Structural, Thermodynamic, and Kinetic Aspects of the Polymorphism

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Structural, Thermodynamic and Kinetic Aspects of the Polymorphism of Trimethylthiourea: The Influence of Kinetics on the Transformations between Polymorphs Christian Näther, Inke Jeß, Peter G. Jones, Christina Taouss, and Nicole Teschmit Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg400005d • Publication Date (Web): 20 Feb 2013 Downloaded from http://pubs.acs.org on February 22, 2013

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Crystal Growth & Design

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Structural, Thermodynamic and Kinetic Aspects of the Polymorphism of Trimethylthiourea: The Influence of Kinetics on the Transformations between Polymorphs Christian Näther,† Inke Jess,† Peter G. Jones*§, Christina Taouss§and Nicole Teschmit§ †

Institut für Anorganische Chemie, Christian-Albrechts-Universität zu Kiel, Max-Eyth-Str. 2, D-24118, Kiel, Germany. §

Institut für Anorganische und Analytische Chemie, Technische Universität Braunschweig, Postfach 3329, D-38023 Braunschweig.

ABSTRACT: Trimethylthiourea crystallizes in two different polymorphic modifications. Polymorph I crystallizes in the monoclinic space group P21/c with Z = 8, whereas polymorph II crystallizes in the alternative setting of the same space group, P21/n with Z = 4. Both polymorphs form chains of molecules linked by hydrogen bonds N–HLS=C via glide planes, with translational repeats after four molecules (the two independent molecules alternate) or two molecules respectively. Interplanar angles between molecules in the chain differ appreciably between I and II, and for I one hydrogen bond is very non-planar with respect to the N2C=S acceptor plane. Solvent-mediated conversion experiments prove that polymorph II is the thermodynamically stable polymorph at room temperature, where I is metastable, and that I can be obtained by solidification of the melt. On heating I transforms slowly into II with no detectable transfer of energy and, on further heating, melting of this polymorph is observed. DSC experiments reveal that I exhibits the higher melting point and the lower heat of fusion ACS Paragon Plus Environment


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and, therefore, the polymorphs are related by enantiotropy, with I being stable at higher temperatures. Isothermic DSC experiments prove that the thermodynamic transition point is between 70 °C and 80 °C, in agreement with the value calculated from the melting enthalpy and the melting point of both polymorphs. Further experiments reveal that at very low heating rates II initially melts and that I crystallizes from the liquid and melts on further heating. This process can only be observed if crystals of polymorph I are present during melting of II, in order to induce crystallization of polymorph I.

INTRODUCTION Polymorphism, which is defined as the ability of a compound to crystallize in different crystal forms, is a widespread phenomenon and is of great importance in academic and industrial research.1-7 Although the differing structural aspects are clearly of importance, one should also investigate how the different polymorphs are thermodynamically related and how a specific polymorph can be prepared selectively and some examples are given in the reference list.1,

8-17

In this context it must also be kept in mind that the kinetics strongly

influence the transformation of the different polymorphs, and thus determine whether they can be observed or not.18-20 We are especially interested in the structures and polymorphism of urea derivatives and, in a recent paper on the polymorphism of 1,3-dimethylurea we provided a selection of some recent specific examples of polymorphism studies taken from our own work.21 We recently determined the structure of trimethylurea, the last remaining gap in the series of methylureas.22 We now turn our attention to methylthioureas, for which the structures of 1methylthiourea23 and 1,1-dimethylthiourea24 have been determined. Here we report the structures and interrelationships between two polymorphs of trimethylthiourea (henceforth TMTU), one of which corresponds to the unit cell reported by Gilli et al (Scheme 1).25

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Scheme 1. Structural formula of trimethylthiourea (TMTU)

EXPERIMENTAL SECTION Chemicals and crystal growth. TMTU was purchased from TCI (Tokyo) and recrystallized from a wide variety of solvent mixtures. Polymorph II (space group P21/n, Z = 4) consisted of colourless tablets and was obtained in almost all cases, the measured crystal being obtained by liquid diffusion of pentane into a solution of TMTU in THF. Crystals of the alternative polymorph I (space group P21/c, Z = 8), in the form of more equidimensional blocks, were obtained on one occasion by liquid diffusion of pentane into a solution of TMTU in dichloromethane. All attempts to repeat this crystallization, even under apparently identical conditions, were unsuccessful. However, we later found that a microcrystalline powder of this polymorph can be obtained on solidification of the melt (see below). X-ray Crystallography. Details of intensity measurements and refinements are given in Table 1. Crystals were mounted in inert oil on glass fibres. Data were measured with an Oxford Diffraction Xcalibur E diffractometer; multi-scan absorption corrections were performed with the routine CrysalisPro from Oxford Diffraction.26 The structures were solved with direct methods using SHELXS-97 and structure refinement was performed with fullmatrix least-squares on F2 using SHELXL-97.27 Molecular graphics were prepared with XP.28 All crystallographic details (excluding structure factors) have been deposited as Supporting Information in the form of crystallographic information files (CIF files).



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X-ray Powder Diffraction. XRPD experiments were performed with Cu Kα radiation (λ =1.5406 Å) using a Transmission Powder Diffraction System from Stoe & Cie, which is equipped with a linear position-sensitive detector (∆2θ = 6.5–7°) and an Image Plate detector (scan range overall: 0–127°) also from Stoe & Cie. It is well known that significant differences can be observed between experimental X-ray powder patterns, which are generally measured at room temperature, and those calculated from single crystal data measured at low temperatures. Therefore, the structure of polymorph II was additionally determined at room temperature in order to recalculate the X-ray powder pattern. Unfortunately, this was not possible for polymorph I because we were not able to prepare further single crystals of this polymorph. Therefore, the lattice parameters at room temperature were determined from a Rietveld fit of an experimental pattern and these parameters were used to calculate the pattern based on the low-temperature single crystal structure determination. By this procedure one obtains an reasonable agreement between the experimental and calculated patterns, but several powder patterns are affected by strong texture effects. Differential Scanning Calorimetry. The DSC experiments were performed using a DSC 1 Star System with STARe Excellence Software from Mettler-Toledo AG. All measurements were performed in Al crucibles under a continuous flow of nitrogen using heating rates between 0.1 and 60 °C/min.


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Table 1. Experimental details of the two structure determinations Polymorph

I

II

Chemical formula

C4H10N2S

C4H10N2S

Mr

118.20

118.20

Crystal system, space group

monoclinic, P21/c

monoclinic, P21/n

Temperature (K)

100

100

a (Å)

8.5206(3)

4.9388(2)

b (Å)

7.8048(3)

11.6530(4)

c (Å)

18.6978(5)

11.0955(5)

β (°)

90.034(3)

101.202(4)

V(Å3)

1243.43(7)

626.40(4)

dcalc (g/cm-3)

1.263

1.253

Z

8

4

Radiation

Mo Kα, λ = 0.71073 Å

Mo Kα, λ = 0.71073 Å

F(000)

512

256

µ (mm–1)

0.40

0.40

Crystal size (mm)

0.2 × 0.18 × 0.18

0.3 × 0.2 × 0.05

Transmissions

0.975–1.000

0.934–1.000

2θmax

55.6

62

No.

of

measured

and 34910, 3225

31347, 1887

independent reflections Completeness

100%

98.6% to 61°

Rint

0.037

0.035

wR(F2) all refl., R1 [F > 0.0632, 0.0253, 1.06

0.0616, 0.0249, 1.06

4σ(F)], S(F2) No. of parameters

141

H atom treatment

NH

∆ρmax,min (e Å–3)

71 free,

rigid

idealized NH

free,

methyls

methyls

0.31, –0.25

0.33, –0.19


rigid

idealized


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RESULTS AND DISCUSSIONS Crystal structure of polymorph II. The molecule of II is shown in Figure 1; it is planar (except for hydrogen atoms) to within an r.m.s. deviation of 0.01 Å. Molecular dimensions may be regarded as normal. Because the molecule is to a reasonable approximation rigid, a librational correction can be applied (see caption to Figure 1). The N3–H group is trans to S=C across the central N3–C2 bond. This is the usual pattern for RNH groups in methylureas where both cis and trans forms would potentially be possible, and one may speculate22 that this facilitates common patterns of hydrogen bonding.29 In thioureas, however, the situation is less clear-cut; in methylthiourea, for instance, the corresponding MeNH moiety has the hydrogen atom cis to C=S in the solid state, whereas both forms coexist in solution.23

Figure 1. The molecule of polymorph II in the crystal. Ellipsoids correspond to 50% probability levels. Molecular dimensions (Å, °): C2–S1 1.7032(9), C2–N1 1.3481(12), N1– C11 1.4626(12), N1–C12 1.4634(11), N3–C2 1.3480(11), N3–C31 1.4543(12), C2–N1–C11 120.98(8), C2–N1–C12 120.64(8), C11–N1–C12 118.37(8), C2–N3–C31 123.40(8), C2–N3– C31 123.40(8), N3–C2–N1 117.02(8), N3–C2–S1 120.25(7), N1–C2–S1 122.73(7). Librationally corrected bond lengths30 (Rlib = 0.055): C2–S1 1.707, C2–N1 1.349, N1–C11 1.466, N1–C12 1.467, N3–C2 1.351, N3–C31 1.455.


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A search of the Cambridge Database31 (CCDC, Version 1.14) for ureas, excluding metal complexes, polyureas and cyclic systems, gave 1131 RNH fragments, of which 1079 had absolute O=C–N–H torsion angles in the range 145–180°; a similar search for thioureas gave 384 fragments, for 241 of which the S=C–N–H torsion angles lay in the range 146–180° (but also 142 between 0° and 21.5°). Allen et al.32 have shown that the C=S group of thioureas is a good hydrogen bond acceptor, much more so than the C=S group of thiones; this may be attributed to resonance effects causing a weakening of the C=S bond (mean bond length in thioureas 1.681 Å) and a transfer of negative charge to the sulfur atom. Consistent with this, the packing of II involves hydrogen bond systems N3–H03LS1=C2, which link the molecules via the n glide plane to form chains with the simple graph set C(4) parallel to [101] (Figure 2a, Table 2).33 Each molecule is translationally equivalent to the molecule two positions farther along the chain. Such chains represent a standard packing pattern for substituted ureas29, and were also observed for trimethylurea22; the interplanar angles between successive molecules in the chain are however completely different, being 72.88(2)° for II but essentially 0° for trimethylurea, which has two independent chains. The H03LC2=S1 angles of 120.4(3)° are consistent with the assumed direction of the lone pairs at sulfur, but the hydrogen lies 0.93(2) Å out of the molecular plane (the tendency of hydrogen bonds at thioureas to be formed well outside the molecular plane of the acceptor sulfur was also established and discussed by Allen et al.32 Contacts H12BLS1, acceptably short and linear enough to be regarded as "weak" hydrogen bonds, although the donor H12B lies as much as 2.5 Å out of the plane of the acceptor molecule, link the chains to form corrugated layers parallel to (10 1 ). It is however difficult to decide whether such contacts represent significant interactions; there are six further HmethylLS1 contacts between 3.04 and 3.32 Å. The chains themselves pack in a slightly distorted hexagonal pattern (Figure 2b).



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Figure 2. Packing diagrams of polymorph II. (a, top): Chains formed by hydrogen bonding. The view direction is perpendicular to (101). Classical hydrogen bonds are drawn as thick dashed lines and "weak" hydrogen bonds as thin dashed lines. (b, below): View projected along the chains.

Crystal structure of polymorph I. The two independent molecules of I are shown in Figure 3. Again a libration correction is possible (see caption to Figure 3). The two molecules are essentially planar except for hydrogen atoms (r.m.s. deviations from planarity 0.04 and 0.05 Å) and are effectively identical to each other and also to the molecule of II; least-squares fits of molecule 1 (unprimed) to molecule 2 (primed), and of molecule 1 to the molecule of II, ACS Paragon Plus Environment

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both show r.m.s. deviations of 0.06 Å. There is some variation in the Cmethyl–N–Cmethyl angle, which in molecule 2 seems rather narrow at 115.00(9)°, but a search of the CCDC returned a mean value of 115.4° for 95 examples of Me2N groups in ureas.

Figure 3. Both independent molecules of polymorph I in the crystal, showing the classical hydrogen bond between them. Ellipsoids correspond to 50% probability levels. Molecular dimensions (Å, °) for both molecules (unprimed molecule first): S1–C2 1.7060(10), 1.7066(11), N1–C2 1.3467(13), 1.3479(14), N1–C12 1.4604(13), 1.4591(14), N1–C11 1.4629(13), 1.4594(14), N3–C2 1.3445(14), 1.3450(14), N3–C31 1.4527(14), 1.4554(14); C2–N1–C12 120.94(9), 122.22(9), C2–N1–C11 120.49(9), 122.73(10), C12–N1–C11 117.54(9), 115.00(9), C2–N3–C31 124.05(9), 123.43(10), N3–C2–N1 117.20(9), 117.10(9), N3–C2–S1 121.28(8), 119.96(8), N1–C2–S1 121.52(8), 122.92(8). Librationally corrected bond lengths30 (Rlib = 0.061, 0.071): C2–S1 1.710, 1.711, C2–N1 1.348, 1.349, N1–C11 1.467, 1.464, N1–C12 1.464, 1.463, N3–C2 1.349, 1.349, N3–C31 1.455, 1.457.

The packing of I is based on the same type of chain as in II (Figure 4), involving hydrogen bond systems N3–H03LS1'=C2' and N3'–H03'LS1=C2, which link the molecules via the c glide plane to form chains parallel to the c axis (Table 2). This is topologically equivalent to a chain parallel to [101] generated via the n glide plane in the alternative setting of P21/c, which is the situation in polymorph II.



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Figure 4. Packing diagrams of polymorph I. (a, top): Chains formed by hydrogen bonding. The view direction is approximately perpendicular to (110). Classical hydrogen bonds are drawn as thick dashed lines. Methyl hydrogen atoms are omitted for clarity. Operators: (i) x, 1½–y, ½+z; (ii) x, 1½–y, –½+z. (b, below): View projected along the chains. Atoms S1 are closer to the local mirror plane of each chain than S1'.

However, there are some important differences. First, the two independent molecules alternate in every chain, and the two C(4) graph sets are formally independent. Secondly, the interplanar angles between molecules of the chain are more varied; considering the sequence of molecules 1ii / 2 / 1 / 2i / 1i (Figure 4a), interplanar angles between neighbouring molecules are alternately 71.26 and 78.06°, whereas the angles 1ii / 1 and 2 / 2i are 47.2 and 7.2° respectively (all e.s.d.'s 0.02°). Only every fourth molecule is equivalent by translation. Thirdly, the H03LS1'=C2' and H03'LS1=C2 angles in the chain are 91.7(3) and 123.2(3)° ACS Paragon Plus Environment

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respectively, but the hydrogen donors lie 0.69(2) and 2.40(1) Å out of the plane of the respective acceptor molecules, and the latter value is formally inconsistent with lone pair directionality at sulfur. Fourthly, there are no HmethylLS contacts < 2.99 Å, but then seven in the range 3.00–3.31 Å for S1 and six in the range 2.99–3.22 Å for S1'. Of these, the bifurcated system (H11F, H12E)LS1 (1–x, ½+y, ½–z) between neighbouring chains, with HLS contact distances of 3.00 and 3.03 Å, may be significant, but is not drawn explicitly in Figure 4a. The chains of polymorph I pack hexagonally, but in a more distorted fashion than II (Figure 4b).

Table 2. Details of hydrogen bonding [Å and °]. Polymorph I ___________________________________________________________________________ D–HLA

d(D–H)

d(HLA)

d(DLA)

Structural, Thermodynamic, and Kinetic Aspects of the Polymorphism

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