Claude Universite

Bernard -Lyon

M Frédéric Fleury

M Hamda

Ben Hadid

M Didier

M Petru Mironescu

F Kennedy

H Kumar

P S Panesar

A Karam

K De Oliveira Vigier

S Marinkovic

B Estrine

C Oldani

F Jerome

Keywords: oxidation, glycosylation, reductive etherification, diglycerol, gluconolactone, diglycerose, bio-based surfactants

The development of bio-based surfactants was studied following the principles of Green Chemistry and sustainable development. Here, two methods have been developed for the synthesis of bio-based surfactants from diglycerol and gluconolactone.

First, the selective oxidation of α,α-diglycerol and α,-diglycerol was studied using oxygen as a clean oxidant via the catalysis of palladium/neocuproine complex, to form α,α-diglycerose and α,-diglycerose with 76 and 51% isolated yield, respectively. Next, the two diglycerose were used as building blocks for the synthesis of Oglycoside surfactants using several fatty alcohols and the desired products were obtained with moderate yields (17-62%).

Second, the acetalization of gluconolactone with fatty aldehydes gave a range of gluconolactone-based acetals with 36-81% yield. These intermediates were treated under hydrogenolysis conditions (H2, Pd/C) to give gluconolactone-based ether surfactants with up to 41% yield.

Overall, these bio-based surfactants are obtained from renewable resources and could be used as green surfactants in a variety of applications.

Premièrement, l'oxydation sélective du ,-diglycérol et du ,-diglycérol a été étudiée en utilisant l'oxygène comme oxydant propre via la catalyse d'un complexe palladium/néocuproine, pour former respectivement du α,α-diglycérose et du ,-diglycérose avec 76 et 51% de rendement isolé. Ensuite, les deux diglycéroses ont été utilisés comme molécules plateformes pour la synthèse de tensioactifs de type O-glycosides avec des alcools gras et les produits désirés ont été obtenus avec des rendements modérés (17-62%).

Deuxièmement, l'acétalisation de la gluconolactone avec des aldéhydes gras dans des conditions acides a donné une gamme d'acétals de gluconolactone avec des rendements de 36-81%. Ces intermédiaires ont été traités dans des conditions d'hydrogénolyse (H2, Pd/C) pour donner des tensioactifs éthers à base de gluconolactone avec des rendements allant jusqu'à 41 %. Dans l'ensemble, ces tensioactifs biosourcés ont été obtenus à partir de ressources renouvelables et pourraient être utilisés comme tensioactifs verts pour un large éventail d'applications.

Mots clés: oxydation, glycosylation, éthérification réductrice, diglycérol, gluconolactone, diglycerose, tensioactifs biosourcés ACKNOWLEDGEMENT Three years are fleeting, at the time of graduation, I have mixed feelings in my heart. There is a Chinese idiom "Time flies like arrows, sun and moon like shuttles", I think it's perfect to describe my psychology at the moment. Three years of studying abroad in a foreign country is a valuable asset for me. During this period, I met knowledgeable teachers, enthusiastic colleagues, lovely friends and friendly strangers.

First and foremost, I want to express my best appreciation to my supervisor, Dr. Nicolas DUGUET. He is always so kind and tolerant, whatever I made some unbelievable mistakes. At the beginning of my PHD, from "0" to start is not easy for me and my project always delayed, whenever this time, he will discuss with me following three foreshadowing: "First, as we can see you are hardworking; then, as we known your project is not easy; but we should…". He always shows respect to every student and take into account the "occasional vulnerability" of us. He is so knowable and patient to help me solve the chemical problems and develop new research, especially the last period for the correction of my thesis. I have learned a lot from him, including how to work on chemistry study, how to organize research topics, and the logical thoughts for writing and presentation. There is no doubt that he is the best teacher, I am so lucky to meet so nice teacher.

I also want to thank my co-supervisor Pr. Marc LEMAIRE. He is very kind, at the beginning of my PHD, my shy character and poor English make me difficult to communicate with others, he is so patient to explain every question to me and care about whether I get used to the study and life here at the beginning of my PHD. I wellremembered that every time when I ask for some permissions that he would reply me "why not?" and express the greatest kindness to help me. He always gives some suggestions for our projects, especially for my thesis he gave me the most detailed comments and corrections. And also, I would like to thank my co-supervisor Dr.

Estelle METAY, who help me solve all the problem in the lab. Every time when something is wrong or not working well, I will bother Estelle and she will find the problem and help me to repair it. She is "omnipotent" for the affairs in our lab and cared my project and my life frequently. For my thesis, thanks for her to help me to correct it meticulously.

Next, I would like to give my special thanks to my jury members, Pr. Mathieu SAUTHIER, from Université de Lille, to Pr. Arnaud TATIBOUËT, from Université d'Orléans, to Pr. Véronique MICHELET, from Université de Nice and to Dr. David GUEYRARD, from UCBL Lyon.

Then, I am so appreciated to meet such clever and nice colleagues. Thanks to my colleagues Dr. Aubin Charvieux, Jérémy Garelli, Dr. Mel La Melissa LANDART, Dr. Thomas DE DIOS MIGUEL and Dr. Romain Chavallard, for helping me enthusiastically when I first joined the research group. I would like to thank Marie-Christine DUCLOS and Dr. Anis TLILI, they are very nice to help me for chemistry and other issues. I think Marie probably have magic hands that every time she can find the stuff that I cannot find for spending 1 h. I would like to particular thank to Dr. Nam VU, who teach me the chemistry operating and help me with the beginning of my PHD project. Dr. Lorenzo Gabriel Borrego Sánchez de la Cuesta, a long-name guy, who is always kind to answer all my questions and accompany me to some government office and acted as my translator. He is also very warm when I make some bad mistakes that he will never blame me and just teach me how to do it next time.

Killian ONIDA, a young but knowledgeable boy in our group, who is my lab neighbor and answered the most questions for me, he is really good at chemistry and geography but for French it seems that there is still some room for improvement, haha. Thank him for always helping me, accompanied with the situation that when something is wrong just "ask Killian". Dan LOUVEL and Dr. Vincent DENAVIT, the funniest guys in our lab, who always make me laughing. Especially when I am not so happy, their jokes and "special voices" would drive away all the shadows and bring happiness to our lab. Moreover, there are two beautiful ladies Leyli IBRAHIMLI and Dr. Marion DELORME, who are very warm and kind. Rodolphe BERTHELON, Alexis TAPONAUD, Alban LAVAUD, Béatrice, Mansouria, Kevin, Aziz, Valentin, Ayman, Rita and Léo, who bring a lot of laughter to me, and I will not forget the names "Mrs. mushroom" and "Mrs. rotavapor". Thanks to them that I got such beautiful names.

In addition, I would like to thank all of the colleagues in ICBMS. Especially thanks to the NMR group and the Mass Spectrometry group, who helped me for the data characterizations of my thesis. At last, I would like to thank my Chinese friends here. Linger LOU, who is my best friend here. She is always the first to show up when I need help. She always expressed her love for me without any hesitation, including helping me purchase all the daily necessities and cooking delicious food for me. Thanks to Lei DONG and Yubo WANG, who helped me for my house renting, bank affaires and so on. In the initial PHD career, they gave me a lot of support and help.

Thanks to Guanfei SHEN, the only Chinese in our group, who always communicate with me to spend the boring time on the way from get off work. Thanks to Yulan PENG, Jie YU, Biwen ZHU, Zhan ZHANG, Shishan WANG, Lianjie WANG, Yuxin SONG, Li ZHONG and Tingting YANG, who accompanied me for the first hardest period and bring me for beautiful vacations. I would like to thank my best friend Chunfang XIAO, who always share the gossip news, beautiful clothes and delicious food with me to bring the warmth from friend. And I would like to thank the two cute kids Jinsi QIN and Jinyi QIN, who always send me the warm words for looking forward my coming back home.

Next, I am really grateful to my master supervisors Pr. Guorong CHEN and Pr. Xiaopeng HE, from ECUST shanghai, China. They gave me a good guide for the chemistry study and helped me a lot for my PHD application.

In particular, I want to thank the China Scholarship Committee (CSC), who provided me with the opportunity to study in France and financial support. I am grateful to my home country, China, for providing masks, medicines and other anti-epidemic supplies, and cares to our international students during the hardest period of the COVID-19.

Finally, I want to express my deep love and thanks to my husband and my family. There is no doubt that I have the best husband who is my emotional support and my best friend. He is the first person I will go to discuss when there is a problem. He is the person that no matter how I am, he will always give support and love to me. I also have the best parents and best parents-in law. They give me care and love without reservation. I have the best brother "handsome Kai", who is more mature and tolerant than me, and always give me warmth from family. I would like to express my most sincere thanks to all my family members, love you forever~

I

General introduction

Surfactants play a crucial role in industry and our daily life, as they exhibit multi-functional properties in cleaning, wetting, dispersing, emulsifying, antistatic, foaming and anti-foaming (Figure 1). Nowadays, surfactants are largely applied in the industrial production of detergents, food processing, textiles, personal care and cosmetic products, paints and coatings, lubricants, plastics and pharmaceuticals.

Figure 1. Surfactant properties and applications.

Among the different families of surfactants, non-ionic surfactants have occupied one of the largest surfactants market share since 2015. This market share is gradually increasing, especially affected by the current COVID-19 crisis that is leading to an increased demand for cleaning supplies.

There is a huge demand for fossil resources (oil, gas, coal) in various industrial fields (such as for the application of lubricants, detergents and dispersants), which is of great significance to chemical industrial products. 1 However, as the main raw material of most surfactants, the harms of the petroleum industry to the environment cannot be ignored. Moreover, the limited resources reserve of petroleum has further increased people's interest in renewable resources and also promoted the research and development of alternative resources. 2 As people's awareness of environmental protection increases, bio-based surfactants gradually replace petroleum-based ones. Some studies on bio-based surfactants also indicated that they can significantly reduce carbon dioxide emissions. 3 , 4 Furthermore, non-ionic surfactants are less irritating and more biodegradable (Figure 2).

Therefore, developing bio-based non-ionic surfactants from renewable resources has gradually become a research hotspot (Figure 2). The synthetic routes start from renewable resources (such as starch, cellulose, sucrose, waste biomass and vegetable oils) via green & sustainable processes to develop multifunctional surfactants for applications in industrial production and daily necessities. The continuous expansion of the biobased surfactant market further promotes the industrial production of surfactants, particularly in the field of cosmetics, detergents and pharmaceutical compounds. In this context, we will focus on the development of original bio-based surfactants.

In this manuscript, our work is divided into 5 chapters:

Chapter 1 details the literature overview of this thesis, including the definition, properties, classifications, market share and applications of surfactants, and their synthetic routes. Chapters 2, 3 and 4 are the "results and discussions" parts.

In chapter 2, the oxidation of diglycerol is studied to give two main products "-diglycerose" and "diglycerose" as novel building blocks for bio-based surfactants.

In chapter 3, the glycosylation of "-diglycerose" is studied to develop bio-based surfactants.

In chapter 4, the synthesis of gluconolactone based ethers is studied to develop novel and green surfactants.

Then, a general conclusion is given to sum up all the results of this thesis.

The final part of this thesis (Chapter 5) is the experimental section, including all the experimental procedures, characterization data and key spectra.

Chapter 1 Literature about surfactants.

1 Introduction.

1.1 Definition, structure, properties and applications of surfactants.

A surfactant refers to a substance that can effectively reduce the surface tension of the target solution, which was owned to its fixed hydrophilic and lipophilic groups that can be aligned on the surface of the solution (Figure 3).6,7 Structurally, a surfactant is typically composed by a hydrophobic "tail" and a hydrophilic "head", thus having amphiphilic characteristics (Figure 4). Polar groups usually play the role of hydrophilic head, acid groups such as carboxylic acid, sulfonic acid, sulfuric acid and their salts, and hydroxyl, amide, ether bond and other groups are important components. Non-polar groups play the role of hydrophobic "tail" which is mainly a non-polar hydrocarbon chain, especially hydrocarbon chains with more than 8 carbon atoms are the most commonly used. Surfactant records were first published around 2700 BC, indicating that sodium carbonate was used as a reagent to make soap via the hydrolysis of esters from fats. There is an increasing interest in the production of surfactants with diversified properties in order to meet the ever-increasing demand in production and daily life. Nowadays, surfactants develop into mature, commercial industrial products and penetrate all aspects of production and life such as in the field of food industry, 11 detergents, 12 cosmetics, 13 pharmaceutical industry 14 and lubricants. 15 As a recent surfactant market data [START_REF]a colorless oil. 1 H NMR (300 MHz, CDCl3): δ = 8.09[END_REF] indicated, Asia Pacific (APAC), Europe and North America occupy the main global surfactant market. It is estimated that by 2025, North America will still occupy the largest surfactant market share in terms of market value (52.4 billion US dollars in 2025) while APAC is expected to overtake North America to be the largest surfactant market from a volume point of view.

Furthermore, another report 17 indicated that COVID-19 lead to an increasing demand for global industrial cleaning market. Especially for the production of hand sanitizer and soap products, which was prospected to increase the market value from 41.5 billion US dollars in 2020 to 54 billion by 2025.

The global surfactant production was 15,642 kilotons in 2014 and is estimated to expand with an annual growth rate of 4.3% within 2022. [START_REF]a white solid. 1 H NMR (500 MHz[END_REF] Interface properties of surfactants are largely influenced by the structural units. The ability of decreasing surface tension, wetting, (de)foaming and detergency is largely affected by polar and non-polar portions. The ratio of these two portions, which defines the surfactants as hydrophilic or lipophilic and is determined by the value of the hydrophilic-lipophilic balance (HLB) (Figure 5). The reduction of HLB value leads to the increasing lipophilicity for the surfactants while increasing HLB value leads the increasing of hydrophilicity. 19 There is another important characteristic parameter that affects the performance of surfactants named 'Critical Micelle Concentration (CMC)'. When dissolved in aqueous solution with low concentration, surfactants exist as single molecules while dissolved with increased concentration led to the formation of micelles to reduce the surface tension of water. Among them, the minimum concentration required for micelle formation is defined as the "critical micelle concentration" (CMC). According to different standards, surfactants can be classified in terms of their nature, structures and applications. However, the classification via the chemical structure is generally preferred. In aqueous solution, it can be defined as ionic or non-ionic surfactant in terms of the generation of ions and the electrical properties (Figure 6). Ionic surfactants can be further divided into anionic, cationic and zwitterionic surfactants by defining the charge at the hydrophilic head. J. Surfactants Deterg., 2007, 11, 1-11. 23 S. Reis-Dennis, Monash Bioeth. Rev., 2020, 38, 83-86. hydrophilic head is mainly composed of carboxyl, phosphate, sulfonate, etc. Here are some examples of commercial anionic surfactants (Figure 7). In addition to being used in the production of soap and hand sanitizer, anionic surfactants have been used as commercial surfactants in the field of cosmetics, pharmaceutical additives, agricultural production formulations, biotechnology molecular engineering and other industrial production. 8). Cationic surfactants exhibit inherent flaws: weaker stability, high price and are not-easily available, which limites the industrial application in the field of detergent. However, they exhibit excellent performance in the field of antistatic and antibacterial and are widely used for the application of food packing, preservation, and pharmaceutical industry.28

1.2.1.3 Zwitterionic surfactants.

Zwitterionic surfactants are a type of surfactants containing both anionic and cationic hydrophilic groups. Due to the high price, the application of zwitterionic surfactants in detergents is limited. However, own to specific properties (cationic in acidic condition; nonelectric ionic in neutral bath), zwitterionic surfactants exhibit significant potential in the field of medicine and cosmetics. 29,30 Here some commercially available zwitterionic surfactants are

given as examples (Figure 9). 1.2.2 Non-ionic surfactants.

Non-ionic surfactants consist of a hydrophobic tail and an uncharged neutral hydrophilic head.

The first example for the production of non-ionic surfactants can be traced back to 1930s.

The industrial production of non-ionic surfactants appeared later than anionic surfactants.

However, recent years there is an increasing interest for the non-ionic surfactants due to the excellent surfactant property. Market data in 2015 indicated that non-ionic surfactants replaced anionic surfactants to occupy the largest market share with 1.99 billion US dollars in the application of personnel care product (Figure 10). 31 Ethoxylate-based, polyol-based surfactants and alkyl polyglycosides (APGs) are the main types of non-ionic surfactants for commercial applications (Figure 11). Compared with other types of surfactants, non-ionic surfactants exhibit more outstanding surfactant performance and better stability. Non-ionic surfactants have a wider range of pH applications, flexibility in formulating and they also show less skin irritant and better biocompatibility.

1.3 Classifications of non-ionic surfactants by linkages.

Non-ionic surfactants have gained more and more attention and are gradually surpassing ionic surfactants in many applications. In terms of the physicochemical properties, they have a lower CMC (Critical Micellar Concentration) than ionic analogues, existing as non-ion form in aqueous medium that led to less sensitive effect to hard water. They are also weakly affected by electrolytes. Moreover, non-ionic surfactants have excellent formulating flexibility, resulting to the fact that they can be connected by different linkages. Non-ionic surfactants can be developed into various surfactants with different stability to adapt the multiple market demands. [START_REF]a white viscous liquid. 1 H NMR (300 MHz, acetone-d6) δH for all isomers: 0.88[END_REF] In terms of different linkages between polar head and non-polar part, non-ionic surfactants could be divided into 6 parts: ester-based, amide-based, acetal-based, glucosidebased, ether-based and C-C bond linked surfactants (Figure 12). 34 Ester-based non-ionic surfactants exhibit weak stability in both basic and acidic conditions and are readily biodegradable, which makes them widely used in detergent, food industry and pharmaceutical production fields.

Generally, the synthesis of ester-based nonionic surfactants is a mature and commercial approach, which can be carried out by the esterification of fatty acids and polyols under chemical or enzymatic conditions. 35 The development of ester-based surfactants has a long research history that some surfactants have already been used in commercial production, such as ethoxylate-based esters (fatty ester ethoxylates), 36 polyol-based ester (fatty acid ester, 37

polyol-based glucamide ester 38 and sorbitan monolaurate 39 ) and carbohydrate-based esters (sucrose palmitate) 40 (Figure 13). Ethoxylate-based non-ionic surfactants are composed of ethylene glycol units and alkyl chain units. Ethoxylate-based surfactants are traditional surfactants with wide applications, which have stronger detergency performance, better hard-surface cleaning ability, lower irritating and relatively lower biological toxicity than alcohol ethoxylate (AE). [START_REF]LRMS (ESI + ): calcd. for C15H34O7 [M + CH3OH] + , 326.2, found 326.3. 39, a white viscous liquid. δ = 0.87 (t[END_REF][START_REF]a white viscous liquid. 1 H NMR (500 MHz, acetone-d6) δH for all isomers: 0.87 (t, J = 6.9 Hz[END_REF] Methyl ester ethoxylates (PEFMe) and polyethoxylated fatty esters (PEF) are the two most common types of surfactants on the commercial market (Figure 14). 43 In addition to traditional synthetic route, in 2019, an interesting procedure for ethoxylatebased esters was reported. Moreover, these ethoxylate-based esters can be used as plasticizers of PVC which exhibit better plasticizing efficiency than methyl-based esters and glycidyl-based esters. Furthermore, the ethoxylate-based esters from waste frying oils exhibit out-bound properties (excellent thermal stability, better migration and more environmentally friendly) which prompt it to be the potential alternatives of commercial plasticizer dioctyl terephthalate. 1.3.1.2 Glycerol-based esters.

Glycerol, also named 1,2,3-propanetriol, the first record of it can be traced back to 2800 BC during the process of heating fats with ash. 49 Glycerol is an important chemical and nowadays it is widely used in chemical transformations for industrial chemicals. A recent report indicated that the global glycerol-based surfactant market size reached about 2.6 billion dollars in 2019, and was estimated to over USD 3.5 billion by 2027. [START_REF]Grand view research: Glycerol Market Size, Share & Trends Analysis Report By Source, Type, End Use, Region and Segment Forecasts[END_REF] It was evaluated as one of the critical building blocks for future biorefineries by the US Department of Energy. [START_REF] Werpy | Top Value Added Chemicals From Biomass[END_REF] Glycerol has been developed into various types of surfactants for various applications via chemical modifications. Especially, glycerol is used in the industrial production of commercial products such as personal care products, pharmaceuticals, tobacco and food industry. It was also used as important additives in other industrial products. [START_REF] Ahuja | Global market insights: Glycerol Market Size By Product Type[END_REF] Glycerol-based esters mainly involve mono-glycerol and polyglycerol esters. Only methyl or ethyl esters of fatty acids are used as biodiesel. [START_REF] Pagliaro | [END_REF] Generally, glycerol-based esters can be obtained by three ways (Scheme 3). [START_REF] Zhou | Synthesis of triglycerides via enzymatic pathway. 1.3.1.3 Sorbitol-based ester surfactants. Sorbitol is a polyol existing in Nature and widely distributed in fruits. It can be produced mainly by glucose reduction with hydrogen over metal catalysts. 61 , 62 Sorbitol has received extensive attention in the industrial production, especially in the production of sweeteners, humectants, bulking agents and softeners. 63 Sorbitol-based esters were applied for the production of commercial surfactants, such as the trademark of Span® and Tween® which exhibit excellent surface properties and flexible hydrophilic lipophilic balances (HLBs). 64 Sorbitol-based esters have been widely used in the field of food industry, pharmaceuticals, cosmetics and military industries. 65,66 Sorbitol-based esters can be produced directly from sorbitol via a one-step process (Scheme 8). Sorbitol was treated with lauric acid, p-TSA (p-toluenesulfonic acid) at 160 o C to yield the desired sorbitol-based monoester as an isomer mixture with over 80% conversion[END_REF] First, they can be synthesized via esterification by treating glycerol with fatty acid (Scheme 3, a). They can also be obtained via transesterification with fatty acid methyl ester under basic condition (Scheme 3, b). Monoglycerides can be obtained directly from the hydrolysis of triglycerides (Scheme 3, c). However, glycerol-based esters are generally obtained as a mixture of mono, di, triglycerides due to the similar position of the three hydroxyl groups. Therefore, there is a big challenge for the selective synthesis of glycerol-based mono-esters.

In 2004, Barrault et al. 57 reported a new procedure for the selective synthesis of monoglycerides via an eco-friendly process (Scheme 5). Glycerol and series of fatty methyl esters were treated with guanidine-based catalyst Me-TBD (7-methyl -1,5,7-triazabicyclo[4.4.0] To date, many investigations were devoted to the development of carbohydrate-based ester surfactants. [START_REF]In addition to acid-catalyzed glycosylation to synthesize O-glycosides, transglycosylation provide another efficient way to synthesize amphiphilic alkylpoly glucosides, especially for long-chain alkyl alcohol-based O-glycosides. 309,310,311 Amberlyst 15 was used as the catalyst for the glycosylation of -methyl -glucopyranoside and n-octanol to give the long-chain Oglycosides with 85% yield (Scheme 112)[END_REF] Series of carbohydrate-based ester surfactants were developed, such as glucose, fructose, sucrose, lactose and maltose. All these feedstocks for the production of sugar-based surfactants can be directly obtained from natural resources. Sucrose can be obtained from sugar beets and sugar cane, lactose can be obtained from milk, maltose can be obtained from staple food crop while fruits and honey are resources of D-glucose and Dfructose. (Figure 15). Generally, the production of carbohydrate-based esters mainly involves two routes: chemical synthesis or biocatalytic process. In addition, there are many other enzymes that play a key role in the production of carbohydrate-based ester surfactants. 88 Interestingly, different lipases exhibited unique substrate preferences in esterification reactions and can even lead to regioselective reactions.

This may be caused by the different binding modes and positions between the substrate and the enzyme. 89 However, there are still some limitations such as the high cost of enzymes and the inevitable deactivation in the catalytic process which are limiting for industrial production. There is another synthetic route for obtaining glucoside-based esters via transesterification with fatty acid esters (Scheme 13). First, methyl glucoside can be obtained by the glycosylation of glucose with methanol and from the hydrolysis of starch or cellulose (Scheme 13, a). Next, methyl glucoside was treated with fatty acid esters under basic condition (K2CO3) at 120 o C to form the product as mixtures of mono-, di, tri-or tetra-glucoside-based esters (Scheme 13, b). [START_REF] Texter | Reactions and synthesis in surfactant systems[END_REF] Scheme 13. Chemical synthesis of glucoside-based esters via transesterification.

In addition to chemical synthetic route, biocatalysis was also applied for the production of glucoside-based surfactants. In 1998, Schmid et al. 93 reported an enzyme-catalyzed method.

D-glucose and its derivatives (alkyl glycoside and salicin) were treated with fatty acids or arylaliphatic carboxylic acids in t-BuOH using Lipase B (Candida antarctica) as a catalyst to form the corresponding product with 14-71% yield (Scheme 14).

Scheme 14. Biocatalytic synthesis of glucoside-based monoesters.

This method avoids toxic reagents, and provided a selective acylation on the primary hydroxyl. Furthermore, the products were tested and exhibited superior surfactant properties.

D-Glucose-based aryl aliphatic esters (Scheme 14, a) have excellent hydrophilic lipophilic balances (HLBs) which was able to apply for the production of detergents and emulsions. D-Glucoside-based aryl aliphatic esters and alkyl esters all exhibited excellent surface activity and suitable hydrophilic lipophilic balances (HLBs) for using as water-soluble emulsifiers and wetting agents. 1.3.1.4.3 Oligosaccharide-based ester surfactants.

Oligosaccharides are usually composed of 3-10 monosaccharide units and can be directly extracted from natural resources (onions, garlic, chicory root, soybeans…). 94 They can also be obtained via the hydrolysis of natural polysaccharides by enzymatic, acid catalysis or physical hydrolysis. 95 Considering the production cost, enzymatic catalysis method is the major way for production.

94 T. Sako, K.Matsumoto, R.Tanaka, Int. Dairy J., 1999, 9, 69-80. 95 F. A. de Moura, F. T. Macagnan, L. P. da Silva, Int. J. Food Sci. Technol., 2015, 50, 275-281. Oligosaccharide-based surfactants are considered as potential alternatives to sucrosebased surfactants due to the large inventory in Nature and similar physical and chemical properties to monosaccharides. With special properties (regulate intestinal flora, regulate blood lipids and promote immune regulation), oligosaccharides have wide range of applications in the field of food ingredients, pharmaceutical industry, and health care products. 96,97,98 Raffinose is the most common oligosaccharide that can be extracted from vegetables.

Raffinose D-Glucosamine is the most common amino-based carbohydrate, which is present in Nature in the form of peptidoglycan. D-Glucosamine derivatives can be found in Nature (Figure 16), such as D-galactamine, 1-amino-1-deoxy-D-mannitol and 7-dimethylribolumazine can be found from plant and microorganisms.

Glucoside-based surfactants (Alkyl polyglucosides).

With the increasing awareness of environmental protection and the exploration of the advantages of bio-based surfactants, more and more efforts were devoted to produce biobased surfactants via green procedures. Alkyl Polyglucosides (APGs) are important bio-based surfactants that are of natural origin and can be produced from vegetable oils and starch. 118 Alkyl polyglucosides (APGs) were first proposed at the end of the 19 th century. 119 In 1980, APGs were developed for industrial application and were widely applied as commercial products in industrial production. Compared with other types of surfactants, APGs have superior properties of non-toxicity, excellent wettability, less skin irritation, safe, broadspectrum antibacterial activity and compatibility, which make them extensively used in the field of detergents, cosmetics, food industries, biochemical production, pesticide additives, pharmaceutical industries and building materials industry. 120,121 In 2015, the production of global bio-based surfactants has reached over 350 KT, among them, APGs occupied over 1/4. Today Europe is the largest producer and consumer of APGs to meet strict regulations for the surfactant markets. The Asia-Pacific market of APGs has developed rapidly in recent years and was predicted to replace Europe as the largest market by 2023. 122,123 In 1893, alkyl glycosides were produced via Fischer glycosylation under enzyme or acid catalysis. 119 The product was obtained as isomer mixtures of mono-glycoside and polyglycosides (Scheme 24). However, only traces amount of alkyl polyglycosides (APGs) were obtained while alkyl glycosides were obtained as major products. In this context, other synthetic procedures were considered.

Scheme 24. Synthesis of APGs via Fischer glycosylation.

In 2007, Wu et al. reported a convenient and efficient method for the synthesis of APGs (Scheme 25). 124 H2SO4/SiO2 was used as a catalyst instead of homogeneous catalyst at 110 o C for 1.5 h that gave 100% conversion of D-glucose. This method is more environmentally friendly and provided alkyl polyglycosides with low degree polymerization (1.37) that exhibited low CMC (0.0104 wt%) for further application.

Scheme 25. One-step synthesis of APGs with solid H2SO4/SiO2 as catalyst.

In 2020, Tao et al. reported a method for the synthesis of branched-chain alkyl polyglucosides (Scheme 26). 125 Via a synergetic catalysis of acid (PTSA) and phase transfer catalyst (tetrabutylammonium bromide, TBA), D-glucose was treated with branched-chain 124 Y. Wu, J. G. Yu, X. F. Ma, J. S. Zhang, Chin. Chem. Lett., 2007, 18, 1173-1175. 125 Y. Tao, X. Wu, W. Zhang, F. Wang, Tenside Surfact. Deterg., 2020, 57, 420-426. alcohol (2-butyl-1-octanol) in ethanol to give alkyl polyglucosides with high selectivity over 95%

(polysaccharides were obtained as major by-products) and the reaction conversion reached 98%.

Scheme 26. Synthesis of branched-chain alkyl polyglucosides (APGs).

In 2013, Marinkovic et al. reported a new synthetic method of APGs based in DMSO (Scheme 27). 126 D-Glucose and decyl alcohol were treated with DMSO (which acts as catalyst and solvent) at 150 o C for 1 h to provide APGs with 64% yield. This method also worked efficiently with D-xylose (74% yield) and L-arabinose (64% yield).

Scheme 27. Synthesis of alkyl polyglucosides based on DMSO.

However, the above synthetic methods still have some inherent defects. For example, the use of corrosive acid catalyst (such as H2SO4 127 ) would bring undesirable environmental impact, 126 C. Ludot, B. Estrine, J. Le Bras, N. Hoffmann, S. Marinkovic, J. Muzart, Green Chem., 2013, 15, 3027. 127 W. von Rybinski, K. Hill, Angew. Chem. Int. Ed. Engl., 1998, 37, 1328-1345. high temperature or pressure were required which would lead to the formation of by-products.

Moreover, the solubility issue is a key challenge, especially for the reaction between D-glucose and long-chain fatty alcohols.

To avoid above limitations, the group of Jérôme have devoted many efforts for the synthesis of alkyl polyglucosides. In 2017, they proposed a novel catalytic acid for the production of APGs (Scheme 28). 128 Series of acid catalysts (H2SO4, SBA-SO3H, Amberlyst-15 and H-BEA-25) were tested and Aquivion PFSA PW98 was selected to be the best catalyst to afford 85% yield of alkyl glycosides (APGs) with reactor productivity comparable to industrial production (477 kg m -3 h -1 ). Aquivion PFSA PW98 was proved to be stable in this catalytic system and can be recycled efficiently for over ten times.

Scheme 28. New synthetic route of APGs.

In 2017, they also reported a synthetic route of APGs directly from cellulose via a twostep process. 129 First, cellulose was treated with acidic condition (Aquivion PFSA PW98) via mechanocatalytic depolymerization, then it directly reacted with n-dodecanol at 150 o C to form alkyl glycosides as an isomer mixture with 85% yield and 97% selectivity, with the reactor productivity of 203 kg m -3 h -1 (Scheme 29). Aquivion PFSA PW98 was proved to work efficiently for 5-times recycling.

Scheme 29. Synthesis of APGs from cellulose.

In 2018, they have developed another procedure to selectively synthesize APGs via a catalyst-free condition. 130 Unprotected carbohydrate (mannose) and alcohols (methanol, ethanol, n-propanol and n-butanol) were treated with high-frequency ultrasound irradiation (550 kHz (0.44 WL -1 )) at 40 o C for 3 h to yield APGs (degree of polymerization: 2-7) with 66-87% yield (Scheme 30). Moreover, this procedure provided selective activation of anomeric hydroxy, and also proved that glucose and xylose as substrates can work effectively to provide APGs.

Scheme 30. Synthesis of APGs with catalyst-free condition under ultrasound. Moreover, during the research process on APGs, it was found that hemicelluloses derived from wheat can produce a new Alkyl PolyPentosides (APPs) based surfactant (Figure 18). 131

Natural resources (wheat bran, wheat straw or poplar) were used as raw materials via a onepot concerted catalysis of hydrolysis and glycosylation under acidic condition to form alkyl polypentosides (APPs) with 77-96% yield. 132 , 133 APPs were investigated to exhibit excellent surface activities similar to APGs. 110,134 Figure 18. New routes for industrial production of APGs and APPs.

Ether-based surfactants.

Ether based non-ionic surfactants are commercially available surfactants and are widely used in industrial production. Amphiphiles are especially demanded as robust surfactants in some special fields, such as in detergents which were used for protein or mineral oils, and in cosmetics and eco-extraction. Fatty alcohol polyoxyethylene ethers (AEO), also known as primary alcohol ethoxylate, is one of the most important nonionic surfactants, and is the most widely used and fastest growing category.136

From a structural point of view, 'R' substituents are usually saturated or unsaturated C12~18 hydrocarbon groups, including linear chain and branched chain hydrocarbon groups (Scheme 31). Due to the excellent surfactant properties, ethoxylate-based ether surfactants are used as detergents137 and pesticides138 in industrial production. Alkylphenol ethoxylates (APE) are important polyoxyethylene type nonionic surfactants. Similar to AEO based surfactants, they have stable properties under acidic/basic conditions. In addition, they are inexpensive, making them one of the main raw materials for the production of highperformance detergents, printing aids and dyeing auxiliaries, and they also have enormous potential for application in the production of pesticides. 137 As mature commercially available surfactants, ethoxylated surfactants have the advantages of excellent performance, low-price and rapid-synthesis. However, there are still some limitations. Generally, the synthesis of ethoxylates required harsh synthetic conditions and the synthesis accompanied by inevitable toxic, carcinogenic, mutagenic and non-biodegradable by-products. 139,140 Thus, the development of surfactants with nontoxic and biodegradable properties as alternatives of ethoxylates are urgently demanded. 1.3.5.2 Glycerol-based ethers.

Generally, glycerol-based ethers involved alkyl connected and alkenyl connected types.

Alkyl connected glycerol ethers are one of the most important surfactants in cosmetics, especially in personal care products 141 and personal cleaning supplies. 142 This procedure is also used in biopharmaceutical field. 143 There are several procedures reported for the synthesis of alkyl connected glycerol ethers while the most common way is Williamson ether synthesis.

As a well-known route to directly synthesize glycerol-based ethers, Williamson ether synthesis has made a great contribution to the development of ether surfactants. 144 However, the special structure of glycerol results in almost no difference in the chemical environment of its three hydroxyl groups. Therefore, the selective synthesis of mono-glycerol based ethers faces huge challenges, that required protection and deprotection of hydroxyl groups at specific positions. 145 Therefore, it is difficult to obtain glycerol ethers directly from glycerol.

In Allyl halide was also used as substrate for the synthesis of glycerol-based ethers via a twostep procedure with allyl ethers as intermediates (Scheme 32, c).149 First, allyl halides (C12-C16) were treated with KOH and TBAB in hexane at 45 o C for 6 h. Then, ally ethers were treated with cetyltrimethylammonium permanganate (CTAP) in dichloromethane at room temperature for 5 h to give the corresponding glycerol-based ethers with 65-69% yield.

There is another method in which octadecyl allyl ether is used as a substrate using perbenzoic acid in CHCl3 at room temperature for 4 days to form glycerol-based ether with 49% yield (Scheme 32, d).150

Furthermore, glycidol151 and ECH (epichlorohydrin)152 were also used as substrates for the synthesis of glycerol-based ethers (Scheme 32, e).

The Williamson ether synthesis usually requires two-step procedures with harsh conditions that are accompanied by high temperature and high pressure. In addition to

Williamson ether synthesis, many efforts have been devoted in our group for developing new synthetic method of glycerol-based ether surfactants.

In 2010, our group has developed the synthesis of glycerol ethers under reductive conditions. Aldehydes with different substituents were used as reagents and were treated with 5% Pd/C (0.5 mol%), H2 (10 bar) and CSA (10 mol%) at 140 o C for 24 h to give the corresponding glycerol-based ethers with 94% and 82% GC yield, respectively. (Scheme 33). 153 Sci. China Chem., 2010, 53, 1953-1956. Moreover, in 2012, our group successfully synthesized glycerol-based ethers by reductive alkylation with acids (Scheme 35). 155 Bio-sourced carboxylic acids with low-price were used as substrates for the synthesis of glyceryl-based ethers. Glycerol and carboxylic acids (with different chain lengths, linear or branched) were treated with 5%-Pd/C (0.5 mol%), H2 (50 bar) and Amberlyst 35 (10 wt%) at 120 o C for 16 h, 28-72% yield and 80% selectivity of linear chain glycerol ethers were obtained while branched chain glycerol ethers were obtained with 47-72% yield with 80% selectivity. The yield decreased with the increase of the alkyl chain length. This reductive alkylation method (involves two steps: 1) esterification, 2) reduction) also worked effectively with cyclobutanecarboxylic acid, cyclopentanecarboxylic acid and cyclohexanecarboxylic acid to form the corresponding ethers with 74, 73 and 71% yield, respectively.

Scheme 35. Synthesis of glycerol-based ethers by reductive alkylation with acids.

In 2013, our group also applied fatty esters as substrates for the synthesis of glycerolbased ethers (Scheme 36, a). 56 The first route was carried out with glycerol and methyl esters (with different chain lengths) as substates, 5%-Pd/C (0.5 mol%), H2 ( 50 Glycerol-based ethers can be obtained by direct etherification with aldehydes, ketones, acids or esters with good yield and selectivity. However, there are still some limitations. High temperature and high hydrogen pressure were required by above process and other alternative methods could be also considered.

There is another way to synthesize glycerol-based ethers through the formation of glycerol carbonate. As glycerol carbonate is a commercial product which greatly promoted its application in the synthesis of surfactants. First, the primary hydroxyl was protected with TIPSCl under the condition of imidazole in DMF at room temperature. Then, other hydroxyls were protected with PMB-Cl in the presence of NaH and TBAB in DMF at room temperature with 61% yield. Next, the crude mixtures were treated with TBAF for the deprotection of the primary hydroxyl. After that, dodecanyl chloride was added to react with primary hydroxyl to produce product D with 85% yield. Finally, deprotection was carried out with CAN in acetonitrile/H2O at room temperature to give glucoside-based ether with 76% yield.

However, this method has obvious limitations that involved several steps for protection and deprotection, which lead to unnecessary resource consumption and poor atom economy (6%). Therefore, it is meaningful to develop new economical and environmentally friendly synthetic routes. It is noted that while the link-form product (n = 9) was treated with UV irradiation for 6 h that isomerization product was obtained with 80% yield (Scheme 47, c).186

Scheme 47. C-C bond-based surfactants from nonulose.

Furthermore, both linear and cyclic forms exhibited interesting surfactant properties (excellent surface activity). The linear form of nonulose-based surfactants can also be further developed into other surfactants via photochemical or chemical modifications.

In addition to 1,3-diketones, phosphonates were also used as nucleophiles for the synthesis of C-glycosid-based surfactants.

In This one-step procedure with neat condition in the presence of base forms the product as a mixture of α/β-C-furanoside and α/β-C-pyranoside via HWE reaction. When treating with H2O as solvent, β-pyranoside was obtained with 100% selectivity. Furthermore, this method was successfully applied to the reaction of D-glucose and phosphonates with different (C3-C19) alkyl chain lengths. In addition to D-glucose, other unprotected carbohydrates (lactose, -Dglucose, D-galactose and D-xylose) were also proved to react efficiently with β-keto phosphonates to produce the corresponding products.

However, the above research provides a simple, one-step synthetic method for the formation of C-C bond-based surfactants. There are still some shortcomings restricting the development of the process, which requires to be further overcome and improved. First, the acetate elimination step involves in the reaction brought unavoidable loss of atom economy.

Moreover, as the substrates of the reaction, nonulose and β-keto phosphonates are not commercially available which requires a complex two-step synthetic method that also causes the low atom economy.

Although the above synthetic methods have certain limitations, C-C bond-based

surfactants were proven to have potential market value. Therefore, it is attractive to develop a green, high atomic economy and simple one-step synthesis under mild conditions with commercially available raw materials as substrates. This method overcomes the drawbacks of previous methods that required protection and deprotection steps. Furthermore, ethanol and H2O were used as solvents providing a green method. In addition, the reduced products exhibit excellent surfactant performances that can Unprotected fructose and series of aldehydes were treated with Me3N and microwave irradiation at 60 °C for 2 h to produce the corresponding products with 11-51% yield. It is interesting that the long chain aldehydes can work with fructose via direct aldolization to form bio-based surfactants. Furthermore, the aldolization products were treated with H2 (40 bar) and 5%-Ru/Al2O3 (5 mol%) in H2O at 60 °C for 2 h to form alkylated heptaols with 84-96% yield.

Inspired by above works and considering that diglycerol has a similar structure than glycerol, we plan to apply this aldolization procedure to produce diglycerol-based hydroxyketone for the production of C-C bond surfactants with increased polar head (Figure 21). In this context, the first step is carried out for the oxidation of diglycerol.

Chapter 2. Selective oxidation of diglycerol.

1 Introduction.

Surfactants have a key role in cleaning, wetting, foaming/anti-foaming, dispersing and emulsifying (Figure 22,a). As a market data reported, since 2015, non-ionic surfactants have occupied the largest market share in personal care (Figure 22,b). 31 Nowadays, non-ionic surfactants are widely used in the field of detergents, cosmetics, food, pharmaceuticals and paints (Figure 22,c). 191 Therefore, the research of non-ionic surfactants has far-reaching significance to our daily lives. Since non-ionic surfactants are less skin irritant and exhibit better stability, the investigations on their stability attracted much attention. It is greatly affected by the type of linkage between the hydrophilic part and the hydrophobic part (Figure 23,a). Among nonionic surfactants, most commercial surfactants are ethoxylated alcohols. However, in the interest of environmental protection, surfactants connecting the polar head and the non-polar tail via an ester bond have attracted the attention of scientists. 192 Ester-linked surfactants are readily biodegradable and exhibit weak stability under either acidic or alkaline conditions.

There is an increased demand for robust surfactants for applications in cosmetics, detergents for protein or mineral oil-based grease, oilfield exploitations and eco-extractions (Figure 23 Since diglycerol shares the same 1,2-diols moiety as glycerol, we plan to apply this work on diglycerol for getting a robust surfactant with an increased polar head.

Diglycerol-based ester and ether surfactants were developed while there are no examples for C-C bond-based surfactants (Figure 24). In order to develop diglycerol-based C-C bond surfactants, the oxidation of diglycerol should be considered first (Figure 24, b andc). 1.1 Diglycerol production and application market.

Diglycerol, a bio-based raw material, can be obtained by direct dehydration of two molecules of glycerol. Glycerol is the simplest polyol with three carbons and its utilization can be traced back to 2800 BC. 193,194 Since the biodiesel industry produces a lot of glycerol (about 10 kg of crude glycerol is formed per 100 kg of biodiesel produced), its valorization has attracted a lot of interest. 195,196 Generally, glycerol is produced by transesterification of triglycerides 197 (obtained from natural oils) or hydrogenolysis of sorbitol 198 (obtained from sugar beets and cane) (Scheme 51, a and b). Then, diglycerol can be produced from the oligomerization of glycerol under acidic or basic conditions (Scheme 51, c). 226 Scheme 51. Preparation of diglycerol form renewable resources.

Current data on diglycerol market are hardly available. In 2017, a report proposed that the global polyglycerols (PGs) market size was valued to reach 1.91 billion dollars and was estimated to increase with 9% annual growth rate within 2025.199 Among PGs, diglycerol occupies about 20% market share and is widely used for the industrial applications in the field of personal care, cosmetics, food and pharmaceuticals. Moreover, diglycerol market share is estimated to grow with 50% from 2012 to 2022. 200 Nowadays, diglycerol is used as a raw material to produce diglycerol based surfactants, such as esters, 201 , 202 , 203 ethers, 204 acetals 205 and other derivatives. 206 Moreover, these surfactants are applied in the field of drug delivery, 207 emulsifier and foaming agent, 199,200 food industry and cosmetics. 201 1.2 Preparation of diglycerol.

Glycerol is a nontoxic, edible and renewable resource that is regarded as an interesting building block for the synthesis of multifunctional surfactants and polyglycerols. Diglycerol is one of the simplest derivatives of glycerol which plays an important role in industrial production. 208 Many efforts have been devoted for the catalytic synthesis of diglycerol via the oligomerization of glycerol under acidic/basic conditions. Catalytic routes involve direct condensation of two glycerol molecules to produce diglycerol. The condensation occurs at intramolecular hydroxyls (primary or secondary hydroxyls) or intermolecular hydroxyls, that leads to the formation of different isomers of diglycerol, which could be branched-, cyclic-or linear-diglycerols (Scheme 52). When the condensation is carried out with primary hydroxyls, linear isomer -diglycerol is obtained while branched isomers (-diglycerol and diglycerol) are obtained via intermolecular condensation of secondary hydroxyls, and cyclic isomers of diglycerol are produced via intramolecular condensation (Scheme 52). 209 Scheme 52. Catalytic oligomerization of glycerol towards diglycerol.

Controlling the glycerol polymerization to selectively produce the desired oligomer diglycerol remains a major scientific challenge. Therefore, it is critical to develop catalytic systems to produce diglycerol with excellent catalytic performance with high selectivity. However, homogeneous catalysts are accompanied by the issues of solubility and postreaction treatment, some heterogeneous catalysts were also used to achieve the conversion of glycerol towards diglycerol.

Heterogeneous base catalysis of glycerol.

It is more likely to form products with large molecular weight in the etherification process using homogeneous catalysts.

Metal oxides are attractive catalysts for glycerol etherification due to its strong alkalinity.

In However, properties of these catalysts remain hard to balance between the conversion of glycerol and the selectivity towards diglycerol. In summary, oligomerization of glycerol via base catalysis provides an extensive catalytic pathway to produce diglycerol. However, it requires high temperature and long reaction time that would lead to adverse effects on the environment.

1.2.2 Oligomerization of glycerol via acid catalysis.

In addition to base catalysis, series of acid catalysts were reported for the oligomerization of glycerol towards diglycerol.

In 2009, a high conversion (90%) of glycerol was obtained with low selectivity (less than 20%) for diglycerol using sulfuric acid (Table 3, entry 1). 221 Another homogeneously-acid catalysed oligomerization was carried out with dodecylbenzene sulphonic acid at 150 o C for 24 h to give 50% glycerol conversion with 33% selectivity for diglycerol (Table 3, entry 2). 209 Metal triflates and triflimidates (Ga(OTf)3, Bi(OTf)3, Fe(TFSI)3 and Al(OTf)3 and Fe(OTf)3) were also used as catalysts for the oligomerization of glycerol. The best result was obtained by Ga(OTf)3 to give 58% glycerol conversion with 31% selectivity towards diglycerol ( entry 3). 222 However, the acid-catalysed procedure via the formation of a cationic intermediate would form undesired polyglycerols with high degree of polymerization as major products. In this case, other types of catalysts were considered. In order to achieve the transformation of glycerol towards diglycerol under mild conditions, some acidic ionomers were reported. It was reported that the oligomerization of glycerol towards diglycerol can be carried out through a falling film reactor with an acidic zeolite (H-Beta) as a catalyst to achieve 80% glycerol conversion with 20% selectivity ( The homogeneous acid catalysis of glycerol towards diglycerol has proved to be an efficient method. Compared with base-catalysed etherification, the homogeneous acid catalysis exhibits higher rate to achieve the formation of diglycerol with higher conversion but lower selectivity.

In summary, there are still some limitations that the polymerization degree is hard to control to reach high diglycerol yield with the inevitable formation of triglycerol, oligoglycerol or other regioisomers. 224 1.3 Selective oxidation of 1,2-diols towards -hydroxyketones.

Selective oxidation of polyols towards aldehydes and ketones is an important chemical transformation in organic synthesis. 225 In particular, the selective conversion to αhydroxyketones provides key intermediates for the synthesis of natural products. 226 However, there are still some challenges due to the difficulties for selective oxidation (Scheme 55, a)

and for limiting overoxidation (Scheme 55, b) or even the oxidative cleavage of C-C bonds (Scheme 55, c). 227 Scheme 55. Challenges of selective oxidation of 1,2-diols (the example of glycerol).

Among α-hydroxyketones, dihydroxyacetone (DHA) oxidized from glycerol is extremely attractive because DHA shows application potential in cosmetics. 228 The transformation of glycerol to DHA also exhibits a huge value as DHA has 250 times more value than glycerol itself.

However, commercial DHA is produced by a microbial fermentation procedure instead of catalytic oxidation due to the strict quality requirements. 229 1.3.1 Selective oxidation of 1,2-diols via metal-free catalysis.

In 2004, Gogoi et al. 230 reported a novel synthetic method to oxidize vicinal diols via I2 catalysis using DMSO and N2H4 . H2O in aqueous solution (Scheme 56). 1,3-Dihydroxyacetone was obtained with 44% yield under these reaction conditions while similar substrates B and C

were obtained with 46 and 45% yield, respectively.

Scheme 56. Selective oxidation of 1,2-diols via non-metal-catalysis.

that when the ring conformation of the substrate was restricted, oxidation only occurred for the axial hydroxyl.

Scheme 58. Oxidation of 1,2-diols via a one-pot procedure.

Me2SnCl2 was also used as a catalyst for chemical transformation via a novel electrochemical oxidation (Scheme 59). 233 Similarly, this method was also applied for linear or cyclic 1,2-diols to afford the desired -hydroxyketones with good yields. KBr was used as a safe oxidant to generate bromide ion in aqueous solution and the base generated via Pt electrodes was used as a catalyst to provide a novel synthetic route for the selective oxidation of 1,2-diols.

Scheme 59. Oxidation of 1,2-diols via electrochemical oxidation.

In addition, it was reported that most chemo-catalytic transformations were carried out using noble metal-based catalytic system. In 2006, Ciriminna et al. 234 proposed a novel electrocatalytic oxidation procedure for the synthesis of dihydroxyacetone (Scheme 60).

Glycerol was treated with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) under acidic conditions in aqueous solution via an electrochemical process (1.1 vs Ag/AgCl) to afford DHA with high selectivity. Hydroxypyruvic acid was obtained as main product with a prolonged reaction time. This procedure supplies a novel, simple and clean route for the production of DHA instead of traditional bio-catalysis procedure. However, the low yield produced by this method means that other procedures should also be considered. In 2012, Kwon et al. 235 reported a novel electrocatalytic oxidation procedure which can achieve 100% selectivity for the synthesis of DHA (Scheme 61). In the bismuth-saturated acidic solution (0.5 V), the oxidation occurs at the secondary alcohol preferentially (Scheme 61, a)

while in the absence of bismuth, the primary alcohol oxidation was the major pathway (Scheme 61, b). The method provides high selective oxidation towards DHA because bismuth inhibits the oxidation of the primary alcohol while providing a dedicated site (Pt-Bi) for the oxidation of the secondary alcohol.

Scheme 61. Selective oxidation of glycerol with electrocatalytic oxidation.

Electrocatalytic oxidation provides an efficient pathway for the production of hydroxyketones, but the catalytic processes usually require noble metals as electrodes with high cost which limit its applications. 1.3.3 Selective dehydrogenative oxidation of 1,2-diols (anaerobic conditions).

In addition, synthesis of 1,2-diols via dehydrogenative oxidation under anaerobic conditions was also reported.

Cu-based catalysts were applied for the synthesis of -hydroxyketones. Synthesis of -hydroxyketones by dehydrogenative oxidation of 1,2-diols is an efficient method. However, the catalytic pathway usually requires high temperature, other procedures should be considered from the perspective of sustainable development. 1.3.4 Selective oxidation of 1,2-diols via metal-catalysis (aerobic conditions).

Generally, -hydroxyketones are obtained via a metal-catalyzed oxidation. 239 It was reported that most chemo-catalytic transformations were carried out under the condition of noble metal-based catalytic system.

In In summary, many efforts have been devoted for the oxidation of 1,2 diols and achieved excellent results.

Waymouth's work.

Palladium-based complexes are a type of commercially available catalysts which were widely investigated for the selective oxidation of primary and secondary alcohols, polyols and carbohydrates. 254,255,256,257 Waymouth's group has made remarkable achievements in the field of palladium-based catalytic aerobic oxidations.

1.3.5.1 Oxidation of 1,2-diols.

In 2007, the group of Waymouth 258 has reported series of palladium-based complex (Pd- 5, entries 1-4), which was promoted by the special structure with acetate ion and triflate ion. The acetate ion affords an alkaline environment to promote deprotonation in oxidation process while noncoordinating triflate ion affords an effective coordination site to prompt the initial oxidation rates.

Pd-5 25

In 2010, they applied Pd-3 on the oxidation of glycerol towards dihydroxyacetone (Scheme 73). 260 Glycerol was treated with Pd-3 by using oxygen or benzoquinone as an oxidant at room temperature to afford dihydroxyacetone with 97% yield and 99% selectivity.

Scheme 73. Selective oxidation of glycerol to dihydroxyacetone.

Moreover, other polyols were investigated using Pd-3, which exhibited faster reaction rates and higher chemo-selectivity for vicinal diols than other primary or secondary alcohols (Scheme 74). 261 (2S,3S)-erythritol and (2R,3R)-erythritol were oxidized via the reported procedure to form the corresponding -hydroxyketones (D-erythrulose and L-erythrulose)

with 86 and 87% yield, respectively (Scheme 74). Furthermore, these two optically active threitols were oxidized to give the corresponding erythrulose with almost complete (97%) retention of configuration. Although the oxidation of erythritol were reported using enzymes or microorganisms, 262 the Pd-3-catalyzed oxidation led to minimal racemization through enolization and was considered to be an attractive strategy. They also explored the oxidation efficiency of this procedure on other polyols. N-Bocsubstituted polyol was oxidized via Pd-3 catalysis to form the corresponding -hydroxyketone with 88% yield (Scheme 75, a), while propane-1,2-diol and butane-1,2,4-triol gave 95% and 72% yield, respectively (Scheme 75, b-c). In addition to linear polyols, the procedure also exhibits excellent catalytic performance for the oxidation of cyclic polyols. Cyclohexane-1,2diol was treated with Pd-3 to give -hydroxyketone with 81% yield (Scheme 75, d). Moreover, internal vicinal diols were also explored, which gave the corresponding -hydroxyketone as an isomeric mixture with 83% yield and 90% selectivity. It was noted that for cyclohexane diols, axial hydroxyls exhibited the oxidation priority (Scheme 75, e).

Scheme 75. Selective oxidation of polyols using Pd-3 catalyst.

Meanwhile, efforts were devoted to apply Pd-3 for the oxidation of unprotected carbohydrates and 15 examples were given with good results. 263 Some important examples are described below (Scheme 76).

Scheme 76. Selective oxidation of unprotected carbohydrates.

Selective catalytic oxidation of unprotected glycosides was carried out in acetonitrile/water system using Pd-3, with O2 (Scheme 76, a) or benzoquinone (BQ) (Scheme 76, b) as an oxidant to form the corresponding 3-ketoses as major products while 4-ketoses formed competitively as by-products. Phenol was used as a co-catalyst which could benefit the catalyst life time (For the corresponding mechanism clarification, see Scheme 79).

Pyranosides were treated with trifluoroethanol (TFE) solvent system, using Pd-3, with BQ as 263 K. Chung, R. M. Waymouth, ACS Catal., 2016, 6, 4653-4659.

an oxidant to form 3-ketose with 70% yield (Scheme 76, c). This procedure provided an efficient strategy for the selective oxidation of unprotected carbohydrates.

Moreover, based on the above research, the group of Waymouth also reported another cationic palladium-based compound Pd-6 liganded by chiral pyOx group (Scheme 77). 264 The oxidation of meso-erythritol using chiral Pd-6 catalyst gave 62% yield for erythrulose with 24% ee. Pd-6 also exhibits excellent catalytic performance for the oxidation of 1,2-propanediol, butane-1,2,4-triol, 1,2-diphenyl-1,2-ethanediol and glycerol, using Pd-6 (10 mol%) and benzoquinone (1.12 eq) in CH3CN/H2O to form the corresponding -hydroxyketone with 71-99% yield.

Scheme 77. Oxidation of vicinal diols via the catalysis of Pd-6.

Inspired by the above research, in 2017, our group proposed a novel method for the selective oxidation of 1,2 diols towards fatty α-hydroxyketones (Scheme 78). 265 The proposed mechanism for the oxidation of primary or secondary alcohols and vicinal diols was discussed by the group of Waymouth (Figure 26). 75,266 When Pd-3 catalyst is dissolved in solvent (such as acetonitrile, water or dimethyl sulfoxide), it would form monomeric complexes. Then, ligand exchange would occur with vicinal diol to form hydroxy alkoxide chelate B (Figure 26, pathway b) while primary or secondary alcohol would form A (Figure 26, pathway a). Next, selective -H elimination was proposed to be the product determining step that occurs at secondary alcohol to form palladium hydride intermediate B2.

Similarly, via -H elimination A1 formed from A. Subsequently, substitution was carried with solvent to release the corresponding hydroxyketones and formed palladium hydride intermediate C. Finally, C is oxidized by benzoquinone or oxygen to regenerate Pd-3 catalyst.

Moreover, oxidation of vicinal diols occurs selectively at the secondary alcohol instead of primary alcohol, which are probably due to the facile production of B2 that is caused by three reasons. First, from the kinetic experiments and DFT calculations, weaker barriers of β-H elimination for secondary alcohol than primary alcohol were observed. Then, ketones exhibit greater thermodynamic stability than aldehydes in the determination of transition state intermediates B1 and B1'. Finally, steric component was calculated for the transition state intermediates B1 and B1', and B1' exhibits a lower dihedral angle than B1 (near-plane Pd-O-C-H element would lead a positive impact for β-H elimination267 ).

In addition, Pd-3 catalyst is favored to oxidize vicinal diols instead of mono-alcohols, which is caused by the differentiation of the rate-determining and product-determining processes.

Figure 26. Proposed mechanism for the alcohol oxidation and Pd-3 catalyst degradation pathway. 261,266 O2 was used for oxidation reactions as a convenient and clean oxidant giving H2O as the only by-product. 268 However, there are still some limitations coming from competitive oxidation pathways of the ligand which could lead to a negative effect for the oxidation results (Figure 26, c andd). 269 Meanwhile, addition of styrene and phenol exhibited a significant benefit for improving the oxidation yield with low catalyst loading (Table 6, entries 1-4). As the proposed mechanism indicated, competitive oxidative degradation occurs at the methyl groups of the neocuproine ligand leading to the formation of an inactive intermediate species. 270 Among these intermediates, "D" is determined to be the inactive compound in the oxidation process (Scheme 79, a). A is formed by hydrogen atom abstraction of carbonhydrogen bond from the methyl group of neocuproine ligand, which reacted with dioxygen to Scheme 79. Proposed mechanism of oxidative degradation pathways. [START_REF]HRMS (ESI + ): calcd. for C8H16NaO5 [M + Na] +[END_REF] Another major pathway for the degradation of catalyst is the formation of Pd black which could significantly affect the lifetime of palladium-based catalyst in the oxidation process (Figure 26, d). Palladium hydride A mediates the generation of palladium black (from active Pd II to inactive Pd 0 ) (Scheme 80, a). High catalyst loading was required in the aerobic oxidation process due to the formation of Pd black that led to a negative effect on the catalyst lifetime.

Therefore, it is crucial to find suitable additives to avoid the formation of inactive Pd black.

In this context, the group of Waymouth proposed that adding styrene could efficiently inhibit the formation of Pd(0). [START_REF]HRMS (ESI + ): calcd. for C8H16NaO5 [M + Na] +[END_REF] As indicated by the oxidation mechanism, 271 a palladium hydride complex A could readily transform into Pd(0) due to its valence-unstable. 272 While the insertion of styrene into palladium-hydride bond would generate immediate "B" which could prevent the degradation pathway (Scheme 80, b). Further insertion of dioxygen and exchange with proton donor would lead to the regeneration of the catalyst "D" with the generation of E which is known as a TON enhancer (Scheme 80, c). In order to simplify the oxidation process and the analysis of the catalytic tests, the purification of crude diglycerol was performed. Keeping this in mind, -diglycerol was prepared via a two-step procedure following a reported method. 273 First, crude diglycerol was treated with dimethyl carbonate (6 equiv) and potassium carbonate (0.006 equiv) at 70 o C for 24 hours, which yield diglycerol dicarbonate as an isomer mixture. Then, selective crystallization was carried out by adding cool ethyl acetate to remove other isomers of diglycerol dicarbonate and collect the filtrate. Finally, cool methanol was added into the solution for crystallization to provide the desired α,α-diglycerol dicarbonate with 56% isolated yield. The ratio of diastereoisomers is 2:1 for d,l and meso, which was determined by 1 H NMR (see experimental part) (Scheme 82). 2.1.2.2 Preparation of Pd-2.

Pd-2 was prepared from the reaction between Pd(OAc)2 and neocuproine following a reported procedure (Scheme 84). 66 Pd(OAc)2 and neocuproine were treated under argon atmosphere at room temperature for overnight to give Pd-2 with 75% yield.

Scheme 84. Synthesis of Pd-2.

Preparation of Pd-3.

Pd-3 was prepared via two steps following a reported procedure (Scheme 85). 82 First, neocuproine was treated with triflic acid in dry acetone under nitrogen atmosphere at room temperature for 30 min. Then, diethyl ether was added into the solution to form neocuproinetriflate salt as a white solid with 78 % yield.

Scheme 85. Synthesis of neocuproine-triflate salt.

2.2 Optimization for the selective mono-oxidation of diglycerol.

Influence of the catalyst nature.

From the previous works about the oxidation of vicinal diols, palladium-based catalysts exhibit high conversion and selectivity towards -hydroxyketones. We started the oxidation of -diglycerol under the same condition as glycerol. 258, 260 -Diglycerol -1 was treated with palladium-based catalysts (Pd-1, Pd-2 and Pd-3) with oxygen as an oxidant in acetonitrile/water (10:1) system at 30°C for 24 hours (Table 7). a Reaction conditions: diglycerol or glycerol (0.45 mmol), Palladium-based catalysts 1-3 (10 mol%), O2

(1 bar), CH3CN/H2O (v/v 10:1, 5.5 mL), 30°C, 24 h. b Yields were determined by 1 H NMR with mesitylene as an internal standard.

It was surprising that neither Pd-1 nor Pd-2 complexes can catalyze the oxidation of diglycerol (Table 7, entries 1-2). For these two reactions, no conversion took place while the same conditions led to good results for the oxidation of glycerol, that gave DHA 5 with 41 and 60% yield, respectively (Table 7, entries 1-2). With Pd-3 as a catalyst, only trace amounts (<5%) of the mono-oxidation product of diglycerol were obtained (Table 7, entry 3). However, Pd-3 exhibits a good catalytic performance for glycerol with more than 90% yield (Table 7, entry 3).

These results were striking that the reported palladium-based catalysts (Pd-1, Pd-2, Pd-3) all showed good catalytic performance on glycerol while they led to poor performance on diglycerol. We assumed that the poor yield for diglycerol oxidation was caused by the solubility issues of diglycerol.

Optimization with diglycerol isomer.

We have observed that the mixture of diglycerols is more soluble in CH3CN/H2O system than the pure -diglycerol isomer, so the diglycerol isomeric mixture was used as a reagent for oxidation (Table 8).

With acetonitrile and water (10:1) as a solvent system, only traces of product were obtained (Table 8, entry 1). Then, oxygen pressure was increased to 3 bar, but it did not lead to a better result (Table 8, entry 2). Finally, benzoquinone was used as an oxidant, but it did not work better as well (Table 8, entry 3). Unfortunately, the solubility issue was not solved by using the isomeric mixture of diglycerols. Therefore, other procedures were considered to solve the solubility issue. a Reaction conditions: diglycerol isomer (0.45 mmol), Pd-3 (10 mol%), O2 (1 or 3 bar) or benzoquinone (3 eq), CH3CN/H2O (10:1, 5.5 mL), 30°C, 24 h. b The conversions and yields were determined by 1 H NMR with mesitylene as an internal standard.

Optimization with pure -diglycerol.

Pure -diglycerol was treated with different conditions for solving the solubility issue (Table 9). First, the pressure of oxygen was increased from 1 bar to 3 bar, but no conversion was observed (Table 9, entries 1-2). Then, benzoquinone was used as an oxidant instead of oxygen, but there was still no conversion (Table 9, entry 3). Next, THF and 1,4-dioxane were used as solvents did it not help the dissolution of -1 (Table 9, entries 4-5). Furthermore, under solvent-free conditions, no conversion was observed (Table 9, entry 6). Finally, the solvent system was changed to CH3CN/H2O (7:1) following a reported procedure 260 with increased ratio of H2O, using these proportions, 7% conversion of the starting material was obtained (Table 9, entry 7). a Reaction conditions: -diglycerol -1 (0.45 mmol), Pd-3 (10 mol%), O2 (1 or 3 bar), solvent (5.5 mL), 30°C, 24 h. b The conversions were determined by 1 H NMR with mesitylene as an internal standard.

Based on the above results, CH3CN/H2O (7:1) was selected as a solvent system for further optimization. In order to further promote the dissolution of diglycerol in this solvent system, the temperature was gradually increased from 30 °C to 80 °C (Figure 30). The oxidation yield was improved with increasing temperature and the best result was obtained at 70 °C with 38% isolated yield. The mono-oxidation product 4 was obtained with 27% yield, accompanied with 11% yield of the bis-oxidation product 6. The formation of this by-product 6 was probably due to the increased temperature and the extended reaction time. At higher temperature (80 o C) no improvement was obtained. It is probably due to high temperatures promote the dissolution of diglycerol in this solvent system but with accompany the harmful effect to catalyst life-time.

Characterization of the product.

Next, in order to determine the structure of the oxidation product, pure mono-oxidation product was isolated by column chromatography from the reaction at 70 o C (27% yield). First, the molecular formula of the compound (C6H12O5) was confirmed to be the expected product by mass spectrometry (HRMS). Subsequently, the product was analyzed by 1 H & 13 C NMR.

From 13 C NMR, an unexpected peak was observed at 94.61 ppm (Cq), characteristic of a cyclic hemi-acetal and only one diastereomer was obtained (Figure 31).

Figure 31. 13 C NMR (75 MHz, CD3OD) of -diglycerose (4)

Then, from 1 H NMR, it was observed that mono-oxidation product 4 exists as an openform (7%) and a cyclic form (93%) under this condition (Figure 32). After derivatization of 4

(see Scheme 100 & Figure 40), relative cis-configuration was determined for the two CH2OH groups.

Figure 32. 1 H NMR (300 MHz, CD3OD) spectrum of mono-oxidation product 4.

The intramolecular ring formation reaction of the oxidation product was carried out during the reaction process, and the cyclic form is predominant (Scheme 87). Mono-oxidation product 4 is favored to form only a six-membered ring.

Scheme 87. Characterization for the mono-oxidation product 4.

Influence of the post-reaction treatment.

The low yield of oxidation product may be caused by many factors which should be considered. The influence of the post-reaction treatment was studied by treating diglycerol with 10 mol% of Pd-3 and oxygen (1 bar) at 70 o C for 24 h. In the previous research for the oxidation of glycerol, the post reaction-treatment was performed following a reported method 260 which requires a short silica column to remove catalyst and washing with acetonitrile (Figure 33). However, the use of this protocol causes loss of product due to the fact that it cannot dilute well in acetonitrile and most of the product remains on silica.

Therefore, we assumed that using other washing solvents with higher polarity will cause less loss of the product (Table 10). Therefore, polar solvents such as MeOH and H2O were used as washing solvents, which led to 53 and 8% yield, respectively (Table 10, entries 1-2). Furthermore, we also tried to directly evaporate the solvent from the crude product without column and a similar yield (54%) was obtained (Table 10, entry 3). This method was selected as a convenient post-reaction treatment for next optimization step.

Influence of solvents.

To further improve the low yield caused by the low solubility of diglycerol and to improve the solubility of oxygen in the reaction medium, various solvents were tested. It was noted that high temperature caused the degradation of the catalyst, leading to the formation of palladium black. 270 Therefore, the temperature was set at 50°C and the time was limited to 2 hours for improving the yield of mono-oxidation product 4 and avoiding the catalyst degradation (Table 11).

First, the reaction was performed under solvent-free condition, but no conversion was obtained (Table 11, entry 1). Next, protic solvents such as methanol and ethanol were tested (Table 11, entries 2-3). Unfortunately, the oxidation did not occur even after 24 h. Then, several ethers were screened. Cyclopentyl methyl ether (CPME) and 2-methyltetrahydrofuran

(2-MeTHF) did not allow the formation of the expected product under the same condition (Table 11, entries 4-5). Ethers did not lead to the formation of the desired product which was caused by its poor solubility for diglycerol. However, the product was formed in tetrahydrofuran (THF) and 1,4-dioxane with 31 and 43% yield, respectively (Table 11, entries 6-7), which was caused by the increased polarity of them. Finally, fluorinated solvents were tested as they are known to well dissolve oxygen. No conversion was obtained by using (trifluoromethyl)benzene (Table 11, entry 8). Satisfyingly, trifluoroethanol (TFE) gave 54% yield with 99% selectivity towards the mono-oxidation product 4. (Table 11, entry 9).

Furthermore, another fluorinated alcohol 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) was also considered, which has greater acidity and better oxygen solubility compared with other solvents such as methanol and TFE (Table 12, entries 1-3). 274,275,276 Pure -diglycerol was treated under the same condition in HFIP and it affords a better result with 76% conversion and the yield was increased to 74% (Table 11, entry 10). The selectivity reached 99% with the ratio of 93% for the cyclic form. mol fractions of gas in liquid.

2.2.6.1 Optimization with TFE as a solvent.

The oxidation was first optimized with TFE from an economical point of view (Table 13).

First, the reaction time was increased from 2 h to 6 h, but the yield did not improve significantly (Table 13, entries 1-3). Then, when the temperature was increased to 60 o C, no improvement was observed for the synthesis of 4 (Table 13, entry 4). a Reaction condition: -1 (0.45 mmol), Pd-3 (10 mol%), O2 (1 bar), solvent (5.5 mL), b The conversions, yields and selectivity for mono-oxidation product were determined by 1 H NMR with mesitylene as an internal standard.

2.2.7 Optimization of diglycerol oxidation with HFIP system.

Considering TFE system did not gave a good oxidation result, HFIP was reconsidered as the solvent for further optimization.

2.2.7.1 Influence of temperature and oxygen pressure.

The influence of temperature was studied at 40 °C and 50 °C (Table 14, entries 1-2). We expected that decreasing the temperature would avoid the catalyst degradation.

Unfortunately, when the temperature was reduced to 40 °C, the conversion also reduced to 63% and the yield reduced to 62%, while the selectivity was still very high (Table 14, entries 1-2). Furthermore, no attempt was devoted to increase the temperature as it was previously reported that it was deleterious for the catalytic system and also due to the limit of low boiling point (HFIP, boiling point at 58.2°C). In this case, 50 °C was selected for further optimization.

In order to investigate the influence of oxygen pressure, the reaction was carried out with 10 mol% of Pd-3 complex with gradually increased oxygen pressure. Compared with previous results under the condition of 1 bar of oxygen, using 3 or 6 bar of oxygen led to a better result with 89 or 94% yield, respectively (Table 14, entries 2-3). The oxygen pressure has a great influence on the oxidation results. a Reaction condition: -1 (0.45 mmol), Pd-3 (10 mol%), O2, HFIP (5.5 mL), reaction was carried out at 50°C for 2 h. b The conversions, yields and selectivity for mono-oxidation product were determined by 1 H NMR with mesitylene as an internal standard. c The reaction was carried out at 40 o C.

Noteworthy, increasing the oxygen pressure did not lead to an increased yield of bisoxidation product 6. Therefore, the oxygen pressure was further increased to 6 bar, the yield of 4 increased to 94% (Table 14, entry 4).

Influence of catalyst loading.

Given that palladium is an expensive metal, the amount of the catalyst loading was reduced (Table 15). The reaction was first carried out with decreased catalyst loading (5 mol%) under 3 or 6 bar of oxygen, which gave 66 and 63% yield, respectively (Table 15, entries 1-3).

Then, further reduction of catalyst loading was carried out with 2.5 mol %, using 3 bar of oxygen that only resulted in 33% yield (Table 15, entry 4). In this case, in order to balance the compromise between economic (with low catalyst loading) and high yield, other optimization procedures were considered. a Reaction condition: -1 (0.45 mmol), Pd-3, O2 (3 or 6 bar), HFIP (5.5 mL), reaction was carried out at 50°C for 2 h. b The conversions, yields and selectivity for mono-oxidation product were determined by 1 H NMR with mesitylene as an internal standard.

Optimization with styrene as an additive.

As previously reported, the critical issue of low yield under these conditions is probably due to the catalyst degradation. Waymouth et al. 270 reported that beneficial effects were obtained on catalyst activity and lifetime for the palladium catalyst Pd-3 by adding additives (such as phenol or styrene). In this case, styrene (5 equiv) was added, using 2.5 mol% catalyst under 3 bar of oxygen, the yield was increased to 75% (Table 16, entries 1-2). In order to further optimize the reaction conditions, the reaction time was extended from 2 h to 6 h, which led to a slightly better result with 77% yield (Table 16, entry 3). When the reaction time was further increased to 18 h, the best result was obtained with 93% yield and almost full conversion (Table 16, entry 4). Only 61% isolated yield was obtained, which is probably due to the loss of purification process on the small scale (Table 16, entry 4, results in brackets). Next, further decreasing the catalyst loading to 1 mol% did not yield a better result, even with an extended reaction time to 30 h (Table 16, entries 5-6). In addition, due to its high price, with same amount of HFIP (5.5 mL) but bigger scale that did not allow an obvious benefit (Table 16, entry 7).

2.2.7.4 Scale-up reaction for the oxidation of diglycerol.

The scale-up was carried out with the optimized conditions (Pd-3 (2.5 mol%), O2 (3 bar) and styrene (5 eq) in HFIP (55 mL) at 50 °C for 18 h), which allowed the formation of monooxidation product -diglycerose 4 with 76% isolated yield (Scheme 88). Mn II (Me2EBC) Cl2 0 0 0 Based on the above investigations, other catalytic systems will be further explored with the oxidation of diglycerol to develop an oxidation procedure acceptable both from the point of views of efficiency and economy.

5 d Ni-Al2O3-SiO2 - 8

Applications of oxidation method on other diols.

The optimized conditions were applied to other 1,2-diols.

Selective oxidation of erythritol.

Meso-erythritol was first used under the optimized conditions (3 bar of O2, Pd-3 catalyst (2.5 mol%), styrene (5 equivalents), HFIP, 50 °C, 18 h). A high isolated yield of 7 (92%) was obtained which exhibits high application prospect for the oxidation of vicinal diols (Scheme 89).

Scheme 89. Oxidation of meso-erythritol.

Moreover, this method was also applied to the oxidation of L-erythritol under same conditions. Satisfyingly, a high isolated yield (86%) was obtained for racemic erythrose 8

(Scheme 90).

Scheme 90. Oxidation of erythritol.

Oxidation of -diglycerol.

After optimizing the oxidation of α,-diglycerol, we turned our attention to its isomer -diglycerol.

Recovery of α,-diglycerol.

The commercial diglycerol exists as a mixture with -form as the major product. In order to oxidize α,-diglycerol, the recovery of pure α,-diglycerol was first considered.

As discussed in chapter 2.1 for the purification of -diglycerol, α,α-diglycerol dicarbonate 2 was obtained selectively by crystallization from the filter residue (Scheme 91, a). Therefore, we tried to obtain α,-diglycerol dicarbonate A from the filtrate (Scheme 91, a). Scheme 91. Recovery of -isomer of diglycerol from the mixture.

After crystallization of α,α-diglycerol dicarbonate 2, the filtrate was collected and analyzed by 13 C NMR, the filtrate consists of diglycerol dicarbonate on -form 2 and form A, B and C. Pure -diglycerol dicarbonate cannot be obtained with this method, even after several crystallizations to remove 2. Therefore, the synthesis of -diglycerol was considered following a reported procedure. 277 2.3.2.2 Synthesis of α,-diglycerol.

First, O-benzyl protected α,-diglycerol dicarbonate 9 was prepared from epichlorohydrin and benzyl alcohol in the presence of KOH, water and using tetra-nbutylammonium iodide as a phase-transfer catalyst at 80 °C for 46 h to give 9 with 73% yield (Scheme 92, a). 277 277 H. Nemoto, J. G. Wilson, H. Nakamura, Y. Yamamoto, J. Org. Chem., 1992, 57, 435-435. In parallel, solketal was treated with tosyl chloride and NaOH in THF at 0 °C overnight. Under these conditions, the tosyl derivative 10 was obtained with 92% yield on the 10-gram scale (Scheme 92, b).278 Scheme 92. Synthesis of -diglycerol via a four-step procedure.

Next, 9 and 10 were treated with NaH in the presence of tetrabutylammonium bromide at 100 °C for 26 h, 11 was obtained with 56% yield (Scheme 92, c).

Finally, deprotection of both the acetonide and the benzyl groups of 11 was carried out under hydrogen in the presence of 10%Pd/C in methanol to give -diglycerol -1 with 97% yield (Scheme 92, d). 279 After 4-step synthesis, -diglycerol -1 was obtained with 37% overall yield on 2.1 g scale.

Selective oxidation of -diglycerol with optimized condition.

With pure -diglycerol in hands, the oxidation of -diglycerol -1 was carried out under the optimized conditions [3 bar of O2, Pd-3 catalyst (2.5 mol%), styrene (5 equivalents), HFIP, 50 °C, 18 h] with a large scale (4.5 mmol of -diglycerol). In this case, the oxidation product also cyclizes to give a six-membered ketose 12 as an isomer mixture with only 4% isolated yield. Bicyclic compound 13 was obtained as the major product with 76% yield. From the NMR experiments, 12 was determined to be pure product which was proposed that the hydroxymethyl group is equatorial, considering its better stability. 13 was formed from diglycerose 12 by dehydration (Scheme 93).

Scheme 93. Oxidation of -diglycerol.

When the oxygen pressure was decreased to 1 bar, with the same condition [-1 (4.5 mmol), Pd-3 catalyst (2.5 mol%), styrene (5 equiv), HFIP, 50 °C, 18 h], the major product diglycerose 12 was obtained with 51% isolated yield, as diastereomers with the ratio of 88:12 for relative trans-and cis-configuration. 13 was obtained with 10% isolated yield (Scheme 94).

Scheme 94. Oxidation of -diglycerol with 1 bar of oxygen.

Characterization of the structure.

In order to assign the structure of the oxidation product, 1D and 2D NMR experiments were carried out. With NMR experiments, the ratio of relative cis-and trans-configuration for 12 were obtained with 12:88 (Scheme 94). In the nuclear overhauser effect spectroscopy (NOESY) experiments, couplings were observed for H 2 and H 3 , H 2 and H 6 , H 5 and H 4 . This indicates that the major compound 12 as a relative trans-configuration, in that case, the two hydroxyl groups are equatorials, which are more stable positions (Figure 34). In conclusion, Pd-3 catalyst also exhibits excellent catalytic performance for the oxidation of -diglycerol to yield -diglycerose, which was regarded as a potential building-block for further applications.

2.4 Kinetic study of the oxidation of -diglycerol and -diglycerol.

Comparison of oxidation rates of -diglycerol and -diglycerol.

In order to further understand the discrepancy of the oxidation rates for ,-diglycerol (,-1) and ,-diglycerol (,-1), the reaction was carried out with the optimized condition under 1 bar of oxygen for sampling. An aliquot of the reaction mixture was sampled at several times and analysed by GC after derivatization (see experimental section for details) (Scheme 95). First, it was worth noting that before injection, the crude mixtures were derivatized. As the results indicated, the oxidation rates of the two substrates did not exhibit significant difference within two-hours. From the second hour of reaction, a faster reaction rate was found for -diglycerol than -diglycerol. When the reaction progressed to 24 hours, the oxidation conversion was 59% for -form while 39% was obtained for -form (Figure 35).

The yield was 44% for -form 4 and 31% for -form 12. Almost no dehydration product was obtained either for -diglycerol or -diglycerol. In conclusion, the oxidation of -diglycerol is faster than -diglycerol.

2.4.2 Comparison of oxidation rates of -diglycerol of 1 and 3 bar of O2.

Next, the reaction process with different oxygen pressure was followed over time. -Diglycerol was used as the oxidation substrate due to its simplier preparation method (Scheme 96).

Scheme 96. Oxidation of -diglycerol with 1 or 3 bar of O2.

By comparison with the oxidation result of -diglycerol with 1 bar of oxygen, the reaction performed under 3 bar of oxygen exhibits a significant faster rate. With 3 bar of O2, the oxidation reaction occurs immediately while with 1 bar of O2, the reaction starts after 2 hours (Figure 36). After 24 h, the conversion with 3 bar of O2 reached over 92% and the yield of -diglycerose 4 was 85%, while under 1 bar of O2 54% conversion and 44% yield were obtained (Figure 36), which indicated that increasing oxygen pressure had a positive effect on the oxidation process. Almost no dehydration product was obtained either with 1 bar or 3 bar of oxygen (Figure 36). Furthermore, considering that oxygen plays an important and indispensable role in the re-oxidation of Pd (0) to Pd (II) process, increasing the oxygen pressure significantly improves the oxidation efficiency by promoting the solubility of O2 in HFIP.

Oxidation rates of crude diglycerol.

The reaction progress of crude diglycerol was also studied. With the optimized conditions, oxidation results were followed with obvious differences for the -form and -form of diglycerol (Scheme 97). It was surprising that during the oxidation process (24 h), almost no oxidation occurred for -diglycerol -1 ( < 3%), while -diglycerol -1 gave 54% conversion, that is similar to the oxidation of pure -diglycerol (59%) (Figure 37). After 24 h, -diglycerol led to the formation of mono-oxidation product 4 with 37% yield while  -diglycerol gave only 3% of the desired product 12 (Figure 37). It is clear that the oxidation rate for -isomer is faster than -form. Moreover, 3% yield of dehydration products were obtained for the oxidation of -diglycerol and diglycerol for 24 h.

This result clearly indicates that the oxidation reaction could be carried out directly from crude diglycerol without purification for large scale, which is more convenient and largely simplify the oxidation process.

2.4.4 Dehydration reaction of diglycerose on -form and -form.

In order to clarify the cause that -diglycerol -1 was more likely to form dehydration product in oxidation process than -diglycerol -1, the dehydration was voluntarily performed. First, the hypothesis that the difference in oxidation rate is responsible for the difference in dehydration was rejected, because -diglycerol was confirmed to exhibit higher oxidation rate than -diglycerol (Figure 35 and 37). Then, the difference in dehydration rate between -diglycerose and -diglycerose was considered. In order to verify this hypothesis, Amberlyst 15 was used as an acid catalyst in dichloromethane to explore the dehydration rate of -diglycerose and -diglycerose within 1 h and 2 h (Scheme 98).

Scheme 98. Dehydration reaction of ,-diglycerose 4 and ,-diglycerose 12. Dehydration conditions: ,or ,-diglycerose 4 or 12 (0.45 mmol), Amberlyst 15 hydrogen form (10 wt.%), dichloromethane (5.5 mL), room temperature, 1 or 2 hours. The conversions and yields were obtained by GC after derivatization with methyl oleate as an internal standard.

4 and 23% yield were obtained for -diglycerose for 1 and 2 h, respectively, while diglycerose gave significant increasing yield with 27% for 1 h and 42% for 2 h (Scheme 98).

From these results, we confirm that the formation of dehydration product for -diglycerose is easier than for -diglycerose under the same conditions.

The different molecular structure of -1 and -1 could be the main factor affecting the dehydration reaction in the oxidation process. As we demonstrated the structure of diglycerose and -diglycerose, the two hydroxy groups that may undergo dehydration reactions are relatively cis for -diglycerol, while for -diglycerol they are relatively trans.

As the proposed mechanism indicated, the dehydration reaction is more likely to occur for -diglycerose than -diglycerose (Figure 38). The mechanism of nucleophilic addition steps indicated that B3 formed 13 is easier than A3 formed 14 (Figure 38, a and b). 2.5 Applications of the diglycerose platform molecules.

Since we have developed an efficient selective catalytic oxidation procedure for diglycerol and some other 1,2-diols (-diglycerol and d,l-or meso-erythritol), we next studied the reactivity of this "ketose-like" product for further applications. We first focused our attention on benzylation and glycosylation reactions.

Benzoylation.

The benzoylation of -diglycerose 4 was performed with benzoyl chloride in the presence of pyridine, following a reported procedure. 280 After 3 h at room temperature, three products were obtained including perbenzoylated cyclic compound 15 with 65% yield while 9% yield for the acyclic compound 16 and 3% yield for bis-benzoylated product 17 were also obtained (Scheme 99).

Scheme 99. Benzoylation of -diglycerose 4.

In order to confirm the structure of -diglycerose, benzoylation was carried out using 4-bromobenzoyl chloride hoping that crystals obtained could be suitable for X-ray analysis (Scheme 100). -Diglycerose was treated with benzoyl chloride at room temperature for 3 h. Cyclic compound 18 was obtained as the major product with 45% yield while the open form 19 was obtained with 9% yield. Satisfyingly, compound 18 was obtained as a solid but the crystals were not good enough to be analyzed by X-ray.

Scheme 100. Benzoylation of -diglycerose 4 with 4-bromobenzoyl chloride.

Compound 18 was analysed by 1 H & 13 C NMR (see experimental section) and 2D NMR experiments. From 1 H NMR, a 3 J coupling of 11.3 Hz between H 3' and H 4 confirmed H 3' to be axial while the 3 J coupling of H 3 -H 4 was determined to be 2.9 Hz that confirmed the H 3 is equatorial (Figure 39). From the NOESY experiment, the relative cis-configuration between H 5 and H 6 was confirmed from the coupling of H 3' -H 2' , H 6 -H 2 ', H 6 -H 2 while no coupling was found for H 6 -H 4 .

(Figure 40). In conclusion, via benzoylation with 4-bromobenzoyl chloride, the mono-oxidation product -diglycerose 4 was confirmed to have a relative cis-configuration for the two hydroxymethyl groups.

Glycosylation.

-Diglycerose can also be used as a substrate for glycosylation-like reaction. -Diglycerose 4 was treated with benzyl alcohol (10 eq) using Amberlyst 15 at room temperature for 4 h to form 33% yield of glycosylation product 20 with 14 as by-product (27% isolated yield) (Scheme 101). The relative cis-configuration of 20 (for the two hydroxymethyl groups) was confirmed by NOESY experiment (see experimental section). Chapter 3. Glycosylation of diglycerose towards bio-based surfactants.

1 Introduction.

Based on the investigations in chapter 2, the oxidation of diglycerol was developed with excellent yield and selectivity to provide -diglycerose and -diglycerose. Therefore, the next step is to investigate the potential applications of diglycerose, notably towards the preparation of bio-based surfactants.

The development of bio-based surfactants based on diglycerose ( and -form) could be achieved by glycosylation, aldolization or esterification to prepared the corresponding glycosides, aldols and esters (Figure 41, a-c). The esterification of -diglycerose is probably difficult to achieve selectively, considering that 3 hydroxyl groups are present on the molecule. This will lead to a mixture of surfactants (up to 7 species) with regioisomeric mixtures and potential mono-, bis-, and triesterification (Figure 42). If regioisomeric mixtures could be interesting for surfactants applications, the presence of 1, 2 or 3 alkyl chains could lead to surfactants with very different HLBs. Moreover, the presence of several isomers could be a drawback from an analytical point of view. diglycerose has a higher ratio of open form (7%), so that there is more chance to get the desired product (Scheme 102, b). However, 5 equivalents of DHA were necessary for the aldolization reaction as reported (Scheme 102, c). 189 Therefore, this procedure was not applicable for diglycerose due to the difficult synthesis of the starting material.

Scheme 102. Synthesis of C-C bond surfactants via aldolization.

In this context, the development of diglycerose-based O-glycoside surfactants via glycosylation with fatty alcohols could be a better choice. As presented in chapter 2, the glycosylation was carried out on -diglycerose with benzyl alcohol. The desired product was isolated with 33% yield, showing that it is a viable strategy (Chapter 2, Scheme 101). Therefore, -diglycerol and fatty alcohols were selected as substrates (Scheme 103).

Scheme 103. Glycosylation of -diglycerose with fatty alcohols.

1.1 Diglycerol-based surfactants.

Diglycerol is a commercially available raw material that is produced from bio-based resources. Diglycerol based surfactants were widely applied in the field of cosmetics, personal care, food and plastics production industry. 281 The physical characteristics of this viscous liquid greatly promote the application of diglycerol-based surfactants as fragrance additives and preservatives in cosmetics and personal care products. 282 1.1.1 Diglycerol-based polymer surfactants.

As an important type of non-ionic surfactant, polyglycerol esters have attracted a lot of interest in the field of cosmetics and food 283,284 because they are environment-harmless. 285 Generally, polyglycerol esters are synthesized via three routes (Scheme 104). First, the most common route to synthesize polyglycerol esters is through the direct esterification of fatty acids and polyglycerol (Scheme 104, a). 286 , 287 Then, it can also be produced via transesterification of methyl acid esters or triglycerides under basic conditions (linear polyglycerol esters) (Scheme 104, b). 288 Finally, it can be obtained via the polymerisation of fatty acids and glycidol under acidic conditions (Scheme 104, c). 289 Based on the above methods, the product was obtained as mixtures determined by the degree of polymerization and the amounts of hydroxyl groups involved in the esterification process.

Scheme 104. Possible routes for the synthesis of polyglycerol esters.

Moreover, many efforts have been devoted for the production of polymers with functional diversity from renewable materials. Diglycerol as an important monomer that is used in polymer application, especially for the production of polyurethanes and polyesters. 290 However, compared with glycerol which has a long history in polymer synthesis, less research was investigated on diglycerol.

In 2009, Shrestha et al. 291 investigated the reverse micelles behavior of commercially available diglycerol-based polyester "diglycerol polyisostearates" (Figure 43). It was found that (iso-C18)2G2, (iso-C18)3G2 and (iso-C18)4G2 can form reverse micelles in organic solvent systems (cyclohexane, n-decane and n-hexadecane) without water at room temperature. The size of micelles decreased as the amount of isostearate chains increased. In summary, diglycerol-based polymer surfactants as important non-ionic surfactants that have been applied in the industrial production of cosmetics, inks, photography and food. 292

1.1.2 Diglycerol ester surfactants.

Diglycerol-based mono-and diesters occupy 20% market share of commercial polyglycerols in 2020. 200 In 1989, Kumar et al. 201 reported a synthetic route of diglycerol-based esters (Scheme 105). The esterification was carried out with diglycerol and several fatty acids (such as undecanoic, lauric, stearic, oleic and ricinoleic acids), using p-toluenesulfonic acid in acetonitrile-tetrahydrofuran solvent system for 24 h to form mono-esters with 31-55% yield.

When the reaction time was increased to 36 h, diesters were obtained with 15-34% yield.

Scheme 105. Synthesis of diglycerol based mono-and di-esters via esterification.

Moreover, it was found that the properties of diglycerol-based ester surfactants are largely influenced by the structure of the fatty acids. Compared with diesters, monoesters exhibit better property for surface tension reduction, emulsification and foaming. The chain length of fatty acids also has a significant effect on the surfactant properties, surfactant with short chains exhibit better properties than the long chains.

Diglycerol-based esters are used as additives for food and medicinal industry. Food safety issues have received widespread attention, especially the degradation problems in the food preservation process (such as bacterial poisoning contamination). 293 Yamazaki et al. 294 studied the enhancement antibacterial effect for essential oils by diglycerol based fatty esters. It was found that the addition of diglycerol monolaurate and Nisin can improve the antibacterial activity, thus reducing the amount of food preservatives.

Moreover, Holstborg et al. 295 observed that diglycerol-based esters exhibit better ability to reduce the interfacial tension between the oil and water phases compared with the corresponding monoglycerides. Compared with food oil emulsions, the synergistic effect of diglycerol fatty ester and oleic acid exhibits better destabilizing effect. 296

In 2005, Plasman et al. 297 reported that diglycerol-based monooleate exhibits excellent antifogging properties (Figure 44). Compared with other polyglycerol esters, diglycerol-based monooleate exhibits a minimum contact angle which can promote the industrial applications as antifogging product for polyolefin and PVC films. In conclusion, there are not many investigations for diglycerol-based ester surfactants,

the current examples show that it has excellent performance in antibacterial and defogging.

It is a kind of potential surfactant for industrial applications.

1.1.3 Diglycerol acetal surfactants.

Acetal surfactants were reported to be synthesized via the acetalization of glycerol and C8-C16 aldehydes. 298 However, the applications of these glycerol-based acetals were limited by the poor aqueous water solubility. 299 In order to solve this issue, it was found that the surfactant properties of glycerol acetal could be improved by the modification of the hydrophilic group. 300 There is another way to improve the surfactant properties by using diglycerol instead of glycerol as a substrate in order to provide an increased polar head. In 2018, Tang et al. 205 reported the synthesis of diglycerol based acetals by acetalization. Diglycerol and n-octanal were treated with p-toluenesulfonic acid (PTSA) at 100 °C for 4 h under solvent-free conditions to give 90% conversion (n-octanal) with 12% selectivity for mono-acetals (Scheme 106, a). The treatment of ZnCl2 led to the increased formation of the desired mono-acetals with 80% conversion (n-octanal) and 84% selectivity (Scheme 106, b).

Scheme 106. Synthesis of diglycerol based mono-acetal with different catalyst.

In conclusion, there are only few examples of diglycerol-based acetal surfactants.

However, the mono-acetals presented above exhibit excellent surfactant properties with good foam stability and alkali tolerance (Scheme 106).

1.1.4 Diglycerol ether surfactants.

In 1992, Burgess et al. 301 reported a two-step procedure to prepare diglycerol-based ethers (Scheme 107). First, 2-(allyloxy)oxirane and dodecyl alcohol were treated with boron trifluoride etherate to form the intermediate A with 65% yield. Then, after epoxidation followed by hydrolysis led to the desired diglycerol-based ether with 85% yield.

Scheme 107. Synthesis of diglycerol-based ether via a two-step procedure.

In addition, many studies were reported by our group for the synthesis of diglycerolbased ethers by reductive etherification. In 2009, Shi et al. 153,154 reported a direct synthesis of diglycerol-based ethers from fatty aldehydes. Diglycerol was treated with valeraldehyde, octanal and dodecanal using 5% Pd/C (0.5 mol%), CSA (10 wt%) and H2 (10 bar) at 140 o C for 24 h to give the corresponding diglycerol ethers with 71-83% yield (Scheme 108, a).

Methyl esters were also used as substrates for the direct synthesis of diglycerol-based ethers. 156 Diglycerol was treated with methyl esters using 5% Pd/C (1 mol%), CSA (10 wt%), H2 In addition, many other homogeneous acids were used for the glycosylation of unprotected carbohydrates. Trifluoromethanesulfonic acid (HOTf) was used for the glycosylation of D-glucose with benzyl alcohol to give 77% yield (Table 19, entry 1). 38 p-Toluenesulfonic acid (PTSA) and acetyl chloride (AcCl) were also reported to efficiently catalyze the glycosylation of D-galactose with hex-5-enol to give the corresponding product with 72 and 71% yield, respectively (Table 19, entries 2-3). 307 Moreover, Pfaffe et al. 308 reported a novel glycosylation procedure under mild conditions.

Mandelic acid was used for the glycosylation of D-ribose and propan-2-ol with Ti(OtBu)4 as cocatalyst at room temperature to give O-glycoside product with 73% yield (Table 19, entry 4). In addition to monosaccharide, the glycosylation of disaccharides was also reported.

MCM-41 modified with Si/Al exhibited excellent catalytic performance on the glycosylation of leucrose and 1-butanol, which gave 91% yield of product on -pyranoside form with 100% selectivity (Table 20, entry 4). In summary, there are many investigations for the glycosylation of unprotected carbohydrates by using acid catalysts or bio-catalysis. These methods achieved excellent results.

2 Results and discussions.

Based on the above research, the investigation of diglycerose-based surfactants via glycosylation was explored (Figure 46). 2.1 Influence of the catalyst nature.

Different acid catalysts were tested for the glycosylation. Homogeneous hydrochloric acid (HCl) was used for glycosylation on -diglycerose and benzyl alcohol, giving 6% yield of the desired O-glycoside based product while the formation of the intramolecular dehydration by-product 14 dominates (19% yield) (Table 22, entry 1).

Next, sulfonic acids were also tested for the glycosylation of -diglycerose and benzyl alcohol. p-Toluenesulfonic acid (PTSA) and camphorsulfonic acid (CSA) gave almost full conversion but only 6 and 17% yield of the desired O-glycoside product, respectively (Table 22, entries 2-3). The main by-products 14 was obtained with 27 and 30% yield, respectively. Acidic resins were also used for the glycosylation. Amberlyst 35 and Amberlyst 36 gave full conversion of -diglycerose as well, while the yield of 20 reached to 12 and 5%, respectively (Table 22, entries 4-5). Amberlyst 15 was used under same conditions to give compound 20 with 30% yield (Table 22, entry 6). Therefore, Amberlyst 15 was selected as the catalyst for further optimization of glycosylation reaction.

Structure characterization.

Preliminary results gave a moderate yield of the desired glycosylation product 20 (Table 22, entry 6). However, high conversion of -diglycerose with low yields of 14 and 20, and an unknown product observed from GC chromatogram caused attention to analyse the glycosylation results (Figure 49).

Characterization of the glycosylation product.

Pure products were obtained by column chromatography, glycosylation product 20 was obtained as main product and intramolecular dehydration product 14 was obtained as byproduct. First, the structure of 14 and 20 were analysed by 1 H & 13 C NMR (See experimental section).

The structure of 20 was analysed by 1D & 2D NMR experiments. From the J coupling of H 3' -H 4 and H 3 -H 4 , the spatial configuration was confirmed as represented in Figure 47. In conclusion, the structure of 20 was confirmed with the two hydroxymethyl groups having a relative cis-configuration. There is a big gap between conversion and yield for the glycosylation results. The GC chromatogram is pretty clean, but there is an unexpected peak at around 4.22 min. In order to investigate the structure of the unknown compound (Figure 49), GC-MS was carried out for the crude glycosylation products.

Figure 49. GC chromatogram of the crude products after derivatization (reaction condition of Table 23, entry 3).

Then, as the GC chromatogram of crude glycosylation products indicated, derivatized products of benzyl alcohol, glycerol, 14 and desired product 20 were clearly confirmed while no derivative product of 4 was observed (Figure 49). The glycosylation reaction mainly formed -diglycerose O-glycoside 20 while 14 was formed as the main by-product (Scheme 114).

Scheme 114. Derivatization for the glycosylation products.

The presence of glycerol was surprising so the source of it was investigated. First, we ruled out the possibility that glycerol was formed during the glycosylation process via 1 H NMR analysis of the crude reaction mixture before derivatization, no new signal of glycerol or glycerol derivative was observed (See experimental section). So, glycerol could be formed from the derivatization of 4. However, when pure -diglycerose 4 was treated with derivatization procedure, no silylated glycerol was formed (Scheme 115, a). Next, pure products 20 and 14 were treated with derivatization procedure respectively, which did not lead to the formation of silylated glycerol as well (Scheme 115, b and c).

Scheme 115. Analysis of the derivatized product.

Next, we assumed that the silylated glycerol was formed in the presence of H2O during the derivatization process performed in THF. Therefore, the reaction was carried out with diglycerose and H2O with and without glycosylation conditions (acid catalysis), using TMSCl-HMDS-pyridine derivative system. All conditions led to the formation of persilylated glycerol (Scheme 116, a and b). It was not surprising because the cleavage of methyl ether by trimethylsilyl chloride have been reported by Sarma et al. in 1986. 321 Scheme 116. Analysis of the derivatized product 4 in the presence of water.

Moreover, the reaction was also carried out with 20 and 14 respectively in the presence of H2O using TMSCl-HMDS-pyridine derivative system. No formation of persilylated glycerol was observed from GC chromatogram (Scheme 117).

Scheme 117. Analysis of the derivatized product 20 and 14 in the presence of water.

To conclude, we confirmed that the formation of glycerol is from the reaction of diglycerose and H2O during the derivatization process. This means that the observed conversion of 4 are over-estimated.

2.3 Optimization with Amberlyst 15 catalysis system.

Based on the above investigations, we now better understand the reaction process and the formation of each product. Next, the optimization was carried out with Amberlyst 15 as a catalyst.

2.3.1 Influence of the amount of alcohol.

First, the influence of the molar ratio of -diglycerose and benzyl alcohol was investigated. -Diglycerose 4 was treated with benzyl alcohol with 5, 10, 20 and 50 equivalents, using A15 as a catalyst at room temperature overnight. Using 5 and 10 equivalents of benzyl alcohol gave 12 and 30% yield of 20, respectively (Table 23, entries 1-2). When using 20 equivalents of benzyl alcohol, 20 was obtained with 51% yield (Table 23, entry 3). Next, the amount of benzyl alcohol was further increased to 50 equivalents that led to only 18% yield which was probably caused by the diluted condition (Table 23, entry 4). The evolution of 20:14 was also obtained, 50 equivalents of benzyl alcohol gave the best results

for the formation of 20 and 14, with the ratio of 64:36 (Table 23, entry 3). Therefore, the condition of 20 equivalents of benzyl alcohol was selected for further optimization.

2.3.2 Influence of catalyst loading and other parameters.

Next, the glycosylation of -diglycerose with benzyl alcohol was studied with different catalyst loading. Using A15 with 5, 10 and 50 wt% gave the desired product 20 with 20, 51 and 11% yield, respectively (Table 24, entries 1-3). Furthermore, the reaction was also carried out at 30 o C instead of room temperature that gave 20% yield of 20, and 14 was obtained with 27% yield as major product (Table 24, entry 4). It seems that increasing the temperature tends to promote the formation of the dehydration product 14. Then, Na2SO4 was added as a water absorbing agent, but it did not affect the glycosylation results (Table 24, entry 5). Finally, anhydrous THF was used as a solvent, but it did not improve the glycosylation yield as well (Table 24, entry 6).

In order to improve the overall yield of 20, it was envisioned that treating the dehydration product 14 with benzyl alcohol using A15 could lead to the formation of 20 (Scheme 118).

However, no transformation of 14 was detected by GC.

Scheme 118. Ring-opening of dehydration product.

Therefore, we selected the glycosylation conditions [A15 (10 wt%), solvent-free, room temperature, overnight] as the method for further applications.

2.4 Scope with different fatty alcohols.

The glycosylation method was applied to fatty alcohols in order to develop bio-based surfactants (Figure 50). with 61 and 50% yield, respectively (Figure 50). Less-polar alcohols 1-butanol, 1-pentanol and 1-heptanol gave the corresponding glycosylation product 23, 24 and 25 with 21, 17 and 17% yield, respectively (Figure 50). As the carbon chain of fatty alcohol increased, the yield of glycosylation product decreased. Furthermore, the glycosylation of long chain alcohols 1-nonanol and 1-dodecanol were also investigated, but it did not give pure product effectively due to the low reactivity and the similar polarity with the dehydration product (Figure 50, 26 and 27).

Next, branched fatty alcohols was also investigated for the glycosylation under the same conditions. The glycosylation reactions for branched fatty alcohols were carried out in anhydrous THF instead of solvent-free conditions due to the poor solubility of these systems.

The glycosylation of 2-propanol, 2-butanol and 2-pentanol all gave no conversion towards the desired O-glycoside product, while no formation of dehydration product was obtained as well (Figure 51, 28, 29 and 30). When the glycosylation was carried out with 3-phenylpropan-1-ol, the corresponding O-glycoside product 31 was not obtained as well. Moreover, the scale up reaction of glycosylation for benzyl alcohol gave 49% yield on 900-mg scale. In conclusion, this glycosylation method of -diglycerose with fatty alcohols gave moderate catalytic performance to form the corresponding O-glycoside surfactants. However, the glycosylation with long-chain alcohol is not working well, which prompted the consideration of other procedures.

Chapter 4. Gluconolactone-based surfactants.

1 Introduction.

With the increasing awareness of environmental protection, the development of new surfactants obtained from renewable resources instead of petroleum-based raw materials has become a new research focus. 9

Sodium lauryl sulfate (SLS) and sodium laureth sulfate (SLES) are the main ingredients of commercially available toiletries due to their excellent degreasing ability and low price (Figure 52). However, the presence of sulfate is skin irritant that is limiting its further development.

Sodium lauryl glucose carboxylate is an alternative to SLS and SLES because most of its constituents are of natural origin, this product has an excellent foaming and degreasing capacity (Figure 52). Moreover, compared with other surfactants, such as alkyl poly-glycosides (APG), sodium lauryl glucose carboxylate exhibits better tensioactive properties and higher solubility in water and is not sensitive to the presence of calcium and magnesium ions in hard water. and other personal care products. However, sodium lauryl glucose carboxylate is produced from alkyl poly glycoside (APG) which is expensive. Therefore, other substrates were considered to take into account economy, non-irritating and excellent surfactant performance.

In this context, we were looking for synthetic pathways of surfactants with molecules of similar structures, namely a hydrophobic part, a second nonionic but hydrophilic part and a third with an ionic polar head (Figure 53). In this context, a potential substitute for sodium lauryl glucose carboxylate could be proposed from gluconolactone via 4 synthetic steps (Scheme 119).

Scheme 119. Synthetic route to gluconolactone-based surfactants.

First, reaction of an aldehyde with gluconolactone to form the acetal-based surfactants that was already reported. Then, hydrogenolysis of the acetals would form ether-based surfactants. Next, methylation and saponification would form the desired surfactant substitute for sodium lauryl glucose carboxylate (Scheme 119). All these conditions were planned to carried out under economic conditions.

1.1 Literature about gluconolactone.

1.1.1 Production of gluconolactone.

Naturally occurring gluconolactone can be found in glucose-rich foods such as honey and fruits. Generally, gluconolactone can be produced via two pathways. First, enzyme catalysis is the major pathway for the production of gluconolactone. It was reported that glucose oxidase 325,326,327 and Zymomonas mobilis 328 can effectively catalyse the reaction to produce gluconolactone (Scheme 120, a). Considering that gluconolactone is a cheap and environmentally-friendly precursor for the synthesis of surfactants, other procedure was also taking into account for developing new eco-friendly surfactants.

2 Results and discussions.

Inspired by the above work, the synthesis of gluconolactone based ether surfactants was first carried out to provide bio-based surfactants with better stability than acetals (Scheme 124). It could be seen as an alternative to sorbitan-ethers that were previously reported in our group. 171 Scheme 124. First step of the project to gluconolactone-based surfactants.

The synthetic route involves two steps. First, gluconolactone-based acetals were synthesized via acetalization from gluconolactone and fatty aldehydes (Scheme 124, a). Then, hydrogenolysis was performed to produce the desired ether surfactants (Scheme 124, b).

2.1 Acetalization. Compared with the reported method, a similar result for the acetalization reaction was obtained. Therefore, the hydrogenolysis step was carried out subsequently. Then, the influence of the acetal concentration was considered. When the reaction was carried out using 0. Furthermore, in order to simplify the analysis of the optimization reactions, a GC method was used for the optimization. First, considering that high hydrogen pressure could lead to over-hydrogenolysis and is potentially dangerous, the hydrogenolysis reaction was carried out under 30 bar of H2, and the crude product was analyzed by GC to give 37 with 17% yield and 97% conversion (Table 27, entry 1). Then, a solution of 34 in CPME was dried over MgSO4 to ensure the reaction system is water-free. Under these conditions, a slight progress was obtained to give 37 with 22% yield (Table 27, entry 1, result in brackets). Therefore, in the following optimization, the raw materials were pretreated with MgSO4 before reaction. Next, the temperature was increased from 130 to 170 o C that led to 33 and 41% yield (Table 27, entries 2-3). Furthermore, when the hydrogen pressure was decreased to 20 bar, it did not lead to a better result (Table 27, entry 4). Finally, the catalyst loading was decreased to 2.5 mol% which still did not benefit the hydrogenolysis yield ( The conversions of 34 and yields of 37 were determined by GC, the sample was derivatized before injection with 1,3,5-trimethoxybenzene as an internal standard. c 34 dissolved in anhydrous CPME was dried over MgSO4 before reaction.

In conclusion, two gluconolactone-based ether surfactant 37 and 42 (the hydrogenolysis product of 36) have been prepared. However, the hydrogenolysis of products 32, 33 and 35

has not been performed yet to develop the corresponding ether surfactants. Eventually, the methylation and saponification of the ether surfactants to form the desired surfactants were not carried out as well. Next, further optimization of the hydrogenolysis procedure and the synthesis of gluconolactone-based surfactants will be continued in our group

General conclusion

During my three-year Ph. D. work, we have developed new bio-based surfactants from diglycerol and gluconolactone (Scheme 126).

Scheme 126. General routes for the synthesis of two bio-based surfactants.

First, we have developed a method to selectively oxidize -diglycerol and diglycerol towards the corresponding diglycerose (Scheme 127). The study was started from -diglycerol, using Pd-3 as a catalyst in HFIP at 50 o C for 18 h, in the presence of oxygen (3 bar) and styrene to give -diglycerose with 93% yield. Then, this oxidation procedure was applied to -diglycerol which led to the formation of an intramolecular dehydration product (76%) as the major product while 4% of the desired -diglycerose was obtained. Next, when the oxygen pressure was decreased to 1 bar, the desired -diglycerose was obtained with 51% yield. Furthermore, the kinetic study of the oxidation was carried out to explore the influence of the different isomers (-diglycerol and -diglycerol) and oxygen pressure. It was proved that the oxidation rate of -diglycerol is faster than -diglycerol, and the increased oxygen pressure can promote the oxidation process. An intramolecular dehydration product was formed during the oxidation process of -diglycerol while no dehydration occured for -diglycerol, which was caused by their different structures. In addition, -diglycerose was also used as a novel building block for some chemical transformations, such as benzoylation. The product 2 was obtained as a white solid with 56% yield (33.9 g). Spectroscopic data was identical to previously published data. 273 b) In a 250-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser, -diglycerol dicarbonate 2 (10 g, 45.9 mmol), methanol (50 mL) and H2O (50 mL)

were placed followed by K2CO3 (2 g, 14.5 mmol, 50 mL, 0.32 equiv). The reaction mixture was heated at reflux (90 o C) for 2 h. The mixture was evaporated to dryness. The residue was dissolved in cold methanol (100 mL). K2CO3 was filtrated off and then the solution was evaporated to dryness. The product -1 was obtained as a light viscous oil with 84% yield (6.2g). a) In a 250-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser, epichlorohydrin (23 g, 0.25 mol,) was added dropwise to a mixture of benzyl alcohol (108 g, 1.0 mol, 104 mL, 4 equiv), tetra-n-butylammonium iodide (18.45 g, 0.05 mol, 0.2 equiv), KOH (42 g, 0.75 mol, 3 equiv) and water (3 mL). The mixture was then stirred at 80 °C for 40 h. After cooling, the reaction mixture was partitioned in dichloromethane (150 mL) and water (150 mL). The organic phase was washed with water for three times and then dried with MgSO4. Then, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (cyclohexane/EtOAc, 3 : 1, v/v) to give 9 as a pale yellow oil with 73% yield (68 g).

b) A solution of NaOH (5N, 60 mL) was added to a solution of solketal (5 g, 37.6 mmol) in THF (40 mL). The mixture was cooled to 0 o C (ice bath). Then, a solution of tosyl chloride (10.8 g, 56.7 mmol, 1.5 equiv) in THF (33 mL) was added dropwise. The mixture was stirred overnight at room temperature. The solvent was evaporated to dryness. Then, water was added and the mixture was extracted with ether (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated under reduced pressure to give 10 as a white solid with 92% yield (9.9 g).

c) In a 100-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser, compound 9 (2.923 g, 10.7 mmol) was added dropwise into the solution of NaH (60% in mineral oil, 514 mg, 21.4 mmol, 2 equiv) in DMF (29.3 mL) at room temperature. The mixture was stirred for 30 min and tetrabutylammonium bromide (691 mg, 2.14 mmol, 0.2 equiv) was added and the mixture was stirred for additional 30 min. Then compound 10 (3.68 mg, 12.9 mmol, 1.2 equiv) was added in one portion. The mixture was heated at 100 °C for 26 h. Then, water (120 mL) was added and extracted with dichloromethane (120 mL). The organic layer was washed with NaHCO3 solution twice (2*80 mL) and dry with MgSO4. Then, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (cyclohexane/EtOAc, 3: 1, v/v) to give 11 as a pale-yellow oil with 56% yield (2.3 g).

d) In a 30-mL round bottom flask equipped with a magnetic stirrer and a reflux condenser, compound 11 (654 mg, 1.7 mmol), MeOH (10 mL) and [Pd/C (Palladium 10% on activated wood carbon, 65.4 mg, 0.17 mmol, 10 wt %)] was added. In the presence of 1 atm of hydrogen balloon the mixture was stirred for 24 h at room temperature. Then, after filtration to remove the catalyst, the solvent was removed under reduced pressure (150 mbar) to give -1 as a pale-yellow oil with 97% yield (272 mg).

1.3 Procedure for the preparation of palladium-based catalyst.

1.3.1 Procedure for the preparation of Pd-1.

Pd(OAc)2 (10 mg, 0.045 mmol) and neocuproine (9.36 mg, 0.045 mmol) were used as a mixture to give catalyst Pd-1.

1.3.2 Procedure for the preparation of Pd-2. 258,259 In a 500-mL round bottom flask equipped with a magnetic stirrer, a solution of neocuproine (2.50 g, 11 mmol) in anhydrous CH2Cl2 (40 mL) was added to a solution of 1.4 General oxidation and dehydration procedure.

1.4.1 Mono-oxidation of -diglycerol.

In a 30-mL round bottom flask equipped with a magnetic stirrer, pure diglycerol -1

(150 mg, 0.9 mmol) dissolved in HFIP (11 mL), Pd-3 (12 mg, 2.5 mol%) and styrene (472 mg, 5 equiv). The reactor was purged twice with O2 and was charged with 3 bar of oxygen. The reactor was heated at 50 °C for 18 h. After cooling to room temperature, the O2 pressure was released, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (CH2Cl2/MeOH, 10: 1, v/v) to give -diglycerose 4.

1.4.2 Bis-oxidation of -diglycerol -1.

In a 30 mL reactor equipped with a magnetic stirrer, -1 (750 mg 4.5 mmol) dissolved in acetonitrile/water (7:1, v/v, 5.5 mL) and Pd-3 (24 mg, 10 mol%) was added. The reactor was heated at 70 °C for 24 h. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (CH2Cl2/MeOH, 10: 1, v/v) to give mono-oxidation product -diglycerose 4 with 27% yield (199 mg) and bisoxidation product 6 with 11% yield (80 mg).

1.4.3 Oxidation of -diglycerol.

In a 100 mL flask equipped with a magnetic stirrer, -1 (750 mg 4.5 mmol) was dissolved in HFIP (55 mL) and Pd-3 (60 mg, 2.5 mol%) and styrene (2.36 g, 5 equiv) were added.

The flask was equipped with 1 balloon (1 atm) of oxygen. The flask was heated at 50 °C for 18 h. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (CH2Cl2/MeOH, 10: 1, v/v) to give 12 with 51% yield (377 mg) and 13 with 10% yield (66 mg).

1.4.4 Oxidation of erythritol.

In a 100-mL flask equipped with a magnetic stirrer, meso-or L-erythriol (549 mg 4.5 mmol) was dissolved in HFIP (55 mL) and Pd-3 (60 mg, 10 mol%) and styrene (2.36 g, 5 equiv) were added. The flask was equipped with 1 balloon (1 atm) of oxygen. The flask was heated at 50 °C for 18 h. After cooling to room temperature, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (CH2Cl2/MeOH, 10: 1, v/v) to give 7 and 8 with 92 and 86% yield, respectively (497 mg, 465 mg).

1.4.5 Dehydration of -diglycerose for the synthesis of 14.

In a 50-mL round bottom flask equipped with a magnetic stirrer, -diglycerose 4 (200 mg, 5.5 mmol) was dissolved in dichloromethane (10 mL) at room temperature for 3 h. Then the catalyst was removed by filtration and the filtrate was collected. The filtrate was dried with Na2SO4. Then, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (cyclohexane/EtOAc, 1: 3, v/v) to give compound 14 as a colorless oil with 48% yield (84 mg).

1.5 Procedure for the benzoylation of -diglycerol.

a) In a 50-mL round bottom flask equipped with a magnetic stirrer, -diglycerose 4 (900 mg, 5.5 mmol) in pyridine (5 mL) was added dropwise into a cooled (-10°C) mixture of pyridine (5 mL), chloroform (10 mL) and benzoyl chloride (3.08 g, 22 mmol, 4 equiv) followed by warming to room temperature for 3 h. Then, water (30 mL) was added and the mixture was extracted with dichloromethane (30 mL). The organic layer was washed with NaHCO3 solution twice (80 mL*2) and dried with MgSO4. Then, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (cyclohexane/EtOAc, 3: 1, v/v) to give compound 15 as a colorless oil with 65% yield (1.7 g), compound 16 as a colorless oil with 9% yield (235 mg) and compound 17 as a colorless oil with 3% yield (61 mg).

b) In a 50-mL round bottom flask equipped with a magnetic stirrer, -diglycerose 4 (300 mg, 5.5 mmol) in pyridine (5 mL) was added dropwise into a cooled (-10°C) mixture of pyridine (5 mL), chloroform (10 mL) and 4-bromobenzoyl chloride (4.80 g, 22 mmol, 4 equiv) followed by warming to room temperature for 3 h. Then water (60 mL) was added and extracted with dichloromethane (60 mL). The organic layer was washed with NaHCO3 solution twice (60 mL*2) and dried with MgSO4. Then, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (cyclohexane/EtOAc, 3: 1, v/v) to give compound 18 as a white solid with 45% yield (583 mg), and compound 19 as a white solid with 6% yield (78 mg).

1.6 Procedure for the glycosylation of -diglycerol.

1.7 GC method.

Gas chromatography (GC) analysis for the starting material (benzyl alcohol) and glycosylation products was carried out on a Shimadzu GC (GC-2025) apparatus using a ZB-5-MS capillary column (30 m, 0.25 mm i.d., 0.25 μm film thickness). The carrier gas was nitrogen with 1.19 mL/min flow rate, the injection mode is split with a ratio of 1:40. The column temperature was initially at 100°C for 2 min, and then was gradually increased to 280°C (36°C/min) and the temperature was kept at 280°C for 5 min. The injector and FID temperature were respectively set at 250°C and 280°C.

1.7.1 Derivatization procedure.

The injection sample of starting material and oxidation products were derivatized via a reported procedure. 176 The crude mixtures were silylated as below. First, 1.5 mL of tetrahydrofuran was added into the small flask with the crude mixture (0.26 mmol), Then, the derivatization solvent system was prepared with 1 mL of pyridine, 0.2 mL of bis(trimethylsilyl)amine and 0.1 mL of trimethylsilyl chloride. Next, 1.5 mL of the derivatization solution was added into the flask. After that, the solution was stirred intensely at 70°C for 15 min and then it was cooled down to room temperature for analysis. Finally, 10 mL of THF was added into the solution to dilute the product, and methyl oleate (0.26 mmol) was added as an internal standard. Before injection, the sample was filtrated by a syringe filter (PTFE; 0.2 µm).

1.8 Characterization of oxidation products. 1H, CqCH2OH), 3.38 (d, J = 11.6 Hz, 1H, CqCH2OH). 13 HSQC of 18 (CDCl3, 500 MHz) Zoom 3.4-5.2ppm, 62- hexafluoro-2-propanol and sodium borohydride were purchased from TCI, Sigma-Aldrich or Alfa-Aesar.

Reactions were monitored by thin layer chromatography (TLC) using aluminium backed silica gel (60 F254, 20 cm* 20 cm). Phosphomolybdic acid solution was used as chromogenic reagent for TLC detection. The purification was carried out via column chromatography performed with silica 60 M (0.04-0.063 mm). 1 H and 13 C NMR experiments were carried out on a Brüker DRX 300 or Brüker ALS 300 in DMSO-d6 CD3OD or CDCl3. Electrospray ionization (ESI), high resolution mass spectra (HRMS) were carried out on a MicroTOFQ-II, Bruker Daltonics spectrometer instrument using standard conditions (ESI, 70 eV).

GC method.

Gas chromatography (GC) analysis for the starting material (benzyl alcohol) and glycosylation products was carried out on a Shimadzu GC (GC-2025) apparatus using a ZB-5-MS capillary column (30 m, 0.25 mm i.d., 0.25 μm film thickness). The carrier gas was nitrogen with 1.19 mL/min flow rate, the injection mode is split with a ratio of 1:40. The column temperature was initially at 100°C for 2 min, and then was gradually increased to 280°C (36°C/min) and the temperature was kept at 280°C for 5 min. The injector and FID temperature were respectively set at 250°C and 280°C.

Derivatization procedure.

The injection sample of starting material and glycosylation products were derivatized via a reported procedure. 176 The crude mixtures were silylated as below. First, 1.5 mL of tetrahydrofuran was added into the small flask with the crude mixture (0.17 mmol), Then, the derivatization solvent system was prepared with 1 mL of pyridine, 0.2 mL of 13 C NMR of 20 (75 MHz, CD3OD, zoom 0-140 ppm). All reagents and solvents were commercially available and was used as received without further purification unless otherwise noted. Valeraldehyde, heptanal, octanal, nonanal, dodecanal, anhydrous cyclopentyl methyl ether (CPME), 5% or 10% Palladium on activated wood carbon were purchased from TCI, Sigma-Aldrich or Alfa-Aesar.

Reactions were monitored by thin layer chromatography (TLC) using aluminium backed silica gel (60 F254, 20 cm* 20 cm). Phosphomolybdic acid solution was used as chromogenic reagent for TLC detection. The purification was carried out via column chromatography performed with silica 60 M (0.04-0.063 mm). 1 H and 13 C NMR experiments were carried out on a Brüker DRX 300 or Brüker ALS 300 in DMSO-d6, CD3OD, acetone-d6 or CDCl3. Electrospray ionization (ESI), high resolution mass spectra (HRMS) were carried out on a MicroTOFQ-II, Bruker Daltonics spectrometer instrument using standard conditions (ESI, 70 eV).

GC method.

Gas chromatography (GC) analysis for the starting material (benzyl alcohol) and glycosylation products was carried out on a Shimadzu GC (GC-2025) apparatus using a ZB-5-MS capillary column (30 m, 0.25 mm i.d., 0.25 μm film thickness). The carrier gas was nitrogen with 1.19 mL/min flow rate, the injection mode is split with a ratio of 1:40. The column temperature was initially at 100°C for 2 min, and then was gradually increased to 220°C (15°C/min) and the temperature was kept at 220°C for 4 min. Then, the column temperature was gradually increased to 280°C (15°C/min) and the temperature was kept at 280°C for 2 min.

The injector and FID temperature were respectively set at 250°C and 280°C.

Derivatization procedure.

The injection sample of starting material and hydrogenolysis products were derivatized via a reported procedure. 176 The crude mixtures were silylated as below. First, 1.5 mL of tetrahydrofuran was added into the small flask with the crude mixture (0.26 mmol), Then, the derivatization solvent system was prepared with 1 mL of pyridine, 0.2 mL of bis(trimethylsilyl)amine and 0.1 mL of trimethylsilyl chloride. Next, 1.5 mL of the derivatization solution was added into the flask. After that, the solution was stirred intensely at 70°C for 15 min and then it was cooled down to room temperature for analysis. Finally, 10 mL of THF was added into the solution to dilute the product, and 1,3,5-trimethoxybenzene (0.26 mmol) was added as an internal standard. Before injection, the sample was filtrated by a syringe filter (PTFE; 0.2 µm). In a-500 mL reactor equipped with a magnetic stirrer and a dean-stark apparatus, gluconolactone (11.4 g, 64 mmol, 1.2 eq) and octanal (6.8 g, 53 mmol, 1 eq) was dissolved in the mixture of cyclohexane (180 mL) and N,N-Dimethylformamide (64 mL), then methanesulfonic acid (1.006 g, 0.68 mL 64 mmol, 20 mol%) was added into the reaction solution. The reactor was heated at 90 °C for 6 h. After cooling to room temperature, triethylamine (1.5 mL, 0.2 eq) was added into the solution to neutralize the acid. The two phases were then separated using a separatory funnel and the DMF phase was collected. 150 mL H2O was added into DMF phase which led to the formation of a white precipitate. The organic phase was extracted with ether (4×120 mL). Then the solution was washed with saturated NaCl solution (4×120 mL) to remove the traces of DMF. Then the crude product was dried with MgSO4 and purified by column chromatography (Cyclohexane/Ethyl acetate, 3:

1, v/v) to give 34 with 71% yield (10.8 g).

3.4 General hydrogenolysis procedure.

In a 30-mL round bottom flask equipped with a magnetic stirrer, acetalization product 34 (1.44g, 5 mmol) dissolved in CPME anhydrous (12.5 mL), 5% Pd/C (535 mg, 5 mol%). The reactor was purged twice with H2 and was charged with 40 bar of hydrogen. The reactor was heated at 130 °C for 24 h. After cooling to room temperature, the H2 pressure was released, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (Cyclohexane/Ethyl acetate, 3: 1, v/v) to give 37 with 33% yield (470 mg).

3.5 Characterization of acetalization product.

32, a white viscous liquid. 1 H NMR (300 MHz, acetone-d6) δH for all isomers: 0.89 (t, J = 7.0 Hz, 3H), 1.33-1.42 (m, 2CH2, 4H), 1.55-1.67 (m, CHCH2, 2H), 3.72-4.87(m, sorbitan protons,

   .................................................................. 1.3 Procedure for the preparation of palladium-based catalyst. ................................................................ 1.3.1 Procedure for the preparation of Pd-1. .......................................................................................... 1.3.2 Procedure for the preparation of Pd-2. 258,259 ................................................................................. 1.3.3 Procedure for the preparation of Pd-3. 271 ...................................................................................... 1.4 General oxidation and dehydration procedure. .................................................................................... 1.4.1 Mono-oxidation of -diglycerol. ................................................................................................. 1.4.2 Bis-oxidation of -diglycerol -1. ............................................................................................ 1.4.3 Oxidation of -diglycerol. ............................................................................................................ 1.4.4 Oxidation of erythritol. ................................................................................................................... 1.4.5 Dehydration of -diglycerose for the synthesis of 14. ............................................................... 1.5 Procedure for the benzoylation of -diglycerol. ............................................................................... 1.6 Procedure for the glycosylation of -diglycerol. ............................................................................... 1.7 GC method. ............................................................................................................................................ 1.7.1 Derivatization procedure. ............................................................................................................... 1.8 Characterization of oxidation products. ................................................................................................ 1.9 Characterization of other products. ...................................................................................................... 1.10 Structure analysis of oxidation products. ............................................................................................ 2 Experimental part for chapter 3. ..................................................................................................................

3. 3

 3 General acetalization procedure. .......................................................................................................... 3.4 General hydrogenolysis procedure. ...................................................................................................... 3.5 Characterization of acetalization product. ............................................................................................ 3.6 Characterization of hydrogenolysis product. ........................................................................................

5

 5

Figure 2 .

 2 Figure 2. General production routes for bio-based surfactants.

Figure 3 .

 3 Figure 3. Amphiphilic surfactant.

Figure 4 .

 4 Figure 4. Structure of amphiphilic surfactants.

Figure 5 .

 5 Figure 5. Surfactant properties influenced by HLB.

21

 21

Figure 6 .

 6 Figure 6. Classification of surfactants.

Figure 7 .

 7 Figure 7. Examples of commercial anionic surfactants.

Figure 8 .

 8 Figure 8. Examples of commercial cationic surfactants.

Figure 9 .

 9 Figure 9. Examples of commercial zwitterionic surfactant.

Figure 10 .

 10 Figure 10. Surfactants market in personal care product, 2015. 31

Figure 12 .

 12 Figure 12. Non-ionic surfactants with different linkages.

Figure 13 .

 13 Figure 13. Examples of commercial ester-based surfactants.

Figure 14 .

 14 Figure 14. Examples of commercial ethoxylate-based ester surfactants.

Figure 15 .

 15 Figure 15. Source of the feedstocks for the production of carbohydrates.

Figure 17 .

 17 Figure 17. Industrial production of APGs.

  Scheme 32. The synthesis of glycerol-based ether through Williamson synthesis.

Scheme 33 .

 33 Scheme 33. Synthesis of glycerol-based ether by reductive alkylation with aldehydes.

  Scheme 36. Synthesis of glycerol-based ether by reductive alkylation with esters.

Figure 19 .

 19 Figure 19. Successful applications of C-glycoside-based products.

  Scheme 48. C-C bond-based surfactants by the HWE reaction.

  190 B. Zhu, N. Duguet, G.-R. Chen, M. Lemaire, ACS Sustain.Chem. Eng., 2018, 6, 11695-11703.

Figure 21 .

 21 Figure 21. Similar chemistry for diglycerol-based surfactants with C-C bond.

Figure 22 .

 22 Figure 22. Surfactants market share and industrial applications.

  , b). Since C-C bond is a robust linkage for surfactants, many efforts have been devoted by our group to develop dihydroxyacetone (DHA)-based and fructose-based surfactants with C-C bond linkage with excellent surfactant performance (Figure 23, c and d).

Figure 23 .

 23 Figure 23. Surfactant stability and market demands, and examples of C-C bond-based surfactants.

Figure 24 .

 24 Figure 24. Diglycerol-based surfactants.

Scheme 60 .

 60 Scheme 60. Synthesis of dihydroxyacetone via electrocatalytic oxidation.

Figure 25 .

 25 Figure 25. Palladium-based catalysts.

  Scheme 78. Selective oxidation of fatty 1,2-diols.

  subsequently form the peroxyl intermediate B. C is formed from B under hydrogen atom donor condition, which is confirmed as a key intermediate leading to the formation of inactive intermediate D. Therefore, in order to inhibit this degradation pathway, the group of Waymouth found that adding phenol additives as hydrogen donors significantly increased the oxidation efficiency (Scheme 79, b).

Figure 27 .

 27 Figure 27. 13 C NMR (DMSO-d6, 75 MHz) spectrum of diglycerol isomeric mixture.

Figure 28 .

 28 Figure 28. Preparation of Pd-1.

Figure 30 .

 30 Figure 30. Effect of the temperature for the oxidation of diglycerol. Reaction conditions: -1 (0.45 mmol), Pd-3 (10 mol%), O2 (1 bar), CH3CN/H2O (v/v 7:1, 5.5 mL), 30-80 o C, 24 h. Yields are isolated yields.

Figure 33 .

 33 Figure 33. Procedure for the post-reaction treatment.

a 1 H

 1 Reaction condition: -1 (0.45 mmol), Pd-3, O2 (3 bar), HFIP (5.5 mL), reaction was carried out at 50°C for 2 h. b The conversions, yields and selectivity for mono-oxidation product were determined by NMR with mesitylene as an internal standard. c No addition of styrene d Isolated yield. e Reaction condition: diglycerol (2.25 mmol), Pd-3 (0.05625 mml, 2.5 mmol%), O2 (3 bar), HFIP (5.5 mL), Styrene (11.25 mmol, 5 equiv), 50°C.

99 a

 99 Reaction conditions: -diglycerol (0.45 mmol), Pd-X (2.5 mmol%), O2 (3 bar), HFIP (5.5 mL), reaction was carried out at 50°C for 2 h.b The conversions, b yields and b selectivity for mono-oxidation product were determined by1 H NMR with mesitylene as an internal standard. c The reaction was carried out with 1 mol% Mn II (Me2EBC)Cl2 and H2O2 as an oxidant at 30 o C and pH=3 for 18 h.d The reaction was carried out with 20 mol% Ni-Al2O3-SiO2 at 220 o C under solvent-free conditions for 24 h.

Figure 34 .

 34 Figure 34. NOESY of 12 (for the major diastereoisomer) (CD3OD, 500 MHz), zoom 3.25-4.00 ppm.

Figure 35 .

 35 Figure 35. Oxidation progress of diglycerol via GC method determined by conversion of diglycerol and yield towards diglycerose. Oxidation conditions: diglycerol (0.45 mmol), Pd-3 (2.5 mol%), O2 (1 bar), styrene (2.25 mmol, 5 eq), HFIP (5.5 mL), 50°C. The conversions and yields were obtained by GC, the sample was treated with derivatization before injection with methyl oleate as an internal standard.

Figure 36 .

 36 Figure 36. Oxidation progress of -diglycerol with 1 or 3 bar O2 via GC method determined by conversion of diglycerol and yield towards diglycerose. Oxidation conditions: -diglycerol (0.45 mmol), Pd-3 (2.5 mol%), O2 (1 or 3 bar), styrene (2.25 mmol, 5 eq), HFIP (5.5 mL), 50°C. The conversions and yields were obtained by GC, the sample was treated with derivatization before injection with methyl oleate as internal standard.

  Scheme 97. Oxidation of crude diglycerol.

Figure 37 .

 37 Figure37. Oxidation progress of crude diglycerol of 1 bar of O2. Oxidation conditions: crude diglycerol (80% -form, 20% -form, 0.45 mmol), Pd-3 (2.5 mol%), O2 (1 bar), HFIP (5.5 mL), styrene (2.25 mmol, 5 eq), 50°C. The conversions and yields were obtained by GC, the sample was treated with derivatization before injection with methyl oleate as an internal standard.

Figure 38 .

 38 Figure 38. Proposed mechanism of dehydration reaction for -diglycerose and -diglycerose.

Figure 39 . 1 H

 391 Figure 39. 1 H NMR of 18 (CDCl3, 500 MHz) Zoom 3.4-5.2 ppm.

Figure 40 .

 40 Figure 40. NOESY spectrum of 18 (CDCl3, 500 MHz, Zoom 3.4-5.2ppm).

Figure 41 .

 41 Figure 41. Diglycerose-based surfactants.

Figure 42 .

 42 Figure 42. Possible esterification products of -diglycerose.

Figure 43 .

 43 Figure 43. Structure of commercial diglycerol polyisostearates.

Figure 44 .

 44 Figure 44. Measurements of antifogging properties for different additives by contact angle.

(

  50 bar), 120 o C for 16 h to give the corresponding diglycerol ethers with 41 and 62% yield, respectively (Scheme 108, b).Moreover, fatty acids were also used for the synthesis of diglycerol-based ether surfactants.155 Diglycerol was treated with fatty acids using 5% Pd/C (1 mol%), Amberlyst 35 (10 wt%) and H2 (50 bar) at 120 o C for 16 h to form the corresponding diglycerol ethers with 38-67% yield (Scheme 108, c). This synthetic procedure by direct reductive alkylation provided an interesting route for the production of bio-based surfactants.

Figure 46 .

 46 Figure 46. Glycosylation of -diglycerose and fatty alcohols.

a

  Reaction condition: -diglycerose (0.183 mmol), benzyl alcohol (10 eq), acid, room temperature, overnight.b The conversions, b yields of 20 and 14, and b the ratio of 20 and 14 were determined by GC with methyl oleate as an internal standard, the sample was derivatized before injection.

Figure 48 .

 48 Figure 48. NOESY spectrum of 20 (DMSO-d6, 300 MHz, zoom 3.3-4.9 ppm, full spectrums see experimental section).

2

 2 Analysis of the glycosylation by-product.

a

  Reaction condition: -diglycerose (0.183 mmol), benzyl alcohol, Amberlyst 15 (10 wt%), room temperature, overnight. b The conversions, b yields of 20 and 14, b the ratio of 20 and 14 were determined by GC with methyl oleate as an internal standard, the sample was derivatized before injection.

a

  Reaction condition: -diglycerose (0.183 mmol), benzyl alcohol (20 eq), Amberlyst 15, room temperature, overnight. b The conversions, b yields of 20 and 14, b the ratio of 20 and 14 were determined by GC with methyl oleate as an internal standard, the sample was derivatized before injection. c The reaction was carried out at 30 o C.

  The substrate scope was first carried out with linear fatty alcohols under the optimized conditions [Amberlyst 15 acid, solvent-free, room temperature, overnight]. Methanol and ethanol were first investigated and gave the corresponding glycosylation products 21 and 22

Figure 50 .

 50 Figure 50. Scope of glycosylation products with linear fatty alcohols.

Figure 51 .

 51 Figure 51. Scope of glycosylation products with branched and aromatic alcohols.

Figure 53

 53 Figure 53 Surfactants with both nonionic hydrophilic chain and polar ionic head.

4

  , a pale-yellow oil.1 H NMR(300 MHz, CD3OD): δ (cyclic form) = 4.16 (dtd, J = 10.9, 4.5, 2.9 Hz, 1H, CH), 3.80 (dd, J = 11.4, 2.8 Hz, 1H, CHCH2O), 3.66 (d, J = 11.5 Hz, 1H, Cq-CH2O), 3.55(d, J = 11.6 Hz, 1H, Cq-CH2O), 3.55 (d, J = 4.6 Hz, 2H, CHCH2OH),3.46 (d, J = 11.6 Hz, 2H, CqCH2OH), 3.38 (d, J = 11.2 Hz, 1H, CHCH2O). δ (open form visible peaks) = 4.3500 (s, 2H, Cq-CH2OH), 4.3000 (s, 2H, Cq-CH2O).

7,

  A light viscous oil.1 H NMR(300 MHz, CD3OD): δ = 4.46(d, J = 7.4 Hz, 2 H), 4.25 (t, J = 4.2 Hz, 1H), 3.75 (dd, J = 4.1, 3.3 Hz, 2H).12, a light viscous oil.1 H NMR (500 MHz, CD3OD): δ (major diastereoisomer) = 3.91 (t, J = 10.9 Hz, 1H, CH2), 3.76(d, J = 11.6 Hz, 1H, CH2), 3.68 (d, J = 11.6 Hz, 1H, CH2), 3.64-3.61 (m, 1 H, CH), 3.59 (d, J = 10.6 Hz, 1H, CH2), 3.55 (dd, J = 13.2, 6.9 Hz, 2H, CH2OH),3.43 (d, J = 11.7 Hz,

14 ,

 14 a light viscous oil.1 H NMR(300 MHz, CD3OD): δ = 4.50 (dd, J = 4.2, 1.0 Hz, 1H, CH), 4.22(d, J = 7.1 Hz, 1H, CH2), 3.88 -3.80 (m, 2H, CH2), 3.67 -3.65 (m, 1H, CH2), 3.64 -3.61 (m, 1H, CH2), 3.60 -3.54 (m, 3H, CH2).1 H NMR (300 MHz, CD3OD): δ = 106.64 (Cq), 76.19 (CH), 70.90 (CH2), 69.93 (CH2), 69.04 (CH2), 63.53 (CH2OH). HRMS (ESI + ): calcd. for C6H10NaO4 [M + Na] + , 169.0471, found 169.0471. 1.9 Characterization of other products. -1, a light viscous oil. 1 H NMR (300 MHz, CD3OD): δ = 3.81-3.74 (m, 2H, CH2CHCH2), 3.61-3.44 (m, 8H, OCH2). 13 C NMR (75 MHz, CD3OD): δ = 73.83 (OCH2), 72.20 (CH), 64.31 (CH2OH). 75.27 (CO-CH2-O), 70.94 (CH), 70.39 (O-CH2-CH), 67.28 (O-CH2-CO), 63.32(CHCH2O). HRMS (ESI + ): calcd. for C27H21Br3NaO8 [M + Na] + , 732.8679, found 732.8669.

3. 1

 1 General information.

3. 2 . 2 Figure 55 .

 2255 Scheme 131. Calibration curve of acetalization product 34.

3. 2 . 3

 23 Calibration curve and GC chromatogram for the hydrogenolysis product.The calibration curve of hydrogenolysis product 37 was prepared based on concentration and the corresponding GC area. The sample was derivatized before injection with 1,3,5trimethoxybenzene as internal standard. The equation and coefficient of determination R 2 were given below (Scheme 132).

am so appreciated for everything I have now, so, please keep lucky and go ahead! ABBREVIATIONS

  Literature about gluconolactone. .......................................................................................................... 1.1.1 Production of gluconolactone. ....................................................................................................... 1.1.2 Gluconolactone-based surfactants. ................................................................................................ 2 Results and discussions. ............................................................................................................................... 2.1 Acetalization. ......................................................................................................................................... 2.2 Hydrogenolysis. ..................................................................................................................................... General conclusion ......................................................................................................................................... Chapter 5 Experimental section. ..................................................................................................................... 1 Experimental part for chapter 2. ..................................................................................................................

	1.1
	AE	Alcohol ethoxylate		HFIP	1,1,1,3,3,3-
						Hexafluoroisopropanol
	APE	Alkylphenol ethoxylate		HLB	Hydrophilic-lipophilic balance
	APG	Alkyl polyglucoside		HMDS	Hexamethyldisiloxane
	APP	Alkyl polypentosides		HOTf	Triflic acid
	AcCl	Acetyl chloride		HWE	Horner-Wadsworth-Emmons
						reaction
	A15	Amberlyst 15		MEE	Methyl ester ethoxylates
	A35	Amberlyst 35		MsOH	Methanesulfonic acid
	A36	Amberlyst 36		NBS	N-Bromosuccinimide
	BnOH	Benzyl alcohol		PTSA	p-Toluenesulfonic acid
	BF3 . OEt2	boron	trifluoride	diethyl	p-TSCl	Tosyl chloride
		etherate
	CAS	Camphorsulfonic acid		PEF	Polyethoxylated fatty esters
	CBAB	Cocamidopropyl betaine		PEG	Poly ethoxylate glycol
	CMC	Critical micelle concentration	SDBS	Sodium	dodecyl	benzene
						sulfonate
	CPME	Cyclopentyl methyl ether		SDS	Sodium dodecyl sulfate
	CTAB	Cetyltrimethylammonium	SFAEs	Sorbitol fatty acid esters
		bromide
	DAC	Dodecyl ammonium chloride	TBAI	Tetra-n-butylammonium iodide
	DHA	1,3-dihydroxyacetone		TBAB	Tetrabutylammonium bromide
	DMAP	4-Dimethylaminopyridine		TBA	Tetrabutylammonium bromide
	DMF	Dimethyl formamide		TFE	Trifluoroethanol
	DMSO	Dimethyl sulfoxide		THF	Tetrahydrofuran
	ECH	Epichlorohydrine		TMDS	1,1,3,3-tetramethyldisiloxane
	EO	Ethylene oxide		TMSCl	Trimethylsilyl chloride
	5-HMF	5-hydroxymethylfurfural

1.1 General information. ............................................................................................................................. 1.2 Procedure for the preparation of pure diglycerol. ................................................................................ 1.2.1 Procedure to purify -diglycerol. 273 ............................................................................................ 1.2.2 Procedure for the preparation of -diglycerol.

  2.1 General information. ............................................................................................................................. 2.2 GC method. ............................................................................................................................................ 2.2.1 Derivatization procedure. ............................................................................................................... 2.2.2 Calibration curves. .......................................................................................................................... 2.2.3 GC chromatogram of glycosylation product 20. ............................................................................. 2.3 General glycosylation procedure. .......................................................................................................... 2.4 Characterization of glycosylation product............................................................................................. 2.5 Structure analysis of glycosylation products. ........................................................................................ 3 Experimental part for chapter 4. .................................................................................................................. 3.1 General information. .............................................................................................................................

3.2 GC method. ............................................................................................................................................ 3.2.1 Derivatization procedure. ............................................................................................................... 3.2.2 Calibration curve and GC chromatogram for the acetalization product. ....................................... 3.2.3 Calibration curve and GC chromatogram for the hydrogenolysis product. ...................................

8

  Syntheticsurfactants were developed in the middle of the 19 th century, and their increasing use makes them one of the World's largest synthetic chemicals currently produced.

9

In 2019, the global surfactants market size was evaluated to 41.3 billion US dollars and was estimated to 58.5 billion US dollars by 2027 with 5.3% annual growth rate.

Surfactants market in personal care by type, 2015

	Figure 11. Commercial non-ionic surfactants.
			Others
	29% Cationic	7%	Non-ionic 32%
		Anioic
		8%		24%
	Non-ionic	Amphoterics	Anioic	Cationic	Others

32

31 Market Report: Global Surfactant Market, 4th edition, 2016. 32 E. Olkowska, M. Ruman, A. Kowalska, Ż.

Polkowska, Ecol. Chem. Eng. S, 2013, 20, 449-461.

  o C for 5 h via Diels-Alder reaction to form derived polyacid (WFOPA) with 86% yield (Scheme 2, c). Finally, WFOPA was treated with methanol under the condition of ptoluenesulfonic acid at 70 o C for 24 h via esterification to form waste frying oil based

	ethoxylated esters with 96% yield (Scheme 2, d)
	o C for 2 h (Scheme 2, a). Then, WFOA was treated with ethane-1,2-diol under basic conditions
	at 180-200 o C for 10 h to form conjugated acid with 87% yield (CWFOA) (Scheme 2, b). Next,

47,48

Series of ethoxylate-based esters with different structure were produced via the esterification of polyethylene glycol monomethyl ether and fatty acids which were derived from waste frying oils. The synthetic route involves 4 steps (Scheme 2).

First, waste frying oil fatty acid (WFOA) was obtained as a mixture of acids via the hydrolysis of waste frying oil (WFO) by treating with NaOH in ethanol and H2O solution at 70 44 I. Hama, T. Okamoto, H. Nakamura, J. Am.

Oil. Chem. Soc., 1995, 72, 781-784. 45

M.

Renkin, S. Fleurackers, I. Szwach, W. Hreczuch, Tenside Surfact. Deterg., 2005, 42, 280-287. 46

I. Hama, T. Okamoto, E. Hidai,K. Yamada, J. Am.

Oil. Chem. Soc., 1997, 74, 19-24. 47

J. Tan, T. Lu, R. Li, S. Zhang, W. Liu, X. Zhu, J. Zhang, J. Xin, ACS Sustain.

Chem. Eng., 2019, 7, 15957- 15965.

120 Scheme 2. Synthesis routes of ethoxylate-based esters from waste frying oil.

  Scheme 3. General synthesis routes of glycerol-based esters.In order to solve the problem that the homogenous acid-catalyzed transesterification reaction inevitably leads to the product degradation, in 2001,Barrault et al. 55 developed a novel procedure for the transesterification of glycerol and fatty ester by using solid basic catalysts (Scheme 4, a). Glycerol and methyl stearate were treated with series of metal oxides

	(ZnO, MgO, CeO2 and La2O3) at 220 o C for 6 h, MgO gave the best result as mono-glycerol based
	ester was obtained with 80% conversion and 38% selectivity. This procedure provided an
	alternative option for the synthesis of mono-esters instead of traditional homogeneous
	systems.
	Moreover, our group have also reported the synthesis of glycerol-based esters by the
	catalysis of metal oxides and achieved excellent yield (Scheme 4, b).

56

Glycerol and triglycerides or methyl esters were treated with BaO/Al2O3 (5 wt% for methyl esters and 10 wt% for triglycerides) as catalyst in the presence of 1,2,3-TMP (for triglycerides) at high temperatures (120 o C for methyl esters and 200 o C for triglycerides) for 24 or 16 h all give 99% yield for methyl pentanoate-based and triglyceride-based monoglyceride.

Scheme 4. Glycerol-based esters by the catalysis of metal oxides.

55 S. Bancquart, C. Vanhove, Y. Pouilloux, J.

Barrault, Appl. Catal. A-Gen., 2001, 218, 1-11. 56

M. Sutter, W.

Dayoub, E. Métay, Y. Raoul, M. Lemaire, Green Chem., 2013, 15, 786-797.

  -based esters have been produced as surfactants. Lu et al. 99 reported a method for

	In conclusion, ester-based surfactants can be obtained by direct esterification of fatty a). Then, fatty acid methyl ester reacts to amino alcohol to form monoethanolamide which is
	acids and polyols or carbohydrates under acidic conditions. Transesterification reactions from treated with oxirane to form the desired ethoxylate-based amide via ethoxylation (Scheme 17,
	esters and alcohols are another effective method for the synthesis of ester-based surfactants, b and c). These surfactants exhibit excellent performance although only partly biosourced. 102
	especially it solves the problem of poor solubility of some carboxylic acids in the esterification
	process. In addition to chemical synthetic method, another biocatalytic esterification catalyzed
	by lipase was reported. Ester-based surfactants are widely used in industrial production of
	detergents because they are biodegradable and environmentally friendly, thus bringing them
	broad prospects and development potential. 100
	the synthesis of raffinose-based ester. Raffinose was treated with fatty acid methyl esters under basic conditions in DMSO at 65 o C with ultrasonic irradiation to give mono-esters with 1.3.2 Amide-based surfactants.
	15-44% yield as isomer mixtures (Scheme 15). With the increasing awareness of environmental protection, the development of bio-
	based surfactants instead of petroleum-based surfactants gradually gained more and more
	attention. Therefore, the development of surfactants that take into account both functional Scheme 18. Synthetic route of glycerol-based amide surfactants.
	performance and environmental protection has become a new challenge. Encouragingly, it is reported that the addition of amide units can significantly improve the biodegradability of 1.3.2.3 Carbohydrate-based amide surfactants.
	nonionic surfactants, such as ethoxylate-based amide surfactants can be degraded via bio-catalysis. 101 Carbohydrate-based amide surfactants were reported to exhibit good surfactant Scheme 17. Synthetic route of ethoxylate-based amides. properties and were used in the field of detergents and personal care. 105 Especially, N-methyl-
	1.3.2.2 Glycerol-based amide surfactants. D-glucamine based surfactants were used in personal care products, biological and medicine 1.3.2.1 Ethoxylate-based amide surfactants. production fields. 106
	Glycerol-based amide surfactants are composed of amino acid-based esters and glycerol. Ethoxylate-based amide surfactants are used in the commercial market, such as oleyl Generally, they were produced from glycerol and amino acid via esterification. 103 amide ethoxylate and stearyl amide ethoxylate (Scheme 16), which can take into account Glycerolesters of amino acid were treated with fatty acid to form the desired glycerol-based environmental protection strategies and excellent surfactant performance. amides (Scheme 18, a). Glycerol-based amides were treated with lipase via the action of
	protease and lipase to form series of mono-or diglycerol-based amide surfactants with 46-98%
	yield (Scheme 18, b). 104
	Scheme 15. Synthesis of raffinose-based ester. Scheme 16. Examples of commercial ethoxylate-based amide surfactants.
	The synthesis of ethoxylate-based amides involves three steps (Scheme 17). First, fatty
	acid is treated with MeOH under acid conditions to form fatty acid methyl ester (Scheme 17, 96 S. I. Mussatto, I. M. Mancilha, Carbohydr. Polym., 2007, 68, 587-597. 97 N. M. Delzenne, Proc. Nutr. Soc., 2003, 62, 177-182. 98 A. Ogura, A. Kurbangalieva, K. Tanaka, Glycoconj. J., 2014, 31, 273-279. 99 Y. Lu, R. Yan, X. Ma, Y. Wang, Eur. Food Res. Technol., 2013, 237, 237-244. 100 I. J. A. Baker, B. Matthews, H. Suares, I. Krodkiewska, D. N. Furlong, F. Grieser, C. I. Drummond, J. Surfactants Deterg., 2000, 3, 1-11. 101 T. Kida, N. Morishima, A. Masuyama, Y. Nakatsuji, J. Am. Oil. Chem. Soc., 1994, 71, 705-710. 102 B. M. Folmer, K. Holmberg, E. G. Klingskog, K. Bergström, J. Surfactants Deterg., 2001, 4, 175-183. 103 C. Morán, M. R. Infante, P. Clapés, J. Chem. Soc., Perkin Trans. 1, 2001, 2063-2070. 104 M. C. Morán, A. Pinazo, L. Pérez, P. Clapés, M. Angelet, M. T. García, M. P. Vinardell, M. R. Infante, Green Chem., 2004, 6, 233-240.

  -based acetal surfactants were applied in many fields. For example, they were used as biodiesel fuel additives (viscosity improver), 112 biodiesel antifreeze, 113 fragrances 114 and disinfectants 115 .In 2010,Silva et al. 113 reported the synthesis of glycerol-based acetals (Scheme 20).Glycerol and aldehydes (with different chain lengths) were treated with Amberlyst 15 in DMF/DMSO at 70 o C for 2 h to form glycerol-based acetals as isomer mixtures (cis/trans five-

	Figure 16. Examples of natural compounds of N-glucosamine based surfactants. Scheme 19. Synthesis of N-methyl-D-glucamine based surfactants.
	The synthesis of N-methyl glucamine was reported in 1989 (Scheme 19, a) 108 via reductive Balzer et al. 109 reported the synthesis of N-methyl-D-glucamine based ester surfactants
	amination, by using glucose and methylamine as substrates which were treated with hydrogen via chemical catalysis (Scheme 19, b). N-methyl-D-glucamine was treated with fatty-acid
	pressure in the presence of nickel or palladium catalysts. Next, N-methyl-D-glucamine based methyl ester in the presence of K2CO3 at 80 o C to form N-methyl-D-glucamine based ester
	surfactants were synthesized via biocatalytic or chemical routes. surfactants.
	107 In addition to chemical synthesis, biocatalytic route was also reported by Maugard et al.
	(Scheme 19, c). 110 N-methyl glucamine and fatty-acid methyl ester were treated with lipase in
	2-methyl-2-butanol at 90 o C to give the desired product with 80% yield.
	Furthermore, in 2021, Palacios et al. 107 reported a method through the reaction between
	N-methyl glucamine and monoepoxides to form series of amphiphiles (Scheme 19, d). N-
	methyl glucamine was treated with epoxy compounds using absolute ethanol at 70 o C to
	provide the corresponding products as diastereomeric mixtures with 40-80% yield.
	107 C. Sosa-Gil, P. Cintas, J. C. Palacios, Carbohydr. Res., 2021, 502, 108278. 108 D. G. Montet, J.; Servat, F.; Renard, G., Rev. Fr. Corps Gras, 1989, 2, 79-83. 780. 106 T. Kida, K. Yurugi, A. Masuyama, Y. Nakatsuji, D. Ono, T. Takeda, J. Am. Oil Chem. Soc., 1995, 72, 773-CRC Press, 1998. 105 A. Lif, M. Hellsten, Nonionic surfactants (Chapter: Nonionic Surfactants Containing an Amide Group), In addition to monosaccharides, polysaccharides were also used to synthesize amide-

109 H. L. D. Balzer, Nonionic Surfactants: Alkyl Polyglucosides, CRC Press, 2000. 110 T. Maugard, M. Remaud-Simeon, D. Petre, P. Monsan, Tetrahedron, 1997, 53, 7629-7634. based surfactants. Chitosan-based surfactants were used in the field of extraction, pharmaceutic production and biological genetic engineering. 111 1.3.3 Acetal-based surfactants. Glycerolmembered and six-membered acetals, no separation was carried out with the four isomeric mixtures) with 17-85% conversion. The glycerol-based acetals were tested and exhibited excellent anti-freezing performance for biodiesel. However, considering that DMSO and DMF are toxic, other methods should be developed. Scheme 20. Synthesis of glycerol-based acetal surfactants. In 2010, Crotti et al. reported a solvent-free method for the synthesis of glycerol-based acetal surfactants (Scheme 21). 116 Glycerol was treated with octanal or benzaldehyde via iridium-catalyzed acetalization at 60 or 40 o C for 1 h to form the corresponding acetals with 71 and 53% yield, respectively. Scheme 21. Synthesis of glycerol-based acetal with solvent-free condition.

In addition, a zeolite-catalyzed method was also reported by Climent et al. to synthesize glycerol-based acetals (Scheme 22). 114 USY-2 zeolite acid was used to catalyze the acetalization of glycerol with phenylacetaldehyde to produce glycerol-based acetals with 93% conversion, 58% yield of the five-membered cyclic acetal and 35% yield of the six-membered cyclic acetal.

The glycerol-based acetals were proved to be usable as flavoring agent. Scheme 22. Synthesis of glycerol-based acetals via zeolite-catalyzed. Moreover, acidic ionic liquids were reported as effective catalysts to synthesize glycerolbased acetals under mild conditions (Scheme 23). 117 Glycerol and benzaldehyde were treated with reflux conditions, using N-butyl-pyridinium bisulfate ([BPy]HSO4) ionic liquid (20 mol%) at 70 o C for 2 h to form glycerol acetals with almost 100% overall yield. 117 B. Wang, Y. Shen, J. Sun, F. Xu, R. Sun, RSC Adv., 2014, 4, 18917. Scheme 23. Synthesis of glycerol-based acetals via the catalysis of acid ionic liquids.

  156 In 2013, our group reported the synthesis of glycerol-based ether via the formation of glycerol carbonate as an intermediate for the synthesis of ethers (Scheme 37).157 The formation of glycerol carbonate can also be obtained via the transformation of EC or DMC with glycerol in the presence of CaO, or obtained from 3-used as sweetener in food and pharmaceutical industries.164 With a similar structure and increased polar head to glycerol, erythritol was also considered as a building block for the synthesis of multifunctional surfactants.Here are two examples for the synthesis of erythritol-based ethers. As a traditional ether synthesis route, Williamson etherification was also used for the synthesis of erythritol-based surfactants.165 In 1982, Nouguier et al.166 reported a new procedure to produce erythritolbased ethers (Scheme 40, a) that involved three steps. Via Williamson etherification, erythritol-based ethers were obtained as an isomer mixture with over 90% overall yield.Unfortunately, only traces of erythritol based mono-ether was obtained.From the perspective of environmental protection, carbohydrate-based surfactants have been a research hotspot in recent years. After long-term research and application development, some carbohydrate-based surfactants occupied a wide range of markets, especially in the field of antibacterial. With the commercialization of sucrose esters and alkyl

	corresponding acetals with 69-91% yield.
	The second step is the hydrogenolysis of erythritol-based acetals. Under H2 (30 bar) in
	CPME at 150 o C for 16 h, in the presence of 5%-Pd/C (5 mol%), the desired erythritol-based
	mono-ethers were obtained as an isomer mixture with 72-86% yield. The performance of polyglycosides (APGs), bio-based carbohydrate surfactants gradually replace petroleum-based erythritol-based mono-ether surfactants were tested and exhibited better hydrophilicity and similar CMC value compared with glycerol ether surfactants. surfactants. 173,174
	As one of the most potential surfactants, the research on glucoside-based ethers is of 1.3.5.4 Carbohydrate-based ethers. great concern. Traditionally, these syntheses involve protection and deprotection steps due to
	Recently, the development of carbohydrate-based surfactants received extensive the special structure.
	attention from scientists, which is attributed to the strengthening of society's awareness of In 2008, Dunne et al. reported a five-step route for the synthesis of glucoside-based
	ethers (Scheme 42).
	erythritol based acetals, erythritol and aldehydes with different chain lengths were treated
	with CSA (Camphorsulfonic acid, 10 mol%) in ethanol at 80 o C for 15 h which led to the

156 B. Schaffner, F. Schaffner, S. P.

Verevkin, A. Borner, Chem. Rev., 2010, 110, 4554-4581. 157

G. Mignani, M.Lemaire, E. D. Silva, W. Dayoub, Y. Raoul, Patent WO2013139995, 2013. is Scheme 40. Synthetic routes of erythritol-based ethers. Recently, our group 167 (Scheme 40, b) developed a new method for the synthesis of erythritol-based mono-ethers via a two-step route. First, for the formation of the intermediate environmental protection. Carbohydrate-based surfactants are a class of non-ionic surfactants.

Their applications in the field of food industry, personal care and biopharmaceuticals gradually occupied a large market share. Since most of them can be directly prepared from natural resources, and are usually non-toxic, low-cost and biodegradable, the research on this type of surfactants has great application prospects.

168

Sorbitol-based surfactants are a class of commercially available nonionic surfactants with a wide range of application markets. 169 However, there are few examples of successful synthesis of sorbitol-based ethers.

In 2012, the first description about sorbitol-based ethers was found in a patent (Scheme 41, a). 170 Tulchinsky et al. reported the synthesis of sorbitol-based ethers via a direct reductive alkylation of sorbitol and aldehydes. Regrettably, this simple method did not provide the desired sorbitol-based ethers with good yield and selectivity.

168 F. W. Lichtenthaler, S. Peters, C. R.

Chim., 2004, 7, 65-90. 169 A. Ducret, A. Giroux, M. Trani, R. Lortie, J. Am. Oil Chem. Soc., 1996, 73, 109-113. 170

M. L. Tulchinsky, S-S. Ng, C. L. Rand, Patent WO2012148530A1, 2012. 175 Scheme 42. Traditional synthetic route of glucoside-based ether.

  Based on the above research context, in order to develop a simple and economical procedure for glycoside-based ethers, many efforts have been devoted in our group. In 2014, we reported a new synthetic procedure. 176 First, direct reductive alkylation was carried out with -D-glucoside and aldehyde, using 5%-Pd/C (0.5 mol%) and H2 (10 bar) at 140 o C for 24 h which was proven to be an effective method to directly synthesize glyceryl ethers (Scheme 43, group also developed a regioselective synthetic procedure of glycoside-based ethers.1,1,3,3-Tetramethyldisiloxane (TMDS) was used as a reductant for the cleavage of acetal ring.177 When treating with AlCl3, primary ethers (6-regioisomer) were obtained (Scheme 44, a) while Cu(OTf)2 gave the secondary formation of ethers (4-regioisomer) (Scheme 44, b) of C-glycosides is not influenced by hydrolases in vivo, so, they are recognized as an alternative to O-glycosides in some specific areas.179 In some cases, C-glycosides has gradually replaced O-glycosides in the field of pharmaceutical and cosmetic ingredients. Here are some examples of C-glycoside-based commercial products (Figure19). Dapagliflozin, canagliflozin and empagliflozin can act as effective ingredients for the treatment of diabetes. 180 Pro-Xylane exhibits anti-aging effects. 181 KRN7000 as a novel immunomodulator exhibits excellent biological activity for the treatment of tumors. 182 Therefore, the investigation of C-glycoside-based surfactants is meaningful and has huge market potential.

	Ester-based, O-glucoside-based and ether-based surfactants all belong to traditional O-
	glycosidic based surfactants. As O-glycosidic bonds are unstable in the presence of some
	specific glycoside hydrolases, they are restricted in some special applications. In contrast, the

a). However, only traces of product were obtained, a two-step synthetic method via the formation of intermediates was reconsidered

(Scheme 43, b)

. Unprotected methyl glucoside and aldehydes with different chain lengths were treated with Amberlyst 15 (20 wt%) and Na2SO4

(1.5 eq)

in THF at 70 o C for 3 h via acetalization to give the corresponding acetals with 26-44% yield. Then, methyl glucoside-based acetals were treated with 5%-Pd/C (5 mol%) and H2 (20 bar) at 120 o C for 15 h to give the corresponding methyl glucoside-based ethers with 37-86% yield. Methyl glucoside-based ethers were obtained as isomer mixtures, preferably forming 6-alkyl regioisomers. Scheme 43. Synthesis of glycoside-based ethers via the formation of acetal intermediate. Our Scheme 44. Synthesis of glycoside-based ethers via reductive cleavage of glycoside-based acetals Moreover, our group also tested the surfactant properties of a glycoside-based ether (C12 alkyl chain), it can effectively reduce the surface tension of water (CMC = 0.012 mN m -1 , sat. = 30 mN m -1 ). It also exhibited excellent antibacterial properties for Gram-positive bacteria (such as L. monocytogenes and S. aureus), which promoted the application in the preparation of preservatives and the additives of antibacterial products. 178 1.3.6 C-C bond-based surfactants. A C-glycosidic is a connection that can link carbohydrate group with other structure component through a C-C bond linkage. Compared with other non-ionic surfactants, surfactants with C-C bond exhibit significantly increased stability.

177 Y.-J. Zhang, W. Dayoub, G.-R. Chen, M. Lemaire, Eur. J.

Org. Chem., 2012, 1960-1966. 178

D. Belmessieri, C. Gozlan, M. C. Duclos, V. Molinier, J. M. Aubry, O. Dumitrescu, G. Lina, A. Redl, N. Duguet, M. Lemaire, Eur. J.

Med. Chem., 2017, 128, 98-106.

stability

  reduce the surface tension of water and the C9-tetraol also shows microemulsion property with high temperature.1.3.6.3 C-C bond surfactants based on fructose.

	Based on the previous work for aldolization, our group also applied this method to
	fructose. In 2018, Zhu et al. developed a synthetic method for fructose-based surfactant with
	C-C bond (Scheme 50).

188 P. M. Walgode, R. P. V. Faria, A. E. Rodrigues, Catal. Rev., 2020, 1-90. 189 B. Zhu, D. Belmessieri, J. F. Ontiveros, J.-M. Aubry, G.-R. Chen, N. Duguet, M. Lemaire, ACS Sustain. Chem. Eng., 2018, 6, 2630-2640. significantly 190 Scheme 50. Direct aldolization of fructose with aldehydes.

  Charles et al. 210 reported the synthesis of diglycerol by using NaOH as catalyst at 240 o C for 8 h to yield diglycerol with 63% conversion and 60% selectivity (Table

	Several homogeneous bases were used for the oligomerization of glycerol towards
	diglycerol, such as alkali hydroxides and carbonates.
	First, metal hydroxides were reported as catalysts for the oligomerization of glycerol
	towards diglycerol. In 2003,

1.2.1 Oligomerization of glycerol via base catalysis. 1.2.1.1 Homogeneous base catalysis of glycerol.

Table 1 .

 1 1, entry 1). In 2012,Ayoub et al. 211 reported the use of LiOH at 240 o C for 4 h that achieved almost full conversion of glycerol with 32% selectivity towards diglycerol (Table1, entry 2).In 2004, 87% glycerol conversion with 50% selectivity for diglycerol was obtained with Na2CO3 at 260 o C for 8 h (Table1, entry 3).212 Compared to sodium hydroxide, sodium carbonate exhibits higher catalytic activity, which is probably due to its higher solubility in glycerol.213 NaHCO3 was also used as a catalyst for the synthesis of linear-diglycerols at 260 o C for 8 h that 62% glycerol conversion with 70% diglycerol selectivity was obtained (Table1, entry 4).214 Furthermore, it was found that extending the reaction time to 24 h led to the increased conversion of glycerol and decreased selectivity for diglycerol (Table1, entry 4, results in brackets), which was due to the further formation of higher oligomers during the reaction process. Oligomerization of glycerol via homogeneous base catalysis.The mechanism for oligomerization of glycerol towards diglycerol was proposed via a SN2 pathway (Scheme 53). Homogeneous catalysts offer OH -to react with glycerol to enhance the nucleophilic properties of the attacking hydroxyl oxygens. Then, the polarized molecule B attacks the CH2 of other glycerol molecule to produce diglycerol. The condensation of glycerol occurs at the position of primary or secondary hydroxyls, leading to the formation of different isomers (-diglycerol, -diglycerol and -diglycerol). Further condensation would lead to the formation of polyglycerols with higher oligomers.

	Entry	Catalyst	T ( o C)	Time (h)	Conversion of	Selectivity of diglycerol
					glycerol (%)	(isomers, %)
	1	NaOH	240	8	63	60
	2	LiOH	240	4	98	32
	3	Na2CO3	260	8	87	50
	4	NaHCO3	260	8-24	~62(100)	~70(<10)
	5	CsHCO3	260	8	64	23
	6	Cs2CO3	260	8	71	39
	7	CsOH	260	8	74	32

Cesium-based catalysts were also used.

In 2008, Richter et al. reported

the synthesis of diglycerol using CsHCO3, Cs2CO3 and CsOH, which led to 64, 71 and 74% of glycerol conversion and 23, 39 and 32% selectivity for diglycerol, respectively (Table 1, entries 5-7). 215 Scheme 53. Mechanism of diglycerol synthesis via base catalysis.

  2008, Ruppert et al. reported that the use of CaO at 220 o C for 20 h led to the formation of diglycerol with 90% glycerol conversion and 60% selectivity (Table2, entry 1).216 Another mixed metal oxides-based catalyst MgAl-Na was also reported to achieve 50% conversion of glycerol with 85% selectivity for diglycerol at 220 o C of 24 h (Table2, entry 2).217 In addition to the traditional metal-based catalysts, clay minerals were also used as catalysts for the synthesis of diglycerol, as they are environmentally friendly, low-cost, simple to operate and recyclable.218 Mesoporous-based catalyst Cs-MCM-41 modified by magnesium was investigated to catalyze the oligomerization of glycerol to diglycerol which offered 25% conversion with 100% selectivity (Table2, entry 3).213 It was reported that 24% glycerol conversion with 17% selectivity for diglycerol was obtained using montmorillonite clay (Mgsaponite) catalyst at 250 o C for 24 h (Table2, entry 4).208 However, the low conversion prompted the further research on montmorillonite. Another montmorillonite clay-based catalyst CLAY Li/MK-10 with intercalated LiOH was reported to exhibit good glycerol conversion (98%) together with high selectivity (53%) for diglycerol (Table2. entry 5).220 It was found that the enhanced conversion and selectivity resulted in the increased alkalinity and pore size of the LiOH-modified CLAY Li/MK-10 based catalyst.

Due to the defined structure and better stability, zeolite-based catalysts attracted a lot of interests. In 2012, Martin et al. reported 70% glycerol conversion with 65% selectivity for diglycerol using basic zeolite (CsX) catalyst at 260 o C for 24 h (Table

2

, entry 6).

219

Zeolite NaX was also reported as an effective catalyst to afford the formation of diglycerol at 245 o C for 12 h with 80% glycerol conversion and 20% selectivity for diglycerol (Table

2

, entry 7).

220

Table 2 .

 2 Oligomerization of glycerol via heterogeneous catalysis.

	Entry	Catalyst	T ( o C)	Time (h)	Conversion of	Selectivity of
					glycerol (%)	diglycerol (%)
	1	CaO	220	20	90	60
	2	Mixed oxides	220	24	50	85
		(MgAl-Na)
	3	Cs-MCM-41	260	8	25	100
	4	Montmorillonite	250	24	24	17
		clay (Mg-saponite)
	5	Montmorillonite	240	12	98	53
		clay (CLAY Li/MK-10)
	6	CsX	260	8	70	65
	7	Zeolite (NaX)	245	12	80	20

Table 3 ,

 3

221 M. A. Medeiros, M. H. Araujo, R. Augusti, L. C. A. Oliveira, R. M. Lago, J.

Braz. Chem. Soc., 2009, 20, 1667-1673.

Table 3

 3 , entry 4).219 Polymer acid-based catalyst Nafion® foil was also used for the oligomerization of glycerol via a vacuum reflux condition at 150 o C for 24 h to achieve 93% glycerol conversion with 84% selectivity towards diglycerol (Table3, entry 5).223

Table 3 .

 3 Oligomerization of glycerol towards diglycerol via acid catalysis. Homogeneous acid conditions would lead to the protonation of glycerol to form the intermediate 'B' (Scheme 54). Then, carbocation 'C' forms by losing one molecule H2O, then reacts with another glycerol molecule via nucleophilic addition. Finally, the desired diglycerol was obtained after the loss of proton. Similarly with base-catalysed oligomerization, the occurrence position (at primary or secondary hydroxyls) of protonation and nucleophilic addition lead to the formation of different isomers (-diglycerol, -diglycerol and diglycerol). 224 Scheme 54. Mechanism of diglycerol synthesis via acid catalysis.

	Entry	Catalyst	T ( o C)	Time (h)	Conversion of	Selectivity of
					glycerol (%)	diglycerol (%)
	1	H2SO4	280	2	90	<20
	2	Dodecylbenzenesul	150	2	50	33
		phonic acid
	3	Triflimidates	150	6	58	31
	4	Zeolite (H-Beta)	145-150	-	80	20
	5	Nafion® foil	150	24	93	84
	The proposed mechanism of acid-catalysed oligomerization of glycerol follows a SN1
	route.

  with 90% selectivity (Scheme 62).236 It was found that the catalytic performance was largely influenced by the surface area of copper-based catalyst and the addition of other metal oxides. The best ratio of metal oxide additives (composition of CuO:ZnO:ZrO2:Al2O3=12:1:2:2) was applied to different 1,2-diols. However, poor yields were obtained caused by the formation of by-products, via the cleavage of C-C bonds.

	Scheme 63. Selective oxidation of fatty 1,2-diols.

Several 1,2-diols were treated with Cu-Zn-Zr-Al-O catalysts at 210 o C to afford -hydroxyketones with 45-73% 235 Y. Kwon, Y. Birdja, I. Spanos, P. Rodriguez, M. T. M. Koper, ACS Catal., 2012, 2, 759-764. yield Scheme 62. Synthesis of -hydroxyketones via dehydrogenation of 1,2-diols.

In 2017, our group proposed a novel method for the dehydrogenative oxidation of fatty vicinal diols under anaerobic conditions (Scheme 63). 237 Methyl 9,10-dihydroxy stearate was treated with Ru-based catalytic system under solvent-free condition that gave monooxidation product with 78% conversion and 90% selectivity. 236 S. Sato, R. Takahashi, T. Sodesawa, H. Fukuda, T. Sekine, E.

Tsukuda, Catal, Comm., 2005, 6, 607-610. 237 N. D. Vu, B. Guicheret, N. Duguet, E. Métay, M. Lemaire, Green Chem., 2017, 19, 3390-3399.

  Moreover, another selective oxidation of fatty 1,2-diols was reported by our group using a cheap catalytic system (Scheme 64). 238 Fatty 1,2-diol was treated with Ni/SiO2 catalyst via dehydrogenative oxidation to afford 99% conversion and 77% selectivity for the corresponding -hydroxyketone. The nickel-based heterogeneous catalytic system can be recycled for 5 times, providing an economical process.

Scheme 64. Selective oxidation of fatty 1,2-diols.

  2004, Plietker et al. 240 reported a synthetic method to produce -hydroxyketones via RuO4-catalysis. Oxone was used as an oxidant in the solvent system of EtOAc/CH3CN/H2O at room temperature to afford -hydroxyketone with 96% conversion and 92% selectivity (Scheme 65). However, this method also brought inevitable C-C bond cleavage.

238

B. Guicheret, Y. Bertholo, P. Blach, Y. Raoul, E. Metay, M.

Lemaire, ChemSusChem, 2018, 11, 3431- 3437. 239

M. Besson, P.

Gallezot, Catal. Today, 2000, 57, 127-141. 240 B. Plietker, M. Niggemann, Org. Biomol. Chem., 2004, 2, 2403-2407.

Table 4 .

 4 Glycerol oxidation towards DHA using Bi-Pt/C based catalysts.

	Entry	Catalyst support T ( o C)	conversion (%)	Selectivity (%)	Yield (%)
	1	Carborafin	50	30	66	20
	2	CECA50S a	60	75	49	37
	3	AC7	120	59	51	37
	4	AC1	70	80	61	49
	In addition to noble metals-based catalysts, other metals-based catalysts were also
	reported for the oxidation of 1,2 diols.

In 2013, Onomura's group applied Me2SnCl2 for the oxidation of 1,2-diols in aqueous solution (Scheme 67).

247

With mild conditions, dibromoisocyanuric acid (DBI) was used as an oxidant that exhibits better activity than N-bromosuccinimide (NBS) in the presence of base to afford the corresponding -hydroxyketones with good yield either for linear or cyclic 1,2diols.

Scheme 72. Selective oxidation of glycerol via gas-phase oxidation.

Table 5

 5 Oxidation of 2-heptanol with Pd-based catalysts.

	Entry	Pd-based catalyst	Yield (%)
	1	Pd-2	7
	2	Pd-3	37
	3	Pd-4	5
	4

Table 6 .

 6 Influence of additives for the oxidation of 1,2-propanediol.

	entry	additives	Time (h)	yield (GC) (%)
	1	none	16	12
	2	2,6-iPr2-phenol (20 mol%)	16	27
	3	none	72	14
	4	Styrene (5 equiv)	72	89

Table 7 .

 7 Oxidation of diglycerol (or glycerol) with palladium-based catalysts. a

	entry	catalyst	Yield of 4 (%) b	Yield of 5 (%) b
	1	Pd-1	0	41
	2	Pd-2	0	60
	3	Pd-3	trace	>90

Table 8 .

 8 Oxidation of diglycerol isomer. a

	Entry	Oxidant	Solvent	Conversion b (%)
	1	O2 (1 bar)	CH3CN/H2O (10:1)	trace
	2	O2 (3 bar)	CH3CN/H2O (10:1)	trace
	3	Benzoquinone (3 eq)	CH3CN/H2O (10:1)	trace

Table 9 .

 9 Oxidation of diglycerol in different solvent systems. a

	Entry	Oxidant	Solvent	Conversion b (%)
	1	O2 (1 bar)	CH3CN/H2O (10:1)	0
	2	O2 (3 bar)	CH3CN/H2O (10:1)	0
	3	Benzoquinone	CH3CN/H2O (10:1)	0
	4	O2 (1 bar)	THF	0
	5	O2 (1 bar)	1,4-dioxane	0
	6	O2 (1 bar)	Solvent-free	0
	7	O2 (1 bar)	CH3CN/H2O (7:1)	7

Table 10 .

 10 Oxidation of diglycerol in different solvent system. a

	entry	Washing liquid	Conversion (%)	Yield of 4 (%) c
	1	H2O	11	8
	2	MeOH	57	53
	3 b	Direct evaporation	57	54

Post-reaction treatment: a Using silica to adsorb catalyst and wash silica with washing liquid. b Direct evaporation. c Yields were determined by 1 H NMR with mesitylene as an internal standard.

Table 11 .

 11 Oxidation of diglycerol in different solvent system. a

	entry	Solvent	Conv.	Yield	Selec.	Cyclic form
			(%)	(%)	(%)	c (%)
	1	Solvent-free	0	0	-	-
	2	MeOH	0	0	0	-
	3	EtOH	0	0	0	-
	4	Cyclopentyl methyl ether (CPME)	0	0	0	-
	5	2-methyltetrahydrofuran (2-	0	0	0	-
		MeTHF)
	6	Tetrahydrofuran (THF)	37	31	99	98
	7	1,4-dioxane	44	43	99	98
	8	(trifluoromethyl)benzene	0	0	0	-
	9	Trifluoroethanol (TFE)	71	54	99	93
	10	1,1,1,3,3,3-	76	74	99	93
		Hexafluoroisopropanol (HFIP)

a Reaction condition: -1 (0.45 mmol), Pd-3 (10 mol%), O2 (1 bar), solvent (5.5 mL), 50 o C, 2h.

b

The conversions, yields and selectivity for mono-oxidation product were determined by 1 H NMR with mesitylene as an internal standard. c Ratio of mono-oxidation product on cyclic form was determined by 1 H NMR.

Table 12 .

 12 pKa and oxygen solubility of different solvents.

	entry	solvent	pKa a	oxygen solubility b
	1	methanol	15.5	4.26
	2	TFE	12	9.29
	3	HFIP	9.3	16.37

a Experiments were carried out at 25 o C. b Experiments were carried out at 283 K and expressed in

10 -4

Table 13 .

 13 Oxidation of diglycerol in TFE. a

	entry	Temp (°C)	Time (h)	Conv. b (%)	Yield b (%)	Selec. b (%)
	1	50	2	71	54	99
	2	50	4	69	53	99
	3	50	6	67	55	99
	4	60	2	57	51	99

Table 14 .

 14 Influence of temperature and oxygen pressure. a

	entry	O2 (bar)	Conv. b (%)	Yield b (%)	Selec. b (%)
	1 c	1	63	62	99
	2	1	76	74	99
	3	3	95	89	98
	4	6	>99	94	98

Table 15 .

 15 Influence of other parameters. a

	entry O2 (bar) Catalyst (mol%) Conv. b (%) Yield b (%) Selec. b (%)
	1	3	10	95	89	98
	2	3	5	69	63	99
	3	6	5	69	66	99
	4	3	2.5	34	33	99

Table 16 .

 16 Influence of the styrene additive. a

	entry Catalyst (mol%) Time (h) Conv. b (%) Yield b (%)	Selec. b (%)
	1 c	2.5	2	34	33	99
	2	2.5	2	79	75	99
	3	2.5	6	79	77	99
	4	2.5	18	>99	93 (61) d	98
	5	1	18	77	74	99
	6	1	30	77	73	99
	7 e	2.5	18	81	73	99

Table 17 .

 17 Influence of different catalyst. a

	entry	catalyst	Conv. b (%) Yield b (%) Selec. b (%)
	1	Pd-1	54	51	99
	2	Pd-2	64	60	99
	3	Pd-3	92	89	99
	4 c

  Scheme 95. Oxidation of diglycerol on -form or  -form with different time.

			H 2 -H 3 Yes
			H 2 -H 6	Yes
			H 5 -H 4 Yes
			H 5 -H 2	No
	H 2	H 5	H 6
	H 4'	H 4
	H 3
	H 6
	H 5
	H 4
	H 3
	H 2
	H 4

3' -H 2' H 3 '-H 2 ' Yes H 6 -H 2' Yes H 6 -H 2 Yes H 6 -H 4 NO H 6 -H 2 '

Table 18 .

 18 Scheme 109. Glycosylation via hydrochloric acid catalysis.In 1995, Ferrières et al. 304 reported the O-glycosylation between unprotected carbohydrates and fatty alcohols using Lewis acid catalyst. D-Mannose and n-octanol were treated with FeCl3 at room temperature for 48 h to form furanose rings (with the ratio of 19:1 for  form) with 58% yield (Scheme 110, a). While treated with boron trifluoride diethyl etherate (BF3 . OEt2), the pyranose rings (with the ratio of 4:1 for  form) was obtained with 40% yield (Scheme 110, b). Moreover, this catalytic procedure was also proved to work well on D-glucose, D-galactose and D-fructose. It is notable that using FeCl3 and BF3 . OEt2 could selectively yield O-glycosysides with furanosides and pyranosides form, respectively, which was caused by that octyl furanoside favored to be obtained with FeCl3, while octyl pyranoside with higher thermodynamically stability formed with BF3 . OEt2. OTf]), D-Glucose, D-galactose, D-mannose, D-xylose, Lfucose, 2-deoxyglucose and N-acetylglucosamine all gave moderate glycosylation results(51- 88% yield) for the corresponding products (Table18, entries 1-7). This ionic liquid promotes the glycosylation to provide a widely applicable procedure for the synthesis of O-glycosidebased surfactants from renewable resources. Glycosylation of unprotected carbohydrates.

			Scheme 110. Glycosylation via Lewis acids catalysis.
	In 2009, another Lewis acid-catalyzed glycosylation in ionic liquid system was reported
	by Augé et al. 305 Glycosylation was carried out with unprotected carbohydrates and octanol
	under	Sc(OTf)3	catalysis	in	ionic	liquid	(1-butyl-3-methylimidazolium

Table 19 .

 19 Homogeneous acid catalyzed glycosylation.Amberlite IR 120 314 and HClO4-SiO238 were also used for the glycosylation of D-glucose and benzyl alcohol to give the corresponding O-glycoside with 60 and 72% yield, respectively (Table20, entries 1-2). Montmorillonite KSF/O was proved to effectively catalyze the glycosylation of D-glucose and 1-butanol to give 78% yield (Table20, entry 3).315

	Entry Carbohydrates	Alcohols	Acids	T ( o C) Time (h) Yield (%)
	1	D-Glucose	Benzyl alcohol	HOTf (0.2 eq)	80	5	77
	2	D-Galactose	Hex-5-enol	PTSA (0.6 eq)	80	24	72
	3

Table 20 .

 20 Heterogeneous acid catalyzed glycosylation.

	Entry Carbohydrates	Alcohols	Acids	T ( o C) Time (h) Yield (%)
	1	D-glucose	Benzyl alcohol	Amberlite IR 120 (50 wt%)	80	24	60
	2	D-glucose	Benzyl alcohol	HClO4-SiO2 (25 wt%)	80	24	72
	3	D-glucose	1-butanol	Montmorillonite KSF/O (5 wt%)	113	1	78
	4	Leucrose	1-butanol	MCM-41 (10 wt.%)	120	24	91
		Furthermore, the proposed mechanism of Fisher glycosylation for unprotected
	carbohydrates were given by Brochette et al. (Figure 45). 44 The proposed mechanism of acid-
	catalyzed Fisher glycosylation of unprotected carbohydrates with fatty alcohols follows a SN1
	route (Figure 45). Acidic condition would lead to protonation of unprotected carbohydrate
	and further formed glucosyl oxonium intermediate A1 (B2) by elimination of one molecule of

Table 21 .

 21 Enzymatic catalysis of glycosylation.

	Entry	Carbohydrates	Alcohols	Acids	T ( o C)	Time (h)	Yield (%)
				-
	1		Glycerol	glucosidase (Duolite S-	40	18	34
				761)
				-
	2		1-Propanol	glucosidase (origin from	60	-	69
				SIGMA)
				-
	3		Ethanol	xylosidase	30	24	84
				(Asp. niger)
	4		Ethanol	Cellulase (Asp. niger)	30	24	64

Table 22 .

 22 Glycosylation of -diglycerose using different acid-catalysts. a

	Entry	Acid	Conv. of 4 b	Yield of 20 b	Yield of 14 b	Ratio of
			(%)	(%)	(%)	20:14 b
	1	HCl (0.7 eq)	-	6	19	24:76
	2	PTSA (10 mol%)	>99%	6	27	18:82
	3	CSA (10 eq)	>99%	17	30	36:64
	4	A35 (10 wt%)	>99%	12	11	52:48
	5	A36 (10 wt%)	>99%	5	6	45:55
	6	A15 (10 wt%)	>99%	30	30	50:50

Table 23 .

 23 Glycosylation of -diglycerose with different stoichiometric ratio. a

	Entry	Alcohol (eq)	Conv. 4 b (%)	Yield of 20 b (%)	Yield of 14 b (%)	Ratio of 20/14 b
	1	5	>99%	12	29	30:70
	2	10	>99%	30	29	51:49
	3	20	>99%	51	28	64:36
	4	50

Table 24 .

 24 Glycosylation of -diglycerose with different catalyst loading. a

	Entry Catalyst	Additives	Conv. (%) b	Yield of 20	Yield of	Ratio of
		loading			b (%)	14 b (%)	20/14 b
	1	5 wt%	-	>99%	20	12	63:37
	2	10 wt%	-	>99%	51	28	64:36
	3	50 wt%	-	>99%	11	27	29:71
	4 c	10 wt%	-	>99%	20	27	42:58
	5	10 wt%	Na2SO4 (1 eq)	>99%	50	28	64:36
	6	10 wt% Anhydrous THF	>99%	35	47	43:57

  322,323 Figure52. Important commercially available surfactants.

	One of the main advantages of sodium lauryl glucose carboxylate is its greater solubility
	in water compared to APG. 324 Nowadays, sodium lauryl glucose carboxylate, commercially
	available from Bayer, is used as an important ingredient for industrial production of cosmetic

322 Sodium lauryl glucose carboxylate, https://www.biobey.be/s/sodium-lauryl-glucose-carboxylate/.

323 R. Korać, D. Krajišnik, S. Savić, I. Pantelić, P. Jovančić, N. Cekić, J. Milić, Colloids Surf. A Physicochem.

Eng. Asp., 2014, 461, 267-278.

  Moreover, gold-based catalysts were also reported toIn 2000, Garésio et al. 335 reported the synthesis of new gluconolactone-based surfactants with an acetal linkage (Scheme 123). Gluconolactone and dodecanal (or tetradecanal) were treated with methanesulfonic acid (MsOH) in the mixture of DMF and cyclohexane at 80 o C for 2 h to give the corresponding acetal surfactants with 70 and 60% yield, respectively.

	Among these, 5-membered gluconolactone formed from 6-membered gluconolactone via a
	ring contraction catalysed by acid.

325 S. B. Bankar, M. V. Bule, R. S. Singhal, L.

Ananthanarayan, Biotechnol. Adv., 2009, 27, 489-501. 326

C. M. Wong, K. H. Wong, X. D. Chen, Appl.

Microbiol. Biotechnol., 2008, 78, 927-938. 327 K. Brudzynski, Food Chem., 2020, 332, 127229. 328

M. Zachariou, R. K. Scopes, J.

Bacteriol., 1986, 167, 863-869.

Scheme 123. Carbohydrate-based surfactants with an acetal linkage.

Table 25 .

 25 Aacetalization of gluconolactone and fatty aldehydes. a

	The acetalization of gluconolactone was carried out with a range of fatty aldehydes
	following the reported conditions. 335 Gluconolactone (1.2 equivalent) was treated with
	pentanal, heptanal, octanal, nonanal or dodecanal, using methanesulfonic acid (MsOH, 20
	mol%) as a catalyst in DMF and cyclohexane at 90 o C for 6 h to form the corresponding acetals
	32-36 with 36-81% yield, respectively (Table 25, entries 1-5). The acetalization product 32 was
	analyzed to be 4 isomers from GC chromatogram, as shown in Figure 55.

Table 26 .

 26 Hydrogenolysis of 34. a

	Entry	Catalyst	Acetal		Isolated yield (%)
		(mol%)	(mol/L)	34	37	38	39	40	41
	1	20 (10%Pd/C)	0.4	0	22	1	38	3	-
	2	20 (5%Pd/C)	0.4	0	32	1	2	-	-
	3	10 (5%Pd/C)	0.4	9	26	1	1	6	-
	4	5 (5%Pd/C)	0.4	5	33	1	-	6	19
	5	5 (5%Pd/C)	1	16	23	3	22	7	28
	6	5 (5%Pd/C)	0.1	53	8	-	9	-	3
	7 b	5 (5%Pd/C)	0.4	-	23 b	-	-	-	-
	a Reaction condition: 34 (5 mmol), Pd/C, H2 (40 bar), anhydrous CPME, 130 o C, 24 h. "-" in the table
		present that the product was not well separated and the yield was not calculated. b The
			hydrogenolysis of 36 (C12) to form 42.

  the synthesis of 37(Table 26, entries 4-6). It was noted that in all cases, hydrolysis products 39 and 41 were formed as the major by-products while traces of over-hydrogenolysis product 38 and by-product 40 were obtained during the reaction process. As shown in Scheme 125, 38 was probably formed during the hydrogenolysis process under the condition of excessive hydrogen. 39 and 41 were probably formed due to the presence of H2O in the reaction system. Moreover, 41 was probably formed via acetal scrambling between two molars of 34. Therefore, ensuring that the reaction system is anhydrous and a suitable amount of reducing agent are essential to increase the yield. Moreover, the hydrogenolysis was also carried out with 36 (C12) under same conditions to give the corresponding ether surfactant 42 with 23% isolated yield (Table26, entry 7).

1, 0.4 and 1 mol/L of acetal, that gave 37 with 8-33% yield. Compared with 1 and 0.1 mol/L of acetal, the hydrogenolysis carried out with 0.4 mol/L of acetal gave the best result for Scheme 125. Pathway of the formation of the by-products in the process of hydrogenolysis.

Table 27 .

 27 Table 27, entry 5). So far, the best result of the hydrogenolysis product 37 was obtained with 41% GC yield and 98% conversion of 34 under the condition of 30 bar of H2, 5 mol% Pd/C, 0.4 mol/L acetal at 170 o C for 24 h. Hydrogenolysis of 34 analyzed by GC. a

	Entry	Catalyst (mol%)	T ( o C)	H2 (bar)	Conv. b (%)	Yield of 37 b (%)
	1	5 (5%Pd/C)	130	30	97 (97 c )	17 (22 c )
	2 c	5 (5%Pd/C)	150	30	93	33
	3 c	5 (5%Pd/C)	170	30	98	41
	4 c	5 (5%Pd/C)	170	20	97	22
	5 c	2.5 (5%Pd/C)	170	30	86	16
	a Reaction condition: 34 (5 mmol), Pd/C, H2 (20 or 30 bar), anhydrous CPME (12.5 mL), 130 o C, 24 h. b

  Scheme 127. General routes for the synthesis of diglycerose-based surfactants. 128. General routes for the synthesis of gluconolactone-based surfactants.Overall, -diglycerose and -diglycerose were developed as important building blocks for chemical transformations. Two types of biobased surfactants (diglycerose-based Oglycosides and gluconolactone-based ethers) were developed. The prospective work will be carried out for other chemical transformations for -diglycerose and -diglycerose. The surfactant properties of the two bio-based surfactants will be measured and the synthesis of gluconolactone-based surfactants will be pursed within our laboratory.

	Chapter 5 Experimental section. 1.2 Procedure for the preparation of pure diglycerol.
	1 Experimental part for chapter 2. 1.2.1 Procedure to purify -diglycerol. 273
	1.1 General information.
	All reagents and solvents were commercially available and were used as received without
	further purification unless otherwise noted. Crude diglycerol (mixtures of isomer, 80% of -
	diglycerol) was purchased from TCI. Glycerol, palladium acetate (Pd (OAc)2), neocuproine,
	ethanol, methanol, chloroform, mesitylene, potassium carbonate (K2CO3), 1,1,1,3,3,3-
	hexafluoroisopropanol (HFIP), cyclopentyl methyl ether (CPME), 2-methyltetrahydrofuran (2-
	MeTHF), benzoyl chloride, tetrahydrofuran (THF), dimethyl carbonate, 1,4-dioxane, 4-
	bromobenzoyl chloride, Amberlyst-15 hydrogen form acid, (trifluoromethyl)benzene, pyridine,
	styrene, 2,2,2,-trifluoroethanol (TFE), dichloromethane, benzyl alcohol and benzoyl chloride
	were purchased from Sigma-Aldrich or Alfa-Aesar. Palladium (10% on activated wood carbon,
	10% Pd/C) and Ni-Al2O3-SiO2 was purchased from Strem Chemicals.
	Reactions were monitored by thin layer chromatography (TLC) using aluminium backed
	silica gel (60 F254, 20 cm* 20 cm). Phosphomolybdic acid solution was used as chromogenic a) In a 250-mL round bottom flask equipped with a magnetic stirrer and a reflux
	reagent for TLC detection. The purification was carried out via column chromatography condenser, a mixture of isomers diglycerol (40 g, 240.1 mmol) and dimethyl carbonate (32.1
	performed with silica 60 M (0.04-0.063 mm). 1 H and 13 C NMR experiments were carried out g, 142.4 mmol, 120 mL, 6 equiv) was placed followed by K2CO3 (200 mg, 1.44 mmol, 0.006
	on a Brüker DRX 300 or Brüker ALS 300 in DMSO-d6, acetonitrile-d3, CD3OD or CDCl3. equiv). The reaction mixture was heated at 70
	Finally, gluconolactone-based ether surfactant was also synthesized (Scheme 128). The Electrospray ionization (ESI), high resolution mass spectra (HRMS) were carried out on a
	study was started from the acetalization of gluconolactone with several fatty aldehydes, using MicroTOFQ-II, Bruker Daltonics spectrometer instrument using standard conditions (ESI, 70
	MsOH as a catalyst in a Dean-Stark apparatus, in cyclohexane and DMF at 90 o C for 6 h to eV).
	form the corresponding acetals with 36-81% yield. Then, the hydrogenolysis of
	gluconolactone-based acetals was carried out with high-pressure hydrogen (30 bar), using
	Pd/C as a catalyst in anhydrous CPME at 170 o C for 24 h to form C8 & C12 gluconolactone-
	based ether surfactants with 41 and 23% yield, respectively.

Next, based on the investigations of -diglycerose, the synthesis of the corresponding O-glycoside based surfactants was developed (Scheme 127). -Diglycerose was treated with several fatty alcohols (linear alcohols, branched alcohols and aromatic alcohols) under acidic conditions (Amberlyst 15) in solvent-free conditions at room temperature overnight, via glycosylation to form the corresponding diglycerose-based O-glycoside surfactants with moderate yields (17-62%).

Scheme o C for 24 h. Then the solvent mixture of dimethyl carbonate and methanol was removed by evaporation. Cold ethyl acetate (200 mL) was added into flask, to precipitate K2CO3. The precipitated catalyst was filtered off and washed with ethyl acetate (200 mL). The filtrate was evaporated to dryness and crystallized from methanol.

  Procedure for the preparation of -diglycerol.

1

H NMR

(300 MHz, CD3OD)

: δ = 3.81-3.74

(m, 2H, CH2CHCH2), 3.61-3.44 (m, 8H, OCH2)

. 13 C NMR (75 MHz, CD3OD): δ = 73.83 (OCH2), 72.20 (CH), 64.31 (CH2OH).

273

1.2.2

  13 C NMR (75 MHz, CD3OD): δ (cyclic form) = 94.61 (Cq), 70.2 (OCH2), 69.94 (CH), 68.58 (OCH2), 67.04 (CH2OH), 62.89 (CH2OH). δ (open form) = 210.45 (Cq), 75.34 (Cq-CH2O), 74.01 (CHOH), 73.74 (CHCH2O), 71.98 (Cq-CH2OH), 68.07 (CHCH2OH). HRMS (ESI + ): calcd. for C6H12NaO5 [M + Na] + , 187.0577, found 187.0576. 6, a pale-yellow oil. 1 H NMR (300 MHz, CD3OD): δ= 4.86 (s, 4 H, 2 CH2), 4.31 (s, 4H, 2 CH2). HRMS (ESI + ): calcd A. for C8H17O6 [M + H] + , 209.1025, found 209, calcd B. for C8H9D8O6 [M + H] + , 217.1527, found 217.

13

C NMR (75 MHz, CD3OD): δ= 212.09 (2 Cq),

66.81 (2 CH2), 83.13 (2 CH2OH)

.

6,

  C NMR (125 MHz, CD3OD): δ (major diastereoisomer) = 93.72 (Cq), 76.72 (CH), 71.03 (CH2), 66.96 (CH2OH), 62.83 (CH2OH), 62.37 (CH2). δ (minor isomer) = 94.42 (Cq), 75.23 (CH), 68.09 (CqCH2O), 63.86 (CqCH2OH), 63.51 (CHCH2O), 61.55 (CHCH2OH). HRMS (ESI + ): calcd. for C6H12NaO5 [M + Na] + , 187.0577, found 187.0581.13, a light viscous oil.1 H NMR (300 MHz, CD3OD): δ = 4.31 (dd, J = 2.2, 1.0 Hz, 1H, CHCH2), 4.28 (dd, J = 2.2, 1.1 Hz, 1H, CHCH2), 4.19 (s, 2H, CH2OH), 4.14 (dd, J = 2.9, 1.7 Hz, 1H, CH2), 4.11 (dd, J = 2.9, 1.7 Hz, 1H, CH2),3.89 (ddd, J = 3.5, 2.2, 1.3 Hz, 1H, CH), 3.41 (s, 2H, CqCH2O). 13 C NMR (75 MHz, CD3OD): δ = 94.75 (Cq), 72.71 (CH), 70.16 (2 CHCH2), 66.20 (CH2), 64.80 (CH2OH). HRMS (ESI + ): calcd. for C6H10NaO4 [M + Na] + , 169.0471, found 169.0471.

  70 ppm HSQC of 12 (CD3OD, 500 MHz)Zoom 3.15-3.80 ppm, 60-77 ppm. NOESY of 12 (CD3OD, 500 MHz) Zoom 3.25-4.00 ppm 2 Experimental part for chapter 3. reagents and solvents were commercially available and was used as received without further purification unless otherwise noted. Methanol, ethanol, 1-butanol, 1-pentanol and 1heptanol, 1-nonanol, 1-dodecanol, 2-propanol, 2-butanol, 2-pentanol, 3-phenylpropan-1-ol, hydrochloric acid, Amberlyst-15 hydrogen form, Amberlyst-35 hydrogen form, Amberlyst-36 hydrogen form, p-toluenesulfonic acid, camphorsulfonic acid, tetrahydrofuran anhydrous,

	1 H NMR of 12 (CD3OD, 500 MHz) Zoom 3.25-4.00 ppm
						H	H 2 -H 3 Yes H 2 -H 6 Yes
							H 5 -H 4 Yes
							H 5 -H 2		No
						H 5
		H 6	H 6	H 4 H 2	H 2	H 2		H 5	H 3	H 6	H 2'	H 3' H 6
		H 4'					H 4
						H 3
										H 6	H 6
	C5			H 2		H 2	H 4	H 5
		H 4'
	C6
						H 3
		H 6
		H 6
	C4
		H 5
	C3 H 4 C5		2		4	5
	C2	4' H 3	2						6		6
	C4	H 2
	C6
		H 2
					3
		H 4
	C2
	C3

2.1 General information.

All

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Summary

Scheme 41. Synthesis of sorbitol-based ethers.

In 2016, our group reported a two-step method for the synthesis of sorbitol-based monoethers (Scheme 41, b). 171 Sorbitan was synthesized from sorbitol under the condition of H2SO4 at 140 o C for 15 h to give 56% isolated yield. Then, sortitan and aldehydes with different chain lengths were treated with CSA (50 mol%) in ethanol at 140 o C for 15 h to give the corresponding sorbitan acetals as isomer mixtures with 29-85% yield. Next, sorbitan-based acetals were treated with 5%-Pd/C (5 mol%) and H2 (30 bar) in CPME at 120 o C for 15 h to form the corresponding sorbitan-based ethers as isomer mixtures with 55-85% yield.

The three regioisomers of sorbitol-based mono-ethers (C12) and their synthetic intermediates all exhibited excellent surfactant performances which are not weaker than the commercially available surfactants (Span 20®). Chem., 2016, 18, 1994-2004. 172 D. Belmessieri, C. Gozlan, M. C. Duclos, O. Dumitrescu, G. Lina, A. Redl, N. Duguet, M. Lemaire, Bioorg. Med. Chem. Lett., 2017, 27, 4660-4663. Another procedure for the synthesis of -hydroxyketone was reported via biocatalytic oxidation (Scheme 57). 231 Meso-erythritol was treated with Gluconobacter frateurii CHM 43 at 37 o C for 2 days to form L-erythrulose with 96% yield while glycerol was treated with the same condition to give 66% yield of -dihydroxyacetone. This method also exhibited good compatibility with other substrates such as ribitol, D-sorbitol and D-mannitol.

Scheme 57. Synthesis of -hydroxyketones via biocatalytic oxidation.

Oxidation of 1,2-diols via metal-free catalysis provides a mild and cheap pathway for the synthesis of -hydroxyketones, but the long reaction time and low oxidative efficiency limited the further applications. Therefore, metal-based catalysis was also reported for the oxidation of 1,2-diols. 1.3.2 Selective oxidation of 1,2-diols via electrochemical catalysis.

In order to solve the issue of C-C bond cleavage (Scheme 55), the group of Onomura reported a one-pot procedure for the selective oxidation of 1,2-diols (Scheme 58). 232 Cyclohexane-1,2-diol was treated with preheating conditions, using nBu2Sn=O as an organotin mediator under reflux conditions to form the intermediate A (Scheme 58, a). Then, Et4NBr was added as an electrolyte at 0 o C to afford the desired -hydroxyketone, thus avoiding the formation of by-product caused by C-C bond cleavage (Scheme 58, b). In addition to cyclic diols, this procedure was also suitable for the catalytic oxidation of linear 1,2-diols to give hydroxyketones with 32-76% yield (Scheme 58, c). It was also determined for the cyclic diols 231 D. Moonmangmee, O. Adachi, E. Shinagawa, H. Toyama, G. Theeragool, N. Lotong, K. Matsushita, Biosci. Biotechnol. Biochem., 2002, 66, 307-318. 232 T. Maki, S. Iikawa, G. Mogami, H. Harasawa, Y. Matsumura, O. Onomura, Chem. Eur. J., 2009, 15, 5364-5370. Scheme 80. Proposed pathway to inhibit the formation of Pd (0) by styrene. [START_REF]HRMS (ESI + ): calcd. for C8H16NaO5 [M + Na] +[END_REF] In summary, many efforts have been devoted for the oxidation of 1,2-diols, especially for the oxidation of glycerol and achieved excellent results. However, to date, no investigation was found for the oxidation of diglycerol.

2 Results and discussions.

Since diglycerol shares the same 1,2-diol moiety as glycerol and palladium-based catalyst Pd-3 exhibits excellent catalytic performance on glycerol oxidation, it was potential and challenging to oxidize diglycerol via the catalysis of palladium-based complexes (Scheme 81).

Therefore, we plan to oxidize diglycerol by using palladium-based catalyst.

Scheme 81. Oxidation of diglycerol by using Pd catalyst.

2.1 Preparation of pure diglycerol and catalyst.

Purification of diglycerol.

From the previous works about oligomerization of glycerol, diglycerol was obtained as a mixture of isomers. Commercially available diglycerol used in this study (supplied by Tokyo Chemical Industry) was found to be ~80% for α,α-isomer, ~20% for α,β-isomer and <1% for β,β-isomer, as determined by 13 C NMR (Figure 27). Finally, α,α-diglycerol α,α-1 was obtained through the hydrolysis of α,α-diglycerol dicarbonate with potassium carbonate (0.32 eq) at 90 o C with 84% yield (Scheme 83).

Scheme 83. Hydrolysis of α,α-diglycerol dicarbonate.

The two-step procedure allows the purification of pure -diglycerol -1 with 47% overall yield on 10 g scale.

Preparation of palladium-based catalysts.

The next step regards the preparation of the catalysts for the oxidation of diglycerol.

Preparation of Pd-1.

Pd-1 is referring to a physical mixture of Pd(OAc)2 and neocuproine, which was directly added into the reaction solution (Figure 28). Neocuproine-triflate salt was treated with Pd(OAc)2 and neocuproine in dry acetone under nitrogen atmosphere at room temperature for 48 h to give Pd-3 with 62% yield (Scheme 86).

Scheme 86. Synthesis of Pd-3.

Pd-3 exists as a mixture of monomer and dimer complex with the ratio of (20:80) as determined by 1 H NMR (Figure 29). On this scale, mono-oxidation product 4 was obtained with 560 mg for further applications.

Oxidation of diglycerol with other catalysts.

In order to further confirm that Pd-3 exhibits the higher activity for the oxidation of diglycerol, other experiments were carried out with different catalysts Pd-1, Pd-2 and Pd-3 under the optimized conditions. -1 (0.45 mmol) was treated with Pd catalyst (2.5 mol%), O2 (3 bar) and styrene (5 eq) in HFIP at 50 °C for 18 h. As we assumed, Pd-3 gave the best result compared with Pd-1 and Pd-2 which significantly increase the oxidation yield to 89% (Table 17, entries 1-3). Same trend was obtained for glycerol (Table 7). Moreover, all Pd-based catalysts gave high selectivity for the mono-oxidation product 4. In addition to Pd based catalysts, Mn II (Me2EBC) Cl2 (which has been described as able to efficiently oxidize cyclohexane-1,2-diol) was also used as a cheaper catalyst for the oxidation of -diglycerol -1, but no conversion was obtained (Table 17, entry 4). Another cheap catalyst Ni-Al2O3-SiO2 gave 4 with 8% GC yield and 99% selectivity (Table 17, entry 5).

Scheme 101. Glycosylation of -diglycerose.

This method provides a new strategy for developing different alkyl chain surfactants based on diglycerose.

Based on the above investigations, further application of -diglycerose were studied towards surfactants (chapter 3). Furthermore, from the NOESY experiment, the relative cis-configuration of the two hydroxymethyl groups of 20 was confirmed from the coupling between H 7 and H 4 (Figure 48). The previously work of our group have reported the synthesis of sorbitan-based ether surfactants via the hydrogenolysis of sorbitan acetals. 171 Therefore, the hydrogenolysis of gluconolactone-based acetals was carried out under this procedure, using octanal-based acetal as a model substrate for the optimization.

First, the influence of catalyst loading was screened. When the reaction was carried out with 20 mol% of Pd/C (10%) and hydrogen (40 bar) in anhydrous CPME at 130 o C for 24 h, almost full conversion was obtained with 22% yield for the desired ether product 37 (the ratio of 37a, 37b, 37c was confirmed to be 4:86:10 from GC chromatogram, as shown in Figure 56), the product 39 was obtained as major by-product with 38% yield (Table 26, entry 1). While treated with 20 mol% Pd/C (5%), the yield of 37 increased to 32% (Table 26, entry 2). 1 mol% of Pd/C (5%) was also used for the hydrogenolysis of 34, which did not result in a large conversion of 34. When the reaction was performed with 10 and 5 mol% Pd/C (5%), 37 was isolated with 26 and 33% yield, respectively (Table 26, entries 3-4). From an economic point of view, 5 mol% Pd/C (5%) was selected for further optimization. bis(trimethylsilyl)amine and 0.1 mL of trimethylsilyl chloride. Next, 1.5 mL of the derivatization solution was added into the flask. After that, the solution was stirred intensely at 70°C for 15 min and then it was cool down to room temperature for analysis. Finally, 10 mL of THF was added into the solution to dilute the product, and methyl oleate (0.17 mmol) was added as an internal standard. Before injection, the sample was filtrated by a syringe filter (PTFE; 0.2 µm).