Direct esterification of carboxylic acids with alcohols catalyzed by Iron(III) acetylacetonate complex

Article abstract of DOI:10.1080/00397911.2012.725265

Direct condensation of carboxylic acids and alcohols with electronic, steric, and functional group variations was carried out using the environmentally benign, moisture-stable, inexpensive, and recoverable iron(III) acetylacetonate [Fe(acac)₃] as catalyst (5 mol%). This iron salt efficiently catalyzed the esterification of several primary and secondary alcohols in refluxing xylene, without the need for a dehydration reagent. The chemoselectivity of the proposed protocol was demonstrated by the selective esterification of primary alcohol functionality in racemic 1-phenylethane-1,2- diol with benzoic acid. The esterification was also applicable to unmasked α-hydroxyacid, guasiaromatic, heterocyclic, and N-protected amino acids. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.725265

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Direct Esterification of Carboxylic Acids with Alcohols
Catalyzed by iron(III) Acetylacetonate Complex
a
a
a
Shiue-Shien Weng , Fong-Kuang Chen & Chih-Shueh Ke
a
Department of Chemistry, ROC Military Academy, Kaohsiung, Taiwan, ROC
Accepted author version posted online: 05 Apr 2013.
To cite this article: Shiue-Shien Weng , Fong-Kuang Chen & Chih-Shueh Ke (2013): Direct Esterification of Carboxylic Acids
with Alcohols Catalyzed by iron(III) Acetylacetonate Complex, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI:10.1080/00397911.2012.725265
To link to this article: http://dx.doi.org/10.1080/00397911.2012.725265
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Direct esterification of carboxylic acids with alcohols catalyzed by iron(III)
acetylacetonate complex
1
,
1
1
Shiue-Shien Weng , Fong-Kuang Chen , Chih-Shueh Ke
1Department of Chemistry, ROC Military Academy, Kaohsiung, Taiwan, ROC
,
Fax: +887(7)7422151; E-mail : Wengss@mail.cma.edu.tw
Abstract
Direct condensation of carboxylic acids and alcohols with electronic, steric, and
functional group variations was carried out using the environmentally benign, moisture-
stable, inexpensive, and recoverable iron(III) acetylacetonate (Fe(acac) ) as catalyst (5
3
mol%). This iron salt efficiently catalyzed the esterification of several primary and
secondary alcohols in refluxing xylene, without the need for a dehydration reagent. The
chemoselectivity of the proposed protocol was demonstrated by the selective
esterification of primary alcohol functionality in racemic 1-phenylethane-1,2-diol with
benzoic acid. The esterification was also applicable to an unmasked α-hydroxyacid,
guasiaromatic, heterocyclic, and N-protected amino acids.
KEYWORDS: esterification; iron(III) β-diketonate species; recoverable catalyst
INTRODUCTION
Direct esterification of carboxylic acids with alcohols, one of the most fundamental
reactions in organic synthesis, is a widely used one-step, atom-efficient method for ester
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[
1]
synthesis. Conventionally, the aforementioned direct condensation is carried out using
excess amounts of one of the starting materials in the presence of strong acids such as
sulfuric acid, boric acid, boronic acids, organic sulfonic acids, and perfluorinated solid
superacids; hence, this reaction has a narrow substrate scope, that is, very few acid-
[
2]
tolerant substrates can be used. Currently, effective Lewis acids such as Ti(IV), Zr(IV),
[
3]
[4]
[5]
Sn(IV), Sc(III), and Hf(IV) salts, oxymetal species, bulky diarylammonium salts,
[6]
and molecular iodine are being used to make the direct esterification reactions more
chemo-, stereo-, and regioselective. Nevertheless, these Lewis acids have limitations due
to poor functional group capabilities and recent trends in environmental and economical
issues of green-process chemistry. Therefore, considerable effort has been devoted to the
development of eco-friendly and recyclable catalysts for direct esterification, with the
[7]
aim of establishing greener, more sustainable synthesis protocols. In this regard,
catalysts based on iron, which is inexpensive, readily available, and environmentally
[8]
benign, have been prepared and reported. Recently, Sugi et al. tested a wide variety of
metal salt catalysts for the esterification of fatty acids and alcohols (in equimolar amounts)
in mesitylene (solvent) under azeotropic reflux conditions and found that ferric salts,
particularly ferric chloride hexahydrate (FeCl
3
·6H
O), were the most effective.[9]
2
Although ferric salts are well suited for the industrial-scale preparation of long-chain
fatty acid steroid esters, they are unsuitable for use with acid-sensitive substrates such as
acetals, tetrahydropyran (THP), silyl ethers, allylic (benzylic) alcohols, heterocyclic
compounds, and α,-β-unsaturated alcohols (acids), since the actual catalytic role of
FeCl
3
·6H O remain elusive in view of the facile intervention of acid (i.e., HCl) catalysis
2
under such reaction conditions.[10] Hence, the application of other iron catalysts in
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catalytic esterification has not been studied extensively till date.
We recently reported that the environmentally benign, moisture-stable, inexpensive, and
recyclable iron(III) β-diketonate species can efficiently catalyze the transesterification of
functionalized esters with complex alcohols under neutral or basic conditions.[11] Where,
the generation of the dimeric µ-alkoxy-bridged iron(III) species resulted from the
associative substitution of the alcohol (protic nucleophile) with the iron(III) β-diketonate
catalyst was response for the catalytic turnover. Consequently, a β-diketone ligand was
released as the only counterpart during the course of the transesterification reaction.
Since the lack of catalytic ability of the weak acidic β-diketone (pKa 9-13 in various
organic solvents), therefore, the background catalysis of Brønsted acid can be excluded in
this system. As an extension of our research on catalytic esterification, we developed a
recyclable protocol for the direct condensation of acids with various acid- and/or base-
sensitive, as well as functionalized alcohols catalyzed by 5mol % Fe(acac) under neutral
3
conditions.
RESULTS AND DISCUSSION
We first investigated the direct condensation of equimolar amounts of benzoic acid 1 and
acid-sensitive 2,3-O-isopropylidene glycerol 2 in the presence of various iron(III) β-
diketonate catalysts (5 mol%) to afford the desired esters 3; the reaction was carried out
in xylene under reflux conditions without using any dehydrating reagent (Table 1). The
catalytic activity was found to be strongly dependent on the electronic (electro-
withdrawing or electro-donating nature) and steric demand of the ligand.[10] Among the
examined catalysts, the least sterically hindered iron(III) acetylacetonate (Fe(acac) ) was
3
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the most effective; when using this catalyst, 3 was obtained in 92% isolated yield after
chromatographic purification (Table 1, entry 1). Unexpectedly, the most electron-
deficient iron(III) 1,1,1,5,5,5-hexafluoropentane-2,4-dionate (Fe(hfacac) ) showed only
3
moderate catalytic reactivity (Table 1, entry 2). This was probably because of the low
o
boiling (bp: 70 C) 1,1,1,5,5,5-hexafluoropentane-2,4-dione ligand at the high reaction
temperature (150 °C), which in turn inhibited the catalytic turnover and interrupted the
catalytic cycle.[11]
Although sterically congested catalysts could catalyze this esterification, prolonged
reaction times (24-36 h) were required for complete conversion (Table 1, entries 3-5). For
solvent screening, the test esterification was carried out in different solvents under reflux
conditions (Table 1, entries 6-10) in the presence of the most efficient catalyst Fe(acac) .
3
The reaction was inhibited in polar coordinating solvents such as diisopropyl ether, 1,4-
dioxane, and DMF because the solvent competed with substrate in coordinating to the
iron center, thus diminishing the Lewis acidity of the catalyst (Table 1, entries 8-10). On
the other hand, the reaction proceeded rapidly in nonpolar hydrocarbon and aromatic
solvents such as heptane and toluene (Table 1, entries 6, 7). However, the reaction in
heptane (under reflux conditions) afforded the ester in moderate yield (bp: 98 °C)
because of the low boiling point of heptane and the poor solubility of 1 in this solvent.
Notably, the catalyst was retained on the silica gel column (because of its strong affinity
for silica) during chromatographic purification of the crude product and could be
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conveniently recovered without loss of activity, by elution with a highly polar mobile
phase such methanol (Table 1, entry 6, data in parentheses).
In order to explore the generality and scope of the direct condensation, the reaction was
further carried out with equimolar amounts of various functionalized alcohols and
carboxylic acids using 5 mol% Fe(acac) catalyst in refluxing xylene. As shown in Table
3
2
, the reactivity rate of 1 toward alcohols with different structural and steric demands
followed the trend 1° (entry 1) > 2° (entries 2 and 5) > α, β-unsaturated 1° (entry 3) >
hindered 2° (entry 4) >> phenolic (entry 6). In general, the reactions with 1° alcohols
were two times faster than those with 2° alcohols (entries 2, 4, and 5 vs. entry 1). The
current protocol was unsuccessful for aromatic alcohols (11%, entry 6) and 3° alcohols
(
entry 7) even when the reaction time was increased, presumably because of the reduced
nucleophilicity of the phenolic substrates and the steric hindrance in 3° alcohols.
To gain insights into the functional group compatibility of this reaction, a diverse array of
substituted acids and acid-sensitive alcohols (in 1:1 ratio) were used. The current protocol
could be extended to acidic substrates such as ferrocene carboxylic acid (guasi-aromatic,
Table 2, entry 8), α, β-unsaturated acids (Table 2, entry 9), the acid- and base-sensitive
tert-butyl ether, Fmoc-protected α-amino acids (Table 2, entry 10), and heterocyclic acids
(
Table 2, entry 11) under the optimal conditions. No decomposition, rearrangement, or
deprotection of the functional groups was observed. An unmasked α-hydroxycarboxylic
acid such as mandelic acid was also esterified smoothly by diphenyl methanol to afford
the desired product 14 in 95% yield, without self-polymerization and racemization (Table
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[12]
2
, entry 12). Acid-sensitive functional groups such as tetrahydropyran (THP), and tert-
butyldimethylsilyl (TBS) ether on the alcohol were well tolerated in this reaction (Table 2,
o
entries 13, and 14). The reaction of carboxylic acid bearing 3 tert-butyl alkyl group with
1
° alcohol was sluggish because of steric hindrance, and the desired ester 17 was isolated
in only 72% yield (Table 2, entry 15). The condensation of long-chain alkenyl oleic acid
with 20-(R)-(3'-methyl)butyl-5-pregnen-3-β-ol proceeded smoothly to give the
corresponding oleate 18 in 96% yield (Table 2, entry 16). In addition, the
chemoselectivity of the protocol was demonstrated by the esterification of racemic 1-
phenylethane-1,2-diol with 1. The 1° hydroxyl group in this diol was exclusively
esterified with nearly complete chemoselectivity, and the corresponding ester was
obtained in 94% yield, along with trace amounts of a dibenzoate product (Table 2, entry
1
7). The protocol could also be applied to the direct amidation of benzoic acid with
benzyl amine, although the reaction rate was lower than that observed when using
corresponding 1° alcohol (Table 2, entry 18).
CONCLUSION
A new catalytic esterification reaction was developed by using the inexpensive, moisture-
stable, and nontoxic Fe(acac) as the catalyst. This direct esterification could be extended
3
to carboxylic acids and alcohols with electronic, steric, and functional group variations.
Notably, the catalyst was easily recovered from the silica gel column after
chromatographic purification of the crude ester. Thus, the proposed method meets the
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criteria for green chemical reaction, and it is expected to find potential applications in
industrial-scale esterification.
EXPERIMENTAL
1
13
H and C NMR spectra were recorded in CDCl
3
using a Jeol JVMEX400 spectrometer
1
13
1
(
400 MHz, H; 100 MHz, C) and Bruker AVANCE 500 spectrometer (500 MHz, H;
1
3
1
25 MHz, C), respectly, with CHCl as internal reference. Electron-impact (ESI) mass
3
spectra were recorded using a Thermo Finnigan spectrometer equipped with LCQ
Advantage ionization and Spectra System detector systems. Analytical GC was carried
out using an Agilent 6890C GC system equipped with an Agilent DB-WAX column (30
m × 0.25 mm). Analytical GC-MS was carried out by a Varian CP-3800 GC/Saturn 2000
GC/MS spectrometer equipped with a CP-5860 column (30 m × 0.25 mm × 0.25 mm)
using helium gas. Analytical TLC plates were visualized under UV light or by spraying
with phosphomolybdic acid (PMA) and KMnO staining agents. All the reactions were
4
performed in nitrogen or argon atmosphere, and the end products were isolated as pure
materials. All the products were purified by column chromatography or distillation under
reduced pressure. Since all the products were known compounds, they were identified by
comparing their physical and spectra data with those reported in the literature.[3,4,11]
Fe(acac) , Fe(hfacac) , Fe(tmhd) , Fe(dbm) , and Fe(bzac) were purchased from
3
3
3
3
3
ACROS or TCI or synthesized according to literature methods.[13]
Representative Procedure For Catalyst Screening (Table 1)
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The iron catalyst (0.10 mmol, 5 mol%) and benzoic acid 1 (224 mg, 2 mmol) were placed
in a 10 mL single-neck round-bottom flask. A solution of 2,3-O-isopropylidene glycerol
2
(264 mg, 2 mmol) in xylene (5 mL) was added to the flask via a syringe, at room
temperature and in nitrogen atmosphere. The resulting mixture was heated to reflux, and
1
the reaction progress was monitored by TLC, H NMR spectroscopy, and GC analysis.
After reaction completion, the reaction mixture was gradually cooled to room
temperature, and the organic solvent was evaporated in vacuum to give the crude product,
which was purified by silica gel column chromatography (1:50-1:10) to afford product 3
(
434 mg, 92% yield).
Representative Esterification Catalyzed By Fe(Acac) (Table 2)
3
Fe(acac) ( 72 mg, 0.20 mmol, 5 mol%) and benzoic acid 1 (4 mmol) were placed in a 10
3
mL single-neck round-bottomed flask. 2-Phenylethanol (4 mmol) in 5 mL xylene was
added to the flask via syringe, at room temperature and in nitrogen atmosphere. The
resulting mixture was heated to reflux and the reaction progress was monitored by TLC,
1H NMR spectroscopy, and GC analysis. Once the reaction proceeded to completion, the
reaction mixture was gradually cooled to room temperature, and the organic solvent was
evaporated in vacuum to give the crude product. The crude product was purified by silica
gel column chromatography, first using EtOAc/hexane (1:50-1:10) to elute ester 4 (876
mg, 97% yield), and then using 100% methanol to eluting the Fe(acac) . The recovered
3
iron catalyst (69 mg, 96% recovery) was dried in vacuum and used for subsequent
reactions without further purification.
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ACKNOWLEDGES
We acknowledge the financial extended by the National Science Council of the Republic
of China (NSC-100-2113-M-145-001-MY2). We also thank the mass laboratory of
National Taiwan Normal University and the NMR laboratory of National Sun Yat-sen
University for assistance in the NMR spectra measurements.
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Watanabe, H.; Nakagawa, S.; Ishihara, K. Chem. Asian J. 2007, 2, 477.
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. Ren, Y.; Cai, C. Synth. Commun. 2010, 40, 1670.
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3
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1
0. The roles of Brøsted acid co-catalysis of metal salts, see: (a) Dumeunier, R.; Marko, I.
E. Tetrahedron Lett. 2004, 45, 825; (b) Le Roux, C.; Dubac, J. Synlett 2002, 2, 181; (c)
Sharghi, H.; Sarvari, M. H. Tetrahedron. 2003, 59, 3627.
11. Weng ,S.-S.; Ke, C.-S.; Chen, F.-K.; Lyu, Y.-F.; Lin, G.-Y. Tetrahedron. 2011, 67,
1
1
640.
2. The optical purity was analysed by chiral HPLC analysis and the absolute
configuration was deduced according to literature reports.
3. (a) Chaudhuri, M. K.; Ghosh, S. K. JCS Dalton transactions 1983, 839; (b) Morris,
1
M. L.; Moshier, R. W.; Sievers, R. E. Inorg. Chem. 1962, 2, 411; (c) Hammond, G. S.;
Nonhebel, D. C.; Wu, C.-H. Inorg. Chem. 1963, 1, 173.
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Table 1. Effects of iron catalysts on the direct esterification of benzoic acid 1 with acid-
sensitive 2,3-O-isopropylidene glycerol
2
.a
Entry Fe(β-diketonate)
3
Solvent
time (h) yield (%)h
16(16)g 92 (90)g
b
o
1
2
3
4
5
6
7
8
9
Fe(acac)
3
xylene (150 C)
Fe(hfacac) c
xylene (150 C)
o
16
63
3
d
o
Fe(tmhd)
3
xylene (150 C)
24(36) 58(76)
16(24) 79(90)
16(24) 75(87)
Fe(dbm) e
xylene (150 C)
o
3
f
o
Fe(bzac)
3
xylene (150 C)
o
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
3
3
3
3
3
toluene (120 C)
20
30
89
67
18
<5
0
o
heptane (100 C)
o
diisopryl ether (80 C) 30
1,4-dioxane
30
30
o
1
0
DMF (140 C)
a
All reactions were performed in refluxed solvent in the presence of 5 mol% iron
catalyst.
b
acac: pentan-2,4-dione.
c
hfacac: 1,1,1,5,5,5-hexafluoro- pentan-2,4-dione.
d
tmhd: 2,2,6,6-tetramethyl heptanes-3,5-dione.
e
dbm: dibenzoylmethan.
f
bzac: 1-benzoylacetone.
g
Recovered catalyst from the first cycle was used.
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2

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h
Yield of isolated product after chromatography.
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3

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Table 2. Direct condensation of functionalized carboxylic acids with various alcohols
catalyzed by Fe(acac)
3
.a
Entry Ester (R1)
alcohols(R -OH)
2
time (h) yield, (%)b
1
2
3
PhCOOH
PhCOOH
PhCOOH
Ph(CH
2
)
2
OH
15
22
30
97 (4)
95 (5)
93 (6)
PhCH(OH)CH
3
OH
4
5
PhCOOH
PhCOOH
L-(-)-menthol
40
26
90 (7)
94 (8)
OH
6
7
8
PhCOOH
PhCOOH
4-methoxyl phenol
Ph COH
PhCH
24
24
20
11 (9)
0
3
COOH
OH
92 (10)
2
Fe
9
1
(CH
3
)
2
C=CHCOOH PhCH
2
2
OH
OH
14
20
95 (11)
88 (12)
0
PhCH
O
O
FmocHN
S
OH
11
COOH
CH
3
(CH
2
)
17OH
18
92 (13)
12
13
14
15
(R)-mandelic acid
CH COOH
Ph(CH COOH
(Ph)
THPO(CH
TBSO(CH
2
CHOH
16
22
20
36
95 (14)
93 (15)
95 (16)
72 (17)
3
2
)
4
OH
2
)
2
)
2 4
OH
(CH
3
)
3
CCOOH
Ph(CH
2
2
) OH
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4

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1
6
oleic acid
20
96 (18)
HO
HO
Ph
OH
*
1
7
8
PhCOOH
PhCOOH
16
28
94 (19)
88 (20)
1
PhCH
2
NH
2
a
All reactions were performed with 1 equiv of ester and protic nucleophile in xylene in
the presence of 5 mol% Fe(acac) under reflux condition.
3
b
Isolated yields after column chromatography.
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5