Efficient and selective formation of mixed acetals by Nafion-H SAC-13 silica nanocomposite solid acid catalyst

Article abstract of DOI:10.1081/SCC-200032419

Various types of hydroxy compounds can readily be converted to the corresponding mixed acetals with dialkoxymethanes in the presence of SAC-13 solid superacid. The transformation is almost instantaneous, product acetals are isolated in good to excellent yields, and the catalyst can be reused with minor loss of activity. Comparative studies were also carried out with p-toluenesulfonic acid and BF₃·OEt₂.

Full text of DOI:10.1081/SCC-200032419

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Efficient and Selective
Formation of Mixed Acetals
by Nafion‐H SAC‐13 Silica
Nanocomposite Solid Acid
Catalyst
István Ledneczki a & Árpád Molnár a
a Department of Organic Chemistry, University of
Szeged, Dóm tér 8, Szeged, H‐6720, Hungary
Version of record first published: 19 Apr 2010.
To cite this article: István Ledneczki & Árpád Molnár (2004): Efficient and
Selective Formation of Mixed Acetals by Nafion‐H SAC‐13 Silica Nanocomposite
Solid Acid Catalyst, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:20, 3683-3690
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 20, pp. 3683–3690, 2004
Efficient and Selective Formation of Mixed
Acetals by Nafion-H SAC-13 Silica
Nanocomposite Solid Acid Catalyst
´
Istvan Ledneczki and Arpad Molnar
*
´
´
´
´ ´
Department of Organic Chemistry, University of Szeged, Dom ter 8,
Szeged H-6720, Hungary
ABSTRACT
Various types of hydroxy compounds can readily be converted to the
corresponding mixed acetals with dialkoxymethanes in the presence of
SAC-13 solid superacid. The transformation is almost instantaneous,
product acetals are isolated in good to excellent yields, and the catalyst
can be reused with minor loss of activity. Comparative studies were
.
also carried out with p-toluenesulfonic acid and BF3 OEt2.
Key Words: Dialkoxymethanes; Hydroxy compounds; Mixed acetals;
Nafion SAC-13; Protecting groups; Superacid.
´
Correspondence: Arpad Molnar, Department of Organic Chemistry, University of
*
´
´ ´
Szeged, Dom ter 8, Szeged H-6720, Hungary; E-mail: amolnar@chem.u-szeged.hu.
´
3683
DOI: 10.1081/SCC-200032419
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

´
Ledneczki and Molnar
3684
INTRODUCTION
The use of solid catalysts in organic synthesis and in the industrial man-
ufacture of chemicals is of increasing importance, because they provide green
alternatives to homogeneous catalysts. This is particularly important in acid
catalysis, where solid acids can be the safe alternatives of such hazardous
and corrosive materials as hydrofluoric acid (HF), sulfuric acid, and nitric acid.
Nafion resins, that is, perfluorinated resinsulfonic acid-based ion-
exchanged polymers, have been widely used in organic synthesis.[1,2]
Recently, a new type of Nafion, a silica nanocomposite material, has
become commercially available (SAC-13, the product of Aldrich). Increased
activity of such Nafion silica nanocomposites has been reported,[3,4] which
results from the large surface area (150–500 m2 g21) and the presence of
small (,100 nm) Nafion particles entrapped in the porous silica framework.
SAC-13 has recently been found to be an efficient catalyst in acylations[5,6]
and the hetero-Michael addition.[7]
We have chosen to test this catalyst in the preparation of mixed acetals,
which have a number of utilizations in organic synthesis. Namely, they are
used in the synthesis of isochromans and phtalans,[8] and may also be used
as aldehyde[9] or ester equivalents.[10] Most important is the common practice
of protecting alcohols as methoxymethyl ethers prepared in an acid-catalyzed
process.[11] The reagents employed for this purpose could be either chloro-
methyl methyl ether or dimetoxymethane. The use of the latter is more
desirable because of the strong carcinogenicity of chloromethyl methyl
ether.[12–15] Higher homologs, however, are rarely applied in synthesis
protocols.[16] A further example is our recent paper describing the use of
higher dialkoxymethanes in the N-alkoxymethylation of carboxamides.[17]
Solid acids, including Nafion-H, have also been applied in this process.[14,16]
RESULTS AND DISCUSSION
We found that when applying Nafion-H SAC-13 silica nanocomposite
solid acid catalyst in the transformation of various primary and secondary
alcohols (open chain and cyclic compounds and a sterol) with four different
dialkoxymethanes (dimethoxy-, diethoxy-, diisopropoxy-, and dibutoxy-
methane), the desired mixed acetals are rapidly formed at reflux temperature
(Sch. 1, Table 1). Following the original observation given in Ref.[14], reac-
tions were run for 10 h (primary alcohols) and 16 h (secondary alcohols). In
later experiments, gas chromatography (GC) and thin-layer chromatography
(TLC) analyses indicated the disappearance of the starting alcohol in a
short time. In fact, product formation is almost instantaneous, and complete

Efficient and Selective Formation of Mixed Acetals
3685
Scheme 1.
conversions are usually achieved in 5 min. The reaction is an SN2-type
substitution of the protonated acetal by the reacting alcohol (Sch. 2, route a).
The transformation is less straightforward for more hindered and tertiary
alcohols. The reaction of 2-methylhexan-2-ol (data not shown) is nonselective,
giving a range of products in low yields. In contrast, 1-phenylethanol (Entry 18)
and adamantan-1-ol (Entry 20) undergo etherification. As observed in the early
study with Nafion-H,[14] this transformation can be highly selective for the latter
compound and was attributed to steric hindrance. It may be surmised, however,
that the reacting alcohol, in these cases, undergoes protonation to form the
corresponding stable benzylic or tertiary carbocation. These, then, are attacked
by the nonprotonated acetal; that is, an SN1-type substitution takes place (Sch. 2,
route b). Benzyl alcohol, which can also give the stable benzylic carbocation,
however, is a nonhindered alcohol and exhibits the usual selectivity to form
the corresponding mixed acetals in high yields (Entry 7). This behavior
clearly indicates the role of steric hindrance in ether formation.
As data in Table 1 show, the best yields of the mixed acetals can be
achieved in almost all cases with diisopropoxy- and dibutoxy-methanes,
particularly for primary alcohols. This is attributed to the fact that in these
cases, reactions are carried out without solvent, in an excess of the reagent,
at the boiling point of the corresponding formal. In contrast, the boiling
points of dimethoxymethane (428C) and diethoxymethane (898C) are much
lower, which does not allow for the reactions to be carried out at the
optimum temperatures. However, when an appropriate cosolvent is used,
yields can be increased substantially. In the reaction of dimethoxymethane,
benzene proved to be the ideal solvent for primary alcohols, whereas toluene
appears to be the solvent of choice when working with diethoxymethane
(Entries 1, 4, and 7), particularly for secondary alcohols (Entries 9 and 12).
Catalyst recycling was also studied. It was found that SAC-13 maintains
high activity even after five consecutive runs (an activity drop of about 5–10%
was observed), provided the catalyst is washed with a polar solvent (ethanol)
after each successive run.
According to the results of comparative studies with traditional catalysts
in the homogeneous phase, p-toluenesulfonic acid gives results similar
to SAC-13, except that the reaction time is somewhat longer (30 min).
.
In contrast, yields and selectivities with BF3 OEt2 are usually inferior to

Table 1. Formation of mixed acetals (data indicate isolated yields).
R0
Entry
R
Catalyst
Me
Et
iPr
Bu
1
2
1-Octyl
SAC-13
p-TsOH
.
BF3 OEt2
62/96a
81
77
85/89b
85
86
85/86b
85
90
100
100
96
99
99
84
91
99
89
94
82
88
92
94
100
100
3
Nonselective
100
4
2-Phenylethyl
SAC-13
p-TsOH
.
BF3 OEt2
70/94a
84
5
100
Nonselective
6
91
7
Benzyl
2-Octyl
SAC-13
p-TsOH
SAC-13a
p-TsOHa
62/90a
27/81a
68/72b
66
87
89
58/79b
58
66
70/83b
68
75
98
99
8
9
88
10
11
12
13
14
83
Nonselective
85
.
BF3 OEt2
57
Cyclohexyl
SAC-13a
76/78b
89
61
p-TsOHa
86
Nonselective
.
BF3 OEt2

15
16
17
18
19
20
21
22
Cholesteryl
SAC-13a
77
80
70
79
67
32
71
7
97
86
83
58
p-TsOHa
.
BF3 OEt2
78
17
81
1-Phenylethyl
1-Adamantyl
SAC-13a
p-TsOHa
SAC-13f
p-TsOHf
5(81c þ 6d)
4(76c þ 14d)
3(93c)
33(3c)
5
0(20c þ 21e þ 59e)
85(8c þ 7d)
10(77c)
42(58c)
84(16c)
20(6c)
16(5c)
0(53c)
7
48(2c)
14(50c)
.
BF3 OEt2
9
aReaction in benzene cosolvent.
bReaction in toluene cosolvent.
cThe corresponding ether of the starting material.
dStyrene.
eUnidentified compounds.
fReactions in chloroform cosolvent.

´
Ledneczki and Molnar
3688
Scheme 2.
those found for the other two catalysts, particularly in the transformation with
dibutoxymethane. This may be attributed to the high reaction temperature,
.
which results in side reactions and the loss of the BF3 OEt2 catalyst due to
its high volatility.
As mentioned, the selectivity of acetal formation is sensitive to reaction
temperature. When working at higher temperatures, we observed the forma-
tion of symmetrical acetals (Table 2). As time dependence of product compo-
sition showed, this is a consecutive reaction step; that is, the initial product
mixed acetals react further with a second molecule of alcohol (Sch. 2, route c).
In summary, we demonstrated that SAC-13 is a highly reactive and
selective catalyst in the formation of mixed acetals in the reaction of alcohols
with dialkoxymethanes. The fast reaction, easy handling, simple workup of
Table 2. Temperature dependence of selectivity of acetal formation in the transform-
ation of 2-phenylethanol.
Diisopropoxymethane
SAC-13 p-TsOH
Dibutoxymethane
Temperature
SAC-13
p-TsOH
1008C
1208C
1788C
99
51/49a
—
99
100
—
91/9a
100
—
67/33a
92/8a
—
aRatio of mixed acetal to symmetric acetal.

Efficient and Selective Formation of Mixed Acetals
3689
the reaction mixture and the possibility of recycling make this new solid acid
the catalyst of choice in the title reaction.
EXPERIMENTAL
All compounds and catalysts were purchased from Aldrich and were
of appropriate purity to be used without further purification. Reaction
mixtures were analyzed by GC [HP 5890 GC, HP-1 column (50 m ꢀ
0.32 mm ꢀ 1.05 mm) flame ionization detector] and TLC. Product identifi-
cation was performed by means of gas chromatography-mass spectrometry
(GC-MS) (HP 5890 GC coupled with a HP 5970 mass selective detector).
In some cases, reaction mixtures were purified by column chromatography
[silica gel (Merck 60, 0.040–0.063 mm), hexane-ethyl acetate (7 : 3)] and
were analyzed by nuclear magnetic resonance (NMR) spectroscopy [Bruker
DRX 500 spectrometer at 500 MHz, CDCl3 as solvent and tetramethylsilane
(TMS) as an internal reference].
General Acetalization Procedure
A stirred solution of the alcohol (2 mmol) and the dialkoxymethane
(47 mmol) was stirred under reflux in the presence of SAC-13 (0.1 g) under
a dry atmosphere.[14] After completion of the reaction, the solid catalyst was
filtered off and washed with dialkoxymethane (or with the corresponding
cosolvent). Catalyst quantities in the homogeneous reactions were 8–10 wt% of
.
p-toluenesulfonic acid (calculated for the alcohol) or 2.4 mmol of BF3 OEt2.
The amounts of dialkoxymethanes were 47 mmol and 108 mmol, respectively.
The workup procedure in these cases included neutralization with 10%
NaHCO3 and washing with brine followed by drying (Na2SO4). In reactions
carried out in cosolvent (8 cm3 of benzene, toluene or chloroform in the case of
adamantanol), the quantity of dialkoxymethanes was decreased to 12 mmol.
ACKNOWLEDGMENT
This work was sponsored by the National Research Foundation of
Hungary (Grant OTKA T042603).
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Received in the UK December 12, 2003