Synthesis of 3-alkoxypropan-1,2-diols from glycidol: Experimental and theoretical studies for the optimization of the synthesis of glycerol derived solvents

Article abstract of DOI:10.1039/c7gc01583f

A straightforward synthetic methodology has been derived for the synthesis of glycerol monoethers from glycidol and alcohols. Several homogeneous and heterogeneous basic catalysts have been tested, the best results being obtained with readily available and inexpensive alkaline metal hydroxides. In the best case, good yield of the desired monoether is obtained under smooth reaction conditions, always with total conversion of glycidol. The selectivity of the reactions mainly depends on the alcohol used, due to the concurrence of undesired side reactions. A mechanistic study carried out through computational DFT calculations, in which solvent effects are taken into account, also complemented the experiments, has allowed to identify the main reaction paths taking place under reaction conditions, giving insights into the main causes affecting the reaction selectivity and also into how it could be improved.

Full text of DOI:10.1039/c7gc01583f

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Synthesis of 3-alkoxypropan-1,2-diols from glycidol: experimental
and theoretical studies for the optimization of the synthesis of
glycerol derived solvents
Received 00th January 20xx,
Accepted 00th January 20xx
A. Leal-Duasoa,b, M. Caballeroa, A. Urriolabeitiaa, J. A. Mayorala,b, J. I. García*b and E. Pires*a,b
DOI: 10.1039/x0xx00000x
A straightforward synthetic methodology has been derived for the synthesis of glycerol monoethers from glycidol and
alcohols. Several homogeneous and heterogeneous basic catalysts have been tested, the best results being obtained with
readily available and inexpensive alkaline metal hydroxides. In the best cases, good yield of the desired monoether is
obtained in smooth reaction conditions, always with total conversion of glycidol. The selectivity of the reactions mainly
depends on the alcohol used, due to the concurrence of undesired side reactions. A mechanistic study, carried out through
computational DFT calculations, in which solvent effects are taken into account, also complemented with experiments, has
allowed to identify the main reaction paths taking place in reaction conditions, giving insights into the main causes affecting
the reaction selectivity and also into how it could be improved.
www.rsc.org/
Lemaire and co-workers have thoroughly reviewed the
synthesis of glycerol ethers.32 These compounds can be
synthesized either directly from glycerol33 or from industrial
Introduction
Depletion of fossil fuels and raw materials has arisen a special
interest in the development of new synthetic processes for the building blocks, such as glycidol, epichlorohydrin or 3-
valorisation of renewables, vegetable oils being among the chloropropane-1,2-diol, which can in turn be prepared from
most widely used. Vegetable oil processing provides glycerol glycerol.32,34 The use of building blocks usually improves the
selectivity of the process and allows to obtain mono-, di- and
and fatty acids or esters, which have a huge number of
applications.1–9 Valorisation of glycerol has become a trending triethers with different alkyl chains in a controlled way. This
topic due to the increasing of biodiesel production since the variability in the nature of the substituents is important in order
year 2000. Many efforts have been devoted to the synthesis of to prepare solvents with tuneable properties, as described by
García et al.35,36
valuable products from this platform molecule, some of them
displaying interesting uses as fuel additives, plasticizers,
Although there is a strong temptation to qualify glycerol-
humectants, surfactants, etc.10–19 In this regard, the use of derived solvents, and particularly glycerol ethers, as green,
glycerol itself and its derivatives as solvents is a field of growing there are some aspects that must be correctly addressed in
order to make this claim. One of them is related with physical
used as solvents and additives in cleaning, cosmetic, food and properties. In this regard, glycerol ethers possess some
pharmaceutical industry.26–30
favourable features, such as high boiling, flash points and low
Glycerol ethers stand out among other glycerol derivatives volatilities. Some of them, like the fluoroalkyl glycerol ethers,
interest.20–25 Glycerol esters, ketals and ethers are commonly
have special properties that made them suitable for the
by their relative chemical inertness, which make them very
suitable as solvents. Apart from the synthesis of glycerol tert- substitution of ionic liquids in some catalytic applications.37–39
butyl ethers from glycerol and isobutene, deeply studied due to Another key point is the toxicological profile of these
their use as biofuel additives,31 the synthesis of alkyl glyceryl compounds, available in some isolated cases,40,41 but currently
under systematic study in our group.42–44 The toxicities reported
ethers from glycerol has been investigated in order to obtain a
large class of compounds with tuneable properties depending so far for this family of compounds are low or negligible in most
on the number and nature of the alkyl chains. Thus, recently, cases. Last, but not least, the synthetic procedures to obtain this
family of glycerol derivatives should meet as much as possible
the principles of Green Chemistry and, in order to be of practical
applicability. For instance, the use of harmful substances, such
a.Dr. E. Pires, Dr. J. A. Mayoral, M. Caballero, A. Urriolabeitia
Department of Organic Chemistry. Faculty of Science
University of Zaragoza
as strong alkylating reagents should be avoided as much as
possible.41,45 Finally, they should also meet economic criteria.
However, as mentioned by Lemaire and co-workers,32 despite
the numerous potential applications of glycerol alkyl ethers,45–
Calle Pedro Cerbuna, 12. E-50009 Zaragoza, Spain
E-mail: epires@unizar.es.
b.Dr. J. I. García, A. Leal-Duaso
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH)
CSIC-University of Zaragoza
Calle Pedro Cerbuna, 12. E-50009 Zaragoza, Spain
E-mail: ji.garcia@csic.es
Electronic Supplementary Information (ESI) available: Experimental details and full
description of calculated geometries and energies. See DOI: 10.1039/x0xx00000x
48
and especially of glycerol monoalkyl ethers (GME), scarce
data on production as well as their demand can be found. This
fact is probably due to the relatively recent interest in these
products, on the one hand, as well as to the difficulty to make
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react selectively just one of the hydroxyl groups of glycerol,
which are too similar in reactivity, on the other.
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DOI: 10.1039/C7GC01583F
Very recently nice works have been published in which good
GME overall yields have been obtained starting from glycidol
with excellent conversions and selectivities by using Lewis acids
as catalysts,49,50 avoiding in a major extent the oligomerization
of glycidol. But with the best catalysts (Bi(OTf)3, Al(OTf)3,
Fe(OTf)3) the formation of two regioisomers (3-alkoxypropan-
1,2-diol and 2-alkoxypropan-1,3-diol) in 2:1 to 4.8:1 molar ratios
are obtained, these compounds being difficult to separate if
necessary.
In this work we present a systematic study of the synthesis
of GME starting from glycidol and several alcohols as reagents,
without the need of an excess of glycidol, since this reagent is
known to be toxic and irritant,51 and reasonably anticipated to
be carcinogen for humans.52 Furthermore, the synthetic
procedure does not require any additional solvent and uses
readily available basic catalysts, with the aim to provide a
greener, more effective synthetic methodology for the
preparation of these compounds, compared to the syntheses
previously described.53 The methodology proposed intends to
be an alternative to previous or similar reported synthesis, in
which metallic sodium has traditionally been used as a
stoichiometric reagent to generate the alkoxide, and
equimolecular amounts of salts are produced in the work up of
the reaction. A greener synthetic procedure should reduce the
amount of by-products and residues, improving both the atom
economy and the E factor, not to mention the avoidance of
using a dangerous reagent, such as metallic sodium or strong
alkylating agents, as mentioned above. To this end,
experimental studies have been complemented with
computational mechanistic studies in order to rationalize the
selectivity observed in the reactions.
Scheme 1. Synthesis of glycerol monoethers [R.0.0] from glycidol
. a) Synthesis previously reported,36 b) This work.
1 and alcohols
2
First, the optimization of the amount of catalyst was done.
Reactions with 10%, 20% and 30% mol of KOH were carried out
at 65 C (the refluxing temperature of methanol). Total
conversions of glycidol were achieved in 120 min both with
˚
1
20% and 30% mol catalyst (Fig. 1), and up to 93% yield of 3-
methoxypropane-1,2-diol (henceforth [1.0.0]) was obtained.
Results and discussion
Screening of the reaction conditions
Previous works on the synthesis of GME described the use of
sodium as starting reagent for the generation of the
corresponding alkoxide and its subsequent reaction with
glycidol
1
(Scheme 1).36 As it has been already commented in
the introduction, GME are promising green solvents and the
need of avoiding the use of hazardous reagents in their
synthesis, such as metallic sodium, prompted us to do a
screening of basic catalysts able to provide GME’s (henceforth
coded as [R.0.0]) in good yields, starting from glycidol
different alcohols
1 and
2
.
Both homogeneous catalysts, such as metal hydroxides or
organic bases like 1,5,7-Triazabicyclo[4.4.0]dec-5-ene (TBD),
and heterogeneous catalysts, such as TBD supported onto silica
or polystyrene, the strongly basic resin Amberlyst® IRA 400 or
mixed oxides, have been tested.
Fig. 1. Optimization of the amount of catalyst in the reaction of glycidol
methanol 2a, catalysed by KOH
1 with
.
When using 10% mol catalyst lower yields and conversions
were observed at the same reaction time. As mentioned in the
Introduction, given the known issues with the use of
glycidol,32,51 it is important that the synthetic procedure assures
its total conversion, thus avoiding its presence during the
product purification steps, as well as in the reaction waste.
From this preliminary study, 20% mol seems to be the most
adequate catalyst proportion for this reaction.
For the initial optimization of the reaction conditions, the
benchmark reaction between glycidol
catalysed by KOH, was studied.
1 and methanol 2a,
The influence of the reaction temperature, catalyst molar
proportion, reagents concentration and speed of glycidol
addition were the parameters considered.
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Next, the effect of reaction temperature was studied using selectivity). After 2 h reaction time, conversion was only 15%,
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20% mol KOH. Three reaction temperatures were considered: with 5% yield of [1.0.0] (33% selectivity). Therefore, although
65, 45, and 25
and in the yield of the desired product was observed with the in the results of the catalysed processes is not to be expected in
decrease of temperature (Table 1). Furthermore, the selectivity most cases.
˚C. A decrease both in the conversion of glycidol the uncatalysed reaction may take place, a strong interference
1
to the desired product also seems to decrease with the reaction
temperature.
To summarize this section and to proceed with the study of
several basic catalysts with different alcohols, the standard
reaction conditions finally chosen were 65 reaction
temperature, using 20% mol catalyst, 15:1 molar ratio of alcohol
to glycidol and slow addition of glycidol to the reaction medium
(15 min, using a syringe pump).
˚C
Table 1. Effect of the temperature in the reaction of glycidol 1 with methanol 2a,
catalysed by KOH (20% mol).a
Conversion (%)
Yield (Selectivity) (%)
Time (min)
65 ºC
45 ºC
25 ºC
65 ºC
45 ºC
25 ºC
Scope of the synthesis with different bases and alcohols
Several metal hydroxides were first tested as homogeneous
catalysts for the synthesis of GME [R.0.0], namely LiOH, NaOH,
KOH and Sr(OH)2. Besides methanol 2a, a set of six alcohols was
selected for the synthesis of [R.0.0] derivatives bearing
different alkyl moieties. Thus, alcohols with linear alkyl chains
(methanol 2a, ethanol 2b and butanol 2c), branched chains
(isopropanol 2d and 2-ethylhexan-1-ol 2e), fluorinated chains
(2,2,2-trifluoroethanol 2f) and aromatics (phenol 2g) were
selected to cover a broad spectrum of properties. These
alcohols are not only expected to display different reactivity,
due to electronic and steric reasons, but, as far as they are also
used as solvents, they are also able to modify to some extent
the polarity of the reaction medium. Selection of these alcohols
was done both due to their different structures, as well as for
the interest of the GME obtained. Thus, fluorinated glycerol
derivatives, such as the closely related 1,3-bis(2,2,2-
trifluoroethoxy)propan-2-ol [3F.0.3F], have been successfully
used as reaction media in epoxidation and enzymatic
reactions.39,54–56 3-(2-ethylhexyloxy)propane-1,2-diol [6(2).0.0]
is a frequent compound in cosmetic formulations.32 Finally,
glyceryl monoaryl ethers are also used in pharmaceutic and
cosmetic formulations, as well as intermediates in the synthesis
of drugs and pharmaceuticals.57–59
15
30
52
70
41
59
71
80
89
94
29
45
58
67
78
84
34(65)
58(83)
73(89)
84(93)
91(93)
93(93)
31(76)
50(85)
63(89)
71(89)
82(92)
89(95)
21(72)
37(82)
49(85)
58(86)
67(86)
74(88)
45
82
60
90
90
97
120
100
a Reaction conditions: 15:1 molar ratio of methanol 2a to glycidol 1 and slow addition of
glycidol 1 to the reaction (15 min).
On the other hand, this selectivity is not constant along the
reaction time, reaching a maximum at the end of the reaction.
We will return on this point in the mechanistic discussion. After
these series of experiments, 65
standard reaction temperature.
An effect of the reagents concentration was also observed
in the synthesis of [1.0.0]. In an attempt of reducing the excess
of methanol 2a from 15 to 7.5 mol per mol of glycidol
the expense of significantly reducing the total reaction volume),
a rise in the conversion of glycidol was observed. Total
conversion was achieved in 90 min reaction time. Nevertheless,
the selectivity towards the desired product [1.0.0] was reduced
from 93% to 83%, and the formation of a higher amount of by-
products was observed by GC.
The effect of the way in which glycidol
reaction medium was also studied (Scheme 2). Adding glycidol
in a dropwise manner strongly improved the selectivity of the
reaction from 70% when glycidol was added at once, to 93%
˚C was therefore chosen as the
1 (but at
The main results of these experiments are gathered in Table
2. When using methanol 2a (Table 2, entry 1), total conversions,
good yields of the desired product are obtained. NaOH and KOH
are the preferred catalysts in this case, since better yields of the
desired product are achieved.
1 was added to the
1
When increasing the length of the alkyl chain of the alcohol
(EtOH 2b, BuOH 2c) (Table 2, entries 2, 3), total conversions of
1
when it was slowly added. This fact is most probably due to the
inhibition of glycidol self-reaction, although other competing
pathways cannot be excluded, as it will be discussed below.
glycidol
1 are still obtained in 2 h reaction time, but the
selectivity of the reaction toward the desired products is
significantly reduced. In this case, the formation of heavier
compounds, involving dimerization of glycidol in one or another
way, was observed by gas chromatography/mass spectrometry.
This fact proves the existence of competitive side reactions,
which will be discussed in the mechanistic study section. This
effect is even more dramatic when using secondary and less
active alcohols, such as isopropanol 2d or 2-ethylhexan-1-ol 2e
(Table 2, entries 4, 5). In all cases, NaOH and KOH seem to be
more suitable as catalysts, as better yields of the target [R.0.0]
are obtained.
Scheme 2. Study of the influence of the addition of glycidol 1 to the reaction media
on the reaction selectivity.
Finally, for the sake of comparison, a reaction was carried
out without a catalyst, otherwise in the same reaction
conditions. In this case, 68% conversion of glycidol
1 was
observed at 48 h reaction time, with 38% yield of [1.0.0] (56%
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Table 2. Conversions and yields in the reaction of glycidol 1 with different alcohols 2, catalysed by metal hydroxides.a
LiOH NaOH
Yield (Sel.) Yield (Sel.)
KOH
Yield (Sel.)
Sr(OH)2
Entry
product
Alcohol
Conv.
(%)
Conv.
(%)
Conv.
(%)
Conv.
(%)
Yield (Sel.)
(%)
(%)
(%)
(%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
MeOH
[1.0.0]
[2.0.0]
100
99
86(86)
47(47)
48(48)
20(23)
17(21)
89(98)
63(68)
100
100
100
100
100
46
92(92)
54(54)
58(58)
27(27)
27(27)
36(78)
48(73)
100
100
100
100
100
44
93(93)
57(57)
60(60)
30(30)
36(36)
35(80)
22(48)
100
83
73(73)
29(35)
42(42)
4(7)
EtOH
BuOH
iPrOH
[4.0.0]
100
86
100
56
[3i.0.0]
[6(2).0.0]
[3F.0.0]
[Ph.0.0]
2-ethylhexan-1-ol
Trifluoroethanol
Phenol
80
55
3(5)
91
53
42(79)
63(76)
2g
92
66
46
83
a Reaction conditions: 20% mol catalyst, 65 ºC, 15:1 molar ratio of alcohol 2 to glycidol 1, with slow addition of glycidol 1 to the reaction (15 min) and 2h reaction time.
Finally, when using more acidic alcohols, such as 2,2,2- yield. Only Amberlyst® IRA-400 led to acceptable results (Fig. 2).
trifluoroethanol 2f (TFE) (Table 2 entry 6), better selectivities In this case, recycle and reuse of the catalyst was studied in
are observed in most cases, compared to the ones obtained order to know if it could be considered as an efficient and
with ethanol 2b (Table 2 entry 2), although the reactions are affordable catalyst for the synthesis of [1.0.0]. Results showed
noticeably slower. This fact seems to indicate that the relative (Fig. 3) that total conversions of glycidol can be achieved,
acidity of the starting alcohol vs. the acidities of glycidol and the keeping an excellent 96% selectivity to [1.0.0], but at the
[R.0.0] product is a determinant factor for the selectivity expense of increasing the reaction time. Unfortunately, the
observed in these reactions, most probably because of the yield of [1.0.0] decreased in each run. In an attempt to recover
inhibition of the formation of the corresponding glycidol and the activity of the catalyst, a sample of solid catalyst used in
[R.0.0] alkoxides (see below).
three runs was treated with a solution of KOH in methanol and
In the case of TFE 2f, LiOH appears to be the best catalyst, then thoroughly washed with methanol. In this case, the activity
with 91% conversion in 2 h (with an excellent 98% selectivity to of the catalyst was partially recovered and the yield was
the corresponding [3F.0.0] product), which can be pushed up to increased from 15 % to 58% at 2h reaction time, with 81%
100% if the reaction time is increased up to 6 h. Similar trends selectivity, which further increased up to 85% after 24 h
are observed when using another acidic alcohol like phenol 2g reaction time.
(Table 2, entry 7).
To summarize, these series of experiments show that NaOH
and, above all, KOH, are the best catalysts in the case of alkyl
alcohols. In all cases, 100% conversion of glycidol is reached at
2 h reaction time. However, the selectivity to the target [R.0.0]
product is strongly dependent on the alcohol. On the other
hand, LiOH is a better catalyst for more acidic alcohols, whose
corresponding alkoxides are less nucleophilic and hence less
Fig. 3. Results of the reuse of Amberlyst® IRA-400 in the reaction of
glycidol 1 with methanol 2a at 2 h and 24 h reaction time.
Amberlyst® IRA-400 was also tested as catalyst in the
reactions with the selected set of alcohols (Fig. 4). Results with
KOH are included for the sake of comparison. Except in the case
of methanol 2a, yields of the [R.0.0] products are always lower
than those obtained using KOH or NaOH as catalysts.
reactive.
Overall, Amberlyst® IRA-400 can be considered a good
catalyst for the synthesis of [1.0.0], with a total turnover
Fig. 2. Comparison of the results of the reaction of glycidol
1 with methanol 2a,
number of 12.1 in three consecutive runs. However, it is worth
mentioning that the price of the catalyst, together with the big
amount needed (71% w/w with respect to glycidol), are strong
difficulties to overcome when scaling up the synthesis of this
glycerol ether. For the rest of alcohols, the activity of
catalysed by different basic solids. Reaction conditions: 20% mol catalyst, 65 ˚C
reaction temperature and 2h reaction time.
Unfortunately, the majority of the heterogeneous catalysts
tested gave poor results both in glycidol conversion and product
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Amberlyst® IRA-400 is too low to be considered for large scale cycles. All of them have been included in the computational
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DOI: 10.1039/C7GC01583F
syntheses of GME.
mechanistic study, but only the two most relevant for the
understanding of the reaction selectivity (after examination of
the different activation barriers involved) will be explicitly
discussed here (Fig. 5; note that the structure numbering has
been kept with regard to Fig. S-30 in the ESI for consistency).
All the reagents, intermediates, transition structures and
products in the seven abovementioned cycles have been
calculated
theoretical level for two alcohols: methanol (2a) and butanol
2c). These alcohols were chosen because of the different
at
the
PCM(solvent)/B3LYP/6-311++G(d,p)
(
selectivities to the corresponding [R.0.0] ether experimentally
observed. A partial computational exploration of the cycles
most relevant for the selectivity (Fig. 5) was also carried out for
2,2,2-trifluoroethanol (TFE) (2f). Complete details concerning
molecular coordinates and energies of all calculated structures
are available in the ESI. It is important to note that glycidol is a
chiral molecule and in this work it has been used in racemic
form, so all the dimerization reactions lead to the formation of
two pairs of diastereomers. This circumstance has also been
Fig. 4. Yields of [R.0.0] in the reaction catalysed by Amberlyst® IRA-400. Results at
2 h and 24 h reaction time. Results with KOH at 2 h reaction time (right column) taken into account in the computational study.
are also included for comparison.
The first point to be discussed is the reaction of formation
of the alkoxide from the alcohol and the metal hydroxide, which
constitutes a precatalytic step (Fig. 5). This process takes place
before adding the second reagent (glycidol) and is an
equilibrium process. The equilibrium constants calculated for
methanol (2a) and butanol (2c) are 1.16 and 0.68, respectively.
However, as the alcohol is in a huge molar excess in reaction
conditions (75:1 with regard to the base), both equilibria are
completely shifted toward the formation of the corresponding
alkoxide, so less than 2% mol of free hydroxide (HO–) is present
at equilibrium. The case of TFE (2f) is even clearer, since the
Mechanistic considerations
The mechanistic study of the reaction of alkoxides with glycidol
is a complex task, given that both glycidol and reaction products
are alcohols, so they may participate in side reactions. In
particular, glycidol has a pKa lower than those of the most
common alkyl alcohols, and therefore it tends to deprotonate
in reaction conditions, favouring self-reaction, except in the
case of the most acidic alcohols like TFE 2f or phenol 2g. On the
other hand, the alkoxide formation from a metal hydroxide and
an alcohol leads to the concomitant formation of a water
molecule, which may also participate in undesired side
reactions (for instance, the formation of glycerol). Fig. S-30
(available in the Electronic Supplementary Information, ESI)
displays up to seven of these possibilities, organized as catalytic
calculated equilibrium constant increases up to 1.85⋅
1011. In
these conditions, catalytic cycles involving HO– should play a
minor role, and will not further discussed here.
Fig. 5. Most relevant catalytic cycles involved in the selectivity of the reactions of glycidol
1 with alcohols 2, catalysed by bases.
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The thorough examination of the remaining possible exclusively with energy landscapes (the so-called E-
concurrent reactions led us to the conclusion that the two representation, following the Kozuch’s and Shaik’s definition)60
possible initial reactions of glycidol shown in Fig. 5 were the and neglect concentration effects, which also appear in the rate
main responsible for the global selectivity towards the desired reaction equation. In our case, concentration effects are not
glycerol monoethers
8
, and therefore will be discussed in detail. negligible, since the alcohol is in a large excess with regard to
both glycidol ( ) and its deprotonated form (15). In order to get
1
insights into the importance of these effects, we carried out a
numerical simulation of the reaction kinetics of the processes
a)
b)
Fig. 6. Calculated reaction coordinate profiles of the different reaction pathways
for the reactions of glycidol with methanol 2a (a) and butanol 2c (b).
1
shown in Fig. 7.
The reaction profiles of these cycles for both methanol 2a
and butanol 2c are displayed in Fig. 6. Concerning methanol, it
can be realized that the reaction of methoxide (3a) with glycidol
Fig. 7. Simulations of the kinetics for the reactions of glycidol
(a) and butanol 2c (b). Continuous lines represent glycidol addition at once, and
dashed lines, dropwise glycidol addition.
1 with methanol 2a
(1
) has an intrinsic activation barrier lower than that of the
dimerization of glycidol, occurring through the reaction of
with oxiran-2-ylmethoxide (15). However, it must be pointed
out that in reaction conditions is easily deprotonated to give
15 (the calculated equilibrium constant at 65 C is 84). In these
Curtin–Hammett conditions the effective activation barrier for
the reaction of glycidol with methoxide turns to be higher by 1.8
kcal mol–1 (Fig. 6a). In the case of butanol (Fig. 6b), the situation
is even worse, since the glycidol deprotonation equilibrium has
a higher equilibrium constant (185), so the first step of the
desired reaction is disfavoured by 3.8 kcal mol–1. These results
indicate that the reaction of dimerization of glycidol is
intrinsically favoured over its reaction with alkoxides, which
explains the difficulty to obtain good selectivities to the desired
1
Rate constants were estimated from the activation barriers
shown in Fig. 6 using equation (1). It is clear that these
calculated values are just a crude approximation to the actual
rate constants, but they include the relative reactivity coming
from the relative activation barriers of both concurrent
processes and hence they still are good to model competitive
kinetics.
1
˚
eq. (1)
Protonation-deprotonation equilibria were also considered,
using the corresponding calculated Keq in each case. Initial
concentrations were set to reproduce the experimental
conditions used. Further details on these simulations can be
found in the ESI.
[R.0.0] products (8).
However, computational mechanistic studies often give a
partial view of the reaction complexity, since they deal
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Fig. 7a displays the time evolution of the concentration of
glycidol ( ), [1.0.0] 8a), and glycidol dimer (18). Continuous
lines represent the kinetics in the case of a reaction in which all
Experimental
Computational methods
View Article Online
DOI: 10.1039/C7GC01583F
1
(
the glycidol is added at once at the beginning. Dashed lines Quantum mechanical calculations were carried out by using the
Gaussian 0961 and ORCA 4.062 packages. All the geometry
represent the kinetics when glycidol is added dropwise during
optimizations and vibrational frequency calculations were
performed at the B3LYP/6-311++G(d,p) theoretical level. The
use of diffuse functions on all atoms is essential to assure a
correct description of the anionic species. As a referee noted,
although it has been reported that B3LYP does not provide quite
accurate results in the case of barrier heights,63 this level of
theory usually gives consistent results in the case of comparing
the first minutes of the reaction. When glycidol is added at
once, there is a smooth decrease until complete disappearance.
Interestingly, the selectivity to the desired [1.0.0] (8a) product
(54% regarding the initial amount of glycidol) is higher than that
to glycidol dimeric products, in spite of the higher activation
barrier of the former process, which illustrates the importance
of concentration effects. When
1
is added dropwise, the relative, rather than absolute, energies,64–66 representing a
compromise between the quality of the results obtained and
the computer time required to complete the study.
Nevertheless, the consistency of this approach has been tested
by using other density functionals to calculate the activation
energy of the reaction between the methoxide anion and
glycidol and, in some cases, also the concurrent glycidol
dimerization reaction (see ESI for details). Some high level
selectivity to 8a further increases up to 68%, an expected
behaviour since the principal side reaction is order 2 in glycidol.
Regarding the reactions with butanol, the time evolution of
the concentrations of 1, 8c and 18 are shown in Fig. 7b. In this
case, the higher barrier difference between both reaction paths
results in a lower selectivity towards the monoether regardless
DLPNO67,68-CCSD(T)/aug-cc-pVTZ
single
point
energy
of the glycidol addition mode. As can be seen, when
at once the selectivity to the desired product [4.0.0]
low as 12%, glycidol dimerization being largely favoured. When
is added dropwise, the selectivity to 8c more than doubles up
1
is added
(
8c) is as calculations were also carried out to check the consistency of
the conclusions reached with the DFT calculations. The results
of these additional calculations are available in the ESI. All
stationary points were characterized by harmonic analysis. In
particular, transition structures were characterized by the
presence of only one imaginary frequency, corresponding to the
atomic movement along the reaction coordinate. Unless
otherwise stated, all Gibbs free energies reported in this paper
correspond to calculations at room temperature. In some cases,
1
to 27%, but dimerization is still the most favoured process. As
happened in the preceding case, the results experimentally
obtained are far better than these (42% selectivity for batch
conditions and 60% for dropwise addition), which is
undoubtedly due to the rough approximation made to estimate
the rate constants values from the calculated activation thermodynamic parameters were also calculated at 65 °C (the
temperature experimentally used in the reactions). Although
barriers. Nevertheless, the kinetic simulations show the same
qualitative trend observed in the experiments, thus confirming
the validity of the mechanistic proposal. It is worth noting that
in butanol, the computational study reveals that the glycidol
dimerization process is faster, with regard to what happens in
methanol (calculated activation barriers are 20.9 and 21.9 kcal
mol–1, respectively), which is also in line with the experimental
the free energy activation barriers increase by ca. 1.3 kcal mol–
1
with regard to the room temperature values, the relative
activation barriers (responsible for reaction selectivity) remain
almost identical. Solvent effects in highly polar media, such as
alcohols, are quite important in the reactions studied. To take
into account these effects, all calculations were carried out
using the polarized-continuum model (IEF-PCM) with the
conversions observed, both in at once and in dropwise addition Gaussian 09 internally stored parameters for methanol, 1-
butanol and 2,2,2-trifluoroethanol. In the case of the DLPNO-
CCSD(T) calculations, the SMD model was employed, as
implemented in the ORCA 4.0 package, with the parameters
internally stored for methanol.
In all cases, the reference state used for the equilibrium
constant and rate coefficient calculations in solution was 1M in
the solute at 298.15 K. Concentrations instead of activities were
used throughout the work.
conditions (see Tables S1, S2 in the Supporting Information). Of
course, the existence of other concurrent reaction pathways
must result in a much more complex product distribution,
resulting in a lower selectivity to the target compounds 8.
Concerning the reactions with more acidic alcohols, the
theoretical calculations carried out for TFE (2f) are consistent
with the different behaviour of these kinds of alcohols. First, the
trifluoroethoxide anion 3f is not able to deprotonate glycidol
(the equilibrium is largely favourable to 3f by 8.2 kcal mol–1).
This results in lower competition of the glycidol dimerization
reaction (although the uncatalysed dimerization still could play
a small role), and hence more selectivity toward the target
General
Gas chromatography analyses were carried out in a Hewlett
Packard 7890 series II gas chromatograph using a column of
phenyl silicone 5.5% (Zebron ZB-5HT Inferno 30 m x 0.25 mm x
compound, [3F.0.0]
(8c). In fact, although the glycidol
0.25 µm), helium as carrier gas, and equipped with a flame
dimerization reaction is still intrinsically favoured over the
epoxide aperture with 3f (21.7 vs. 23.5 kcal mol–1), taking into
account the previous glycidol deprotonation equilibrium the
situation completely reverses (29.9 vs. 23.5 kcal mol–1), making
the latter favourable by 6.4 kcal mol–1). Note that the activation
ionization detector (FID).
1H-, 13C-, and 19F-NMR spectra (DMSO-d6,
δ ppm, J Hz) were
obtained using a Bruker AV-400 instrument with TMS as
standard. MS spectra were obtained using a Bruker MicroTof-Q
spectrometer with electrospray ionization. Boiling points were
determined using Differential Scanning Calorimetric (DSC)
analysis in a TA Instruments DSC-Q20, calibrated with indium,
using micropore aluminium pans, in a range of 298–673 K, at
atmospheric pressure. Boiling points were determined using
onset temperature.
barrier for the reaction of 3f with
1 is higher than any of those
calculated for 3a and 3c, in agreement with the observed
relative reactivity of the three alcohols. The kinetic simulations
in this case lead to selectivities over 99% both with dropwise
and at once addition of glycidol, again in line with the behaviour
experimentally observed.
Glycidol, diglyme, 1,5,7-Triazabicyclo[4.4.0]dec-5-ene
(TBD), TBD-PS, TBD-silica, hydrotalcite, magnesium oxide,
anisole and lithium hydroxide were purchased from Sigma–
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Aldrich. Methanol, ethanol, isopropanol, potassium hydroxide
and sodium hydroxide were purchased from Scharlab. Butanol,
2,2,2-trifluoroethanol, 2-ethylhexan-1-ol, phenol and strontium
hydroxide were purchased from Alfa Aesar. Basic resin
Amberlyst® IRA-400 was purchased from Carlo Erba. All the
alcohols were dried and distilled over calcium hydride prior to
use. The metal hydroxides purity was determined by titration
using potassium hydrogen phtalate as titrating agent. TBD-PS,
TBD-silica and Amberlyst® IRA-400 were dried at 55 °C in
vacuum previous to use. Hydrotalcite and magnesium oxide
were calcined at 450 °C prior to use.
trifluoroethanol (above all in the reactions catalysed by LiOH) is
DOI: 10.1039/C7GC01583F
in line with this mechanistic view. In the best case, total glycidol
conversion with 93% selectivity to the desired product can be
achieved. Finally, in the case of methanol, homogeneous
alkaline hydroxides could be replaced by a recoverable basic
heterogeneous catalyst (Amberlyst® IRA 400).
View Article Online
Acknowledgements
The authors acknowledge financial support from MINECO
(project CTQ2014-52367-R), Gobierno de Aragón (Group E11)
and the European Regional Development Funds. We are
indebted to the Galicia Supercomputation Center (CESGA) for
computing facilities. A. Leal acknowledges the MECD for a FPU
Synthesis of glycerol monoethers [R.0.0]
The appropriate amount of alcohol (1500% mol with respect to
glycidol), the catalyst (10, 20 or 30% mol with respect to
glycidol), and diglyme or anisole as internal standard (15% w/w
with respect to glycidol) were placed into a round bottomed
flask. The reaction was stirred and heated at the desired
temperature (65, 45, or 25 °C) under argon until total
dissolution of the catalyst. Then, glycidol (4.35 mmol) was
added dropwise for 15 min. The reaction was monitored at
different times by extracting samples that were neutralized
with HCl 0.3 M previous to injection in GC. After total
consumption of glycidol, in the case of using homogeneous
catalysts, the reaction was quenched with HCl 0.3 M and salts
were filtered off. Whereas in the case of heterogeneous
catalysts the solid was just filtered off. Finally, the excess of the
starting alcohol was eliminated by reduced pressure distillation
and glycerol monoether was purified by vacuum distillation.
Conversions and yields during the reaction were determined by
grant
.
Notes and references
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