60th Annual Report on Research 2015

A. Background and significance.

Synthetic methodology to rapidly and efficiently prepare multifunctional molecules continues to leverage discoveries in disciplines spanning materials science and chemical biology.  One approach to discrete multifunctional molecules is illustrated in Figure 1.  A statistical mixture (with the percentages shown) results if the reaction rates between reagent site B and positions A, A′, and A″ are identical (top pathway).  If each successive functionalization reaction sufficiently deactivates the remaining reactive sites, and a reactivity gradient is established, a one-pot sequential multifunctionalization can be executed (bottom pathway).

Figure 1. The kinetics associated with statistical and non-statistical syntheses of discrete multifunctional molecules from a three-fold symmetrical precursor.

We recently reported that benzotrifuranone (BTF) (Scheme 1) is uniquely suited for multifunctionalization through sequential aminolysis reactions.  The platform affords rapid access to mono- (1), di- (2), and trifunctionalized (3) targets provided routine control of temperature and amine reagent stoichiometry, and lends itself to the one-pot synthesis of multifunctionalized 3 (i.e., 3R¹R²R³) from 1 in high yield (> 80%) and a single day.  During the last two funding periods we obtained a more comprehensive understanding of the aminolysis behavior of BTF through comparative kinetics measurements, X-ray crystal structure analysis, and quantum chemical calculations.  Particularly useful for the studies was BTF’s six-membered lactone congener, benzotripyranone (BTP, Table 1).  Data from the studies, the basis for a nearly complete full paper, pointed strongly to “ring strain” as a significant reactivity driver for BTF.  Work this past year has sought to (a) validate the ring strain hypothesis through additional quantum chemical calculations and (b) apply the multifunctionalization capabilities of 1 to the synthesis of a molecular dye that functions through an energy transfer cascade. 

Figure 2. Aminolysis of benzotrifuranone (BTF).

B. A Ring Strain Gradient as a Sequential Aminolysis Selectivity Driver.

During this last reporting period we performed a series of theoretical (DFT; B3LYP/6-31+G**) calculations to estimate the “strain energy” of the suite of compounds shown in Table 1.  The model heterocycles represent substructures of the species formed along the aminolysis pathways of both BTF and BTP.  To evaluate strain, theoretical heats of formation at 298 K (Δ_fH_gas-calcd) —determined from appropriate homodesmotic equations involving experimental Δ_fH_gas values—were compared to values determined for hypothetical “unstrained” molecules (through strain-free group increments).  The trends in strain energy values are consistent with the overall aminolysis rate behavior found for the individual BTF and BTP series.  That is, k_BTF > k_BDF > k_BTP > k_BDP (on a per lactone basis) as strain (on a per lactone basis) decreases as BTF > BDF > BTP > BDP.  Moreover, the difference in BT-->BD strain loss between BTF and BTP (10.4–6.3 = 4.1 kcal mol^-1) is in the ballpark of the activation energy difference (~ 3 kcal mol^-1) that corresponds to the 125-fold difference in experimental monoaminolysis rate between the compounds.  More interesting is that the change in ring strain along BTF-->BDF-->BMF is not constant; the strain loss (10.4 kcal mol^-1) is greater in the first step than the second (9.1 kcal mol^-1).  Such is not the case for BTP-->BDP-->BMP where the same magnitude of strain release (6.3 kcal mol^-1) is found for both steps.  The “gradient” observed in the BTF series is a novel observation among reactive small-molecule systems and helps to rationalize the unusual aminolysis reactivity of the parent molecule.                              

Table 1. Theoretically determined heats of formation (gas phase, 298 K) and associated strain energies for the heterocycles involved in the sequential aminolysis of BTF and BTP.  The strain trends parallel experimental aminolysis rate trends described previously and support the hypothesis that strain release is an important driver of aminolysis selectivity in the systems.  All values are in kcal mol^-1.  GAV = strain-free group additivity value.  

C. BTF Multifunctionalization to Access FRET Cassettes.

In a separate line of investigation (summarized in Figure 3) we are using the BTF multifunctionalization chemistry to prepare unique dye “cassettes” that function through an internal energy transfer (FRET) cascade.  The target is shown as 4 and borrows a family of dyes originally reported in 2013 by Das and co-workers: a naphthalene (FRET donor #1), a pyrene (FRET acceptor #1 and donor #2), and a coumarin (FRET acceptor #2).  To date, all of the possible mono- and dichromophore control compounds have been prepared (5–10) and fully analyzed by UV-Vis absorption and fluorescence emission spectroscopy in CHCl₃.  The coumarin is attached via the “click” chemistry described in the previous annual report.  Quantum yield determinations have provided a way to quantify the energy transfer efficiency in the dyads, which is ~ 95% in 8 and 9 (consistent with their designed FRET pairs), and a lower ~ 68% in 10 (donor #1 to acceptor #2).  We anticipate a correspondingly high energy transfer efficiency (~ 90%) in 4 wherein excitation at 284 nm will produce emission at 449 nm (for an effective Stokes shift of 165 nm).  Unique about the cassettes (versus ones potentially derived from cyanuric chloride) is the opportunity for their attachment to other organic molecules through the free phenolic (OH) positions.                     

Figure 3. A FRET cassette (4) available through sequential multifunctionalization of BTF; the superdye functions through an internal energy transfer cascade.  Model compounds 5–10 have been prepared and evaluated spectroscopically during the reporting period.      

D. Final Remarks.

Synthetic multifunctionalization strategies are critical for realizing sophisticated properties from molecules sufficient for their broad applications in the biological and materials sciences.  The chemistry described above, performed by several graduate students and one undergraduate, is working towards this goal.  The grant has had an enormous impact on the students involved in the project, particularly with respect to their hands-on training in the chemical sciences.