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FULL PAPER a Self-Assembled Cage with Endohedral Acid Groups Both FULL PAPER A Self-Assembled Cage with Endohedral Acid Groups both Catalyzes Substitution Reactions and Controls their Molecularity Paul M. Bogie, Lauren R. Holloway, Courtney Ngai, Tabitha F. Miller, Divine K. Grewal, and Richard J. Hooley[a]* [16],[17] Abstract: A self-assembled Fe4L6 cage complex internally decorated many possibilities in controlled biomimetic catalysis, above with acid functions is capable of accelerating the thioetherification of and beyond simply increasing the effective concentration of activated alcohols, ethers and amines by up to 1000-fold. No product bound substrate. The incorporation of active functions in an inhibition is seen, and effective supramolecular catalysis can occur enclosed space enables reagent-controlled reactions to take with as little as 5 % cage. The substrates are bound in the host with place in enclosed cavities, as opposed to cycloadditions[18]-[20] or up to micromolar affinities, whereas the products show binding that is unimolecular rearrangements, [21],[22] which are still the most an order of magnitude weaker. Most importantly, the cage host alters common reactions studied in synthetic hosts. By internalizing the molecularity of the reaction: whereas the reaction catalyzed by reactive functional groups in a cage, the effect of substrate simple acids is a unimolecular, SN1-type substitution process, the rate binding on nucleophilic substitution reactions can be investigated. of the host-mediated process is dependent on the concentration of nucleophile. The molecularity of the cage-catalyzed reaction is substrate-dependent, and can be up to bimolecular. In addition, the catalysis can be prevented by a large excess of nucleophile, where substrate inhibition dominates, and the use of tritylated anilines as substrates causes a negative feedback loop, whereby the liberated product destroys the catalyst and stops the reaction. Introduction Enzymes are commonly thought of as “perfect” catalysts, showing extremely high rate accelerations and high substrate selectivity compared to small molecule catalytic processes.[1] As well as providing a favorable environment for reaction, varying the molecularity of the rate determining step is possible. A common example is general acid-base catalysis,[2] whereby sidechains directly involve themselves in the rate equation.[3] Using synthetic host molecules to mimic a variety of types of enzymatic behavior has led to numerous successes in recent years,[4]-[7] including examples of rate accelerations[8]-[10] and binding affinities[11] that even exceed those of natural enzymes. However, altering the molecularity of a reaction with a synthetic host is far less common: cycloadditions and unimolecular rearrangements can be II accelerated by increased effective concentration upon binding, Figure 1. Enzymatic catalysis in a functionalized cage. a) Structure of Fe 4L6 acid cage 1 and a minimized structure of its S4 isomer (SPARTAN, semi- without the need for functional groups oriented towards an internal empirical calculations); b) control meso-helicate 2; c) summary of the acid cavity. catalyzed substitution processes tested. To achieve this type of reactivity, co-encapsulation of multiple substrates is required, in the presence of acidic and/or basic functional groups in a defined cavity. Self-assembled capsules Polar reactions can be challenging for host molecules to capable of co-encapsulation are often unfunctionalized, and do promote or catalyze, especially nucleophilic substitutions. Metal- not contain internal acidic or basic groups. [12] A solution lies in ligand cage hosts can be sensitive to strong nucleophiles, which endohedrally functionalized cage complexes, [13]-[15] which offer have a tendency to destroy the structural M-L contacts. However, there are some exquisite examples of host complexes directing the outcome of SN2 processes in the literature: aromatic panels in Ga-catecholate tetrahedra invert the stereochemistry in [*] P. M. Bogie, L. R. Holloway, C. Ngai, T. F. Miller, D. K. Grewal, and [23] Prof. R.J. Hooley encapsulated substitutions, and Menshutkin reactions can be University of California - Riverside, Department of Chemistry, accelerated in deep cavitands with internal acid groups. [24] Other Riverside, CA, 92521, U.S.A. E-mail: [email protected]. examples of polar reactions include eliminations, [8],[9] [25] [26] Supporting information for this article is given via a link at the end of Knoevenagel condensations, epoxide openings, and the document. additions to imines[27] or organic cations. [28],[29] Compared to the FULL PAPER wealth of cycloadditions and rearrangements promoted or are well-known “SN1” substrates that can undergo various catalyzed by self-assembled hosts, though, polar reactions substitution reactions via their highly stabilized cationic remain rare. intermediates. [31] As cage 1 is sensitive to a variety of different nucleophiles, some as mild as chloride, [32] we focused on mild, neutral nucleophiles for the reactivity tests. The combination of tri- Results and Discussion or diphenylmethyl electrophiles with thiols in highly acidic media is a well-precedented method of thioether synthesis, [33],[34] and We recently described the synthesis of endohedrally occurs via an acid-catalyzed dissociative substitution mechanism. functionalized acid cage 1, and investigated its ability to catalyze We initially used n-propanethiol (PrSH) as the nucleophile, paired the deprotection of acetals and effect tandem reactions. [30] The with different catalysts in CD3CN, and monitored the relative high rate accelerations observed, and the fact that the cage binds reaction rates by 1H NMR, as shown in Figure 2a. Significant rate 4 -1 benzaldehyde dimethylacetal with Ka = 1.3 x 10 M suggested accelerations were observed for the reaction of both 4a and 4b that cage 1 would be an effective supramolecular catalyst for with PrSH in the presence of 5 % cage 1 as catalyst. The reaction other acid-mediated reactions. Here we show that the cage can was complete after 8 h at 80 °C, and 100 % conversion was catalyze a substitution reaction, effecting rate acceleration and observed in both cases, with no evidence of product inhibition. variable molecularity on the process that is dependent on The conversion is clean, and only the cage, the reactants and substrate molecular recognition. propyl trityl sulfide product 5a are observed in the NMR spectra (see Supporting Information for full spectra). Most importantly, cage 1 remains intact throughout the process, and is completely tolerant to thiol nucleophiles, even at reflux. The characteristic peaks for the imine region of the C3 and S4 isomers of cage 1 at δ 8.9-9.1 ppm are shown in Figure 2b, [30] and no cage decomposition products are formed. To ensure that the cage was the active catalyst rather than small amounts of leached Fe2+ ions, the reaction was repeated with meso-helicate 2 as catalyst, as that assembly does not contain a defined cavity or acidic functions. In that case, no reaction was observed even after 48 h heating. The effectiveness of the acidic cage was then compared to an equivalent concentration of free acid groups by reacting PrSH with 4a and 4b in the presence of 30 % control acid 3. No conversion was observed after 10 h heating at 80 °C for either electrophile (Figure 2a). Even 24 h reflux only gave 1% conversion. The observed initial rates and relative rate accelerations of the thioetherification process are shown in Table 1. The self- assembled cage shows up to a 1023-fold acceleration in rate when compared to a “free” acid catalyst that contains the same functional groups (i.e. 3). The relative rates of substitution of the trityl electrophiles 4a and 4b were very similar, and showed similar (~1000-fold) accelerations. The difference in basicity between 4a and 4b (conjugated acid pKa of ~-3.5 vs -2) was not observed to be a determining factor, as the reactions rates are essentially identical. The far less basic trifluoroethyl ether 4c showed no reactivity, however, even after extended reaction times. Benzhydrol 4d was less reactive than 4a, and displayed Figure 2. Accelerated Substitution Catalyzed by Cage 1. a) Reaction only 58 % conversion after 72 h, but a rate acceleration of at least progress over time for the transformation of electrophiles 4a and 4b with either 1 5 % cage 1 or 30 % control acid 3 catalyst (CD3CN, 353 K). b) H NMR spectra 100-fold was observed with 5 % 1 as catalyst as compared to that of the reaction of 4a with PrSH catalyzed by 1 at various intervals (CD3CN, 400 with 30 % 3. MHz, 298 K). Blue = PrSH; Red = thioether product 5a; downfield inset shows The cage-catalyzed substitution reaction can also be the imine CH region of the C3/S4 isomers of 1, and that cage 1 remains intact throughout the reaction. performed with other mild nucleophiles. The more hindered cyclohexanethiol (CySH) showed a slightly slowed initial rate of reaction compared to PrSH, but both 4a and 4b were smoothly The reaction is shown in Figure 1: we chose a mild, acid- converted to product with 5 % 1. The reaction of p-tolylthiol catalyzed substitution reaction to prevent destruction of the cage (TolSH) was complicated by the formation of significant amounts complex. Four different activated electrophiles were tested that of oxidation byproduct p-tolyldisulfide. In the case of all the other thiols, no disulfide was observed at any point during the reaction, vary in reactivity; triphenylmethanol 4a, its ethyl (4b) and despite the fact that the reactions were performed
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