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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 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, Nitroxide-Mediated Free Radical Polymerization, Development of Tailored Materials for Applications in Nanotechnology, Nitroxide-based Sensors

Our research group is focused on reactions involving free radical intermediates.  Much of the work involves the synthesis and use of designed nitroxides for the preparation of specialized polymers for applications in nanotechnology, and as sensors via fluorescence quenching.  We are also engaged in the development of new synthetic methodologies via free radical intermediates.

Alpha-H Nitroxides to Prepare Tailored Polymers for Applications in Nanotechnology

Stereochemistry of Prochiral Radicals coupling with Chiral Nitroxides: the genesis TIPNO in Nitroxide-Mediated “Living” Free Radical Polymerization (NMRP)

The N-alkoxyamine coupling product 1 was found to be excellent at controlling the polymerization of styrenes, acrylates, acrylamides, acrylonitrile, (and dienes), to give living polymers with low polydispersity indices (JACS 1999, 121, 3904). Initiator 1 and close derivatives, and the key nitroxide “TIPNO” (tert-butyl isopropyl phenyl nitroxide) are widely utilized by polymer chemists.

Designed Nitroxides to Prepare Tailored Polymers for Applications in Nanotechnology

We have synthesized a number of derivatives of TIPNO as initiators for polymerization (Synthesis, 2005, 9, 1496).  We have also carried out an in-depth study on the products and mechanism of the thermal decomposition: key to the success of these alpha-hydrogen containing nitroxide in controlled polymerization (J. Poly. Sci. A, 2006, 44, 697).

           Decomposition of TIPNO:

Polymer Chain End Functionalization

1.   Functionalized Nitroxide “caps”

           Ketone bearing nitroxide (Macromolecules, 2007, 40, 7848): Ketones are extremely useful functionalities, as chemoselective ligation of specialized groups by hydrazone or oxime formation can be carried out under very mild conditions.

              Carboxylic acid functionalized nitroxide (Reactive & Functional Polymers, in press): We have developed a carboxylic acid derivative of TEMPO that is convenient for preparing biopolymer hybrid materials.

              Primary alcohol functionalized nitroxide (Reactive & Functional Polymers, in press):

Oxidative Alkoxyamine Cleavage with CAN: trapping with Nucleophiles

           The nitroxide group can be removed following polymerization upon treatment with CAN. For polystyrenes, the transient terminal benzylic cation can be trapped with nucleophiles to afford semitelechelic polymers.  Addition of a catalytic amount of TEMPO to aqueous mixtures affords ketone-terminated polymers (Macromolecules, 2006, 39, 9010).

           Thermolytic nitroxide exchange: addition to enol ethers

We have developed a post-polymerization thermolysis method using a benzyl enol ether introduces a ketone onto the polymer terminus (Reactive & Functional Polymers 2008, 68, 396).

           Exchange of Nitroxide for Azide        

Using the reagent ethylsulfonyl azide, polystyrenes undergo end-group functionalization to give azide-terminated polymers, ideal for use in copper catalyzed Huisgen [1,3] dipolar cycloaddition, popularized as “Click Chemistry” (Polymer, in press).

2.  Functionalized “Feet”

We have developed synthetic routes to convert the readily available benzyl chloride initiator to a variety of functionalized initiators including thiol and disulfide initiators (Reactive & Functional Polymers 2008, 68, 361), as well as azide, amine, benzyl alcohol and carboxylic acid-derivatized initiators (J. Poly. Sci. A, 2007, 45, 2341).

Bidirectional Initiators

We have developed two types of bidirectional initiators:

1.   “Inside-Out” Bidirectional Initiator

This initiator is indeed “living” at both ends, and is useful in the preparation of symmetrical amphiphilic ABA triblock copolymers (Polymer 2007, 48(9), 2564). In the presence of a soluble diamine, these amphiphiles self-assemble into discrete particles via salt bridges:

2.  “Outside-In” Bidirectional Initiator

We have designed and synthesized a central bisnitroxide to form an initiator that adds new monomers at the middle of the growing polymer chain:

This bidirectional initiator performs beautifully, forming very controlled homopolymers, as well as excellent triblock copolymers (Macromolecules, 2005, 38, 9066). Interestingly, it effects polymerizations at a much faster rate than either the monodirectional initiator, or the “inside-out” initiator, effecting polymerizations at temperatures as low as 70° C.  Low temperature EPR studies indicate a very strong spin-spin interaction for the bisnitroxide: the nitroxide moieties are about 5 Å apart.  This supports a resonance-stabilized delocalization of the key polymerization intermediate (Macromolecules 2008, 41, 1972-1982; J. Poly. Sci. A, 2007, 45, 2015).

Cyclic Polymers

1.  Cyclic Alkoxyamine Initiator       

2.  Post-polymerization “Click” Reaction to form Macrocycles

              Using our CAN-mediated oxidative removal of the nitroxide polymer “head” by trapping with propargyl alcohol, and azide functionalization of the “foot,” we have utilized the “Click” chemistry to prepare cyclic polymers under high dilution (Polymer, in press).

Nitroxides as Fluorescence Quenchers

The synthesis and applications of profluorescent nitroxides is the newest endeavor in our labs, recently becoming a major focus. Profluorescent nitroxides quench fluorescence of closely tethered fluorophores; fluorescence is restored upon reaction of the nitroxide, typically to from the alkoxyamine or hydroxylamine.  Profluorescent nitroxides have been studied for about 20 years by a number of research groups.

Nitroxides + “Quantum Dots”

              Using our thiol or disulfide functionalized alkoxyamines, we have been collaborating with our UCSC colleagues Prof. Jin Zhang and Prof. Shaowei Chen in anchoring our initiators onto metal nanoparticles. An obvious extension is the exploration of the ability of nitroxides to quench highly fluorescent “quantum dots”.

We have demonstrated restoration of fluorescence upon trapping the nitroxide moiety with ethyl radical to form alkoxyamine.

Detection of Urushiol from Poison Oak/Ivy/Sumac with Profluorescent Nitroxides

Contact with poison oak, poison ivy or poison sumac elicits contact dermatitis in about 70% of the population.  Avoidance of the invisible oil is the best way to prevent the annoying and in some cases medically incapacitating immunoresponse.   The Braslau group is working on a method to detect the active component urushiol using profluorescent nitroxides.

Initial reactions using catechol as a model for urushiol show extremely promising results. We envision development of a spray that will allow detection of microgram quantities of urushiol from skin, tools and clothing, enabling removal of the oil before a skin rash develops.  A preliminary patent has been filed on this exciting methodology.

A variety of other detection methodologies based on profluorescent nitroxides are now under development in the laboratory.

Synthetic Methodologies

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 (JOC, 2005, 70, 10854). This strategy is quite novel; the substrates are easily prepared, and the reaction proceeds under very mild conditions. We can control the endo vs. exo regioselectivity by preparing either branched or linear allylic sulfide terminating groups, respectively.

Acyl Radical Generation and Cyclizations

          In another synthetic methodology project, we have developed a method to stoichiometrically generate acyl radicals from acyl hydrazines (Tetrahedron, 2002, 58,  5513).

These can be used in 5-exo and 6-exo cyclization reactions:

Synthesis of N-Alkoxyamines      

Selected Publications:

J. Ruehl, N. Ningnuek, T. Thongpaisanwong, R. Braslau* “Cyclic Alkoxyamines for Nitroxide Mediated Radical Polymerization,” Journal of Polymer Science Part A: Polymer Chemistry, in press.

G. O’Bryan, N. Ningnuek, R. Braslau* “Cyclization of a-w Heterotelechelic Polystyrene Prepared by Nitroxide-Mediated Radical Polymerization” Polymer, in press.

J. Ruehl, C. Morimoto, D. J. Stevens, G. Millhauser, R. Braslau* “Carboxylic Acid and Hydroxy-Functionalized Alkoxyamine Initiators for Nitroxide," Reactive & Functional Polymers, in press.

J. Ruehl, N. L. Hill, E. D. Walter, G. Millhauser, R. Braslau* “A proximal bisnitroxide initiator: Studies in low-temperature nitroxide-mediated polymerizations” Macromolecules 2008, 41, 1972-1982.

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 2008, 68, 361-368.

W. Chau; R. Turner; R. Braslau* “Ketone ω-Functionalization of Polymers Prepared by Nitroxide-Mediated Polymerization via Addition to a Benzyl Enol Ether” Reactive & Functional Polymers 2008, 68, 396-405.

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.

J. Ruehl; A. Nilsen; S. Born; P. Thoniyot; L. Xu; S. Chen; 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. 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 Alpha-Hydrogen Nitroxides for "Living" Free Radical Polymerization” Synthesis, 2005, 9, 1496-1506.

R. Braslau,* A. Tsimelzon, and J. Gewandter “A Novel Methodology for the Synthesis of N-Alkoxyamines” Organic Letters, 2004, 6, 2233-2235.

R. Braslau,*V. Chaplinski, A. Nilsen, N. Arulsamy, “Stereochemical Studies Of Chiral Acyclic Nitroxides Coupling With A Prochiral Radical” Synthetic Communications, 2004, 34, 2433-2442.

R. Braslau,*  M. O. Anderson, F. Rivera, T. Haddad, A. Jimenez, and J. R. Axon, “Acyl Hydrazines as Precursors to Acyl Radicals” Tetrahedron, 2002, 58,  5513-5523.

R. Braslau,* M. O. Anderson, "Nitroxides”  in Free Radicals in Organic Synthesis, P. Renaud, M. Sibi, Eds.; Wiley-VCH: Weinheim, 2001, Chap. 3, Vol. 2, pp. 127-149.

R. Braslau,* N. Naik, H. Zipse, "Studies on the Stereoselective Coupling     of Prochiral Radicals with a Chiral C-2 Symmetric Nitroxide, " J. Am. Chem. Soc., 2000, 122, 8421-8434.

R. Braslau,* J. R. Axon, B. Lee, "Synthesis of N-Hydroxy Peptides: Chemical Ligation of O-Acyl Hydroxamic Acids," Org. Lett., 2000, 2, 1399-1401.

D. Benoit, V. Chaplinski, R. Braslau,* C. J. Hawker *   "Development of a Universal Alkoxyamine for 'Living' Free Radical Polymerizations"  Journal of the American Chemical Society, 1999, 121, 3904-3920.

R. Braslau,* V. Chaplinski, P. Goodson  “Symmetrical Nitroxide Synthesis: meso      verses d,l  Diastereomer Formation”  Journal of Organic Chemistry,  1998, 63, 9857-9864.      

R. Braslau,* M. O. Anderson,  "Abstraction of Deuterium from Dideuteroglycine by Aryl Radicals: A Model for 1,4-Benzene Diradical Reactions with Proteins," Tetrahedron Letters, 1998, 39, 4227-4230.

N. Naik, R. Braslau,* "Synthesis and Applications of Optically Active Nitroxides," Tetrahedron Reports, 1998, 54, 667-696.

R. Braslau,* L. C. Burrill II, V. Chaplinski, R. Howden, P. W. Papa, "Studies In the Stereoselective Trapping of Prochiral Carbon Radicals by Optically Active Camphoxyl Nitroxides,"Tetrahedron Asymmetry, 1997, 8 3209-3212.

R. Braslau,* L. C. Burrill II, M. Siano, N. Naik, R. K. Howden and L. K. Mahal, "Low Temperature Preparations of Unimolecular Nitroxide Initiators for "Living" Free Radical Polymerizations," Macromolecules, 1997, 30, 6445-6450.

R. Braslau,* L. C. Burrill II, L. K. Mahal and T. Wedeking, "A Totally Radical Approach to the Control of Stereochemistry: Coupling of Prochiral Radicals with Chiral Nitroxyl Radicals," Angew. Chem.  Int. Ed.  Eng.,1997, 36, 237-238.

R. Braslau,* H. Kuhn, L. C. Burrill II, K. Lanham and C. J. Stenland, "Synthesis of Several Novel Optically Active Nitroxyl Radicals,"  Tetrahedron Letters, 1996, 37, 7933-7936.