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; acanelxa@quimica.udl.cat (A.C.-X.); merce.balcells@udl.cat (M.B.);
gemma.villorbina@udl.cat (G.V.)
2 Department of Crop and Forest Sciences, University of Lleida-Agrotecnio Center, Av. Rovira Roure 191,
25198 Lleida, Spain; christou@pvcf.udl.cat
3 ICREA, Catalan Institute for Research and Advanced Studies, Passeig Lluıís Companys 23,
08010 Barcelona, Spain
* Correspondence: ramon.canela@udl.cat

Academic Editor: Monica Nardi




Received: 22 April 2020; Accepted: 25 May 2020; Published: 28 May 2020

Abstract: Crude glycerol (C3 H8 O3 ) 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 (C3 H8 O3 ) 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. Figure 1 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
R1 R2 OH 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
H3C
HO OH HYDROCHLORINATION
OH
REDUCTION
H2, cat. OH HCl, cat.

OH OH
cat.
R OH
OR 1 O
RCOO OH

OR 3 OR 2 R OH
H+ OH RCOO OH RCOO
ETHERIFICATION cat, O2
-H2O ESTERIFICATION

H2C O OH
O
DEHIDRATION
OH OH OH COOH
O2, cat. OH OH

O
COOHCOOH OH CHO
OH OXIDATION
CH2
Acrilic acid.

Figure 1. Reactions
Figure in1.which glycerol is
Reactions inused as a building
which blockisto make
glycerol used more-complex molecules
as a building 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 K2 [54] and erythritol [55].
efficiency of this yeast in converting crude glycerol to citric 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
perspectives
2. From Glycerol of these Intermediates
to Synthetic compounds 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
chlorohydrins [32,34,43,44,51,56–58].
2.1. Synthesis Figure
of Chlorohydrins 2 showsHydrochlorination
by Glycerol 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

OH

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

Figure 2. Syntesis
Figure of of
2. Syntesis DCH byby
DCH two-step glycerol
two-step hydrochlorination.
glycerol hydrochlorination.

Table 1 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

The
Molecules 2020, 25, most
2511 prevalent synthetic procedures for glycerol chlorination [66,67] are based on the
6 of 38
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
The most prevalent
disadvantages, such synthetic procedures
as the loss for glycerol
of the catalyst chlorination
at high [66,67] are based
reaction temperatures (dueontotheitsreaction
low boiling
of glycerol
point) and the production of water, which causes an increase in the reaction time has
with an aqueous solution of hydrochloric acid [34,56,68–73]. The synthetic process andbeen
makes it
scaleddifficult
up to an industrial scale [74,75].
to separate the end products. However, this process has a number of disadvantages, such as
the loss of This
the catalyst at high reaction temperatures (due to its low boiling point)
reaction can be carried using glycerol and gaseous HCl. The resulting mixture of isomersand the production of
water,has
which causes an increase in the reaction time and makes it difficult to separate
been investigated in great detail [76–78]. The reaction is carried out isothermically, allowing the the end products.
This
controlreaction
of sidecan be carried
reactions [44].using glycerol and gaseous HCl. The resulting mixture of isomers
has been investigated in great detail [76–78]. The
In the first step, monochlorohydrins reaction
(mainly is carried out isothermically,
1-monochlorohydrine, 1-MCH, and allowing the
small amounts
control
of of side reactions [44].
2-monochlorohydrine, 2-MCH) are obtained by the nucleophilic substitution of OH by Cl.
In the
Moreover,first step,
1-MCHmonochlorohydrins
is favored by(mainly 1-monochlorohydrine,
a kinetic control of the process 1-MCH, and [79].small
In aamounts
subsequent
of 2-monochlorohydrine, 2-MCH) are obtained by the nucleophilic
hydrochlorination reaction, monochlorohydrins are converted to dichlorohydrins substitution of OH by Cl. Moreover, (mainly
1-MCH is favored by a kinetic control of the process [79]. In a subsequent
1,3-dichlorohydrins, 1,3-DCH, and small amounts of 1,2-dichlorohydrins, 1,2-DCH) (Error! R hydrochlorination reaction,
monochlorohydrins
eference source arenotconverted
found.).to dichlorohydrins
This mixture reach(mainly
on 1,3-DCH1,3-dichlorohydrins,
is very interesting 1,3-DCH,
in the and small of
preparation
amounts of 1,2-dichlorohydrins, 1,2-DCH)
epichlorohydrin, as is discussed below. (Figure 2). This mixture reach on 1,3-DCH is very interesting
in the preparation of epichlorohydrin,
These reactions are catalyzed asbyis discussed below. acids, usually acetic acid. Depending on the
short carboxylic
These reactions are catalyzed by short
HCl concentration, the reaction can lead to the MCH carboxylic acids, usually
isomersacetic
oracid.
to theDepending
DCH isomers.on the TheHCl ratio
concentration,
between MCH the reaction
and DCH can lead to the on
depends MCHtheisomers
reactionorconditions.
to the DCHSantacesaria
isomers. Theetratio al. between
have already
MCHreviewed
and DCHthat depends
process and have summarized the studies in terms of catalysts, reactionthat
on the reaction conditions. Santacesaria et al. have already reviewed process,
process and haveand
mechanism summarized
kinetics, and thereactors
studies andin terms of catalysts,
processes 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%) (Figure 3). 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] from chlorohydrins.
Several 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
2.2.1.
The Enzymatically
intramolecular Catalyzeddisplacement
nucleophile Synthesis of ECH
of vicinal halohydrins to the corresponding epoxides
can be catalyzed by halohydrin dehalogenases
The intramolecular nucleophile displacement(HHDHs,ofHheC vicinaland EC 4.5.1.X)tofrom
halohydrins the microbial
corresponding
originepoxides
[87–89]. However,
can be catalyzed by halohydrin dehalogenases (HHDHs, HheC and EC into
a number of studies reported that the biotransformation of 1,3-DCH ECH from
4.5.1.X)
by recombinant Escherichia coli expressing halohydrin dehalogenase is limited by product
microbial origin [87–89]. However, a number of studies reported that the biotransformation of inhibition,
one of the reasons
1,3-DCH for the
into ECH low ECH productivity
by recombinant [90].expressing
Escherichia coli Zou et al. proposeddehalogenase
halohydrin a resin-based ISPR by
is limited
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
(Table 2, 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 (Table 2, entry 2.4) [91]. Improved ee (99%) and similar yield
(92%) were achieved by using halohydrin dehalogenases (HHDHs) coupled to epoxide hydrolases
(EH) (Table 2, 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 (Table 2, 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%) (Table 2,
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 (Table 2, 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%) (Table 2,
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)
NO2 , pH5,
2.3 HHDH Agrobacterium radiobacter R-ECH 99 41 [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 (Table 3) 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,
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
Molecules 2020, 25, 2511 8 of 38
approach allows the synthesis of the S-ECH enantiomer with a 99% ee. In addition, the
biotechnological approaches avoid the presence of by-products, such as chloroacetone, glycidol,
diglycidyl etherwere
solid catalysts and prepared
polyglycerols,
by thethat are very usual when
equivalent-volume ECH is method,
impregnation synthesized byγ-Al
using using the
2 O3 as
chemical
a carrier, approaches.
whereas nitratesMoreover, the use of
and chlorides of the
alkaline
three hydroxides
alkaline earthleads to a(Mg,
metals largeCaamount
and Ba)ofwere
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-Al2 O3
allow
at 270 working
◦ C [101]. in higher reagent
Chemical reactionsconcentration thanwith
can provide ECH biotechnological approaches,
yields up to 99%, a usualhigher
a value slightly drawback
than
of
thethe biotechnological
best yield obtained approaches
using HHDH+HEfrom an[91].
industrial
The usepoint of view.
of this biotechnological approach allows the
synthesis of the S-ECH enantiomer with a 99% ee. In addition, the biotechnological approaches avoid
Table 3. ECH synthesis using basic catalysts.
the presence of by-products, such as chloroacetone, glycidol, diglycidyl ether and polyglycerols, that are
very usual when ECH is synthesized by using the chemical approaches. Moreover, the use of alkaline
Temperature
Reagent leads to a large
hydroxides Catalyst Reactor
amount of salt wastes, thusSystem
compromising the sustainability Yield
of % Ref.
the technology.
(°C)
Nevertheless, chemical approaches allow working in higher reagent concentration than biotechnological
Continuous
1,3-DCH NaOH
approaches, a usual drawback of the biotechnological approaches from an 30–70 50–99
industrial point of view. [59]
millireactor
1,3-DCH:1,2- Ca(OH)2:CaCO3:H2O Pre-reactor/reactor [98,1
Table 3. ECH synthesis using basic catalysts.51/64 85–90
DCH(98:2) (96:4:1, w/w%) Stripping column 02]
1,3-DCH:Reagent 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 millireactor
Fixed-bed reactor 150–300 10–90 [101]
Ca(OH)2 :CaCO3 :H2 O Pre-reactor/reactor
1,3-DCH:1,2-
1,3-DCH:1,2-DCH(98:2)
(96:4:1, w/w%) Stripping column
51/64 85–90 [98,102]
DCH1,3-DCH: 1,2-DCHHeterogeneous NaOH Continuous-flow
Microreactor 50–80 92 [97]
Ba, Ca and 200 60 [60]
Aqueous (5– 1,3-DCH hydrotalcite fixed-bed
Fixed-bed reactor 150–300 10–90 [101]
Ba/γ-Al2 O32
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
Thematerials
starting one-pot andsynthesis of chlorinated derivatives
chlorotrimethylsilane (CTMS) wasby using crude
described by theglycerol
authors’orresearch
other polyols
group
as starting
(Figure materials
4) [103]. andchlorinated
These chlorotrimethylsilane
derivatives (CTMS)
showedwasno described
effect overbyfungi
the authors’ research
and bacteria in
group (Figure 4) [103]. These chlorinated derivatives showed no effect over fungi and
preliminary studies, (unpublished results), indicating that these compounds are less toxic than the bacteria in
preliminary
parent studies, (unpublished
chlorohydrins. results),
Consequently, theyindicating
could bethat these
used compounds
instead are lessin
of 1,3-DCH toxic
somethanequivalent
the parent
chlorohydrins. Consequently, they could be used instead of 1,3-DCH in some equivalent reactions.
reactions.
OH Cl
R1 CTMS R1
OR 3
(CH2 )n + H3C n (CH2 )n
R2 O R2
OR 4 OCO(CH2 ) nCH3

n= 0-4 ; R1 =H, CH3 ; R2 = H, CH3 , CH2 CH3 , -O-, CH2 Cl; R3 = H, CH3 ; R4 = H, -(CH3 ) 2 -C-

Figure
Figure 4.
4. Synthesis
Synthesisof
ofchlorohydrin
chlorohydrinester,
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 (Figure 5).
 Theofsynthesis
the use hydratedofaluminum
chlorohydrin estersasfrom
chloride glycerol
a chlorine usingavoiding
source, an ionicthe
liquid as CTMS,
use of a solvent and
a more
hydrated aluminum chloride as a source of chlorine was also described [106]. This
expensive reagent. Alkyl and aryl acids were used to synthesize chlorohydrin esters, although yieldsapproach allowed
the use ofdepended
largely hydrated aluminum
on the chloride as a chlorine
carboxylic acid used.source,Nevertheless,
avoiding the use theof CTMS, a more
corresponding
expensive reagent. Alkyl and aryl acids were used to synthesize
1,3-dichloro-2-propyl ester was always the main regioisomer (Figure 5). chlorohydrin esters, although yields
largely depended
Molecules 2020, 25, 2511 on the carboxylic acid used. Nevertheless, the corresponding 9 of 38
R
1,3-dichloro-2-propyl esterOHwas always O the main
AlCl 6H Oregioisomer
R Cl (Figure
3
. 5). 2 Cl
+ O O O
R OH O +
OHOH OH [BMiM][PF6]
R Cl
O AlCl3.6H2O R Cl Cl
+ Cl
O O O
R OH O +
R=
OHalkylOH
or aryl [BMiM][PF6]
Cl Cl

Figure 5. Synthesis R=ofalkyl

dichloropropyl
or aryl esters from glycerol and a carboxylic acid, using an ionic
liquid.
5. Synthesis
Figure 5.
Figure Synthesis of
ofdichloropropyl
dichloropropylesters from
esters glycerol
from andand
glycerol a carboxylic acid, acid,
a carboxylic usingusing
an ionic
anliquid.
ionic
3. liquid.
3. From
From Building
Building Blocks
Blocks toto End
End Products.
Products

3. From
3.1.
3.1. Building
Synthesis
Synthesis of Blocks toCompounds
of Non-Cyclic
Non-Cyclic End Products.
Compounds

3.1. Synthesis
3.1.1.
3.1.1. of Non-Cyclic
Synthesis
Synthesis of Allyl
of Compounds
Allyl Esters
Esters
The synthesis
synthesis of of allyl
allyl fatty
fatty esters by using various fatty materials (soy oil, frying oils, palm oil,
3.1.1.The
Synthesis of Allyl Esters esters by using various fatty materials (soy oil, frying oils, palm oil,
waste animal
waste animal fats,
fats, etc.)
etc.) and
and crude
crude glycerol
glycerol was
was described
describedby bythe
theauthors’
authors’research
researchgroup
group(Figure
(Figure6).6).
AllylThe synthesis
esters were of allyl
prepared fatty esters
through aby using
two-step various fatty
reaction, materials
using both (soy oil,
conventional
Allyl esters were prepared through a two-step reaction, using both conventional and microwave frying oils,
and palm
microwave oil,
waste
heating
heating animal
[79]. fats,
[79].The etc.)
Thefirst
first and
step
step crude glycerol
consisted
consisted of of was
thethe described
synthesis
synthesis ofby the authors’
chlorohydrin
of chlorohydrin research
esters,
esters, as group (Figure
described
as described above. 6).
above.
The
Allyl esters
The second
second were
stepstep
waswas prepared through a two-step reaction,
a Finkelstein-rearrangement–elimination
a Finkelstein-rearrangement–elimination using both
reaction
reaction conventional
inducedbybyNaI.
induced and
NaI.The microwave
The reactions
reactions
heating
were [79].
carried The
out first
by step
using consisted
butanone of the
[107] synthesis
or BuOH of chlorohydrin
[79], two solvents esters,
that
were carried out by using butanone [107] or BuOH [79], two solvents that allowed the substitutionas described
allowed the above. The
substitution of
second step
aofchlorine
a chlorine was
atomatom a
bybyFinkelstein-rearrangement–elimination
oneoneiodine
iodineatom.
atom.Subsequently,
Subsequently,the reaction
thenecessary induced
necessaryacyl by NaI.
acyl rearrangement The
rearrangement and reactions
and halide
halide
were carriedtook
elimination
elimination out by
took using
place.
place. butanone
The
The reaction
reaction [107]
wasorperformed
was BuOH [79],
performed by
by two solvents
using
using that allowed
conventional
conventional the substitution
or microwave
or microwave of
heating.
heating.
aConventional
chlorine atom
Conventional by one
heating
heating iodine
yielded
yielded atom.
better
better Subsequently,
conversion
conversion rates the(about
(about
rates necessary
90%,90%, acyl
except forrearrangement
exceptolive
foroil oil and
and cocoa
olive and halide
industry
cocoa
elimination
industry took
wastes). Although place.
wastes). Although The
microwave reaction was
heating showed
microwave performed
heatinga lower
showedby using
conversion conventional
a lower rate, and a dark
conversion or microwave
rate,colour
and awasdark heating.
observed
colour
Conventional
in crude
was observed heating
products
in crude yielded
(suggesting
products better conversion
degradation),
(suggesting rates (about
the second
degradation), step
thewas90%, except
completed
second step wasfor olive25oil
in only
completed and
min, cocoa
inwhereas
only 25
industry wastes).
conventional Although
heating requiredmicrowave
48 h [50].
min, whereas conventional heating required 48 h [50].heating showed 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 conventional
O
heating required 48 h [50].
O OH R
R Cl R
CTMS NaI/nBuOH
R1 O Cl
+ + O O CH
O O O O O
2

D* D*
R2 O O OHOH OH Cl R
R Cl Cl
O O CTMS NaI/nBuOH R
O Cl
R3 + + O O CH
O O O O
2

D* D*
R2 O OH OH Cl Cl
O O
R= Fatty acyl
R3

Figure 6. 6.
Figure Synthesis of allyl
Synthesis offatty
allylesters, using
fatty varioususing
esters, fatty materials.
variousStep 1: Conventional
fatty materials. heating
Step 1: at
R= Fatty acyl
115 ◦ C/48 h and microwave (MW) were 225 ◦ C, 300 W, 17 atm for 3h. Step 2: Conventional heating was
Conventional heating at 115 °C/48 h and microwave (MW) were 225 °C, 300 W, 17 atm
115 ◦ C/486.h, and
Figure MW wasof
Synthesis
◦ C for 25 min.
150allyl fatty was
esters,
for 3h. Step 2: Conventional heating 115 using various
°C/48 h, and MW fatty
wasmaterials. Step
150°C for 25 1:
min.
Conventional heating at 115 °C/48 h and microwave (MW) were 225 °C, 300 W, 17 atm
Several
for 3h. Stepcompounds containing an allylwas
2: Conventional group are biologically active as150°C
insecticides, acaricides
Several compounds containingheating
an allyl group115are
°C/48 h, and MW
biologically wasas
active for 25 min.
insecticides, 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
Several [111].
compounds
against termites [111]. containing an allyl group are biologically active as insecticides, acaricides
In addition, an ovicidal
and insect repellents effect
[108–110]. against
Allyl Cydia
fatty pomonella
acids (L.) was
esters have beendescribed foras
suggested allyl carboxylates
wood [112].
preservatives
Anothertermites
against application of allyl ester mixtures of higher fatty acids is in polymer synthesis. Highly effective
[111].
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) (Figure 7). 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].
was used to prepare S-4-chloro-3-hydroxybutanenitrile Cl Cl 40 C, 1h, pH= 7,5(S-CHBN)
W249mutant (H SO ) Cl CN(Figure 7). The synthesis of
o
2 4
OH OH
S-CHBN from R,S-ECH yielded a modest enantiomeric excess, whereas the use of 1,3-DCH as
PBS +NaCN

Figure
substrate led 7. Continuous
to S-CHBN, withsynthesis
97.3%
Cl
of (S)-4-chloro-3-hydroxybutanenitrile
Clee after pH
40 C, 1h, optimization.
pH= 7,5 (H SO ) Cl
o CN S-CHBN (S-CHBN)was also from
2 4
1,3-DCH
prepared and
from
NaCN
1,3-DCH, with ancatalyzed
86% yield by halohydrin
and a 97.5% dehalogenase
ee in 1 h, (HheC). using W249F a HheC mutant constructed by
Figure 7. Continuous
Molecules 2020, 25, 2511
site-directed mutagenesis [114]. synthesis of (S)-4-chloro-3-hydroxybutanenitrile (S-CHBN) from 1,3-DCH 10 of 38and
The enantiomer
NaCN catalyzed R-CHBN
by halohydrin was synthesized
dehalogenase (HheC). from 1,3-DCH by using recombinant HheB from
Corynebacterium sp. N-1074. TheOHfinal yield was 65%, and
W249mutant OH the product had an ee of 95.2% [115].
PBS +NaCN
The enantiomer R-CHBN was synthesized
Chiral C4 compounds are synthetic units useful for the from 1,3-DCH byproduction
using recombinant
of variousHheB from
pharmaceuticals
Corynebacterium
and chiralsp.polymers
N-1074. The final
[116]. Cl yield
As an was
Cl
example,65%,
40 C, 1h, pH= 7,5 and
(H SO ) the
S-CHBN Cl
o
product
CN
is used had asana eeprecursor
2 4of 95.2% [115].
of atorvastatin, a
Chiral C4 compounds
cholesterol-lowering
Figure 7. Continuous are
drugsynthetic
[114].
synthesis units useful for the production
of (S)-4-chloro-3-hydroxybutanenitrile (S-CHBN)offrom
various
1,3-DCHpharmaceuticals
and
Figure 7.NaCN
Continuous synthesis of (S)-4-chloro-3-hydroxybutanenitrile (S-CHBN) from 1,3-DCH and
and chiral polymers [116]. As an example, S-CHBN is used as a precursor of atorvastatin, a
catalyzed by halohydrin dehalogenase (HheC).
NaCN catalyzed by halohydrin dehalogenase (HheC).
cholesterol-lowering
3.1.3. Synthesis drug [114].Derivatives
of Azide
Chiral C4 compounds are synthetic units useful for the production of various pharmaceuticals
Theand chiral polymers
enantiomer R-CHBN[116].was an example, S-CHBN
As synthesized is used as
from 1,3-DCH byausing
precursor of atorvastatin,
recombinant HheB from
3.1.3. Synthesis
Synthesis of
ofAzide
DiazidesDerivatives
a cholesterol-lowering drug [114].
Corynebacterium sp. N-1074. The final yield was 65%, and the product had an ee of 95.2% [115].
Chiral ToSynthesis
prepare the are
corresponding diazide
usefulderivatives, 1,3-Dichloroprop-2-yl esters were used
Synthesis ofC4
3.1.3. compounds
Diazides of Azide synthetic units
Derivatives for the production of various pharmaceuticals
(Figure
and chiral 8) [117,118].
polymers [116].The
Assubstitution
an example, process
S-CHBNwas carried
is usedoutas by using a conventional
a precursor methodology
of atorvastatin, a
Synthesis of Diazides
Toto prepare
prepare the corresponding
azides
cholesterol-lowering drug [114]. [119]. The diazide
reaction derivatives,
of 1,3-Dichloroprop-2-yl
1,3-dichloroprop-2-yl ester with esters
NaN were
3 used
(Figure 8, See
To
(FigureSupplementary prepare
8) [117,118]. The the corresponding
substitution
Materials diazide
process
Section derivatives,
1.1.2)was carried
yielded 1,3-Dichloroprop-2-yl esters
out by using a conventional
1,3-diazidoprop2-yl were
esters (70%–86% used
methodology
yield), which
(Figure 8) [117,118]. The substitution process was carried out by using a conventional methodology to
to prepare
3.1.3. can beazides
Synthesis as[119].
of Azide
used The reaction
Derivatives
crude material of 1,3-dichloroprop-2-yl
for further reactions. ester with NaN3 (Figure 8, See
prepare azides [119]. The reaction of 1,3-dichloroprop-2-yl ester with NaN3 (Figure 8, See Supplementary
Supplementary Materials Section 1.1.2)
Materials Section 1.1.2) yielded
yielded 1,3-diazidoprop2-yl esters (70%–86%
1,3-diazidoprop2-yl esters (70–86% yield), which can be
yield), which
used as crude
OH O
Synthesis
can be used ofasDiazides
material crude material
for further for further reactions.
reactions. O CTMS
R
O
Cl
NaN
R N3 3
+ R
O o O
OH OH OH 100 oC, 48h 100 C, o/n
To prepare the corresponding
OH
O
diazide derivatives, O
1,3-Dichloroprop-2-yl
Cl O esters
N3 were used
CTMS NaN 3
R N
(Figure 8) [117,118]. The substitution
+ R process was carried
R
O
Cl
out by using aOconventional methodology
3
o
OH OH OH 100 C, 48h o 100 C, o/n
to prepare azides [119]. The reaction of 1,3-dichloroprop-2-yl ester withN3NaN3 (Figure 8, See
R= (C H ) CH;6CH CH (CH
5 2) C; CH (CH
3 ) (n=6,
2
Cl
11-16) 3 2 3 2 n

Supplementary Materials Section 1.1.2) yielded 1,3-diazidoprop2-yl esters (70%–86% yield), which
Figure 8. Synthesis of azides from glycerol and carboxylic acids.
can be used as crude R=material for further reactions.
(C H ) CH; CH CH (CH ) C; CH (CH ) (n=6, 11-16)
6 5 2 3 2 3 2 3 2 n

Figure 8. Synthesis of azides from glycerol and carboxylic acids.

Synthesis Figure
of Mononoamide
SynthesisDerivatives
8. OH
O
of azides from Oglycerol and carboxylic
O acids.
CTMS NaN3
R N3
Synthesis of Mononoamide
+ Derivatives
R R Cl
O
The synthesis OH of OH nine monoamides
OH 100 C, 48h from crude glycerol and carboxylic
o O acids (C8-C18) was 100 oC, o/n
Synthesis of Mononoamide
The synthesis of nineDerivatives
monoamides from crude glycerol Cl N3
and carboxylic acids (C8-C18) was
described by the authors’ research group [120]. Diazides were synthesized through the pathway
described by the authors’ research group [120]. Diazides were synthesized through the pathway shown
The synthesis
shown of nine
in Figure monoamides
8. Diazides were from crude
reduced glycerol
by catalytic and carboxylic
hydrogenation, acidsmild
under (C8-C18) was using
conditions,
in Figure 8. Diazides
R= (C H ) were
6 5 2reduced
CH; CH CH 3 by(CHcatalytic
(CH ) C; CH 2 hydrogenation, under mild conditions, using Pd/C.
) (n=6, 11-16)
3 2 3 2 n
described
Pd/C.
Thebyreduction
thereduction
The authors’
resultedresearch
resulted
in an O- toin group [120].
an O-migration
N-acyl to N-acylDiazides awere
migration
to yield synthesized
to yield
monoamide 9).through the
a monoamide
(Figure pathway
(Figure 9).
shown in Figure Figure
8. Diazides were reduced by catalytic hydrogenation,
8. Synthesis of azides from glycerol and carboxylic acids. under mild conditions, using
O
Pd/C. The reduction resulted in an O O- to N-acyl migration to yield a monoamide OH
(Figure 9).
R N3 R NH
Synthesis of Mononoamide Derivatives O
Pd/C(10%), N 2

r.t., 72h O
N3 H2N
O
The synthesis of Rnine monoamides
N3 from crude Rglycerol
Pd/C(10%), N NH and carboxylic acids (C8-C18) was
OH
57-88%
2

described by the authors’ research

O
N3
group [120]. Diazides Hwere
r.t., 72h 2N
synthesized through the pathway
R= (C H ) CH; CH CH (CH ) C; CH (CH ) (n=6, 11-16)
shown in Figure 8. Diazides were reduced by catalytic hydrogenation,
6 5 2 3 2 3 2
57-88%
3
under mild conditions, using
2 n

Pd/C. The reduction resulted

Figure in an
9. Synthesis of O- to N-acyl
monoamides migration to
by hydrogenation of yield a monoamide
the corresponding (Figure 9).
diazides.
R= (C6H5)2CH; CH3CH2(CH3)2C; CH3(CH2)n (n=6, 11-16)

The use of monoamides as phase change materials O (PCM) in thermal energy storage was
O
investigated. The enthalpy of the monoamides ranged from 25.8 to OH149.7 kJ/kg. The highest values
R N3 Pd/C(10%), N2 R NH
of latent heat were ofOthe same order as those of commercial PCMs with low latent heat values, such
r.t., 72h H2N
as paraffin wax (146–210 kJ/kg)
N3 [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= (C6H5)2CH; CH3CH2(CH3)2C; CH3(CH2)n (n=6, 11-16)

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
bonds
bonds and
and alkyl
alkyl chain
chain on
on their
their thermal
thermal properties
properties [120].
[120].

3.1.4.
3.1.4. Sulfonamides
Sulfonamides
Lupasçu
Lupasçu et et al.
al. described
described the
the synthesis
synthesis of
of water-soluble
water-soluble rutin-sulfonamide
rutin-sulfonamide derivatives
derivatives with
with high
high
Molecules
yields 2020, 25, 2511The reaction was carried out by using 1,3-DCH as the linker of rutin and several
(83%–94%). 11 of 38
yields (83%–94%). The reaction was carried out by using 1,3-DCH as the linker of rutin and several
sulfonamides,
sulfonamides, resulting
resulting in
in some
some water-soluble
water-soluble sulfonamide
sulfonamide derivatives
derivatives (Figure
(Figure 10).
10). The
The derivatives
derivatives
with
with pyridine (sulfapyridine)
pyridine resulting
sulfonamides, (sulfapyridine) and
in someand chloropyridazine
chloropyridazine
water-soluble (sulfachloropyridazine)
(sulfachloropyridazine)
sulfonamide showed
derivatives (Figureshowed
10). Theanan equal
equal oror
derivatives
even higher
even pyridine
with antibacterial
higher antibacterial
(sulfapyridine)activity
activity than co-trimoxazole,
than co-trimoxazole,
and chloropyridazine an antibiotic used
an antibiotic used
(sulfachloropyridazine) to treat
to treat
showed a variety
a variety
an equal of
of
or even
bacterial
bacterial infections.
infections. Co-trimoxazole
Co-trimoxazole consists
consists of
of one
one part
part of
of trimethoprim
trimethoprim to
to five
higher antibacterial activity than co-trimoxazole, an antibiotic used to treat a variety of bacterialfive parts
parts of
of
sulfamethoxazole
sulfamethoxazole [122].
[122]. consists of one part of trimethoprim to five parts of sulfamethoxazole [122].
infections. Co-trimoxazole

1)CH
1)CH3ONa, 30min, reflux
3ONa, 30min, reflux
2)
2)
OH
OH OH
OH OH
OH CH3
CH3
OH
OH OO NH
NH
HHOO OO Cl Cl
Cl Cl HHOO OO
SO2
SO2
ram-glu 3)
OO ram-glu 3) ram-glu HHNN
OO ram-glu RR
OH H2
H2NN SO2
OH OO SO2 OH OO
reflux, OH
reflux,6h
6h NH
NHRR

R=
R=
H3CO H3
H3CO H3CC OO NN
NN NN NN NN NN SS
NN OO NN
OCH3
OCH3 Cl
Cl NN
NN NN H3
NN H3CC CH3 CH3
CH3
CH3

Figure
Figure 10.
10. Synthesis
Figure of
of rutine-sulphonamide
10. Synthesis
Synthesis of rutine-sulphonamide derivatives,
rutine-sulphonamide derivatives,
derivatives, using
using 1,3
1,3-DCH
1,3-DCH
using as
as aa linker.
as a linker.
-DCH linker.

3.1.5. Synthesis
3.1.5. of Polynuclear Metals
3.1.5. Synthesis
Synthesisof
of Polynuclear
PolynuclearMetals
Metals
Thesynthesis
The
The synthesis of
synthesis ofdinucleating
of dinucleating ligands
dinucleating ligands was
ligands was carried
wascarried out
carried out by
outby using 1,3-DCH
byusing
using 1,3-DCH [123,124].
1,3-DCH [123,124].
[123,124].TheThesynthesis
The synthesis
synthesis
was
was aaatwo-step
was two-stepreaction
two-step reaction(Figure
reaction (Figure
(Figure11)11)[124,125].
11) [124,125].TheThe
[124,125]. symmetrical
The symmetrical
symmetricaldinucleating
dinucleatingligand
dinucleating (H3 hpnbpd)
ligand
ligand ((H holds
H33hpnbpd)
hpnbpd)
two
holds carboxyl
holds two groups
two carboxyl and
carboxyl groups two
groups and pyridine
and two arms.
two pyridine While
pyridine arms. Patra
arms. While et al.
While Patra synthesized
Patra et et al. the
al. synthesized ligand
synthesized the by reacting
the ligand
ligand byby
glycine
reacting with 1,3-DCH in the first step and obtaining the ligand with a 75%
reacting glycine with 1,3-DCH in the first step and obtaining the ligand with a 75% yield after aa
glycine with 1,3-DCH in the first step and obtaining the ligand with yield
a 75%after
yielda second
after
reactionreaction
second
second step with
reaction 1-chloromethylpyridine,
step
step with
with 1-chloromethylpyridine,
1-chloromethylpyridine,Haldar etHaldar
al. used
Haldar etβ-alanine
et al.
al. used instead ofinstead
used β-alanine
β-alanine glycineof
instead asglycine
of a reagent,
glycine as
as
achieving
aa reagent, the corresponding
reagent, achieving
achieving the ligand,
the corresponding with
corresponding ligand, a 73% yield.
ligand, with
with aa 73%
73% yield.
yield.
OO
OH
OH
(CH2)n
(CH2)n OH
OH
Cl
Cl
OH HHOO (CH2)n
(CH2)n OO
NN .HCl/LiOH/H o
OH NH
NH2(CH2)nCOOH
.
HCl/LiOH/H2OO00 Co -> r.t.,1 day
C -> r.t.,1 day
2(CH2)nCOOH (CH2)n OH O 2 NN NN
(CH2)nOH O
OO NH OH
1)LiOH/H 40 oC, NH OH OH
Cl
Cl Cl
Cl 1)LiOH/H2O, o 3 days
2O, 40 C, 3 days NH
NH(CH2)n
2)HBr/H
2)HBr/H2O to pH=5
2O to pH=5 NN OH NN
(CH2)n
2)HBr/H
2)HBr/H2OOtotopH=5
pH=5
2

n=1,2
n=1,2

Figure 11.
Figure Synthesis of the
the H33hpnbpda ligand.
Figure 11.
11. Synthesis
Synthesis ofof the H H 3hpnbpda
hpnbpda ligand.
ligand.
Cooper (II) complexes were also obtained via the synthesis of a bipyrazolic ligand, bearing two
Cooper
Cooper (II)(II) complexes
complexes were
were also
also obtained
obtained via
via the
the synthesis
synthesis ofof aa bipyrazolic
bipyrazolic ligand,
ligand, bearing
bearing two
two
carboxyl groups (Figure 12). The first step was similar to the previous one, 1,3-DCH reacted with two
carboxyl
carboxyl groups
groups (Figure
(Figure 12).
12). The
The first
first step
step was
was similar
similar to
to the
the previous
previous one,
one, 1,3-DCH
1,3-DCH reacted
reacted with
with
molecules of the corresponding pyrazole derivative. The final Cu(II) complex showed good catalytic
two
two molecules
molecules of of the
the corresponding
corresponding pyrazole
pyrazole derivative.
derivative. TheThe final
final Cu(II)
Cu(II) complex
complex showed
showed good
good
properties in25,
Molecules 2020, the oxidation
x FOR of catechol [126].
PEER REVIEW 12 of 39
catalytic properties in the oxidation of catechol
catalytic properties in the oxidation of catechol [126].[126].
H3C N H
CO2 Et CO2 Et HO2 C CO2 H O O O O
N
1)tBuOK, reflux, 30min N OH N NaOH/H2O N OH N Cu
CH3COCH3 -
--

N- - -
--

CO2 Et OH N N N N OH N
24h, r.t. -> 0 oC CuCl2/H2O r.t.
2) ,reflux, 15h N N
H3C CH3 H3C CH3 until cristallization
( 2-5 days) H3C CH3
Cl Cl

Figure
Figure 12.12. Synthesisof
Synthesis of the
the copper
coppercomplexes CuL1.
complexes CuL1.

Polynuclear
Polynuclear metals have
metals manymany
have potential applications,
potential e.g., therapeutic
applications, agents (e.g., photocleavage
e.g., therapeutic agents (e.g.,
of
photocleavage of DNA), photovoltaic components, photocatalysts, magneticand
DNA), photovoltaic components, photocatalysts, magnetic materials tuneable
materials and chemical
tuneable
sensors [127–130].
chemical sensors [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].
 ( 2 5 days) 3 3
Cl Cl

Figure 12. Synthesis of the copper complexes CuL1.

Polynuclear metals have many potential applications, e.g., therapeutic agents (e.g.,
photocleavage
Molecules of DNA), photovoltaic components, photocatalysts, magnetic materials and
2020, 25, 2511 tuneable
12 of 38
chemical sensors [127–130].

3.1.6.3.1.6.
Glycoconjugate Synthesis
Glycoconjugate Synthesis
In theInsynthesis of 1,2-cis-alkyl
the synthesis glycosides,
of 1,2-cis-alkyl 1,3-DCH
glycosides, waswas
1,3-DCH used. Figure
used. 13 13
Figure shows
showsthethe
synthesis
synthesis of
of 1,3-dichoroprop-2-yl-2,3,4,6-tetra-O-acetyl-α-d-galactopyranoside. The first step consisted
1,3-dichoroprop-2-yl-2,3,4,6-tetra-O-acetyl-α-D-galactopyranoside. The first step consisted of the
of the
substitution of theofthiophenoxy
substitution the thiophenoxygroup of theofhemithioacetal
group of β-d-galactopyranoside
the hemithioacetal by 1,3-DHC.
of β-D-galactopyranoside by 1,3-DHC.
This This
substitution allowed
substitution the synthesis
allowed of the
the synthesis ofcorresponding α-d-galactopyranoside
the corresponding α-D-galactopyranosidealkylalkyl
isomer.
isomer.
Finally, the peracetylation of the free alcohol led to the final product, with an 84.9% yield [131].
Finally, the peracetylation of the free alcohol led to the final product, with an 84.9% yield [131].

OH OAc
HO AcO
HO OH O O
OH O
HO
1) O
H SPh 1h, N atm, r.t. Ac2O, DMAP, Pyridine AcO
OH 2 OH
O OAc
O
Cl Cl 2) -30 oC-->NIS, TMSOTf r.t., o/n Cl
2h
Cl
Cl Cl

84,9%

Figure13.
Figure Synthesis ofof
13. Synthesis 1,2-cis-alkyl tetra-O-acetyl
1,2 -cis-alkyl glycosides,
tetra-O-acetyl using 1,3-DCH.
glycosides, 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
(BF3 ), to yield the corresponding alkyl sugar. The substitution of both chlorine atoms by the azide
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 theFOR
expected diamide, obtaining the cyclic coupling products instead (Figure 14).13 of 39
not provide
Molecules the expected
2020, 25, x diamide, obtaining the cyclic coupling products instead (Figure 14).
PEER REVIEW

OAc
OAc
O O
AcO
AcO OAc OAc OAc
OH O OAc OAc
OAc OAc O NaN3 O
OAc AcO O AcO O
AcO O AcO O
O O
OAc OAc OAc DMF, 80 oC, 24h OAc OAc OAc
Cl Cl
CH2Cl2(anhydr) 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 O O *
AcO AcO O
AcO O AcO
O O O N
OAc OAc OAc OAc
OAc OAc
NHCOCnH2n+1 N CnH2 n + 1
NHCOCnH2n+1 H

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

2)Amberlite 120(H+)

OH
OH
O O
HO
HO O
O N
OH OH OH *
N CnH2 n + 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
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 K2 CO3 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. K2 CO3 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
compounds
Molecules 2020, 25, 2511 synthesized by Shamroukh et al. showed remarkable cytotoxicity 14activityof 38 against
MCF-7 and HepG2 cell lines [141].
HO

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)

HO

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

N
H3C

CH3
O

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

65%
(b)

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 NaH/DMF,
(c) 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 of Aziridine
Figure Derivatives
15. Synthesis of pyridine derivatives (a) Moustafa et al. synthesis [139]; (b) synthesis
Lebel described by Saad
et al. described theetsynthesis
al. [140];of
(c)aShamroukh et al. niconitrile
N-tosyloxycarbamate using synthesis [141].tosyl chloride.
1,3-DCH and
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,
Synthesis of xAziridine
FOR PEER REVIEW
Derivatives 15 of 39

Synthesis Lebel et al. described

of Aziridine the synthesis of a N-tosyloxycarbamate using 1,3-DCH and tosyl chloride.
Derivatives
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].
The
Molecules use
2020, of a chiral bis(oxazoline) copper complex with the N-tosyloxycarbamate yielded
25, 2511 15 of 38 the
asymetric aziridines with a enantiomeric R/S ratio of 4:1 (Figure 16)H3[149].
C CH3
O
H3C O
H3CH3C N CH3
CH3N Cl Cl
O Ph CH3
H3C O Ph
O 1)MeCN, 3h r.t.
OH Cl H3C N N Ph(6%) CH3
NH2OH.HCl, imidazole, 16h, r.t. O ClO ClO
N N CH3
+ N Cl Ph Cu(CH3CN)4PF6 (5%)
O NHOTs Ph N
NO 3h r.t.0oC + Tosylchloride
2)Ether,
1)MeCN,
OHCl Cl . Cl - Ph(6%) K CO
NH2OHEtHCl, imidazole, 16h, r.t. O 4 Nitrostyrene, O O
3N, 2h, r.t 2 3
+ N N Cu(CH 3CN)4PF 6 (5%)
o
N Cl CH , MS 4A, 23 3C
N o
2)Ether, 0 C + Tosylchloride O NHOTs N
Cl Cl NO2
Et3N, 2h, r.t 4-Nitrostyrene, K2CO3
CH3, MS 4A, 23 oC
59% 16%
NO2

Figure 16. Synthesis of aziridine

59%
derivatives using 1,3 -DCH.
16%

Figure 16. Synthesis of aziridine derivatives using 1,3-DCH.

AziridinesFigure
are the16.smallest
Synthesis of aziridine derivatives
nitrogen-containing using 1,3
heterocycles. -DCH. aziridine moiety is
Although
presentare
Aziridines inthe
few natural
smallest products [153], heterocycles.
nitrogen-containing they displayAlthough
important biological
aziridine moietyactivities
is present[154,155].
Aziridines are the smallest nitrogen-containing heterocycles. Although aziridine moiety is
Aziridines
in few natural have[153],
products been they
introduced
displayinto variousbiological
important structures, to create
activities novel chemotherapeutic
[154,155]. Aziridines have agents
present in few natural products [153], they display important biological activities [154,155].
[156,157].into various structures, to create novel chemotherapeutic agents [156,157].
been introduced
Aziridines have been introduced into various structures, to create novel chemotherapeutic agents
In organicIn organic chemistry,
chemistry, aziridines
aziridines are valuable
are valuable buildingbuilding
blocks. blocks.
As an Asexample,
an example,
theirtheir reaction with
reaction
[156,157].
with many nucleophiles can result in ring-opening reactions [158–161]. They can also be used asused
many nucleophiles can result in ring-opening reactions [158–161]. They can also be key as key
In organic chemistry, aziridines are valuable building blocks. As an example, their reaction with
intermediates
intermediates in diversity-oriented
in diversity-oriented synthesis synthesis of alkaloids
of alkaloids [162]. Aziridines
[162]. Aziridines have
have been been
used in used
the in the
many nucleophiles can result in ring-opening reactions [158–161]. They can also be used as key
asymmetric
asymmetric total syntheses
total syntheses of renieramycins
of renieramycins M and GMand andjorumycin,
G and jorumycin, marine bioactive
marine bioactive compounds compounds
intermediates in diversity-oriented synthesis of alkaloids [162]. Aziridines have been used in the
from
from a blue a blueand
sponge sponge and respectively
a molusc, a molusc, respectively [163]. are
[163]. Aziridines Aziridines
masked are maskedthat
1,3-dipoles 1,3-dipoles
react with that react
asymmetric total syntheses of renieramycins M and G and jorumycin, marine bioactive compounds
alkenes, with alkenes,
alkynes, alkynes,
nitriles nitriles and
and carbonyl carbonyltocompounds
compounds to produce
produce various [3+2] various [3+2] cycloadducts
cycloadducts [164]. [164].
from a blue sponge and a molusc, respectively [163]. Aziridines are masked 1,3-dipoles that react
with
Synthesis alkenes,
of alkynes,
1,2,4-Triazinones
Synthesis of nitriles andDerivatives
Derivatives
1,2,4-Triazinones carbonyl compounds to produce various [3+2] cycloadducts [164].

The synthesis
The
Synthesis of S-alkyl
synthesis of 4-amino-3-mercapto-6-(2-(2-thienyl)vinyl)
S-alkyl
of 1,2,4-Triazinones 4-amino-3-mercapto-6-(2-(2-thienyl)vinyl)
Derivatives -1,2,4-triazin -5(4H)-one
-1,2,4-triazin -5(4H)-one
derivatives, using 1,3-DCH
derivatives, or ECH,
using 1,3-DCH or is shown
ECH, in Figure
is shown 17. Potassium
in Figure 17. Potassiumcarbonate
carbonatein in
DMFDMF was
was again
again used The
as a synthesis
base, to of S-alkyl
improve the 4-amino-3-mercapto-6-(2-(2-thienyl)vinyl)
nucleophilicity of the S atom, preserving the -1,2,4-triazin
epoxy group -5(4H)-one
in the
used as a base, to improve the nucleophilicity of the S atom, preserving the epoxy group in the final
derivatives,
final product. Theseusing 1,3-DCH showed
compounds or ECH,moderate
is shown anticancer
in Figure 17. Potassium
activity [147]. carbonate in DMF was again
product. These compounds showed moderate anticancer activity [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 anticancer S activity [147].
OH K2CO3, DMF
o.n./r.t. S N
N 55%
S OH
OHCl Cl K2CO3, DMF
O N S
o.n./r.t. N
N NH2 55%
S Cl
Cl Cl N OH
N O N S
S
NH2
O N SH Cl
N
N NH2
Cl S N N
O
O O N SH S 65%
K2CO3, DMF N
NH2
o.n./r.t. N O
N NH2
Cl O
O S 65%
K2CO3, DMF N
Synthesis
Figure 17.Figure of 1,2,4-triazine
17. Synthesis -thiophene-
of 1,2,4-triazine
o.n./r.t.
O NH
derivatives.
-thiophene- derivatives. 2

Synthesis of Pthalazine Derivatives

Figure 17. Synthesis of 1,2,4-triazine -thiophene- derivatives.
Synthesis of Pthalazine Derivatives
The reaction of 1,3-DCH and ECH with arylphthalazinone yielded phthalazin
SynthesisTheofreaction of 1,3-DCH
Pthalazine and ECH with arylphthalazinone yielded phthalazin derivatives [142–
Derivatives
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 the
Thenitrogen
reaction in the phthalazinone
of 1,3-DCH on 1,3-DCH
and ECH with (33% to 36%
arylphthalazinone yield)phthalazin
yielded or ECH (51% to 54%[142–
derivatives
nitrogen in the phthalazinone on 1,3-DCH (33% to 36% yield) or ECH (51% to 54% yield). This attack
yield).144,147]. Figure
This attack was18a shows by
promoted thethe
N-alkyl products
presence of K2 CO resulting from
3 . The loss the nucleophilic
of aromaticity, whenattack
an arylof the
was promoted by the presence of K2CO3. The loss of aromaticity, when an aryl radical was
nitrogen
radical in the phthalazinone
was substituted on 1,3-DCH
by a benzyl radical, (33%
allowed thetoregiospecific
36% yield) or ECH (51% attack
nucleophilic to 54%ofyield). This attack
the oxygen
substituted by a benzyl radical, allowed the regiospecific nucleophilic attack of the oxygen instead of
was
instead of promoted
the nitrogenbyonthe presence
1,3-DCH andofECH
K2CO 3. The18b)
(Figure loss[144].
of aromaticity,
The reactionwhen
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
substituted byclosing
ring opening–ring a benzylof radical, allowed
the oxirane the regiospecific
nucleus (54% yield), whilenucleophilic attackwith
the reaction of the oxygen instead
1,3-DCH, was of
opening–ring closing of the oxirane nucleus (54% yield), while the reaction with 1,3-DCH, was
the nitrogen
described on 1,3-DCH
as a SN2 reaction and
to yield ECH (Figure 18b) [144]. The
O-(3-chloro-2-hydroxypropyl) reaction (36%
phthalazine of ECH occurred
yield). Finally, via
Se- ring
opening–ring
and S-alkyl closing
phthalazines were ofalso
the synthesized,
oxirane nucleus (54% yield),
with yields whileofthe
in the range reaction
71–72% and with
62–75% 1,3-DCH,
for 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%–
75% for2020,
Molecules the25,
1,3-DCH
2511 and ECH, respectively (Figure 18c). All compounds showed moderate-to-high
16 of 38
antimicrobial activity in comparison with standard drugs [142,143].

(a)
Ar
OH Cl
K2CO3, DMF N
N 33-36%
Cl Cl Ar OH
O
N
NH
Ar
O
Cl N
O 51-54%
K2CO3, DMF N 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

(c)
Cl
OH K2CO3, DMF N N
Ar Y OH

71-72%
Cl Cl Ar
CH3
N
Ar=
NH

Y H3C CH3
N N
O
Cl Ar Y
O K2CO3, DMF 62-75% Y= S- Se

Figure 18. (a) Synthesis of N-alkylated phtalazines [142]; (b) synthesis of 1-oxo alkylated phtalazine [144];
Figure
(c) 18. (a)
synthesis of Synthesis of N-alkylated
Se- and S-alkyl phtalazines
phthalazines [142];
derivatives (b) synthesis of 1-oxo alkylated phtalazine
[143].
[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.
De Espinosa
The diene et al. described
was prepared a plant-oil-based
by the esterification diene carboxylic
of ω–alkenyl containingacids
hydroxyl groups
(Figure ten years
19) with ago.
1,3-DCH.
AThe diene was prepared
phase-transfer catalystby theused
was esterification
due to theof ω–alkenyl carboxylic
high difference acids (Figure
of polarity between19)both
with reagents.
1,3-DCH.
A phase-transfer
The catalyst was
dimer was polymerized used
via ADMETdue topolymerization,
the high difference
usingofapolarity between both
Hoveyda–Grubbs 2ndreagents.
generationThe
dimer was
catalyst. polymerized
It was via ADMET
also copolymerized with polymerization,
an α,ω-diene bearingusinga aDOPO
Hoveyda–Grubbs
pendant group, 2ndalso
generation
using a
catalyst.
Grubbs It was
2nd also copolymerized
generation with
catalyst (Figure 20).anThe
α,ω-diene bearing
resulting a DOPO pendant polyesters
phosphorus-containing group, alsoshowed
using a
Grubbs 2nd
molecular generation
weights up to catalyst
7000 Da(Figure 20).crystallinity
[165]. The The resultingof phosphorus-containing
these polyesters decreasedpolyesters showed
as the amount
ofmolecular
DOPO-basedweights up to 7000(M2)
comonomer Da [165]. The crystallinity
increased. of these polyesters
Totally amorphous polymersdecreased as the for
were obtained amount
the
of DOPO-based
highest M2 content. comonomer (M2)plant-oil-based
Some of these increased. Totally amorphous
polymers showed polymers were obtained
glass transition for the
temperatures
highest from
ranging M2 content. ◦ C, good
35 to 52 Some of these plant-oil-based
thermal stability andpolymers
relativelyshowed glassretardancy,
good flame transition despite
temperatures
their
ranging
high from(fatty
aliphatic 35 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
+ H2C
O
Cl Cl O
Cl Cl

DMF,toluene K2CO3, TBAH

DMF,toluene K2CO3, TBAH

OH
OH
OO O
O
H2C
H2C CH2
CH2
OO O
O

++
O
O
OO CH
CH
22
H2C
H2C O
O
OO
OH
OH

Figure
Figure 19.19.Dimer
Dimersynthesis
Dimer synthesisof
ofalkenyl
alkenyl fatty
fatty acids,
acids, using
using1,3-DCH
1,3-DCHasasa alinker.
linker.
OH OH
O OH OH
O O O
H2C O H2C O O CH2
H2C O O CH2 + CH2
O CH2 + H2C
O O
O O O
O

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

HO
O (CH2 ) n O P
HO O
O O
H2C O O
(CH2(CH
) n )m O P O
2 x O O
O O O
O O O CH2
H2C (CH2 )m y
O x O
n=0, m=1 CH2
O
n=1, m=0 95% y
n=0, m=1
n=1, m=0 95%
Figure 20. Synthesis of phosphorus-containing polyesters via ADMET copolymerization in presence of
Grubbs 2nd generation
Figure 20. Synthesis catalyst (C2).
of phosphorus -containing polyesters via ADMET
copolymerization in presence of Grubbs 2nd generation catalyst (C2).
Figure 20.1,3-DCH Synthesis of used
phosphorus
Moreover, was also to prepare-containing
polymers withpolyesters via
specific properties ADMET
[166]. These
copolymerization
polymers are used in in
many presence
areas, of Grubbs
because good 2nd
flamegeneration
retardancy catalyst
for (C2).
polymeric materials is These
of great
Moreover, 1,3-DCH was also used to prepare polymers with specific properties [166].
concern to both consumers and manufacturers [167].
polymers are used in many areas, because good 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].
polymers
3.2. Cyclic are used in many areas, because good flame retardancy for polymeric materials is of great
Compounds
concern to both consumers and manufacturers [167].
3.2. Cyclic Compounds
3.2.1. Synthesis of Oxo-Heterocycles
3.2.3.2.1.
Cyclic Compounds
Synthesis ofoxetane
Oxo-Heterocycles
To synthesize and carbonate compounds, 1,3-DCH and ECH were used, respectively.
In addition, 1,3-DCH
To synthesize was used
oxetane andto synthesize a 1,3-dichloroprop-2-yl
carbonate compounds, 1,3-DCH and ether
ECH bywere
the catalyzed Rh2 (OAc)4-
used, respectively.
3.2.1. Synthesis of Oxo-Heterocycles
substitution
In addition, of an imino group
1,3-DCH (Figure
was used to 21). The subsequent
synthesize abstraction of the
a 1,3-dichloroprop-2-yl by theofcatalyzed
β-proton
ether the diester
by Rh To
NaH synthesize oxetane
led 4-tosubstitution
2(OAc) of and
the corresponding carbonate
group compounds,
chloromethyloxetane
an imino 1,3-DCH
with
(Figure 21). The a 77%and ECH
yield
subsequent were of
[168].
abstraction used, respectively.
the β-proton of
In the
addition, 1,3-DCH was used to synthesize a 1,3-dichloroprop-2-yl
diester by NaH led to the corresponding chloromethyloxetane with a 77% yield [168]. ether by 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
MoleculesMolecules
2020, 25, 2020,
2511 25, x FOR PEER REVIEW 18 of 38 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 OO Cl
OH O Rh2(OAc)4 O O NaH
O Cl OO
+ H3C HNO H3C H3C
OH O O PhH,Rh (OAc)
o O O NaH O
Cl Cl O O 802 C 4
DMF, 25 oC O
+ O O
O HO
3C O
Cl Cl+ OO PhH, 80 Co
H3C O
O DMF, 25 oC H3C OO
O O H3C
Cl Cl PhH, 80 oC H3C DMF, 25 oC
H3C OO OC
H3
HO
3C
H3C 77% H3C
H3C
77%
77%
Figure 21. Synthesis of oxetane rings described by Davis et al. [169].
Figure
Figure 21. 21. Synthesis
Synthesis of oxetane
of oxetane rings described
rings described by DavisbyetDavis et al. [169].
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
Oxetane
widely used Oxetane is a found
motif found
isasa intermediates
motif in in natural
innatural
chemical productsproducts
synthesis, andsuchandasbiologically
biologically
featuringactive active
ring compounds.
compounds.
expansion Oxetanes are
Oxetanes
and opening
Oxetane
widely usedis aasmotif found in natural
intermediates in chemicalproducts and biologically
synthesis, such as active compounds.
featuring ring expansionOxetanes are
are[170–177],
widely used as intermediates
rearrangement processes in [178,179]
chemical or synthesis,
in polymer such as featuring
synthesis ring They
[180–188]. are and
expansion and
used opening
in
widely used asrearrangement
intermediates processes
in chemical synthesis, such as featuring ring[180–188].
expansionTheyand opening
drug[170–177],
opening [170–177],[189–195],
discovery rearrangement as they processes [178,179]
[178,179]
are considered ororinin
stable polymer
polymer
adjuncts synthesis
synthesis
to adapt [180–188].lipophilicity
solubility, They are usedareandused in
[170–177],
drug rearrangement
discovery [189–195], processes
as they [178,179]
are or
considered in polymer
stable synthesis
adjuncts to [180–188].
adapt They
solubility, are used inand
lipophilicity
in other
drug discovery [189–195],
physicochemical as they are
properties considered
toward stable
drug-like adjuncts to
molecules adapt solubility, lipophilicity
[90,189,190,196,197]. As an example,and
drug discovery
other [189–195], as
physicochemical they are considered
properties toward stable adjuncts
drug-like molecules to adapt solubility, lipophilicity
[90,189,190,196,197]. As oxygen and
an example,
other physicochemical
oxetans show, as a resultproperties
of their toward drug-like
low lipophilicity, molecules
a higher [90,189,190,196,197].
metabolic robustness than As an example,
larger
other physicochemical
oxetans show, as aof properties
result toward drug-like molecules [90,189,190,196,197]. As anlarger
example,
oxetans show, as
heterocycles a result
[198,199]. theirof their
low low lipophilicity,
lipophilicity, a highera metabolic
higher metabolic
robustness robustness than
than larger oxygenoxygen
oxetans show,
heterocycles as a result of their low lipophilicity, a higher metabolic robustness than larger oxygen
heterocycles
Bobbink et al.[198,199].
[198,199]. described the synthesis of a cyclic carbonate by the cycloaddition of CO2 to ECH
heterocycles
Bobbink[198,199].
et al. described the synthesis of acarbonate
cyclic carbonate by the cycloaddition of 2ECH
CO to ECH
Bobbink
(Figure 22). et
Theal.reaction
described the synthesis
catalyzed by an of a cyclic
imidazolium salt led by
to the cycloaddition
selective of CO
addition of2COto to 2the
Bobbink
(Figure etThe
22). al. described
reaction the synthesis
catalyzed by anofimidazolium
a cyclic carbonate
salt ledbytothe
the cycloaddition
selective of COof2 to
addition CO ECH2 to the
(Figure 22). The reaction catalyzed by an imidazolium salt led to the
epoxide with a 99% yield—a very high yield, considering the thermodynamic stability of CO22. This selective addition of CO to
(Figure 22). The
epoxide with reaction
a 99% catalyzed
yield—a by high
very an imidazolium
yield, salt led the
considering to the selective addition
thermodynamic of CO
stability of2 to the
CO 2. This
the epoxide is
approach withof aparticular
99% yield—a veryinhigh
interest CO2yield, considering
gas recovery, the cyclic
since thermodynamic
carbonatesstability
may beofused CO2 .in
epoxide with
approach a 99% yield—a
is particular
of particular very high
interest yield,
in CO considering
gas recovery, the thermodynamic stability of CO 2. This
This approach
polymer is of
synthesis [200]. interest in CO gas2 recovery, sincesince
cycliccyclic carbonates
carbonates may be mayusedbeinused in
approach
polymer is synthesis
of particular [200]. interest in CO22 gas recovery, since cyclic carbonates may be used in
polymer synthesis [200].
polymer synthesis [200].
imidazolium salt ionic liquid O
o
CO2 (2,5MPa), 130salt
imidazolium C ionic liquid
O O
Cl CO2salt
(2,5MPa), 130 Co O
imidazolium ionic liquid O
O
Cl O
(2,5MPa), 130 oCCl
CO215h O
Cl O O
15h Cl O
O Cl
99%
15h
99%
99%
Figure
Figure 22.22. Synthesis
Synthesis of cyclic
of cyclic carbonates,
carbonates, using
using vinyl-functionalized
vinyl-functionalized di-imidazolium
di-imidazolium salts salts polymers
polymers as
as theFigure 22.
catalyst. Synthesis of cyclic carbonates, using vinyl-functionalized di-imidazolium salts polymers
the catalyst.
Figure 22.catalyst.
Synthesis of cyclic carbonates, using vinyl-functionalized di-imidazolium salts polymers
as the
as the catalyst.
3.2.2.
3.2.2. Synthesis
Synthesis ofof Aza-Heterocycles
Aza-Heterocycles
3.2.2. Synthesis of Aza-Heterocycles
3.2.2. Synthesis
Moreover,
Moreover, of Aza-Heterocycles
1,3-DCH
1,3-DCH and ECH
and ECH were
werealso used
also usedto to
prepare oxazolidinones
prepare oxazolidinones and triazoles.
and triazoles.
Moreover, 1,3-DCH and ECH were also used to prepare oxazolidinones and triazoles.
Synthesis Moreover,
of of 1,3-DCH and ECH were also used to prepare oxazolidinones and triazoles.
Oxazolidinones
Synthesis Oxazolidinones
Synthesis of Oxazolidinones
The synthesis
Synthesis
The of oxazolidinones
of Oxazolidinones
synthesis was described
of oxazolidinones was bydescribed
using 1,3-DCH
by [145,146], or 1,3-dichloropropan-
using 1,3-DCH [145,146], or
2-yl The Figure
esters [118]. synthesis
1,3-dichloropropan-2-yl of the
23 shows
esters oxazolidinones
synthesis
[118]. Figureof was the
described
23oxozalidinones,
shows by
starting
synthesis using
offrom 1,3-DCH [145,146],
1,3-dichloropropan-2-yl
oxozalidinones, starting from or
The synthesis of oxazolidinones
1,3-dichloropropan-2-yl esters [118]. was23 described
Figure shows the by using
synthesis of 1,3-DCH [145,146],
oxozalidinones, starting or
from
esters described by the authors’ research group [118].
1,3-dichloropropan-2-yl esters described by the authors’ research group [118].
1,3-dichloropropan-2-yl esters [118]. Figure 23 shows the synthesis
1,3-dichloropropan-2-yl esters described by the authors’ research group [118].of oxozalidinones, starting from
1,3-dichloropropan-2-ylO esters described by the authors’ research group [118].
R Cl O OH
O NaN3 H2, Pd/C 10%
O R N3
O R NH NH2OH
OR Cl NaN3 O R H2, Pd/C 10%
Cl N3
R O Cl DMF, 100 oC, o/n O R NH
OH NH2
NaN3 N3 H2, Pd/C
MeOH, 10%
r.t., 48h O
Cl R ON
O DMF, 100 oC, o/n 3 R NH NH2
O N3 MeOH, r.t., 48h O
Cl
DMF, 100 oC, o/n
N3 MeOH, r.t., 48h 1) CO 2 O 2) Urea

MeOH 1) CO 2 2) Urea
80KPa
R= (C6H5)2CH; CH3CH2(CH3)2C; CH3(CH2)n (n=6, 16) 1) CO 2) Urea
9000KPa, 150 C, 24h 2 MeOH
o
150 oC, 3h80KPa
R= (C6H5)2CH; CH3CH2(CH3)2C; CH3(CH2)n (n=6, 16) MeOH 80KPa
9000KPa, 150 oC, 24h 150 oC, 3h
R= (C6H5)2CH; CH3CH2(CH3)2C; CH3(CH2)n (n=6, 16)
9000KPa, 150 oC, 24h 150 oC, 3h
O
NH O
NH
R
O NH
O NH
R
NH O
NHO
R O
1) 7-9%
O O
2)14-59%
1) 7-9%
2)14-59%
1) 7-9%
Figure Synthesis
23.23.
Figure of of
Synthesis oxazolidinones from
oxazolidinones fromdicholoralcohol esters.
dicholoralcohol esters. 2)14-59%

Figure 23. Synthesis of oxazolidinones from dicholoralcohol esters.

The first step was the preparation
Figure of the
23. Synthesis diazide as previously
of oxazolidinones described (Section
from dicholoralcohol esters. 3.1.3; Figure 8).
The first step was the preparation of the diazide as previously described (Section 3.1.3; Figure
The hydrogenation
The firstofstep
thewas
azide derivatives
the ledoftothe
preparation thediazide
corresponding monoamide O- to N-acyl
by a(Section
8). The hydrogenation of the azide derivatives led to theascorresponding
previously described
monoamide by a3.1.3; Figure
O- to
The first step was the preparation of the diazide as previously described
8). The hydrogenation of the azide derivatives led to the corresponding monoamide (Section 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

migration (Figure 23)(Figure

N-acyl migration [120]. The monoamide
23) [120]. reacted with
The monoamide urea orwith
reacted CO2urea
, under the2conditions
or CO , under theshown in
conditions
Figure 23, (see Supplementary Materials Section 1.2.2) to achieve the
shown in Figure 23, (see Supplementary Materials Section 1.2.2) to achieve the corresponding corresponding oxazolidinone.
The final yield, determined
oxazolidinone. by 1 Hdetermined
The final yield, RMN, for the by urea reaction
1H RMN, for ranged
the urea from 14% to
reaction 59%. from
ranged When14% the to
reaction was carried out with CO at a high pressure and temperature,
59%. When the reaction was 2 carried out with CO2 at a high pressure and temperature, the the corresponding urethane
was obtained with
corresponding a 7% towas
urethane 9%obtained
yield. Unfortunately,
with a 7% to 9% these urethanes
yield. showed
Unfortunately, lowurethanes
these stability when
showed
purified [118]. when purified [118].
low stability
Both
Both1,3-DCH
1,3-DCH and chlorosulphonyl
and chlorosulphonyl isocyanate
isocyanate were
werethethe
starting
starting materials to to
materials obtain a carbamate
obtain a carbamate
which
which waswasused
usedafterward
afterward to to synthesize sulfonamides bearing
synthesize sulfonamides bearingoxazolidinone
oxazolidinonerings rings [145,146].
[145,146]. The
The resulting carbamate reacted with oxazolidinones yielding N-oxazolinone
resulting carbamate reacted with oxazolidinones yielding N-oxazolinone sulfonamide. Finally, the sulfonamide. Finally,
theaddition
additionofof a base
a base (K(K 2 CO
2CO 3 ) allowed
3) allowed the the reaction
reaction of NH
of the the NH
in the insulfonamide
the sulfonamide
with onewithofone
theof the
carbons
carbons
bonded bonded
to a to a chlorine
chlorine atom, atom, yielding
yielding the the corresponding
corresponding N,N-bis-oxazolidinones-sulfones.
N,N-bis-oxazolidinones-sulfones. The
The compound with an isobutyl radical was synthesized with a 90% yield,
compound with an isobutyl radical was synthesized with a 90% yield, while the benzyl substitutedwhile the benzyl substituted
compound
compound waswassynthesized
synthesized withwithonly
only a 9%
a 9%yield (Figure
yield (Figure24,24,
R).R).
Alternatively,
Alternatively,thethereaction
reactionbetween
between
thethe
carbamate
carbamate andandamines
aminesledledto to
substituted
substituted sulfamides.
sulfamides. Finally,
Finally, thethe
carboxylsulfamides
carboxylsulfamides in in
presence
presence
of of
potassium
potassium carbonate
carbonate in in
acetonitrile
acetonitrile ledled
to 5-chloromethyl-2-oxazolidinone
to 5-chloromethyl-2-oxazolidinone sulphonamides
sulphonamides with a a
with
chiral center
chiral at the
center 5-position
at the 5-position(90% (90%to 98%
to 98% yield) (Figure
yield) (Figure24,24,
R1 )R[145,146].
1) [145,146].The antibacterial
The antibacterial activity of of
activity
these compounds was evaluated. Most of the compounds showed
these compounds was evaluated. Most of the compounds showed moderate-to-good antibacterialmoderate-to-good antibacterial
activity [145].
activity [145].

OH O
O CH2Cl2
N 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
K2CO3, CH3CN inert atm.
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

Figure
Figure 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 Derivatives
of Triazole Derivatives
TriazolesTriazoles
are important molecules
are important for chemical
molecules synthesissynthesis
for chemical and alsoand
as also
bioactive molecules.
as bioactive molecules.
Figure 25 shows
Figure the
25 synthesis
shows of an
the S-acyclonucleoside
synthesis of by
an alkylation of 5-(2-methylthio)phenyl-
S-acyclonucleoside by alkylation of
1,2,4-triazole-3-thiol with 1,3-DCH or ECH. The 1,2,4-triazole
5-(2-methylthio)phenyl-1,2,4-triazole-3-thiol thioglycoside
with 1,3-DCH was 1,2,4-triazole
or ECH. The obtained by using
thioglycoside
potassium wascarbonate
obtained byin using
DMF. potassium
Potassiumcarbonate
carbonatein was
DMF.again used as
Potassium a base was
carbonate to improve theas a base
again used
nucleophilicity of the S atom preserving the epoxy group in the final product [148].
to improve the nucleophilicity of the S atom preserving the epoxy group in the final product [148].

H2N
S O
N
K2CO3/DMF/reflux, 7h
N 60%
O N
Cl
H2N S
SH CH3
N

N N Cl
S
H2N
OH CH3 S
N OH 80%

N
N
Cl Cl
K2CO3/DMF/reflux, 1h S
CH3

Synthesis
Figure 25.Figure of triazole-thioglycoside
25. Synthesis from ECHfrom
of triazole-thioglycoside andECH
DCH.and DCH.

Triazole Triazole
acyclic nucleosides synthesized
acyclic nucleosides from ECH
synthesized fromhaveECHmoderate-to-high
have moderate-to-high antifungal and
antifungal and
antibacterial activities compared to standard drugs [148]. Another application
antibacterial activities compared to standard drugs [148]. Another application of triazoles of triazoles is the is the
preparation of microliter
preparation plates. Microliter
of microliter plates were
plates. Microliter platescoated
werewith
coatedhydrocarbon
with hydrocarbonchains bearing a
chains bearing a
sugar moiety. This sugar motif was attached to the alkane by a 1,3-dipolar cycloaddition.
sugar moiety. This sugar motif was attached to the alkane by a 1,3-dipolar cycloaddition. These These coated
plates were usedplates
coated to develop new microfabrication
were used methods for application
to develop new microfabrication methods in for
theapplication
screening ofinbioactive
the screening of
carbohydrates andcarbohydrates
bioactive enzymatic activities [201]. Based
and enzymatic on this[201].
activities idea, Based
the synthesis
on thisofidea,
novel thecompounds
synthesis of novel
with alkyl chains bearing
compounds withtwo
alkylsugar
chains moieties
bearing pertwochain in their
sugar headper
moieties waschain
designed.
in theirThe synthesis
head was
was designed. The
carried out by using
synthesis wasdiazide
carriedderivatives
out by using and alkinylderivatives
diazide glycosides, which
and were
alkinyl preparedwhich
glycosides, by using were theprepared
Fischer glycosilation
by using thereaction
Fischer[23]. The corresponding
glycosilation reaction triazole
[23]. The derivatives were synthesized
corresponding by the
triazole derivatives were
1,4-regioselectivity copper(I)-catalyzed azide-alkyne cycloaddition reaction (CuAAC).
synthesized by the 1,4-regioselectivity copper(I)-catalyzed azide-alkyne cycloaddition reaction This approach
allowed (CuAAC).
the synthesis of 1,4-disubstituted
This approach allowed 1,2,3-triazoles
the synthesis as unique regioisomers [202].
of 1,4-disubstituted Yields ranged
1,2,3-triazoles as unique
from 40% to 57%, after column purification (see Supplementary Materials Section
regioisomers [202]. Yields ranged from 40% to 57%, after column purification (see Supplementary2.2.2).
Microliter
Materialsplates bearing
Section the synthesized compounds were prepared. The interactions between
2.2.2).
the alkane sugars and C-lectin
Microliter glycoproteins
plates bearing were measured
the synthesized compounds by using
were surface
prepared. plasmon resonancebetween
The interactions
spectroscopy (SPR) in a high-throughput multichannel mode with a GLC chip.
the alkane sugars and C-lectin glycoproteins were measured by using surface plasmon However, no response resonance
was achieved on SPR sensograms,
spectroscopy (SPR) in a even at the higher concentration
high-throughput multichannel (100mode µMwithsolution).
a GLC chip. However, no
Polymers
responsebearing one sugaronmoiety
was achieved per chain act
SPR sensograms, as competitors
even at the higherfor gp120, an epitope
concentration (100 μM of solution).
AIDS,
to interact with DC-SIGN [203]. Considering this, the authors’ research group planned
Polymers bearing one sugar moiety per chain act as competitors for gp120, an epitope of AIDS, the synthesis
of polymeric structures
to interact similar to[203].
with DC-SIGN thoseConsidering
already described
this, the[203] but with
authors’ twogroup
research sugarplanned
moietiesthe persynthesis
chain and using glycerol as a starting material. Figure 26 shows the synthetic
of polymeric structures similar to those already described [203] but with two sugar moieties strategy used to per
prepare chain
the corresponding monomer. Then, 1,3-DCH was prepared from crude
and using glycerol as a starting material. Figure 26 shows the synthetic strategy used to glycerol, using
chlorotrimethylsilane and acetic acidmonomer.
prepare the corresponding as the catalystThen,[105]. The reaction
1,3-DCH of 1,3-DCH
was prepared fromwith propargyl
crude glycerol, using
alcohol in basic media afforded 1,3-bis(prop-2-yn-1-yloxy)propan-2-ol. The basic media
chlorotrimethylsilane and acetic acid as the catalyst [105]. The reaction of 1,3-DCH with propargyl increased
the nucleophilicity of themedia
alcohol in basic hydroxyl in propargyl
afforded alcohol, which is more acidic than
1,3-bis(prop-2-yn-1-yloxy)propan-2-ol. The thebasicsecondary
media increased
alcohol of
the nucleophilicity of the hydroxyl in propargyl alcohol, which is more acidic thanyielded
1,3-DCH. The esterification of 1,3-dialkynyloxy-2-propanol with acryloyl chloride the secondary
1,3-bis(prop-2-yn-1-yloxyl)propan-2-yl
alcohol of 1,3-DCH. The esterification prop-2-enoate (see Supplementary Materials
of 1,3-dialkynyloxy-2-propanol 2.2.5) [118].
with acryloyl 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
Molecules 2020, 25, x FOR PEER REVIEW O OH H2C 21 of 39
OH HO O
N3 O
OH OH O HO OH N
CH2 O O
CTMS, CH3COOH Propargyl alcohol Acryloyl chloride
O OH N
H2C
OH O O N
O HO O
OH OH OH 80 oC, 48h OH NaOH, reflux, 3h Et3N O O O HO 4OH
CuSO
N3
. 5H2O, NaAsc. 24h, r.t. O N OH
Cl Cl CH2 O O O
CTMS, CH3COOH Propargyl alcohol Acryloyl chloride
CH2Cl2 0 oC-->r.t. N HO OH
N OH
O O
CH CH THF:H2 O, Hydroquinone (10%)
80 oC, 48h
OH OH Cl Cl NaOH, reflux, 3h
Et3N O O
CH CuSOCH
4 . 5H2O, NaAsc. 24h, r.t. N ON OH OH
CH2Cl2 0 oC-->r.t.
O N O
HO HOH
O OH
CH CH THF:H2O, Hydroquinone (10%) OH OH
95% N
CH CH N OH
N O
HO OH 24%
95% OH

24%

Figure
Figure 26. Synthesis
26. Synthesis of bismonomers
of bis-triazol -triazol monomers from glycerol.
from glycerol.

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

Finally, the reaction
Finally, of 1,3-bis(prop-2-yn-1-yloxyl)propan-2-yl
the reaction prop-2-enoate
of 1,3-bis(prop-2-yn-1-yloxyl)propan-2-yl with a sugar
prop-2-enoate with azide
a sugar azide
led to theleddesired
to the monomer throughthrough
desired monomer a CuAAC reaction.reaction.
a CuAAC This lastThis
steplast
wasstep
performed in H2 O:THF
was performed in H2O:THF
Finally, the reaction of 1,3-bis(prop-2-yn-1-yloxyl)propan-2-yl prop-2-enoate with a sugar azide
(1:1), with a 10% hydroquinone as a polymerization inhibitor.
(1:1), with a 10% hydroquinone as a polymerization inhibitor.
led to the desired monomer through a CuAAC reaction. This last step was performed in H2O:THF
The polymerization of the glycomonomer
The polymerization of theD-mannose was intended,
glycomonomer using Cu(0)/Cu(II)/Me
D-mannose 6 TREN using
was intended,
(1:1), with a 10% hydroquinone as a polymerization inhibitor.
as a catalyst with EBiB as
Cu(0)/Cu(II)/Me initiator
6TREN as a(Figure 27).with
catalyst Although
EBiB astheinitiator
expected polymer
(Figure 27).with the terminal
Although the expected
The polymerization of the glycomonomer D-mannose was intended, using
brominepolymer
was not detected
with thethrough
terminalusing the MALDI-ToF
bromine was not technique, dead polymer
detected through using chains (with terminal
the MALDI-ToF technique,
Cu(0)/Cu(II)/Me6TREN as a catalyst with EBiB as initiator (Figure 27). Although the expected
hydrogen) deadandpolymer
two-to-five added
chains (withchains werehydrogen)
terminal obtained. The
and exchange
two-to-fiveof the bromine
added chainsbywere
the proton
obtained. The
polymer with the terminal bromine was not detected through using the MALDI-ToF technique,
was mainly causedofby
exchange disproportionation
the bromine by the protonand chain
was transfer side reaction,
mainly caused which led to the and
by disproportionation loss chain
of the transfer
dead polymer chains (with terminal hydrogen) and two-to-five added chains were obtained. The
terminalside
bromine (seewhich
reaction, Supplementary Materials
led to the loss of the Section
terminal2.2.6) [118].(see Supplementary Materials 2.2.6) [118].
bromine
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 Supplementary O
Materials 2.2.6) [118].
H3C Br
O
CH3 n
O H3C
O O
H3C Br
O N
CH3 n
H3N
C O O
NO O
N
HO O N
N O OOH
N N N
OH
HO O HON HO O
OH OH
H2C N N
Cu ( 0 )/Cu(II) OH
O O OH
Me6TREN HO
Br O HO HO O
OH
H3C O
+

H3C CH3 H2C Cu ( 0 )/Cu(II) OH

O O O
N Me6TREN HO
Br O O DMSO, 25ºC, 24h
H3C O N N
+

H3C CH3
O N
N N HO O
O N
DMSO,
OH 25ºC, 24h
HO NON
OH HO
N HO
N HO
HO O
N
HO OH
HO O
OH HO O
HO HO H
HO H3C O
CH3 n
O H3C
O O
H3C H
O N
CH3 n
H3N
C O O
NO O
N
HO O N
N O OOH
N N N
OH
HO O
HON HO O
OH OH
N N
OH OH
HO HO O HO
OH
n=2-5
OH
HO

Figure 27. Proposed structure for the dead polymer synthesized through SET-LRP polymerization.
Figure 27. Proposed structure for the dead polymer synthesized through
n=2-5 SET-LRP polymerization.

A similar
Figurestarting approach
27. Proposed was for
structure described
the deadby Legrossynthesized
polymer et al. for thethrough
synthesis of novel
SET-LRP β-cyclodextrin
polymerization.
A similar starting approach was described by Legros et al. for 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.APropargyl
similar alcohol
startingand
approach
butynol was
were described by Legrosreagents.
used as nucleophilic et al. for the synthesis
A phase of novel
transfer catalysis
NaOH as a basic catalyst. Propargyl alcohol and butynol were used as nucleophilic reagents. A
(Buβ-cyclodextrin
4 NBr) was alsodimers.
used in Glycerol-type linkingECH
the reaction between armsand
were synthesized
butynol (Figurefrom 1,3-DCH or ECH, using
28) [118].
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,
Molecules 2020, 25,
25, x
x FOR
FOR PEER
PEER REVIEW
REVIEW 22 of
22 of 39
39
OH
OH

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

n=1,2
n=1,2

Figure Synthesis glycerol-type linking arms based on alkenyl motifs using DCH and ECH.
Figure 28.
28. Synthesis
Synthesis of
of glycerol-type linking arms based on alkenyl motifs using DCH and ECH.

These
These glycerol-type linkerswere
were used to synthesize β-CD dimers by a CuAAC reaction
These glycerol-type
glycerol-type linkers
linkers were used
used to
to synthesize
synthesize β-CD
β-CD dimers
dimers by
by aa CuAAC
CuAAC reaction
reaction (Figure
(Figure
(Figure
29) 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
[204–207]. One of these CD dimers showed unusual conformations in aqueous solutions. These
These conformations depended
conformations on the length of the linking arm between the two cyclodextrins [208,209].
conformations depended
depended onon the
the length
length of
of the
the linking
linking arm
arm between
between the
the two
two cyclodextrins
cyclodextrins [208,209].
[208,209].
(RO-) 6 N3
CH2 (RO-) 6 N3
OH CH2
OH CH2
Br CH2
Br
CH2 O
CH2 O
O O N N O N N
O O R=H N N O N NN
R=H N
R=Me (RO) 14 N O O N
NaH, DMF O O R=Me (RO) 14 O O
NaH, DMF O O
CH CH r.t., o.n. H2 C CH2
CH CH r.t., o.n. CuSO4 .. H2SO4, NaASc(aq) H2 C CH2
CuSO4 H2SO4, NaASc(aq)
DMSO, 25 ooC (RO-) 6
CH CH DMSO, 25 C (RO-) 6 (-OR) 6
CH CH (-OR) 6

(RO) 14
(RO) 14 (RO) 14
(RO) 14

R=H; 14%
R=H;
R=Me,14%
53%
R=Me, 53%

29. Synthesis β-CD

FigureSynthesis
Figure of β-CD dimerswith
with a functionalized glycerol linker.
Figure 29.
29. Synthesis of
of β-CD dimers
dimers with aa functionalized
functionalized glycerol
glycerol linker.
linker.
Due to their unique cup-like structures, CDs are known to form inclusion complexes in aqueous
Due to
to their
Due CDs their unique cup-like structures, CDs are known to form inclusion complexes in
solution. haveunique
a widecup-like
range ofstructures,
applicationsCDsthatare known
include theto form
areas of inclusion complexes
drug delivery in
[210,211],
aqueous solution.
aqueous solution. CDs have a wide range of applications that include the areas of drug delivery
analytical chemistryCDs have
[212], a wide
artificial range [213],
enzymes of applications
photochemicalthat include the areas
sensors [214], food of drug delivery
technology [215],
[210,211],
[210,211], analytical
analytical chemistry
chemistry [212],
[212], artificial
artificial enzymes
enzymes [213],
[213], photochemical
photochemical sensors
sensors [214],
[214], food
food
catalysis [216] and nanostructured functional materials [217]. In comparison with CD monomers,
technology
technology [215],
[215], catalysis
catalysis [216]
[216] and
and nanostructured
nanostructured functional
functional materials
materials [217].
[217]. In
In comparison
comparison with
with
bridged bis(β-CD) derivatives allow two hydrophobic cavities to be in close vicinity, thus improving
CD monomers,
CD desired
monomers, bridged bis(β-CD)
bridgedMoreover,
bis(β-CD)the derivatives
derivatives allow
allow two
two hydrophobic
hydrophobic cavities
cavities to
to be in
in close
beCDs close vicinity,
vicinity,
the properties. presence of functional linkers between the two can supply a
thus
thus improving
improving the
the desired
desired properties.
properties. Moreover,
Moreover, the
the presence
presence of
of functional
functional linkers
linkers between
between the
the
well-organized pseudo-cavity that may afford supplementary binding properties [218,219].
two
two CDsCDs can
can supply
supply aa well-organized
well-organized pseudo-cavity
pseudo-cavity thatthat may
may afford
afford supplementary
supplementary binding
binding
properties
properties
3.2.3. [218,219].
[218,219].
Synthesis of Ionic Compounds Based on Quaternary Bis-Ammonium Salts

3.2.3.In the study, 1,3-DCH was used to synthesize gemini imidazolium salts,Salts with an hydroxyl in the
3.2.3. Synthesis
Synthesis of of Ionic
Ionic Compounds
Compounds Based Based on on Quaternary
Quaternary Bis-Ammonium
Bis-Ammonium Salts
spacer group and lateral chains of different length (Figure 30a) [220]. A similar reaction with amines
In
In the
the study,
study, 1,3-DCH
1,3-DCH was
was used
used to synthesize gemini imidazolium salts,
salts, with an
an hydroxyl in
instead of imidazole was described byto synthesize
Song gemini
et al., who imidazolium
synthesized bis-quaternarywithammonium
hydroxylsalt
in
the
the spacer
spacer group
group and
and lateral
lateral chains
chains of
of different
different length
length (Figure
(Figure 30a)
30a) [220].
[220]. A
A similar
similar reaction
reaction with
with
(BQAS) with a hydroxyl in the spacer group [221]. This salt was synthesized by the reaction of 1,3-DCH
amines
amines instead of of imidazole
imidazole was described by
by aSong et al.,
al., who synthesized bis-quaternary
with N,Ninstead
dimethyldodecylamine was[221],
described
achieving Song
90% etyield. who
BQASsynthesized bis-quaternary
exhibited broad-spectrum
ammonium
ammonium salt
salt (BQAS)
(BQAS) with
with a
a hydroxyl
hydroxyl in
in the
the spacer
spacer group
group [221].
[221]. This
This salt
salt was
was synthesized
synthesized by
by the
the
bactericidal activity [221]. Another BQAS was synthesized by using monoamides of α,ω-diamines
reaction of
reaction30b). 1,3-DCH
of 1,3-DCH with N,N
with N,N dimethyldodecylamine
dimethyldodecylamine [221], achieving
[221], achieving a 90%
a 90% yield. BQAS exhibited
(Figure All of these syntheses are based on the nucleophylic attack of ayield. BQAS
tertiary exhibited
amine to the
broad-spectrum
broad-spectrum bactericidal
bactericidal activity
activity [221].
[221]. Another
Another BQAS waswas synthesized by
by using monoamides of
carbons of 1,3-DCH supporting the chlorine atoms.BQASThe presence synthesized
of a hydroxyl using monoamides
in the spacer group of
α,ω-diamines
α,ω-diamines (Figure
(Figure 30b).
30b). All
All of
of these
these syntheses
syntheses are
are based
based on
on the
the nucleophylic
nucleophylic attack
attack of
of a
a tertiary
tertiary
confers tuneable properties to these compounds [222,223].
amine
amine to
to the
the carbons
carbons of
of 1,3-DCH
1,3-DCH supporting
supporting the chlorine
chlorine atoms.
the thermal atoms. The presence of
of aa hydroxyl in
in the
Imidazolium derivatives showed higher stabilityThe presence
than conventional hydroxyl the
quaternary
spacer
spacer group
group confers
confers tuneable
tuneable properties
properties to
to these
these compounds
compounds [222,223].
[222,223].
ammonium gemini surfactants and two-phase transitions before decomposition [220]. Amide-based
Imidazolium
Imidazolium derivatives
derivatives showed
showed higher thermal
thermal stability
highersurface/interfacial
stability than
than conventional
conventional quaternary
quaternary
gemini cationic surfactants presented superior activities and easy biodegradables,
ammonium
ammoniumthem gemini
gemini surfactants
surfactants and two-phase
and two-phase transitions
transitions before
before decomposition [220]. Amide-based
suggesting as potential products in industrial fields, such asdecomposition
surfactant flooding[220].[224].
Amide-based
gemini
gemini cationic
cationic surfactants
surfactants presented
presented superior
superior surface/interfacial
surface/interfacial activities
activities and
and easy
easy biodegradables,
biodegradables,
suggesting
suggesting them
them as as potential
potential products
products in in industrial
industrial fields,
fields, such
such as as surfactant
surfactant flooding
flooding [224].
[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
+
N2(atm) N
OH

HO
Cl Cl DMF, 120 oC, 28h N
+

-
N Cl
CH2 (CH2 ) nCH3

52-75%

(b)
O CH3
N N2(atm)
OH C n-1 H2n-1 NH CH3 H3C CH3
Cl- N+ NH C n-1 H2n-1

Cl Cl Propanol, Na2CO3 (0,3%wt) HO - O

+ Cl
reflux,60 oC, 4-6h N NH
H3C C n-1 H2n-1
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
Figure
gemini cationic 30. (a) using
surfactants Synthesis of gemini imidazolium salts using 1,3 -DCH. (b) Synthesis of
1,3-DCH.
lineal amide-based gemini cationic surfactants using 1,3-DCH.
Gemini compounds have high surface activity and low critical micelle concentration (CMC). These
Gemini
properties enhance compounds
their water-solubilityhave high and surface
confer aactivity and lowthan
better viscosity critical micelle concentration
single-chain surfactants (CMC).
These properties enhance their water-solubility and
at equal molar mass concentration [116,225–231]. Consequently, their efficiency is improved confer a better viscosity than single-chain
[232],
allowing surfactants
them to be used at equal molarquantities
in smaller mass concentration
compared to[116,225–231].
conventional Consequently,
surfactants [232]. their efficiency is
These
improved [232], allowing them to be used in smaller
properties enable their industrial use in various fields, such as antiseptics, printing and dyeing, quantities compared to conventional
corrosion surfactants [232]. These
inhibition, improved properties
oil recovery andenable
synthesis their
of industrial use in various
inorganic materials fields, such
[224,233–236]. Theyascan antiseptics,
printing
also be used and dyeing, corrosion
in electro-decoating, stabilizationinhibition,
of adhesiveimprovedpolymers, oil recovery
anti-friction andagents,
synthesis of inorganic
mining,
materials [224,233–236]. They can also be used in electro-decoating,
paper-making, cosmetics and, more recently, in drug design and delivery [237,238]. Most of them also stabilization of adhesive
polymers,
show strong anti-friction
antibacterial agents, mining,
and antifungal activities,paper-making,
becoming safety cosmetics
weapons and, more recently, in
[230,235,239–241]. drug design
Their
mechanism of action is based on the amphiphilic nature of the gemini group, which allows them toactivities,
and delivery [237,238]. Most of them also show strong antibacterial and antifungal
becoming
interact with the cellsafety
membraneweapons of the [230,235,239–241].
microorganisms,Their causing mechanism
them to lose of action is based on the
their permeability amphiphilic
[242].
nature
Gemini of the are
compounds gemini group,
also used which
as ionic allows
liquids themIonic
(DDIL). to interact withare
liquids (ILs) thecharacterized
cell membrane by of the
microorganisms, causing them to lose their permeability [242].
unique properties, such as non-volatility, low flammability, tuneable hydrophobicity, environmentally
friendly nature, Gemini compounds areand
easy recoverability alsorecyclability
used as ionic liquids
[243]. They (DDIL).
are ofIonic liquids interest
recognized (ILs) arefor characterized
a
wide rangeby ofunique properties,
applications, such as such as non-volatility,
for solvents, in chemical lowandflammability,
enzymatic catalysis tuneable hydrophobicity,
[244–246],
in carbonenvironmentally
dioxide capture friendly nature, easy
and separation, recoverability
in hydrogen and recyclability
generation, in converting [243]. They are
thermal of recognized
energy
interest
into electrical for a for
energy, wide range of applications,
electrochemical energy storagesuch asand for forsolvents, in chemical
converting electrical andenergy
enzymaticinto catalysis
mechanical energy [247]. It is well-known that the physical and chemical properties of an IL can be thermal
[244–246], in carbon dioxide capture and separation, in hydrogen generation, in converting
energy
tailored by varyingintothe
electrical
structure energy, for electrochemical
of constituent cations andenergy anionsstorage[248,249]. andDicationic
for converting electrical energy
ionic liquids
into mechanical
(DDIL) contain energylinked
two head groups, [247]. Itbyisa well-known
rigid or flexible thatspacer
the physical
[250]. Thisandtypechemical properties of an IL can
of IL demonstrates
be tailored by varying the structure of constituent cations
unique characteristics not found in monocationic ILs and other traditional solvents [251]. Moreover, and anions [248,249]. Dicationic ionic
the change in the length of the spacer and the incorporation of functional groups such as thiol,This
liquids (DDIL) contain two head groups, linked by a rigid or flexible spacer [250]. ether,type of IL
hydroxyl demonstrates
and amino groups uniquein thecharacteristics
cations allows not found the
tailoring in monocationic
physical properties ILs and other for
of DDIL traditional
specific solvents
applications [252]. The DDIL PEG based [253] have also been used as a powerful catalysts for various groups
[251]. Moreover, the change in the length of the spacer and the incorporation of functional
synthetic such as thiol, ether,
transformations hydroxyl and amino groups in the cations allows tailoring the physical
[254,255].
Moreover, ionic liquids (IL) specific
properties of DDIL for applications
have recently [252]. Thefor
been proposed DDIL PEGstorage
thermal based [253] have also
applications been used as
[237].
a powerful catalysts for various synthetic transformations [254,255].
ILs have thermophysical and chemical properties that may be suitable to be used as heat transfer fluid
(HTF) in powerMoreover, ionic
plants, using liquids (IL)
parabolic troughhave recently
solar been as
collectors, proposed
stated by forVanthermal storageetapplications
Valkenburg al. [238]. [237].
ILs have thermophysical and chemical properties that may
The authors’ research group described the use of crude glycerol, N-butylimidazole and carboxylic be suitable to be used as heat transfer
fluid (HTF)
acids [256,257] in power
to synthesize plants, using parabolic
diimidazol-1-ium trough solar
esters, DDILs, with high collectors,
capacity as stated by Van
for energy Valkenburg et
storage
al. A[238].
(Figure 31). Theion
counter authors’
swap was research group described
also achieved with KPFthe use of crude glycerol, N-butylimidazole and
6 , as shown in Figure 31.
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

CH3 CH3

O CH3 N
N N
N -
Ar(atm) + Cl- + PF 6
R O N O N
O KPF6

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

CH3 CH3

31-89%
47-89%

R=(CH3)3C; CH3(CH2)14; C10H7

Figure
Figure Synthesis of
31.31.Synthesis of ionic
ioniccompounds fromfrom
compounds chlorohydrin esters. esters.
chlorohydrin

The final
The yields
final were
yields highly
were dependent
highly on the
dependent oncarboxylic acid used.
the carboxylic acid The setThe
used. of bis-imidazolium ester
set of bis-imidazolium
chlorides showed interesting
ester chlorides energy-storage
showed interesting properties, as
energy-storage indicated as
properties, above. However,
indicated the However,
above. substitutionthe
of substitution
chloride ionsof chloride ions by hexafluorophosphate ions yielded a set of compounds withPCM
by hexafluorophosphate ions yielded a set of compounds with lower lower
capability [256].
PCM capability [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 (Table 4). 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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