TABLE 1. Rate Constants (kQ) for the Total Quenching of Singlet
Oxygen by Chlorpromazine (1), N-Methylphenothiazine (2), and
Chlorpromazine Hydrochloride (1‚HCl)
TABLE 2. Conversion and Product Distribution in the Reaction of
1 with Singlet Oxygen in MeOH
Product Distributiona
kQ (M-1 s-1
)
kQ (M-1 s-1
)
reaction time
conversion
6
7
8
DMF
compound
CD3OD
MeCN
10 min
1 h
1%
5%
49%
49%
7%
7%
5%
5%
40%
40%
1
2
7.28 × 107 a
3.79 × 107 b
1.63 × 107
1.36 × 108
3.68 × 107
2.56 × 107
a Errors are ca. 5% on the molar amount for all of the products with the
exception of DMF, for which the error is ca. 20%. CH2O (not quantitated)
was also detected in the reaction mixture.
1‚HCl
a A value of 3.5 × 107 M-1 s-1 is reported in bromobenzene/MeOH
2:1.5a b Much lower values, ca. 106 M-1 s-1, have been reported5a,12 that,
however, were obtained in competitive experiments (Monroe method).13
rophenothiazine (6), the only product according to the previous
report, N,N-dimethylformamide (DMF), N-formyl-2-chlorophe-
nothiazine (7), N-(3-methylaminopropyl)-2-chlorophenothiazine
(8), and formaldehyde were also detected. No sulfoxidation
products were formed. When the irradiation time was extended
(from 10 min to 1 h), the product distribution remained
unchanged, as shown in Table 2.
The relatively high quenching rate of the phenothiazines
investigated (all above 107 M-1 s-1) is mainly due to the
presence of the nitrogen atom, with the sulfur playing an almost
negligible role. Accordingly, it is well-known that aromatic
amines quench 1O2 much more efficiently than aromatic
sulfides.11 Pertinent to the case in point is that the quenching
rate of diphenylamine14 is almost 2 orders of magnitude higher
than that of diphenyl sulfide.15 Both in CD3OD and MeCN, 1
is a 2-3 times faster quencher than 2, an effect suggesting a
favorable role of the side-chain nitrogen atom with respect to
the interaction with singlet oxygen. This suggestion is supported
by the observation that 1‚HCl, where the lone pair of the
dimethylamino nitrogen is no longer available for the formation
Almost identical results were obtained when promazine (5)
was irradiated in the place of 1 (Figure S4). Clearly, as expected,
the chloro substituent plays no role in the reaction of 1
1
with O2.
From the results in Table 2, it can be noted that DMF is
formed in amounts approximately comparable (the quantitative
analysis of small amounts of DMF was subject to considerable
error) with those of 6 and 7. This observation and the formation
of the N-demethylated product 8 suggest, in agreement with
kinetic results, that the reaction center is the N-dimethylamino
nitrogen and not the ring nitrogen as previously hypothesized.
It follows that the side-chain reactivity of chlorpromazine 1 is
determined by the dimethylamino functionality in the side
chain.17 In other words, 1 substantially behaves as an aliphatic
1
of a CT complex with O2,16 exhibits a quenching rate lower
than those of 1 and 2. Thus, the kinetic data cast serious doubts
on the hypothesis that the ring nitrogen is the actual reactive
1
center of 1 in the chemical quenching of O2.
Product Study. The irradiations (400-600 nm) were carried
out in a photoreactor using rose bengal (10-4 M) as the
sensitizer, at 25°C. Substrate concentrations in oxygen-saturated
solvents were 10-2 M, and irradiation times ranged from 10
min to 3 h (maximum conversion 12%). Product analysis was
carried out by GC and GC-MS by comparison with authentic
specimens. In a number of experiments, a 5% K2Cr2O7 filter (1
cm width) was used to be certain to ensure a wavelength cutting
<400 nm. In all cases, no products were observed when
irradiations were performed in the absence of rose bengal or
O2. The mass balance was always greater than 95%.
1
7,9
tertiary amine that exhibits also chemical quenching of O2
and not as an aromatic amine (like 2 and 3) that exhibits only
physical quenching.
Thus, a reasonable mechanism is that a CT complex is formed
1
involving the N-dimethylamino nitrogen of 1 and O2. This
complex, in addition to intersystem crossing (the main process,
vide infra), undergoes R-hydrogen abstraction to form two
transient R-amino carbon radicals, 9 and 10 (Scheme 1, paths
a and b). From 9, the formation of 8 can follow the pathway
proposed for N-demethylation of trialkylamines7,9 (Scheme 1,
path c). Very likely, 6 and 7 as well as DMF should derive
from 10 (path d). The formation of DMF clearly indicates a
bond cleavage between the carbon atoms R and â to the side-
chain nitrogen, but at this stage, no further hypothesis on the
cleavage mechanism is possible.
It was therefore decided to study a chlorpromazine analogue,
such as 4, with a side-chain alkylamino group heavier than the
dimethylamino group of 1. 4 should behave as 1, but product
identification and quantitative analysis should be easier also
because the ring hydrogens in N-alkylpiperidines are not reactive
toward 1O2.9a The decision turned out to be rewarding because
the rose bengal sensitized irradiation of 4, in addition to the
expected 6, 7, and N-formylpiperidine 11, gave another prod-
uct: the N-(formylmethyl)-2-chlorophenothiazine 12 (Table 3).
12, however, practically disappears at longer reaction times
(3 h), presumably producing 6 and 7 (vide infra).
Reactions in MeOH. The reaction of 2 with 1O2 (1 h
irradiation) in MeOH confirmed previous results,5a affording
exclusively the corresponding sulfoxide. No side-chain cleavage
products were observed. In 2, however, the nitrogen is bonded
to a methyl group and not to a methylene group as the ring
nitrogen in 1. Thus, N-ethylphenothiazine (3) was also inves-
tigated, but the result was the same as for 2. The reaction product
was the sulfoxide, and no side-chain cleavage products were
observed. These results are described in Figure S1 of the
Supporting Information.
Several differences with respect to the previous study5a were
instead observed when the reaction of 1 was investigated.
Exclusive side-chain cleavage was observed, but besides 2-chlo-
(11) Wilkinson, F.; Helman, W. P.; Ross, A. B. J. Phys. Chem. Ref.
Data 1995, 24, 663.
(12) Hovey, M. C. J. Am. Chem. Soc. 1982, 104, 4196.
(13) Monroe, B. M. Photochem. Photobiol. 1979, 29, 761.
(14) Young, R. H.; Martin, R. L.; Feriozi, D.; Brewer, D.; Kayser, R.
Photochem. Photobiol. 1973, 17, 233.
(15) Kacher, M. L.; Foote, C. S. Photochem. Photobiol. 1979, 29, 765.
(16) (a) There is wide consensus that amines quench 1O2 via the
preliminary formation of a charge transfer complex (exciplex) involving
the nitrogen atom lone pair.16b,c (b) Gorman, A. A. AdV. Photochem. 1992,
17, 217. (c) Schweitzer, C.; Schmidt, R. Chem. ReV. 2003, 103, 1685.
These results clearly indicate that, also with 4, the interaction
1
with O2 concerns the side-chain nitrogen almost exclusively.
(17) When 1‚HCl is used as the substrate, the side-chain cleavage
becomes a minor reaction, with sulfoxidation being the main process (see
Supporting Information).
J. Org. Chem, Vol. 72, No. 15, 2007 5913