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Project Report, PRF #47632-AC1 (Year 2)

The goal of the proposed research was to use template-controlled photochemical reactions in the solid state to construct a ladderane framework that can be converted into naturally-occurring lipid. The solid-state synthesis is designed to make the natural product readily available, particularly as compared to recently-reported approaches that afford ladderanes in low yields (i.e. < 1%). Solid-state reactions are beneficial since solvent is not required for the critical covalent-bond-forming step. Solid-state reactions, thus, have direct relevance to the field of green chemistry and sustainability.

Principal project goals: (1) determine how hydrogen-bond-acceptor templates can be used to synthesize a [5]-ladderane dicarboxylic acid in the solid state and (2) determine how a [5]-ladderane obtained from a template-controlled solid-state synthesis can be converted to the natural product. The research developed in the grant was also supplemented by a SUMR undergraduate student in Summer 2008. The goals of the student were to study the ability of the templates and reactants to self-assemble via solvent-free and liquid-assisted grinding. From the work of the SUMR student, we also pursued a new avenue of research on the ability of our templates to direct solid-state reactivity catalytically via mechanochemistry.

Period 09/01/09 – 08/31/10

For Year 2, our research developed into two main lines of investigation. First, we expanded our co-crystallizations and mechanochemistry to the remaining members of the trans-bis(n-pyridyl)ethylene family using resorcinol, and derivatives, as templates. Second, we discovered the ability of a triene studied in Year 1 to undergo a rare trimerization to afford a bicyclobutyl product. Our work on supramolecular catalysis in the solid state was also published in Angewante Chemie in 2010 (Sokolov, A.N.; Bucar, D.-K.; Baltrusaitis, J.; Gu, S.X.; MacGillivray, L.R., “Supramolecular Catalysis in the Organic Solid State via Dry Grinding”, Angew. Chem., Int. Ed. 2010, 49, 4273-4277). The paper was highlighted in ChemCatChem (Ma, D.-Y.; Warnmark, K., “Mechanoassisted Supramolecular Catalysis in Solid State Synthesis”, ChemCatChem 2010, 2, 1059-1060).

i) Expansion of Mechanochemsitry. Having achieved the use of dry mortar-and-pestle grinding to form our reactive co-crystals, we turned to determine the scope of the mechanochemistry as applied to all six members of the trans-bis(n-pyridyl)ethylene family of olefins (i.e. 2,2’-bpe, 2,3’-bpe, 2,4’-bpe, 3,4’-bpe, 3,3’-bpe). Thus, resorcinol, and derivatives, were ground with each olefin under dry conditions, with the resulting solids being studied using powder X-ray diffraction (PXRD). Our experiments revealed the co-crystallizations to occur upon grinding to afford reactive co-crystalline solids. Application of UV-light demonstrated cyclobutane formation, which confirmed that the resorcinols can be used as templates to achieve reactivity involving all six members of the olefin family. The resulting co-crystals afforded the head-to-tail and head-to-head cyclobutane products in up to quantitative yield.

ii) Discovery of Trimerization. During our work on the use of hydrogen-bond-acceptor templates to direct reactivity of muconic acid and derivatives, we discovered the ability of the diene (E,E)-2,5-dimethylmuconic acid to undergo a trimerization in the solid state to afford a bicyclobutyl. The pure crystalline diene underwent a trimerization to give a bicyclobutyl hexaacid diene and related anti photodimer. Whereas olefinic mono- (e.g. cinnamic acid) and dicarboxylic acids (e.g. fumaric acid) have been central to understanding the origins of the [2+2] photodimerizations in solids, the diene represents the first case wherein an olefinic carboxylic acid undergoes a trimerization to give a bicyclobutyl. To understand the origin of the photoreactivity, and to circumvent difficulties encountered to grow single crystals of the diene, we also turned to PXRD to determine the solid-state packing of the diene. The work was performed in collaboration with Professor Robert E. Dinnebier and postdoctoral fellow Ivan Halasz, Max-Planck-Institute for Solid State Research, Germany. The X-ray studies revealed the diene to self-assemble in 1D hydrogen-bonded polymers sustained by carboxylic-acid dimers. The C=C bonds of nearest-neighbor dienes were parallel such that each C=C bond was in close proximity to two adjacent C=C bonds at separations of 3.79 Å and 3.89 Å. The geometry satisfied the criteria of Schmidt for a photodimerization wherein the diene reacted to give the trimer and related photodimer. Difficulties to isolate and grow single crystals of the photoproduct forced us to apply the process of co-crystallization to separate the trimer from the dimer and confirm the stereochemistry of the bicyclobutyl by single-crystal X-ray diffraction. The study represented a rare example of using a co-crystallization to structurally-authenticate a molecule.

The work has been accepted for publication in ChemCommun (Atkinson, M.B.J.; Bucar, D.-K.; Halaszb, I.; Bucar, D.-K.; Dinnebier, R.E.; MacGillivray, L.R. “A Solid-state Trimerisation of a Muconic Acid Affords a Bicyclobutane: Diene Structure from X-ray Powder Data and Product Separation and Structure Determination via Co-crystallisation”, Chem. Commun., in press). The manuscript will appear in an ‘Emerging Investigators’ themed issue.

Impact of Research on Career and Students

In addition to moving closer to the synthesis of ladderane lipids via the solid state, the research opened two major avenues of research for our group. First, our results suggest that the organic solid state can be used as a general medium for supramolecular catalysis. Prior to our work, efforts on supramolecular catalysis had been more geared to studies in solution. We are now positioned to study how our template method can be generalized as a form of catalysis in solids. Second, the research enabled the development of a collaboration that focuses upon using PXRD data to determine solid-state structure. We expect the collaboration to be invaluable for studies involving additional reactive co-crystals based on templates. The research enabled the completion of a Ph.D. thesis in 2008-2009 (Poonam Kaushik, currently: Research Scientist, Ranbaxy) and served as a foundation for an ongoing Ph.D. student (Manza B.J. Atkinson, Ph.D. projected: December 2010). Mr. Atkinson also mentored the SUMR student (Mahmood Bilal, currently: Interdisciplinary Graduate Program, Immunology, University of Iowa).