Manon Bergez-Lacoste

Sophie Thiebaud-Roux

Pascale De Caro

Jean-François Fabre

From chemical platform molecules to new biosolvents: Design engineering as a substitution methodology

Keywords: biosolvents, substitution methodologies, reverse design, furfural

The substitution of conventional solvents, in line with regulation changes, requires the use of appropriate methodologies able to generate candidate molecules. Starting from the widely used trial and error approach, we developed two improved, time-and cost-saving methodologies, involving the prediction of molecule properties and reverse design. Reverse design is an innovative methodology to design biosolvents through a virtual laboratory: stages of generation of molecular structures and properties prediction are integrated into a computer-aided molecular design tool providing solutions that meet targeted specifi cations. These two substitution methodologies were applied in a case study aiming at replacing acetone and methyl ethyl ketone for the solubilization of epoxy resin prepolymers. The generation of performing biosolvents was carried out from furfural as a bio-based platform molecule, thanks to the prediction of different relevant properties (physico-chemical, safety, and environmental characteristics). The reverse design succeeded in ranking these solvent candidates according to their capacity to match the required specifi cations.

Introduction

S

olvents play a major role in the chemical industry.

ey are essential for many applications, including cleaning, pesticide delivery, coatings, and synthetic chemistry. 1 e market for conventional solvents totals 18 million tonnes per year worldwide, and 4 million tonnes per year in Europe. e most commonly used solvents to date have been of petrochemical origin. ese conventional solvents include aliphatics, aromatics, halogenated hydrocarbons, terpenes, alcohols, esters, ketones, and glycol ethers. ey account for about 20% of the volatile organic compound (VOC) emissions and are, therefore, a major environmental concern, due to their contribution to the accumulation of tropospheric ozone through photochemical reactions in the atmosphere. ey therefore play an indirect role in the greenhouse e ect. Moreover, conventional solvents are o en highly ammable and high vapor pressures, for the solubilization of epoxy resin prepolymers: DGEBA (bisphenol A diglycidyl ether) and TGPA (triglycidyl p-aminophenol ether). ese polymers are widely used in industry as starting monomers for the production of epoxy resins and polycarbonates, polymers widespread in several industrial sectors, including the petrochemical industry, packaging, restoration, adhesives, panels, and composites.

Substitution of conventional solvents

Criteria for the selection of new alternatives e goal of substitution approaches is to move progressively to the use of safer products and processes, in accordance with legislation, public concern, and customer needs. However, clear criteria must be de ned for the identi cation of a safer alternative with a similar technical characteristics pro le and production price. us, for the design of eco-friendly solvents, the following criteria must be considered: 1 -Technical speci cations: linked to the desired performance for the targeted application and the required safety properties. -Environmental and health properties: to meet particular requirements in terms of regulations, standards, and ecolabel speci cations. -Ecocompatibility of the process for biosolvent production: it must respect most of the 12 principles of green chemistry proposed by Anastas and Warner. [START_REF] Anastas | Green Chemistry: Theory and Practice[END_REF] e cost of the biosolvent, depending on the raw materials and the processes used for their transformation. ese criteria can be checked by evaluating several properties, by experimental or predictive methods (Table 1).

In this context, the selection of biosolvents is based on the determination of several parameters described below.

Solubility power may be assessed by various experimental and theoretical methods:

e Kauri-butanol index, which indicates the maximum amount of solvent that can be added to a solution of Kauri gum in n-butanol without causing cloudiness.

is measurement is described by ASTM D1133 and provides a scaleless index.

e Kamlet Ta solvatochromic scale is a widely used multiparameter scale for investigating and predicting solvent behavior. [START_REF] Kamlet | The solvatochromic comparison method. I. The β-scale of solvent hydrogen-bond acceptor (HBA) basicities[END_REF][START_REF] Kamlet | The solvatochromic comparison method. 6. The π* scale of solvent polarities[END_REF][START_REF] Kamlet | Linear solvation energy relationships. 23. A comprehensive collection of the solvatochromic parameters, π*, α, and β, and some methods for simplifying the generalized solvatochromic equation[END_REF] e Kamlet-Ta solvent parameters toxic, and their manufacture is also dependent on fossil resources. is context has tended to modify the array of solvents used in industry, and regulations have evolved with advances in our understanding of the potential e ects of solvents on the environment and human health. Solvent use is governed by several European directives: directive 1999/13/CE limits VOC emissions from industrial equipment; directive 2004/42/CE concerns the VOC content of solvents used to dilute architectural paints and varnishes and car re nishing paints; and directives 64/548/CEE and 1999/45/CE govern the use of dangerous chemicals. In addition, petrochemical solvents have been subject to REACH regulations since 2007. is regulatory context resulted, for example, in the banning of dichloromethane in paint strippers in 2012 (REACH 276/2010 regulation). us, many studies are currently focusing on the replacement of hazardous solvents with more environment-friendly alternatives, according to the ecodesign approach. [START_REF] Jessop | Searching for green solvents[END_REF] In recent years, solvent-free processes, ionic liquids, eutectic solvents, uorous solvents, supercritical uids, and water as a reaction medium have emerged as interesting alternatives. [START_REF] Sheldon | Green solvents for sustainable organic synthesis: State of the art[END_REF][START_REF] Desimone | Practical approaches to green solvents[END_REF] For other applications, however, such as industrial cleaning, these alternatives are not applicable and the replacement of conventional solvents remains di cult. Biomass-derived chemicals o er promising opportunities in the search for eco-friendly, 'sustainable', or 'green' solvents. [START_REF] Bandres | Green syntheses of biobased solvents[END_REF] e market for bio-based solvents in Europe is currently 60 000 tonnes, but is expected to expand over the next few years, in a context of changes to the regulations in force. Biosolvents are not universal solvents like most of the chlorinated or hydrocarbon solvents for which substitutions are required. ey are therefore o en suitable only for speci c applications. For instance, fatty-acid methyl esters have proved e ective solvents for cleaning purposes. Dimethyl carbonate is used as a toluene substitute in the pharmaceutical industry. Methyl THF is an interesting solvent for organic synthesis. is lower level of versatility means that a larger number of biosolvents are required to cover the principal applications.

New tools and methodologies are being developed in the face of the need for alternative solvents. Selecting new solvents is a laborious, time-consuming task, as the new solvents must have technical performances at least as good as those of the conventional solvents they replace, together with better health, safety, and environmental pro les.

ree di erent types of methodology can be applied in the substitution approach. We will introduce these methodologies here, comparing their e ciency through an example of substitution. In the case study presented, the aim is to replace acetone or methyl ethyl ketone, both of which have [START_REF] Hildebrand | The solubility of Non-Electrolytes[END_REF] It is derived from the cohesive energy density of the solvent, which is linked to the heat of vaporization.

-Hansen solubility parameters are derived from Hansen theory, which describes the cohesion of a substance as the result of the combination of three intermolecular interactions. ese interactions correspond to three parameters dividing the Hildebrand parameter into three parts: δD re ects the non-polar interactions derived from London dispersion forces, δP represents the polar interactions linked to Keesom forces and δH re ects the ability to form hydrogen bonds. ese parameters are used as coordinates, to place solvents or solutes in a three-dimensional space. e a nity of a solvent and solute increases with the closeness of their Hansen parameters. Hansen solubility parameters can be determined experimentally by solubility tests in a set of solvents with known Hansen parameters. e solubility sphere includes the maximum number of miscible solvents and no non miscible solvents. is sphere is characterized by a radius. e RED number, re ecting the relative energy di erence, is de ned as the ratio D/R, where D is the distance between a solute and a solvent (or two solvents), and R is the radius. is number is, thus, a powerful indicator of predicted solubility (or miscibility). If RED < 1, the studied solvent is within the solubility sphere and should dissolve the target. If RED > 1, its position outside the sphere indicates that it is not environmental impact of a chemical substance: these indicators are assessed through their action on sample populations of living organisms (measurements of median lethal concentration and of the concentrations of substances accumulating in speci c organisms). Economic aspects can be evaluated in terms of the cost of the raw materials and processes involved in the production chain. Raw materials should be renewable, easily available, a ordable and should not also be used in the food industry (to avoid competition between the two sectors, pushing up food prices).

e processes should be evaluated by green metrics, which can be calculated from the mass balance by EATOS so ware. [START_REF] Eissen | Environmental performance metrics for daily use in synthetic chemistry[END_REF] All of these critical factors are taken into account in solvent substitution. In all the various alternative approaches described since the 1990s by Fishkov et al., [START_REF] Filskov | Substitutes for Hazardous Chemicals in the Workplace[END_REF][START_REF] Goldschmidt | An analytical approach for reducing workplace hazards through substitution[END_REF] the British Health and Safety Executive, [START_REF]HSE, 7 Steps to Succesful Substitution of Hazardous Substances[END_REF] or Collaton and Green, [START_REF] Callahan | Hazardous Solvent Source Reduction[END_REF] similar criteria were taken into account in the analysis of needs: technical e ciency, health aspects, safety, protection of the environment, process ecoe ciency, economic aspects, and human and organizational factors.

Solvent substitution methodologies

Computing resources, such as the CAGE (coating alternatives guide) or SAGE (solvent alternative guide) so ware developed by the Research Triangle Institute, can be used to nd substitutes for cleaning and paint solvents. [START_REF] Cornstubble | CAGE 1.0 -Coating Alternatives Guide -User's Guide[END_REF][START_REF] Monroe | Solvent Alternatives Guides (SAGE), Computer assisted guidance for solvent replacement. CFC and Halon Alternatives Conference -Stratospheric Ozone Protection for the 90s[END_REF] However, these tools are not suitable for the identi cation of appropriate alternatives for all applications.

Various di erent methodologies have been developed for the substitution of conventional solvents. predicted to be a good candidate. is notion is illustrated in Fig. 1. e solubility spheres of epoxy resin prepolymers (studied in the next section) are represented.

eir conventional solvents, methyl ethyl ketone (MEK) and acetone, have been also located with non-solvents in the Hansen space.

-COSMO-RS (Conductor-like Screening Model for Real Solvents) is a new approach for the classi cation of organic solvents. [START_REF] Durand | Classifi cation of organic solvents revisited by using the COSMO-RS approach[END_REF] It is based purely on solvent structure and the solvents are located in a pseudo 3D-space on the basis of principal component analysis and clustering procedures. is representation of solvents as a function of their electron density, sigma pro les and chemical potential may facilitate the identi cation of potential alternatives to an undesirable solvent. [START_REF] Moity | Panorama of sustainable solvents using the COSMO-RS approach[END_REF] VOC emissions are strictly limited by regulations and the VOC emissions of industrial equipment must thus be carefully controlled. Vapor pressure and boiling point are good indicators of solvent volatility. A high evaporation rate is useful for limiting drying time (for applications such as coatings, nail polish, and paints), but a compromise must be found to decrease VOC emissions.

Flash point is related to ammability and must be high enough for safety purposes during the production, conditioning, and transportation steps.

e impact on the environment is correlated with solvent biodegradability, the ability of the compound to be broken down by natural micro-organisms into water, carbon dioxide, and biomass. Products with a biodegradability rate of more than 60% in 28 days are generally described as easily biodegradable. Bioaccumulation and ecotoxicity can also be used as indicators of the organic synthesis program able to suggest virtual compounds from one bio-based platform molecule. [START_REF] Moity | In silico design of bio-based commodity chemicals: Application to itaconic acid based solvents[END_REF] Before testing these molecules in the laboratory, they are subjected to a screening process: their properties are predicted with the various tools listed in Table 2 and compared with the speci cations. is makes it possible to eliminate any molecules with predicted properties not meeting the de ned speci cations. e selected molecules are synthesized and tested. is methodology is clearly more productive, because only potentially interesting molecules (predicted properties consistent with the specications) are synthesized, saving time, energy and raw materials.

e models implemented in the IBSS tool were selected based on their ability regarding the comparison between predicted properties and experimental properties for a series of known compounds.

All these computational systems were developed to overcome the lack of experimental data for many chemicals. Indeed, physico-chemical properties have been experimentally determined for less than 1% of the approximately 100 000 chemicals registered in the REACH program. [START_REF]SPARC Performs Automated Reasoning in Chemistry[END_REF] ey are based on property modeling and must be handled with care, as their domain of applicability determines the molecules to which they can be applied.

IBSS is a CAPD (computer-aided product design) tool developed by the Laboratoire de Génie Chimique (Toulouse, France) for the InBioSynSolv project, a research program supported by the French National Research Agency. [START_REF] Heintz | Chemical enterprise model and decision-making framework for sustainable chemical product design[END_REF] e CAPD approach is an extension to multicomponent mixtures of the CAMD (computer-aided molecular design) approach, which principle is described in the next section. Within this tool, a library of property prediction methods is available including physicochemical properties, as well as toxicity and ecotoxicity models. Once target property values are de ned, they can be aggregated into a performance function enabling to check the match of a molecule or mixture with property speci cations. Some of the other tools are dedicated to the prediction of chemical and physical properties, whereas others speci cally predict the toxicity and ecotoxicity properties. HSPiP was developed by Professor Abbot and its main application is the prediction of Hansen solubility parameters, although it can also be used to predict various other properties. [START_REF] Abbott | The Offi cial Hansen Solubility Parameter Site[END_REF] Sci Finder is a well known database of chemical abstracts with integrated ACD/Labs so ware for the prediction of some properties. SPARC (Sparc Performs Automated Reasoning in Chemistry) was developed by EPA (Environment Protection Agency) researchers and is

Trial and error methodology

'Trial and error' is an experimental problem-solving method that can be seen as a basic approach built on practical experiments. For a conventional solvent to be replaced, one or several hypothetical candidates are identi ed and tested (trials). If these molecules do not match requirements (errors), they are eliminated and others are proposed and tested, with a view to identifying a suitable substitution solvent. Bégin and Gérin have described this methodology for solvent substitution in greater detail, focusing on the following major steps: [START_REF] Bégin | Substitution des Solvants[END_REF] -Identi cation of the solvent to be replaced for reasons of toxicity, a poor environmental footprint, high costs, etc. -Proposition of alternative solvents by a chemist able to select bio-based building blocks and to propose derived compounds. e choice of the proposed alternative solvents is generally guided by existing solvent classi cations, which are based on dipolar moment, dielectric constant and protic character, but also on the Hansen solubility parameters or Kamlet Ta parameters or the COSMO-RS approach. [START_REF] Moity | Panorama of sustainable solvents using the COSMO-RS approach[END_REF] -Tests of candidates for the target application, such as solubilization of the active principle or industrial cleaning. -Finally, candidate selection tends to be based on a compromise between several criteria. is methodology has been depicted and used in several case studies aiming to replace trichloroethylene or xylene, for instance. [START_REF] Bégin | Substitution des Solvants[END_REF] Ethyl lactate was identi ed by the same authors as a good biosolvent for paint stripper, degreasing agents and precision cleaning. [START_REF] Bégin | La substitution des solvants par le lactate d'éthyle[END_REF] is method is time-consuming; every solution has to be tested. Moreover, the selected solvent may not necessarily be the best alternative.

Predictive methodology

is methodology was developed as an improvement of the trial and error method, based on prediction of the properties of the molecules proposed by the chemist. As for the trial and error method, the substitution problem and the associated speci cations are rst identi ed and alternative solvents are then proposed by the chemist. In this case, the chemist, in charge of the generation of molecules derived from bio-based building blocks, selects the transformation routes respecting green chemistry principles. He may be then helped by a computer-assisted SMILES notation or molecule-drawing so ware is required as an input for these tools, with the predicted properties as the output.

In the absence of experimental information for a candidate molecule, prediction tools are useful for the primary selection of molecules.

Reverse design

is methodology, which combines the chemist's knowledge and CAMD, is suitable for use in the substitution of conventional solvents and has already proven successful for the identi cation of alternative products in various elds, such as processes, solvent design, refrigerant uids, and polymer design. [START_REF] Song | Computer-aided molecular design of environmentally friendly solvents for separation processes[END_REF][START_REF] Sherman | Solvent replacement for green processing[END_REF][START_REF] Sinha | Environmentally begnin solvent design by global optimization[END_REF][START_REF] Constantinou | Computer aided product design: Problem formulations, methodology and applications[END_REF][START_REF] Maranas | Optimization accounting for property prediction uncertainty in polymer design[END_REF] Indeed, computer-aided available online. [START_REF]SPARC Performs Automated Reasoning in Chemistry[END_REF] It uses computational algorithms based on fundamental chemical structure theory to estimate a large array of physical/chemical properties. PBT (Persistance, Bioaccumulation Toxicity), Caesar (Computer-Assisted Evaluation of industrial chemical Substances According to Regulations), Epi suite (Estimation Program Interface), and Toxpredict were developed more speci cally for predicting the impact of products on human health and the environment. [START_REF] Pbt Profi Ler | Persistent, Bioaccumulative, and Toxic Profi les Estimated for Organic Chemicals[END_REF][START_REF]Computer Assisted Evaluation of Industrial Chemical Substances According to Regulations (CAESAR)[END_REF] e PBT and Epi suite were designed under contract for the O ce of Chemical Safety and Pollution Prevention of the US Environmental Protection Agency. Caesar and Toxpredict were developed with funding from the European Community. ese predictive tools are available either online or as free downloads. Melting point Marrero, 2001 [START_REF] Marrero | Group-contribution based estimation of pure component properties[END_REF] Reid, 1987 [START_REF] Reid | The Properties of Gases and Liquids[END_REF] Reid 1987 [START_REF] Reid | The Properties of Gases and Liquids[END_REF] ; Gold, 1969 [START_REF] Gold | Estimating thermophysical properties of liquids. Part 4 -Boiling, freezing and triple-point temperatures[END_REF] Joback, 1987 [START_REF] Joback | Estimation of pure-component properties from group-contributions[END_REF] Boiling point Marrero, 2001 [START_REF] Marrero | Group-contribution based estimation of pure component properties[END_REF] Stein, 1994 [START_REF] Stein | Estimation of normal boiling points from group contributions[END_REF] Joback, 1987 [START_REF] Joback | Estimation of pure-component properties from group-contributions[END_REF] ACD/Labs [START_REF]Advanced Chemistry Development (ACD/Labs), Software V[END_REF] Hilal, 2003 [START_REF] Hilal | Prediction of the vapor pressure boiling point, heat of vaporization and diffusion coeffi cient of organic compounds[END_REF] Flash point Catoire, 2006 [START_REF] Catoire | Estimation of closed cup fl ash points of combustible solvent blends[END_REF] Yamamoto [START_REF] Yamamoto | About the Pirika[END_REF] ACD/Labs [START_REF]Advanced Chemistry Development (ACD/Labs), Software V[END_REF] Vapor pressure Riedel, 1954 [START_REF] Riedel | Eine neue universelle admpfdruckformel untersuchungen über eine Erweiterung des Theorems der übereinstimmenden Zustände. Teil I[END_REF] Lyman, 1990 [START_REF] Lyman | Handbook of Chemical Property Estimation Methods[END_REF] Lyman, 1990 [START_REF] Lyman | Handbook of Chemical Property Estimation Methods[END_REF] Lyman, 1985 [START_REF] Lyman | Environmental Exposure From Chemicals[END_REF] Riedel, 1954 [START_REF] Riedel | Eine neue universelle admpfdruckformel untersuchungen über eine Erweiterung des Theorems der übereinstimmenden Zustände. Teil I[END_REF] Hilal, 2003 [START_REF] Hilal | Prediction of the vapor pressure boiling point, heat of vaporization and diffusion coeffi cient of organic compounds[END_REF] Molecular volume Yamada, 1973 [START_REF] Yamada | Saturated liquid molar volumes. Rackett equation[END_REF] Yen, 1966 [START_REF] Lc | A generalized equation for computer calculation of liquid densities[END_REF] Hilal, 2007 [START_REF] Hilal | Calculating physical properties of organic compounds for environmental modeling from molecular structure[END_REF] Density Hukkerikar, 2012 [START_REF] Hukkerikar | Group-contribution+ (GC+) based estimation of properties of pure components: Improved property estimation and uncertainty analysis[END_REF] Yen, 1966 [START_REF] Lc | A generalized equation for computer calculation of liquid densities[END_REF] Hilal, 2007 [START_REF] Hilal | Calculating physical properties of organic compounds for environmental modeling from molecular structure[END_REF] Water solubility Marrero, 2002 [START_REF] Marrero | Group-contribution-based estimation of octanol/water partition coeffi cient and aqueous solubility[END_REF] Meylan, 1996 [START_REF] Meylan | Improved method for estimating water solubility from octanol/water partition coeffi cient[END_REF] Meylan, 1994 [START_REF] Meylan | Validation of Water Solubility Estimation Methods Using Log Kow for Application in PCGEMS & EPI. Offi ce of Pollution Prevention and Toxics[END_REF] Hilal, 2004 [START_REF] Hilal | Prediction of the solubility, activity coeffi cient and liquid/liquid partition coeffi cient of organic compounds[END_REF] Hansen parameters Hukkerikar, 2012 [START_REF] Hukkerikar | Group-contribution+ (GC+) based estimation of properties of pure components: Improved property estimation and uncertainty analysis[END_REF] Yamamoto [START_REF] Yamamoto | About the Pirika[END_REF] Viscosity Joback, 1987 [START_REF] Joback | Estimation of pure-component properties from group-contributions[END_REF] Joback, 1987 [START_REF] Joback | Estimation of pure-component properties from group-contributions[END_REF] Superfi cial tension Conte, 2008 [START_REF] Conte | Combined groupcontribution and atom connectivity index-based methods for estimation of surface tension and viscosity[END_REF] Toxicity/ecotoxicity IBSS PBT Epi suite Caesar f Toxpredict g Persistence Meylan, 1993 [START_REF] Meylan | Computer estimation of the atmospheric gas-phase reaction rate of organic compounds with hydroxyl radicals and ozone[END_REF] Boethling, 1994 [START_REF] Boethling | Group contribution method for predicting probability and rate of aerobic biodegradation[END_REF] Bioaccumulation Meylan, 1999 [START_REF] Meylan | Improved method for estimating bioconcentration/bioaccumulation factor from octanol/water partition coeffi cient[END_REF] Toxicity ECOSAR program [START_REF]Ecological Structure Activity Relationships (ECOSAR)[END_REF] Kow Marrero, 2002 [START_REF] Marrero | Group-contribution-based estimation of octanol/water partition coeffi cient and aqueous solubility[END_REF] Meylan, 2005 [START_REF] Meylan | Estimating octanol-air partition coeffi cients with octanol-water partition coeffi cients and Henry's law constants[END_REF] Meylan, 2005 [START_REF] Meylan | Estimating octanol-air partition coeffi cients with octanol-water partition coeffi cients and Henry's law constants[END_REF] LC_ 50 Martin, 2001 [START_REF] Martin | Prediction of the acute toxicity (96-h LC50) of organic compounds to the fathead minnow (Pimephales promelas) using a group contribution method[END_REF] Patlewicz, 2008 [START_REF] Patlewicz | An evaluation of the implementation of the Cramer classifi cation scheme in the Toxtree software[END_REF] BCF Veith, 1975 [START_REF] Veith | Structure-activity correlations in studies of toxicity and bioconcentration with aquatic organisms[END_REF] Meylan, 1999 [START_REF] Meylan | Improved method for estimating bioconcentration/bioaccumulation factor from octanol/water partition coeffi cient[END_REF] Dimitrov, 2005 [START_REF] Dimitrov | Base-line model for identifying the bioaccumulation potential of chemicals[END_REF] Developmental toxicity Cassano, 2010 [START_REF] Cassano | CAESAR models for developmental toxicity[END_REF] Skin sensitivity less strict target property value speci cations can be set for such properties. Once candidate molecules have been selected, syntheses and tests are performed. is methodology is highly innovative and the most exhaustive, because speci cations and renewable materials are used for the generation of alternative solvents. Although it does not take into account the ecocompatibility of the synthesis process (greenness of the reaction) according to the 24 principles of green chemistry and green engineering, the multicriterion search of the CAPD makes it possible to achieve 'the greenest solvent' in terms of health, safety, and environmental considerations for its use while at the same time, considering technical. [START_REF] Capello | What is a green solvent? A comprehensive framework for the environmental assessment of solvents[END_REF] e ecocompatibility of the process can be evaluated further, by calculating green metrics. [START_REF] Andraos | Unifi cation of reaction metrics for green chemistry II: Evaluation of named organic reactions and application to reaction discovery[END_REF][START_REF] Constable | Metrics to 'green' chemistry-which are the best?[END_REF] e three methodologies are depicted in Fig. 2. e results provided by the second and third methodologies will be compared through a case study.

Case study: substitution of common epoxy prepolymer solvents

e substitution methodologies described above are illustrated here for the replacement of conventional solvents for the solubilization of epoxy resins.

Targeted application: cleaning of resins by solubilization

e aim is to design an e cient biosolvent for the solubilization of two epoxy resin prepolymers presented in Fig. 3: bisphenol A diglycidyl ether (DGEBA) and triglycidyl p-aminophenol ether (TGPA).

ese prepolymers are widely used in industry as basic monomers for the production of two major polymers: epoxy resins and polycarbonates. e cleaning of manufacturing and conditioning materials requires conventional volatile solvents, such as acetone and methyl ethyl ketone (MEK). Alternative solvents are now required, to limit the emission of VOCs. [START_REF] Medina-Gonzalez | The role of co-additive on epoxy resin pre-polymers solubilization in supercritical CO 2[END_REF] e speci cations for this context are listed in Table 3, for de nition of the required technical and environmental properties of the substitution solvent.

e Hansen parameters of the prepolymers were determined experimentally in a previous study, [START_REF] Gonzalez | Fatty acid methyl esters as biosolvents of epoxy resins: A physicochemical study[END_REF] from the solubility spheres of radii, R = 23.7 MPa 1/2 for DGEBA and R = 12.3 MPa 1/2 for TGPA (Fig. 1).

Both the predictive and reverse design methods were used, with a selected bio-based building block, furfural, as the starting material. molecular design has emerged as a powerful tool, given the progress made with group contribution methods in the estimation of values for particular properties. e CAMD method consists in nding molecules satisfying a set of requirements de ned a priori. Alternative structures are generated by an optimization technique; their properties are predicted and compared to the requirements transformed into property value speci cations; and molecules are ranked according to their match with the speci cations. e chemist can then select candidate molecules, based on the feasibility of their synthesis. e IBSS tool developed for the InBioSynSolv project is an innovative CAMD tool dedicated to the design of bio-based solvents. [START_REF] Heintz | Chemical enterprise model and decision-making framework for sustainable chemical product design[END_REF][START_REF] Heintz | Systemic approach and decision process for sustainability in chemical engineering: Application to computer aided product design[END_REF] Indeed, in addition to the abovementioned characteristics of CAMD implemented with a genetic algorithm, a speci c functionality has been added for molecular architecture: the ability to impose one or more bio-based building blocks as fragment in the molecule structure, to ensure the development of bio-based solvent.

e speci cations are provided as target property values to build a performance objective function in the CAMD tool. us, the targeted properties are de ned as constraints of the optimization problem to be met by the generated structures. e other input of IBSS so ware is a platform molecule. A bio-based building-block (like furfural) is thus given as the starting point for molecular architecture. Common functional groups (simple ones like -CH 3 , >C=O, -OH or complex ones like -COOH) are also listed in the CAMD tool as elementary blocks. By connecting these building blocks together, IBSS generates molecules containing the bio-based core, predicts their properties and compares them to the speci cations. A large set of property models can be used in the speci cations, including technical performance (melting point, boiling point), Hansen solubility parameters, safety properties ( ash point), and environmental impact (vapor pressure, bioaccumulation factor, and LC 50 acute toxicity). A er a given number of algorithm generations, a population of 100 molecules is obtained. ese molecules are ranked according to their performances describing how well they match the speci cations. Di erent weighting factors can be applied to the properties in the performance function, to weight the selection criteria as a function of the targeted application. e choice of weighting factors is usually done based on the user perception of each property importance for his problem to be solved. As the CAPD approach relies upon property prediction methods, a lower weight may be attributed for properties with methods having poor known prediction accuracy, so as to enable the search to nd good compromise solutions. Alternatively, Fig ure 2. Substitution methodologies: Trial and error, predictive method, and reverse design.

Bio-based platform molecule

O O 1: Trial and error methodology

2: Predictive Methodology

Prediction of properties and selection of candidates matching specifications

3: Reverse design

Selection among the candidates listed by the CAMD tool

Chemist knowledge of chemical transformations CAMD tool + Substitution specifications

Experimental evaluation with targeted application

Bio-based solvents

Pool of derived molecules

In silico candidates

Substitution methodology

Furfural as a platform molecule

Furfural is a widely used platform molecule with several advantages for the preparation of new eco-friendly solvents. [START_REF] Hoydonckx | Ullmann's Encyclopedia of Industrial Chemistry[END_REF] It is readily available, exclusively from plant feedstock, as no synthetic route exists. Furfural is thus prepared by dehydration of the xylose present in the hemicellulose of plant waste. [START_REF] Mamman | Furfural: Hemicellulose/xylosederived biochemical[END_REF] e annual production of furfural worldwide is 250 000 tonnes, 60% of which is converted into furfuryl alcohol.

e rest is used as a selective solvent for the re nement IBSS (Table 4) were correlated and validated with the results obtained with other tools (e.g. Sparc, HSPiP), for the selection of promising candidates. e most promising molecule (A) is selected by comparing the predicted properties with the speci cations. e actual properties of the candidate molecule can be cheked a er synthesis.

Results for the reverse design

e innovative IBSS tool was also used to nd alternative solvents for the solubilization of epoxy resins. e specications de ned in Table 3 were taken as the functional objectives and furfural was used as the platform molecule. IBSS can build furfural-derived molecules and predict their properties, for comparison with the speci cations. A selection of molecules ranked by IBSS is depicted in Fig. 6, and their predicted properties are gathered in Table 5 as well as the weights attributed to the considered properties in the performance function. e molecule (A) selected by the predictive methodology is among the molecules selected by CAMD, but this tool also proposes new structures. e chemist must consider the feasibility of lubricating oils, or as a synthesis intermediate for the production of furan and tetrahydrofuran (Fig. 4). [START_REF] Hoydonckx | Ullmann's Encyclopedia of Industrial Chemistry[END_REF] is upgrading scheme is consistent with the condition that bio-based chemistry should not compete with the food industry. Di erent types of agricultural waste are used, depending on the country: corn cobs in China, sugarcane bagasse in India, the black liquor from wood pulping in Austria, and apricot and olive seeds in Spain.

Alternative structures derived from furfural were screened by the predictive methodology. For the reverse design, furfural was used as the initial building block for CAMD.

Results for the predictive methodology

Several chemical transformations consistent with the principles of green chemistry (e.g. atom economy, small number of steps, limited waste and energy) were considered and applied to the platform molecule. is led to the identi cation of several candidate compounds, presented in Fig. 5.

e predictive tools were applied only to molecules that could be synthesized easily. e properties predicted by and relative costs of the various syntheses when choosing a candidate from the results obtained with IBSS. is innovative reverse design methodology has proved e cient for the generation of alternative solvents in accordance with de ned speci cations. IBSS seems to be a valuable tool for the rapid design of bio-based molecular architectures (a few minutes of calculation).

The performances of the two alternative solvents selected (A and B) by the predictive methodology and reverse design were experimentally validated for the solubilization of DGEBA and TGPA. A solubility of 100 g/L was achieved, confirming the satisfactory performances of these two solvents for resin dissolution in industrial cleaning, for example. The corresponding boiling points are 205 °C for (A) and 225 °C for (B). And the Hansen solubility parameters were determined for (B): δD = 17.1, δP = 8.6, δH = 9.7 with RED DGEBA = 0.09, RED TGPA = 0.33. The experimental values were then compared with the predicted properties, and were found in agreement.

Conclusion

Research into green solvents is o en a complex issue for the chemical industry. is study highlights the importance of using a rational methodology to achieve highperformance substitutions.

Both predictive methodology and reverse design proved e ective for the development of new functional solvents meeting speci cations. We checked the performances of the furfural derivatives selected with these methodologies for solubilization of the targeted solutes, DGEBA and TGPA.

Several tools for the prediction of solvent properties have been described. In combination with the predictive methodology, they facilitate the transition from conventional solvents to eco-friendly solvents. is approach saves time and reduces costs, by ensuring that only the best candidates are synthesized. e predictive methodology is easy to apply when alternative structures have already been identi ed by the chemist.

However, when starting from a bio-based building block, the reverse design is the most complete and rapid methodology, as all steps are managed by the CAMD tool, including the generation of derivative molecules. e reverse design approach goes further than other methodologies: it has the advantage of integrating constraints relating to both properties and molecular structures.

Moreover, the CAMD tool IBSS is being extended for prediction of the properties of mixtures, opening up new possibilities for increasing the substitution potential of biosolvents. [START_REF] Heintz | An integrated framework for product formulation by computer aided mixture design[END_REF] Finally, the substitution process deserves to be complemented by a 'green chemistry' approach to the chemical conversion step. Green metrics, such as atom economy and environmental factors, can then be taken into account in the selection of ecofriendly processes for the preparation of biosolvents.

Figure 1 .

 1 Figure 1. Hansen solubility spheres for (a) DGEBA and (b) TGPA: epoxy resin prepolymers, conventional solvents and non solvents.

Fig ure 3 .Table 3 . 3 δD = 15 . 5 , 29 R

 33315529 Fig ure3. Epoxy resin prepolymers.

Fig ure 4 .Fig ure 5 .Figu re 6 .

 456 Fig ure4. Furfural as a platform molecule.

Table 1 . Criteria for the selection of new biosolvents.

 1

	Criteria	Properties	Associated measurements	Experimental methods	Predictive tools*
	Technical	Solubility power	-Kauri-butanol index	ASTM e D1133	-
				-Kamlet Taft parameters	Solvatochromic method	-
				-Hildebrand solubility parameter	ASTM D3132	HSPiP
				-Hansen solubility parameters	Calculation	HSPiP
				-Sigma profi le, chemical potential	-	COSMO-RS
			Physical state	-Melting point	ISO f 1392	IBSS, HSPiP
	Technical/Environmental	Volatility	-Vapor pressure	ASTM D2879	IBSS, HSPiP
				-Boiling point	ISO 918	IBSS, HSPiP
				-Evaporation rate	ASTM D3539	HSPiP
	Technical/Safety	Flammability	-Flash point	ASTM D92	IBSS, HSPiP
	Sanitary	Toxicity	-IC50 a	OECD g section 4	-
	Environmental	Biodegradability	-Biodegradation rate	OECD 301	Epi suite, PBT
			Bioaccumulation	-log Kow b	OECD 107	IBSS, PBT
				-BCF c	OECD section 3	IBSS, Epi suite
			Ecotoxicity	-LC50 d	OECD section 2	Tox Predict
			Raw materials	-Origin	-	-
	Economic/Environmental		-Availability	-	-
				-Cost	-	-
			Chemical process -Green chemistry indicators	Calculation from fl owsheet	EATOS h
				-Cost
	*Tools described in the predictive methodology section
	a IC50: half inhibitory concentration; b log kow: octanol-water partition coeffi cient,
	c BCF: BioConcentration Factor; d LC50: median lethal concentration.
	e ASTM (American Society for Testing and Materials); f ISO (International Organization for Standardization); g OECD (Organisation for
	Economic Co-operation and Development), guidelines for the testing of chemicals; h EATOS: Environmental Assessment Tool for Organic
	Synthesis.
		are hydrogen bond donation ability α, hydrogen bond
		acceptor ability β, dipolarity-polarizability π*, and a
		correction term, δ. ese parameters were recently
		measured by Jessop et al for solvents of interest in
		green chemistry. 10
	-	e Hildebrand solubility parameter δ indicates the
		relative solvency behavior of a speci c solvent.

Table 2 . Properties determined with predictive tools and predictive models.

 2

	Properties		Predictive tools and associated models
	Physico-chemistry IBSS a	PBT b	Epi suite c	HSPIP d	Sci Finder	Spare e

Table 4 . Properties predicted by IBSS for comparison with specifications.

 4 RED = distance between epoxy prepolymer resin and solvent/radius of the resin solubility sphere. Bold values are in agreement with the specifi cations.

		O	O O	O	O O	O	O	OH	O	N	Specifi cations
	Melting Point [ºC]		3		0	-81	-15			109	≤0
	Boiling Point [ºC]	200		236	77	163			201	100 <…< 250
	Flash Point [ºC]		59		88	-12	69			35	>61
	Vapor Pressure(@293.15K) [Pa]		26		4	12839	59			3	<10
	BCF		4		39	2	0			2	<500
	Log(Kow)		1.6		2.7	1.2	0.4		2.9	<3
	Hansen solubility parameters
	δD [MPa 1/2 ]		17.3		17.0	16.8	18.0		17.5
	δP [MPa 1/2 ]		7.3		6.5	5.0	9.5		10.9	close to resins
	δH [MPa 1/2 ]		8.5		6.6	4.0	18.5		8.8
	RED* DGEBA		0.02		0.07	0.20	0.45		0.34	<1
	RED* TGPA		0.19		0.07	0.23	1.02		0.50	<1

*

Table 5 . Properties predicted by IBSS and comparison with specifications.

 5 RED = distance between epoxy prepolymer resin and solvent/radius of the resin solubility sphere. Bold values are in agreement with the specifi cations.

	O	O O CH 3	O	O H 3 C	CH 3	O	O O	O	O O	O HO	OH NH 2	Specifi cations Weight
	Melting Point [ºC]	4		6			0		29	169	≤0	3
	Boiling Point [ºC]	221		223			236		289	278	100 <...< 250	1
	Flash Point [ºC]	79		91			88		155	181	>61	1
	Vapor Pressure(@293.15K) [P a ]	4.8		12			4.0		0.04	0.003	<10	1
	BCF	1		2			39		2	2	<500	1
	Log(Kow)	1.7		2.3			2.7		2.8	1.8	<3	1
	Hansen solubility parameters
	δD	17.2		17.1			17.0		19.0	18.6		-
	δP	6.3		7.0			6.5		6.9	7.8	close to resins	-
	δH	8.8		6.9			6.6		6.5	20.9		-
	RED* DGEBA	0.03		0.06		0.07		0.17	0.6	<1	4
	RED* TGPA	0.19		0.09		0.07		0.27	1.2	<1	4

*

Acknowledgement

e InBioSynSolv project is supported by the French ANR CP2D program (Grant No. ANR-CP2D2009-08).

Jean-François Fabre

Dr Jean-François Fabre is a Physico-Chemistry Engineer at Laboratoire de Chimie Agro-Industrielle, Toulouse. His research interests include extraction and valorization of agricultural derived products with particular emphasis on colloids chemistry and molecular modeling.

Sophie Thiebaud-Roux

Dr Sophie Thiebaud-Roux is Associate Professor and head of the Department of Chemistry at INP-ENSIACET in Toulouse (France). She holds a PhD degree in organic chemistry applied to agro-molecules. During the last ten years, her research work focuses on the development of bio-solvents under reaction conditions close to the principles of Green chemistry.

Vincent Gerbaud

Dr Vincent Gerbaud is a research director at the French National Scientific Research Center CNRS at Laboratoire de Génie Chimique in Toulouse. His research field concerns modeling and simulation in process system engineering, with a strong interest in small scale modeling: molecular simulation, thermodynamics, computer aided molecular and mixture design. At the process scale, He also focuses with the design and synthesis of distillation processes, like extractive and azeotropic distillation.

Pascale de Caro

Dr Pascale de Caro is an associate Professor at INPT-ENSIACET in Toulouse. She is graduated from the Chemical Engineer School of Toulouse. Her research work in Laboratoire de Chimie Agro-Industrielle is focused on the development of bio-based functional products from vegetable raw materials, according to a green chemistry approach.

Zéphirin Mouloungui

Dr Zephirin Mouloungui is a research director at INRA (Institut National pour la Recherche Agronomique), at the head of the research team for the chemical reactivity of agromolecules and oleochemicals, in Laboratoire de Chimie Agro-Industrielle. His expertise deals with the development of the renewable resources in the fields of chemistry, bioproducts and neo-materials, according to innovating integrated schemes of production.