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Goals:  Thermal and photochemical Bergman and related cyclizations of (Z)-hexa-3-ene-1,5-diynes, or enediynes, have a wide range of applications from DNA cleaving agents to materials chemistry.  Our group is currently exploring the effect of increased conjugation on enediyne reactivity.  In this work, we have developed three routes to prepare highly conjugated enediyne chromophores to study thermal and photochemical reactivity.  In the second year of this grant we focused our efforts on continuing photochemical studies of arylethynyl enediynes along with the  syntheses and thermal studies of aryl-fused quinoxalenediynes. 

Results:  To examine the effect of extended chromophores appended to the enediyne alkyne we prepared a series of highly conjugated enediynes possessing naphthalen-1-yl, naphthalen-2-yl, phenanthren-9-yl, and anthracen-9-yl substituents.  As expected, the added steric bulk increased the thermal barrier towards cyclization for each derivative as monitored by differential scanning calorimetry and measured computationally.  Upon irradiation at 350 nm, the naphthalen-1-yl and phenanthren-9-yl derivatives undergo a novel tandem 2+2 photocyclization with no evidence of C1-C6 or C1-C5 cyclization products.  In comparison, the naphthalen-2-yl derivative is stable upon irradiation at 350 nm and slowly degrades at 300 nm.  The anthracen-9-yl analog shows complex reactivity at 300 nm, 350 nm, and 419 nm that is currently under investigation.  Interestingly, incorporation of methoxy substituents were found to facilitate enediyne reactivity as evidenced by the improved C1-C6 photocyclization yields of 1,2-bis(6-methoxynaphthalen-2-ylethynyl)benzene at 300 nm (32%) compared to the bis-naphthalen-2-yl derivative (0%) and the parent 1,2-bis(phenylethynyl)benzene (<10%).  We have also prepared 2-methoxynaphthalen-1-yl and 4-methoxynaphthalen-1-yl derivatives  and are currently examining their photoreactivity. 

In a second approach to extend conjugation to the enediyne core we prepared a series of aryl-fused quinoxalenediynes to examine the effect of extended benzannelation on thermal reactivity.  We prepared a series of seven terminal quinoxalenediyne models to examine solid state and solution reactivity.  In the solid state, extended benzannelation increased the thermal barrier towards cyclization as measured by DSC.  In solution, the parent terminal quinoxalenediyne and phenanthroquinoxalenediyne undergo C1-C6 cyclization upon heating at 180 °C in the presence of 1,4-cyclohexadiene.  Upon cyclization, however, the benzoquinoxaline core is reduced to the corresponding 5,10-dihydrobenzoquinoxaline ring system.  Upon treatment with DDQ the fully aromatic product is readily obtained.  To further examine this system the parent 6,7-diethynylquinoxaline was converted to the corresponding 6,7-bis(phenylethynyl) derivative and subjected to thermal cyclization conditions.  Upon heating at 200 °C an unoptimized mixture of C1-C6 as well as C1-C5 cyclization products were obtained.  We are currently measuring activation barriers toward C1-C6 and C1-C5 cyclizations for terminal and phenylethynyl quinoxalenediynes computationally to determine if extended benzannelation can lead predominately to C1-C5 cyclization pathways.  Photochemical studies for this series are currently ongoing.

Research Support:  We have continued our collaboration with Marilyn Olmstead at the University of California, Davis, X-Ray Crystallography Facility to obtain crystal structures of our highly conjugated enediynes and their cyclization products.  In addition, we continue to work with Benjamin Gherman, a computational/physical chemist at CSU Sacramento, to determine activation barriers towards C1-C6 and C1-C5 cyclizations of arylethynyl enediynes as well as aryl-fused quinoxalenediynes.  Recent funding from the NSF-MRI program provided a 500 MHz NMR spectrometer to further support this work.  Financial support from the College of Natural Sciences and Mathematics at CSU Sacramento provided funding for supplies during the 2009-2010 academic year as well as summer salary for one undergraduate student conducting computational studies.

Personnel and Undergraduate Training:  During the 2009-2010 academic year the principal investigator was on paternity leave for a significant portion of the spring term and the entire summer period.  As a result, no summer stipends were issued limiting our research progress and expenditures during this reporting period.  However, during the reporting period six undergraduate students continued to work on this project.  Five of these students graduated in the spring of 2010 after completing two years of research in our group:  Michael L. Chang (BS, currently at Amgen Pharmaceuticals), Nicola A. Clayton (BA, currently in pharmacy program at UC San Francisco), Nicholas P. Genovia (BS, currently in MS chemistry graduate program at CSU Sacramento), Nadezhda V. Korovina (BS, currently in PhD chemistry graduate program at USC), and Trang T. Nguyen (BS, currently in PhD chemistry graduate program at University of Nevada, Reno).  Participation in research during their junior and senior year (including the summer of their junior year) made these students highly attractive candidates who were heavily recruited to enter the chemical workforce or pursue advanced degrees in chemistry/pharmacy.  Overall, their work resulted in six presentations at national American Chemical Society meetings and five regional undergraduate meetings during the 2009-2010 academic year.