AREQUIPA –PERU
INTOXICACION POR ORGANOS FOSFORADOS
2. MARCO CONCEPTUAL 1 La Intoxicación
2.7. Cuadro Clínico
1.0
Introduction
The importance of free radicals in organic synthesis and the necessity for the development of clean free radical precursors has been discussed in Chapter 1. Apart from peroxides and azo-compounds, the range of molecules suitable for direct photolysis is quite limited. The photolytic dissociation of these suitable molecules could be followed very efficiently using ESR spectroscopy. Furthermore, the determination of radical concentrations and therefore the assessment of kinetic data in radical process can be performed using ESR spectroscopy.
1.1 Electron Spin Resonance Spectroscopy (ESR).
Electron spin resonance spectroscopy (ESR), also known as electron paramagnetic resonance (EPR), is related to the study of species containing one or more unpaired electrons and therefore can be applied to the study of free radicals. The technique was first developed in 1945 and since then has found many applications in physics, chemistry and biology. The technique is extremely sensitive and can be used to detect radicals down to concentrations of 10-9M.1
The principles of ESR are closely related to those of NMR spectroscopy. Just like the proton in NMR spectroscopy, the electron spin in ESR has an associated magnetic moment. Consequently, the electron will have two distinct energy levels in an applied magnetic field and will undergo transitions between spin states if energy of the correct frequency is applied.
ESR records the magnetic resonance spectrum of unpaired electrons. The ESR spectrum of a paramagnetic compound in an external magnetic field B can be described using a Hamiltonian operator (Eqn 1).
H = HEZ+ HNZ+ HEN+ HQ Eqn 1
HEZ is the electronic Zeeman operator, which represents the interaction between the
electron spin S and the external field B. Unpaired electrons have a non-classical intrinsic angular momentum called spin. The spin is characterised by the quantum number Ms= (+/-)
1/2, that gives two spin states differing in Ms.
Ms= + 1/2: spin up( )orα
The magnetic momentμ is derived from the spin state using the equationμ= -gβMs,
where Msis the electron spin,β is the Bohr magneton (eh/4πm = 9.2733E-24 JT-1), where e
and m are the charge and the mass of the electron and h = 6.624E-27 is the Planck constant), and g is a dimensionless number whose value for a free electron is 2.0023. The interaction of this magnetic moment and the applied magnetic field can therefore be described by (Eqn 2).
HEZ =-πB= gβMsB Eqn 2
In the absence of a magnetic field the two spin states are degenerate, i.e. they have the same energy. When the magnetic field B, is applied it interacts with the magnetic moment and the spin states are no longer degenerate. This is known as the Zeeman effect and the
difference in energy between the levels is given by the equation ΔE = gβB. If electromagnetic radiation of a frequency equivalent to this value of ΔE is applied, absorption takes place and
transitions from the lower energy state to the higher energy state and vice-versa can occur. In a field of 3400 Gauss, the Larmor frequency of a free electron will be 9.2 GHz, therefore ESR spectra are recorded in the microwave region of the electro-magnetic spectrum.
The spin state of a free electron is influenced by its local atomic environment, which in turn affects the g-factor of the electron and its magnetic moment. In a magnetic field the unpaired electron possesses, in addition to its spin angular momentum, a small amount of extra orbital angular momentum. It is the interaction between these, called spin-orbit coupling, which results in electrons having a different effective magnetic moment from that of the free electron. Since the equation for energy required for resonance is dependent on the magnetic moment, this implies that radicals of differing g-factors will resonate at different field strengths.
The nuclear Zeeman operator,HNZrepresents the interaction between the nuclear spin
and the external magnetic field Bo. This value is very small and is often negligible as the
the Zeeman energy is very much smaller than its electronic counterpart and can often be ignored.
The termHENdescribes the interaction between the electron spin and the local nuclear
spins. Hyperfine splitting into a number of distinct lines can occur when there is an interaction between the electron magnetic moment and the magnetic moment of neighbouring magnetic nuclei and, analogous to NMR, the number of lines arising from hyperfine splitting is dependent on the number of nuclear spin orientations.
If paramagnetic compounds contain one magnetic nucleus in close proximity to the free electron, the unpaired electron will experience a local magnetic field arising from the magnetic nucleus. For example, the proton spin has two possible orientations which are parallel and antiparallel to the electron. There are four possible transitions but since the nuclear spin quantum number (MI) cannot change during a transition, only two transitions are
allowed. For this reason the hydrogen atom will therefore give an ESR spectrum of two lines of equal intensity. The separation between the two lines is known as the hyperfine splitting and in general can be used to deduce structural information about a free radical. As a general rule the spectrum will contain (2nI+1) lines where I is the spin quantum number of the nucleus andnis the number of equivalent nuclei present.
HQ describes the nuclear quadrupolar energy. This occurs when some nuclei with
spins of 1 or more possess an electric quadrupole moment, as the distribution of charge density within the nucleus is not spherical. This does not occur in the organic molecules described in this thesis and can be ignored here.
The net result of eliminating these operations from the Hamiltonian operator given in (Eqn 1), gives a simplified equation for the spectrum observed using ESR in solution (Eqn 3).
H = gβBoSz+αSzIz Eqn 3
In solids the radicals are fixed and can be orientated in any direction with respect to the applied magnetic field. This means that theα- and g- values take on a number of different values. However in solution phase ESR, molecular tumbling averages the values of α and g resulting in simplified spectra.
As was mentioned earlier, a deep understanding of the kinetics of radical cyclization is necessary for the planning and understanding of radical reactions. ESR has been applied to the study of both dissociation and cyclisation kinetics and has provided valuable information for planning synthetic strategies.
1.2 Oxime Derivatives as Photochemical Radical Precursors.
1.2.1 Oxime esters as iminyl and alkyl radicals precursors.In the 1980’s Hasebe and co-workers2-4demonstrated that benzophenone oxime esters
2 could readily be photolysed to generate alkyl radicals 5 together with the diphenyl iminyl radical3(Scheme 1).
The photolysis reactions were carried out in benzene or carbon tetrachloride. The diphenyliminyl radical either dimerised to give the benzophenone azine 6 or else abstracted hydrogen to give an imine which was subsequently hydrolysed to the corresponding ketone7. The radical R.
(
5) could then undergo classic free radical chemistry to give alkanes 8, alkyl aromatics9and alkyl chlorides10.5The homolytic chemistry of oxime esters was further investigated by Walton and co- workers.6,7 It was determined that the efficiency of oxime ester photolysis could be improved through the incorporation of methoxy substituents into the aromatic ring and through the use of photosensitisers. Oxime ester 11 was used in the preparation of cyclopentane ring 14 in good yield (Scheme 2).
Ph Ph N OH ArCOCl Base Ph Ph N O R O hv Ph Ph N + O R O R RH 8 RAr 9 RCl 10 Ph Ph N N Ph Ph Ph Ph O 1 2 3 4 5 6 7
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Scheme 1The oxime ester 11on photolysis, cleaves at the N-O bond giving the iminyl and the acyloxyl radical which rapidly loses CO2to give the alkyl radical13. This can then undergo a
5-exo mode cyclisation, followed by hydrogen-atom abstraction from the solvent to give methylenecyclopentane14in 77% yield.
1.2.2 Oxime oxalate amides as precursors of iminyl and carbamoyl radicals.
It was apparent from the work of Hasebe2-5and Walton6,7that the oxime functionality was a suitable radical precursor for iminyl and alkyl radicals. Walton’s group proposed to study oxime oxalate amides as a precursor of iminyl and carbamoyl radicals. The oxime oxalate amide still incorporates the weak N-O oxime bond and should function as a radical precursor. The resulting acyloxyl radical 17 would then lose CO2 to give the carbamoyl
radical18(Scheme 3).8
This methodology was applied in the synthesis of the β-lactam 23 from the corresponding oxime oxalate amide 19. Upon irradiation of 19 in the presence of photosensitizer in toluene iminyl radical 20 was produced as co-intermediate with the aminoacyl 21. This aminoacyl radical underwent 4-exo ring closure to afford the secondary radical 22. Interestingly, however, the product isolated was the hydroxylated compound 23
probably by reaction of22with dissolved dioxygen in toluene (Scheme 4).
hv Scheme 4 Ph N O O O N Ph PhCH3,MAP Ph N N Ph O 4-exo + N O Ph H H N O Ph H H