2,2-Dichlorination of aldehydes with the 2,6-lutidine·HCl/Cl2/CH2Cl2 system: An environmentally benign process suitable for scale up

Article abstract of DOI:10.1016/S0040-4020(00)00640-2

An effective and environmentally benign preparation of 2,2-dichloroaldehydes has been achieved by chlorination of aldehydes with Cl₂(g) in CH₂Cl₂, using 2,6-lutidine hydrochloride as recoverable catalyst. Remarkable qualif

Full text of DOI:10.1016/S0040-4020(00)00640-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7507–7511
2
,2-Dichlorination of Aldehydes with the
2
,6-Lutidine·HCl/Cl /CH Cl System: an Environmentally Benign
2
2
2
Process Suitable for Scale Up
a
b
a,
a
a
*
Franco Bellesia, Laurent De Buyck, Franco Ghelfi, Emanuela Libertini, Ugo Maria Pagnoni
a
and Fabrizio Roncaglia
a
Dipartimento di Chimica, Universit a` degli Studi di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, University of Ghent,
b
Coupure Links 653, B-9000 Ghent, Belgium
Received 13 April 2000; revised 3 July 2000; accepted 13 July 2000
Abstract—An effective and environmentally benign preparation of 2,2-dichloroaldehydes has been achieved by chlorination of aldehydes
with Cl (g) in CH Cl , using 2,6-lutidine hydrochloride as recoverable catalyst. Remarkable qualities of the process are: easy work up, high
purity products, HCl as the only ‘waste’ stream and inherent bias to the scale up. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
2
2
2
Introduction
a special interest in preparative organic chemistry. These
compounds are used in a variety of applications; for
example, the pivotal role played by the 2,2-dichloro-
carboxylic acids in a novel synthetic route to 2-pyrrolidi-
nones.19
2
,2-Dichloroaldehydes are a useful class of starting materi-
1
,2
als in the field of agrochemicals, and the Cl,Cl-acetal
carbon near the carbonyl group makes them valuable
and very promising dissonant bifunctional substrates in
synthetic organic chemistry from several varied stand-
In spite of this useful reactivity and chemistry, the prepa-
ration of 2,2-dichloroaldehydes still suffers from the lack of
an efficient, economic and convenient protocol. Procedures
for the direct chlorination of aldehydes to produce 2,2-
dichloroalkanals have in fact met with only limited
3
points. In fact important synthons, such as a-ketoaldehydes
and a-ketoacetals, can be easily prepared starting from
,2-dichloroalkanals by treatment with alkaline alkoxides;
also, interesting molecules such as 2,2-dichloroaldehyde
4
2
2
0
N-acyl hemiaminals, 2,2-disulphenylated aldehydes, 2-
success, and indirect approaches exploiting the chlorina-
1
21,22
chloroesters, or chlorinated vinyl phosphates can be5
tion of enamines with Cl
cinimide
2
or imines with N-chlorosuc-
23,24
attained through nucleophilic attack with primary amides,
were generally preferred.
6
7
8
sodium thiolates, cyanide ion or phosphites.
Some years ago one of us smoothly achieved dihalogenation
1
5,16
The versatility and usefulness of 2,2-dichloroaldehydes in
organic synthesis has been especially shown by a number
of reactions, mainly with C-nucleophiles, to build furan
of alkanals with the Cl
then, to our knowledge, only two additional protocols for
direct dihalogenation have been reported: one uses Cl
2
/DMF/HCl system,
and since
/
2
9
10
25
derivatives, (E)-a,b-unsaturated ketones, DDT ana-
pyrrolidinecarboxaldehyde/HCl, whereas the other uses
tetraethylammonium trichloride. These methods are not
1
2
26
logues, pyridine derivatives or chiral 4-substituited
1
1
2
-oxetanones. Furthermore, reactions with metals and
suited for large-scale preparation: (i) the catalysts are
treated as a waste, (ii) the solvents used are either cargino-
1
2,13
C-electrophiles are also reported.
genic (CHCl ) or difficult to remove (DMF), and (iii) the
3
The oxidation of 2,2-dichloroaldehydes to 2,2-dichloro-
15,16
reaction mixtures are dilute.
1
4
alkanoic acids with Cl /2-picoline·HCl,
KMnO4,
2
1
5
15,16
K Cr O
2
or H O /NaHCO ,
and their reduction to
As a consequence of the need to minimize the amount of
toxic wastes and by-products from chemical processes, and
in order to work with more environmentally friendly
synthetic protocols, we have recently improved the Cl2/
DMF/HCl method, by replacing DMF/HCl with 2-pico-
2
2
7
2
2
3
1
7,18
,2-dichloroalkanols with NaBH4 have recently aroused
Keywords: aldehydes; catalysts; halogenation; halogens and compounds.
Corresponding author. Tel.: ϩ39-059-2055043; fax: ϩ39-059-373543;
e-mail: ghelfi.franco@unimo.it
*
1
4
line·HCl, which is a recoverable catalyst. In spite of the
0
040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00640-2

7
508
F. Bellesia et al. / Tetrahedron 56 (2000) 7507–7511
Scheme 1.
high yield obtained, the process still lacks those features that
characterize an ideal plant process and are requisite to the
hydes is clearly acid-catalysed, while the second chlori-
nation is base-catalysed or combined-acid-base-
2
7
2
8
scale up: in fact (i) a harmful solvent like CHCl is used, (ii)
catalysed. Combination of an organic nitrogen base and
HCl appears to be a particularly suitable catalyst for the
enolization of carbonyl compounds and 2,2-dihalogena-
3
recycle–regeneration of 2-picoline·HCl is a lengthy and
expensive process, (iii) aqueous work up decreases product
specifications due to contamination with the hydrate form,
and (iv) waste gas vented from the reactor is a dangerous
mixture of HCl/Cl2.
5
,29
tion,
as it assures the indispensable base-catalysis,
which is required for a rapid second chlorination step;
indeed, it is well known that the small, symmetrical and
densely charged chloride ion is a strong Brønsted base in
1
6,30–32
Aiming at a safer and economically and ecologically more
sound process for the perchlorination of aldehydes at the
C(2) site, we are now in a position to report that the
previously listed drawbacks can be overcome by the halo-
genating system Cl /2,6-lutidine·HCl/CH Cl .
aprotic solvents (Scheme 2).
The activity of 2-picoline·HCl rests on three fundamental
features: (i) solubility in the reaction medium, (ii) survival
of the molecular structure during the chlorination step, and
2
2
2
(
iii) cooperative action of a proton donor and a proton
acceptor. In principle, a wide choice of catalysts of this
type may be identified; thus, looking for a catalyst more
active and convenient than 2-picoline·HCl, a number of
Results and Discussion
†
aromatic bases (2-ethyl-pyridine, 2,6-lutidine, 2,4-lutidine,
The dichlorination of aldehydes needs two successive enoli-
zation steps and for a successful transformation the reaction
has to be performed under acid catalysis; in fact in an
alkaline medium the halogenation would result in oxidation
and aldol condensation. However, the functionalization,
under acid catalysis, also suffers a major disadvantage,
which is the slowness of the second enolization step
3
,4-lutidine, 2,4,6-collidine, 2-phenyl-pyridine, 5-ethyl-2-
0
methyl-pyridine, 2,2 -dipyridyl) hydrochlorides (15 mol
%
) were tested with pentanal (0.25 mol) at 60ЊC in CHCl
3
14
1
5
and 35% HCl (2 ml), using the reactor A (Fig. 1).
Obviously, only the soluble hydrochlorides turned out to
be active, the best result being afforded by 2-picoline·HCl,
2
,6-lutidine·HCl (LHC) or 2,4,6-collidine·HCl. 2-Picoline
(
Scheme 1). In fact, the basicity of the carbonyl group is
hydrochloride must be melted and used while liquid,
decreased considerably by a 2-halogen substituent, and the
applied procedure frequently yields products contaminated
with substantial amounts of 2-monochloroaldehydes.
The introduction of the first chlorine substituent in the alde-
Figure 1.
†
Aliphatic tertiary amine hydrochlorides were discarded because they
1
4
Scheme 2.
were not resistant enough to the reaction conditions.

F. Bellesia et al. / Tetrahedron 56 (2000) 7507–7511
7509
2 2
Table 1. 2,2-Dichlorination of aldehydes carried out in reactor B (0.25 mol of substrate and 25 ml of CH Cl were used)
a
b
No.
R
Catalyst (%)
35% HCl
T (ЊC)
Conversion (%)
Yield (%)
1
2
3
n-Propyl
n-Propyl
n-Propyl
n-Propyl
i-Propyl
Methyl
2,6-Lutidine·HCl (15%)
2,6-Lutidine·HCl (15%)
2-Picoline·HCl (15%)
2,6-Lutidine·HCl (15%)
2,6-Lutidine·HCl (15%)
2,6-Lutidine·HCl (15%)
2,6-Lutidine·HCl (15%)
2,6-Lutidine·HCl (15%)
Yes
No
No
No
No
No
No
No
65
65
65
70
75
75
75
75
100
100
100
100
100
100
100
100
59
86
91
92
88
90
90
84
c
4
5
6
7
8
Benzyl
n-Hexyl
a
b
c
Temperature of the heating fluid.
Determined on isolated material.
0
2 2
.50 mol of substrate and 50 ml of CH Cl were used.
whereas other hydrochlorides can be more easily handled as
solids, because the two methyl groups flanking the aromatic
nitrogen strongly decrease their hygroscopicity, and since
(absence of the hydrate form). Moreover, solvents can be
recovered, isolated by fractional distillation and recycled. It
should be noticed that even though 2-picoline·HCl is some-
what more active than LHC (Table 1, items 2 and 3), the
difference disappears on a larger scale (Table 1, item 4). The
optimized protocol was then applied to other aldehydes, and
has worked excellently in all cases (Table 1).
2
,6-lutidine is cheaper and less toxic than 2,4,6-collidine,
the successive optimization steps were performed using
its salt. The involvement of a chloride ion in the dihalo-
genation mechanism was clearly confirmed by the sharp
efficiency loss, observed when 2,6-lutidinium tosylate
(
8
yield 58%), a poorly basic salt, replaced LHC (yield
0%).
To get the highest yields, substrate feeding needs to be
regulated in order to maintain in some excess the steady
flow of chlorine. This leads to an excessive chlorine
consumption (ϳ2 mol), with negative consequences for
the environment and the process economy: the unreacted
halogen adds to HCl in the waste gas stream. Taking
advantage of the large difference between the boiling points
Fluorobenzene, trifluorotoluene, ethyl acetate and CH Cl ,
safer solvents than CHCl , were then tested for LHC solu-
bility and tolerance to reaction conditions. Only dichloro-
2
2
3
3
3
methane, a cheap, easy recyclable, and non-carcinogenic
solvent (by NTP and OSHA), largely used in pharma-
ceutical products synthesis, got through both tests. Unfortu-
nately, the first runs in CH Cl were disappointing nor the
change to the more functional reactor B (Fig. 1) improved
appreciably the performances (Table 1, item 1). A break-
through arrived when we did not add HCl (Table 1, item 2),
a modification that proved crucial also for the economy of
the process, as the reaction procedure and work up were
both simplified. In fact, on diluting the final reaction mixture
of Cl and HCl (Ϫ34ЊC and Ϫ85ЊC), the two compounds
2
were separated: the halogen was kept inside the reaction
chamber by fitting reactor B with a cold-finger condenser
(Fig. 1, C) set at Ϫ78ЊC (acetone/dry ice).
2
2
This more efficient chlorine utilization made it possible to
employ an almost stoichiometric amount of gas, but imme-
diately we understood how reactor and chemistry inside it
3
4
are correlated. Indeed, notwithstanding a number of varia-
tions of the experimental protocol, trials to produce
2,2-dichloropentanal in C were unsatisfactory, since yields
never went beyond 79% (Table 2, item 1). When, however,
the reaction scale was risen from 0.25 to 0.5 mol, results
became excellent (Table 2, items 2–4); also, under identical
reaction conditions, equally good results were obtained by
all the other aldehydes tested (Table 2). Maybe, operating at
the top volume allowed by the reaction chamber, the reactor
‡
with n-hexane or ether, LHC (but not the 2-picoline·HCl)
salted out and was quantitatively recovered by filtration.
The collected material showed no activity decline, and
was confidently re-used. As no water enters in the work
up step, there is no need for drying salts, nor waste waters
are produced and the 2,2-dichloroaldehydes purity increase
‡
shape allows a more efficient Cl uptake from the inner
Less flammable n-heptane or t-butylmethyl ether are preferable on large
2
scale production.
atmosphere.
Table 2. 2,2-Dichlorination of aldehydes carried out in reactor C (0.50 mol of substrate and 50 ml of CH
2
Cl
2
were used)
a
b
No.
R
Catalyst (%)
T (ЊC)
Conversion (%)
Yield (%)
c
1
n-Ethyl
n-Ethyl
n-Ethyl
n-Ethyl
i-Propyl
i-Propyl
i-Propyl
Benzyl
2,6-Lutidine (15%)
2,6-Lutidine (15%)
2,6-Lutidine (30%)
2,6-Lutidine (15%)
2,6-Lutidine (30%)
2,6-Lutidine (30%)
2,6-Lutidine (15%)
2,6-Lutidine (30%)
70
50
30
45
30
45
55
45
100
100
100
100
100
100
100
100
79
94
97
95
91
98
98
95
2
3
4
5
6
7
8
a
b
c
Temperature of the heating fluid.
Determined on isolated material.
0
2 2
.25 mol of substrate and 25 ml of CH Cl were used.

7
510
F. Bellesia et al. / Tetrahedron 56 (2000) 7507–7511
Assembly C even has a good influence on the reactor
100 ml) output too: since no halogen is vented out, the
feeding rate of the educts could be speeded up from 1 to
mmol/(cc·h). The chlorine flow can be easily monitored
and adjusted looking at its dropping rate from the bottom of
the cold-finger condenser. At 35ЊC, owing to the low initial
acidity of the reaction mixture, the halogenation showed for
all the substrates tested an induction period, which
decreases to zero by increasing the reaction temperature
or the catalyst amount (Table 2, items 2–4).
Special case. With 3-phenylpropanal, ethyl ether had to
replace n-hexane to achieve LHC precipitation.
(
2
2,2-Dichloro-pentanal. Colourless liquid, bp 140–143ЊC.
1
H NMR (CDCl ): d 1.04 (3H, t, Jˆ7.3 Hz), 1.56–1.88 (2H,
Ϫ1
3
m), 2.16–2.43 (2H, m), 9.27 (1H, s). IR (film) 1747 (CvO)
cm . MS (EI, m/z): 125 (30, M Ϫ29), 112 (24), 89 (62), 55
ϩ
(100). Anal. Calcd for C H Cl O: C, 38.74; H, 5.20. Found:
5
8
2
C, 38.60; H, 5.20.
2
,2-Dichloro-3-methyl-butanal. Colourless liquid, bp
1
In conclusion, the perchlorination of aldehydes at C(2) with
Cl /2,6-lutidine·HCl/CH Cl here described displays several
useful features: high selectivity, considerable productivity,
easy recycling of the catalyst and solvent, easy work up, and
HCl as the only waste. These characteristics make the
process economic and environmentally safe, therefore a
good candidate for scale up. Finally, the easy access to
137–141ЊC. H NMR (CDCl ): d 1.68 (6H, d, Jˆ6.6 Hz),
3
2.60 (1H, hept, Jˆ6.6 Hz), 9.27 (1H, s). IR (film) 1745
2
2
2
Ϫ1
ϩ
(CvO) cm . MS (EI, m/z): 154 (1, M ), 125 (78), 112
(70), 89 (57), 55 (100). Anal. Calcd for C H Cl O: C,
38.74; H, 5.20. Found: C, 38.7; H, 5.1.
5
8
2
1
2,2-Dichloro-propanal. Colourless liquid, bp 83–85ЊC. H
2
,2-dichloroaldehydes will certainly give new impetus to
NMR (CDCl ): d 2.17 (3H, s), 9.27 (1H, s). IR (film) 1746
(CvO) cm . MS (EI, m/z): 126 (6, M ), 97 (33), 91 (46),
3
Ϫ1
ϩ
the chemistry of this interesting functional group.
6
2 (100). Anal. Calcd for C H Cl O: C, 28.38; H, 3.18.
3 4 2
Found: C, 28.3; H, 3.3.
Experimental
3
7
7
-Phenyl-2,2-dichloro-propanal. Colourless liquid, bp
1
1
H NMR, IR and MS spectra were recorded respectively on
5–82ЊC/0.05 mmHg. H NMR (CDCl ): d 3.66 (2H, s),
3
Ϫ1
Bruker DPX200, Philips PU 9716 and HP 5890 GC–HP
5
.40 (5H, bs), 9.32 (1H, s) 1745 (CvO) cm . MS (EI,
ϩ
989A MS Engine. Reagents were standard grade commer-
m/z): 206 (1, M ), 173 (1), 167 (6), 103 (9), 91 (100).
cial products, purchased from Aldrich or Fluka, and used
without further purification. Chlorine (99.99%) was
supplied by SIAD. The reactors A (flask volume 250 ml),
B (reaction chamber volume 100 ml) and C are sketched in
Fig. 1. Chlorinations in A were carried out according to the
Anal. Calcd for C H Cl O: C, 53.23; H, 3.97. Found: C,
9
8
2
5
3.2; H, 4.0.
2
1
1
,2-Dichloro-octanal. Colourless liquid, bp 81–86ЊC/
1
1 mmHg. H NMR (CDCl ): d 0.93 (3H, t, Jˆ6.4 Hz),
3
1
4
literature.
.21–1.53 (6H, m), 1.54–1.80 (2H, m), 2.22–2.38 (2H,
Ϫ1
m), 9.27 (1H, s). IR (film) 1748 (CvO) cm . MS (EI,
m/z): 167 (M Ϫ29, 4), 131 (25), 112 (33), 100 (46), 95
ϩ
Preparations of aromatic base hydrochlorides
(
100). Anal. Calcd for C H Cl O: C, 48.75; H, 7.16.
8 14 2
The catalysts were prepared by adding a 10% excess of 35%
aq. HCl to aromatic bases and then drying at the rotavapor.
Found: C, 48.6; H, 7.1.
2
,2-Dichloro-butanal. Colourless liquid, bp 113–116ЊC.
1
Typical procedure, reactor B
H NMR (CDCl ): d 1.22 (3H, t, Jˆ7.2 Hz), 2.34 (2H, q,
3
Ϫ1
Jˆ7.2 Hz), 9.28 (1H, s). IR (film) 1746 (CvO) cm . MS
ϩ
The apparatus was fitted with an efficient coil condenser
(EI, m/z): 140 (1, M ), 111 (20), 76 (19), 75 (26), 41 (100).
(
coolant temperature Ϫ12ЊC/Ϫ18ЊC) to accomplish the
Anal. Calcd for C H Cl O: C, 34.07; H, 4.29. Found: C,
34.1; H, 4.2.
4
6
2
separation of CH Cl from the outlet gases (Cl and HCl).
2
2
2
Ϫ2
A solution of LHC (3.75×10 mol) in CH Cl (25 ml) was
2
2
§
flushed with O , maintaining a small and steady flow for the
2
Typical procedure, reactor C
duration of the reaction. Then a controlled flow of Cl2
(
0.6 g/min) was turned on to saturate the mixture, the appa-
When the short coil and cold-finger condensers were cooled
§
ratus wrapped with a black cloth and the heating fluid
respectively to Ϫ20 and Ϫ78ЊC, the previously prepared
(
Table 1 for temperature setting) put in circulation. A few
Ϫ2
mixture of LHC (7.5×10 mol) in CH Cl (50 ml) was
2
2
minutes later, aldehyde (0.25 mol) addition was started
through a syringe pump, at such a rate sufficient to maintain
flushed with O (a small and steady flow was maintained
2
for the duration of the reaction) and saturated with Cl until
2
some excess of Cl in the reaction chamber. When the
addition of aldehyde was completed (2.5 h), the Cl flow
was turned off after 10 min and the mixture was further
stirred for another 20 min. The heating device was then
switched off and the reaction mixture stripped with O to
2
a fast dropping rate of liquid halogen from the cold-finger
2
bottom was observed. The Cl flow was then turned off, the
2
apparatus wrapped with a black cloth and the heating fluid
(
Table 2 for temperature setting) put in circulation. After
2
five minutes, aldehyde (0.5 mol) addition through a syringe
remove residual Cl . Finally, dilution with n-hexane
2
pump was begun and, as soon as the reaction got under
(
50–100 ml) salted out the LHC, which was filtered off.
k
way, the Cl flow was restarted, at a rate sufficient to
2
The 2,2-dichloroaldehydes were isolated from the crude
by distillation under reduced pressure.
k
If the halogenation does not start, the aldehyde addition must be shut off
and the temperature increased step by step until reaction clearly begins
(evident chlorine uptake).
§
To avoid by-products from radical chlorination.

F. Bellesia et al. / Tetrahedron 56 (2000) 7507–7511
7511
maintain some excess of Cl2 in the reaction chamber
evident dropping). The addition of aldehyde was completed
13. Shchepin, V. V.; Severova, T. V.; Russkikh, N. Yu.; Fotin,
V. V. Zh. Obshch. Khim. 1989, 59, 1814–1818.
(
in 2.5 h. The same work up procedure reported for reactor B
was followed.
14. Bellesia, F.; De Buyck, L.; Ghelfi, F. Synlett 2000, 146–148.
15. De Buyck, L.; Verh e´ , R.; De Kimpe, N.; Courtheyn, D.;
Schamp, N. Bull. Soc. Chim. Belgium 1980, 89, 441–458.
16. De Buyck, L.; Casaert, F.; De Lepeleire, C.; Schamp, N. Bull.
Soc. Chim. Belgium 1988, 97, 525–533.
Special case. With 3-phenylpropanal, ethyl ether had to
replace n-hexane to achieve LHC precipitation.
1
7. Salgado, A.; Huybrechts, T.; De Buyck, L.; Czombos, J.;
Tkachev, A.; De Kimpe, N. Synth. Commun. 1999, 29, 57–63.
Acknowledgements
1
1
1
8. De Buyck, L.; Van Hulle, P. Bull. Soc. Chim. Belgium 1992,
01, 329–336.
9. Ghelfi, F.; Bellesia, F.; Forti, L.; Ghirardini, G.; Grandi, R.;
We thank the Ministero della Universit a` e della Ricerca
Scientifica e Tecnologica (MURST) and the Belgian
N.F.W.O. and I.W.T. for financial assistance.
Libertini, E.; Montemaggi, M. C.; Pagnoni, U. M.; Pinetti, A.;
De Buyck, L.; Parsons, A. F. Tetrahedron 1999, 55, 5839–5852.
2
2
1
2
2
1
2
5
2
0. Dick, C. R. J. Org. Chem. 1961, 27, 272–274.
1. Duhamel, L.; Duhamel, P.; Poirier, J.-M. Tetrahedron Lett.
973, 14, 4237–4240.
2. Poirier, J.-M. Bull. Soc. Chim. France 1982, II, 17–22.
3. Verh e´ , R.; De Kimpe, N.; De Buyck, L.; Schamp, N. Synthesis
975, 455–456.
4. Stevens, C.; De Kimpe, N. Org. Prep. Proc. Int. 1990, 22,
89–595.
5. Pews, R. G.; Lysenko, Z. Synth. Commun. 1985, 15, 977–984.
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