Giant strain geared to transformable H-bonded network in compressed -d-mannose

Networks of OH O bonds in sugars and H2O ices are hardly affected by temperature, but transform under pressure. Such a transition at 1.95 GPa in b-D-mannose induces strong strain, non-destructive for the single crystal and easily visible in its shape deformation. This transition occurs at the lowest pressure of all sugars investigated at high pressure so far. The giant strain propagates perpendicular to the clearly visible zero-strain planes. The transition reconstructs the 3-dimensional pattern of OH O hydrogen bonds, changes the conformation of molecules and preserves the space-group symmetry, like the analogous transitions of a-D-glucose and D-sucrose. However, new repulsing O O contacts have been generated at high pressure in D-mannose only.


Introduction
Hydrogen bonds and their transformations are immanent parts of biological systems and life processes at the molecular level. 1,2 Equally important are hydrogen bonds for geology and properties of rocks, as the minerals in Earth's crust contain more water than all seas and oceans. 3,4 The immense pressure in the deep-crust deposits strongly distorts the structure of minerals and most of all their softest interactions, including the hydrogen bonds. 5,6 Therefore, an understanding of the pressure effects on the hydrogen bonds is important. This information about H-bond transformations is also essential for designing new functional materials, 7 such as ferroelectrics and relaxors [8][9][10] for electronic applications, as well as for obtaining new polymorphs of pharmaceutical active ingredients. [11][12][13][14] It was shown recently that pressure significantly modifies the 3-dimensional OHÁ Á ÁO bond motifs of D-sucrose and a-D-glucose. 15,16 In this respect sugars resemble the structures of H 2 O ices, similarly governed by OHÁ Á ÁO bonds building the frameworks, hardly affected by temperature, but efficiently destabilized by pressure. [17][18][19][20] However, in contrast to H 2 O ices, it is characteristic that high-pressure transitions of D-sucrose, at 4.8 GPa, and a-D-glucose, at 5.4 GPa, preserve their space-group symmetry and lattice translations, an occurrence encountered at high pressure for quite a few compounds. [21][22][23][24][25] Presently, we found that a much lower pressure induces an exceptionally strong transformation between Phases I and II of b-D-mannose. Such major microscopic changes may lead to notable macroscopic effects. 26,27 The giant strain in the transforming D-mannose crystal is clearly visible under the microscope (Fig. 1).
D-Mannose, a close isomer of D-glucose, in its metabolism significantly differs from other sugars, mainly the energy carriers. are marked in red and green, respectively. The crystal axes and Miller indices of selected faces are indicated in plate (a). Angle f, between the direction of zero strain and the x axis calculated according to eqn (1) in the text, is marked in plate (c). Small ruby chips for pressure calibration are scattered in the DAC chamber.
Metabolized D-mannose is incorporated into glycolipids and glycoproteins, so its role is mainly structural. 28 Moreover, it exhibits antibacterial and antiviral properties, hence, it is used to treat and prevent recurrent urinary tract infections. 29,30 Owing to the slower absorption compared to other sugars, D-mannose travels in blood to the urinary tract, where it binds competitively to Escherichia coli bacteria, preventing their adhesion to mucous membranes and leading to their efficient excretion. 31 For these and other reasons D-mannose is an important active pharmaceutical ingredient (API) often described as a healing sugar. 32 The considerably different metabolism of D-mannose and D-glucose results from their different codes of H-donor and H-acceptor hydroxyl groups, 33 convertible conformation and intermolecular interactions 34 adjusting to various environments. 35 The structure of the b-anomer of D-mannose crystals, despite its diverse applications, 29,30 has remained unknown until now.

Experimental
A single crystal of b-D-mannose (analytical grade; from VEB Berlin-Chemie) was installed in a modified Merrill-Bassett diamond-anvil cell (DAC). 36 The gasket was made of 0.3 mm tungsten foil with a spark-eroded hole, 0.3-0.4 mm in diameter. The sample position in the DAC chamber was fixed with a few cellulose fibers or a small amount of glue. Ethanol solution saturated with D-mannose, fluorinert or an n-pentane : isopentane (vol 1 : 1) mixture was used as hydrostatic medium. Pressure inside the DAC was measured according to the ruby fluorescence method 37 using an enhanced Photon Control Inc. spectrometer, affording an accuracy of 0.02 GPa. Diffraction data were collected at 0.48, 1.00, 1.60, 1.90, 2.02, 2.10 and 2.35 GPa (Fig. S1, ESI †) on a four-cycle KUMA KM4-CCD X-ray diffractometer using graphite monochromated MoKa radiation, and at 2.85 GPa using a 4-cycle Xcalibur diffractometer equipped with the EOS CCD detector and an AgKa radiation source. The crystal and DAC centering were performed according to the methods described previously. 38 Low-temperature data (150-295 K range; Fig. S2, ESI †) were measured using a 4-circle SuperNova diffractometer, CuKa radiation, and an Oxford Cryosystems attachment. For data collection, UB-matrix determination, absorption correction and data reduction, the program CrysAlisPro 39 was used. The crystal structures were solved by direct methods using SHELXS 40 and refined with the program SHELXL. 41 Hydrogen atoms were located by molecular geometry with U iso equal to 1.2U eq for C-carriers and 1.5U eq for O-carriers, and with the O-H and C-H bond lengths fixed at the distances of 0.82 Å for oxygen atoms, and 0.98 or 0.97 Å for tertiary and secondary carbon atoms, respectively. To allow the gradual transformation of the sample between the phases and the recording of the visual changes in the b-D-mannose crystal shape (Fig. 1, Movies S1-S4, ESI †), a membrane DXR-GM DAC from Diacell was applied for finetuning the pressure through the phase transition.
We found that b-D-mannose is compressed monotonically up to 1.95(2) GPa, when it undergoes a phase transition. It retains the symmetry of the orthorhombic space group P2 1 2 1 2 1 and such phase transitions are described as isostructural, isomorphic, and sometimes as isosymmetric. 21 Crystallographic data for b-D-mannose in ambient and high-pressure phases are compared in Table 1 (cf. Tables S1 and S2 in the ESI †) CCDC 1450799-1450809.
Compressibility parameters b x = À1/xqx/qp, where x represents the measured unit-cell dimensions V, a, b, and c, have been fitted with quadratic polynomials for Phase I and the exponential decay function for Phase II (Table S7, ESI †). Intermolecular interactions have been analysed for the structures with C-H and O-H bonds normalized to the neutron-determined distances of 0.97 Å for oxygen atoms, and, respectively, 1.098 and 1.091 Å for tertiary and secondary carbon atoms, according to Allen and Bruno. 42 Contacts have been classified as hydrogen bonds OHÁ Á ÁO for OÁ Á ÁO distances shorter than 3.04 Å (i.e. the sum of van der Waals radii 43 ); as CHÁ Á ÁO bonds for HÁ Á ÁO distances shorter than 2.72 Å and for the C-HÁ Á ÁO angle higher than 1101; 43,44 and as HÁ Á ÁH contacts for distances shorter than 2.4 Å. 43

Results and discussion
The giant strain between b-D-mannose Phases I and II, the largest ever recorded for sugars, allows the clear visual observation of the transformation fronts, passing through the crystal (Fig. 1).
The transition abruptly reduces the crystal volume by nearly 4% (Fig. 2). This transition strongly rearranges hydrogen bonds OHÁ Á ÁO, and changes the molecular aggregation. In Phase I each molecule is the H-donor in five OHÁ Á ÁO bonds and the H-acceptor in five H-bonds, and in Phase II seven independent OHÁ Á ÁO bonds are formed, as illustrated in Fig. 3 It is noteworthy, that ten hydrogen bonds OHÁ Á ÁO per each b-mannose molecule in Phase I form a 3-dimensional supramolecular network of multitude of interconnected rings and chains/helices. 15 The network of 14 OHÁ Á ÁO bonds per molecule in Phase II is even more complex. The unequivocal description of these networks exceeds the capabilities of graph descriptors used for the H-bonding patterns. 46 Therefore we have applied the rigorous ORTEP symmetry codes for precisely describing the H-bonds of one molecule in its nearest vicinity. The symmetry transformations described in superscripts by 4-digit ORTEP codes 47 are explicitly listed in Table S3 (ESI †). The extent of the transformations in the OHÁ Á ÁO bonding network is quantitatively illustrated in Fig. 4, where the OÁ Á ÁO and HÁ Á ÁO distances of all H-bonds present either in Phase I or II are plotted. The transition considerably changes the distances of intermolecular OÁ Á ÁO contacts, even by more than 2 Å for the H-bonds O1HÁ Á ÁO6 3655 and O3HÁ Á ÁO3 4465 formed in Phase II. The shortest of contacts OÁ Á ÁO and HÁ Á ÁO are only compressed from 2.70 Å to 2.56 Å and from 1.80 Å to 1.67 Å, respectively. High pressure slightly reduces the CÁ Á ÁO distances, however the shortest of (C)HÁ Á ÁO contacts in Phase II are longer than those in Phase I (Fig. S8 in the ESI †). In this respect the shortest OHÁ Á ÁO and CHÁ Á ÁO bonds behave differently than in the pressuretransformed sucrose and glucose, where in Phase II the OÁ Á ÁO distances are somewhat longer and CHÁ Á ÁO bonds shorter than before the transition in Phase I. However, it is a common feature of the b-mannose, sucrose and glucose structures that the excess of H-acceptor sites (general for sugars) at high pressure is balanced by the formation of bifurcated OHÁ Á ÁO bonds and new CHÁ Á ÁO bonds.
The shortest of HÁ Á ÁH contacts in Phase II is only about 0.3 Å shorter than that in Phase I, and this compression is stronger than that observed for the other types of contacts (Fig. S11, ESI †). All dimensions of intermolecular contacts ( Fig. 4 and Fig. S4-S11, ESI †) are consistent with the strong molecular rearrangement and compression of the structure. The reduction of HÁ Á ÁH distances is consistent with the collapse of the small voids in Phase I. The voids are contained between the molecules arranged in a herringbone pattern in Phase I, while above 1.95 GPa the molecules are nearly parallel along the plane (bc), as can be seen in the structures and their schemes in Fig. 5. To accommodate these molecular rotations, the crystal shrinks along a and expands along b. Moreover, the longest dimension of the molecule between atoms O2 and O6 becomes better aligned along b within the (bc) plane just above the transition, which is consistent with the more pronounced compression of the crystal along c and expansion along b.
The considerable volume collapse at P c allows the transition in b-mannose to be induced in gradually increasing portions of the sample crystal by a very slow increase in the volume reduction of the DAC chamber. In principle, if all the sample volume V s collapses by DV s at P c , then the reduction of the volume of the DAC chamber by DV s from the start of the transition does not increase the pressure in the DAC until the entire sample has  (Table S8, ESI †). Critical pressure P c of the phase transition is marked by the vertical dashed line. The insets show a sample in Phases I (green octagonal rim) and II (red), as well as for the transforming stages (green/red).  (Fig. 2a). This feature illustrates the possible applications of such materials for shock-absorbing or stress-compensating devices, but it also allows observations of the transition front propagating through the sample (Fig. 1). It is remarkable that the giant strain in the b-mannose crystal does not break the sample. This infers that the transition front proceeds along the planes that minimize the local strain. It can be seen in Fig. 1 that the transition fronts only approximately progress along crystal planes (AE1 AE1 0). For the crystal exhibiting negative linear compressibility, such as b-mannose, there are directions of zero strain and these directions can be calculated from the strain tensor between Phases I and II at P c . For the transition in b-mannose the strongest strain is generated within the (ab) plane, due to the strongest positive and negative linear compression of the crystal along a and b, respectively, (Fig. 1). Owing to the coexistence of positive and negative linear compression within the (ab) plane, there are directions of zero strain along the planes parallel to (c) and inclined to axis a by angle f where indices in unit-cell dimensions a I , b I , a II and b II refer to Phases I and II, respectively. For the zero-strain transition fronts parallel to the c axis, the f angle calculated in this way is 43.831, in accordance with the microscopic visual observations (cf. Fig. 1 and Movies S1-S4 in the ESI †).

Conclusions
The high-pressure effects in b-D-mannose strikingly resemble those in D-sucrose and a-D-glucose. In all these systems, crystals transform with no space-group symmetry change, when the OHÁ Á ÁO bonding network reconstructs to a tighter version, with more bifurcated OHÁ Á ÁO bonds and more CHÁ Á ÁO bonds compensating for the insufficient number of hydroxyl donors. The transition in b-D-mannose, occurring at considerably lower pressure than those in D-sucrose and a-D-glucose, induces a giant anomalous strain, which is coupled to the molecular rearrangement. It appears that the sophisticated geometric code of H-donors and H-acceptors in sugars controls the monotonic and discontinuous strain in the compressed crystals. The experimental measurements of crystal compression are presently available for three sugars only, however it is already an intriguing result that each of these sugars undergoes only one isostructural phase transition in the high-pressure range, where several phase transitions occur for the H 2 O ices, built of considerably simpler and more symmetric (C 2v ) molecules. It shows that the small H 2 O molecules cannot control the crystal symmetry and directions of crystal transformations in such a precise and unique way as the much more complex molecules of sugars. This conclusion   is partly supported by the relatively scarce occurrence of polymorphs in sugars, reported-aside from the high-pressure transformations in a-D-glucose, b-D-mannose, and D-sucrose-for D-ribose, 49 b-D-allose, 50,51 lactose, 52,53 a,a-trehalose 54,55 and cellulose. 56 Clearly, further studies are needed for the better understanding of external-stimuli effects and functional responses of H-bonded networks, which will ultimately allow their rational control and applications.