
Special details top

Geometry. ENTER SPECIAL DETAILS OF THE MOLECULAR GEOMETRY

Refinement. Refinement was performed using all reflections. The weighted R-factor (wR) and goodness of fit (S) are based on F2. R-factor (gt) are based on F. The threshold expression of F2 > 2.0 sigma(F2) is used only for calculating R-factor (gt).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.50724 (8)0.36301 (14)0.55427 (6)0.0306 (3)
O20.59579 (8)0.20106 (16)0.65080 (6)0.0376 (3)
O30.50832 (10)0.40323 (16)0.70903 (7)0.0420 (3)
O40.35411 (10)0.51340 (17)0.66066 (8)0.0517 (4)
O50.11203 (7)0.32905 (14)0.18040 (5)0.0258 (3)
O60.03845 (8)0.26591 (16)0.05233 (6)0.0334 (3)
N10.33525 (9)0.22648 (17)0.46307 (7)0.0269 (3)
N20.52004 (8)0.22122 (16)0.59592 (6)0.0235 (3)
N30.42160 (10)0.39309 (17)0.66489 (8)0.0331 (3)
C10.35750 (10)0.08081 (19)0.51259 (8)0.0228 (3)
C20.44436 (10)0.07215 (18)0.57820 (8)0.0217 (3)
C30.46459 (10)0.08259 (19)0.62744 (8)0.0240 (3)
C40.39807 (11)0.23130 (19)0.61328 (8)0.0265 (3)
C50.31178 (11)0.2314 (2)0.55030 (9)0.0308 (4)
C60.29284 (11)0.0811 (2)0.50082 (9)0.0284 (3)
C70.25803 (11)0.2181 (2)0.38831 (8)0.0282 (3)
C80.24450 (11)0.4040 (2)0.34585 (9)0.0288 (3)
C90.17168 (10)0.37890 (18)0.26557 (8)0.0243 (3)
C100.06282 (10)0.37334 (18)0.26141 (8)0.0224 (3)
C110.00532 (10)0.33682 (18)0.18985 (8)0.0215 (3)
C120.03522 (11)0.30424 (19)0.12024 (8)0.0243 (3)
C130.14211 (11)0.3120 (2)0.12406 (8)0.0287 (3)
C140.21010 (11)0.3498 (2)0.19655 (9)0.0285 (3)
C150.15456 (11)0.3490 (2)0.25142 (8)0.0275 (3)
C160.00099 (14)0.2459 (3)0.02060 (9)0.0421 (4)
H10.3796 (14)0.313 (3)0.4672 (10)0.034 (5)*
H30.52370.08520.67030.0288*
H50.26630.33560.54180.0369*
H60.23480.08410.45710.0340*
H7A0.18980.17790.40000.0339*
H7B0.28040.12460.35250.0339*
H8A0.21460.49530.37860.0346*
H8B0.31330.45080.33800.0346*
H100.03560.39500.30850.0269*
H130.16960.29140.07700.0345*
H140.28350.35560.19830.0342*
H15A0.23100.33570.23790.0330*
H15B0.13670.47180.27480.0330*
H15C0.12520.25320.29030.0330*
H16A0.04810.14150.01580.0505*
H16B0.03490.35990.03130.0505*
H16C0.06020.22260.06480.0505*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0342 (6)0.0262 (6)0.0283 (5)0.0051 (5)0.0016 (5)0.0046 (4)
O20.0286 (6)0.0401 (7)0.0363 (6)0.0076 (5)0.0125 (5)0.0083 (5)
O30.0509 (7)0.0392 (7)0.0350 (6)0.0064 (6)0.0061 (6)0.0117 (5)
O40.0535 (8)0.0356 (7)0.0713 (9)0.0086 (6)0.0254 (7)0.0133 (7)
O50.0189 (5)0.0352 (6)0.0215 (5)0.0017 (4)0.0004 (4)0.0005 (4)
O60.0329 (6)0.0477 (7)0.0178 (5)0.0003 (5)0.0007 (4)0.0013 (5)
N10.0223 (6)0.0273 (7)0.0277 (6)0.0026 (5)0.0037 (5)0.0001 (5)
N20.0212 (6)0.0261 (6)0.0217 (6)0.0013 (5)0.0006 (5)0.0002 (5)
N30.0419 (8)0.0260 (7)0.0356 (7)0.0003 (6)0.0179 (6)0.0039 (6)
C10.0189 (6)0.0258 (7)0.0236 (6)0.0024 (5)0.0037 (5)0.0035 (6)
C20.0193 (6)0.0240 (7)0.0218 (6)0.0008 (5)0.0042 (5)0.0031 (5)
C30.0248 (7)0.0276 (7)0.0205 (6)0.0021 (6)0.0067 (5)0.0020 (6)
C40.0307 (7)0.0243 (7)0.0269 (7)0.0016 (6)0.0114 (6)0.0016 (6)
C50.0279 (8)0.0277 (8)0.0384 (8)0.0052 (6)0.0107 (6)0.0041 (6)
C60.0212 (7)0.0315 (8)0.0306 (7)0.0017 (6)0.0008 (6)0.0040 (6)
C70.0234 (7)0.0283 (7)0.0287 (7)0.0004 (6)0.0054 (6)0.0003 (6)
C80.0227 (7)0.0270 (8)0.0326 (8)0.0015 (6)0.0051 (6)0.0012 (6)
C90.0226 (7)0.0186 (6)0.0290 (7)0.0000 (5)0.0016 (6)0.0041 (6)
C100.0233 (7)0.0211 (7)0.0218 (6)0.0016 (5)0.0018 (5)0.0012 (5)
C110.0206 (7)0.0195 (6)0.0230 (7)0.0020 (5)0.0013 (5)0.0034 (5)
C120.0268 (7)0.0236 (7)0.0208 (6)0.0027 (6)0.0003 (5)0.0041 (6)
C130.0308 (8)0.0302 (8)0.0268 (7)0.0026 (6)0.0097 (6)0.0051 (6)
C140.0205 (7)0.0278 (8)0.0368 (8)0.0008 (6)0.0045 (6)0.0061 (6)
C150.0231 (7)0.0331 (8)0.0265 (7)0.0012 (6)0.0053 (6)0.0029 (6)
C160.0505 (10)0.0546 (11)0.0210 (7)0.0033 (8)0.0068 (7)0.0018 (7)
Geometric parameters (Å, º) top
O4—N31.2262 (18)C14—C131.3959 (19)
O3—N31.2286 (17)C13—C121.380 (2)
O2—N21.2258 (14)C12—C111.407 (2)
O1—N21.2361 (15)C11—C101.3831 (18)
O6—C121.3764 (16)N1—H10.844 (18)
O6—C161.426 (2)C3—H30.950
O5—C111.3670 (16)C6—H60.950
O5—C151.4306 (18)C5—H50.950
N3—C41.4556 (19)C7—H7A0.990
N2—C21.4487 (17)C7—H7B0.990
N1—C11.3417 (18)C8—H8A0.990
N1—C71.4588 (17)C8—H8B0.990
C4—C31.369 (2)C14—H140.950
C4—C51.3913 (19)C13—H130.950
C3—C21.3886 (19)C10—H100.950
C2—C11.4252 (17)C15—H15A0.980
C1—C61.430 (2)C15—H15B0.980
C5—C61.364 (2)C15—H15C0.980
C7—C81.516 (2)C16—H16A0.980
C8—C91.5122 (19)C16—H16B0.980
C9—C141.379 (3)C16—H16C0.980
C9—C101.4046 (19)
C12—O6—C16116.71 (12)C7—N1—H1116.5 (11)
C11—O5—C15116.64 (10)C4—C3—H3120.512
O4—N3—O3123.71 (13)C2—C3—H3120.513
O4—N3—C4117.89 (12)C1—C6—H6118.934
O3—N3—C4118.38 (13)C5—C6—H6118.938
O2—N2—O1122.15 (12)C4—C5—H5120.152
O2—N2—C2118.85 (11)C6—C5—H5120.153
O1—N2—C2118.98 (10)N1—C7—H7A109.218
C1—N1—C7122.78 (12)N1—C7—H7B109.214
N3—C4—C3118.06 (12)C8—C7—H7A109.220
N3—C4—C5120.42 (13)C8—C7—H7B109.228
C3—C4—C5121.50 (13)H7A—C7—H7B107.910
C4—C3—C2118.98 (12)C7—C8—H8A109.992
N2—C2—C3115.45 (11)C7—C8—H8B109.991
N2—C2—C1122.18 (12)C9—C8—H8A109.984
C3—C2—C1122.32 (12)C9—C8—H8B109.977
N1—C1—C2124.47 (12)H8A—C8—H8B108.366
N1—C1—C6120.17 (12)C9—C14—H14119.710
C2—C1—C6115.36 (12)C13—C14—H14119.718
C1—C6—C5122.13 (13)C14—C13—H13119.748
C4—C5—C6119.69 (14)C12—C13—H13119.746
N1—C7—C8111.96 (12)C9—C10—H10119.473
C7—C8—C9108.53 (11)C11—C10—H10119.473
C8—C9—C14121.27 (13)O6—C16—H16A109.482
C8—C9—C10119.74 (13)O6—C16—H16B109.472
C14—C9—C10118.87 (12)O6—C16—H16C109.471
C9—C14—C13120.57 (14)H16A—C16—H16B109.469
C14—C13—C12120.51 (14)H16A—C16—H16C109.468
O6—C12—C13125.24 (14)H16B—C16—H16C109.464
O6—C12—C11115.16 (13)O5—C15—H15A109.479
C13—C12—C11119.60 (12)O5—C15—H15B109.477
O5—C11—C12115.71 (11)O5—C15—H15C109.466
O5—C11—C10124.91 (13)H15A—C15—H15B109.476
C12—C11—C10119.38 (13)H15A—C15—H15C109.468
C9—C10—C11121.05 (14)H15B—C15—H15C109.462
C1—N1—H1117.9 (11)
C16—O6—C12—C134.7 (2)N2—C2—C1—C6177.12 (11)
C16—O6—C12—C11175.43 (12)C3—C2—C1—N1179.48 (13)
C15—O5—C11—C12175.81 (10)C3—C2—C1—C60.2 (2)
C15—O5—C11—C104.10 (18)N1—C1—C6—C5179.15 (13)
O4—N3—C4—C3168.68 (13)C2—C1—C6—C51.5 (2)
O4—N3—C4—C513.0 (2)C1—C6—C5—C41.7 (3)
O3—N3—C4—C312.6 (2)N1—C7—C8—C9174.50 (11)
O3—N3—C4—C5165.72 (13)C7—C8—C9—C1495.55 (15)
O2—N2—C2—C31.08 (18)C7—C8—C9—C1080.42 (15)
O2—N2—C2—C1176.42 (11)C8—C9—C14—C13174.79 (11)
O1—N2—C2—C3179.69 (11)C8—C9—C10—C11175.15 (11)
O1—N2—C2—C12.20 (19)C14—C9—C10—C110.92 (19)
C1—N1—C7—C8177.32 (12)C10—C9—C14—C131.2 (2)
C7—N1—C1—C2168.31 (12)C9—C14—C13—C120.4 (2)
C7—N1—C1—C610.9 (2)C14—C13—C12—O6179.16 (12)
N3—C4—C3—C2179.12 (12)C14—C13—C12—C110.7 (2)
N3—C4—C5—C6177.78 (13)O6—C12—C11—O51.03 (17)
C3—C4—C5—C60.5 (3)O6—C12—C11—C10178.89 (11)
C5—C4—C3—C20.8 (3)C13—C12—C11—O5179.09 (12)
C4—C3—C2—N2178.41 (12)C13—C12—C11—C101.00 (19)
C4—C3—C2—C10.9 (2)O5—C11—C10—C9179.91 (11)
N2—C2—C1—N12.2 (3)C12—C11—C10—C90.18 (19)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N1—H1···O10.844 (18)2.029 (18)2.6495 (15)129.8 (15)
N1—H1···O1i0.844 (18)2.822 (18)3.644 (1)165.3 (15)
Symmetry code: (i) x+1, y+1, z+1.
(C16H16N2O6S) N-(4-Methylsulfonyl-2-nitrophenyl)-L-phenylalanine top
Crystal data top
C16H16N2O6SF(000) = 760.00
Mr = 364.38Dx = 1.428 Mg m3
Monoclinic, C2Melting point: 443 K
Hall symbol: C 2yMo Kα radiation, λ = 0.71075 Å
a = 21.260 (3) ÅCell parameters from 9423 reflections
b = 5.7264 (6) Åθ = 3.1–30.2°
c = 14.2762 (16) ŵ = 0.23 mm1
β = 103.456 (7)°T = 173 K
V = 1690.3 (4) Å3Blade, yellow
Z = 40.80 × 0.14 × 0.04 mm
Data collection top
Rigaku XtaLAB mini
diffractometer
4851 independent reflections
Radiation source: fine focus sealed tube4201 reflections with I > 2σ(I)
Detector resolution: 6.827 pixels mm-1Rint = 0.029
ω scansθmax = 30.0°, θmin = 3.1°
Absorption correction: multi-scan
(REQAB; Rigaku, 1998)
h = 2929
Tmin = 0.815, Tmax = 0.991k = 88
10478 measured reflectionsl = 2020
Refinement top
Refinement on F2Hydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.039H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.092 w = 1/[σ2(Fo2) + (0.0425P)2 + 0.4064P]
where P = (Fo2 + 2Fc2)/3
S = 1.03(Δ/σ)max = 0.001
4851 reflectionsΔρmax = 0.30 e Å3
235 parametersΔρmin = 0.29 e Å3
1 restraintAbsolute structure: Flack x determined using 1620 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
Primary atom site location: structure-invariant direct methodsAbsolute structure parameter: 0.01 (4)
Secondary atom site location: difference Fourier map
Crystal data top
C16H16N2O6SV = 1690.3 (4) Å3
Mr = 364.38Z = 4
Monoclinic, C2Mo Kα radiation
a = 21.260 (3) ŵ = 0.23 mm1
b = 5.7264 (6) ÅT = 173 K
c = 14.2762 (16) Å0.80 × 0.14 × 0.04 mm
β = 103.456 (7)°
Data collection top
Rigaku XtaLAB mini
diffractometer
4851 independent reflections
Absorption correction: multi-scan
(REQAB; Rigaku, 1998)
4201 reflections with I > 2σ(I)
Tmin = 0.815, Tmax = 0.991Rint = 0.029
10478 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.039H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.092Δρmax = 0.30 e Å3
S = 1.03Δρmin = 0.29 e Å3
4851 reflectionsAbsolute structure: Flack x determined using 1620 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
235 parametersAbsolute structure parameter: 0.01 (4)
1 restraint
Special details top

Geometry. ENTER SPECIAL DETAILS OF THE MOLECULAR GEOMETRY

Refinement. Refinement was performed using all reflections. The weighted R-factor (wR) and goodness of fit (S) are based on F2. R-factor (gt) are based on F. The threshold expression of F2 > 2.0 sigma(F2) is used only for calculating R-factor (gt).

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
S10.92742 (3)0.54808 (11)0.78047 (4)0.03167 (15)
O10.78519 (8)1.3718 (4)0.54188 (12)0.0359 (4)
O20.75778 (10)1.1853 (5)0.65814 (15)0.0512 (6)
O30.88106 (10)0.5710 (5)0.83856 (14)0.0491 (6)
O40.94245 (9)0.3156 (4)0.75374 (14)0.0391 (5)
O50.93194 (10)1.4082 (4)0.35172 (17)0.0527 (6)
O60.96349 (9)1.0683 (4)0.30252 (14)0.0378 (5)
N10.84399 (10)1.1274 (4)0.43040 (13)0.0287 (5)
N20.79068 (9)1.2052 (4)0.59793 (14)0.0305 (5)
C10.86254 (10)0.9947 (4)0.50992 (15)0.0248 (5)
C20.83769 (10)1.0258 (5)0.59353 (14)0.0255 (5)
C30.85673 (11)0.8860 (5)0.67428 (15)0.0269 (5)
C40.90084 (11)0.7118 (5)0.67551 (16)0.0280 (5)
C50.92597 (11)0.6716 (5)0.59408 (17)0.0307 (5)
C60.90701 (11)0.8090 (5)0.51391 (16)0.0296 (5)
C71.00056 (16)0.6784 (7)0.8408 (2)0.0517 (8)
C80.86037 (10)1.0792 (5)0.33917 (14)0.0259 (5)
C90.92279 (11)1.2061 (5)0.33397 (16)0.0299 (5)
C100.80554 (11)1.1692 (5)0.25657 (17)0.0325 (6)
C110.81931 (11)1.1159 (5)0.15974 (16)0.0298 (5)
C120.80202 (14)0.9045 (6)0.11519 (19)0.0414 (7)
C130.81573 (17)0.8542 (6)0.0269 (2)0.0536 (9)
C140.84734 (16)1.0163 (7)0.01718 (19)0.0528 (8)
C150.86431 (15)1.2275 (7)0.0258 (2)0.0483 (8)
C160.85063 (14)1.2780 (5)0.11417 (18)0.0365 (6)
H10.8200 (15)1.248 (6)0.435 (3)0.036 (8)*
H30.83910.91120.72880.0323*
H50.95610.54890.59470.0368*
H60.92420.77880.45940.0355*
H610.9935 (18)1.151 (7)0.294 (3)0.053 (11)*
H7A0.99240.83960.85780.0620*
H7B1.03100.67820.79870.0620*
H7C1.01910.59010.89950.0620*
H80.86600.90720.33200.0310*
H10A0.76431.09480.26080.0389*
H10B0.80091.34010.26320.0389*
H120.78040.79180.14520.0497*
H130.80340.70800.00320.0643*
H140.85720.98110.07720.0634*
H150.88551.34010.00480.0580*
H160.86281.42490.14370.0438*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.0401 (3)0.0313 (3)0.0267 (3)0.0028 (3)0.0140 (2)0.0060 (3)
O10.0402 (10)0.0352 (11)0.0334 (9)0.0080 (8)0.0112 (8)0.0037 (8)
O20.0602 (13)0.0562 (15)0.0498 (12)0.0232 (11)0.0380 (10)0.0124 (11)
O30.0652 (13)0.0524 (14)0.0400 (10)0.0162 (12)0.0330 (9)0.0151 (11)
O40.0469 (11)0.0327 (11)0.0434 (10)0.0028 (9)0.0223 (9)0.0046 (9)
O50.0466 (12)0.0436 (13)0.0776 (16)0.0149 (10)0.0339 (11)0.0275 (12)
O60.0339 (9)0.0347 (11)0.0502 (10)0.0036 (9)0.0209 (8)0.0006 (10)
N10.0315 (10)0.0345 (12)0.0222 (9)0.0049 (9)0.0109 (8)0.0009 (8)
N20.0320 (10)0.0347 (12)0.0264 (10)0.0040 (9)0.0103 (8)0.0026 (9)
C10.0231 (10)0.0300 (14)0.0221 (10)0.0025 (9)0.0068 (8)0.0024 (9)
C20.0248 (10)0.0297 (12)0.0234 (9)0.0009 (10)0.0085 (8)0.0022 (10)
C30.0286 (11)0.0316 (13)0.0229 (10)0.0008 (10)0.0104 (9)0.0028 (10)
C40.0304 (11)0.0322 (13)0.0230 (10)0.0000 (10)0.0092 (9)0.0017 (10)
C50.0310 (12)0.0356 (15)0.0278 (11)0.0058 (10)0.0114 (9)0.0004 (11)
C60.0295 (11)0.0390 (14)0.0229 (10)0.0039 (10)0.0111 (9)0.0007 (10)
C70.0612 (19)0.050 (2)0.0350 (14)0.0043 (16)0.0064 (13)0.0109 (14)
C80.0296 (10)0.0292 (14)0.0202 (9)0.0006 (10)0.0086 (8)0.0006 (9)
C90.0313 (12)0.0357 (14)0.0247 (11)0.0010 (11)0.0104 (9)0.0043 (10)
C100.0312 (12)0.0392 (15)0.0268 (11)0.0004 (11)0.0064 (9)0.0050 (11)
C110.0338 (12)0.0310 (14)0.0223 (10)0.0004 (10)0.0017 (9)0.0032 (9)
C120.0530 (16)0.0331 (15)0.0331 (13)0.0051 (13)0.0006 (12)0.0026 (11)
C130.079 (3)0.0386 (18)0.0330 (14)0.0070 (17)0.0074 (14)0.0092 (13)
C140.0698 (19)0.063 (3)0.0234 (12)0.0159 (18)0.0067 (12)0.0060 (14)
C150.0620 (19)0.057 (2)0.0280 (13)0.0010 (16)0.0145 (13)0.0061 (13)
C160.0527 (16)0.0325 (15)0.0242 (11)0.0031 (12)0.0089 (11)0.0013 (10)
Geometric parameters (Å, º) top
S1—O31.434 (2)C11—C161.389 (3)
S1—O41.441 (2)C12—C131.388 (4)
S1—C71.759 (3)C13—C141.381 (5)
S1—C41.746 (2)C14—C151.366 (5)
O2—N21.233 (3)C15—C161.390 (4)
O1—N21.233 (3)O6—H610.83 (4)
O5—C91.191 (3)N1—H10.87 (3)
O6—C91.324 (3)C7—H7A0.980
N2—C21.445 (3)C7—H7B0.980
N1—C11.346 (3)C7—H7C0.980
N1—C81.451 (3)C5—H50.950
C4—C51.407 (3)C6—H60.950
C4—C31.367 (3)C3—H30.950
C5—C61.370 (3)C8—H81.000
C6—C11.415 (3)C10—H10A0.990
C1—C21.424 (3)C10—H10B0.990
C2—C31.384 (3)C12—H120.950
C8—C91.530 (3)C13—H130.950
C8—C101.541 (3)C14—H140.950
C10—C111.509 (3)C15—H150.950
C11—C121.377 (4)C16—H160.950
O3—S1—O4117.54 (13)C14—C15—C16120.2 (4)
O3—S1—C7109.04 (15)C11—C16—C15120.7 (3)
O3—S1—C4108.56 (12)C9—O6—H61107 (3)
O4—S1—C7107.24 (16)C1—N1—H1117 (2)
O4—S1—C4108.43 (12)C8—N1—H1119 (2)
C7—S1—C4105.36 (13)S1—C7—H7A109.477
O2—N2—O1122.7 (3)S1—C7—H7B109.475
O2—N2—C2118.4 (3)S1—C7—H7C109.473
O1—N2—C2118.9 (2)H7A—C7—H7B109.471
C1—N1—C8124.4 (3)H7A—C7—H7C109.464
S1—C4—C5120.8 (2)H7B—C7—H7C109.466
S1—C4—C3119.15 (19)C4—C5—H5119.936
C5—C4—C3120.0 (3)C6—C5—H5119.943
C4—C5—C6120.1 (3)C5—C6—H6119.025
C5—C6—C1122.0 (3)C1—C6—H6119.023
N1—C1—C6121.3 (3)C4—C3—H3120.015
N1—C1—C2122.9 (3)C2—C3—H3120.011
C6—C1—C2115.8 (2)N1—C8—H8109.758
N2—C2—C1121.4 (2)C9—C8—H8109.750
N2—C2—C3116.5 (2)C10—C8—H8109.747
C1—C2—C3122.1 (3)C8—C10—H10A109.420
C4—C3—C2120.0 (3)C8—C10—H10B109.411
N1—C8—C9110.20 (18)C11—C10—H10A109.422
N1—C8—C10109.05 (19)C11—C10—H10B109.413
C9—C8—C10108.3 (2)H10A—C10—H10B108.036
O5—C9—O6124.3 (3)C11—C12—H12119.607
O5—C9—C8123.5 (3)C13—C12—H12119.609
O6—C9—C8112.1 (3)C12—C13—H13119.945
C8—C10—C11111.1 (2)C14—C13—H13119.927
C10—C11—C12120.9 (3)C13—C14—H14120.141
C10—C11—C16120.7 (3)C15—C14—H14120.129
C12—C11—C16118.5 (3)C14—C15—H15119.912
C11—C12—C13120.8 (3)C16—C15—H15119.899
C12—C13—C14120.1 (3)C11—C16—H16119.643
C13—C14—C15119.7 (3)C15—C16—H16119.655
O3—S1—C4—C5161.93 (17)N1—C1—C2—C3179.22 (19)
O3—S1—C4—C320.3 (3)C6—C1—C2—N2178.42 (18)
O4—S1—C4—C533.2 (2)C6—C1—C2—C31.2 (3)
O4—S1—C4—C3149.08 (17)N2—C2—C3—C4179.73 (18)
C7—S1—C4—C581.4 (2)C1—C2—C3—C40.1 (4)
C7—S1—C4—C396.4 (2)N1—C8—C9—O549.8 (3)
O2—N2—C2—C1160.08 (19)N1—C8—C9—O6133.64 (19)
O2—N2—C2—C319.5 (3)N1—C8—C10—C11178.12 (18)
O1—N2—C2—C120.2 (3)C9—C8—C10—C1161.9 (3)
O1—N2—C2—C3160.22 (18)C10—C8—C9—O569.4 (3)
C1—N1—C8—C992.0 (3)C10—C8—C9—O6107.1 (2)
C1—N1—C8—C10149.3 (2)C8—C10—C11—C1286.3 (3)
C8—N1—C1—C67.9 (4)C8—C10—C11—C1692.8 (3)
C8—N1—C1—C2170.10 (18)C10—C11—C12—C13178.9 (2)
S1—C4—C5—C6176.78 (15)C10—C11—C16—C15178.89 (19)
S1—C4—C3—C2176.55 (15)C12—C11—C16—C150.2 (4)
C5—C4—C3—C21.2 (4)C16—C11—C12—C130.2 (4)
C3—C4—C5—C60.9 (4)C11—C12—C13—C140.3 (5)
C4—C5—C6—C10.4 (4)C12—C13—C14—C150.9 (5)
C5—C6—C1—N1179.5 (2)C13—C14—C15—C160.9 (5)
C5—C6—C1—C21.4 (4)C14—C15—C16—C110.4 (5)
N1—C1—C2—N20.4 (4)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O6—H61···O4i0.83 (4)1.90 (4)2.720 (3)168 (4)
N1—H1···O10.87 (3)1.98 (4)2.642 (3)132 (3)
Symmetry code: (i) x+2, y+1, z+1.

Experimental details

(C16H17N3O6)(C16H16N2O6S)
Crystal data
Chemical formulaC16H17N3O6C16H16N2O6S
Mr347.33364.38
Crystal system, space groupMonoclinic, P21/cMonoclinic, C2
Temperature (K)173173
a, b, c (Å)13.0087 (12), 7.2092 (6), 17.0024 (16)21.260 (3), 5.7264 (6), 14.2762 (16)
β (°) 101.297 (7) 103.456 (7)
V3)1563.6 (3)1690.3 (4)
Z44
Radiation typeMo KαMo Kα
µ (mm1)0.120.23
Crystal size (mm)0.30 × 0.23 × 0.110.80 × 0.14 × 0.04
Data collection
DiffractometerRigaku XtaLAB miniRigaku XtaLAB mini
Absorption correctionMulti-scan
(REQAB; Rigaku, 1998)
Multi-scan
(REQAB; Rigaku, 1998)
Tmin, Tmax0.828, 0.9870.815, 0.991
No. of measured, independent and
observed reflections
16236, 3578, 2913 [F2 > 2.0σ(F2)]10478, 4851, 4201 [I > 2σ(I)]
Rint0.0300.029
(sin θ/λ)max1)0.6490.704
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.039, 0.102, 1.03 0.039, 0.092, 1.03
No. of reflections35784851
No. of parameters232235
No. of restraints01
H-atom treatmentH atoms treated by a mixture of independent and constrained refinementH atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å3)0.25, 0.210.30, 0.29
Absolute structure?Flack x determined using 1620 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
Absolute structure parameter?0.01 (4)

Computer programs: CrystalClear-SM Expert (Rigaku, 2011), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), CrystalMaker (Palmer, 2013), CrystalStructure (Rigaku, 2010).

Hydrogen-bond geometry (Å, º) for (C16H17N3O6) top
D—H···AD—HH···AD···AD—H···A
N1—H1···O10.844 (18)2.029 (18)2.6495 (15)129.8 (15)
N1—H1···O1i0.844 (18)2.822 (18)3.644 (1)165.3 (15)
Symmetry code: (i) x+1, y+1, z+1.
Hydrogen-bond geometry (Å, º) for (C16H16N2O6S) top
D—H···AD—HH···AD···AD—H···A
O6—H61···O4i0.83 (4)1.90 (4)2.720 (3)168 (4)
N1—H1···O10.87 (3)1.98 (4)2.642 (3)132 (3)
Symmetry code: (i) x+2, y+1, z+1.
 

Follow Acta Cryst. C
Sign up for e-alerts
Follow Acta Cryst. on Twitter
Follow us on facebook
Sign up for RSS feeds