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Chemically triggered C–ON bond homolysis of alkoxyamines. Part 4: solventeffect†

G�erard Audran, Paul Br�emond, Sylvain R. A. Marque* and Germain Obame

Received 26th June 2012, Accepted 16th July 2012

DOI: 10.1039/c2py20447a

In a recent work (Org. Lett., 2012, 14, 358), we showed that the rate constants kd for the C–ON bond

homolysis of chemically activated alkoxyamines were subject to solvent effects. We then investigated

solvent effects on the non-activated alkoxyamine 1 ((diethyl(1-(tert-butyl(1-(pyridin-4-yl)ethoxy)

amino)-2,2-dimethylpropyl) phosphonate) and its N+–O� oxide activated version 2, using 14 solvents

exhibiting different solvent parameters – dipolar moments m, dielectrical constants 3, cohesive pressures

c, Reichardt solvent polarity constants ET, viscosity h, hydrogen bond donor and hydrogen bond

acceptor constants a and b, respectively, and nitrogen hyperfine coupling constants aN. Weak solvent

effects were observed both for 1 (4–5-fold from n-octane to 2,2,2-trifluoroethanol TFE) and for

2 (2-fold from n-octane to water) although kd increased 27-fold in n-octane and 19-fold in TFE from

1 to 2. It was shown that the C–ON bond homolysis rate constant kd increased with the aN values,

meaning that the stabilization of the nitroxide was the main factor involved in the solvent effect.

Approaches relying on the Koppel–Palm and Kalmet–Abboud–Taft relationships failed to describe the

solvent effect for all diastereoisomers of 1 and 2. Nevertheless, the solvent polarity/polarizability (p*)

and hydrogen bond donor (a) properties are the main effects involved in the solvent effects at TS and on

products.

Introduction

Since the pioneering work of Rizzardo4 and the seminal work of

Georges,5 Nitroxide Mediated Polymerization (NMP) has

become a mature technology that is applied everyday in

academic laboratories and factories to prepare new materials.6

Although the various effects influencing the homolysis rate

constants kd of alkoxyamines have been investigated for 25

years,7–9 only two studies dealing with several solvents,6,7 to the

best of our knowledge, have been reported without covering the

main properties of solvent.10,11 Some authors reported that

solvent effects occur during NMP experiments12–15 or with a few

solvents.16,17 Furthermore, these studies were focused on

alkoxyamines or macroalkoxyamines which were not subject to

solvent effects, because there is no possibility for strong

hydrogen bonding occurrence, weakly polar alkyl fragment on

the alkoxyamine, etc. Hence, only a weak solvent effect was

reported involving the stabilization of the nitroxide. However,

Zaremski et al.18 investigated the solvent effect on several macro-

alkoxyamines and did not observe a striking effect of solvent

except for poly(acrylic acid)-SG1 based alkoxyamines for which

the C–ON bond homolysis rate constant was increased 20-times

Aix-Marseille Universit�e, CNRS, ICR, UMR 7273, case 551, AvenueEscadrille Normandie-Niemen, 13397 Marseille, Cedex 20, France.E-mail: sylvain.marque@univ-amu.fr

† For parts 1–3 see ref. 1–3.

This journal is ª The Royal Society of Chemistry 2012

from dioxane to formamide. Consequently, the solvent effect is

in general weak except for alkoxyamines exhibiting good H-

bonding properties. Thus, an investigation of the solvent effect

on alkoxyamines prone to solvent effects is timely.

In this report, we investigated the effect of 15 solvents covering

the main effects, i.e., polarity, solvation, intermolecular

hydrogen bonding, stabilization of the nitroxide with alkoxy-

amine 1 (Fig. 1), which is non-activated but capable of inter-

molecular hydrogen bonding with a hydrogen bond donor

(HBD) solvent, and with alkoxyamine 2, which is activated

(kd,2 z 19–27kd,1). We showed that the solvent effect was

ascribed to the stabilization of the nitroxide as well as that of TS

for 1 and 2.

Experimental section

Alkoxyamines 1 and 2were prepared as previously reported.1,3 kdvalues were measured in 15 solvents using 31P NMR with

TEMPO as an alkyl radical scavenger as reported and as

Fig. 1 Alkoxyamines investigated and structures of SG1(N-(2-

methylpropyl)-N-(1-diethylphosphono-2,2-dimethylpropyl)-N-oxyl) and

TEMPO (2,2,6,6-tetramethylpiperidin-N-oxyl) nitroxide.

Polym. Chem., 2012, 3, 2901–2908 | 2901

Fig. 2 Homolysis of alkoxyamines.

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exemplified in Fig. 2.1–3,19 0.1 ml of DMSO-d6 was used as a

deuterated solvent and (MeO)3PO was used as an internal

reference (31P NMR, d ¼ 0 ppm) for 0.6 ml of solution.

kd values were given by eqn (1), with C0 being the initial

concentration of alkoxyamine and t the time.19 The activation

energies Ea were given by eqn (2) with the frequency factor A ¼2.4 � 1014 s�1, T the temperature and the constant R ¼ 8.314 J�1

K�1 mol�1:20

lnC

C0

¼ �kdt (1)

kd ¼ Ae�Ea/RT (2)

Results

Alkoxyamine 1 is soluble in 14 over 15 solvents reported in Table

1 except water for which kd was measured in a mixture of water–

methanol (v/v: 1 : 1).2 Alkoxyamine 2 is soluble in the 15 solvents

reported in Table 1. A few examples of semi-log log(C/C0) vs. t

plots are displayed in Fig. 3a and b for 1 and 2, respectively. kdvalues for 1 and 2 are gathered in Tables 2 and 3, respectively.

The parameters selected for the correlations, i.e., the normalized

Reichardt solvent polarity parameter ENT,

21 the nitrogen hyper-

fine coupling constant aN,TEMPO and aN,SG1 of 4-amino

TEMPO22,23 and SG1,23 respectively, the intrinsic volume VX as

given by McGowan,24,25 the hydrogen bond donor (HBD)

a,21,24,26 the hydrogen bond acceptor (HBA) b,21,27 the polarity/

polarizability parameter p*,21,28 the relative permittivity 3r,28 the

cohesive pressure c,21,28 the molar volume VM,28 the refractive

Table 1 Values of nitrogen hyperfine coupling constants aN,TEMPO and aNsolvent VX, refractive index n, molar volume VM, relative permittivity 3r, cohes(HBD) parameter a, hydrogen bond acceptor (HBA) parameter b, polarity/term d

Solventa aN,TEMPOb,c aN,SG1

b,c ENTd Vx

e,f

1 n-Octane 15.22 13.50 0.012 123.62 n-Bu2O 15.36 13.50 0.071 129.53 TEG 15.30 13.62 0.682 118.94 t-BuPh 15.47 13.70 0.099i 113.9j

5 t-BuOH 15.91 13.90 0.389 73.16 t-BuPh–CH2Cl2 (v/v 1 : 1) 15.61 13.90 —k —k

7 NMF 15.77 14.10 0.722 50.68 DMF 15.67 13.90 0.386 58.19 EtOH 16.08 14.00 0.654 44.910 DCE 15.71 13.90 0.327 63.511 DMSO 15.77 13.80 0.444 61.312 F 16.20 14.40 0.775 36.513 H2O–MeOH (v/v 1 : 1) 16.72 14.50 0.710l —k

14 TFE 16.78 14.70 0.898 41.515 Water 16.99 14.90 1 16.7

a t-BuPh: tert-butylbenzene, DMF: N,N-dimethylformamide, DCE: 1,2-dichlotriethylene glycol, F: formamide, TFE: 2,2,2-trifluoroethanol. b See ref. 22 andMPa. i In toluene. j In cumene. k Not available. l In water–EtOH (v/v 20 : 80

2902 | Polym. Chem., 2012, 3, 2901–2908

index n,28 the discontinuous polarizability correction term d,21

and the solvent basicity parameter B as given by Koppel–Palm28

are listed in Table 1.

Correlations with non-specific properties of the solvent

The investigation of the effect of the conventional solvent

parameters such as m, 3r, h and n afforded only shotgun-like plots

(not shown) for both 1 and 2. Multiparameter correlations did

not improve the plots and the statistics.

Correlations with cybotactic29,30 parameters

As the non-specific properties of solvent (m, 3r, h, and n) were not

suitable to describe the reactivity reported, several cybotactic

parameters were investigated21,24,28 such as c (square of the

Hildebrand solubility parameter dH), ENT, VX, a, and aN, which is

known to probe the cybotactic effect at the nitroxyl moiety. The

cohesive pressure and the HBD properties afforded scattered

plots. VX afforded good correlations (R2 > 0.8, Tables 4 and 5)

for 1 and 2, which highlights the organization of the first solvent

layer around the products and the reactants. The good correla-

tions (R2 > 0.8, Tables 4 and 5) obtained for ENT suggested an

influence of the polarity of the solvent although data were still

scattered. When the reaction investigated involved a nitroxide,

aN,TEMPO values are often used to probe the solvent effect. Thus,

moderate to good correlations were observed for the aN,TEMPO

values conventionally used in the literature (Tables 4 and 5).22

However, in a recent work,23 we showed that the cybotactic

effect29,30 depended dramatically on the structure of the nitroxyl

moiety as well as on structure of the solvent. Hence, a 1.5-fold

higher slope was observed for aN,SG1 than for aN,TEMPO for 1,

whereas similar values were observed for 2. The good correla-

tions observed for aN,TEMPO and aN,SG1 mean that the stabili-

zation of the released nitroxide played a role in the increase of the

reactivity.

,SG1, normalized Reichardt polarity parameter ENT, intrinsic volume of

ive pressure c, Koppel–Palm basicity parameter B, hydrogen bond donorpolarizability parameter p*, and discontinuous polarizability correction

ng VMf,g 3r

g cd,g,h Bg ad bd p*d,g dd

1.39743 162.56 1.948 240.3 0 0 0 0.01 01.39925 169.3 3.080 250.4 285 0 0.46 0.18 01.45310 133.48 23.69 786.4 260 0.66i,j 0.69 0.88 01.49266 154.79 2.366 289.0 60 0 0.18j 0.41j 11.38779 93.95 12.47 461.8 247 0.42 0.93 0.41 0—k —k —k —k —k —k —k —k 11.43190 58.48 182.4 875 287 0.62 0.80 0.90 01.43050 77.4 36.71 613.6 294 0 0.69 0.88 01.36139 58.41 24.55 676 235 0.86 0.75 0.54 01.44480 80.16 10.36 396.4 40 0.09 0.10 0.82 0.51.41770 71.4 46.45 634.9 362 0 0.76 1 01.44754 39.54 109.5 368.6 270 0.71 0.48 0.97 0—k —k —k —k —k —k —k —k 01.29070 72.4e 26.67 573e —k 1.51 0 0.73 0.51.33300 18.0 78.36 2290 156 1.17 0.47 1.09 0

roethane, NMF: N-methylformamide, DMSO: dimethylsulfoxide, TEG:23. c In gauss. d See ref. 21. e See ref. 24. f In cm3 mol�1. g See ref. 28. h In).

This journal is ª The Royal Society of Chemistry 2012

Fig. 3 Plots of ln(C/C0) vs. t for t-BuOH (:), DMSO (;), formamide (A), DMF (+), and TFE (1) as solvents for the minor (left) and major (right)

diastereoisomers of 1 at ca. 80 �C (a) and 2 at 60 �C (b).

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The diastereoisomers of 1 and 2 experienced the same cybo-

tactic effect, as highlighted by very similar slopes (Tables 4 and

5). Indeed, for 1, the diastereomeric ratio of the homolysis rate

constants kd,minor/kd,major ranged from 0.94 to 1.13, except for

EtOH (0.68), DMSO (0.83), and TFE (1.33). For 2, these values

Table 2 kd values and activation energies Ea measured in solvents 1–14 andisomers of 1

SolventT(�C)

Minor isomer (RR/SS)a

kd (10�4 s�1)b Ea (kJ mol�1)c kd

0 (10�

1 80 1.6 122.8 1.32 80 1.6 122.8 1.33 80 2.4 121.6 2.04 85 2.5 121.5 1.6e

5 80 3.0 121.0 2.56f 80 3.1 120.9 2.67 80 3.6 120.5 3.08 79 3.3 120.4 3.19 79 3.6 120.4 3.110 80 4.0 120.2 3.311 80 4.0 120.2 3.312 80 4.7 119.7 4.013 80 5.6 119.4 4.514 80 7.0 118.4 6.4

a As defined in ref. 1. b Statistical error is less than 10%. c Estimated using tfrequency factor given in footnote c combined with the data in the fourthisomer. e Data averaged with those reported in ref. 1, Ea ¼ 123.0 kJ mol�1 fo

This journal is ª The Royal Society of Chemistry 2012

spanned a larger range, from 0.81 to 1.25, except for EtOH

(0.76), DMSO (0.67) and DMF (0.60). However, taking into

account the conventional error of 1 kJ mol�1 for Ea implies that

significance occurs for a ratio larger than 1.44 and smaller than

0.7. Consequently, these data will not be discussed further,

the re-estimated kd0 values at 60 �C for the minor and major diastereo-

Major isomer (RS/SR)a

5 s�1)d kd (10�4 s�1)b Ea (kJ mol�1)c kd

0 (10�5 s�1)d

1.5 123.0 1.21.6 122.8 1.32.3 121.8 1.92.3 121.8 1.5e

2.8 121.2 2.32.7 121.3 2.33.4 120.6 2.94.2 119.7 4.53.6 120.4 3.13.6 120.5 3.04.6 119.7 4.03.3 120.7 2.85.3 119.2 4.85.6 119.2 4.8

he average value of A ¼ 2.4 � 1014 s�1. See ref. 8. d Estimated using thecolumn for the minor isomer and the seventh column for the majorr both diastereoisomers. f Given in ref. 3.

Polym. Chem., 2012, 3, 2901–2908 | 2903

Table 3 kd values at 60�C and activation energies Ea measured in solvents 1–5, 7–12, 14, and 15 for the minor and major diastereoisomers of 2

Solvent

Minor isomer (RR/SS)a Major isomer (RS/SR)a

T (�C) kd (10�4 s�1)b Ea (kJ mol�1)c kd (10

�4 s�1)b Ea (kJ mol�1)c

1 60 3.4 113.8 3.7 113.92 60 3.4 113.8 4.2 113.23 60 4.5 113.0 4.2 113.24 61 3.7 113.9 4.1 113.65 60 4.4 113.1 4.3 113.17 60 5.3 112.6 6.4 112.08 60 4.4 113.1 7.3 111.79 60 5.7 112.4 7.5 111.610 60 5.3 112.6 6.2 112.111 60 4.9 112.8 7.3 111.712 60 6.0 112.2 4.8 112.814 60 8.4 111.3 6.9 111.815 60 7.0 111.8 7.3 111.7

a As defined in ref. 1. b Statistical error less than 10%. c Estimated using the average value of A ¼ 2.4 � 1014 s�1. See ref. 8.

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except that the low value of DMF and DMSO for 2might denote

a different solvation between the two diastereoisomers.

For each plot, some outliers are observed. Taking into account

that the accepted error on Ea values is around 1 kJ mol�1,

implying an error of 0.1 unit of log for kd, the outlying data

reported for the minor diastereoisomer of 2 forVX (3), aN,TEMPO,

and ENT are not significant.

Correlations with the Koppel–Palm21,28 and the Kalmet–Abboud–

Taft21 relationships

As mono-parameter correlations cannot describe perfectly our

results, multi-parameter relationships based on the Koppel–

Palm (KP) and the Kalmet–Abboud–Taft (KAT) relationships

(19) and (21), respectively, which are often used to investigate the

solvent effects, were tested.21,28 The KP relationship is a 6

parameter relationship combining two non-specific parameters

(the polarizability parameter given by (n2 � 1)/(2n2 + 1) or

(n2 � 1)/(n2 + 2) based on the refractive index n and the Kirk-

wood function21 given by (3r � 1)/(23r + 1) or (3r � 1)/(3r + 2)

based on the relative permittivity 3r) and four cybotactic

parameters: the solvent basicity parameter B, the normalized

Reichardt polarity solvent ENT, the Hildebrand’s solubility

parameter d, and the molar volume VM of the solvent:

Table 4 Linear correlations y ¼ a + bx for log(kd0 s�1) vs. cybotactic param

minor diastereoisomers of 1 and 2 and their subsequent statistical outputs

Equation Alkoxyamine Parameter y-Intercepta

3 1 VX �4.25 (5)4 2 VX �3.14 (2)5 1 EN

T �4.82 (5)6 2 EN

T �3.48 (2)7 1 aN,TEMPO �10.34 (90)8 2 aN,TEMPO �7.14 (56)9 1 aN,SG1 �11.81 (78)10 2 aN,SG1 �6.84 (51)

a In parentheses are errors given on the last digit. b Square of the linear redisplayed in Fig. 4.

2904 | Polym. Chem., 2012, 3, 2901–2908

log kd0 ¼ log kd,0

0 + a1f(n2) + a2f(3) + a3B + a4d

2

+ a5ENT + a6VM (19)

For both 1 and 2, none of the possible combinations of the KP

relationship parameters afforded significant statistical outputs

(i.e., R2 < 0.7, F-test < 95%, and t-test < 90%), implying that the

reported reactivity cannot be described by the conventional

parameters. The modified KP relationship (20) for which the

cybotactic parameters (B, d, ENT, and VM) were replaced by

aN,SG1 (vide infra) was applied. Only the bi-parameter equation

involving the relative permittivity 3r (Kirkwood function) and the

nitrogen hyperfine coupling constant of SG1, aN,SG1, for 1

afforded significant statistics. The positive slopes observed for

f(3r) and aN,SG1 mean that polar solvents stabilize the products or

TS more than the reactants. However, KP relationships failed to

describe the data for the major diastereoisomer of 2.

log kd0 ¼ log kd;0

0 þ a23r � 1

23r þ 1þ a7aN;SG1 (20)

Solvent effects are also described by the KAT relationship (21)

relying on 4 cybotactic parameters: the polarity/polarizability

term p*, the discontinuous polarizability correction term d, the

HBA (basicity) b and the HBD (acidity) a. Indeed, the KAT

relationship describes the solvent effect using cybotactic

eters (VX, ENT, aN,TEMPO and aN,SG1) in various solvents at 60 �C for the

Slopea R2b Nc SDd Outlierse

�0.0044 (5) 0.87 11 0.06 3, 14�0.0028 (3) 0.94 11 0.03 14

0.60 (10) 0.79 12 0.10 30.32 (4) 0.90 11 0.04 3, 140.36 (6) 0.77 14 0.10 No0.24 (4) 0.83 12 0.05 150.52 (6) 0.88 13 0.08 110.25 (4) 0.81 13 0.05 No

gression coefficient. c Number of data. d Standard deviation. e Outliers

This journal is ª The Royal Society of Chemistry 2012

Fig. 4 Linear correlations for log(kd s�1) vs. cybotactic parameters (from top to bottom: VX, E

NT, aN,TEMPO and aN,SG1) for the minor (left) and the

major (right) diastereoisomers of 1 (-, C) and 2 (:, ;) at 60 �C in various solvents (see Tables 1–3). Empty symbols are for outliers.

This journal is ª The Royal Society of Chemistry 2012 Polym. Chem., 2012, 3, 2901–2908 | 2905

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Table 5 Linear correlations y ¼ a + bx for log(kd0 s�1) vs. cybotactic parameters (VX, E

NT, aN,TEMPO and aN,SG1) in various solvents at 60 �C for the

major diastereoisomers of 1 and 2 and their subsequent statistical outputs

Equation Alkoxyamine Parameter y-Intercepta Slopea R2b Nc SDd Outlierse

11 1 VX �4.17 (7) �0.0050 (8) 0.85 11 0.08 1212 2 VX �3.03 (4) �0.0031 (5) 0.79 11 0.06 10, 1213 1 EN

T �4.80 (7) 0.53 (13) 0.62 12 0.13 314 2 EN

T �3.45 (4) 0.27 (6) 0.74 9 0.06 8–1115 1 aN,TEMPO �9.90 (72) 0.33 (5) 0.85 12 0.08 8, 1116 2 aN,TEMPO �5.91 (36) 0.16 (2) 0.90 8 0.04 7–1117 1 aN,SG1 �10.85 (84) 0.45 (6) 0.85 12 0.08 8, 1118 2 aN,SG1 �6.13 (75) 0.20 (5) 0.69 8 0.06 8–11

a In parentheses are errors given on the last digit. b Square of the linear regression coefficient. c Number of data. d Standard deviation. e Outliersdisplayed in Fig. 4.

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parameters in contrast to the KP relationship for which the non-

specific properties of the solvent (n and 3r) are described by the

cybotactic parameter p*.

log kd0 ¼ log kd,0

0 + a2(p* + d � d) + a7a + bb (21)

Statistical analysis showed that d as well as b were non-

significant as both 1 and 2 did not carry ‘‘acidic’’ protons.

Correlations were good for 1 and sufficiently good for 2 using p*

and a as parameters. The slopes of p* and a are positive,

implying that kd0 increased with the polarity/polarizability and

the HBD properties of solvent, and that consequently products

or TS were better stabilized than the starting materials. However,

the outliers are different from those reported in Tables 4 and 5

(for aN,TEMPO and aN,SG1) which means that the KAT relation-

ship does not account for the results correctly.

Discussion

It is commonly accepted that an increase of rate constant is due

to the stabilization of TS or product by the solvent.21 Hence, the

negative slopes of VX and the positive slopes of ENT, aN, and

aN,SG1 implied that its effect both on TS and on the products was

greater than its effect on the starting materials.

Correlations showed that the physical properties of the

solvents as well as the KP relationship were not able to describe

correctly the reactivity reported for 1 and 2, implying that this

reactivity was more related to the effect of the first layer of

solvent (cybotactic effect). The parameter VX is used to describe

the effect of the size of the solvent on the solvation of the solute.24

Hence, the negative slopes reported for the plot of log kd against

Table 6 Coefficients and statistical outputs for the KP and KAT relationsh

Eqn Type log(kd0 s�1)a a2

a t-Testb

22 1g KPh �10.88 (68) 0.55 (20)i,j 96.5723 1l KPh �10.50 (94) 0.50 (23)i,j 92.2724 2g KPh �5.59 (44) 0.47 (12)i,m 99.6025 1g KAT �4.90 (3) 0.43 (5)i,o 99.9926 1l KAT �4.94 (3) 0.56 (4)i,q 99.9927 2g KAT �3.49 (2) 0.15 (4)i,s 99.80

a In parentheses are errors given on the last digit. b Student’s t-test. c Squarf Student–Fischer F-test given at 99.99% confidence. g Minor diastereoisoestimated with equations given in ref. 20. j wf(3r)

¼ 24%. k waN,SG1 ¼ 76%. l

p wa ¼ 47%. q wp* ¼ 69%. r wa ¼ 31%. s wp* ¼ 37%. t wa ¼ 63%.

2906 | Polym. Chem., 2012, 3, 2901–2908

VX point to products being better solvated by small molecules

than by large ones. The positive slopes of the plot of log kdagainst EN

T (Fig. 4) show that the higher the solvent polarity the

larger kd meaning that either TS or products are more stabilized

than the starting materials for both 1 and 2. Interestingly, the

effect of the solvent polarity is larger for 1 than for 2, as given by

their respective slopes. In the past, we reported that kd values

increased with the increasing stabilization of the nitroxide.20,31

The importance of the stabilization of the nitroxide is readily

probed by investigating the effect of the solvent polarity on the

aN values, that is, the higher the solvent polarity ENT the higher

the aN values, and hence, the more stabilized the nitroxide, as the

zwitterionic mesomeric form B is favoured over the non-polar

mesomeric form A (Fig. 6).32

In a recent work,23 we showed that the cybotactic effect was

dramatically dependent on the structure of the nitroxide as well

as on the solvent. The positive slopes of the plots of aN,SG1 (or

aN,TEMPO) against log kd0 show that the higher the aN,SG1 (or

aN,TEMPO) values, the more stabilized the nitroxide, and the

higher kd values, confirming the importance of the nitroxide

stabilization effect on the C–ON bond homolysis event. As the

homolysis of both 1 and 2 released the same nitroxide SG1, one

would expect the same slope, in contrast with the difference

observed. The smaller slope for 2 than for 1 is due to stronger

stabilization of the starting materials for 2 than for 1, which

partly balances the effect of the stabilization of the nitroxide.

To get deeper insight into the solvent effects, modified and

conventional KP relationships (eqn (19) and (20), respectively)

were tested and afforded strikingly different results. For

example, the conventional KP relationship failed for both dia-

stereoisomers of both 1 and 2 whereas the modified KP

ips for 1 and 2

a7a t-Testb R2c SDd Ne F-Testf

0.44 (5)i,k 99.98 0.97 0.05 9 930.38 (7)i,k 99.827 0.93 0.06 9 400.15 (3)i,n 99.82 0.90 0.04 12 400.23 (3)i,p 99.97 0.95 0.05 10 730.15 (3)i,r 99.92 0.97 0.04 9 1290.17 (2)i,t 99.99 0.93 0.04 12 56

e of the regression coefficient. d Standard deviation. e Number of data.mer. h Modified KP relationship (20). i Weight of the coefficient wX

Major diastereoisomer. m wf(3r)¼ 45%. n waN,SG1 ¼ 55%. o wp* ¼ 53%.

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Fig. 5 Plots of the improved KP (a) and of the KAT (b) relationships for the minor (-) and the major (C) diastereoisomers of 1, and the minor (:)

diastereoisomer of 2. Empty symbols are for outliers.

Fig. 6 Mesomeric forms of the nitroxyl moiety.

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relationship improved the statistics of the mono-parameter

correlation for aN,SG1 when the Kirkwood function of 3r was

applied to 1 and to the minor diastereoisomer of 2 (Table 6 eqn

(22)–(24), Fig. 5a). Moreover, the weight of each effect was

different for 1 and 2, i.e., for 1 wf(3r)¼ 24% and waN,SG1 ¼ 76%

whereas for 2, wf(3r)¼ 45% and waN,SG1 ¼ 55%. Values of aN are

known to encompass several solvent effects such as the polarity

and the HBD a effects of the solvent. Hence, the extra effect of

the polarity (f(3r)) might be due to extra stabilization at TS which

would be the same for 1 and 2. On the other hand, one would

expect the same stabilization effect for 1 and 2 as it is the same

nitroxide which is released. Consequently, the modified KP

relationship did not afford straightforward discussion about the

solvent effects.

As aN,TEMPO and aN,SG1 values encompass the effect described

by p* and a – the polarity/polarizability and the HBD properties

of the solvent, respectively, both favouring the form B over the

Fig. 7 Energy diagram describing the occurrence of p* (in red) and a (in

blue) effects.

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form A (Fig. 6), the KAT relationship (20) was tested with all

parameters. Only the aforementioned parameters afforded

statistically significant results (Table 6, eqn (25)–(27), Fig. 5b).

Interestingly, the HBD effects of solvents were nearly the same

for the minor and the major diastereoisomers of 1 whereas the

polarity/polarizability p* effect was clearly larger for the major

diastereoisomer of 1, implying a 69% and 31% distribution for p*

and a of the major diastereoisomer, respectively, and a roughly

50% distribution for the minor diastereoisomer. As only SG1 was

released as nitroxide, the same p* and a effects were expected,

which was roughly observed for a. Consequently, as the slope of

p* was positive, this extra polarity effect should be ascribed to a

better stabilization at TS due to better solvation for the major

diastereoisomer of 1. This denotes a polar character (likely

appearance of partial charges) at TS. Consequently, the stabili-

zation at TS depends on the configuration of the alkoxyamine.

Although the slope of the a effect for 2 was very similar to that

reported for 1, as expected, its weight (63%) was greater.

However, a clear 2.5–3.5-fold decrease was observed for the slope

of the p* effect, implying a lower stabilization at TS. For the

same configuration (minor diastereoisomer) of 1 and 2, no

conformational changes were expected upon oxidation of 1 into

2. Consequently, the N+–O� moiety decreased the difference in

solvation between TS and products implying an increase in Ea.

The good correlations observed for aN,SG1 for 1 and 2 suggest

weak effect of the alkyl fragment when the solvent is varied.

Moreover, the main effect of the alkyl fragment is expected to be

due to the H-bonding between HBD solvents and either the

nitrogen lone pair of the pyridyl fragment of 1 or the oxygen lone

pairs of the N+–O� moiety of 2. As the values for the coefficient

of a are very close for 1 and 2, the effect of HBD solvent is either

the same for both alkyl fragments or the same for starting

materials and products.

Conclusion

Solvent effects are larger at TS and on products than on the

reactant as p*, (HBD) a, and aN,SG1 exhibit positive slopes

(Fig. 7). It should be noted that the a effect occurred mainly for

the nitroxide as highlighted by the good correlations between kd

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and aN,SG1. This study shows that the C–ON bond in alkoxy-

amines 1 and 2 experiences very different cybotactic effects (rc)

which depend both on the diastereoisomers and alkoxyamines,

that is, for the minor and the major diastereoisomers of 1 (rc ¼kd,TFE

0/kd,n-octane0) from n-octane to TFE rc ¼ 8 and rc ¼ 4,

respectively, whereas for 2 rc ¼ 2.5 and rc ¼ 1.9 from n-octane to

ethanol (rc ¼ kd,EtOH0/kd,n-octane0), respectively. This means that

the two diastereoisomers did not experience the same cybotactic

effect and that this effect also depends on the type of alkoxy-

amine. However, the cybotactic effect did not exceed a factor 3

for these alkoxyamines which are prone to solvent effects (lone

pair for H-bonding, strongly polar), meaning that for most of the

alkoxyamines the solvent effect is expected to be weak as already

reported for SG1 derivatives.11,18 Furthermore, our results are

very well in agreement with the investigations of the solvent

effect on poly(3-vinylpyridine)-TEMPO based alkoxyamines.12,13

Notes and references

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2 Part 2: E. Bagryanskaya, P. Br�emond, M. Edeleva, S. R. A. Marque,D. Parkhomenko, V. Roubaud and D. Siri, Macromol. RapidCommun., 2012, 33, 152–157.

3 Part 3: P. Br�emond, A. Ko€ıta, S. R. A.Marque, V. Pesce, V. Roubaudand D. Siri, Org. Lett., 2012, 14, 358–361.

4 D. H. Solomon, E. Rizzardo and P. Cacioli, 1985, EP, Appl. 135280;D. H. Solomon, E. Rizzardo and P. Cacioli,US Pat., 4,581,429, 1986;D. H. Solomon, E. Rizzardo and P. Cacioli, Chem. Abstr., 1985, 102,221335q.

5 M. K. Georges, R. P. N. Veregin, P. M. Kazmaier and G. K. Hamer,Macromolecules, 1993, 26, 2987–2988.

6 S. Marque and D. Gigmes, Nitroxide-mediated Polymerization and itsApplications in Encyclopedia of Radicals in Chemistry, Biology andMaterials, ed. C. Chatgilialoglu and A. Studer, John Wiley & SonsLtd, Chichester, UK, 2012, pp. 1813–1850.

7 D. Bertin, D. Gigmes, S. R. A. Marque and P. Tordo, Chem. Soc.Rev., 2011, 40, 2189–2198.

8 D. Bertin, D. Gigmes and S. R. A. Marque, Recent Res. Dev. Org.Chem., 2006, 10, 63–121.

9 L. Tebben andA. Studer,Angew.Chem., Int. Ed., 2011, 50, 5034–5068.10 G. Moad and E. Rizzardo, Macromolecules, 1995, 28, 8722–8728.

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11 O. Guerret, J.-L. Couturier, F. Chauvin, H. El-Bouazzy, D. Bertin,D. Gigmes, S. Marque, H. Fischer and P. Tordo, ACS Symp. Ser.,2003, 854, 412–423.

12 X. Z. Ding, A. Fischer, A. Brembilla and P. Lochon, J. Polym. Sci.,Part A: Polym. Chem., 2000, 38, 3067–3073.

13 X. Z. Ding, A. Fischer, S. W. Yang, P. Wu, A. Brembilla andP. Lochon, Eur. Polym. J., 2001, 37, 1561–1569.

14 M. Chenal, S. Mura, C. Marchal, D. Gigmes, B. Charleux, E. Fattal,P. Couvreur and J. Nicolas, Macromolecules, 2010, 43, 9291.

15 K. H. Kuo, W. Y. Chiu and K. C. Cheng, Polym. Int., 2008, 57, 730.16 D.W. Grattan, D. J. Carlsson and J. A. Howard,Can. J. Chem., 1979,

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Polym. Sci., Part A: Polym. Chem., 2012, 50, 3437–3443.19 D. Bertin, D. Gigmes, S. Marque and P. Tordo, e-Polym., 2003, 2, 1–

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Macromolecules, 2005, 38, 2638–2650.21 C. Reichardt and T. Welton, Solvent and Solvent Effect in Organic

Chemistry, Wiley-VCH, 4th edn, 2011.22 B. Knauer and J. J. Napier, J. Am. Chem. Soc., 1976, 98, 4395–4400.23 G. Audran, P. Br�emond, S. R. A. Marque and G. Obame,

ChemPhysChem, 2012, in press.24 Y. Marcus, ‘‘The Properties of Solvents’’ in Solution Chemistry, John

Wiley & Sons, Chichester, 1998, vol. 4.25 J. C. McGowan, J. Appl. Chem. Biotechnol., 1978, 28, 599.26 M. H. Abraham, P. L. Grellier, D. V. Prior, P. P. Duce, J. J. Morris

and P. J. Taylor, J. Chem. Soc., Perkin Trans. 2, 1989, 699–711.27 M. H. Abraham, P. L. Grellier, D. V. Prior, J. J. Morris and

P. J. Taylor, J. Chem. Soc., Perkin Trans. 2, 1990, 521–529.28 G. E. Zaikov, R. G. Makitra, G. G. Midyana and L. I. Bazylyak,

‘‘Influence of the Solvent on Some Radical Reaction’’ in ChemistryResearch and Applications Series, Nova Science Publishers Inc.,New York, 2010.

29 As quoted by Reichardt (ref. 21): ‘‘A cybotactic region may be definedas the volume around a solute molecule in which the ordering of thesolvent molecules has been influenced by the solute, including boththe first solvation shell and the transition region’’ see ref. 30.Several parameters are used to describe the related effects

30 E. M. Kosower, ‘‘An Introduction to Physical Organic Chemistry’’,Wiley, New York, 1968.

31 H. Fischer, A. Kramer, S. R. A. Marque and P. Nesvadba,Macromolecules, 2005, 38, 9974–9984.

32 H. Karoui, F. Le Moigne, O. Ouari and P. Tordo, in Stable Radicals:Fundamentals and Applied Aspects of Odd-Electron Compounds, ed. R.Hicks, John Wiley & Sons, 2010, pp. 173–229.

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