Development of a universal alkoxyamine for "living" free radical polymerizations

Article abstract of DOI:10.1021/ja984013c

Examination of novel alkoxyamines has demonstrated the pivotal role that the nitroxide plays in mediating the "living" or controlled polymerization of a wide range of vinyl monomers. Surveying a variety of different alkoxyamine structures led to α-hydrido derivatives based on a 2,2,5-trimethyl-4-phenyl-3-azahexane-3-oxy, 1, skeleton which were able to control the polymerization of styrene, acrylate, acrylamide, and acrylonitrile based monomers. For each monomer set, the molecular weight could be controlled from 1000 to 200 000 amu with polydispersities typically 1.05-1.15. Block and random copolymers based on combinations of the above monomers could also be prepared with similar control. In comparison with 2,2,6,6-tetramethylpiperidinoxy (TEMPO), these new systems represent a dramatic increase in the range of monomers that can be polymerized under controlled conditions and overcome many of the limitations associated with nitroxide-mediated "living" free radical procedures. Monomer selection and functional group compatibility now approach those of ATRP-based systems.

Full text of DOI:10.1021/ja984013c

3904
J. Am. Chem. Soc. 1999, 121, 3904-3920
Development of a Universal Alkoxyamine for “Living” Free Radical
Polymerizations
Didier Benoit,† Vladimir Chaplinski,‡ Rebecca Braslau,*,‡ and Craig J. Hawker*,†
Contribution from the IBM Almaden Research Center, NSF Center for Polymeric Interfaces and
Macromolecular Assemblies, 650 Harry Road, San Jose, California 95120-6099, and Department of
Chemistry and Biochemistry, UniVersity of California, Santa Cruz, California 95064
ReceiVed NoVember 20, 1998
Abstract: Examination of novel alkoxyamines has demonstrated the pivotal role that the nitroxide plays in
mediating the “living” or controlled polymerization of a wide range of vinyl monomers. Surveying a variety
of different alkoxyamine structures led to R-hydrido derivatives based on a 2,2,5-trimethyl-4-phenyl-3-azahexane-
3-oxy, 1, skeleton which were able to control the polymerization of styrene, acrylate, acrylamide, and acrylonitrile
based monomers. For each monomer set, the molecular weight could be controlled from 1000 to 200 000 amu
with polydispersities typically 1.05-1.15. Block and random copolymers based on combinations of the above
monomers could also be prepared with similar control. In comparison with 2,2,6,6-tetramethylpiperidinoxy
(TEMPO), these new systems represent a dramatic increase in the range of monomers that can be polymerized
under controlled conditions and overcome many of the limitations associated with nitroxide-mediated “living”
free radical procedures. Monomer selection and functional group compatibility now approach those of ATRP-
based systems.
Introduction
nitroxide-mediated processes4 and atom transfer radical proce-
dures (ATRP).5 In both strategies, the synthesis of functionalized
unimolecular initiators6 permits the preparation of a wide range
of different materials which are either difficult to prepare or
not available via other polymerization processes. For example,
the architecture or topology of the polymer (i.e., comb, star,
dendritic, etc.),7 composition of the backbone (i.e., random,
gradient, or block copolymer),8 inclusion of functionality (i.e.,
chain-end, site-specific, etc.)9 can all be readily manipulated
using living free radical methodologies while still retaining a
high degree of control over the molecular weight and polydis-
The desire to prepare advanced materials with new and/or
improved properties is a continuing focus in many academic
and industrial laboratories. The driving force is the belief that
these materials will offer substantial benefits in areas ranging
from microelectronic fabrication, to catalyst design, to biotech-
nology. In the macromolecular arena, a common feature of many
of these new materials is their well-defined nature with the
number of functional groups, molecular weight, polydispersity,
and the presence or absence of branching being precisely
controlled.1 Traditionally, such well-defined macromolecules
were only available from living procedures,2 such as anionic
polymerization, which are synthetically challenging and not
amenable to significant changes in the structure of the macro-
molecule, or the presence of functional groups. For example,
simple random copolymers of styrene and methyl methacrylate
cannot be prepared by living anionic procedures. Conversely,
these random copolymers are trivially prepared using traditional
free radical chemistry; however, the level of control is severely
compromised leading to ill-defined, polydisperse materials. The
desire to develop a simple and versatile method for the
preparation of wide variety of well-defined polymeric materials
has continued unabated, resulting in the recent development of
“living” free radical polymerization techniques.
(4) Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer, G. K.
Macromolecules 1993, 26, 2987; Hawker, C. J.; Barclay, G. G.; Orellana,
A.; Dao, J.; Devonport, W. Macromolecules 1996, 29, 5245; Hammouch,
S. O.; Catala, J. M. Macromol. Rapid Commun. 1996, 17, 149; Li, I. Q.;
Howell, B. A.; Koster, R. A.; Priddy, D. B. Macromolecules 1996, 29, 8554;
Fukuda, T.; Terauchi, T.; Goto, A.; Ohno, K.; Tsujii, Y.; Yamada, B.
Macromolecules 1996, 29, 6393; Moad, G.; Rizzardo, E. Macromolecules
1995, 28, 8722; Odell, P. G.; Veregin, R. P. N.; Michalak, L. M.; Georges,
M. K. Macromolecules 1997, 30, 2232.
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Wang, J. S.; Matyjaszewski, K. J. Am. Chem. Soc. 1995, 117, 5614; Patten,
T. E.; Xia, J.; Abernathy, T.; Matyjaszewski, K. Science 1996, 272, 866;
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Granel, C.; DuBois, P.; Jerome, R.; Teyssie, P. Macromolecules 1996, 29,
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1998, 31, 6715; Percec, V.; Barboui, B.; van der Sluis, M. Macromolecules
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K. Macromolecules 1998, 31, 5958.
The field of living free radical polymerization3 has expanded
rapidly in recent years with major advances occurring in both
* To whom correspondence should be addressed.
† NSF Center for Polymeric Interfaces and Macromolecular Assemblies.
‡ University of California at Santa Cruz.
(1) Webster, O. W. Science 1994, 251, 887; Fre´chet, J. M. J. Science
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10.1021/ja984013c CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/10/1999

Alkoxyamine for Controlled Polymerizations
J. Am. Chem. Soc., Vol. 121, No. 16, 1999 3905
persity. Similar capabilities have also been reported for the
recently introduced radical addition and fragmentation technique
(RAFT).10
Scheme 1
In many respects, all of the living free radical techniques
(nitroxide, ATRP, RAFT) are similar in their overall scope,
although there are a number of subtle differences which affect
the applicability and suitability of each system for specific
applications. For example, nitroxide-mediated processes are
potentially simpler since they do not require an added metal
complex and this absence leads to a greater functional group
tolerance and easier purification (no metal ion contamination).
However, the major limitation of nitroxide-mediated procedures
is their incompatibility with most vinyl monomer families.
Typically, these are limited to styrene-based systems, and the
level of control afforded to homopolymerization of acrylate/
methacrylates and even random copolymers with high acrylates/
methacrylate levels has been poor.11 In contrast, ATRP tech-
niques have been successfully applied to a wide range of
monomer families, including styrenics, acrylates, methacrylates,
and acrylonitrile. To greatly extend the field of living free radical
polymerization, the development of a nitroxide-based system
for the controlled polymerization of nonstyrenic monomers is
therefore highly desirable.
Initial efforts to develop such a system has relied on the use
of nitroxides other than 2,2,6,6-tetramethylpiperidinoxy (TEMPO)
as the mediating radical. The Xerox group has polymerized
acrylates at 145-155 °C in the presence of 4-oxo-TEMPO, 2,
as the mediating nitroxide, and while this is a significant
improvement when compared to TEMPO, polydispersities were
still between 1.40 and 1.67.12 More recently, the same group
has introduced the use of reducing additives such as hydroxy-
acetone as a method for controlling the concentration of free
nitroxide in these systems.13 A significant increase in the rate
of polymerization is observed; however, polydispersities are still
between 1.40 and 1.95. The most successful approach to
overcoming this limitation is the introduction of the phosphonate
derivative, 3, by Gnanou and Tordo14 for the controlled
polymerization of acrylates. In this seminal report, an initiating
system consisting of a 2.5:1 mixture of 3 and AIBN gave poly-
(acrylates) with polydispersities as low as 1.11. Interestingly,
the structure of 3 is significantly different from that of other
nitroxides that have been examined. This suggests that the
nitroxide structure plays a crucial role in the success or failure
of living free radical polymerizations, and the key to extending
the scope of this reaction is in designing more effective
nitroxides. On the basis of these pioneering results, we have
explored a range of different nitroxides and their associated
alkoxyamines in an effort to develop a universal system suitable
for the polymerization of a significantly wider selection of
monomers than is currently available. Such a system would be
analogous to the sulfonyl halides that have been introduced by
Percec as universal initiators for ATRP.15
(7) Weimer, M. W.: Gitsov, I. Fre´chet, J. M. J. J. Polym. Sci.: Polym.
Chem. Part A: 1998, 36, 955; Gaynor, S. G.; Edelman, S.; Matyjaszewski,
K. Macromolecules 1996, 29, 1079; Matyjaszewski, K.; Gaynor, S. G.;
Kulfan, A.; Podwika, M. Macromolecules 1997, 30, 5192; Hawker, C. J.
Angew Chem., Int. Ed. Engl. 1995, 34, 1456; Grubbs, R. B.; Hawker, C. J.;
Dao J.; Fre´chet, J. M. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 270;
Hawker, C. J.; Mecerreyes, D.; Elce, E.; Dao, J.; Hedrick, J. L.; Barakat,
I.; Dubois, P.; Jerome, R.; Volksen, W. Macromol. Chem. Phys. 1997, 198,
155; Puts, R. D.; Sogah, D. Y. Macromolecules 1997, 30, 7050; Stehling,
U. M.; Malmstrom, E. E.; Waymouth, R. M.; Hawker, C. J. Macromolecules
1998, 31, 4396.
Results and Discussion
A range of structurally diverse alkoxyamines were employed
in this study. These were prepared from the corresponding
nitroxides, many of which were available from the earlier work
of Braslau et al.16 in examining the stereoselective coupling of
chiral nitroxides with prochiral carbon radicals.
(8) Kazmaier, P. M.; Daimon, K.; Georges, M. K.; Hamer, G. K.;
Veregin, R. P. N. Macromolecules 1997, 30, 2228; Li, I. Q.; Howell, B.
A.; Dineen, M. T.; Kastl, P. E.; Lyons, J. W.; Meunier, D. M.; Smith, P.
B.; Priddy, D. B. Macromolecules 1997, 30, 5194; Chen, X.; Gao, B.; Kops,
J.; Batsberg, W. Polymer 1998, 39, 911; Hawker, C. J.; Elce, E.; Dao, J.;
Volksen, W.; Russell, T. P.; Barclay, G. G. Macromolecules 1996, 29, 4167;
Schmidt-Naake, G.; Butz, S. Macromol. Rapid Commun. 1996, 17, 661;
Wei, Y.; Connors, E. J.; Jia, X.; Wang, C. J. Polym. Sci., Part A: Polym.
Chem. 1998, 36, 761; Yoshida, E.; Sugita, A. Macromolecules 1996, 29,
6422; Muhlebach, A.; Gaynor, S. G.; Matyjaszewski, K. Macromolecules
1998, 31, 6046; Hawker, C. J.; Hedrick, J. L.; Malmstrom, E. E.; Trollsas,
M.; Mecerreys, D.; Dubois, Ph.; Jerome, R. Macromolecules 1998, 31, 213.
(9) Kim, C. S.; Oh, S. M.; Kim, S.; Cho, C. G. Macromol. Rapid
Commun. 1998, 19, 191; Haddleton, D. M.; Waterson, C.; Derrick, P. J.;
Jasieczek, C. B.; Shooter, A. J. J. Chem. Soc., Chem. Commun. 1997, 683;
Hawker, C. J.; Hedrick, J. L. Macromolecules 1995, 28, 2993; Baumert,
M.; Mulhaupt, R. Macromol. Rapid Commun. 1997, 18, 787; Matyjaszewski,
K.; Nakagawa, Y.; Gaynor, S. G. Macromol. Rapid Commun. 1997, 18,
1057; Nakagawa, Y.; Matyjaszewski, K. Polymer J. 1998, 30, 138.
(10) Chiefari, J.; Chong, Y. K.; Ercole, F.; Krstina, J.; Jeffery, J.; Le, T.
P. T.; Mayadunne, R. T. A.; Meijs, G. F.; Moad, C. L.; Moad, G.; Rizzardo,
E.; Thang, S. H. Macromolecules 1998, 31, 5559.
A synthetic strategy was developed for the synthesis of a
series of acyclic R-hydrogen bearing nitroxides, 4, which were
prepared from the corresponding tertiary nitro compounds and
aldehydes according to Scheme 1. On the basis of the earlier
work of Gnanou and Tordo, these were considered prime
candidates due to their lower stability compared to traditional
nitroxides such as TEMPO. Reductive condensation of 2-meth-
yl-2-nitropropane, 6, with a range of aldehydes gave the desired
nitrones, 5, in a single high-yielding step, which obviates the
(13) Colombani, D.; Steenbock, M.; Klapper, M.; Mullen K. Macromol.
Rapid Commun. 1997, 18, 243; Thang, S. H.; Chong, B. Y. K.; Ercole, F.;
Moad, G.; Rizzardo, E.; Anderson, A. G. Proc. 37th IUPAC Macromol.
Symp. 1998, 236.
(14) Benoit, D.; Grimaldi, S.; Finet, J. P.; Tordo, P.; Fontanille, M.;
Gnanou, Y. Polym. Prepr. 1997, 38, 729; Benoit, D.; Grimaldi, S.; Finet,
J. P.; Tordo, P.; Fontanille, M.; Gnanou, Y. ACS Symposium Series 685;
Matyjaszewski, K. Ed.; American Chemical Society: Washington, DC,
1998; p 225.
(11) Listigovers, N. A.; Georges, M. K.; Odell, P. G.; Keoshkerian, B.
Macromolecules 1996, 29, 8992.
(15) Percec, V.; Barboui, B.; Kim, H. J. J. Am. Chem. Soc. 1998, 120,
305.
(12) Keoshkerian, B.; Georges, M. K.; Quinlan, M.; Veregin, R.;
Goodbrand R. Macromolecules 1998, 31, 7559.
(16) Braslau, R.; Burrill, L. C., II; Mahal, L. K.; Wedeking, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 237.

3906 J. Am. Chem. Soc., Vol. 121, No. 16, 1999
Benoit et al.
Scheme 2
need to isolate the easily oxidizable alkyl hydroxylamine
intermediates. Addition of a variety of aryl Grignards according
to the method of Reznikov and Volodarsky,17 followed by
copper(II) catalyzed oxidation under ambient atmosphere re-
sulted in the formation of the desired nitroxides 4.
should substantially decrease the stability of the corresponding
nitroxide, 14. By using the same procedure as above, 2-nitro-
propane, 15, was condensed with either isobutyryl aldehyde or
trimethylacetaldehyde to give the nitrone derivatives, 16-17,
in good yield. Unfortunately, the treatment of 16-17 with
phenylmagnesium bromide followed by copper-catalyzed oxida-
tion did not yield isolatable amounts of the nitroxides, 14a-b.
In the case of the isopropyl nitrone, 16, no product was observed,
while for the sterically more demanding tert-butyl nitrone, 17,
the corresponding nitroxide could be observed by TLC but was
not sufficiently stable to be isolated by chromatography or
stored. To overcome the instability of these nitroxides, the
intermediate hydroxyamines, 18, were not oxidized with copper
and air but were instead used directly in the formation of the
alkoxyamines. In this way the hydroxyamines are oxidized in
situ by PbO2 to give the unstable nitroxides which can be trapped
to give the alkoxyamines, 41-42. This strategy proved suc-
cessful and the desired alkoxyamines could be prepared, purified
and stored under normal conditions (Scheme 3).
In the above strategies, a variety of aryl Grignard reagents
can be used in the addition step; however, the yield of nitroxide
obtained for sterically demanding Grignards, such as 2,4,6-
trimethylphenylmagnesium bromide, was significantly decreased
(ca. 25%), presumable due to steric congestion. Interestingly,
attempts to extend this protocol to the Grignard reagent derived
from bromopentafluorobenzene (Scheme 4) did not result in the
perfluoroaryl nitroxide, 19, but rather in the fused ring com-
pound 20, which presumably derives from a [2 + 3] dipolar
addition to a benzyne intermediate.
An improved procedure for the phosphonate nitroxide 2, first
described by Tordo et al.,21 was also developed due to
difficulties experienced in following the reported procedures.
Addition of diethyl phosphite to the imine, 21 (prepared by
condensation of pivalaldehyde with N-tert-butylamine) gave the
amino derivative, 22, which was oxidized with mCPBA to give
the nitroxide, 3, in 24% overall yield (Scheme 5).
Synthesis of the alkoxyamine initiators from these nitroxides
was then accomplished by two different methodologies. The
nitroxide, 23, could be coupled with the 1-phenethyl radical
generated from PbO2 oxidation of 1-phenethyl hydrazine as
detailed recently by Braslau.22 Alternatively, the nitroxide, 23,
could be added to styrene in the presence of Jacobsen’s reagent
While 2-methyl-2-nitropropane, 6, was primarily used as a
starting material, the greater availability of 2-methyl-2-nitro-
propan-1-ol, 7,18 coupled with the presence of a functionalizable
primary alcohol, suggested that 7 could also be a useful starting
material. Application of the above procedure to 7 was compli-
cated by the cyclization of the intermediate â-hydroxynitrone,
8, to give an 3:2 equilibrium mixture of 8 and the hydroxyl-
amine, 9. Deprotonation of this mixture with phenylmagnesium
bromide followed by addition of a second equivalent of Grignard
reagent to the nitrone did not lead to the desired nitroxide, 10.
Instead, degradation was observed, presumably due to elimina-
tion of formaldehyde from the â-hydroxy hydroxyamine. This
instability necessitated the protection of the hydroxy functional-
ity; either the nitro derivative, 7, could be protected as a
trimethylsilyl ether, 11, which could then be carried through
the synthesis in high yields to give the protected nitroxide, 12,
or the equilibrium mixture of 8 and 9 could be treated with
trimethylsilyl chloride and pyridine (Scheme 2). Although
literature precedent19 suggests that acylation of N-2-hydroxy-
alkylnitrones gives the cyclic product, it was found that silylation
gave only the desired open chain form, 13, which could then
be arylated with phenylmagnesium bromide, followed by
oxidation to give the nitroxide, 12.
One advantage of this strategy is that, after deprotection of
the silyl group, the resulting nitroxide, or alkoxyamine, has a
reactive hydroxy functionality which can be used to prepare
telechelic polymers and chromophore-labeled materials for
further study.20 While the presence of the R-hydrogen decreases
the stability of the nitroxide when compared to TEMPO, all of
the above compounds were stable to storage at room temperature
and could be purified by normal procedures, such as flash
chromatography.
In an effort to further decrease the stability of the nitroxide,
the R-tertiary carbon atom in 6 was replaced by a secondary
carbon atom. The presence of an additional R-hydrogen atom
(17) Reznikov, V. A.; Gutorov, I. A.; Gatlov, Y. V.; Rybalova, T. V.;
Volodarsky, L. B. Russ. Chem. Bull. 1996, 45, 384.
(18) 2-Methyl-2-nitropropan-1-ol, 7, is substantially cheaper ($88 per
kg) than 2-methyl-2-nitropropane, 6, ($3000 per kg).
(19) Kliegel, W.; Enders, B.; Becker, H. Chem. Ber. 1983, 116, 27.
(20) Frank, B.; Gast, A. P.; Russell, T. P.; Brown, H. R.; Hawker, C. J.
Macromolecules 1996, 29, 6531; Hedrick, J. L.; Hawker, C. J.; Dipietro,
R.; Jerome, R.; Charlier, Y. Polymer 1995, 36, 4855.
(21) Grimaldi, S.; Finet, J. P.; Zeghdaoui, A.; Tordo, P.; Benoit, D.;
Gnanou, Y.; Fontanille, M.; Nicol, P.; Pierson, J. F. Polym. Prepr. 1997,
38, 651.
(22) Braslau, R.; Burrill, L. C., II; Siano, M.; Naik, N.; Howden, R. K.;
Mahal, L. K. Macromolecules 1997, 30, 6445.

Alkoxyamine for Controlled Polymerizations
J. Am. Chem. Soc., Vol. 121, No. 16, 1999 3907
Scheme 3
Scheme 4
Scheme 6
at 125 °C under nitrogen for 16 h. The polymeric product was
then examined in terms of molecular weight, Mn, and polydis-
persity.
Scheme 5
As can been seen from Table 1, the structure of the nitroxide
has a significant effect on the ability of the alkoxyamines, 24-
42, to control the polymerization of both styrene and n-butyl
acrylate. As expected from previous work, a larger range of
alkoxyamine structures were able to control the polymerization
of styrene, with most compounds giving experimental molecular
weights within 10% of the theoretical molecular weights24 and
polydispersities (PD) between 1.14 and 1.21. The exceptions
were the cis- and trans-isoindole derivatives, 30 a-b, the doxyl
derivatives, 32, and 39, and the R-phenyl-R-tert-butyl derivative,
31. The lowest polydispersities and highest rates of polymeri-
zation were obtained for the 2,5-dimethyl-2,5-diphenylpyrroli-
din-1-oxy derivative, 26, and the R-phenyl-R-isopropyl deriva-
tives 29, 33, 35, 37, and 38. The results for 26 are consistent
with the previous work of Puts and Sogah25 who demonstrated
that the use of DDPO as the mediating nitroxide leads to a faster
rate of polymerization when compared to the use of TEMPO.
In comparison, the polymerization of n-butyl acrylate with
the library of alkoxyamines, 24-42, resulted in little, if any,
control. With the exception of those of 29, 33, 35, and 37, all
molecular weights were significantly different from the theoreti-
cal molecular weights, and polydispersities were 1.75 or greater.
For 29 and 33, the experimentally determined molecular weights
as described by Hawker;23 the alkoxyamines, 24, were obtained
in 40-70% yield after purification (Scheme 6). In the case of
the chiral R-hydrogen nitroxides, mixtures of diastereomers were
obtained which were not separated and in all subsequent
experiments they were employed as diastereomeric mixtures.
A complete list of alkoxyamine structures employed in this
study is shown in Figure 1. For evaluating this library of
alkoxyamines, the initial screening procedure involved the
polymerization of 200 equiv of styrene, or 200 equiv of n-butyl
acrylate, in the presence of 1.0 equiv of the selected alkoxyamine
(24) Theoretical molecular weight is calculated from the molar ratio of
styrene to initiator and is based on a conversion of 90%.
(25) Puts, R. D.; Sogah, D. Y. Macromolecules 1996, 29, 3323.
(23) Dao, J.; Benoit, D,; Hawker, C. J. J. Polym. Sci., Part A: Polym.
Chem. 1998, 36, 2161.

3908 J. Am. Chem. Soc., Vol. 121, No. 16, 1999
Benoit et al.
Figure 1. Library of alkoxyamine structures evaluated as initiators for the living free radical polymerization of styrene and n-butyl acrylate.
of 26 500 (PD ) 1.44) and 27 000 (PD ) 1.40) were similar to
the theoretical molecular weight of 24 000. These promising
results coupled with the ready synthesis of 29 and 33 and their
corresponding nitroxides prompted a full investigation into the
ability of this family of alkoxyamines to control vinyl polym-
erization. The large-scale synthesis of 33 is especially attractive
due to the low cost of 2-methyl-2-nitropropan-1-ol, 7, isobu-
tyrlaldehyde, and phenylmagnesium bromide.
Two interesting features that emerge from the above study
are the insensitivity of the alkoxyamine to the presence, or
absence, of a substituent â to the nitrogen. The relative ability
of 29, 33, and 35 to control the polymerization of styrene is
approximately the same even though they have hydrogen,
hydroxy, and trimethylsiloxy substituents in the â position. It
will be shown below that this relationship also holds for acrylate-
based monomers and opens up the possibility of attaching
functional moieties, such as chromophores to the nitroxide, or
in the preparation of telechelic polymers.20 In contrast, replace-
ment of the tert-butyl group bonded to the nitrogen atom with
an isopropyl group resulted in a dramatically reduced ability of
41 and 42 to control polymerization. A rationale for these poor
polymerization results can be made based on the following.
Replacement of the tert-butyl group leads to a nitroxide with
two R-hydrogens, which is inherently unstable, especially at
elevated temperatures. This destabilization results in extensive
decomposition of the nitroxide during the polymerization, and
as a result the concentration of surviving nitroxide is now
insufficient to mediate the polymerization. This explanation is
partially supported by the observation that the nitroxide, 14a,
precursor of 41, is less stable than the nitroxide, 14b, precursor
of 42, which correlates with the substantially reduced ability
of 41 to mediate polymerization when compared to 42.
Polymerization of Styrene
The effectiveness of 29 or 33 for the living free radical
polymerization of styrene was probed under bulk conditions at
123 °C with special attention being paid to molecular weight
and polydispersity control. With no degassing or purification
of the styrene, the polymerization was essentially complete
within 18 h, and the molecular weight could be controlled up

Alkoxyamine for Controlled Polymerizations
J. Am. Chem. Soc., Vol. 121, No. 16, 1999 3909
Table 1. Molecular Weight, Mn, and Polydispersity of Product
Obtained from the Bulk Polymerization of 200 Equiv of Styrene, or
n-Butyl Acrylate, with Various Alkoxyamines, at 123 °C
polystyrene
poly(n-butyl acrylate)
alkoxyamine
Mn
polydispersity
Mn
polydispersity
24
25
26
27
28
29
30a
30b
31
32
33
34
35
36
37
38
39
40
41
42
22 000
22 500
26 500
28 000
21 000
21 500
33 000
22 000
30 500
50 000
22 000
23 000
22 500
24 000
22 000
25 000
42 000
20 000
38 000
25 000
1.16
1.18
1.17
1.21
1.2
3 000
9 000
32 000
22 000
7 500
2.45
1.8
2.05
1.9
1.75
1.44
2.52
2.25
1.75
3.81
1.40
1.90
1.45
1.55
1.50
1.55
2.80
1.95
2.10
1.70
1.14
1.71
1.49
1.39
1.72
1.14
1.23
1.15
1.19
1.16
1.15
1.65
1.25
1.68
1.30
26 500
41 500
26 000
12 000
57 000
27 000
28 000
26 500
32 500
29 000
27 500
61 000
45 000
95 000
38 000
Figure 3. Evolution of experimental molecular weight, Mn, and
polydispersity with theoretical MW for the polymerization of styrene
and 29 at 123 °C for 12 h in the presence of acetic anhydride.
Figure 4. Evolution of experimental molecular weight, Mn, and
polydispersity with theoretical MW for the polymerization of styrene
and 29 at 123 °C for 4 h after purification of the monomer.
Figure 2. Evolution of experimental molecular weight, Mn, and
polydispersity with theoretical MW for the polymerization of styrene
and 33 at 123 °C for 18 h with no degassing or purification.
decreased from 18 to 12 h, and a linear relationship between
experimental and theoretical molecular weights, Mn, could now
be obtained up to 100 000 amu (Figure 3). This reduced effect
may actually be due to the different nature of the mediating
nitroxide radical. While TEMPO is fairly stable and does not
undergo a significant amount of decomposition during the course
of the polymerization, the R-hydrogen nitroxide, 1, derived from
29 is susceptible to oxidation and nitrone formation. Therefore,
additives such as acetic anhydride, or camphor sulfonic acid,
which primarily affect the important autopolymerization step
during TEMPO-mediated polymerization, may have a smaller
effect in polymerizations mediated by 1 due to enhanced
nitroxide decomposition pathways. The effect of oxidants or
other radical sources, such as molecular oxygen, on the
polymerization was then studied in detail. By carefully distilling
and degassing the styrene monomer and performing the po-
lymerization under argon in a sealed tube, a dramatic increase
in the polymerization rate was observed with high conversions
being obtained after ca. 4 h. In this case, the molecular weight
control was excellent, up to 200 000 amu, and polydispersities
were less than 1.10 up to 75 000 amu and then only increased
slightly to 1.20-1.25 up to 200 000 amu (Figure 4). Interest-
ingly, the effect of acetic anhydride on the degassed and purified
system was minimal with no significant improvement in rate
or degree of control being observed. A similar effect has been
to 70 000 amu with polydispersities between 1.08 and 1.13
(Figure 2). A linear relationship between ln([M]o/[M]) vs time
was also observed which indicates no detectable termination is
occurring in this systems. The observed reduction in control
for polymers with molecular weights in excess of 70 000 is
similar to that observed originally for TEMPO26 and is primarily
due to the competing effects of autopolymerization, as well as
termination at higher molecular weights.
Previously, a number of additives, such as camphor sulfonic
acid or acetic anhydride, have been shown to accelerate
TEMPO-based polymerization with a concomitant increase in
the degree of control over the polymerization.27 To investigate
whether the same acceleration is observed with these new
nitroxides, 2.0 equiv of acetic anhydride was added to the
polymerization mixture of 29 and styrene. An effect similar to
that observed for TEMPO was found, although the magnitude
was reduced. Using this procedure, polymerization times were
(26) Hawker, C. J. J. Am. Chem. Soc. 1994, 116, 11314.
(27) Georges, M. K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer, G.
K.; Saban, M. Macromolecules 1994, 27, 7228; Malmstrom, E. E.; Miller,
R. D.; Hawker, C. J. Tetrahedron 1997, 53, 15225.

3910 J. Am. Chem. Soc., Vol. 121, No. 16, 1999
Benoit et al.
Table 2. Bulk Polymerization of Styrene in the Presence of 29 and
2.0 equiv of Acetic Anhydride at 85 and 100 °C
temperature
theoretical Mn
experimental Mn
polydispersity
100 °C
4 500
8 900
25 000
7 500
4 900
9 500
26 500
7 900
1.09
1.09
1.07
1.18
1.13
85 °C
25 000
24 000
observed by Percec and Matyjasewski28 during copper-mediated
ATRP procedures, where the use of the monomer as received,
coupled with sealing in air, results in a reduction in the rate of
polymerization and a slight increase in polydispersity.
The efficient polymerization of styrene at the traditionally
elevated temperature of 123 °C prompted an examination into
the use of lower polymerization temperatures. Such a lowering
in reaction temperature would not only be more energy efficient
but would also permit the polymerization of temperature-
sensitive monomers such as p-tert-butoxycarbonyloxystyrene
which has found great utility as a photoresist component.29 In
the presence of 2.0 equiv of acetic anhydride, polymerization
of styrene at both 100 and 85 °C led to well-defined materials
with controlled molecular weights and low polydispersities
(Table 2). Interestingly, the polydispersities obtained at 100°C
were as low as those obtained at the more conventional 123°C,
although the length of time required to reach high conversion
(ca. 80-90%) increased to 24 h at 100°C and 90 h at 85°C.
The 1:1 copolymerization of styrene and tert-butoxycarbonyl-
oxystyrene was then conducted at 100°C to give a well-defined
random copolymer (Mn ) 23 000, PD ) 1.15) with no detectable
loss of tert-butoxycarbonyl groups to give p-vinyl phenol units.
In contrast, the polymerization at 125°C resulted in precipitation
of the growing polymer chains to give a chloroform insoluble
material which was shown to be a random copolymer of p-vinyl
phenol and styrene with complete loss of the tert-butoxycarbonyl
groups.
Figure 5. Effect of added nitroxide, 1, on the percent conversion and
polydispersity of poly(butyl acrylate) prepared by the polymerization
of n-butyl acrylate and 29 at 123 °C for 24 h.
Figure 6. Comparison of GPC traces for poly(n-butyl acrylate)
prepared by the polymerization of n-butyl acrylate (200 equiv) at 123
°C in the presence of (a) 1.0 equiv of 29 and 0.05 equiv of 1 and (b)
1.0 equiv of 24 and 0.05 equiv of TEMPO.
Polymerization of Acrylates
The high degree of control afforded by 29 and 33 in the
polymerization of styrene prompted a thorough investigation
into the polymerization of other monomers, such as acrylates,
etc. In our original screening process, a polydispersity of 1.44
was obtained for the polymerization of n-butyl acrylate; while
this is less than the theoretical lower limit of 1.50 for a normal
free radical polymerization, polydispersities of this magnitude
cannot be considered controlled. A detailed investigation into
the effect of polymerization conditions was therefore undertaken
in an effort to decrease the polydispersity and increase the level
of control during nitroxide-mediated polymerization of acrylates.
The addition of additives, such as acetic anhydride, to the
polymerization of butyl acrylate and 29 at 120 °C was initially
examined. Significantly faster polymerization rates were ob-
served, ca. 90% completion in 1-2 h; however, the control was
poor with polydispersities being obtained in the range 1.50-
2.20. This rapid polymerization is primarily due to the very high
rate of polymerization of acrylate monomers, kp ) 11 000 L
mol-1 s-1 at 120 °C, in comparison to styrene at 120 °C, kp )
1800 L mol-1 s-1. To decrease the rate of polymerization and
afford better control, varying amounts of free nitroxide, 1, were
added to the polymerization mixture. Interestingly, the addition
of free nitroxide has a marked effect on the degree of control
afforded these polymerizations with significantly lower poly-
dispersities being obtained. Addition of 0.01 equiv of 1 (with
respect to the alkoxyamine 29) resulted in a polydispersity of
1.25 and a degree of conversion of 95% after 16 h. Increasing
the amount of added nitroxide gave lower polydispersities,
1.06-1.13, with a minimum of 1.06 being obtained for 0.05
equiv (Figure 5). However, the rate of polymerization was
observed to slow upon addition of large amounts of free
nitroxide, with ca. 40-45% conversion being obtained on
addition of 0.5 equiv of 1 after 16 h. These results may be
explained by the generation of an artifical persistent radical
effect upon addition of excess nitroxide, similar to the persistent
radical effect described by Fischer.3a It can therefore be
concluded that the alkoxyamine, 29, can indeed control the
polymerization of acrylates and the optimal reaction conditions
involve the addition of 0.05 equiv of free nitroxide. This feature
can be better appreciated if the GPC traces for poly(butyl
acrylate) grown in the presence of 29 and 1 is compared to
poly(butyl acrylate) grown in the presence of TEMPO (Figure
6). It should also be noted that the polymerization of acrylates
may also be conducted at lower temperatures (ca. 95-100 °C)
(28) Percec, V.; Kim, H.-J.; Barboiu, B. Macromolecules 1997, 30, 6702;
Matyjaszewski, K.; Coca, S.; Gaynor, S. G.; Wei, M.; Woodworth, B. E.
Macromolecules 1998, 31, 5967.
(29) Frechet, J. M. J.; Eichler, E.; Ito, H.; Willson, C. G. Polymer 1983,
24, 995; Willson, C. G.; Ito, H.; Frechet, J. M. J.; Tessier, T. G.; Houlihan,
F. M. J. Electrochem. Soc. 1986, 133, 181.

Alkoxyamine for Controlled Polymerizations
J. Am. Chem. Soc., Vol. 121, No. 16, 1999 3911
Figure 7. Evolution of molecular weight, Mn, with percent conversion
for the polymerization of n-butyl acrylate (250 equiv) in the presence
of 29 (1.0 equiv) and 1 (0.05 equiv) at 123 °C for 16 h.
Figure 8. 1H NMR spectrum of oligomeric poly(tert-butyl acrylate),
44, prepared by the polymerization of tert-butyl acrylate (25 equiv) at
123 °C in the presence of 1.0 equiv of 43 and 0.05 equiv of 1.
Scheme 7
with similar levels of control, although, as with the styrene, the
time required to reach high conversion is increased to 48 h.
The living nature of this new bimolecular alkoxyamine/
nitroxide-initiating system was then probed by polymerizing 250
equiv of n-butyl acrylate with 1.0 equiv of 29 and 0.05 equiv
of 1 at 120 °C under argon. As can be seen in Figure 7, the
evolution of molecular weight with conversion is linear, and
the polydispersity in each case was 1.05-1.10, which is fully
consistent with a controlled or living free radical polymerization.
A linear relationship between ln([M]o/[M]) vs time was also
observed which indicates no detectable termination is occurring
in this system. Initiator efficiency was examined by preparing
short oligomeric chains from the chloromethyl functionalized
initiator, 43 (Scheme 7). For example, a mixture of 25 equiv of
tert-butyl acrylate, 1.0 equiv of 43, and 0.05 equiv of 1 were
heated at 125 °C under argon for 24 h to give the oligomer, 44,
which was shown to have a molecular weight, Mn of 2800 amu,
and a polydispersity of 1.09 after purification. As shown in
Figure 8, the 1H NMR spectrum of 44 clearly shows the
resonance for the chloromethyl group of the initiating chain end
at 4.48 ppm and the R-hydrogen of the nitroxide chain end at
3.25 ppm. Integration of these resonances reveals a ca. 1:1 ratio
and gives a molecular weight, Mn, of 2700 amu which is
consistent with controlled growth and no detectable termination.
Interestingly, the absence of resonances at 6.7 and 5.8 ppm for
an alkene-terminated chain, the result of nitroxide elimination,
further supports a living process.
Figure 9. Relationship between experimental molecular weight, Mn,
and theoretical molecular weight for the polymerization of n-butyl
acrylate in the presence of 29 (1.0 equiv) and 1 (0.05 equiv) at 123 °C
for 16 h.
weight that these systems afford. This control over molecular
weight has been amply demonstrated for styrenic-based systems
and for acrylate-based systems using ATRP.30 The ability of
these new alkoxyamines, such as 29, to control molecular weight
was examined under the conditions defined above. On the basis
of the assumption that one polymer chain is initiated per
alkoxyamine molecule and the length of the polymer chain is
dictated by the molar ratio of monomer to alkoxyamine, with
no contribution from added nitroxide, the observed relationship
between theoretical and experimental molecular weight is
excellent.31 For molecular weights below 50 000, the polydis-
persity is low, ca. 1.05-1.10, and only increases slightly, ca.
1.10-1.30, at higher molecular weights (Figure 9). The level
of degree of control afforded by 29 for the nitroxide-mediated
polymerization of acrylates is therefore comparable to ATRP
systems, as well as the recently introduced RAFT procedures.10
Random Copolymers
In comparison with other living techniques, two of the unique
features of living free radical polymerizations is their compat-
(30) Qui, J.; Matyjaszewski, K. Macromolecules 1997, 30, 5176.
(31) All experimental molecular weights, except those for random and
block copolymers, were determined using gel permeation chromatography
using the appropriate standards.
One of the prime advantages of using alkoxyamines as
unimolecular initiators is the accurate control over molecular

3912 J. Am. Chem. Soc., Vol. 121, No. 16, 1999
Benoit et al.
Table 3. Homopolymerization of Acrylonitrile* and
N,N-dimethylacrylamide Using 29 as an Initiator at 120 °C
ratio of
monomer/29
monomer
acrylonitrile
Mn
polydispersitya
50/1
200/1
500/1
4 500
22 000
55 000
1.12
1.16
1.13
N,N-dimethylacrylamide
50/1
100/1
200/1
500/1
4 000
8 500
21 500
48 000
1.15
1.12
1.14
1.21
a Polymerization of acrylonitrile was conducted in a 50 wt % DMF
solution; polydispersity and Mn of poly(acrylonitrile) samples were
determined by GPC using DMF as solvent.
simply varying the molar ratio of 29 and the total monomer
concentration, confirms the living nature of these random
copolymerizations. For example, the molecular weight, Mn, of
a series of 3:7 styrene/n-butyl acrylate random copolymers was
within 10% of the theoretical value for molecular weights in
the range of 2000 to 100 000.
Figure 10. Relationship between polydispersity of the resulting random
copolymers and mol % of styrene in the feed mixture for the
copolymerization of (i) styrene and n-butyl acrylate (9), (ii) styrene
and methyl methacrylate (b) mediated by TEMPO-based systems, 24,
compared with (iii) styrene and n-butyl acrylate (O), and (iv) styrene
and methyl methacrylate (0) mediated by 29 or 33.
In an effort to further extend the scope of nitroxide-mediated
living free radical polymerization, the random copolymerization
of acrylates and methacrylates was studied by means of a
procedure similar to that for the homopolymerization of
acrylates. For example, a mixture of tert-butyl acrylate (100
equiv) and methyl methacrylate (100 equiv) was heated at 125
°C in the presence of 1.0 equiv of 29 and 0.05 equiv of the free
nitroxide 1. The copolymer obtained was shown to be a
ibility with a wide range of functional groups, coupled with
their ability to prepare well-defined random copolymers.32 While
it has been shown that TEMPO-mediated living free radical
polymerizations can produce random copolymers of styrene with
either acrylate or methacrylate monomers,11 the degree of control
drops significantly as the mole percentage of styrene decreases
below 60%. The ability of 29 to mediate the homopolymeri-
zation of acrylates should alleviate this problem and permit a
much greater range of well-defined random copolymers to be
prepared.
In examining this possibility, the polymerization of styrene
and butyl acrylate mixtures in the presence of 29 and acetic
anhydride at 125 °C was conducted. In contrast to the results
obtained with TEMPO, both molecular weight and polydisper-
sity control was excellent, with all of the molecular weights
being within 10% of the theoretical molecular weights and
polydispersities between 1.08 and 1.20. Given the control
afforded by 29 in the homopolymerization of both styrenics and
acrylates, this ability to prepare well-defined random copolymers
is expected. However a more surprising result was obtained
when the random copolymerization of styrene and methyl
methacrylate was examined. In this case, well-defined random
copolymers could be obtained up to very high methyl meth-
acrylate ratios (ca. 85%), and only at methacrylate ratios of
greater than 90% did the polydispersity become greater than
1.50. Significantly, no resonances were observed in the 5.50-
6.20 ppm region, characteristic of alkene-terminated chains.
To better appreciate these results, the polydispersities obtained
for the random copolymerization of styrene/butyl acrylate and
styrene/methyl methacrylate mixtures initiated by 29 were
compared with those for TEMPO-based systems. Significantly
greater control is observed with 29 compared to TEMPO at
essentially all molar ratios and becomes exacerbated at molar
percentages of styrene of less than 60% (Figure 10).
1
statistical random copolymer by H NMR spectroscopy and
analysis by GPC, Mn ) 22 000, PD ) 1.24, demonstrating that
the level of control was similar to that found above for the
styrene/methacrylate random copolymers. This was further
confirmed by examination of a wide range of copolymer ratios
which showed that well-defined materials (PD < 1.35) were
obtained for up to 80% of methyl methacrylate, and only at
higher methacrylate ratios did polydispersities become greater
than 1.50. It should be noted, however, that the level of control
at all molar ratios was significantly greater than for the
copolymerization of styrene and methyl methacrylate mediated
by TEMPO, while the copolymerizations of acrylates and methyl
methacrylate by TEMPO fail to give polymers.
Acrylamides, Acryonitrile and other Functionalized Mono-
mers. The ability of 29 to control the homopolymerization of
acrylates suggested that this system may be applicable to an
even wider selection of monomer units, similar to ATRP
procedures. If this was indeed the case, many of the challenges
and problems typically associated with nitroxide-mediated
polymerizations would be overcome. Brittain has recently
reported33 the polymerization of N,N-dimethylacrylamide using
TEMPO as the mediating radical and obtained poly(acrylamide)
derivatives with polydispersities ranging from 1.55 to greater
than 2.0. In contrast, the polymerization of N,N-dimethylacryl-
amide in the presence of 29 and 0.05 equiv of 1 proved to be
a well-controlled process leading to poly(N,N-dimethylacryl-
amide) with polydispersities ranging from 1.12 to 1.21. Simi-
larly, the homopolymerization of acrylonitrile was found to be
a controlled process when initiated by 29, both in the absence
and presence of excess nitroxide. In both cases the molecular
weight could be controlled from 4000 to 50 000 as shown in
Table 3. The ability to homopolymerize or copolymerize
acrylonitrile to high molecular weight is in contrast to the results
obtained with ATRP systems which are limited to molecular
The linear nature of the relationship between molecular
weight, Mn, and conversion, coupled with the ability to readily
control the molecular weights of these random copolymers by
(32) Kotani, Y.; Kamigaito, M.; Sawamoto, M. Macromolecules 1998,
31, 5582; Haddleton, D. M.; Crossman, M. C.; Hunt, K. H.; Topping, C.;
Waterson, C.; Suddaby, K. G. Macromolecules 1997, 30, 3992; Greszta,
D.; Matyjaszewski, K. Polym. Prepr. (Am. Chem. Soc., DiV. Polym. Chem.)
1996, 37 (1), 569.
(33) Li, D.; Brittain, W. J. Macromolecules 1998, 31, 3852.

Alkoxyamine for Controlled Polymerizations
J. Am. Chem. Soc., Vol. 121, No. 16, 1999 3913
Table 4. Polydispersity and Polystyrene Equivalent Molecular
Weights, Mn, for the Bulk Random Copolymerization of Styrene
and a Variety of Functionalized Monomers (200 equiv) in the
Presence of 29 at 120 °C
Table 5. Polydispersity and Polystyrene Equivalent Molecular
Weights, Mn, for the Bulk Random Copolymerization of Butyl
Acrylate and a Variety of Functionalized Monomers (200 equiv) in
the Presence of 29 and 1 (0.05 Equiv) at 120 °C
weights of less than 15 000.34 Presumably this is due to the
slow deactivation of the copper catalyst with poly(acrylonitrile)
with time and demonstrates that the lack of a metal catalyst
requirement with nitroxide-mediated procedures is beneficial
for certain systems.
Functionalized Monomers
The ability to polymerize functionalized monomers under
controlled conditions is a major advantage of living free radical
procedures.7,35 The demonstrated capacity of 29 to polymerize
a wide variety of monomer families suggested that it might also
be compatible with reactive functional groups such as carboxylic
acids, epoxides, etc. This feature was probed by copolymerizing
mixtures of styrene, or butyl acrylate, with a variety of reactive
monomer units. As shown in Tables 4 and 5, a high degree of
control was maintained over the random copolymerization even
in the presence of a significant amount of the reactive monomer
unit, ca. 1:1. At low levels of incorporation, ca. <25%, the
influence of functionalized monomers on the level of control
was negligible. For a range of functional groups, from basic
amine, acidic carboxylate, and fluorocarbon to hydrophilic
groups, low polydispersity and well-defined polymer were
obtained. Only at high loading levels (ca. 50%) and in select
cases, such as acrylic acid and glycidyl acrylate, did the
polydispersities rise to 1.5-1.55. Similar difficulties in the
polymerization of acrylic acid were observed in ATRP proce-
dures by Matyjaszewski and are again due to catalyst deactiva-
tion by the coordinating ability of the monomer.34
exploited by numerous groups.36 While the block copolymers
available from living free radical procedures may not be as well
defined as the best examples available from anionic techniques,
they have the advantage of greater availability and a significantly
greater tolerance of functional groups. Technological applica-
tions that have been examined for these block copolymer include
dispersants for pigments,37 precursors to shell cross-linked
nanoparticles for drug delivery,38 supports for combinatorial
chemistry,39 and resist materials for photolithography.40
In exploiting these opportunities, nitroxide-mediated systems
have lagged behind ATRP-based systems, primarily due to the
more limited choice of monomer units that could be efficiently
homopolymerized. The ability of 29 to overcome this limitation
opens up the possibility of preparing a wide range of block
copolymer structures using nitroxide-mediated procedures.
(36) Paik, H. J.; Gaynor, S. G.; Matyjaszewski, K. Macromol. Rapid
Commun. 1998, 19, 47; Mecerreyes, D.; Moineau, G.; Dubois, Ph.; Jerome,
R.; Hedrick, J. L.; Hawker, C. J.; Malmstrom, E. E.; Trollsas, M. Angew.
Chem., Int. Ed. Engl. 1998, 37, 1274; Bertin, D.; Boutevin, B. Polym. Bull.
1996, 37, 337; Kobatake, S.; Harwood: H. J.; Quirk, R. P.; Priddy, D. B.
Macromolecules 1998, 31, 3735; Butz, S.; Baethge, H.; Schmidt-Naake,
G.; Macromol. Rapid Commun. 1997, 18, 1049; Edgecombe, B. D.; Stein,
J. A.; Frechet, J. M. J.; Xu, Z.; Kramer, E. J. Macromolecules 1998, 31,
1292; Nishikawa, T.; Ando, T.; Kamigaito, M.; Sawamoto, M. Macromol-
ecules 19978, 30, 2244.
From these experiments it can be concluded that the
alkoxyamines 29 and 33 are capable of controlling the homo-
and copolymerization of a wide range of monomer units, i.e.,
styrenics, acrylates, acrylamides, and acrylonitrile, while at the
same time being compatible with a variety of functional groups.
(37) Keoshkerian, B.; Georges, M. K.; Boils-Boissier, D. Macromolecules
1995, 28, 6381; Bouix, M.; Gouzi, J.; Charleux, Vairon, J. P.; Guinot, P.
Macromol. Rapid Commun. 1998, 19, 209.
(38) Huang, H.; Remsen, E. E.; Wooley, K. L. J. Chem. Soc., Chem.
Commun. 1998, 1415; Huang, H.; Kowalewski, T.; Remsen, E. E.;
Gertzmann, R. Wooley, K. L. J. Am. Chem. Soc. 1997, 119, 11653.
(39) Gravert, D. J.; Datta, A.; Wentworth, P., Jr.; Janda, K. D. J. Am.
Chem. Soc. 1998, 120, 9481.
Block Copolymers
The presence of dormant initiating centers at the chain end/s
of linear polymers prepared by both nitroxide-mediated and
ATRP procedures provides unique opportunities for the prepara-
tion of block copolymer structures, and this feature has been
(34) Patten, T. E.; Matyjaszewski, K. AdV. Mater. 1998, 10, 901.
(35) Zhang, X.; Xia, J.; Matyjaszewski, K. Macromolecules 1998, 31,
5167; Matyjaszewski, K.; Coca, S.; Jasieczek, C. B. Macromol. Chem. Phys.
1997, 198, 4011.
(40) Barclay, G. G.; King, M.; Orellana, A.; Malenfant, P. R. F.; Sinta,
R. F.; Malmstrom, E. E.; Ito, H.; Hawker, C. J. In Organic Thin Films:
Structure and Applications; Frank, C. W., Ed,; ACS Symposium Series
695; American Chemical Society: Washington,DC, 1998; p 360.

3914 J. Am. Chem. Soc., Vol. 121, No. 16, 1999
Benoit et al.
Scheme 8
Table 6. Molecular Weight, Mn, and Polydispersity for Poly(n-butyl Acrylate)-b-polystyrene Block Copolymers, 48, Prepared Using 29 under
Bulk Conditions at 120 °C
poly(n-butyl acrylate) starting block
P(n-BA)-b-PSt block copolymerb
Mn
polydispersity
compositiona Sty/n-BA
Mn
polydispersity
2 100
4 500
7 800
7 800
7 800
7 800
7 800
7 800
7 800
23 500
23 500
23 500
32 500
32 500
32 500
76 500
76 500
76 500
1.08
1.05
1.08
1.08
1.08
1.08
1.08
1.08
1.08
1.09
1.09
1.09
1.06
1.06
1.06
1.1
85/15
80/20
85/15
80/20
70/30
60/40
50/50
43/57
32/68
73/27
57/43
40/60
70/30
42/58
33/67
73/27
50/50
30/70
12 500
26 000
42 000
37 000
31 000
21 000
17 500
14 500
11 000
85 000
68 000
44 000
111 000
61 000
49 000
205 000
145 000
105 000
1.06
1.09
1.07
1.12
1.09
1.07
1.1
1.12
1.09
1.19
1.16
1.13
1.16
1.13
1.09
1.32
1.28
1.19
1.1
1.1
1
a Determined by H NMR spectroscopy. b Polystyrene equivalent molecular weights.
Initially, a starting polystyrene block, 45 (Mn ) 4500 amu, PD
) 1.08), was prepared from 29 and 50 equiv of styrene in the
presence of acetic anhydride and purified by repeated precipita-
tion into methanol. A second poly(n-butyl acrylate) block was
then grown by dissolution of 45 in butyl acrylate (500 equiv),
addition of 0.05 equiv of nitroxide, 1, followed by heating at
123 °C under argon. As evidenced by the GPC traces for the
block copolymer, 46, versus the starting material, 45, controlled
growth is achieved with no evidence of homopolymer contami-
nation. However, when higher molecular weight starting poly-
styrene blocks were used, or when a similarly sized polyacrylate
block was grown, there was a substantial low molecular weight
shoulder observed. The exact nature of this shoulder, whether
it is unreacted or terminated starting polystyrene block, is
unknown. Attempts to overcome this unexpected lack of
reactivity by the addition of solvent, etc. were unsuccessful.
The difficulty in preparing block copolymers by initially
growing a polystyrene block followed by growth of a second
polyacrylate block prompted an investigation of the reverse
strategy. Interestingly, this reverse strategy proved to be
extremely successful and allowed the preparation of well-defined
block copolymers with levels of control comparable to those
of ATRP procedures. In this strategy (see Scheme 8), an
alkoxyamine-functionalized poly(n-butyl acrylate) block, 47 (Mn
) 7800, PD ) 1.08), was initially grown and then used to
polymerize 200 equiv of styrene in the presence of acetic
anhydride (1.0 equiv) at 123 °C under argon for 8 h. This
resulted in 92% conversion and gave the block copolymer, 48,
analysis of which revealed the expected increase in molecular
weight (Mn ) 28 000, PD ) 1.09), while the polydispersity
remained very low and there was no detectable amount of
unreacted starting poly(acrylate) block as analyzed by a
combination of GPC and HPLC. techniques (Figure 11). This
block copolymer formation proved to be a general procedure
and permitted a wide compositional range of poly(n-butyl
acrylate)-b-polystyrene block copolymers to be prepared with
accurate control of molecular weight up to 200 000 amu and
polydispersities typically in the range of 1.06-1.19 (Table 6).
The same chemistry can be used to prepare functionalized
block copolymers. For example, a starting block can be prepared
from heptafluorobutyl acrylate and then a second nonflourinated
block grown by polymerization of n-butyl acrylate. In this case
the low solubility of the starting fluorinated block in n-butyl
acrylate was overcome by the addition of an equivalent amount,
by weight, of hexafluorobenzene to the polymerization mixture.
While the addition of a cosolvent reduced the polymerization
rate (ca. 30 h for high conversion), growth was still controlled
and a well-defined block copolymer, 49, Mn ) 116 000, PD )
1.18, was obtained.

Alkoxyamine for Controlled Polymerizations
J. Am. Chem. Soc., Vol. 121, No. 16, 1999 3915
mmol), ammonium chloride (29.4 g, 550 mmol), and 1000 mL of water
were cooled to 0 °C in an ice-bath, and 500 mL of diethyl ether was
then added to partially dissolve the crystallized 2-methyl-2-nitropropane.
Zinc powder (130 g, 2.00 mol) was added in small portions over 1 h
with stirring. After 8 h, the mixture was filtered through a sintered
glass filter and the residue washed three times with 300 mL of methanol.
The product was extracted four times with 500 mL of dichloromethane.
The organic layers were combined and washed with 800 mL of brine,
dried over magnesium sulfate, and concentrated in vacuo to give 59.9
g (84% yield) of crude nitrone 5a as a colorless, low-melting solid,
partially crystallized at room temperature. TLC 10:1 ethyl acetate/
methanol, molybdenum stain, Rf ) 0.49. 1H NMR (250 MHz, CDCl3)
δ 6.52 (s, 1H), 2.10 (m, 1H), 1.42 (d, 6H), 1.21 (s, 9H); 13C NMR (63
MHz, CDCl3) δ 139.55, 69.21, 30.67, 28.49, 26.10.
2,2,5-Trimethyl-4-phenyl-3-azahexane-3-nitroxide (1). N-tert-bu-
tyl-R-iso-propylnitrone (5a) (66.0 g, 461 mmol) was dissolved in 500
mL of THF and the solution cooled to 0 °C. A 3.0 M solution of
phenylmagnesium bromide (310 mL, 920 mmol) in diethyl ether was
added by cannula at this temperature over 5 min. During the addition
some precipitate formed. The mixture was allowed to warm to room
temperature. After 12 h, excess Grignard reagent was decomposed by
the addition of 100 mL of concentrated ammonium chloride solution
followed by 300 mL of water until all solids had dissolved. The organic
layer was separated, and the aqueous layer was extracted with 500 mL
of diethyl ether. The organic layers were combined, dried over
magnesium sulfate, filtered, and concentrated, and the residue was
treated with a mixture of 2000 mL of methanol, 150 mL of concentrated
NH4OH, and 4.59 mg (23 mmol) of Cu(OAc)2 to give a pale yellow
solution. A stream of air was bubbled through the yellow solution until
it became dark blue (5-10 min). This was concentrated and the residue
dissolved in a mixture of 2000 mL of chloroform, 500 mL of
concentrated NaHSO4 solution, and 2000 mL of water. The organic
layer was separated, and the aqueous layer was extracted with 500 mL
of chloroform. The organic layers were combined and washed with
600 mL of saturated sodium bicarbonate solution, dried over magnesium
sulfate, and concentrated in vacuo to give 101.6 g of crude nitroxide.
The nitroxide was then purified by flash column chromatography (20:1
hexane/ethyl acetate) to afford 72.6 g (71% yield) of pure 1 as an orange
oil, which crystallized at temperatures below 4 °C. TLC 16:1 hexane/
ethyl acetate, molybdenum stain, Rf ) 0.49; 1H NMR (250 MHz,
CDCl3, in the presence of pentafluorophenyl hydrazine) δ 7.60-7.25
(m, 5H, Ph), 3.41 (d, 1H, J ) 6.5 Hz), 2.28 (m, 1H), 1.44 and 0.97 (s,
9H), 1.20 and 0.58 (d, 6H, J ) 6.8 Hz);13C NMR (62.5 MHz, CDCl3)
in the presence of pentafluorophenyl hydrazine, δ 154.26, 142.06,
141.20, 136.02, 129.50, 128.77, 128.43, 127.82, 127.25, 126.61, 73.37,
71.31, 63.30, 59.10, 31.51, 31.23, 30.19, 26.85, 21.54, 20.55, and 18.48.
Figure 11. Comparison of GPC traces for (a) the starting poly(n-butyl
acrylate) polymer, 47, and (b) the poly(n-butyl acrylate)-b-polystyrene
block copolymer, 48, obtained after chain extension with styrene.
Conclusion
By the synthesis of a library of different nitroxides and their
associated alkoxyamines, the R-hydrido family of unimolecular
initiators, in particular 29 and 33, has been identified as universal
initiators for nitroxide-mediated living free radical polymeriza-
tions. In comparison with traditional TEMPO-based systems,
their performance is significantly improved and permits the
controlled polymerization of a wide variety of monomer
families. Acrylates, acrylamides, and acrylonitrile-based mono-
mers can now be polymerized with accurate control of molecular
weights and polydispersities as low as 1.06. The versatile nature
of these initiators can also be used to control the formation of
random and block copolymers from a wide selection of
monomer units containing reactive functional groups, such as
amino, carboxylic acid, and glycidyl. The universal nature of
these initiators overcomes many of the limitations typically
associated with nitroxide-mediated systems and leads to a level
of versatility approaching ATRP-based systems.
Experimental Section
General. All reactions were run under N2 unless noted. Solvents
were dried as follows: THF and toluene were distilled under N2 from
sodium benzophenone, and CH2Cl2 was distilled from calcium hydride.
m-Chloroperbenzoic acid was purified by the procedure of Fieser and
Fieser. Analytical thin-layer chromatography (TLC) was performed on
commercial Merck plates coated with silica gel GF254 (0.25 mm thick).
Silica gel for flash chromatography was either Merck Kieselgel 600
(230-400 mesh) or Universal Scientific Inc. silica gel 63-200. Nuclear
magnetic resonance (NMR) spectroscopy was performed on a Bruker
ACF 250, AM 500 MHz, or Varian Unity 500 MHz NMR spectrometer
using deuterated chloroform (CDCl3) as solvent and the internal solvent
peak as the reference. ESR spectra were measured on a Bruker ESP
300 spectrometer operated in continuous wave (CV) mode with a TE102
rectangular cavity. Gel permeation chromatography (GPC) was carried
out on a Waters chromatograph (four Waters Styragel HR columns
HR1, HR2, HR4, and HR5E in series) connected to a Waters 410
differential refractometer with THF as the carrier solvent. IR spectra
were recorded in CDCl3 solution. Mass spectra were obtained at the
University of Illinois using magic bullet or fast atom bombardment
(FAB); electrospray mass spectroscopy (ESMS) was taken at University
of California at Santa Cruz using a Quattro II Triplequadrupole mass
spectrometer. Melting points are uncorrected. The following alkoxyamines
has been reported previously, 24,6 25,4 and 28.6
N-tert-Butyl-R-tert-butylnitrone (51). The nitrone 51 was prepared
from pivalaldehyde as described above and was obtained in 62% yield
as a colorless solid; TLC 10:1 ethyl acetate/methanol, molybdenum
stain, Rf ) 0.76.1H NMR (250 MHz, CDCl3) δ 6.52 (s, 1H), 1.42 (s,
9H), 1.21 (s, 9H); 13C NMR (63 MHz, CDCl3) δ 139.74, 69.63, 32.54,
28.24, 26.18.
2,2,5,5-Tetramethyl-4-phenyl-3-azahexane 3-nitroxide (52). The
nitroxide 52 was prepared from N-tert-butyl-R-tert-butylnitrone, 51 (800
mg, 5.09 mmol), as described above and was obtained as an orange
oil (83% yield), which crystallized at temperatures below 4 °C. TLC:
16:1 hexane/ethyl acetate, molybdenum stain, Rf ) 0.48.
2,2,5-Trimethyl-4-(4-trifluoromethylphenyl)-3-azahexane-3-ni-
troxide (53). The trifluoromethyl-substituted nitroxide, 53, was prepared
from p-trifluoromethyl phenylmagnesium bromide and N-tert-butyl-
R-iso-propylnitrone, 5a, using the general procedure outlined above.
The nitroxide, 53, was purified by flash column chromatography, eluting
with 16:1 hexane/ethyl acetate and was obtained as an orange solid
(74% yield); TLC 16:1 hexane/ethyl acetate, molybdenum stain, Rf )
0.34; mp 80-81 °C; IR(CDCl3) 2977, 1617, 1325, 1168, 1130, 1068
cm-1; ESR (CH2Cl2) doubled triplet, an ) 15.249 G, ah ) 2.639 G;
MS (FAB) m/z 288 ([M]+, 36), 274 (28), 232 (100), 201 (19); HRMS
exact mass calcd for [M+] C15H21F3NO 288.1576, found 288.1576; 1H
NMR (250 MHz, CDCl3, in the presence of phenyl hydrazine) δ 1.12
(d, 3H, J ) 6.5 Hz), 0.90 (s, 9H), 0.55 (d, 3H, J ) 6.8 Hz).
N-tert-Butyl-R-iso-propylnitrone (5a). A mixture of 2-methyl-2-
nitropropane, 6 (51.5 g, 500 mmol), isobutyraldehyde (36.0 g, 500

3916 J. Am. Chem. Soc., Vol. 121, No. 16, 1999
Benoit et al.
2,2,5,5-Tetramethyl-4-(4-trifluoromethylphenyl0-3-azahexane 3-ni-
troxide (54). The nitroxide, 54, was prepared from N-tert-butyl-R-tert-
butylnitrone, 52, and 4-trifluoromethylphenylmagnesium bromide as
described above and isolated as an orange solid (29% yield) TLC 16:1
hexane/ethyl acetate, molybdenum stain, Rf ) 0.52; mp 86-87 °C;
IR(CDCl3) 2974, 1617, 1326, 168, 1130, 1069 cm-1; ESR (CH2Cl2)
doubled triplet, an ) 15.021 G, ah ) 2.198 G; MS (FAB) m/z 304 ([M
+ 1]+, 62), 288 (68), 246 (76), 154 (100), 136 (69); HRMS exact mass
calcd for [M + 2]+ C16H25F3NO 304.1890, found 304.1886; 1H NMR
(250 MHz, CDCl3, in the presence of phenyl hydrazine) δ 3.65 (s, 1H),
0.96 (s, 9H), 0.93 (s, 9H).
cooled in an ice bath while Zn dust (13.0 g, 200.0 mmol) was added
in small portions over 15 min, and the resulting mixture was stirred
for 4 h at room temperature under nitrogen. The mixture was filtered
through a glass filter, and the cake was washed with hot 95% ethanol
(70 mL) and hot chloroform (70 mL). The combined organic layers
were evaporated, and the resulting clear oil was redissolved in
chloroform (50 mL), dried over potassium carbonate, and filtered. To
the chloroform solution of 2-hydroxyamino-2-methylpropan-1-ol was
added isobutyraldehyde (5.44 mL, 60.0 mmol) and dried sodium
carbonate, and the reaction mixture stirred at room temperature for 24
h. Purification by flash column chromatography, eluting with 5:1 ethyl
acetate/methanol, afforded the desired nitrone as a 3:2 mixture of nitrone
and cyclic oxazolidine tautomers, 8 and 9 (6.43 g, 82% yield); TLC
2,3-Di-tert-butyl-4,5,6,7-tetrafluoro-1,2-benzisoxazolidine (20). To
a stirred suspension of magnesium turnings (101 mg, 4.20 mmol) and
3 mL of THF under nitrogen were added 200 mL of bromopentafluo-
robenzene. After 5 min, the rest of the bromopentafluorobenzene (300
mL, for a combined total of 500 mL, 4.00 mmol) was added over 10
min. The mixture was then stirred 1.5 h until most of the magnesium
had disappeared. To this freshly prepared Grignard solution was added
a solution of N-tert-butyl-R-tert-butylnitrone, 52 (315 mg, 2.00 mmol),
in 3 mL of THF, and the light-brown homogeneous solution was stirred
at room-temperature overnight. The excess Grignard reagent was
decomposed by the addition of 10 mL of concentrated ammonium
chloride solution and then 5 mL of water; all solids dissolved. The
organic layer was separated, and the aqueous layer was extracted with
10 mL of diethyl ether. The organic layers were combined and
concentrated, and to the residue was added 10 mL of methanol (some
precipitate formed), 0.5 mL of concentrated NH4OH, and 20.0 mg (0.10
mmol) of Cu(OAc)2. A stream of air was bubbled through the yellow
solution; no change of color was observed over a 1-h period. The
mixture was left to stir overnight in an open flask and was concentrated,
and the residue was dissolved in the mixture of 20 mL of chloroform,
5 mL of concentrated NaHSO4 solution, and 20 mL of water. The
organic layer was washed with 6 mL of saturated sodium bicarbonate
solution, dried over magnesium sulfate, filtered, and concentrated in
vacuo to give the isoxazolidine, 20, as a colorless solid (374 mg, 61%
1
5:1 ethyl acetate/methanol, molybdenum stain, Rf ) 0.61, H NMR
(250 MHz, CDCl3, both tautomers) δ 7.2-6.8 (br s, 1H, cyclic form),
6.72 (d, 1H, J ) 7.3 Hz, nitrone), 5.34 (br s, 1H, nitrone), 4.21 (d, 1H,
J ) 7.0 Hz, cyclic form), 3.73 (s, 2H, nitrone), 3.62 (q, 2H, J ) 7.8
Hz, cyclic form), 3.3-3.1 (m, 1H, nitrone), 1.45 (s, 6H, nitrone), 1.20
(s, 6H, cyclic form), 1.12 (d, 6H, J ) 7.3 Hz, nitrone), 0.99 (d, 6H, J
) 7.0 Hz, cyclic form), 13C NMR (APT) (63 MHz, CDCl3, both
diastereomers) δ 144.7 (d), 144.4 (s), 101.8 (d), 71.8 (t), 68.3 (t), 26.0
(q), 23.4 (q), 18.8 (q). HRMS exact mass calcd for [M + 1]+ C8H17-
NO2 159.1259, found 159.1261.
1-Trimethylsilyloxy-2-methyl-2-nitropropane (11). 2-Methyl-2-
nitropropan-1-ol, 7, (5.95 g, 50.0 mmol) and pyridine (4.03 mL, 50.0
mmol) were dissolved in 50 mL of diethyl ether. Trimethylchlorosilane
(6.34 mL, 50.0 mmol) was added dropwise at room temperature and
the reaction mixture stirred for 2 h under nitrogen. Filtration of the
precipitated pyridinium hydrochloride, followed by removal of the
solvent gave the crude trimethylsilyl ether, 11, which was purified by
1
distillation (bp, 80 °C, 5 mm Hg) (8.15 g, 85% yield), H NMR (250
MHz, CDCl3) δ 3.83 (s, 2H), 1.55 (s, 6H), 0.09 (s, 9H); 13C NMR
(APT) (63 MHz, CDCl3) δ 88.6 (s), 68.7 (t), 22.7 (q), -0.7 (q).
N-(2-Trimethylsilyloxy-1,1-dimethylethyl)-R-isopropylnitrone (13).
A mixture of 1-trimethylsilyloxy-2-methyl-2-nitropropane, 11 (4.03 g,
21.0 mmol), isobutyraldehyde (3.8 mL, 42 mmol), ammonium chloride
(1.23 g, 23.0 mmol), diethyl ether (15 mL), and water (40 mL) was
cooled to 0 °C, and Zn powder (5.46 g, 8.40 mmol) was added in small
portions over 1 h with stirring. The resulting mixture was stirred for
24 h at room temperature under nitrogen and filtered, and the precipitate
was washed twice with 5 mL of methanol. The product was extracted
with dichloromethane (4 × 20 mL), and the combined organic layers
were dried (MgSO4) and concentrated in vacuo. The crude product was
purified by flash chromatography eluting with ethyl acetate, to give
the nitrone, 13, as a colorless oil (6.24 g, 57% yield); TLC ethyl acetate,
molybdenum stain, Rf ) 0.37, IR(CDCl3) 2964, 1587, 1253, 1104, 874,
842 cm-1, 1H NMR (250 MHz, CDCl3, both tautomers) δ 6.51 (d, 1H,
J ) 7.0 Hz), 3.61 (s, 2H), 3.10 (m, 1H), 1.33 (s, 6H), 1.02 (d, 6H, J
) 6.8 Hz), 0.01 (s, 9H), 13C NMR (APT) (63 MHz, CDCl3, both
diastereomers) δ 142.2 (d), 71.8 (s), 67.3 (t), 26.0 (d), 22.8 (q), 19.0
(q), -0.7 (q). HRMS exact mass calcd for [M + 1]+ C11H25NO2Si
231.1655, found 231.1654.
1
yield); TLC pure hexanes, molybdenum stain, Rf ) 0.58; H NMR
(250 MHz, CDCl3) δ 4.32 (s, 1H), 1.06 (s, 9H), 0.93 (s, 9H); 13C NMR
(APT) (63 MHz, CDCl3) δ 143.0-111.9 (many peaks due to C-F
coupling), 70.3 (d), 61.6 (s), 36.8 (s), 26.1 (q), 25.6 (q); ESMS m/e
306.10.
2,2,5,5-Tetramethyl-4-diethylphosphono-3-azahexane 3-nitroxide
(3). The N-tert-butyl-R-tert-butylimine (500 mg, 3.50 mmol) and diethyl
phosphite (distilled under nitrogen, 480 mg, 3.50 mmol) were heated
1
to 75 °C and monitored by H NMR aliquots. After 4 h, little imine
starting material could be seen by NMR. The reaction mixture was
cooled, and diluted with 10 mL of diethyl ether, and washed twice
with 3 mL of saturated sodium bicarbonate solution. After the mixture
was dried over magnesium sulfate, all volatiles were removed in vacuo
to give 562 mg of crude 22 as an oil (56% yield). This oil was directly
submitted to oxidation. The amine, 22 (547 mg, 1.96 mmol), was
dissolved in 4.0 mL of dichloromethane and cooled to 0 °C. A solution
of purified m-chloroperbenzoic acid (509 mg, 2.94 mmol) in 7.0 mL
of dichloromethane was added dropwise by cannula. The reaction
mixture quickly became yellow. It was allowed to warm to room
temperature and stirred for 1.5 h with the addition of enough
dichloromethane to dissolve the precipitated m-chlorobenzoic acid.
Anhydrous sodium carbonate (312 mg, 2.94 mmol) was added, and
the bright orange reaction mixture was shaken with 10 mL of saturated
sodium bicarbonate solution until all of the solids dissolved. The organic
layer was dried over magnesium sulfate and the solvent evaporated to
provide an orange-yellow oil. Purification by flash column chroma-
tography, eluting with 2:1 hexane/ethyl acetate, gave the nitroxide 3
(246 mg, 43% yield); TLC 2:1 hexane/ethyl acetate, molybdenum stain,
Preparation of N-(2-Trimethylsilyloxy-1,1-dimethylethyl)-R-iso-
propylnitrone (13) from 8 and 9. The mixture of tautomers, 8 and 9
(477 mg, 3.00 mmol), and pyridine (0.363 mL, 4.5 mmol) was dissolved
in 6 mL of diethyl ether. Trimethylchlorosilane (0.57 mL, 4.5 mmol)
was added dropwise and the reaction mixture stirred at room temper-
ature for 12 h. The precipitate was then filtered and washed with
dichloromethane, and the filtrate was evaporated to dryness. The crude
product was purified by flash chromatography, eluting with ethyl
acetate, to give the nitrone, 13, as a colorless oil (493 mg, 71% yield).
Spectral characteristics were the same as those described above.
1-Trimethylsilyloxy-2,2,5-trimethyl-4-phenyl-3-azahexane 3-ni-
troxide (12). N-(2-Trimethylsilyloxy-1,1-dimethylethyl)-R-isopropylni-
trone, 13 (8.34 g, 35.9 mmol), was dissolved under nitrogen in dry
THF (50 mL) and cooled to 0 °C. A 3.0 M solution of phenylmagne-
sium bromide (23.9 mL, 71.8 mmol) in diethyl ether was added
dropwise by cannula at this temperature over 10 min. During the
addition the mixture turned dark, and some precipitate formed. After
the mixture had been stirred at room temperature for 2 h, excess
Grignard reagent was decomposed by the addition of concentrated
1
Rf ) 0.45; H NMR (250 MHz, CDCl3, in the presence of phenylhy-
drazine) δ 3.89 (d, 1H, J ) 9.3 Hz), 3.72 (d, 1H, J ) 9.3 Hz), 2.50 (br
s), 1.75 (br s), 1.70-1.40 (m), 1.27-0.75 (m).
N-(2-Hydroxy-1,1-dimethylethyl)-R-isopropylnitrone. Mixture of
Linear Nitrone and Cyclic Oxazolidine Tautomers 8 and 9. A
solution of ammonium chloride (3.21 g, 60.0 mmol) in water (40 mL)
was added to a solution of 2-methyl-2-nitropropanol-1, 7 (5.95 g, 50.0
mmol), in ethanol (120 mL). The combined solution was stirred and

Alkoxyamine for Controlled Polymerizations
J. Am. Chem. Soc., Vol. 121, No. 16, 1999 3917
ammonium chloride (50 mL) and water (25 mL) until all of the solids
dissolved. The organic layer was separated, and the aqueous layer was
extracted with diethyl ether (2 × 40 mL). The combined organic layers
were then washed with brine (20 mL), and the residue was treated with
a mixture of methanol (150 mL), concentrated NH4OH (4 mL), and
Cu(OAc)2 (359 mg, 1.80 mmol) to give a brown solution. A stream of
air was bubbled through the solution for 30 min during which time it
turned dark green. This was concentrated and the residue partitioned
between chloroform (50 mL) and 2 M NH4OH (50 mL). The organic
layer was separated, and the aqueous layer was extracted with
chloroform (2 × 20 mL). The combined organic layers were then
washed with 20 mL of brine (light emulsion), dried over magnesium
sulfate, and concentrated in vacuo. The crude product was purified by
flash chromatography eluting with 16:1 hexane/ethyl acetate to afford
the nitroxide, 12, as an orange oil (3.85 g, 35% yield); TLC 16:1 hexane/
ethyl acetate, molybdenum stain, Rf ) 0.53, IR(CDCl3) 2960, 1252,
2H, J ) 6.5 Hz, both diastereomers), 3.41 (d, 1H, J ) 10.8 Hz, major
diastereomer), 3.29 (d, 1H, J ) 10.8 Hz, minor diastereomer), 2.35
(two m, 2H, both diastereomers), 1.62 (d, 3H, J ) 6.8 Hz, major
diastereomer), 1.54 (d, 3H, J ) 7.0 Hz, minor diastereomer), 1.31 (d,
3H, J ) 6.3 Hz, major diastereomer), 1.04 (s, 9H, minor diastereomer),
0.92 (d, 3H, minor diastereomer), 0.77 (s, 9H, major diastereomer),
0.54 (d, 3H, J ) 6.5 Hz, major diastereomer), 0.22 (d, 3H, J ) 6.5 Hz,
minor diastereomer); 13C NMR (APT) (63 MHz, CDCl3, both diaster-
eomers) δ 145.87 (s), 145.08 (s), 142.56 (s), 142.35 (s), 131.03 (d),
128.15 (d), 127.46 (d), 127.37 (d), 127.28 (d), 127.09 (d), 126.70 (d),
126.43 (d), 126.25 (d), 83.58 (d), 82.91 (d), 72.30 (d), 72.21 (d), 60.59
(s), 60.45 (s), 32.12 (d), 31.69 (d), 28.48 (q), 28.3 (q), 24.81 (q), 23.26
(q), 23.23 (q), 22.05 (q), 21.26 (q), 21.14 (q). MS (FAB) m/z 326 ([M
+ 1]+, 3), 221 (11), 178 (31), 148 (15), 133 (75), 122 (21), 106 (17),
105 ([C8H9]+, 100); HRMS exact mass calcd for [M + 1]+ C22H32NO
326.2484, found 326.2485.
1
1102, 874, 842 cm-1; H NMR (250 MHz, CDCl3, in the presence of
1-(trans-2,5-Dimethyl-2,5-diphenylpyrrolidine-1-oxy)-1-phenyl-
ethane (26). The alkoxyamine, 26, was prepared from the C2-symmetric
nitroxide trans-2,5-dimethyl-2,5-diphenylpyrrolidine-1-oxyl, 55, using
the general PbO2 procedure as described above. Purification by flash
column chromatography, eluting with 95:5 hexane/ethyl acetate, gave
the desired alkoxyamine, 26, as a colorless oil (62% yield). The major
and minor diastereomers were obtained as an inseparable mixture in a
2.5:1 ratio as elucidated by integration of the 500 MHz 1H NMR
spectrum; TLC 95:5 hexane/ethyl acetate, UV, p-anisaldehyde stain,
phenyl hydrazine) δ 3.44 (d, 1H, Jgem ) 9.5 Hz), 3.32 (d, 1H, Jgem
)
9.5 Hz), 1.18 (d, 3H, J ) 6.5 Hz), 1.14 (s, 3H), 0.78 (s, 3H), 0.61 (d,
3H, J ) 6.8 Hz), 0.05 (s, 9H); HRMS exact mass calcd for [M + 1]+
C17H30NO2Si 308.2045, found 308.2049.
N-iso-propyl-r-iso-propylnitrone (16). A mixture of 2-nitropro-
pane, 15 (445 mg, 5.0 mmol), isobutyraldehyde (453 mL, 5.0 mmol),
ammonium chloride (294 mg, 5.5 mmol), and water (20 mL) was cooled
to 0 °C in an ice-bath under ambient atmosphere. While stirring, Zn
powder (1.30 g, 20.0 mol) was added over 30 s, and the resulting
mixture was allowed to stir in the ice-bath and warm overnight. After
that, the mixture was filtered through a glass filter and the cake washed
twice with 2 mL of methanol. The product was extracted four times
with 10 mL of dichloromethane. The combined organic layers were
then dried over magnesium sulfate and concentrated in vacuo to give
the nitrone, 16, as a colorless low-melting solid (1.01 g, 78% yield);
1H NMR (250 MHz, CDCl3) δ 6.59 (d, 1H, J ) 7.3 Hz), 4.00 (hept,
1H, J ) 6.5 Hz), 3.18 (m, 1H), 1.41 (d, 6H, J ) 6.5 Hz), 0.60 (d, 6H,
J ) 7.3 Hz); 13C NMR (APT) (63 MHz, CDCl3) δ 141.8 (d), 65.8 (d),
25.4 (d), 20.5 (q), 18.7 (q).
N-iso-Propyl-r-tert-butylnitrone (17). The nitrone, 17, was pre-
pared from pivalaldehyde (900 mg, 10.5 mmol), 2-nitropropane, 15
(890 mg, 10.0 mmol), ammonium chloride (588 mg, 11.0 mmol), and
Zn powder (2.60 g, 40.0 mol) in 20 mL of water as described above.
The desired nitrone, 17, was isolated as a colorless solid (70% yield);
1H NMR (250 MHz, CDCl3) δ 6.52 (s, 1H), 3.98 (hept, 1H), 1.39 (d,
6H, J ) 6.5 Hz), 1.27 (s, 9H); 13C NMR (APT) (63 MHz, CDCl3) δ
142.0 (d), 66.8 (d), 32.5 (s), 26.1 (q), 20.8 (q).
1
Rf ) 0.3; IR(CDCl3) 2966, 1461, 1379, 1261, 1091, 1014 cm-1; H
NMR (500 MHz, CD3OD, major and minor diastereomers) δ 6.96-
7.69 (m, 30H), 4.22 (major, q, 1H, J ) 6.5), 4.23 (minor, q, 1H, J )
6.5), 2.46-2.66 (m, 2H), 2.12-2.22 (m, 2H), 1.86-2.04 (m, 4H), 1.57
(minor, s, 3H), 1.22 (major, s, 3H), 1.20 (minor, d, 3H, J ) 6.5), 1.04
(major, s, 3H), 1.03 (minor, s, 3H), 1.00 (major, d, 3H, J ) 6.5); 13C
NMR (125 MHz, CD3OD, major and minor diastereomers) δ 153.61
(s), 153.36 (s), 145.71 (s), 145.71 (s), 145.05 (s), 144.84 (s), 129.78
(d), 129.04 (d), 128.97 (d), 128.81 (d), 128.54 (d), 128.44 (d), 128.11
(d), 127.80 (d), 127.69 (d), 127.48 (d), 127.32 (d), 126.94 (d), 82.73
(major, d), 81.88 (minor, d), 70.80 (minor, s), 69.75 (major, s), 69.75
(minor, s), 68.9 (major, s) 41.63(major, t), 41.48 (minor, t), 34.95
(minor, t), 34.71 (major, t), 30.51 (major, q), 30.51 (minor, q), 25.02
(minor, q), 23.61 (major, q), 22.43 (minor, q), 22.26 (major, q); LRMS
m/z 372 [M + H]+, 356, 267, 252, 190, 118, 105; HRMS Calcd for
C26H29NO 372.2327 [M + H], found 372.2325.
2,2,5,5-Tetramethyl-3-(1-phenylethoxy)-4-diethylphosphono-3-
azahexane (27). The alkoxyamine, 27, was prepared from 2,2,5,5-
tetramethyl-4-diethylphosphono-3-azahexane-3-nitroxide, 3, using the
general PbO2 procedure as described above. Purification by flash
column chromatography (2:1 pentane/diethyl ether) afforded 27 as a
colorless oil, 34% yield that was determined to be a 1:1.6 mixture of
the diastereomers by integration of the methine hydrogens at δ 5.24
and 4.99 ppm, respectively. In this case the diastereomers were
separated by flash chromatography fraction I: TLC 1:1 pentane/diethyl
General Procedure for the Formation of Alkoxyamines using
PbO2. 2,2,5-Trimethyl-3-(1-phenylethoxy)-4-phenyl-3-azahexane
(29). A two-phase mixture of 1-bromoethylbenzene (11.1 g, 60.0 mmol)
and fuming hydrazine (19.2 mL, 600 mmol) was solicited for 30 min
under nitrogen until a single cloudy phase was observed. The mixture
was diluted with 10 mL of diethyl ether, and the organic and hydrazine
layers were separated. The hydrazine layer was washed with 500 mL
of diethyl ether. The organic phases were combined and washed with
250 mL of 10% aqueous potassium hydroxide followed by 250 mL of
brine, dried over magnesium sulfate, and filtered. Volatiles were
removed in vacuo to give a slightly yellow oil which was diluted with
toluene (50 mL) and cooled to -78 °C. In a separate flask, lead dioxide
(21.5 g, 90 mmol), 2,2,5-trimethyl-4-phenyl-3-azahexane 3-nitroxide,
1 (6.61 g, 30 mmol), and toluene (50 mL) were sonicated under nitrogen
for 5 min and then cooled to -78 °C. The benzylic hydrazine solution
was added by cannula, and the residues were washed in with an
additional 25 mL of toluene. The reaction mixture was allowed to warm
to room temperature over 1 h, diluted with 500 mL of diethyl ether,
filtered through Celite, and washed with 250 mL of diethyl ether.
Volatiles were removed in vacuo to give a colorless oil. Purification
by flash column chromatography (100:1 hexane/ethyl acetate) afforded
7.10 g of alkoxyamine, 29, as a colorless oil (73% yield). The coupling
product was determined to be a 1:1.3 mixture of the diastereomers as
indicated by integration of the methyl hydrogens at δ 0.54 and 0.22
ppm. TLC 100:1 hexane/ethyl acetate, molybdenum stain, Rf ) 0.48;
1
ether, molybdenum stain, Rf ) 0.57; H NMR (250 MHz, CDCl3) δ
7.5-7.2 (m, 5H), 5.24 (q, 1H, J ) 6.5 Hz), 4.05-3.75 (m, 2H), 3.41
(d, 1H, J ) 26.0 Hz), 3.50-3.30 (m, 2H), 1.56 (d, 3H, J ) 6.5 Hz),
1.3-1.1 (m, 21H), 0.88 (t, 3H, J ) 7.0 Hz); fraction II TLC 1:1 pentane/
diethyl ether, molybdenum stain, Rf ) 0.44; 1H NMR (250 MHz,
CDCl3) δ 7.5-7.2 (m, 5H), 4.99 (q, 1H, J ) 6.5 Hz), 4.5-3.9 (m,
4H), 3.35 (d, 1H, J ) 26.0 Hz), 1.60 (d, 3H, J ) 6.5 Hz), 1.4-1.2 (m,
15H), 0.84 (s, 9H).
cis-1,3-Dimethyl-2-(1-phenylethoxy)-1,3-diphenylisoindoline (30a).
The alkoxyamine, 30a, was prepared from meso-1,3-dimethyl-1,3-
diphenylisoindolin-2-yloxyl, 56, using the general PbO2 procedure as
described above. Purification by flash column chromatography, eluting
with 50:1 to 16:1 hexane/ethyl acetate, afforded 30a as a colorless oil,
(32% yield). TLC 32:1 hexane/ethyl acetate, molybdenum stain, Rf )
1
0.30; IR(CDCl3) 3025, 2990, 1602, 1496, 1449, 1301, 1067 cm-1; H
NMR (250 MHz, CDCl3) δ 7.60 (d, 2H, J ) 7.3 Hz), 7.5-6.7 (m,
17H), 4.12 (q, 1H, J ) 6.5 Hz), 1.99 (s, 3H), 1.86 (s, 3H), 0.84 (d, 3H,
J ) 6.5 Hz); 13C NMR (APT) (63 MHz, CDCl3) δ 148.29 (s), 147.99
(s), 146.35 (s), 145.87 (s), 143.68 (d), 128.16 (d), 127.8 (d), 127.73
(d), 127.6 (d), 127.53 (d), 126.92 (d), 126.76 (d), 126.49 (d), 126.37
(d), 123.3 (d), 80.85 (d), 73.11 (s), 72.88 (s), 22.75 (q), 22.59 (q), 21.78
1
IR(CDCl3) 2956, 1492, 1452, 1382, 1207, 1061 cm-1; H NMR (250
MHz, CDCl3, both diastereomers) δ 7.5-7.1 (m, 20H), 4.90 (q + q,

3918 J. Am. Chem. Soc., Vol. 121, No. 16, 1999
Benoit et al.
(q). MS (FAB) m/e 420 ([M+ + 1], 18), 315 ([nitroxide+ + 1], 88),
300 ([nitroxide+ - CH2], 100), 104 ([styrene+], 79); HRMS exact mass
calcd for [M+ + 1] C30H30NO 420.23274, found 420.2328.
eluting with hexane/ethyl acetate 30:1 to give the hydroxy-function-
alized alkoxyamine, 33, as a colorless oil (77 mg, 93% yield); TLC
hexane/ethyl acetate 4:1, molybdenum stain, Rf ) 0.25, IR(CDCl3) 3063,
2978, 1452, 1366, 1058 cm-1 1H NMR (250 MHz, CDCl3, both
;
trans-1,3-Dimethyl-2-(1-phenylethoxy)-1,3-diphenylisoindoline
(30b). The alkoxyamine, 35, was prepared from d,l-1,3-dimethyl-1,3-
diphenylisoindoline 2-nitroxide, 57, using the general PbO2 procedure
as described above. Purification by flash column chromatography,
eluting with 5:1 hexane/dichloromethane, afforded 30b as a colorless
oil, 81% yield which was determined to be a 2.2:1 mixture of
diastereomers (as indicated by integration of the methyl hydrogens at
δ 2.16 and 1.73 ppm); TLC 5:1 hexane/dichloromethane, molybdenum
stain, Rf ) 0.28; IR(CDCl3) 3061, 3032, 2977, 2931, 1600, 1493, 1448,
diastereomers) δ 7.5-7.1 (m, 20H), 5.0-4.8 (m, 2H), 3.7-2.2 (m, 9H),
1.65 (d, 3H, J ) 6.8 Hz), 1.56 (d, 3H, J ) 6.8 Hz), 1.5-1.4 (m, 1H),
1.35 (d, 3H, J ) 6.3 Hz), 1.27 (s, 3H), 1.11 (s, 3H), 0.86 (s, 3H), 0.85
(d, 3H, J ) 6.3 Hz), 0.68 (s, 3H), 0.58 (d, 3H, J ) 6.8 Hz), 0.41 (s,
3H), 0.22 (d, 3H, J ) 6.5 Hz); 13C NMR (APT) (63 MHz, CDCl3,
both diastereomers) δ 144.5 (s), 144.2 (s), 141.5 (s), 141.2 (s), 130.6
(d), 130.6 (d), 128.4 (d), 128.3 (d), 127.7 (d), 127.5 (d), 127.5 (d),
127.0 (d), 126.9 (d), 126.7 (d), 126.1 (d), 83.4 (d), 83.4 (d), 72.5 (d),
72.1 (d), 70.1 (t), 69.6 (t), 63.7 (s), 63.3 (s), 31.9 (d), 31.2 (d), 25.4
(q), 25.0 (q), 24.4 (q), 23.2 (q), 22.1 (q), 22.1 (q), 21.2 (q), 20.9 (q),
20.1 (q), 19.4 (q); HRMS exact mass calcd for [M + 1]+ C22H31NO2
341.2354, found 341.2355.
1
1370, 1070 cm-1; H NMR (500 MHz, C6D6, both diastereomers) δ
7.8-6.6 (m, 19H), 4.51-4.44 (q + q, 1H, both diastereomers), 2.16
(s, 3H, minor diastereomer), 1.73 (s, 3H, major diastereomer), 1.62 (s,
3H, major diastereomer), 1.57 (s, 3H, minor diastereomer), 1.54 (d,
3H, J ) 6.5 Hz, minor diastereomer), 1.12 (d, 3H, J ) 7.0 Hz, major
diastereomer); 13C NMR (APT) (63 MHz, CDCl3, both diastereomers)
δ 148.7 (s), 147.6 (s), 144.0 (s), 143.6 (s), 143.2 (s), 129.9 (d), 129.7
(d), 128.2 (d), 128.1 (d), 128.0 (d), 127.9 (d), 127.73 (d), 127.65 (d),
127.5 (d), 127.4 (d), 127.0 (d), 126.9 (d), 126.82 (d), 126.76 (d), 126.5
(d), 126.3 (d), 123.5 (d), 123.3 (d), 121.6 (d), 81.7 (d), 80.4 (d), 72.5
(s), 72.2 (s), 29.1 (q), 28.3 (q), 22.7 (q), 22.5 (q), 21.1 (q), 20.1 (q).
MS (FAB) m/e 420 ([M+ + 1], 15), 315 ([nitroxide+ + 1], 100), 300
([nitroxide+ - CH2], 77), 104 ([styrene]+, 63); HRMS exact mass calcd
for [M+ + 1] C30H30NO 420.2327, found 420.2328.
2,2,5,5-Tetramethyl-3-(1-phenylethoxy)-4-phenyl-3-azahexane (31).
The alkoxyamine, 31, was prepared from 2,2,5,5-tetramethyl-4-phenyl-
3-azahexane-3-nitroxide, 52 (70.3 mg, 0.30 mmol), using the general
PbO2 procedure as described above. Purification by flash column
chromatography, eluting with pure hexanes, afforded 31 as a colorless
oil, 59% yield which was determined to be a 1:1.3 mixture of the
diastereomers by integration of the methine hydrogens at δ 5.25 and
5.10 ppm; TLC hexanes, molybdenum stain, Rf ) 0.27; IR(CDCl3)
2973, 1481, 1451, 1362, 1198, 1059 cm-1; 1H NMR (250 MHz, CDCl3,
both diastereomers) δ 7.6-7.0 (m, 20H), 5.25 (q, 1H, J ) 6.5 Hz,
minor diastereomer), 5.10 (q, 1H, J ) 6.8 Hz, major diastereomer),
3.85 (s, 1H, minor diastereomer), 3.76 (s, 1H, major diastereomer),
1.67 (d, 3H, J ) 6.8 Hz, major diastereomer), 1.62 (d, 3H, J ) 6.5 Hz,
minor diastereomer), 1.09 (s, 9H, minor diastereomer), 1.07 (s, 9H,
major diastereomer), 0.93 (s, 9H, minor diastereomer), 0.72 (s, 9H,
major diastereomer); 13C NMR (APT) (63 MHz, CDCl3, both diaster-
eomers) δ 145.59 (s), 144.20 (s), 140.35 (s), 139.63 (s), 132.95 (d),
128.22 (d), 128.07 (d), 127.85 (d), 127.64 (d), 127.21 (d), 127.03 (d),
126.76 (d), 126.55 (d), 126.47 (d), 126.16 (d), 126.03 (d), 82.65 (d),
77.91 (d), 74.27 (d), 74.12 (d), 61.65 (s), 61.41 (s), 35.67 (s), 35.48
(s), 29.42 (q), 29.28 (q), 29.0 (q), 24.14 (q), 22.90 (s). MS (FAB) m/z
340 ([M+1]+, 1), 234 ([nitroxide]+, 38), 179 (14), 178 ([nitroxide-
C4H8]+, 100), 147 (32), 122 (18), 105 ([C8H9]+, 56); HRMS exact mass
calcd for [M+1]+ C23H34NO 340.2640, found 340.2640.
Methyl 2-(trans-2,5-dimethyl-2,5-diphenylpyrrolidine-1-oxy) pro-
pionate (34). A solution of methyl propionate (43 µl, 0.450 mmol) in
1.6 mL of THF was cooled to -78 °C, and 2 M LDA in heptane/
THF/ethylbenzene (300 µl, 0.600 mmol) was added. The mixture was
stirred at -78 °C for 3 h and added dropwise to a mixture of the C2
symmetric nitroxide trans-2,5-dimethyl-2,5-diphenylpyrrolidine-1-oxyl
(79.9 mg, 0.300 mmol) and CuCl2 (anhyd, 64.5 mg, 0.480 mmol) in
THF (1.5 mL), cooled to -78 °C. The reaction mixture was allowed
to warm to room temperature overnight, diluted with ether (20 mL),
and washed with saturated NaHSO4 (10 mL) and saturated NaCl (10
mL). The ether layer was dried over magnesium sulfate and filtered,
and the volatiles were removed in vacuo to give a yellow oil, which
was purified by flash column chromatography, eluting with 93:7 hexane/
ethyl acetate, to give the alkoxyamine, 34, as a pale yellow oil (58
mg, 55% yield). The major and minor diastereomers were obtained as
an inseparable mixture in a 1.1:1 ratio as elucidated by integration of
1
the 500 MHz H NMR spectrum in CDCl3; TLC 93:7 hexane/ethyl
acetate, UV, p-anisaldehyde stain, Rf ) 0.44; IR(CDCl3) 2978, 1743,
1490, 1449, 1373, 1279, 1208, 1091 cm-1;1H NMR (500 MHz, CDCl3,
major and minor diastereomers) δ 7.18-7.77 (m, 20H), 4.22 (minor,
q, 1H, J ) 7.5), 3.97 (major, q, 1H, J ) 7), 3.73 (major, s, 3H), 3.15
(minor, s, 3H), 2.52-2.62 (m, 2H), 2.14-2.30 (m, 2H), 1.90-2.06
(m, 4H), 1.60 (s, 3H), 1.59 (s, 3H), 1.37 (s, 3H), 1.15 (s, 3H), 1.14
(minor, d, 3H, J ) 7.5), 0.97 (d, 3H, J ) 7); 13C NMR (125 MHz,
CDCl3, major and minor diastereomers) δ 174.00 (major, s), 173.76
(minor, s), 151.60 (s), 151.52 (s), 142.93 (major, s), 142.93 (minor, s),
128.47 (d), 128.25 (d), 128.05 (d), 127.83 (d), 127.60 (d), 127.52 (d),
126.68 (d), 126.54 (d), 126.15 (d), 125.95 (d), 125.81 (d), 125.75 (d),
125.56 (d), 125.40 (d), 80.56 (minor, d), 79.25 (major, d), 69.95 (minor,
s), 68.49 (minor, s), 68.32 (minor, s), 67.26 (major, s), 51.44 (q), 51.05
(minor, q), 40.35 (minor, t), 40.21 (major, t), 33.17 (minor, t), 32.83
(major, t), 29.90 (major, q), 29.51 (minor, q), 23.99 (minor, q), 22.58
(major, q), 17.52 (major, q), 17.38 (minor, q); LRMS m/z 354 [M +
H]+, 338, 266, 250, 236, 222, 157, 131, 118; HRMS Calcd for C22H27-
NO3 353.1990 [M], found 353.1990.
3,3′-Dimethyl-N-(1′-phenylethoxy)-1-oxa-4-aza-spiro[4,5]-
decane (32). The alkoxyamine, 32, was prepared from 3,3′-dimethyl-
N-(oxyl)-1-oxa-4-azaspiro[4,5]decane, 58, using the general PbO2
procedure as described above. Purification by flash column chroma-
tography, eluting with 16:1 hexane/ethyl acetate, afforded 35 as a
colorless oil, (33%, yield); IR (CDCl3) 3036, 2931, 2247, 1598, 1486,
1-Trimethylsilyloxy-2,2,5-trimethyl-3-(1-phenylethoxy)-4-phenyl-
3-azahexane (35). The alkoxyamine, 35, was prepared from 1-tri-
methylsilyloxy-2,2,5-tetramethyl-4-phenyl-3-azahexane-3-nitroxide, 12,
using the general PbO2 procedure as described above. Purification by
flash column chromatography, eluting with hexane/ethyl acetate 30:1,
afforded 35 as a colorless oil, 66% yield which was determined to be
a 1:1 mixture of diastereomers; TLC hexane/ethyl acetate, 30:1,
1
1446, 1262, 1210, 1059, 927, 894, 697 cm-1; H NMR (250 MHz,
CDCl3) δ 7.32-7.34 (m, 5H), 4.61 (q, 1H, J ) 6.6 Hz), 3.4-3.6 (m,
2H), 1.0-2.0 (m, 6H), 1.48 (d, 3H, J ) 6.6 Hz), 1.28 (s, 1.5H), 1.26
(s, 1.5H), 1.07 (s, 1.5H), 0.71 (s, 1.5H); 13C NMR (APT) (63 MHz,
CDCl3) δ 143.8 (4°), 128.6 (d), 128.1 (d), 127.5 (d), 127.4 (d), 99.5
(4°), 99.0 (4°), 82.1 (d), 74.2 (t), 73.7 (t), 63.8 (4°), 63.4 (4°), 38.0 (t),
37.3 (t), 32.8 (t), 32.7 (t), 27.2 (q), 27.0 (q), 25.7 (t), 25.4 (t), 24.0 (t),
23.9 (t), 23.2 (t), 23.1 (t), 21.9 (q), 21.4 (q); Anal. Calcd for C18H27-
NO2 C, 74.7; H, 9.4; N, 4.8. Found C, 74.56; H, 9.28, N, 4.75.
1-Hydroxy-2,2,5-trimethyl-3-(1-phenylethoxy)-4-phenyl-3-aza-
hexane (33). To a solution of 1-trimethylsilyloxy-2,2,5-trimethyl-3-
(1-phenylethoxy)-4-phenyl-3-azahexane, 35 (100 mg, 0.241 mmol), in
methanol (5 mL) was added citric acid (50 mg), and the reaction was
stirred at room temperature for 5 min. The solution was concentrated
in vacuo and the crude product purified by flash chromatography,
molybdenum stain, Rf ) 0.43; IR(CDCl3) 2957, 1251, 1092, 1060 cm-1
;
1H NMR (250 MHz, CDCl3, both diastereomers) δ 7.6-7.1 (m, 20H),
5.0-4.8 (m, 2H), 3.6-3.3 (m, 2H), 3.0-2.9 (m, 2H), 2.4-2.3 (m, 1H),
1.62 (d, 3H, J ) 6.8 Hz), 1.53 (d, 3H, J ) 6.8 Hz), 1.4-1.3 (m, 1H),
1.31 (d, 3H, J ) 6.5 Hz), 1.09 (s, 3H), 0.93 (s, 3H + d, 2H), 0.86 (s,
3H), 0.54 (s, 3H + d, 2H), 0.20 (d, 3H, J ) 6.8 Hz), 0.08 (s, 9H),
-0.16 (s, 9H); 13C NMR (APT) (63 MHz, CDCl3, both diastereomers)
δ 145.7 (s), 145.0 (s), 142.7 (s), 132.4 (s), 130.9 (d), 128.3 (d), 128.1
(d), 127.9 (d), 127.5 (d), 127.4 (d), 127.3 (d), 127.0 (d), 126.9 (d),
126.5 (d), 126.2 (d), 83.6 (d), 82.7 (d), 72.1 (d), 72.0 (d), 69.5 (t), 69.2
(t), 64.4 (s), 64.3 (s), 32.0 (d), 31.6 (d), 24.8 (q), 23.5 (q), 23.2 (q),
23.2 (q), 22.1 (q), 21.9 (q), 21.7 (q), 21.3 (q), 21.2 (q), 20.4 (q), -0.4

Alkoxyamine for Controlled Polymerizations
J. Am. Chem. Soc., Vol. 121, No. 16, 1999 3919
(q), -0.6 (q); HRMS exact mass calcd for [M + 1]+ C25H39NO2Si
413.2749, found 413.2747.
diastereomer), 1.08 (s, 9H, minor diastereomer), 0.95 (m, 3H, minor
diastereomer), 0.79 (s, 9H, major diastereomer), 0.61 (d, 3H, J ) 6.5
Hz, major diastereomer) and 0.30 (d, 3H, J ) 6.5 Hz, minor
diastereomer); 13C NMR (APT) (63 MHz, CDCl3, both diastereomers)
δ 146.10 (s), 145.18 (s), 142.61 (s), 142.33 (s), 135.73 (d), 130.97 (d),
128.40 (d), 127.37 (d), 127.32 (d), 127.21 (d), 127.00 (d), 126.49 (d),
126.37 (d), 126.21 (d), 83.17 (d), 82.25 (d), 72.17 (d), 72.14 (d), 60.49
(s), 60.45 (s), 46.23 (t), 32.02 (d), 31.72 (d), 28.39 (q), 28.22 (q), 24.68
(q), 23.10 (q), 23.03 (q), 22.09 (q), 21.33 (q), 21.12 (q); Anal. Calcd
for C23H32ClNO C, 73.9; H, 8.62; N, 3.75. Found C, 74.1; H, 8.84; N,
3.77.
2,2,5,5-Tetramethyl-3-(1-phenylethoxy-4-(4-trifluoromethylphen-
yl)-3-azahexane (36). The alkoxyamine, 36, was prepared from 2,2,5,5-
tetramethyl-4-(4-trifluoromethylphenyl)-3-azahexane-3-nitroxide, 54,
using the general PbO2 procedure as described above. Purification by
flash column chromatography (pure hexanes) afforded 36 as a colorless
oil, 88% yield which was determined to be a 1:1.8 mixture of the
diastereomers by integration of the methine hydrogens at δ 5.25 and
5.14 ppm; TLC pure hexanes, molybdenum stain, Rf ) 0.49; 1H NMR
(500 MHz, CDCl3, both diastereomers) δ 7.8-7.2 (m, 18H), 5.25 (q,
1H, J ) 6.8 Hz, minor diastereomer), 5.14 (q, 1H, J ) 7.0 Hz, major
diastereomer), 3.94 (s, 3H, minor diastereomer), 3.86 (s, 3H, major
diastereomer), 1.71 (d, 3H, J ) 7.0 Hz, major diastereomer), 1.65 (d,
3H, J ) 6.8 Hz, minor diastereomer), 1.12 (s, 3H, minor diastereomer),
1.10 (s, 3H, major diastereomer), 0.95 (s, 3H, minor diastereomer),
0.76 (s, 3H, major diastereomer); 13C NMR (APT) (125 MHz, CDCl3,
both diastereomers) δ 145.3 (s), 145.08 (s), 143.9 (s), 133.2 (d), 132.5
(d), 128.5 (d), 128.2 (d), 127.4 (d), 127.2 (d), 126.5 (d), 123.7 (d),
123.5 (d), 83.0 (d), 78.6 (d), 73.9 (d), 73.8 (d), 61.9 (s), 61.7 (s), 35.8
(s), 35.6 (s), 29.3 (q), 29.2 (q), 29.1 (q), 29.0 (q), 24.0 (q), 23.1 (q).
MS (FAB) m/z 408 ([M + 1]+, 26), 302 ([nitroxide]+, 57), 286 (51),
246 (64); HRMS exact mass calcd for [M + 1]+ C24H33F3NO 408.2515,
found 408.2509.
4,4-Dimethyl-2,2-dipentyl-N-(1′-phenylethoxy)-1-oxa-3-azacyclo-
pentane (39). The alkoxyamine, 39, was prepared from 4,4-dimethyl-
2,2-dipentyl-N-(oxyl)-1-oxa-3-azacyclopentane, 60, using the general
manganese procedure as described above. Purification by flash column
chromatography, eluting with 1:3 dichloromethane/hexane, afforded 39
as a colorless oil, (60% yield); IR (CDCl3) 2950, 1600, 1490, 1210,
1
1065, and 710 cm-1; H NMR (250 MHz, CDCl3) δ 7.30-7.40 (m,
5H), 4.60 (q, 1H, J ) 6.6 Hz), 3.4-3.6 (m, 2H), and 1.0-2.0 (m,
31H); 13C NMR (APT) (63 MHz, CDCl3) δ 144.51, 128.65, 128.12,
127.63, 127.41, 99.33, 83.03, 74.15, 63.48, 38.03, 37.94, 27.24, 27.08,
26.88, 25.95, 25.49, 23.67, 23.40, 21.9, 20.58, 19.62, and 19.06; Anal.
Calcd for C23H39NO2 C, 76.4; H, 10.87; N, 3.87. Found C, 76.2; H,
10.93, N, 4.01.
1-(3-cyano-2,2,5,5-tetramethylpyrrolidine-1-oxy)-1-phenylethane
(40). The alkoxyamine, 40, was prepared from the 3-cyano-2,2,5,5-
tetramethylpyrrolidine-1-oxyl, 59, using the general manganese pro-
cedure as described above. Purification by flash column chromatog-
raphy, eluting with 1:3 dichloromethane/hexane, gradually increasing
to 3:1 dichloromethane/hexane, gave the desired alkoxyamine, 40, as
a colorless oil (71% yield); 1H NMR (500 MHz, CDCl3) δ 7.25-7.40
(m, 5H), 4.44 (q, 1H, J ) 6.5), 3.23 (q, 1H), 1.80-2.10 (m, 2H), 1.55
(d, 3H), 0.75, 0.91, 1.04, and 1.22 (each s, 12H); 13C NMR (125 MHz,
CDCl3) δ 145.60, 129.81, 128.85, 128.45, 128.32, 127.80, 126.90,
82.54, 41.14, 30.50, 29.63, 25.00, 23.65, 22.89, and 22.20; Anal. Calcd
for C17H24N2O C, 79.02; H, 9.36; N, 10.84. Found C, 79.1; H, 9.45;
N, 10.62.
2,5-Dimethyl-3-(1-phenylethoxy)-4-phenyl-3-azahexane (41). N-iso-
propyl-R-iso-propylnitrone, 16 (1.00 g, 7.75 mmol), was dissolved under
nitrogen in 20 mL of dry THF. A 3.0 M solution of phenylmagnesium
bromide (5.17 mL, 15.5 mmol) in diethyl ether was added dropwise
by cannula at room temperature over 2 min. The reaction mixture was
then stirred at room temperature for 12 h, excess Grignard reagent was
decomposed by the addition of 20 mL of concentrated ammonium
chloride solution, and 10 mL of water was added until all of the solids
dissolved. The organic layer was separated, and the aqueous layer was
extracted with 10 mL of diethyl ether. The combined organic layers
were then dried over magnesium sulfate, filtered, and concentrated in
vacuo to give 1.57 g of crude hydroxyamine, 18a, as a pale yellow oil.
This compound was immediately used for the coupling reaction without
further purification. Formation of the alkoxyamine, 41, was achieved
using the PbO2 procedure defined above except that the crude
hydroxyamine derivative was employed in the place of the nitroxide.
This gave the alkoxyamine, 41, which was purified by flash chroma-
tography, eluting with 33:1 hexane/ethyl acetate, and obtained as a
colorless oil (333 mg, 28% yield); TLC: 33:1 hexane/ethyl acetate,
molybdenum stain, Rf ) 0.39, 1H NMR (250 MHz, CDCl3, both
diastereomers) δ 7.6-6.9 (m, 20H), 5.0-4.8 (m, 2H), 3.1-2.8 (m, 2H),
2.5-2.2 (m, 2H), 1.54 (d, 3H), 1.6-1.1 (m, 6H), 1.03 (d, 3H), 1.0-
0.8 (m, 15H), 0.75 (d, 3H); 13C NMR (APT) (63 MHz, CDCl3, both
diastereomers) δ 145.8 (s), 144.6 (s), 141.3 (s), 143.2 (s), 130.2 (d),
128.9 (d), 128.8 (d), 128.5 (d), 128.3 (d), 128.3 (d), 128.1 (d), 127.8
(d), 127.6 (d), 127.6 (d), 127.4 (d), 127.3 (d), 127.2 (d), 127.2 (d),
127.0 (d), 126.7 (d), 81.5 (d), 74.6 (d), 47.3 (d), 46.5 (d), 29.3 (d),
22.7 (q), 22.5 (q), 21.4 (q), 18.0 (q). HRMS exact mass calcd for [M
+ 1]+ C21H29NO 311.2249, found 311.2252.
2,2,5-Trimethyl-3-(1-phenylethoxy)-4-(4-trifluoromethylphenyl)-
3-azahexane (37). The alkoxyamine, 37, was prepared from 2,2,5-
trimethyl-4-(4-trifluoromethylphenyl)-3-azahexane-3-nitroxide, 53 (70.3
mg, 0.30 mmol), using the general PbO2 procedure as described above.
Purification by flash column chromatography (pure hexanes) afforded
37 as a colorless oil, 58% yield which was determined to be a 1:1.1
mixture of the diastereomers by integration of the methyl hydrogens
at δ 1.04 and 0.77 ppm; TLC pure hexanes, molybdenum stain, Rf )
0.44; IR (CDCl3) 2976, 1617, 1363, 1326, 1166, 1127, 1068 cm-1; 1H
NMR (250 MHz, CDCl3, both diastereomers) δ 7.7-7.2 (m, 18H), 5.0-
4.8 (m, 1H), 3.49 (d, 1H, J ) 10.5 Hz, major diastereomer), 3.36 (d,
1H, J ) 11.0 Hz, minor diastereomer), 1.63 (d, 3H, J ) 6.8 Hz, minor
diastereomer), 1.55 (d, 3H, J ) 6.8 Hz, major diastereomer), 1.32 (d,
3H, J ) 6.3 Hz, major diastereomer), 1.04 (s, 9H, minor diastereomer),
0.93 (d, 3H, J ) 6.3 Hz, minor diastereomer), 0.77 (s, 9H, major
diastereomer), 0.53 (d, 3H, J ) 6.5 Hz, major diastereomer), 0.19 (d,
3H, J ) 6.5 Hz, minor diastereomer); 13C NMR (APT) (63 MHz,
CDCl3, both diastereomers) δ 145.9 (s), 146.6 (s), 145.5 (s), 144.7 (s),
131.2 (d), 128.4 (d), 128.3 (d), 127.6 (d), 127.1 (d), 126.9 (d), 126.2
(d), 124.3 (d), 124.2 (d), 124.1 (d), 83.8 (d), 83.2 (d), 71.8 (d), 71.7
(d), 60.7 (s), 60.6 (s), 32.1 (d), 31.6 (d), 28.5 (q), 28.3 (q), 24.7 (q),
23.1 (q), 22.1 (q), 22.0 (q), 21.1 (q), 20.9 (q). MS (FAB) m/z 394 ([M
+ 1]+, 1.7), 302 ([nitroxide]+, 57), 246 (18), 201 (23), 159 (24), 105
(100); HRMS exact mass calcd for [M + 1]+ C23H31F3NO 394.2357,
found 394.2356.
General Procedure for Alkoxyamine Formation by Manganese
Coupling. 2,2,5-Trimethyl-3-(1-(4′-chloromethyl)phenylethoxy)-4-
phenyl-3-azahexane (43). To a solution of p-vinyl benzyl chloride (6.10
g, 40.0 mmol) and 2,2,5-trimethyl-4-phenyl-3-azahexane-3-nitroxide,
1 (4.40 g, 20.0 mmol), in 1:1 toluene/ethanol (150 mL) was added
[N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminato] man-
ganese(III) chloride (2.80 g, 4.0 mmol) followed by di-tert-butyl
peroxide (4.30 g, 30.0 mmol) and sodium borohydride (2.28 g, 60.0
mmol). The reaction mixture was then stirred at room temperature for
12 h, evaporated to dryness, and partitioned between dichloromethane
(150 mL) and water (200 mL). The aqueous layer was further extracted
with dichloromethane (3 × 100 mL). The combined organic layers were
then dried and evaporated to dryness, and the crude product was purified
by flash chromatography, eluting with 1:9 hexane gradually increasing
to 1:3 dichloromethane/hexane. The desired chloromethyl alkoxyamine,
43, was obtained as a colorless oil, (4.03 g, 62% yield); IR(CDCl3)
2950, 1490, 1450, 1390, 1210, 1065 cm-1; 1H NMR (250 MHz, CDCl3,
both diastereomers) δ 7.4-7.1 (m, 18H), 4.95 (q + q, 2H, J ) 6.5 Hz,
both diastereomers), 4.67 and 4.63 (each s, 4H, CH2Cl), 3.49 (d, 1H,
J ) 10.8 Hz, major diastereomer), 3.36 (d, 1H, J ) 10.8 Hz, minor
diastereomer), 2.38 (two m, 2H, both diastereomers), 1.66 (d, 3H, J )
6.8 Hz, major diastereomer), 1.34 (d, 3H, J ) 7.0 Hz, minor
2,5,5-Trimethyl-3-(1-phenylethoxy)-4-phenyl-3-azahexane (42).
The crude hydroxylamine, 18b, was prepared from N-iso-propyl-R-
tert-butylnitrone, 17, and phenylmagnesium bromide as described
above. This compound was immediately used for the coupling reaction
without further purification. Formation of the alkoxyamine, 42, was

3920 J. Am. Chem. Soc., Vol. 121, No. 16, 1999
Benoit et al.
achieved using the PbO2 procedure as defined for 41. This gave the
alkoxyamine, 42, which was purified by flash chromatography, eluting
with 33:1 hexane/ethyl acetate and obtained as a colorless oil (515 mg,
55% yield); the coupling product was determined to be a 1:1.13 mixture
of the diastereomeres as indicated by integration of the methyl
hydrogens at δ 1.01 and 0.95 ppm; TLC: 50:1 hexane/ethyl acetate,
molybdenum stain, Rf ) 0.39, 1H NMR (250 MHz, CDCl3, both
diastereomers) δ 7.7-7.1 (m, 20H), 5.1-4.9 (m, 2H, both diastereo-
mers), 3.55 (s, 1H, major diastereomer), 3.40 (s, 1H, minor diastere-
omer), 1.54-1.49 (d + d, 6H, both diastereomers), 1.01 (s, 9H, minor
diastereomer), 0.95 (s, 9H, major diastereomer), 0.9-0.6 (m, 6H, both
diastereomers), 0.59 (d, 3H, J ) 6.5 Hz, minor diastereomer), 0.36 (d,
3H, J ) 6.5 Hz, major diastereomer); 13C NMR (APT) (63 MHz,
CDCl3, both diastereomers) δ 144.9 (s), 144.4 (s), 141.0 (s), 140.3 (s),
131.8 (d), 128.8 (d), 128.3 (d), 128.2 (d), 128.2 (d), 127.8 (d), 127.6
(d), 127.3 (d), 127.3 (d), 127.2 (d), 127.1 (d), 127.0 (d), 126.8 (d),
126.5 (d), 126.4 (d), 126.1 (d), 80.8 (d), 79.5 (d), 75.3 (d), 56.5 (d),
55.8 (d), 35.5 (s), 35.3 (s), 29.1 (q), 28.9 (q), 23.1 (q), 22.4 (q), 21.6
(q), 18.5 (q), 18.0 (q), 17.7 (q). HRMS exact mass calcd for [M + 1]+
C22H31NO 325.2406, found 325.2409.
and dried to give the desired poly(n-butyl acrylate), 47, as a colorless
gum (26.9 g, 83.2% yield), Mn ) 24 000, PD ) 1.09.
General Procedure for Block Copolymer Formation; Preparation
of Poly(n-butyl acrylate)-b-polystyrene, 48, from 29. A mixture of
the desired alkoxyamine, 29 (32.5 mg, 0.1 mmol), the corresponding
nitroxide, 1 (1.1 mg, 0.005 mmol), and n-butyl acrylate (3.20 g, 25
mmol) were degassed by three freeze/thaw cycles, sealed under argon,
and heated at 125 °C under nitrogen for 16 h. The viscous reaction
mixture was then dissolved in dichloromethane (50 mL) and precipitated
(2×) into methanol (2 L). The gummy precipitate was then collected
and dried to give the desired poly(n-butyl acrylate), 47, as a colorless
gum (2.60 g, 80.4% yield), Mn ) 23 500, PD ) 1.09. The poly(n-
butyl acrylate), 47, starting block (2.00 g, 0.085 mmol) was then
redissolved in styrene (3.00 g, 28.8 mmol), acetic anhydride (17 mg,0.17
mmol) was added, and the polymerization reaction mixture was heated
at 125 °C for 8 h. The solidified reaction mixture was then dissolved
in dichloromethane (10 mL) and precipitated (2×) into methanol (500
mL). The precipitate was then collected by vacuum filtration and dried
to give the desired block copolymer, 48, as a white solid (4.46 g, 89.2%
yield), Mn ) 68 000, PD ) 1.16.
General Procedure for Styrene Polymerization; Preparation of
Polystyrene, 45, of DP ) 250 from 29. A mixture of the desired
alkoxyamine, 29 (325 mg, 1.0 mmol), acetic anhydride (204 mg, 2.0
mmol), and styrene (26.0 g, 250 mmol) were degassed by three freeze/
thaw cycles, sealed under argon, and heated at 125 °C under nitrogen
for 8 h. The solidified reaction mixture was then dissolved in
dichloromethane (50 mL) and precipitated (2×) into methanol (2 L).
The precipitate was then collected by vacuum filtration and dried to
give the desired polystyrene, 45, as a white solid (23.1 g, 87.8% yield),
Mn ) 23 000, PD ) 1.08.
General Procedure for Acrylate Polymerization; Preparation of
Poly(n-butyl acrylate), 47, of DP ) 250 from 29. A mixture of the
desired alkoxyamine, 29 (325 mg, 1.0 mmol), the corresponding
nitroxide, 1 (11 mg, 0.05 mmol), and n-butyl acrylate (32.0 g, 250
mmol) were degassed by three freeze/thaw cycles, sealed under argon,
and heated at 125 °C under nitrogen for 16 h. The viscous reaction
mixture was then dissolved in dichloromethane (50 mL) and precipitated
(2×) into methanol (2 L). The gummy precipitate was then collected
Acknowledgment. This paper is dedicated to Professor Keith
Ingold on the occasion of his 70th birthday. We thank the
MRSEC Program of the National Science Foundation under
Award Number DMR-9808677 for the Center for Polymeric
Interfaces and Macromolecular Assemblies, the National Science
Foundation (CHE-9527647), and the IBM Corporation for
financial support of this work. Dr. D. Joe Anderson and
Professor Glenn Millhauser are acknowledged for assistance
with the ESR spectra. Electrospray mass spectra were taken on
a MICROMASS Quattro II triplequadrupole instrument, the
purchase of which was made possible by a generous gift from
the W. M. Keck Foundation. We also thank Dr. Neeta Naik for
the preparation of both 26 and 34.
JA984013C