Photodegradation of aryl sulfonamides: N-tosylglycine
Roger R. Hill,* Graham E. Jeffs, David R. Roberts and Sharon A. Wood
Department of Chemistry, The Open University, Milton Keynes, UK, MK7 6AA. E-mail: r.r.hill@open.ac.uk
Received (in Cambridge, UK) 2nd July 1999, Accepted 2nd August 1999
Continuing uncertainty about pathways and consequences
of the photolability of aryl sulfonamides is partly resolved by
the results of comprehensive product analysis in the
photolysis of aqueous N-tosylglycine, which indicate that
intramolecular electron or hydrogen transfer (according to
conditions) promote the widely reported S–N cleavage and
reveal the nature of subsequent and competing processes.
sulfonamide photochemistry reported separately.3 Reaction (i)
indicates a cyclic abstraction of H–Ca and reaction (ii) suggests
b-homolysis of a bond known to be involved in the p?p state
*
of analogous carboxamides11 and dimerization of the compar-
atively stable amido-methylene radical.7 The major route,
reaction (iii), reflects the known behaviour of excited aryl
sulfonamides as electron acceptors,12 and generates an inter-
mediate from which observed products are derived by loss of
CO2 alone [reaction (iv)] or with concomitant S–N cleavage
[reaction (vi)], and, more speculatively, via cyclizations and
hydrolysis [reactions (v) and (vii)]. Such processes would
require particular orbital alignments, so product distribution
would be determined largely by the conformations available in
the short-lived intermediates.
Aryl sulfonamides are of topical interest photochemically for
two reasons: as photolabile pharmaceutical compounds1 and as
photolabile protected amines, peptides and proteins, the latter
attracting continuing study2 despite subsequent results3 detract-
ing from their early promise.4 Regulatory demands for increas-
ingly detailed stability data5 contrast with rudimentary knowl-
edge of the photochemistry of existing sulfonamide drugs, and
prompt increasing attention to those in development. The
variable and generally unsatisfactory results of attempted
photodeprotections have been attributed to side reactions that
can be reduced in some cases by structural modification3 or the
addition of further reagents,6 but remain largely unknown.
In a continuing study of the photochemistry of peptide
derivatives,7,8 we have monitored products during the photol-
ysis of aqueous N-tosylglycine (1) and, observing a high mass
balance early in the reaction, are able to propose a sequence of
events that both explains the product distributions and im-
plicates processes that may direct photolytic outcomes with
other aryl sulfonamides.
The percentage assigned to each route in Scheme 1
corresponds with the observed yield values of uniquely
associated products. The accumulated values implicated for
coproducts formed in more than one route [CO2 (68%), NH3
(58%) and TsH (58%)] are in fair agreement with those
observed, and would be more so if the value for HCHO reflected
some losses, directly or indirectly, by the unassigned reducing
capacity available from reaction (ii). The latter would, in any
case, account for loss of some material and this is incorporated
in the mass balance data of Table 1. Scheme 1 is also supported
by product correlations (e.g. TsH vs. NH3, r2 = 0.998, slope
1.1; TsH vs. HCHO + glyoxylic acid, r2 = 0.984, slope = 0.9)
and by the main differences in outcome when the substrate is not
ionized. In that case, lower yields of principal products by
reaction (iii) are consistent with the need for H-atom transfer,13
making other pathways, including reactions (i) and (ii), slightly
more competitive. The lack of TsNHCH3 and the enhanced
yield of TsOH may be associated with the inability to generate
the sulfonyl group directly in reactions (iv) and the easier
hydrolysis anticipated for the protonated intermediate in
reactions (vii), respectively. While quantitation at 20% conver-
sion is intrinsically more accurate, the scope for complication
by secondary processes is increased. The data remain consistent
with Scheme 1, however.
Photolyses were carried out under nitrogen with 10-2 mol
dm-3 aqueous solutions of N-tosylglycine, either unadjusted (pH
3) or adjusted to pH 9 with NaOH, in quartz tubes and using a
carousel surrounding a 400 W medium pressure mercury arc as
previously described.7 Products were identified by diagnostic
chromatographic comparison with standards and quantified by
HPLC9 (formaldehyde and glyoxylic acid as DNP derivatives;
glycine as AccQ.Tag® derivative by fluorescence detection10)
and gas electrode analysis (CO2 and NH3).7
The data in Table 1 are consistent with the sequence of
reactions in Scheme 1 (shown for 7% reaction at pH 9), which
also accords collectively with several earlier observations of
It would appear from these results that electron or hydrogen-
atom transfer to the sulfonyl group will be prominent in the
photochemistry of aryl sulfonamides, with b-homolysis a
Table 1 Product distributions (mol%) in the photolysis of N-tosylglycine
7% reactiona
20% reactionb
pH 9 pH 3 pH 9
49
Product
pH 3
NH3
CO2
TsHc
47
34
28
29
13
19
13
5
49
80
68
51
7
50
32
31
29
8
87
62
35
4
HCHO
OHCCO2H
TsOH
H3N+CH2CO2
TsNH2
7
6
8
3
3
—
5
2
d
—
7
TsNHCH3
(TsNHCH2)2
Mass balancef
0
8
9
> 90
1
8
60
6
5
60
e
14
80
c
a
b
Error < ± 4. Error < ± 2. Standard: Li salt (98%), Sigma-Aldrich
d
e
Ltd. Not measured. Standard tosylation of diamine, mp 161 °C (lit.,
160 °C). f According to Scheme 1 (see text); error < ± 11 and < ± 6 at 7
and 20% reaction, respectively.
Scheme 1
Chem. Commun., 1999, 1735–1736
1735