Homolysis/mesolysis of alkoxyamines activated by chemical oxidation and photochemical-triggered radical reactions at room temperature †

Alkoxyamines, which are connected with a phenol moiety by a (substituted) methylene bridge undergo homolytic cleavage upon chemical oxidation or a photo-induced hydrogen transfer. This selectively triggered reaction yields a nitroxide radical. In the presence of an excess of lead dioxide as the oxidant in tert -butylbenzene as solvent, spontaneous, instantaneous and almost quantitative generations of nitrox-ides from various alkoxyamines are observed at room temperature, which support activation energies for the cleavage lower than 100 kJ mol − 1 . The rate and the amount of released nitroxide depend on the amount of “ catalyst ” and the structure of alkoxyamines.


Introduction
In the last decade, the concept of smart alkoxyamines has been developed. 1These are highly stable alkoxyamines with half-lives of several hundred years, which can be selectively transformed into highly labile species with half-lives of seconds or minutes through chemical, 2-5 photochemical [6][7][8][9] or biochemical 10,11 events.][15][16][17][18] While the focus of these studies has been on triggering alkoxyamine homolysis, to form a nitroxide and carbon-centred radical, recently it has been shown that upon oxidation, through electrochemical [19][20][21][22][23] or photoredox 24,25 methods, alkoxyamines can spontaneously undergo mesolytic cleavage instead.Depending on the leaving group and other species present, this process can yield nitroxides and carbocations, or alternatively oxoamoniums and carbon-centred radicals.In some cases, oxidation simply generates reactive intermediates capable of undergoing S N 2 reactions with nucleophiles.These processes have been developed into successful alkylation methods in small molecule synthesis, 21,24 and likely have broader applications for the on-demand generation of carbon-centred radicals and cations.Moreover, it is thought that this mesolytic cleavage pathway may even be operative upon photochemical excitation of certain photoactive alkoxyamines. 26o date, oxidative alkoxyamine cleavage has been achieved using either electrochemical [19][20][21][22][23] or photoredox 24 methods, but the use of simple chemical oxidation under mild conditions has not yet been reported.Indeed, while PbO 2 has been shown to generate phenoxyl radicals from phenol-based anti-oxidants through proton-coupled electron transfer (PCET), 27 preliminary results with 3c show only very low conversion into nitroxide 3 • using PbO 2 as oxidant.Here, we report on the preparation phenol-based alkoxyamines 1a-5a,3e (Chart 1) and the benzyl protected homologues 1b-5b,3d (Chart 1).We have investigated their reaction pathways in t-BuPh as the solvent.At room temperature 1a-5a reacted with PbO 2 affording almost quantitative conversions to the corresponding nitroxides.Kinetic investigations by EPR, product analysis, NMR/CIDNP, and DFT calculations of 1a-5a are used to unveil the pathways leading both to the decay of alkoxyamines and to the generation of nitroxides.
The same procedures as displayed in Scheme 1 are applied for the preparation of 1d, 3d, and 3e starting from meta-vinylphenol in 25%, 55%, and 74% yields, respectively.

Thermal homolysis
Effects of various substituents attached to the nitroxyl moiety on the homolysis rate constant k d of the C-ON bond in alkoxyamines (Scheme 2) have been thoroughly investigated [30][31][32][33] and it was shown that steric, polar and stabilization effects are strongly entangled. 34,35Noteworthy, for the thermal C-ON bond homolysis, differences of E a of ca.5-7 kJ mol −1 between 1a and 3a, of ca.5-7 kJ mol −1 between 3a and 4a, of ca.2-4 kJ mol −1 between 3a and 5a are in the range of differences observed for analogue alkoxyamines.It means that the C-ON bond homolysis of 1a, 3a-5a is ruled by the polarity and bulkiness of the nitroxyl fragment, and stabilization of the released nitroxide as previously reported. 34Therefore, the thermal-triggered homolysis of 1a-5a occurs via the established mechanism 34 displayed in Scheme 2. Importantly, at high temperatures, in the presence of O 2 , the generation of alkyl radicals, peroxyl radicals, alkoxyl radicals and nitroxides do not alter the kinetics.Hence, the mechanism of homolysis via a selfcatalytic event in which the phenoxyl moiety would play the role of radical scavenger, analogous to the Denisov cycle, 36 is highly unlikely.
Effects of para-aryl substituent for 1-37 and 3-based 38 alkoxyamines have been thoroughly investigated and linear free energy relationships (LFER) were observed for 1-based alkoxyamines 37 with the Hammett constant σ p (ref.39) and for 3-based alkoxyamines 38 with localized polar effect for parasubstituted phenyl groups σ L,4-X-C 6 H 4 . 40,41Thus, E a of 134.3 kJ mol −1 ¶ and 126.2 kJ mol −1 ∥ are estimated for 1a and 3a, respectively, in nice agreement with the experimental values reported in Table 1.Moreover, very similar values of E a are expected for 1a and 1b** as well as for 3a and 3b † † agreeing with the values reported in Table 1.The trends in E a observed for 1a-5a are also observed for 1b-5b.Hence, the C-ON bond homolysis for 1a,b-5a,b occur through TS exhibiting the same features: 34

Chemical oxidation
Taking into account the half-life times of 1a-5a at 25 °C (t 1/2 = 24 days for 4a is the shortest, Table 1), these alkoxyamines are considered as stable during the 60 seconds of experimental time, i.e., thermal homolysis of 0.1 mM of 4a affords 0.7 nM of Chart 1 Alkoxyamines and nitroxides investigated.
Scheme 1 Preparation of 1a-5a.Scheme 2 Geometrical parameters and orbital interactions expected in starting materials, TS, and products during the homolysis event.‡ Disappointingly, all attempts for the preparation of 1a, 2a, and 5a using the procedure described in § failed.§ Alkoxyamines 3a and 4a are also prepared by the coupling of nitroxides 3 • and 4 • with the commercially available para-vinyl phenol using the procedure Mn (salen) (Scheme 1a).¶ σ p,OH = −0.37,see ref. 39, and equation in Fig. 2  ‡ ‡ In general, this angle exhibit a deviation less than ±20°meaning that a very nitroxide, below the threshold of detection of EPR at ca. 10 nM.PbO 2 is currently used to oxidize phenolic anti-oxidant into their corresponding phenoxyl radical for their detection by EPR. 42Adding PbO 2 to 0.1 mM solution of 1a-5a at room temperature does not generate the EPR signal of the corresponding phenoxyl radical but an instantaneous raise of EPR signals corresponding to nitroxides 1 • -5 • .The intensity of the EPR signal of 1 • -5 • is PbO 2 -concentration dependent affording bellshaped curves (Fig. 1).On the left-hand side of the top of bell curve, concentration in PbO 2 is too low for complete oxidation § § whereas on the right-hand side, concentration in PbO 2 is too large that it reacts with nitroxides.Nitroxides 4 • and 5 • are not displayed in Fig. 1 due to their too high reactivity with PbO 2 impeding any significant growth of the EPR signal whatever the concentrations in PbO 2 .PbO 2 -oxidation of 3e affords only 17% conversion in 3 • as expected when less stabilized alkyl species is released from the meta-regioisomer of alkoxyamine.¶ ¶

Chemical activation via H-abstraction reaction
The use of PbO 2 as an oxidant generally also involves the transfer of protons.Since the reduction (of PbO 2 ) is accompanied by proton transfer, it formally corresponds to a H-atom transfer reaction.Accordingly, we have performed H-abstraction reactions induced by the photolysis of di-tertbutyl peroxide.
The t-BuO • radical (Scheme 3a) is able to primarily abstract the phenolic H-atom to generate a phenoxyl radical (Scheme 3d). 43he latter can undergo fragmentation into a nitroxide and a methyne quinone like-product (Scheme 3e).Indeed, as soon as light is turned on, in a solution containing 3a and di-tertbutyl peroxide EPR signal of 3 • raised affording around 80% conversion after a very long time (larger than 10 hours) of irradiation and for less than 5% (v/v) of di-tertbutyl peroxide (Table 2).Disappointingly, a large amount of 40% conversion 3a into 3 • is observed after 12 hours of UV-irradiation in the absence of peroxide.Thus, 3a as well as 1a and 2a are light sensitive.Nevertheless, the kinetics of generation of 3 • are dramatically  f Averaged values of E a reported in footnote e. g First fraction in chromatography.h Relative configurations were not determined.i Second fraction in chromatography.j See ref. 34.
Fig. 1 Plots of nitroxide conversion vs. equivalents in PbO 2 with t-BuPh as solvent for 1 • (red squares), 2 • (black circles), and 3 • (blue and magenta triangles) from 1a, 2a, 3a and 3e, respectively.Lines (second order polynomes) are for an easy reading of the trend.§ § Several vigorous hand-shakings did not increase the EPR signal.¶ ¶ Stabilities of 1 • , 3 • -5 • were investigated by EPR. 1 • is stable in the presence of PbO 2 , 3 • moderately stable, 4 • and 5 • decay quickly impeding all chances of detection when generated from their corresponding alkoxyamines.For 3 • and 4 • , the signal of another radical carrying a phosphorylated moiety is observed but not identified.This species is unstable and decay quickly however, the side species of 3 • is not obseverved during the oxidation of 3a.
faster in the presence of more than 1% of (tBuO) 2 than in its absence (Fig. 2), that is, during the first 3 hours of irradiation, kinetics for the generation of 3 • are the same for 0.1% in (tBuO) 2 and without whereas, in this time, amounts of 3 • reached a plateau and completely decayed for amounts in (tBuO) 2 larger than 1% (Fig. 2).Notably, the plateau is reached faster for lower amounts of 3 • , i.e., 30% released in 1000 s in 10% (tBuO) 2 versus 70% released in 10 hours for 0.5% in (tBuO) 2 .This striking dependence on time for decomposition of 3a into nitroxide 3 • is due to several competitive reactions involving 3 • , t-BuO • , and side-products.Di-tertbutyl peroxide generates tert-butoxyl radicals under UV-irradiation (Scheme 3d).The latter reacts either by H-abstraction on the phenol moiety of 3a to generate a transient phenoxyl radical (Scheme 3b) or by β-fragmentation to afford acetone and methyl radicals (Scheme 3b).These methyl radicals either react with 3 • by the coupling reaction leading to the formation of stable alkoxyamines, and, hence, to the decay of 3 • or they react with O 2 to afford oxidation products or some other radicals able to react with 3 • .Consequently, several of these reactions depend dramatically on concentration of starting materials (tBu 2 O 2 and 3a), of product (3 • and possibly acetone and methine quinone like-compound), and also of intermediates such as t-BuO • and Me • radicals.Therefore, these differences in reactivity, account for the striking differences in conversion and in time to reach maximal conversion (Table 2).

HPLC-ESI analysis
For HPLC experiments, chemical oxidation of 3a,e (10 −2 M) was performed in a 1 : 1 (v : v) MeOH/water mixture and afforded the same EPR results as in t-BuPh as solvent when 500 eq.PbO 2 were added.Authentic compounds displayed in Chart 2 are either prepared as described in literature (A and B) or purchased (C and D).∥∥*** † † † Compounds C-E are expected to be generated in the case of a mesolysis event  a Density: d = 0.796.b Highest conversion observed.c Time for which the maximum conversion reported in the 4 th column is observed.d When experiment was stopped.e When [3a] = 1 mM, no significant differences are observed both in conversion and in kinetics.
Chart 2 Potential product formed from 3a (10 −2 M) upon the oneelectron oxidation process by PbO 2 (500 eq.) in MeOH as solvent, at room temperature.
∥∥ Preparation of E and F is tedious, and as no unknown compounds is detected, no more efforts were devoted to their preparations.*** Compounds issued from the degradation of 3e under chemical oxidation conditions were not prepared as the degradation processes are not clearly unveiled.† † † Oxidations of 3a and 3e were performed in THF in the same conditions.In this case, the oxidation of 3a afforded mainly 3 • and B as main products due to the traces of water in THF.For 3e, results in THF were similar to those in MeOH.See ESI.
releasing benzylic type radical and oxonium (route a in Scheme 4).HPLC analysis of the decomposition of 3e (Table 3) displays only peaks corresponding to 3e (only 30% conversion) and to some traces of 3 • (less than 10% in agreement with EPR results) meaning that the pathways of decomposition affording 3 • are minor events (see section DFT calculations section and Fig. 7).
As displayed in Fig. 3, only 3a, 3 • and A are observed for the decomposition of 3a in the presence of PbO 2 .No traces of other chemicals displayed in Chart 2 are detected.Mass balances (Table 3) for 3a (84% conversion) and 3 • (80% conversion) agree with the EPR results.On the other hand, a clear discrepancy is observed in the mass balance for 3 • (8 nmol against 5.1 nmol for A) meaning that most of the radical cation decomposes into nitroxide and benzylic-type carbo-cation a+ (route b, Scheme 4) which, is scavenged by MeOH to generate A provided the elimination reaction to afford C does not compete.The discrepancy observed is likely due to the occurrence of route c (Scheme 4) generating a phenoxyl radical 3a • which decomposes into nitroxide 3 • and methine quinonetype compound F or to the loss of H+ from a+ to afford F. The latter cannot be detected under our experimental conditions.
Importantly, only 3a, 3 • , and C are detected by ESI-MS (Table 3).Indeed, for A and B, ESI detects only C, meaning that MeOH-or water-elimination occurs in the course of the ESI experiment.The HPLC mass balance shows that the decomposition of the radical cation of alkoxyamine 3a+ • does not occur through route a (Scheme 4).
The same experiments have been performed with 3a in THF affording very similar results except that a+ is scavenged by traces of water in THF to yield B (see ESI table and figure †).When experiments are performed with 3e, similar results to those reported in Table 3 are observed (see ESI table †).Thus, all observations for 3a and 3e in MeOH/water mixture apply also to experiments performed in THF as solvent.It was assumed that the same reactivity would be expected for other phenol-based alkoxyamines not investigated by HPLC.
Scheme 4 Different routes of decay of 3a+ • describing HPLC observations reported in Table 3 and ESI.† Table 3 Retention times in HPLC using UV detection (λ = 210 nm), mass analysis (ESI-MS), and mass balances for pure A-C, 3a, and 3b, and for 3a and 3e in the presence of 500 eq. of PbO 2 in a MeOH/water (v : v 1 : 1) solvent mixture

CIDNP experiments
The experiments described above indicate that the formal abstraction of the phenolic H atom induces the formation of the nitroxyl radical.To shed light on the mechanism of the underlying reaction sequence at a µs time scale, we performed photo-induced TR-CIDNP (Time-Resolved Chemically Induced Dynamic Nuclear Polarization) experiments. 45,46As an example, we present the results obtained with 3a (see ESI † for more derivatives).We have used benzophenone (BP) as the photo-activated hydrogen acceptor.It reacts in an analogous way as the t-BuO • radical (see above Scheme 3d) and can be conveniently activated at 366 nm (NdYAG laser, used in our CIDNP system).We have utilized this approach to successfully study various H-transfer reactions. 47,48n the CIDNP experiment, free radical pairs are generated thermally or photochemically inside the strong magnetic field of the NMR magnet.At the time scale of the CIDNP experiment, the primary radicals undergo reactions, which are spin selective.This leads to a non-Boltzmann population of magnetic energy levels and manifests itself in NMR signals with "unusual" intensities, i.e. enhanced absorption or emission (enhancement factors up to 10 5 ) when the corresponding products are formed via radical pairs.The intensities of these polarized signals (of the products) provide information about the isotropic hyperfine coupling constants in the short-lived radical intermediates.To produce primary radical pairs, we used the photo-induced (NdYAG laser, 355 nm, 8 ns) reaction of the triplet-excited state of BP ( 3 *BP) with alkoxyamine in acetonitrile-d 3 /D 2 O (Scheme 5).Primarily, 3 *BP should abstract the phenolic hydrogen 49,50 and the corresponding follow-up products are observed in CIDNP spectrum with the chemical shifts representing the products and the polarized line intensities indicating the intermediate radicals (Scheme 5).As an example, the 1 H NMR and CIDNP spectra obtained from 3a together with assignments of selected lines are shown in Fig. 7.The most prominent polarizations in the CIDNP spectrum (7.7 ppm and 8-8.2 ppm) can be attributed to the reversible hydrogen transfer from BPH • to 3a • re-generating BP and 3a (Scheme 5).This is in concert with an intermediate phenoxyl radical where the predominant spin population is located on the phenyl ring of 3a in agreement with B3LYP/ TZVP calculations. 51,52Clearly, an electron transfer producing a basically nitrogen centred radical cation from 3a to 3 *BP, would have produced an entirely different polarization pattern than that observed in our experiment (see ESI † for the com-   parison with additional radicals).The remaining polarizations at 2.55 ppm (doublet) and 7.7 ppm (doublet) can be assigned to a methyne quinone like-product F (Chart 2 and Fig. 6) formed via the homolytic cleavage of the C-O bond in 3a • .This intermediate is too short lived to be detected in the steady-state NMR taken after the CIDNP experiment.The fragmentation of 3a • yielding nitroxyl radical 3 • is confirmed by the detection of the corresponding EPR spectrum taken from the NMR tube after accomplishing the NMR experiment.
For derivative 3b, in which the phenolic hydrogen is replaced by the benzyl group, the fragmentation reaction cannot be established by CIDNP (see ESI †); moreover, weak EPR signal is detected.This clearly indicates that the abstraction of the phenolic hydrogen is crucial for the formation of nitroxyl radical 3 • .

Chemical activation via H-abstraction reaction
The generation of 3a • through H-abstraction by t-BuO • radicals and its β-fragmentation into 3 • and F, which are entangled with (several) light-initiated reactions, are nicely confirmed by CIDNP experiments by using benzophenone as radical initiator.Moreover, DFT calculations support the occurrence of Path3a(III) which exhibit clear negative value of ΔG with ΔG ‡ lower than 90 kJ mol −1 as expected for the occurrence of spontaneous and instantaneous reactions.As the same kinetic trends are observed (Table 2) for 1a, and 2a, it is assumed that the observations for 3a apply to these also.

Activation by electron transfer event
Previous studies have examined the behaviour of amoniumyl radical cations generated upon oxidation of alkoxyamines by electrochemical [19][20][21][22][23] or photoredox 24 19,23 and one would expect analogous behaviour for 3c, given that the leaving group is identical.Whatever the amounts of PbO 2 added to a solution of 3c in t-BuPh, less than 4% of signal is detected by EPR.When the same experiments are performed with 3e, less than 20% of 3 • are detected by EPR (Fig. 1) in agreement with HPLC measurements (Table 3), and calculations meaning that path(II) ( path3e(II) in Fig. 7) is a minor event in the generation of 3 • by chemical oxidation process when the released benzylic-cation is not stabilized.This also holds for other alkoxyamines investigated in this article (vide infra).
The quantitative generation of 1 • and 2 • is observed upon addition of PbO 2 to a solution of 1a and 2a, meaning that comments done for 3a hold.
Addition of PbO 2 to 4a and 5a does not generate significant amounts of the corresponding nitroxides 4 • and 5 • due to their low stability in the experimental conditions.¶ ¶ Nevertheless, it is assumed that the same chemistry as described for 3a holds for 4a and 5a.

Impact on the fragmentation pathway
It has to be mentioned that, whatever the experimental conditions, the phenoxyl radical and radical cation are not detected by EPR meaning a very fast decomposition into the nitroxide.Thus, the generation of nitroxide cannot occur as described in Scheme 2 in which flattening at N-and C-atoms is required.Recent DFT calculations showed that C-ON bond homolysis is controlled by two geometrical requirements (Scheme 2): (i) flattening at N-and C-atoms, and (ii) dihedral angle θ 〈OCaryl〉 close to 90°and dihedral angle θ 1 〈n N NOC〉 close to 0°.It was also shown that alkoxyamines exhibiting angle θ close to 90°and θ 1 close to 0°are stable at room temperature meaning that the flattening at C-and N-atoms are the key events which must occur during the raise of temperature when homolysis is performed.Thus, two pathways of decay are offered to the radical cation: route (a) for which the radical cation collapses into nitroxide and benzylic-type cation and route (b) which correspond to the release of phenoxyl radical.Interestingly, both routes exhibit strong similarities for stereoelectronic interactions at TS (Scheme 6), i.e., mesomeric forms H of phenoxyl radical G and J of radical cation I display a significant spin population at the position ipso.Such forms H/J favour the rotation around the C-aryl bond to shift θ angle from 60° § § § to 90°(see TS section in ESI †) aiming to favour hyperconjugative interaction SOMOπ → σ* C-O between the Scheme 6 Generation of nitroxide from alkoxyamine through a PCET process coupled with the β-fragmentation of phenoxyl radical (route a) and the mesolysis of radical cation (route b), and geometrical parameters and orbital interaction at their respective TS. ‡ ‡ ‡ Noteworthily, the addition of PbO 2 on molecules exhibiting phenol moieties is well known to generate phenoxyl radical through a Proton-Coupled Electron Transfer (PCET, see ref. 54 and 27) via the generation of radical cation and loss of proton to provide a phenoxyl radical.§ § § For most 3-based alkoxyamines carrying an aryl moiety on the alkyl fragment, the dihedral angle θ is close to 60°.SOMO of π-type and the antibonding orbital σ* C-O of the C-O bond.Such an interaction at TS favours undoubtedly the β-fragmentation event of the O-C bond affording two highly stabilized molecules: a nitroxide and a conjugated keto diene despite aromaticity is lost for the fragmentation of phenoxyl radical, and a nitroxide and a benzylic-type cation for the mesolysis of the radical cation.In such a process involving early TS, i.e., reactant-like TS, neither the unfavoured N-flattening event nor the N-O bond rotation occur leading to a room temperature spontaneously and instantaneously thermodynamically-driven fragmentation.
Our experimental observations and the computational results indicate that the very efficient production of the nitroxide (e.g. 3 • ) is based either on the primary generation of a phenoxyl radical via hydrogen abstraction or PCET (which cannot be distinguished at the time scale of our experiments) or the mesolysis of the corresponding radical cation.The main prerequisite for an efficient reaction, however, is that an alkyl fragment carrying a p-phenolic moiety as exemplified with 1a-5a.
Here the release of the nitroxide can be either triggered thermally by PbO 2 or by photo-induced reactions.Thus, the caged nitroxides introduced in this work have the potential of being applied in biology and polymer chemistry (e.g., as selectively activable labels).It is likely that the scope of ( photo)oxidants can be enhanced.

Synthetic procedures
Solvents and reactants for the preparation of alkoxyamines were used as received.Routine reaction monitoring was performed using silica gel 60 F254 TLC plates; spots were visualized upon exposure to UV light and a phosphomolybdic acid solution in EtOH, followed by heating.Purifications were performed on Reveleris® X2 Flash System BUCHI Switzerland.Cartouches flash Reveleris® et GraceResolv™: silica 40 μm. 1 H, 13 C, and 31 P NMR spectra were recorded in CDCl 3 on a 300 or 400 MHz spectrometer.Chemical shifts (δ) in ppm were reported using residual nondeuterated solvents as internal references for 1 H and 13 C NMR spectra, and 85% H 3 PO 4 for 31 P-NMR spectra.High-resolution mass spectra (HRMS) were performed on a SYNAPT G2 HDMS (Waters) spectrometer equipped with a pneumatically assisted atmospheric pressure ionization source (API).Positive mode electrospray ionization was used on samples: electrospray voltage (ISV): 2800 V; opening voltage (OR): 20 V; nebulizer gas pressure (nitrogen): 800 L h −1 .Low resolution mass spectra were recorded on the ion trap AB SCIEX 3200 QTRAP equipped with an electrospray source.The parent ion [M + H] + is quoted.
General procedure for the preparation of 1b-5b.To a stirred solution of Salen ligand (0.15 eq.) in i-PrOH was added MnCl 2 (0.15 eq.) in an open flask.After 30 minutes of stirring at room temperature, a solution of nitroxyde 1 • -5 • (1 eq.) and 4-vinylbenzylphenol 6 (1.1 eq.) in i-PrOH was added first, then solid NaBH 4 (5 eq.) in small portions.The resulting suspension was stirred at room temperature for 7 h.It was then diluted with EtOAc (100 mL) and 1 M aq.HCl was carefully added.Solid NaHCO 3 was then added until neutralization.The layers were separated, and the organic phase was washed with water, brine and dried over MgSO 4 .After concentration under reduced pressure, the residue was purified by column chromatography ( petroleum ether/EtOAc) to afford the corresponding alkoxyamines 1b-5b.
General procedure of hydrogenation for the preparation of 1a-5a.To a stirred solution of benzylated alkoxyamine 1b-5b (1 eq.) in EtOAc was added Pd/C (10% w/w) with a flow of hydrogen for 30 minutes.After a complete consumption of starting material monitored by TLC, the solution was filtered on Celite.It was then concentrated under reduced pressure and the residue was purified, if necessary, by column chromatography ( petroleum ether/EtOAc) to afford the corresponding alkoxyamines 1a-5a.

Chemical oxidation as trigger
Addition of several equivalents of lead dioxide PbO 2 to a 0.1 mM solution of alkoxyamines 1a-5a, and after a vigorous 20 seconds hand-shaking, provides an EPR signal.Then, using this procedure, effect of 10 equivalents to 1500 equivalents of PbO 2 on alkoxyamines 1a-5a was tested (ESI Table 1 †).Nitroxides 4 • and 5 • are not stable in the presence of PbO 2, presumably due to further oxidation to oxoamoniums, impeding the growth of significant EPR signals upon oxidation of the corresponding alkoxyamines (only a few percent of conversion were detected).For low amounts of PbO 2 , more vigorous handshakings do not increase the amount of released nitroxide.

CIDNP experiments
1 H NMR and CIDNP spectra were recorded on a 200 MHz Bruker AVANCE DPX spectrometer.In situ irradiation of samples inside NMR magnet was carried out by using a frequency-tripled Quantel Brilliant B Nd:YAG laser (355 nm, 8 ns, ca.70 mJ per pulse) The following pulse sequence was used: presaturation (laser flash)-(RF)-(detection pulse, 2 us)-(free induction decay).Dark spectra (without the laser flash) were always recorded as a reference for a proper suppression of the background NMR transitions.
Deuterated solvents were purchased from Sigma-Aldrich and used without additional treatment.All the samples were deaerated by bubbling with N 2 for 5 minutes prior to the CIDNP experiment.

DFT calculations
All calculations were performed using the Gaussian 16 electronic structure package 55 at the M06-2X/6-31+G(d,p) level of theory, 53 and the nature of all stationary points confirmed with frequency calculations at the same level.Gas-phase Gibbs free energies at 298.15 K were calculated using standard textbook formulae based upon the statistical thermodynamics of an ideal gas under the harmonic oscillator and rigid-rotor approximations.Solvent corrections were obtained with the SMD continuum solvent model for methanol, 56 and the thermocycle approach was employed to determine Gibbs free energies in solution. 57All energies given are from conformationally-searched and Boltzmann-weighted conformer distributions.

HPLC measurements and mass spectral analyses
Alkoxyamines and their homolysed products were separated and monitored by HPLC using an Agilent 1260 apparatus equipped with a UV-Vis absorption and MS detector.Typically, 1 μl of a sample was injected on C18 column (Phenomenex, Luna Omega Polar 1.6 μm, 100 × 2.1 mm) equilibrated with acetonitrile/water mobile phase (15/85 v/v) containing 0.1% formic acid.Compounds were separated by a linear increased of the acetonitrile concentration from 15 to 100% over 8 min.Next, the concentration of acetonitrile was kept at this level for 13 min.All analytes, were eluted at a flow rate of 0.14 ml min −1 .The absorption traces were collected at 230 nm.The structural identity of products was confirmed by MS analysis using an Agilent 6120 quadrupole mass spectrometer equipped with electrospray ion source.The compounds were detected in the positive-ion mode.

Kinetic measurements
Rate constants k d for the homolysis of the C-ON bond of alkoxyamines 1a,b-5a,b (Scheme 7) are determined using eqn (2) and by monitoring the growth of nitroxide by EPR, using O 2 as alkyl radical scavenger as previously reported. 58For all alkoxyamines, a plateau in nitroxides is reached for more than 90% conversion at any temperatures.For the sake of simplicity, activation energies E a are estimated using the Arrhenius equation in conjunction with the averaged frequency factor A = 2.4 10 14 s −1 . 34For ease of discussion, values of k′ d at 120 °C are obtained from the Arrhenius equation, and half lives (t flattening at the N-and C-atoms of the C-ON moiety, rotation around the N-O bond to reach the dihedral angle 〈nitrogen lone pair NOC〉 at 0° ‡ ‡ and rotation around the C-aryl bond to reach the dihedral angle 〈OCaryl〉 at 90°.These geometric requirements favour the donating interactions n N → σ* O-C of the nitrogen lone pair n N into the C-O antibonding orbital σ* O-C , which in turn favours the donating interaction σ O-C → π*aryl of the O-C bonding orbital σ O-C into the antibonding orbital π* of the aryl moiety (Scheme 2).
34) and values of T and k given in second and third columns, respectively.c Values estimated at T = 120 °C assuming an averaged frequency factor A = 2.4 × 10 14 s −1 (see ref. 34) and values of E a given in fourth columns.d Given at 25 °C and using values of k d estimated as described in footnote c. e At T = 139 °C, k d = 3.8 10 −3 s −1 (eqn (2)), E a = 132.7 kJ mol −1 (see footnote b), and at T = 120 °C, k d = 0.9 10 −3 s −1 (eqn (2)), E a = 131.1 kJ mol −1 (see footnote b).

Scheme 3
Scheme 3 Elementary reactions involved during the generation of 3 • under light-irradiation of a solution of 3a with (t-BuO) 2 .

a
Retention time in min.b m e /z and m o /z are for the expected and observed masses by ESI-MS, respectively, in MeOH/H 2 O (1 : 1 v : v), given at ±0.1 u. c In 10 −8 moles at ±0.01.n a , n 3 • , and n o number of moles for alkoxyamines, 3 • , and other molecules, respectively.d n.a.: not applicable.e As displayed in Fig. 3, 20% of impurities are detected.f Mixture of 2 diastereoisomers.g Only one diastereoisomers was available.h Amount of A.

Fig. 7
Fig. 7 Selected ( preferred) pathways of decomposition radicals based on 3a and 3e according to M06-2X/6-31+G(d,p) calculations.Reactions leading to the release of nitroxyl radicals are marked with red boxes.

Table 1
Homolysis rate constants k d for alkoxyamines (0.1 mM) 1a,d-5a,b, and 3d,e at various temperatures T in tert-butylbenzene as solvent and their corresponding activation energies E a , homolysis rate constants k' d at 120 °C and half-life time t 1/2 at 25 °C Values determined by EPR and using eqn (2).b Assuming an averaged frequency factor A = 2.4 × 10 14 s −1 (see ref.

Table 2
Maximum conversion (%) and the corresponding time (t max ) for the generation of 1 • -3 • by the photolysis of tert-butylbenzene solutions (0.1 mM) of 1a-3a, and 3e in the presence (0%-10%) of di-tert-butyl peroxide t-Bu 2 O 2 at room temperature ) 1/2 ) are obtained assuming first order kinetics.All data are gathered in Table 1.ln ½nitroxide 1 À ½nitroxide t ½nitroxide 1 ¼ Àk d Á t ð2Þ Conclusions Oxidation of bench stable alkoxyamines yields highly reactive intermediates capable of undergoing S N 2 reactions with nucleophiles and/or mesolytic cleavage to form carbon-centred radicals or carbocations for use in chemical synthesis.To date electrochemical and photoredox methods have been used for this purpose; in this contribution we show that chemical oxidation provides a mild and convenient alternative.Moreover, when the nitroxide bears phenolic leaving groups we show that alkoxyamine cleavage can also be triggered by proton coupled electron transfer followed by a β-fragmentation reaction to afford methine quinone like-compounds.Both processes have potential to expand the scope of smart alkoxyamines in chemical synthesis, and as reporter molecules of oxidising environments.Open Access Article.Published on 14 October 2021.Downloaded on 9/22/2023 4:21:09 AM.This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.