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A Dehydrogenative Dehydro-Diels-Alder Reaction and its Application to Fluorescent Tools and Natural Product Synthesis

Kocsis, Laura/S (2015) A Dehydrogenative Dehydro-Diels-Alder Reaction and its Application to Fluorescent Tools and Natural Product Synthesis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Functionalized naphthalenes are valuable building blocks in many areas of chemistry, such as natural products, drugs, and fluorescent dyes, but advances in new synthetic methods to generate naphthalenes have been limited. We have developed a microwave-assisted, intramolecular dehydrogenative dehydro-Diels–Alder (DDDA) reaction of styrenyl derivatives which affords cyclopenta[b]naphthalene products that cannot be accessed using existing synthetic strategies. The DDDA reaction can be performed in as little as 30 minutes to provide diverse naphthalene compounds exclusively and in high yields; only in examples involving heteroatom substitution of the styrene-yne tether were mixtures of naphthalene and dihydronaphthalene products obtained.

In order to better understand and control the selectivity of DDDA reactions resulting in product mixtures, the mechanisms of formation for the naphthalene and dihydronaphthalene substrates were investigated. Isotopic labeling experiments and gas detection studies revealed that these two products were generated via diverging mechanisms of a common intermediate, where dihydronaphthalene substrates were produced via a radical pathway, while naphthalene compounds were yielded by unimolecular elimination of hydrogen gas. As an additional outcome of these mechanistic studies, reaction conditions were established for the selective production of either naphthalene or dihydronaphthalene products in high yields.

The synthetic utility of the DDDA reaction was demonstrated by its application to the synthesis of eight aryldihydronaphthalene and arylnaphthalene lignan natural products, including taiwanin C and justicidin B. Computational methods for chemical shift assignment were developed, which showed good correlation with experimental spectra and allowed for regioisomeric lignans to be distinguished. The synthetic utility of DDDA reaction was also realized by a single-step conversion of halogenated cyclopenta[b]naphthalene substrates to solvatochromic fluorophores. These fluorescent dyes displayed red-shifted spectral properties compared to PRODAN, a commonly used and structurally related fluorescent biological probe, making them potentially valuable for study in biological systems. Moreover, structure-photophysical property relationships (SPPR) of cyclopenta[b]naphthalene dyes were determined by utilizing the DDDA reaction to introduce systematic variations in fluorophore structure, such as changes in donor position, which significantly altered the dyes’ photophysical properties. The SPPR determined will allow for the future rational design and tuning of fluorophore structure and photophysical properties to address specific needs in biological applications.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Kocsis, Laura/Slsk16@pitt.eduLSK16
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberArmitage,
Committee MemberCurran, Dennis/Pcurran@pitt.eduCURRAN
Committee MemberHorne, Sethhorne@pitt.eduHORNE
Committee ChairBrummond, Kay/Mkbrummon@pitt.eduKBRUMMON
Date: 13 January 2015
Date Type: Publication
Defense Date: 26 August 2014
Approval Date: 13 January 2015
Submission Date: 18 August 2014
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 413
Institution: University of Pittsburgh
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Chemistry, organic, Ph.D.
Date Deposited: 13 Jan 2015 19:49
Last Modified: 15 Nov 2016 14:23


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