Polymorphism and phase transition behavior of 6,6′-bis­(chloro­meth­yl)-1,1′,4,4′-tetra­methyl-3,3′-(p-phenyl­enedimethyl­ene)bis­(piperazine-2,5-dione)

Abstract

A crystallographic investigation of the title compound, C₂₂H₂₈Cl₂N₄O₄, using crystals obtained under different crystallization conditions, revealed the presence of two distinct polymorphic forms. The mol­ecular conformation in the two polymorphs is very different: one adopts a ‘C’ shape, whereas the other adopts an ‘S’ shape. In the latter, the molecule lies across a crystallographic twofold axis. The ‘S’-shaped polymorph undergoes a reversible ortho­rhom­bic-to-monoclinic phase transition on cooling, whereas the structure of the ‘C’-shaped polymorph is temperature insensitive.

Comment

Sporidesmins are a diverse class of natural products con­taining mol­ecules with one or two epidithio­dioxopiperazine (ETP) rings that display a wide variety of biological activities (Waksman & Bugie, 1944 ▶; Saito et al., 1988 ▶; Fujimoto et al., 2004 ▶; Gardiner et al., 2005 ▶; Li et al., 2006 ▶). While toxic to mammalian cells, studies have suggested that certain sporidesmins, namely bis-ETPs chetomin (Waksman & Bugie, 1944 ▶) and chaetocin (Hauser et al., 1970 ▶), may possess anti­cancer activity due to their ability to suppress neovascularization (Waksman & Bugie, 1944 ▶; Hauser et al., 1970 ▶; McInnes et al., 1976 ▶; Brewer et al., 1978 ▶; Kung et al., 2004 ▶). In order to understand better the chemistry and biology of the bridged bis-ETPs, diketopiperazines (1,4-piperazine-2,5-diones, DKPs) (Martins & Carvalho, 2007 ▶) and bridged bis-DKP structures lacking a disulfide bridge must also be studied. Even in the absence of the disulfide bridge many compounds of this class exhibit a broad spectrum of inter­esting biological activity. Natural products, such as ditryptophenaline (Springer et al., 1977 ▶), WIN-64821,WIN-64745 (Barrow et al., 1993 ▶; Popp et al., 1994 ▶) and leptosin S (Yamada et al., 2004 ▶) incorporate a 3a,3a′-bis­pyrrolidinoindoline core with contiguous stereogenic quaternary carbons and display cytotoxicity in various cell lines. Perhaps the most inter­esting is a C ₂-symmetrical piperazine-2,5-dione (WIN-64821), which is a competitive substance-P antagonist against the human NK1 receptor at submicromolar concentrations (Barrow et al., 1993 ▶; Popp et al., 1994 ▶; Oleynek et al., 1994 ▶; Sedlock et al., 1994 ▶) and also serves as an antagonist of the cholecystokinin type-B receptor (Hiramoto et al., 1994 ▶). The title compound, (I), was synthesized as part of a wider project to develop new synthetic methods for the preparation of bridged bis-DKPs (Polaske et al., 2009 ▶). Unlike other model compounds, which we observed to crystallize consistently in one form only, this compound crystallizes as at least two polymorphic forms, obtained by different methods of crystallization. The mol­ecular structures of the polymorphs are very different: one adopts a ‘C’ shape, (1), while the other adopts an ‘S’ shape, (2). The ‘S’-shaped polymorph also undergoes a reversible ortho­rhom­bic-to-monoclinic phase transition upon cooling (the ‘C’-shaped structure is insensitive to temperature).

The mol­ecular structure of polymorph (1) is shown in Fig. 1 ▶. The ‘C’ shape is supported by weak distorted intra- and inter­molecular C—H⋯O inter­actions (Table 1 ▶) and by Cl⋯Cl inter­actions (Fig. 2 ▶). The Cl1⋯Cl2ⁱ [symmetry code: (i) x − 1, y, z − 1] distance is 3.445 (4) Å and the pertinent angles are C5—Cl1⋯Cl2ⁱ = 143.9 (4)° and C22ⁱ—Cl2ⁱ⋯Cl1 = 168.9 (5)°. This is slightly longer than the mean Cl⋯Cl distance of 3.38 Å obtained by a search of the Cambridge Structural Database (CSD, Version 5.30 plus three updates; Allen, 2002 ▶) for Cl⋯Cl contact distances between two Cl atoms (not including those reported structures with Cl⋯Cl inter­actions between dichloro­methane and chloro­form), yielding 774 hits. Two (8) rings, one inter­molecular and one intra­molecular, are formed by C—H⋯O inter­actions. In all cases, the C—H⋯O inter­actions are weak, with poorly activated H atoms, long H⋯O distances and the motif is rather distorted. Nevertheless, these motifs represent the favorable arrangement of mildy electropositive and electronegative sites such as to maximize electrostatic inter­action; they are not a direct cause of the ‘C’ shape, nor are they merely an effect of the shape.

Figure 1.

The ‘C’-shaped mol­ecular structure of polymorph (1), with displacement ellipsoids at the 30% probability level and H atoms omitted.

Table 1. Hydrogen-bond geometry (Å, °) for polymorph (1) .

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C2—H2⋯O3i	1.00	2.49	3.487 (14)	173
C4—H4⋯O4	1.00	2.64	3.379 (13)	131
C18—H18⋯O1	1.00	2.39	3.372 (14)	167

Symmetry code: (i) .

Figure 2.

Weak C—H⋯O (dotted blue lines in the electronic version of the paper) and Cl⋯Cl (dotted green lines) link adjacent mol­ecules of polymorph (1) into a chain. (In the electronic version of the paper, red dotted lines indicate continuation of the inter­actions.)

The mol­ecular structure of the polymorph determined at room temperature, (2rt), is shown in Fig. 3 ▶. The ‘S’-shaped mol­ecule has crystallographic twofold rotational symmetry and as with polymorph (1) the crystal packing is dominated by an extensive network of weak inter­molecular C—H⋯O inter­actions (Table 2 ▶) with all O atoms acting as bifurcated ‘acceptors’ although as in the case of polymorph (1) the geometry of the inter­actions and the poorly acidic nature of each donor H atom are indicative of very weak hydrogen bonding. In this structure, but here the Cl1⋯Cl1ⁱ [symmetry code: (i) 2 − x, 1 − y, z] distance, at 3.319 (1) Å, is shorter than that observed in (1). The arrangement of C—H⋯O inter­actions is difficult to visualize with one simple diagram; contacts from the discrete crystallographically unique mol­ecule touch eight adjacent mol­ecules but do not form small cyclic motifs as in (1) and this is most easily seen by considering a perspective c-axis plot (Fig. 4 ▶). In Fig. 4 ▶, the discrete unique mol­ecule is shown at the centre of the plot and hydrogen-bonding contacts have been expanded to show all eight acceptor mol­ecules.

Figure 3.

The ‘S’-shaped mol­ecular structure of room-temperature polymorph (2rt), with displacement ellipsoids at the 30% probability level and H atoms omitted. [Symmetry code (twofold rotation): (i) −x + 1, −y, z.]

Table 2. Hydrogen-bond geometry (Å, °) for polymorph (2rt) .

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C6—H6C⋯O1i	0.96	2.42	3.255 (4)	145
C8—H8B⋯O1ii	0.97	2.68	3.463 (3)	138
C5—H5B⋯O2iii	0.97	2.67	3.323 (3)	125
C7—H7C⋯O2iv	0.96	2.50	3.415 (4)	158

Symmetry codes: (i) ; (ii) ; (iii) , ; (iv) .

Figure 4.

A perspective c-axis plot of part of the crystal packing of room-temperature polymorph (2rt). The discrete unique mol­ecule in the centre of the plot (colored red in the electronic version of the paper) is surrounded by eight hydrogen-bonding acceptor mol­ecules, although hydrogen bonding does not form small cyclic motifs as in polymorph (1).

The structural behavior of polymorph (2) was first noted by comparison of experimental X-ray powder diffraction patterns, which were measured at room temperature, with calculated X-ray powder diffraction patterns based on a low-temperature (100 K) single-crystal structure. The two did not match and it was then that a room-temperature single-crystal analysis was carried out. Although we have not carried out a systematic variable-temperature study of this compound, flash cooling to 100 K produces a single-crystal structure, (2lt), with some striking differences when compared with (2rt). The compound undergoes an ortho­rhom­bic-to-monoclinic phase transition; the obvious effect of this reduction in symmetry is loss of the twofold axis and consequently loss of crystallographically imposed symmetry on the discrete mol­ecule (Fig. 5 ▶). Although the mol­ecule retains an ‘S’ shape, the two piperazinedione rings are able to twist further away from the central benzene ring. In (2lt), the torsion angles about the methyl­ene linker are 109.9 (3) (C2—C8—C9—C14) and 94.2 (4)° (C13—C12—C15—C16), whereas in (2rt) the equivalent torsion angle is 76.0 (3)°. This reduction in symmetry also causes the onset of nonmerohedral twinning in the monoclinic structure; this is typical behavior in such situations. The crystal packing of (2lt) is not significantly different from that of (2rt) except that the twisting of the piperazinedione rings causes a change in the weak hydrogen-bonding geometry (Table 3 ▶), resulting in shorter H⋯O distances. For example, in (2rt), the approximate distance between H2 and O1ⁱ [symmetry code: (i)  + x, y, 1 − z] is approximately 2.81 Å; in (2lt) the equivalent distance, H2⋯O3^vi [symmetry code: (vi) −x,  + y, 1 − z] is approximately 2.56 Å. The Cl1⋯Cl2ⁱⁱ [symmetry code: (ii) x,  + y, z − 1] distance in (2lt) is the shortest of all three structures at 3.2414 (11) Å. This behaviour of polymorph (2) was found to be reversible and the crystal suffered no physical defects (e.g. cracking) as a result of the phase change.

Figure 5.

The ‘S’-shaped mol­ecular structure of low-temperature polymorph (2lt), with displacement ellipsoids at the 30% probability level and H atoms omitted.

Table 3. Hydrogen-bond geometry (Å, °) for polymorph (2lt) .

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C2—H2⋯O3i	1.00	2.56	3.362 (4)	137
C4—H4⋯O4ii	1.00	2.56	3.296 (4)	130
C5—H5A⋯O2iii	0.99	2.52	3.167 (4)	123
C6—H6B⋯O3i	0.98	2.30	3.215 (4)	154
C7—H7B⋯O4ii	0.98	2.43	3.361 (4)	159
C8—H8A⋯O1iv	0.99	2.68	3.539 (4)	145
C15—H15A⋯O3v	0.99	2.60	3.307 (4)	129
C20—H20B⋯O1vi	0.98	2.33	3.246 (4)	154
C21—H21B⋯O2vii	0.98	2.40	3.353 (4)	165
C22—H22A⋯O2vii	0.99	2.63	3.302 (4)	125
C22—H22A⋯O4viii	0.99	2.70	3.371 (4)	125

Symmetry codes: (i) ; (ii) ; (iii) , ; (iv) ; (v) ; (vi) ; (vii) ; (viii) .

In summary, two polymorphs of the title compound have been identified. Both polymorphs differ entirely in their mol­ecular conformation and consequently in the crystal packing. ‘C’-shaped monoclinic polymorph (1) is insensitive to temperature change; ‘S’-shaped polymorph (2) is ortho­rhom­bic at room temperature but forms a monoclinic nonmerohedrally twinned structure when flash cooled to 100 K. The weak inter- and intra­molecular inter­actions in (1) are more conducive to retaining the ‘C’ shape as is and probably prevent such temperature-induced behavior.

Experimental

To a suspension of 6,6′-dihydroxy-1,1′,4,4′-tetra­methyl-3,3′-(p-phenyl­enedimethyl­ene)bis­(piperazine-2,5-dione) (Polaske et al., 2009 ▶) (45 mg, 0.10 mmol) in CH₂Cl₂ (5 ml), triphenyl­phosphine (130 mg, 0.50 mmol) and hexa­chloro­acetone (76 µl, 0.50 mmol) were added. After stirring at room temperature for 18 h, the solvent was removed and the residue resuspended in a 1:1 mixture of acetonitrile and water (5 ml). The solids were filtered off and the filtrate was purified by semipreparative HPLC using a 5–95% gradient of 0.05% trifluoro­acetic acid in acetonitrile, yielding crystals of form (1) as small colorless rods. Recrystallization of (1) from ethanol yielded crystals of form (2) (26 mg, 54% yield) as colorless prisms. ¹H NMR (500 MHz, CDCl₃): δ 6.95 (4H, s), 4.28 (2H, br t, J = 2.5 Hz), 4.02 (2H, dd, J = 12.5 Hz and 1.5 Hz), 3.74 (2H, dd, J = 12.5 Hz and 3.5 Hz), 3.43 (2H, dd, J = 14 Hz and 2.5 Hz), 3.24 (2H, br s), 3.11 (2H, dd, J = 14 Hz and 5 Hz), 3.06 (6H, s), 2.88 (6H, s). ¹³C NMR (150 MHz, CDCl₃): δ 165.6, 163.6, 134.2, 129.8, 69.24, 60.52, 44.19, 37.16, 32.63, 30.68. HRMS (FAB, [M + H]⁺) found: 483.1570, C₂₂H₂₉Cl₂N₄O₄ requires 483.1566.

Polymorph (1)

Crystal data

• C₂₂H₂₈Cl₂N₄O₄

• M _r = 483.38

• Monoclinic,

• a = 8.4158 (17) Å

• b = 14.779 (3) Å

• c = 10.438 (2) Å

• β = 110.58 (3)°

• V = 1215.3 (4) ų

• Z = 2

• Mo Kα radiation

• μ = 0.30 mm⁻¹

• T = 150 K

• 0.32 × 0.13 × 0.07 mm

Data collection

• Nonius KappaCCD diffractometer

• Absorption correction: multi-scan (SADABS; Sheldrick, 1996 ▶) T _min = 0.664, T _max = 0.917

• 8536 measured reflections

• 1649 independent reflections

• 1123 reflections with I > 2σ(I)

• R _int = 0.128

• θ_max = 22.5°

Refinement

• R[F ² > 2σ(F ²)] = 0.080

• wR(F ²) = 0.134

• S = 1.18

• 1649 reflections

• 293 parameters

• 1 restraint

• H-atom parameters constrained

• Δρ_max = 0.30 e Å⁻³

• Δρ_min = −0.29 e Å⁻³

Polymorph (2) at room temperature, (2rt)

Crystal data

• C₂₂H₂₈Cl₂N₄O₄

• M _r = 483.38

• Orthorhombic,

• a = 9.7566 (5) Å

• b = 12.7626 (6) Å

• c = 9.3138 (4) Å

• V = 1159.75 (9) ų

• Z = 2

• Mo Kα radiation

• μ = 0.32 mm⁻¹

• T = 296 K

• 0.20 × 0.15 × 0.09 mm

Data collection

• Bruker Kappa APEXII DUO CCD diffractometer

• Absorption correction: numerical (SADABS; Sheldrick, 1996 ▶) T _min = 0.641, T _max = 0.745

• 15349 measured reflections

• 2288 independent reflections

• 1847 reflections with I > 2σ(I)

• R _int = 0.025

Refinement

• R[F ² > 2σ(F ²)] = 0.037

• wR(F ²) = 0.102

• S = 1.03

• 2288 reflections

• 148 parameters

• H-atom parameters constrained

• Δρ_max = 0.22 e Å⁻³

• Δρ_min = −0.18 e Å⁻³

• Absolute structure: Flack (1983 ▶)

• Flack parameter: −0.03 (8)

Polymorph (2) at low temperature, (2lt)

Crystal data

• C₂₂H₂₈Cl₂N₄O₄

• M _r = 483.38

• Monoclinic,

• a = 9.2208 (13) Å

• b = 12.6517 (19) Å

• c = 9.6894 (15) Å

• β = 92.123 (2)°

• V = 1129.6 (3) ų

• Z = 2

• Mo Kα radiation

• μ = 0.33 mm⁻¹

• T = 100 K

• 0.19 × 0.16 × 0.10 mm

Data collection

• Bruker Kappa APEXII DUO CCD diffractometer

• Absorption correction: multi-scan (TWINABS; Sheldrick, 1996 ▶) T _min = 0.632, T _max = 0.746

• 2919 measured reflections

• 2919 independent reflections

• 2603 reflections with I > 2σ(I)

• R _int = 0.034

Refinement

• R[F ² > 2σ(F ²)] = 0.035

• wR(F ²) = 0.085

• S = 1.02

• 2919 reflections

• 294 parameters

• 1 restraint

• H-atom parameters constrained

• Δρ_max = 0.32 e Å⁻³

• Δρ_min = −0.23 e Å⁻³

• Absolute structure: Flack (1983 ▶)

• Flack parameter: 0.07 (7)

Polymorph (1) showed surprisingly weak diffraction, necessitating exposures of 120 s per frame and even this was sufficient only to yield data with an Rσ < 30% cutoff of 2θ = 45°. Owing to this, the value of the Flack absolute structure parameter (Flack, 1983 ▶) is indeterminate and Friedel pairs were merged, while polymorph (2rt) has a Flack parameter of −0.03 (8) from 953 Friedel pairs, while polymorph (2lt) has a Flack parameter of 0.07 (7) from 2657 Friedel pairs and a nonmerohedral twin scale factor of 0.447 (3). For all structures, H atoms were either placed geometrically [for (1)] or first located in a difference map [for (2)] and then refined with U _iso(H) = 1.5U _eq(C) for methyl H atoms and U _iso(H) = 1.2U _eq(C) for all other H atoms. Fixed C—H distances of 0.95 (ar­yl), 0.98 (methyl and R ₃CH) and 0.99 Å (methyl­ene) were used.

Data collection: COLLECT (Nonius, 1998 ▶) for (1); APEX2 (Bruker, 2007 ▶) for (2). Cell refinement: EVALCCD (Duisenberg et al., 2003 ▶) for (1); SAINT (Bruker, 2007 ▶) for (2rt); CELL_NOW (Sheldrick, 2004 ▶) and SAINT for (2lt). Data reduction: EVALCCD for (1); SAINT for (2). For all compounds, program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶) and Mercury (Macrae et al., 2008 ▶); software used to prepare material for publication: SHELXTL, publCIF (Westrip, 2009 ▶) and local programs.