59th Annual Report on Research 2014

Progress towards the synthesis of C₄ symmetric oxacalixarenes.  As indicated by the title, the main goal stated in this proposal was to synthesize and characterize a C₄ symmetric oxacalixarene.  The initial C₄ target that we identified was oxacalixarene 1 because both the electrophilic and nucleophilic portions of the molecule can be derived from commercially available diphenol 2.  As reported last year we sought to access oxacalixarene 1 by activating the hydroxyl groups to afford compound 3 and subsequently react them by nucleophilic aromatic substitution (S_NAr).  However all S_NAr, Ullman, and fluorination reactions we attempted were proceeding sluggishly due to the two strong electron withdrawing groups (EWGs).  As outlined last year we turned our attention to chlorination (AG = Cl) with chlorinating reagents (POCl₃, PCl₅, SOCl₂), but we could not identify compound 3 regardless of chlorinating reagent, catalyst, and/or solvent employed.  Since we hypothesize that the strong electron withdrawing nature of the acyl groups (s^- = 0.75) was the source of our problem we sought two possible solutions that are outlined below. 

First, we decided to continue using commercially available compound 2 and instead of replacing the hydroxyl group with a good leaving group we decided to attempt converting it to the poor leaving group methoxide.  Initial, unoptimized results indicate that we can synthesize dimethylated compound 4 from 2.  Though methoxide is a poor leaving group they have been shown to act as leaving groups in S_NAr reactions because the rate limiting step typically does not involve leaving group departure and thus the nature of the leaving group is less important.  Furthermore the presence of two strong EWGs conjugated to the methoxy groups should allow sufficient activation for substitution.  An S_NAr reaction will be attempted first with p-cresol to investigate feasibility and subsequently with 5 to synthesize macrocycle 1.

Second, we decided to switch our focus away from the strong acyl EWG and use the more moderate iodo EWG (s^- = 0.27).  Since diiodo compound 6 is not commercially available we first synthesized it via a known procedure.  With 6 in hand we were able to displace the hydroxyl groups with a chlorination reaction.  Though this reaction is currently unoptimized we were able to identify dichlorodiiodobenzene 7 as the likely major product of this reaction indicating that the acyl groups were indeed inhibiting our first strategy.  Next we plan to investigate the ability of 7 to react under S_NAr conditions to show feasibility and then react it with 6 to afford oxacalixarene 8.

Oxaquinonacyclophanes from dichloronaphthoquinone.  The proposal stated that our lab would investigate substitution reactions of 2,3-, 2,6-, and 2,4-dichloro-p-benzoquinones toward the synthesis of macrocyclic quinonal ethers (oxaquinonacyclophanes).  We selected to use 2,3-dichloronaphthoquinone as our initial electrophilic species because it is commercially available, inexpensive, and does not contain problematic hydrogens on the quinone ring.  Last year we reported the utility of 2,3-dichloronaphthoquinone to undergo cyclization reactions.  As we continued investigating these reactions we discovered that not all of the molecules reported last year were formed in the shapes reported, however all reported cyclization reactions did occur and in the reported yields.  With this knowledge we decided to focus on oxaquinonacyclophane 9 because the x-ray crystal structure showed that this molecule has an appropriate shape to act as a redox active supramolecular host molecule.  Since last year’s report we have not only obtained the crystal structure of 9 (courtesy of Prof. MacGillivray’s group, University of Iowa), but also we have substantially improved the yield, synthesized the compound on a relatively large scale (>1 g) using less expensive potassium carbonate as the base and with less solvent, and begun to investigate the kinetics of naphthoquinone substitution.

            Future research on this project will involve investigating the redox chemistry and host-guest interactions of 9 and varying the geometry of the dihalo-p-benzoquinones to the 2,6- and 2,4-systems.

            This research was highlighted in a talk and three undergraduate research posters at the 248th American Chemical Society National Meeting & Exposition, San Francisco, CA, August 10-14, 2014.  Additionally, the first graduate from our lab, who was supported by this PRF grant in the previous year, is currently an organic chemistry graduate student at the University of Wisconsin – Madison.