Chemistry Reference
In-Depth Information
In recent years, PAL has been applied to some areas of medicine where new
synthetic photoprobes with highly efficient covalent linking with biomolecules are
required.
65
In nuclear medicine, useful diagnostic and therapeutic radionuclides
(
99m
Tc,
109
Pd,
186
Re) must be attached to monoclonal antibodies often projected
as “magic bullets” to target cancerous cells.
8,82,83
In these PAL experiments,
bifunctional photoprobes with a perfluorophenyl azide, on one side of the molecule,
and a chelating agent, that forms stable complexes with radionuclides, have been
prepared and used to label several macromolecules like lipids. The efficiency to form
stable covalent bonds with a target macromolecule is very important, since the
radionuclide usually has a short half-life.
8
As mentioned earlier, the application of aryl azides in PAL has been limited by the
poor reactivity of the nitrene intermediates generated by photochemical fragmentation
of simple aryl azides.
12,13
At ambient temperature,
1
PhN undergoes ring expansion to
DA and polymerizes to tar in the absence of a nucleophilic molecule.
12,13
At cryogenic
temperatures,
1
PhN undergoes ISC to
3
PhN that abstracts hydrogen atoms from
hydrocarbons to form radical pairs that combine under matrix conditions.
20
However,
these low temperature conditions are not appropriate for PAL experiments of certain
biomolecules like enzymes.
The experimental observation that FPhN
3
undergo photochemical insertion
reactions with several solvents led to many research groups to systematically study
the reactions of this type of azides.
20,21
It was demonstrated that two fluorine atoms
adjacent to the azide group in perfluorophenyl azides inhibit ring expansion and favor
1
FPhN reactions.
22,30
In general, the insertion (Table 11.3) of a
1
FPhN derived from a perfluorophenyl
azide has a good efficiency (30-60%).
20-22,30,32
The substitution of other electron-
withdrawing groups (nitro, carbonyl, and cyano) in the
para
position of the azide
group increases C
H insertion while electron-donating groups (NH
2
, NHMe, and
NMe
2
) decreases it.
84
These latter substituents may reduce the electrophilicity of the
singlet nitrene and therefore decrease its reactivity.
65
Platz and Marcineck
85
investigated the differential activation parameters for
singlet nitrene insertion, into a C
H bond of an alkane, versus ISC to lower-
energy-state triplet nitrene. Their observations explained the effect of substituents on
the reactivity of singlet nitrene. The activation energy for C
H insertion is 4-
5 kcal/mol larger than the one for ISC. Furthermore, the Arrhenius pre-exponential
factor for C
H insertion is 10
3
-10
5
times larger than the one for ISC. Only a highly
electrophilic nitrene could overcome the large barriers imposed.
Para
-substituted perfluorophenyl azides have a strong absorption around 260 nm
where most proteins and nucleic acids also have strong absorptions.
84
In spite of
this, in PAL experiments, photolysis of an aryl azide is complete before any
damage to biomolecules takes place. This is probably due to the strong liability of
aryl azides.
65
Keana et al.
84
prepared methyl 4-azido-2-nitro-3,5,6-trifluoroben-
zoate to investigate the effect of the nitro group. For this derivative, the absorption
increased to longer wavelength (
350 nm) and the photolysis time
decreased.
84
The increased yields of aniline indicated that the nitro group
accelerated ISC and only triplet nitrene-derived products were formed. Similar
l
max
¼
