Simple Zn(II) Salts as Efficient Catalysts for the Homogeneous Trans-Esterification of Methyl Esters

Article abstract of DOI:10.1007/s10562-016-1733-6

Abstract: This study aimed to optimize the zinc-catalyzed trans-esterification, and pointed to assess the effect of the solvent, the catalyst, its loading and the nature of the substrate. The screening disclosed the remarkable ability of zinc(II) acetate to promote the reaction in refluxing toluene at low catalyst loading. A significant improvement ensued with respect to recently results on the same reactions, in terms of less restrictive conditions and more convenient catalyst precursors. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10562-016-1733-6

Catal Lett
DOI 10.1007/s10562-016-1733-6
Simple Zn(II) Salts as Efficient Catalysts for the Homogeneous
Trans-Esterification of Methyl Esters
Maria E. Cucciolito1,2 Matteo Lega3 Veronica Papa1,4 Francesco Ruffo1,2
•
•
•
Received: 7 March 2016 / Accepted: 10 March 2016
Ó Springer Science+Business Media New York 2016
Abstract This study aimed to optimize the zinc-cat-
alyzed trans-esterification, and pointed to assess the effect
of the solvent, the catalyst, its loading and the nature of the
substrate. The screening disclosed the remarkable ability of
zinc(II) acetate to promote the reaction in refluxing toluene
at low catalyst loading. A significant improvement ensued
with respect to recently results on the same reactions, in
terms of less restrictive conditions and more convenient
catalyst precursors.
Keywords Trans-esterification Á Zinc Á Homogeneous
catalysis Á Esters
1 Introduction
Trans-esterification is a fundamental reaction for the syn-
thesis of esters [1]. It is often more advantageous than the
direct esterification of carboxylic acids or acyl halides with
alcohols, particularly when these species are labile and
difficult to isolate. Esters, especially methyl derivatives,
are instead readily available and therefore can be conve-
niently used as starting materials. Furthermore, carboxylic
acids are often insoluble in organic solvents and hence
react with difficulty, while esters are commonly soluble,
stable and easy to handle.
Graphical Abstract
O
Zn(OAc)2, 1%
toluene,
O
Δ
R
+
O
O
MeOH
+
R H
O
ROH
n-butanol
n-esanol
n-hexadecanol
For these reasons, trans-esterification has a central role
in various fields, comprising the production of polymers,
the synthesis of highly functionalized esters for pharma-
ceutical uses, and the synthesis of biodiesel. For example,
trans-esterification is of primary importance in the pro-
duction of (i) common polyesters, which are obtained
combining dimethyl terephthalate and ethylene glycol [2],
(ii) polyphosphoester (PPEs), materials suitable for bio-
logical applications for their biocompatibility and similar-
ity to biopolymer [3], (iii) biofuels and chemicals starting
from biomass [4]. Trans-esterification is also useful for
preparing many fine chemicals, for example macrolides,
natural compounds obtained by lactonization of x-hy-
droxyesters [2].
allyl alcohol
cinnamyl alcohol
geraniol
benzyl alcohol
& Maria E. Cucciolito
cuccioli@unina.it
1
`
Dipartimento di Scienze Chimiche, Universita di Napoli
‘‘Federico II’’, Complesso Universitario di Monte S. Angelo,
via Cintia 21, 80126 Naples, Italy
2
`
Consorzio Interuniversitario di Reattivita Chimica e Catalisi
(CIRCC), via Celso Ulpiani 27, 70126 Bari, Italy
Trans-esterification is an equilibrium reaction, and the
achievement of high yields requires an adequate control of
the experimental conditions. Typically, the reaction is
conducted under reflux in a high boiling solvent in order to
shift the equilibrium towards the formation of the products.
3
4
Fater SPA, via Ardeatina 100, 00040 Pomezia, Roma, Italy
Present Address: Leibniz-Institut fu¨r Katalyse e.V., an der
¨
Universitat Rostock, Albert Einstein Strasse 29a,
18059 Rostock, Germany
¨
123

M. E. Cucciolito et al.
2.2 Catalysis
The presence of a catalyst is also beneficial for
enhancing the rate of the reaction. Classical Brønsted acids
and bases catalyze trans-esterification, although their use is
often not recommended because they are poorly tolerated
by some organic functions and often difficult to separate at
the end of the reaction. Catalysts based on Lewis acid
metals have been developed [5, 6], which are capable of
promoting the reaction in high yields and environmentally
friendly conditions. In this case, the carbonyl group of the
reagent becomes positively polarized by coordination to
the metal ion, which favors the attack by the alcohol.
Tomita and Ida [5] disclosed a relationship between the
Lewis acidity and the activity of several metal ions. Within
this frame, zinc(II) occupies a privileged role, both for its
activity and for availability and low toxicity [7]. As a
consequence, a few studies on the homogenous trans-es-
terification catalyzed by complexes of Zn(II) have been
described [8–17]. However, this process is still far from
being economic and of easy applicability, and as a result it
can be stated that still much can be done to improve the
reaction of trans-esterification in terms of efficiency and
compatibility.
A mixture of the appropriate zinc salt, methyl-3-phenylpro-
pionate, alcohol, and toluene was refluxed for 18 h. In each
test the concentration of the reagents was kept constant:
(alcohol) = 0.6 mol L-1 and(methylester) = 0.5 mol L-1
.
After each run the reaction mixtures were dried under vac-
uum, and the crude product was subjected to 1H-NMR
analysis.
2.2.1 Allyl-3-Phenylpropionate
1H-NMR (400 MHz, CDCl3) d 2.70 (t, 2H, PhCH2CH2–),
3.00 (t, 2H, PhCH2CH2–), 4.63 (d, 2H, –OCH2–), 5.25 (d,
1H, =CHH), 5.32 (d, 1H, =CHH), 5.95 (m, 1H, –CH=),
7.10–7.25 (m, 5H, Ph).
2.2.2 Benzyl-3-Phenylpropionate
1
colorless oil; H-NMR (400 MHz, CDCl3) d 2.63 (t, 2H,
PhCH2CH2), 2.93 (t, 2H, PhCH2CH2), 5.06 (s, 2H,
OCH2Ph), 7.10–7.30 (m, 10H, Ph).
The present study aimed to optimize the zinc-catalyzed
trans-esterification by using several salts, and pointed to
assess the effect of the solvent, the catalyst, its loading and
the nature of the substrate. A clear improvement has been
achieved in comparison to what reported in literature for
the same reaction [10]. Actually, the catalyst precursors are
cheaper and easily available, the catalyst loading has been
significantly reduced, and the reaction conditions are less
restrictive because it is not necessary the use of dry sol-
vents and inert atmosphere. Furthermore, a rationalization
of the effects of the counterion is also proposed.
2.2.3 Butyl-3-Phenylpropionate (Silica Gel, Hexane/
EtOAc = 15/1)
yellow oil; 1H-NMR (400 MHz, CDCl3) d 0.84 (t, 3H,
MeCH2–), 1.27 (sx, 2H, MeCH2–), 1.53 (qt, 2H, –OCH2
CH2–), 2.55 (t, 2H, PhCH2CH2–), 2.88 (t, 2H, PhCH2CH2–),
4.0 (t, 2H, –OCH2–), 7.15–7.25 (m, 5H, Ph).
2.2.4 Cinnamyl-3-Phenylpropionate
1H-NMR (400 MHz, CDCl3) d 2.70 (t, 2H, PhCH2CH2–),
3.00 (t, 2H, PhCH2CH2–), 4.75 (d, 2H, –OCH2–), 6.15 (dt,
1H, =CHCH2–), 6.65 (d, 1H, =CHPh), 7.10–7.25 (m, 10H,
Ph).
2 Experimental
2.1 Materials
2.2.5 (E)-3,7-Dimethylocta-2,6-Dienyl-3-Phenylpropionate
All solvents and reagents were purchased by Sigma-
Aldrich and were used without further purification. The
analytical thin-layer chromatography (TLC) was carried
out on sheet of silica (ALUGRAM SIL G/UV, thickness
0:20 mm) supplied by Macherey–Nagel. The chromatog-
raphy was carried out using as stationary phase silica gel
with a particle size of 0040–0063 mm (Silica Gel 60)
supplied by Sigma-Aldrich. Protonic NMR spectra were
recorded in CDCl3, using a Bruker 400 DRX spectrometer.
The following abbreviations were used for describing
NMR multiplicities: s, singlet; d, doublet; t, triplet; dt,
double triplet; m, multiplet; qt, quintuplet; sx, sextuplet.
Methyl-3-phenylpropionate was prepared according to a
described procedure [18].
1
colorless oil; H-NMR (400 MHz, CDCl3) d 1.63 (s, 3H,
Me), 1.73 (s, 6H, Me), 2.0–2.1 (m, 4H, –CH2CH2–), 2.68
(t, 2H, PhCH2CH2–), 2.97 (t, 2H, PhCH2CH2–), 4.61 (d,
2H, –OCH2–), 5.12 (m, 1H, –CH=), 5.33 (m, 1H, –CH=),
7.15–7.35 (m, 5H, Ph).
2.2.6 Hexadecanoyl-3-Phenylpropionate
1
colorless oil; H-NMR (400 MHz, CDCl3) d 0.80 (t, 3H,
Me), 1.19 (m, 26H, Me(CH2)13–), 1.51 (m, 2H, –OCH2
CH2–), 2.55 (t, 2H, PhCH2CH2–), 2.88 (t, 2H, PhCH2CH2–),
4.0 (t, 2H, –OCH2–), 7.10–7.25 (m, 5H, Ph).
123

Simple Zn(II) Salts as Efficient Catalysts for the Homogeneous Trans-Esterification of…
2.2.7 Hexyl-3-Phenylpropionate
–
Screening of alcohols.
The trans-esterification described in Scheme 1 was not
1H-NMR (400 MHz, CDCl3) d 0.81 (t, 3H, Me), 1.22–1.28
(m, 6H, MeCH2–), 1.51 (m, 2H, –OCH2CH2–), 2.55 (t, 2H,
PhCH2CH2–), 2.88 (t, 2H, PhCH2CH2–), 4.0 (t, 2H,
–OCH2–), 7.05–7.25 (m, 5H, Ph).
observed in toluene at room temperature, even in the
presence of a catalytic amount of Zn(OAc)2 (entries 1 and
2 of Table 1). The same catalyzed reaction was found to
proceed in refluxing toluene with an acceptable yield (entry
4), while no conversion was observed at this temperature
without catalyst (entry 3).
3 Result and Discussion
A screening of solvents was carried out as reported in
Table 2 in the presence of zinc acetate. The reactions were
performed at reflux with a 20 % excess of benzyl alcohol.
Experiments were also performed without any solvent
(entry 8), or by using the same benzyl alcohol as solvent
(entry 9). After each run the crude product was subjected to
analysis.
Trans-esterification between methyl-3-phenylpropionate
and benzyl alcohol was selected as representative reaction
(Scheme 1).
The study of trans-esterification catalyzed by zinc salts
was systematically conducted according to the following:
–
Screening of solvents and investigation of solventless
conditions.
An acceptable conversion was observed in toluene (en-
try 1), while it was not satisfactory in other solvents.
Notably, the conversions in toluene and dioxane were
dramatically different (entry 1 vs. entry 5) despite their
–
–
Screening of catalysts.
Screening of the substrate/catalyst ratio.
O
O
O
H
O
O
+
+
MeOH
Scheme 1 Representative trans-esterification reaction
Table 1 Effects of the presence
Entry
Temperature (°C)
Time (h)
Zn(OAc)2 (mol%)
Conversiona (%)
of Zn(OAc)2 and of the
temperature on the trans-
esterification of Scheme 1
1
2
3
4
25
25
18
18
18
18
–
1
–
1
0
0
111
111
0
72
Reaction conditions: toluene (1.7 mL), 18 h, substrate/benzyl alcohol = 1 mmol/1.2 mmol
a
1
Evaluated by H-NMR spectroscopy on the crude reaction mixture in CDCl3
Table 2 Effect of the solvent
on the trans-esterification of
Scheme 1 by using Zn(AcO)2 as
catalyst
Entry
Solvent (1.7 mL)
Temperature (°C)
Conversion (%)a
1
2
3
4
5
6
7
8
9
Toluene (reflux)
111
66
72
5
Tetrahydrofuran (reflux)
Diethyl ether (reflux)
Acetonitrile (reflux)
Dioxane (reflux)
34
\1
\1
\1
\1
8
82
101
56
Acetone (reflux)
Di-i-propyl ether (reflux)
Solventless
68
145
145
76
99
Benzyl alcohol
Reaction conditions: 18 h, substrate/benzyl alcohol = 1 mmol/1.2 mmol, substrate/Zn(OAc)2 = 100/1
a
1
Evaluated by H-NMR spectroscopy on the crude reaction mixture in CDCl3
123

M. E. Cucciolito et al.
similar boiling temperatures. The same behavior was
observed in the other solvents, i.e., acetonitrile, acetone,
ethers. In order to understand if the results were due to the
nature of these solvents, trans-esterification in toluene was
carried out at 82 °C, where it was observed a still signifi-
cant activity (58 %). This outcome suggests that coordi-
nating solvents depress the performance of the catalyst,
plausibly because their molecules occupy the zinc active
sites.
Table 4 Screening of the substrate/catalyst ratios in the trans-ester-
ification of Scheme 1
Entry
Sub/Cat
Salt
Conversion (%)a
1
10/1
Zn(OAc)2Á2H2O
Zn(OCOCF3)2ÁH2O
Zn(NO3)2Á6H2O
Zn(OAc)2Á2H2O
Zn(OCOCF3)2ÁH2O
Zn(NO3)2Á6H2O
Zn(OAc)2Á2H2O
Zn(OCOCF3)2ÁH2O
Zn(NO3)2Á6H2O
Zn(OAc)2Á2H2O
Zn(OCOCF3)2ÁH2O
Zn(NO3)2Á6H2O
99
99
99
99
99
99
86
93
93
9
2
10/1
3
10/1
4
20/1
5
20/1
6
20/1
The solventless reaction showed a good conversion
(76 %) at 145 °C (entry 8). When benzyl alcohol was used
as solvent, the conversion was complete (entry 9), plausi-
bly because the large excess of alcohol shifts the equilib-
rium towards the product. Nevertheless, its separation from
the excess of alcohol was found to be uneasy, as a flash
distillation was necessary to isolate it in pure form.
On the grounds of the above results, the subsequent
screenings were carried out in refluxing toluene, by
employing several common zinc(II) salts (Table 3).
The results disclose that a fine tuning of the Lewis
acidity is necessary for high conversion. This property can
be controlled by an adequate choice of the counterion:
strong Lewis bases (Cl-, Br-, I-) are expected to compete
with the substrate in the coordination to the metal site, thus
inhibiting its activity (entries 1–3). On the other hand,
weak donors (triflate, tetrafluoroborate, perchlorate)
enhance the acidity of the metal center, and therefore an
‘‘irreversible’’ coordination of the carbonyl group can
determine its deactivation (entries 4, 7, 8). Therefore, the
delicate balance was seemingly satisfied by the interme-
diate behavior of acetate, trifluoroacetate and nitrate, which
promoted a significant conversion (entries 9–11).
7
100/1
100/1
100/1
250/1
250/1
250/1
8
9
10
11
12
25
10
Reaction conditions: 18 h, refluxing toluene (1.7 mL), substrate/
benzyl alcohol = 0.5 mol.L-1/0.6 mol.L-1
a
1
Evaluated by H-NMR spectroscopy on the crude reaction mixture
in CDCl3
Once identified the three best catalysts, the study con-
tinued by selecting different substrate/catalyst ratios
(Table 4) in order to discriminate between the three anions.
Quantitative conversions were observed with 10/1 and
20/1 ratios, but optimized conditions were identified with a
100/1 ratio, because both activity and productivity were
satisfactory (entry 7–9). It should be noted that these values
demonstrate that simple salts are more active than the
previously reported tetranuclear zinc salt [9], which is
laborious to obtain and promotes the same conversion at
significantly higher loading (fivefold based on Zn ions).
Low catalyst loading (entries 10–12) allowed identify-
ing zinc trifluoroacetate as the most effective catalyst.
However, zinc acetate dihydrate was preferred for the
subsequent alcohol screening, due to its amenable handling
which allowed weighing small amounts. Both Zn(NO3)2Á
6H2O and Zn(OCOCF3)2ÁH2O are moisture sensitive,
which prevented their use in air.
Table 3 Screening of Zn(II) salts as catalysts in the trans-esterifi-
cation of Scheme 1
Entry
Salt
Conversion (%)a
1
ZnCl2
37
\5
\5
6
2
ZnBr2
3
ZnI2
Primary alcohols (aliphatic with short or long chains,
unsaturated or functionalized alcohols) and one secondary
alcohol (menthol) were selected for the screening
(Table 5). The trans-esterification of methyl-3-phenylpro-
pionate with aliphatic alcohols was efficiently catalyzed by
Zn(OAc)2Á2H2O (entries 1–3). The products could be iso-
lated in good yields through chromatography on silica gel
by using suitable eluents.
4
Zn(triflate)2
ZnO
5
29
72
8
6
Zn(OAc)2
7
Zn(BF4)2Á6H2O
Zn(ClO4)2Á6H2O
Zn(OAc)2Á2H2O
Zn(OCOCF3)2ÁH2O
Zn(NO3)2Á6H2O
8
6
9
86
93
93
10
11
The low conversion of the simple allyl alcohol (entry 4)
was plausibly an effect of its relatively low boiling point,
which subtracted the substrate from the liquid catalytic
phase. Accordingly, higher conversions were instead
observed for the other two unsaturated substrates (cinnamyl
Reaction conditions: 18 h, refluxing toluene (1.7 mL), substrate/
benzyl alcohol = 1 mmol/1.2 mmol, substrate/catalyst = 100/1
a
1
Evaluated by H-NMR spectroscopy on the crude reaction mixture
in CDCl3
123

Simple Zn(II) Salts as Efficient Catalysts for the Homogeneous Trans-Esterification of…
Table 5 Trans-esterification of
Entry
Alcohol
Conversion (%)a
Isolated yield (%)
Eluting mixture
methyl-3-phenylpropionate with
selected alcohols by using
Zn(OAc)2Á2H2O as catalyst
1
2
3
4
5
6
7
8
n-Butanol
89
98
71
27
48
84
86
0
74
98
65
–
EtOAc:hexane 1:15
n-Hexanol
n-Hexadecanol
Allyl alcohol
Cinnamyl alcohol
Geraniol
EtOAc:hexane 1:35
–
77
79
–
EtOAc:hexane 1:40
EtOAc:hexane 1:40
Benzyl alcohol
Menthol
Reaction conditions: 18 h, refluxing toluene (1.7 mL), substrate/alcohol = 1 mmol/1.2 mmol, substrate/
Zn(OAc)2Á2H2O = 100/1
Evaluated by H-NMR spectroscopy on the crude reaction mixture in CDCl3
a
1
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This study aimed to optimize the zinc-catalyzed trans-
esterification, a reaction of great relevance within organic
synthesis. A screening was carried out by using zinc(II)
salts as catalysts, and aimed to assess the effect of the
solvent, the catalyst, its loading and the nature of the
substrate.
The results demonstrated the remarkable ability of zin-
c(II) acetate to promote the reaction in refluxing toluene at
low catalyst loading, and disclosed a very efficient method
for the friendly conversion of methyl esters in the presence
of a variety of primary alcohols.
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