Chapter 7
Kinetic Studies of Elementary Reactions in SET-LRP / SARA ATRP Julien Nicolas,1 Sebastian Perrier,2,3 and Simon Harrisson4,* 1Institut
Galien Paris-Sud, Univ Paris-Sud, UMR CNRS 8612, Faculté de Pharmacie, 5 rue Jean-Baptiste Clément, F-92296 Châtenay-Malabry cedex, France 2Department of Chemistry, The University of Warwick, Gibbet Hill, Coventry, CV4 7AL, United Kingdom 3Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia 4Laboratoire des Interactions Moleculaires et de la Reactivité Chimique et Photochimique, UMR CNRS 5623, Université de Toulouse, 31062 Toulouse, France *E-mail:
[email protected] A kinetic scheme for controlled radical polymerization in the presence of copper is developed, first neglecting comproportionation or disproportionation reactions, then taking them into account. Experimental results on the kinetics of the elementary reactions of comproportionation, activation by copper(0) and biradical termination are presented, showing solvent effects on activation and comproportionation reactions and chain length dependence of activation and termination. Unusually high rates of termination are observed in controlled radical polymerizations in the presence of copper; around an order of magnitude faster than in conventional or RAFT polymerizations.
Introduction The history of metallic copper in radical polymerization begins in 1967, when Otsu et al. reported that radical polymerizations could be initiated by the combination of copper metal and an alkyl halide (1). After the development of © 2015 American Chemical Society
atom transfer radical polymerization (ATRP) (2, 3), the effect of copper metal was reexamined, both as an additional component in an ATRP reaction (4) and as the sole catalytic species (4, 5). These early works established that copper(0) participated in two key reactions: activation of alkyl (or sulfonyl) halides, and reduction of copper(II) to copper (I) (Scheme 1). The relative significance of these two reactions was an important subject of the ensuing debate over the mechanism of controlled radical polymerization (CRP) in the presence of copper, known variously as Single Electron Transfer Living Radical Polymerization (SET-LRP) (6) or Supplemental Activator and Reducing Agent ATRP (SARA ATRP) (7).
Scheme 1. Reactions of copper metal in atom transfer radical polymerization. Note that Cu(I) and Cu(II) represent all dissolved copper(I) and copper(II) species – the presence of solubilizing ligands is assumed.
Development of copper-based CRP continued through the 2000s, with two schools of thought emerging. With the introduction of ARGET (activator regenerated by electron transfer) ATRP (8, 9) Matyjaszewski and coworkers demonstrated that the addition of copper metal (among other reducing agents) allowed ATRP polymerizations to be carried out at extremely low copper concentrations while continuously regenerating the copper(I) activating species by reduction of copper(II). Meanwhile, Percec and coworkers carried out copper-metal mediated polymerizations of vinyl chloride in biphasic mixtures of water and THF (10) and of methyl acrylate and methyl methacrylate in DMSO solution (6). The observation of disproportionation of copper(I) salts in water and of copper(I)/ligand complexes in DMSO led this group to propose that in these systems (and many others which had been considered to follow the ATRP mechanism) copper(0) was the primary activating species, and that concentrations of copper(I) were essentially zero as a result of rapid disproportionation. Additionally, the generation of copper(II) was thought to remove the need for build-up of copper(II) deactivating species via the persistent radical effect, thus providing low (or even zero (11–14)) levels of termination from the beginning of the reaction. Thus two conflicting mechanisms for CRP in the presence of copper(0) were established – one (ARGET) dominated by comproportionation with copper(I) as the main activating species (15), the other (SET-LRP) dominated by disproportionation with activation primarily by copper(0) (Scheme 2). The ARGET mechanism in presence of copper was later renamed SARA, reflecting the role of copper(0) as both Supplemental Activator and Reducing Agent (7). 130
Scheme 2. SARA (left) and SET (right) mechanisms of polymerization. Key differences in the mechanisms include: No activation by copper(I) in SET-LRP; no biradical termination in SET-LRP; comproportionation dominates disproportionation in SARA ATRP. Note that Cu(I) and Cu(II) represent all dissolved copper(I) and copper(II) species – the presence of ligands is assumed and rate constants shown are aggregate rate constants.
The full story of the development of the two mechanisms is beyond the scope of this contribution, and different viewpoints can be found in recent reviews (12, 16–18). The mechanisms are chiefly distinguished by the relative rates of four reactions, viz.: the rates of comproportionation (kcomp) and disproportionation (kdisp) (in SET-LRP, disproportionation dominates; in SARA ATRP the equilibrium favors comproportionation); the rates of activation by copper(0) (ka0) and copper(I) (ka1) (in SET-LRP, all activation occurs by reaction with copper(0)); and the rate of bimolecular termination (zero or negligible in SET-LRP). The measurement of the rates of these elementary reactions has been a significant focus of our (19–21) and other groups’ (22–25) work in this field. In this paper, we develop a kinetic scheme for CRP in the presence of copper, first neglecting comproportionation or disproportionation reactions, then taking them into account, and present some experimental results on the kinetics of the elementary reactions of comproportionation, activation by copper(0) and biradical termination.
Results and Discussion Polymerization in Noncomproportionating, Nondisproportionating Solvents Comproportionation and disproportionation reactions take place very slowly in nonpolar solvents such as toluene. Thus performing polymerization in the presence of copper(0) in toluene (19, 26, 27) is a useful model for SET-LRP or SARA ATRP reactions in solvents that favor disproportionation or comproportionation, as equilibration between copper species can be neglected, leading to the simplified mechanism shown in Scheme 3. 131
Scheme 3. SARA/SET-LRP polymerization in toluene. Rates of comproportionation and disproportionation are negligible. Note that Cu(I) and Cu(II) represent all dissolved copper(I) and copper(II) species – the presence of ligands is assumed and rate constants shown are aggregate rate constants. It is immediately apparent from Scheme 3 that the reaction involves net consumption of copper(0) and generation of dead polymer – indeed it could be summarized as:
The rates of generation of the various soluble copper species and radicals are given in the equations below (SCu/V represents the ratio of copper surface area to the total reaction volume):
From these equations we can derive two useful identities:
It is clear from equation 4 that the total dissolved copper concentration will steadily increase. As this occurs, the rates of activation by copper(I) and deactivation by copper(II) will also increase, causing the ratio of copper(I) to copper(II) to approach the value given by the ATRP equilibrium (19) (note that the concentration of copper(II) will always be slightly below the ATRP equilibrium value as a result of the continuing generation of copper(I) from copper(0)): 132
Assuming negligible changes in the radical concentration (the steady state approximation), [PnX] (low levels of termination) and the copper surface area, we arrive at the following expressions for the steady state radical concentration (equation 8) and the overall rate of polymerization (equation 9):
where φ represents the fraction of total copper present in the form of copper(II):
The value of φ can vary between 0 (very slow activation by copper(I)) and 1 (very rapid activation by copper(I)), so that:
Thus the rate of polymerization is primarily determined by the rate of activation of dormant polymer by copper(0), and is proportional to the square roots of the copper surface area and dormant polymer/initiator concentration. Kinetically, the reaction resembles ICAR (initiators for continuous activator regeneration) ATRP (28), with the copper(0)/PnX couple playing the role of the radical initiator. In ICAR, the rate of reaction is determined by the rate of initiator decomposition, according to the equation below (28):
An advantage of SARA ATRP in toluene over ICAR is that the dormant polymer itself serves as the supplementary source of radicals, thus the final polymer is not contaminated by end-groups derived from the supplemental initiator (e.g. cyanoisopropyl groups from AIBN). On the other hand, the copper concentration continually increases as the reaction proceeds, which may result in higher overall levels of copper in the final product. 133
Polymerization in Comproportionating and/or Disproportionating Solvents Comproportionation and disproportionation reactions take place more rapidly in polar solvents such as acetonitrile, DMSO and water, and can no longer be neglected. Disproportionation, according to the proposed SET-LRP mechanism, results in the formation of nanosized ‘nascent’ copper particles which are assumed to be highly reactive. Thus we assume that the copper(0) produced as a result of disproportionation immediately reacts with dormant polymer to generate a propagating radical and regenerate copper(I) (Scheme 4).
Scheme 4. Rapid activation by ‘nascent’ copper produced as a result of disproportionation. If it is assumed that both disproportionation and comproportionation reactions may take place, the equations for the rates of generation of soluble copper species become the following:
Note that equation 5 remains valid, while the total change in copper concentration is now equal to
and the rate of change in the radical concentration equals:
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with φ now equal to (20, 21)
As the concentration of copper(II) species is not constant, equation 17 is difficult to solve, but the radical concentration can be approximated by (20):
Significant levels of comproportionation create a feedback loop in which the increasing copper concentration leads to an increased rate of comproportionation. The radical concentration is predicted to increase exponentially, although in reality increased radical generation as a result of comproportionation would be offset by a decrease in the dormant polymer concentration due to high levels of termination. High levels of comproportionation are thus incompatible with a well-controlled polymerization, which probably explains the poor control observed in acetonitrile, a solvent which strongly favors comproportionation. It is important to note that the polymerization system as described above is not at equilibrium with respect to comproportionation and disproportionation. The reactions of activation by copper(I) (ka1) and biradical termination (kt) maintain a net flow of copper(I) to copper(II). Thus if the system is at equilibrium before the addition of dormant polymer (e.g. as a result of disproportionation of copper(I) salts), the addition of the dormant polymer will deplete the copper(I) concentration, shifting the equilibrium towards comproportionation. The copper(I) concentration will remain depleted with respect to the equilibrium until all dormant polymer has been converted to dead polymer through biradical termination reactions. This is true regardless of the value of the equilibrium constant of disproportionation, even in solvents such as water in which a large excess of Cu(II) over Cu(I) is typically present at equilibrium.
Simultaneous Measurement of Rates of Comproportionation and Activation by Copper(0) The preparation of alkoxyamine initiators by reaction of alkyl halides with copper metal in the presence of a nitroxide radical (29, 30) provides an example of the autocatalytic effect of comproportionation (Scheme 5). When the reaction is carried out in acetonitrile an exponential increase in the rate of reaction is observed, as copper(I) generated by the reaction of copper(0) with alkyl halide reacts with a second molecule of alkyl halide to form copper(II), which in turn reacts with copper(0) to regenerate copper(I). Copper(II) is thus both a product and a catalyst for the reaction. 135
Scheme 5. Preparation of ethyl isobutyryl-SG1 adduct by reaction of ethyl bromoisobutyrate with copper metal in the presence of SG1 and N,N,N′,N″,N″-pentamethyl diethylene triamine (PMDETA).
Experiments carried out in a variety of solvents showed autocatalytic effects in acetonitrile, DMF, ethanol and DMSO, while no autocatalysis was observed in toluene, ethyl acetate or a mixture of ethanol and water (Figure 1). Analysis of the reaction kinetics shows that the initiator conversion is given by (20):
Fitting the observed kinetics to equations of the form conversion = A.exp(k.t) allowed the simultaneous determination of ka0 and kcomp. The results obtained are shown in Table 1. It is notable that ka0 shows relatively little variation (typically 10-4-10-3 cm.s-1), while kcomp varies across several orders of magnitude. DMSO, the solvent of choice for SET-LRP, exhibits a high ka0 and relatively low kcomp, while MeCN has a relatively low ka0 and high kcomp. The significant rate of comproportionation observed in DMSO is in accordance with previous observations that Cu(I) is quite stable towards disproportionation in DMSO in the presence of sufficient Me6tren ligand (31). The ethanol/water mixture and ethyl acetate are characterized by moderate ka0 and negligible kcomp, suggesting that these solvents are good candidates for rapid, well-controlled polymerizations. Interestingly, activation rate constants of a secondary initiator, methyl 2-bromopropionate, in the presence of Me6tren ligand in DMSO (32) or water (24) have been reported as 1.8 × 10-4 cm.s-1 and 1.0 × 10-5 cm.s-1, respectively, indicating that the change from a tertiary to a secondary initiator results in a 5-fold reduction in ka0, and that water is a very poor solvent for the activation reaction, presumably due to the instability of Cu(I) species in aqueous solution. Even the highest values of ka0 measured here are slow in comparison to typical rate constants for activation by copper(I) (e.g. 2.7 M 1 s-1 for ethyl bromoisobutyrate in MeCN/PMDETA at 35°C (33)), which lends support to the SARA mechanism in which most activation of dormant polymer occurs through reaction with copper(I).
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Figure 1. Conversion of ethyl bromoisobutyrate to the SG1 adduct in the presence of copper metal and PMDETA in non-comproportionating (A) and comproportionating (B) solvents, with exponential fits up to 80% conversion. Reproduced with permission from reference (20). Copyright 2012 American Chemical Society.
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Table 1. Values of ka0 and kcomp obtained from kinetic analysis of the preparation of ethyl 2-methyl-2-[N-tert-butyl-N-(1-diethoxyphosphoryl-2,2dimethylpropyl)aminoxy]propionate from ethyl bromoisobutyrate and SG1 nitroxide (N-tert-butyl-N-(1-diethylphosphono-2,2-dimethylpropyl)-N-oxyl) in the presence of N,N,N′,N″,N″-pentamethyldiethylene triamine. Solvent
ka0 × 103 (cm.s-1)a
kcomp × 103 (cm.s-1)a
kcomp/ka0
DMSO
1.05
2.8
2.8
EtOH/H2O
0.72
