Polymorphism, Phase Transitions, and Thermal Stability of l

DOI: 10.1021/cg100260f

Polymorphism, Phase Transitions, and Thermal Stability of L-Pyroglutamic Acid

2010, Vol. 10 3141–3148

Han Wu,† Nik Reeves-McLaren,† Jan Pokorny,†,‡ Jack Yarwood,§ and Anthony R. West*,† †

Department of Engineering Materials, University of Sheffield, Sheffield, S1 3JD, U.K., Institute of Physics, Academy of Sciences of the Czech Republic, Na Slovance 2, Prague 8, Czech Republic, and §Materials and Engineering Research Institute, Sheffield Hallam University, Norfolk Building, Howard Street, Sheffield, S1 1WB, U.K. ‡

Received February 25, 2010; Revised Manuscript Received June 3, 2010

ABSTRACT: L-Pyroglutamic acid undergoes a phase transition, R f β, at ∼68 °C on heating, which is reversible with hysteresis depending on the cooling rate, before melting at ∼162 °C. On cooling, a further reversible transition, R f R0 , which shows martensitic characteristics, occurs at ∼ -140 °C. The structural changes at the transitions were studied by variable temperature X-ray powder diffraction and Raman spectroscopy and compared with reports of single crystal structure determinations. Differences in Raman spectra were attributed to differences in intermolecular N-H 3 3 3 O interactions in the three enantiotropic polymorphs. By optical microscopy, crystals frequently jumped around the microscope slide on passing through the R/β transition; this is attributed to discontinuous changes in the unit cell dimensions leading to a spring effect in the crystals.

1. Introduction The pyroglutamic acid, 2-oxopyrrolidone-5-carboxylic acid (P), Figure 1a, is a five-membered lactam of glutamic acid (Glu), Figure 1b. Both P and Glu are chiral molecules, with the chiral centers marked by an asterisk in Figure 1. P is the chain-terminator or N-terminal residue of a number of biologically significant proteins and peptides.1-3 It occurs naturally in fruits, some plant foods, dairy, and fermented products such as soy sauce and can be produced by thermal dehydration and cyclization of Glu.4,5 In neurology, the brain-boosting effects of P were discovered in 1984.6 It plays an important role in the preservation and activity of the key neurotransmitters acetylcholine, gamma-aminobutyric acid (GABA) and Glu;6-8 it readily passes the blood-brain barrier to stimulate cognitive-enhancing function in rats9 and reduce age-associated memory decline in humans.10 In drug delivery, P esters can be used as dermal penetration enhancers for therapeutic agents having poor skin permeation11 or hair growth agents.12 In chemical synthesis, it has been used as a versatile chiral building block in asymmetric synthesis of alkaloids,13 pharmaceuticals, and many other natural products;14-18 its derivatives have been extensively applied for enantioselective synthesis.19,20 L-P is also known as a novel organic nonlinear optical (NLO) material for tunable UV harmonic generation down to 266 nm at room temperature.21 Most organic NLO materials containing nitro groups have the following characteristics. They are not transparent in the UV region; difficult to grow as large optical-quality single crystals; susceptible to damage during processing; and not suitable for commercial applications due to their poor thermal, mechanical, and chemical stability.22 In spite of this, however, L-P containing an amide group instead of a nitro group was reported recently to show good NLO performance:23,24 large single crystals grown from

Figure 1. (a) Pyroglutamic acid, P, and (b) glutamic acid, Glu.

suitable solution are chemically stable and have relatively high melting point and good hardness. Although L-P has numerous applications, little information is available on its thermal stability and any possible decomposition products or polymorphic transformations. Recently, we discovered that at elevated temperatures, L-P forms by cyclization of L-Glu, even in the absence of a catalyst or aqueous solution.25 The complete transformation sequence on heating L-Glu appears to be R L-Glu f β L-Glu f P f polyglutamic acid, PGA L-Glu is a widely used food additive and flavor enhancer in its

*Author for correspondence: Tel: þ44(0)114 2225501. Fax: þ44(0)114 2225943. E-mail: [email protected].

sodium salt form and also has many applications for treatment of neurological disorders.26-28 The thermal stability of both L-Glu and L-P is, therefore, important in the food and pharmaceutical industries. The crystal structures of L- and DL-forms of P have been reported.29,30 There is a suggestion that L-P is dimorphic and that solution-grown single crystals of two polymorphs can be obtained from different solvents,24 but this claim appears to be based entirely on crystal morphology without any other characterization such as crystal structure data. There is also a suggestion of a structural change at 64 °C by Fourier transform IR (FTIR) and differential scanning calorimetry (DSC) results,32 but no crystallographic characterization of the high temperature structure was reported. In this paper, we report a study of the thermal stability of L-P and find evidence for both a high temperature polymorph

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that we label β, the ambient temperature polymorph, R (note: we use R, β as polymorphic labels and do not refer to substituents on specific C atoms) and a low temperature polymorph, R0 . To study the phase transformations, a set of complementary techniques, X-ray powder diffraction (XRD), Raman spectroscopy, thermogravimetry (TGA), DSC, and optical microscopy, was used. 2. Experimental Section All experiments were performed with high-purity L-P (purity reported to be >99%, Sigma-Aldrich, UK). As shown later, however, a small amount (∼1.4%) of racemic DL-P was found to be present. Phase characterization and determination of unit cell parameters of L-P at different temperatures were performed using a STOE STADI P X-ray powder diffractometer, Mo KR1, λ = 0.70926 A˚, equipped with a linear position sensitive detector (PSD), over the 2θ range 4.5° to 24.0°, in Debye-Scherrer geometry. Temperature control was obtained by an Oxford Systems Cryo Cooler 700, with a built-in thermocouple measuring the temperature (in the range -180 to 120 °C with a temperature stability of 0.1 °C) at the bottom of the nozzle, underneath which a capillary sample was located. Thermal transformations of L-P were analyzed by DSC using two different instruments, a Perkin-Elmer DSC 7 under dry Ar and Perkin-Elmer DSC 1 equipped with liquid N2 cooling system under dry He. Heat flow was calibrated using In (MPt = 156.6 °C, ΔH = 28.45 J/g). The powder was weighed into an Al sample pan fitted with a perforated lid. Samples were heated/cooled between -155 and 200 °C. Rates varied from 1 to 50 °C/min. The weight loss during heating was quantified by thermogravimetric analysis (TGA) using a Perkin-Elmer Pyris1 TGA system. Samples were heated from 30 to 300 at 10 °C/min in flowing dry N2. In situ monitoring of L-P on heating was performed using hot-stage Raman spectroscopy. Unpolarized Raman spectra were excited with the 514.5 nm line of an Ar laser and recorded in back scattering geometry using a Renishaw InVia micro-Raman spectrometer. Laser power of ∼20 mW was focused on a ∼2 μm spot. The spectrometer was equipped with a Peltier-cooled multichannel CCD detector and diffraction grating 2400 L/mm with slit opening 65 μm and spectral resolution ∼1 cm-1. Temperature was controlled in the range -190 to 100 °C with 0.1 °C accuracy by a Linkam THMS 600 heating and cooling stage equipped with a TMS 94 temperature controller and LNP 94 liquid nitrogen cooling system. Samples were also observed directly as a function of temperature using a hot-stage polarizing microscope.

3. Results 3.1. DSC Results. A selection of DSC data obtained on various heat-cool cycles starting with L-P and using data from two different instruments is shown in Figure 2 and Supporting Information, Figure S1. In summary, five different heat effects are seen between -155 and 200 °C. On heating from room temperature to 200 °C, three endotherms, 1, 2, and 3, are seen at ∼68 (ΔH1 =0.53 kJ/mol), ∼ 154 (ΔH2 =1.83 kJ/mol), and ∼162 °C (ΔH3 = 16.79 kJ/mol), Figure 2b. The behavior on cooling is, however, more complex. On cooling from temperatures above that of the first endotherm, for example, from 80 °C, an exotherm (ΔH10 =-0.55 kJ/mol) is observed at 54 °C, Figure 2c, but which exhibits considerable hysteresis, especially at faster cooling rates, Figure S1, and is observed at, for example, 3 °C with a cooling rate of 120 °C/min. This indicates that the associated transformation is sluggish on cooling but nevertheless, is reversible. On cooling from temperatures above that of the second endotherm, for example, from 156.5 °C, two exotherms are observed (not shown) with significant hysteresis for peak 2 as well as for peak 1. On cooling from temperatures above peak 3, for example, from 200 °C, without significant holding time prior to cooling, no exotherms are observed, Figure 2b.

Figure 2. (a) TGA curve on heating L-P from 30 to 300 at 10 °C/min. (b) DSC curves on heating/cooling L-P between 30 and 200 °C. DSC heating rate 10 °C/min from 30 to 140 °C, then 2 °C/min to 200 °C. (The change of heating rate at 140 °C, shown by the baseline discontinuity, was to avoid potential contamination/damage of the facility by sample escaping from the container at high temperature.) Cooling rate 10 °C/ min. Temperatures marked refer to peak maxima. (c) DSC curves on cooling and heating L-P between 80 and 20 °C. Heating/cooling rate 10 °C/min. (d) DSC (using Perkin-Elmer DSC 1 coupled with liquid N2 cooling system) curves on cooling and heating L-P between -10 and -155 °C. Heating/cooling rate 10 °C/min between -100 and -10 °C, 5 °C/min between -155 and -100 °C.

We attribute peak 1 to a solid-solid polymorphic phase transformation and label the polymorphs as R and β. The temperature of peak 3 is very close to the reported melting

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Figure 3. XRD patterns of L-P at temperatures between -180 and 120 °C.

temperature of P, ∼162-163 °C,31 and, by visual observation, we confirmed that the sample had melted above ∼160 °C. We attribute peak 2 to the presence of a small amount of DL-P impurity which leads to the onset of melting of L-DL mixtures at the eutectic temperature, ∼154 °C; this will be described and discussed in a subsequent publication. From the literature, there is similar evidence from DSC for the existence of polymorph β, although the DSC peak that was observed at 64 °C was not attributed to a polymorphic transition.32 There is also a claim for the existence of two polymorphs at room temperature based on two different crystal growth morphologies,24 but no further characterization studies were reported. We note, however, that although the β f R transformation can be suppressed by rapid cooling, Figure S1, the β polymorph does not exhibit any longtime stability at room temperature, and we would not expect, with our materials and conditions, to observe a second, longlived polymorph at room temperature. DSC data between -155 °C and -10 °C are shown in Figure 2d. A reversible phase transition with some hysteresis is seen at ∼ -126 °C, which is attributed to a low-temperature polymorphic transition; we label the low-temperature polymorph R0 . On cooling, the R/R0 exotherm has sawtooth character, Figure 2d inset, which may indicate that the transition occurs in bursts, typical of a martensitic transition. In addition, the baseline on subsequent heating shows a broad discontinuity at ∼ -70 °C. We might have attributed this to a glass transition in the sample, but since the sample is crystalline and not amorphous, an alternative explanation is required. At this stage, we do not know the nature of the changes responsible for this heat effect. In summary, the polymorphism of L-P may be represented as follows: ∼ - 126°C

∼68°C

∼162°C

R0 s R s β s liquid R0 , R, and β are enantiotropically related polymorphs. The R0 /R and R/β transitions are reversible on cooling, with hysteresis dependent on cooling rate. The transition temperatures

define the temperature at which the stability relationship between each pair of polymorphs becomes inverted (i.e., their free energy is equal at the transition temperature). However, crystallization of liquid L-P is a relatively slow process and was not observed under the DSC conditions used in our experiments. 3.2. Thermogravimetry. TGA data on heating L-P between room temperature and 300 °C are shown in Figure 2a. Sample mass is constant to ∼190 °C then decreases at higher temperatures. We do not know whether the weight loss is associated with volatilization of the sample or its decomposition. The TGA results do, however, show that the polymorphic transitions at lower temperature and the sample melting do not involve any loss of weight. 3.3. Variable Temperature X-ray Diffraction. A small section of the powder XRD pattern of L-P is shown on an expanded scale for several temperatures in Figure 3. Over the range -100 to 63 °C, small shifts in peak positions to lower 2θ values are seen, consistent with thermal expansion of the R polymorph. Between 63 and 80 °C, significant changes in the positions of several peaks are seen (although no new peaks appear and none disappear). The pattern of the β polymorph at 80 °C can therefore be indexed on the same orthorhombic unit cell, space group P212121, as the R polymorph, but with significantly different lattice parameters, as shown in Table 1 and Figure 4. Basically, a and c expand at the R/β transition, whereas b contracts. This anisotropic change in cell dimensions accounts for the change in XRD patterns, in which some peaks (e.g., (130), (131), and (230)) displace to higher 2θ, others (e.g., (101), (102), (200), and (201)) displace to lower 2θ, and the remainder are essentially unchanged in position. Although individual cell parameters change by ∼1% at the transition, these effects cancel in the unit cell volume, which shows no significant discontinuity, Figure 4d. There are, presumably, small changes in the molecular packing details at the transition, but this result shows that the overall molar volume is essentially unchanged. Over the temperature range -180 to -100 °C, discontinuous changes in the positions of many peaks (e.g., (101), (102), (112), (130), (131), and (104)) occur together with

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Table 1. Lattice Parameters of β, R, and R0 Polymorphs of L-P Determined from Powder XRD at Various Temperatures, in Comparison with Reported R and R0 Data29,33 lattice parameters temperature (°C)

polymorph

a (A˚)

80 40 -180 2529 -15033

β R R0 R29 R0 33

9.086 (6) 8.964 (4) 8.146(2) 9.018 (8)29 8.1972(10)33

b (A˚)

c (A˚)

V (A˚3)

13.140 (6) 13.349 (6) 14.269 (4) 13.495 (8)29 14.340(2)33

14.586 (7) 14.49 (1) 14.610 (5) 14.662 (4)29 14.6661 (15)33

1741 (1) 1733 (1) 1698.2 (6) 1784.3329 1724.1 (4)33

Figure 4. (a-d) Lattice parameters of L-P versus temperature.

significant changes in the intensities of some peaks (e.g., (112) and (130)), Figure 3. Nevertheless, the XRD pattern at -180 °C can also be indexed on an orthorhombic unit cell, space group P212121, as summarized in Table 1 for the lattice parameters of R0 , R, and β polymorphs. Fully indexed X-ray powder diffraction data for R0 (at -180 °C), R (at 40 °C), and β (at 80 °C) are included in Supporting Information and will also be submitted to the International Centre for Diffraction Data for inclusion in the Powder Diffraction File. 3.4. Raman Spectra of r0 , r, and β Polymorphs. Raman spectra of R0 , R, and β polymorphs at -180, 25, and 100 °C, respectively, are shown in Figure 5a. A small number of peaks that are multiplets in the R form become singlets in the β form and triplets in the R0 form. This is seen clearly for the peaks at 3300-3500 cm-1, attributed to NH vibrations, but also for numerous other sets of peaks (unassigned) throughout the spectrum, Figure S2. The changes in Raman spectra associated with NH vibrations over the range -180 to þ80 °C are shown in Figure 5b together with assignment of the spectra to different polymorphs or polymorphic mixtures. Over the range -160 to -130 °C, mixtures of R0 and R are seen, whose relative amounts change systematically with temperature. Similar phase mixtures were seen in XRD data over this temperature range (not shown). The R0 /R transition is characterized by discontinuities in peak positions together with a gradual increase in line widths. Three broad peaks are seen in the R spectrum over most of the temperature range, but these become a single broad peak at the R/β transition.

3.5. Hot Stage Optical Microscopy. By hot stage optical microscopy, significant changes to crystals of L-P were seen on both heating and cooling through the R T β transition, Figure 6. Specifically, some crystals, especially larger ones, jumped around the glass slide holding the samples, as shown by the sequence of micrographs on heating (1-4) and subsequent cooling (5-8). Starting with six crystals in the field of view at 30 and 68 °C, three of these disappeared on increasing the temperature to 69 °C and a further one disappeared on holding at 69 °C. On subsequent cooling, one of the two remaining crystals jumped out of the field of vision at 55 °C and the other one also disappeared on holding at 55 °C. These changes were not associated with evaporation of the sample since no weight loss is seen by TGA but with physical displacement of crystals on passing through the transition. This effect can be explained by the anisotropic change in unit cell dimensions shown in Figure 4. Significant change in crystal dimensions effectively provided a spring-board for some of the crystals to jump off the surface of the glass slide. In these particular examples, the crystals appeared to retain their integrity on passing through the transition. In other cases, however, crystals were seen to fragment, presumably because those crystals were either unable to withstand the dimensional changes and retain their single crystal integrity or were polycrystalline aggregates. Using polarizing microscopy at room temperature in transmission mode, on samples before and after cycling through the R/β transition, it was clear that there remained an abundance of reasonablesized single crystals after cycling. This showed that the dimensional changes associated with the R/β transition were

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Figure 5. Raman spectra of (a) three L-P polymorphs at -180, 25, and 100 °C; (b) R f β and R0 f R phase transitions on expanded scale from -180 to þ80 °C.

Figure 6. Hot-stage polarizing microscope pictures of L-P crystals at different temperatures on heating (1-4) and subsequent cooling (5-8) (Crystals move at ∼69 °C on heating and ∼55 °C on cooling).

not totally disruptive but could be accommodated by a large number of the crystals. 4. Discussion 4.1. Crystal Structures of r and r0 Polymorphs. Crystal structure data are available in the literature on L-P based on single crystal X-ray diffraction data collected at both room temperature29 and -150 °C.33 The low-temperature data are reported in a crystal structure database, but no comparison was made with the room temperature data. Careful comparison of the unit cell parameters of the two data sets with those obtained from our variable temperature powder diffraction

data, Table 1, shows that almost certainly, the low-temperature structure is that of R0 , whereas the room temperature structure is that of R. We are therefore able to make a detailed comparison from these literature data of the structures of R, R0 polymorphs. The R and R0 polymorphs share similar packing arrangements, as shown for a segment of the unit cell of each in Figure 7. Each has chains of L-P molecules parallel to c. Within each chain, molecules are linked via O-H 3 3 3 O hydrogen bonding (HB) between the amide carbonyl and the carboxyl group on neighboring molecules. These chains are then linked together into a three-dimensional structure by N-H 3 3 3 O interactions between amide -NH groups in one chain and sufficiently close acid carbonyl oxygen atoms in neighboring chains. A comparison of the crystal structures indicates that, in both R and R0 , there are three distinct N-H bonds which may, or may not, take part in HB interactions. These are labeled in Figure 8; to facilitate comparison, the atoms in the original structure reports have been relabeled. The transition on cooling from R to R0 is accompanied by a ∼3.4% reduction in unit cell volume, and as a result, the crystal structure of R0 is significantly more compact. There is a concomitant reduction in some of the distances between N and O atoms in neighboring chains, Table 2. Figure 8 shows the structures of R and R0 polymorphs as viewed down [001]. The N1-H 3 3 3 O1 distance is the shortest intermolecular N-H 3 3 3 O distance in both polymorphs, but decreases from 3.058 A˚ in R to 2.983 A˚ in R0 . Positions of the H atoms

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Wu et al. Table 2. Selected Bond Distances/Angles for R and R0 L-Pa R0 33

R29 N1-H 3 3 3 O1 N2-H 3 3 3 O2 N2-H 3 3 3 O3 N3-H 3 3 3 O3 H(N1) 3 3 3 O1 H(N2) 3 3 3 O2 H(N2) 3 3 3 O3 H(N3) 3 3 3 O3

distance (A˚)

angle (deg)

distance (A˚)

angle (deg)

3.06 3.29 3.09 3.16 2.32 3.04 2.30 2.71

140.2 100.8 164.5 120.5

2.98 3.21 3.09 3.07 2.12 2.47 2.49 2.22

166.4 142.1 125.7 161.6

a The atom labels refer to those given in Figure 8, with hydrogens referred to by the N to which they are bonded. Bond angles are suggestive, based on proposed, rather than determined, positions for H.29,33

Figure 7. Molecular arrangements for (a) R0 and (b) R L-P viewed down [010]. The atoms are represented by spheres (H (turquoise), C (red), N (green), O (blue)), while intrachain O-H 3 3 3 O HBs are indicated with black dashed lines. Interchain N-H 3 3 3 O distances shorter than 3.4 A˚ are marked with red lines. Structure visualization was obtained using Balls & Sticks.34

Figure 8. Molecular arrangements for (a) R0 and (b) R L-P, viewed down [001]. The atoms are represented by spheres (H (turquoise), C (red), N (green), O (blue)).

were not determined experimentally, and so comments on N-H 3 3 3 O angles would be rather speculative. Neutron diffraction studies to locate H atoms and determine the structure of the high temperature β polymorph are planned. 4.2. Interpretation of Variable Temperature Raman Spectra. Several bands (from internal modes) in the Raman

spectra of R L-P have a multiplet structure. These include the ν(NH) stretching bands at 3340 and 3405 cm-1, and bands near 1220 and 530 cm-1, Figures 5a and S2. In each case, one or two components of the multiplet disappear at the transition from R to β at ∼68 °C. Such multiplets in the spectra of molecular crystals have several possible origins. These include splitting of mode degeneracy and crystal field splitting due to n (here n = 12) molecules per unit cell. However, the most likely scenario, in this case, is that two (or more) different “environments” exist of, at least, one chemical group. Such different “environments” are usually caused by molecular interactions, for example, the HB of the -NH group to an oxygen-containing group on a neighboring molecule. The ν(NH) band of R L-P near 3300 cm-1 shows three components, which are probably associated with three crystallographically distinct N atoms (in both R and R0 ), Table 2. These may be influenced to different degrees by interactions of the -NH groups with the acid CdO groups on the neighboring chains. In R these are at 3400, 3387(sh), and 3340 cm-1 at 25 °C, Figure 5b. The low frequency component (3340 cm-1) of the N-H band disappears (reversibly) at the R/β transition temperature (TRfβ). It seems likely, therefore, that the -NH groups find themselves in at least three different environments, one of which is lost, on conversion to the β phase. We do not know how many of the three bands near 3300 cm-1 are affected by HB; possibly all three are affected by HB, since ν(NH) bands are notoriously weak and perhaps only those vibrations perturbed by HB are seen in the Raman spectra. It seems likely, however, that at least two of the bands are influenced by HB. Consideration of the N-H 3 3 3 O distances and angles in Table 2 reveals which of these groupings are likely to show HB. Three criteria may be used as an indicator of possible HB: the H 3 3 3 O distance, the N-H 3 3 3 O distance (conventionally set at a maximum value of 3.07 A˚, which is equal to the sum of the van der Waals radii of N and O35), and the N-H 3 3 3 O angle (general consensus is that linear bonds at 150-180° are structurally significant for the occurrence of HB; however, 110° is also used as a lower limit36). Given that H 3 3 3 O distances and N-H 3 3 3 O angles are not known with certainty, of the four groupings listed in R, N1-H 3 3 3 O1 and N2-H 3 3 3 O3 are most likely to show HB. The Raman spectra are therefore in line with the structural data and out of line with the older literature,32 which claims that the -NH group is “free” in the HB sense: one N-H bond could be free, but not the other two. The component in R that appears to be most strongly hydrogen bonded, at 3340 cm-1, is considerably broader

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than the more weakly bonded component (half widths 38 and 24 cm-1, respectively) and is “red-shifted” (62 cm-1) to lower frequency (as expected). As the sample transforms to β, the band broadens even more (half width e50 cm-1 at 100 °C). On cooling to reach the R0 phase, there are now three well-established and relatively narrow bands in the Raman spectra at 3378, 3343, and 3305 cm-1 with half widths 4, 7, and 7 cm -1 . This again ties in nicely with three N-H 3 3 3 O interactions in the crystal structure, two of which are similar. However, the N-H 3 3 3 O interactions are not necessarily the same in R0 as in R. Specifically, the N1-H 3 3 3 O1 distance appears most likely to show HB in both but N3-H 3 3 3 O3 appears to be more favorable in R0 whereas N2-H 3 3 3 O3 appears to be less likely. The shift to lower frequency of one component (3305 cm-1), relative to that in R, may reflect the more compact structure of R0 , with shorter N-H 3 3 3 O distances and consequent strengthening of the N-H 3 3 3 O interactions. The assignment of Raman bands to individual N-H 3 3 3 O interactions needs to be further explored. In addition, other bands in the Raman spectra show a doublet structure, and the implication is that these also arise, at least partly, from differences in N-H 3 3 3 O interactions. The γ and δ(NH) bands are predicted to be in the 588 and 1467 cm-1 regions,37 where we do not find any special doubling effects. However, there are doublet bands at 1220 and 530 cm-1, which again become a single band above TRfβ. 4.3. Martensitic Character of the r f r0 Transition. The R f R0 transition on cooling appears as a DSC exotherm at ∼ -140 °C but, instead of a smooth exotherm, it has sawtooth character, Figure 2d. This is characteristic of transitions of martensitic character that occur in bursts because of constraints imposed by changes in shape/volume at the interface between transformed and untransformed crystal. Consequently, the complete transition occurs over a range of temperatures. The XRD results on cooling (not shown) also show the transition to occur over a range of temperatures since mixtures of R and R0 are seen at both -150 and -170 °C. 5. Conclusions Pyroglutamic acid exists in three enantiotropic polymorphic forms, each with its own temperature range of thermodynamic stability. Although the high temperature, β, and low temperature, R0 , forms had not been recognized previously, evidence for their existence was provided by earlier IR/DSC data (β) and differences in crystal structures at low temperature (R0 ) and room temperature (R). All three polymorphs have the same space group, P212121, which is perhaps somewhat unusual. Structural differences are associated with detailed molecular packing arrangements and in particular, the interchain HBs. Differences in the Raman spectra between R and R0 polymorphs can be interpreted by their different HB arrangements; from the Raman spectra of the β polymorph, suggestions concerning its HB arrangements are made. The R/R0 transition on cooling appears to be Martensitic in character in which strain at the R/R0 interface in partially transformed crystals causes the transformation to occur in bursts with increased undercooling. There is considerable hysteresis between the temperatures of the R/β transition on

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heat/cool cycles, and, in particular, the β f R transition can be suppressed significantly at fast cooling rates. Although there is little change in overall volume of crystals on passing through the R/β transition, there are significant changes, ∼1%, in the individual unit cell parameters and therefore in crystal dimensions on passing through the transition in either direction; this has the effect of causing crystals to jump off a solid surface, such as a microscope slide, on passing through the transition. The sluggishness of the R/β transition is probably connected to strong HB between pyroglutamic acid molecules in the crystalline state and may also be responsible for the large undercooling of liquid pyroglutamic acid for which no crystallization exotherm was seen under the normal DSC conditions. Acknowledgment. We thank X. Zeng for training in, and use of, the hot-stage microscope. We also thank Rob Hanson for his help with low temperature DSC measurements. Supporting Information Available: DSC data showing Peak 1 temperature on heating and cooling at different heating/cooling rates (Figure S1), Raman spectrum of three polymorphs of L-P on expanded scale (Figure S2) and indexed powder XRD of β L-P (Table S1), R L-P (Table S2), and R’ L-P (Table S3). This material is available free of charge via the Internet at http://pubs.acs.org.

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Polymorphism, Phase Transitions, and Thermal Stability of l

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