Breakthrough in the α-perchlorination of acyl chlorides

Article abstract of DOI:10.1055/s-0031-1289678

The preparation of -perchloroacyl chlorides, from reaction of the corresponding unfunctionalized acyl halides with chlorine, was efficiently achieved under base-catalysis, using a tetraalkylammonium chloride as catalyst. The process is solvent-free and th

Full text of DOI:10.1055/s-0031-1289678

PAPER
605
Breakthrough in the a-Perchlorination of Acyl Chlorides
Franco Bellesia,a Francesca D’Anna,b Fulvia Felluga,c Vincenzo Frenna,b Franco Ghelfi,*a Andrew F. Parsons,d
Federico Reverberi,*a Domenico Spinellie
a
Dipartimento di Chimica, Università degli Studi di Modena e Reggio Emilia, Via Campi 183, 41125 Modena, Italy
Fax +39(59)373543; E-mail: franco.ghelfi @unimore.it
Dipartimento di Chimica Organica ‘E. Paternò’, Università degli Studi di Palermo, Viale delle Scienze-Parco D’Orleans II,
b
90128 Palermo, Italy
c
Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Via L. Giorgeri 1, 34127 Trieste, Italy
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Dipartimento di Chimica ‘G. Ciamician’, Università degli Studi di Bologna, Via Selmi 2, 40126 Bologna, Italy
d
e
Received 25 October 2011; revised 7 December 2011
Dedicated to my mentor Dr. Laurent De Buyck for his contribution to chlorine chemistry
When, however, unfunctionalized 2,2-dichloroalkanoic
acids are needed, a non-connective approach is more ap-
propriate. This can be accomplished by: (i) dichloro-
deoxo-bisubstitution of b-oxo esters,2f,13 (ii) chlorination
Abstract: The preparation of a-perchloroacyl chlorides, from reac-
tion of the corresponding unfunctionalized acyl halides with chlo-
rine, was efficiently achieved under base-catalysis, using a
tetraalkylammonium chloride as catalyst. The process is solvent-
free and the procedure is easy, inexpensive, and suitable for scale- of b-haloenolates,14 (iii) oxidation of the trichlorovinyl
unit in RCCl=CCl2,15 (iv) chlorination–oxidation of cyclic
up.
acetals with trichloroisocyanuric acid,16 (v) a,a¢-perchlo-
Key words: acyl chlorides, halogenation, chlorine, base catalysis,
2,2-dichloroacyl chlorides
rination of methyl ketones, followed by haloformic cleav-
age,17 or (vi) oxidation of 2,2-dichloroaldehydes.5c,18 All
these processes have a common and intrinsic drawback:
they use highly functionalized starting materials that are
not straightforward to prepare.
2,2-Dichloroalkanoic acids, and derivatives, are valuable
and versatile substrates in organic chemistry,1 owing to
the bifunctional arrangement RCCl2COY (Y = OH, OR
etc.), which endows these molecules with a rich chemis-
try.2–6 Of particular importance for the preparation of C–
C bonds is the smooth generation of Ca radicals5 or b-Cl
enolates, through homolytic cleavage or reduction of one
C–Cl bond.6
Notwithstanding, until recently, 2,2-dichlorocarboxylic
acids 1, which were required to sustain our research on the
copper-catalyzed atom-transfer radical cyclization
(ATRC)
of
unsaturated
a-perchloroamides
3
(Scheme 1),5a,b were secured, on a large scale, by the oxi-
dation of 2,2-dichloroaldehydes.18a,19
These a-perhalogenated substances have been widely
used as starting materials to prepare natural compounds
(e.g., dipeptides,3g tyromycine,7a chaetomellic anhydride
A,5d,7b,c indolactam V,7d muscarines,4c and the unusual C9-
amino acid MeBmt7e) or synthetic drugs (e.g., hypoglyce-
mic agents7f). In addition, they can be components of bio-
active structures,8a,b or be exploited for their intrinsic
biological properties, e.g. 2,2-dichloropropanoic and 2,2-
dichlorobutanoic acids are well-known herbicides,8c
while w-substituted long-chain 2,2-dichloroaliphatic
acids are promising antidiabetics.8d Other interesting ap-
plications include use as acid catalysts9a,b or as substruc-
tures of reagents.9c,d
(COCl)2
DMF
R2
N
Cl Cl
R1
Cl Cl
R1
Cl Cl
R1
HN(All)R2
OH
Cl
O
1
O
2
O
3
R1
Cl
N
R2
N
Cl Cl
Cl
CuCl
R1
O
O
3
R2
4
Scheme 1 Typical reaction scheme for the preparation of a g-lactam
by ATRC
2,2-Dichloroalkanoic acids (and their derivatives) can be
prepared through connective strategies, following ionic,10
radical,11 or even pericyclic12 routes, largely based on the
use of [CCl2COY]– anions (or the corresponding ketene
acetals), CCl2COY radicals, or 2,2-dichloroketene. These
reactive intermediates are invariably obtained by the ma-
nipulation of di- or trichloroacetic acid derivatives.
However, we were conscious that the development of an
alternative, more economic, and less time-consuming
method to produce 2,2-dichloro acids 1 would be benefi-
cial. Now, we report that 2,2-dichloroacyl chlorides, acti-
vated derivatives of the a-perchloro acids, have been
successfully prepared by a-perhalogenation of unfunc-
tionalized acyl chlorides with chlorine under unprece-
dented chloride anion catalysis. The new process fills a
gap in the halogenation of acyl chlorides, and allows
straightforward access to a-perchloroacyl chlorides.
SYNTHESIS 2012, 44, 605–609
x
x
.x
x
.2
0
1
1
Advanced online publication: 26.01.2012
DOI: 10.1055/s-0031-1289678; Art ID: Z100911SS
© Georg Thieme Verlag Stuttgart · New York

606
F. Bellesia et al.
PAPER
These substances are indeed more useful and versatile ad- carboxylic acid derivatives as the primary products, which
ducts than the corresponding acids. For example, from our require a final hydrolysis step to free the carboxylic func-
perspective, a noteworthy benefit is the bypass of the ac- tion.
tivation step of 1, on the way to preparing the unsaturated
amides 3 (Scheme 1).
The only way to improve the preparation of 2,2-dichloro-
carboxylic acids, using the HVZ reaction, is to speed up
The Hell–Volhard–Zelinsky (HVZ) reaction is an old but the keto–enol equilibrium of the intermediate chloroacyl
useful way to achieve the a-halogenation of carboxylic chloride 8. This effect can be secured through the use of
acids 5 (Scheme 2).19 Some inorganic compounds, such as an appropriate base catalyst, which exploits the higher
thionyl chloride, phosphorus trichloride, or chlorosulfonic acidity of the Ca–H in 8. However, until now, this poten-
acid have been employed to catalyze the process and guar- tial solution has not been explored.
antee regioselective a-functionalization.19,20 Undesired
Some years ago we investigated an analogous halogena-
radical halogenations were suppressed through the addi-
tion; the a-perchlorination of aldehydes with chlorine.25
tion of a radical scavenger, usually oxygen, to the reaction
On that occasion the double halogenation at Ca was as-
sisted by the addition of a soluble chloride carrier to the
mixture.20a,d The mechanism of the a-halogenation relies
on the acid-catalyzed enolization of the key intermediate
reaction mixture. In fact, the small, symmetrical and
acyl chloride 6, formed by reaction between the inorganic
additive and the starting acid 5 (Scheme 2).20
densely charged Cl– ion can act as a ‘relatively’ strong
Brønsted base in aprotic solvents.26,27
We thus decided to test the same trick in the halogenation
of carboxylic acids with chlorine. Practically, we attempt-
ed the chlorination of neat pentanoic acid (5a), in the pres-
ence of thionyl chloride (to form some acyl chloride in the
reaction mixture) and tetraethylammonium chloride as the
halide carrier. Unfortunately, all the trials were disap-
pointing, yielding insignificant amounts of the expected
2,2-dichloro acid.
H
H
H
H H
H+
ClSO3H
OH
Cl
Cl
R
R
R
O
5
O
OH
7
6
H
Cl
H
Cl2
Cl
Cl
R
R
– HCl
O
8
OH
7
H
H
H
R
H
Cl
H
Cl
H
Cl2
a)
H
H
Cl
H
Cl Cl
Cl2/H+
– HCl
TBAC
Cl
OH
OH
+
Cl
+
Cl
Cl
Cl
R
R
R
R
R
R
– HCl
O
6
O
5
O
O
8
O
6
O
8
O
2
9
a
c
d
e
f
b
Scheme 2 Chlorosulfonic acid catalyzed a-halogenation of car-
boxylic acids20b
R
Pr
Hex
i-Pr
Me
Et
Ph
b)
Cl
The chlorination is typically accompanied by the second-
ary formation of a,a-dihalo adducts, whose yields in-
crease, extending the reaction times. However,
impractically long reaction times are required (even start-
ing from acyl chlorides 6) to achieve a reasonable amount
of a-perchlorinated products.20g This course likely stems
from the reduced basicity of the a-chloroacyl chloride
C=O, brought about by the electron-withdrawing effect of
the a-Cl, which makes 8 less prone to acid-catalyzed eno-
lization.20b,h As a consequence, successful a-perchlorina-
tion of acids or acyl chlorides requires severe conditions
(high temperatures, well above 150 °C and long reaction
times), as reported in the patent literature.3a,21 Phosphorus
pentachloride was also used as the halogenating agent
(again under harsh conditions), but this was only success-
ful when using phenylacetic acids.4b,22,23b
Cl
Cl Cl
H
Cl
Cl
Cl
R
R
O
O
H
H
Cl
Cl
8
10
Scheme 3 (a) The two step pathway for the a-perchlorination of
acyl chlorides 6; (b) plausible mechanism for the Cl– catalyzed enoli-
zation of haloacyl chlorides 8 followed by halogenation of the resul-
ting enols 10
We were not discouraged and attributed the reason for the
failure to the protic nature of the substrate, which, on sol-
vating the chloride anion, makes it less basic. Thus, we
tested the aprotic acyl chlorides 6, as substrates [Scheme 3
(a)]. But, due to the less polar nature of 6, tetraethylam-
monium chloride was insoluble and had to be replaced by
the more lipophilic tetrabutylammonium chloride. To our
great pleasure, the flow of chlorine/oxygen through a so-
lution of tetrabutylammonium chloride (10 mol%) in 6a,
at 110 °C (2 h), gave the a-chloroacyl chloride 8a and the
a,a-dichloroacyl chloride 2a in a 27:71 ratio. This prom-
ising result was the proof that the enolization of the
chloroacyl chlorides 8 is effectively promoted by Cl–
For the sake of completeness two other viable alterna-
tives, to the HVZ reaction, are the a-perchlorination of
nitriles, using chlorine/iodine or phosphorus pentachlo-
ride,24 or the a-perchlorination of amides (after their pre-
liminary conversion into the readily enolizable imidoyl
chlorides), with phosphorus pentachloride or chlorine.23
Even if these methods operate under milder conditions,
they are not really appealing since they form inactivated
Synthesis 2012, 44, 605–609
© Thieme Stuttgart · New York

PAPER
a-Perchlorination of Acyl Chlorides
607
[Scheme 3 (b)]. The chloride anion, furthermore, is also
continuously regenerated during the reaction [Scheme 3
(b)].25
Table 2 Larger-Scale Chlorination of Acyl Chlorides 6 Using Chlo-
rine and Tetrabutylammonium Chloridea
Entry Sub- TBAC Temp, time
strate (mol%)
Conv.b Ratiob Yieldc of
(%) 2/8 2 (%)
Table 1 Chlorination of Acyl Chlorides 6 with Chlorine and
Tetrabutylammonium Chloridea
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6e
6f
10
10
10
5
120→125 °C, 9 h 100
115→125 °C, 10 h 100
120→125 °C, 9 h 100
90→125 °C, 12 h 100
105→120 °C, 12 h 100
100→125 °C, 13 h 100
120→125 °C, 10 h 100
91:3 81
96:1 81
95:1 85
95:1 70
89:2 70
94:1 77
93:3 83
Entry Substrate (mL) Time (h) Conv.b (%) Ratiob 2/8 PHPc (%)
1
2
3
6a (10)
6b (10)
6c (14)
2
3
3
100
100
100
96:2
93:6
87:3
2
1
10
6
a Cl2 flow = 35–45 mL/min, O2 flow = 40–50 mL/min; conditions
TBAC (15 mol%), 120 °C.
1
b GC values.
7.7
c Polyhalogenated products.
a Substrate = 100 mL, Cl2 flow = 30–40 mL/min, O2 flow = 40–50
mL/min.
b GC values.
Several tests were then carried out on the reference sub-
strates 6a–c to optimize the reaction conditions and the
best results are collected in Table 1. During these studies,
we made a crucial observation; the chlorine flow rate can-
not be increased at will. If the chlorine feed exceeds the
halogen uptake by the reaction mixture, the catalytic pow-
er of Cl– declines, perhaps due to the formation of the less
c Determined on isolated product.
drohalogenation of 2, during its isolation via direct
distillation of the reaction mixture, if the distillation pot
reaches high temperatures (e.g., 105 °C for 2c).
Finally, we found that tetrabutylammonium chloride can
be recovered from the undistilled residue, after dilution
with dichloromethane and extraction with water. Water is
then removed by azeotropic distillation with toluene (no
attempt was made to purify and recycle the recovered tet-
rabutylammonium chloride).
– 28
basic trihalide anion Cl3 .
Encouraged by these good results, since we were, indeed,
interested in the preparation of large amounts of a-per-
chloroacyl chlorides 2, the scale-up of the process to a
mini-pilot plant, able to process 100 mL of substrate at a
time, was tried.
Cl2
TBAC
Cl
Cl2/H+
– HCl
Cl Cl
Cl Cl
As tetrabutylammonium chloride is rather expensive, the
relatively high percentage of catalyst (15 mol%), previ-
ously determined, could handicap the method, particular-
ly when used on very large scale. However, on
considering that the 10 times larger volume of the reaction
mixture and the choice to slightly decrease the chlorine
flow (from 40 to 35 mL/min) better satisfied the restric-
tion on chlorine intake, we reduced the catalyst charge to
10 mol%. Notwithstanding the lower amount of
tetrabutylammonium chloride, we were happy to see that
the halogenation of acyl halides 6 in the mini-pilot plant,
proceeded smoothly (Table 2, entries 1–3), affording even
better results than on a small scale.
Cl
Cl
Cl
O
2e
O
Cl
O
12
11
Scheme 4 Example of formation of a polyhalogenated byproduct
through elimination of HCl from an acyl chloride, and chlorine addi-
tion to the unsaturated intermediate
In this work we have described the first base-catalyzed a-
perhalogenations with chlorine of unfunctionalized acyl
chlorides. The catalytic action was brought about by na-
ked chloride anions, derived from a soluble tetraalkylam-
monium salt (tetrabutylammonium chloride). The process
The favorable conditions meant that the amount of cata- works excellently on a mini-pilot scale and benefits from
lyst could be further decreased to around 5 mol% without a number of useful properties: it is straightforward (many
compromising the outcome of the reactions (entries 4–7). acyl chlorides are commercially available or, alternative-
Indeed, the butanoyl chloride 6e gave the best perfor- ly, can be easily secured by chloro-de-hydroxylation of
mance with a tetrabutylammonium chloride charge as low carboxylic acids), inexpensive and solvent-free, it runs
as 1 mol% (entries 5 and 6). This improvement in selec- under relatively mild conditions and in reasonable times,
tivity is due to a reduction in polyhalogenated byproducts, it uses low charges of catalyst, and the catalyst can be
most likely those stemming from the chloride ion promot- even recovered. This novel method is, therefore, valuable
ed dehydrohalogenation of 2e (Scheme 4). We believe for laboratory preparations and, with the future in mind,
that the minimization of this side reaction, when small suitable for industrial applications.
amounts of tetrabutylammonium chloride are used, could
be a general phenomenon. The ability of Cl– to act as a
Acyl chlorides 6 were standard grade commercial substances, used
without further purification. TBAC was an Aldrich product of puri-
ty grade ‘purum’ (≥97%). O2 (3.5) and Cl2 (2.8) cylinders were sup-
base in elimination reactions is indeed well-document-
ed.26 It also accounts for the undesired Cl– induced dehy-
© Thieme Stuttgart · New York
Synthesis 2012, 44, 605–609

608
F. Bellesia et al.
PAPER
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2,2-Dichlorooctanoyl Chloride (2c); Typical Procedure
The core of the mini-pilot plant was made up of a cylindrical reactor
(140 mL, external diameter = 4.0 cm) fitted with a Liebig condens-
er, magnetic stirring bar, and a screw-capped adapter with a septum,
through which passes the Teflon pipe for delivering the Cl2/O2
downstream. The reaction chamber, filled with TBAC (16.23 g,
58.4 mmol) and octanoyl chloride (100 mL, 584 mmol), was heated
to 120 °C, while O2 was bubbled through the solution (40–50 mL/
min). When 120 °C was reached, the stream of Cl2 (35–45 mL/min)
was open and mixed to the O2 flow. After 5 h the temperature was
raised to 125 °C, and after a further 4 h at this temperature, the re-
action was stopped. The crude mixture was poured into a 500-mL
round-bottom flask and hexadec-1-ene was added to remove resid-
ual Cl2. The entire reaction sequence was repeated and the com-
bined crude mixtures were fractionally distilled, under vacuum,
through a packed column, to give clean 2,2-dichlorooctanoyl chlor-
ide (2c) (229.6 g, 85%) as a colorless liquid; bp 84–86 °C/1.6 mbar.
IR (film): 1786 cm–1 (C=O).
1H NMR (500 MHz, CDCl3): d = 0.89 (t, J = 6.9 Hz, 3 H), 1.31 (m,
6 H), 1.58 (m, 2 H), 2.44 (m, 2 H).
13C NMR (125.68 MHz, CDCl3): d = 14.1, 22.6, 25.0, 28.5, 31.4,
45.0, 90.1, 168.3 (C=O).
MS (EI, 70 eV): m/z (%) = 195 (1) [M+ – 35], 146 (9), 131 (20), 95
(100), 89 (30).
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Acknowledgment
We thank the Ministero dell’Istruzione, dell’Università e della
Ricerca (MIUR) for financial support (PRIN 20085E2LXC-004,
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Synthesis 2012, 44, 605–609
© Thieme Stuttgart · New York

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