Preparation and Uses of Chlorinated Glycerol Derivatives

molecules

Review Preparation and Uses of Chlorinated Glycerol Derivatives

Anna Canela-Xandri 1 , Mercè Balcells 1 , Gemma Villorbina 1 , Paul Christou 2,3 and Ramon Canela-Garayoa 1,*

1 Department of Chemistry, University of Lleida-Agrotecnio Centre and DBA center, Av. Alcalde Rovira Roure, 191, 25198 Lleida, Spain; [email protected] (A.C.-X.); [email protected] (M.B.); [email protected] (G.V.) 2 Department of Crop and Forest Sciences, University of Lleida-Agrotecnio Center, Av. Rovira Roure 191, 25198 Lleida, Spain; [email protected] 3 ICREA, Catalan Institute for Research and Advanced Studies, Passeig Lluıís Companys 23, 08010 Barcelona, Spain * Correspondence: [email protected]

Academic Editor: Monica Nardi Received: 22 April 2020; Accepted: 25 May 2020; Published: 28 May 2020

Abstract: Crude glycerol (C3H8O3) is a major by-product of biodiesel production from vegetable oils and animal fats. The increased biodiesel production in the last two decades has forced glycerol production up and prices down. However, crude glycerol from biodiesel production is not of adequate purity for industrial uses, including food, cosmetics and pharmaceuticals. The purification process of crude glycerol to reach the quality standards required by industry is expensive and dificult. Novel uses for crude glycerol can reduce the price of biodiesel and make it an economical alternative to diesel. Moreover, novel uses may improve environmental impact, since crude glycerol disposal is expensive and dificult. Glycerol is a versatile molecule with many potential applications in fermentation processes and synthetic chemistry. It serves as a glucose substitute in microbial growth media and as a precursor in the synthesis of a number of commercial intermediates or fine chemicals. Chlorinated derivatives of glycerol are an important class of such chemicals. The main focus of this review is the conversion of glycerol to chlorinated derivatives, such as epichlorohydrin and chlorohydrins, and their further use in the synthesis of additional downstream products. Downstream products include non-cyclic compounds with allyl, nitrile, azide and other functional groups, as well as oxazolidinones and triazoles, which are cyclic compounds derived from ephichlorohydrin and chlorohydrins. The polymers and ionic liquids, which use glycerol as an initial building block, are highlighted, as well.

Keywords: bioeconomy; chlorohydrins; epichlorohydrin; hydrocloride derivatives; glycerol

1. Introduction Society currently faces the twin challenge of resource depletion and waste accumulation. This challenge leads to a rapid increase in the costs of raw materials and waste disposal, which is subject to restrictive and burdensome legislation. Thus, environmental pollution and waste accumulation are key factors in valorising biomass in the transition to a low-carbon economy society and the decarbonization of carbon-intensive sectors. An essential component of this valorization is the “zero-waste” concept [1–3]. Eﬃcient use of biomass as a source of ﬁne chemicals will play an important role in sustainable development and mitigating global warming [4,5].

Molecules 2020, 25, 2511; doi:10.3390/molecules25112511 www.mdpi.com/journal/molecules Molecules 2020, 25, 2511 2 of 38

Biomass can also be used to obtain biofuels such as bioethanol, biomethane and biodiesel [6–9]. Replacing fossil fuels with renewable resources will lead to the reduction of waste accumulation by revaluating industrial by-products and reducing resource depletion [10,11]. Moreover, rising crude oil prices have stimulated interest in developing alternative renewable biofuels in the recent past. More recently, however, oil prices have collapsed; it is unclear what the impact of this might be on the continuing use of biofuels, particularly if oil prices remain low indefinitely. Biodiesel can be produced from many renewable sources. These include vegetable oils and animal fats. The process usually involves transesterification of acylglycerides into fatty acid methyl esters (FAME), with glycerol (C3H8O3) as the major by-product. On a molar basis, one mole of glycerol is produced for every three moles of FAME. Hence, 10% of the initial acylglycerides are roughly converted to glycerol. Crude glycerol resulting from the biodiesel industry becomes, itself, a source of biomass. Glycerol is a versatile molecule with many potential applications [12–18]. In fact, novel uses of glycerol may be instrumental in making biodiesel a competitive alternative fuel to petroleum-based fuels. Pure glycerol is physiologically innocuous, and it is currently used in a large variety of applications, primarily in the cosmetic, food and pharmaceutical industries. However, the use of glycerol in these industries is limited by strict physical, chemical and biological requirements. Requirements that crude glycerol resulting from biodiesel production does not meet [19]. In 2011, it was estimated that two million tons (or just 40%) of a total of 5.1 million tons of glycerol were used [19]. However, the volume of glycerol has been steadily increasing because global biodiesel production has been growing in recent years. It is estimated that the biodiesel production could reach 41 Mm3 in 2022 [19], considering the 9.3% year increase in world glycerol production between 2008 and 2012. Thus, the glycerol market is becoming a bottleneck on biodiesel production [19,20]. Glycerol can be used as both an energy source and a platform chemical. Direct pyrolysis [21], direct combustion and hydrogen production are usual processes where crude glycerol can be used as energy source [22]. However, glycerol high viscosity hinders flow spraying, pumping and flame stability. Uncontrolled burning produces acrolein (2-propenal), an unsaturated aldehyde with severe detrimental effects on the human health [19]. Moreover, hydrogen preparation from crude glycerol involves high production costs [23–26]. The transformation of glycerol into fine chemicals can be performed by chemical and biological processes. However, most of these glycerol derivatives are currently produced by expensive processes, and therefore their utilization on an industrial scale is still limited [27]. Glycerol can be converted into more complex intermediates and products through a number of different chemical reactions. Figure1 shows the most reactions in which glycerol can be involved as a building block [ 28]. Despite the large number of theoretical possibilities, in practice, there are two possible areas to use up the large amount of glycerol produced by the biodiesel industry: as feedstock for commodity chemicals [29–34], or for producing oxygenated additives for fuels [27,35–38]. As an example, glycerol can be thermochemically converted to propylene glycol [29–31] and acrolein; the latter can be oxidized to acrylic acid [39–41]. Glycerol can be esterified to acylglycerides and glycerol carbonates [42]. It can also be used to prepare chlorinated derivatives. Synthetic pathways to chlorhydrines have been described, many of them leading to a mixture of isomers [32,34,43–45]. These products exhibit some degree of toxicity [46–49]. As an alternative, the authors’ research group has described the synthesis of chlorohydrin esters by using crude glycerol and different fatty acids. These esters are less volatile than the corresponding chlorohydrins, which, in principle, reduce their toxicity as chemical reagents [50]. Molecules 2020, 25, 2511 3 of 38 Molecules 2020, 25, x FOR PEER REVIEW 3 of 39

R R

O O O O OH

OH OH R1 R2 O

O O O O OH Cl R1 R2 Epichlorohydrin ACETAL FORMATION O

NaOH R1 R2 CO+ H2 Syngas OH Cl cat.

CO2, cat. OH Cl Cl OH Cl H C 3 HYDROCHLORINATION OH HO OH REDUCTION H2, cat. OH HCl, cat.

OH OH cat. R OH OR1 O RCOO OH

OR3 OR2 R OH + OH RCOO OH RCOO H cat, O ETHERIFICATION 2 ESTERIFICATION -H2O

O H2C OH O DEHIDRATION OH OH OH COOH

O2, cat. OH OH

O COOHCOOH OH CHO OH OXIDATION

CH2 Acrilic acid. Figure 1. ReactionsFigure in 1. whichReactions glycerol is in used which as a building glycerol block is to makeused more-complex as a building molecules block [51 ]. to make more-complex molecules [51]. Glycerol is also involved in biological transformations. Crude glycerol is a suitable feedstock in microbial fermentation. It has been used for the production of succinic acid, using the bacterium Glycerol is also involved in biological transformations. Crude glycerol is a suitable feedstock in Anaerobiospirillum succiniciproducens [52] and citric acid, using the yeast Yarrowia lipolytica. The eﬃciency microbial fermentation. It has been used for the production of succinic acid, using the bacterium of this yeast in converting crude glycerol to citric acid is similar to that from glucose [53]. Crude Anaerobiospirillum succiniciproducens [52] and citric acid, using the yeast Yarrowia lipolytica. The glycerol has also been used as carbon source to obtain vitamin K [54] and erythritol [55]. efficiency of this yeast in converting crude glycerol to citric2 acid is similar to that from glucose [53]. The main objective of this review is to highlight the use of crude glycerol as starting material for Crude glycerol has also been used as carbon source to obtain vitamin K2 [54] and erythritol [55]. chlorinated intermediates and end products. In particular, we discuss the state-of-the-art in several The main objective of this review is to highlight the use of crude glycerol as starting material for processes for the synthesis of these compounds, with emphasis on the improvements made in the last chlorinated intermediates and end products. In particular, we discuss the state-of-the-art in several two decades. Firstly, the manuscript describes the synthetic methods for chlorinated derivatives of processes for the synthesis of these compounds, with emphasis on the improvements made in the glycerol. The further transformation of chlorinated derivatives in additional downstream products last two decades. Firstly, the manuscript describes the synthetic methods for chlorinated derivatives is also described. The more recent contributions of the authors’ research group in the application of glycerol. The further transformation of chlorinated derivatives in additional downstream of chlorinated derivatives of glycerol are also presented. Finally, some future perspectives of these products is also described. The more recent contributions of the authors’ research group in the compounds and the evolution of the biodiesel and other related industries are discussed. application of chlorinated derivatives of glycerol are also presented. Finally, some future 2. From Glycerolperspectives to Synthetic of these Intermediatescompounds and the evolution of the biodiesel and other related industries are discussed. 2.1. Synthesis of Chlorohydrins by Glycerol Hydrochlorination 2. From Glycerol to Synthetic Intermediates An application of glycerol that has attracted significant attention is the production of chlorohydrins2.1. Synthesis[32,34,43 ,of44 Chlorohydrins,51,56–58]. Figure by Glycerol2 shows Hydrochlorination the synthesized chlorohydrins, using this approach. An application of glycerol that has attracted significant attention is the production of chlorohydrins [32,34,43,44,51,56–58]. Figure 2 shows the synthesized chlorohydrins, using this approach. Molecules 2020, 25, 2511 4 of 38 Molecules 2020, 25, x FOR PEER REVIEW 4 of 39

HCl

RCOOH Cl Cl OH 1,3-Dichlorohydrin HCl (1,3-DCH) RCOOH Cl OH OH 1-Monochlorohydrin

OH OH HCl Cl Glycerol RCOOH

Cl OH HCl 1,2-Dichlorohydrin (1,2-DCH) RCOOH Cl

OH OH 2-Monochlorohydrin FigureFigure 2. Syntesis2. Syntesis of of DCH DCH by by two-step two-step glycerol glycerol hydrochlorination. hydrochlorination. Table1 shows the current approaches to synthesize dichlorohydrins (DCH) by the Table 1 shows the current approaches to synthesize dichlorohydrins (DCH) by the hydrochlorination of glycerol [12,32,34,43,44,51,59–61]. Moreover, some approaches have been hydrochlorination of glycerol [12,32,34,43,44,51,59–61]. Moreover, some approaches have been described where crude glycerol was used because the puriﬁcation of glycerol involves high costs and described where crude glycerol was used because the purification of glycerol involves high costs is not economically feasible for small- and medium-size plants [62,63]. Crude glycerol chlorination and is not economically feasible for small- and medium-size plants [62,63]. Crude glycerol should represent an economic advantage over the traditional propylene-based process, as the cost of chlorination should represent an economic advantage over the traditional propylene-based process, this glycerol is minimal [64,65]. as the cost of this glycerol is minimal [64,65]. Molecules 2020, 25, 2511 5 of 38

Table 1. Eﬀect of several conditions on the synthesis of DCH.

Reagents Catalyst P (atm)/T(◦C) Procedure Reaction Period 1,3-DCH (Yield %) Comments Ref. HCl(g) 93% DCH HCl pressure has a great eﬀect on Batch (glycerol) +wet glycerol Acetic acid (5%) 7.5/110 4 (46:1) glycerol consumption rate and [44] Continuous (HCl) (9%) (1,3-DCH:2,3-DCH) product distribution. Non-catalytic hydrochlorination is a HCl(g) Acetic acid 0.25–1/105 Semibatch 3 N.P. major inconvenient at [43] +glycerol (0–50%) high temperatures... No correlation between the acidity HCl(g) Batch(glycerol) Propionic acid 8% 1/100 3 41% strength of the catalyst and the [32] +glycerol Continuous (HCl) reaction activity was demonstrated. HCl (g) Hexanoic acid 7.5/110 Semibacth 3 N.P. [61] +glycerol (5%) Correlation between catalyst pKa HCl(g) Carboxylic acid Batch(glycerol) value and its selectivity toward N.P. N.P. N.P. [34] +glycerol studied Continuous (HCl) mono- (pKa < 3) or dichlorinated (pKa > 4) compounds was found. N.P., not provided; DCH, dichlorohydrins; MCH, monochlorohydrins. Molecules 2020, 25, x FOR PEER REVIEW 6 of 39

Molecules 2020The, 25 ,most 2511 prevalent synthetic procedures for glycerol chlorination [66,67] are based6 of 38 on the reaction of glycerol with an aqueous solution of hydrochloric acid [34,56,68–73]. The synthetic process has been scaled up to an industrial scale [74,75]. However, this process has a number of Thedisadvantages, most prevalent such synthetic as the loss procedures of the catalyst for glycerol at high chlorination reaction temperature [66,67] are baseds (due on to the its reaction low boiling of glycerolpoint) with and an the aqueous production solution of ofwater, hydrochloric which caus acides [34 an,56 increase,68–73]. Thein the synthetic reaction process time hasand been makes it scaleddifficult up to an to industrial separate the scale end [74 products.,75]. However, this process has a number of disadvantages, such as the loss ofThis the catalyst reaction at can high be reaction carried temperatures using glycerol (due and to gaseous its low boiling HCl. The point) resulting and the mixture production of isomers of water,has which been causes investigated an increase in great in the detail reaction [76– time78]. The and reaction makes it is di carriedfficult to out separate isothermically the end products., allowing the Thiscontrol reaction of side can reactions be carried [44] using. glycerol and gaseous HCl. The resulting mixture of isomers has been investigatedIn the first step in, great monochlorohydrins detail [76–78]. The (mainly reaction 1-monochlorohydrine, is carried out isothermically, 1-MCH, and allowing small amounts the controlof of2- sidemonochlorohydrine, reactions [44]. 2-MCH) are obtained by the nucleophilic substitution of OH by Cl. InMoreover, the first step,1-MCH monochlorohydrins is favored by (mainly a kinetic 1-monochlorohydrine, control of the process 1-MCH, and[79].small In a amounts subsequent of 2-monochlorohydrine,hydrochlorination 2-MCH)reaction are, monochlorohydrins obtained by the nucleophilic are converted substitution to of dichlorohydrins OH by Cl. Moreover, (mainly 1-MCH1,3 is-dichlorohydrins, favored by a kinetic 1,3- controlDCH, andof the small process amounts [79]. In ofa subsequent 1,2-dichlorohydrins, hydrochlorination 1,2-DCH) reaction, (Error! R monochlorohydrinseference source are not converted found.). toThis dichlorohydrins mixture reach (mainly on 1,3-DCH 1,3-dichlorohydrins, is very interesting 1,3-DCH, in the andpreparation small of amountsepichlorohydrin of 1,2-dichlorohydrins,, as is discussed 1,2-DCH) below (Figure. 2). This mixture reach on 1,3-DCH is very interesting in the preparationThese reactions of epichlorohydrin, are catalyzed as by is discussedshort carboxylic below. acids, usually acetic acid. Depending on the TheseHCl concentration, reactions are catalyzed the reaction by short can carboxylic lead to the acids, MCH usually isomers acetic or acid. to the Depending DCH isomers. on the TheHCl ratio concentration,between MCH the reaction and DCH can leaddepends to the on MCH the isomers reaction or conditions. to the DCH Santacesaria isomers. The et ratio al. betweenhave already MCHreviewed and DCH that depends process on andthe reaction have summarized conditions. the Santacesaria studies in et terms al. have of alreadycatalysts, reviewed reaction thatprocess, processmechanism and have and summarized kinetics, and the reactors studies and in terms processes of catalysts, used [51 reaction]. process, mechanism and kinetics, and reactors and processes used [51]. 2.2. Synthesis of Epichlorohydrin 2.2. Synthesis of Epichlorohydrin Epichlorohydrin (ECH) is a chemical used in the production of synthetic elastomers, sizing Epichlorohydrin (ECH) is a chemical used in the production of synthetic elastomers, sizing agents for the papermaking industry, epoxyresins and plasticizers [34,44,51,80]. Some pheromones, agents for the papermaking industry, epoxyresins and plasticizers [34,44,51,80]. Some pheromones, anisomycin, propranolol analogues and β-blockers also have ECH as an intermediate [81,82]. anisomycin, propranolol analogues and β-blockers also have ECH as an intermediate [81,82]. Moreover, Moreover, enantiopure ECH is an important intermediate for the production of optically active enantiopure ECH is an important intermediate for the production of optically active pharmaceuticals, pharmaceuticals, such as atorvastatin and L-carnitine, and the preparation of ferroelectric liquid such as atorvastatin and L-carnitine, and the preparation of ferroelectric liquid crystals [83]. crystals [83]. Industrial methods to synthesize ECH include the use of a mixture of 1,2-DCH (70%) and 1,3-DCH Industrial methods to synthesize ECH include the use of a mixture of 1,2-DCH (70%) and (30%) (Figure3). This is a disadvantage of the process, since 1,2-DCH is much less reactive than 1,3-DCH (30%) (Figure 3). This is a disadvantage of the process, since 1,2-DCH is much less reactive 1,3-DCH [32–34,51]. This mixture is currently obtained by propylene chlorination. The alkali treatment than 1,3-DCH [32–34,51]. This mixture is currently obtained by propylene chlorination. The alkali of this mixture yielded ECH [44]. ECH can also be obtained by the allyl acetate method. Allyl treatment of this mixture yielded ECH [44]. ECH can also be obtained by the allyl acetate method. acetate is hydrolyzed to allyl alcohol, which is chlorinated [44,45]. Both methods are based on the Allyl acetate is hydrolyzed to allyl alcohol, which is chlorinated [44,45]. Both methods are based on oil industry, since the starting materials are obtained from refinery processes [78]. An additional the oil industry, since the starting materials are obtained from refinery processes [78]. An additional disadvantage of the process is that the raw materials, such as propylene and chlorine, are flammable disadvantage of the process is that the raw materials, such as propylene and chlorine, are flammable and toxic, respectively [61]. These factors have prompted the search for alternative procedures based and toxic, respectively [61]. These factors have prompted the search for alternative procedures based on sustainable methods and renewable raw materials to synthesize ECH [44]. on sustainable methods and renewable raw materials to synthesize ECH [44].

Cl OH Alkali(OH) O + + Alkaly salt+ H2O Cl OH Cl Cl Cl Figure 3. ECH synthesis by alkali treatment of 1,3-DCH. Figure 3. ECH synthesis by alkali treatment of 1,3-DCH. Several chemical and biological approaches [84–86] have been suggested as alternatives to prepare ECH [86] fromSeveral chlorohydrins. chemical and biological approaches [84–86] have been suggested as alternatives to prepare ECH [86] from chlorohydrins. 2.2.1. Enzymatically Catalyzed Synthesis of ECH The2.2.1. intramolecular Enzymatically nucleophile Catalyzed displacementSynthesis of ECH of vicinal halohydrins to the corresponding epoxides can be catalyzedThe intramolecular by halohydrin nucleophile dehalogenases displacement (HHDHs, of HheCvicinal and halohydrins EC 4.5.1.X) to from the microbial corresponding originepoxide [87–89].s However,can be cataly a numberzed by of studieshalohydrin reported dehalogenases that the biotransformation (HHDHs, HheC of 1,3-DCHand EC into 4.5.1.X) ECH from by recombinantmicrobial originEscherichia [87–89 coli]. expressingHowever, halohydrina number of dehalogenase studies reported is limited that by the product biotransformation inhibition, of one of1,3 the-DCH reasons into ECH for theby recombinant low ECH productivity Escherichia coli [90 ].expressing Zou et al. halohydrin proposed dehalogenase a resin-based is limited ISPR by biocatalytic process to avoid this inhibition [90]. The method consists in the addition of HZD-9 Molecules 2020, 25, 2511 7 of 38 macroporous resin. HZD-9 improved the overall productivity of the process yielding 88% of ECH (Table2, entry 2.2) [ 90]. This high yield demonstrated that this method was an eﬀective way to eliminate product inhibition. Alternatively, halohydrin dehalogenases insensitive to product inhibition have been described [85,91,92]. Thus, S-ECH was produced in good enantiomeric excess (92.3% ee) and 92% yield, using a HheC mutant (Table2, entry 2.4) [ 91]. Improved ee (99%) and similar yield (92%) were achieved by using halohydrin dehalogenases (HHDHs) coupled to epoxide hydrolases (EH) (Table2, entry 2.5) [ 91]. The production of ECH was also described by using a novel HHDHTm, from Tistrella mobilis ZJB1405 (cloned and over-expressed in E. coli), with a 75% yield, but with low enantioselectivity compared to other reported HHDHs (Table2, entry 2.1) [ 92]. In addition, HheC in presence of NO2 allowed the synthesis of R-ECH with high ee (99%) but low yield (41%) (Table2, entry 2.3) [85]. An alternative method for preparing chiral ECH is the kinetic resolution of its racemate by epoxide hydrolases (EH), which catalyze the opening of the epoxide ring to the corresponding diol in the presence of water [93,94]. It should be noted that HHDH produces mainly S-ECH and recombinant EH produces R-ECH. As an example, Kim et al. performed the resolution of R,S-ECH by using recombinant EH, yielding enantiopure (100% ee) R-ECH (Table2, entry 2.6) [ 95]. Lee et al. prepared R-ECH with almost similar yield (28.5%) and ee (99%) [96]. Jin et al. improved the yield (42.7%) (Table2, entry 2.8) but reported substrate and product inhibition when the substrate concentration was higher than 320 mM [84]. It should be highlighted that 50% is the highest yield that can be achieved when performing kinetic resolution of a racemate.

Table 2. ECH synthesis using biotechnological approaches.

Entry Enzyme Type Enzyme from/Mutant Isomer ee (%) Yield (%) Comments Ref. Tistrella mobilis ZJB1405 Alkaline pH, 2.1 HHDH S-ECH N.P. 75 [92] (E. coli) 45 ◦C HZD-9 resin at 2.2 HHDH E.coli BL21(DE3) ECH N.P. 88.3 [90] 10% (w/v) NO , pH5, 2.3 HHDH Agrobacterium radiobacter R-ECH 99 41 2 [85] 37 ◦C, 18 min 2.4 HHDH P175S/W249P S-ECH 92.3 93.2. pH = 10 [91] Enzyme 2.5 HHDH + EH N.P. S-ECH 99 91.2 [91] combination Pichia pastoris harboring 2.6 EH the Rhodotorula glutinis R-ECH 100 26.4 [95] EH 2.7 EH N.P. R-ECH 99 28.5 [96] Subtract and 2.8 EH A. radiobacter R-ECH 99 42.7 product [84] ≥ inhibition N.P., not provided.

2.2.2. Chemical Synthesis of ECH The chemical synthesis of ECH from dichlorohydrins has been studied extensively. Typically, 1,3-DCH and 1,2-DCH can be transformed into ECH by dehydrochlorination in the presence of alkali hydroxides. Alkaline hydroxides increase the nucleophilicity of OH, which produces the epoxide by substituting one of the chlorines. This reaction is very fast and requires special attention due to the easy occurrence of side reactions. Various studies (Table3) have been devoted to the reaction conditions. The composition of the reactive mixtures was studied [97], concluding that 1,2-DCH is much less reactive than 1,3-DCH, although primary alkyl alcohols are more acidic than secondary alkyl alcohols. The influence of the reactor on the reaction kinetics [98,99] and of the cation on the 1,3-DCH dehydrochlorination [59,61,97,100] was also studied. Lari et al. carried out dehydrochlorination of DCH in the gas phase, in the presence of mixed heterogeneous oxide prepared from hydrotalcite of Al and Mg, which allowed yields of ECH up to 60% [60]. However, this is the lowest yield compared to other chemical processes (Table3). Alternatively, Molecules 2020, 25, x FOR PEER REVIEW 8 of 39 Various studies have been devoted to the reaction conditions. The composition of the reactive mixtures was studied [97], concluding that 1,2-DCH is much less reactive than 1,3-DCH, although primary alkyl alcohols are more acidic than secondary alkyl alcohols. The influence of the reactor on the reaction kinetics [98,99] and of the cation on the 1,3-DCH dehydrochlorination [59,61,97,100] was also studied. Lari et al. carried out dehydrochlorination of DCH in the gas phase, in the presence of mixed heterogeneous oxide prepared from hydrotalcite of Al and Mg, which allowed yields of ECH up to 60% [60]. However, this is the lowest yield compared to other chemical processes (Table 3). Alternatively, solid catalysts were prepared by the equivalent-volume impregnation method, using γ-Al2O3 as a carrier, whereas nitrates and chlorides of the three alkaline earth metals (Mg, Ca and Ba) were employed as precursors. Under optimized conditions, a 90% yield was achieved by using 10BaO/γ-Al2O3 at 270 °C [101]. Chemical reactions can provide ECH with yields up to 99%, a value slightly higher than the best yield obtained using HHDH+HE [91]. The use of this biotechnological approachMolecules 2020 allows, 25, 2511 the synthesis of the S-ECH enantiomer with a 99% ee. In addition,8 of the 38 biotechnological approaches avoid the presence of by-products, such as chloroacetone, glycidol, diglycidyl ether and polyglycerols, that are very usual when ECH is synthesized by using the solid catalysts were prepared by the equivalent-volume impregnation method, using γ-Al2O3 as chemicala carrier, approaches.whereas nitrates Moreover, and chlorides the use of of the alkaline three hydroxides alkaline earth leads metals to a(Mg, large Ca amount and Ba) of were salt wastes, thus compromising the sustainability of the technology. Nevertheless, chemical approaches employed as precursors. Under optimized conditions, a 90% yield was achieved by using 10BaO/γ-Al2O3 allow working in higher reagent concentration than biotechnological approaches, a usual drawback at 270 ◦C[101]. Chemical reactions can provide ECH with yields up to 99%, a value slightly higher than ofthe the best biotechnological yield obtained approaches using HHDH from+HE an [ 91industrial]. The use point of this of view. biotechnological approach allows the synthesis of the S-ECH enantiomer with a 99% ee. In addition, the biotechnological approaches avoid the presence of by-products, suchTable as chloroacetone,3. ECH synthesis glycidol, using basic diglycidyl catalysts ether. and polyglycerols, that are very usual when ECH is synthesized by using the chemical approaches.Temperature Moreover, the use of alkaline Reagent Catalyst Reactor System Yield % Ref. hydroxides leads to a large amount of salt wastes, thus compromising the sustainability(°C) of the technology. Nevertheless, chemical approaches allow workingContinuous in higher reagent concentration than biotechnological 1,3-DCH NaOH 30–70 50–99 [59] approaches, a usual drawback of the biotechnologicalmillireactor approaches from an industrial point of view. 1,3-DCH:1,2- Ca(OH)2:CaCO3:H2O Pre-reactor/reactor [98,1 51/64 85–90 DCH(98:2) (96:4:1, w/wTable%) 3. ECHStripping synthesis using column basic catalysts. 02] 1,3-DCHReagent: Catalyst Reactor System Temperature ( C) Yield % Ref. NaOH Microreactor 50–80◦ 92 [97] 1,2-DCH Continuous 1,3-DCH NaOH 30–70 50–99 [59] 1,3-DCH Ba, Ca and Ba/γ-Al2O32 Fixedmillireactor-bed reactor 150–300 10–90 [101] Ca(OH) :CaCO :H O Pre-reactor/reactor 1,3-DCH:1,2-DCH(98:2) 2 3 2 51/64 85–90 [98,102] 1,3-DCH:1,2- (96:4:1, w/w%) Stripping column DCH1,3-DCH: 1,2-DCHHeterogeneous NaOH Continuous Microreactor-flow 50–80 92 [97] Ba, Ca and 200 60 [60] Aqueous (51,3-DCH– hydrotalcite Fixed-bedfixed-bed reactor 150–300 10–90 [101] Ba/γ-Al2O32 10 wt%)1,3-DCH:1,2-DCH Heterogeneous Continuous-flow 200 60 [60] Aqueous (5–10 wt%) hydrotalcite N.P., notfixed-bed provided. N.P., not provided. 2.3. Sinthesis of Dichloropropyl Esters from Glycerol 2.3. Sinthesis of Dichloropropyl Esters from Glycerol The one-pot synthesis of chlorinated derivatives by using crude glycerol or other polyols as startingThe material one-pots and synthesis chlorotrimethylsilane of chlorinated derivatives(CTMS) was by described using crude by the glycerol authors or’ research other polyols group (Figureas starting 4) [ materials103]. These and chlorinated chlorotrimethylsilane derivatives (CTMS)showed wasno described effect over by fungi the authors’ and bacteria research in preliminarygroup (Figure studies,4)[ 103 (unpublished]. These chlorinated results), derivativesindicating that showed these no compounds effect over are fungi less and toxic bacteria than the in parentpreliminary chlorohydrins studies, (unpublished. Consequently, results), they indicating could be that used these instead compounds of 1,3- areDCH less in toxic some than equivalent the parent reactionschlorohydrins.. Consequently, they could be used instead of 1,3-DCH in some equivalent reactions.

OH Cl R 1 OR CTMS R1 (CH )n 3 2 + H3C n (CH2)n R 2 O R2 OR 4 OCO(CH2)nCH3

n= 0-4 ; R1=H, CH3; R2= H, CH3, CH2CH3, -O-, CH2Cl; R3= H, CH3; R4= H, -(CH3)2-C-

FigureFigure 4. 4. SynthesisSynthesis of of c chlorohydrinhlorohydrin ester ester,, using using carboxyl carboxyl derivatives, derivatives, glycerol glycerol and and CTMS CTMS as as reagents. reagents.

The alkyl chain structure of the carboxylic acid had a clear inﬂuence on the regioselectivity of the reaction. Long chains increased the regioselectivity toward the α-chloroalkyl and 1,3 dichloroprop-2-yl radicals, whereas short chains and electron withdrawing substituents on the α carbon reduced regioselectivity [104]. An increase in the degree of substitution of functional groups with α-electron donors led to an increase in the regioselectivity of the reaction [79]. Regioselectivity decreased with increasing temperature, which indicated a kinetic control of the process [105]. The synthesis of chlorohydrin esters from glycerol using an ionic liquid as a solvent and hydrated aluminum chloride as a source of chlorine was also described [106]. This approach allowed the use of hydrated aluminum chloride as a chlorine source, avoiding the use of CTMS, a more expensive reagent. Alkyl and aryl acids were used to synthesize chlorohydrin esters, although yields largely depended on the carboxylic acid used. Nevertheless, the corresponding 1,3-dichloro-2-propyl ester was always the main regioisomer (Figure5). Molecules 2020, 25, x FOR PEER REVIEW 9 of 39 MoleculesThe 20 alkyl20, 25, xchain FOR PEER structure REVIEW of the carboxylic acid had a clear influence on the regioselectivity 9 of 39of the reaction. Long chains increased the regioselectivity toward the α-chloroalkyl and 1,3 dichloropropThe alkyl-2 chain-yl radicals structure, whereas of the carboxylic short chains acid and had electron a clear withdrawinginfluence on the substituents regioselectivity on the of α thecarbon reaction. reduce d Long regioselectivity chains increase [104]. dAn the increase regioselectivity in the degree toward of substitution the α-chloroalkyl of functional and group 1,3s dichloropropwith α-electron-2- yldonors radicals led, towhereas an increase short in chains the regioselectivity and electron withdrawingof the reaction substituents [79]. Regioselectivity on the α carbondecreased reduce withd increasingregioselectivity temperature [104]. An, which increase indicated in the degreea kinetic of control substitution of the ofprocess functional [105] .group s with Theα-electron synthesis donors of chlorohydrinled to an increase esters in fromthe regioselectivity glycerol using of anthe ionic reaction liquid [79 ] as. Regioselectivity a solvent and decreasedhydrated aluminum with increasing chloride temperature as a source, which of chlorine indicated was alsoa kinetic described control [106 of ]the. This process approach [105 ]allowed. the useThe ofsyn hydratedthesis of aluminum chlorohydrin chloride esters as from a chlorine glycerol source, using avoiding an ionic the liquid use ofas CTMS a solvent, a more and hydratedexpensive aluminum reagent. Alkyl chloride and asaryl a sourceacids were of chlorine used to was synthesi also describedze chlorohydrin [106]. This esters approach, although allowed yields thelargely use ofdepend hydrateded aluminumon the chloride carboxylic as a chlorine acid used source,. Nevertheless, avoiding the usethe of CTMS corresponding, a more expensive1,3-dichloro reagent.-2-propyl Alkyl ester and was aryl always acids thewere main used regioisomer to synthesi z(Figuree chlorohydrin 5). esters, although yields largelyMolecules 2020depend, 25, 2511ed on the carboxylic acid used. Nevertheless, the corresponding9 of 38 OH R 1,3-dichloro-2-propyl ester was alwaysO the mainAlCl .6H OregioisomerR Cl (Figure 5). 3 2 Cl + O O O R OH O + OH OH [BMiM][PF6] OH R Cl O AlCl .6H O R Cl Cl 3 2 Cl + O O O R OH O + R=OH alkylO orH aryl [BMiM][PF6] Cl Cl

Figure 5. Synthesis R=of alkyl dichloropropyl or aryl esters from glycerol and a carboxylic acid, using an ionic

liquid. FigureFigure 5. Synthesis ofof dichloropropyl dichloropropyl esters esters from from glycerol glycerol and and a carboxylic a carboxylic acid, acid using, using an ionic an liquid. ionic 3.3. From Fromliquid. Building Building Blocks Blocks to to End End Products Products.

3.3.1.3.1. From Synthesis Synthesis Building of of Non Non-Cyclic Blocks-Cyclic to Compounds Compounds End Products .

3.1.3.1.1.3.1.1. Synthesis Synthesis Synthesis of Nonof of Allyl Allyl-Cyclic Esters Esters Compounds The synthesis of allyl fatty esters by using various fatty materials (soy oil, frying oils, palm oil, 3.1.1.T Synthesishe synthesis of Allyl of allyl Esters fatty esters by using various fatty materials (soy oil, frying oils, palm oil, waste animal fats fats,, etc. etc.)) and and crude crude glycerol glycerol was was described described by by the the authors authors’’ research research group group (Figure (Figure 6)6).. AAllylllylT estershe synthesis were preparedof allyl fatty through esters a by two-steptwo using-step various reactionreaction, fatty, using materials both conventional(soy oil, frying and oils, microwave palm oil, wasteheatingheating animal [ [7979]].. The fats The ,first etc. ﬁrst )step and step consist crude consisted edglycerol of ofthethe wassynthesis synthesis described of chlorohydrin of by chlorohydrin the authors esters’ esters,research, as described as group described above.(Figure above. The 6). AsecondThellyl second esters step step were waswas a prepared Finkelstein a Finkelstein-rearrangement–elimination through-rearrangement a two-step–elimination reaction, using reaction reaction both induced conventional induced by by NaI NaI. and. The The microwave reaction reactionss heatingwere carried carried [79]. Theout out byfirst by using using step butanoneconsist butanoneed [of107 [107 the] ]or orsynthesis BuOH BuOH [79 [of79] ,chlorohydrin ],two two solvents solvents thatesters that allow, allowedas describeded the the substitution substitutionabove. The of secondaof chlorine a chlorine step atom was atom by a by Finkelsteinone one iodine iodine-rearrangement atom. atom. Subsequently, Subsequently,–elimination the the necessary necessary reaction acylinduced acyl rearrangement rearrangement by NaI. The and and reaction halides wereeliminationelimination carried took tookout by place. place. using The The butanone reaction reaction [107 was was] or performed performed BuOH [79 by] by, two using using solvents conventional conventional that allow or ored microwave microwave the substitution heating. heating. of aConventionalConventional chlorine atom heating heating by one yielded yield iodineed better better atom. conversion conversion Subsequently, rates rates (about the (about necessary 90%, 90%, except acyl except for rearrangement olive for oil olive and cocoaoil and and industry halide cocoa eliminationindustrywastes). Althoughwastes). took place. Although microwave The microwavereaction heating was showed heating performed alower show by conversioned usinga lower conventional rate,conversion and a dark rateor microwave colour, and a was dark observedheating. colour Conventionalwasin crude observed products i heatingn crude (suggesting yieldproductsed degradation),better (suggesting conversion degradation), the second rates (about step the was second 90%, completed except step wa for ins onlycompleted olive 25 oil min, and in whereas only cocoa 25 industrymin,conventional whereas wastes). heatingconventional Although required heatingmicrowave 48 h [required50]. heating 48 hshow [50].ed a lower conversion rate, and a dark colour was observed in crude products (suggesting degradation), the second step was completed in only 25 R1 min, whereas conventionalO heating required 48 h [50]. R O OH R Cl CTMS NaI/nBuOH R R Cl 1 + O O O + CH2 O O O O O D* D* R O OH OH R 2 O OH R Cl Cl Cl O O CTMS NaI/nBuOH R O Cl + O O CH O R3 + 2 O D* O O OH OH D* R2 O Cl Cl O O R= Fatty acyl R3 Figure 6. Synthesis of allyl fatty esters, using various fatty materials. Step 1: Conventional heating at FigureR= Fatty acyl 6. Synthesis of allyl fatty esters, using various fatty materials. Step 1:

Conventional115 ◦C/48 h and microwaveheating at (MW) 115 °C/48 were 225 h and◦C, 300 microwave W, 17 atm for(MW) 3h. Stepwere 2: 225 Conventional °C, 300 W, heating 17 atm was 115 C/48 h, and MW was 150 C for 25 min. Figurefor ◦3h. Step 6. Synthesis 2: Conventional of allyl◦ heating fatty was esters, 115 using°C/48 h, various and MW fatty was materials. 150°C for 25 Step min. 1: Conventional heating at 115 °C/48 h and microwave (MW) were 225 °C, 300 W, 17 atm Several compounds containing an allyl group are biologically active as insecticides, acaricides forSeveral 3h. Stepcompounds 2: Conventional containing heating an allyl was group 115 are °C/48 biologically h, and MW active was as 150°C insecticides, for 25 min.acaricides and insect repellents [108–110]. Allyl fatty acids esters have been suggested as wood preservatives and insect repellents [108–110]. Allyl fatty acids esters have been suggested as wood preservatives against termites [111]. againstSeveral termites compounds [111]. containing an allyl group are biologically active as insecticides, acaricides and insectIn addition, repellents an ovicidal [108–110 eﬀ]ect. Allyl against fattyCydia acids pomonella esters have(L.) wasbeen described suggested for as allyl wood carboxylates preservatives [112]. againstAnother termites application [111 of]. allyl ester mixtures of higher fatty acids is in polymer synthesis. Highly eﬀective and generally useful copolymers have been prepared from allyl esters [113].

3.1.2. Synthesis of Nitrile Derivatives Using halohydrin dehalogenase (HheC) from Agrobacterium radiobacter, 1,3-DCH or R,S-ECH was used to prepare S-4-chloro-3-hydroxybutanenitrile (S-CHBN) (Figure7). The synthesis of S-CHBN from R,S-ECH yielded a modest enantiomeric excess, whereas the use of 1,3-DCH as substrate led to S-CHBN, with 97.3% ee after pH optimization. S-CHBN was also prepared from 1,3-DCH, with an 86% yield and a 97.5% ee in 1 h, using W249F a HheC mutant constructed by site-directed mutagenesis [114]. The enantiomer R-CHBN was synthesized from 1,3-DCH by using recombinant HheB from Corynebacterium sp. N-1074. The ﬁnal yield was 65%, and the product had an ee of 95.2% [115]. Molecules 2020, 25, x FOR PEER REVIEW 10 of 39

Molecules 2020In, 25 addition,, x FOR PEER an REVIEW ovicidal effect against Cydia pomonella (L.) was described for allyl 10carboxylates of 39 [112]. Another application of allyl ester mixtures of higher fatty acids is in polymer synthesis. Highly Ineffective addition, and an generallyovicidal effectuseful against copoly mersCydia havepomonella been (L.)prepared was described from allyl for esters allyl [113 carboxylates]. [112]. Another application of allyl ester mixtures of higher fatty acids is in polymer synthesis. Highly effective3.1.2. and Synthesis generally of useful Nitrile copoly Derivativesmers have been prepared from allyl esters [113]. Using halohydrin dehalogenase (HheC) from Agrobacterium radiobacter, 1,3-DCH or R,S-ECH 3.1.2.Molecules Synthesis 2020, 25, xof FOR Nitrile PEER DerivativesREVIEW 10 of 39 was used to prepare S-4-chloro-3-hydroxybutanenitrile (S-CHBN) (Figure 7). The synthesis of UsingInS -addition,CHBN halohydrin from an ovicidal R,S dehalogenase-ECH effect yielded against (HheC) a modestCydia from pomonella enantiomericAgrobacterium (L.) was excess, radiobacter described whereas, 1,3for- DCHallyl the usecarboxylatesor R,S of -1,3ECH-DCH as was[112 ].used Anothersubstrate to prepareapplication led to S-CHBN4 -ofchloro allyl, with- ester3-hydroxybutanenitrile 97.3%mixtures ee afterof higher pH optimization.fatty(S-CHBN acids) is(Figure in S -polymerCHBN 7). was Thesynthesis. also synthesis prepared Highly of from Seffective-CHBN1,3 and- fromDCH generally ,R,S with-ECH an useful 86% yielded copolyyield a and modestmers a have97.5% enantiomeric been ee in prepared 1 h , excess,using from W249F whereas allyl estersa HheC the [113 use mutant] . of 1,3 - constructedDCH as by substratesite - leddirected to S-CHBN mutagenesis, with 97.3%[114]. ee after pH optimization. S-CHBN was also prepared from 1,33.1.2.-DCH Synthesis, with anof Nitrile86% yield Derivatives and a 97.5% ee in 1 h, using W249F a HheC mutant constructed by W249mutant site-directed mutagenesis [114]. OH OH Using halohydrin dehalogenase (HheC) from PBSAgrobacterium +NaCN radiobacter, 1,3-DCH or R,S-ECH was used to prepare S-4-chloro-3-hydroxybutanenitrileCl Cl o (S-CHBNCl )CN (Figure 7). The synthesis of W249mutant40 C, 1h, pH= 7,5 (H2SO4) OH OH PBS +NaCN S-CHBN from R,S-ECH yielded a modest enantiomeric excess, whereas the use of 1,3-DCH as

Figure 7. Continuous synthesis of (S)o-4-chloro-3-hydroxybutanenitrileCl CN (S-CHBN) from 1,3-DCH and substrate led to S-CHBN, with 97.3%Cl Clee after40 C, 1h, pH pH= 7,5 optimization. (H2SO4) S-CHBN was also prepared from

1,3-DCH, withNaCN an cataly 86%z edyield by halohydrinand a 97.5% dehalogenase ee in 1 h, (HheC).using W249F a HheC mutant constructed by site-directedFigureMolecules 7. mutagenesisContinuous2020, 25, 2511 synthesis [114]. of (S)-4-chloro-3-hydroxybutanenitrile (S-CHBN) from 1,3-DCH10 of 38 and NaCN catalyThe enantiomerzed by halohydrin R-CHBN dehalogenase was synthesi (HheC).zed from 1,3-DCH by using recombinant HheB from

W249mutant Corynebacterium sp. N-1074. TheOH final yield was 65%, andOH the product had an ee of 95.2% [115]. PBS +NaCN The enantiomerChiral C4 compoundsR-CHBN was are synthesi syntheticzed units from useful 1,3-DCH for the by production using recombinant of various HheB pharmaceuticals from Cl Cl 40 oC, 1h, pH= 7,5 (H SO ) Cl CN Corynebacterium sp. N-1074. The final yield was 65%, and2 4 the product had an ee of 95.2% [115]. and chiral polymers [116]. As an example, S-CHBN is used as a precursor of atorvastatin, a Chiralcholesterol C4Figure compounds- 7.loweringContinuous aredrug synthesis synthetic [114 of].( S )-4-chloro-3-hydroxybutanenitrile units useful for the production (S-CHBN) of from var 1,3-DCHious pharmaceuticals and Figure 7. Continuous synthesis of (S)-4-chloro-3-hydroxybutanenitrile (S-CHBN) from 1,3-DCH and and chiral polymersNaCN catalyzed [116 by]. halohydrin As an dehalogenaseexample, S (HheC).-CHBN is used as a precursor of atorvastatin, a NaCN catalyzed by halohydrin dehalogenase (HheC). cholesterol3.1.3.-lowering SyntChiralhesis C4 drug compounds of Azide [114] Derivatives. are synthetic units useful for the production of various pharmaceuticals Theand enantiomer chiral polymers R-CHBN [116]. was As synthesi an example,zed Sfrom-CHBN 1,3 is-DCH used asby ausing precursor recombinant of atorvastatin, HheB from 3.1.3. SyntSynthesisa cholesterol-loweringhesis of of Azide Diazides Derivatives drug [114]. Corynebacterium sp. N-1074. The final yield was 65%, and the product had an ee of 95.2% [115]. To prepare the corresponding diazide derivatives, 1,3-Dichloroprop-2-yl esters were used SynthesisChiral3.1.3. of C4 D Synthesisiazides compounds of Azide are Derivatives synthetic units useful for the production of various pharmaceuticals and chiral(Figure polymers 8) [117,118 [116]. ]The. As substitution an example, process S-CHBN was carried is used out as by a precursorusing a conventional of atorvastatin, metho adology Synthesis of Diazides cholesterolToto prepare prepare-lowering the azides drug corresponding [[119114]].. The diazide reaction derivatives, of 1,3-dichloroprop 1,3-Dichloroprop-2-yl ester-2 -ylwith esters NaN were3 (Figure used 8, See (FigureS upplementary8) [117,118To prepare]. The M the aterialssubstitution corresponding Section process diazide 1.1.2 )was yielded derivatives, carried 1,3 1,3-Dichloroprop-2-ylout-diazidoprop2 by using a- conventionalyl esters esters (70 were% metho– used86% dologyyield), which (Figure8)[ 117,118]. The substitution process was carried out by using a conventional methodology to to3.1.3. prepare Syntcan hesisbe azides used of Azide as[119 crude] .Derivatives The material reaction for further of 1,3- dichloropropreactions. -2-yl ester with NaN3 (Figure 8, See prepare azides [119]. The reaction of 1,3-dichloroprop-2-yl ester with NaN (Figure8, See Supplementary Supplementary Materials Section 1.1.2) yielded 1,3-diazidoprop2-yl3 esters (70%–86% yield), which Materials Section 1.1.2) yieldedOH 1,3-diazidoprop2-yl esters (70–86% yield), which can be used as crude O O O CTMS NaN3 canSynthesis be usedmaterial of asD iazidescrude for further material reactions. for further reactions. R N3 + R R Cl O o O OH 100 oC, 48h 100 C, o/n OH OH N OH Cl 3 To prepare the corresponding diazide derivatives,O 1,3-DichloropropO -2-yl esters were used O CTMS NaN3 R N3 (Figure 8) [117,118]. The substitution+ R process wasR carriedCl out by using a conventional methodology O o O OH OH OH 100 oC, 48h 100 C, o/n R= (C H ) CH; CH CH (CH ) C; CH (CH ) (n=6, 11-16)Cl N3 to prepare azides [119]. The 6 reaction5 2 3 2 of3 2 1,33 -dichloroprop2 n -2-yl ester with NaN3 (Figure 8, See Supplementary Materials Section 1.1.2) yielded 1,3-diazidoprop2-yl esters (70%–86% yield), which R= (CFigureH ) CH; CH8. CHSynthesis(CH ) C; CH (CH of) (n=6, azide 11-16) s from glycerol and carboxylic acids. can be used as crude material6 5 2 for3 2 further3 2 3 reactions.2 n Figure 8. Synthesis of azides from glycerol and carboxylic acids. OH Synthesis Figureof Mononoamide 8. Synthesis D oferivatives azides from Oglycerol and carboxylicO acids. O CTMS NaN3 R N3 Synthesis of Mononoamide+ DerivativesR R Cl O o O The synthesisOH ofOH nine monoamidesOH 100 oC, 48h from crude 100 glycerol C, o/n and carboxylic acids (C8-C18) was Synthesis of Mononoamide Derivatives Cl N3 describedThe synthesis by the authors of nine monoamides’ research group from crude [120] glycerol. Diazides and carboxylic were synthesized acids (C8-C18) through was the pathway described by the authors’ research group [120]. Diazides were synthesized through the pathway shown Theshown synthesis in Figure of nine8. Diazides monoamides were reduced from crude by catalytic glycerol hydrogenation and carboxylic, under acids mild (C8 conditions-C18) was, using in Figure8. DiazidesR= (C6H5) were2CH; CH3 reducedCH2(CH3)2C; CH by3(CH catalytic2)n (n=6, 11-16) hydrogenation, under mild conditions, using Pd /C. describedPd/C.The by reductionThe the reduction authors resulted’ researchresulted in an O- to ingroupN an-acyl O migration-[ 120to N]. -acylDiazides to yieldmigration a were monoamide to synthesized yield (Figure a monoamide9 ). through the(Figure pathway 9). shown in Figure Figure8. Diazides 8. Synthesis were reduced of azide bys catalyticfrom glycerol hydrogenation and carboxylic, under mildacids conditions. , using O Pd/C. The reduction resulted in anO O- to N-acyl migration to yield a monoamide (Figure 9). OH R N3 Pd/C(10%), N R NH Synthesis of Mononoamide Derivatives 2 O O r.t., 72h H2N O N3 OH The synthesis of R nine monoamidesN3 from crude R glycerolNH and carboxylic acids (C8-C18) was Pd/C(10%), N2 57-88% O described by the authors’ research groupr.t., 72h[120]. Diazides H were2N synthesized through the pathway N3 R= (C6H5)2CH; CH3CH2(CH3)2C; CH3(CH2)n (n=6, 11-16) shown in Figure 8. Diazides were reduced by catalytic hydrogenation57-88% , under mild conditions , using Pd/C. The reductionFigure resulted 9. Synthesis in an of O monoamides- to N-acyl by hydrogenationmigration to of yield the corresponding a monoamide diazides. (Figure 9). R= (C H ) CH; CH CH (CH ) C; CH (CH ) (n=6, 11-16) 6 5 2 3 2 3 2 3 2 n The use of monoamides as phase change materialsO (PCM) in thermal energy storage was O investigated. The enthalpy of the monoamides ranged from 25.8 toOH 149.7 kJ/kg. The highest values R N3 R NH Pd/C(10%), N2 of latent heat were ofO the same order as those of commercial PCMs with low latent heat values, such r.t., 72h H2N as paraﬃn wax (146–210 kJ/Nkg)3 [121]. These compounds, which can form at least 4 hydrogen bonds, a powerful assembly tool in terms of PCM activity, were used57-88% to demonstrate the eﬀect of hydrogen bonds and alkyl chain on their thermal properties [120]. R= (C H ) CH; CH CH (CH ) C; CH (CH ) (n=6, 11-16) 6 5 2 3 2 3 2 3 2 n 3.1.4. Sulfonamides Lupasçu et al. described the synthesis of water-soluble rutin-sulfonamide derivatives with high yields (83–94%). The reaction was carried out by using 1,3-DCH as the linker of rutin and several Molecules 2020, 25, x FOR PEER REVIEW 11 of 39 Molecules 2020, 25, x FOR PEER REVIEW 11 of 39

FigureFigure 9.9. SynthesisSynthesis ofof monoamidesmonoamides byby hydrogenationhydrogenation ofof thethe correspondingcorresponding diazides.diazides.

TheThe use use of of monoamides monoamides as as phase phase change change materia materialsls (PCM) (PCM) in in thermal thermal energy energy storage storage was was investigated.investigated. TheThe enthalpyenthalpy ofof thethe monoamidesmonoamides rangedranged fromfrom 25.825.8 toto 149.7149.7 kJ/kg.kJ/kg. TheThe highesthighest valuesvalues ofof latentlatent heatheat werewere ofof thethe samesame orderorder asas thosethose ofof commercialcommercial PCMsPCMs withwith lowlow latentlatent heatheat valuesvalues,, suchsuch asas paraffinparaffin waxwax (146(146––210210 kJ/kg)kJ/kg) [[121121]].. TheseThese compounds,compounds, whichwhich cancan formform atat leastleast 44 hydrogenhydrogen bonds,bonds, aa powerfulpowerful assemblyassembly tooltool inin termsterms ofof PCMPCM activity,activity, werewere usedused toto demonstratedemonstrate thethe effecteffect ofof hydrogenhydrogen bondsbonds andand alkylalkyl chainchain onon theirtheir thermalthermal propertiesproperties [[120120]]..

3.1.4.3.1.4. SulfonamidesSulfonamides LupasçuLupasçu etet al.al. describeddescribed thethe synthesissynthesis ofof waterwater--solublesoluble rutinrutin--sulfonamidesulfonamide derivativesderivatives withwith highhigh Molecules 2020, 25, 2511 11 of 38 yieldsyields (83(83%%––94%).94%). TheThe reactionreaction waswas carriedcarried outout byby usingusing 1,31,3--DCHDCH asas thethe linkerlinker ofof rutinrutin andand severalseveral sulsulffonaonamidemidess,, resultingresulting inin somesome waterwater--solublesoluble sulfonamidesulfonamide derivativesderivatives (Figure(Figure 10).10). TheThe derivativesderivatives withwithsulfonamides, pyridine pyridine (sulfapyridine)resulting (sulfapyridine) in some andand water-soluble chloropyridazinechloropyridazine sulfonamide ( (sulfachloropyridazinesulfachloropyridazine derivatives (Figure)) showedshowed 10). The anan derivatives equal equal or or evenwitheven pyridinehigherhigher antibacterialantibacterial (sulfapyridine) activity activity and chloropyridazine than than co co--trimoxazoletrimoxazole (sulfachloropyridazine),, an an antibiotic antibiotic usedused showed to to treat treat an equal a a variety variety or even of of bacterialbacterialhigher antibacterial infections. infections. activity Co Co--trimoxazoletrimoxazole than co-trimoxazole, consists consists of of an one one antibiotic part part ofof used trimethoprimtrimethoprim to treat a variety to to five five of parts partsbacterial ofof sulfamethoxazolesulfamethoxazoleinfections. Co-trimoxazole [[122122]].. consists of one part of trimethoprim to ﬁve parts of sulfamethoxazole [122].

1)CH3ONa, 30min, reflux 1)CH3ONa, 30min, reflux 2)2) OH OH OH OH CH OH OH CH33 OOHH OO NNHH HHOO OO Cl Cl Cl Cl HHOO OO SOSO2 ram-glu 2 ram-glu 3)3) ram-glu HN OO ram-glu HN OO RR OH O H2N SO2 OH O H2N SO2 OH O reflux, 6h OH O reflux, 6h NNHHRR

R=R=

H3CO H3C H3CO H3C N N O N N N N NN NN O S N N N OO S N OCH3 Cl N N OCH3 Cl N N N N NN N HH3CC CH N 3 CH3 CH33 CH3 FigureFigure 10.Figure10. SynthesisSynthesis 10. Synthesis ofof rutinerutine of rutine-sulphonamide--sulphonamidesulphonamide derivatives, derivatives, using usingusing 1,3-DCH 1,31,3--DCHDCH as a linker. asas aa linker.linker.

3.1.5. Synthesis of Polynuclear Metals 3.1.5.3.1.5. SynthesisSynthesis ofof PPolynuclearolynuclear MMetalsetals TheThe synthesissynthesis ofof dinucleatingdinucleating ligandsligands was was carried carried out out by by usingusing 1,31,3 1,3-DCH--DCHDCH [123,124 [[123,124123,124]].].. TT Thehehe synthesis synthesis was a two-step reaction (Figure 11)[124,125]. The symmetrical dinucleating ligand (H3hpnbpd)3 holds waswas aa two two--stepstep reaction reaction (Figure(Figure 11) 11) [124,125[124,125]].. TheThe symmetrical symmetrical dinucleating dinucleating ligand ligand ((HH 3hpnbpd)hpnbpd) holdsholdstwo carboxyl twotwo carboxylcarboxyl groups groupsgroups and two and and pyridine two two pyridine pyridine arms. While arms. arms. PatraWhileWhile et PatraPatra al. synthesized etet al. al. synthesizedsynthesized the ligand the the by ligand ligand reacting byby reactingreactingglycine withglycineglycine 1,3-DCH withwith 1,31,3 in--DCHDCH the ﬁrst inin thethe step firstfirst and stepstep obtaining andand obtainingobtaining the ligand thethe withligandligand a 75%withwith yieldaa 75%75% after yieldyield a after secondafter aa β secondsecondreaction reactionreaction step with stepstep 1-chloromethylpyridine, withwith 11--chloromethylpyridinechloromethylpyridine Haldar, et, HaldarHaldar al. used etet al.al.-alanine usedused ββ instead--alaninealanine of insins glycineteadtead ofof as glycineglycine a reagent, asas aaachieving reagent,reagent, achieving theachieving corresponding thethe correspondingcorresponding ligand, with ligandligand a 73%,, withwith yield. aa 73%73% yield.yield.

OO OH (CHOH) OH (CH22n)n OH ClCl (CH ) O OH HO . o (CH22n)n O OH NH (CH )nCOOH HO N HCl/LiOH/H. 2O 0 Co -> r.t.,1 day NH2 (CH2 )nCOOH N HCl/LiOH/H2O 0 C -> r.t.,1 day 2 2 (CH ) OH O N N (CH22n)nOH O N N O NH o O NH OH 1)LiOH/H O, 40 C,o 3 days OH 2)HBr/H O to pH=5 OH Cl Cl 1)LiOH/H2 O, 40 C, 3 days NH(CH2)n 2)HBr/H2 O to pH=5 OH Cl Cl 2 NH(CH2)n 2 NN NN 2)HBr/H2O to pH=5 2)HBr/H2O to pH=5

n=1,2 n=1,2 Figure 11. Synthesis of the H3hpnbpda ligand. FigureFigure 11.11. SynthesisSynthesis ofof thethe HH33hpnbpdahpnbpda ligand.ligand. Cooper (II) complexes were also obtained via the synthesis of a bipyrazolic ligand, bearing two CooperCooper (II)(II) complexescomplexes werewere alsoalso obtainedobtained viavia thethe synthesissynthesis ofof aa bipyrazolicbipyrazolic ligand,ligand, bearingbearing twotwo carboxyl groups (Figure 12). The ﬁrst step was similar to the previous one, 1,3-DCH reacted with two carboxylcarboxyl groupsgroups ((FigureFigure 1212)).. TheThe firstfirst stepstep waswas similarsimilar toto thethe previousprevious one,one, 1,31,3--DCHDCH reactedreacted withwith molecules of the corresponding pyrazole derivative. The ﬁnal Cu(II) complex showed good catalytic twotwo molecules molecules of of the the corresponding corresponding pyrazole pyrazole derivative. derivative. The The final final Cu(II) Cu(II) complex complex showshoweded goodgood propertiesMolecules 2020 in, 2 the5, x FOR oxidation PEER REVIEW of catechol [126]. 12 of 39 catalyticcatalytic propropertiesperties inin thethe oxidationoxidation ofof catecholcatechol [[126126]]..

H3C N H CO Et CO Et HO2C CO2H O O O N 2 2 O t 1) BuOK, reflux, 30min Cu- - - - N OH N NaOH/H2O N OH N CH3COCH3 N- - - - N CO2Et OH N N o N N OH 24h, r.t. -> 0 C CuCl /H O r.t. 2) ,reflux, 15h 2 2 N N H3C CH3 H3C CH3 until cristallization ( 2-5 days) H3C CH3 Cl Cl FigureFigure 12. 12.SynthesisSynthesis of of the coppercopper complexes complexes CuL1. CuL1.

Polynuclear metals metals have have many many potential potential applications, applications e.g., therapeutic, e.g., therapeutic agents (e.g., photocleavage agents (e.g., ofphotocleavage DNA), photovoltaic of DNA), components,photovoltaic components, photocatalysts, photocatalysts, magnetic materials magnetic and materials tuneable and chemicaltuneable sensorschemical [127 sensors–130]. [127–130].

3.1.6. Glycoconjugate Synthesis In the synthesis of 1,2-cis-alkyl glycosides, 1,3-DCH was used. Figure 13 shows the synthesis of 1,3-dichoroprop-2-yl-2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside. The first step consisted of the substitution of the thiophenoxy group of the hemithioacetal of β-D-galactopyranoside by 1,3-DHC. This substitution allowed the synthesis of the corresponding α-D-galactopyranoside alkyl isomer. Finally, the peracetylation of the free alcohol led to the final product, with an 84.9% yield [131].

OAc HO OH AcO HO OH O OH O O HO 1) H O SPh 1h, N atm, r.t. Ac O, DMAP, Pyridine AcO OH 2 OH 2 O OAc Cl Cl o -- O 2) -30 C >NIS, TMSOTf r.t., o/n Cl 2h Cl Cl Cl 84,9% Figure 13. Synthesis of 1,2-cis-alkyl tetra-O-acetyl glycosides, using 1,3-DCH.

In a similar approach, Salman et al. described the attempt to synthesize diamide-linked bi-antennary surfactants with close structural similarity to natural glycol-glycerolipids [132]. The starting peracetylated disaccharide reacted with 1,3-DCH, in the presence of a Lewis acid (BF3), to yield the corresponding alkyl sugar. The substitution of both chlorine atoms by the azide group led to the corresponding diazide. However, the Staudinger-based coupling of fatty acid chlorides did not provide the expected diamide, obtaining the cyclic coupling products instead (Figure 14).

Molecules 2020, 25, x FOR PEER REVIEW 12 of 39

Polynuclear metals have many potential applications, e.g., therapeutic agents (e.g., Moleculesphotocleavage2020, 25, 2511 of DNA), photovoltaic components, photocatalysts, magnetic materials and12 oftuneable 38 chemical sensors [127–130].

3.1.6.3.1.6. Glycoconjugate Glycoconjugate Synthesis Synthesis In theIn synthesis the synthesis of 1,2- ofcis 1,2-alkyl-cis-alkyl glycosides, glycosides 1,3-DCH, 1,3-DCH was was used. used Figure. Figure 13 13shows shows the the synthesis synthesis of of 1,3-dichoroprop-2-yl-2,3,4,6-tetra-1,3-dichoroprop-2-yl-2,3,4,6-tetraO--acetyl-O-acetylα--αd--galactopyranoside.D-galactopyranoside The. The ﬁrst first step step consisted consisted of the of the substitutionsubstitution of the of thiophenoxy the thiophenoxy group group of the of hemithioacetal the hemithioacetal of β- dof-galactopyranoside β-D-galactopyranoside by 1,3-DHC. by 1,3-DHC. ThisThis substitution substitution allowed allowed the synthesisthe synthesis of the of correspondingthe correspondingα-d-galactopyranoside α-D-galactopyranoside alkyl alkyl isomer. isomer. Finally,Finally, the peracetylation the peracetylation of the of free the alcohol free alcohol led to led the to ﬁnal the product,final product with, anwith 84.9% an 84.9% yield [yield131]. [131].

OAc HO OH AcO HO OH O OH O O HO 1) H O SPh 1h, N atm, r.t. Ac O, DMAP, Pyridine AcO OH 2 OH 2 O OAc Cl Cl o -- O 2) -30 C >NIS, TMSOTf r.t., o/n Cl 2h Cl Cl Cl 84,9% FigureFigure 13. 13. Synthesis of of 1,2- 1,2cis--alkylcis-alkyl tetra- tetraO-acetyl-O- glycosides,acetyl glycosides, using 1,3-DCH. using 1,3-DCH. In a similar approach, Salman et al. described the attempt to synthesize diamide-linked In a similar approach, Salman et al. described the attempt to synthesize diamide-linked bi-antennary surfactants with close structural similarity to natural glycol-glycerolipids [132]. bi-antennary surfactants with close structural similarity to natural glycol-glycerolipids [132]. The The starting peracetylated disaccharide reacted with 1,3-DCH, in the presence of a Lewis acid starting peracetylated disaccharide reacted with 1,3-DCH, in the presence of a Lewis acid (BF3), to (BF ), to yield the corresponding alkyl sugar. The substitution of both chlorine atoms by the azide 3 yield the corresponding alkyl sugar. The substitution of both chlorine atoms by the azide group led group led to the corresponding diazide. However, the Staudinger-based coupling of fatty acid chlorides to the corresponding diazide. However, the Staudinger-based coupling of fatty acid chlorides did did not provide the expected diamide, obtaining the cyclic coupling products instead (Figure 14). Moleculesnot provide 2020, 25, xthe FOR expected PEER REVIEW diamide , obtaining the cyclic coupling products instead (Figure 14)13. of 39

OAc OAc O AcO O AcO OAc OAc OAc OH O OAc OAc OAc OAc O NaN O OAc AcO O 3 AcO O AcO AcO O O O O OAc DMF, 80 oC, 24h OAc OAc Cl Cl OAc OAc OAc CH Cl (anhydr) 2 2 Cl N3 BF3 xEt2O Cl N3 3h, r.t.

1)PPh3 2)CnH2n+1COCl/CH2Cl2, - until N2 was completely liberated r.t., 7 15h

OAc OAc OAc OAc O AcO O O O * AcO AcO O O AcO O OAc O N OAc OAc OAc OAc OAc NHCOC H n 2n+1 N CnH2n+1 NHCOCnH2n+1 H

1)MeOH, NaOMe, r.t., o/n

2)Amberlite 120(H+)

OH OH O HO O HO O O N OH * OH OH N CnH2n+1 H

93-94%

Figure 14. Staudinger reaction of lactose based diazides with fatty acids. Figure 14. Staudinger reaction of lactose based diazides with fatty acids.

Carbohydrates and glycoconjugates are essential components of the cell membrane. They participate in many functions [133]. Therefore, the chemical synthesis of these glycoconjugates (proteoglycans, glycolipids and glycoproteins) is important for the study of their biological functions. As an exemple, glycol-glycerol lipid amide analogues exhibit very high Krafft temperatures [132]. Anomerically pure alkyl glycosides are used as building blocks to achieve stereoselective synthesis of these structures. Some of them (mostly propargyl and allyl glycosides) [134,135] are also essential components for the construction of microarrays [136,137] and glycodendrimers [138].

3.1.7. Funcionalization of Aza-Heterocyclic Compounds Chlorohydrins and ECH were used to prepare derivatives of pyridine [139–141], phtalazines [142–144], oxazolidinone [122,145,146], triazinones [147], thioglycoside [148] and aziridines [149]. N-Heterocycles have wide applicability as antibiotics [150–152]. The evaluation of novel agents for antimicrobial activity is a very important field of study due to the emergence of bacterial resistance to classical antibiotics.

Molecules 2020, 25, 2511 13 of 38

Carbohydrates and glycoconjugates are essential components of the cell membrane. They participate in many functions [133]. Therefore, the chemical synthesis of these glycoconjugates (proteoglycans, glycolipids and glycoproteins) is important for the study of their biological functions. As an exemple, glycol-glycerol lipid amide analogues exhibit very high Kraﬀt temperatures [132]. Anomerically pure alkyl glycosides are used as building blocks to achieve stereoselective synthesis of these structures. Some of them (mostly propargyl and allyl glycosides) [134,135] are also essential components for the construction of microarrays [136,137] and glycodendrimers [138].

3.1.7. Funcionalization of Aza-Heterocyclic Compounds Chlorohydrins and ECH were used to prepare derivatives of pyridine [139–141], phtalazines [142–144], oxazolidinone [122,145,146], triazinones [147], thioglycoside [148] and aziridines [149]. N-Heterocycles have wide applicability as antibiotics [150–152]. The evaluation of novel agents for antimicrobial activity is a very important ﬁeld of study due to the emergence of bacterial resistance to classical antibiotics.

Pyridine Derivatives The synthesis of O-alkyl nicotinonitriles by the reaction of 1,3-DCH or ECH with pyridin- 2(1H)-one in presence of K2CO3 is shown in Figure 15a,b. A similar reaction is described in Figure 15c. The 1,3-DCH or ECH reacted with pyridin-2(1H)-one in the presence of NaH, aﬀording the corresponding N-linked products. K2CO3 favored the O-alkylation of the lactam, while NaH favored the N-alkylation. The derivative synthesized from ECH by Moustafa et al. showed moderate antibacterial activity compared to the standard drug, while the dichloropropanol derivative showed no activity against the tested microorganisms [140]. The compounds synthesized by Saad et al. showed antibacterial eﬀects but no activity against the target fungal strains [140]. However, the compounds synthesized by Shamroukh et al. showed remarkable cytotoxicity activity against MCF-7 and HepG2 cell lines [141]. Molecules 2020, 25, x FOR PEER REVIEW 14 of 39 no activity against the tested microorganisms [140]. The compounds synthesized by Saad et al. showed antibacterial effects but no activity against the target fungal strains [140]. However, the Molecules 2020compounds, 25, 2511 synthesized by Shamroukh et al. showed remarkable cytotoxicity 14 activity of 38 against MCF-7 and HepG2 cell lines [141].

Cl OH NC O K2CO3/DMF,  Cl NH 48% Cl Cl O NC S NH

S O Cl NC O O Cl NH 71%

K2CO3/DMF, r.t. Cl S (a)

Cl OH NC O H3C K2CO3/DMF, , 5h NH Cl Cl O 60% H3C NC N NH

N H3C

CH3 O

NC O H3C O NH

K CO /DMF,, 5h H3C Cl 2 3 N

(b) 65%

Cl OH OH OH NaH/DMF, NC N 47%

Cl Cl O Cl Cl NC NH

O OH Cl Cl NC O N 51%

Cl (c) NaH/DMF, Cl Cl

Figure 15. Synthesis of pyridine derivatives (a) Moustafa et al. synthesis [139]; (b) synthesis described

by Saad et al. [140]; (c) Shamroukh et al. niconitrile synthesis [141].

Synthesis ofFigure Aziridine 15. Synthesis Derivatives of pyridine derivatives (a) Moustafa et al. synthesis [139]; (b) synthesis Lebeldescribed et al. described by Saad the et synthesis al. [140]; of(c) a ShamroukhN-tosyloxycarbamate et al. niconitrile using synthesis 1,3-DCH and[141] tosyl. chloride. The use of a chiral bis(oxazoline) copper complex with the N-tosyloxycarbamate yielded the asymetric aziridines with a enantiomeric R/S ratio of 4:1 (Figure 16)[149].

Molecules 2020, 25, x FOR PEER REVIEW 15 of 39 MoleculesSynthesis 2020, 2of5, xAziridine FOR PEER REVIEWDerivatives 15 of 39 SynthesisLebel of Aziridine et al. described Derivatives the synthesi s of a N-tosyloxycarbamate using 1,3-DCH and tosyl chloride. The use of a chiral bis(oxazoline) copper complex with the N-tosyloxycarbamate yielded the Lebel et al. described the synthesis of a N-tosyloxycarbamate using 1,3-DCH and tosyl chloride. asymetric aziridines with a enantiomeric R/S ratio of 4:1 (Figure 16) [149]. MoleculesThe2020 use, 25 , 2511of a chiral bis(oxazoline) copper complex with the N-tosyloxycarbamate yielded15 of 38 the H C asymetric aziridines with a enantiomeric R/S ratio of 4:1 (Figure 16) 3[149CH]3. O H3C O H3CH C N N CH3 3 CH3 Cl Cl CH O Ph 3 H3C O Ph O 1)MeCN, 3h r.t. OH Cl H C N CH . 3 NPh(6%) 3 ClO ClO NH2OH HCl, imidazole, 16h, r.t. O N N Cu(CH CN) PFC H(5%) + N Ph 3 4 6 3 Cl Ph NO 1)MeCN,2)Ether, 3h r.t. 0oC + Tosylchloride O NHOTs N OHCl Cl . Cl - Ph(6%) NH OH EtHCl,N, 2h, imidazole, r.t 16h, r.t. O 4 Nitrostyrene, K2CO3 O O N 2 3 + N Cu(CH3CN)4PF6 (5%)o N Cl CH3, MS 4A, 23 C N 2)Ether, 0oC + Tosylchloride O NHOTs N Cl Cl NO2 4-Nitrostyrene, K CO Et3N, 2h, r.t 2 3 o CH3, MS 4A, 23 C 59% 16% NO2

59% Figure 16. Synthesis of aziridine derivatives using 1,3-16%DCH. Figure 16. Synthesis of aziridine derivatives using 1,3-DCH. AziridinesFigure are the 16. smallest Synthesis nitrogen of aziridine-containing derivatives heterocycles. using 1,3 Although-DCH. aziridine moiety is Aziridinespresent are in the few smallest natural nitrogen-containing products [153], heterocycles.they display Although important aziridine biological moiety activities is present [154,155]. Aziridines are the smallest nitrogen-containing heterocycles. Although aziridine moiety is in few naturalAziridines products have [153been], theyintroduced display into important various biological structures activities, to create [154 novel,155]. chemotherapeutic Aziridines have agents present in few natural products [153], they display important biological activities [154,155]. been introduced[156,157] into. various structures, to create novel chemotherapeutic agents [156,157]. Aziridines have been introduced into various structures, to create novel chemotherapeutic agents In organicIn organic chemistry, chemistry aziridines, aziridines are valuable are valuable building building blocks. blocks. As an As example, an example, their their reaction reaction with [156,157]. with manymany nucleophiles nucleophiles can canresult result in ring-opening in ring-opening reactions reactions [158– 161[158].– They161]. canThey also can be also used be as used key as key In organic chemistry, aziridines are valuable building blocks. As an example, their reaction with intermediatesintermediates in diversity-oriented in diversity-oriented synthesis synthesis of alkaloids of alkaloids [162]. Aziridines [162]. Aziridines have been have used been in used the in the many nucleophiles can result in ring-opening reactions [158–161]. They can also be used as key asymmetricasymmetric total syntheses total syntheses of renieramycins of renieramycins M and G M and and jorumycin, G and jorumycin marine, bioactivemarine bioactive compounds compounds intermediates in diversity-oriented synthesis of alkaloids [162]. Aziridines have been used in the from a bluefrom sponge a blue and sponge a molusc, and respectivelya molusc, respectively [163]. Aziridines [163]. areAziridines masked are 1,3-dipoles masked that 1,3- reactdipoles with that react asymmetric total syntheses of renieramycins M and G and jorumycin, marine bioactive compounds alkenes,with alkynes, alkenes, nitriles alkynes, and carbonyl nitriles and compounds carbonyl to compounds produce various to produce [3+2] various cycloadducts [3+2] cycloadducts [164]. [164]. from a blue sponge and a molusc, respectively [163]. Aziridines are masked 1,3-dipoles that react SynthesiswithSynthesis ofalkenes, 1,2,4-Triazinones of alkynes, 1,2,4-T riazinonesnitriles Derivatives and D carbonylerivatives compounds to produce various [3+2] cycloadducts [164].

TheSynthesis synthesisThe of 1,2,4 synthesis of-TS-alkylriazinones of 4-amino-3-mercapto-6-(2-(2-thienyl)vinyl)S-alkyl Derivatives 4-amino -3-mercapto-6-(2-(2-thienyl)vinyl) -1,2,4-triazin -1,2,4- -5(4H)-onetriazin -5(4H)-one derivatives,derivative usings, 1,3-DCH using 1,3 or-DCH ECH, or isECH shown, is shown in Figure in Figure 17. Potassium17. Potassium carbonate carbonate in in DMF DMF was was again The synthesis of S-alkyl 4-amino-3-mercapto-6-(2-(2-thienyl)vinyl) -1,2,4-triazin -5(4H)-one again usedused as as a base,a base to, to improve improve the the nucleophilicity nucleophilicity of theof the S atom, S atom preserving, preserving the the epoxy epoxy group group in thein the final derivatives, using 1,3-DCH or ECH, is shown in Figure 17. Potassium carbonate in DMF was again ﬁnal product.product These. These compounds compounds showed showed moderate moderate anticancer anticancer activity activity [147 [147]. ]. used as a base, to improve the nucleophilicity of the S atom, preserving the epoxy group in the final product. These compounds showed moderate anticancerS activity [147].

OH K2CO3, DMF o.n./r.t. S N N 55% S OHCl Cl K CO , DMF OH 2 3 O N S o.n./r.t. N N NH2 55% S Cl Cl Cl N OH N O N S S NH O N SH 2 Cl N N NH2 S N N Cl O O O N SH S 65% K2CO3, DMF N NH2 o.n./r.t. N ON NH Cl 2 O O S 65% K2CO3, DMF N Figure 17.FigureSynthesis 17.o.n./r.t. Synthesis of 1,2,4-triazine of 1,2,4O -thiophene--triazineNH -thiophene derivatives.- derivatives. 2 Synthesis of Pthalazine Derivatives Synthesis of PthalazineFigure Derivatives 17. Synthesis of 1,2,4-triazine -thiophene- derivatives. The reaction of 1,3-DCH and ECH with arylphthalazinone yielded phthalazin SynthesisThe of reaction Pthalazine of 1,3Derivatives-DCH and ECH with arylphthalazinone yielded phthalazin derivatives [142– derivatives [142–144,147]. Figure 18a shows the N-alkyl products resulting from the nucleophilic 144,147]. Figure 18a shows the N-alkyl products resulting from the nucleophilic attack of the attack of theThe nitrogen reaction inof 1,3 the-DCH phthalazinone and ECH with on 1,3-DCH arylphthalazinone (33% to 36% yield yield)ed phthalazin or ECH (51% derivatives to 54% [142– nitrogen in the phthalazinone on 1,3-DCH (33% to 36% yield) or ECH (51% to 54% yield). This attack yield).144,147 This attack]. Figure was 18a promoted shows by the the N- presencealkyl products of K2CO resulting3. The loss from of aromaticity,the nucleophilic when attack an aryl of the was promoted by the presence of K2CO3. The loss of aromaticity, when an aryl radical was radicalnitrogen was substituted in the phthalazinone by a benzyl radical,on 1,3-DCH allowed (33% the to regiospeciﬁc 36% yield) or nucleophilic ECH (51% attackto 54% of yield). the oxygen This attack substituted by a benzyl radical, allowed the regiospecific nucleophilic attack of the oxygen instead of insteadwas of promotedthe nitrogen by on the 1,3-DCH presence and of ECH K2CO (Figure3. The 18 lossb) [ 144 of ]. aromaticity The reaction, when of ECH an occurred aryl radical via was the nitrogen on 1,3-DCH and ECH (Figure 18b) [144]. The reaction of ECH occurred via ring ring opening–ringsubstituted by closing a benzyl of radical the oxirane, allowed nucleus the regiospecific (54% yield), whilenucleophilic the reaction attack with of the 1,3-DCH, oxygen instead was of opening–ring closing of the oxirane nucleus (54% yield), while the reaction with 1,3-DCH, was describedthe nitrogen as a SN2 reactionon 1,3-DCH to yield andO -(3-chloro-2-hydroxypropyl) ECH (Figure 18b) [144]. The phthalazine reaction (36% of ECH yield). occurred Finally, via Se- ring and Sopening-alkyl phthalazines–ring closing were of also the synthesized, oxirane nucleus with yields(54% yield), in the range while of the 71–72% reaction and with 62–75% 1,3 for-DCH the, was 1,3-DCH and ECH, respectively (Figure 18c). All compounds showed moderate-to-high antimicrobial activity in comparison with standard drugs [142,143]. Molecules 2020, 25, x FOR PEER REVIEW 16 of 39

described as a SN2 reaction to yield O-(3-chloro-2-hydroxypropyl) phthalazine (36% yield). Finally, Se- and S-alkyl phthalazines were also synthesized, with yields in the range of 71%–72% and 62%– Molecules75% for2020 the, 25 1,3, 2511-DCH and ECH, respectively (Figure 18c). All compounds showed moderate-to16- ofhigh 38 antimicrobial activity in comparison with standard drugs [142,143].

(a)

Ar OH K CO , DMF Cl 2 3 N N 33-36% Cl Cl Ar OH O N NH Ar O Cl N O N O 51-54% K2CO3, DMF O

Ar=C6H5, p-Cl(C6H4), p-CH3(C6H4).

(b)

OH K2CO3, DMF

O Cl Cl Cl N N 36% OH

OH N N

Cl O 54% O O N N K2CO3, DMF

71-72% Cl Cl Ar

CH3 N Ar= NH

Y H C 3 CH3 N N O Cl Ar Y O 62-75% K2CO3, DMF Y= S- Se

Figure 18. (a) Synthesis of N-alkylated phtalazines [142]; (b) synthesis of 1-oxo alkylated phtalazine [144]; (cFigure) synthesis 18. (a of) S Se-ynthesis and S-alkyl of N-alkylated phthalazines phtalazines derivatives [142 [143]; (b].) synthesis of 1-oxo alkylated phtalazine [144]; (c) synthesis of Se- and S-alkyl phthalazines derivatives [143]. 3.1.8. Synthesis of Polymers 3.1.8. Synthesis of Polymers De Espinosa et al. described a plant-oil-based diene containing hydroxyl groups ten years ago. The dieneDe Espinosa was prepared et al. described by the esterification a plant-oil of-basedω–alkenyl diene carboxyliccontaining acidshydroxyl (Figure groups 19) with ten years 1,3-DCH. ago. AThe phase-transfer diene was prepared catalyst by was the used esterification due to the of ω high–alkenyl difference carboxylic of polarity acids (Figure between 19)both with reagents.1,3-DCH. TheA phase dimer-transfer was polymerized catalyst was via used ADMET due to polymerization, the high difference using of apolarity Hoveyda–Grubbs between both 2nd reagents. generation The catalyst.dimer was It was pol alsoymerized copolymerized via ADMET with polymerization an α,ω-diene bearing, using aa DOPO Hoveyda pendant–Grubbs group, 2nd also generation using a Grubbscatalyst. 2nd It was generation also copolymerized catalyst (Figure with 20 ).an The α,ω resulting-diene bearing phosphorus-containing a DOPO pendant polyestersgroup, also showed using a molecularGrubbs 2nd weights generation up to catalyst 7000 Da (Figure [165]. The 20). crystallinity The resulting of phosphorus these polyesters-containing decreased polyesters as the amount showed ofmolecular DOPO-based weights comonomer up to 7000 (M2) Da [165 increased.]. The crystallinity Totally amorphous of these polyesters polymers decreased were obtained as the foramount the highestof DOPO M2-based content. comonomer Some of these (M2) plant-oil-based increased. Totally polymers amorphous showed polymers glass transition were obtained temperatures for the ranginghighest fromM2 content. 35 to 52 Some◦C, good of these thermal plant stability-oil-based and polymers relatively show gooded flame glass retardancy, transition despitetemperatures their highranging aliphatic from (fatty35 to acid)52 °C, content. good thermal stability and relatively good flame retardancy, despite their high aliphatic (fatty acid) content.

Molecules 2020, 25, 2511 17 of 38 Molecules 2020, 25, x FOR PEER REVIEW 17 of 39 Molecules 2020, 25, x FOR PEER REVIEW 17 of 39 OH OH OH + H2C OH H C + 2 O Cl Cl O Cl Cl

DMF,toluene K CO , TBAH DMF,toluene 2 3 K2CO3, TBAH

OOHH OO O H C CH 2H2C CH2 2 OO O

++ O OO CCHH H C 2 2 H2C2 OO OO OOHH FigureFigure 19. 19. Dimer Dimer synthesis synthesis of of alkenyl alkenyl fatty fatty acids acids,,, usingusing 1,3 1,3 1,3-DCH-DCH-DCH as as a alinker linker linker.. .

OH OH O OH OH O O O H C O O O CH 2 O O CH + H2C 2 H2C 2 + H C CH2 O CH2 2 O O O O O O

O P O O O P H C O O 2 O H2C O O O CH O 2 o O CH 1)C2, 70 C, 2h (N2) 2 2)Ethyl vinil ether, r.t., 20min 1)C2, 70 oC, 2h (N ) CH2=CH2 2 2)Ethyl vinil ether, r.t., 20min CH2=CH2

HO O (CH ) O P HO 2 n O O O H C O O(CH ) O P O 2 2(CHn 2)m O O O x O O O O O CH2 H2C (CH )m y 2 x O n=0, m=1 O O CH2 n=1, m=0 95% y n=0, m=1 Figure 20.n=1, m=0Synthesis of phosphorus-containing polyesters95% via ADMET copolymerization in presence of GrubbsFigure 2nd generation20. Synthesis catalyst (C2). of phosphorus -containing polyesters via ADMET copolymerization in presence of Grubbs 2nd generation catalyst (C2). Moreover,Figure 20. 1,3-DCH Synthesis was also of used phosphorus to prepare-containing polymers with polyesters speciﬁc properties via ADMET [166]. These copolymerization in presence of Grubbs 2nd generation catalyst (C2). polymersMoreover, are used 1,3 in-DCH many was areas, also because used to good prepare ﬂame polymers retardancy with for specific polymeric properties materials [166 is]. These of great concernpolymers to both are used consumers in many and areas manufacturers, because good [167 flame]. retardancy for polymeric materials is of great Moreover, 1,3-DCH was also used to prepare polymers with specific properties [166]. These concern to both consumers and manufacturers [167]. 3.2.polymers Cyclic are Compounds used in many areas, because good flame retardancy for polymeric materials is of great concern3.2. Cyclic to both Compounds consumers and manufacturers [167]. 3.2.1. Synthesis of Oxo-Heterocycles 3.2. Cyclic Compounds 3.2.1.To synthesizeSynthesis of oxetane Oxo-Heterocycles and carbonate compounds, 1,3-DCH and ECH were used, respectively. In addition, 1,3-DCH was used to synthesize a 1,3-dichloroprop-2-yl ether by the catalyzed Rh (OAc) 3.2.1. SynthesisTo synthesi of Ozexo oxetane-Heterocycles and carbonate compounds, 1,3-DCH and ECH were used, respectively.2 4- substitutionIn addition, of an1,3 imino-DCH group was used (Figure to 21 synthesize). The subsequent a 1,3-dichloroprop abstraction-2- ofyl the etherβ-proton by the of cataly the diesterzed byRh NaHT2(OAc)o synthesi led4 to- substitution theze corresponding oxetane of andan imino carbonate chloromethyloxetane group compounds,(Figure 21). The with 1,3 subsequent-DCH a 77% and yield abstractionECH [168 were]. ofused, the βrespectively.-proton of In the addition, diester by1,3 NaH-DCH led was to the used corresponding to synthesize chloromethyloxetane a 1,3-dichloroprop with- 2a- 77%yl ether yield [by168 the]. catalyzed Rh2(OAc)4- substitution of an imino group (Figure 21). The subsequent abstraction of the β-proton of the diester by NaH led to the corresponding chloromethyloxetane with a 77% yield [168].

Molecules 2020, 25, x FOR PEER REVIEW 18 of 39 Molecules 2020, 25, 2511 18 of 38 Molecules 2020, 25, x FOR PEER REVIEW 18 of 39 Molecules 2020, 25, x FOR PEER REVIEW Cl O Cl 18 of 39 O Cl O H3C HN Cl H3C OH Rh2(OAc)4 NaH O O Cl O O Cl O H3C HN Cl H3C O Cl OH O Rh2(OAc)4 O O NaH O O O Cl O O + H3C HN H3C OH O O Rh (OAc)o H3C NaH O Cl Cl PhH,O 802 C 4 O O o + O O DMF, 25 C O O H C O OO o O3 O Cl Cl PhH, 80 C O DMF, 25 oC O + H3C O H C O O O o H3C 3 Cl Cl PhH, 80 C H C o H C 3 OO DMF, 25 C O 3 H3C H C H C O3 3 77% H3C H3C 77% Figure 21. Synthesis of oxetane rings described by Davis et al. [16977%]. Figure 21.FigureSynthesis 21. Synthesis of oxetane of o ringsxetane described rings described by Davis by et Davis al. [169 et]. al. [169]. Figure 21. Synthesis of oxetane rings described by Davis et al. [169]. Oxetane is a motif found in natural products and biologically active compounds. Oxetanes are widelyOxetane usedOxetane is as a intermediates motif is a foundmotif found inin naturalchemical in natural products synthesis products and, such biologicallyand as biologically featuring active ring active compounds. expansion compounds. and Oxetanes openingOxetanes are Oxetane is a motif found in natural products and biologically active compounds. Oxetanes are are[170 widely–widely177], usedrearrangement used as as intermediates intermediates processes in in [178,179 chemicalchemical] or synthesis,synthesis in polymer, such synthe as as featuring featuringsis [180 –ring188 ring] .expansion T expansionhey are andused and opening in widely used as intermediates in chemical synthesis, such as featuring ring expansion and opening openingdrug [170discovery [170–177–177], ], [189rearrangement rearrangement–195], as they processes processes are considered [[178,179178,179 stable]] oror in in adjuncts polymer polymer to synthesis adaptsynthe solubility,sis [180 [180–188–188]. lipophilicity They]. They are usedare and used in [170–177], rearrangement processes [178,179] or in polymer synthesis [180–188]. They are used in inother drugdrug discoveryphysicochemical discovery [189– [189195 properties],–195 as they], as aretheytoward considered are considereddrug-like stable molecules stable adjuncts adjuncts to[90,189,190,196,197 adapt to adapt solubility, solubility, lipophilicity]. As an lipophilicity example, and and drug discovery [189–195], as they are considered stable adjuncts to adapt solubility, lipophilicity and otheroxetans physicochemicalother show physicochemical, as a result properties of theirproperties towardlow lipophilicity toward drug-like drug, moleculesa -higherlike molecules metabolic [90,189 [90,189,190,196,197,190 robustness,196,197]. than As anlarger]. example,As oxygenan example, other physicochemical properties toward drug-like molecules [90,189,190,196,197]. As an example, oxetansheterocyclesoxetans show, as[198,199show a result, as]. a of result their of low their lipophilicity, low lipophilicity a higher, a metabolichigher metabolic robustness robustness than larger than oxygenlarger oxygen oxetansheterocycles show, as [198,199 a result] .of their low lipophilicity, a higher metabolic robustness than larger oxygen heterocyclesBobbink [198 et,199 al. ].described the synthesis of a cyclic carbonate by the cycloaddition of CO2 to ECH heterocycles [198,199]. Bobbink et al. described the synthesis of a cyclic carbonate by the cycloaddition of CO2 to ECH (FigureBobbink 22). etThe al. reaction described cataly thez synthesised by an ofimidazolium a cyclic carbonate salt led byto the cycloadditionselective addition of CO of2 COto2 ECH to the Bobbink et al. described the synthesis of a cyclic carbonate by the cycloaddition of CO2 to ECH (Figure 22). The reaction catalyzed by an imidazolium salt led to the selective addition of CO2 to the (Figureepoxide 22 ).with The a reaction99% yield catalyzed—a very byhigh an yield imidazolium, considering salt the led thermodynamic to the selective additionstability of of CO CO22. Thisto (Figure 22). The reaction catalyzed by an imidazolium salt led to the selective addition of CO2 to the epoxide with a 99% yield—a very high yield, considering the thermodynamic stability of CO2. This theapproach epoxide iswith of a particular 99% yield—a interest very in high CO2 yield, gas recovery, considering since the c thermodynamicyclic carbonates stability may be of used CO2 .in epoxide with a 99% yield—a very high yield, considering the thermodynamic stability of CO2. This Thispolymer approachapproach synthesis is ofis particularof [200 particular]. interest interest in CO in 2 COgas2 recovery,gas recovery, since since cyclic c carbonatesyclic carbonates may be may used be in used in approach is of particular interest in CO2 gas recovery, since cyclic carbonates may be used in polymerpolymer synthesis synthesis [200]. [200]. polymer synthesis [200]. imidazolium salt ionic liquid O CO (2,5MPa), 130 oC 2 imidazolium salt ionic liquid O O Cl o O imidazoliumCO 2salt (2,5MPa), ionic liquid 130 C O OCl o O CO215h (2,5MPa), 130 CCl O O O Cl 15h Cl O O 15h 99%Cl 99% 99% FigureFigure 22. 22.Synthesis Synthesis of cyclicof cyclic carbonates, carbonates using, using vinyl-functionalized vinyl-functionalized di-imidazolium di-imidazolium salts salts polymers polymers as Figure 22. Synthesis of cyclic carbonates, using vinyl-functionalized di-imidazolium salts polymers theas catalyst. the catalyst. Figureas the 22. catalyst.Synthesis of cyclic carbonates, using vinyl-functionalized di-imidazolium salts polymers as the catalyst. 3.2.2.3.2.2. Synthesis Synthesis of of Aza-Heterocycles Aza-Heterocycles 3.2.2. Synthesis of Aza-Heterocycles 3.2.2.Moreover,Moreover, Synthesis 1,3-DCH 1,3 of- DCHAza and-H andeterocycles ECH ECH were were also also used used to to prepare prepare oxazolidinones oxazolidinones and and triazoles. triazoles. Moreover, 1,3-DCH and ECH were also used to prepare oxazolidinones and triazoles. Moreover, 1,3-DCH and ECH were also used to prepare oxazolidinones and triazoles. SynthesisSynthesis of of Oxazolidinones Oxazolidinones Synthesis of Oxazolidinones SynthesisTheThe synthesis synthesisof Oxazolidinones of oxazolidinones of oxazolidinones was described was bydescribed using 1,3-DCH by [145using,146 ],1,3 or-DCH 1,3-dichloropropan- [145,146], or 2-yl1,3 esters-dichloropropan [118The]. Figure synthesis-2 23-yl shows esters of the[118 oxazolidinones synthesis]. Figure of23 oxozalidinones, showswas thedescribed synthesis starting byof from oxozalidinonesusing 1,3-dichloropropan-2-yl 1,3-DCH, starting [145,146 from], or The synthesis of oxazolidinones was described by using 1,3-DCH [145,146], or esters1,3-dichloropropan described1,3-dichloropropan by the-2- authors’yl -esters2-yl esters researchdescribed [118 group] .by Figure the [118 authors 23]. shows’ research the synthesis group [of118 oxozalidinones]. , starting from 1,3-1,3dichloropropan-dichloropropan-2-yl-2 esters-yl esters [118 described]. Figure 23by showsthe authors the synthesis’ research of group oxozalidinones [118]. , starting from 1,3-dichloropropanO -2-yl esters described by the authors’ research group [118]. R Cl O OH O NaN3 H , Pd/C 10% R N 2 O O3 R NH NH OR Cl NaN 2OH Cl 3 O H2, Pd/C 10% O DMF, 100 oC, o/n OR N3 R Cl R ONH NH2 NaN3 N3 H , Pd/C 10% O Cl R O N MeOH,2 r.t., 48h O DMF, 100 oC, o/n 3 R NH NH N 2 Cl O 3 MeOH, r.t., 48h O DMF, 100 oC, o/n N3 MeOH, r.t., 48h O 2) Urea 1) CO2 MeOH 1) CO 2) Urea 2 80KPa 2) Urea R= (C6H5)2CH; CH3CH2(CH3)2C; CH3(CH2)n (n=6, 16) o 1) CO2MeOH 9000KPa, 150 C, 24h 150 oC, 3h80KPa R= (C6H5)2CH; CH3CH2(CH3)2C; CH3(CH2)n (n=6, 16) MeOHo 80KPa 9000KPa, 150 C, 24h 150 oC, 3h R= (C6H5)2CH; CH3CH2(CH3)2C; CH3(CH2)n (n=6, 16) o 9000KPa, 150 C, 24h 150 oC, 3h O NH O NH R O NH O NH NRH O NH R O O 1) 7-9% O 2)14-59% O 1) 7-9% 2)14-59% 1) 7-9% Figure 23. Synthesis of oxazolidinones from dicholoralcohol2)14-59% esters. Figure 23. Synthesis of oxazolidinones from dicholoralcohol esters. Figure 23. Synthesis of oxazolidinones from dicholoralcohol esters. The ﬁrst step was theFigure preparation 23. Synthesis of the of o diazidexazolidinone as previouslys from dicholoralcoh describedol (Section esters. 3.1.3; Figure8). The first step was the preparation of the diazide as previously described (Section 3.1.3; Figure The hydrogenation of the azide derivatives led to the corresponding monoamide by a O- to N-acyl 8). The hydrogenationThe first step wa of s the the azide preparation derivatives of the led diazide to the as corresponding previously described monoamide (Section by a3.1.3 O- ; toFigure 8)The. The first hydrogenation step was the preparation of the azide of derivatives the diazide led as topreviously the corresponding described ( monoamideSection 3.1.3 ; by Figure a O- to 8). The hydrogenation of the azide derivatives led to the corresponding monoamide by a O- to

Molecules 2020, 25, 2511 19 of 38 Molecules 2020, 25, x FOR PEER REVIEW 19 of 39 migrationN-acyl migration (Figure 23 )[(Figure120]. The23) [ monoamide120]. The monoamide reacted with reacted urea or with CO 2urea, under or CO the2 conditions, under the shown conditions in Figureshown 23 ,in (see Figure Supplementary 23, (see S Materialsupplementary Section Material 1.2.2)s to Section achieve 1 the.2.2) corresponding to achieve the oxazolidinone. corresponding 1 Theoxazolidinone. ﬁnal yield, determined The final yield by H, determined RMN, for the by urea1H RMN reaction, for rangedthe urea from reaction 14% toranged 59%. from When 14 the% to reaction59%. When was carried the reaction out with was CO 2carriedat a high out pressure with CO and2 temperature,at a high pressure the corresponding and temperature urethane, the wascorresponding obtained with urethane a 7% to was 9% obtained yield. Unfortunately, with a 7% to 9% these yield urethanes. Unfortunately, showed these low urethanes stability whenshowed puriﬁedlow stability [118]. when purified [118]. BothBoth 1,3-DCH 1,3-DCH and and chlorosulphonyl chlorosulphonyl isocyanate isocyanate were were the the starting starting materials material tos to obtain obtain acarbamate a carbamate whichwhich was was used used afterward afterward toto synthesizesynthesize s sulfonamidesulfonamides bearing bearing oxazolidinone oxazolidinone rings rings [145,146 [145,146]. The]. Theresulting resulting carbamate carbamate react reacteded with with oxazolidinones oxazolidinones yielding yielding NN-oxazolinone-oxazolinone sulfonamide. sulfonamide. Finally, Finally, the theaddition addition of of a base a base (K (K2CO2CO3) allowed3) allowed the thereaction reaction of the of NH the NHin the in sulfonamide the sulfonamide with one with of one the ofcarbon the s carbonsbonded bonded to a tochlorine a chlorine atom atom,, yielding yielding the the corresponding corresponding N,N-,bisN-bis-oxazolidinones-sulfones.-oxazolidinones-sulfones. The Thecompound compound with with an an isobutyl isobutyl radical radical was was synthesi synthesizedzed withwith aa 90%90% yield, yield, while while the the benzyl benzyl substituted substituted compoundcompound was was synthesized synthesized with with only only a 9%a 9% yield yield (Figure (Figure 24 ,24, R). R Alternatively,). Alternatively, the the reaction reaction between between thethe carbamate carbamate and and amines amines led led to to substituted substituted sulfamides. sulfamides. Finally, Finally, the the carboxylsulfamides carboxylsulfamides in in presence presence ofof potassium potassium carbonate carbonate in in acetonitrile acetonitrile led led to 5-chloromethyl-2-oxazolidinoneto 5-chloromethyl-2-oxazolidinone sulphonamides sulphonamides with with a a chiralchiral center center at theat the 5-position 5-position (90% (90 to% 98%to 98% yield) yield) (Figure (Figure 24 ,R24,1 )[R1145) [145,14,146].6 The]. The antibacterial antibacterial activity activity of of thesethese compounds compounds was was evaluated. evaluated. Most Most of of the the compounds compounds showed showed moderate-to-good moderate-to-good antibacterial antibacterial activityactivity [145 [145]. ].

OH O O N CH2Cl2 NH Cl + S O Cl O S O O 0 oC, 30min O Cl Cl Cl Cl

Et3N, CH2Cl2

O oC, 2h

+ OXAZOLIDINONE (R)

+ PRIMARY/SECONDARY AMINES (R1)

O O NH O S N O O O O Cl NH Cl R O Cl S O O R1 Cl

inert atm. K2CO3, CH3CN r.t., 1,5h inert atm. K2CO3, CH3CN r.t., 1,5h

O O Cl O R1 N S N O O S O N O O Cl R O O

9-90% 90 -98%

R: i-but; Bn R1 : CH3(CH2)2NH-

CH3

FigureFigure 24. 24.Synthesis Synthesis of of sulphamoyloxazolidinones sulphamoyloxazolidinones from from 1,3-DCH. 1,3-DCH.

Molecules 2020, 25, 2511 20 of 38 Molecules 2020, 25, x FOR PEER REVIEW 20 of 39 SynthesisSynthesis of Triazole of T Derivativesriazole Derivatives TriazolesTriazoles are important are important molecules molecules for chemical for chemical synthesis synthesis and also and as also bioactive as bioactive molecules. molecules. Figure 25Figure shows the 25 synthesis shows of the an S-acyclonucleosidesynthesis of anby alkylationS-acyclonucleoside of 5-(2-methylthio)phenyl- by alkylation of 1,2,4-triazole-3-thiol5-(2-methylthio)phenyl with 1,3-DCH-1,2,4 or-triazole ECH. The-3-thiol 1,2,4-triazole with 1,3-DCH thioglycoside or ECH. The was 1,2,4 obtained-triazole by usingthioglycoside potassiumwas carbonate obtained by in using DMF. potassium Potassium carbonate carbonate in wasDMF again. Potassium used ascarbonate a base was to improve again used the as a base nucleophilicityto improve of the the S atomnucleophilicity preserving of the the epoxy S atom group preserving in theﬁnal the epoxy product group [148 ].in the final product [148].

H N 2 O N S

K2CO3/DMF/reflux, 7h N 60% O N Cl S H2N CH N SH 3

N N Cl S H2N OH CH 3 N S OH 80%

N N Cl Cl K2CO3/DMF/reflux, 1h S CH3 Figure 25.FigureSynthesis 25. Synthesis of triazole-thioglycoside of triazole-thioglycoside from ECH from and ECH DCH. and DCH.

TriazoleT acyclicriazole nucleosides acyclic nucleoside synthesizeds synthesi fromzed ECH from have ECH moderate-to-high have moderate- antifungalto-high antifungal and and antibacterialantibacterial activities activities compared compared to standard to standard drugs [148 drugs]. Another [148]. Another application application of triazoles of triazoles is the is the preparationpreparation of microliter of microliter plates. Microliterplates. Microliter plates were plates coated were withcoated hydrocarbon with hydrocarbon chains bearing chains bearing a a sugar moiety.sugar This moiety sugar. This motif sugar was attachedmotif was to theattached alkane to by the a 1,3-dipolar alkane by cycloaddition. a 1,3-dipolar Thesecycloaddition. coated These plates werecoated used plates to develop were used new microfabricationto develop new microfabrication methods for application methods in for the application screening of in bioactive the screening of carbohydratesbioactive and carbohyd enzymaticrates activities and enzymatic [201]. Based activities on this [201 idea,]. Based the synthesis on this of idea, novel the compounds synthesis of novel with alkylcompounds chains bearing with twoalkyl sugar chains moieties bearing per two chain sugar in theirmoieties head per was chain designed. in their The head synthesis was designed was . The carried outsynthesis by using was diazide carried derivatives out by using and diazide alkinyl derivatives glycosides, and which alkinyl were glycosides prepared, which by using were the prepared Fischer glycosilationby using the reaction Fischer [ 23glycosilation]. The corresponding reaction triazole[23]. The derivatives corresponding were synthesized triazole derivatives by the were 1,4-regioselectivitysynthesized copper(I)-catalyzed by the 1,4-regioselectivity azide-alkyne copper(I) cycloaddition-catalyz reactioned azide (CuAAC).-alkyne cycloaddition This approach reaction allowed(CuAAC) the synthesis. This of 1,4-disubstituted approach allowed 1,2,3-triazoles the synthesis as unique of 1,4 regioisomers-disubstituted [202 1,2,3]. Yields-triazoles ranged as unique from 40%regioisomers to 57%, after [202 column]. Yields purification ranged from (see Supplementary 40% to 57%, after Materials column Section purification 2.2.2). (see Supplementary MicroliterMaterial platess Section bearing 2.2.2 the). synthesized compounds were prepared. The interactions between the alkane sugarsMicroliter and C-lectinplates bearing glycoproteins the synthesized were measured compounds by using were surfaceprepared. plasmon The interactions resonance between spectroscopythe alkane (SPR) insugars a high-throughput and C-lectin glycoproteins multichannel modewere withmeasured a GLC by chip. using However, surface noplasmon response resonance was achievedspectroscopy on SPR sensograms, (SPR) in a even high- atthroughput the higher concentrationmultichannel (100 modeµM with solution). a GLC chip. However, no Polymersresponse bearing was achieved one sugar on moiety SPR sensograms per chain act, even as competitorsat the higher for concentration gp120, an epitope (100 μM of solution). AIDS, to interact withPolymers DC-SIGN bearing [203]. one Considering sugar moiety this, per the chain authors’ act researchas competitors group for planned gp120 the, an synthesis epitope of AIDS, of polymericto interact structures with DC similar-SIGN to [203 those]. Consi alreadydering described this, the [ 203authors’] but withresearch two group sugar planned moieties the per synthesis chain andof usingpolymer glycerolic structures as a starting similar material. to those already Figure described26 shows [ the203 synthetic] but with strategy two sugar used moieties to per preparechain the corresponding and using glycerol monomer. as a Then,starting 1,3-DCH material. was Figure prepared 26 shows from the crude synthetic glycerol, strategy using used to chlorotrimethylsilaneprepare the corresponding and acetic acid monomer. as the catalyst Then, [105 1,3].-DCH The reaction was prepared of 1,3-DCH from with crude propargyl glycerol, using alcohol inchlorotrimethylsilane basic media afforded and 1,3-bis(prop-2-yn-1-yloxy)propan-2-ol. acetic acid as the catalyst [105]. The reaction The basic of media1,3-DCH increased with propargyl the nucleophilicityalcohol in basic of the media hydroxyl afforded in propargyl 1,3-bis(prop alcohol,-2-yn which-1-yloxy)propan is more acidic-2-ol. thanThe thebasic secondary media increased alcohol ofthe 1,3-DCH. nucleophilicity The esterification of the hydroxyl of 1,3-dialkynyloxy-2-propanol in propargyl alcohol, which with is acryloyl more acid chlorideic than yielded the secondary 1,3-bis(prop-2-yn-1-yloxyl)propan-2-ylalcohol of 1,3-DCH. The esterification prop-2-enoate of 1,3-dia (seelkynyloxy Supplementary-2-propanol Materials with acryloyl 2.2.5) [118 chloride]. yielded 1,3-bis(prop-2-yn-1-yloxyl)propan-2-yl prop-2-enoate (see Suplementary Materials 2.2.5) [118].

Molecules 2020, 25, x FOR PEER REVIEW 21 of 39 Molecules 2020, 25, 2511 21 of 38

O OH Molecules 2020, 25, x FOR PEER REVIEW H2C 21 of 39 OH O HO O OH O N3 N OH HO OH O CTMS, CH COOH CH O 3 Propargyl alcohol Acryloyl chlorideO 2 OH H C N 2 N OH O O HO O o O OH 80 C, 48h O N3 OH OH OH NaOH, reflux, 3h Et3N O O CuSOHO . 5H O, NaAsc. 24h, r.t. N OH Cl Cl 4OH 2 O O CTMS, CH COOH Propargyl alcohol Acryloyl chloride o --CH2 O O 3 CH2Cl2 0 C >r.t. N N HO OH O O OH o CH CH THF:H2O, Hydroquinone (10%) OH OH 80 C, 48h NaOH, reflux, 3h Et N O O N OH Cl Cl 3 CH CuSOC4H . 5H2O, NaAsc. 24h, r.t. N OH o -- O O CH Cl 0 C >r.t. N O 2 2 HO OH HOOH OH CH CH THF:H2O, Hydroquinone (10%) OH 95% N CH CH N OH N O HO OH 24% 95% OH

24%

FigureFigure 26. Synthesis 26. Synthesis of bis-triazol of bis monomers-triazol monomers from glycerol. from glycerol.

Finally, theFinally, reaction theFigure reaction of 1,3-bis(prop-2-yn-1-yloxyl)propan-2-yl 26. Synthesisof 1,3-bis(prop of bis-2--triazolyn-1-yloxyl)propan monomers prop-2-enoate from-2-yl propglycerol.-2 with-enoate a sugar with azidea sugar azide led to theled desired to the monomerdesired monomer through through a CuAAC a CuAAC reaction. reaction This last. This step last was step performed was performed in H O:THF in H2O:THF Finally, the reaction of 1,3-bis(prop-2-yn-1-yloxyl)propan-2-yl prop-2-enoate with a sugar2 azide (1:1), with(1:1) a 10%, with hydroquinone a 10% hydroquinone as a polymerization as a polymerization inhibitor. inhibitor. led to the desired monomer through a CuAAC reaction. This last step was performed in H2O:THF The polymerizationThe polymerization of the glycomonomer of the D-mannose glycomonomer was intended, D-mannose using Cu(0) was/Cu(II) / intendedMe TREN, using (1:1), with a 10% hydroquinone as a polymerization inhibitor. 6 as a catalystCu(0)/Cu(II)/Me with EBiB as6TREN initiator as a (Figure catalyst 27 ). with Although EBiB as the initiator expected (Figure polymer 27). with Although the terminal the expected The polymerization of the glycomonomer D-mannose was intended, using brominepolymer was not detected with the through terminal using bromine the MALDI-ToF was not technique,detected through dead polymer using chains the MALDI (with terminal-ToF technique, Cu(0)/Cu(II)/Me6TREN as a catalyst with EBiB as initiator (Figure 27). Although the expected hydrogen)dead and polymer two-to-ﬁve chains added (with chains terminal were hydrogen) obtained. Theand exchangetwo-to-five of theadded bromine chains by were the protonobtained. The polymer with the terminal bromine was not detected through using the MALDI-ToF technique, was mainlyexchange caused of by the disproportionation bromine by the proton and chain was transfermainly caused side reaction, by disproportionation which led to the and loss chain of the transfer dead polymer chains (with terminal hydrogen) and two-to-five added chains were obtained. The terminalside bromine reaction (see, which Supplementary led to the loss Materials of the Sectionterminal 2.2.6) bromine [118]. (see Supplementary Materials 2.2.6) [118]. exchange of the bromine by the proton was mainly caused by disproportionation and chain transfer

side reaction, which led to the loss of the terminal bromine (see SupplementaryO Materials 2.2.6) [118]. Br H C O 3 CH n H C 3 O 3 O O Br H C O N 3 CH n H NC 3 O O 3 NO O N HO O N N O OH N N N OH HO O HO O N HO OH OH H C N 2 Cu ( 0 )/Cu(II) N OH O O OH Me6TREN O HO Br O HO HO

+ OH H C O 3 CH H C H C 3 2 Cu ( 0 )/Cu(II) OH O 3 O O N Me6TREN HO Br O O DMSO, 25ºC, 24h H C O + N N 3 CH H C 3 3 O N N N N HO O O DMSO,OH 25ºC, 24h HO NON OH HO N N HO HO N HO O HO OH HO O OH HO O HO HO H H C O HO 3 CH n H C 3 O 3 O O H H C O N 3 CH n H NC 3 O O 3 NO O N HO O N N O OH N N N OH HO O HO O N HO OH OH N N OH OH HO HO O HO OH On=2-5H HO Figure 27. Proposed structure for the dead polymer synthesized through SET-LRP polymerization. Figure 27. Proposed structure for the dead polymer synthesized throughn=2-5 SET-LRP polymerization. A similar starting approach was described by Legros et al. for the synthesis of novel β-cyclodextrin FigureA 27. similar Proposed starting structure approach for the dead was polymer described synthesized by Legros through et SET al.- LRPfor polymerization.the synthesis of novel dimers. Glycerol-type linking arms were synthesized from 1,3-DCH or ECH, using NaOH as a basic β-cyclodextrin dimers. Glycerol-type linking arms were synthesized from 1,3-DCH or ECH, using catalyst.A Propargyl similar alcoholstarting and approach butynol was were described used as nucleophilic by Legros reagents. et al. for A phase the synthesistransfer catalysis of novel NaOH as a basic catalyst. Propargyl alcohol and butynol were used as nucleophilic reagents. A (Buβ4-NBr)cyclodextr was alsoin dimers. used in G thelycerol reaction-type between linkingECH arms and were butynol synthesized (Figure from 28)[ 1181,3-].DCH or ECH, using phase transfer catalysis (Bu4NBr) was also used in the reaction between ECH and butynol (Figure 28) NaOH as a basic catalyst. Propargyl alcohol and butynol were used as nucleophilic reagents. A [118]. phase transfer catalysis (Bu4NBr) was also used in the reaction between ECH and butynol (Figure 28) [118].

Molecules 2020, 25, 2511 22 of 38 Molecules 2020, 25, x FOR PEER REVIEW 22 of 39 Molecules 2020, 25, x FOR PEER REVIEW 22 of 39 OH OH

OH OH Propargyl alcohol Butynol O Propargyl alcohol O O Butynol O (CH2)n O O (CH2)n (CH2)n (CH2)n Cl Cl NaOH(aq), reflux, 3h, r.t. NaOH(aq), Bu NBr, ether, 18h, r.t. Cl Cl NaOH(aq), reflux, 3h, r.t. 4 Cl CH CH NaOH(aq), Bu4NBr, ether, 18h, r.t. Cl CH CH

n=1,2 n=1,2 Figure 28. Synthesis of glycerol-type linking arms based on alkenyl motifs using DCH and ECH. Figure 28. Synthesis of glycerol-type linking arms based on alkenyl motifs using DCH and ECH. These glycerol-type linkers were used to synthesize β-CD dimers by a CuAAC reaction These glycerol-type linkers were used to synthesize β-CD dimers by a CuAAC reaction (Figure (Figure 29)[204–207]. One of these CD dimers showed unusual conformations in aqueous solutions. 29) [204–207]. One of these CD dimers showed unusual conformations in aqueous solutions. These These conformations depended on the length of the linking arm between the two cyclodextrins [208,209]. conformations depended on the length of the linking arm between the two cyclodextrins [208,209].

N (RO-)6 3 CH (RO-) N3 OH CH2 6 OH 2 Br CH2 Br CH2 CH O CH2 O O O 2 N N O N N O O R=H N N R=H N N O N N R=Me (RO)14 N O O N NaH, DMF O O R=Me (RO) O O O 14 NaH,r.t., o.n.DMF O CH CH r.t., o.n. . H2C CH2 CH CH CuSO4 . H2SO4, NaASc(aq) H2C CH2 CuSO4 H2SO4, NaASc(aq) DMSO, 25 oC (RO-)6 CH CH DMSO, 25 oC (RO-)6 (-OR)6 CH CH (-OR)6

(RO)14 (RO)14 (RO)14 (RO)14 R=H; 14% R=Me,R=H; 14% 53% R=Me, 53% Figure 29. Synthesis of β-CD dimers with a functionalized glycerol linker. Figure 29. Synthesis of β-CD dimers with a functionalized glycerol linker. Due to their unique cup-like structures, CDs are known to form inclusion complexes in aqueous Due to their unique cup-like structures, CDs are known to form inclusion complexes in solution.Due CDsto their have unique a wide cup range-like of structures, applications CDs that are include known the to areas form of inclusiondrug delivery complexes [210,211 in], aqueous solution. CDs have a wide range of applications that include the areas of drug delivery analyticalaqueous solution. chemistry CDs [212 have], artificial a wide enzymes range [of213 applications], photochemical that include sensors [the214 ],areas food of technology drug delivery [215], [210,211], analytical chemistry [212], artificial enzymes [213], photochemical sensors [214], food catalysis[210,211], [216analytical] and nanostructured chemistry [212 functional], artificial materials enzymes [217[213].], Inphotochemical comparison with sensors CD monomers,[214], food technology [215], catalysis [216] and nanostructured functional materials [217]. In comparison with bridgedtechnology bis( [β215-CD)], catalysis derivatives [216 allow] and twonanostructured hydrophobic functional cavities to materials be in close [217 vicinity,]. In com thusparison improving with CD monomers, bridged bis(β-CD) derivatives allow two hydrophobic cavities to be in close vicinity, theCD desiredmonomers, properties. bridged Moreover, bis(β-CD) the derivatives presence ofallow functional two hydrophobic linkers between cavities the twoto be CDs in close can supply vicinity, a thus improving the desired properties. Moreover, the presence of functional linkers between the well-organizedthus improving pseudo-cavity the desired properties that may. a ff Mordoreover, supplementary the presence binding of functional properties linkers [218,219 between]. the two CDs can supply a well-organized pseudo-cavity that may afford supplementary binding 3.2.3.properties Synthesis [218,219 of Ionic]. Compounds Based on Quaternary Bis-Ammonium Salts In the study, 1,3-DCH was used to synthesize gemini imidazolium salts, with an hydroxyl in the 3.2.3. Synthesis of Ionic Compounds Based on Quaternary Bis-Ammonium Salts spacer group and lateral chains of different length (Figure 30a) [220]. A similar reaction with amines In the study, 1,3-DCH was used to synthesize gemini imidazolium salts, with an hydroxyl in insteadIn the of imidazole study, 1,3 was-DCH described was used by to Song synthesize et al., who gemini synthesized imidazolium bis-quaternary salts, with ammoniuman hydroxyl salt in the spacer group and lateral chains of different length (Figure 30a) [220]. A similar reaction with (BQAS)the spacer with group a hydroxyl and lateral in the spacerchains groupof different [221]. Thislength salt (Figure was synthesized 30a) [220] by. A the similar reaction reaction of 1,3-DCH with amines instead of imidazole was described by Song et al., who synthesized bis-quaternary withaminesN ,N insteaddimethyldodecylamine of imidazole was [221 described], achieving by aSong 90% et yield. al., wh BQASo synthesi exhibitedzed broad-spectrum bis-quaternary ammonium salt (BQAS) with a hydroxyl in the spacer group [221]. This salt was synthesized by the bactericidalammonium salt activity (BQAS) [221 with]. Another a hydroxyl BQAS in was the synthesizedspacer group by [221 using]. This monoamides salt was synthesized of α,ω-diamines by the reaction of 1,3-DCH with N,N dimethyldodecylamine [221], achieving a 90% yield. BQAS exhibited (Figurereaction 30 ofb). 1,3 All-DCH of thesewith N syntheses,N dimethyldodecylamine are based on the nucleophylic[221], achieving attack a 90% of ayield. tertiary BQAS amine exhibited to the broad-spectrum bactericidal activity [221]. Another BQAS was synthesized by using monoamides of carbonsbroad-spectrum of 1,3-DCH bactericidal supporting activity the chlorine[221]. Another atoms. BQAS The presence was synthesi of a hydroxylzed by using in the monoamides spacer group of α,ω-diamines (Figure 30b). All of these syntheses are based on the nucleophylic attack of a tertiary confersα,ω-diamines tuneable (Figure properties 30b). toAll these of these compounds synthese [s222 are,223 based]. on the nucleophylic attack of a tertiary amine to the carbons of 1,3-DCH supporting the chlorine atoms. The presence of a hydroxyl in the amineImidazolium to the carbons derivatives of 1,3-DCH showed supporting higher the thermalchlorine atoms. stability The than presence conventional of a hydroxyl quaternary in the spacer group confers tuneable properties to these compounds [222,223]. ammoniumspacer group gemini confers surfactants tuneable properties and two-phase to these transitions compounds before [222,223 decomposition]. [220]. Amide-based Imidazolium derivatives showed higher thermal stability than conventional quaternary geminiImidazolium cationic surfactants derivatives presented showed superior higher surface thermal/interfacial stability activities than conventional and easy biodegradables, quaternary ammonium gemini surfactants and two-phase transitions before decomposition [220]. Amide-based suggestingammonium them gemini as potentialsurfactants products and two in-phase industrial transitions fields, suchbefore as decomposition surfactant flooding [220] [. 224Amide]. -based gemini cationic surfactants presented superior surface/interfacial activities and easy biodegradables, suggesting them as potential products in industrial fields, such as surfactant flooding [224].

Molecules 2020, 25, 2511 23 of 38 Molecules 2020, 25, x FOR PEER REVIEW 23 of 39

(a) Cl- CH2(CH2)nCH3 CH2(CH2)nCH3 N N N + N (atm) N OH 2

HO o + Cl Cl DMF, 120 C, 28h N - N Cl CH2(CH2)nCH3

52-75% (b) O CH3 N OH N (atm) Cn-1H2n-1 NH CH3 2 H C 3 CH3 + C H Cl- N NH n-1 2n-1

Cl Cl Propanol, Na CO (0,3%wt) HO - O 2 3 + Cl o - N reflux,60 C, 4 6h NH Cn-1H2n-1 H3C CH3 O

n=8,12,16 96-98% Figure 30. (a) Synthesis of gemini imidazolium salts using 1,3-DCH. (b) Synthesis of lineal amide-based gemini cationicFigure surfactants 30. (a) usingSynthesis 1,3-DCH. of gemini imidazolium salts using 1,3-DCH. (b) Synthesis of lineal amide-based gemini cationic surfactants using 1,3-DCH. Gemini compounds have high surface activity and low critical micelle concentration (CMC). These properties enhanceGemini their compounds water-solubility have high and surface confer aactivity better viscosity and low than critical single-chain micelle concentration surfactants (CMC). at equal molarThese mass properties concentration enhance [116 their,225 water–231].-solubility Consequently, and confer their eaffi ciencybetter viscosityis improved than [232 single], -chain allowingsurfactants them to be usedat equal in smaller molar quantities mass concentration compared to[116,225 conventional–231]. Consequently, surfactants [232 their]. These efficiency is propertiesimproved enable their [232 industrial], allowing use them in various to be fields, used suchin smaller as antiseptics, quantities printing compared and dyeing, to conventional corrosionsurfactants inhibition, improved [232]. These oil recoveryproperties and enable synthesis their of industrial inorganic materialsuse in various [224,233 fields–236,]. such They as can antiseptics, also be usedprinting in electro-decoating, and dyeing, corrosion stabilization inhibition, of adhesive improved polymers, oil recovery anti-friction andagents, synthesis mining, of inorganic paper-making,materials cosmetics [224,233 and,–236 more]. They recently, can in also drug be design used and in deliveryelectro-deco [237,ating,238]. Most stabilization of them also of adhesive show strongpolymers, antibacterial anti-friction and antifungal agents, mining, activities, paper becoming-making safety, cosmetics weapons and, [230 mo,235re, 239recently,–241]. in Their drug design mechanismand of delivery action is based[237,238 on].the Most amphiphilic of them nature also show of the strong gemini antibacterial group, which and allows antifungal them to activities, interact withbecoming the cell safety membrane weapons of the [230,235,239 microorganisms,–241]. Their causing mechanism them to loseof action their permeabilityis based on the [242 amphiphilic]. Gemininature compounds of the aregemini also used group as, ionicwhich liquids allows (DDIL). them Ionic to interac liquidst (ILs) with are the characterized cell membrane by of the unique properties,microorganisms such as, non-volatility,causing them to low lose flammability, their permeability tuneable [242 hydrophobicity,]. environmentally friendly nature,Gemini easy recoverabilitycompounds are and also recyclability used as ionic [243 liquids]. They (DDIL). are of Ionic recognized liquids interest(ILs) are forcharacterized a wide rangeby of unique applications, propert suchies, assuch for solvents,as non-volatility, in chemical low and flammability, enzymatic catalysistuneable [244 hydrophobicity,–246], in carbonenvironmentally dioxide capture friendly and separation, nature, easy in hydrogen recoverability generation, and recyclability in converting [243] thermal. They a energyre of recognized into electricalinterest energy, for a forwide electrochemical range of applications energy, storage such as and for forsolvents converting, in chemical electrical and energy enzymatic into catalysis mechanical[244 energy–246], [in247 carbon]. It is well-knowndioxide capture that and the separation, physical and in chemicalhydrogen properties generation, of in an converting IL can be thermal tailored byene varyingrgy into the electrical structure energy, of constituent for electrochemical cations and energy anions storage [248,249 and]. Dicationic for converting ionic liquidselectrical energy (DDIL) containinto mechanical two head groups, energy linked[247]. It by is a well rigid-known or flexible that spacer the physical [250]. This and typechemical of IL demonstratesproperties of an IL can unique characteristicsbe tailored by not varying found in the monocationic structure of ILs constituent and other cations traditional and solvents anions [248,249 [251]. Moreover,]. Dicationic ionic the changeliquids in the ( lengthDDIL) ofcontain the spacer two head and the groups, incorporation linked by of a functional rigid or flexible groups spacer such as [250 thiol,]. This ether, type of IL hydroxyldemonstrate and amino groupss unique in the characteristics cations allows not tailoring found thein monocationic physical properties ILs and of DDIL other for traditional specific solvents applications[251 [252]. Moreover]. The DDIL, the PEG change based in [the253 ]length have also of the been spacer used and as a the powerful incorporation catalysts of for functional various groups syntheticsuch transformations as thiol, ether, [254, 255 hydroxyl]. and amino groups in the cations allows tailoring the physical Moreover,properties ionic of liquids DDIL (IL)for specific have recently applications been proposed [252]. The for DDIL thermal PEG storagebased [253 applications] have also [237 been]. used as ILs have thermophysicala powerful catalysts and chemical for various properties synthetic that transformations may be suitable [254,255 to be used]. as heat transfer fluid (HTF) in powerMoreover, plants, using ionic parabolic liquids (IL) trough have solar recently collectors, been asproposed stated by for Van thermal Valkenburg storage et applications al. [238]. [237]. The authors’ILs have research thermophysical group described and thechemical use of properties crude glycerol, that mayN-butylimidazole be suitable to be and used carboxylic as heat transfer acids [256fluid,257] (HTF) to synthesize in power diimidazol-1-ium plants, using parabolic esters, DDILs,trough solar with highcollectors capacity, as stated for energy by Van storage Valkenburg et (Figure 31al.). A[238 counter]. The ion authors’ swap was research also achieved group descr withibed KPF the6, as use shown of crude in Figure glycerol, 31. N-butylimidazole and carboxylic acids [256,257] to synthesize diimidazol-1-ium esters, DDILs, with high capacity for energy storage (Figure 31). A counter ion swap was also achieved with KPF6, as shown in Figure 31.

Molecules 2020, 25, 2511 24 of 38 Molecules 2020, 25, x FOR PEER REVIEW 24 of 39

CH CH3 3

CH O N 3 N N N - Ar(atm) + Cl- + PF 6 R O N O N O KPF6

O 110 oC, 48h R O R Cl Cl + 15min, r.t. + N N - - Cl PF N N 6

CH3 CH3

31-89% 47-89%

R=(CH ) C; CH (CH ) ; C H 3 3 3 2 14 10 7 FigureFigure 31. 31. SynthesisSynthesis of ionicionic compounds compounds from from chlorohydrin chlorohydrin esters. esters.

TheThe final final yields yields were were highly highly dependent dependent on the on carboxylic the carboxylic acid used. acid Theused. set The of bis-imidazolium set of bis-imidazolium ester chloridesester chlorides showed interestingshowed interesting energy-storage energy properties,-storage asproperties indicated, as above. indicated However, above the. However,substitution the ofsubstitution chloride ions of chloride by hexafluorophosphate ions by hexafluorophosphate ions yielded ions a setyielded of compounds a set of compounds with lower with PCM lower capabilityPCM capability [256]. [256]. 4. Future Perspectives 4. Future Perspectives It is clear from the above studies that finding cost-effective alternatives to the use of crude It is clear from the above studies that finding cost-effective alternatives to the use of crude glycerol is an active field of research. The synthesis of DCH and dichloropropyl esters is possible glycerol is an active field of research. The synthesis of DCH and dichloropropyl esters is possible from crude glycerol, which implies that ECH and other derivatives can also be synthesized from from crude glycerol, which implies that ECH and other derivatives can also be synthesized from crude glycerol. Moreover, the synthesis of ECH is faster from 1,3-DCH, the main chlorohydrin isomer crude glycerol. Moreover, the synthesis of ECH is faster from 1,3-DCH, the main chlorohydrin synthesized from glycerol, than from 1,2-DCH, the main isomer resulting from propene chlorination. isomer synthesized from glycerol, than from 1,2-DCH, the main isomer resulting from propene Nevertheless, although three companies (Dow Chemicals, Solvay EPICEROLTechnology and CONSER chlorination. Nevertheless, although three companies (Dow Chemicals, Solvay SpA ECH-EF = Eco Friendly) have developed their own process for producing dichlorohydrins from EPICEROLTechnology and CONSER SpA ECH-EF = Eco Friendly) have developed their own glycerol and HCl, further work is necessary to identify the most-reliable catalytic mechanism and the process for producing dichlorohydrins from glycerol and HCl, further work is necessary to identify best catalyst [51]. Dichloropropyl esters may be a less toxic substitute of 1,3-DCH for some synthesis. the most-reliable catalytic mechanism and the best catalyst [51]. Dichloropropyl esters may be a less However, the current processes to prepare these esters with high yield need expensive reagents (CTMS) toxic substitute of 1,3-DCH for some synthesis. However, the current processes to prepare these or solvents (IL). Further work is necessary to identify cost-effective synthesis for these esters. Crude esters with high yield need expensive reagents (CTMS) or solvents (IL). Further work is necessary to glycerol can also be used as a carbon source in fermentative processes, although intensive research is identify cost-effective synthesis for these esters. Crude glycerol can also be used as a carbon source still necessary to improve the use of crude glycerol in most of the fermentative processes currently used. in fermentative processes, although intensive research is still necessary to improve the use of crude Products synthesized from chlorinated glycerol derivatives have applications in areas such as glycerol in most of the fermentative processes currently used. agriculture, chemistry, healthcare and materials (Table4). Electrophilic and nucleophilic reagents, Products synthesized from chlorinated glycerol derivatives have applications in areas such as as well as some compounds with catalytic and photocatalytic properties, have also been prepared from agriculture, chemistry, healthcare and materials (Table 4). Electrophilic and nucleophilic reagents, as these chlorinated compounds. Antimicrobial and anticancerinogenic compounds are the main targets well as some compounds with catalytic and photocatalytic properties, have also been prepared from for the compounds prepared to be used in medicine, although antiviral, antihypertensive, diuretic and these chlorinated compounds. Antimicrobial and anticancerinogenic compounds are the main hypoglycemic properties are also present in some of the synthesized compounds. Finally, polymers targets for the compounds prepared to be used in medicine, although antiviral, antihypertensive, with different properties, surfactants, ionic solvents and phase-change materials are the main targets in diuretic and hypoglycemic properties are also present in some of the synthesized compounds. the field of materials. Finally, polymers with different properties, surfactants, ionic solvents and phase-change materials Despite recognized advances in this field, only a few of the synthesized compounds are already are the main targets in the field of materials. commercial products, while many others are still at the research stage. Further work is therefore Despite recognized advances in this field, only a few of the synthesized compounds are already needed to synthesize novel compounds with improved properties and to demonstrate the actual commercial products, while many others are still at the research stage. Further work is therefore application of those compounds still at the research stages. The authors’ research group has also needed to synthesize novel compounds with improved properties and to demonstrate the actual recently demonstrated that crude glycerol can be used to prepare novel deep eutectic solvents (DES), application of those compounds still at the research stages. The authors’ research group has also similar to those based on choline chloride. Chloline chloride is substituted by a quaternary ammonium recently demonstrated that crude glycerol can be used to prepare novel deep eutectic solvents (DES), salt synthesized from 1-MCH [258]. This also opens up new opportunities for adding value to similar to those based on choline chloride. Chloline chloride is substituted by a quaternary crude glycerol. ammonium salt synthesized from 1-MCH [258]. This also opens up new opportunities for adding value to crude glycerol.

Molecules 2020, 25, 2511 25 of 38

Table 4. Summary of the properties of the diﬀerent products obtained from glycerol based on chloroderivatives.

Field of Property Current Status Chemical Compounds Starting Materials Section Application Agricul-ture Pesticide Research Allyl esters Chorohydrin esters 3.1.1 Commercial Antimicrobial 1,2,4-Triazinones DCH/ECH 3.1.7 product Commercial Chemis-try Reagent DCH Glycerol 2.1 product Commercial Reagent ECH/(S)-CHBN DCH 2.2/3.1.2 product Reagent Research Chlorohydrin esters Glycerol 2.3 Reagent Research Diazides/Monoamides Chorohydrin esters 3.1.3 Alkyl Reagent Research DCH 3.1.6/3.1.7/3.1.8 glycosides/Azidirines/Oxetanes Commercial Reagent Cyclic carbonates ECH 3.1.8 product DCH/Chorohydrin Reagent Research Oxazolidinones 3.2.2 esters Polynuclear metals /Alkyl Analytic sensors Research DCH 3.1.5/3.1.6 glycosides Analytic sensors Research Triazoles DCH/ECH 3.2.2 Catalyst Research Polynuclear metals DCH 3.1.5 Commercial Health Anti-microbial Sulfonamides DCH 3.1.4 product Anti-microbial Research Pyridine derivatives DCH/ECH 3.1.7 Azidirines/Phthalazines/ Anti-microbial Research Oxazolidinones/gemini DCH 3.1.7/3.2.2/3.2.3 imidazolium salts Anticancer Research Azidirines DCH 3.1.7 Anticancer Research Pyridine derivatives DCH/ECH 3.1.7 Sulfonamides/Polynuclear Antiviral DCH 3.1.4/3.1.5 metals Anti-hyper-tensive Sulfonamides DCH 3.1.4 Diuretic Sulfonamides DCH 3.1.4 Hypo-glycemic Sulfonamides DCH 3.1.4 Materials Polymers Research Allyl esters Chorohydrin esters 3.1.1 Polymers Research Polyesters DCH 3.1.8 Flame retar-dants Research Polyesters DCH 3.1.8 Gemini imidazolium and Surfactants Research DCH 3.2.3 ammonium salts Gemini imidazolium and Ionic Solvents Research DCH 3.2.3 ammonium salts Monoamides/gemini Chorohydrin PCM Research imidazolium and 3.1.3/3.2.3 esters/DCH ammonium salts Magnetic materials Research Polynuclear metals DCH 3.1.5 Photo-voltaic Research Polynuclear metals DCH 3.1.5 component

These studies should also consider alternative approaches under study to prepare biofuels from vegetable oils and fats, avoiding glycerol generation. Gliperol, DMC-Biod or Ecodiesel, likewise, another renewable diesel fuel, known as “green diesel”, are produced by treatment of vegetable oils (cracking, pyrolysis, hydrodeoxygenation and hydrotreating). Other strategies aim to reduce the high viscosity of vegetable oils by mixing them with low-viscosity solvents, in the right proportions, to obtain suitable fuels. In this way, the costs associated with the transformation of vegetable oils and fats can be reduced. Eﬀorts are also devoted to the puriﬁcation of crude glycerol, although the current processes are still considered too expensive for the actual industrial application, at least for small biodiesel producers [259]. Nevertheless, crude glycerol is also a by-product of the biolubricants industries, one of the top 20 innovative bio-based products described in a recent EU study [260]. Consequently, the production of crude glycerol seems to be a reality for a long time forward.

5. Conclusions Although pure glycerol is currently used in a wide variety of applications, primarily in he cosmetic, food and pharmaceutical industries, the purity of glycerol resulting from the biodiesel industry is far Molecules 2020, 25, 2511 26 of 38 from meeting the purity needed for these applications. This glycerol, also currently known as glycerine (the former name of glycerol), can directly be used as an energy source and as a starting material in chemical synthesis. This latter approach seems more proﬁtable than simply burning glycerol as waste. It has already been demonstrated that chlorohydrins and chlorohydrin esters can be prepared from crude glycerol. Luckily, glycerol is a polyol with many potential applications. Hence, it is easy to substitute some of its hydroxyl groups to obtain chlorohydrins. Chlorine atoms can afterward be substituted by other nucleophiles, resulting in ECH. This intermolecular substitution is favored from 1,3-DCH, the main regioisomer obtained from glycerol. Intramolecular substitutions lead to a large number of intermediate and end products from single molecules to large polymers with applications in agriculture, chemistry, medicine and materials. Among them, the preparation of gemini ionic compounds seems to be one of the more promising areas, considering their properties. Novel DES can be also prepared starting from chlorohydrins. In fact, the more options there are for the applications of glycerol, the more likely it is that biodiesel and biolubricants will become real alternatives for fuel and lubricants in the future. Consequently, interest in developing novel value-added uses for glycerol is increasing.

Supplementary Materials: The following are available online, Oxazolidinones, materials and methods pages S1–S3; Triazole derivatives synthesis, materials and methods (synthetic process) pages S6–S10. Author Contributions: Conceptualization, R.C.-G.; methodology, A.C.-X.; software, A.C.-X.; validation, R.C.-G.; formal analysis, A.C.-X.; investigation, A.C.-X.; resources, M.B.; data curation, R.C.-G.; writing—original draft preparation, A.C.-X.; writing—review and editing, R.C.-G. and P.C.; visualization, R.C.-G. and G.V.; supervision, R.C.-G.; project administration M.B.; funding acquisition, R.C.-G. All authors have read and agreed to the published version of the manuscript. Funding: This work was partially funded by the Ministerio de Ciencia, Innovación y Universidades de España (grants: MINECO/FEDER CTQ2015-70982-C3-1-R) and by the Generalitat de Catalunya, Grant 2017 SGR 828, to the Agricultural Biotechnology and Bioeconomy Unit (ABBU). Acknowledgments: The authors would like to thank David Haddleton from the Warwick University for his disposition and acceptance of A.C-X. for an internship in his lab. Many thanks. Conﬂicts of Interest: The authors declare no conﬂict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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