[delta]-Sulfanilamide

The [delta] polymorph of sulfanilamide (or 4-amino­benzene­sul­fon­amide), C₆H₈N₂O₂S, displays an overall three-dimensional hydrogen-bonded network that is dominated by a two-dimensional substructure with R²₂(8) rings; these result from dimeric N-H...O inter­actions between adjacent sulfonamide groups. This study shows how the polymorphism of sulfanil­amide is linked to its versatile hydrogen-bonding capabilities.

S1. Comment

The antibacterial activity of sulfanilamide, (I), was first recognized in 1936 (Buttle et al., 1936). This followed the introduction of prontosil as an antibacterial agent (Domagk, 1935), the activity of which depends on its conversion to sulfanilamide. The use of sulfanilamide was eclipsed by its prodrugs, the more effective sulfadrugs, shortly afterwards. The sulfadrugs are remarkably polymorphic. We are aware of only sulfadiazine amongst the commercial antibacterial sulfonamides as being monomorphic. We have previously reported new structures of polymorphs of sulfathiazole (Hughes et al., 1999) and sulfapyridine (Gelbrich et al., 2007). The polymorphism of sulfanilamide was extensively but sporadically investigated over a number of years (Burger, 1973). There are three well known polymorphs, usually designated α (space group Pbca), β (P2₁/c) and γ (P2₁/c). The crystal structures of these have been determined (Alléaume & Decap, 1965a,b; O'Connor & Maslen, 1965; O'Connell & Maslen, 1967), as well as that of an elusive hydrate (Alléaume & Decap, 1968). The thermodynamic relationships between these polymorphs is still uncertain (Portieri et al., 2004). There have been several accounts of the existence of other polymorphs, although no structures of these have been reported (McLachlan, 1957; Lin & Guillory, 1970; Lin et al., 1974; Sekiguchi et al., 1975; Portieri et al., 2004).

During an investigation of the polymorphism, transformation and solvate forming propensities of the sulfadrugs (Bingham et al., 2001), we prepared several solvates of sulfanilamide by crystallization from both common and uncommon liquids. The structure of an isolated crystal from the preparation of the diethyl suberate solvate of sulfanilamide proved to be that of a new polymorph, here named δ-sulfanilamide. The data collection took place many months after the crystallization and isolation. It therefore appears to be a form of higher kinetic stability than the α and γ forms, both of which revert to the β form, which is the thermodynamically stable form at room temperature, over a period of several months.

δ-Sulfanilamide crystallizes in the space group Pbca with one independent molecule. The geometric parameters of the molecule, which is shown in Fig. 1, are unexceptional. The sulfonamide (s) and aniline (a) NH₂ groups provide hydrogen-bond donor functionalities, while the O and N atoms are potential hydrogen-bond acceptor sites. Atom O1 accepts two hydrogen bonds from (s)NH₂ groups of two neighbouring molecules. Thus, dimers with a central R²₂(8) ring (Bernstein et al., 1995) are formed, and four such dimers are joined together by R⁴₆(16) rings. Both ring types are centrosymmetric. The resulting extended two-dimensional hydrogen-bonded structure, illustrated in Fig. 2(a), lies parallel to the ab plane. It consists of two antiparallel sublayers of molecules, enabling close head-to-head contacts of their respective sulfonamide units (Fig 2b), while the two sets of aniline units point in opposite directions away from the central hydrogen-bonded sheet. Antiparallel aniline fragments originating from two adjacent (s)NH···O(s)-bonded planes form a common stack. This enables the (a)NH₂ groups to engage in a second set of interactions with the sulfonylamide groups of a neighbouring plane, (a)NH···O(s), using the sulfonyl O atom that is not employed in the primary contacts, and (a)NH···N(s). The extended two-dimensional structure shown in Fig. 2(c) arises from these two secondary interactions in addition to the dimeric (s)NH···O(s) contacts. The two (a)NH···A interactions involving the aniline NH₂ group are secondary in the sense that their H···A distances (> 2.5 Å) are considerably longer than the (s)NH···O(s) bonds (Table 1). Together, primary and secondary NH···A bonds generate an overall three-dimensional framework of hydrogen-bonded sulfanilamide molecules.

A recurring feature of all four forms of (I) is the presence of (s)NH···O(s)-bonded chains enabled by head-to-head contacts of adjacent sulfonyl groups, which always result in (s)NH···O(s)-bonded planes, and neighbouring planes of this kind are always separated by antiparallel stacked aniline fragments. Fig 3(a) illustrates the toplogy of the (s)NH···O(s)-bonded planes in form δ, which is based on dimeric R²₂(8) rings. The same dimer is also present in forms α and γ, which adopt a common topolgy (Fig. 3b), where each of the two sulfonyl O atoms is engaged in one (s)NH···O(s) bond, in contrast to polymorph δ where just one O atom is employed twice. The β polymorph also contains an extended two-dimensional structure arising from (s)NH···O(s) bonds, but it is not composed of dimers and the characteristic R²₂(8) rings are absent from this structure (Fig. 3c). This is also the only of the four modification without a hierarchy of shorter (s)NH···O(s) and longer (a)NH···A bonds.

Using the XPac program (Gelbrich & Hursthouse, 2005), the packing of the sulfanilamide molecules in the four polymorphs was analyzed. It was found that the (s)NH···O(s)-bonded dimer present in α, γ and δ is the only packing fragment that occurs in more than one of these structures. Beyond these individual dimeric units, the common two-dimensional topology of α and γ (Fig. 3b) translates into two different spatial arrangements of sulfanilamide molecules. The comparison of molecular volumes determined at 150 K (188.0 ų for α, 184.6 ų for β, 187.1 ų for γ and 188.4 ų for δ; Hursthouse et al., 1999a,b, 1998), shows that the stable β form is also the polymorph with the highest density. The occurrence of the other three forms may be attributed to a competing aggregation preference of sulfanilamide molecules for (s)NH···O(s)-bonded dimers.

Related literature

For related literature, see: Alléaume & Decap (1965a, 1965b, 1968); Bernstein et al. (1995); Bingham et al. (2001); Burger (1973); Buttle et al. (1936); Domagk (1935); Gelbrich & Hursthouse (2005); Gelbrich et al. (2007); Hughes et al. (1999); Hursthouse et al. (1998, 1999a, 1999b); Lin & Guillory (1970); Lin et al. (1974); McLachlan (1957); O'Connell & Maslen (1967); O'Connor & Maslen (1965); Portieri et al. (2004); Sekiguchi et al. (1975).

S2. Experimental

An isolated crystal of δ-sulfanilamide was obtained from the preparation of the diethyl suberate solvate of sulfanilamide.

S3. Refinement

All H atoms were identified in a difference map. Benzyl H atoms were positioned geometrically (C—H = 0.95 Å). H atoms attached to N were refined with restrained distances [N—H = 0.88 (2) Å]. The U_iso parameters of all H atoms were refined freely.

Computing details

Data collection: COLLECT (Hooft, 1998); cell refinement: DENZO (Otwinowski & Minor, 1997) and COLLECT (Hooft, 1998); data reduction: DENZO (Otwinowski & Minor, 1997) and COLLECT (Hooft, 1998); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP (Bruker, 1998) and Mercury (Bruno et al., 2002); software used to prepare material for publication: publCIF (Westrip, 2008).

Figures

	Fig. 1. The molecular structure of (I), showing the atomic numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. Details of the three-dimensional hydrogen-bonding network of δ-sulfanilamide, with atoms participating in the drawn hydrogen-bonds represented as spheres. (a) Two-dimensional structure arising from primary (s)NH···O(s) interactions between sulfamide groups. (b) The same hydrogen-bonded sheet rotated by 90°, showing the two groups of molecules with their sulfamide groups aligned head-to-head. (c) Two-dimensional structure arising from secondary hydrogen bonds in combination with primary dimers. Key: dot–dashed lines (a)NH···N(s), dashed lines (a)NH···O(s), dotted lines (s)NH···O(s) dimers.
	Fig. 3. The topology of the extended two-dimensional structures arising from (s)NH···O(s) interactions in modifications of sulfanilamide. Molecules are represented by their sulfonamide groups (arrows denote NH···O bonds, circles represent O atoms): (a) R^22(8) dimers fused with R^46(16) rings in form δ (see also Fig. 2(a); (b) R^22(8) dimers fused with R^66(20) rings in forms α and γ; and (c) fused R^44(16) and R^44(24) rings in form β.

4-aminobenzenesulfonamide

Crystal data

C6H8N2O2S	F(000) = 720
Mr = 172.20	Dx = 1.518 Mg m^−3
Orthorhombic, Pbca	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ac 2ab	Cell parameters from 4820 reflections
a = 9.7056 (19) Å	θ = 2.9–27.4°
b = 8.6794 (17) Å	µ = 0.38 mm^−1
c = 17.890 (4) Å	T = 150 K
V = 1507.0 (5) Å^3	Block, colourless
Z = 8	0.20 × 0.20 × 0.15 mm

Data collection

Bruker–Nonius KappaCCD diffractometer	1346 independent reflections
Radiation source: Bruker–Nonius FR591 rotating anode	978 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.061
Detector resolution: 9.091 pixels mm^-1	θmax = 25.2°, θmin = 3.1°
ϕ & ω scans	h = −11→11
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	k = −10→10
Tmin = 0.928, Tmax = 0.939	l = −20→19
4580 measured reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.042	H atoms treated by a mixture of independent and constrained refinement
wR(F^2) = 0.106	w = 1/[σ^2(Fo^2) + (0.0525P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 1.00	(Δ/σ)max = 0.001
1346 reflections	Δρmax = 0.31 e Å^−3
121 parameters	Δρmin = −0.39 e Å^−3
4 restraints	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0046 (13)

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
S1	0.42202 (6)	0.22836 (8)	0.54583 (4)	0.0234 (3)
O1	0.55830 (17)	0.1800 (2)	0.52415 (10)	0.0290 (5)
O2	0.38835 (18)	0.3887 (2)	0.53998 (10)	0.0287 (5)
N1	0.3592 (3)	0.0760 (3)	0.86600 (14)	0.0425 (7)
H1N	0.317 (3)	0.147 (3)	0.8920 (16)	0.045 (10)*
H2N	0.430 (3)	0.030 (4)	0.8877 (18)	0.066 (12)*
N2	0.3175 (2)	0.1376 (3)	0.49140 (13)	0.0286 (6)
H3N	0.2304 (19)	0.159 (3)	0.4970 (14)	0.025 (7)*
H4N	0.332 (3)	0.040 (2)	0.4921 (19)	0.057 (11)*
C1	0.3708 (3)	0.1078 (3)	0.79075 (15)	0.0296 (7)
C2	0.4660 (3)	0.0300 (3)	0.74670 (15)	0.0352 (7)
H2	0.5223	−0.0474	0.7686	0.035 (8)*
C3	0.4802 (3)	0.0630 (3)	0.67213 (15)	0.0306 (7)
H3	0.5471	0.0099	0.6432	0.027 (7)*
C4	0.3973 (2)	0.1737 (3)	0.63874 (14)	0.0234 (6)
C5	0.2975 (3)	0.2475 (3)	0.68141 (16)	0.0312 (7)
H5	0.2378	0.3206	0.6587	0.034 (8)*
C6	0.2848 (3)	0.2150 (3)	0.75644 (16)	0.0345 (7)
H6	0.2166	0.2664	0.7852	0.049 (10)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0203 (4)	0.0229 (4)	0.0271 (4)	−0.0006 (3)	0.0008 (3)	0.0015 (3)
O1	0.0196 (10)	0.0331 (12)	0.0342 (12)	0.0020 (8)	0.0034 (7)	0.0008 (8)
O2	0.0316 (11)	0.0195 (10)	0.0350 (12)	0.0012 (8)	0.0009 (8)	0.0039 (8)
N1	0.058 (2)	0.0417 (17)	0.0275 (16)	−0.0026 (15)	0.0039 (13)	0.0022 (13)
N2	0.0204 (13)	0.0321 (15)	0.0333 (15)	−0.0009 (11)	−0.0023 (10)	0.0004 (11)
C1	0.0342 (16)	0.0283 (16)	0.0264 (17)	−0.0109 (13)	0.0004 (12)	−0.0002 (12)
C2	0.0328 (16)	0.0396 (17)	0.0332 (18)	0.0040 (14)	−0.0031 (13)	0.0089 (14)
C3	0.0249 (15)	0.0316 (16)	0.0353 (17)	0.0052 (12)	0.0009 (12)	0.0011 (13)
C4	0.0219 (14)	0.0233 (14)	0.0250 (16)	−0.0019 (12)	−0.0002 (10)	0.0000 (11)
C5	0.0263 (16)	0.0306 (17)	0.0368 (18)	0.0022 (12)	0.0030 (13)	0.0043 (13)
C6	0.0385 (17)	0.0286 (16)	0.0365 (18)	0.0008 (13)	0.0141 (13)	−0.0023 (13)

Geometric parameters (Å, º)

S1—O2	1.4335 (19)	C1—C6	1.393 (4)
S1—O1	1.4408 (18)	C2—C3	1.371 (4)
S1—N2	1.611 (2)	C2—H2	0.9500
S1—C4	1.745 (3)	C3—C4	1.388 (4)
N1—C1	1.379 (4)	C3—H3	0.9500
N1—H1N	0.877 (18)	C4—C5	1.390 (3)
N1—H2N	0.885 (18)	C5—C6	1.377 (4)
N2—H3N	0.872 (17)	C5—H5	0.9500
N2—H4N	0.863 (18)	C6—H6	0.9500
C1—C2	1.390 (4)
O2—S1—O1	118.19 (11)	C3—C2—C1	121.1 (3)
O2—S1—N2	106.67 (13)	C3—C2—H2	119.5
O1—S1—N2	105.84 (13)	C1—C2—H2	119.5
O2—S1—C4	107.59 (11)	C2—C3—C4	120.4 (3)
O1—S1—C4	107.66 (11)	C2—C3—H3	119.8
N2—S1—C4	110.86 (12)	C4—C3—H3	119.8
C1—N1—H1N	115 (2)	C3—C4—C5	119.1 (2)
C1—N1—H2N	117 (2)	C3—C4—S1	121.2 (2)
H1N—N1—H2N	117 (3)	C5—C4—S1	119.6 (2)
S1—N2—H3N	115.8 (17)	C6—C5—C4	120.2 (3)
S1—N2—H4N	112 (2)	C6—C5—H5	119.9
H3N—N2—H4N	112 (3)	C4—C5—H5	119.9
N1—C1—C2	120.7 (3)	C5—C6—C1	120.9 (3)
N1—C1—C6	121.0 (3)	C5—C6—H6	119.6
C2—C1—C6	118.3 (3)	C1—C6—H6	119.6

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N2—H3N···O1^i	0.87 (2)	2.21 (2)	2.985 (3)	148 (2)
N2—H4N···O1^ii	0.86 (2)	2.20 (2)	3.022 (3)	159 (3)
N1—H1N···N2^iii	0.88 (2)	2.58 (2)	3.372 (4)	151 (3)
N1—H2N···O2^iv	0.89 (2)	2.51 (2)	3.388 (4)	173 (3)

Symmetry codes: (i) x−1/2, −y+1/2, −z+1; (ii) −x+1, −y, −z+1; (iii) x, −y+1/2, z+1/2; (iv) −x+1, y−1/2, −z+3/2.