Direct ester condensation from a 1:1 mixture of carboxylic acids and alcohols catalyzed by hafnium(IV) or zirconium(IV) salts

Article abstract of DOI:10.1016/S0040-4020(02)00966-3

To promote atom efficiency in synthesis and to avoid the generation of environmental waste, the use of stoichiometric amounts of condensing reagents or excess substrates should be avoided. In esterification, excess amounts of either carboxylic acids or alcohols are normally needed. We found that the direct condensation of equimolar amounts of carboxylic acids and alcohols could be achieved using hafnium(IV) or zirconium(IV) salts. These metal salts are highly effective as catalysts for the selective esterification of primary alcohols with carboxylic acids in the presence of secondary alcohols or aromatic alcohols. The present methods can be applied to direct polyesterification and may be suitable for large-scale operations.

Full text of DOI:10.1016/S0040-4020(02)00966-3

Tetrahedron 58 (2002) 8179–8188
Direct ester condensation from a 1:1 mixture of carboxylic acids
and alcohols catalyzed by hafnium(IV) or zirconium(IV) salts
†
,
*
Kazuaki Ishihara, Masaya Nakayama, Suguru Ohara and Hisashi Yamamoto
Graduate School of Engineering, Nagoya University, SORST, Japan Science and Technology Corporation (JST), Chikusa,
Nagoya 464-8603, Japan
Received 22 March 2002; accepted 7 May 2002
Abstract—To promote atom efficiency in synthesis and to avoid the generation of environmental waste, the use of stoichiometric amounts of
condensing reagents or excess substrates should be avoided. In esterification, excess amounts of either carboxylic acids or alcohols are
normally needed. We found that the direct condensation of equimolar amounts of carboxylic acids and alcohols could be achieved using
hafnium(IV) or zirconium(IV) salts. These metal salts are highly effective as catalysts for the selective esterification of primary alcohols with
carboxylic acids in the presence of secondary alcohols or aromatic alcohols. The present methods can be applied to direct polyesterification
and may be suitable for large-scale operations. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
(calcium hydride in a Soxhlet thimble) for 1.5 h (condition
3m,n
A in Table 1). Both ZrCl4
effective catalysts for the present reaction (entries 5, 6, 12,
and HfCl4 were highly
Replacing current chemical processes with more environ-
mentally benign alternatives is an increasingly attractive
subject.1 Esterification is one of the most fundamental and
important reactions in organic synthesis.2 Although several
methods have been explored and developed,2 the use of
large amounts of condensing reagents and activators should
be avoided to promote green chemistry and atom efficiency.
The direct condensation of carboxylic acids with alcohols
using small amounts of catalysts is the most ideal method,
but in most cases, large excess amounts of either carboxylic
acids or alcohols are used in this condensation to give esters
in high yield.3 We describe highly efficient and direct ester
condensation using equimolar amounts of carboxylic acids
and alcohols catalyzed by Hf(IV)4 or Zr(IV) salts.5
3i
and 13). While Zr(Oi-Pr)4 and Hf(Ot-Bu)4 were also
effective catalysts (entries 7 and 16), their metal(IV)
hydroxides and oxides were inert (entries 9, 10, and 18).
Although Ti(IV)3h,i and Sn(IV)3j–l salts are well known to
be good esterification catalysts, their catalytic activities
were lower than those of Hf(IV) and Zr(IV) salts (entries
1–4). Various other metal salts and organometallics such as
3,4,5-F3C6H2B(OH)2,6 BCl3,3d,e AlCl3,3f SiCl4,3g ScCl3,
Sc(OTf)3,7 FeCl3, CoCl2, NiCl2, ZnCl2, GaCl3, GeCl4,
SbCl5, LaCl3, and PbCl2 were either less active or inert.
Next, to identify esterification catalysts with a high turnover
frequency (TOF), several metal salts, which were suggested
by the above screening, were examined again for the same
reaction as above under different conditions (reflux for 12 h
in the presence of 1 mol% of catalysts; condition B in Table
1). As expected, ZrCl4·(THF)2, Zr(Oi-Pr)4, HfCl4·(THF)2,
Cp2HfCl2, and Hf(Ot-Bu)4 gave the corresponding esters
quantitatively (entries 6, 7, 13, 14, and 16), while Sn(IV)
gave only a low yield (entry 1). Cp2HfCl2 was gradually
decomposed during the esterification (entry 14). Interest-
ingly, Ti(IV) gave better results than other metal halides and
metal alkoxides, except Hf(IV) and Zr(IV) (entries 3 and 4).
2. Results and discussion
2.1. Catalytic activities of metal salts for direct ester
condensation
We first investigated the catalytic activities of various metal
salts (10 mol%) which promote the model reaction of
4-phenylbutyric acid (1 equiv.) with benzyl alcohol
(1 equiv.) in toluene at reflux with the removal of water
Green catalysts require not only high catalytic activity and
atom efficiency, but also low toxicity, low cost, and ease of
handling. Fortunately, Hf(IV) and Zr(IV) compounds
generally have low toxicity (LD50 [HfCl4, oral, rat]¼2400
mg kg21; LD50 [ZrCl4, oral, rat]¼1688 mg kg21), and are
not considered particularly poisonous.8 Commercially
available HfCl4·(THF)2 and ZrCl4·(THF)2 are hydrolytically
Keywords: hafnium(IV); zirconium(IV); direct ester condensation;
esterification; chemoselective; catalysts; dehydration.
*
Corresponding author. Tel.: þ81-52-789-3331; fax: þ81-52-789-3222;
e-mail: yamamoto@cc.nagoya-u.ac.jp; yamamoto@uchicago.edu
Present address: Department of Chemistry, University of Chicago, 5735
South Ellis Avenue, Chicago, 60637, USA.
†
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00966-3

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K. Ishihara et al. / Tetrahedron 58 (2002) 8179–8188
Table 1. Direct esterification of 4-phenylbutyric acid and benzyl alcohol under different conditions
Entry
Catalyst
Yield (%)
Condition Aa
Condition Bb
1
2
SnCl4
SnBr4
34
12
48
–
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
TiCl4
Ti(Oi-Pr)4
ZrCl4
ZrCl4·(THF)2
Zr(Oi-Pr)4
ZrOCl2·8H2O
Zr(OH)4
ZrO2
28
34
77
84
74
–
Trace
Trace
Trace
83
73
82
–
99
97
53
–
–
–
–
.99
.99
–
.99
–
–
–
–
HfF4
HfCl4
HfCl4·(THF)2
Cp2HfCl2
CppHfCl3
Hf(Ot-Bu)4
HfOCl2
HfO2
Hf(OTf)4
Sc(OTf)3
82
76
51
82
35
Trace
Tracec
Tracec
The esterification of 4-phenylbutyric acid (1 mmol) and benzyl alcohol (1 mmol) in toluene (5 mL) was carried out in a flask fitted with a pressure-equalized
addition funnel (containing a cotton plug and ,1 g of calcium hydride and acting as a Soxhlet extractor) surmounted by a reflux condenser under argon.
For A, the reaction mixture was heated under reflux conditions in the presence of 10 mol% of catalyst for 1.5 h.
a
b
For B, the reaction mixture was heated under reflux conditions in the presence of 1 mol% of catalyst for 12 h.
2- and 4-Benzyltoluenes were obtained quantitatively by dehydrative coupling of benzyl alcohol and toluene.
c
more stable and less expensive than the corresponding
metal(IV) alkoxides. The ability of HfCl4, ZrCl4, and their
THF complexes to tolerate water was investigated by
comparing their catalytic activities to those upon exposure
to air (Table 2). As expected, the coordination of THF to
HfCl4 and ZrCl4 effectively showed their hydrolysis. Thus,
Hf(IV) was shown to be the most effective metal catalyst for
direct esterification.
NMR analysis (Fig. 1). We found that heating the reaction
mixture in toluene under azeotropic reflux conditions to
remove water through a Soxhlet thimble with molecular
˚
sieves 4 A gave the best result. However, heating the
reaction mixture without solvents at the same temperature
as above was less effective, and the reaction rate was
reduced after ,2 h. A similar tendency was observed in
control experiments in the absence of any catalysts. These
experimental results indicate that not only catalytic activity
but also the efficiency of water removal are highly
significant for the present esterification system.
To optimize the reaction conditions regarding the removal
of water and solvents for the esterification of 4-phenyl-
butyric acid with cyclohexanol in the presence of 0.2 mol%
of HfCl4·(THF)2, the percentage of cyclohexanol condensed
To explore the generality and scope of the above Hf(IV)-
catalyzed esterification, the reaction was examined with
1
with 4-phenylbutyric acid over time was evaluated by H
Table 2. Water tolerability of esterification catalysts
Duration
(h) of exposure to aira
Conversion
(%) to cyclohexyl 4-phenylbutyrate
HfCl4
HfCl4·(THF)2
ZrCl4
ZrCl4·(THF)2
0
40
47.5
60
65
96
137
74
–
63
31
–
71
70
71
68
67
65
61
71
65
49
8
5
5
69
75
–
–
65
62
48
–
–
–
a
Catalysts were exposed to air (ca. 50% humidity) at 208C.

K. Ishihara et al. / Tetrahedron 58 (2002) 8179–8188
8181
Figure 1. The percentage of cyclohexanol condensed with 4-phenylbutyric acid over time under different conditions was evaluated by 1H NMR, from the
integration ratio of the protons of cyclohexanol and the esterification product, cyclohexyl 4-phenylbutyrate.
various structurally diverse carboxylic acids and alcohols
(Table 3). Less than 0.2 mol% of HfCl4·(THF)2 was suitable
for condensing various carboxylic acids with not only
primary alcohols but also sterically hindered secondary
alcohols. However, esterification with tertiary alcohols
did not proceed (entry 6). Although aromatic substrates
such as benzoic acid and phenol were less reactive than
aliphatic substrates, their reactions proceeded very well
when o-xylene or mesitylene was used instead of toluene or
the amount of HfCl4·(THF)2 was increased to 1 mol%
(entries 7 and 12). ZrCl4·(THF)2 could be used
instead of HfCl4· (THF)2 under the same conditions (entries
1 and 2).
as methanol (Eq. (1)). The reaction proceeded in alcohols at
room temperature (rt) without the removal of water.
ð1Þ
To demonstrate the effectiveness of Hf(IV) salts as
esterification catalysts, polyesters were synthesized by
polycondensing v-hydroxy carboxylic acids or equimolar
amounts of aliphatic dicarboxylic acids and aliphatic diols
in the presence of 0.2 mol% of HfCl4·(THF)2 in o-xylene
with the removal of water for 1 day.11 In most cases,
polycondensation proceeded quantitatively (Table 5).
Although no polycondensation of aromatic dicarboxylic
acids and aromatic diols occurred due to the insolubility of
aromatic carboxylic acids in o-xylene and the lower
nucleophilicity of aromatic diols, polycondensation to
semiaromatic polyesters proceeded successfully.
Moreover, the HfCl4·(THF)2-catalyzed esterification reac-
tion was examined with various functionalized carboxylic
acids and alcohols (Table 4). a,b-Unsaturated alcohols
(entries 1 and 2), a,b-unsaturated carboxylic acids (entries
11–17), and acid-sensitive substrates (entries 3–6 and 20)
such as a benzylic secondary alcohol, a tetrahydropyranyl
(THP) ether, a tert-butyldimethylsilyl ether, a nitrile, and
tetrahydro-2-furoic acid, could all be used under these
conditions. In particular, the resulting a,b-unsaturated
esters are industrially important polymer materials. Besides
these examples, cyclopropanecarboxylic acid, 4-nitro-
phenylacetic acid, a-alkoxycarboxylic acids and a
perfluorocarboxylic acid could also be used (entries 10,
18, 19, and 21). Notably, direct thioesterifications pro-
ceeded quantitatively in the presence of 5 mol% of
HfCl4·(THF)2 or ZrCl4 (entries 7–9).9
2.2. Selective esterification of primary alcohols in the
presence of secondary alcohols or aromatic alcohols
Selective esterification of primary alcohols in the presence
of secondary alcohols is often required. Several sophisti-
cated and relatively expensive reagents have been
developed for this purpose.12–14 However, the use of large
amounts of condensing reagents or activators and the use of
highly toxic or hazardous reagents and solvents such as
antimony compounds, tin compounds, acyl halides, and
dichloromethane should be avoided to promote atom
Furthermore, HfCl4·(THF)2 was highly effective for the
esterification of carboxylic acids with volatile alcohols such

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K. Ishihara et al. / Tetrahedron 58 (2002) 8179–8188
Table 3. Direct esterification of carboxylic acids with alcohols catalyzed by HfCl4·(THF)2
Entry
RCO2H
ROH
HfCl4·(THF)2 (mol%)a
Time (h)
Yield (%)
1b
2b
3d
0.1
18
18
24
.99
99
ZrCl4·(THF)2 (0.1)c
0.2
EtC(CH2OH)3
.99
4
0.2
5
94 (36)e
5
l-Menthol
Et3COH
PhOH
0.2
1.0
0.2
36
24
36
.99
0
6
7f
91
8
0.2
7
96
9
Et2CHCO2H
PhCO2H
0.2
0.2
60
15
98
92
10
11
0.2
1.0
0.2
10
24
10
92
12g
13
PhCO2H
3,5-Me2C6H3OH
95
96h
14
0.2
10
94h
Unless otherwise noted, the esterification of carboxylic acid (10 mmol) with alcohol (10 mmol) in toluene (2 mL) was carried out in a flask fitted with a
˚
pressure-equalized addition funnel (containing a cotton plug and ca. 1.5 g of molecular sieves 4 A (pellets) and acting as a Soxhlet extractor) surmounted by a
reflux condenser under argon.
a
Values on the basis of hydroxy groups in alcohols are indicated.
Toluene (5 mL) was used.
ZrCl4·(THF)2 was used instead of HfCl4·(THF)2.
4-Phenylbutyric acid (36 mmol) and toluene (4 mL) were used.
Data for the uncatalyzed reaction are indicated.
o-Xylene (2 mL) was used.
1,3,5-Mesitylene (2 mL) was used.
Yield of lactones is indicated.
b
c
d
e
f
g
h
efficiency and reduce the generation of environmental
waste. To the best of our knowledge, there are no reported
catalytic methods for the selective ester condensation of
primary alcohols with carboxylic acids. We describe an
extremely simple and environmentally benign procedure for
the selective esterification of primary alcohols in the
presence of secondary alcohols catalyzed by HfCl4·(THF)2
or ZrCl4·(THF)2.5b
but also chemoselectivity (entry 1 versus entries 2 and 3).
The low chemoselectivity observed in the reaction catalyzed
by TiCl4 may be ascribed to transesterification.
Actually, Ti(IV) salts are known to be good catalysts for the
transesterification of esters with alcohols.10 Surprisingly,
HfCl4·(THF)2 and ZrCl4·(THF)2 did not catalyze the
transesterification at all (Eq. (2)). These experimental
results can be understood by assuming that the active
intermediates that are generated in esterification are Hf(IV)
carboxylates, Zr(IV) carboxylates, and Ti(IV) alkoxides,
respectively. However, their roles are still not clear.
The substantial difference in reaction rates between primary
and secondary alcohols in Hf(IV)-catalyzed esterification
prompted us to examine the selective esterification of a
primary alcohol in the presence of a secondary alcohol.
First, we chose to investigate the selectivity in the
esterification of a 1:1 mixture of 1-octanol and cyclohexanol
with several carboxylic acids in the presence of 2 mol% of
HfCl4·(THF)2. Some of our results, summarized in Table 6,
strongly suggest that the steric hindrance of carboxylic acid
plays a crucial role in the chemoselectivity of the reaction.
The use of 1-adamantanecarboxylic acid gave the 1-octyl
ester in .99% selectivity and quantitative yield (entry 5). A
similar chemoselectivity and reactivity were observed using
ZrCl4·(THF)2 (entry 6). Interestingly, TiCl4 was inferior to
HfCl4 and ZrCl4 with respect to not only catalytic activity
ð2Þ
To explore the generality and scope of the above selective
esterification catalyzed by HfCl4·(THF)2, the esterification
was examined with various structurally diverse primary
and secondary alcohols. Several features of the results

K. Ishihara et al. / Tetrahedron 58 (2002) 8179–8188
Table 4. Direct esterification of carboxylic acids with alcohols catalyzed by HfCl4·(THF)2
8183
Entry
RCO2H
ROH
HfCl4·(THF)2 (mol%)a
Time (h)
Yield (%)
1
2
0.2
0.2
6
97
92
24
3
0.2
13
.99
4
5
6
THOP(CH2)8OH
0.2
0.2
0.2
18
24
24
95
93
94
t-BuMe2SiO(CH2)8OH
7b
8b
9
5
5
24
17
24
17
97(,2)c
.99
n-C10H21SH
n-C12H25SH
n-C11H23CO2H
5
.99(93)d
95
10
0.2
11
0.2
1.0
1.0
1.0
10
38
38
38
92
.99
94
12e
13e
14e
.99
15e
16e
17e
1.0
1.0
1.0
45
40
40
.99
.99
99
18
1.0
0.2
18
13
98
98
19f
20
21
0.2
0.2
6
.99
C7F15CO2H
11
82
Unless otherwise noted, the esterification of carboxylic acid (10 mmol) with alcohol (10 mmol) in toluene (2 mL) was carried out in a flask fitted with a
˚
pressure-equalized addition funnel (containing a cotton plug and ca. 1.5 g of molecular sieves 4 A (pellets) and acting as a Soxhlet extractor) surmounted by a
reflux condenser under argon.
a
Values on the basis of hydroxy groups in alcohols are indicated.
1.2 equiv. of thiol was used.
Data for the uncatalyzed reaction are indicated.
ZrCl4 was used instead of HfCl4·(THF)2.
Benzene was used instead of toluene.
Enantiomerically pure carboxylic acid was used. The enantiomeric purity of the ester was 84%.
b
c
d
e
f
shown in Table 7 deserve comment: (1) the use of
1-adamantanecarboxylic acid generally gave primary alkyl
esters in high selectivity and in high yield (entries 4 and 6),
and (2) primary alcohols were esterified in high selectivity
with even less bulky 4-phenylbutyric acid in the presence of
aromatic alcohols (entries 7 and 8). It has been reported that
aromatic alcohols are predominantly acylated in the
presence of aliphatic alcohols under basic or nucleophilic
conditions.7 On the other hand, we recently found that
aliphatic alcohols were chemoselectively acylated with
carboxylic anhydrides in the presence of catalytic amounts
of Sc(OTf)3.7 The present method is a green alternative to
the latter reaction.
As a logical extension of this methodology, we further
investigat ed the potential of HfCl4·(THF)2 as a catalyst for
the selective esterification of a less-hindered hydroxy group
in a series of structurally diverse primary–secondary diols.
The results are shown in Table 8. The distance between the
two hydroxy groups in the diols strongly affected the
reactivity: the reactivity and chemoselectivity for the
esterification increased in the order 1,2-, 1,3-, and 1,4-

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K. Ishihara et al. / Tetrahedron 58 (2002) 8179–8188
Table 5. Direct polyesterification catalyzed by HfCl4·(THF)2
Polyester
Yielda (%)
DPb
Mnb,c(/104)
Mwc(/104)
HO[CO(CH2)9O]nH
HO[CO(CH2)11O]nH
HO[CO(CH2)2CO2(CH2)6O]nH
HO[CO(CH2)7CO2(CH2)10O]nH
95
97 (88)d
98
.200
.200 (45)d
.200
1.82[.3.40]
3.40
7.24
3.87
5.83
2.77[.3.96] 2[(0.89)d]
2.24[.4.00]
2.69[.6.52]
97
.200
96e
.200e
2[.6.09]e
–
Unless otherwise noted, polyesterification was carried out in the presence of 0.2 mol% of HfCl4·(THF)2 for 1 day.
a
Isolated yield.
b
Average degrees of polymerization (DP) and Mn values in brackets were determined by 1H NMR.
Two linear TSK-gel-GMHXL GPC columns were used. The polymers were run at 0.2 wt% in THF at 408C with a polystyrene standard.
Data in parentheses are for the non-catalyzed thermal polyesterification.
The reaction was carried out in the presence of 1 mol% of HfCl4·(THF)2 for 4 days.
c
d
e
Table 6. Selective esterification of octanol in the presence of cyclohexanol
Entry
Catalyst
(mmol)
R2
Time
(h)
Yield
(%)a
Ratiob
(1/2)
(1þ2)
1
2
3
4
5
6
TiCl4 (0.02)
Ph(CH2)3
Ph(CH2)3
Ph(CH2)3
c-C6H11
1-Adamantyl
1-Adamantyl
10
5.5
5.5
10
11
11
.99
98
99
96
.99
97
66:34
88:12
89:11
93:7
.99:1
99:1
ZrCl4·(THF)2 (0.02)
HfCl4·(THF)2 (0.01)
HfCl4·(THF)2 (0.02)
HfCl4·(THF)2 (0.02)
ZrCl4·(THF)2 (0.02)
See Section 4.3.
a
Esters were purified as a mixture of 1 and 2 by flash column chromatography on silica gel.
Determined by 1H NMR.
b
Table 7. Selective esterification of primary alcohols in the presence of secondary alcohols or phenols
Entry
R0
R00
R2
Catalyst (mol%)
Yield (%)a (3þ4)
Ratiob (3/4)
1
2
3
4
5
6
7
8
Bn
Bn
Bn
Bn
n-C8H17
n-C8H17
n-C8H17
c-C6H11
PhMeCH
PhMeCH
PhMeCH
PhMeCH
2-C8H17
2-C8H17
p-MeC6H4
p-MeC6H4
Ph(CH2)3
Ph(CH2)3
c-C6H11
1-Adamantyl
Ph(CH2)3
1-Adamantyl
Ph(CH2)3
Ph(CH2)3
Zr(Oi-Pr)4 (2)
98
91
97
98
.99
96
94
84
89:11
94:6
96:4
98:2
96:4
.99:1
99:1
86:14
HfCl4·(THF)2 (0.5)
HfCl4·(THF)2 (2)
HfCl4·(THF)2 (2)
HfCl4·(THF)2 (0.5)
HfCl4·(THF)2 (2)
HfCl4·(THF)2 (2)
HfCl4·(THF)2 (2)
See Section 4.3.
a
Esters were purified as a mixture of 3 and 4 by flash column chromatography on silica gel.
Determined by 1H NMR.
b
diol. No esterification product was obtained by heating a 1:1
secondary monoesters was obtained in 79% yield. The
reaction of 1,5-hexanediol gave the primary ester with
.99% selectivity and in 94% yield. Production of the
corresponding diesters increased in the order 1,5-, 1,4-, and
1,3-diol. These experimental results suggest that an internal
acyl transfer between primary and secondary hydroxy
mixture of 1,2-butanediol and 1-adamantanecarboxylic acid
in toluene in the presence of 2 mol% of HfCl4·(THF)2. In the
reaction of 1,3-butanediol, a 72:28 mixture of primary and
secondary monoesters was obtained in 37% yield. In the
reaction of 1,4-pentanediol, a 95:4 mixture of primary and

K. Ishihara et al. / Tetrahedron 58 (2002) 8179–8188
Table 8. Selective esterification of the primary hydroxy group of primary–secondary diols
8185
Entry
Diol
Time
(h)
Yield
(%)a
(5þ6)
Ratiob
(5/6)
Yield
(%)
(7)
1
2
11
16
0
–
0
37
72:28
,10
3
4
5
16
16c
13
79
49c
94
95:4
,7
,23c
,4
72:28c
.99:1
See Section 4.3.
a
Esters were purified as a mixture of 5 and 6 by flash column chromatography on silica gel.
Determined by 1H NMR.
4-Phenylbutyric acid was used instead of 1-adamantanecarboxylic acid.
b
c
groups occurs in the reaction of diols.15,16 Interestingly, the
chemoselectivity in the reaction of 1,4-pentanediol with 4-
phenylbutyric acid was much lower than that with
1-adamantanecarboxylic acid, and the diesters were
relatively increased. This means that the steric bulkiness
of the adamantyl group suppressed internal acyl transfer. In
addition, the lower reactivity of diols may be due to tight
chelation between diols and Hf(IV).
Furthermore, HfCl4·(THF)2 was examined for the chemo-
selective esterification of structurally rigid diols which were
unable to chelate with Hf(IV) in a bidentate manner. In the
reaction of betulin with cyclohexanecarboxylic acid, the
primary monoester was obtained in 91% yield (Eq. (3)). In
the reaction of 3-(4-hydroxyphenyl)-1-propanol with
4-phenylbutylic acid, the primary monoester was obtained
in 93% yield (Eq. (4)).
ð4Þ
3. Conclusion
In direct esterification, the catalytic use of inorganic salts is
quite practical in view of its simplicity and applicability to
large-scale operations. Hf(IV) and Zr(IV) salts are
extremely active catalysts for direct esterification and
polycondensation to polyesters. Due to the ease of handling,
HfCl4·(THF)2 and ZrCl4·(THF)2, which are hydrolytically
more stable, are recommended as dehydration catalysts. The
present method offers considerable advantages in terms of
simplicity, high chemoselectivity, high atom efficiency, and
low environmental impact.
4. Experimental
4.1. General
ð3Þ
Infrared (IR) spectra were recorded on a Shimadzu FT-IR

8186
K. Ishihara et al. / Tetrahedron 58 (2002) 8179–8188
1
8100 spectrometer. H NMR spectra were measured on a
Varian Gemini-300 spectrometer. Tetramethylsilane was
4.3. General procedure for the selective esterification of
primary alcohols in the presence of secondary alcohols
or aromatic alcohols (Tables 6 and 7)
1
used as an internal standard for HNMR (d 0.00 ppm). For
thin layer chromatography (TLC) analysis throughout this
work, Merck precoated TLC plates (silica gel 60 GF254
,
A flame-dried, 5 mL, single-necked, round-bottomed flask
equipped with a Teflon-coated magnetic stirring bar and a
5 mL pressure-equalized addition funnel (containing a
cotton plug and calcium hydride (ca. 1 g)) surmounted by
a reflux condenser was charged with a primary alcohol
(2.2 mmol), a secondary alcohol (2.2 mmol), and a
carboxylic acid (2.0 mmol) as substrates and HfCl4·(THF)2
(0.04 mmol) as a catalyst in toluene (4 mL). The mixture
was brought to reflux with the removal of water. After
6–12 h, the resulting mixture was cooled to ambient
temperature and water (ca. 100 mL) was added. After
being stirred for 10 min, the resultant mixture was dried
over magnesium sulfate, filtered, and concentrated under
vacuum. The crude products were purified by flash column
chromatography on silica gel eluted with hexane–ethyl
acetate to provide the corresponding primary alkyl ester in
quantitative yield.
0.25 mm) were used. The products were purified by
preparative column chromatography on silica gel E. Merck
9385. Toluene, xylene, and mesitylene were freshly distilled
from calcium hydride. All materials, reagents and catalysts
were obtained commercially. Number average molecular
weights (Mn) were determined by gel phase chromatography
(GPC) on a Waters GPC-224 system equipped with a
refractive index detector and two linear TSK-gel-GMHXL
GPC columns. The mobile phase, tetrahydrofuran, was used
at a flow rate of 1.0 mL/min. Calibration was performed
with polystyrene standards. Values of Mn were also
determined from the relative area intensities of signals
from the polymer end groups to those of the repeat units.
The following obtained esters are known compounds:
benzyl 4-phenylbutyrate17 (Tables 1, 3, and 7), cyclohexyl
4-phenylbutyrate18 (Tables 2 and 7), l-menthyl 4-phenyl-
butyrate19 (Table 3), phenyl 4-phenylbutyrate20 (Table 3),
benzyl cyclohexanecarboxylate21 (Tables 3 and 7), benzyl
adamantanecarboxylate22 (Tables 3 and 7), 3,5-dimethyl-
phenyl benzoate23 (Table 3), cinnamyl 4-phenylbutyrate24
(Table 4), benzyl cyclopropanecarboxylate25 (Table 4),
benzyl (E,E)-2,4-hexadienoate26 (Table 4), benzyl croto-
nate27 (Table 4), benzyl 3,3-dimethylacrylate28 (Table 4),
benzyl p-nitrophenylacetate29 (Table 4), benzyl 2-methoxy-
phenylacetate30 (Table 4), benzyl tetrahydrofuroate31
(Table 4), benzyl perfluorooctanoate32 (Table 4), poly(10–
hydroxydecanoic acid)33 (Table 5), poly(12-hydroxy-
dodecanoic acid)34 (Table 5), poly(hexamethylene succi-
nate)35 (Table 5), poly(decamethylene azelate)36 (Table 5),
poly(decamethylene isophthalate)37 (Table 5), octyl 4-
4.3.1. 1,1,1-Tri(4-phenylbutyroxymethyl)propane (Table
3). IR (film) 3027, 1730, 1497, 1458, 1140, 747, 700 cm21
;
1H NMR (CDCl3) d 0.88 (t, J¼7.8 Hz, 3H), 1.46 (q,
J¼7.8 Hz, 2H), 1.93 (quintet, J¼7.8 Hz, 6H), 2.32 (t,
J¼7.8 Hz, 6H), 2.63 (t, J¼7.8 Hz, 6H), 4.01 (s, 6H),
7.17–7.28 (m, 15H). Anal. Calcd for C36H44O6: C, 75.50;
H, 7.74. Found: C, 75.56; H, 7.43.
4.3.2. Benzyl 2-ethylbutyrate (Table 3). IR (film) 2965,
1734, 1458, 1173, 1144, 749, 698 cm21; 1H NMR (CDCl3)
d 0.88 (t, J¼7.2 Hz, 6H), 1.46–1.73 (m, 4H), 2.22–2.32 (m,
1H), 5.13 (s, 2H), 7.25–7.37 (m, 5H). Anal. Calcd for
C13H18O2: C, 75.69; H, 8.79. Found: C, 75.64; H, 8.73.
phenylbutyrate38 (Tables
6 and 7), octyl cyclo-
hexanecarboxylate39 (Table 6), and octyl adamantane-
carboxylate40 (Table 7). The following obtained esters
are commercially available: benzyl benzoate (Table 3),
d-valerolactone (Table 3), 1-caprolactone (Table 3), benzyl
cinnamoate (Table 4), benzyl acrylate (Table 4), benzyl
methacrylate (Table 4), benzyl tiglate (Table 4), methyl
4-phenylbutyrate (Eq. (1)), and benzyl isovalerate
(Eq. (2)).
4.3.3. Phenylpropargyl 4-phenylbutyrate (Table 4). IR
(film) 1744, 1491, 1138, 756, 691 cm21; 1H NMR (CDCl3)
d 1.94–2.06 (m, 2H), 2.41 (t, J¼7.2 Hz, 2H), 2.68 (t,
J¼7.2 Hz, 2H), 2.90 (s, 2H), 7.19–7.50 (m, 10H). Anal.
Calcd for C19H18O2: C, 81.99; H, 6.52. Found: C, 81.96; H,
6.59.
4.3.4. 1-(Phenyl)ethyl 4-phenylbutyrate (Table 4). IR
(film) 1730, 1497, 1455, 1375, 1065, 1080, 750, 700 cm21
;
1H NMR (CDCl3) d 1.53 (d, J¼6.6 Hz, 3H), 1.95 (quintet,
J¼7.5 Hz, 2H), 2.35 (dd, J¼6.9, 8.1 Hz, 2H), 2.62 (t,
J¼8.1 Hz, 2H), 5.90 (q, J¼6.6 Hz, 1H), 7.13–7.36 (m,
10H). Anal. Calcd for C18H20O2: C, 80.56; H, 11.92. Found:
C, 80.59; H, 11.90.
4.2. General procedure for polycondensation reactions
(Table 5)
A flame-dried, 5 mL, single-necked, round-bottomed flask
equipped with a Teflon-coated magnetic stirring bar and a
5 mL pressure-equalized addition funnel (containing a
4.3.5. 8-(Tetrahydropyranyl-2-oxy)octyl 4-phenylbuty-
rate (Table 4). IR (film) 2936, 2857, 1736, 1455, 1140,
˚
cotton plug and molecular sieves 4 A (ca. 1.5 g))
1
surmounted by a reflux condenser was charged with
a,v-hydroxycarboxylic acid (10 mmol) or a,v-dicarboxylic
acid (10.0 mmol) and a,v-diol (10.0 mmol) as substrates
and HfCl4·(THF)2 (0.200 mmol) as a catalyst in o-xylene
(2 mL). The mixture was brought to reflux with the
removal of water. After 1 day, the resulting mixture
was cooled to ambient temperature, dissolved with
chloroform, and precipitated with acetone or methanol to
furnish pure polyester as a white solid in quantitative
yield.
1032, 700 cm21; H NMR (CDCl3) d 1.26–1.38 (br, 8H),
1.46–1.89 (m, 10H), 1.96 (quintet, J¼7.2 Hz, 2H), 2.32 (t,
J¼7.2 Hz, 2H), 2.65 (t, J¼7.2 Hz, 2H), 3.38 (dt, J¼9.6,
6.6 Hz, 1H), 3.46–3.54 (m, 1H), 3.73 (dt, J¼9.6, 6.6 Hz, 1H),
3.82–3.92 (m, 1H), 4.05 (t, J¼6.6 Hz, 2H), 4.55–4.59 (m,
1H), 7.16–7.22 (m, 3H), 7.27–7.32 (m, 2H). Anal. Calcd for
C23H36O4: C, 73.37; H, 9.64. Found: C, 74.61; H, 9.55.
4.3.6. 8-tert-Butyldimethylsiloxyoctyl 4-phenylbutyrate
(Table 4). IR (film) 2930, 2857, 1736, 1500, 1254, 1100,

K. Ishihara et al. / Tetrahedron 58 (2002) 8179–8188
8187
1
835 cm21; H NMR (CDCl3) d 0.00 (s, 6H), 0.85 (s, 9H),
1.30–2.20 (m, 22H), 3.73–3.86 (m, 1H), 4.06 (t, J¼6.6 Hz,
2H). Anal. Calcd for C17H28O3: C, 72.82; H, 10.06. Found:
C, 72.79; H, 10.11.
1.15–1.35 (br, 8H), 1.40–1.62 (m, 4H), 1.91 (quintet,
J¼7.2 Hz, 2H), 2.28 (t, J¼7.2 Hz, 2H), 2.61 (t, J¼7.5 Hz,
2H), 3.55 (t, J¼6.6 Hz, 2H), 4.01 (t, J¼6.6 Hz, 2H), 7.11–
7.18 (m, 3H), 7.22–7.27 (m, 2H). Anal. Calcd for
C24H42O3Si: C, 70.88; H, 10.41. Found: C, 70.92; H, 10.38.
4.3.14. Betulin cyclohexanecarboxylate (esterification to
a primary hydroxy group) (Eq. (3)). IR (CHCl3) 3700–
3250 (br), 2941, 1717 cm21; 1H NMR (CDCl3) d 0.65–2.00
(m, 53H), 2.24–2.38 (m, 1H), 2.38–2.50 (m, 1H), 3.16–
3.20 (m, 1H), 3.83 (d, J¼10.8 Hz, 1H), 4.26 (d, J¼10.8 Hz,
1H), 4.59 (s, 1H), 4.69 (s, 1H). Anal. Calcd for C37H60O3: C,
80.38; H, 10.94. Found: C, 80.41; H, 10.89.
4.3.7. 2-Cyanoethyl 4-phenylbutyrate (Table 4). IR (film)
1
1740, 1497, 1455, 1240, 1144, 1042, 749, 702 cm21; H
NMR (CDCl3) d 1.98 (quintet, J¼8.7 Hz, 2H), 2.39 (t,
J¼7.5 Hz, 2H), 2.64–2.71 (m, 4H), 4.26 (t, J¼6.3 Hz, 2H),
7.17–7.33 (m, 5H). Anal. Calcd for C13H15NO2: C, 71.87;
H, 6.96. Found: C, 71.92; H, 6.95.
4.3.15. 3-(p-Hydroxyphenyl)propyl 4-phenylbutyrate
1
(Eq. (4)). IR (film) 3600–3100 (br), 1734, 1516 cm21; H
4.3.8. S-Benzyl 4-phenylbutanethioate (Table 4). IR
1
NMR (CDCl3) d 1.86–2.01 (m, 4H), 2.34 (t, J¼7.2 Hz, 2H),
2.58–2.68 (m, 4H), 4.08 (t, J¼6.6 Hz, 2H), 5.09 (br, 1H),
6.74–6.78 (m, 2H), 7.01–7.06 (m, 2H), 7.17–7.22 (m, 3H),
7.26–7.32 (m, 2H). Anal. Calcd for C19H22O3: C, 76.48; H,
7.43. Found: C, 76.51; H, 7.40.
(film) 1686, 1497, 1456, 698 cm21; H NMR (CDCl3) d
2.00 (quintet, J¼7.2 Hz, 2H), 2.58 (t, J¼7.2 Hz, 2H), 2.65
(t, J¼7.2 Hz, 2H), 4.12 (s, 2H), 7.14–7.34 (m, 10H). Anal.
Calcd for C17H18OS: C, 75.52; H, 6.71. Found: C, 75.58; H,
6.69.
4.3.9. S-Decyl 4-phenylbutanethioate (Table 4). IR (film)
2926, 1680, 1497, 994, 745 cm21; 1H NMR (CDCl3) d 0.87
(t, J¼6.0 Hz, 3H), 1.20–1.40 (br, 14H), 1.50–1.65 (m, 2H),
1.99 (quintet, J¼7.2 Hz, 2H), 2.57 (t, J¼7.2 Hz, 2H), 2.65
(t, J¼6.6 Hz, 2H), 2.87 (t, J¼6.6 Hz, 2H), 7.15–7.25 (m,
3H), 7.25–7.33 (m, 2H). Anal. Calcd for C20H32OS: C,
74.94; H, 10.06. Found: C, 74.93; H, 10.02.
References
1. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice. Oxford University: Oxford, 1988.
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4.3.10. S-Dodecyl dodecanoate (Table 4). IR (KBr) 2919,
1
2849, 1696, 1471, 1464, 963 cm21; H NMR (CDCl3) d
0.88 (t, J¼6.3 Hz, 6H), 1.25 (br, 34H), 1.50–1.70 (m, 4H),
2.53 (t, J¼7.5 Hz, 2H), 2.86 (t, J¼7.2 Hz, 2H). Anal. Calcd
for C24H48OS: C, 74.93; H, 12.58. Found: C, 74.89; H,
12.60.
4.3.11. A 72:28 mixture of 1-adamantanecarboxy-3-
hydroxybutane and 3-adamantanecarboxy-1-hydroxy-
butane (Table 8). IR (film) 3700–3100 (br), 1720, 1455,
1271, 1238, 1078, 783 cm21
;
1H NMR (CDCl3) for
1-adamantanecarboxy-3-hydroxybutane d 1.20–2.20 (m,
21H), 3.48–3.59 (m, 1H), 3.60–3.67 (m, 1H), 5.10 (ddt,
J¼3.3, 16.2, 6.3 Hz, 1H); 1H NMR (CDCl3) for
3-adamantanecarboxy-1-hydroxybutane d 1.20–2.20 (m,
21H), 3.78–3.92 (m, 1H), 4.05–4.12 (m, 1H), 4.33–4.41
(m, 1H). Anal. Calcd for C15H24O3: C, 71.39; H, 9.59.
Found: C, 71.44; H, 9.56.
4.3.12. A 95:4 mixture of 1-adamanetanecarboxy-4-
hydroxypentane and 4-adamanetanecarboxy-1-hydro-
xypentane (Table 8). IR (film) 3700–3100 (br), 2907,
1728, 1705, 1456, 1237, 1078 cm21; 1H NMR (CDCl3) for
1-adamanetanecarboxy-4-hydroxypentane d 1.20–2.20 (m,
23H), 3.84–2.59 (m, 1H), 3.60–3.67 (m, 1H), 5.10 (ddt,
J¼3.3, 16.2, 6.3 Hz, 1H); 1H NMR (CDCl3) for
4-adamanetanecarboxy-1-hydroxypentane d 1.20–2.20 (m,
23H), 3.66 (t, J¼6.3 Hz, 2H), 4.88–4.95 (m, 1H). Anal.
Calcd for C16H26O3: C, 72.14; H, 9.84. Found: C, 72.48; H,
9.89.
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