Triclosan

The title compound [systematic name: 5-chloro-2-(2,4-di­chloro­phen­oxy)phenol], C₁₂H₇Cl₃O₂, is a biologically relevant mol­ecule with biocide activity. It crystallizes in the chiral trigonal space group P3₁ with one mol­ecule in the asymmetric unit. As in biological adducts, the two aromatic rings are almost mutually perpendicular, with this structural feature leading to a distribution of the pendant –OH groups to maximize the formation of O—H...O hydrogen bonds. This arrangement leads to a chain of mol­ecules running parallel to the c axis and having a C(2) graph-set motif at its core.

S1. Comment

Triclosan [5-chloro-2-(2,4-dichlorophenoxy)phenol], (I), is a broad-spectrum biocide widely employed as an antimicrobial ingredient in household- and healthcare-related products. The most common use is in antimicrobial hand soaps, but it can also be found in consumer products such as liquid dishwashing soaps, deodorants and toothpastes at concentrations ranging from 0.15 to 0.3% (Campbell & Zirwas, 2007). Triclosan may also be employed in healthcare at dosages of 1% for use in high-risk high-frequency handwashing (Kampf & Kramer, 2004). The compound features good activity against Gram-positive bacteria and yeasts but is somewhat less active against Gram-negative organisms, and features limited activity against mycobacteria and dermatophytes and little activity against viruses (Regös et al., 1979; Jones et al., 2000). Additionally, there are some triclosan-resistant pathogens, the most well described example being Pseudomonas aeruginosa (Russell, 2004). It is highly effective at reducing the spread of infection in the healthcare setting. Triclosan has also been described as a potential inducer of acquired bacterial resistance to biocides, but whether it actually induces resistance in real-world settings remains to be demonstrated (Campbell & Zirwas, 2007; Heath & Rock, 2000). It is, thus, surprising to conclude that the crystal structure of tricolosan has never been fully determined to date, as unequivocally confirmed by a search of the Cambridge Structural Database (CSD, November 2008 version with three updates; Allen, 2002). In addition, it is also important to emphasize that many of its biological functions (e.g. as an enoyl reductase inhibitor; Roujeinikova et al., 1999; Stewart et al., 1999) seem to be strongly related to its molecular recognition process through, for example, π–π stacking with diazaborine molecules.

In recent years we have been interested in the use of cyclodextrins as molecular carriers for the delivery of anti-tumoural agents based on organometallic coordination complexes. Because single crystals are very rarely isolated, we developed a strategy which uses Monte Carlo optimization to derive, from powder X-ray data (either laboratory-scale or from a synchrotron source), reliable structural models (Marques et al., 2008, 2009; Pereira et al., 2007, 2008), for which good crystallographic determinations of the guest species need to be available in the literature. More recently, we have focused on the use of biologically active organic molecules, such as the title compound, (I). In this paper we report the crystal structure of triclosan determined at 150 K.

Compound (I) crystallizes in the chiral space group P3₁ with one molecule composing the asymmetric unit (Fig. 1). The two aromatic rings [C1–C6 (the 2,4-dichlorophenoxyl ring) and C1'–C6' (the 2-substituted 5-chlorophenol ring)] are not coplanar, subtending an angle of 87.98 (8)°. This arrangement minimizes the steric repulsion between spatially close chloro and hydroxyl groups and further promotes π–π stacking in the crystal structure (see below). It is worth emphasizing that this mutual arrangement of the aromatic rings has been previously described for adducts of triclosan with, for example, NADH and diazaborine (Roujeinikova et al., 1999; Stewart et al., 1999), and also in the β-cyclodextrin supramolecular adduct reported by Paulidou et al. (2008).

The pendant hydroxyl group is approximately in the average plane of the C1'–C6' ring (torsion angle C6—C1—O1—H1 = 11°), which maximizes the O—H···O hydrogen-bonding interactions between adjacent triclosan molecules (see Fig. 2 and Table 1 for dimensions). These connections are further strengthened by the presence of weak offset π–π stacking interactions between the C1–C6 ring (centroid Cg1) of one molecule and the C1'–C6' ring (centroid Cg2) of the adjacent ring at (-x + y, -x, -1/3 + z); the Cg1···Cg2 separation is 3.9156 (9) Å. This cooperative effect between the O—H···O hydrogen bonds and the π–π contacts leads to the formation of a one-dimensional chain having at its core a chain-type C(2) graph-set motif (Bernstein et al., 1995). Individual chains are close-packed in the solid state with only van der Waals contacts between them.

S2. Experimental

Triclosan was purchased from Alfa Aesar (99% purity) and used as received without further purification. Large single crystals suitable for crystallographic studies were isolated over a period of one week by slow evaporation of an ethanolic solution.

S3. Refinement

H atoms bound to O and C were located at their idealized positions and were included in the final structural model in a riding-motion approximation, with C—H = 0.95 Å and O—H = 0.84 Å, and with U_iso(H) = 1.2U_eq(C) or 1.5U_eq(O). [Please check added text]

Computing details

Data collection: APEX2 (Bruker, 2006); cell refinement: APEX2 (Bruker, 2006); data reduction: SAINT-Plus (Bruker, 2005); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg, 2009); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures

	Fig. 1. The molecule of triclosan, showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 80% probability level and H atoms are shown as small spheres of arbitrary radii.
	Fig. 2. Schematic representation of the O—H···O hydrogen-bonding interactions (dashed lines) connecting adjacent triclosan molecules along the [001] direction of the unit cell, leading to a supramolecular chain described as a C(2) graph-set motif. The presence of π–π stacking interactions between adjacent molecular units is emphasized.

5-chloro-2-(2,4-dichlorophenoxy)phenol

Crystal data

C12H7Cl3O2	Dx = 1.590 Mg m^−3
Mr = 289.53	Mo Kα radiation, λ = 0.71073 Å
Trigonal, P31	Cell parameters from 9906 reflections
Hall symbol: P 31	θ = 3.3–32.6°
a = 12.5225 (1) Å	µ = 0.74 mm^−1
c = 6.6809 (1) Å	T = 150 K
V = 907.29 (2) Å^3	Needle, colourless
Z = 3	0.22 × 0.08 × 0.06 mm
F(000) = 438

Data collection

Bruker APEXII X8 KappaCCD diffractometer	5670 independent reflections
Radiation source: fine-focus sealed tube	4382 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.044
ω/ϕ scans	θmax = 36.3°, θmin = 3.6°
Absorption correction: multi-scan (SADABS; Sheldrick, 1998)	h = −19→20
Tmin = 0.854, Tmax = 0.957	k = −20→20
35385 measured reflections	l = −11→11

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)] = 0.037	H-atom parameters constrained
wR(F^2) = 0.070	w = 1/[σ^2(Fo^2) + (0.030P)^2 + 0.0459P] where P = (Fo^2 + 2Fc^2)/3
S = 1.03	(Δ/σ)max < 0.001
5670 reflections	Δρmax = 0.38 e Å^−3
155 parameters	Δρmin = −0.28 e Å^−3
1 restraint	Absolute structure: Flack (1983), with 2729 estimated Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.02 (3)

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.

A total of 2729 estimated Friedel pairs have not been merged and were used as independent data for the structure refinement. The Flack parameter (Flack, 1983) converged to -0.02 (3), ultimately assuring a valid absolute structure determination from the single-crystal data set.

Data sets collected with resolution up to 0.77 Å could be systematically solved in either P3₁ or P3₂, with identical final R-factors. The ambiguity in the space group selection could only be solved when a freshly isolated crystal was collected up to 0.60 Å of resolution, of which only space group P3₁ could produce a sensible overall structural refinement.

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

	x	y	z	Uiso*/Ueq
C1	0.13930 (12)	0.20835 (12)	0.8248 (2)	0.0142 (2)
C2	0.21766 (13)	0.27043 (13)	0.6665 (2)	0.0169 (3)
C3	0.28032 (14)	0.39805 (14)	0.6578 (2)	0.0237 (3)
H3	0.3315	0.4393	0.5462	0.028*
C4	0.26835 (15)	0.46577 (14)	0.8121 (2)	0.0252 (3)
H4	0.3104	0.5533	0.8071	0.030*
C5	0.19371 (13)	0.40282 (13)	0.9731 (2)	0.0197 (3)
C6	0.12885 (13)	0.27524 (13)	0.9825 (2)	0.0171 (3)
H6	0.0781	0.2341	1.0945	0.021*
O1	0.07514 (9)	0.08182 (9)	0.81936 (14)	0.01613 (19)
H1	0.0217	0.0549	0.9103	0.024*
Cl5	0.18177 (4)	0.48547 (4)	1.17285 (6)	0.03084 (10)
O1'	0.22597 (9)	0.20292 (9)	0.50694 (14)	0.0185 (2)
C1'	0.31738 (12)	0.17225 (12)	0.5162 (2)	0.0164 (2)
C2'	0.32767 (13)	0.10907 (13)	0.3522 (2)	0.0163 (3)
C3'	0.41482 (14)	0.07173 (14)	0.3475 (2)	0.0200 (3)
H3'	0.4211	0.0287	0.2351	0.024*
C4'	0.49253 (13)	0.09872 (15)	0.5104 (2)	0.0228 (3)
C5'	0.48531 (14)	0.16287 (16)	0.6735 (2)	0.0246 (3)
H5'	0.5404	0.1821	0.7830	0.030*
C6'	0.39716 (13)	0.19884 (14)	0.6762 (2)	0.0222 (3)
H6'	0.3914	0.2421	0.7886	0.027*
Cl2'	0.23162 (3)	0.07755 (3)	0.14807 (5)	0.01930 (7)
Cl4'	0.60016 (4)	0.04946 (4)	0.50482 (6)	0.03456 (11)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0142 (6)	0.0150 (6)	0.0146 (6)	0.0081 (5)	−0.0018 (5)	−0.0001 (5)
C2	0.0174 (6)	0.0190 (6)	0.0150 (6)	0.0097 (5)	0.0000 (5)	−0.0010 (5)
C3	0.0231 (7)	0.0203 (7)	0.0225 (8)	0.0069 (6)	0.0045 (6)	0.0020 (6)
C4	0.0295 (8)	0.0149 (6)	0.0268 (8)	0.0080 (6)	0.0000 (6)	−0.0005 (6)
C5	0.0238 (7)	0.0200 (7)	0.0185 (7)	0.0135 (6)	−0.0029 (5)	−0.0045 (5)
C6	0.0182 (6)	0.0201 (6)	0.0149 (6)	0.0111 (5)	0.0015 (5)	0.0001 (5)
Cl5	0.0411 (2)	0.02597 (19)	0.0295 (2)	0.01984 (17)	0.00034 (17)	−0.00977 (16)
O1	0.0175 (5)	0.0146 (4)	0.0147 (5)	0.0068 (4)	0.0015 (3)	0.0001 (4)
O1'	0.0184 (5)	0.0238 (5)	0.0146 (5)	0.0117 (4)	0.0011 (4)	−0.0027 (4)
C1'	0.0151 (6)	0.0163 (6)	0.0162 (6)	0.0068 (5)	0.0021 (5)	0.0017 (5)
C2'	0.0164 (6)	0.0180 (6)	0.0127 (6)	0.0072 (5)	−0.0005 (5)	0.0005 (5)
C3'	0.0231 (7)	0.0228 (7)	0.0161 (7)	0.0130 (6)	0.0012 (5)	−0.0002 (5)
C4'	0.0207 (7)	0.0290 (8)	0.0232 (7)	0.0159 (6)	−0.0009 (6)	0.0007 (6)
C5'	0.0227 (7)	0.0336 (8)	0.0177 (7)	0.0141 (7)	−0.0047 (6)	−0.0015 (6)
C6'	0.0233 (7)	0.0251 (7)	0.0161 (7)	0.0104 (6)	−0.0007 (5)	−0.0030 (6)
Cl2'	0.02057 (15)	0.02406 (17)	0.01361 (14)	0.01141 (14)	−0.00251 (12)	−0.00153 (12)
Cl4'	0.0334 (2)	0.0527 (3)	0.0324 (2)	0.0326 (2)	−0.00715 (17)	−0.00585 (19)

Geometric parameters (Å, º)

Cl2'—C2'	1.7287 (14)	C5'—H5'	0.9500
Cl4'—C4'	1.7407 (15)	C6'—C1'	1.385 (2)
Cl5—C5	1.7405 (15)	C6'—H6'	0.9500
O1'—C1'	1.3789 (17)	C1—C2	1.387 (2)
O1'—C2	1.3961 (17)	C1—C6	1.392 (2)
O1—C1	1.3727 (16)	C2—C3	1.385 (2)
O1—H1	0.8400	C3—C4	1.390 (2)
C2'—C3'	1.386 (2)	C3—H3	0.9500
C2'—C1'	1.3943 (19)	C4—C5	1.384 (2)
C3'—C4'	1.385 (2)	C4—H4	0.9500
C3'—H3'	0.9500	C5—C6	1.385 (2)
C4'—C5'	1.383 (2)	C6—H6	0.9500
C5'—C6'	1.385 (2)
C1'—O1'—C2	117.26 (10)	C6'—C1'—C2'	118.84 (12)
C1—O1—H1	109.5	O1—C1—C2	117.92 (11)
C3'—C2'—C1'	121.42 (13)	O1—C1—C6	122.55 (12)
C3'—C2'—Cl2'	118.69 (11)	C2—C1—C6	119.53 (12)
C1'—C2'—Cl2'	119.88 (10)	C3—C2—C1	120.82 (13)
C4'—C3'—C2'	118.38 (13)	C3—C2—O1'	119.73 (13)
C4'—C3'—H3'	120.8	C1—C2—O1'	119.28 (12)
C2'—C3'—H3'	120.8	C2—C3—C4	120.08 (14)
C5'—C4'—C3'	121.27 (14)	C2—C3—H3	120.0
C5'—C4'—Cl4'	120.65 (12)	C4—C3—H3	120.0
C3'—C4'—Cl4'	118.08 (12)	C5—C4—C3	118.50 (13)
C4'—C5'—C6'	119.53 (14)	C5—C4—H4	120.7
C4'—C5'—H5'	120.2	C3—C4—H4	120.7
C6'—C5'—H5'	120.2	C4—C5—C6	122.12 (13)
C1'—C6'—C5'	120.55 (14)	C4—C5—Cl5	119.45 (11)
C1'—C6'—H6'	119.7	C6—C5—Cl5	118.43 (11)
C5'—C6'—H6'	119.7	C5—C6—C1	118.86 (13)
O1'—C1'—C6'	124.54 (12)	C5—C6—H6	120.6
O1'—C1'—C2'	116.62 (12)	C1—C6—H6	120.6
C1'—C2'—C3'—C4'	0.0 (2)	O1—C1—C2—C3	176.72 (13)
Cl2'—C2'—C3'—C4'	179.16 (11)	C6—C1—C2—C3	−3.6 (2)
C2'—C3'—C4'—C5'	−0.9 (2)	O1—C1—C2—O1'	1.58 (18)
C2'—C3'—C4'—Cl4'	179.05 (11)	C6—C1—C2—O1'	−178.77 (12)
C3'—C4'—C5'—C6'	1.3 (2)	C1'—O1'—C2—C3	91.92 (15)
Cl4'—C4'—C5'—C6'	−178.67 (12)	C1'—O1'—C2—C1	−92.88 (15)
C4'—C5'—C6'—C1'	−0.7 (2)	C1—C2—C3—C4	2.1 (2)
C2—O1'—C1'—C6'	3.11 (19)	O1'—C2—C3—C4	177.26 (14)
C2—O1'—C1'—C2'	−177.55 (12)	C2—C3—C4—C5	0.4 (2)
C5'—C6'—C1'—O1'	179.10 (13)	C3—C4—C5—C6	−1.6 (2)
C5'—C6'—C1'—C2'	−0.2 (2)	C3—C4—C5—Cl5	177.53 (12)
C3'—C2'—C1'—O1'	−178.78 (13)	C4—C5—C6—C1	0.1 (2)
Cl2'—C2'—C1'—O1'	2.03 (17)	Cl5—C5—C6—C1	−179.02 (11)
C3'—C2'—C1'—C6'	0.6 (2)	O1—C1—C6—C5	−177.86 (12)
Cl2'—C2'—C1'—C6'	−178.59 (11)	C2—C1—C6—C5	2.50 (19)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O1^i	0.84	1.97	2.8058 (10)	171

Symmetry code: (i) −y, x−y, z+1/3.