Aromatic chlorination of ω-phenylalkylamines and ω- phenylalkylamides in carbon tetrachloride and α,α,α- trifluorotoluene

Article abstract of DOI:10.1039/b605010g

The aromatic halogenation of simple alkylbenzenes with chlorine proceeds smoothly in acetic acid but is much less efficient in less polar solvents. By contrast chlorination of ω-phenylalkylamines, such as 3-phenylpropylamine, occurs readily in either acetic acid, carbon tetrachloride or α,α,α-trifluorotoluene, and in the latter solvents gives high proportions of ortho-chlorinated products. These effects are attributable to the involvement of N-chloroamines as reaction intermediates, with intramolecular delivery of the chlorine electrophile. ω-Phenylalkylamides, such as 3-phenylpropionamide, also easily undergo aromatic chlorination in carbon tetrachloride and α,α,α-trifluorotoluene. These reactions generally show a first-order dependence on the substrate concentration, but not on the amount of chlorine. With carbon tetrachloride, very similar reaction rates are observed with chlorine concentrations ranging from 0.1-1.5 M. In α,α,α-trifluorotoluene, the rates reach a plateau at a chlorine concentration of approximately 0.2 M. These features indicate that the reactions proceed via the formation of intermediates which evidence suggests may be the corresponding O-chloroimidates. Irrespective of the mechanistic details, the reactions are remarkably rapid, being faster than analogous reactions in acetic acid and three to four orders of magnitude more rapid than reactions of simple alkylbenzenes in carbon tetrachloride. Therefore, chlorination of the amines and amides may be accomplished without the need for highly polar solvents, added catalysts or large excesses of chlorine, which are often employed for electrophilic aromatic substitutions. Although the use of carbon tetrachloride is becoming increasingly impractical due to environmental concerns, the trifluorotoluene is a suitable alternative. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b605010g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Aromatic chlorination of x-phenylalkylamines and x-phenylalkylamides in
carbon tetrachloride and a,a,a-trifluorotoluene
Jenny L. O’Connell,†a Jamie S. Simpson,‡a Paul G. Dumanski,a Gregory W. Simpsonb and
Christopher J. Easton*a
Received 6th April 2006, Accepted 25th May 2006
First published as an Advance Article on the web 8th June 2006
DOI: 10.1039/b605010g
The aromatic halogenation of simple alkylbenzenes with chlorine proceeds smoothly in acetic acid but
is much less efficient in less polar solvents. By contrast chlorination of x-phenylalkylamines, such as
3-phenylpropylamine, occurs readily in either acetic acid, carbon tetrachloride or a,a,a-trifluorotoluene,
and in the latter solvents gives high proportions of ortho-chlorinated products. These effects are
attributable to the involvement of N-chloroamines as reaction intermediates, with intramolecular
delivery of the chlorine electrophile. x-Phenylalkylamides, such as 3-phenylpropionamide, also easily
undergo aromatic chlorination in carbon tetrachloride and a,a,a-trifluorotoluene. These reactions
generally show a first-order dependence on the substrate concentration, but not on the amount of
chlorine. With carbon tetrachloride, very similar reaction rates are observed with chlorine
concentrations ranging from 0.1–1.5 M. In a,a,a-trifluorotoluene, the rates reach a plateau at a chlorine
concentration of approximately 0.2 M. These features indicate that the reactions proceed via the
formation of intermediates which evidence suggests may be the corresponding O-chloroimidates.
Irrespective of the mechanistic details, the reactions are remarkably rapid, being faster than analogous
reactions in acetic acid and three to four orders of magnitude more rapid than reactions of simple
alkylbenzenes in carbon tetrachloride. Therefore, chlorination of the amines and amides may be
accomplished without the need for highly polar solvents, added catalysts or large excesses of chlorine,
which are often employed for electrophilic aromatic substitutions. Although the use of carbon
tetrachloride is becoming increasingly impractical due to environmental concerns, the trifluorotoluene
is a suitable alternative.
involves intermolecular delivery of the chlorine to the aromatic
moiety, except in the case of the acetanilides where one of the
proposed mechanisms for aromatic substitution involves migra-
tion of chlorine within the conjugated p-system. Intramolecular
Introduction
Electrophilic aromatic substitution is one of the most widely
used and extensively studied classes of organic reactions.1 Some
of the factors that affect the reactivity towards substitution
delivery of a nitro group through coordination to a functionalised
include substituents on the aromatic substrate, the nature of
alkyl substituent has been exploited to enhance reaction rates and
control the regioselectivity in electrophilic aromatic nitrations7
but, to the best of our knowledge, no such chaperon effect has
been reported for aromatic chlorinations. In this context, we now
report the efficient chlorination of x-arylalkylamines and amides
in either carbon tetrachloride or a,a,a-trifluorotoluene, without
added catalyst. The latter solvent is attracting increasing attention
as an environmentally benign option that is resistant to both free
radical and ionic processes.8
the electrophile and the polarity of the solvent. Chlorination
of monoalkylbenzenes with chlorine typically requires a polar
solvent, such as acetic acid, or a Lewis acid catalyst such
as iron or aluminium trichloride. Amines have been found to
catalyse chlorination of activated aromatic species in non-polar
solvents and this has been attributed to in situ formation of N-
chloroamines.2 N-Chloroamines have also been used directly as
reagents for aromatic chlorination, usually in acidic media.3 N-
Chlorosuccinimide is reported to effect aromatic chlorination in
carbon tetrachloride in the presence of silica.4 Amides react with
molecular chlorine to give N-haloamides5 and, in the case of
acetanilides, such species are known to rearrange under acidic
conditions to give aromatic chlorides.6 Each of the above processes
Results and discussion
For the purpose of comparison, we first examined the chlorination
of compounds 1a–5a in acetic acid. The reactions proceed
◦
smoothly using 0.1–1.0 M chlorine at 25 C over 4–48 h, to give
aResearch School of Chemistry, Australian National University, Canberra,
ACT, 0200, Australia. E-mail: easton@rsc.anu.edu.au
clean mixtures of the ortho- and para-substituted monochlorides
1b,c–5b,c. These were identified either by comparison with litera-
ture data and authentic samples or through full characterisation.
The rates of reaction were examined in acetic acid-d4 but under
otherwise identical conditions, to allow for direct analysis using 1H
NMR spectroscopy. As expected,9 the reactions are second order,
bCSIRO Molecular and Health Technologies, Clayton, VIC, 3169, Australia
† Current address: CSIRO Molecular and Health Technologies, Clayton
VIC 3169, Australia
‡ Current address: Department of Medicinal Chemistry, Victorian College
of Pharmacy, Monash University, Parkville VIC 3052, Australia
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Table 1 Rate constants and product ratios for chlorination of compounds
Table 2 Product ratios for chlorination of the amines 6a–8a in various
1a–5a in CD3CO2D at 25 ◦
C
solvents at 25 ◦
C
Product ratio 6b–8b : 6c–8c
Starting material
CD3CO2D
CCl4
CF3Ph
Ph(CH2)2NH2 (6a)
Ph(CH2)3NH2 (7a)
Ph(CH2)4NH2 (8a)
—
60 : 40
—
>95:5a
77 : 23
62 : 38
81 : 19
67 : 33
60 : 40
a One product within limits of detection using 1H NMR spectroscopy.
Product ratio
1b–5b : 1c–5c
Rate constant
Starting material
k/M−1 s−1
◦
for reaction of 3-phenylpropylamine (7a) in acetic acid at 25 C
was determined to be 7.6 × 10−5 M−1 s−1, similar to those
values obtained for compounds 1a–5a in this solvent. In contrast,
whereas compounds 1a–5a are much less reactive in either
carbon tetrachloride or a,a,a-trifluorotoluene, the reactivity of
the amines 6a–8a in these solvents is qualitatively similar to
that in acetic acid. The reactions of the amines 6a–8a in carbon
tetrachloride and a,a,a-trifluorotoluene are heterogeneous, with a
colourless precipitate forming in each case, so it was impractical
to determine rate constants for these processes. Nevertheless, in
either acetic acid, carbon tetrachloride or a,a,a-trifluorotoluene
with approximately 1 M chlorine, the reactions proceed to 90%
completion in 10 h. This compares with less than 5% reaction
after four days for the reactions of compounds 1a–5a in carbon
tetrachloride, and is particularly remarkable considering that the
reactions of the amines 6a–8a in either carbon tetrachloride or
a,a,a-trifluorotoluene are heterogeneous and presumably require
exchange between the solid and solution phases for complete
reaction to occur.
PhMe (1a)
56 : 44
52 : 48
38 : 62
50 : 50
51 : 49
2.7 × 10−4
2.2 × 10−4
1.2 × 10−4
2.6 × 10−5
2.2 × 10−5
PhEt (2a)
Ph-i-Bu (3a)
Ph(CH2)2CO2H (4a)
Ph(CH2)2CO2Me (5a)
depending directly on the concentrations of both the substrates
1a–5a and chlorine. The second order reaction rate constants and
the ratios of the products 1b–5b : 1c–5c are summarised in Table 1.
The data for the reactions of toluene (1a) and ethylbenzene (2a)
are in good agreement with literature values.10 Isobutylbenzene
(3a) is less reactive than either of these and affords a smaller
proportion of the ortho-substituted product 3b, presumably due
to the greater bulk of the alkyl substituent. The ratios of formation
of the chlorides 4b,c and 5b,c are very similar to that of the
ethylbenzene derivatives 2b and 2c, but the reaction rates for the
acid 4a and the ester 5a are around an order of magnitude slower
than those of the alkylbenzenes 1a–3a. This decrease is too large
to be attributed to remote inductive deactivation by the carboxyl
groups of the acid 4a and the ester 5a and is more consistent with
a general field effect.
When each of the amines 6a–8a was added to a solution of
chlorine in carbon tetrachloride, a precipitate formed almost
1
instantaneously. The H NMR spectra of the filtered solutions
Using either carbon tetrachloride or a,a,a-trifluorotoluene
instead of acetic acid, but under otherwise identical conditions,
the reactivity of the alkylbenzenes 1a–5a is reduced by at least two
to three orders of magnitude. For example, in carbon tetrachloride
are quite different to those of the parent amines 6a–8a. For 2-
phenylethylamine (6a) the triplet methylene resonances move from
d 2.7 and 2.9 ppm, to d 3.1 and 3.9 ppm, while for the propylamine
7a and the butylamine 8a, one of the triplet methylene resonances
shifts downfield by around 0.9 ppm. This is consistent with the
formation of N-chloroamines.3 The hydrogen chloride by-product
likely results in the formation of the corresponding N-chloroamine
hydrochlorides, which would account for the observed precipitates.
A simple explanation for the high reactivity of the amines 6a–
8a in carbon tetrachloride and a,a,a-trifluorotoluene is therefore
that the reactions are proceeding via the corresponding N-
chloroamines, with intramolecular delivery of the chlorine. This
would account for the formation of the greater proportion of
the ortho-chlorinated product 6b from the more constrained
ethylamine 6a, an effect that is also observed to some extent with
the propylamine 7a.
1
there is no evidence of chlorination of compounds 1a–5a by H
NMR spectroscopy after four days, indicating that the second or-
der rate constants for these processes are <3 × 10−7 M−1 s−1. The re-
duced rates are consistent with the lower polarity of these solvents.
Such marked solvent effects on the reaction rates are not seen
with either the amines 6a–8a or the amides 9a–16a. Reactions
of the amines 6a–8a in either acetic acid, carbon tetrachloride
or a,a,a-trifluorotoluene cleanly give the chlorides 6b,c–8b,c, that
were characterised as their acetate salts by comparison with
literature data.11
Relative to the reactions of compounds 1a–5a, the amines
6a–8a give higher proportions of the ortho-chlorinated products
6b–8b, particularly in the cases of the ethylamine 6a and the
propylamine 7a and their reactions in carbon tetrachloride and
a,a,a-trifluorotoluene (Table 2). The second order rate constant
Reactions of the amides 9a–16a give clean mixtures of the chlo-
rides 9b,c–16b,c. These compounds were either fully characterised
or identified by comparison with literature data. In acetic acid,
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the chlorination of 3-phenylpropionamide (10a) affords a 61 : 39
ratio of the products 10b and 10c. The reaction was established
to be a second order process, for which the rate constant was
determined to be 4.1 × 10−5 M−1 s−1, similar to those values
obtained for compounds 1a–5a and 7a in this solvent. The ratios
of the products of the reactions of the amides 9a–16a in carbon
tetrachloride and a,a,a-trifluorotoluene, and the pseudo-first order
rate constants for the reactions of the primary and secondary
amides 9a–15a are summarised in Table 3. In these solvents the
reactions of the primary and secondary amides 9a–15a generally
show a first-order dependence on the substrate concentration, but
not on the amount of chlorine. With carbon tetrachloride, very
similar reaction rates are observed with chlorine concentrations
ranging from 0.1–1.5 M. In a,a,a-trifluorotoluene, the rates reach
a plateau at a chlorine concentration of approximately 0.2 M. The
onset of the pseudo-first order reactions of the acetamides 12a–14a
is delayed, by approximately one hour for the phenylethylamide
12a and ten minutes in the other two cases. These induction periods
correspond to approximately 10% of the time taken for reaction
of 90% of the substrates. The reaction of the tertiary amide 16a in
carbon tetrachloride is even more peculiar, showing no evidence
of reaction detectable by H NMR spectroscopy for the first 6–
7 hours, but then effectively going to completion within the next
3 hours.
These features indicate that the reactions of the amides 9a–
15a in carbon tetrachloride and a,a,a-trifluorotoluene proceed
via the formation of intermediates, which react to give the
chlorides 9b,c–15b,c in rate-determining first order processes,
the rates of which are not proportional to the concentration of
chlorine. The 1H NMR spectra recorded at early stages of reaction
indicate formation of another species that, in the cases of the
acetamide 9a, the propionamide 10a, the acetamide 12a and the N-
methylpropionamide 15a were identified as the corresponding N-
chloroamides by comparison with authentic samples. Alone, such
1
Table 3 Rate constants and product ratios for chlorination of the amides 9a–16a in various solvents at 25 ◦
C
Starting material
Solvent
[Cl2]/M
Product ratioa 9b–16b : 9c–16c
Rate constant kꢀ/s−1
9a
CCl4
CF3Ph
0.88
0.05
1.01
0.13
0.05
1.01
1.29
0.05
1.01
1.04b
0.90b
0.94b
1.28
63 : 37
64 : 36
2.1 × 10−6
7.5 × 10−7
3.8 × 10−6
1.7 × 10−4
4.4 × 10−4
8.8 × 10−4
4.4 × 10−4
7.8 × 10−4
2.6 × 10−3
8.5 × 10−5
3.1 × 10−4
3.8 × 10−4
8.9 × 10−5
n/ac
10a
11a
CCl4
CF3Ph
55 : 45
55 : 45
CCl4
CF3Ph
45 : 55
55 : 45
12a
13a
14a
15a
16a
CCl4
CCl4
CCl4
CCl4
CCl4
48 : 52
40 : 60
40 : 60
55 : 45
60 : 40
a Yields of the crude mixtures of the chlorides 9b,c–16b,c were essentially quantitative. b Reactions displayed first order kinetics after an induction period
of approximately 1 h for 12a and 10 min for 13a and 14a. c Reaction of the tertiary amide 16a displayed neither first nor second order kinetics, going to
completion within 3 h after an induction period of 6–7 h.
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materials do not account for the formation of the chlorides 9b,c–
15b,c, however, as the chloride derived from the propionamide 10a
was found to be inert when left to stand in carbon tetrachloride
in the absence of chlorine, for extended periods at 25 ◦C. It
was also considered that the reactive intermediates could be
the protonated N-chloroamides, formed through reaction with
hydrogen chloride that would be present as a by-product of the
N-chloroamide formation. This possibility was also discounted,
however, as the N-chloropropionamide does not react when left
to stand in carbon tetrachloride containing added hydrogen
chloride, but in the absence of chlorine, for extended periods at
25 ◦C. Adding hydrogen chloride part-way through the reaction of
the propionamide 10a with chlorine also has no effect on the rate of
aromatic chlorination. On this basis we tentatively suggest that the
reactive intermediates are O-chloroimidates 19 present as minor
components in equilibrium with amides 17 and N-chloroamides
18, with the equilibration requiring both chlorine and hydrogen
chloride (Scheme 1), possibly as the hydrogen chloride perchloride
complex.12 The equilibration must then be rapid relative to the rate
of the subsequent aromatic substitution.
similar chlorine concentrations are 1.7 × 10−4 s−1 (0.13 M chlorine)
in carbon tetrachloride and 4.4 × 10−4 s−1 (0.05 M chlorine) in
a,a,a-trifluorotoluene.
It seems likely that the reactions of the amides 9a–16a in-
volve mostly intramolecular delivery of the chlorine electrophile,
however, the corresponding intermolecular reactions are also
accelerated. This is demonstrated by the increase in the pseudo-
first order rate constant for the reaction of toluene (1a) in carbon
tetrachloride with 1 M chlorine, from <3 × 10−7 s−1 to 1.5 ×
10−6 s−1, through the addition of 0.015 M 3-phenylpropionamide
(10a). This preliminary experiment shows that simple amides
might also find application as chlorination catalysts in non-
polar solvents. In any event, the reactions of the amines 6a–
8a and the amides 9a–16a in carbon tetrachloride and a,a,a-
trifluorotoluene proceed efficiently, without the need for either
highly polar solvents, added catalysts or large excesses of chlorine,
that are often employed for electrophilic aromatic chlorinations.
Experimental
General experimental
NMR spectra were recorded on either a Varian Gemini 300
spectrometer or a Varian Inova 500 spectrometer. Electron impact
mass spectra (MS) were recorded on a VG Autospec double
focussing trisector mass spectrometer operating at 70 eV. The
Research School of Chemistry Analytical Services Unit at the
Australian National University carried out the elemental analyses.
Melting points (mp) were determined on a Kofler hot-stage
melting point apparatus under a Reichert microscope and are
uncorrected. Chromatography was performed on a Chromatotron
model 7924T using plates prepared with Merck-Silica gel 60 PF254
containing gypsum. HPLC was performed using a reverse-phase
YMC-Pack ODS-AQ 250 × 20 mm column, eluting with a mixture
of acetonitrile–water at a flow rate of 10 mL min−1.
Scheme 1 Putative formation of O-chloroimidate reaction intermediates.
The tertiary amide 16a is unable to react to give either an N-
chloroamide or an O-chloroimidate, with hydrogen chloride as
Chlorine was provided by BOC Gases. Toluene (1a) and ethyl-
benzene (2a) were purchased from Ajax. Acetic acid, carbon tetra-
chloride, (2-methylpropyl)benzene (3a), 3-phenylpropionic acid
(4a), 3-phenylpropylamine (7a) and 4-phenylbutylamine (8a) were
obtained from Sigma-Aldrich. 2-Chlorotoluene (1b) was bought
from EGA-Chemie. 4-Chlorotoluene (1c) and 2-phenylethylamine
(6a) were purchased from BDH. a,a,a-Trifluorotoluene was ob-
tained from Fluka and acetic acid-d4 from Cambridge Isotope
Laboratories Inc., MA. Carbon tetrachloride was purified ac-
cording to the procedure described by Armarego and Perrin.13 To
ensure that acetic acid and acetic acid-d4 were free of water, they
were each treated with 1% (v/v) of the corresponding anhydride.
Stock solutions of chlorine in acetic acid, acetic acid-d4,
carbon tetrachloride and a,a,a-trifluorotoluene were prepared by
passing chlorine through the solvents at room temperature until
the solutions were bright yellow. Chlorine concentrations were
determined by measuring the absorbance at 380 nm. Calibration
graphs of absorbance versus chlorine concentration were prepared
by iodometric titration of iodine, produced by adding potassium
iodide to the solutions.14
a by-product. It follows that, in this case, the reaction probably
+
=
involves analogous charged species [e.g., RC(OCl) N Me2]. Pre-
sumably the reason for the peculiar delay observed in the onset of
this reaction is that the acid required for catalytic formation of the
reactive intermediates only becomes available through the initial
stages of the electrophilic aromatic substitution. The reaction then
becomes autocatalytic.
Irrespective of the mechanistic details of the reactions of the
amides 9a–15a in carbon tetrachloride and a,a,a-trifluorotoluene,
they are remarkably rapid. To draw a meaningful comparison
between these pseudo-first order chlorinations and others that
are second order, it is necessary to specify a chlorine concen-
tration. Accordingly, with 0.13 M chlorine, the reaction of the
propionamide 10a in carbon tetrachloride (kꢀ = 1.7 × 10−4 s−1)
is approximately thirty times faster than its reaction in acetic
acid (kꢀ = 5.3 × 10−6 s−1 = 0.13 × (k) 4.1 × 10−5 M−1 s−1).
Furthermore, using 0.1 M chlorine, the reactions of the amides
9a–15a are typically three to four orders of magnitude faster
than those of compounds 1a–5a in carbon tetrachloride. For
example, with 0.1 M chlorine the second and pseudo-first order
rate constants for the reactions of compounds 1a–5a are all <3 ×
10−7 M−1 s−1 and <3 × 10−8 s−1, respectively, whereas the first order
rate constants for the reactions of the phenylpropionamide 10a at
The amides 9a–11a, 15a and 16a were prepared by treatment of
the corresponding carboxylic acids with thionyl chloride and then
either ammonia, methylamine or dimethylamine. The acetamides
12a–14a were prepared from the corresponding amines 6a–8a by
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acetylation with acetic anhydride. The physical and spectroscopic
data for these compounds are consistent with literature values.15
(CD3CO2D) d 7.28 (m, 4H), 3.06 (t, J 8.0 Hz, 2H), 2.70 (t, J
8.0 Hz, 2H); 1H NMR (CDCl3) d 7.28 (m, 4H), 3.08 (t, J 7.5 Hz,
2H), 2.72 (t, J 7.5 Hz, 2H); HPLC acetonitrile–water (60 : 40), RT
5.6 min. The spectroscopic data for this compound are consistent
with literature values.19 For 3-(4-chlorophenyl)propionic acid (4c):
colourless crystals; 42%; mp 119–121 ◦C (lit.20 mp 120–122 ◦C); 1H
NMR (CD3CO2D) d 7.27 (d, J 8.5 Hz, 2H), 7.20 (d, J 8.5 Hz, 2H),
Methyl 3-phenylpropionate (5a). 3-Phenylpropionic acid (4a)
(1.5 g, 10 mmol) was stirred with thionyl chloride (1.2 g, 10 mmol)
for 0.5 h, then the resultant mixture was added dropwise to dry
methanol (50 mL) cooled to 0 ◦C. The solution was stirred at
room temperature for 0.5 h, and then it was concentrated under
reduced pressure. Chromatography of the residue on silica, eluting
with dichloromethane, gave the ester 5a as a colourless oil (1.54 g,
1
2.92 (t, J 8.0 Hz, 2H), 2.68 (t, J 8.0 Hz, 2H); H NMR (CDCl3)
d 7.27 (d, J 8.5 Hz, 2H), 7.14 (d, J 8.5 Hz, 2H), 2.93 (t, J 7.5 Hz,
2H), 2.67 (t, J 7.5 Hz, 2H); HPLC acetonitrile–water (60 : 40), RT
6.4 min. The spectroscopic data for this compound are consistent
with literature values.20
1
95%). H NMR (CDCl3) d 7.35 (m, 5H), 3.68 (s, 3H), 2.96 (t, J
8.0 Hz, 2H), 2.64 (t, J 8.0 Hz, 2H). The physical and spectroscopic
data for this compound are consistent with literature values.16
General procedure for preparation of the chlorides 1b,c–5b,c.
Solutions of compounds 1a–5a (2–10 mmol) in acetic acid
(100 mL) containing chlorine (1 M) were left to stand in the dark
Methyl 3-(2-chlorophenyl)propionate (5b) and methyl 3-(4-
chlorophenyl)propionate
(5c). Reaction
of
methyl
3-
phenylpropionate (5a) with chlorine in acetic acid according to
the general procedure gave a 51 : 49 mixture of the chlorides
5b and 5c, which were separated by HPLC. For methyl 3-(2-
chlorophenyl)propionate (5b): colourless oil; 41%; 1H NMR
(CD3CO2D) d 7.24 (m, 4H), 3.66 (s, 3H), 3.04 (t, J 8.0 Hz, 2H),
◦
at 25 C for 4–48 h, until all of the starting materials 1a–5a had
been consumed as determined by TLC analysis. Excess chlorine
was then removed by passing nitrogen through the solutions until
the yellow colour faded, then the mixtures were concentrated
under reduced pressure. HPLC of the residues, followed by
recrystallisation in the cases of the chlorides 4b,c, afforded the
products 1b,c–5b,c either as discrete compounds or as mixtures of
the regioisomers.
1
2.66 (t, J 8.0 Hz, 2H); H NMR (CDCl3) d 7.22 (m, 4H), 3.68
(s, 3H), 3.08 (t, J 8.0 Hz, 2H), 2.65 (t, J 8.0 Hz, 2H); HPLC
acetonitrile–water (60 : 40), RT 10.2 min. The spectroscopic
data for this compound are consistent with literature values21
and those of an authentic sample prepared by treatment of
the acid 4b with thionyl chloride and methanol. For methyl
3-(4-chlorophenyl)propionate (5c): colourless oil; 41%; 1H NMR
(CCl4) d 7.25 (d, J 8.5 Hz, 2H), 7.17 (d, J 8.5 Hz, 2H), 3.65 (s,
2-Chlorotoluene (1b) and 4-chlorotoluene (1c). Reaction of
toluene (1a) with chlorine in acetic acid according to the general
procedure gave a 92% yield of a 56 : 44 mixture of the chlorides
1b and 1c, which was characterised by comparison of its 1H NMR
spectrum with those of commercial samples of the individual
components. 1H NMR (CD3CO2D) d 7.19 (m, 4H), 2.34 (s, 0.56 ×
3H), 2.29 (s, 0.44 × 3H).
2-Chloroethylbenzene (2b) and 4-chloroethylbenzene (2c). Re-
action of ethylbenzene (2a) with chlorine in acetic acid according
to the general procedure gave a 90% yield of a 52 : 48 mixture of
the chlorides 2b and 2c as a colourless oil, which was characterised
by comparison of its 1H NMR spectrum with literature data.17 1H
NMR (CCl4) d 7.15 (m, 4H), 2.74 (q, J 7.5 Hz, 0.52 × 2H), 2.60
(q, J 7.5 Hz, 0.48 × 2H), 1.24 (t, J 7.5 Hz, 0.52 × 3H), 1.22 (t, J
7.5 Hz, 0.48 × 3H); 1H NMR (CD3CO2D) d 7.21 (m, 4H), 2.73 (q,
J 7.5 Hz, 0.52 × 2H), 2.59 (q, J 7.5 Hz, 0.48 × 2H), 1.20 (m, 3H).
1
3H), 2.90 (t, J 8.0 Hz, 2H), 2.64 (t, J 8.0 Hz, 2H); H NMR
(CD3CO2D) d 7.26 (d, J 8.5 Hz, 2H), 7.17 (d, J 8.5 Hz, 2H),
3.65 (s, 3H), 2.90 (t, J 7.5 Hz, 2H), 2.63 (t, J 7.5 Hz, 2H); HPLC
acetonitrile–water (60 : 40), RT 11.7 min. The spectroscopic data
for this compound are consistent with literature values22 and
those of an authentic sample prepared by treatment of the acid 4c
with thionyl chloride and methanol.
Determination of the rates of reaction of compounds 1a–5a with
chlorine
Solutions of compounds 1a–5a (ca. 1 mg) in acetic acid-d4 (0.5 mL)
containing chlorine (0.1–1.0 M), in NMR tubes sealed with
2-Chloro-(2-methylpropyl)benzene (3b) and 4-chloro-(2-methyl-
propyl)benzene (3c). Reaction of (2-methylpropyl)benzene (3a)
with chlorine in acetic acid according to the general procedure
gave an 85% yield of a 38 : 62 mixture of the chlorides 3b and 3c as
a colourless oil. 1H NMR (CD3CO2D) d 7.24 (m, 4H), 2.60 (d, J
7.0 Hz, 0.38 × 2H), 2.44 (d, J 7.0 Hz, 0.62 × 2H), 1.96 (m, 0.38 ×
1H), 1.82 (m, 0.62 × 1H), 0.90 (m, 6H); 13C NMR (CDCl3) d 143.2,
140.0, 139.2, 131.3, 130.4, 129.4, 128.1, 127.1, 126.3, 44.7, 42.6,
Rototiteꢀ valves, were maintained in the dark at 25 ◦C for 4–
R
1
48 h. H NMR spectra of the mixtures were recorded at regular
intervals and integrated to determine the ratios of the residual
starting materials 1a–5a and the products 1b,c–5b,c. Second order
rate constants, k, for the reactions were then derived from these
data according to eqn (1),23 where [A] is the concentration of
compound 1a–5a. The rate constants are summarised in Table 1.
The ratios of the products 1b,c–5b,c formed in these reactions
are indistinguishable from those of the reactions carried out in
unlabelled acetic acid.
•
•
30.2, 28.7, 22.4, 22.2; MS m/z (%) 170 (M+ , 10), 168 (M+ , 25),
127 (35), 125 (100); (Found: C, 71.08; H, 7.71%. C10H13Cl requires
C, 71.21; H, 7.77%).
3-(2-Chlorophenyl)propionic acid (4b) and 3-(4-chlorophenyl)-
propionic acid (4c). Reaction of 3-phenylpropionic acid (4a)
with chlorine in acetic acid according to the general procedure
gave a 1 : 1 mixture of the chlorides 4b and 4c, which were
separated by HPLC. For 3-(2-chlo◦rophenyl)propionic acid (4b):
colourless crystals; 37%; mp 94–96 C (lit.18 mp 96 ◦C); 1H NMR
−d[A]/dt = k[A][Cl2]
(1)
Using carbon tetrachloride as the solvent but under otherwise
identical conditions, there was no evidence of chlorination of
compounds 1a–5a after 4 days, even at the highest chlorine
concentration (1.0 M).
2720 | Org. Biomol. Chem., 2006, 4, 2716–2723
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General procedure for preparation of the chlorides 6b,c–8b,c
7.2 min. The spectroscopic data for this compound are consistent
with literature values.26
Reactions of compounds 6a–8a with chlorine as described above
for the synthesis of the chlorides 1b,c–5b,c, except that the reac-
tions were carried out in either acetic acid, carbon tetrachloride or
a,a,a-trifluorotoluene, and the heterogeneous mixtures involved
when using the latter two solvents were stirred, affording the
chlorides 6b,c–8b,c, which were treated with acetic acid and
characterised as their colourless acetate salts by comparison with
literature data.11 The ratios of formation of the regioisomers 6b,c–
8b,c in the various solvents are summarised in Table 2.
3-(4-Chlorophenyl)propionamide (10c). Colourless crystals;
◦
◦
mp 127–128 C (lit.27 129–130 C); H NMR (CCl4) d 7.19 (d,
J 8.5 Hz, 2H), 7.09 (d, J 8.5 Hz, 2H), 5.50 (bs, 1H), 5.00 (bs, 1H),
2.87 (t, J 7.5 Hz, 2H), 2.37 (t, J 7.5 Hz, 2H); 1H NMR (CD3CO2D)
d 7.26 (d, J 8.5 Hz, 2H), 7.20 (d, J 8.5 Hz, 2H), 2.92 (t, J 8.0 Hz,
2H), 2.58 (t, J 8.0 Hz, 2H); HPLC acetonitrile–water (60 : 40), RT
7.9 min.
1
4-(2-Chlorophenyl)butyramide (11b). Colourless crystals; mp
96–97 ◦C; 1H NMR (CCl4) d 7.17 (m, 4H), 2.75 (t, J 7.5 Hz, 2H),
2.11 (t, J 7.5 Hz, 2H), 1.89 (m, 2H); 1H NMR (CDCl3) d 7.24 (m,
4H), 5.65 (bs, 2H), 2.79 (t, J 7.5 Hz, 2H), 2.28 (t, J 7.5 Hz, 2H),
1.98 (apparent quintet, J 7.5 Hz, 2H); 13C NMR (CDCl3) d 175.2,
138.9, 133.9, 130.5, 129.5, 127.5, 126.8, 35.0, 32.7, 25.3; MS m/z
2-(2-Chlorophenyl)ethylamine (6b). 1H NMR (CD3CO2D) d
7.29 (m, 4H), 3.32 (t, J 8.0 Hz, 2H), 3.15 (t, J 8.0 Hz, 2H); HPLC
acetonitrile–water–acetic acid (49 : 49 : 2), RT 5.8 min.
2-(4-Chlorophenyl)ethylamine (6c). 1H NMR (CD3CO2D) d
7.32 (m, 4H), 3.30 (t, J 8.0 Hz, 2H), 3.01 (t, J 8.0 Hz, 2H); HPLC
acetonitrile–water–acetic acid (49 : 49 : 2), RT 6.2 min.
•
•
(%) 199 (M+ , 5), 197 (M+ , 16), 162 (23), 125 (26), 89 (18), 59
(100); HPLC acetonitrile–water (60 : 40), RT 7.9 min; (Found: C,
60.55; H, 5.98; N, 6.98%. C10H12ClNO requires C, 60.76; H, 6.12;
N, 7.09%).
3-(2-Chlorophenyl)propylamine (7b). 1H NMR (CD3CO2D) d
7.28 (m, 4H), 3.14 (t, J 7.5 Hz, 2H), 2.84 (t, J 7.5 Hz, 2H), 2.07 (m,
2H); HPLC acetonitrile–water–acetic acid (49 : 49 : 2), RT 6.1 min.
4-(4-◦Chlorophenyl)butyramide (11c). Colourless crystals; mp
3-(4-Chlorophenyl)propylamine (7c). 1H NMR (CD3CO2D) d
7.30 (m, 4H), 3.09 (t, J 7.5 Hz, 2H), 2.70 (t, J 7.5 Hz, 2H), 2.09 (m,
2H); HPLC acetonitrile–water–acetic acid (49 : 49 : 2), RT 6.4 min.
◦
1
95–98 C (lit.28 mp 112–113 C); H NMR (CCl4) d 7.18 (d, J
8.0 Hz, 2H), 7.07 (d, J 8.0 Hz, 2H), 5.59 (bs, 1H), 5.05 (bs, 1H),
1
2.61 (t, J 7.5 Hz, 2H), 2.09 (t, J 7.5 Hz, 2H), 1.89 (m, 2H); H
4-(2-Chlorophenyl)butylamine (8b). 1H NMR (CD3CO2D) d
7.26 (m, 4H), 3.12 (m, 2H), 2.77 (t, J 8.0 Hz, 2H), 1.80 (m, 4H);
HPLC acetonitrile–water–acetic acid (49 : 49 : 2), RT 5.9 min.
NMR (CDCl3) d 7.24 (d, J 8.0 Hz, 2H), 7.10 (d, J 8.0 Hz, 2H),
5.50 (bs, 2H), 2,64 (t, J 7.5 Hz, 2H), 2.22 (t, J 7.5 Hz, 2H), 1.95
(apparent quintet J 7.5 Hz, 2H); 13C NMR (CDCl3) d 176.9, 139.5,
•
131.7, 129.8. 128.5, 34.7, 34.3, 26.6; MS m/z (%) 199 (M+ , 8), 197
4-(4-Chlorophenyl)butylamine (8c). 1H NMR (CD3CO2D) d
7.25 (m, 4H), 3.10 (m, 2H), 2.63 (t, J 8.0 Hz, 2H), 1.85 (m, 4H);
HPLC acetonitrile–water–acetic acid (49 : 49 : 2), RT 6.2 min.
•
(M+ , 27), 125 (27), 59 (100); HPLC acetonitrile–water (60 : 40),
RT 9.1 min; (Found: C, 60.63; H, 6.20; N, 7.04%. C10H12ClNO
requires C, 60.76; H, 6.12; N, 7.09%).
N-(2-(2-Chlorophenyl)ethyl)acetamide (12b). Colourless oil;
1H NMR (CCl4) d 7.22 (m, 4H), 5.38 (b, 1H), 3.42 (apparent
q, J 7.0 Hz, 2H), 3.92 (t, J 7.0 Hz, 2H), 1.64 (s, 3H); H NMR
(CDCl3) d 7.28 (m, 4H), 5.53 (b, 1H), 3.53 (apparent q, J 7.0 Hz,
2H), 2.96 (t, J 7.0 Hz, 2H), 1.95 (s, 3H); HPLC acetonitrile–water
(60 : 40), RT 9.5 min. The spectroscopic data for this compound
are consistent with literature values.29
General procedure for preparation of the chlorides 9b,c–16b,c
1
Reactions of compounds 9a–16a with chlorine as described above
for the synthesis of the chlorides 1b,c–5b,c, except that the reac-
tions were carried out in either acetic acid, carbon tetrachloride
or a,a,a-trifluorotoluene, afforded the chlorides 9b,c–16b,c. The
ratios of formation of the regioisomers 9b,c–16b,c in the various
solvents are summarised in Table 3. The pairs of regioisomers
9b–16b and 9c–16c were separated using HPLC.
N-(2-(4-Chlo◦rophenyl)ethyl)acetamide (12c). Colourless crys-
tals; mp 94–95 C (lit.29 mp 96 ◦C); 1H NMR (CCl4) d 7.23 (d, J
8.0 Hz, 2H), 7.09 (d, J 8.0 Hz, 2H), 5.20 (b, 1H), 3.37 (apparent q, J
7.0 Hz, 2H), 2.75 (t, J 7.0 Hz, 2H), 1.83 (s, 3H); 1H NMR (CDCl3)
d 7.26 (d, J 8.5 Hz, 2H), 7.12 (d, J 8.5 Hz, 2H), 5.45 (b, 1H), 3.48
(apparent q, J 7.0 Hz, 2H), 2.79 (t, J 7.0 Hz, 2H), 1.94 (s, 3H);
HPLC acetonitrile–water (60 : 40), RT 10.2 min. The spectroscopic
data for this compound are consistent with literature values.29
2-(2-C◦hlorophenyl)acetamid◦e (9b). Colourless crystals; mp
171–172 C (lit.24 mp 168–172 C); 1H NMR (CCl4) d 7.35 (m, 4H),
1
3.66 (s, 2H); H NMR (CD3CO2D) d 7.34 (m, 4H), 3.78 (s, 2H);
HPLC acetonitrile–water (50 : 50), RT 8.0 min. The spectroscopic
data for this compound are consistent with literature values.24
2-(4-Chlorophenyl)acetamide (9c). Colourless crystals; mp
◦
◦
1
180–182 C (lit.24 mp 180–182 C); H NMR (CCl4) d 7.35 (d,
N-(3-(2-Chlorophenyl)propyl)acetamide (13b). Colourless oil;
1H NMR (CCl4) d 7.17 (m 4H), 3.39 (apparent q, J 7.0 Hz, 2H),
2.74 (t, J 7.5 Hz, 2H), 1.85 (s, 3H), 1.79 (m, 2H); 1H NMR (CDCl3)
d 7.23 (m, 4H), 5.58 (b, 1H), 3.29 (apparent q, J 7.0 Hz, 2H), 2.76
(t, J 7.5 Hz, 2H), 1.96 (s, 3H), 1.83 (m, 2H); 13C NMR (CDCl3)
d 170.1, 138.9, 133.7, 130.4, 129.5, 127.5, 126.9, 39.1, 30.9, 29.5,
1
J 8.0 Hz, 2H), 7.25 (d, J 8.0 Hz, 2H), 3.39 (s, 2H); H NMR
(CD3CO2D) d 7.30 (m, 4H), 3.61 (s, 2H); HPLC acetonitrile–water
(50 : 50), RT 8.4 min. The spectroscopic data for this compound
are consistent with literature values.24
3-(2-Chlorophenyl)propionamide (10b). Colourless crystals;
mp 115–116 ◦C (lit.25 119 ◦C); 1H NMR (CCl4) d 7.19 (m, 4H), 5.70
(bs, 1H), 5.51 (bs, 1H), 3.02 (t, J 7.5 Hz, 2H), 2.43 (t, J 7.5 Hz,
•
•
23.3; MS m/z (%) 213 (M+ , 18), 211 (M+ , 59), 176 (19), 152 (29),
125 (34), 117 (53), 103 (25), 89 (17), 73 (100); HPLC acetonitrile–
water (60 : 40), RT 9.0 min; (Found: C, 62.40; H, 6.99; N, 6.43%.
C11H14ClNO requires C, 62.41; H, 6.67; N, 6.62%).
1
2H); H NMR (CD3CO2D) d 7.20 (m, 4H), 3.06 (t, J 7.0 Hz,
2H), 2.61 (t, J 7.0 Hz, 2H); HPLC acetonitrile–water (60 : 40), RT
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•
N-(3-(4-Chlorophenyl)propyl)acetamide (13c). Colourless oil;
1H NMR (CCl4) d 7.18 (d, J 8.0 Hz, 2H), 7.06 (d, J 8.0 Hz, 2H),
5.55 (b, 1H), 3.15 (apparent q, J 7.5 Hz, 2H), 2.58 (t, J 7.5 Hz,
126.9, 37.2, 35.4, 33.3, 29.5; MS m/z (%) 211 (M+ , 4), 176 (100),
139, (21) 125 (28), 102 (24), 72 (27); HPLC acetonitrile–water (60 :
40), RT 12.0 min; (Found: C, 62.70; H, 6.51; N, 6.53%. C11H14ClNO
requires C, 62.41; H, 6.67; N, 6.62%).
1
2H), 1.83 (s, 3H), 1.75 (m, 2H); H NMR (CDCl3) d 7.23 (d, J
8.5 Hz, 2H), 7.09 (d, J 8.5 Hz, 2H), 5.60 (b, 1H), 3.26 (apparent
q, J 7.0 Hz, 2H), 2.61 (t, J 8.0 Hz, 2H), 1.95 (s, 3H), 1.78 (m, 2H);
13C NMR (CDCl3) d 170.2, 139.8, 131.7, 129.7, 128.5, 39.2, 32.5,
31.3, 23.3; MS m/z (%) 213 (M+ , 11), 211 (M+ , 39), 176 (13), 152
(27), 125 (24), 117 (48), 73 (100); HPLC acetonitrile–water (60 :
40), RT 9.8 min; (Found: C, 62.20; H, 6.69; N, 6.83%. C11H14ClNO
requires C, 62.41; H, 6.67; N, 6.62%).
N,N-Dimethyl-3-(4-chlorophenyl)propionamide (16c). Colour-
1
less oil; H NMR (CCl4) d 7.17 (d, J 8.5 Hz, 2H), 7.10 (d, J
•
•
8.0 Hz, 2H), 3.30 (s, 3H), 2.86 (m, 5H), 2.46 (t, J 7.5 Hz, 2H); 1H
NMR (CDCl3) d 7.25 (d, J 8.5 Hz, 2H), 7.15 (d, J 8.5 Hz, 2H),
2.94 (t, J 7.5 Hz, 2H), 2.92 (s, 6H), 2.59 (t, J 7.5 Hz, 2H); 13C
NMR (CDCl3) d 171.9, 139.9, 131.8, 129.8, 128.5. 37.1, 35.5, 35.0,
•
•
30.6; MS m/z (%) 213 (M+ , 35), 211 (M+ , 100), 138 (44), 125
(84), 103 (44), 86 (42), 72 (73); HPLC acetonitrile–water (60 : 40),
RT 13.5 min; (Found: C, 62.71; H, 6.61; N, 6.62%. C11H14ClNO
requires C, 62.41; H, 6.67; N, 6.62%).
N-(4-(2-Chlorophenyl)butyl)acetamide (14b). Colourless oil;
1H NMR (CCl4) d 7.11 (m 4H), 5.50 (b, 1H) 3.19 (apparent q,
J 7.0 Hz, 2H), 2.73 (t, J 7.5 Hz, 2H), 1.84 (s, 3H), 1.63 (m, 2H),
1
1.54 (m, 2H); H NMR (CDCl3) d 7.23 (m, 4H), 5.50 (b, 1H),
Determination of the rates of reaction of compounds 9a–16a with
chlorine
3.27 (apparent q, J 6.5 Hz, 2H), 2.75 (t, J 7.0 Hz, 2H), 1.97 (s,
3H), 1.83 (m, 4H); 13C NMR (CDCl3) d 170.3, 140.4, 131.5, 129.7,
•
128.4, 39.5, 34.7, 29.0, 28.5, 23.1; MS m/z (%) 227 (M+ , 45), 225
The rate of reaction of the amide 10a in acetic acid was determined
as described above for the rates of reaction of compounds 1a–5a.
The reactions of the amides 9a–15a in carbon tetrachloride, and
of 9a–11a in a,a,a-trifluorotoluene, were examined in a similar
fashion, except that the results were not consistent with second
order reactions, so instead pseudo-first order rate constants, kꢀ,
for the reactions were derived from the data according to eqn
(2).23 The reaction of the tertiary amide 16a did not follow either
first or second order kinetics. The rate constants for the reactions
of 9a–15a and the ratios of formation of the products 9b,c–16b,c
are summarised in Table 3.
•
(M+ , 91), 148 (24), 131 (36), 125 (80), 100 (100), 87 (98), 72 (92);
HPLC acetonitrile–water (55 : 45), RT 7.3 min; (Found: C, 63.36;
H, 7.07; N, 6.04%. C12H16ClNO requires C, 63.86; H, 7.14; N,
6.21%).
N-(4-(4-Chlo◦rophenyl)butyl)acetamide (14c). Colourless nee-
dles; mp 89–90 C; 1H NMR (CCl4) d 7.18 (d, J 8.5 Hz, 2H), 7.04
(d, J 8.5 Hz, 2H), 5.15 (b, 1H), 3.17 (apparent q, J 7.0 Hz, 2H),
2.60 (t, J 7.5 Hz, 2H), 1.84 (s, 3H), 1.61 (m, 2H), 1.46 (m, 2H); 1H
NMR (CDCl3) d 7.25 (d, J 8.5 Hz, 2H), 7.15 (d, J 8.5 Hz, 2H), 5.95
(b, 1H), 3.23 (apparent q, J 6.5 Hz, 2H), 2.58 (t, J 7.0 Hz, 2H),
1.96 (s, 3H), 1.55 (m, 4H); 13C NMR (CDCl3) d 170.3, 140.4, 131.5,
−d[A]/dt = kꢀ[A]
(2)
•
129.7, 128.4, 39.5, 34.7, 29.0, 28.5, 23.1; MS m/z (%) 227 (M+ ,
•
27), 225 (M+ , 86), 138 (28), 100 (78), 87 (100), 72 (85); HPLC
Preparation of the N-chloride of 3-phenylpropionamide 10a
acetonitrile–water (55 : 45), RT 8.1 min; (Found: C, 63.44; H, 7.20;
N, 6.75%. C12H16ClNO requires C, 63.86; H, 7.14; N, 6.21%).
The amide 10a was treated with an equimolar quantity of tert-butyl
hypochlorite in chloroform and the solution was stirred at room
temperature in the dark for 24 h. The solvent was then removed
under reduced pressure and the residue was chromatographed
on silica, eluting with dichloromethane, to give N-chloro-3-
N-Methyl-3-(2-chlorophenyl)propionamide (15b). Colourless
oil; 1H NMR (CCl4) d 7.18 (m, 4H), 6.05 (b, 1H), 2.98 (t, J 7.5 Hz,
2H), 2.67 (d, J 5.0 Hz, 3H), 2.37 (t, J 7.5 Hz, 2H); 13C NMR
(CDCl3) d 172.5, 138.3, 133.7, 130.7, 129.5, 127.8, 127.0, 36.3,
1
phenylpropionamide; colourless liquid; H NMR (CCl4) d 7.08
•
29.2, 26.3; MS m/z (%) 197 (M+ , 2), 162 (100), 125 (28), 103
(m, 5H), 6.30 (b, 1H), 2.95 (t, J 7.5 Hz, 2H), 2.53 (t, J 7.5 Hz, 2H);
(26); HPLC acetonitrile–water (60 : 40), RT 10.5 min; (Found: C,
60.55; H, 6.09; N, 7.18%. C10H12ClNO requires C, 60.76; H, 6.12;
N, 7.09%).
13C NMR (CDCl3) d 172.2, 139.9, 128.6, 128.2, 126.4, 36.7, 31.7;
•
•
MS m/z (%) 186 (M+ , 10), 184 (M+ , 18), 148 (85), 117 (56), 105
(88), 91 (100); (Found: C, 58.64; H, 5.52; N, 7.87%. C9H10ClNO
requires C, 58.87; H, 5.49; N, 7.63%).
N-Methyl-3-(4-chlorophenyl)propionamide (15c). Colourless
◦
1
needles; mp 126–127 C; H NMR (CCl4) d 7.18 (d, J 8.5 Hz,
2H), 7.07 (d, J 8.5 Hz, 2H), 5.00 (b, 1H), 2.87 (t, J 7.5 Hz, 2H),
2.70 (d, J 5.0 Hz, 3H), 2.28 (t, J 7.5 Hz, 2H); 13C NMR (CDCl3) d
172.3, 139.4, 131.9, 129.7, 128.6, 38.2, 31.0, 26.3; MS m/z (%) 199
Acknowledgements
Support of this work by the Australian Research Council and the
Plastics and Chemicals Industries Association Inc. (Australia),
and the award of an Australian Postgraduate Award (Industry) to
P. G. D. in collaboration with Australian Vinyls Corp. Ltd., are
gratefully acknowledged.
•
•
(M+ , 28), 197 (M+ , 100), 138 (57), 103 (39); HPLC acetonitrile–
water (60 : 40), RT 11.6 min; (Found: C, 60.34; H, 5.94; N, 7.02%.
C10H12ClNO requires C, 60.76; H, 6.12; N, 7.09%).
N,N-Dimethyl-3-(2-chlorophenyl)propionamide (16b). Colour-
less oil; 1H NMR (CCl4) d 7.19 (m, 4H), 2.99 (t, J 7.5 Hz, 2H), 2.91
(s, 3H), 2.86 (s, 3H), 2.50 (t, J 7.5 Hz, 2H); H NMR (CDCl3) d
References
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2H); 13C NMR (CDCl3) d 171.9, 138.9, 133.9, 130.9, 129.4, 127.7,
2722 | Org. Biomol. Chem., 2006, 4, 2716–2723
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The Royal Society of Chemistry 2006
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