Graphene-catalyzed transacetalization under acid-free conditions

Article abstract of DOI:10.1016/j.tetlet.2016.09.022

1,2- and 1,3-Diols are readily protected as cyclic acetals and ketals through a graphene-catalyzed transacetalization process. The methodology features an atom economic procedure since quasi-stoichiometric conditions have been developed. Unlike prior systems, the graphene-catalyzed transacetalization is performed under Br?nsted and Lewis acid-free conditions and without solvent. Our method has been applied to several volatile compounds that are unsuitable for complex work-up and extensive purification steps. The very unusual catalytic properties of graphene for transacetalization reactions are ascribed to molecular charge transfer between graphene and substrates.

Full text of DOI:10.1016/j.tetlet.2016.09.022

Tetrahedron Letters 57 (2016) 4637–4639
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Graphene-catalyzed transacetalization under acid-free conditions
Medy C. Nongbe a,b, Nicolas Oger a, Tchirioua Ekou b, Lynda Ekou b, Benjamin K. Yao c, Erwan Le Grognec a,
François-Xavier Felpin a,d,
⇑
a Université de Nantes, UFR des Sciences et des Techniques, CNRS UMR 6230, CEISAM, 2 rue de la Houssinière, 44322 Nantes Cedex 3, France
b Université Nangui Abrogoua, Laboratoire de Thermodynamique et de Physico-Chimie du Milieu, 02 BP 801 Abidjan 02, Cote d’Ivoire
c Institut National Polytechnique Houphouët BOIGNY, Laboratoire de Procédés Industriels, de Synthèse, de l’Environnement et des Energies Nouvelles, Bp 1093 Yamoussoukro,
Cote d’Ivoire
d Institut Universitaire de France, 1 rue Descartes, 75231 Paris Cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2016
Revised 31 August 2016
Accepted 6 September 2016
Available online 9 September 2016
1,2- and 1,3-Diols are readily protected as cyclic acetals and ketals through a graphene-catalyzed transac-
etalization process. The methodology features an atom economic procedure since quasi-stoichiometric
conditions have been developed. Unlike prior systems, the graphene-catalyzed transacetalization is per-
formed under Brønsted and Lewis acid-free conditions and without solvent. Our method has been applied
to several volatile compounds that are unsuitable for complex work-up and extensive purification steps.
The very unusual catalytic properties of graphene for transacetalization reactions are ascribed to molec-
ular charge transfer between graphene and substrates.
Keywords:
Graphene
Transacetalization
Diol
Ó 2016 Elsevier Ltd. All rights reserved.
Heterogeneous catalysis
Acid-free conditions
The formation of cyclic acetals and ketals for the transient
protection of 1,2- and 1,3-diols has been massively employed in
multi-step synthesis and many well established methods are
now routinely used by synthetic chemists.1 Methods for the
protection of diols as cyclic acetals and ketals are traditionally exe-
cuted with acetone, benzaldehyde, or their dimethyl acetal deriva-
tives (Scheme 1). All variations of these methods usually require
the use of homogeneous Brønsted or Lewis acid catalysts such as
p-TsOH and BF3ꢀEt2O under anhydrous conditions.
O
R1 R2
OH OH
R1 R2
or
Brønsted or
Lewis acid
O
O
+
n
MeO
OMe
n
n = 0, 1
R1 R2
Scheme 1. General equation for cyclic acetals or ketals formation from diols.
While homogeneous catalysts usually provide high selectivities
and excellent reaction yields, extra neutralization steps and both
recovery and corrosive issues are prohibiting for sustainable and/
or large scale processes. These last years, environmental concerns
have led to the resurgence of this transformation in order to find
active catalyst systems compatible with the principle of green
chemistry, especially through the use of heterogeneous cata-
lysts.2–5 Moreover, acetalization reactions are key transformations
for the preparation of biodiesel additives from glycerol6 and many
heterogeneous catalysts have shown great potential as traditional
homogeneous acid surrogates.7–10 The catalytic activity of most
heterogeneous catalysts reported in the literature, results from
non-easily quantifiable contributions of both Brønsted and Lewis
acid properties complicating the fine-tuning of catalytic properties
and corrosion issues cannot be addressed with heterogeneous acid
catalysts. While a few homogeneous neutral catalysts based on the
use of molecular iodine have been reported,11–13 we reasoned that
discovering a heterogeneous neutral catalyst showing strong activ-
ities for (trans)acetalization processes would be of great interest.
We recently unveiled the peculiar properties of graphene that
promoted the acetalization of glycerol without any external source
of Brønsted or Lewis acid.14 Graphene being a non-Lewis and non-
Brønsted acid platform, the unprecedented catalytic activity
recorded for the acetalization of glycerol was attributed to the
peculiar electronic properties of the honeycomb-structured 2D
material.15–19 This acid-free process was successfully developed
for the valorization of glycerol with a variety of carbonyl com-
pounds including ketones and aldehydes, giving the corresponding
cyclic ketal or acetal in high yields. However, a large excess of the
⇑
Corresponding author. Tel.: +33 025 112 5422; fax: +33 025 112 5402.
E-mail address: fx.felpin@univ-nantes.fr (F.-X. Felpin).
http://dx.doi.org/10.1016/j.tetlet.2016.09.022
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

4638
M. C. Nongbe et al. / Tetrahedron Letters 57 (2016) 4637–4639
carbonyl source (10 equiv) with respect to glycerol was used and a
more atom-economic process is therefore required for increasing
its practical usefulness. In this Letter we describe an optimized
process whose scope was extended to several 1,2- and 1,3-diols
leading to five- and six-membered acetals respectively. We espe-
cially explored the synthesis of volatile cyclic acetals which are
unsuitable for complex work-up and column chromatography
purification, and therefore require a procedure generating mini-
mum amounts of by-products and waste.
The graphene catalyst used in this study was prepared from
commercially available and inexpensive graphite following a scal-
able procedure recently developed in our laboratory (Scheme 2).20
Briefly, graphite was oxidized into graphene oxide following a
two-step approach. A first pre-oxidation was carried out with
potassium persulfate in sulfuric acid at 80 °C for 2 h followed by
a second and stronger oxidation step using potassium perman-
ganate in aqueous sulfuric acid at 35 °C for 3 h. The oxidized gra-
phite was exfoliated under ultrasound into isolated sheets of
graphene oxide. The exfoliated sheets of graphene oxide were then
reduced to graphene by hydrazine. The successful exfoliation was
assessed by XRD, and we determined that graphene contained an
average of only four stacked sheets while 85 stacked sheets were
determined for graphite. This parameter is crucial for the success
of our methodology, since more exfoliated the graphene is, more
important its electronic properties increase with respect to charge
transfer.
The two main aims of this work with respect to our previous
research results were to significantly reduce the carbonyl-to-diol
molar ratio and optimize the mass loading of graphene. We rea-
soned that the need for a large excess of carbonyl compounds to
reach high conversion of the acetalization could be attributed to
the formation of water, allowing the reaction to reverse. To address
this point we reasoned that performing the process with carbonyl
dimethyl acetals as carbonyl surrogates will suppress the forma-
tion of water, avoiding the reaction to reverse. In order to settle
this hypothesis, we optimized a benchmark reaction involving
the transacetalization of 2,20-dimethylpropan-1,3-diol with ben-
zaldehyde dimethyl acetal 2 using graphene as catalyst under sol-
vent-free conditions. The expected cyclic acetal 3 being rather
volatile and unsuitable for extended work-up manipulations, the
transacetalization process must minimize the formation by- and
side-products. As expected, when using a 10:1 2-to-1 molar ratio
at 100 °C with graphene as catalyst (25 mg per mmol of diol 1), a
quantitative yield of the corresponding acetal 3 was obtained but
the remaining starting material 2 was almost impossible to remove
from 3 either under vacuum or by column chromatography due to
their similar volatility and polarity (entry 1). Interestingly, the
decrease of the 2-to-1 molar ratio from 10:1 to only 1.25:1 did
not affect the reaction yield at 100 °C and a quantitative yield for
3 was obtained, indicating that after a simple filtration to remove
the graphene catalyst, cyclic acetal 3 was obtained with an
excellent purity (>95%) with only a trace amount of remaining 2
as detected by 1H NMR (entry 4). By contrast, reducing the temper-
ature to 80 °C significantly altered the reaction conversion suggest-
ing that this parameter could not be modulated (entry 5). The
reaction time was also optimized and we were able to preserve
the reaction yield within 10 hours of stirring (entry 6), but upon
a further decrease an incomplete conversion was obtained (entry
7). The mass loading of graphene was also significantly reduced
from 25 to 6 mg of graphene per mmol of diol 1 without affecting
both the reaction yield and rate (entry 9). The background reac-
tions showed that the transacetalization marginally occurred in
the absence of graphene, leading to the corresponding acetal 3 in
22% yield (entry 10) while graphite and graphene oxide catalyzed
the transacetalization with a reduced efficiency, highlighting the
peculiar properties of graphene (entries 12–13). The activity of gra-
phene oxide is not surprising since this material possesses signifi-
cant Brønsted acid properties due to the presence of carboxylic
acid functions. We also confirmed that under optimized conditions,
the use of benzaldehyde instead of benzaldehyde dimethyl acetal 2
significantly altered the reaction yield (77%), confirming the detri-
mental effect of water that favors the reaction to reverse and
decrease the conversion (entry 11) (Table 1).
With these optimized conditions in hand, we set out to explore
the scope of this process (Table 2). The transacetalization of 1,2-
and 1,3-diols with benzaldehyde dimethyl acetal 2 proceeded in
high yields, providing the corresponding five- and six-membered
cyclic acetal respectively (compounds 3–9). Both, primary and sec-
ondary alcohols were well tolerated but steric hindrance might
require a slightly higher loading of graphene (12.5 mg/mmol vs
6 mg/mmol) for reaching a high yield of the cyclic acetal (com-
pounds 4 and 7). Beside benzaldehyde dimethyl acetal 2, cyclohex-
ane dimethyl acetal and 2,20-dimethoxypropane were also
successfully involved in the graphene-catalyzed transacetalization
reaction (compounds 9–12). The inertness of 1,2-hexadecanediol
required an excess of 2,20-dimethoxypropane for reaching
a
Table 1
Optimization studies
MeO
OMe
O
O
Graphene
HO
OH
+
see Table 1
3
1
2
Entrya Compound 2
Graphene (mg/
mmol)
Time
(h)
Temp
(°C)
Yieldb
(%)
(equiv)
1
2
3
4
5
6
7
8
10
5
2.5
25
25
25
25
25
25
25
12.5
6
0
6
6
6
14
14
14
14
14
10
6
10
10
10
10
10
10
100
100
100
100
80
100
100
100
100
100
100
100
100
>97
>97
>97
>97
90
>97
94
>97
>97
22
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
1.25
HO2C
O
1. K2S2O8, P2O5
H2SO4, 80 °C, 2 h
HO2C
O
9
10
11c
12d
13e
HO
2. KMnO4, H2SO4
H2O, 0-35 °C, 3 h
OH
77
86
85
O
O
Graphene oxide
Oxidation-Exfoliation
a
Optimized reaction conditions: Diol 1 (1 mmol), benzaldehyde dimethyl acetal
Graphite
2, (1.25 mmol) and graphene (6 mg) were stirred for 10 hours at 100 °C in a sealed
NH2-NH2, H2O
tube.
b
Yield determined by 1H NMR using 1,2,4-trimethylbenzene as internal
reflux, 24 h
standard.
Reduction
c
Graphene
Benzaldehyde was used instead of benzaldehyde dimethyl acetal.
Graphite was used instead of graphene.
Graphene oxide was used instead of graphene.
d
e
Scheme 2. Synthesis of graphene.

M. C. Nongbe et al. / Tetrahedron Letters 57 (2016) 4637–4639
4639
Table 2
Scope of the reaction
for acid-sensitive substrates. The quasi-stoichiometric carbonyl
dimethyl acetal-to-diol molar ratio and the heterogeneous nature
of graphene simplify the work-up and purification steps since they
allow recovering the reaction product with a high purity. We
believe that such a methodology will be of great interest for
synthetic chemists working with acid-sensitive substrates and/or
volatile intermediates that are not suitable for purification by
column chromatography.
Graphene
R1 R2
OH OH
(6 mg.mmol-1
)
MeO
OMe
O
O
+
n
neat
R1 R2
n
n = 0, 1
O
O
O
O
O
O
O
O
O
O
O
O
Acknowledgments
We gratefully acknowledge the University of Nantes, the
‘‘Centre National de la Recherche Scientifique” (CNRS) and the
‘‘Région Pays de la Loire” in the framework of a ‘‘recrutement sur
poste stratégique”. Medy C. Nongbe thanks the ‘‘Ministère de
l’Enseignement Supérieur et de la Recherche Scientifique de Côte
d’Ivoire” for a visiting grant in France. François-Xavier Felpin is a
member of the ‘‘Institut Universitaire de France” (IUF).
a
7, >97%a
8, 68%
3
4
5
6
, 72%
, >97%
, 95%
, 92%
O
O
O
O
O
O
O
O
O
O
O
O
References and notes
OTBS
a
b
9, 73%a
10
11
, 76%
13
, 86%
12, 67%a
, >97% 14
, 86%
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b 12 mg of graphene per mmol of diol were used and 10 equiv of 2,2-
dimethoxypropane.
quantitative yield due to its very low solubility and high crys-
tallinity. With the exception of 12, most acetals prepared in this
study were quite volatile and unsuitable for purification by column
chromatography. However, it must be mentioned that even for
acetals not produced in quantitative yields, unreacted diols were
not detected in the crude mixture after filtration, suggesting that
it might be stacked on graphene and the cyclic acetals were
obtained with ꢁ95% purity as determined by 1H NMR.21 Impor-
tantly, the methodology is compatible with acid-sensitive sub-
strates as highlighted in the preparation of acetal 14 bearing a
silyl ether protecting group. While at this stage it is premature to
definitively conclude on a reaction mechanism, the unusual activ-
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charge transfer between graphene and reacting molecules; gra-
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reaction allowing the transacetalization of 2,20-dimethylpropan-
1,3-diol with benzaldehyde dimethyl acetal 2. After each run the
catalyst was recovered by filtration, thoroughly washed with ace-
tone, and dried under vacuum before being reengaged in a further
cycle. We observed a slight decrease of the reaction yield upon suc-
cessive reuses since 93 and 87% yield were obtained after the 2nd
and 3rd reuses respectively. This decrease was attributed to the
surface graphene poisoning by starting materials as we previously
observed on related transformations.14
20. Oger, N.; Lin, Y. F.; Labrugère, C.; Le Grognec, E.; Rataboul, F.; Felpin, F.-X.
Carbon 2016, 96, 342–350.
21. For a representative procedure: A mixture of diol 1 (1 mmol), benzaldehyde
dimethyl acetal (1.25 mol) and graphene (6 mg) were stirred for 10 h at 100 °C.
The resulting mixture was filtered on a nylon membrane, washed with a
minimum amount of acetone and the crude was carefully concentrated under
vacuum giving the corresponding cyclic acetal in excellent purity (>90%)
without further purification. IR (KBr)
m 1100, 1216, 1389, 1455, 1469, 2844,
2953 cmꢂ1 1H NMR (CDCl3, 300 MHz) d 0.81 (s, 3H), 1.31 (s, 3H), 3.66 (d, 2 H,
.
J = 9 Hz), 3.78 (d, 2H, J = 12 Hz), 5.41 (s, 1H), 7.34–7.42 (m, 3H), 7.51–7.54 (m,
2H). 13C NMR (CDCl3, 75 MHz) d 21.8, 23.0, 30.2, 77.6, 101.7, 126.1, 128.2,
128.8, 138.4. MS (CI/NH3): 193 (M+H+), 210 (M+NH4+).
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a graphene-catalyzed transac-
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etalization process for the formation of cyclic acetals from 1,2-
and 1,3-diols. The methodology features an experimentally simple
protocol under solvent-free conditions and does not require
Bronsted or Lewis acid; this latter point is of synthetic relevance