Screening ionic liquids for dissolving hemicellulose by COSMO-RS based on the selective model

The utilization of biomass resources has attracted more and more attention due to the consumption of non-renewable resources. Compared with cellulose and lignin, hemicellulose has been less studied. Some ionic liquids (ILs) have been proved to be excellent solvents for lignocellulosic pretreatment. However, screening of more efficient ILs is difficult due to numerous possible ILs. Computational chemistry has been proved effective in solvent screening, but a precise model is indispensable. In this work, we focused on building several appropriate models and selected the most suitable one. According to the structure of hemicellulose, six hemicellulose models were constructed and the mid-dimer of the xylan chain hemicellulose (MDXC) model was proved to be the best compared with the reported experimental results. Based on the MDXC model, 1368 ILs were screened to evaluate their ability to dissolve hemicellulose by Conductor-like Screening Model for Real Solvents (COSMO-RS). The activity coefficient (γ), excess enthalpy (HE), and σ-profile indicated that the hydrogen-bond (H-bond) played a vital role in the dissolution of hemicellulose. Anions played a more critical role than cations, where small anions with H-bond acceptor groups could enhance the molecular interactions with hemicellulose. This work provided a thermodynamic understanding of hemicellulose and IL solvent systems. It highlights the importance of building appropriate solute models, which may be necessary to predict of the other thermodynamic properties in the future.


Introduction
Lignocellulosic biomass is considered one of the most abundant renewable sources in nature. Compared with fossil resources, lignocellulosic biomass has the advantages of being renewable, environmentally friendly, and of large yield. [1][2][3] Hemicellulose is a polymer with xylan as the main chain, and is an essential component of lignocellulose. 3 It can be successfully converted into biofuels, materials, chemicals, and functional food ingredients due to its bioactivity, biocompatibility, and biodegradability. [4][5][6] In the cell wall, hemicellulose is bonded to cellulose by hydrogen bonds and to lignin by covalent bonds. 7 The hydrogen bonds and covalent interactions with other cell wall constituents restrict the release of hemicelluloses from the plant cell wall. 1 It is necessary to extract hemicelluloses thoroughly before converting them into value-added products. The common approaches are the alkaline solvent system method and the hydrothermal method, which usually cause environmental problems and hemicellulose degradation into by-products. [8][9][10] Therefore, it is of great signicance to explore new green solvents that can fully and efficiently dissolve hemicelluloses for applying to utilize lignocellulosic biomass.
Ionic liquids (ILs) have several remarkable properties such as having low vapor pressure, excellent chemical and thermal stability, and being nonammable. [11][12][13][14][15] As a new type of green solvents, ILs can dissolve carbohydrates, swell the cell walls, and decrease the crystallinity of cellulose. 9 It have been reported 16 that imidazole-based ILs with anions of Ac À , Cl À , Br À , I À could dissolve hemicellulose efficiently at temperatures ranging from 80 to 150 C. Peng 17 found that two hydroxyl groups of the xylan chain in hemicellulose can form electron donor-electron acceptant (EDA) with [Bmim]Cl, which could accelerate the hemicellulose dissolution process. Morais 18 studied the interaction between ILs and hemicellulose through NMR. They concluded that the anion alkalinity was the key for hemicellulose dissolution. Cheng 19 showed the advantages of conducting a suitable model compound to explain the dissolution mechanism of the experimental results. Up to now, hundreds of ILs with excellent solubility to cellulose or lignocellulose have been found, 20-23 but hemicelluloses were relatively few investigated. Due to the complexity of hemicellulose, its dissolution in ILs and its interaction with ILs were still unclear. 2 As the numerous potential ILs with different cations and anions bring difficulty to screen, it is important to use a high- efficiency method to predict hemicellulose solubility in ILs. 24 Conductor-like Screening Model for Real Solvents (COSMO-RS) is a model based on the continuum solvation theory for a specic problem in the molecular structures. 25 H-bonds, van der Waals, and mists interactions in the solvent systems are combined to predict the logarithmic activity coefficient (ln g) at innite dilution. 15 The ln g can reect the solubility of solute in ILs. Combining statistical thermodynamics and quantum chemistry, COSMO-RS is considered 25 to be one of the most high-efficiency methods for prediction and screening of ILs.
In recent years, several studies [26][27][28][29] have demonstrated that COSMO-RS could predict ILs dissolving capabilities. It has been proved that low activity coefficient and low numerical H E of lignocellulose in ILs were related to high solubility. 26 Kahlen et al. 30 screened more than 2000 ILs for dissolving cellulose and showed that the anion was the major determinant in the dissolving process based on COSMO-RS calculation. Liu 15 emphasized the importance of suitable models in investigating the dissolving process, the mid-monomer part of cellotriose was proved to be the most consistent with the experimental results. Moreover, different conformations of the molecules in the dissolved system led to different termodynamic properties predicted by COSMO-RS. 31 He et al. 32 developed an automated computational framework MoDoop based on COMSO-RS to predict the lignin solubility in ILs. In Mohans' studies, 33,34 the researchers used cellobiose as a model for cellulose, whereas hemicellulose is represented with an equimolar combination of both glucose and xylose. The ln g of cellulose and hemicellulose in thousands of ILs have been predicted by COSMO at room temperature, and the interaction between solute and solvent has been analyzed using a variety of computational methods combined with experiments, which is a relatively complete and systematic work. However, the solute model has great inuence on the calculation results, a suitable solute model determines the accuracy of the prediction, and is essential for future hemicellulose studies. The fact that different solute model can drastically change the thermodynamic estimations using COSMO-RS is of signicant concern.
This study focuses on the construction and selection of suitable hemicellulose models, aiming to obtain the most appropriate hemicellulose model and screen a large amount of ILs. Understand the thermodynamic properties of hemicellulose dissolution in ILs. ILs with different cations, anions (bounded with several types of functional groups) were considered due to their accessibility and eco-friendly properties. We developed six different models, and the reported experimental data 16,35 were used to verify the predictions of several hemicellulose models' ln g at innite dilution. The mid-dimer of xylan chain (MDXC, Model 3) was proved to be the best model. This study also summarizes the dissolution rules of ILs for hemicellulose from the perspectives of cation type and alkylchain length, and complementarity of the s-prole between anion-solute molecules was quantied and the rationality of this screening method was conrmed.

COSMO-RS computation details
In this study, the quantum chemistry Turbomole (TmoleX) package was used to optimize the molecular geometries of ions and solutes of the studied compounds at the B3LYP/6-31 ++ G (d,p) level, and COSMO continuum solution models were calculated using the BP-TZVP-FINE level theory. The conformations of all the molecules and ions used in the calculations were provided in ESI Table S1. † The logarithmic activity coefficient, excess enthalpy, s-potential, and s-prole were determined by COSMO-RS (implementation: COSMOtherm 2020 version 20.0.0, revision 5273, COSMOlogic, Leverkusen, Germany). In the reported work, 33,34 most of calculation studies on hemicellulose are room temperature or below 100 C. However, experimental studies 16,35 have conrmed that most ILs have better dissolution effects on biomass solution at higher temperatures(>100 C). Therefore, different from Mohan's work, 33 the calculation temperature for COSMO-RS was set to 130 C in this work, and the experimental determination of bamboo solubility was measured at the same temperature. 16,35 This is more consistent with the temperature range of biomass dissolution and degradation in production and application.
To calculate excess enthalpies in the COSMO-RS program, the molar fraction of hemicellulose, IL cation, and IL anion was Fig. 1 Schematic representation of hemicellulose. 37 Inter-and intramolecular hydrogen bonds are also shown. set to 0.5, 0.25, 0.25, respectively. The method to calculate ln g at innite dilution and H E was described in previous studies. 31,36

Hemicellulose models and model validation
Hemicellulose is an amorphous polymer containing a main chain of xylan (Fig. 1). The composition of branched chains in hemicellulose varies with the type of biomass. A suitable hemicellulose model is crucial for COSMO-RS to nd ILs with a good ability to dissolve hemicellulose. In the reported studies, D-xylose (a hexose sugar) and D-glucose (a pentose sugar) were the most popular models. 33,34 The authenticity and objectivity of solute theoretical models have been largely ignored. In this study, one of our purposes is to establish a model for the main chain structure of hemicellulose. The experimental solubility data of hemicellulose in this work comes from bamboo hemicellulose, in which xylan accounts for about 70% of the hemicellulose component. Six potential models based on different xylan chains were proposed. Based on the COSMO-RS calculations, the end groups of the polymer for repeating units are deactivated using a "weighted string" function. 26 The ln g at innite dilution of solute is oen considered as a qualitative measurement of solute solubility. According to Formula 1, the reciprocal of the activity coefficient represents the solubility of hemicellulose in their respective ILs. 30 In this formula, x L i represents the mole fraction of dissolved i versus undissolved i in a saturated solution. Dh m,i , T m i represents the  In COSMO-RS, s-potential 25 measures the system's affinity to a surface of polarity s. Three regions dened based on spotential: H-bond donor region (s <À0.0082 eÅ À2 ), H-bond acceptor region (s >+0.0082 eÅ À2 ), and non-polar region (À0.0082< s <+0.0082 eÅ À2 ). The s-potential lines of Models 3 to 6 almost overlap in the whole region (Fig. 3), which means that their representation of hemicellulose is almost identical in the solution system based on COSMO-RS calculation. The spotential of Model 1 is more negative than that of other models in the H-bond acceptor region, which means that Model 1 has more affinity to H-bond acceptor surfaces than other models. Model 3 has the strongest hydrogen-bonding acceptor affinity due to a more negative s-potential in the H-bond donor region and a more positive s-potential in the H-bond acceptor region. The performance of Model 2 is somehow in between.
The ln g of the six hemicellulose models by COSMOtherm along with the experimental bamboo solubilitie 16,35 is in the ten ILs were listed in Table 1. Linear regression was performed between ln g and experimental solubilities. R 2 , RSS, and optimization time, which characterize the performance of the models were listed in Fig. 4. R 2 of the longer xylan chain (R 2 ¼    0.82) models were higher among the six hemicellulose models. R 2 of the intermediate trimer, tetramer, and pentamer models were the same as those of the mid-dimer models. However, the RSS values of the mid-dimer of xylan chain model (MDXC, Model 3) in the ten ILs was smaller. With the increase of chain length, the molecular structure's optimizing time of more complex models increased sharply. It showed that Model 3 was a good representation of the long-chain structure of   hemicellulose. Combined with the calculation time of different models, Model 3 was the best among the six models.

Structure of cations and anions
We considered 36 cations (Table 2) including pyrrolidiniumbased, morpholinium-based, quaternary ammonium-based with the functional groups of methyl, allyl, hydroxyethyl, methoxyethyl and ester. These cations formed 1368 ILs, combining with the 38 anions (Table 3) studied in this work.

Prediction of the logarithmic activity coefficient at innite dilution
The predicted ln g (methods described in Section 2.2) of Model 3 in 1368 ILs were depicted in Fig. 5. The cations and anions were listed in the order of the calculated logarithmic activity coefficient values. The ILs with high solubility were shown in the upper-le corner of the image, and the ILs with low solubility were shown in the down-right corner. The red and blue dotted lines roughly divided 1368 ILs into three regions according to the ln g. The ln g varies notably between different kinds of anions (Fig. 5). However, little difference was found between different cations, indicating that the dissolution of hemicellulose in ILs was mainly attributed to the anion. It could be explained that ILs containing the anions including Cl À , Ac À , HCOO À , Gly À , Br À had a strong ability to dissolve hemicellulose. It is consistent with the experimental results of Santo et al., 38 where they indicated the relative interaction strength between smaller anions and cations were stronger, 38,39 and could promote the dissolution of xylan chain. It has been widely recognized that anions played a signicant role in the dissolution of lignocellulose. But the cations cannot be ignored in the dissolution of hemicellulose. In Mohan's calculation 34 of the ln g at room temperature, the cation species had little inuence on the ln g. In this work, it can be seen that cation type and cation branched-chain type has a more signicant effect on hemicellulose in ILs at 130 C (Fig. 5), which may be caused by the temperature effect. Higheffective ILs can be obtained by designing ILs cations with different functional groups. The hemicellulose has a relative high solubility in pyrrolidinium-based ILs than other ILs (Fig. 6a). The second highest are the ILs with ethyl-morpholine, and followed by methyl-morpholine, imidazolium, and pyridinium ILs. Fig. 6b showed the average ln g of 30 cations with ve different R-group, where the order of solubility is methyl > allyl > methoxyethyl > hydroxyethyl > ethoxy-2-oxoethyl. The presence of alkaline oxygen atoms in the side chain could interfere with hydrogen-bond formation between the anions and the hydroxyl groups in the xylan chain, for example, cations with alkoxy or alkoxyalkyl groups. 40 In this work, we compared the methylmorpholinium-based and ethyl-morpholinium-based ILs. We found that cation with longer alkyl chain had a negative effect on the dissolution of hemicellulose compared with shorter alkyl-chain. To investigate the effect of the cation alkyl chain length on hemicellulose dissolution, methylimidazolyl-based and methylpyrrolidiniumbased ILs with alkyl chain of different lengths were selected from the COSMOtherm ILs database. Aer combining with the 38 anions, the ln g of those ILs were calculated. The results were shown in Fig. 7, which veries the inhibition long alkyl chain on hemicellulose dissolution, which is consistent with the experimental phenomenon. 41 Pyrrolidinium ILs were more affected by the length of alkyl chain than imidazole ILs (Fig. 7c).

Prediction of excess enthalpy
As the temperature derivative of Gibbs free energy, excess enthalpy (H E ) which is attributed to H-bonds, mists and van der Waals forces, reected the behavior of different solute in solution. Casas et al. 39 pointed out that the H-bond energy calculated by COSMO-RS reected the affinity between ILs and lignocellulose, thus a low H-bond energy value represent higher solubility of lignocellulose in ILs. The histogram showed that the H-bond interaction between the hemicellulose model and ILs apparently inuences hemicellulose solubility (Fig. 8), followed by mists and van der Waals force. The ILs with the same cation and different anions had different excess enthalpies, which is not shown in ILs with the same anion and different cations. The result further conrmed that anion plays a more critical role in hemicellulose dissolution than cation.

Prediction of s-prole
The calculation results of ln g and H E showed that the dissolution of hemicellulose is strongly dependent on the anion. In addition, the s-prole curve of COSMO-RS theory can reect the relative number of environmental polar fragments on the molecular surface. The complementarity of the curve peak in the H-bond acceptor region can be used to describe the interaction ability between ions and solute molecules. 31 The ILs anions were classied into categories I, II and III according to their ability to dissolve hemicellulose (Fig. 9a). The s-prole curves of the category I anions had better complementarity with the curve of hemicellulose model in the polar region (+0.015-+0.022). Then, we tried to nd the most appropriate way to quantify this feature. Aer analyzing the anions' s-prole curves in the polar region, we found that the integral area under the s-prole curves of the anions can reect the complementarity between anions and the hemicellulose model better (Fig. 9b). We calculated the integral areas under the s-prole curve of 38 anions in the polar region (+0.015-+0.023) and correlated them with the average ln g of each anion's ILs. In order to determine the most appropriate complementary region, we took multiple regions for calculation and comparison. We found that data points of the 38 anions had the best correlation (R 2 ¼ 0.779) in the range of (+0.016-+0.021) (Fig. 9c, other interval data detailed in ESI, Table S3 †). The method can quantify the complementarity of the s-proles curves between compounds in the vital interval of the polarity region. The anions with the largest integral area within the region were highly consistent with the anions with better solubility. In addition, the curve of s-proles in the H-bond acceptor region also showed that the interaction between the anions and the hydroxyl group of the hemicellulose plays an essential role in the dissolution process. The solubility followed the hydrogen bonding acceptor affinity or alkalinity 42 of the anion. The s-prole method for ILs was a new and more intuitive method for the high throughput screening of ILs.
To further verify the reliability of the s-prole, we used molecular dynamics (MD) simulation for three ILs with different abilities in dissolving hemicellulose. The cation is [Bmim] + , and the three anions are [Cl] À , [BEN] À and [TF 2 N] À , respectively. The simulations were performed with GROMACS soware package. 43,44 Each system contains 1000 ILs and 15 molecules (Model 3), and the content of the molecule is 1.48 mol%. The initial conguration was generated by randomly placing Model 3 in the ILs by Packmol package. 45 Then energy was minimized, followed by NVT and NPT simulation. The equilibration simulation was extended to 50 ns, and production phase lasted for another 50 ns at 130 C. The cutoff distance between LJ and Coulomb interaction is 1.2 nm. Temperature control using Nosé-Hoover thermostat 46 with  Fig. 10a shows the radial distribution functions (RDFs) between the hydroxyl H on the two middle rings of hemicellulose and the anion. By comparison, it is found that the interaction between H atom and oxygen atom in [TF 2 N] À is much smaller than the interaction for [Cl] À or carbonyl O in [BEN] À . This is consistent with the poor solubility of [Bmim][TF 2 N]. The spatial distribution function (SDF) reects the density distribution of components from a three-dimensional perspective intuitively, which represents the interaction strength of all components. We calculated the SDF of anions around hemicellulose, as shown in Fig. 10b-d. The anions are mainly distributed around the hydroxyl of the hemicellulose molecules, because their interaction is mainly the H-bond between the hemicellulose and the negatively charged atoms on the anion. The difference between the three anions is obvious, the H-bond interactions from strong to weak are [Cl] À , [BEN] À to [TF 2 N] À , which is consistent with the result of the above s-prole. To sum up, the s-prole prediction method is effective and reliable.

Conclusion
In this study, a variety of hemicellulose models were tested in COSMO-RS calculation. And the result show that the MDXC is the best model to well correlated with the experimental data (R 2 ¼ 0.82). The ln g is a reliable character reecting the solubility in ILs with different cations and anions. Especially, ILs with anions of Ac À , Cl À , HCOO À , Gly À and DMSO À were predicted to have a promising advantage for the hemicellulose dissolution. Compared with the reported work, cations have a greater inuence on the dissolution of hemicellulose by increasing the temperature. In terms of cations, pyrrolidinium-based and quaternary ammonium-based ILs have strong H-bond formation ability with hemicellulose, which accelerate the dissolution process. The order of R-groups contribute to solubility is methyl > allyl > methoxyethyl > hydroxyethyl > ethoxy-2-oxoethyl. The solubility of ILs for hemicellulose is decreased with the extend of alkyl chain length in cation. The H-bond interaction is the primary contributor in the dissolution of hemicellulose, with mists' force and van der Waals force being subsequent ones. Further, the s-prole method is effective for large-scale ILs screening. In all, this work highlighted the importance of selecting an appropriate solute model, and it provided an understand of the thermodynamic behavior of hemicellulose and ILs solvent systems, which is necessary for predicting the other thermodynamic properties.

Conflicts of interest
There are no conicts to declare.