
<ref name=yeon2001>Younghee Yeon (2001): "[https://koreascience.kr/article/JAKO200111920935778.pdf The crystal and molecular structures of ''neo''-inositol and two forms of ''scyllo''-inositol]". ''Korean Journal of Crystallography'', volume 12, issue 3, pages 150-156.</ref>

<ref name=beko2014>Sándor L. Bekö, Edith Alig, Martin U. Schmidt, Jacco van de Streek (2014): "On the correlation between hydrogen bonding and melting points in the inositols". ''International Union of Crystallography Journal'' (''IUCrJ''), volume 1, part 1, pages 61-73. {{doi|10.1107/S2052252513026511}}<!--myo-inositol crystallizes in three polymorphs. L and D chiro-inositol crystallize with 1/3(?) H2O. Monoclinic lattices for rac-1 and 5-A and orthorhombic lattices for 5-D, 5-E and 7-C.  Unit-cell volumes of 713.03 Å3 for rac-1, 743.02 Å3 for 5-A, 1466.88 Å3 for 5-D, 1442.97 Å3 for 5-E and 721.24 Å3 for 7-C. Z = 4, 4, 8, 8 and 4 molecules in the unit cell for rac-1, 5-A, 5-D, 5-E and 7-C, respectively (all anhydrous). Space groups were determined to be P21/c for rac-1, P21/n for 5-A, Pbca for 5-D, P212121 for 5-E and Pca21 for 7-C.   It is highly likely that the H atoms involved in intramolecular hydrogen bonds in the high-temperature phase 5-D, and probably also in 5-E, are also disordered.  Thirteen new phases were found. </ref>

<ref name=monn2020>Irina Monnard, Thierry Bénet, Rosemarie Jenni, Sean Austin, Irma Silva-Zolezzi, Jean-Philippe Godin (2020): "Plasma and urinary inositol isomer profiles measured by UHPLC-MS/MS reveal differences in scyllo-inositol levels between non-pregnant and pregnant women". ''Analytical and Bioanalytical Chemistry'', volume 412, pages 7871–7880. {{doi|10.1007/s00216-020-02919-8}}<!--Finds ''epi'', ''chiro'', ''neo'', ''myo'', and ''scyllo''-inositol in the urine of women, pregnant or not.  Both ''epi'' and ''neo'' are always in small amounts. ''chiro'' is small amounts too except in the second trimester of pregnancy.  But Figure does not match claim in abstract. Must check whole article.--></ref>

<ref name=yama2011>Masaru Yamaoka, Shin Osawa, Tetsuro Morinaga, Shinji Takenaka, Ken-ichi Yoshida (2011): "A cell factory of ''Bacillus subtilis'' engineered for the simple bioconversion of ''myo''-inositol to ''scyllo''-inositol, a potential therapeutic agent for Alzheimer's disease". ''Microbial Cell Factories'', volume 10, article number 69. {{doi|10.1186/1475-2859-10-69}}<!-- In plants, myo-inositol hexakisphosphate or phytic acid often occurs in high bran cereals, serving as the principal storage form of phosphate. This is the main industrial source of myo-inositol.--></ref>

<ref name=simp2006>Alexandra Simperler, Stephen W. Watt, P. Arnaud Bonnet, William Jones,  W. D. Samuel Motherwell (2006): "Correlation of melting points of inositols with hydrogen bonding patterns". ''CrystEngComm'', volume 8, pages 589-600 {{doi|10.1039/B606107A}}<!--Finds a clear correlation between melting points and the number and type of chains of hydrogen-bonded hydroxyls.--></ref>

<ref name=sher1968>William R. Sherman, Mark A. Stewart, Mary M. Kurien, Sally L. Goodwin (1968): "The measurement of myo-inositol, myo-inosose-2 and scyllo-inositol in mammalian tissues". ''Biochimica et Biophysica Acta'' (''BBA''), volume 158, issue 2, pages 197-205 {{doi|10.1016/0304-4165(68)90131-1}}</ref>


<ref name=>  (): "". '''',  {{doi|}}</ref>

<ref name=>  (): "". '''',  {{doi|}}</ref>

----------------------------------------------------------------------
from <ref name=simp2006/>

Table 1 Properties of the inositol crystals

Tm     = melting point, C
dens   = density g/mL
a/e    = hydroxyl position ratio axial/equatorial Space group
nHB    = number of hydrogen-bonded neighbor molecules. 
CSD id = Cambridge Structural Database identifier

isomer   Tm    dens  a/e  group Z Zc   nHB  CSD id Ref
-------- ----  ----  ---  ----- - ---- ---  ------ -----------------------------------
scyllo   350   1.58  0/6  P1¯   2  1     8  —a     [14]
neo      315b  1.69  2/4  P1¯   1  0.5   6  YEPNOW [18]
epi      304b  1.66  2/4  P21/c 4  1     7  EPINOS [19]
muco     290b  1.65  3/3  P21 4 1  1     1  MUINOS [20]
L-chiro  246   1.60  2/4  P21 2 1  1     2  FOPKOK [21]
myo      225b  1.58  1/5  P21/c 8  2     7  MYINOL [22]
allo     180   1.68  3/3  P21/n 4  1     8  —a     [15]

a Recently determined unpublished structures, melting points determined by DSC. b Chapman and Hall, Dictionary of Organic Compounds,
vol. 4, 6th edn (Electronic Publishing Division, 1996), otherwise Tm taken from ref. c Zc defines the number of molecules in the asymmetric
unit; however, scyllo-inositol has two half molecules per asymmetric unit, giving two independent molecules.


----------------------------------------------------------------------
From <ref name=beko2014/>
The crystal structures of all eight ordered phases could be determined, of which seven were determined from laboratory X-ray powder diffraction data. The remaining five phases turned out to be rotator phases and only their unit cells could be determined. Melting points and phase-transition temperatures were recorded for investigated phases. An overview of the results is given in Tables 1[link] and 2[link].

Table 1
Overview of the polymorphs (not including hydrates) of the inositols and their phase transition temperatures

<ref name=jeff1987>Jeffrey & Yeon (1987): Jeffrey, G. A. & Yeon, Y. (1987). Carbohydr. Res. 159, 211-216.</ref>

<ref name=dayg2006>Graeme M. Day, Jacco van de Streek, Arnaud Bonnet, Jonathan C. Burley, William Jones, and W. D. Sam Motherwell (2006):  "Polymorphism of ''scyllo''-inositol:  Joining crystal structure prediction with experiment to elucidate the structures of two polymorphs".  ''Crystal Growth & Design'', volume 6, issue 10, pages 2301-2307. {{doi|10.1021/cg060179a}}</ref>

<ref name=craig1979>Craig & James (1979[Craig, D. C. & James, V. J. (1979). Cryst. Struct. Commun. 8, 629-633.])</ref>
<ref name=bonn2006a>Bonnet et al. (2006a[Bonnet, A., Jones, W. & Motherwell, W. D. S. (2006a). Acta Cryst. E62, o2578-o2579.])</ref>
<ref name=rabi1964>Rabinovich & Kraut (1964[Rabinovich, I. N. & Kraut, J. (1964). Acta Cryst. 17, 159-168.])</ref>
<ref name=khan2007>Khan et al. (2007[Khan, U., Qureshi, R. A., Saeed, S. & Bond, A. D. (2007). Acta Cryst. E63, o530-o532.])</ref>
<ref name=jeff1971>Jeffrey & Kim (1971[Jeffrey, G. A. & Kim, H. S. (1971). Acta Cryst. B27, 1812-1817.])</ref>


Isomer       |   Phase  | ρ (g cm−3) | Goup        | Tm (°C)   | ΔHt(J/g)  | Phase transition       |  Reference
D-(+)-chiro  |   D-1-A  | 1.60      | P21         | 201       | 181.9     | Conversion to 1-B       | This work
D-(+)-chiro  |   D-1-B  | 1.50      | F***†       | 245‡      | 17.0      | Melting                 | This work

L-(−)-chiro  |   L-1-A  | 1.60      | P21         | 202       | 191.0     | Conversion to 1-B       | <ref name=jeff1987>
L-(−)-chiro  |   L-1-B  | 1.50      | F***†       | 246‡      | 16.4      | Melting                 | This work

racemic      |   rac-1  | 1.69      | P21/c       | 250‡      | 243.1     | Melting                 | This work

scyllo       |   2-A    | 1.57      | P21/c       | 358§      | 263.1     | Decomposition           | <ref name=yeon2001/>, <ref name=dayg2006/>
scyllo       |   2-B    | 1.66      | [P\b1]      | 360§      | –         | –                       | <ref name=yeon2001/>, <ref name=dayg2006/>

neo          |   3      | 1.70      | [P\b1]      | 315¶      | –         | Melting                 | <ref name=yeon2001/><ref name=simp2006/>

muco         |   4      | 1.65      | P21/c       | 290¶      | –         | Melting                 | <ref name=craig1979/><ref name=simp2006/>

cis          |   5-A    | 1.61      | P21/n       | 152       | 136.8     | Conversion to 5-B       | This work
cis          |   5-B    | 1.51      | P3**/P6**†† | 215       | > 3.6‡‡   | Conversion to 5-C       | This work
cis          |   5-C    | 1.47      | F***†       | 351       | 313.6     | Decomposition           | This work
cis          |   5-D    | 1.63      | Pbca        | 156       | 93.6      | Conversion to 5-B       | This work
cis          |   5-E    | 1.66      | P212121     | 57        | 12.5      | Conversion to 5-D       | This work

allo         |   6-A    | 1.68      | P21/n       | 184       | 197.2     | Conversion to 6-B       | <ref name=bonn2006a/>
allo         |   6-B    | 1.50      | F***†       | 319‡      | 23.04     | Melting                 | This work

myo          |   7-A    | 1.58      | P21/c       | 225‡      | 242.7     | Melting                 | <ref name=rabi1964/>
myo          |   7-B    | 1.65      | Pna21       | –         | –         | –                       | <ref name=khan2007/>
myo          |   7-C    | 1.66      | Pca21       | 170       | -31.8     | Conversion to 7-A       | This work

epi          |   8      | 1.66      | P21/c       | 304¶      | –         | Melting                 | <ref name=jeff1971/><ref name=simp2006/>

†Rotator phase, cubic, space group unknown, see text.
‡Onset/offset melting point from DSC measurements in this publication.
§Melting points of 2-A and 2-B given as 360 °C by <ref name=yeon2001/>; we observed decomposition at 358 °C for 2-A.
¶See Simperler et al. (2006)<ref name=simp2006/>.
††Rotator phase, hexagonal, space group unknown, see text.
‡‡Conversion is incomplete.


Table 2
Crystallographic data for the structures determined from X-ray powder diffraction data
Crystal data

      ~ | System,Group          | T(K)|       a(Å)  |    b(Å)      |  c(Å)        |  α(°) |  β(°)        | γ(°)   V(Å3)       | Vmol(Å3) |  Z  |   μ(mm−1) | SpecimenShape,size(mm)
  rac-1 | Monoclinic,P21/c      | 293 | 10.1435(6)  |  8.1542(4)   |  8.6239(4)   |  90   |  92.3556(15) | 90     712.70(7)   | 178      |  4  |   1.33    | Cylinder,10×0.7
  D-1-A | Monoclinic,P21        | 293 |  6.86637(11)|  9.12272(14) |  6.21914(10) |  90   |  106.5963(6) | 90     373.338(10) | 187      |  2  |   1.27    | Cylinder,10×0.7
    5-A | Monoclinic,P21/n      | 293 | 11.58792(19)| 12.2101(2)   |  5.25364(10) |  90   |   90.5649(7) | 90     743.30(2)   | 186      |  4  |   1.28    | Cylinder,10×0.7
    5-D | Orthorhombic,Pbca     | 408 | 14.1313(2)  | 11.0757(2)   |  9.36191(18) |  90   |   90         | 90    1465.27(5)   | 183      |  8  |   1.30    | Cylinder,10×0.7
    5-E | Orthorhombic,P212121  | 293 | 14.01476(14)| 11.03782(11) |  9.33193(12) |  90   |   90         | 90    1443.58(3)   | 180      |  8  |   1.31    | Cylinder,10×0.7
    7-C | Orthorhombic,Pca21    | 293 | 11.8577(3)  |  7.01486(16) |  8.68032(19) |  90   |   90         | 90     722.03(3)   | 181      |  4  |   1.31    | Cylinder,10×0.7


~        rac-1   D-1-A   5-A     5-D     5-E     7-C
Crystal system,space group     Monoclinic,P21/c       Monoclinic,P21 Monoclinic,P21/n       Orthorhombic,Pbca      Orthorhombic,P212121   Orthorhombic,Pca21
Temperature(K) 293     293     293     408     293     293
a(Å)  10.1435(6)     6.86637(11)    11.58792(19)   14.1313(2)     14.01476(14)   11.8577(3)
b(Å)  8.1542(4)      9.12272(14)    12.2101(2)     11.0757(2)     11.03782(11)   7.01486(16)
c(Å)  8.6239(4)      6.21914(10)    5.25364(10)    9.36191(18)    9.33193(12)    8.68032(19)
α(°) 90      90      90      90      90      90
β(°) 92.3556(15)    106.5963(6)    90.5649(7)     90      90      90
γ(°) 90      90      90      90      90      90
V(Å3) 712.70(7)      373.338(10)    743.30(2)      1465.27(5)     1443.58(3)     722.03(3)
Vmol(Å3)      178     187     186     183     180     181
Z       4       2       4       8       8       4
μ(mm−1)     1.33    1.27    1.28    1.30    1.31    1.31
SpecimenShape,size(mm)       Cylinder,10×0.7     Cylinder,10×0.7     Cylinder,10×0.7     Cylinder,10×0.7     Cylinder,10×0.7     Cylinder,10×0.7

Radiation type  Cu Kα1, λ = 1.54056 Å
	 	 	 	 	 	 
rac-1	Monoclinic, P21/c
D-1-A	Monoclinic, P21	
5-A     Monoclinic, P21/n
5-D	Orthorhombic, Pbca
5-E	Orthorhombic, P212121
7-C	Orthorhombic, Pca21

Crystal data
Crystal system, space group


Data collection
Diffractometer	Stoe Stadi-P diffractometer
Specimen mounting	Glass capillary
Data collection mode	Transmission
Scan method	Step
2θ values(°)	2θmin = 2.0, 2θmax = 79.99, 2θstep = 0.01
 	 	 	 	 	 	 
Refinement†
Rwp	0.0577	0.0329	0.0408	0.0356	0.0331	0.04336
Rp	0.0411	0.0252	0.0304	0.0259	0.0244	0.0326
Rexp	0.0198	0.0239	0.0302	0.0274	0.0274	0.0369
Rwp′	0.1235	0.0787	0.0827	0.0816	0.0686	0.1021
Rp′	0.1024	0.0793	0.0779	0.0758	0.0611	0.1117
Rexp′	0.0423	0.0571	0.0613	0.0628	0.0567	0.0870
χ2	8.510	1.896	1.825	1.687	1.464	1.378
No. of data points	7800	7800	7800	7800	7800	7599
No. of parameters	102	69	64	65	90	65
No. of restraints	66	66	66	66	132	66
H-atom treatment	Calculated ‡	Calculated ‡	Calculated ‡	Calculated ‡	Calculated ‡	Calculated ‡
†R′wp, R′p and R′exp denote the values after background subtraction.
‡Calculated by molecular dynamics followed by energy-minimization with DFT-D (see text).
3.2. chiro-Inositols (1)
chiro-Inositol (1) exists in two enantiomers, D-(+)- and L-(−)-chiro-inositol. Both pure enantiomers and the racemate, rac-1, were investigated.

3.2.1. D-(+)- and L-(−)-chiro-inositols

The crystals initially obtained for D-(+)-chiro-inositol turned out to be a 1/3 hydrate, D-1·1/3H2O, as determined by single-crystal analysis. Hydrates are also known for cis-inositol (Freeman et al., 1996[Freeman, H. C., Langs, D. A., Nockolds, C. E. & Oh, Y. L. (1996). Aust. J. Chem. 49, 413-424.]) and for myo-inositol (Bonnet et al., 2006b[Bonnet, A., Jones, W. & Motherwell, W. D. S. (2006b). Acta Cryst. E62, o2902-o2904.]; CSD reference code MYTOLD01). DSC analysis of D-1·1/3H2O shows a broad­ened endothermic signal with an onset at about 74 °C resulting from the loss of water and conversion of the 1/3 hydrate to the known anhydrate (D-1-A) (Jeffrey & Yeon, 1987[Jeffrey, G. A. & Yeon, Y. (1987). Carbohydr. Res. 159, 211-216.]). The TGA curve shows a mass loss of about 2.98% between 83 and 93 °C corresponding to a loss of approximately 0.3 water molecules per D-(+)-chiro-inositol molecule (Fig. 2[link]).

[Figure 2]
Figure 2
Combined DSC (red) and TGA (black) traces of the 1/3 hydrate of D-(+)-chiro-inositol (D-1·1/3H2O) measured from 20 to 400 °C.
In the DSC, three further endothermic signals could be observed; the first sharp peak at 201 °C resulting from a phase transition to the high-temperature polymorph, (D-1-B), the second sharp peak at 245 °C from melting and a third broad signal between 281 and 337 °C resulting from decomposition. The enthalpy of the phase transition at 201 °C is remarkably large, whereas the melting enthalpy at 245 °C is remarkably small. This is because the high-temperature phase (D-1-B) is a rotator phase (see §3.9[link]) and the major part of the melting process takes place at 201 °C, with only the translational order of the centres of mass of the molecules remaining. This translational order is then lost when the final melting takes place at 245 °C.

The phases were identified by measuring T-XRPD patterns before and after the phase transitions (see Fig. 3[link]).

[Figure 3]
Figure 3
Temperature-dependent X-ray powder diffraction traces of D-(+)-chiro-inositol (D-1) at 25, 100 and 210 °C showing the phase transitions from the 1/3 hydrate (black) (D-1·1/3H2O) to the anhydrate (red) (D-1-A) and to the high-temperature polymorph (blue) (D-1-B).
The DSC and TGA curves and the XRPD patterns of L-1 are the same as for its enantiomer D-1.

The crystal structures of the two 1/3 hydrates, L-1·1/3H2O and D-1·1/3H2O, will not be discussed in this paper, and this paper therefore only reports and discusses 11 of the 13 new phases.

The crystal structure of the room-temperature phase L-1-A was determined by Jeffrey & Yeon (1987[Jeffrey, G. A. & Yeon, Y. (1987). Carbohydr. Res. 159, 211-216.]). The enantiomeric crystal structure of D-1-A was established by Rietveld refinement (see the supporting information for full details). The molecules are connected to their neighbours by 12 hydrogen bonds (as determined with Mercury; Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., Van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]). Each —OH group acts as a donor and as an acceptor for one intermolecular hydrogen bond each, resulting in a three-dimensional network.

D-1-A does not rehydrate upon cooling to room temperature. The reversibility of the melting process and of the transition from 1-A to 1-B was not investigated. For structural investigations of the high-temperature rotator phases L-1-B and D-1-B, see §3.9[link].

3.2.2. Racemic chiro-inositol
The DSC analysis of rac-chiro-inositol, rac-1, shows only one endothermic signal at 250 °C from melting, which is 4–5 °C higher than for the pure enantiomers. Decomposition occurs as a broad signal between 308 and 344 °C. The TGA curve shows no mass loss before melting (see Fig. 4[link]).

[Figure 4]
Figure 4
Combined DSC (red) and TGA (black) traces of rac-chiro-inositol (rac-1) measured from 20 to 400 °C showing the melting of rac-1 at 250 °C.
The crystal structure of rac-1 (see Fig. 5[link]) was determined from powder diffraction data (the Rietveld refinement plot is shown in the supporting information). The compound crystallizes in the space group P21/c with one molecule in the asymmetric unit. Each molecule is connected to the other molecules through 12 hydrogen bonds. In contrast to D-1-A and L-1-A, one O atom (O3) accepts two hydrogen bonds, while another (O2) accepts none.

[Figure 5]
Figure 5
Crystal structure of racemic chiro-inositol (rac-1). Space group P21/c, view along the b axis (a axis shown in red, c axis shown in blue). Hydrogen bonds are indicated as dashed blue lines, H atoms have been omitted for clarity.

3.3. scyllo-Inositol (2)

DSC analysis of 2-A shows only one sharp endothermic signal at 358 °C resulting from decomposition. TGA measurements show no mass loss or gain until 330 °C. Further heating results in decomposition (see Fig. 6[link]).

[Figure 6]
Figure 6
Combined DSC (red) and TGA (black) traces of scyllo-inositol (2-A) measured from 20 to 500 °C showing the decomposition of 2-A at 358 °C.


To determine the unknown melting point of the second reported polymorph of scyllo-inositol<ref name=yeon2001/><ref name=dayg2006/>, a sample of pure 2-B had to be prepared. Whereas samples of 100% 2-A can be routinely obtained, 2-B always crystallizes in the presence of 2-A <ref name=yeon2001/><ref name=dayg2006/>. Repeated attempts to crystallize 2-B using crystallization experiments from methanol/water as indicated in the publication of Day et al. failed to reproduce the polymorph. Vapour diffusion experiments were performed by dissolving 50, 40 and 30 mg samples of 2-A in 3 ml water using an ultrasonic bath. The solutions were filtered using a filter paper with a porosity under 2.7 µm and filled into vials. The first set of solutions (containing 50, 40 and 30 mg dissolved in 3 ml water) were deposited without a lid into screw-top jars containing 10 ml methanol. In order to minimize the diffusion velocity of methanol into the solutions containing scyllo-inositol, the second set of vials was closed with snap-on lids perforated with a 0.9 mm cannula. Additionally, antisolvent crystallization experiments were performed by dissolving scyllo-inositol in the same manner as for the vapour diffusion experiments. Afterwards, portions of about 7 ml methanol were added, at first fast to each of the first set of experiments using a syringe and then slowly by placing methanol carefully over the solution containing scyllo-inositol to yield a two-phase system. In each experiment, different ratios of 2-A and 2-B were obtained, but these experiments also failed to produce pure 2-B. We were therefore not able to determine the melting point of 2-B. The DSC measurements of the mixtures of 2-A and 2-B showed two separate but barely resolved events, with onsets at about 359 and 364 °C.

The crystal structures of both polymorphs were reported by <ref name=yeon2001/>; CSD reference codes EFURIH01 and EFURIH02 for 2-A and 2-B, respectively.

3.4. neo-Inositol (3) and muco-inositol (4)

The crystal structures of neo-inositol (3) and muco-inositol (4) were reported by Yeon <ref name=yeon2001/> (CSD reference code YEPNOW01) and <ref name=craig1979/> (CSD reference code MUINOS), respectively. For their melting points, see Simperler et al. (2006<ref name=simp2006/>). Considering the number of new phases discovered in our relatively straightforward heating experiments, it must be assumed that additional experiments on neo- and muco-inositol (not considered in our experiments) will reveal additional phases.

3.5. cis-Inositol (5)

DSC analysis of 5-A shows a sharp endothermic signal at 152 °C resulting from the phase transition to a high-temperature form 5-B. Furthermore, 5-B shows a phase transition to another high-temperature form labelled as 5-C. As was the case for D-1-B, the high value of the phase transition enthalpy from 5-A to 5-B is due to the fact that 5-B and 5-C are rotator phases. Upon further heating, a simultaneous melting/decomposition process occurs at 350 °C (Fig. 7[link]).

[Figure 7]
Figure 7
Combined DSC (red) and TGA (black) traces of cis-inositol (5-A) measured from 20 to 400 °C showing the phase transition of polymorph 5-A to 5-B at 152 °C and 5-B to 5-C at 215 °C until melting/decomposition of 5-C at 350 °C.

For identification of the polymorphs, T-XRPD patterns were measured before and after the phase transitions as shown in Fig. 8[link]. The XRPD patterns show that the transition from 5-B to 5-C at 215 °C is incomplete, resulting in a mixture of 5-B and 5-C. However, the newly appearing peaks in 5-C have a very different peak width (as measured by the full width at half maximum) than the peaks from 5-B, which indicates that 5-C is a true separate phase.

[Figure 8]
Figure 8
Temperature-dependent X-ray powder diffraction traces of cis-inositol (5) at 20, 200 and up to 227 °C showing the phase transition of polymorph 5-A (black) to the first high-temperature polymorph 5-B (red) to the second high-temperature polymorph 5-C (blue). The asterisks (green) denote new reflections caused by polymorph 5-C.

When polymorph 5-B is cooled from 200 °C to room temperature, it does not convert back to 5-A, but forms two new polymorphs: at 141 °C form 5-B transforms to 5-D, which at 57 °C converts to form 5-E (Fig. 9[link]). Therefore, it can be assumed that 5-D is an additional high-temperature form of cis-inositol. To identify the polymorphic forms that appeared during DSC measurement, T-XRPD patterns were recorded as shown in Fig. 10[link].

[Figure 9]
Figure 9
DSC trace of cis-inositol measured from 200 °C down to room temperature showing the phase transition of polymorph 5-B to 5-D at 141 °C and 5-D to 5-E at 57 °C.
[Figure 10]
Figure 10
Temperature-dependent X-ray powder diffraction traces of cis-inositol (5) at 200, 135 and down to 20 °C showing the phase transitions of polymorph 5-B (black) to polymorph 5-D (red) to polymorph (5-E) (blue). 5-D and 5-E can be indexed with the same unit cell; the asterisks (green) denote the reflections that are visible in 5-E but that are systematic absences in 5-D.

These transformations are reversible: upon heating, 5-E changes back to 5-D at 57 °C, to 5-B at 156 °C and to 5-C at 215 °C, which finally shows a melting/decomposition point at 351 °C (Fig. 11[link]). For the identification of the polymorphs occurring during the DSC measurement, T-XRPD patterns were measured before and after the phase transitions as shown in Fig. 12[link]. After all T-XRPD measurements, a final rapid cooling process from 227 to 20 °C led to a conversion of polymorph 5-C to 5-E. The TGA curves show no mass loss or gain during these heating and cooling processes, except at the melting/decomposition points.

[Figure 11]
Figure 11
DSC trace of cis-inositol (5) measured from 20 up to 400 °C showing the phase transition of polymorph 5-E back to 5-D at 57 °C, 5-D back to 5-B at 156 °C and 5-B to 5-C at 215 °C until melting/decomposition of 5-C at 351 °C.
[Figure 12]
Figure 12
Temperature-dependent X-ray powder diffraction traces of cis-inositol (5) at 20, 135, 200 and up to 227 °C showing the phase transitions of 5-E (black) to polymorph 5-D (red) to polymorph 5-B (blue) and finally to a mixture of polymorphs 5-B and 5-C (green).

The crystal structures of the ordered phases 5-A, 5-D and 5-E were solved and refined from laboratory X-ray powder diffraction data. The Rietveld plots are shown in the supporting information.

In 5-A, each molecule forms one intramolecular hydrogen bond and ten intermolecular hydrogen bonds (five as donors, five as acceptors; Fig. 13[link]).

[Figure 13]
Figure 13
Crystal structure of 5-A. Space group P21/n, view along the c axis (a axis shown in red, b axis shown in green). Hydrogen bonds are indicated as dashed blue lines, H atoms have been omitted for clarity.

5-D is a high-temperature polymorph that only exists above 57 °C and that converts to 5-E on cooling. The crystal structures of 5-D and 5-E are very similar and share the same unit-cell parameters. The phase transition corresponds to the loss of the inversion symmetry to lower the space-group symmetry from Pbca, Z′ = 1 to one of its maximum subgroups P212121, Z′ = 2 (see overlay in Fig. 14[link]). In 5-D and 5-E, each molecule forms one intramolecular and ten intermolecular hydrogen bonds.

[Figure 14]
Figure 14
Overlay of the crystal structures of 5-D (red, Pbca, Z′ = 1) and 5-E (blue, P212121, Z′ = 2). View approximately along the c axis (a axis shown in red, b axis shown in green, c axis shown in blue), H atoms have been omitted for clarity.

Interestingly, the C3v-symmetrical cis-inositol (σ = 3) has five different polymorphs, of which two are rotator phases, the first even at quite a low temperature (156 °C). In contrast, the D3d-symmetrical scyllo-inositol (σ = 6) exhibits neither a rotator phase nor any other phase transition up to its decomposition at 355 °C.

The crystal structure of cis-inositol monohydrate (5·H2O) was determined by Freeman et al. (1996[Freeman, H. C., Langs, D. A., Nockolds, C. E. & Oh, Y. L. (1996). Aust. J. Chem. 49, 413-424.]). This inositol phase is the only previously reported inositol phase with less than 12 hydrogen bonds per molecule. 5·H2O crystallizes in P21/c with two molecules in the asymmetric unit; one molecule forms 11 hydrogen bonds, the other only ten.

3.6. allo-Inositol (6)

DSC analysis of allo-inositol shows a sharp endothermic signal with a minimum at about 184 °C resulting from the phase transition from polymorph 6-A to the high-temperature polymorph 6-B. Two further endothermic signals could be observed; the first onset at 319 °C resulting from melting of polymorph 6-B and the second sharp endothermic signal at 334 °C resulting from decomposition. 6-B is another rotator phase, again explaining the unusually high enthalpy of the transition from 6-A to 6-B (Fig. 15[link]).

[Figure 15]
Figure 15
DSC trace of allo-inositol measured from 20 up to 400 °C showing the phase transition of polymorph 6-A to 6-B at 184 °C, melting of 6-B at 319 °C and decomposition at 334 °C.

T-XRPD measurements were performed before and after the phase transition as observed in the DSC (Fig. 15[link]), see Fig. 16[link].

[Figure 16]
Figure 16
Temperature-dependent X-ray powder diffraction traces of allo-inositol (6) at 20, 170 and 200 °C showing the phase transition of polymorph 6-A (black and red), which is stable up to the minimum 170 °C, to polymorph 6-B at 200 °C (blue).

The crystal structure of the room-temperature phase 6-A was determined by Bonnet et al. (2006a[Bonnet, A., Jones, W. & Motherwell, W. D. S. (2006a). Acta Cryst. E62, o2578-o2579.]; CSD reference code IFAKAC); for the rotator phase 6-B see §3.9[link].

3.7. myo-Inositol (7)

We redetermined the melting point of polymorph 7-A using DSC measurement (Fig. 17[link]). The crystal structure of 7-A was published by Rabinovich & Kraut (1964[Rabinovich, I. N. & Kraut, J. (1964). Acta Cryst. 17, 159-168.]; CSD reference code MYINOL).

[Figure 17]
Figure 17
DSC trace of myo-inositol (7) measured from 20 up to 400 °C showing its melting point of polymorph 7-A at 225 °C and its decomposition between 306 and 363 °C.

To determine the unknown melting point of the second reported polymorph of myo-inositol (7-B, Khan et al., 2007[Khan, U., Qureshi, R. A., Saeed, S. & Bond, A. D. (2007). Acta Cryst. E63, o530-o532.]; CSD reference code MYINOL01), a sample of 7-B had to be prepared. Repeated attempts to crystallize 7-B including crystallizations from ethanol/ethyl acetate 60:40 as indicated in the publication of Khan et al. and additional solvent-assisted grinding experiments failed to reproduce the polymorph. The authors of the paper were contacted, but the sample was no longer available. We were therefore not able to determine the melting point of 7-B.

Although we did not obtain 7-B, we could observe a third polymorph of myo-inositol (7-C) during thermal analyses on polymorph 7-A. Polymorph 7-C was obtained during DSC measurements by heating 7-A to 280 °C until 7-A had melted completely. During the cooling down process to 20 °C, 7-C crystallizes from the melt at 189 °C and is stable at 20 °C (Fig. 18[link]). It appears that a slow cooling rate yields form 7-C from the melt, whereas a fast cooling rate yields form 7-A from the melt.

[Figure 18]
Figure 18
DSC trace of myo-inositol (7) measured from 280 down to 20 °C showing the transformation from the melt to polymorph 7-C at 189 °C.

Heating 7-C to 280 °C, at 170 °C it transforms back to 7-A, which melts at 225 °C (see Fig. 19[link]); this transition is reproducible.

[Figure 19]
Figure 19
DSC trace of myo-inositol (7) measured from 20 up to 280 °C showing the phase transition of 7-C back to 7-A at 170 °C, and the melting point of polymorph 7-A at 225 °C.

T-XRPD measurements with the HUBER heater device and an imaging-plate position-sensitive detector were performed before and after the phase transitions observed in the DSC measurements (Fig. 20[link]).

[Figure 20]
Figure 20
Temperature-dependent X-ray powder diffraction traces of myo-inositol (7) at 20 up to 280 down to 20 and up to 200 °C showing the melt of polymorph 7-A (black and red), recrystallization to 7-C (blue) and phase transition back to 7-A (green).

A final cool-down of the melt shown in Fig. 19[link] led to the recrystallization of polymorph 7-A (see Fig. S13[link] in the supporting information).

At room temperature, 7-C slowly converts to 7-A over time. See the supporting information for further information.

The crystal structure of 7-C was solved from laboratory X-ray powder diffraction data using real-space methods. The Rietveld refinement is shown in the supporting information.

The new polymorph of myo-inositol (7-C) crystallizes in Pca21 with one molecule in the asymmetric unit. Each molecule is connected to the other molecules through 12 hydrogen bonds (Fig. 21[link]).

[Figure 21]
Figure 21
Crystal structure of 7-C. Space group Pca21, view along the b axis (a axis shown in red, c axis shown in blue). Hydrogen bonds are indicated as dashed blue lines, H atoms have been omitted for clarity.

3.8. epi-Inositol (8)

The crystal structure of epi-inositol (8) was determined by Jeffrey & Kim (1971[Jeffrey, G. A. & Kim, H. S. (1971). Acta Cryst. B27, 1812-1817.]; CSD reference code EPINOS). For the melting point, see Simperler et al. (2006<ref name=simp2006/>). Considering the number of new phases discovered in our relatively straightforward heating experiments, it must be assumed that additional experiments on epi-inositol, not considered in our experiments, will reveal additional phases.

3.9. Rotator phases

The peak positions and intensities in the X-ray powder patterns of D-1-B, L-1-B, 5-C and 6-B are the same, and it must therefore be assumed that these phases – though consisting of chemically different molecules – are isostructural. The patterns contain only six peaks, which can be indexed with an orthorhombic, a tetragonal, a hexagonal or a cubic unit cell; these unit cells all have unit-cell parameters in common. Only the unit-cell volume of the cubic unit cell is chemically sensible, with the other unit-cell volumes being smaller than the volume of a single inositol molecule at room temperature. The volume of the cubic unit cell is 800 Å3 (a = 9.3 Å) and based on the systematic absences, it must be F-centred; this yields a plausible molecular volume of 200 Å3, which is about 8% larger than the molecular volume in the room-temperature phases. The Pawley refinements can be found in the supporting information.

We conclude from the unusually high space-group symmetry, the low densities, the high temperatures at which these phases occur and the high enthalpies for the transitions between the ordered phases to these high-temperature phases that these structures are rotator phases. That also explains how the crystal structures of three chemically different species can be isostructural.

The X-ray powder pattern of 5-B consists of only nine reflections. The powder pattern could be indexed by a hexagonal cell without ambiguity (a = 6.575, c = 10.580 Å); the unit-cell volume is 396.05 Å3, corresponding to Z = 2. The Pawley refinement can be found in the supporting information.

As was the case for D-1-B, L-1-B, 5-C and 6-B, we conclude from the unusually high space-group symmetry, the low density, the high temperature at which this phase occurs and from the high transition energy between 5-A and 5-B, that 5-B is also a rotator phase.

3.10. Calculation of corrected melting points

Equation (4) in the paper by Wei (1999[Wei, J. (1999). Ind. Eng. Chem. Res. 38, 5019-5027.])

[T_{\rm{m}}^{'} = {{{T_{\rm{m}}}} \over {\displaystyle 1 + {{R\ln ({\rm{\sigma }}){T_{\rm{m}}}} \over {{H_{\rm{m}}}}}}} \eqno(1)]

allows the calculation of corrected melting points: the melting point a compound would have if it had no internal symmetry. It is these corrected melting points that should be correlated with e.g. lattice energies, densities or number of hydrogen bonds. In equation (1)[link], [T{\,}'_{\rm m}] is the corrected melting point, Tm is the experimental melting point, Hm is the melting enthalpy and σ is the molecule's symmetry number. Because of the observed polymorphism, it would be incorrect to speak of `the' melting point for an inositol: each polymorph has its own Tm, Hm and Tm′, just like each polymorph has its own hydrogen-bonding pattern and lattice energy.

The quantitative evaluation of the corrected melting points through equation (1)[link] is hampered by several problems:

(1) The definition of the molecular symmetry number σ in equation (1)[link] assumes that the molecules are rigid. In our values for σ, we have ignored the flexible H atoms of the hydroxyl groups [a more rigorous calculation of σ for flexible molecules has been published (Gilson & Irikura, 2010[Gilson, M. K. & Irikura, K. K. (2010). J. Phys. Chem. B, 114, 16304-16317.]), but this is beyond the scope of this paper].

(2) Many polymorphs show phase transitions below their melting point, in which case Tm and Hm cannot be measured directly (see Fig. 22[link]). In principle, these values can be derived from other experimental data (Yu, 1995[Yu, L. (1995). J. Pharm. Sci. 84, 966-974.]), but this has not been attempted in the current paper.

(3) scyllo-Inositol and cis-inositol decompose before melting.

(4) The correction that is applied is based on the assumption that the molecules in the liquid phase can rotate freely whereas those in the solid state do not rotate at all, causing the large difference in rotational entropy between the solid and the liquid phase. The rotator phases D-1-B, L-1-B, 5-B, 5-C and 6-B, however, clearly violate this assumption.

[Figure 22]
Figure 22
Virtual melting point Tm,A of phase A: the Gibbs free energies of phase A, phase B and the liquid as a function of temperature are shown. Phase A is the most stable phase at low temperature, and when the temperature increases phase A converts to phase B before melting. Tm,A and Hm,A cannot be measured directly (at ambient pressure), but Tm,A must lie between TA→B and Tm,B. The temperature dependence of the Gibbs free energies is represented as straight lines for clarity, in reality these lines are curved. A similar situation occurs when a phase decomposes before melting. The most stable phase at each temperature is shown in bold.

Given these complications, we are not able to give a rigorous quantitative analysis of the melting points of the inositols. The only corrected melting point that can be calculated with the current data is that of rac-chiro-inositol (rac-1), for which Tm′ = 221 °C.

4. Conclusions

The aims of this work were to find the high-melting polymorph of allo-inositol (6-B), to determine Hm of scyllo-inositol (2-A), to determine the melting point of the second polymorph of myo-inositol (7-B) and to determine the crystal structures and corrected melting points of rac-chiro-inositol (rac-1) and cis-inositol (5).

We were able to identify the high-melting polymorph of allo-inositol (6-B) as a rotator phase, establish its unit cell and measure its melting point. HA→B and Hm,B were also measured. scyllo-Inositol (2-A) decomposes before melting, and we were therefore not able to measure Hm. The second known polymorph (2-B) could not be reproduced in pure form. The second polymorph of myo-inositol (7-B) proved elusive. A third polymorph was discovered (7-C), but it converts to the known first polymorph (7-A) before melting. Although Hm,A was measured, myo-inositol has no molecular symmetry and its melting point remains at 225 °C. We were able to solve the crystal structure of rac-chiro-inositol and to measure Hm and Tm to determine its corrected melting point as 221 °C. The phase behaviour of cis-inositol turned out to be unexpectedly complex. Five polymorphs were identified; for three of these (5-A, 5-D and 5-E), the crystal structures were solved from XRPD data, the remaining two structures are rotator phases (5-B and 5-C). cis-Inositol decomposes before melting. Additionally, we established that the phase behaviour and crystal structures of L-chiro-inositol and D-chiro-inositol are the same, as expected.

Including hydrates and rotator phases, and counting enantiomers separately, 13 new phases are reported in this paper, bringing the total number of known phases for the inositols to 24, of which four are hydrates and five are rotator phases.

Our experiments have revealed a complex picture of phases, rotator phases and phase transitions, in which a simple correlation between melting points and hydrogen-bonding patterns is not feasible. A thorough discussion of the melting points of these 24 phases requires future work to determine the virtual melting points.

CCDC deposition numbers: 891302–891305, 891307 and 891309.

Supporting information
CCDC references: 891302; 891303; 891304; 891305; 891307; 891309

Crystal structure: contains datablocks global, 5-A, 5-D, 5-E, 7-C, D-1-A, rac-1. DOI: https://doi.org/10.1107/S2052252513026511/bi5002sup1.cif

Rietveld powder data: contains datablock 5-A. DOI: https://doi.org/10.1107/S2052252513026511/bi50025-Asup2.rtv

Rietveld powder data: contains datablock 5-D. DOI: https://doi.org/10.1107/S2052252513026511/bi50025-Dsup3.rtv

Rietveld powder data: contains datablock 5-E. DOI: https://doi.org/10.1107/S2052252513026511/bi50025-Esup4.rtv

Rietveld powder data: contains datablock 7-C. DOI: https://doi.org/10.1107/S2052252513026511/bi50027-Csup5.rtv

Rietveld powder data: contains datablock D-1-A. DOI: https://doi.org/10.1107/S2052252513026511/bi5002D-1-Asup6.rtv

Rietveld powder data: contains datablock rac-1. DOI: https://doi.org/10.1107/S2052252513026511/bi5002rac-1sup7.rtv

Electronic Supplementary Material. DOI: https://doi.org/10.1107/S2052252513026511/bi5002sup8.pdf


3D view

Powder plots


Supplementary crystallographic information
 cis-1,2,3,4,5,6-cyclohexanehexol (5-A)
 cis-1,2,3,4,5,6-cyclohexanehexol (5-D)
 cis-1,2,3,4,5,6-cyclohexanehexol (5-E)
 cis-1,2,3,5-trans-4,6-cyclohexanehexol (7-C)
 cis-1,2,4-trans-3,5,6-cyclohexanehexol (D-1-A)
 rac-chiro-1,2,3,4,5,6-cyclohexanehexol (rac-1)
Acknowledgements
Dr S. X. M. Boerrigter is gratefully acknowledged for bringing to our attention the paper by J. Wei (1999). Dr I. B. Rietveld is gratefully acknowledged for helpful discussions on the interpretation of virtual corrected melting points. The Lundbeck Foundation (Denmark) is gratefully acknowledged for financial support (grant No. R49-A5604).

Funding information
Funding for this research was provided by: Lundbeck Foundation (Denmark) (award No. R49-A5604).

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