Review pubs.acs.org/CR
Scavenging of Organic C‑Centered Radicals by Nitroxides Elena G. Bagryanskaya*,†,‡,⊥ and Sylvain R. A. Marque*,§ †
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Pr. Lavrentjeva 9, Novosibirsk 630090, Russia ‡ International Tomography Center, Siberian Branch of the Russian Academy of Sciences, Institutskaya 3A, Novosibirsk 630090, Russia ⊥ Novosibirsk State University, Pirogova 2, Novosibirsk 630090, Russia § Aix-Marseille Université, CNRS, ICR UMR 7273, case 551, Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France S Supporting Information *
3.1. General Comments on the Re-Evaluated Effects of the C-Centered Radical Structure on kc 3.2. Correlations of BDE(C−H) vs log kc 3.3. Multiparameter Approach 3.3.1. Stabilization Effect 3.3.2. Steric Effect 3.3.3. Polar Effect 3.4. Summary 4. Nitroxides 4.1. General Comments 4.2. Steric Effect 4.3. Polar Effect 4.4. Summary 5. Miscelleaneous 5.1. Solvent Effects 5.1.1. Cohesive Pressure c 5.1.2. Solvent Polarity 5.1.3. Solvent Viscosity 5.1.4. Multiparameter Approach to the Solvent effects 5.2. Acid Effect 5.3. Chain Length Effect 5.4. Configuration Effect 5.5. Side Reactions 5.5.1. Intramolecular Proton Transfer 5.5.2. Intermolecular Hydrogen Atom Transfer 6. Calculations and Pathway for the Cross-Coupling Reaction and the HAT Side Reaction 6.1. Computed Approaches of Correlations 6.2. Pathway Calculations 6.3. Proposal for Transition States 7. Perspectives and Conclusion Associated Content Supporting Information Author Information Corresponding Authors Notes Biographies
CONTENTS 1. Introduction 2. General Scope 2.1. Application of Nitroxides/Alkoxyamines in the Design of Organic Radical Reactions 2.2. Application of Nitroxides/Alkoxyamines in Mechanistic Investigations in Chemistry and Biology 2.3. Application of Nitroxides/Alkoxyamines in Polymer Chemistry 2.4. Electronic Structures and Conformations of Nitroxides and C-Centered Radicals 2.4.1. Electronic Structures and Conformations of Nitroxides 2.4.2. Electronic Structures and Conformations of C-Centered radicals 2.5. Techniques of Measurement 2.5.1. Laser Flash Photolysis−Kinetic Absorption Spectroscopy 2.5.2. Radical Clock Method 2.5.3. C-Centered Radical Nitroxide Trapping (Competitive Method) 2.5.4. Time-Resolved Chemically Induced Dynamic Nuclear Polarization by 1H NMR and a Derived Method 2.5.5. Radical Nitroxide Recombination− Pulsed Lamp Photolysis−Size Exclusion Chromatography 2.5.6. Kinetics of Polymerization: The Persistent Radical Effect 2.6. kc Values 2.7. Arrhenius Parameters: Pre-Exponetial Factor Ac and Activation Energy Ea 3. C-Centered Radicals
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Received: February 13, 2013 Published: February 26, 2014 © 2014 American Chemical Society
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radicals as the main reaction are out of the scopeexcept the side reactions mentioned in this reviewas well as the experiments performed in water under radiolysis conditions.15,16,31 This review is divided into five sections: (i) general scope, dealing with techniques and Arrhenius parameters, (ii) influence of the C-centered radical structure on kc, (iii) influence of the nitroxide structure on kc, (iv) miscelleaneous, i.e., solvent effects, chain length effects, diastereoselectivity, and side reactions, and finally (v) calculations and pathway for the recombination reaction. We stress that a few papers or data may have escaped our scrutiny of the literature and have not been cited in this review, regardless of their quality. Some other papers have not been reported because either the absolute rate constants were not available or the product formation was not determined with good reliability, and the readers are invited to check the data listed in refs 15 and 16. In sections 2 and 3, using multiparameter correlations, we show that the kc values are ruled by several effectssteric, polar, and stabilization effectsin both nitroxide and alkyl radicals which occur either in the radicals or at the transition state (TS). Indeed, the cross-coupling reaction (formation of the C−ON bond) between a nitroxide and an alkyl radical (Scheme 1) involves the overlapping of their singly occupied molecular orbitals (SOMOs). In general, the reactivity is controlled by the strength of this interaction, which, in turn, depends on the bulkiness (large steric hindrance, weakening the interaction), on the stabilization (low electron density on the coupling sites, weakening the interaction), and on the polarity (EWG modifying the stabilization, matching of electrophilic/nucleophilic character) of the radicals. Importantly, we stress that part of the data (sections 3.2 and 3.3, part of sections 4 and 5.1) collected have been re-evaluated and discussed in light of the most recent results. We expect that this review will provide physical and polymer chemists with a new perspective regarding their own experiments relying on cross-coupling reactions.
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1. INTRODUCTION For more than two decades, from the 1960s to the mid-1980s, fundamental research in radical chemistry aroused tremedeous interest in the physical, chemical, and biological fields.1−3 The fundamentals in the chemistry of organic free radicals (named radicals in the foregoing text) were set and allowed the expansion of radical chemistry.1−4 Over those years, it became clear that radicals did not react randomly and that it was possible to control their reactivity. Several concepts such as polar reversible catalysis,5 the persistent radical effect (PRE; vide infra),6 captodative radicals,7 nucleophilic/electrophilic radicals,8 and many reactions such as the Barton reaction,9 the Barton−McCombie deoxygenation reaction,10 radical hydrogenation,2 etc. were developed and are nowadays applied for total synthesis or for the preparation of new materials.2,3,11 It emerged that the whole radical reactivity relies on the competition between several reactions and, consequently, depends on their kinetics.1,3,5,11 Hence, the development of useful radical reactions requires the accurate determination of their respective rate constants. Thus, since midcentury, a tremendous effort has been devoted to the development of new techniques to measure the rate constants of radical reactions.1,12−14 Regularly, efforts are provided to prepare compendiums of rate constants, such as the Landolt− Borsnstein series,15,16 and to publish comprehensive reviews on radical reactivity, for example, those of Buback et al.,17 Ingold et al.,18 Fischer et al.,19 etc. As soon as they were discovered,20 nitroxides21 aroused keen interest in the scientific community, as this family of radicals is of easy access and many organic nitroxides can be handled with no special care.22,23 Promptly, the C-centered radical scavenging capacities of nitroxides were recognized (Scheme 1), and it was accepted
2. GENERAL SCOPE All structures discussed in this review are displayed in Figures 1 and 2. C-centered radicals are labeled from R1 to R61, and as for the ester or aryl fragment, for example, the alkyl group is varied and noted Xn. The heteroatom-centered radicals are labeled from H1 to H6. The nitroxides are gathered by families (see section 2.4.1).32 N1 and N2 belong to the family of noncyclic nitroxides carrying no H-atom at the β-position of the nitroxyl moiety. N3−N7, N8−N10, N11, and N12 belong to the families of noncyclic nitroxides carrying one H-atom and a phenyl ring, a phosphoryl group, or a sulfonyl group, respectively, at the β-position. N13−N52, N53−N87, N88− N90, and N91−N94 belong to the families of five-, six-, seven-, and eight-membered rings, respectively. N95 and N96 belong to the family of nitroxides33,34 for which the abstraction of the Hatom from the bridgehead of a bicyclic compound to afford a double bond leading to a nitrone is forbidden by Bredt’s rule.35 N97 belongs to the family of aryl nitroxides. In general, the reaction between a C-centered radical and a nitroxide affords an alkoxyamine (Scheme 1). In Figure 3, several nitroxides also known by their nicknames are shown, as well as an example of alkoxyamine N53R2, which is composed of nitroxide N53 (Figure 2) and C-centered radical R2 (Figure 1). The use of nitroxides as C-centered radical scavengers in mechanistic studies soon aroused interest for the determination of kc values.36−39 Before the first measurements of kc for the re-
Scheme 1. Cross-Coupling Reaction between a Nitroxide and a C-Centered Radical
that the scavenging rate constants kc were close to the diffusioncontrolled rate constants, i.e., 109−1010 M−1 s−1.15,16 However, it was only at the end of the 1980s that intensive and thorough studies of the various effects influencing kc in organic solvents were initiated.16,24,25 Although the cross-coupling reactions between nitroxides and C-centered radicals (Scheme 1) are involved in several fields (nitroxides are used as stabilizers for polymeric materials,26 spin probes in biophysics,27 mechanistic probes in organic chemistry,28 and especially controllers for nitroxide-mediated polymerization29,30), no comprehensive review on kc covering the past three decades is available in the literature. Therefore, gathering all the data from the literature as well as thoroughly analyzing the structural effects on kc of both nitroxides and C-centered radicals is due. This review is intended to be as exhaustive as possible and to be critical of the techniques as well as of the discussion of the data. However, data related to reactions which do not involve the cross-coupling reaction between nitroxides and C-centered 5012
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Figure 1. Structures of C-centered (R) and heteroatom-centered (H) radicals.
development of NMP led several groups to turn their interest toward the measurements of kc for growing polymer chains. In this section, we summarize the kc values published and critically overview the few techniques and approaches suitable to measure kc for molecular and polymeric species.37,39,51−53 The Arrhenius parametersthe frequency factor Ac and the activation energy Ea for the re-formation reactionare also discussed.
formation reactions in organic solvents which were performed in the mid-1980s,40−42 kc values were somewhat investigated using time-resolved (KESR)43 and steady-state (SESR)44−47 electron spin resonance and chemiluminescence48,49 techniques. Until recently, the measurements of kc were focused on the molecular species which are of primary importance for physical chemists to understand the various effects involved in the formation of alkoxyamines (Scheme 1),50,51 while the 5013
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Figure 2. continued
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Figure 2. Nitroxides discussed in this review.
2.1. Application of Nitroxides/Alkoxyamines in the Design of Organic Radical Reactions
the role of kc is not often highlighted, too high kc values would lead to very long experimental times or too high temperatures, favoring the occurrence of side reactions, and too low kc values would also favor side reactions. The importance of each rate constant was discussed in the seminal and general paper by Fischer on the PRE (see section 2.3).58
The importance of kc for the design of organic radical reactions is nicely highlighted both by the use of nitroxides for oxidations under mild conditions54−56 and by some cross-coupling reactions,57 such as displayed in Scheme 2a. Indeed, although 5015
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Figure 3. Abbreviations of several common nitroxides and one example of an alkoxyamine.
Scheme 2. (a) Application of the Cross-Coupling Reaction and (b) Radical Cyclization in Which the Cross-Coupling Reaction Plays a Key Role
Scheme 3. Importance of kc in Performing Efficient Radical Cyclizationa
a
Reprinted with permission from ref 68. Copyright 2012 Elsevier.
Scheme 4. Side Reactions (Right) Favored over Cyclization Reactions (Left)a
a
Reprinted with permission from ref 68. Copyright 2012 Elsevier.
Relying on this seminal work58 and on the application of nitroxides as controlling agents for NMP,59 Studer60 showed that alkoxyamines were suitable to initiate and control cascade radical cyclizations (Scheme 2b). Several other types of cyclizations were performed according to this approach.61,62 It was also possible to develop new metalfree reactions such as metal-free carbonylation63 and tandem
homolytic aromatic substitution/Horner−Wadsworth−Emmons olefination.64 Although not mentioned in the corresponding papers, the value of kc is also an important factor in the success of this chemistry. Hence, due to the recombination reaction between a C-centered radical and a nitroxide occurring with a suitable rate constant, it was possible to perform the addition on both an unactivated65 and an activated66 alkene with high yields, as well 5016
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Scheme 5. Scavenging Nitroxide Method Applied to the Investigation of the β-Fragmentation of an Alkoxyl Radical (a) and of Addition/Abstraction vs Abstraction/Addition Reactions (b)a
a
Reprinted from ref 81. Copyright 2004 American Chemical Society.
Scheme 6. Side Reaction Competing with HATa
a
Reprinted with permission from ref 68. Copyright 2012 Elsevier.
as to perform carboxyaminoxylations.67 That is, whatever the radical reaction, a low kc value will favor the occurrence of an undesired side reaction and a high kc value will dramatically slow the rate of the radical reaction. This was recently highlighted when the radical cyclization was applied to form 5-, 13-, and 14-membered ring products.68 In fact, 5-membered ring formation was observed in moderate yield (66%) as described in Scheme 3, whereas such a reaction has been reported, in general, in much higher yields,60−62 and the observed alkene was due to the intermolecular H-atom transfer (HAT) side reaction (see section 5.5.2). On the other hand, the formation of 13- or 14-membered ring alkoxyamines was never observed, and a new side compound (carbonate of hydroxylamine) was mainly observed (80%) instead of the expected alkene side product (20%, Scheme 4).68 However, taking into account the persistent radical effect (see section 2.3),58,69 a longer lifetime for the alkoxyamine should have been observed as for N53R1.70 More examples of applications of the cross-coupling reaction between a C-centered radical and a nitroxide are available in several reviews and books.3,71−76
reliable kc values, as well as being able to estimate them, is a crucial issue in accurately discussing the results. Moreover, a very low kc value favors the occurrence of an unexpected side reaction68,84 (75% yield of the carbonate of hydroxylamine) with oxygen at the expense of the conventional85,86 intermolecular HAT side reaction (25% yield of methyl methacrylate and the hydroxylamine of N8; see section 5.5.2) as highlighted in Scheme 6. 2.3. Application of Nitroxides/Alkoxyamines in Polymer Chemistry
For decades, hindered amine light stabilizers (HALSs) have played an important role in the protection of coatings, plastics, and rubbers.87 The mechanism of protection (Figure 4)
2.2. Application of Nitroxides/Alkoxyamines in Mechanistic Investigations in Chemistry and Biology
It is well-known that C-centered radicals are transient species and, therefore, very difficult to observe directly via spectroscopic methods. Therefore, their scavenging by a nitroxide has proved to be a powerful tool for the mechanistic studies of radical reactions.77 Nitroxides are commonly used to investigate the decomposition of radical initiators by scavenging the Ccentered radical generated (Scheme 5a),11,78,79 to investigate the factors affecting the rates of addition of radicals onto alkenes,80 to investigate mechanisms such as abstraction/ addition vs addition/abstraction, as exemplified by the reaction of N61 with cyclohexene (Scheme 5b),81 or to investigate the effect of antioxidants in the biomedical field.82,83 However, as C-centered radicals are highly reactive species, the scavenging reaction (Scheme 1) competes with many other possible pathways for the reaction, such as hydrogen atom transfer (see section 2.3). Consequently, having accurate and
Figure 4. HALS mechanism. Reprinted from ref 89. Copyright 2012 American Chemical Society.
includes the generation of nitroxides from amines via various processes.88,89 Thanks to their scavenging capacities, these nitroxides partly disrupt the oxidative propagating chains by cross-coupling with polymeric radicals.90−92 The design of more efficient HALSs depends on the knowledge of the kc values.93 Furthermore, the recent development of the NMP technique has allowed the preparation on the industrial scale of polymers with well-defined and elaborate structures such as comb-, star-, and π-shaped polymers using the very robust radical polymerization route.11,94−96 Like conventional radical polymerization, NMP involves three stages, initiation, propagation, and 5017
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termination, with the difference that the re-formation of the initiator occurs during the first two stages, leading to the near cancellation of the conventional self-termination reactions (Scheme 7).69,97−99 Indeed, when the kinetic equations were Scheme 7. Three-Stage Kinetic Scheme for NMPa
Figure 5. Fischer’s phase diagram. Adapted with permission from ref 101. Copyright 2001 Wiley.
polymerization, zone Y (Figure 5) above the black line ϕ and below the red line δ will provide poorly living and poorly controlled polymerization, that is, an unsuccessful NMP experiment, zones C and B (Figure 5) both below the red line δ and below the black line ϕ will provide poorly controlled but highly living NMP experiments in a given time depending on the green time line t, and zones D and A (Figure 5) below the black line ϕ and above the red line δ will provide highly living and highly controlled NMP experiments, that is, successful NMP experiments in a given time depending on the green time line t. Obviously, for NMP the properties of livingness and control do not mutually imply each other.101 Importantly, it must be stressed that the construction of this diagram is based on an ideal case with no addition of an extra nitroxide, no additional C-centered radical generation, no side reactions, and assuming that the initiation stage is of no importance.95,99,102 A nice example of the importance of kc in the fate of NMP was given by Guillaneuf et al.103 Indeed, they investigated the NMP of methyl methacrylate (MMA) initiated by N8R4X6 and controlled by N8. Successful NMP was predicted by Fischer’s phase diagram99,102 based on the kd and kc values of N8R4X1 (Figure 6a),103 in sharp contrast with the failure reported. Indeed, the authors noticed a dramatic effect of the polymer chain length on kc, and this fact being included in their simulations, it became obvious that the NMP of MMA under these conditions can only fail.103 Another nice example was provided by Siegenthaler and Studer,104 who investigated the NMP of styrene with alkoxyamines N70R2, N71R2, and N87R2. Although N70R2 and N71R2 exhibited close kd values (kd = 6.7 × 10−4 s−1 at 90 °C), very different kinetic behaviors were observed; i.e., the polymerization was much faster with N71 as the controlling agent (6 h for 50% conversion and PDI = 1.15) than with N70 (29 h for 50% conversion and PDI = 1.15), both polymerizations exhibiting good control. On the other hand, for the polymerization controlled by N87 (for N87R2, kd = 4.9 × 10−3 s−1 at 90 °C), the polymerization time was even shorter (2 h to reach 67% conversion) with poor control (PDI = 1.76). Such striking dif ferences in polymerization fate were attributed to dramatic variations in kc,ds values. In a recent paper,32 by plotting Fischer’s diagram (Figure 6b) using the kc values estimated from our empirical multiparameter relationship (for a discussion see section 4), we highlighted the importance of the kc values on the fate of NMP and showed that N87 was very close to the zone of poorly controlled and poorly living NMP. On the other hand, N71 and N70 are located in a zone of living
a
Rate constants not described in the text are defined in the Glossary. Reprinted with permission from ref 69. Copyright 2011 Royal Society of Chemistry.
developed for NMP, it appeared that two rate constants played a pivotal role in the fate of NMP: kd (and kd,ds) for the homolysis of the C−ON bond in alkoxyamines (or in dormant species, ds) and kc (and kc,ds) for the re-formation of these species.6,11,94,97−100 Therefore, as for the principal properties of NMP, the polymerization time (eq 1) for a given conversion depends on the square root of kc, and the controllinear evolution of the averaged molar masses Mn with the conversion related to the low polydispersity index (PDI) (eq 2) that highlights the control of the polymerizationdepends on the reciprocal of the square root of kc, as does the dead fraction ϕ (eq 3) that highlights the living character (so-called livingness) of the polymerization, i.e., the capacity to reinitiate a polymerization with a new monomer and then to prepare block copolymers. [I]0 is the initial concentration of alkoxyamine, [M]0 is the initial concentration of monomer, [M] is the concentration of monomer at a given time, kt is the termination reaction rate constant, and kp is the propagation rate constant, as displayed in Scheme 7. 1/3 [M]0 3 ⎛ k [I]0 ⎞ 2/3 = k p⎜ d ⎟ t [M] 2 ⎝ 3kc k t ⎠
(1)
⎛ πk 3[I] ⎞1/2 [I]0 p 0 ⎟ PDI∞ = 1 + + ⎜⎜ ⎟ [M]0 ⎝ kdkck t ⎠
(2)
⎛ 2k k ln([M] /[M]) ⎞1/2 0 ⎟⎟ φ = ⎜⎜ d t kck p[I]0 ⎝ ⎠
(3)
ln
With the equations displayed above, it is possible to plot a phase diagram that shows different sections highlighting NMP experiments of various qualities (Figure 5). Therefore, the zone above “the dead fraction line” (black line) affords poorly living polymerization, the zone below “the PDI line” (red line) affords poorly controlled polymerization, and the “time line” (green line) affords hints on the duration of the polymerization. Hence, zone X (Figure 5) above the red line δ (δ = PDI − 1) and the black line ϕ will provide highly controlled but poorly living 5018
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Figure 6. Fischer’s phase diagram for the NMP (a, left) of MMA, controlled by N8 at 45 °C (bottom square for N8R4X1 and top square for N8R44 with a methyl group instead of a t-Bu group), and (b, right) of styrene, controlled by N70 (■), N71 (●), and N87 (★) at 90 °C. (a) Reprinted with permission from ref 103. Copyright 2007 Wiley. (b) Reprinted from ref 32. Copyright 2012 American Chemical Society.
substituents R1 and R2; i.e., the stronger the electronwithdrawing capacities of R1 and R2, the less stabilized the nitroxide. In a recent paper,32 the geometries and conformations of the 10 aforementioned nitroxide families were discussed on the grounds of X-ray analysis and EPR data. These 10 families of nitroxides exhibit 6 types of conformations and geometries around the N−O• moiety (Figure 8): one with a syn and an anti β-alkyl group (N1 and N2), one with an anti β-hydrogen atom and a syn β-alkyl group (N3−N7), one with an anti alkyl group and an anti hydrogen atom (N8−N12),105 one with an anti ring (N13−N94), one with two syn hydrogen atoms (Bredt-type nitroxides N95 and N96), and the last one with the N−O• moiety conjugated and fused to the aromatic ring (N97). 2.4.2. Electronic Structures and Conformations of CCentered radicals. C-centered radicals belong to two families: π radicals for which the odd electron is localized either on the π* orbital (Figure 9a) or on the sp2-hybridized atom (Figure 9b) and σ radicals for which the odd electron is localized either on the sp3-hybidized atom (Figure 9c) or on the vinyl moiety (Figure 9d). To the best of our knowledge, no kc values for π radicals exhibiting the odd electron localized on π* orbitals (type a in Figure 9) are available. σ radicals of type c (Figure 9) are observed when either two or three highly electronegative groups X (such as fluorine) are attached to the radical center (no example in Figure 1) or when internal strain forces the pyramidalization (sp3 hybridizization) of the radical center (often due to cyclic strain as exemplified with R13 and R14 in Figure 1). Radicals R38, R57, and R59 are the only examples of σ radical of type d reported in the literature for which a kc value is available (Figure 1 and Table 1). All other C-centered radicals displayed in Figure 1 are π radicals of type b (Figure 9). For a vinyl-like moiety (aromatic ring, carbonyl, and cyano function) or a heteroatom carrying available lone pairs attached to the radical center, the delocalization of the odd electron is observed, except for R18, for which a lower delocalization is observed due to a propeller-like structure caused by the steric hindrance of three phenyl groups attached to the radical center (Figure 1).
and controlled polymerization (successful, but slow, NMP), with N71 promoting even faster NMP than N70. It would have been possible to predict the fate of the NMP experiments, provided a reliable and accurate estimate of kc values had been available when the NMP experiments were performed. There is no doubt that these two examples highlight very well the importance of kc in the fate of NMP experiments. A more detailed discussion and more examples of the importance of kc in NMP were provided in recent reviews.29,69 2.4. Electronic Structures and Conformations of Nitroxides and C-Centered Radicals
Reactivity in organic chemistry depends only on a few factors: stabilization, polar, steric, and stereoelectronic effects of the reactants/TS/products. In turn, these effects are straightforwardly related to the structure (polarity and bulkiness) of the groups attached to the reactive center. Thus, the development of structure−reactivity relationships (sections 3 and 4) requires a brief discussion of the electronic structures and the conformations of both the nitroxides and the C-centered radicals investigated in this review. 2.4.1. Electronic Structures and Conformations of Nitroxides. The electronic structures of nitroxides have been well documented for decades.74 It should be pointed out that the odd electron is located in an antibonding π* orbital, forming a three-electron π double bond between the nitrogen and oxygen atoms (Figure 7). Therefore, the electronic structure of a nitroxide can be described by two canonical forms: a zwiterrionic form A and a neutral form B (Figure 7). This threeelectron bond accounts for the strong stabilization of the nitroxyl moiety, and the presence of the zwiterrionic form A makes the stabilization of the nitroxide sensitive to the polaritymainly the electron-withdrawing capacityof the
2.5. Techniques of Measurement
The typical values of kc are close to the recombination rate constants of fast radical reactions and cover the range 106−109 M−1 s−1. Thus, the direct measurement of kc requires techniques with nanosecond time resolutionpulsed radiolysis106,107 or
Figure 7. Different representations of the nitroxyl moiety and its orbital diagram. 5019
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Figure 8. Newman projections around the nitroxide moiety for the six families.
centered radicals are generated by photolysis (reaction 1 in Scheme 8) of symmetrical ketones (Norrish 1 type decomScheme 8. Reactions Required for the LFP-D Method Figure 9. Electronic structures of C-centered radicals.
laser flash photolysis−kinetic absorption spectroscopy (LFP− KAS). In both cases the measured value corresponds to the decay of the C-centered radicals, measured via their UV absorbance. Another possibility to measure kc is based on nondirect measurements using the following techniques: modification of LFP−KAS using an additional probe (LFP-P), time-resolved chemically induced dynamic nuclear polarization (TR-CIDNP), CIDNP with fast switching of the external magnetic field (SEMF-CIDNP), the radical clock method, Ccentered radical nitroxide trapping (competitive method), and radical nitroxide recombination−pulsed lamp photolysis−size exclusion chromatography (RNR−PLP−SEC). In all these techniques the measured parameter (nuclear spin polarization intensity, degree of polymerization, etc.), which helps to determine kc values, is strongly dependent on the coupling reaction. Hereafter, these various approaches for kc measurements are presented and briefly discussed. 2.5.1. Laser Flash Photolysis−Kinetic Absorption Spectroscopy. LFP−KAS is the most widely used and most convenient technique to study fast radical reactions, and it has been accurately described in many books and papers.39,50,51,108−112 Briefly, it involves generation of radicals using laser irradiation followed by UV−vis detection of the kinetics of short-lived intermediates on the nanosecond time scale. The LFP−KAS experimental setup includes a pulse laser and a digital oscilloscope. The time resolution of LFP−KAS is determined by the duration of the laser pulse and the response time of the oscilloscope and is typically 1−10 ns. The applicability of LFP−KAS to measure recombination rate constants kc depends on the UV spectra (absorption coefficients ε at different wavelengths λ) of all species (reactants, radical intermediates, and products). In some cases (low ε of radical intermediates or overlap of nitroxide and C-centered radical UV spectra), LFP−KAS with direct detection of radical kinetics (noted LFP-D in Table 1) does not allow the measurement of kc, and thus, the other methods should be applied. 2.5.1.1. LFP−KAS with Direct Detection (LFP-D). LFP−KAS was adapted, for the first time, by Ingold’s and Beckwith’s groups for the determination of kc.24,25 In most cases C-
position) or of symmetrical acyl peroxides followed by monitoring of the C-centered radical UV absorption A. In the presence of a large excess of nitroxide (reaction 3 in Scheme 8), a pseudo-first-order decay is monitored,37,39,51 and kexptl is given by eq 4. In cases where the large excess of nitroxide cannot be applied (high absorbance of nitroxides at the wavelength of irradiating light, overlap of nitroxide and C-centered radical UV spectra, side reactions74,113−118 of nitroxides, etc.), kexptl is contributed by both first- and second-order decays and is given by eq 5.50 In both cases, kc is obtained by plotting kexptl against the nitroxide concentration [R1R2NO•] (eq 6). Here A0 and At are the absorptions at the initial time and at any following time t, respectively, k0 includes all reactions except for the coupling between the C-centered radical and nitroxide, d is the optical density, and kt is the self-termination of the C-centered radicals. A ln t = −kexptlt A0 (4) At = d
kexptl 2k t ⎡ ε ⎢ ⎣
(1 +
kexptl d 2k t / ε A 0
)e
kexptl = k 0 + kc[R1R 2NO•]
kexptlt
⎤ − 1⎥ ⎦
(5) (6)
The main drawback of this method is the tedious preparation of elaborate radical initiators. The low extinction coefficient of C-centered radicals, or the overlap of the absorption spectra of the C-centered radicals and the reactants or products, can complicate LFP-D or even make its application to k c measurements impossible. 2.5.1.2. LFP−KAS with Probe Detection (LFP-P). In the cases where direct detection of C-centered radical decay is not possible, kc can be measured using the LFP approach developed by Paul and co-workers.119 They proposed to trap C-centered radicals using probe molecules (e.g., 1,1-diphenylethylene (DPE), reaction 4 in Scheme 9) and monitor the kinetics of the spin adduct formed (1,1-diphenylcarbinyl radical), which exhibits very strong absorption at 330 nm. In the absence of 5020
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Scheme 9. Reactions Required for the LFP-P Method
Scheme 11. Reactions Involved in Affording ThirdGeneration C-Centered Radicals
nitroxide and at high DPE concentration, a pseudo-first-order growth of the spin adduct absorbance signal is recorded (eq 7). The measurements of kinetics at different DPE concentrations without nitroxide makes it possible to obtain the rate constant k4. In the presence of nitroxide at various concentrations and at high constant DPE concentration (k4[DPE] ≫ kt[R]), a pseudo-first-order growth is observed, affording kc from eq 8. If the excess of nitroxide is not large enough, a complicated kinetic order is observed, with kexptl given by eq 9 (where εR and εR−DPE are the extinction coefficients of the C-centered radical and of the spin adduct, respectively).50 In both cases, keeping the DPE concentration constant, kc can be obtained by plotting kexptl − k4[DPE] against [R1R2NO•] (eq 8, k0 encompassing all other processes). Here At and A∞ refer to the absorptions of the spin adduct of DPE at various times t and at the plateau, respectively. A∞ = kexptlt ln A∞ − A t (7) kexptl = k 0 + k4[DPE] + kc[R1R 2NO•]
(8)
⎡ ⎡ A ⎤ ⎢ ∞ ln⎢ ⎥ = ln⎢ − A A ⎣ ∞ t⎦ ⎢⎣ 1 −
(9)
1 εR εR−DPE
⎤ ⎥ + kexptlt kexptl ⎥ ⎥ k4[DPE] ⎦
third-generation radical, LFP-3G).120 The irradiation of a peroxide (reaction 1, Scheme 11) yielded alkoxyl radicals that abstracted the H-atom from the amine (reaction 2, Scheme 11), generating an aminoalkyl radical. In the case of a large excess of monomer, the aminoalkyl radical added preferentially onto the monomer (reaction 3, Scheme 11) to generate a new radical. The latter was scavenged by the nitroxide (reaction 4, Scheme 11). As aminoalkyl and C-centered radicals exhibit very different extinction coefficients ε and wavelengths λ, the monitoring of the absorption of C-centered radicals of the third generation afforded kc values using the equations proposed above. The main drawbacks of this approach are the need to determine the suitable ratio peroxide/amine/alkene to avoid undesired reactions with the nitroxide or the alkene and the impossibility of investigating “original” C-centered radicals (radicals with no penultimate unit effect). Photocleavable alkoxyamines can significantly simplify the application of the LFP technique to kc measurements.51 In this case, light-induced homolysis of an alkoxyamine leads directly to the generation of a nitroxide and a C-centered radical (Scheme 12). The monitoring of the C-centered radical decay is Scheme 12. Reactions Involved in the Generation of CCentered Radicals from Photocleavable Alkoxyamines
The drawbacks of LFP-P are the same as those of LFP-D concerning the position of the absorption lines for each reactant/intermediate/product. 2.5.1.3. Radical Generation in LFP−KAS. In most cases the photolytic decomposition of symmetrical diacyl peroxides (reaction 1 in Scheme 10) or ketones (Norrish type 1 reaction, Scheme 10. C-Centered Radicals Generated from the Decomposition of Diacyl Peroxides (Reaction 1), Ketones (Reaction 2), and Dialkyl Peroxides (Reactions 3 and 4)
performed either under the PRE conditions (single-cell approach; the cross-coupling reaction is preponderant) or in the presence of an excess of nitroxide (multiple-cell approach). The main drawback is the possible tedious preparation of alkoxyamines carrying photocleavable groups exhibiting an absorbance that is different from that of the generated Ccentered radicals. 2.5.2. Radical Clock Method. The so-called “radical clock” method of kc measurements is used in cases where the Ccentered radical R• is rearranged into A• with the known rate constant kR. The presence of an excess of nitroxide R1R2NO• leads to kinetic competition between (i) direct radical trapping of R• by nitroxide and (ii) radical trapping by nitroxide of the intermediate rearranged radical A •, resulting from the unimolecular clock reaction. These two trapping reactions afford two products, R1R2NOR and R1R2NOA (Scheme 13). The competition is governed by the pseudo-first-order equation. The product concentration is often estimated by high-performance liquid chromatography (HPLC) combined with UV−vis detection or any other technique able to reliably estimate the ratio of the products. It is easy to show that the reaction of radicals R• and A• with the solvent does not affect the [R1R2NOR]/[R1R2NOA] ratio. Thus, kc can be obtained by
reaction 2 in Scheme 10) is used for the generation of Ccentered radicals. The preparation of such initiators may sometimes be tedious work or even not possible. In some cases the absorption bands for the starting materials overlap with the bands for the transient species. To overcome these drawbacks, the alkoxyl radicals are generated photochemically or thermally (reaction 3, Scheme 10) and then generate the targeted Ccentered radical by H-abstraction on the suitable alkane (reaction 4 in Scheme 10, LFP of second-generation radical, LFP-2G), and the measurement of cross-coupling rate constant values is performed in the same way as described above. The main drawbacks of this approach are the same as those mentioned above and the availability of the suitable alkane. Another way to generate a C-centered radical from a monomer was proposed by Lalevee et al. (Scheme 11, LFP of 5021
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Scheme 13. Reactions Involved in the “Radical Clock” Approach
various reactions involved can be unveiled. Moreover, the timeresolved CIDNP version allows measurements of reaction rate constants with microsecond time resolution.123−126 Using the example of N53 and R1, Fischer et al.70 showed that the TRCIDNP experiments are suitable for the determination of the kc values. The experimental setup for TR-CIDNP has been described in detail.127 Laser flash photolysis of degassed dialkyl ketone solutions inside the NMR spectrometer probehead provides a convenient, clean, and “instantaneous” source of Ccentered radicals. The NMR spectra of the reaction products are recorded in the absence and in the presence of nitroxide and at different time delays between the laser pulse and radio frequency pulse τ0.123−126 The measurements of the CIDNP intensity of the alkoxyamine on time delay τ0 provide the observed alkoxyamine formation rate constant kobsd. The dependence of kobsd on the nitroxide concentration provides the value of kc, and that can be obtained using eq 6 displayed in section 2.5.1. If the value of kc is high, the 1 μs time resolution of CIDNP is not sufficient to provide for accurate measurements. Therefore, the SEMF-CIDNP method was developed to circumvent such a problem.128−130 In this method irradiation of the investigated solution is performed in a separate magnet with a magnetic field B1. After variable time delays t, the magnetic field B1 is switched to a second magnetic field B2 for a fixed time t0. Finally, the magnetic field is switched back to B1. Thus, the CIDNP detected on the protons of the alkoxyamine results from the evolution of the nuclear polarization of C-centered radicals in different magnetic fields during different time delays. The resulting nuclear polarization is monitored using an NMR spectrometer after transfer of the reaction mixture to the NMR probe. The theoretical background of SEMF-CIDNP was adapted to the coupling reaction of the alkyl radicals and nitroxides, and the analytical solution of the corresponding set of kinetic equations was found.52 In the case of low initial concentrations of radicals R•, the SEMF-CIDNP kinetics are expected to be monoexponential with a decay equal to kc[Y] + 1/T1, where [Y] is the concentration of nitroxyl radicals and T1 the electron−nuclear relaxation time of transient radicals. Thus, the dependence of the CIDNP intensity on the time delay t provides the rate of alkoxyamine formation, whereas the dependence of the observed rate on the nitroxide concentration allows one to obtain the cross-coupling rate constant kc. The two main drawbacks of SEMF-CIDNP are the need to take into account magnetic and spin effects in radical reactions and the sensitivity to a large excess of paramagnetic species in the reaction, which can lead to fast nuclear relaxation and hence to the disappearance of the polarized NMR signals during transfer of the reaction mixture to the NMR sample tube. In this case, it is very difficult or even impossible to work with concentrations of stable radicals above ca. 20 mM. Therefore, the relatively low rate constants (ca. σI,N71 (−0.06)237 and eq 39 as well as kc,ds,N70 ≈ kc,ds,N88. Interestingly, when kc,ds is estimated by mimicking the chain length with the penultimate unit, S−S• 238 for PS•,239 BA−BA• 238 for PBA•,240 and MMA−MMA• 238 for PMMA•,241 using eqs 35 and 37 for N8 and N53, respectively, the values obtained are very close (kc,ds(N8 + S−S•) = 2.5 × 105 M−1 s−1, kc,ds(N8 + MMA−MMA•) = 2.2 × 104 M−1 s−1, and kc,ds(N53 + S−S•) = 1.7 × 108 M−1 s−1) to the values measured using the RNR−PLP−SEC method (entries 5, 6, 9, and 21 in Table 11), whereas the agreement is less good (kc,ds(N8 + BA− 5044
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Scheme 16. Kinetic Scheme of the Procedure Developed To Determine Unambiguously the Rate Constants for IPT (kdD) and for HAT (kcD)a
a
Reprinted with permission from ref 86. Copyright 2009 Wiley.
BA•) = 5.1 × 106 M−1 s−1) for the data estimated using the PRE method. A 17-fold difference is observed between the predicted value for N1 and S−S• 239 (eq 34 in Table 7, kc,ds = 2.0 × 108 M−1 s−1) and the value measured using the PRE method. Nevertheless, the multiparameter equations look robust enough to be applied as a predictive tool to estimate the kc,ds of polymeric radicals, taking only the PUE into account.
presented in section 2.5; (ii) investigation of the alkoxyamine decomposition in the presence of a C-centered radical scavenger and/or a nitroxide reductant to determine kd and kdD (kdD being given by the monoexponentional growth of the alkene signal), given by
5.4. Configuration Effect
Several nitroxides, such as N3, N8, N11, N38, N71, N90, and N93, are chiral. All secondary C-centered radicals, for example, R2, R5, R23, and R43, as well as some tertiary C-centered radicals, such as R42, R47, and R49, are prochiral. In such cases, the value of kc for the cross-coupling between a chiral nitroxide and a prochiral C-centered radical might be configuration dependent. Thus, Braslau et al.242,243 investigated the crosscoupling reaction between the chiral nitroxide N38 and prochiral radicals such as R2 and homologues. They reported moderate to good yields of cross-coupling products exhibiting low diastereosiomeric ratios (less than 7:1). Ananchenko et al.154,244,245 determined the kc values or the rate constant ratios for the formation of several diasteroisomers of N8- and N53-based alkoxyamines and reported only minor differences (less than a factor of 2).
[alkoxyamine]t = [alkoxyamine]0 e−kobsdt
(61)
kobsd = kd + kdD
(62)
k [alkane] = d [alkene] kdD
(63)
(iii) investigation of the alkoxyamine decomposition in the absence of any scavenger/reductant, affording the global amount of alkene generated. Then kcD is given by kobsd = kdD +
kcDkd = kdD + kdfD = kd(fdD + fD ) kcD + kc (64)
Thus, this procedure affords both the disproportionation fraction f D due to HAT and the IPT concerted elimination (Cope-type reaction) fraction fdD = kdD/kd. Edeleva et al.86 showed that the fdD values ranged from 0%, i.e., no IPT, like for N53R4X5,85 N16R4X2, N18R4X5, N18R2, and N27R4X5, to 31%, like for N14R4X5, and cannot be predicted or assumed by simply glancing at the molecular structure. With a different approach, Skene et al.159 showed that IPT occurred for N53R2 and not for N53R24. It is worth mentioning that the procedure developed by Edeleva et al.85,86 avoids fastidious discussions based on several assumptions, although an in-cage hydrogen atom transfer cannot be differentiated from IPT. DFT calculations showed that all the aforementioned molecules exhibit the same transition state for IPT, with very close activation energies despite very different structures and fdD values.248 Furthermore, all of them already exhibit the required conformation in the initial state.248 In fact, it was shown that the occurrence of the IPT reaction depended on the difference in energy between the TS for IPT and the TS for C−ON bond homolysis modulated only by the position of the TS of the latter; hence, a small energy gap favors IPT.248 The chain length effect as well as other events occurring during the polymerization might dramatically change the observations and expectations from the model experiments. 5.5.2. Intermolecular Hydrogen Atom Transfer. HAT has mainly been investigated for alkoxyamine models based on R2, R4, and R5 radicals as well as during the polymerization of the corresponding momoners using several techniques. The main approach to investigate the HAT event is to monitor the
5.5. Side Reactions
Although nitroxides have found many applications, for example, as radical clocks, spin probes, and antioxidants,3,4 and despite the tremendeous growing interest aroused by NMP, the intermolecular HAT (kcD in Scheme 16),246 which is the main side reaction of the cross-coupling reaction (kc in Schemes 7 and 13), has been little investigated even though its occurrence can be dramatic for the fate of NMP experiments. For practical reasons (vide infra), the HAT reaction was mainly investigated during the thermal decomposition of alkoxyamine models or during polymerization experiments. As displayed in Scheme 16, the HAT event affords an alkene and a hydroxylamine, which are the same side products yielded by the intramolecular proton transfer (IPT) event (the side reaction occurring during the homolysis in Scheme 16). Thus, the IPT reaction will also be discussed in this section, although it is not related to the side reaction occurring during the cross-coupling reaction. 5.5.1. Intramolecular Proton Transfer. An alkene and a hydroxylamine were reported during the decomposition of N53R2159 and of N53R5X2247 and ascribed to the IPT event, although no clear-cut evidence was provided because no procedures were available. Such procedures were developed by Edeleva et al.85 using a three-step scheme (Scheme 16):86 (i) determination of kc in an independent way using the methods 5045
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Table 12. Disproportionation Factor f D and HAT Rate Constants kcD for Various C-Centered Radicals and Nitroxides at Different Temperatures entry
nitroxide
C-centered radical
f D (%)
T (°C)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
N1 N1 N3 N6 N7 N8 N8 N8 N8 N8 N8 N8 N8 N8 N8 N8 N8 N8 N8 N14 N16 N17 N18 N18 N27 N27 N39 N39 N40 N41 N42 N43 N43 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N53 N61
R2 PtBA• R2 R2 R2 R2 R2 PS• R4X1 R4X2 R4X2 R4X6 PMMA• PMMA• R5X1 R5X9 R44h PBA• R47 R4X5 R4X2 R4X2 R2 R4X5 R4X5 R4X5 R2 R40 R4X5 R4X5 R4X5 R4X5 R4X5 R1 R1 R2 R2 R2 R2 R4X2 R4X2 R5X2 R5X8 R4X5 R39 R40 R41 R42 R43 R44 R45 R46 R47 R48 R49 R50 PS• PS• BPO• k R2
0.86 1.1 0.3 0.7 0.4 ∼0 0.16
