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Chemistry and Biochemistry
University of California
230 Physical Sciences Bldg.
Santa Cruz, CA 95064
Phone: (831) 459-4002
Fax: (831) 459-2935
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Rebecca Braslau Associate Professor of Chemistry B.A., Reed College Ph.D., University of Wisconsin, Madison Office: 342 PSB Phone: (831) 459-3087 Fax: (831) 459-2935 braslau@chemistry.ucsc.edu

Braslau Research Group Department of Chemistry University of California 1156 High Street Santa Cruz, CA 95064 Office Hours Class Times & Locations Labs: 395 PSB, 9-3663 Braslau Research Group

RESEARCH INTERESTS: Synthetic Organic Chemistry, Organic Free Radicals, Nitroxides, Development of Tailored Materials for Applications in Nanotechnology

Our research group uses free radicals in organic synthesis for a wide variety of applications. Free radicals are generally highly reactive, transient intermediates. Their use allows reactions to be carried out under mild conditions, and opens access to transformations that are often unavailable by more traditional methods. Our  current research covers both synthetic organic chemistry, and the newer area of the preparation of designed polymers for specific applications in nanotechnology

Radical [n+1] Cyclizations with SO₂
We have developed a convergent [n+1] radical annulation using SO2 to prepare 5-7-membered cyclic sulfones in one step under very mild conditions. We can control the endo vs. exo regioselectivity by

preparing either branched or linear allylic sulfide terminating groups. Substrates incorporating a triple bond in place of the monosubstituted double bond also work in both the endo and exo modes.

Synthesis of N-Alkoxyamines
We have developed a preparation of N-alkoxyamines (used as initiators in Nitroxide Mediated Polymerization) entailing silyl radical abstraction from alkyl halide precursors. This method allows for the preparation of 1°, 2° and 3° alkyl groups on the oxygen, as well as being compatible with various

nitroxides, including the thermally labile a-H nitroxides utilized widely in polymerization reactions. The reaction is chemoselective, enabling the introduction of functional groups onto the alkyl “foot” of the polymer.

Nitroxide-Mediated Polymerization
During a series of stereochemical studies between chiral nitroxides and prochiral carbon radicals, we entered a collaboration with Craig Hawker (at that time at IBM) developing a class of alpha hydrogen-substituted nitroxides as mediators for  highly controlled "living" polymerizations. The nitroxides are utilized as their corresponding N-alkoxyamines. For example, the use of the "Braslau-Vladimir Initiator" based on the nitroxide “TIPNO” leads to polymers with very low polydispersities from a wide class of monomer substrates, including acrylates, styrenes, acrylamides, acrylic acid, acrylonitrile and dienes. At 120° C, the nitroxide functions as a reversible radical cap to minimize the number of reactive free radical polymer chains present at any given time. This inhibits competing chain termination resulting from carbon radical coupling or disproportionation, and thus allowing chain extension to proceed uniformly for all polymer chains.

In newer work , we examined the effect on polymerization efficacy when we replace the t-butyl group of TIPNO with an adamantyl group (AD), or diol-derivatives shown below. Compared to TIPNO, AD performed slightly better with t-butyl acrylate, whereas both diol derivatives were less effective.

Thermal α-Hydrogen Nitroxide Decomposition Studies
The key to the superior performance of TIPNO in nitroxide-mediated polymerization lies in the thermal instability of this a-hydrogen containing nitroxide.  We have found that heating TIPNO at 120 °C analogous to the polymerization conditions results in clean formation of oxime. We have developed a new mechanistic hypothesis, which ties together the known redox chemistry of nitroxides with our decomposition studies.  Key is the rapid loss of t-butyl cation from the nitrone intermediate, which is so sterically hindered that the phenyl group is twisted out of plane, and cannot enjoy p stabilization between the phenyl group and the nitrone moiety. Fragmentation by loss of t-butyl cation forms the conjugated oxime.

To confirm the viability of this scenario, we synthesized a series of nitrones, in which the isopropyl group was replaced with progressively smaller groups: Et, Me and H.  Both UV/Vis studies and thermal stability studies confirmed this picture: the λ_max of the nitrones with increasing the steric bulk, approaching the λ _maxof an isolate phenyl ring at 254 nm. The therma stability of these nitrones also

fits with this picture: those with small substituents (H and Me)  show only small amounts of decomposition upon heating, whereas the Et substituted nitrone is somewhat less stable, and the iPr substituted nitrone undergoes 91% decomposition at 110 °C after only 2 hours.

Designed Polymers for Applications in Nanotechnology

Amphiphilic ABA Triblock Copolymers as Lipid Bilayer Mimics
In collaboration with Prof. Dave Deamer and Dr. Mark Akeson in conjunction with their alpha-hemolysin Nanopore Project (web link: http://www.cbse.ucsc.edu/research/research_nano.shtml), we are developing ABA hydrophilic, hydrophobic, hydrophilic triblock polymers with cross-linkable carboxylic acids pendant to the hydrophilic A portion. These designed polymers are expected to self assemble, to provide a tunable membrane for use in their nanopore, or to develop vesicles for biomedical applications such as drug delivery . Towards this

goal, we have developed two types of bidirectional initiators: an “Inside-Out” Initiator based on an inner phenethyl “foot” and two terminal nitroxides, and the complimentary “Outside-In” Initiator based on an inner bisnitroxide and outer phenethyl “feet.”   In both cases, the new blocks are grown simultaneously, resulting in ABA triblock copolymers that are symmetrical.  By growing from the inside-out, or the outside-in, we can now design block copolymers with a versatile combination of inside and outside blocks.

Using the “Inside-Out” bidirectional initiator, ABA triblocks with very short hydrophilic outer A blocks (such as the polyacrylic acid, poly-n-butylacrylate polymer shown below) self-assemble in water to form what appear to be vesicles:

The newer bisnitroxide based “Outside-In” initiator also performs beautifully, forming very controlled homopolymers, as well as triblock copolymers.

Polymer Chain End Functionalization
We are working on the design of both functionalized nitroxides, and functionalized phenethyl “feet,” to allow for the preparation of telechelic polymers that can be conveniently manipulated for applications in nanotechnology.  For example , we have recently utilized our silyl abstraction  methodology for the synthesis of N-alkoxyamines to introduce a pyrene-labeled polymer terminus. As a demonstration, short amphiphilic di-block copolymers self assemble in aqueous THF to form round bodies that are very clearly visible by fluorescence microscopy.

SELECTED PUBLICATIONS

N. L. Hill, J. L. Jarvis, F. Pettersson, R. Braslau* "Synthesis of Thiol-Derivatized Initiators for Nitroxide-Mediated Radical Polymerization: Reversible Disulfide Formation" Reactive & Functional Polymers 2007, in press: doi:10.1016/j.reactfunctpolym.2007.07.050.

G. O'Bryan, A. Nilsen, R. Braslau "Ketone Functionalized Nitroxides: Synthesis, Evaluation of N-Alkoxyamine Initiators, and Derivatization of Polymer Termini" Macromolecules, 2007, 40, 7848-7854.

W. Chau; R. Turner; R. Braslau* "Ketone _-Functionalization of Polymers Prepared by Nitroxide-Mediated Polymerization via Addition to a Benzyl Enol Ether" Reactive and Functional Poly. 2007, in press: doi:10.1016/j.reactfunctpolym.2007.07.006. 

J. K. Ruehl; A. Nilsen; S. Born; P. Thoniyot; R. Braslau* "Nitroxide-Mediated Polymerization to Form Symmetrical ABA Triblock Copolymers from a Bidirectional Alkoxyamine Initiator" Polymer 2007, 48(9), 2564-2571.

N. L. Hill; R. Braslau* "Synthesis of Arylethyl Functionalized N-Alkoxyamine Initiators and use in Nitroxide-Mediated Radical Polymerization" Journal of Polymer Science Part A: Polymer Chemistry, 2007, 45, 2341-2349.

J. K. Ruehl; R. Braslau* "A Bidirectional ATRP-NMRP Initiator: The Effect of Nitroxide Size on the Rate of Nitroxide-Mediated Polymerization" Journal of Polymer Science Part A: Polymer Chemistry, 2007, 45, 2015-2025.

J. Jiang, I. Kurnikov, N. A. Belikova, J. Xiao, Q. Zhao, I. L. Vlasova, A. A. Amoscato, R. Braslau, A. Studer, M. P. Fink, J. S. Greenberger, P. Wipf, V. E. Kagan* "Structural requirements for optimized delivery, inhibition of oxidative stress and anti-apoptotic activity of targeted nitroxides" J. Pharm. Exp. Therapeutics, 2007, 320, 1050-1060.

G. O'Bryan, R. Braslau* "Terminal Functionalization of Polymers via Single Electron Oxidation of N-Alkoxyamines," Macromolecules, 2006, 39, 9010-9017.

A. Nilsen, R. Braslau* "Nitroxide Decomposition," invited "Highlight" article for Journal of Polymer Science Part A: Polymer Chemistry, 2006, 44, 697-717.

A. Tsimelzon, D. Deamer, R. Braslau,* "Synthesis and Self-Assembly of Amphiphilic Diblock Copolymers using a Fluorescent Labeled N-Alkoxyamine Initiator," Macromolecular Rapid Communications, 2005, 26, 1872-1877.

A. Tsimelzon, R. Braslau* "N+1 Radical Annulations with SO2," Journal of Organic Chemistry, 2005, 70, 10854-10859.

N. Hill, R. Braslau* "Synthesis and Characterization of a Novel Bisnitroxide Initiator for Effecting "Outside-In" Polymerization" Macromolecules, 2005, 38, 9066-9074.

R. Braslau,* G. O'Bryan, A. Nilsen, J. Henise, T. Thongpaisanwong, E. Murphy, L. Mueller, J. Ruehl "The Synthesis and Evaluation of New Éø-Hydrogen Nitroxides for "Living" Free Radical Polymerization" Synthesis, 2005, 9, 1496-1506.