One-Pot Microwave-Assisted Synthesis of Water-Soluble Pyran-2,4,5-triol Glucose Amine Schiff Base Derivative: XRD/HSA Interactions, Crystal Structure, Spectral, Thermal and a DFT/TD-DFT

: The(3R,4R,6R)-3-(((E)-2-hydroxybenzylidene)amino)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol water-soluble Glucose amine Schiff base (GASB-1) product was made available by condensation of 2-hydroxybenzaldehyde with (3R,6R)-3-amino-6-(hydroxymethyl)-tetra-hydro-2H-pyran-2,4,5-triol under mono-mode microwave heating. A one-pot 5-minute microwave-assisted reaction was required to complete the condensation reaction with 90% yield and without having byproducts. The 3D structure of GASB-1 was solved from single crystal X-ray diffraction data and computed by DFT/6-311G(d,p). The Hirshfeld surface analysis (HSA), molecular electronic potential (MEP), Mulliken atomic charge (MAC), and natural population analysis (NPA) were performed. The IR and UV-Vis spectra were matched to their density functional theory (DFT) relatives and the thermal behavior was resolved in an open-room condition via thermogravimetry/Derivative thermogravimetry (TG/DTG) and differential scanning calorimetry (DSC). The highest occupied molecular orbital/lowest unoccupied molecular orbital (HOMO/LUMO), density of state (DOS), and time-dependence TD-DFT computations were correlated to the experimental electron transfer in water and acrylonitrile solvents. attributed to the contributions of HOMO-1 → LUMO+1(97%) and HOMO-2 → LUMO+1(3%). The second band at 309.1 nm was due to HOMO-2 → LUMO(20%), HOMO- 1 → LUMO(73%) HOMO-4 → LUMO (5%), and the third band at 545.9 nm was due to HOMO → LUMO+1(100%) electron transfers. In the TD-DFT of the GASB-1, the protic (water) and aprotic (acetonitrile) solvents showed similar behavior. Moreover, a good agreement between the experimental and the theoretical solvato-behavior using protic and aprotic solvents was recorded.


Introduction
Glucose amine Schiff bases (GASBs) are common chiral organic compounds that were synthesized decades ago [1][2][3][4][5]. GASBs are an important class of artificial compounds since they have several applications in many life fields [6]. For example, such Schiff bases from food derivatives are used in antibacterial, antimicrobial, antiviral, and other biological activities [7]. Moreover, they have been used in tumor cell imaging, conductive polymers, and optical sensors, as well as for detection of amino acids, fluoride, iron, and other heavy metals [8][9][10].
In terms of complexes, the greatest benefits of GASBs as ligands are their solubility in water and multidentate coordination possibilities. Moreover, the ring conformations or configurations of the pyran ring in glucose center increase the chance of bonding in different coordination modes. The complexes of such GASBs with metal ions have several applications as catalysts, for example, in oxygenations, hydrolysis, and anticorrosion [11][12][13][14][15]. The presence of several chiral centers loaded in GASBs backbone increases the possibility of using their complexes to prepare chiral catalysts or chiral reagents. For example, vanadium oxides/GASB was used in chiral oxidation of sulfides [16].
Recently, microwave technology has been used in Schiff base preparation instead of traditional methods, as this technology has achieved global acceptance in accelerating the reaction and increasing its selectivity, which has reduced the formation of side products. Moreover, the displayed reactions without or with a minimum number of solvents has increased the chance of imposing green chemistry technology [17][18][19].
In this work, we report efficient ecofriendly microwave synthesis under mild condition of a water-soluble sugar derivative GASB-1 within 5 min at 60 • C under microwave heating conditions. The pyran chair conformation structure was confirmed by single-crystal X-ray diffraction (XRD) where no ring opening was detected. Furthermore, the XRD/Hirshfeld surface analysis (HSA) interactions and XRD/DFT analyses were performed, and the physicochemical properties, such as IR and UV-visible, were matched to B3LYP and TD-DFT, respectively. The thermal properties were also evaluated through TG/DTG and DSC.

Measurements
The Fourier transform infrared spectrum (FT-IR) (MID. 4000-400 cm −1 ) was recorded in solid state using a PerkinElmer Spectrum 1000 FT-IR Spectrometer (PerkinElmer Inc., Waltham, MA, USA). The UV-Vis measurements were performed in water solvent using a TU-1901 double-beam spectrophotometer (Purkinje General Instrument Co., Ltd., Beijing, China). The TG spectra were recorded using a TGA-7 PerkinElmer (PerkinElmer Inc., Waltham, MA, USA) in 25 to 600 • C temperature range and with heat rate = 5 • C min −1 . The microwave reactions were carried out with a Biotage initiator 8 instrument (Biotage, Uppsala, Sweden).

Crystal Data
Suitable single crystals for X-ray diffraction were selected based on the size and sharpness of the diffraction spots. The data collections were carried out on a D8 Venture diffractometer using Cu-Kα radiation (Bruker GmbH, Berline, Germany). Data processing and all refinements were performed with the APEX3 and Jana2006 program package, respectively [24,25]. Multiscan absorption corrections using SADABS were applied for data collection details, as shown in Table 1.

GASB-1 Synthesis
Glucosamine hydrochloride (0.884 gm, 1 mmol) was treated in 4 mL ethanol with triethylamine. To the mixture, salicylaldehyde (0.432 mL, 1.1 mmol) was added in a microwave vial. The vial was capped and heated in the microwave synthesizer at 60 • C for 5 min, which led immediately to the formation of a bright yellow precipitate. The vial was then cooled to room temperature. The yellow solid was filtered and washed with cold ethanol then recrystallized from ethanol to afford the desired GASB-1 (90%) as bright-yellow crystals. Recrystallization from ethanol again provided very nice yellow crystals which were used for X-ray diffraction.

Microwave Synthesis
The use of microwave-assisted techniques in the preparation of Schiff bases is of high interest in the organic green synthesis field. The condensation of (3R,6R)-3-amino-6-(hydroxymethyl)-tetrahydro-2H-pyran-2,4,5-triol with 2-hydroxybenzaldehyde under nonroutine microwaved condition using ethanol solvent revealed the formation of the desired GASB-1 in 90% yield, as illustrated in Scheme 1. A 5-minute reaction is required to synthesize the desired ligand without byproducts. Moreover, microwave-assisted techniques involve simple handling, making them a cheaper and quicker synthetic method than the classical methods reported [16][17][18][19]

XRD and DFT
The desired ligand was subjected to XRD and DFT calculation, and the Oak Ridge Thermal Ellipsoid Plot (ORTEP) and B3LYP/6-311G(d,p)-optimized diagram are illustrated in Figure 1a and Figure 1b, respectively. The DFT/XRD angles and bond lengths are illustrated in Table 2. A packing diagram, viewed down the b axis, is given in Figure  1c. The desired compound was crystallized in a monoclinic, C2 space group (Z = 4). The stair-like structure is two-dimensional. In the flat aromatic ring C8-C9-C0-C11-C12-C13, all the carbon atoms have an sp 2 hybridization, whereas in the pyranose ring O1-C1-C2-C3-C4-O5, which has a chair conformation [26] with the puckering parameters Q = 0.584(9) Å, θ = 2.6(9)° and φ = 65(16)° [27], all the atoms have an sp 3 hybridization.   The experimental XRD angles and bond distances were emulated to the DFT/B3LYP/6-311++G(d,p) as showed in Figure   The experimental XRD angles and bond distances were emulated to the DFT/B3LYP/6-311++G(d,p) as showed in

XRD Packing and HSA
In the XRD packing result, several short interactions stabilized the crystal lattice of the desired Schiff base, as seen in Table 3 and Figure 3. The first interaction was detected as an intra-hydrogen bond, such as O-H . . . .N=C, with 1.864 Å forming a close S6 as seen in Figure 3a.

XRD Packing and HSA
In the XRD packing result, several short interactions stabilized the crystal lattice of the desired Schiff base, as seen in Table 3 and Figure 3. The first interaction was detected as an intra-hydrogen bond, such as O-H…..N=C, with 1.864 Å forming a close S6 as seen in Figure 3a. The second type of interaction was 1D hydrogen bond, such as Ph-H….O-C with 2.580 Å, resulting a continuous chain as seen in Figure 3b. The third type was 2D-S6synthon with two hydrogen bonds, such as O-H….O, with 1.953 Å and Ph-H…O with 2.563 Å, as seen in Figure 3c. The fourth type was a 2D-S4 synthon with three hydrogen bonds of type O-H….O with 2.089 Å, 2.568 Å, and 2.005 Å, as seen in Figure 3d. The fifth interaction was H…πC9-C8 type with 2.840 Å as seen in Figure 3e.  The HSA calculation of the prepared Schiff base was carried using the CIF file generated from single crystal XRD. The interactions were shown as a red point on the GASB-1 surface [28][29][30][31][32][33][34][35]. The desired Schiff base contains many OH and O atoms in the sugar part together with N=C in the Schiff base part. Therefore, nine red spots were detected by dnorm on the surface, reflecting the presence of different types of [OH….O] hydrogen bonds connected the computed surface of the molecule with its surrounding neighboring molecules. Moreover, a big red spot occurred around the N atom due to the [O-H….N] intra-hydrogen bond (Figure 4a). The presence of only one type of H….πC=C interaction was confirmed by the shape index as seen in Figure 4b. Moreover, the fingerprint (FP) H-to-atom connection ratio plot reflected the diversity of the percentage contribution. The highest interaction ration was H····H bonds contribution with 45.5%, while the lowest interaction ration was N····H contribution with 0.5%. The FP result revealed all the H-connections percentage contributions in the following order: [H···H>O····H(14.6%)>C····H(8.9%)>N····H(0.5%)]. The HSA calculation of the prepared Schiff base was carried using the CIF file generated from single crystal XRD. The interactions were shown as a red point on the GASB-1 surface [28][29][30][31][32][33][34][35]. The desired Schiff base contains many OH and O atoms in the sugar part together with N=C in the Schiff base part. Therefore, nine red spots were detected by d norm on the surface, reflecting the presence of different types of [OH . . . .O] hydrogen bonds connected the computed surface of the molecule with its surrounding neighboring molecules. Moreover, a big red spot occurred around the N atom due to the [O-H . . . .N] intra-hydrogen bond (Figure 4a). The presence of only one type of H . . . .π C=C interaction was confirmed by the shape index as seen in Figure 4b. Moreover, the fingerprint (FP) H-to-atom connection ratio plot reflected the diversity of the percentage contribution. The highest interaction ration was H····H bonds contribution with 45.5%, while the lowest interaction ration was N····H contribution with 0.5%. The

Molecular Electrostatic Potential (MEP), Mulliken Atomic Charge (MAC), and Natural Population Analysi (NPA)
On the surface of the desired molecule, the MEP calculation revealed the presence of red (nucleophilic), blue (electrophilic), and green (not polarized) positions [26][27][28][29][30]. All the O and N atoms and some C atoms were nucleophilic in their nature. Moreover, all the H atoms attached to O atoms were blue in color, resulting in electrophilic centers ( Figure  5a). The other centers in the compounds were green since they were in between electrophilic and nucleophilic centers. The presence of H, acceptors together with electron donor centers, encourage the formation of intra-[H…..N] and inter-[H….O] hydrogen bonds.
The NPA and MAC supported the MEP result in founding both e-rich/poor atoms sites on the molecule. The NPA-and MAC-computed charges revealed all the atoms with a negative or positive quantity of charge as represented in Figure 5b and Table 4. Usually, the NPA displayed higher atomic charges compared to the MAC. As expected, the MAC and NPA evidenced all O, N, C1-C6, and C13 atoms with negative charges and all the H, C14-C17, and C12 atoms are with positive charges. H31 is among the highest atoms with a positive charge. Therefore, it is responsible for forming the intra-H-bond of type O-H….N bond. The NPA and MAC charge model reflected a high degree of matching, and R 2 = 0.9462 was detected, as shown in Figure 5c. The MAC, NPA, and MEP data are highly harmonic with HSA and XRD results.

Molecular Electrostatic Potential (MEP), Mulliken Atomic Charge (MAC), and Natural Population Analysi (NPA)
On the surface of the desired molecule, the MEP calculation revealed the presence of red (nucleophilic), blue (electrophilic), and green (not polarized) positions [26][27][28][29][30]. All the O and N atoms and some C atoms were nucleophilic in their nature. Moreover, all the H atoms attached to O atoms were blue in color, resulting in electrophilic centers (Figure 5a). The other centers in the compounds were green since they were in between electrophilic and nucleophilic centers.

IR, B3LYP, and NMR Investigation
In the IR spectrum shown in Figure 6a, the stretching vibration bands at 3405 cm −1 , 3070 cm −1 , 2960-2860 cm −1 , 1630 cm −1 , 1200-1000 cm −1 , and 1100-900 cm −  The structure of GASB-1 was elucidated and confirmed by the data obtained from the 1 H NMR and 13 C-NMR spectra in DMSO-d6 presented in Figure 7a and 7b, respectively. In the 1 HNMR, the spectra displayed several bands. The sugar protons were recorded at 2.5-5.5 ppm, the aromatic protons at 6.5-7.5 ppm, and the acidic phenolic proton and imine proton appeared at 13.20 ppm 8.25 ppm, respectively. In 13 C-NMR, the sugar carbons were detected in between 60-100 ppm, the aromatic carbons in between 115-135 ppm, and the imine and phenolic carbon signals appeared at 167.21 ppm and 160.99 ppm, respectively (see the experimental part). The protons and carbons NMR chemical shifts are consistent with the proposed structure solved by single-crystal XRD. The structure of GASB-1 was elucidated and confirmed by the data obtained from the 1 H NMR and 13 C-NMR spectra in DMSO-d6 presented in Figure 7a and Figure 7b, respectively. In the 1 HNMR, the spectra displayed several bands. The sugar protons were recorded at 2.5-5.5 ppm, the aromatic protons at 6.5-7.5 ppm, and the acidic phenolic proton and imine proton appeared at 13.20 ppm 8.25 ppm, respectively. In 13 C-NMR, the sugar carbons were detected in between 60-100 ppm, the aromatic carbons in between 115-135 ppm, and the imine and phenolic carbon signals appeared at 167.21 ppm and 160.99 ppm, respectively (see the experimental part). The protons and carbons NMR chemical shifts are consistent with the proposed structure solved by single-crystal XRD.

HOMO/LUMO and Absorption/TD-DFT
The HOMOLUMO orbital shapes ( Figure 8a) and energy diagrams were performed using GaussView 5.0 software. The LUMO and HOMO molecular orbital energy levels both had negative values. Thus, the stability and softness of the GASB-1 were increased. The ΔEHOMO/LUMO was found to be 1.730 eV, whereas the ΔEDOS was 1.784 eV. A negligible deviation between the two methods was detected.
The UV-visible for the desired sugar derivative Schiff base was measured in water and acetonitrile solvents in the scale of 200-800 nm, parallel to that ground-state TD-DFT/B3LYP/6-31G(d,p) scale of theory computation. The measurement was performed to collect the oscillator strength (f), vertical excitation energies and absorption wavelength (nm) as seen in Table 5. The λmax in the spectrum reconciled to vertical excitation as per the Frank-Condon principle. Both of theoretical and experimental spectra are plotted in Figure 8b. The experimental UV-visible in water indicated the presence of four peaks. The first three bands at λmax = 215 nm, 255 nm, and 328 nm are attributed to π→π*, π→n, and n→π* electron transfer in the desired Schiff base, respectively. Meanwhile, the fourth peak, which was detected at λmax = 395 nm, can be attributed to the dissociation of the phenol to form the phenolate ion in aqueous polar medium as indicated in Scheme 2. The absence of this band in nonpolar solvent as CH3CN confirmed this aspect (Figure 8b).

HOMO/LUMO and Absorption/TD-DFT
The HOMO→LUMO orbital shapes ( Figure 8a) and energy diagrams were performed using GaussView 5.0 software. The LUMO and HOMO molecular orbital energy levels both had negative values. Thus, the stability and softness of the GASB-1 were increased. The ∆E HOMO/LUMO was found to be 1.730 eV, whereas the ∆E DOS was 1.784 eV. A negligible deviation between the two methods was detected.
The UV-visible for the desired sugar derivative Schiff base was measured in water and acetonitrile solvents in the scale of 200-800 nm, parallel to that ground-state TD-DFT/B3LYP/6-31G(d,p) scale of theory computation. The measurement was performed to collect the oscillator strength (f), vertical excitation energies and absorption wavelength (nm) as seen in Table 5. The λ max in the spectrum reconciled to vertical excitation as per the Frank-Condon principle. Both of theoretical and experimental spectra are plotted in Figure 8b. The experimental UV-visible in water indicated the presence of four peaks. The first three bands at λ max = 215 nm, 255 nm, and 328 nm are attributed to π→π*, π→n, and n→π* electron transfer in the desired Schiff base, respectively. Meanwhile, the fourth peak, which was detected at λ max = 395 nm, can be attributed to the dissociation of the phenol to form the phenolate ion in aqueous polar medium as indicated in Scheme 2. The absence of this band in nonpolar solvent as CH 3 CN confirmed this aspect (Figure 8b).  The DFT calculations for B3LYP/6-31G(d,p) in the same solvents demonstrated the presence of three main bands at λmax = 247.5 nm, 309.1 nm, and 545.9 nm, with oscillator strengths of 0.5811, 0.0205, and 0.0116, respectively. The band at 247.5 nm can be attributed to the contributions of HOMO-1 → LUMO+1(97%) and HOMO-2 → LUMO+1(3%). The second band at 309.1 nm was due to HOMO-2→LUMO(20%), HOMO-1→LUMO(73%) HOMO-4→LUMO (5%), and the third band at 545.9 nm was due to HOMO→LUMO+1(100%) electron transfers. In the TD-DFT of the GASB-1, the protic (water) and aprotic (acetonitrile) solvents showed similar behavior. Moreover, a good agreement between the experimental and the theoretical solvato-behavior using protic and aprotic solvents was recorded.