Selective acylation of a sterically hindered hydroxyl group of unsymmetrical diols containing a primary hydroxyl group such as 1,5-hexanediol in the presence of silica gel with acetyl chloride

Article abstract of DOI:10.1002/poc.622

The selective acetylation of sterically hindered hydroxyl groups of 1,5-hexanediol preadsorbed on silica gel was reported. The relation between the adsorption of the diol on SiO₂ and its reactivity for selective acetylation was studied. Results demonstrated that unsymmetrical diols get adsorbed on the surface of SiO₂ preferentially via a primary OH group, leaving the non-adsorbed OH group available for reaction.

Full text of DOI:10.1002/poc.622

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2003; 16: 355–358
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/poc.622
Short Communication
Selective acylation of a sterically hindered hydroxyl
group of unsymmetrical diols containing a primary
hydroxyl group such as 1,5-hexanediol in the presence
of silica gel with acetyl chloride
Haruo Ogawa,1* Yuko Ide,1 Ryoichi Honda1 and Teiji Chihara2
1Department of Chemistry, Tokyo Gakugei University, Koganei Tokyo 184-8501, Japan
2Institute of Physical and Chemical Research (RIKEN), Wako, Saitama 351-0106, Japan
Received 10 September 2002; revised 24 January 2003; accepted 30 January 2003
ABSTRACT: The more hindered monoacetates were selectively formed in the presence of silica gel with acetyl
chloride by refluxing a suspension of unsymmetrical diols containing a primary hydroxyl group such as 1,5-
hexanediol preadsorbed on silica gel. Such regioselectivity was observed through preferential adsorption via a
primary hydroxyl group of the diols. Copyright  2003 John Wiley & Sons, Ltd.
KEYWORDS: monoacylation; monoacetylation; unsymmetrical diol; 1,5-hexanediol; silica gel; acetyl chloride;
adsorption isotherm
The application of solid adsorbents such as alumina and
silica gel (SiO2) as solid supports in organic synthesis
affords new procedures for selective reactions1–3 invol-
ving oxidation,4 alkylation,5 condensation,6 monomethyl
esterification7 and acetylation.8 The significant potential
of adsorbents can be recognized more fully for milder
reactions conditions and selective organic transforma-
tions. It is important for organic chemists to develop
methods that permit the selective protection or functio-
nalization of one functional group of a bi- or multiple-
functional molecule. Protection of hydroxyl groups by
acylation is common in organic syntheses. In the case of
polyols, monoprotection is achieved in some cases by
carefully controlled reaction conditions,9 continuous
extraction,10 the use of SiO2,11 alumina,12 phase-transfer
catalysts13 and insoluble polymer supports,14 or via the
formation of cyclic compounds.15 We have previously
reported selective monoacylation of symmetrical diols on
SiO2,11c and we chose here the acylation of unsymme-
trical diols because of the synthetic importance of this
procedure.9b Recently, several methods have been
developed for the selective acylation at the less hindered
site16 or at the more hindered site17 of an unsymmetrical
diol. We report here the direct and notably preferential
acetylation of sterically hindered hydroxyl groups of
diols on SiO2 and the relationship between the adsorption
of the diol 1,5-hexanediol and its reactivity for selective
acetylation.
Acetylation of unsymmetrical diols adsorbed on SiO2
was performed via the following method (adsorption
method) (Scheme 1). Alcohols were adsorbed on SiO2
(C-200, Wako Chemicals) as follows: 1 g of SiO2 was
added to an Et2O solution of the alcohol; solvent was then
eliminated under reduced pressure. The solid obtained
(adsorption sample) and acetyl chloride (AcCl) were
added to 50–100 ml of cyclohexane and refluxed for 2 h.
The reaction period of 2 h was sufficient for the reaction
to reach completion. After the reaction the mixture had
been filtered the solid was washed with distilled water
and DMF. The washings plus the filtrate were concen-
trated and the products were analyzed by GLC with
triphenylmethane as an internal standard. The products
were identified spectrometrically via comparison with
authentic samples.
The results of acylation of unsymmetrical diols are
listed in Table 1. Selectivity for the formation of
monoacetates is defined by
Smono ˆ 100‰yields of monoacetates=
ꢀyields of monoacetates ‡ yield of diacetate†Š
*Correspondence to: H. Ogawa, Department of Chemistry, Tokyo
Gakugei University, Koganei Tokyo 184-8501, Japan.
E-mail: ogawah@u-gakugei.ac.jp
Scheme 1
Copyright  2003 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2003; 16: 355–358

356
H. OGAWA ET AL.
Table 1. Selective monoacetylation of unsymmetrical diols
on SiO2
89.6% for Shind (entry 3). Breton et al. reported a
successful investigation using Al2O3 in 1,5-hexanediol,
a
recording values of 53% as the yield of monoacetates,
Entry Substrate
Yieldb (%)
Selectivity (%)
17a
68% for Smono and 46% for Shind
.
In our adsorption
c
d
method using Merck neutral Al2O3 (specific surface
area = 108 m2 À1), we obtained a 40.5% yield of
monoacetates, 62.4% for Smono and 25.8% for Shind
Smono
Shind
g
1
2
3
4
5
6
60.2e
56.0
69.2
56.6
52.8
51.9
78.0
64.2
87.3
78.2
69.1
54.0
69.8
48.9
89.6
71.4
36.0
35.1
.
(0°C)f
Different surface coverages of 1,5-hexanediol on Al2O3
would cause the different selectivities. SiO2 was an
effective adsorbent in our method to achieve direct and
notably selective acetylation of the sterically hindered
site of the diols.
(Kieselgel)g
(Mixing)h
(Homogeneous)i
7
8
83.3
99.9
78.1
51.9
58.2
87.4
99.9
88.8
74.7
99.2
38.4
71.8
32.6
96.5
73.4
The dependence of the surface coverage ꢀ of 1,5-
hexanediol on SiO2 on Shind was investigated (Fig. 1).
The saturation amount (ꢀ = 1) was estimated as 3.9 mmol
gÀ1 SiO2 by measurement of the adsorption isotherm,
discussed later. High selectivities were obtained, on the
whole, compared with that under homogeneous reaction
conditions. A slight increase in Shind was observed with
increase in ꢀ, and Shind showed a constant value of ca.
70% in the range of ꢀ values exceeding ca 0.3. The
inherent reactivities of the hydroxyl groups of alcohols
were evaluated under homogeneous reaction conditions
by competitive acylation of appropriate monofunctional
alcohols, 1-hexanol (primary), 2-hexanol (secondary)
and 3-methyl-3-pentanol (tertiary), in the absence of
pyridine. In general, a base such as pyridine is frequently
added to combine with the HCl formed during the
reaction, but it is not essential and is not always needed
for the reaction.18 The resulting reactivities decreased in
the order prim-OH >sec-OH, tert-OH (Table 2). The
reactivities changed on adsorption on SiO2 to the
following order: sec-OH, tert-OH >prim-OH. SiO2
suppressed the reactivity of primary OH. The relatively
weak adsorption of a counterpart of OH to prim-OH
would affect Shind in unsymmetrical diols. This seems to
lead to preferential acylation of sterically hindered OH
groups. Acetylation has the possibility of intramolecular
transfer of an acetyl group in the case of a 1,2-diol
9
10
11
a
An adsorption sample containing 0.3 mmol gÀ1 SiO2 of each alcohol was
refluxed for 2 h in cyclohexane with AcCl (1.5 equiv.). SiO2 [Wakogel C-
200, specific surface area (s) = 371 m2 gÀ1].
b
Combined yield of both isomeric monoacetates.
Selectivity for monoacetates: Smono = [monoacetates/(monoacetates ‡
c
diacetate)] Â 100.
d
Selectivity for sterically hindered monoacetate: Shind = (sterically hin-
dered monoacetate/monoacetates) Â 100.
e
An adsorption sample containing 2.0 mmol gÀ1 SiO2 of 1,5-hexanediol
was used.
f
Reaction period was 18 h.
g
SiO2 (Merck Kieselgel 60, s = 357 m2 gÀ1).
h
Mixing method: SiO2 (100 mg) was added to a 1,4-dioxane solution
(5.8 ml) of 1,5-hexanediol (23.6 mg, 0.20 mmol), and the suspension
obtained was refluxed for 2 h. A 0.20 mmol amount of 1,5-hexanediol
corresponds to 2.0 mmol gÀ1 of SiO2 loaded amount if all the diol adsorbs
on SiO2.
i
0.034 mol lÀ1 solution of 1,5-hexanediol in 1,4-dioxane in the presence of
pyridine (1 equiv.) was refluxed.
Selectivity for the formation of sterically hindered
monoacetate is defined by
Shind ˆ 100ꢀyield of sterically hindered monoacetate/
yields of monoacetates†
According to the adsorption method, high selectivities of
Smono were observed for the diols, and the corresponding
monoacetates were selectively formed. High selectivities
of Shind were also observed, and the corresponding
sterically hindered monoacetates were selectively ob-
tained except for the cases of 1,3-butanediol and 1,2-
hexanediol (entries 7 and 9). In the case of 1,5-hexanediol
as a model compound, both Smono and Shind were notably
improved compared with those in a homogeneous
reaction conditions (entry 6). The selectivities were not
significantly improved by the mixing method (entry 5).
Higher Smono and Shind were observed with higher loading
amounts and lower temperatures (entries 1 and 3). Merck
Kieselgel was also an effective adsorbent for this method
(entry 4). The highest selectivities were observed at a
reaction temperature of 0°C to give 87.3% for Smono and
Figure 1. Dependence of surface coverage of 1,5-hexane-
diol on selectivity Shind. The dashed line shows the value of
Shind in homogeneous reaction. Shind shows high selectivities,
on the whole, with a slight increase with increase in ꢀ
Copyright  2003 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2003; 16: 355–358

SELECTIVE ACYLATION OF STERICALLY HINDERED OH GROUPS
Table 2. Competitive acetylation of mono-olsa
357
area of the SiO2 used is 371 m2 gÀ1 by BET measure-
ment. Hence the saturation amount of 1,5-hexanediol
gives an estimation of E? of 3.9 mmol gÀ1 SiO2, whereas
E? is estimated as 2.9 mmol gÀ1 SiO2 in the case of the
compact adsorption of the alcohol in a bidentate fashion.
The good agreement between the isotherm and the
molecular modeling indicates that 1,5-hexanediol ad-
sorbs on the surface via a single OH group. The results of
a series of investigations imply that unsymmetrical diols
adsorb on the surface of SiO2 preferentially via a primary
OH group, leaving the non-adsorbed OH group available
for reaction. In addition, adsorption of the group on the
surface would create a sterically congested environment
which shields it from added reagents as suggested in
recent papers.1–3,7a,16d,17a,19 These would allow selective
monoacylation at the more sterically hindered, non-
adsorbed, site to give sterically hindered secondary and
tertiary monoacetates.
Methodb
Substratec
Relative reactivityd
primary: secondary: tertiary
Homogeneous 1° ‡ 2°
Homogeneous 1° ‡ 3°
1e:
1f:
1g:
1h:
0.75
1.69
0.67
1.38
Adsorption
Adsorption
1° ‡ 2°
1° ‡ 3°
a
Each experiment was carried out under reflux for 2 h with AcCl (1 equiv.)
in the absence of pyridine.
b
Homogeneous: homogeneous reaction (0.03 mol lÀ1 solution of each
alcohol in 1,4-dioxane). Adsorption: adsorption method (3.0 mmol gÀ1
SiO2 of each alcohol, ꢀ = 0.8).
c
1°, 1-hexanol; 2°, 2-hexanol; 3°, 3-methyl-3-pentanol.
d
Relative reactivity of each alcohol based on a yield of primary acetate.
e–h
Yields of 1-hexyl acetate correspond to
62.8%,
62.7%,
43.6% and
e
f
g
h
41.1%.
acetylation of 1-phenyl-1,2-ethanediol in homogeneous
reaction conditions, as shown in entry 6 in Table 1 at a
temperature 0°C, showed values 55.3% for Shind, and the
value of Shind was changed slightly by refluxing to 51.0%;
the transfer would occur under homogeneous reaction
conditions. Acetylation of 1-phenyl-1,2-ethanediol in a
homogeneous reaction under the same reaction condi-
tions as in entry 6 in Table 1 gave values of Smono and
Shind of 50.8% and 51.4%, respectively, and moreover the
reaction mixture was used in a reaction by the adsorption
method in the absence of AcCl. The composition of the
mixture did not change. This indicates that the transfer
does not proceed by an adsorption method.
The adsorption isotherm of 1,5-hexandiol on SiO2 in
1,4-dioxane showed Langmuir-type adsorption and
reached a saturation E? of 3.9 mmol gÀ1 SiO2 with an
adsorption constant Kad = 38 l molÀ1. Table 3 sum-
marizes the relative Kad for appropriate monofunctional
alcohols in addition to that for 1,5-hexanediol. A primary
alcohol interacts more easily with the surface of SiO2 and
adsorbs more preferentially than secondary and tertiary
alcohols. From molecular modeling, one molecule of 1,5-
hexanediol, adsorbed on the surface via a single OH
group with the free counterpart of the residue remote
from the surface, occupies 0.16 nm2. The specific surface
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