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The goal of the proposed research is to use template-controlled photochemical reactions conducted 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%).  In addition to being able to provide access to products difficult to achieve in solution, 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.

Principal goals of the current project are: (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.  In addition to these goals, the research developed in the grant was 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 initial work of the SUMR student, we have pursued a new avenue of research that investigates the ability of our templates to direct solid-state reactivity catalytically.

Period 03/01/08 – 08/31/09

For Year 1, our research developed into three lines of investigation.  In addition to pursuing the original goal of using our templates to construct ladderanes with carboxylic acid groups, we built on the project of the SUMR student by expanding the application of solvent-free grinding to catalysis.  Furthermore, unexpected developments encountered in the co-crystallization experiments of the first goal led us to a line of investigation whereby we incorporate ‘sacrificial esters' into the olefins to achieve cyclobutane products lined with acid groups.

i) Co-crystallization experiments. Our initial work in Year 1 focused on co-crystallization experiments that involve hydrogen-bond-acceptor templates with muconic acid and derivatives.  Although our original goal involved the related triene as the reactant, solubility experiments demonstrated the dienes to be more suitable for the solvent-mediated co-crystallizations.  More specifically, we determined that co-crystallization of 2,3-bis(4-pyridyl)naphthalene template (2,3-naph) with either muconic acid or dimethylmuconic acid (muconic acid) afforded, as anticipated, molecular assemblies of composition (2,3-naph)∙(muconic acid) sustained by O-H∙∙∙∙N hydrogen bonds.  In contrast to our design, however, the components self-assembled to form infinite, as opposed to discrete structures.  As a result, the olefins of the solids were separated at distances > 4.2 Å and the solids were determined to, thus, be photostable.  To build on this work, we turned to the related 1,8-bis(4-pyridyl)naphthalene (1,8-naph) as a template.  In particular, co-crystallization of 1,8-naph with muconic acid, in contrast to (2,3-naph)∙(muconic acid), afforded discrete hydrogen-bonded structures.  In the assemblies, the dienes were aligned parallel and separated on the order of 3.80 Å.  When subjected to UV-radiation, the assemblies underwent a photocycloaddition to give the corresponding head-to-head monocyclobutane product.  We, thus, achieved our goal of installing carboxylic acid groups on the products of a solid-state reaction of a polyene.  We are now working to further 1,8-naph, and its derivatives, as templates to direct solid-state photoreactions of di- and trienes to give ladderane acids.  We are also working to perform decarboxylations on the cyclobutane products as outlined in the second main goal.  The work is currently in preparation for publication.

ii) Supramolecular Catalysis in the Solid State (SUMR-related Project). In addition to using solvent as a means to achieve co-crystal formation, we developed a new project that stemmed from the work of our SUMR student on the green chemistry of templated solid-state reactions.  In particular, we investigated the ability of the templates to direct solid-state reactivity catalytically.  Whereas solvent-free and liquid-assisted preparations of co-crystals are rapidly-expanding areas, applications of these methods to prepare solids that undergo the photodimerization have been rare.  Moreover, we have shown that solvent-free grinding of our hydrogen-bond-acceptor and -donor templates with olefins affords reactive and discrete crystalline assemblies wherein the olefins are aligned for photodimerization.  Given this success, we immediately recognized that it could also be possible to use our templates as catalysts in the organic solid state whereby we grind, under solvent-free conditions, sub-stoichiometric amounts of template with olefin to afford reactive crystalline assemblies.  UV-radiation of the solids would afford a cyclobutane product whereby a subsequent regrind could be used to achieve turnover.  The proof-of-principle experiments have now been achieved for a system involving hydrogen-bond-donor templates based on resorcinol.  We are now working to study the related hydrogen-bond acceptor templates.  The work is currently in press in the journal Angewandte Chemie.

iii) Sacrificial Esters.  Given that the co-crystallizations of 2,3-naph with the muconic acids produced infinite, as opposed to a discrete, hydrogen-bonded structures we considered an alternative approach to install carboxylic acids into the products.  One avenue that we have pursued is the incorporation ester groups.  Esters readily undergo hydrolysis to give carboxylic acids.  Thus, we expected that co-crystallization of a hydrogen-bond-acceptor or -donor template with an olefin lined with an ester group could afford a reactive assembly that affords the corresponding ester-substituted cyclobutane product.  Post-synthetic modification of the ester by hydrolysis could then afford the corresponding acid.  To demonstrate this principle, we have performed co-crystallization experiments of resorcinols, and derivatives, with stilbazoles lined with ester groups.  The co-crystallizations afforded discrete hydrogen-bonded assemblies that undergo photoreaction to produce the ester-substituted cyclobutanes in quantitative yield.  We are now working to expand this approach to our hydrogen-bond-acceptor templates in relation to our work on the ladderanes.