Article NMR and EPR Study of Homolysis of Diastereomeric Alkoxyamines
Sergey Cherkasov 1,2, Dmitriy Parkhomenko 1 , Alexander Genaev 1, Georgii Salnikov 1, Mariya Edeleva 1, Denis Morozov 1 , Tatyana Rybalova 1 , Igor Kirilyuk 1 , Sylvain R. A. Marque 3 and Elena Bagryanskaya 1,*
1 N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, Pr. Lavrentjeva 9, 630090 Novosibirsk, Russia; [email protected] (S.C.); [email protected] (D.P.); [email protected] (A.G.); [email protected] (G.S.); [email protected] (M.E.); [email protected] (D.M.); [email protected] (T.R.); [email protected] (I.K.) 2 National Research University—Novosibirsk State University, 630090 Novosibirsk, Russia 3 Aix Marseille Univ, CNRS, ICR, UMR 7273, case 551, Avenue Escadrille Normandie-Niemen, 13397 Marseille CEDEX 20, France; [email protected] * Correspondence: [email protected]
Academic Editor: Derek J. McPhee Received: 10 October 2020; Accepted: 30 October 2020; Published: 1 November 2020
Abstract: Three alkoxyamines based on imidazoline radicals with a pyridine functional group—potential initiators of nitroxide-mediated, controlled radical polymerization—were synthesized. Electron Paramagnetic Resonance (EPR) measurements reveal biexponential kinetics for the thermolysis for diastereomeric alkoxyamines and monoexponential kinetics for an achiral alkoxyamine. For comparison, the thermolysis of all three alkoxyamines was studied by NMR in the presence of three different scavengers, namely tetramethylpiperidine-N-oxyl (TEMPO), thiophenol (PhSH), and β-mercaptoethanol (BME), and detailed analysis of products was performed. NMR differentiates between N-inversion, epimerization, and homolysis reactions. The choice of scavenger is crucial for making a reliable and accurate estimate of the true homolysis rate constant.
Keywords: nitroxide; alkoxyamine; nitroxide mediated polymerization; kinetics; scavenger; imidazoline radical; homolysis; nitrogen inversion; chirality; stereoisomerization
1. Introduction Alkoxyamines have been used for three decades [1] as initiators in Nitroxide-Mediated Polymerization (NMP) [2–15]. The main parameters determining the applicability of alkoxyamines for NMP are the rate constants of their homolysis, kd, the rate of recombination of the corresponding alkyl and nitroxide radicals, kc (Scheme1), and the absence of substantial side reactions. Each of the kd and kc rate constants depend on the structure of both the nitroxide and the alkyl radicals. The equilibrium constants vary over a wide range depending on the steric and/or electronic effects of substituents in both the nitroxyl [16–19] and the alkyl parts [19–22]. In addition, the alkoxyamine homolysis parameters can be varied via the introduction of functional groups capable of reversible protonation [23–25], hydrogen bonding [26] or coordination with metals [21,27–29] (for example, pyridine or OH groups) in so-called “switchable” alkoxyamines [30–32]; another such factor is light in photo-cleavable alkoxyamines [33]. For example, the introduction of a pyridine group into the alkoxyamine produced up to a 30-fold increase or decrease of kd upon complexation [21,28–30]. In the present work, we investigate the homolysis of alkoxyamines composed of imidazoline radicals with a pyridine functional group capable of complexation with metals (Chart1). Sterically hindered imidazoline radicals have shown their applicability to NMPs [34]. However,
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Molecules 2020, 25, 5080 2 of 20 the introduction of bulky groups often leads to chiral alkoxyamines, which raises the question of whether the rate kd and kc constants can be different for different stereoisomers. In particular, Ananchenko et al. studiedScheme tetramethylpiperidine-N-oxyl 1. C–ON bond homolysis in (TEMPO) alkoxyamines. and N-(2-methylpropan-2-yl)- N-(1-diethylphosphono-2,2-dimethylpropyl)-aminoxyl)-based alkoxyamines by 1H and 31P NMR spectroscopyIn the present [35–37 work,]. They we showed investigate that the the diastereomeric homolysis of alkoxyamines excess upon homolysis composed and of reformationimidazoline radicalsof the diastereomeric with a pyridine alkoxyamines functional group depends capable strongly of complexation on the structure with of metals both the(Chart nitroxyl 1). Sterically and the hinderedreleased alkyl imidazoline part. radicals have shown their applicability to NMPs [34]. However, the Molecules 2020, 25, x FOR PEER REVIEW 2 of 20 introduction of bulky groups often leads to chiral alkoxyamines, which raises the question of whether the rate kd and kc constants can be different for different stereoisomers. In particular, Ananchenko et al. studied tetramethylpiperidine-N-oxyl (TEMPO) and N-(2-methylpropan-2-yl)-N-(1- diethylphosphono-2,2-dimethylpropyl)-aminoxyl)-based alkoxyamines by 1H and 31P NMR spectroscopy [35–37]. They showed that the diastereomeric excess upon homolysis and reformation of the diastereomeric alkoxyamines depends strongly on the structure of both the nitroxyl and the released alkyl part. SchemeScheme 1.1. C–ONC–ON bondbond homolysishomolysis inin alkoxyamines.alkoxyamines.
In the present work, we investigate the homolysis of alkoxyamines composed of imidazoline radicals with a pyridine functional group capable of complexation with metals (Chart 1). Sterically hindered imidazoline radicals have shown their applicability to NMPs [34]. However, the introduction of bulky groups often leads to chiral alkoxyamines, which raises the question of whether the rate kd and kc constants can be different for different stereoisomers. In particular, Ananchenko et al. studied tetramethylpiperidine-N-oxyl (TEMPO) and N-(2-methylpropan-2-yl)-N-(1- diethylphosphono-2,2-dimethylpropyl)-aminoxyl)-based alkoxyamines by 1H and 31P NMR spectroscopy [35–37]. They showed that the diastereomeric excess upon homolysis and reformation of the diastereomeric alkoxyamines depends strongly on the structure of both the nitroxyl and the released alkyl part.
• RRRR/SS/SS RSRS/RS/RS Chart 1.1. StructuresStructures ofof thethenitroxide nitroxide ( 1(1•),), alkoxyamines alkoxyamines ( 2(2 , 22 , ,3),3), and and scavengers scavengers (TEMPO, (TEMPO, thiophenol (PhSH), β-mercaptoethanol-mercaptoethanol (BME)).
The coupling of a chiral nitroxyl radical with a prochiral alkyl radical produces an alkoxyamine exhibiting two chiral centers: one on the the alkyl alkyl fragment fragment and and one one on on the the nitroxyl nitroxyl fragment. fragment. In In addition, addition, the NN-atom-atom could could be be considered considered as a as third a third pseudo-chiral pseudo-c centerhiral becausecenter because of its three of diitsfferent three substituent different substituentgroups, with groups, its electron with its lone electron pair as lone the fourthpair as group.the fourth The group. chiral nitrogenThe chiral implies nitrogen the implies possibility the possibilityof configuration of configuration inversion at inversion the N-atom at the through N-atom a flip-flop through or a inversionflip-flop or process. inversion These process. three These chiral threecenters chiral could centers undergo could two independentundergo two processes: independent (a) nitrogen processes: inversion (a) nitrogen and (b) stereoisomerizationinversion and (b) stereoisomerizationof the alkyl part following of the alkoxyaminealkyl part following homolysis alkoxyamine and recombination homolysis (Scheme and recombination2). Hereafter, ( weScheme will 2refer). Hereafter, to this second we will process refer to as this epimerization. second process as epimerization. TheChart homolysis 1. Structures of of alkoxyaminesthe nitroxide (1• commonly), alkoxyamines has (2RR/SS a monoexponential, 2RS/RS, 3), and scavengers time (TEMPO, dependence, and consequently,thiophenol (PhSH), EPR β-mercaptoethanol is often used to (BME)). study the kinetics of the homolysis reaction. In such experiments, the oxygen dissolved in the sample is used as a scavenger for the alkyl radicals, so that the increasingThe coupling nitroxyl of radical a chiral concentration nitroxyl radical reveals with the a kineticsprochiral of alkyl the homolysis radical produces reaction an [38 alkoxyamine]. However, thisexhibiting approach two is chiral not useful centers: for one the on more the complicated,alkyl fragment non-monoexponential and one on the nitroxyl kinetics fragment. caused In addition, by side reactions.the N-atom In suchcould cases, be considered NMR spectroscopy as a third is usedpseudo-c to detecthiral and center monitor because the reactionof its three intermediates different andsubstituent final products groups, [ 39with–41 ].its Here, electron we lone used pair three as di thefferent fourth scavengers, group. The namely chiral TEMPO,nitrogen thiophenolimplies the (PhSH),possibility and ofβ -mercaptoethanolconfiguration inversion (BME) at (Chart the N1),-atom to show through the importance a flip-flop ofor theinversion selection process. of a radical These trapthree for chiral NMR centers measurements could undergo of different two alkoxyamines.independent processes: We examine (a) hownitrogen various inversion processes and can(b)
stereoisomerization of the alkyl part following alkoxyamine homolysis and recombination (Scheme 2). Hereafter, we will refer to this second process as epimerization.
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manifest themselves and show that only a careful analysis by the NMR method allows us to draw conclusions about the processes that take place. Molecules 2020, 25, x FOR PEER REVIEW 3 of 20
Scheme 2. 2. EpimerizationEpimerization and and thermolysis thermolysis in the in presence the presence of a scavenger. of a scavenger.
2. ResultsThe homolysis and Discussion of alkoxyamines commonly has a monoexponential time dependence, and consequently, EPR is often used to study the kinetics of the homolysis reaction. In such experiments, 2.1.the Nitrogen oxygen dissolved Inversion in the sample is used as a scavenger for the alkyl radicals, so that the increasing nitroxyl radical concentration reveals the kinetics of the homolysis reaction [38]. However, this Two diastereomers 2RS/SR and 2RR/SS were studied by NMR in the 265–331 K temperature range. approach is not useful for the more complicated, non-monoexponential kinetics caused by side RS/SR Bothreactions. diastereomers In such cases, were NMR found spectroscopy to undergo is usedN-inversion: to detect and for monitor the 2 the diastereomer,reaction intermediates the invertomer RR/SS ratioand isfinal 1:3; products and for 2[39–41]., theHere, invertomer we used three ratio different is 1:30 at scavengers, room temperature namely TEMPO, (Figure thiophenol1, SI p. S3–S23). (PhSH), and β-mercaptoethanol (BME) (Chart 1), to show the importance of the selection of a radical trap for NMR measurements of different alkoxyamines. We examine how various processes can RS/SR manifest themselves and show that only a2 careful analysis by the NMR method allows us to draw conclusions about the processes that take place.
2. Results and Discussion
2.1. Nitrogen Inversion RR/SS Two diastereomers 2RS/SR and 2RR/SS were2 studied by NMR in the 265–331 K temperature range. Both diastereomers were found to undergo N-inversion: for the 2RS/SR diastereomer, the invertomer ratio is 1:3; and for 2RR/SS, the invertomer ratio is 1:30 at room temperature (Figure 1, SI p. S3–S23).
RS/SR Py Py Et 2 H 5 O N Ph 4 Ph 6.86.66.46.26.05.85.65.45.2 Et N N H O N δ, E E ppm 3 2 Et 1 Et RS/SR 1 2 2RS/SR Figure 1.Figure 1H NMR 1. H-NMR spectra spectrain the region in the regionof the ofproton the proton at the at tertiary the tertiary chiral chiral carbon carbon center center forfor the the two two RS/SR RR/SS major minor diastereomersRS/SR 2 RR/SS and 2 . For each diastereomer, the highlighted regions correspond to the diastereomers 2 and 2 . For each diastereomer,RR/SS the highlighted regionsPy correspondPy to the respective respective invertomers. 2 Et 5 O invertomers. 4 5 4 E H N E N Et N N H 1 O Ph 1 Ph The nitrogen inversion rate constants were determined3 in the temperature3 2 rangeEt 265–311 K by 2D 2 Et NOESY/Exchange Spectroscopy (EXSY) and at 302-331 K by DynamicRR/SS NuclearRR/SS Magnetic Resonance RS/SR 2 2 (DNMR) for the 2 diastereomer, which was possible becausemajor of the substantialminor signal from its minor invertomer.6,86,66,46,26,05,85,65,45,2 Under such conditions, the nitrogen inversion is slow on the NMR time scale; δ, ppm plus, the alkoxyamine epimerization process is negligible and does not affect nitrogen inversion. The signals of protons at tertiary chiral carbon centers from DNMR and cross-peaks of the α-pyridine Figure 1. 1H-NMR spectra in the NOESY region of the proton at the tertiary chiral carbon center for the two protonsdiastereomers from NOESY 2RS/SR/EXSY -210and 2RR/SS (Figure .DNMR For 2each; SI p.diastereomer, S180) were the used. highlighted regions correspond to the Approximation Inrespective the case invertomers. of NOESY /EXSY, the nitrogen inversion rate constant kAB is [42]: -220 /h)) B K IAA + KIBB + (K + 1)Icross -230 kAB = ln (1) (K + 1)τ I + KIBB (K + 1)Icross AA − /T)-ln(k
AB -240
R(ln(k -250
-260
-3.8 -3.7 -3.6 -3.5 -3.4 -3.3 -3.2 -3.1 -3.0 -1000/T
Figure 3. Eyring plot for the nitrogen inversion of the 2RS/SR diastereomer.
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The nitrogen inversion rate constants were determined in the temperature range 265–311 K by 2DMolecules NOESY/Exchange2020, 25, 5080 Spectroscopy (EXSY) and at 302-331 K by Dynamic Nuclear Magnetic4 of 20 Resonance (DNMR) for the 2RS/SR diastereomer, which was possible because of the substantial signal from its minor invertomer. Under such conditions, the nitrogen inversion is slow on the NMR time where K is the equilibrium constant; τ—the mixing time (0.1 s); I and I —the integral intensity scale; plus, the alkoxyamine epimerization process is negligibleAA and doesBB not affect nitrogen of the diagonal peaks; I = (I + I )/2; and I and I —the integral intensity of the cross peaks inversion. The signals ofcross protonsAB at tertiaryBA chiralAB carbonBA centers from DNMR and cross-peaks of the (Figure2). For the DNMR line shape analysis, we used the DNMR5 software package [43]. α-pyridine protons from NOESY/EXSY (Figure 2; SI p. S180) were used.
2RS/SR
2RR/SS
6.86.66.46.26.05.85.65.45.2 1 RS/SR Figure 2. Center—1HH DNMR spectraδ, ppm of 22RS/SR atat different different temperatures. temperatures. Right—fragment Right—fragment of of the the 2D RS/SR NOESY/EXSYNOESY/EXSY spectrum ofof 22RS/SR atat 290 290 K K showing showing the the signals signals from from th thee proton proton highlighted highlighted on on the the Left. Left. Figure 1. 1H NMR spectra in the region of the proton at the tertiary chiral carbon center for the two diastereomersInEnthalpy the case and of 2 RS/SRNOESY/EXSY, entropy and 2 ofRR/SS activation. For the each nitrogen werediastereomer, calculatedinversion the rate usinghighlighted constant the Eyring regions kAB is equation: correspond [42]: to the respective invertomers. K IKIKI+++(1) , = , , AA BB cross ∆Gk = ∆H T∆Sln= RT(ln(kAB/T) ln(kB/h)) (1)(2) AB (1)KIKIKI−++−+τ − (1)− AA BB cross G, H, S, where ∆K is ,the∆ equilibrium, and ∆ are constant; the Gibbs’ τ—the free mixing energy, time enthalpy, (0.1 s); and IAA entropy and IBB—the of activation, integral respectively;intensity of k k h theAB —thediagonal nitrogen peaks; I inversioncross = (IAB+I rateBA)/2;constant; and IAB andB I—theBA—the Boltzmann integral intensity constant; of the—Planck’s cross peaks constant; (Figure 2).and For R—the the DNMR universal line gas shape constant analysis, (Figure we 3used, SI p.the S180). DNMR5 The software transmission package coe ffi[43].cient was taken as 1. Enthalpy and entropy of activation were calculated using the Eyring equation: ≠≠ ≠ Δ=Δ−Δ=−GHTSRTkTkh NOESY (ln( / ) − ln( / )) (2) -210 DNMR AB B Approximation where ΔG≠, ΔH≠, and ΔS≠ are the Gibbs’ free energy, enthalpy, and entropy of activation, respectively; -220
kAB—the nitrogen inversion rate/h)) constant; kB—the Boltzmann constant; h—Planck’s constant; and R— B the universal gas constant (Figure-230 3, SI p. S180). The transmission coefficient was taken as 1. /T)-ln(k
AB -240
NOESY R(ln(k -250 -210 DNMR Approximation -220-260 /h)) B -3.8 -3.7 -3.6 -3.5 -3.4 -3.3 -3.2 -3.1 -3.0 -230 -1000/T
/T)-ln(k Figure 3. EyringAB -240 plot for the nitrogen inversion of the 2RS/SR diastereomer. Figure 3. Eyring plot for the nitrogen inversion of the 2RS/SR diastereomer.
Determination of theR(ln(k nitrogen-250 inversion rate constants for alkoxyamine 3 was performed in the temperature range 342–376 K by 2D NOESY/EXSY. The nitrogen inversion is much slower in 3 than in -260 RS/SR 1 –1 2 (0.086/0.36 s− vs. 48/115 s at 342 K in toluene-d8 for the rates of the more populated invertomer to/from the less populated invertomer).-3,8 -3,7 The -3,6 ratio -3,5 -3,4of isomers -3,3 -3,2 for -3,1 nitrogen -3,0 inversion in 3 is 4:1. Due to the specific steric hindrances in alkoxyamines-1000/T 2 and 3, nitrogen inversion is always accompanied by a rotation around the N–O bond. The sequence of these two events could follow two alternative processesFigure 3. Eyring shown plot in Schemefor the nitrogen3a,b. However, inversion accordingof the 2RS/SR todiastereomer. DFT calculations (Figure4, SI p. S205–S213), planarizing the N-atom coordination center and the rotation of the N—O bond do not occur sequentially. The two events are concerted, and the reaction path of nitrogen inversion contains Molecules 2020, 25, x FOR PEER REVIEW 5 of 20
Determination of the nitrogen inversion rate constants for alkoxyamine 3 was performed in the temperatureMolecules 2020 ,range 25, x FOR 342–376 PEER REVIEW K by 2D NOESY/EXSY. The nitrogen inversion is much slower5 of 20in 3 than in 2RS/SR (0.086/0.36 s–1 vs. 48/115 s–1 at 342 K in toluene-d8 for the rates of the more populated Determination of the nitrogen inversion rate constants for alkoxyamine 3 was performed in the invertomer to/from the less populated invertomer). The ratio of isomers for nitrogen inversion in 3 is temperature range 342–376 K by 2D NOESY/EXSY. The nitrogen inversion is much slower in 3 than 4:1. in 2RS/SR (0.086/0.36 s–1 vs. 48/115 s–1 at 342 K in toluene-d8 for the rates of the more populated invertomerDue to theto/from specific the less steric populated hindrances invertomer). in alkoxyamines The ratio of isomers 2 and for3, nitrogennitrogen inversion inversion in 3is is always accompanied4:1. by a rotation around the N–O bond. The sequence of these two events could follow two alternativeDue processesto the specific shown steric in hindrancesSchemes 3a in andalkoxyamines 3b. However, 2 and according 3, nitrogen to inversionDFT calculations is always (Figure Molecules4, SIaccompanied p. S205-S213),2020, 25, 5080by a planarizingrotation around the the N-atom N–O bond. coordination The sequence center of these and thetwo rotation events could of the follow N—O two bond 5 of do 20 notalternative occur sequentially. processes shown The intwo Schemes events 3a are and concerte 3b. However,d, and according the reaction to DFT path calculations of nitrogen (Figure inversion contains4, SI p. S205-S213),no additional planarizing intermediates. the N-atom The coordination N-O-C fragment center and turns the rotationinto the of plane the N—O of the bond imidazoline do not occur sequentially. The two events are concerted, and the reaction path of nitrogen inversion noring additional in the transition intermediates. state (TS). The An N-O-C introduction fragment turnsof bulky into substituents the plane of to the the imidazoline carbon atom ring of in this the contains no additional intermediates. The N-O-C fragment turns into the plane of the imidazoline transitionfragment would state (TS). make An TS introduction less favorable of bulky and substituentsraise the energy to the barrier. carbon The atom steric of this factor fragment of a methyl would ring in the transition state (TS). An introduction of bulky substituents to the carbon atom of this makegroup TS is greater less favorable than that and of raise phenyl the and energy especially barrier. of The a hydrogen steric factor atom; of a ther methylefore, group nitrogen is greater inversion than thatfragment of phenyl would and make especially TS less of favorable a hydrogen and raise atom; th therefore,e energy barrier. nitrogen The inversionsteric factor in of3, a which methyl contains in 3group, which is greater contains than two that methyl of phenyl groups, and especially should beof a slower hydrogen than atom; that ther in efore,2RS/SR .nitrogen inversion two methyl groups, should be slower than that in 2RS/SR. in 3, which contains two methyl groups, should be slower than that in 2RS/SR.
SchemeScheme 3. 3. Process Process involvinginvolving eithereither ( a( )a nitrogen) nitrogen inversion inversion and and N–O N–O bond bondrotation rotation or (b) N–O or (b bond) N–ON–O bondbond rotationrotation and and nitrogennitrogen nitrogen inversioninversion an andandd expected expectedexpected transition transitiontransition state statestate (TS) (TS) (TS)for the forfor nitrogen thethe nitrogennitrogen inversion inversioninversion event. event.event.
RS/SR RS/SR 2 TS Invertomer of 2 2RS/SR TS Invertomer of 2RS/SR Figure 4. Geometries of the 2RS/SR invertomers and the transition state of nitrogen inversion calculated RS/SR Figureby Density 4. Geometries Functional of Theory/P the 2 erdew-Birke-Ernzerhofinvertomers and the (DFT/PBE)/ transitionΛ01. state of nitrogen inversion calculated byFigure Density 4. Geometries Functional of Theory the 2RS/SR/Perdew-Birke-Ernzerhof invertomers and the transition (DFT/PBE) stat/Λe01. of nitrogen inversion calculated 2.2.by EPR Density Study Functional of Alkoxyamines Theory/P Homolysiserdew-Birke-Ernzerhof (DFT/PBE)/Λ01. 2.2. EPR Study of Alkoxyamines Homolysis Homolysis kinetics were investigated by EPR with oxygen as a scavenger for both diastereomers 2.2.2 RS/SREPRHomolysis and Study 2RR/SS of kinetics, asAlkoxyamines well as were for alkoxyamine investigated Homolysis 3.by As EPRexpected, with alkoxyamine oxygen as a 3 scavenger exhibited monoexponential for both diastereomers RS/SR RR/SS 2 and 2 , as well as for alkoxyamine 3d . As expected,–4 –1 alkoxyamine 3 exhibited monoexponential kinetics;Homolysis the homolysis kinetics wererate investigatedconstant was byk EPR= 2.5 with× 10 oxygen s (Figure as a scavenger 5, green). forIn bothcontrast, diastereomers for kinetics;alkoxyamines the homolysis 2RS/SR and 2 rateRR/SS, constantbi-exponential was kineticsk = 2.5 were 10observed4 s 1 (Figure(Figure 5,5, blue green). and red), In contrast,as 2RS/SR and 2RR/SS, as well as for alkoxyamine 3. Asd expected,× alkoxyamine− − 3 exhibited monoexponential forevident alkoxyamines in the upward2RS/SR deviationand 2RR/ SSin, concentration bi-exponential of kineticsnitroxide were at short observed times. In (Figure general,5, blue such and a red), kinetics; the homolysis rate constant was kd = 2.5 × 10–4 s–1 (Figure 5, green). In contrast, for as evident in the upward deviation in concentration of nitroxide at short times. In general, such a alkoxyamines 2RS/SR and 2RR/SS, bi-exponential kinetics were observed (Figure 5, blue and red), as dependence is typical of a mixture of diastereomers, such as a mixture of 2RS/SR and 2RR/SS. However, evident in the upward deviation in concentration of nitroxide at short times. In general, such a the samples studied here contain only minor impurities of the corresponding diastereomers, which does not account for the deviations from monoexponential decay.
2.3. NMR Study of Alkoxyamine Homolysis As mentioned above, the NMR experiments are affected by two dynamic processes in these alkoxyamines: (i) nitrogen inversion and (ii) homolysis of the C–ON bond followed by recombination of the nitroxyl and alkyl radicals giving either of the two diastereomers (epimerization). The kinetics of homolysis can be observed by the addition of a radical scavenger to convert the generated radicals (or at least only the alkyl radicals) into diamagnetic products. The epimerization reaction relies on homolysis of the C–ON bond to generate two radicals with a loss of chirality at both N- and C-atoms, Molecules 2020, 25, 5080 6 of 20 Molecules 2020, 25, x FOR PEER REVIEW 6 of 20 dependencebut chirality is regenerates typical of upona mixture coupling. of diastereomers, Thus, the ∆G such, of epimerizationas a mixture of should 2RS/SR beand close 2RR/SS to. theHowever,∆G, of thehomolysis samples and studied larger here than contain 110 kJ/ mol.only Fromminor the impurities little data of available the corresponding in the literature diastereomers, concerning which labile doesalkoxyamines not account [44 for,45], the the deviations∆G, of nitrogen from monoexponential inversion is around decay. 60–75 kJ/mol for non-sterically hindered alkoxyamines and close to ∆G, of homolysis when sterically hindered [46].
0.0 0.0 ) 0 -0.5 -0.5
347K ln(C/C -1.0 ) 0 -1.0
0 5000 10,000 15,000 20,000 Time, s ln(C/C -1.5 376K RR/SS -2.0 3 2 2RS/SR -2.5 0 10,000 20,000 30,000 40,000 50,000 60,000 326 327 328 329 330 Time, s Field, mT
(a) (b)
Figure 5. (a) Kinetic curves of alkoxyamine decomposition at semi-log scale of 3 at 376 K (green); RS/SR Figure2RS/SR 5.(blue) a) Kinetic and 2curvesRR/SS(red) of alkoxyamine at 347K in decomposition toluene (left) measured at semi-log using scale the of 3 second at 376 K integral (green); of 2 EPR (blue) and 2RR/SS(red) at 347K in toluene (left) measured using the second integral of EPR spectrum of spectrum of formed radical 1• (right); (b) EPR spectrum of formed radical 1•. formed radical 1• (right); b) EPR spectrum of formed radical 1• In 1H-NMR spectra, the signals of the α-protons of pyridine moieties are easily recognized by the 2.3.reduced NMR spin–spinStudy of Alkoxyamine coupling constant Homolysis with the neighboring proton ( 5 Hz) and are in the low-field ≈ regionAs ofmentioned the spectrum, above, not the overlapping NMR experiments with the are signals affected of other by two protons. dynamic Therefore, processes in reactionsin these α alkoxyamines:where the pyridine (i) nitrogen ring is inversion not affected, and the (ii) totalhomolysis integral of the of theC–ON entire bond region followed of -pyridine by recombination protons of ofthe the starting nitroxyl materials and alkyl and radicals products givi canng eitherbe taken of the as unity two diastereomers and used as an (epimerization “internal standard”). The kinetics in the ofprocessing homolysis of can kinetic be observed data. In by addition, the addition in reactions of a radical in which scavenger the nitroxide to convert radical the generated1• is the radicals starting 1 (ormaterial at least or only the product, the alkyl the radicals)H spectrum into diamagne containstic two products. relatively The narrow, epimerization precisely reaction integrable relies signals, on δ homolysis= 7.7 and of 8.9the ppm,C–ON with bond a half-widthto generate oftwo about radicals 20 Hzwith and a loss each of withchirality an intensity at both N- of and 1H, C-atoms, which is butpresumably chirality regenerates related to the upon pyridine coupling. fragment. Thus, Thethe Δ largeG≠ ofchemical epimerization shifts should difference be close of the to ethyl the Δ groupG≠ of homolysisprotons is noteworthyand larger than and 110 is due kJ/mol. to the From specific the little spatial data structure available of in this the alkoxyamine literature concerning (SI, p. S10). labile alkoxyamines [44,45], the ΔG≠ of nitrogen inversion is around 60–75 kJ/mol for non-sterically 2.4. Homolysis of Alkoxyamines in the Absence of Scavengers (Epimerization) hindered alkoxyamines and close to ΔG≠ of homolysis when sterically hindered [46]. InThe 1H-NMR main reaction spectra, upon the signals heating of of the alkoxyamineα-protons of solutionpyridine ismoieties the homolysis are easily of the recognized C–ON bond by thewith reduced the formation spin–spin of acoupling nitroxyl consta and ant planar with alkylthe neighboring radical with proton a subsequent (≈5 Hz) and recombination are in the low-field of these regionradicals of to the form spectrum, one of the not diastereomers. overlapping with In the the absence signals of of any other alkyl protons. radical traps,Therefore, including in reactions oxygen, wherethe only the one pyridine side reaction ring is not is a affected, recombination the total of integral two alkyl of radicals. the entire It region leads to of the α-pyridine accumulation protons of anof theexcess starting of the materials stable nitroxyl and products radical, can forcing be taken the recombination as unity and used of nitroxyl as an “internal and alkyl standard” radical to in be the the processingmain reaction of kinetic occurring data. in ourIn addition, experimental in reactions conditions in which [36–38 ,the47]. nitroxide Toluene wasradical chosen 1• is as the the starting solvent materiaafter carefull or the consideration product, the of1H thespectrum NMR andcontains EPR experiments,two relatively takingnarrow, into precisely account integrable the advantage signals, of δusing = 7.7non-polar and 8.9 ppm, solvents with in a EPR half-width experiments of about on the 20 oneHz handand each and thewith typical an intensity activation of energy1H, which of this is presumablyreaction (and related temperature to the pyridine range) on fragment. the other The hand. large chemical shifts difference of the ethyl group protonsKinetic is noteworthy data were and collected is due to for the the specific proton spatial located structure at the stereogenic of this alkoxyamine carbon center (SI, p. (Figure S10). 1). The kinetic scheme was the conventional reversible conversion 2RS/SR 2RR/SS (Figure6, Table1). 2.4. Homolysis of Alkoxyamines in the Absence of Scavengers (Epimerization) The main reaction upon heating of the alkoxyamine solution is the homolysis of the C–ON bond with the formation of a nitroxyl and a planar alkyl radical with a subsequent recombination of these radicals to form one of the diastereomers. In the absence of any alkyl radical traps, including oxygen, Molecules 2020, 25, x FOR PEER REVIEW 7 of 20 the only one side reaction is a recombination of two alkyl radicals. It leads to the accumulation of an excess of the stable nitroxyl radical, forcing the recombination of nitroxyl and alkyl radical to be the main reaction occurring in our experimental conditions [36–38,47]. Toluene was chosen as the solvent after careful consideration of the NMR and EPR experiments, taking into account the advantage of using non-polar solvents in EPR experiments on the one hand and the typical activation energy of this reaction (and temperature range) on the other hand. MoleculesKinetic2020, data25, 5080 were collected for the proton located at the stereogenic carbon center (Figure 1).7 The of 20 kinetic scheme was the conventional reversible conversion 2RS/SR ⇄ 2RR/SS (Figure 6, Table 1).
1.0 1.0 2RR/SS 2RS/SR RS/SR RR/SS 0.8 2 0.8 2
0.6 0.6
0.4 0.4 Mole fraction Mole fraction
0.2 0.2
0.0 0.0 0 20,000 40,000 60,000 0 20,000 40,000 60,000 Time, s Time, s
FigureFigure 6. 6.Kinetic Kinetic curves curves for for the the epimerization epimerization reaction reaction of of alkoxyamines alkoxyamines2 RS2RS/SR/SR and 2RR/SSRR/SS. .
Table 1. Rate constants ( 10 5 s 1) for the reactions of alkoxyamines ( 0.02 mol/L) with BME (2 mol/L), Table 1. Rate constants (×10–5− s–1−) for the reactions of alkoxyamines (≈0.02 mol/L) with BME (2 mol/L), × a ≈ PhSH (2 mol/L) and TEMPO (3 eqv. ) in toluene-d8 at 347 K by NMR. PhSH (2 mol/L) and TEMPO (3 eqv.a) in toluene-d8 at 347 K by NMR.
None TEMPO TEMPO BME BME PhSH PhSH 2RS2/SRRS/SR 10.510.5bb 5.05.0 cc 8.38.3 16.3 16.3 2RR2/SSRR/SS 6.06.0b b 2.22.2 cc 2.52.5 7.0 7.0 c d e 3 3 0.330.33 c 0.810.81 d 0.360.36 e • f 1 21 6400 f 1• 21 6400 aA lower concentration of TEMPO was essential to get resolved NMR spectra. a A lower concentration of TEMPO was essential to get resolved NMR spectra. b Epimerization. c To simplify b comparisonEpimerization. of rate constants, the initial concentration of the substrate was taken as 1. To obtain the formally correct cvalueTo simplify (as for bimolecular comparison reaction of rate with constants, TEMPO), the the initia ratel constant concentration must be of divided the substrate by the initial wasconcentration taken as 1. To of 2 or 3 (0.033 mol/L), see SI p. S189. d Interpolated to 347 K from the rates at 342 K and 376 K (the reaction was carried obtain the formally correct value (as for bimolecular reaction with TEMPO), the rate constant must be out at a different temperature so that broadening due to nitrogen inversion would be less disturbing). At T = 342 K, 6 1 4 1 e 4 1 dividedk = 4.1 10 by− thes− . initialT = 376 concentration K, k = 3.1 10− ofs 2− or. 3Extrapolated (0.033 mol/L), to 347see KSIfrom p. S189. rate at T = 376K, kd = 1.9 10− s− . f # dInterpolatedExtrapolated toto 347 347 K K from from the the rates rates at 300 at K 342 bythe K and Eyring 376 equation K (the with reaction∆S = was0 (the carried reaction out is very at a fast different even at room temperature, incl. at increased speed is not measured). temperature so that broadening due to nitrogen inversion would be less disturbing). At T = 342 K, k = 4.1 10−6 s−1. T = 376 K, k = 3.1 10−4 s−1.
eForExtrapolated the calculation to 347 K of from the energetic rate at T = parameters 376K, kd = 1.9 of 10 the−4 s reaction,−1. a number of experiments at different temperaturesfExtrapolated were to 347 performed K from the (SI, rates p. at S181–S186). 300 K by the Eyring The enthalpy equation andwith entropyΔS# = 0 (the of reaction the reaction is very were obtainedfast even using: at room temperature, incl. at increased speed is not measured). ∆G0 = ∆H0 T∆S0 = RT ln Keq (3) For the calculation of the energetic parameters− of− the reaction, a number of experiments at differentwhere Keq temperaturesis the equilibrium were constant performed of the (SI, reaction. p. S181 The–S186). calculated The enthalpy values are and∆H entropy0 = 0.021 of the0.046 reaction kJ/mol ± wereand ∆ obtainedS0 = 2.33 using:0.33 J/mol/K. Since the equilibrium constant is practically independent of temperature, ± the enthalpy of the reaction is close to zero. Δ=Δ−Δ=−GHTSRTKln (3) In addition, the enthalpy and00 entropy of activation 0 wereeq calculated for the epimerization wherereaction Keq using is the the equilibrium Eyring equation, constant in of the the same reaction. way as The for calculated nitrogen inversion. values are Energy ΔH0 =parameters 0.021 ± 0.046 of , , kJ/mol∆H = and121.50 ΔS0 2.5= 2.33 kJ/mol ± 0.33 and J/mol/K.∆S = 29.6 Since 6.2the J /equilibriummol/K (Figure constant7) were is obtained. practically independent of ± ± temperature, the enthalpy of the reaction is close to zero. 2.5. HomolysisIn addition, of Alkoxyamines the enthalpy in and the Presence entropy of of Scavengers activation were calculated for the epimerization reactionThe using decomposition the Eyring ofequation, alkoxyamines in the same2RS/SR wa, 2yRR as/SS for, and nitrogen3 was inversion. studied in Energy the presence parameters of three of ΔdiHff≠erent = 121.50 scavengers—TEMPO, ± 2.5 kJ/mol and ΔS PhSH,≠ = 29.6 and ± 6.2 BME. J/mol/K (Figure 7) were obtained. Heating of 3 with TEMPO as an alkyl radical scavenger leads to a complete decomposition of the alkoxyamine (Scheme4, SI p. S187, S188). TEMPO is not the best scavenger to use in such a case, as TEMPO-based alkoxyamines carrying a tertiary alkyl fragment with a functional group in general exhibit an Ea lower than 120 kJ/mol[20]. Here, TEMPO is efficient due to the H-abstraction from the tertiary alkyl radical converting it to an olefin [39]. The signals of the reaction products nitroxide 1• and tert-butylmetacrylate 5 in stoichiometric amounts are present in the NMR spectra Molecules 2020, 25, x FOR PEER REVIEW 8 of 20
-240
-260 /h)) B
-280 /T)-ln(k AB Molecules 2020, 25, 5080 -300 8 of 20 R(ln(k -320 (SI p. S39–S43). The absence of signals of the hydroxylamine TEMPO-H in NMR is likely due to the fastMolecules exchange—TEMPO 2020, 25, x FOR PEER+ REVIEWTEMPO-H-340 TEMPO-H + TEMPO—on the NMR time scale. 8 of 20 -3.0 -2.9 -2.8 -2.7 -2.6 -2.5 -2.4 -2.3 -2.2 -1000/T
-240 Figure 7. Eyring plot for epimerization reaction of 2RS/SR diastereomer. -260 /h))
2.5. Homolysis of AlkoxyaminesB in the Presence of Scavengers
The decomposition of -280alkoxyamines 2RS/SR, 2RR/SS, and 3 was studied in the presence of three different scavengers—TEMPO,/T)-ln(k PhSH, and BME. AB Heating of 3 with TEMPO-300 as an alkyl radical scavenger leads to a complete decomposition of
the alkoxyamine (Scheme 4,R(ln(k SI p. S187,S188). TEMPO is not the best scavenger to use in such a case, as TEMPO-based alkoxyamines-320 carrying a tertiary alkyl fragment with a functional group in general exhibit an Ea lower than 120 kJ/mol[20]. Here, TEMPO is efficient due to the H-abstraction from the tertiary alkyl radical converting-340 it to an olefin [39]. The signals of the reaction products nitroxide 1• -3.0 -2.9 -2.8 -2.7 -2.6 -2.5 -2.4 -2.3 -2.2 and tert-butylmetacrylate 5 in stoichiometric amounts are present in the NMR spectra (SI p. S39–S43). -1000/T The absence of signals of the hydroxylamine TEMPO-H in NMR is likely due to the fast exchange— TEMPO + TEMPO-H ⇄ TEMPO-H + TEMPO—on the NMR timeRS scale./SR FigureFigure 7.7. EyringEyring plotplot forfor epimerizationepimerization reactionreaction ofof2 2RS/SR diastereomer.diastereomer.
2.5. Homolysis of Alkoxyamines in the Presence of Scavengers
The decomposition of alkoxyamines 2RS/SR, 2RR/SS, and 3 was studied in the presence of three different scavengers—TEMPO, PhSH, and BME. Heating of 3 with TEMPO as an alkyl radical scavenger leads to a complete decomposition of the alkoxyamine (Scheme 4, SI p. S187,S188). TEMPO is not the best scavenger to use in such a case, as TEMPO-based alkoxyamines carrying a tertiary alkyl fragment with a functional group in general exhibit an Ea lower than 120 kJ/mol[20]. Here, TEMPO is efficient due to the H-abstraction from the tertiary alkyl radical converting it to an olefin [39]. The signals of the reaction products nitroxide 1• and tert-butylmetacrylate 5 in stoichiometric amounts are present in the NMR spectra (SI p. S39–S43). The absence of signals of the hydroxylamine TEMPO-H in NMR is likely due to the fast exchange— TEMPO + TEMPO-H ⇄ TEMPO-H + TEMPO—on the NMR time scale.
Scheme 4. TheThe mechanism mechanism of of decomposition decomposition of of alkoxyamine 3 in the presence of TEMPO.
RS/SR In sharp sharp contrast contrast to to the the results results observed observed for for 33, ,the the reaction reaction of of 22RS/SR withwith anan excess excess of ofTEMPO TEMPO at 347at 347 K does K does not reach not reach completion. completion. Even when Even the when expe theriment experiment is performed is performed at 367 K in at the 367 presence K in the of TEMPOpresence offor TEMPO 8 h, decomposition for 8 h, decomposition is not iscomplete, not complete, and andan equilibrium an equilibrium is isobserved observed with with the RR/SS RS/SR RR/SS epimerization product 2RR/SS. Moreover,. Moreover, a asteady-state steady-state is is also also observed observed between between 22RS/SR + 2+RR/SS2 and andthe TEMPO-basedthe TEMPO-based alkoxyamine alkoxyamine 6 (SI6 (SI p. p.S44–S61). S44–S61). This This additional additional equilibrium equilibrium (Scheme (Scheme 5)5) is established substantially faster than the epimerization of alkoxyamine 2, its equilibriumequilibrium constantconstant beingbeing 0.3.0.3. Thus, when the Ea of TEMPO-based alkoxyamines is lower than that of the starting material, the use of TEMPO must comply with the requirement: the presence of a hydrogen at the carbon atom in the α-position to the radical center in the released alkyl radical to favor the conversion of the latter into an olefin. Unexpectedly, least-squares fitting of the kinetics data for the reversible reaction of 2RS/SR with TEMPOScheme revealed 4. The thatmechanism the rate of constantsdecomposition for theof alkoxyamine direct epimerization 3 in the presence2RS/SR of TEMPO.2RR/SS became significantly lower (SI, p. S189). In the presence of TEMPO, the diastereomers of 2 are transformed into eachIn other sharp via contrast the intermediate to the results formation observed of 6 foronly. 3, the Such reaction unusual of behavior2RS/SR with could an excess be explained of TEMPO byan at unfavorable347 K does not recombination reach completion. of chiral Even1• andwhen prochiral the expe7riment• in the is opposite performed diastereomeric at 367 K in the configuration, presence of TEMPO for 8 h, decomposition is not complete, and an equilibrium is observed with the epimerization product 2RR/SS. Moreover, a steady-state is also observed between 2RS/SR + 2RR/SS and the TEMPO-based alkoxyamine 6 (SI p. S44–S61). This additional equilibrium (Scheme 5) is established substantially faster than the epimerization of alkoxyamine 2, its equilibrium constant being 0.3.
Molecules 2020, 25, x FOR PEER REVIEW 9 of 20
Thus, when the Ea of TEMPO-based alkoxyamines is lower than that of the starting material, the use of TEMPO must comply with the requirement: the presence of a hydrogen at the carbon atom in the α-position to the radical center in the released alkyl radical to favor the conversion of the latter into an olefin. Unexpectedly, least-squares fitting of the kinetics data for the reversible reaction of 2RS/SR with TEMPO revealed that the rate constants for the direct epimerization 2RS/SR ⇄ 2RR/SS became Moleculessignificantly2020, 25 lower, 5080 (SI, p. S189). In the presence of TEMPO, the diastereomers of 2 are transformed9 of 20 into each other via the intermediate formation of 6 only. Such unusual behavior could be explained by an unfavorable recombination of chiral 1• and prochiral 7• in the opposite diastereomeric whileconfiguration, still in the while solvent still cavity. in the Letsolvent us assume cavity. that Let theus assume opposite that diastereomer the opposite can diastereomer be formed either can be in theformed cavity either after in reorientation the cavity after of the reorientation radicals or of after the leaving radicals the or cavity.after leaving Although the stericcavity. hindrances Although couldsteric hindrances prohibit reorientation could prohibit in the reorientation cavity, free radical in the cavity,7• out offree the radical cavity 7 would• out of be the rapidly cavity scavenged would be byrapidly the more scavenged active TEMPO.by the more active TEMPO.
Scheme 5. The equilibrium between alkoxyamines 2 and TEMPO.
In the the case case of of PhSH PhSH as as a scavenger, a scavenger, monoexpo monoexponentialnential kinetics kinetics were were observed observed (Figure (Figure 8) for8 )2 forand 23 and(SI p.3 S190–S193).(SI p. S190–S193). In contrast In contrast to TEMPO, to TEMPO, PhSH reduces PhSH the reduces radicals the 1 radicals•, 4•, and1 7•,• 4from•, and the7 •homolysisfrom the homolysisreaction, converting reaction, convertingitself into diphenyl itself intodisulfide. diphenyldisulfide. As the result, As alkyl the radicals result, alkyl 4• and radicals 7• would4• andobtain7• wouldan additional obtain anH-atom additional from H-atom the scavenger, from the scavenger,while nitroxide while nitroxide1• would1 •bewould reduced be reduced mainly mainlyto the tocorresponding the corresponding amine amine 8 (Scheme8 (Scheme 6, SI p.6, SIS62–S91). p. S62–S91). The same The sameamine amine is formed is formed in the in reduction the reduction of pure of purenitroxide nitroxide 1• with1• with PhSH, PhSH, with with a much a much faster faster rate rate (Table (Table 1,1 ,SI SI p. p. S92–S113, S92–S113, S194). Additional minorminor products werewere alsoalso detected detected by by NMR NMR in in the the reaction reaction mixtures, mixtures, such such as adducts as adducts of the of nitroxide the nitroxide1• with 1• thewith scavenger. the scavenger. Molecules 2020, 25, x FOR PEER REVIEW 10 of 20
RR/SS 0.8 2 2RS/SR
0.6 0
C/C 0.4
0.2
0.0 0 10,000 20,000 30,000 40,000 50,000 60,000 Time, s
RS/SR RR/SS FigureFigure 8. Kinetic 8. Kinetic curves curves of alkoxyaminesof alkoxyamines decomposition decomposition of of2 2RS/SR andand 2RR/SS2 at 347at 347K in K toluene-d in toluene-d8 in 8 in the presencethe presence of spin of spin trap trap PhSH. PhSH.
WhenWhen BME BME was was used used as as the the radical radical scavenger,scavenger, bi-exponential bi-exponential kinetics kinetics were were observed observed for for Scheme 6. Decomposition of alkoxyamines 2RS/SR and 3 in the presence of PhSH. alkoxyaminesalkoxyamines2RS/2SRRS/SRand and2 RR2RR/SS/SS (Figure(Figure 9),9), and and 3 (SI3 (SI p. p.S195–S197). S195–S197). For 2 ForRS/SR2 andRS/SR 2RR/SSand, the2RR decay/SS, the was decay was fitfit withwith a a 4-reaction 4-reaction kinetic kinetic scheme: scheme: 2RS/SR → 2RR/SS kAB RS/SR RR/SS 2RR/SS → 2RS/SR2 kkBA → AB RS/SR → 2RR/SS Products2RS/SR k kAP → BA 2RR/SS → Products kBP 2RS/SR Products k → AP RR/SS where kAB, kBA are the epimerization rate2 constantProductss for the two kBP diastereomers; and kAP, kBP are the rate constants of the reactions of each diastereomer→ with BME. To solve the kinetic equations, we assume relationships K = kAB/kBA and kP = kAP/kBP and obtained the constants (at 347 K): kAB = (8.29 ± 0.58) × 10−5 s−1, K = 1.33 ± 0.2, kAP = (8.27 ± 6.1) × 10−5 s−1, and kP = 3.25 ± 0.75.
0.8 2RS/SR RR/SS 0.7 2
0.6
0.5
0.4
0.3 Mole fraction
0.2
0.1
0.0 0 10000 20000 30000 40000 50000 Time, s
(a) Molecules 2020, 25, x FOR PEER REVIEW 9 of 20
Thus, when the Ea of TEMPO-based alkoxyamines is lower than that of the starting material, the use of TEMPO must comply with the requirement: the presence of a hydrogen at the carbon atom in the α-position to the radical center in the released alkyl radical to favor the conversion of the latter into an olefin. Unexpectedly, least-squares fitting of the kinetics data for the reversible reaction of 2RS/SR with TEMPO revealed that the rate constants for the direct epimerization 2RS/SR ⇄ 2RR/SS became significantly lower (SI, p. S189). In the presence of TEMPO, the diastereomers of 2 are transformed into each other via the intermediate formation of 6 only. Such unusual behavior could be explained by an unfavorable recombination of chiral 1• and prochiral 7• in the opposite diastereomeric configuration, while still in the solvent cavity. Let us assume that the opposite diastereomer can be formed either in the cavity after reorientation of the radicals or after leaving the cavity. Although steric hindrances could prohibit reorientation in the cavity, free radical 7• out of the cavity would be rapidly scavenged by the more active TEMPO.
Molecules 2020, 25, x FOR PEER REVIEW 10 of 20 Scheme 5. The equilibrium between alkoxyamines 2 and TEMPO. 2RR/SS In0.8 the case of PhSH as a scavenger, monoexponential kinetics were observed (Figure 8) for 2 and RS/SR Molecules3 (SI p. S190–S193).2020, 25, 5080 In contrast to TEMPO, 2PhSH reduces the radicals 1•, 4•, and 7• from the homolysis10 of 20 • • reaction,0.6 converting itself into diphenyldisulfide. As the result, alkyl radicals 4 and 7 would obtain an additional H-atom from the scavenger, while nitroxide 1• would be reduced mainly to the 0 wherecorresponding kAB, kBA areamine the 8 epimerization (Scheme 6, SI rate p. S62–S91). constants The for thesame two am diastereomers;ine is formed andin the kAP reduction, kBP are theof pure rate
C/C 0.4 constantsnitroxide of1• thewith reactions PhSH, with of each a much diastereomer faster rate with (Table BME. 1, To SI solve p. S92–S113, the kinetic S194). equations, Additional we assume minor relationshipsproducts were K =alsokAB detected/kBA and by kP NMR= kAP in/kBP theand reac obtainedtion mixtures, the constants such as (at adducts 347 K): kofAB the= (8.29nitroxide0.58) 1• 5 1 5 1 ± 10 s0.2 ,K = 1.33 0.2, k = (8.27 6.1) 10 s , and k = 3.25 0.75. ×with− the− scavenger. ± AP ± × − − P ±
0.0 0 10000 20000 30000 40000 50000 60000 Time, s
Figure 8. Kinetic curves of alkoxyamines decomposition of 2RS/SR and 2RR/SS at 347 K in toluene-d8 in the presence of spin trap PhSH.
When BME was used as the radical scavenger, bi-exponential kinetics were observed for alkoxyamines 2RS/SR and 2RR/SS (Figure 9), and 3 (SI p. S195–S197). For 2RS/SR and 2RR/SS, the decay was fit with a 4-reaction kinetic scheme: 2RS/SR → 2RR/SS kAB
2RR/SS → 2RS/SR kBA
2RS/SR → Products kAP
2RR/SS → Products kBP
where kAB, kBA are the epimerization rate constants for the two diastereomers; and kAP, kBP are the rate constants of the reactions of each diastereomer with BME. To solve the kinetic equations, we assume RSRS/SR/SR relationships K = kAB/kBA and kP = kSchemeAPScheme/kBP and 6. 6. Decomposition obtainedDecomposition the constants of of alkoxyamines alkoxyamines (at 347 K):2 2 kAB = and (8.29 3 inin± 0.58)the the presence presence × of PhSH. 10−5 s−1, K = 1.33 ± 0.2, kAP = (8.27 ± 6.1) × 10−5 s−1, andMolecules kP = 3.25 2020 ± 0.75., 25, x FOR PEER REVIEW 11 of 20
RS/SR 1.0 0.8 2 2RS/SR RR/SS RR/SS 0.7 2 2 0.8 0.6
0.5 0.6
0.4 0.4 0.3 Mole fraction Mole fraction 0.2 0.2 0.1
0.0 0.0 0 10,000 20,000 30,000 40,000 50,000 0 10,000 20,000 30,000 40,000 50,000 Time, s Time, s
(a) (b)
Figure 9. KineticRS curves/SR for decompositionRR/SS of 2RS/SR and 2RR/SS at 347 K in toluene-d8 in the presence of Figure 9. Kinetic curves for decomposition of 2 and 2 at 347 K in toluene-d8 in the presence of RS/SR RR/SS spin trap BME. (a) Initial mole fractionspin trap of BME.2RS/SRa) Initialis equal mole to 1fraction while ofof 22RR/SS is isequal equal to to1 while zero. of (b 2) Initial is equal to zero. b) Initial RR/SS RS/SR mole fraction of 2RR/SS is equalmole to 1 whilefraction of of22RS/SR is isequal equal to 1 to while zero. of 2 is equal to zero. Our numerous experiments on the destruction kinetics of the alkoxyamines in the presence of Our numerous experiments on the destruction kinetics of the alkoxyamines in the presence of BME showed several contradicting but systematically reproducible features which were not observed BME showed several contradicting but systematically reproducible features which were not observed either with PhSH or with TEMPO (Table 1). either with PhSH or with TEMPO• (TableThe rate1). constants for the reaction of 2RS/SR and 2RR/SS with PhSH are slightly higher than the rate constants for their epimerization. This is not surprising and can be explained by the The rate constants for the reaction of 2RS/SR and 2RR/SS with PhSH are slightly higher than the • influence of the different medium with a large excess of the spin trap. In contrast, the rate rate constants for their epimerization.constants This for is the not reaction surprising of 2RS/SR andand can especially be explained of 2RR/SS by thewith influence BME are substantially lower of the different medium with athan large the excess epimerization of the spin rate trap. constants. In contrast, the rate constants for the RS/SR RR/SS reaction of 2 and especially• In of contrast2 withto the BME behavior are substantially of 2RS/SR and lower 2RR/SSthan (see theitem epimerization above), the rate constant for the rate constants. reaction of 3 with BME is significantly higher than rate constant for its reaction with PhSH. • Quite unexpected is the much lower reactivity of 2RR/SS with BME in comparison with its diastereomer 2RS/SR. It can hardly be explained by steric differences in the substrates: the starting diastereomers have very similar energies, and the transition states should be close to the corresponding alkyl and nitroxide radicals, which are identical for both diastereomers. • The decay rates of the alkoxyamines monotonically increase with increasing BME concentration but do not reach a plateau even at a 100-fold excess of BME. These unexpected results clearly point out that the reactions of alkoxyamines with PhSH and BME have different mechanisms. It may even be possible that BME reacts with alkoxyamines without a preceding homolysis step. This supposition forced us to perform a thorough NMR study on the products formed in the decomposition of 2RS/SR, 3, and 1• in the presence of BME. The structures and the complete NMR signal assignments for all the main components of the reaction mixtures, including assignments for nuclei that differ from each other only in their spatial configuration, were unambiguously determined by 2D NMR (HSQC, HMBC, 1H-15N HMBC, COSY, NOESY, and DOSY); see SI. Decay of 2RS/SR and 2RR/SS with an excess of BME afforded products analogous to those of the reaction with PhSH. However, the reaction with BME proceeds much less selectively (SI p. S114– S138). The alkyl radical 7• formed by decomposition of the alkoxyamine tends to disproportionate, giving the expected ethyl-2-phenylacetate 7 along with oxidized forms 9 and 10 (7:9:10 = 1:0.7:0.9) (Chart 2). The nitroxide radical 1•, as in the case of PhSH, was mainly reduced to the corresponding amine 8 along with minor adducts with BME. Similar adducts of nitroxide radicals with thiols were reported earlier [48]. Surprisingly, a substantial additional product 1,3-dimethylimidazo [1,5- a]pyridine 11 was detected in the reaction mixture (8:adducts:11 = 1:0.6:0.5). The heterocyclic skeleton Molecules 2020, 25, 5080 11 of 20
In contrast to the behavior of 2RS/SR and 2RR/SS (see item above), the rate constant for the reaction • of 3 with BME is significantly higher than rate constant for its reaction with PhSH. Quite unexpected is the much lower reactivity of 2RR/SS with BME in comparison with its • diastereomer 2RS/SR. It can hardly be explained by steric differences in the substrates: the starting diastereomers have very similar energies, and the transition states should be close to the corresponding alkyl and nitroxide radicals, which are identical for both diastereomers. The decay rates of the alkoxyamines monotonically increase with increasing BME concentration • but do not reach a plateau even at a 100-fold excess of BME.
These unexpected results clearly point out that the reactions of alkoxyamines with PhSH and BME have different mechanisms. It may even be possible that BME reacts with alkoxyamines without a preceding homolysis step. This supposition forced us to perform a thorough NMR study on the products RS/SR formed in the decomposition of 2 , 3, and 1• in the presence of BME. The structures and the complete NMR signal assignments for all the main components of the reaction mixtures, including assignments for nuclei that differ from each other only in their spatial configuration, were unambiguously determined by 2D NMR (HSQC, HMBC, 1H-15N HMBC, COSY, NOESY, and DOSY); see SI. Decay of 2RS/SR and 2RR/SS with an excess of BME afforded products analogous to those of the reaction with PhSH. However, the reaction with BME proceeds much less selectively (SI p. S114–S138). The alkyl radical 7• formed by decomposition of the alkoxyamine tends to disproportionate, giving the expected ethyl-2-phenylacetate 7 along with oxidized forms 9 and 10 (7:9:10 = 1:0.7:0.9) (Chart2). The nitroxide radical 1•, as in the case of PhSH, was mainly reduced to the corresponding amine 8 along with minor adducts with BME. Similar adducts of nitroxide radicals with thiols were reported earlier [48]. Surprisingly, a substantial additional product 1,3-dimethylimidazo [1,5-a]pyridine 11 was Molecules 2020, 25, x FOR PEER REVIEW 12 of 20 detected in the reaction mixture (8:adducts:11 = 1:0.6:0.5). The heterocyclic skeleton of 11 is completely different from that of the original alkoxyamine (Chart2), and even traces of this heterocycle were not of 11 is completely different from that of the original alkoxyamine (Chart 2), and even traces of this observed after the homolysis of 2 with PhSH. heterocycle were not observed after the homolysis of 2 with PhSH.
Chart 2. StructuresChart of2. 7, 8, 9, 10, 11.
For the the case case of of decay decay of ofalkoxyamine alkoxyamine 3 in3 thein presence the presence of BME, of BME, tert-butylisobutyrate tert-butylisobutyrate 4 and amine4 and amine8 were8 alsowere detected also detected in the in thereaction reaction mixture, mixture, as asexpected. expected. However, However, the the main main products products of alkoxyamine decaydecay were were now now the the same same heterocycle heterocycle11, which11, which was was already already observed observed in the in case the of case2RS/ SRof and2RS/SR2 RRand/SS ,2 andRR/SS, tert-butyl-2-methyl-2-(pentan-3-ylideneaminooxy)propanoateand tert-butyl-2-methyl-2-(pentan-3-ylideneaminooxy)propanoate12 (11 12,12 (:114,8,12=:1:0.6)4,8 = (Chart1:0.6) (Chart3, SI p.3, S139–S157SI p. S139-S157).). It is It important is important to noteto note that that the the structure structure of of product product12 12 precludesprecludes every mechanism proceedingproceeding through through homolysis homolysis of of the the substrate substrate to alkyl to alkyl and and nitroxide nitroxide radicals. radicals. Oxime Oxime ether 12ethercan 12 be can formed be formed only throughonly through rearrangement rearrangement of the of originalthe original alkoxyamine alkoxyamine3. A 3. minor A minor amount amount of diethylketoneof diethylketone13 13was was additionally additionally observed, observed, which which originated originated apparently apparently from from oxime oxime ether ether12. 12.
Chart 3.
A small amount of compound 11 and diethylketone 13 (10%) were detected even in the reaction of nitroxide 1• with BME, along with the expected major reduction products (SI p. S158–S179, S198). An analogous product mixture was also observed after the thermolysis of alkoxyamines at 150 °C in DMSO or o-dichlorobenzene in the absence of scavengers (SI, p. S199). Apparently, the essential side reaction of either alkoxyamine 2 or 3, or nitroxide 1• with BME breaks the imidazoline ring followed by cyclization with the nitrogen of the pyridine residue. The mechanism of this unexpected rearrangement will be the subject of a more detailed study in the future. However, it is clear that this side reaction complicates the reaction mixtures and significantly shifts the numeric results of kinetics measurements. Instead of the expected alkoxyamine homolysis kinetics, the data reflect some aggregate of parallel homolysis and heterocyclic rearrangement under the influence of BME. Hence, the choice of scavenger is crucial for a reliable and accurate estimate of the true homolysis rate constant. Thus, the upward deviation in EPR kinetics obtained with a less efficient scavenger is ascribed to the time needed to reach a pseudo-equilibrium in the reaction. Then, after this pseudo-equilibrium is reached, a mono exponential decay is observed. When the experiment is performed in the presence of a really efficient radical scavenger, free of side processes, such as PhSH (vide infra), a mono-
Molecules 2020, 25, x FOR PEER REVIEW 12 of 20
of 11 is completely different from that of the original alkoxyamine (Chart 2), and even traces of this heterocycle were not observed after the homolysis of 2 with PhSH.
Chart 2.
For the case of decay of alkoxyamine 3 in the presence of BME, tert-butylisobutyrate 4 and amine 8 were also detected in the reaction mixture, as expected. However, the main products of alkoxyamine decay were now the same heterocycle 11, which was already observed in the case of 2RS/SR and 2RR/SS, and tert-butyl-2-methyl-2-(pentan-3-ylideneaminooxy)propanoate 12 (11,12:4,8 = 1:0.6) (Chart 3, SI p. S139-S157). It is important to note that the structure of product 12 precludes every mechanism proceeding through homolysis of the substrate to alkyl and nitroxide radicals. Oxime Moleculesether 122020 can, 25 be, 5080 formed only through rearrangement of the original alkoxyamine 3. A minor amount12 of 20 of diethylketone 13 was additionally observed, which originated apparently from oxime ether 12.
Chart 3. StructuresChart of 3.4 , 8, 11, 12, 13.
AA smallsmall amountamount ofof compoundcompound 1111 andand diethylketonediethylketone 1313 (10%)(10%) werewere detecteddetected eveneven inin thethe reactionreaction • ofof nitroxidenitroxide 11• withwith BME,BME, alongalong withwith thethe expectedexpected majormajor reductionreduction productsproducts (SI(SI p.p. S158–S179, S198). AnAn analogousanalogous productproduct mixturemixture waswas alsoalso observedobserved afterafter thethe thermolysisthermolysis ofof alkoxyaminesalkoxyamines atat 150150 ◦°CC inin DMSODMSO oror o-dichlorobenzeneo-dichlorobenzene inin thethe absenceabsence ofof scavengersscavengers (SI,(SI, p.p. S199).S199). • Apparently,Apparently, the the essential essential side side reaction reaction of eitherof either alkoxyamine alkoxyamine2 or 32, oror nitroxide3, or nitroxide1• with 1 BME with breaks BME thebreaks imidazoline the imidazoline ring followed ring followed by cyclization by cyclization with the nitrogen with the of nitrogen the pyridine of the residue. pyridine The residue. mechanism The ofmechanism this unexpected of this rearrangement unexpected rearrangement will be the subject will ofbe a the more subject detailed of a study more in detailed the future. study However, in the itfuture. is clear However, that this sideit is clear reaction that complicates this side reaction the reaction complicates mixtures the andreaction significantly mixtures shifts and significantly the numeric resultsshifts the of kineticsnumeric measurements. results of kinetics Instead measuremen of the expectedts. Instead alkoxyamine of the expected homolysis alkoxyamine kinetics, homolysis the data reflectkinetics, some the data aggregate reflect ofsome parallel aggregate homolysis of para andllel heterocyclichomolysis and rearrangement heterocyclic rearrangement under the influence under ofthe BME. influence of BME. Hence,Hence, thethe choicechoice ofof scavengerscavenger isis crucialcrucial forfor aa reliablereliable andand accurate estimateestimate ofof thethe true homolysis raterate constant.constant. Thus,Thus, thethe upwardupward deviation deviation in in EPR EPR kinetics kinetics obtained obtained with with a lessa less effi efficientcient scavenger scavenger is ascribedis ascribed to theto the time time needed needed to reachto reach a pseudo-equilibrium a pseudo-equilibrium in thein the reaction. reaction. Then, Then, after after this this pseudo-equilibrium pseudo-equilibrium is reached,is reached, a mono a mono exponential exponential decay decay is observed. is observed. When When the the experiment experiment is performed is performed in the in presencethe presence of a reallyof a really efficient efficient radical radical scavenger, scavenger, free of sidefree processes,of side processes, such as PhSH such (videas PhSH infra), (vide a mono-exponential infra), a mono- decay in 1H NMR and a mono-exponential nitroxide growth in EPR provide the same rate constant as expected.
3. Experimental Routine 1H and 13C-NMR spectra were recorded on Bruker AV-300, AV-400, and DRX-500 instruments. The structures, including spatial structure, and the complete NMR signal assignments of alkoxyamines and their decomposition products were determined by 2D NMR (COSY, HSQC, HMBC, 1H-15N HMBC, NOESY, ROESY, and DOSY) on a Bruker Avance-III 600 instrument at 600.30 MHz, 150.96 MHz and 60.85 MHz for 1H, 13C and 15N, respectively. Chemical shifts were measured for 1H 13 and C relative to the residual signals of solvents (CDCl3: δH 7.24 ppm, δC 76.9 ppm; toluene-d8: 15 δH 2.13 ppm, δC 20.1 ppm; DMSO: δH 2.51 ppm), and for N relative to an external NH3 standard (δN = 0 ppm). IR spectra were acquired on an FTIR spectrometer in KBr or neat and are reported in wavenumbers 1 (cm− ). Reactions were monitored by TLC using UV light (254 nm) and/or aqueous permanganate for visualization. Column chromatography was performed on silica gel 60, (70–230 Mesh).
Synthesis (Scheme 7) 5,5-Diethyl-2,4-dimethyl-2-(pyridin-2-yl)-2,5-dihydro-1H-imidazol 1-oxyl (1 ). Synthesis was in analogy • to the literature procedures [49]. To a stirred solution of 3-hydroxylamino-3-ethylpentan-2-one hydrochloride (14; 2.50 g, 13.8 mmol) in MeOH (20 mL), ammonia acetate (3.18 g, 41.3 mmol) and 2-acetylpyridine (1.87 g, 15.1 mmol) were added. The reaction mixture was stirred at +60 ◦C for 4 h; then, it was cooled to room temperature and allowed to stand overnight. Then, the mixture was diluted with 20 mL of H O and kept at 10 C overnight. A crystalline precipitate of 5,5-diethyl-2,4-dimethyl- 2 − ◦ 2-(pyridin-2-yl)-2,5-dihydro-1H-imidazol 1-ol (15) was filtered off and washed with cold H2O. To a stirred Molecules 2020, 25, 5080 13 of 20
suspension of 15 in CHCl3 (25 mL), MnO2 (7 g, 80.5 mmol) was added portion-wise. After the reaction was complete (monitored by TLC analysis; CHCl3 + CH3OH 20:1), the manganese oxides were filtered off, and the solvent was removed in vacuum to yield radical 1 as a yellow crystals. •
5,5-diethyl-2,4-dimethyl-2-(pyridin-2-yl)-2,5-dihydro-1H-imidazol 1-ol (15): Yield 60%, colorless crystals, 1 m.p. 187 ◦C (decomp.). H-NMR (400 MHz, CDCl3 + CD3OD): δ = 0.61 (t, 3H, J = 7.32 Hz, CH3), 1.01 (t, 3H, J = 7.44 Hz, CH3), 1.50 (m, 1H, CH2), 1.59 (m, 1H, CH2), 1.71 (m, 1H, CH2), 1.73 (s, 3H, CH3), 1.99 (m, 1H, CH2), 2.02 (s, 3H, CH3), 4.35 (s, 1H, OH), 7.23 (m, 1H, Py), 7.60 (m, 1H, Py), 7.73 (m, 1H, Py), 13 8.51 (m, 1H, Py). C-NMR (100 MHz, CDCl3 + CD3OD): δ = 8.85 (CH3CH2), 10.74 (CH3CH2), 26.64 (CH3CH2), 30.26 (CH3CH2), 80.86 (CEt2), 95.11 (NCN), 121.43, 122.88 (CH, 3-Py and 5-Py), Molecules137.66 2020 (CH,, 25, 4-Py),x FOR PEER 148.54 REVIEW (C H, 6-Py), 165.50 (CH, 2-Py), 177.85 (C=N). UV (EtOH):13 of 20 λmax (log ε) = 260 (3.99). IR (neat): 756, 795, 991, 1043, 1095, 1352, 1385, 1431, 1462, 1568, 1 exponential1581, 1651, 2877, decay 2904, in 1H 2966, NMR 2995, and 3047, a mono-exponential 3144 cm− . Anal. nitroxide calcd. for growth C14H21 inN 3EPRO: C, provide 67.98; H, the 8.56; same N, rate16.99; constant found: as C, expected. 68.26; H, 8.45; N, 16.93.
3.5,5-Diethyl-2,4-dimethyl-2-(pyridin-2-yl)-2,5-dihydro-1H-imidazol Experimental 1-oxyl (1 ): Yield 90%, yellow crystals, • m.p. 51–52 C (hexane). UV (EtOH): λmax (log ε) = 260 (3.57). IR (neat): 754, 787, 876, 924, 997, Routine◦ 1H and 13C-NMR spectra were recorded on Bruker AV-300, AV-400, and DRX-500 instruments.1049, 1095, 1146, The structures, 1178, 1257, including 1300, 1358, spatial 1387, structure, 1433, 1462, and 1572, the complete 1587, 1641, NMR 2879, signal 2937, assignments 2964, 2978, 1 of3059 alkoxyamines cm− . Anal. and calcd. their for decomposition C14H20N3O: C, products 68.26; H, 8.18;were N,determined 17.06; found: by C,2D 68.46;NMR H, (COSY, 8.23; N, HSQC, 17.25. 1H-NMR spectrum (600 MHz): SI, p S24. EPR spectrum: SI, p S217; hyperfine coupling 1.351 mT, HMBC, 1H-15N HMBC, NOESY, ROESY, and DOSY) on a Bruker Avance-III 600 instrument at 600.30 g = 2.00608. MHz, 150.96 MHz and 60.85 MHz for 1H, 13C and 15N, respectively. Chemical shifts were measured for 1H and 13C relative to the residual signals of solvents (CDCl3: δH 7.24 ppm, δC 76.9 ppm; toluene- Synthesis of alkoxyamines 2 and 3 (General procedure). The alkoxyamines were prepared using the d8: δH 2.13 ppm, δC 20.1 ppm; DMSO: δH 2.51 ppm), and for 15N relative to an external NH3 standard method developed by Matyjaszewski et al. [50] (Scheme7). A mixture of the nitroxide 1 (2.2 mmol), (δN = 0 ppm). • tert 2-bromo-2-methylpropionicIR spectra were acquired acid on -butylan FTIR ester spectr (2.25ometer mmol) in or 2-bromo-2-phenylacetaticKBr or neat and are reported acid ethyl in ester (2.25 mmol), Cu powder (140 mg, 2.25 mmol), 4,4’-di-tert-butyl-2,2’-bipyridine (24 mg, 0.09 mmol), wavenumbers (cm−1). Reactions were monitored by TLC using UV light (254 nm) and/or aqueous permanganateCu(OTf)2 (8 mg, for 0.023 visualization. mmol), and Column benzene chromatography (5 mL) was placed was intoperformed a Schlenk on flasksilica and gel degassed60, (70 - 230 by Mesh).three freeze–pump–thaw cycles. The solution was stirred for 24 h at 50 ◦C. Benzene was removed in vacuum, and the residue was separated by column chromatography (silica gel, hexane-diethyl ether Synthesis1:6 for 2 and (Scheme hexane–ethyl 7) acetate 2:1 for 3).
Scheme 7. SynthesisSynthesis of of alkoxyamines 2 and 3..
(R,R)-Ethyl-2-(5,5-diethyl-2,4-dimethyl-2-(pyridin-2-yl)-2,5-dihydro-1H-imidazol-1-yloxy)-2-phenylacetate5,5-Diethyl-2,4-dimethyl-2-(pyridin-2-yl)-2,5-dihydro-1H-imidazol 1-oxyl (1•). Synthesis was in analogy RR/SS 1 δ to(2 the ):literature Yield 30%, procedures colorless [49]. oil. ToH-NMR a stirred (400 solution MHz, CDCl of 3-hydroxylam3): = 0.37 (t,ino-3-ethylpentan-2-one 3H, J = 7.3 Hz, CH3), hydrochloride1.04 (t, 3H, J = (147.3; 2.50 Hz g, CH 13.83), mmol) 1.12 (t, in 3H, MeOHJ = 7.3(20 Hz,mL), CH ammonia3), 1.48 acetate (ABq, 1H,(3.18J g,= 41.37.3, mmol) 14 Hz, and CH 22-), acetylpyridine1.67 (ABq, 1H, J (1.87= 7.3, g, 14 15.1 Hz, CHmmol)2), 1.73 were (s, 3H,added. CH3 The), 1.81 reaction (ABq, 1H, mixtureJ = 7.3, was 14 Hz, stirred CH2 ),at 1.98 +60 (s, °C 3H, for CH 4 h;3), then, it was cooled to room temperature and allowed to stand overnight. Then, the mixture was diluted with 20 mL of H2O and kept at –10 °C overnight. A crystalline precipitate of 5,5-diethyl-2,4- dimethyl-2-(pyridin-2-yl)-2,5-dihydro-1H-imidazol 1-ol (15) was filtered off and washed with cold H2O. To a stirred suspension of 15 in CHCl3 (25 mL), MnO2 (7 g, 80.5 mmol) was added portion-wise. After the reaction was complete (monitored by TLC analysis; CHCl3 + CH3OH 20:1), the manganese oxides were filtered off, and the solvent was removed in vacuum to yield radical 1• as a yellow crystals.
5,5-diethyl-2,4-dimethyl-2-(pyridin-2-yl)-2,5-dihydro-1H-imidazol 1-ol (15): Yield 60%, colorless crystals, m.p. 187 °C (decomp.). 1H-NMR (400 MHz, CDCl3 + CD3OD): δ = 0.61 (t, 3H, J = 7.32 Hz, CH3), 1.01 (t, 3H, J = 7.44 Hz, CH3), 1.50 (m, 1H, CH2), 1.59 (m, 1H, CH2), 1.71 (m, 1H, CH2), 1.73 (s, 3H, CH3), 1.99 (m, 1H, CH2), 2.02 (s, 3H, CH3), 4.35 (s, 1H, OH), 7.23 (m, 1H, Py), 7.60 (m, 1H, Py), 7.73 (m, 1H, Py), 8.51 (m, 1H, Py). 13C-NMR (100 MHz, CDCl3 + CD3OD): δ = 8.85 (CH3CH2), 10.74 (CH3CH2), 26.64
Molecules 2020, 25, 5080 14 of 20
2.47 (ABq, 1H, J = 7.3, 14 Hz, CH2), 3.97 (ABq, 1H, J = 7.0, 17.9 Hz, CH2-O), 4.10 (ABq, 1H, J = 7.0, 17.9 Hz, CH2-O), 6.04 (s, 1H, CH-Ph), 7.11–7.15 (m, 1H, Py), 7.30–7.37 (m, 3H, Ph), 7.38–7.41 (m, 1H, Py), 7.49–7.54 (m, 2H, Ph), 7.55–7.59 (m, 1H, Py), 8.64–8.68 (m, 1H, Py). 13C NMR (CDCl3, 125 MHz): δ = 8.75, 10.79 (2*CH3, Et), 13.88 (CH3, EtO), 16.63 (CH3-CNN), 23.59 (CH3-C=N), 27.17, 29.71 (2*CH2, Et), 60.29 (CH2, EtO), 82.01 (CEt2), 83.32 (CH-O-N), 96.87 (Py-C-CH3), 119.91, 121.55, 127.45, 128.19, 128.29 (Ar), 135.47 (CH, 4-Py), 135.60 (iPh), 148.58 (CH, 2-Py), 164.82 (iPy), 172.51 (C=O), 174.25 (C=N). UV (EtOH): λmax (log ε) = 256 (4.28). IR(neat): 623, 696, 750, 789, 1063, 1095, 1180, 1205, 1273, 1375, 1431, 1454, 1468, 1587, 1664, 1747, 2875, 2935, 2962. Anal. calcd. for C24H31N3O3: C, 70.39; H, 7.63; N, 10.26; found: C, 70.49; H, 7.58; N, 10.18. NMR assignments (600 MHz): SI, p S3–S8.
(R,S)-Ethyl-2-(5,5-diethyl-2,4-dimethyl-2-(pyridin-2-yl)-2,5-dihydro-1H-imidazol-1-yloxy)-2-phenylacetate RS/SR 1 (2 ): Yield 45%, colorless crystals, m.p. 81–83 ◦C (hexane). H-NMR (400 MHz, CDCl3): δ = 0.38 (t, 3H, J = 7 Hz, CH3), 1.02 (t, 3H, J = 7 Hz CH3), 1.19 (t, 3H, J = 7 Hz, CH3), 1.25–1.33 (m, 2H, CH2), 1.53 (ABq, 1H, J = 7, 14 Hz, CH2), 1.82 (ABq, 1H, J = 7, 14 Hz, CH2), 1.95 (s, 3H, CH3), 2.00 (s, 3H, CH3), 4.04 (ABq, 1H, J = 7, 17.9 Hz, CH2-O), 4.13 (ABq, 1H, J = 7, 17.9 Hz, CH2-O), 5.74 (s, 1H, CH-Ph), 7.18-7.22 (m, 1H, Py), 7.30–7.35 (m, 3H, Ph), 7.36–7.41 (m, 2H, Ph), 7.48–7.53 (m, 1H, Py), 7.61–7.67 (m, 13 1H, Py), 8.69–8.73 (m, 1H, Py). C-NMR (100 MHz, CDCl3): δ = 8.68, 10.50 (2*CH3, Et), 13.80 (CH3, EtO), 16.74 (CH3-CNN), 23.30 (CH3-C=N), 27.42, 29.86 (2*CH2, Et), 60.59 (CH2, EtO), 81.20 (CEt2), 84.81 (CH-O-N), 96.34 (Py-C-CH3), 119.84, 121.62, 128.01, 128.07, 128.29 (Ar), 135.62 (CH, 4-Py), 137.37 i i ( Ph), 148.53 (CH, 2-Py), 164.99 ( Py), 170.81 (C=O), 173.47 (C=N). UV (EtOH): λmax (log ε) = 255 (4.27). IR (neat): 623, 696, 752, 791, 1066, 1086, 1176, 1201, 1331, 1371, 1433, 1468, 1585, 1659, 1741, 2874, 2933, 1 2978 cm− . Anal. calcd. for C24H31N3O3: C, 70.39; H, 7.63; N, 10.26; found: C,70.55; H, 7.84; N, 10.29. NMR assignments (600 MHz): SI, p. S9–S23.
(tert-Butyl-2-((5,5-diethyl-2,4-dimethyl-2-(pyridin-2-yl)-2,5-dihydro-1H-imidazol-1-yl)oxy)-2-methylpropanoate) 1 Et (3). Yield 84%. Colorless oil. H NMR (500 MHz, CDCl3): δ = 0.71 (t, 3H, J = 7.3 Hz, CH3), Et 0.98 (t, 3H, J = 7.3 Hz CH3), 0.99 (s, 3H, CH3), 1.23 (s, 3H, CH3), 1.32 (s, 9H, 3*CH3), 1.60 (ABq, 1H, J = 7.3, 14 Hz, CH2), 1.66-1.77 (m, 2H, CH2), 1.86 (s, 3H, CH3), 1.93 (s, 3H, CH3), 2.00 (ABq, 1H, J = 7.3, 14 Hz, CH2), 7.04–7.08 (m, 1H, Py), 7.40–7.43 (m, 1H, Py), 7.49–7.54 (m, 2H, Ph), 13 7.52–7.57 (m, 1H, Py), 8.49–8.52 (m, 1H, Py). C-NMR (CDCl3, 125 MHz): δ = 9.05, 10.80 (2*CH3, Et), 17.26 (CH3-CNN), 21.73, 24.15, 24.70 (3*CH3), 27.35, 28.97 (2*CH2, Et), 27.67 (3*CH3, tBu), 80.53, 81.12, t 81.85 (CMe2, CEt2,C Bu), 95.70 (Py-C-CH3), 121.33, 121.66 (2*CH, Py), 135.45 (CH, 4-Py), 147.74 (CH, 2-Py), 163.94 (iPy), 173.36, 173.53 (C=O, C=N). NMR assignments (600 MHz): SI, p S25–S38.
UV (EtOH): λmax (log ε) = 256 (3.51).
IR(neat): 750, 788, 848, 1099, 1138, 1160, 1254, 1292, 1367, 1431, 1468, 1572, 1587, 1662, 1728, 2877, 2933, 2978.
Anal. calcd. for C22H35N3O3: C, 67.83; H, 9.06; N, 10.79; found: C, 67.69; H, 8.89; N, 10.51.
XRD analysis of alkoxyamine 2RS/SR. XRD data were obtained at room teperature on a Bruker Kappa Apex II CCD diffractometer using ϕ, ω scans of narrow (0.5◦) frames with Mo Kα radiation (λ = 0.71073 Å), and a graphite monochromator. Absorption corrections were applied empirically using SADABS programs [51]. The structures were solved by direct methods and refined by full-matrix least-squares method against all F2 in anisotropic approximation (beside the atoms H) using the SHELX-97 programs set [52]. The H atoms positions were calculated with the riding model (Figure 10).
RS/SR Crystallographic data for 2 : T 296(2) K,C24H31N3O3, FW = 409.52, monoclinic, P21/c, a = 9.9606(4), ´ 3 3 b = 20.3503(8), c = 11.7648(5)Å, β = 108.819(2)◦, V = 2257.3(2)Å , Z = 4, Dcalc = 1.205 g cm− , Molecules 2020, 25, x FOR PEER REVIEW 15 of 20
7.3, 14 Hz, CH2), 7.04–7.08 (m, 1H, Py), 7.40–7.43 (m, 1H, Py), 7.49–7.54 (m, 2H, Ph), 7.52–7.57 (m, 1H, Py), 8.49–8.52 (m, 1H, Py). 13C-NMR (CDCl3, 125 MHz): δ = 9.05, 10.80 (2*CH3, Et), 17.26 (CH3-CNN), 21.73, 24.15, 24.70 (3*CH3), 27.35, 28.97 (2*CH2, Et), 27.67 (3*CH3, tBu), 80.53, 81.12, 81.85 (CMe2, CEt2, CtBu), 95.70 (Py-C-CH3), 121.33, 121.66 (2*CH, Py), 135.45 (CH, 4-Py), 147.74 (CH, 2-Py), 163.94 (iPy), 173.36, 173.53 (C=O, C=N). NMR assignments (600 MHz): SI, p S25–S38.
UV (EtOH): λmax (log ε) = 256 (3.51).
IR(neat): 750, 788, 848, 1099, 1138, 1160, 1254, 1292, 1367, 1431, 1468, 1572, 1587, 1662, 1728, 2877, 2933, 2978.
Anal. calcd. for C22H35N3O3: C, 67.83; H, 9.06; N, 10.79; found: C, 67.69; H, 8.89; N, 10.51.
Molecules 2020, 25, 5080 15 of 20 XRD analysis of alkoxyamine 2RS/SR. XRD data were obtained at room teperature on a Bruker Kappa Apex II CCD diffractometer using φ, ω scans of narrow (0.5°) frames with Mo Kα radiation (λ = 1 µ0.71073(Mo-K αÅ),) = and0.080 a graphite mm− , F monochromator.(000) = 880, 72,240 Absorp measuredtion corrections reflections were (θmax applied= 27.19 empirically◦, completeness using 99.4%),SADABS 5005 programs independent [51].The (R intstructures= 0.0388), were 285 solved parameters, by directR1 = methods0.0616(for and 3991 refined observed by full-matrixI > 2σ(I)), wRleast-squares= 0.2000 (allmethod data) ,againstGooF = all1.03, F2 largestin anisotropic diff. peak approximation and hole 0.61 and(beside0.47 the e.A atoms3. The H) C7-methyl using the 2 − − groupSHELX-97 is disordered programs by set two [52]. positions The H atoms C7a and positions C7b with were 0.55:0.45(3) calculated occupation with the ratio.riding model (Figure 10). CCDC 1,829,288 contain the supplementary crystallographic data for this paper. These data can beCrystallographic obtained free ofdata charge for 2 viaRS/SR http:: T 296(2)//www.ccdc.cam.ac.uk K, C24H31N3O3, FW/cgi-bin = 409.52,/catreq.cgi monoclinic,, or from P21/c, the a Cambridge= 9.9606(4), Crystallographicb = 20.3503(8), c = Data11.7648(5) Centre,Ǻ, β 12 = 108.819(2)°, Union Road, V Cambridge= 2257.3(2)Å CB23, Z = 1EZ, 4, Dcalc UK; = 1.205 fax: (g+ 44)cm− 12233, μ(Mo- 336K 033;α) = or0.080 e-mail: mm [email protected].−1, F(000) = 880, 72,240 measured reflections (θmax = 27.19°, completeness 99.4%), 5005 independentMolecules (R2intRS =/ SR0.0388),adopt 285 conformations parameters,that R1 = are 0.0616(for stabilized 3991 by observed two weak I intramolecular> 2σ(I)), wR2 = 0.2000 hydrogen (all −3 bonds:data), GooF one = between 1.03, largest the diff. nitrogen peak ofand the hole pyridine 0.61 and moiety −0.47 e.A and. the The methynic C7-methyl proton group ( disH disorderedN = 2.59, ···· dbyC twoN = positions3.172(3) ÅandC7a and
RS/SR FigureFigure 10.10. XRDXRD structurestructure ofof 22RS/SR. .(Displacement (Displacement ellipsoids ellipsoids are are draw drawnn at at the the 30% 30% probability probability level.). level).
EPRMolecules experiments. 2RS/SR adoptAll the conformations EPR experiments that are were stabilized performed by two on theweak Bruker intramolecular Elexys E540 hydrogen X-band spectrometer,bonds: one between using toluenethe nitrogen (0.2 mL) of the as py solvent.ridine Themoiety concentration and the methynic of species proton in all (d theH····N experiments = 2.59, dC····N was 2 10 4 M. These solutions have been prepared by the dilution method, from the stock solution of × − 10 2 M (1 mL of toluene, 4 mg of alkoxyamine or 2.5 mg of radical 1 ). EPR of radical 1 : g-factor − • • of radical 1 was calculated from the reference spectrum of TEMPO, g(TEMPO) = 2.00623 [57]. • The EPR spectrum of 1 was recording at the following parameters: microwave power 2 mW, • resolution—1024 points, number of scans 24, conversion time 20.74 ms, modulation amplitude 0.5 G, time constant 20.48 ms. Kinetics of alkoxyamine homolysis by EPR: to perform the experiments, the oxygen that is in the solvent was used as an alkyl radical trap. The kinetic data were collected as a growing second intergral EPR signal of forming nitroxyl radical. The EPR spectra of all the alkoxyamines were recorded at the following parameters: microwave power 2 mW, resolution—1024 points, conversion time 19.55 ms, modulation amplitude 1 G, time constant 20.48 ms. Homolysis of alkoxyamines in the absence of scavengers (Epimerization). The epimerization reaction was investigated by NMR. The experiments were performed as follows: 0.01 mmol ( 5 mg) of alkoxyamine ≈ Molecules 2020, 25, 5080 16 of 20
2 was solved in 0.58 mL of toluene-d8 in NMR tube. The solution was blown with Ar, the tube was sealed with a PTFE cap, and a heat-shrinkable tube. The process of epimerization was carried out at 345 K directly in the probe head of the NMR spectrometer. Homolysis of alkoxyamines in the presence of scavengers. Experiments were performed by the above procedure with 0.50 mL toluene-d8 and 1 mmol of scavenger (0.080 mL BME or 0.115 mL PhSH) as the reaction medium. The experimental kinetic data were evaluated by numerical integration of the differential equations followed by a nonlinear least square fitting of the involved rate constants. The complete processing algorithm was implemented in the form of SciLab[58] script [59] (SI p. S200–S204). Quantum chemical calculations. These were performed using a fast DFT code implemented in the PRIRODA program [60] and employing a PBE functional [61] with full-electron basis Λ01 [62] (similar to the cc-pVDZ basis) as a gas-phase model. The transition states were connected with corresponding minima using the intrinsic reaction coordinate (IRC) procedure. Conformational analysis was performed with the computer program scan from Tinker package (MMFF94 force field) [63] and with the CREST program (GFN2-xTB method) [64]. Then, the geometries of all the conformers were optimized on the DFT/PBE/Λ01 level.
4. Conclusions We synthesized three alkoxyamines based on the imidazoline radical with a pyridine functional group capable of complexation with metals. EPR and NMR were used to investigate the thermolysis of chiral alkoxyamines 2RR/SS, 2RS/RS, and the results were compared with those for non-diastereomeric alkoxyamine 3. For NMR experiments, we used three different scavengers, namely β-mercaptoethanol, thiophenol, and TEMPO, to show the importance of choosing an appropriate radical trap. For EPR measurements, we used oxygen as a radical scavenger possessing different rate constants with alkyl radicals formed during the decay of alkoxyamines. That revealed that oxygen can produce incorrect results due to its low recombination rate constant with alkyl radicals. The biexponential growth of nitroxide can be obtained if additional processes such as isomerization occur with comparable rates. It is shown that only a careful analysis by NMR provides valid conclusions about the processes that take place. Careful analysis of the thermolysis products of the investigated alkoxyamines differentiated between N-inversion, epimerization, and reactions with radical scavengers. Kinetic measurements at different temperatures determined the activation energy of N-inversion and the rate constants for homolysis. Additional side reactions of alkoxyamines with BME were detected and identified. The alkoxyamine chirality affected our experiments with more than a two-fold difference in the homolysis rates for the two diastereomers (Table1). The influence of alkoxyamine chirality on polymerization needs further study.
Supplementary Materials: The following are available online. NMR and EPR study of Diastereomeric Alkoxyamine’s Homolysis. Author Contributions: Conceptualization, E.B., S.R.A.M., I.K.; methodology, G.S., A.G., M.E.; software, D.P., A.G.; formal analysis, S.C., G.S., A.G., investigation, D.M., I.K. S.C., T.R., G.S., A.G.; writing- S.C., G.S., A.G., writing—review and editing, E.B.; supervision, E.B. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the Ministry of Education and Science of the Russian Federation (state contract no. №14.W03.31.0034) and RFBR (grant No 20-33-90133). Acknowledgments: The authors thank the Multi-Access Chemical Research Center of the Siberian Branch of the Russian Academy of Sciences, for spectral and analytical measurements. Support from the Supercomputer Center of the Novosibirsk State University is also appreciated. The authors are thankful to Professor Michael Bowman for fruitful discussion. Conflicts of Interest: The authors declare no conflict of interest. Molecules 2020, 25, 5080 17 of 20
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Sample Availability: Samples of the compounds alkoxyamines 2RS/SR, 2RR/SS and 3 are available from the authors.
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