A safe production method for acetone cyanohydrin

Article abstract of DOI:10.1016/j.tetlet.2010.06.004

An easily amenable method is presented to produce acetone cyanohydrin on mole scale (output 39 g/h), using a continuous flow system to overcome the high risks associated with the large-scale use of hydrogen cyanide.

Full text of DOI:10.1016/j.tetlet.2010.06.004

Tetrahedron Letters 51 (2010) 4189–4191
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A safe production method for acetone cyanohydrin
*
Thomas S. A. Heugebaert , Bart I. Roman , Ann De Blieck , Christian V. Stevens
Research Group SynBioC, Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
An easily amenable method is presented to produce acetone cyanohydrin on mole scale (output 39 g/h),
using a continuous flow system to overcome the high risks associated with the large-scale use of hydro-
gen cyanide.
Received 27 April 2010
Revised 30 May 2010
Accepted 1 June 2010
Available online 15 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cyanohydrins
Continuous flow chemistry
Ketones
Condensation
Cyanide
1. Introduction
available microreactor system on a scale easily amenable to the
standard organic chemical lab.
Acetone cyanohydrin is a widely used source of hydrogen cya-
nide. Its liquid state allows safe and convenient handling and in con-
trast to cyanide salts, no acid is needed to liberate the hydrogen
cyanide. Given these advantages, acetone cyanohydrin has fre-
quentlybeenusedinrecentliteratureasa sourceofnucleophiliccya-
nide.1 Some examples are Strecker syntheses,2 Appel and Mitsunobu
type reactions,3 Michael additions to unsaturated compounds4 and
the rearrangement of 3-oxo alkenyl esters to acyl diketones.5
Furthermore, acetone cyanohydrin is an important industrial inter-
mediate in the synthesis of methacrylamide and methacrylates.
However, despite the importance of this simple molecule, many
suppliers have stopped the distribution of acetone cyanohydrin to
research laboratories. This presents a major issue for many research-
ers. Although the synthesis of acetone cyanohydrin is well described
in the literature, it mostly involves the generation of one or more
equivalents of hydrogen cyanide in the reaction vessel.6 This poses
high risks: in case of spillage or accidental leakage, large amounts
of hydrogen cyanide will be liberated into the working environment.
To overcome these problems, closed continuous flow systems in
which only minute amounts of hydrogen cyanide are generated,
have been reported.7 These reports however, are mostly situated
in patent literature and as such these systems are not readily avail-
able to the organic chemist. In this Letter we present a safe synthe-
sis of acetone cyanohydrins (Scheme 1), using a commercially
Microreactor technology is a relatively young field: the first
microreactor system was described in a German patent dated
1986. Microreactors offer a myriad of advantages over classical
batch processes: miniaturization obviously leads to the use of
smaller quantities of materials, providing economical and environ-
mental benefits and easier control of the reactions’ safety; flow con-
ditions ensure good mixing of the reagents and strictly respected
stoichiometry. Another important convenience of the technology
is the increased surface to-volume ratio and the heat-exchange effi-
ciency, which allows better thermal control of the reactions and
makes microreactors suitable for exothermic reactions, sometimes
even eliminating the need for external cooling and thus decreasing
the overall process energy demands. Additionally, thanks to the
enhanced temperature distribution, it is also possible to reduce
the reaction time under carefully controlled conditions by increas-
ing the temperature while avoiding the formation of side products.
The main asset of microreactor technology adding an industrially
important significance is its scalability, often mentioned as ‘scale-
out’ instead of ‘scale-up’.8
2. Results and discussion
In this study, the CYTOS College System, a microreactor manu-
factured by CPC—Cellular Process Chemistry Systems GmbH, was
OH
O
N
KCN, HOAc
* Corresponding author. Tel.: +32 92645860; fax: +32 92646243.
E-mail address: Chris.Stevens@UGent.be (C.V. Stevens).
In equal contribution.
Scheme 1. Acetone cyanohydrin synthesis.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.004

4190
T. S. A. Heugebaert et al. / Tetrahedron Letters 51 (2010) 4189–4191
and hydrogen cyanide gas is disfavored at higher temperatures
due to an amplification of entropic effects. Lowering the tempera-
ture (entry 5) causes an even greater drop in yield. This is ac-
counted for by the lower reaction speed.
When adding 5 mol % LiCl to the aqueous solution as a Lewis
acid to activate the acetone, and thereby increasing the reaction
rate, a significant drop in yield is observed (entries 7 and 8). This
can be attributed to aldol condensation of acetone, which was
shown to occur by isolation of the resulting polymeric material.9
It should be noted that, when using LiCl, the yields drop upon
increasing the reaction times. Both acetone cyanohydrin formation
and aldol condensation are reversible processes, and as reaction
time increases, the thermodynamically more favored aldol conden-
sation takes the upper hand.
The same problem with aldol condensation was encountered
when increasing the flow rate of the acetone/acetic acid solution
to provide a larger excess of acetone (entry 6). This causes an ex-
cess of acetic acid, leading to aldol condensation.
Figure 1. The Cytos College System microreactor.
used (Fig. 1). This device consists of a stacked plate microreactor
with an internal volume of 2 ml and a residence time unit (RTU),
that is, an insulated tube with an internal volume of 45 ml to in-
crease the reaction time. The microreactor itself has a mixing zone
and a reaction zone. Pumping of the reagents through the system is
pressure driven.
Inside the microreactor, hydrogen cyanide is generated from
two solutions containing potassium cyanide and acetic acid,
respectively. Due to limitations on the flow rate through the mic-
roreactor system, high concentrations of these reagents are needed
to provide an acceptable output. Furthermore, no precipitation of
the reagents may occur during the reaction in order to avoid clog-
ging of the microchannels. Combining these two facts, water (and
to a lesser extent methanol) is the only viable solvent for potas-
sium cyanide. Acetone is used as the solvent for acetic acid, provid-
ing an excess of the electrophile.
With this solvent system, several runs were performed, as de-
picted in Table 1. The microreactor was allowed to reach steady
state conditions by running the reaction for a period representing
twice the retention time. Subsequently, a sample of 40 ml was col-
lected and extracted with diethylether, delivering pure acetone
cyanohydrin with the indicated yield. For safety reasons, the col-
lection flask is placed under a gentle flow of nitrogen gas, flushing
any liberated excess of hydrogen cyanide through two consecutive
traps containing a 1 M KOH solution and a 1 M Na2S2O3 solution. A
first attempt using a 300 ml/h flow for both the acetone and cya-
nide solution gave quite satisfactory results. A yield of 64% was ob-
tained, delivering a product output of 62.6 g/h.
Lowering the flow rates to 180 ml/h (entry 2) and 90 ml/h (en-
try 3) to increase the retention time, improved this yield to 71%
and 76%, respectively. However, this gain in yield does not justify
the considerable drop in output from 62.6 g/h to 41.7 g/h and
22.3 g/h, respectively. Increasing the reaction temperature (entry
4) caused a slight drop of the yield. The condensation of acetone
It is however possible to increase the excess of acetone present
without altering the equivalents of acetic acid. In runs 9 and 10 the
concentration of acetic acid was reduced by a factor two and the
flow rate of the acetone/acetic acid solution was doubled. During
these runs there is no excess of acetic acid while the acetone over
cyanide ratio is increased to 6.3. These conditions do indeed largely
improve the product formation. Entry 9 presents a yield of 99% and
an output of 39 g/h, a scale which one would hesitate to attempt in
a batch. Although this output is somewhat lower than that for en-
tries 1 and 2, only a small amount (1%) of HCN is lost during this
reaction, as opposed to 36% and 29% for entries 1 and 2. Therefore,
this entry represents a satisfactory method to produce acetone
cyanohydrin in a straightforward way.
3. Conclusion
A safe protocol for the mole scale production of acetone cyano-
hydrin was developed. The synthesis takes advantage of the assets
of microreactor technology avoiding the formation of large
amounts of hydrogen cyanide. Acetone cyanohydrin is formed
quantitatively from potassium cyanide and acetone with an output
of 39 g/h.
4. Experimental section
The CYTOS College System, a microreactor manufactured by
CPC—Cellular Process Chemistry Systems GmbH. was allowed to
reach 30 °C, using the Unistat Tango thermostat. Inlet A was
equipped with a 3.8 M (0.25 g/ml) aqueous solution of KCN. Inlet
B was equipped with a 1.9 M (0.114 g/ml) solution of acetic acid
in acetone. Flowrates were set at 120 ml/h for inlet A and
240 ml/h for inlet B (delivering 456 mmol/h of both acetic acid
Table 1
Optimisation of conditions for acetone cyanohydrin synthesis
Entry
t (°C)
QA (ml/h)
QB (ml/h)
CKCN (M)
Cacetone (M)
CHOAc (M)
Equiv acetone/KCN
Equiv HOAc/KCN
Mol % LiCl
Y (%)
Output (g/h)
1
2
3
4
5
6
7
8
9
30
30
30
45
5
30
30
30
30
30
300
180
90
300
180
150
180
90
300
180
90
300
180
300
180
90
3.8
3.8
3.8
3.8
3.8
3.8
3.8
3.8
3.8
3.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
10.8
12.1
12.1
3.8
3.8
3.8
3.8
3.8
3.8
3.8
3.8
1.9
1.9
2.8
2.8
2.8
2.8
2.8
5.6
2.8
2.8
6.3
6.3
1
1
1
1
1
2
1
1
1
1
0
0
0
0
0
0
5
5
0
0
64
71
76
60
3
62.6
41.7
22.3
58.7
1.8
1.5
28.8
5.9
3
49
20
99
92
120
60
240
120
39.1
18.0
10
t: temperature; Q: flowrate (A: KCN/H2O, B: HOAc/acetone); C: concentration; Y: yield.

T. S. A. Heugebaert et al. / Tetrahedron Letters 51 (2010) 4189–4191
4191
Thoraval, D.; Totleben, M.; Vanyo, D.; Vemishetti, P.; Wasylak, J.; Wei, C. Org.
Process Res. Dev. 2009, 13, 716–728; (b) Park, E. J.; Lee, S.; Chang, S. J. Org. Chem.
2010, 75, 2760–2762.
and KCN). The reaction was run for 16 min (2.04 s) after which
product collection was started for 6 min 40 s (40 ml). This (aque-
ous) sample was extracted with diethyl ether and dried using
MgSO4. After filtration, the volatiles were removed in vacuo at
30 °C, delivering 98+% pure (by GC-FID analysis) acetone cyanohy-
drin in 99% yield.
2. (a) Patterson, S.; Jones, D. C.; Shanks, E. J.; Frearson, J. A.; Gilbert, I. H.; Wyatt, P.
G.; Fairlamb, A. H. ChemMedChem 2009, 4, 1341–1353; (b) Heugebaert, T. S. A.;
Stevens, C. V. Can. Pat. Appl. 2009, CAN 151, 508486; (c) Heugebaert, T. S. A.; Van
Hevele, J.; Couck, W.; Bruggeman, V.; Van der Jeught, S.; Masschelein, K.;
Stevens, C. V. Eur. J. Org. Chem. 2010, 6, 1017–1020.
3. (a) Uchida, K.; Yokoshima, S.; Kan, T.; Fukuyama, T. Heterocycles 2009, 77, 1219–
1234; (b) Klein, J. E. M. N.; Mueller-Bunz, H.; Evans, P. Org. Biomol. Chem. 2009, 7,
986–995; (c) Gioia, C.; Hauville, A.; Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem.,
Int. Ed. 2008, 47, 9236–9239.
4. (a) Wolberg, M.; Dassen, B. H. N.; Schuermann, M.; Jennewein, S.; Wubbolts, M.
G.; Schoemaker, H. E.; Mink, D. Adv. Synth. Catal. 2009, 350, 1751–1759; (b)
Anderson, J. C.; Blake, A. J.; Mills, M.; Ratcliffe, P. D. Org. Lett. 2008, 10, 4141–
4143.
Acknowledgments
Financial support for this research from the Fund for Scientific
Research Flanders (FWO Vlaanderen; B.R. and T.H.) and the Ghent
University Research Fund (A.D.B.) is gratefully acknowledged.
5. (a) Lakhvich, F. A.; Petrusevich, I. I.; Ogeiko, N. G.; Sergeeva, A. N. Russ. J. Org.
Chem. 2008, 44, 1444–1450; (b) Pashkovskii, F. S.; Shchukina, E. M.; Gribovskii,
M. G.; Lakhvich, F. A. Russ. J. Org. Chem. 2008, 44, 657–670.
Supplementary data
6. (a) Clarke, H. T.; Bean, H. J. Org. Synth. 1931, 11, 4–11; (b) Cox, R. F. B.; Stormont,
R. T. Org. Synth. 1935, 15, 1–2.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.06.004.
7. (a) Gropp, U.; Weber, R.; Schaefer, T.; Perl, A.; Sing, R.; Mertz, T. PCT Int. Appl.
2008, CAN 149, 81679; (b) Decourcy, M. S. Eur. Pat. Appl. 2003, CAN 140, 28761.
8. (a) Cukalovic, A.; Monbaliu, J.-C. M. R.; Stevens, C. V. Top. Heterocycl. Chem. 2010,
23, 161–198; (b) Wiles, C.; Watts, P. Eur. J. Org. Chem. 2008, 10, 1655–1671.
9. The presence of polymers originating from the selfcondensation of acetone was
shown by the evaporation of the crude reaction mixture (before extraction). The
obtained solids were washed with water to remove LiCl and KOAc salts. Infrared
analysis of the residual, non-water soluble solid showed the presence of highly
conjugated double bonds (1564 cmÀ1) and methyl ketone groups (1398 cmÀ1).
References and notes
1. (a) Pesti, J.; Chen, C. K.; Spangler, L.; DelMonte, A. J.; Benoit, S.; Berglund, D.;
Bien, J.; Brodfuehrer, P.; Chan, Y.; Corbett, E.; Costello, C.; DeMena, P.; Discordia,
R. P.; Doubleday, W.; Gao, Z.; Gingras, S.; Grosso, J.; Haas, O.; Kacsur, D.; Lai, C.;
Leung, S.; Miller, M.; Muslehiddinoglu, J.; Nguyen, N.; Qiu, J.; Olzog, M.; Reiff, E.;